Series of nitrogen-containing bridge heterocyclic compounds and preparation method thereof

Abstract

The invention discloses a series of nitrogen-containing bridge heterocyclic compounds and a preparation method thereof, and particularly discloses compounds shown in a formula (I) and pharmaceutically acceptable salts thereof. Specifically, the invention also relates to a preparation method of the compound, a pharmaceutical composition and application of the compound in treating inflammatory diseases. # imgabs0 #

Description

A series of nitrogen-bridged heterocyclic compounds and their preparation methods

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and benefits to Chinese invention patent application No. 202211064029.7 filed with the State Intellectual Property Office of China on August 29, 2022, Chinese invention patent application No. 202211231001.8 filed with the State Intellectual Property Office of China on October 9, 2022, and Chinese invention patent application No. 2023110663471 filed with the State Intellectual Property Office of China on August 22, 2023, and all the contents disclosed in said applications are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention relates to a series of nitrogen-bridged heterocyclic compounds and preparation methods thereof, and particularly to compounds represented by formula (I) and pharmaceutically acceptable salts thereof. Background Art

[0004] The complement system, composed of over 50 precisely regulated proteins, is a crucial component of the body's innate immunity and serves as a bridge between innate and adaptive immunity. The complement system is activated primarily through three pathways: the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP).

[0005] All three activation pathways are centered around the formation of C3 convertase and C5 convertase. By cleaving C3 and C5, they generate corresponding bioactive fragments, further amplifying the complement response. These fragments modify target surfaces and promote processes such as phagocytosis, inflammation, and immunomodulation. The process from contact with the activation initiator to the generation of C3 convertase (and subsequent cleavage of C3) can be considered the front-end reactions of these activation pathways. Although the front-end reactions of these activation pathways vary, they share a common terminal pathway: the generation of C5 convertase, which cleaves C5 to form the C5b fragment, which sequentially reacts with C6, C7, C8, and C9 to ultimately form the membrane attack complex (MAC), exerting a cytolytic effect.

[0006] Complement Factor B acts on the AP pathway. Inhibiting Factor B activity can prevent AP pathway activation without interfering with the CP and LP pathways, thereby reducing the risk of infection caused by increased complement system inhibition. Currently, there are no small molecule Factor B inhibitors on the market. Novartis' Factor B inhibitor LNP023 is in Phase III clinical trials for the treatment of diseases such as PNH, IgAN, and C3G. Therefore, it is necessary to develop new small molecule inhibitors of the complement system Factor B, increase clinical research and validation, and use them in the treatment of various diseases caused by complement abnormalities, providing new treatment options for unmet clinical needs.

[0007] Summary of the Invention

[0008] The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0009] in,

[0010] R1 is selected from H, D, F, Cl, Br, I, CN, OH, NH2, C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy groups are each independently optionally substituted with 1, 2 or 3 R a replace;

[0011] R2 is selected from H, D, F, Cl, Br, I, CN, OH, NH2, C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy groups are each independently optionally substituted with 1, 2 or 3 R b replace;

[0012] R3 is selected from H, D, F, Cl, Br, I, CN, OH, NH2, C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy groups are each independently optionally substituted with 1, 2 or 3 R c replace;

[0013] R4 is selected from C 1-6 Alkylthio, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, the C 1-6 Alkylthio, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6The cycloalkyl and 3-6 membered heterocyclic groups are each independently optionally substituted by 1, 2, 3 or 4 R d replace;

[0014] Each R5 is independently selected from D, F, Cl, Br, I, CN, OH, NH2, C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy groups are each independently optionally substituted with 1, 2 or 3 R e replace;

[0015] Each R a are independently selected from D, F, Cl, Br and I;

[0016] Each R b are independently selected from D, F, Cl, Br and I;

[0017] Each R c are independently selected from D, F, Cl, Br and I;

[0018] Each R d are independently selected from D, F, Cl, Br, I, CN, OH, NH2, C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy groups are each independently optionally substituted with 1, 2 or 3 R;

[0019] Each R e are independently selected from D, F, Cl, Br and I;

[0020] Each R is independently selected from D, F, Cl, Br and I;

[0021] m is selected from 0, 1, 2 and 3.

[0022] The present invention also provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0023] in,

[0024] R1 is selected from H, D, F, Cl, Br, I, CN, OH, NH2, C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy groups are each independently optionally substituted with 1, 2 or 3 R a replace;

[0025] R2 is selected from H, D, F, Cl, Br, I, CN, OH, NH2, C1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy groups are each independently optionally substituted with 1, 2 or 3 R b replace;

[0026] R3 is selected from H, D, F, Cl, Br, I, CN, OH, NH2, C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy groups are each independently optionally substituted with 1, 2 or 3 R c replace;

[0027] R4 is selected from C 1-6 Alkylthio, C 2-6 Alkenyl, C 2-6 Alkynyl and C 3-6 Cycloalkyl, the C 1-6 Alkylthio, C 2-6 Alkenyl, C 2-6 Alkynyl and C 3-6 Cycloalkyl is optionally substituted by 1, 2, 3 or 4 R d replace;

[0028] Each R5 is independently selected from H, D, F, Cl, Br, I, CN, OH, NH2, C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1- 3 alkoxy groups are each independently optionally substituted by 1, 2 or 3 R e replace;

[0029] Each R a are independently selected from D, F, Cl, Br and I;

[0030] Each R b are independently selected from D, F, Cl, Br and I;

[0031] Each R c are independently selected from D, F, Cl, Br and I;

[0032] Each R d Each independently selected from H, D, F, Cl, Br, I, CN, OH, NH2, C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1- 3 alkoxy groups are each independently optionally substituted with 1, 2 or 3 R;

[0033] Each Re are independently selected from D, F, Cl, Br and I;

[0034] Each R is independently selected from D, F, Cl, Br and I;

[0035] m is selected from 0, 1, 2 and 3.

[0036] In some embodiments of the present invention, the above R d are independently selected from D, F, Cl, CN, OH, NH2, C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy group is optionally substituted with 1, 2 or 3 R groups, each independently, and the other variables are as defined herein.

[0037] In some embodiments of the present invention, the above R d Each independently selected from F and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R groups, and the other variables are as defined herein.

[0038] In some embodiments of the present invention, the above R d are independently selected from F, methyl and ethyl, said methyl and ethyl being independently optionally substituted with 1, 2 or 3 R, and other variables are as defined herein.

[0039] In some embodiments of the present invention, the above R d are independently selected from F and methyl, and other variables are as defined in the present invention.

[0040] In some embodiments of the present invention, the above R d are independently selected from D, F and Cl, and other variables are as defined in the present invention.

[0041] In some embodiments of the present invention, the above R d are independently selected from F, and other variables are as defined in the present invention.

[0042] In some embodiments of the present invention, the above R d are independently selected from H and F, and other variables are as defined in the present invention. In some embodiments of the present invention, each of the above R a , each R b , each R c , each R e and each R is independently selected from D and F, and other variables are as defined in the present invention.

[0043] In some embodiments of the present invention, the above R a , each Rb , each R c , each R e and each R is independently selected from D, and other variables are as defined in the present invention.

[0044] In some embodiments of the present invention, the above R1 is selected from C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R a Replacement, R a and other variables are as defined in the present invention.

[0045] In some embodiments of the present invention, the above R1 is selected from CH3, and the CH3 is optionally replaced by 1, 2 or 3 R a Replacement, R a and other variables are as defined in the present invention.

[0046] In some embodiments of the present invention, the above R1 is selected from CH3 and CD3, and other variables are as defined in the present invention.

[0047] In some embodiments of the present invention, the above R1 is selected from CH3, and other variables are as defined in the present invention.

[0048] In some embodiments of the present invention, the above R2 is selected from C 1-3 Alkoxy, the C 1-3 The alkoxy group is optionally substituted with 1, 2 or 3 R b Replacement, R b and other variables are as defined in the present invention.

[0049] In some embodiments of the present invention, the above R2 is selected from OCH3, and the OCH3 is optionally replaced by 1, 2 or 3 R b Replacement, R b and other variables are as defined in the present invention.

[0050] In some embodiments of the present invention, the above R2 is selected from OCH3 and OCD3, and other variables are as defined in the present invention.

[0051] In some embodiments of the present invention, the above R2 is selected from OCH3, and other variables are as defined in the present invention.

[0052] In some embodiments of the present invention, the above R3 is selected from H, F and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R c Substitution, other variables are as defined in the present invention.

[0053] In some embodiments of the present invention, the above R3 is selected from H, F and CH3, and other variables are as defined in the present invention.

[0054] In some embodiments of the present invention, the above R3 is selected from H, and other variables are as defined in the present invention.

[0055] In some embodiments of the present invention, the above R4 is selected from C 1-6 Alkylthio, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl, the C 1-6 Alkylthio, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2, 3 or 4 R d Substitution, other variables are as defined in the present invention.

[0056] In some embodiments of the present invention, the above R4 is selected from C 1-6 Alkylthio, C 2-6 Alkenyl, C 2-6 Alkynyl and C 3-6 Cycloalkyl, the C 1-6 Alkylthio, C 2-6 Alkenyl, C 2-6 Alkynyl and C 3-6 The cycloalkyl groups are each independently optionally substituted with 1, 2, 3 or 4 R d Substitution, other variables are as defined in the present invention.

[0057] In some embodiments of the present invention, the above R4 is selected from C 1-3 Alkylthio, C 2-3 Alkenyl, C 2-3 Alkynyl and C 3-4 Cycloalkyl, the C 1-3 Alkylthio, C 2-3 Alkenyl, C 2-3 Alkynyl and C 3-4 The cycloalkyl groups are each independently optionally substituted with 1, 2, 3 or 4 R d Replacement, R d and other variables are as defined in the present invention.

[0058] In some embodiments of the present invention, the above R4 is selected from described are independently optionally replaced by 1, 2, 3 or 4 R d Replacement, R d and other variables are as defined in the present invention.

[0059] In some embodiments of the present invention, the above R4 is selected from Other variables are as defined in the present invention.

[0060] In some embodiments of the present invention, the above R4 is selected from described are independently optionally replaced by 1, 2, 3 or 4 R d Replacement, R d and other variables are as defined in the present invention.

[0061] In some embodiments of the present invention, the above R4 is selected from Other variables are as defined in the present invention.

[0062] In some embodiments of the present invention, the above R4 is selected from C 1-3 Alkylthio and C 3-6 Cycloalkyl, the C 1-3 Alkylthio and C 3-6 The cycloalkyl groups are each independently optionally substituted with 1, 2, 3 or 4 R d Substitution, other variables are as defined in the present invention.

[0063] In some embodiments of the present invention, the above R4 is selected from C 1-3 Alkylthio and C 3-4 Cycloalkyl, the C 1-3 Alkylthio and C 3-4 Cycloalkyl is optionally substituted by 1, 2, 3 or 4 R d Substitution, other variables are as defined in the present invention.

[0064] In some embodiments of the present invention, the above R4 is selected from C 3-4 Cycloalkyl, the C 3-4 The cycloalkyl group is optionally substituted with 1, 2, 3 or 4 R d Substitution, other variables are as defined in the present invention.

[0065] In some embodiments of the present invention, the above R4 is selected from described are independently optionally replaced by 1, 2, 3 or 4 R d Replacement, R d and other variables are as defined in the present invention.

[0066] In some embodiments of the present invention, the above R4 is selected from Other variables are as defined in the present invention.

[0067] In some embodiments of the present invention, the above R4 is selected from Other variables are as defined in the present invention.

[0068] In some embodiments of the present invention, the above R4 is selected from Other variables are as defined in the present invention.

[0069] In some embodiments of the present invention, the above R4 is selected from Other variables are as defined in the present invention.

[0070] In some embodiments of the present invention, the above R4 is selected from Other variables are as defined in the present invention.

[0071] In some embodiments of the present invention, each R5 is independently selected from F or C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R e Substitution, other variables are as defined in the present invention.

[0072] In some embodiments of the present invention, each R5 is independently selected from F, and other variables are as defined in the present invention.

[0073] In some embodiments of the present invention, each R5 is independently selected from H, and other variables are as defined in the present invention.

[0074] In some embodiments of the present invention, the above m is selected from 0, and other variables are as defined in the present invention.

[0075] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (P),

[0076] wherein R1, R2, R3 and R4 are as defined in the present invention.

[0077] In some embodiments of the present invention, the compound of formula (I) or formula (P) or a pharmaceutically acceptable salt thereof is selected from the compound of formula (P-1) or the compound of formula (P-2),

[0078] wherein R1, R2 and R4 are as defined in the present invention.

[0079] In some embodiments of the present invention, the above-mentioned formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound of formula (P), the compound of formula (P-1) or the compound of formula (P-2), wherein,

[0080] R1 is selected from C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R a replace;

[0081] R2 is selected from C 1-3 Alkoxy, the C 1-3 The alkoxy group is optionally substituted with 1, 2 or 3 R b replace;

[0082] R3 is selected from H;

[0083] R4 is selected from C 1-3 Alkylthio, C 2-3 Alkenyl, C 2-3 Alkynyl and C 3-4 Cycloalkyl, the C 1-3 Alkylthio, C 2-3 Alkenyl, C 2-3 Alkynyl and C 3-4 Cycloalkyl is optionally substituted by 1, 2, 3 or 4 R d replace;

[0084] Each R a are independently selected from D, F, Cl, Br and I;

[0085] Each R b are independently selected from D, F, Cl, Br and I;

[0086] Each R d are independently selected from D, F, Cl, Br, I, C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy groups are each independently optionally substituted with 1, 2 or 3 R;

[0087] Each R is independently selected from D, F, Cl, Br and I.

[0088] In some embodiments of the present invention, R4 in the compound of formula (P-1) or the compound of formula (P-2) is as defined above for the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0089] Some other solutions of the present invention are derived from any combination of the above variables.

[0090] The present invention also provides the following compounds or pharmaceutically acceptable salts thereof:

[0091] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,

[0092] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, and further comprising a pharmaceutically acceptable carrier.

[0093] The present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating diseases related to complement factor B.

[0094] The present invention also provides a method for treating diseases associated with complement factor B, comprising administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a mammal (preferably a human) in need of such treatment.

[0095] The present invention also provides use of the compound of the present invention or a pharmaceutically acceptable salt thereof in treating diseases related to complement factor B.

[0096] The present invention also provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in treating a disease associated with complement factor B.

[0097] In some embodiments of the present invention, the complement factor B-related disease is selected from inflammatory disorders and autoimmune diseases.

[0098] In some embodiments of the present invention, the pharmaceutically acceptable salt is selected from pharmaceutically acceptable acid addition salts.

[0099] In some embodiments of the present invention, the pharmaceutically acceptable salt is selected from pharmaceutically acceptable inorganic acid salts, organic acid salts and amino acid salts.

[0100] In some embodiments of the present invention, the pharmaceutically acceptable salt is selected from formates.

[0101] Stereoisomers and / or tautomers of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are also included in the scope of the present invention.

[0102] The present invention also provides a method for synthesizing the above-mentioned compound, and the synthetic route is as follows:

[0103] Synthesis Route 1:

[0104] Among them, R 4 As defined above.

[0105] In some embodiments of the present invention, R 4 Selected from

[0106] The present invention also provides a biological test method for the above compound:

[0107] Experimental test method 1: Wieslab complement alternative pathway activation inhibition (enzyme activity test)

[0108] Purpose of the experiment:

[0109] pass The complement system alternative pathway kit is used to determine the inhibitory activity of test compounds against the complement alternative pathway in human serum.

[0110] Experimental plan:

[0111] Dilute the serum with diluent (1:23). Add the drug to the diluted serum, with 8 concentration gradients, up to 10mM or 50mM, and 5-fold gradient dilution. Incubate at room temperature for 15 minutes. Add the compound and serum mixture to the 96-well plate provided by the kit (100μL / well) and activate at 37 degrees for 1 hour. Wash three times with wash buffer. Add the detection antibody provided by the kit (100μL) and incubate at room temperature for 30 minutes. Wash three times with wash buffer. Add the substrate (100μL) and incubate at room temperature for 30 minutes. Detect the absorbance at 405nM using an enzyme reader.

[0112] Conclusion: The compounds of the present invention have significant inhibitory activity on the activation of human serum bypass pathway.

[0113] Experimental test method 2: Complement human Factor B protein binding test (TR-FRET method)

[0114] Purpose of the experiment:

[0115] The TR-FRET method was used to determine the binding activity of test compounds to human complement factor B protein.

[0116] Experimental plan:

[0117] Drugs were added to phosphate-buffered saline (PBS) (pH 7.4) at a starting concentration of 10 μM and diluted fourfold to a total of 10 concentrations. Biotinylated Factor B (25 nM) was added to the sample in the absence or presence of varying concentrations of the test compound. Cy5-labeled probe (75 nM) and europium chelate-labeled streptavidin (Perkin Elmer #AD0060; 0.225 nM) were then incubated at room temperature for 2 hours. Time-resolved fluorescence energy transfer (TR-FRET) data were measured using an excitation wavelength of 330 nm and an emission wavelength of 665 nm.

[0118] Conclusion: The compounds of the present invention have significant binding activity to human complement Factor B protein.

[0119] Experimental Test Method 3: Pharmacokinetic Study in Rat

[0120] Purpose of the experiment:

[0121] Male SD rats were used as test animals, and the drug concentrations in the plasma of the rats at different time points after oral gavage of the compound of the present invention were determined by LC / MS / MS to study the pharmacokinetic behavior of the compound of the present invention in rats and evaluate its pharmacokinetic characteristics.

[0122] Test plan:

[0123] Healthy male rats weighing 200-300 g were used, with 2 rats in each group.

[0124] The compound of the present invention was prepared into a 1 mg / mL clear solution using an aqueous solution of 0.5% MC (4000 cP) / 0.5% Tween 80. The rats were fasted overnight and given the drug at a dose of 10 mg / kg by oral gavage. Blood was collected before and 0.25, 0.5, 1, 2, 4, 7, and 24 hours after administration. The blood was placed in a heparinized anticoagulant tube and centrifuged at 7000 rpm (5204 g) at 4°C to separate the plasma and store at -80°C. The rats were fed 4 hours after administration. The content of the test compound in the plasma of the rats after oral administration was determined by LC / MS / MS. The plasma samples were pretreated with precipitated proteins before analysis.

[0125] Conclusion: The compound of the present invention has good oral exposure and long half-life, and has excellent pharmacokinetic properties.

[0126] Experimental test method 4: LPS-induced complement activation in vivo PD model in mice

[0127] Purpose of the experiment:

[0128] The inhibitory effect of the compounds of the present invention on complement activation induced by LPS stimulation in mice was investigated.

[0129] Experimental animals:

[0130] Female C57BL / 6J mice, 7-9 weeks old, weighing 17-23 g; supplier: Shanghai Xipu-Bikai Laboratory Animal Co., Ltd.

[0131] Experimental process:

[0132] Four hours before administration, 100 μg of lipopolysaccharide (LPS) from Salmonella typhimurium (Sigma) was dissolved in 100 μL of sterile PBS (phosphate buffer pH 7.2-7.4) and injected intraperitoneally to induce complement activation in mice. Normal mouse group (negative control): Animals received an intraperitoneal injection of 100 μL of sterile PBS and were administered the vehicle alone by gavage (PO). Model group (positive control): Animals received intraperitoneal LPS and PO administration of the vehicle (20% PEG400 / 10% solutol / 70% water). Drug group: Samples were collected 4 hours after administration of the compound (vehicle: 20% PEG400 / 10% solutol / 70% water, administration volume: 5 mL / kg, dose: 10 mg / kg).

[0133] Sample Collection: 0.3 mL of blood was collected from the orbital venous plexus. All blood samples were placed in 1.5 mL commercial EDTA-K2 anticoagulant tubes (supplier: Jiangsu Kangjian Medical Supplies Co., Ltd.). Within half an hour of blood collection, the tubes were centrifuged at 3000 g for 10 minutes at 4°C. The supernatant plasma was aspirated, quickly placed on dry ice, and stored at -80°C for Western blot analysis of C3d protein levels downstream of complement activation.

[0134] Sample analysis: Mix mouse plasma (5 μL) + Lysis buffer (27.5 μL) + Loading buffer (12.5 μL) + Reducing buffer (5 μL) and incubate at 100°C for 15 min. The sample volume is 5 μL / well, i.e., the plasma sample volume per well is 0.5 μL.

[0135] Experimental conclusion: Compared with the normal group and the model group, the compound of the present invention can or can significantly inhibit LPS-stimulated complement activation.

[0136] Technical Effects

[0137] The compounds of the present invention have significant inhibitory activity against activation of the human serum bypass pathway and also have significant binding activity to human complement Factor B protein; they have moderate plasma protein binding rates in the plasma of various species, indicating that the free drug concentration ratio of the compounds of the present invention in the plasma of various species is moderate; they have good pharmacokinetic properties (such as AUC or F) and good metabolic stability in liver microsomes; the compounds have good permeability; they can significantly inhibit LPS-stimulated complement activation and can be developed into new small molecule inhibitors of the complement system Factor B.

[0138] Related definitions

[0139] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0140] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0141] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, which are prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases, having specific substituents. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the compounds with a sufficient amount of base in neat solution or a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the compounds with a sufficient amount of acid in neat solution or a suitable inert solvent. Certain specific compounds of the present invention contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0142] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two.

[0143] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0144] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0145] Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability to rotate freely about double bonds or single bonds forming ring carbon atoms.

[0146] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

[0147] Unless otherwise indicated, "(+)" indicates dextrorotatory, "(-)" indicates levorotatory, and "(±)" indicates racemic.

[0148] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed key Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond or straight dashed key

[0149] Unless otherwise indicated, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and can readily interconvert into each other. If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur via the reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Tautomers and mixtures thereof are encompassed within the scope of the present invention.

[0150] Unless otherwise indicated, the terms "enriched in one isomer", "isomerically enriched", "enriched in one enantiomer" or "enantiomerically enriched" mean that the content of one isomer or enantiomer is less than 100%, and the content of that isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0151] Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.

[0152] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C). For example, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of this invention.

[0153] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0154] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be any on the basis of chemical achievable.

[0155] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may optionally be substituted with up to two Rs, and each R has independent options. For example, if a group is substituted with 0 Rs, the group is unsubstituted. Furthermore, combinations of substituents and / or variants thereof are permitted only if such combinations result in stable compounds.

[0156] When the substituents listed do not specify through which atom they are connected to the substituted group, such substituents can be bonded through any atom thereof. For example, a pyridyl substituent can be connected to the substituted group through any carbon atom on the pyridine ring.

[0157] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds, and become a group with a corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. Straight dotted key or wavy lines For example, the straight solid bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups; The wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group; Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least In these four connection methods, even if an H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become a corresponding monovalent piperidine group.

[0158] When a variable (e.g., R) is substituted on one ring of a polycyclic ring system, unless otherwise specified, the variable (e.g., R) is designated as substituted on that ring and not on other rings of the polycyclic ring system, e.g., represents that ring A and ring B are fused together, substituent R1 is a substituent of ring A, and substituent R2 is a substituent of ring B, It means that the five-membered ring in the spirocyclic system is replaced by n Rs.

[0159] Unless otherwise specified, the term “C 1-3 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-6 Alkyl groups include C 1-2 and C 2-3 Alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-Examples of 3-alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0160] Unless otherwise specified, the term “C 1-3 "Alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule via an oxygen atom. The C 1-3 Alkoxy groups include C 1-2 、C 2-3 , C3 and C2 alkoxy, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0161] Unless otherwise specified, the term “C 1-6 "Alkylthio" refers to those alkyl groups containing 1 to 6 carbon atoms which are linked to the rest of the molecule via a sulfur atom. 1-6 Alkylthio includes C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6, C5, C4, C3 and C2 alkylthio, etc. 1-6 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, and the like.

[0162] Unless otherwise specified, the term “C 1-3 "Alkylthio" refers to those alkyl groups containing 1 to 3 carbon atoms which are linked to the rest of the molecule via a sulfur atom. 1-3 Alkylthio includes C 1-3 、C 1-2 and C3 alkylthio, etc. 1-3 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, and the like.

[0163] Unless otherwise specified, “C 2-6 "Alkenyl" is used to refer to a linear or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. 2-6 Alkenyl groups include C 2-4 、C 2-3 , C4, C3 and C2 alkenyl, etc.; which may be monovalent, divalent or polyvalent. 2-6 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, piperyl, hexadienyl, and the like.

[0164] Unless otherwise specified, “C 2-3 "Alkenyl" is used to refer to a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. 2-3 Alkenyl includes C3 and C2 alkenyl; the C 2-3 Alkenyl groups can be monovalent, divalent, or polyvalent. 2-3 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, and the like.

[0165] Unless otherwise specified, “C 2-6 "Alkynyl" is used to represent a linear or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. 2-6 Alkynyl groups include C 2-4 、C 2-3 , C4, C3 and C2 alkynyl, etc. It can be monovalent, divalent or polyvalent. 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.

[0166] Unless otherwise specified, “C 2-3 "Alkynyl" is used to represent a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. It may be monovalent, divalent or polyvalent. The C 2-3 Alkynyl groups include C3 and C2 alkynyl groups. 2-3 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, and the like.

[0167] Unless otherwise specified, “C 3-6 "Cycloalkyl" means a saturated monocyclic hydrocarbon group consisting of 3 to 6 carbon atoms, wherein the C 3-6 Cycloalkyl groups include C 3-4 、C 3-5 、C 4-5 、C 4-6 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0168] Unless otherwise specified, “C 3-4 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 4 carbon atoms, which is a monocyclic system. 3-4 Cycloalkyl groups include C3 and C4 cycloalkyl groups, etc.; they may be monovalent, divalent, or polyvalent. 3-4 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl and cyclobutyl.

[0169] Unless otherwise specified, the term "3-6 membered heterocyclyl" by itself or in combination with other terms means a saturated or partially unsaturated monocyclic ring group consisting of 3 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). In addition, with respect to the "3-6 membered heterocyclyl", a heteroatom may occupy the position at which the heterocyclyl is attached to the rest of the molecule. The 3-6 membered heterocyclyl includes 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocyclyls. Examples of 3-6 membered heterocyclic groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, wait.

[0170] Unless otherwise specified, "4-6 membered heterocycloalkyl" refers to a fully saturated 4-6 membered heterocycloalkyl. Such 4-6 membered heterocycloalkyl groups include 4-5 membered, 5-6 membered, 4 membered, 5 membered, and 6 membered heterocycloalkyl groups. Non-limiting examples of 4 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Examples of 5 membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl. Examples of 6 membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl.

[0171] Unless otherwise specified, C n-n+m or C n -C n+m Any specific case including n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 , and C 12 , also includes any range from n to n+m, such as C 1-12 Including C 1- 6. C 1-6、C 1-9 、C 3-6 、C 3-9 、C 3-12 、C 6-9 、C 6-12 , and C 9-12 Similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any range from n to n+m, for example, a 3-12-membered ring includes a 3-6-membered ring, a 3-9-membered ring, a 5-6-membered ring, a 5-7-membered ring, a 6-7-membered ring, a 6-8-membered ring, and a 6-10-membered ring, etc.

[0172] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0173] The structures of the compounds of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compounds, the absolute configuration can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data on the cultured single crystal using a Bruker D8 venture diffractometer, using CuKα radiation as the light source and scanning mode: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0174] The solvents used in the present invention can be obtained commercially. Software naming, commercially available compounds use supplier catalog names. BRIEF DESCRIPTION OF THE DRAWINGS

[0175] Figure 1: Experimental results of LPS-induced complement activation in the PD model in mice. DETAILED DESCRIPTION

[0176] The present invention is described in detail below by way of examples, but is not intended to limit the present invention in any way. While the present invention has been described in detail herein, and specific embodiments thereof have been disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0177] Reference Example 1: Synthesis of Intermediate Nc

[0178] first step

[0179] To a solution of compound Na (0.5 g, 3.10 mmol) in tetrahydrofuran (5 mL) at 15°C, di-tert-butyl dicarbonate (812.33 mg, 3.72 mmol) and N,N-diisopropylethylamine (37.89 mg, 310.17 μmol) were added. The reaction solution was stirred at 15°C for 1 hour. The reaction solution was added to water (15 mL) and stirred for 5 minutes. The liquid was separated, and the aqueous phase was extracted three times with ethyl acetate (20 mL). The combined organic layer was washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0:1 to 1:10) to obtain compound Nb. 1 H NMR (400MHz, CDCl3) δppm 7.54-7.48(m,1H),6.90-6.84(m,1H),6.77-6.70(m,1H),6.50-6.43(m,1H),3.9 0-3.77(m,3H),2.70-2.55(m,3H),1.66-1.61(m,9H); LC-MS: m / z=206.1[M-56+H] + .

[0180] Step 2

[0181] To a nitrogen-protected solution of N-methyl-N-formylaniline (459.93 mg, 3.40 mmol) in dichloromethane (2.7 mL) at 15°C was slowly added dropwise oxalyl chloride (431.90 mg, 3.40 mmol). After the addition was complete, the reaction solution was stirred at 15°C for 12 hours and then added dropwise to a -14°C solution of compound Nb (0.684 g, 2.62 mmol) in dichloromethane (2.8 mL). After the addition was complete, the reaction solution was stirred at -15°C for 1.5 hours. The reaction solution was poured into ice water (20 mL) and stirred for 5 minutes. The aqueous phase was extracted three times with ethyl acetate (20 mL). The combined organic phases were washed three times with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was isolated and purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0:1 to 1:10) to obtain compound Nc. 1H NMR(400MHz,DMSO-d6)δppm 10.61-10.41(m,1H),7.91-7.71(m,1H),7.38-7.21(m,1H),7.07-6.97(m,1H),3 .97-3.93(m,3H),2.63-2.59(m,3H),1.60-1.58(m,9H); LC-MS: m / z=290.1[M+H] + .

[0182] Reference Example 2: Synthesis of intermediate Mc

[0183] first step

[0184] Benzylamine (194.62 g, 1.82 mol) was slowly added to acetic acid (103.88 mL, 1.82 mol) in water (850 mL). The reaction system was cooled to 0-10°C, and 1,3-acetonedicarboxylic acid (265.36 g, 1.82 mol) was then slowly added in portions. The reaction solution was allowed to react at 0°C for 0.5 hours. A solution of compound Ma (170 g, 908.15 mmol) in dioxane (850 mL) was slowly added to the reaction system. The reaction solution was slowly allowed to return to room temperature and then reacted at 45°C for 12 hours. The reaction solution was cooled to room temperature and then extracted with ethyl acetate (500 mL x 2). The organic phases were combined and washed sequentially with saturated sodium bicarbonate (500 mL) and saturated sodium chloride solution (500 mL). After drying over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was stirred in a mixed solvent of n-heptane and methyl tert-butyl ether (1:1, 500 mL) for 0.5 h, and the solid was collected by filtration to obtain compound Mb. LC-MS: m / z = 317.1 [M+H] + .

[0185] Step 2

[0186] Compound Mb (220 g, 696.20 mmol) was dissolved in acetonitrile (1700 mL), then heated to 70°C and stirred for 2 hours. L-dibenzoyltartaric acid (200 g, 558.66 mmol) was slowly added with stirring. The reaction mixture was stirred at 70°C for another 2 hours, then slowly returned to 25°C and stirred for 12 hours. The solid was collected by filtration, and the filter cake was washed with acetonitrile (400 mL x 2). The filtered solid was added to 1000 mL of water, and the pH was adjusted to 8 with 1 M NaOH aqueous solution. The mixture was then extracted with ethyl acetate (2000 mL x 2). The organic phases were combined and washed with saturated brine (2000 mL x 2). The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield compound Mc (retention time: 2.175 min, ee = 99.1%). LC-MS: m / z = 317.1 [M+H] + SFC analysis method: chromatographic column: Chiralpak AD 50×4.6 mm ID, 3 μm, mobile phase: A: CO2, B: methanol (0.05% diethylamine), gradient B%: 5%-40%.

[0187] Example 1

[0188] first step

[0189] To a solution of compound Mc (30 g, 94.82 mmol) in methanol (150 mL) and acetonitrile (150 mL) at 0°C, sodium borohydride (3.95 g, 104.30 mmol) was added portionwise. The temperature was slowly raised to 20°C and stirred at 20°C for 2 hours. 1 M dilute hydrochloric acid was slowly added dropwise to the reaction mixture to quench the reaction until no bubbles formed. The pH was then adjusted to 7-8 with saturated sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate (500 mL x 2). The combined organic phases were washed with saturated brine (600 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Hydrochloric acid / ethyl acetate (4 M, 31.80 mL) was slowly added to a solution of the crude product (27 g, 84.80 mmol) in methyl tert-butyl ether (135 mL) at 25°C. Stirring was continued at 25°C for 2 hours. A solid precipitated, which was filtered and collected. Water (200 mL) and methyl tert-butyl ether (300 mL) were then added to the resulting solid, and the pH was adjusted to 7 to 8 with aqueous sodium hydroxide solution (4 M). The mixture was extracted with methyl tert-butyl ether (300 mL). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 1-1. LC-MS: m / z = 319.3 [M+H] + .

[0190] Step 2

[0191] Compound 1-1 (10 g, 31.41 mmol) and triethylamine (4.77 g, 47.11 mmol) were dissolved in dichloromethane (100 mL). The temperature was lowered to -20°C, and methylsulfonyl chloride (5.32 g, 46.48 mmol) was slowly added dropwise. The reaction mixture was stirred at -20°C for 1 hour. The reaction was quenched by the slow addition of 200 mL of water at -20°C. Dichloromethane (250 mL x 2) was then added for extraction. The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:10 to 1:3) to obtain compound 1-2. LC-MS: m / z = 397.1 [M+H] + .

[0192] Step 3

[0193] Ethanethiol (8.94 g, 143.82 mmol) was dissolved in tetrahydrofuran (60 mL), and sodium hydride (6.14 g, 127.84 mmol, 50% purity) was added under nitrogen. The reaction mixture was stirred at 20°C for 0.5 hours. Compound 1-2 (6.4 g, 15.98 mmol) in N,N-dimethylformamide (60 mL) was then slowly added to the reaction mixture. The reaction mixture was stirred at 70°C for 2 hours. The reaction mixture was quenched by adding 100 mL of saturated aqueous ammonium chloride at 0°C, followed by dilution with 100 mL of water. Ethyl acetate (500 mL x 2) was added for extraction. The organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:20 to 1:8) to yield compound 1-3. LC-MS: m / z=363.1[M+H] + .

[0194] Step 4

[0195] Compound 1-3 (1.5 g, 4.14 mmol) was dissolved in tert-butanol (25 mL), potassium tert-butoxide (1.39 g, 12.41 mmol) was added, and the reaction solution was stirred at 70°C for 0.5 hours. The reaction solution was cooled to 20°C, diluted with 100 mL of water, and extracted with ethyl acetate (200 mL*2). The organic phases were combined, washed with saturated brine (100 mL*2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 1-4. LC-MS: m / z = 381.1 [M+H] + .

[0196] Step 5

[0197] Compound 1-4 (1.5 g, 3.94 mmol) was dissolved in methanol (30 mL), and N,N-dimethylformamide dimethyl acetal (1.41 g, 11.83 mmol) was added. The reaction solution was stirred at 70°C for 12 hours. The reaction solution was cooled to 20°C, diluted with 100 mL of water, and extracted with ethyl acetate (200 mL*2). The organic phases were combined and washed with saturated brine (100 mL*2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 1-5. LC-MS: m / z = 396.3 [M+H] + .

[0198] Step 6

[0199] Compound 1-5 (1.0 g, 2.53 mmol) was dissolved in methanol (30 mL). Concentrated hydrochloric acid (614.51 mg, 5.06 mmol, 37% purity) and wet palladium on carbon (3 g, 10% purity) were added sequentially under nitrogen. The atmosphere was replaced with hydrogen three times. The mixture was stirred at 50°C under a hydrogen atmosphere for 2 hours. The reaction mixture was cooled to 20°C, filtered, and the filtrate was concentrated to obtain compound 1-6. LC-MS: m / z = 306.1 [M+H] + .

[0200] Step 7

[0201] Compound 1-6 (400 mg, 1.31 mmol) and compound Nc (341.01 mg, 1.18 mmol) were dissolved in 1,4-dioxane (10 mL). Pyridine (124.31 mg, 1.57 mmol) and boron trifluoride etherate (223.05 mg, 1.57 mmol) were added sequentially. Polymethylsiloxane (787.43 mg, 13.10 mmol) was then added. The reaction mixture was stirred at 100°C under nitrogen for 12 hours. The reaction mixture was cooled to 20°C and diluted with 100 mL of water. Ethyl acetate (200 mL x 2) was added for extraction. The organic phases were combined, washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:20 to 1:5) to obtain compound 1-7. LC-MS: m / z = 579.3 [M+H] + .

[0202] Step 8

[0203] To a solution of compound 1-7 (450 mg, 777.52 μmol) in tetrahydrofuran (5 mL) and methanol (5 mL) was added aqueous lithium hydroxide solution (4 M, 1.94 mL), and the mixture was stirred at 50°C for 2 hours. The reaction mixture was concentrated, and the pH of the residue was adjusted to 7 with acetic acid, followed by concentration under reduced pressure. The residue was purified by high-performance liquid chromatography (column: Phenomenex C18 150 × 40 mm × 15 μm; mobile phase: A: water (0.225% formic acid), B: acetonitrile, method B: 16%-46%) to afford the formate salts of compound 1A and compound 1B.

[0204] Characterization of the formate salt of compound 1A: (retention time: 1.692 min, HPLC analysis method: chromatographic column: Kinetex EVO C18 50×4.6 mm, 5 μm, mobile phase: A: water (0.0375% trifluoroacetic acid), B: acetonitrile (0.01875% trifluoroacetic acid), gradient B%: 10%-80%), 1 H NMR(400MHz,DMSO-d6)δppm 10.83(br s,1H),8.18(s,1H),7.98(d,J=8.4Hz,2H),7.74(d,J=8.4Hz,2H),7.27(t,J=2.8Hz,1H),6.67(s,1H),6.47(d,J=2.6Hz,1H),3.78(br d,J=12.2Hz,1H),3.73(s,3H),3.22-3.11(m,3H),2.59(q,J=7.4Hz,2H),2.43(s,3H),2.19-1.94(m,5H),1.85(br s,1H),1.64(br d, J=7.3Hz, 1H), 1.55-1.47 (m, 1H), 1.20 (t, J=7.4Hz, 3H); LC-MS: m / z=465.2[M+H] + .

[0205] Characterization of the formate salt of compound 1B: (retention time: 1.779 min, HPLC analysis method: chromatographic column: Kinetex EVO C18 50×4.6 mm, 5 μm, mobile phase: A: water (0.0375% trifluoroacetic acid), B: acetonitrile (0.01875% trifluoroacetic acid), gradient B%: 10%-80%), 1H NMR(400MHz,DMSO-d6)δppm 10.87(br s,1H),8.19(s,1H),7.99(d,J=8.4Hz,2H),7.79(d,J=8.4Hz,2H),7.28(t,J=2.8Hz,1H),6.68(s,1H),6.51(d,J=2.6Hz,1H),3.79(br d,J=12.2Hz,1H),3.76(s,3H),3.21-3.19(m,3H),2.61(q,J=7.4Hz,2H),2.47(s,3H),2.19-1.95(m,5H),1.88(br s,1H),1.66(br d, J=7.3Hz, 1H), 1.56-1.43 (m, 1H), 1.22 (t, J=7.4Hz, 3H); LC-MS: m / z=465.2[M+H] + .

[0206] The retention time of compound 1A in the chiral chromatographic column is shorter than that of compound 1B, while the retention time of compound 1B in the chiral chromatographic column is longer than that of compound 1A.

[0207] Example 2

[0208] first step

[0209] To a solution of compound 1-2 (2 g, 5.04 mmol) in N,N-dimethylformamide (30 mL) at room temperature, sodium thiomethoxide (1.41 g, 20.18 mmol) was added and the mixture was heated to 50°C and allowed to react for 16 hours. The reaction solution was cooled to room temperature, 100 mL of water was added, and then extracted with ethyl acetate (50 mL*3), washed with saturated brine (60 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:10) to obtain compound 2-1. LC-MS: m / z = 349.3 [M+H] + .

[0210] Step 2

[0211] Potassium tert-butoxide (1.39 g, 12.40 mmol) was added to a solution of compound 2-1 (1.44 g, 4.13 mmol) in tert-butanol (20 mL) at room temperature, and the temperature was raised to 50°C and the reaction was allowed to proceed for 4 hours. The reaction solution was cooled to room temperature, diluted with 20 mL of water, and then extracted with ethyl acetate (50 mL*3). The organic phases were combined and washed with saturated brine (50 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 2-2. LC-MS: m / z = 367.3 [M+H] + .

[0212] Step 3

[0213] To a methanol solution (20 mL) of compound 2-2 (1 g, 2.73 mmol), N,N-dimethylformamide dimethyl acetal (975.35 mg, 8.19 mmol) was added and the mixture was heated to 50°C for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:10) to obtain compound 2-3. LC-MS: m / z = 382.3 [M+H] + .

[0214] Step 4

[0215] Under nitrogen, wet palladium on carbon (1 g, 10% purity) and concentrated hydrochloric acid (254.84 mg, 2.10 mmol, 37% purity) were added to a solution of compound 2-3 (0.8 g, 2.10 mmol) in methanol (10 mL). The atmosphere was replaced with hydrogen three times and the mixture was allowed to react at 60°C for 6 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to obtain compound 2-4. LC-MS: m / z = 292.4 [M+H] + .

[0216] Step 5

[0217] To a solution of compound 2-4 (300 mg, 1.03 mmol) in 1,4-dioxane (3 mL) were added Nc (357.43 mg, 1.24 mmol), pyridine (97.72 mg, 1.24 mmol), boron trifluoride etherate (175.34 mg, 1.24 mmol), and polymethylsiloxane (619.03 mg, 10.29 mmol) at room temperature. The mixture was heated to 100°C and allowed to react for 16 hours. After cooling to room temperature, the reaction mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was washed sequentially with citric acid (1 mL x 2), saturated sodium bicarbonate (1 mL x 2), and saturated brine (1 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was isolated and purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:10) to obtain compound 2-5. LC-MS: m / z = 565.4 [M+H] + .

[0218] Step 6

[0219] To a solution of compound 2-5 (0.37 g, 655.18 μmol) in methanol (3 mL) and tetrahydrofuran (3 mL) was added aqueous lithium hydroxide (4 M, 3 mL) and stirred at 50°C for 3 hours. After completion of the reaction, the mixture was cooled to room temperature, the pH was adjusted to approximately 7 by adding acetic acid, and the residue was concentrated to obtain a residue. The residue was purified by HPLC (column: Phenomenex luna C18 250×80 mm, 10 μm; mobile phase: A: water (0.225% formic acid); B: acetonitrile; Method B: 30%-60%) to obtain the formate salts of compound 2A and compound 2B.

[0220] Characterization of the formate salt of compound 2A: (Retention time: 1.612 min, HPLC analysis method: chromatographic column: Kinetex EVO C18 50×4.6 mm, 5 μm, mobile phase: A: water (0.0375% trifluoroacetic acid), B: acetonitrile (0.01875% trifluoroacetic acid), gradient B%: 10%-80%), 1 H NMR(400MHz,DMSO-d6)δppm 10.89-10.71(m,1H),8.03-7.88(m,2H),7.80-7.67(m,2H),7.29-7.20(m,1H),6.69-6. 58(m,1H),6.50-6.39(m,1H),3.82-3.74(m,1H),3.73-3.67(m,3H),3.18-3.11(m,2H),3 .10-2.97(m,2H),2.43-2.37(m,3H),2.13-2.08(m,2H),2.08-2.06(m,3H),2.05-1.97( m,3H),1.92-1.76(m,1H),1.71-1.52(m,1H),1.52-1.37(m,1H); LC-MS: m / z=451.3[M+H] + .

[0221] Characterization of the formate salt of compound 2B: (Retention time: 1.677 min, HPLC analysis method: chromatographic column: Kinetex EVO C18 50×4.6 mm, 5 μm, mobile phase: A: water (0.0375% trifluoroacetic acid), B: acetonitrile (0.01875% trifluoroacetic acid), gradient B%: 10%-80%), 1H NMR(400MHz,DMSO-d6)δppm 10.90-10.68(m,1H),8.15-8.07(m,1H),7.99-7.87(m,2H),7.79-7.67(m,2H),7.30-7 .17(m,1H),6.72-6.59(m,1H),6.52-6.40(m,1H),3.78-3.70(m,1H),3.70-3.66(m,3H ),3.22-3.13(m,3H),3.14-3.03(m,2H),2.41-2.36(m,3H),2.35-2.23(m,1H),2.18-2 .08(m,2H),2.07(s,3H),2.02-1.89(m,2H),1.50-1.36(m,1H); LC-MS: m / z=451.3[M+H] + .

[0222] The retention time of compound 2A in the chiral chromatographic column is shorter than that of compound 2B, while the retention time of compound 2B in the chiral chromatographic column is longer than that of compound 2A.

[0223] Example 3

[0224] first step

[0225] Potassium tert-butoxide (1.84 g, 16.44 mmol) was added to a solution of compound Mc (2 g, 6.32 mmol) and (3-bromopropyl)triphenylphosphonium bromide (3.81 g, 8.22 mmol) in tetrahydrofuran (30 mL) at room temperature. The temperature was raised to 50°C and the reaction was allowed to proceed under nitrogen for 16 hours. After the reaction, the reaction solution was cooled to room temperature and 100 mL of water was added. The solution was then extracted with ethyl acetate (100 mL), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was isolated and purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0:1 to 1:15) to obtain compound 3-1. LC-MS: m / z = 341.2 [M+H] + .

[0226] Step 2

[0227] To a solution of compound 3-1 (1 g, 2.94 mmol) in N,N-dimethylformamide (10 mL) at room temperature was added benzenesulfonylhydrazide (1.52 g, 8.81 mmol), and the temperature was raised to 100°C for 3 hours. The reaction solution was cooled to room temperature, diluted with 50 mL of water, and then extracted with ethyl acetate (50 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was isolated and purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0:1 to 1:10) to obtain compound 3-2. LC-MS: m / z = 343.4 [M+H] + .

[0228] Step 3

[0229] To a solution of compound 3-2 (0.62 g, 1.81 mmol) in dimethyl sulfoxide (5 mL) at room temperature were added potassium carbonate (275.22 mg, 1.99 mmol) and hydrogen peroxide (307.89 mg, 2.72 mmol, 30% aqueous solution). The mixture was heated to 40°C and reacted for 5 hours. The reaction solution was cooled to room temperature and added to 20 mL of water. Solid precipitated, which was collected by filtration and dried to obtain compound 3-3. LC-MS: m / z = 361.4 [M+H] + .

[0230] Step 4

[0231] To a solution of compound 3-3 (0.62 g, 1.72 mmol) in methanol (25 mL) was added N,N-dimethylformamide dimethyl acetal (614.83 mg, 5.16 mmol), and the temperature was raised to 60°C for 16 hours. The reaction solution was cooled to room temperature, diluted with 30 mL of water, and then extracted with ethyl acetate (30 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 3-4. LC-MS: m / z = 376.4 [M+H] + .

[0232] Step 5

[0233] Under nitrogen protection, wet palladium carbon (0.6 g, 10% purity) and concentrated hydrochloric acid (266.31 μL, 37% purity) were added to a solution of compound 3-4 (0.6 g, 1.60 mmol) in methanol (15 mL). The mixture was replaced with hydrogen three times and reacted at 50°C under a hydrogen atmosphere for 3 hours. The reaction solution was cooled to room temperature and filtered, and the filtrate was concentrated. Ethyl acetate (15 mL) was added to the residue for dilution, the pH was adjusted to 9 with saturated sodium bicarbonate, and ethyl acetate (15 mL) was added for extraction. The mixture was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 3-5. LC-MS: m / z = 286.4 [M+H] + .

[0234] Step 6

[0235] To a solution of compound 3-5 (0.29 g, 1.02 mmol) in 1,4-dioxane (5 mL) were added compound Nc (382.21 mg, 1.32 mmol), pyridine (96.46 mg, 1.22 mmol), boron trifluoride etherate (173.07 mg, 1.22 mmol), and polymethylsiloxane (609.71 mg, 10.16 mmol) at room temperature. The mixture was heated to 90°C and reacted for 16 hours. The mixture was cooled to room temperature and diluted with 20 mL of water. The mixture was then extracted with ethyl acetate (20 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was isolated and purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:20 to 1:5) to obtain compound 3-6. LC-MS: m / z = 559.3 [M+H] + .

[0236] Step 7

[0237] To a solution of compound 3-6 (0.51 g, 912.82 μmol) in methanol (5 mL) and tetrahydrofuran (5 mL) was added aqueous lithium hydroxide solution (4 M, 5 mL) and stirred at 50°C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, the pH was adjusted to approximately 7 by adding acetic acid, and the residue was concentrated to obtain a residue. The residue was purified by HPLC (column: Phenomenex luna C18 250×50 mm, 10 μm; mobile phase: A: water (0.225% formic acid); B: acetonitrile; method B: 25%-40%) to obtain compound 3. LC-MS: m / z = 445.3 [M+H] + .

[0238] Step 8

[0239] Compound 3 was separated using a chiral column (chromatographic column: Daicel ChiralPak IC 250×30 mm, 10 μm, mobile phase: A: carbon dioxide, B: isopropanol (0.1% ammonia water), mobile phase: B: 40%-40%) to give Compound 3A and Compound 3B.

[0240] Characterization of compound 3A: (retention time: 4.007 min, ee = 100%, SFC analysis method: chromatographic column: Chiralpak IC-3 50×4.6 mm ID, 3 μm, mobile phase: A: carbon dioxide, B: 40% methanol + 60% acetonitrile (0.05% diethylamine), gradient B%: 0%-40%), 1 H NMR(400MHz,DMSO-d6)δppm 10.81(s,1H),7.98-7.96(d,J=8.0Hz,2H),7.76-7.74(d,J=8.0Hz,2H),7.36-7.16(m,1H ),6.71-6.63(m,1H),6.55-6.50(m,1H),3.80-3.74(m,4H),3.49-3.41(m,2H),3.23-3.14 (m,3H),2.42(s,3H),2.19-1.94(m,2H),1.68-1.58(m,1H),1.55-1.46(m,1H),1.32-1.18 (m,2H),0.68-0.50(m,1H),0.39-0.26(m,2H),0.15-0.05(m,2H); LC-MS: m / z=445.3[M+H] + .

[0241] Compound 3B characterization: (retention time: 4.505 min, ee = 100%, SFC analysis method: chromatographic column: Chiralpak IC-3 50×4.6 mm ID, 3 μm, mobile phase: A: carbon dioxide, B: 40% methanol + 60% acetonitrile (0.05% diethylamine), gradient B%: 0%-40%), 1H NMR(400MHz,DMSO-d6)δppm 10.82(s,1H),8.01-7.88(d,J=8.0Hz,2H),7.79-7.68(d,J=8.0Hz,2H),7.31-7.21( m,1H),6.70-6.62(m,1H),6.59-6.52(m,1H),3.81-3.73(m,4H),3.49-3.41(m,2H),3 .23-3.14(m,3H),2.43(s,3H),2.33-2.06(m,2H),1.89-1.76(m,2H),1.34-1.17(m,2 H),0.99-0.90(m,1H),0.48-0.37(m,2H),0.04-0.06(m,2H); LC-MS: m / z=445.3[M+H] + .

[0242] The retention time of compound 3A in the chiral chromatographic column is shorter than that of compound 3B, while the retention time of compound 3B in the chiral chromatographic column is longer than that of compound 3A.

[0243] Biological testing section

[0244] Experimental Example 1: Complement Human Factor B Protein Binding Assay (Surface Plasmon Resonance (SPR) Method)

[0245] Experimental purpose: To detect the kinetic constant and affinity of the binding between the test compound and human complement factor B using the SPR method.

[0246] Experimental plan:

[0247] A 1:1 mixture of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and sodium N-hydroxysulfosuccinimide (NHS) was used. Complement factor B was diluted to 20 μg / ml in acetic acid (pH 5.5). Using a Biacore 8K biomolecular interaction analyzer, the EDC / NHS solution, the FB protein solution, and a 1M ethanolamine-HCl solution were added to the assay plate according to the program settings. The assay plate was placed in the instrument's detection chamber, and the EDC / NHS mixture, the FB protein solution, and the 1M ethanolamine-HCl solution were sequentially injected onto the CM5 chip surface according to the program for chip activation, ligand coupling, and deactivation. Flow cell 1 in each channel served as a reference channel for surface activation and deactivation only, without injection of the FB protein solution. All sample stock solutions were diluted with running buffer (PBST), and all samples were serially diluted two-fold in duplicate for six points. Prepared samples were transferred to the assay plate according to the protocol settings and placed in the sample compartment of the Biacore 8K. The assay program was run, and samples were sequentially injected into each channel of the chip, with an association time of 120 s, a dissociation time of 600 s, and a flow rate of 30 μL / min. Data were analyzed using Biacore Insight Evaluation Software. The data were fitted using a 1:1 Binding Kinetics model to determine the association rate constant (k), dissociation rate constant (koff), and dissociation equilibrium constant (KD) for each test sample binding to complement factor B protein.

[0248] Experimental results:

[0249] The binding activity of the test compounds to human complement factor B protein is shown in Table 1. Where A represents: IC 50 Value < 100nM; B represents: 100nM ≤ IC 50 Value ≤ 1000nM; C represents: IC 50 Value>1000nM.

[0250] Table 1: Results of in vitro human complement factor B protein binding activity screening test of the compounds of the present invention

[0251] Conclusion: The compounds of the present invention have significant binding activity to human complement Factor B protein.

[0252] Experimental Example 2: LPS-induced complement activation in PD mouse model

[0253] Experimental purpose: To investigate the inhibitory effect of the compounds of the present invention on complement activation induced by LPS stimulation in mice.

[0254] Experimental animals: female C57BL / 6J mice, 7-9 weeks old, weighing 17-23 g; supplier: Shanghai Xipu-Bikai Laboratory Animal Co., Ltd.

[0255] Experimental process:

[0256] Four hours before administration, 100 μg of lipopolysaccharide (LPS) in Escherichia coli (Sigma, L2880) was dissolved in 100 μL of sterile PBS (phosphate buffer pH 7.2-7.4) and injected intraperitoneally to induce complement activation in mice. Normal mouse group (negative control): animals received an intraperitoneal injection of 100 μL of sterile PBS and were administered the vehicle alone by gavage (IO). Model group (positive control): animals received intraperitoneal LPS and PO administration of the vehicle (20% PEG400 / 10% solutol / 70% water). Drug group: 4 hours after administration of the compound (vehicle: 20% PEG400 / 10% solutol / 70% water, administration volume: 5 mL / kg, dose: 10 mg / kg), samples were collected.

[0257] Sample Collection: 0.3 mL of blood was collected from the orbital venous plexus. All blood samples were placed in 1.5 mL commercial EDTA-K2 anticoagulant tubes (supplier: Jiangsu Kangjian Medical Supplies Co., Ltd.). Within half an hour of blood collection, the tubes were centrifuged at 3000 g for 10 minutes at 4°C. The supernatant plasma was aspirated, quickly placed on dry ice, and stored at -80°C for Western blot analysis of C3d protein levels downstream of complement activation.

[0258] Sample analysis: Mouse plasma (5 μL) + Lysis buffer (27.5 μL) + Loading buffer (12.5 μL) + Reducing buffer (5 μL) were mixed and incubated at 100°C for 15 minutes. The sample volume was 5 μL / well, that is, the plasma sample volume per well was 0.5 μL. Experimental results:

[0259] After inducing complement activation in mice by intraperitoneal injection, the C3d protein level in the serum of the model group mice increased by 60% to 90% compared with the normal group. After oral administration of the compound of the present invention, the C3d protein level in the serum of the mice in each drug group decreased by 70% to 90% relative to the modeling group, and the C3d protein level decreased significantly. The specific experimental results are shown in Figure 1.

[0260] Experimental conclusion: Compared with the normal group and the model group, the compound of the present invention can significantly inhibit LPS-stimulated complement activation.

[0261] Experimental Example 3 Plasma protein binding test of the compound

[0262] Experimental purpose: Equilibrium dialysis was used to evaluate the protein binding of the compounds of the present invention in the plasma of CD-1 mice, SD rats, beagle dogs, cynomolgus monkeys and humans.

[0263] Test plan:

[0264] The test compound was diluted with dialysis buffer into the plasma of the five species mentioned above to a final concentration of 2 μM. The sample was then added to a 96-well equilibrium dialysis apparatus and dialyzed against phosphate buffer at 37°C for 4 hours. Warfarin was used as a control compound. The concentrations of the test compound and warfarin in the plasma and buffer were determined by LC-MS / MS. The free rate of the compound was calculated using the following formula: PPB_Unbound (%) = 100*F C / T C , where F C is the concentration of the compound at the buffer end of the dialysis plate; T C is the concentration of the compound at the plasma end of the dialysis plate; T0 is the concentration of the compound in the plasma sample at time zero. The experimental results are shown in Table 2.

[0265] Table 2 Plasma protein binding results of the compounds of the present invention

[0266] Conclusion: The compounds of the present invention have moderate plasma protein binding rates in the plasma of various species, indicating that the free drug concentration ratio of the compounds of the present invention in the plasma of the above-mentioned various species is moderate and has good drug-forming properties.

[0267] Experimental Example 4: In vitro liver microsome stability test of compounds

[0268] Experimental Materials

[0269] Liver microsomes: purchased from Corning or Xenotech, stored in a -80°C freezer; reduced nicotinamide adenine dinucleotide phosphate (NADPH), supplier: Chem-impex international, product number: 00616; control compounds: testosterone, diclofenac, propafenone.

[0270] Experimental procedures

[0271] (1) Preparation of working fluid

[0272] Stock solution: 10 mM DMSO solution; working concentration preparation: diluted to 100 μM in 100% acetonitrile (organic phase content: 99% acetonitrile, 1% DMSO).

[0273] (2) Experimental steps

[0274] Prepare two 96-well incubation plates, named T60 incubation plate and NCF60 incubation plate respectively.

[0275] 445 μL of microsomal working solution (liver microsomal protein concentration is 0.56 mg / mL) was added to the T60 incubation plate and the NCF60 incubation plate, respectively, and then the above incubation plates were placed in a 37° C. water bath for pre-incubation for about 10 minutes.

[0276] After the preincubation period, 5 μL of the test or control compound working solution was added to each well of the T60 and NCF60 plates and mixed thoroughly. The reaction was initiated by adding 50 μL of potassium phosphate buffer to each well of the NCF60 plate. To the T0 stop plate, 180 μL of stop solution (containing 200 ng / mL tolbutamide and 200 ng / mL labetalol in acetonitrile) and 6 μL of NADPH regeneration system working solution were added. A 54 μL sample was removed from the T60 plate and transferred to the T0 stop plate (T0 sample generation). To initiate the reaction, 44 μL of NADPH regeneration system working solution was added to each well of the T60 plate. To the blank plate, only 54 μL of microsome working solution, 6 μL of NADPH regeneration system working solution, and 180 μL of stop solution were added. Therefore, in the sample of the test or control compound, the final reaction concentration of the compound, testosterone, diclofenac and propafenone was 1 μM, the concentration of liver microsomes was 0.5 mg / mL, and the final concentrations of DMSO and acetonitrile in the reaction system were 0.01% (v / v) and 0.99% (v / v), respectively.

[0277] After incubation for an appropriate time (e.g., 5, 15, 30, 45, and 60 minutes), 180 μL of stop solution (containing 200 ng / mL tolbutamide and 200 ng / mL labetalol in acetonitrile) was added to each sample well of the stop plate, and then 60 μL of sample was removed from the T60 incubation plate to terminate the reaction.

[0278] All samples were shaken and centrifuged at 3220 × g for 20 minutes. 80 μL of supernatant from each well was then diluted into 240 μL of pure water for analysis by liquid chromatography-tandem mass spectrometry. The results are shown in Table 3.

[0279] Table 3: Results of liver microsomal stability test of compounds of the present invention

[0280] Conclusion: The compounds of the present invention showed good metabolic stability in the human liver microsome test.

[0281] Experimental Example 5: Pharmacokinetic Evaluation in Mice

[0282] The test compound was mixed with 5% DMSO / 10% polyethylene glycol-15-hydroxystearate / 85% water, vortexed, and sonicated to prepare a 0.2 mg / mL clear solution, which was then filtered through a microporous filter and used for later use. Male Balb / c mice weighing 18 to 20 grams were administered intravenously with a 1 mg / kg dose of the candidate compound solution and orally with a 10 mg / kg dose of the test compound solution. Whole blood was collected at specific times to prepare plasma, and drug concentrations were analyzed by LC-MS / MS. Pharmacokinetic parameters (C0: required concentration immediately after intravenous injection; C: required concentration immediately after intravenous injection) were calculated using Phoenix WinNonlin software (Pharsight, USA). max : the highest blood drug concentration after administration; T max T: the time required to reach the peak drug concentration after administration; 1 / 2 : the time required for the blood drug concentration to drop by half; V dss : Apparent distribution volume, which refers to the proportional constant between the amount of drug in the body and the blood concentration when the drug reaches dynamic equilibrium in the body. Cl: Clearance, which refers to the apparent distribution volume of the drug cleared from the body per unit time; AUC 0-last : Area under the drug-time curve, which refers to the area enclosed by the blood drug concentration curve relative to the time axis; F: bioavailability).

[0283] The compounds of the present invention exhibit a longer half-life and a higher drug exposure, and have good in vivo pharmacokinetic properties.

[0284] Experimental Example 6: Pharmacokinetic Study in Rats

[0285] Male SD rats (6-8 weeks old, weighing 200-300 g) were selected.

[0286] For injection (IV), the dose is 1 mpk, the concentration is 0.20 mg / mL, and the solvent is 20% PEG400 / 10% solutol / 70% water; for oral administration (PO), the dose is 10 mpk, the concentration is 1 mg / mL, and the solvent is 20% PEG400 / 10% solutol / 70% water.

[0287] Sample Collection: 0.03 mL of blood was collected from the experimental animals via saphenous vein puncture at each time point, and the actual time of blood collection was recorded. All blood samples were placed in 1.5 mL commercial EDTA-K2 anticoagulant tubes. After blood sample collection, DDV was added to the plasma matrix as a stabilizer, with a plasma:DDV solution ratio of 40:1 (40 mM DDV in acetonitrile / water (1:1)). Within half an hour, the samples were centrifuged at 3000 g for 10 minutes at 4°C. The supernatant plasma was aspirated, immediately placed on dry ice, and stored at -80°C for LC-MS / MS analysis.

[0288] The plasma concentration was processed using a non-compartmental model in Phoenix WinNonlin 6.3 pharmacokinetic software, and the pharmacokinetic parameters were calculated using the linear logarithmic trapezoidal method. C0: instantaneous required concentration after intravenous injection; C max : the highest blood drug concentration after administration; T max : time required to reach peak drug concentration after administration; T 1 / 2 : the time required for the blood drug concentration to drop by half; V dss : Apparent distribution volume, which refers to the proportional constant between the amount of drug in the body and the blood concentration when the drug reaches dynamic equilibrium in the body. Cl: Clearance, which refers to the apparent distribution volume of the drug cleared from the body per unit time; AUC 0- last : Area under the drug-time curve, which refers to the area enclosed by the blood drug concentration curve relative to the time axis; F: Bioavailability. The experimental results are shown in Table 4.

[0289] Table 4 PK results of the compounds of the present invention in rats

[0290] “--” means not tested or data not available.

[0291] Experimental conclusion: The compound of the present invention exhibits a long half-life and a high oral plasma exposure, and has good pharmacokinetic properties.

[0292] Experimental Example 7: In vitro Caco-2 cell permeability test

[0293] Cell culture:

[0294] Cells were cultured in MEM (minimum essential medium) supplemented with 2 mM L-glutamine, 10% fetal bovine serum (FBS), 100 U / mL penicillin-G, and 100 μg / mL streptomycin. Cell culture conditions were 37 ± 1°C, 5% CO2, and saturated humidity. When the cells reached 80-90% confluence, trypsin (0.05%, w / v) / EDTA (0.02%, w / v) digestion solution was added to digest the cells and then plated. Cells were seeded in BD Falcon Transwell-96 well plates at a seeding density of 1 × 10 5 cells / cm 2 The cells were cultured in a CO2 incubator for 22 days before use in transport experiments.

[0295] Transport experiment:

[0296] This study used Hank's balanced salt buffer (pH 7.40 ± 0.05) containing 10 mM HEPES as the transport buffer. Bidirectional transport of the test compound and the positive drug digoxin was tested at a concentration of 2 μM. Two replicates were used to test the transport of fenoterol and propranolol from the apical to basolateral (AB) region. The DMSO concentration in the incubation system was kept below 1%. After sample addition, the cell plates were incubated at 37 ± 1°C, 5% CO2, and saturated humidity for 120 minutes. All samples were vortexed and centrifuged at 3220 rpm at 20°C for 20 minutes. The control and test samples were diluted 1:1 (v:v) with ultrapure water and stored at 4°C. Analysis was performed using liquid chromatography tandem mass spectrometry (LC / MS / MS).

[0297] Sample analysis:

[0298] In this study, liquid chromatography tandem mass spectrometry (LC / MS / MS) was used to semi-quantitatively analyze the peak area ratios of the test compounds and reference substances, fenoterol, propranolol, and digoxin, to the internal standard in the starting solution, receiving solution, and supernatant of the dosing well. The apparent permeability coefficient (P app ,cm / s), efflux rate and recovery rate:

[0299] (1)P app =(dC r / d t )×V r / (A×C0), dC r / d t is the cumulative concentration of the compound at the receiving end per unit time (μM / s); V r is the volume of the solution at the receiving end (the volume of the solution at the apical and basal ends is 0.075 mL and 0.250 mL, respectively); A is the relative surface area of ​​the cell monolayer (0.0804 cm 2 ); C0 is the starting concentration of the test substance at the dosing end (nM) or the peak area ratio of the reference substance. (2) Exclusion ratio = P app (BA) / P app (AB)

[0300] (3) Recovery rate (%) = 100 × [(V r ×C r )+(V d ×C d )] / (V d × C0), C0 is the starting concentration of the test substance at the dosing end (nM) or the peak area ratio of the reference substance; V d is the volume of the dosing end (0.075 mL on the apical side and 0.250 mL on the basolateral side); C d and C rare the final concentration (nM) of the test sample at the dosing end and the receiving end or the peak area ratio of the reference sample.

[0301] The experimental results are shown in Table 5.

[0302] Table 5. Caco-2 cell permeability test results

[0303] Conclusion: The compound of the present invention has good permeability.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, in, R1 is selected from H, D, F, Cl, Br, I, CN, OH, NH2, C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy groups are each independently optionally substituted with 1, 2 or 3 R a replace; R2 is selected from H, D, F, Cl, Br, I, CN, OH, NH2, C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy groups are each independently optionally substituted with 1, 2 or 3 R b replace; R3 is selected from H, D, F, Cl, Br, I, CN, OH, NH2, C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy groups are each independently optionally substituted with 1, 2 or 3 R c replace; R4 is selected from C 1-6 Alkylthio, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, the C 1-6 Alkylthio, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 The cycloalkyl and 3-6 membered heterocyclic groups are each independently optionally substituted by 1, 2, 3 or 4 R d replace; Each R5 is independently selected from D, F, Cl, Br, I, CN, OH, NH2, C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy groups are each independently optionally substituted with 1, 2 or 3 R e replace; Each R a are independently selected from D, F, Cl, Br and I; Each R b are independently selected from D, F, Cl, Br and I; Each R c are independently selected from D, F, Cl, Br and I; Each R d are independently selected from D, F, Cl, Br, I, CN, OH, NH2, C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy groups are each independently optionally substituted with 1, 2 or 3 R; Each R e are independently selected from D, F, Cl, Br and I; Each R is independently selected from D, F, Cl, Br and I; m is selected from 0, 1, 2 and 3.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Each R d are independently selected from D, F, Cl, CN, OH, NH2, C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy group is optionally substituted with 1, 2 or 3 R groups, each independently; or d Each independently selected from F and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R; or, each R d are independently selected from F and methyl.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R a Substituted; or, R1 is selected from CH3, said CH3 optionally substituted by 1, 2 or 3 R a substituted; or R1 is selected from CH3 and CD3.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is selected from C 1-3 Alkoxy, the C 1-3 The alkoxy group is optionally substituted with 1, 2 or 3 R b Substituted; or, R2 is selected from OCH3, said OCH3 optionally substituted by 1, 2 or 3 R b substituted; or, R2 is selected from OCH3 and OCD3.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R3 is selected from H, F and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R c substituted; or, R3 is selected from H, F and CH3; or, R3 is selected from H.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R4 is selected from C 1-6 Alkylthio, C 2-6 Alkenyl, C 2-6 Alkynyl and C 3-6 Cycloalkyl, the C 1-6 Alkylthio, C 2-6 Alkenyl, C 2-6 Alkynyl and C 3-6 Cycloalkyl is optionally substituted by 1, 2, 3 or 4 R d Substituted; or, R4 is selected from C 1-3 Alkylthio, C 2-3 Alkenyl, C 2-3 Alkynyl and C 3-4 Cycloalkyl, the C 1-3 Alkylthio, C 2-3 Alkenyl, C 2-3 Alkynyl and C 3-4 Cycloalkyl is optionally substituted by 1, 2, 3 or 4 R d replace.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein: R4 is selected from described are independently optionally replaced by 1, 2, 3 or 4 R d Substituted; or, R4 is selected from described are independently optionally replaced by 1, 2, 3 or 4 R d Substituted; or, R4 is selected from Alternatively, R4 is selected from 8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein m is selected from 0.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each of the above R a , each R b , each R c , each R e and each R is independently selected from D and F.

10. The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, which is selected from the compound of formula (P), the compound of formula (P-1) or the compound of formula (P-2), in, R1, R2, R3 and R4 are as defined in any one of claims 1 to 9.

11. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R a replace; R2 is selected from C 1-3 Alkoxy, the C 1-3 The alkoxy group is optionally substituted with 1, 2 or 3 R b replace; R3 is selected from H; R4 is selected from C 1-3 Alkylthio, C 2-3 Alkenyl, C 2-3 Alkynyl and C 3-4 Cycloalkyl, the C 1-3 Alkylthio, C 2-3 Alkenyl, C 2-3 Alkynyl and C 3-4 Cycloalkyl is optionally substituted by 1, 2, 3 or 4 R d replace; Each R a are independently selected from D, F, Cl, Br and I; Each R b are independently selected from D, F, Cl, Br and I; Each R d are independently selected from D, F, Cl, Br, I, C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy groups are each independently optionally substituted with 1, 2 or 3 R; Each R is independently selected from D, F, Cl, Br and I.

12. The following compound or a pharmaceutically acceptable salt thereof:

13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

14. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, and optionally further comprising a pharmaceutically acceptable carrier.

15. Use of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14, in the preparation of a medicament for treating diseases associated with complement factor B.

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