WO2023237041A1 - Bicyclic substituted aromatic carboxylic acid ester compound - Google Patents

Bicyclic substituted aromatic carboxylic acid ester compound Download PDF

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Publication number
WO2023237041A1
WO2023237041A1 PCT/CN2023/099083 CN2023099083W WO2023237041A1 WO 2023237041 A1 WO2023237041 A1 WO 2023237041A1 CN 2023099083 W CN2023099083 W CN 2023099083W WO 2023237041 A1 WO2023237041 A1 WO 2023237041A1
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compound
alkyl
pharmaceutically acceptable
acceptable salt
optionally substituted
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PCT/CN2023/099083
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French (fr)
Chinese (zh)
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丁照中
颜小兵
杨玲
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 WO2023237041A1 publication Critical patent/WO2023237041A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems

Definitions

  • the present invention relates to bicyclic substituted aromatic carboxylic acid ester compounds, specifically to the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • 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).
  • 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.
  • the complement system 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.
  • Complement 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.
  • Factor B inhibitors 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 for unmet clinical needs.
  • the present invention provides compounds represented by formula (I) or pharmaceutically acceptable salts thereof,
  • T 1 and T 2 are independently selected from CH or N;
  • R 1 , R 5 , R 6 , R 8 , R 9 and R 10 are each independently selected from H or D;
  • R 2 and R 3 together with the atoms to which they are connected form a 3-6 membered heterocyclyl group.
  • 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;
  • 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 .
  • 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 or 3 R a substitution;
  • R 7 is selected from C 1-6 alkyl, phenyl, The C 1-6 alkyl group is optionally substituted by 1, 2, 3, 4 or 5 F, and the phenyl group is optionally substituted by 1, 2 or 3 R c ;
  • R 11 is selected from C 1-6 alkyl or C 1-6 alkoxy, which is independently optionally substituted by 1, 2, 3 , 4 or 5. F substitution; each R a is independently selected from D, -F, -Cl, -Br or -I;
  • the alkyl groups are each independently optionally substituted by 1, 2, 3, 4 or 5 R;
  • Each R c is independently selected from -F, -Cl, -Br, -I, C 1-6 alkyl or C 1-6 alkoxy, the C 1-6 alkyl or C 1-6 alkyl
  • the oxygen groups are independently optionally substituted by 1, 2, 3, 4 or 5 F;
  • Each R is independently selected from D, -F, -Cl, -Br, -I or -OH;
  • n is selected from 0, 1 or 2.
  • each R is independently selected from D, -F or -Cl, and other variables are as defined in the invention.
  • each R is independently selected from D or -F, and other variables are as defined in the invention.
  • each R a is independently selected from D, -F or -Cl, and other variables are as defined in the invention.
  • each R a is independently selected from D or -F, and other variables are as defined in 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. .
  • each R b is independently selected from D or -CD 2 CD 3 , and other variables are as defined in 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.
  • each R b is independently selected from -CH 2 CF 3 , and other variables are as defined in the invention.
  • T 1 is selected from CH
  • T 2 is selected from CH
  • other variables are as defined in the invention.
  • T 1 is selected from CH
  • T 2 is selected from N
  • other variables are as defined in the invention.
  • T 1 is selected from N
  • T 2 is selected from CH
  • other variables are as defined in the 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.
  • the R 2 and R 3 together with the atoms to which they are connected form an azacyclopentyl group.
  • 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.
  • the R 2 and R 3 together with the atoms to which they are connected form an azacyclopentyl group.
  • the R 4 is selected from -OCH 3 or -OCD 3 , and other variables are as in the present invention. defined.
  • the R 2 and R 3 together with the atoms to which they are connected form an azacyclopentyl group.
  • the R 4 is selected from -OCH 2 CH 3 or -OCD 2 CD 3 , others Variables are as defined herein.
  • 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 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.
  • R 11 is selected from -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 or -C(CH 3 ) 3 , and the -CH 3.
  • -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 or -C(CH 3 ) 3 are each independently optionally substituted by 1, 2, 3, 4 or 5 F, Other variables are as defined in the present invention.
  • R 11 is selected from -C(CH 3 ) 3 , and other variables are as defined in the invention.
  • R 7 is selected from -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , phenyl,
  • the -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 or -CH(CH 3 ) 2 are independently optionally substituted by 1, 2, 3, 4 or 5 F, and other variables are as follows defined by invention.
  • R 7 is selected from -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 ,
  • the -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 or -CH(CH 3 ) 2 are independently optionally substituted by 1, 2, 3, 4 or 5 F, and other variables are as follows defined by invention.
  • R 7 is selected from -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , Other variables are as defined in the present invention.
  • R 7 is selected from -CH 3 , -CH 2 CH 3 , Other variables are as defined in the present invention.
  • R 7 is selected from -CH 3 or -CH 2 CH 3 , and other variables are as defined in the invention.
  • R 7 is selected from -CH 3 , and other variables are as defined in the invention.
  • n is selected from 2, and other variables are as defined in the invention.
  • the 3-6-membered heterocyclyl group is selected from 3-6-membered saturated heterocyclyl groups containing N or O.
  • 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 structural unit Selected from phenyl, pyridyl or pyridazinyl, other variables are as defined in the present invention.
  • 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 7 , R b , T 1 and T 2 are as defined in 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 atom with "*" It is a chiral carbon atom and exists 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 7 , T 1 and T 2 are as defined in the present invention.
  • the compound or a pharmaceutically acceptable salt thereof is selected from,
  • R 1 , R 4 and R 7 are as defined in the present invention.
  • the present invention also provides the following compounds or pharmaceutically acceptable salts thereof,
  • the compound or a pharmaceutically acceptable salt thereof is selected from,
  • 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 present invention also provides a method for preparing a compound of formula (I), which includes: reacting a compound of formula (II) with R 7 -OH to obtain a compound of formula (I),
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , T 1 and T 2 are as described for the compound of formula (I) of the present invention.
  • the invention also provides a preparation method of compound M1, which includes: (1) Compound Ma reacts with compound R p -NH 2 and 1,3-acetone dicarboxylic acid to obtain compound M-b'; (2) Compound M-b 'Compound M-c' is obtained by separation with a chiral reagent; (3) Compound M-c' undergoes a reduction reaction to obtain compound M-d'; (4) Compound M-d' reacts with an ethylation reagent to obtain compound M-e '; (5) Compound M-e' undergoes hydrolysis reaction to obtain compound M-f'; (6) Compound M-f' reacts with methylating reagent to obtain compound M-g'; (7) Compound M-g' occurs Deprotection reaction yields compound Mh; (8) Compound Mh reacts with compound Nc to yield compound Mi; (9) Compound Mi undergoes deprotection reaction to yield compound M1.
  • Rp is selected from Bn or PMB.
  • the preparation method of compound M1, wherein the chiral reagent in step (2) is selected from L-di-tere-benzoyltartaric acid or D-di-tere-benzoyltartaric acid.
  • the preparation method of compound M1, wherein the reducing agent in step (3) is selected from diisobutylaluminum hydride, sodium borohydride, tri-sec-butyllithium borohydride or diisobutyl Aluminum hydride.
  • the preparation method of compound M1, wherein the ethylation reagent in step (4) is selected from ethyl iodide, ethyl bromide or diethyl sulfate.
  • the preparation method of compound M1, wherein the methylating reagent in step (6) is selected from sulfoxide chloride/methanol, methanol hydrochloride or DMF-DMA/methanol.
  • the present invention also provides a method for preparing intermediate compound Me for the preparation of compound M1, which includes: (1) reacting compound Ma with benzylamine and 1,3-acetone dicarboxylic acid to obtain compound Mb; (2) separating compound Mb with a chiral reagent Obtain compound Mc; (3) Compound Mc undergoes reduction reaction to obtain compound Md; (4) Compound Md reacts with ethyl ester reagent to obtain compound Me;
  • the preparation method of compound M-e, wherein the reaction conditions are as described in the preparation method of compound M1.
  • the present invention also provides the following compounds or pharmaceutically acceptable salts thereof:
  • the present invention also provides the use of the above compounds M-e, M-f, M-g, M-h in preparing compound M1.
  • the compound of the present invention can significantly inhibit complement activation stimulated by LPS, has good pharmacokinetic properties, and can be developed into a new small molecule inhibitor of the 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases.
  • 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.
  • 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.
  • 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.
  • diastereomer refers to stereoisomers whose molecules have two or more chiral centers and are in a non-mirror image relationship between the molecules.
  • 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
  • wedge-shaped solid line key or wedge-shaped dotted key or use tilde Represents a straight solid line key or straight dotted key
  • the following formula (A) indicates that the compound exists as a single isomer of formula (A-1) or formula (A-2) or as two isomers of formula (A-1) and formula (A-2) exists in the form of a mixture;
  • the following formula (B) indicates that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2) or in the form of both formula (B-1) and formula (B-2) Exists as a mixture of isomers.
  • 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.
  • 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.
  • proton tautomers also called proton transfer tautomers
  • proton migration 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.
  • keto-enol tautomerization is the tautomerization between pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • 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.
  • oxygen it means that 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 1-6 alkyl is used to mean a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms.
  • the C 1-6 alkyl group includes C 1-4 , C 1-3 , C 2-4, C 2-3 , C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkyl groups, etc.; It can be monovalent (such as methyl), bivalent (such as methylene) or polyvalent (such as methine).
  • Examples of C 1-5 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • 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.
  • C 1-6 alkoxy means those alkyl groups containing 1 to 6 carbon atoms that are attached to the remainder of the molecule through an oxygen atom.
  • the C 1-6 alkoxy group includes C 1-4 , C 1-3 , C 2-4, C 2-3 , C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy group wait.
  • Examples of C 1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • 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
  • 4-6 membered saturated heterocyclyl by itself or in combination with other terms respectively means a saturated monocyclic cyclic group consisting of 4 to 6 ring atoms, of which 1, 2, 3 or 4 Two ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, in which the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms can 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.
  • Examples of 4-6 membered saturated heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidiny
  • 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.
  • 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.
  • 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.
  • SXRD single crystal X-ray diffraction
  • the light source is CuK ⁇ radiation
  • the scanning mode is: ⁇ / ⁇ scanning.
  • Shelxs97 can confirm the absolute configuration by analyzing the crystal structure.
  • 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.
  • Benzylamine (194.62g) was slowly added to water (850mL) dissolved in acetic acid (103.88mL). The reaction system was cooled to 0-10°C, then 1,3-acetone dicarboxylic acid (265.36g) was slowly added in batches, and the reaction solution was allowed to react at 0°C for 0.5 hours. A solution of compound Ma (170 g) dissolved in dioxane (850 mL) 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.
  • N,N-dimethylformamide dimethyl acetal (59.81g) was added to a solution of compound Mf (99g) in methanol (1000mL), and the reaction solution was heated to 40°C and stirred for 16 hours. The reaction solution was directly concentrated under reduced pressure to obtain the residue. Ethyl acetate (1000 mL) was added to the residue, and then washed with water (500 mL) and saturated brine (500 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound Mg, which was directly used in the next step.
  • reaction solution was cooled to room temperature, the reaction solution was filtered under reduced pressure and continued to be purified with a chromatographic column (chromatographic column: Unisil 3-100 C18 Ultra 150*50mm*3 ⁇ m; mobile phase: A: water (0.025% formic acid), B: acetonitrile, Method: B: 20%-50%), add saturated sodium bicarbonate aqueous solution (50mL) to the reaction solution, and extract with ethyl acetate (50mL*2). The combined organic phases were washed with saturated brine (50 mL*2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 6.
  • N,N-diisopropylethylamine 179.14 ⁇ L
  • chloromethyl pivalate 154.89 mg
  • the liquid was heated to 60°C and stirred for 2 hours.
  • reaction solution was cooled to room temperature, concentrated under reduced pressure, and continued to be purified with a chromatographic column (chromatographic column: Phenomenex luna C18 150*25mm*10 ⁇ m; mobile phase: A: water (0.025% formic acid), B: acetonitrile, method: B: 26% -56%), add saturated sodium bicarbonate aqueous solution to the reaction solution to adjust the pH to 8, concentrate under reduced pressure to remove the solvent acetonitrile, and extract with ethyl acetate (50 mL*2). The combined organic phases were washed with saturated brine (50 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 8.
  • chromatographic column Phenomenex luna C18 150*25mm*10 ⁇ m; mobile phase: A: water (0.025% formic acid), B: acetonitrile, method: B: 26% -56%
  • 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: The results of pharmacokinetic parameters are shown in Table 1.
  • 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.
  • ND The blood drug concentration is lower than the detection limit and not fitted; ND*: Not fitted within 24 hours.
  • Experimental animals female C57BL/6J mice, 7-9 weeks old, weighing 17-23 grams; supplier: Shanghai Sipur-Bika Experimental Animal Co., Ltd. experiment procedure:
  • LPS lipopolysaccharide
  • Salmonella typhimurium Salmonella typhimurium
  • sterile PBS phosphate buffer pH 7.2-7.4
  • PO gavage
  • 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, centrifuge them at 4°C and 3000g for 10 minutes within half an hour. 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 20 minutes, and load the sample The amount is 5 ⁇ L/well, that is, the serum loading amount in each well is 0.025 ⁇ L.
  • C3d and transferrin protein levels were detected by Western Blotting.
  • the C3d protein level in the serum of mice in the model group increased by 45% to 55% compared with the normal group.
  • the C3d protein level in the serum of mice in each drug group increased by 45% to 55%.
  • the protein level decreased by 60% to 80% compared to the modeling group, and the C3d protein level decreased significantly.
  • the compound of the present invention can or can significantly inhibit complement activation stimulated by LPS.

Abstract

Disclosed in the present invention is a bicyclic substituted aromatic carboxylic acid ester compound. Specifically, disclosed are a compound as represented by formula (I) and a pharmaceutically acceptable salt thereof.

Description

双环取代的芳香羧酸酯类化合物Bicyclic substituted aromatic carboxylic acid esters
相关申请的交叉引用Cross-references to related applications
本申请要求于2022年06月10日向中国国家知识产权局提交的第202210658423.7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. 202210658423.7 submitted to the State Intellectual Property Office of China on June 10, 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酯类化合物，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 ester compounds, specifically to the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
背景技术Background technique
补体系统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，同时补体系统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。补体系统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，补体系统被全面激活，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，能够避免因补体系统抑制增加感染风险。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系统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，为未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 for unmet 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、R8、R9和R10分别独立地选自H或D； R 1 , R 5 , R 6 , R 8 , R 9 and R 10 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或3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 or 3 R a substitution;
R7选自C1-6烷基、苯基、所述C1-6烷基任选被1、2、3、4或5个F取代，所述苯基任选被1、2或3个Rc取代；R 7 is selected from C 1-6 alkyl, phenyl, The C 1-6 alkyl group is optionally substituted by 1, 2, 3, 4 or 5 F, and the phenyl group is optionally substituted by 1, 2 or 3 R c ;
R11选自C1-6烷基或C1-6烷氧基，所述C1-6烷基或C1-6烷氧基分别独立地任选被1、2、3、4或5个F取代；每个Ra各自独立地选自D、-F、-Cl、-Br或-I； R 11 is selected from C 1-6 alkyl or C 1-6 alkoxy, which is independently optionally substituted by 1, 2, 3 , 4 or 5. F substitution; each R a is independently selected from D, -F, -Cl, -Br or -I;
每个Rb各自独立地选自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Rc各自独立地选自-F、-Cl、-Br、-I、C1-6烷基或C1-6烷氧基，所述C1-6烷基或C1-6烷氧基分别独立地任选被1、2、3、4或5个F取代；Each R c is independently selected from -F, -Cl, -Br, -I, C 1-6 alkyl or C 1-6 alkoxy, the C 1-6 alkyl or C 1-6 alkyl The oxygen groups are independently optionally substituted by 1, 2, 3, 4 or 5 F;
每个R各自独立地选自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.
在本发明的一些方案中，每个R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 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，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，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，每个Ra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 a 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，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-CH3、-CD3、-CD2CD3、-CH2CH3、-CH2CH2F、-CH2CHF2、-CH2CF3、-C(＝O)CH3或-S(＝O)2CH3，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 3 , -CD 3 , -CD 2 CD 3 , -CH 2 CH 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -C(=O)CH 3 or -S(=O) 2 CH 3 , 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、-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Rb各自独立地选自-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 CF 3 , and other variables are as defined in the invention.
在本发明的一些方案中，T1选自CH，T2选自CH，其他变量如本发明所定义。In some aspects of the invention, T 1 is selected from CH, T 2 is selected from CH, and other variables are as defined in the invention.
在本发明的一些方案中，T1选自CH，T2选自N，其他变量如本发明所定义。In some aspects of the invention, T 1 is selected from CH, T 2 is selected from N, and other variables are as defined in the invention.
在本发明的一些方案中，T1选自N，T2选自CH，其他变量如本发明所定义。In some aspects of the invention, T 1 is selected from N, T 2 is selected from CH, 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，R11选自-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2或-C(CH3)3，所述-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2或-C(CH3)3分别独立地任选被1、2、3、4或5个F取代，其他变量如本发明所定义。In some embodiments of the invention, R 11 is selected from -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 or -C(CH 3 ) 3 , and the -CH 3. -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 or -C(CH 3 ) 3 are each independently optionally substituted by 1, 2, 3, 4 or 5 F, Other variables are as defined in the present invention.
在本发明的一些方案中，R11选自-C(CH3)3，其他变量如本发明所定义。 In some aspects of the invention, R 11 is selected from -C(CH 3 ) 3 , and other variables are as defined in the invention.
在本发明的一些方案中，R7选自-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、苯基、 所述-CH3、-CH2CH3、-CH2CH2CH3或-CH(CH3)2分别独立地任选被1、2、3、4或5个F取代，其他变量如本发明所定义。In some aspects of the invention, R 7 is selected from -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , phenyl, The -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 or -CH(CH 3 ) 2 are independently optionally substituted by 1, 2, 3, 4 or 5 F, and other variables are as follows defined by invention.
在本发明的一些方案中，R7选自-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、所述-CH3、-CH2CH3、-CH2CH2CH3或-CH(CH3)2分别独立地任选被1、2、3、4或5个F取代，其他变量如本发明所定义。In some aspects of the invention, R 7 is selected from -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , The -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 or -CH(CH 3 ) 2 are independently optionally substituted by 1, 2, 3, 4 or 5 F, and other variables are as follows defined by invention.
在本发明的一些方案中，R7选自-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、其他变量如本发明所定义。In some aspects of the invention, R 7 is selected from -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , Other variables are as defined in the present invention.
在本发明的一些方案中，R7选自-CH3、-CH2CH3、其他变量如本发明所定义。In some aspects of the invention, R 7 is selected from -CH 3 , -CH 2 CH 3 , Other variables are as defined in the present invention.
在本发明的一些方案中，R7选自-CH3或-CH2CH3，其他变量如本发明所定义。In some embodiments of the invention, R 7 is selected from -CH 3 or -CH 2 CH 3 , and other variables are as defined in the invention.
在本发明的一些方案中，R7选自-CH3，其他变量如本发明所定义。In some embodiments of the invention, R 7 is selected from -CH 3 , and other variables are as defined in the invention.
在本发明的一些方案中，m选自2，其他变量如本发明所定义。In some aspects of the invention, m is selected from 2, 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R10选自H或D时，式(I)所示化合物中的结构单元-C(R10)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 10 is selected from H or When D, the structural unit -C(R 10 ) 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，所述结构单元选自苯基、吡啶基或哒嗪基，其他变量如本发明所定义。In some aspects of the invention, the structural unit Selected from phenyl, pyridyl or 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、R7、Rb、T1和T2如本发明所定义；R 1 , R 4 , R 7 , R b , T 1 and T 2 are as defined in the present invention;
当R4不为H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；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 is not H, 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 atom with "*" It is a chiral carbon atom and exists 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，R1、R4、R7、T1和T2如本发明所定义。Among them, R 1 , R 4 , R 7 , T 1 and T 2 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，R1、R4和R7如本发明所定义。 Among them, R 1 , R 4 and R 7 are as defined in 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,

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,

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.
另一方面，本发明还提供一种式(I)化合物的制备方法，包括：式(II)化合物与R7-OH反应得到式(I)化合物，
On the other hand, the present invention also provides a method for preparing a compound of formula (I), which includes: reacting a compound of formula (II) with R 7 -OH to obtain a compound of formula (I),
其中，R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、T1和T2如本发明式(I)化合物所述。Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , T 1 and T 2 are as described for the compound of formula (I) of the present invention.
本发明还提供一种化合物M1的制备方法，包括：(1)化合物M-a与化合物Rp-NH2和1,3-丙酮二羧酸反应得到化合物M-b’；(2)化合物M-b’经手性试剂拆分得到化合物M-c’；(3)化合物M-c’发生还原反应得到化合物M-d’；(4)化合物M-d’与乙基化试剂反应得到化合物M-e’；(5)化合物M-e’发生水解反应得到化合物M-f’；(6)化合物M-f’与甲基化试剂反应得到化合物M-g’；(7)化合物M-g’发生脱保护反应得到化合物M-h；(8)化合物M-h与化合物N-c反应得到化合物M-i；(9)化合物M-i发生脱保护反应得到化合物M1。
The invention also provides a preparation method of compound M1, which includes: (1) Compound Ma reacts with compound R p -NH 2 and 1,3-acetone dicarboxylic acid to obtain compound M-b'; (2) Compound M-b 'Compound M-c' is obtained by separation with a chiral reagent; (3) Compound M-c' undergoes a reduction reaction to obtain compound M-d'; (4) Compound M-d' reacts with an ethylation reagent to obtain compound M-e '; (5) Compound M-e' undergoes hydrolysis reaction to obtain compound M-f'; (6) Compound M-f' reacts with methylating reagent to obtain compound M-g'; (7) Compound M-g' occurs Deprotection reaction yields compound Mh; (8) Compound Mh reacts with compound Nc to yield compound Mi; (9) Compound Mi undergoes deprotection reaction to yield compound M1.
其中，Rp选自Bn或PMB。Among them, Rp is selected from Bn or PMB.
在本发明的一些方案中，所述化合物M1的制备方法，其中步骤(2)所述手性试剂选自L-二对苯甲酰酒石酸或D-二对苯甲酰酒石酸。In some aspects of the present invention, the preparation method of compound M1, wherein the chiral reagent in step (2) is selected from L-di-tere-benzoyltartaric acid or D-di-tere-benzoyltartaric acid.
在本发明的一些方案中，所述化合物M1的制备方法，其中步骤(3)所述还原剂选自二异丁基氢化铝、硼氢化钠、三仲丁基硼氢化锂或二异丁基氢化铝。 In some aspects of the present invention, the preparation method of compound M1, wherein the reducing agent in step (3) is selected from diisobutylaluminum hydride, sodium borohydride, tri-sec-butyllithium borohydride or diisobutyl Aluminum hydride.
在本发明的一些方案中，所述化合物M1的制备方法，其中步骤(4)所述乙基化试剂选自碘乙烷、溴乙烷或硫酸二乙酯。In some aspects of the present invention, the preparation method of compound M1, wherein the ethylation reagent in step (4) is selected from ethyl iodide, ethyl bromide or diethyl sulfate.
在本发明的一些方案中，所述化合物M1的制备方法，其中步骤(6)所述甲基化试剂选自氯化亚砜/甲醇、盐酸甲醇或DMF-DMA/甲醇。In some aspects of the present invention, the preparation method of compound M1, wherein the methylating reagent in step (6) is selected from sulfoxide chloride/methanol, methanol hydrochloride or DMF-DMA/methanol.
本发明还提供化合物M1的制备中间体化合物M-e的制备方法，包括：(1)化合物M-a与苄胺和1,3-丙酮二羧酸反应得到化合物M-b；(2)化合物M-b经手性试剂拆分得到化合物M-c；(3)化合物M-c发生还原反应得到化合物M-d；(4)化合物M-d与乙酯试剂反应得到化合物M-e；
The present invention also provides a method for preparing intermediate compound Me for the preparation of compound M1, which includes: (1) reacting compound Ma with benzylamine and 1,3-acetone dicarboxylic acid to obtain compound Mb; (2) separating compound Mb with a chiral reagent Obtain compound Mc; (3) Compound Mc undergoes reduction reaction to obtain compound Md; (4) Compound Md reacts with ethyl ester reagent to obtain compound Me;
在本发明的一些方案中，所述化合物M-e的制备方法，其中反应条件如化合物M1的制备方法所述。In some aspects of the present invention, the preparation method of compound M-e, wherein the reaction conditions are as described in the preparation method of compound M1.
本发明还提供下述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:
本发明还提供上述化合物M-e、M-f、M-g、M-h在制备化合物M1中的应用。The present invention also provides the use of the above compounds M-e, M-f, M-g, M-h in preparing compound M1.
技术效果Technical effect
本发明化合物能够显著抑制LPS刺激的补体激活，且具有良好的药代动力学性质，可以发展成为新的补体系统Factor B小分子抑制剂。The compound of the present invention can significantly inhibit complement activation stimulated by LPS, has good pharmacokinetic properties, and can be developed into a new small molecule inhibitor of the 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。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。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. 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. 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) indicates that the compound exists as a single isomer of formula (A-1) or formula (A-2) or as two isomers of formula (A-1) and formula (A-2) exists in the form of a mixture; the following formula (B) indicates that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2) or in the form of both formula (B-1) and formula (B-2) Exists as a mixture of isomers. 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 that 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“C1-6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团。所述C1-6烷基包括C1-4、C1-3、C2-4、C2-3、C1、C2、C3、C4、C5和C6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)。C1-5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 1-6 alkyl" is used to mean a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1-6 alkyl group includes C 1-4 , C 1-3 , C 2-4, C 2-3 , C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkyl groups, etc.; It can be monovalent (such as methyl), bivalent (such as methylene) or polyvalent (such as methine). Examples of C 1-5 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“C1-6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6个碳原子的烷基基团。所述C1-6烷氧基包括C1-4、C1-3、C2-4、C2-3、C1、C2、C3、C4、C5和C6烷氧基等。C1-6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 1-6 alkoxy" means those alkyl groups containing 1 to 6 carbon atoms that are attached to the remainder of the molecule through an oxygen atom. The C 1-6 alkoxy group includes C 1-4 , C 1-3 , C 2-4, C 2-3 , C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy group wait. Examples of C 1-6 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，术语“4-6元饱和杂环基”本身或者与其他术语联合分别表示由4至6个环原子组成的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。4-6元饱和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、异噻唑烷基等。Unless otherwise specified, the term "4-6 membered saturated heterocyclyl" by itself or in combination with other terms respectively means a saturated monocyclic cyclic group consisting of 4 to 6 ring atoms, of which 1, 2, 3 or 4 Two ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, in which the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms can 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. Examples of 4-6 membered saturated heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, etc.
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：φ/ω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, in single crystal X-ray diffraction (SXRD), the cultured single crystal is used to collect diffraction intensity data using a Bruker D8venture diffractometer. The light source is CuKα radiation, and the scanning mode is: φ/ω scanning. After collecting relevant data, the direct method is further used ( Shelxs97) can confirm the absolute configuration by analyzing the crystal structure.
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-c
Reference Example 1: Intermediate Nc
第一步first step
在15℃，向化合物N-a(0.5g)的四氢呋喃(5mL)溶液中加入二碳酸二叔丁酯(812.33mg)和N,N-二异丙基乙基胺(37.89mg)。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*3)萃取。合并的有机层用饱和食盐水(20mL*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＝0:1至1:10)，得到化合物N-b。To a solution of compound N-a (0.5 g) in tetrahydrofuran (5 mL) were added di-tert-butyl dicarbonate (812.33 mg) and N,N-diisopropylethylamine (37.89 mg) at 15°C. 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. Separate the liquids, and extract the aqueous phase with ethyl acetate (20mL*3). The combined organic layers were washed with saturated brine (20 mL*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 = 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)的二氯甲烷(2.7mL)溶液中缓慢滴加草酰 氯(431.90mg)。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)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*3)萃取，合并的有机相用饱和食盐水(20mL*3)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＝0:1至1:10)，得到化合物N-c。To a solution of N-methyl-N-formylanilide (459.93 mg) in dichloromethane (2.7 mL) under nitrogen protection, oxalyl was slowly added dropwise at 15°C. Chlorine (431.90mg). 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) in methylene chloride (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 with ethyl acetate (20 mL*3), and the combined organic phases were washed with saturated brine (20 mL*3), 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] + .
参考例2：中间体M1的合成
Reference Example 2: Synthesis of Intermediate M1
第一步first step
将苄胺(194.62g)缓慢加入到溶有醋酸(103.88mL)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)，反应液在0℃下反应0.5小时。将溶有化合物M-a(170g)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) was slowly added to water (850mL) dissolved in acetic acid (103.88mL). The reaction system was cooled to 0-10°C, then 1,3-acetone dicarboxylic acid (265.36g) was slowly added in batches, and the reaction solution was allowed to react at 0°C for 0.5 hours. A solution of compound Ma (170 g) dissolved in dioxane (850 mL) 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)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-二对苯甲酰基酒石酸(200g)，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％。Compound Mb (220g) was dissolved in acetonitrile (1700mL), then the temperature was raised to 70°C and stirred for 2 hours. L-di-p-benzoyltartaric acid (200g) was slowly added under stirring, and the reaction solution continued to stir at 70°C. 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)溶于四氢呋喃(750mL)中，然后加入水(10.71mL)，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)。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,30％纯度)，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*2)萃取。有机相通过饱和食盐水(1000mL*2)洗涤，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 OJ 50×4.6mm I.D.,3μm，流动相:A:CO2，B:甲醇(0.05％二乙胺)，梯度B％：5％-40％。Compound Mc (94g) was dissolved in tetrahydrofuran (750mL), then water (10.71mL) was added, nitrogen was replaced three times, the temperature was cooled to -40°C, and tri-sec-butyllithium borohydride (1M) was slowly added dropwise at this temperature. ,356.52mL). After the dropwise addition is completed, stirring is continued at this temperature for 30 minutes. Slowly add hydrogen peroxide (102.77 mL, 30% purity) into the reaction solution, and control the temperature below 0°C. Then slowly add a solution of sodium sulfite (135g) in water (1000mL), and add methyl tert-butyl ether (500mL*2) for extraction. The organic phase was washed with saturated brine (1000 mL*2), 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 OJ 50×4.6mm ID, 3μm, mobile phase: A: CO 2 , B: methanol (0.05% diethylamine), gradient B%: 5%-40%.
第四步the fourth step
将化合物M-d(7g)溶于N,N-二甲基甲酰胺(35mL)中,氮气置换3次，降温至0℃，然后加入叔丁醇钠(6.34g)，搅拌30min。降温至-10℃并在该温度下缓慢滴加硫酸二乙酯(6.78g)。滴加完毕，在该温度下继续搅拌2小时。将反应液加入到水(160mL)中，用柠檬酸固体调节pH＝5～6，加入乙酸乙酯(100mL)萃取。有机相依次用饱和碳酸钠水溶液(50mL)和食盐水(100mL)洗涤，干燥后过滤，滤液减压浓缩得到化合物M-e。LC-MS:m/z＝347.2[M+H]+。Compound Md (7g) was dissolved in N,N-dimethylformamide (35mL), replaced with nitrogen three times, cooled to 0°C, then sodium tert-butoxide (6.34g) was added, and stirred for 30 minutes. The temperature was lowered to -10°C and diethyl sulfate (6.78g) was slowly added dropwise at this temperature. After the dropwise addition is completed, stirring is continued at this temperature for 2 hours. The reaction solution was added to water (160 mL), the pH was adjusted to 5-6 with solid citric acid, and ethyl acetate (100 mL) was added for extraction. The organic phase was washed with saturated aqueous sodium carbonate solution (50 mL) and brine (100 mL) in sequence, dried and filtered, and the filtrate was concentrated under reduced pressure to obtain compound Me. LC-MS: m/z=347.2[M+H] + .
第五步the fifth step
在20℃下，向溶有化合物M-e(8g)的二甲基亚砜(40mL)溶液中加入碳酸钾(3.51g)，然后缓慢滴加双氧水(3.33mL,30％纯度)。滴加完成后反应液升温至40℃，搅拌16小时。反应液降至室温后缓慢加入到冰水中(150mL)，在0℃下搅拌1小时。析出固体，过滤，滤饼干燥得到化合物M-f。LC-MS:m/z＝365.2[M+H]+。At 20°C, potassium carbonate (3.51g) was added to a solution of compound Me (8g) dissolved in dimethyl sulfoxide (40mL), and then hydrogen peroxide (3.33mL, 30% purity) was slowly added dropwise. After the dropwise addition was completed, the temperature of the reaction solution was raised to 40°C and stirred for 16 hours. After the reaction solution cooled to room temperature, it was slowly added to ice water (150 mL) and stirred at 0°C for 1 hour. The solid was precipitated, filtered, and the filter cake was dried to obtain compound Mf. LC-MS: m/z=365.2[M+H] + .
第六步Step 6
在室温下，往化合物M-f(99g)的甲醇(1000mL)溶液中，加入N,N-二甲基甲酰胺二甲基缩醛(59.81g)，反应液升温至40℃，搅拌16小时。反应液直接减压浓缩后得到剩余物。向剩余物中加入乙酸乙酯(1000mL)，然后依次用水(500mL)和饱和食盐水(500mL)洗涤，无水硫酸钠干燥，过滤后滤液浓缩得到化合物M-g直接用于下一步。LC-MS:m/z＝380.2[M+H]+。At room temperature, N,N-dimethylformamide dimethyl acetal (59.81g) was added to a solution of compound Mf (99g) in methanol (1000mL), and the reaction solution was heated to 40°C and stirred for 16 hours. The reaction solution was directly concentrated under reduced pressure to obtain the residue. Ethyl acetate (1000 mL) was added to the residue, and then washed with water (500 mL) and saturated brine (500 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound Mg, which was directly used in the next step. LC-MS: m/z=380.2[M+H] + .
第七步Step 7
在20℃下，氮气氛围下，向化合物M-g(4g)的甲醇(40mL)溶液中依次加入浓盐酸(975μL,36％纯度)和湿钯碳(1g,10％含量)，氢气置换3次，反应液在50℃下搅拌1.5小时。反应液过滤，减压浓缩得到粗品化合物M-h直接用于下一步。LC-MS:m/z＝290.1[M+H]+。At 20°C, under a nitrogen atmosphere, concentrated hydrochloric acid (975 μL, 36% purity) and wet palladium on carbon (1g, 10% content) were sequentially added to a solution of compound Mg (4g) in methanol (40mL), and replaced with hydrogen three times. The reaction solution was stirred at 50°C for 1.5 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain crude compound Mh, which was used directly in the next step. LC-MS: m/z=290.1[M+H] + .
第八步 Step 8
在15℃和氮气氛围下，向化合物M-h(1g)和化合物N-c(999.85mg)的乙腈(15mL)溶液中加入吡啶(836.80μL)，三甲基氯硅烷(938.60mg)，苯基硅烷(560.93mg)。反应液在70℃搅拌16小时后，反应液加入到水(100mL)中，用乙酸乙酯(100mL*2)萃取，合并有机相，用饱和食盐水(100mL*2)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到M-i。LC-MS:m/z＝563.5[M+H]+。Under a nitrogen atmosphere at 15°C, pyridine (836.80 μL), trimethylchlorosilane (938.60 mg), and phenylsilane (560.93 mg). After the reaction solution was stirred at 70°C for 16 hours, the reaction solution was added to water (100mL), extracted with ethyl acetate (100mL*2), the organic phases were combined, washed with saturated brine (100mL*2), and anhydrous sodium sulfate Dry, filter, and concentrate under reduced pressure to obtain Mi. LC-MS: m/z=563.5[M+H] + .
第九步Step 9
在15℃氮气保护下，向化合物M-i(5g)的四氢呋喃(50mL)和甲醇(50mL)的混合溶液中加入氢氧化锂(1M,50.00mL)水溶液。反应液升温至50℃，搅拌16小时。反应液冷却至室温，用冰醋酸调节pH至6～7。混合物减压浓缩，得到粗品通过色谱柱纯化(色谱柱:Phenomenex Luna C18(250*80mm*15μm)；流动相：A：水(0.05％盐酸)，B：乙腈，方法：B：20％-50％)得到化合物M1。Under nitrogen protection at 15°C, an aqueous solution of lithium hydroxide (1M, 50.00mL) was added to a mixed solution of compound M-i (5g) in tetrahydrofuran (50mL) and methanol (50mL). The reaction solution was heated to 50°C and stirred for 16 hours. The reaction solution was cooled to room temperature, and the pH was adjusted to 6-7 with glacial acetic acid. The mixture was concentrated under reduced pressure to obtain a crude product that was purified through a chromatography column (chromatography column: Phenomenex Luna C18 (250*80mm*15μm); mobile phase: A: water (0.05% hydrochloric acid), B: acetonitrile, method: B: 20%-50 %) to obtain compound M1.
1H NMR(400MHz,DMSO-d6)δ＝13.21(br s,1H),11.29-11.18(m,1H),9.86-9.62(m,1H),8.13(br d,J＝ 1 H NMR (400MHz, DMSO-d 6 ) δ = 13.21 (br s, 1H), 11.29-11.18 (m, 1H), 9.86-9.62 (m, 1H), 8.13 (br d, J＝
7.8Hz,2H),8.04-7.82(m,2H),7.43(br s,1H),6.82(s,1H),6.38(br s,1H),4.07-3.93(m,3H),3.86(s,3H),3.60(br s,1H),3.40(q,J＝7.2Hz,2H),3.33(s,3H),2.92-2.80(m,2H),2.80-2.65(m,2H),2.64-2.55(m,7.8Hz,2H),8.04-7.82(m,2H),7.43(br s,1H),6.82(s,1H),6.38(br s,1H),4.07-3.93(m,3H),3.86(s ,3H),3.60(br s,1H),3.40(q,J＝7.2Hz,2H),3.33(s,3H),2.92-2.80(m,2H),2.80-2.65(m,2H),2.64 -2.55(m,
1H),2.39-2.26(m,1H),2.04(br d,J＝15.2Hz,2H),1.13(t,J＝7.2Hz,3H)；LC-MS:m/z＝449.3[M+H]+。1H), 2.39-2.26 (m, 1H), 2.04 (br d, J＝15.2Hz, 2H), 1.13 (t, J＝7.2Hz, 3H); LC-MS: m/z＝449.3[M+H ] + .
参考例3：中间体M2和M3的合成
Reference Example 3: Synthesis of Intermediates M2 and M3
第一步first step
在0℃，向化合物M-d(5g)的N,N-二甲基甲酰胺(25mL)溶液中加入叔丁醇钠(4.53g)，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)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D-1。LC-MS:m/z＝336.2[M+H]+。At 0°C, sodium tert-butoxide (4.53g) was added to a solution of compound Md (5g) in N,N-dimethylformamide (25mL). The reaction solution was stirred for 0.5 hours. The reaction solution was cooled to -10°C and added Deuterated methyl iodide (2.23g) and stirring was 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 D-1. LC-MS: m/z=336.2[M+H] + .
第二步 Step 2
在0℃下，向化合物D-1(2.1g)的二甲基亚砜溶液(20mL)中加入碳酸钾(951.71mg)，然后滴加过氧化氢溶液(902.27μL,30％纯度)，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D-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) was added to a solution of compound D-1 (2.1 g) in dimethyl sulfoxide (20 mL), then hydrogen peroxide solution (902.27 μL, 30% purity) was added dropwise, and After completion, the reaction solution was raised to 40°C and stirred for 1 hour. Water (30 mL) was added to the reaction solution to precipitate a solid, filtered, and the filter cake was collected to obtain crude compound D-2, which was directly used in the next step. LC-MS: m/z=354.2[M+H] + .
第三步third step
在25℃下，向化合物D-2(1.6g)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)，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D-3粗品，直接用于下一步。LC-MS:m/z＝369.2[M+H]+。At 25°C, N,N-dimethylformamide dimethyl acetal (1.08g) was added to a solution of compound D-2 (1.6g) in anhydrous methanol (16mL). After the addition, the reaction solution was heated to Continue stirring at 75°C for 16 hours under nitrogen protection. 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 D-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D-3(1.46g)的无水甲醇溶液(15mL)中加入盐酸(472.11μL,36％纯度)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。反应液倒入硅藻土减压抽滤，滤液减压浓缩，得到化合物D-4粗品，直接用于下一步。LC-MS:m/z＝279.1[M+H]+。At 25°C, add hydrochloric acid (472.11 μL, 36% purity) and wet palladium on carbon (0.2g, 10% content) to an anhydrous methanol solution (15mL) of compound D-3 (1.46g), and replace with nitrogen three times. The reaction liquid was heated to 50°C under hydrogen gas (15 Psi) and reacted for 2 hours. The reaction solution was poured into diatomaceous earth and filtered under reduced pressure, and the filtrate was concentrated under reduced pressure to obtain crude compound D-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D-4(0.8g)的N,N-二甲基甲酰胺溶液(10mL)中加入中间体化合物N-c(831.51mg)，吡啶(695.91μL)，苯硅烷(466.50mg)，三甲基氯硅烷(780.58mg)，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*2)萃取。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M2。LC-MS:m/z＝552.3[M+H]+。At 25°C, intermediate compound Nc (831.51 mg), pyridine (695.91 μL), and phenylsilane (466.50 mg) were added to a solution (10 mL) of compound D-4 (0.8 g) in N,N-dimethylformamide. , trimethylsilyl chloride (780.58mg), after the addition was completed, nitrogen was replaced three times, and the reaction solution was stirred at 60°C for 16 hours. The reaction solution was cooled to room temperature, quenched by adding water (10 mL), and extracted with ethyl acetate (10 mL*2). 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 M2. LC-MS: m/z=552.3[M+H] + .
第六步Step 6
在25℃下，向化合物M2(0.4g)的四氢呋喃(2mL)和无水甲醇(2mL)混合溶液中加入氢氧化锂水溶液(1M,3.63mL)，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M3的盐酸盐。At 25°C, add lithium hydroxide aqueous solution (1M, 3.63mL) to a mixed solution of compound M2 (0.4g) in tetrahydrofuran (2mL) and anhydrous methanol (2mL). After the addition, the reaction solution is heated to 50°C for reaction 16 Hour. 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 M3.
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]+。 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1
Example 1
在15℃下，向化合物M1(2g)的二氯甲烷(20mL)溶液中加入甲醇(1.67mL)，4-二甲氨基吡啶(1.51g)，1- (3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐(790.49mg)。反应液在10℃搅拌16小时后，减压浓缩移除溶剂，得到粗品通过色谱柱纯化(色谱柱:Phenomenex luna C18 150*40mm*15μm；流动相：A：水(0.225％甲酸)，B：乙腈，方法：B：20％-50％)，制备分离得到的溶液用饱和碳酸氢钠水溶液调节pH值约为8，减压浓缩移除溶剂乙腈，水相用乙酸乙酯(300mL x 2)萃取。合并有机相，用饱和食盐水(300mL x 2)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到化合物1。To a solution of compound M1 (2g) in dichloromethane (20mL) at 15°C, methanol (1.67mL), 4-dimethylaminopyridine (1.51g), 1- (3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (790.49 mg). After the reaction solution was stirred at 10°C for 16 hours, the solvent was concentrated under reduced pressure to obtain a crude product that was purified through a chromatography column (chromatography column: Phenomenex luna C18 150*40mm*15μm; mobile phase: A: water (0.225% formic acid), B: Acetonitrile, method: B: 20%-50%), prepare the separated solution and adjust the pH value to about 8 with saturated sodium bicarbonate aqueous solution, concentrate under reduced pressure to remove the solvent acetonitrile, and use ethyl acetate (300mL x 2) for the aqueous phase extraction. The organic phases were combined, washed with saturated brine (300 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1.
LC-MS:m/z＝463.3[M+H]+；1H NMR(400MHz,DMSO-d6)δ＝10.81(br s,1H),7.98(br d,J＝8.4Hz,2H),7.78(br d,J＝8.4Hz,2H),7.26(br s,1H),6.66(s,1H),6.52(br s,1H),3.85(s,3H),3.78-3.65(m,5H),3.39(q,J＝6.8Hz,2H),3.33(s,1H),3.19(br d,J＝12.4Hz,1H),3.06(br s,1H),2.42(s,3H),2.20(br dd,J＝4.8,14.0Hz,1H),2.10-1.91(m,5H),1.51(br d,J＝14.0Hz,1H),1.11(t,J＝7.2Hz,3H)。LC-MS: m/z=463.3[M+H] + ; 1 H NMR (400MHz, DMSO-d 6 ) δ=10.81 (br s, 1H), 7.98 (br d, J=8.4Hz, 2H), 7.78(br d,J＝8.4Hz,2H),7.26(br s,1H),6.66(s,1H),6.52(br s,1H),3.85(s,3H),3.78-3.65(m,5H ),3.39(q,J＝6.8Hz,2H),3.33(s,1H),3.19(br d,J＝12.4Hz,1H),3.06(br s,1H),2.42(s,3H),2.20 (br dd,J＝4.8,14.0Hz,1H),2.10-1.91(m,5H),1.51(br d,J＝14.0Hz,1H),1.11(t,J＝7.2Hz,3H).
实施例2
Example 2
在15℃下，向化合物M1(0.5g)的二氯甲烷(10mL)溶液中加入乙醇(474.92mg)，4-二甲氨基吡啶(503.78mg)，1-(3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐(395.25mg)。反应液在10℃搅拌16小时后，减压浓缩移除溶剂，得到粗品通过色谱柱纯化(色谱柱:Phenomenex luna C18 150*25mm*10μm；流动相：A：水(0.225％甲酸)，B：乙腈，方法：B：27％-47％)，制备分离得到的溶液，用饱和碳酸氢钠水溶液调节pH＝8，减压浓缩移除溶剂乙腈，水相用乙酸乙酯(50mLx2)萃取。合并有机相，用饱和食盐水(50mL x2)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到化合物2。To a solution of compound M1 (0.5g) in dichloromethane (10mL) at 15°C, ethanol (474.92mg), 4-dimethylaminopyridine (503.78mg), 1-(3-dimethylaminopropyl) were added )-3-ethylcarbodiimide hydrochloride (395.25 mg). After the reaction solution was stirred at 10°C for 16 hours, the solvent was concentrated under reduced pressure to obtain a crude product that was purified through a chromatography column (chromatography column: Phenomenex luna C18 150*25mm*10μm; mobile phase: A: water (0.225% formic acid), B: Acetonitrile, method: B: 27%-47%), prepare the separated solution, adjust pH=8 with saturated aqueous sodium bicarbonate solution, concentrate under reduced pressure to remove the solvent acetonitrile, and extract the aqueous phase with ethyl acetate (50 mLx2). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 2.
LC-MS:m/z＝477.3[M+H]+；1H NMR(400MHz,DMSO-d6)δ＝10.82(br s,1H),7.98(d,J＝8.4Hz,2H),7.78(d,J＝8.4Hz,2H),7.26(t,J＝2.4Hz,1H),6.66(s,1H),6.52(d,J＝2.4Hz,1H),4.32(q,J＝7.2Hz,2H),3.72(s,3H),3.70(br s,2H),3.39(q,J＝7.2Hz,2H),3.30(s,1H),3.19(d,J＝12.0Hz,1H),3.05(br s,1H),2.42(s,3H),2.20(br dd,J＝4.8,14.4Hz,1H),2.10-1.92(m,5H),1.51(br d,J＝14.0Hz,1H),1.32(t,J＝7.2Hz,3H),1.11(t,J＝7.2Hz,3H)。LC-MS: m/z=477.3[M+H] + ; 1 H NMR (400MHz, DMSO-d 6 ) δ=10.82 (br s, 1H), 7.98 (d, J=8.4Hz, 2H), 7.78 (d,J＝8.4Hz,2H),7.26(t,J＝2.4Hz,1H),6.66(s,1H),6.52(d,J＝2.4Hz,1H),4.32(q,J＝7.2Hz ,2H),3.72(s,3H),3.70(br s,2H),3.39(q,J＝7.2Hz,2H),3.30(s,1H),3.19(d,J＝12.0Hz,1H), 3.05(br s,1H),2.42(s,3H),2.20(br dd,J＝4.8,14.4Hz,1H),2.10-1.92(m,5H),1.51(br d,J＝14.0Hz,1H ), 1.32 (t, J = 7.2Hz, 3H), 1.11 (t, J = 7.2Hz, 3H).
实施例3
Example 3
在15℃下，向化合物M1(0.5g)的二氯甲烷(10mL)溶液中加入化合物3-1(268.24mg)，4-二甲氨基吡啶(503.78mg)，1-(3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐(395.25mg)。反应液在10℃搅拌16小时后，减压浓缩移除溶剂，得到粗品通过色谱柱纯化(色谱柱:Phenomenex C18 75*30mm*3μm；流动相：A：水(0.225％甲酸)，B：乙腈，方法：B：20％-50％)，制备回来的溶液，用饱和碳酸氢钠水溶液调节pH＝8，减压浓缩移除溶剂乙腈，水相用乙酸乙酯(50mL x2)萃取。合并有机相，用饱和食盐水(50mL x2)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到化合物3。To a solution of compound M1 (0.5 g) in dichloromethane (10 mL), compound 3-1 (268.24 mg), 4-dimethylaminopyridine (503.78 mg), 1-(3-dimethylamine) were added at 15°C. Propyl)-3-ethylcarbodiimide hydrochloride (395.25 mg). After the reaction solution was stirred at 10°C for 16 hours, the solvent was concentrated under reduced pressure to obtain a crude product that was purified through a chromatography column (chromatography column: Phenomenex C18 75*30mm*3μm; mobile phase: A: water (0.225% formic acid), B: acetonitrile , Method: B: 20%-50%), prepare the solution, adjust pH=8 with saturated sodium bicarbonate aqueous solution, concentrate under reduced pressure to remove the solvent acetonitrile, and extract the aqueous phase with ethyl acetate (50mL x2). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 3.
LC-MS:m/z＝561.4[M+H]+；1H NMR(400MHz,DMSO-d6)δ＝10.82(br s,1H),8.00(d,J＝8.4Hz,2H),7.79(br d,J＝8.4Hz,2H),7.26(t,J＝2.8Hz,1H),6.65(s,1H),6.56-6.50(m,1H),5.22(s,2H),3.76-3.66(m,5H),3.39(q,J＝7.2Hz,2H),3.31(s,2H),3.18(d,J＝12.4Hz,1H),3.05(br s,1H),2.42(s,3H),2.24-2.16(m,4H),2.08-2.03(m,1H),2.02-1.94(m,3H),1.51(br d,J＝14.4Hz,1H),1.11(t,J＝7.2Hz,3H)。LC-MS: m/z=561.4[M+H] + ; 1 H NMR (400MHz, DMSO-d 6 ) δ=10.82 (br s, 1H), 8.00 (d, J=8.4Hz, 2H), 7.79 (br d,J＝8.4Hz,2H),7.26(t,J＝2.8Hz,1H),6.65(s,1H),6.56-6.50(m,1H),5.22(s,2H),3.76-3.66 (m,5H),3.39(q,J＝7.2Hz,2H),3.31(s,2H),3.18(d,J＝12.4Hz,1H),3.05(br s,1H),2.42(s,3H ),2.24-2.16(m,4H),2.08-2.03(m,1H),2.02-1.94(m,3H),1.51(br d,J＝14.4Hz,1H),1.11(t,J＝7.2Hz ,3H).
实施例4
Example 4
在15℃下，向化合物M1(0.2g)的乙腈(3mL)溶液中加入N,N-二异丙基乙胺(159.88mg)和特戊酸氯甲酯(124.21mg)。反应液在60℃搅拌2小时后，减压浓缩移除溶剂，得到粗品通过色谱柱纯化(色谱柱:3_Phenomenex Luna C18 75*30mm*3μm；流动相：A：水(0.05％盐酸)，B：乙腈，方法：B：34％-54％)，制备回来的溶液，用饱和碳酸氢钠水溶液调节pH＝8，减压浓缩移除溶剂乙腈，水相用乙酸乙酯(50mL)萃取2次。合并有机相，用饱和食盐水(50mL*2)洗涤，无水硫酸钠干燥，过滤，减压浓缩。加水后冻干浓缩得到化合物4。To a solution of compound M1 (0.2 g) in acetonitrile (3 mL) at 15°C were added N,N-diisopropylethylamine (159.88 mg) and chloromethyl pivalate (124.21 mg). After the reaction solution was stirred at 60°C for 2 hours, the solvent was concentrated under reduced pressure to obtain a crude product that was purified through a chromatographic column (chromatographic column: 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase: A: water (0.05% hydrochloric acid), B: Acetonitrile (method: B: 34%-54%), the prepared solution was adjusted to pH=8 with saturated sodium bicarbonate aqueous solution, concentrated under reduced pressure to remove the solvent acetonitrile, and the aqueous phase was extracted twice with ethyl acetate (50 mL). Combine the organic phases, wash with saturated brine (50 mL*2), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. After adding water, it was freeze-dried and concentrated to obtain compound 4.
LC-MS:m/z＝563.3[M+H]+；1H NMR(400MHz,DMSO-d6)δ＝10.82(br s,1H),7.99(d,J＝8.4Hz,2H),7.81(d,J＝8.4Hz,2H),7.26(t,J＝2.8Hz,1H),6.65(s,1H),6.52(d,J＝2.8Hz,1H),5.97(s,2H),3.75-3.64(m,5H),3.40(q,J＝6.8Hz,2H),3.30(s,3H),3.20(br d,J＝12.0Hz,1H),3.07(br d,J＝2.4Hz,1H),2.42(s,3H),2.20(br dd,J＝4.4,14.0Hz,1H),2.11–1.95(m,3H),1.56-1.47(m,1H),1.18-1.06(m,12H)。LC-MS: m/z=563.3[M+H] + ; 1 H NMR (400MHz, DMSO-d 6 ) δ=10.82 (br s, 1H), 7.99 (d, J=8.4Hz, 2H), 7.81 (d,J＝8.4Hz,2H),7.26(t,J＝2.8Hz,1H),6.65(s,1H),6.52(d,J＝2.8Hz,1H),5.97(s,2H),3.75 -3.64(m,5H),3.40(q,J＝6.8Hz,2H),3.30(s,3H),3.20(br d,J＝12.0Hz,1H),3.07(br d,J＝2.4Hz, 1H),2.42(s,3H),2.20(br dd,J＝4.4,14.0Hz,1H),2.11–1.95(m,3H),1.56-1.47(m,1H),1.18-1.06(m,12H ).
实施例5
Example 5
在20℃，向化合物M2(300.00mg)中加入盐酸/甲醇溶液(4M,2.45mL)。反应液在20℃继续搅拌2小时。反应液冷却至室温后加入饱和碳酸氢钠水溶液(50mL)，反应液减压过滤，继续用色谱柱纯化(色谱柱:Phenomenex Luna C18 75*30mm*3μm；流动相：A：水(0.05％盐酸)，B：乙腈，方法：B：24％-44％)，反应液加入饱和碳酸氢钠水溶液(50mL)，乙酸乙酯(50mL*2)萃取。合并的有机相用饱和食盐水(50mL*2)洗涤，无水硫酸钠干燥，过滤。滤液减压浓缩得到化合物5。To compound M2 (300.00 mg) was added hydrochloric acid/methanol solution (4M, 2.45 mL) at 20°C. The reaction solution was continued to stir at 20°C for 2 hours. After the reaction solution was cooled to room temperature, saturated sodium bicarbonate aqueous solution (50 mL) was added, the reaction solution was filtered under reduced pressure, and continued to be purified with a chromatography column (chromatography column: Phenomenex Luna C18 75*30mm*3μm; mobile phase: A: water (0.05% hydrochloric acid) ), B: acetonitrile, method: B: 24%-44%), add saturated sodium bicarbonate aqueous solution (50mL) to the reaction solution, and extract with ethyl acetate (50mL*2). The combined organic phases were washed with saturated brine (50 mL*2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 5.
LC-MS:m/z＝452.2[M+H]+；1H NMR(400MHz,DMSO-d6)δ＝10.82(br s,1H),7.99(d,J＝8.4Hz,2H),7.79(d,J＝8.4Hz,2H),7.27(t,J＝2.4Hz,1H),6.66(s,1H),6.50(dd,J＝2.0,2.8Hz,1H),3.86(s,3H),3.73(s,3H),3.60(br t,J＝4.4Hz,1H),3.19(d,J＝12.0Hz,1H),3.11-3.03(m,1H),2.43(s,3H),2.39(br s,1H),2.36(br d,J＝7.2Hz,1H),2.21(br dd,J＝5.2,14.8Hz,1H),2.08-1.97(m,4H),1.92(br d,J＝6.8Hz,1H),1.62-1.48(m,1H)。LC-MS: m/z=452.2[M+H] + ; 1 H NMR (400MHz, DMSO-d 6 ) δ=10.82 (br s, 1H), 7.99 (d, J=8.4Hz, 2H), 7.79 (d,J＝8.4Hz,2H),7.27(t,J＝2.4Hz,1H),6.66(s,1H),6.50(dd,J＝2.0,2.8Hz,1H),3.86(s,3H) ,3.73(s,3H),3.60(br t,J＝4.4Hz,1H),3.19(d,J＝12.0Hz,1H),3.11-3.03(m,1H),2.43(s,3H),2.39 (br s,1H),2.36(br d,J＝7.2Hz,1H),2.21(br dd,J＝5.2,14.8Hz,1H),2.08-1.97(m,4H),1.92(br d,J =6.8Hz,1H),1.62-1.48(m,1H).
实施例6
Example 6
在20℃下，向化合物M3的盐酸盐(300.00mg)的二氯甲烷(10mL)溶液中加入4-二甲氨基吡啶(251.29mg)，1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(262.88mg)和乙醇(371.60μL)。反应液在20℃继续搅拌2小时。反应液冷却至室温后，反应液减压过滤，继续用色谱柱纯化(色谱柱:Unisil 3-100 C18 Ultra 150*50mm*3μm；流动相：A：水(0.025％甲酸)，B：乙腈，方法：B：20％-50％)，反应液加入饱和碳酸氢钠水溶液(50mL)，乙酸乙酯(50mL*2)萃取。合并的有机相用饱和食盐水(50mL*2)洗涤，无水硫酸钠干燥，过滤。滤液减压浓缩得到化合物6。To a solution of the hydrochloride salt of compound M3 (300.00 mg) in dichloromethane (10 mL) was added 4-dimethylaminopyridine (251.29 mg), 1-(3-dimethylaminopropyl)- 3-Ethylcarbodiimide hydrochloride (262.88 mg) and ethanol (371.60 μL). The reaction solution was continued to stir at 20°C for 2 hours. After the reaction solution was cooled to room temperature, the reaction solution was filtered under reduced pressure and continued to be purified with a chromatographic column (chromatographic column: Unisil 3-100 C18 Ultra 150*50mm*3μm; mobile phase: A: water (0.025% formic acid), B: acetonitrile, Method: B: 20%-50%), add saturated sodium bicarbonate aqueous solution (50mL) to the reaction solution, and extract with ethyl acetate (50mL*2). The combined organic phases were washed with saturated brine (50 mL*2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 6.
LC-MS:m/z＝466.2[M+H]+；1H NMR(400MHz,DMSO-d6)δ＝10.90-10.74(m,1H),8.05-7.92(m,2H),7.78(br d,J＝8.4Hz,2H),7.33-7.21(m,1H),6.72-6.61(m,1H),6.52(br s,1H),4.44-4.23(m,2H),3.73(s,4H),3.62-3.54(m,1H),3.23-3.16(m,1H),3.11-3.01(m,1H),2.45-2.40(m,3H),2.40-2.33(m,1H),2.26-2.14(m,1H),2.11-1.97(m,4H),1.96-1.86(m,1H),1.63-1.50(m,1H),1.33(t,J＝7.2Hz,3H)。 LC-MS: m/z=466.2[M+H] + ; 1 H NMR (400MHz, DMSO-d 6 ) δ=10.90-10.74(m,1H),8.05-7.92(m,2H),7.78(br d,J＝8.4Hz,2H),7.33-7.21(m,1H),6.72-6.61(m,1H),6.52(br s,1H),4.44-4.23(m,2H),3.73(s,4H ),3.62-3.54(m,1H),3.23-3.16(m,1H),3.11-3.01(m,1H),2.45-2.40(m,3H),2.40-2.33(m,1H),2.26-2.14 (m,1H),2.11-1.97(m,4H),1.96-1.86(m,1H),1.63-1.50(m,1H),1.33(t,J＝7.2Hz,3H).
实施例7
Example 7
在20℃下，向化合物M3的盐酸盐(300.00mg)的二氯甲烷(10mL)溶液中加入4-二甲氨基吡啶(251.29mg)，1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(262.88mg)和化合物7-1(223.00mg)。反应液在20℃继续搅拌2小时。反应液冷却至室温后加入饱和碳酸氢钠水溶液(10mL)反应液减压过滤，剩余物用制备色谱板分离纯化(石油醚:乙酸乙酯＝0:1)，得到化合物7。To a solution of the hydrochloride salt of compound M3 (300.00 mg) in dichloromethane (10 mL) was added 4-dimethylaminopyridine (251.29 mg), 1-(3-dimethylaminopropyl)- 3-Ethylcarbodiimide hydrochloride (262.88 mg) and compound 7-1 (223.00 mg). The reaction solution was continued to stir at 20°C for 2 hours. After the reaction solution was cooled to room temperature, a saturated aqueous sodium bicarbonate solution (10 mL) was added and the reaction solution was filtered under reduced pressure. The residue was separated and purified using a preparative chromatography plate (petroleum ether: ethyl acetate = 0:1) to obtain compound 7.
LC-MS:m/z＝550.2[M+H]+；1H NMR(400MHz,DMSO-d6)δ＝10.91-10.76(m,1H),8.04-7.97(m,2H),7.80(br d,J＝8.4Hz,2H),7.38-7.21(m,1H),6.72-6.60(m,1H),6.58-6.44(m,1H),5.26-5.19(m,2H),3.79-3.69(m,4H),3.63-3.56(m,1H),3.19(br d,J＝12.0Hz,1H),3.07(br s,1H),2.43(s,3H),2.38-2.31(m,1H),2.23(s,3H),2.21-2.14(m,1H),2.10-1.97(m,4H),1.94-1.85(m,1H),1.60-1.49(m,1H)。LC-MS: m/z=550.2[M+H] + ; 1 H NMR (400MHz, DMSO-d 6 ) δ=10.91-10.76 (m, 1H), 8.04-7.97 (m, 2H), 7.80 (br d,J＝8.4Hz,2H),7.38-7.21(m,1H),6.72-6.60(m,1H),6.58-6.44(m,1H),5.26-5.19(m,2H),3.79-3.69( m,4H),3.63-3.56(m,1H),3.19(br d,J＝12.0Hz,1H),3.07(br s,1H),2.43(s,3H),2.38-2.31(m,1H) ,2.23(s,3H),2.21-2.14(m,1H),2.10-1.97(m,4H),1.94-1.85(m,1H),1.60-1.49(m,1H).
实施例8
Example 8
在25℃下，向化合物M3的盐酸盐(0.3g)的乙腈(5mL)溶液中加入N,N-二异丙基乙胺(179.14μL)和特戊酸氯甲酯(154.89mg)反应液升温至60℃搅拌2小时。反应液冷却至室温后减压浓缩，继续用色谱柱纯化(色谱柱:Phenomenex luna C18 150*25mm*10μm；流动相：A：水(0.025％甲酸)，B：乙腈，方法：B：26％-56％)，反应液加入饱和碳酸氢钠水溶液调节pH至8，减压浓缩移除溶剂乙腈，乙酸乙酯(50mL*2)萃取。合并的有机相用饱和食盐水(50mL*2)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到化合物8。At 25°C, N,N-diisopropylethylamine (179.14 μL) and chloromethyl pivalate (154.89 mg) were added to a solution of the hydrochloride salt of compound M3 (0.3 g) in acetonitrile (5 mL) for reaction. The liquid was heated to 60°C and stirred for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and continued to be purified with a chromatographic column (chromatographic column: Phenomenex luna C18 150*25mm*10μm; mobile phase: A: water (0.025% formic acid), B: acetonitrile, method: B: 26% -56%), add saturated sodium bicarbonate aqueous solution to the reaction solution to adjust the pH to 8, concentrate under reduced pressure to remove the solvent acetonitrile, and extract with ethyl acetate (50 mL*2). The combined organic phases were washed with saturated brine (50 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 8.
LC-MS:m/z＝552.3[M+H]+；1H NMR(400MHz,DMSO-d6)δ＝10.83(br s,1H),7.99(d,J＝8.4Hz,2H),7.80(d,J＝8.4Hz,2H),7.25(t,J＝2.4Hz,1H),6.65(s,1H),6.53-6.46(m,1H),5.96(s,2H),3.76-3.68(m,4H),3.59(br t,J＝4.4Hz,1H),3.31(s,1H),3.18(d,J＝12.0Hz,1H),3.06(br s,1H),2.42(s,3H),2.39-2.32(m,1H),2.19(br dd,J＝5.2,14.8Hz,1H),2.05-1.95(m,3H),1.93-1.85(m,1H),1.54(br d,J＝14.0Hz,1H),1.15(s,9H)。 LC-MS: m/z=552.3[M+H] + ; 1 H NMR (400MHz, DMSO-d 6 ) δ=10.83 (br s, 1H), 7.99 (d, J=8.4Hz, 2H), 7.80 (d,J＝8.4Hz,2H),7.25(t,J＝2.4Hz,1H),6.65(s,1H),6.53-6.46(m,1H),5.96(s,2H),3.76-3.68( m,4H),3.59(br t,J＝4.4Hz,1H),3.31(s,1H),3.18(d,J＝12.0Hz,1H),3.06(br s,1H),2.42(s,3H ),2.39-2.32(m,1H),2.19(br dd,J＝5.2,14.8Hz,1H),2.05-1.95(m,3H),1.93-1.85(m,1H),1.54(br d,J =14.0Hz,1H),1.15(s,9H).
生物化学检测Biochemical testing
实验例1：大鼠药代动力学研究Experimental Example 1: 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本发明的化合物及其羧酸代谢产物的药物浓度。研究本发明的化合物及其羧酸代谢产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 concentrations of the compound of the present invention and its carboxylic acid metabolites in the plasma of 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 and its carboxylic acid metabolite 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 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：药代动力学参数结果见表1。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: The results of pharmacokinetic parameters are shown in Table 1.
表1：本发明化合物大鼠药代动力学数据
Table 1: 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。ND：血药浓度低于检测限，未拟合得到；ND*：24小时内未拟合得到。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. ND: The blood drug concentration is lower than the detection limit and not fitted; ND*: Not fitted within 24 hours.
结论：本发明化合物口服给药后，其羧酸代谢产物在体内暴露量高，药代动力学性质优良。Conclusion: After oral administration of the compound of the present invention, its carboxylic acid metabolite has high exposure in the body and has excellent pharmacokinetic properties.
实验例2：LPS诱导补体激活小鼠体内PD模型Experimental Example 2: LPS-induced complement activation in vivo mouse PD model
实验目的：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。Experimental purpose: To investigate the inhibitory effect of the compound of the present invention on complement activation in mice induced by LPS stimulation.
实验动物：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。实验过程：Experimental animals: female C57BL/6J mice, 7-9 weeks old, weighing 17-23 grams; supplier: Shanghai Sipur-Bika Experimental Animal Co., Ltd. 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(PO)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 an intraperitoneal injection of 100 μL of sterile PBS, and vehicle alone was administered by gavage (PO). 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, centrifuge them at 4°C and 3000g for 10 minutes within half an hour. 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20min，上样量为5μL/孔，即每孔血清上样量为0.025μL。通过Western Blotting检测C3d及transferrin蛋白水平。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 20 minutes, and load the sample The amount is 5 μL/well, that is, the serum loading amount in each well is 0.025 μL. C3d and transferrin protein levels were detected by Western Blotting.
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45％～55％，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 45% to 55% 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 45% to 55%. The protein level decreased by 60% to 80% compared to the modeling group, and the C3d protein level decreased 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，本发明化合物能够或者能够显著抑制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 or 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、R8、R9和R10分别独立地选自H或D；R 1 , R 5 , R 6 , R 8 , R 9 and R 10 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或3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 or 3 R a substitution;
    R7选自C1-6烷基、苯基、所述C1-6烷基任选被1、2、3、4或5个F取代，所述苯基任选被1、2或3个Rc取代；R 7 is selected from C 1-6 alkyl, phenyl, The C 1-6 alkyl group is optionally substituted by 1, 2, 3, 4 or 5 F, and the phenyl group is optionally substituted by 1, 2 or 3 R c ;
    R11选自C1-6烷基或C1-6烷氧基，所述C1-6烷基或C1-6烷氧基分别独立地任选被1、2、3、4或5个F取代；每个Ra各自独立地选自D、-F、-Cl、-Br或-I； R 11 is selected from C 1-6 alkyl or C 1-6 alkoxy, which is independently optionally substituted by 1, 2, 3 , 4 or 5. F substitution; each R a is independently selected from D, -F, -Cl, -Br or -I;
    每个Rb各自独立地选自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Rc各自独立地选自-F、-Cl、-Br、-I、C1-6烷基或C1-6烷氧基，所述C1-6烷基或C1-6烷氧基分别独立地任选被1、2、3、4或5个F取代；Each R c is independently selected from -F, -Cl, -Br, -I, C 1-6 alkyl or C 1-6 alkoxy, the C 1-6 alkyl or C 1-6 alkyl The oxygen groups are independently optionally substituted by 1, 2, 3, 4 or 5 F;
    每个R各自独立地选自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.
  2. 根据权利要求1所述化合物或其药学上可接受的盐，其中，每个R各自独立地选自D、-F或-Cl。The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each R is independently selected from D, -F or -Cl.
  3. 根据权利要求1所述化合物或其药学上可接受的盐，其中，每个Ra各自独立地选自D、-F或-Cl。The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each R a is independently selected from D, -F or -Cl.
  4. 根据权利要求1所述化合物或其药学上可接受的盐，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 according to claim 1 or a pharmaceutically acceptable salt thereof, 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 , 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;
    或者，每个Rb各自独立地选自-CH3、-CD3、-CD2CD3、-CH2CH3、-CH2CH2F、-CH2CHF2、-CH2CF3、-C(＝O)CH3或-S(＝O)2CH3；Alternatively, each R b is independently selected from -CH 3 , -CD 3 , -CD 2 CD 3 , -CH 2 CH 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -C(=O)CH 3 or -S(=O) 2 CH 3 ;
    或者，每个Rb各自独立地选D、-CH2CH3、-CH2CH2F、-CH2CHF2、-CH2CF3、-C(＝O)CH3、-S(＝O)2CH3、-CD2CD3、-CD2CF3、-C(＝O)CD3或-S(＝O)2CD3；Or, each R b independently selects 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 ;
    或者，每个Rb各自独立地选自-CH2CF3。Alternatively, each R b is independently selected from -CH 2 CF 3 .
  5. 根据权利要求1所述化合物或其药学上可接受的盐，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 according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 together with the atoms to which they are connected form an azetidinyl, azetipentyl or azetidinyl group, 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 ;
    或者，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。Alternatively, R 2 and R 3 together with the atoms to which they are connected form an azacyclopentyl group, and in this case, the R 4 is selected from -OCH 3 , -OCH 2 CH 3 , -OCD 3 or -OCD 2 CD 3 .
  6. 根据权利要求1所述化合物或其药学上可接受的盐，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 according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 4 together with the atoms to which they are connected form oxetanyl, oxanyl, oxanyl, azacyclic Butyl, azetanyl or azehexyl, the oxetanyl, oxetanyl, oxetanyl, azetidinyl, azetyl or azetyl respectively Independently optionally substituted by 1, 2 or 3 R b , in this case, the R 3 is selected from H or D;
    或者，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。Alternatively, R 2 and R 4 together with the atoms to which they are attached form oxanyl or azahyl, which are each independently optionally substituted with 1, 2 or 3 R b , at this time, the R 3 is selected from H.
  7. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R11选自-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2或-C(CH3)3，所述-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2或-C(CH3)3分别独立地任选被1、2、3、4或5个F取代；The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 11 is selected from -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 or -C (CH 3 ) 3 , the -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 or -C(CH 3 ) 3 are independently optionally substituted by 1 or 2 , 3, 4 or 5 F substitutions;
    或者，R11选自-C(CH3)3。Alternatively, R 11 is selected from -C(CH 3 ) 3 .
  8. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R7选自-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、所述-CH3、-CH2CH3、-CH2CH2CH3或-CH(CH3)2分别独立地任选被1、2、3、4或5个F取代；The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , The -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 or -CH(CH 3 ) 2 are each independently optionally substituted by 1, 2, 3, 4 or 5 F;
    或者，R7选自-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、所述-CH3、-CH2CH3、-CH2CH2CH3或-CH(CH3)2分别独立地任选被1、2、3、4或5个F取代；Alternatively, R 7 is selected from -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , The -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 or -CH(CH 3 ) 2 are each independently optionally substituted by 1, 2, 3, 4 or 5 F;
    或者，R7选自-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、 Alternatively, R 7 is selected from -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 ,
  9. 根据权利要求1所述化合物或其药学上可接受的盐，其中，结构单元选自 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from
    或者，结构单元选自 Or, structural unit Selected from
  10. 根据权利要求1所述化合物或其药学上可接受的盐，其中，结构单元选自苯基、吡啶基或哒嗪基；The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from phenyl, pyridyl or pyridazinyl;
    或者，结构单元选自 Or, structural unit Selected from
  11. 根据权利要求1～10任意一项所述化合物或其药学上可接受的盐，其中，化合物选自，
    The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein the compound is selected from,
    其中，R1、R4、R7、Rb、T1和T2如权利要求1所定义；Wherein, R 1 , R 4 , R 7 , R b , T 1 and T 2 are as defined in claim 1;
    当R4不为H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 is not H, 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.
  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. 根据权利要求12所述化合物或其药学上可接受的盐，其中，化合物选自，

    The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from,

  14. 一种药物组合物，其含有治疗有效量的权利要求1～13任意一项所述的化合物或其药学上可接受的盐。A pharmaceutical composition containing a therapeutically effective amount of the compound described in any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.
  15. 根据权利要求1～13任意一项所述的化合物或其药学上可接受的盐或权利要求14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 according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 14 in the preparation of a drug for treating diseases related to complement factor B.
PCT/CN2023/099083 2022-06-10 2023-06-08 Bicyclic substituted aromatic carboxylic acid ester compound WO2023237041A1 (en)

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