WO2023237012A1 - Bicyclic substituted aromatic carboxylic acid-type deuterated compound - Google Patents

Bicyclic substituted aromatic carboxylic acid-type deuterated compound Download PDF

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Publication number
WO2023237012A1
WO2023237012A1 PCT/CN2023/098918 CN2023098918W WO2023237012A1 WO 2023237012 A1 WO2023237012 A1 WO 2023237012A1 CN 2023098918 W CN2023098918 W CN 2023098918W WO 2023237012 A1 WO2023237012 A1 WO 2023237012A1
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compound
formula
alkyl
acid
present
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PCT/CN2023/098918
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French (fr)
Chinese (zh)
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丁照中
颜小兵
陈曙辉
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正大天晴药业集团股份有限公司
南京明德新药研发有限公司
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Publication of WO2023237012A1 publication Critical patent/WO2023237012A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the complement system is an important component of the body's innate immunity against infections such as foreign pathogens, bacteria, and parasites.
  • the complement system is also an important component of the connection between innate immunity and adaptive immunity.
  • Complement consists of plasma proteins, including soluble proteins, membrane-bound proteins and complement receptors. It is mainly produced by membrane proteins expressed in the liver or cell surface and plays a role in plasma, tissues or cells.
  • the complement system is mainly activated through three pathways: the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP).
  • Each R is independently selected from D, -F, -Cl, -Br, -I or -OH;
  • T 1 is selected from CH
  • T 2 is selected from N
  • other variables are as defined in the present invention.
  • the R 2 and R 4 together with the atoms to which they are connected form oxetanyl, oxetanyl, oxetanyl, azetidinyl, azetanyl Or azetidinyl, the oxetanyl, oxetanyl, oxetanyl, azetidinyl, azetyl or azetyl are independently optionally substituted by 1, 2 Or substituted by 3 R b , in this case, the R 3 is selected from H or D, and other variables are as defined in the present invention.
  • the R 2 and R 4 together with the atoms to which they are connected form an oxanyl or azacyclohexyl group, which are independently optionally replaced by 1 , 2 or 3 R b substitutions, at this time, the R 3 is selected from H, and other variables are as defined in the present invention.
  • each R b is independently selected from -CH 2 CH 3 , -CH 2 CHF 2 or -CH 2 CF 3 , and other variables are as defined in the invention.
  • the 3-6 membered heterocyclyl group is selected from 4-6 membered saturated heterocyclyl groups containing one N or one O.
  • the 3-6 membered heterocyclyl group is selected from 4-6 membered saturated heterocyclyl groups containing one N.
  • the 3-6 membered heterocyclyl group is selected from 4-6 membered saturated heterocyclyl groups containing one O.
  • the structural unit Selected from Other variables are as defined in the present invention.
  • the structural unit Selected from Other variables are as defined in the present invention.
  • the compound or a pharmaceutically acceptable salt thereof is selected from,
  • R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R b , n, T 1 and T 2 are as defined for the compound of formula (I) of the present invention.
  • the carbon atom with "#" is a chiral carbon atom, existing in the form of (R) or (S) single enantiomer or enriched in one enantiomer;
  • the carbon atoms with "*" are chiral carbon atoms, which exist in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
  • the compound or a pharmaceutically acceptable salt thereof is selected from,
  • R 1 , R 4 , R 5 , R 6 , R 9 and R b are as defined for the compound of formula (I) of the present invention.
  • the carbon atom with "#" is a chiral carbon atom, existing in the form of (R) or (S) single enantiomer or enriched in one enantiomer;
  • the carbon atoms with "*" are chiral carbon atoms, which exist in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
  • the compound or a pharmaceutically acceptable salt thereof is selected from,
  • R 4 is selected from deuterated C 1-3 alkoxy; R 6 and R 9 are each independently selected from H or D.
  • the compound or a pharmaceutically acceptable salt thereof is selected from,
  • R 4 , R 6 and R 9 are as defined for the compound of formula (I) of the present invention.
  • the present invention also provides the following compounds or pharmaceutically acceptable salts thereof,
  • the present invention also provides the following compounds or pharmaceutically acceptable salts thereof,
  • the present invention also provides a pharmaceutical composition, which contains a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. Furthermore, a pharmaceutically acceptable carrier is also included.
  • the present invention also provides the use of the compound of the present invention or a pharmaceutically acceptable salt thereof in the preparation of medicaments for treating diseases related to complement factor B.
  • the present invention also provides a method for treating diseases related to 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.
  • the present invention also provides the use of the compound of the present invention or a pharmaceutically acceptable salt thereof in the treatment of diseases related to complement factor B.
  • the present invention also provides compounds of the present invention or pharmaceutically acceptable salts thereof for the treatment of diseases associated with complement factor B.
  • the complement factor B-related disease is selected from the group consisting of inflammatory disorders and autoimmune diseases.
  • the pharmaceutically acceptable salt is selected from pharmaceutically acceptable acid addition salts. 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.
  • examples of pharmaceutically acceptable salts include inorganic acid salts
  • the inorganic acids include, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, phosphoric acid Dihydrogen, sulfuric acid, hydrogen sulfate, hydriodic acid, phosphorous acid, etc.; and organic acid salts, including formic acid, acetic acid, propionic acid, trifluoroacetic acid, isobutyric acid, maleic acid, propylene glycol, etc.
  • Acid benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid and similar acids; Also included are salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid.
  • the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, nitrate, carbonate, bicarbonate, phosphate, monohydrogen phosphate, and dihydrogen phosphate.
  • Salt sulfate, bisulfate, hydroiodide, phosphite, formate, acetate, propionate, trifluoroacetate, isobutyrate, maleate, malonic acid Salt, benzoate, succinate, suberate, fumarate, lactate, mandelate, phthalate, benzenesulfonate, p-toluenesulfonate, lemon Acid, tartrate, methanesulfonate, arginine and glucuronate.
  • the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, formate and trifluoroacetate.
  • the compound of the present invention has obvious inhibitory activity on the activation of human serum alternative pathway, and has a significant inhibitory effect on complement activation stimulated by LPS.
  • the compound of the present invention also has good pharmacokinetic properties and can be developed into a new small molecule inhibitor of complement system Factor B.
  • the term "pharmaceutically acceptable” 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 human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • 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, diastereoisomers isomer, the (D)-isomer, the (L)-isomer, as well as their racemic mixtures and other mixtures, such as enantiomeric or diastereomerically enriched mixtures, all of which belong to the present invention. within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
  • diastereomer refers to stereoisomers whose molecules have two or more chiral centers and are in a non-mirror image relationship between the molecules.
  • the following formula (A) represents the compound as a single isomer of formula (A-1) or formula (A-2) It exists in the form or in the form of a mixture of two isomers of formula (A-1) and formula (A-2);
  • the following formula (B) represents that the compound is in the form of formula (B-1) or formula (B-2) It exists as a single isomer or as a mixture of two isomers of formula (B-1) and formula (B-2).
  • the following formula (C) indicates that the compound exists in the form of a single isomer of formula (C-1) or formula (C-2) or in the form of two isomers of formula (C-1) and formula (C-2). Exists in mixture form.
  • the terms “enriched in an isomer,” “enantiomerically enriched,” “enriched in an enantiomer,” or “enantiomerically enriched” refer to one of the isomers or enantiomers.
  • the content of the enantiomer is less than 100%, and the content of the 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%.
  • isomeric 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%, then the isomer or enantiomeric excess (ee value) is 80% .
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterated drugs can be replaced by heavy hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce side effects and increase drug stability. , enhance efficacy, extend drug biological half-life and other advantages. All variations in the isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable.
  • it means two hydrogen atoms are replaced.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical achievability.
  • any variable e.g., R
  • its definition in each instance is independent.
  • said group may optionally be substituted by up to two R's, with independent options for R in each case.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • the substituent can be bonded through any atom thereof.
  • a pyridyl group as a substituent can be bonded through any one of the pyridine rings.
  • the carbon atom is attached to the substituted group.
  • the direction of connection is arbitrary, for example, The middle linking group L is -MW-.
  • -MW- can be connected to ring A and ring B in the same direction as the reading order from left to right. You can also connect ring A and ring B in the opposite direction to the reading order from left to right.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • connection mode of the chemical bond is non-positioned and there are H atoms at the connectable site, when the chemical bond is connected, the number of H atoms at the site will be reduced correspondingly with the number of connected chemical bonds and become the corresponding valence. group.
  • the chemical bond connecting the site to other groups can be a straight solid line bond straight dashed key or wavy lines express.
  • the straight solid line bond in -OCH 3 means that it is connected to other groups through the oxygen atom in the group;
  • the straight dotted bond in means that it is connected to other groups through both ends of the nitrogen atoms in the group;
  • the wavy lines in indicate that the phenyl group is connected to other groups through the 1 and 2 carbon atoms in the phenyl group;
  • variable such as R
  • the variable is designated as being substituted on that ring and cannot be substituted on other rings of the polycyclic system, For example Indicates that ring A and ring B are combined rings, and the substituent R 1 is a substituent of ring A, and the substituent R 2 is a substituent of ring B, Indicates that the five-membered ring in the spiro ring system is replaced by n R's.
  • halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • C 1-3 alkyl is used to mean a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Examples of C 1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n - propyl and isopropyl), and the like.
  • C 1-3 alkoxy means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups, etc.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • deuterated means that 1, 2, 3 or more H atoms in a substituent are replaced by its isotope deuterium atoms.
  • deuterated C 1-3 alkyl means that 1, 2, 3 or more H atoms in a C 1-3 alkyl group are replaced by its isotope deuterium atoms, deuterated C 1-3 Examples of alkyl groups include, but are not limited to -CD 3 , -CD 2 CD 3 and the like.
  • deuterated C 1-3 alkoxy means that 1, 2, 3 or more H atoms in a C 1-3 alkoxy group are replaced by their isotopic deuterium atoms, deuterated C 1
  • deuterated C 1 Examples of -3 alkoxy include but are not limited to -OCD 3 , -OCD 2 CD 3 and the like.
  • the term "3-6 membered heterocyclyl" by itself or in combination with other terms respectively represents a saturated or partially unsaturated monocyclic cyclic group consisting of 3 to 6 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the remainder are carbon atoms, wherein the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S (O) p , p is 1 or 2). Furthermore, in the case of the "3-6 membered heterocyclyl", the heteroatom may occupy the attachment position of the heterocyclyl to the rest of the molecule.
  • the 3-6-membered heterocyclic groups include 4-6-membered, 5-6-membered, 4-membered, 5-membered and 6-membered heterocyclic groups, etc.
  • Examples of 3-6 membered heterocyclyl 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) Aldinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc
  • C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also include any range from n to n+m, for example, C 1-12 includes C 1- 3. 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 yuan to n+m means that the number of atoms in the ring is n to n+m.
  • 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, and a 9-membered ring.
  • Ring, 10-membered ring, 11-membered ring, and 12-membered ring also include any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6 ring, 5-7-membered ring, 6-7-membered ring, 6-8-membered ring, and 6-10-membered ring, etc.
  • 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 methods well known to those skilled in the art. Equivalent alternatives and preferred embodiments include, but are not limited to, embodiments of the present invention.
  • the solvent used in the present invention is commercially available.
  • Compounds are named according to conventional naming principles in the field or use For software naming, commercially available compounds adopt supplier catalog names.
  • Figure 1 is a diagram of the PD model in mice induced by LPS activation of complement.
  • the complement system alternative pathway kit is used to determine the inhibitory activity of the test compound against the complement alternative pathway in human serum.
  • the compound of the present invention has obvious inhibitory activity on the activation of human serum bypass pathway.
  • the compound of the present invention was prepared into a clear solution of 3 mg/mL using 20% PEG400/10% solution/70% water. Rats were fasted overnight before administration, dose: 30 mg/kg, administration method: oral gavage. Collect blood before and 0.25, 0.5, 1, 2, 4, 7, and 24 hours after administration, place it in a heparinized anticoagulant test tube, centrifuge at 7000 rpm (5204g), 4°C, separate plasma, and store at -80°C save. Eat 4 hours after dosing. The LC/MS/MS method was used to determine the content of the test compound in rat plasma after oral administration. Plasma samples were analyzed after pretreatment with precipitated proteins. Experimental results:
  • C max peak concentration
  • T maax peak time
  • T 1/2 drug elimination half-life
  • AUC 0-last 0-area under the drug-time curve within the last sampling time.
  • mice Female C57BL/6J mice, 7-9 weeks old, weighing 17-23 grams; supplier: Shanghai Sipur-Bika Experimental Animal Co., Ltd.
  • LPS lipopolysaccharide
  • Salmonella typhimurium Salmonella typhimurium
  • sterile PBS phosphate buffer pH 7.2-7.4
  • Normal mouse group negative control: animals received i.p. Inject 100 ⁇ L of sterile PBS and administer vehicle alone by gavage (IO).
  • Model group positive control: animals received intraperitoneal LPS and PO administration of vehicle (20% PEG400/10% solutol/70% water).
  • Drug group Samples were collected 4 hours after compound administration (vehicle: 20% PEG400/10% solution/70% water, administration volume: 5 mL/kg, dose: 10 mg/kg).
  • Sample collection 0.3 mL of blood sample was collected from the orbital venous plexus. All blood samples were added into commercial EDTA-K2 anticoagulant tubes with a specification of 1.5 mL (supplier is Jiangsu Kangjian Medical Products Co., Ltd.). After blood samples are collected, within half an hour, centrifuge at 4°C and 3000g for 10 minutes to aspirate the supernatant plasma, quickly transfer it to dry ice, and store it in a -80°C refrigerator for Western blot analysis of downstream C3d protein levels after complement activation.
  • Mouse plasma (5 ⁇ L) + Lysis buffer (lysis buffer, 27.5 ⁇ L) + Loading buffer (loading buffer, 12.5 ⁇ L) + Reducing buffer (reducing buffer, 5 ⁇ L), mix well, incubate at 100°C for 15 minutes, and load the sample
  • the volume is 5 ⁇ L/well, that is, the plasma loading volume per well is 0.5 ⁇ L.
  • the C3d protein level in the serum of mice in the model group increased by 40% to 50% compared with the normal group.
  • the C3d protein level in the serum of mice in each drug group increased by 40% to 50%.

Abstract

Provided are a compound as represented by formula (I) and a pharmaceutically acceptable salt thereof.

Description

双环取代的芳香羧酸类氘代化合物Bicyclic substituted aromatic carboxylic acid deuterated compounds
相关申请的交叉引用Cross-references to related applications
本申请要求于2022年06月07日向中国国家知识产权局提交的第202210640584.3号中国发明专利申请的优先权和权益，所述申请公开的全部内容通过引用整体并入本文中。This application claims the priority and rights of the Chinese invention patent application No. 202210640584.3 submitted to the State Intellectual Property Office of China on June 7, 2022. The entire disclosure of the application is incorporated herein by reference.
技术领域Technical field
本发明涉及双环取代的芳香羧酸类氘代化合物，具体涉及式(I)所示化合物或其药学上可接受的盐。The present invention relates to bicyclic substituted aromatic carboxylic acid deuterated compounds, specifically to the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
背景技术Background technique
补体***是人体抵抗外源病原体、细菌和寄生虫等感染的重要的先天免疫组成，同时补体***也是先天免疫与适应性免疫衔接的重要组成。补体由血浆蛋白组成，包括可溶性蛋白、膜结合性蛋白和补体受体，主要由肝脏或细胞表面表达的膜蛋白产生，在血浆，组织或细胞内发挥作用。补体***主要通过三条通路激活：经典通路(classical pathway，CP)、凝集素通路(lectin pathway，LP)以及旁路通路(alternative pathway，AP)。The complement system is an important component of the body's innate immunity against infections such as foreign pathogens, bacteria, and parasites. The complement system is also an important component of the connection between innate immunity and adaptive immunity. Complement consists of plasma proteins, including soluble proteins, membrane-bound proteins and complement receptors. It is mainly produced by membrane proteins expressed in the liver or cell surface and plays a role in plasma, tissues or cells. The complement system is mainly activated through three pathways: the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP).
健康个体的正常生理状态下，AP通路一直保持低水平的活化状态以随时监测外来病原体入侵状态。补体蛋白分布在凋亡细胞表面，补体激活受到严格的调节，仅仅用于清除凋亡的细胞，而不会进一步激活其他先天免疫或适应性免疫反应。在外来病原体感染的情况下，补体***被全面激活，产生炎性反应，调理作用或吞噬作用等，破坏病原体并最终激活适应性免疫反应。补体的低效和过度刺激都可能对人体有害，并且与感染或非传染性疾病的易感性增加有关，比如自身免疫疾病，慢性炎症，血栓性微血管病，移植排斥和肿瘤等。Under normal physiological conditions of healthy individuals, the AP pathway always maintains a low-level activation state to monitor the invasion status of foreign pathogens at any time. Complement proteins are distributed on the surface of apoptotic cells, and complement activation is strictly regulated and is only used to clear apoptotic cells without further activating other innate or adaptive immune responses. In the case of infection by foreign pathogens, the complement system is fully activated, producing inflammatory responses, opsonization or phagocytosis, etc., destroying the pathogens and ultimately activating the adaptive immune response. Both complement inefficiency and overstimulation can be harmful and are associated with increased susceptibility to infections or non-communicable diseases, such as autoimmune diseases, chronic inflammation, thrombotic microangiopathies, transplant rejection and tumors.
补体因子B(Factor B)作用于AP通路，抑制Factor B活性能够阻止API通路激活，且不干扰CP和LP通路，能够避免因补体***抑制增加感染风险。目前尚无小分子Factor B抑制剂上市，Novartis的factor B抑制剂LNP023处于临床III期研究阶段，用于PNH、IgAN、C3G等疾病的治疗。因此，有必要开发新型补体***Factor B小分子抑制剂，增加临床研究和验证并用于补体异常导致的各种疾病的治疗，为满足临床需求提供新的治疗手段。Complement factor B (Factor B) acts on the AP pathway. Inhibiting Factor B activity can prevent the activation of the API pathway without interfering with the CP and LP pathways, and can avoid increasing the risk of infection due to complement system inhibition. There are currently no small molecule Factor B inhibitors on the market. Novartis' factor B inhibitor LNP023 is in the clinical phase III research stage and is used for the treatment of PNH, IgAN, C3G and other diseases. Therefore, it is necessary to develop new small molecule inhibitors of the complement system Factor B, increase clinical research and verification, and use them in the treatment of various diseases caused by complement abnormalities to provide new treatment methods to meet clinical needs.
发明内容Contents of the invention
本发明提供了式(I)所示化合物或其药学上可接受的盐，
The present invention provides compounds represented by formula (I) or pharmaceutically acceptable salts thereof,
其中，in,
T1和T2分别独立地选自CH或N； T 1 and T 2 are independently selected from CH or N;
R1、R5、R6、R7、R8和R9分别独立地选自H或D；R 1 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from H or D;
R2和R3与它们连接的原子一起形成3-6元杂环基，此时，R4选自H、D、卤素、C1-3烷基、C1-3烷氧基、氘代C1-3烷基或氘代C1-3烷氧基；R 2 and R 3 together with the atoms to which they are connected form a 3-6 membered heterocyclyl group. At this time, R 4 is selected from H, D, halogen, C 1-3 alkyl, C 1-3 alkoxy, deuterated C 1-3 alkyl or deuterated C 1-3 alkoxy;
或者，R2和R4与它们连接的原子一起形成3-6元杂环基，所述3-6元杂环基任选被1、2或3个Rb取代，此时，R3选自H、D、卤素、C1-3烷基或C1-3烷氧基，所述C1-3烷基或C1-3烷氧基分别独立地任选被1、2、3、4或5个Ra取代；Alternatively, R 2 and R 4 together with the atoms to which they are connected form a 3-6 membered heterocyclyl group, and the 3-6 membered heterocyclyl group is optionally substituted by 1, 2 or 3 R b . In this case, R 3 is selected from From H, D, halogen, C 1-3 alkyl or C 1-3 alkoxy, the C 1-3 alkyl or C 1-3 alkoxy is independently optionally substituted by 1, 2, 3, 4 or 5 R a substitutions;
每个Ra分别独立地选自D、-F、-Cl、-Br或-I；Each R a is independently selected from D, -F, -Cl, -Br or -I;
每个Rb分别独立地选自D、卤素、C1-3烷基、C1-3烷氧基、-C(＝O)-C1-3烷基或-S(＝O)m-C1-3烷基，所述C1-3烷基、C1-3烷氧基、-C(＝O)-C1-3烷基或-S(＝O)m-C1-3烷基分别独立地任选被1、2、3、4或5个R取代；Each R b is independently selected from D, halogen, C 1-3 alkyl, C 1-3 alkoxy, -C(=O)-C 1-3 alkyl or -S(=O) m - C 1-3 alkyl, the C 1-3 alkyl, C 1-3 alkoxy, -C(=O)-C 1-3 alkyl or -S(=O) m -C 1-3 The alkyl groups are each independently optionally substituted by 1, 2, 3, 4 or 5 R;
每个R分别独立地选自D、-F、-Cl、-Br、-I或-OH；Each R is independently selected from D, -F, -Cl, -Br, -I or -OH;
m选自0、1或2；m is selected from 0, 1 or 2;
n选自0或1；n is selected from 0 or 1;
条件是，R1、R3、R4、R5、R6、R7、R8、R9、Ra、Rb和R中至少有一个选自D或氘代基团。The condition is that at least one of R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R a , R b and R is selected from D or a deuterated group.
在本发明的一些方案中，所述T1选自CH，T2选自CH，其他变量如本发明所定义。In some aspects of the present invention, T 1 is selected from CH, T 2 is selected from CH, and other variables are as defined in the present invention.
在本发明的一些方案中，所述T1选自CH，T2选自N，其他变量如本发明所定义。In some aspects of the present invention, T 1 is selected from CH, T 2 is selected from N, and other variables are as defined in the present invention.
在本发明的一些方案中，所述T1选自N，T2选自CH，其他变量如本发明所定义。In some aspects of the present invention, T 1 is selected from N, T 2 is selected from CH, and other variables are as defined in the present invention.
在本发明的一些方案中，所述R1选自D，其他变量如本发明所定义。In some aspects of the invention, the R 1 is selected from D, and other variables are as defined in the invention.
在本发明的一些方案中，所述R2和R3与它们连接的原子一起形成氮杂环丁基、氮杂环戊基或氮杂环己基，此时，所述R4选自H、D、-CH3、-CH2CH3、-OCH3、-OCH2CH3、-CD3、-CD2CD3、-OCD3或-OCD2CD3，其他变量如本发明所定义。In some aspects of the present invention, the R 2 and R 3 together with the atoms to which they are connected form an azetidinyl, azetipentyl or azetidinyl group, and at this time, the R 4 is selected from H, D. -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -CD 3 , -CD 2 CD 3 , -OCD 3 or -OCD 2 CD 3 , and other variables are as defined in the present invention.
在本发明的一些方案中，所述R2和R3与它们连接的原子一起形成氮杂环戊基，此时，所述R4选自-OCH3、-OCH2CH3、-OCD3或-OCD2CD3，其他变量如本发明所定义。In some aspects of the invention, the R 2 and R 3 together with the atoms to which they are connected form an azacyclopentyl group. In this case, the R 4 is selected from -OCH 3 , -OCH 2 CH 3 , -OCD 3 or -OCD 2 CD 3 , other variables are as defined in the present invention.
在本发明的一些方案中，所述R2和R3与它们连接的原子一起形成氮杂环戊基，此时，所述R4选自-OCH3或-OCD3，其他变量如本发明所定义。In some embodiments of the present invention, the R 2 and R 3 together with the atoms to which they are connected form an azacyclopentyl group. In this case, the R 4 is selected from -OCH 3 or -OCD 3 , and other variables are as in the present invention. defined.
在本发明的一些方案中，所述R2和R3与它们连接的原子一起形成氮杂环戊基，此时，所述R4选自-OCH2CH3或-OCD2CD3，其他变量如本发明所定义。In some embodiments of the present invention, the R 2 and R 3 together with the atoms to which they are connected form an azacyclopentyl group. In this case, the R 4 is selected from -OCH 2 CH 3 or -OCD 2 CD 3 , others Variables are as defined herein.
在本发明的一些方案中，所述R2和R3与它们连接的原子一起形成氮杂环戊基，此时，所述R4选自氘代C1-3烷基或氘代C1-3烷氧基，其他变量如本发明所定义。In some embodiments of the present invention, the R 2 and R 3 together with the atoms to which they are connected form an azacyclopentyl group. In this case, the R 4 is selected from deuterated C 1-3 alkyl or deuterated C 1 -3 alkoxy, other variables are as defined in the present invention.
在本发明的一些方案中，所述R2和R3与它们连接的原子一起形成氮杂环戊基，此时，所述R4选自氘代C1-3烷氧基，其他变量如本发明所定义。In some embodiments of the present invention, the R 2 and R 3 together with the atoms to which they are connected form an azacyclopentyl group. In this case, the R 4 is selected from deuterated C 1-3 alkoxy, and other variables are such as defined by the present invention.
在本发明的一些方案中，所述R2和R3与它们连接的原子一起形成氮杂环戊基，此时，所述R4选自-OCD3或-OCD2CD3，其他变量如本发明所定义。In some embodiments of the present invention, the R 2 and R 3 together with the atoms to which they are connected form an azacyclopentyl group. In this case, the R 4 is selected from -OCD 3 or -OCD 2 CD 3 , and other variables are such as defined by the present invention.
在本发明的一些方案中，所述R2和R4与它们连接的原子一起形成氧杂环丁基、氧杂环戊基、氧杂环己基、氮杂环丁基、氮杂环戊基或氮杂环己基，所述氧杂环丁基、氧杂环戊基、氧杂环己基、氮杂环丁基、氮杂环戊基或氮杂环己基分别独立地任选被1、2或3个Rb取代，此时，所述R3选自H或D，其他变量如本发明所定义。 In some embodiments of the invention, the R 2 and R 4 together with the atoms to which they are connected form oxetanyl, oxetanyl, oxetanyl, azetidinyl, azetanyl Or azetidinyl, the oxetanyl, oxetanyl, oxetanyl, azetidinyl, azetyl or azetyl are independently optionally substituted by 1, 2 Or substituted by 3 R b , in this case, the R 3 is selected from H or D, and other variables are as defined in the present invention.
在本发明的一些方案中，所述R2和R4与它们连接的原子一起形成氧杂环己基或氮杂环己基，所述氧杂环己基或氮杂环己基分别独立地任选被1、2或3个Rb取代，此时，所述R3选自H或D，其他变量如本发明所定义。In some embodiments of the invention, the R 2 and R 4 together with the atoms to which they are connected form an oxanyl or azacyclohexyl group, which are independently optionally replaced by 1 , 2 or 3 R b substitutions, at this time, the R 3 is selected from H or D, and other variables are as defined in the present invention.
在本发明的一些方案中，所述R2和R4与它们连接的原子一起形成氧杂环己基或氮杂环己基，所述氧杂环己基或氮杂环己基分别独立地任选被1、2或3个Rb取代，此时，所述R3选自H，其他变量如本发明所定义。In some embodiments of the invention, the R 2 and R 4 together with the atoms to which they are connected form an oxanyl or azacyclohexyl group, which are independently optionally replaced by 1 , 2 or 3 R b substitutions, at this time, the R 3 is selected from H, and other variables are as defined in the present invention.
在本发明的一些方案中，“R2和R3与它们连接的原子一起形成”是指R2和R3与它们连接的碳原子及这两个碳原子之间的N原子一起形成。In some aspects of the invention, "R 2 and R 3 are formed together with the atoms to which they are connected" means that R 2 and R 3 are formed together with the carbon atoms to which they are connected and the N atom between the two carbon atoms.
在本发明的一些方案中，“R2和R4与它们连接的原子一起形成”是指R2和R4与它们连接的碳原子及这两个碳原子之间的亚甲基一起形成。In some aspects of the invention, "R 2 and R 4 are formed together with the atoms to which they are connected" means that R 2 and R 4 are formed together with the carbon atoms to which they are connected and the methylene group between the two carbon atoms.
在本发明的一些方案中，每个Rb各自独立地选自D、-F、-CH3、-CH2CH3、-OCH3、-OCH2CH3、-C(＝O)CH3、-C(＝O)CH2CH3、-SCH3、-SCH2CH3、-S(＝O)CH3或-S(＝O)2CH3，所述-CH3、-CH2CH3、-OCH3、-OCH2CH3、-C(＝O)CH3、-C(＝O)-CH2CH3、-SCH3、-SCH2CH3、-S(＝O)CH3或-S(＝O)2CH3分别独立地任选被1、2、3、4或5个R取代，其他变量如本发明所定义。In some aspects of the invention, each R b is independently selected from D, -F, -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -C(=O)CH 3 , -C(=O)CH 2 CH 3 , -SCH 3 , -SCH 2 CH 3 , -S(=O)CH 3 or -S(=O) 2 CH 3 , the -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -C(=O)CH 3 , -C(=O)-CH 2 CH 3 , -SCH 3 , -SCH 2 CH 3 , -S(=O) CH 3 or -S(=O) 2 CH 3 are each independently optionally substituted by 1, 2, 3, 4 or 5 R, and other variables are as defined in the present invention.
在本发明的一些方案中，每个Rb各自独立地选自D、-CH2CH3、-C(＝O)CH3或-S(＝O)2CH3，所述-CH2CH3、-C(＝O)CH3或-S(＝O)2CH3分别独立地任选被1、2、3、4或5个R取代，其他变量如本发明所定义。In some aspects of the invention, each R b is independently selected from D, -CH 2 CH 3 , -C(=O)CH 3 or -S(=O) 2 CH 3 , said -CH 2 CH 3. -C(=O)CH 3 or -S(=O) 2 CH 3 are each independently optionally substituted by 1, 2, 3, 4 or 5 R, and other variables are as defined in the present invention.
在本发明的一些方案中，每个Rb各自独立地选自D、-CH2CH3、-C(＝O)CH3或-S(＝O)2CH3，所述-CH2CH3、-C(＝O)CH3或-S(＝O)2CH3分别独立地任选被1、2、3、4或5个D和F取代，其他变量如本发明所定义。In some aspects of the invention, each R b is independently selected from D, -CH 2 CH 3 , -C(=O)CH 3 or -S(=O) 2 CH 3 , said -CH 2 CH 3. -C(=O)CH 3 or -S(=O) 2 CH 3 are independently optionally substituted by 1, 2, 3, 4 or 5 D and F, and other variables are as defined in the present invention.
在本发明的一些方案中，每个Rb各自独立地选自D、-CH2CH3、-CH2CH2F、-CH2CHF2、-CH2CF3、-C(＝O)CH3、-S(＝O)2CH3、-CD2CD3、-CD2CF3、-C(＝O)CD3或-S(＝O)2CD3，其他变量如本发明所定义。In some aspects of the invention, each R b is independently selected from D, -CH 2 CH 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -C(=O) CH 3 , -S(=O) 2 CH 3 , -CD 2 CD 3 , -CD 2 CF 3 , -C(=O)CD 3 or -S(=O) 2 CD 3 , other variables are as mentioned in the present invention. definition.
在本发明的一些方案中，每个Rb各自独立地选自D、-CH2CH3、-CH2CHF2、-CH2CF3或-CD2CD3，其他变量如本发明所定义。In some aspects of the invention, each R b is independently selected from D, -CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 or -CD 2 CD 3 , and other variables are as defined in the invention. .
在本发明的一些方案中，每个Rb各自独立地选自D或-CD2CD3，其他变量如本发明所定义。In some aspects of the invention, each R b is independently selected from D or -CD 2 CD 3 , and other variables are as defined in the invention.
在本发明的一些方案中，每个Rb各自独立地选自-CH2CH3、-CH2CHF2或-CH2CF3，其他变量如本发明所定义。In some aspects of the invention, each R b is independently selected from -CH 2 CH 3 , -CH 2 CHF 2 or -CH 2 CF 3 , and other variables are as defined in the invention.
在本发明的一些方案中，每个Ra各自独立地选自D、-F或-Cl，其他变量如本发明所定义。In some aspects of the invention, each R a is independently selected from D, -F or -Cl, and other variables are as defined in the invention.
在本发明的一些方案中，所述m选自2，其他变量如本发明所定义。In some aspects of the present invention, the m is selected from 2, and other variables are as defined in the present invention.
在本发明的一些方案中，所述n选自1，其他变量如本发明所定义。In some aspects of the invention, n is selected from 1, and other variables are as defined in the invention.
在本发明的一些方案中，每个R各自独立地选自D或-F，其他变量如本发明所定义。In some aspects of the invention, each R is independently selected from D or -F, and other variables are as defined in the invention.
在本发明的一些方案中，所述3-6元杂环基选自含有N或O的3-6元饱和杂环基。In some aspects of the invention, the 3-6-membered heterocyclyl group is selected from 3-6-membered saturated heterocyclyl groups containing N or O.
在本发明的一些方案中，所述3-6元杂环基选自含有一个N或一个O的4-6元饱和杂环基。In some aspects of the invention, the 3-6 membered heterocyclyl group is selected from 4-6 membered saturated heterocyclyl groups containing one N or one O.
在本发明的一些方案中，所述3-6元杂环基选自含有一个N的4-6元饱和杂环基。In some aspects of the invention, the 3-6 membered heterocyclyl group is selected from 4-6 membered saturated heterocyclyl groups containing one N.
在本发明的一些方案中，所述3-6元杂环基选自含有一个O的4-6元饱和杂环基。In some aspects of the invention, the 3-6 membered heterocyclyl group is selected from 4-6 membered saturated heterocyclyl groups containing one O.
应当理解，当R1选自H或D时，式(I)所示化合物中的结构单元(R1)3C-相应的分别是-CH3或-CD3；当R7选自H或D时，式(I)所示化合物中的结构单元-C(R7)3相应的分别是-CH3或-CD3，其他变量如本发明所定义。 It should be understood that when R 1 is selected from H or D, the structural unit (R 1 ) 3 C- in the compound represented by formula (I) is correspondingly -CH 3 or -CD 3 respectively; when R 7 is selected from H or When D, the structural unit -C(R 7 ) 3 in the compound represented by formula (I) is correspondingly -CH 3 or -CD 3 respectively, and other variables are as defined in the present invention.
应当理解，式(I)所示化合物中的两个R8是相同的，即当其中一个R8为H或D时，另一个R8相应的分别为H或D，其他变量如本发明所定义。It should be understood that the two R 8 in the compound represented by formula (I) are the same, that is, when one of the R 8 is H or D, the other R 8 is H or D respectively, and other variables are as described in the present invention. definition.
在本发明的一些方案中，所述结构单元选自 其他变量如本发明所定义。In some aspects of the invention, the structural unit Selected from Other variables are as defined in the present invention.
在本发明的一些方案中，所述结构单元选自 其他变量如本发明所定义。In some aspects of the invention, the structural unit Selected from Other variables are as defined in the present invention.
在本发明的一些方案中，所述结构单元选自其他变量如本发明所定义。In some aspects of the invention, the structural unit Selected from Other variables are as defined in the present invention.
在本发明的一些方案中，所述结构单元选自其他变量如本发明所定义。In some aspects of the invention, the structural unit Selected from Other variables are as defined in the present invention.
在本发明的一些方案中，所述结构单元选自苯基、吡啶基和哒嗪基，其他变量如本发明所定义。 In some aspects of the invention, the structural unit Selected from phenyl, pyridyl and pyridazinyl, other variables are as defined in the present invention.
在本发明的一些方案中，所述结构单元选自 其他变量如本发明所定义。In some aspects of the invention, the structural unit Selected from Other variables are as defined in the present invention.
在本发明的一些方案中，所述结构单元为其他变量如本发明所定义。In some aspects of the invention, the structural unit for Other variables are as defined in the present invention.
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其化合物选自，
In some aspects of the invention, the compound or a pharmaceutically acceptable salt thereof is selected from,
其中，in,
R1、R4、R5、R6、R7、R8、R9、Rb、n、T1和T2如本发明式(I)化合物所定义；R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R b , n, T 1 and T 2 are as defined for the compound of formula (I) of the present invention;
当R4、R5不相同时，带“#”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；When R 4 and R 5 are different, the carbon atom with "#" is a chiral carbon atom, existing in the form of (R) or (S) single enantiomer or enriched in one enantiomer;
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。The carbon atoms with "*" are chiral carbon atoms, which exist in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其化合物选自，
In some aspects of the invention, the compound or a pharmaceutically acceptable salt thereof is selected from,
其中，in,
R1、R4、R5、R6、R9和Rb如本发明式(I)化合物所定义；R 1 , R 4 , R 5 , R 6 , R 9 and R b are as defined for the compound of formula (I) of the present invention;
当R4、R5不相同时，带“#”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；When R 4 and R 5 are different, the carbon atom with "#" is a chiral carbon atom, existing in the form of (R) or (S) single enantiomer or enriched in one enantiomer;
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。The carbon atoms with "*" are chiral carbon atoms, which exist in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其化合物选自，
In some aspects of the invention, the compound or a pharmaceutically acceptable salt thereof is selected from,
其中，R4选自氘代C1-3烷氧基；R6和R9分别独立地选自H或D。Among them, R 4 is selected from deuterated C 1-3 alkoxy; R 6 and R 9 are each independently selected from H or D.
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其化合物选自，
In some aspects of the invention, the compound or a pharmaceutically acceptable salt thereof is selected from,
其中，R4、R6和R9如本发明式(I)化合物所定义。Among them, R 4 , R 6 and R 9 are as defined for the compound of formula (I) of the present invention.
本发明还有一些方案由所述变量任意组合而来。There are also some solutions of the present invention derived from any combination of the above-mentioned variables.
本发明还提供了下列所示化合物或其药学上可接受的盐，


The present invention also provides the following compounds or pharmaceutically acceptable salts thereof,


本发明还提供了下列所示化合物或其药学上可接受的盐，


The present invention also provides the following compounds or pharmaceutically acceptable salts thereof,


本发明还提供一种药物组合物，其含有治疗有效量的本发明的化合物或其药学上可接受的盐。进一步地，还包括药学上可接受的载体。The present invention also provides a pharmaceutical composition, which contains a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. Furthermore, a pharmaceutically acceptable carrier is also included.
本发明还提供了本发明的化合物或其药学上可接受的盐在制备治疗与补体因子B相关疾病的药物中的应用。The present invention also provides the use of the compound of the present invention or a pharmaceutically acceptable salt thereof in the preparation of medicaments for treating diseases related to complement factor B.
本发明还提供治疗与补体因子B相关疾病的方法，包括对需要该治疗的哺乳动物(优选人类)给予治疗有效量的本发明的化合物或其药学上可接受的盐。The present invention also provides a method for treating diseases related to 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.
本发明还提供本发明的化合物或其药学上可接受的盐在治疗与补体因子B相关疾病中的应用。The present invention also provides the use of the compound of the present invention or a pharmaceutically acceptable salt thereof in the treatment of diseases related to complement factor B.
本发明还提供用于治疗与补体因子B相关疾病的本发明的化合物或其药学上可接受的盐。The present invention also provides compounds of the present invention or pharmaceutically acceptable salts thereof for the treatment of diseases associated with complement factor B.
本发明的一些方案中，所述补体因子B相关疾病选自炎性障碍和自身免疫性疾病。In some aspects of the invention, the complement factor B-related disease is selected from the group consisting of inflammatory disorders and autoimmune diseases.
本发明的一些方案中，所述药学上可接受的盐选自药学上可接受的酸加成盐。本发明的一些方案中，所述药学上可接受的盐选自药学上可接受的无机酸盐、有机酸盐和氨基酸盐。In some embodiments of the present invention, the pharmaceutically acceptable salt is selected from pharmaceutically acceptable acid addition salts. 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.
本发明的一些方案中，所述药学上可接受的盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如甲酸、乙酸、丙酸、三氟乙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。In some embodiments of the present invention, examples of pharmaceutically acceptable salts include inorganic acid salts, and the inorganic acids include, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, phosphoric acid Dihydrogen, sulfuric acid, hydrogen sulfate, hydriodic acid, phosphorous acid, etc.; and organic acid salts, including formic acid, acetic acid, propionic acid, trifluoroacetic acid, isobutyric acid, maleic acid, propylene glycol, etc. Acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid and similar acids; Also included are salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid.
本发明的一些方案中，所述药学上可接受的盐选自盐酸盐、氢溴酸盐、硝酸盐、碳酸盐、碳酸氢盐、磷酸盐、磷酸一氢根盐、磷酸二氢根盐、硫酸盐、硫酸氢根盐、氢碘酸盐、亚磷酸盐、甲酸盐、乙酸盐、丙酸盐、三氟乙酸盐、异丁酸盐、马来酸盐、丙二酸盐、苯甲酸盐、琥珀酸盐、辛二酸盐、反丁烯二酸盐、乳酸盐、扁桃酸盐、邻苯二甲酸盐、苯磺酸盐、对甲苯磺酸盐、柠檬酸盐、酒石酸盐、甲磺酸盐、精氨酸盐和葡糖醛酸盐。In some embodiments of the present invention, the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, nitrate, carbonate, bicarbonate, phosphate, monohydrogen phosphate, and dihydrogen phosphate. Salt, sulfate, bisulfate, hydroiodide, phosphite, formate, acetate, propionate, trifluoroacetate, isobutyrate, maleate, malonic acid Salt, benzoate, succinate, suberate, fumarate, lactate, mandelate, phthalate, benzenesulfonate, p-toluenesulfonate, lemon Acid, tartrate, methanesulfonate, arginine and glucuronate.
本发明的一些方案中，所述药学上可接受的盐选自盐酸盐、甲酸盐和三氟乙酸盐。In some embodiments of the present invention, the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, formate and trifluoroacetate.
本发明的一些方案中，所述药学上可接受的盐选自盐酸盐。In some embodiments of the invention, the pharmaceutically acceptable salt is selected from hydrochloride.
技术效果Technical effect
本发明化合物对人血清旁路通路激活抑制活性明显，且对LPS刺激的补体激活有显著的抑制作用。本发明的化合物还具有良好的药代动力学性质，可以发展成为新的补体***Factor B小分子抑制剂。The compound of the present invention has obvious inhibitory activity on the activation of human serum alternative pathway, and has a significant inhibitory effect on complement activation stimulated by LPS. The compound of the present invention also has good pharmacokinetic properties and can be developed into a new small molecule inhibitor of complement system Factor B.
相关定义Related definitions
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。 Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear in the absence of a specific definition, but should be understood in its ordinary meaning. Where a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。As used herein, the term "pharmaceutically acceptable" 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 human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。The term "pharmaceutically acceptable salts" refers to salts of compounds of the present invention prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydriodic acid, phosphorous acid, etc.; and organic acid salts, including acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases. In general, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。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, diastereoisomers isomer, the (D)-isomer, the (L)-isomer, as well as their racemic mixtures and other mixtures, such as enantiomeric or diastereomerically enriched mixtures, all of which belong to the present invention. within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。Unless otherwise stated, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of each other.
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。Unless otherwise stated, the term "cis-trans isomers" or "geometric isomers" refers to the inability of the double bonds or single bonds of the carbon atoms in the ring to rotate freely.
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。Unless otherwise stated, the term "diastereomer" refers to stereoisomers whose molecules have two or more chiral centers and are in a non-mirror image relationship between the molecules.
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。Unless otherwise stated, "(+)" means right-handed, "(-)" means left-handed, and "(±)" means racemic.
除非另有说明，用楔形实线键和楔形虚线键表示一个立体中心的绝对构型，用直形实线键和直形虚线键表示立体中心的相对构型，用波浪线表示楔形实线键或楔形虚线键或用波浪线表示直形实线键或直形虚线键 Unless otherwise stated, use wedge-shaped solid line keys and wedge-shaped dotted keys Represents the absolute configuration of a three-dimensional center, using straight solid line keys and straight dotted keys Represent the relative configuration of the three-dimensional center with a wavy line Represents wedge-shaped solid line key or wedge-shaped dotted key or use tilde Represents a straight solid line key or straight dotted key
除非另有说明，当化合物中存在双键结构，如碳碳双键、碳氮双键和氮氮双键，且双键上的各个原子均连接有两个不同的取代基时(包含氮原子的双键中，氮原子上的一对孤对电子视为其连接的一个取代基)，如果该化合物中双键上的原子与其取代基之间用波浪线连接，则表示该化合物的(Z)型异构体、(E)型异构体或两种异构体的混合物。例如下式(A)表示该化合物以式(A-1)或式(A-2)的单一异构体 形式存在或以式(A-1)和式(A-2)两种异构体的混合物形式存在；下式(B)表示该化合物以式(B-1)或式(B-2)的单一异构体形式存在或以式(B-1)和式(B-2)两种异构体的混合物形式存在。下式(C)表示该化合物以式(C-1)或式(C-2)的单一异构体形式存在或以式(C-1)和式(C-2)两种异构体的混合物形式存在。
Unless otherwise stated, when there are double bond structures in the compound, such as carbon-carbon double bonds, carbon-nitrogen double bonds, and nitrogen-nitrogen double bonds, and each atom on the double bond is connected to two different substituents (including nitrogen atoms In a double bond, a lone pair of electrons on the nitrogen atom is regarded as a substituent connected to it), if a wavy line is used between the atom on the double bond and its substituent in the compound If connected, it means the (Z) isomer, (E) isomer or a mixture of the two isomers of the compound. For example, the following formula (A) represents the compound as a single isomer of formula (A-1) or formula (A-2) It exists in the form or in the form of a mixture of two isomers of formula (A-1) and formula (A-2); the following formula (B) represents that the compound is in the form of formula (B-1) or formula (B-2) It exists as a single isomer or as a mixture of two isomers of formula (B-1) and formula (B-2). The following formula (C) indicates that the compound exists in the form of a single isomer of formula (C-1) or formula (C-2) or in the form of two isomers of formula (C-1) and formula (C-2). Exists in mixture form.
除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。Unless otherwise stated, the term "tautomer" or "tautomeric form" means that at room temperature, isomers with different functional groups are in dynamic equilibrium and can quickly convert into each other. If tautomers are possible (eg in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also called proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enol isomerization. Amine isomerization. Valence tautomers include interconversions through the reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the tautomerization between pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。Unless otherwise stated, the terms "enriched in an isomer," "enantiomerically enriched," "enriched in an enantiomer," or "enantiomerically enriched" refer to one of the isomers or enantiomers. The content of the enantiomer is less than 100%, and the content of the 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%.
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。Unless otherwise stated, the term "isomeric 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%, then the isomer or enantiomeric excess (ee value) is 80% .
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C). For another example, deuterated drugs can be replaced by heavy hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce side effects and increase drug stability. , enhance efficacy, extend drug biological half-life and other advantages. All variations in the isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。The terms "optionally" or "optionally" mean that the subsequently described event or condition may, but need not, occur, and that the description includes instances in which the stated event or condition occurs and instances in which it does not. .
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，取代基可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两 个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e. =O), it means two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical achievability.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each instance is independent. Thus, for example, if a group is substituted by 0-2 R, then said group may optionally be substituted by up to two R's, with independent options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
当一个连接基团的数量为0时，比如-(CRR)0-，表示该连接基团为单键。When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。When one of the variables is selected from a single bond, it means that the two groups it is connected to are directly connected. For example, when L in A-L-Z represents a single bond, it means that the structure is actually A-Z.
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。When a substituent is vacant, it means that the substituent does not exist. For example, when X in A-X is vacant, it means that the structure is actually A.
当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。When the listed substituent does not specify which atom it is connected to the substituted group through, the substituent can be bonded through any atom thereof. For example, a pyridyl group as a substituent can be bonded through any one of the pyridine rings. The carbon atom is attached to the substituted group.
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When the listed linking groups do not specify the direction of connection, the direction of connection is arbitrary, for example, The middle linking group L is -MW-. At this time, -MW- can be connected to ring A and ring B in the same direction as the reading order from left to right. You can also connect ring A and ring B in the opposite direction to the reading order from left to right. Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键直形虚线键或波浪线表示。例如-OCH3中的直形实线键表示通过该基团中的氧原子与其他基团相连；中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连；中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连；表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括 这4种连接方式，即使-N-上画出了H原子，但是仍包括 这种连接方式的基团，只是在连接1个化学键时，该位点的H会对应减少1个变成相应的一价哌啶基。Unless otherwise specified, when a certain group has one or more attachable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the connection mode of the chemical bond is non-positioned and there are H atoms at the connectable site, when the chemical bond is connected, the number of H atoms at the site will be reduced correspondingly with the number of connected chemical bonds and become the corresponding valence. group. The chemical bond connecting the site to other groups can be a straight solid line bond straight dashed key or wavy lines express. For example, the straight solid line bond in -OCH 3 means that it is connected to other groups through the oxygen atom in the group; The straight dotted bond in means that it is connected to other groups through both ends of the nitrogen atoms in the group; The wavy lines in indicate that the phenyl group is connected to other groups through the 1 and 2 carbon atoms in the phenyl group; Indicates that any connectable 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 H atoms are drawn on -N-, still includes For groups with this type of connection, only when a chemical bond is connected, the H at that position will be reduced by one and become the corresponding monovalent piperidinyl group.
当变量(例如R)取代在多环体系的其中一个环上时，除非另有规定，所述变量(例如R)指定为在该环上取代，而不能取代在多环体系的其它环上，例如表示环A与环B并环且取代基R1为环A的取代基、取代基R2为环B的取代基，表示螺环体系中的五元环被n个R所取代。When a variable (such as R) is substituted on one of the rings of a polycyclic system, unless otherwise specified, the variable (such as R) is designated as being substituted on that ring and cannot be substituted on other rings of the polycyclic system, For example Indicates that ring A and ring B are combined rings, and the substituent R 1 is a substituent of ring A, and the substituent R 2 is a substituent of ring B, Indicates that the five-membered ring in the spiro ring system is replaced by n R's.
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。Unless otherwise specified, the term "halogen" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
除非另有规定，术语“C1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C1-3烷基包括C1-2和C2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C1- 3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。Unless otherwise specified, the term "C 1-3 alkyl" is used to mean a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) . Examples of C 1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n - propyl and isopropyl), and the like.
除非另有规定，术语“C1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C1-3烷氧基包括C1-2、C2-3、C3和C2烷氧基等。C1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。Unless otherwise specified, the term "C 1-3 alkoxy" means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through an oxygen atom. The C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups, etc. Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
除非另有规定，术语“氘代”表示取代基中的1、2、3个或更多个H原子替换成其同位素氘原子。Unless otherwise specified, the term "deuterated" means that 1, 2, 3 or more H atoms in a substituent are replaced by its isotope deuterium atoms.
除非另有规定，术语“氘代C1-3烷基”表示C1-3烷基中的1、2、3个或更多个H原子替换成其同位素氘原子，氘代C1-3烷基的实例包括但不限于-CD3、-CD2CD3等。Unless otherwise specified, the term "deuterated C 1-3 alkyl" means that 1, 2, 3 or more H atoms in a C 1-3 alkyl group are replaced by its isotope deuterium atoms, deuterated C 1-3 Examples of alkyl groups include, but are not limited to -CD 3 , -CD 2 CD 3 and the like.
除非另有规定，术语“氘代C1-3烷氧基”表示C1-3烷氧基中的1、2、3个或更多个H原子替换成其同位素氘原子，氘代C1-3烷氧基的实例包括但不限于-OCD3、-OCD2CD3等。Unless otherwise specified, the term "deuterated C 1-3 alkoxy" means that 1, 2, 3 or more H atoms in a C 1-3 alkoxy group are replaced by their isotopic deuterium atoms, deuterated C 1 Examples of -3 alkoxy include but are not limited to -OCD 3 , -OCD 2 CD 3 and the like.
除非另有规定，术语“3-6元杂环基”本身或者与其他术语联合分别表示由3至6个环原子组成的饱和或部分不饱和的单环环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。此外，就该“3-6元杂环基”而言，杂原子可以占据杂环基与分子其余部分的连接位置。所述3-6元杂环基包括4-6元、5-6元、4元、5元和6元杂环基等。3-6元杂环基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、等。Unless otherwise specified, the term "3-6 membered heterocyclyl" by itself or in combination with other terms respectively represents a saturated or partially unsaturated monocyclic cyclic group consisting of 3 to 6 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the remainder are carbon atoms, wherein the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S (O) p , p is 1 or 2). Furthermore, in the case of the "3-6 membered heterocyclyl", the heteroatom may occupy the attachment position of the heterocyclyl to the rest of the molecule. The 3-6-membered heterocyclic groups include 4-6-membered, 5-6-membered, 4-membered, 5-membered and 6-membered heterocyclic groups, etc. Examples of 3-6 membered heterocyclyl 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) Aldinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), di Oxalkyl, dithialkyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, wait.
除非另有规定，Cn-n+m或Cn-Cn+m包括n至n+m个碳的任何一种具体情况，例如C1-12包括C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、和C12，也包括n至n+m中的任何一个范围，例如C1-12包括C1- 3、C1-6、C1-9、C3-6、C3-9、C3-12、C6-9、C6-12、和C9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。Unless otherwise specified, C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also include any range from n to n+m, for example, C 1-12 includes C 1- 3. 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 yuan to n+m 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, and a 9-membered ring. Ring, 10-membered ring, 11-membered ring, and 12-membered ring, also include any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6 ring, 5-7-membered ring, 6-7-membered ring, 6-8-membered ring, and 6-10-membered ring, etc.
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。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 methods well known to those skilled in the art. Equivalent alternatives and preferred embodiments include, but are not limited to, embodiments of the present invention.
缩略语：psi代表磅力每平方英寸，为压强单位；eq代表等量；mol代表摩尔；mmol代表毫摩尔；g代表克；mg代表毫克；mL代表毫升；mm代表毫米；h代表小时；min代表分钟。Abbreviations: psi stands for pounds force per square inch, which is the unit of pressure; eq stands for equivalent quantity; mol stands for mole; mmol stands for millimole; g stands for gram; mg stands for milligram; mL stands for milliliter; mm stands for millimeter; h stands for hour; min represents minutes.
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。The structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD) uses a Bruker D8venture diffractometer to collect diffraction intensity data on the cultured single crystal. The light source is CuKα radiation. The scanning method is: After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure, and the absolute configuration can be confirmed.
本发明所使用的溶剂可经市售获得。化合物依据本领域常规命名原则或者使用软件命名，市售化合物采用供应商目录名称。The solvent used in the present invention is commercially available. Compounds are named according to conventional naming principles in the field or use For software naming, commercially available compounds adopt supplier catalog names.
附图说明Description of the drawings
图1为LPS诱导补体激活小鼠体内PD模型图。Figure 1 is a diagram of the PD model in mice induced by LPS activation of complement.
具体实施方式Detailed ways
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。The present invention is described in detail below through examples, which do not mean any adverse limitations to the present invention. The present invention has been described in detail herein, and its specific embodiments are also disclosed. For those skilled in the art, various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. will be obvious.
参考例1：中间体N-1和N-2的合成
Reference Example 1: Synthesis of Intermediates N-1 and N-2
第一步first step
在15℃，向化合物N-a(0.5g,3.10mmol,1eq)的四氢呋喃(5mL)溶液中加入二碳酸二叔丁酯(812.33mg,3.72mmol,855.09μL,1.2eq)和N,N-二异丙基乙基胺(37.89mg,310.17μmol,0.1eq)。反应液在15℃下搅拌1小时。反应液加入水(15mL)中，继续搅拌5分钟。分液，水相用乙酸乙酯(20mL)萃取3次。合并的有机层用饱和食盐水(20mL)洗涤2次，无水硫酸钠干燥，过滤，滤液减压浓缩。剩余物用硅胶柱层析法分离纯化(乙酸乙酯:石油醚＝0:1至1:10)，得到化合物N-b。To a solution of compound N-a (0.5g, 3.10mmol, 1eq) in tetrahydrofuran (5mL) at 15°C, di-tert-butyl dicarbonate (812.33mg, 3.72mmol, 855.09μL, 1.2eq) and N,N-diiso Propylethylamine (37.89 mg, 310.17 μmol, 0.1 eq). The reaction solution was stirred at 15°C for 1 hour. The reaction solution was added to water (15 mL), and stirring was continued for 5 minutes. The liquids were separated, and the aqueous phase was extracted three times with ethyl acetate (20 mL). The combined organic layers were 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 N-b.
1H 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),3.90-3.77(m,3H),2.70-2.55(m,3H),1.66-1.61(m,9H)；LC-MS:m/z＝206.1[M-56+H]+。 1 H NMR (400MHz, CDCl 3 ) 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),3.90-3.77( m,3H), 2.70-2.55(m,3H), 1.66-1.61(m,9H); LC-MS: m/z=206.1[M-56+H] + .
第二步Step 2
在15℃下，向氮气保护的N-甲基-N-甲酰基苯胺(459.93mg,3.40mmol,418.12μL,1.3eq)的二氯甲烷(2.7 mL)溶液中缓慢滴加草酰氯(431.90mg,3.40mmol,297.86μL,1.3eq)。加完后，反应液在15℃下搅拌12小时后，逐滴加入到-14℃的化合物N-b(0.684g,2.62mmol,1eq)的二氯甲烷(2.8mL)溶液中。加完后反应液继续在-15℃下搅拌1.5小时。反应液倒入冰水(20mL)中，继续搅拌5分钟。水相用乙酸乙酯(20mL)萃取3次，合并的有机相用饱和食盐水(20mL)洗涤3次，无水硫酸钠干燥，过滤。滤液减压浓缩，剩余物用硅胶柱层析法分离纯化(乙酸乙酯:石油醚＝0:1至1:10)，得到化合物N-c。Add N-methyl-N-formylanilide (459.93mg, 3.40mmol, 418.12μL, 1.3eq) to dichloromethane (2.7 mL) solution, slowly add oxalyl chloride (431.90mg, 3.40mmol, 297.86μL, 1.3eq) dropwise. After the addition was completed, the reaction solution was stirred at 15°C for 12 hours, and then added dropwise to a solution of compound Nb (0.684g, 2.62mmol, 1eq) in dichloromethane (2.8mL) at -14°C. After the addition was completed, the reaction solution was continued to stir at -15°C for 1.5 hours. The reaction solution was poured into ice water (20 mL), and stirring was continued for 5 minutes. The aqueous phase was extracted three times with ethyl acetate (20 mL), and 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 separated 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]+。 1 H NMR (400MHz, DMSO-d 6 ) 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] + .
第三步third step
在0℃下，向氮气保护的化合物N-c(5.24g,18.11mmol,1eq)的四氢呋喃(20mL)和甲醇(20mL)溶液中缓慢加入硼氢化钠(1.71g,45.28mmol,2.5eq)。加完后，反应液在15℃下搅拌0.5小时后，继续缓慢加入稀盐酸(0.5M,20mL)。加完后反应液继续搅拌20分钟。混合物用乙酸乙酯(60mL)萃取3次，合并的有机相用饱和食盐水(60mL)洗涤2次，无水硫酸钠干燥，过滤。滤液减压浓缩，剩余物用硅胶柱层析法分离纯化(乙酸乙酯:石油醚＝1:10至1:3)，得到化合物N-1。To a solution of nitrogen-protected compound N-c (5.24g, 18.11mmol, 1eq) in tetrahydrofuran (20mL) and methanol (20mL) at 0°C, sodium borohydride (1.71g, 45.28mmol, 2.5eq) was slowly added. After the addition was completed, the reaction solution was stirred at 15°C for 0.5 hours, and then continued to slowly add dilute hydrochloric acid (0.5M, 20mL). After the addition was completed, the reaction solution was continued to stir for 20 minutes. The mixture was extracted three times with ethyl acetate (60 mL), and the combined organic phases were washed twice with saturated brine (60 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:10 to 1:3) to obtain compound N-1.
1H NMR(400MHz,CDCl3)δppm 7.59-7.50(m,1H),6.80-6.70(m,1H),6.66-6.60(m,1H),4.97-4.85(m,2H),3.96-3.86(m,3H),2.68-2.58(m,3H),1.65-1.63(m,9H)。 1 H NMR (400MHz, CDCl 3 ) δppm 7.59-7.50(m,1H),6.80-6.70(m,1H),6.66-6.60(m,1H),4.97-4.85(m,2H),3.96-3.86( m,3H),2.68-2.58(m,3H),1.65-1.63(m,9H).
第四步the fourth step
在15℃下，向氮气保护的化合物N-1(0.3g,1.03mmol,1eq)的二氯甲烷(6.87mL)溶液中加入(氯亚甲基)二甲基氯化铵(197.71mg,1.54mmol,1.5eq)。加完后，反应液在15℃下搅拌1小时。反应液降温至0℃，加入碳酸氢钠水溶液(5％，30mL)，二氯甲烷(20mL)萃取3次。合并的有机相用饱和食盐水(10mL)洗涤2次，无水硫酸钠干燥，过滤。滤液减压浓缩，得到化合物N-2。To a solution of nitrogen-protected compound N-1 (0.3g, 1.03mmol, 1eq) in dichloromethane (6.87mL) was added (chloromethylene)dimethylammonium chloride (197.71mg, 1.54 mmol,1.5eq). After the addition was completed, the reaction solution was stirred at 15°C for 1 hour. The reaction solution was cooled to 0°C, sodium bicarbonate aqueous solution (5%, 30 mL) was added, and dichloromethane (20 mL) was extracted three times. The combined organic phases were washed twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound N-2.
1H NMR(400MHz,DMSO-d6)δppm 7.73-7.61(m,1H),6.91-6.86(m,1H),6.82-6.75(m,1H),4.99-4.91(m,2H),3.89-3.82(m,3H),2.56-2.54(m,3H),1.60-1.57(m,9H)。 1 H NMR (400MHz, DMSO-d 6 ) δppm 7.73-7.61(m,1H),6.91-6.86(m,1H),6.82-6.75(m,1H),4.99-4.91(m,2H),3.89- 3.82(m,3H),2.56-2.54(m,3H),1.60-1.57(m,9H).
参考例2：中间体M-d的合成
Reference Example 2: Synthesis of Intermediate Md
第一步first step
将苄胺(194.62g,1.82mol,2eq)缓慢加入到溶有醋酸(103.88mL,1.82mol,2eq)的水(850mL)中。将反应体系降温至0-10℃，然后缓慢分批加入1,3-丙酮二羧酸(265.36g,1.82mol,2eq)，反应液在0℃下反应0.5小时。将溶有化合物M-a(170g,908.15mmol,1eq)的二氧六环(850mL)溶液缓慢加入到反应体系中，将反应液缓慢恢复到室温，然后在45℃下反应12小时。反应液降至室温，然后加入乙酸乙酯萃取(500mL*2)，合并有机相，依次用饱和碳酸氢钠(500mL)和饱和氯化钠水溶液(500mL)洗涤，无水硫酸钠干燥后，滤液减压浓缩得到粗品。粗品在正庚烷和甲基叔丁基醚(1:1，500mL)混合溶剂中搅拌0.5小时，过滤并收集固体，得到化合物M-b。LC-MS:m/z＝317.1[M+H]+。 Benzylamine (194.62g, 1.82mol, 2eq) was slowly added to water (850mL) dissolved in acetic acid (103.88mL, 1.82mol, 2eq). Cool the reaction system to 0-10°C, then slowly add 1,3-acetone dicarboxylic acid (265.36g, 1.82mol, 2eq) in batches, and react at 0°C for 0.5 hours. A solution of compound Ma (170g, 908.15mmol, 1eq) dissolved in dioxane (850mL) was slowly added to the reaction system, the reaction solution was slowly returned to room temperature, and then reacted at 45°C for 12 hours. The reaction solution was brought to room temperature, then ethyl acetate was added for extraction (500mL*2), the organic phases were combined, washed with saturated sodium bicarbonate (500mL) and saturated aqueous sodium chloride solution (500mL), and dried over anhydrous sodium sulfate. Concentrate under reduced pressure to obtain 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 hours, filtered and collected the solid to obtain compound Mb. LC-MS: m/z=317.1[M+H] + .
第二步Step 2
将化合物M-b(220g,1eq)溶于乙腈(1700mL)中，然后升温到70℃下搅拌2小时，在搅拌下慢慢加入L-型二苯甲酰基酒石酸(200g,0.8eq)，反应液继续在70℃下搅拌2小时，然后缓慢恢复到25℃，并搅拌12小时。过滤并收集固体，再用乙腈(400mL*2)洗涤滤饼。将过滤得到的固体加入到1000mL水中，搅拌下加入1M NaOH水溶液调节pH至8，然后加入乙酸乙酯萃取(2000mL*2)。合并有机相，并用饱和的食盐水(2000mL*2)洗涤，有机相用无水硫酸钠干燥，过滤后减压浓缩滤液得到化合物M-c(保留时间:2.175min，ee＝99.1％)。LC-MS:m/z＝317.1[M+H]+。SFC分析方法：色谱柱:Chiralpak AD 50×4.6mm I.D.,3μm，流动相:A:CO2，B:甲醇(0.05％二乙胺)，梯度B％：5％-40％。Dissolve compound Mb (220g, 1eq) in acetonitrile (1700mL), then raise the temperature to 70°C and stir for 2 hours. Slowly add L-type dibenzoyl tartaric acid (200g, 0.8eq) while stirring, and the reaction solution continues Stir at 70°C for 2 hours, then slowly return to 25°C and stir for 12 hours. Filter and collect the solid, then wash the filter cake with acetonitrile (400mL*2). Add the filtered solid to 1000 mL of water, add 1 M NaOH aqueous solution with stirring to adjust the pH to 8, and then add ethyl acetate for extraction (2000 mL*2). The organic phases were combined and washed with saturated brine (2000 mL*2). The organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 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 50×4.6mm ID, 3 μm, mobile phase: A: CO 2 , B: methanol (0.05% diethylamine), gradient B%: 5%-40%.
第三步third step
将化合物M-c(94g,297.10mmol,1eq)溶于四氢呋喃(750mL)中，然后加入水(10.71mL,594.19mmol,2eq)，氮气置换3次，降温至-40℃，并在该温度下缓慢滴加三仲丁基硼氢化锂(1M,356.52mL,1.2eq)。滴加完毕，在该温度下继续搅拌30分钟。向反应液中缓慢滴加双氧水(102.77mL,1.07mol,30％纯度,3.6eq)，控制温度在0℃以下。然后缓慢加入溶有亚硫酸钠(135g)的水(1000mL)溶液，并加入甲基叔丁基醚(500mL)萃取2次。有机相通过饱和食盐水(1000mL)洗涤2次，干燥后过滤，减压浓缩得到化合物M-d(保留时间:1.197min，ee＝96.9％)。LC-MS:m/z＝319.1[M+H]+。SFC分析方法：色谱柱:Chiralcel OJ50×4.6mm I.D.,3μm，流动相:A:CO2，B:甲醇(0.05％二乙胺)，梯度B％：5％-40％。Dissolve compound Mc (94g, 297.10mmol, 1eq) in tetrahydrofuran (750mL), then add water (10.71mL, 594.19mmol, 2eq), replace with nitrogen three times, cool to -40°C, and slowly drip at this temperature Add tri-sec-butyllithium borohydride (1M, 356.52mL, 1.2eq). After the dropwise addition is completed, stirring is continued at this temperature for 30 minutes. Slowly add hydrogen peroxide (102.77mL, 1.07mol, 30% purity, 3.6eq) into the reaction solution, and control the temperature below 0°C. Then, a solution of sodium sulfite (135g) dissolved in water (1000mL) was slowly added, and methyl tert-butyl ether (500mL) was added for extraction twice. The organic phase was washed twice with saturated brine (1000 mL), dried, filtered, and concentrated under reduced pressure to obtain compound Md (retention time: 1.197 min, ee=96.9%). LC-MS: m/z=319.1[M+H] + . SFC analysis method: Chromatographic column: Chiralcel OJ50×4.6mm ID, 3μm, mobile phase: A: CO 2 , B: methanol (0.05% diethylamine), gradient B%: 5%-40%.
实施例1
Example 1
第一步first step
在0℃，向化合物M-d(5g,15.70mmol,1eq)的N,N-二甲基甲酰胺(25mL)溶液中加入叔丁醇钠(4.53g,47.11mmol,3eq)，反应液搅拌0.5小时，反应液降温至-10℃，加入氘代碘甲烷(2.23g,15.70mmol,1eq)并继续搅拌2小时。反应液冷却至室温后，在0℃加入水(50mL)淬灭，用柠檬酸调节pH到5-6，乙酸乙酯(50mL*2)萃取。合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤。滤液减压浓缩，剩余物用硅胶柱层析法分离纯化(乙酸乙酯:石油醚＝1:4)，得到化合物1-1。LC-MS:m/z＝336.2[M+H]+。 At 0°C, sodium tert-butoxide (4.53g, 47.11mmol, 3eq) was added to a solution of compound Md (5g, 15.70mmol, 1eq) in N,N-dimethylformamide (25mL), and the reaction solution was stirred for 0.5 hours. , the reaction solution was cooled to -10°C, deuterated methyl iodide (2.23g, 15.70mmol, 1eq) was added and stirring continued for 2 hours. After the reaction solution was cooled to room temperature, water (50 mL) was added at 0°C to quench, the pH was adjusted to 5-6 with citric acid, and extracted with ethyl acetate (50 mL*2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:4) to obtain compound 1-1. LC-MS: m/z=336.2[M+H] + .
第二步Step 2
在0℃下，向化合物1-1(2.1g,6.26mmol,1eq)的二甲基亚砜溶液(20mL)中加入碳酸钾(951.71mg,6.89mmol,1.1eq)，然后滴加过氧化氢溶液(902.27μL,9.39mmol,30％纯度,1.5eq)，加完后反应液升至40℃，搅拌1小时。反应液加入水(30mL)析出固体，过滤，收集滤饼得到化合物1-2粗品，直接用于下一步。LC-MS:m/z＝354.2[M+H]+。At 0°C, potassium carbonate (951.71 mg, 6.89 mmol, 1.1 eq) was added to a dimethyl sulfoxide solution (20 mL) of compound 1-1 (2.1 g, 6.26 mmol, 1 eq), and then hydrogen peroxide was added dropwise. solution (902.27 μL, 9.39 mmol, 30% purity, 1.5 eq). After the addition, the reaction solution was raised to 40°C and stirred for 1 hour. Water (30 mL) was added to the reaction solution to precipitate solid, filtered, and the filter cake was collected to obtain crude compound 1-2, which was used directly in the next step. LC-MS: m/z=354.2[M+H] + .
第三步third step
在25℃下，向化合物1-2(1.6g,4.53mmol,1eq)的无水甲醇(16mL)溶液中加入N,N-二甲基甲酰胺二甲基缩醛(1.08g,9.05mmol,2eq)，加完后反应液升温至75℃继续在氮气保护下搅拌16小时。反应液减压浓缩后加入水(16mL)，乙酸乙酯(16mL*2)萃取。合并有机相，用饱和食盐水(16mL)洗涤，无水硫酸钠干燥，过滤。滤液减压浓缩，得到化合物1-3粗品，直接用于下一步。LC-MS:m/z＝369.2[M+H]+。To a solution of compound 1-2 (1.6g, 4.53mmol, 1eq) in anhydrous methanol (16mL) was added N,N-dimethylformamide dimethyl acetal (1.08g, 9.05mmol, 2eq), after the addition, the reaction solution was heated to 75°C and continued to stir under nitrogen protection for 16 hours. The reaction solution was concentrated under reduced pressure, water (16 mL) was added, and extracted with ethyl acetate (16 mL*2). The organic phases were combined, washed with saturated brine (16 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude compound 1-3, which was directly used in the next step. LC-MS: m/z=369.2[M+H] + .
第四步the fourth step
在25℃下，向化合物1-3(1.46g,3.96mmol,1eq)的无水甲醇溶液(15mL)中加入盐酸(472.11μL,4.75mmol,36％纯度,1.2eq)和湿钯碳(0.2g,10％含量)，氮气置换三次，反应液在氢气(15Psi)下升温至50℃反应2小时。反应液过滤，滤液减压浓缩，得到化合物1-4粗品，直接用于下一步。LC-MS:m/z＝279.1[M+H]+。To a solution (15 mL) of compound 1-3 (1.46 g, 3.96 mmol, 1 eq) in anhydrous methanol, hydrochloric acid (472.11 μL, 4.75 mmol, 36% purity, 1.2 eq) and wet palladium on carbon (0.2 g, 10% content), nitrogen was replaced three times, and the reaction solution was heated to 50°C under hydrogen (15 Psi) for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 1-4, which was directly used in the next step. LC-MS: m/z=279.1[M+H] + .
第五步the fifth step
在25℃，向化合物1-4(0.8g,2.87mmol,1eq)的N,N-二甲基甲酰胺溶液(10mL)中加入化合物N-c(831.51mg,2.87mmol,1eq)，吡啶(695.91μL,8.62mmol,3eq)，苯硅烷(466.50mg,4.31mmol,1.5eq)，三甲基氯硅烷(780.58mg,7.18mmol,2.5eq),加完后氮气置换3次，反应液在60℃下搅拌16小时。反应液冷却至室温后加入水(10mL)淬灭，乙酸乙酯(10mL)萃取2次。合并有机相，用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤。滤液减压浓缩。剩余物用硅胶柱层析法分离纯化(乙酸乙酯:石油醚＝1:1)，得到化合物1-5。LC-MS:m/z＝552.3[M+H]+。At 25°C, compound Nc (831.51 mg, 2.87 mmol, 1 eq) and pyridine (695.91 μL) were added to a solution of compound 1-4 (0.8 g, 2.87 mmol, 1 eq) in N, N-dimethylformamide (10 mL). , 8.62mmol, 3eq), phenylsilane (466.50mg, 4.31mmol, 1.5eq), trimethylchlorosilane (780.58mg, 7.18mmol, 2.5eq), after addition, nitrogen was replaced three times, and the reaction solution was heated at 60°C Stir for 16 hours. The reaction solution was cooled to room temperature, quenched by adding water (10 mL), and extracted twice with ethyl acetate (10 mL). The organic phases were combined, washed with saturated brine (10 mL), 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=1:1) to obtain compound 1-5. LC-MS: m/z=552.3[M+H] + .
第六步Step 6
在25℃下，向化合物1-5(0.4g,725.05μmol,1eq)的四氢呋喃(2mL)和无水甲醇(2mL)混合溶液中加入一水合氢氧化锂(1M,3.63mL,5eq)，加完后反应液升温至50℃反应16小时。反应液冷却至室温后，用醋酸调节pH至6-7，减压浓缩，剩余物用高效液相色谱法纯化(色谱柱:Phenomenex Luna C18 75×30mm×3μm；流动相：A：水(0.05％盐酸)，B：乙腈，方法：B：16％-36％)得到化合物1的盐酸盐。1H NMR(400MHz,DMSO-d6)δ＝13.35-13.05(m,1H),11.32-11.15(m,1H),9.67-9.50(m,1H),8.15(br d,J＝7.9Hz,3H),8.02-7.97(m,1H),7.60-7.37(m,1H),6.90(d,J＝1.4Hz,1H),6.40-6.27(m,1H),3.87(s,3H),3.76-3.72(m,1H),3.55-3.49(m,1H),2.95-2.82(m,2H),2.82-2.73(m,2H),2.73-2.65(m,2H),2.48-2.41(m,2H),2.37-2.24(m,2H),2.09(br d,J＝15.6Hz,3H)；LC-MS:m/z＝438.2[M+H]+。At 25°C, add lithium hydroxide monohydrate (1M, 3.63mL, 5eq) to a mixed solution of compound 1-5 (0.4g, 725.05μmol, 1eq) in tetrahydrofuran (2mL) and anhydrous methanol (2mL), and add After completion, the reaction solution was heated to 50°C and reacted for 16 hours. After the reaction solution was cooled to room temperature, the pH was adjusted to 6-7 with acetic acid, concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (chromatographic column: Phenomenex Luna C18 75 × 30 mm × 3 μm; mobile phase: A: water (0.05 % hydrochloric acid), B: acetonitrile, method: B: 16%-36%) to obtain the hydrochloride salt of compound 1. 1 H NMR (400MHz, DMSO-d 6 ) δ = 13.35-13.05 (m, 1H), 11.32-11.15 (m, 1H), 9.67-9.50 (m, 1H), 8.15 (br d, J = 7.9Hz, 3H),8.02-7.97(m,1H),7.60-7.37(m,1H),6.90(d,J＝1.4Hz,1H),6.40-6.27(m,1H),3.87(s,3H),3.76 -3.72(m,1H),3.55-3.49(m,1H),2.95-2.82(m,2H),2.82-2.73(m,2H),2.73-2.65(m,2H),2.48-2.41(m, 2H), 2.37-2.24 (m, 2H), 2.09 (br d, J = 15.6Hz, 3H); LC-MS: m/z = 438.2 [M+H] + .
实施例2

Example 2

第一步first step
在0℃下，向化合物M-d(6g,18.84mmol,1eq)的N,N-二甲基甲酰胺(30mL)溶液中加入叔丁醇钠(5.43g,56.53mmol,3eq)然后缓慢滴加氘代溴乙烷(2.58g,22.61mmol,1.2eq)，该反应液在0℃下反应1小时。反应液缓慢滴加到冰水中(150mL)，然后用柠檬酸调节pH＝5～6，用乙酸乙酯(150mL*3)萃取。合并的有机层用饱和食盐水(100mL*2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，剩余物用硅胶柱层析法分离纯化(乙酸乙酯:石油醚＝1:3)，得到化合物2-1。LCMS:m/z＝352.2[M+H]+。At 0°C, add sodium tert-butoxide (5.43g, 56.53mmol, 3eq) to a solution of compound Md (6g, 18.84mmol, 1eq) in N,N-dimethylformamide (30mL) and then slowly add deuterium dropwise Bromoethane (2.58g, 22.61mmol, 1.2eq), the reaction solution was reacted at 0°C for 1 hour. The reaction solution was slowly added dropwise to ice water (150 mL), then the pH was adjusted to 5-6 with citric acid, and extracted with ethyl acetate (150 mL*3). The combined organic layers were washed with saturated brine (100mL*2), 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=1:3) , compound 2-1 was obtained. LCMS: m/z=352.2[M+H] + .
第二步Step 2
向化合物2-1(3.3g,9.39mmol,1eq)的二甲基亚砜(30mL)溶液中加入碳酸钾(1.43g,10.33mmol,1.1eq)和双氧水(1.35mL,14.08mmol,30％纯度,1.5eq)，在40℃下搅拌16小时。将反应液缓慢滴加到搅拌的冰水中(150mL)，继续搅拌0.5小时，过滤，滤饼用水(50mL*3)淋洗。滤饼减压真空干燥得到化合物2-2。LCMS:m/z＝370.2[M+H]+。To a solution of compound 2-1 (3.3g, 9.39mmol, 1eq) in dimethyl sulfoxide (30mL) were added potassium carbonate (1.43g, 10.33mmol, 1.1eq) and hydrogen peroxide (1.35mL, 14.08mmol, 30% purity ,1.5eq), stir at 40°C for 16 hours. Slowly add the reaction solution dropwise to the stirring ice water (150 mL), continue stirring for 0.5 hours, filter, and rinse the filter cake with water (50 mL*3). The filter cake was dried under reduced pressure to obtain compound 2-2. LCMS: m/z=370.2[M+H] + .
第三步third step
向化合物2-2(240.00mg,649.51μmol,1eq)的甲醇(5mL)溶液中加入N,N-二甲基甲酰胺二甲基缩醛(154.79mg,1.30mmol,2eq)，在70℃下搅拌16小时。反应液减压浓缩除去溶剂，剩余物加入乙酸乙酯(50mL)溶解，然后用水(30mL*3)洗涤，饱和食盐水(30mL*2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品化合物2-3。LCMS:m/z＝385.1[M+H]+。To a solution of compound 2-2 (240.00mg, 649.51μmol, 1eq) in methanol (5mL), N,N-dimethylformamide dimethyl acetal (154.79mg, 1.30mmol, 2eq) was added at 70°C. Stir for 16 hours. The reaction solution was concentrated under reduced pressure to remove the solvent. The residue was dissolved in ethyl acetate (50mL), then washed with water (30mL*3), washed with saturated brine (30mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Crude compound 2-3 was obtained. LCMS: m/z=385.1[M+H] + .
第四步the fourth step
将化合物2-3(220.00mg,572.14μmol,1eq)，湿钯碳(100mg,10％含量)和浓盐酸(68.17μL,686.57μmol,36％纯度,1.2eq)溶于甲醇(10mL)中，并用氮气置换3次，反应液在50℃，氮气保护下搅拌2小时。将反应液冷却并过滤，得到的滤液减压浓缩，剩余物加入水(50mL)，用1M的氢氧化钠水溶液调节pH＝9～10，乙酸乙酯(50mL*3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品化合物2-4。LCMS:m/z＝295.2[M+H]+。Compound 2-3 (220.00 mg, 572.14 μmol, 1 eq), wet palladium on carbon (100 mg, 10% content) and concentrated hydrochloric acid (68.17 μL, 686.57 μmol, 36% purity, 1.2 eq) were dissolved in methanol (10 mL). The mixture was replaced with nitrogen three times, and the reaction solution was stirred for 2 hours at 50°C under nitrogen protection. The reaction solution was cooled and filtered. The obtained filtrate was concentrated under reduced pressure. Water (50mL) was added to the residue. The pH was adjusted to 9~10 with 1M sodium hydroxide aqueous solution. Extracted with ethyl acetate (50mL*3). The organic phases were combined. Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude compound 2-4. LCMS: m/z=295.2[M+H] + .
第五步the fifth step
向化合物2-4(0.16g,543.48μmol,1eq)和化合物N-c(157.24mg,543.48μmol,1eq)的N,N-二甲基甲酰胺(5mL)溶液中加入吡啶(131.60μL,1.63mmol,3eq)，三甲基氯硅烷(147.61mg,1.36mmol,2.5eq)和苯硅烷(88.21mg,815.22μmol,1.5eq)，反应液在100℃，氮气保护下搅拌3小时。向反应液中加入水(50mL)，用乙酸乙酯(50mL*2)萃取。合并有机相用饱和食盐水(50mL*2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，剩余物用硅胶柱层析法分离纯化(乙酸乙酯:石油醚＝1:3)，得到化合物2-5。LCMS:m/z＝568.3[M+H]+。Pyridine (131.60 μL, 1.63 mmol, 3eq), trimethylchlorosilane (147.61mg, 1.36mmol, 2.5eq) and phenylsilane (88.21mg, 815.22μmol, 1.5eq). The reaction solution was stirred at 100°C under nitrogen protection for 3 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL*2). The combined organic phases were washed with saturated brine (50mL*2), 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=1:3). Compound 2-5 was obtained. LCMS: m/z=568.3[M+H] + .
第六步 Step 6
向化合物2-5(180.96mg,318.75μmol,1eq)的四氢呋喃(3mL)和甲醇(3mL)溶液中加入氢氧化锂水溶液(1M,3mL,9.41eq)，在50℃下搅拌16小时。将反应液降至室温后用醋酸调节pH到7，然后减压浓缩，得到的残留物用高效液相色谱法纯化(色谱柱:Phenomenex C18 75×30mm×3μm；流动相：A：水(0.05％盐酸)，B：乙腈，梯度：B：22％-42％)得到化合物2的盐酸盐。1H NMR(400MHz,DMSO-d6)δ＝13.22(br s,1H),11.25(br s,1H),9.75(br s,1H),8.13(br d,J＝8.0Hz,2H),8.06-7.75(m,2H),7.43(t,J＝2.8Hz,1H),6.82(s,1H),6.39(br s,1H),4.06-3.93(m,3H),3.86(s,3H),3.60(br s,1H),2.93-2.79(m,2H),2.74-2.71(m,1H),2.64-2.55(m,1H),2.53-2.51(m,2H),2.47-2.45(m,1H),2.40-2.27(m,2H),2.03(br d,J＝16Hz,2H)；LC-MS:m/z＝454.2[M+H]+。To a solution of compound 2-5 (180.96 mg, 318.75 μmol, 1 eq) in tetrahydrofuran (3 mL) and methanol (3 mL) was added an aqueous lithium hydroxide solution (1 M, 3 mL, 9.41 eq), and the mixture was stirred at 50°C for 16 hours. After the reaction solution was brought to room temperature, the pH was adjusted to 7 with acetic acid, and then concentrated under reduced pressure. The obtained residue was purified by high performance liquid chromatography (chromatographic column: Phenomenex C18 75 × 30 mm × 3 μm; mobile phase: A: water (0.05 % hydrochloric acid), B: acetonitrile, gradient: B: 22%-42%) to obtain the hydrochloride salt of compound 2. 1 H NMR (400MHz, DMSO-d 6 ) δ = 13.22 (br s, 1H), 11.25 (br s, 1H), 9.75 (br s, 1H), 8.13 (br d, J = 8.0Hz, 2H), 8.06-7.75(m,2H),7.43(t,J＝2.8Hz,1H),6.82(s,1H),6.39(br s,1H),4.06-3.93(m,3H),3.86(s,3H ),3.60(br s,1H),2.93-2.79(m,2H),2.74-2.71(m,1H),2.64-2.55(m,1H),2.53-2.51(m,2H),2.47-2.45( m, 1H), 2.40-2.27 (m, 2H), 2.03 (br d, J = 16Hz, 2H); LC-MS: m/z = 454.2 [M+H] + .
参照实施例1和2的方法，由片段A和片段B制备下表1中的化合物：Referring to the methods of Examples 1 and 2, the compounds in Table 1 below were prepared from fragment A and fragment B:
表1







Table 1







生物化学检测Biochemical testing
实验例1：Wieslab补体旁路通路活化抑制(酶活测试)Experimental Example 1: Wieslab complement alternative pathway activation inhibition (enzyme activity test)
实验目的：Purpose:
通过补体***旁路通路试剂盒，对待测化合物针对人血清中补体旁路通路的抑制活性的测定。实验方案：pass The complement system alternative pathway kit is used to determine the inhibitory activity of the test compound against the complement alternative pathway in human serum. Experimental program:
用稀释液将血清进行稀释(1：23)。向稀释的血清中加入药物，8个浓度梯度，最高10mM或50mM，5倍梯度稀释。室温孵育15min。将化合物和血清混合物加入试剂盒提供的96孔板(100μL/孔)，在37度激活1小时。用洗涤缓冲液清洗三遍。加入试剂盒提供的检测抗体(100μL)在室温进行孵育30min。用洗涤缓冲液清洗三遍。加入底物(100μL)在室温进行孵育30min。酶标仪405nM处检测吸光度。Dilute the serum with diluent (1:23). Add the drug to the diluted serum in 8 concentration gradients, up to 10mM or 50mM, in 5-fold gradient dilutions. Incubate at room temperature for 15 minutes. Add the compound and serum mixture to the 96-well plate provided in the kit (100 μL/well) and activate at 37 degrees for 1 hour. Wash three times with wash buffer. Add the detection antibody (100 μL) provided by the kit and incubate at room temperature for 30 minutes. Wash three times with wash buffer. Add substrate (100 μL) and incubate at room temperature for 30 min. The absorbance was measured at 405nM with a microplate reader.
实验结果：Experimental results:
测试化合物对补体旁路通路抑制活性结果如表2所示。其中A代表：IC50值＜100nM；B代表：100nM≤IC50值≤1000nM；C代表：IC50值＞1000nM。The results of the inhibitory activity of the test compounds on the complement alternative pathway are shown in Table 2. Among them, A represents: IC 50 value <100nM; B represents: 100nM ≤ IC 50 value ≤ 1000nM; C represents: IC 50 value > 1000nM.
表2：本发明化合物体外酶活性筛选试验结果
Table 2: In vitro enzyme activity screening test results of the compounds of the present invention
结论：本发明化合物对人血清旁路通路激活抑制活性明显。Conclusion: The compound of the present invention has obvious inhibitory activity on the activation of human serum bypass pathway.
实验例2：大鼠药代动力学研究Experimental Example 2: Pharmacokinetic Study in Rats
实验目的：Purpose:
以雄性SD大鼠为受试动物，应用LC/MS/MS法测定大鼠口服灌胃给予本发明的化合物后不同时刻血浆中的药物浓度。研究本发明的化合物在大鼠体内的药代动力学行为，评价其药代动力学特征。Male SD rats were used as test animals, and the LC/MS/MS method was used to determine the drug concentration in the plasma of the rats at different times after oral administration of the compound of the present invention. Study the pharmacokinetic behavior of the compound of the present invention in rats and evaluate its pharmacokinetic characteristics.
试验方案：Test plan:
健康雄性大鼠200-300g，每组2只。Healthy male rats weighing 200-300g, 2 rats per group.
将本发明化合物，用20％PEG400/10％solutol/70％水配制成3mg/mL的澄清溶液。大鼠禁食一夜后给药，剂量：30mg/kg，给药方式：口服灌胃。于给药前及给药后0.25、0.5、1、2、4、7、24小时采血，置于肝素化抗凝试管中，7000rpm(5204g)、4℃下离心，分离血浆，于-80℃保存。给药后4小时进食。用LC/MS/MS法测定口服给药后大鼠血浆中的待测化合物含量。血浆样品经沉淀蛋白预处理后进行分析。实验结果：The compound of the present invention was prepared into a clear solution of 3 mg/mL using 20% PEG400/10% solution/70% water. Rats were fasted overnight before administration, dose: 30 mg/kg, administration method: oral gavage. Collect blood before and 0.25, 0.5, 1, 2, 4, 7, and 24 hours after administration, place it in a heparinized anticoagulant test tube, centrifuge at 7000 rpm (5204g), 4°C, separate plasma, and store at -80°C save. Eat 4 hours after dosing. The LC/MS/MS method was used to determine the content of the test compound in rat plasma after oral administration. Plasma samples were analyzed after pretreatment with precipitated proteins. Experimental results:
药代动力学参数结果见表3。The results of pharmacokinetic parameters are shown in Table 3.
表3：本发明化合物大鼠药代动力学数据
Table 3: Rat pharmacokinetic data of the compounds of the present invention
注：Cmax：达峰浓度；Tmaax：达峰时间；T1/2：药物消除半衰期；AUC0-last：0-末次取样时间内的药物-时间曲线下面积。Note: C max : peak concentration; T maax : peak time; T 1/2 : drug elimination half-life; AUC 0-last : 0-area under the drug-time curve within the last sampling time.
结论：本发明化合物具有较好的口服暴露量和较长的半衰期，药代动力学性质优良。Conclusion: The compound of the present invention has good oral exposure, long half-life, and excellent pharmacokinetic properties.
实验例3：LPS诱导补体激活小鼠体内PD模型Experimental Example 3: LPS-induced complement activation in vivo mouse PD model
实验目的：Purpose:
考察本发明化合物对LPS刺激诱导小鼠补体激活的抑制作用。The inhibitory effect of the compounds of the present invention on complement activation in mice induced by LPS stimulation was examined.
实验动物：Experimental animals:
雌性C57BL/6J小鼠，7-9周龄，体重17-23克；供应商：上海西普尔-必凯实验动物有限公司。Female C57BL/6J mice, 7-9 weeks old, weighing 17-23 grams; supplier: Shanghai Sipur-Bika Experimental Animal Co., Ltd.
实验过程：experiment procedure:
在给药前4小时，将鼠伤寒沙门氏菌(Sigma)中的100μg脂多糖(LPS)溶解在100μL无菌PBS(磷酸盐缓冲液pH 7.2-7.4)中通过腹腔内注射诱导小鼠补体激活。正常小鼠组(阴性对照)：动物接受腹膜内 注射100μL无菌PBS，并通过灌饲法(IO)单独给药溶媒。模型组(阳性对照)：动物接受腹腔内LPS和PO给药溶媒(20％PEG400/10％solutol/70％水)。药物组：给药化合物(溶媒：20％PEG400/10％solutol/70％水，给药体积：5mL/kg，剂量：10mg/kg)后4小时，进行样品采集。Complement activation was induced in mice by intraperitoneal injection of 100 μg lipopolysaccharide (LPS) from Salmonella typhimurium (Sigma) dissolved in 100 μL sterile PBS (phosphate buffer pH 7.2-7.4) 4 hours before administration. Normal mouse group (negative control): animals received i.p. Inject 100 μL of sterile PBS and administer vehicle alone by gavage (IO). Model group (positive control): animals received intraperitoneal LPS and PO administration of vehicle (20% PEG400/10% solutol/70% water). Drug group: Samples were collected 4 hours after compound administration (vehicle: 20% PEG400/10% solution/70% water, administration volume: 5 mL/kg, dose: 10 mg/kg).
样品采集：从眼眶静脉丛采集血液样本0.3mL。所有血样均加入规格为1.5mL的商品化EDTA-K2抗凝管中(供应商为江苏康健医疗用品有限公司)。血样采集后，在半小时内，于4℃、3000g离心10分钟吸取上清血浆，迅速至于干冰中，于-80℃冰箱保存，用于Western blot分析补体激活后下游C3d蛋白水平。Sample collection: 0.3 mL of blood sample was collected from the orbital venous plexus. All blood samples were added into commercial EDTA-K2 anticoagulant tubes with a specification of 1.5 mL (supplier is Jiangsu Kangjian Medical Products Co., Ltd.). After blood samples are collected, within half an hour, centrifuge at 4°C and 3000g for 10 minutes to aspirate the supernatant plasma, quickly transfer it to dry ice, and store it in a -80°C refrigerator for Western blot analysis of downstream C3d protein levels after complement activation.
样品分析：小鼠血浆(5μL)+Lysis buffer(裂解液，27.5μL)+Loading buffer(上样缓冲液，12.5μL)+Reducing buffer(还原缓冲液，5μL)混匀100℃孵育15min，上样量为5μL/孔，即每孔血浆上样量为0.5μL。Sample analysis: Mouse plasma (5 μL) + Lysis buffer (lysis buffer, 27.5 μL) + Loading buffer (loading buffer, 12.5 μL) + Reducing buffer (reducing buffer, 5 μL), mix well, incubate at 100°C for 15 minutes, and load the sample The volume is 5 μL/well, that is, the plasma loading volume per well is 0.5 μL.
实验结果：Experimental results:
通过腹腔内注射诱导小鼠补体激活后，模型组小鼠血清中C3d蛋白水平与正常组相比升高40％～50％，在口服给药本发明化合物后，各药物组小鼠血清中C3d蛋白水平相对造模组下降了60％～80％，C3d蛋白水平下降显著，具体实验结果见附图1。After inducing complement activation in mice through intraperitoneal injection, the C3d protein level in the serum of mice in the model group increased by 40% to 50% compared with the normal group. After oral administration of the compound of the present invention, the C3d protein level in the serum of mice in each drug group increased by 40% to 50%. The protein level dropped by 60% to 80% compared to the modeling group, and the C3d protein level dropped significantly. The specific experimental results are shown in Figure 1.
实验结论：与正常组和模型造模组相比，本发明化合物能够显著抑制LPS刺激的补体激活。 Experimental conclusion: Compared with the normal group and the model group, the compound of the present invention can significantly inhibit complement activation stimulated by LPS.

Claims (15)

  1. 式(I)所示化合物或其药学上可接受的盐，
    The compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
    其中，in,
    T1和T2分别独立地选自CH或N；T 1 and T 2 are independently selected from CH or N;
    R1、R5、R6、R7、R8和R9分别独立地选自H或D；R 1 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from H or D;
    R2和R3与它们连接的原子一起形成3-6元杂环基，此时，R4选自H、D、卤素、C1-3烷基、C1-3烷氧基、氘代C1-3烷基或氘代C1-3烷氧基；R 2 and R 3 together with the atoms to which they are connected form a 3-6 membered heterocyclyl group. At this time, R 4 is selected from H, D, halogen, C 1-3 alkyl, C 1-3 alkoxy, deuterated C 1-3 alkyl or deuterated C 1-3 alkoxy;
    或者，R2和R4与它们连接的原子一起形成3-6元杂环基，所述3-6元杂环基任选被1、2或3个Rb取代，此时，R3选自H、D、卤素、C1-3烷基或C1-3烷氧基，所述C1-3烷基或C1-3烷氧基分别独立地任选被1、2、3、4或5个Ra取代；Alternatively, R 2 and R 4 together with the atoms to which they are connected form a 3-6 membered heterocyclyl group, and the 3-6 membered heterocyclyl group is optionally substituted by 1, 2 or 3 R b . In this case, R 3 is selected from From H, D, halogen, C 1-3 alkyl or C 1-3 alkoxy, the C 1-3 alkyl or C 1-3 alkoxy is independently optionally substituted by 1, 2, 3, 4 or 5 R a substitutions;
    每个Ra分别独立地选自D、-F、-Cl、-Br或-I；Each R a is independently selected from D, -F, -Cl, -Br or -I;
    每个Rb分别独立地选自D、卤素、C1-3烷基、C1-3烷氧基、-C(＝O)-C1-3烷基或-S(＝O)m-C1-3烷基，所述C1-3烷基、C1-3烷氧基、-C(＝O)-C1-3烷基或-S(＝O)m-C1-3烷基分别独立地任选被1、2、3、4或5个R取代；Each R b is independently selected from D, halogen, C 1-3 alkyl, C 1-3 alkoxy, -C(=O)-C 1-3 alkyl or -S(=O) m - C 1-3 alkyl, the C 1-3 alkyl, C 1-3 alkoxy, -C(=O)-C 1-3 alkyl or -S(=O) m -C 1-3 The alkyl groups are each independently optionally substituted by 1, 2, 3, 4 or 5 R;
    每个R分别独立地选自D、-F、-Cl、-Br、-I或-OH；Each R is independently selected from D, -F, -Cl, -Br, -I or -OH;
    m选自0、1或2；m is selected from 0, 1 or 2;
    n选自0或1；n is selected from 0 or 1;
    条件是，R1、R3、R4、R5、R6、R7、R8、R9、Ra、Rb和R中至少有一个选自D或氘代基团。The condition is that at least one of R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R a , R b and R is selected from D or a deuterated group.
  2. 根据权利要求1所述的式(I)化合物，其中，T1选自CH，T2选自CH；或者T1选自CH，T2选自N；或者T1选自N，T2选自CH。The compound of formula (I) according to claim 1, wherein T 1 is selected from CH and T 2 is selected from CH; or T 1 is selected from CH and T 2 is selected from N; or T 1 is selected from N and T 2 is selected from N. Since CH.
  3. 根据权利要求1所述的式(I)化合物，其中，R2和R3与它们连接的原子一起形成氮杂环丁基、氮杂环戊基或氮杂环己基，此时，所述R4选自H、D、-CH3、-CH2CH3、-OCH3、-OCH2CH3、-CD3、-CD2CD3、-OCD3或-OCD2CD3。The compound of formula (I) according to claim 1, wherein R 2 and R 3 together with the atoms to which they are connected form azetidinyl, azepanyl or azetidinyl, at this time, the R 4 is selected from H, D, -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -CD 3 , -CD 2 CD 3 , -OCD 3 or -OCD 2 CD 3 .
  4. 根据权利要求1所述的式(I)化合物，其中，R2和R4与它们连接的原子一起形成氧杂环丁基、氧杂环戊基、氧杂环己基、氮杂环丁基、氮杂环戊基或氮杂环己基，所述氧杂环丁基、氧杂环戊基、氧杂环己基、氮杂环丁基、氮杂环戊基或氮杂环己基分别独立地任选被1、2或3个Rb取代，此时，所述R3选自H或D。The compound of formula (I) according to claim 1, wherein R 2 and R 4 together with the atoms to which they are connected form oxetanyl, oxetanyl, oxetanyl, azetidinyl, Azetidinyl or azehexyl, the oxetanyl, oxetyl, oxetanyl, azetidinyl, azetyl or azetyl are independently any It is selected to be replaced by 1, 2 or 3 R b . At this time, the R 3 is selected from H or D.
  5. 根据权利要求1所述的式(I)化合物，其中，每个Rb各自独立地选自D、-F、-CH3、-CH2CH3、-OCH3、-OCH2CH3、-C(＝O)CH3、-C(＝O)CH2CH3、-SCH3、-SCH2CH3、-S(＝O)CH3或-S(＝O)2CH3，所述-CH3、 -CH2CH3、-OCH3、-OCH2CH3、-C(＝O)CH3、-C(＝O)-CH2CH3、-SCH3、-SCH2CH3、-S(＝O)CH3或-S(＝O)2CH3分别独立地任选被1、2、3、4或5个R取代。The compound of formula (I) according to claim 1, wherein each R b is independently selected from D, -F, -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , - C(=O)CH 3 , -C(=O)CH 2 CH 3 , -SCH 3 , -SCH 2 CH 3 , -S(=O)CH 3 or -S(=O) 2 CH 3 , as described -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -C(＝O)CH 3 , -C(＝O)-CH 2 CH 3 , -SCH 3 , -SCH 2 CH 3 , -S( =O)CH 3 or -S(=O) 2 CH 3 are each independently optionally substituted with 1, 2, 3, 4 or 5 R.
  6. 根据权利要求1所述的式(I)化合物，其中，每个R各自独立地选自D或-F。The compound of formula (I) according to claim 1, wherein each R is independently selected from D or -F.
  7. 根据权利要求1所述的式(I)化合物，其中，结构单元选自 The compound of formula (I) according to claim 1, wherein the structural unit Selected from
  8. 根据权利要求1所述的式(I)化合物，其中，结构单元选自苯基、吡啶基和哒嗪基。The compound of formula (I) according to claim 1, wherein the structural unit Selected from phenyl, pyridyl and pyridazinyl.
  9. 根据权利要求1所述的式(I)化合物，其中，化合物选自，
    The compound of formula (I) according to claim 1, wherein the compound is selected from,
    其中，in,
    R1、R4、R5、R6、R7、R8、R9、Rb、n、T1和T2如权利要求1所定义； R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R b , n, T 1 and T 2 are as defined in claim 1;
    当R4、R5不相同时，带“#”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；When R 4 and R 5 are different, the carbon atom with "#" is a chiral carbon atom, existing in the form of (R) or (S) single enantiomer or enriched in one enantiomer;
    带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。The carbon atoms with "*" are chiral carbon atoms, which exist in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
  10. 根据权利要求1所述的式(I)化合物，其中，化合物选自，
    The compound of formula (I) according to claim 1, wherein the compound is selected from,
    其中，in,
    R1、R4、R5、R6、R9和Rb如权利要求1所定义；R 1 , R 4 , R 5 , R 6 , R 9 and R b are as defined in claim 1;
    当R4、R5不相同时，带“#”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；When R 4 and R 5 are different, the carbon atom with "#" is a chiral carbon atom, existing in the form of (R) or (S) single enantiomer or enriched in one enantiomer;
    带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。The carbon atoms with "*" are chiral carbon atoms, which exist in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
  11. 下列所示化合物或其药学上可接受的盐，

    The following compounds or pharmaceutically acceptable salts thereof,

  12. 下列所示化合物或其药学上可接受的盐，


    The following compounds or pharmaceutically acceptable salts thereof,


  13. 一种药物组合物，其含有治疗有效量的权利要求1所述的式(I)化合物或其药学上可接受的盐。A pharmaceutical composition containing a therapeutically effective amount of the compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.
  14. 权利要求1所述的式(I)化合物或其药学上可接受的盐或权利要求13所述的药物组合物在制备治疗与补体因子B相关疾病的药物中的应用。Use of the compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 13 in the preparation of a medicament for treating diseases related to complement factor B.
  15. 权利要求1所述的式(I)化合物或其药学上可接受的盐或权利要求13所述的药物组合物在治疗与补体因子B相关疾病中的应用。 Use of the compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 13 in the treatment of diseases related to complement factor B.
PCT/CN2023/098918 2022-06-07 2023-06-07 Bicyclic substituted aromatic carboxylic acid-type deuterated compound WO2023237012A1 (en)

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CN114057692A (en) * 2020-08-07 2022-02-18 上海美悦生物科技发展有限公司 Heterocyclic compound, preparation method and application thereof
CN114057758A (en) * 2020-08-07 2022-02-18 上海美悦生物科技发展有限公司 Complement factor B inhibitor and pharmaceutical composition, preparation method and application thereof
WO2022218429A1 (en) * 2021-04-16 2022-10-20 正大天晴药业集团股份有限公司 Bicyclic substituted aromatic carboxylic acid compounds
WO2022256586A2 (en) * 2021-06-03 2022-12-08 Chinook Therapeutics, Inc. Substituted indole compounds and methods of use thereof
WO2023020566A1 (en) * 2021-08-18 2023-02-23 四川海思科制药有限公司 Benzo nitrogen-containing heteroaromatic ring derivative and use thereof in medicine
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114057692A (en) * 2020-08-07 2022-02-18 上海美悦生物科技发展有限公司 Heterocyclic compound, preparation method and application thereof
CN114057758A (en) * 2020-08-07 2022-02-18 上海美悦生物科技发展有限公司 Complement factor B inhibitor and pharmaceutical composition, preparation method and application thereof
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