Multi-substituted indole compound, and preparation method therefor and use thereof

Abstract

The present invention relates to a multi-substituted indole compound, and a preparation method therefor and a use thereof. Specifically, disclosed in the present invention is a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or a prodrug thereof. The compound is a complement factor B inhibitor, has a significant inhibitory effect on a complement factor B, and has high bioavailability and excellent pharmacokinetics.

Description

A multi-substituted indole compound, its preparation method and uses Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a multisubstituted indole compound, its preparation method, and its uses. Background Technology

[0002] The complement system is a key component of the immune system, involving a variety of soluble pattern recognition molecules that exist inactive forms under natural conditions but can be activated through various immunological mechanisms to exert effector functions. Activation of the complement system involves three main pathways: the classical pathway, the lectin pathway, and the alternative pathway, which ultimately converge on a common terminal pathway. Complement factor B plays a central role in the activation of the alternative pathway, and its abnormal activation is associated with a number of diseases, such as paroxysmal nocturnal hemoglobinuria (PNH), IgA nephropathy (IgAN), and age-related macular degeneration (AMD).

[0003] Currently, several drugs and treatments exist for complement system-related diseases, such as eculizumab for treating PNH. However, existing treatments have limitations, such as high cost, the need for continuous blood transfusions, the inconvenience of intravenous administration, and potential side effects. Novartis' iptacopan (code-name LNP023) is a first-in-class, oral, potent, selective, small-molecule, reversible complement factor B (FB) inhibitor. FB is a key serine protease in the complement system's alternative pathway. iptacopan acts upstream of the C5 terminal pathway of the complement system, blocking intravascular hemolysis (IVH) and extravascular hemolysis (EVH) in adults with hemolytic PNH. It may treat diseases caused by dysfunction of multiple alternative pathways without affecting the immune response to microbial invasion mediated by other complement pathways, reducing the risk of infection for patients. Previously, iptacopan received Breakthrough Therapy Designation from the FDA and EMA for the treatment of PNH and C3G; it also received Rare Pediatric Disease Designation from the FDA for the treatment of C3G.

[0004] Therefore, there is an urgent need in this field to develop a novel complement factor B inhibitor to provide more small molecule drugs for the treatment / prevention of complement system-related diseases. Summary of the Invention

[0005] The purpose of this invention is to provide a multi-deuterated indole compound, its preparation method and uses, wherein the compound has a significant inhibitory effect on complement factor B, and the compound has high bioavailability and excellent pharmacokinetics.

[0006] In a first aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a prodrug thereof:

[0007] in,

[0008] R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 Each is independently hydrogen or deuterium, and the compound does not include the following structures:

[0009] In another preferred embodiment, at least one of R1, R2, R3, R4 and R5 is deuterium.

[0010] In another preferred embodiment, R1 and R2 are deuterium.

[0011] In another preferred embodiment, R1, R2, R3, R4 and R5 are deuterium.

[0012] In another preferred embodiment, the compound is selected from the group consisting of:

[0013] In another preferred embodiment, the compound is selected from the group consisting of:

[0014] In another preferred embodiment, the compound is

[0015] A second aspect of the present invention provides a pharmaceutical composition comprising:

[0016] (a) a compound as described in the first aspect of the invention, or a pharmaceutically acceptable salt thereof, or a prodrug thereof; and

[0017] (b) Pharmaceutically acceptable carriers or excipients.

[0018] A third aspect of the invention provides the use of the compound as described in the first aspect of the invention for preparing a complement factor B inhibitor, said inhibitor for the prevention and / or treatment of complement system-related diseases.

[0019] In another preferred embodiment, the complement system-related diseases are selected from the group consisting of: IgA nephropathy, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome, age-related macular degeneration, cardiovascular disease, and tumors.

[0020] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0021] Through extensive and in-depth research, the inventors have provided a multi-deuterated indole compound. Through deuteration modification (especially deuteration of R1, R2, R3, R4, and R5), this compound exhibits significant inhibitory activity against complement factor B, and also possesses high bioavailability and excellent pharmacokinetics. Based on this, the inventors completed this invention.

[0022] the term

[0023] In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0024] As used herein, the terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed. In other words, the terms also include “consistently made of” or “composed of”.

[0025] Deuterium is a stable isotope of hydrogen. CD bonds are more stable than CH bonds, therefore they are less prone to breakage and may have a longer half-life. The acidity and hydrophobicity of CD bonds differ from those of CH bonds, leading to variations in their hydrophobic-driven accumulation, clustering, or aggregation in vivo, as well as their stability and selectivity in binding with living matter. The metabolic processes of living systems are complex, and the metabolic and excretion kinetics of deuterated molecules are influenced by many factors, exhibiting corresponding complexity. Therefore, compared to non-deuterated molecules, the biological activity of deuterated molecules exhibits great randomness and unpredictability; deuteration at many sites can reduce or degrade the molecule's biological activity. Furthermore, certain hydrogen sites in organic molecules are difficult or impossible to deuterate due to limitations in synthetic methods. Therefore, deuteration of organic molecules is not arbitrary; the sites of deuteration are unpredictable, and their biological activity is also unpredictable.

[0026] As used herein, “deuterated” means that one or more hydrogen atoms in a compound or group are replaced by deuterium. Deuteration can be monosubstituted, disubstituted, polysubstituted, or total substituted. The terms “one or more deuterated” and “one or more deuterated” are used interchangeably.

[0027] As used in this article, "non-deuterated" means that the proportion of deuterium isotopes in each hydrogen atom is no higher than the natural deuterium isotope content (approximately 0.015%).

[0028] As used herein, the term "active ingredient" refers to polydeuterated indole compounds. It should be understood that the term also includes mixtures of such compounds.

[0029] In this invention, "each independently" means that when several substituents defined at the same time are selected from the same series of candidate groups, they do not affect each other; they can be the same or different.

[0030] Complement factor B inhibitors - deuterated indole compounds

[0031] This invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a prodrug thereof:

[0032] The groups are defined above.

[0033] In another preferred embodiment, in the compound, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 Each of these refers independently to the corresponding functional group in the specific compound described in this invention.

[0034] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by the compounds of the present invention with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include both inorganic and organic salts. A preferred class of salts are those formed by the compounds of the present invention with an acid. Suitable acids for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0035] Another preferred class of salts are salts formed by the compounds of the present invention with a base, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (such as lower alkanol ammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0036] Furthermore, the compounds of this invention also include prodrugs of compounds represented by Formula I. The term "prodrug" includes compounds that are themselves biologically active or inactive, and which, upon administration by an appropriate method, are metabolized or chemically reacted in the human body to form compounds of Formula I, or salts or solutions of compounds of Formula I. The prodrugs include (but are not limited to) carboxylic acid esters, carbonates, phosphate esters, nitrate esters, sulfate esters, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, etc.

[0037] The methods for preparing the compounds of Formula I described below do not constitute any limitation on the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art.

[0038] It should be understood that, unless otherwise specified, the raw materials and reagents used in the preparation process of the compounds of this invention can be purchased commercially.

[0039] Pharmaceutical Compositions and Administration

[0040] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. The term "safe and effective range" indicates that, compared to subjects not receiving treatment at that dose, subjects receiving that dose experience a cure, improvement, effective prevention, or a significant reduction in the incidence of lesions or side effects; furthermore, it includes effective doses that enhance normal physiological function. "Safe" means that the amount of the active ingredient is sufficient to significantly improve the condition without causing serious side effects.

[0041] In the pharmaceutical composition, the compound of the present invention serves as the active ingredient, comprising 0.1% to 99.9% of the total weight of the pharmaceutical composition, with the remainder being pharmaceutical excipients. The preferred ratio of the compound of the present invention to the excipients is: the compound of the present invention as the active ingredient comprises more than 60% of the total weight, with the remainder comprising 0-40% of the total weight, preferably 1-20%, and most preferably 1-10%. Typically, the pharmaceutical composition contains 1-2000 mg of active ingredient per dose, more preferably 10-200 mg of active ingredient per dose. Preferably, "one dose" refers to one tablet.

[0042] As used herein, the term "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here refers to the ability of the components in the composition to interact with and incorporate with the active ingredient of the invention without significantly reducing the efficacy of the active ingredient. Examples of pharmaceutically acceptable carriers include, but are not limited to, cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), and emulsifiers (such as Tween). ), wetting agents (such as sodium dodecyl sulfate), etc.

[0043] In addition to comprising the compound of general formula (I) as the active ingredient, the pharmaceutical composition may further comprise one or more other therapeutic agents. The "other therapeutic agents" are complement factor B inhibitors.

[0044] Adjuvants commonly used in the preparation of pharmaceutical compositions may also include flavoring agents, colorings, preservatives, and antioxidants, such as vitamin E, vitamin C, BHT, and BHA.

[0045] The compounds or pharmaceutical compositions described in this invention can be formulated into various dosage forms, such as tablets, capsules, powders, syrups, solutions, suspensions, sprays, creams, ointments, gels, transdermal patches, microneedles, etc., based on conventional processes in the pharmaceutical formulation field, and can be present in suitable solid or liquid carriers or diluents. The pharmaceutical compositions of this invention can also be stored in suitable sterile injection or infusion apparatus. From the standpoint of ease of preparation and administration, preferred pharmaceutical compositions are solid compositions, especially tablets and solid-filled or liquid-filled capsules.

[0046] The compounds or pharmaceutical compositions described in this invention can be used clinically in mammals, including humans and animals. There are no particular limitations on the route of administration; representative routes include, but are not limited to, oral administration, nasal inhalation, topical application, intravenous injection, intramuscular injection, and subcutaneous injection. Preferably, the preferred route of administration for the compounds or pharmaceutical compositions described in this invention is oral administration.

[0047] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0048] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0049] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active ingredient, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0050] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0051] In addition to the active ingredient, the suspension may contain suspending agents, such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0052] Injectable formulations include, but are not limited to, sterile, injectable, aqueous, oil-containing solutions, suspensions, emulsions, etc. These formulations can also be formulated with suitable parenteral diluents, dispersants, wetting agents, suspending agents, etc. Such injectable formulations can be sterilized by filtration through a bacteria-retaining filter. These formulations can also be formulated with bactericides dissolved or dispersed in an injectable medium or using other methods known in the art.

[0053] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0054] The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.

[0055] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 50–1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skills of a skilled physician.

[0056] When used as a pharmaceutical preparation, the compounds or pharmaceutical compositions shown in this invention may be administered once daily or in divided doses. Regardless of the method of administration, the optimal dosage for an individual should be determined based on the specific treatment. Generally, it is advisable to start with a small dose and gradually increase the dose until the most suitable dosage is found.

[0057] Compared with the prior art, the main advantages of the present invention are:

[0058] (1) Compared with Iptacopan, the deuterated indole compounds of the present invention have more significant inhibitory activity against complement factor B in human serum.

[0059] (2) Compared with Iptacopan, the deuterated indole compounds of the present invention significantly increase blood drug concentration and prolong metabolic half-life, and have higher oral bioavailability.

[0060] (3) The multi-deuterated indole compounds of the present invention are beneficial to reducing drug dosage, reducing side effects, and expanding the therapeutic window.

[0061] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0062] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0063] Unless otherwise stated, the purification in the following examples was performed on a Waters-AutoP 3767+QDA (column: YMC Triart C18 ExRS 30×150mm 5um), with the following mobile phase: A: water (10mmol ammonium bicarbonate) B: acetonitrile; flow rate: 30 mL / min; gradient: A%-B% 30-65; 20 min.

[0064] Preparation of intermediates

[0065] Example 1: Synthesis of Compound III'

[0066] Step 1: 1-(tert-Butoxycarbonyl)-5-methoxy-7-methyl-1H-indole-4-carboxylic acid

[0067] 4-Aldehyde-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (8.0 g, 27.65 mmol) was dissolved in tert-butanol (300 mL), and 2-methylbut-2-ene (19.4 g, 276.50 mmol), sodium dihydrogen phosphate (26.5 g, 221.20 mmol), and sodium perchlorate (12.5 g, 138.25 mmol) were added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction was monitored by LCMS until completion. The reaction solution was concentrated under vacuum, and the crude product was purified by silica gel column chromatography to give the target compound III'-1 (5.3 g). LCMS (ESI, m / z): 294 [M+H] + .

[0068] Step 2: 4-(hydroxymethyl-d2)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0069] Compound III'-1 (4.5 g, 14.74 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL), and N,N'-carbonyldiimidazole (2.4 g, 14.74 mmol) was added. The mixture was stirred at room temperature for 2.5 hours, followed by the addition of sodium deuterated borohydride (925 mg, 22.11 mmol). The reaction was continued for 5 hours, concentrated under reduced pressure, and the residue was diluted with water, extracted with ethyl acetate, and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the target compound III' (3.8 g). LCMS (ESI, m / z): 306 [M+H] + .

[0070] Example 2 Synthesis of tert-butyl 4-formyl-5-(methoxy-d3)-7-methyl-1H-indole-1-carboxylic acid (IIIb)

[0071] Following the synthesis described in Example 8 of patent CN112513025A, using 3,5-dimethyl-4-nitrophenol as a starting material, and employing deuterated iodomethane as a deuterating methylation agent in the final step, intermediate IIIb was prepared. LCMS (ESI, m / z): 293 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ10.52(s,1H),7.79(d,1H),7.31(d,1H),7.02(s,1H),2.61(s,3H),1.60(s,9H).

[0072] Preparation of compounds

[0073] Example 1

[0074] Synthesis of 4-((2S,4S)-4-(ethoxy-d5)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid (I-1)

[0075] Step 1: (2S,4S)-4-(ethoxy-d5)-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid benzyl ester (V)

[0076] Under nitrogen protection, the reaction apparatus was cooled to 0°C. Compound VI (1.0 g, 2.71 mmol) and sodium hydride (196.2 mg, 8.18 mmol, 60% wt) were dissolved in dimethylformamide (10.00 mL), and stirred for 1 hour. 1-Bromo-1,1,2,2,2-pentadeuterium ethane (617.2 mg, 5.41 mmol) was added to the solution, and the reaction was stirred for another hour. The reaction was monitored by TLC until complete. The reaction was quenched with saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (100 mL × 3), and the organic phases were combined, washed with brine (100 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give the target compound V (0.50 g, white solid). LCMS (ESI, m / z): 403 [M+H] + .

[0077] Step 2: Methyl 4-((2S,4S)-4-(ethoxy-d5)piperidin-2-yl)benzoate (IV)

[0078] In a 50 mL round-bottom flask, compound V (390.0 mg, 0.97 mmol) and 10% wt palladium on carbon (50.0 mg) were dissolved in tetrahydrofuran (6.0 mL) and methanol (3.0 mL). The mixture was purged three times with a hydrogen balloon, and the reaction apparatus was kept under a hydrogen atmosphere. The mixture was stirred at room temperature for 2 hours, and the reaction was monitored for completion by LC-MS. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the target compound IV (260.0 mg, brown gel). LC-MS (ESI, m / z): 269 [M+H] + .

[0079] Step 3: 4-(((2S,4S)-4-(ethoxy-d5)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (II)

[0080] In a 40 mL flask, compound IV (260.0 mg, 0.97 mmol) and tert-butyl-4-methoxy-5-methylindole-1-carboxylic acid tert-butyl ester (280.4 mg, 0.97 mmol) were dissolved in tetrahydrofuran (10.0 mL). The solution was cooled to 0 °C, and then tetraethoxytitanium (442.1 mg, 1.94 mmol) was added. The mixture was transferred to room temperature and stirred for 1 hour. Finally, sodium cyanoboronide (231.9 mg, 3.88 mmol) was added in portions, and the reaction was stirred for another 2 hours. The reaction was monitored by LC-MS until complete. The reaction was quenched with water (50 mL), extracted with dichloromethane (50 mL × 3), and the organic phases were combined. The mixture was then filtered with anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give the target compound II (200.0 mg, brown solid). LC-MS (ESI, m / z): 542 [M+H] + .

[0081] Step 4: 4-((2S,4S)-4-(ethoxy-d5)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid (I-1)

[0082] In a 40 mL flask, compound II (200.0 mg, 0.37 mmol) was dissolved in tetrahydrofuran / methanol / methanol (3.00 mL, V / V / V = 1 / 1 / 1). Sodium hydroxide (147.6 mg, 3.69 mmol) was added, and the mixture was stirred for 24 hours at room temperature. The reaction was monitored by LC-MS until complete. The reaction solution was neutralized to pH 5 with 1 N hydrochloric acid and extracted with dichloromethane (50 mL × 3). The organic phase was separated from anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by reversed-phase high-performance liquid chromatography to give the target compound I-1 (70 mg, white solid). LC-MS (ESI, m / z): 428 [M+H] + ;1 H NMR(400MHz,DMSO-d6)δ10.79(s,1H),7.95(d,2H),7.64(d,2H),7.24(t,1H),6.64(s,1H),6.46–6.43(m,1H),3 .70(s,3H),3.61–3.47(m,3H),3.22(d,2H),2.41(s,3H),2.31(dd,1H),1.82(d,1H),1.69(t,2H),1.47(t,1H).

[0083] Example 2

[0084] Synthesis of 4-((2S,4S)-4-(ethoxy-1,1-D2)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid (I-2)

[0085] Compound I-2 was prepared from bromoethane-1,1-d2 following the synthetic steps of compound I-1 in Example 1 of the compound preparation section. LCMS (ESI, m / z): 428 [M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ10.85(t,1H),7.84(d,2H),7.72(d,2H),7.30(t,1H),6.72(s,1H),6.53(t,1H),3.76(s,3H), 3.28(d,2H),2.53(t,1H),2.48(s,3H),2.41–2.25(m,1H),1.88(dq,1H),1.70(tt,2H),1.58–1.35(m,1H),1.14(s,3H).

[0086] Example 3

[0087] Synthesis of 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl-d2)piperidin-2-yl)benzoic acid (I-3)

[0088] Step 1: 4-(((2S,4S)-4-ethoxy-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl-d2)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (I-3-2)

[0089] Compound III' (891 mg, 3.04 mmol) and triethylamine (922 mg, 9.11 mmol) were dissolved in dichloromethane (15 mL), cooled to 0 °C, and methanesulfonyl chloride (383 mg, 3.34 mmol) was added. The reaction was allowed to proceed for 1 hour, followed by the addition of compound I-3-1 (800 mg, 3.04 mmol). The mixture was then slowly heated to room temperature and reacted for 5 hours. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound I-3-2 (720 mg). LCMS (ESI, m / z): 538 [M+H] + .

[0090] Step 2: 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl-d2)piperidin-2-yl)benzoic acid (I-3)

[0091] Compound I-3-2 (400 mg, 0.74 mmol) was dissolved in methanol (20 mL), cooled to 0 °C, and sodium hydroxide (594 mg, 14.85 mmol) and water (2 mL) were added. The reaction mixture was stirred at room temperature for 24 hours. The crude product was purified by high-performance preparative liquid chromatography (HPLC) to give the target compound I-3 (133.0 mg, white solid). LCMS (ESI, m / z): 425 [M+H] + .; 1 H NMR (400MHz, DMSO-d6): δ10.70(t,1H),7.91(d,2H),7.61(d,2H),7.20(t,1H),6.62(s,1H),6.45(t,1H),3.75(s,3H), 3.55(q,2H),2.42(t,1H),2.46(s,3H),2.32–2.18(m,1H),1.86(dq,1H),1.60(tt,2H),1.52–1.33(m,1H),1.18(t,3H).

[0092] Example 4

[0093] Synthesis of 4-((2S,4S)-4-ethoxy-1-((5-(methoxy-d3)-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid (I-4)

[0094] Using compound IIIb as a starting material, and following the synthetic steps of compound I-1 in Example 1 of the compound preparation section, the target compound I-4 was prepared. LCMS (ESI, m / z): 426 [M+H] + ; 1H NMR (400MHz, DMSO-d6): δ10.82(t,1H),7.97(d,2H),7.67(d,2H),7.26(t,1H),6.66(s,1H),6.46(t,1H),3.57(q,2H), 3.23(d,2H),2.47(t,1H),2.43(s,3H),2.39–2.24(m,1H),1.85(dq,1H),1.71(tt,2H),1.52–1.38(m,1H),1.19(t,3H).

[0095] Comparative Example 1

[0096] Synthesis of 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid (I-5, i.e., Iptacopan)

[0097] Step 1: 4-(((2S,4S)-4-ethoxy-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (I-5-1)

[0098] Compound I-3-1 (250.0 mg, 0.95 mmol) was dissolved in methanol (20 mL), followed by the addition of compound IIIa (275.0 mg, 0.95 mmol) and tetraethoxytitanium (650.0 mg, 2.85 mmol). The mixture was heated to 60 °C and stirred for 2 hours, then cooled to 25 °C. Sodium cyanoborohydride (239.0 mg, 3.80 mmol) was added, and stirring continued for 1 hour. Once the reaction was complete, saturated sodium bicarbonate aqueous solution (50 mL) was added, followed by extraction with ethyl acetate (3 x 30 mL). The solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE / EtOAc) to give compound I-5-1 (400.0 mg, white solid). LCMS (ESI, m / z): 537 [M+H] + .

[0099] Step 2: 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid (I-5, i.e., Iptacopan)

[0100] Compound I-5-1 (400.0 mg, 0.75 mmol) was dissolved in methanol (20 mL), cooled to 0 °C, and sodium hydroxide (596.0 mg, 14.91 mmol) and water (2 mL) were added. The reaction mixture was stirred at room temperature for 24 hours. The crude product was purified by high-performance preparative liquid chromatography (HPLC) to give the target compound I-5 (113.0 mg, white solid). LCMS (ESI, m / z): 423 [M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ10.79(t,1H),7.95(d,2H),7.65(d,2H),7.24(t,1H),6.64(s,1H),6.44(t,1H),3.70(s,3H),3.56(q ,2H),3.22(d,2H),2.46(t,1H),2.41(s,3H),2.37–2.22(m,1H),1.82(dq,1H),1.69(tt,2H),1.56–1.37(m,1H),1.16(t,3H).

[0101] Test Example 1: Complement Hemolytic Activity Detection

[0102] Experimental methods:

[0103] 1. Preparation of rabbit red blood cells

[0104] 1) Take 1 mL of 4% rabbit red blood cells into a 2 mL EP tube and centrifuge at 9500 xg at room temperature for 1 min.

[0105] 2) Remove the supernatant and add 1 mL of EGTA-Mg to the rabbit red blood cell precipitate. 2+ Add GVB buffer (slowly, adhering to the vessel wall), gently pipette to mix, and centrifuge at 9500 xg at room temperature for 1 min. Repeat this step twice, for a total of three times.

[0106] 3) After the final centrifugation, remove the supernatant and add 1 mL of EGTA-Mg to the rabbit red blood cell pellet. 2+ -GVB buffer, gently pipette to mix, take a small amount of rabbit red blood cells and dilute 500 times with 0.9% sodium chloride solution for subsequent counting.

[0107] 4) Count live cells using a cell counter. Take an appropriate amount of rabbit red blood cells and count them using EGTA-Mg... 2+ - Adjust the rabbit red blood cell concentration to 5 x 10⁻⁶ using GVB buffer. 8 per mL.

[0108] 2. Preparation of test subjects

[0109] The test substance was diluted with physiological saline, starting at a concentration of 120 mM, followed by 16-fold dilution, for a total of 3 concentration gradients.

[0110] 3. Pre-incubation of samples with complement from normal human serum

[0111] Add the following components to a 96-well plate, mix well, and incubate at room temperature for 15 minutes. Perform two replicates for each sample.

[0112] 1) Test sample well: 80 μL EGTA-Mg 2+ - GVB buffer, 10 μL normal human serum complement, 10 μL test substance diluent

[0113] 2) Background wells: 80 μL EGTA-Mg 2+ - GVB buffer, 10 μL normal human serum complement, 4 μL 0.5 M EDTA solution, 6 μL physiological saline

[0114] 3) 100% hemolysis well: 80 μL EGTA-Mg 2+ - GVB buffer, 10 μL normal human serum complement, 10 μL physiological saline

[0115] 4. Rabbit erythrocyte hemolysis

[0116] 1) Add 20 μL of a solution with a concentration of 5 x 10 to the incubated mixture of the test sample and normal human serum. 8 Rabbit red blood cells / mL, meaning the cell count in the system is 1 x 10⁻⁶. 7 The total volume of the system was 120 μL, and the final serum concentration in the system was 8.33%. The final concentration of the test substance was initially 10 μM, followed by 16-fold dilutions, resulting in a total of 3 concentrations.

[0117] 2) Place the 96-well plate on a constant temperature microplate shaker at 200 rpm and 37°C for 30 min.

[0118] 3) Centrifuge at 2000 xg at room temperature for 2 min. Transfer 100 μL of supernatant from each well into a new 96-well plate.

[0119] 4) Use an ELISA reader to measure the OD value of the supernatant at 415 nm.

[0120] 5) Calculate the hemolysis rate for each sample using the following formula:

[0121] Hemolysis rate % = 100 x (OD) 受试物孔平均值 –OD 背景孔平均值 ) / (OD 100％溶血孔平均值 –OD 背景孔平均值 )

[0122] Experimental results:

[0123] The complement hemolytic activity test results of the compounds in some embodiments of the present invention are shown in Table 1.

[0124] Table 1

[0125] Experimental results show that compound I-1 has significantly better inhibitory activity against complement factor B in human serum than the control compound, indicating that the compound of the present invention can effectively inhibit the activity of complement factor B in human serum and prevent hemolysis caused by its attack on rabbit erythrocytes.

[0126] Test Example 2: In vivo pharmacokinetic study

[0127] Experimental methods:

[0128] 1. Preparation of test sample

[0129] Injection (iv): 5% DMSO / 10% Solutol / 30% PEG 400 / 55% Water

[0130] Oral administration (po): 0.5% MC

[0131] The specific preparation methods are shown in Tables 2, 3, and 4.

[0132] Table 2. Preparation of storage solutions for test samples administered via injection (iv).

[0133] Table 3. Preparation of formulation solutions for injection administration route (iv) of the test sample

[0134] Table 4. Preparation of formulation solutions for oral (po) administration of test samples Note: (DMSO: dimethyl sulfoxide, Solutol: polyethylene glycol-15-hydroxydicarboxylate, PEG 400: polyethylene glycol 400, Water: ultrapure water, MC: methylcellulose)

[0135] 2. Laboratory animals

[0136] Species: Healthy male Sprague Dawley (SD) rats (SPF grade), weighing 180–220g.

[0137] Source: Experimental Animal Management Department, Shanghai Institute of Family Planning Science; animals transferred from the experimental institution's animal reserve (999M-017).

[0138] Number: 12 males

[0139] Animal selection: No random grouping.

[0140] 3. Administration method and blood collection time

[0141] Weigh the patient before administration and calculate the dosage based on their body weight. Administer via intravenous injection, gavage, or oral administration.

[0142] The rats were administered the drug by gavage (5 mg / kg). Blood samples of 0.2 ml were collected from the jugular vein at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after administration. Plasma was prepared by separation and the concentration of compounds in the plasma was determined by LC-MS / MS.

[0143] The rats were administered blood intravenously (0.5 mg / kg). Blood samples of 0.2 ml were collected from the jugular vein at 0.0833 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h and 24 h after administration. The blood samples were anticoagulated with EDTA-K2 and placed on ice after collection.

[0144] 4. Plasma sample processing

[0145] Blood samples were placed on ice after collection and centrifuged within 1 hour to separate the plasma (centrifugation conditions: 6800g, 6 minutes, 2-8℃). Plasma samples were stored at -80℃ before analysis.

[0146] 5. Sample Analysis

[0147] 1) Sample preparation for LC-MS / MS determination:

[0148] For I-1 and Iptacopan (positive control): Take 50 μL of plasma sample, add 5 μL of methanol, then precipitate the protein with 200 μL of methanol / acetonitrile (V / V = 1 / 1) containing 10 ng / mL IS (IS is verapamil). Vortex the mixture for 1 minute, then centrifuge for 15 minutes (4000 rpm). Finally, transfer the supernatant to a 96-well plate. Take 1 μL of the supernatant for LC-MS / MS analysis.

[0149] 2) LC-MS / MS analysis method:

[0150] Mobile phase A: 5 mM ammonium acetate and 0.1% formic acid aqueous solution;

[0151] Mobile phase B: 0.1% formic acid acetonitrile solution;

[0152] Column: ACQUITY UPLC BEH C18 1.7μm 2.1*50mm;

[0153] Flow rate: 0.60 mL / min;

[0154] Column temperature: 25℃.

[0155] The LC-MS / MS gradient elution program is shown in Table 5.

[0156] Table 5

[0157] 3) Results Analysis

[0158] Pharmacokinetic parameters were calculated using a non-compartmental model based on blood drug concentration data at different time points using Phoenix WinNonlin 7.0 software, providing AUC. inf C max T max、 T 1 / 2 And parameters such as bioavailability.

[0159] The pharmacokinetic results of the compounds in some embodiments of the present invention are shown in Table 6.

[0160] Table 6

[0161] Experimental results showed that, compared with the positive control compound Iptacopan, the deuterated compound I-1 showed a lower C after injection. max Increased by 32%, AUC increased to 13%, and T after oral administration 1 / 2 It was extended by 28%, and the AUC increased by 46%.

[0162] Therefore, the deuterated modified compound I-1 of this invention can significantly increase blood drug concentration and prolong metabolic half-life, which helps to reduce the dosage, decrease side effects, and expand the therapeutic window. This invention shows great promise as a drug for treating complement factor-related diseases.

[0163] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, or a prodrug thereof: in, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 Each is independently hydrogen or deuterium, and the compound does not include the following structures:

2. The compound according to claim 1, characterized in that, At least one of R1, R2, R3, R4 and R5 is deuterium.

3. The compound according to claim 1, characterized in that, R1 and R2 are deuterium.

4. The compound according to claim 1, characterized in that, R1, R2, R3, R4, and R5 are deuterium.

5. The compound according to claim 1, characterized in that, The compounds are selected from the group consisting of:

6. The compound according to claim 1, characterized in that, The compounds are selected from the group consisting of:

7. The compound according to claim 1, characterized in that, The compound is 8. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises: (a) the compound of claim 1, or a pharmaceutically acceptable salt thereof, or a prodrug thereof; and (b) Pharmaceutically acceptable carriers or excipients.

9. The use of the compound as claimed in claim 1, characterized in that, This is used to prepare complement factor B inhibitors, which are used for the prevention and / or treatment of complement system-related diseases.

10. The use as described in claim 9, characterized in that, The complement system-related diseases are selected from the following group: IgA nephropathy, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome, age-related macular degeneration, cardiovascular disease, and tumors.

Images