WO2023237041A1 - Composé ester d'acide carboxylique aromatique substitué bicyclique - Google Patents

Composé ester d'acide carboxylique aromatique substitué bicyclique Download PDF

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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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English (en)
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/fr

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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.

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Abstract

La présente invention concerne un composé ester d'acide carboxylique aromatique substitué bicyclique. L'invention concerne spécifiquement un composé tel que représenté par la formule (I) et un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2023/099083 2022-06-10 2023-06-08 Composé ester d'acide carboxylique aromatique substitué bicyclique WO2023237041A1 (fr)

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Citations (6)

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Publication number Priority date Publication date Assignee Title
CN109414441A (zh) * 2016-06-27 2019-03-01 艾其林医药公司 治疗医学障碍的喹唑啉和吲哚化合物
CN111032042A (zh) * 2017-08-31 2020-04-17 诺华股份有限公司 哌啶基-吲哚衍生物的新用途
CN112513025A (zh) * 2018-07-16 2021-03-16 诺华股份有限公司 用于制备苯基哌啶基吲哚衍生物的化学方法
CN114057758A (zh) * 2020-08-07 2022-02-18 上海美悦生物科技发展有限公司 补体因子b抑制剂及其药物组合物、制备方法和用途
TW202229271A (zh) * 2020-12-30 2022-08-01 大陸商江蘇恆瑞醫藥股份有限公司 含氮橋雜環化合物、其製備方法及其在醫藥上的應用
WO2022218429A1 (fr) * 2021-04-16 2022-10-20 正大天晴药业集团股份有限公司 Composés d'acide carboxylique aromatique substitués bicycliques

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109414441A (zh) * 2016-06-27 2019-03-01 艾其林医药公司 治疗医学障碍的喹唑啉和吲哚化合物
CN111032042A (zh) * 2017-08-31 2020-04-17 诺华股份有限公司 哌啶基-吲哚衍生物的新用途
CN112513025A (zh) * 2018-07-16 2021-03-16 诺华股份有限公司 用于制备苯基哌啶基吲哚衍生物的化学方法
CN114057758A (zh) * 2020-08-07 2022-02-18 上海美悦生物科技发展有限公司 补体因子b抑制剂及其药物组合物、制备方法和用途
TW202229271A (zh) * 2020-12-30 2022-08-01 大陸商江蘇恆瑞醫藥股份有限公司 含氮橋雜環化合物、其製備方法及其在醫藥上的應用
WO2022218429A1 (fr) * 2021-04-16 2022-10-20 正大天晴药业集团股份有限公司 Composés d'acide carboxylique aromatique substitués bicycliques

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