WO2024008121A1 - Difluoro-substituted azabicyclo compounds and uses thereof - Google Patents

Difluoro-substituted azabicyclo compounds and uses thereof Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
compound
alkyl
pharmaceutically acceptable
present
optionally substituted
Prior art date
Application number
PCT/CN2023/105913
Other languages
French (fr)
Chinese (zh)
Inventor
陈曙辉
张杨
张丽
张浩宇
Original Assignee
南京明德新药研发有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 南京明德新药研发有限公司 filed Critical 南京明德新药研发有限公司
Publication of WO2024008121A1 publication Critical patent/WO2024008121A1/en

Links

Classifications

    • 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

Disclosed are a series of difluoro-substituted azabicyclo compounds and uses thereof, and specifically disclosed are a compound represented by formula (V) and a pharmaceutically acceptable salt thereof.

Description

二氟取代的氮杂双环化合物及其应用Difluoro-substituted azabicyclic compounds and their applications
本申请主张如下优先权：This application claims the following priority rights:
CN202210800800.6，申请日：2022年07月06日；CN202210800800.6, application date: July 6, 2022;
CN202210917090.5，申请日：2022年08月01日；CN202210917090.5, application date: August 1, 2022;
CN202211282922.7，申请日：2022年10月19日；CN202211282922.7, application date: October 19, 2022;
CN202310066225.6，申请日：2023年01月17日；CN202310066225.6, application date: January 17, 2023;
CN202310193538.8，申请日：2023年03月02日；CN202310193538.8, application date: March 2, 2023;
CN202310365727.9，申请日：2023年04月04日。CN202310365727.9, application date: April 4, 2023.
技术领域Technical field
本发明涉及一系列二氟取代的氮杂双环化合物及其应用，具体涉及式(V)所示化合物及其药学上可接受的盐。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.
背景技术Background technique
补体是存在于人或脊柱动物血清与组织液中的一组具有酶活性的蛋白质。补体系统是先天免疫系统的一部分，与人体抵抗外源病原体、细菌和寄生虫等感染等起着重要的作用，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。补体系统的激活反应再体内收到一系列精细调节，以保持补体激活与灭活的动态平衡，从而防止补体成分的过度消耗和对自身组织的损伤。因此补体的不正常激活会导致各种免疫异常疾病。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. At the same time, 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.
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)。补体因子D(Factor D)位于补体系统旁路通路的前端，通过抑制补体因子D选择性抑制旁路通路，而不干扰补体经典通路和凝集素通路，能够治疗免疫异常相关疾病，且不增加感染风险。目前尚无小分子Factor D抑制剂上市，Alexion的factor D抑制剂ALXN2040、ALXN2050处于临床II期研究阶段，用于PNH、IgAN、C3G等疾病的治疗。同时Biocryst的factor D抑制剂BCX9930也处于临床II期研究阶段用于PNH疾病的治疗。因此，有必要开发新型补体系统Factor D小分子抑制剂，增加临床研究和验证并用于补体异常导致的各种疾病的治疗，为满足临床需求提供新的治疗手段。Complement 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. At the same time, 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.
发明内容Contents of the invention
本发明提供了式(V)所示化合物或其药学上可接受的盐，
The present invention provides compounds represented by formula (V) or pharmaceutically acceptable salts thereof,
其中， in,
R1选自F、Cl、Br、I、C1-4烷基、C1-4烷氧基、C1-4烷氨基、C1-4烷硫基、-C(＝O)-C1-4烷基、-C(＝O)-C1-4烷氨基、-C(＝O)-NH2和-NH-C(＝O)-C1-4烷基，所述C1-4烷基、C1-4烷氧基、C1-4烷氨基、C1-4烷硫基、-C(＝O)-C1-4烷基、-C(＝O)-C1-4烷氨基、-C(＝O)-NH2和-NH-C(＝O)-C1-4烷基分别独立地任选被1、2或3个Ra取代；R 1 is selected from F, Cl, Br, I, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkylthio, -C(=O)-C 1-4 alkyl, -C(=O)-C 1-4 alkylamino, -C(=O)-NH 2 and -NH-C(=O)-C 1-4 alkyl, the C 1 -4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkylthio, -C(=O)-C 1-4 alkyl, -C(=O)-C 1-4 alkylamino, -C(=O)-NH 2 and -NH-C(=O)-C 1-4 alkyl are independently optionally substituted by 1, 2 or 3 R a ;
R2选自5-6元杂芳基和8-10元杂环基，所述5-6元杂芳基和8-10元杂环基分别独立地任选被1、2或3个Rb取代；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;
R3和R4分别独立地选自H、F、Cl、Br、I和C1-4烷基，所述C1-4烷基任选被1、2或3个Rd取代；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 ;
各R5分别独立地选自F、Cl、Br、I、NH2、OH和C1-4烷基，所述C1-4烷基任选被1、2或3个Re取代；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 ;
T1选自CH和N；T 1 is selected from CH and N;
T2选自CH和N；T 2 is selected from CH and N;
环A选自5-6元杂芳基，所述5-6元杂芳基任选被1、2或3个Rc取代；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 ;
各Ra、各Rd和各Re分别独立地选自F、Cl、Br、I、NH2和OH；Each R a , each R d and each R e are independently selected from F, Cl, Br, I, NH 2 and OH;
各Rb和各Rc分别独立地选自F、Cl、Br、I、NH2、OH、CN、C1-4烷基、C1-4烷氧基、C1-4烷氨基、C1-4烷硫基、C3-6环烷基和4-6元杂环烷基，所述C1-4烷基、C1-4烷氧基、C1-4烷氨基、C1-4烷硫基、C3-6环烷基和4-6元杂环烷基分别独立地任选被1、2或3个F取代；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选自0、1、2和3；n is selected from 0, 1, 2 and 3;
m选自1、2和3；m is selected from 1, 2 and 3;
所述5-6元杂芳基、8-10元杂环基和4-6元杂环烷基的“杂”分别表示1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。The "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.
本发明还提供了式(V)所示化合物或其药学上可接受的盐，
The present invention also provides compounds represented by formula (V) or pharmaceutically acceptable salts thereof,
其中，in,
R1选自F、Cl、Br、I、C1-4烷基、C1-4烷氧基、C1-4烷氨基、C1-4烷硫基、-C(＝O)-C1-4烷基、-C(＝O)-C1-4烷氨基、-C(＝O)-NH2和-NH-C(＝O)-C1-4烷基，所述C1-4烷基、C1-4烷氧基、C1-4烷氨基、C1-4烷硫基、-C(＝O)-C1-4烷基、-C(＝O)-C1-4烷氨基、-C(＝O)-NH2和-NH-C(＝O)-C1-4烷基分别独立地任选被1、2或3个Ra取代；R 1 is selected from F, Cl, Br, I, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkylthio, -C(=O)-C 1-4 alkyl, -C(=O)-C 1-4 alkylamino, -C(=O)-NH 2 and -NH-C(=O)-C 1-4 alkyl, the C 1 -4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkylthio, -C(=O)-C 1-4 alkyl, -C(=O)-C 1-4 alkylamino, -C(=O)-NH 2 and -NH-C(=O)-C 1-4 alkyl are independently optionally substituted by 1, 2 or 3 R a ;
R2选自5-6元杂芳基，所述5-6元杂芳基分别独立地任选被1、2或3个Rb取代；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 ;
R3和R4分别独立地选自H、F、Cl、Br、I和C1-4烷基，所述C1-4烷基任选被1、2或3个Rd取代；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 ;
各R5分别独立地选自F、Cl、Br、I、NH2、OH和C1-4烷基，所述C1-4烷基任选被1、2或3个Re取代；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 ;
T1选自CH和N；T 1 is selected from CH and N;
T2选自CH和N；T 2 is selected from CH and N;
环A选自5-6元杂芳基，所述5-6元杂芳基任选被1、2或3个Rc取代；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 ;
各Ra、各Rd和各Re分别独立地选自F、Cl、Br、I、NH2和OH；Each R a , each R d and each R e are independently selected from F, Cl, Br, I, NH 2 and OH;
各Rb和各Rc分别独立地选自F、Cl、Br、I、NH2、OH、CN、C1-4烷基、C1-4烷氧基、C1-4烷氨基、C1-4烷 硫基、C3-6环烷基和4-6元杂环烷基，所述C1-4烷基、C1-4烷氧基、C1-4烷氨基、C1-4烷硫基、C3-6环烷基和4-6元杂环烷基分别独立地任选被1、2或3个F取代；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选自0、1、2和3；n is selected from 0, 1, 2 and 3;
m选自1、2和3；m is selected from 1, 2 and 3;
所述5-6元杂芳基和4-6元杂环烷基的“杂”分别表示1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。The "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.
本发明还提供了式(II)所示化合物或其药学上可接受的盐，
The present invention also provides compounds represented by formula (II) or pharmaceutically acceptable salts thereof,
其中，in,
R1选自F、Cl、Br、I、C1-4烷基、C1-4烷氧基、C1-4烷氨基、C1-4烷硫基、-C(＝O)-C1-4烷基、-C(＝O)-C1-4烷氨基、-C(＝O)-NH2和-NH-C(＝O)-C1-4烷基，所述C1-4烷基、C1-4烷氧基、C1-4烷氨基、C1-4烷硫基、-C(＝O)-C1-4烷基、-C(＝O)-C1-4烷氨基、-C(＝O)-NH2和-NH-C(＝O)-C1-4烷基分别独立地任选被1、2或3个Ra取代；R 1 is selected from F, Cl, Br, I, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkylthio, -C(=O)-C 1-4 alkyl, -C(=O)-C 1-4 alkylamino, -C(=O)-NH 2 and -NH-C(=O)-C 1-4 alkyl, the C 1 -4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkylthio, -C(=O)-C 1-4 alkyl, -C(=O)-C 1-4 alkylamino, -C(=O)-NH 2 and -NH-C(=O)-C 1-4 alkyl are independently optionally substituted by 1, 2 or 3 R a ;
R2选自5-6元杂芳基，所述5-6元杂芳基分别独立地任选被1、2或3个Rb取代；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 ;
R3和R4分别独立地选自H、F、Cl、Br、I和C1-4烷基，所述C1-4烷基任选被1、2或3个Rd取代；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 ;
各R5分别独立地选自F、Cl、Br、I、NH2、OH和C1-4烷基，所述C1-4烷基任选被1、2或3个Re取代；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 ;
T1选自CH和N；T 1 is selected from CH and N;
环A选自5-6元杂芳基，所述5-6元杂芳基任选被1、2或3个Rc取代；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 ;
各Ra、各Rd和各Re分别独立地选自F、Cl、Br、I、NH2和OH；Each R a , each R d and each R e are independently selected from F, Cl, Br, I, NH 2 and OH;
各Rb和各Rc分别独立地选自F、Cl、Br、I、NH2、OH、C1-4烷基、C1-4烷氧基、C1-4烷氨基、C1-4烷硫基、C3-6环烷基和4-6元杂环烷基，所述C1-4烷基、C1-4烷氧基、C1-4烷氨基、C1-4烷硫基、C3-6环烷基和4-6元杂环烷基分别独立地任选被1、2或3个F取代；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选自0、1、2和3；n is selected from 0, 1, 2 and 3;
m选自1、2和3；m is selected from 1, 2 and 3;
所述5-6元杂芳基和4-6元杂环烷基的“杂”分别表示1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。The "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.
本发明还提供了式(I)所示化合物或其药学上可接受的盐，
The present invention also provides compounds represented by formula (I) or pharmaceutically acceptable salts thereof,
其中，in,
R1选自F、Cl、Br、I、C1-4烷基、C1-4烷氧基、C1-4烷氨基、C1-4烷硫基、-C(＝O)-C1-4烷基、-C(＝O)-C1-4烷氨基、-C(＝O)-NH2和-NH-C(＝O)-C1-4烷基，所述C1-4烷基、C1-4烷氧基、C1-4烷氨基、C1-4烷硫基、-C(＝O)-C1-4烷基、-C(＝O)-C1-4烷氨基、-C(＝O)-NH2和-NH-C(＝O)-C1-4烷基分别独立地任选被1、2或3个Ra取代；R 1 is selected from F, Cl, Br, I, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkylthio, -C(=O)-C 1-4 alkyl, -C(=O)-C 1-4 alkylamino, -C(=O)-NH 2 and -NH-C(=O)-C 1-4 alkyl, the C 1 -4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkylthio, -C(=O)-C 1-4 alkyl, -C(=O)-C 1-4 alkylamino, -C(=O)-NH 2 and -NH-C(=O)-C 1-4 alkyl are independently optionally substituted by 1, 2 or 3 R a ;
R2选自5-6元杂芳基，所述5-6元杂芳基分别独立地任选被1、2或3个Rb取代；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 ;
R3和R4分别独立地选自H、F、Cl、Br、I和C1-4烷基，所述C1-4烷基任选被1、2或3个Rd取代；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 ;
各R5分别独立地选自F、Cl、Br、I、NH2、OH和C1-4烷基，所述C1-4烷基任选被1、2或3个Re取代；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 ;
T1选自CH和N；T 1 is selected from CH and N;
环A选自5-6元杂芳基，所述5-6元杂芳基任选被1、2或3个Rc取代；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 ;
各Ra、各Rd和各Re分别独立地选自F、Cl、Br、I、NH2和OH；Each R a , each R d and each R e are independently selected from F, Cl, Br, I, NH 2 and OH;
各Rb和各Rc分别独立地选自F、Cl、Br、I、NH2、OH、C1-4烷基、C1-4烷氧基、C1-4烷氨基、C1-4烷硫基、C3-6环烷基和4-6元杂环烷基，所述C1-4烷基、C1-4烷氧基、C1-4烷氨基、C1-4烷硫基、C3-6环烷基和4-6元杂环烷基分别独立地任选被1、2或3个F取代；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选自0、1、2和3；n is selected from 0, 1, 2 and 3;
所述5-6元杂芳基和4-6元杂环烷基的“杂”分别表示1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。The "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.
本发明还提供了式(I)所示化合物或其药学上可接受的盐，
The present invention also provides compounds represented by formula (I) or pharmaceutically acceptable salts thereof,
其中，in,
R1选自F、Cl、Br、I、C1-4烷基、C1-4烷氧基、C1-4烷氨基、C1-4烷硫基、-C(＝O)-C1-4烷基、-C(＝O)-C1-4烷氨基、-C(＝O)-NH2和-NH-C(＝O)-C1-4烷基，所述C1-4烷基、C1-4烷氧基、C1-4烷氨基、C1-4烷硫基、-C(＝O)-C1-4烷基、-C(＝O)-C1-4烷氨基、-C(＝O)-NH2和-NH-C(＝O)-C1-4烷基分别独立地任选被1、2或3个Ra取代；R 1 is selected from F, Cl, Br, I, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkylthio, -C(=O)-C 1-4 alkyl, -C(=O)-C 1-4 alkylamino, -C(=O)-NH 2 and -NH-C(=O)-C 1-4 alkyl, the C 1 -4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkylthio, -C(=O)-C 1-4 alkyl, -C(=O)-C 1-4 alkylamino, -C(=O)-NH 2 and -NH-C(=O)-C 1-4 alkyl are independently optionally substituted by 1, 2 or 3 R a ;
R2选自5-6元杂芳基，所述5-6元杂芳基分别独立地任选被1、2或3个Rb取代；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 ;
R3和R4分别独立地选自H、F、Cl、Br、I和C1-4烷基，所述C1-4烷基任选被1、2或3个Rd取代； 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 ;
各R5分别独立地选自F、Cl、Br、I、NH2、OH和C1-4烷基，所述C1-4烷基任选被1、2或3个Re取代；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 ;
T1选自CH和N；T 1 is selected from CH and N;
环A选自5-6元杂芳基，所述5-6元杂芳基任选被1、2或3个Rc取代；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 ;
各Ra、各Rd和各Re分别独立地选自F、Cl、Br、I、NH2和OH；Each R a , each R d and each R e are independently selected from F, Cl, Br, I, NH 2 and OH;
各Rb和各Rc分别独立地选自F、Cl、Br、I、NH2、OH、C1-4烷基、C1-4烷氧基、C1-4烷氨基、C1-4烷硫基、C3-6环烷基和4-6元杂环烷基，所述C1-4烷基、C1-4烷氧基、C1-4烷氨基、C1-4烷硫基、C3-6环烷基和4-6元杂环烷基分别独立地任选被1、2或3个F取代；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选自0、1、2和3；n is selected from 0, 1, 2 and 3;
所述5-6元杂芳基和4-6元杂环烷基的“杂”分别表示1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。The "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.
在本发明的一些方案中，上述各Rb分别独立地选自F、Cl、Br、I、CH3和CF3，其他变量如本发明所定义。In some aspects of the present invention, 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.
在本发明的一些方案中，上述各Rb分别独立地选自F、Cl、Br、I、CN、CH3和CF3，其他变量如本发明所定义。In some aspects of 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.
在本发明的一些方案中，上述各Rc分别独立地选自F、Cl、Br、I、CH3和CF3，其他变量如本发明所定义。In some aspects of 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.
在本发明的一些方案中，上述R1选自F、Cl、Br、I、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、C(CH3)3、OCH3、OCH2CH3、OCH2CH2CH3、OCH(CH3)2、NHCH3、NHCH2CH3、N(CH3)2、SCH3、SCH2CH3、-C(＝O)-CH3、-C(＝O)-NH2、-C(＝O)-NHCH3和-NH-C(＝O)-CH3，所述CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、C(CH3)3、OCH3、OCH2CH3、OCH2CH2CH3、OCH(CH3)2、NHCH3、NHCH2CH3、N(CH3)2、SCH3、SCH2CH3、-C(＝O)-CH3、-C(＝O)-NH2、-C(＝O)-NHCH3和-NH-C(＝O)-CH3分别独立地任选被1、2或3个Ra取代，各Ra及其他变量如本发明所定义。In some aspects of the invention, the above-mentioned R 1 is selected from F, Cl, Br, I, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , NHCH 3 , NHCH 2 CH 3 , N(CH 3 ) 2 , SCH 3 , SCH 2 CH 3 , -C(=O )-CH 3 , -C(=O)-NH 2 , -C(=O)-NHCH 3 and -NH-C(=O)-CH 3 , the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , NHCH 3 , NHCH 2 CH 3 , N( CH 3 ) 2 , SCH 3 , SCH 2 CH 3 , -C(=O)-CH 3 , -C(=O)-NH 2 , -C(=O)-NHCH 3 and -NH-C(=O )-CH 3 are each independently optionally substituted by 1, 2 or 3 Ra , and each Ra and other variables are as defined in the present invention.
在本发明的一些方案中，上述R1选自-C(＝O)-CH3，其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 1 is selected from -C(=O)-CH 3 , and other variables are as defined in the present invention.
在本发明的一些方案中，上述R2选自嘧啶基、吡啶基、吡嗪基、哒嗪基、咪唑基、吡唑基和所述嘧啶基、吡啶基、吡嗪基、哒嗪基、咪唑基、吡唑基和分别独立地任选被1、2或3个Rb取代，各Rb及其他变量如本发明所定义。In some aspects of the invention, the above R 2 is selected from pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl and The pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl and Each is independently optionally substituted by 1, 2 or 3 R b , and each R b and other variables are as defined in the present invention.
在本发明的一些方案中，上述R2选自嘧啶基、吡啶基、吡嗪基、哒嗪基、吡咯基、咪唑基、吡唑基、三唑基、噻吩基、噻唑基和噁唑基，所述嘧啶基、吡啶基、吡嗪基、哒嗪基、吡咯基、咪唑基、吡唑基、三唑基、噻吩基、噻唑基和噁唑基分别独立地任选被1、2或3个Rb取代，各Rb及其他变量如本发明所定义。In some aspects of the invention, 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.
在本发明的一些方案中，上述R2选自嘧啶基、吡啶基、吡嗪基和哒嗪基，所述嘧啶基、吡啶基、吡嗪基和哒嗪基分别独立地任选被1、2或3个Rb取代，各Rb及其他变量如本发明所定义。In some aspects of the 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.
在本发明的一些方案中，上述R2选自嘧啶基，所述嘧啶基地任选被1、2或3个Rb取代，各Rb及其他变量如本发明所定义。 In some embodiments of 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.
在本发明的一些方案中，上述R2选自 其他变量如本发明所定义。In some aspects of the invention, the above-mentioned R 2 is selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述R2选自 其他变量如本发明所定义。In some aspects of the invention, the above-mentioned R 2 is selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述R2选自其他变量如本发明所定义。In some aspects of the invention, the above-mentioned R 2 is selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述R2选自其他变量如本发明所定义。In some aspects of the invention, the above-mentioned R 2 is selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述R3选自H和CH3，其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 3 is selected from H and CH 3 , and other variables are as defined in the present invention.
在本发明的一些方案中，上述R4选自H和CH3，其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 4 is selected from H and CH 3 , and other variables are as defined in the present invention.
在本发明的一些方案中，上述各R5分别独立地选自F、Cl、Br、I、NH2、OH、CH3和CF3，其他变量如本发明所定义。In some aspects of 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.
在本发明的一些方案中，上述T1选自N，其他变量如本发明所定义。In some solutions of the present invention, the above-mentioned T 1 is selected from N, and other variables are as defined in the present invention.
在本发明的一些方案中，上述T2选自N，其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned T 2 is selected from N, and other variables are as defined in the present invention.
在本发明的一些方案中，上述T2选自CH，其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned T 2 is selected from CH, and other variables are as defined in the present invention.
在本发明的一些方案中，上述环A选自嘧啶基、吡啶基、吡嗪基、哒嗪基、咪唑基和吡唑基，所述嘧啶基、吡啶基、吡嗪基、哒嗪基、咪唑基和吡唑基分别独立地任选被1、2或3个Rc取代，各Rc及其他变量如本发明所定义。In some aspects of the 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.
在本发明的一些方案中，上述环A选自其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned ring A is selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述环A选自其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned ring A is selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述环A选自其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned ring A is selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述环A选自其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned ring A is selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述环A选自其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned ring A is selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述结构单元选自其他变量如本发明所定义。In some solutions of the present invention, the above structural units Selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述结构单元选自其他变量如本发明所定义。In some solutions of the present invention, the above structural units Selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述结构单元选自其他变量如本发明所定义。In some solutions of the present invention, the above structural units Selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述结构单元选自R1、R2及其他变量如本发明所定义。In some solutions of the present invention, the above structural units Selected from R 1 , R 2 and other variables are as defined in the present invention.
在本发明的一些方案中，上述结构单元选自R2及其他变量如本发明所定义。In some solutions of the present invention, the above structural units Selected from R2 and other variables are as defined in the present invention.
在本发明的一些方案中，上述结构单元选自其他变量如本发明所定义。 In some solutions of the present invention, the above structural units Selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述结构单元选自其他变量如本发明所定义。In some solutions of the present invention, the above structural units Selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述结构单元选自其他变量如本发明所定义。In some solutions of the present invention, the above structural units Selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述结构单元选自其他变量如本发明所定义。In some solutions of the present invention, the above structural units Selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述结构单元选自其他变量如本发明所定义。In some solutions of the present invention, the above structural units Selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述结构单元选自其他变量如本发明所定义。In some solutions of the present invention, the above structural units Selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述结构单元选自 其他变量如本发明所定义。In some solutions of the present invention, the above structural units Selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述结构单元选自其他变量如本发明所定义。In some solutions of the present invention, the above structural units Selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述结构单元选自其他变量如本发明所定义。 In some solutions of the present invention, the above structural units Selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述结构单元选自其他变量如本发明所定义。In some solutions of the present invention, the above structural units Selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上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 present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof, the compound thereof is selected from,
其中，T1、环A、R1、R2、R5和n如本发明所定义。Among them, T 1 , ring A, R 1 , R 2 , R 5 and n are as defined in the present invention.
在本发明的一些方案中，上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 present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof, the compound thereof is selected from,
其中，T1、环A、R1、R2、R5和n如本发明所定义。Among them, T 1 , ring A, R 1 , R 2 , R 5 and n are as defined in the present invention.
在本发明的一些方案中，上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 present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof, the compound thereof is selected from,
其中， in,
R2选自嘧啶基、吡啶基、吡嗪基、哒嗪基、咪唑基、吡唑基和所述嘧啶基、吡啶基、吡嗪基、哒嗪基、咪唑基、吡唑基和分别独立地任选被1、2或3个Rb取代；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 ;
R3选自H、F、Cl、Br、I、CH3和CF3；R 3 is selected from H, F, Cl, Br, I, CH 3 and CF 3 ;
环A选自5-6元杂芳基，所述5-6元杂芳基任选被1、2或3个Rc取代；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 ;
各Rb分别独立地选自F、Cl、Br、I、CN、CH3和CF3；Each R b is independently selected from F, Cl, Br, I, CN, CH 3 and CF 3 ;
各Rc分别独立地选自F、Cl、Br、I、CH3和CF3。Each R c is independently selected from F, Cl, Br, I, CH 3 and CF 3 .
在本发明的一些方案中，上述式(VI-1)化合物或其药学上可接受的盐选自，
In some aspects of the present invention, the compound of the above formula (VI-1) or a pharmaceutically acceptable salt thereof is selected from,
其中，R2选自嘧啶基、吡啶基、吡嗪基、哒嗪基、咪唑基、吡唑基和所述嘧啶基、吡啶基、吡嗪基、哒嗪基、咪唑基、吡唑基和分别独立地任选被1、2或3个Rb取代；Wherein, 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 ;
R3选自H、F、Cl、Br、I、CH3和CF3；R 3 is selected from H, F, Cl, Br, I, CH 3 and CF 3 ;
环A选自5-6元杂芳基，所述5-6元杂芳基任选被1、2或3个Rc取代；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 ;
各Rb分别独立地选自F、Cl、Br、I、CN、CH3和CF3；Each R b is independently selected from F, Cl, Br, I, CN, CH 3 and CF 3 ;
各Rc分别独立地选自F、Cl、Br、I、CH3和CF3。Each R c is independently selected from F, Cl, Br, I, CH 3 and CF 3 .
在本发明的一些方案中，上述式(VI-1)化合物或其药学上可接受的盐选自，
In some aspects of the present invention, the compound of the above formula (VI-1) or a pharmaceutically acceptable salt thereof is selected from,
其中，in,
R2选自嘧啶基、吡啶基、吡嗪基、哒嗪基、咪唑基、吡唑基和所述嘧啶基、吡啶基、吡嗪基、哒嗪基、咪唑基、吡唑基和分别独立地任选被1、2或3个Rb取代；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 ;
R3选自H、F、Cl、Br、I、CH3和CF3；R 3 is selected from H, F, Cl, Br, I, CH 3 and CF 3 ;
环A选自5-6元杂芳基，所述5-6元杂芳基任选被1、2或3个Rc取代；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 ;
各Rb分别独立地选自F、Cl、Br、I、CN、CH3和CF3；Each R b is independently selected from F, Cl, Br, I, CN, CH 3 and CF 3 ;
各Rc分别独立地选自F、Cl、Br、I、CH3和CF3。Each R c is independently selected from F, Cl, Br, I, CH 3 and CF 3 .
在本发明的一些方案中，上述式(VI-1)、(VI-1a)或(VI-1b)化合物或其药学上可接受的盐，所述R2选自嘧啶基、吡啶基、吡嗪基、哒嗪基，所述嘧啶基、吡啶基、吡嗪基、哒嗪基分别独立地任选被1、2或3个Rb取代，其他变量如本发明所定义。In some aspects of the present invention, 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.
在本发明的一些方案中，上述式(VI-1)、(VI-1a)或(VI-1b)化合物或其药学上可接受的盐，所述R2选自嘧啶基，所述嘧啶基任选被1、2或3个Rb取代，其他变量如本发明所定义。In some aspects of the present invention, in 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, and the pyrimidinyl Optionally substituted by 1, 2 or 3 R b , and other variables are as defined in the present invention.
在本发明的一些方案中，上述式(VI-1)、(VI-1a)或(VI-1b)化合物或其药学上可接受的盐，所述R2选自其他变量如本发明所定义。In some aspects of the present invention, for the above-mentioned compound of formula (VI-1), (VI-1a) or (VI-1b) or a pharmaceutically acceptable salt thereof, the R 2 is selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述式(VI-1)、(VI-1a)或(VI-1b)化合物或其药学上可接受的盐，所述R3选自H和CH3，其他变量如本发明所定义。In some aspects of 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.
在本发明的一些方案中，上述式(VI-1)、(VI-1a)或(VI-1b)化合物或其药学上可接受的盐，所述环A选自吡啶基，所述吡啶基任选被1、2或3个Rc取代，其他变量如本发明所定义。In some aspects of 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 pyridyl, and the pyridyl Optionally substituted by 1, 2 or 3 Rc , other variables are as defined in the present invention.
在本发明的一些方案中，上述式(VI-1)、(VI-1a)或(VI-1b)化合物或其药学上可接受的盐，所述环A选自其他变量如本发明所定义。In some aspects of 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.
本发明还有一些方案由上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 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，上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 present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof, the compound thereof is selected from,



本发明还提供了上述化合物或其药学上可接受的盐在制备治疗Factor D抑制剂相关疾病的药物中的应用。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.
本发明还提供了下列合成方法：The invention also provides the following synthesis methods:
方法1：

method 1:

方法2：
Method 2:
方法3：
Method 3:
技术效果Technical effect
本发明化合物与补体因子D有较好的结合，能显著抑制补体因子D活性，对人血清旁路通路激活抑制活性明显；本发明化合物药代动力学性质优良：半衰期长，清除率低，血浆暴露量和生物利用度高；在各种属中都具有优异的肝微粒体代谢稳定性，在人肝细胞中也具有优异的肝微粒体代谢稳定性。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.
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 specific term or phrase without specifying meaning should not be considered uncertain or unclear, but should be understood according to 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 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
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,""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%.
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 ( 3H ), iodine-125 ( 125I ) or C-14 ( 14C ). 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；表示R可以任意连接在双键的两端，即表示 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 - straight shape in OCH 3 Solid-line bonds indicate attachment to other groups through oxygen atoms 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 connection method, when connecting a chemical bond, the H at that position will be reduced by one and become the corresponding monovalent piperidinyl group; It means that R can be connected at both ends of the double bond arbitrarily, which means
除非另有规定，术语“C1-4烷基”用于表示直链或支链的由1至4个碳原子组成的饱和碳氢基团。所述C1-4烷基包括C1-2、C1-3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)。C1-4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)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)等。Unless otherwise specified, the term "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.
除非另有规定，术语“C1-4烷氧基”本身或者与另一术语联合，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4个碳原子的烷基基团。所述C1-5烷氧基包括C1-2、C1-3、C2-3、C2-4、C3-4、C3和C4烷氧基等。其可以是一价、二价或者多价。C1-4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)、丁氧基(包括n-丁氧基、异丁氧基、s-丁氧基和t-丁氧基)等。Unless otherwise specified, the term "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.
除非另有规定，术语“C1-4烷硫基”本身或者与另一术语联合，表示通过硫原子连接到分子的其余部分的那些包含1至4个碳原子的烷基基团。所述C1-5烷硫基包括C1-2、C1-3、C2-3、C2-4、C3-4、C3和C4烷硫基等。其可以是一价、二价或者多价。C1-4烷硫基的实例包括但不限于-SCH3、-SCH2CH3、-SCH2CH2CH3、-SCH2(CH3)2等。Unless otherwise specified, the term "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.
除非另有规定，术语“C1-4烷氨基”本身或者与另一术语联合，表示通过氮原子连接到分子的其余部分的那些包含1至4个碳原子的烷基基团。所述C1-4烷氨基包括C1-2、C1-3、C2-3、C2-4、C3-4、C3和C4烷氨基等。其可以是一价、二价或者多价。C1-4烷氨基的实例包括但不限于-NHCH3、-N(CH3)2、-NHCH2CH3、-NHCH2CH2CH3、-NHCH2(CH3)2等。Unless otherwise specified, the term "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.
除非另有规定，“C3-6环烷基”本身或者与其他术语联合分别表示由3至6个碳原子组成的饱和单环碳氢基团，所述C3-6环烷基包括C3-5、C4-5和C5-6环烷基等；其可以是一价、二价或者多价。C3-6环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基等。Unless otherwise specified, "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.
除非另有规定，术语“4-6元杂环烷基”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单环基团，其1、2、3或4个环原子为独立选自O、S、NH和N的杂原子或杂原子团，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“4-6元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述3-6元杂环烷基包括4-5元、5-6元、4元、5元和6元杂环烷基等。其可以是一价、二价或者多价。4-6元杂环烷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-噻嗪基或六氢哒嗪基等。Unless otherwise specified, the term "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, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl or hexahydropyridazinyl, etc.
除非另有规定，术语“8-10元杂环基”本身或者与其他术语联合分别表示由8至10个环原子组成的饱和或部分不饱和的环状基团，其1、2、3、4或5个环原子为独立选自O、S、NH和N的杂原子或杂原子团，其余为碳原子，其中碳原子任选地被氧化(即CO)，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“8-10元杂环基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述8-10元杂环基包括8元、9元和10元杂环基等。所述8-10元杂环基包括单环、和多环，例如螺环、并环、桥环。其可以是一价、二价或者多价。8-10元杂环基的实例包括但不限于 等。Unless otherwise specified, 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). Furthermore, in the case of the "8-10 membered heterocyclyl", a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule. 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.
除非另有规定，本发明术语“5-6元杂芳环”和“5-6元杂芳基”可以互换使用，术语“5-6元杂芳基”本身或者与其他术语联合分别表示由5至6个环原子组成的具有共轭π电子体系的单环基团，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)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-6元杂芳基包括5元杂芳基和6元杂芳基。所述5元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)等。所述6元杂芳基的实例包括但不限于吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)等。Unless otherwise specified, 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 π 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-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-isoxazolyl, etc.) -thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl, 3-thienyl, etc.), etc. Examples of the 6-membered heteroaryl 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.
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 , 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. 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. , 10-membered ring, 11-membered ring, and 12-membered ring, also including any range from n to n+m, for example, 3-12-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.
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲核取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。The term "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. For example, 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.
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基， 例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)；叔丁基二苯基硅烷基(TBDPS)等等。The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "thiol protecting group". The term "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. The term "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.
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.
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 D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。The structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD) uses a Bruker D8 venture diffractometer to collect diffraction intensity data on the cultured single crystal. The light source is CuKα radiation. The scanning method is: After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure, and the absolute configuration can be confirmed.
本发明采用下述缩略词：PE代表石油醚；EA或EtOAc代表乙酸乙酯。The following abbreviations are used in the present invention: PE represents petroleum ether; EA or EtOAc represents ethyl acetate.
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.
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.化合物A和补体因子D的蛋白结合模式图。Figure 1. Protein binding pattern diagram of compound A and complement factor D.
图2.化合物B和补体因子D的蛋白结合模式图。Figure 2. Protein binding pattern diagram of compound B and complement factor D.
图3.化合物C和补体因子D的蛋白结合模式图。Figure 3. Protein binding pattern diagram of compound C and complement factor D.
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.
计算例1
Calculation example 1
分子对接过程是通过使用Maestro中的Glide SP[1]和默认选项进行的。选取补体因子D与选择性小分子抑制剂的复合物晶体结构(PDB:5NB7)做为对接模板。为了准备蛋白质，使用Maestro[2]的蛋白质准备向导模块添加氢原子，并使用OPLS4力场。对于配体的准备，使用LigPrep生成了分子的三维结构，并进行了能量最小化[3]，使用confgen模块对小分子构象进行采样。以5NB7中的配体 分子作为质心生成了边长为的立方体对接网格。在分子对接过程中放置参考化合物。分析蛋白质受体与配体的相互作用类型，分析蛋白质受体与配体的相互作用类型，然后根据计算得到的docking score以及结合模式选择并保存了合理对接构象。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. To prepare the protein, hydrogen atoms were added using the Protein Preparation Wizard module of Maestro [2] and the OPLS4 force field was used. For the preparation of ligands, 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. With 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.
[1]Glide,LLC,New York,NY,2022.[1]Glide, LLC,New York,NY,2022.
[2]Maestro,LLC,New York,NY,2022.[2]Maestro, LLC,New York,NY,2022.
[3]LigPrep,LLC,New York,NY,2022.[3]LigPrep, LLC,New York,NY,2022.
结论：本发明化合物与补体因子D有较好的结合。Conclusion: The compound of the present invention binds well to complement factor D.
参考例1中间体化合物M的合成
Reference Example 1 Synthesis of Intermediate Compound M
氮气氛围下，将化合物M-1(18g,75.29mmol)和化合物M-2(20.77g,150.58mmol)溶于300mL1,4-二氧六环和30mL水的混合溶剂中，加入[1,1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷(3.07g,3.76mmol)和碳酸钾(20.81g,150.58mmol)，然后将混合物置于90℃搅拌2小时。加入200mL水，再加入200mL乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，粗品经硅胶柱(PE:EA＝1/0-1/1)纯化得化合物M。MS(ESI):m/z＝253.0[M+H]+。Under nitrogen atmosphere, compound M-1 (18g, 75.29mmol) and compound M-2 (20.77g, 150.58mmol) were dissolved in a mixed solvent of 300mL 1,4-dioxane and 30mL water, and [1,1 -bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane (3.07g, 3.76mmol) and potassium carbonate (20.81g, 150.58mmol), and then the mixture was stirred at 90°C for 2 hours. Add 200 mL of water, then add 200 mL of ethyl acetate for extraction, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate. The crude product is purified through a silica gel column (PE:EA=1/0-1/1) to obtain compound M. MS (ESI): m/z=253.0[M+H] + .
参考例2中间体化合物N的合成
Reference Example 2 Synthesis of Intermediate Compound N
第一步first step
将化合物N-1(100g,960.58mmol)溶于二氯甲烷(1500mL)中，加入咪唑(78.47g,1.15mol)，冷却至0℃下，缓慢滴加叔丁基二苯基氯硅烷(290.43g,1.06mol)，反应液缓慢升温至25℃下搅拌12小时。将反应液过滤，滤饼用二氯甲烷(500mL×2)洗涤，收集滤液，滤液用1N稀盐酸(300mL)洗涤，用饱和碳酸氢钠水溶液(300mL)洗涤，饱和食盐水(500mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到产物N-2。1H NMR(400MHz,CDCl3)δppm 7.69-7.72(m,4H)7.38-7.45(m,6H)4.25(s,2H)4.16(q,J＝7.19Hz,2H)1.23(t,J＝7.15Hz,3H)1.11(s,9H)。Dissolve compound N-1 (100g, 960.58mmol) in dichloromethane (1500mL), add imidazole (78.47g, 1.15mol), cool to 0°C, and slowly add tert-butyldiphenylsilyl chloride (290.43 g, 1.06 mol), the reaction solution was slowly heated to 25°C and stirred for 12 hours. Filter the reaction solution, wash the filter cake with dichloromethane (500 mL Wash, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain product N-2. 1 H NMR (400MHz, CDCl 3 ) δppm 7.69-7.72 (m, 4H) 7.38-7.45 (m, 6H) 4.25 (s, 2H) 4.16 (q, J = 7.19Hz, 2H) 1.23 (t, J = 7.15 Hz,3H)1.11(s,9H).
第二步Step 2
将化合物N-2(329g,960.58mmol)溶于四氢呋喃(1645mL)中，缓慢滴加氢氧化钠水溶液(1M,1.92L)，反 应液在25℃下搅拌6小时。将反应液中的四氢呋喃减压浓缩除去，剩余的水相经甲基叔丁基醚(500mL×8)洗涤，再向水相中滴加2M稀盐酸调节pH值为4～5，用乙酸乙酯(1000mL×3)萃取，合并有机相，用饱和食盐水(500mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到产物N-3。1H NMR(400MHz,CDCl3)δppm 7.58-7.64(m,4H)7.28-7.39(m,6H)4.07(s,2H)1.03(s,9H)。Compound N-2 (329g, 960.58mmol) was dissolved in tetrahydrofuran (1645mL), and sodium hydroxide aqueous solution (1M, 1.92L) was slowly added dropwise. The solution was stirred at 25°C for 6 hours. The tetrahydrofuran in the reaction solution was concentrated under reduced pressure and the remaining aqueous phase was washed with methyl tert-butyl ether (500 mL Extract with ester (1000 mL × 3), combine the organic phases, wash with saturated brine (500 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain product N-3. 1 H NMR (400MHz, CDCl 3 ) δ ppm 7.58-7.64 (m, 4H) 7.28-7.39 (m, 6H) 4.07 (s, 2H) 1.03 (s, 9H).
第三步third step
将化合物N-3(218g,693.27mmol)溶于二氯甲烷(1635mL)中，冷却至0℃下，缓慢滴加草酰氯(114.39g,901.26mmol)，然后滴加N,N-二甲基甲酰胺(2.53g,34.66mmol)，反应液缓慢升温至25℃下搅拌2小时。将反应液减压浓缩，加入二氯甲烷(500mL×3)稀释，减压浓缩，得到产物N-4，直接用于下一步反应。Compound N-3 (218g, 693.27mmol) was dissolved in dichloromethane (1635mL), cooled to 0°C, oxalyl chloride (114.39g, 901.26mmol) was slowly added dropwise, and then N,N-dimethyl was added dropwise. Formamide (2.53g, 34.66mmol), the reaction solution was slowly heated to 25°C and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with dichloromethane (500 mL×3), and concentrated under reduced pressure to obtain product N-4, which was directly used in the next reaction.
第四步the fourth step
氮气氛围下，将化合物N-5(81.70g,570.75mmol)和化合物N-4(190g,570.75mmol)溶于四氢呋喃(900mL)，0℃下缓慢滴加叔丁醇锂(1M的四氢呋喃溶液,570.75mL)，恢复至25℃反应2小时。向反应液中缓慢加入500mL水，用500mL乙酸乙酯萃取，合并有机相，用500mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物N-6。LC-MS:m/z＝462.1[M+Na]+。Under nitrogen atmosphere, compound N-5 (81.70g, 570.75mmol) and compound N-4 (190g, 570.75mmol) were dissolved in tetrahydrofuran (900mL), and lithium tert-butoxide (1M tetrahydrofuran solution) was slowly added dropwise at 0°C. 570.75mL), return to 25°C and react for 2 hours. Slowly add 500 mL of water to the reaction solution, extract with 500 mL of ethyl acetate, combine the organic phases, wash with 500 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound N-6. LC-MS: m/z=462.1[M+Na] + .
第五步the fifth step
氮气氛围下，将化合物N-6(200g,454.98mmol)溶于甲苯(1200mL)，-78℃下滴加三乙基硼氢化锂(1M的四氢呋喃溶液,545.98mL)，-78℃反应2小时。滴加二异丙基乙胺(321.94g,2.49mol)和三氟乙酸酐(142.69g,679.36mmol)，-65℃反应2小时，恢复至25℃反应14小时。加入1500mL水淬灭，再用2000mL乙酸乙酯萃取。分液，有机相用2000mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩得粗品。粗品经硅胶柱(PE:EA＝1/0-1/5)纯化得化合物N-7。LC-MS:m/z＝446.1[M+Na]+。Under nitrogen atmosphere, 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. The liquids were separated, and the organic phase was washed with 2000 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column (PE:EA=1/0-1/5) to obtain compound N-7. LC-MS: m/z=446.1[M+Na] + .
第六步Step 6
氮气氛围下，将化合物N-7(30g,70.83mmol)溶于无水甲苯(300mL)，加入四丁基溴化铵(684.95mg,2.12mmol)，升温至110℃，滴加(溴二氟甲基)三甲基硅烷(21.58g,106.24mmol)，110℃反应4小时。将反应液减压浓缩，粗品经硅胶柱(PE:EA＝1/0-1/5)纯化得化合物N。LC-MS:m/z＝496.3[M+Na]+。Under nitrogen atmosphere, compound N-7 (30g, 70.83mmol) was dissolved in anhydrous toluene (300mL), tetrabutylammonium bromide (684.95mg, 2.12mmol) was added, the temperature was raised to 110°C, and (bromodifluoride) was added dropwise. Methyl)trimethylsilane (21.58g, 106.24mmol), react at 110°C for 4 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column (PE:EA=1/0-1/5) to obtain compound N. LC-MS: m/z=496.3[M+Na] + .
实施例1

Example 1

第一步first step
将化合物1-1(10g，38.87mmol)溶于50mL的二氯甲烷中，加入三氟乙酸(44.32g，388.68mmol)，25℃搅拌3小时。将反应液直接浓缩得化合物1-2的三氟乙酸盐粗品。MS(ESI):m/z＝158.1[M+H]+；1H NMR(400MHz,DMSO-d6)δppm 1.02(d,3H)1.84-2.02(m,1H)2.23-2.36(m,2H)3.63-3.70(s,3H)4.06-4.19(t,1H)7.93-8.06(s,1H)。Compound 1-1 (10 g, 38.87 mmol) was dissolved in 50 mL of dichloromethane, trifluoroacetic acid (44.32 g, 388.68 mmol) was added, and the mixture was stirred at 25° C. for 3 hours. The reaction solution was directly concentrated to obtain the crude trifluoroacetate salt of compound 1-2. MS (ESI): m/z=158.1[M+H] + ; 1 H NMR (400MHz, DMSO-d 6 ) δppm 1.02 (d, 3H) 1.84-2.02 (m, 1H) 2.23-2.36 (m, 2H )3.63-3.70(s,3H)4.06-4.19(t,1H)7.93-8.06(s,1H).
第二步Step 2
将化合物1-2的三氟乙酸盐粗品(2.94g)、二异丙基乙基胺(7.25g，56.14mmol)和苄氧乙酰氯(3.8g，20.58mmol)溶于80mL的四氢呋喃中，0℃下加入氢化钠(0.82g，20.58mmol，60％纯度)，搅拌30分钟。将反应液倒入200mL冰水中，加入300mL乙酸乙酯，萃取，合并有机相，无水硫酸钠干燥，过滤，滤液浓缩得化合物1-3。MS(ESI):m/z＝306.1[M+H]+。Dissolve the crude trifluoroacetate salt of compound 1-2 (2.94g), diisopropylethylamine (7.25g, 56.14mmol) and benzyloxyacetyl chloride (3.8g, 20.58mmol) in 80 mL of tetrahydrofuran. Sodium hydride (0.82g, 20.58mmol, 60% purity) was added at 0°C and stirred for 30 minutes. Pour the reaction solution into 200 mL of ice water, add 300 mL of ethyl acetate, extract, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain compound 1-3. MS (ESI): m/z=306.1[M+H] + .
第三步third step
将化合物1-3(800mg，2.62mmol)溶于10mL的甲苯中，-78℃滴加三乙基硼氢化锂四氢呋喃溶液(1M，3.14mL)，-78℃下搅拌2小时。0℃下加入20mL的冰水，加入20mL乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，滤液浓缩得化合物1-4。MS(ESI):m/z＝330.1[M+Na]+。Compound 1-3 (800 mg, 2.62 mmol) was dissolved in 10 mL of toluene, and a solution of lithium triethylborohydride in tetrahydrofuran (1M, 3.14 mL) was added dropwise at -78°C, and stirred at -78°C for 2 hours. Add 20 mL of ice water at 0°C, add 20 mL of ethyl acetate for extraction, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain compound 1-4. MS (ESI): m/z=330.1[M+Na] + .
第四步the fourth step
将化合物1-4(800mg，2.60mmol)溶于10mL的四氢呋喃中，-65℃加入二异丙基乙基胺(2.49mL，14.32mmol)滴加三氟乙酸酐(710.71mg，3.38mmol)，-65℃下搅拌1小时，逐渐升温至25℃，25℃下搅拌2小时。加入10mL的水，再加入30mL乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，滤液浓缩，粗品经硅胶柱(PE:EA＝1:0-3:1)纯化得化合物1-5。MS(ESI):m/z＝290.0[M+H]+。Compound 1-4 (800 mg, 2.60 mmol) was dissolved in 10 mL of tetrahydrofuran, diisopropylethylamine (2.49 mL, 14.32 mmol) was added at -65°C, and trifluoroacetic anhydride (710.71 mg, 3.38 mmol) was added dropwise. Stir at -65°C for 1 hour, gradually raise the temperature to 25°C, and stir at 25°C for 2 hours. Add 10 mL of water, then add 30 mL of ethyl acetate for extraction, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. The crude product is purified through a silica gel column (PE:EA=1:0-3:1) to obtain compound 1- 5. MS (ESI): m/z=290.0[M+H] + .
第五步the fifth step
将化合物1-5(500mg，1.73mmol)和氟化锂(5mg，0.173mmol)溶于20mL的甲苯中，在氮气保护下120℃搅拌1小时后，再缓慢滴加三甲基硅烷基-2-(氟磺酰基)二氟乙酸酯(865mg，3.46mmol)的5mL甲苯溶液，120℃下搅拌5小时。反应液直接浓缩得化合物1-6。MS(ESI):m/z＝340.1[M+H]+。Compound 1-5 (500 mg, 1.73 mmol) and lithium fluoride (5 mg, 0.173 mmol) were dissolved in 20 mL of toluene. After stirring at 120°C for 1 hour under nitrogen protection, trimethylsilyl-2 was slowly added dropwise. -(Fluorosulfonyl)difluoroacetate (865 mg, 3.46 mmol) in 5 mL of toluene, stirred at 120°C for 5 hours. The reaction solution was directly concentrated to obtain compound 1-6. MS (ESI): m/z=340.1[M+H] + .
第六步Step 6
将化合物1-6(240mg，0.71mmol)溶于1mL的四氢呋喃1mL甲醇和2mL水的混合溶液中，加入氢氧化锂(67.8mg，2.83mmol)，25℃下搅拌16小时。反应液直接浓缩，混合物用1N的氢氧化钠溶液溶解并调节至pH＝10后，用10mL乙酸乙酯洗涤，收集水相再用1N的盐酸调节至pH＝3，再用10mL乙酸乙酯萃取，有机相经无水硫酸钠干燥，过滤，浓缩，得化合物1-7。MS(ESI):m/z＝326.1[M+H]+。Compound 1-6 (240 mg, 0.71 mmol) was dissolved in a mixed solution of 1 mL of tetrahydrofuran, 1 mL of methanol and 2 mL of water, lithium hydroxide (67.8 mg, 2.83 mmol) was added, and the mixture was stirred at 25°C for 16 hours. The reaction solution was concentrated directly, and the mixture was dissolved with 1N sodium hydroxide solution and adjusted to pH=10, then washed with 10mL ethyl acetate, the aqueous phase was collected, adjusted to pH=3 with 1N hydrochloric acid, and extracted with 10mL ethyl acetate. , the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 1-7. MS (ESI): m/z=326.1[M+H] + .
第七步Step 7
将化合物1-7(150mg，0.46mmol)溶于10mL的1,2-二氯乙烷中，25℃下加入2-乙氧基-1-乙氧碳酰基-1,2-二氢喹啉(228mg，0.92mmol)、6-溴-3-甲基吡啶-2-胺(86mg，0.46mmoL)和二异丙基乙基胺(66 mg，0.51mmol)，85℃下搅拌16小时。反应液直接浓缩，粗品经硅胶柱(PE:EA＝1/0-5/1)纯化得化合物1-8。MS(ESI):m/z＝494.0,496.0[M+H]+。Compound 1-7 (150 mg, 0.46 mmol) was dissolved in 10 mL of 1,2-dichloroethane, and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline was added at 25°C. (228mg, 0.92mmol), 6-bromo-3-methylpyridin-2-amine (86mg, 0.46mmoL) and diisopropylethylamine (66 mg, 0.51 mmol), stirred at 85°C for 16 hours. The reaction solution was directly concentrated, and the crude product was purified by silica gel column (PE:EA=1/0-5/1) to obtain compound 1-8. MS (ESI): m/z=494.0,496.0[M+H] + .
第八步Step 8
将化合物1-8(50mg，0.1mmol)溶于5mL的二氯甲烷中，氮气保护下0℃加入三溴化硼(78mg，0.31mmol)，反应逐渐升温至25℃，并在25℃下搅拌2小时。加入10mL冰水和10mL乙酸乙酯，萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，粗品经硅胶板(PE:EA＝1:1)纯化得化合物1-9。MS(ESI):m/z＝404.0,406.0[M+H]+。Compound 1-8 (50 mg, 0.1 mmol) was dissolved in 5 mL of dichloromethane, and boron tribromide (78 mg, 0.31 mmol) was added at 0°C under nitrogen protection. The reaction was gradually heated to 25°C and stirred at 25°C. 2 hours. Add 10 mL ice water and 10 mL ethyl acetate, extract, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate. The crude product is purified on a silica gel plate (PE:EA=1:1) to obtain compound 1-9. MS (ESI): m/z=404.0,406.0[M+H] + .
第九步Step 9
将化合物1-9(60mg，0.15mmoL)、化合物M(37mg，0.15mmol)和三苯基膦(78mg，0.30mmol)溶于1mL四氢呋喃中，0℃下滴加偶氮二甲酸二异丙酯(30mg，0.15mmol)并在25℃下搅拌2小时。反应液浓缩，剩余物经硅胶板(PE:EA＝1:1)纯化得化合物1。MS(ESI):m/z＝638.0,640.0[M+H]+；1H NMR(400MHz,CDCl3)δppm 1.25(s,3H)2.00(s,3H)2.65(s,3H)2.72-2.75(m,4H)3.44-3.49(m,1H)4.94(d,J＝6.8Hz,1H)5.35(q,J＝16.8Hz,2H)7.15-7.21(m,2H)7.29(d,J＝8.0Hz,1H)7.48-7.65(m,2H)8.45-8.64(m,2H)8.81-8.88(m,2H)。Compound 1-9 (60 mg, 0.15 mmoL), compound M (37 mg, 0.15 mmol) and triphenylphosphine (78 mg, 0.30 mmol) were dissolved in 1 mL tetrahydrofuran, and diisopropyl azodicarboxylate was added dropwise at 0°C. (30 mg, 0.15 mmol) and stirred at 25°C for 2 hours. The reaction solution was concentrated, and the residue was purified through silica gel plate (PE:EA=1:1) to obtain compound 1. MS (ESI): m/z=638.0,640.0[M+H] + ; 1 H NMR (400MHz, CDCl 3 ) δppm 1.25 (s, 3H) 2.00 (s, 3H) 2.65 (s, 3H) 2.72-2.75 (m,4H)3.44-3.49(m,1H)4.94(d,J＝6.8Hz,1H)5.35(q,J＝16.8Hz,2H)7.15-7.21(m,2H)7.29(d,J＝8.0 Hz,1H)7.48-7.65(m,2H)8.45-8.64(m,2H)8.81-8.88(m,2H).
经二维核磁确定化合物1的具体结构为： The specific structure of compound 1 was determined by two-dimensional NMR as:
实施例2
Example 2
第一步 first step
将化合物N(15g,31.67mmol)溶于四氢呋喃(150mL)，甲醇(150mL)和水(70mL)的混合溶剂中，加入氢氧化锂(3.99g,95.02mmol)，25℃搅拌3小时。反应液用1N盐酸调pH＝6～7后减压浓缩除去有机溶剂，剩余物用200mL乙酸乙酯萃取，有机相再依次用300mL水和300mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩得化合物2-1。MS(ESI):m/z＝482.1[M+Na]+。Compound N (15g, 31.67mmol) was dissolved in a mixed solvent of tetrahydrofuran (150mL), methanol (150mL) and water (70mL), lithium hydroxide (3.99g, 95.02mmol) was added, and the mixture was stirred at 25°C for 3 hours. The reaction solution was adjusted to pH=6~7 with 1N hydrochloric acid, then concentrated under reduced pressure to remove the organic solvent. The residue was extracted with 200 mL of ethyl acetate. The organic phase was washed with 300 mL of water and 300 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain compound 2-1. MS (ESI): m/z=482.1[M+Na] + .
第二步Step 2
将化合物2-1(15.00g,32.64mmol)溶于无水二氯甲烷(150mL)，加入草酰氯(39.17mmol,3.43mL)和N,N-二甲基甲酰胺(1.63mmol,125.57μL)，25℃搅拌2小时。反应液减压浓缩。向剩余物中再加入四氢呋喃(150mL)和6-溴-3-甲基吡啶-2-胺(5.28g,28.24mmol)，0℃下滴加叔丁醇锂(1M的四氢呋喃溶液,31.38mL)，25℃搅拌2小时。向反应液中加入100mL水淬灭，用200mL乙酸乙酯萃取，收集有机相，用200mL饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩得粗品。粗品经硅胶柱(石油醚：乙酸乙酯＝100:0～20:80)纯化得化合物2-2。MS(ESI):m/z＝628.1/630.1[M+H]+。Compound 2-1 (15.00g, 32.64mmol) was dissolved in anhydrous dichloromethane (150mL), and oxalyl chloride (39.17mmol, 3.43mL) and N,N-dimethylformamide (1.63mmol, 125.57μL) were added. , stir for 2 hours at 25°C. The reaction solution was concentrated under reduced pressure. Tetrahydrofuran (150 mL) and 6-bromo-3-methylpyridin-2-amine (5.28 g, 28.24 mmol) were added to the residue, and lithium tert-butoxide (1M tetrahydrofuran solution, 31.38 mL) was added dropwise at 0°C. , stir for 2 hours at 25°C. Add 100 mL of water to the reaction solution to quench, extract with 200 mL of ethyl acetate, collect the organic phase, wash with 200 mL of saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product was purified through silica gel column (petroleum ether: ethyl acetate = 100:0 ~ 20:80) to obtain compound 2-2. MS (ESI): m/z=628.1/630.1[M+H] + .
第三步third step
将化合物2-2(4.00g,6.36mmol)溶于四氢呋喃(40mL)，加入4-二甲氨基吡啶(77.74mg,636.36μmol)和二碳酸二叔丁酯(2.08g,9.55mmol)，25℃搅拌16小时。加入20mL水，50mL乙酸乙酯萃取。有机相再用50mL饱和食盐水洗，无水硫酸钠干燥，减压浓缩得化合物2-3。MS(ESI):m/z＝750.1/752.1[M+Na]+。Dissolve compound 2-2 (4.00g, 6.36mmol) in tetrahydrofuran (40mL), add 4-dimethylaminopyridine (77.74mg, 636.36μmol) and di-tert-butyl dicarbonate (2.08g, 9.55mmol), 25°C Stir for 16 hours. Add 20 mL of water and extract with 50 mL of ethyl acetate. The organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 2-3. MS (ESI): m/z=750.1/752.1[M+Na] + .
第四步the fourth step
化合物2-3(4g,5.49mmol)溶于四氢呋喃(40mL)，0℃下滴加70％氟化氢吡啶溶液(2.83mL,21.96mmol)，25℃搅拌2小时。加入30mL水淬灭，50mL乙酸乙酯萃取，有机相用50mL饱和食盐水洗，无水硫酸钠干燥，减压浓缩得粗品。粗品经硅胶柱(石油醚：乙酸乙酯＝100:0～30:70)纯化得化合物2-4。MS(ESI):m/z＝512.1/514.1[M+Na]+。Compound 2-3 (4g, 5.49mmol) was dissolved in tetrahydrofuran (40mL), 70% hydrogen fluoride pyridine solution (2.83mL, 21.96mmol) was added dropwise at 0°C, and stirred at 25°C for 2 hours. Add 30 mL of water to quench, extract with 50 mL of ethyl acetate, wash the organic phase with 50 mL of saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product was purified by silica gel column (petroleum ether: ethyl acetate = 100:0~30:70) to obtain compound 2-4. MS (ESI): m/z=512.1/514.1[M+Na] + .
第五步the fifth step
将化合物2-4(1.8g,3.67mmol)和化合物M(926.15mg,3.67mmol)溶于四氢呋喃(40mL)，加入三苯基膦(1.93g,7.34mmol)和偶氮二甲酸二异丙酯(742.37mg,3.67mmol)，25℃搅拌2小时。反应液减压浓缩，剩余物经硅胶柱(石油醚：乙酸乙酯＝100:0～25:75)纯化得化合物2-5。MS(ESI):m/z＝724.2/726.1[M+H]+。Compound 2-4 (1.8g, 3.67mmol) and compound M (926.15mg, 3.67mmol) were dissolved in tetrahydrofuran (40mL), and triphenylphosphine (1.93g, 7.34mmol) and diisopropyl azodicarboxylate were added. (742.37 mg, 3.67 mmol), stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified through a silica gel column (petroleum ether: ethyl acetate = 100:0 to 25:75) to obtain compound 2-5. MS (ESI): m/z=724.2/726.1[M+H] + .
第六步Step 6
将化合物2-5(1000mg,1.38mmol)溶于二氯甲烷(5mL)，0℃滴加三氟乙酸(5.13mL,69.01mmol)，25℃反应1小时。0℃下向反应液中滴加饱和碳酸氢钠溶液调节pH＝7,加入20mL二氯甲烷萃取，有机相用20mL饱和食盐水洗，无水硫酸钠干燥，减压浓缩的粗品。粗品经硅胶柱(二氯甲烷：甲醇＝100:0～100:2)纯化得化合物2。MS(ESI):m/z＝624.2/626.2[M+H]+；1H NMR(400MHz,CDCl3)δ＝8.90(s,2H),8.84(s,1H),8.58(s,1H),7.61(d,J＝8.8Hz,1H),7.56(d,J＝8.8Hz,1H),7.35(d,J＝8Hz,1H),7.24(d,J＝8Hz,1H),5.52-5.38(m,2H),5.10-4.98(m,1H),4.00-3.89(m,1H),3.08-2.98(m,1H),2.80(s,3H),2.78-2.73(m,1H),2.72(s,3H),2.59-2.47(m,1H),2.07(s,3H)。Compound 2-5 (1000 mg, 1.38 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5.13 mL, 69.01 mmol) was added dropwise at 0°C, and the reaction was carried out at 25°C for 1 hour. Add saturated sodium bicarbonate solution dropwise to the reaction solution at 0°C to adjust the pH to 7, add 20 mL of methylene chloride for extraction, wash the organic phase with 20 mL of saturated brine, dry over anhydrous sodium sulfate, and concentrate the crude product under reduced pressure. The crude product was purified through silica gel column (dichloromethane: methanol = 100:0~100:2) to obtain compound 2. MS (ESI): m/z=624.2/626.2[M+H] + ; 1 H NMR (400MHz, CDCl 3 ) δ=8.90 (s, 2H), 8.84 (s, 1H), 8.58 (s, 1H) ,7.61(d,J＝8.8Hz,1H),7.56(d,J＝8.8Hz,1H),7.35(d,J＝8Hz,1H),7.24(d,J＝8Hz,1H),5.52-5.38 (m,2H),5.10-4.98(m,1H),4.00-3.89(m,1H),3.08-2.98(m,1H),2.80(s,3H),2.78-2.73(m,1H),2.72 (s,3H),2.59-2.47(m,1H),2.07(s,3H).
实施例3

Example 3

第一步first step
将四氢呋喃(60mL)，化合物N(4.0g,8.45mmol)加入100mL单口瓶中，再加入70％氢氟酸/吡啶溶液(4.35mL,33.78mmol,)，室温17℃，反应13小时。向反应体系中加入150mL水后，用50mL甲基叔丁基醚洗涤。水相加入饱和碳酸钠溶液将pH调至8～9后，加入二氯甲烷萃取(40mL×3)，得到有机相加入无水硫酸钠干燥后，过滤，滤液在45℃下进行减压浓缩得到化合物3-1。MS(ESI):m/z＝236.1[M+H]+。Add tetrahydrofuran (60 mL) and compound N (4.0 g, 8.45 mmol) into a 100 mL single-neck bottle, then add 70% hydrofluoric acid/pyridine solution (4.35 mL, 33.78 mmol,), and react at room temperature 17°C for 13 hours. After adding 150 mL of water to the reaction system, wash with 50 mL of methyl tert-butyl ether. Add saturated sodium carbonate solution to the aqueous phase to adjust the pH to 8-9, then add methylene chloride for extraction (40mL Compound 3-1. MS (ESI): m/z=236.1[M+H] + .
第二步Step 2
将四氢呋喃(32mL)，化合物M(600mg,2.38mmol)，化合物3-1(932.27mg,3.96mmol)加入100mL单口瓶中；氮气置换后，依次加入三苯基磷(1.56g,5.95mmol)，偶氮二甲酸二异丙酯(961.87mg,4.76mmol)，室温20℃，反应1.5小时。向反应体系中加入50mL饱和氯化铵溶液及30mL乙酸乙酯后，分液；有机相用50mL饱和食盐水洗涤后，加入无水硫酸钠干燥，过滤，滤液在45℃下进行减压浓缩。剩余物通过硅胶柱层析分离纯化(梯度洗脱：石油醚:乙酸乙酯＝100:0～20:80)，得到化合物3-2。MS(ESI):m/z＝470.0[M+H]+。Add tetrahydrofuran (32mL), compound M (600mg, 2.38mmol), and compound 3-1 (932.27mg, 3.96mmol) into a 100mL single-neck bottle; after nitrogen replacement, add triphenylphosphorus (1.56g, 5.95mmol) in sequence, Diisopropyl azodicarboxylate (961.87 mg, 4.76 mmol), room temperature 20°C, react for 1.5 hours. Add 50 mL of saturated ammonium chloride solution and 30 mL of ethyl acetate to the reaction system, and separate the layers; wash the organic phase with 50 mL of saturated brine, add anhydrous sodium sulfate, dry, filter, and concentrate the filtrate under reduced pressure at 45°C. The residue was separated and purified by silica gel column chromatography (gradient elution: petroleum ether: ethyl acetate = 100:0 to 20:80) to obtain compound 3-2. MS (ESI): m/z=470.0[M+H] + .
第三步third step
将甲醇(9mL)，四氢呋喃(9mL)，水(4.5mL)，化合物3-2(450mg,958.59μmol)加入50mL单口瓶中，搅拌下加入一水合氢氧化锂(120.67mg,2.88mmol)，室温20℃，反应2小时。向反应体系中加入30mL水后，反应液减压浓缩除去有机溶剂后剩余的水相用甲基叔丁基醚(20mL×2)洗涤，得到的水相再用2N盐酸将pH值调至3～4后，加入二氯甲烷/乙醇(10:1，30mL×4)萃取。合并有机相，加入无水硫酸钠干燥后，过滤，滤液减压浓缩。剩余物中加入3mL乙腈搅拌10min后，过滤，收集滤饼得到化合物3-3。MS(ESI):m/z＝456.2[M+H]+。Add methanol (9mL), tetrahydrofuran (9mL), water (4.5mL), and compound 3-2 (450mg, 958.59μmol) into a 50mL single-mouth bottle, add lithium hydroxide monohydrate (120.67mg, 2.88mmol) under stirring, and keep at room temperature. 20℃, react for 2 hours. After adding 30 mL of water to the reaction system, the reaction solution was concentrated under reduced pressure to remove the organic solvent. The remaining aqueous phase was washed with methyl tert-butyl ether (20 mL × 2). The obtained aqueous phase was then adjusted to pH 3 with 2N hydrochloric acid. After ~4, add methylene chloride/ethanol (10:1, 30mL×4) for extraction. The organic phases were combined, dried by adding anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Add 3 mL of acetonitrile to the residue and stir for 10 minutes, then filter and collect the filter cake to obtain compound 3-3. MS (ESI): m/z=456.2[M+H] + .
第四步the fourth step
将二氯甲烷(6mL)，化合物3-3(60mg,131.75μmol)，6-溴-3-氟吡啶-2-胺(25.16mg,131.75μmol)加入反应瓶中，开始搅拌。0～5℃下依次加入吡啶(53.17μL,658.74μmol)，三氯氧磷(13.51μL,144.92μmol)，升至室温15℃，反应2小时。反应液减压浓缩，然后加入20mL二氯甲烷后，用饱和氯化铵溶液洗涤(15mL×3)。有机相用无水硫酸钠干燥，过滤，滤液在40℃下进行减压浓缩。剩余物通过硅胶柱层析分离纯化(石油醚:乙酸乙酯＝100:0～20:80)，再通过硅胶柱层析分离纯化(石油醚:乙酸乙酯＝1:0～0:1)，得到粗品。粗品再加入2mL乙醇搅拌15min后，过滤，收集滤饼得到化合物3。MS(ESI):m/z＝628.0,630.0[M+H]+；1H NMR(400MHz,CDCl3)δ＝8.92(s,2H),8.74-8.67(m,1H),8.60(s,1H),7.69-7.67(m,1H),7.58-7.56(m,1H),7.35-7.29(m,2H),5.51-5.40(m,2H),5.13-5.11(m,1H),3.92-3.88(m,1H),3.14-3.06(m,1H),2.82(s,3H),2.80-2.76(m,1H),2.74(s,3H),2.58-2.48(m,1H)。Add dichloromethane (6 mL), compound 3-3 (60 mg, 131.75 μmol), and 6-bromo-3-fluoropyridin-2-amine (25.16 mg, 131.75 μmol) into the reaction bottle, and start stirring. Add pyridine (53.17 μL, 658.74 μmol) and phosphorus oxychloride (13.51 μL, 144.92 μmol) in sequence at 0 to 5°C, raise to room temperature 15°C, and react for 2 hours. The reaction solution was concentrated under reduced pressure, then 20 mL of methylene chloride was added, and washed with saturated ammonium chloride solution (15 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 40°C. The residue is separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:0 ~ 20:80), and then separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0 ~ 0:1) , get crude product. Add 2 mL of ethanol to the crude product and stir for 15 min, then filter and collect the filter cake to obtain compound 3. MS (ESI): m/z=628.0, 630.0[M+H] + ; 1 H NMR (400MHz, CDCl 3 ) δ=8.92 (s, 2H), 8.74-8.67 (m, 1H), 8.60 (s, 1H),7.69-7.67(m,1H),7.58-7.56(m,1H),7.35-7.29(m,2H),5.51-5.40(m,2H),5.13-5.11(m,1H),3.92- 3.88(m,1H),3.14-3.06(m,1H),2.82(s,3H),2.80-2.76(m,1H),2.74(s,3H),2.58-2.48(m,1H).
实施例4
Example 4
将二氯甲烷(6mL)，化合物3-3(60mg,131.75μmol)，6-溴-3-氯吡啶-2-胺(27.33mg,131.75μmol)加入反应瓶中，开始搅拌；0～5℃下依次加入吡啶(53.17μL,658.74μmol)，三氯氧磷(13.51μL,144.92μmol)，升至室温15℃，反应3小时。反应液减压浓缩，然后加入20mL二氯甲烷，用饱和氯化铵溶液洗涤(15mL×3)；得到的有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。剩余物通过硅胶柱层析分离纯化(石油醚:乙酸乙酯＝1:0～0:1)，再经制备高效液相色谱分离(色谱柱:Phenomenex Luna C18 100*30mm*3μm；流动相:A(水，含0.04％盐酸)和B(乙腈)；梯度：B％:25％-50％)得到化合物4。MS(ESI):m/z＝643.9/645.9[M+H]+。1H NMR(400MHz,CDCl3)δ＝8.92(s,2H),8.82-8.75(m,1H),8.60(s,1H),7.66-7.64(m,1H),7.57-7.51(m,2H),7.24-7.22(m,1H),5.50-5.39(m,2H),5.25-5.17(m,1H),3.99-3.95(m,1H),3.06-3.02(m,1H),2.82-2.73(m,7H),2.62-2.58(m,1H)。Add dichloromethane (6mL), compound 3-3 (60mg, 131.75μmol), 6-bromo-3-chloropyridin-2-amine (27.33mg, 131.75μmol) into the reaction bottle and start stirring; 0~5℃ Add pyridine (53.17 μL, 658.74 μmol) and phosphorus oxychloride (13.51 μL, 144.92 μmol) in sequence, raise the temperature to room temperature 15°C, and react for 3 hours. The 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 residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0~0:1), and then separated by preparative high performance liquid chromatography (chromatographic column: Phenomenex Luna C18 100*30mm*3μm; mobile phase: A (water, containing 0.04% hydrochloric acid) and B (acetonitrile); gradient: B%: 25%-50%) gave compound 4. MS (ESI): m/z=643.9/645.9[M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ = 8.92 (s, 2H), 8.82-8.75 (m, 1H), 8.60 (s, 1H), 7.66-7.64 (m, 1H), 7.57-7.51 (m, 2H) ),7.24-7.22(m,1H),5.50-5.39(m,2H),5.25-5.17(m,1H),3.99-3.95(m,1H),3.06-3.02(m,1H),2.82-2.73 (m,7H),2.62-2.58(m,1H).
实施例5
Example 5
第一步first step
将化合物5-1(12g,35.38mmol)和双联嚬哪醇硼酸酯(22.46g,88.45mmol)溶于1,4-二氧六环(50mL)中，加入醋酸钾(10.42g,106.14mmol)和[1,1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷(1.44g,1.77mmol)，反应液在氮气气氛下，90℃下搅拌反应12小时。反应液过滤，滤液浓缩得到粗品。粗品经柱层析纯化(石油醚:乙 酸乙酯＝100:0～85:15)得到化合物5-2。LCMS:m/z＝409.0[M+Na]+。Compound 5-1 (12g, 35.38mmol) and bis-zonalcol boronic acid ester (22.46g, 88.45mmol) were dissolved in 1,4-dioxane (50mL), and potassium acetate (10.42g, 106.14 mmol) and [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane (1.44g, 1.77mmol), the reaction solution was stirred and reacted at 90°C for 12 hours under a nitrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated to obtain crude product. The crude product was purified by column chromatography (petroleum ether: ethanol Acid ethyl ester=100:0～85:15) to obtain compound 5-2. LCMS: m/z=409.0[M+Na] + .
第二步Step 2
将化合物5-2(400mg,1.04mmol)，5-溴-2-甲基吡啶-3-腈(204.05mg,1.04mmol)加入二氧六环(10mL)和水(2mL)中；氮气置换后，在氮气流下依次将碳酸钾(429.39mg,3.11mmol)，[1,1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(84.57mg,103.56μmol)加入其中，升温至95℃，反应7小时。向反应体系中加入30mL水后，加入乙酸乙酯萃取(15mL×2)；得到的有机相用15mL饱和食盐水洗涤后，加入无水硫酸钠干燥，过滤，滤液减压浓缩；得到的粗品加入2mL乙酸乙酯搅拌10min后，过滤，滤饼干燥得到化合物5-3。MS(ESI):m/z＝277.1[M+Na]+。Compound 5-2 (400 mg, 1.04 mmol) and 5-bromo-2-methylpyridine-3-carbonitrile (204.05 mg, 1.04 mmol) were added to dioxane (10 mL) and water (2 mL); after nitrogen replacement , add potassium carbonate (429.39mg, 3.11mmol) and [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (84.57mg, 103.56μmol) in sequence under nitrogen flow. Among them, the temperature was raised to 95°C and the reaction was carried out for 7 hours. After adding 30mL of water to the reaction system, add ethyl acetate for extraction (15mL×2); wash the obtained organic phase with 15mL of saturated brine, add anhydrous sodium sulfate, dry, filter, and concentrate the filtrate under reduced pressure; add the crude product 2 mL of ethyl acetate was stirred for 10 min, then filtered, and the filter cake was dried to obtain compound 5-3. MS (ESI): m/z=277.1[M+Na] + .
第三步third step
将四氢呋喃(8mL)，化合物5-3(130mg,470.52μmol)，化合物3-1(170.24mg,723.40μmol)加入50mL反应瓶中，开始搅拌；氮气置换后，将三苯基磷(308.53mg,1.18mmol)，偶氮二甲酸二异丙酯(190.29mg,941.03μmol,182.44μL)依次加入其中，室温20℃，反应1.5小时。向反应体系中加入20ml水后，加入20mL乙酸乙酯萃取，得到的有机相加入无水硫酸钠干燥后，过滤，滤液减压浓缩。粗品通过硅胶柱层析分离纯化(石油醚:乙酸乙酯＝100:0～20:80)，得到化合物5-4。MS(ESI):m/z＝494.2[M+H]+。Add tetrahydrofuran (8mL), compound 5-3 (130mg, 470.52μmol), and compound 3-1 (170.24mg, 723.40μmol) into a 50mL reaction flask and start stirring; after nitrogen replacement, add triphenylphosphine (308.53mg, 1.18 mmol), diisopropyl azodicarboxylate (190.29 mg, 941.03 μmol, 182.44 μL) were added in sequence, and the reaction was carried out at room temperature 20°C for 1.5 hours. After adding 20 ml of water to the reaction system, 20 ml of ethyl acetate was added for extraction. The obtained organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:0~20:80) to obtain compound 5-4. MS (ESI): m/z=494.2[M+H] + .
第四步the fourth step
将四氢呋喃(10mL)，甲醇(10mL)，水(5mL)，化合物5-4(200mg,405.30μmol)加入反应瓶中，开始搅拌；然后加入一水合氢氧化锂(68.03mg,1.62mmol)，室温反应2小时。向反应体系中加入30mL水后，反应液减压浓缩，得到的水相用甲基叔丁基醚(30mL×2)洗涤，得到的水相用2N盐酸将pH值调至3～4后，加入二氯甲烷(30mL×4)萃取。得到的有机相加入无水硫酸钠干燥后，过滤，滤液减压浓缩。得到化合物5-5。MS(ESI):m/z＝480.1[M+H]+。Add tetrahydrofuran (10 mL), methanol (10 mL), water (5 mL), and compound 5-4 (200 mg, 405.30 μmol) into the reaction flask, and start stirring; then add lithium hydroxide monohydrate (68.03 mg, 1.62 mmol) at room temperature. Reaction takes 2 hours. After adding 30 mL of water to the reaction system, the reaction solution was concentrated under reduced pressure. The obtained aqueous phase was washed with methyl tert-butyl ether (30 mL × 2). After the pH value of the obtained aqueous phase was adjusted to 3 to 4 with 2N hydrochloric acid, Add dichloromethane (30mL×4) and extract. The obtained organic phase was dried by adding anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 5-5 was obtained. MS (ESI): m/z=480.1[M+H] + .
第五步the fifth step
将二氯甲烷(4mL)，化合物5-5(40mg,83.43μmol)，2-氨基-3-甲基-6-溴吡啶(15.60mg,83.43μmol)加入反应瓶中，开始搅拌；氮气置换后，将温度降至0～5℃，依次将吡啶(46.20mg,584.02μmol,47.14μL)，三氯氧磷(19.19mg,125.15μmol,11.66μL)加入其中，升温至15℃，反应2小时。反应液在45℃下进行减压浓缩，然后加入20mL二氯甲烷后，用饱和氯化铵溶液洗涤(15ml×3)；得到的有机相用加入无水硫酸钠干燥，过滤，滤液在40℃下进行减压浓缩。粗品通过硅胶柱层析分离纯化(石油醚:乙酸乙酯＝100:0～20:80)，得到的粗品加入1.5mL乙酸乙酯搅拌15min后，过滤，滤饼干燥得到化合物5。MS(ESI):m/z＝648.0/650.0[M+H]+。1H NMR(400MHz,CDCl3)δ＝8.96(d,J＝2.0Hz,1H),8.58(s,1H),8.52-8.37(m,1H),8.15(d,J＝2.4Hz,1H),7.68-7.64(m,1H),7.59-7.57(m,1H),7.38-7.36(m,1H),7.23-7.25(m,1H),5.53-5.40(m,2H),5.07-5.05(m,1H),3.96-3.93(m,1H),3.14-3.10(m,1H),2.85-2.73(m,7H),2.58-2.47(m,1H),2.08(s,3H)。Add dichloromethane (4mL), compound 5-5 (40mg, 83.43μmol), and 2-amino-3-methyl-6-bromopyridine (15.60mg, 83.43μmol) into the reaction flask and start stirring; after nitrogen replacement , lower the temperature to 0~5°C, add pyridine (46.20 mg, 584.02 μmol, 47.14 μL) and phosphorus oxychloride (19.19 mg, 125.15 μmol, 11.66 μL) in sequence, raise the temperature to 15°C, and react for 2 hours. The reaction solution was concentrated under reduced pressure at 45°C, then 20 mL of dichloromethane was added, and washed with saturated ammonium chloride solution (15 ml × 3); the obtained organic phase was dried by adding anhydrous sodium sulfate, filtered, and the filtrate was heated at 40°C Concentrate under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:0 ~ 20:80). The crude product was added with 1.5 mL of ethyl acetate and stirred for 15 min, then filtered and the filter cake was dried to obtain compound 5. MS (ESI): m/z=648.0/650.0[M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ = 8.96 (d, J = 2.0Hz, 1H), 8.58 (s, 1H), 8.52-8.37 (m, 1H), 8.15 (d, J = 2.4Hz, 1H) ,7.68-7.64(m,1H),7.59-7.57(m,1H),7.38-7.36(m,1H),7.23-7.25(m,1H),5.53-5.40(m,2H),5.07-5.05( m,1H),3.96-3.93(m,1H),3.14-3.10(m,1H),2.85-2.73(m,7H),2.58-2.47(m,1H),2.08(s,3H).
实施例6
Example 6
第一步first step
将化合物5-2(400mg,1.04mmol)，2-溴-5-甲基吡嗪(179.17mg,1.04mmol)加入二氧六环(10mL)，水(2mL)中；氮气置换后，在氮气流下依次加入碳酸钾(429.39mg,3.11mmol)，[1,1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(84.57mg,103.56μmol)，升温至95℃，反应8小时。向反应体系中加入30mL水后，加入乙酸乙酯萃取(15mL×2)；合并有机相用15mL饱和食盐水洗涤后，加入无水硫酸钠干燥，过滤，滤液减压浓缩；剩余物通过硅胶柱层析分离纯化(石油醚:乙酸乙酯＝100:0～50:50)，得到化合物6-1。MS(ESI):m/z＝253.1[M+H]+。Compound 5-2 (400 mg, 1.04 mmol) and 2-bromo-5-methylpyrazine (179.17 mg, 1.04 mmol) were added to dioxane (10 mL) and water (2 mL); after nitrogen replacement, under nitrogen Potassium carbonate (429.39 mg, 3.11 mmol) and [1,1-bis(diphenylphosphine)ferrocene] dichloride palladium dichloromethane complex (84.57 mg, 103.56 μmol) were added in sequence under the flow, and the temperature was raised to 95 ℃, react for 8 hours. After adding 30 mL of water to the reaction system, add ethyl acetate for extraction (15 mL × 2); wash the combined organic phases with 15 mL of saturated brine, add anhydrous sodium sulfate, dry, filter, and concentrate the filtrate under reduced pressure; the residue is passed through a silica gel column Chromatography separation and purification (petroleum ether:ethyl acetate=100:0~50:50) gave compound 6-1. MS (ESI): m/z=253.1[M+H] + .
第二步Step 2
将四氢呋喃(6mL)，化合物6-1(130mg,515.32μmol)，化合物3-1(186.45mg,793.40μmol)加入反应瓶中，开始搅拌；氮气置换后，依次将三苯基磷(337.91mg,1.29mmol)，偶氮二甲酸二异丙酯(208.41mg,1.03mmol)加入其中，18℃反应1小时。向反应体系中加入20mL水后，加入20mL乙酸乙酯萃取；得到的有机相加入无水硫酸钠干燥，过滤，滤液减压浓缩。剩余物通过硅胶柱层析分离纯化(石油醚:乙酸乙酯＝100:0～20:80)，得到化合物6-2。MS(ESI):m/z＝470.1[M+H]+。Add tetrahydrofuran (6mL), compound 6-1 (130mg, 515.32μmol), and compound 3-1 (186.45mg, 793.40μmol) into the reaction bottle and start stirring; after nitrogen replacement, add triphenylphosphine (337.91mg, 337.91mg, 1.29mmol), diisopropyl azodicarboxylate (208.41mg, 1.03mmol) was added, and the reaction was carried out at 18°C for 1 hour. After adding 20 mL of water to the reaction system, add 20 mL of ethyl acetate for extraction; the obtained organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:0~20:80) to obtain compound 6-2. MS (ESI): m/z=470.1[M+H] + .
第三步third step
将四氢呋喃(8mL)，甲醇(8mL)，水(4mL)，化合物6-2(170mg,362.13μmol)加入反应瓶中，开始搅拌；然后将一水合氢氧化锂(60.78mg,1.45mmol)加入其中，18℃反应1小时。向反应体系中加入30mL水后，反应液减压浓缩除去有机溶剂；剩余的水相用甲基叔丁基醚洗涤(20mL×2)，得到的水相用2N盐酸将pH值调至3～4后，加入二氯甲烷(30mL×4)萃取；得到的有机相加入无水硫酸钠干燥后，过滤，滤液在45℃下进行减压浓缩，剩余物中加入2mL乙酸乙酯后搅拌10min，过滤，收集滤饼得到化合物6-3。MS(ESI):m/z＝456.1[M+H]+。Add tetrahydrofuran (8mL), methanol (8mL), water (4mL), and compound 6-2 (170mg, 362.13μmol) into the reaction flask and start stirring; then add lithium hydroxide monohydrate (60.78mg, 1.45mmol). , react at 18°C for 1 hour. After adding 30 mL of water to the reaction system, the reaction solution was concentrated under reduced pressure to remove the organic solvent; the remaining aqueous phase was washed with methyl tert-butyl ether (20 mL × 2), and the pH value of the obtained aqueous phase was adjusted to 3~3 with 2N hydrochloric acid. After 4, add dichloromethane (30mL×4) for extraction; add anhydrous sodium sulfate to the obtained organic phase, dry it, filter, and concentrate the filtrate under reduced pressure at 45°C. Add 2mL of ethyl acetate to the residue and stir for 10 minutes. Filter and collect the filter cake to obtain compound 6-3. MS (ESI): m/z=456.1[M+H] + .
第四步the fourth step
将化合物6-3(50mg,109.79μmol)，2-氨基-3-甲基-6-溴吡啶(20.53mg,109.79μmol)加入二氯甲烷(5mL)中，开始搅拌；氮气置换后，将温度降至0～5℃，依次加入吡啶(62.03μL,768.53μmol)，三氯氧磷(15.35μL,164.69μmol)，升温至15℃，反应2小时。反应液减压浓缩，然后加入15mL二氯甲烷后，用饱和氯化铵溶液洗涤(15mL×3)；得到的有机相用无水硫酸钠干燥，过滤，滤液在40℃下进行减压浓缩。剩余物经薄层色谱制备分离(石油醚:乙酸乙酯＝0:1)得到化合物6。MS(ESI):m/z＝624.2/626.2[M+H]+。1H NMR(400MHz,CDCl3)δ＝9.03(s,1H),8.96(s,1H),8.58-8.44(m,2H),8.22-8.19(m,1H),7.55(d,J＝8.8Hz,1H),7.35(d,J＝8.0Hz,1H),7.26-7.24(m,1H),5.51-5.38(m,2H),5.05-5.03(m,1H),3.94-3.91(m,1H),3.14-3.04(m,1H),2.82-2.73(m,4H),2.64(s,3H),2.54-2.46(m,1H),2.05(s,3H)。Add compound 6-3 (50 mg, 109.79 μmol) and 2-amino-3-methyl-6-bromopyridine (20.53 mg, 109.79 μmol) into dichloromethane (5 mL) and start stirring; after nitrogen replacement, increase the temperature Lower the temperature to 0~5°C, add pyridine (62.03 μL, 768.53 μmol) and phosphorus oxychloride (15.35 μL, 164.69 μmol) in sequence, raise the temperature to 15°C, and react for 2 hours. The reaction solution was concentrated under reduced pressure, then 15 mL of methylene chloride 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 at 40°C. The residue was preparatively separated by thin layer chromatography (petroleum ether:ethyl acetate=0:1) to obtain compound 6. MS (ESI): m/z=624.2/626.2[M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ = 9.03 (s, 1H), 8.96 (s, 1H), 8.58-8.44 (m, 2H), 8.22-8.19 (m, 1H), 7.55 (d, J = 8.8 Hz,1H),7.35(d,J＝8.0Hz,1H),7.26-7.24(m,1H),5.51-5.38(m,2H),5.05-5.03(m,1H),3.94-3.91(m, 1H),3.14-3.04(m,1H),2.82-2.73(m,4H),2.64(s,3H),2.54-2.46(m,1H),2.05(s,3H).
实施例7

Example 7

第一步first step
将化合物7-1(5g,23.69mmol)溶于二氯甲烷(50mL)中，加入二碳酸二叔丁酯(7.76g,35.54mmol)和三乙胺(7.19g,71.07mmol)，分批次加入4-二甲胺基吡啶(289.42mg,2.37mmol)，25℃下搅拌反应2小时。反应液减压浓缩得到粗品。粗品经柱层析纯化(石油醚:乙酸乙酯＝100:0～60:40)得到化合物7-2。Dissolve compound 7-1 (5g, 23.69mmol) in dichloromethane (50mL), add di-tert-butyl dicarbonate (7.76g, 35.54mmol) and triethylamine (7.19g, 71.07mmol) in batches 4-Dimethylaminopyridine (289.42 mg, 2.37 mmol) was added, and the reaction was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=100:0~60:40) to obtain compound 7-2.
第二步Step 2
将化合物7-2(3.3g,10.61mmol)和2-甲基嘧啶-5-硼酸(2.19g,15.91mmol)溶于二氧六环(5mL)和水(0.5mL)中，加入碳酸钾(2.93g,21.21mmol)，[1,1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷(433.02mg,530.25μmol)，反应液在90℃、氮气保护下搅拌反应3小时。反应液冷却至室温，过滤，滤液减压浓缩得到粗品，粗品经柱层析纯化(二氯甲烷:甲醇＝100:0～99:1)，得到化合物7-3。MS(ESI):m/z＝224.9[M+H]+。Compound 7-2 (3.3g, 10.61mmol) and 2-methylpyrimidine-5-boronic acid (2.19g, 15.91mmol) were dissolved in dioxane (5mL) and water (0.5mL), and potassium carbonate ( 2.93g, 21.21mmol), [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane (433.02mg, 530.25μmol), the reaction solution was stirred at 90°C under nitrogen protection for reaction 3 Hour. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (dichloromethane:methanol=100:0~99:1) to obtain compound 7-3. MS (ESI): m/z=224.9[M+H] + .
第三步third step
将化合物7-3(1.8g,8.03mmol)溶于四氢呋喃(20mL)中，加入叔丁醇钾(2.25g,20.07mmol)，碘(3.06g,12.04mmol)，反应液在25℃下搅拌反应1小时。然后反应液在搅拌下加入饱和亚硫酸氢钠溶液淬灭，搅拌15分钟，过滤，滤饼干燥得到化合物7-4。Dissolve compound 7-3 (1.8g, 8.03mmol) in tetrahydrofuran (20mL), add potassium tert-butoxide (2.25g, 20.07mmol) and iodine (3.06g, 12.04mmol), and stir the reaction solution at 25°C. 1 hour. Then, the reaction solution was quenched by adding saturated sodium bisulfite solution while stirring, stirred for 15 minutes, filtered, and the filter cake was dried to obtain compound 7-4.
第四步the fourth step
将化合物7-4(1g,2.86mmol)溶于甲苯(10mL)，甲醇(10mL)中，加入三乙胺(433.48mg,4.28mmol)，加入[1,1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷(104.48mg,142.79μmol)，氮气置换三次，一氧化碳气体置换三次，反应液在80℃下、一氧化碳氛围(15psi)下搅拌反应16小时。补加三乙胺(433.47mg,4.28mmol)，[1,1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷(104.48mg,142.79μmol)，反应液继续在80℃下、一氧化碳氛围(15psi)下搅拌反应24小时。反应液冷却至室温，经过滤，滤液浓缩得到粗品。粗品经柱层析纯化(二氯甲烷:甲醇＝100:0～98:2)，得到化合物7-5。MS(ESI):m/z＝283.1[M+H]+。Compound 7-4 (1g, 2.86mmol) was dissolved in toluene (10mL), methanol (10mL), triethylamine (433.48mg, 4.28mmol) was added, and [1,1-bis(diphenylphosphine)bis Ferrocene] Palladium dichloride dichloromethane (104.48 mg, 142.79 μmol), replaced three times with nitrogen and three times with carbon monoxide gas. The reaction solution was stirred and reacted for 16 hours at 80°C in a carbon monoxide atmosphere (15 psi). Triethylamine (433.47mg, 4.28mmol), [1,1-bis(diphenylphosphine)ferrocene] dichloride palladium dichloromethane (104.48mg, 142.79μmol) were added, and the reaction solution continued to be heated at 80°C The reaction was stirred for 24 hours under carbon monoxide atmosphere (15 psi). The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to obtain crude product. The crude product was purified by column chromatography (dichloromethane:methanol=100:0~98:2) to obtain compound 7-5. MS (ESI): m/z=283.1[M+H] + .
第五步the fifth step
将化合物7-5溶于四氢呋喃(4mL)、水(4mL)、甲醇(4mL)中，加入一水合氢氧化锂(209.58mg,4.99mmol)，反应液在80℃搅拌反应12小时。反应液冷却至室温，反应液减压浓缩除去有机溶剂，剩余物用1M稀盐酸调节pH至3-4，然后经乙酸乙酯(10mL×3)萃取，有机相经饱和食盐水洗涤，无水硫酸钠干燥，过滤， 滤液浓缩得到粗品。粗品经柱层析纯化(二氯甲烷:甲醇＝100:0～80:20)，得到化合物7-6。MS(ESI):m/z＝269.1[M+H]+。Compound 7-5 was dissolved in tetrahydrofuran (4 mL), water (4 mL), and methanol (4 mL), lithium hydroxide monohydrate (209.58 mg, 4.99 mmol) was added, and the reaction solution was stirred at 80°C for 12 hours. The reaction solution was cooled to room temperature, and the reaction solution was concentrated under reduced pressure to remove the organic solvent. The pH of the residue was adjusted to 3-4 with 1M dilute hydrochloric acid, and then extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated brine and anhydrous. Dry over sodium sulfate, filter, The filtrate was concentrated to obtain crude product. The crude product was purified by column chromatography (dichloromethane:methanol=100:0~80:20) to obtain compound 7-6. MS (ESI): m/z=269.1[M+H] + .
第六步Step 6
将化合物7-6(430mg,1.60mmol)和O,N-二甲基羟基胺盐酸盐(187.62mg,1.92mmol)溶于N,N-二甲基甲酰胺(5mL)中，加入N,N-二异丙基乙胺(621.48mg,4.81mmol)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.22g,3.21mmol)，反应液在25℃下搅拌反应12小时。向反应液中加水(5mL)，然后用(10mL×3)萃取，有机相浓缩得到粗品。粗品经柱层析纯化(二氯甲烷:甲醇＝100:0～98:2)，得到化合物7-7。MS(ESI):m/z＝312.2[M+H]+。Compound 7-6 (430mg, 1.60mmol) and O,N-dimethylhydroxylamine hydrochloride (187.62mg, 1.92mmol) were dissolved in N,N-dimethylformamide (5mL), and N, N-diisopropylethylamine (621.48mg, 4.81mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.22 g, 3.21 mmol), the reaction solution was stirred and reacted at 25°C for 12 hours. Water (5 mL) was added to the reaction solution, and then extracted with (10 mL × 3). The organic phase was concentrated to obtain a crude product. The crude product was purified by column chromatography (dichloromethane:methanol=100:0~98:2) to obtain compound 7-7. MS (ESI): m/z=312.2[M+H] + .
第七步Step 7
将化合物7-7(0.8g,2.57mmol)溶于四氢呋喃(8mL)中，在氮气气氛下，-78℃下滴加甲基溴化镁(3M的四氢呋喃溶液,4.28mL)，然后反应液缓慢升温至0℃，搅拌反应2小时。在氮气气氛下向反应液中缓慢滴加水淬灭。加入1N盐酸(10mL)，用乙酸乙酯(10mL×3)萃取，合并有机相，经饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。剩余物经柱层析纯化(二氯甲烷:甲醇＝100:0～98:2)得到粗品。粗品再加入甲醇(3mL)搅拌10min，过滤，收集滤饼得到化合物7-8。MS(ESI):m/z＝266.9[M+H]+。Compound 7-7 (0.8g, 2.57mmol) was dissolved in tetrahydrofuran (8mL), and methylmagnesium bromide (3M tetrahydrofuran solution, 4.28mL) was added dropwise under a nitrogen atmosphere at -78°C, and then the reaction solution was slowly The temperature was raised to 0°C and the reaction was stirred for 2 hours. Water was slowly added dropwise to the reaction solution to quench it under a nitrogen atmosphere. Add 1N hydrochloric acid (10 mL), extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol=100:0~98:2) to obtain crude product. Methanol (3 mL) was added to the crude product, stirred for 10 min, filtered, and the filter cake was collected to obtain compound 7-8. MS (ESI): m/z=266.9[M+H] + .
第八步Step 8
将化合物7-8(100mg,375.52μmol)和化合物2-4(276.17mg,563.28μmol)溶于四氢呋喃(4mL)中，加入三苯基磷(98.50mg,375.52μmol)、偶氮二甲酸二异丙酯(72.80μL,375.52μmol,)，反应液在氮气气氛、25℃条件下搅拌反应4小时。然后减压浓缩得到粗品。粗品经柱层析纯化(二氯甲烷:甲醇＝100:0～99:1)得到化合物7-9。MS(ESI):m/z＝738.2/740.2[M+H]+。Compound 7-8 (100 mg, 375.52 μmol) and compound 2-4 (276.17 mg, 563.28 μmol) were dissolved in tetrahydrofuran (4 mL), and triphenylphosphine (98.50 mg, 375.52 μmol) and diisoazodicarboxylate were added. Propyl ester (72.80 μL, 375.52 μmol,), the reaction solution was stirred and reacted for 4 hours in a nitrogen atmosphere at 25°C. Then concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography (dichloromethane:methanol=100:0~99:1) to obtain compound 7-9. MS (ESI): m/z=738.2/740.2[M+H] + .
第九步Step 9
将化合物7-9(400mg,541.58μmol)溶于二氯甲烷(2mL)中，加入三氟乙酸(1mL)，反应液在25℃搅拌反应12小时。然后向反应液中加入饱和碳酸氢钠溶液调节pH至6-7，反应液经二氯甲烷(5mL×3)萃取，有机相减压浓缩得到粗品。粗品经高效液相色谱法制备分离(column:C18 100×40mm；流动相：A相水(三氟乙酸)，B相为乙腈，梯度为B％：26％-56％)纯化，所得样品溶液减压浓缩后用饱和碳酸氢钠溶液调节pH至7-8，经二氯甲烷(5mL×3)萃取，合并的有机相经饱和食盐水洗涤(10mL)，无水硫酸钠干燥，过滤浓缩得到化合物7。MS(ESI):m/z＝638.1/640.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ＝10.45(s,1H),9.02(s,2H),8.32(s,1H),7.6-7.6(m,2H),7.45(d,J＝7.8Hz,1H),6.0-6.2(m,1H),5.7-5.8(m,1H),4.75(dd,J＝4.8,9.0Hz,1H),4.57(dd,J＝4.9,9.2Hz,1H),3.0-3.1(m,1H),2.6-2.7(m,10H),2.4-2.5(m,1H),2.03(s,3H)。Compound 7-9 (400 mg, 541.58 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and the reaction solution was stirred and reacted at 25°C for 12 hours. Then, saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to 6-7. The reaction solution was extracted with dichloromethane (5 mL × 3), and the organic phase was concentrated under reduced pressure to obtain a crude product. 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] + . 1 H NMR (400MHz, DMSO-d6) δ = 10.45 (s, 1H), 9.02 (s, 2H), 8.32 (s, 1H), 7.6-7.6 (m, 2H), 7.45 (d, J = 7.8Hz ,1H),6.0-6.2(m,1H),5.7-5.8(m,1H),4.75(dd,J＝4.8,9.0Hz,1H),4.57(dd,J＝4.9,9.2Hz,1H), 3.0-3.1(m,1H),2.6-2.7(m,10H),2.4-2.5(m,1H),2.03(s,3H).
参照实施例1～7的合成步骤，制备如下表A化合物：Referring to the synthetic steps of Examples 1 to 7, the following compounds in Table A were prepared:
表A



Table A



生物测试数据Biological test data
实验例1：Wieslab补体旁路通路活化抑制Experimental Example 1: Wieslab complement alternative pathway activation inhibition
实验目的：Purpose:
通过补体系统旁路通路试剂盒，测定本发明化合物针对人血清中补体旁路通路的抑制活性。实验方案：pass Complement system alternative pathway kit is used to measure the inhibitory activity of the compound of the present invention against the complement alternative pathway in human serum. Experimental program:
用稀释液将血清进行稀释(1：19)。向稀释的血清中加入药物，8个浓度梯度，最高1μM，4倍梯度稀释。室温孵育15min。将测试化合物和血清混合物加入试剂盒提供的96孔板(100μL/孔)，在37℃激活1小时。用洗涤缓冲液清洗三遍。加入试剂盒提供的检测抗体(100μL)在室温进行孵育30min。用洗涤缓冲液清洗三遍。加入底物(100μL)在室温进行孵育30min。酶标仪405nM处检测吸光度。Dilute the serum with diluent (1:19). Add the drug to the diluted serum in 8 concentration gradients, up to 1 μM, in 4-fold gradient dilutions. Incubate at room temperature for 15 minutes. Add the test compound and serum mixture to the 96-well plate provided in the kit (100 μL/well) and activate at 37°C for 1 hour. Wash three times with wash buffer. Add the detection antibody (100 μL) provided by the kit and incubate at room temperature for 30 minutes. Wash three times with wash buffer. Add substrate (100 μL) and incubate at room temperature for 30 min. The absorbance was measured at 405nM with a microplate reader.
实验结果：结果如表1所示。Experimental results: The results are shown in Table 1.
表1：体外酶活性筛选试验结果
Table 1: In vitro enzyme activity screening test results
结论：本发明化合物对人血清旁路通路激活抑制活性明显。Conclusion: The compound of the present invention has obvious inhibitory activity on the activation of human serum bypass pathway.
实验例2：小鼠药代动力学研究试验Experimental Example 2: Mouse Pharmacokinetics Research Test
实验目的：Purpose:
考察本发明化合物单次静脉注射和灌胃给药后雄性CD-1(ICR)小鼠体内血浆药代动力学。The plasma pharmacokinetics in male CD-1 (ICR) mice after single intravenous injection and intragastric administration of the compound of the present invention were investigated.
实验动物：Experimental animals:
雄性CD-1(ICR)小鼠，7-9周龄，体重35-40克；供应商：北京维通利华实验动物技术有限公司实验过程：Male CD-1 (ICR) mice, 7-9 weeks old, weighing 35-40 grams; supplier: Beijing Vitong Lihua Experimental Animal Technology Co., Ltd. Experimental process:
注射给药(IV)：溶媒为10％DMSO/10％solutol/80％H2O，浓度为0.20mg/mL，给药剂量为1mg/kg；口服给药(PO)：溶媒为10％DMSO/10％solutol/80％H2O，浓度为1mg/mL，化合物1和2的给药剂量为10mg/kg，化合物15的给药剂量5mg/kg。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; Oral administration (PO): The solvent is 10% DMSO /10%solutol/80% H2O , the concentration is 1mg/mL, the dosage of compounds 1 and 2 is 10mg/kg, and the dosage of compound 15 is 5mg/kg.
样品采集：实验动物每个时间点从隐静脉穿刺采集血液样本0.025mL，记录实际采血时间。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℃、3200g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LC-MS/MS分析。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.
实验结果：Experimental results:
采用WinNonlinTMVersion6.3(Pharsight,MountainView,CA)药动学软件的非房室模型处理血浆浓度，使用线性对数梯形法方法计算药动学参数(Cl：表观清除率；T1/2：清除一半化合物所需时长；Cmax：达峰浓度；AUC0-last：0-末次取样时间内的浓度积分面积；F％：生物利用度)。结果见表2。The non-compartmental model of WinNonlin TM Version6.3 (Pharsight, MountainView, CA) pharmacokinetic software was used to process plasma concentration, and the linear logarithmic trapezoidal method was used to calculate pharmacokinetic parameters (Cl: apparent clearance; T 1/2 : the time required to eliminate half of the compound; C max : peak concentration; AUC 0-last : 0-concentration integrated area during the last sampling time; F%: bioavailability). The results are shown in Table 2.
表2本发明化合物小鼠PK结果
Table 2 Mouse PK results of the compounds of the present invention
实验结论：小鼠药代动力学研究结果显示，本发明化合物的半衰期长，血浆暴露量高，生物利用度高，具 有优良的药代动力学性质。Experimental conclusion: The results of the mouse 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.
实验例3：大鼠药代动力学研究试验Experimental Example 3: Rat pharmacokinetics research test
实验目的：Purpose:
考察本发明化合物单次静脉注射和灌胃给药后雄性SD大鼠体内血浆药代动力学。The plasma pharmacokinetics of the compound of the present invention in male SD rats after single intravenous injection and intragastric administration were investigated.
实验动物：Experimental animals:
雄性SD大鼠，7-9周龄，体重219-225克；供应商：北京维通利华实验动物技术有限公司Male SD rats, 7-9 weeks old, weight 219-225 grams; Supplier: Beijing Vitong Lihua Experimental Animal Technology Co., Ltd.
实验过程：experiment procedure:
注射给药(IV)：溶媒为10％DMSO/10％solutol/80％H2O，浓度为0.20mg/mL，剂量为1mpk；口服给药(PO)：溶媒为10％DMSO/10％solutol/80％H2O，浓度为1mg/mL，剂量为10mpk。Injection administration (IV): The solvent is 10% DMSO/10% solutol/80% H 2 O, the concentration is 0.20 mg/mL, the dose is 1 mpk; Oral administration (PO): the solvent is 10% DMSO/10% solutol /80%H 2 O, the concentration is 1mg/mL, the dose is 10mpk.
样品采集：实验动物每个时间点从颈静脉穿刺采集血液样本约约0.250mL，记录实际采血时间。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，于4℃、3200g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LC-MS/MS分析。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.
实验结果：Experimental results:
采用Phoenix WinNonlin 6.3药动学软件的非房室模型处理血浆浓度，使用线性对数梯形法方法计算药动学参数(Cl：表观清除率；T1/2：清除一半化合物所需时长；Cmax：达峰浓度；AUC0-last：0-末次取样时间内的浓度积分面积；F％：生物利用度)，结果见表3。The non-compartmental model of Phoenix WinNonlin 6.3 pharmacokinetic software was used to process the plasma concentration, and the linear logarithmic trapezoidal method was used to calculate the pharmacokinetic parameters (Cl: apparent clearance; T 1/2 : the time required to eliminate half of the compound; C max : peak concentration; AUC 0-last : 0-concentration integrated area during the last sampling time; F%: bioavailability), the results are shown in Table 3.
表3本发明化合物大鼠PK结果
Table 3 Rat PK results of the compounds of the present invention
实验结论：大鼠药代动力学研究结果显示，本发明化合物清除率低、血浆暴露量高、生物利用度高，具有优良的药代动力学性质。Experimental conclusion: The results of the rat pharmacokinetic study show that the compound of the present invention has a low clearance rate, high plasma exposure, high bioavailability, and excellent pharmacokinetic properties.
实验例4：肝微粒体代谢稳定性测试Experimental Example 4: Liver Microsome Metabolism Stability Test
实验目的：Purpose:
考察本发明化合物在各种属肝微粒体中的代谢稳定性。The metabolic stability of the compound of the present invention in various hepatic microsomes was investigated.
实验材料：Experimental Materials:
肝微粒体：人和动物微粒体购买于Corning或Xenotech，储存于-80℃冰箱。Liver microsomes: Human and animal microsomes were purchased from Corning or Xenotech and stored in a -80°C refrigerator.
还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)，供应商：BONTAC，货号：BT04。Reduced nicotinamide adenine dinucleotide phosphate (NADPH), supplier: BONTAC, product number: BT04.
对照化合物：睾酮，双氯芬酸，普罗帕酮。Control compounds: testosterone, diclofenac, propafenone.
终止液：tolbutamide(甲苯磺丁脲)，labetalol(拉贝洛尔)。Stop solution: tolbutamide, labetalol.
实验步骤：Experimental steps:
(1)工作液的配制(1) Preparation of working fluid
储备液：10mM DMSO溶液；Stock solution: 10mM DMSO solution;
工作浓度配制：用100％乙腈稀释到100μM；Working concentration preparation: dilute to 100μM with 100% acetonitrile;
(2)实验步骤(2)Experimental steps
准备2块96孔孵育板，分别命名为T60孵育板和NCF60孵育板。Prepare two 96-well incubation plates, named T60 incubation plate and NCF60 incubation plate respectively.
在T60孵育板和NCF60孵育板上分别加入445μL微粒体工作液(肝微粒体蛋白浓度为0.56mg/mL)， 然后将上述孵育板放置于37℃水浴锅中预孵育大约10分钟。Add 445 μL of microsomal working solution (liver microsomal protein concentration is 0.56 mg/mL) to the T60 incubation plate and NCF60 incubation plate respectively. Then place the above-mentioned incubation plate in a 37°C water bath for pre-incubation for about 10 minutes.
预孵育结束后，在T60孵育板和NCF60孵育板上分别加入5μL供试品或对照化合物工作液，混匀。在NCF60孵育板上每孔添加50μL磷酸钾盐缓冲液启动反应；在T0终止板中加入180μL的终止液(含200ng/mL tolbutamide和200ng/mL labetalol的乙腈溶液)和6μL的NADPH再生体系工作液，从T60孵育板中取出54μL样品至T0终止板(T0样品产生)。在T60孵育板上每孔添加44μL NADPH再生体系工作液启动反应。在Blank板中只添加54μL微粒体工作液、6μL的NADPH再生体系工作液和180μL的终止液。因此，在供试品或对照化合物的样品中，化合物、睾酮、双氯芬酸和普罗帕酮的反应终浓度为1μM，肝微粒体的浓度为0.5mg/mL，DMSO和乙腈在反应体系中的终浓度分别为0.01％(v/v)和0.99％(v/v)。After the pre-incubation, add 5 μL of test product or control compound working solution to the T60 incubation plate and NCF60 incubation plate respectively, and mix well. Add 50 μL potassium phosphate buffer to each well of the NCF60 incubation plate to start the reaction; add 180 μL stop solution (acetonitrile solution containing 200ng/mL tolbutamide and 200ng/mL labetalol) and 6 μL NADPH regeneration system working solution to the T0 stop plate. , remove 54 μL of sample from the T60 incubation plate to the T0 stop plate (T0 sample generation). Add 44 μL of NADPH regeneration system working solution to each well of the T60 incubation plate to start the reaction. Add only 54 μL of microsome working solution, 6 μL of NADPH regeneration system working solution and 180 μL of stop solution to the Blank plate. Therefore, in the sample of the test product or control compound, the final concentration of the compound, testosterone, diclofenac and propafenone in the reaction is 1 μM, the concentration of liver microsomes is 0.5 mg/mL, and the final concentration of DMSO and acetonitrile in the reaction system 0.01% (v/v) and 0.99% (v/v) respectively.
孵育适当时间(5分钟、15分钟、30分钟、45分钟和60分钟)后，分别在每个终止板的样品孔中加入180μL的终止液(含200ng/mL tolbutamide和200ng/mL labetalol的乙腈溶液)，之后从T60孵育板中取出60μL样品以终止反应。After incubating for an appropriate time (5 minutes, 15 minutes, 30 minutes, 45 minutes and 60 minutes), add 180 μL of stop solution (acetonitrile solution containing 200ng/mL tolbutamide and 200ng/mL labetalol) to the sample wells of each stop plate. ), then remove 60 μL of sample from the T60 incubation plate to terminate the reaction.
所有样品板摇匀并在3220g离心20分钟，然后每孔取80μL上清液稀释到240μL纯水中用于液相色谱串联质谱分析。All sample plates were shaken and centrifuged at 3220 g for 20 minutes, and then 80 μL of the supernatant from each well was diluted into 240 μL of pure water for liquid chromatography-tandem mass spectrometry analysis.
实验结果：结果见表4。Experimental results: The results are shown in Table 4.
表4本发明化合物在各种属肝微粒体中的代谢稳定性结果
Table 4 Metabolic stability results of compounds of the present invention in various hepatic microsomes
实验结论：本发明化合物在各种属肝微粒体中具有优异的代谢稳定性。Experimental conclusion: The compound of the present invention has excellent metabolic stability in various hepatic microsomes.
实验例5：人肝细胞代谢稳定性测试Experimental Example 5: Human liver cell metabolic stability test
实验目的：Purpose:
考察本发明化合物在人肝细胞中的代谢稳定性。The metabolic stability of the compound of the present invention in human liver cells was investigated.
实验步骤：Experimental steps:
准备若干96孔样品沉淀板，分别命名为T0、T15、T30、T60、T90、T90、T0-MC、T90-MC和空白基质。提前取出复苏培养液和孵育培养液，放置在37℃水浴锅中预热。从液氮罐中取出冻存的肝细胞，立即浸没到37℃水浴中(约90秒)。待冻存部分溶化松动后，分别倒入含有40mL复苏培养液的离心管中，轻柔的颠倒让细胞在复苏培养液中重悬。室温条件下，100×g离心5分钟，移除上清液，用适当体积的孵育培养液重悬肝细胞，用台盼蓝染色法计算细胞活率。将198μL的肝细胞混悬液(0.51×106cells/mL)加入到已预热的孵育板中，培养液对照组加入198μL不含肝细胞的孵育培养液至T0-MC和T90-MC孵育板中，所有孵育板在37℃培养箱中预孵育10分钟。Prepare several 96-well sample precipitation plates, named T0, T15, T30, T60, T90, T90, T0-MC, T90-MC and blank matrix respectively. Remove the recovery culture medium and incubation culture medium in advance and place them in a 37°C water bath to preheat. Remove the frozen hepatocytes from the liquid nitrogen tank and immediately immerse them in a 37°C water bath (about 90 seconds). After the frozen parts are thawed and loosened, pour them into centrifuge tubes containing 40 mL of recovery culture medium, and gently invert to resuspend the cells in the recovery culture medium. Centrifuge at 100×g for 5 minutes at room temperature, remove the supernatant, resuspend the liver cells in an appropriate volume of incubation medium, and calculate the cell viability using trypan blue staining. Add 198 μL of hepatocyte suspension (0.51×10 6 cells/mL) to the preheated incubation plate, and add 198 μL of hepatocyte-free incubation medium to the culture medium control group to incubate T0-MC and T90-MC. Plate, pre-incubate all incubated plates in a 37 °C incubator for 10 min.
然后加入2μL供试品工作液，混匀，立即将孵育板放入培养箱内的摇板机中，启动计时器开始反应。每个化合物的每个时间点准备2个重复样本。孵育条件为37℃、饱和湿度、含5％CO2。测试体系中，供试品的终浓度为1μM，肝细胞的终浓度为0.5×106cells/mL，总有机溶剂的终浓度为0.96％，其中DMSO的终浓度为0.1％。相应时间点孵育结束时，取出孵育板，取出25μL化合物与细胞的混合液加入到含有125μL终止液(含有200ng/mL甲苯磺丁脲和拉贝诺尔的乙腈溶液)的样品板中。对于培养液对照组样品板，直接加入25μL不含肝细胞的孵育培养液。所有样品板封膜后在摇板机上以500rpm摇10分钟后，在4℃下3220×g离心20分钟。供试品上清液用超纯水以1:3的比例稀释。所有样品混匀后用LC/MS/MS的 方法进行分析。Then add 2 μL of the working solution of the test product, mix well, immediately put the incubation plate into the shaker in the incubator, and start the timer to start the reaction. Prepare 2 replicate samples for each time point for each compound. Incubation conditions were 37°C, saturated humidity, and 5% CO 2 . In the test system, the final concentration of the test product is 1 μM, the final concentration of liver cells is 0.5×10 6 cells/mL, the final concentration of total organic solvents is 0.96%, and the final concentration of DMSO is 0.1%. At the end of the incubation at the corresponding time point, remove the incubation plate and add 25 μL of the mixture of compound and cells to the sample plate containing 125 μL of stop solution (acetonitrile solution containing 200 ng/mL tolbutamide and labenol). For the culture medium control sample plate, directly add 25 μL of incubation medium without hepatocytes. After all sample plates were sealed, they were shaken on a shaker at 500 rpm for 10 minutes, and then centrifuged at 3220 × g for 20 minutes at 4°C. The supernatant of the test sample was diluted with ultrapure water at a ratio of 1:3. After all samples were mixed, LC/MS/MS method for analysis.
实验结果见表5。The experimental results are shown in Table 5.
表5本发明化合物在人肝细胞中的代谢稳定性结果
Table 5 Metabolic stability results of compounds of the present invention in human liver cells
实验结论：本发明化合物在人肝细胞中具有中等到较慢的清除速率，具有优异的代谢稳定性。 Experimental conclusion: The compound of the present invention has a medium to slow clearance rate in human liver cells and has excellent metabolic stability.

Claims (16)

  1. 式(V)所示化合物或其药学上可接受的盐，
    The compound represented by formula (V) or a pharmaceutically acceptable salt thereof,
    其中，in,
    R1选自F、Cl、Br、I、C1-4烷基、C1-4烷氧基、C1-4烷氨基、C1-4烷硫基、-C(＝O)-C1-4烷基、-C(＝O)-C1-4烷氨基、-C(＝O)-NH2和-NH-C(＝O)-C1-4烷基，所述C1-4烷基、C1-4烷氧基、C1-4烷氨基、C1-4烷硫基、-C(＝O)-C1-4烷基、-C(＝O)-C1-4烷氨基、-C(＝O)-NH2和-NH-C(＝O)-C1-4烷基分别独立地任选被1、2或3个Ra取代；R 1 is selected from F, Cl, Br, I, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkylthio, -C(=O)-C 1-4 alkyl, -C(=O)-C 1-4 alkylamino, -C(=O)-NH 2 and -NH-C(=O)-C 1-4 alkyl, the C 1 -4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkylthio, -C(=O)-C 1-4 alkyl, -C(=O)-C 1-4 alkylamino, -C(=O)-NH 2 and -NH-C(=O)-C 1-4 alkyl are independently optionally substituted by 1, 2 or 3 R a ;
    R2选自5-6元杂芳基和8-10元杂环基，所述5-6元杂芳基和8-10元杂环基分别独立地任选被1、2或3个Rb取代；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;
    R3和R4分别独立地选自H、F、Cl、Br、I和C1-4烷基，所述C1-4烷基任选被1、2或3个Rd取代；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 ;
    各R5分别独立地选自F、Cl、Br、I、NH2、OH和C1-4烷基，所述C1-4烷基任选被1、2或3个Re取代；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 ;
    T1选自CH和N；T 1 is selected from CH and N;
    T2选自CH和N；T 2 is selected from CH and N;
    环A选自5-6元杂芳基，所述5-6元杂芳基任选被1、2或3个Rc取代；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 ;
    各Ra、各Rd和各Re分别独立地选自F、Cl、Br、I、NH2和OH；Each R a , each R d and each R e are independently selected from F, Cl, Br, I, NH 2 and OH;
    各Rb和各Rc分别独立地选自F、Cl、Br、I、NH2、OH、CN、C1-4烷基、C1-4烷氧基、C1-4烷氨基、C1-4烷硫基、C3-6环烷基和4-6元杂环烷基，所述C1-4烷基、C1-4烷氧基、C1-4烷氨基、C1-4烷硫基、C3-6环烷基和4-6元杂环烷基分别独立地任选被1、2或3个F取代；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选自0、1、2和3；n is selected from 0, 1, 2 and 3;
    m选自1、2和3；m is selected from 1, 2 and 3;
    所述5-6元杂芳基、8-10元杂环基和4-6元杂环烷基的“杂”分别表示1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。The "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.
  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，各Rb分别独立地选自F、Cl、Br、I、CN、CH3和CF3。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R b is independently selected from F, Cl, Br, I, CN, CH 3 and CF 3 .
  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，各Rc分别独立地选自F、Cl、Br、I、CH3和CF3。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R c is independently selected from F, Cl, Br, I, CH 3 and CF 3 .
  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，R1选自F、Cl、Br、I、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、C(CH3)3、OCH3、OCH2CH3、OCH2CH2CH3、OCH(CH3)2、NHCH3、NHCH2CH3、N(CH3)2、SCH3、SCH2CH3、-C(＝O)-CH3、-C(＝O)-NH2、-C(＝O)-NHCH3和-NH-C(＝O)-CH3，所述CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、C(CH3)3、OCH3、OCH2CH3、OCH2CH2CH3、OCH(CH3)2、NHCH3、NHCH2CH3、N(CH3)2、SCH3、SCH2CH3、-C(＝O)-CH3、-C(＝O)-NH2、-C(＝O)-NHCH3和-NH-C(＝O)-CH3分别独立地任选被1、2或3个Ra取代；或者，R1选自-C(＝O)-CH3。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from F, Cl, Br, I, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2. C(CH 3 ) 3 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , NHCH 3 , NHCH 2 CH 3 , N( CH 3 ) 2 , SCH 3 , SCH 2 CH 3 , -C(=O)-CH 3 , -C(=O)-NH 2 , -C(=O)-NHCH 3 and -NH-C(=O)-CH 3 , the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , NHCH 3. NHCH 2 CH 3 , N(CH 3 ) 2 , SCH 3 , SCH 2 CH 3 , -C(＝O)-CH 3 , -C(＝O)-NH 2 , -C(＝O)-NHCH 3 and -NH-C(=O)-CH 3 are each independently optionally substituted by 1, 2 or 3 Ra ; alternatively, R 1 is selected from -C(=O)-CH 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选自嘧啶基、吡啶基、吡嗪基、哒嗪基、咪唑基、吡唑基和所述嘧啶基、吡啶基、吡嗪基、哒嗪基、咪唑基、吡唑基和分别独立地任选被1、2或3个Rb取代；或者，R2选自嘧啶基、吡啶基、吡嗪基和哒嗪基，所述嘧啶基、吡啶基、吡嗪基和哒嗪基分别独立地任选被1、2或3个Rb取代；或者，R2选自 或者，R2选自 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl and The pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl and are independently optionally substituted by 1, 2 or 3 R b ; alternatively, R 2 is selected from pyrimidinyl, pyridyl, pyrazinyl and pyridazinyl, the pyrimidinyl, pyridyl, pyrazinyl and pyridazinyl The groups are independently optionally substituted by 1, 2 or 3 R b ; alternatively, R 2 is selected from Alternatively, R 2 is selected from
  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，R3选自H和CH3，R4选自H和CH3。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from H and CH 3 and R 4 is selected from H and CH 3 .
  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，各R5分别独立地选自F、Cl、Br、I、NH2、OH、CH3和CF3。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 5 is independently selected from F, Cl, Br, I, NH 2 , OH, CH 3 and CF 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，T1选自N。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein T1 is selected from N.
  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，环A选自嘧啶基、吡啶基、吡嗪基、哒嗪基、咪唑基和吡唑基，所述嘧啶基、吡啶基、吡嗪基、哒嗪基、咪唑基和吡唑基分别独立地任选被1、2或3个Rc取代；或者，环A选自 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from the group consisting of pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl, imidazolyl and pyrazolyl, and the pyrimidinyl, pyridyl , pyrazinyl, pyridazinyl, imidazolyl and pyrazolyl are independently optionally substituted by 1, 2 or 3 R c ; alternatively, ring A is 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 或者，结构单元选自或者，结构单元选自 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Or, structural unit Selected from Or, structural unit Selected from
  11. 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 或者，结构单元选自 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Or, structural unit Selected from
  12. 根据权利要求1～11任意一项所述化合物或其药学上可接受的盐，其化合物选自，
    The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from,
    其中，T1、环A、R1、R2、R5和n如权利要求1～11任意一项所定义。Among them, T 1 , ring A, R 1 , R 2 , R 5 and n are as defined in any one of claims 1 to 11.
  13. 根据权利要求1～11任意一项所述化合物或其药学上可接受的盐，其化合物选自，
    The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from,
    其中， in,
    R2选自嘧啶基、吡啶基、吡嗪基、哒嗪基、咪唑基、吡唑基和所述嘧啶基、吡啶基、吡嗪基、哒嗪基、咪唑基、吡唑基和分别独立地任选被1、2或3个Rb取代；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 ;
    R3选自H、F、Cl、Br、I、CH3和CF3；R 3 is selected from H, F, Cl, Br, I, CH 3 and CF 3 ;
    环A选自5-6元杂芳基，所述5-6元杂芳基任选被1、2或3个Rc取代；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 ;
    各Rb分别独立地选自F、Cl、Br、I、CN、CH3和CF3；Each R b is independently selected from F, Cl, Br, I, CN, CH 3 and CF 3 ;
    各Rc分别独立地选自F、Cl、Br、I、CH3和CF3。Each R c is independently selected from F, Cl, Br, I, CH 3 and CF 3 .
  14. 下列化合物或其药学上可接受的盐，

    The following compounds or pharmaceutically acceptable salts thereof,

  15. 根据权利要求14所述化合物或其药学上可接受的盐，其选自，



    The compound according to claim 14 or a pharmaceutically acceptable salt thereof, which is selected from,



  16. 权利要求1～15任意一项所述化合物或其药学上可接受的盐在制备治疗Factor D抑制剂相关疾病的药物中的应用。 Use of the compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating diseases related to Factor D inhibitors.
PCT/CN2023/105913 2022-07-06 2023-07-05 Difluoro-substituted azabicyclo compounds and uses thereof WO2024008121A1 (en)

Applications Claiming Priority (12)

Application Number Priority Date Filing Date Title
CN202210800800 2022-07-06
CN202210800800.6 2022-07-06
CN202210917090.5 2022-08-01
CN202210917090 2022-08-01
CN202211282922 2022-10-19
CN202211282922.7 2022-10-19
CN202310066225 2023-01-17
CN202310066225.6 2023-01-17
CN202310193538.8 2023-03-02
CN202310193538 2023-03-02
CN202310365727.9 2023-04-04
CN202310365727 2023-04-04

Publications (1)

Publication Number Publication Date
WO2024008121A1 true WO2024008121A1 (en) 2024-01-11

Family

ID=89454429

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/105913 WO2024008121A1 (en) 2022-07-06 2023-07-05 Difluoro-substituted azabicyclo compounds and uses thereof

Country Status (1)

Country Link
WO (1) WO2024008121A1 (en)

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106413707A (en) * 2014-02-25 2017-02-15 艾其林医药公司 Amide compounds for treatment of complement mediated disorders
CN108024992A (en) * 2015-08-26 2018-05-11 艾其林医药公司 For treating the aryl, heteroaryl and heterocyclic compound of medical disorder
WO2019227102A1 (en) * 2018-05-25 2019-11-28 Achillion Pharmaceuticals, Inc. Complement alternative pathway-associated nephropathy biomarkers
CN110603252A (en) * 2017-03-01 2019-12-20 艾其林医药公司 Aryl, heteroaryl and heterocyclic pharmaceutical compounds for the treatment of medical disorders
WO2020041301A1 (en) * 2018-08-20 2020-02-27 Achillion Pharmaceuticals, Inc. Pharmaceutical compounds for the treatment of complement factor d medical disorders
CN111163767A (en) * 2017-08-02 2020-05-15 艾其林医药公司 Treatment regimen for paroxysmal nocturnal hemoglobinuria
WO2021168320A1 (en) * 2020-02-20 2021-08-26 Achillion Pharmaceuticals, Inc. Heteroaryl compounds for treatment of complement factor d mediated disorders
WO2021183555A1 (en) * 2020-03-10 2021-09-16 Achillion Pharmaceuticals, Inc. Ocular drug depot for complement-mediated disorders
WO2021202977A1 (en) * 2020-04-03 2021-10-07 Biocryst Pharmaceuticals, Inc. Pyrrolopyrimidine amines as complement inhibitors

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106413707A (en) * 2014-02-25 2017-02-15 艾其林医药公司 Amide compounds for treatment of complement mediated disorders
CN108024992A (en) * 2015-08-26 2018-05-11 艾其林医药公司 For treating the aryl, heteroaryl and heterocyclic compound of medical disorder
CN110603252A (en) * 2017-03-01 2019-12-20 艾其林医药公司 Aryl, heteroaryl and heterocyclic pharmaceutical compounds for the treatment of medical disorders
CN111163767A (en) * 2017-08-02 2020-05-15 艾其林医药公司 Treatment regimen for paroxysmal nocturnal hemoglobinuria
WO2019227102A1 (en) * 2018-05-25 2019-11-28 Achillion Pharmaceuticals, Inc. Complement alternative pathway-associated nephropathy biomarkers
WO2020041301A1 (en) * 2018-08-20 2020-02-27 Achillion Pharmaceuticals, Inc. Pharmaceutical compounds for the treatment of complement factor d medical disorders
WO2021168320A1 (en) * 2020-02-20 2021-08-26 Achillion Pharmaceuticals, Inc. Heteroaryl compounds for treatment of complement factor d mediated disorders
WO2021183555A1 (en) * 2020-03-10 2021-09-16 Achillion Pharmaceuticals, Inc. Ocular drug depot for complement-mediated disorders
WO2021202977A1 (en) * 2020-04-03 2021-10-07 Biocryst Pharmaceuticals, Inc. Pyrrolopyrimidine amines as complement inhibitors

Similar Documents

Publication Publication Date Title
WO2022222995A1 (en) Picolinamide compound
WO2020239076A1 (en) Pyridazinone derivatives as thyroxine receptor-β agonists and application thereof
WO2021110168A1 (en) Spiro compound serving as erk inhibitor, and application thereof
WO2019185026A1 (en) Glucoside derivatives acting as inhibitors of sglts, and use thereof
CN112771045B (en) Quinopyrrolopyrrolidine-2-one derivatives and use thereof
WO2021238999A1 (en) Fluoropyrrolopyridine compound and application thereof
CN113874379B (en) Tetraheterocyclic compounds as Cdc7 inhibitors
KR102500569B1 (en) Pyrazolopyridine-based compounds as selective BTK kinase inhibitors
WO2024008121A1 (en) Difluoro-substituted azabicyclo compounds and uses thereof
WO2023217045A1 (en) Fluoroquinoxalinone derivative for selectively inhibiting parp1
WO2021129817A1 (en) Pyrimidine-based compound having inhibitory effect of ketohexokinase (khk)
WO2021098691A1 (en) Pyrrolotriazine compounds acting as mnk inhibitor
CN114761407A (en) Compound serving as highly selective ROS1 inhibitor and application thereof
WO2020063965A1 (en) Pyrazolopyrimidine derivative as selective trk inhibitor
WO2022166721A1 (en) Fused ring derivatives containing 1,4-oxazepane
WO2023001069A1 (en) Macrocyclic amide compounds and application thereof
WO2022199635A1 (en) Benzylaminoquinazoline derivatives
WO2022156765A1 (en) Pyrazolopyrazine-linked tricyclic compound and application thereof
CN113811530B (en) Pyrimidone compounds serving as chymase inhibitors and application thereof
WO2020156568A1 (en) Fluorovinylbenzamide compound as pd-l1 immunomodulator
CN113166055A (en) Estrogen receptor antagonists
WO2023241618A1 (en) Aminopyrimidine compounds and use thereof
TWI825800B (en) Sulfinimine compounds and their applications
WO2023208127A1 (en) Heteroaryl-substituted bicyclic compound and use thereof
WO2021098810A1 (en) Compound used as selective androgen receptor modulator

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23834888

Country of ref document: EP

Kind code of ref document: A1