Pharmaceutical compositions of benzazabicyclic aromatic ring derivatives and their medical applications

Abstract

The present invention provides a pharmaceutical composition of a benzoaza aromatic ring derivative and its pharmaceutical application, the pharmaceutical composition comprising an active ingredient A and a pharmaceutical excipient, wherein the active ingredient A is selected from the group consisting of a compound represented by general formula (I) and a stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, and cocrystal thereof, and the pharmaceutical composition contains 1 to 1000 mg of the active ingredient A, the content of which is selected from the range of 1.0% to 90.0%. The present invention further relates to the application of the pharmaceutical composition to the manufacture of a related medicament for treating kidney diseases. [C1] TIFF2026507026000044.tif50156

Description

[Technical Field]

[0001] The present invention relates to the field of pharmaceutical preparations, specifically to a pharmaceutical composition comprising a therapeutically effective amount of an active ingredient A and a pharmaceutical excipient, wherein the active ingredient A is selected from the group consisting of a compound represented by general formula (I) and its stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal, and the pharmaceutical composition contains 1-1000 mg of the active ingredient A, with the content of the active ingredient A being selected from 1.0%-90.0%. The present invention further relates to the application of the pharmaceutical composition to the preparation of a related medicament for treating kidney diseases. [Background technology]

[0002] Complement factor B, a part of the alternative complement pathway, is involved in both specific and nonspecific immune mechanisms in the body. It contains a serine protease (SP) domain and, upon activation, provides the catalytic activity of alternative pathway C3 and C5 convertases. Complement factor B is a key enzyme in the activation process of the alternative complement pathway and may be a suitable target for inhibiting the complement activation pathway.

[0003] Patent PCT / CN2022 / 113216 describes compound 1, which has good complement factor B inhibitory activity and a good in vivo C3a level inhibitory rate. When used as a therapeutic agent for treating humans, administering a therapeutically effective amount can be problematic, potentially leading to toxic side effects or loss of therapeutic efficacy. Therefore, there is a great need to develop pharmaceutical compositions or pharmaceutical formulations with good safety, efficacy, and stability. [ka] Summary of the Invention [Means for solving the problem]

[0004] The object of the present invention is to provide a pharmaceutical composition comprising an active ingredient A and a pharmaceutical excipient, wherein the active ingredient A is selected from the group consisting of a compound according to general formula (I) or a stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof. The present invention further relates to the application of the pharmaceutical composition for the preparation of a related medicament for treating kidney diseases.

[0005] The pharmaceutical composition of the present invention has stable quality, good dissolution properties, good absorbability, low irritation, good safety, high bioavailability, and can be orally absorbed.

[0006] The present invention relates to a pharmaceutical composition, which comprises a therapeutically effective amount of an active ingredient A and pharmaceutical excipients, and the pharmaceutical composition may be in the form of a unit dosage form.

[0007] The present invention relates to a pharmaceutical composition, wherein the pharmaceutical composition comprises an active ingredient A and a pharmaceutical excipient, wherein the active ingredient A is selected from a compound according to general formula (I) or a stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof; [ka] [ka] teeth, [ka] Selected from R 1 is selected from -OCH3 or -OCD3, R 2 is selected from -CH3 or -CD3, and n is selected from 1, 2 or 3; The content of the active ingredient A is selected from the range of 1.0% to 90.0%, preferably selected from the range of 5.0% to 75.0%, and more preferably selected from the range of 10.0% to 50.0%.

[0008] In some embodiments, the structure of the compound according to general formula (I) is selected from one of the structures shown in Table S-1:

[0009] [Table 1-1] [Table 1-2] , In some embodiments, the compound according to general formula (I) is selected from Compound 1, whose structure is: [ka] and In some embodiments, the pharmaceutically acceptable salt of the compound according to general formula (I) is selected from a trifluoroacetate salt or a succinate salt, and the molar ratio of compound 1 to the succinate salt is 1:0.75.

[0010] In one embodiment, the pharmaceutical composition comprises 1 to 1000 mg of active ingredient A (calculated as the free base), In some embodiments, the pharmaceutical composition comprises 5 to 900 mg of Active Ingredient A (calculated as the free base), In some embodiments, the pharmaceutical composition comprises 10 to 800 mg of Active Ingredient A (calculated as the free base), In some embodiments, the pharmaceutical composition comprises 10 to 400 mg of Active Ingredient A (calculated as the free base), In some embodiments, the pharmaceutical composition comprises 20 to 400 mg of Active Ingredient A (calculated as the free base), In some embodiments, the pharmaceutical composition comprises 30 to 300 mg of Active Ingredient A (calculated as the free base), In some embodiments, the pharmaceutical composition comprises 20 to 200 mg of Active Ingredient A (calculated as the free base), In some embodiments, the pharmaceutical composition comprises 30 to 200 mg of Active Ingredient A (calculated as the free base), In some embodiments, the pharmaceutical composition comprises 30 to 100 mg of Active Ingredient A (calculated as the free base), In some embodiments, the pharmaceutical composition comprises 50 to 100 mg of Active Ingredient A (calculated as the free base), In some embodiments, the pharmaceutical composition comprises 5 to 100 mg of Active Ingredient A (calculated as the free base), In some embodiments, the pharmaceutical composition comprises 5 mg of Active Ingredient A (calculated as the free base), In some embodiments, the pharmaceutical composition comprises 10 mg of Active Ingredient A (calculated as the free base), In some embodiments, the pharmaceutical composition comprises 20 mg of Active Ingredient A (calculated as the free base), In some embodiments, the pharmaceutical composition comprises 25 mg of Active Ingredient A (calculated as the free base), In some embodiments, the pharmaceutical composition comprises 30 mg of Active Ingredient A (calculated as the free base), In some embodiments, the pharmaceutical composition comprises 40 mg of Active Ingredient A (calculated as the free base), In some embodiments, the pharmaceutical composition comprises 50 mg of Active Ingredient A (calculated as the free base), In some embodiments, the pharmaceutical composition comprises 75 mg of Active Ingredient A (calculated as the free base), In some embodiments, the pharmaceutical composition comprises 100 mg of Active Ingredient A (calculated as the free base), In some embodiments, the pharmaceutical composition comprises 125 mg of Active Ingredient A (calculated as the free base), In some embodiments, the pharmaceutical composition comprises 150 mg of Active Ingredient A (calculated as the free base), In some embodiments, the pharmaceutical composition comprises 200 mg of Active Ingredient A (calculated as the free base), In some embodiments, the pharmaceutical composition comprises 300 mg of Active Ingredient A (calculated as the free base), In some embodiments, the pharmaceutical composition comprises 400 mg of Active Ingredient A (calculated as the free base), In some embodiments, the pharmaceutical composition comprises 500 mg of Active Ingredient A (calculated as the free base), In some embodiments, the pharmaceutical composition comprises 600 mg of Active Ingredient A (calculated as the free base), In some embodiments, the pharmaceutical composition comprises 700 mg of Active Ingredient A (calculated as the free base), In some embodiments, the pharmaceutical composition comprises 800 mg of Active Ingredient A (calculated as the free base).

[0011] In another aspect, the content of the active ingredient A in the pharmaceutical composition is selected from 1.0% to 90.0%, preferably selected from 5.0% to 75.0%, and more preferably selected from 10.0% to 50.0%; In some embodiments, the active ingredient A in the aforementioned pharmaceutical composition is selected from Compound 1 or a succinate salt thereof; In some embodiments, the active ingredient A in the pharmaceutical composition is a succinate salt of Compound 1, and preferably, the molar ratio of Compound 1 to succinic acid is 1:0.75; In some embodiments, the content of active ingredient A is 1.0% to 90.0%, in some embodiments, the content of active ingredient A is 1.0% to 80.0%, in some embodiments, the content of active ingredient A is 1.0% to 70.0%, in some embodiments, the content of active ingredient A is 1.0% to 60.0%, in some embodiments, the content of active ingredient A is 1.0% to 50.0%, in some embodiments, the content of active ingredient A is 1.0% to 40.0%, In some embodiments, the content of active ingredient A is 1.0% to 30.0%, and in some embodiments, the content is 1.0% to 20.0%, and in some embodiments, the content of active ingredient A is 1.0% to 10.0%, and in some embodiments, the content of active ingredient A is 5.0% to 90.0%, and in some embodiments, the content of active ingredient A is 5.0% to 80.0%, and in some embodiments, the content of active ingredient A is 5.0% to 70.0%, and in some embodiments, the content of active ingredient A is In some embodiments, the content of active ingredient A is 5.0% to 60.0%, and in some embodiments, the content of active ingredient A is 5.0% to 50.0%, in some embodiments, the content of active ingredient A is 5.0% to 40.0%, in some embodiments, the content of active ingredient A is 5.0% to 30.0%, in some embodiments, the content of active ingredient A is 5.0% to 20.0%, in some embodiments, the content of active ingredient A is 5.0% to 10.0%, and in some embodiments, the content of active ingredient A is 10.0% to In some embodiments, the content of active ingredient A is 10.0% to 90.0%, in some embodiments, the content of active ingredient A is 10.0% to 80.0%, in some embodiments, the content of active ingredient A is 10.0% to 70.0%, in some embodiments, the content of active ingredient A is 10.0% to 60.0%, in some embodiments, the content of active ingredient A is 10.0% to 50.0%, in some embodiments, the content of active ingredient A is 10.0% to 40.0%, and in some embodiments, the content of active ingredient A is 10.0% to 30.In some embodiments, the content of Active Ingredient A is 10.0% to 20.0%, and in some embodiments, the content of Active Ingredient A is 10.0%.

[0012] In another aspect, the pharmaceutical excipient in the aforementioned pharmaceutical composition is selected from one or more of a filler, a disintegrant, an adhesive, a glidant, a lubricant; In some embodiments, the filler is selected from one or more of microcrystalline cellulose, mannitol, lactose, sucrose, sorbitol, dextran, pregelatinized starch, calcium phosphate monobasic, starch; In some embodiments, the filler content is selected from 10.0% to 90.0%, preferably selected from 20.0% to 80.0%; In some embodiments, the filler content is 10.0% to 90.0%, in some embodiments, 20.0% to 90.0%, in some embodiments, 30.0% to 90.0%, in some embodiments, 40.0% to 90.0%, in some embodiments, 50.0% to 90.0%, in some embodiments, 60.0% to 90.0%, in some embodiments, 70.0% to 90.0%, in some embodiments, 10.0% to 80.0%, in some embodiments, 20.0% to 80.0%, in some embodiments, 30.0% to 80.0%, in some embodiments, 40.0% to 80.0%, in some embodiments, 50.0% to 80.0%, in some embodiments, 60.0% to 80.0%, and in some embodiments, 70.0% to 80.0%.

[0013] In some embodiments, the filler is selected from a composition of microcrystalline cellulose and lactose, and its content is selected from 10% to 90%, preferably selected from 20% to 80%, wherein the content ratio of microcrystalline cellulose to lactose is 2:1 to 1:3, preferably selected from 1:1 to 1:2; In some embodiments, the filler is selected from a composition of microcrystalline cellulose and lactose, and the content ratio of microcrystalline cellulose to lactose is 1:1 to 1:3; in some embodiments, the content ratio of microcrystalline cellulose to lactose is 1:1 to 1:2; in some embodiments, the content ratio of microcrystalline cellulose to lactose is 1:1 to 1:2.5; and in some embodiments, the content ratio of microcrystalline cellulose to lactose is 1:1 to 1:1.5.

[0014] In some embodiments, the filler is selected from a composition of microcrystalline cellulose and lactose, and the microcrystalline cellulose content is 15.0% to 80.0% of the total content; in some embodiments, the microcrystalline cellulose content is 30.0% to 80.0% of the total content; in some embodiments, the microcrystalline cellulose content is 20.0% of the total content; in some embodiments, the lactose content is 30.0% to 60.0% of the total content; in some embodiments, the lactose content is 15.0% to 60.0% of the total content; and in some embodiments, the lactose content is 40.0% to 55.0% of the total content.

[0015] In some embodiments, the disintegrant is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, and calcium carboxymethyl cellulose, and the content thereof is selected from 1.0% to 10.0%, preferably 3.0% to 8.0%; In some embodiments, the disintegrant is selected from sodium carboxymethyl starch, and the content thereof is 1.0% to 8.0% of the total content, in some embodiments, 3.0% to 8.0% of the total content, in some embodiments, 3.0% to 5.0% of the total content, and in some embodiments, 3.0% of the total content.

[0016] In some embodiments, the adhesive is selected from one or more of povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and methylcellulose, and the content thereof is selected from 1.0% to 10.0%, preferably selected from 2.0% to 8.0%; In some embodiments, the adhesive is selected from copovidone, and the content thereof is 1.0% to 8.0% of the total content, in some embodiments, the content thereof is 3.0% to 8.0% of the total content, in some embodiments, the content thereof is 3.0% to 5.0% of the total content, and in some embodiments, the content thereof is 3.0% of the total content.

[0017] In some embodiments, the wetting agent is selected from one or two of water and ethanol.

[0018] In some embodiments, the glidant is selected from one or more of talc, silica, microparticulate silica gel, polyethylene glycol, and magnesium dodecyl sulfate, and the content thereof is selected from 0.1% to 3.0%; In some embodiments, the glidant is selected from silica, and its content is 0.1% to 3.0% of the total content, in some embodiments, the content is 0.1% to 2.0% of the total content, in some embodiments, the content is 0.1% to 1.0% of the total content, in some embodiments, the content is 0.5% to 2.0% of the total content, in some embodiments, the content is 0.5% to 1.0% of the total content, in some embodiments, the content is 1.0% to 3.0% of the total content, and in some embodiments, the content is 1.0% of the total content.

[0019] In some embodiments, the lubricant is selected from one or more of magnesium stearate, calcium stearate, stearic acid, and sodium stearyl fumarate, and the content thereof is selected from 0.1% to 3.0%; In some embodiments, the lubricant is selected from sodium stearyl fumarate, and the content thereof is 0.1% to 3.0% of the total content, in some embodiments, the content thereof is 0.1% to 2.0%, in some embodiments, the content thereof is 0.1% to 1.0%, in some embodiments, the content thereof is 0.5% to 2.0%, in some embodiments, the content thereof is 0.5% to 1.0%, in some embodiments, the content thereof is 1.0% to 3.0%, and in some embodiments, the content thereof is 1.0% of the total content.

[0020] In some embodiments, the pharmaceutical excipient further comprises one or more of a flavoring agent, an antioxidant, a preservative, an opacifier, and a film coating premix.

[0021] The pharmaceutical composition according to any one of the embodiments of the present invention comprises the active ingredient A in any one of the above-mentioned embodiments, wherein the active ingredient A is preferably Compound 1 and its succinate salt or a crystalline form thereof, wherein the pharmaceutical excipients include a filler and a disintegrant, and preferably further contain one or more of an adhesive, a glidant, a lubricant, and a pH adjuster, wherein the pharmaceutical composition comprises: (i) Active ingredient A, the content is 1.0% to 90.0%, in some embodiments, 1.0% to 80.0%, in some embodiments, 1.0% to 70.0%, in some embodiments, 1.0% to 60.0%, in some embodiments, 1.0% to 50.0%, in some embodiments, 1.0% to 40.0%, in some embodiments, 1.0% to 30.0%, in some embodiments, 1.0% to 20.0%, in some embodiments, 1.0% to 10.0%, in some embodiments, 5.0% to 90.0%, in some embodiments, 5.0% to 80.0%, in some embodiments, 5.0% to 70.0%, in some embodiments, 5.0% to 60.0%, and in some embodiments, 5.0% to 50.0%, in some embodiments, 5.0% to 40.0%, in some embodiments, 5.0% to 30.0%, in some embodiments, 5.0% to 20.0%, in some embodiments, 5.0% to 10.0%, in some embodiments, 10.0% to 90.0%, in some embodiments, 10.0% to 80.0%, in some embodiments, 10.0% to 70.0%, in some embodiments, 10.0% to 60.0%, in some embodiments, 10.0% to 50.0%, in some embodiments, 10.0% to 40.0%, in some embodiments, 10.0% to 30.0%, in some embodiments, 10.0% to 20.0%, and in some embodiments, 10.0%. (ii) a filler, the filler being a composition of microcrystalline cellulose and lactose, the filler content being 50.0% to 90.0%, in some embodiments 60.0% to 90.0%, in some embodiments 70.0% to 90.0%, in some embodiments 50.0% to 80.0%, in some embodiments 60.0% to 80.0%, in some embodiments 70.0% to 85.0%, in some embodiments 75.0% to 82.0%, and further, in some embodiments, the content ratio of microcrystalline cellulose to lactose is 1:1 to 1:2, and in some embodiments, the content ratio of microcrystalline cellulose to lactose is 1:1 to 1:1.5, (iii) the disintegrant is croscarmellose sodium, and the content is 1.0% to 8.0%, and in some embodiments, the content is 1% to 3% of the total content, and in some embodiments, the content is 3.0% to 8.0% of the total content, and in some embodiments, the content is 3% of the total content; (iv) the adhesive is copovidone, and the content is 1.0% to 8.0%, and in some embodiments, the content is 1.0% to 3.0% of the total content, and in some embodiments, the content is 3.0% to 8.0% of the total content, and in some embodiments, the content is 3.0% of the total content; (v) the lubricant is sodium stearyl fumarate, present in an amount of 0.1% to 3.0%, and in some embodiments, in an amount of 0.1% to 2.0%, and in some embodiments, in an amount of 0.1% to 1.0%, and in some embodiments, in an amount of 0.5% to 2.0%, and in some embodiments, in an amount of 0.5% to 1.0%, and in some embodiments, in an amount of 1.0% to 3.0%, and in some embodiments, in an amount of 1.0%; (vi) The glidant is silica, present in an amount of 0.1% to 3.0%, in some embodiments, 0.1% to 2.0% of the total amount, in some embodiments, 0.1% to 1.0% of the total amount, in some embodiments, 0.5% to 2.0%, in some embodiments, 0.5% to 1.0%, in some embodiments, 1.0% to 3.0%, and in some embodiments, 1.0% of the total amount.

[0022] The pharmaceutical composition according to any one of the embodiments of the present invention comprises: (i) Compound 1 or its succinate salt is present in an amount of 1.0% to 90.0%, and optionally, (ii) Pharmaceutical excipients include one or more of fillers, adhesives, wetting agents, disintegrants, glidants, and lubricants.

[0023] (iii) Fillers include one or more of microcrystalline cellulose, mannitol, lactose, sucrose, sorbitol, dextran, pregelatinized starch, calcium dihydrogen phosphate, and starch.

[0024] (iv) The adhesive comprises one or more of povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and methylcellulose.

[0025] (v) The wetting agent includes one or more of water, ethanol.

[0026] (vi) Disintegrants include one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, and calcium carboxymethyl cellulose.

[0027] (vii) Glidants include one or more of talc, silica, particulate silica gel, polyethylene glycol, magnesium dodecyl sulfate.

[0028] (viii) Lubricants include magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate.

[0029] (ix) may further comprise one or more of flavoring agents, antioxidants, preservatives, opacifiers, and film coating premixes.

[0030] Optionally, in the pharmaceutical composition according to any one of the above aspects, the pharmaceutical composition may be prepared as a formulation selected from tablets, granules, powders, oral solutions, emulsions, and capsules.

[0031] Optionally, in the pharmaceutical formulation according to any one of the above embodiments, the adhesive may be added in a solution state or in a powder state, and the disintegrant may be added in an internal or external manner.

[0032] The present invention further provides the application of said pharmaceutical composition for producing related medicines for treating kidney diseases.

[0033] Unless stated to the contrary, terms used in the specification and claims of this application have the following meanings.

[0034] "Preparation specifications" refers to the weight of the active ingredient (active ingredient A) contained in one unit dosage form, one tablet, or each other unit dosage form.

[0035] Carbon, hydrogen, oxygen, sulfur, nitrogen, or F, Cl, Br, I in the groups and compounds described in the present invention all include their isotopic status, and carbon, hydrogen, oxygen, sulfur, or nitrogen in the groups and compounds described in the present invention are optionally further substituted with one or more corresponding isotopes, where the carbon isotope is: 12 C and13 C and 14 C, isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called tritium), and isotopes of oxygen include 16 O and 17 O and 18 Isotopes of sulfur include O and 32 S and 33 S and 34 S and 36 S and nitrogen isotopes include 14 N and 15 N and fluorine isotopes include 17 F and 19 The isotopes of chlorine include F and 35 Cl and 37 The isotopes of bromine include Cl and 79 Br and 81 Contains Br.

[0036] "Optionally" or "optionally" means that the subsequently described event or circumstance may, but does not necessarily, occur, and the description includes both cases where the event or circumstance occurs and cases where it does not occur. For example, "an alkyl group optionally substituted with F" means that the alkyl group may, but is not necessarily, substituted with F, and includes cases where the alkyl group is substituted with F and cases where the alkyl group is not substituted with F.

[0037] "Pharmaceutically acceptable salt" or "a pharmaceutically acceptable salt thereof" refers to a salt in which the compounds of the present invention retain the biological effectiveness and properties of the free acid or free base and which is obtained by reaction of said free acid with a non-toxic inorganic or organic base, or by reaction of said free base with a non-toxic inorganic or organic acid.

[0038] A "pharmaceutical composition" refers to a mixture of one or more compounds according to the present invention, or stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or co-crystals thereof, and other chemical components, where "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic agents.

[0039] A "carrier" refers to a material that does not cause significant irritation to an organism and does not abolish the biological activity and properties of the administered compound.

[0040] "Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, adhesives, and disintegrating agents.

[0041] "Prodrug" refers to a compound that can be converted in vivo through metabolism to a biologically active compound of the present invention. Prodrugs of the present invention are prepared by modifying an amino or carboxyl group in a compound of the present invention so that the modification can be removed, either by conventional manipulation or in vivo, to yield the parent compound. When a prodrug of the present invention is administered to a mammalian subject, the prodrug cleaves to form a free amino or carboxyl group.

[0042] A "cocrystal" refers to a crystalline body formed by the association of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) through hydrogen bonding or other non-covalent bonds, where the API and CCF are both solids in their pure states at room temperature and there is a fixed stoichiometric ratio between the components. Cocrystals are multi-component crystalline bodies, and include not only binary cocrystals formed between two neutral solids, but also multi-component cocrystals formed between a neutral solid and a salt or solvate.

[0043] "Animal" includes mammals such as humans, companion animals, zoo animals, and farm animals, and is preferably a human, horse, or dog.

[0044] "Stereoisomer" refers to isomers that result from differences in the way atoms in molecules are arranged in space, and includes cis-trans isomers, enantiomers, and conformational isomers.

[0045] "Tautomer" refers to a functional isomer produced when an atom in a molecule rapidly shifts between two positions, such as keto-enol isomers and amide-imide alcohol isomers.

[0046] "I C 50 " is the concentration of a drug or inhibitor required to inhibit a specified biological process (or some component in that process, e.g., enzyme, receptor, cell, etc.) by half.

[0047] Unless otherwise specified, the "content %" of a substance in a pharmaceutical composition in this application refers to the proportion of the weight of the substance to the total weight of the pharmaceutical composition.

[0048] The "content %" in measuring the content of a formulation refers to the percentage of the weight of the active ingredient in the formulation measured according to the measurement method relative to the administered weight of the active ingredient in the formulation. DETAILED DESCRIPTION OF THE INVENTION

[0049] The following examples will illustrate the technical solutions of the present invention in detail, and the protection scope of the present invention includes but is not limited to them.

[0050] The compounds used in the reactions described herein are prepared by organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" are those obtained from legitimate commercial sources, including companies such as Taitan Technology, Ananji Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical, Nanjing Yaoshi, Yaoming Kangde, and Bailingwei Technology.

[0051] The structure of the compound was confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR displacements (δ) were 10 -6 The NMR data were given in units of ppm. NMR measurements were performed using nuclear magnetometers (Bruker Avance III 400 and Bruker Avance 300), solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS). MS measurements were performed using Agilent 6120B (ESI) and Agilent 6120B (APCI). HPLC measurements were performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM). Thin layer chromatography silica gel plates, Yantai Yellow Sea HSGF 254 Or Aoshima GF 254 Silica gel plates are used for thin layer chromatography (TLC), with a thickness of 0.15mm to 0.20mm. For product separation and purification by thin layer chromatography, a thickness of 0.4mm to 0.5mm is used. For column chromatography, Yantai Yellow Sea silica gel with 200-300 mesh was generally used as the carrier. Boc: tert-butoxycarbonyl group Ts: p-toluenesulfonyl group Cbz: benzyloxycarbonyl group TMS: Trimethylsilyl group

[0052] Example 1: Preparation of Compound 1 [ka]

[0053] Step 1: Compound A (162 mg, 0.625 mmol) was dissolved in 5 mL of isopropyl acetate, and maleic acid (73 mg, 0.628 mmol) was added. The reaction mixture was then reacted at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give a crude product (235 mg). The crude product (235 mg) was dissolved in 10 mL of ethanol, and 4-formyl-5-trideuteromethoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (165 mg, 0.564 mmol) was added. 20 mg of Ir(CO)2acac was added, and the mixture was purged with hydrogen gas three times. The mixture was heated to 80 °C and reacted under a hydrogen gas balloon atmosphere for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was then separated and extracted by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10:1) to give compound B (200 mg, yield: 60%). LCMS m / z=536.3[M+1] +

[0054] Step 2: Compound B (200 mg, 0.37 mmol) was dissolved in 5 mL of methanol, solid potassium carbonate (257 mg, 1.86 mmol) was added, and the mixture was heated to 80 °C and refluxed for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in a mixed solvent of 5 mL of THF and 1 mL of water, and lithium hydroxide monohydrate (155 mg, 3.7 mmol) was added and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was passed through pre-HPLC (instrument and preparative column: Glison GX-281 preparative column, model number Sunfire C18, 5 μm, inner diameter × length = 30 mm × 150 mm). Preparation method: The crude product was dissolved in methanol and dimethyl sulfoxide and filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase: acetonitrile / water (containing 0.1% TFA). Gradient elution: 60% acetonitrile was dissolved in a 5% gradient (elution time: 15 min), and the trifluoroacetate salt of Compound 1 (125 mg) was obtained by lyophilization.

[0055] 1H NMR (400MHz,CD3OD) δ 8.28- 8.18 (m,2H),7.77- 7.68 (m,2H),7.36- 7.30 (m,1H),6.77 (s,1H),6.32 (d,1H),4.48 (dd,1H),4.40- 4.29 (m,1H),4.18- 4.08 (m,1H),3.62- 3.52 (m,1H),3.30- 3.21 (m,1H),2.51 (s,3H),2.25- 2.12 (m,1H),2.09 -1.85 (m,2H),1.79- 1.60 (m,1H),1.20- 1.03 (m,1H),0.67- 0.53 (m,1H),0.52- 0.40 (m,2H),0.26- 0.12 (m,2H). LCMS m / z=422.2[M+1] +

[0056] To 125 mg of the trifluoroacetate salt of Compound 1, 10 mL of 2-methyltetrahydrofuran and 50 mL of saturated sodium bicarbonate solution were added, stirred for 15 minutes, extracted, and the organic phase was concentrated to dryness to obtain Compound 1 (60 mg).

[0057] Example 1-1: Succinate of Compound 1 Approximately 250 mg of compound 1 was taken, and 7.5 mL of ethanol and 2.5 mL of water were added. The mixture was stirred at 25°C, and 15 mL of a 47 mg / mL aqueous succinic acid solution was added. After stirring for 2 hours, the mixture was filtered under suction. The filter cake was rinsed with a 30% aqueous ethanol solution and dried under vacuum to obtain the succinate salt of compound 1.

[0058] 1 H NMR showed that the ratio of the number of H atoms between the chemical shift methyl peak (2.42 ppm, 3H) of compound 1 and the methylene succinate peak (2.41 ppm, 4H) was 1:1, and the molar ratio of compound 1 to succinic acid was preliminarily determined to be 1:0.75. Example 2: [ka]

[0059] Compound 2 or a trifluoroacetate thereof was obtained by following the production method of Compound 1.

[0060] Trifluoroacetate of Compound 2 1 H NMR (400MHz,CD3OD) δ 8.23 ​​(d,2H),7.73 (d,2H),7.33 (d,1H),6.77 (s,1H),6.33 (d,1H),4.48 (dd,1H),4.38 - 4.31 (m,1H),4.17 - 4.09 (m,1H),3.76 (s,3H),3.62 - 3.53 (m,1H),3.30 - 3.21 (m,1H),2.51 (s,3H),2.25 - 2.11 (m,1H),2.05 - 1.88 (m,2H),1.78 - 1.60 (m,1H),1.21 - 1.05 (m,1H),0.65 - 0.53 (m,1H),0.51 - 0.39 (m,2H),0.24 - 0.14 (m,2H). LCMS m / z=419.2[M+1] + Example 2-1: [ka]

[0061] Step 1: Preparation of 5b-1 5a (3.7 g, 9.45 mmol) was added to 50 mL of ultra-dehydrated DMF, and solid benzenesulfonyl hydrazide (8.2 g, 47.6 mmol) was added under a nitrogen atmosphere. The mixture was heated to 100 °C and reacted for 16 h. The reaction mixture was cooled to room temperature, 100 mL of ethyl acetate was added, and the organic phase was washed three times with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 15:1) to give 5b-1 (0.7 g, yield: 19%).

[0062] Rf value of compound 5b-1: 0.36 (developing solvent: ethyl acetate / petroleum ether (v / v) = 1:10) Nuclear magnetic resonance of compound 5b-1: 1 H NMR (400MHz,CDCl3) δ 8.04 - 7.90 (m,2H),7.50 - 7.10 (m,7H),5.75 - 5.45 (m,1H),5.19 (s,2H),4.40 - 4.05 (m,1H),3.85 (s,3H),2.84 - 2.66 (m,1H),2.54 - 2.33 (m,1H),1.84 - 1.55 (m,2H),1.45 - 1.18 (m,1H),0.72 - 0.27 (m,4H),0.09 - -0.06 (m,2H). LCMS m / z=394.2[M+1] +

[0063] Step 2: Preparation of the maleate salt of 5c-1 5b-1 (1.0 g, 2.54 mmol) was dissolved in 10 mL of acetonitrile, and iodotrimethylsilane (2.54 g, 12.7 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 30 min. 10 mL of methanol was added to the reaction mixture, and the pH of the mixture was adjusted to 2-3 with 2 mol / L dilute hydrochloric acid. The organic phase was extracted with 20 mL of ethyl acetate, and the pH of the aqueous phase was adjusted to 10 with 2 mol / L sodium hydroxide solution. The mixture was extracted three times with 100 mL of dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 5c-1 (diastereomer 2) (0.6 g). Compound 5c-1 (diastereomer 2) (0.6 g, 2.31 mmol) was dissolved in 10 mL of isopropyl acetate, and maleic acid (270 mg, 2.33 mmol) was added. The mixture was allowed to react at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to give crude maleate of 5c-1 (0.85 g).

[0064] Step 3: Fabrication of 5d-1 The maleate salt of 5c-1 (0.85 g) was dissolved in 10 mL of ethanol, and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (0.67 g, 2.32 mmol) (see WO2015009616 for synthetic methods) was added. 80 mg of Ir(CO)2acac was added, the mixture was heated to 80 °C, and the reaction was carried out for 16 h under a hydrogen gas balloon atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was separated and extracted by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 15:1) to obtain 5d-1 (850 mg, yield: 69%).

[0065] Compound 5d-1 Nuclear Magnetic Resonance: 1 H NMR (400MHz,CDCl3) δ 8.08 - 7.96 (m,2H),7.67 - 7.56 (m,2H),7.48 (d,1H),6.71 (d,1H),6.67 (s,1H),3.91 (s,3H),3.80 (s,3H),3.74 - 3.64 (m,1H),3.60 - 3.50 (m,1H),3.44 - 3.33 (m,1H),2.76 - 2.65 (m,1H),2.59 (s,3H),2.45 - 2.32 (m,1H),1.96 - 1.50 (m,13H),1.23 - 1.10 (m,1H),0.90 - 0.75 (m,1H),0.57 - 0.41 (m,2H),0.10 - 0.01 (m,2H). LCMS m / z=533.3[M+1] +

[0066] Step 4: Preparation of the trifluoroacetate salt of compound 2-1 5d-1 (850 mg, 1.596 mmol) was dissolved in 10 mL of methanol, solid potassium carbonate (1.1 g, 7.96 mmol) was added, and the mixture was heated to 80 °C and refluxed for 3 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in a mixed solvent of 10 mL of THF and 2 mL of water, and lithium hydroxide monohydrate (670 mg, 15.97 mmol) was added. The mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, and the crude product was passed through a pre-HPLC (instrument and preparative column: Glison GX-281 preparative column, model Sunfire C18, 5 μm, inner diameter × length = 30 mm × 150 mm). Preparation method: The crude product was dissolved in methanol and dimethyl sulfoxide and filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase: acetonitrile / water (containing 0.1% TFA). Gradient elution: 60% acetonitrile was dissolved in a 5% gradient (elution time: 15 min), and the resulting solution was lyophilized to give the trifluoroacetate salt of compound 2-1 (400 mg).

[0067] 1 H NMR (400MHz,CD3OD) δ 8.29 - 8.18 (m,2H),7.79 - 7.72 (m,2H),7.37 - 7.32 (m,1H),6.78 (s,1H),6.38 (d,1H),4.83 - 4.78 (m,1H),4.41 - 4.32 (m,1H),4.30 - 4.20 (m,1H),3.77 (s,3H),3.65 - 3.42 (m,2H),2.51 (s,3H),2.40 - 2.25 (m,1H),2.18 - 2.02 (m,2H),1.98 - 1.82 (m,1H),1.52 - 1.38 (m,1H),1.18 - 1.04 (m,1H),0.72 - 0.60 (m,2H),0.25 - 0.17 (m,2H). LCMS m / z=419.2[M+1] +

[0068] The trifluoroacetate of compound 5-1 is clearly attached to the C1 hydrogen on the piperidine ring and the C6 hydrogen of the cyclopropyl group. 1 H- 1There was a H NOESY signal which demonstrated that the configuration of compound 5-1 was as shown below. [ka] Example 3: [ka]

[0069] Step 1: 14c (0.40 g, 1.38 mmol), the maleate salt of compound A (0.62 g), and 4 Å molecular sieves (100 mg) were placed in a reaction flask, and glacial acetic acid (0.5 mL) and dichloroethane (10 mL) were added. The mixture was heated to 60 °C and reacted for 16 h. The reaction mixture was cooled to room temperature, and sodium triacetoxyborohydride (0.88 g, 4.15 mmol) was added. The mixture was reacted at room temperature for 6 h. 20 mL of saturated aqueous sodium bicarbonate was added dropwise to the reaction mixture, and the insoluble matter was filtered through diatomaceous earth. The filtrate was collected and extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 10:1 to 1:0) to give crude product 15a (102 mg). LCMS m / z=434.3[M+1] +

[0070] Step 2: To the crude product 15a (102 mg), solid sodium hydroxide (100 mg, 2.50 mmol) was added, followed by 5 mL of methanol and 5 mL of water. The mixture was heated to 75 °C and refluxed for 0.5 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was then subjected to pre-HPLC (instrument and preparative column: SHIMADZU LC-20AP preparative liquid chromatography, model number: Phenomenex C18). Preparation method: The crude product was dissolved in methanol and dimethyl sulfoxide and filtered through a 0.45 μm filter to prepare the sample solution. Mobile phase: acetonitrile / 10 mmol / L aqueous ammonium bicarbonate solution. Gradient elution: Acetonitrile was used in a gradient of 15% to 45% (elution time: 10 min), followed by lyophilization to obtain compound 3 (9 mg, two-step yield from compound 14c: 2%).

[0071] 1 H NMR (400MHz,CD3OD) δ 8.16 - 8.06 (m,2H),7.98 (s,1H),7.65 - 7.56 (m,2H),7.06 (s,1H),4.30 - 3.83 (m,3H),3.79 (s,3H),3.40 - 3.32 (m,1H),2.56 (s,3H),2.17 - 2.03 (m,1H),1.99 - 1.76 (m,2H),1.74 - 1.52 (m,1H),1.09 - 0.93 (m,1H),0.67 - 0.52 (m,1H),0.50 - 0.36 (m,2H),0.23 - 0.10 (m,2H). LCMS m / z=420.2[M+1] + Example 4: [ka]

[0072] 16a (see WO2022028507 for synthetic methods) (165 mg, 0.868 mmol) was dissolved in 10 mL of dichloromethane, and triethylamine (260.78 mg, 2.6 mmol), (Boc)2O (227.0 mg, 1.04 mmol), and 4-dimethylaminopyridine (5.3 mg, 0.043 mmol) were added sequentially. The mixture was allowed to react at room temperature for 1 h. 50 mL of dichloromethane was added to the reaction mixture, and the organic phase was washed sequentially with 0.5 mol / L aqueous hydrochloric acid (30 mL × 2), water (30 mL × 2), and saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3:1) to obtain crude product 1 (0.22 g). The crude product 1 (70 mg) was dissolved in 10 mL of 1,2-dichloroethane, and the maleate salt of compound A (91 mg), solid sodium bicarbonate (61 mg, 0.726 mmol), and 0.02 mL of acetic acid were added in that order. The mixture was stirred at room temperature for 0.5 hours, then heated to 70°C, and reacted for 16 hours. The reaction mixture was cooled to room temperature, and sodium triacetoxyborohydride (102 mg, 0.48 mmol) was added, followed by reaction at room temperature for 16 hours. The reaction mixture was added with 50 mL of saturated aqueous sodium bicarbonate and extracted with ethyl acetate (50 mL × 2). The organic phase was washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:3) to obtain 40 mg of crude product. The crude product was then subjected to pre-HPLC (instrument and preparative column: SHIMADZU LC-20AP preparative liquid, model number: Phenomenex C18). Preparation method: The crude product was dissolved in methanol and dimethyl sulfoxide and filtered through a 0.45 μm filter to prepare the sample solution. Mobile phase: acetonitrile / 10 mmol / L aqueous ammonium bicarbonate solution. Gradient elution: Acetonitrile was eluted with a gradient of 35% to 65% (elution time: 10 min) to obtain crude product 2 (8 mg).The crude product 2 (8 mg) was dissolved in 2 mL of a mixed solvent of methanol and 2 mL of water. Solid sodium hydroxide (4 mg, 0.1 mmol) was added, and the mixture was heated to 75 °C and reacted for 2 h. The reaction mixture was cooled to room temperature, the pH was adjusted to 8 with 1 mol / L aqueous hydrochloric acid, and the crude product was subjected to pre-HPLC (instrument and preparative column: SHIMADZU LC-20AP preparative liquid chromatography, model number: Phenomenex C18). Preparation method: The crude product was dissolved in methanol and dimethyl sulfoxide and filtered through a 0.45 μm filter to prepare the sample solution. Mobile phase: acetonitrile / 10 mmol / L aqueous ammonium bicarbonate solution. Gradient elution: Acetonitrile was diluted to 65% with a gradient of 35% (elution time: 10 min) to obtain compound 4 (4 mg, yield: 3%).

[0073] 1 H NMR (400MHz,CD3OD) δ 8.00 (s,1H),7.94 - 7.84 (m,2H),7.48 - 7.36 (m,2H),6.68 (s,1H),4.20 - 3.70 (m,3H),3.59 (s,3H),3.23 - 3.09 (m,1H),2.90 - 2.66 (m,1H),2.38 (s,3H),2.00 - 1.87 (m,1H),1.81 - 1.66 (m,2H),1.60 - 1.40 (m,1H),0.96 - 0.78 (m,1H),0.50 - 0.35 (m,1H),0.34 - 0.20 (m,2H),0.07 - 0.05 (m,2H). LCMS m / z=420.3[M+1] +

[0074] Formulation Examples: Unless otherwise specified, percentages (%) refer to the weight of an ingredient as a percentage of the total weight of the formulation.

[0075] The succinate salt of Compound 1 was used in a molar ratio of 1:0.75 unless otherwise specified. 1. Formulation 1-1: Specifications 200 mg / tablet (calculated as free base):

[0076] [Table 2]

[0077] 2. Formulation 1-2: 200 mg / tablet (calculated as free base):

[0078] [Table 3]

[0079] 3. Formulations 1-3: 200 mg / tablet (calculated as free base): (300 tablets manufactured)

[0080] [Table 4]

[0081] The above formulations 1-1 to 1-3 were prepared using the following process. 1) Weighing: Each raw material excipient (content equivalent to the active pharmaceutical ingredient) was weighed according to the prescription.

[0082] 2) Mixing: The active ingredient, adhesive, glidant, disintegrant, and filler were mixed for 5 minutes, and then the lubricant was added and mixed for 2 minutes.

[0083] 3) Tableting: Using a shallow concave mold with a diameter of 11 mm, the powder in 2 was tableted, controlling the tablet weight to 575 mg and the hardness to 70N to 130N. 4. Formulations 1-4: 200 mg / tablet (calculated as free base):

[0084] [Table 5]

[0085] The formulation process for formulations 1-4 is as follows: Pre-mixing: The active ingredient and microcrystalline cellulose are mixed for 1 minute, then sieved using a mill / sieve sizer. After sieving, the mixture is mixed with crospovidone in a wet granulator for 5 minutes to obtain a mixture. Adhesive formulation: 8.7% povidone solution Granulation: The wet granulator was started and 8.0% povidone solution was slowly added followed by stirring for 120 seconds to produce a soft material.

[0086] Granulation and drying: The soft material was wet-granulated using a swing granulator by passing it through a 14-mesh sieve to obtain wet granules, and the wet granules were dried in an oven at 80°C to control the moisture content to 3.5% or less. The wet granules were then dry-granulated using a swing granulator by passing it through an 18-mesh sieve to obtain sized, dry granules, which were then ready for use.

[0087] Final blending: The sized dry granules were taken and put into a hopper mixer, then magnesium stearate was added and mixed for 8 minutes to obtain the final blended granules.

[0088] Tableting: Based on the theoretical tablet weight, the mixture was tableted using a φ10 mm shallow concave die, and the tablet weight was controlled to within ±5% of the theoretical tablet weight, and the hardness was controlled to 70N to 130N to obtain uncoated tablets.

[0089] 5. Formulations 1-5: 50 mg / tablet (calculated as free base)

[0090] [Table 6]

[0091] 6. Formulations 1-6: Specifications 100 mg / tablet (calculated as free base)

[0092] [Table 7]

[0093] 7. Formulations 1-7: 200 mg / tablet (calculated as free base)

[0094] [Table 8]

[0095] 8. Formulations 1-8: 200 mg / tablet (calculated as free base)

[0096] [Table 9]

[0097] 9. Formulations 1-9: 400 mg / tablet (calculated as free base)

[0098] [Table 10]

[0099] 10. Formulations 1-10: 30 mg / tablet (calculated as free base)

[0100] [Table 11]

[0101] 11. Formulations 1-11: 500 mg / tablet (calculated as free base)

[0102] [Table 12]

[0103] 12. Formulations 1-12: 700 mg / tablet (calculated as free base)

[0104] [Table 13]

[0105] 13. Formulations 1-13: 800 mg / tablet (calculated as free base)

[0106] [Table 14]

[0107] Formulations 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-11, 1-12, and 1-13 were manufactured using a similar formulation process to that of formulation 1-4. Purified water was used as a wetting agent during the formulation manufacturing process.

[0108] Formulation testing example: 1. Content measurement: High-performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Four General Principles) tests were performed using octadecylsilane-bonded silica gel as the packing material (ACE Excel5 C18PFP, 4.6mm x 250mm, 5μm). Mobile phase A was 0.02mol / L ammonium acetate buffer salt-methanol (850:150) (weigh out 1.54g of ammonium acetate, add 1000ml of water to dissolve, filter through a 0.45μm filter, remove 850ml, and mix evenly with 150ml of methanol). Mobile phase B was acetonitrile. Elution was performed isocratically at a mobile phase A-mobile phase B ratio of 80:20 for 30 minutes. The detection wavelength was 222nm, the column temperature was 30℃, and the flow rate was 1.0ml / min.

[0109] The content measurements were carried out for Examples 1-1 to 1-13 above, and the content test results are shown in Table 15 below.

[0110] [Table 15]

[0111] Conclusion: The contents of the preparations manufactured using the technology of the present invention all meet the quality requirements.

[0112] 2. Dissolution measurement Dissolution measurements were carried out for the above Examples 1-1 to 1-13.

[0113] Test Method: Medium: pH 1.0 dissolution medium, volume: 900 mL, method: paddle method, rotation speed: 50 rpm, time: 30 minutes, temperature: 37°C ± 0.5°C.

[0114] The test results are shown in Table 16 below.

[0115] [Table 16]

[0116] Conclusion: The formulations produced using the technology of the present invention have high dissolution rates.

[0117] Biological test examples 1. Alternative complement pathway inhibitory activity test The inhibitory effects of compounds on the alternative complement pathway were detected using the IBL Alternative Pathway Kit (COMPL AP330 RUO). Serum was collected from healthy volunteers, and one portion was diluted 50% (v / v) with 20 mM EDTA gelatin buffer (0.15 mM CaCl2, 141 mM NaCl, 4.5 mM MgCl2, 4.2 mM HEPES, 0.1% gelatin at pH 7.4). The other portion was diluted 50% (v / v) with 20 mM EGTA gelatin buffer. DMSO was used to prepare the compound at a working concentration 100 times the final concentration. Before use, each of the 50% serum samples was diluted 1 / 18 with the AP diluent provided in the kit. 99 parts diluted EGTA-containing serum was added to 1 part compound working solution (v / v) or DMSO (positive control PC) for 30 min pretreatment. 99 parts diluted EDTA-containing serum was added to 1 part DMSO (v / v) as a negative control (NC). The serum pretreated with the above compounds (or DMSO) was added to a 96-well plate coated with LPS at 100 mL / well and incubated at 37°C for 1 h. After washing three times with kit wash buffer, a conjugated chromogenic substrate was added according to the kit instructions, and the absorbance at 405 nm was read using a microplate reader. The inhibitory activity of the compound on the alternative pathway was calculated using the following formula:

number

[0118] Using graphpad, nonlinear regression was performed on the final compound concentration and the inhibition rate to determine the IC value of the compound's inhibition of the alternative pathway. 50 obtained.

[0119] IC of alternative pathway inhibition 50 The resulting values ​​are shown in Table 17.

[0120] [Table 17]

[0121] A:<200nM, Conclusion: The compounds of the present invention have significant inhibitory effects on the alternative complement pathway.

[0122] 2. Pharmacokinetic study in rats Experimental objective: In this study, the test substance was administered to SD rats by intravenous and oral gavage at a single dose, and the concentration of the test substance in the rat plasma was measured to evaluate the pharmacokinetic properties of the test substance in the rat body.

[0123] Test animals: male SD rats, 200-250 g, 6-8 weeks old, 6 rats / compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0124] Test method: On the day of the test, six SD rats were randomly divided into groups according to their weight. One day before administration, they were fasted for 12-14 hours without water prohibition, and fed 4 hours after administration.

[0125] [Table 18]

[0126] *Dose is as free base.

[0127] Sampling: Before and after administration, 0.15 mL of blood was collected from the orbit using isoflurane anesthesia and placed in an EDTAK2 centrifuge tube. The blood was centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma.

[0128] Plasma collection time points for IV&PO group: 0, 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, 24 h.

[0129] Prior to analytical detection, all samples were stored at −60° C. Quantitative analysis of the samples was performed by LC-MS / MS.

[0130] [Table 19]

[0131] *Note: ig compounds were administered (by gavage) Conclusion: The compounds of the present invention have good oral absorption in rats, and compared with LNP023, the trifluoroacetate salt of Compound 1 has higher maximum blood concentration and oral bioavailability in rats.

[0132] Structure of the control compound (LNP023): [ka]

[0133] 3. Pharmacokinetic studies in dogs Experimental Objective: In this study, the test substance was administered to beagle dogs by intravenous and oral gavage at a single dose, and the concentration of the test substance in the beagle dogs' plasma was measured to evaluate the pharmacokinetic properties of the test substance in the beagle dogs' bodies.

[0134] Test animals: male beagle dogs, 8-11 kg, 1-3 years old, 6 dogs / compound. Purchased from Beijing Masu Biotechnology Co., Ltd.

[0135] Test method: On the day of the test, six beagle dogs were randomly assigned to groups based on their weight. One day before administration, they were fasted for 14 to 18 hours without water restriction, and were fed 4 hours after administration.

[0136] [Table 20]

[0137] *Dose is as free base.

[0138] Sampling: Before and after administration, 1.0 mL of blood was collected from the jugular vein or limb vein and placed in an EDTAK2 centrifuge tube. The tube was centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma.

[0139] Plasma collection times for the IV & PO group: 0, 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, 10, 12, 24 h.

[0140] Prior to analytical detection, all samples were stored at −60° C. Quantitative analysis of the samples was performed by LC-MS / MS.

[0141] [Table 21]

[0142] *Note: ig compounds were administered (by gavage) Conclusion: The compound of the present invention had good oral absorption in beagle dogs.

[0143] 4. Pharmacokinetic studies in monkeys Experimental Objective: In this study, the test substance was administered to cynomolgus monkeys by intravenous and oral gavage in a single dose, and the concentration of the test substance in monkey plasma was measured to evaluate the pharmacokinetic properties of the test substance in the monkey body.

[0144] Test animals: male cynomolgus monkeys, 3-5 kg, 3-6 years old, 6 animals / compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0145] Test method: On the day of the test, six monkeys were randomly divided into groups according to their weight. One day before administration, they were fasted for 14 to 18 hours without water prohibition, and were fed 4 hours after administration.

[0146] [Table 22]

[0147] *Dose is as free base.

[0148] Sampling: Before and after administration, 1.0 mL of blood was collected from a limb vein and placed in an EDTAK2 centrifuge tube. The tube was centrifuged at 5,000 rpm at 4°C for 10 minutes to collect plasma.

[0149] Plasma collection times for the IV & PO group: 0, 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, 10, 12, 24 h.

[0150] Prior to analytical detection, all samples were stored at −60° C. Quantitative analysis of the samples was performed by LC-MS / MS.

[0151] [Table 23]

[0152] *Note: ig compounds were administered (by gavage).

[0153] Conclusion: The compounds of the present invention have good oral absorption in monkeys, and compared with the trifluoroacetate salt of LNP023, the trifluoroacetate salt of Compound 1 has higher oral exposure and bioavailability in monkeys.

[0154] 5. Caco2 Permeability Assay The test was performed using monolayers of Caco-2 cells incubated in triplicate in a 96-well Transwell plate. Transport buffer solution (HBSS, 10 mM HEPES, pH 7.4 ± 0.05) containing a compound of the present invention (2 μM) or control compounds digoxin (10 μM), nadolol (2 μM), and metoprolol (2 μM) was placed in the apical or basal wells of the dosing end. The corresponding wells of the receiving end were filled with transport buffer solution containing DMSO. After 2 hours of incubation at 37 ± 1°C, the cell plate was removed, and appropriate samples were taken from the apical and basal wells and placed in a new 96-well plate. Proteins were then precipitated by adding acetonitrile containing an internal standard. The samples were analyzed by LC-MS / MS to measure the concentrations of the compounds of the present invention and the control compounds. The concentration data were used to calculate the apparent permeability coefficients for transport from the apical to the basal side of the monolayer cells and from the basal to the apical side, thereby calculating the efflux rates. The integrity of the cell monolayer after 2 hours of incubation was assessed by fluorescein leakage.

[0155] [Table 24]

[0156] Conclusion: The compounds of the present invention have good Caco2 permeability, and compared with the trifluoroacetate salt of LNP023, the trifluoroacetate salt of Compound 1 has better permeability and a lower excretion rate.

Claims

1. A pharmaceutical composition comprising an active ingredient A and a pharmaceutical excipient, wherein the active ingredient A is selected from a compound according to general formula (I) or a stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof; 【Chemistry 1】 【Chemistry 2】 teeth, 【Transformation 3】 is selected from R １ is -OCH ３ or -OCD ３ is selected from R ２ is -CH ３ or -CD ３ is selected from n is selected from 1, 2 or 3; A pharmaceutical composition, wherein the content of the active ingredient A is selected from the range of 1.0% to 90.0%, preferably selected from the range of 5.0% to 75.0%, and more preferably selected from the range of 10.0% to 50.0%.

2. 2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises 10 to 800 mg of active ingredient A (calculated as the free base).

3. 3. The pharmaceutical composition according to claim 2, wherein the pharmaceutical composition comprises 10 to 400 mg of active ingredient A (calculated as the free base).

4. 4. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition comprises 20 to 400 mg of active ingredient A (calculated as the free base).

5. 5. The pharmaceutical composition according to claim 4, wherein the pharmaceutical composition comprises 30 to 200 mg of active ingredient A (calculated as the free base).

6. 3. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition comprises 30 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg of active ingredient A (calculated as the free base).

7. The pharmaceutical composition according to claim 1, comprising an active ingredient A and a pharmaceutical excipient, wherein the active ingredient A is selected from a compound represented by general formula (I) or a stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, wherein the structure of the compound represented by general formula (I) is selected from one of the structures shown in Table S-1.

8. The structure of the compound represented by general formula (I) is 【Chemistry 4】 The pharmaceutical composition of claim 1, wherein the structure is selected from the following:

9. 2. The pharmaceutical composition according to claim 1, wherein the active ingredient A is selected from Compound 1 or a succinate salt of Compound 1, preferably, the molar ratio of Compound 1 to succinic acid is 1:0.

75.

10. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical excipient is selected from one or more of a filler, a disintegrant, an adhesive, a glidant, and a lubricant.

11. 11. The pharmaceutical composition of claim 10, wherein the filler is selected from one or more of microcrystalline cellulose, mannitol, lactose, sucrose, sorbitol, dextran, pregelatinized starch, dibasic calcium phosphate, and starch.

12. The pharmaceutical composition according to claim 11, wherein the content of the filler is selected from the range of 10.0% to 90.0%, preferably selected from the range of 20.0% to 80.0%.

13. The pharmaceutical composition according to claim 11, wherein the filler is selected from a composition of microcrystalline cellulose and lactose, and the content thereof is selected from 10.0% to 90.0%, preferably selected from 20.0% to 80.0%, and the content ratio of microcrystalline cellulose to lactose is 2:1 to 1:3, preferably 1:1 to 1:

2.

14. The pharmaceutical composition according to claim 10, wherein the disintegrant is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, and calcium carboxymethyl cellulose, and the content thereof is selected from 1.0% to 10.0%, preferably selected from 3.0% to 8.0%.

15. The pharmaceutical composition according to claim 10, wherein the adhesive is selected from one or more of povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and methylcellulose, and the content thereof is selected from 1.0% to 10.0%, preferably selected from 2.0% to 8.0%.

16. 11. The pharmaceutical composition of claim 10, wherein the wetting agent is selected from one or two of water and ethanol.

17. The pharmaceutical composition according to claim 10, wherein the glidant is selected from one or more of talc, silica, fine particle silica gel, polyethylene glycol, and magnesium dodecyl sulfate, and the content thereof is selected from 0.1% to 3.0%.

18. The pharmaceutical composition according to claim 10, wherein the lubricant is selected from one or more of magnesium stearate, calcium stearate, stearic acid, and sodium stearyl fumarate, and the content thereof is selected from 0.1% to 3.0%.

19. 11. The pharmaceutical composition of claim 10, wherein the pharmaceutical excipient further comprises one or more of a flavoring agent, an antioxidant, a preservative, an opacifier, and a film coating premix.

20. Application of the pharmaceutical composition according to any one of claims 1 to 19 for the manufacture of a related medicament for treating kidney diseases.

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