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WO2022143610A1 - Novel amide pyrrole compounds and use thereof in medicaments - Google Patents

Novel amide pyrrole compounds and use thereof in medicaments Download PDF

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Publication number
WO2022143610A1
WO2022143610A1 PCT/CN2021/141926 CN2021141926W WO2022143610A1 WO 2022143610 A1 WO2022143610 A1 WO 2022143610A1 CN 2021141926 W CN2021141926 W CN 2021141926W WO 2022143610 A1 WO2022143610 A1 WO 2022143610A1
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alkyl
butyl
och
compound
group
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PCT/CN2021/141926
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French (fr)
Chinese (zh)
Inventor
张英俊
刘辛昌
任青云
王猛
冀石龙
颜光华
雷斗兴
余国森
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广东东阳光药业有限公司
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Publication of WO2022143610A1 publication Critical patent/WO2022143610A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—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 two 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention belongs to the field of medicine. Specifically, it relates to a novel amide pyrrole compound and its use as a medicine, especially as a medicine for the treatment and/or prevention of hepatitis B.
  • the present invention also relates to the compositions comprising these novel amide pyrroles and other antiviral agents, and their application in the treatment and/or prevention of hepatitis B virus (HBV) infection.
  • HBV hepatitis B virus
  • Hepatitis B virus belongs to the Hepatoviridae family. It can cause acute and/or progressive chronic disease. Hepatitis B virus can also cause many other clinical manifestations of pathological morphology - especially chronic inflammation of the liver, cirrhosis and carcinogenesis of hepatocytes. According to World Health Organization estimates, 2 billion people worldwide have been infected with HBV, about 350 million people are chronically infected, and about 1 million people die each year from liver failure, cirrhosis and primary hepatocellular carcinoma caused by HBV infection ( hepatocellular carcinoma, HCC).
  • HBV hepatocellular carcinoma
  • the current treatment for chronic hepatitis B is mainly antiviral therapy.
  • Interferon alpha IFN-alpha
  • pegylated IFN-alpha and 5 nucleoside (acid) analogs (lamivudine, adefovir dipivoxil, entecavir, telbivudine and tenofovir) Approved by the U.S. Food and Drug Administration (FDA) for clinical use.
  • FDA U.S. Food and Drug Administration
  • Interferon is the earliest anti-HBV drug approved by the FDA. It mainly achieves the effect of clearing the virus through direct antiviral effect and inducing the body's immune response. However, due to its low response rate, it has various side effects, high price and limited treatment targets.
  • nucleoside (acid) drugs For many reasons, its application is subject to many restrictions.
  • the common point of nucleoside (acid) drugs against HBV is that they specifically act on the viral DNA polymerase, which has a strong effect of inhibiting viral replication, and patients have better tolerance to drugs than interferon.
  • nucleoside (acid) drugs can induce the mutation of DNA polymerase to form drug resistance, resulting in the continuous emergence of drug-resistant strains, so that the treatment is far from reaching the ideal curative effect.
  • the present invention relates to novel amide pyrrole compounds and their use in preparing medicines for treating and preventing HBV infection.
  • the present invention relates to a novel amide pyrrole compound and a pharmaceutically acceptable composition thereof.
  • the compound has the advantages of good solubility, good stability, basically no induction effect on liver drug enzymes and less toxicity. , especially with very good pharmacokinetic properties.
  • the compound of the present invention can effectively inhibit HBV infection, and has a good application prospect in anti-HBV.
  • the present invention relates to a compound of formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmacy of a compound of formula (I) an acceptable salt or a prodrug thereof,
  • each of R 5a , R 5b , R 5c , R 5d , R 5e , R 2 and R 3 is independently hydrogen, deuterium, F, Cl, Br, I, CN, SF 5 , amino, nitro, methyl , ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 1-4 haloalkyl, trifluoromethoxy, methoxy or ethoxy;
  • Ring B is a C 6-10 aryl group, a heteroaryl group composed of 5-6 ring atoms, wherein, the C 6-10 aryl group and the heteroaryl group composed of 5-6 ring atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 R 6 ;
  • Each of R 1a , R 1b , R 1 , R 4 , Ra and R b is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl , tert-butyl or C 1-4 haloalkyl;
  • R 2a , R 2b and R 2c is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or C 1-4 Haloalkyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and C 1-4 haloalkyl groups are each independently unsubstituted or replaced by 1, 2, 3 or 4 R w2 ;
  • R 3a , R 3b , R 3c , R 4a , R 4b and R 4c is independently a C 1-6 alkyl group, a C 6-10 aryl group or a heteroaryl group consisting of 5-6 ring atoms, wherein the The C 6-10 aryl group and the heteroaryl group composed of 5-6 ring atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 R w3 ;
  • L 1 is a single bond, methylene or ethylene; wherein, the methylene and ethylene are independently unsubstituted or substituted by 1, 2 or 3 R w4 ;
  • L 2 is a single bond or -NR b -;
  • Ring A is a cyclohexyl group, a monocyclic heterocyclic group consisting of 5-6 ring atoms, a fused bicyclic heterocyclic group consisting of 8-10 ring atoms or a bridged ring heterocyclic group consisting of 6-10 ring atoms, wherein , the cyclohexyl group, the monocyclic heterocyclic group composed of 5-6 ring atoms, the fused bicyclic heterocyclic group composed of 8-10 ring atoms and the bridged bicyclic heterocyclic group composed of 6-10 ring atoms are each independently unsubstituted or substituted with 1 , 2, 3, 4, or 5 Rx;
  • the ring B of the present invention is phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, Wherein, the phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are each independently unsubstit
  • each of R 1a , R 2a , R 3a , R 4a , R 1b , R 2b , R 3b , R 4b , R 2c , R 3c , R 4c and R 6 has the meaning described in the present invention.
  • each of R 3a , R 3b , R 3c , R 4a , R 4b and R 4c described herein is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, sec-butyl, tert-butyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadi azolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein said phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl , imidazolyl, triazolyl, t
  • Ring A of the present invention is The formula (II-1), formula (II-2), formula (II-3), formula (II-4), formula (II-5), formula (II-6), formula (II- 7), formula (II-8), formula (II-9), formula (II-10), formula (II-11), formula (II-12), formula (II-13) and formula (II-14) ) are each independently unsubstituted or substituted with 1 , 2, 3, 4, or 5 Rx, wherein each Rx has the meaning described herein.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable adjuvant.
  • the pharmaceutical composition of the present invention further comprises other anti-HBV drugs.
  • the pharmaceutical composition of the present invention wherein the other anti-HBV drug is an HBV polymerase inhibitor, an immunomodulator, or an interferon.
  • the pharmaceutical composition of the present invention wherein the other anti-HBV drug is lamivudine, telbivudine, tenofovir dipivoxil, entecavir, adefovir dipivoxil, Alfaferone, Alloferon , Simoleukin, Clavudine, Emtricitabine, Faciclovir, Interferon, Baoganling CP, Interferon, Interferon alpha-1b, Interferon alpha, Interferon alpha-2a, Interferon beta -1a, interferon alfa-2, interleukin-2, mivotiate, nitazoxanide, peginterferon alfa-2a, ribavirin, rasteron-A, sizoran, Euforavac, Ampligen, Phosphazid, Heplisav, interferon alfa-2b, levamisole, or propagium.
  • the other anti-HBV drug is lamivudine,
  • it comprises the structure of one of the following, or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
  • the present invention also provides the use of the compound or the pharmaceutical composition in the preparation of a medicament for preventing, treating or alleviating a viral disease of a patient.
  • the use of the present invention wherein the viral disease refers to hepatitis B virus infection or a disease caused by hepatitis B virus infection.
  • the use of the present invention, wherein the disease caused by hepatitis B virus infection refers to liver cirrhosis or hepatocellular carcinoma.
  • the present invention relates to the use of the compound or pharmaceutical composition in the preparation of a medicament for preventing, treating or alleviating hepatitis B disease in a patient, comprising administering an effective therapeutic dose of the compound or the present invention
  • the pharmaceutical composition is administered to a patient.
  • Another aspect of the present invention pertains to a method of preventing, treating or alleviating an HBV disorder in a patient, the method comprising administering to the patient a pharmaceutically acceptable effective dose of a compound of the present invention.
  • Another aspect of the present invention pertains to a method of preventing, treating or alleviating an HBV disorder in a patient, the method comprising administering to the patient a pharmaceutically acceptable effective dose of a pharmaceutical composition comprising a compound of the present invention.
  • Another aspect of the present invention pertains to the use of a compound of the present invention for the manufacture of a medicament for the prevention or treatment of HBV disorders in a patient, and to lessen the severity thereof.
  • Another aspect of the present invention pertains to the use of a pharmaceutical composition comprising a compound of the present invention for the manufacture of a medicament for the prevention or treatment of HBV disorders in a patient, and to lessen the severity thereof.
  • Another aspect of the present invention pertains to a method of inhibiting HBV infection, the method comprising contacting a cell with a compound or pharmaceutical composition of the present invention in an amount effective to inhibit HBV. In other embodiments, the method further comprises contacting the cells with other anti-HBV therapeutics.
  • Another aspect of the present invention pertains to a method of treating HBV disease in a patient, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof. In other embodiments, the method further comprises administering to a patient in need thereof a therapeutically effective amount of another anti-HBV drug.
  • Another aspect of the present invention pertains to a method of inhibiting HBV infection in a patient, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof. In other embodiments, the method further comprises administering to a patient in need thereof a therapeutically effective amount of another anti-HBV drug.
  • Another aspect of the present invention relates to processes for the preparation, isolation and purification of compounds encompassed by formula (I).
  • the compounds involved in the present invention can effectively inhibit HBV infection.
  • the salts are pharmaceutically acceptable salts.
  • pharmaceutically acceptable includes substances or compositions that must be chemically or toxicologically suitable in relation to the other components that make up the formulation and the mammal for which it is to be treated.
  • the salts of the compounds of the present invention also include intermediates used in the preparation or purification of the compounds of formula (I) or salts of separated enantiomers of the compounds of formula (I), but are not necessarily pharmaceutically acceptable Salt.
  • the desired salts may be prepared by any suitable method provided in the literature, for example, using mineral acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids and the like.
  • mineral acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids and the like.
  • organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, malic acid, 2-hydroxypropionic acid, citric acid, oxalic acid, glycolic acid and salicylic acid ; Pyranonic acids, such as glucuronic and galacturonic acids; Alpha-hydroxy acids, such as citric and tartaric acids; Amino acids, such as aspartic and glutamic acids; Aromatic acids, such as benzoic and cinnamic acids; Sulfonic acids, such as p-toluenesulfonic acid, benzenesulfonic acid, methane
  • the desired salts can be prepared by suitable methods, eg, using inorganic or organic bases such as ammonia (primary, secondary, tertiary), alkali metal hydroxides, ammonium , N + (R 14 ) 4 salts and alkaline earth metal hydroxides, etc.
  • inorganic or organic bases such as ammonia (primary, secondary, tertiary), alkali metal hydroxides, ammonium , N + (R 14 ) 4 salts and alkaline earth metal hydroxides, etc.
  • Suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, such as primary, secondary and tertiary ammonia, salts of N + (R 14 ) 4 , such as R 14 is H, C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl, etc., and cyclic ammonia, such as piperidine, morpholine and piperazine, etc., and from sodium, Calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium give inorganic salts.
  • amino acids such as glycine and arginine
  • ammonia such as primary, secondary and tertiary ammonia
  • salts of N + (R 14 ) 4 such as R 14 is H, C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl, etc.
  • cyclic ammonia such as piper
  • nontoxic ammonium, quaternary ammonium salts, and amine cations that resist counterion formation such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 sulfonates and Aromatic sulfonates.
  • the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the general formula above, or as in the Examples, subclasses, and subclasses encompassed by the present invention. a class of compounds.
  • substituents of the compounds of the present invention are disclosed in terms of group type or scope. Specifically, the present invention includes each and every independent subcombination of each member of these group species and ranges.
  • C1-6 alkyl specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl groups .
  • alkyl as used herein includes saturated straight or branched monovalent hydrocarbon groups of 1 to 20 carbon atoms, wherein the alkyl group may be independently optionally substituted with one or more substituents described herein.
  • the alkyl group contains 1-12 carbon atoms, in other embodiments, the alkyl group contains 1-10 carbon atoms, and in still other embodiments, the alkyl group contains 1-8 carbon atoms.
  • carbon atoms in other embodiments, the alkyl group contains 1-6 carbon atoms, in other embodiments, the alkyl group contains 1-4 carbon atoms, and in still other embodiments, the alkyl group contains Contains 1-3 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me, -CH3 ), ethyl (Et, -CH2CH3), n - propyl (n - Pr, -CH2CH2 ) CH3 ), isopropyl (i-Pr, -CH( CH3 ) 2 ), n-butyl (n - Bu, -CH2CH2CH2CH3 ), 2 - methylpropyl or isobutyl (i-Bu, -CH2CH( CH3 ) 2 ), 1 -methylpropyl or sec-butyl (s-Bu, -CH( CH3 ) CH2CH3 ) , tert-butyl (t-Bu , -C( CH3 ) 3 ), n-pentyl ( -CH2CH2CH2CH3 ), 2 - pentyl (-CH( CH3 ) CH2CH2CH3 ) , 3 - pentyl (
  • alkylene refers to a saturated divalent or polyvalent hydrocarbon group obtained by removing two or more hydrogen atoms from a saturated straight or branched chain hydrocarbon group. Unless otherwise specified, alkylene groups contain 1-12 carbon atoms. In some embodiments, the alkylene group contains 1-6 carbon atoms; in other embodiments, the alkylene group contains 1-4 carbon atoms; in still some embodiments, the alkylene group The group contains 1-3 carbon atoms; in still other embodiments, the alkylene group contains 1-2 carbon atoms.
  • alkylene groups include, but are not limited to, methylene ( -CH2- ), ethylene ( -CH2CH2- ) , n - propylene ( -CH2CH2CH2- ) , isopropylene base (-CH(CH 3 )CH 2 -) and the like.
  • hydroxyalkyl and “hydroxyalkoxy” mean alkyl or alkoxy, as the case may be, substituted with one or more hydroxy groups, wherein “hydroxyalkyl”, “hydroxyalkylene”” and “hydroxyalkyl” can be used interchangeably with each other, such examples include, but are not limited to, hydroxymethyl (-CH 2 OH), hydroxyethyl (-CH 2 CH 2 OH, -CHOHCH 3 ), Hydroxypropyl (eg, -CH2CH2CH2OH , -CH2CHOHCH3 , -CHOHCH2CH3 ) , hydroxymethoxy ( -OCH2OH ) , and the like.
  • alkynyl means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least CC in one position is an sp triple bond, wherein the alkynyl group can be independently unsubstituted or substituted by one or more substituents described herein, specific examples include, but are not limited to, ethynyl ( -C ⁇ CH), propargyl (-CH 2 C ⁇ CH), propynyl (-C ⁇ C-CH 3 ), 1-alkynylbutyl (-CH 2 CH 2 C ⁇ CH), 2-alkynyl Butyl ( -CH2C ⁇ CCH3 ), 3 - alkynylbutyl ( -C ⁇ CCH2CH3 ), and the like, wherein the alkynyl groups may independently be unsubstituted or replaced by one or more of the present invention substituted with the described
  • haloalkyl means an alkyl, alkenyl or alkoxy group substituted with one or more halogen atoms, wherein alkyl, alkenyl and alkoxy Basic has the meaning described in the present invention.
  • carboxyalkyl means an alkyl group substituted with one or two carboxy substituents, wherein alkyl and carboxy have the meanings described herein. Such examples include, but are not limited to, -CH2COOH , -CH2CH2COOH , -CH2CH2CH2COOH , -CH2CH2CH2COOH , and the like .
  • alkoxy means that an alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy groups contain 1-12 carbon atoms. In some embodiments, alkoxy groups contain 1-8 carbon atoms; in other embodiments, alkoxy groups contain 1-6 carbon atoms; in other embodiments, alkoxy groups groups contain 1-4 carbon atoms; in yet other embodiments, alkoxy groups contain 1-3 carbon atoms. The alkoxy groups may be optionally substituted with one or more substituents described herein.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-propoxy, n -PrO, n-propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n -BuO, n-butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butoxy (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy , -OC(CH 3 ) 3 ), 1-pentyloxy (n-pentyloxy, -OCH 2 CH 2 CH 2 CH
  • MM 1 ring atoms or “consisting of MM 1 atoms” means that the cyclic group consists of MM 1 ring atoms including carbon atoms and/or O, N, S, P and other heteroatoms.
  • heteroaryl of 6-10 atoms means that it includes a heteroaryl group of 6, 7, 8, 9 or 10 ring atoms.
  • cycloalkyl refers to a saturated, monocyclic, bicyclic or tricyclic ring system having one or more points of attachment to the remainder of the molecule, containing from 3 to 12 ring carbon atoms.
  • the cycloalkyl group is a spirobicycloalkyl group composed of 6-10 atoms; in other embodiments, the cycloalkyl group is a fused bicycloalkyl group composed of 6-10 atoms; in other embodiments, the cycloalkane group
  • cycloalkyl is a ring system containing 3-8 ring carbon atoms; in other embodiments, cycloalkyl is a ring system containing 3-7 ring carbon atoms carbon atoms; in other embodiments, cycloalkyl is a ring system containing 5-8 ring carbon atoms; in other embodiments, cycloalkyl is a ring system containing 3-6 ring carbon atoms;
  • heterocyclyl includes monocyclic, bicyclic or polycyclic fused, spiro or bridged ring systems.
  • heterocyclyl and heterocycle are used interchangeably herein and both refer to a saturated or partially unsaturated, non-aromatic monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 ring atoms, wherein At least one ring atom is selected from nitrogen, sulfur and oxygen atoms, and the ring system has one or more points of attachment to the rest of the molecule.
  • heterocyclyl includes monocyclic heterocyclyls, bicyclic or polycyclic fused heterocyclyls, spiro or bridged heterocyclic heterocyclyls, and also wherein heterocycles may be combined with one or more non-aromatic carbocyclic rings or a heterocyclic ring or a polycyclic ring system in which one or more aromatic rings or combinations thereof are fused, wherein the atomic group or point of attachment is on the heterocyclic ring.
  • Bicyclic heterocyclic groups include bridged bicyclic heterocyclic groups, fused bicyclic heterocyclic groups, and spirobicyclic heterocyclic groups.
  • Ring sulfur atoms can optionally be oxidized to S-oxides.
  • the nitrogen atoms of the rings can be optionally oxidized to N-oxygen compounds.
  • heterocyclyl is a ring system of 3-12 ring atoms; in some embodiments, heterocyclyl is a monocyclic heterocyclyl of 4-7 ring atoms; in some embodiments , the heterocyclyl group is a monocyclic heterocyclyl group composed of 5-6 ring atoms; in some embodiments, the heterocyclyl group is a fused bicyclic heterocyclyl group composed of 7-10 ring atoms; in some embodiments, Heterocyclyl is a fused bicyclic heterocyclyl of 8-10 ring atoms; in some embodiments, heterocyclyl is a bridged bicyclic heterocyclyl of 6-10 ring atoms; in other embodiments, Heterocyclyl is a ring system of 3-8 ring atoms; in other embodiments, heterocyclyl is a ring system of 3-6 ring atoms; in other embodiments, heterocyclyl is 5- A ring system consisting of 7 ring atoms
  • heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxetanyl Propyl, Azacycloheptyl, Oxepeptyl, Thiepanyl, Oxazepinyl, Diazepanyl, Thiazepinyl, 2-Pyrrololinyl, 3-Pyrrololinyl , Indoline, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxopentyl,
  • the heterocyclyl group may be optionally substituted with one or more substituents described herein.
  • fused bicyclic means fused bicyclic
  • fused ring means fused bicyclic
  • fused bicyclic group refers to monovalent or polyvalent, saturated or partially unsaturated, non-aromatic A ring system in which two rings share a bond.
  • Such systems may contain independent or conjugated unsaturated systems, but whose core structure does not contain aromatic rings or aromatic heterocycles (although aromatic groups may serve as substituents thereon).
  • spirocyclyl spirocycle
  • spirobicyclyl spirobicycle
  • a saturated ring system (rings C and B') is referred to as a "fused bicyclic", while rings A' and B share a carbon atom, referred to as a “spiro ring” or “spirobicyclic”.
  • Each ring of the fused bicyclyl and spirobicyclyl groups can be carbocyclyl or heterocyclyl, and each ring is optionally substituted with one or more substituents described herein.
  • fused bicyclic heterocyclyl refers to a monovalent saturated or partially unsaturated non-aromatic bicyclic ring system. Such systems may contain independent or conjugated unsaturation, but their core structure does not contain aromatic or aromatic heterocycles (although aromatics may be used as substituents thereon). Each ring in the ring system contains 3-7 atoms, and at least one ring contains one or more heteroatoms, i.e.
  • the fused bicyclic heterocyclyl is 7 - A fused bicyclic heterocyclyl of 10 ring atoms; in some embodiments, a fused bicyclic heterocyclyl is a fused bicyclic heterocyclyl of 8-10 ring atoms; such examples include, but do not Limited to, 3-aza-fused[3.1.0]hexane, 3-azabicyclo[3.3.0]octane, hexahydro-furan[3,4-c]pyrrolyl, hexahydro-thiophene[3, 4-c] pyrrolyl, 3,4,5,6-tetrahydro-cyclopentane[c]thienyl, Wait.
  • the fused heterobicyclyl group is optionally substituted with one or more
  • bridged bicyclyl refers to a saturated or partially unsaturated non-aromatic bridged ring system, as shown in formula (b), that is, ring A1 and ring A2 share an alkane chain or a heteroalkane chain, wherein X 3 is C , N, O, P, S; j is 1, 2, 3 or 4.
  • Such systems may contain independent or conjugated unsaturation, but whose core structure does not contain aromatic or aromatic rings (although aromatics may be substituents thereon).
  • each ring, such as A1 or A2 contains 3-7 atoms, such examples include, but are not limited to, bicyclo[2.2.1]heptyl, 2-methyl-diazabicyclo[2.2. 1] Heptyl, etc.
  • the bridged bicyclyl is optionally substituted with one or more substituents described herein.
  • bridged carbobicyclyl refers to a saturated or partially unsaturated non-aromatic bridged bicyclic ring system wherein each ring contains 3-7 carbon atoms, examples of which include, but are not limited to, bicyclic [2.2.1] Heptyl, etc.
  • the bridged bicyclyl is optionally substituted with one or more substituents described herein.
  • bridged bicyclic heterocyclyl denotes a saturated or partially unsaturated non-aromatic bridged bicyclic ring system wherein each ring contains 3-7 atoms and at least one ring contains one or more heteroatoms, i.e., contains 1- 6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to obtain like SO, SO 2 , PO, PO 2
  • the group, in some embodiments, bridged bicyclic heterocyclyl is a bridged bicyclic heterocyclyl consisting of 6-10 ring atoms, such examples include, but are not limited to 2-oxo-5-azabicyclo[2.2 .1]heptyl, 2-thio-5-azabicyclo[2.2.1]heptyl, 2-oxo-5-azabicyclo[2.2.1]heptyl, 2,5-di azabicyclo[2.2.1]heptyl, 2-methyl-2,5-di
  • aryl refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing 6-14 carbon atoms, or 6-12 carbon atoms, or 6-10 carbon atoms, wherein at least one ring system are aromatic in which each ring system contains a ring of 3-7 carbon atoms with one or more points of attachment to the rest of the molecule.
  • aryl may be used interchangeably with the term “aromatic ring” or "aromatic ring”, eg aryl may include phenyl, naphthyl and anthracenyl.
  • the aryl groups may independently be unsubstituted or substituted with one or more of the substituents described herein.
  • heteroaryl refers to a monocyclic, bicyclic or tricyclic ring system containing 5 to 16 ring atoms, at least one of which is aromatic and at least one of which contains one or more heteroatoms, wherein Each ring system contains a ring of 5-7 ring atoms with one or more points of attachment to the rest of the molecule.
  • heteroaryl may be used interchangeably with the terms “heteroaromatic ring” or “heteroaromatic”.
  • a heteroaryl group is a heteroaryl group consisting of 5-14 ring atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N.
  • the heteroaryl group is a heteroaryl group consisting of 5-12 ring atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 5-10 ring atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 5-8 ring atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 5-7 ring atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.
  • the heteroaryl group is a heteroaryl group consisting of 5-6 ring atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 5 ring atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 6 ring atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.
  • heteroaryl groups include, but are not limited to, the following monocyclic groups: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazole base, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl , 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazine base), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5H-tetrazolyl, 2H-tetrazolyl), triazolyl (such as 2-triazolyl, 5-triazolyl, 5-tri
  • the structural formulae described herein include all isomeric forms (eg, enantiomers, diastereomers, and geometrical isomers (or conformations): for example, R containing an asymmetric center , S configuration, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers.
  • R containing an asymmetric center , S configuration for example, R containing an asymmetric center , S configuration, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers.
  • the individual stereochemical isomers of the compounds of the present invention or their enantiomers Isomers, diastereomers, or mixtures of geometric isomers (or conformational isomers) are within the scope of the present invention.
  • prodrug refers to the conversion of a compound into a compound of formula (I) in vivo. Such conversion is effected by hydrolysis of the prodrug in blood or enzymatic conversion to the parent structure in blood or tissue.
  • the prodrug compounds of the present invention can be esters.
  • esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonate esters , carbamates and amino acid esters.
  • a compound of the present invention contains a hydroxyl group, which can be acylated to give the compound in prodrug form.
  • prodrug forms include phosphates, such as these phosphates are phosphorylated by the hydroxyl group on the parent.
  • phosphates such as these phosphates are phosphorylated by the hydroxyl group on the parent.
  • a complete discussion of prodrugs can be found in the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008 , 51, 2328-2345.
  • Metal refers to a product obtained by metabolism of a specific compound or salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and their activity can be characterized using assays as described herein. Such products may be obtained by subjecting the administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.
  • stereochemistry in the present invention is generally referred to by S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S. ., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.
  • the compounds of the present invention may contain asymmetric or chiral centers and therefore exist in different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including, but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute the part.
  • optically active compounds that is, they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D, L or R, S are used to denote the absolute configuration of the chiral center of the molecule.
  • the prefixes d, l or (+), (-) are used to designate the sign of the plane-polarized light rotation of the compound, (-) or l means the compound is levorotatory, and the prefix (+) or d means the compound is dextrorotatory.
  • the chemical structures of these stereoisomers are the same, but their steric structures are not the same.
  • a specific stereoisomer may be an enantiomer, and a mixture of isomers is often referred to as an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can result in no stereoselectivity or stereospecificity during chemical reactions.
  • racemic mixture and racemate refer to an equimolar mixture of two enantiomers, devoid of optical activity.
  • tautomer or “tautomeric form” means that isomers of structures of different energies can be interconverted through a low energy barrier.
  • proton tautomers ie, prototropic tautomers
  • prototropic tautomers include interconversions by migration of protons, such as keto-enol and imine-enamine isomerizations.
  • Valence (valence) tautomers include interconversions that recombine bond electrons. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
  • pharmaceutically acceptable salts refer to organic and inorganic salts of the compounds of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19, 1977.
  • Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups including hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or obtained by other methods such as ion exchange methods described in books and literature these salts.
  • salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate , borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate acid salt, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactic acid Salt, laurate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate , pectinate, persulfate, 3-pheny
  • Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also contemplates quaternary ammonium salts formed from any compound containing an N-group. Water- or oil-soluble or dispersible products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations that resist counterion formation, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1 -8 Sulfonates and aromatic sulfonates.
  • a “solvate” of the present invention refers to an association of one or more solvent molecules with a compound of the present invention.
  • Solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, aminoethanol.
  • hydrate refers to an association in which the solvent molecule is water.
  • protecting group refers to a substituent that is commonly used to block or protect a particular functionality when it reacts with another functional group.
  • protecting group for amino refers to a substituent attached to the amino group to block or protect the functionality of the amino group in the compound.
  • Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc).
  • hydroxyl protecting group refers to a substituent of a hydroxy group used to block or protect the functionality of the hydroxy group
  • suitable protecting groups include acetyl and silyl.
  • Carboxyl protecting group means that the substituent of the carboxyl group is used to block or protect the functionality of the carboxyl group.
  • General carboxyl protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilane) yl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl) phosphino)ethyl, nitroethyl, and the like.
  • protecting groups reference can be made to the literature: TW. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
  • the pharmaceutical composition of the present invention features a compound of formula (I), a compound listed in the present invention, or an example compound, and a pharmaceutically acceptable excipient.
  • the compounds in the pharmaceutical composition of the present invention can effectively inhibit hepatitis B virus, and are suitable for the treatment of diseases caused by viruses, especially acute and chronic persistent HBV infection. Hepatitis virus infection can lead to cirrhosis and/or hepatocellular carcinoma in many cases.
  • An area of disease treatment that may be mentioned for the compounds of the present invention is, for example, the treatment of acute and chronic viral infections that may lead to infectious hepatitis, eg, hepatitis B virus infection.
  • the compounds of the present invention are particularly suitable for the treatment of chronic hepatitis B infection and acute and chronic hepatitis B virus infection.
  • the present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, also contain one or more compounds of formula (I) of the present invention or their pharmaceutical compositions or one or more active ingredients of formula (I) The compound or the pharmaceutical composition of the present invention.
  • compositions described above may also contain other active pharmaceutical ingredients than compounds of formula (I).
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other that can be administered directly or indirectly according to the needs of the patient Adducts or derivatives, compounds described in other aspects of the invention, metabolites thereof or residues thereof.
  • the pharmaceutical composition of the present invention comprises any one of the compounds represented by formula (I) of the present invention, and further comprises pharmaceutically acceptable excipients, such as those used in the present invention, including any solvent , solid excipients, diluents, binders, disintegrants, or other liquid excipients, dispersing agents, flavoring or suspending agents, surfactants, isotonic agents, thickening agents, emulsifiers, preservatives agents, solid binders or lubricants, etc., suitable for the particular target dosage form.
  • pharmaceutically acceptable excipients such as those used in the present invention, including any solvent , solid excipients, diluents, binders, disintegrants, or other liquid excipients, dispersing agents, flavoring or suspending agents, surfactants, isotonic agents, thickening agents, emulsifiers, preservatives agents, solid binders or lubricants, etc., suitable for the particular target dosage form.
  • Substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances such as phosphate; glycine; sorbic acid; Potassium sorbate; partial glyceride mixture of saturated vegetable fatty acids; water; salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; Vinylpyrrolidones; polyacrylates; waxes; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxylate Sodium methylcellulose, ethylcellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such
  • compositions of the compounds of the present invention may be administered in any of the following ways: oral administration, spray inhalation, topical administration, rectal administration, nasal administration, topical administration, vaginal administration, parenteral administration
  • the drug is administered as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, or intracranial injection or infusion, or by means of an explanted reservoir.
  • the preferred mode is oral administration, intramuscular injection, intraperitoneal administration or intravenous injection.
  • the compounds of the present invention or pharmaceutical compositions thereof may be administered in unit dosage form.
  • the dosage form for administration can be a liquid dosage form, a solid dosage form.
  • Liquid dosage forms can be true solutions, colloids, microparticles, and suspensions.
  • Other dosage forms such as tablets, capsules, dropping pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, lyophilized powders, inclusions, implants, patches, wipes agent, etc.
  • Oral tablets and capsules may contain excipients such as binders, such as syrup, acacia, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, such as lactose, sucrose, cornstarch, calcium phosphate, sorbitol, amino acids acetic acid; lubricants such as magnesium stearate, talc, polyethylene glycol, silica; disintegrants such as potato starch; or acceptable emollients such as sodium lauryl sulfate. Tablets can be coated by methods known in pharmacy.
  • binders such as syrup, acacia, sorbitol, tragacanth, or polyvinylpyrrolidone
  • fillers such as lactose, sucrose, cornstarch, calcium phosphate, sorbitol, amino acids acetic acid
  • lubricants such as magnesium stearate, talc, polyethylene glycol, silica
  • disintegrants such as
  • Oral solutions can be prepared as suspensions, solutions, emulsions, syrups or elixirs in hydrated oils, or they can be prepared as dry products for replenishment with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, sorbitol, cellulose methyl ether, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible Fats, emulsifiers such as lecithin, sorbitan monooleate, acacia; or non-aqueous excipients (may contain edible oils) such as almond oil, oils such as glycerol, glycol, or ethanol; preservatives, Such as methyl or propyl paraben, sorbic acid. Flavoring or coloring agents may be added if desired.
  • Suppositories may contain conventional suppository bases such as cocoa butter or other glycerides.
  • liquid dosage forms are usually prepared from the compound and a sterile excipient.
  • the first choice for excipients is water.
  • the compound can be dissolved in the excipient or made into a suspension solution.
  • the compound is first dissolved in water, filtered and sterilized, and then put into a sealed bottle or ampule.
  • the compounds of the present invention may be formulated in the form of a suitable ointment, lotion, or cream in which the active ingredient is suspended or dissolved in one or more excipients which may be used in the ointment formulation including but Not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water; excipients that can be used in lotions and creams include but are not limited to: mineral oil, sorbitan monohydrate Stearate, Tween 60, cetyl ester wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the active compounds according to the invention in a total amount of about 0.5-500 mg per 24 hours, preferably 1-100 mg/kg body weight, if appropriate divided into Multiple single doses are administered to achieve the desired effect.
  • the amount of active compound contained in a single dose is preferably about 1-80 mg, more preferably 1-50 mg/kg body weight, but may not be in accordance with the above-mentioned doses, i.e. depending on the type and body weight of the subject, the nature and severity of the disease , the type of preparation and the mode of administration of the drug, and the period or interval of administration.
  • the pharmaceutical composition provided by the present invention also includes an anti-HBV drug.
  • the anti-HBV drug is HBV polymerase inhibitor, immunomodulator or interferon.
  • the anti-HBV drugs include lamivudine, telbivudine, tenofovir dipivoxil, entecavir, adefovir dipivoxil, Alfaferone, Alloferon, simoleukin, clavudine, emtricitabine, faprol Wei, interferon, Baoganling CP, interferon, interferon alpha-1b, interferon alpha, interferon alpha-2a, interferon beta-1a, interferon alpha-2, interleukin-2, mivo Tietate, Nitazoxanide, Pegylated Interferon alfa-2a, Ribavirin, Rosferon-A, Sizoran, Euforavac, Ampligen, Phosphazid, Heplisav, Interferon alfa-2b, Levamisole Or propagium and so on.
  • Hepatitis B disease refers to liver disease caused by hepatitis B virus infection or hepatitis B infection, including acute hepatitis, chronic hepatitis, liver cirrhosis and stem cell cancer.
  • Acute HBV infection can be asymptomatic or present with acute hepatitis symptoms.
  • Patients with chronic viral infection have active disease that can develop cirrhosis and liver cancer.
  • the anti-HBV drug may be administered separately from the composition comprising the compound of the present invention as part of a multiple dosing regimen.
  • those drugs may be part of a single dosage form that is mixed with the compounds of the present invention to form a single composition.
  • the two active agents can be delivered to each other simultaneously, continuously or over a period of time, to achieve the desired agent activity.
  • the amount of compounds and pharmaceutical compositions that can be combined with excipient substances to produce a single dosage form varies depending on the indication and the particular mode of administration. Normally, the amount of the pharmaceutical composition of the present invention will not exceed the amount in which the composition contains as the only active agent normally administered. On the other hand, the amounts of the presently disclosed pharmaceutical compositions range from about 50% to 100% of the normal amount of existing pharmaceutical compositions, containing the agent as the only active therapeutic agent. In those included compositions, the compositions will act synergistically with the compounds of the present invention.
  • the compounds of the present invention show strong antiviral effects. Such compounds have unexpected antiviral activity against HBV and are therefore suitable for the treatment of various diseases caused by viruses, especially diseases caused by acute and chronic persistent HBV infection. Chronic viral diseases caused by HBV can lead to syndromes of varying severity, and chronic HBV infection is known to lead to cirrhosis and/or hepatocellular carcinoma.
  • indications that can be treated with the compounds of the present invention are acute and chronic viral infections that can lead to infectious hepatitis, such as hepatitis B virus infection.
  • infectious hepatitis such as hepatitis B virus infection.
  • Particularly preferred are chronic hepatitis B infection and acute hepatitis B virus infection.
  • the present invention also relates to the use of the compounds and pharmaceutical compositions of the present invention for the preparation of medicaments for the treatment and prevention of viral diseases, especially hepatitis B.
  • the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, wherein the substituents are as defined in formula (I).
  • the following synthetic schemes and examples serve to further illustrate the content of the present invention.
  • the chromatographic column used silica gel column, and silica gel (200-300 mesh) was purchased from Qingdao Ocean Chemical Factory. NMR spectra were performed with CDC13, DMSO - d6, CD3OD or acetone - d6 as solvents (reported in ppm), with TMS (0 ppm) or chloroform (7.25 ppm) as reference standards.
  • MS data were determined by an Agilent 6320 Series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30°C), a G1329A autosampler and a G1315B DAD detector for analysis , ESI source applied to LC-MS spectrometer.
  • MS data were also determined by an Agilent 6120 Series LC-MS spectrometer equipped with a G1311A quaternary pump and G1316A TCC (column temperature maintained at 30°C), a G1329A autosampler and a G1315D DAD detector for analysis , ESI source applied to LC-MS spectrometer.
  • each ring B, R 5a , R 5b , R 5c , R 5d , R 5e , R x , R 1 , R 2 , R 3 and R 4 has the meaning as described in the present invention.
  • the compound represented by formula (a-6) can be prepared by the method described in Synthesis Scheme 1, wherein, the Y is O or S; X is chlorine or bromine.
  • Compound (a-1) (which can be obtained by referring to the synthesis method of compound M in Example 11 of WO2015132276) reacts with compound (a-2) under basic conditions (eg, sodium hydride, etc.) to form compound (a-3); then , compound (a-3) removes the Boc protecting group under suitable conditions (eg, trifluoroacetic acid) to obtain compound (a-4) or its salt; finally, compound (a-5) (refer to WO2017156255 specification page 101 , compound 42 obtained by the synthesis method) and compound (a-4) or its salt under suitable conditions (such as under HATU and DIPEA) to undergo condensation reaction to obtain compound (a-6).
  • suitable conditions such as under HATU and DIPEA
  • the compound represented by formula (b-4) can be prepared by the method described in Synthesis Scheme 2, wherein D is 4-7 optionally substituted by 1, 2, 3, 4, or 5 R x N-containing monocyclic heterocyclic group composed of ring atoms or N-containing bridged bicyclic heterocyclic group composed of 6-10 ring atoms; X is chlorine or bromine.
  • Compound (a-5) is subjected to condensation reaction with compound (b-1) under suitable conditions (eg, under HATU and DIPEA) to form compound (b-2); then, compound (b-2) is reacted under suitable conditions (eg, trifluoroacetic acid) to remove the Boc protecting group to obtain compound (b-3) or its salt; finally, compound (b-3) or its salt and compound (a-2) under basic conditions (eg, potassium carbonate, etc.) to react to obtain compound (b-4).
  • suitable conditions eg, trifluoroacetic acid
  • the compound represented by formula (b-4) can also be prepared by the method described in the synthetic scheme 3, wherein, D is 4-7 optionally substituted by 1, 2, 3, 4, or 5 R x N-containing monocyclic heterocyclic group composed of ring atoms or N-containing bridged bicyclic heterocyclic group composed of 6-10 ring atoms; X is chlorine or bromine.
  • Compound (a-2) reacts with compound (b-1) under basic conditions (eg, potassium carbonate, etc.) to generate compound (c-1); then, compound (c-1) is reacted under suitable conditions ( For example, trifluoroacetic acid) removes the Boc protecting group to obtain compound (c-2) or its salt; finally, compound (c-2) or its salt is combined with compound (a-5) under suitable conditions (eg, as in HATU and DIPEA) undergo a condensation reaction to obtain compound (b-4).
  • suitable conditions eg, trifluoroacetic acid
  • Substitute 2-(chloromethyl)-3,4-dimethoxypyridine for 1-(bromomethyl)-2-chloro-4-fluorobenzene refer to the synthetic method of compound 1, and prepare the target product as a white solid (384 mg, 51%).
  • Compound F4 (its synthesis method is: replace (S)-piperazine-2-carboxylic acid dihydrochloride with (R)-piperazine-2-carboxylic acid dihydrochloride, obtained with reference to the synthesis method of F1) and compound F3 Substituting compound F1 and 1-(bromomethyl)-2-chloro-4-fluorobenzene respectively, referring to the synthesis method of compound 1, the target product was prepared as a yellow solid (350 mg, 71%, ).
  • Compound F5 (which is obtained by referring to the synthesis method of Step 1 to Step 2 in Example 39 of WO2015144093A1) is replaced with 1-(bromomethyl)-2-chloro-4-fluorobenzene, and the target product is prepared by referring to the synthesis method of Compound 1 as a yellow solid (220 mg, 53%).
  • Substitute (R)-3-methylpiperazine-1-carboxylate tert-butyl ester for piperazine-1-carboxylate tert-butyl ester refer to the synthetic method of compound 9, and prepare the target product as a yellow solid (280mg, 46% ).
  • Substitute 2,5-diazabicyclo[2.2.2]octane-2-carboxylate tert-butyl ester for piperazine-1-carboxylate tert-butyl ester refer to the synthetic method of compound 9, and prepare the target product as a yellow solid (670 mg, 95%).
  • Substitute 3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester for piperazine-1-carboxylic acid tert-butyl ester refer to the synthetic method of compound 9, and prepare the target product as a yellow solid (670 mg, 95%).
  • HepAD38 Ladner et al. (Ladner, Otto et al. 1997) linked the tetracycline-sensitive cytomegalovirus CMV promoter to the PBR322 plasmid and linked the ayw subtype HBV DNA to the ptetHBV plasmid, and transfected HepG2 cells to obtain the HepAD38 cell line. Due to the disruption of the pre-C region gene, the HBV DNA yield was approximately 11-fold higher than that of HepG2.2.15 cells.
  • Tetracycline can be used to regulate HBV replication, and the time required for culturing is only half of that of HepG2.2.15 cells, which is suitable for the study of HBV replication process and replication intermediates and the screening of anti-HBV drugs.
  • HepAD38 was cultured in DMEM/F-12K medium containing 10% FBS and 1% double antibody (also containing Tetracycline at a final concentration of 300 ng/ml and G418 at a final concentration of 400 ⁇ g/ml)
  • the viral particle DNA secreted by HepAD38 cells can be quantified by qPCR, and the effects of compounds on viral replication can be detected.
  • HepAD38 was revived, digested and counted after the cells were in good condition, and diluted with DMEM/F-12K medium containing 10% FBS and 1% double antibody to a concentration of 1 ⁇ 10 5 /mL cell suspension.
  • the amount of 100 ⁇ L was inoculated in a 96-well plate (the whole plate was covered), and incubated in a 37° C., 5% CO 2 constant temperature incubator for 24 h. After 24 hours, the old medium was discarded, and 200 ⁇ L of fresh DMEM/F-12K medium containing 2% FBS and 1% double antibody was added.
  • Compound formulation and cell treatment in in vitro cytotoxicity assays Compounds were dissolved in DMSO to 20 mM, followed by 8 dilutions of 4-fold dilutions, with a maximum concentration of 20 mM. Add 1 ⁇ L of serially diluted compounds to each well of the above cell plate, and the highest final concentration in the experiment is 100 ⁇ M (200-fold dilution). Staurosporine (staurosporine, Selleck, CAS No. 62996-74-1) was used as a positive control compound at a maximum concentration of 1 ⁇ M. Negative control wells were added with 1 ⁇ L DMSO at a final concentration of 0.5%.
  • Tetracycline final concentration of 300ng/ml
  • G418 final concentration of 400 ⁇ g/ml
  • DMEM/F-12K medium containing 10% FBS (containing Tetracycline at a final concentration of 300 ng/ml and G418 at a final concentration of 400 ⁇ g/ml, 1% double antibody) was diluted to a concentration of 2 ⁇ 10 5 /mL cell suspension , inoculate 100 ⁇ L per well in a 96-well plate (the whole plate is covered), and incubate in a 37° C., 5% CO 2 constant temperature incubator for 24 h. After 24 hours, the old medium was discarded, and 200 ⁇ L of fresh DMEM/F-12K medium containing 2% FBS and 1% double antibody was added.
  • FBS containing Tetracycline at a final concentration of 300 ng/ml and G418 at a final concentration of 400 ⁇ g/ml, 1% double antibody

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Abstract

Disclosed are novel amide pyrrole compounds and the use thereof in medicaments, especially the use thereof as a medicament for treating and preventing hepatitis B. In particular, the present invention relates to a compound as represented by general formula (I) or a stereoisomer, a tautomer, an oxynitride, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and the use thereof as a medicament, especially a medicament for treating and/or preventing hepatitis B.

Description

新型酰胺吡咯类化合物及其在药物中的应用Novel amide pyrroles and their application in medicine 技术领域technical field
本发明属于医药领域。具体涉及一种新型酰胺吡咯类化合物及其作为药物的用途，尤其是作为用于治疗和/或预防乙型肝炎的药物的用途。本发明还涉及这些含新型酰胺吡咯类化合物同其他抗病毒剂组成的组合物，及其在用于治疗和/或预防乙型肝炎病毒(HBV)感染中的应用。The present invention belongs to the field of medicine. Specifically, it relates to a novel amide pyrrole compound and its use as a medicine, especially as a medicine for the treatment and/or prevention of hepatitis B. The present invention also relates to the compositions comprising these novel amide pyrroles and other antiviral agents, and their application in the treatment and/or prevention of hepatitis B virus (HBV) infection.
背景技术Background technique
乙型肝炎病毒属于肝病毒科。它可引起急性的和/或持续渐进的慢性病。乙型肝炎病毒还可引起病理形态中的许多其他的临床表征——尤其是肝脏的慢性炎症、肝硬化和肝细胞的癌变。据世界卫生组织估计，全球有20亿人感染过HBV，约有3.5亿的慢性感染者，每年大约有100万人死于HBV感染所致的肝衰竭、肝硬化和原发性肝细胞癌(hepatocellular carcinoma，HCC)。Hepatitis B virus belongs to the Hepatoviridae family. It can cause acute and/or progressive chronic disease. Hepatitis B virus can also cause many other clinical manifestations of pathological morphology - especially chronic inflammation of the liver, cirrhosis and carcinogenesis of hepatocytes. According to World Health Organization estimates, 2 billion people worldwide have been infected with HBV, about 350 million people are chronically infected, and about 1 million people die each year from liver failure, cirrhosis and primary hepatocellular carcinoma caused by HBV infection ( hepatocellular carcinoma, HCC).
目前对于慢性乙型肝炎(Chronic hepatitis B，CHB)的治疗主要为抗病毒治疗。干扰素α(IFN-α)和聚乙二醇化IFN-α及5种核苷(酸)类似物(拉米夫定、阿德福韦酯、恩替卡韦、替比夫定和替诺福韦)被美国食品药品监督管理局(FDA)批准用于临床治疗。干扰素是最早通过FDA批准的抗HBV药物，其主要通过直接抗病毒作用及诱导机体的免疫反应以达到清除病毒的效果，但因其应答率低，具有多种副作用，价格昂贵且治疗对象局限等原因，其应用受到很多限制。核苷(酸)类药物抗HBV共同点是特异性作用于病毒DNA聚合酶，具有强大的抑制病毒复制的效果，患者对药物的耐受性比干扰素好。但是核苷(酸)类药物的广泛长期使用，可诱导DNA聚合酶突变形成耐药性，导致耐药株的不断出现，使治疗远不能达到理想疗效。The current treatment for chronic hepatitis B (CHB) is mainly antiviral therapy. Interferon alpha (IFN-alpha) and pegylated IFN-alpha and 5 nucleoside (acid) analogs (lamivudine, adefovir dipivoxil, entecavir, telbivudine and tenofovir) Approved by the U.S. Food and Drug Administration (FDA) for clinical use. Interferon is the earliest anti-HBV drug approved by the FDA. It mainly achieves the effect of clearing the virus through direct antiviral effect and inducing the body's immune response. However, due to its low response rate, it has various side effects, high price and limited treatment targets. For many reasons, its application is subject to many restrictions. The common point of nucleoside (acid) drugs against HBV is that they specifically act on the viral DNA polymerase, which has a strong effect of inhibiting viral replication, and patients have better tolerance to drugs than interferon. However, the extensive and long-term use of nucleoside (acid) drugs can induce the mutation of DNA polymerase to form drug resistance, resulting in the continuous emergence of drug-resistant strains, so that the treatment is far from reaching the ideal curative effect.
因此，目前仍然需要有新的能够有效地用作抗病毒药物的化合物，尤其是用作治疗和/或预防乙型肝炎的药物。Therefore, there is still a need for new compounds that can be effectively used as antiviral drugs, especially for the treatment and/or prevention of hepatitis B.
发明内容SUMMARY OF THE INVENTION
本发明涉及新型酰胺吡咯类化合物和其在制备用于治疗与预防HBV感染的药物中的用途。特别地，本发明涉及一种新型酰胺吡咯类化合物，及其药学上可接受的组合物，该化合物具有溶解性好、稳定性好、对肝药酶基本无诱导作用和较小的毒性等优点，尤其具有非常好的药代动力学性质。本发明化合物可以有效抑制HBV感染，其在抗HBV方面有很好的应用前景。The present invention relates to novel amide pyrrole compounds and their use in preparing medicines for treating and preventing HBV infection. In particular, the present invention relates to a novel amide pyrrole compound and a pharmaceutically acceptable composition thereof. The compound has the advantages of good solubility, good stability, basically no induction effect on liver drug enzymes and less toxicity. , especially with very good pharmacokinetic properties. The compound of the present invention can effectively inhibit HBV infection, and has a good application prospect in anti-HBV.
一方面，本发明涉及一种如式(I)所示的化合物或如式(I)所示的化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，In one aspect, the present invention relates to a compound of formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmacy of a compound of formula (I) an acceptable salt or a prodrug thereof,
Figure PCTCN2021141926-appb-000001
Figure PCTCN2021141926-appb-000001
其中，各R 5a、R 5b、R 5c、R 5d、R 5e、R 2和R 3独立地为氢、氘、F、Cl、Br、I、CN、SF 5、氨基、硝基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、C 1-4卤代烷基、三氟甲氧基、甲氧基或乙氧基； wherein each of R 5a , R 5b , R 5c , R 5d , R 5e , R 2 and R 3 is independently hydrogen, deuterium, F, Cl, Br, I, CN, SF 5 , amino, nitro, methyl , ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 1-4 haloalkyl, trifluoromethoxy, methoxy or ethoxy;
环B为C 6-10芳基、5-6个环原子组成的杂芳基、
Figure PCTCN2021141926-appb-000002
Figure PCTCN2021141926-appb-000003
其中，所述的C 6-10芳基和5-6个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个R 6所取代； Ring B is a C 6-10 aryl group, a heteroaryl group composed of 5-6 ring atoms,
Figure PCTCN2021141926-appb-000002
Figure PCTCN2021141926-appb-000003
Wherein, the C 6-10 aryl group and the heteroaryl group composed of 5-6 ring atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 R 6 ;
各R 6独立地为氘、F、Cl、Br、I、CN、-OH、-COOH、硝基、氨基、-C(＝O)OC 1-6烷基、-OC 1-6亚烷基-OC 1-6烷基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 2-6烯基、C 2-6炔基或羧基C 1-6烷基，其中，所述的氨基、-C(＝O)OC 1-6烷基、-OC 1-6亚烷基-OC 1-6烷基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 2-6烯基、C 2-6炔基和羧基C 1-6烷基各自独立地未被取代或被1、2、3或4个R w1所取代； Each R is independently deuterium, F, Cl , Br, I, CN, -OH, -COOH, nitro, amino, -C(=O)OC 1-6 alkyl, -OC 1-6 alkylene -OC 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkyne group or carboxyl C 1-6 alkyl group, wherein, the amino group, -C(=O)OC 1-6 alkyl group, -OC 1-6 alkylene group, -OC 1-6 alkyl group, C 1-6 Alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl and carboxy C 1-6 alkyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 R w1 ;
各R 1a、R 1b、R 1、R 4、R a和R b独立地为氢、氘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基或C 1-4卤代烷基； Each of R 1a , R 1b , R 1 , R 4 , Ra and R b is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl , tert-butyl or C 1-4 haloalkyl;
各R 2a、R 2b和R 2c独立地为氢、氘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基或C 1-4卤代烷基，其中，所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基和C 1-4卤代烷基各自独立地未被取代或被1、2、3或4个R w2所取代； Each of R 2a , R 2b and R 2c is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or C 1-4 Haloalkyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and C 1-4 haloalkyl groups are each independently unsubstituted or replaced by 1, 2, 3 or 4 R w2 ;
各R 3a、R 3b、R 3c、R 4a、R 4b和R 4c独立地为C 1-6烷基、C 6-10芳基或5-6个环原子组成的杂芳基，其中，所述的C 6-10芳基和5-6个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个R w3所取代； Each of R 3a , R 3b , R 3c , R 4a , R 4b and R 4c is independently a C 1-6 alkyl group, a C 6-10 aryl group or a heteroaryl group consisting of 5-6 ring atoms, wherein the The C 6-10 aryl group and the heteroaryl group composed of 5-6 ring atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 R w3 ;
L 1为单键、亚甲基或亚乙基；其中，所述的亚甲基和亚乙基各自独立地未被取代或被1、2或3个R w4所取代； L 1 is a single bond, methylene or ethylene; wherein, the methylene and ethylene are independently unsubstituted or substituted by 1, 2 or 3 R w4 ;
L 2为单键或-NR b-； L 2 is a single bond or -NR b -;
各R w1、R w2、R w3、R w4和R w5独立地为氘、F、Cl、Br、CN、-OH、-COOH、硝基、-C(＝O)OC 1-6烷基、氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、羧基C 1-6烷基、C 1-6卤代烷基或C 1-6烷氧基； Each R w1 , R w2 , R w3 , R w4 and R w5 is independently deuterium, F, Cl, Br, CN, -OH, -COOH, nitro, -C(=O)OC 1-6 alkyl, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carboxy C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 alkoxy;
环A为环己基、5-6个环原子组成的单环杂环基、8-10个环原子组成的稠合双环杂环基或6-10个环原子组成的桥环杂环基，其中，所述的环己基、5-6个环原子组成的单环杂环基、8-10个环原子组成的稠合双环杂环基和6-10个环原子组成的桥双环杂环基各自独立地未被取代或被1、2、3、4、或5个R x所取代； Ring A is a cyclohexyl group, a monocyclic heterocyclic group consisting of 5-6 ring atoms, a fused bicyclic heterocyclic group consisting of 8-10 ring atoms or a bridged ring heterocyclic group consisting of 6-10 ring atoms, wherein , the cyclohexyl group, the monocyclic heterocyclic group composed of 5-6 ring atoms, the fused bicyclic heterocyclic group composed of 8-10 ring atoms and the bridged bicyclic heterocyclic group composed of 6-10 ring atoms are each independently unsubstituted or substituted with 1 , 2, 3, 4, or 5 Rx;
各R x独立地为氘、＝O、＝S、F、Cl、Br、CN、-OH、-COOH、硝基、-CONH 2、-C(＝O)OC 1-6烷基、-C 1-4亚烷基-N(R a)S(＝O) 2C 1-6烷基、羟基C 1-6烷基、氨基、C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6亚烷基、C 2-6烯基、C 2-6炔基、羧基C 1-6烷基或C 1-6卤代烷基，其中，所述的-CONH 2、-C(＝O)OC 1-6烷基、-C 1-4亚烷基-N(R a)S(＝O) 2C 1-6烷基、羟基C 1-6烷基、氨基、C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6亚烷基、C 2-6烯基、C 2-6炔基、羧基C 1-6烷基和C 1-6卤代烷基各自独立地未被取代或被1、2、3或4个R w5所取代。 Each R x is independently deuterium, =O, =S, F, Cl, Br, CN, -OH, -COOH, nitro, -CONH 2 , -C(=O)OC 1-6 alkyl, -C 1-4 alkylene-N(R a )S(=O) 2 C 1-6 alkyl, hydroxy C 1-6 alkyl, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkylene, C 2-6 alkenyl, C 2-6 alkynyl, carboxy C 1-6 alkyl or C 1-6 haloalkyl, wherein the- CONH 2 , -C(=O)OC 1-6 alkyl, -C 1-4 alkylene-N(R a )S(=O) 2 C 1-6 alkyl, hydroxy C 1-6 alkyl , amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy, C 1-6 alkylene, C 2-6 alkenyl, C 2-6 alkynyl, carboxyl C 1 -6 alkyl and C 1-6 haloalkyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 R w5 .
在一些实施方案中，本发明所述的环B为苯基、萘基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基、嘧啶基、
Figure PCTCN2021141926-appb-000004
其中，所述的苯基、萘基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基各自独立地未被取代或被1、2、3或4个R 6所取代； In some embodiments, the ring B of the present invention is phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl,
Figure PCTCN2021141926-appb-000004
Wherein, the phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 R6;
其中，各R 1a、R 2a、R 3a、R 4a、R 1b、R 2b、R 3b、R 4b、R 2c、R 3c、R 4c和R 6具有本发明所述的含义。 Wherein, each of R 1a , R 2a , R 3a , R 4a , R 1b , R 2b , R 3b , R 4b , R 2c , R 3c , R 4c and R 6 has the meaning described in the present invention.
在一些实施方案中，本发明所述的各R 6独立地为氘、F、Cl、Br、I、CN、-OH、-COOH、硝基、氨基、-C(＝O)OC 1-4烷基、-OC 2-4亚烷基-OC 1-4烷基、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 2-4烯基、C 2-4炔基或羧基C 1-4烷基，其中，所述的氨基、-C(＝O)OC 1-4烷基、-OC 2-4亚烷基-OC 1-4烷基、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 2-4烯基、C 2-4炔基和羧基C 1-4烷基各自独立地未被取代或被1、2、3或4个R w1所取代，其中，各R w1具有本发明所述的含义。 In some embodiments, each R 6 described herein is independently deuterium, F, Cl, Br, I, CN, -OH, -COOH, nitro, amino, -C(=O)OC 1-4 Alkyl, -OC 2-4 alkylene-OC 1-4 alkyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl or carboxy C 1-4 alkyl, wherein the amino group, -C(=O)OC 1-4 alkyl, -OC 2-4 alkylene- OC 1-4 alkyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl and carboxyC 1-4 alkyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 R w1 , wherein each R w1 has the meaning described in the present invention.
在一些实施方案中，本发明所述的各R 6独立地为氘、F、Cl、Br、I、CN、-OH、-COOH、硝基、氨基、-C(＝O)O甲基、-C(＝O)O乙基、-C(＝O)O正丙基、-C(＝O)O异丙基、-OCH 2CH 2CH 2-OCH 3、-OCH 2CH 2CH 2-OCH 2CH 3、-OCH 2CH 2CH 2CH 2-OCH 3、-OCH 2CH 2CH 2CH 2-OCH 2CH 3、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、C 1-4卤代烷基、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-l-丙氧基、2-丁氧基、-OCH 2F、-OCH 2Cl、-OCHF 2、-OCHCl 2、-OCF 3、-OCH 2CH 2F、-OCH 2CH 2Cl、-OCH 2CHF 2、-OCH 2CHCl 2、-OCHFCH 2F、-OCHClCH 2Cl、-OCH 2CF 3、-OCH(CF 3) 2、-OCF 2CH 2CH 3、-OCH 2CH 2CH 2F、-OCH 2CH 2CHF 2、-OCH 2CH 2CF 3、C 2-4烯基、C 2-4炔基或羧基C 1-4烷基，其中，所述的氨基、-C(＝O)O甲基、-C(＝O)O乙基、-C(＝O)O正丙基、-C(＝O)O异丙基、-OCH 2CH 2CH 2-OCH 3、-OCH 2CH 2CH 2-OCH 2CH 3、-OCH 2CH 2CH 2CH 2-OCH 3、-OCH 2CH 2CH 2CH 2-OCH 2CH 3、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、C 1-4卤代烷基、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-l-丙氧基、2-丁氧基、-OCH 2F、-OCH 2Cl、-OCHF 2、-OCHCl 2、-OCH 2CH 2F、-OCH 2CH 2Cl、-OCH 2CHF 2、-OCH 2CHCl 2、-OCHFCH 2F、-OCHClCH 2Cl、-OCH 2CF 3、-OCH(CF 3) 2、-OCF 2CH 2CH 3、-OCH 2CH 2CH 2F、-OCH 2CH 2CHF 2、-OCH 2CH 2CF 3、C 2-4烯基、C 2-4炔基和羧基C 1-4烷基各自独立地未被取代或被1、2、3或4个R w1所取代，其中，各R w1具有本发明所述的含义。 In some embodiments, each R 6 described herein is independently deuterium, F, Cl, Br, I, CN, -OH, -COOH, nitro, amino, -C(=O)Omethyl, -C(=O)O ethyl, -C(=O)O n-propyl, -C(=O)O isopropyl, -OCH 2 CH 2 CH 2 -OCH 3 , -OCH 2 CH 2 CH 2 -OCH 2 CH 3 , -OCH 2 CH 2 CH 2 CH 2 -OCH 3 , -OCH 2 CH 2 CH 2 CH 2 -OCH 2 CH 3 , methyl, ethyl, n-propyl, isopropyl, n-butyl base, isobutyl, sec-butyl, tert-butyl, C 1-4 haloalkyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl -1-propoxy, 2-butoxy, -OCH 2 F, -OCH 2 Cl, -OCHF 2 , -OCHCl 2 , -OCF 3 , -OCH 2 CH 2 F, -OCH 2 CH 2 Cl, -OCH2CHF2 , -OCH2CHCl2 , -OCHFCH2F , -OCHClCH2Cl , -OCH2CF3 , -OCH ( CF3 ) 2 , -OCF2CH2CH3 , -OCH2CH2CH 2 F, -OCH 2 CH 2 CHF 2 , -OCH 2 CH 2 CF 3 , C 2-4 alkenyl, C 2-4 alkynyl or carboxy C 1-4 alkyl, wherein the amino, -C (=O)O methyl, -C(=O)O ethyl, -C(=O)O n-propyl, -C(=O)O isopropyl, -OCH 2 CH 2 CH 2 -OCH 3 , -OCH 2 CH 2 CH 2 -OCH 2 CH 3 , -OCH 2 CH 2 CH 2 CH 2 -OCH 3 , -OCH 2 CH 2 CH 2 CH 2 -OCH 2 CH 3 , methyl, ethyl, n-propyl base, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 1-4 haloalkyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1 -Butoxy, 2 -methyl- l -propoxy, 2 - butoxy, -OCH2F, -OCH2Cl , -OCHF2, -OCHCl2 , -OCH2CH2F, -OCH2 CH2Cl , -OCH2CHF2 , -OCH2CHCl2 , -OCHFCH2F , -OCHClCH2Cl , -OCH2CF3 , -OCH ( CF3 ) 2 , -OCF2CH2CH3 , -OCH 2 CH 2 CH 2 F, -O CH 2 CH 2 CHF 2 , -OCH 2 CH 2 CF 3 , C 2-4 alkenyl, C 2-4 alkynyl and carboxy C 1-4 alkyl are each independently unsubstituted or substituted by 1, 2, 3 or Replaced by 4 R w1s , wherein each R w1 has the meaning described in the present invention.
在一些实施方案中，本发明所述的各R 3a、R 3b、R 3c、R 4a、R 4b和R 4c独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、苯基、萘基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中，所述的苯基、萘基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基各自独立地未被取代或被1、2、3或4个R w3所取代，其中，各R w3具有本发明所述的含义。 In some embodiments, each of R 3a , R 3b , R 3c , R 4a , R 4b and R 4c described herein is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, sec-butyl, tert-butyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadi azolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein said phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl , imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and The pyrimidinyl groups are each independently unsubstituted or substituted with 1, 2, 3 or 4 R w3 , wherein each R w3 has the meaning described in the present invention.
在一些实施方案中，本发明所述的各R w1、R w2、R w3、R w4和R w5独立地为氘、F、Cl、Br、CN、-OH、-COOH、硝基、-C(＝O)OC 1-4烷基、氨基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、C 2-4烯基、C 2-4炔基、羧基C 1-4烷基、C 1-4卤代烷基或C 1-4烷氧基。 In some embodiments, each of R w1 , R w2 , R w3 , R w4 and R w5 described herein is independently deuterium, F, Cl, Br, CN, -OH, -COOH, nitro, -C (=O)OC 1-4 alkyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 2-4 alkenyl, C 2-4 alkynyl, carboxy C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 alkoxy.
在一些实施方案中，本发明所述的各R w1、R w2、R w3、R w4和R w5独立地为氘、F、Cl、Br、CN、-OH、-COOH、硝基、-C(＝O)O甲基、-C(＝O)O乙基、-C(＝O)O正丙基、-C(＝O)O异丙基、氨基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、C 2-4烯基、C 2-4炔基、羧基C 1-4烷基、C 1-4卤代烷基或C 1-4烷氧基。 In some embodiments, each of R w1 , R w2 , R w3 , R w4 and R w5 described herein is independently deuterium, F, Cl, Br, CN, -OH, -COOH, nitro, -C (=O)O methyl, -C(=O)O ethyl, -C(=O)O n-propyl, -C(=O)O isopropyl, amino, methyl, ethyl, n-propyl base, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 2-4 alkenyl, C 2-4 alkynyl, carboxy C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 alkoxy.
在一些实施方案中，本发明所述的环A为
Figure PCTCN2021141926-appb-000005
Figure PCTCN2021141926-appb-000006
Figure PCTCN2021141926-appb-000007
其中所述的式(II-1)、式(II-2)、式(II-3)、式(II-4)、式(II-5)、式(II-6)、式(II-7)、式(II-8)、式(II-9)、式(II-10)、式(II-11)、式(II-12)、式(II-13)和式(II-14)各自独立地未被取代或被1、2、3、4、或5个R x所取代，其中，各R x具有本发明所述的含义。 In some embodiments, Ring A of the present invention is
Figure PCTCN2021141926-appb-000005
Figure PCTCN2021141926-appb-000006
Figure PCTCN2021141926-appb-000007
The formula (II-1), formula (II-2), formula (II-3), formula (II-4), formula (II-5), formula (II-6), formula (II- 7), formula (II-8), formula (II-9), formula (II-10), formula (II-11), formula (II-12), formula (II-13) and formula (II-14) ) are each independently unsubstituted or substituted with 1 , 2, 3, 4, or 5 Rx, wherein each Rx has the meaning described herein.
在一些实施方案中，本发明所述的各R x独立地为氘、＝O、＝S、F、Cl、Br、CN、-OH、-COOH、硝基、-CONH 2、-C(＝O)OC 1-4烷基、-C 1-3亚烷基-N(R a)S(＝O) 2C 1-4烷基、羟基C 1-4烷基、氨基、C 1-4烷基、C 1-4烷氧基、C 1-4烷氧基C 1-4亚烷基、C 2-4烯基、C 2-4炔基、羧基C 1-4烷基或C 1-4卤代烷基，其中，所述的-CONH 2、-C(＝O)OC 1-4烷基、-C 1-3亚烷基-N(R a)S(＝O) 2C 1-4烷基、羟基C 1-4烷基、氨基、C 1-4烷基、C 1-4烷氧基、C 1-4烷氧基C 1-4亚烷基、C 2-4烯基、C 2-4炔基、羧基C 1-4烷基和C 1-4卤代烷基各自独立地未被取代或被1、2、3或4个R w5所取代，其中，各R a和R w5具有本发明所述的含义。 In some embodiments, each R x described herein is independently deuterium, =O, =S, F, Cl, Br, CN, -OH, -COOH, nitro, -CONH2 , -C(= O)OC 1-4 alkyl, -C 1-3 alkylene-N(R a )S(=O) 2 C 1-4 alkyl, hydroxy C 1-4 alkyl, amino, C 1-4 Alkyl, C 1-4 alkoxy, C 1-4 alkoxy, C 1-4 alkylene, C 2-4 alkenyl, C 2-4 alkynyl, carboxy C 1-4 alkyl or C 1 -4 haloalkyl, wherein the -CONH 2 , -C(=O)OC 1-4 alkyl, -C 1-3 alkylene-N(R a )S(=O) 2 C 1- 4 alkyl, hydroxy C 1-4 alkyl, amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy C 1-4 alkylene, C 2-4 alkenyl , C 2-4 alkynyl, carboxyl C 1-4 alkyl and C 1-4 haloalkyl are each independently unsubstituted or substituted by 1, 2, 3 or 4 R w5 , wherein each R a and R w5 has the meaning described in the present invention.
在一些实施方案中，本发明所述的各R x独立地为氘、＝O、＝S、F、Cl、Br、CN、-OH、-COOH、硝基、-CONH 2、-C(＝O)O甲基、-C(＝O)O乙基、-C(＝O)O正丙基、-C(＝O)O异丙基、-亚甲基-N(R a)S(＝O) 2甲基、-亚甲基-N(R a)S(＝O) 2乙基、-亚甲基-N(R a)S(＝O) 2正丙基、-亚甲基-N(R a)S(＝O) 2异丙基、-亚甲基-N(R a)S(＝O) 2正丁基、-亚甲基-N(R a)S(＝O) 2异丁基、-亚乙基-N(R a)S(＝O) 2甲基、-亚乙基-N(R a)S(＝O) 2乙基、-亚乙基-N(R a)S(＝O) 2正丙基、-亚乙基-N(R a)S(＝O) 2异丙基、-亚乙基-N(R a)S(＝O) 2正丁基、-亚乙基-N(R a)S(＝O) 2异丁基、羟基甲基、羟基乙基、羟基正丙基、羟基正丁基、氨基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-l-丙氧基、2-丁氧基、甲氧基甲基、乙氧基甲基、1-丙氧基甲基、2-丙氧基甲基、1-丁氧基甲基、甲氧基甲基、乙氧基乙基、1-丙氧基乙基、2-丙氧基乙基、1-丁氧基乙基、C 2-4烯基、C 2-4炔基、羧基C 1-4烷基或C 1-4卤代烷基，其中，所述的-CONH 2、-C(＝O)O甲基、-C(＝O)O乙基、-C(＝O)O正丙基、-C(＝O)O异丙基、-亚甲基-N(R a)S(＝O) 2甲基、-亚甲基-N(R a)S(＝O) 2乙基、-亚甲基-N(R a)S(＝O) 2正丙基、-亚甲基-N(R a)S(＝O) 2异丙基、-亚甲基-N(R a)S(＝O) 2正丁基、-亚甲基-N(R a)S(＝O) 2异丁基、-亚乙基-N(R a)S(＝O) 2甲基、-亚乙基-N(R a)S(＝O) 2乙基、-亚乙基-N(R a)S(＝O) 2正丙基、-亚乙基-N(R a)S(＝O) 2异丙基、-亚乙基-N(R a)S(＝O) 2正丁基、-亚乙基-N(R a)S(＝O) 2异丁基、羟基甲基、羟基乙基、羟基正丙基、羟基正丁基、氨基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-l-丙氧基、2-丁氧基、甲氧基甲基、乙氧基甲基、1-丙氧基甲基、2-丙氧基甲基、1-丁氧基甲基、甲氧基甲基、乙氧基乙基、1-丙氧基乙基、2-丙氧基乙基、1-丁氧基乙基、C 2-4烯基、C 2-4炔基、羧基C 1-4烷基和C 1-4卤代烷基各自独立地未被取代或被1、2、3或4个R w5所取代，其中，各R a和R w5具有本发明所述的含义。 In some embodiments, each R x described herein is independently deuterium, =O, =S, F, Cl, Br, CN, -OH, -COOH, nitro, -CONH2 , -C(= O)O methyl, -C(=O)O ethyl, -C(=O)O n-propyl, -C(=O)O isopropyl, -methylene-N(R a )S( =O) 2methyl , -methylene-N(R a )S(=O) 2ethyl, -methylene-N(R a )S(=O) 2 - n-propyl, -methylene -N(R a )S(=O) 2isopropyl, -methylene-N(R a )S(=O) 2 - n-butyl, -methylene-N(R a )S(=O ) 2 isobutyl, -ethylene-N(R a )S(=O) 2methyl , -ethylene-N(R a )S(=O) 2ethyl , -ethylene-N (R a )S(=O) 2 n-propyl, -ethylene-N(R a )S(=O) 2 isopropyl, -ethylene-N(R a )S(=O) 2 n-butyl, -ethylene-N(R a )S(=O) 2 isobutyl, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, hydroxy-n-butyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, methoxymethyl, ethoxymethyl, 1-propoxymethyl, 2-propoxymethyl, 1-butoxy Methyl, methoxymethyl, ethoxyethyl, 1-propoxyethyl, 2-propoxyethyl, 1-butoxyethyl, C 2-4 alkenyl, C 2-4 Alkynyl, carboxyl C 1-4 alkyl or C 1-4 haloalkyl, wherein the -CONH 2 , -C(=O)O methyl, -C(=O)O ethyl, -C( =O)O n-propyl, -C(=O)O isopropyl, -methylene-N(R a )S(=O) 2methyl , -methylene-N(R a )S( =O) 2ethyl , -methylene-N(R a )S(=O) 2 -n-propyl, -methylene-N(R a )S(=O) 2 isopropyl, -methylene Base-N(R a )S(=O) 2 -n-butyl, -methylene-N(R a )S(=O) 2 -isobutyl, -ethylene-N(R a )S(= O) 2methyl , -ethylene-N(R a )S(=O) 2ethyl, -ethylene-N(R a )S(=O) 2 - n-propyl, -ethylene- N(R a )S(=O) 2isopropyl, -ethylene-N(R a )S(=O) 2 - n-butyl, -ethylene-N(R a )S(=O) 2 isobutyl, hydroxymethyl, hydroxyethyl, hydroxyn-propyl, hydroxyn-butyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl , tert-butyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l -Propoxy, 2-butoxy, methoxymethyl, ethoxymethyl, 1-propoxymethyl, 2-propoxymethyl, 1-butoxymethyl, methoxy Methyl, ethoxyethyl, 1-propoxyethyl, 2-propoxyethyl, 1-butoxyethyl, C 2-4 alkenyl, C 2-4 alkynyl, carboxy C 1 -4 alkyl and C 1-4 haloalkyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 R w5 , wherein each R a and R w5 have the meanings described herein.
另一方面，本发明还提供了一种药物组合物，包含本发明所述的化合物，及药学上可接受的辅料。On the other hand, the present invention also provides a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable adjuvant.
在一些实施方案中，本发明所述的药物组合物，其进一步地包含其它抗HBV药物。In some embodiments, the pharmaceutical composition of the present invention further comprises other anti-HBV drugs.
在一些实施方案中，本发明所述的药物组合物，其中所述其它抗HBV药物为HBV聚合酶抑制剂、免疫调节剂或干扰素。In some embodiments, the pharmaceutical composition of the present invention, wherein the other anti-HBV drug is an HBV polymerase inhibitor, an immunomodulator, or an interferon.
在一些实施方案中，本发明所述的药物组合物，其中所述其它抗HBV药物为拉米夫定、替比夫定、 替诺福韦酯，恩替卡韦、阿德福韦酯、Alfaferone、Alloferon、西莫白介素、克拉夫定、恩曲他滨、法昔洛韦、干扰素、宝甘灵CP、因特芬、干扰素α-1b、干扰素α、干扰素α-2a、干扰素β-1a、干扰素α-2、白细胞介素-2、米伏替酯、硝唑尼特、聚乙二醇干扰素α-2a、病毒唑、罗扰素-A、西佐喃、Euforavac、安普利近、Phosphazid、Heplisav、干扰素α-2b、左旋咪唑或丙帕锗。In some embodiments, the pharmaceutical composition of the present invention, wherein the other anti-HBV drug is lamivudine, telbivudine, tenofovir dipivoxil, entecavir, adefovir dipivoxil, Alfaferone, Alloferon , Simoleukin, Clavudine, Emtricitabine, Faciclovir, Interferon, Baoganling CP, Interferon, Interferon alpha-1b, Interferon alpha, Interferon alpha-2a, Interferon beta -1a, interferon alfa-2, interleukin-2, mivotiate, nitazoxanide, peginterferon alfa-2a, ribavirin, rasteron-A, sizoran, Euforavac, Ampligen, Phosphazid, Heplisav, interferon alfa-2b, levamisole, or propagium.
在一些实施方案中，其包含以下其中之一的结构，或其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，In some embodiments, it comprises the structure of one of the following, or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
Figure PCTCN2021141926-appb-000008
Figure PCTCN2021141926-appb-000008
Figure PCTCN2021141926-appb-000009
Figure PCTCN2021141926-appb-000009
Figure PCTCN2021141926-appb-000010
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另一方面，本发明还提供了所述化合物或所述药物组合物在制备用于预防、治疗或减轻患者病毒性疾病的药物中的用途。In another aspect, the present invention also provides the use of the compound or the pharmaceutical composition in the preparation of a medicament for preventing, treating or alleviating a viral disease of a patient.
在一些实施方案中，本发明所述的用途，其中所述病毒性疾病是指乙型肝炎病毒感染或乙型肝炎病毒感染引起的疾病。In some embodiments, the use of the present invention, wherein the viral disease refers to hepatitis B virus infection or a disease caused by hepatitis B virus infection.
在另外一些实施方案中，本发明所述的用途，其中所述乙型肝炎病毒感染引起的疾病是指肝硬化或肝细胞癌变。In other embodiments, the use of the present invention, wherein the disease caused by hepatitis B virus infection refers to liver cirrhosis or hepatocellular carcinoma.
另一方面，本发明涉及所述的化合物或药物组合物在制备用于预防、治疗或减轻患者乙型肝炎疾病的药物中的用途，包括给予有效治疗剂量的本发明所述的化合物或本发明所述的药物组合物对患者进行给药。In another aspect, the present invention relates to the use of the compound or pharmaceutical composition in the preparation of a medicament for preventing, treating or alleviating hepatitis B disease in a patient, comprising administering an effective therapeutic dose of the compound or the present invention The pharmaceutical composition is administered to a patient.
本发明另一方面涉及预防、治疗或减轻患者HBV病症的方法，所述方法包含使用药学上可接受的有效剂量的本发明的化合物对患者进行给药。Another aspect of the present invention pertains to a method of preventing, treating or alleviating an HBV disorder in a patient, the method comprising administering to the patient a pharmaceutically acceptable effective dose of a compound of the present invention.
本发明另一方面涉及预防、治疗或减轻患者HBV病症的方法，所述方法包含使用药学上可接受的有 效剂量的含有本发明的化合物的药物组合物对患者进行给药。Another aspect of the present invention pertains to a method of preventing, treating or alleviating an HBV disorder in a patient, the method comprising administering to the patient a pharmaceutically acceptable effective dose of a pharmaceutical composition comprising a compound of the present invention.
本发明另一方面涉及使用一种本发明的化合物来制备用于预防或治疗患者HBV病症，并减轻其严重程度的药物的用途。Another aspect of the present invention pertains to the use of a compound of the present invention for the manufacture of a medicament for the prevention or treatment of HBV disorders in a patient, and to lessen the severity thereof.
本发明另一方面涉及使用一种包含本发明的化合物的药物组合物来制备用于预防或治疗患者HBV病症，并减轻其严重程度的药物的用途。Another aspect of the present invention pertains to the use of a pharmaceutical composition comprising a compound of the present invention for the manufacture of a medicament for the prevention or treatment of HBV disorders in a patient, and to lessen the severity thereof.
本发明另一方面涉及一种抑制HBV感染的方法，该方法包含将细胞与能有效抑制HBV的剂量的本发明的化合物或药物组合物接触。另外一些实施例是，所述方法更进一步地包含将细胞与其它抗HBV治疗剂接触。Another aspect of the present invention pertains to a method of inhibiting HBV infection, the method comprising contacting a cell with a compound or pharmaceutical composition of the present invention in an amount effective to inhibit HBV. In other embodiments, the method further comprises contacting the cells with other anti-HBV therapeutics.
本发明另一方面涉及对患者HBV疾病的治疗方法，该方法包含向需要治疗的患者施用有效治疗剂量的本发明的化合物或其药物组合物。另外一些实施例是，所述方法更进一步地包含向需要治疗的患者施用有效治疗剂量的其它抗HBV药物。Another aspect of the present invention pertains to a method of treating HBV disease in a patient, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof. In other embodiments, the method further comprises administering to a patient in need thereof a therapeutically effective amount of another anti-HBV drug.
本发明另一方面涉及一种抑制患者HBV感染的方法，该方法包含向需要治疗的患者施用有效治疗剂量的本发明的化合物或其药物组合物。另外一些实施例是，所述方法更进一步地包含向需要治疗的患者施用有效治疗剂量的其它抗HBV药物。Another aspect of the present invention pertains to a method of inhibiting HBV infection in a patient, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof. In other embodiments, the method further comprises administering to a patient in need thereof a therapeutically effective amount of another anti-HBV drug.
本发明另一方面涉及式(I)所包含的化合物的制备、分离和纯化的方法。Another aspect of the present invention relates to processes for the preparation, isolation and purification of compounds encompassed by formula (I).
本发明所涉及的化合物，及其药学上可接受的组合物，都可以有效抑制HBV感染。The compounds involved in the present invention, and their pharmaceutically acceptable compositions, can effectively inhibit HBV infection.
除非其他方面表明，本发明的化合物所有的立体异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，药学上可接受的盐和前药都属于本发明的范围。Unless otherwise indicated, all stereoisomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs of the compounds of the present invention are within the scope of the present invention .
具体地说，盐是药学上可接受的盐。术语“药学上可接受的”包括物质或组合物必须是适合化学或毒理学地，与组成制剂的其他组分和用于治疗的哺乳动物有关。Specifically, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes substances or compositions that must be chemically or toxicologically suitable in relation to the other components that make up the formulation and the mammal for which it is to be treated.
本发明的化合物的盐还包括用于制备或纯化式(I)所示化合物的中间体或式(I)所示化合物分离的对映异构体的盐，但不一定是药学上可接受的盐。The salts of the compounds of the present invention also include intermediates used in the preparation or purification of the compounds of formula (I) or salts of separated enantiomers of the compounds of formula (I), but are not necessarily pharmaceutically acceptable Salt.
如果本发明的化合物是碱性的，则想得到的盐可以通过文献上提供的任何合适的方法制备得到，例如，使用无机酸，如盐酸、氢溴酸、硫酸、硝酸和磷酸等等。或者使用有机酸、如乙酸、马来酸、琥珀酸、扁桃酸、富马酸、丙二酸、丙酮酸、苹果酸、2-羟基丙酸、枸橼酸、草酸、羟乙酸和水杨酸；吡喃糖酸，如葡萄糖醛酸和半乳糖醛酸；α-羟酸，如柠檬酸和酒石酸；氨基酸，如天门冬氨酸和谷氨酸；芳香族酸，如苯甲酸和肉桂酸；磺酸，如对甲苯磺酸、苯磺酸、甲磺酸、乙磺酸、三氟甲磺酸等等或它们的组合。If the compounds of the present invention are basic, the desired salts may be prepared by any suitable method provided in the literature, for example, using mineral acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids and the like. Alternatively use organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, malic acid, 2-hydroxypropionic acid, citric acid, oxalic acid, glycolic acid and salicylic acid ; Pyranonic acids, such as glucuronic and galacturonic acids; Alpha-hydroxy acids, such as citric and tartaric acids; Amino acids, such as aspartic and glutamic acids; Aromatic acids, such as benzoic and cinnamic acids; Sulfonic acids, such as p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, and the like, or combinations thereof.
如果本发明的化合物是酸性的，则想得到的盐可以通过合适的方法制备得到，如，使用无机碱或有机碱，如氨(伯氨，仲氨，叔氨)，碱金属氢氧化物，铵，N +(R 14) 4的盐和碱土金属氢氧化物，等等。合适的盐包括，但并不限于，从氨基酸得到的有机盐，如甘氨酸和精氨酸，氨，如伯氨、仲氨和叔氨，N +(R 14) 4的盐，如R 14是H、C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基等，和环状氨，如哌啶、吗啉和哌嗪等，和从钠、钙、钾、镁、锰、铁、铜、锌、铝和锂得到无机盐。也包括适当的，无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物、氢氧化物、羧化物、硫酸化物、磷酸化物、硝酸化物、C 1-8磺酸化物和芳香磺酸化物。 If the compounds of the present invention are acidic, the desired salts can be prepared by suitable methods, eg, using inorganic or organic bases such as ammonia (primary, secondary, tertiary), alkali metal hydroxides, ammonium , N + (R 14 ) 4 salts and alkaline earth metal hydroxides, etc. Suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, such as primary, secondary and tertiary ammonia, salts of N + (R 14 ) 4 , such as R 14 is H, C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl, etc., and cyclic ammonia, such as piperidine, morpholine and piperazine, etc., and from sodium, Calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium give inorganic salts. Also included are suitable, nontoxic ammonium, quaternary ammonium salts, and amine cations that resist counterion formation, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 sulfonates and Aromatic sulfonates.
前面所述内容只概述了本发明的某些方面，但并不限于这些方面。这些方面及其他的方面的内容将在下面作更加具体完整的描述。The foregoing has outlined only certain aspects of the invention, but is not limited to these aspects. These and other aspects are described in more detail below.
定义和一般术语Definitions and General Terms
本发明将会把确定的具体化的内容所对应的文献详细列出，实施例都伴随有结构式和化学式的图解。本发明有预期地涵盖所有的选择余地、变体和同等物，这些可能像权利要求所定义的那样包含在现有发明领域。所属领域的技术人员将识别许多类似或等同于在此所描述的方法和物质，这些可以应用于本发明的 实践中去。本发明绝非限于方法和物质的描述。有很多文献和相似的物质与本发明申请相区别或抵触，其中包括但绝不限于术语的定义，术语的用法，描述的技术，或像本发明申请所控制的范围。The present invention will list the documents corresponding to the determined concrete contents in detail, and the embodiments are accompanied by diagrams of structural formula and chemical formula. The present invention is intended to cover all alternatives, modifications and equivalents, which may be included within the prior art as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the description of the methods and materials. There are numerous documents and similar materials that differ from or contradict this application, including, but not limited to, definitions of terms, usage of terms, techniques described, or the likes of which this application controls.
本发明将应用以下定义除非其他方面表明。根据本发明的目的，化学元素根据元素周期表，CAS版本和化学药品手册，75， thEd，1994来定义。另外，有机化学一般原理见"Organic Chemistry,"Thomas Sorrell,University Science Books,Sausalito:1999,and"March's Advanced Organic Chemistry,"by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007，因此所有的内容都融合了参考文献。 The present invention shall apply the following definitions unless otherwise indicated. For the purposes of the present invention, chemical elements are defined according to the Periodic Table of the Elements, CAS Version and Handbook of Chemicals, 75, th Ed, 1994. In addition, general principles of organic chemistry are found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, so all The content is integrated with references.
像本发明所描述的，本发明的化合物可以任选地被一个或多个取代基所取代，如上面的通式化合物，或者像实施例里面特殊的例子，子类，和本发明所包含的一类化合物。As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the general formula above, or as in the Examples, subclasses, and subclasses encompassed by the present invention. a class of compounds.
在本说明书的各部分，本发明化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C 1-6烷基”特别指独立公开的甲基、乙基、C 3烷基、C 4烷基、C 5烷基和C 6烷基。 In various sections of this specification, substituents of the compounds of the present invention are disclosed in terms of group type or scope. Specifically, the present invention includes each and every independent subcombination of each member of these group species and ranges. For example, the term " C1-6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl groups .
本发明使用的术语“烷基”包括1-20个碳原子饱和直链或支链的单价烃基，其中烷基可以独立任选地被一个或多个本发明所描述的取代基所取代。其中一些实施例是，烷基基团含有1-12个碳原子，另外一些实施例是，烷基基团含有1-10个碳原子，另外一些实施例是，烷基基团含有1-8个碳原子，另外一些实施例是，烷基基团含有1-6个碳原子，另外一些实施例是，烷基基团含有1-4个碳原子，另外一些实施例是，烷基基团含有1-3个碳原子。烷基基团更进一步的实例包括，但并不限于，甲基(Me，-CH 3)、乙基(Et，-CH 2CH 3)、正丙基(n-Pr，-CH 2CH 2CH 3)、异丙基(i-Pr，-CH(CH 3) 2)、正丁基(n-Bu，-CH 2CH 2CH 2CH 3)、2-甲基丙基或异丁基(i-Bu，-CH 2CH(CH 3) 2)、1-甲基丙基或仲丁基(s-Bu，-CH(CH 3)CH 2CH 3)、叔丁基(t-Bu，-C(CH 3) 3)、正戊基(-CH 2CH 2CH 2CH 2CH 3)、2-戊基(-CH(CH 3)CH 2CH 2CH 3)、3-戊基(-CH(CH 2CH 3) 2)、2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)、3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)、3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)、2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)、正己基(-CH 2CH 2CH 2CH 2CH 2CH 3)、2-己基(-CH(CH 3)CH 2CH 2CH 2CH 3)、3-己基(-CH(CH 2CH 3)(CH 2CH 2CH 3))、2-甲基-2-戊基(-C(CH 3) 2CH 2CH 2CH 3)、3-甲基-2-戊基(-CH(CH 3)CH(CH 3)CH 2CH 3)、4-甲基-2-戊基(-CH(CH 3)CH 2CH(CH 3) 2)、3-甲基-3-戊基(-C(CH 3)(CH 2CH 3) 2)、2-甲基-3-戊基(-CH(CH 2CH 3)CH(CH 3) 2)、2,3-二甲基-2-丁基(-C(CH 3) 2CH(CH 3) 2)、3,3-二甲基-2-丁基(-CH(CH 3)C(CH 3) 3)、正庚基、正辛基，等等。 The term "alkyl" as used herein includes saturated straight or branched monovalent hydrocarbon groups of 1 to 20 carbon atoms, wherein the alkyl group may be independently optionally substituted with one or more substituents described herein. In some embodiments, the alkyl group contains 1-12 carbon atoms, in other embodiments, the alkyl group contains 1-10 carbon atoms, and in still other embodiments, the alkyl group contains 1-8 carbon atoms. carbon atoms, in other embodiments, the alkyl group contains 1-6 carbon atoms, in other embodiments, the alkyl group contains 1-4 carbon atoms, and in still other embodiments, the alkyl group contains Contains 1-3 carbon atoms. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH3 ), ethyl (Et, -CH2CH3), n - propyl (n - Pr, -CH2CH2 ) CH3 ), isopropyl (i-Pr, -CH( CH3 ) 2 ), n-butyl (n - Bu, -CH2CH2CH2CH3 ), 2 - methylpropyl or isobutyl (i-Bu, -CH2CH( CH3 ) 2 ), 1 -methylpropyl or sec-butyl (s-Bu, -CH( CH3 ) CH2CH3 ) , tert-butyl (t-Bu , -C( CH3 ) 3 ), n-pentyl ( -CH2CH2CH2CH2CH3 ), 2 - pentyl (-CH( CH3 ) CH2CH2CH3 ) , 3 - pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 ) )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 ) CH 2 CH 3 ), n-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH (CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH( CH3 )CH( CH3 ) CH2CH3 ), 4-methyl- 2-pentyl (-CH(CH3)CH2CH(CH3)2 ) , 3 - methyl-3 -Pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-di Methyl-2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2 ), 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 ), n-heptyl, n-octyl, etc.
术语“羰基”，无论是单独使用还是和其他术语连用(如“氨基羰基”或“酰氧基”)，表示-(C＝O)-。The term "carbonyl", whether used alone or in combination with other terms (eg "aminocarbonyl" or "acyloxy"), means -(C=O)-.
术语“亚烷基”表示从饱和的直链或支链烃基中去掉两个或多个氢原子所得到的饱和的二价或多价烃基基团。除非另外详细说明，亚烷基基团含有1-12个碳原子。在一些实施方案中，亚烷基基团含有1-6个碳原子；在另一些实施方案中，亚烷基基团含有1-4个碳原子；还在一些实施方案中，亚烷基基团含有1-3个碳原子；还在另一些实施方案中，亚烷基基团含有1-2个碳原子。亚烷基的实例包括，但不限于亚甲基(-CH 2-)，亚乙基(-CH 2CH 2-)，亚正丙基(-CH 2CH 2CH 2-),亚异丙基(-CH(CH 3)CH 2-)等等。 The term "alkylene" refers to a saturated divalent or polyvalent hydrocarbon group obtained by removing two or more hydrogen atoms from a saturated straight or branched chain hydrocarbon group. Unless otherwise specified, alkylene groups contain 1-12 carbon atoms. In some embodiments, the alkylene group contains 1-6 carbon atoms; in other embodiments, the alkylene group contains 1-4 carbon atoms; in still some embodiments, the alkylene group The group contains 1-3 carbon atoms; in still other embodiments, the alkylene group contains 1-2 carbon atoms. Examples of alkylene groups include, but are not limited to, methylene ( -CH2- ), ethylene ( -CH2CH2- ) , n - propylene ( -CH2CH2CH2- ) , isopropylene base (-CH(CH 3 )CH 2 -) and the like.
术语“羟基烷基”和“羟基烷氧基”表示烷基或烷氧基，视情况而定，被一个或多个羟基基团所取代，其中，“羟基烷基”、“羟基亚烷基”与“羟烷基”相互之间可以交换使用，这样的实例包含，但并不限于，羟基甲基(-CH 2OH)、羟基乙基(-CH 2CH 2OH,-CHOHCH 3)、羟基丙基(如，-CH 2CH 2CH 2OH,-CH 2CHOHCH 3,-CHOHCH 2CH 3)、羟基甲氧基(-OCH 2OH)等。 The terms "hydroxyalkyl" and "hydroxyalkoxy" mean alkyl or alkoxy, as the case may be, substituted with one or more hydroxy groups, wherein "hydroxyalkyl", "hydroxyalkylene"" and "hydroxyalkyl" can be used interchangeably with each other, such examples include, but are not limited to, hydroxymethyl (-CH 2 OH), hydroxyethyl (-CH 2 CH 2 OH, -CHOHCH 3 ), Hydroxypropyl (eg, -CH2CH2CH2OH , -CH2CHOHCH3 , -CHOHCH2CH3 ) , hydroxymethoxy ( -OCH2OH ) , and the like.
术语“烯基”表示含有2-12个碳原子，或2-8个碳原子，或2-6个碳原子，或2-4个碳原子的直链或支链的一价烃基，其中至少有一个位置的C-C为sp 2双键，其中烯基的基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代，包括有“顺”、“反”或"Z"、"E"异构体，其中具体的实例包括，但并不限于，乙烯基(-CH＝CH 2)，丙烯基(-CH＝CHCH 3)、烯丙基(-CH 2CH＝CH 2)等等，其中所述烯基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。 The term "alkenyl" refers to a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least There is a position CC for sp 2 double bond, wherein the alkenyl group can be independently unsubstituted or substituted by one or more substituents described in the present invention, including "cis", "trans" or "Z","E" isomers, specific examples of which include, but are not limited to, vinyl (-CH=CH 2 ), propenyl (-CH=CHCH 3 ), allyl (-CH 2 CH= CH2 ) and the like, wherein the alkenyl groups may independently be unsubstituted or substituted with one or more substituents described herein.
术语“炔基”表示含有2-12个碳原子，或2-8个碳原子，或2-6个碳原子，或2-4个碳原子的直链或支链的一价烃基，其中至少有一个位置的C-C为sp三键，其中炔基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代，具体的实例包括，但并不限于，乙炔基(-C≡CH)、炔丙基(-CH 2C≡CH)、丙炔基(-C≡C-CH 3)、1-炔丁基(-CH 2CH 2C≡CH)、2-炔丁基(-CH 2C≡CCH 3)、3-炔丁基(-C≡CCH 2CH 3)等等，其中所述炔基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。 The term "alkynyl" means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least CC in one position is an sp triple bond, wherein the alkynyl group can be independently unsubstituted or substituted by one or more substituents described herein, specific examples include, but are not limited to, ethynyl ( -C≡CH), propargyl (-CH 2 C≡CH), propynyl (-C≡C-CH 3 ), 1-alkynylbutyl (-CH 2 CH 2 C≡CH), 2-alkynyl Butyl ( -CH2C≡CCH3 ), 3 - alkynylbutyl ( -C≡CCH2CH3 ), and the like, wherein the alkynyl groups may independently be unsubstituted or replaced by one or more of the present invention substituted with the described substituents.
术语“卤代烷基”、“卤代烯基”或“卤代烷氧基”表示烷基，烯基或烷氧基基团被一个或多个卤素原子所取代，其中，烷基、烯基和烷氧基具有本发明所述的含义。这样的实例包含，但并不限于，二氟乙基(-CH 2CHF 2,-CF 2CH 3,-CHFCH 2F)、三氟乙基(-CH 2CF 3,-CF 2CH 2F,-CFHCHF 2)、三氟甲基(-CF 3)、三氟甲氧基(-OCF 3)、氟乙烯基(-CH＝CHF,-CF＝CH 2)等。 The terms "haloalkyl", "haloalkenyl" or "haloalkoxy" mean an alkyl, alkenyl or alkoxy group substituted with one or more halogen atoms, wherein alkyl, alkenyl and alkoxy Basic has the meaning described in the present invention. Such examples include, but are not limited to, difluoroethyl ( -CH2CHF2 , -CF2CH3 , -CHFCH2F ) , trifluoroethyl ( -CH2CF3 , -CF2CH2F ) , -CFHCHF 2 ), trifluoromethyl (-CF 3 ), trifluoromethoxy (-OCF 3 ), fluorovinyl (-CH=CHF, -CF=CH 2 ) and the like.
术语“羧基烷基”表示烷基被一个或2个羧基取代基所取代，其中，烷基和羧基具有本发明所述的含义。这样的实例包含，但并不限于，-CH 2COOH、-CH 2CH 2COOH、-CH 2CH 2CH 2COOH、-CH 2CH 2CH 2CH 2COOH等。 The term "carboxyalkyl" means an alkyl group substituted with one or two carboxy substituents, wherein alkyl and carboxy have the meanings described herein. Such examples include, but are not limited to, -CH2COOH , -CH2CH2COOH , -CH2CH2CH2COOH , -CH2CH2CH2CH2COOH , and the like .
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中烷基基团具有如本发明所述的含义。除非另外详细说明，所述烷氧基基团含有1-12个碳原子。在一些实施方案中，烷氧基基团含有1-8个碳原子；在另一些实施方案中，烷氧基基团含有1-6个碳原子；在另一些实施方案中，烷氧基基团含有1-4个碳原子；在又一些实施方案中，烷氧基基团含有1-3个碳原子。所述烷氧基基团可以任选地被一个或多个本发明描述的取代基所取代。The term "alkoxy" means that an alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy groups contain 1-12 carbon atoms. In some embodiments, alkoxy groups contain 1-8 carbon atoms; in other embodiments, alkoxy groups contain 1-6 carbon atoms; in other embodiments, alkoxy groups groups contain 1-4 carbon atoms; in yet other embodiments, alkoxy groups contain 1-3 carbon atoms. The alkoxy groups may be optionally substituted with one or more substituents described herein.
烷氧基基团的实例包括，但并不限于，甲氧基(MeO、-OCH 3)，乙氧基(EtO、-OCH 2CH 3)，1-丙氧基(正丙氧基、n-PrO、n-丙氧基、-OCH 2CH 2CH 3)，2-丙氧基(i-PrO、i-丙氧基、-OCH(CH 3) 2)，1-丁氧基(n-BuO、n-丁氧基、-OCH 2CH 2CH 2CH 3)，2-甲基-l-丙氧基(i-BuO、i-丁氧基、-OCH 2CH(CH 3) 2)，2-丁氧基(s-BuO、s-丁氧基、-OCH(CH 3)CH 2CH 3)，2-甲基-2-丙氧基(t-BuO、t-丁氧基、-OC(CH 3) 3)，1-戊氧基(n-戊氧基、-OCH 2CH 2CH 2CH 2CH 3)，2-戊氧基(-OCH(CH 3)CH 2CH 2CH 3)，3-戊氧基(-OCH(CH 2CH 3) 2)，2-甲基-2-丁氧基(-OC(CH 3) 2CH 2CH 3)，3-甲基-2-丁氧基(-OCH(CH 3)CH(CH 3) 2)，3-甲基-l-丁氧基(-OCH 2CH 2CH(CH 3) 2)，2-甲基-l-丁氧基(-OCH 2CH(CH 3)CH 2CH 3)，等等。 Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-propoxy, n -PrO, n-propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n -BuO, n-butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butoxy (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy , -OC(CH 3 ) 3 ), 1-pentyloxy (n-pentyloxy, -OCH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyloxy (-OCH(CH 3 )CH 2 CH 2CH3 ), 3 -pentyloxy (-OCH( CH2CH3 ) 2 ), 2 -methyl- 2 -butoxy (-OC( CH3 ) 2CH2CH3 ), 3 -methyl -2-Butoxy(-OCH( CH3 ) CH ( CH3 ) 2 ), 3-methyl-1-butoxy(-OCH2CH2CH( CH3 ) 2 ), 2 -methyl- l-Butoxy ( -OCH2CH ( CH3 ) CH2CH3 ) , and the like.
术语“M-M 1个环原子组成的”或“M-M 1个原子组成的”表示所述环状基团由M-M 1个环原子所组成，所述的环原子包括碳原子和/或O、N、S、P等杂原子。例如，“6-10个原子组成的杂芳基”代表其包括6、7、8、9或10个环原子组成的杂芳基。 The term "consisting of MM 1 ring atoms" or "consisting of MM 1 atoms" means that the cyclic group consists of MM 1 ring atoms including carbon atoms and/or O, N, S, P and other heteroatoms. For example, "heteroaryl of 6-10 atoms" means that it includes a heteroaryl group of 6, 7, 8, 9 or 10 ring atoms.
术语“环烷基”是指有一个或多个连接点连接到分子的其余部分，饱和的，含有3-12个环碳原子的单环，双环或三环体系。其中一些实施例，环烷基是6-10个原子组成的螺双环烷基；另外一些实施例，环烷基是6-10个原子组成的稠合双环烷基；另外一些实施例，环烷基是含3-10个环碳原子的环体系；另外一些实施例，环烷基是含3-8个环碳原子的环体系；另外一些实施例，环烷基是含3-7个环碳原子的环体系；另外一些实施例，环烷基是含5-8个环碳原子的环体系；另外一些实施例，环烷基是含3-6个环碳原子的环体系；另外一些实施例，环烷基是含5-6个环碳原子的环体系；环烷基基团的实例包含，但并不限于，环丙基，环丁基，环戊基，环己基等等，且所述环烷基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。The term "cycloalkyl" refers to a saturated, monocyclic, bicyclic or tricyclic ring system having one or more points of attachment to the remainder of the molecule, containing from 3 to 12 ring carbon atoms. In some embodiments, the cycloalkyl group is a spirobicycloalkyl group composed of 6-10 atoms; in other embodiments, the cycloalkyl group is a fused bicycloalkyl group composed of 6-10 atoms; in other embodiments, the cycloalkane group In other embodiments, cycloalkyl is a ring system containing 3-8 ring carbon atoms; in other embodiments, cycloalkyl is a ring system containing 3-7 ring carbon atoms carbon atoms; in other embodiments, cycloalkyl is a ring system containing 5-8 ring carbon atoms; in other embodiments, cycloalkyl is a ring system containing 3-6 ring carbon atoms; For example, cycloalkyl is a ring system containing 5-6 ring carbon atoms; examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, And the cycloalkyl groups may independently be unsubstituted or substituted with one or more of the substituents described herein.
术语“杂环基”包括单环、双环或多环稠合、螺式或桥连环环系。术语“杂环基”和“杂环”在此处可交换使用，都是指包含3-12个环原子的饱和或部分不饱和的，非芳香性的单环、双环或三环体系，其中至少有一个环原子选自氮，硫和氧原子，且此环体系有一个或多个连接点与分子的其余部分相连。术语“杂环基”包括单环杂环基、双环或多环稠合杂环基、螺式或桥连杂环杂环基，还包括其中杂环可与一个或多个非芳香族碳环或杂环或一个或多个芳环或其组合稠合的多环环系，其中连接的原子团或点在杂环上。双环杂环基包括桥双环杂环基、稠合双环杂环基和螺双环杂环基。除非另外说明，杂环基的-CH 2-基团可以任选地被-C(＝O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。在一些实施方案中，杂环基为3-12个环原子组成的环体系；在一些实施方案中，杂环基为4-7个环原子组 成的单环杂环基；在一些实施方案中，杂环基为5-6个环原子组成的单环杂环基；在一些实施方案中，杂环基为7-10个环原子组成的稠合双环杂环基；在一些实施方案中，杂环基为8-10个环原子组成的稠合双环杂环基；在一些实施方案中，杂环基为6-10个环原子组成的桥双环杂环基；在其它一些实施方案中，杂环基为3-8个环原子组成的环体系；在其它一些实施方案中，杂环基为3-6个环原子组成的环体系；在其他一些实施方案中，杂环基为5-7个环原子组成的环体系；在其他一些实施方案中，杂环基为5-8个环原子组成的环体系；在其他一些实施方案中，杂环基为6-8个环原子组成的环体系；在其他一些实施方案中，杂环基为5-6个环原子组成的环体系；在其它一些实施方案中，杂环基为3个环原子组成的环体系；在其他一些实施方案中，杂环基为4个环原子组成的环体系；在其他一些实施方案中，杂环基为5个环原子组成的环体系；在其他一些实施方案中，杂环基为6个环原子组成的环体系；在其他一些实施方案中，杂环基为7个环原子组成的环体系；在其他一些实施方案中，杂环基为8个环原子组成的环体系。 The term "heterocyclyl" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged ring systems. The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and both refer to a saturated or partially unsaturated, non-aromatic monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 ring atoms, wherein At least one ring atom is selected from nitrogen, sulfur and oxygen atoms, and the ring system has one or more points of attachment to the rest of the molecule. The term "heterocyclyl" includes monocyclic heterocyclyls, bicyclic or polycyclic fused heterocyclyls, spiro or bridged heterocyclic heterocyclyls, and also wherein heterocycles may be combined with one or more non-aromatic carbocyclic rings or a heterocyclic ring or a polycyclic ring system in which one or more aromatic rings or combinations thereof are fused, wherein the atomic group or point of attachment is on the heterocyclic ring. Bicyclic heterocyclic groups include bridged bicyclic heterocyclic groups, fused bicyclic heterocyclic groups, and spirobicyclic heterocyclic groups. Unless otherwise specified, the -CH2- group of a heterocyclyl group can be optionally replaced by -C(=O)-. Ring sulfur atoms can optionally be oxidized to S-oxides. The nitrogen atoms of the rings can be optionally oxidized to N-oxygen compounds. In some embodiments, heterocyclyl is a ring system of 3-12 ring atoms; in some embodiments, heterocyclyl is a monocyclic heterocyclyl of 4-7 ring atoms; in some embodiments , the heterocyclyl group is a monocyclic heterocyclyl group composed of 5-6 ring atoms; in some embodiments, the heterocyclyl group is a fused bicyclic heterocyclyl group composed of 7-10 ring atoms; in some embodiments, Heterocyclyl is a fused bicyclic heterocyclyl of 8-10 ring atoms; in some embodiments, heterocyclyl is a bridged bicyclic heterocyclyl of 6-10 ring atoms; in other embodiments, Heterocyclyl is a ring system of 3-8 ring atoms; in other embodiments, heterocyclyl is a ring system of 3-6 ring atoms; in other embodiments, heterocyclyl is 5- A ring system consisting of 7 ring atoms; in other embodiments, a heterocyclyl group is a ring system consisting of 5-8 ring atoms; in other embodiments, a heterocyclyl group is a ring system consisting of 6-8 ring atoms ring systems; in other embodiments, heterocyclyl is a ring system of 5-6 ring atoms; in other embodiments, heterocyclyl is a ring system of 3 ring atoms; in other embodiments In other embodiments, heterocyclyl is a ring system of 4 ring atoms; in other embodiments, heterocyclyl is a ring system of 5 ring atoms; in other embodiments, heterocyclyl is a ring system of 6 ring atoms In other embodiments, heterocyclyl is a ring system of 7 ring atoms; in other embodiments, heterocyclyl is a ring system of 8 ring atoms.
杂环的实例包括，但并不限于，吡咯烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，四氢吡喃基，二氢吡喃基，四氢噻喃基，哌啶基，吗啉基，硫代吗啉基，噻噁烷基，哌嗪基，高哌嗪基，氮杂环丁基，氧杂环丁基，硫杂环丁基，高哌啶基，氧杂环丙基，氮杂环庚基，氧杂环庚基，硫杂环庚基，氧氮杂卓基，二氮杂卓基，硫氮杂卓基，2-吡咯啉基，3-吡咯啉基，二氢吲哚基，2H-吡喃基，4H-吡喃基，二氧杂环己基，1,3-二氧戊基，吡唑啉基，二噻烷基，二噻茂烷基，二氢噻吩基，吡唑烷基，咪唑啉基，咪唑烷基，1,2,3,4-四氢异喹啉基，3-氮杂双环[3.1.0]己基，3-氮杂双环[4.1.0]庚基，氮杂双环[2.2.2]己基，3H-吲哚基喹嗪基和N-吡啶基尿素。杂环基团的实例还包括，1,1-二氧硫代吗啉基；其中，环上碳原子被氧代(＝O)基团所取代的实例包括，但不限于嘧啶二酮基、1,2,4-噻二唑-5(4H)-酮基，1,2,4-噁二唑-5(4H)-酮基，1H-1,2,4-三唑-5(4H)-酮基等；其中环上碳原子被＝S基团所取代的实例包括，但不限于1,2,4-噁二唑-5(4H)-硫酮基，1,3,4-噁二唑-2(3H)-硫酮基等。所述的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxetanyl Propyl, Azacycloheptyl, Oxepeptyl, Thiepanyl, Oxazepinyl, Diazepanyl, Thiazepinyl, 2-Pyrrololinyl, 3-Pyrrololinyl , Indoline, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxopentyl, pyrazolinyl, dithianyl, dithianyl, Dihydrothienyl, pyrazolidine, imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo [4.1.0]Heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinazinyl and N-pyridylurea. Examples of heterocyclic groups also include, 1,1-dioxothiomorpholinyl; examples in which the carbon atoms on the ring are replaced by oxo (=O) groups include, but are not limited to, pyrimidinedione, 1,2,4-thiadiazole-5(4H)-keto, 1,2,4-oxadiazole-5(4H)-keto, 1H-1,2,4-triazole-5(4H )-keto, etc.; examples in which the carbon atoms on the ring are replaced by =S groups include, but are not limited to, 1,2,4-oxadiazole-5(4H)-thione, 1,3,4- Oxadiazole-2(3H)-thione, etc. The heterocyclyl group may be optionally substituted with one or more substituents described herein.
术语“稠合双环”，“稠环”，“稠合双环基”和“稠环基”在此处可交换使用，都是指单价或多价的，饱和或部分不饱和的非芳香性的环体系，所述环体系中的两个环共用一个键。这样的体系可以包含独立的或共轭的不饱和体系，但其核心结构不包含芳香环或芳杂环(但是芳香族基团可以作为其上的取代基)。The terms "fused bicyclic", "fused ring", "fused bicyclic group" and "fused ring group" are used interchangeably herein and refer to monovalent or polyvalent, saturated or partially unsaturated, non-aromatic A ring system in which two rings share a bond. Such systems may contain independent or conjugated unsaturated systems, but whose core structure does not contain aromatic rings or aromatic heterocycles (although aromatic groups may serve as substituents thereon).
术语“螺环基”，“螺环”，“螺双环基”或“螺双环”在此处可交换使用，是指单价或多价的，饱和或部分不饱和的非芳香性的环体系，其中一个环起源于另一个环上特定的环碳原子，并且两个环只共用一个原子。The terms "spirocyclyl", "spirocycle", "spirobicyclyl" or "spirobicycle" are used interchangeably herein to refer to a monovalent or polyvalent, saturated or partially unsaturated, non-aromatic ring system, One of the rings originates from a specific ring carbon atom on the other, and the two rings share only one atom.
例如，像下面式a-1所描述的，一个饱和的环体系(环C和B′)被称为“稠合双环”，而环A′和环B共享一个碳原子，被称为“螺环”或“螺双环”。稠合双环基和螺双环基的每个环都可以是碳环基或杂环基，并且每个环任选地被一个或多个本发明所描述的取代基所取代。For example, as depicted in formula a-1 below, a saturated ring system (rings C and B') is referred to as a "fused bicyclic", while rings A' and B share a carbon atom, referred to as a "spiro ring" or "spirobicyclic". Each ring of the fused bicyclyl and spirobicyclyl groups can be carbocyclyl or heterocyclyl, and each ring is optionally substituted with one or more substituents described herein.
Figure PCTCN2021141926-appb-000018
Figure PCTCN2021141926-appb-000018
术语“稠合双环杂环基”表示单价的饱和或部分不饱和的非芳香性并环体系。这样的体系可以包含独立的或共轭的不饱和状态，但其核心结构不包含芳香环或芳杂环(但是芳香族可以作为其上的取代基)。所述环体系中的每一个环包含3-7个原子，且至少一个环包含一个或多个杂原子，即包含1-6个碳原子和选自N，O，P，S的1-3个杂原子，在此S或P任选地被一个或多个氧原子所取代得到像SO，SO 2，PO，PO 2的基团，在一些实施方案中，稠合双环杂环基为7-10个环原子组成的稠合双环杂环基；在一些实施方案中，稠合双杂环基为8-10个环原子组成的稠合双环杂环基；这样的实例包括，但并不限于，3-氮杂稠合[3.1.0]己烷、3-氮杂双环[3.3.0]辛烷、六氢-呋喃[3,4-c]吡咯基、六氢-噻吩[3,4-c] 吡咯基、3,4,5,6-四氢-环戊烷[c]噻吩基、
Figure PCTCN2021141926-appb-000019
等。所述稠合杂双环基任选地被一个或多个本发明所描述的取代基所取代。 The term "fused bicyclic heterocyclyl" refers to a monovalent saturated or partially unsaturated non-aromatic bicyclic ring system. Such systems may contain independent or conjugated unsaturation, but their core structure does not contain aromatic or aromatic heterocycles (although aromatics may be used as substituents thereon). Each ring in the ring system contains 3-7 atoms, and at least one ring contains one or more heteroatoms, i.e. 1-6 carbon atoms and 1-3 selected from N, O, P, S heteroatoms, where S or P are optionally substituted with one or more oxygen atoms to give groups like SO, SO2, PO, PO2 , and in some embodiments, the fused bicyclic heterocyclyl is 7 - A fused bicyclic heterocyclyl of 10 ring atoms; in some embodiments, a fused bicyclic heterocyclyl is a fused bicyclic heterocyclyl of 8-10 ring atoms; such examples include, but do not Limited to, 3-aza-fused[3.1.0]hexane, 3-azabicyclo[3.3.0]octane, hexahydro-furan[3,4-c]pyrrolyl, hexahydro-thiophene[3, 4-c] pyrrolyl, 3,4,5,6-tetrahydro-cyclopentane[c]thienyl,
Figure PCTCN2021141926-appb-000019
Wait. The fused heterobicyclyl group is optionally substituted with one or more substituents described herein.
术语“桥双环基”表示饱和或部分不饱和的非芳香性的桥环体系，如式(b)所示，即环A1与环A2共有一个烷链或一个杂烷链，其中X 3为C，N，O，P，S；j为1、2、3或4。这样的体系可以包含独立的或共轭的不饱和状态，但其核心结构不包含芳香环或芳环(但是芳香族可以作为其上的取代基)。其中每一个环，如A1或A2，包含3-7个原子，这样的实例包括，但并不限于，双环[2.2.1]庚烷基，2-甲基-二氮杂二环[2.2.1]庚烷基等。所述桥双环基任选地被一个或多个本发明所描述的取代基所取代。 The term "bridged bicyclyl" refers to a saturated or partially unsaturated non-aromatic bridged ring system, as shown in formula (b), that is, ring A1 and ring A2 share an alkane chain or a heteroalkane chain, wherein X 3 is C , N, O, P, S; j is 1, 2, 3 or 4. Such systems may contain independent or conjugated unsaturation, but whose core structure does not contain aromatic or aromatic rings (although aromatics may be substituents thereon). wherein each ring, such as A1 or A2, contains 3-7 atoms, such examples include, but are not limited to, bicyclo[2.2.1]heptyl, 2-methyl-diazabicyclo[2.2. 1] Heptyl, etc. The bridged bicyclyl is optionally substituted with one or more substituents described herein.
Figure PCTCN2021141926-appb-000020
Figure PCTCN2021141926-appb-000020
术语“桥碳双环基”表示饱和或部分不饱和的非芳香性的桥双环体系，其中每一个环包含3-7个碳原子，这样的实例包括，但并不限于，双环[2.2.1]庚烷基等。所述桥双环基任选地被一个或多个本发明所描述的取代基所取代。The term "bridged carbobicyclyl" refers to a saturated or partially unsaturated non-aromatic bridged bicyclic ring system wherein each ring contains 3-7 carbon atoms, examples of which include, but are not limited to, bicyclic [2.2.1] Heptyl, etc. The bridged bicyclyl is optionally substituted with one or more substituents described herein.
术语“桥双环杂环基”表示饱和或部分不饱和的非芳香性的桥双环体系，其中每一个环包含3-7个原子，且至少一个环包含一个或多个杂原子，即包含1-6个碳原子和选自N，O，P，S的1-3个杂原子，在此S或P任选地被一个或多个氧原子所取代得到像SO，SO 2，PO，PO 2的基团，在一些实施方案中，桥双环杂环基为6-10个环原子组成的桥双环杂环基，这样的实例包括，但并不限于2-氧-5-氮杂双环[2.2.1]庚烷基，2-硫代-5-氮杂双环[2.2.1]庚烷基，2-氧代-5-氮杂双环[2.2.1]庚烷基，2,5-二氮杂二环[2.2.1]庚烷基，2-甲基-2,5-二氮杂二环[2.2.1]庚烷基、
Figure PCTCN2021141926-appb-000021
等。所述桥双环杂环基任选地被一个或多个本发明所描述的取代基所取代。 The term "bridged bicyclic heterocyclyl" denotes a saturated or partially unsaturated non-aromatic bridged bicyclic ring system wherein each ring contains 3-7 atoms and at least one ring contains one or more heteroatoms, i.e., contains 1- 6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to obtain like SO, SO 2 , PO, PO 2 The group, in some embodiments, bridged bicyclic heterocyclyl is a bridged bicyclic heterocyclyl consisting of 6-10 ring atoms, such examples include, but are not limited to 2-oxo-5-azabicyclo[2.2 .1]heptyl, 2-thio-5-azabicyclo[2.2.1]heptyl, 2-oxo-5-azabicyclo[2.2.1]heptyl, 2,5-di azabicyclo[2.2.1]heptyl, 2-methyl-2,5-diazabicyclo[2.2.1]heptyl,
Figure PCTCN2021141926-appb-000021
Wait. The bridged bicyclic heterocyclyl is optionally substituted with one or more substituents described herein.
术语“芳基”表示含有6-14个碳原子，或6-12个碳原子，或6-10个碳原子的单环，双环，和三环的碳环体系，其中，至少有一个环体系是芳香族的，其中每一个环体系包含3-7个碳原子组成的环，且有一个或多个附着点与分子的其余部分相连。术语“芳基”可以和术语“芳环”或“芳香环”交换使用，如芳基可以包括苯基，萘基和蒽基。所述芳基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。The term "aryl" refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing 6-14 carbon atoms, or 6-12 carbon atoms, or 6-10 carbon atoms, wherein at least one ring system are aromatic in which each ring system contains a ring of 3-7 carbon atoms with one or more points of attachment to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring" or "aromatic ring", eg aryl may include phenyl, naphthyl and anthracenyl. The aryl groups may independently be unsubstituted or substituted with one or more of the substituents described herein.
术语“杂芳基”表示含有5-16个环原子的单环，双环或三环体系，其中至少有一个环体系是芳香族的，且至少有一个环体系包含一个或多个杂原子，其中每一个环体系包含5-7个环原子组成的环，且有一个或多个附着点与分子其余部分相连。术语“杂芳基”可以与术语“杂芳环”或“杂芳族化合物”交换使用。在一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-14个环原子组成的杂芳基。在另一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-12个环原子组成的杂芳基。在另一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-10个环原子组成的杂芳基。在另一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-8个环原子组成的杂芳基。在另一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-7个环原子组成的杂芳基。在另一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-6个环原子组成的杂芳基。在另一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5个环原子组成的杂芳基。在另一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的6个环原子组成的杂芳基。The term "heteroaryl" refers to a monocyclic, bicyclic or tricyclic ring system containing 5 to 16 ring atoms, at least one of which is aromatic and at least one of which contains one or more heteroatoms, wherein Each ring system contains a ring of 5-7 ring atoms with one or more points of attachment to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic". In some embodiments, a heteroaryl group is a heteroaryl group consisting of 5-14 ring atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 5-12 ring atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 5-10 ring atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 5-8 ring atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 5-7 ring atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 5-6 ring atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 5 ring atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 6 ring atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.
另外一些实施例是，杂芳基包括以下的单环基团，但并不限于这些单环基团：2-呋喃基，3-呋喃基，N-咪唑基，2-咪唑基，4-咪唑基，5-咪唑基，3-异噁唑基，4-异噁唑基，5-异噁唑基，2-噁唑基，4-噁唑基，5-噁唑基，N-吡咯基，2-吡咯基，3-吡咯基，2-吡啶基，3-吡啶基，4-吡啶基，2-嘧啶基，4-嘧啶基，5-嘧啶基，哒嗪基(如3-哒嗪基)，2-噻唑基，4-噻唑基，5-噻唑基，四唑基(如5H-四唑基，2H-四唑基)，三唑基(如2-三唑基，5-三唑基，4H-1,2,4-三唑基，1H-1,2,4-三唑基，1,2,3-三唑基)，2-噻吩基，3-噻吩基，吡唑基(如，2-吡唑基和3-吡唑基)，异噻唑基，1,2,3-噁二唑基，1,2,5-噁二唑基，1,2,4-噁二唑基，1,3,4-噁二唑基，1,2,3-硫代二唑基，1,3,4-硫代二唑基，1,2,5-硫代二唑基，吡嗪基，1,3,5-三嗪基；也包括以下的双或者三环基团，但绝不限于这些基团：苯并咪唑基，苯并呋喃基，苯并噻吩基，吲哚基(如2-吲哚基)，嘌呤基，喹啉基(如2-喹啉基，3-喹啉基，4-喹啉基)，异喹啉基(如1-异喹啉基，3-异喹啉基或4-异喹啉基)，吩噁噻基，二苯并咪唑基，二苯并呋喃基或二苯并噻吩基等。所述杂芳基基团任选地被一个或多个本发明所描述的取代基所取代。In other embodiments, heteroaryl groups include, but are not limited to, the following monocyclic groups: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazole base, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl , 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazine base), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5H-tetrazolyl, 2H-tetrazolyl), triazolyl (such as 2-triazolyl, 5-triazolyl azolyl, 4H-1,2,4-triazolyl, 1H-1,2,4-triazolyl, 1,2,3-triazolyl), 2-thienyl, 3-thienyl, pyrazole radicals (eg, 2-pyrazolyl and 3-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiooxadiazolyl, 1,3,4-thiooxadiazolyl, 1,2,5-thiooxadiazolyl , pyrazinyl, 1,3,5-triazinyl; also include the following bi- or tricyclic groups, but are by no means limited to these groups: benzimidazolyl, benzofuranyl, benzothienyl, indium dolyl (such as 2-indolyl), purinyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (such as 1-isoquinolinyl) , 3-isoquinolinyl or 4-isoquinolinyl), phenoxthiyl, dibenzimidazolyl, dibenzofuranyl or dibenzothienyl, etc. The heteroaryl group is optionally substituted with one or more substituents described herein.
另外，需要说明的是，除非以其他方式明确指出，在本文中通篇采用的描述方式“各…和…独立地为”、“…和…各自独立地为”和“…和…分别独立地为”可以互换，应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。In addition, it should be noted that, unless expressly stated otherwise, the descriptions used throughout this document "each ... and ... are independently", "... and ... are each independently" and "... and ... are each independently "" can be interchanged and should be understood in a broad sense. It can either mean that in different groups, the specific options expressed by the same symbol do not affect each other, or it can mean that in the same group, the same symbol is the same. The specific options expressed between them do not affect each other.
除非其他方面表明，本发明所描述的结构式包括所有的同分异构形式(如对映异构，非对映异构，和几何异构(或构象异构)：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体，和(Z)、(E)的构象异构体。因此，本发明的化合物的单个立体化学异构体或其对映异构体，非对映异构体，或几何异构体(或构象异构体)的混合物都属于本发明的范围。Unless otherwise indicated, the structural formulae described herein include all isomeric forms (eg, enantiomers, diastereomers, and geometrical isomers (or conformations): for example, R containing an asymmetric center , S configuration, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Thus, the individual stereochemical isomers of the compounds of the present invention or their enantiomers Isomers, diastereomers, or mixtures of geometric isomers (or conformational isomers) are within the scope of the present invention.
本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C 1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14 of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51，2328-2345。 The term "prodrug" as used in the present invention refers to the conversion of a compound into a compound of formula (I) in vivo. Such conversion is effected by hydrolysis of the prodrug in blood or enzymatic conversion to the parent structure in blood or tissue. The prodrug compounds of the present invention can be esters. In the existing invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonate esters , carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxyl group, which can be acylated to give the compound in prodrug form. Other prodrug forms include phosphates, such as these phosphates are phosphorylated by the hydroxyl group on the parent. A complete discussion of prodrugs can be found in the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008 , 51, 2328-2345.
除非其他方面表明，本发明的化合物的所有互变异构形式都包含在本发明的范围之内。另外，除非其他方面表明，本发明所描述的化合物的结构式包括一个或多个不同的原子的富集同位素。Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are included within the scope of the present invention. Additionally, unless otherwise indicated, the structural formulae of the compounds described herein include enriched isotopes of one or more different atoms.
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化、还原、水解、酰氨化、脱酰氨作用、酯化、脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。"Metabolite" refers to a product obtained by metabolism of a specific compound or salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and their activity can be characterized using assays as described herein. Such products may be obtained by subjecting the administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.
本发明中立体化学的定义和惯例的使用通常参考以下文献：S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons,Inc.,New York,1994.本发明的化合物可以包含不对称中心或手性中心，因此存在不同的立体异构体。本发明的化合物所有的立体异构形式，包括但绝不限于，非对映体，对映异构体，阻转异构体，和它们的混合物，如外消旋混合物，组成了本发明的一部分。很多有机化合物都以光学活性形式存在，即它们有能力旋转平面偏振光的平面。在描述光学活性化合物时，前缀D、L或 R、S用来表示分子手性中心的绝对构型。前缀d、l或(+)、(-)用来命名化合物平面偏振光旋转的符号，(-)或l是指化合物是左旋的，前缀(+)或d是指化合物是右旋的。这些立体异构体的化学结构是相同的，但是它们的立体结构不一样。特定的立体异构体可以是对映体，异构体的混合物通常称为对映异构体混合物。50：50的对映体混合物被称为外消旋混合物或外消旋体，这可能导致化学反应过程中没有立体选择性或立体定向性。术语“外消旋混合物”和“外消旋体”是指等摩尔的两个对映异构体的混合物，缺乏光学活性。术语“互变异构体”或“互变异构的形式”是指不同能量的结构的同分异构体可以通过低能垒互相转化。例如质子互变异构体(即质子移变的互变异构体)包括通过质子迁移的互变，如酮式-烯醇式和亚胺-烯胺的同分异构化作用。原子价(化合价)互变异构体包括重组成键电子的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。Use of definitions and conventions of stereochemistry in the present invention is generally referred to by S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S. ., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric or chiral centers and therefore exist in different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including, but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute the part. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D, L or R, S are used to denote the absolute configuration of the chiral center of the molecule. The prefixes d, l or (+), (-) are used to designate the sign of the plane-polarized light rotation of the compound, (-) or l means the compound is levorotatory, and the prefix (+) or d means the compound is dextrorotatory. The chemical structures of these stereoisomers are the same, but their steric structures are not the same. A specific stereoisomer may be an enantiomer, and a mixture of isomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can result in no stereoselectivity or stereospecificity during chemical reactions. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers, devoid of optical activity. The term "tautomer" or "tautomeric form" means that isomers of structures of different energies can be interconverted through a low energy barrier. For example, proton tautomers (ie, prototropic tautomers) include interconversions by migration of protons, such as keto-enol and imine-enamine isomerizations. Valence (valence) tautomers include interconversions that recombine bond electrons. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,66:1-19,1977.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、高氯酸盐、和有机酸盐如乙酸盐、草酸盐、马来酸盐、酒石酸盐、柠檬酸盐、琥珀酸盐、丙二酸盐、或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐、苹果酸盐、2-羟基丙酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、环戊基丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、反丁烯二酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖醛酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐，等等。通过适当的碱得到的盐包括碱金属，碱土金属，铵和N +(C 1-4烷基) 4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠、锂、钾、钙、镁，等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物、氢氧化物、羧化物、硫酸化物、磷酸化物、硝酸化物、C 1-8磺酸化物和芳香磺酸化物。 As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19, 1977. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups including hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or obtained by other methods such as ion exchange methods described in books and literature these salts. Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate , borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate acid salt, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactic acid Salt, laurate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate , pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoic acid Salts, valerates, etc. Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts. The present invention also contemplates quaternary ammonium salts formed from any compound containing an N-group. Water- or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations that resist counterion formation, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1 -8 Sulfonates and aromatic sulfonates.
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水、异丙醇、乙醇、甲醇、二甲亚砜、乙酸乙酯、乙酸、氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。A "solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association in which the solvent molecule is water.
术语“保护基团”或“Pg”是指一个取代基与别的官能团起反应的时候，通常用来阻断或保护特殊的功能性。例如，“氨基的保护基团”是指一个取代基与氨基基团相连来阻断或保护化合物中氨基的功能性，合适的氨基保护基团包括乙酰基、三氟乙酰基、叔丁氧羰基(BOC)、苄氧羰基(CBZ)和9-芴亚甲氧羰基(Fmoc)。相似地，“羟基保护基团”是指羟基的取代基用来阻断或保护羟基的功能性，合适的保护基团包括乙酰基和甲硅烷基。“羧基保护基团”是指羧基的取代基用来阻断或保护羧基的功能性，一般的羧基保护基包括-CH 2CH 2SO 2Ph、氰基乙基、2-(三甲基硅烷基)乙基、2-(三甲基硅烷基)乙氧基甲基、2-(对甲苯磺酰基)乙基、2-(对硝基苯磺酰基)乙基、2-(二苯基膦基)乙基、硝基乙基，等等。对于保护基团一般的描述可参考文献：T W.Greene,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005。 The term "protecting group" or "Pg" refers to a substituent that is commonly used to block or protect a particular functionality when it reacts with another functional group. For example, "protecting group for amino" refers to a substituent attached to the amino group to block or protect the functionality of the amino group in the compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxyl protecting group" refers to a substituent of a hydroxy group used to block or protect the functionality of the hydroxy group, suitable protecting groups include acetyl and silyl. "Carboxyl protecting group" means that the substituent of the carboxyl group is used to block or protect the functionality of the carboxyl group. General carboxyl protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilane) yl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl) phosphino)ethyl, nitroethyl, and the like. For a general description of protecting groups, reference can be made to the literature: TW. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
本发明的化合物的药物组合物，制剂，给药和化合物及药物组合物的用途Pharmaceutical Compositions, Formulations, Administration and Use of Compounds and Pharmaceutical Compositions of the Invention
根据另一方面，本发明的药物组合物的特点包括式(I)的化合物，本发明所列出的化合物，或实施例化合物，和药学上可接受的辅料。本发明的药物组合物中化合物能有效的抑制乙型肝炎病毒，适用于病毒 引起的疾病尤其是急性和慢性持续的HBV感染的治疗，HBV引发的慢性病毒病可能导致病态变严重，慢性乙型肝炎病毒感染在许多情况下可导致肝硬化和/或肝细胞癌变。According to another aspect, the pharmaceutical composition of the present invention features a compound of formula (I), a compound listed in the present invention, or an example compound, and a pharmaceutically acceptable excipient. The compounds in the pharmaceutical composition of the present invention can effectively inhibit hepatitis B virus, and are suitable for the treatment of diseases caused by viruses, especially acute and chronic persistent HBV infection. Hepatitis virus infection can lead to cirrhosis and/or hepatocellular carcinoma in many cases.
对本发明的化合物来说，可能被提及的疾病治疗的区域是，例如：可能导致传染性肝炎的急性和慢性病毒感染的治疗，例如，乙肝病毒感染。本发明的化合物尤其适合治疗慢性乙肝感染和急性和慢性乙肝病毒感染。An area of disease treatment that may be mentioned for the compounds of the present invention is, for example, the treatment of acute and chronic viral infections that may lead to infectious hepatitis, eg, hepatitis B virus infection. The compounds of the present invention are particularly suitable for the treatment of chronic hepatitis B infection and acute and chronic hepatitis B virus infection.
本发明包括药物制剂，除了无毒，惰性的制药学上合适的辅料外，还含有一种或多种本发明的式(I)化合物或其药物组合物或含有一种或多种活性成分式(I)化合物或本发明的药物组合物。The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, also contain one or more compounds of formula (I) of the present invention or their pharmaceutical compositions or one or more active ingredients of formula (I) The compound or the pharmaceutical composition of the present invention.
上述药物制剂也可以包含式(I)化合物以外的其他活性药物成分。The pharmaceutical formulations described above may also contain other active pharmaceutical ingredients than compounds of formula (I).
本发明的化合物存在自由形态，或合适的、作为药学上可接受的衍生物。根据本发明，药学上可接受的衍生物包括，但并不限于，药学上可接受的前药，盐，酯，酯类的盐，或能直接或间接地根据患者的需要给药的其他任何加合物或衍生物，本发明其他方面所描述的化合物，其代谢产物或它的残留物。The compounds of the present invention exist in free form, or as suitable, as pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other that can be administered directly or indirectly according to the needs of the patient Adducts or derivatives, compounds described in other aspects of the invention, metabolites thereof or residues thereof.
像本发明所描述的，本发明药物组合物包含任何一种本发明的式(I)所示化合物，进一步包含药学上可接受的辅料，这些辅料，例如像本发明所应用的，包括任何溶剂、固体赋形剂、稀释剂、粘合剂、崩解剂、或其他液体赋形剂、分散剂、矫味剂或悬浮剂、表面活性剂、等渗剂、增稠剂、乳化剂、防腐剂，固体粘合剂或润滑剂，等等，适合于特有的目标剂型。如以下文献所描述的：In Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams& Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York,综合此处文献的内容，表明不同的辅料可应用于药学上可接受的组合物的制剂和它们公知的制备方法。除了任何常规的辅料与本发明的化合物不相容的范围，例如所产生的任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式产生的相互作用，它们的用途也是本发明所考虑的范围。As described in the present invention, the pharmaceutical composition of the present invention comprises any one of the compounds represented by formula (I) of the present invention, and further comprises pharmaceutically acceptable excipients, such as those used in the present invention, including any solvent , solid excipients, diluents, binders, disintegrants, or other liquid excipients, dispersing agents, flavoring or suspending agents, surfactants, isotonic agents, thickening agents, emulsifiers, preservatives agents, solid binders or lubricants, etc., suitable for the particular target dosage form. As described in: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988- 1999, Marcel Dekker, New York, synthesizing the contents of the literature herein, shows that different excipients can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. Except to the extent that any conventional excipients are incompatible with the compounds of the present invention, such as any adverse biological effect or interaction in a detrimental manner with any other component of a pharmaceutically acceptable composition, their Use is also contemplated by the present invention.
可作为药学上可接受的辅料的物质包括，但并不限于，离子交换剂；铝；硬脂酸铝；卵磷脂；血清蛋白，如人血清蛋白；缓冲物质如磷酸盐；甘氨酸；山梨酸；山梨酸钾；饱和植物脂肪酸的部分甘油酯混合物；水；盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐；胶体硅；三硅酸镁；聚乙烯吡咯烷酮；聚丙烯酸脂；蜡；聚乙烯-聚氧丙烯-阻断聚合体；羊毛脂；糖，如乳糖，葡萄糖和蔗糖；淀粉如玉米淀粉和土豆淀粉；纤维素和它的衍生物如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；树胶粉；麦芽；明胶；滑石粉；辅料如可可豆脂和栓剂蜡状物；油如花生油，棉子油，红花油，麻油，橄榄油，玉米油和豆油；二醇类化合物，如丙二醇和聚乙二醇；酯类如乙基油酸酯和乙基月桂酸酯；琼脂；缓冲剂如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等渗盐；林格(氏)溶液；乙醇；磷酸缓冲溶液；和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁；着色剂；释放剂；包衣衣料；甜味剂；调味剂；香料；防腐剂和抗氧化剂。Substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances such as phosphate; glycine; sorbic acid; Potassium sorbate; partial glyceride mixture of saturated vegetable fatty acids; water; salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; Vinylpyrrolidones; polyacrylates; waxes; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxylate Sodium methylcellulose, ethylcellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil , olive oil, corn oil and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; Alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol; phosphate buffered solution; and other nontoxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; colorants; release agents ; Coatings; Sweeteners; Flavourings; Perfumes; Preservatives and Antioxidants.
本发明化合物的药物组合物，可以以下方面的任意方式施用：口服给药，喷雾吸入法，局部给药，经直肠给药，经鼻给药，局部给药，阴道给药，非肠道给药如皮下，静脉，肌内，腹腔内，鞘内，心室内，胸骨内，或颅内注射或输液，或借助一种外植的储器用药。优选的方式为口服给药，肌注，向腹膜内给药或静脉注射。The pharmaceutical compositions of the compounds of the present invention may be administered in any of the following ways: oral administration, spray inhalation, topical administration, rectal administration, nasal administration, topical administration, vaginal administration, parenteral administration The drug is administered as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, or intracranial injection or infusion, or by means of an explanted reservoir. The preferred mode is oral administration, intramuscular injection, intraperitoneal administration or intravenous injection.
本发明化合物或其药物组合物可以是以单位剂量形式给药。给药剂型可以是液体剂型、固体剂型。液体剂型可以是真溶液类、胶体类、微粒剂型、混悬剂型。其他剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉针剂、包合物、埋植剂、贴剂、擦剂等。The compounds of the present invention or pharmaceutical compositions thereof may be administered in unit dosage form. The dosage form for administration can be a liquid dosage form, a solid dosage form. Liquid dosage forms can be true solutions, colloids, microparticles, and suspensions. Other dosage forms such as tablets, capsules, dropping pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, lyophilized powders, inclusions, implants, patches, wipes agent, etc.
口服片剂和胶囊可以含有赋形剂如粘合剂，如糖浆，阿拉伯胶，山梨醇，黄芪胶，或聚乙烯吡咯烷酮；填充剂，如乳糖，蔗糖，玉米淀粉，磷酸钙，山梨醇，氨基乙酸；润滑剂，如硬脂酸镁，滑石，聚乙二醇， 硅土；崩解剂，如马铃薯淀粉；或可接受的增润剂如月桂醇钠硫酸盐。片剂可以用制药学上公知的方法包衣。Oral tablets and capsules may contain excipients such as binders, such as syrup, acacia, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, such as lactose, sucrose, cornstarch, calcium phosphate, sorbitol, amino acids acetic acid; lubricants such as magnesium stearate, talc, polyethylene glycol, silica; disintegrants such as potato starch; or acceptable emollients such as sodium lauryl sulfate. Tablets can be coated by methods known in pharmacy.
口服液可以制成水合油的悬浮液，溶液，乳浊液，糖浆或酏剂，也可以制成干品，用前补充水或其它合适的媒质。这种液体制剂可以包含常规的添加剂，如悬浮剂，山梨醇，纤维素甲醚，葡萄糖糖浆，凝胶，羟乙基纤维素，羧甲基纤维素，硬脂酸铝凝胶，氢化的食用油脂，乳化剂，如卵磷脂，山梨聚醣单油酸盐，阿拉伯胶；或非水辅料(可能包含可食用油)，如杏仁油，油脂如甘油，乙二醇，或乙醇；防腐剂，如对羟基苯甲酸甲酯或丙酯，山梨酸。如需要可添加调味剂或着色剂。Oral solutions can be prepared as suspensions, solutions, emulsions, syrups or elixirs in hydrated oils, or they can be prepared as dry products for replenishment with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, sorbitol, cellulose methyl ether, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible Fats, emulsifiers such as lecithin, sorbitan monooleate, acacia; or non-aqueous excipients (may contain edible oils) such as almond oil, oils such as glycerol, glycol, or ethanol; preservatives, Such as methyl or propyl paraben, sorbic acid. Flavoring or coloring agents may be added if desired.
栓剂可包含常规的栓剂基质，如可可黄油或其他甘油酯。Suppositories may contain conventional suppository bases such as cocoa butter or other glycerides.
对胃外投药，液态剂型通常由化合物和一种消毒的辅料制成。辅料首选水。依照所选辅料和药物浓度的不同，化合物既可溶于辅料中也可制成悬浮溶液，在制成注射用溶液时先将化合物溶于水中，过滤消毒后装入封口瓶或安瓿中。For parenteral administration, liquid dosage forms are usually prepared from the compound and a sterile excipient. The first choice for excipients is water. According to the different excipients and drug concentrations selected, the compound can be dissolved in the excipient or made into a suspension solution. When preparing a solution for injection, the compound is first dissolved in water, filtered and sterilized, and then put into a sealed bottle or ampule.
当皮肤局部施用时，本发明化合物可以制成适当的软膏，洗剂，或霜剂的形式，其中活性成分悬浮或溶解于一种或多种的辅料中，其中软膏制剂可以使用的辅料包括但不局限于：矿物油，液体凡士林，白凡士林，丙二醇，聚氧化乙烯，聚氧化丙烯，乳化蜡和水；洗剂和霜剂可使用的辅料包括但不限于：矿物油，脱水山梨糖醇单硬脂酸酯，吐温60，十六烷酯蜡，十六碳烯芳醇，2-辛基十二烷醇，苄醇和水。When applied topically to the skin, the compounds of the present invention may be formulated in the form of a suitable ointment, lotion, or cream in which the active ingredient is suspended or dissolved in one or more excipients which may be used in the ointment formulation including but Not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water; excipients that can be used in lotions and creams include but are not limited to: mineral oil, sorbitan monohydrate Stearate, Tween 60, cetyl ester wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
一般而言，已经证明有利的是无论在人体医药还是在兽医药中，本发明活性化合物的给药总量每24小时为约0.5-500mg，优选1-100mg/kg体重，如果合适的话，分多次单剂量给药，以达到所要求的效果。单剂量中含活性化合物的量优选为约1-80mg，更优选为1-50mg/kg体重，但也可以不按照上述的剂量，即取决于治疗对象的种类和体重、疾病的性质和严重程度、制剂的类型和药物的给药方式，以及给药周期或时间间隔。In general, it has proven to be advantageous, both in human and veterinary medicine, to administer the active compounds according to the invention in a total amount of about 0.5-500 mg per 24 hours, preferably 1-100 mg/kg body weight, if appropriate divided into Multiple single doses are administered to achieve the desired effect. The amount of active compound contained in a single dose is preferably about 1-80 mg, more preferably 1-50 mg/kg body weight, but may not be in accordance with the above-mentioned doses, i.e. depending on the type and body weight of the subject, the nature and severity of the disease , the type of preparation and the mode of administration of the drug, and the period or interval of administration.
本发明提供的药物组合物中还包含抗HBV药物。其中抗HBV药物为HBV聚合酶抑制剂、免疫调节剂或干扰素。The pharmaceutical composition provided by the present invention also includes an anti-HBV drug. The anti-HBV drug is HBV polymerase inhibitor, immunomodulator or interferon.
所述抗HBV药物有拉米夫定、替比夫定、替诺福韦酯，恩替卡韦、阿德福韦酯、Alfaferone、Alloferon、西莫白介素、克拉夫定、恩曲他滨、法普洛韦、干扰素、宝甘灵CP、因特芬、干扰素α-1b、干扰素α、干扰素α-2a、干扰素β-1a、干扰素α-2、白细胞介素-2、米伏替酯、硝唑尼特、聚乙二醇干扰素α-2a、病毒唑、罗扰素-A、西佐喃、Euforavac、安普利近、Phosphazid，Heplisav、干扰素α-2b、左旋咪唑或丙帕锗等。The anti-HBV drugs include lamivudine, telbivudine, tenofovir dipivoxil, entecavir, adefovir dipivoxil, Alfaferone, Alloferon, simoleukin, clavudine, emtricitabine, faprol Wei, interferon, Baoganling CP, interferon, interferon alpha-1b, interferon alpha, interferon alpha-2a, interferon beta-1a, interferon alpha-2, interleukin-2, mivo Tietate, Nitazoxanide, Pegylated Interferon alfa-2a, Ribavirin, Rosferon-A, Sizoran, Euforavac, Ampligen, Phosphazid, Heplisav, Interferon alfa-2b, Levamisole Or propagium and so on.
本发明另一方面涉及一种本发明的化合物或药物组合物来制备用于预防、治疗或减轻患者乙型肝炎疾病的药品的用途，包括给予患者药学上可接受的有效剂量对患者进行给药。乙型肝炎疾病是指由乙肝病毒感染或乙型肝炎感染导致引起的肝脏疾病，包括急性肝炎、慢性肝炎，肝硬化和干细胞癌。急性乙型肝炎病毒感染可以是无症状或表现为急性肝炎症状。慢性病毒感染患者患有活动性疾病，可发展为肝硬化和肝癌。Another aspect of the present invention relates to the use of a compound or pharmaceutical composition of the present invention to prepare a medicament for preventing, treating or alleviating hepatitis B disease in a patient, including administering to the patient a pharmaceutically acceptable effective dose. . Hepatitis B disease refers to liver disease caused by hepatitis B virus infection or hepatitis B infection, including acute hepatitis, chronic hepatitis, liver cirrhosis and stem cell cancer. Acute HBV infection can be asymptomatic or present with acute hepatitis symptoms. Patients with chronic viral infection have active disease that can develop cirrhosis and liver cancer.
抗HBV药物可以与包含本发明的化合物的组合物分开给药，作为多次给药方案的一部分。或者，那些药物可以是单剂型的一部分，与本发明的化合物混合在一起形成单个组合物。如果给药作为多次给药方案的一部分，两个活性剂可以同时连续地或在一段时间内互相传递，从而得到目标试剂活性。The anti-HBV drug may be administered separately from the composition comprising the compound of the present invention as part of a multiple dosing regimen. Alternatively, those drugs may be part of a single dosage form that is mixed with the compounds of the present invention to form a single composition. If administered as part of a multiple-dosing regimen, the two active agents can be delivered to each other simultaneously, continuously or over a period of time, to achieve the desired agent activity.
可以结合辅料物质产生单剂型的化合物和药物组合物的用量(那些包含一个药物组合物像本发明所描述的)的改变取决于主治和特殊给药模式。正常地，本发明的药物组合物的量将不超过组合物包含作为唯一的活性剂的正常给药的量。另一方面，现公开的药物组合物的量的范围大约是现有药物组合物正常量的50％-100％，包含的试剂作为唯一活性治疗剂。在那些包含的组合物中，组合物将与本发明的化合物起协同作用。The amount of compounds and pharmaceutical compositions that can be combined with excipient substances to produce a single dosage form (those comprising a pharmaceutical composition as described herein) varies depending on the indication and the particular mode of administration. Normally, the amount of the pharmaceutical composition of the present invention will not exceed the amount in which the composition contains as the only active agent normally administered. On the other hand, the amounts of the presently disclosed pharmaceutical compositions range from about 50% to 100% of the normal amount of existing pharmaceutical compositions, containing the agent as the only active therapeutic agent. In those included compositions, the compositions will act synergistically with the compounds of the present invention.
本发明的化合物显示出较强的抗病毒作用。这类化合物对HBV具有出乎预料的抗病毒活性，因此适于用来治疗病毒引起的各种疾病，尤其是急性和慢性持久性HBV感染引起的疾病。由HBV引起的慢性病毒性疾病可以导致各种不同严重程度的综合症状，众所周知，慢性乙肝病毒感染可导致肝硬化和/或肝细胞癌。The compounds of the present invention show strong antiviral effects. Such compounds have unexpected antiviral activity against HBV and are therefore suitable for the treatment of various diseases caused by viruses, especially diseases caused by acute and chronic persistent HBV infection. Chronic viral diseases caused by HBV can lead to syndromes of varying severity, and chronic HBV infection is known to lead to cirrhosis and/or hepatocellular carcinoma.
可用本发明化合物治疗的适应症的实例有：可导致感染性肝炎的急性和慢性病毒感染，例如乙型肝炎病毒感染。特别优选的是慢性乙型肝炎感染和急性乙型肝炎病毒感染。Examples of indications that can be treated with the compounds of the present invention are acute and chronic viral infections that can lead to infectious hepatitis, such as hepatitis B virus infection. Particularly preferred are chronic hepatitis B infection and acute hepatitis B virus infection.
本发明还涉及，本发明的化合物和药物组合物用于制备治疗和预防病毒性疾病特别是乙型肝炎的药物的用途。The present invention also relates to the use of the compounds and pharmaceutical compositions of the present invention for the preparation of medicaments for the treatment and prevention of viral diseases, especially hepatitis B.
一般合成方法General synthetic methods
一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如式(I)所示。下面的合成方案和实施例用于进一步举例说明本发明的内容。In general, the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, wherein the substituents are as defined in formula (I). The following synthetic schemes and examples serve to further illustrate the content of the present invention.
所属领域的技术人员将认识到：本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的试剂除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare many other compounds of the present invention, and that other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modifying methods, such as appropriate protection of interfering groups, by using other known reagents in addition to those described herein, or by combining The reaction conditions were modified routinely. In addition, the reactions disclosed herein or known reaction conditions are also acknowledged to be applicable to the preparation of other compounds of the present invention.
下面所描述的实施例，除非其他方面表明所有的温度定为摄氏度(℃)。试剂购买于商品供应商如Aldrich Chemical Company,Arco Chemical Company and Alfa Chemical Company，使用时都没有经过进一步纯化，除非其他方面表明。一般的试剂从汕头西陇化工厂，广东光华化学试剂厂，广州化学试剂厂，天津好寓宇化学品有限公司，青岛腾龙化学试剂有限公司，和青岛海洋化工厂购买得到。In the examples described below, unless otherwise indicated, all temperatures are in degrees Celsius (°C). Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. Common reagents were purchased from Shantou Xilong Chemical Reagent Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.
色谱柱使用硅胶柱，硅胶(200-300目)购于青岛海洋化工厂。核磁共振光谱以CDC1 3,DMSO-d 6,CD 3OD或丙酮-d 6为溶剂(报导以ppm为单位)，用TMS(0ppm)或氯仿(7.25ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰),d(doublet，双峰),t(triplet，三重峰),m(multiplet，多重峰),q(quartets，四重峰),br(broadened，宽峰),dd(doublet of doublets，双二重峰),dt(doublet of triplets，双三重峰),br.s(broadened singlet，宽单峰),td(three doublets,三二重峰)。偶合常数J，单位用赫兹(Hz)表示。 The chromatographic column used silica gel column, and silica gel (200-300 mesh) was purchased from Qingdao Ocean Chemical Factory. NMR spectra were performed with CDC13, DMSO - d6, CD3OD or acetone - d6 as solvents (reported in ppm), with TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiplets are present, the following abbreviations are used: s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), m (multiplet, multiplet), q (quartets, four doublet), br (broadened, broad peak), dd (doublet of doublets, double doublet), dt (doublet of triplets, double triplet), br.s (broadened singlet, broad singlet), td (three doublets, triple doublets). The coupling constant, J, is expressed in Hertz (Hz).
低分辨率质谱(MS)数据通过配备G1312A二元泵和a G1316A TCC(柱温保持在30℃)的Agilent 6320系列LC-MS的光谱仪来测定，G1329A自动采样器和G1315B DAD检测器应用于分析，ESI源应用于LC-MS光谱仪。Low-resolution mass spectrometry (MS) data were determined by an Agilent 6320 Series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30°C), a G1329A autosampler and a G1315B DAD detector for analysis , ESI source applied to LC-MS spectrometer.
低分辨率质谱(MS)数据还通过配备G1311A四元泵和G1316A TCC(柱温保持在30℃)的Agilent 6120系列LC-MS的光谱仪来测定，G1329A自动采样器和G1315D DAD检测器应用于分析，ESI源应用于LC-MS光谱仪。Low-resolution mass spectrometry (MS) data were also determined by an Agilent 6120 Series LC-MS spectrometer equipped with a G1311A quaternary pump and G1316A TCC (column temperature maintained at 30°C), a G1329A autosampler and a G1315D DAD detector for analysis , ESI source applied to LC-MS spectrometer.
以上两种光谱仪都配备了Agilent Zorbax SB-C18柱，规格为2.1×30mm，5μm。注射体积是通过样品浓度来确定；流速为0.6mL/min；HPLC的峰值是通过在210nm和254nm处的UV-Vis波长来记录读取的。流动相为0.1％的甲酸乙腈溶液(相A)和0.1％的甲酸超纯水溶液(相B)。梯度洗脱条件如表1所示：Both of the above spectrometers were equipped with an Agilent Zorbax SB-C18 column with a size of 2.1×30mm, 5μm. Injection volume was determined by sample concentration; flow rate was 0.6 mL/min; HPLC peaks were read by recording UV-Vis wavelengths at 210 nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (phase A) and 0.1% formic acid in ultrapure water (phase B). The gradient elution conditions are shown in Table 1:
表1：梯度洗脱条件Table 1: Gradient elution conditions
时间(min)time (min) A(CH 3CN，0.1％HCOOH) A( CH3CN , 0.1% HCOOH) B(H 2O，0.1％HCOOH) B( H2O , 0.1% HCOOH)
0-30-3 5-1005-100 95-095-0
3-63-6 100100 00
6-6.16-6.1 100-5100-5 0-950-95
6.1-86.1-8 55 9595
化合物纯度是通过Agilent 1100系列高效液相色谱(HPLC)来评价的，其中UV检测在210nm和254nm处，Zorbax SB-C18柱，规格为2.1×30mm，4μm，10分钟，流速为0.6mL/min，5-95％的(0.1％甲酸乙腈溶液)的(0.1％甲酸水溶液)，柱温保持在40℃。Compound purity was assessed by Agilent 1100 series high performance liquid chromatography (HPLC) with UV detection at 210 nm and 254 nm, Zorbax SB-C18 column, 2.1 x 30 mm, 4 μm, 10 min, flow rate 0.6 mL/min , 5-95% (0.1% formic acid in acetonitrile) in (0.1% formic acid in water), and the column temperature was kept at 40°C.
下面简写词的使用贯穿本发明：The following abbreviations are used throughout this disclosure:
MeOH  甲醇                                         HATU  O-(7-氮杂苯并三唑-1-MeOH Methanol          
MeOH-d 4/CD 3OD  氘代甲醇                            基)-N,N,N′,N′-四甲基脲六氟磷酸酯 MeOH-d 4 /CD 3 OD (deuterated methanol)-N,N,N',N'-tetramethylurea hexafluorophosphate
DCM,CH 2Cl 2  二氯甲烷                               h  小时 DCM, CH2Cl2 dichloromethane h h
CDC1 3  氘代氯仿                                    DIPEA  N,N-二异丙基乙胺 CDC1 3 Deuterated chloroform DIPEA N,N-diisopropylethylamine
TFA  三氟乙酸                                      DMF  N,N-二甲基甲酰胺TFA Trifluoroacetic acid DMF N,N-dimethylformamide
(Boc) 2O  二碳酸二叔丁酯                            THF  四氢呋喃 (Boc) 2 O Di-tert-butyl dicarbonate THF Tetrahydrofuran
NBS  N-溴代琥珀酰亚胺                              DMSO  二甲基亚砜NBS N-bromosuccinimide DMSO Dimethyl sulfoxide
DDQ  2,3-二氯-5,6-二氰基苯琨                       DMSO-d 6  氘代二甲基亚砜 DDQ 2,3-dichloro-5,6-dicyanobenzene DMSO-d 6 -deuterated dimethyl sulfoxide
PE  石油醚                                         t 1/2  半衰期 PE Petroleum ether t 1/2 half-life
EtOAc,EA  乙酸乙酯                                 AUC  药时曲线下面积EtOAc, EA Ethyl acetate
EtOH  乙醇                                         Vss  稳态表观分布容积EtOH Ethanol Vss Steady State Apparent Volume of Distribution
Et 3N,TEA  三乙胺                                   CL,clearance  清除率 Et 3 N,TEA Triethylamine CL,clearance Clearance
mL,ml  毫升                                        F,absolute bioavailability  生物利用度mL,ml Milliliter F,absolute bioavailability
RT,rt  室温                                        Dose  剂量RT,rt Room temperature Dose Dose Dose
Rt  保留时间                                       T max  达峰时间 Rt retention time T max peak time
LDA  二异丙基氨基锂                                C max  最大浓度 LDA lithium diisopropylamide Cmax maximum concentration
CDI  N,N'-羰基二咪唑                               hr *ng/mL  血药浓度*时间 CDI N,N'-carbonyldiimidazole hr * ng/mL plasma concentration * time
1atm  101.325kPa1atm 101.325kPa
合成方法resolve resolution
以下合成方案列出了制备本发明中公开化合物的实验步骤。其中，各环B、R 5a、R 5b、R 5c、R 5d、R 5e、R x、R 1、R 2、R 3和R 4具有如本发明所述的含义。 The following synthetic schemes list experimental procedures for the preparation of compounds disclosed in this invention. Wherein, each ring B, R 5a , R 5b , R 5c , R 5d , R 5e , R x , R 1 , R 2 , R 3 and R 4 has the meaning as described in the present invention.
合成方案1Synthesis Scheme 1
Figure PCTCN2021141926-appb-000022
Figure PCTCN2021141926-appb-000022
式(a-6)所示化合物可以通过合成方案1中所描述的方法制备得到，其中，所述Y为O或S；X为氯或溴。化合物(a-1)(可参考WO2015132276实施例11中化合物M的合成方法得到)与化合物(a-2)在碱性条件下(如，氢化钠等)反应生成化合物(a-3)；然后，化合物(a-3)在合适的条件下(如，三氟乙酸)脱去Boc保护基得到化合物(a-4)或其盐；最后，化合物(a-5)(可参考WO2017156255说明书101页，化合物42的合成方法得到)与化合物(a-4)或其盐在合适的条件下(如在HATU和DIPEA下)发生缩合反应，得到化合物(a-6)。The compound represented by formula (a-6) can be prepared by the method described in Synthesis Scheme 1, wherein, the Y is O or S; X is chlorine or bromine. Compound (a-1) (which can be obtained by referring to the synthesis method of compound M in Example 11 of WO2015132276) reacts with compound (a-2) under basic conditions (eg, sodium hydride, etc.) to form compound (a-3); then , compound (a-3) removes the Boc protecting group under suitable conditions (eg, trifluoroacetic acid) to obtain compound (a-4) or its salt; finally, compound (a-5) (refer to WO2017156255 specification page 101 , compound 42 obtained by the synthesis method) and compound (a-4) or its salt under suitable conditions (such as under HATU and DIPEA) to undergo condensation reaction to obtain compound (a-6).
合成方案2Synthesis Scheme 2
Figure PCTCN2021141926-appb-000023
Figure PCTCN2021141926-appb-000023
式(b-4)所示化合物可以通过合成方案2中所描述的方法制备得到，其中，D为任选地被1、2、3、4、或5个R x所取代的4-7个环原子组成的含N的单环杂环基或6-10个环原子组成的含N的桥双环杂环基；X为氯或溴。化合物(a-5)与化合物(b-1)在合适的条件下(如，如在HATU和DIPEA下)发生缩合反应，生成化合物(b-2)；然后，化合物(b-2)在合适的条件下(如，三氟乙酸)脱去Boc保护基得到化合物(b-3)或其盐；最后，化合物(b-3)或其盐与化合物(a-2)在碱性的条件下(如，碳酸钾等)反应，得到化合物(b-4)。 The compound represented by formula (b-4) can be prepared by the method described in Synthesis Scheme 2, wherein D is 4-7 optionally substituted by 1, 2, 3, 4, or 5 R x N-containing monocyclic heterocyclic group composed of ring atoms or N-containing bridged bicyclic heterocyclic group composed of 6-10 ring atoms; X is chlorine or bromine. Compound (a-5) is subjected to condensation reaction with compound (b-1) under suitable conditions (eg, under HATU and DIPEA) to form compound (b-2); then, compound (b-2) is reacted under suitable conditions (eg, trifluoroacetic acid) to remove the Boc protecting group to obtain compound (b-3) or its salt; finally, compound (b-3) or its salt and compound (a-2) under basic conditions (eg, potassium carbonate, etc.) to react to obtain compound (b-4).
合成方案3Synthesis Scheme 3
Figure PCTCN2021141926-appb-000024
Figure PCTCN2021141926-appb-000024
式(b-4)所示化合物还可以通过合成方案3中所描述的方法制备得到，其中，D为任选被1、2、3、4、或5个R x所取代的4-7个环原子组成的含N的单环杂环基或6-10个环原子组成的含N的桥双环杂环基；X为氯或溴。化合物(a-2)与化合物(b-1)在碱性的条件下(如，碳酸钾等)反应，生成化合物(c-1)；然后，化合物(c-1)在合适的条件下(如，三氟乙酸)脱去Boc保护基得到化合物(c-2)或其盐；最后，化合物(c-2)或其盐与化合物(a-5)在合适的条件下(如，如在HATU和DIPEA下)发生缩合反应，得到化合物(b-4)。 The compound represented by formula (b-4) can also be prepared by the method described in the synthetic scheme 3, wherein, D is 4-7 optionally substituted by 1, 2, 3, 4, or 5 R x N-containing monocyclic heterocyclic group composed of ring atoms or N-containing bridged bicyclic heterocyclic group composed of 6-10 ring atoms; X is chlorine or bromine. Compound (a-2) reacts with compound (b-1) under basic conditions (eg, potassium carbonate, etc.) to generate compound (c-1); then, compound (c-1) is reacted under suitable conditions ( For example, trifluoroacetic acid) removes the Boc protecting group to obtain compound (c-2) or its salt; finally, compound (c-2) or its salt is combined with compound (a-5) under suitable conditions (eg, as in HATU and DIPEA) undergo a condensation reaction to obtain compound (b-4).
具体实施方式Detailed ways
以下实施例用于说明本发明，但不用来限制本发明的范围。The following examples are intended to illustrate the present invention, but not to limit the scope of the present invention.
制备实施例Preparation Examples
在以下制备实施例中，发明人以本发明的部分化合物为例，详细描述了本发明化合物的制备过程。表一、化合物编号及其对应的结构In the following preparation examples, the inventors take some compounds of the present invention as examples to describe the preparation process of the compounds of the present invention in detail. Table 1. Compound numbers and their corresponding structures
Figure PCTCN2021141926-appb-000025
Figure PCTCN2021141926-appb-000025
Figure PCTCN2021141926-appb-000026
Figure PCTCN2021141926-appb-000026
Figure PCTCN2021141926-appb-000027
Figure PCTCN2021141926-appb-000027
Figure PCTCN2021141926-appb-000028
Figure PCTCN2021141926-appb-000028
Figure PCTCN2021141926-appb-000029
Figure PCTCN2021141926-appb-000029
Figure PCTCN2021141926-appb-000030
Figure PCTCN2021141926-appb-000030
Figure PCTCN2021141926-appb-000031
Figure PCTCN2021141926-appb-000031
Figure PCTCN2021141926-appb-000032
Figure PCTCN2021141926-appb-000032
Figure PCTCN2021141926-appb-000033
Figure PCTCN2021141926-appb-000033
Figure PCTCN2021141926-appb-000034
Figure PCTCN2021141926-appb-000034
化合物1的合成Synthesis of Compound 1
Figure PCTCN2021141926-appb-000035
Figure PCTCN2021141926-appb-000035
步骤1：化合物1-1的合成Step 1: Synthesis of Compound 1-1
将化合物F1(1.5g,6.20mmol，参考WO2015132276实施例11中化合物M的合成方法得到)溶于DMF(20mL)中，0℃下将氢化钠(0.4g,10mmol,60mass％)加入体系，反应1h后将1-(溴甲基)-2-氯-4-氟苯(1.7g,7.6mmol)缓慢地加入反应体系，之后室温下搅拌反应6h后，加入水(5mL)淬灭反应，之后加入DCM(10mL)和水(10mL)，弃去水相，有机相依次用水(10mL×2)、饱和食盐水(20mL)洗涤，无水硫酸钠干燥，旋干溶剂，残留物经硅胶柱层析(PE/EA(V/V)＝10/1)纯化，得到白色固体(1.32g,55％)。MS(ESI,pos.ion)m/z:328.2[M-56+H] +。 Compound F1 (1.5 g, 6.20 mmol, obtained with reference to the synthesis method of compound M in Example 11 of WO2015132276) was dissolved in DMF (20 mL), and sodium hydride (0.4 g, 10 mmol, 60 mass%) was added to the system at 0 °C, and the reaction was carried out. After 1 h, 1-(bromomethyl)-2-chloro-4-fluorobenzene (1.7 g, 7.6 mmol) was slowly added to the reaction system, then the reaction was stirred at room temperature for 6 h, water (5 mL) was added to quench the reaction, and then DCM (10 mL) and water (10 mL) were added, the aqueous phase was discarded, the organic phase was washed successively with water (10 mL×2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was spin-dried, and the residue was filtered through a silica gel column layer. Purification by analytical (PE/EA(V/V)=10/1) gave a white solid (1.32 g, 55%). MS (ESI, pos.ion) m/z: 328.2 [M-56+H] + .
步骤2：化合物1-2的合成Step 2: Synthesis of Compounds 1-2
将化合物1-1(650mg,1.69mmol)溶于DCM(5mL)中，之后加入三氟乙酸(3mL)，室温下搅拌反应3h后，减压浓缩，得标题化合物为棕色油状物(673mg,99％)，直接投下一步。Compound 1-1 (650 mg, 1.69 mmol) was dissolved in DCM (5 mL), then trifluoroacetic acid (3 mL) was added, the reaction was stirred at room temperature for 3 h, and then concentrated under reduced pressure to give the title compound as a brown oil (673 mg, 99 %), directly to the next step.
步骤3：化合物1的合成Step 3: Synthesis of Compound 1
将化合物F2(682mg,2.028mmol,参考WO2017156255说明书101页，化合物42的合成方法得到)、DIPEA(0.9mL,5mmol)和HATU(880mg,2.199mmol)溶于DMF(20mL)中，搅拌十分钟后将化合物1-2(673mg,1.69mmol)加入体系，室温下搅拌反应21h后，加入水(20mL)和DCM(20mL)，分离有机层，有机层分别用稀盐酸(1M,20mL×1)、氢氧化钠溶液(1M,20mL×1)和饱和食盐水(20mL×1)洗涤，无水硫酸钠干燥，旋干溶剂，残留物经柱层析(PE/EA(V/V)＝1/2)纯化，得到标题化合物为白色固体(737mg,73％)。MS(ESI,pos.ion)m/z:602.1[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ(ppm)10.46(s,1H),7.86(dd,J＝13.0,7.5Hz,1H),7.50–7.33(m,4H),7.27–7.19(m,1H),4.49–4.29(m,3H),3.85–3.63(m,2H),3.60(d,J＝3.6Hz,3H),3.46–3.38(m,1H),3.17–3.07(m,1H),3.06–3.00(m,1H),2.95–2.85(m,2H),2.83–2.70(m,1H),2.46(s,3H),2.25(d,J＝2.1Hz,3H). Compound F2 (682 mg, 2.028 mmol, refer to page 101 of the WO2017156255 specification, obtained by the synthesis method of compound 42), DIPEA (0.9 mL, 5 mmol) and HATU (880 mg, 2.199 mmol) were dissolved in DMF (20 mL) and stirred for ten minutes. Compound 1-2 (673 mg, 1.69 mmol) was added to the system, and after stirring the reaction at room temperature for 21 h, water (20 mL) and DCM (20 mL) were added, and the organic layer was separated. Sodium hydroxide solution (1M, 20mL×1) and saturated brine (20mL×1) were washed, dried over anhydrous sodium sulfate, the solvent was spin-dried, and the residue was subjected to column chromatography (PE/EA(V/V)=1/ 2) Purification to give the title compound as a white solid (737 mg, 73%). MS (ESI, pos.ion) m/z: 602.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm) 10.46 (s, 1H), 7.86 (dd, J=13.0, 7.5Hz, 1H), 7.50–7.33 (m, 4H), 7.27–7.19 (m, 1H), 4.49–4.29 (m, 3H), 3.85–3.63 (m, 2H), 3.60 (d, J=3.6Hz ,3H),3.46–3.38(m,1H),3.17–3.07(m,1H),3.06–3.00(m,1H),2.95–2.85(m,2H),2.83–2.70(m,1H),2.46 (s,3H),2.25(d,J=2.1Hz,3H).
化合物2的合成Synthesis of Compound 2
将2-(氯甲基)-3,4-二甲氧基吡啶替换1-(溴甲基)-2-氯-4-氟苯，参考化合物1的合成方法，制备得到目标产物为白色固体(384mg,51％)。MS(ESI,pos.ion)m/z:611.2[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ(ppm)10.49(s,1H),8.53(t,J＝7.2Hz,1H),7.92–7.82(m,1H),7.56(t,J＝5.5Hz,1H),7.49–7.33(m,2H),4.57(d,J＝10.6Hz,2H),4.41(dd,J＝40.6,11.8Hz,1H),4.10(d,J＝3.6Hz,3H),3.87(d,J＝6.9Hz,3H),3.83–3.65(m,2H),3.60(s,3H),3.55–3.37(m,2H),3.20–3.3.02(m,2H),2.95–2.69(m,2H),2.46(s,3H),2.25(s,3H). Substitute 2-(chloromethyl)-3,4-dimethoxypyridine for 1-(bromomethyl)-2-chloro-4-fluorobenzene, refer to the synthetic method of compound 1, and prepare the target product as a white solid (384 mg, 51%). MS (ESI, pos.ion) m/z: 611.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm) 10.49 (s, 1H), 8.53 (t, J=7.2 Hz ,1H),7.92–7.82(m,1H),7.56(t,J=5.5Hz,1H),7.49–7.33(m,2H),4.57(d,J=10.6Hz,2H),4.41(dd, J=40.6, 11.8Hz, 1H), 4.10(d, J=3.6Hz, 3H), 3.87(d, J=6.9Hz, 3H), 3.83–3.65(m, 2H), 3.60(s, 3H), 3.55–3.37 (m, 2H), 3.20–3.3.02 (m, 2H), 2.95–2.69 (m, 2H), 2.46 (s, 3H), 2.25 (s, 3H).
化合物3的合成Synthesis of Compound 3
将2-(氯甲基)-3-甲基-4-(2,2,2-三氟乙氧基)吡啶替换1-(溴甲基)-2-氯-4-氟苯，制备参考化合物1的合成方法，得到目标产物为白色固体(358mg,44％)。MS(ESI,pos.ion)m/z:663.2[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ(ppm)10.50(s,1H),8.71(s,1H),7.87(s,1H),7.58(s,1H),7.43(s,2H),5.16(s,2H),4.62(d,J＝9.3Hz,2H),4.41(dd,J＝38.9,10.4Hz,1H),3.96–3.64(m,2H),3.60(s,3H),3.55–3.35(m,2H),3.20–3.05(m,1H),3.02–2.75(m,3H),2.46(s,3H),2.25(s,6H). Substituting 2-(chloromethyl)-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine for 1-(bromomethyl)-2-chloro-4-fluorobenzene, prepared reference The synthetic method of compound 1 gave the target product as a white solid (358 mg, 44%). MS (ESI, pos.ion) m/z: 663.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm) 10.50 (s, 1H), 8.71 (s, 1H), 7.87 (s,1H),7.58(s,1H),7.43(s,2H),5.16(s,2H),4.62(d,J=9.3Hz,2H),4.41(dd,J=38.9,10.4Hz, 1H), 3.96–3.64 (m, 2H), 3.60 (s, 3H), 3.55–3.35 (m, 2H), 3.20–3.05 (m, 1H), 3.02–2.75 (m, 3H), 2.46 (s, 3H), 2.25(s, 6H).
化合物4的合成Synthesis of compound 4
将2-(氯甲基)-4-(3-甲氧基丙氧基)-3-甲基吡啶替换1-(溴甲基)-2-氯-4-氟苯，制备参考化合物1的合成方法，制备得到目标产物为白色固体(356mg,44％)。MS(ESI,pos.ion)m/z:653.3[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ(ppm)10.50(s,1H),8.74–8.58(m,1H),7.97–7.80(m,1H),7.60–7.53(m,1H),7.46–7.38(m,2H),4.62(d,J＝10.8Hz,2H),4.50–4.33(m,3H),3.88–3.65(m,2H),3.60(s,3H),3.51(s,3H),3.45–3.35(m,1H),3.26(s,3H),3.20–3.06(m,2H),3.02–2.72(m,2H),2.46(s,3H),2.30–2.17(m,6H),2.06(s,2H) Substitute 2-(chloromethyl)-4-(3-methoxypropoxy)-3-methylpyridine for 1-(bromomethyl)-2-chloro-4-fluorobenzene to prepare reference compound 1 Synthetic method, the target product was prepared as a white solid (356 mg, 44%). MS (ESI, pos.ion) m/z: 653.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm) 10.50 (s, 1H), 8.74–8.58 (m, 1H) ,7.97–7.80(m,1H),7.60–7.53(m,1H),7.46–7.38(m,2H),4.62(d,J=10.8Hz,2H),4.50–4.33(m,3H),3.88 –3.65(m, 2H), 3.60(s, 3H), 3.51(s, 3H), 3.45 – 3.35(m, 1H), 3.26(s, 3H), 3.20 – 3.06(m, 2H), 3.02 – 2.72 (m, 2H), 2.46(s, 3H), 2.30–2.17(m, 6H), 2.06(s, 2H)
化合物5的合成Synthesis of compound 5
Figure PCTCN2021141926-appb-000036
Figure PCTCN2021141926-appb-000036
将化合物F3(即(R)-6-(溴甲基)-4-(2-氯-4-氟苯基)-2-(噻唑-2-基)-1,4-二氢嘧啶-5-甲酸甲酯，参考WO2015078391A1实施例11化合物W2的合成方法得到)替换1-(溴甲基)-2-氯-4-氟苯，参考化合物1的合成方法，制备得到目标产物为黄色固体(351mg,66％)。MS(ESI,pos.ion)m/z:823.2[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ(ppm)10.46(d,J＝4.8Hz,1H),9.62(s,0.5H),9.05(d,J＝17.8Hz,0.5H),8.03–7.97(m,1H),7.95–7.81(m,2H),7.43(s,4H),7.25–7.13(m,1H),6.07–5.90(m,1H),4.70–4.59(m,1H),4.55–4.30(m,2H),3.90–3.68(m,3H),3.60(d,J＝6.4Hz,3H),3.55(d,J＝8.0Hz,3H),3.50–3.42(m,1H),3.28–3.07(m,2H),3.02–2.87(m,1H),2.85–2.72(m,1H),2.45(d,J＝5.6Hz,3H),2.30–2.17(m,3H). Compound F3 (ie (R)-6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5 - methyl formate, obtained with reference to the synthetic method of WO2015078391A1 embodiment 11 compound W2) to replace 1-(bromomethyl)-2-chloro-4-fluorobenzene, with reference to the synthetic method of compound 1, the prepared target product is a yellow solid ( 351 mg, 66%). MS (ESI, pos.ion) m/z: 823.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm) 10.46 (d, J=4.8 Hz, 1 H), 9.62 (s ,0.5H),9.05(d,J＝17.8Hz,0.5H),8.03-7.97(m,1H),7.95-7.81(m,2H),7.43(s,4H),7.25-7.13(m,1H) ), 6.07–5.90 (m, 1H), 4.70–4.59 (m, 1H), 4.55–4.30 (m, 2H), 3.90–3.68 (m, 3H), 3.60 (d, J=6.4Hz, 3H), 3.55(d,J=8.0Hz,3H),3.50-3.42(m,1H),3.28-3.07(m,2H),3.02-2.87(m,1H),2.85-2.72(m,1H),2.45( d, J=5.6Hz, 3H), 2.30–2.17(m, 3H).
化合物6的合成Synthesis of compound 6
Figure PCTCN2021141926-appb-000037
Figure PCTCN2021141926-appb-000037
将化合物F4(其合成方法为：将(R)-哌嗪-2-甲酸二盐酸盐替换(S)-哌嗪-2-甲酸二盐酸盐，参考F1的合成方法得到)和化合物F3分别替换化合物F1和1-(溴甲基)-2-氯-4-氟苯，参考化合物1的合成方法，制备得到目标产物为黄色固体(350mg,71％,)。MS(ESI,pos.ion)m/z:823.0[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)9.69(d,J＝7.6Hz,1H),8.11(d,J＝17.3Hz,1H),7.85(d,J＝3.0Hz,1H),7.78–7.73(m,1H),7.46(dd,J＝2.9,1.5Hz,1H),7.28–7.23(m,2H),7.21–7.12(m,2H),6.95–6.88(m,1H),6.21(d,J＝2.2Hz,1H),4.44(dd,J＝17.7,6.4Hz,1H),4.18–4.10(m,1H),3.95(d,J＝17.6Hz,1H),3.71(d,J＝2.2Hz,3H),3.62(d,J＝2.4Hz,3H),3.56(d,J＝8.3Hz,2H),3.51–3.43(m,2H),3.02–2.86(m,1H),2.82(s,2H),2.70–2.60(m,1H),2.51(d,J＝1.6Hz,3H),2.42(d,J＝2.1Hz,3H). Compound F4 (its synthesis method is: replace (S)-piperazine-2-carboxylic acid dihydrochloride with (R)-piperazine-2-carboxylic acid dihydrochloride, obtained with reference to the synthesis method of F1) and compound F3 Substituting compound F1 and 1-(bromomethyl)-2-chloro-4-fluorobenzene respectively, referring to the synthesis method of compound 1, the target product was prepared as a yellow solid (350 mg, 71%, ). MS (ESI, pos.ion) m/z: 823.0 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 9.69 (d, J=7.6 Hz, 1 H), 8.11 (d, J =17.3Hz,1H),7.85(d,J=3.0Hz,1H),7.78-7.73(m,1H),7.46(dd,J=2.9,1.5Hz,1H),7.28-7.23(m,2H) , 7.21–7.12 (m, 2H), 6.95–6.88 (m, 1H), 6.21 (d, J=2.2Hz, 1H), 4.44 (dd, J=17.7, 6.4Hz, 1H), 4.18–4.10 (m ,1H),3.95(d,J＝17.6Hz,1H),3.71(d,J＝2.2Hz,3H),3.62(d,J＝2.4Hz,3H),3.56(d,J＝8.3Hz,2H ), 3.51–3.43 (m, 2H), 3.02–2.86 (m, 1H), 2.82 (s, 2H), 2.70–2.60 (m, 1H), 2.51 (d, J=1.6Hz, 3H), 2.42 ( d, J=2.1Hz, 3H).
化合物7的合成Synthesis of compound 7
Figure PCTCN2021141926-appb-000038
Figure PCTCN2021141926-appb-000038
将化合物F5(其为参考WO2015144093A1实施例39步骤1至步骤2的合成方法得到)替换1-(溴甲基)-2-氯-4-氟苯，参考化合物1的合成方法，制备得到目标产物为黄色固体(220mg,53％)。MS(ESI,pos.ion)m/z:823.1[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)8.98(d,J＝15.4Hz,1H),7.86(d,J＝3.0Hz,1H),7.76–7.68(m,1H),7.65–7.42(m,2H),7.39–7.33(m,1H),7.20–7.14(m,2H),7.02–6.88(m,1H),6.20–6.08(m,1H),4.85–4.55(m,3H),4.15–3.80(m,3H),3.72(d,J＝4.5Hz,3H),3.66–3.60(m,3H),3.30–3.10(m,3H),2.94–2.74(m,2H),2.51(d,J＝3.1Hz,3H),2.44–2.39(m,3H). Compound F5 (which is obtained by referring to the synthesis method of Step 1 to Step 2 in Example 39 of WO2015144093A1) is replaced with 1-(bromomethyl)-2-chloro-4-fluorobenzene, and the target product is prepared by referring to the synthesis method of Compound 1 as a yellow solid (220 mg, 53%). MS (ESI, pos.ion) m/z: 823.1 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.98 (d, J=15.4 Hz, 1 H), 7.86 (d, J = 3.0Hz, 1H), 7.76–7.68 (m, 1H), 7.65–7.42 (m, 2H), 7.39–7.33 (m, 1H), 7.20–7.14 (m, 2H), 7.02–6.88 (m, 1H) ), 6.20–6.08 (m, 1H), 4.85–4.55 (m, 3H), 4.15–3.80 (m, 3H), 3.72 (d, J=4.5Hz, 3H), 3.66–3.60 (m, 3H), 3.30–3.10 (m, 3H), 2.94–2.74 (m, 2H), 2.51 (d, J=3.1Hz, 3H), 2.44–2.39 (m, 3H).
化合物8的合成Synthesis of Compound 8
步骤1：F6的合成Step 1: Synthesis of F6
Figure PCTCN2021141926-appb-000039
Figure PCTCN2021141926-appb-000039
于反应瓶中依次加入化合物F1(10g,41.4mmol)和无水甲苯(200mL)，氮气保护下加入五硫化二磷(4.61g,20.7mmol)，升温至115℃反应，保温反应6h，降温至室温，加入水(100mL)和二氯甲烷(200mL)，萃取分层，有机层浓缩，浓缩残留物经硅胶柱层析分离(PE/EA(V/V)＝1/1)纯化，得白色固体(3.12g,29.2％)。MS(ESI,pos.ion)m/z:258.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)6.58(s,1H),4.37(d,J＝10.8Hz,1H),4.32–4.00(m,2H),3.96–3.84(m,1H),3.73(t,J＝9.5Hz,1H),3.28–3.18(m,1H),3.07–2.94(m,1H),2.84(s,1H),2.71(s,1H),1.47(s,9H)。 Compound F1 (10 g, 41.4 mmol) and anhydrous toluene (200 mL) were sequentially added to the reaction flask, phosphorus pentasulfide (4.61 g, 20.7 mmol) was added under nitrogen protection, the temperature was raised to 115 ° C for reaction, the reaction was incubated for 6 h, cooled to room temperature, and added Water (100 mL) and dichloromethane (200 mL) were extracted and separated, the organic layer was concentrated, and the concentrated residue was separated and purified by silica gel column chromatography (PE/EA(V/V)=1/1) to obtain a white solid (3.12 g, 29.2%). MS (ESI, pos.ion) m/z: 258.2 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 6.58 (s, 1H), 4.37 (d, J=10.8 Hz, 1H ), 4.32–4.00 (m, 2H), 3.96–3.84 (m, 1H), 3.73 (t, J=9.5Hz, 1H), 3.28–3.18 (m, 1H), 3.07–2.94 (m, 1H), 2.84(s, 1H), 2.71(s, 1H), 1.47(s, 9H).
步骤2：化合物8的合成Step 2: Synthesis of Compound 8
将化合物F6替换化合物F1，参考化合物1的合成方法，制备得到目标产物为白色固体(40mg,16％)。MS(ESI,pos.ion)m/z:618.1[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)7.76–7.68(m,1H),7.58–7.46(m,2H),7.20–7.13(m,2H),7.04–6.97(m,1H),5.09–4.92(m,2H),4.75–4.58(m,2H),4.05–3.90(m,1H),3.75–3.60(m,2H),3.71(d,J＝6.2Hz,3H),3.30–3.18(m,2H),3.11–2.88(m,1H),2.73–2.65(m,1H),2.50(d,J＝6.7Hz,3H),2.41(d,J＝7.9Hz,3H)。 Compound F6 was replaced with compound F1, and the target product was prepared by referring to the synthesis method of compound 1 as a white solid (40 mg, 16%). MS (ESI, pos.ion) m/z: 618.1 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 7.76–7.68 (m, 1H), 7.58–7.46 (m, 2H) ,7.20–7.13(m,2H),7.04–6.97(m,1H),5.09–4.92(m,2H),4.75–4.58(m,2H),4.05–3.90(m,1H),3.75–3.60( m, 2H), 3.71 (d, J=6.2Hz, 3H), 3.30–3.18 (m, 2H), 3.11–2.88 (m, 1H), 2.73–2.65 (m, 1H), 2.50 (d, J= 6.7Hz, 3H), 2.41 (d, J=7.9Hz, 3H).
化合物9的合成Synthesis of compound 9
Figure PCTCN2021141926-appb-000040
Figure PCTCN2021141926-appb-000040
步骤1：化合物9-1的合成Step 1: Synthesis of Compound 9-1
将化合物F2(1.0g,3.0mmol)溶于DMF(10mL)中，之后加入DIPEA(1.6mL,8.7mmol)和HATU(2.4g,6.0mmol)，搅拌两分钟后将哌嗪-1-羧酸叔丁酯(830mg,4.456mmol)加入体系，室温下搅拌反应13h后，加入水(10mL)淬灭反应。之后加入DCM(20mL)，静置分层，水相用DCM(20mL)萃取。合并有机相，有机相用1M稀盐酸洗涤两次(20mL×2)，无水硫酸钠干燥。旋干溶剂，所得残留物经硅胶柱层析(PE/EA(V/V)＝1/1)纯化，得到目标化合物为白色固体(1.13g,75％)。MS(ESI,pos.ion)m/z:449.60[M-56+H] +。 Compound F2 (1.0 g, 3.0 mmol) was dissolved in DMF (10 mL), then DIPEA (1.6 mL, 8.7 mmol) and HATU (2.4 g, 6.0 mmol) were added, and after stirring for two minutes, piperazine-1-carboxylic acid was added. Tert-butyl ester (830 mg, 4.456 mmol) was added to the system, and the reaction was stirred at room temperature for 13 h, and then water (10 mL) was added to quench the reaction. After that, DCM (20 mL) was added, the layers were allowed to stand, and the aqueous phase was extracted with DCM (20 mL). The organic phases were combined, washed twice with 1M dilute hydrochloric acid (20 mL×2), and dried over anhydrous sodium sulfate. The solvent was spun dry, and the obtained residue was purified by silica gel column chromatography (PE/EA(V/V)=1/1) to obtain the title compound as a white solid (1.13 g, 75%). MS (ESI, pos.ion) m/z: 449.60 [M-56+H] + .
步骤2：化合物9-2的合成Step 2: Synthesis of Compound 9-2
将化合物9-1(371mg,0.74mmol)溶于DCM(3mL)中，加入三氟乙酸(5mL)，室温下搅拌反应1h后，旋干溶剂，得产物粗品(381mg,100％)，直接投下一步。Compound 9-1 (371 mg, 0.74 mmol) was dissolved in DCM (3 mL), trifluoroacetic acid (5 mL) was added, the reaction was stirred at room temperature for 1 h, and the solvent was spin-dried to obtain a crude product (381 mg, 100%), which was directly added step.
步骤3：化合物9的合成Step 3: Synthesis of Compound 9
室温下将化合物F3(364mg,0.82mmol)和化合物9-2(381mg,0.74mmol)溶于无水乙醇(4mL)中，之后加入碳酸钾(339mg,2.45mmol)，40℃下搅拌反应4h后，垫硅藻土，过滤出固体。固体用DCM(10mL)洗涤，旋干溶剂，所得残留物经硅胶柱层析(PE/EA(V/V)＝1/2)纯化，得到标题化合物为黄色固体(210mg,37％)。MS(ESI,pos.ion)m/z:768.3[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ(ppm)10.47(s,1H),9.69(s,1H),8.03(d,J＝3.1Hz,1H),7.95(d,J＝3.1Hz,1H),7.87(dd,J＝12.5,7.2Hz,1H),7.48–7.35(m,4H),7.17(td,J＝8.5,2.5Hz,1H),6.05(s,1H),4.08–3.88(m,2H),3.67(s,2H),3.61(s,3H),3.52(s,3H),3.42–3.36(m,2H),2.65(s,2H),2.59(d,J＝6.0Hz,2H),2.48(s,3H),2.28(s,3H). Compound F3 (364 mg, 0.82 mmol) and compound 9-2 (381 mg, 0.74 mmol) were dissolved in absolute ethanol (4 mL) at room temperature, then potassium carbonate (339 mg, 2.45 mmol) was added, and the reaction was stirred at 40 °C for 4 h. , pad with diatomaceous earth, filter out the solid. The solid was washed with DCM (10 mL), the solvent was spin-dried, and the resulting residue was purified by silica gel column chromatography (PE/EA(V/V)=1/2) to give the title compound as a yellow solid (210 mg, 37%). MS (ESI, pos.ion) m/z: 768.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm) 10.47 (s, 1H), 9.69 (s, 1H), 8.03 (d, J=3.1Hz, 1H), 7.95 (d, J=3.1Hz, 1H), 7.87 (dd, J=12.5, 7.2Hz, 1H), 7.48–7.35 (m, 4H), 7.17 (td, J=8.5, 2.5Hz, 1H), 6.05(s, 1H), 4.08–3.88(m, 2H), 3.67(s, 2H), 3.61(s, 3H), 3.52(s, 3H), 3.42–3.36 (m, 2H), 2.65(s, 2H), 2.59(d, J=6.0Hz, 2H), 2.48(s, 3H), 2.28(s, 3H).
化合物10的合成Synthesis of Compound 10
将2-(氯甲基)-4-(3-甲氧基丙氧基)-3-甲基吡啶替换化合物F3，参考化合物9的合成方法，制备得到目标产物为白色固体(284mg,80％)。MS(ESI,pos.ion)m/z:598.2[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ(ppm)10.52(s,1H),8.55(d,J＝6.1Hz,1H),7.87(dd,J＝11.8,7.1Hz,1H),7.51–7.31(m,3H),4.31(t,J＝5.1Hz,2H),4.17(s,3H),3.74(s,3H),3.61(s,3H),3.55–3.43(m,5H),2.86(d,J＝21.9Hz,4H),2.47(s,3H),2.26(s,3H),2.19(s,3H),2.07–1.95(m,2H). Substituting 2-(chloromethyl)-4-(3-methoxypropoxy)-3-methylpyridine for compound F3, referring to the synthetic method of compound 9, the target product was prepared as a white solid (284 mg, 80% ). MS (ESI, pos.ion) m/z: 598.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm) 10.52 (s, 1H), 8.55 (d, J=6.1 Hz ,1H),7.87(dd,J=11.8,7.1Hz,1H),7.51–7.31(m,3H),4.31(t,J=5.1Hz,2H),4.17(s,3H),3.74(s, 3H), 3.61(s, 3H), 3.55–3.43(m, 5H), 2.86(d, J=21.9Hz, 4H), 2.47(s, 3H), 2.26(s, 3H), 2.19(s, 3H) ), 2.07–1.95 (m, 2H).
化合物11的合成Synthesis of Compound 11
将2-(氯甲基)-3-甲基-4-(2,2,2-三氟乙氧基)吡啶替换化合物F3，参考化合物9的合成方法，制备得到目标产物为白色固体(52mg,21％)。MS(ESI,pos.ion)m/z:608.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)8.82(s,1H),8.70(d,J＝4.6Hz,1H),7.79–7.72(m,1H),7.34–7.30(m,1H),7.17–7.10(m,2H),4.62(q,J＝7.5Hz,2H),4.02(s,2H),3.85(s,2H),3.67(s,3H),3.56(s,2H),2.89–2.84(m,2H),2.82–2.76(m,2H),2.51(s,3H),2.34(s,6H). Substitute 2-(chloromethyl)-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine for compound F3 and refer to the synthetic method of compound 9 to obtain the target product as a white solid (52 mg ,twenty one%). MS (ESI, pos.ion) m/z: 608.2 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.82 (s, 1H), 8.70 (d, J=4.6 Hz, 1H ), 7.79–7.72 (m, 1H), 7.34–7.30 (m, 1H), 7.17–7.10 (m, 2H), 4.62 (q, J=7.5Hz, 2H), 4.02 (s, 2H), 3.85 ( s, 2H), 3.67 (s, 3H), 3.56 (s, 2H), 2.89–2.84 (m, 2H), 2.82–2.76 (m, 2H), 2.51 (s, 3H), 2.34 (s, 6H) .
化合物12的合成Synthesis of Compound 12
将(R)-3-甲基哌嗪-1-羧酸叔丁酯替换哌嗪-1-羧酸叔丁酯，参考化合物9的合成方法，制备得到目标产 物为黄色固体(280mg,46％)。MS(ESI,pos.ion)m/z:782.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)8.18(d,J＝19.7Hz,1H),7.90(d,J＝3.0Hz,1H),7.78–7.70(m,1H),7.64–7.60(m,1H),7.26–7.24(m,1H),7.23–7.12(m,2H),7.05–6.95(m,1H),6.19(d,J＝7.8Hz,1H),4.60–4.30(m,4H),4.05–3.97(m,1H),3.70(s,3H),3.63(s,3H),3.59–3.48(m,2H),3.17–2.96(m,2H),2.51(d,J＝4.0Hz,3H),2.40(d,J＝8.7Hz,3H),1.73–1.58(m,3H) Substitute (R)-3-methylpiperazine-1-carboxylate tert-butyl ester for piperazine-1-carboxylate tert-butyl ester, refer to the synthetic method of compound 9, and prepare the target product as a yellow solid (280mg, 46% ). MS (ESI, pos.ion) m/z: 782.2 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.18 (d, J=19.7 Hz, 1 H), 7.90 (d, J = 3.0Hz, 1H), 7.78–7.70 (m, 1H), 7.64–7.60 (m, 1H), 7.26–7.24 (m, 1H), 7.23–7.12 (m, 2H), 7.05–6.95 (m, 1H) ), 6.19(d, J=7.8Hz, 1H), 4.60-4.30(m, 4H), 4.05-3.97(m, 1H), 3.70(s, 3H), 3.63(s, 3H), 3.59-3.48( m, 2H), 3.17–2.96 (m, 2H), 2.51 (d, J=4.0Hz, 3H), 2.40 (d, J=8.7Hz, 3H), 1.73–1.58 (m, 3H)
化合物13的合成Synthesis of Compound 13
将2,5-二氮杂双环[2.2.2]辛烷-2-羧酸叔丁酯替换哌嗪-1-羧酸叔丁酯，参考化合物9的合成方法，制备得到目标产物为黄色固体(670mg,95％)。MS(ESI,pos.ion)m/z:794.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)7.87(d,J＝7.9Hz,1H),7.77–7.58(m,1H),7.49–7.30(m,2H),7.25–7.12(m,2H),7.08–6.81(m,2H),6.16(d,J＝9.7Hz,1H),4.96–4.73(m,2H),4.38–3.74(m,4H),3.72–3.65(m,3H),3.63(s,3H),2.63–2.36(m,6H),2.35–2.05(m,2H),1.35–1.25(m,2H),0.94–0.78(m,2H). Substitute 2,5-diazabicyclo[2.2.2]octane-2-carboxylate tert-butyl ester for piperazine-1-carboxylate tert-butyl ester, refer to the synthetic method of compound 9, and prepare the target product as a yellow solid (670 mg, 95%). MS (ESI, pos.ion) m/z: 794.2 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 7.87 (d, J=7.9 Hz, 1 H), 7.77-7.58 (m , 1H), 7.49–7.30 (m, 2H), 7.25–7.12 (m, 2H), 7.08–6.81 (m, 2H), 6.16 (d, J=9.7Hz, 1H), 4.96–4.73 (m, 2H) ), 4.38–3.74 (m, 4H), 3.72–3.65 (m, 3H), 3.63 (s, 3H), 2.63–2.36 (m, 6H), 2.35–2.05 (m, 2H), 1.35–1.25 (m ,2H),0.94–0.78(m,2H).
化合物14的合成Synthesis of compound 14
将3,8-二氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯替换哌嗪-1-羧酸叔丁酯，参考化合物9的合成方法，制备得到目标产物为黄色固体(670mg,95％)。MS(ESI,pos.ion)m/z:794.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)8.10(d,J＝3.7Hz,1H),7.89(t,J＝3.0Hz,1H),7.79–7.70(m,1H),7.59(t,J＝2.7Hz,1H),7.36–7.30(m,1H),7.27–7.22(m,1H),7.21–7.11(m,1H),7.02-6.94(m,1H),6.22(d,J＝1.8Hz,1H),4.91–4.78(m,1H),4.32(dd,J＝16.5,5.3Hz,1H),4.22–4.07(m,2H),3.70(d,J＝1.5Hz,3H),3.62(s,3H),3.36–2.99(m,4H),2.49(d,J＝1.9Hz,3H),2.47–2.42(m,1H),2.40(s,3H),2.14–2.07(m,1H),1.30–1.25(m,1H),0.90–0.85(m,1H). Substitute 3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester for piperazine-1-carboxylic acid tert-butyl ester, refer to the synthetic method of compound 9, and prepare the target product as a yellow solid (670 mg, 95%). MS (ESI, pos.ion) m/z: 794.2 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.10 (d, J=3.7 Hz, 1 H), 7.89 (t, J =3.0Hz,1H),7.79-7.70(m,1H),7.59(t,J=2.7Hz,1H),7.36-7.30(m,1H),7.27-7.22(m,1H),7.21-7.11( m,1H),7.02-6.94(m,1H),6.22(d,J=1.8Hz,1H),4.91-4.78(m,1H),4.32(dd,J=16.5,5.3Hz,1H),4.22 –4.07(m,2H),3.70(d,J=1.5Hz,3H),3.62(s,3H),3.36–2.99(m,4H),2.49(d,J=1.9Hz,3H),2.47– 2.42(m,1H), 2.40(s,3H), 2.14–2.07(m,1H), 1.30–1.25(m,1H), 0.90–0.85(m,1H).
化合物15的合成Synthesis of compound 15
将化合物F7(其参考WO2015078391中实施例8步骤1至步骤2的合成方法得到)替换化合物F3，参考化合物9的合成方法，制备得到目标产物为黄色固体(570mg,75％)。MS(ESI,pos.ion)m/z:854.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)7.93–7.84(m,2H),7.78–7.71(m,1H),7.55(d,J＝2.9Hz,1H),7.44–7.37(m,1H),7.24–7.19(m,1H),7.15(dd,J＝9.8,7.5Hz,1H),7.03–6.98(m,1H),6.29(s,1H),4.95(q,J＝7.1Hz,1H),4.42(s,2H),4.25–4.17(m,2H),4.14–4.00(m,2H),3.80(s,2H),3.72(d,J＝2.5Hz,3H),3.28–3.10(m,4H),2.52(s,3H),2.42(s,3H),1.32(d,J＝7.1Hz,3H),1.28(t,J＝7.1Hz,3H). Compound F7 (obtained with reference to the synthesis method of Example 8, Step 1 to Step 2 in WO2015078391) was replaced with Compound F3, and the target product was prepared as a yellow solid (570 mg, 75%) with reference to the synthesis method of Compound 9. MS (ESI, pos.ion) m/z: 854.2 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 7.93–7.84 (m, 2H), 7.78–7.71 (m, 1H) ,7.55(d,J=2.9Hz,1H),7.44-7.37(m,1H),7.24-7.19(m,1H),7.15(dd,J=9.8,7.5Hz,1H),7.03-6.98(m ,1H),6.29(s,1H),4.95(q,J＝7.1Hz,1H),4.42(s,2H),4.25–4.17(m,2H),4.14–4.00(m,2H),3.80( s, 2H), 3.72(d, J=2.5Hz, 3H), 3.28–3.10(m, 4H), 2.52(s, 3H), 2.42(s, 3H), 1.32(d, J=7.1Hz, 3H ),1.28(t,J=7.1Hz,3H).
化合物16的合成Synthesis of compound 16
将(1R,4R)-2,5-二氮杂双环[2.2.1]辛烷-2-羧酸叔丁酯替换哌嗪-1-羧酸叔丁酯，参考化合物9的合成方法，制备得到目标产物为黄色固体(150mg,50％)。MS(ESI,pos.ion)m/z:780.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)9.54(d,J＝13.3Hz,1H),8.04(d,J＝10.0Hz,1H),7.85–7.64(m,2H),7.41(dd,J＝14.7,3.1Hz,1H),7.29–7.25(m,1H),7.23–7.11(m,2H),6.98–6.89(m,1H),6.18(d,J＝5.4Hz,1H),5.01–4.36(m,1H),4.26(d,J＝17.4Hz,1H),4.14(d,J＝17.4Hz,1H),3.74–3.66(m,5H),3.58(d,J＝16.9Hz,3H),3.55–3.46(m,1H),3.14–2.97(m,2H),2.51(d,J＝16.6Hz,3H),2.43(d,J＝14.0Hz,3H),2.14(t,J＝9.7Hz,1H),1.95–1.85(m,1H). Substitute (1R,4R)-2,5-diazabicyclo[2.2.1]octane-2-carboxylic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester, and prepare with reference to the synthetic method of compound 9 The desired product was obtained as a yellow solid (150 mg, 50%). MS (ESI, pos.ion) m/z: 780.2 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 9.54 (d, J=13.3 Hz, 1 H), 8.04 (d, J = 10.0Hz, 1H), 7.85–7.64 (m, 2H), 7.41 (dd, J=14.7, 3.1Hz, 1H), 7.29–7.25 (m, 1H), 7.23–7.11 (m, 2H), 6.98– 6.89(m,1H),6.18(d,J=5.4Hz,1H),5.01–4.36(m,1H),4.26(d,J=17.4Hz,1H),4.14(d,J=17.4Hz,1H) ), 3.74–3.66 (m, 5H), 3.58 (d, J=16.9Hz, 3H), 3.55–3.46 (m, 1H), 3.14–2.97 (m, 2H), 2.51 (d, J=16.6Hz, 3H), 2.43(d, J=14.0Hz, 3H), 2.14(t, J=9.7Hz, 1H), 1.95–1.85(m, 1H).
化合物17的合成Synthesis of compound 17
将(1S,4S)-2,5-二氮杂双环[2.2.1]辛烷-2-羧酸叔丁酯替换哌嗪-1-羧酸叔丁酯，参考化合物9的合成方法，制备得到目标产物为黄色固体(230mg,77％)。MS(ESI,pos.ion)m/z:780.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)9.62(d,J＝10.5Hz,1H),8.22(d,J＝16.2Hz,1H),7.84–7.51(m,2H),7.43(dd,J＝15.4,3.1Hz,1H),7.28–7.18(m,2H),7.17–7.09(m,2H),6.95–6.88(m,1H),6.20(d,J＝7.6Hz,1H),4.50–4.31(m,2H),4.00–3.80(m,2H),3.70(s,3H),3.65–3.42(m,5H),3.22–3.10(m,1H),3.03–2.90(m,1H),2.51(d,J＝ 18.3Hz,3H),2.44(d,J＝27.2Hz,3H),2.14–2.05(m,1H),1.87(dd,J＝16.7,10.3Hz,1H). Substitute (1S,4S)-2,5-diazabicyclo[2.2.1]octane-2-carboxylate tert-butyl ester instead of piperazine-1-carboxylate tert-butyl ester, refer to the synthetic method of compound 9 to prepare The desired product was obtained as a yellow solid (230 mg, 77%). MS (ESI, pos.ion) m/z: 780.2 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 9.62 (d, J=10.5 Hz, 1 H), 8.22 (d, J = 16.2Hz, 1H), 7.84–7.51 (m, 2H), 7.43 (dd, J=15.4, 3.1Hz, 1H), 7.28–7.18 (m, 2H), 7.17–7.09 (m, 2H), 6.95– 6.88(m, 1H), 6.20(d, J=7.6Hz, 1H), 4.50-4.31(m, 2H), 4.00-3.80(m, 2H), 3.70(s, 3H), 3.65-3.42(m, 5H), 3.22–3.10 (m, 1H), 3.03–2.90 (m, 1H), 2.51 (d, J=18.3Hz, 3H), 2.44 (d, J=27.2Hz, 3H), 2.14–2.05 (m ,1H),1.87(dd,J=16.7,10.3Hz,1H).
化合物18的合成Synthesis of compound 18
将(S)-2-甲基哌嗪-1-羧酸叔丁酯替换哌嗪-1-羧酸叔丁酯，参考化合物9的合成方法，制备得到目标产物为黄色固体(290mg,59％)。MS(ESI,pos.ion)m/z:782.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)9.72(d,J＝10.0Hz,1H),7.86(t,J＝3.5Hz,1H),7.79–7.71(m,1H),7.67(s,1H),7.49–7.45(m,1H),7.31–7.27(m,1H),7.20–7.13(m,2H),6.95–6.88(m,1H),6.22(d,J＝5.2Hz,1H),4.35–4.26(m,1H),4.15(dd,J＝17.7,7.3Hz,1H),4.02(dd,J＝17.7,3.9Hz,1H),3.73(d,J＝4.8Hz,3H),3.62(d,J＝1.6Hz,3H),3.57–3.47(m,1H),3.45–3.33(m,1H),3.25–3.17(m,1H),3.15–3.08(m,1H),2.93–2.73(m,2H),2.54(d,J＝4.5Hz,3H),2.47(d,J＝3.0Hz,3H),1.28(d,3H). (S)-2-methylpiperazine-1-carboxylate tert-butyl ester was replaced with piperazine-1-carboxylate tert-butyl ester, referring to the synthetic method of compound 9, the target product was prepared as a yellow solid (290mg, 59% ). MS (ESI, pos.ion) m/z: 782.2 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 9.72 (d, J=10.0 Hz, 1 H), 7.86 (t, J = 3.5Hz, 1H), 7.79–7.71 (m, 1H), 7.67 (s, 1H), 7.49–7.45 (m, 1H), 7.31–7.27 (m, 1H), 7.20–7.13 (m, 2H), 6.95–6.88 (m, 1H), 6.22 (d, J=5.2Hz, 1H), 4.35–4.26 (m, 1H), 4.15 (dd, J=17.7, 7.3Hz, 1H), 4.02 (dd, J= 17.7, 3.9Hz, 1H), 3.73 (d, J=4.8Hz, 3H), 3.62 (d, J=1.6Hz, 3H), 3.57–3.47 (m, 1H), 3.45–3.33 (m, 1H), 3.25–3.17 (m, 1H), 3.15–3.08 (m, 1H), 2.93–2.73 (m, 2H), 2.54 (d, J=4.5Hz, 3H), 2.47 (d, J=3.0Hz, 3H) ,1.28(d,3H).
化合物19的合成Synthesis of compound 19
将3,6-二氮杂双环[3.1.1]辛烷-6-羧酸叔丁酯替换哌嗪-1-羧酸叔丁酯，参考化合物9的合成方法，制备得到目标产物为黄色固体(360mg,49％)。MS(ESI,pos.ion)m/z:780.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)9.65(d,J＝5.4Hz,1H),7.95–7.82(m,2H),7.76–7.68(m,1H),7.46(d,J＝3.1Hz,1H),7.28–7.23(m,1H),7.20–7.10(m,2H),6.96–6.86(m,1H),6.18(d,J＝6.5Hz,1H),4.29–4.09(m,1H),4.05–3.94(m,1H),3.92–3.79(m,3H),3.74(d,J＝2.0Hz,3H),3.72–3.60(m,2H),3.50(d,J＝10.4Hz,3H),3.03–2.92(m,1H),2.59(d,J＝3.1Hz,3H),2.52(s,3H),1.78–1.69(m,2H). Substitute 3,6-diazabicyclo[3.1.1]octane-6-carboxylic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester, refer to the synthesis method of compound 9, and prepare the target product as a yellow solid (360 mg, 49%). MS (ESI, pos.ion) m/z: 780.2 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 9.65 (d, J=5.4 Hz, 1 H), 7.95-7.82 (m ,2H),7.76–7.68(m,1H),7.46(d,J=3.1Hz,1H),7.28–7.23(m,1H),7.20–7.10(m,2H),6.96–6.86(m,1H) ), 6.18 (d, J=6.5Hz, 1H), 4.29–4.09 (m, 1H), 4.05–3.94 (m, 1H), 3.92–3.79 (m, 3H), 3.74 (d, J=2.0Hz, 3H), 3.72–3.60 (m, 2H), 3.50 (d, J=10.4Hz, 3H), 3.03–2.92 (m, 1H), 2.59 (d, J=3.1Hz, 3H), 2.52 (s, 3H) ),1.78–1.69(m,2H).
化合物20的合成Synthesis of Compound 20
Figure PCTCN2021141926-appb-000041
Figure PCTCN2021141926-appb-000041
步骤1：化合物20-1的合成Step 1: Synthesis of Compound 20-1
将化合物F3(608mg,1.37mmol)、碳酸钾(755mg,5.46mmol)和(R)-3-甲基哌嗪-1-羧酸叔丁酯(410mg,2.05mmol)溶于DMF(6mL)中，室温下搅拌反应15h后，加入乙酸乙酯(10mL)和水(10mL)，弃去水相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，旋干溶剂，残留物经硅胶柱层析(PE/EA(V/V)＝2/1)纯化，得到目标化合物为黄色固体(600mg,78％)。MS(ESI,pos.ion)m/z：564.2[M+H] +。 Compound F3 (608 mg, 1.37 mmol), potassium carbonate (755 mg, 5.46 mmol) and (R)-tert-butyl 3-methylpiperazine-1-carboxylate (410 mg, 2.05 mmol) were dissolved in DMF (6 mL) , after the reaction was stirred at room temperature for 15 h, ethyl acetate (10 mL) and water (10 mL) were added, the aqueous phase was discarded, the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was spin-dried. Purification by silica gel column chromatography (PE/EA(V/V)=2/1) gave the title compound as a yellow solid (600 mg, 78%). MS (ESI, pos.ion) m/z: 564.2 [M+H] + .
步骤2：化合物20-2的合成Step 2: Synthesis of Compound 20-2
将化合物20-1(600mg,1.06mmol)溶于DCM(14mL)中，之后加入三氟乙酸(7mL)，室温下搅拌反应0.5h后，旋干溶剂，得褐色油状物(615mg,100％)，直接投下一步。Compound 20-1 (600 mg, 1.06 mmol) was dissolved in DCM (14 mL), then trifluoroacetic acid (7 mL) was added, the reaction was stirred at room temperature for 0.5 h, and the solvent was spin-dried to obtain a brown oil (615 mg, 100%) , directly to the next step.
步骤3：化合物20的合成Step 3: Synthesis of Compound 20
将化合物F2(357mg,1.06mmol)、DIPEA(0.7mL,4mmol)和HATU(554mg,1.38mmol)溶于DCM(10mL)中，搅拌十分钟后将化合物20-2(615mg,1.06mmol)加入体系，室温下搅拌反应15h后加入水(20mL)洗涤，有机相再分别用稀盐酸(1M,20mL×2)、氢氧化钠(1M,10mL)和饱和食盐水(10mL)洗涤，然后无水硫酸钠干燥，然后旋干溶剂，所得残留物经硅胶柱层析(PE/EA(V/V)＝1/1)纯化，得到目标化合物为黄色固体(200mg,24％)。MS(ESI,pos.ion)m/z:782.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)8.15 (s,1H),7.93–7.86(m,1H),7.79-7.71(m,1H),7.60(t,J＝3.4Hz,1H),7.36(dd,J＝14.2,7.5Hz,1H),7.27–7.22(m,1H),7.21–7.10(m,2H),7.05–6.98(m,1H),6.18(d,J＝7.7Hz,1H),5.02–4.82(m,1H),4.48–4.35(m,3H),4.01–3.74(m,4H),3.70(d,J＝2.4Hz,3H),3.64(s,3H),3.48–3.35(m,1H),2.51(d,J＝3.4Hz,3H),2.37(s,3H),1.60(dd,J＝34.2,5.5Hz,3H). Compound F2 (357 mg, 1.06 mmol), DIPEA (0.7 mL, 4 mmol) and HATU (554 mg, 1.38 mmol) were dissolved in DCM (10 mL), and after stirring for ten minutes, compound 20-2 (615 mg, 1.06 mmol) was added to the system , the reaction was stirred at room temperature for 15h, and then water (20mL) was added for washing. The organic phase was washed with dilute hydrochloric acid (1M, 20mL×2), sodium hydroxide (1M, 10mL), and saturated brine (10mL), respectively, and then anhydrous sulfuric acid was used. After drying over sodium, the solvent was spin-dried, and the obtained residue was purified by silica gel column chromatography (PE/EA(V/V)=1/1) to obtain the title compound as a yellow solid (200 mg, 24%). MS (ESI, pos.ion) m/z: 782.2 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.15 (s, 1H), 7.93–7.86 (m, 1H), 7.79 -7.71(m,1H),7.60(t,J=3.4Hz,1H),7.36(dd,J=14.2,7.5Hz,1H),7.27-7.22(m,1H),7.21-7.10(m,2H) ), 7.05–6.98 (m, 1H), 6.18 (d, J=7.7Hz, 1H), 5.02–4.82 (m, 1H), 4.48–4.35 (m, 3H), 4.01–3.74 (m, 4H), 3.70(d, J＝2.4Hz, 3H), 3.64(s, 3H), 3.48–3.35(m, 1H), 2.51(d, J＝3.4Hz, 3H), 2.37(s, 3H), 1.60(dd ,J=34.2,5.5Hz,3H).
化合物21的合成Synthesis of Compound 21
将3,8-二氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯替换(R)-3-甲基哌嗪-1-羧酸叔丁酯，参考化合物20的合成方法，制备得到目标产物为黄色固体(105mg,25％)。MS(ESI,pos.ion)m/z:794.3[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)8.39(d,J＝8.4Hz,1H),7.93–7.87(m,1H),7.80–7.72(m,1H),7.60(dd,J＝6.1,3.0Hz,1H),7.47–7.38(m,1H),7.21–7.08(m,2H),7.03(td,J＝8.4,2.3Hz,1H),6.16(s,1H),4.71–4.48(m,3H),4.45–4.33(m,2H),4.22–4.12(m,1H),3.89(d,J＝13.8Hz,1H),3.70(s,3H),3.63(d,J＝2.5Hz,3H),3.59–3.55(m,1H),2.54(d,J＝4.0Hz,3H),2.49–2.40(m,2H),2.37(d,J＝5.7Hz,3H),2.28–2.05(m,2H) Substitute 3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester for (R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester, refer to the synthesis method of compound 20 , the target product was prepared as a yellow solid (105 mg, 25%). MS (ESI, pos.ion) m/z: 794.3 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.39 (d, J=8.4 Hz, 1 H), 7.93-7.87 (m ,1H),7.80–7.72(m,1H),7.60(dd,J=6.1,3.0Hz,1H),7.47–7.38(m,1H),7.21–7.08(m,2H),7.03(td,J = 8.4, 2.3Hz, 1H), 6.16 (s, 1H), 4.71–4.48 (m, 3H), 4.45–4.33 (m, 2H), 4.22–4.12 (m, 1H), 3.89 (d, J=13.8 Hz, 1H), 3.70 (s, 3H), 3.63 (d, J=2.5Hz, 3H), 3.59–3.55 (m, 1H), 2.54 (d, J=4.0Hz, 3H), 2.49–2.40 (m ,2H),2.37(d,J＝5.7Hz,3H),2.28–2.05(m,2H)
化合物22的合成Synthesis of compound 22
将(S)-2-甲基哌嗪-1-羧酸叔丁酯替换(R)-3-甲基哌嗪-1-羧酸叔丁酯，参考化合物20的合成方法，制备得到目标产物为黄色固体(590mg,78％)。MS(ESI,pos.ion)m/z:782.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)9.54(s,1H),7.82(dd,J＝12.1,9.0Hz,2H),7.78–7.71(m,1H),7.46(dd,J＝3.0,1.6Hz,1H),7.23–7.13(m,3H),6.97–6.88(m,1H),6.21(d,J＝1.8Hz,1H),4.85–4.75(m,1H),4.58–4.52(m,1H),4.08(dd,J＝17.1,2.3Hz,1H),3.93–3.83(m,2H),3.72(s,3H),3.60(d,J＝2.5Hz,3H),3.58–3.53(m,1H),3.40–3.29(m,1H),3.07–3.01(m,1H),2.80–2.65(m,1H),2.53(s,3H),2.46(d,J＝6.0Hz,3H),1.54–1.47(m,3H). Substitute (S)-2-methylpiperazine-1-carboxylate tert-butyl ester for (R)-3-methylpiperazine-1-carboxylate tert-butyl ester, refer to the synthetic method of compound 20 to prepare the target product as a yellow solid (590 mg, 78%). MS (ESI, pos.ion) m/z: 782.2 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 9.54 (s, 1H), 7.82 (dd, J=12.1, 9.0 Hz ,2H),7.78–7.71(m,1H),7.46(dd,J=3.0,1.6Hz,1H),7.23–7.13(m,3H),6.97–6.88(m,1H),6.21(d,J = 1.8Hz, 1H), 4.85–4.75 (m, 1H), 4.58–4.52 (m, 1H), 4.08 (dd, J=17.1, 2.3Hz, 1H), 3.93–3.83 (m, 2H), 3.72 ( s, 3H), 3.60 (d, J=2.5Hz, 3H), 3.58–3.53 (m, 1H), 3.40–3.29 (m, 1H), 3.07–3.01 (m, 1H), 2.80–2.65 (m, 1H), 2.53(s, 3H), 2.46(d, J=6.0Hz, 3H), 1.54–1.47(m, 3H).
化合物23的合成Synthesis of compound 23
将将哌嗪-1-羧酸叔丁酯和化合物F5分别替换成(R)-3-甲基哌嗪-1-羧酸叔丁酯和化合物F3，参考化合物20的合成方法，制备得到目标产物为黄色固体(230mg,50％)。MS(ESI,pos.ion)m/z:768.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)9.56(s,1H),8.26(s,1H),7.85(d,J＝3.1Hz,1H),7.79–7.73(m,1H),7.47(d,J＝3.1Hz,1H),7.30–7.25(m,1H),7.18–7.12(m,2H),6.92(td,J＝8.3,2.5Hz,1H),6.21(s,1H),4.12(d,J＝17.2Hz,1H),3.93–3.81(m,3H),3.71(s,3H),3.61(s,3H),3.54(brs,2H),2.69(brs,2H),2.62(brs,2H),2.50(s,3H),2.41(s,3H). Substitute (R)-3-methylpiperazine-1-carboxylate tert-butyl ester and compound F5 with (R)-3-methylpiperazine-1-carboxylate tert-butyl ester and compound F3, respectively, referring to the synthetic method of compound 20 to prepare the target The product was a yellow solid (230 mg, 50%). MS (ESI, pos.ion) m/z: 768.2 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 9.56 (s, 1H), 8.26 (s, 1H), 7.85 (d , J=3.1Hz, 1H), 7.79–7.73 (m, 1H), 7.47 (d, J=3.1Hz, 1H), 7.30–7.25 (m, 1H), 7.18–7.12 (m, 2H), 6.92 ( td, J=8.3, 2.5Hz, 1H), 6.21(s, 1H), 4.12(d, J=17.2Hz, 1H), 3.93–3.81(m, 3H), 3.71(s, 3H), 3.61(s ,3H),3.54(brs,2H),2.69(brs,2H),2.62(brs,2H),2.50(s,3H),2.41(s,3H).
化合物24的合成Synthesis of compound 24
步骤1：化合物F8的合成:Step 1: Synthesis of Compound F8:
Figure PCTCN2021141926-appb-000042
Figure PCTCN2021141926-appb-000042
于干燥反应瓶中依次加入化合物F3(145.9g,328.1mmol)、甲苯(1200mL)和DDQ(82.0g,361.2mmol)，升温至110℃反应，保温搅拌1.5h，降温至室温，反应液依次用10％氢氧化钠水溶液(500mL×2)和饱和食盐水(500mL×2)洗涤，有机层减压浓缩，残留物经硅胶柱层析分离(PE/EA(V/V)＝3/1)纯化，得米黄色固体(80.2g.55.2％)。Compound F3 (145.9 g, 328.1 mmol), toluene (1200 mL) and DDQ (82.0 g, 361.2 mmol) were successively added to a dry reaction flask, the temperature was raised to 110 °C for reaction, kept stirring for 1.5 h, cooled to room temperature, and the reaction solution was successively mixed with Washed with 10% aqueous sodium hydroxide solution (500 mL×2) and saturated brine (500 mL×2), the organic layer was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (PE/EA(V/V)=3/1) Purification gave a beige solid (80.2 g. 55.2%).
步骤2：化合物24的合成Step 2: Synthesis of Compound 24
将哌嗪-1-羧酸叔丁酯和化合物F8分别替换成(R)-3-甲基哌嗪-1-羧酸叔丁酯和化合物F3，制备参考化合物20的合成方法，得到目标产物为褐色固体(330mg,78％)。MS(ESI,pos.ion)m/z:766.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)8.09(d,J＝3.1Hz,1H),8.05(s,1H),7.78–7.71(m,1H),7.61(d,J＝3.1Hz,1H),7.41(dd,J＝8.5,5.9Hz,1H),7.27–7.20(m,2H),7.17–7.10(m,2H),4.03(s,2H),3.68(s,6H),3.64(s,2H),3.32(s,2H),2.61(brs,2H),2.52(s,2H),2.46(s,3H),2.37(s,3H). Substitute (R)-3-methylpiperazine-1-carboxylate tert-butyl ester and compound F8 with (R)-3-methylpiperazine-1-carboxylate tert-butyl ester and compound F3 respectively, and prepare the synthetic method of reference compound 20 to obtain the target product As a brown solid (330 mg, 78%). MS (ESI, pos.ion) m/z: 766.2 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.09 (d, J=3.1 Hz, 1 H), 8.05 (s, 1 H ), 7.78–7.71 (m, 1H), 7.61 (d, J=3.1Hz, 1H), 7.41 (dd, J=8.5, 5.9Hz, 1H), 7.27–7.20 (m, 2H), 7.17–7.10 ( m, 2H), 4.03(s, 2H), 3.68(s, 6H), 3.64(s, 2H), 3.32(s, 2H), 2.61(brs, 2H), 2.52(s, 2H), 2.46(s ,3H),2.37(s,3H).
化合物25的合成Synthesis of compound 25
将3,6-二氮杂双环[3.1.1]辛烷-6-羧酸叔丁酯替换(R)-3-甲基哌嗪-1-羧酸叔丁酯，参考化合物20的合成方法，制备得到目标产物为黄色固体(300mg,44％)。MS(ESI,pos.ion)m/z:780.3[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)9.51(d,J＝7.3Hz,1H),7.80(t,J＝2.8Hz,1H),7.78–7.67(m,2H),7.46(dd,J＝2.9,1.5Hz,1H),7.31–7.28(m,1H),7.22–7.13(m,3H),6.98–6.90(m,1H),6.21(d,J＝2.6Hz,1H),4.73–4.53(m,2H),4.35–4.08(m,2H),3.72(d,J＝1.0Hz,3H),3.61(d,J＝4.6Hz,3H),3.43–3.34(m,2H),3.32–3.21(m,2H),2.79–2.72(m,1H),2.64–2.58(m,1H),2.50(d,J＝3.3Hz,3H),2.47(s,3H). Substitute 3,6-diazabicyclo[3.1.1]octane-6-carboxylate tert-butyl ester for (R)-3-methylpiperazine-1-carboxylate tert-butyl ester, refer to the synthetic method of compound 20 , the target product was prepared as a yellow solid (300 mg, 44%). MS (ESI, pos.ion) m/z: 780.3 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 9.51 (d, J=7.3 Hz, 1 H), 7.80 (t, J = 2.8Hz, 1H), 7.78–7.67 (m, 2H), 7.46 (dd, J=2.9, 1.5Hz, 1H), 7.31–7.28 (m, 1H), 7.22–7.13 (m, 3H), 6.98– 6.90(m,1H),6.21(d,J=2.6Hz,1H),4.73-4.53(m,2H),4.35-4.08(m,2H),3.72(d,J=1.0Hz,3H),3.61 (d, J=4.6Hz, 3H), 3.43–3.34 (m, 2H), 3.32–3.21 (m, 2H), 2.79–2.72 (m, 1H), 2.64–2.58 (m, 1H), 2.50 (d , J=3.3Hz, 3H), 2.47(s, 3H).
化合物26的合成Synthesis of compound 26
将(S)-3-(羟甲基)哌嗪-1-羧酸叔丁酯替换(R)-3-甲基哌嗪-1-羧酸叔丁酯，参考化合物20的合成方法，制备得到目标产物为黄色固体(430mg,90％)。MS(ESI,pos.ion)m/z:798.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)9.67(d,J＝11.1Hz,1H),8.23–8.00(m,1H),7.84(d,J＝3.0Hz,1H),7.79–7.66(m,1H),7.47(d,J＝2.9Hz,1H),7.27–7.22(m,1H),7.19–7.09(m,2H),6.97–6.87(m,1H),6.19(d,J＝7.4Hz,1H),4.45(d,J＝17.6Hz,1H),4.10–3.92(m,2H),3.87–3.72(m,2H),3.70(d,J＝6.4Hz,3H),3.62(d,J＝2.6Hz,3H),3.59–3.44(m,2H),3.23–3.12(m,1H),3.09–3.00(m,1H),2.87–2.77(m,1H),2.65(d,J＝12.7Hz,1H),2.50(d,J＝6.7Hz,3H),2.39(d,J＝4.0Hz,3H). Substitute (S)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester for (R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester, and prepare with reference to the synthetic method of compound 20 The desired product was obtained as a yellow solid (430 mg, 90%). MS (ESI, pos.ion) m/z: 798.2 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 9.67 (d, J=11.1 Hz, 1 H), 8.23-8.00 (m ,1H),7.84(d,J＝3.0Hz,1H),7.79-7.66(m,1H),7.47(d,J＝2.9Hz,1H),7.27-7.22(m,1H),7.19-7.09( m, 2H), 6.97–6.87 (m, 1H), 6.19 (d, J=7.4Hz, 1H), 4.45 (d, J=17.6Hz, 1H), 4.10–3.92 (m, 2H), 3.87–3.72 (m, 2H), 3.70 (d, J=6.4Hz, 3H), 3.62 (d, J=2.6Hz, 3H), 3.59–3.44 (m, 2H), 3.23–3.12 (m, 1H), 3.09– 3.00 (m, 1H), 2.87–2.77 (m, 1H), 2.65 (d, J=12.7Hz, 1H), 2.50 (d, J=6.7Hz, 3H), 2.39 (d, J=4.0Hz, 3H) ).
化合物27的合成Synthesis of compound 27
化合物F9的合成路线：Synthetic route of compound F9:
Figure PCTCN2021141926-appb-000043
Figure PCTCN2021141926-appb-000043
步骤1：化合物F9-1的合成Step 1: Synthesis of Compound F9-1
将化合物F9-0(5.0g,14.3mmol)溶于四氢呋喃(50mL)中，降温至-20℃，向其中缓慢加入氢化钠(1.1g,28mmol,60mass％)，反应5min后向其中加入碘甲烷(1.3mL,21mmol)，加毕，缓慢升至室温继续反应5h。加入水(20mL)淬灭反应，用乙酸乙酯(20mL×3)萃取，合并有机相，合并的有机相用饱和食盐水洗涤(50mL)，无水硫酸钠干燥，减压浓缩，所得残留物经硅胶柱层析分离(PE/EA(V/V)＝3/1)纯化，得目标化合物为无色油状物(2.81g,54％)。MS(ESI,pos.ion)m/z:365.2[M+H] +。 Compound F9-0 (5.0g, 14.3mmol) was dissolved in tetrahydrofuran (50mL), cooled to -20°C, sodium hydride (1.1g, 28mmol, 60mass%) was slowly added to it, and methyl iodide was added to it after the reaction for 5min (1.3 mL, 21 mmol), after the addition was completed, the reaction was slowly raised to room temperature for 5 h. Water (20 mL) was added to quench the reaction, extracted with ethyl acetate (20 mL×3), the organic phases were combined, the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. Purified by silica gel column chromatography (PE/EA(V/V)=3/1), the title compound was obtained as a colorless oil (2.81 g, 54%). MS (ESI, pos.ion) m/z: 365.2 [M+H] + .
步骤2：化合物F9的合成Step 2: Synthesis of Compound F9
于干燥反应瓶中依次加入化合物F9-1(2.51g,6.89mmol)、10％Pd/C(251mg)和甲醇(20mL)中，氢气氛围中于室温下搅拌4h。过滤，滤饼用二氯甲烷(20mL)洗涤，滤液减压浓缩，得目标化合物为白色固体(1.58g,99％)。MS(ESI,pos.ion)m/z:231.2[M+H] +。 Compound F9-1 (2.51 g, 6.89 mmol), 10% Pd/C (251 mg) and methanol (20 mL) were sequentially added to a dry reaction flask, and the mixture was stirred at room temperature for 4 h under a hydrogen atmosphere. After filtration, the filter cake was washed with dichloromethane (20 mL), and the filtrate was concentrated under reduced pressure to obtain the target compound as a white solid (1.58 g, 99%). MS (ESI, pos.ion) m/z: 231.2 [M+H] + .
步骤3：化合物27的合成Step 3: Synthesis of Compound 27
将化合物F9替换(R)-3-甲基哌嗪-1-羧酸叔丁酯，参考化合物20的合成方法，制备得到目标产物为黄 色固体(350mg,72％)。MS(ESI,pos.ion)m/z:812.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)9.54(d,J＝4.7Hz,1H),8.63(s,0.5H),8.37(s,0.5H),7.84(dd,J＝4.1,3.3Hz,1H),7.80–7.71(m,1H),7.47(dd,J＝4.3,3.3Hz,1H),7.37–7.29(m,2H),7.20–7.11(m,2H),6.98–6.88(m,1H),6.18(d,J＝1.2Hz,1H),4.88–4.81(m,0.5H),4.53–4.48(m,0.5H),3.98–3.87(m,3H),3.84–3.78(m,1H),3.69(d,J＝4.5Hz,3H),3.61(s,3H),3.57–3.42(m,1H),3.32–3.19(m,4H),3.17–3.05(m,1H),2.97–2.70(m,1H),2.55–2.50(m,1H),2.49(d,J＝4.2Hz,3H),2.43–2.37(m,4H). Substitute compound F9 for (R)-tert-butyl 3-methylpiperazine-1-carboxylate, and refer to the synthesis method of compound 20 to prepare the target product as a yellow solid (350 mg, 72%). MS (ESI, pos.ion) m/z: 812.2 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 9.54 (d, J=4.7 Hz, 1 H), 8.63 (s, 0.5 H), 8.37 (s, 0.5H), 7.84 (dd, J=4.1, 3.3Hz, 1H), 7.80–7.71 (m, 1H), 7.47 (dd, J=4.3, 3.3Hz, 1H), 7.37– 7.29 (m, 2H), 7.20–7.11 (m, 2H), 6.98–6.88 (m, 1H), 6.18 (d, J=1.2Hz, 1H), 4.88–4.81 (m, 0.5H), 4.53–4.48 (m, 0.5H), 3.98–3.87 (m, 3H), 3.84–3.78 (m, 1H), 3.69 (d, J=4.5Hz, 3H), 3.61 (s, 3H), 3.57–3.42 (m, 1H), 3.32–3.19 (m, 4H), 3.17–3.05 (m, 1H), 2.97–2.70 (m, 1H), 2.55–2.50 (m, 1H), 2.49 (d, J=4.2Hz, 3H) ,2.43–2.37(m,4H).
化合物28的合成Synthesis of Compound 28
将化合物F9替换哌嗪-1-羧酸叔丁酯，参考化合物9的合成方法，制备得到目标产物为黄色固体(320mg,80％)。MS(ESI,pos.ion)m/z:812.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)9.69(d,J＝7.6Hz,1H),8.11(d,J＝17.3Hz,1H),7.87–7.83(m,1H),7.79-7.73(m,1H),7.46(dd,J＝2.9,1.5Hz,1H),7.28–7.22(m,2H),7.21–7.11(m,2H),6.96–6.87(m,1H),6.21(d,J＝2.2Hz,1H),4.44(dd,J＝17.7,6.4Hz,1H),4.15–4.02(m,1H),3.95(d,J＝17.6Hz,1H),3.71(d,J＝2.2Hz,3H),3.62(d,J＝2.4Hz,3H),3.58–3.42(m,5H),3.24(d,J＝31.5Hz,3H),3.02–2.85(m,2H),2.72–2.57(m,1H),2.51(d,J＝1.6Hz,3H),2.42(d,J＝2.1Hz,3H). Compound F9 was replaced with tert-butyl piperazine-1-carboxylate, and the target product was prepared by referring to the synthesis method of compound 9 as a yellow solid (320 mg, 80%). MS (ESI, pos.ion) m/z: 812.2 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 9.69 (d, J=7.6 Hz, 1 H), 8.11 (d, J = 17.3Hz, 1H), 7.87–7.83 (m, 1H), 7.79–7.73 (m, 1H), 7.46 (dd, J=2.9, 1.5Hz, 1H), 7.28–7.22 (m, 2H), 7.21– 7.11 (m, 2H), 6.96–6.87 (m, 1H), 6.21 (d, J=2.2Hz, 1H), 4.44 (dd, J=17.7, 6.4Hz, 1H), 4.15–4.02 (m, 1H) ,3.95(d,J＝17.6Hz,1H),3.71(d,J＝2.2Hz,3H),3.62(d,J＝2.4Hz,3H),3.58–3.42(m,5H),3.24(d, J=31.5Hz, 3H), 3.02–2.85 (m, 2H), 2.72–2.57 (m, 1H), 2.51 (d, J=1.6Hz, 3H), 2.42 (d, J=2.1Hz, 3H).
化合物29的合成Synthesis of compound 29
将(R)-3-(羟甲基)哌嗪-1-羧酸叔丁酯替换(R)-3-甲基哌嗪-1-羧酸叔丁酯，参考化合物20的合成方法，制备得到目标化合物为黄色固体(30mg,7％)。MS(ESI,pos.ion)m/z:798.2[M+H] +。 Substitute (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester for (R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester, and prepare with reference to the synthetic method of compound 20 The title compound was obtained as a yellow solid (30 mg, 7%). MS(ESI, pos.ion) m/z: 798.2 [M+H] + .
化合物30的合成Synthesis of compound 30
将(R)-3-(羟甲基)哌嗪-1-羧酸叔丁酯替换哌嗪-1-羧酸叔丁酯，参考化合物9的合成方法，制备得到目标产物为黄色固体(145mg,16％)。MS(ESI,pos.ion)m/z:798.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)8.93–8.73(m,1H),7.88(d,J＝2.6Hz,1H),7.85–7.73(m,1H),7.65–7.61(m,1H),7.37–7.26(m,2H),7.23–7.17(m,1H),7.13(dd,J＝18.2,9.0Hz,1H),7.05–6.98(m,1H),6.16(s,1H),4.55(d,J＝22.9Hz,2H),4.45–4.35(m,1H),4.30–4.20(m,1H),4.19–4.05(m,2H),3.93–3.74(m,2H),3.67(d,J＝3.1Hz,3H),3.63(d,J＝3.7Hz,3H),3.42–3.34(m,1H),3.31–3.22(m,1H),3.15–3.05(m,1H),2.52(d,J＝13.0Hz,3H),2.38(d,J＝3.9Hz,3H). (R)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl ester was replaced with piperazine-1-carboxylate tert-butyl ester, referring to the synthetic method of compound 9, the target product was prepared as a yellow solid (145mg , 16%). MS (ESI, pos.ion) m/z: 798.2 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.93-8.73 (m, 1 H), 7.88 (d, J=2.6 Hz ,1H),7.85–7.73(m,1H),7.65–7.61(m,1H),7.37–7.26(m,2H),7.23–7.17(m,1H),7.13(dd,J=18.2,9.0Hz ,1H),7.05–6.98(m,1H),6.16(s,1H),4.55(d,J=22.9Hz,2H),4.45–4.35(m,1H),4.30–4.20(m,1H), 4.19–4.05 (m, 2H), 3.93–3.74 (m, 2H), 3.67 (d, J=3.1Hz, 3H), 3.63 (d, J=3.7Hz, 3H), 3.42–3.34 (m, 1H) ,3.31–3.22(m,1H),3.15–3.05(m,1H),2.52(d,J=13.0Hz,3H),2.38(d,J=3.9Hz,3H).
化合物31的合成Synthesis of compound 31
Figure PCTCN2021141926-appb-000044
Figure PCTCN2021141926-appb-000044
步骤1：化合物31-1的合成Step 1: Synthesis of Compound 31-1
将化合物F10(500mg,0.91mmol，参考WO2020135439中实施例1步骤1的合成方法得到)溶于DCM(10mL)中，之后将NBS(169mg,0.95mmol)分批加入体系，40℃下搅拌反应3h后旋干溶剂，得黄色油状物(550mg,95.8％)，直接投下一步。MS(ESI,pos.ion)m/z:530.1[M+H-100] +。 Compound F10 (500 mg, 0.91 mmol, obtained by referring to the synthesis method of Example 1, Step 1 in WO2020135439) was dissolved in DCM (10 mL), then NBS (169 mg, 0.95 mmol) was added to the system in batches, and the reaction was stirred at 40 °C for 3 h After the solvent was spin-dried, a yellow oil (550 mg, 95.8%) was obtained, which was directly used in the next step. MS (ESI, pos.ion) m/z: 530.1 [M+H-100] + .
步骤2：化合物31-2的合成Step 2: Synthesis of Compound 31-2
室温下将化合物31-1(550mg,0.87mmol)、DIPEA(0.6mL,4mmol)和化合物9-2(450mg,0.87mmol)溶于DCM(6mL)中，室温下搅拌反应15h后,加入水(10mL)和乙酸乙酯(15mL)，水相用乙酸乙酯(10mL×2)萃取，合并有机相，饱和食盐水洗涤(30mL)，无水硫酸钠干燥，旋干溶剂，所得残留物经硅胶柱层析(PE/EA(V/V)＝1/1)纯化，得到黄色固体(520mg,62.7％)。MS(ESI,pos.ion)m/z:954.3[M+H] +。 Compound 31-1 (550 mg, 0.87 mmol), DIPEA (0.6 mL, 4 mmol) and compound 9-2 (450 mg, 0.87 mmol) were dissolved in DCM (6 mL) at room temperature, and after the reaction was stirred at room temperature for 15 h, water ( 10 mL) and ethyl acetate (15 mL), the aqueous phase was extracted with ethyl acetate (10 mL×2), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and the solvent was spin-dried. The obtained residue was filtered through silica gel Purification by column chromatography (PE/EA(V/V)=1/1) gave a yellow solid (520 mg, 62.7%). MS (ESI, pos.ion) m/z: 954.3 [M+H] + .
步骤3：化合物31-3的合成Step 3: Synthesis of Compound 31-3
室温下将化合物31-3(520mg,0.55mmol)、氢氧化钠(110mg,2.75mmol)溶于甲醇(6mL)、水(2mL)和THF(4mL)中，之后加热至70℃下搅拌反应10h，然后加入水(10mL)和乙酸乙酯(15mL)，用1M的稀盐酸调节溶液的pH至4～5。水相用乙酸乙酯(10mL×2)萃取，合并有机相，有机相用饱和食盐水洗涤(30mL×1)，无水硫酸钠干燥，旋干溶剂，得到黄色固体(330mg,70.9％)。MS(ESI,pos.ion)m/z:854.1[M+H] +。 Compound 31-3 (520 mg, 0.55 mmol), sodium hydroxide (110 mg, 2.75 mmol) were dissolved in methanol (6 mL), water (2 mL) and THF (4 mL) at room temperature, then heated to 70 °C and stirred for 10 h. , and then water (10 mL) and ethyl acetate (15 mL) were added, and the pH of the solution was adjusted to 4-5 with 1 M dilute hydrochloric acid. The aqueous phase was extracted with ethyl acetate (10 mL×2), the organic phases were combined, the organic phase was washed with saturated brine (30 mL×1), dried over anhydrous sodium sulfate, and the solvent was spin-dried to obtain a yellow solid (330 mg, 70.9%). MS (ESI, pos.ion) m/z: 854.1 [M+H] + .
步骤4：化合物31的合成Step 4: Synthesis of Compound 31
将化合物31-3(330mg,0.39mmol)溶于1,4-二氧六环(3mL)中，之后加入氯化氢1,4-二氧六环溶液(4mL,16mmol,4mol/L)，室温下搅拌反应18h。旋干溶剂，所得残留物经硅胶柱层析分离(DCM/CH 3OH(V/V)＝25/1)纯化，得到黄色固体(53mg,18％)。MS(ESI,pos.ion)m/z:754.1[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)8.39(s,1H),7.88(d,J＝2.7Hz,1H),7.72–7.64(m,1H),7.58(d,J＝2.8Hz, 1H),7.27–7.22(m,2H),7.12(dd,J＝10.6,8.5Hz,2H),6.89–6.80(m,1H),6.11(s,1H),4.58–4.40(m,2H),3.88–3.75(m,2H),3.67(s,3H),3.62–3.40(m,6H),3.20–3.10(m,2H),2.49(s,3H),2.30(s,3H). Compound 31-3 (330 mg, 0.39 mmol) was dissolved in 1,4-dioxane (3 mL), followed by adding hydrogen chloride 1,4-dioxane solution (4 mL, 16 mmol, 4 mol/L), at room temperature The reaction was stirred for 18h. The solvent was spun dry, and the resulting residue was purified by silica gel column chromatography (DCM/CH 3 OH (V/V)=25/1) to give a yellow solid (53 mg, 18%). MS (ESI, pos.ion) m/z: 754.1 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.39 (s, 1H), 7.88 (d, J=2.7 Hz, 1H ), 7.72–7.64 (m, 1H), 7.58 (d, J=2.8Hz, 1H), 7.27–7.22 (m, 2H), 7.12 (dd, J=10.6, 8.5Hz, 2H), 6.89–6.80 ( m, 1H), 6.11 (s, 1H), 4.58–4.40 (m, 2H), 3.88–3.75 (m, 2H), 3.67 (s, 3H), 3.62–3.40 (m, 6H), 3.20–3.10 ( m, 2H), 2.49(s, 3H), 2.30(s, 3H).
化合物32的合成Synthesis of compound 32
Figure PCTCN2021141926-appb-000045
Figure PCTCN2021141926-appb-000045
步骤1：化合物32-1的合成Step 1: Synthesis of Compound 32-1
将化合物F2(500mg,1.49mmol)和HATU(895mg,2.24mmol)溶于DMF(5mL)中，向其中分别加入DIPEA(578mg,4.46mmol)和(S)-1-叔丁基2-甲基哌嗪-1,2-二羧酸酯(363mg,1.49mmol)，室温下搅拌24h。向其中加入水(20mL)淬灭反应，用二氯甲烷(50mL)萃取，有机层用饱和食盐水洗涤(50mL×2)，无水硫酸钠干燥，旋干，所得残留物经硅胶柱层析分离(PE/EA(V/V)＝1/3)纯化，得标题化合物为棕色固体(650mg,78％)。MS(ESI,pos.ion):m/z 507.2[M-56+H] +。 Compound F2 (500 mg, 1.49 mmol) and HATU (895 mg, 2.24 mmol) were dissolved in DMF (5 mL), to which was added DIPEA (578 mg, 4.46 mmol) and (S)-1-tert-butyl 2-methyl, respectively Piperazine-1,2-dicarboxylate (363 mg, 1.49 mmol), stirred at room temperature for 24 h. To this was added water (20 mL) to quench the reaction, extracted with dichloromethane (50 mL), the organic layer was washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, spin-dried, and the obtained residue was subjected to silica gel column chromatography Separation (PE/EA(V/V)=1/3) and purification gave the title compound as a brown solid (650 mg, 78%). MS (ESI, pos.ion): m/z 507.2 [M-56+H] + .
步骤2：化合物32-2的合成Step 2: Synthesis of Compound 32-2
将化合物32-1(600mg,1.07mmol)溶于四氢呋喃(5mL)和水(5mL)混合溶剂中，向其中加入一水合氢氧化锂(90mg,2.15mmol)，室温下搅拌2h。向其中加入水(100mL)，用乙酸乙酯萃取(50mL×2)，水相用1M盐酸调pH至3～4，有大量固体析出，搅拌30min后抽滤，滤饼干燥，得标题化合物为棕色固体(550mg,94％)。MS(ESI,pos.ion):m/z 493.2[M-56+H] +。 Compound 32-1 (600 mg, 1.07 mmol) was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and water (5 mL), lithium hydroxide monohydrate (90 mg, 2.15 mmol) was added thereto, and the mixture was stirred at room temperature for 2 h. Water (100 mL) was added to it, extracted with ethyl acetate (50 mL×2), the pH of the aqueous phase was adjusted to 3-4 with 1M hydrochloric acid, a large amount of solid was precipitated, stirred for 30 min, filtered with suction, and the filter cake was dried to obtain the title compound as Brown solid (550 mg, 94%). MS (ESI, pos.ion): m/z 493.2 [M-56+H] + .
步骤3：化合物32-3的合成Step 3: Synthesis of Compound 32-3
将化合物32-2(200mg,0.36mmol)、HATU(212mg,0.55mmol)和DIPEA(95mg,0.73mmol)溶于DMF(5mL)中，然后向其中加入氯化铵(39mg,0.73mmol)，室温下搅拌12h，再向其中加入水(20mL)淬灭反应，加入乙酸乙酯(80mL)，有机层分别用1M稀盐酸(50mL)、饱和食盐水(50mL×2)洗涤，无 水硫酸钠干燥，旋干，所得残留物经硅胶柱层析分离(DCM/MeOH(V/V)＝20/1)纯化，得标题化合物为棕色固体(150mg,75％)。MS(ESI,pos.ion):m/z 492.2[M-56+H] +。 Compound 32-2 (200 mg, 0.36 mmol), HATU (212 mg, 0.55 mmol) and DIPEA (95 mg, 0.73 mmol) were dissolved in DMF (5 mL), to which was added ammonium chloride (39 mg, 0.73 mmol), room temperature The mixture was stirred for 12 h, water (20 mL) was added to quench the reaction, ethyl acetate (80 mL) was added, and the organic layer was washed with 1M dilute hydrochloric acid (50 mL) and saturated brine (50 mL×2), respectively, and dried over anhydrous sodium sulfate. , spin-dried, and the obtained residue was purified by silica gel column chromatography (DCM/MeOH (V/V)=20/1) to obtain the title compound as a brown solid (150 mg, 75%). MS (ESI, pos.ion): m/z 492.2 [M-56+H] + .
步骤4：化合物32-4的合成Step 4: Synthesis of Compound 32-4
将32-3(200mg,0.37mmol)悬浮于二氯甲烷(2mL)中，向其中缓慢加入三氟乙酸(2mL)，室温下搅拌20min。直接旋干，得标题化合物三氟乙酸盐为棕色油状物(200mg,98％)。32-3 (200 mg, 0.37 mmol) was suspended in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was slowly added thereto, and the mixture was stirred at room temperature for 20 min. Spin dry directly to give the title compound trifluoroacetate as a brown oil (200 mg, 98%).
步骤5：化合物32的合成Step 5: Synthesis of Compound 32
将化合物32-4(200mg,0.36mmol)和DIPEA(140mg,1.08mmol)溶于二氯甲烷(10mL)中，向其中加入化合物F3(175mg,0.39mmol)，室温下搅拌16h，然后减压浓缩，所得残留物经硅胶柱层析(DCM/MeOH(V/V)＝20/1)纯化，得标题化合物为黄色固体(180mg,62％)。MS(ESI,pos.ion):m/z 811.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)9.64–9.49(m,1H),8.58–8.26(m,1H),7.90–7.80(m,1H),7.78–7.70(m,1H),7.60–7.40(m,1H),7.35–7.25(m,1H),7.20–7.10(m,2H),7.03–6.85(m,2H),6.21–6.12(m,1H),6.00–5.83(m,1H),4.39–4.19(m,1H),3.96–3.72(m,1H),3.68(s,3H),3.65–3.52(m,5H),3.48–3.04(m,4H),2.87–2.54(m,1H),2.48(d,J＝3.9Hz,3H),2.37(d,J＝6.3Hz,3H). Compound 32-4 (200 mg, 0.36 mmol) and DIPEA (140 mg, 1.08 mmol) were dissolved in dichloromethane (10 mL), compound F3 (175 mg, 0.39 mmol) was added thereto, stirred at room temperature for 16 h, and then concentrated under reduced pressure , and the obtained residue was purified by silica gel column chromatography (DCM/MeOH (V/V)=20/1) to obtain the title compound as a yellow solid (180 mg, 62%). MS (ESI, pos.ion): m/z 811.2 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 9.64–9.49 (m, 1H), 8.58–8.26 (m, 1H) ,7.90–7.80(m,1H),7.78–7.70(m,1H),7.60–7.40(m,1H),7.35–7.25(m,1H),7.20–7.10(m,2H),7.03–6.85( m, 2H), 6.21–6.12 (m, 1H), 6.00–5.83 (m, 1H), 4.39–4.19 (m, 1H), 3.96–3.72 (m, 1H), 3.68 (s, 3H), 3.65– 3.52 (m, 5H), 3.48–3.04 (m, 4H), 2.87–2.54 (m, 1H), 2.48 (d, J=3.9Hz, 3H), 2.37 (d, J=6.3Hz, 3H).
化合物33的合成Synthesis of compound 33
将化合物32-2替换化合物32-3，参考化合物32中步骤4至步骤5的合成方法，制备得到目标产物为黄色固体(200mg,69％)。MS(ESI,pos.ion)m/z:812.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)9.00–8.71(m,1H),7.92(dd,J＝8.3,2.9Hz,1H),7.79–7.69(m,1H),7.65(t,J＝3.1Hz,1H),7.37–7.29(m,2H),7.19–7.07(m,2H),7.04–6.92(m,1H),6.22(s,1H),4.58(d,J＝16.5Hz,1H),4.38(dd,J＝29.4,16.7Hz,1H),4.27–3.96(m,2H),3.97–3.75(m,2H),3.70–3.51(m,8H),3.11–2.74(m,1H),2.46(d,J＝6.6Hz,3H),2.30(d,J＝5.0Hz,3H). Compound 32-2 was replaced by compound 32-3, and the target product was prepared as a yellow solid (200 mg, 69%) by referring to the synthesis method of step 4 to step 5 in compound 32. MS (ESI, pos.ion) m/z: 812.2 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 9.00-8.71 (m, 1H), 7.92 (dd, J=8.3, 2.9Hz, 1H), 7.79–7.69 (m, 1H), 7.65 (t, J=3.1Hz, 1H), 7.37–7.29 (m, 2H), 7.19–7.07 (m, 2H), 7.04–6.92 (m ,1H),6.22(s,1H),4.58(d,J＝16.5Hz,1H),4.38(dd,J＝29.4,16.7Hz,1H),4.27–3.96(m,2H),3.97–3.75( m, 2H), 3.70–3.51 (m, 8H), 3.11–2.74 (m, 1H), 2.46 (d, J=6.6Hz, 3H), 2.30 (d, J=5.0Hz, 3H).
化合物34的合成Synthesis of compound 34
将(2S,4S)-1-叔丁基2-甲基4-氨基吡咯烷-1,2-二羧酸酯替换哌嗪-1-羧酸叔丁酯，参考化合物9的合成方法，制备得到目标产物为黄色固体(72mg,71％)。MS(ESI,pos.ion)m/z:826.0[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)9.61(s,1H),7.83(d,J＝8.0Hz,1H),7.72(s,1H),7.67–7.57(m,2H),7.32–7.21(m,2H),7.15–7.01(m,3H),6.92–6.84(m,1H),6.14(d,J＝6.7Hz,1H),4.71–4.60(m,1H),4.35(d,J＝17.4Hz,1H),4.12(d,J＝17.4Hz,1H),3.74–3.61(m,4H),3.57(d,J＝4.7Hz,6H),3.18(d,J＝9.5Hz,1H),2.95(dd,J＝9.3,4.1Hz,1H),2.76–2.65(m,1H),2.29(s,3H),2.23(s,3H),2.18–2.08(m,1H). Substitute (2S,4S)-1-tert-butyl 2-methyl 4-aminopyrrolidine-1,2-dicarboxylate for piperazine-1-carboxylate tert-butyl ester, and prepare with reference to the synthetic method of compound 9 The desired product was obtained as a yellow solid (72 mg, 71%). MS (ESI, pos.ion) m/z: 826.0 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 9.61 (s, 1H), 7.83 (d, J=8.0 Hz, 1H ), 7.72(s, 1H), 7.67–7.57(m, 2H), 7.32–7.21(m, 2H), 7.15–7.01(m, 3H), 6.92–6.84(m, 1H), 6.14(d, J = 6.7Hz, 1H), 4.71–4.60 (m, 1H), 4.35 (d, J=17.4Hz, 1H), 4.12 (d, J=17.4Hz, 1H), 3.74–3.61 (m, 4H), 3.57 (d, J=4.7Hz, 6H), 3.18 (d, J=9.5Hz, 1H), 2.95 (dd, J=9.3, 4.1Hz, 1H), 2.76–2.65 (m, 1H), 2.29 (s, 3H), 2.23(s, 3H), 2.18–2.08(m, 1H).
化合物35的合成Synthesis of compound 35
将(2R,4R)-4-((叔丁氧羰基)氨基)吡咯烷-2-羧酸甲酯替换(R)-3-甲基哌嗪-1-羧酸叔丁酯，参考化合物20的合成方法，制备得到目标产物为黄色固体(60mg,59％)。MS(ESI,pos.ion)m/z:826.0[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)9.68(s,1H),7.82(d,J＝8.0Hz,1H),7.69–7.59(m,2H),7.55(s,1H),7.31–7.21(m,2H),7.16–7.03(m,3H),6.94–6.84(m,1H),6.15(d,J＝6.1Hz,1H),4.72–4.62(m,1H),4.36(d,J＝17.4Hz,1H),4.13(d,J＝17.5Hz,1H),3.78–3.64(m,4H),3.59(s,6H),3.19(d,J＝9.7Hz,1H),3.02–2.90(m,1H),2.78–2.66(m,1H),2.31(s,3H),2.25(s,3H),2.17–2.10(m,1H). Substitute (2R,4R)-4-((tert-butoxycarbonyl)amino)pyrrolidine-2-carboxylate methyl ester for (R)-3-methylpiperazine-1-carboxylate tert-butyl ester, reference compound 20 , the target product was prepared as a yellow solid (60 mg, 59%). MS (ESI, pos.ion) m/z: 826.0 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 9.68 (s, 1H), 7.82 (d, J=8.0 Hz, 1H ), 7.69–7.59(m, 2H), 7.55(s, 1H), 7.31–7.21(m, 2H), 7.16–7.03(m, 3H), 6.94–6.84(m, 1H), 6.15(d, J = 6.1Hz, 1H), 4.72–4.62 (m, 1H), 4.36 (d, J=17.4Hz, 1H), 4.13 (d, J=17.5Hz, 1H), 3.78–3.64 (m, 4H), 3.59 (s, 6H), 3.19 (d, J=9.7Hz, 1H), 3.02–2.90 (m, 1H), 2.78–2.66 (m, 1H), 2.31 (s, 3H), 2.25 (s, 3H), 2.17–2.10(m,1H).
化合物36的合成Synthesis of compound 36
于干燥反应瓶中依次加入化合物34(0.2g,0.24mmol)和四氢呋喃(5mL)，搅拌均匀后加入氢氧化锂一水合物(20mg,0.48mmol)的水(1mL)溶液，室温搅拌12h，然后向反应液中加入水(10mL)和乙酸乙酯(20mL)，萃取分层，有机层用饱和食盐水洗涤(20mL×2)，无水硫酸钠干燥，过滤，滤液浓缩，残留物经硅胶柱层析分离(DCM/CH 3OH(V/V)＝10/1)纯化，得到目标产物为黄色固体(120mg,61％)。MS(ESI,pos.ion)m/z:812.1[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)9.01(s,1H),7.91–7.61(m,3H),7.35– 7.20(m,2H),7.19–6.95(m,3H),6.11(d,J＝33.5Hz,1H),4.63(s,2H),3.91(d,J＝14.5Hz,1H),3.82–3.41(m,7H),3.27–3.09(m,1H),2.82–2.59(m,1H),2.36(s,3H),2.31–2.14(m,5H). Compound 34 (0.2 g, 0.24 mmol) and tetrahydrofuran (5 mL) were added to a dry reaction flask in sequence, stirred evenly, and a solution of lithium hydroxide monohydrate (20 mg, 0.48 mmol) in water (1 mL) was added, stirred at room temperature for 12 h, and then Water (10 mL) and ethyl acetate (20 mL) were added to the reaction solution, and the layers were extracted. The organic layer was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was filtered through a silica gel column. Purification by chromatography (DCM/CH3OH (V/V) = 10/1) gave the desired product as a yellow solid (120 mg, 61%). MS (ESI, pos.ion) m/z: 812.1 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 9.01 (s, 1H), 7.91–7.61 (m, 3H), 7.35 – 7.20 (m, 2H), 7.19–6.95 (m, 3H), 6.11 (d, J=33.5Hz, 1H), 4.63 (s, 2H), 3.91 (d, J=14.5Hz, 1H), 3.82– 3.41 (m, 7H), 3.27–3.09 (m, 1H), 2.82–2.59 (m, 1H), 2.36 (s, 3H), 2.31–2.14 (m, 5H).
化合物37合成Compound 37 Synthesis
将化合物35替换化合物34，参考化合物36合成方法，制备得到目标产物为黄色固体(120mg,68％)。MS(ESI,pos.ion)m/z:812.1[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)8.99(s,1H),7.95–7.64(m,3H),7.35–7.23(m,2H),7.15–6.95(m,3H),6.15(s,1H),4.63(s,2H),3.91(d,J＝13.2Hz,1H),3.81–3.56(m,6H),3.54–3.41(m,1H),3.25–3.10(m,1H),2.66(s,1H),2.45–2.31(m,4H),2.29–2.19(m,4H). Substitute compound 35 for compound 34, and refer to the synthesis method of compound 36 to obtain the target product as a yellow solid (120 mg, 68%). MS (ESI, pos.ion) m/z: 812.1 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.99 (s, 1H), 7.95–7.64 (m, 3H), 7.35 –7.23(m, 2H), 7.15 – 6.95(m, 3H), 6.15(s, 1H), 4.63(s, 2H), 3.91(d, J=13.2Hz, 1H), 3.81 – 3.56(m, 6H) ), 3.54–3.41 (m, 1H), 3.25–3.10 (m, 1H), 2.66 (s, 1H), 2.45–2.31 (m, 4H), 2.29–2.19 (m, 4H).
化合物38的合成Synthesis of compound 38
化合物F11的合成路线：Synthetic route of compound F11:
Figure PCTCN2021141926-appb-000046
Figure PCTCN2021141926-appb-000046
步骤1：化合物F11-1的合成Step 1: Synthesis of Compound F11-1
将化合物F11-0(1.35g,4.28mmol)和三乙胺(866mg,8.56mmol)溶于二氯甲烷(15mL)中，冰水浴下向其中加入甲基磺酰氯(588mg,5.13mmol)，加毕，室温下搅拌15h，然后减压浓缩，所得残留物经硅胶柱层析(PE/EA(V/V)＝1/1)纯化，得标题化合物为白色固体(1.21g,72％)。MS(ESI,pos.ion):m/z 416.1[M+Na] +。 Compound F11-0 (1.35 g, 4.28 mmol) and triethylamine (866 mg, 8.56 mmol) were dissolved in dichloromethane (15 mL), to which was added methanesulfonyl chloride (588 mg, 5.13 mmol) under an ice-water bath, followed by After completion, the mixture was stirred at room temperature for 15 h, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (PE/EA(V/V)=1/1) to obtain the title compound as a white solid (1.21 g, 72%). MS(ESI, pos.ion): m/z 416.1[M+Na] + .
步骤2：化合物F11-2的合成Step 2: Synthesis of Compound F11-2
将化合物F11-1(1.21g,3.07mmol)溶于二氯甲烷(10mL)，向其中加入三氟乙酸(10mL)，室温下搅拌20h，减压浓缩，得标题化合物的三氟乙酸盐为棕色油状物(1.18g,91.1％)。MS(ESI,pos.ion):m/z 194.1[M+H] + Compound F11-1 (1.21 g, 3.07 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (10 mL) was added to it, stirred at room temperature for 20 h, and concentrated under reduced pressure to obtain the trifluoroacetic acid salt of the title compound as Brown oil (1.18 g, 91.1%). MS(ESI,pos.ion): m/z 194.1[M+H] +
步骤3：化合物F11的合成Step 3: Synthesis of Compound F11
将化合物F11-2(1.10g,2.61mmol)溶于二氯甲烷(10mL)中，向其中加入三乙胺(1.32g,13.0mmol)，冰水浴下向其中缓慢加入(Boc) 2O(513mg,2.35mmol)，加毕，继续在该温度下反应14h，旋干，所得残留物经硅胶柱层析(DCM/MeOH(V/V)＝10/1)，得标题化合物为白色固体(630mg,82％)。MS(ESI,pos.ion):m/z 294.2[M+H] +。 Compound F11-2 (1.10 g, 2.61 mmol) was dissolved in dichloromethane (10 mL), triethylamine (1.32 g, 13.0 mmol) was added thereto, and (Boc) 2 O (513 mg) was slowly added thereto under an ice-water bath. , 2.35 mmol), after the addition was completed, the reaction was continued at this temperature for 14 h, and the resulting residue was subjected to silica gel column chromatography (DCM/MeOH (V/V)=10/1) to obtain the title compound as a white solid (630 mg , 82%). MS (ESI, pos.ion): m/z 294.2 [M+H] + .
步骤4：化合物38的合成Step 4: Synthesis of Compound 38
将化合物F11替换(R)-3-甲基哌嗪-1-羧酸叔丁酯，参考化合物20的合成方法，得到目标产物为黄色固体(130mg,50％)。MS(ESI,pos.ion)m/z:875.0[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)9.52(d,J＝63.3Hz,1H),8.60(d,J＝32.8Hz,1H),7.93–7.85(m,1H),7.76–7.63(m,1H),7.52–7.40(m,1H),7.33–7.24(m,2H),7.21–7.09(m,2H),7.00–6.88(m,2H),6.20–6.17(m,1H),4.98–4.42(m,1H),4.19–3.93(m,2H),3.88–3.79(m,1H),3.69–3.64(m,4H),3.60(d,J＝4.2Hz,3H),3.55–3.43(m,1H),3.12–3.02(m,1H),2.98–2.87(m,1H),2.84–2.65(m,2H),2.65–2.61(m,2H),2.58–2.47(m,4H),2.45–2.35(m,4H). Compound F11 was replaced with (R)-tert-butyl 3-methylpiperazine-1-carboxylate, and the synthetic method of compound 20 was referred to to obtain the target product as a yellow solid (130 mg, 50%). MS (ESI, pos.ion) m/z: 875.0 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 9.52 (d, J=63.3 Hz, 1 H), 8.60 (d, J = 32.8Hz, 1H), 7.93–7.85 (m, 1H), 7.76–7.63 (m, 1H), 7.52–7.40 (m, 1H), 7.33–7.24 (m, 2H), 7.21–7.09 (m, 2H) ), 7.00–6.88 (m, 2H), 6.20–6.17 (m, 1H), 4.98–4.42 (m, 1H), 4.19–3.93 (m, 2H), 3.88–3.79 (m, 1H), 3.69–3.64 (m, 4H), 3.60 (d, J=4.2Hz, 3H), 3.55–3.43 (m, 1H), 3.12–3.02 (m, 1H), 2.98–2.87 (m, 1H), 2.84–2.65 (m ,2H),2.65–2.61(m,2H),2.58–2.47(m,4H),2.45–2.35(m,4H).
化合物39的合成Synthesis of compound 39
Figure PCTCN2021141926-appb-000047
Figure PCTCN2021141926-appb-000047
将化合物F11替换哌嗪-1-羧酸叔丁酯，参考化合物9的合成方法，制备得到目标产物为黄色固体(120mg,51％)。MS(ESI,pos.ion)m/z:875.0[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)9.50(d,J＝6.6Hz,1H),8.62(d,J＝22.7Hz,1H),7.83(d,J＝2.7Hz,1H),7.75–7.66(m,1H),7.45(t,J＝3.4Hz,1H),7.31–7.23(m,2H),7.16–7.07(m,2H),6.97–6.85(m,1H),6.16(d,J＝8.9Hz,1H),5.97–5.51(m,1H),4.51–4.41(m,1H),4.22–3.97(m,2H),3.70–3.63(m,4H),3.59(s,3H),3.56–3.45(m,2H),3.37–3.29(m,2H),3.07–2.99(m,1H),2.97–2.88(m,4H),2.62–2.52(m,1H),2.46(d,J＝5.7Hz,3H),2.32(d,J＝5.7Hz,3H). Compound F11 was replaced with tert-butyl piperazine-1-carboxylate, and the target product was prepared by referring to the synthesis method of compound 9 as a yellow solid (120 mg, 51%). MS (ESI, pos.ion) m/z: 875.0 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 9.50 (d, J=6.6 Hz, 1 H), 8.62 (d, J =22.7Hz,1H),7.83(d,J=2.7Hz,1H),7.75-7.66(m,1H),7.45(t,J=3.4Hz,1H),7.31-7.23(m,2H),7.16 –7.07 (m, 2H), 6.97–6.85 (m, 1H), 6.16 (d, J=8.9Hz, 1H), 5.97–5.51 (m, 1H), 4.51–4.41 (m, 1H), 4.22–3.97 (m, 2H), 3.70–3.63 (m, 4H), 3.59 (s, 3H), 3.56–3.45 (m, 2H), 3.37–3.29 (m, 2H), 3.07–2.99 (m, 1H), 2.97 –2.88(m,4H),2.62–2.52(m,1H),2.46(d,J=5.7Hz,3H),2.32(d,J=5.7Hz,3H).
生物学测试biological test
HepAD38细胞评价化合物细胞毒性及抑制HBV DNA复制活性(qPCR法)Evaluation of compound cytotoxicity and inhibition of HBV DNA replication in HepAD38 cells (qPCR method)
HBV细胞株及培养条件HBV cell lines and culture conditions
HepAD38：Ladner等(Ladner,Otto et al.1997)将对四环素敏感的巨细胞病毒CMV启动子连接到PBR322质粒上并于ayw亚型HBV DNA连接成ptetHBV质粒，转染HepG2细胞获得HepAD38细胞株，由于前C区基因受到破坏，HBV DNA产量比HepG2.2.15细胞高约11倍。可利用四环素对HBV复制进行调控，培养所需的时间只有HepG2.2.15细胞的一半，适用于研究HBV复制过程和复制中间型以及抗HBV药物筛选。HepAD38培养于含10％FBS及1％双抗的DMEM/F-12K培养基(另包含终浓度为300ng/ml的Tetracycline以及终浓度为400μg/ml的G418)HepAD38: Ladner et al. (Ladner, Otto et al. 1997) linked the tetracycline-sensitive cytomegalovirus CMV promoter to the PBR322 plasmid and linked the ayw subtype HBV DNA to the ptetHBV plasmid, and transfected HepG2 cells to obtain the HepAD38 cell line. Due to the disruption of the pre-C region gene, the HBV DNA yield was approximately 11-fold higher than that of HepG2.2.15 cells. Tetracycline can be used to regulate HBV replication, and the time required for culturing is only half of that of HepG2.2.15 cells, which is suitable for the study of HBV replication process and replication intermediates and the screening of anti-HBV drugs. HepAD38 was cultured in DMEM/F-12K medium containing 10% FBS and 1% double antibody (also containing Tetracycline at a final concentration of 300 ng/ml and G418 at a final concentration of 400 μg/ml)
HepAD38细胞分泌的病毒粒子DNA可以通过qPCR的方法来定量，并由此检测化合物对病毒复制的影响。The viral particle DNA secreted by HepAD38 cells can be quantified by qPCR, and the effects of compounds on viral replication can be detected.
体外细胞毒性测定In vitro cytotoxicity assay
将HepAD38复苏，待细胞状态良好长满后消化、计数，用含10％FBS及1％双抗的DMEM/F-12K培养基稀释成浓度为1×10 5/mL细胞悬液，以每孔100μL的量接种于96孔板(整块板铺满)，置于37℃、5％CO 2恒温培养箱中孵育24h。24h后，弃去旧培养基，加入200μL新鲜的含2％FBS及1％双抗DMEM/F-12K培养基。 HepAD38 was revived, digested and counted after the cells were in good condition, and diluted with DMEM/F-12K medium containing 10% FBS and 1% double antibody to a concentration of 1×10 5 /mL cell suspension. The amount of 100 μL was inoculated in a 96-well plate (the whole plate was covered), and incubated in a 37° C., 5% CO 2 constant temperature incubator for 24 h. After 24 hours, the old medium was discarded, and 200 μL of fresh DMEM/F-12K medium containing 2% FBS and 1% double antibody was added.
体外细胞毒性实验中化合物配制和细胞处理：用DMSO溶解化合物至20mM，然后进行8个稀释度的4倍稀释，最高浓度为20mM。加系列稀释的化合物1μL每孔到上述细胞板中，实验最高终浓度为100μM(200倍稀释)。Staurosporine(星苞菌素，Selleck,CAS No.62996-74-1)作为阳性对照化合物，最高浓度为1μM。阴性对照孔加入1μL DMSO，终浓度为0.5％.Compound formulation and cell treatment in in vitro cytotoxicity assays: Compounds were dissolved in DMSO to 20 mM, followed by 8 dilutions of 4-fold dilutions, with a maximum concentration of 20 mM. Add 1 μL of serially diluted compounds to each well of the above cell plate, and the highest final concentration in the experiment is 100 μM (200-fold dilution). Staurosporine (staurosporine, Selleck, CAS No. 62996-74-1) was used as a positive control compound at a maximum concentration of 1 μM. Negative control wells were added with 1 μL DMSO at a final concentration of 0.5%.
72h后，弃去旧培养基，加入含有10％CCK8溶液的培养基，孵育20-40min,于酶标仪中检测，得到OD值，导出数据计算抑制率，利用Graphpad Prism 5软件非线性回归模型处理并绘制曲线计算化合物的CC 50。实验结果见表1。 After 72h, discard the old medium, add medium containing 10% CCK8 solution, incubate for 20-40min, detect in the microplate reader, get the OD value, export the data to calculate the inhibition rate, use the nonlinear regression model of Graphpad Prism 5 software Process and plot a curve to calculate the CC50 of the compound. The experimental results are shown in Table 1.
体外抗HBV活性测定In vitro anti-HBV activity assay
将HepAD38复苏待细胞状态良好后，于培养基中加入Tetracycline(终浓度为300ng/ml)以及G418(终浓度为400μg/ml)，Tetracycline存在下病毒不表达，待长满后消化，计数，用含10％FBS的DMEM/F-12K培养基(包含终浓度为300ng/ml的Tetracycline以及终浓度为400μg/ml的G418，1％双抗)稀释成浓度为2×10 5/mL细胞悬液，以每孔100μL的量接种于96孔板(整块板铺满)，置于37℃、5％CO 2恒温培养箱中孵育24h。24h后，弃去旧培养基，加入200μL新鲜的含2％FBS及1％双抗DMEM/F-12K培养基。 After recovering HepAD38 and waiting for the cells to be in good condition, add Tetracycline (final concentration of 300ng/ml) and G418 (final concentration of 400μg/ml) to the culture medium. The virus does not express in the presence of Tetracycline. Digest and count after the cells are grown. DMEM/F-12K medium containing 10% FBS (containing Tetracycline at a final concentration of 300 ng/ml and G418 at a final concentration of 400 μg/ml, 1% double antibody) was diluted to a concentration of 2×10 5 /mL cell suspension , inoculate 100 μL per well in a 96-well plate (the whole plate is covered), and incubate in a 37° C., 5% CO 2 constant temperature incubator for 24 h. After 24 hours, the old medium was discarded, and 200 μL of fresh DMEM/F-12K medium containing 2% FBS and 1% double antibody was added.
抗病毒实验中化合物配制和细胞处理：用DMSO溶解化合物至20mM，进一步用DMSO稀释化合物到800μM，然后进行8个稀释度的4倍稀释，最高浓度为800μM。加系列稀释的化合物1μL每孔到上述细胞板中，实验最高终浓度为4μM(200倍稀释)。TDF(富马酸替诺福韦二吡呋酯,Selleck,Cat S1400)作为阳性对照化合物，最高浓度为4μM。阴性对照孔加入1μL DMSO，终浓度为0.5％.Compound formulation and cell treatment in antiviral experiments: Compounds were dissolved in DMSO to 20 mM, further diluted in DMSO to 800 μM, and then 4-fold dilution was performed in 8 dilutions, with a maximum concentration of 800 μM. Add 1 μL of serially diluted compounds to each well of the above cell plate, and the highest final concentration in the experiment is 4 μM (200-fold dilution). TDF (tenofovir disoproxil fumarate, Selleck, Cat S1400) was used as a positive control compound at a maximum concentration of 4 μM. Negative control wells were added with 1 μL DMSO at a final concentration of 0.5%.
HBV DNA Q-PCRHBV DNA Q-PCR
使用圣湘生物48人份(PCR-荧光探针法)一步法的乙型肝炎病毒核酸定量测定试剂盒进行Q-PCR，吸取2.5μL上清进行Q-PCR，使用前待试剂盒试剂融化后涡旋混匀，离心后将酶混合液放置冰上待用，并保证后续步骤在冰上完成。于Q-PCR板中每孔加入2.5μL样本释放剂，2.5μL测试样本上清(实验组，对照组，标准曲线组)。QPCR反应后得到各孔病毒DNA拷贝数。用Graphpad Prism 5软件处理浓度-病毒拷贝数，通过四参数非线性回归模型计算化合物对病毒复制的EC 50。实验结果见表1。 Use Shengxiang Biological 48 (PCR-fluorescent probe method) one-step hepatitis B virus nucleic acid quantitative determination kit to perform Q-PCR, aspirate 2.5 μL of supernatant for Q-PCR, and wait until the kit reagents are thawed before use. Vortex to mix well. After centrifugation, place the enzyme mixture on ice for later use, and ensure that subsequent steps are completed on ice. 2.5 μL of sample release agent and 2.5 μL of test sample supernatant were added to each well of the Q-PCR plate (experimental group, control group, standard curve group). After the QPCR reaction, the number of viral DNA copies in each well was obtained. Concentration-viral copy number was processed with Graphpad Prism 5 software, and the EC50 of compounds for viral replication was calculated by a four-parameter nonlinear regression model. The experimental results are shown in Table 1.
表1：本发明化合物体外抗HBV活性和细胞毒性实验结果Table 1: In vitro anti-HBV activity and cytotoxicity test results of the compounds of the present invention
化合物compound EC 50(nM) EC50 (nM) CC 50(μM) CC 50 (μM)
11 5555 N/AN/A
22 157157 9898
33 4545 N/AN/A
44 190190 N/AN/A
55 120120 >100>100
66 8484 >100>100
88 131131 N/AN/A
99 2929 >100>100
1010 129129 N/AN/A
1111 8686 N/AN/A
1212 21twenty one >100>100
1313 145145 >100>100
1414 8686 >100>100
1616 4646 >100>100
1717 8181 >100>100
1818 2020 >100>100
1919 2020 >100>100
2020 4848 >100>100
21twenty one 4040 >100>100
22twenty two 8080 >100>100
24twenty four 120120 >100>100
2525 152152 >100>100
2626 2727 N/AN/A
2727 109109 >100>100
2828 5858 >100>100
2929 3434 N/AN/A
3030 8080 >100>100
3232 5555 6262
3434 167167 >100>100
3838 164164 >100>100
注明：N/A表示未测Note: N/A means not tested
结论：实验结果表明，本发明化合物对HBV具有较好的抑制活性，并且本发明化合物对细胞的毒性小。Conclusion: The experimental results show that the compounds of the present invention have good inhibitory activity against HBV, and the compounds of the present invention are less toxic to cells.

Claims (13)

  1. 一种化合物，其为如式(I)所示的化合物或如式(I)所示的化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，A compound, which is a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable compound of the compound represented by formula (I) the accepted salt or its prodrug,
    Figure PCTCN2021141926-appb-100001
    Figure PCTCN2021141926-appb-100001
    其中，各R 5a、R 5b、R 5c、R 5d、R 5e、R 2和R 3独立地为氢、氘、F、Cl、Br、I、CN、SF 5、氨基、硝基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、C 1-4卤代烷基、三氟甲氧基、甲氧基或乙氧基； wherein each of R 5a , R 5b , R 5c , R 5d , R 5e , R 2 and R 3 is independently hydrogen, deuterium, F, Cl, Br, I, CN, SF 5 , amino, nitro, methyl , ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 1-4 haloalkyl, trifluoromethoxy, methoxy or ethoxy;
    环B为C 6-10芳基、5-6个环原子组成的杂芳基、
    Figure PCTCN2021141926-appb-100002
    Figure PCTCN2021141926-appb-100003
    其中，所述的C 6-10芳基和5-6个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个R 6所取代；     Ring B is a C 6-10 aryl group, a heteroaryl group composed of 5-6 ring atoms,
    Figure PCTCN2021141926-appb-100002
    Figure PCTCN2021141926-appb-100003
    Wherein, the C 6-10 aryl group and the heteroaryl group composed of 5-6 ring atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 R 6 ;
    各R 6独立地为氘、F、Cl、Br、I、CN、-OH、-COOH、硝基、氨基、-C(＝O)OC 1-6烷基、-OC 1-6亚烷基-OC 1-6烷基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 2-6烯基、C 2-6炔基或羧基C 1-6烷基，其中，所述的氨基、-C(＝O)OC 1-6烷基、-OC 1-6亚烷基-OC 1-6烷基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 2-6烯基、C 2-6炔基和羧基C 1-6烷基各自独立地未被取代或被1、2、3或4个R w1所取代； Each R is independently deuterium, F, Cl , Br, I, CN, -OH, -COOH, nitro, amino, -C(=O)OC 1-6 alkyl, -OC 1-6 alkylene -OC 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkyne group or carboxyl C 1-6 alkyl group, wherein, the amino group, -C(=O)OC 1-6 alkyl group, -OC 1-6 alkylene group, -OC 1-6 alkyl group, C 1-6 Alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl and carboxy C 1-6 alkyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 R w1 ;
    各R 1a、R 1b、R 1、R 4、R a和R b独立地为氢、氘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基或C 1-4卤代烷基； Each of R 1a , R 1b , R 1 , R 4 , Ra and R b is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl , tert-butyl or C 1-4 haloalkyl;
    各R 2a、R 2b和R 2c独立地为氢、氘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基或C 1-4卤代烷基，其中，所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基和C 1-4卤代烷基各自独立地未被取代或被1、2、3或4个R w2所取代； Each of R 2a , R 2b and R 2c is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or C 1-4 Haloalkyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and C 1-4 haloalkyl groups are each independently unsubstituted or replaced by 1, 2, 3 or 4 R w2 ;
    各R 3a、R 3b、R 3c、R 4a、R 4b和R 4c独立地为C 1-6烷基、C 6-10芳基或5-6个环原子组成的杂芳基，其中，所述的C 6-10芳基和5-6个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个R w3所取代； Each of R 3a , R 3b , R 3c , R 4a , R 4b and R 4c is independently a C 1-6 alkyl group, a C 6-10 aryl group or a heteroaryl group consisting of 5-6 ring atoms, wherein the The C 6-10 aryl group and the heteroaryl group composed of 5-6 ring atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 R w3 ;
    L 1为单键、亚甲基或亚乙基；其中，所述的亚甲基和亚乙基各自独立地未被取代或被1、2或3个R w4所取代； L 1 is a single bond, methylene or ethylene; wherein, the methylene and ethylene are independently unsubstituted or substituted by 1, 2 or 3 R w4 ;
    L 2为单键或-NR b-； L 2 is a single bond or -NR b -;
    各R w1、R w2、R w3、R w4和R w5独立地为氘、F、Cl、Br、CN、-OH、-COOH、硝基、-C(＝O)OC 1-6烷基、氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、羧基C 1-6烷基、C 1-6卤代烷基或C 1-6烷氧基； Each R w1 , R w2 , R w3 , R w4 and R w5 is independently deuterium, F, Cl, Br, CN, -OH, -COOH, nitro, -C(=O)OC 1-6 alkyl, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carboxy C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 alkoxy;
    环A为环己基、5-6个环原子组成的单环杂环基、8-10个环原子组成的稠合双环杂环基或6-10个环原子组成的桥环杂环基，其中，所述的环己基、5-6个环原子组成的单环杂环基、8-10个环原子组成的稠合双环杂环基和6-10个环原子组成的桥双环杂环基各自独立地未被取代或被1、2、3、4、或5个R x所取代； Ring A is a cyclohexyl group, a monocyclic heterocyclic group consisting of 5-6 ring atoms, a fused bicyclic heterocyclic group consisting of 8-10 ring atoms or a bridged ring heterocyclic group consisting of 6-10 ring atoms, wherein , the cyclohexyl group, the monocyclic heterocyclic group composed of 5-6 ring atoms, the fused bicyclic heterocyclic group composed of 8-10 ring atoms and the bridged bicyclic heterocyclic group composed of 6-10 ring atoms are each independently unsubstituted or substituted with 1 , 2, 3, 4, or 5 Rx;
    各R x独立地为氘、＝O、＝S、F、Cl、Br、CN、-OH、-COOH、硝基、-CONH 2、-C(＝O)OC 1-6烷基、-C 1-4亚烷基-N(R a)S(＝O) 2C 1-6烷基、羟基C 1-6烷基、氨基、C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6亚烷基、C 2-6 烯基、C 2-6炔基、羧基C 1-6烷基或C 1-6卤代烷基，其中，所述的-CONH 2、-C(＝O)OC 1-6烷基、-C 1-4亚烷基-N(R a)S(＝O) 2C 1-6烷基、羟基C 1-6烷基、氨基、C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6亚烷基、C 2-6烯基、C 2-6炔基、羧基C 1-6烷基和C 1-6卤代烷基各自独立地未被取代或被1、2、3或4个R w5所取代。 Each R x is independently deuterium, =O, =S, F, Cl, Br, CN, -OH, -COOH, nitro, -CONH 2 , -C(=O)OC 1-6 alkyl, -C 1-4 alkylene-N(R a )S(=O) 2 C 1-6 alkyl, hydroxy C 1-6 alkyl, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkylene, C 2-6 alkenyl, C 2-6 alkynyl, carboxy C 1-6 alkyl or C 1-6 haloalkyl, wherein the- CONH 2 , -C(=O)OC 1-6 alkyl, -C 1-4 alkylene-N(R a )S(=O) 2 C 1-6 alkyl, hydroxy C 1-6 alkyl , amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy, C 1-6 alkylene, C 2-6 alkenyl, C 2-6 alkynyl, carboxyl C 1 -6 alkyl and C 1-6 haloalkyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 R w5 .
  2. 根据权利要求1所述的化合物，其中，所述的环B为苯基、萘基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基、嘧啶基、
    Figure PCTCN2021141926-appb-100004
    其中，所述的苯基、萘基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基各自独立地未被取代或被1、2、3或4个R 6所取代。     The compound according to claim 1, wherein the ring B is phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl,
    Figure PCTCN2021141926-appb-100004
    Wherein, the phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 R6.
  3. 根据权利要求1或2所述的化合物，所述的各R 6独立地为氘、F、Cl、Br、I、CN、-OH、-COOH、硝基、氨基、-C(＝O)OC 1-4烷基、-OC 2-4亚烷基-OC 1-4烷基、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 2-4烯基、C 2-4炔基或羧基C 1-4烷基，其中，所述的氨基、-C(＝O)OC 1-4烷基、-OC 2-4亚烷基-OC 1-4烷基、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 2-4烯基、C 2-4炔基和羧基C 1-4烷基各自独立地未被取代或被1、2、3或4个R w1所取代。 The compound according to claim 1 or 2, wherein each R 6 is independently deuterium, F, Cl, Br, I, CN, -OH, -COOH, nitro, amino, -C(=O)OC 1-4 alkyl, -OC 2-4 alkylene-OC 1-4 alkyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy group, C 2-4 alkenyl group, C 2-4 alkynyl group or carboxy C 1-4 alkyl group, wherein the amino group, -C(=O)OC 1-4 alkyl group, -OC 2-4 alkylene group Alkyl-OC 1-4 alkyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 2-4 alkenyl, C 2- 4Alkynyl and carboxyC1-4alkyl are each independently unsubstituted or substituted with 1 , 2, 3 or 4 R w1 .
  4. 根据权利要求1-3任意一项所述的化合物，其中，所述的各R 6独立地为氘、F、Cl、Br、I、CN、-OH、-COOH、硝基、氨基、-C(＝O)O甲基、-C(＝O)O乙基、-C(＝O)O正丙基、-C(＝O)O异丙基、-OCH 2CH 2CH 2-OCH 3、-OCH 2CH 2CH 2-OCH 2CH 3、-OCH 2CH 2CH 2CH 2-OCH 3、-OCH 2CH 2CH 2CH 2-OCH 2CH 3、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、C 1-4卤代烷基、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-l-丙氧基、2-丁氧基、-OCH 2F、-OCH 2Cl、-OCHF 2、-OCHCl 2、-OCF 3、-OCH 2CH 2F、-OCH 2CH 2Cl、-OCH 2CHF 2、-OCH 2CHCl 2、-OCHFCH 2F、-OCHClCH 2Cl、-OCH 2CF 3、-OCH(CF 3) 2、-OCF 2CH 2CH 3、-OCH 2CH 2CH 2F、-OCH 2CH 2CHF 2、-OCH 2CH 2CF 3、C 2-4烯基、C 2-4炔基或羧基C 1-4烷基，其中，所述的氨基、-C(＝O)O甲基、-C(＝O)O乙基、-C(＝O)O正丙基、-C(＝O)O异丙基、-OCH 2CH 2CH 2-OCH 3、-OCH 2CH 2CH 2-OCH 2CH 3、-OCH 2CH 2CH 2CH 2-OCH 3、-OCH 2CH 2CH 2CH 2-OCH 2CH 3、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、C 1-4卤代烷基、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-l-丙氧基、2-丁氧基、-OCH 2F、-OCH 2Cl、-OCHF 2、-OCHCl 2、-OCH 2CH 2F、-OCH 2CH 2Cl、-OCH 2CHF 2、-OCH 2CHCl 2、-OCHFCH 2F、-OCHClCH 2Cl、-OCH 2CF 3、-OCH(CF 3) 2、-OCF 2CH 2CH 3、-OCH 2CH 2CH 2F、-OCH 2CH 2CHF 2、-OCH 2CH 2CF 3、C 2-4烯基、C 2-4炔基和羧基C 1-4烷基各自独立地未被取代或被1、2、3或4个R w1所取代。 The compound according to any one of claims 1-3, wherein each R is independently deuterium, F, Cl , Br, I, CN, -OH, -COOH, nitro, amino, -C (=O)O methyl, -C(=O)O ethyl, -C(=O)O n-propyl, -C(=O)O isopropyl, -OCH 2 CH 2 CH 2 -OCH 3 , -OCH 2 CH 2 CH 2 -OCH 2 CH 3 , -OCH 2 CH 2 CH 2 CH 2 -OCH 3 , -OCH 2 CH 2 CH 2 CH 2 -OCH 2 CH 3 , methyl, ethyl, n-propyl base, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 1-4 haloalkyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1 -Butoxy, 2 -methyl- l -propoxy, 2 - butoxy, -OCH2F, -OCH2Cl , -OCHF2, -OCHCl2 , -OCF3 , -OCH2CH2F , -OCH 2 CH 2 Cl, -OCH 2 CHF 2 , -OCH 2 CHCl 2 , -OCHFCH 2 F, -OCHClCH 2 Cl, -OCH 2 CF 3 , -OCH(CF 3 ) 2 , -OCF 2 CH 2 CH 3 , -OCH 2 CH 2 CH 2 F, -OCH 2 CH 2 CHF 2 , -OCH 2 CH 2 CF 3 , C 2-4 alkenyl, C 2-4 alkynyl or carboxy C 1-4 alkyl, wherein , the amino, -C(=O)O methyl, -C(=O)O ethyl, -C(=O)O n-propyl, -C(=O)O isopropyl, -OCH 2 CH 2 CH 2 -OCH 3 , -OCH 2 CH 2 CH 2 -OCH 2 CH 3 , -OCH 2 CH 2 CH 2 CH 2 -OCH 3 , -OCH 2 CH 2 CH 2 CH 2 -OCH 2 CH 3 , Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 1-4 haloalkyl, methoxy, ethoxy, 1-propoxy , 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, -OCH 2 F, -OCH 2 Cl, -OCHF 2 , -OCHCl 2 , -OCH 2CH2F , -OCH2CH2Cl , -OCH2CHF2 , -OCH2CHCl2 , -OCHFCH2F , -OCHClCH2Cl , -OCH2CF3 , -OCH ( CF3 ) 2 , -OCF 2 CH 2 CH 3 , -OCH 2 CH 2 CH 2 F, -OCH 2 CH 2 CHF 2 , -OCH 2 CH 2 CF 3 , C 2-4 alkenyl, C 2-4 alkynyl and carboxy C 1-4 alkyl are each independently unsubstituted or 1, 2, 3 or 4 R w1 .
  5. 根据权利要求1-4任意一项所述的化合物，其中，所述的各R 3a、R 3b、R 3c、R 4a、R 4b和R 4c独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、苯基、萘基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中，所述的苯基、萘基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基各自独立地未被取代或被1、2、3或4个R w3所取代。 The compound according to any one of claims 1-4, wherein each of said R 3a , R 3b , R 3c , R 4a , R 4b and R 4c is independently methyl, ethyl, n-propyl, Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl , isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein the phenyl, naphthyl, pyrrole base, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, Pyrazinyl, pyridazinyl and pyrimidinyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 Rw3 .
  6. 根据权利要求1-5任意一项所述的化合物，其中，所述的各R w1、R w2、R w3、R w4和R w5独立地为氘、F、Cl、Br、CN、-OH、-COOH、硝基、-C(＝O)OC 1-4烷基、氨基、甲基、乙基、正丙基、异丙基、正 丁基、异丁基、仲丁基、叔丁基、C 2-4烯基、C 2-4炔基、羧基C 1-4烷基、C 1-4卤代烷基或C 1-4烷氧基。 The compound according to any one of claims 1-5, wherein each of said R w1 , R w2 , R w3 , R w4 and R w5 is independently deuterium, F, Cl, Br, CN, -OH, -COOH, nitro, -C(=O)OC 1-4 alkyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl , C 2-4 alkenyl, C 2-4 alkynyl, carboxy C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 alkoxy.
  7. 根据权利要求1-6任意一项所述的化合物，所述的环A为
    Figure PCTCN2021141926-appb-100005
    Figure PCTCN2021141926-appb-100006
    Figure PCTCN2021141926-appb-100007
    其中所述的式(II-1)、式(II-2)、式(II-3)、式(II-4)、式(II-5)、式(II-6)、式(II-7)、式(II-8)、式(II-9)、式(II-10)、式(II-11)、式(II-12)、式(II-13)和式(II-14)各自独立地未被取代或被1、2、3、4、或5个R x所取代。     The compound according to any one of claims 1-6, wherein the ring A is
    Figure PCTCN2021141926-appb-100005
    Figure PCTCN2021141926-appb-100006
    Figure PCTCN2021141926-appb-100007
    The formula (II-1), formula (II-2), formula (II-3), formula (II-4), formula (II-5), formula (II-6), formula (II- 7), formula (II-8), formula (II-9), formula (II-10), formula (II-11), formula (II-12), formula (II-13) and formula (II-14) ) are each independently unsubstituted or substituted with 1 , 2, 3, 4, or 5 Rx.
  8. 根据权利要求1-7任意一项所述的化合物，所述的各R x独立地为氘、＝O、＝S、F、Cl、Br、CN、-OH、-COOH、硝基、-CONH 2、-C(＝O)OC 1-4烷基、-C 1-3亚烷基-N(R a)S(＝O) 2C 1-4烷基、羟基C 1-4烷基、氨基、C 1-4烷基、C 1-4烷氧基、C 1-4烷氧基C 1-4亚烷基、C 2-4烯基、C 2-4炔基、羧基C 1-4烷基或C 1-4卤代烷基，其中，所述的-CONH 2、-C(＝O)OC 1-4烷基、-C 1-3亚烷基-N(R a)S(＝O) 2C 1-4烷基、羟基C 1-4烷基、氨基、C 1-4烷基、C 1-4烷氧基、C 1-4烷氧基C 1-4亚烷基、C 2-4烯基、C 2-4炔基、羧基C 1-4烷基和C 1-4卤代烷基各自独立地未被取代或被1、2、3或4个R w5所取代。 The compound according to any one of claims 1-7, wherein each R x is independently deuterium, =O, =S, F, Cl, Br, CN, -OH, -COOH, nitro, -CONH 2 , -C(=O)OC 1-4 alkyl, -C 1-3 alkylene-N(R a )S(=O) 2 C 1-4 alkyl, hydroxy C 1-4 alkyl, Amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy, C 1-4 alkylene, C 2-4 alkenyl, C 2-4 alkynyl, carboxyl C 1- 4 alkyl or C 1-4 haloalkyl, wherein the -CONH 2 , -C(=O)OC 1-4 alkyl, -C 1-3 alkylene-N(R a )S(= O) 2 C 1-4 alkyl, hydroxy C 1-4 alkyl, amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy C 1-4 alkylene, C 2-4 alkenyl, C 2-4 alkynyl, carboxy C 1-4 alkyl and C 1-4 haloalkyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 R w5 .
  9. 根据权利要求1-8任意一项所述的化合物，所述的各R x独立地为氘、＝O、＝S、F、Cl、Br、CN、-OH、-COOH、硝基、-CONH 2、-C(＝O)O甲基、-C(＝O)O乙基、-C(＝O)O正丙基、-C(＝O)O异丙基、-亚甲基-N(R a)S(＝O) 2甲基、-亚甲基-N(R a)S(＝O) 2乙基、-亚甲基-N(R a)S(＝O) 2正丙基、-亚甲基-N(R a)S(＝O) 2异丙基、-亚甲基-N(R a)S(＝O) 2正丁基、-亚甲基-N(R a)S(＝O) 2异丁基、-亚乙基-N(R a)S(＝O) 2甲基、-亚乙基-N(R a)S(＝O) 2乙基、-亚乙基-N(R a)S(＝O) 2正丙基、-亚乙基-N(R a)S(＝O) 2异丙基、-亚乙基-N(R a)S(＝O) 2正丁基、-亚乙基-N(R a)S(＝O) 2异丁基、羟基甲基、羟基乙基、羟基正丙基、羟基正丁基、氨基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-l-丙氧基、2-丁氧基、甲氧基甲基、乙氧基甲基、1-丙氧基甲基、2-丙氧基甲基、1-丁氧基甲基、甲氧基甲基、乙氧基乙基、1-丙氧基乙基、2-丙氧基乙基、1-丁氧基乙基、C 2-4烯基、C 2-4炔基、羧基C 1-4烷基或C 1-4卤代烷基，其中，所述的-CONH 2、-C(＝O)O甲基、-C(＝O)O乙基、-C(＝O)O正丙基、-C(＝O)O异丙基、-亚甲基-N(R a)S(＝O) 2甲基、-亚甲基-N(R a)S(＝O) 2乙基、-亚甲基-N(R a)S(＝O) 2正丙基、-亚甲基-N(R a)S(＝O) 2异丙基、-亚甲基-N(R a)S(＝O) 2正丁基、-亚甲基-N(R a)S(＝O) 2异丁基、-亚乙基-N(R a)S(＝O) 2甲基、-亚乙基-N(R a)S(＝O) 2乙基、-亚乙基-N(R a)S(＝O) 2正丙基、-亚乙基-N(R a)S(＝O) 2异丙基、-亚乙基-N(R a)S(＝O) 2正丁基、-亚乙基-N(R a)S(＝O) 2异丁基、羟基甲基、羟基乙基、羟基正丙基、羟基正丁基、氨基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-l-丙氧基、2-丁氧基、甲氧基甲基、乙氧基甲基、1-丙氧基甲基、2-丙氧基甲基、1-丁氧基甲基、甲氧基甲基、乙氧基乙基、1-丙氧基乙基、2-丙氧基乙基、1-丁氧基乙基、C 2-4烯基、C 2-4 炔基、羧基C 1-4烷基和C 1-4卤代烷基各自独立地未被取代或被1、2、3或4个R w5所取代。 The compound according to any one of claims 1-8, wherein each R x is independently deuterium, =O, =S, F, Cl, Br, CN, -OH, -COOH, nitro, -CONH 2 , -C(=O)O methyl, -C(=O)O ethyl, -C(=O)O n-propyl, -C(=O)O isopropyl, -methylene-N (R a )S(=O) 2methyl , -methylene-N(R a )S(=O) 2ethyl, -methylene-N(R a )S(=O) 2 - n-propyl base, -methylene-N(R a )S(=O) 2isopropyl, -methylene-N(R a )S(=O) 2 - n-butyl, -methylene-N(R a ) S(=O) 2 isobutyl, -ethylene-N(R a )S(=O) 2methyl , -ethylene-N(R a )S(=O) 2ethyl , -Ethylene-N(R a )S(=O) 2 -n-propyl, -Ethylene-N(R a )S(=O) 2 -isopropyl, -Ethylene-N(R a ) S(=O) 2 -n-butyl, -ethylene-N(R a )S(=O) 2 -isobutyl, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, hydroxy-n-butyl, amino, Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, methoxymethyl, ethoxymethyl, 1-propoxymethyl, 2-propoxymethyl , 1-butoxymethyl, methoxymethyl, ethoxyethyl, 1-propoxyethyl, 2-propoxyethyl, 1-butoxyethyl, C 2-4 ene group, C 2-4 alkynyl, carboxy C 1-4 alkyl or C 1-4 haloalkyl, wherein the -CONH 2 , -C(=O)O methyl, -C(=O)O Ethyl, -C(=O)O n-propyl, -C(=O)O isopropyl, -methylene-N(R a )S(=O) 2methyl , -methylene-N (R a )S(=O) 2 -ethyl, -methylene-N(R a )S(=O) 2 -n-propyl, -methylene-N(R a )S(=O) 2 -iso Propyl, -methylene-N(R a )S(=O) 2n - butyl, -methylene-N(R a )S(=O) 2isobutyl , -ethylene-N( R a )S(=O) 2methyl , -ethylene-N(R a )S(=O) 2ethyl, -ethylene-N(R a )S(=O) 2 - n-propyl , -Ethylene-N(R a )S(=O) 2isopropyl, -Ethylene-N(R a )S(=O) 2 - n-butyl, -Ethylene-N(R a )S(=O) 2 isobutyl, hydroxymethyl, hydroxyethyl, hydroxyn-propyl, hydroxyn-butyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isopropyl Butyl, sec-butyl, tert-butyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy group, 2-methyl-1-propoxy, 2-butoxy, methoxymethyl, ethoxymethyl, 1-propoxymethyl, 2-propoxymethyl, 1-butanyl Oxymethyl, methoxymethyl, ethoxyethyl, 1-propoxyethyl, 2-propoxyethyl, 1-butoxyethyl, C 2-4 alkenyl, C 2 -4alkynyl , carboxyC 1-4 alkyl and C 1-4 haloalkyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 R w5 .
  10. 根据权利要求1-9任意一项所述的化合物，其包含以下其中之一的结构：The compound according to any one of claims 1-9, comprising the structure of one of the following:
    Figure PCTCN2021141926-appb-100008
    Figure PCTCN2021141926-appb-100008
    Figure PCTCN2021141926-appb-100009
    Figure PCTCN2021141926-appb-100009
    Figure PCTCN2021141926-appb-100010
    Figure PCTCN2021141926-appb-100010
    Figure PCTCN2021141926-appb-100011
    Figure PCTCN2021141926-appb-100011
    Figure PCTCN2021141926-appb-100012
    Figure PCTCN2021141926-appb-100012
    Figure PCTCN2021141926-appb-100013
    Figure PCTCN2021141926-appb-100013
    Figure PCTCN2021141926-appb-100014
    Figure PCTCN2021141926-appb-100014
    Figure PCTCN2021141926-appb-100015
    Figure PCTCN2021141926-appb-100015
    Figure PCTCN2021141926-appb-100016
    Figure PCTCN2021141926-appb-100016
    Figure PCTCN2021141926-appb-100017
    Figure PCTCN2021141926-appb-100018
    或其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药。
    Figure PCTCN2021141926-appb-100017
    Figure PCTCN2021141926-appb-100018
    or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof.
  11. 一种药物组合物，包含权利要求1-10任意一项所述的化合物，及其药学上可接受的辅料。A pharmaceutical composition, comprising the compound of any one of claims 1-10, and pharmaceutically acceptable excipients thereof.
  12. 根据权利要求11所述的药物组合物，其更进一步地包含其它抗HBV药物，其中所述其它抗HBV药物为HBV聚合酶抑制剂、免疫调节剂或干扰素，其中所述其它抗HBV药物为拉米夫定、替比夫定、替诺福韦酯，恩替卡韦、阿德福韦酯、Alfaferone、Alloferon、西莫白介素、克拉夫定、恩曲他滨、法昔洛韦、宝甘灵CP、因特芬、干扰素α-1b、干扰素α、干扰素α-2a、干扰素β-1a、干扰素α-2、白细胞介素-2、米伏替酯、硝唑尼特、聚乙二醇干扰素α-2a、病毒唑、罗扰素-A、西佐喃、Euforavac、安普利近、Phosphazid，Heplisav、干扰素α-2b、左旋咪唑或丙帕锗。The pharmaceutical composition according to claim 11, further comprising other anti-HBV drugs, wherein the other anti-HBV drugs are HBV polymerase inhibitors, immunomodulators or interferons, wherein the other anti-HBV drugs are Lamivudine, Telbivudine, Tenofovir disoproxil, Entecavir, Adefovir dipivoxil, Alfaferone, Alloferon, Simoleukin, Clavudine, Emtricitabine, Faciclovir, Progenin CP , interferon, interferon alpha-1b, interferon alpha, interferon alpha-2a, interferon beta-1a, interferon alpha-2, interleukin-2, mivotiate, nitazoxanide, poly Glycol Interferon alfa-2a, Ribavirin, Rointerferon-A, Sizoran, Euforavac, Ampligen, Phosphazid, Heplisav, Interferon alfa-2b, Levamisole, or Propagium.
  13. 权利要求1-10任意一项所述的化合物或权利要求11-12任意一项所述的药物组合物在制备用于预防、处理、治疗或减轻患者病毒性疾病的药物中的用途，其中所述病毒性疾病是指乙型肝炎病毒感染或乙型肝炎病毒感染引起的疾病，其中所述乙型肝炎病毒感染引起的疾病是指肝硬化或肝细胞癌变。Use of the compound of any one of claims 1-10 or the pharmaceutical composition of any one of claims 11-12 in the preparation of a medicament for preventing, treating, treating or alleviating a viral disease in a patient, wherein the The viral disease refers to hepatitis B virus infection or a disease caused by hepatitis B virus infection, wherein the disease caused by hepatitis B virus infection refers to liver cirrhosis or hepatocellular carcinoma.
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