WO2024008121A1 - Composés azabicyclo difluoro-substitués et leurs utilisations - Google Patents

Composés azabicyclo difluoro-substitués et leurs utilisations Download PDF

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WO2024008121A1
WO2024008121A1 PCT/CN2023/105913 CN2023105913W WO2024008121A1 WO 2024008121 A1 WO2024008121 A1 WO 2024008121A1 CN 2023105913 W CN2023105913 W CN 2023105913W WO 2024008121 A1 WO2024008121 A1 WO 2024008121A1
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compound
alkyl
pharmaceutically acceptable
present
optionally substituted
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PCT/CN2023/105913
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English (en)
Chinese (zh)
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陈曙辉
张杨
张丽
张浩宇
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南京明德新药研发有限公司
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Publication of WO2024008121A1 publication Critical patent/WO2024008121A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a series of difluoro-substituted azabicyclic compounds and their applications, specifically to the compounds represented by formula (V) and their pharmaceutically acceptable salts.
  • Complement is a group of proteins with enzymatic activity present in the serum and tissue fluid of humans or vertebrate animals.
  • the complement system is part of the innate immune system and plays an important role in the body's resistance to 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.
  • the activation response of the complement system undergoes a series of fine adjustments in the body to maintain the dynamic balance of complement activation and inactivation, thereby preventing excessive consumption of complement components and damage to own tissues. Therefore, abnormal activation of complement can lead to various immune abnormalities.
  • 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).
  • Complement factor D (Factor D) is located at the front end of the bypass pathway of the complement system. By inhibiting complement factor D, it selectively inhibits the bypass pathway without interfering with the classical complement pathway and the lectin pathway. It can treat diseases related to immune abnormalities without increasing infections. risk. There are currently no small molecule Factor D inhibitors on the market.
  • Alexion’s factor D inhibitors ALXN2040 and ALXN2050 are in the clinical phase II research stage and are used for the treatment of PNH, IgAN, C3G and other diseases.
  • Biocryst’s factor D inhibitor BCX9930 is also in phase II clinical research for the treatment of PNH disease. Therefore, it is necessary to develop new small molecule inhibitors of the complement system Factor D, increase clinical research and verification, and use them in the treatment of various diseases caused by complement abnormalities to provide new treatment methods to meet clinical needs.
  • the present invention provides compounds represented by formula (V) or pharmaceutically acceptable salts thereof,
  • R 2 is selected from 5-6 membered heteroaryl and 8-10 membered heterocyclyl, which are independently optionally substituted by 1, 2 or 3 R b replaced;
  • R 3 and R 4 are independently selected from H, F, Cl, Br, I and C 1-4 alkyl, and the C 1-4 alkyl is optionally substituted by 1, 2 or 3 R d ;
  • Each R 5 is independently selected from F, Cl, Br, I, NH 2 , OH and C 1-4 alkyl, and the C 1-4 alkyl is optionally substituted by 1, 2 or 3 Re ;
  • T 2 is selected from CH and N;
  • Ring A is selected from 5-6 membered heteroaryl groups, and the 5-6 membered heteroaryl groups are optionally substituted by 1, 2 or 3 R c ;
  • Each R a , each R d and each R e are independently selected from F, Cl, Br, I, NH 2 and OH;
  • Each R b and each R c are independently selected from F, Cl, Br, I, NH 2 , OH, CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkylthio group, C 3-6 cycloalkyl group and 4-6 membered heterocycloalkyl group, the C 1-4 alkyl group, C 1-4 alkoxy group, C 1-4 alkylamino group, C 1 -4 alkylthio, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl are independently optionally substituted by 1, 2 or 3 F;
  • n is selected from 0, 1, 2 and 3;
  • n is selected from 1, 2 and 3;
  • hetero of the 5-6-membered heteroaryl, 8-10-membered heterocyclyl and 4-6-membered heterocycloalkyl respectively represents 1, 2, 3 or 4 independently selected from -NH-, -O- , -S- and N heteroatoms or heteroatom groups.
  • the present invention also provides compounds represented by formula (V) or pharmaceutically acceptable salts thereof,
  • R 2 is selected from 5-6 membered heteroaryl groups, and the 5-6 membered heteroaryl groups are independently optionally substituted by 1, 2 or 3 R b ;
  • R 3 and R 4 are independently selected from H, F, Cl, Br, I and C 1-4 alkyl, and the C 1-4 alkyl is optionally substituted by 1, 2 or 3 R d ;
  • Each R 5 is independently selected from F, Cl, Br, I, NH 2 , OH and C 1-4 alkyl, and the C 1-4 alkyl is optionally substituted by 1, 2 or 3 Re ;
  • T 1 is selected from CH and N;
  • T 2 is selected from CH and N;
  • Ring A is selected from 5-6 membered heteroaryl groups, and the 5-6 membered heteroaryl groups are optionally substituted by 1, 2 or 3 R c ;
  • Each R a , each R d and each R e are independently selected from F, Cl, Br, I, NH 2 and OH;
  • Each R b and each R c are independently selected from F, Cl, Br, I, NH 2 , OH, CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkanes Thio group, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, the C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkylthio
  • the base, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl are independently optionally substituted by 1, 2 or 3 F;
  • n is selected from 0, 1, 2 and 3;
  • n is selected from 1, 2 and 3;
  • hetero of the 5-6-membered heteroaryl and 4-6-membered heterocycloalkyl groups respectively represents 1, 2, 3 or 4 hetero groups independently selected from -NH-, -O-, -S- and N. Atoms or groups of heteroatoms.
  • the present invention also provides compounds represented by formula (II) or pharmaceutically acceptable salts thereof,
  • R 2 is selected from 5-6 membered heteroaryl groups, and the 5-6 membered heteroaryl groups are independently optionally substituted by 1, 2 or 3 R b ;
  • R 3 and R 4 are independently selected from H, F, Cl, Br, I and C 1-4 alkyl, and the C 1-4 alkyl is optionally substituted by 1, 2 or 3 R d ;
  • Each R 5 is independently selected from F, Cl, Br, I, NH 2 , OH and C 1-4 alkyl, and the C 1-4 alkyl is optionally substituted by 1, 2 or 3 Re ;
  • T 1 is selected from CH and N;
  • Ring A is selected from 5-6 membered heteroaryl groups, and the 5-6 membered heteroaryl groups are optionally substituted by 1, 2 or 3 R c ;
  • Each R a , each R d and each R e are independently selected from F, Cl, Br, I, NH 2 and OH;
  • Each R b and each R c are independently selected from F, Cl, Br, I, NH 2 , OH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1- 4 alkylthio, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, the C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 Alkylthio, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 F;
  • n is selected from 0, 1, 2 and 3;
  • n is selected from 1, 2 and 3;
  • hetero of the 5-6-membered heteroaryl and 4-6-membered heterocycloalkyl groups respectively represents 1, 2, 3 or 4 hetero groups independently selected from -NH-, -O-, -S- and N. Atoms or groups of heteroatoms.
  • the present invention also provides compounds represented by formula (I) or pharmaceutically acceptable salts thereof,
  • R 2 is selected from 5-6 membered heteroaryl groups, and the 5-6 membered heteroaryl groups are independently optionally substituted by 1, 2 or 3 R b ;
  • R 3 and R 4 are independently selected from H, F, Cl, Br, I and C 1-4 alkyl, and the C 1-4 alkyl is optionally substituted by 1, 2 or 3 R d ;
  • Each R 5 is independently selected from F, Cl, Br, I, NH 2 , OH and C 1-4 alkyl, and the C 1-4 alkyl is optionally substituted by 1, 2 or 3 Re ;
  • T 1 is selected from CH and N;
  • Ring A is selected from 5-6 membered heteroaryl groups, and the 5-6 membered heteroaryl groups are optionally substituted by 1, 2 or 3 R c ;
  • Each R a , each R d and each R e are independently selected from F, Cl, Br, I, NH 2 and OH;
  • Each R b and each R c are independently selected from F, Cl, Br, I, NH 2 , OH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1- 4 alkylthio, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, the C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 Alkylthio, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 F;
  • n is selected from 0, 1, 2 and 3;
  • hetero of the 5-6-membered heteroaryl and 4-6-membered heterocycloalkyl groups respectively represents 1, 2, 3 or 4 hetero groups independently selected from -NH-, -O-, -S- and N. Atoms or groups of heteroatoms.
  • the present invention also provides compounds represented by formula (I) or pharmaceutically acceptable salts thereof,
  • R 2 is selected from 5-6 membered heteroaryl groups, and the 5-6 membered heteroaryl groups are independently optionally substituted by 1, 2 or 3 R b ;
  • R 3 and R 4 are independently selected from H, F, Cl, Br, I and C 1-4 alkyl, and the C 1-4 alkyl is optionally substituted by 1, 2 or 3 R d ;
  • Each R 5 is independently selected from F, Cl, Br, I, NH 2 , OH and C 1-4 alkyl, and the C 1-4 alkyl is optionally substituted by 1, 2 or 3 Re ;
  • T 1 is selected from CH and N;
  • Ring A is selected from 5-6 membered heteroaryl groups, and the 5-6 membered heteroaryl groups are optionally substituted by 1, 2 or 3 R c ;
  • Each R a , each R d and each R e are independently selected from F, Cl, Br, I, NH 2 and OH;
  • Each R b and each R c are independently selected from F, Cl, Br, I, NH 2 , OH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1- 4 alkylthio, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, the C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 Alkylthio, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 F;
  • n is selected from 0, 1, 2 and 3;
  • hetero of the 5-6-membered heteroaryl and 4-6-membered heterocycloalkyl groups respectively represents 1, 2, 3 or 4 hetero groups independently selected from -NH-, -O-, -S- and N. Atoms or groups of heteroatoms.
  • each R b mentioned above is independently selected from F, Cl, Br, I, CH 3 and CF 3 , and other variables are as defined in the present invention.
  • each R b mentioned above is independently selected from F, Cl, Br, I, CN, CH 3 and CF 3 , and other variables are as defined in the present invention.
  • each of the above R c is independently selected from F, Cl, Br, I, CH 3 and CF 3 , and other variables are as defined in the present invention.
  • the above R 2 is selected from pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl and
  • the above R 2 is selected from pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thienyl, thiazolyl and oxazolyl , the pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thienyl, thiazolyl and oxazolyl groups are independently optionally substituted by 1, 2 or 3 R b substitutions, each R b and other variables are as defined in the present invention.
  • the above-mentioned R 2 is selected from pyrimidinyl, pyridyl, pyrazinyl and pyridazinyl, and the pyrimidinyl, pyridyl, pyrazinyl and pyridazinyl are independently optionally substituted by 1, 2 or 3 R b substitutions, each R b and other variables are as defined in the present invention.
  • the above-mentioned R 2 is selected from pyrimidinyl group, and the pyrimidine base is optionally substituted by 1, 2 or 3 R b , and each R b and other variables are as defined in the present invention.
  • R 2 is selected from Other variables are as defined in the present invention.
  • R 2 is selected from Other variables are as defined in the present invention.
  • R 2 is selected from Other variables are as defined in the present invention.
  • R 2 is selected from Other variables are as defined in the present invention.
  • R 3 is selected from H and CH 3 , and other variables are as defined in the present invention.
  • R 4 is selected from H and CH 3 , and other variables are as defined in the present invention.
  • each R 5 mentioned above is independently selected from F, Cl, Br, I, NH 2 , OH, CH 3 and CF 3 , and other variables are as defined in the present invention.
  • T 1 is selected from N, and other variables are as defined in the present invention.
  • T 2 is selected from N, and other variables are as defined in the present invention.
  • T 2 is selected from CH, and other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl, imidazolyl and pyrazolyl, and the pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl,
  • the imidazolyl and pyrazolyl groups are each independently optionally substituted by 1, 2 or 3 R c , and each R c and other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from Other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from Other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from Other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from Other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from Other variables are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof, the compound thereof is selected from,
  • T 1 , ring A, R 1 , R 2 , R 5 and n are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof, the compound thereof is selected from,
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof, the compound thereof is selected from,
  • R 2 is selected from pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl and The pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl and Each independently optionally substituted by 1, 2 or 3 R b ;
  • Ring A is selected from 5-6 membered heteroaryl groups, and the 5-6 membered heteroaryl groups are optionally substituted by 1, 2 or 3 R c ;
  • Each R b is independently selected from F, Cl, Br, I, CN, CH 3 and CF 3 ;
  • Each R c is independently selected from F, Cl, Br, I, CH 3 and CF 3 .
  • the compound of the above formula (VI-1) or a pharmaceutically acceptable salt thereof is selected from,
  • R 2 is selected from pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl and The pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl and Each independently optionally substituted by 1, 2 or 3 R b ;
  • R 3 is selected from H, F, Cl, Br, I, CH 3 and CF 3 ;
  • Ring A is selected from 5-6 membered heteroaryl groups, and the 5-6 membered heteroaryl groups are optionally substituted by 1, 2 or 3 R c ;
  • Each R b is independently selected from F, Cl, Br, I, CN, CH 3 and CF 3 ;
  • Each R c is independently selected from F, Cl, Br, I, CH 3 and CF 3 .
  • the compound of the above formula (VI-1) or a pharmaceutically acceptable salt thereof is selected from,
  • R 2 is selected from pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl and The pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl and Each independently optionally substituted by 1, 2 or 3 R b ;
  • R 3 is selected from H, F, Cl, Br, I, CH 3 and CF 3 ;
  • Ring A is selected from 5-6 membered heteroaryl groups, and the 5-6 membered heteroaryl groups are optionally substituted by 1, 2 or 3 R c ;
  • Each R b is independently selected from F, Cl, Br, I, CN, CH 3 and CF 3 ;
  • Each R c is independently selected from F, Cl, Br, I, CH 3 and CF 3 .
  • the compound of the above formula (VI-1), (VI-1a) or (VI-1b) or a pharmaceutically acceptable salt thereof, the R 2 is selected from pyrimidinyl, pyridyl, pyridinyl, Azinyl, pyridazinyl, the pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl are independently optionally substituted by 1, 2 or 3 R b , and other variables are as defined in the present invention.
  • the R 2 is selected from pyrimidinyl, and the pyrimidinyl Optionally substituted by 1, 2 or 3 R b , and other variables are as defined in the present invention.
  • the R 2 is selected from Other variables are as defined in the present invention.
  • the compound of the above formula (VI-1), (VI-1a) or (VI-1b) or a pharmaceutically acceptable salt thereof, the R 3 is selected from H and CH 3 , and other variables As defined herein.
  • the compound of the above formula (VI-1), (VI-1a) or (VI-1b) or a pharmaceutically acceptable salt thereof, the ring A is selected from pyridyl, and the pyridyl Optionally substituted by 1, 2 or 3 Rc , other variables are as defined in the present invention.
  • the compound of the above formula (VI-1), (VI-1a) or (VI-1b) or a pharmaceutically acceptable salt thereof, the ring A is selected from Other variables are as defined in the present invention.
  • the present invention also provides the following compounds or pharmaceutically acceptable salts thereof,
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof, the compound thereof is selected from,
  • the present invention also provides the use of the above-mentioned compounds or pharmaceutically acceptable salts thereof in the preparation of drugs for treating diseases related to Factor D inhibitors.
  • the invention also provides the following synthesis methods:
  • the compound of the present invention has a good combination with complement factor D, can significantly inhibit the activity of complement factor D, and has obvious inhibitory activity on the activation of the human serum bypass pathway; the compound of the present invention has excellent pharmacokinetic properties: long half-life, low clearance rate, plasma High exposure and bioavailability; excellent hepatic microsomal metabolic stability in various genera and excellent hepatic microsomal metabolic stability in human hepatocytes.
  • 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.
  • 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 Indicate the relative configuration of the three-dimensional center, using wavy lines Represents wedge-shaped solid line key or wedge-shaped dotted key or use tilde Represents a straight solid line key or straight dotted key
  • 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,”"enantiomericallyenriched,””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 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 ( 3H ), iodine-125 ( 125I ) or C-14 ( 14C ).
  • 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 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.
  • C 1-4 alkyl is used to mean a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms.
  • the C 1-4 alkyl group includes C 1-2 , C 1-3 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 1-4 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , s-butyl and t-butyl), etc.
  • C 1-4 alkoxy by itself or in combination with another term, means those alkyl groups containing 1 to 4 carbon atoms that are attached to the remainder of the molecule through an oxygen atom.
  • the C 1-5 alkoxy group includes C 1-2 , C 1-3 , C 2-3 , C 2-4 , C 3-4 , C 3 and C 4 alkoxy groups, etc. It can be monovalent, bivalent or polyvalent.
  • Examples of C 1-4 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy Oxygen, s-butoxy and t-butoxy), etc.
  • C 1-4 alkylthio by itself or in combination with another term, means those alkyl groups containing 1 to 4 carbon atoms that are attached to the remainder of the molecule through a sulfur atom.
  • the C 1-5 alkylthio group includes C 1-2 , C 1-3 , C 2-3 , C 2-4 , C 3-4 , C 3 and C 4 alkylthio groups, etc. It can be monovalent, bivalent or polyvalent.
  • Examples of C 1-4 alkylthio groups include, but are not limited to, -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH 2 (CH 3 ) 2 , and the like.
  • C 1-4 alkylamino by itself or in combination with another term, means those alkyl groups containing 1 to 4 carbon atoms that are attached to the remainder of the molecule through a nitrogen atom.
  • the C 1-4 alkylamino group includes C 1-2 , C 1-3 , C 2-3 , C 2-4 , C 3-4 , C 3 and C 4 alkylamino groups, etc. It can be monovalent, bivalent or polyvalent.
  • Examples of C 1-4 alkylamino include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH 2 (CH 3 ) 2 and the like.
  • C 3-6 cycloalkyl by itself or in combination with other terms respectively represents a saturated monocyclic hydrocarbon group composed of 3 to 6 carbon atoms, and the C 3-6 cycloalkyl group includes C 3-5 , C 4-5 and C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or multivalent.
  • Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • 4-6 membered heterocycloalkyl by itself or in combination with other terms means a saturated monocyclic group consisting of 4 to 6 ring atoms, with 1, 2, 3 or 4 ring atoms. are heteroatoms or heteroatom groups independently selected from O, S, NH and N, and the remainder are carbon atoms, in which 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 "4-6 membered heterocycloalkyl", a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule.
  • the 3-6-membered heterocycloalkyl group includes 4-5-membered, 5-6-membered, 4-membered, 5-membered and 6-membered heterocycloalkyl groups, etc. It can be monovalent, bivalent or polyvalent.
  • Examples of 4-6 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidin
  • the term "8-10 membered heterocyclyl" by itself or in combination with other terms refers to a saturated or partially unsaturated cyclic group consisting of 8 to 10 ring atoms, of which 1, 2, 3, 4 or 5 ring atoms are heteroatoms or heteroatom groups independently selected from O, S, NH and N, and the remainder are carbon atoms, wherein the carbon atoms are optionally oxidized (i.e. CO), and the nitrogen atoms are optionally quaternized. ation, nitrogen and sulfur heteroatoms may optionally be oxidized (i.e. NO and S(O) p , p is 1 or 2).
  • the 8-10-membered heterocyclic groups include 8-membered, 9-membered and 10-membered heterocyclic groups, etc.
  • the 8-10 membered heterocyclyl group includes single rings and polycyclic rings, such as spiro rings, paracyclic rings, and bridged rings. It can be monovalent, bivalent or polyvalent. Examples of 8-10 membered heterocyclyl groups include, but are not limited to wait.
  • the terms “5-6 membered heteroaromatic ring” and “5-6 membered heteroaryl” in the present invention can be used interchangeably, and the term “5-6 membered heteroaryl” by itself or in combination with other terms means respectively A monocyclic group with a conjugated ⁇ electron system composed of 5 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms.
  • the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2).
  • a 5-6 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl group includes 5-membered heteroaryl group and 6-membered heteroaryl group.
  • Examples of the 5-membered heteroaryl include but are not limited to pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl) etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl) base, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2, 4-triazoly
  • 6-membered heteroaryl examples include, but are not limited to, pyridyl (including 2-pyridyl, 3-pyridyl, 4-pyridyl, etc.), pyrazinyl, pyrazinyl or pyrimidinyl (including 2-pyrimidinyl) and 4-pyrimidinyl, etc.) etc.
  • C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , and C12 , also include any range from n to n+m, for example, C1-12 includes C1-3 , 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 , etc.; similarly, n yuan to n The +m member indicates 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.
  • 3-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, and 6-10 membered ring, etc.
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction, such as a nucleophilic substitution reaction.
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonate Ester, etc.; acyloxy group, such as acetoxy group, trifluoroacetoxy group, etc.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the nitrogen position of an amino group.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and so on.
  • acyl such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as
  • hydroxyl protecting group refers to a protecting group suitable for preventing hydroxyl side reactions.
  • Representative hydroxyl protecting groups include, but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl groups; acyl groups, For example, alkanoyl (such as acetyl); arylmethyl, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl) Methyl, DPM); silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS); tert-butyldiphenylsilyl (TBDPS) and so on.
  • alkyl groups such as methyl, ethyl, and tert-butyl groups
  • acyl groups For example, alkanoyl (such as acetyl);
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives and preferred embodiments include, but are not limited to, embodiments of the present invention.
  • the 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.
  • single crystal X-ray diffraction uses a Bruker D8 venture diffractometer to collect diffraction intensity data on the cultured single crystal.
  • the light source is CuK ⁇ radiation.
  • the scanning method is: After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure, and the absolute configuration can be confirmed.
  • PE represents petroleum ether
  • EA or EtOAc represents ethyl acetate
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives and preferred embodiments include, but are not limited to, embodiments of the present invention.
  • the solvent used in the present invention is commercially available.
  • Compounds are named according to conventional naming principles in the field or use For software naming, commercially available compounds adopt supplier catalog names.
  • FIG. 1 Protein binding pattern diagram of compound A and complement factor D.
  • the molecular docking process was performed using Maestro Performed in Glide SP [1] and default options.
  • the crystal structure of the complex of complement factor D and a selective small molecule inhibitor (PDB: 5NB7) was selected as the docking template.
  • PDB selective small molecule inhibitor
  • LigPrep was used to generate the three-dimensional structure of the molecule and energy minimization was performed [3] , and the confgen module was used to sample the small molecule conformation.
  • ligands in 5NB7 The molecule serves as the center of mass and generates a side length of of cube docking mesh.
  • Place reference compounds during molecular docking Analyze the interaction type between the protein receptor and the ligand, analyze the interaction type between the protein receptor and the ligand, and then select and save a reasonable docking conformation based on the calculated docking score and binding mode.
  • compound N-6 (200g, 454.98mmol) was dissolved in toluene (1200mL), lithium triethylborohydride (1M tetrahydrofuran solution, 545.98mL) was added dropwise at -78°C, and the reaction was carried out at -78°C for 2 hours. .
  • Diisopropylethylamine (321.94g, 2.49mol) and trifluoroacetic anhydride (142.69g, 679.36mmol) were added dropwise, and the reaction was carried out at -65°C for 2 hours, then returned to 25°C for 14 hours. Add 1500 mL of water to quench, and then extract with 2000 mL of ethyl acetate.
  • reaction solution was concentrated under reduced pressure, then 20 mL of dichloromethane was added, and washed with saturated ammonium chloride solution (15 mL ⁇ 3); the obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the crude product was purified by high performance liquid chromatography (column: C18 100 ⁇ 40mm; mobile phase: phase A water (trifluoroacetic acid), phase B is acetonitrile, gradient B%: 26%-56%), and the resulting sample solution After concentration under reduced pressure, adjust the pH to 7-8 with saturated sodium bicarbonate solution, extract with dichloromethane (5mL ⁇ 3), wash the combined organic phase with saturated brine (10mL), dry over anhydrous sodium sulfate, filter and concentrate to obtain Compound 7.
  • MS (ESI): m/z 638.1/640.1[M+H] + .
  • the compound of the present invention has obvious inhibitory activity on the activation of human serum bypass pathway.
  • Injection (IV) The solvent is 10% DMSO/10% solution/80% H 2 O, the concentration is 0.20 mg/mL, and the dosage is 1 mg/kg;
  • Sample collection 0.025mL of blood sample was collected from the saphenous vein puncture of the experimental animals at each time point, and the actual blood collection time was recorded. All blood samples were added into commercial EDTA-K2 anticoagulant tubes with a specification of 1.5 mL (supplier is Jiangsu Kangjian Medical Products Co., Ltd.). After blood samples are collected, within half an hour, centrifuge at 4°C and 3200g for 10 minutes to absorb the supernatant plasma, quickly place it in dry ice, and store it in a -80°C refrigerator for LC-MS/MS analysis.
  • mice pharmacokinetic study show that the compound of the present invention has a long half-life, high plasma exposure, high bioavailability, and It has excellent pharmacokinetic properties.
  • Sample collection About 0.250 mL of blood samples were collected from jugular vein puncture of experimental animals at each time point, and the actual blood collection time was recorded. 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 at 4°C and 3200g for 10 minutes to absorb the supernatant plasma, quickly place it in dry ice, and store it in a -80°C refrigerator for LC-MS/MS analysis.
  • Liver microsomes Human and animal microsomes were purchased from Corning or Xenotech and stored in a -80°C refrigerator.
  • NADPH Reduced nicotinamide adenine dinucleotide phosphate
  • Control compounds testosterone, diclofenac, propafenone.
  • Working concentration preparation dilute to 100 ⁇ M with 100% acetonitrile
  • T60 incubation plate Prepare two 96-well incubation plates, named T60 incubation plate and NCF60 incubation plate respectively.
  • microsomal working solution live microsomal protein concentration is 0.56 mg/mL
  • test product or control compound working solution After the pre-incubation, add 5 ⁇ L of test product or control compound working solution to the T60 incubation plate and NCF60 incubation plate respectively, and mix well.
  • the final concentration of the compound, testosterone, diclofenac and propafenone in the reaction is 1 ⁇ M
  • the concentration of liver microsomes is 0.5 mg/mL
  • the final concentration of DMSO and acetonitrile in the reaction system 0.01% (v/v) and 0.99% (v/v) respectively.
  • stop solution acetonitrile solution containing 200ng/mL tolbutamide and 200ng/mL labetalol
  • the compound of the present invention has excellent metabolic stability in various hepatic microsomes.
  • the metabolic stability of the compound of the present invention in human liver cells was investigated.
  • the test product is 1 ⁇ M
  • the final concentration of liver cells is 0.5 ⁇ 10 6 cells/mL
  • the final concentration of total organic solvents is 0.96%
  • the final concentration of DMSO is 0.1%.
  • the compound of the present invention has a medium to slow clearance rate in human liver cells and has excellent metabolic stability.

Abstract

L'invention concerne une série de composés azabicyclo difluoro-substitués et leurs utilisations, et spécifiquement un composé représenté par la formule (V) et un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2023/105913 2022-07-06 2023-07-05 Composés azabicyclo difluoro-substitués et leurs utilisations WO2024008121A1 (fr)

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CN202211282922 2022-10-19
CN202211282922.7 2022-10-19
CN202310066225.6 2023-01-17
CN202310066225 2023-01-17
CN202310193538 2023-03-02
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WO2019227102A1 (fr) * 2018-05-25 2019-11-28 Achillion Pharmaceuticals, Inc. Biomarqueurs de néphropathie associés à la voie alternative du complément
CN110603252A (zh) * 2017-03-01 2019-12-20 艾其林医药公司 用于治疗医学障碍的芳基、杂芳基和杂环药物化合物
WO2020041301A1 (fr) * 2018-08-20 2020-02-27 Achillion Pharmaceuticals, Inc. Composés pharmaceutiques pour le traitement de troubles médicaux du facteur d du complément
CN111163767A (zh) * 2017-08-02 2020-05-15 艾其林医药公司 治疗阵发性睡眠性血红蛋白尿症的治疗方案
WO2021168320A1 (fr) * 2020-02-20 2021-08-26 Achillion Pharmaceuticals, Inc. Composés hétéroaryle pour le traitement de troubles médiés par le facteur d du complément
WO2021183555A1 (fr) * 2020-03-10 2021-09-16 Achillion Pharmaceuticals, Inc. Dépôt de médicament oculaire pour troubles à médiation par le complément
WO2021202977A1 (fr) * 2020-04-03 2021-10-07 Biocryst Pharmaceuticals, Inc. Pyrrolopyrimidine amines en tant qu'inhibiteurs du complément

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Publication number Priority date Publication date Assignee Title
CN106413707A (zh) * 2014-02-25 2017-02-15 艾其林医药公司 用于治疗补体介导的疾病的酰胺化合物
CN108024992A (zh) * 2015-08-26 2018-05-11 艾其林医药公司 用于治疗医学障碍的芳基、杂芳基和杂环化合物
CN110603252A (zh) * 2017-03-01 2019-12-20 艾其林医药公司 用于治疗医学障碍的芳基、杂芳基和杂环药物化合物
CN111163767A (zh) * 2017-08-02 2020-05-15 艾其林医药公司 治疗阵发性睡眠性血红蛋白尿症的治疗方案
WO2019227102A1 (fr) * 2018-05-25 2019-11-28 Achillion Pharmaceuticals, Inc. Biomarqueurs de néphropathie associés à la voie alternative du complément
WO2020041301A1 (fr) * 2018-08-20 2020-02-27 Achillion Pharmaceuticals, Inc. Composés pharmaceutiques pour le traitement de troubles médicaux du facteur d du complément
WO2021168320A1 (fr) * 2020-02-20 2021-08-26 Achillion Pharmaceuticals, Inc. Composés hétéroaryle pour le traitement de troubles médiés par le facteur d du complément
WO2021183555A1 (fr) * 2020-03-10 2021-09-16 Achillion Pharmaceuticals, Inc. Dépôt de médicament oculaire pour troubles à médiation par le complément
WO2021202977A1 (fr) * 2020-04-03 2021-10-07 Biocryst Pharmaceuticals, Inc. Pyrrolopyrimidine amines en tant qu'inhibiteurs du complément

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