Salt of polycyclic spiro compound and crystal form thereof, preparation method therefor and medical use thereof

Abstract

The present invention relates to a salt of a polycyclic spiro compound and a crystal form thereof, a preparation method therefor, and a medical use thereof, and in particular, to a salt of a compound represented by general formula (I) and a crystal form thereof, a preparation method therefor, and a pharmaceutical composition containing a therapeutically effective amount of the crystal form, and a pharmaceutical use thereof for treating diseases or conditions associated with activation of the complement alternative pathway.

Description

A salt of a polynary spirocyclic compound and its crystal form, preparation method and medical use thereof Technical Field

[0001] The present invention belongs to the field of biomedicine, and specifically relates to a salt of a polynary spiro compound and its crystal form, a preparation method and medical use thereof. Background Art

[0002] The complement system is part of innate immune surveillance and plays a key role in pathogen elimination and 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). The CP and LP pathways are initiated on target surfaces by the binding of immune complexes, mannan-binding lectins, or ficolins, respectively, to specific patterns of microbial carbohydrate moieties. However, the AP does not require specific initiation. The AP cascade is initiated by the spontaneous hydrolysis (tick-over) of C3 and the subsequent deposition of C3b on activated surfaces. The three complement activation pathways converge on two major events: C3 cleavage and C5 cleavage. C3 convertase cleaves C3 into C3a and C3b. C3b forms additional APs, C3 convertase (amplification), and C5 convertase. C5 convertase cleaves C5 into C5a and C5b. The resulting C5b initiates the formation of the C5b-9 membrane attack complex (MAC) with C6-C9, which inserts into membranes, leading to bacterial and cell lysis. The cleavage products C3a and C5a act as anaphylatoxins, promoting proinflammatory responses through the activation and chemotaxis of leukocytes. C3b also plays a key role in removing bacteria and cellular waste, such as immune complexes and apoptotic cells, by promoting phagocytosis through opsonization. (Front Immunol. 2015Jun 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 by "tick over". In addition, even if initiated by other CPs or LPs, AP contributes more than 80% of the terminal cleavage pathway activation (MAC formation) through the amplification loop. (Harboe, M., Garred, P., E., Lindstad, J.K., Stahl, G.L., Mollnes, T.E., 2009). The downstream effects of mannan-induced lectin complement pathway activation are quantitatively dependent on amplification of the alternative pathway (Mol. Immunol. 47, 373–380. https: / / doi.org / 10.1016 / j.molimm.2009.09.005). Spontaneously activated C3 binds to factor B (FB) to form C3 convertase. After factor D cleaves FB into Bb, C3b and Bb generate AP-C3 convertase (C3bBb). The newly formed C3bBb cleaves more C3 to generate more AP-C3 convertase, leading to amplification of the complement cascade. Because AP is ready to exert full complement activity within seconds, improper control can cause damage to normal tissues. (J Clin Invest. 2020 May 1; 130(5): 2152-2163. doi: 10.1172 / JCI136094. Complementopathies and precision medicine. Eleni Gavriilaki, Robert A Brodsky). Dysregulation of complement activation has 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 through FB inhibition may be a powerful strategy to limit excessive activation of the complement pathway.

[0003] Examples of complement factor B inhibitors are described in the following documents: Advanced Vision Therapies Inc, WO2008 / 106644, entitled "Treatment of inflammatory diseases"; Wellstate Immunotherapy patent publication WO2012 / 151468, entitled "Complement factor B analogs and uses thereof"; William Marsh Rice University, WO2014 / 035876, entitled "Heat-inactivated complement factor B compositions and methods"; Muse Research and Development Foundation, US1999 / 023485, entitled "Blocking factor B to treat complement-mediated immune diseases"; and Novartis patents, WO2013 / 192345 and US2015 / 126592, entitled "Complement pathway modulators and uses thereof." Other complement factor B inhibitors are described in Novartis patents WO2015 / 06241, US2016 / 311779, WO215 / 009166, US2016 / 152605, WO2014 / 14638, and US2016 / 024079. Another example of a complement factor B inhibitor is IONIS Pharmaceuticals' WO2015 / 038939, entitled "Complement factor B modulators." Granted patents covering complement factor B inhibitors include US9452990, US9676728, US9682968, and US9475806.

[0004] Given the large number of diseases caused by an overactive complement pathway, there is a high and unmet need for patients with complement diseases. The present invention is directed to providing compounds that modulate factor B and treat diseases associated with complement pathway dysregulation.

[0005] PCT / CN2023 / 117941 discloses the structures of a series of piperidindole compounds. In subsequent research and development, in order to facilitate the handling, filtration and drying of the products, and to seek suitable crystals that are easy to store and have long-term stability, the present invention conducted a comprehensive study on the crystal forms of the above-mentioned compounds. Summary of the Invention

[0006] All contents involved in patent PCT / CN2023 / 117941 are added to the present invention by reference.

[0007] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), its racemate, stereoisomer, tautomer, isotope-labeled form, solvate, polymorph, or pharmaceutically acceptable salt thereof as an active ingredient, and at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in the form of an oral immediate-release formulation, an oral sustained-release formulation, or a topical formulation;

[0008] and / or, the pharmaceutical composition is in the form of tablets, capsules, liquids, injections, pills, transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, and powders, preferably coated tablets, buccal tablets, sublingual tablets, buccal patches, chewable tablets, dispersible tablets, effervescent tablets, vaginal tablets, sustained-release tablets, controlled-release tablets, enteric-coated tablets, oral tablets, hard capsules, soft capsules, controlled-release capsules, enteric-coated capsules, more preferably immediate-release tablets, sustained- and controlled-release tablets, sustained- and controlled-release capsules, or immediate-release capsules;

[0009] in,

[0010] R1 is selected from C1-C3 alkyl or C3-C6 cycloalkyl;

[0011] R2 is selected from C1-C3 alkyl, C1-C3 alkoxy or C3-C6 cycloalkyl;

[0012] R3 is selected from -COOH, -C(O)NHSO2CH3 or -S(O)NHCH3;

[0013] R4 and R5 are each independently selected from hydrogen or halogen;

[0014] n is 0, 1, 2 or 3; preferably n is 1.

[0015] In a preferred embodiment of the present invention, it is characterized in that, in the compound of general formula (I),

[0016] R1 is selected from C1-C3 alkyl;

[0017] R2 is selected from C1-C3 alkoxy or cyclopropyl;

[0018] R3 is selected from –COOH;

[0019] R4 and R5 are each independently selected from hydrogen or halogen;

[0020] n is 1 or 2.

[0021] In a preferred embodiment of the present invention, it is characterized in that the compound of general formula (I) is selected from the following compounds 1 or 2,

[0022] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), an isomer, solvate, hydrate, or pharmaceutically acceptable salt thereof as an active ingredient, and at least one pharmaceutically acceptable excipient, wherein the excipient is selected from a filler, a disintegrant, a lubricant, a wetting agent, a binder, a preservative, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a glidant, a thickener, a pharmaceutical solvent, a stabilizer, an antioxidant, a light-shielding agent, a colorant, an anti-adhesion agent, a solubilizer, a plasticizer, a dispersant, or a coating agent; preferably, the pharmaceutical composition comprises at least a filler and a disintegrant, or the pharmaceutical composition comprises at least gelatin and / or a plasticizer; wherein the compound of formula (I) is as described above.

[0023] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), an isomer, solvate, hydrate, or pharmaceutically acceptable salt thereof as an active ingredient, wherein the pharmaceutical composition is administered orally, to the eye, mucosa, or lungs, or by intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion, or intracranial administration; wherein the compound of formula (I) is as described above.

[0024] In one aspect, the present invention provides a pharmaceutically acceptable acid salt or basic salt of a compound of formula (I), wherein the compound of formula (I) is a compound according to any one of claims 1 to 3.

[0025] In a preferred embodiment of the present invention, the acid in the acidic salt or basic salt is selected from an inorganic acid or an organic acid, and the base is selected from an organic base or an inorganic base.

[0026] A preferred embodiment of the present invention is that the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid; the organic acid is selected from 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, capric acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid , tartaric acid, dodecyl sulfuric acid, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactosonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalene disulfonic 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, p-toluenesulfonic acid, or L-malic acid;

[0027] The organic base is selected from sodium methoxide, potassium ethoxide, trimethylamine, diethylamine, triethylamine, triethanolamine, pyridine, piperidine, morpholine, diisopropylethylamine, lithium diisopropylamide, lithium diethylamide, lithium bis(trimethylsilyl)amide, potassium acetate, sodium acetate, lithium isopropylcyclohexylamide or a mixture thereof; the inorganic base is selected from potassium phosphate, potassium phosphate trihydrate, potassium phosphate dihydrate, potassium phosphate monohydrate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, potassium hydride, sodium hydride, lithium hydroxide and a mixture thereof.

[0028] A preferred embodiment of the present invention is that the inorganic acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid; the organic acid is selected from 1,5-naphthalene disulfonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic 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 camphoric acid, palmitic acid; preferably, the acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, hydrochloric acid, benzenesulfonic acid, p-toluenesulfonic acid, isethionic acid, palmitic acid; further preferably, the acid is selected from hydrochloride;

[0029] The organic base is selected from sodium methoxide, potassium ethoxide, trimethylamine, diethylamine, triethylamine or triethanolamine; the inorganic base is selected from potassium hydroxide, sodium hydroxide, potassium hydride, sodium hydride, lithium hydroxide and mixtures thereof.

[0030] A preferred embodiment of the present invention is that the inorganic acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid; the organic acid is selected from 1,5-naphthalene disulfonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic 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 camphoric acid, palmitic acid; preferably, the acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, hydrochloric acid, benzenesulfonic acid, p-toluenesulfonic acid, isethionic acid, palmitic acid; further preferably, the acid is selected from hydrochloride;

[0031] The organic base is selected from sodium methoxide, potassium ethoxide, trimethylamine, diethylamine, triethylamine or triethanolamine; the inorganic base is selected from potassium hydroxide, sodium hydroxide, potassium hydride, sodium hydride, lithium hydroxide and mixtures thereof.

[0032] In a preferred embodiment of the present invention, the number of acids or bases is 0.2-3, 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.

[0033] A preferred embodiment of the present invention is that the acid salt or basic salt is a hydrate or an anhydrate; when the acid salt or basic salt is a hydrate, the number of water is 0.2-3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3.

[0034] A preferred embodiment of the present invention is wherein the acid salt or basic salt of Compound 1 is in crystalline form.

[0035] In a preferred embodiment of the present invention, the crystalline form of the acid salt of Compound 1 is selected from hydrobromide crystalline form A, hydrochloride crystalline form A, hydrochloride crystalline form B, hydrochloride crystalline form C, sulfate crystalline form A, p-toluenesulfonate crystalline form A, isethionate crystalline form A, benzenesulfonate crystalline form A, and palmitate crystalline form A.

[0036] In a further preferred embodiment of the present invention, the hydrobromide salt form A has an X-ray powder diffraction pattern comprising one or more diffraction peaks at 2θ (±0.2°) of 9.1, 9.6, 10.3, 12.5, 15.6, 17.3, 19.0, 21.7, 23.6 and 26.1; preferably, it comprises characteristic peaks at any of 2, 4, 6 or 8 of them.

[0037] In a further preferred embodiment of the present invention, the hydrobromide salt form A has an X-ray powder diffraction pattern at 2θ (±0.2°) at 9.1, 12.5, 15.6 and 23.6 having one or more characteristic peaks; preferably comprising 2-4 of them, more preferably comprising 3-4, most preferably comprising 4; preferably, further comprising one or more characteristic peaks at 2θ (±0.2°) of 9.6 and 26.1; further preferably, further comprising one or more characteristic peaks at 2θ (±0.2°) of 10.3 and 17.3; more preferably, further comprising a characteristic peak at 2θ (±0.2°) of 19.0.

[0038] For example, the X-ray powder diffraction pattern of hydrobromide salt form A has diffraction peaks at 2θ (±0.2°) at the following positions:

[0039] 9.1, 12.5, 15.6, 23.6;

[0040] or, 9.1, 10.3, 12.5, 17.3, 26.1;

[0041] or, 10.3, 12.5, 15.6, 17.3, 19.0, 26.1;

[0042] or, 9.6, 10.3, 15.6, 17.3, 19.0, 23.6, 26.1;

[0043] or, 9.1, 9.6, 10.3, 12.5, 15.6, 17.3, 19.0, 23.6, 26.1;

[0044] Using Cu-Kα radiation, the X-ray characteristic diffraction peaks expressed in terms of 2θ angles and interplanar spacing d values ​​are shown in Table 1.

[0045] Table 1

[0046] The compound of the present invention is a hydrobromide salt crystalline form A, and its X-ray powder diffraction pattern is substantially as shown in FIG1 ; its DSC pattern is substantially as shown in FIG2 .

[0047] In a further preferred embodiment of the present invention, the hydrochloride salt form A has an X-ray powder diffraction pattern comprising one or more diffraction peaks at 2θ (±0.2°) of 8.7, 9.4, 9.9, 10.5, 12.1, 13.7, 16.6, 16.9, 17.8, 18.8, 19.7, 21.2, 21.8, 22.9, and 26.6; preferably, it comprises characteristic peaks at any of 2, 4, 6, and 8 of them.

[0048] In a further preferred embodiment of the present invention, the hydrochloride salt form A has an X-ray powder diffraction pattern at 2θ (± 0.2°) at 8.7, 9.4, 13.7, 16.9 and 21.8 having one or more characteristic peaks; preferably comprising 2-4 of them, more preferably comprising 3-4, most preferably comprising 4; preferably, further comprising 2θ (± 0.2°) at 10.5, 17.8 and 22.9 having one or more characteristic peaks; further preferably, further comprising 2θ (± 0.2°) at 19.7 and 26.6 having one or more characteristic peaks; more preferably, further comprising 2θ (± 0.2°) at 9.9, 12.1, and 21.2 having characteristic peaks.

[0049] For example, the X-ray powder diffraction pattern of hydrochloride crystal form A has diffraction peaks at 2θ (±0.2°) at the following positions:

[0050] 8.7, 9.4, 13.7, 16.6

[0051] Or, 8.7, 9.9, 13.7, 16.9

[0052] Or, 10.5, 17.8, 21.8, 26.6

[0053] or, 9.9, 13.7, 16.9, 21.8;

[0054] or, 8.7, 9.4, 13.7, 16.9, 17.8, 21.8;

[0055] or, 8.7, 9.9, 12.1, 16.6, 18.8, 21.2;

[0056] or, 9.4, 10.5, 13.7, 16.9, 17.8, 18.8;

[0057] or, 9.9, 13.7, 16.9, 17.8, 18.8, 21.2;

[0058] or, 8.7, 9.9, 10.5, 13.7, 16.6, 16.9, 17.8, 18.8;

[0059] or, 9.4, 10.5, 12.1, 13.7, 16.9, 17.8, 18.8, 19.7;

[0060] or, 10.5, 16.9, 18.8, 19.7, 21.2, 21.7, 22.9, 26.6;

[0061] or, 8.7, 9.4, 10.5, 12.1, 13.7, 16.6, 18.8, 22.9;

[0062] or, 9.9, 12.1, 13.7, 16.6, 18.8, 21.2, 21.8, 26.6;

[0063] or, 9.9, 10.5, 12.1, 13.7, 16.6, 17.8, 18.8, 21.2, 21.8;

[0064] Using Cu-Kα radiation, the X-ray characteristic diffraction peaks expressed in terms of 2θ angles and interplanar spacing d values ​​are shown in Table 2.

[0065] Table 2

[0066] The compound represented by general formula (I) of the present invention is hydrochloride crystal form A, and its X-ray powder diffraction pattern is substantially as shown in FIG3 ; its DSC pattern is substantially as shown in FIG4 ; and its TGA pattern is substantially as shown in FIG5 .

[0067] In a further preferred embodiment of the present invention, the hydrochloride form B has an X-ray powder diffraction pattern comprising one or more diffraction peaks at 2θ (±0.2°) of 9.4, 9.8, 13.2, 16.3, 16.9, 18.9, 19.7, and 22.9; preferably, it comprises characteristic peaks at any of 2, 4, 6, and 8 of these peaks.

[0068] In a further preferred embodiment of the present invention, the hydrochloride salt form B has an X-ray powder diffraction pattern at 2θ (± 0.2°) at 9.4, 13.2, 16.3 and 19.7 having one or more characteristic peaks; preferably comprising 2-4 of them, more preferably comprising 3-4, most preferably comprising 4; preferably, further comprising 2θ (± 0.2°) at 16.9 and 22.9 having one or more characteristic peaks; further preferably, further comprising 2θ (± 0.2°) at 9.8 and 18.9 having one or more characteristic peaks.

[0069] For example, the X-ray powder diffraction pattern of hydrochloride crystal form B has diffraction peaks at 2θ (±0.2°) at the following positions:

[0070] Or, 9.8, 13.2, 16.3; 16.9;

[0071] or, 9.8, 13.2, 16.3, 16.9;

[0072] or, 9.4, 13.2, 16.3, 18.9;

[0073] or, 9.4, 9.8, 13.2, 16.3, 16.9, 18.9;

[0074] or, 9.4, 9.8, 13.2, 16.3, 18.9, 19.7;

[0075] or, 9.8, 13.2, 16.3, 16.9, 18.9, 19.7;

[0076] or, 9.4, 9.8, 13.2, 16.3, 16.9, 18.9, 19.7;

[0077] The characteristic X-ray diffraction peaks expressed by 2θ angle and interplanar spacing d value using Cu-Kα radiation are shown in Table 3.

[0078] Table 3

[0079] The compound represented by general formula (I) of the present invention is a hydrochloride salt crystal form B, and its X-ray powder diffraction pattern is substantially as shown in FIG6 ; its DSC pattern is substantially as shown in FIG7 .

[0080] In a further preferred embodiment of the present invention, the hydrochloride salt form C has an X-ray powder diffraction pattern comprising one or more diffraction peaks at 2θ (±0.2°) of 7.3, 7.7, 9.3, 10.3, 11.0, 14.0, 14.8, 16.3, 18.7, 21.4, 22.2, and 23.1; preferably, it comprises characteristic peaks at any of 2, 4, 6, and 8 of them.

[0081] In a further preferred embodiment of the present invention, the hydrochloride salt form C has an X-ray powder diffraction pattern at 2θ (± 0.2°) having one or more characteristic peaks at 7.7, 11.0, 16.3 and 21.4; preferably, it contains 2-4 of them, more preferably 3-4, and most preferably 4; preferably, it also contains one or more characteristic peaks at 2θ (± 0.2°) of 7.3 and 22.2; further preferably, it also contains one or more characteristic peaks at 2θ (± 0.2°) of 14.0, 18.7 and 23.1.

[0082] For example, the X-ray powder diffraction pattern of hydrochloride crystal form C has diffraction peaks at 2θ (±0.2°) at the following positions:

[0083] 7.3, 7.7, 9.3, 10.3;

[0084] Or, 7.3, 7.7, 9.3, 10.0;

[0085] or, 7.7, 9.3, 10.0, 11.0;

[0086] or, 7.3, 9.3, 11.0, 14.0;

[0087] Or, 7.3, 7.7, 9.3, 10.0, 11.0, 14.0;

[0088] or, 7.7, 9.3, 10.3, 11.0, 14.0, 16.3;

[0089] or, 7.3, 9.3, 10.3, 14.0, 16.3, 18.7;

[0090] or, 7.3, 7.7, 9.3, 10.3, 16.3, 18.7;

[0091] or, 7.3, 7.7, 9.3, 10.3, 11.0, 14.0, 16.3, 18.7;

[0092] or, 7.7, 9.3, 10.3, 11.0, 14.0, 16.3, 18.7, 21.4;

[0093] or, 7.3, 9.3, 10.3, 11.0, 14.0, 16.3, 18.7, 22.2;

[0094] or, 7.3, 7.7, 9.3, 16.3, 18.7, 21.4, 22.2, 23.1;

[0095] The characteristic X-ray diffraction peaks expressed by 2θ angle and interplanar spacing d value using Cu-Kα radiation are shown in Table 4.

[0096] Table 4

[0097] The compound represented by general formula (I) of the present invention is a hydrochloride salt crystal form C, and its X-ray powder diffraction pattern is substantially as shown in FIG8 ; its DSC pattern is substantially as shown in FIG9 .

[0098] In a further preferred embodiment of the present invention, the sulfate crystalline form A has an X-ray powder diffraction pattern comprising one or more diffraction peaks at 2θ (±0.2°) of 7.0, 11.3, 19.4, and 23.3; preferably, comprising characteristic peaks at any two or four of the peaks;

[0099] In a further preferred embodiment of the present invention, the sulfate crystalline form A has an X-ray powder diffraction pattern at 2θ (±0.2°) at 7.0, 11.3, 19.4 and 23.3 having one or more characteristic peaks; preferably comprising 2-3 of them, more preferably comprising 3-4, and most preferably comprising 4;

[0100] For example, the X-ray powder diffraction pattern of sulfate crystal form A has diffraction peaks at 2θ (±0.2°) at the following positions:

[0101] 7.0, 11.3, 19.4, 23.3;

[0102] The characteristic X-ray diffraction peaks using Cu-Kα radiation, expressed as 2θ angles and interplanar spacing d values, are shown in Table 5.

[0103] Table 5

[0104] The compound represented by general formula (I) of the present invention is sulfate crystal form A, and its X-ray powder diffraction pattern is substantially as shown in FIG10 ; its DSC pattern is substantially as shown in FIG11 .

[0105] In a further preferred embodiment of the present invention, the p-toluenesulfonate crystalline form A has an X-ray powder diffraction pattern comprising one or more diffraction peaks at 2θ (±0.2°) of 6.0, 7.9, 9.1, 10.0, 13.1, 15.3, 15.8, 18.4, and 19.0; preferably, it comprises characteristic peaks at any of 2, 4, 6, and 8 of them.

[0106] In a further preferred embodiment of the present invention, the p-toluenesulfonate salt form A has an X-ray powder diffraction pattern at 2θ (±0.2°) at 6.0, 9.1, 10.0 and 19.0 having one or more characteristic peaks; preferably comprising 2-4 of them, more preferably comprising 3-4, most preferably comprising 4; preferably, further comprising 2θ (±0.2°) at 7.9 and 15.3 having one or more characteristic peaks; further preferably, further comprising 2θ (±0.2°) at 15.8 and 18.4 having one or more characteristic peaks.

[0107] For example, the X-ray powder diffraction pattern of p-toluenesulfonate crystalline form A has diffraction peaks at 2θ (±0.2°) at the following positions:

[0108] 6.0, 9.1, 10.0, 19.0;

[0109] or, 7.9, 9.1, 10.0, 15.3, 19.0;

[0110] or, 6.0, 7.9, 9.1, 10.0, 15.3, 18.4;

[0111] or, 7.9, 9.1, 15.3, 15.8, 18.4, 19.0;

[0112] Or, 6.0, 7.9, 9.1, 10.0, 15.3, 15.8, 18.4, 19.0.

[0113] The characteristic X-ray diffraction peaks using Cu-Kα radiation, expressed as 2θ angles and interplanar spacing d values, are shown in Table 5.

[0114] Table 6

[0115] The compound represented by general formula (I) of the present invention is a p-toluenesulfonate crystalline form A, and its X-ray powder diffraction pattern is substantially as shown in FIG12 ; its DSC pattern is substantially as shown in FIG13 .

[0116] In a further preferred embodiment of the present invention, the isethionate salt crystalline form A has an X-ray powder diffraction pattern comprising one or more diffraction peaks at 2θ (±0.2°) of 8.6, 9.3, 9.9, 16.6, 19.9, 21.7 and 24.4; preferably, the pattern comprises characteristic peaks at any two, four or six of the diffraction peaks.

[0117] In a further preferred embodiment of the present invention, the isethionate salt crystalline form A has an X-ray powder diffraction pattern having one or more characteristic peaks at 8.6, 9.3, 16.6 and 19.9 at 2θ (±0.2°); preferably, it contains 2-4 of these peaks, more preferably, it contains 3-4, and most preferably, it contains 4; preferably, it also contains one or more characteristic peaks at 9.9 and 24.4 at 2θ (±0.2°); further preferably, it also contains a characteristic peak at 21.7 at 2θ (±0.2°).

[0118] For example, the X-ray powder diffraction pattern of the isethionate salt form A has diffraction peaks at the following positions at 2θ (±0.2°):

[0119] 8.6, 9.3, 16.6, 19.9;

[0120] or, 8.6, 9.9, 16.6, 19.9, 24.4;

[0121] or, 9.3, 9.9, 16.6, 19.9, 24.4;

[0122] Or, 8.6, 9.3, 9.9, 16.6, 19.9, 21.7, 24.4.

[0123] Using Cu-Kα radiation, the X-ray characteristic diffraction peaks expressed in terms of 2θ angles and interplanar spacing d values ​​are shown in Table 7.

[0124] Table 7

[0125] The compound represented by general formula (I) of the present invention is a crystalline form A of the isethionate salt, and its X-ray powder diffraction pattern is substantially as shown in FIG14 ; its DSC pattern is substantially as shown in FIG15 .

[0126] In a further preferred embodiment of the present invention, the benzenesulfonate salt form A has an X-ray powder diffraction pattern comprising one or more diffraction peaks at 2θ (±0.2°) of 9.4, 9.9, 17.8, 18.8, 19.7, 21.2, 22.9, and 26.5; preferably, it comprises characteristic peaks at any of 2, 4, 6, and 8 of them.

[0127] In a further preferred embodiment of the present invention, the benzenesulfonate salt form A has an X-ray powder diffraction pattern having one or more characteristic peaks at 2θ (± 0.2°) 9.4, 9.9, 17.8 and 19.7; preferably, it also includes one or more characteristic peaks at 2θ (± 0.2°) of 18.8 and 21.2; further preferably, it also includes one or more characteristic peaks at 2θ (± 0.2°) of 22.9 and 26.5.

[0128] For example, the X-ray powder diffraction pattern of benzenesulfonate crystalline form A has diffraction peaks at 2θ (±0.2°) at the following positions:

[0129] 9.4, 9.9, 17.8, 19.7;

[0130] or, 9.9, 17.8, 19.7, 21.2;

[0131] or, 9.4, 18.8, 19.7, 22.9, 26.5;

[0132] or, 9.4, 17.8, 19.7, 22.9, 26.5;

[0133] Or, 9.4, 9.9, 17.8, 18.8, 19.7, 21.2, 22.9, 26.5.

[0134] Using Cu-Kα radiation, the X-ray characteristic diffraction peaks expressed in terms of 2θ angles and interplanar spacing d values ​​are shown in Table 8.

[0135] Table 8

[0136] The compound represented by general formula (I) of the present invention is a benzenesulfonate crystalline form A, and its X-ray powder diffraction pattern is substantially as shown in FIG16 ; its DSC pattern is substantially as shown in FIG17 .

[0137] In a further preferred embodiment of the present invention, the palmitate salt form A has an X-ray powder diffraction pattern containing one or more diffraction peaks at 2θ (±0.2°) of 7.4, 8.2, 21.7, and 24.2; preferably, it contains characteristic peaks at any two or four of them.

[0138] In a further preferred embodiment of the present invention, the palmitate salt crystalline form A has an X-ray powder diffraction pattern with one or more characteristic peaks at 7.4, 8.2, 21.7, and 24.2 at 2θ (±0.2°).

[0139] For example, the X-ray powder diffraction pattern of palmitate salt form A has diffraction peaks at 2θ (±0.2°) at the following positions:

[0140] 7.4, 8.2, 21.7, 24.2.

[0141] Using Cu-Kα radiation, the X-ray characteristic diffraction peaks expressed in terms of 2θ angles and interplanar spacing d values ​​are shown in Table 9.

[0142] Table 9

[0143] The compound represented by general formula (I) of the present invention is palmitate crystalline form A, and its X-ray powder diffraction pattern is basically shown in Figure 18; its DSC pattern is basically shown in Figure 19.

[0144] In a further preferred embodiment of the present invention, the above-mentioned crystal form is a solvent-containing crystal form, wherein the solvent is selected from water, methanol, acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, 2-methyl-tetrahydrofuran, 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.

[0145] In a further preferred embodiment of the present invention, the number of the solvents is 0.2-3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3.

[0146] The present invention also provides a method for preparing a salt of the compound represented by general formula (I) and its crystal form, which specifically comprises the following steps:

[0147] 1) Weigh an appropriate amount of free base and dissolve it in a benign solvent;

[0148] 2) Weighing an appropriate amount of counterion acid or counterion base and dissolving it in an organic solvent; the amount of counterion acid is preferably 1 equivalent;

[0149] 3) combining the above two solutions and stirring to dissolve out;

[0150] 4) optionally centrifuging and drying to obtain the target product;

[0151] or,

[0152] 1) Weigh an appropriate amount of free base and dissolve it in a benign solvent;

[0153] 2) Weighing an appropriate amount of counterion acid or counterion base and dissolving it in an organic solvent; the amount of counterion acid is preferably 1 equivalent;

[0154] 3) combining the above two solutions and stirring to dissolve out;

[0155] 4) adding an appropriate solvent A to the obtained solid product, volatilizing and drying to obtain the target product;

[0156] in:

[0157] The benign solvent is selected from methanol, ethyl acetate, dichloromethane, acetone, tetrahydrofuran, isopropanol or 2-butanone; preferably methanol, ethyl acetate or acetone;

[0158] 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;

[0159] The solvent A is selected from acetone, ethanol, acetonitrile, tetrahydrofuran, dichloromethane, toluene, ethyl acetate, methyl tert-butyl ether or water;

[0160] The counterion acid is selected from an organic acid or an inorganic acid; the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid; the organic acid is selected from 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, capric acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid acid, tartaric acid, dodecyl sulfuric acid, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactosonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalene disulfonic 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, p-toluenesulfonic acid, or L-malic acid;

[0161] The counter ion base is selected from an organic base or an inorganic base; the organic base is selected from sodium methoxide, potassium ethoxide, trimethylamine, diethylamine, triethylamine, triethanolamine, pyridine, piperidine, morpholine, diisopropylethylamine, lithium diisopropylamide, lithium diethylamide, lithium bis(trimethylsilyl)amide, potassium acetate, sodium acetate, lithium isopropylcyclohexylamide or a mixture thereof; the inorganic base is selected from potassium phosphate, potassium phosphate trihydrate, potassium phosphate dihydrate, potassium phosphate monohydrate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, potassium hydride, sodium hydride, lithium hydroxide or a mixture thereof.

[0162] Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of the acid salt crystalline form of the compound of general formula (I) described above, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0163] In a further preferred embodiment of the present invention, the amount of the acid salt or basic salt of the compound is about 0.1% to 95% by weight of the free base; preferably, about 0.5% to 85% by weight of the free base;

[0164] More preferably, about 1% to 60% by weight of the free base;

[0165] Even more preferably, about 10% to 50% by weight of the free base;

[0166] More preferably, the amount is about 15% to 40% by weight of the free base;

[0167] Still further preferably, about 20% to 30% by weight of the free base;

[0168] Most preferably, it is about 20% to 25% by weight of the free base.

[0169] In a further preferred embodiment of the present invention, wherein the amount of the acid salt or basic salt of the compound is about 1-1000 mg based on the weight of the free base;

[0170] Preferably, about 1-500 mg by weight of the free base;

[0171] More preferably, about 5-200 mg based on the weight of the free base;

[0172] More preferably, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg, 300 mg, 400 mg or 500 mg by weight of the free base.

[0173] The present invention further relates to a method for treating a disease or condition associated with activation of the complement alternative pathway in a subject in need thereof, comprising administering to the subject an effective amount of an acid salt or base salt of the compound of formula (I) described above, or the pharmaceutical composition described above.

[0174] In a further preferred embodiment of the present invention, the present invention further relates to a method for treating a disease or condition associated with activation of the complement alternative pathway in a subject in need thereof by regulating complement factor B, comprising administering to the subject an effective amount of the acid salt form of the compound of general formula (I) described above, or the pharmaceutical composition described above.

[0175] Further, wherein the disease or condition is selected from age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, avian needle retinochoroiditis, sympathetic eye inflammation, ophthalmic pemphigoid, ocular pemphigus, retinal vein occlusion, nervous system disease, multiple sclerosis, stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, inappropriate or suboptimal complement activation disorders, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 therapy, inflammatory diseases, inflammation of autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion conditions, myocardial infarction, balloon angioplasty, post-pump syndrome in extracorporeal circulation or renal bypass, atherosclerosis, blood Fluid dialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infectious diseases or sepsis, immune complex diseases and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus, SLE nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease, emphysema, pulmonary embolism and infarction, pneumonia, fibrogenic dust disease, pulmonary fibrosis, asthma, allergies, bronchitis Contraction, hypersensitivity pneumonitis, parasitic diseases, 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 and middle-stage age-related macular degeneration (e / i AMD), idiopathic membranous nephropathy, immune complex membranoproliferative glomerulonephritis (IC-MPGN). BRIEF DESCRIPTION OF THE DRAWINGS

[0176] FIG1 is an XRPD diagram of hydrobromide salt form A.

[0177] FIG2 is a DSC diagram of hydrobromide salt form A.

[0178] FIG3 is an XRPD diagram of hydrochloride salt form A.

[0179] FIG4 is a DSC diagram of hydrochloride form A.

[0180] FIG5 is a TGA diagram of hydrochloride form A.

[0181] FIG6 is an XRPD diagram of hydrochloride Form B.

[0182] FIG7 is a DSC diagram of hydrochloride form B.

[0183] FIG8 is an XRPD diagram of hydrochloride salt form C.

[0184] FIG9 is a DSC diagram of hydrochloride salt form C.

[0185] FIG10 is an XRPD diagram of sulfate salt Form A.

[0186] FIG11 is a DSC diagram of sulfate salt form A.

[0187] FIG12 is an XRPD diagram of p-toluenesulfonic acid salt Form A.

[0188] FIG13 is a DSC diagram of p-toluenesulfonate crystalline form A.

[0189] FIG14 is an XRPD diagram of Form A of the isethionate salt.

[0190] FIG15 is a DSC diagram of Form A of the isethionate salt.

[0191] FIG16 is an XRPD diagram of Form A of the besylate salt.

[0192] FIG17 is a DSC diagram of benzenesulfonate Form A.

[0193] FIG18 is an XRPD diagram of palmitate salt Form A.

[0194] FIG19 is a DSC diagram of palmitate salt Form A. DETAILED DESCRIPTION

[0195] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0196] In the present invention, an alkyl group refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain 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, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof.

[0197] The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred in the present invention; the hydroxy-substituted alkyl may be 2-hydroxyisopropyl or 1-hydroxyethyl.

[0198] In the present invention, heterocyclic group refers to a saturated or partially unsaturated monocyclic or polycyclic heterocyclic group containing 3 to 20 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m(wherein m is an integer from 0 to 2) heteroatoms, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 10 ring atoms; and further preferably, it contains 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, pyrrolidonyl, piperidin-2-onyl, 3,4-dihydropyridin-2(1H)-onyl, 4,5-dihydropyridazin-3(2H)-onyl, azetidinyl, oxetanyl, oxanyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc.; preferably pyrrolidyl, pyrrolidonyl, piperidin-2-one, 3,4-dihydropyridin-2 (1H) -one, 4,5-dihydropyridazine-3 (2H) -one, azetidinyl, oxetanyl, dihydropyrrolyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, Piperazinyl and pyranyl; more preferably dihydropyrrolyl, pyrrolidinyl, pyrrolidonyl, piperidin-2-onyl, 3,4-dihydropyridin-2 (1H) -onyl, 4,5-dihydropyridazin-3 (2H) -onyl, azetidinyl, oxetanyl, oxanyl, morpholinyl, piperidinyl, piperazinyl, Pyranyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged heterocyclic groups are optionally connected to other groups through single bonds, or further connected to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups through any two or more atoms on the ring.

[0199] The heterocyclyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0200] In the present invention, aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, more preferably 6- to 8-membered, such as phenyl and naphthyl, preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring connected to the parent structure is the aryl ring, non-limiting examples of which include:

[0201] In the present invention, alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein the definition of alkyl 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 preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate;

[0202] Non-limiting examples of alkoxy also include propan-2-oxy and the like.

[0203] In the present invention, haloalkyl refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above. Non-limiting examples of haloalkyl include: trifluoromethyl, trifluoroethyl;

[0204] Non-limiting examples of haloalkyl also include difluoromethyl, 1,1,2,2-tetrafluoroethyl, perfluoroethyl, and the like.

[0205] In the present invention, haloalkoxy refers to an alkoxy group substituted by one or more halogens, wherein alkoxy is as defined above;

[0206] The halogenated alkoxy group may be fully halogenated or partially halogenated, and the number of halogenations may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.; the halogen is preferably F, Cl, Br, I; for example, it may be trifluoromethoxy, difluoromethoxy, 1,1,2,2-tetrafluoroethoxy, perfluoroethoxy, etc.

[0207] In the present invention, hydroxyalkyl refers to an alkyl group substituted by a hydroxy group, wherein the alkyl group is as defined above.

[0208] In the present invention, haloalkyl refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.

[0209] In the present invention, a haloalkoxy group refers to an alkoxy group substituted by one or more halogen groups, wherein the alkoxy group is as defined above.

[0210] "Hydroxy" refers to an -OH group.

[0211] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0212] "Amino" refers to -NH2.

[0213] "Cyano" refers to -CN.

[0214] "Nitro" refers to -NO2.

[0215] "THF" refers to tetrahydrofuran.

[0216] "EtOAc" refers to ethyl acetate.

[0217] "DMSO" refers to dimethyl sulfoxide.

[0218] "LDA" refers to lithium diisopropylamide.

[0219] "DMAP" refers to 4-dimethylaminopyridine.

[0220] "EtMgBr" refers to ethylmagnesium bromide.

[0221] "HOSu" refers to N-hydroxysuccinimide.

[0222] "EDCl" refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[0223] "IPA" refers to isopropyl alcohol.

[0224] "MeOH" refers to methanol.

[0225] "EtOH" refers to ethanol.

[0226] "DMF" refers to N,N-dimethylformamide.

[0227] "DIPEA" refers to N,N-diisopropylethylamine.

[0228] "HEPES" refers to 4-hydroxyethylpiperazineethanesulfonic acid.

[0229] Different expressions 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, that is, X can be any one or more of A, B, and C.

[0230] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and where it does not.

[0231] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0232] "Stereoisomerism" includes three types: geometric isomerism (cis-trans isomerism), optical isomerism, and conformational isomerism.

[0233] As used herein, the name of a compound is intended to encompass all possible isomeric forms, including stereoisomers (eg, enantiomers, diastereomers, racemates or racemic mixtures, and any mixtures thereof) of the compound.

[0234] The hydrogen atoms described in the present invention can all be replaced by their isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.

[0235] "Pharmaceutical composition" means a mixture containing 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 a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity. It will be understood by those skilled in the art that the composition contains at least one pharmaceutically acceptable excipient, which is selected from fillers, disintegrants, lubricants, wetting agents, binders, preservatives, sweeteners, flavorings, emulsifiers, suspending agents, glidants or thickeners, pharmaceutical solvents, stabilizers, or antioxidants. It means that it can contain one or more functional ingredients, such as a filler and a disintegrant, or it can refer to one or more substances containing a certain functional ingredient, for example, it can contain two fillers of different types.

[0236] "Hydrate" crystalline forms include hemihydrate, monohydrate, dihydrate, etc. Other hydrate forms such as channel hydrates are also included within the meaning of this term.

[0237] An X-ray powder diffraction pattern (XRPD) refers to an experimentally observed diffraction pattern or parameters derived therefrom, characterized by peak position (abscissa) and peak intensity (ordinate). Those skilled in the art will appreciate that experimental errors depend on instrument conditions, sample preparation, and sample purity. In particular, it is well known to those skilled in the art that X-ray diffraction patterns typically vary with instrument conditions, and those skilled in the art will appreciate that suitable error tolerances for XRPD may be: 2θ±0.5°; 2θ±0.4°; 2θ±0.3°; 2θ±0.2°. It is particularly important to note that the relative intensities of X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or determining factor. Furthermore, experimental factors such as sample height can cause an overall shift in peak angles, and a certain amount of shift is generally tolerated. Therefore, those skilled in the art will appreciate that any crystalline form having characteristic peaks identical or similar to those in the pattern of the present invention falls within the scope of the present invention.

[0238] "TGA" refers to a thermogravimetric analysis (TGA) experiment.

[0239] "DSC" refers to a differential scanning calorimetry (DSC) experiment.

[0240] "HPLC" refers to high performance liquid chromatography (HPLC) experiments.

[0241] "PK" refers to pharmacokinetic (PK) studies.

[0242] “KF” refers to the Karl Fischer water determination (KF) experiment.

[0243] The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

[0244] Preparation of compounds

[0245] The following examples are intended to illustrate the present invention, but should not be construed as limiting the scope of the present invention. Unless otherwise specified in the examples, the specific conditions of the experimental methods were generally based on the conventional conditions or recommended conditions of the raw materials and product manufacturers. Reagents for which the specific sources are not indicated are commercially available conventional reagents.

[0246] The structure of each compound was identified by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR chemical shifts (δ) were expressed in 10 -6 The NMR spectra were measured on a Varian Mercury 300 MHz and a Bruker Avance III 400 MHz instrument. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD).

[0247] High-performance liquid chromatography (HPLC) was performed using an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18 150×4.6 mm column). Liquid chromatography-mass spectrometry (LCMS) was performed using an Agilent 1200 high-pressure liquid chromatograph & mass spectrometer (Sunfire C18 4.6×50 mm 3.5 μm column) and an Agilent 19091S-433HP-5 high-pressure liquid chromatograph & mass spectrometer (XBridge C18 4.6×50 mm 3.5 μm column).

[0248] SFC Thar 80&150&200 (waters) determination of chiral high performance liquid chromatography (HPLC).

[0249] The average ATPase inhibition rate and IC were determined using a Victor Nivo multi-mode microplate reader (PerkinElmer, USA). 50 value.

[0250] The thin layer silica gel plates used in thin layer chromatography were Yantai Xinnuo silica gel plates. The plates used in TLC were sized from 0.15 mm to 0.2 mm, and the plates used in thin layer chromatography for product purification were sized from 0.4 mm to 0.5 mm.

[0251] Column chromatography generally uses Qingdao Haiyang 200 to 300 mesh silica gel as the carrier.

[0252] The known raw materials of the present invention can be prepared by conventional synthesis methods in the prior art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc or Dari Chemical Company, etc.

[0253] MS is mass spectrometry, where (+) refers to the positive mode which typically gives an M+1 (or M+H) absorption, where M = molecular weight.

[0254] Example 1 Preparation of Compound 1

[0255] Synthesis process:

[0256] Synthesis of tert-butyl 4-(chloromethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate Int A

[0257] At room temperature, under nitrogen, to a solution of tert-butyl 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (CAS: 1644667-10-6-950mg, 3.45mmol) in CH2Cl2 (10mL) was added (chloromethylene) dimethylimino chloride (711mg, 5.56mmol) in a single portion, and the mixture was stirred at this temperature for 2 hours. The reaction mixture was cooled to 0°C and then quenched with 5% NaHCO3 aqueous solution. The mixture was extracted with CH2Cl2 (3x 20mL). The combined organic layers were washed with brine (20mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product, tert-butyl 4-(chloromethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate Int A (900mg), was obtained as a yellow oil. LCMS (m / z): [M-Cl] + C 16 H 20NO3 calculated, 274.1; measured, 274.1.

[0258] Step 1

[0259] A solution of 1-oxo-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester (750 mg, 3.94 mmol), 3-((trimethylsilyl)-methyl)but-3-ene-1-amine (1.12 g, 7.10 mmol) and AcOH (355 mg, 5.91 mmol) in MeOH was stirred at 50 ° C for 40 hours. The reaction mixture was neutralized with saturated NaHCO solution and then extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column chromatography (PE / EtOAc = 1 / 1) to give compound a (860 mg, 85%) as a black oil. MS: m / z = 258.1 (M+1, ESI+).

[0260] Step 2

[0261] At 0 ° C, under nitrogen, to a stirred solution of 4'-methylene-2,3-dihydrospiro[indene-1,2'-piperidine]-5-carboxylic acid methyl ester (820 mg, 3.19 mmol) and K2CO3 (1.32 g, 9.56 mmol) in THF (10 mL) was added dropwise Cbz-Cl (815 mg, 4.78 mmol). The reaction mixture was stirred at 25 ° C for 16 hours. The reaction mixture was quenched with NaHCO3 solution (30 mL) and then extracted with EtOAc (30 mLx3). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column chromatography (PE / EtOAc = 5 / 1) to give 1'-benzyl 5-methyl 4'-methylene-2,3-dihydrospiro[indene-1,2'-piperidine]-1',5-dicarboxylate b (1.05 g, 84%) as a colorless oil. MS: m / z = 391.9 (M+1, ESI+).

[0262] Step 3

[0263] At 20 ° C, under a nitrogen atmosphere, to a suspension of Cu-Zn (3.5 g, 3% Cu) and 4'-methylene-2,3-dihydrospiro[indene-1,2'-piperidine]-1',5-dicarboxylic acid methyl ester b (1.0 g, 2.4 mmol, 1.0 equivalent) in dioxane (20 mL, 20 V) was added trichloroacetyl chloride (4.4 g, 24 mmol, 10 equivalents) within 30 minutes. The mixture was heated to 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 brine (40 mL, 40 V). The combined filtrates were dried over Na2SO4 and concentrated in vacuo to give an oily crude product, 1'-benzyl 5"-methyl 2,2-dichloro-3-oxo-2",3"-dihydrodispiro[cyclobutane-1,4'-piperidin-2',1"-indene]-1',5"-dicarboxylate c (1.2 g crude), which was used in the next step without further purification. LCMS (m / z): [M+H] + C 26 H 26 Calculated Cl2NO5, 502.1; measured, 502.3.

[0264] Step 4

[0265] To a solution of 2,2-dichloro-3-oxo-2",3"-dihydrodispiro[cyclobutane-1,4'-piperidine-2',1"-indene]-1',5"-dicarboxylic acid 1'-benzyl 5"-methyl ester c (1.2 g, crude product) in MeOH (50 mL) were added NH4Cl (2.6 g, 48 mmol) and zinc (1.6 g, 24 mmol) at room temperature. The reaction mixture was stirred at 60°C for 2 hours and then filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (ethyl acetate:petroleum ether = 2 / 1) to give the product 3-oxo-2",3"-dihydrodispiro[cyclobutane-1,4'-piperidine-2',1"-indene]-1',5"-dicarboxylic acid 1'-benzyl 5"-methyl ester d as an oil (500 mg, 50% yield over two steps). LCMS (m / z): [M+H] + C 26 H 28 NO5 calculated, 434.2; measured, 434.0.

[0266] Step 5

[0267] 3-Oxo-2",3"-dihydrodispiro[cyclobutane-1,4'-piperidin-2',1"-indene]-1',5"-dicarboxylic acid 1'-benzyl 5"-methyl ester d (500 mg, 1.15 mmol) was dissolved in BAST (1.5 mL) at 0°C. The reaction mixture was stirred at 50°C for 12 hours. The reaction was cooled to room temperature and 15 mL of ethyl acetate was added. The reaction mixture was poured very carefully into ice (20 mL). The residue was washed with dichloromethane (30 mL x 4 HCl). 3) extraction, washed with brine (30 mL), and dried over Na2SO4. The filtrate was concentrated in vacuo and purified by silica gel flash column chromatography (ethyl acetate:petroleum ether = 1 / 5) to give the product 3,3-difluoro-2",3"-dihydrodispiro[cyclobutane-1,4'-piperidin-2',1"-indene]-1',5"-dicarboxylic acid 1'-benzyl 5"-methyl ester e as an oil (300 mg, 57% yield). LCMS (m / z): [M+H] + C 26 H 28 F2NO4 calculated, 456.2; measured, 456.0.

[0268] Step 6

[0269] To a stirred solution of 1'-benzyl 5"-methyl 3,3-difluoro-2",3"-dihydrodispiro[cyclobutane-1,4'-piperidin-2',1"-indene]-1',5"-dicarboxylate e (240 mg, 0.527 mmol) in MeOH (5 mL) at 25°C was added Pd(OH)2 / C (100 mg). The reaction mixture was stirred at 25°C under H2 for 2 hours. After filtration, the solution was concentrated in vacuo to give methyl 3,3-difluoro-2",3"-dihydrodispiro[cyclobutane-1,4'-piperidin-2',1"-indene]-5"-carboxylate f as an oil (155 mg, 92% yield). LCMS (m / z): [M+H] + C 18 H 22 F2NO2 calculated, 322.1; measured, 322.1.

[0270] Step 7

[0271] A solution of methyl 3,3-difluoro-2",3"-dihydrodispiro[cyclobutane-1,4'-piperidine-2',1"-indene]-5"-carboxylate f (155 mg, 0.48 mmol), tert-butyl 4-(chloromethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (180 mg, 0.58 mmol), Cs2CO3 (471 mg, 1.45 mmol) and NaI (109 mg, 0.72 mmol) in acetonitrile (3 mL) was stirred at 80 °C for 2 hours. After filtration, the solution was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (PE / EtOAc=10 / 1) to give methyl 1'-((1-(tert-butoxycarbonyl)-5-methoxy-7-methyl-1H-indol-4-yl)methyl)-3,3-difluoro-2",3"-dihydrodispiro[cyclobutane-1,4'-piperidine-2',1"-indene]-5"-carboxylate (180 mg, 63%) as a white solid. LCMS (m / z): [M+H] + C 34 H 41 Calculated F2N2O5, 595.1; measured, 595.1.

[0272] Step 8

[0273] A solution of methyl 1'-((1-(tert-butoxycarbonyl)-5-methoxy-7-methyl-1H-indol-4-yl)methyl)-3,3-difluoro-2",3"-dihydrodispiro[cyclobutane-1,4'-piperidine-2',1"-indene]-5"-carboxylate (180 mg, 0.30 mmol) and NaOH (60 mg, 1.51 mmol) in MeOH / THF / HO (1 / 1 / 0.2 mL) was stirred at 60° C. for 1 hour. The reaction mixture was neutralized with saturated citric acid solution and then extracted with DCM / MeOH (10 / 1, 20 mL×3). The combined organic layers were concentrated in vacuo, and the residue was purified by preparative HPLC (acetonitrile-H2O, 0.1% FA) and SFC (column: CHIRALPAK AD-H 250 mm x 20 mm, 5 μm; mobile phase: 40% EtOH [0.2% NH4OH] in CO2; flow rate: 12.5 mL / min; column temperature: 38°C, retention time = 3.54 min) to obtain compound 1 (36.27 mg, 25%).

[0274] 1HNMR(400MHz,CD3OD)δ8.08(m,1H),7.98(s,1H),7.60(d,J=8.1Hz,1H),7.28(d ,J=3.1Hz,1H),6.70(s,1H),6.23(d,J=3.0Hz,1H),4.15-4.04(m,1H),4.02-3. 89(m,1H),3.65(s,3H),3.52-3.41(m,2H),3.27-3.11(m,2H),2.95-2.75(m,2H ),2.73-2.60(m,1H),2.56-2.42(m,6H),2.40-2.29(m,1H),2.11-1.94(m,3H).

[0275] Example 2 Preparation of Compound 2

[0276] The following examples were synthesized using the above ester hydrolysis procedure and appropriate starting materials:

[0277] Example 3

[0278] A pharmaceutical composition tablet comprising Compound 1 of the present invention, comprising 1.4 mg of Compound 1, 120 mg of corn starch, and 28.6 mg of hydroxyethyl cellulose.

[0279] The tablets containing the above components are prepared using the following preparation method:

[0280] (1) Weighing: Weigh the raw and auxiliary materials according to the quantity of the core material.

[0281] (2) Mixing

[0282] (3) Dry granulation

[0283] (4) Tablet pressing: Calculate the tablet weight according to the particle content, adjust the tablet weight and hardness to meet the requirements, and then press the tablets;

[0284] (5)Packaging.

[0285] Biological test evaluation

[0286] The present invention is further described and explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0287] Biological Example 1. Factor B Binding Assay by TR-FRET

[0288] Materials and reagents

[0289] 1. Recombinant human factor B catalytic domain (aa470-764, C-terminal histidine tag, produced in-house)

[0290] 2. 5X Kinase Buffer A (Thermo Fisher, CAT#PV3189)

[0291] 3. LANCE Eu-W1024 anti-6xHis antibody (PerkinElmer, CAT#AD0401)

[0292] 4. Probe (TRFRET_tool 2, reported in WO 2015 / 009616)

[0293] 5.DMSO(Thermo Fisher Scientific)

[0294] 6. Compounds - 10 mM stock solution in DMSO

[0295] 7. Victor Nivo Multimode Microplate Reader (PerkinElmer)

[0296] 8. OptiPlate-384, white opaque 384-well microplate (PerkinElmer, CAT# 6007290)

[0297] Experimental process

[0298] The Factor B binding affinity of each test compound was determined using time-resolved fluorescence resonance energy transfer (TR-FRET) technology. 10 nM recombinant histidine-tagged Factor B catalytic domain, varying concentrations of inhibitor, 4 nM LANCE Eu-W1024 anti-6xHis antibody, and 100 nM TRFRET_tool2 tracer were incubated in 1X kinase buffer A for 1 hour. Measurements were performed in a 15 μL reaction volume by adding 5 μL of test compound, 5 μL of Factor B / antibody mixture, and 5 μL of tracer to a white opaque 384-well assay plate. TR-FRET signals were read on a plate reader with an excitation wavelength of 340 nm and detection wavelengths of 615 and 665 nm. The IC was estimated from [Compound] relative to the emission ratio by measuring the TR-FRET signal for varying concentrations of compound and plotting the relative fluorescence emission ratio (665 nm / 615 nm) versus inhibitor concentration using a four-parameter dose-response inhibition curve with a variable slope model in GraphPad Prism. 50 , to determine the binding affinity of each compound.

[0299] The binding affinity of the compounds of the present invention to the catalytic domain of recombinant factor B was determined by the above assay, IC 50 The values ​​(nM) are shown in the table below.

[0300] Table 10. IC values ​​of the compounds of the present invention for human factor B 50 Value (nM)

[0301] Biological Example 2: Target Retention Time of Factor B Inhibitors Determined by Surface Plasmon Resonance (SPR)

[0302] Materials and reagents

[0303] 1. Recombinant human factor B catalytic domain (aa470-764, C-terminal histidine tag, produced in-house)

[0304] 2. PBS-P+ buffer 10X (Cytiva, CAT#28995084)

[0305] 3. Series S Sensor Chip NTA (Cytiva, CAT#BR100532)

[0306] 4. Amine coupling kit (Cytiva, CAT#BR100050)

[0307] 5. DMSO (Millipore Sigma, CAT#34869-1L)

[0308] 6. Greiner 96-well plates, polypropylene (Sigma-Aldrich, CAT#M7310-100EA)

[0309] 7. Microplate foil, 96 wells (Cytiva, CAT# 28975816)

[0310] 8. Biacore 8k (Cytiva)

[0311] Experimental process

[0312] A Biacore 8k instrument was loaded with 1X PBS-P+ buffer and then docked to a Cytiva NTA chip. 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) to a level of approximately 5,000 resonance units (RU). Protein ligands were further cross-linked to the sensor chip surface using an amine coupling kit. Immobilization and binding experiments were performed at room temperature.

[0313] The buffer solution was replaced with 1X PBS-P+ buffer containing 2% (v / v) DMSO, and then a pre-run of at least 30 minutes was performed at a flow rate of 30 μl / min to obtain a stable surface. The kinetic constants of the compound were determined by single-cycle kinetics (or multi-cycle kinetics of eight continuous injections) of six consecutive injections of the compound at increasing concentrations of 0.8 to 200 nM, 12.5 to 400 nM, 4.1 to 1,000 nM or 41 to 10,000 nM (depending on efficacy). Single-cycle kinetics experiments (or 120 seconds of dissociation time for multi-cycle kinetics experiments) were performed with an association time of 60 seconds per concentration and a dissociation time of 300 seconds. A flow rate of 30 μl / min was used. Before injecting the compound, a blank run was performed under the same conditions.

[0314] SPR sensorgrams were analyzed using a dual-reference method using Biacore Insight Evaluation Software. The resulting curves were fitted with a 1:1 binding model. The replicate kinetic constants (ka, kd, KD) were averaged. Retention time (tR) was calculated based on the dissociation constant kd using the formula tR = 1 / kd. Binding half-life (t1 / 2) was calculated based on the dissociation constant kd using the formula t1 / 2 = ln2 / kd.

[0315] The example compounds of the present invention were tested in the above assay and showed K D (nM) ranges from 0.5 to 250 nM.

[0316] Biological Example 3: Inhibition of Human MAC Deposition

[0317] To quantify the inhibitory effect of compounds on complement protein deposition following LPS activation of the alternative complement pathway, an AP deposition assay was performed. Compounds were tested starting at 11.1 μM or 3.70 μM and diluted three-fold in DMSO to generate eight concentration points, each of which was tested in technical triplicate. Human serum was mixed with the test compound in GVB buffer containing 5 mM MgCl2 and 10 mM EGTA and added to LPS-coated black Maxisorp plates. After incubation, the plates were inverted and complement proteins bound to LPS were detected by ELISA. A primary antibody detecting human C5b-9 was used, followed by a compatible HRP-conjugated secondary antibody. Peroxidase activity was detected using the QuantaBlu Fluorescent Peroxidase Substrate Kit, and fluorescence was measured at 340 nm / 435 nm using an i3x plate reader to determine the amount of alternative pathway complement protein deposition.

[0318] Table 11. Inhibition of MAC (Membrane Attack Complex) Formation

[0319] Biological Example 4: Inhibition of AP-dependent hemolysis

[0320] To quantify the inhibitory effect of compounds on the hemolytic activity of the alternative complement pathway, an AP hemolysis assay was performed. Compounds were tested starting at 100 μM and diluted 3-fold in DMSO, yielding 8 to 11 concentration points, each tested in technical triplicate. Human serum was added to rabbit reticulocytes in GVB buffer containing MgCl2 and EGTA. After incubation at 37°C, spontaneous lysis of rabbit erythrocytes due to serum AP complement activity was quantified using OD405 absorbance (measured using an i3x plate reader).

[0321] Table 12. Inhibition of rabbit reticulocyte hemolysis

[0322] Biological Example 5. Factor B Inhibition Assay

[0323] CVF (1 μM), FB (1 μM) and FD (300 nM) were incubated in PBS at pH 7.4 containing 10 mM MgCl2 and 0.05% (w / v) CHAPS (assay buffer) at room temperature for 3 hours to allow all FB to be activated by cleavage of FD into Ba and enzymatically active CVF:Bb complex (C3 convertase). Human CVF:Bb complex (3 nM concentration) was pre-incubated with different compound concentrations in assay buffer at room temperature for 2 hours. The enzymatic reaction was started by adding C3 to a final concentration of 1 μM diluted in assay buffer. After incubation for 2 hours at room temperature, the enzyme reaction was stopped by adding a protease inhibitor cocktail (Roche complete inhibitor tablets). The production of C3a was quantified by enzyme-linked immunosorbent assay (ELISA). An aliquot (3 μL) of the reaction sample was pipetted into a 384-well high-capacity protein binding plate (NUNC Maxisorp TM ), the plate was pre-filled with 97 μL / well of 100 mM sodium carbonate buffer, pH 9.0, containing 1 M NaCl.

[0324] After incubation at 4°C overnight, the assay plates were washed with TBS containing 0.05% (v / v) Tween 20 (wash buffer). TMThe remaining free binding capacity was saturated with blocking buffer (#37536, ThermoScientific) for 5 minutes, and the assay plate was washed again with wash buffer. Anti-C3a neoepitope antibody (#C7850-13G, USBIOlogical, Swampscott, MA, USA) was added to each well (diluted in wash buffer; 0.2 μg / well), followed by incubation at room temperature for 60 minutes, and excess antibody was removed by washing with wash buffer. HRP-labeled goat anti-mouse antibody (#A2554, Sigma) was then added (1:30,000 in wash buffer) and incubated at room temperature for 60 minutes. Excess antibody was removed by extensive washing with wash buffer.

[0325] Table 13. Experimental results

[0326] Biological Example 6: Pharmacokinetic Study in Rats

[0327] Experimental Method 1

[0328] Three-month-old brown Norway rats were intravenously administered the example compound (0.5 mg / kg dose, formulation: 10% 1,2-propylene glycol + 25% (20% solutol HS15 aqueous solution) + 65% phosphate buffered saline, 0.1 mg / mL) and orally administered with a 2 mg / kg dose of a clear solution (0.5% MC + 0.5% Tween 80 aqueous solution, 1 mg / mL). Plasma was collected from the rats at each time point of 0.25, 0.5, 1, 6, and 24 hours after administration. The concentration of the test substance in plasma was measured by HPLC-MS / MS, with two separate plasma samples for each time point. Chromatographic separation was performed on a Waters BEH C18 Column (2.1×50 mm, 1.7 μm) (MAC-MOD Analytical, Chadds Ford, PA) using a gradient elution method of water and acetonitrile, both containing 0.025% formic acid-1 mM NH4OAc. Mass spectrometry measurements in positive electrospray ionization were designed to quantify [M+H] as precursor ions on an API 6500 triple quadrupole mass spectrometer (Sciex, Framingham, MA). + The relevant pharmacokinetic parameters were estimated using non-compartmental methods using WinNonlin (Enterprise, version 8.2).

[0329] Table 14.1. PK study results obtained in rats (0.5 mpk IV and 2 mpk PO)

[0330] Experimental conclusion: The pharmacokinetic absorption of the compounds of the present disclosure in rats is good. 1 / 2 There is a significant shortening, which can reduce or avoid the accumulation of drugs in the body in clinical practice, which is beneficial for determining the patient's dosage and avoiding the risks caused by accumulation.

[0331] Experimental Method 2

[0332] Six 8-week-old Sprague-Dawley rats were orally gavaged with the example compound as a clear solution (1 mg / mL) in 0.5% methylcellulose + 0.5% Tween 80 aqueous solution. Ocular tissue and plasma were collected from both eyes of the rats at each time point of 0.25, 0.5, 1, 6, and 24 hours after administration. The ocular tissues collected were the retina and posterior eye cup (RPE / choroid and posterior sclera). The tissues were diluted with phosphate-buffered saline containing 10% acetonitrile and homogenized and centrifuged before analysis. At each time point, the concentration of the test article in plasma and eye homogenate supernatant was measured by HPLC-MS / MS in four independent retina, four independent posterior eye cup, and two independent plasma samples. Chromatographic separation was performed on a Waters BEH C18 column (2.1×50 mm, 1.7 μm) (MAC-MOD Analytical, Chadds-Ford, PA) using a gradient elution method of water and acetonitrile, both containing 0.025% formic acid-1 mM NH4OAc. Mass spectrometric measurements in positive electrospray ionization were aimed at quantifying [M+H] as the parent ion on an API 6500 triple quadrupole mass spectrometer (Sciex, Framingham, MA). + Relevant pharmacokinetic parameters were estimated using non-compartmental methods using WinNonlin (Enterprise, version 8.2).

[0333] Table 14.2 Experimental results

[0334] Experimental conclusion: The compounds of the examples of the present application have better exposure in the retinal compartment and can be more highly distributed in disease-related biological compartments. The final dosing regimen will require a lower total dose and correspondingly lead to a lower relative plasma exposure and a lower relative exposure to healthy organs.

[0335] Salt and crystal form research

[0336] 1.1 Experimental Instruments

[0337] 1.1.1 Some parameters of physical and chemical testing instruments are shown in Table 15

[0338] Table 15

[0339] 1.2 Instruments and liquid analysis conditions

[0340] 1.2.1 Instruments and equipment are shown in Table 16

[0341] Table 16

[0342] 1.2.2 Chromatographic conditions are shown in Table 17

[0343] Table 17

[0344] 2. Screening of compound salt crystal forms

[0345] 2.1.1 Experimental Purpose

[0346] Select different counterions and use appropriate crystallization methods to detect which counterions can form compound salts.

[0347] 2.1.2 Experimental steps

[0348] 1) Instruments and equipment are shown in Table 18

[0349] Table 18

[0350] 2) Operating procedures

[0351] ① Preparation of Hydrochloride Form A of the Compound of Example 1

[0352] Approximately 20.35 mg of the compound of Example 1 was weighed and placed in a 2 mL glass vial. 500 μL of methanol was added to completely dissolve the compound. 50 μL of a 1 mol / L methanol solution of hydrochloric acid was slowly added dropwise at a molar ratio of 1:1.2, and the mixture was gradually mixed. The precipitated sample was magnetically stirred for 2 hours, and the solid was collected by centrifugation and dried in vacuo at 40°C overnight. The resulting solid was characterized by XRPD to obtain hydrochloride Form A. Hydrochloride Form A is a monohydrate.

[0353] Approximately 300.82 mg of the compound of Example 1 was weighed and placed in an 8 mL glass vial. 750 μL of methanol was added to completely dissolve the mixture. 50 μL of a methanolic hydrochloric acid solution was slowly added dropwise and gradually mixed. The precipitated sample was magnetically stirred for 2 hours. The solid was collected by centrifugation and dried in vacuo at 40°C overnight. The resulting solid was characterized by XRPD to obtain hydrochloride Form A, which was then characterized by DSC and TGA. Hydrochloride Form A is a monohydrate.

[0354] ②Salt type screening of ethyl acetate system

[0355] Approximately 10 mg of compound Example 1 was weighed and placed in a 2 mL glass vial. 300 μL of ethyl acetate was added to completely dissolve each compound. A methanol solution of the counterion was slowly added dropwise at a molar ratio of 1:1.2 (50 μL of a 1 mol / L acid solution in methanol) and mixed thoroughly. The precipitated sample was magnetically stirred at room temperature, and the resulting clear solution slowly evaporated at room temperature. After 3 days, the resulting solid was characterized by XRPD, DSC, and TGA. The phenomena observed during the experiment and the characterization results are shown in Table 19 below:

[0356] The volatile screening results showed that the hydrobromide salt form A, sulfate salt form A, isethionate salt form A and benzenesulfonate salt form A had good crystallinity. DSC and TGA characterization were performed. The methanesulfonate salt form A and p-toluenesulfonate salt form A had poor crystallinity.

[0357] Table 19

[0358] ②Salt type screening of acetone system

[0359] Approximately 10 mg of compound Example 1 was weighed and placed in a 2 mL glass vial. 200 μL of acetone was added to each vial to completely dissolve the compound. A methanol solution of the counterion was slowly added dropwise at a molar ratio of 1:1.1 and mixed thoroughly. The resulting clear solution was allowed to evaporate slowly at room temperature. After overnight, the precipitated solid was subjected to XRPD to obtain palmitate salt Form A (solvate), which was then characterized by DSC and TGA. The phenomena observed during the experiment and the characterization results are shown in Table 20 below:

[0360] Table 20

[0361] ③ Preparation of hydrochloride crystal form B

[0362] Approximately 15 mg of hydrochloride Form A was weighed and placed in a 2 mL glass bottle. An appropriate volume of solvent was added and slurried at room temperature. The resulting clear solution was evaporated at room temperature and the suspension was magnetically stirred. After 6 days, the solid was collected by centrifugation and vacuum dried at 40°C for 4 h. The precipitated solid was characterized by XRPD.

[0363] The results of the stable crystal screening of the hydrochloride salt are shown in Table 21, and hydrochloride crystal form B was obtained.

[0364] Table 21

[0365] ④ Preparation of hydrochloride crystal form C

[0366] Approximately 180.61 mg of compound 1 was weighed and placed in an 8 mL glass bottle. 8 mL of ethyl acetate was added to completely dissolve it to obtain a clear solution. 420 μL of a solution of hydrochloric acid in ethyl acetate was slowly added dropwise to quickly precipitate. 2 mL of ethyl acetate was added, and the resulting suspension was magnetically stirred for 2 h. The solid was collected by centrifugation and dried in vacuo at 40°C overnight. The obtained solid was characterized by XRPD and determined to be hydrochloride Form C.

[0367] 3. Solid Stability Test

[0368] 3.1 Experimental Purpose

[0369] (1) The physicochemical stability of the compounds at different salt types at high temperature of 60°C, high humidity RH = 92.5% and high temperature of 50°C, high humidity RH = 75% was investigated to provide a basis for salt type screening and compound salt storage.

[0370] 3.2 Experimental plan

[0371] ① Approximately 1 mg of hydrochloride Form A was weighed into a 2 mL glass vial and placed under conditions of 60°C (GW, closed), 50°C / 75% RH (WS, open), and room temperature / 92.5% RH (GS, open) for 7 days, 14 days, and 30 days. Samples were taken at different time points and analyzed by HPLC. The content was determined by the external standard method, and the changes in salt-related substances were calculated by chromatographic peak area normalization. The experimental results are shown in Table 22 below.

[0372] Experimental conclusion: Compound 1 hydrochloride form A has good stability and good drugability.

[0373] 4. Pharmacokinetic study of hydrochloride crystal form A in rats

[0374] SD rats were used as test animals to study the pharmacokinetic behavior of hydrochloride crystal form A in rats (plasma) after a single oral administration (PO) and to compare the changes in exposure.

[0375] Weigh 33.87 mg of Compound 1 hydrochloride Form A into a 20 mL glass bottle, add 10 mL of 0.5% HPMC K4M aqueous solution, and sonicate for about 10 min to obtain an off-white suspension with a free base concentration of Compound 1 of 3 mg / mL. Shake well before use.

[0376] Weigh 111.45 mg of Compound 1 hydrochloride Form A into a 20 mL glass bottle, add 10 mL of 0.5% HPMC K4M aqueous solution, and sonicate for about 10 min to obtain an off-white suspension with a free base concentration of Compound 1 of 10 mg / mL. Shake well before use.

[0377] The PK experimental results are shown in Table 23. The hydrochloride crystal form A of the present invention has a higher plasma exposure.

[0378] Table 1 PK test results of hydrochloride crystal form A in rats

Claims

1. A pharmaceutical composition comprising a compound of formula (I), a tautomer, a polymorph, or a pharmaceutically acceptable salt thereof as an active ingredient, and at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in the form of an oral immediate-release formulation, an oral sustained-release formulation, or a topical formulation; and / or, the pharmaceutical composition is in the form of tablets, capsules, liquids, injections, pills, transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, and powders, preferably coated tablets, buccal tablets, sublingual tablets, buccal patches, chewable tablets, dispersible tablets, effervescent tablets, vaginal tablets, sustained-release tablets, controlled-release tablets, enteric-coated tablets, oral tablets, hard capsules, soft capsules, controlled-release capsules, enteric-coated capsules, more preferably immediate-release tablets, sustained- and controlled-release tablets, sustained- and controlled-release capsules, or immediate-release capsules; in, R1 is selected from C1-C3 alkyl or C3-C6 cycloalkyl; R2 is selected from C1-C3 alkyl, C1-C3 alkoxy or C3-C6 cycloalkyl; R3 is selected from -COOH, -C(O)NHSO2CH3 or -S(O)NHCH3; R4 and R5 are each independently selected from hydrogen or halogen; n is 0, 1, 2 or 3; preferably n is 1.

2. The pharmaceutical composition according to claim 1, characterized in that In the compound of general formula (I), R1 is selected from C1-C3 alkyl; R2 is selected from C1-C3 alkoxy or cyclopropyl; R3 is selected from –COOH; R4 and R5 are each independently selected from hydrogen or halogen; n is 1 or 2.

3. The pharmaceutical composition according to any one of claims 1-2, characterized in that The specific structure of the compound is as follows:

4. A pharmaceutical composition comprising a compound of formula (I), a tautomer, a polymorph, or a pharmaceutically acceptable salt as an active ingredient, and at least one pharmaceutically acceptable excipient selected from a filler, a disintegrant, a lubricant, a wetting agent, a binder, a preservative, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a glidant, a thickener, a pharmaceutical solvent, a stabilizer, an antioxidant, a sunscreen, a colorant, an anti-adhesive agent, a solubilizer, a plasticizer, a dispersant, or a coating agent, wherein: The compound of general formula (I) is a compound according to any one of claims 1 to 3; Preferably, the pharmaceutical composition comprises at least a filler and a disintegrant, or the pharmaceutical composition comprises at least gelatin and / or a plasticizer.

5. A pharmaceutical composition comprising a compound of formula (I), a tautomer, a polymorph, a pharmaceutically acceptable salt as an active ingredient, wherein the pharmaceutical composition is administered orally, to the eye, mucosa or lung, or by intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion or intracranial administration; in, The compound of general formula (I) is the compound according to any one of claims 1 to 3.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the amount of the compound, its tautomer, polymorph or pharmaceutically acceptable salt is about 0.1% to 95% by weight of the free base; preferably, about 0.5% to 85% by weight of the free base; More preferably, about 1% to 60% by weight of the free base; Even more preferably, about 10% to 50% by weight of the free base; More preferably, the amount is about 15% to 40% by weight of the free base; Still further preferably, about 20% to 30% by weight of the free base; Most preferably, it is about 20% to 25% by weight of the free base.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the unit dose of the compound, its tautomer, polymorph or pharmaceutically acceptable salt is about 1-1000 mg by weight of the free base; Preferably, about 1-500 mg by weight of the free base; More preferably, about 3-300 mg by weight of the free base; Further preferably, about 5-200 mg based on the weight of the free base; More preferably, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg, 300 mg, 400 mg or 500 mg by weight of the free base.

8. A pharmaceutically acceptable acid salt or basic salt of a compound of formula (I): in, The acid is selected from an inorganic acid or an organic acid, and the base is selected from an organic base or an inorganic base; Preferably, the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid; the organic acid is selected from 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, capric acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid , camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, lauryl sulfate, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactosonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, Lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalene disulfonic 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, p-toluenesulfonic acid or L-malic acid; an organic base selected from sodium methoxide, potassium ethoxide, trimethylamine, diethylamine, triethylamine, triethanolamine Amine, pyridine, piperidine, morpholine, diisopropylethylamine, lithium diisopropylamide, lithium diethylamide, lithium bis(trimethylsilyl)amide, potassium acetate, sodium acetate, lithium isopropylcyclohexylamide or a mixture thereof; the inorganic base is selected from potassium phosphate, potassium phosphate trihydrate, potassium phosphate dihydrate, potassium phosphate monohydrate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, potassium hydride, sodium hydride, lithium hydroxide or a mixture thereof; More preferably, the inorganic acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid; the organic acid is selected from 1,5-naphthalene disulfonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic 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 camphoric acid or palmitic acid; the organic base is selected from sodium methoxide, potassium ethoxide, trimethylamine, diethylamine, triethylamine or triethanolamine; the inorganic base is selected from potassium hydroxide, sodium hydroxide, potassium hydride, sodium hydride, lithium hydroxide or a mixture thereof; Further preferably, the inorganic acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid or hydrochloric acid; the organic acid is selected from benzenesulfonic acid, p-toluenesulfonic acid, isethionic acid or palmitic acid; More preferably, the inorganic acid is hydrochloric acid; The compound of general formula (I) is the compound according to any one of claims 1 to 3.

9. The acid salt or basic salt of the compound according to claim 8, characterized in that The number of acids or bases is 0.2-3, preferably 0.2, 0.5, 1, 1.5, 1.2, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3, further preferably 1.

10. The acid salt or basic salt of the compound according to any one of claims 6 to 7, characterized in that: The acid salt or basic salt is a hydrate or an anhydrate; when the acid salt or basic salt is a hydrate, the number of water is 0.2-3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3.

11. The acid salt or basic salt of the compound according to any one of claims 8 to 10, characterized in that: The acid salt or basic salt of the compound of general formula (I) is a crystalline form.

12. The acid salt or basic salt of the compound according to claim 11, characterized in that The crystalline form is the hydrobromide crystalline form A, hydrochloride crystalline form A, hydrochloride crystalline form B, hydrochloride crystalline form C, sulfate crystalline form A, p-toluenesulfonate crystalline form A, isethionate crystalline form A, benzenesulfonate crystalline form A or palmitate crystalline form A of compound 1; Hydrobromide salt form A, whose X-ray powder diffraction pattern has a diffraction peak at 2θ (±0.2°) of 9.1; or a diffraction peak at 9.6; or a diffraction peak at 10.3; or a diffraction peak at 12.5; or a diffraction peak at 15.6; or a diffraction peak at 17.3; or a diffraction peak at 19.0; or a diffraction peak at 21.8; or a diffraction peak at 23.6; or a diffraction peak at 26.1; or a diffraction peak at 9.6; or a diffraction peak at 9.6; or a diffraction peak at 9.6; preferably contains any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably contains any 6, 7 or 8 thereof; The hydrochloride crystalline form A has an X-ray powder diffraction pattern with a diffraction peak at 2θ (±0.2°) of 8.7; or a diffraction peak at 9.4; or a diffraction peak at 9.9; or a diffraction peak at 10.5; or a diffraction peak at 12.1; or a diffraction peak at 13.7; or a diffraction peak at 16.6; or a diffraction peak at 16.9; or a diffraction peak at 17.8; or at 18.8 has a diffraction peak; or a diffraction peak at 19.7; or a diffraction peak at 21.2; or a diffraction peak at 21.8; or a diffraction peak at 22.9; or a diffraction peak at 26.6; preferably includes any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably includes any 6, 7 or 8 thereof; Hydrochloride Form B, whose X-ray powder diffraction pattern has a diffraction peak at 2θ (±0.2°) of 9.4; or a diffraction peak at 9.8; or a diffraction peak at 13.2; or a diffraction peak at 16.3; or a diffraction peak at 16.9; or a diffraction peak at 18.9; or a diffraction peak at 19.7; or a diffraction peak at 22.9; preferably including any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably including any 6, 7 or 8 thereof; Hydrochloride Form C, whose X-ray powder diffraction pattern has a diffraction peak at 2θ (±0.2°) of 7.3; or a diffraction peak at 7.7; or a diffraction peak at 9.3; or a diffraction peak at 10.3; or a diffraction peak at 11.0; or a diffraction peak at 14.0; or a diffraction peak at 14.8; or a diffraction peak at 16.3; or a diffraction peak at 18.7; or a diffraction peak at 21.4; or a diffraction peak at 22.2; or a diffraction peak at 23.1; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably comprising any 6, 7 or 8 thereof; Sulfate crystalline form A, whose X-ray powder diffraction pattern has a diffraction peak at 2θ (±0.2°) of 7.0; or a diffraction peak at 11.3; or a diffraction peak at 19.4; or a diffraction peak at 23.3; preferably includes any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably includes any 6, 7 or 8 thereof; p-Toluenesulfonate crystalline form A, whose X-ray powder diffraction pattern has a diffraction peak at 2θ (±0.2°) of 6.0; or a diffraction peak at 7.9; or a diffraction peak at 9.1; or a diffraction peak at 10.0; or a diffraction peak at 13.1; or a diffraction peak at 15.3; or a diffraction peak at 15.8; or a diffraction peak at 18.4; or a diffraction peak at 19.0; preferably including any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably including any 6, 7 or 8 thereof; Isethionate salt crystalline form A, whose X-ray powder diffraction pattern has a diffraction peak at 2θ (±0.2°) of 8.6; or a diffraction peak at 9.3; or a diffraction peak at 9.9; or a diffraction peak at 16.6; or a diffraction peak at 19.9; or a diffraction peak at 21.7; or a diffraction peak at 24.4; or a diffraction peak at; or a diffraction peak at; preferably contains any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably contains any 6, 7 or 8 thereof; Benzenesulfonate salt form A, whose X-ray powder diffraction pattern has a diffraction peak at 2θ (±0.2°) of 9.4; or a diffraction peak at 9.9; or a diffraction peak at 17.8; or a diffraction peak at 18.8; or a diffraction peak at 19.7; or a diffraction peak at 21.2; or a diffraction peak at 22.9; or a diffraction peak at 26.5; or a diffraction peak at; preferably including any 2-5 of the above diffraction peaks, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, more preferably including any 6, 7 or 8 thereof; Palmitate salt form A, whose X-ray powder diffraction pattern has a diffraction peak at 2θ (±0.2°) of 7.4; or a diffraction peak at 8.2; or a diffraction peak at 21.7; or a diffraction peak at 24.2; or a diffraction peak at; or a diffraction peak at; preferably includes any 2-5 of the above diffraction peaks, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, and more preferably includes any 6, 7 or 8 of them.

13. The crystalline form of the acid salt or basic salt of the compound according to any one of claims 11 to 12, characterized in that: Hydrobromide salt form A, whose X-ray powder diffraction pattern has one or more characteristic peaks at 9.1, 12.5, 15.6 and 23.6 at 2θ (±0.2°); preferably contains 2-4 of them, more preferably contains 3-4, and most preferably contains 4; preferably, also contains one or more characteristic peaks at 9.6 and 26.1 at 2θ (±0.2°); further preferably, also contains one or more characteristic peaks at 10.3 and 17.3 at 2θ (±0.2°); more preferably, also contains a characteristic peak at 19.0 at 2θ (±0.2°); For example, the X-ray powder diffraction pattern of hydrobromide salt form A has diffraction peaks at 2θ (±0.2°) at the following positions: 9.1、12.5、15.6、23.6； or, 9.1, 10.3, 12.5, 17.3, 26.1; or, 10.3, 12.5, 15.6, 17.3, 19.0, 26.1; or, 9.6, 10.3, 15.6, 17.3, 19.0, 23.6, 26.1; or, 9.1, 9.6, 10.3, 12.5, 15.6, 17.3, 19.0, 23.6, 26.1; Hydrochloride Form A, whose X-ray powder diffraction pattern has one or more characteristic peaks at 8.7, 9.4, 10.5, 13.7, 16.9 and 21.8 at 2θ (±0.2°); preferably contains 2-4 of them, more preferably contains 3-4, and most preferably contains 4; preferably, also contains one or more characteristic peaks at 17.8 and 22.9 at 2θ (±0.2°); further preferably, also contains one or more characteristic peaks at 19.7 and 26.6 at 2θ (±0.2°); more preferably, also contains characteristic peaks at 9.9 and 21.2 at 2θ (±0.2°); For example, the X-ray powder diffraction pattern of hydrochloride crystal form A has diffraction peaks at 2θ (±0.2°) at the following positions: 8.7、9.4、13.7、16.6 Or, 8.7, 9.9, 13.7, 16.9 or, 8.7, 9.4, 13.7, 16.9, 17.8, 21.8; or, 8.7, 9.9, 12.1, 16.6, 18.8, 21.2; or, 8.7, 9.9, 10.5, 13.7, 16.6, 16.9, 17.8, 18.8; or, 9.4, 10.5, 12.1, 13.7, 16.9, 17.8, 18.8, 19.7; Hydrochloride Form B, whose X-ray powder diffraction pattern has one or more characteristic peaks at 9.4, 13.2, 16.3 and 19.7 at 2θ (±0.2°); preferably contains 2-4 of them, more preferably contains 3-4, and most preferably contains 4; preferably, also contains one or more characteristic peaks at 16.9 and 22.9 at 2θ (±0.2°); further preferably, also contains one or more characteristic peaks at 9.8 and 18.9 at 2θ (±0.2°); For example, the X-ray powder diffraction pattern of hydrochloride crystal form B has diffraction peaks at 2θ (±0.2°) at the following positions: Or, 9.8, 13.2, 16.3; 16.9; or, 9.8, 13.2, 16.3, 16.9; or, 9.4, 9.8, 13.2, 16.3, 16.9, 18.9; or, 9.4, 9.8, 13.2, 16.3, 18.9, 19.7; or, 9.4, 9.8, 13.2, 16.3, 16.9, 18.9, 19.7; or, 9.4, 9.8, 13.2, 16.3, 16.9, 18.9, 19.7, 22.9; Hydrochloride Form C, whose X-ray powder diffraction pattern has one or more characteristic peaks at 7.7, 11.0, 16.3 and 21.4 at 2θ (±0.2°); preferably contains 2-4 of them, more preferably contains 3-4, and most preferably contains 4; preferably, also contains one or more characteristic peaks at 7.3 and 22.2 at 2θ (±0.2°); further preferably, also contains one or more characteristic peaks at 14.0, 18.7 and 23.1 at 2θ (±0.2°); For example, the X-ray powder diffraction pattern of hydrochloride crystal form C has diffraction peaks at 2θ (±0.2°) at the following positions: 7.3、7.7、9.3、10.3； Or, 7.3, 7.7, 9.3, 10.0; Or, 7.3, 7.7, 9.3, 10.0, 11.0, 14.0; or, 7.7, 9.3, 10.3, 11.0, 14.0, 16.3; or, 7.3, 7.7, 9.3, 10.3, 11.0, 14.0, 16.3, 18.7; or, 7.7, 9.3, 10.3, 11.0, 14.0, 16.3, 18.7, 21.4; Sulfate crystalline form A, whose X-ray powder diffraction pattern has one or more characteristic peaks at 7.0, 11.3, 19.4 and 23.3 at 2θ (±0.2°); preferably contains 2-3 of them, more preferably contains 3-4, and most preferably contains 4; For example, the X-ray powder diffraction pattern of sulfate crystal form A has diffraction peaks at 2θ (±0.2°) at the following positions: 7.0、11.3、19.4、23.3； The p-toluenesulfonate salt form A has an X-ray powder diffraction pattern at 2θ (±0.2°) having one or more characteristic peaks at 6.0, 9.1, 10.0 and 19.0; preferably comprising 2-4 of these peaks, more preferably comprising 3-4, and most preferably comprising 4; preferably, further comprising one or more characteristic peaks at 2θ (±0.2°) of 7.9 and 15.3; further preferably, further comprising one or more characteristic peaks at 2θ (±0.2°) of 15.8 and 18.4; For example, the X-ray powder diffraction pattern of p-toluenesulfonate crystalline form A has diffraction peaks at 2θ (±0.2°) at the following positions: 6.0、9.1、10.0、19.0； or, 7.9, 9.1, 10.0, 15.3, 19.0; or, 6.0, 7.9, 9.1, 10.0, 15.3, 18.4; or, 7.9, 9.1, 15.3, 15.8, 18.4, 19.0; or, 6.0, 7.9, 9.1, 10.0, 15.3, 15.8, 18.4, 19.0; Isethionate salt crystalline form A, whose X-ray powder diffraction pattern has one or more characteristic peaks at 8.6, 9.3, 16.6 and 19.9 at 2θ (±0.2°); preferably contains 2-4 of these peaks, more preferably contains 3-4, and most preferably contains 4; preferably, also contains one or more characteristic peaks at 9.9 and 24.4 at 2θ (±0.2°); further preferably, also contains a characteristic peak at 21.7 at 2θ (±0.2°); For example, the X-ray powder diffraction pattern of the isethionate salt form A has diffraction peaks at the following positions at 2θ (±0.2°): 8.6、9.3、16.6、19.9； or, 8.6, 9.9, 16.6, 19.9, 24.4; or, 9.3, 9.9, 16.6, 19.9, 24.4; or, 8.6, 9.3, 9.9, 16.6, 19.9, 21.7, 24.4; The benzenesulfonate salt form A has an X-ray powder diffraction pattern having one or more characteristic peaks at 2θ (±0.2°) of 9.4, 9.9, 17.8 and 19.7; preferably, it also includes one or more characteristic peaks at 2θ (±0.2°) of 18.8 and 21.2; further preferably, it also includes one or more characteristic peaks at 2θ (±0.2°) of 22.9 and 26.5; more preferably, it also includes a characteristic peak at 2θ (±0.2°); For example, the X-ray powder diffraction pattern of benzenesulfonate crystalline form A has diffraction peaks at 2θ (±0.2°) at the following positions: 9.4、9.9、17.8、19.7； or, 9.9, 17.8, 19.7, 21.2; or, 9.4, 18.8, 19.7, 22.9, 26.5; or, 9.4, 17.8, 19.7, 22.9, 26.5; or, 9.4, 9.9, 17.8, 18.8, 19.7, 21.2, 22.9, 26.5; Palmitate salt form A, having an X-ray powder diffraction pattern at 2θ (±0.2°) having one or more characteristic peaks at 7.4, 8.2, 21.7, and 24.2; For example, the X-ray powder diffraction pattern of benzenesulfonate crystalline form A has diffraction peaks at 2θ (±0.2°) at the following positions: 7.4、8.2、21.7、24.2。 14. The crystalline form of the acid salt or basic salt of the compound according to claims 11-13, characterized in that: Hydrobromide salt form A, whose X-ray powder diffraction pattern includes one or more diffraction peaks at 2θ (±0.2°) of 9.1, 9.6, 10.3, 12.5, 15.6, 17.3, 19.0, 21.7, 23.6 and 26.1; preferably, it includes characteristic peaks at any of 2, 4, 6 or 8 of them; For example, the X-ray powder diffraction pattern of hydrobromide salt form A has diffraction peaks at 2θ (±0.2°) at the following positions: 9.6、12.5、15.6、23.6； or, 9.6, 10.3, 12.5, 17.3, 26.1; or, 10.3, 12.5, 15.6, 17.3, 19.0, 23.6; or, 9.6, 15.6, 17.3, 19.0, 23.6, 26.1; or, 9.6, 10.3, 12.5, 15.6, 17.3, 19.0, 23.6, 26.1; Hydrochloride Form A, whose X-ray powder diffraction pattern includes one or more diffraction peaks at 2θ (±0.2°) of 8.7, 9.4, 9.9, 10.5, 12.1, 13.7, 16.6, 16.9, 17.8, 18.8, 19.7, 21.2, 21.8, 22.9, and 26.6; preferably, it includes characteristic peaks at any of 2, 4, 6, or 8 of them; For example, the X-ray powder diffraction pattern of hydrochloride crystal form A has diffraction peaks at 2θ (±0.2°) at the following positions: 10.5、17.8、21.8、26.6 or, 9.9, 13.7, 16.9, 21.8; or, 9.4, 10.5, 13.7, 16.9, 17.8, 18.8; or, 9.9, 13.7, 16.9, 17.8, 18.8, 21.2; or, 10.5, 16.9, 18.8, 19.7, 21.2, 21.8, 22.9, 26.6; or, 8.7, 9.4, 10.5, 12.1, 13.7, 16.6, 18.8, 22.9; or, 9.9, 12.1, 13.7, 16.6, 18.8, 21.2, 21.8, 26.6; or, 9.9, 10.5, 12.1, 13.7, 16.6, 17.8, 18.8, 21.2, 21.8; Hydrochloride Form B, whose X-ray powder diffraction pattern includes one or more diffraction peaks at 2θ (±0.2°) of 9.4, 9.8, 13.2, 16.3, 16.9, 18.9, 19.7, and 22.9; preferably, it includes characteristic peaks at any of 2, 4, 6, or 8 of these peaks; For example, the X-ray powder diffraction pattern of hydrochloride crystal form B has diffraction peaks at 2θ (±0.2°) at the following positions: or, 9.4, 13.2, 16.3, 18.9; or, 9.8, 13.2, 16.3, 16.9, 18.9, 19.7; or, 9.4, 9.8, 13.2, 16.3, 16.9, 18.9, 19.7; Hydrochloride Form C, whose X-ray powder diffraction pattern includes one or more diffraction peaks at 2θ (±0.2°) of 7.3, 7.7, 11.0, 14.0, 14.8, 16.3, 18.7, 21.4, 22.2, and 23.1; preferably, it includes characteristic peaks at any of 2, 4, 6, or 8 of them; For example, the X-ray powder diffraction pattern of hydrochloride crystal form C has diffraction peaks at 2θ (±0.2°) at the following positions: 7.7、9.3、10.0、11.0； or, 7.3, 9.3, 11.0, 14.0; or, 7.3, 9.3, 10.3, 14.0, 16.3, 18.7; or, 7.3, 7.7, 9.3, 10.3, 16.3, 18.7; or, 7.3, 9.3, 10.3, 11.0, 14.0, 16.3, 18.7, 22.2; or, 7.3, 7.7, 9.3, 16.3, 18.7, 21.4, 22.2, 23.1; Sulfate crystalline form A, whose X-ray powder diffraction pattern contains one or more diffraction peaks at 2θ (±0.2°) of 7.0, 11.3, 19.4, and 23.3; preferably, it contains characteristic peaks at any two or four of them; For example, the X-ray powder diffraction pattern of sulfate crystal form A has diffraction peaks at 2θ (±0.2°) at the following positions: 7.0、11.3、19.4、23.3； The p-toluenesulfonate salt form A has an X-ray powder diffraction pattern comprising one or more diffraction peaks at 2θ (±0.2°) of 6.0, 7.9, 9.1, 10.0, 13.1, 15.3, 15.8, 18.4, and 19.0; preferably, the characteristic peaks are selected from 2, 4, 6, or 8 of the peaks; For example, the X-ray powder diffraction pattern of p-toluenesulfonate crystalline form A has diffraction peaks at 2θ (±0.2°) at the following positions: 9.1、10.0、19.0、15.3； or, 7.9, 10.0, 15.3, 19.0; or, 6.0, 9.1, 10.0, 15.3, 19.0; or, 6.0, 9.1, 15.8, 18.4, 19.0; or, 6.0, 7.9, 9.1, 10.0, 15.8, 18.4; Isethionate salt crystalline form A, whose X-ray powder diffraction pattern comprises one or more diffraction peaks at 2θ (±0.2°) of 8.6, 9.3, 9.9, 16.6, 19.9, 21.7 and 24.4; preferably, it comprises characteristic peaks at any two, four or six of the diffraction peaks; For example, the X-ray powder diffraction pattern of the isethionate salt form A has diffraction peaks at the following positions at 2θ (±0.2°): 8.6、9.3、16.6、24.4； or, 9.3, 16.6, 19.9, 24.4; or, 9.9, 16.6, 19.9, 21.7; or, 8.6, 9.9, 16.6, 19.9, 21.7, 24.4; The benzenesulfonate salt form A has an X-ray powder diffraction pattern comprising one or more diffraction peaks at 2θ (±0.2°) of 9.4, 9.9, 17.8, 18.8, 19.7, 21.2, 22.9, and 26.5; preferably, the characteristic peaks are selected from 2, 4, 6, or 8 of the peaks; For example, the X-ray powder diffraction pattern of benzenesulfonate crystalline form A has diffraction peaks at 2θ (±0.2°) at the following positions: 9.4、9.9、17.8、21.2； or, 9.4, 17.8, 19.7, 21.2, 22.9; or, 9.9, 18.8, 19.7, 22.9, 26.5; or, 9.4, 17.8, 19.7, 21.2, 22.9; or, 9.4, 9.9, 17.8, 18.8, 19.7, 21.2, 22.9, 26.5; Palmitate salt form A, whose X-ray powder diffraction pattern includes one or more diffraction peaks at 2θ (±0.2°) of 7.4, 8.2, 21.7, and 24.2; preferably, it includes characteristic peaks at any two or four of the peaks; For example, the X-ray powder diffraction pattern of palmitate salt form A has diffraction peaks at 2θ (±0.2°) at the following positions: 7.4、8.2、21.7、24.2。 15. The crystalline form of the acid salt or basic salt of the compound according to claims 11-14, characterized in that: The X-ray powder diffraction pattern of the hydrobromide salt form A is substantially as shown in FIG1 ; the DSC pattern thereof is substantially as shown in FIG2 ; The X-ray powder diffraction pattern of the hydrochloride crystal form A is substantially as shown in FIG3 ; the DSC pattern thereof is substantially as shown in FIG4 ; and the TGA pattern thereof is substantially as shown in FIG5 ; The X-ray powder diffraction pattern of the hydrochloride crystal form B is substantially as shown in FIG6 ; the DSC pattern thereof is substantially as shown in FIG7 ; The X-ray powder diffraction pattern of the hydrochloride crystal form C is substantially as shown in FIG8 ; and the DSC pattern thereof is substantially as shown in FIG9 ; The X-ray powder diffraction pattern of the sulfate crystal form A is substantially as shown in FIG10 ; the DSC pattern thereof is substantially as shown in FIG11 ; The X-ray powder diffraction pattern of the p-toluenesulfonate crystalline form A is substantially as shown in FIG12 ; the DSC pattern thereof is substantially as shown in FIG13 ; The X-ray powder diffraction pattern of the isethionate salt form A is substantially as shown in FIG14 ; its DSC pattern is substantially as shown in FIG15 ; The X-ray powder diffraction pattern of the benzenesulfonate salt form A is substantially as shown in FIG16 ; the DSC pattern thereof is substantially as shown in FIG17 ; The X-ray powder diffraction pattern of the palmitate salt form A is basically shown in Figure 18; its DSC pattern is basically shown in Figure 19.

16. A method for preparing an acid salt or a basic salt of the compound according to any one of claims 11 to 15, comprising the following steps: 1) Weigh an appropriate amount of free base and dissolve it in a benign solvent; 2) Weighing an appropriate amount of counterion acid or counterion base and dissolving it in an organic solvent; the amount of counterion acid is preferably 1 equivalent; 3) combining the above two solutions and stirring to dissolve out; 4) optionally centrifuging and drying to obtain the target product; or, 1) Weigh an appropriate amount of free base and dissolve it in a benign solvent; 2) Weighing an appropriate amount of counterion acid or counterion base and dissolving it in an organic solvent; the amount of counterion acid is preferably 1 equivalent; 3) combining the above two solutions and stirring to dissolve out; 4) adding an appropriate solvent A to the obtained solid product, volatilizing and drying to obtain the target product; in: The benign solvent is selected from methanol, ethyl acetate, dichloromethane, acetone, tetrahydrofuran, isopropanol or 2-butanone; preferably methanol, ethyl acetate or acetone; 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; The solvent A is selected from acetone, ethanol, acetonitrile, tetrahydrofuran, dichloromethane, toluene, ethyl acetate, methyl tert-butyl ether or water; The counterion acid is selected from an organic acid or an inorganic acid; the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid; the organic acid is selected from 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, capric acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid acid, tartaric acid, dodecyl sulfuric acid, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactosonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalene disulfonic 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, p-toluenesulfonic acid, or L-malic acid; The counter ion base is selected from an organic base or an inorganic base; the organic base is selected from sodium methoxide, potassium ethoxide, trimethylamine, diethylamine, triethylamine, triethanolamine, pyridine, piperidine, morpholine, diisopropylethylamine, lithium diisopropylamide, lithium diethylamide, lithium bis(trimethylsilyl)amide, potassium acetate, sodium acetate, lithium isopropylcyclohexylamide or a mixture thereof; the inorganic base is selected from potassium phosphate, potassium phosphate trihydrate, potassium phosphate dihydrate, potassium phosphate monohydrate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, potassium hydride, sodium hydride, lithium hydroxide or a mixture thereof.

17. A pharmaceutical composition comprising a therapeutically effective amount of an acid salt or a basic salt of the compound according to any one of claims 8 to 16, and one or more pharmaceutically acceptable carriers, diluents or excipients.

18. The pharmaceutical composition according to claim 17, wherein the amount of the acid salt or basic salt of the compound is about 0.1% to 95% by weight of the free base; preferably, about 0.5% to 85% by weight of the free base; More preferably, about 1% to 60% by weight of the free base; Even more preferably, about 10% to 50% by weight of the free base; More preferably, the amount is about 15% to 40% by weight of the free base; Still further preferably, about 20% to 30% by weight of the free base; Most preferably, it is about 20% to 25% by weight of the free base.

19. The pharmaceutical composition according to any one of claims 17-18, wherein the amount of the acid salt or basic salt of the compound is about 1-1000 mg based on the weight of the free base; Preferably, about 1-500 mg by weight of the free base; More preferably, about 3-300 mg by weight of the free base; Further preferably, about 5-200 mg based on the weight of the free base; More preferably, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg, 300 mg, 400 mg or 500 mg by weight of the free base.

20. Use of an acid salt or basic salt of the compound according to any one of claims 8 to 16, or a pharmaceutical composition according to claims 17 to 19, for preparing a medicament for treating a disease or condition associated with activation of the alternative complement pathway.

21. The use according to claim 20, characterized in that The disease or condition is a disease or condition associated with activation of the alternative complement pathway that is treated by modulating complement factor B.

22. The use according to any one of claims 20 or 21, characterized in that The disease or condition is selected from age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, avian needle retinochoroiditis, sympathetic eye inflammation, ophthalmic pemphigoid, ocular pemphigus, retinal vein occlusion, nervous system disease, multiple sclerosis, stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, Sen's disease, disorders of inappropriate or suboptimal complement activation, complications of hemodialysis, hyperacute allograft rejection, xenograft rejection, interleukin-2-induced toxicity during IL-2 therapy, inflammatory diseases, inflammation in autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, postischemic reperfusion conditions, myocardial infarction, balloon angioplasty, post-pump syndrome during extracorporeal circulation or renal bypass, atherosclerosis, hemodialysis, renal ischemia, mesenteric artery revascularization after aortic reconstruction Perfusion, infectious diseases or sepsis, immune complex diseases and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus, SLE nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease, emphysema, pulmonary embolism and infarction, pneumonia, fibrogenic dust disease, pulmonary fibrosis, asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, 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 and intermediate age-related macular degeneration (e / iAMD), idiopathic membranous nephropathy, immune complex membranoproliferative glomerulonephritis (IC-MPGN).

Images