WO2018086530A1 - Sulfonamide compound as cccdna inhibitor - Google Patents

Sulfonamide compound as cccdna inhibitor Download PDF

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Publication number
WO2018086530A1
WO2018086530A1 PCT/CN2017/109922 CN2017109922W WO2018086530A1 WO 2018086530 A1 WO2018086530 A1 WO 2018086530A1 CN 2017109922 W CN2017109922 W CN 2017109922W WO 2018086530 A1 WO2018086530 A1 WO 2018086530A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
pharmaceutically acceptable
group
acceptable salt
Prior art date
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PCT/CN2017/109922
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French (fr)
Chinese (zh)
Inventor
付志飞
张杨
罗妙荣
陈曙辉
黎健
徐宏江
杨玲
张喜全
Original Assignee
正大天晴药业集团股份有限公司
南京明德新药研发股份有限公司
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Application filed by 正大天晴药业集团股份有限公司, 南京明德新药研发股份有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to CN201780064038.7A priority Critical patent/CN109843855B/en
Publication of WO2018086530A1 publication Critical patent/WO2018086530A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
    • C07D231/24—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms having sulfone or sulfonic acid radicals in the molecule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/14—Nitrogen atoms not forming part of a nitro radical

Definitions

  • the present application relates to a series of sulfonamide compounds as cccDNA inhibitors.
  • the present application relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, as a cccDNA inhibitor.
  • Hepatitis B is caused by hepatitis B virus (HBV). HBV infection can not only lead to acute, chronic viral hepatitis and severe hepatitis, but also closely related to the occurrence and development of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). 20% of patients with chronic hepatitis B will develop cirrhosis, and people with chronic HBV infection will be 100 times more likely to develop HCC than normal people.
  • HBV infection can not only lead to acute, chronic viral hepatitis and severe hepatitis, but also closely related to the occurrence and development of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). 20% of patients with chronic hepatitis B will develop cirrhosis, and people with chronic HBV infection will be 100 times more likely to develop HCC than normal people.
  • LC liver cirrhosis
  • HCC hepatocellular carcinoma
  • HBV cccDNA hepatitis B virus covalently closed circular DNA
  • HBV cccDNA hepatitis B virus covalently closed circular DNA
  • interferons alpha interferon.
  • IFN- ⁇ alpha interferon- ⁇
  • HBV still has the ability to infect new hepatocytes during these antiviral treatments, and these antiviral drugs are ineffective in clearing cccDNA and are prone to relapse after discontinuation. Therefore, it is necessary to treat antiviral drugs for patients with chronic hepatitis B for a long time.
  • WO2013130703 discloses inhibitors of HBV cccDNA formation and methods of use thereof.
  • the present application provides a series of sulfonamide compounds as cccDNA inhibitors, and the compounds of the present application have a strong inhibitory effect on the formation of cccDNA, making it possible to completely cure HBV.
  • the application relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from hydrogen or methyl
  • R 2 is selected from C 1-3 alkyl
  • the C 1-3 alkyl group is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino or cyano.
  • Ring A is selected from The A ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl;
  • B ring is selected from The B ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl;
  • D is independently selected from -O-, -S-, and -NH-;
  • R 3 is selected from hydrogen and C 3-6 cycloalkyl, a C 3-6 cycloalkyl optionally substituted with one or more substituents selected from fluoro, chloro, bromo, iodo, hydroxy, amino, cyano, methyl Or a group of a trifluoromethyl group;
  • L 2 is selected from a single bond
  • L 3 is selected from a single bond or -CH 2 -;
  • L 4 is selected from
  • R 2 is selected from C 1-3 alkyl
  • the C 1-3 alkyl group is optionally substituted with three or more fluorines, Optionally substituted by one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl, preferably optionally 1, 2 or 3 Substituted from a group of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
  • R 2 is selected from C 1-3 alkyl
  • the C 1-3 alkyl group is optionally substituted by one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino or cyano, preferably optionally substituted with 3 or more fluorines, Said Optionally substituted by one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl, preferably optionally 1, 2 or 3 Substituted from a group of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
  • R 2 is selected from C 1-3 alkyl
  • the C 1-3 alkyl group is optionally substituted by one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino or cyano, preferably optionally substituted with 3 or more fluorines, Said Optionally substituted by one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl, preferably optionally 1, 2 or 3 Substituted from a group of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
  • R 2 is selected from C 1-3 alkyl
  • the C 1-3 alkyl group is optionally substituted by one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino or cyano, preferably optionally substituted with 3 or more fluorines, Said Optionally substituted by one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl, preferably optionally 1, 2 or 3 Substituted from a group of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
  • R 2 is selected from C 1-3 alkyl
  • the C 1-3 alkyl group is optionally substituted by one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino or cyano, preferably optionally substituted with 3 or more fluorines, Said Optionally substituted by one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl, preferably optionally 1, 2 or 3 Substituted from a group of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
  • R 2 is selected from C 1-3 alkyl
  • the C 1-3 alkyl group is optionally substituted by one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino or cyano, preferably optionally substituted with 3 or more fluorines, Said Optionally substituted by one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl, preferably optionally 1, 2 or 3 Substituted from a group of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
  • R 2 is selected from C 1-3 alkyl
  • the C 1-3 alkyl group is optionally substituted with one or more fluorines, preferably optionally with 3 or more fluorines, Optionally substituted by one or more groups selected from chloro, cyano or trifluoromethyl, preferably optionally 1, 2 or 3 groups selected from chloro, cyano or trifluoromethyl Replace.
  • R 2 is selected from Further preferably
  • the A ring is selected from The A ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
  • the A ring is selected from The A ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
  • the A ring is selected from The A ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
  • the A ring is selected from The A ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
  • the A ring is selected from The A ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
  • the A ring is selected from The A ring is optionally substituted with one or more groups selected from chlorine, bromine, cyano or methyl groups, more preferably, the A ring is optionally selected from one or more selected from the group consisting of chlorine, bromine or Substituted by a methyl group.
  • the A ring is selected from Further preferably
  • the B ring is selected from The B ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
  • the B ring is selected from The B ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
  • the B ring is selected from The B ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
  • the B ring is selected from The B ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
  • the B ring is selected from The B ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
  • the B ring is selected from The B ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
  • the B ring is selected from The B ring is optionally substituted with one or more fluorines.
  • the B ring is selected from Said Can be further selected from
  • R 3 is selected from hydrogen or cyclopropyl, and the cyclopropyl is optionally selected from one or more selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or The group of the trifluoromethyl group is substituted.
  • R 3 is cyclopropyl
  • L 2 is selected from a single bond or
  • L 4 is selected from
  • L 3 is -CH 2 - and L 4 is
  • L 3 is a single bond and L 4 is selected from
  • the structural unit in the compound of formula (I) Selected from among them Can be further selected from
  • the structural unit in the compound of formula (I) Selected from among them Can be further selected from
  • the structural unit in the compound of formula (I) Selected from Can be further selected from
  • the present application is directed to a compound of Formula (Ia) or a compound of Formula (Ib), or a pharmaceutically acceptable salt thereof,
  • the present application is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof,
  • R 4 is each independently selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, methyl or trifluoromethyl;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • n is selected from 1, 2 or 3.
  • R 4 is independently selected from chloro, cyano or trifluoromethyl.
  • the present application is directed to a compound of Formula (IIa) or a compound of Formula (IIb), or a pharmaceutically acceptable salt thereof,
  • the present application is directed to a compound of formula (III), or a pharmaceutically acceptable salt thereof,
  • R 2 is selected from C 1-3 alkyl, said C 1-3 alkyl optionally substituted with one or more substituents selected from fluoro, chloro, bromo, iodo, hydroxy, amino or cyano group;
  • R 5 is each independently selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • R 2 is selected from C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with one or more fluorine.
  • R 2 is selected from
  • R 5 is independently selected from chloro or bromo.
  • m is selected from 0 or 1.
  • the present application is directed to a compound of Formula (IIIa) or a compound of Formula (IIIb), or a pharmaceutically acceptable salt thereof,
  • the present application is directed to a compound of formula (IV), or a pharmaceutically acceptable salt thereof,
  • the present application is directed to a compound of Formula (IVa), a compound of Formula (IVb), a compound of Formula (IVc) or a compound of Formula (IVd), or a pharmaceutically acceptable salt thereof,
  • the present application is directed to a compound of Formula (IVe), a compound of Formula (IVf), a compound of Formula (IVg) or a compound of Formula (IVh), or a pharmaceutically acceptable salt thereof,
  • the present application relates to a compound of formula (V), or a pharmaceutically acceptable salt thereof,
  • R 1 , A ring, T and R 3 are as defined for the compound of formula (I); the definition of R 4 and n, and the structural unit The definition is the same as the compound of formula (II).
  • the present application is directed to a compound of Formula (Va), a compound of Formula (Vb), a compound of Formula (Vc) or a compound of Formula (Vd), or a pharmaceutically acceptable salt thereof,
  • the present application is directed to a compound of Formula (Ve), a compound of Formula (Vf), a compound of Formula (Vg), or a compound of Formula (Vh), or a pharmaceutically acceptable salt thereof,
  • the present application relates to a compound of formula (VI), or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , R 3 and T are as defined for the compound of formula (I); the definition of R 5 and m, and the structural unit The definition is the same as the compound of formula (III).
  • the present application is directed to a compound of Formula (VIa), a compound of Formula (VIb), a compound of Formula (VIc) or a compound of Formula (VId), or a pharmaceutically acceptable salt thereof,
  • the present application is directed to a compound of Formula (VIe), a compound of Formula (VIf), a compound of Formula (VIg), or Formula (VIh) a compound or a pharmaceutically acceptable salt thereof,
  • the present application relates to a compound of formula (VII), or a pharmaceutically acceptable salt thereof,
  • R 6 is each independently selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, methyl or trifluoromethyl;
  • p is selected from 0, 1, 2, 3 or 4;
  • R 1 , R 2 , A ring, T, R 3 , L 1 and L 4 , and structural unit The definition is the same as the compound of formula (I).
  • p is selected from 0 or 1.
  • R 6 is fluoro
  • the present application relates to a compound of formula (VIII), or a pharmaceutically acceptable salt thereof,
  • R 1 , R 3 , R 6 , p and L 4 and structural unit Definition of a compound of the same formula (VII); definition of R 4 and n, and a structural unit Definition of a compound of the same formula (II); definition of R 5 and m, and a structural unit
  • the definition is the same as the compound of formula (III).
  • n is selected from 1 or 2.
  • R 4 is independently selected from chloro, cyano or trifluoromethyl.
  • R 5 is chloro
  • n is one.
  • p is selected from 0 or 1.
  • R 6 is fluoro
  • the present application relates to the following compounds or pharmaceutically acceptable salts thereof:
  • the present application relates to a pharmaceutical composition
  • a pharmaceutical composition comprising Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (IIa), Formula (IIb), Formula (III) of the present application.
  • the pharmaceutical compositions of the present application also include pharmaceutically acceptable excipients.
  • the present application relates to a method of treating a disease mediated by a cccDNA in a mammal comprising administering to the mammal, preferably a human, in need of such treatment a therapeutically effective amount of Formula (I), Formula (Ia), Formula (Ib) , formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), formula (IIIb), formula (IV), formula (IVa), formula (IVb), formula (IVc) , formula (IVd), formula (IVe), formula (IVf), (IVg), Formula (IVh), Formula (V), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), Formula (Vf), Formula (Vg), Formula (Vh), Formula (VI), Formula (VIa), Formula (VIb), Formula (VIc), Formula (VId), Formula (VIe), Formula (VIf), Formula (VIg), Formula (VIh), Formula (VI), Formula (VIa), Formula (VIb), Formula (
  • the present application relates to formula (I), formula (Ia), formula (Ib), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), formula (IIIb) ), Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), Formula (IVf), Formula (IVg), Formula (IVh), Formula (V) ), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), Formula (Vf), Formula (Vg), Formula (Vh), Formula (VI), Formula (VIa) a compound of the formula (VIb), formula (VIc), formula (VId), formula (VIe), formula (VIf), formula (VIg), formula (VIh), formula (VII), Formula (VIa) a compound of the formula (VIb), formula (VIc), formula (VId), formula (VIe), formula (VIf), formula (VIg), formula (VIh), formula (VII) or formula (VIII) or
  • the present application relates to formula (I), formula (Ia), formula (Ib), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), formula (IIIb) ), Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), Formula (IVf), Formula (IVg), Formula (IVh), Formula (V) ), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), Formula (Vf), Formula (Vg), Formula (Vh), Formula (VI), Formula (VIa) a compound of the formula (VIb), formula (VIc), formula (VId), formula (VIe), formula (VIf), formula (VIg), formula (VIh), formula (VII), Formula (VIa) a compound of the formula (VIb), formula (VIc), formula (VId), formula (VIe), formula (VIf), formula (VIg), formula (VIh), formula (VII) or formula (VIII) or
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent as long as the valence of the particular atom is normal and the substituted compound is stable.
  • C mn herein means that the moiety has an integer number of carbon atoms in a given range.
  • C 1-3 means that the group may have 1 carbon atom, 2 carbon atoms or 3 carbon atoms
  • C 3-6 means that the group may have 3 carbon atoms and 4 carbons Atom, 5 carbon atoms or 6 carbon atoms.
  • a structural unit include or
  • variable eg, D, T or R 4
  • its definition in each case is independent.
  • hydroxy refers to an -OH group.
  • cyano refers to a -CN group.
  • amino means -NH 2 group.
  • trifluoromethyl refers to a -CF 3 group.
  • alkyl refers to a hydrocarbon group of the formula C n H 2n +.
  • the alkyl group can be straight or branched.
  • C 1 - 3 alkyl refers to alkyl groups containing 3 (e.g., methyl, ethyl, n-propyl, isopropyl) of 1 to 3 carbon atoms.
  • cycloalkyl refers to a carbocyclic ring that is fully saturated and can exist as a single ring, bridged ring or spiro ring. Unless otherwise indicated, the carbocyclic ring is typically a 3 to 10 membered ring.
  • Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, diamond Alkyl and the like.
  • treating means administering a compound or formulation described herein to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • terapéuticaally effective amount means (i) treating or preventing a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying The amount of a compound of the present application in which one or more symptoms of a particular disease, condition, or disorder are described herein.
  • the amount of a compound of the present application which constitutes a “therapeutically effective amount” depends on the compound, the state of the disease and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art Knowledge and the public Determine the content.
  • pharmaceutically acceptable is for those compounds, materials, compositions and/or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues without Many toxic, irritating, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, or the like can be mentioned.
  • pharmaceutical composition refers to a mixture of one or more compounds of the present application or a salt thereof and a pharmaceutically acceptable adjuvant.
  • the purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.
  • pharmaceutically acceptable excipient refers to those excipients which have no significant irritating effect on the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water soluble and/or water swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that are interconvertible via a low energy barrier.
  • proton tautomers also known as proton transfer tautomers
  • proton transfer tautomers include interconversions via proton transfer, such as keto-enol and imine-enamine isomerization.
  • a specific example of a proton tautomer is an imidazole moiety in which a proton can migrate between two ring nitrogens.
  • Valence tautomers include recombination through some recombination of bonding electrons.
  • the present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but in which one or more atoms are replaced by an atomic weight or mass number different from the atomic mass or mass number normally found in nature.
  • isotopes that may be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 respectively.
  • isotopically-labeled compounds of the present application can be used in compound and/or substrate tissue distribution assays.
  • the ruthenium (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred due to their ease of preparation and detectability.
  • Positron emitting isotopes such as 15 O, 13 N, 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • Isotopically labeled compounds of the present application can generally be prepared by substituting an isotopically labeled reagent for an unisotopically labeled reagent by procedures similar to those disclosed in the schemes and/or examples disclosed below.
  • substitution with heavier isotopes such as deuterium (ie, 2 H) can provide certain therapeutic advantages resulting from higher metabolic stability (eg, increased in vivo half-life or reduced dosage requirements), and thus in some cases
  • the hydrazine substitution may be partial or complete, and the partial hydrazine substitution means that at least one hydrogen is replaced by hydrazine.
  • Wedge key unless otherwise stated Represents the absolute configuration of a stereocenter.
  • the compounds of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers are included within the scope of this application, such as enantiomers and diastereomers. E.g, include also include For example, given in the embodiments of the present application described below with Representing them separately or One of them, and different from each other.
  • the asymmetric carbon atom-containing compounds of the present application can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from the racemic mixture or synthesized by using a chiral starting material or a chiral reagent.
  • compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, as solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • suitable pharmaceutically acceptable excipients for example, as solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes of administration of a compound of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present application can be produced by a method well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a sugar-coating method, a grinding method, an emulsification method, a freeze-drying method, and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical composition can be formulated by admixing the active compound with pharmaceutically acceptable excipients which are well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the active compound with a solid adjuvant, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to give tablets. Or the core of the sugar coating. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in a suitable unit dosage form.
  • the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, combinations thereof with other chemical synthesis methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the present application.
  • the compounds of formula (IV) of the present application can be prepared by those skilled in the art of organic synthesis by standard methods in the art using Route 1:
  • X is selected from halogen and may, for example, be chlorine.
  • the compounds of formula (IV) of the present application can be prepared by those skilled in the art of organic synthesis by standard methods in the art using Route 2:
  • X is selected from halogen and may, for example, be chlorine.
  • the compounds of formula (IV) of the present application can be prepared by those skilled in the art of organic synthesis by standard methods in the art using Route 3:
  • X is selected from halogen and may, for example, be chlorine.
  • the compounds of formula (IV) of the present application can be prepared by those skilled in the art of organic synthesis by standard methods in the art using Route 4:
  • X is selected from halogen and may, for example, be chlorine.
  • Compounds of formula (VIb), formula (VIc), formula (VId), formula (VIe), formula (VIf), formula (VIg) or formula (VIh) can be prepared by the methods of Schemes 1-4 above.
  • the compounds of Formula (VII) of the present application can be prepared by those skilled in the art of organic synthesis by standard methods in the art using Route 5:
  • X is selected from halogen, for example, may be chlorine; L 4 is
  • the compounds of Formula (VII) of the present application can be prepared by those skilled in the art of organic synthesis by standard methods in the art using Route 6:
  • X is selected from halogen, for example, may be chlorine; L 4 is
  • the compounds of formula (VII) herein can be prepared by those skilled in the art of organic synthesis by standard methods in the art using Route 7:
  • X is selected from halogen, for example, may be chlorine; L 4 is
  • the compounds of formula (VII) herein can be prepared by one skilled in the art of organic synthesis by standard methods in the art using Route 8:
  • X is selected from halogen, for example, may be chlorine; L 4 is R 3 is hydrogen.
  • the compounds of formula (VII) herein can be prepared by those skilled in the art of organic synthesis by standard methods in the art using Route 9:
  • X is selected from halogen, for example, may be chlorine; L 4 is In some embodiments, compounds of formula (VIII) can be prepared by the methods of Schemes 5-9 above.
  • the present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; CDI stands for carbonyl diimidazole; DCM stands for Chloroform; PE stands for petroleum ether; EA stands for ethyl acetate; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for ethyl acetate EtOH stands for ethanol; MeOH stands for methanol; CBz stands for benzyloxycarbonyl which is an
  • Step 1 Synthesis of Compound BB-3-3
  • Reference compound BB-4 was synthesized from the compound BB-4-1, BB-3-2, and the synthesis procedure of the compound BB-3 in Reference Example 3. MS (ESI) m / z: 198 [M+H] + .
  • Step 1 Synthesis of Compound BB-11-3
  • Step 1 Synthesis of Compound BB-18-2
  • Step 1 Synthesis of Compound BB-20-2
  • Step 2 Synthesis of Compound BB-20-3
  • Compound BB-22 was synthesized by the method of synthesizing compound 0493-3 with reference to the synthesis of Step 1-2 in Example 1 using Compound BB-21, Compound 0493-1 as a starting material.
  • Reference compound BB-24-1, BB-1-2 was used as a starting material, and Reference Example BB-24 was synthesized by referring to Synthesis Compound BB-1 in Reference Example 1.
  • the compound 049-25 was synthesized by the method of synthesizing the compound 0493-3 in the synthesis of the step 1-2 in Example 1.
  • the compound BB-1 was synthesized by referring to the synthesis procedure of the compound BB-1 in Reference Example 1. MS (ESI) m / z: 337[M+H] + .
  • Step 1 Synthesis of Compound 0512-2
  • Step 1 Synthesis of Compound 0517-2
  • Step 1 Synthesis of Compound 0516-2
  • Step 1 Synthesis of Compound 0500-2
  • Step 1 Synthesis of Compound 0508-2
  • Step 1 Synthesis of Compound 0523 and Compound 0524
  • Compound 0001 (i.e., compound CCC-0975 in WO2013130703A2) was synthesized by the method of WO2013130703A2.
  • Compound 0080 (i.e., compound CCC-Lu25-54 in WO2013130703A2) was synthesized by the method of WO2013130703A2.
  • a novel drug capable of inhibiting the formation of HBV cccDNA was developed through a stable cccDNA detection platform.
  • HepDES19 is a cell line derived from human hepatoma cell line HepG2, carrying the 1.1-fold DNA of the HBV genome regulated by tetracycline. This cell line is characterized by a high cccDNA content. HepDES19 cells are widely used in HBV research and anti-HBV drug testing. In the present experiment, the inhibitory activity of the test compound on the cccDNA formation process was determined by Southern blot analysis of the content of HBV cccDNA in HepDES19 cells treated with the test compound.
  • HepDES 19 cells from the American Institute of Hepatitis and Viruses
  • Cell culture medium DMEM/F12 (Invitrogen, Cat. #11330057) medium, plus 10% fetal bovine serum (FBS, Corning, Cat. #35-076-CV), 1% glutamine (Invitrogen, Cat. #25030081), 1% MEM NEAA (Invitrogen, Cat. #11140076) and 1% double antibody (penicillin 5000 IU/mL, streptomycin 10 mg/mL, Hyclone, Cat. #SV30010).
  • FBS fetal bovine serum
  • FBS fetal bovine serum
  • glutamine Invitrogen, Cat. #25030081
  • MEM NEAA Invitrogen, Cat. #11140076
  • double antibody penicillin 5000 IU/mL, streptomycin 10 mg/mL, Hyclone, Cat. #SV30010
  • Tetracycline hydrochloride (Sigma, Cat. #T7660).
  • RNase A (Sigma, Cat. #R4642).
  • Phenol chloroform isoprene glycol Biotech, Cat. #PD0419-1).
  • Southern neutralizing solution (1 M Tris. HCl, pH 7.4 and 1.5 M NaCl).
  • HepDES19 cells were cultured in DMEM/F12 medium containing 10% serum and 1 ng/ml tetracycline. When the cell confluence in the logarithmic growth phase reached 80% or more, it was digested with trypsin, resuspended in DMEM/F12 medium containing 2% serum and removed with tetracycline, and counted in each well of a 12-well cell culture plate. 2.5 x 10 5 HepDES19 cells were added and cultured overnight at 37 ° C, 5% CO 2 . On day 2, cells in a 12-well plate were treated with a concentration of compound diluted with DMSO, and a DMSO well containing no compound was used as a control.
  • step 1 The cells collected in step 1 were lysed with 1 ml of lysate (containing 10 mmol/L Triza, 10 mmol/L EDTA and 0.7% SDS) at room temperature for 30 minutes, and then added to a concentration of 0.24 ml of 5 mol/ The sodium chloride solution was incubated overnight at 4 °C. On the next day, after centrifugation at 12,000 ⁇ g for 30 minutes at 4 ° C, 900 ⁇ l of the supernatant was transferred to a new centrifuge tube, and 3 ⁇ l of a 10 mg/ml RNase A solution was added and incubated at 37 ° C for 1 hour. Remove RNA.
  • lysate containing 10 mmol/L Triza, 10 mmol/L EDTA and 0.7% SDS
  • the above solution was extracted three times with 900 ⁇ l of a mixed solvent of phenol:chloroform:isoprenediol (three in a volume ratio of 25:24:1), and then 0.7 times by volume of isopropanol and 5 ⁇ l of glycoblue were added.
  • the precipitant was thoroughly mixed and allowed to stand at room temperature for 1 hour. 12,000 x g was centrifuged at 4 ° C for 30 minutes to precipitate DNA. The supernatant was discarded, washed twice with 1 ml of 70% ethanol, excess ethanol was discarded, dried at room temperature, and the resulting DNA pellet was dissolved in 30 ⁇ l of TE.
  • the gel was immersed in 250 mmol/L hydrochloric acid, shaken for 7 minutes on a shaker to dissociate the DNA, and washed with distilled water for several seconds with a denaturing solution (containing 0.5 mol/L sodium hydroxide and 1.5 mol/L).
  • a denaturing solution containing 0.5 mol/L sodium hydroxide and 1.5 mol/L.
  • Sodium chloride denatured for 30 minutes, washed with distilled water for several seconds, neutralized with a neutralizing solution (containing 1 mol/L Tris hydrochloric acid and 1.5 mol/L sodium chloride, pH 7.4) for 30 minutes, washed with distilled water and condensed.
  • the DNA on the gel was transferred to the solid phase nylon membrane by capillary siphon blotting.
  • the nylon membrane was taken out, immersed in 2 ⁇ SSC solution for several minutes after UV crosslinking, and the membrane was placed on a filter paper to be dried.
  • the membrane was then placed in a hybridization flask, 10 ml of the hybridization solution was added, and the hybridization solution was pre-hybridized at 60 ° C for 1 hour, and the hybridization solution containing the probe labeled with digoxin was added to hybridize overnight.
  • 2 ⁇ SSC, 0.1% SDS was washed at room temperature for 2 ⁇ 5 minutes, then washed with 0.1 ⁇ SSC, 0.1% SDS at 60° C. for 3 ⁇ 20 minutes, and then the membrane was quickly washed with 1 ⁇ maleic acid 2 ⁇ 5. minute.
  • the antibody dilution was incubated for 30 minutes. After washing the cleaning solution for 3 ⁇ 15 minutes, CDP-star was added, the film was exposed and developed in a dark room, the exposure time was controlled, the exposed film was dried, and the DNA band was analyzed by scanning with a scanner.
  • the film was scanned into a picture format by a scanner, and the inhibition effect of the compound on cccDNA was judged by directly observing the strength of the cccDNA band in the picture.
  • the experimental results are shown in Table 6.
  • the activity values indicate the lowest concentration that can exhibit an inhibitory effect on cccDNA at a given test concentration, and the inhibitory effect at a specific concentration is judged by observing the strength of the cccDNA band by comparison with the DMSO control.
  • the compound of the present invention has a good inhibitory effect on the formation of hepatitis B virus cccDNA
  • the compounds of the invention have good ADME and PK properties.

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Abstract

Provided is a series of sulfonamide compounds as a cccDNA inhibitor. Particularly, the present invention relates to a compound represented by formula (I) as a cccDNA inhibitor or a pharmaceutically acceptable salt thereof.

Description

作为cccDNA抑制剂的磺酰胺类化合物Sulfonamides as cccDNA inhibitors
相关申请的引用Reference to related application
本申请要求于2016年11月08日向中华人民共和国知识产权局提交的申请号为CN201610980092.3的中国发明专利申请的权益，该中国发明专利申请通过援引整体上并入本申请。The present application claims the benefit of the Chinese Patent Application Serial No. CN201610980092.3, filed on November 8, 2016, the disclosure of which is hereby incorporated by reference.
技术领域Technical field
本申请涉及一系列作为cccDNA抑制剂的磺酰胺类化合物。具体地，本申请涉及作为cccDNA抑制剂的式(Ⅰ)化合物或其药学上可接受的盐。The present application relates to a series of sulfonamide compounds as cccDNA inhibitors. In particular, the present application relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, as a cccDNA inhibitor.
背景技术Background technique
乙型病毒性肝炎(hepatitis B,HB)是由乙型肝炎病毒(hepatitis B virus,HBV)引起的。HBV的感染不仅可以导致急性、慢性病毒性肝炎和重型肝炎，而且还与肝硬化(liver cirrhosis,LC)和肝细胞癌(hepatocellular carcinoma,HCC)的发生、发展密切相关。20﹪的慢性乙肝患者将发展成为肝硬化，HBV慢性感染的人罹患HCC的危险性是正常人的100倍。Hepatitis B (HB) is caused by hepatitis B virus (HBV). HBV infection can not only lead to acute, chronic viral hepatitis and severe hepatitis, but also closely related to the occurrence and development of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). 20% of patients with chronic hepatitis B will develop cirrhosis, and people with chronic HBV infection will be 100 times more likely to develop HCC than normal people.
HBV cccDNA(乙型肝炎病毒共价闭合环状DNA)存在于肝细胞核内，是病毒成功感染肝细胞的标志，也是慢性乙型肝炎持久存在的关键。HBV cccDNA (hepatitis B virus covalently closed circular DNA) is present in the nucleus of hepatocytes, which is a sign that the virus successfully infects hepatocytes and is also the key to the persistence of chronic hepatitis B.
到目前为止，获得美国食品与药物管理局(Food and Drug Administration,FDA)批准并在临床应用的抗HBV药物有两大类：干扰素及核苷类似物，它们的代表药物分别是α干扰素(interferon-α,IFN-α)及拉米夫定(Lamivudine,3CT)。So far, there have been two major categories of anti-HBV drugs approved by the US Food and Drug Administration (FDA) and used in clinical applications: interferons and nucleoside analogues. Their representative drugs are alpha interferon. (interferon-α, IFN-α) and lamivudine (3CT).
一般认为α干扰素和拉米夫定均不能清除细胞内HBV cccDNA，在这些抗病毒药物治疗期间HBV仍有能力感染新的肝细胞，并且这些抗病毒药物对清除cccDNA无效，停药后容易复发，因而需要对慢乙肝患者长期使用抗病毒药物治疗。It is generally believed that both alpha interferon and lamivudine cannot clear intracellular HBV cccDNA. HBV still has the ability to infect new hepatocytes during these antiviral treatments, and these antiviral drugs are ineffective in clearing cccDNA and are prone to relapse after discontinuation. Therefore, it is necessary to treat antiviral drugs for patients with chronic hepatitis B for a long time.
WO2013130703公开了HBV cccDNA形成的抑制剂及其使用方法。本申请提供了一系列作为cccDNA抑制剂的磺酰胺类化合物，本申请的化合物对cccDNA的形成有强烈抑制作用，使彻底治愈HBV成为可能。WO2013130703 discloses inhibitors of HBV cccDNA formation and methods of use thereof. The present application provides a series of sulfonamide compounds as cccDNA inhibitors, and the compounds of the present application have a strong inhibitory effect on the formation of cccDNA, making it possible to completely cure HBV.
发明内容Summary of the invention
一方面，本申请涉及式(Ⅰ)化合物或其药学上可接受的盐，In one aspect, the application relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof,
Figure PCTCN2017109922-appb-000001
Figure PCTCN2017109922-appb-000001
其中，among them,
R1选自氢或甲基；R 1 is selected from hydrogen or methyl;
R2选自C1-3烷基、
Figure PCTCN2017109922-appb-000002
所述C1-3烷基任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基或氰基的基团取代，所述
Figure PCTCN2017109922-appb-000003
任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代； R 2 is selected from C 1-3 alkyl,
Figure PCTCN2017109922-appb-000002
The C 1-3 alkyl group is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino or cyano.
Figure PCTCN2017109922-appb-000003
Optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl;
A环选自
Figure PCTCN2017109922-appb-000004
所述A环任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代；Ring A is selected from
Figure PCTCN2017109922-appb-000004
The A ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl;
B环选自
Figure PCTCN2017109922-appb-000005
所述B环任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代；B ring is selected from
Figure PCTCN2017109922-appb-000005
The B ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl;
D分别独立地选自-O-、-S-和-NH-；D is independently selected from -O-, -S-, and -NH-;
T分别独立地选自-CH＝和-N＝；T is independently selected from -CH= and -N=;
R3选自氢和C3-6环烷基，所述C3-6环烷基任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代；R 3 is selected from hydrogen and C 3-6 cycloalkyl, a C 3-6 cycloalkyl optionally substituted with one or more substituents selected from fluoro, chloro, bromo, iodo, hydroxy, amino, cyano, methyl Or a group of a trifluoromethyl group;
L1选自-C(＝O)-或-S(＝O)2-；L 1 is selected from -C(=O)- or -S(=O) 2 -;
L2选自单键、
Figure PCTCN2017109922-appb-000006
L 2 is selected from a single bond,
Figure PCTCN2017109922-appb-000006
L3选自单键或-CH2-；L 3 is selected from a single bond or -CH 2 -;
L4选自
Figure PCTCN2017109922-appb-000007
Figure PCTCN2017109922-appb-000008
L 4 is selected from
Figure PCTCN2017109922-appb-000007
Figure PCTCN2017109922-appb-000008
在一些实施方案中，R2选自C1-3烷基、
Figure PCTCN2017109922-appb-000009
所述C1-3烷基任选地被三个以上的氟取代，所述
Figure PCTCN2017109922-appb-000010
任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代，优选为任选地被1、2或3个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代。In some embodiments, R 2 is selected from C 1-3 alkyl,
Figure PCTCN2017109922-appb-000009
The C 1-3 alkyl group is optionally substituted with three or more fluorines,
Figure PCTCN2017109922-appb-000010
Optionally substituted by one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl, preferably optionally 1, 2 or 3 Substituted from a group of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
在一些实施方案中，R2选自C1-3烷基、
Figure PCTCN2017109922-appb-000011
所述C1-3烷基任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基或氰基的基团取代，优选为任选地被3个以上的氟取代，所述
Figure PCTCN2017109922-appb-000012
任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代，优选为任选地被1、2或3个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代。 In some embodiments, R 2 is selected from C 1-3 alkyl,
Figure PCTCN2017109922-appb-000011
The C 1-3 alkyl group is optionally substituted by one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino or cyano, preferably optionally substituted with 3 or more fluorines, Said
Figure PCTCN2017109922-appb-000012
Optionally substituted by one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl, preferably optionally 1, 2 or 3 Substituted from a group of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
在一些优选实施方案中，R2选自C1-3烷基、
Figure PCTCN2017109922-appb-000013
所述C1-3烷基任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基或氰基的基团取代，优选为任选地被3个以上的氟取代，所述
Figure PCTCN2017109922-appb-000014
Figure PCTCN2017109922-appb-000015
任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代，优选为任选地被1、2或3个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代。In some preferred embodiments, R 2 is selected from C 1-3 alkyl,
Figure PCTCN2017109922-appb-000013
The C 1-3 alkyl group is optionally substituted by one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino or cyano, preferably optionally substituted with 3 or more fluorines, Said
Figure PCTCN2017109922-appb-000014
Figure PCTCN2017109922-appb-000015
Optionally substituted by one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl, preferably optionally 1, 2 or 3 Substituted from a group of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
在一些优选实施方案中，R2选自C1-3烷基、
Figure PCTCN2017109922-appb-000016
所述C1-3烷基任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基或氰基的基团取代，优选为任选地被3个以上的氟取代，所述
Figure PCTCN2017109922-appb-000017
任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代，优选为任选地被1、2或3个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代。In some preferred embodiments, R 2 is selected from C 1-3 alkyl,
Figure PCTCN2017109922-appb-000016
The C 1-3 alkyl group is optionally substituted by one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino or cyano, preferably optionally substituted with 3 or more fluorines, Said
Figure PCTCN2017109922-appb-000017
Optionally substituted by one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl, preferably optionally 1, 2 or 3 Substituted from a group of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
在一些优选实施方案中，R2选自C1-3烷基、
Figure PCTCN2017109922-appb-000018
所述C1-3烷基任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基或氰基的基团取代，优选为任选地被3个以上的氟取代，所述
Figure PCTCN2017109922-appb-000019
任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代，优选为任选地被1、2或3个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代。In some preferred embodiments, R 2 is selected from C 1-3 alkyl,
Figure PCTCN2017109922-appb-000018
The C 1-3 alkyl group is optionally substituted by one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino or cyano, preferably optionally substituted with 3 or more fluorines, Said
Figure PCTCN2017109922-appb-000019
Optionally substituted by one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl, preferably optionally 1, 2 or 3 Substituted from a group of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
在一些更优选的实施方案中，R2选自C1-3烷基、
Figure PCTCN2017109922-appb-000020
所述C1-3烷基任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基或氰基的基团取代，优选为任选地被3个以上的氟取代，所述
Figure PCTCN2017109922-appb-000021
任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代，优选为任选地被1、2或3个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲 基的基团取代。In some more preferred embodiments, R 2 is selected from C 1-3 alkyl,
Figure PCTCN2017109922-appb-000020
The C 1-3 alkyl group is optionally substituted by one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino or cyano, preferably optionally substituted with 3 or more fluorines, Said
Figure PCTCN2017109922-appb-000021
Optionally substituted by one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl, preferably optionally 1, 2 or 3 Substituted from a group of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
在一些更优选的实施方案中，R2选自C1-3烷基、
Figure PCTCN2017109922-appb-000022
所述C1-3烷基任选地被一个或多个氟取代，优选为任选地被3个以上的氟取代，所述
Figure PCTCN2017109922-appb-000023
任选地被一个或多个选自氯、氰基或三氟甲基的基团取代，优选为任选地被1、2或3个选自氯、氰基或三氟甲基的基团取代。In some more preferred embodiments, R 2 is selected from C 1-3 alkyl,
Figure PCTCN2017109922-appb-000022
The C 1-3 alkyl group is optionally substituted with one or more fluorines, preferably optionally with 3 or more fluorines,
Figure PCTCN2017109922-appb-000023
Optionally substituted by one or more groups selected from chloro, cyano or trifluoromethyl, preferably optionally 1, 2 or 3 groups selected from chloro, cyano or trifluoromethyl Replace.
在一些更优选的实施方案中，R2选自
Figure PCTCN2017109922-appb-000024
Figure PCTCN2017109922-appb-000025
进一步优选为
Figure PCTCN2017109922-appb-000026
In some more preferred embodiments, R 2 is selected from
Figure PCTCN2017109922-appb-000024
Figure PCTCN2017109922-appb-000025
Further preferably
Figure PCTCN2017109922-appb-000026
在一些实施方案中，A环选自
Figure PCTCN2017109922-appb-000027
所述A环任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代。In some embodiments, the A ring is selected from
Figure PCTCN2017109922-appb-000027
The A ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
在一些优选实施方案中，A环选自
Figure PCTCN2017109922-appb-000028
所述A环任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代。In some preferred embodiments, the A ring is selected from
Figure PCTCN2017109922-appb-000028
The A ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
在一些优选实施方案中，A环选自
Figure PCTCN2017109922-appb-000029
所述A环任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代。In some preferred embodiments, the A ring is selected from
Figure PCTCN2017109922-appb-000029
The A ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
在一些更优选实施方案中，A环选自
Figure PCTCN2017109922-appb-000030
所述A环任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代。In some more preferred embodiments, the A ring is selected from
Figure PCTCN2017109922-appb-000030
The A ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
在一些更优选实施方案中，A环选自
Figure PCTCN2017109922-appb-000031
Figure PCTCN2017109922-appb-000032
所述A环任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代。In some more preferred embodiments, the A ring is selected from
Figure PCTCN2017109922-appb-000031
Figure PCTCN2017109922-appb-000032
The A ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
在一些更优选实施方案中，A环选自
Figure PCTCN2017109922-appb-000033
Figure PCTCN2017109922-appb-000034
所述A环任选地被一个或多个选自氯、溴、氰基或甲基的基团取代，更优选地，所述A环任选地被一个或多个选自氯、溴或甲基的基团取代。In some more preferred embodiments, the A ring is selected from
Figure PCTCN2017109922-appb-000033
Figure PCTCN2017109922-appb-000034
The A ring is optionally substituted with one or more groups selected from chlorine, bromine, cyano or methyl groups, more preferably, the A ring is optionally selected from one or more selected from the group consisting of chlorine, bromine or Substituted by a methyl group.
在一些更优选实施方案中，A环选自
Figure PCTCN2017109922-appb-000035
Figure PCTCN2017109922-appb-000036
进一步优选为
Figure PCTCN2017109922-appb-000037
In some more preferred embodiments, the A ring is selected from
Figure PCTCN2017109922-appb-000035
Figure PCTCN2017109922-appb-000036
Further preferably
Figure PCTCN2017109922-appb-000037
在一些更优选实施方案中，结构单元
Figure PCTCN2017109922-appb-000038
选自
Figure PCTCN2017109922-appb-000039
Figure PCTCN2017109922-appb-000040
Figure PCTCN2017109922-appb-000041
进一步优选为
Figure PCTCN2017109922-appb-000042
In some more preferred embodiments, the structural unit
Figure PCTCN2017109922-appb-000038
Selected from
Figure PCTCN2017109922-appb-000039
Figure PCTCN2017109922-appb-000040
Figure PCTCN2017109922-appb-000041
Further preferably
Figure PCTCN2017109922-appb-000042
在一些优选实施方案中，B环选自
Figure PCTCN2017109922-appb-000043
所述B环任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代。In some preferred embodiments, the B ring is selected from
Figure PCTCN2017109922-appb-000043
The B ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
在一些优选实施方案中，B环选自
Figure PCTCN2017109922-appb-000044
所述B环任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代。In some preferred embodiments, the B ring is selected from
Figure PCTCN2017109922-appb-000044
The B ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
在一些优选实施方案中，B环选自
Figure PCTCN2017109922-appb-000045
所述B环任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代。In some preferred embodiments, the B ring is selected from
Figure PCTCN2017109922-appb-000045
The B ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
在一些优选实施方案中，B环选自
Figure PCTCN2017109922-appb-000046
所述B环任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代。 In some preferred embodiments, the B ring is selected from
Figure PCTCN2017109922-appb-000046
The B ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
在一些优选实施方案中，B环选自
Figure PCTCN2017109922-appb-000047
所述B环任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代。In some preferred embodiments, the B ring is selected from
Figure PCTCN2017109922-appb-000047
The B ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
在一些更优选实施方案中，B环选自
Figure PCTCN2017109922-appb-000048
所述B环任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代。In some more preferred embodiments, the B ring is selected from
Figure PCTCN2017109922-appb-000048
The B ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
在一些更优选实施方案中，B环选自
Figure PCTCN2017109922-appb-000049
所述B环任选地被一个或多个氟取代。In some more preferred embodiments, the B ring is selected from
Figure PCTCN2017109922-appb-000049
The B ring is optionally substituted with one or more fluorines.
在一些更优选实施方案中，B环选自
Figure PCTCN2017109922-appb-000050
所述
Figure PCTCN2017109922-appb-000051
可进一步选自
Figure PCTCN2017109922-appb-000052
In some more preferred embodiments, the B ring is selected from
Figure PCTCN2017109922-appb-000050
Said
Figure PCTCN2017109922-appb-000051
Can be further selected from
Figure PCTCN2017109922-appb-000052
在一些优选实施方案中，R3选自氢或环丙基，所述环丙基任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代。In some preferred embodiments, R 3 is selected from hydrogen or cyclopropyl, and the cyclopropyl is optionally selected from one or more selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or The group of the trifluoromethyl group is substituted.
在一些更优选实施方案中，R3为环丙基。In some more preferred embodiments, R 3 is cyclopropyl.
在一些优选实施方案中，L2选自单键或
Figure PCTCN2017109922-appb-000053
In some preferred embodiments, L 2 is selected from a single bond or
Figure PCTCN2017109922-appb-000053
在一些优选实施方案中，L4选自
Figure PCTCN2017109922-appb-000054
In some preferred embodiments, L 4 is selected from
Figure PCTCN2017109922-appb-000054
在一些优选实施方案中，L1为-C(＝O)-，且L2为单键。In some preferred embodiments, L 1 is -C(=O)- and L 2 is a single bond.
在一些优选实施方案中，L1为-S(＝O)2-，且L2选自单键或
Figure PCTCN2017109922-appb-000055
In some preferred embodiments, L 1 is -S(=O) 2 -, and L 2 is selected from a single bond or
Figure PCTCN2017109922-appb-000055
在一些优选实施方案中，L3为-CH2-，且L4为
Figure PCTCN2017109922-appb-000056
In some preferred embodiments, L 3 is -CH 2 - and L 4 is
Figure PCTCN2017109922-appb-000056
在一些优选实施方案中，L3为单键，且L4选自
Figure PCTCN2017109922-appb-000057
In some preferred embodiments, L 3 is a single bond and L 4 is selected from
Figure PCTCN2017109922-appb-000057
在一些优选实施方案中，式(Ⅰ)化合物中结构单元
Figure PCTCN2017109922-appb-000058
选自
Figure PCTCN2017109922-appb-000059
Figure PCTCN2017109922-appb-000060
In some preferred embodiments, the structural unit in the compound of formula (I)
Figure PCTCN2017109922-appb-000058
Selected from
Figure PCTCN2017109922-appb-000059
Figure PCTCN2017109922-appb-000060
在一些更优选实施方案中，式(Ⅰ)化合物中结构单元
Figure PCTCN2017109922-appb-000061
选自
Figure PCTCN2017109922-appb-000062
Figure PCTCN2017109922-appb-000063
其中
Figure PCTCN2017109922-appb-000064
可进一步选自
Figure PCTCN2017109922-appb-000065
In some more preferred embodiments, the structural unit in the compound of formula (I)
Figure PCTCN2017109922-appb-000061
Selected from
Figure PCTCN2017109922-appb-000062
Figure PCTCN2017109922-appb-000063
among them
Figure PCTCN2017109922-appb-000064
Can be further selected from
Figure PCTCN2017109922-appb-000065
在一些更优选实施方案中，式(Ⅰ)化合物中结构单元
Figure PCTCN2017109922-appb-000066
选自
Figure PCTCN2017109922-appb-000067
Figure PCTCN2017109922-appb-000068
In some more preferred embodiments, the structural unit in the compound of formula (I)
Figure PCTCN2017109922-appb-000066
Selected from
Figure PCTCN2017109922-appb-000067
Figure PCTCN2017109922-appb-000068
在一些更优选实施方案中，式(Ⅰ)化合物中结构单元
Figure PCTCN2017109922-appb-000069
选自
Figure PCTCN2017109922-appb-000070
Figure PCTCN2017109922-appb-000071
其中
Figure PCTCN2017109922-appb-000072
可进一步选自
Figure PCTCN2017109922-appb-000073
In some more preferred embodiments, the structural unit in the compound of formula (I)
Figure PCTCN2017109922-appb-000069
Selected from
Figure PCTCN2017109922-appb-000070
Figure PCTCN2017109922-appb-000071
among them
Figure PCTCN2017109922-appb-000072
Can be further selected from
Figure PCTCN2017109922-appb-000073
在一些更优选实施方案中，式(Ⅰ)化合物中结构单元
Figure PCTCN2017109922-appb-000074
选自
Figure PCTCN2017109922-appb-000075
Figure PCTCN2017109922-appb-000076
可进一步选自
Figure PCTCN2017109922-appb-000077
In some more preferred embodiments, the structural unit in the compound of formula (I)
Figure PCTCN2017109922-appb-000074
Selected from
Figure PCTCN2017109922-appb-000075
Figure PCTCN2017109922-appb-000076
Can be further selected from
Figure PCTCN2017109922-appb-000077
在一些实施方案中，本申请涉及式(Ⅰa)化合物或式(Ⅰb)化合物或其药学上可接受的盐，In some embodiments, the present application is directed to a compound of Formula (Ia) or a compound of Formula (Ib), or a pharmaceutically acceptable salt thereof,
Figure PCTCN2017109922-appb-000078
Figure PCTCN2017109922-appb-000078
其中，among them,
R1、R2、A环、B环、R3、L1、L2、L3和L4的定义，以及结构单元
Figure PCTCN2017109922-appb-000079
Figure PCTCN2017109922-appb-000080
的定义同式(Ⅰ)化合物。Definitions of R 1 , R 2 , A ring, B ring, R 3 , L 1 , L 2 , L 3 and L 4 , and structural units
Figure PCTCN2017109922-appb-000079
Figure PCTCN2017109922-appb-000080
The definition is the same as the compound of formula (I).
在一些实施方案中，本申请涉及式(Ⅱ)化合物或其药学上可接受的盐，In some embodiments, the present application is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof,
Figure PCTCN2017109922-appb-000081
Figure PCTCN2017109922-appb-000081
其中，among them,
R4分别独立地选自氟、氯、溴、碘、氰基、甲基或三氟甲基；R 4 is each independently selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, methyl or trifluoromethyl;
n选自0、1、2、3、4或5； n is selected from 0, 1, 2, 3, 4 or 5;
R1、A环、B环、T、R3、L2、L3和L4的定义，以及结构单元
Figure PCTCN2017109922-appb-000082
Figure PCTCN2017109922-appb-000083
的定义同式(Ⅰ)化合物。Definition of R 1 , A ring, B ring, T, R 3 , L 2 , L 3 and L 4 , and structural unit
Figure PCTCN2017109922-appb-000082
Figure PCTCN2017109922-appb-000083
The definition is the same as the compound of formula (I).
在一些实施方案中，结构单元
Figure PCTCN2017109922-appb-000084
选自
Figure PCTCN2017109922-appb-000085
In some embodiments, the structural unit
Figure PCTCN2017109922-appb-000084
Selected from
Figure PCTCN2017109922-appb-000085
在一些优选实施方案中，n选自1、2或3。In some preferred embodiments, n is selected from 1, 2 or 3.
在一些优选实施方案中，R4分别独立地选自氯、氰基或三氟甲基。In some preferred embodiments, R 4 is independently selected from chloro, cyano or trifluoromethyl.
在一些更优选的实施方案中，结构单元
Figure PCTCN2017109922-appb-000086
选自
Figure PCTCN2017109922-appb-000087
Figure PCTCN2017109922-appb-000088
In some more preferred embodiments, the structural unit
Figure PCTCN2017109922-appb-000086
Selected from
Figure PCTCN2017109922-appb-000087
Figure PCTCN2017109922-appb-000088
在一些实施方案中，本申请涉及式(Ⅱa)化合物或式(Ⅱb)化合物或其药学上可接受的盐，In some embodiments, the present application is directed to a compound of Formula (IIa) or a compound of Formula (IIb), or a pharmaceutically acceptable salt thereof,
Figure PCTCN2017109922-appb-000089
Figure PCTCN2017109922-appb-000089
其中，among them,
R1、R4、n、A环、B环、T、R3、L2、L3和L4的定义，以及结构单元
Figure PCTCN2017109922-appb-000090
Figure PCTCN2017109922-appb-000091
的定义同式(Ⅱ)化合物。Definitions of R 1 , R 4 , n, A ring, B ring, T, R 3 , L 2 , L 3 and L 4 , and structural units
Figure PCTCN2017109922-appb-000090
Figure PCTCN2017109922-appb-000091
The definition is the same as the compound of formula (II).
在一些实施方案中，本申请涉及式(Ⅲ)化合物或其药学上可接受的盐， In some embodiments, the present application is directed to a compound of formula (III), or a pharmaceutically acceptable salt thereof,
Figure PCTCN2017109922-appb-000092
Figure PCTCN2017109922-appb-000092
其中，among them,
R2选自C1-3烷基，所述C1-3烷基任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基或氰基的基团取代；R 2 is selected from C 1-3 alkyl, said C 1-3 alkyl optionally substituted with one or more substituents selected from fluoro, chloro, bromo, iodo, hydroxy, amino or cyano group;
R5分别独立地选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基；R 5 is each independently selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl;
m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
R1、B环、T、R3、L2、L3和L4的定义，以及结构单元
Figure PCTCN2017109922-appb-000093
Figure PCTCN2017109922-appb-000094
的定义同式(Ⅰ)化合物。Definition of R 1 , B ring, T, R 3 , L 2 , L 3 and L 4 , and structural unit
Figure PCTCN2017109922-appb-000093
Figure PCTCN2017109922-appb-000094
The definition is the same as the compound of formula (I).
在一些优选的实施方案中，R2选自C1-3烷基，所述C1-3烷基任选地被一个或多个氟取代。In some preferred embodiments, R 2 is selected from C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with one or more fluorine.
在一些更优选的实施方案中，R2选自
Figure PCTCN2017109922-appb-000095
In some more preferred embodiments, R 2 is selected from
Figure PCTCN2017109922-appb-000095
在一些实施方案中，结构单元
Figure PCTCN2017109922-appb-000096
选自
Figure PCTCN2017109922-appb-000097
优选为
Figure PCTCN2017109922-appb-000098
In some embodiments, the structural unit
Figure PCTCN2017109922-appb-000096
Selected from
Figure PCTCN2017109922-appb-000097
Preferred
Figure PCTCN2017109922-appb-000098
在一些优选的实施方案中，R5分别独立地选自氯或溴。In some preferred embodiments, R 5 is independently selected from chloro or bromo.
在一些优选的实施方案中，m选自0或1。In some preferred embodiments, m is selected from 0 or 1.
在一些更优选的实施方案中，结构单元
Figure PCTCN2017109922-appb-000099
In some more preferred embodiments, the structural unit
Figure PCTCN2017109922-appb-000099
在一些实施方案中，本申请涉及式(Ⅲa)化合物或式(Ⅲb)化合物或其药学上可接受的盐， In some embodiments, the present application is directed to a compound of Formula (IIIa) or a compound of Formula (IIIb), or a pharmaceutically acceptable salt thereof,
Figure PCTCN2017109922-appb-000100
Figure PCTCN2017109922-appb-000100
其中，among them,
R1、R2、B环、T、R5、m、R3、L2、L3和L4的定义，以及结构单元
Figure PCTCN2017109922-appb-000101
Figure PCTCN2017109922-appb-000102
的定义同式(Ⅲ)化合物。Definition of R 1 , R 2 , B ring, T, R 5 , m, R 3 , L 2 , L 3 and L 4 , and structural unit
Figure PCTCN2017109922-appb-000101
Figure PCTCN2017109922-appb-000102
The definition is the same as the compound of formula (III).
在一些实施方案中，本申请涉及式(Ⅳ)化合物或其药学上可接受的盐，In some embodiments, the present application is directed to a compound of formula (IV), or a pharmaceutically acceptable salt thereof,
Figure PCTCN2017109922-appb-000103
Figure PCTCN2017109922-appb-000103
其中，among them,
R1、R2、A环、R3和L1的定义，以及结构单元
Figure PCTCN2017109922-appb-000104
的定义同式(Ⅰ)化合物。Definition of R 1 , R 2 , A ring, R 3 and L 1 , and structural unit
Figure PCTCN2017109922-appb-000104
The definition is the same as the compound of formula (I).
在一些实施方案中，本申请涉及式(Ⅳa)化合物、式(Ⅳb)化合物、式(Ⅳc)化合物或式(Ⅳd)化合物或其药学上可接受的盐，In some embodiments, the present application is directed to a compound of Formula (IVa), a compound of Formula (IVb), a compound of Formula (IVc) or a compound of Formula (IVd), or a pharmaceutically acceptable salt thereof,
Figure PCTCN2017109922-appb-000105
Figure PCTCN2017109922-appb-000105
其中，among them,
R1、R2、A环、R3和L1的定义，以及结构单元
Figure PCTCN2017109922-appb-000106
的定义同式(Ⅳ)化合物。Definition of R 1 , R 2 , A ring, R 3 and L 1 , and structural unit
Figure PCTCN2017109922-appb-000106
The definition is the same as the compound of formula (IV).
在一些实施方案中，本申请涉及式(Ⅳe)化合物、式(Ⅳf)化合物、式(Ⅳg)化合物或式(Ⅳh)化合物或其药学上可接受的盐，In some embodiments, the present application is directed to a compound of Formula (IVe), a compound of Formula (IVf), a compound of Formula (IVg) or a compound of Formula (IVh), or a pharmaceutically acceptable salt thereof,
Figure PCTCN2017109922-appb-000107
Figure PCTCN2017109922-appb-000107
其中，among them,
R1、R2、A环、R3和L1的定义，以及结构单元
Figure PCTCN2017109922-appb-000108
的定义同式(Ⅳ)化合物。Definition of R 1 , R 2 , A ring, R 3 and L 1 , and structural unit
Figure PCTCN2017109922-appb-000108
The definition is the same as the compound of formula (IV).
在一些实施方案中，本申请涉及一种式(Ⅴ)化合物或其药学上可接受的盐，In some embodiments, the present application relates to a compound of formula (V), or a pharmaceutically acceptable salt thereof,
Figure PCTCN2017109922-appb-000109
Figure PCTCN2017109922-appb-000109
其中，among them,
R1、A环、T和R3的定义同式(Ⅰ)化合物；R4和n的定义，以及结构单元
Figure PCTCN2017109922-appb-000110
的定义同式(Ⅱ)化合物。R 1 , A ring, T and R 3 are as defined for the compound of formula (I); the definition of R 4 and n, and the structural unit
Figure PCTCN2017109922-appb-000110
The definition is the same as the compound of formula (II).
在一些实施方案中，本申请涉及式(Ⅴa)化合物、式(Ⅴb)化合物、式(Ⅴc)化合物或式(Ⅴd)化合物或其药学上可接受的盐， In some embodiments, the present application is directed to a compound of Formula (Va), a compound of Formula (Vb), a compound of Formula (Vc) or a compound of Formula (Vd), or a pharmaceutically acceptable salt thereof,
Figure PCTCN2017109922-appb-000111
Figure PCTCN2017109922-appb-000111
其中，among them,
R1、A环、T、R3、R4和n的定义，以及结构单元
Figure PCTCN2017109922-appb-000112
的定义同式(Ⅴ)化合物。Definition of R 1 , A ring, T, R 3 , R 4 and n, and structural unit
Figure PCTCN2017109922-appb-000112
The definition of a compound of the same formula (V).
在一些实施方案中，本申请涉及式(Ⅴe)化合物、式(Ⅴf)化合物、式(Ⅴg)化合物或式(Ⅴh)化合物或其药学上可接受的盐，In some embodiments, the present application is directed to a compound of Formula (Ve), a compound of Formula (Vf), a compound of Formula (Vg), or a compound of Formula (Vh), or a pharmaceutically acceptable salt thereof,
Figure PCTCN2017109922-appb-000113
Figure PCTCN2017109922-appb-000113
其中，among them,
R1、A环、T、R3、R4和n的定义，以及结构单元
Figure PCTCN2017109922-appb-000114
的定义同式(Ⅴ)化合物。 Definition of R 1 , A ring, T, R 3 , R 4 and n, and structural unit
Figure PCTCN2017109922-appb-000114
The definition of a compound of the same formula (V).
在一些实施方案中，本申请涉及一种式(Ⅵ)化合物或其药学上可接受的盐，In some embodiments, the present application relates to a compound of formula (VI), or a pharmaceutically acceptable salt thereof,
Figure PCTCN2017109922-appb-000115
Figure PCTCN2017109922-appb-000115
其中，among them,
R1、R2、R3和T的定义同式(Ⅰ)化合物；R5和m的定义，以及结构单元
Figure PCTCN2017109922-appb-000116
的定义同式(Ⅲ)化合物。R 1 , R 2 , R 3 and T are as defined for the compound of formula (I); the definition of R 5 and m, and the structural unit
Figure PCTCN2017109922-appb-000116
The definition is the same as the compound of formula (III).
在一些实施方案中，本申请涉及式(Ⅵa)化合物、式(Ⅵb)化合物、式(Ⅵc)化合物或式(Ⅵd)化合物或其药学上可接受的盐，In some embodiments, the present application is directed to a compound of Formula (VIa), a compound of Formula (VIb), a compound of Formula (VIc) or a compound of Formula (VId), or a pharmaceutically acceptable salt thereof,
Figure PCTCN2017109922-appb-000117
Figure PCTCN2017109922-appb-000117
其中，among them,
R1、R2、R3、T、R5和m的定义，以及结构单元
Figure PCTCN2017109922-appb-000118
的定义同式(Ⅵ)化合物。Definition of R 1 , R 2 , R 3 , T, R 5 and m, and structural unit
Figure PCTCN2017109922-appb-000118
The definition is the same as the compound of formula (VI).
在一些实施方案中，本申请涉及式(Ⅵe)化合物、式(Ⅵf)化合物、式(Ⅵg)化合物或式(Ⅵh) 化合物或其药学上可接受的盐，In some embodiments, the present application is directed to a compound of Formula (VIe), a compound of Formula (VIf), a compound of Formula (VIg), or Formula (VIh) a compound or a pharmaceutically acceptable salt thereof,
Figure PCTCN2017109922-appb-000119
Figure PCTCN2017109922-appb-000119
其中，among them,
R1、R2、R3、T、R5和m的定义，以及结构单元
Figure PCTCN2017109922-appb-000120
的定义同式(Ⅵ)化合物。Definition of R 1 , R 2 , R 3 , T, R 5 and m, and structural unit
Figure PCTCN2017109922-appb-000120
The definition is the same as the compound of formula (VI).
在一些实施方案中，本申请涉及一种式(Ⅶ)化合物或其药学上可接受的盐，In some embodiments, the present application relates to a compound of formula (VII), or a pharmaceutically acceptable salt thereof,
Figure PCTCN2017109922-appb-000121
Figure PCTCN2017109922-appb-000121
其中，among them,
R6分别独立地选自氟、氯、溴、碘、氰基、甲基或三氟甲基；R 6 is each independently selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, methyl or trifluoromethyl;
p选自0、1、2、3或4；p is selected from 0, 1, 2, 3 or 4;
R1、R2、A环、T、R3、L1和L4的定义，以及结构单元
Figure PCTCN2017109922-appb-000122
的定义同式(Ⅰ)化合物。Definition of R 1 , R 2 , A ring, T, R 3 , L 1 and L 4 , and structural unit
Figure PCTCN2017109922-appb-000122
The definition is the same as the compound of formula (I).
在一些实施方案中，结构单元
Figure PCTCN2017109922-appb-000123
选自
Figure PCTCN2017109922-appb-000124
In some embodiments, the structural unit
Figure PCTCN2017109922-appb-000123
Selected from
Figure PCTCN2017109922-appb-000124
在一些优选实施方案中，p选自0或1。 In some preferred embodiments, p is selected from 0 or 1.
在一些优选实施方案中，R6为氟。In some preferred embodiments, R 6 is fluoro.
在一些优选实施方案中，结构单元
Figure PCTCN2017109922-appb-000125
选自
Figure PCTCN2017109922-appb-000126
Figure PCTCN2017109922-appb-000127
In some preferred embodiments, the structural unit
Figure PCTCN2017109922-appb-000125
Selected from
Figure PCTCN2017109922-appb-000126
Figure PCTCN2017109922-appb-000127
在一些优选实施方案中，结构单元
Figure PCTCN2017109922-appb-000128
选自
Figure PCTCN2017109922-appb-000129
In some preferred embodiments, the structural unit
Figure PCTCN2017109922-appb-000128
Selected from
Figure PCTCN2017109922-appb-000129
在一些更优选实施方案中，结构单元
Figure PCTCN2017109922-appb-000130
选自
Figure PCTCN2017109922-appb-000131
Figure PCTCN2017109922-appb-000132
In some more preferred embodiments, the structural unit
Figure PCTCN2017109922-appb-000130
Selected from
Figure PCTCN2017109922-appb-000131
Figure PCTCN2017109922-appb-000132
在一些实施方案中，本申请涉及一种式(Ⅷ)化合物或其药学上可接受的盐，In some embodiments, the present application relates to a compound of formula (VIII), or a pharmaceutically acceptable salt thereof,
Figure PCTCN2017109922-appb-000133
Figure PCTCN2017109922-appb-000133
其中，among them,
T分别独立地选自‐CH＝和‐N＝；T are independently selected from ‐CH= and ‐N=;
R1、R3、R6、p和L4的定义，以及结构单元
Figure PCTCN2017109922-appb-000134
的定义同式(Ⅶ) 化合物；R4和n的定义，以及结构单元
Figure PCTCN2017109922-appb-000135
的定义同式(Ⅱ)化合物；R5和m的定义，以及结构单元
Figure PCTCN2017109922-appb-000136
的定义同式(Ⅲ)化合物。Definition of R 1 , R 3 , R 6 , p and L 4 , and structural unit
Figure PCTCN2017109922-appb-000134
Definition of a compound of the same formula (VII); definition of R 4 and n, and a structural unit
Figure PCTCN2017109922-appb-000135
Definition of a compound of the same formula (II); definition of R 5 and m, and a structural unit
Figure PCTCN2017109922-appb-000136
The definition is the same as the compound of formula (III).
在一些优选实施方案中，结构单元
Figure PCTCN2017109922-appb-000137
选自
Figure PCTCN2017109922-appb-000138
In some preferred embodiments, the structural unit
Figure PCTCN2017109922-appb-000137
Selected from
Figure PCTCN2017109922-appb-000138
在一些优选实施方案中，n选自1或2。In some preferred embodiments, n is selected from 1 or 2.
在一些优选实施方案中，R4分别独立地选自氯、氰基或三氟甲基。In some preferred embodiments, R 4 is independently selected from chloro, cyano or trifluoromethyl.
在一些更优选的实施方案中，结构单元
Figure PCTCN2017109922-appb-000139
选自
Figure PCTCN2017109922-appb-000140
In some more preferred embodiments, the structural unit
Figure PCTCN2017109922-appb-000139
Selected from
Figure PCTCN2017109922-appb-000140
在一些优选实施方案中，结构单元
Figure PCTCN2017109922-appb-000141
选自
Figure PCTCN2017109922-appb-000142
In some preferred embodiments, the structural unit
Figure PCTCN2017109922-appb-000141
Selected from
Figure PCTCN2017109922-appb-000142
在一些优选的实施方案中，R5为氯。In some preferred embodiments, R 5 is chloro.
在一些优选的实施方案中，m为1。In some preferred embodiments, m is one.
在一些更优选的实施方案中，结构单元
Figure PCTCN2017109922-appb-000143
为
Figure PCTCN2017109922-appb-000144
In some more preferred embodiments, the structural unit
Figure PCTCN2017109922-appb-000143
for
Figure PCTCN2017109922-appb-000144
在一些实施方案中，结构单元
Figure PCTCN2017109922-appb-000145
选自
Figure PCTCN2017109922-appb-000146
In some embodiments, the structural unit
Figure PCTCN2017109922-appb-000145
Selected from
Figure PCTCN2017109922-appb-000146
在一些优选实施方案中，p选自0或1。In some preferred embodiments, p is selected from 0 or 1.
在一些优选实施方案中，R6为氟。In some preferred embodiments, R 6 is fluoro.
在一些优选实施方案中，结构单元
Figure PCTCN2017109922-appb-000147
选自
Figure PCTCN2017109922-appb-000148
Figure PCTCN2017109922-appb-000149
In some preferred embodiments, the structural unit
Figure PCTCN2017109922-appb-000147
Selected from
Figure PCTCN2017109922-appb-000148
Figure PCTCN2017109922-appb-000149
在一些优选实施方案中，结构单元
Figure PCTCN2017109922-appb-000150
选自
Figure PCTCN2017109922-appb-000151
In some preferred embodiments, the structural unit
Figure PCTCN2017109922-appb-000150
Selected from
Figure PCTCN2017109922-appb-000151
在一些更优选实施方案中，结构单元
Figure PCTCN2017109922-appb-000152
选自
Figure PCTCN2017109922-appb-000153
Figure PCTCN2017109922-appb-000154
In some more preferred embodiments, the structural unit
Figure PCTCN2017109922-appb-000152
Selected from
Figure PCTCN2017109922-appb-000153
Figure PCTCN2017109922-appb-000154
在一些实施方案中，本申请涉及以下化合物或其药学上可接受的盐：In some embodiments, the present application relates to the following compounds or pharmaceutically acceptable salts thereof:
Figure PCTCN2017109922-appb-000155
Figure PCTCN2017109922-appb-000155
Figure PCTCN2017109922-appb-000156
Figure PCTCN2017109922-appb-000156
Figure PCTCN2017109922-appb-000157
Figure PCTCN2017109922-appb-000157
Figure PCTCN2017109922-appb-000158
Figure PCTCN2017109922-appb-000158
另一方面，本申请涉及药物组合物，其包含本申请的式(Ⅰ)、式(Ⅰa)、式(Ⅰb)、式(Ⅱ)、式(Ⅱa)、式(Ⅱb)、式(Ⅲ)、式(Ⅲa)、式(Ⅲb)、式(Ⅳ)、式(Ⅳa)、式(Ⅳb)、式(Ⅳc)、式(Ⅳd)、式(Ⅳe)、式(Ⅳf)、式(Ⅳg)、式(Ⅳh)、式(Ⅴ)、式(Ⅴa)、式(Ⅴb)、式(Ⅴc)、式(Ⅴd)、式(Ⅴe)、式(Ⅴf)、式(Ⅴg)、式(Ⅴh)、式(Ⅵ)、式(Ⅵa)、式(Ⅵb)、式(Ⅵc)、式(Ⅵd)、式(Ⅵe)、式(Ⅵf)、式(Ⅵg)、式(Ⅵh)、式(Ⅶ)或式(Ⅷ)化合物或其药学上可接受的盐。在一些实施方案中，本申请的药物组合物还包括药学上可接受的辅料。In another aspect, the present application relates to a pharmaceutical composition comprising Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (IIa), Formula (IIb), Formula (III) of the present application. , (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg) , (IVh), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh) , (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII) Or a compound of formula (VIII) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions of the present application also include pharmaceutically acceptable excipients.
另一方面，本申请涉及治疗哺乳动物由cccDNA介导的疾病的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的式(Ⅰ)、式(Ⅰa)、式(Ⅰb)、式(Ⅱ)、式(Ⅱa)、式(Ⅱb)、式(Ⅲ)、式(Ⅲa)、式(Ⅲb)、式(Ⅳ)、式(Ⅳa)、式(Ⅳb)、式(Ⅳc)、式(Ⅳd)、式(Ⅳe)、式(Ⅳf)、式 (Ⅳg)、式(Ⅳh)、式(Ⅴ)、式(Ⅴa)、式(Ⅴb)、式(Ⅴc)、式(Ⅴd)、式(Ⅴe)、式(Ⅴf)、式(Ⅴg)、式(Ⅴh)、式(Ⅵ)、式(Ⅵa)、式(Ⅵb)、式(Ⅵc)、式(Ⅵd)、式(Ⅵe)、式(Ⅵf)、式(Ⅵg)、式(Ⅵh)、式(Ⅶ)或式(Ⅷ)化合物或其药学上可接受的盐、或其药物组合物，所述疾病包括乙型病毒性肝炎In another aspect, the present application relates to a method of treating a disease mediated by a cccDNA in a mammal comprising administering to the mammal, preferably a human, in need of such treatment a therapeutically effective amount of Formula (I), Formula (Ia), Formula (Ib) , formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), formula (IIIb), formula (IV), formula (IVa), formula (IVb), formula (IVc) , formula (IVd), formula (IVe), formula (IVf), (IVg), Formula (IVh), Formula (V), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), Formula (Vf), Formula (Vg), Formula (Vh), Formula (VI), Formula (VIa), Formula (VIb), Formula (VIc), Formula (VId), Formula (VIe), Formula (VIf), Formula (VIg), Formula (VIh), Formula (VII) or a compound of the formula (VIII), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, the disease comprising hepatitis B virus
另一方面，本申请涉及式(Ⅰ)、式(Ⅰa)、式(Ⅰb)、式(Ⅱ)、式(Ⅱa)、式(Ⅱb)、式(Ⅲ)、式(Ⅲa)、式(Ⅲb)、式(Ⅳ)、式(Ⅳa)、式(Ⅳb)、式(Ⅳc)、式(Ⅳd)、式(Ⅳe)、式(Ⅳf)、式(Ⅳg)、式(Ⅳh)、式(Ⅴ)、式(Ⅴa)、式(Ⅴb)、式(Ⅴc)、式(Ⅴd)、式(Ⅴe)、式(Ⅴf)、式(Ⅴg)、式(Ⅴh)、式(Ⅵ)、式(Ⅵa)、式(Ⅵb)、式(Ⅵc)、式(Ⅵd)、式(Ⅵe)、式(Ⅵf)、式(Ⅵg)、式(Ⅵh)、式(Ⅶ)或式(Ⅷ)化合物或其药学上可接受的盐、或其药物组合物在制备预防或者治疗cccDNA介导的疾病的药物中的用途，所述疾病包括乙型病毒性肝炎。In another aspect, the present application relates to formula (I), formula (Ia), formula (Ib), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), formula (IIIb) ), Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), Formula (IVf), Formula (IVg), Formula (IVh), Formula (V) ), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), Formula (Vf), Formula (Vg), Formula (Vh), Formula (VI), Formula (VIa) a compound of the formula (VIb), formula (VIc), formula (VId), formula (VIe), formula (VIf), formula (VIg), formula (VIh), formula (VII) or formula (VIII) or a pharmaceutical thereof Use of an acceptable salt, or a pharmaceutical composition thereof, for the manufacture of a medicament for preventing or treating a cccDNA mediated disease, including hepatitis B virus.
另一方面，本申请涉及式(Ⅰ)、式(Ⅰa)、式(Ⅰb)、式(Ⅱ)、式(Ⅱa)、式(Ⅱb)、式(Ⅲ)、式(Ⅲa)、式(Ⅲb)、式(Ⅳ)、式(Ⅳa)、式(Ⅳb)、式(Ⅳc)、式(Ⅳd)、式(Ⅳe)、式(Ⅳf)、式(Ⅳg)、式(Ⅳh)、式(Ⅴ)、式(Ⅴa)、式(Ⅴb)、式(Ⅴc)、式(Ⅴd)、式(Ⅴe)、式(Ⅴf)、式(Ⅴg)、式(Ⅴh)、式(Ⅵ)、式(Ⅵa)、式(Ⅵb)、式(Ⅵc)、式(Ⅵd)、式(Ⅵe)、式(Ⅵf)、式(Ⅵg)、式(Ⅵh)、式(Ⅶ)或式(Ⅷ)化合物或其药学上可接受的盐、或其药物组合物在预防或者治疗cccDNA介导的疾病中的用途，所述疾病包括乙型病毒性肝炎。In another aspect, the present application relates to formula (I), formula (Ia), formula (Ib), formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), formula (IIIb) ), Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), Formula (IVf), Formula (IVg), Formula (IVh), Formula (V) ), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), Formula (Vf), Formula (Vg), Formula (Vh), Formula (VI), Formula (VIa) a compound of the formula (VIb), formula (VIc), formula (VId), formula (VIe), formula (VIf), formula (VIg), formula (VIh), formula (VII) or formula (VIII) or a pharmaceutical thereof Use of an acceptable salt, or a pharmaceutical composition thereof, for preventing or treating a cccDNA mediated disease, including hepatitis B virus.
定义definition
除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的术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，而应该按照本领域普通的含义去理解。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 as used in this application have the following meanings. A particular term should not be considered as undefined or unclear without a particular definition, and should be understood in the ordinary meaning of the art. When a trade name appears in this document, it is intended to refer to its corresponding commodity or its active ingredient.
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，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。The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent as long as the valence of the particular atom is normal and the substituted compound is stable.
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被氟取代，指乙基可以是未被取代的(CH2CH3)、单取代的(如CH2CH2F)、多取代的(如CHFCH2F、CH2CHF2等)或完全被取代的(CF2CF3)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。例如，
Figure PCTCN2017109922-appb-000159
任选地被1、2或3个三氟甲基取代，当D选自-O-或-S-，且T为-N＝时，
Figure PCTCN2017109922-appb-000160
不存在被3个三氟甲基取代的模式。The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, the description including the occurrence of the event or condition and the occurrence of the event or condition. For example, an ethyl group "optionally" substituted by fluorine, means ethyl may be unsubstituted (CH 2 CH 3), monosubstituted (e.g., CH 2 CH 2 F), polysubstituted (e.g. CHFCH 2 F, CH 2 CHF 2, etc.) or completely substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and/or which cannot be synthesized is introduced. E.g,
Figure PCTCN2017109922-appb-000159
Optionally substituted with 1, 2 or 3 trifluoromethyl groups, when D is selected from -O- or -S-, and T is -N=,
Figure PCTCN2017109922-appb-000160
There is no pattern substituted by 3 trifluoromethyl groups.
本文中的Cm-n，是指该部分具有给定范围中的整数个碳原子。例如“C1-3”是指该基团可具有1个碳原子、2个碳原子或3个碳原子；“C3-6”是指该基团可具有3个碳原子、4个碳原子、5个碳原子或6个碳 原子。C mn herein means that the moiety has an integer number of carbon atoms in a given range. For example, "C 1-3 " means that the group may have 1 carbon atom, 2 carbon atoms or 3 carbon atoms; "C 3-6 " means that the group may have 3 carbon atoms and 4 carbons Atom, 5 carbon atoms or 6 carbon atoms.
本文中的结构单元或者基团中的虚线
Figure PCTCN2017109922-appb-000161
表示共价键。Dotted lines in structural units or groups herein
Figure PCTCN2017109922-appb-000161
Represents a covalent bond.
本文中的某些结构单元或者基团中表示的共价键(例如，
Figure PCTCN2017109922-appb-000162
中的虚线
Figure PCTCN2017109922-appb-000163
)未与具体的原子连接时，表示该共价键可以与该结构单元中的任意原子连接，只要不违背价键连接规则。因此，例如，结构单元
Figure PCTCN2017109922-appb-000164
包括
Figure PCTCN2017109922-appb-000165
或
Figure PCTCN2017109922-appb-000166
Certain structural units or covalent bonds represented in the group herein (for example,
Figure PCTCN2017109922-appb-000162
Dotted line
Figure PCTCN2017109922-appb-000163
When not connected to a specific atom, it means that the covalent bond can be connected to any atom in the structural unit as long as it does not violate the valence bond connection rule. So, for example, a structural unit
Figure PCTCN2017109922-appb-000164
include
Figure PCTCN2017109922-appb-000165
or
Figure PCTCN2017109922-appb-000166
当任何变量(例如D、T或R4)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，(R4)n表示一个基团被n个R4所取代，则每个R4都有独立的选项；具体而言，例如，当n＝2时，(R4)n表示一个基团被2个R4所取代，且每个R4都有独立的选项。When any variable (eg, D, T or R 4 ) occurs more than once in the composition or structure of the compound, its definition in each case is independent. Thus, for example, (R 4 ) n represents that one group is replaced by n R 4 , and each R 4 has an independent option; specifically, for example, when n=2, (R 4 ) n represents One group is replaced by two R 4 and each R 4 has an independent option.
术语“羟基”指-OH基团。The term "hydroxy" refers to an -OH group.
术语“氰基”指-CN基团。The term "cyano" refers to a -CN group.
术语“氨基”指-NH2基团。The term "amino" means -NH 2 group.
术语“三氟甲基”指-CF3基团。The term "trifluoromethyl" refers to a -CF 3 group.
术语“烷基”是指通式为CnH2n+1的烃基。该烷基可以是直链或支链的。例如，术语“C1-3烷基”指含有1至3个碳原子的烷基(例如甲基、乙基、正丙基、异丙基)。The term "alkyl" refers to a hydrocarbon group of the formula C n H 2n +. The alkyl group can be straight or branched. For example, the term "C 1 - 3 alkyl" refers to alkyl groups containing 3 (e.g., methyl, ethyl, n-propyl, isopropyl) of 1 to 3 carbon atoms.
术语“环烷基”指完全饱和的并且可以以呈单环、桥环或螺环存在的碳环。除非另有指示，该碳环通常为3至10元环。环烷基非限制性实例包括但不限于环丙基、环丁基、环戊基、环己基、降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基等。The term "cycloalkyl" refers to a carbocyclic ring that is fully saturated and can exist as a single ring, bridged ring or spiro ring. Unless otherwise indicated, the carbocyclic ring is typically a 3 to 10 membered ring. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, diamond Alkyl and the like.
术语“治疗”意为将本申请所述化合物或制剂进行给药以预防、改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：The term "treating" means administering a compound or formulation described herein to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
(i)预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时；(i) preventing a disease or disease state from occurring in a mammal, particularly when such a mammal is susceptible to the disease state but has not been diagnosed as having the disease state;
(ii)抑制疾病或疾病状态，即遏制其发展；(ii) inhibiting the disease or disease state, ie, curbing its development;
(iii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。(iii) alleviating the disease or condition, even if the disease or condition resolves.
术语“治疗有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄，但可例行性地由本领域技术人员根据其自身的知识及本公 开内容而确定。The term "therapeutically effective amount" means (i) treating or preventing a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying The amount of a compound of the present application in which one or more symptoms of a particular disease, condition, or disorder are described herein. The amount of a compound of the present application which constitutes a "therapeutically effective amount" depends on the compound, the state of the disease and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art Knowledge and the public Determine the content.
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。The term "pharmaceutically acceptable" is for those compounds, materials, compositions and/or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues without Many toxic, irritating, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
作为药学上可接受的盐，例如，可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。As the pharmaceutically acceptable salt, for example, a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, or the like can be mentioned. .
术语“药物组合物”是指一种或多种本申请的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or a salt thereof and a pharmaceutically acceptable adjuvant. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。The term "pharmaceutically acceptable excipient" refers to those excipients which have no significant irritating effect on the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water soluble and/or water swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。The word "comprise" or "comprise" and its English variants such as "comprises" or "comprising" shall be understood to mean an open, non-exclusive meaning, ie "including but not limited to".
本申请的中间体和化合物还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本申请的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺异构化。质子互变异构体的具体实例是咪唑部分，其中质子可在两个环氮间迁移。价互变异构体包括通过一些成键电子的重组的互变。The intermediates and compounds of the present application may also exist in different tautomeric forms, and all such forms are included within the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is an imidazole moiety in which a proton can migrate between two ring nitrogens. Valence tautomers include recombination through some recombination of bonding electrons.
本申请还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本申请化合物。可结合到本申请化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、123I、125I和36Cl等。The present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but in which one or more atoms are replaced by an atomic weight or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that may be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 respectively. N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, and the like.
某些同位素标记的本申请化合物(例如用3H及14C标记的那些)可用于化合物和/或底物组织分布分析中。氚(即3H)和碳-14(即14C)同位素由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如15O、13N、11C和18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本申请化合物。Certain isotopically-labeled compounds of the present application (such as those labeled with 3 H and 14 C) can be used in compound and/or substrate tissue distribution assays. The ruthenium (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes such as 15 O, 13 N, 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by substituting an isotopically labeled reagent for an unisotopically labeled reagent by procedures similar to those disclosed in the schemes and/or examples disclosed below.
此外，用较重同位素(诸如氘(即2H))取代可以提供某些由更高的代谢稳定性产生的治疗优点(例如增加的体内半衰期或降低的剂量需求)，并且因此在某些情形下可能是优选的，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被氘取代。Furthermore, substitution with heavier isotopes such as deuterium (ie, 2 H) can provide certain therapeutic advantages resulting from higher metabolic stability (eg, increased in vivo half-life or reduced dosage requirements), and thus in some cases The following may be preferred, wherein the hydrazine substitution may be partial or complete, and the partial hydrazine substitution means that at least one hydrogen is replaced by hydrazine.
除非另有说明，用楔形键
Figure PCTCN2017109922-appb-000167
表示一个立体中心的绝对构型。 Wedge key unless otherwise stated
Figure PCTCN2017109922-appb-000167
Represents the absolute configuration of a stereocenter.
本申请化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括在本申请的范围内，如对映异构体和非对映异构体。例如，
Figure PCTCN2017109922-appb-000168
包括
Figure PCTCN2017109922-appb-000169
也包括
Figure PCTCN2017109922-appb-000170
Figure PCTCN2017109922-appb-000171
举例而言，在本申请的下文描述的实施例中所给出的
Figure PCTCN2017109922-appb-000172
和
Figure PCTCN2017109922-appb-000173
分别代表它们是
Figure PCTCN2017109922-appb-000174
或者
Figure PCTCN2017109922-appb-000175
中的一个，且互不相同。本申请的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。The compounds of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers are included within the scope of this application, such as enantiomers and diastereomers. E.g,
Figure PCTCN2017109922-appb-000168
include
Figure PCTCN2017109922-appb-000169
also include
Figure PCTCN2017109922-appb-000170
Figure PCTCN2017109922-appb-000171
For example, given in the embodiments of the present application described below
Figure PCTCN2017109922-appb-000172
with
Figure PCTCN2017109922-appb-000173
Representing them separately
Figure PCTCN2017109922-appb-000174
or
Figure PCTCN2017109922-appb-000175
One of them, and different from each other. The asymmetric carbon atom-containing compounds of the present application can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from the racemic mixture or synthesized by using a chiral starting material or a chiral reagent.
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, as solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
给予本申请化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、***内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。Typical routes of administration of a compound of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。 The pharmaceutical composition of the present application can be produced by a method well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a sugar-coating method, a grinding method, an emulsification method, a freeze-drying method, and the like.
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by admixing the active compound with pharmaceutically acceptable excipients which are well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the active compound with a solid adjuvant, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to give tablets. Or the core of the sugar coating. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。The pharmaceutical compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in a suitable unit dosage form.
本申请所述的式(Ⅰ)、式(Ⅰa)、式(Ⅰb)、式(Ⅱ)、式(Ⅱa)、式(Ⅱb)、式(Ⅲ)、式(Ⅲa)、式(Ⅲb)、式(Ⅳ)、式(Ⅳa)、式(Ⅳb)、式(Ⅳc)、式(Ⅳd)、式(Ⅳe)、式(Ⅳf)、式(Ⅳg)、式(Ⅳh)、式(Ⅴ)、式(Ⅴa)、式(Ⅴb)、式(Ⅴc)、式(Ⅴd)、式(Ⅴe)、式(Ⅴf)、式(Ⅴg)、式(Ⅴh)、式(Ⅵ)、式(Ⅵa)、式(Ⅵb)、式(Ⅵc)、式(Ⅵd)、式(Ⅵe)、式(Ⅵf)、式(Ⅵg)、式(Ⅵh)、式(Ⅶ)或式(Ⅷ)化合物的所有施用方法中，每天给药的剂量为0.01到200mg/kg体重，以单独或分开剂量的形式给药。Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (IIa), Formula (IIb), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), Formula (IVf), Formula (IVg), Formula (IVh), Formula (V), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), Formula (Vf), Formula (Vg), Formula (Vh), Formula (VI), Formula (VIa), All methods of application of a compound of formula (VIb), formula (VIc), formula (VId), formula (VIe), formula (VIf), formula (VIg), formula (VIh), formula (VII) or formula (VIII) The daily dose is from 0.01 to 200 mg/kg body weight, administered in separate or separate doses.
本申请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申请的实施例。The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, combinations thereof with other chemical synthesis methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the present application.
本申请具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。The chemical reactions of the specific embodiments of the present application are accomplished in a suitable solvent which is suitable for the chemical changes of the present application and the reagents and materials required thereof. In order to obtain the compounds of the present application, it is sometimes necessary for those skilled in the art to modify or select the synthetic steps or reaction schemes based on the prior embodiments.
本领域合成路线规划中的一个重要考量因素是为反应性官能团(如本申请中的氨基)选择合适的保护基，例如，可参考Greene's Protective Groups in Organic Synthesis(4th Ed).Hoboken,New Jersey:John Wiley&Sons,Inc.本申请引用的所有参考文献整体上并入本申请。An important consideration in the art of synthetic route planning is the selection of suitable protecting groups for reactive functional groups (such as amino groups in the present application), for example, reference to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc. All references cited herein are hereby incorporated by reference in their entirety.
在一些实施方案中，本申请通式(Ⅳ)的化合物可以由有机合成领域技术人员通过路线1用本领域的标准方法来制备：In some embodiments, the compounds of formula (IV) of the present application can be prepared by those skilled in the art of organic synthesis by standard methods in the art using Route 1:
路线1： Route 1:
Figure PCTCN2017109922-appb-000176
Figure PCTCN2017109922-appb-000176
其中X选自卤素，例如可以为氯。Wherein X is selected from halogen and may, for example, be chlorine.
在一些实施方案中，本申请式(Ⅳ)化合物可以由有机合成领域技术人员通过路线2用本领域的标准方法来制备：In some embodiments, the compounds of formula (IV) of the present application can be prepared by those skilled in the art of organic synthesis by standard methods in the art using Route 2:
路线2：Route 2:
Figure PCTCN2017109922-appb-000177
Figure PCTCN2017109922-appb-000177
其中X选自卤素，例如可以为氯。Wherein X is selected from halogen and may, for example, be chlorine.
在一些实施方案中，本申请式(Ⅳ)化合物可以由有机合成领域技术人员通过路线3用本领域的标准方法来制备：In some embodiments, the compounds of formula (IV) of the present application can be prepared by those skilled in the art of organic synthesis by standard methods in the art using Route 3:
路线3： Route 3:
Figure PCTCN2017109922-appb-000178
Figure PCTCN2017109922-appb-000178
其中X选自卤素，例如可以为氯。Wherein X is selected from halogen and may, for example, be chlorine.
在一些实施方案中，本申请式(Ⅳ)化合物可以由有机合成领域技术人员通过路线4用本领域的标准方法来制备：In some embodiments, the compounds of formula (IV) of the present application can be prepared by those skilled in the art of organic synthesis by standard methods in the art using Route 4:
路线4：Route 4:
Figure PCTCN2017109922-appb-000179
Figure PCTCN2017109922-appb-000179
其中X选自卤素，例如可以为氯。Wherein X is selected from halogen and may, for example, be chlorine.
在一些实施方案中，式(Ⅳa)、式(Ⅳb)、式(Ⅳc)、式(Ⅳd)、式(Ⅳe)、式(Ⅳf)、式(Ⅳg)、式(Ⅳh)、式(Ⅴ)、式(Ⅴa)、式(Ⅴb)、式(Ⅴc)、式(Ⅴd)、式(Ⅴe)、式(Ⅴf)、式(Ⅴg)、式(Ⅴh)、式(Ⅵ)、式(Ⅵa)、式(Ⅵb)、式(Ⅵc)、式(Ⅵd)、式(Ⅵe)、式(Ⅵf)、式(Ⅵg)或式(Ⅵh)化合物可参照上述路线1-4的方法制备。In some embodiments, Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe), Formula (IVf), Formula (IVg), Formula (IVh), Formula (V) , (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (VI), (VIa) Compounds of formula (VIb), formula (VIc), formula (VId), formula (VIe), formula (VIf), formula (VIg) or formula (VIh) can be prepared by the methods of Schemes 1-4 above.
在一些实施方案中，本申请式(Ⅶ)的化合物可以由有机合成领域技术人员通过路线5用本领域的标准方法来制备：In some embodiments, the compounds of Formula (VII) of the present application can be prepared by those skilled in the art of organic synthesis by standard methods in the art using Route 5:
路线5: Route 5:
Figure PCTCN2017109922-appb-000180
Figure PCTCN2017109922-appb-000180
其中X选自卤素，例如可以为氯；L4为
Figure PCTCN2017109922-appb-000181
Wherein X is selected from halogen, for example, may be chlorine; L 4 is
Figure PCTCN2017109922-appb-000181
在一些实施方案中，本申请式(Ⅶ)的化合物可以由有机合成领域技术人员通过路线6用本领域的标准方法来制备：In some embodiments, the compounds of Formula (VII) of the present application can be prepared by those skilled in the art of organic synthesis by standard methods in the art using Route 6:
路线6:Route 6:
Figure PCTCN2017109922-appb-000182
Figure PCTCN2017109922-appb-000182
其中X选自卤素，例如可以为氯；L4为
Figure PCTCN2017109922-appb-000183
Wherein X is selected from halogen, for example, may be chlorine; L 4 is
Figure PCTCN2017109922-appb-000183
在一些实施方案中，本申请式(Ⅶ)化合物可以由有机合成领域技术人员通过路线7用本领域的标准方法来制备： In some embodiments, the compounds of formula (VII) herein can be prepared by those skilled in the art of organic synthesis by standard methods in the art using Route 7:
Figure PCTCN2017109922-appb-000184
Figure PCTCN2017109922-appb-000184
其中X选自卤素，例如可以为氯；L4为
Figure PCTCN2017109922-appb-000185
Wherein X is selected from halogen, for example, may be chlorine; L 4 is
Figure PCTCN2017109922-appb-000185
在一些实施方案中，本申请式(Ⅶ)化合物可以由有机合成领域技术人员通过路线8用本领域的标准方法来制备：In some embodiments, the compounds of formula (VII) herein can be prepared by one skilled in the art of organic synthesis by standard methods in the art using Route 8:
路线8:Route 8:
Figure PCTCN2017109922-appb-000186
Figure PCTCN2017109922-appb-000186
其中X选自卤素，例如可以为氯；L4为
Figure PCTCN2017109922-appb-000187
R3为氢。Wherein X is selected from halogen, for example, may be chlorine; L 4 is
Figure PCTCN2017109922-appb-000187
R 3 is hydrogen.
在一些实施方案中，本申请式(Ⅶ)化合物可以由有机合成领域技术人员通过路线9用本领域的标准方法来制备：In some embodiments, the compounds of formula (VII) herein can be prepared by those skilled in the art of organic synthesis by standard methods in the art using Route 9:
路线9: Route 9:
Figure PCTCN2017109922-appb-000188
Figure PCTCN2017109922-appb-000188
其中X选自卤素，例如可以为氯；L4为
Figure PCTCN2017109922-appb-000189
在一些实施方案中，式(Ⅷ)化合物可参照上述路线5-9的方法制备。Wherein X is selected from halogen, for example, may be chlorine; L 4 is
Figure PCTCN2017109922-appb-000189
In some embodiments, compounds of formula (VIII) can be prepared by the methods of Schemes 5-9 above.
本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并***-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；EA代表乙酸乙酯；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，其是一种胺保护基团；BOC代表叔丁基羰基，其是一种胺保护基团；HOAc代表乙酸；NaCNBH3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl2代表氯化亚砜；CS2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基氨基锂。The present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; CDI stands for carbonyl diimidazole; DCM stands for Chloroform; PE stands for petroleum ether; EA stands for ethyl acetate; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for ethyl acetate EtOH stands for ethanol; MeOH stands for methanol; CBz stands for benzyloxycarbonyl which is an amine protecting group; BOC stands for t-butylcarbonyl which is an amine protecting group; HOAc stands for acetic acid; and NaCNBH 3 stands for cyano boron Sodium hydride; rt stands for room temperature; O/N stands for overnight; THF stands for tetrahydrofuran; Boc 2 O stands for di-tert-butyl dicarbonate; TFA stands for trifluoroacetic acid; DIPEA stands for diisopropylethylamine; SOCl 2 stands for chlorine Sulfoxide; CS 2 represents carbon disulfide; TsOH represents p-toluenesulfonic acid; NFSI stands for N-fluoro-N-(phenylsulfonyl)benzenesulfonamide; NCS stands for 1-chloropyrrolidine-2,5-dione; n- Bu 4 NF-generation Tetrabutylammonium fluoride; iPrOH represents 2-propanol; mp Representative mp; Representative LDA lithium diisopropylamide.
具体实施方式detailed description
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。本申请所使用的所有溶剂是市售的， 无需进一步纯化即可使用。本申请用于合成的初始化合物原料通过市售获得，也可以通过现有技术的方法制备。The invention is described in detail below by the examples, but is not intended to limit the invention. The present invention has been described in detail herein, the embodiments of the present invention are disclosed herein, and various modifications and changes may be made to the embodiments of the present invention without departing from the spirit and scope of the invention. It will be obvious. All solvents used in this application are commercially available. It can be used without further purification. The starting material raw materials for the synthesis of the present application are commercially available, and can also be produced by a method of the prior art.
本申请使用的快速制备色谱仪型号：CombiFlash RF,Teledyne isco。The Rapid Preparative Chromatograph model used in this application: CombiFlash RF, Teledyne isco.
参考例1：化合物BB-1的合成Reference Example 1: Synthesis of Compound BB-1
Figure PCTCN2017109922-appb-000190
Figure PCTCN2017109922-appb-000190
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000191
Figure PCTCN2017109922-appb-000191
将化合物BB-1-1(2.00g)溶于吡啶(20.00mL)中，然后在0℃下加入化合物BB-1-2(2.16g)，在0℃条件下该反应液搅拌5小时。用2N盐酸在0℃的条件下萃灭反应。将反应液用乙酸乙酯(20mL*3)萃取，有机相合并，食盐水洗(20mL*2)，无水硫酸钠干燥，过滤减压浓缩得粗品。该粗品经快速制备色谱仪(石油醚：乙酸乙酯＝20：1)得目标化合物BB-1(黄色固体，900mg)。MS(ESI)m/z：392[M+Na]+。Compound BB-1-1 (2.00 g) was dissolved in pyridine (20.00 mL), and then compound BB-1-2 (2.16 g) was added at 0 ° C, and the mixture was stirred at 0 ° C for 5 hours. The reaction was extracted with 2N hydrochloric acid at 0 °C. The reaction mixture was extracted with EtOAc (EtOAc)EtOAc. The crude product was purified by flash chromatography (EtOAc:EtOAc:EtOAc) MS (ESI) m / z: 392 [M+Na] + .
参考例2：化合物BB-2的合成Reference Example 2: Synthesis of Compound BB-2
Figure PCTCN2017109922-appb-000192
Figure PCTCN2017109922-appb-000192
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000193
Figure PCTCN2017109922-appb-000193
将化合物BB-2-1(1.00g)和化合物BB-2-2(1.81g)溶于N,N-二甲基甲酰胺(50.00mL)，在25℃的条件下将HATU(4.83g)和N,N-二异丙基乙胺(3.28g)分别加入到上述的反应液中，在25℃的条件下搅拌14小时。该粗品经快速色谱制备仪(石油醚：乙酸乙酯＝1：1)纯化得到目标化合物BB-2(无色油状液体，1.40g)。MS(ESI)m/z：259[M+H-tBu]+。Compound BB-2-1 (1.00 g) and compound BB-2-2 (1.81 g) were dissolved in N,N-dimethylformamide (50.00 mL), and HATU (4.83 g) was obtained at 25 °C. N,N-diisopropylethylamine (3.28 g) was added to the above reaction solution, respectively, and the mixture was stirred at 25 ° C for 14 hours. The crude product was purified by flash chromatography (EtOAc:EtOAc:EtOAc) MS (ESI) m / z: 259 [M+H-tBu] + .
参考例3：化合物BB-3的合成 Reference Example 3: Synthesis of Compound BB-3
Figure PCTCN2017109922-appb-000194
Figure PCTCN2017109922-appb-000194
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000195
Figure PCTCN2017109922-appb-000195
步骤1：化合物BB-3-3的合成Step 1: Synthesis of Compound BB-3-3
将化合物BB-3-1(1.00g)溶于二氯甲烷(15.00mL)中，再加入化合物BB-3-2(465.64mg)，反应液在15℃下反应1小时。反应液浓缩得到粗品。粗品用15mL二氯甲烷溶解，采用快速制备色谱仪分离(二氯甲烷：甲醇＝梯度洗脱，从1：0到10：1)得到目标化合物BB-3-3(白色固体，1.50g)。MS(ESI)m/z：298[M+H]+。Compound BB-3-1 (1.00 g) was dissolved in dichloromethane (15.00 mL), and then compound BB-3-2 (465.64 mg) was added, and the reaction mixture was reacted at 15 ° C for 1 hour. The reaction solution was concentrated to give a crude material. The crude product was dissolved in EtOAc (EtOAc) (EtOAc:EtOAc) MS (ESI) m / z: 298 [M+H] + .
步骤2：化合物BB-3的合成Step 2: Synthesis of Compound BB-3
将化合物BB-3-3(1.50g)溶于二氯甲烷(5.00mL)中，再加入盐酸的二氧六环溶液(4mol/L，5.62mL)，混合液在15℃下反应1.5小时。反应液浓缩得到目标化合物BB-3(淡黄色固体，1.40g，盐酸盐)，直接用于下一步反应。MS(ESI)m/z：198[M+H]+。1H NMR(400MHz，DMSO-d6)：δ＝9.19(br.s.，1H)，8.94(br.s.，1H)，3.08-3.20(m，2H)，2.86-3.01(m，2H)，2.64-2.78(m，1H)，2.43-2.49(m，1H)，2.38(tt，J＝6.90，3.64Hz，1H)，1.56-1.87(m，4H)，1.06-1.19(m，1H)，0.51-0.60(m，2H)，0.28-0.35(m，2H)。The compound BB-3-3 (1.50 g) was dissolved in dichloromethane (5.00 mL), and then a solution of hydrochloric acid in dioxane (4 mol/L, 5.62 mL) was added, and the mixture was reacted at 15 ° C for 1.5 hours. The reaction mixture was concentrated to give the title compound BB-3 (yellow yellow solid, 1.40 g, hydrochloride). MS (ESI) m / z: 198 [M+H] + . 1 H NMR (400MHz, DMSO- d6): δ = 9.19 (br.s., 1H), 8.94 (br.s., 1H), 3.08-3.20 (m, 2H), 2.86-3.01 (m, 2H) , 2.64-2.78 (m, 1H), 2.43-2.49 (m, 1H), 2.38 (tt, J = 6.90, 3.64 Hz, 1H), 1.56-1.87 (m, 4H), 1.06-1.19 (m, 1H) , 0.51-0.60 (m, 2H), 0.28-0.35 (m, 2H).
参考例4：化合物BB-4的合成Reference Example 4: Synthesis of Compound BB-4
Figure PCTCN2017109922-appb-000196
Figure PCTCN2017109922-appb-000196
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000197
Figure PCTCN2017109922-appb-000197
以化合物BB-4-1，BB-3-2为原料，参考参考例3中化合物BB-3合成步骤，合成参考例BB-4。MS(ESI)m/z：198[M+H]+。Reference compound BB-4 was synthesized from the compound BB-4-1, BB-3-2, and the synthesis procedure of the compound BB-3 in Reference Example 3. MS (ESI) m / z: 198 [M+H] + .
参考例5：化合物BB-5的合成 Reference Example 5: Synthesis of Compound BB-5
Figure PCTCN2017109922-appb-000198
Figure PCTCN2017109922-appb-000198
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000199
Figure PCTCN2017109922-appb-000199
步骤1：化合物BB-5的合成Step 1: Synthesis of Compound BB-5
将化合物BB-1-1(1.00g)溶于吡啶(20.00mL)，然后在0℃分批加入化合物BB-5-2(1.19g)。该反应液在15℃搅拌16小时。将反应液放入100mL乙酸乙酯中，用稀盐酸进行洗涤，洗至反应液pH约为2，得到有机相。将有机相用无水硫酸钠进行干燥，用旋转蒸发仪进行浓缩得到粗产品。该粗品通过快速制备色谱仪(石油醚：乙酸乙酯＝10：1)纯化，纯化后得到目标化合物BB-5(淡红色固体，879mg)。MS(ESI)m/z：414，416[M+H]+。Compound BB-1-1 (1.00 g) was dissolved in pyridine (20.00 mL), then compound BB-5-2 (1.19 g) was added portionwise at 0 °C. The reaction solution was stirred at 15 ° C for 16 hours. The reaction solution was placed in 100 mL of ethyl acetate, washed with dilute hydrochloric acid and washed to pH 2 to give an organic phase. The organic phase was dried over anhydrous sodium sulfate and concentrated using a rotary evaporator to afford crude. The crude product was purified by EtOAc (EtOAc:EtOAc:EtOAc) MS (ESI) m / z: 414, 416 [M+H] + .
参考例6：化合物BB-6的合成Reference Example 6: Synthesis of Compound BB-6
Figure PCTCN2017109922-appb-000200
Figure PCTCN2017109922-appb-000200
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000201
Figure PCTCN2017109922-appb-000201
以化合物BB-6-1，BB-3-2为原料，参考参考例3中化合物BB-3合成步骤，合成化合物BB-6。MS(ESI)m/z：198[M+H]+。Starting from the compound BB-6-1, BB-3-2, the compound BB-6 was synthesized by referring to the synthesis procedure of the compound BB-3 in Reference Example 3. MS (ESI) m / z: 198 [M+H] + .
参考例7：化合物BB-7的合成Reference Example 7: Synthesis of Compound BB-7
Figure PCTCN2017109922-appb-000202
Figure PCTCN2017109922-appb-000202
合成路线： synthetic route:
Figure PCTCN2017109922-appb-000203
Figure PCTCN2017109922-appb-000203
将化合物BB-7-2(260.00mg)，4-(4，6-二甲氧基均三嗪)-4-甲基吗啉盐酸盐(898.48mg)溶于甲醇(10.00mL)，然后加入N-甲基***啉(1.26g)和化合物BB-7-1(802.85mg)，该反应液在20℃搅拌48小时。将反应液用油泵旋干，得到淡棕色油状粗产品。将该淡棕色粗产品通过快速制备色谱仪分离纯化(石油醚：乙酸乙酯＝1：2)。纯化后得到目标化合物BB-7(无色油状液体，200mg，粗品)，直接用于下一步反应。MS(ESI)m/z：245[M+H-tBu]+。Compound BB-7-2 (260.00 mg), 4-(4,6-dimethoxy-s-triazine)-4-methylmorpholine hydrochloride (898.48 mg) was dissolved in methanol (10.00 mL) then N-methylmorpholine (1.26 g) and compound BB-7-1 (802.85 mg) were added, and the reaction mixture was stirred at 20 ° C for 48 hours. The reaction solution was dried with an oil pump to give a crude brown oil. The light brown crude product was isolated and purified by flash chromatography ( petroleum ether: ethyl acetate = 1:2). After purification, the title compound BB-7 (colorless oily liquid, 200 mg, crude) was obtained. MS (ESI) m / z: 245 [M+H-tBu] + .
参考例8：化合物BB-8的合成Reference Example 8: Synthesis of Compound BB-8
Figure PCTCN2017109922-appb-000204
Figure PCTCN2017109922-appb-000204
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000205
Figure PCTCN2017109922-appb-000205
将化合物BB-8-1(400.00mg)溶于N,N-二甲基甲酰胺(15.00mL)中，依次加入化合物BB-8-2(988.13mg)，HATU(1.75g)，N,N-二异丙基乙胺(1.49g)，反应液在15℃下反应1.5小时。向反应液中加入30mL乙酸乙酯，饱和食盐水洗涤(30mL*4)，收集有机相，无水硫酸钠干燥，过滤，滤液浓缩得到粗品。粗品用15mL乙酸乙酯溶解，二氧化硅拌样，采用快速制备色谱仪分离(石油醚：乙酸乙酯＝梯度洗脱，从1：0到1：4)得到目标化合物BB-8(淡黄色油状液体，800mg)。MS(ESI)m/z：245[M+H-tBu]+。Compound BB-8-1 (400.00 mg) was dissolved in N,N-dimethylformamide (15.00 mL). Compound BB-8-2 (988.13 mg), HATU (1.75 g), N, N Diisopropylethylamine (1.49 g), and the reaction solution was reacted at 15 ° C for 1.5 hours. 30 mL of ethyl acetate was added to the reaction mixture, and brine (30 mL*4) was evaporated. The crude product was dissolved in 15 mL of ethyl acetate. The mixture was applied to silica gel, and purified by flash chromatography ( petroleum ether: ethyl acetate = gradient elution from 1:0 to 1:4) to give the title compound BB-8 (light yellow) Oily liquid, 800 mg). MS (ESI) m / z: 245 [M+H-tBu] + .
参考例9：化合物BB-9的合成Reference Example 9: Synthesis of Compound BB-9
Figure PCTCN2017109922-appb-000206
Figure PCTCN2017109922-appb-000206
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000207
Figure PCTCN2017109922-appb-000207
以化合物BB-9-1，BB-9-2为原料，参考参考例7中化合物BB-7合成步骤，合成化合物BB-9。MS(ESI)m/z：323[M+Na]+。 Starting from the compound BB-9-1, BB-9-2, the compound BB-9 was synthesized by referring to the synthesis procedure of the compound BB-7 in Reference Example 7. MS (ESI) m / z: 323 [M+Na] + .
参考例10：化合物BB-10的合成Reference Example 10: Synthesis of Compound BB-10
Figure PCTCN2017109922-appb-000208
Figure PCTCN2017109922-appb-000208
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000209
Figure PCTCN2017109922-appb-000209
以化合物BB-10-1，BB-10-2为原料，参考参考例7中化合物BB-7合成步骤，合成化合物BB-10。MS(ESI)m/z：301[M+H]+。Starting from the compound BB-10-1, BB-10-2, the compound BB-10 was synthesized by referring to the synthesis procedure of the compound BB-7 in Reference Example 7. MS (ESI) m / z: 301 [M+H] + .
参考例11：化合物BB-11的合成Reference Example 11: Synthesis of Compound BB-11
Figure PCTCN2017109922-appb-000210
Figure PCTCN2017109922-appb-000210
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000211
Figure PCTCN2017109922-appb-000211
步骤1：化合物BB-11-3的合成Step 1: Synthesis of Compound BB-11-3
将化合物BB-1-1(1.28g)溶于吡啶(15.00mL)，然后在0℃缓慢加入化合物BB-11-2(1.00g)，该反应液在15℃搅拌12小时。将反应液倒入30mL乙酸乙酯中，过滤除去析出的白色固体，剩余有机相用2mol/L的稀盐酸洗涤至pH为2。然后有机相用无水硫酸钠干燥，过滤，浓缩得到粗品。该粗品通过快速制备色谱仪分离纯化(石油醚：乙酸乙酯＝3：1)得到目标化合物BB-11-3(白色固体，1.00g)。MS(ESI)m/z：478[M+H]+。Compound BB-1-1 (1.28 g) was dissolved in pyridine (15.00 mL), then compound BB-11-2 (1.00 g) was slowly added at 0 ° C, and the mixture was stirred at 15 ° C for 12 hours. The reaction liquid was poured into 30 mL of ethyl acetate, and the precipitated white solid was removed by filtration, and the remaining organic phase was washed with 2 mol/L of diluted hydrochloric acid to pH 2. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated The crude product was separated and purified (EtOAc:EtOAc:EtOAc) MS (ESI) m / z: 478[M+H] + .
步骤2：化合物BB-11的合成Step 2: Synthesis of Compound BB-11
将化合物BB-11-3(1.00g)溶于1,4-二氧六环(10.00mL)，然后加入氢氧化钾水溶液(4mol/L，2.09mL)，该反应液在100℃搅拌1小时。将反应液浓缩，剩余水相用乙酸乙酯(10mL*3)萃取，有机相用无水硫酸钠干燥，过滤，浓缩得到淡黄色粗产品。该产品通过石油醚(10mL)打浆纯化。纯化后旋干得到目标化合物BB-11(淡黄色固体，350mg)。MS(ESI)m/z：337[M+H]+。Compound BB-11-3 (1.00 g) was dissolved in 1,4-dioxane (10.00 mL), then aqueous potassium hydroxide solution (4 mol/L, 2.09 mL) was added, and the mixture was stirred at 100 ° C for 1 hour. . The reaction mixture was concentrated, EtOAcqqqqqqqqqq The product was purified by pulping with petroleum ether (10 mL). After purification, it was dried to give the title compound BB-11 (light yellow solid, 350 mg). MS (ESI) m / z: 337[M+H] + .
参考例12：化合物BB-12的合成 Reference Example 12: Synthesis of Compound BB-12
Figure PCTCN2017109922-appb-000212
Figure PCTCN2017109922-appb-000212
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000213
Figure PCTCN2017109922-appb-000213
将化合物BB-12-1(1.00g，)和吡啶(29.40g，30.00mL)置于反应瓶中，0℃下缓慢加入化合物BB-1-2(2.13g)，反应液升温至15℃下反应16小时。反应液用6mol/L的盐酸水溶液调节pH至4左右，乙酸乙酯萃取(20mL*3)，合并有机相并用无水硫酸钠干燥，过滤浓缩得到粗品。粗品用15mL乙酸乙酯溶解，用二氧化硅拌样，采用快速制备色谱仪分离(石油醚：乙酸乙酯＝梯度洗脱，从1：0到10：1)得到目标化合物BB-12(白色固体，2.00g)。MS(ESI)m/z：274[M+H]+。Compound BB-12-1 (1.00 g,) and pyridine (29.40 g, 30.00 mL) were placed in a reaction flask, and compound BB-1-2 (2.13 g) was slowly added at 0 ° C, and the reaction solution was heated to 15 ° C. The reaction was continued for 16 hours. The reaction mixture was adjusted to pH 4 with a 6 mol/L aqueous solution of hydrochloric acid, and ethyl acetate (20 mL*3). The crude product was dissolved in 15 mL of ethyl acetate, and the mixture was applied to silica, and purified by flash chromatography ( petroleum ether: ethyl acetate = gradient elution from 1:0 to 10:1) Solid, 2.00 g). MS (ESI) m / z: 274 [M+H] + .
参考例13：化合物BB-13的合成Reference Example 13: Synthesis of Compound BB-13
Figure PCTCN2017109922-appb-000214
Figure PCTCN2017109922-appb-000214
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000215
Figure PCTCN2017109922-appb-000215
将化合物BB-1-1(300.00mg)溶于N,N-二甲基甲酰胺(2.00mL)中，将反应体系温度降至0℃，将氢化钠(79.60mg，60％纯度)加入反应体系，然后在0℃下将化合物BB-13-1(307.40mg)加入反应体系，20℃下搅拌2小时。将水(10mL)加入反应体系，乙酸乙酯(3*15mL)萃取，无水硫酸钠干燥，将有机相旋干得黄色油状物的粗产物。粗产物经柱层析(石油醚：乙酸乙酯＝4：1)得目标化合物BB-13(淡黄色油状物，215mg)。MS(ESI)m/z：342[M+H]+。Compound BB-1-1 (300.00 mg) was dissolved in N,N-dimethylformamide (2.00 mL), the temperature of the reaction system was lowered to 0 ° C, and sodium hydride (79.60 mg, 60% purity) was added to the reaction. The system was then charged with compound BB-13-1 (307.40 mg) at 0 ° C and stirred at 20 ° C for 2 hours. Water (10 mL) was added to aq. The title compound BB-13 (yield: EtOAc, EtOAc) MS (ESI) m / z: 342[M+H] + .
参考例14：化合物BB-14的合成Reference Example 14: Synthesis of Compound BB-14
Figure PCTCN2017109922-appb-000216
Figure PCTCN2017109922-appb-000216
合成路线： synthetic route:
Figure PCTCN2017109922-appb-000217
Figure PCTCN2017109922-appb-000217
将化合物BB-14-1(1.00g)与吡啶(24.50g，25.00mL)置于反应瓶中，0℃下缓慢加入化合物BB-1-2(1.31g)，再升温至15℃下反应16小时。反应液用6mol/L的盐酸水溶液调节pH至4左右，乙酸乙酯萃取(20mL*3)，合并并用无水硫酸钠干燥有机相，过滤浓缩得到粗品。粗品采用15mL乙酸乙酯溶解，二氧化硅拌样，采用快速制备色谱仪分离(石油醚：乙酸乙酯＝梯度洗脱，从1：0到10：1)得到目标化合物BB-14(浅棕色固体，1.75g)。MS(ESI)m/z：336[M+H]+。Compound BB-14-1 (1.00 g) and pyridine (24.50 g, 25.00 mL) were placed in a reaction flask, and compound BB-1-2 (1.31 g) was slowly added at 0 ° C, and the temperature was raised to 15 ° C to react 16 hour. The reaction mixture was adjusted to pH 4 with a 6 mol/L aqueous hydrochloric acid solution, and ethyl acetate (20 mL*3) was evaporated. The crude product was dissolved in 15 mL of ethyl acetate, and the mixture was mixed with silica, and purified by rapid preparative chromatography ( petroleum ether: ethyl acetate = gradient elution from 1:0 to 10:1) to give the title compound BB-14 (light brown) Solid, 1.75 g). MS (ESI) m / z: 336 [M+H] + .
参考例15：化合物BB-15的合成Reference Example 15: Synthesis of Compound BB-15
Figure PCTCN2017109922-appb-000218
Figure PCTCN2017109922-appb-000218
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000219
Figure PCTCN2017109922-appb-000219
将化合物BB-1-1(1.00g)溶于N,N-二甲基甲酰胺(10.00mL)，然后0℃加入氢化钠(306.60mg，60％纯度)，搅拌0.5小时后缓慢分批加入化合物BB-15-1(1.11g，)，该反应液在20℃搅拌40分钟。反应完毕后，再加入30mL乙酸乙酯，并用水(10mL*3)洗涤，有机相用无水硫酸钠干燥，过滤。浓缩得到目标产物的粗产品。该粗产品通过快速制备色谱仪(石油醚：乙酸乙酯＝5：1)纯化后得到目标化合物BB-15(淡黄色固体，1.50g)。MS(ESI)m/z：376[M+H]+。Compound BB-1-1 (1.00 g) was dissolved in N,N-dimethylformamide (10.00 mL), then sodium hydride (306.60 mg, 60% purity) was added at 0 ° C, stirred for 0.5 hour and then slowly added in portions. Compound BB-15-1 (1.11 g,), the reaction was stirred at 20 ° C for 40 min. After completion of the reaction, 30 mL of ethyl acetate was added and washed with water (10 mL*3). Concentration gives the crude product of the desired product. The crude product was purified by EtOAc (EtOAc:EtOAc:EtOAc) MS (ESI) m / z: 376 [M+H] + .
参考例16：化合物BB-16的合成Reference Example 16: Synthesis of Compound BB-16
Figure PCTCN2017109922-appb-000220
Figure PCTCN2017109922-appb-000220
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000221
Figure PCTCN2017109922-appb-000221
步骤1：化合物BB-16-2的合成Step 1: Synthesis of Compound BB-16-2
将化合物BB-16-1(5.00g)溶于醋酸(100.00mL)中，再加入铁粉(5.37g)，反应液在100℃下反应2小时。反应液过滤，滤液浓缩得到粗品，粗品再加20mL水稀释，用4mol/L氢氧化钠水溶液调节pH至8左右，再用乙酸乙酯萃取(35mL*3)，无水硫酸钠干燥，过滤，滤液浓缩得到粗品。所得的粗品用20mL乙酸乙酯溶解，二氧化硅拌样，采用快速制备色谱仪分离(石油醚：乙酸乙酯＝梯度洗脱，从1：0到20：1)得到目标化合物BB-16-2(浅棕色油状液体，3.75g)。MS(ESI)m/z：230[M+H]+。Compound BB-16-1 (5.00 g) was dissolved in acetic acid (100.00 mL), and then iron powder (5.37 g) was added, and the reaction mixture was reacted at 100 ° C for 2 hours. The reaction liquid was filtered, and the filtrate was concentrated to give a crude product. The crude product was diluted with 20 mL of water, and the pH was adjusted to about 8 with 4 mol/L sodium hydroxide aqueous solution, and then extracted with ethyl acetate (35 mL*3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give a crude material. The obtained crude product was dissolved in 20 mL of ethyl acetate, and the mixture was mixed with silica, and then purified by a rapid preparative chromatograph ( petroleum ether: ethyl acetate = gradient elution from 1:0 to 20:1) to obtain the target compound BB-16- 2 (light brown oily liquid, 3.75 g). MS (ESI) m / z: 230 [M+H] + .
步骤2：化合物BB-16-3的合成Step 2: Synthesis of Compound BB-16-3
将化合物BB-16-2(2.00g)溶于吡啶(40.00mL)中，在0℃下加入化合物BB-1-2(5.50g)，反应液在15℃下反应16小时。反应液加水60mL稀释，6mol/L盐酸水溶液调节pH至5左右，乙酸乙酯萃取(40mL*3)，收集有机相并用无水硫酸钠干燥，过滤，浓缩得到粗品。粗品采用30mL二氯甲烷溶解，二氧化硅拌样，采用快速制备色谱仪分离(石油醚：二氯甲烷＝梯度洗脱，从1：0到4：1)得到目标化合物BB-16-3(白色固体，3.30g)。MS(ESI)m/z：580[M+H]+。Compound BB-16-2 (2.00 g) was dissolved in pyridine (40.00 mL), and compound BB-1-2 (5.50 g) was added at 0 ° C, and the reaction mixture was reacted at 15 ° C for 16 hours. The reaction solution was diluted with water (60 mL), and the mixture was adjusted to pH 5 with a 6 mol/L aqueous hydrochloric acid solution, and ethyl acetate (40 mL*3) was obtained. The organic phase was collected and dried over anhydrous sodium sulfate. The crude product was dissolved in 30 mL of dichloromethane, and the mixture was mixed with silica. The title compound BB-16-3 was obtained by rapid preparative chromatography (petroleum ether: dichloromethane = gradient elution from 1:0 to 4:1). White solid, 3.30 g). MS (ESI) m/z: 580[M+H] + .
步骤3：化合物BB-16的合成Step 3: Synthesis of Compound BB-16
将化合物BB-16-3(1.00g)溶于1,4-二氧六环(6.00mL)和水(4.00mL)中，再加入氢氧化钾(194.14mg)，反应液在100℃下反应3小时。反应液浓缩，再加10mL水，6mol/L盐酸调节pH至7左右，乙酸乙酯萃取(20mL*3)，收集并用无水硫酸钠干燥有机相，过滤，浓缩得到目标化合物BB-16(灰白色固体，700mg)。MS(ESI)m/z：404[M+H]+。Compound BB-16-3 (1.00 g) was dissolved in 1,4-dioxane (6.00 mL) and water (4.00 mL), then potassium hydroxide (194.14 mg) was added and the reaction was reacted at 100 ° C 3 hours. The reaction solution was concentrated, and then added with 10 mL of water, and the pH was adjusted to about 7 with 6 mol/L hydrochloric acid, and extracted with ethyl acetate (20 mL*3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the object compound BB-16 Solid, 700 mg). MS (ESI) m / z: 404 [M+H] + .
参考例17：化合物BB-17的合成 Reference Example 17: Synthesis of Compound BB-17
Figure PCTCN2017109922-appb-000222
Figure PCTCN2017109922-appb-000222
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000223
Figure PCTCN2017109922-appb-000223
将化合物BB-1-1(3.00g)加入到吡啶(30.00mL)中，再在0℃下加入化合物BB-17-1(2.59g)，该反应液在15℃下反应16小时。反应液加200mL乙酸乙酯萃取，有机相用2mol/L盐酸水溶液洗至pH值小于4，饱和碳酸氢钠(50mL)洗涤，饱和食盐水洗涤(50mL)，无水硫酸钠干燥，过滤，滤液旋干得到目标化合物BB-17(白色固体，4.60g)。MS(ESI)m/z：300[M+H]+。Compound BB-1-1 (3.00 g) was added to pyridine (30.00 mL), and compound BB-17-1 (2.59 g) was added at 0 ° C, and the reaction mixture was reacted at 15 ° C for 16 hours. The reaction mixture was extracted with 200 mL of ethyl acetate. The organic phase was washed with 2 mol/L hydrochloric acid aqueous solution to pH value less than 4, washed with saturated sodium hydrogen carbonate (50 mL), brine (50 mL), dried over anhydrous sodium sulfate The title compound BB-17 (white solid, 4.60 g) was obtained. MS (ESI) m / z: 300 [M+H] + .
参考例18：化合物BB-18的合成Reference Example 18: Synthesis of Compound BB-18
Figure PCTCN2017109922-appb-000224
Figure PCTCN2017109922-appb-000224
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000225
Figure PCTCN2017109922-appb-000225
步骤1：化合物BB-18-2的合成Step 1: Synthesis of Compound BB-18-2
将化合物BB-18-1(1.00g)，氢氧化铵(425.78mg)溶于N,N-二甲基甲酰胺(10.00mL)，然后加入HATU(1.97g)和N,N-二异丙基乙胺(1.54g)，该反应液在20℃搅拌16小时。将反应液倒入20mL乙酸乙酯中，并用水(10mL*2)和饱和食盐水(5mL)洗涤，分液后，有机相用无水硫酸钠干燥，过滤，浓 缩得到淡黄色目标产物的粗产品(淡黄色固体)。该淡黄色固体通过石油醚打浆纯化得到目标化合物BB-18-2(淡黄色固体，800mg)。MS(ESI)m/z：251[M+H]+。Compound BB-18-1 (1.00 g), ammonium hydroxide (425.78 mg) was dissolved in N,N-dimethylformamide (10.00 mL), then HATU (1.97 g) and N,N-diisopropyl Ethylethylamine (1.54 g), the reaction was stirred at 20 ° C for 16 hours. The reaction mixture was poured into ethyl acetate (20 mL), EtOAc (EtOAc) Product (light yellow solid). The pale yellow solid was purified by petroleum ether to afford title compound </RTI> MS (ESI) m / z: 251 [M+H] + .
步骤2：化合物BB-18-4的合成Step 2: Synthesis of Compound BB-18-4
将化合物BB-18-2(300.00mg)，化合物BB-18-3(199.56mg)溶于EA(2.00mL)，然后加入三氟乙酸银(406.42mg)，并将该反应液在70℃搅拌20小时。将反应液过滤，滤液旋干得到淡黄色粗产品。该粗产品通过快速制备色谱仪分离纯化(石油醚：乙酸乙酯＝2：1)后得到目标化合物BB-18-4(无色油状液体，120mg)。MS(ESI)m/z：259[M+H-tBu]+。Compound BB-18-2 (300.00 mg), compound BB-18-3 (199.56 mg) was dissolved in EA (2.00 mL), then silver trifluoroacetate (406.42 mg) was added, and the reaction mixture was stirred at 70 ° C. 20 hours. The reaction solution was filtered, and the filtrate was evaporated to dryness. The crude product was isolated and purified by EtOAc (EtOAc:EtOAc:EtOAc) MS (ESI) m / z: 259 [M+H-tBu] + .
步骤3：化合物BB-18的合成Step 3: Synthesis of Compound BB-18
将化合物BB-18-4(120.00mg)溶于二氯甲烷(1.00mL)，然后加入盐酸的二氧六环溶液(4mol/L，1.00mL)，该反应液在20℃搅拌1小时。将反应液浓缩得到目标化合物BB-18(白色固体，90mg，盐酸盐)，未经纯化直接用于下一步反应。MS(ESI)m/z：215[M+H]+。Compound BB-18-4 (120.00 mg) was dissolved in dichloromethane (1.00 mL), then a solution of hydrochloric acid in dioxane (4 mol/L, 1.00 mL) was added, and the mixture was stirred at 20 ° C for 1 hour. The reaction mixture was concentrated to give the title compound br. MS (ESI) m / z: 215 [M+H] + .
参考例19：化合物BB-19的合成Reference Example 19: Synthesis of Compound BB-19
Figure PCTCN2017109922-appb-000226
Figure PCTCN2017109922-appb-000226
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000227
Figure PCTCN2017109922-appb-000227
以化合物BB-19-1和化合物BB-1-2为原料，参考参考例1中化合物BB-1合成步骤，合成化合物BB-19。MS(ESI)m/z：327[M+H]+。Starting from the compound BB-19-1 and the compound BB-1-2, the compound BB-19 was synthesized by referring to the synthesis procedure of the compound BB-1 in Reference Example 1. MS (ESI) m / z: 327[M+H] + .
参考例20：化合物BB-20的合成Reference Example 20: Synthesis of Compound BB-20
Figure PCTCN2017109922-appb-000228
Figure PCTCN2017109922-appb-000228
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000229
Figure PCTCN2017109922-appb-000229
步骤1：化合物BB-20-2的合成Step 1: Synthesis of Compound BB-20-2
将化合物BB-20-1(1.00g)溶于二氯甲烷(10.00mL)，然后加入甲烷磺酰氯(698.71mg)和N,N-二 异丙基乙胺(772.86mg)，该反应液在20℃搅拌1小时，反应完毕后将反应液倒入20mL二氯甲烷中并用水10mL洗涤，有机相浓缩后得到目标化合物BB-20-2(淡黄色油状液体，1.47g)，未经纯化直接用于下一步反应。MS(ESI)m/z：246[M+H]+。Compound BB-20-1 (1.00 g) was dissolved in dichloromethane (10.00 mL), then methanesulfonyl chloride (698.71 mg) and N,N-diisopropylethylamine (772.86 mg) were added. After stirring at 20 ° C for 1 hour, the reaction mixture was poured into 20 mL of dichloromethane and washed with water (10 mL), and the organic phase was concentrated to give the title compound BB-20-2 (light yellow oily liquid, 1.47 g) Used for the next reaction. MS (ESI) m / z: 246[M+H] + .
步骤2：化合物BB-20-3的合成Step 2: Synthesis of Compound BB-20-3
将化合物BB-20-2(1.40g)溶于N,N-二甲基甲酰胺(10.00mL)然后加入叠氮钠(630.00mg)，该反应液在60℃搅拌1.5小时。将反应液倒入50mL乙酸乙酯中，并用饱和碳酸氢钠溶液(10mL*3)和水(10mL*2)洗涤，有机相干燥后浓缩至10mL，得到目标化合物BB-20-3的乙酸乙酯溶液，该目标化合物的乙酸乙酯溶液直接用于下一步反应。MS(ESI)m/z：193[M+H]+。Compound BB-20-2 (1.40 g) was dissolved in N,N-dimethylformamide (10.00 mL) and then sodium azide (630.00 mg) was added, and the mixture was stirred at 60 ° C for 1.5 hours. The reaction solution was poured into 50 mL of ethyl acetate and washed with a saturated sodium hydrogen carbonate solution (10 mL*3) and water (10 mL*2), and the organic phase was dried and concentrated to 10 mL to give the title compound BB-20-3 The ester solution, the ethyl acetate solution of the target compound was directly used for the next reaction. MS (ESI) m / z: 193 [M+H] + .
步骤3：化合物BB-20的合成Step 3: Synthesis of Compound BB-20
向步骤2中拿到的化合物BB-20-3(780.00mg)的乙酸乙酯溶液(10mL)中加入Pd/C(100.00mg，10％纯度)，并在氢气(15psi)的氛围下20℃搅拌2小时。将反应液过滤后浓缩得到目标化合物BB-20(淡黄色油状液体，670.00mg)。MS(ESI)m/z：167[M+H]+。To a solution of compound BB-20-3 (780.00 mg) in ethyl acetate (10 mL) obtained in step 2, Pd/C (100.00 mg, 10% purity) was added, and under a hydrogen atmosphere (15 psi) at 20 ° C Stir for 2 hours. The reaction mixture was filtered and concentrated to give the title compound 246. MS (ESI) m / z: 167[M+H] + .
参考例21：化合物BB-21的合成Reference Example 21: Synthesis of Compound BB-21
Figure PCTCN2017109922-appb-000230
Figure PCTCN2017109922-appb-000230
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000231
Figure PCTCN2017109922-appb-000231
以化合物BB-21-1，BB-1-2为原料，参考参考例1中化合物BB-1合成步骤，合成化合物BB-21。MS(ESI)m/z：336[M+H]+。Starting from the compound BB-21-1, BB-1-2, the compound BB-21 was synthesized by referring to the synthesis procedure of the compound BB-1 in Reference Example 1. MS (ESI) m / z: 336 [M+H] + .
参考例22：化合物BB-22的合成 Reference Example 22: Synthesis of Compound BB-22
Figure PCTCN2017109922-appb-000232
Figure PCTCN2017109922-appb-000232
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000233
Figure PCTCN2017109922-appb-000233
以化合物BB-21，化合物0493-1为原料，参考实施例1中合成步骤1-2合成化合物0493-3的方法，合成化合物BB-22。MS(ESI)m/z：422[M+H]+。Compound BB-22 was synthesized by the method of synthesizing compound 0493-3 with reference to the synthesis of Step 1-2 in Example 1 using Compound BB-21, Compound 0493-1 as a starting material. MS (ESI) m / z: 422[M+H] + .
参考例23：化合物BB-23的合成Reference Example 23: Synthesis of Compound BB-23
Figure PCTCN2017109922-appb-000234
Figure PCTCN2017109922-appb-000234
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000235
Figure PCTCN2017109922-appb-000235
将化合物BB-23-1(1.00g)溶于乙醇(10.00mL)，然后加入雷尼镍(239.02mg)和氨水(1.00mL)， 用氮气置换三次后，反应液在氢气(15psi)氛围下25℃搅拌16小时。反应完毕后将反应液过滤，滤液浓缩得到粗产品。该粗产品通过快速制备色谱仪分离纯化(石油醚：乙酸乙酯＝1：1)后得到目标化合物BB-23(无色油状液体，120.00mg)。MS(ESI)m/z：184[M+H]+。Compound BB-23-1 (1.00 g) was dissolved in ethanol (10.00 mL), then Raney nickel (239.02 mg) and aqueous ammonia (1.00 mL) were added, and after replacing three times with nitrogen, the reaction solution was under hydrogen (15 psi) atmosphere. Stir at 25 ° C for 16 hours. After completion of the reaction, the reaction liquid was filtered, and the filtrate was concentrated to give a crude product. The crude product was isolated and purified by EtOAc (EtOAc:EtOAc:EtOAc) MS (ESI) m / z: 184 [M+H] + .
参考例24：化合物BB-24的合成Reference Example 24: Synthesis of Compound BB-24
Figure PCTCN2017109922-appb-000236
Figure PCTCN2017109922-appb-000236
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000237
Figure PCTCN2017109922-appb-000237
以化合物BB-24-1，BB-1-2为原料，参考参考例1中化合物BB-1合成步骤1，合成参考例BB-24。MS(ESI)m/z：293[M+H]+。Reference compound BB-24-1, BB-1-2 was used as a starting material, and Reference Example BB-24 was synthesized by referring to Synthesis Compound BB-1 in Reference Example 1. MS (ESI) m / z: 293 [M+H] + .
参考例25：化合物BB-25的合成Reference Example 25: Synthesis of Compound BB-25
Figure PCTCN2017109922-appb-000238
Figure PCTCN2017109922-appb-000238
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000239
Figure PCTCN2017109922-appb-000239
以化合物BB-24，化合物0493-1为原料，参考实施例1中合成步骤1-2合成化合物0493-3的方法，合成化合物BB-25。MS(ESI)m/z：379[M+H]+。Using the compound BB-24, the compound 0493-1 as a starting material, the compound 049-25 was synthesized by the method of synthesizing the compound 0493-3 in the synthesis of the step 1-2 in Example 1. MS (ESI) m / z: 379[M+H] + .
参考例26：化合物BB-26的合成Reference Example 26: Synthesis of Compound BB-26
Figure PCTCN2017109922-appb-000240
Figure PCTCN2017109922-appb-000240
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000241
Figure PCTCN2017109922-appb-000241
以化合物BB-26-1，BB-1-2为原料，参考参考例1中化合物BB-1合成步骤，合成化合物BB-26。MS(ESI)m/z：294[M+H]+。Starting from the compound BB-26-1, BB-1-2, the compound BB-26 was synthesized by referring to the synthesis procedure of the compound BB-1 in Reference Example 1. MS (ESI) m / z: 294[M+H] + .
参考例27：化合物BB-27的合成Reference Example 27: Synthesis of Compound BB-27
Figure PCTCN2017109922-appb-000242
Figure PCTCN2017109922-appb-000242
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000243
Figure PCTCN2017109922-appb-000243
以化合物BB-27-1，BB-1-2为原料，参考参考例1中化合物BB-1合成步骤，合成化合物BB-27。MS(ESI)m/z：337[M+H]+。Using the compound BB-27-1, BB-1-2 as a starting material, the compound BB-1 was synthesized by referring to the synthesis procedure of the compound BB-1 in Reference Example 1. MS (ESI) m / z: 337[M+H] + .
参考例28：化合物BB-28的合成Reference Example 28: Synthesis of Compound BB-28
Figure PCTCN2017109922-appb-000244
Figure PCTCN2017109922-appb-000244
合成路线： synthetic route:
Figure PCTCN2017109922-appb-000245
Figure PCTCN2017109922-appb-000245
以化合物BB-28-1，化合物BB-1-2为原料，参考参考例1中化合物BB-1合成步骤，合成化合物BB-28。MS(ESI)m/z：288[M+H]+。Starting from the compound BB-28-1, the compound BB-1-2, the compound BB-28 was synthesized by referring to the synthesis procedure of the compound BB-1 in Reference Example 1. MS (ESI) m / z: 288[M+H] + .
参考例29：化合物BB-29的合成Reference Example 29: Synthesis of Compound BB-29
Figure PCTCN2017109922-appb-000246
Figure PCTCN2017109922-appb-000246
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000247
Figure PCTCN2017109922-appb-000247
以化合物BB-29-1，化合物BB-1-2为原料，参考参考例1中化合物BB-1合成步骤，合成化合物BB-29。MS(ESI)m/z：274[M+H]+。Compound BB-29-1, compound BB-1-2 was used as a starting material, and compound BB-29 was synthesized by referring to the synthesis procedure of compound BB-1 in Reference Example 1. MS (ESI) m / z: 274 [M+H] + .
参考例30：化合物BB-30的合成Reference Example 30: Synthesis of Compound BB-30
Figure PCTCN2017109922-appb-000248
Figure PCTCN2017109922-appb-000248
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000249
Figure PCTCN2017109922-appb-000249
以化合物BB-1-1，化合物BB-30-1为原料，参考参考例17中化合物BB-17合成步骤，合成化合物BB-30。MS(ESI)m/z：334[M+H]+。Starting from the compound BB-1-1, the compound BB-30-1, the compound BB-30 was synthesized by referring to the synthesis procedure of the compound BB-17 in Reference Example 17. MS (ESI) m/z: 384[M+H] + .
参考例31：化合物BB-31的合成 Reference Example 31: Synthesis of Compound BB-31
Figure PCTCN2017109922-appb-000250
Figure PCTCN2017109922-appb-000250
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000251
Figure PCTCN2017109922-appb-000251
以化合物BB-31-1，化合物BB-1-1为原料，参考参考例1中化合物BB-1合成步骤，合成化合物BB-31。MS(ESI)m/z：340[M+H]+。Starting from the compound BB-31-1, the compound BB-1-1, the compound BB-1 was synthesized by referring to the synthesis procedure of the compound BB-1 in Reference Example 1. MS (ESI) m / z: 340 [M+H] + .
参考例32：化合物BB-32的合成Reference Example 32: Synthesis of Compound BB-32
Figure PCTCN2017109922-appb-000252
Figure PCTCN2017109922-appb-000252
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000253
Figure PCTCN2017109922-appb-000253
以化合物BB-32-1，化合物BB-1-1为原料，参考参考例1中化合物BB-1合成步骤，合成化合物BB-32。MS(ESI)m/z：340[M+H]+。Starting from the compound BB-32-1, the compound BB-1-1, the compound BB-32 was synthesized by referring to the synthesis procedure of the compound BB-1 in Reference Example 1. MS (ESI) m / z: 340 [M+H] + .
参考例33：化合物BB-33的合成Reference Example 33: Synthesis of Compound BB-33
Figure PCTCN2017109922-appb-000254
Figure PCTCN2017109922-appb-000254
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000255
Figure PCTCN2017109922-appb-000255
以化合物BB-1-2，化合物BB-33-1为原料，参考参考例1中化合物BB-1合成步骤，合成化合物BB-33。MS(ESI)m/z：343[M+H]+。Starting from the compound BB-1-2, the compound BB-33-1, the compound BB-1 was synthesized by referring to the synthesis procedure of the compound BB-1 in Reference Example 1. MS (ESI) m / z: 343[M+H] + .
参考例34：化合物BB-34的合成 Reference Example 34: Synthesis of Compound BB-34
Figure PCTCN2017109922-appb-000256
Figure PCTCN2017109922-appb-000256
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000257
Figure PCTCN2017109922-appb-000257
以化合物BB-1-1，化合物BB-34-1为原料，参考参考例1中化合物BB-1合成步骤，合成化合物BB-34。MS(ESI)m/z：340[M+H]+。Starting from the compound BB-1-1, the compound BB-34-1, the compound BB-1 was synthesized by referring to the synthesis procedure of the compound BB-1 in Reference Example 1. MS (ESI) m / z: 340 [M+H] + .
参考例35：化合物BB-35的合成Reference Example 35: Synthesis of Compound BB-35
Figure PCTCN2017109922-appb-000258
Figure PCTCN2017109922-appb-000258
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000259
Figure PCTCN2017109922-appb-000259
以化合物BB-27-1，化合物BB-34-1为原料，参考参考例1中化合物BB-1合成步骤，合成化合物BB-35。MS(ESI)m/z：307[M+H]+。Starting from the compound BB-27-1, the compound BB-34-1, the compound BB-1 was synthesized by referring to the synthesis procedure of the compound BB-1 in Reference Example 1. MS (ESI) m / z: 307 [M+H] + .
参考例36：化合物BB-36的合成Reference Example 36: Synthesis of Compound BB-36
Figure PCTCN2017109922-appb-000260
Figure PCTCN2017109922-appb-000260
合成路线： synthetic route:
Figure PCTCN2017109922-appb-000261
Figure PCTCN2017109922-appb-000261
步骤1：化合物BB-36-2的合成Step 1: Synthesis of Compound BB-36-2
将化合物BB-1(900.00mg)溶于四氢呋喃(10.00mL)，冷却至0℃，加入氢化钠(213.84mg，纯度60％)，0℃反应0.5小时，然后加入溴乙酸乙酯(BB-36-1,649.30mg)，升温至25℃反应12小时。加入饱和氯化氨溶液(30mL)淬灭反应，反应液用乙酸乙酯萃取(20mL*2)，合并有机相，饱和食盐水洗涤(10mL*2)，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品经硅胶柱层析(石油醚：乙酸乙酯＝10：1)纯化得到目标化合物BB-36-2(浅黄色固体，700mg)。MS(ESI)m/z：456[M+H]+。Compound BB-1 (900.00 mg) was dissolved in tetrahydrofuran (10.00 mL), cooled to 0 ° C, sodium hydride (213.84 mg, purity 60%) was added, and reacted at 0 ° C for 0.5 hour, then ethyl bromoacetate (BB-36) was added. -1,649.30 mg), and the mixture was heated to 25 ° C for 12 hours. The reaction was quenched with aq. EtOAc (EtOAc) (EtOAc (EtOAc) Crude. The crude product was purified by silica gel chromatography chromatography eluting elut elut elut elut MS (ESI) m / z: 456 [M+H] + .
步骤2：化合物BB-36的合成Step 2: Synthesis of Compound BB-36
将化合物BB-36-2(700.00mg)溶于1,4-二氧六环(10.00mL)和水(1.00mL)中，加入一水合氢氧化锂(250.00mg)，此反应液于25℃反应3小时。减压蒸馏下除去1,4-二氧六环，水相用2mol/L的盐酸水溶液调节pH至2，乙酸乙酯萃取(20mL*2)，合并有机相，无水硫酸钠干燥，过滤，浓缩得到目标化合物BB-36(浅黄色固体，600mg)。MS(ESI)m/z：428[M+H]+。Compound BB-36-2 (700.00 mg) was dissolved in 1,4-dioxane (10.00 mL) and water (1.00 mL), and lithium hydroxide monohydrate (250.00 mg) was added at 25 ° C Reaction for 3 hours. The 1,4-dioxane was removed by distillation under reduced pressure, and the aqueous phase was adjusted to pH 2 with 2 mol/L aqueous hydrochloric acid, ethyl acetate (20 mL*2). Concentration gave the title compound BB-36 (light yellow solid, 600mg). MS (ESI) m / z: 428 [M+H] + .
实施例1：化合物0493的合成Example 1: Synthesis of Compound 0493
Figure PCTCN2017109922-appb-000262
Figure PCTCN2017109922-appb-000262
合成路线： synthetic route:
Figure PCTCN2017109922-appb-000263
Figure PCTCN2017109922-appb-000263
步骤1：化合物0493-2的合成Step 1: Synthesis of Compound 0493-2
将化合物BB-1(1.00g)，化合物0493-1(374.67mg)溶于甲苯(15.00mL)中，再依次加入偶氮二甲酸二异丙酯(573.27mg，)，三苯基磷(743.59mg)，反应液在氮气保护下90℃反应16小时。反应液浓缩得到粗品。粗品用20mL二氯甲烷溶解，二氧化硅拌样，采用快速制备色谱仪分离(石油醚：乙酸乙酯＝梯度洗脱，从1：0到10：1)得到目标化合物0493-2(白色固体，1.05g)。MS(ESI)m/z：484[M+H]+。Compound BB-1 (1.00 g), compound 0493-1 (374.67 mg) was dissolved in toluene (15.00 mL), followed by diisopropyl azodicarboxylate (573.27 mg,), triphenylphosphine (743.59) Mg), the reaction solution was reacted at 90 ° C for 16 hours under a nitrogen atmosphere. The reaction solution was concentrated to give a crude material. The crude product was dissolved in 20 mL of dichloromethane, and the mixture was applied to silica gel, and purified by flash chromatography (ethyl ether: ethyl acetate = gradient elution from 1:0 to 10:1) to give the title compound , 1.05g). MS (ESI) m / z: 484 [M+H] + .
步骤2：化合物0493-3的合成Step 2: Synthesis of Compound 0493-3
将化合物0493-2(1.05g)溶于四氢呋喃(30.00mL)和水(10.00mL)中，再加入一水合氢氧化锂(136.58mg)，反应液在15℃下反应48小时。反应液浓缩，再加5mL水稀释，用6mol/L的盐酸水溶液调节pH至4左右，再用乙酸乙酯萃取(15mL*3)，合并干燥并浓缩有机相得到粗品。粗品用15mL乙酸乙酯溶解，二氧化硅拌样，采用快速制备色谱仪分离(石油醚：乙酸乙酯＝梯度洗脱，从1：0到3：1)得到目标化合物0493-3(米白色固体，400mg)。MS(ESI)m/z：456[M+H]+。Compound 0493-2 (1.05 g) was dissolved in tetrahydrofuran (30.00 mL) and water (10.00 mL), and then lithium hydroxide monohydrate (136.58 mg) was added, and the reaction mixture was reacted at 15 ° C for 48 hours. The reaction mixture was concentrated, diluted with 5 mL of water, and then adjusted to pH 4 with 6 mol/L aqueous hydrochloric acid, and then extracted with ethyl acetate (15 mL*3), dried and concentrated to give a crude product. The crude product was dissolved in 15 mL of ethyl acetate. EtOAc (EtOAc) Solid, 400 mg). MS (ESI) m / z: 456 [M+H] + .
步骤3：化合物0493的合成Step 3: Synthesis of Compound 0493
将化合物0493-3(1.10g)溶于N,N-二甲基甲酰胺(20.00mL)中，依次加入化合物BB-3(561.27mg，盐酸盐)，HATU(913.03mg)，N,N-二异丙基乙胺(1.03g)，反应液在15℃下反应1小时。反应液加水80mL稀释，乙酸乙酯萃取(25mL*3)，合并有机相，用无水硫酸钠干燥，过滤，浓缩得到粗品。粗品用20mL乙酸乙酯溶解，二氧化硅拌样，采用快速制备色谱仪分离(石油醚：乙酸乙酯＝梯度洗脱，从1：0到1：4)得到目标化合物0493(490mg)。MS(ESI)m/z：657[M+Na]+。Compound 0493-3 (1.10 g) was dissolved in N,N-dimethylformamide (20.00 mL). Compound BB-3 (561.27 mg, hydrochloride), HATU (913.03 mg), N, N Diisopropylethylamine (1.03 g), and the reaction solution was reacted at 15 ° C for 1 hour. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The crude product was dissolved in ethyl acetate (20 mL), EtOAc (EtOAc:EtOAc) MS (ESI) m/z: 657[M+Na] + .
1H NMR(400MHz，MeOD-d4)：δ＝7.14-8.09(m，7H)，5.28-5.47(m，1H)，4.01-4.72(m，2H)，2.28-3.29(m，5H)，1.17-2.10(m，7H)，0.63-0.89(m，5H)，0.41-0.60(m，2H). 1 H NMR (400 MHz, MeOD-d4): δ=7.14-8.09 (m, 7H), 5.28-5.47 (m, 1H), 4.01-4.72 (m, 2H), 2.28-3.29 (m, 5H), 1.17 -2.10 (m, 7H), 0.63-0.89 (m, 5H), 0.41-0.60 (m, 2H).
实施例2：化合物0499的合成 Example 2: Synthesis of Compound 0499
Figure PCTCN2017109922-appb-000264
Figure PCTCN2017109922-appb-000264
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000265
Figure PCTCN2017109922-appb-000265
步骤1：化合物0499-1的合成Step 1: Synthesis of Compound 0499-1
将化合物BB-2(200.00mg)和化合物BB-1(203.85mg)溶于甲苯(6.00mL)中，再加入三苯基磷(148.80mg)和偶氮二甲酸二异丙酯(114.72mg)，反应液在110℃下氮气保护下反应6小时。反应液浓缩得到粗品。粗品采用快速制备色谱仪分离(石油醚：乙酸乙酯＝梯度洗脱，从1：0到3：1)得到目标化合物0499-1(淡黄色油状液体，170mg)。MS(ESI)m/z：566[M+H-Boc]+。Compound BB-2 (200.00 mg) and compound BB-1 (203.85 mg) were dissolved in toluene (6.00 mL), followed by triphenylphosphine (148.80 mg) and diisopropyl azodicarboxylate (114.72 mg). The reaction solution was reacted at 110 ° C for 6 hours under nitrogen atmosphere. The reaction solution was concentrated to give a crude material. The crude product was isolated using EtOAc (EtOAc:EtOAc:EtOAc:EtOAc MS (ESI) m/z: 564[M+H-Boc] + .
步骤2：化合物0499-2的合成Step 2: Synthesis of Compound 0499-2
将化合物0499-1(80.00mg)溶于二氯甲烷(2.00mL)中，再加入氯化氢的乙酸乙酯溶液(4M，3.00mL)，反应液在15℃下反应30min。反应浓缩得到目标化合物0499-2(淡黄色固体，70mg，盐酸盐)，直接用于下一步反应。MS(ESI)m/z：566[M+H]+。Compound 0499-1 (80.00 mg) was dissolved in dichloromethane (2.00 mL), and then ethyl hydrogen chloride in ethyl acetate (4M, 3.00 mL). The reaction was concentrated to give the title compound (md. MS (ESI) m / z: 566 [M+H] + .
步骤3：化合物0499的合成Step 3: Synthesis of Compound 0499
将化合物0499-2(70.00mg)溶于二氯甲烷(2.00mL)，再加入化合物BB-3-2(12.32mg)，N,N-二异丙基乙胺(47.91mg，64.74uL)，反应液在15℃下反应30min。反应液浓缩得到粗品。粗品用5mL甲醇溶解，采用高效液相色谱(DuraShell 150*25mm*5um，水(0.05％HCl)-ACN)分离得到目标化合物0499(6mg)。MS(ESI)m/z：649[M+H]+。Compound 0499-2 (70.00 mg) was dissolved in dichloromethane (2.00 mL), then compound BB-3-2 (12.32 mg), N,N-diisopropylethylamine (47.91 mg, 64.74 uL), The reaction solution was reacted at 15 ° C for 30 min. The reaction solution was concentrated to give a crude material. The crude product was dissolved in 5 mL of MeOH (methanol) (m.). MS (ESI) m / z: 495[M+H] + .
1HNMR(400MHz，MeOD-d4)：δ＝7.52-8.07(m，7H)，4.98-5.21(m，1H)，4.06-4.57(m，2H)，2.25-3.52(m，5H)，1.29-2.09(m，6H)，0.77-1.26(m，6H)，0.41-0.74(m，4H). 1 H NMR (400 MHz, MeOD-d4): δ=7.52-8.07 (m, 7H), 4.98-5.21 (m, 1H), 4.06-4.57 (m, 2H), 2.25-3.52 (m, 5H), 1.29- 2.09 (m, 6H), 0.77-1.26 (m, 6H), 0.41-0.74 (m, 4H).
实施例3：化合物0512的合成 Example 3: Synthesis of Compound 0512
Figure PCTCN2017109922-appb-000266
Figure PCTCN2017109922-appb-000266
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000267
Figure PCTCN2017109922-appb-000267
步骤1：化合物0512-2的合成Step 1: Synthesis of Compound 0512-2
将化合物BB-12(500.00mg)溶于甲苯(18.00mL)中，再依次加入化合物0512-1(226.99mg)，三苯基磷(503.99mg)，偶氮二甲酸二异丙酯(388.55mg)，反应液在氮气气氛下90℃反应16小时。反应液浓缩得到粗品。粗品用15mL乙酸乙酯溶解，二氧化硅拌样，采用快速制备色谱仪分离(石油醚：乙酸乙酯＝梯度洗脱，从1：0到3：1)得到目标化合物0512-2(淡黄色油状液体，500mg)。MS(ESI)m/z：374[M+H]+。Compound BB-12 (500.00 mg) was dissolved in toluene (18.00 mL), followed by compound 0512-1 (226.99 mg), triphenylphosphine (503.99 mg), diisopropyl azodicarboxylate (388.55 mg). The reaction solution was reacted at 90 ° C for 16 hours under a nitrogen atmosphere. The reaction solution was concentrated to give a crude material. The crude product was dissolved in 15 mL of ethyl acetate. EtOAc (EtOAc) Oily liquid, 500 mg). MS (ESI) m / z: 374 [M+H] + .
步骤2：化合物0512-3的合成Step 2: Synthesis of Compound 0512-3
将化合物0512-2(200.00mg)溶于四氢呋喃(5.00mL)和水(2.00mL)中，再加入一水合氢氧化锂(33.68mg)，反应液在15℃下反应5小时。反应液浓缩得到粗品，粗品加5mL水稀释，6mol/L的盐酸水溶液调节pH至6左右，乙酸乙酯萃取(10mL*3)，收集并用无水硫酸钠干燥有机相，过滤，浓缩得到粗品。粗品采用10mL乙酸乙酯溶解，二氧化硅拌样，采用快速制备色谱仪分离(石油醚：乙酸乙酯＝梯度洗脱，从1：0到1：4)得到目标化合物0512-3(淡黄色油状液体，150mg)。产物经SFC确认已经发生消旋。MS(ESI)m/z：360[M+H]+。Compound 0512-2 (200.00 mg) was dissolved in tetrahydrofuran (5.00 mL) and water (2.00 mL), and then lithium hydroxide monohydrate (33.68 mg) was added, and the reaction mixture was reacted at 15 ° C for 5 hours. The reaction mixture was concentrated to give a crude material. EtOAc EtOAc m. The crude product was dissolved in 10 mL of ethyl acetate, and the mixture was mixed with silica, and purified by a rapid preparative chromatography ( petroleum ether: ethyl acetate = gradient elution from 1:0 to 1:4) to give the title compound 0512-3 (light yellow) Oily liquid, 150 mg). The product was confirmed to have been racemized by SFC. MS (ESI) m / z: 360 [M+H] + .
步骤3：化合物0512的合成Step 3: Synthesis of Compound 0512
将化合物0512-3(100.00mg)溶于N,N-二甲基甲酰胺(5.00mL)中，再依次加入化合物BB-3(77.97mg，盐酸盐)，HATU(126.83mg)，N,N-二异丙基乙胺(143.70mg)，反应液在15℃下反应1小时。反应液加水15mL稀释，乙酸乙酯萃取(15mL*3)，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品用5mL甲醇溶 解，采用高效液相色谱(Phenomenex Gemini C18 250*21.2mm*5um，水(0.05％HCl)-ACN)分离得到目标化合物0512(75mg)。MS(ESI)m/z：539[M+H]+。Compound 0512-3 (100.00 mg) was dissolved in N,N-dimethylformamide (5.00 mL), then compound BB-3 (77.97 mg, hydrochloride), HATU (126.83 mg), N, N-diisopropylethylamine (143.70 mg) was reacted at 15 ° C for 1 hour. The reaction mixture was diluted with water (15 mL). The crude product was dissolved in 5 mL of MeOH (methanol) (m.p.). MS (ESI) m / z: 539 [M+H] + .
1HNMR(400MHz，MeOD-d4)：δ＝7.82-7.93(m，2H)，7.61-7.70(m，2H)，4.43-4.70(m，2H)，3.66-4.40(m，3H)，2.19-3.20(m，5H)，1.12-1.90(m，7H)，0.84-0.99(m，3H)，0.76(d，J＝6.27Hz，2H)，0.54(br.s.，2H). 1 H NMR (400 MHz, MeOD-d4): δ=7.82-7.93 (m, 2H), 7.61-7.70 (m, 2H), 4.43-4.70 (m, 2H), 3.66-4.40 (m, 3H), 2.19- 3.20 (m, 5H), 1.12-1.90 (m, 7H), 0.84-0.99 (m, 3H), 0.76 (d, J = 6.27 Hz, 2H), 0.54 (br.s., 2H).
实施例4：化合物0517的合成Example 4: Synthesis of Compound 0517
Figure PCTCN2017109922-appb-000268
Figure PCTCN2017109922-appb-000268
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000269
Figure PCTCN2017109922-appb-000269
步骤1：化合物0517-2的合成Step 1: Synthesis of Compound 0517-2
将化合物0493-3(300.00mg)，化合物0517-1(176.17mg)溶于N,N-二甲基甲酰胺(2.00mL)，然后加入HATU(300.01mg)和N,N-二异丙基乙胺(254.93mg)，该反应液在20℃搅拌2小时。将反应液倒入20mL乙酸乙酯中，然后用水(10mL*3)洗涤。将有机相浓缩后得到淡棕色油状粗产品。该粗产品通过快速制备色谱仪分离纯化(石油醚：乙酸乙酯＝3：1)得到目标化合物0517-2(无色油状液体，300mg)。MS(ESI)m/z：683[M+Na]+。Compound 0493-3 (300.00 mg), compound 0517-1 (176.17 mg) was dissolved in N,N-dimethylformamide (2.00 mL), then HATU (300.01 mg) and N,N-diisopropyl Ethylamine (254.93 mg) was stirred at 20 ° C for 2 hours. The reaction solution was poured into 20 mL of ethyl acetate and then washed with water (10 mL*3). The organic phase was concentrated to give a crude brown oil. The crude product was isolated and purified by EtOAc (EtOAc:EtOAc:EtOAc) MS (ESI) m / z: 683 [M+Na] + .
步骤2：化合物0517-3的合成Step 2: Synthesis of Compound 0517-3
将化合物0517-2(300.00mg)溶于二氯甲烷(2.00mL)，然后加入氯化氢的二氧六环溶液(4mol/L，5.00mL)，该反应液在20℃搅拌4小时。将反应液浓缩得到目标化合物0517-3(淡棕色油状液体，200mg，盐酸盐)，未经纯化直接用于下一步反应。MS(ESI)m/z：561[M+H]+。 Compound 0517-2 (300.00 mg) was dissolved in dichloromethane (2.00 mL), then hydrogen chloride in dioxane (4 mol/L, 5.00 mL) was added and the mixture was stirred at 20 ° C for 4 hours. The reaction mixture was concentrated to give the title compound (m.p. MS (ESI) m / z: 564 [M+H] + .
步骤3：化合物0517的合成Step 3: Synthesis of Compound 0517
将化合物0517-3(200.00mg)溶于二氯甲烷(4.00mL)，然后加入N,N-二异丙基乙胺(92.08mg)和化合物BB-3-2(29.60mg)，该反应液在20℃搅拌12小时。将反应液浓缩得到淡黄色油状粗产品。该粗产品通过高效液相色谱(Phenomenex Gemini C18 250*21.2mm*5um，水(0.05％HCl)-ACN)分离纯化得到目标化合物0517(77mg)。MS(ESI)m/z：666[M+Na]+。Compound 0517-3 (200.00 mg) was dissolved in dichloromethane (4.00 mL), then N,N-diisopropylethylamine (92.08 mg) and compound BB-3-2 (29.60 mg). Stir at 20 ° C for 12 hours. The reaction mixture was concentrated to give a crude yellow oil. The crude product was isolated and purified by high-performance liquid chromatography (Phenomenex Gemini C18 250*21.2 mm*5 um, water (0.05% HCl)-ACN) to afford the title compound 0517 (77 mg). MS (ESI) m / z: 666 [M+Na] + .
1HNMR(400MHz，MeOD-d4)：δ＝8.97-9.15(m，1H)，7.99-8.28(m，3H)，7.26-7.76(m，6H)，4.62-4.66(m，1H)，4.35-4.45(m，2H)，2.69-2.73(m，1H)，1.23-1.70(m，2H)，0.81-0.85(m，5H)，0.62-0.79(m，2H). 1 H NMR (400 MHz, MeOD-d4): δ=8.97-9.15 (m, 1H), 7.99-8.28 (m, 3H), 7.26-7.76 (m, 6H), 4.62-4.66 (m, 1H), 4.35- 4.45 (m, 2H), 2.69-2.73 (m, 1H), 1.23-1.70 (m, 2H), 0.81-0.85 (m, 5H), 0.62-0.79 (m, 2H).
实施例5：化合物0516的合成Example 5: Synthesis of Compound 0516
Figure PCTCN2017109922-appb-000270
Figure PCTCN2017109922-appb-000270
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000271
Figure PCTCN2017109922-appb-000271
步骤1：化合物0516-2的合成Step 1: Synthesis of Compound 0516-2
将化合物0493-3(500.00mg)，化合物0516-1(217.23mg)溶于N,N-二甲基甲酰胺(2.00mL)，然后加入HATU(500.02mg)和N,N-二异丙基乙胺(424.89mg)，该反应液在20℃搅拌1小时。将反应液倒入20mL乙酸乙酯中，然后用水(10mL*3)洗涤。将有机相浓缩后得到淡棕色油状粗产品。该粗产品通过快速制备色谱仪分离纯化(石油醚：乙酸乙酯＝3：1)得到目标化合物0516-2(无色油状液体，600mg)。MS(ESI)m/z：625[M+Na]+。Compound 0493-3 (500.00 mg), Compound 0516-1 (217.23 mg) was dissolved in N,N-dimethylformamide (2.00 mL), then HATU (500.02 mg) and N,N-diisopropyl Ethylamine (424.89 mg) was stirred at 20 ° C for 1 hour. The reaction solution was poured into 20 mL of ethyl acetate and then washed with water (10 mL*3). The organic phase was concentrated to give a crude brown oil. The crude product was isolated and purified by EtOAc (EtOAc:EtOAc:EtOAc) MS (ESI) m / z: 625 [M+Na] + .
步骤2：化合物0516-3的合成Step 2: Synthesis of Compound 0516-3
将化合物0516-2(600.00mg)溶于四氢呋喃(5.00mL)和水(3.00mL)，然后加入一水合氢氧化锂 (132.17mg)，该反应液在20℃搅拌5小时。将反应液浓缩，剩余水相用2mol/L的盐酸水溶液调节至pH＝2，过滤，收集白色固体，该白色固体即是目标化合物0516-3(白色固体，500mg)。MS(ESI)m/z：611[M+Na]+。Compound 0516-2 (600.00 mg) was dissolved in tetrahydrofuran (5.00 mL) and water (3.00 mL), and then lithium hydroxide monohydrate (132.17 mg) was added, and the mixture was stirred at 20 ° C for 5 hours. The reaction mixture was concentrated, and the aqueous layer was evaporated to m.j. MS (ESI) m / z: 611 [M+Na] + .
步骤3：化合物0516的合成Step 3: Synthesis of Compound 0516
将化合物0516-3(200.00mg)，化合物0516-4(23.25mg，28.35uL)溶于N,N-二甲基甲酰胺(3.00mL)然后加入HATU(167.73mg)和N,N-二异丙基乙胺(131.56mg，177.78uL)，该反应液在20℃搅拌2小时。将反应液过滤，滤液通过高效液相色谱(Phenomenex Gemini 150*25mm*10um，水(0.05％HCl)-ACN)分离纯化得到目标化合物0516(70mg盐酸盐)。MS(ESI)m/z：628[M+H]+。Compound 0516-3 (200.00 mg), compound 0516-4 (23.25 mg, 28.35 uL) was dissolved in N,N-dimethylformamide (3.00 mL) then HATU (167.73 mg) and N,N-di Propylethylamine (131.56 mg, 177.78 uL), the reaction was stirred at 20 ° C for 2 hours. The reaction solution was filtered, and the filtrate was separated and purified by high-pressure liquid chromatography (Phenomenex Gemini 150*25mm*10um, water (0.05% HCl)-ACN) to give the title compound 0516 (70 mg of hydrochloride). MS (ESI) m / z: 628[M+H] + .
1H NMR(400MHz，CD3OD)：δ＝7.74-8.09(m，6H)，7.46-7.55(m，5H)，4.67-4.71(m，1H)，4.33-4.43(m，2H)，2.84-2.87(m，1H)，1.23-1.69(m，2H)，0.79-0.85(m，5H)，0.63-0.65(m，2H). 1 H NMR (400 MHz, CD 3 OD): δ=7.74-8.09 (m, 6H), 7.46-7.55 (m, 5H), 4.67-4.71 (m, 1H), 4.33-4.43 (m, 2H), 2.84 -2.87 (m, 1H), 1.23-1.69 (m, 2H), 0.79-0.85 (m, 5H), 0.63-0.65 (m, 2H).
实施例6：化合物0500的合成Example 6: Synthesis of Compound 0500
Figure PCTCN2017109922-appb-000272
Figure PCTCN2017109922-appb-000272
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000273
Figure PCTCN2017109922-appb-000273
步骤1：化合物0500-2的合成Step 1: Synthesis of Compound 0500-2
将化合物BB-16(200.00mg)溶于甲苯(5.00mL)中，再依次加入化合物0500-1(70.07mg)，三苯基磷(136.13mg)，偶氮二甲酸二异丙酯(104.95mg)，反应液在90℃下反应16小时。反应液浓缩得到粗品。粗品采用10mL乙酸乙酯溶解，二氧化硅拌样，采用快速制备色谱仪分离(石油醚：乙酸乙酯＝梯度洗脱，从1：0到4：1)得到目标化合物0500-2(淡黄色油状液体，190mg)。MS(ESI)m/z：504[M+H]+。Compound BB-16 (200.00 mg) was dissolved in toluene (5.00 mL), followed by the compound 0500-1 (70.07 mg), triphenylphosphine (136.13 mg), diisopropyl azodicarboxylate (104.95 mg). The reaction solution was reacted at 90 ° C for 16 hours. The reaction solution was concentrated to give a crude material. The crude product was dissolved in 10 mL of ethyl acetate. The mixture was mixed with silica and purified by flash chromatography ( petroleum ether: ethyl acetate = gradient elution from 1:0 to 4:1). Oily liquid, 190 mg). MS (ESI) m / z: 504 [M+H] + .
步骤2：化合物0500-3的合成Step 2: Synthesis of Compound 0500-3
将化合物0500-2(120.00mg)溶于1，2-二氯乙烷(5.00mL)中，再加入三甲基氢氧化锡(214.95mg)，反应液在80℃下反应16小时。反应液浓缩得到粗品，粗品加5mL水稀释，6mol/L盐酸水溶液调节pH 至4左右，乙酸乙酯萃取(10mL*2)，收集并用无水硫酸钠干燥有机相，过滤浓缩得到粗品。粗品用快速制备色谱仪分离(石油醚：乙酸乙酯＝梯度洗脱，从1：0到3：1)得到目标化合物0500-3(淡黄色固体，50mg)。MS(ESI)m/z：490[M+H]+。Compound 0500-2 (120.00 mg) was dissolved in 1,2-dichloroethane (5.00 mL), then trimethyltin hydroxide (214.95 mg) was added, and the reaction mixture was reacted at 80 ° C for 16 hours. The reaction mixture was concentrated to give a crude material. EtOAc EtOAc m. The crude product was isolated using EtOAc (EtOAc:EtOAc:EtOAc:EtOAc MS (ESI) m / z: 490 [M+H] + .
步骤3：化合物0500的合成Step 3: Synthesis of Compound 0500
将化合物0500-3(50.00mg)溶于N,N-二甲基甲酰胺(2.00mL)中，再依次加入化合物BB-3(24.12mg)，HATU(46.49mg)，N,N-二异丙基乙胺(52.67mg)，反应液在15℃下反应1小时。反应液加水5mL稀释，乙酸乙酯(10mL*2)萃取，收集有机相并用无水硫酸钠干燥，过滤浓缩得到粗品。粗品用5mL甲醇溶剂溶解，采用高效液相色谱(Phenomenex Gemini C18 250*21.2mm*5um，水(0.05％HCl)-ACN)分离得到目标化合物0500(15mg)。MS(ESI)m/z：669[M+H]+。Compound 0500-3 (50.00 mg) was dissolved in N,N-dimethylformamide (2.00 mL), followed by compound BB-3 (24.12 mg), HATU (46.49 mg), N,N-di Propylethylamine (52.67 mg) was reacted at 15 ° C for 1 hour. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) The crude product was dissolved in 5 mL of methanol solvent, and the title compound 0500 (15 mg) was obtained by high-performance liquid chromatography (Phenomenex Gemini C18 250*21.2 mm*5 um, water (0.05% HCl)-ACN). MS (ESI) m/z: 266[M+H] + .
H NMR(400MHz，CD3OD)：δ＝7.21-8.19(m，6H)，5.26-5.47(m，1H)，4.14-4.51(m，2H)，2.28-3.46(m，5H)，1.21-2.10(m，7H)，0.66-0.88(m，5H)，0.40-0.60(m，2H).H NMR (400 MHz, CD 3 OD): δ = 7.21 - 8.19 (m, 6H), 5.26 - 5.47 (m, 1H), 4.14 - 4.51 (m, 2H), 2.28 - 3.46 (m, 5H), 1. 2.10 (m, 7H), 0.66-0.88 (m, 5H), 0.40-0.60 (m, 2H).
实施例7：化合物0508的合成Example 7: Synthesis of Compound 0508
Figure PCTCN2017109922-appb-000274
Figure PCTCN2017109922-appb-000274
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000275
Figure PCTCN2017109922-appb-000275
步骤1：化合物0508-2的合成Step 1: Synthesis of Compound 0508-2
将化合物BB-17(1.00g)加入到N,N-二甲基甲酰胺(10.00mL)，再加入化合物0508-1(1.81g)，碘化钠(100.13mg)，碳酸铯(3.26g)，该反应液在15℃下反应16小时。反应液加200mL乙酸乙酯，有机相用饱和食盐水洗涤(50mLx4)，无水硫酸钠干燥，过滤，滤液旋干得粗品。粗品经快速制备色谱仪纯化(0-20％乙酸乙酯在石油醚中)得到目标化合物0508-2(白色固体，800mg)。MS(ESI)m/z：400[M+H]+。Compound BB-17 (1.00 g) was added to N,N-dimethylformamide (10.00 mL), then compound 0508-1 (1.81 g), sodium iodide (100.13 mg), cesium carbonate (3.26 g) The reaction solution was reacted at 15 ° C for 16 hours. The reaction mixture was combined with ethyl acetate (200 mL). The crude product was purified by EtOAc (EtOAc) MS (ESI) m / z: 400 [M+H] + .
步骤2：化合物0508-3的合成 Step 2: Synthesis of Compound 0508-3
将化合物0508-2(300.00mg)加入到四氢呋喃(6.00mL)和水(2.00mL)，再加入一水氢氧化锂(69.27mg)，该反应液在15℃下反应5小时。反应液加1mol/L的盐酸水溶液调节pH至2，用乙酸乙酯(50mL*2)萃取，有机相用食盐水洗(50mL*2)，无水硫酸钠干燥，过滤，滤液旋干得到目标化合物0508-3(白色固体，290mg，粗品)。MS(ESI)m/z：386[M+H]+。Compound 0508-2 (300.00 mg) was added to tetrahydrofuran (6.00 mL) and water (2.00 mL), and then lithium hydroxide monohydrate (69.27 mg) was added, and the reaction mixture was reacted at 15 ° C for 5 hours. The reaction mixture was adjusted to pH 2 with 1 mol/L aqueous hydrochloric acid, and extracted with ethyl acetate (50 mL*2). The organic phase was washed with brine (50 mL*2), dried over anhydrous sodium sulfate, filtered, 0508-3 (white solid, 290 mg, crude). MS (ESI) m / z: 386 [M+H] + .
步骤3：化合物0508的合成Step 3: Synthesis of Compound 0508
将化合物0508-3(100.00mg)加入到N,N-二甲基甲酰胺(2.00mL)，再加入化合物BB-3(61.37mg)，HATU(118.28mg)，N,N-二异丙基乙胺(67.00mg)，该反应液在15℃下反应2小时。反应液过滤。滤液经高效液相色谱(柱：DYA-5C18 150*25mm*5um；流动相：[水(0.05％HCl)-ACN]；B％：36％-62％，10min)分离得到目标化合物0508(40mg)。MS(ESI)m/z：565[M+H]+。Compound 0508-3 (100.00 mg) was added to N,N-dimethylformamide (2.00 mL), then compound BB-3 (61.37 mg), HATU (118.28 mg), N,N-diisopropyl Ethylamine (67.00 mg) was reacted at 15 ° C for 2 hours. The reaction solution was filtered. The filtrate was separated by high performance liquid chromatography (column: DYA-5C18 150*25mm*5um; mobile phase: [water (0.05% HCl)-ACN]; B%: 36%-62%, 10 min) to obtain the target compound 0508 (40 mg). ). MS (ESI) m / z: 565 [M+H] + .
1H NMR(400MHz，CD3OD)：δ＝8.36-8.46(m，1H)，7.17-7.58(m，7H)，5.57-5.66(m，1H)，3.93-4.99(m，2H)，2.50-3.30(m，5H)，1.24-2.07(m，7H)，0.85-1.06(m，3H)，0.81-0.66(m，2H)，0.60-0.46(m，2H)。 1 H NMR (400 MHz, CD 3 OD): δ= 8.36-8.46 (m, 1H), 7.17-7.58 (m, 7H), 5.57-5.66 (m, 1H), 3.93-4.99 (m, 2H), 2.50 - 3.30 (m, 5H), 1.24 - 2.07 (m, 7H), 0.85-1.06 (m, 3H), 0.81 - 0.66 (m, 2H), 0.60 - 0.46 (m, 2H).
实施例8：化合物0529的合成Example 8: Synthesis of Compound 0529
Figure PCTCN2017109922-appb-000276
Figure PCTCN2017109922-appb-000276
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000277
Figure PCTCN2017109922-appb-000277
步骤1：化合物0529的合成Step 1: Synthesis of Compound 0529
将化合物BB-18(51.66mg)，化合物0493-3(100.00mg)溶于N,N-二甲基甲酰胺(2.00mL)，然后加入HATU(108.34mg)和N,N-二异丙基乙胺(84.98mg)，该反应液在20℃搅拌2小时。将该反应液过滤。滤液通过高效液相色谱(Waters Xbridge 150*25 5u，水(10mM NH4HCO3)-ACN)分离纯化得到目标化合物0529(20.00mg)。MS(ESI)m/z：652[M+H]+。Compound BB-18 (51.66 mg), compound 0493-3 (100.00 mg) was dissolved in N,N-dimethylformamide (2.00 mL), then HATU (108.34 mg) and N,N-diisopropyl Ethylamine (84.98 mg) was stirred at 20 ° C for 2 hours. The reaction solution was filtered. The filtrate was separated and purified by high-performance liquid chromatography (Waters Xbridge 150*25 5u, water (10 mM NH4HCO3)-ACN) to afford the title compound 0529 (20.00 mg). MS (ESI) m / z: 652 [M+H] + .
1H NMR(400MHz，CD3OD)：δ＝7.93.-8.01(m，3H)，7.54-7.77(m，3H)，7.74-7.50(m，6H)，4.69-4.73(m，1H)，4.33-4.42(m，2H)，1.86-1.90(m，2H)，1.68-1.69(m，1H)，0.82-0.94(m，7H). 1 H NMR (400 MHz, CD 3 OD): δ = 7.93. - 8.01 (m, 3H), 7.54 - 7.77 (m, 3H), 7.74 - 7.50 (m, 6H), 4.69 - 4.73 (m, 1H), 4.33-4.42 (m, 2H), 1.86-1.90 (m, 2H), 1.68-1.69 (m, 1H), 0.82-0.94 (m, 7H).
实施例9：化合物0523和化合物0524的合成 Example 9: Synthesis of Compound 0523 and Compound 0524
Figure PCTCN2017109922-appb-000278
Figure PCTCN2017109922-appb-000278
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000279
Figure PCTCN2017109922-appb-000279
步骤1：化合物0523和化合物0524的合成Step 1: Synthesis of Compound 0523 and Compound 0524
50mg化合物0520采用SFC(AS(250mm*30mm，5um)，0.1％NH3.H2O ETOH)分离。拆分得到化合物0523(21.00mg，SFC：RT＝3.793)和化合物0524(21.00mg，SFC：RT＝4.259)。MS(ESI)m/z：601[M+H]+。化合物0523：1H NMR(400MHz，MeOD)：δ＝7.47-7.70(m，8H)，5.31(m，1H)，4.07-4.38(m，2H)，2.39-3.45(m，5H)，1.24-2.06(m，7H)，0.79-0.91(m，3H)，0.69(br d，J＝6.27Hz，2H)，0.48(br d，J＝14.05Hz，2H)。50mg Compound 0520 using SFC (AS (250mm * 30mm, 5um), 0.1% NH 3 .H2O ETOH) was separated. The compound was obtained by the resolution of Compound 052 (21.00 mg, SFC: RT = 3.793) MS (ESI) m / z: 601 [M+H] + . Compound 0523: 1 H NMR (400 MHz, MeOH): δ = 7.47-7.70 (m, 8H), 5.31 (m, 1H), 4.07 - 4.38 (m, 2H), 2.39 - 3.45 (m, 5H), 2.06 (m, 7H), 0.79-0.91 (m, 3H), 0.69 (brd, J = 6.27 Hz, 2H), 0.48 (brd, J = 14.05 Hz, 2H).
化合物0524：1H NMR(400MHz，MeOD)：δ＝7.45-7.74(m，8H)，5.22-5.40(m，1H)，4.02-4.39(m，2H)，2.42-3.35(m，5H)，1.26-2.00(m，7H)，0.64-0.95(m，5H)，0.41-0.56(m，2H)。Compound 0524: 1 H NMR (400 MHz, MeOH): δ = 7.45 - 7.74 (m, 8H), 5.22 - 5.40 (m, 1H), 4.02-4.39 (m, 2H), 2.42-3.35 (m, 5H), 1.26-2.00 (m, 7H), 0.64-0.95 (m, 5H), 0.41 - 0.56 (m, 2H).
实施例10：化合物0530的合成Example 10: Synthesis of Compound 0530
Figure PCTCN2017109922-appb-000280
Figure PCTCN2017109922-appb-000280
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000281
Figure PCTCN2017109922-appb-000281
将化合物0516-3(200.00mg)，氯化铵(36.30mg)溶于N,N-二甲基甲酰胺(2.00mL)，然后加入N,N-二异丙基乙胺(131.56mg)和HATU(193.53mg)，该反应液在20℃搅拌2小时。将反应液过滤，滤液通过 高效液相色谱(Agela ASB 150*25mm*5um，水(0.05％HCl)-ACN)分离纯化得到目标化合物0530(100.00mg)。MS(ESI)m/z：588[M+H]+。Compound 0516-3 (200.00 mg), ammonium chloride (36.30 mg) was dissolved in N,N-dimethylformamide (2.00 mL), then N,N-diisopropylethylamine (131.56 mg) and HATU (193.53 mg), the reaction was stirred at 20 ° C for 2 hours. The reaction solution was filtered, and the filtrate was separated and purified by high-purpur chromatography (Agela ASB 150*25mm*5 um, water (0.05% HCl)-ACN) to give the title compound 0530 (100.00 mg). MS (ESI) m / z: 588 [M+H] + .
1H NMR(400MHz，CD3OD)：δ＝9.11-8.81(m，1H)，7.32-7.96(m，11H)，4.69(dd，J＝4.8，10.8Hz，1H)，4.45-4.36(m，2H)，1.67(s，1H)，1.35-1.17(m，1H)，0.83(t，J＝7.4Hz，3H)。 1 H NMR (400 MHz, CD 3 OD): δ = 9.11 - 8.81 (m, 1H), 7.32 - 7.96 (m, 11H), 4.69 (dd, J = 4.8, 10.8 Hz, 1H), 4.45 - 4.36 (m) , 2H), 1.67 (s, 1H), 1.35-1.17 (m, 1H), 0.83 (t, J = 7.4 Hz, 3H).
实施例11：化合物0536的合成Example 11: Synthesis of Compound 0536
Figure PCTCN2017109922-appb-000282
Figure PCTCN2017109922-appb-000282
合成路线：synthetic route:
Figure PCTCN2017109922-appb-000283
Figure PCTCN2017109922-appb-000283
以化合物0493-3，BB-23为原料，参考实施例5中合成化合物0516-3的合成步骤，合成化合物0536。MS(ESI)m/z：607[M+H]+。Using the compound 0493-3, BB-23 as a starting material, the synthesis of compound 0516-3 in Example 5 was carried out to synthesize compound 0536. MS (ESI) m / z: 607[M+H] + .
实施例12：化合物0464的合成Example 12: Synthesis of Compound 0464
Figure PCTCN2017109922-appb-000284
Figure PCTCN2017109922-appb-000284
合成路线： synthetic route:
Figure PCTCN2017109922-appb-000285
Figure PCTCN2017109922-appb-000285
步骤1：化合物0464-2的合成Step 1: Synthesis of Compound 0464-2
将化合物0493-3(100.00mg)和化合物0464-1(93.94mg)溶于N,N-二甲基甲酰胺(1.00mL)，加入N,N-二异丙基乙胺(113.30mg)和HATU(125.00mg)，该反应混和液于24℃下反应16小时。加入5mL水，乙酸乙酯萃取(5mL*3)，合并有机相，无水硫酸钠干燥，过滤，滤液于减压蒸馏下旋干，使用硅胶柱层析法进行纯化(石油醚：乙酸乙酯＝4：1)。得到目标化合物0464-2(无色液体，85.00mg)。MS(ESI)m/z：652[M+H]+。Compound 0493-3 (100.00 mg) and compound 0464-1 (93.94 mg) were dissolved in N,N-dimethylformamide (1.00 mL), and N,N-diisopropylethylamine (113.30 mg) and HATU (125.00 mg), the reaction mixture was reacted at 24 ° C for 16 hours. Add 5 mL of water, extract with ethyl acetate (5 mL*3), and the organic phase is combined, dried over anhydrous sodium sulfate, and filtered, and the filtrate is evaporated to dryness under vacuum distillation and purified by silica gel column chromatography ( petroleum ether: ethyl acetate =4:1). The title compound 0464-2 (colorless liquid, 85.00 mg) was obtained. MS (ESI) m / z: 652 [M+H] + .
步骤2：化合物0464-3的合成Step 2: Synthesis of Compound 0464-3
将化合物0464-2(85.00mg)溶于二氯甲烷(1.00mL)，加入氯化氢的二氧六环溶液(4mol/L，1.00mL)，反应混和液于24℃下反应1小时。反应液于减压蒸馏下旋干。得到目标化合物0464-3(无色液体，80.00mg，盐酸盐)。MS(ESI)m/z：552[M+H+]。Compound 0464-2 (85.00 mg) was dissolved in dichloromethane (1.00 mL), and a hydrogen chloride in dioxane solution (4 mol/L, 1.00 mL) was added, and the reaction mixture was reacted at 24 ° C for 1 hour. The reaction solution was evaporated to dryness under reduced pressure. The title compound 0464-3 (colorless liquid, 80.00 mg, hydrochloride) was obtained. MS (ESI) m / z: 552 [M+H + ].
步骤3：化合物0464的合成Step 3: Synthesis of Compound 0464
将化合物0516-4(9.31mg)溶于二氯甲烷(1.00mL)，加入N,N-二异丙基乙胺(35.11mg)和CDI(26.43mg)，该混和液于24℃下搅拌1小时，然后加入化合物0464-3(80.00mg，盐酸盐)，该反应液于24℃下反应16小时。反应液于减压蒸馏下旋干，溶于3mL甲醇，过滤，滤液通过高效液相色谱(Phenomenex Synergi C18 150*30mm*4um水(0.05％HCl)-ACN)分离得到目标化合物0464(40.63mg)。MS(ESI)m/z：657[M+Na+]。1H NMR(400MHz，MeOD-d4)：δ＝7.14-8.10(m，7H)，5.26-5.47(m，1H)，4.09-4.62(m，2H)，2.26-3.31(m，5H)，1.21-2.00(m，7H)，0.65-0.91(m，5H)，0.43-0.61(m，2H)。Compound 0516-4 (9.31 mg) was dissolved in dichloromethane (1.00 mL), N,N-diisopropylethylamine (35.11 mg) and CDI (26.43 mg) were added, and the mixture was stirred at 24 ° C. After an hour, compound 0464-3 (80.00 mg, hydrochloride) was added and the reaction was allowed to react at 24 ° C for 16 hours. The reaction solution was dried under reduced pressure and evaporated to dryness.mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjs . MS (ESI) m/z: 657 [M+Na + ]. 1 H NMR (400 MHz, MeOD-d 4 ): δ=7.14-8.10 (m, 7H), 5.26-5.47 (m, 1H), 4.09-4.62 (m, 2H), 2.26-3.31 (m, 5H), 1.21-2.00 (m, 7H), 0.65-0.91 (m, 5H), 0.43-0.61 (m, 2H).
参照实施例1(化合物0493的合成)中步骤1-3的合成方法，以表1中相应的化合物1、化合物2和化合物3为原料，合成表1中各实施例对应的目标化合物：The target compound corresponding to each of the examples in Table 1 was synthesized by referring to the corresponding synthesis of Compound 1, Compound 2 and Compound 3 in Table 1 by referring to the synthesis methods of Steps 1-3 in Example 1 (Synthesis of Compound 0493):
表1 Table 1
Figure PCTCN2017109922-appb-000286
Figure PCTCN2017109922-appb-000286
参照实施例2(化合物0499)中步骤1-3的合成方法，以表2中相应的化合物1和化合物2为原料，分别替代实施例2中的化合物BB-2和化合物BB-1，合成表2中各实施例对应的目标化合物：Referring to the synthesis method of the steps 1-3 in Example 2 (Compound 0499), the corresponding Compound 1 and Compound 2 in Table 2 were used as raw materials, respectively, instead of Compound BB-2 and Compound BB-1 in Example 2, the synthesis table was synthesized. Target compounds corresponding to the respective examples in 2:
表2Table 2
Figure PCTCN2017109922-appb-000287
Figure PCTCN2017109922-appb-000287
Figure PCTCN2017109922-appb-000288
Figure PCTCN2017109922-appb-000288
Figure PCTCN2017109922-appb-000289
Figure PCTCN2017109922-appb-000289
参照实施例3(化合物0512的合成)中步骤1-3的合成方法，以表3中相应的化合物1、化合物2和化合物3为原料，合成表3中各实施例对应的目标化合物：Referring to the synthesis method of the steps 1-3 in Example 3 (synthesis of the compound 0512), the corresponding compounds of the respective examples in Table 3 were synthesized by using the corresponding compound 1, the compound 2 and the compound 3 in Table 3 as raw materials:
表3table 3
Figure PCTCN2017109922-appb-000290
Figure PCTCN2017109922-appb-000290
Figure PCTCN2017109922-appb-000291
Figure PCTCN2017109922-appb-000291
参照实施例5(化合物0516)中步骤1-3的合成方法，以表4中相应的化合物1、化合物2和化合物3为原料，合成表4中各实施例对应的目标化合物：Referring to the synthesis method of the steps 1-3 in Example 5 (Compound 0516), the corresponding compounds of the respective examples in Table 4 were synthesized by using the corresponding Compound 1, Compound 2 and Compound 3 in Table 4 as raw materials:
表4Table 4
Figure PCTCN2017109922-appb-000292
Figure PCTCN2017109922-appb-000292
参照实施例7(化合物0508)中步骤1-3的合成方法，以表5中相应的化合物1、化合物2和化合物3为原料，合成表5中各实施例对应的目标化合物：Referring to the synthesis method of the steps 1-3 in Example 7 (Compound 0508), the corresponding compounds of the respective examples in Table 5 were synthesized by using the corresponding Compound 1, Compound 2 and Compound 3 in Table 5 as raw materials:
表5 table 5
Figure PCTCN2017109922-appb-000293
Figure PCTCN2017109922-appb-000293
对照例1：化合物0001的合成Comparative Example 1: Synthesis of Compound 0001
Figure PCTCN2017109922-appb-000294
Figure PCTCN2017109922-appb-000294
以专利WO2013130703A2方法合成化合物0001(即WO2013130703A2中的化合物CCC-0975)。Compound 0001 (i.e., compound CCC-0975 in WO2013130703A2) was synthesized by the method of WO2013130703A2.
对照例2：化合物0080的合成Comparative Example 2: Synthesis of Compound 0080
Figure PCTCN2017109922-appb-000295
Figure PCTCN2017109922-appb-000295
以专利WO2013130703A2方法合成化合物0080(即WO2013130703A2中的化合物CCC-Lu25-54)。Compound 0080 (i.e., compound CCC-Lu25-54 in WO2013130703A2) was synthesized by the method of WO2013130703A2.
实验例1：体外评价Experimental Example 1: In vitro evaluation
实验目的：Purpose:
通过稳定的cccDNA检测平台，开发能够抑制HBV cccDNA形成的新型药物。A novel drug capable of inhibiting the formation of HBV cccDNA was developed through a stable cccDNA detection platform.
背景介绍： Background introduction:
HepDES19是来源于人肝癌细胞HepG2的细胞系，携带受四环素调控的HBV基因组1.1倍体DNA。该细胞系的特点是cccDNA含量高。HepDES19细胞被广泛应用于HBV研究及抗HBV药物的测试。在本实验中，通过Southern blot检测受试化合物处理后的HepDES19细胞内的HBV cccDNA的含量来测定受试化合物对cccDNA形成过程的抑制活性。HepDES19 is a cell line derived from human hepatoma cell line HepG2, carrying the 1.1-fold DNA of the HBV genome regulated by tetracycline. This cell line is characterized by a high cccDNA content. HepDES19 cells are widely used in HBV research and anti-HBV drug testing. In the present experiment, the inhibitory activity of the test compound on the cccDNA formation process was determined by Southern blot analysis of the content of HBV cccDNA in HepDES19 cells treated with the test compound.
实验材料：Experimental Materials:
细胞系：HepDES 19细胞，来自美国肝炎和病毒研究所Cell line: HepDES 19 cells from the American Institute of Hepatitis and Viruses
细胞培养液：DMEM/F12(Invitrogen，Cat.#11330057)培养液，加10％胎牛血清(FBS，Corning，Cat.#35-076-CV)，1％的谷氨酰胺(Invitrogen，Cat.#25030081)，1％MEM NEAA(Invitrogen，Cat.#11140076)和1％双抗(青霉素5000IU/mL，链霉素10mg/mL，Hyclone，Cat.#SV30010)。Cell culture medium: DMEM/F12 (Invitrogen, Cat. #11330057) medium, plus 10% fetal bovine serum (FBS, Corning, Cat. #35-076-CV), 1% glutamine (Invitrogen, Cat. #25030081), 1% MEM NEAA (Invitrogen, Cat. #11140076) and 1% double antibody (penicillin 5000 IU/mL, streptomycin 10 mg/mL, Hyclone, Cat. #SV30010).
胰酶(Invitrogen，Cat.#25300062)。Trypsin (Invitrogen, Cat. #25300062).
DPBS(Hyclone，Cat.#SH30028.01B)。DPBS (Hyclone, Cat. #SH30028.01B).
四环素盐酸盐(Sigma，Cat.#T7660)。Tetracycline hydrochloride (Sigma, Cat. #T7660).
琼脂糖(Biowest，Cat.#111860)。Agarose (Biowest, Cat. #111860).
RNA酶A(Sigma，Cat.#R4642)。RNase A (Sigma, Cat. #R4642).
酚氯仿异戊二醇(生工，Cat.#PD0419-1)。Phenol chloroform isoprene glycol (Biotech, Cat. #PD0419-1).
Glyco Blue Coprecipitant(Ambion，Cat.#9515)。Glyco Blue Coprecipitant (Ambion, Cat. #9515).
Southern变性液(0.5M NaOH，1.5M NaCl)。Southern denaturing solution (0.5 M NaOH, 1.5 M NaCl).
Southern中和液(1M Tris.HCl，pH7.4and 1.5M NaCl)。Southern neutralizing solution (1 M Tris. HCl, pH 7.4 and 1.5 M NaCl).
Buffer 20*SSC(Shuiyuan Bio)。Buffer 20*SSC (Shuiyuan Bio).
DIG Easy Hyb(Roche，Cat.#11603558001)。DIG Easy Hyb (Roche, Cat. #11603558001).
DIG Wash and Block Buffer Set(Roche，Cat.#11585762001)。DIG Wash and Block Buffer Set (Roche, Cat. #11585762001).
Anti-Digoxigenin-AP(Roche，Cat.#11093274910)。Anti-Digoxigenin-AP (Roche, Cat. #11093274910).
CDP-Star(Roche，Cat.#11759051001)。CDP-Star (Roche, Cat. #11759051001).
CO2培养箱，Thermo 240 I。CO2 incubator, Thermo 240 I.
Nanodrop 1000，Thermo。Nanodrop 1000, Thermo.
实验步骤和方法：Experimental steps and methods:
1.化合物处理细胞Compound treatment of cells
HepDES19细胞用含10％血清和1ng/ml四环素的DMEM/F12培养基培养。处于对数生长期的细胞汇合度达到80％以上时，用胰酶进行消化，用含2％血清并去除四环素的DMEM/F12培养基重悬细胞并计数，于12孔细胞培养板中每孔加入2.5×105个HepDES19细胞，37℃，5％CO2过夜培养。第2天加入用经DMSO稀释的一定浓度的化合物对12孔板里的细胞进行处理，并设不含化合物的DMSO孔作为对照。37℃，5％CO2培养3天至第5天，弃去培养液，更换含相同浓度化合物的培养液继续培养3天至第8天，再次弃去培养液，并更换含相同浓度化合物的培养液继续培养3天至第11天，弃去培养液收集细胞，保存于-20℃或者立即进行Hirt DNA提取。 HepDES19 cells were cultured in DMEM/F12 medium containing 10% serum and 1 ng/ml tetracycline. When the cell confluence in the logarithmic growth phase reached 80% or more, it was digested with trypsin, resuspended in DMEM/F12 medium containing 2% serum and removed with tetracycline, and counted in each well of a 12-well cell culture plate. 2.5 x 10 5 HepDES19 cells were added and cultured overnight at 37 ° C, 5% CO 2 . On day 2, cells in a 12-well plate were treated with a concentration of compound diluted with DMSO, and a DMSO well containing no compound was used as a control. Incubate at 37 ° C, 5% CO 2 for 3 days to 5 days, discard the culture solution, replace the culture solution containing the same concentration of compound, continue to culture for 3 days to the 8th day, discard the culture solution again, and replace the compound containing the same concentration. The culture medium was further cultured for 3 days to the 11th day, and the culture medium was discarded to collect the cells, and stored at -20 ° C or immediately subjected to Hirt DNA extraction.
2.Hirt DNA提取2.Hirt DNA extraction
将步骤1收集的细胞用1毫升裂解液(含10毫摩尔/升的Triza，10毫摩尔/升的EDTA和0.7％的SDS)在常温下裂解30分钟后，加入0.24毫升浓度为5摩尔/升的氯化钠溶液，于4℃孵育过夜。第二天在12,000×g，4℃离心30分钟后，取900微升上清液转移至新的离心管中，加入3微升浓度为10mg/ml的RNA酶A溶液，37℃孵育1小时去除RNA。分别使用酚：氯仿：异戊二醇(三者体积比例为25：24：1)的900微升混合溶剂对上述溶液萃取3次，之后加入0.7倍体积的异丙醇和5微升的glycoblue共沉淀剂，充分混匀后室温放置1小时。12,000×g，4℃离心30分钟以沉淀DNA。弃上清，加入1毫升70％的乙醇洗涤两次，弃去多余的乙醇，室温干燥，将得到的DNA沉淀溶于30微升的TE中。The cells collected in step 1 were lysed with 1 ml of lysate (containing 10 mmol/L Triza, 10 mmol/L EDTA and 0.7% SDS) at room temperature for 30 minutes, and then added to a concentration of 0.24 ml of 5 mol/ The sodium chloride solution was incubated overnight at 4 °C. On the next day, after centrifugation at 12,000 × g for 30 minutes at 4 ° C, 900 μl of the supernatant was transferred to a new centrifuge tube, and 3 μl of a 10 mg/ml RNase A solution was added and incubated at 37 ° C for 1 hour. Remove RNA. The above solution was extracted three times with 900 μl of a mixed solvent of phenol:chloroform:isoprenediol (three in a volume ratio of 25:24:1), and then 0.7 times by volume of isopropanol and 5 μl of glycoblue were added. The precipitant was thoroughly mixed and allowed to stand at room temperature for 1 hour. 12,000 x g was centrifuged at 4 ° C for 30 minutes to precipitate DNA. The supernatant was discarded, washed twice with 1 ml of 70% ethanol, excess ethanol was discarded, dried at room temperature, and the resulting DNA pellet was dissolved in 30 μl of TE.
3.Southern blot检测cccDNA3. Southern blot detection of cccDNA
用1×TAE电泳缓冲液配制浓度为1.2％的琼脂糖凝胶，每个凝胶孔加入10微升步骤2中提取得到的Hirt DNA电泳样品(与上样缓冲液混匀后上样)，并加入大小为3.2kb，2.0kb和1.3kb的HBV片段混合液作为分子质量标志对照。凝胶置于80伏特的恒压下电泳3到4个小时以分离不同大小的DNA片段。电泳结束后，将胶浸入250毫摩尔/升的盐酸中，摇床孵育7分钟以使DNA脱嘌呤，蒸馏水洗涤数秒后用变性液(含0.5摩尔/升的氢氧化钠和1.5摩尔/升的氯化钠)变性30分钟，蒸馏水洗涤数秒后用中和液(含1摩尔/升的Tris盐酸和1.5摩尔/升的氯化钠，PH值为7.4)中和30分钟，蒸馏水洗涤后将凝胶上的DNA通过毛细管虹吸印迹法转移到固相的尼龙膜上，转移结束后取出尼龙膜，经紫外交联后浸入2×SSC溶液洗涤数分钟，将膜置于滤纸上干燥。然后将膜放入杂交瓶中，加入10毫升的杂交液，60℃预杂交1小时后弃去杂交液，加入含有经地高辛标记的探针的杂交液杂交过夜。第二天经2×SSC，0.1％SDS室温洗涤2×5分钟，再经0.1×SSC，0.1％SDS于60℃洗涤3×20分钟，然后将膜用1×马来酸快速清洗2×5分钟。再经封闭液封闭50分钟后，用抗体稀释液孵育30分钟。清洗液清洗3×15分钟后，加入CDP-star，将膜在暗室里进行曝光显影，控制好曝光时间，将曝光好的胶片干燥，经扫描仪扫描后对DNA条带进行分析。Prepare a 1.2% agarose gel in 1×TAE running buffer, and add 10 μl of Hirt DNA electrophoresis sample extracted in step 2 to each gel well (mixed with loading buffer and loaded). A mixture of HBV fragments of 3.2 kb, 2.0 kb and 1.3 kb in size was added as a molecular mass marker control. The gel was electrophoresed at a constant pressure of 80 volts for 3 to 4 hours to separate DNA fragments of different sizes. After the end of the electrophoresis, the gel was immersed in 250 mmol/L hydrochloric acid, shaken for 7 minutes on a shaker to dissociate the DNA, and washed with distilled water for several seconds with a denaturing solution (containing 0.5 mol/L sodium hydroxide and 1.5 mol/L). Sodium chloride) denatured for 30 minutes, washed with distilled water for several seconds, neutralized with a neutralizing solution (containing 1 mol/L Tris hydrochloric acid and 1.5 mol/L sodium chloride, pH 7.4) for 30 minutes, washed with distilled water and condensed. The DNA on the gel was transferred to the solid phase nylon membrane by capillary siphon blotting. After the transfer, the nylon membrane was taken out, immersed in 2×SSC solution for several minutes after UV crosslinking, and the membrane was placed on a filter paper to be dried. The membrane was then placed in a hybridization flask, 10 ml of the hybridization solution was added, and the hybridization solution was pre-hybridized at 60 ° C for 1 hour, and the hybridization solution containing the probe labeled with digoxin was added to hybridize overnight. The next day, 2×SSC, 0.1% SDS was washed at room temperature for 2×5 minutes, then washed with 0.1×SSC, 0.1% SDS at 60° C. for 3×20 minutes, and then the membrane was quickly washed with 1× maleic acid 2×5. minute. After blocking for 50 minutes via blocking solution, the antibody dilution was incubated for 30 minutes. After washing the cleaning solution for 3×15 minutes, CDP-star was added, the film was exposed and developed in a dark room, the exposure time was controlled, the exposed film was dried, and the DNA band was analyzed by scanning with a scanner.
4.数据处理和分析4. Data processing and analysis
将胶片通过扫描仪扫描成图片格式，通过直接观察图片中cccDNA条带的强弱来判断化合物对cccDNA的抑制效果，实验结果如表6所示。活性数值表示在给定的几个测试浓度下，能显示出对cccDNA有抑制效果的最低浓度，在特定浓度下的抑制效果通过与DMSO对照对比，观察cccDNA条带的强弱来判断。The film was scanned into a picture format by a scanner, and the inhibition effect of the compound on cccDNA was judged by directly observing the strength of the cccDNA band in the picture. The experimental results are shown in Table 6. The activity values indicate the lowest concentration that can exhibit an inhibitory effect on cccDNA at a given test concentration, and the inhibitory effect at a specific concentration is judged by observing the strength of the cccDNA band by comparison with the DMSO control.
表6Table 6
Figure PCTCN2017109922-appb-000296
Figure PCTCN2017109922-appb-000296
Figure PCTCN2017109922-appb-000297
Figure PCTCN2017109922-appb-000297
结论：本发明化合物对乙型肝炎病毒cccDNA的形成有很好的抑制作用；Conclusion: The compound of the present invention has a good inhibitory effect on the formation of hepatitis B virus cccDNA;
本发明化合物具有良好的ADME和PK属性。 The compounds of the invention have good ADME and PK properties.

Claims (51)

  1. 式(Ⅰ)化合物或其药学上可接受的盐：a compound of formula (I) or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2017109922-appb-100001
    Figure PCTCN2017109922-appb-100001
    其中，among them,
    R1选自氢或甲基；R 1 is selected from hydrogen or methyl;
    R2选自C1-3烷基、
    Figure PCTCN2017109922-appb-100002
    所述C1-3烷基任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基或氰基的基团取代，所述
    Figure PCTCN2017109922-appb-100003
    任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代；    R 2 is selected from C 1-3 alkyl,
    Figure PCTCN2017109922-appb-100002
    The C 1-3 alkyl group is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino or cyano.
    Figure PCTCN2017109922-appb-100003
    Optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl;
    A环选自
    Figure PCTCN2017109922-appb-100004
    所述A环任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代；    Ring A is selected from
    Figure PCTCN2017109922-appb-100004
    The A ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl;
    B环选自
    Figure PCTCN2017109922-appb-100005
    所述B环任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代；    B ring is selected from
    Figure PCTCN2017109922-appb-100005
    The B ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl;
    D分别独立地选自-O-、-S-和-NH-；D is independently selected from -O-, -S-, and -NH-;
    T分别独立地选自-CH＝和-N＝；T is independently selected from -CH= and -N=;
    R3选自氢和C3-6环烷基，所述C3-6环烷基任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代；R 3 is selected from hydrogen and C 3-6 cycloalkyl, a C 3-6 cycloalkyl optionally substituted with one or more substituents selected from fluoro, chloro, bromo, iodo, hydroxy, amino, cyano, methyl Or a group of a trifluoromethyl group;
    L1选自-C(＝O)-或-S(＝O)2-；L 1 is selected from -C(=O)- or -S(=O) 2 -;
    L2选自单键、
    Figure PCTCN2017109922-appb-100006
    L 2 is selected from a single bond,
    Figure PCTCN2017109922-appb-100006
    L3选自单键或-CH2-；L 3 is selected from a single bond or -CH 2 -;
    L4选自
    Figure PCTCN2017109922-appb-100007
    Figure PCTCN2017109922-appb-100008
    L 4 is selected from
    Figure PCTCN2017109922-appb-100007
    Figure PCTCN2017109922-appb-100008
  2. 权利要求1的化合物或其药学上可接受的盐，其中R2选自C1-3烷基、
    Figure PCTCN2017109922-appb-100009
    所述C1-3烷基任选地被三个以上的氟取代，所述
    Figure PCTCN2017109922-appb-100010
    任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代，优选为任选地被1、2或3个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代。    The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from C 1-3 alkyl,
    Figure PCTCN2017109922-appb-100009
    The C 1-3 alkyl group is optionally substituted with three or more fluorines,
    Figure PCTCN2017109922-appb-100010
    Optionally substituted by one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl, preferably optionally 1, 2 or 3 Substituted from a group of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
  3. 权利要求1的化合物或其药学上可接受的盐，其中R2选自C1-3烷基、
    Figure PCTCN2017109922-appb-100011
    所述C1-3烷基任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基或氰基的基团取代，优选为任选地被3个以上的氟取代，所述
    Figure PCTCN2017109922-appb-100012
    任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代，优选为任选地被1、2或3个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代。    The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from C 1-3 alkyl,
    Figure PCTCN2017109922-appb-100011
    The C 1-3 alkyl group is optionally substituted by one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino or cyano, preferably optionally substituted with 3 or more fluorines, Said
    Figure PCTCN2017109922-appb-100012
    Optionally substituted by one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl, preferably optionally 1, 2 or 3 Substituted from a group of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
  4. 权利要求3的化合物或其药学上可接受的盐，其中R2选自C1-3烷基、
    Figure PCTCN2017109922-appb-100013
    所述C1-3烷基任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基或氰基的基团取代，优选为任选地被3个以上的氟取代，所述
    Figure PCTCN2017109922-appb-100014
    任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代，优选为任选地被1、2或3个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代；优选地，R2选自C1-3烷基、
    Figure PCTCN2017109922-appb-100015
    所述C1-3烷基任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基或氰基的基团取代，优选为任选地被3个以上的氟取代，所述
    Figure PCTCN2017109922-appb-100016
    任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代，优选为任选地被1、2或3个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代。    The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from C 1-3 alkyl,
    Figure PCTCN2017109922-appb-100013
    The C 1-3 alkyl group is optionally substituted by one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino or cyano, preferably optionally substituted with 3 or more fluorines, Said
    Figure PCTCN2017109922-appb-100014
    Optionally substituted by one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl, preferably optionally 1, 2 or 3 Substituted from a group of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl; preferably, R 2 is selected from C 1-3 alkyl,
    Figure PCTCN2017109922-appb-100015
    The C 1-3 alkyl group is optionally substituted by one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino or cyano, preferably optionally substituted with 3 or more fluorines, Said
    Figure PCTCN2017109922-appb-100016
    Optionally substituted by one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl, preferably optionally 1, 2 or 3 Substituted from a group of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
  5. 权利要求3或4的化合物或其药学上可接受的盐，其中R2选自C1-3烷基、
    Figure PCTCN2017109922-appb-100017
    所述C1-3烷基任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基或氰基的基团取代，优选为任选地被3个以上的氟取代，所述
    Figure PCTCN2017109922-appb-100018
    任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代，优选为任选地被1、2或3个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代。    The compound of claim 3 or 4, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from C 1-3 alkyl,
    Figure PCTCN2017109922-appb-100017
    The C 1-3 alkyl group is optionally substituted by one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino or cyano, preferably optionally substituted with 3 or more fluorines, Said
    Figure PCTCN2017109922-appb-100018
    Optionally substituted by one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl, preferably optionally 1, 2 or 3 Substituted from a group of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
  6. 权利要求5的化合物或其药学上可接受的盐，其中R2选自C1-3烷基、
    Figure PCTCN2017109922-appb-100019
    所述C1-3烷基任选地被一个或多个氟取代，优选为任选地被3个以上的氟取代，所述
    Figure PCTCN2017109922-appb-100020
    Figure PCTCN2017109922-appb-100021
    任选地被一个或多个选自氯、氰基或三氟甲基的基团取代，优选为任选地被1、2或3个选自氯、氰基或三氟甲基的基团取代。    A compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from C 1-3 alkyl,
    Figure PCTCN2017109922-appb-100019
    The C 1-3 alkyl group is optionally substituted with one or more fluorines, preferably optionally with 3 or more fluorines,
    Figure PCTCN2017109922-appb-100020
    Figure PCTCN2017109922-appb-100021
    Optionally substituted by one or more groups selected from chloro, cyano or trifluoromethyl, preferably optionally 1, 2 or 3 groups selected from chloro, cyano or trifluoromethyl Replace.
  7. 权利要求6的化合物或其药学上可接受的盐，其中R2选自
    Figure PCTCN2017109922-appb-100022
    Figure PCTCN2017109922-appb-100023
    The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from
    Figure PCTCN2017109922-appb-100022
    Figure PCTCN2017109922-appb-100023
  8. 权利要求1的化合物或其药学上可接受的盐，其中A环选自
    Figure PCTCN2017109922-appb-100024
    Figure PCTCN2017109922-appb-100025
    所述A环任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代。    A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the ring A is selected from
    Figure PCTCN2017109922-appb-100024
    Figure PCTCN2017109922-appb-100025
    The A ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
  9. 权利要求8的化合物或其药学上可接受的盐，其中A环选自
    Figure PCTCN2017109922-appb-100026
    Figure PCTCN2017109922-appb-100027
    所述A环任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代。     A compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein the ring A is selected from
    Figure PCTCN2017109922-appb-100026
    Figure PCTCN2017109922-appb-100027
    The A ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
  10. 权利要求8的化合物或其药学上可接受的盐，其中A环选自
    Figure PCTCN2017109922-appb-100028
    Figure PCTCN2017109922-appb-100029
    所述A环任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代。    A compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein the ring A is selected from
    Figure PCTCN2017109922-appb-100028
    Figure PCTCN2017109922-appb-100029
    The A ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
  11. 权利要求10的化合物或其药学上可接受的盐，其中A环选自
    Figure PCTCN2017109922-appb-100030
    Figure PCTCN2017109922-appb-100031
    所述A环任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代，优选地，所述A环任选地被一个或多个选自氯、溴、氰基或甲基的基团取代，更优选地，所述A环任选地被一个或多个选自氯、溴或甲基的基团取代。    A compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein the ring A is selected from
    Figure PCTCN2017109922-appb-100030
    Figure PCTCN2017109922-appb-100031
    The A ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl, preferably the ring A is optional The ground is replaced by one or more groups selected from chlorine, bromine, cyano or methyl groups, more preferably, the A ring is optionally substituted by one or more groups selected from chlorine, bromine or methyl groups. .
  12. 权利要求11的化合物或其药学上可接受的盐，其中A环选自
    Figure PCTCN2017109922-appb-100032
    Figure PCTCN2017109922-appb-100033
    进一步优选为
    Figure PCTCN2017109922-appb-100034
    A compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein the ring A is selected from
    Figure PCTCN2017109922-appb-100032
    Figure PCTCN2017109922-appb-100033
    Further preferably
    Figure PCTCN2017109922-appb-100034
  13. 权利要求1的化合物或其药学上可接受的盐，其中结构单元
    Figure PCTCN2017109922-appb-100035
    选自
    Figure PCTCN2017109922-appb-100036
    Figure PCTCN2017109922-appb-100037
    Figure PCTCN2017109922-appb-100038
    进一步优选为
    Figure PCTCN2017109922-appb-100039
    The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit
    Figure PCTCN2017109922-appb-100035
    Selected from
    Figure PCTCN2017109922-appb-100036
    Figure PCTCN2017109922-appb-100037
    Figure PCTCN2017109922-appb-100038
    Further preferably
    Figure PCTCN2017109922-appb-100039
  14. 权利要求1的化合物或其药学上可接受的盐，其中B环选自
    Figure PCTCN2017109922-appb-100040
    Figure PCTCN2017109922-appb-100041
    所述B环任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代。     A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the ring B is selected from
    Figure PCTCN2017109922-appb-100040
    Figure PCTCN2017109922-appb-100041
    The B ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
  15. 权利要求14的化合物或其药学上可接受的盐，其中B环选自
    Figure PCTCN2017109922-appb-100042
    所述B环任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代。    The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein the ring B is selected from
    Figure PCTCN2017109922-appb-100042
    The B ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
  16. 权利要求15的化合物或其药学上可接受的盐，其中B环选自
    Figure PCTCN2017109922-appb-100043
    Figure PCTCN2017109922-appb-100044
    所述B环任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代。    The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein the ring B is selected from
    Figure PCTCN2017109922-appb-100043
    Figure PCTCN2017109922-appb-100044
    The B ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
  17. 权利要求15的化合物或其药学上可接受的盐，其中B环选自
    Figure PCTCN2017109922-appb-100045
    所述B环任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代。    The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein the ring B is selected from
    Figure PCTCN2017109922-appb-100045
    The B ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl.
  18. 权利要求16或17的化合物或其药学上可接受的盐，其中B环选自
    Figure PCTCN2017109922-appb-100046
    Figure PCTCN2017109922-appb-100047
    所述B环任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代，优选地，所述B环任选地被一个或多个氟取代。    The compound of claim 16 or 17, or a pharmaceutically acceptable salt thereof, wherein the ring B is selected from
    Figure PCTCN2017109922-appb-100046
    Figure PCTCN2017109922-appb-100047
    The B ring is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl, preferably, the B ring is optional The ground is replaced by one or more fluorines.
  19. 权利要求18的化合物，其中B环选自
    Figure PCTCN2017109922-appb-100048
    所述
    Figure PCTCN2017109922-appb-100049
    可进一步选自
    Figure PCTCN2017109922-appb-100050
    The compound of claim 18, wherein the B ring is selected from
    Figure PCTCN2017109922-appb-100048
    Said
    Figure PCTCN2017109922-appb-100049
    Can be further selected from
    Figure PCTCN2017109922-appb-100050
  20. 权利要求1的化合物或其药学上可接受的盐，其中R3选自氢或环丙基，所述环丙基任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基的基团取代，优选地，所述R3为环丙基。A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from hydrogen or cyclopropyl, said cyclopropyl optionally being selected from one or more selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, Substituting a group of an amino group, a cyano group, a methyl group or a trifluoromethyl group, preferably, the R 3 is a cyclopropyl group.
  21. 权利要求1的化合物或其药学上可接受的盐，其中L2选自单键或
    Figure PCTCN2017109922-appb-100051
    The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L 2 is selected from a single bond or
    Figure PCTCN2017109922-appb-100051
  22. 权利要求1的化合物或其药学上可接受的盐，其中L4选自
    Figure PCTCN2017109922-appb-100052
    Figure PCTCN2017109922-appb-100053
    A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 4 is selected from
    Figure PCTCN2017109922-appb-100052
    Figure PCTCN2017109922-appb-100053
  23. 权利要求1的化合物或其药学上可接受的盐，其中L1选自-C(＝O)-，且L2选自单键。A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 1 is selected from -C(=O)-, and L 2 is selected from a single bond.
  24. 权利要求1的化合物或其药学上可接受的盐，其中L1选自-S(＝O)2-，且L2选自单键或
    Figure PCTCN2017109922-appb-100054
    A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 1 is selected from -S(=O) 2 -, and L 2 is selected from a single bond or
    Figure PCTCN2017109922-appb-100054
  25. 权利要求1的化合物或其药学上可接受的盐，其中L3选自-CH2-，且L4选自
    Figure PCTCN2017109922-appb-100055
    The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L 3 is selected from -CH 2 - and L 4 is selected from
    Figure PCTCN2017109922-appb-100055
  26. 权利要求1的化合物或其药学上可接受的盐，其中L3选自单键，且L4选自
    Figure PCTCN2017109922-appb-100056
    Figure PCTCN2017109922-appb-100057
    The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L 3 is selected from the group consisting of a single bond, and L 4 is selected from the group consisting of
    Figure PCTCN2017109922-appb-100056
    Figure PCTCN2017109922-appb-100057
  27. 权利要求1的化合物或其药学上可接受的盐，其中式(Ⅰ)化合物中结构单元
    Figure PCTCN2017109922-appb-100058
    选自
    Figure PCTCN2017109922-appb-100059
    The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit of the compound of formula (I)
    Figure PCTCN2017109922-appb-100058
    Selected from
    Figure PCTCN2017109922-appb-100059
  28. 权利要求1的化合物或其药学上可接受的盐，其中式(Ⅰ)化合物中结构单元
    Figure PCTCN2017109922-appb-100060
    选自
    Figure PCTCN2017109922-appb-100061
    Figure PCTCN2017109922-appb-100062
    其中
    Figure PCTCN2017109922-appb-100063
    可进一步选自
    Figure PCTCN2017109922-appb-100064
    The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit of the compound of formula (I)
    Figure PCTCN2017109922-appb-100060
    Selected from
    Figure PCTCN2017109922-appb-100061
    Figure PCTCN2017109922-appb-100062
    among them
    Figure PCTCN2017109922-appb-100063
    Can be further selected from
    Figure PCTCN2017109922-appb-100064
  29. 权利要求1的化合物或其药学上可接受的盐，其中式(Ⅰ)化合物中结构单元
    Figure PCTCN2017109922-appb-100065
    选自
    Figure PCTCN2017109922-appb-100066
    The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit of the compound of formula (I)
    Figure PCTCN2017109922-appb-100065
    Selected from
    Figure PCTCN2017109922-appb-100066
  30. 权利要求1的化合物或其药学上可接受的盐，其中式(Ⅰ)化合物中结构单元
    Figure PCTCN2017109922-appb-100067
    选自
    Figure PCTCN2017109922-appb-100068
    Figure PCTCN2017109922-appb-100069
    Figure PCTCN2017109922-appb-100070
    其中
    Figure PCTCN2017109922-appb-100071
    可进一步选自
    Figure PCTCN2017109922-appb-100072
    Figure PCTCN2017109922-appb-100073
    The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit of the compound of formula (I)
    Figure PCTCN2017109922-appb-100067
    Selected from
    Figure PCTCN2017109922-appb-100068
    Figure PCTCN2017109922-appb-100069
    Figure PCTCN2017109922-appb-100070
    among them
    Figure PCTCN2017109922-appb-100071
    Can be further selected from
    Figure PCTCN2017109922-appb-100072
    Figure PCTCN2017109922-appb-100073
  31. 权利要求1的化合物或其药学上可接受的盐，其中式(Ⅰ)化合物中结构单元
    Figure PCTCN2017109922-appb-100074
    选自
    Figure PCTCN2017109922-appb-100075
    Figure PCTCN2017109922-appb-100076
    Figure PCTCN2017109922-appb-100077
    其中
    Figure PCTCN2017109922-appb-100078
    可进一步选自
    Figure PCTCN2017109922-appb-100079
    The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit of the compound of formula (I)
    Figure PCTCN2017109922-appb-100074
    Selected from
    Figure PCTCN2017109922-appb-100075
    Figure PCTCN2017109922-appb-100076
    Figure PCTCN2017109922-appb-100077
    among them
    Figure PCTCN2017109922-appb-100078
    Can be further selected from
    Figure PCTCN2017109922-appb-100079
  32. 权利要求1‐31中任一项的化合物或其药学上可接受的盐，其中式(Ⅰ)化合物为式(Ⅰa)化合物或式(Ⅰb)化合物，The compound of any one of claims 1 to 31, wherein the compound of formula (I) is a compound of formula (Ia) or a compound of formula (Ib), or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2017109922-appb-100080
    Figure PCTCN2017109922-appb-100080
  33. 权利要求1‐22、24‐29中任一项的化合物或其药学上可接受的盐，其中式(Ⅰ)化合物为式(Ⅱ)化合物， The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (II),
    Figure PCTCN2017109922-appb-100081
    Figure PCTCN2017109922-appb-100081
    其中，among them,
    R4分别独立地选自氟、氯、溴、碘、氰基、甲基或三氟甲基，优选为氯、氰基或三氟甲基；R 4 is each independently selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, methyl or trifluoromethyl, preferably chloro, cyano or trifluoromethyl;
    n选自0、1、2、3、4或5，优选为1、2或3。n is selected from 0, 1, 2, 3, 4 or 5, preferably 1, 2 or 3.
  34. 权利要求33的化合物或其药学上可接受的盐，结构单元
    Figure PCTCN2017109922-appb-100082
    选自
    Figure PCTCN2017109922-appb-100083
    优选选自
    Figure PCTCN2017109922-appb-100084
    Figure PCTCN2017109922-appb-100085
    The compound of claim 33 or a pharmaceutically acceptable salt thereof, structural unit
    Figure PCTCN2017109922-appb-100082
    Selected from
    Figure PCTCN2017109922-appb-100083
    Preferred from
    Figure PCTCN2017109922-appb-100084
    Figure PCTCN2017109922-appb-100085
  35. 权利要求1‐22、24‐31中任一项的化合物或其药学上可接受的盐，其中式(Ⅰ)化合物为式(Ⅲ)化合物，The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (III),
    Figure PCTCN2017109922-appb-100086
    Figure PCTCN2017109922-appb-100086
    其中，among them,
    R2选自C1-3烷基，所述C1-3烷基任选地被一个或多个选自氟、氯、溴、碘、羟基、氨基或氰基的基团取代，优选地，所述C1-3烷基任选地被一个或多个氟取代，最优选地，R2选自
    Figure PCTCN2017109922-appb-100087
    R 2 is selected from C 1-3 alkyl, said C 1-3 alkyl optionally substituted with one or more substituents selected from fluoro, chloro, bromo, iodo, hydroxy, amino or cyano group, preferably Said C 1-3 alkyl group is optionally substituted by one or more fluorines, most preferably R 2 is selected from
    Figure PCTCN2017109922-appb-100087
    R5分别独立地选自氟、氯、溴、碘、羟基、氨基、氰基、甲基或三氟甲基，优选为氯或溴；R 5 is each independently selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl or trifluoromethyl, preferably chlorine or bromine;
    m选自0、1、2、3、4或5，优选为0或1。 m is selected from 0, 1, 2, 3, 4 or 5, preferably 0 or 1.
  36. 权利要求35的化合物或其药学上可接受的盐，其中结构单元
    Figure PCTCN2017109922-appb-100088
    选自
    Figure PCTCN2017109922-appb-100089
    Figure PCTCN2017109922-appb-100090
    优选为
    Figure PCTCN2017109922-appb-100091
    最优选为
    Figure PCTCN2017109922-appb-100092
    The compound of claim 35 or a pharmaceutically acceptable salt thereof, wherein the structural unit
    Figure PCTCN2017109922-appb-100088
    Selected from
    Figure PCTCN2017109922-appb-100089
    Figure PCTCN2017109922-appb-100090
    Preferred
    Figure PCTCN2017109922-appb-100091
    Most preferably
    Figure PCTCN2017109922-appb-100092
  37. 权利要求1‐25、27‐31中任一项的化合物或其药学上可接受的盐，其中式(Ⅰ)化合物为式(Ⅳ)化合物，The compound of any one of claims 1-25, 27-31, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (IV),
    Figure PCTCN2017109922-appb-100093
    Figure PCTCN2017109922-appb-100093
  38. 权利要求37的化合物或其药学上可接受的盐，其中式(Ⅳ)化合物为式(Ⅳa)化合物、式(Ⅳb)化合物、式(Ⅳc)化合物或式(Ⅳd)化合物，A compound according to claim 37, wherein the compound of the formula (IV) is a compound of the formula (IVa), a compound of the formula (IVb), a compound of the formula (IVc) or a compound of the formula (IVd), or a pharmaceutically acceptable salt thereof.
    Figure PCTCN2017109922-appb-100094
    Figure PCTCN2017109922-appb-100094
  39. 权利要求37的化合物或其药学上可接受的盐，其中式(Ⅳ)化合物为式(Ⅴ)化合物， The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (IV) is a compound of formula (V),
    Figure PCTCN2017109922-appb-100095
    Figure PCTCN2017109922-appb-100095
  40. 权利要求37的化合物或其药学上可接受的盐，其中式(Ⅳ)化合物为式(Ⅵ)化合物，The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (IV) is a compound of formula (VI),
    Figure PCTCN2017109922-appb-100096
    Figure PCTCN2017109922-appb-100096
  41. 权利要求1‐24、26‐31中任一项的化合物或其药学上可接受的盐，其中式(Ⅰ)化合物为式(Ⅶ)化合物，The compound of any one of claims 1 - 24, 26-31, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (VII),
    Figure PCTCN2017109922-appb-100097
    Figure PCTCN2017109922-appb-100097
    其中，among them,
    R6分别独立地选自氟、氯、溴、碘、氰基、甲基或三氟甲基，优选为氟；R 6 is each independently selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, methyl or trifluoromethyl, preferably fluoro;
    p选自0、1、2、3或4，优选为0或1；p is selected from 0, 1, 2, 3 or 4, preferably 0 or 1;
    R1、R2、A环、T、R3、L1和L4的定义同权利要求1。R 1 , R 2 , A ring, T, R 3 , L 1 and L 4 are as defined in claim 1.
  42. 权利要求41的化合物或其药学上可接受的盐，其中结构单元
    Figure PCTCN2017109922-appb-100098
    选自
    Figure PCTCN2017109922-appb-100099
    Figure PCTCN2017109922-appb-100100
    The compound of claim 41 or a pharmaceutically acceptable salt thereof, wherein the structural unit
    Figure PCTCN2017109922-appb-100098
    Selected from
    Figure PCTCN2017109922-appb-100099
    Figure PCTCN2017109922-appb-100100
  43. 权利要求41的化合物或其药学上可接受的盐，其中结构单元
    Figure PCTCN2017109922-appb-100101
    选自
    Figure PCTCN2017109922-appb-100102
    Figure PCTCN2017109922-appb-100103
    优选选自
    Figure PCTCN2017109922-appb-100104
    The compound of claim 41 or a pharmaceutically acceptable salt thereof, wherein the structural unit
    Figure PCTCN2017109922-appb-100101
    Selected from
    Figure PCTCN2017109922-appb-100102
    Figure PCTCN2017109922-appb-100103
    Preferred from
    Figure PCTCN2017109922-appb-100104
  44. 权利要求41的化合物或其药学上可接受的盐，其中结构单元
    Figure PCTCN2017109922-appb-100105
    选自
    Figure PCTCN2017109922-appb-100106
    The compound of claim 41 or a pharmaceutically acceptable salt thereof, wherein the structural unit
    Figure PCTCN2017109922-appb-100105
    Selected from
    Figure PCTCN2017109922-appb-100106
  45. 权利要求41的化合物或其药学上可接受的盐，其中式(Ⅶ)化合物为式(Ⅷ)化合物，The compound of claim 41 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (VII) is a compound of formula (VIII),
    Figure PCTCN2017109922-appb-100107
    Figure PCTCN2017109922-appb-100107
    其中，among them,
    T分别独立地选自‐CH＝和‐N＝。T is independently selected from -CH= and ‐N=.
  46. 权利要求45的化合物或其药学上可接受的盐，其中结构单元
    Figure PCTCN2017109922-appb-100108
    选自
    Figure PCTCN2017109922-appb-100109
    优选选自
    Figure PCTCN2017109922-appb-100110
    The compound of claim 45 or a pharmaceutically acceptable salt thereof, wherein the structural unit
    Figure PCTCN2017109922-appb-100108
    Selected from
    Figure PCTCN2017109922-appb-100109
    Preferred from
    Figure PCTCN2017109922-appb-100110
  47. 权利要求45的化合物或其药学上可接受的盐，其中结构单元
    Figure PCTCN2017109922-appb-100111
    选自
    Figure PCTCN2017109922-appb-100112
    优选为
    Figure PCTCN2017109922-appb-100113
    The compound of claim 45 or a pharmaceutically acceptable salt thereof, wherein the structural unit
    Figure PCTCN2017109922-appb-100111
    Selected from
    Figure PCTCN2017109922-appb-100112
    Preferred
    Figure PCTCN2017109922-appb-100113
  48. 权利要求1的化合物或其药学上可接受的盐，其中式(Ⅰ)化合物选自以下化合物：A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the group consisting of:
    Figure PCTCN2017109922-appb-100114
    Figure PCTCN2017109922-appb-100114
    Figure PCTCN2017109922-appb-100115
    Figure PCTCN2017109922-appb-100115
    Figure PCTCN2017109922-appb-100116
    Figure PCTCN2017109922-appb-100116
    Figure PCTCN2017109922-appb-100117
    Figure PCTCN2017109922-appb-100117
  49. 药物组合物，其包含权利要求1-48任一项的化合物或其药学上可接受的盐。A pharmaceutical composition comprising a compound of any one of claims 1-48, or a pharmaceutically acceptable salt thereof.
  50. 治疗哺乳动物由cccDNA介导的疾病的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的权利要求1-48任一项的化合物或其药学上可接受的盐或者权利要求49的药物组合物。A method of treating a disease mediated by a cccDNA in a mammal, comprising administering to a mammal in need of such treatment, preferably a human, a therapeutically effective amount of a compound of any one of claims 1-48, or a pharmaceutically acceptable salt thereof, or a claim 49 pharmaceutical composition.
  51. 权利要求1-48任一项的化合物或其药学上可接受的盐、权利要求49的药物组合物在制备预防或者治疗cccDNA介导的疾病的药物中的用途。 Use of a compound according to any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 49, for the manufacture of a medicament for preventing or treating a cccDNA mediated disease.
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