WO2020143604A1 - 一种二氢异喹啉类化合物 - Google Patents

一种二氢异喹啉类化合物 Download PDF

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WO2020143604A1
WO2020143604A1 PCT/CN2020/070633 CN2020070633W WO2020143604A1 WO 2020143604 A1 WO2020143604 A1 WO 2020143604A1 CN 2020070633 W CN2020070633 W CN 2020070633W WO 2020143604 A1 WO2020143604 A1 WO 2020143604A1
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alkyl
substituted
butyl
methoxy
tert
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PCT/CN2020/070633
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English (en)
French (fr)
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彭程
张绍云
赖小刚
龚超骏
韩健
徐宝林
邹罡
李丹彬
袁海卿
邬征
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苏州爱科百发生物医药技术有限公司
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Priority to KR1020217024571A priority Critical patent/KR20210111807A/ko
Priority to EP20739024.6A priority patent/EP3909951A4/en
Priority to JP2021539952A priority patent/JP2022516985A/ja
Priority to US17/421,411 priority patent/US20220081434A1/en
Publication of WO2020143604A1 publication Critical patent/WO2020143604A1/zh
Priority to JP2023125287A priority patent/JP2023145644A/ja

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    • 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
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/10—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 two hetero rings linked by a carbon chain containing aromatic rings
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
    • C07D455/06—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine containing benzo [a] quinolizine ring systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of medicinal chemistry, and specifically relates to a thiazole ring-substituted dihydroisoquinoline compound, and a mixture or composition containing the dihydroisoquinoline compound, in particular to a method for preventing and treating hepatitis B A dihydroisoquinoline compound substituted with a thiazole ring of a virus infection and a mixture or composition containing the dihydroisoquinoline compound.
  • Hepatitis B virus is one of the most common pathogens in the world. Hepatitis B virus is an infectious disease caused by hepatitis B virus (HBV), spread through blood and body fluids, and mainly caused by liver damage. A serious public health problem, the disease poses a great threat to human health. According to statistics, about one-third of the world's population has been infected with hepatitis B, of which 350 to 500 million people are carriers of chronic hepatitis B virus (HBV). Hepatitis B virus infection not only causes acute hepatitis, it can also cause chronic hepatitis, induce cirrhosis and eventually lead to liver cancer. HBV can infect the human body through a variety of ways, causing the spread of liver disease. Each year, the number of deaths due to acute or chronic hepatitis B infection is approximately 800,000.
  • Hepatitis B virus is a circular double-stranded DNA virus containing part of a single-stranded region, and its genome length is about 3.2 kb, belonging to the family Hepadnavividae.
  • the nucleotide sequence heterogeneity of HBV whole gene is about 8%, and the nucleotide sequence heterogeneity of S gene region is 4.2%.
  • the HBV genotype can be divided into A-H 8 types.
  • the distribution of HBV genotypes has ethnic and geographical differences. Distribution in Asia is mainly B and C genotypes, A and D genotypes are often distributed in Africa, Europe and the Indian Peninsula, E type is distributed in West Africa, F type is distributed in Central and South America, and G genotype is often distributed in France , Germany and North America.
  • the HBV genome contains four open reading frames, encoding core protein, polymerase, membrane protein and protein X.
  • Hepatitis B virus infection depends on the sodium ion-taurocholic acid-co-transporter (NTCP) receptor on the liver cell membrane. After hepatitis B virus infects hepatocytes, part of the double-stranded viral DNA is transported to the nucleus and forms a covalent closure Circular DNA (covalently closed circular DNA, cccDNA), cccDNA is a transcription template for hepatitis B virus pre-genomic RNA (pgRNA) and subgenomic RNA.
  • the core protein contains pgRNA and polymerase together for replication (Lamontagne RJ, et al. Hepatoma Res 2016; 2:163-86.).
  • Hepatitis B virus has a 7nm thick outer membrane protein layer containing phospholipids, called hepatitis B surface antigen (HBsAg).
  • Membrane proteins are divided into three types: large, middle, and small (HBsAg). They are encoded by the S gene of HBV, but the transcription start site is different. The C end of the S area is the same area.
  • the membrane protein is integrated into the endoplasmic reticulum membrane under the guidance of the N-terminal signal sequence. On the one hand, membrane proteins will become important structural proteins of mature hepatitis B virus particles; on the other hand, membrane proteins will form spherical or filamentous subviral particles (SVPs).
  • SVPs subviral particles
  • HBV surface antigen positive for more than 6 months is a sign of chronic HBV infection.
  • subviral particles are not infectious, they have an important effect on the host's immune response.
  • Hepatitis B surface antigen can inhibit the activation of monocytes in the innate immune system (Vanlandschoot P, et al, J Gen Virol. 2002 Jun; 83 (Pt 6): 1281-9), destroying the function of dendritic cells (Marjoleine L) et al , Immunology.
  • the drugs currently approved by the FDA for clinical use include interferon and nucleoside drugs.
  • Interferons include common interferon and pegylated interferon.
  • the nucleoside drugs are lamivudine (Hepuding), adefovir (Heweili), entecavir (Borudine) and telbivudine (Subifu), tenofovir (Viridine).
  • Interferon can control the HBV by regulating the host immune system to activate immune cells and induce the production of multiple antiviral factors. While anti-virus, it can also improve the body's immunity, the effect is more durable, can reduce the incidence of liver cirrhosis and liver cancer.
  • the disadvantage is that the antiviral effect is not strong, accompanied by more side effects, which may cause flu-like symptoms, muscle pain, thrombocytopenia, hair loss, depression and other symptoms.
  • Long-term interferon treatment can only obtain 2.25% of the population of Western countries and 0.43% of hepatitis B surface antigen clearance in the population of Western countries (CM Chun et al, Antivir Ther. 2010; 15(2): 133-43).
  • Nucleoside drugs can inhibit hepatitis B DNA synthesis.
  • Lamivudine was once used as a drug for the treatment of AIDS. After oral administration, it is rapidly absorbed. It can obviously inhibit the replication of HBV and reduce the total load of the virus. Its effect is strong, safe, and has few adverse reactions.
  • WO2018/130152A1 a dihydroisoquinoline compound, which can be used to treat and prevent hepatitis B virus infection.
  • the activity of the compound disclosed in this patent is not very high and needs to be compared Only a large dose can achieve better prevention and treatment of hepatitis B. Therefore, in the field of the prevention and treatment of hepatitis B, there is an urgent need to provide a compound that can achieve higher prevention and treatment of hepatitis B at a lower dose.
  • the purpose of the present invention is to provide a novel thiazole ring-substituted dihydroisoquinoline compound, which has a very strong activity to inhibit hepatitis B surface antigens, and at the same time has a very strong activity to inhibit hepatitis B DNA, and such compounds
  • the bioavailability is high, and the drug effect can be exerted at a lower dose, which reduces the potential toxicity of the compound.
  • the present invention provides a compound of formula I or a pharmaceutically acceptable salt, ester, isomer, solvate, hydrate, prodrug or isotope label thereof.
  • the structure of the compound of formula I is:
  • R 1 is any one of hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkylamino, and C 1-6 alkoxy;
  • R 2 is hydrogen, deuterium, halo, C 1-6 alkyl, fluoro substituted with at least one C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkylamino, C 1-6 Any one of alkoxy and heterocycloalkyl;
  • R 3 is any of hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkylamino, C 1-6 alkoxy, heterocycloalkyl
  • R 4 is any one of hydrogen, deuterium, and C 1-6 alkyl
  • R 5 is hydrogen, deuterium, C 1-6 alkyl, fluoro substituted with at least one C 1-6 alkyl, C 3-7 cycloalkyl any one;
  • R is a substituted or unsubstituted following group: C 1-6 alkyl, amino, C 1-6 alkoxy, C 3-7 cycloalkoxy, C 6-10 aryloxy, C 3-7 ring Alkyl, 3-7 membered heterocycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, or carbamoyl, and excludes R as unsubstituted methyl.
  • the R is substituted with the following groups: C 1-6 alkyl, amino, C 1-6 alkoxy, C 3-7 cycloalkoxy, C 6-10 aryloxy, C 3- 7 cycloalkyl, 3-7 membered heterocycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, carbamoyl, the substitution is substituted by one or more of the following groups: hydroxy, Hydroxy-C 1-6 alkyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkoxy, C 1-6 alkoxy-C 1-6 alkyl or C 1-6 alkoxy substituted with at least one halogen atom.
  • the R is substituted with the following groups: C 1-6 alkyl, amino, C 1-6 alkoxy, C 3-7 cycloalkoxy, C 3-7 cycloalkyl, 3-7 Member heterocycloalkyl, C 5-10 heteroaryl, carbamoyl, the substitution is substituted by one or more of the following groups: hydroxy, hydroxy-C 1-6 alkyl, halogen, C 1-3 Alkyl, C 1-3 alkoxy, C 1-3 alkoxy-C 1-6 alkyl, C 3-7 cycloalkoxy, C 1-3 alkoxy substituted with at least one halogen atom.
  • the compound of formula I has the structure of formula I-1:
  • R 1 is any one of hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkylamino, and C 1-6 alkoxy;
  • R 2 is hydrogen, deuterium, halo, C 1-6 alkyl, substituted by at least one halogen C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkylamino, C 1-6 Any one of alkoxy and heterocycloalkyl;
  • R 3 is any of hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkylamino, C 1-6 alkoxy, heterocycloalkyl
  • R 4 is any one of hydrogen, deuterium, and C 1-6 alkyl
  • R 5 is hydrogen, deuterium, C 1-6 alkyl, substituted by at least one halogen C 1-6 alkyl, C 3-7 cycloalkyl any one;
  • X is O, N, S, SO, SO 2 , or C(R 6 ) 2 ;
  • Y is 0, 1, 2, 3, 4 or 5
  • Z is 0, 1 or 2;
  • Each R 6 is independently selected from hydrogen, deuterium, hydroxy, cyano, amino, C 1-6 alkylamino, halogen, C 1-6 alkyl, substituted by at least one halogen atom, a C 1-6 alkoxy Group, C 1-6 alkyl or C 1-6 alkoxy substituted by hydroxy.
  • X is O or C(R 6 ) 2 ;
  • Y is 0, 1 or 2;
  • R 6 is independently selected from hydrogen, deuterium, hydroxyl, cyano, amino, methylamino, ethylamino, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy Radical, methyl, ethyl, n-propyl, isopropyl substituted with at least one fluorine or chlorine or hydroxyl.
  • the compound of formula I has the structure of formula I-2:
  • R 1 is any one of hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkylamino, and C 1-6 alkoxy;
  • R 2 is hydrogen, deuterium, halo, C 1-6 alkyl, substituted by at least one halogen C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkylamino, C 1-6 Any one of alkoxy and heterocycloalkyl;
  • R 3 is any of hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkylamino, C 1-6 alkoxy, heterocycloalkyl
  • R 4 is any one of hydrogen, deuterium, and C 1-6 alkyl
  • R 5 is hydrogen, deuterium, C 1-6 alkyl, substituted by at least one halogen C 1-6 alkyl, C 3-7 cycloalkyl any one;
  • R 7 and R 8 each independently selected from hydrogen, deuterium, C 1-6 alkyl, at least one halogen atom, C 1-6 alkoxy or hydroxy-substituted C 1-6 alkyl.
  • R 7 and R 8 are independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, methoxyethyl, methyl substituted by at least one fluorine, chlorine or hydroxyl Group, ethyl, n-propyl or isopropyl.
  • the compound of formula I has the structure of formula I-3:
  • R 1 is any one of hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkylamino, and C 1-6 alkoxy;
  • R 2 is hydrogen, deuterium, halo, C 1-6 alkyl, substituted by at least one halogen C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkylamino, C 1-6 Any one of alkoxy and heterocycloalkyl;
  • R 3 is any of hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkylamino, C 1-6 alkoxy, heterocycloalkyl
  • R 4 is any one of hydrogen, deuterium, and C 1-6 alkyl
  • R 5 is hydrogen, deuterium, C 1-6 alkyl, substituted by at least one halogen C 1-6 alkyl, C 3-7 cycloalkyl any one;
  • R 9, R 10 and R 11 are each independently selected from hydrogen, deuterium, C 1-6 alkyl, hydroxy, substituted by at least one halogen atom or a C 1-6 alkyl hydroxy substituted C 1-6 alkyl group , C 1-6 alkoxy unsubstituted or substituted by at least one halogen atom, C 3-7 cycloalkoxy unsubstituted or substituted by at least one halogen atom or C 1-6 alkyl, or R 9 , Any of R 10 and R 11 may form a substituted or unsubstituted C 3-7 cycloalkyl group, and R 9 , R 10 and R 11 are not hydrogen at the same time.
  • R 9 , R 10 and R 11 are independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, hydroxy, methoxy, ethoxy, cyclopropoxy, Methyl, ethyl, n-propyl, isopropyl or C 1-3 alkoxy substituted by at least one fluorine or chlorine or hydroxy group, the substituted C 3-7 cycloalkyl is substituted by at least one halogen atom, C 1-6 alkyl or C 1-6 alkoxy substituted.
  • said R is a substituted or unsubstituted following group: piperidinyl, pyrrolidinyl, azetidine, morpholinyl, C 1-3 alkyl.
  • said R is a substituted or unsubstituted following group: piperidinyl, azetidinyl, C 1-6 alkoxy, cyclobutyl, propyl, C 1-3 alkyl or Carbamoyl.
  • said R is substituted or unsubstituted piperidin-1-yl, substituted or unsubstituted azetidine-1-yl, cyclopropyl, substituted or unsubstituted cyclobutyl, propyl , C 1-6 alkoxy substituted methyl or ethyl, wherein the substituted piperidin-1-yl is replaced by at least one hydroxy-C 1-6 alkyl, C 1-6 alkyl or hydroxy Substitution, preferably by hydroxy-C 1-6 alkyl or by both C 1-6 alkyl and hydroxy; the substituted azetidine-1-yl is by at least one halogen atom or C 1-6 Substituted by alkoxy; the substituted cyclobutyl is substituted by at least one halogen atom, C 1-6 alkyl or C 1-6 alkoxy.
  • the R is a substituted piperidin-1-yl
  • the substituted piperidin-1-yl is substituted by at least one hydroxy-C 1-3 alkyl, C 1-6 alkoxy, C 1 -3 alkyl or hydroxy is substituted, preferably by hydroxy-C 1-3 alkyl or by both C 1-3 alkyl and hydroxy.
  • the R is a substituted or unsubstituted azetidine-1-yl, the substituted azetidine-1-yl is substituted by 1-3 halogen atoms or C 1-3 alkane Oxygen substituted.
  • said R is C 1-6 alkoxy substituted methyl or ethyl or isopropyl, preferably methoxy, ethoxy, propoxy or isopropoxy substituted methyl or Ethyl or isopropyl.
  • R 1 is hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, t-butyl, methylamino, ethylamino, methoxy, ethoxy, isopropoxy Any of
  • R 2 is hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, trifluoromethylmethyl, cyclopropyl, cyclopentyl, methylamino , Ethylamino, methoxy, ethoxy, isopropoxy, pyrrolidinyl, morpholinyl;
  • R 3 is any one of hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, cyano;
  • R 4 is any one of hydrogen, deuterium, methyl and ethyl
  • R 5 is any of hydrogen, deuterium, methyl, ethyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, trifluoromethyl, trifluoromethylmethyl, cyclopropyl One kind.
  • R 1 is any one of hydrogen, deuterium, halogen, C 1-6 alkoxy;
  • R 2 is any one of hydrogen, deuterium, halogen, C 1-6 alkylamino, and C 1-6 alkoxy;
  • R 3 is any one of hydrogen, deuterium and halogen
  • R 4 is hydrogen or deuterium
  • R 5 is hydrogen, deuterium, C 1-6 alkyl, fluoro substituted with at least one C 1-6 alkyl group, any one of a C 3-7 cycloalkyl group.
  • R 1 is hydrogen or deuterium
  • R 2 is any one of hydrogen, deuterium, halogen, C 1-6 alkoxy
  • R 3 is hydrogen or deuterium
  • R 4 is hydrogen or deuterium
  • R 5 is any of hydrogen, deuterium, methyl, ethyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, trifluoromethyl, trifluoromethylmethyl, cyclopropyl
  • R is a substituted or unsubstituted following group: piperidinyl, azetidine, morpholinyl, amino, cyclopropyl, propyl, C 1-3 alkyl, C 1-3 alkoxy, Cyclobutyl, or carbamoyl, the substitution is substituted by one or more of the following groups: hydroxy, hydroxy-C 1-6 alkyl, halogen, C 1-3 alkyl, C 1-3 alkoxy Group, C 1-3 alkoxy-C 1-6 alkyl, C 1-3 alkoxy or C 3-7 cycloalkoxy substituted with at least one halogen atom.
  • the compound of general formula I is any of the following:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising any one of the above-mentioned compounds of general formula I or a pharmaceutically acceptable salt, ester, isomer, solvate, hydrate, prodrug or isotope thereof Mark.
  • the present invention also provides a pharmaceutical preparation comprising any of the above-mentioned compounds having the structure of Formula I or pharmaceutically acceptable salts, esters, hydrates, solvates, stereoisomers, tautomers thereof Body, cis-trans isomers, isotope markers or prodrugs or the aforementioned pharmaceutical composition, the preparations are tablets, capsules, injections, granules, powders, suppositories, pills, creams, pastes, gels Any of medicines, powders, oral solutions, inhalants, suspensions, dry suspensions, patches, lotions.
  • the present invention also provides any of the above-mentioned compounds having the structure of Formula I or pharmaceutically acceptable salts, esters, hydrates, solvates, stereoisomers, tautomers, cis-trans isomers , Isotope markers or prodrugs, or the aforementioned pharmaceutical compositions, or the aforementioned pharmaceutical preparations, which are used for the prevention and treatment of hepatitis B.
  • the present invention also provides any of the above-mentioned compounds having the structure of Formula I or pharmaceutically acceptable salts, esters, hydrates, solvates, stereoisomers, tautomers, cis-trans isomers
  • the body, isotope marker or prodrug, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation is used for the prevention and/or treatment of hepatitis B.
  • the present invention also provides a compound having the structure of Formula I or a pharmaceutically acceptable salt, ester, hydrate, solvate, stereoisomer, tautomer, and cis-trans isomer according to any one of the above
  • the present invention also provides a method for preventing and/or treating hepatitis B, which comprises the steps of: hydrating a therapeutically effective amount of the compound having the structure of any one of the above formula I or a pharmaceutically acceptable salt thereof Compounds, solvates, stereoisomers, tautomers, cis-trans isomers, isotope labels or prodrugs, or the aforementioned pharmaceutical composition, or the aforementioned pharmaceutical preparations are administered to patients in need thereof.
  • the present invention also provides a pharmaceutical combination comprising any of the above-mentioned compounds having the structure of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, and tautomer , Cis-trans isomers, isotope markers or prodrugs, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparations, and at least one additional hepatitis B therapeutic agent.
  • the present invention also provides a method for preventing and/or treating hepatitis B, which comprises the steps of: hydrating a therapeutically effective amount of the compound having the structure of any one of the above formula I or a pharmaceutically acceptable salt thereof Compounds, solvates, stereoisomers, tautomers, cis-trans isomers, isotope labels or prodrugs, or the aforementioned pharmaceutical composition, or the aforementioned pharmaceutical preparation, and at least one additional type B Hepatitis treatment agents are administered to patients in need thereof.
  • novel thiazole ring-substituted dihydroisoquinoline compound of the present invention has extremely strong activity to inhibit hepatitis B surface antigens, and at the same time has extremely strong activity to inhibit hepatitis B DNA, and the bioavailability of such compounds is relatively high. At lower doses, the drug effects can be exerted, reducing the potential toxicity of the compound.
  • the present invention provides a compound of general formula I or a pharmaceutically acceptable salt, ester, isomer, solvate, hydrate, prodrug or isotope label thereof.
  • the structure of the compound of general formula I is:
  • R 1 is any one of hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkylamino, and C 1-6 alkoxy;
  • R 2 is hydrogen, deuterium, halo, C 1-6 alkyl, fluoro substituted with at least one C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkylamino, C 1-6 Any one of alkoxy and heterocycloalkyl;
  • R 3 is any of hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkylamino, C 1-6 alkoxy, heterocycloalkyl
  • R 4 is any one of hydrogen, deuterium, and C 1-6 alkyl
  • R 5 is hydrogen, deuterium, C 1-6 alkyl, fluoro substituted with at least one C 1-6 alkyl, C 3-7 cycloalkyl any one;
  • R is a substituted or unsubstituted following group: C 1-6 alkyl, amino, C 1-6 alkoxy, C 3-7 cycloalkoxy, C 6-10 aryloxy, C 3-7 ring Alkyl, 3-7 membered heterocycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, carbamoyl, and exclude R as unsubstituted methyl.
  • C 1-6 alkyl represents, individually or in combination, a saturated linear or branched alkyl group containing 1-6, especially 1-4 carbon atoms, including methyl, ethyl, propyl, Isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2- Butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2 -Pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3 ,-Dimethyl-2-butyl, etc.
  • C 1-6 alkyl is any one of methyl, ethyl, n-propyl, isopropyl, and tert-butyl.
  • C 1-3 alkyl represents a saturated linear or branched alkyl group containing 1-3 carbon atoms, alone or in combination, including methyl, ethyl, propyl, isopropyl, etc. .
  • C 3-7 cycloalkyl represents a saturated cycloalkyl group having 3 to 7, especially 3 to 6 carbon atoms, alone or in combination, including cyclopropyl, cyclobutyl, cyclopentyl, cyclo Hexyl, cycloheptyl, etc.
  • Special "C 3-7 cycloalkyl” is cyclopropyl, cyclopentyl, cyclohexyl and the like.
  • amino represents a primary amino group (-NH 2 ), a secondary amino group (-NH-) or a tertiary amino group, alone or in combination
  • C 1-6 alkylamino represents an amino group as defined above, alone or in combination, wherein the hydrogen atom of the amino group is substituted with at least one C 1-6 alkyl group
  • C 1-6 alkyl "Group” means as defined above, and accordingly, "C 1-6 alkylamino” includes methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, isobutylamino, 2-butylamino, tert-butylamino, n-pentylamino, 2-pentylamino, 3-pentylamino, 2-methyl-2-butylamino, 3-methyl-2-butylamino, 3-methyl-1-butylamino, 2-methyl-1-butylamino, n-hexylamino, 2-hexylamino, 3-hexylamino, 2-methyl-2-pentylamino, 3-methyl Yl-2-pent
  • C 1-6 alkoxy represents the group C 1-6 alkyl-O- alone or in combination, wherein “C 1-6 alkyl” means as defined above, which includes (but is not limited to) Methoxy (-OCH 3 ), ethoxy (-OCH 2 CH 3 ), n-propoxy (-OCH 2 CH 2 CH 3 ), isopropoxy (-OCH(CH 3 ) 2 ), n-butyl Oxygen (-OCH 2 CH 2 CH 2 CH 3 ), sec-butoxy (-OCH(CH 3 )CH 2 CH 3 ), isobutoxy (-OCH 2 CH(CH 3 ) 2 ), tert-butoxy Radical (-OC(CH 3 ) 3 ), n-pentyloxy (-OCH 2 CH 2 CH 2 CH 2 CH 3 ), neopentyloxy (-OCH 2 C(CH 3 ) 3 ), etc.
  • C 1-3 alkoxy represents the group C 1-3 alkyl-O
  • C 3-7 cycloalkoxy represents the group C 3-7 cycloalkyl-O- alone or in combination, wherein C 3-7 cycloalkyl means as defined above.
  • halogen represents fluorine, chlorine, bromine, or iodine, alone or in combination. Especially fluorine, chlorine or bromine.
  • heterocycloalkyl refers to a saturated or partially unsaturated (including 1 or 2 double bonds) non-aromatic cyclic group composed of carbon atoms and heteroatoms such as nitrogen, oxygen or sulfur. This cyclic group may It is a monocyclic or bicyclic group. In the present invention, the number of carbon atoms in the heterocyclic alkyl group is 2-11, and the number of hetero atoms is preferably 1, 2, 3, or 4. The nitrogen and carbon in the heterocyclic alkyl group Or sulfur atoms can be optionally oxidized.
  • the hydrogen atoms on the "heterocycloalkyl” are independently optionally substituted with one or more substituents described in the present invention.
  • the "heterocycloalkyl” can be linked to the parent molecule through any ring atom on the ring.
  • 3-7 membered heterocycloalkyl refers to a monocyclic heterocycloalkyl containing 3-7 carbon atoms and heteroatoms; for example aziridinyl, azetidinyl, oxetanyl, pyrrole Alkyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl.
  • C 3-7 cycloalkylamino means an amino group as defined above, alone or in combination, wherein the hydrogen atom of the amino group is substituted with at least one C 3-7 cycloalkyl group, "C 3- 7 " Cycloalkyl” means as defined above.
  • 3-7 membered heterocycloalkylamino means an amino group as defined above, alone or in combination, wherein the hydrogen atom of the amino group is replaced by at least one 3-7 membered heterocycloalkyl group, "3 "-7-membered heterocycloalkyl” means as defined above.
  • aryl means any stable 6-10 membered monocyclic or bicyclic aromatic group, including phenyl, naphthyl, tetrahydronaphthyl, indanyl or biphenyl, and the like.
  • the hydrogen atoms on the “aryl” are independently optionally substituted with one or more substituents described in the present invention.
  • heteroaryl refers to an aromatic ring group formed by replacing carbon atoms on the ring with at least one heteroatom selected from sulfur, oxygen, or nitrogen.
  • This aromatic ring group may be a 5-7 membered monocyclic ring or 7-12 Bicyclic group.
  • the number of hetero atoms in the heteroaryl group is preferably 1, 2, 3, or 4, such as thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridine-2(1H)-keto, Pyridine-4(1H)-keto, pyrrolyl, pyrazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, tetrazolyl, isothiazole , Oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, naphthyl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinoline Base, isoquinolinyl, quinazolinyl, etc.
  • the hydrogen atoms on the "heteroaryl" are independently optionally substituted
  • C 5-10 heteroaryl denotes an aromatic heterocycle having 5-10 carbon atoms, wherein aromatic heterocycle means as defined above.
  • C 6-10 aryl means an aryl group having 6-10 carbon atoms, where aryl means as defined above.
  • C 6-10 aryloxy means the group C 6-10 aryl-O-, wherein C 6-10 aryl means as defined above.
  • aryl C 1-6 alkyl means that the C 1-6 alkyl group is substituted with one or more aryl groups, and the aryl and C 1-6 alkyl means as defined above.
  • heteroaryl C 1-6 alkyl means that the C 1-6 alkyl group is substituted with one or more heteroaryl groups, and heteroaryl and C 1-6 alkyl means as defined above.
  • cyano alone or in combination refers to the group -CN.
  • hydroxyl alone or in combination refers to the group -OH.
  • isomeric forms including enantiomers, diastereomers, tautomers, and geometric isomers including cis-trans isomers. Therefore, the individual stereochemical isomers or enantiomers, diastereomers, tautomers, or geometric isomers (or cis-trans isomers) of the compounds designed in the present invention Mixtures are within the scope of the present invention.
  • pharmaceutically acceptable salts means that the compounds of the present invention exist in the form of their pharmaceutically acceptable salts, including acid addition salts and base addition salts.
  • Pharmaceutically acceptable salts are described in the pharmaceutically salts described by SMBerge in J. Pharmaceutical Sciences (Vol. 66: pages 1-19, 1977).
  • a pharmaceutically acceptable non-toxic acid addition salt means a salt formed by a compound of the present invention and an organic or inorganic acid, including but not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodine Acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, P-toluenesulfonic acid, malic acid, etc.
  • an organic or inorganic acid including but not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodine Acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesul
  • a pharmaceutically acceptable non-toxic base addition salt means a salt formed by a compound of the present invention and an organic or inorganic base, including but not limited to alkali metal salts, such as lithium, sodium, or potassium salts; alkaline earth metal salts, such as calcium Or magnesium salts; organic base salts, such as ammonium salts or N + (C 1-6 alkyl) 4 salts formed with N group-containing organic bases, preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, Sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, calcium carbonate, ammonia, triethylamine, tetrabutylammonium hydroxide, etc.
  • alkali metal salts such as lithium, sodium, or potassium salts
  • alkaline earth metal salts such as calcium Or magnesium salts
  • organic base salts such as ammonium salts or N + (C 1-6 alkyl) 4 salts formed with N group-containing organic bases, preferably lithium hydroxide,
  • solvate means an association of one or more solvent molecules with the compound of the present invention.
  • Solvent-forming solvents include, but are not limited to, water, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, and the like.
  • “Pharmaceutically acceptable salts” can be synthesized by general chemical methods.
  • esters are used to mean organic esters, including monoesters, diesters, triesters, and more commonly polyesters.
  • hydrate refers to an association of water and the compound of the present invention.
  • prodrug means a chemical derivative that is a compound of the present invention, and this derivative is converted into a compound represented by Formula I by a chemical reaction in the body.
  • isotopic derivative means an isotope derivative obtained by replacing a hydrogen atom in Formula I with 1-6 deuterium atoms, and an isotope derivative obtained by replacing a carbon atom in Formula I with 1-3 carbon 14 atoms Thing.
  • the R is substituted with the following groups: C 1-6 alkyl, amino, C 1-6 alkoxy, C 3-7 cycloalkoxy, C 6-10 aryl Oxygen, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, carbamoyl, the substitution is by one or more of the following groups Group substitution: hydroxy, hydroxy-C 1-6 alkyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkoxy, C 1-6 alkoxy-C 1 -6 alkyl or C 1-6 alkoxy substituted with at least one halogen atom.
  • R is substituted with the following groups: C 1-6 alkyl, amino, C 1-6 alkoxy, C 3-7 cycloalkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, C 5-10 heteroaryl, carbamoyl, the substitution is substituted by one or more of the following groups: hydroxy, hydroxy-C 1-6 alkyl , Halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkoxy-C 1-6 alkyl, C 3-7 cycloalkoxy, C 1- substituted with at least one halogen atom alkoxy.
  • the compound of formula I has the structure of formula 1-1:
  • R 1 is any one of hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkylamino, and C 1-6 alkoxy;
  • R 2 is hydrogen, deuterium, halo, C 1-6 alkyl, substituted by at least one halogen C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkylamino, C 1-6 Any one of alkoxy and heterocycloalkyl;
  • R 3 is any of hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkylamino, C 1-6 alkoxy, heterocycloalkyl
  • R 4 is any one of hydrogen, deuterium, and C 1-6 alkyl
  • R 5 is hydrogen, deuterium, C 1-6 alkyl, substituted by at least one halogen C 1-6 alkyl, C 3-7 cycloalkyl any one;
  • X is O, N, S, SO, SO 2 , or C(R 6 ) 2 ;
  • Y is 0, 1, 2, 3, 4 or 5
  • Z is 0, 1 or 2;
  • Each R 6 is independently selected from hydrogen, deuterium, hydroxy, cyano, amino, C 1-6 alkylamino, halogen, C 1-6 alkyl, substituted by at least one halogen atom, a C 1-6 alkoxy Group, C 1-6 alkyl or C 1-6 alkoxy substituted by hydroxy.
  • Y (R 6 ) represents the substitution of Y R 6 groups, and Y has the above definition.
  • said X is O or C(R 6 ) 2 ;
  • Y is 0, 1 or 2;
  • R 6 is independently selected from hydrogen, deuterium, hydroxyl, cyano, amino, methylamino, ethylamino, fluorine, chlorine, C 1-3 alkyl, C 1-3 substituted with at least one fluorine or chlorine C 1-3 alkyl or C 1-3 alkoxy substituted with alkyl, hydroxy.
  • the compound of formula I has the structure of formula I-2:
  • R 1 is any one of hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkylamino, and C 1-6 alkoxy;
  • R 2 is hydrogen, deuterium, halo, C 1-6 alkyl, substituted by at least one halogen C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkylamino, C 1-6 Any one of alkoxy and heterocycloalkyl;
  • R 3 is any of hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkylamino, C 1-6 alkoxy, heterocycloalkyl
  • R 4 is any one of hydrogen, deuterium, and C 1-6 alkyl
  • R 5 is hydrogen, deuterium, C 1-6 alkyl, substituted by at least one halogen C 1-6 alkyl, C 3-7 cycloalkyl any one;
  • R 7 and R 8 each independently selected from hydrogen, deuterium, C 1-6 alkyl, substituted by at least one halogen atom, C 1-6 alkoxy substituted C 1-6 alkyl or hydroxy C 1- 6 alkyl.
  • said R 7 and R 8 are independently selected from hydrogen, deuterium, C 1-6 alkyl, substituted by at least one halogen or C 1-6 alkoxy or hydroxyl C 1-6 alkyl.
  • the compound of formula I has the structure of formula I-3:
  • R 1 is any one of hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkylamino, and C 1-6 alkoxy;
  • R 2 is hydrogen, deuterium, halo, C 1-6 alkyl, substituted by at least one halogen C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkylamino, C 1-6 Any one of alkoxy and heterocycloalkyl;
  • R 3 is any of hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkylamino, C 1-6 alkoxy, heterocycloalkyl
  • R 4 is any one of hydrogen, deuterium, and C 1-6 alkyl
  • R 5 is hydrogen, deuterium, C 1-6 alkyl, substituted by at least one halogen C 1-6 alkyl, C 3-7 cycloalkyl any one;
  • R 9, R 10 and R 11 are each independently selected from hydrogen, deuterium, C 1-6 alkyl, hydroxy, substituted by at least one halogen atom or a C 1-6 alkyl hydroxy substituted C 1-6 alkyl group , C 1-6 alkoxy unsubstituted or substituted by at least one halogen atom, C 3-7 cycloalkoxy unsubstituted or substituted by at least one halogen atom or C 1-6 alkyl, or R 9 , Any of R 10 and R 11 may form a substituted or unsubstituted C 3-7 cycloalkyl group, and R 9 , R 10 and R 11 are not hydrogen at the same time.
  • R 9 , R 10 and R 11 are each independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, hydroxyl, methoxy, ethoxy , Cyclopropoxy, methyl, ethyl, n-propyl, isopropyl or C 1-3 alkoxy substituted with at least one fluorine or chlorine or hydroxy, the substituted C 3-7 cycloalkyl is Substituted by at least one halogen atom, C 1-6 alkyl or C 1-6 alkoxy, preferably, the substituted C 3-7 cycloalkyl is substituted by 1-3 fluorine, chlorine, bromine, methyl Substituted by oxy or ethoxy, the C 3-7 cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • said R is a substituted or unsubstituted following group: piperidinyl, pyrrolidinyl, azetidine, morpholinyl, C 1-3 alkyl.
  • said R is a substituted or unsubstituted following group: piperidinyl, azetidine, C 1-6 alkoxy, cyclobutyl, C 1-3 Alkyl, carbamoyl.
  • said R is substituted or unsubstituted piperidin-1-yl, substituted or unsubstituted azetidine-1-yl, cyclopropyl, substituted or unsubstituted Cyclobutyl, propyl, methyl or ethyl substituted with C 1-6 alkoxy, wherein the substituted piperidin-1-yl is substituted with at least one hydroxy-C 1-6 alkyl, C 1 -6 alkyl or hydroxy substituted, preferably substituted by hydroxy-C 1-6 alkyl or by both C 1-6 alkyl and hydroxy; the substituted azetidine-1-yl is substituted by at least one Halogen atom or C 1-6 alkoxy group, more preferably substituted with 1-3 fluorine, chlorine, bromine, methoxy or ethoxy; the substituted cyclobutyl is substituted with at least one halogen atom, C 1-6 alkyl or C 1-6 alkoxy is substituted
  • said R is substituted piperidin-1-yl, said substituted piperidin-1-yl is substituted by at least one hydroxy-C 1-3 alkyl, C 1- 6 alkoxy, C 1-3 alkyl or hydroxy, preferably substituted by hydroxy-C 1-3 alkyl or by both C 1-3 alkyl and hydroxy.
  • said R is a substituted or unsubstituted azetidine-1-yl, said substituted azetidine-1-yl is substituted by 1-3 halogens Atom or C 1-3 alkoxy substituted.
  • said R is C 1-6 alkoxy substituted methyl or ethyl or isopropyl, preferably methoxy, ethoxy, propoxy or isopropyl Oxygen substituted methyl or ethyl or isopropyl.
  • R 1 is hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, tert-butyl, methylamino, ethylamino, methoxy , Any of ethoxy, isopropoxy;
  • R 2 is hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, trifluoromethylmethyl, cyclopropyl, cyclopentyl, methylamino , Ethylamino, methoxy, ethoxy, isopropoxy, pyrrolidinyl, morpholinyl;
  • R 3 is any one of hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, cyano;
  • R 4 is any one of hydrogen, deuterium, methyl and ethyl
  • R 5 is any of hydrogen, deuterium, methyl, ethyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, trifluoromethyl, trifluoromethylmethyl, cyclopropyl One kind.
  • the R 1 is any one of hydrogen, deuterium, halogen, C 1-6 alkoxy;
  • R 2 is any one of hydrogen, deuterium, halogen, C 1-6 alkylamino, and C 1-6 alkoxy;
  • R 3 is any one of hydrogen, deuterium and halogen
  • R 4 is hydrogen or deuterium
  • R 5 is hydrogen, deuterium, C 1-6 alkyl, fluoro substituted with at least one C 1-6 alkyl group, any one of a C 3-7 cycloalkyl group.
  • R 1 is hydrogen or deuterium
  • R 2 is any one of hydrogen, deuterium, halogen, C 1-6 alkoxy
  • R 3 is hydrogen or deuterium
  • R 4 is hydrogen or deuterium
  • R 5 is any of hydrogen, deuterium, methyl, ethyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, trifluoromethyl, trifluoromethylmethyl, cyclopropyl
  • R is substituted or unsubstituted piperidinyl, azetidine, morpholinyl, amino, cyclopropyl, propyl, C 1-3 alkyl, C 1-3 alkoxy, cyclobutyl, Or carbamoyl, the substitution is substituted by one or more of the following groups: hydroxy, hydroxy-C 1-6 alkyl, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1 -3 alkoxy-C 1-6 alkyl, C 1-3 alkyl substituted with at least one halogen atom, C 3-7 cycloalkoxy.
  • the compound of general formula I is any of the following:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising any one of the above-mentioned compounds of general formula I or a pharmaceutically acceptable salt, ester, isomer, solvate, hydrate, prodrug or isotope thereof Mark.
  • the aforementioned pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
  • the aforementioned pharmaceutical composition further comprises:
  • the present invention also provides a pharmaceutical preparation comprising the above-mentioned compound having the structure of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, and cis-trans isomer , Isotope markers or prodrugs or the pharmaceutical composition
  • the preparations are tablets, capsules, injections, granules, powders, suppositories, pills, creams, pastes, gels, powders, oral solutions , Inhalation, suspension, dry suspension, patch, lotion.
  • the present invention also provides the above compound having the structure of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, or prodrug thereof , Or the pharmaceutical composition, or the pharmaceutical preparation, which is used for the prevention and treatment of hepatitis B.
  • the present invention also provides the above compound having the structure of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, or prodrug thereof , Or the pharmaceutical composition, or the pharmaceutical preparation is used for the prevention and/or treatment of hepatitis B.
  • the present invention also provides the above compound having the structure of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, or prodrug thereof , Or the use of the pharmaceutical composition or the pharmaceutical preparation in the preparation of drugs for the prevention and/or treatment of hepatitis B.
  • the present invention also provides a method for preventing and/or treating hepatitis B, which comprises the following steps: a therapeutically effective amount of the above-mentioned compound having the structure of formula I or a pharmaceutically acceptable salt, hydrate, solvate thereof, Stereoisomers, tautomers, cis-trans isomers, isotope labels or prodrugs, or the pharmaceutical composition or the pharmaceutical preparation is administered to patients in need thereof.
  • terapéuticaally effective amount refers to a dose of a pharmaceutical active ingredient capable of inducing a biological or medical response in a cell, tissue, organ, or organism (eg, patient).
  • administering refers to applying a pharmaceutical active ingredient (such as a compound of the present invention) or a pharmaceutical composition containing the pharmaceutical active ingredient (such as the pharmaceutical composition of the present invention) to a patient or its cells, tissues, organs, biological fluids, etc.
  • a pharmaceutical active ingredient such as a compound of the present invention
  • a pharmaceutical composition containing the pharmaceutical active ingredient such as the pharmaceutical composition of the present invention
  • Common modes of administration include, but are not limited to, oral administration, subcutaneous administration, intramuscular administration, subperitoneal administration, ocular administration, nasal administration, sublingual administration, rectal administration, vaginal administration, and the like.
  • needles for it refers to the judgment of the doctor or other nursing staff on the patient's needs or the benefit from the prevention and/or treatment process, which is based on the doctor or other nursing staff in their areas of expertise Kinds of factors.
  • patient refers to a human or non-human animal (eg, mammal).
  • the present invention also provides a pharmaceutical combination comprising the above-mentioned compound having the structure of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, and cis-trans isomer Body, isotope markers or prodrugs, or the pharmaceutical composition, or the pharmaceutical preparation, and at least one additional hepatitis B therapeutic agent.
  • the drug combination also contains at least one of the following substances:
  • HBV polymerase inhibitor interferon alpha-2a; interferon alpha-2b; pegylated interferon alpha-2a; ribavirin; HBV preventive vaccine; HBV therapeutic vaccine; HBV capsid inhibitor; HBV RNA replication Inhibitors; siRNA; HBsAg production or secretion inhibitors; HBV antibodies or TLR7 agonists.
  • the present invention also provides a method for preventing and/or treating hepatitis B, which comprises the steps of: adding a therapeutically effective amount of the above-mentioned compound having the structure of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, or stereo Isomers, tautomers, cis-trans isomers, isotope labels or prodrugs, or the pharmaceutical composition, or the pharmaceutical preparation, and at least one additional hepatitis B therapeutic agent For patients in need of it.
  • the present invention also provides a compound having the structure of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or pro
  • a typical synthetic route of the compound represented by the general formula I to further describe the technical scheme of the present invention.
  • Product 2 is reacted with aldehyde 3 in the presence of EtONa to obtain product 4;
  • Compound 10 is coupled with double-linked pinacol borate to obtain product 11;
  • Product 11 is coupled with substituted bromothiazole to give product 12;
  • the product 12 is hydrolyzed by sodium hydroxide or lithium hydroxide to obtain the product 13.
  • AUC 0-12 area under the drug concentration-time curve from 0 hours to 12 hours
  • AUC INF area under the drug concentration-time curve extrapolated from 0 hours to infinity
  • FeCl 3 ferric chloride
  • Oxalyl chloride Oxalyl chloride
  • PBS phosphate buffered saline
  • Pd(PPh 3 ) 4 tetrakis(triphenylphosphine)palladium
  • Tmax peak time of plasma concentration
  • Vss apparent volume of distribution
  • intermediate and final products are separated and purified by chromatography column, preparative chromatography plate and ICSO rapid preparative chromatography system.
  • the LC-MS liquid-mass spectrometry chromatograph uses Waters' ACQUITY Arc equipped with QDa Detector.
  • Mass spectrometry uses an ESI source and only indicates the molecular weight M of the parent molecule, usually reported as [M+H] + .
  • the injection volume is determined by the sample concentration; the flow rate is: 1.2 mL/min; the peak of HPLC is recorded by the UV-Vis wavelength at 220 nm and 254 nm.
  • the mobile phase was an ultrapure aqueous solution of 0.01% formic acid (mobile phase A) and 0.01% formic acid in acetonitrile (mobile phase B).
  • the gradient elution conditions are shown in Table 1 and Table 2 below:
  • the NMR spectrum is obtained using a Varian 400MHz nuclear magnetic resonance spectrometer, often using CDCl 3 and DMSO-d 6 as solvents, and reporting chemical shifts in ppm.
  • the various peaks are described as follows: s (single peak), d (doublet), t (triplet), q (quartet), m (multiplet), dd (double doublet).
  • the coupling constant is expressed in Hz.
  • Step 1a Preparation of 6-tert-butyl-10-methoxy-2-oxo-9-(4,4,5,5-tetramethyl-1,3,2-dioxolane 2-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester
  • Step 1b Preparation of 1-(5-bromothiazol-2-yl)piperidin-4-ol
  • Step 1c Preparation of 6-tert-butyl-9-[2-(4-hydroxypiperidin-1-yl)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro -2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester
  • Step 1d Preparation of 6-tert-butyl-9-[2-(4-hydroxypiperidin-1-yl)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro -2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid
  • Step 2a Preparation of [1-(5-bromothiazol-2-yl)piperidin-4-yl]methanol
  • Step 2b Preparation of 6-tert-butyl-9- ⁇ 2-[4-(hydroxymethyl)piperidin-1-yl]thiazol-5-yl ⁇ -10-methoxy-2-oxo-6, 7-Dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester
  • Step 2c Preparation of 6-tert-butyl-9- ⁇ 2-[4-(hydroxymethyl)piperidin-1-yl]thiazol-5-yl ⁇ -10-methoxy-2-oxo-6, 7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid
  • 6-tert-butyl-9- ⁇ 2-[4-(hydroxymethyl)piperidin-1-yl]thiazol-5-yl ⁇ -10-methoxy-2-oxo-6,7-di Hydrogen-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester (48 mg, 0.09 mmol) was prepared in a manner similar to step 1d of Example 1 to obtain a yellow solid 6-tert-butyl-9- ⁇ 2-[4-(hydroxymethyl)piperidin-1-yl]thiazol-5-yl ⁇ -10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2, 1-a] Isoquinoline-3-carboxylic acid (11.2 mg).
  • Step 3a Preparation of 2-(azetidin-1-yl)-5-bromothiazole
  • Step 3b Preparation of 9-[2-(azetidin-1-yl)thiazol-5-yl]-6-tert-butyl-10-methoxy-2-oxo-6,7-dihydro -2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester
  • Step 3c 9-[2-(azetidin-1-yl)thiazol-5-yl]-6-tert-butyl-10-methoxy-2-oxo-6,7-dihydro- 2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid
  • Step 4a Preparation of 2-(3,3-difluoroazetidin-1-yl)-5-bromothiazole
  • 2,5-Dibromothiazole 300 mg, 1.23 mmol
  • 3,3-difluoroazetidine 138 mg, 1.48 mmol
  • 2-(3 ,3-difluoroazetidin-1-yl)-5-bromothiazole 260 mg
  • Step 4b Preparation of 6-tert-butyl-9-[2-(3,3-difluoroazetidin-1-yl)thiazol-5-yl]-10-methoxy-2-oxo- 6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester
  • Step 4c Preparation of 6-tert-butyl-9-[2-(3,3-difluoroazetidin-1-yl)thiazol-5-yl]-10-methoxy-2-oxo- 6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid
  • 6-tert-butyl-9-[2-(3,3-difluoroazetidin-1-yl)thiazol-5-yl]-10-methoxy-2-oxo-6,7 -Dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester (70 mg, 0.13 mmol) was prepared in a manner similar to step 1d of Example 1 to obtain a yellow solid 6-tert-butyl- 9-[2-(3,3-Difluoroazetidin-1-yl)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro-2H-pyridine And [2,1-a]isoquinoline-3-carboxylic acid (31.8mg).
  • Step 5b Preparation of 6-tert-butyl-10-methoxy-9-(2-morpholinothiazol-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2, 1-a]isoquinoline-3-carboxylic acid ethyl ester
  • Step 5c Preparation of 6-tert-butyl-10-methoxy-9-(2-morpholinothiazol-5-yl)-2-oxo-6,7-dihydro-2H-pyrido[2, 1-a]isoquinoline-3-carboxylic acid
  • Step 6b Preparation of 6-tert-butyl-9-[2-(dimethylamino)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido [2,1-a]isoquinoline-3-carboxylic acid ethyl ester
  • 6-tert-butyl-10-methoxy-2-oxo-9-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl )-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester 250 mg, 0.52 mmol
  • 5-bromo-2-(dimethylamino)thiazole (128mg, 0.45mmol) was prepared in a manner similar to Step 1c of Example 1 to obtain a yellow solid 6-tert-butyl-9-[2-(dimethylamino)thiazol-5-yl]-10-methoxy- 2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester (71 mg).
  • Step 6c 6-tert-butyl-9-[2-(dimethylamino)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[ 2,1-a]isoquinoline-3-carboxylic acid
  • Isoquinoline-3-carboxylic acid ethyl ester (71 mg, 0.15 mmol) was prepared in a similar manner to step 1d of Example 1 to obtain a yellow solid 6-tert-butyl-9-[2-(dimethylamino) Thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid (30.2 mg).
  • Step 7a Preparation of 1-(5-bromothiazol-2-yl)-4-methylpiperidin-4-ol
  • Step 7b Preparation of 6-tert-butyl-9-[2-(4-hydroxy-4-methylpiperidin-1-yl)thiazol-5-yl]-10-methoxy-2-oxo-6 ,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester
  • 6-tert-butyl-10-methoxy-2-oxo-9-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl )-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester 150 mg, 0.32 mmol
  • 1-(5-bromothiazol-2-yl)-4 -Methylpiperidin-4-ol 104 mg, 0.37 mmol
  • Step 7c Preparation of 6-tert-butyl-9-[2-(4-hydroxy-4-methylpiperidin-1-yl)thiazol-5-yl]-10-methoxy-2-oxo-6 ,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid
  • 6-tert-butyl-9-[2-(4-hydroxy-4-methylpiperidin-1-yl)thiazol-5-yl]-10-methoxy-2-oxo-6,7- Dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester (100 mg, 0.18 mmol) was prepared in a manner similar to step 1d of Example 1 to obtain 6-tert-butyl-9 as a yellow solid -[2-(4-hydroxy-4-methylpiperidin-1-yl)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[ 2,1-a]isoquinoline-3-carboxylic acid (65.9 mg).
  • Step 8a Preparation of 5-bromo-2-(4-methoxypiperidin-1-yl)thiazole
  • Step 8b Preparation of 6-tert-butyl-10-methoxy-9-[2-(4-methoxypiperidin-1-yl)thiazol-5-yl]-2-oxo-6,7- Dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester
  • 6-tert-butyl-10-methoxy-2-oxo-9-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl )-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester 150 mg, 0.32 mmol
  • 5-bromo-2-(4-methoxypiperidine -1-yl)thiazole 104 mg, 0.37 mmol
  • Step 8c Preparation of 6-tert-butyl-10-methoxy-9-[2-(4-methoxypiperidin-1-yl)thiazol-5-yl]-2-oxo-6,7- Dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid
  • 6-tert-butyl-10-methoxy-9-[2-(4-methoxypiperidin-1-yl)thiazol-5-yl]-2-oxo-6,7-dihydro- 2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester (100 mg, 0.18 mmol) was prepared in a manner similar to step 1d of Example 1 to obtain 6-tert-butyl-10-methoxy yellow solid Yl-9-[2-(4-methoxypiperidin-1-yl)thiazol-5-yl]-2-oxo-6,7-dihydro-2H-pyrido[2,1-a] Isoquinoline-3-carboxylic acid (72.1 mg).
  • Step 9a Preparation of 5-bromo-2-(3-methoxyazetidin-1-yl)thiazole
  • Step 9b Preparation of 6-tert-butyl-10-methoxy-9-[2-(3-methoxyazetidin-1-yl)thiazol-5-yl]-2-oxo-6 ,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester
  • 6-tert-butyl-10-methoxy-2-oxo-9-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl )-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester 150 mg, 0.32 mmol
  • 5-bromo-2-(3-methoxyaza) Cyclobutan-1-yl)thiazole (93 mg, 0.37 mmol) was prepared in a manner similar to step 1c of Example 1 to obtain a yellow solid 6-tert-butyl-10-methoxy-9-[2-(3-methyl Oxyazetidin-1-yl)thiazol-5-yl]-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl Ester (100mg).
  • Step 9c Preparation of 6-tert-butyl-10-methoxy-9-[2-(3-methoxyazetidin-1-yl)thiazol-5-yl]-2-oxo-6 ,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid
  • 6-tert-butyl-10-methoxy-9-[2-(3-methoxyazetidin-1-yl)thiazol-5-yl]-2-oxo-6,7- Dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester (100 mg, 0.18 mmol) was prepared in a manner similar to step 1d of Example 1 to obtain 6-tert-butyl-10 as a yellow solid -Methoxy-9-[2-(3-methoxyazetidin-1-yl)thiazol-5-yl]-2-oxo-6,7-dihydro-2H-pyrido[ 2,1-a]isoquinoline-3-carboxylic acid (30.9 mg).
  • Step 10a Preparation of thiazol-2-ylmethanol
  • Step 10d Preparation of 6-tert-butyl-10-methoxy-9-[2-(methoxymethyl)thiazol-5-yl]-2-oxo-6,7-dihydro-2H-pyridine [2,1-a]isoquinoline-3-carboxylic acid ethyl ester
  • 6-tert-butyl-10-methoxy-2-oxo-9-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl )-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester 150 mg, 0.32 mmol
  • 5-bromo-2-(methoxymethyl)thiazole 78 mg, 0.37 mmol
  • Step 10e Preparation of 6-tert-butyl-10-methoxy-9-[2-(methoxymethyl)thiazol-5-yl]-2-oxo-6,7-dihydro-2H-pyridine [2,1-a]isoquinoline-3-carboxylic acid
  • 6-tert-butyl-10-methoxy-9-[2-(methoxymethyl)thiazol-5-yl]-2-oxo-6,7-dihydro-2H-pyrido[2 ,1-a]isoquinoline-3-carboxylic acid ethyl ester 150 mg, 0.31 mmol
  • 6-tert-butyl-10-methoxy-9-[2 -(Methoxymethyl)thiazol-5-yl]-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid 49.8 mg.
  • Step 11a Preparation of 5-bromo-2-(3-fluoroazetidin-1-yl)thiazole
  • Step 11b Preparation of 6-tert-butyl-9-[2-(3-fluoroazetidin-1-yl)thiazol-5-yl]-10-methoxy-2-oxo-6,7 -Dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester
  • 6-tert-butyl-10-methoxy-2-oxo-9-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl )-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester 150 mg, 0.32 mmol
  • 5-bromo-2-(3-fluoroazetidine Alkan-1-yl)thiazole 89 mg, 0.37 mmol
  • Step 11c Preparation of 6-tert-butyl-9-[2-(3-fluoroazetidin-1-yl)thiazol-5-yl]-10-methoxy-2-oxo-6,7 -Dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid
  • 6-tert-butyl-9-[2-(3-fluoroazetidin-1-yl)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro -2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ethyl ester (100 mg, 0.19 mmol) was prepared in a similar manner to step 1d of Example 1 to obtain 6-tert-butyl-9 as a yellow solid -[2-(3-fluoroazetidin-1-yl)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2, 1-a] Isoquinoline-3-carboxylic acid ethyl ester (61.9 mg).
  • Step 12a Preparation of 5-bromo-2-methoxythiazole
  • Step 12b Preparation of 6-tert-butyl-10-methoxy-9-(2-methoxythiazol-5-yl)-2-oxo-6,7-dihydro-2H-pyridine[2,1 -a]isoquinoline-3-carboxylic acid ethyl ester
  • 6-tert-butyl-10-methoxy-2-oxo-9-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl )-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester 150 mg, 0.375 mmol
  • 5-bromo-2-methoxythiazole 73 mg, 0.375 mmol
  • Step 12c Preparation of 6-tert-butyl-10-methoxy-9-(2-methoxythiazol-5-yl)-2-oxo-6,7-dihydro-2H-pyridine[2,1 -a]isoquinoline-3-carboxylic acid
  • Step 13b Preparation of 6-tert-butyl-9-[2-(ethoxy)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro-2H-pyridine[2 ,1-a]isoquinoline-3-carboxylic acid ethyl ester
  • Step 13c Preparation of 6-tert-butyl-9-[2-(ethoxy)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro-2H-pyridine[2 ,1-a]isoquinoline-3-carboxylic acid
  • Isoquinoline-3-carboxylic acid ethyl ester 120 mg, 0.25 mmol was prepared in a similar manner to step 1d of Example 1 to obtain a pale yellow solid 6-tert-butyl-9-[2-(ethoxy)thiazole -5-yl]-10-methoxy-2-oxo-6,7-dihydro-2H-pyridine[2,1-a]isoquinoline-3-carboxylic acid (50 mg).
  • 2-ethoxymethylthiazole (0.33 g, 2.30 mmol) was prepared in a similar manner to step 10c of Example 10 to obtain 5-bromo-2-ethoxymethylthiazole (110 mg) as a white solid.
  • Step 14c Preparation of 6-tert-butyl-9-[2-(ethoxymethyl)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro-2H-pyridine [2,1-a]isoquinoline-3-carboxylic acid ethyl ester
  • 6-tert-butyl-10-methoxy-2-oxo-9-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl )-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester 180 mg, 0.45 mmol
  • 5-bromo-2-ethoxymethylthiazole 110 mg, 0.50 mmol
  • Step 14d Preparation of 6-tert-butyl-9-[2-(ethoxymethyl)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro-2H-pyridine [2,1-a]isoquinoline-3-carboxylic acid
  • Isoquinoline-3-carboxylic acid ethyl ester 80 mg, 0.16 mmol was prepared in a manner similar to step 1d of Example 1 to obtain a white solid 6-tert-butyl-9-[2-(ethoxymethyl )Thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro-2H-pyridine[2,1-a]isoquinoline-3-carboxylic acid (30 mg).
  • Step 15a Preparation of 1-(thiazol-2-yl)ethan-1-ol
  • 1-(thiazol-2-yl)ethan-1-one (1.0 g, 7.86 mmol) was prepared in a manner similar to step 10a of Example 10 to obtain 1-(thiazol-2-yl)ethan-1 as a colorless oily liquid -Alcohol (1.0 g).
  • Step 15b Preparation of 1-(5-bromothiazol-2-yl)ethan-1-ol
  • Step 15d Preparation of 6-tert-butyl-10-methoxy-9-[2-(1-methoxyethyl)thiazol-5-yl]-2-oxo-6,7-dihydro-2H -Pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester
  • 6-tert-butyl-10-methoxy-2-oxo-9-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl )-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester 150 mg, 0.32 mmol
  • 5-bromo-2-(1-methoxyethyl ) Thiazole (83mg, 0.37mmol) was prepared in a manner similar to step 1c of Example 1 to obtain a yellow solid 6-tert-butyl-10-methoxy-9-[2-(1-methoxyethyl)thiazole- 5-yl]-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester (100 mg).
  • Step 15e Preparation of 6-tert-butyl-10-methoxy-9-[2-(1-methoxyethyl)thiazol-5-yl]-2-oxo-6,7-dihydro-2H -Pyrido[2,1-a]isoquinoline-3-carboxylic acid
  • 6-tert-butyl-10-methoxy-9-[2-(1-methoxyethyl)thiazol-5-yl]-2-oxo-6,7-dihydro-2H-pyrido [2,1-a]Isoquinoline-3-carboxylic acid ethyl ester (100 mg, 0.20 mmol) was prepared in a manner similar to step 1d of Example 1 to obtain a yellow solid 6-tert-butyl-10-methoxy-9- [2-(1-methoxyethyl)thiazol-5-yl]-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ( 26.4mg).
  • Step 16a Preparation of 6-tert-butyl-9-[2-(1-hydroxyethyl)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro-2H-pyridine [2,1-a]isoquinoline-3-carboxylic acid ethyl ester
  • 6-tert-butyl-10-methoxy-2-oxo-9-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl )-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester 150 mg, 0.32 mmol
  • 1-(5-bromothiazol-2-yl)ethyl- 1-Alcohol (78 mg, 0.37 mmol) was prepared in a similar manner to Step 1c of Example 1 to obtain a yellow solid 6-tert-butyl-9-[2-(1-hydroxyethyl)thiazol-5-yl]-10- Methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester (80 mg).
  • Step 16b Preparation of 6-tert-butyl-9-[2-(1-hydroxyethyl)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro-2H-pyridine [2,1-a]isoquinoline-3-carboxylic acid
  • 6-tert-butyl-9-[2-(1-hydroxyethyl)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2 ,1-a]isoquinoline-3-carboxylic acid ethyl ester (80 mg, 0.16 mmol) was prepared in a manner similar to step 1d of Example 1 to obtain a yellow solid 6-tert-butyl-9-[2-(1-hydroxyethyl Yl)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid (20.8 mg).
  • Step 17a Preparation of 2-(thiazol-2-yl)propan-2-ol
  • methyl magnesium bromide (8.0 mL, 24.00) was added dropwise to a solution of 1-(thiazol-2-yl)ethan-1-one (2.0 g, 15.73 mmol) in tetrahydrofuran (20 mL) at -78°C. mmol). The mixture was stirred at -78°C for 2 hours.
  • Step 17b Preparation of 2-(5-bromothiazol-2-yl)propan-2-ol
  • Step 17c Preparation of 5-bromo-2-(2-methoxyprop-2-yl)thiazole
  • Step 17d Preparation of 6-tert-butyl-10-methoxy-9-[2-(2-methoxyprop-2-yl)thiazol-5-yl]-2-oxo-6,7-di Hydrogen-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester
  • 6-tert-butyl-10-methoxy-2-oxo-9-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl )-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester 150 mg, 0.32 mmol
  • 5-bromo-2-(2-methoxyprop- 2-yl)thiazole 88 mg, 0.37 mmol
  • Step 17e Preparation of 6-tert-butyl-10-methoxy-9-[2-(2-methoxyprop-2-yl)thiazol-5-yl]-2-oxo-6,7-di Hydrogen-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid
  • 6-tert-butyl-10-methoxy-9-[2-(2-methoxyprop-2-yl)thiazol-5-yl]-2-oxo-6,7-dihydro-2H -Pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester 120 mg, 0.23 mmol was prepared in a manner similar to step 1d of Example 1 to obtain a yellow solid 6-tert-butyl-10-methoxy -9-[2-(2-methoxyprop-2-yl)thiazol-5-yl]-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquine Porphyrin-3-carboxylic acid (26.4 mg).
  • Step 18b Preparation of 6-tert-butyl-10-methoxy-2-oxo-9-(2-propylthiazol-5-yl)-6,7-dihydro-2H-pyrido[2,1 -a]isoquinoline-3-carboxylic acid ethyl ester
  • Step 18c Preparation of 6-tert-butyl-10-methoxy-2-oxo-9-(2-propylthiazol-5-yl)-6,7-dihydro-2H-pyrido[2,1 -a]isoquinoline-3-carboxylic acid
  • 6-tert-butyl-10-methoxy-2-oxo-9-(2-propylthiazol-5-yl)-6,7-dihydro-2H-pyrido[2,1-a] Isoquinoline-3-carboxylic acid ethyl ester (73 mg, 0.152 mmol) was prepared in a manner similar to step 1d of Example 1 to obtain a yellow solid 6-tert-butyl-10-methoxy-2-oxo-9-(2 -Propylthiazol-5-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid (53.5 mg).
  • Step 19b Preparation of 6-tert-butyl-10-methoxy-9-[2-(methylcarbamoyl)thiazol-5-yl]-2-oxo-6,7-dihydro-2H-pyridine [2,1-a]isoquinoline-3-carboxylic acid ethyl ester
  • Step 19c Preparation of 6-tert-butyl-10-methoxy-9-[2-(methylcarbamoyl)thiazol-5-yl]-2-oxo-6,7-dihydro-2H-pyridine [2,1-a]isoquinoline-3-carboxylic acid
  • 6-tert-butyl-10-methoxy-9-[2-(methylcarbamoyl)thiazol-5-yl]-2-oxo-6,7-dihydro-2H-pyrido[2 ,1-a]isoquinoline-3-carboxylic acid ethyl ester (42mg, 0.085mmol) was prepared in a similar manner to step 1d of Example 1 to obtain a yellow solid 6-tert-butyl-10-methoxy-9-[2 -(Methylcarbamoyl)thiazol-5-yl]-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid (33 mg).
  • Step 20a Preparation of 5-bromo-N-ethylthiazole-2-carboxamide
  • Step 20b Preparation of 6-tert-butyl-9-[2-(ethylcarbamoyl)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro-2H-pyridine [2,1-a]isoquinoline-3-carboxylic acid ethyl ester
  • Step 20c Preparation of 6-tert-butyl-9-[2-(ethylcarbamoyl)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro-2H-pyridine [2,1-a]isoquinoline-3-carboxylic acid
  • 6-tert-butyl-9-[2-(ethylcarbamoyl)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2 ,1-a]isoquinoline-3-carboxylic acid ethyl ester (15 mg, 0.029 mmol) was prepared in a manner similar to step 1d of Example 1 to obtain a yellow solid 6-tert-butyl-9-[2-(ethylcarbamate Acyl)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid (8.6 mg).
  • Step 21a Preparation of 5-bromo-2-(2-methoxyethoxy)thiazole
  • Step 21b Preparation of 6-tert-butyl-10-methoxy-9-[2-(2-methoxyethoxy)thiazol-5-yl]-2-oxo-6,7-dihydro-2H -Pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester
  • 6-tert-butyl-10-methoxy-2-oxo-9-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl )-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester (146 mg, 0.30 mmol) and 5-bromo-2-(methoxyethoxy)thiazole (90 mg, 0.38 mmol) was prepared in a manner similar to step 1c of Example 1 to obtain a yellow solid 6-tert-butyl-10-methoxy-9-[2-(2-methoxyethoxy)thiazole-5- Yl]-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester (140 mg).
  • Step 21c 6-tert-butyl-10-methoxy-9-[2-(2-methoxyethoxy)thiazol-5-yl]-2-oxo-6,7-dihydro-2H- Pyrido[2,1-a]isoquinoline-3-carboxylic acid
  • Step 22a Preparation of 5-bromo-N-(2-methoxyethyl)thiazole-2-carboxamide
  • 5-Bromothiazole-2-carboxylic acid 200 mg, 0.96 mmol
  • 2-methoxyethylamine 144 mg, 1.92 mmol
  • 5-bromo-N-(2 -Methoxyethyl)thiazole-2-carboxamide 19 mg
  • Step 22b Preparation of 6-tert-butyl-10-methoxy-9- ⁇ 2–[(2-methoxyethyl)carbamoyl]thiazol-5-yl ⁇ -2-oxo-6,7 -Dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester
  • Step 22c Preparation of 6-tert-butyl-10-methoxy-9- ⁇ 2-((2-methoxyethyl)carbamoyl]thiazol-5-yl ⁇ -2-oxo-6,7 -Dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid
  • 6-tert-butyl-10-methoxy-9- ⁇ 2–[(2-methoxyethyl)carbamoyl]thiazol-5-yl ⁇ -2-oxo-6,7-dihydro- 2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester (77 mg, 0.143 mmol) was prepared in a similar manner to step 1d of Example 1 to obtain a yellow solid 6-tert-butyl-10-methoxy Yl-9- ⁇ 2–[(2-methoxyethyl)carbamoyl]thiazol-5-yl ⁇ -2-oxo-6,7-dihydro-2H-pyrido[2,1-a ] Isoquinoline-3-carboxylic acid (57.5 mg).
  • Step 23c Preparation of 6-tert-butyl-9- ⁇ 2-[(difluoromethoxy)methyl]thiazol-5-yl ⁇ -10-methoxy-2-oxo-6,7-dihydro -2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester
  • 6-tert-butyl-10-methoxy-2-oxo-9-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl )-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester 150 mg, 0.32 mmol
  • 5-bromo-2-[(difluoromethoxy) Methyl]thiazole 91 mg, 0.37 mmol
  • a yellow solid 6-tert-butyl-9- ⁇ 2-[(difluoromethoxy)methyl]thiazole-5- Group ⁇ -10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester 120 mg.
  • Step 23d Preparation of 6-tert-butyl-9- ⁇ 2-[(difluoromethoxy)methyl]thiazol-5-yl ⁇ -10-methoxy-2-oxo-6,7-dihydro -2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid
  • 6-tert-butyl-9- ⁇ 2-[(difluoromethoxy)methyl]thiazol-5-yl ⁇ -10-methoxy-2-oxo-6,7-dihydro-2H- Pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester 120 mg, 0.23 mmol was prepared in a manner similar to step 1d of Example 1 to obtain a yellow solid 6-tert-butyl-9- ⁇ 2-[ (Difluoromethoxy)methyl]thiazol-5-yl ⁇ -10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline- 3-carboxylic acid (35.2 mg).
  • Step 24a Preparation of 5-bromo-2-(bromomethyl)thiazole
  • Step 24c Preparation of 6-tert-butyl-9-[2-(cyclopropoxymethyl)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro-2H- Pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester
  • 6-tert-butyl-10-methoxy-2-oxo-9-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl )-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester 250 mg, 0.52 mmol
  • 5-bromo-2-(cyclopropoxymethyl)thiazole 80 mg, 0.34 mmol
  • Step 24d 6-tert-butyl-9-[2-(cyclopropoxymethyl)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro-2H-pyridine [2,1-a]isoquinoline-3-carboxylic acid
  • 6-tert-butyl-9-[2-(cyclopropoxymethyl)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[ 2,1-a]isoquinoline-3-carboxylic acid ethyl ester (110mg, 0.21mmol) was prepared in a manner similar to step 1d of Example 1 to obtain a yellow solid 6-tert-butyl-9-[2-(cyclopropoxy Methyl)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid (58.1mg ).
  • Step 25a Preparation of 3,3-difluorocyclobutane-1-thioformamide
  • Step 25c Preparation of 5-bromo-2-(3,3-difluorocyclobutyl)thiazole
  • Step 25d Preparation of 6-tert-butyl-9-[2-(3,3-difluorocyclobutyl)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro -2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester
  • Step 25e Preparation of 6-tert-butyl-9-[2-(3,3-difluorocyclobutyl)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro -2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid
  • 6-tert-butyl-9-[2-(3,3-difluorocyclobutyl)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro-2H- Pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester (100 mg, 0.19 mmol) was prepared in a manner similar to step 1d of Example 1 to obtain a yellow solid 6-tert-butyl-9-[2-( 3,3-difluorocyclobutyl)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline- 3-carboxylic acid (2.1 mg).
  • Step 26a Preparation of 5-bromo-2-(3-fluorocyclobutyl)thiazole
  • Step 26b Preparation of 6-tert-butyl-9-[2-(3-fluorocyclobutyl)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro-2H- Pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester
  • 6-tert-butyl-10-methoxy-2-oxo-9-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl )-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester (226 mg, 0.47 mmol) and 5-bromo-2-(3-fluorocyclobutyl) Thiazole (100 mg, 0.42 mmol) was prepared in a manner similar to step 1c of Example 1 to obtain a yellow solid 6-tert-butyl-9-[2-(3-fluorocyclobutyl)thiazol-5-yl]-10-methyl Ethoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester (65 mg).
  • Step 26c Preparation of 6-tert-butyl-9-[2-(3-fluorocyclobutyl)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro-2H- Pyrido[2,1-a]isoquinoline-3-carboxylic acid
  • 6-tert-butyl-9-[2-(3-fluorocyclobutyl)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[ 2,1-a]isoquinoline-3-carboxylic acid ethyl ester (65 mg, 0.13 mmol) was prepared in a manner similar to step 1d of Example 1 to obtain a yellow solid 6-tert-butyl-9-[2-(3-fluoro (Cyclobutyl)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid (22.3mg ).
  • Step 27a Preparation of 5-bromo-2-(3-methoxycyclobutyl)thiazole
  • Step 27b Preparation of 6-tert-butyl-10-methoxy-9-[2-(3-methoxycyclobutyl)thiazol-5-yl]-2-oxo-6,7-dihydro- 2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester
  • Step 27c Preparation of 6-tert-butyl-10-methoxy-9-[2-(3-methoxycyclobutyl)thiazol-5-yl]-2-oxo-6,7-dihydro- 2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid
  • HBV cell line HBV HBV cell line
  • HepG2.2.15 cells are inserted into the entire HBV genome and can continuously express HBV (Sells et al, Proc Natl Acad Sci US A. 1987 Feb; 84(4): 1005-9.).
  • the culture conditions were DMEM medium containing 10% serum and 400 ⁇ g/mg G418.
  • the cells were placed in a 5% CO 2 incubator and incubated at 37°C.
  • HBsAg hepatitis B surface antigen
  • HepG2.2.15 cells at 3x10 4 / hole seeded into 96-well culture plate The next day, the drug dissolved in DMSO was diluted 5-fold and added to the cells. 0.5% DMSO was added alone as a control. After 4 days of drug action, the supernatant was collected to detect the surface antigen content of hepatitis B.
  • the hepatitis B virus surface antigen quantitative detection kit (chemiluminescence method) was used for the measurement of the hepatitis B virus surface antigen.
  • the specific operation is as follows, 50 ⁇ L of the cell culture supernatant is taken and transferred to the detection plate. After adding 50 ⁇ L ELISA reagent, the reaction plate was sealed. Incubate for 1 hour at room temperature. After that, it was washed six times with PBS, and finally the residual liquid was removed by flicking the plate. Add 25 ⁇ L of substrates A and B respectively, and after ten minutes of reaction, pass the microplate reader (Tecan F200) detection. The IC 50 is calculated by dose-response curve fitting.
  • Examples IC 50 (nM) Examples IC 50 (nM) 1 0.33 2 0.06 3 0.07 4 0.045 5 0.3 6 0.3 7 0.08 8 0.2 9 0.03 10 0.2 11 0.09 12 0.45 13 0.2 14 0.2 15 0.2 16 0.1 17 0.3 18 0.09 19 0.3 20 0.3
  • HepG2.2.15 cells at 4x10 4 / hole seeded into 96-well culture plate After 4 hours, the drug dissolved in DMSO was diluted 4-fold and added to the cells. 0.5% DMSO was added alone as a control. On the fourth day of the drug action, the old supernatant was removed and the drug was added again. After 7 days of drug action, the supernatant was collected and treated with lysate. Hepatitis B DNA was measured using real-time fluorescence quantitative polymerase chain reaction (qPCR). After the qPCR operation is completed, the data is exported from the instrument and analyzed. The antiviral activity IC 50 is calculated by fitting the dose-response curve.
  • Examples IC 50 (nM) Examples IC 50 (nM) 2 0.11 4 0.26 7 0.15 9 0.10 10 0.13 11 0.13 13 0.31 16 0.41 18 0.06 twenty three 0.84 twenty four 0.45 A A
  • the compounds involved in the aforementioned compound represented by the general formula I, the different implementation of the compound represented by the general formula I, and the specific examples of the compound represented by the general formula I can be prepared Into corresponding isomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts.
  • the compound is made into a pharmaceutically acceptable derivative, and the derivative is any one of a prodrug, a salt, an ester, an amide, an ester salt, an amide salt, and a metabolite.
  • pharmaceutically acceptable salts include the use of inorganic acids (such as hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid or phosphoric acid, etc.), or organic acids (such as acetic acid, oxalic acid, maleic acid, Fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, malic acid, etc.) Salt obtained from conventional non-toxic salts.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid or phosphoric acid, etc.
  • organic acids such as acetic acid, oxalic acid, maleic acid, Fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid,
  • Pharmaceutically acceptable salts also include salts formed by the compounds of the present invention and organic or inorganic bases, including but not limited to alkali metal salts, such as lithium, sodium, or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; Organic alkali salts, such as ammonium salts or N + (C 1-6 alkyl) 4 salts formed with organic bases containing N groups, preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, carbonic acid Sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, calcium carbonate, ammonia, triethylamine, tetrabutylammonium hydroxide, etc.
  • alkali metal salts such as lithium, sodium, or potassium salts
  • alkaline earth metal salts such as calcium or magnesium salts
  • Organic alkali salts such as ammonium salts or N + (C 1-6 alkyl) 4 salts formed with organic bases containing N groups, preferably lithium hydroxide,
  • an isotope can be introduced into any compound involved in the present invention, and the introduced isotope can be 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P , 32 P, 35 S, 18 F, 36 Cl, specific isotope derivatives can be prepared by conventional techniques.
  • an actual product it can also be made into tablets, capsules, injections, granules, powders, suppositories, pills, creams, pastes, gels, powders, oral solutions, inhalants, suspensions , Dry suspension, patch, lotion.
  • a pharmaceutically acceptable carrier or adjuvant or excipient may also form a mixture with any of the following substances: a pharmaceutically acceptable carrier or adjuvant or excipient.
  • a composition may be formed with any of the following substances: HBV polymerase inhibitor; interferon ⁇ -2a; interferon ⁇ -2b; pegylated interferon ⁇ -2a; ribavirin Lin; HBV preventive vaccine; HBV therapeutic vaccine; HBV capsid inhibitor; HBV RNA replication inhibitor; siRNA; HBsAg production or secretion inhibitor; HBV antibody; any of TLR7 agonist.
  • All the compounds according to the present invention and mixtures, compositions, etc. containing the compounds of the present invention can be administered into a living body by any route of administration.
  • the administration route can be oral administration, intravenous injection, intramuscular injection, subcutaneous injection, rectal administration, vaginal administration, sublingual administration, nasal inhalation, oral inhalation, eye drops, or local or systemic transdermal administration.
  • All the compounds involved in the present invention and mixtures, compositions, etc. containing the compounds of the present invention can be formulated into a single dose, which contains the active compound of the present invention, carriers, excipients, etc.
  • the dosage form can be tablets or capsules , Injections, granules, powders, suppositories, pills, creams, pastes, gels, powders, oral solutions, inhalants, suspensions, dry suspensions, patches, lotions, etc.
  • These dosage forms may contain ingredients commonly used in pharmaceutical preparations, such as diluents, absorbents, wetting agents, binders, disintegrating agents, coloring agents, pH adjusting agents, antioxidants, bacteriostatic agents, isotonic adjusting agents, Anti-sticking agent, etc.
  • Suitable formulations for the above types of dosage forms are available from public sources, such as Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, published in 2006, and Rowe, Raymond, C. Handbook, Pharmaceutical, and Pharmaceutical, Excipients, Chicago, Pharmaceutical Press in 2005 Published annually. Therefore, those skilled in the art can easily prepare it.
  • the dosage of the compound of the present invention can be 0.01 to 500 mg/kg per day
  • the preferred daily dose is 1-100 mg/kg, which can be administered single or multiple times.
  • hepatitis B surface antigen HBV
  • the new compound can be used to treat and prevent HBV infection.
  • HBsAg hepatitis B surface antigen
  • It can be used to treat and prevent HBV infection.
  • the compound of general formula I of the present invention can be used in combination with other drugs, including HBV polymerase inhibitors, such as lamivudine, telbivudine, tenofovir disoproxil fumarate, adefo Weiwei ester, entecavir or tenofovir alafenamide fumaric acid; interferon ⁇ -2a; interferon ⁇ -2b; pegylated interferon ⁇ -2a; ribavirin; HBV preventive vaccine; HBV treatment Vaccine; HBV capsid inhibitor; HBV RNA replication inhibitor, siRNA; HBsAg production or secretion inhibitor; HBV antibody; TLR 7 agonist.
  • HBV polymerase inhibitors such as lamivudine, telbivudine, tenofovir disoproxil fumarate, adefo Weiwei ester, entecavir or tenofovir alafenamide fumaric acid

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Abstract

本发明提供了一种二氢异喹啉类化合物或其药学上可接受的盐、酯、异构体、溶剂化物、水合物、前药或同位素标记物，具有通式Ⅰ化合物的结构：（I），该类化合物具有极强的抑制乙肝表面抗原的活性，同时具有极强的抑制乙肝DNA的活性，并且该类化合物的生物利用度较高，在较低的剂量下就可发挥药效，降低了化合物的潜在毒性。

Description

一种二氢异喹啉类化合物
相关申请的引用
本发明要求2019年1月8日在中国提交的，名称为“一种二氢异喹啉类化合物”、申请号为201910016095.9的发明专利申请的优先权，并通过引用方式将其全部内容并入本文。
技术领域
本发明属于药物化学领域，具体涉及一种噻唑环取代的二氢异喹啉类化合物，以及含有二氢异喹啉类化合物的混合物或者组合物，尤其是一种用于预防和治疗乙型肝炎病毒感染的噻唑环取代的二氢异喹啉类化合物及含有该二氢异喹啉类化合物的混合物或者组合物。
背景技术
乙型肝炎病毒(HBV)是世界上最常见的病原体之一，乙型病毒性肝炎是由乙肝病毒(HBV)引起的、通过血液与体液传播的、以肝脏损害为主的传染病，是一个严重的公共卫生问题，该疾患对人类健康的威胁很大。据统计，全球约有大约三分之一的人群受到过乙肝感染，其中3.5到5亿人为慢性乙肝病毒(HBV)携带者。乙肝病毒感染不仅会引起急性肝炎，还可能导致慢性肝炎，诱发肝硬化并最终导致肝癌。HBV可通过多种途径感染人体，引起肝病的传播。每年，因乙肝急性或慢性感染导致的死亡人数约为80万。
虽然安全、有效的HBV疫苗已问世，广泛的新生儿疫苗接种也带来感染率的大幅下降，甚至肝癌发生率的下降。然而由于部分地区疫苗覆盖率不够，受经济条件制约等因素，很多感染的患者不能得到及时诊断和治疗，全球HBV疾病负担仍然沉重。近年来，随着对乙肝感染抑制的深入研究，以及新的诊断和治疗的应用，乙肝治疗和预防取得了很大的进展。但是，彻底的治愈乙肝感染还没有实现，巨大的医疗需求依然存在。
乙肝病毒为一个含有部分单链区的环状双链DNA病毒，其基因组长约3.2kb，属于嗜肝DNA病毒科(hepadnavividae)。HBV全基因核苷酸序列异源性约8％，以S基因区核苷酸序列异源性4.2％为标准，HBV基因型可分为A-H 8种。HBV基因型的分布具有人种和地域差异。分布在亚洲的主要是B和C基因型，A和D基因型常分布于非洲、欧洲和印度半岛，E型分布于西非，F型分布于中美洲和南美洲，G基因型常分布于法国、德国和北美。乙肝病毒的基因组包含四个开放阅读框，编码核心蛋白、聚合酶、膜蛋白和X蛋白。乙肝病毒的感染依赖于肝细胞膜上的钠离子-牛磺胆酸-协同转运蛋白(NTCP)受体，在乙肝病毒感染肝细胞之后，部分双链的病毒DNA被转运到细胞核并且形成共价闭合环状DNA(covalently closed circular DNA，cccDNA)，cccDNA是乙肝病毒前基因组RNA(pgRNA)和亚基因组RNA的转录模板。核心蛋白将pgRNA和聚合酶包含在一起进行复制(Lamontagne RJ，et al.Hepatoma Res 2016；2：163-86.)。
乙肝病毒具有7nm厚的含磷脂外膜蛋白层，称为乙肝表面抗原(HBsAg)。膜蛋白分为大、中、小三种类型(large、middle、small HBsAg)，它们由HBV的S基因编码，但转录起始位点不同。其中S区域的C端为相同区域。膜蛋白在N端信号序列的指导下整合进入内质网膜。一方面，膜蛋白会成为成熟乙肝病毒颗粒的重要结构蛋白；另一方面，膜蛋白会形成球状或丝状亚病毒颗粒(subviral  particles，SVPs)。在病人血清中，亚病毒颗粒的含量通常为成熟病毒颗粒的1000倍以上。血清学检测中，乙肝表面抗原阳性超过6个月为HBV慢性感染标志。虽然亚病毒颗粒不具有感染性，但是其对宿主的免疫应答有着重要影响。乙肝表面抗原可以抑制先天免疫系统中单核细胞的活化(Vanlandschoot P et al，J Gen Virol.2002 Jun；83(Pt 6)：1281-9)，破坏树突状细胞的功能(Marjoleine L et al，Immunology.2009 Feb；126(2)：280–289.)以及破坏自然杀伤细胞的功能(Yang Y etal，Int Immunopharmacol.2016 Sep；38：291-7)。持续性乙肝表面抗原以及其它病毒抗原的暴露也导致了HBV特异性T细胞的功能缺失，从而引起宿主对乙肝病毒的免疫耐受(Carolina B et al，J Virol.2007 Apr；81(8)：4215–4225)。乙肝病人的表面抗原清除是临床诊断和治疗的重要生物标记。乙肝表面抗原的血清学清除被认为是临床上的乙肝治愈。
目前临床上获得FDA批准使用的药物包括干扰素和核苷类药。干扰素有普通干扰素和聚乙二醇干扰素。核苷类药有拉米夫定(贺普丁)、阿德福韦(贺维力)、恩替卡韦(博路定)和替比夫定(素比伏)、替诺福韦(韦瑞德)。干扰素可以通过调节宿主免疫系统来激活免疫细胞，诱导产生多种抗病毒因子来实现对HBV的控制。在抗病毒的同时还可以提高机体的免疫力，作用比较持久，可以减少肝硬化和肝癌的发生率。存在的缺点是抗病毒作用不强，伴随着较多的副作用，可能引起流感样症状、肌肉疼痛、血小板减少、脱发、抑郁等症状。长期的干扰素治疗也只可以每年在西方国家人群获得2.25％以及亚洲国家人群获得0.43％的乙肝表面抗原清除(CM Chun et al，Antivir Ther.2010；15(2)：133-43)。核苷类药物可以抑制乙肝DNA的合成。拉米夫定曾经被用于治疗艾滋病的药物，口服后吸收迅速，可以明显抑制HBV的复制从而减少病毒的总负荷量，其作用效果强、安全、不良反应少，但长期服用会产生耐药性。阿德福韦治疗效果优于拉米夫定，抗病毒疗效好，对拉米夫定耐药病人仍有效，具有良好的耐受性和安全性，但是长期使用会有肾毒性。核苷类药物的长期治疗也只可以使每年0.5–1％的病人获得乙肝表面抗原清除(E Loggi et al，Dig Liver Dis.2015 Oct；47(10)：836-41)。
综上所述，由于HBV在肝细胞内持续存在和复制，而且HBV在治疗过程中会不断发生变异和产生突变，目前的抗病毒药物还不能彻底清除HBV。为了抑制病毒的复制，大多数患者需要长期治疗，给乙肝患者以及社会带来了巨大的经济和社会负担，乙肝的治疗存在着巨大的市场需求。乙肝表面抗原的清除将可能打破宿主对乙肝病毒的免疫耐受，重新恢复宿主对HBV的免疫应答，从而达到治疗乙肝的目的，为治疗乙肝提供新的方向。因此开发乙肝表面抗原抑制剂对于乙肝的治疗将产生重要的影响，产生巨大的经济和社会效益。
本发明的申请人在WO2018/130152A1中报道了一种二氢异喹啉类化合物，其可以用于治疗和预防乙肝病毒感染，然而该专利所公开的化合物活性并不是很高，且需要在较大的剂量下才能实现较好的预防和治疗乙型肝炎的效果。因此，在该预防和治疗乙型肝炎的领域中，迫切的需要提供一种能够活性更高、以更低剂量即可实现预防和治疗乙型肝炎目的的化合物。
发明内容
发明要解决的问题
本发明的目的在于如何提供新型的噻唑环取代的二氢异喹啉类化合物，该类化合物具有极强的抑制乙肝表面抗原的活性，同时具有极强的抑制乙肝DNA的活性，并且该类化合物的生物利用度较高，在较低的剂量下就可发挥药效，降低了化合物的潜在毒性。
用于解决问题的方案
为实现上述目的，本发明提供一种通式Ⅰ化合物或其药学上可接受的盐、酯、异构体、溶剂化物、水合物、前药或同位素标记物，通式Ⅰ化合物结构为：
Figure PCTCN2020070633-appb-000001
其中：
R 1是氢、氘、卤素、C 1-6烷基、C 1-6烷基氨基、C 1-6烷氧基中的任一种；
R 2是氢、氘、卤素、C 1-6烷基、被至少一个氟所取代的C 1-6烷基、C 3-7环烷基、C 1-6烷基氨基、C 1-6烷氧基、杂环烷基中的任一种；
R 3是氢、氘、卤素、氰基、C 1-6烷基、C 3-7环烷基、C 1-6烷基氨基、C 1-6烷氧基、杂环烷基中的任一种；
R 4是氢、氘、C 1-6烷基中的任一种；
R 5是氢、氘、C 1-6烷基、被至少一个氟所取代的C 1-6烷基、C 3-7环烷基中的任一种；
R是取代或未取代的下列基团：C 1-6烷基、氨基、C 1-6烷氧基、C 3-7环烷氧基、C 6-10芳氧基、C 3-7环烷基、3-7元杂环烷基、C 6-10芳基、C 5-10杂芳基或氨基甲酰基，且排除R为未取代的甲基。
优选的，所述R是取代的下列基团：C 1-6烷基、氨基、C 1-6烷氧基、C 3-7环烷氧基、C 6-10芳氧基、C 3-7环烷基、3-7元杂环烷基、C 6-10芳基、C 5-10杂芳基、氨基甲酰基，所述取代是被一个或多个下列基团所取代：羟基、羟基-C 1-6烷基、卤素、C 1-6烷基、C 1-6烷氧基、C 3-7环烷氧基、C 1-6烷氧-C 1-6烷基或被至少一个卤素原子取代的C 1-6烷氧基。
优选的，所述R是取代的下列基团：C 1-6烷基、氨基、C 1-6烷氧基、C 3-7环烷氧基、C 3-7环烷基、3-7 元杂环烷基、C 5-10杂芳基、氨基甲酰基，所述取代是被一个或多个下列基团所取代：羟基、羟基-C 1-6烷基、卤素、C 1-3烷基、C 1-3烷氧基、C 1-3烷氧-C 1-6烷基、C 3-7环烷氧基、被至少一个卤素原子取代的C 1-3烷氧基。
优选的，所述式Ⅰ化合物具有通式Ⅰ-1的结构：
Figure PCTCN2020070633-appb-000002
其中：
R 1是氢、氘、卤素、C 1-6烷基、C 1-6烷基氨基、C 1-6烷氧基中的任一种；
R 2是氢、氘、卤素、C 1-6烷基、被至少一个卤素所取代的C 1-6烷基、C 3-7环烷基、C 1-6烷基氨基、C 1-6烷氧基、杂环烷基中的任一种；
R 3是氢、氘、卤素、氰基、C 1-6烷基、C 3-7环烷基、C 1-6烷基氨基、C 1-6烷氧基、杂环烷基中的任一种；
R 4是氢、氘、C 1-6烷基中的任一种；
R 5是氢、氘、C 1-6烷基、被至少一个卤素所取代的C 1-6烷基、C 3-7环烷基中的任一种；
X为O、N、S、SO、SO 2、或C(R 6) 2；
Y为0、1、2、3、4或5
Z为0、1或2；
每一个R 6为独立地选自氢、氘、羟基、氰基、氨基、C 1-6烷基氨基、卤素、C 1-6烷基、被至少一个卤素原子所取代的C 1-6烷基、羟基取代的C 1-6烷基或C 1-6烷氧基。
优选的，所述X为O或者C(R 6) 2；Y为0、1或2；
R 6为独立地选自氢、氘、羟基、氰基、氨基、甲基氨基、乙基氨基、氟、氯、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、被至少一个氟或氯或羟基取代的甲基、乙基、正丙基、异丙基。
优选的，所述式Ⅰ化合物具有通式Ⅰ-2的结构：
Figure PCTCN2020070633-appb-000003
其中：
R 1是氢、氘、卤素、C 1-6烷基、C 1-6烷基氨基、C 1-6烷氧基中的任一种；
R 2是氢、氘、卤素、C 1-6烷基、被至少一个卤素所取代的C 1-6烷基、C 3-7环烷基、C 1-6烷基氨基、C 1-6烷氧基、杂环烷基中的任一种；
R 3是氢、氘、卤素、氰基、C 1-6烷基、C 3-7环烷基、C 1-6烷基氨基、C 1-6烷氧基、杂环烷基中的任一种；
R 4是氢、氘、C 1-6烷基中的任一种；
R 5是氢、氘、C 1-6烷基、被至少一个卤素所取代的C 1-6烷基、C 3-7环烷基中的任一种；
R 7和R 8分别独立的选自氢、氘、C 1-6烷基、被至少一个卤素原子、C 1-6烷氧基或羟基取代的C 1-6烷基。
优选的，所述的R 7和R 8分别独立的选自氢、氘、甲基、乙基、正丙基、异丙基、甲氧乙基、被至少一个氟、氯或羟基取代的甲基、乙基、正丙基或异丙基。
优选的，所述式Ⅰ化合物具有通式I-3的结构：
Figure PCTCN2020070633-appb-000004
其中：
R 1是氢、氘、卤素、C 1-6烷基、C 1-6烷基氨基、C 1-6烷氧基中的任一种；
R 2是氢、氘、卤素、C 1-6烷基、被至少一个卤素所取代的C 1-6烷基、C 3-7环烷基、C 1-6烷基氨基、C 1-6烷氧基、杂环烷基中的任一种；
R 3是氢、氘、卤素、氰基、C 1-6烷基、C 3-7环烷基、C 1-6烷基氨基、C 1-6烷氧基、杂环烷基中的任一种；
R 4是氢、氘、C 1-6烷基中的任一种；
R 5是氢、氘、C 1-6烷基、被至少一个卤素所取代的C 1-6烷基、C 3-7环烷基中的任一种；
R 9、R 10和R 11分别独立的选自氢、氘、C 1-6烷基、羟基、被至少一个卤素原子所取代的C 1-6烷基或羟基取代的C 1-6烷基、未取代或被至少一个卤素原子所取代的C 1-6烷氧基、未取代或被至少一个卤素原子或C 1-6烷基所取代的C 3-7环烷氧基、或R 9、R 10和R 11中的任两个可以形成取代或未取代的C 3-7环烷基，且R 9、R 10和R 11不同时为氢。
优选的，R 9、R 10和R 11分别独立的选自氢、氘、甲基、乙基、正丙基、异丙基、羟基、甲氧基、乙氧基、环丙氧基、被至少一个氟或氯或羟基取代的甲基、乙基、正丙基、异丙基或C 1-3烷氧基，所述取代的C 3-7环烷基是被至少一个卤素原子、C 1-6烷基或C 1-6烷氧基所取代。
优选的，所述的R为取代或未取代的下列基团：哌啶基、吡咯烷基、氮杂环丁烷基、吗啉基、C 1-3烷基。
优选的，所述的R为取代或未取代的下列基团：哌啶基、氮杂环丁烷基、C 1-6烷氧基、环丁基、丙基、C 1-3烷基或氨基甲酰基。
优选的，所述的R为取代或未取代的哌啶-1-基，取代或未取代的氮杂环丁烷-1-基，环丙基，取代或未取代的环丁基，丙基，C 1-6烷氧基取代的甲基或乙基，其中，所述取代的哌啶-1-基是被至 少一个羟基-C 1-6烷基、C 1-6烷基或羟基所取代，优选被羟基-C 1-6烷基或同时被C 1-6烷基和羟基所取代；所述取代的氮杂环丁烷-1-基是被至少一个卤素原子或C 1-6烷氧基所取代；所述取代的环丁基是被至少一个卤素原子、C 1-6烷基或C 1-6烷氧基所取代。
优选的，所述的R为取代的哌啶-1-基，所述取代的哌啶-1-基是被至少一个羟基-C 1-3烷基、C 1-6烷氧基、C 1-3烷基或羟基所取代，优选被羟基-C 1-3烷基或同时被C 1-3烷基和羟基所取代。
优选的，所述的R为取代或未取代的氮杂环丁烷-1-基，所述取代的氮杂环丁烷-1-基是被1-3个卤素原子或C 1-3烷氧基所取代。
优选的，所述的R为C 1-6烷氧基取代的甲基或乙基或异丙基，优选为甲氧基、乙氧基、丙氧基或异丙氧基取代的甲基或乙基或异丙基。
优选的，R 1是氢、氘、氟、氯、溴、甲基、乙基、异丙基、叔丁基、甲基氨基、乙基氨基、甲氧基、乙氧基、异丙氧基中的任一种；
R 2是氢、氘、氟、氯、溴、甲基、乙基、异丙基、叔丁基、三氟甲基、三氟甲基甲基、环丙基、环戊基、甲基氨基、乙基氨基、甲氧基、乙氧基、异丙氧基、吡咯烷基、吗啉基中的任一种；
R 3是氢、氘、氟、氯、溴、甲基、乙基、氰基中的任一种；
R 4是氢、氘、甲基、乙基中的任一种；
R 5是氢、氘、甲基、乙基、异丙基、丁基、仲丁基、异丁基、叔丁基、三氟甲基、三氟甲基甲基、环丙基中的任一种。
优选的，R 1是氢、氘、卤素、C 1-6烷氧基中的任一种；
R 2是氢、氘、卤素、C 1-6烷基氨基、C 1-6烷氧基中的任一种；
R 3是氢、氘、卤素中的任一种；
R 4是氢或氘；
R 5是氢、氘、C 1-6烷基、被至少一个氟所取代的C 1-6烷基、C 3-7环烷基中的任一种。
优选的，R 1是氢或氘；
R 2是氢、氘、卤素、C 1-6烷氧基中的任一种；
R 3是氢或氘；
R 4是氢或氘；
R 5是氢、氘、甲基、乙基、异丙基、丁基、仲丁基、异丁基、叔丁基、三氟甲基、 三氟甲基甲基、环丙基中的任一种；
R为取代或未取代的下列基团：哌啶基、氮杂环丁烷基、吗啉基、氨基、环丙基、丙基、C 1-3烷基、C 1-3烷氧基、环丁基、或氨基甲酰基，所述取代是被一个或多个下列基团所取代：羟基、羟基-C 1-6烷基、卤素、C 1-3烷基、C 1-3烷氧基、C 1-3烷氧基-C 1-6烷基、至少一个卤素原子取代的C 1-3烷氧基或C 3-7环烷氧基。
优选的，所述通式Ⅰ的化合物为如下任一种：
6-叔丁基-9-[2-(4-羟基哌啶-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-9-{2-[4-(羟甲基)哌啶-1-基]噻唑-5-基}-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
9-[2-(氮杂环丁烷-1-基)噻唑-5-基]-6-叔丁基-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-9-[2-(3,3-二氟氮杂环丁烷-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-10-甲氧基-9-(2-吗啉代噻唑-5-基)-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-9-[2-(二甲基氨基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-9-[2-(4-羟基-4-甲基哌啶-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-10-甲氧基-9-[2-(4-甲氧基哌啶-1-基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-10-甲氧基-9-[2-(3-甲氧基氮杂环丁烷-1-基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-10-甲氧基-9-[2-(甲氧基甲基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-9-[2-(3-氟氮杂环丁烷-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-10-甲氧基-9-(2-甲氧基噻唑-5-基)-2-氧代-6,7-二氢-2H-吡啶[2,1-a]异喹啉-3-甲酸；
6-叔丁基-9-[2-(乙氧基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶[2,1-a]异喹啉-3-甲酸；
6-叔丁基-9-[2-(乙氧基甲基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶[2,1-a]异喹啉-3-甲酸；
6-叔丁基-10-甲氧基-9-[2-(1-甲氧基乙基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-9-[2-(1-羟乙基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-10-甲氧基-9-[2-(2-甲氧基丙-2-基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-10-甲氧基-2-氧代-9-(2-丙基噻唑-5-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-10-甲氧基-9-[2-(甲基氨基甲酰基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-9-[2-(乙基氨基甲酰基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-10-甲氧基-9-[2-(2-甲氧乙氧基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-10-甲氧基-9-{2–[(2-甲氧基乙基)氨基甲酰基]噻唑-5-基}-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-9-{2-[(二氟甲氧基)甲基]噻唑-5-基}-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-9-[2-(环丙氧基甲基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-9-[2–(3,3-二氟环丁基)噻唑-5-基}-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-9-[2-(3-氟环丁基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异 喹啉-3-甲酸；
6-叔丁基-10-甲氧基-9-[2-(3-甲氧基环丁基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸。
本发明还提供了一种药物组合物，其包含上述任一所述的一种通式Ⅰ化合物或其药学上可接受的盐、酯、异构体、溶剂化物、水合物、前药或同位素标记物。
本发明还提供了一种药物制剂，其包括上述任一所述的具有式I结构的化合物或其药学上可接受的盐、酯、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药或者上述的药物组合物，所述制剂为片剂、胶囊剂、注射剂、颗粒剂、粉剂、栓剂、丸剂、乳膏剂、糊剂、凝胶剂、散剂、口服溶液、吸入剂、混悬剂、干悬剂、贴剂、洗剂中的任一种。
本发明还提供了上述任一所述的具有式I结构的化合物或其药学上可接受的盐、酯、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药，或者上述的药物组合物，或者上述的药物制剂，其用作预防和治疗乙型肝炎。
本发明还提供给了上述任一所述的具有式I结构的化合物或其药学上可接受的盐、酯、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药，或者上述的药物组合物，或者上述的药物制剂用作预防和/或治疗乙型肝炎的用途。
本发明还提供了上述任一项所述的具有式I结构的化合物或其药学上可接受的盐、酯、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药，或者上述的药物组合物，或者上述的药物制剂在制备预防和/或治疗乙型肝炎药物中的应用。
本发明还提供了一种预防和/或治疗乙型肝炎的方法，其包括下列步骤：将治疗有效量的上述任一所述的具有式I结构的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药，或者上述的药物组合物，或者上述的药物制剂施用于对其有需求的患者。
本发明还提供了一种药物联合形式，其包含上述任一所述的具有式I结构的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药，或者上述的药物组合物，或者上述的药物制剂，以及至少一种额外的乙型肝炎治疗剂。
本发明还提供了一种预防和/或治疗乙型肝炎的方法，其包括下列步骤：将治疗有效量的上述任一所述的具有式I结构的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药，或者上述的药物组合物，或者上述的药物制剂，以及至少一种额外的乙型肝炎治疗剂施用于对其有需求的患者。
取得的技术效果
本发明新型的噻唑环取代的二氢异喹啉类化合物，具有极强的抑制乙肝表面抗原的活性，同时具有极强的抑制乙肝DNA的活性，并且该类化合物的生物利用度较高，在较低的剂量下就可发挥药效，降低了化合物的潜在毒性。
具体实施方式
为了更为清晰的描述本发明的内容，本申请中所涉及的全部术语定义如下：
首先，本发明提供了一种通式Ⅰ化合物或其药学上可接受的盐、酯、异构体、溶剂化物、水合物、前药或同位素标记物，通式Ⅰ化合物结构为：
Figure PCTCN2020070633-appb-000005
其中：
R 1是氢、氘、卤素、C 1-6烷基、C 1-6烷基氨基、C 1-6烷氧基中的任一种；
R 2是氢、氘、卤素、C 1-6烷基、被至少一个氟所取代的C 1-6烷基、C 3-7环烷基、C 1-6烷基氨基、C 1-6烷氧基、杂环烷基中的任一种；
R 3是氢、氘、卤素、氰基、C 1-6烷基、C 3-7环烷基、C 1-6烷基氨基、C 1-6烷氧基、杂环烷基中的任一种；
R 4是氢、氘、C 1-6烷基中的任一种；
R 5是氢、氘、C 1-6烷基、被至少一个氟所取代的C 1-6烷基、C 3-7环烷基中的任一种；
R是取代或未取代的下列基团：C 1-6烷基、氨基、C 1-6烷氧基、C 3-7环烷氧基、C 6-10芳氧基、C 3-7环烷基、3-7元杂环烷基、C 6-10芳基、C 5-10杂芳基、氨基甲酰基，且排除R为未取代的甲基。
术语“C 1-6烷基”单独或者以组合方式表示包含1-6个、特别是1-4个碳原子的饱和直链或支链的烷基，包括甲基、乙基、丙基、异丙基、丁基、仲丁基、异丁基、叔丁基、正戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、正己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2- 丁基、3,3,-二甲基-2-丁基等。优选地，“C 1-6烷基”是甲基、乙基、正丙基、异丙基、叔丁基中的任一种。类似的，术语“C 1-3烷基”单独或者以组合方式表示包含1-3个碳原子的饱和直链或支链的烷基，包括甲基、乙基、丙基、异丙基等。
术语“C 3-7环烷基”单独或者以组合方式表示具有3到7个、特别是3-6个碳原子的饱和环烷基，包括环丙基、环丁基、环戊基、环己基、环庚基等。特别的“C 3-7环烷基”是环丙基、环戊基、环己基等。
术语“氨基”单独或者以组合方式表示伯氨基(-NH 2)，仲氨基(-NH-)或叔氨基
Figure PCTCN2020070633-appb-000006
术语“C 1-6烷基氨基”单独或者以组合方式表示如上所定义的氨基基团，其中氨基基团的氢原子被至少一个C 1-6烷基所取代，其中“C 1-6烷基”表示如以上所定义，相应地，“C 1-6烷基氨基”包括甲基氨基、乙基胺基、丙基氨基、异丙基氨基、正丁基胺基、异丁基氨基、2-丁基氨基、叔丁基氨基、正戊基氨基、2-戊基氨基、3-戊基氨基、2-甲基-2-丁基氨基、3-甲基-2-丁基氨基、3-甲基-1-丁基氨基、2-甲基-1-丁基氨基、正己基氨基、2-己基氨基、3-己基氨基、2-甲基-2-戊基氨基、3-甲基-2-戊基氨基、4-甲基-2-戊基氨基、3-甲基-3-戊基氨基、2-甲基-3-戊基氨基、2,3-二甲基-2-丁基氨基、3,3-二甲基-2-丁基氨基等。特别的“C 1-6烷基氨基”是甲基氨基、乙基氨基、异丙基氨基、叔丁基氨基等。
术语“C 1-6烷氧基”单独或者以组合方式表示基团C 1-6烷基-O-，其中“C 1-6烷基”表示如以上所定义，其包括(但不限于)甲氧基(-OCH 3)、乙氧基(-OCH 2CH 3)、正丙氧基(-OCH 2CH 2CH 3)、异丙氧基(-OCH(CH 3) 2)、正丁氧基(-OCH 2CH 2CH 2CH 3)、仲丁氧基(-OCH(CH 3)CH 2CH 3)、异丁氧基(-OCH 2CH(CH 3) 2)、叔丁氧基(-OC(CH 3) 3)、正戊氧基(-OCH 2CH 2CH 2CH 2CH 3)、新戊氧基(-OCH 2C(CH 3) 3)等。类似的，术语“C 1-3烷氧基”单独或者以组合方式表示基团C 1-3烷基-O-，其中“C 1-3烷基”表示如以上所定义。
术语“C 3-7环烷氧基”单独或者以组合方式表示基团C 3-7环烷基-O-,其中C 3-7环烷基表示如以上所定义。
术语“氨基甲酰基”是指-C(＝0)-氨基或-C(＝0)-取代的氨基。
术语“卤素”单独或者以组合方式表示氟、氯、溴或碘。特别的是氟、氯或溴。
术语“杂环烷基”指由碳原子与氮、氧或硫等杂原子组成的饱和或部分不饱和(包含1或2个双键)的非芳香环状基团，此环状基团可以是单环或双环基团，在本发明中，杂环烷基中碳原子个数为2-11个，杂原子个数优选1、2、3或4,杂环烷基中的氮、碳或硫原子可任选地被氧化。“杂环烷基”上的氢原子独立任选地被一个或多个本发明所描述的取代基所取代。“杂环烷基”可以通过环上任意的环原子链接到母体分子上。
术语“3-7元杂环烷基”是指单环杂环烷基中包含3-7个碳原子和杂原子；例如氮丙啶基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、四氢噻吩基、哌啶基、吗啉基、哌嗪基、硫代吗啉基、四氢吡喃基、1,1-二氧硫代吗啉基。
术语“C 3-7环烷基氨基”表示单独或者以组合方式表示如上所定义的氨基基团，其中氨基基团的氢原子被至少一个C 3-7环烷基所取代，“C 3-7环烷基”表示如以上所定义。
术语“3-7元杂环烷基氨基”表示单独或者以组合方式表示如上所定义的氨基基团，其中氨基基团的氢原子被至少一个3-7元杂环烷基所取代，“3-7元杂环烷基”表示如以上所定义。
术语“芳基”表示任何稳定的6-10元单环或双环芳香族基团，包括苯基、萘基、四氢萘基、2,3-二氢化茚基或联苯基等。“芳基”上的氢原子独立任选地被一个或多个本发明所描述的取代基所取代。
术语“杂芳基”表示环上的碳原子被至少一个选自硫、氧或氮的杂原子置换形成的芳香环基团，此芳香环基团可以是5-7元单环或7-12双环基团。在本发明中，杂芳基中杂原子个数优选1、2、3或4,例如噻吩基、吡啶基、嘧啶基、吡嗪基、哒嗪基、吡啶-2(1H)-酮基、吡啶-4(1H)-酮基、吡咯基、吡唑基、噻唑基、1,2,3-三唑基、1,2,4-三唑基、咪唑基、四氮唑基、异噻唑基、噁唑基、异噁唑基、噻二唑基、噁二唑基、萘基、苯并噻吩基、吲哚基、苯并咪唑基、苯并噻唑基、苯并呋喃基、喹啉基、异喹啉基、喹唑啉基等。“杂芳基”上的氢原子独立任选地被一个或多个本发明所描述的取代基所取代。
术语“C 5-10杂芳基”表述具有5-10个碳原子的芳杂环，其中芳杂环表示如以上所定义。
术语“C 6-10芳基”表示具有6-10个碳原子的芳基，其中芳基表示如以上所定义。
术语“C 6-10芳氧基”表示基团C 6-10芳基-O-,其中C 6-10芳基表示如以上所定义。
术语“芳基C 1-6烷基”表示C 1-6烷基基团被一个或多个芳基基团所取代，芳基和C 1-6烷基表示如以上所定义。
术语“杂芳基C 1-6烷基”表示C 1-6烷基基团被一个或多个杂芳基基团所取代，杂芳基和C 1-6烷基表示如以上所定义。
术语“氰基”单独或组合的是指基团-CN。
术语“羧基”单独或组合的是指基团-COOH。
术语“羟基”单独或组合的是指基团-OH。
术语“异构体”包含所有的同分异构形式包括对映异构体、非对映异构体、互变异构体、和几何异构体包括顺反异构体。因此，本发明中所设计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、互变异构体、或几何异构体(或顺反异构体)的混合物都属于本发明的范围。
术语“药学上可接受的盐”表示本发明的化合物以它们的药用盐的形式存在，包括酸加成盐和碱加成盐。药学上可接受的盐在S.M.Berge在J.Pharmaceutical Sciences(66卷:1-19页,1977年)中描述的pharmaceutically salts中有所描述。在本发明中，药学上可接受的无毒的酸加成盐表示本发明中的化合物与有机或无机酸形成的盐，有机或无机酸包括但不限于盐酸、硫酸、氢溴酸、氢碘酸、磷酸、硝酸、高氯酸、乙酸、草酸、马来酸、富马酸、酒石酸、苯磺酸、甲磺酸、水杨酸、琥珀酸、柠檬酸、乳酸、丙酸、苯甲酸、对甲苯磺酸、苹果酸等。药学上可接受的无毒的碱加成盐表示本发明中的化合物与有机或无机碱所形成的盐，包括但不限于碱金属盐，例如锂、钠或钾盐；碱土金属盐，例如钙或镁盐；有机碱盐，例如通过与含N基团的有机碱形成的铵盐或N +(C 1-6烷基) 4盐，优选为氢氧化锂、氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾、碳酸镁、碳酸钙、氨水、三乙胺、四丁基氢氧化铵等。
术语“溶剂化物”表示一个或多个溶剂分子与本发明中的化合物所形成的缔合物。形成溶剂化物的溶剂包括但不限于水、甲醇、乙醇、异丙醇、乙酸乙酯、四氢呋喃、N,N-二甲基甲酰胺、二甲亚砜等。“药学上可接受的盐”可通过一般的化学方法合成。
术语“酯”用于表示有机酯，包括单酯、二酯、三酯、和更通常地多酯。
术语“水合物”是指水与本发明中的化合物形成的缔合物。
术语“前药”表示作为本发明的化合物的化学衍生物，该衍生物在体内通过发生化学反应转换成通式I所表示的化合物。
术语“同位素衍生物”表示通式I中的氢原子被1-6个氘原子所取代得到的同位素衍生物、通式I中的碳原子被1-3个碳14原子所取代得到的同位素衍生物。
以上对本发明的涉及的术语进行了定义，本领域技术人员还可以结合现有技术对以上术语进行理解，以下基于本发明的内容以及对术语的定义进一步进行描述。
在一项优选的实施方案中，所述R是取代的下列基团：C 1-6烷基、氨基、C 1-6烷氧基、C 3-7环烷氧基、C 6-10芳氧基、C 3-7环烷基、3-7元杂环烷基、C 6-10芳基、C 5-10杂芳基、氨基甲酰基，所述取代是被一个或多个下列基团所取代：羟基、羟基-C 1-6烷基、卤素、C 1-6烷基、C 1-6烷氧基、C 3-7环烷氧基、C 1-6烷氧-C 1-6烷基或至少一个卤素原子取代的C 1-6烷氧基。
在一项更优选的实施方案中，所述R是取代的下列基团：C 1-6烷基、氨基、C 1-6烷氧基、C 3-7环烷氧基、C 3-7环烷基、3-7元杂环烷基、C 5-10杂芳基、氨基甲酰基，所述取代是被一个或多个下列基团所取代：羟基、羟基-C 1-6烷基、卤素、C 1-3烷基、C 1-3烷氧基、C 1-3烷氧-C 1-6烷基、C 3-7环烷氧基、至少一个卤素原子取代的C 1-3烷氧基。
在一项优选的实施方案中，所述式Ⅰ化合物具有通式Ⅰ-1的结构：
Figure PCTCN2020070633-appb-000007
其中：
R 1是氢、氘、卤素、C 1-6烷基、C 1-6烷基氨基、C 1-6烷氧基中的任一种；
R 2是氢、氘、卤素、C 1-6烷基、被至少一个卤素所取代的C 1-6烷基、C 3-7环烷基、C 1-6烷基氨基、C 1-6 烷氧基、杂环烷基中的任一种；
R 3是氢、氘、卤素、氰基、C 1-6烷基、C 3-7环烷基、C 1-6烷基氨基、C 1-6烷氧基、杂环烷基中的任一种；
R 4是氢、氘、C 1-6烷基中的任一种；
R 5是氢、氘、C 1-6烷基、被至少一个卤素所取代的C 1-6烷基、C 3-7环烷基中的任一种；
X为O、N、S、SO、SO 2、或C(R 6) 2；
Y为0、1、2、3、4或5
Z为0、1或2；
每一个R 6为独立地选自氢、氘、羟基、氰基、氨基、C 1-6烷基氨基、卤素、C 1-6烷基、被至少一个卤素原子所取代的C 1-6烷基、羟基取代的C 1-6烷基或C 1-6烷氧基。
其中“ Y(R 6)”表示Y个R 6基团取代，所述Y具有上述的定义。
在一项更优选的实施方案中，所述的X为O或者C(R 6) 2；
Y为0、1或2；
R 6为独立地选自氢、氘、羟基、氰基、氨基、甲基氨基、乙基氨基、氟、氯、C 1-3烷基、被至少一个氟或氯所取代的C 1-3烷基、羟基取代的C 1-3烷基或C 1-3烷氧基。
在一项优选的实施方案中，所述式Ⅰ化合物具有通式Ⅰ-2的结构：
Figure PCTCN2020070633-appb-000008
其中：
R 1是氢、氘、卤素、C 1-6烷基、C 1-6烷基氨基、C 1-6烷氧基中的任一种；
R 2是氢、氘、卤素、C 1-6烷基、被至少一个卤素所取代的C 1-6烷基、C 3-7环烷基、C 1-6烷基氨基、C 1-6烷氧基、杂环烷基中的任一种；
R 3是氢、氘、卤素、氰基、C 1-6烷基、C 3-7环烷基、C 1-6烷基氨基、C 1-6烷氧基、杂环烷基中的任一种；
R 4是氢、氘、C 1-6烷基中的任一种；
R 5是氢、氘、C 1-6烷基、被至少一个卤素所取代的C 1-6烷基、C 3-7环烷基中的任一种；
R 7和R 8分别独立的选自氢、氘、C 1-6烷基、被至少一个卤素原子、C 1-6烷氧基所取代的C 1-6烷基或羟基取代的C 1-6烷基。
在一项更优选的实施方案中，所述的R 7和R 8分别独立的选自氢、氘、C 1-6烷基、被至少一个卤素或C 1-6烷氧基或羟基所取代的C 1-6烷基。
在一项优选的实施方案中，所述式Ⅰ化合物具有通式Ⅰ-3的结构：
Figure PCTCN2020070633-appb-000009
其中：
R 1是氢、氘、卤素、C 1-6烷基、C 1-6烷基氨基、C 1-6烷氧基中的任一种；
R 2是氢、氘、卤素、C 1-6烷基、被至少一个卤素所取代的C 1-6烷基、C 3-7环烷基、C 1-6烷基氨基、C 1-6烷氧基、杂环烷基中的任一种；
R 3是氢、氘、卤素、氰基、C 1-6烷基、C 3-7环烷基、C 1-6烷基氨基、C 1-6烷氧基、杂环烷基中的任一种；
R 4是氢、氘、C 1-6烷基中的任一种；
R 5是氢、氘、C 1-6烷基、被至少一个卤素所取代的C 1-6烷基、C 3-7环烷基中的任一种；
R 9、R 10和R 11分别独立的选自氢、氘、C 1-6烷基、羟基、被至少一个卤素原子所取代的C 1-6烷基或羟基取代的C 1-6烷基、未取代或被至少一个卤素原子所取代的C 1-6烷氧基、未取代或被至少一个卤素原子或C 1-6烷基所取代的C 3-7环烷氧基、或R 9、R 10和R 11中的任两个可以形成取代或未取代的C 3-7环烷基，且R 9、R 10和R 11不同时为氢。
在一项更优选的实施方案中，R 9、R 10和R 11分别独立的选自氢、氘、甲基、乙基、正丙基、异丙基、羟基、甲氧基、乙氧基、环丙氧基、被至少一个氟或氯或羟基取代的甲基、乙基、正丙基、异丙基或C 1-3烷氧基，所述取代的C 3-7环烷基是被至少一个卤素原子、C 1-6烷基或C 1-6烷氧基所取代，优选的，所述取代的C 3-7环烷基是被1-3个氟、氯、溴、甲氧基或乙氧基所取代，所述C 3-7环烷基可以是环丙基、环丁基、环戊基或环己基。
在一项优选的实施方案中，所述的R为取代或未取代的下列基团：哌啶基、吡咯烷基、氮杂环丁烷基、吗啉基、C 1-3烷基。
在一项优选的实施方案中，所述的R为取代或未取代的下列基团：哌啶基、氮杂环丁烷基、C 1-6烷氧基、环丁基、C 1-3烷基、氨基甲酰基。
在一项更优选的实施方案中，所述的R为取代或未取代的哌啶-1-基，取代或未取代的氮杂环丁烷-1-基，环丙基，取代或未取代的环丁基，丙基，C 1-6烷氧基取代的甲基或乙基，其中，所述取代的哌啶-1-基是被至少一个羟基-C 1-6烷基、C 1-6烷基或羟基所取代，优选被羟基-C 1-6烷基或同时被C 1-6烷基和羟基所取代；所述取代的氮杂环丁烷-1-基是被至少一个卤素原子或C 1-6烷氧基所取代，更优选被1-3个氟、氯、溴、甲氧基或乙氧基所取代；所述取代的环丁基是被至少一个卤素原子、C 1-6烷基或C 1-6烷氧基所取代，更优选是被1-3个氟、氯、溴、甲基、乙基、异丙基、正丙基、甲氧基、乙氧基、正丙氧基或异丙氧基所取代。在一项更优选的实施方案中，所述的R为取代的哌啶-1-基，所述取代的哌啶-1-基是被至少一个羟基-C 1-3烷基、C 1-6烷氧基、C 1-3烷基或羟基所取代，优选被羟基-C 1-3烷基或同时被C 1-3烷基和羟基所取代。
在一项更优选的实施方案中，所述的R为取代或未取代的氮杂环丁烷-1-基，所述取代的氮杂环丁烷-1-基是被1-3个卤素原子或C 1-3烷氧基所取代。
在一项更优选的实施方案中，所述的R为C 1-6烷氧基取代的甲基或乙基或异丙基，优选为甲氧基、乙氧基、丙氧基或异丙氧基取代的甲基或乙基或异丙基。
在一项更优选的实施方案中，所述R 1是氢、氘、氟、氯、溴、甲基、乙基、异丙基、叔丁基、甲基氨基、乙基氨基、甲氧基、乙氧基、异丙氧基中的任一种；
R 2是氢、氘、氟、氯、溴、甲基、乙基、异丙基、叔丁基、三氟甲基、三氟甲基甲基、环丙基、环戊基、甲基氨基、乙基氨基、甲氧基、乙氧基、异丙氧基、吡咯烷基、吗啉基中的任一种；
R 3是氢、氘、氟、氯、溴、甲基、乙基、氰基中的任一种；
R 4是氢、氘、甲基、乙基中的任一种；
R 5是氢、氘、甲基、乙基、异丙基、丁基、仲丁基、异丁基、叔丁基、三氟甲基、三氟甲基甲基、环丙基中的任一种。
优选的，所述R 1是氢、氘、卤素、C 1-6烷氧基中的任一种；
R 2是氢、氘、卤素、C 1-6烷基氨基、C 1-6烷氧基中的任一种；
R 3是氢、氘、卤素中的任一种；
R 4是氢或氘；
R 5是氢、氘、C 1-6烷基、被至少一个氟所取代的C 1-6烷基、C 3-7环烷基中的任一种。
更优选的，所述R 1是氢或氘；
R 2是氢、氘、卤素、C 1-6烷氧基中的任一种；
R 3是氢或氘；
R 4是氢或氘；
R 5是氢、氘、甲基、乙基、异丙基、丁基、仲丁基、异丁基、叔丁基、三氟甲基、三氟甲基甲基、环丙基中的任一种；
R为取代或未取代的哌啶基、氮杂环丁烷基、吗啉基、氨基、环丙基、丙基、C 1-3烷基、C 1-3烷氧基、环丁基、或氨基甲酰基，所述取代是被一个或多个下列基团所取代：羟基、羟基-C 1-6烷基、卤素、C 1-3烷基、C 1-3烷氧基、C 1-3烷氧基-C 1-6烷基、至少一个卤素原子取代的C 1-3烷基、C 3-7环烷氧基。
在一项更优选的实施方案中，所述通式Ⅰ的化合物为如下任一种：
6-叔丁基-9-[2-(4-羟基哌啶-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-9-{2-[4-(羟甲基)哌啶-1-基]噻唑-5-基}-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
9-[2-(氮杂环丁烷-1-基)噻唑-5-基]-6-叔丁基-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-9-[2-(3,3-二氟氮杂环丁烷-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-10-甲氧基-9-(2-吗啉代噻唑-5-基)-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-9-[2-(二甲基氨基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-9-[2-(4-羟基-4-甲基哌啶-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-10-甲氧基-9-[2-(4-甲氧基哌啶-1-基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-10-甲氧基-9-[2-(3-甲氧基氮杂环丁烷-1-基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-10-甲氧基-9-[2-(甲氧基甲基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-9-[2-(3-氟氮杂环丁烷-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-10-甲氧基-9-(2-甲氧基噻唑-5-基)-2-氧代-6,7-二氢-2H-吡啶[2,1-a]异喹啉-3-甲酸；
6-叔丁基-9-[2-(乙氧基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶[2,1-a]异喹啉-3-甲酸；
6-叔丁基-9-[2-(乙氧基甲基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶[2,1-a]异喹 啉-3-甲酸；
6-叔丁基-10-甲氧基-9-[2-(1-甲氧基乙基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-9-[2-(1-羟乙基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-10-甲氧基-9-[2-(2-甲氧基丙-2-基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-10-甲氧基-2-氧代-9-(2-丙基噻唑-5-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-10-甲氧基-9-[2-(甲基氨基甲酰基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-9-[2-(乙基氨基甲酰基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-10-甲氧基-9-[2-(2-甲氧乙氧基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-10-甲氧基-9-{2–[(2-甲氧基乙基)氨基甲酰基]噻唑-5-基}-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-9-{2-[(二氟甲氧基)甲基]噻唑-5-基}-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-9-[2-(环丙氧基甲基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-9-[2–(3,3-二氟环丁基)噻唑-5-基}-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-9-[2-(3-氟环丁基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
6-叔丁基-10-甲氧基-9-[2-(3-甲氧基环丁基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸。
本发明还提供了一种药物组合物，其包含上述任一所述的一种通式Ⅰ化合物或其药学上可接受的盐、酯、异构体、溶剂化物、水合物、前药或同位素标记物。
在本发明的一些实施方案中，上述药物组合物还包含药学上可接受的载体。
在一项更优选的实施方案中，上述药物组合物还包括：
-药学上可接受的载体；
-辅剂；和/或
-赋形剂。
本发明还提供了一种药物制剂，其包括上述具有式I结构的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药或者所述的药物组合物，所述制剂为片剂、胶囊剂、注射剂、颗粒剂、粉剂、栓剂、丸剂、乳膏剂、糊剂、凝胶剂、散剂、口服溶液、吸入剂、混悬剂、干悬剂、贴剂、洗剂中的任一种。
本发明还提供了上述具有式I结构的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药，或者所述的药物组合物，或者所述的药物制剂，其用作预防和治疗乙型肝炎的用途。
本发明还提供了上述具有式I结构的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药，或者所述的药物组合物，或者所述的药物制剂用作预防和/或治疗乙型肝炎的用途。
本发明还提供了上述具有式I结构的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药，或者所述的药物组合物，或者所述的药物制剂在制备预防和/或治疗乙型肝炎药物中的应用。
本发明还提供了一种预防和/或治疗乙型肝炎的方法，其包括下列步骤：将治疗有效量的上述具有式I结构的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药，或者所述的药物组合物，或者所述的药物制剂施用于对其有需求的患者。
术语“治疗有效量”是指能够诱发细胞、组织、器官或生物体(例如患者)产生生物或医学反应的药物活性成分的剂量。
术语“施用”是指将药物活性成分(比如本发明的化合物)或包含药物活性成分的药物组合物(例如本发明的药物组合物)应用于患者或其细胞、组织、器官、生物流体等部位，以便使药物活性成分或药物组合物与患者或其细胞、组织、器官、生物流体等部位接触的过程。常见的施用方式包括(但不限于)口服施用、皮下施用、肌内施用、腹膜下施用、眼部施用、鼻部施用、舌下施用、直肠施用、阴道施用等。
术语“对其有需求”是指医生或其他护理人员对患者需要或者将要从预防和/或治疗过程中获益的判断，该判断的得出基于医生或其他护理人员在其专长领域中的各种因素。
术语“患者”(或称受试者)是指人类或非人类的动物(例如哺乳动物)。
本发明还提供了一种药物联合形式，其包含上述具有式I结构的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药，或者所述的药物组合物，或者所述的药物制剂，以及至少一种额外的乙型肝炎治疗剂。
优选地，所述的药物联合形式还含有如下至少一种物质：
HBV聚合酶抑制剂；干扰素α-2a；干扰素α-2b；聚乙二醇干扰素α-2a；利巴韦林；HBV预防疫苗；HBV治疗疫苗；HBV衣壳抑制剂；HBV RNA复制抑制剂；siRNA；HBsAg生成或分泌抑制剂；HBV抗体或TLR7激动剂。
本发明还提供一种预防和/或治疗乙型肝炎的方法，其包括下列步骤：将治疗有效量的上述具有 式I结构的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药，或者所述的药物组合物，或者所述的药物制剂，以及至少一种额外的乙型肝炎治疗剂施用于对其有需求的患者。
本发明还提供了一种具有式I结构的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药的制备方法，以下通过描述了通式I所示化合物的一种典型的合成路线，以进一步描述本发明的技术方案，具体结合以下示出的反应路线可以看出：
化合物1与TsNHNH 2缩合得到产物2；
产物2与醛3在EtONa的存在下反应得到产物4；
产物4与醋酸铵还原氨化后得到产物5；
产物5经甲酸酰化后得到酰胺6；
酰胺6经草酰氯处理，在FeCl 3存在下反应，分离后的粗品与浓硫酸在甲醇中反应得到化合物7；
化合物7与2-(乙氧基亚甲基)-3-氧代-丁酸乙酯8经关环反应得到产物9；
通过四氯苯醌将产物9氧化脱氢后，得到化合物10；
化合物10与双联频哪醇硼酸酯偶联，得到产物11；
产物11与取代的溴代噻唑偶联得到产物12；
产物12通过氢氧化钠或氢氧化锂水解酯基得到产物13。
Figure PCTCN2020070633-appb-000010
下面的实施例可以对本发明做进一步的描述，然而，这些实施例不应作为对本发明的范围的限制。
本发明中使用的缩写如下：
AUC 0-12:从0小时到12小时的药物浓度-时间曲线下面积
AUC INF:从0小时外推至无穷大的药物浓度-时间曲线下面积
CDCl 3：氘代氯仿
dioxane：1,4-二氧六环
CL：表观清除率
Cmax:药物峰浓度
CO 2：二氧化碳
conc.H 2SO 4：浓硫酸
DCM：二氯甲烷
Dioxane:1,4-二氧六环
DME：乙二醇二甲醚
DMF：N,N-二甲基甲酰胺
DMSO：二甲亚砜
DMSO-d 6：氘代二甲亚砜
EtOH：乙醇
EtONa：乙醇钠
F:生物利用度
FeCl 3：三氯化铁
g：克
HCOOH：甲酸
Hz：赫兹
h：小时
IC 50：半最大抑制浓度
LiOH：氢氧化锂
MeOH：甲醇
mg：毫克
mL：毫升
mL/hr/kg:毫升/小时/公斤
mL/kg：毫升/公斤
mmol：毫摩尔
MHz：兆赫兹
NaBH 3CN：氰基硼氢化钠
NaOH：氢氧化钠
ng/mL*hr:纳克/毫升*小时
NH 4OAc：醋酸铵
NMR：核磁共振
M：摩尔浓度
Oxalyl chloride：草酰氯
PBS：磷酸缓冲盐溶液
PdCl 2(dppf)：[1,1'-双(二苯基膦基)二茂铁]二氯化钯
Pd(PPh 3) 4:四(三苯基膦)钯
t 1/2:消除半衰期
TCQ：四氯苯醌
Tmax:血药浓度达峰时间
TLC：薄层色谱
TsNHNH 2：对甲基苯磺酰肼
uM：微摩尔/升
Vss:表观分布容积
μg：微克
μL：微升
δ：化学位移
以下描述本发明实施例中通用试验条件：
首先，实施例中的反应一般在氮气保护下进行。
进一步地，中间体和最终产物通过色谱柱、制备色谱板和ICSO快速制备色谱系统分离纯化。
进一步地，LC-MS液质联用色谱仪使用Waters公司ACQUITY Arc配备QDa Detector。质谱(MS)采用ESI源，仅指示母体分子的分子量M，通常汇报[M+H] +。注射体积是通过样品浓度来确定；流速为：1.2mL/min；HPLC的峰值是通过在220nm和254nm处的UV-Vis波长来记录读取的。流动相为0.01％甲酸的超纯水溶液(流动相A)和0.01％甲酸的乙腈溶液(流动相B)。梯度洗脱条件如下表1和表2所示：
表1：梯度洗脱条件1
时间(min) A(H 2O,0.01％HCOOH) B(CH 3CN,0.01％HCOOH)
0.0-0.3 95-85 5-15
0.3-3.2 85-20 15-80
3.2-3.8 20-5 80-95
3.8-3.81 5-95 95-5
3.81-4.0 95 5
表2：梯度洗脱条件2
时间(min) A(H 2O,0.01％HCOOH) B(CH 3CN,0.01％HCOOH)
0.00-5.90 95-5 5-95
5.90-5.91 5-95 95-5
5.91-6.00 95 5
进一步地，NMR谱图采用Varian 400MHz核磁共振谱仪获得数据，常以CDCl 3，DMSO-d 6作为溶剂，以ppm报告化学位移。各种峰的描述如下：s(单峰)，d(双峰)，t(三重峰)，q(四重峰)，m(多重峰)，dd(双二重峰)。偶合常数使用Hz表示。
实施例1：
6-叔丁基-9-[2-(4-羟基哌啶-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000011
步骤1a：制备6-叔丁基-10-甲氧基-2-氧代-9-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯
Figure PCTCN2020070633-appb-000012
氮气保护下，向9-溴-6-叔丁基-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶[2,1-a]异喹啉-3-甲酸乙酯(制备方法见WO 2018130152中实施例8)(3.0g,6.91mmol)的1,4-二氧六环(50mL)溶液中加入双联频哪醇硼酸酯(3.5g,13.81mmol),乙酸钾(1.4g,13.81mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(505mg，0.69mmol).将混合物在100℃搅拌1小时。将混合物用二氯甲烷(100mL)稀释，然后用水(100mL)和饱和食盐水(100mL)洗涤，然后无水硫酸钠干燥，过滤，减压浓缩得到粗产品，将粗产品通过柱层析纯化得到粗品黑色固体6-叔丁基-10-甲氧基-2-氧代-9-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(3g)。
步骤1b：制备1-(5-溴噻唑-2-基)哌啶-4-醇
Figure PCTCN2020070633-appb-000013
向2,5-二溴噻唑(500mg,2.06mmol)的1,4-二氧六环(30mL)溶液中加入哌啶-4-醇(250mg,2.47mmol)和N,N-二异丙基乙胺(372mg，2.88mmol)。将混合物在80℃搅拌8小时。将混合物用乙酸乙酯(100mL)稀释，然后用水(100mL)和饱和食盐水(100mL)洗涤，然后无水硫酸钠干燥，过滤，减压浓缩得到粗产品，将粗产品通过柱层析纯化得到棕色固体1-(5-溴噻唑-2-基)哌啶-4-醇(310mg)。
步骤1c：制备6-叔丁基-9-[2-(4-羟基哌啶-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2，1-a]异喹啉-3-甲酸乙酯
Figure PCTCN2020070633-appb-000014
氮气保护下，向6-叔丁基-10-甲氧基-2-氧代-9-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(100mg，0.21mmol)的N,N-二甲基甲酰胺(2mL)溶液中加入1-(5-溴噻唑-2-基)哌啶-4-醇(82mg,0.31mmol)，碳酸钾(58mg，0.41mmol)和四(三苯基磷)钯(48mg,0.04mmol)。将混合物在90℃搅拌4小时。将混合物用二氯甲烷(50mL)稀释，然后用水(50mL)和饱和食盐水(50mL)洗涤，然后无水硫酸钠干燥，过滤，减压浓缩得到粗产品，将粗产品通过柱层析纯化得到黄色固体6-叔丁基-9-[2-(4-羟基哌啶-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2，1-a]异喹啉-3-甲酸乙酯(40mg)。
步骤1d：制备6-叔丁基-9-[2-(4-羟基哌啶-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000015
向6-叔丁基-9-[2-(4-羟基哌啶-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2，1-a]异喹啉-3-甲酸乙酯(40mg，0.07mmol)的乙醇(4mL)溶液中加入10％的氢氧化钠溶液(1mL)，将混合物室温搅拌2小时。混合物浓缩得到粗产品。将粗品溶解在水(10mL)中，将溶液用1M的盐酸溶液调节pH至2，然后用二氯甲烷(10mL×3)萃取。合并有机相并用水(30mL×3)洗涤，然后浓缩得到黄色固体6-叔丁基-9-[2-(4-羟基哌啶-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H- 吡啶并[2,1-a]异喹啉-3-甲酸(9.9mg)。 1HNMR(DMSO-d 6,400MHz):δ8.75(s,1H),7.89(s,1H),7.69(s,1H),7.60(s,2H),4.61(d,J＝5.2Hz,1H),4.00(s,3H),3.83–3.72(m,5H),2.93–2.88(m,2H),1.86–1.81(s,2H),1.49–1.49(m,2H),0.74(s,9H)。MS实测值(ESI +)[(M+H) +]:510。
实施例2：
6-叔丁基-9-{2-[4-(羟甲基)哌啶-1-基]噻唑-5-基}-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000016
步骤2a：制备[1-(5-溴噻唑-2-基)哌啶-4-基]甲醇
Figure PCTCN2020070633-appb-000017
将2,5-二溴噻唑(100mg,0.41mmol)和哌啶-4-基甲醇(57mg,0.49mmol)按照类似于实施例1步骤1b的方法制备得到白色固体[1-(5-溴噻唑-2-基)哌啶-4-基]甲醇(51mg)。
步骤2b：制备6-叔丁基-9-{2-[4-(羟甲基)哌啶-1-基]噻唑-5-基}-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯
Figure PCTCN2020070633-appb-000018
将6-叔丁基-10-甲氧基-2-氧代-9-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(100mg,0.21mmol)和[1-(5-溴噻唑-2-基)哌啶-4-基]甲醇(58mg,0.21mmol)按照类似于实施例1步骤1c的方法制备得到黄色固体6-叔丁基-9-{2-[4-(羟甲基)哌啶-1-基]噻唑-5-基}-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(48mg)。
步骤2c：制备6-叔丁基-9-{2-[4-(羟甲基)哌啶-1-基]噻唑-5-基}-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000019
将6-叔丁基-9-{2-[4-(羟甲基)哌啶-1-基]噻唑-5-基}-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(48mg,0.09mmol)按照类似于实施例1步骤1d的方法制备得到黄色固体6-叔丁基-9-{2-[4-(羟甲基)哌啶-1-基]噻唑-5-基}-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸(11.2mg)。 1HNMR(DMSO-d 6,400MHz):δ8.75(s,1H),7.87(s,1H),7.67(s,1H),7.60(s,1H),7.59(s,1H),4.60(d,J＝5.2Hz,1H),4.00(s,3H),3.96(s,1H),3.32-3.28(m,4H),3.07(t,J＝12.0Hz,2H),1.77(d,J＝12.0Hz,2H),1.65(s,1H),1.25-1.20(m,2H),0.74(s,9H)。MS实测值(ESI +)[(M+H) +]:524。
实施例3：
9-[2-(氮杂环丁烷-1-基)噻唑-5-基]-6-叔丁基-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000020
步骤3a：制备2-(氮杂环丁烷-1-基)-5-溴噻唑
Figure PCTCN2020070633-appb-000021
将2,5-二溴噻唑(300mg,1.23mmol)和氮杂环丁烷(85mg,1.48mmol)按照类似于实施例1步骤1b的方法制备得到白色固体2-(氮杂环丁烷-1-基)-5-溴噻唑(55mg)。
步骤3b：制备9-[2-(氮杂环丁烷-1-基)噻唑-5-基]-6-叔丁基-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯
Figure PCTCN2020070633-appb-000022
将6-叔丁基-10-甲氧基-2-氧代-9-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(100mg,0.21mmol)和2-(氮杂环丁烷-1-基)-5-溴噻唑 (50mg,0.23mmol)按照类似于实施例1步骤1c的方法制备得到黄色固体9-[2-(氮杂环丁烷-1-基)噻唑-5-基]-6-叔丁基-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(14mg)。
步骤3c：9-[2-(氮杂环丁烷-1-基)噻唑-5-基]-6-叔丁基-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000023
将9-[2-(氮杂环丁烷-1-基)噻唑-5-基]-6-叔丁基-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(14mg,0.03mmol)按照类似于实施例1步骤1d的方法制备得到黄色固体9-[2-(氮杂环丁烷-1-基)噻唑-5-基]-6-叔丁基-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸(3.3mg)。 1HNMR(DMSO-d 6,400MHz):δ8.76(s,1H),7.94(s,1H),7.74(s,1H),7.63(s,1H),7.61(s,1H),4.61(d,J＝6.4Hz,1H),4.16–4.12(m,4H),4.01(s,3H),3.42-3.35(m.,2H),2.46(d,J＝6.8Hz,2H),0.74(s,9H)。MS实测值(ESI +)[(M+H) +]:466。
实施例4：
6-叔丁基-9-[2-(3,3-二氟氮杂环丁烷-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000024
步骤4a：制备2-(3,3-二氟氮杂环丁烷-1-基)-5-溴噻唑
Figure PCTCN2020070633-appb-000025
将2,5-二溴噻唑(300mg,1.23mmol)和3,3-二氟氮杂环丁烷(138mg,1.48mmol)按照类似于实施例1步骤1b的方法制备得到白色固体2-(3,3-二氟氮杂环丁烷-1-基)-5-溴噻唑(260mg)。
步骤4b：制备6-叔丁基-9-[2-(3,3-二氟氮杂环丁烷-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯
Figure PCTCN2020070633-appb-000026
将6-叔丁基-10-甲氧基-2-氧代-9-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(100mg,0.21mmol)和2-(3,3-二氟氮杂环丁烷-1-基)-5-溴噻唑(58mg,0.23mmol)按照类似于实施例1步骤1c的方法制备得到黄色固体6-叔丁基-9-[2-(3,3-二氟氮杂环丁烷-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(70mg)。
步骤4c：制备6-叔丁基-9-[2-(3,3-二氟氮杂环丁烷-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000027
将6-叔丁基-9-[2-(3,3-二氟氮杂环丁烷-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(70mg,0.13mmol)按照类似于实施例1步骤1d的方法制备得到黄色固体6-叔丁基-9-[2-(3,3-二氟氮杂环丁烷-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸(31.8mg)。 1HNMR(DMSO-d 6,400MHz):δ16.56(s,1H),8.76(s,1H),7.94(s,1H),7.79(s,1H),7.63(s,1H),7.61(s,1H),4.62–4.61(m,1H),4.58–4.52(m,4H),4.01(s,3H)3.38-3.33(m,2H),0.74(s,9H)。MS实测值(ESI +)[(M+H) +]:502。
实施例5：
6-叔丁基-10-甲氧基-9-(2-吗啉代噻唑-5-基)-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000028
步骤5a：制备4-(5-溴噻唑-2-基)吗啉
Figure PCTCN2020070633-appb-000029
将2,5-二溴噻唑(300mg,1.23mmol)和吗啡啉(129mg,1.48mmol)按照类似于实施例1步骤1b的方法制备得到白色固体4-(5-溴噻唑-2-基)吗啉(300mg)。
步骤5b：制备6-叔丁基-10-甲氧基-9-(2-吗啉代噻唑-5-基)-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯
Figure PCTCN2020070633-appb-000030
将6-叔丁基-10-甲氧基-2-氧代-9-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(100mg,0.21mmol)和4-(5-溴噻唑-2-基)吗啉(62mg,0.23mmol)按照类似于实施例1步骤1c的方法制备得到黄色固体6-叔丁基-10-甲氧基-9-(2-吗啉代噻唑-5-基)-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(100mg)。
步骤5c：制备6-叔丁基-10-甲氧基-9-(2-吗啉代噻唑-5-基)-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000031
将6-叔丁基-10-甲氧基-9-(2-吗啉代噻唑-5-基)-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(100mg,0.19mmol)按照类似于实施例1步骤1d的方法制备得到黄色固体6-叔丁基-10-甲氧基-9-(2-吗啉代噻唑-5-基)-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸(29.1mg)。 1HNMR(DMSO-d 6,400MHz):δ8.75(s,1H),7.90(s,1H),7.70(s,1H),7.60(s,1H),7.59(s,1H),4.63–4.60(m,1H),4.00(s,3H),3.76–3.70(m,4H),3.48–3.42(m,4H),3.38-3.34(m,2H),0.74(s,9H)。MS实测值(ESI +)[(M+H) +]:496。
实施例6：
6-叔丁基-9-[2-(二甲基氨基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000032
步骤6a：制备5-溴-2-(二甲基胺基)噻唑
Figure PCTCN2020070633-appb-000033
将2,5-二溴噻唑(300mg,2.47mmol)和二甲胺(1.447g,12.35mmol)按照类似于实施例1步骤1b的方法制备得白色固体5-溴-2-(二甲基胺基)噻唑(128mg)
步骤6b：制备6-叔丁基-9-[2-(二甲基氨基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯
Figure PCTCN2020070633-appb-000034
将6-叔丁基-10-甲氧基-2-氧代-9-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(250mg,0.52mmol)和5-溴-2-(二甲基胺基)噻唑(128mg，0.45mmol)按照类似于实施例1步骤1c的方法制备得到黄色固体6-叔丁基-9-[2-(二甲基氨基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(71mg)。
步骤6c：6-叔丁基-9-[2-(二甲基氨基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000035
将6-叔丁基-9-[2-(二甲基氨基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(71mg,0.15mmol)按照类似于实施例1步骤1d的方法制备得到黄色固体6-叔丁基-9-[2-(二甲基氨基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸(30.2mg)。 1HNMR(DMSO-d 6,400MHz):δ16.61(s,1H),8.75(s,1H),7.87(s,1H),7.65(s,1H),7.58(s,2H),4.60(d,J＝5.2Hz,1H),4.00(s,3H),3.49(d,J＝5.2Hz,2H),3.10(s,6H),0.74(s,9H)。MS实测值(ESI +)[(M+H) +]:454。
实施例7：
6-叔丁基-9-[2-(4-羟基-4-甲基哌啶-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000036
步骤7a：制备1-(5-溴噻唑-2-基)-4-甲基哌啶-4-醇
Figure PCTCN2020070633-appb-000037
将2,5-二溴噻唑(500mg,2.06mmol)和4-甲基哌啶-4-醇(285mg,2.47mmol)按照类似于实施例1步骤1b的方法制备得到白色固体1-(5-溴噻唑-2-基)-4-甲基哌啶-4-醇(390mg)。
步骤7b：制备6-叔丁基-9-[2-(4-羟基-4-甲基哌啶-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯
Figure PCTCN2020070633-appb-000038
将6-叔丁基-10-甲氧基-2-氧代-9-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(150mg,0.32mmol)和1-(5-溴噻唑-2-基)-4-甲基哌啶-4-醇(104mg,0.37mmol)按照类似于实施例1步骤1c的方法制备得到黄色固体6-叔丁基-9-[2-(4-羟基-4-甲基哌啶-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(100mg)。
步骤7c：制备6-叔丁基-9-[2-(4-羟基-4-甲基哌啶-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000039
将6-叔丁基-9-[2-(4-羟基-4-甲基哌啶-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(100mg,0.18mmol)按照类似于实施例1步骤1d的方法制备得 到黄色固体6-叔丁基-9-[2-(4-羟基-4-甲基哌啶-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸(65.9mg)。 1HNMR(DMSO-d 6,400MHz):δ8.76(s,1H),7.90(s,1H),7.70(s,1H),7.61(s,1H),7.60(s,1H),4.61(d,J＝5.6Hz,1H),4.01(s,3H),3.71-3.70(m,2H),3.50-3.32(m,4H),1.62-1.56(m.,4H),1.18(s,3H),0.74(s,9H)。MS实测值(ESI +)[(M+H) +]:524。
实施例8：
6-叔丁基-10-甲氧基-9-[2-(4-甲氧基哌啶-1-基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000040
步骤8a：制备5-溴-2-(4-甲氧基哌啶-1-基)噻唑
Figure PCTCN2020070633-appb-000041
将2,5-二溴噻唑(500mg,2.06mmol)和4-甲氧基哌啶(285mg,2.47mmol)按照类似于实施例1步骤1b的方法制备得到白色固体5-溴-2-(4-甲氧基哌啶-1-基)噻唑(390mg)。
步骤8b：制备6-叔丁基-10-甲氧基-9-[2-(4-甲氧基哌啶-1-基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯
Figure PCTCN2020070633-appb-000042
将6-叔丁基-10-甲氧基-2-氧代-9-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(150mg,0.32mmol)和5-溴-2-(4-甲氧基哌啶-1-基)噻唑(104mg,0.37mmol)按照类似于实施例1步骤1c的方法制备得到黄色固体6-叔丁基-10-甲氧基-9-[2-(4-甲氧基哌啶-1-基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(100mg)。
步骤8c：制备6-叔丁基-10-甲氧基-9-[2-(4-甲氧基哌啶-1-基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000043
将6-叔丁基-10-甲氧基-9-[2-(4-甲氧基哌啶-1-基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(100mg,0.18mmol)按照类似于实施例1步骤1d的方法制备得到黄色固体6-叔丁基-10-甲氧基-9-[2-(4-甲氧基哌啶-1-基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸(72.1mg)。 1HNMR(DMSO-d 6,400MHz):δ8.75(s,1H),7.88(s,1H),7.68(s,1H),7.60(s,1H),7.59(s,1H),4.61(d,J＝4.8Hz,1H),4.00(s,3H),3.76-3.75(m,4H),3.48-3.45(m,1H),3.36–3.33(m,2H),3.29(s,3H),1.95–1.92(m.,2H),1.56–1.54(m,2H),0.74(s,9H)。MS实测值(ESI +)[(M+H) +]:524。
实施例9：
6-叔丁基-10-甲氧基-9-[2-(3-甲氧基氮杂环丁烷-1-基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000044
步骤9a：制备5-溴-2-(3-甲氧基氮杂环丁烷-1-基)噻唑
Figure PCTCN2020070633-appb-000045
将2,5-二溴噻唑(500mg,2.06mmol)和3-甲氧基氮杂环丁烷(215mg,2.47mmol)按照类似于实施例1步骤1b的方法制备得到白色固体5-溴-2-(3-甲氧基氮杂环丁烷-1-基)噻唑(370mg)。
步骤9b：制备6-叔丁基-10-甲氧基-9-[2-(3-甲氧基氮杂环丁烷-1-基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯
Figure PCTCN2020070633-appb-000046
将6-叔丁基-10-甲氧基-2-氧代-9-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6,7-二氢 -2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(150mg,0.32mmol)和5-溴-2-(3-甲氧基氮杂环丁烷-1-基)噻唑(93mg,0.37mmol)按照类似于实施例1步骤1c的方法制备得到黄色固体6-叔丁基-10-甲氧基-9-[2-(3-甲氧基氮杂环丁烷-1-基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(100mg)。
步骤9c：制备6-叔丁基-10-甲氧基-9-[2-(3-甲氧基氮杂环丁烷-1-基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000047
将6-叔丁基-10-甲氧基-9-[2-(3-甲氧基氮杂环丁烷-1-基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(100mg,0.18mmol)按照类似于实施例1步骤1d的方法制备得到黄色固体6-叔丁基-10-甲氧基-9-[2-(3-甲氧基氮杂环丁烷-1-基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸(30.9mg)。 1HNMR(DMSO-d 6,400MHz):δ16.59(s,1H),8.75(s,1H),7.87(s,1H),7.71(s,1H),7.60(s,1H),7.59(s,1H),4.61(d,J＝6.0Hz,1H),4.42-4.38(m,1H),4.28-4.23(m,2H),4.00(s,3H),3.90–3.88(m,2H),3.38–3.34(m,2H),3.26(s,3H),0.74(s,9H)。MS实测值(ESI +)[(M+H) +]:496。
实施例10：
6-叔丁基-10-甲氧基-9-[2-(甲氧基甲基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000048
步骤10a：制备噻唑-2-基甲醇
Figure PCTCN2020070633-appb-000049
0℃下，向噻唑-2-甲醛(1.0g,8.84mmol)的甲醇(10mL)溶液中加入硼氢化钠(800mg,21.21mmol)。将混合物在室温搅拌2小时。将混合物用水(10mL)淬灭，加乙酸乙酯(50mL)稀释，然后用水(50mL)和饱和食盐水(50mL)洗涤，然后无水硫酸钠干燥，过滤，减压浓缩得到粗产品， 将粗产品通过柱层析纯化得到白色固体噻唑-2-基甲醇(1.0g)。
步骤10b：制备2-(甲氧基甲基)噻唑
Figure PCTCN2020070633-appb-000050
在0℃中，向噻唑-2-基甲醇(1.0g,8.68mmol)的四氢呋喃(10mL)溶液中加入60％氢化钠(521mg,13.30mmol)。将混合物在室温搅拌半小时。再向溶液中加入碘甲烷(0.6mL,9.55mmol),将混合物在室温搅拌2小时。将混合物用水(10mL)淬灭，加乙酸乙酯(50mL)稀释，然后用水(50mL)和饱和食盐水(50mL)洗涤，然后无水硫酸钠干燥，过滤，减压浓缩得到粗产品，将粗产品通过柱层析纯化得到无色液体2-(甲氧基甲基)噻唑(920mg)。
步骤10c：制备5-溴-2-(甲氧基甲基)噻唑
Figure PCTCN2020070633-appb-000051
向2-(甲氧基甲基)噻唑(920mg,7.12mmol)的N,N-二甲基甲酰胺(5mL)溶液中加入N-溴代丁二酰亚胺(1.9g，10.68mmol)。将混合物在室温搅拌1小时。将混合物用乙酸乙酯(50mL)稀释，然后用水(50mL)和饱和食盐水(50mL)洗涤，然后无水硫酸钠干燥，过滤，减压浓缩得到粗产品，将粗产品通过柱层析纯化得到白色固体5-溴-2-(甲氧基甲基)噻唑(900mg)。
步骤10d：制备6-叔丁基-10-甲氧基-9-[2-(甲氧基甲基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯
Figure PCTCN2020070633-appb-000052
将6-叔丁基-10-甲氧基-2-氧代-9-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(150mg,0.32mmol)和5-溴-2-(甲氧基甲基)噻唑(78mg,0.37mmol)按照类似于实施例1步骤1c的方法制备得到黄色固体6-叔丁基-10-甲氧基-9-[2-(甲氧基甲基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(150mg)。
步骤10e：制备6-叔丁基-10-甲氧基-9-[2-(甲氧基甲基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000053
将6-叔丁基-10-甲氧基-9-[2-(甲氧基甲基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(150mg,0.31mmol)按照类似于实施例1步骤1d的方法制备得到黄色固体6-叔丁基-10-甲氧基-9-[2-(甲氧基甲基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸(49.8mg)。 1HNMR(DMSO-d 6,400MHz):δ8.78(s,1H),8.38(s,1H),7.95(s,1H),7.70(s,1H),7.67(s,1H),4.74(s,2H),4.64(d,J＝5.6Hz,1H),4.05(s,3H),3.42(s,3H),3.39-3.32(m,2H),0.74(s,9H)。MS实测值(ESI +)[(M+H) +]:455。
实施例11：
6-叔丁基-9-[2-(3-氟氮杂环丁烷-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000054
步骤11a：制备5-溴-2-(3-氟氮杂环丁烷-1-基)噻唑
Figure PCTCN2020070633-appb-000055
将2,5-二溴噻唑(500mg,2.06mmol)和3-氟氮杂环丁烷(185mg,2.47mmol)按照类似于实施例1步骤1b的方法制备得到白色固体5-溴-2-(3-氟氮杂环丁烷-1-基)噻唑(210mg)。
步骤11b：制备6-叔丁基-9-[2-(3-氟氮杂环丁烷-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯
Figure PCTCN2020070633-appb-000056
将6-叔丁基-10-甲氧基-2-氧代-9-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6,7-二氢 -2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(150mg,0.32mmol)和5-溴-2-(3-氟氮杂环丁烷-1-基)噻唑(89mg,0.37mmol)按照类似于实施例1步骤1c的方法制备得到黄色固体6-叔丁基-9-[2-(3-氟氮杂环丁烷-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(100mg)。
步骤11c：制备6-叔丁基-9-[2-(3-氟氮杂环丁烷-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000057
将6-叔丁基-9-[2-(3-氟氮杂环丁烷-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯乙酯(100mg,0.19mmol)按照类似于实施例1步骤1d的方法制备得到黄色固体6-叔丁基-9-[2-(3-氟氮杂环丁烷-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(61.9mg)。 1HNMR(DMSO-d 6,400MHz):δ16.57(s,1H),8.75(s,1H),7.89(s,1H),7.73(s,1H),7.61(s,1H),7.60(s,1H),5.56(d,J＝56.0Hz,1H),4.61(d,J＝5.2Hz,1H),4.44-4.34(m,2H),4.21-4.12(m,2H),4.00(s,3H),3.42-3.33(m,2H),0.74(s,9H)。MS实测值(ESI +)[(M+H) +]:484。
实施例12：
6-叔丁基-10-甲氧基-9-(2-甲氧基噻唑-5-基)-2-氧代-6,7-二氢-2H-吡啶[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000058
步骤12a：制备5-溴-2-甲氧基噻唑
Figure PCTCN2020070633-appb-000059
向2,5-二溴噻唑(500mg,2.06mmol)的无水甲醇(5mL)溶液中，加入甲醇钠(333.6mg，6.17mmol)。反应混合物加热至30℃并在30℃下搅拌12小时。用5mL水淬灭反应，再加入20mL 水，有机相被分离，水相再用20mL乙酸乙酯萃取三次，合并的有机相浓缩后经过柱层析得到无色油状物5-溴-2-甲氧基噻唑(230mg)。
步骤12b：制备6-叔丁基-10-甲氧基-9-(2-甲氧基噻唑-5-基)-2-氧代-6,7-二氢-2H-吡啶[2,1-a]异喹啉-3-甲酸乙酯
Figure PCTCN2020070633-appb-000060
将6-叔丁基-10-甲氧基-2-氧代-9-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(150mg，0.375mmol)和5-溴-2-甲氧基噻唑(73mg,0.375mmol)按照类似于实施例1步骤1c的方法制备得到黄色固体6-叔丁基-10-甲氧基-9-(2-甲氧基噻唑-5-基)-2-氧代-6,7-二氢-2H-吡啶[2,1-a]异喹啉-3-甲酸乙酯(110mg)。
步骤12c：制备6-叔丁基-10-甲氧基-9-(2-甲氧基噻唑-5-基)-2-氧代-6,7-二氢-2H-吡啶[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000061
将6-叔丁基-10-甲氧基-9-(2-甲氧基噻唑-5-基)-2-氧代-6,7-二氢-2H-吡啶[2,1-a]异喹啉-3-甲酸乙酯(110mg，0.234mmol)按照类似于实施例1步骤1d的方法制备得到淡黄色色固体6-叔丁基-10-甲氧基-9-(2-甲氧基噻唑-5-基)-2-氧代-6,7-二氢-2H-吡啶[2,1-a]异喹啉-3-甲酸(40mg)。 1H NMR(DMSO-d 6,400MHz):δ8.77(s,1H),7.88(s,1H),7.82(s,1H),7.66(s,1H),7.64(s,1H),4.63–4.62(m,1H),4.06(s,3H),4.02(s,3H),3.39–3.34(m,2H),0.74(s,9H).MS实测值(ESI +)[(M+H) +]:441。
实施例13：
6-叔丁基-9-[2-(乙氧基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000062
步骤13a：制备5-溴-2-乙氧基噻唑
Figure PCTCN2020070633-appb-000063
将2,5-二溴噻唑(500mg,2.06mmol)和乙醇钠(420.21mg，6.17mmol)按照类似于实施例12步骤12a的方法制备得到无色油状物5-溴-2-乙氧基噻唑(95mg)。
步骤13b：制备6-叔丁基-9-[2-(乙氧基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶[2,1-a]异喹啉-3-甲酸乙酯
Figure PCTCN2020070633-appb-000064
将6-叔丁基-10-甲氧基-2-氧代-9-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(180mg，0.45mmol)和5-溴-2-乙氧基噻唑(94mg,0.45mmol)按照类似于实施例1步骤1c的方法制备得到黄色固体6-叔丁基-9-[2-(乙氧基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶[2,1-a]异喹啉-3-甲酸乙酯(120mg)。
步骤13c：制备6-叔丁基-9-[2-(乙氧基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000065
将6-叔丁基-9-[2-(乙氧基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶[2,1-a]异喹啉-3-甲酸乙酯(120mg，0.25mmol)按照类似于实施例1步骤1d的方法制备得到淡黄色色固体6-叔丁基-9-[2-(乙氧基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶[2,1-a]异喹啉-3-甲酸(50mg)。 1H NMR(DMSO-d 6,400MHz):δ8.77(s,1H),7.86(s,1H),7.80(s,1H),7.65(s,1H),7.63(s,1H),4.62–4.61(m,1H),4.48–4.43(m,2H),4.01(s,3H),3.46–3.38(m,2H),1.38(t,J＝8.0Hz,3H),0.74(s,9H).MS实测值(ESI +)[(M+H) +]:455。
实施例14：
6-叔丁基-9-[2-(乙氧基甲基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000066
步骤14a：制备2-乙氧甲基噻唑
Figure PCTCN2020070633-appb-000067
将2-噻唑甲醇(450mg，3.91mmol)和碘乙烷(914.3mg，5.86mmol)按照类似于实施例10步骤10b的方法制备得到无色油状物2-乙氧甲基噻唑(330mg)。
步骤14b：制备5-溴-2-乙氧甲基噻唑
Figure PCTCN2020070633-appb-000068
将2-乙氧甲基噻唑(0.33g，2.30mmol)按照类似于实施例10步骤10c的方法制备得到白色固体5-溴-2-乙氧甲基噻唑(110mg)。
步骤14c：制备6-叔丁基-9-[2-(乙氧基甲基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶[2,1-a]异喹啉-3-甲酸乙酯
Figure PCTCN2020070633-appb-000069
将6-叔丁基-10-甲氧基-2-氧代-9-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(180mg，0.45mmol)和5-溴-2-乙氧甲基噻唑(110mg，0.50mmol)按照类似于实施例1步骤1c的方法制备得到黄色固体6-叔丁基-9-[2-(乙氧基甲基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶[2,1-a]异喹啉-3-甲酸乙酯(80mg)。
步骤14d：制备6-叔丁基-9-[2-(乙氧基甲基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000070
将6-叔丁基-9-[2-(乙氧基甲基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶[2,1-a]异喹啉-3-甲酸乙酯(80mg，0.16mmol)按照类似于实施例1步骤1d的方法制备得到白色固体6-叔丁基-9-[2-(乙氧基甲基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶[2,1-a]异喹啉-3-甲酸(30mg)。 1H NMR(DMSO-d 6,400MHz):δ8.78(s,1H),8.37(s,1H),7.92(s,1H),7.69(s,1H),7.66(s,1H),4.77(s,2H),4.64–4.63(m,1H),4.05(s,3H),3.65–3.60(m,2H),3.43–3.38(m,2H),1.19(t,J＝8.0Hz,3H),0.74(s,9H).MS实测值(ESI +)[(M+H) +]:469。
实施例15：
6-叔丁基-10-甲氧基-9-[2-(1-甲氧基乙基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000071
步骤15a：制备1-(噻唑-2-基)乙-1-醇
Figure PCTCN2020070633-appb-000072
将1-(噻唑-2-基)乙-1-酮(1.0g,7.86mmol)按照类似于实施例10步骤10a的方法制备得到无色油状液体1-(噻唑-2-基)乙-1-醇(1.0g)。
步骤15b：制备1-(5-溴噻唑-2-基)乙-1-醇
Figure PCTCN2020070633-appb-000073
将1-(噻唑-2-基)乙-1-醇(1.0g,7.74mmol)按照类似于实施例10步骤10c的方法制备得到白色固体1-(5-溴噻唑-2-基)乙-1-醇(1.0g)。
步骤15c：制备5-溴-2-(1-甲氧基乙基)噻唑
Figure PCTCN2020070633-appb-000074
将1-(5-溴噻唑-2-基)乙-1-醇(500mg,2.4mmol)按照类似于实施例10步骤10b的方法制备得到白色固体5-溴-2-(1-甲氧基乙基)噻唑(100mg)。
步骤15d：制备6-叔丁基-10-甲氧基-9-[2-(1-甲氧基乙基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯
Figure PCTCN2020070633-appb-000075
将6-叔丁基-10-甲氧基-2-氧代-9-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(150mg,0.32mmol)和5-溴-2-(1-甲氧基乙基)噻唑(83mg,0.37mmol)按照类似于实施例1步骤1c的方法制备得到黄色固体6-叔丁基-10-甲氧基-9-[2-(1-甲氧基乙基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(100mg)。
步骤15e：制备6-叔丁基-10-甲氧基-9-[2-(1-甲氧基乙基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000076
将6-叔丁基-10-甲氧基-9-[2-(1-甲氧基乙基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(100mg,0.20mmol)按照类似于实施例1步骤1d的方法制备得到黄色固体6-叔丁基-10-甲氧基-9-[2-(1-甲氧基乙基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸(26.4mg)。 1HNMR(DMSO-d 6,400MHz):δ16.51(s,1H),8.78(s,1H),8.35(s,1H),7.92(s,1H),7.70(s,1H),7.67(s,1H),4.72-4.63(m,2H),4.05(s,3H),3.41-3.37(m,2H),3.36(s,3H),1.50(d,J＝5.6Hz,3H),0.74(s,9H)。MS实测值(ESI +)[(M+H) +]:469。
实施例16：
6-叔丁基-9-[2-(1-羟乙基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹 啉-3-甲酸
Figure PCTCN2020070633-appb-000077
步骤16a：制备6-叔丁基-9-[2-(1-羟乙基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯
Figure PCTCN2020070633-appb-000078
将6-叔丁基-10-甲氧基-2-氧代-9-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(150mg,0.32mmol)和1-(5-溴噻唑-2-基)乙-1-醇(78mg,0.37mmol)按照类似于实施例1步骤1c的方法制备得到黄色固体6-叔丁基-9-[2-(1-羟乙基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(80mg)。
步骤16b：制备6-叔丁基-9-[2-(1-羟乙基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000079
将6-叔丁基-9-[2-(1-羟乙基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(80mg,0.16mmol)按照类似于实施例1步骤1d的方法制备得到黄色固体6-叔丁基-9-[2-(1-羟乙基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸(20.8mg)。 1HNMR(DMSO-d 6,400MHz):δ16.52(s,1H),8.78(s,1H),8.29(s,1H),7.88(s,1H),7.69(s,1H),7.66(s,1H),6.14(d,J＝5.2Hz,1H),4.98-4.94(m,1H),4.63(d,J＝5.2Hz,1H),4.04(s,3H),3.40–3.35(m,2H),1.47(d,J＝7.0Hz,3H),0.74(s,9H)。MS实测值(ESI +)[(M+H) +]:455。
实施例17：
6-叔丁基-10-甲氧基-9-[2-(2-甲氧基丙-2-基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a] 异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000080
步骤17a：制备2-(噻唑-2-基)丙-2-醇
Figure PCTCN2020070633-appb-000081
氮气保护下，在-78℃向1-(噻唑-2-基)乙-1-酮(2.0g,15.73mmol)的四氢呋喃(20mL)溶液中逐滴加入甲基溴化镁(8.0mL,24.00mmol)。将混合物在-78℃搅拌2小时。将混合物用饱和氯化铵水溶液(10mL)淬灭，加乙酸乙酯(50mL)稀释，然后用水(50mL)和饱和食盐水(50mL)洗涤，然后无水硫酸钠干燥，过滤，减压浓缩得到粗产品，将粗产品通过柱层析纯化得到白色固体2-(噻唑-2-基)丙-2-醇(1.6g)。
步骤17b：制备2-(5-溴噻唑-2-基)丙-2-醇
Figure PCTCN2020070633-appb-000082
将2-(噻唑-2-基)丙-2-醇(1.6g,11.17mmol)按照类似于实施例10步骤10c的方法制备得到白色固体2-(5-溴噻唑-2-基)丙-2-醇(1.6g)。
步骤17c：制备5-溴-2-(2-甲氧基丙-2-基)噻唑
Figure PCTCN2020070633-appb-000083
将2-(5-溴噻唑-2-基)丙-2-醇(500mg,2.25mmol)按照类似于实施例10步骤10b的方法制备得到白色固体5-溴-2-(2-甲氧基丙-2-基)噻唑(300mg)。
步骤17d：制备6-叔丁基-10-甲氧基-9-[2-(2-甲氧基丙-2-基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯
Figure PCTCN2020070633-appb-000084
将6-叔丁基-10-甲氧基-2-氧代-9-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(150mg,0.32mmol)和5-溴-2-(2-甲氧基丙-2-基)噻唑(88mg,0.37mmol)按照类似于实施例1步骤1c的方法制备得到黄色固体6-叔丁基-10-甲氧基-9-[2-(2-甲氧基丙-2-基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(120mg)。
步骤17e：制备6-叔丁基-10-甲氧基-9-[2-(2-甲氧基丙-2-基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000085
将6-叔丁基-10-甲氧基-9-[2-(2-甲氧基丙-2-基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(120mg,0.23mmol)按照类似于实施例1步骤1d的方法制备得到黄色固体6-叔丁基-10-甲氧基-9-[2-(2-甲氧基丙-2-基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸(26.4mg)。 1HNMR(DMSO-d 6,400MHz):δ16.51(s,1H),8.78(s,1H),8.31(s,1H),7.90(s,1H),7.69(s,1H),7.67(s,1H),4.64(s,1H),4.04(s,3H),3.40–3.35(m,2H),3.20(s,3H),1.57(s,6H),0.74(s,9H)。MS实测值(ESI +)[(M+H) +]:483。
实施例18：
6-叔丁基-10-甲氧基-2-氧代-9-(2-丙基噻唑-5-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000086
步骤18a:制备5-溴-2-丙基噻唑
Figure PCTCN2020070633-appb-000087
将2-丙基噻唑(264mg,2mmol)按照类似于实施例10步骤10c的方法制备得到5-溴-2-丙基 噻唑(320mg)。
步骤18b:制备6-叔丁基-10-甲氧基-2-氧代-9-(2-丙基噻唑-5-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯
Figure PCTCN2020070633-appb-000088
将6-叔丁基-10-甲氧基-2-氧代-9-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(193mg,0.4mmol)和5-溴-2-丙基噻唑(107mg,0.52mmol)按照类似于实施例1步骤1c的方法制备得到6-叔丁基-10-甲氧基-2-氧代-9-(2-丙基噻唑-5-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(73mg)。
步骤18c:制备6-叔丁基-10-甲氧基-2-氧代-9-(2-丙基噻唑-5-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000089
将6-叔丁基-10-甲氧基-2-氧代-9-(2-丙基噻唑-5-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(73mg,0.152mmol)按照类似于实施例1步骤1d的方法制备得到黄色固体6-叔丁基-10-甲氧基-2-氧代-9-(2-丙基噻唑-5-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸(53.5mg)。 1H NMR(DMSO-d 6,400MHz):δ16.48(s,1H),8.76(s,1H),8.28(s,1H),7.88(s,1H),7.67(s,1H),7.64(s,1H),4.62(s,1H),4.03(s,3H),3.63–3.51(m,2H),2.96(t,J＝7.2Hz,2H),1.79–1.74(m,2H),0.96(t,J＝7.2Hz,3H),0.74(s,9H)。MS实测值(ESI +)[(M+H) +]:453。
实施例19：
6-叔丁基-10-甲氧基-9-[2-(甲基氨基甲酰基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000090
步骤19a:制备5-溴-N-甲基噻唑-2-甲酰胺
Figure PCTCN2020070633-appb-000091
向5-溴噻唑-2-羧酸(200mg,0.96mmol)的二氯甲烷(5mL)溶液中加入一滴N,N-二甲基甲酰胺和草酰氯(246μL,2.88mmol)。该混合物在室温下搅拌一小时后，减压浓缩，残留物溶解在四氢呋喃(5mL)溶液中，然后在冰浴条件下缓慢滴加甲胺的四氢呋喃溶液(2M,960μL)，该混合物在室温下搅拌6h。反应结束后，减压浓缩，加入二氯甲烷(10mL)溶液，水和饱和氯化钠溶液各洗涤两遍，有机层用无水硫酸钠干燥，减压浓缩得到粗产品，将粗产品通过快速柱层析色谱纯化得到白色固体5-溴-N-甲基噻唑-2-甲酰胺(180mg)。
步骤19b:制备6-叔丁基-10-甲氧基-9-[2-(甲基氨基甲酰基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯
Figure PCTCN2020070633-appb-000092
将6-叔丁基-10-甲氧基-2-氧代-9-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(193mg,0.4mmol)和5-溴-N-甲基噻唑-2-甲酰胺(115mg,0.52mmol)按照类似于实施例1步骤1c的方法制备得到6-叔丁基-10-甲氧基-9-[2-(甲基氨基甲酰基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(42mg)
步骤19c:制备6-叔丁基-10-甲氧基-9-[2-(甲基氨基甲酰基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000093
将6-叔丁基-10-甲氧基-9-[2-(甲基氨基甲酰基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(42mg,0.085mmol)按照类似于实施例1步骤1d的方法制备得到黄色固体6-叔丁基-10-甲氧基-9-[2-(甲基氨基甲酰基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸(33mg)。 1H NMR(DMSO-d 6,400MHz):δ8.81(s,1H),8.59(s,1H),8.51(s,1H),8.04(s,1H),7.61(s,1H),7.18(s,1H),4.38(s,1H),4.08(s,3H),3.33–3.32(m,2H),2.81(d,J＝4.4Hz,3H),0.74(s,9H).MS实测值(ESI +)[(M+H) +]:468。
实施例20：
6-叔丁基-9-[2-(乙基氨基甲酰基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000094
步骤20a:制备5-溴-N-乙基噻唑-2-甲酰胺
Figure PCTCN2020070633-appb-000095
将5-溴噻唑-2-羧酸(200mg,0.96mmol)和乙胺的四氢呋喃溶液(2M,960μL)按照类似于实施例19步骤19a的方法制备得到5-溴-N-乙基噻唑-2-甲酰胺(210mg)。
步骤20b:制备6-叔丁基-9-[2-(乙基氨基甲酰基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯
Figure PCTCN2020070633-appb-000096
将6-叔丁基-10-甲氧基-2-氧代-9-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(193mg,0.4mmol)和5-溴-N-乙基噻唑-2-甲酰胺(122mg,0.52mmol)按照类似于实施例1步骤1c的方法制备得到6-叔丁基-9-[2-(乙基氨基甲酰基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(15mg)。
步骤20c:制备6-叔丁基-9-[2-(乙基氨基甲酰基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000097
将6-叔丁基-9-[2-(乙基氨基甲酰基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(15mg,0.029mmol)按照类似于实施例1步骤1d的方法制备得到黄色固体6-叔丁基-9-[2-(乙基氨基甲酰基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸(8.6mg)。 1H NMR(DMSO-d 6,400MHz):δ16.42(s,1H),8.89(t,J＝5.2Hz,1H),8.78(s,1H),8.61(s,1H),8.09(s,1H),7.73(s,1H),7.69(s,1H),4.64(d,J＝2.4Hz,1H),4.09(s,3H),3.46–3.43(m,2H),3.30(d,J＝6.8Hz,2H),1.13(t,J＝7.2Hz,3H),0.75(s,9H).MS实测值(ESI +)[(M+H) +]:482。
实施例21：
6-叔丁基-10-甲氧基-9-[2-(2-甲氧乙氧基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000098
步骤21a：制备5-溴-2-(2-甲氧乙氧基)噻唑
Figure PCTCN2020070633-appb-000099
将2,5-二溴噻唑(200mg,0.82mmol)和乙二醇单甲醚(6mL)按照类似于实施例12步骤12a的方法制备得白色固体5-溴-2-(2-甲氧乙氧基)噻唑(90mg)。
步骤21b：制备6-叔丁基-10-甲氧基-9-[2-(2-甲氧乙氧基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯
Figure PCTCN2020070633-appb-000100
将6-叔丁基-10-甲氧基-2-氧代-9-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(146mg,0.30mmol)和5-溴-2-(甲氧乙氧基)噻唑(90mg，0.38mmol)按照类似于实施例1步骤1c的方法制备得到黄色固体6-叔丁基-10-甲氧基-9-[2-(2-甲氧乙氧基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(140mg)。
步骤21c：6-叔丁基-10-甲氧基-9-[2-(2-甲氧乙氧基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000101
将6-叔丁基-10-甲氧基-9-[2-(2-甲氧乙氧基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(140mg,0.27mmol)按照类似于实施例1步骤1d的方法制备得到黄色固体6-叔丁基-10-甲氧基-9-[2-(2-甲氧乙氧基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸(47mg)。 1HNMR(DMSO-d 6,400MHz):δ8.75(s,1H),7.85(s,1H),7.80(s,1H),7.65 (s,1H),7.60(s,1H),4.62(d,J＝4.4Hz,1H),4.53(t,J＝4.0Hz,2H),4.00(s,3H),3.72–3.67(m,2H),3.45–3.35(m,2H),3.33(s,3H),0.74(s,9H)。MS实测值(ESI +)[(M+H) +]:485。
实施例22：
6-叔丁基-10-甲氧基-9-{2–[(2-甲氧基乙基)氨基甲酰基]噻唑-5-基}-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000102
步骤22a:制备5-溴-N-(2-甲氧基乙基)噻唑-2-甲酰胺
Figure PCTCN2020070633-appb-000103
将5-溴噻唑-2-羧酸(200mg,0.96mmol)和2-甲氧基乙胺(144mg,1.92mmol)按照类似于实施例19步骤19a的方法制备得到5-溴-N-(2-甲氧基乙基)噻唑-2-甲酰胺(192mg)。
步骤22b:制备6-叔丁基-10-甲氧基-9-{2–[(2-甲氧基乙基)氨基甲酰基]噻唑-5-基}-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯
Figure PCTCN2020070633-appb-000104
将6-叔丁基-10-甲氧基-2-氧代-9-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(193mg,0.4mmol)和5-溴-N-(2-甲氧基乙基)噻唑-2-甲酰胺(138mg,0.52mmol)按照类似于实施例1步骤1c的方法制备得到6-叔丁基-10-甲氧基-9-{2–[(2-甲氧基乙基)氨基甲酰基]噻唑-5-基}-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(77mg)。
步骤22c:制备6-叔丁基-10-甲氧基-9-{2–[(2-甲氧基乙基)氨基甲酰基]噻唑-5-基}-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000105
6-叔丁基-10-甲氧基-9-{2–[(2-甲氧基乙基)氨基甲酰基]噻唑-5-基}-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(77mg,0.143mmol)按照类似于实施例1步骤1d的方法制备得到黄色固体6-叔丁基-10-甲氧基-9-{2–[(2-甲氧基乙基)氨基甲酰基]噻唑-5-基}-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸(57.5mg)。 1H NMR(DMSO-d 6,400MHz):δ16.48(s,1H),8.80(s,1H),8.77(s,1H),8.62(s,1H),8.10(s,1H),7.75(s,1H),7.70(s,1H),4.65(d,J＝5.6Hz,1H),4.10(s,3H),3.48–3.44(m,4H),3.43–3.33(m,2H),3.27(s,3H),0.75(s,9H).MS实测值(ESI +)[(M+H) +]:512。
实施例23：
6-叔丁基-9-{2-[(二氟甲氧基)甲基]噻唑-5-基}-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000106
步骤23a：制备2-[(二氟甲氧基)甲基]噻唑
Figure PCTCN2020070633-appb-000107
氮气保护下，在50℃下，向噻唑-2-基甲醇(2.0g,17.37mmol)和碘化亚铜(662mg,3.47mmol)的乙腈(20mL)溶液中逐滴加入2,2-二氟-2-(氟磺酰基)乙酸(3.1g,17.37mmol)。将混合物在50℃搅拌8小时。将混合物加乙酸乙酯(50mL)稀释，然后用水(50mL)和饱和食盐水(50mL)洗涤，然后无水硫酸钠干燥，过滤，减压浓缩得到粗产品，将粗产品通过柱层析纯化得到白色固体2–[(二氟甲氧基)甲基]噻唑(310mg)。
步骤23b：制备5-溴-2-[(二氟甲氧基)甲基]噻唑
Figure PCTCN2020070633-appb-000108
将2-[(二氟甲氧基)甲基]噻唑(310mg,1.88mmol)按照类似于实施例10步骤10c的方法制备得到白色固体5-溴-2-[(二氟甲氧基)甲基]噻唑(211mg)。
步骤23c：制备6-叔丁基-9-{2-[(二氟甲氧基)甲基]噻唑-5-基}-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯
Figure PCTCN2020070633-appb-000109
将6-叔丁基-10-甲氧基-2-氧代-9-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(150mg,0.32mmol)和5-溴-2-[(二氟甲氧基)甲基]噻唑(91mg,0.37mmol)按照类似于实施例1步骤1c的方法制备得到黄色固体6-叔丁基-9-{2-[(二氟甲氧基)甲基]噻唑-5-基}-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(120mg)。
步骤23d：制备6-叔丁基-9-{2-[(二氟甲氧基)甲基]噻唑-5-基}-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000110
将6-叔丁基-9-{2-[(二氟甲氧基)甲基]噻唑-5-基}-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(120mg,0.23mmol)按照类似于实施例1步骤1d的方法制备得到黄色固体6-叔丁基-9-{2-[(二氟甲氧基)甲基]噻唑-5-基}-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸(35.2mg)。 1HNMR(DMSO-d 6,400MHz):δ8.79(s,1H),8.45(s,1H),7.99(s,1H),7.72(s,1H),7.69(s,1H),6.91(t,J＝74.0Hz,1H),5.26(s,2H),4.64(s,1H),4.06(s,3H),3.42-3.36(m,2H),0.74(s,9H)。MS实测值(ESI +)[(M+H) +]:491。
实施例24：
6-叔丁基-9-[2-(环丙氧基甲基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000111
步骤24a：制备5-溴-2-(溴甲基)噻唑
Figure PCTCN2020070633-appb-000112
室温下将5-溴-2-甲基噻唑(1g,5.62mmol)和过氧化苯甲酰(14mg,0.11mmol)加入N-溴代琥珀酰亚胺(1.2g,6.74mmol)的四氯化碳溶液(10mL)里，然后升温至80℃并在80℃下搅拌6小时。反应用水稀释，用二氯甲烷(50mL×3)萃取。收集有机相，用饱和食盐水洗并用无水硫酸钠干燥。旋干后得红色油状粗品。粗品由快速色谱柱纯化得黄色液体5-溴-2-(溴甲基)噻唑(1g)。
步骤24b：制备5-溴-2-(环丙氧甲基)噻唑
Figure PCTCN2020070633-appb-000113
于0℃，氮气保护下将环丙醇(0.03mg,0.43mmol)的四氢呋喃(5mL)溶液加入到氢化钠(43mg,1.17mmol)里并搅拌30分钟。然后将5-溴-2-(溴甲基)噻唑(100mg,0.39mmol)加入溶液中，升温至室温并在室温下搅拌4小时。反应用水淬灭，用乙酸乙酯(30mL×3)萃取。收集有机相，用饱和食盐水洗并用无水硫酸钠干燥。旋干后得淡黄色油状粗品。粗品由快速色谱柱纯化得黄色固体5-溴-2-(环丙氧甲基)噻唑(80mg)。
步骤24c：制备6-叔丁基-9-[2-(环丙氧基甲基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯
Figure PCTCN2020070633-appb-000114
将6-叔丁基-10-甲氧基-2-氧代-9-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(250mg,0.52mmol)和5-溴-2-(环丙氧甲基)噻唑(80mg，0.34mmol)按照类似于实施例1步骤1c的方法制备得到黄色固体6-叔丁基-9-[2-(环丙氧基甲基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(110mg)。
步骤24d：6-叔丁基-9-[2-(环丙氧基甲基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000115
将6-叔丁基-9-[2-(环丙氧基甲基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(110mg,0.21mmol)按照类似于实施例1步骤1d的方法制备得到黄色固体6-叔丁基-9-[2-(环丙氧基甲基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸(58.1mg)。 1HNMR(CDCl 3,400MHz):δ8.50(s,1H),8.21(s,1H),7.50(s,1H),7.27(s,1H),7.20(s,1H),4.88(s,2H),4.12-4.07(m,1H),4.03(s,3H),3.58-3.52(m,1H),3.35-3.26(m,2H),0.85(s,9H),0.76-0.72(m,2H),0.61-0.55(m,2H)。MS实测值(ESI +)[(M+H) +]:481。
实施例25：
6-叔丁基-9-[2-(3,3-二氟环丁基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000116
步骤25a：制备3,3-二氟环丁烷-1-硫代甲酰胺
Figure PCTCN2020070633-appb-000117
向3,3-二氟环丁烷-1-甲酰胺(2.0g,14.80mmol)的1,2-二氯乙烷(20mL)溶液中加入劳森试剂(3.0g,7.40mmol)。将混合物在85℃搅拌2小时。将混合物减压浓缩得到粗产品，将粗产品通过柱层析纯化得到黄色固体3,3-二氟环丁烷-1-硫代甲酰胺(2.0g)。
步骤25b：制备2-(3,3-二氟环丁基)噻唑
Figure PCTCN2020070633-appb-000118
向3,3-二氟环丁烷-1-硫代甲酰胺(2.0g,12.23mmol)的乙醇(10mL)溶液中加入40％氯乙醛(7.8mL,39.69mmol)水溶液。将混合物在100℃搅拌四小时。将混合物减压浓缩得到粗产品，将粗产品通过柱层析纯化得到白色固体2-(3,3-二氟环丁基)噻唑(340mg)。
步骤25c：制备5-溴-2-(3,3-二氟环丁基)噻唑
Figure PCTCN2020070633-appb-000119
将2-(3,3-二氟环丁基)噻唑(340mg,1.94mmol)和N-溴代丁二酰亚胺(380mg，2.13mmol)按照类似于实施例10步骤10c的方法制备得到白色固体5-溴-2-(3,3-二氟环丁基)噻唑(300mg)。
步骤25d：制备6-叔丁基-9-[2-(3,3-二氟环丁基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯
Figure PCTCN2020070633-appb-000120
将6-叔丁基-10-甲氧基-2-氧代-9-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(150mg,0.32mmol)和5-溴-2-(3,3-二氟环丁基)噻唑(95mg,0.37mmol)按照类似于实施例1步骤1c的方法制备得到棕色固体6-叔丁基)-9-[2-(3,3-二氟环丁基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(100 mg)。
步骤25e：制备6-叔丁基-9-[2-(3,3-二氟环丁基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000121
将6-叔丁基-9-[2-(3,3-二氟环丁基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(100mg,0.19mmol)按照类似于实施例1步骤1d的方法制备得到黄色固体6-叔丁基-9-[2-(3,3-二氟环丁基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸(2.1mg)。 1HNMR(DMSO-d 6,400MHz)δ8.79(s,1H),8.37(s,1H),7.93(s,1H),7.70(s,1H),7.67(s,1H),4.64(d,J＝5.2Hz,1H),4.04(s,3H),3.88-3.84(m,1H),3.45-3.38(m,2H).3.16-3.09(m,2H),2.98-2.91(m,2H),0.74(s,9H)。MS实测值(ESI +)[(M+H) +]:501。
实施例26：
6-叔丁基-9-[2-(3-氟环丁基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000122
步骤26a：制备5-溴-2-(3-氟环丁基)噻唑
Figure PCTCN2020070633-appb-000123
将2-(3-氟环丁基)噻唑(100mg,0.64mmol)和N-溴代丁二酰亚胺(124mg，0.70mmol)按照类似于实施例10步骤10c的方法制备得到白色固体5-溴-2-(3-氟环丁基)噻唑(100mg)。
步骤26b：制备6-叔丁基-9-[2-(3-氟环丁基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯
Figure PCTCN2020070633-appb-000124
将6-叔丁基-10-甲氧基-2-氧代-9-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(226mg,0.47mmol)和5-溴-2-(3-氟环丁基)噻唑(100mg,0.42mmol)按照类似于实施例1步骤1c的方法制备得到黄色固体6-叔丁基-9-[2-(3-氟环丁基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(65mg)。
步骤26c：制备6-叔丁基-9-[2-(3-氟环丁基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000125
将6-叔丁基-9-[2-(3-氟环丁基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(65mg,0.13mmol)按照类似于实施例1步骤1d的方法制备得到黄色固体6-叔丁基-9-[2-(3-氟环丁基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸(22.3mg)。 1HNMR(DMSO-d 6,400MHz)δ16.57(s,1H),8.79(s,1H),8.37(s,1H),7.65(s,1H),7.61(s,1H),7.59(s,1H),5.26(d,J＝56.0Hz,1H),4.64(d,J＝5.2Hz,1H),4.04(s,3H),3.88-3.84(m,1H),3.43-3.35(m,2H),2.82-2.76(m,2H).2.55-2.48(m,2H),0.74(s,9H)。MS实测值(ESI +)[(M+H) +]:483。
实施例27：
6-叔丁基-10-甲氧基-9-[2-(3-甲氧基环丁基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000126
步骤27a：制备5-溴-2-(3-甲氧基环丁基)噻唑
Figure PCTCN2020070633-appb-000127
将2-(3-甲氧基环丁基)噻唑(70mg,0.41mmol)和N-溴代丁二酰亚胺(80mg，0.45mmol)按照类似于实施例10步骤10c的方法制备得到白色固体5-溴-2-(3-甲氧基环丁基)噻唑(32mg)。
步骤27b：制备6-叔丁基-10-甲氧基-9-[2-(3-甲氧基环丁基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯
Figure PCTCN2020070633-appb-000128
将6-叔丁基-10-甲氧基-2-氧代-9-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(67mg,0.14mmol)和5-溴-2-(3-甲氧基环丁基)噻唑(32mg,0.13mmol)按照类似于实施例1步骤1c的方法制备得到棕色固体6-叔丁基-10-甲氧基-9-[2-(3-甲氧基环丁基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(20mg)。
步骤27c：制备6-叔丁基-10-甲氧基-9-[2-(3-甲氧基环丁基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸
Figure PCTCN2020070633-appb-000129
将6-叔丁基-10-甲氧基-9-[2-(3-甲氧基环丁基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸乙酯(20mg,0.038mmol)按照类似于实施例1步骤1d的方法制备得到黄色固体6-叔丁基-10-甲氧基-9-[2-(3-甲氧基环丁基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸(5.1mg)。 1HNMR(DMSO-d 6,400MHz)δ16.56(s,1H),8.77(s,1H),7.90(s, 1H),7.73(s,1H),7.63(s,1H),7.62(s,1H),4.61(d,J＝6.0Hz,1H),4.00(s,3H),3.90–3.83(m,1H),3.38–3.34(m,2H),3.29(s,3H),2.74-2.68(m,2H),2.48-2.40(m,2H),0.75(s,9H)。MS实测值(ESI +)[(M+H) +]:495。
以下具体描述了生物学实施数据，以进一步阐述本发明技术方案。
材料和方法
HBV细胞株：
HepG2.2.15细胞中插入了HBV全基因组，可以持续表达HBV(Sells et al,Proc Natl Acad Sci U S A.1987 Feb；84(4):1005-9.)。培养条件为DMEM培养基含10％血清和400μg/mg G418。细胞放置于5％CO 2温箱，37℃培养。
乙肝表面抗原(HBsAg)检测：
HepG2.2.15细胞以3x10 4/孔种到96孔培养板中。第二天，溶解在DMSO中的药物按照5倍稀释后加入细胞。0.5％DMSO单独加入作为对照。药物作用4天后收取上清检测乙肝表面抗原含量。
乙肝表面抗原的测定使用乙肝病毒表面抗原定量检测试剂盒(化学发光法)。具体操作如下，取50μL的细胞培养上清，转移至检测板中。加入50μL酶联试剂后封住反应板。室温孵育1小时。之后用PBS洗六次，最后通过甩板将残余液体去除。分别加入25μL底物A和B，反应十分钟后通过酶标仪(Tecan
Figure PCTCN2020070633-appb-000130
F200)检测。IC 50通过剂量-反应曲线拟合后计算得到。
检测结果
按上述方法测定本发明的实施例1至实施例27所涉及的化合物对于抑制HBsAg的活性，结果总结在表3中。
表3：实施例化合物抑制HBsAg的活性数据
实施例 IC 50(nM) 实施例 IC 50(nM)
1 0.33 2 0.06
3 0.07 4 0.045
5 0.3 6 0.3
7 0.08 8 0.2
9 0.03 10 0.2
11 0.09 12 0.45
13 0.2 14 0.2
15 0.2 16 0.1
17 0.3 18 0.09
19 0.3 20 0.3
21 0.3 22 0.4
23 0.2 24 0.2
25 0.24 26 0.1
27 0.1    
HBV DNA检测：
HepG2.2.15细胞以4x10 4/孔种到96孔培养板中。4小时后溶解在DMSO中的药物按照4倍稀释后加入细胞。0.5％DMSO单独加入作为对照。药物作用第四天去掉旧的上清液后重新加药，药物作用共7天后收取上清，用裂解液处理。乙肝DNA的测定使用实时荧光定量聚合酶链式反应(qPCR)。qPCR运行完毕后从仪器中导出数据并分析，抗病毒活性IC 50通过剂量-反应曲线拟合后计算得到。
检测结果
按上述方法测定本发明所涉及的化合物对于抑制HBV DNA的活性，结果总结在表4中。
表4：实施例化合物抑制HBV DNA活性数据
实施例 IC 50(nM) 实施例 IC 50(nM)
2 0.11 4 0.26
7 0.15 9 0.10
10 0.13 11 0.13
13 0.31 16 0.41
18 0.06 23 0.84
24 0.45    
对本发明中多个实施例的应用于ICR小鼠的代谢动力学实验，分别采取单次静脉注射(剂量2mg/kg)和单次口服给药(剂量10mg/kg)，分别于给药前及给药后5分钟、15分钟、30分钟、1小时、2小时、4小时、8小时、12小时和24小时采血测定血浆中待测化合物的浓度。对照化合物(来自专利WO2018130152A1中实施例28)及本专利中实施例10和19在小鼠血浆中的药代动力学数据如下表5-表7所示：
表5：对照化合物的小鼠体内PK参数
Figure PCTCN2020070633-appb-000131
Figure PCTCN2020070633-appb-000132
表6：实施例10的小鼠体内PK参数
Figure PCTCN2020070633-appb-000133
表7：实施例19的小鼠体内PK参数
Figure PCTCN2020070633-appb-000134
从以上表中可以看出，同样剂量下，实施例10和19经静脉注射和口服后在小鼠血浆中的暴露量显著高于对照化合物。该结果表明与对照化合物相比，本专利化合物可以在更低的剂量下给药用于治疗或预防HBV感染
进一步地，本领域技术人员理解，前述涉及的通式I所示化合物、通式I所示化合物不同的实现方式以及通式I所示化合物的具体实施例所涉及的全部化合物，均可以被制成对应的异构体、溶剂化物、水合物、前药、稳定的同位素衍生物及药学上可接受的盐。优选地，所述化合物被制成药学上可接受的衍生物，所述衍生物为前药、盐、酯、酰胺、酯类的盐、酰胺类的盐、代谢产物中的任一种。
进一步地，药学上可接受的盐包括通过用无机酸(例如盐酸、氢溴酸、氢碘酸、高氯酸、硫酸或者磷酸等)，或者用有机酸(例如乙酸、草酸、马来酸、富马酸、酒石酸、苯磺酸、甲磺酸、水杨酸、琥珀酸、柠檬酸、乳酸、丙酸、苯甲酸、对甲苯磺酸、苹果酸等)使本发明涉及的任一化合物成盐获得的常规非毒性盐。对于合适的药用盐的综述可以参考Berge S.M等，J.Pharm.Sci.1977，66，1-19；Gould P.L.Int.J.Pharm 1986，33，201-277以及Bighley等，药学技术百科全书，Marcel Dekker Inc，纽约1996，第13卷，第453-497页。药学上可接受的盐还包括通过本发明中的化合物与有机或无机碱所形成的盐，包括但不限于碱金属盐，例如锂、钠或钾盐；碱土金属盐，例如钙或镁盐；有机碱盐，例如通过与含N基团的有机碱形成的铵盐或N +(C 1-6烷基) 4盐，优选为氢氧化锂、氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾、碳酸镁、碳酸钙、氨水、三乙胺、四丁基氢氧化铵等。
进一步地，稳定的同位素衍生物，可以将同位素引入本发明涉及的任一化合物中，引入的同位素可以是 2H、 3H、 13C、 14C、 15N、 17O、 18O、 31P、 32P、 35S、 18F、 36Cl，具体的同位素衍生物可以通过常规技术制备。
进一步地，其作为实际产品还可以被制成片剂、胶囊剂、注射剂、颗粒剂、粉剂、栓剂、丸剂、乳膏剂、糊剂、凝胶剂、散剂、口服溶液、吸入剂、混悬剂、干悬剂、贴剂、洗剂中的任一种。
进一步地，在上述基础上，还可以与以下任一物质形成混合物：药学上可接受的载体或者辅剂或者赋形剂。
进一步地，在上述基础上，还可以与以下任一物质形成组合物：HBV聚合酶抑制剂；干扰素α-2a；干扰素α-2b；聚乙二醇干扰素α-2a；利巴韦林；HBV预防疫苗；HBV治疗疫苗；HBV衣壳抑制剂；HBV RNA复制抑制剂；siRNA；HBsAg生成或分泌抑制剂；HBV抗体；TLR7激动剂中的任一种。
本发明所涉及的全部化合物及包含本发明化合物的混合物、组合物等，可以经任一给药途径给予到生物体内。给药途径可以是口服给药、静脉注射、肌肉注射、皮下注射、直肠给药、阴道给药、舌下含化、鼻腔吸入、口腔吸入、滴眼、也可局部或全身经皮给药。
本发明所涉及的全部化合物及包含本发明化合物的混合物、组合物等，可以配制成单一剂量，其中含有本发明的活性化合物以及载体、赋形剂等，给药剂型可以是片剂、胶囊剂、注射剂、颗粒剂、粉剂、栓剂、丸剂、乳膏剂、糊剂、凝胶剂、散剂、口服溶液、吸入剂、混悬剂、干悬剂、贴剂、洗剂等。这些剂型中可以含有药物制剂常用的成分，例如稀释剂、吸收剂、润湿剂、粘合剂、崩解剂、着色剂、pH调节剂、抗氧剂、抑菌剂、等渗调节剂、抗粘剂等。
上述各类剂型的合适配方可从公开途径获得，例如Remington：The Science and Practice of Pharmacy,第21版，Lippincott Williams&Wilkins于2006年出版和Rowe,Raymond C.Handbook of Pharmaceutical Excipients,Chicago,Pharmaceutical Press于2005年出版.因此本领域的技 术人员可以容易的制备。
根据不同个体所患疾病的性质，强度，患者的年龄、性别、体重，给药途径等因素，可以选择不同的给药剂量，本发明的化合物的给药剂量可以为每日0.01至500mg/kg,优选每日剂量为1-100mg/kg，可单次或多次给药。
本领域技术人员理解，作为本发明的所涉及的全部化合物及包含本发明化合物的混合物、组合物等，其典型的应用为医学应用，特别是用于预防或治疗乙肝病毒感染，具体的适应症如下：
可以抑制乙肝表面抗原(HBsAg)的产生或者分泌，该新型化合物可用于治疗和预防HBV感染。
可用于抑制乙肝表面抗原(HBsAg)的产生或者分泌。
可用于治疗和预防HBV感染。
进一步地，本发明通式I的化合物可以与其他药物组合使用，包括HBV聚合酶抑制剂，例如拉米夫定、替比夫定、富马酸替诺福韦二吡呋酯、阿德福韦酯、恩替卡韦或替诺福韦艾拉酚胺富马酸；干扰素α-2a；干扰素α-2b；聚乙二醇干扰素α-2a；利巴韦林；HBV预防疫苗；HBV治疗疫苗；HBV衣壳抑制剂；HBV RNA复制抑制剂、siRNA；HBsAg生成或分泌抑制剂；HBV抗体；TLR 7激动剂。
以上对本发明的具体实施例进行了描述。需要理解的是，本发明并不局限于上述特定实施方式，本领域技术人员可以在权利要求的范围内做出各种变形或修改，这并不影响本发明的实质内容。

Claims (27)

  1. 一种通式Ⅰ化合物或其药学上可接受的盐、酯、异构体、溶剂化物、水合物、前药或同位素标记物，通式Ⅰ化合物结构为：
    Figure PCTCN2020070633-appb-100001
    其中：
    R 1是氢、氘、卤素、C 1-6烷基、C 1-6烷基氨基、C 1-6烷氧基中的任一种；
    R 2是氢、氘、卤素、C 1-6烷基、被至少一个氟所取代的C 1-6烷基、C 3-7环烷基、C 1-6烷基氨基、C 1-6烷氧基、杂环烷基中的任一种；
    R 3是氢、氘、卤素、氰基、C 1-6烷基、C 3-7环烷基、C 1-6烷基氨基、C 1-6烷氧基、杂环烷基中的任一种；
    R 4是氢、氘、C 1-6烷基中的任一种；
    R 5是氢、氘、C 1-6烷基、被至少一个氟所取代的C 1-6烷基、C 3-7环烷基中的任一种；
    R是取代或未取代的下列基团：C 1-6烷基、氨基、C 1-6烷氧基、C 3-7环烷氧基、C 6-10芳氧基、C 3-7环烷基、3-7元杂环烷基、C 6-10芳基、C 5-10杂芳基或氨基甲酰基，且排除R为未取代的甲基。
  2. 如权利要求1所述的一种通式Ⅰ化合物或其药学上可接受的盐、酯、异构体、溶剂化物、水合物、前药或同位素标记物，其特征在于，所述R是取代的下列基团：C 1-6烷基、氨基、C 1-6烷氧基、C 3-7环烷氧基、C 6-10芳氧基、C 3-7环烷基、3-7元杂环烷基、C 6-10芳基、C 5-10杂芳基、氨基甲酰基，所述取代是被一个或多个下列基团所取代：羟基、羟基-C 1-6烷基、卤素、C 1-6烷基、C 1-6烷氧基、C 3-7环烷氧基、C 1-6烷氧-C 1-6烷基或被至少一个卤素原子取代的C 1-6烷氧基。
  3. 如权利要求1或2所述的一种通式Ⅰ化合物或其药学上可接受的盐、酯、异构体、溶剂化物、水合物、前药或同位素标记物，其特征在于，所述R是取代的下列基团：C 1-6烷基、氨基、C 1-6烷氧基、C 3-7环烷氧基、C 3-7环烷基、3-7元杂环烷基、C 5-10杂芳基、氨基甲酰基，所述取代是被一个或多个下列基团所取代：羟基、羟基-C 1-6烷基、卤素、C 1-3烷基、C 1-3烷氧基、C 1-3烷氧-C 1-6烷基、C 3-7环烷氧基、被至少一个卤素原子取代的C 1-3烷氧基。
  4. 如权利要求1-3任一项所述的一种通式Ⅰ化合物或其药学上可接受的盐、酯、异构体、溶剂化物、水合物、前药或同位素标记物，其特征在于，所述式Ⅰ化合物具有通式Ⅰ-1的结构：
    Figure PCTCN2020070633-appb-100002
    其中：
    R 1是氢、氘、卤素、C 1-6烷基、C 1-6烷基氨基、C 1-6烷氧基中的任一种；
    R 2是氢、氘、卤素、C 1-6烷基、被至少一个卤素所取代的C 1-6烷基、C 3-7环烷基、C 1-6烷基氨基、C 1-6烷氧基、杂环烷基中的任一种；
    R 3是氢、氘、卤素、氰基、C 1-6烷基、C 3-7环烷基、C 1-6烷基氨基、C 1-6烷氧基、杂环烷基中的任一种；
    R 4是氢、氘、C 1-6烷基中的任一种；
    R 5是氢、氘、C 1-6烷基、被至少一个卤素所取代的C 1-6烷基、C 3-7环烷基中的任一种；
    X为O、N、S、SO、SO 2、或C(R 6) 2；
    Y为0、1、2、3、4或5
    Z为0、1或2；
    每一个R 6为独立地选自氢、氘、羟基、氰基、氨基、C 1-6烷基氨基、卤素、C 1-6烷基、被至少一个卤素原子所取代的C 1-6烷基、羟基取代的C 1-6烷基或C 1-6烷氧基。
  5. 如权利要求4所述的一种通式Ⅰ化合物或其药学上可接受的盐、酯、异构体、溶剂化物、水合物、前药或同位素标记物，其特征在于，
    X为O或者C(R 6) 2；
    Y为0、1或2；
    R 6为独立地选自氢、氘、羟基、氰基、氨基、甲基氨基、乙基氨基、氟、氯、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、被至少一个氟或氯或羟基取代的甲基、乙基、正丙基、异丙基。
  6. 如权利要求1-3任一项所述的一种通式Ⅰ化合物或其药学上可接受的盐、酯、异构体、溶剂化物、水合物、前药或同位素标记物，其特征在于，所述式Ⅰ化合物具有通式Ⅰ-2的结构：
    Figure PCTCN2020070633-appb-100003
    其中：
    R 1是氢、氘、卤素、C 1-6烷基、C 1-6烷基氨基、C 1-6烷氧基中的任一种；
    R 2是氢、氘、卤素、C 1-6烷基、被至少一个卤素所取代的C 1-6烷基、C 3-7环烷基、C 1-6烷基氨基、C 1-6烷氧基、杂环烷基中的任一种；
    R 3是氢、氘、卤素、氰基、C 1-6烷基、C 3-7环烷基、C 1-6烷基氨基、C 1-6烷氧基、杂环烷基中的任一种；
    R 4是氢、氘、C 1-6烷基中的任一种；
    R 5是氢、氘、C 1-6烷基、被至少一个卤素所取代的C 1-6烷基、C 3-7环烷基中的任一种；
    R 7和R 8分别独立的选自氢、氘、C 1-6烷基、被至少一个卤素原子、C 1-6烷氧基或羟基取代的C 1-6烷基。
  7. 如权利要求6所述的一种通式Ⅰ化合物或其药学上可接受的盐、酯、异构体、溶剂化物、水合物、前药或同位素标记物，其特征在于，所述的R 7和R 8分别独立的选自氢、氘、甲基、乙基、正丙基、异丙基、甲氧乙基、被至少一个氟、氯或羟基取代的甲基、乙基、正丙基或异丙基。
  8. 如权利要求1-3任一项所述的一种通式Ⅰ化合物或其药学上可接受的盐、酯、异构体、溶剂化物、水合物、前药或同位素标记物，其特征在于，所述式Ⅰ化合物具有通式I-3的结构：
    Figure PCTCN2020070633-appb-100004
    其中：
    R 1是氢、氘、卤素、C 1-6烷基、C 1-6烷基氨基、C 1-6烷氧基中的任一种；
    R 2是氢、氘、卤素、C 1-6烷基、被至少一个卤素所取代的C 1-6烷基、C 3-7环烷基、C 1-6烷基氨基、C 1-6烷氧基、杂环烷基中的任一种；
    R 3是氢、氘、卤素、氰基、C 1-6烷基、C 3-7环烷基、C 1-6烷基氨基、C 1-6烷氧基、杂环烷基中的任一种；
    R 4是氢、氘、C 1-6烷基中的任一种；
    R 5是氢、氘、C 1-6烷基、被至少一个卤素所取代的C 1-6烷基、C 3-7环烷基中的任一种；
    R 9、R 10和R 11分别独立的选自氢、氘、C 1-6烷基、羟基、被至少一个卤素原子所取代的C 1-6烷基或羟基取代的C 1-6烷基、未取代或被至少一个卤素原子所取代的C 1-6烷氧基、未取代或被至少一个卤素原子或C 1-6烷基所取代的C 3-7环烷氧基、或R 9、R 10和R 11中的任两个可以形成取代或未取代的C 3-7环烷基，且R 9、R 10和R 11不同时为氢。
  9. 如权利要求8所述的一种通式Ⅰ化合物或其药学上可接受的盐、酯、异构体、溶剂化物、水合物、前药或同位素标记物，其特征在于，R 9、R 10和R 11分别独立的选自氢、氘、甲基、乙基、正丙基、异丙基、羟基、甲氧基、乙氧基、环丙氧基、被至少一个氟或氯或羟基取代的甲基、乙基、正丙基、异丙基或C 1-3烷氧基，所述取代的C 3-7环烷基是被至少一个卤素原子、C 1-6烷基或C 1-6烷氧基所取代。
  10. 如权利要求1-3任一项所述的一种通式Ⅰ化合物或其药学上可接受的盐、酯、异构体、溶剂化物、水合物、前药或同位素标记物，其特征在于，所述的R为取代或未取代的下列基团：哌啶基、吡咯烷基、氮杂环丁烷基、吗啉基、C 1-3烷基。
  11. 如权利要求1-3任一项所述的一种通式Ⅰ化合物或其药学上可接受的盐、酯、异构体、溶剂化物、水合物、前药或同位素标记物，其特征在于，所述的R为取代或未取代的下列基团：哌啶基、氮杂环丁烷基、C 1-6烷氧基、环丁基、丙基、C 1-3烷基或氨基甲酰基。
  12. 如权利要求1-3任一项所述的一种通式Ⅰ化合物或其药学上可接受的盐、酯、异构体、溶剂化物、水合物、前药或同位素标记物，其特征在于，所述的R为取代或未取代的哌啶-1-基，取代或未取代的氮杂环丁烷-1-基，环丙基，取代或未取代的环丁基，丙基，C 1-6烷氧基取代的甲基或乙基，其中，所述取代的哌啶-1-基是被至少一个羟基-C 1-6烷基、C 1-6烷基或羟基所取代，优选被羟基-C 1-6烷基或同时被C 1-6烷基和羟基所取代；所述取代的氮杂环丁烷-1-基是被至少一个卤素原子或C 1-6烷氧基所取代；所述取代的环丁基是被至少一个卤素原子、C 1-6烷基或C 1-6烷氧基所取代。
  13. 如权利要求1-3任一项所述的一种通式Ⅰ化合物或其药学上可接受的盐、酯、异构体、溶剂化物、水合物、前药或同位素标记物，其特征在于，所述的R为取代的哌啶-1-基，所述取代的哌啶-1-基是被至少一个羟基-C 1-3烷基、C 1-6烷氧基、C 1-3烷基或羟基所取代，优选被羟基-C 1-3烷基或同时被C 1-3烷基和羟基所取代。
  14. 如权利要求1-3任一项所述的一种通式Ⅰ化合物或其药学上可接受的盐、酯、异构体、溶剂化物、水合物、前药或同位素标记物，其特征在于，所述的R为取代或未取代的氮杂环丁烷-1-基，所述取代的氮杂环丁烷-1-基是被1-3个卤素原子或C 1-3烷氧基所取代。
  15. 如权利要求1-3任一项所述的一种通式Ⅰ化合物或其药学上可接受的盐、酯、异构体、溶剂化物、水合物、前药或同位素标记物，其特征在于，所述的R为C 1-6烷氧基取代的甲基或乙基或异丙基，优选为甲氧基、乙氧基、丙氧基或异丙氧基取代的甲基或乙基或异丙基。
  16. 如权利要求1-15任一项所述的一种通式Ⅰ化合物或其药学上可接受的盐、酯、异构体、溶剂化物、水合物、前药或同位素标记物，其特征在于，
    R 1是氢、氘、氟、氯、溴、甲基、乙基、异丙基、叔丁基、甲基氨基、乙基氨基、甲氧基、乙氧基、异丙氧基中的任一种；
    R 2是氢、氘、氟、氯、溴、甲基、乙基、异丙基、叔丁基、三氟甲基、三氟甲基甲基、环丙基、环戊基、甲基氨基、乙基氨基、甲氧基、乙氧基、异丙氧基、吡咯烷基、吗啉基中的任一种；
    R 3是氢、氘、氟、氯、溴、甲基、乙基、氰基中的任一种；
    R 4是氢、氘、甲基、乙基中的任一种；
    R 5是氢、氘、甲基、乙基、异丙基、丁基、仲丁基、异丁基、叔丁基、三氟甲基、三氟甲基甲基、环丙基中的任一种。
  17. 如权利要求16所述的一种通式Ⅰ化合物或其药学上可接受的盐、酯、异构体、溶剂化物、水 合物、前药或同位素标记物，其特征在于，
    R 1是氢、氘、卤素、C 1-6烷氧基中的任一种；
    R 2是氢、氘、卤素、C 1-6烷基氨基、C 1-6烷氧基中的任一种；
    R 3是氢、氘、卤素中的任一种；
    R 4是氢或氘；
    R 5是氢、氘、C 1-6烷基、被至少一个氟所取代的C 1-6烷基、C 3-7环烷基中的任一种。
  18. 如权利要求1-3任一项所述的一种通式Ⅰ化合物或其药学上可接受的盐、酯、异构体、溶剂化物、水合物、前药或同位素标记物，其特征在于，
    R 1是氢或氘；
    R 2是氢、氘、卤素、C 1-6烷氧基中的任一种；
    R 3是氢或氘；
    R 4是氢或氘；
    R 5是氢、氘、甲基、乙基、异丙基、丁基、仲丁基、异丁基、叔丁基、三氟甲基、三氟甲基甲基、环丙基中的任一种；
    R为取代或未取代的下列基团：哌啶基、氮杂环丁烷基、吗啉基、氨基、环丙基、丙基、C 1-3烷基、C 1-3烷氧基、环丁基、或氨基甲酰基，所述取代是被一个或多个下列基团所取代：羟基、羟基-C 1-6烷基、卤素、C 1-3烷基、C 1-3烷氧基、C 1-3烷氧基-C 1-6烷基、至少一个卤素原子取代的C 1-3烷氧基或C 3-7环烷氧基。
  19. 如权利要求1-18任一项所述的一种通式Ⅰ化合物或其药学上可接受的盐、酯、异构体、溶剂化物、水合物、前药或同位素标记物，其特征在于，所述通式Ⅰ的化合物为如下任一种：
    6-叔丁基-9-[2-(4-羟基哌啶-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
    6-叔丁基-9-{2-[4-(羟甲基)哌啶-1-基]噻唑-5-基}-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
    9-[2-(氮杂环丁烷-1-基)噻唑-5-基]-6-叔丁基-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
    6-叔丁基-9-[2-(3,3-二氟氮杂环丁烷-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡 啶并[2,1-a]异喹啉-3-甲酸；
    6-叔丁基-10-甲氧基-9-(2-吗啉代噻唑-5-基)-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
    6-叔丁基-9-[2-(二甲基氨基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
    6-叔丁基-9-[2-(4-羟基-4-甲基哌啶-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
    6-叔丁基-10-甲氧基-9-[2-(4-甲氧基哌啶-1-基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
    6-叔丁基-10-甲氧基-9-[2-(3-甲氧基氮杂环丁烷-1-基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
    6-叔丁基-10-甲氧基-9-[2-(甲氧基甲基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
    6-叔丁基-9-[2-(3-氟氮杂环丁烷-1-基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
    6-叔丁基-10-甲氧基-9-(2-甲氧基噻唑-5-基)-2-氧代-6,7-二氢-2H-吡啶[2,1-a]异喹啉-3-甲酸；
    6-叔丁基-9-[2-(乙氧基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶[2,1-a]异喹啉-3-甲酸；
    6-叔丁基-9-[2-(乙氧基甲基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶[2,1-a]异喹啉-3-甲酸；
    6-叔丁基-10-甲氧基-9-[2-(1-甲氧基乙基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
    6-叔丁基-9-[2-(1-羟乙基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
    6-叔丁基-10-甲氧基-9-[2-(2-甲氧基丙-2-基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
    6-叔丁基-10-甲氧基-2-氧代-9-(2-丙基噻唑-5-基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
    6-叔丁基-10-甲氧基-9-[2-(甲基氨基甲酰基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
    6-叔丁基-9-[2-(乙基氨基甲酰基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
    6-叔丁基-10-甲氧基-9-[2-(2-甲氧乙氧基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
    6-叔丁基-10-甲氧基-9-{2–[(2-甲氧基乙基)氨基甲酰基]噻唑-5-基}-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
    6-叔丁基-9-{2-[(二氟甲氧基)甲基]噻唑-5-基}-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
    6-叔丁基-9-[2-(环丙氧基甲基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
    6-叔丁基-9-[2–(3,3-二氟环丁基)噻唑-5-基}-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
    6-叔丁基-9-[2-(3-氟环丁基)噻唑-5-基]-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸；
    6-叔丁基-10-甲氧基-9-[2-(3-甲氧基环丁基)噻唑-5-基]-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-甲酸。
  20. 一种药物组合物，其包含权利要求1-19任一项所述的一种通式Ⅰ化合物或其药学上可接受的盐、酯、异构体、溶剂化物、水合物、前药或同位素标记物。
  21. 一种药物制剂，其包括权利要求1至19中任一项所述的具有式I结构的化合物或其药学上可接受的盐、酯、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药或者权利要求20所述的药物组合物，所述制剂为片剂、胶囊剂、注射剂、颗粒剂、粉剂、栓剂、丸剂、乳膏剂、糊剂、凝胶剂、散剂、口服溶液、吸入剂、混悬剂、干悬剂、贴剂、洗剂中的任一种。
  22. 权利要求1至19中任一项所述的具有式I结构的化合物或其药学上可接受的盐、酯、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药，或者权利要求20所述的药物组合物，或者权利要求21所述的药物制剂，其用作预防和治疗乙型肝炎。
  23. 权利要求1至19中任一项所述的具有式I结构的化合物或其药学上可接受的盐、酯、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药，或者权利要求20所述的药 物组合物，或者权利要求21所述的药物制剂用作预防和/或治疗乙型肝炎的用途。
  24. 权利要求1至19中任一项所述的具有式I结构的化合物或其药学上可接受的盐、酯、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药，或者权利要求20所述的药物组合物，或者权利要求21所述的药物制剂在制备预防和/或治疗乙型肝炎药物中的应用。
  25. 一种预防和/或治疗乙型肝炎的方法，其包括下列步骤：将治疗有效量的根据权利要求1至19中任一项所述的具有式I结构的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药，或者权利要求20所述的药物组合物，或者权利要求21所述的药物制剂施用于对其有需求的患者。
  26. 一种药物联合形式，其包含根据权利要求1至19中任一项所述的具有式I结构的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药，或者权利要求20所述的药物组合物，或者权利要求21所述的药物制剂，以及至少一种额外的乙型肝炎治疗剂。
  27. 一种预防和/或治疗乙型肝炎的方法，其包括下列步骤：将治疗有效量的根据权利要求1至19中任一项所述的具有式I结构的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药，或者权利要求20所述的药物组合物，或者权利要求21所述的药物制剂，以及至少一种额外的乙型肝炎治疗剂施用于对其有需求的患者。
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