WO2020135439A1 - Deuterated dihydropyrimidine compound and use thereof as drug - Google Patents
Deuterated dihydropyrimidine compound and use thereof as drug Download PDFInfo
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- WO2020135439A1 WO2020135439A1 PCT/CN2019/128015 CN2019128015W WO2020135439A1 WO 2020135439 A1 WO2020135439 A1 WO 2020135439A1 CN 2019128015 W CN2019128015 W CN 2019128015W WO 2020135439 A1 WO2020135439 A1 WO 2020135439A1
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- alkyl
- deuterium
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- 0 C*CC(*1)=NC(N)=C1c1ccc(*)cc1 Chemical compound C*CC(*1)=NC(N)=C1c1ccc(*)cc1 0.000 description 27
- WZCVQEPQYRZMHO-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CC(C2)(C2N2)N1C2=O)=O Chemical compound CC(C)(C)OC(N(CC1)CC(C2)(C2N2)N1C2=O)=O WZCVQEPQYRZMHO-UHFFFAOYSA-N 0.000 description 1
- DGPLYBDSJHLYKS-MRVPVSSYSA-N CC(C)(C)OC(N(CC1)C[C@@H](CN2)N1C2=O)=O Chemical compound CC(C)(C)OC(N(CC1)C[C@@H](CN2)N1C2=O)=O DGPLYBDSJHLYKS-MRVPVSSYSA-N 0.000 description 1
- BGULEIXYTQYDLE-LBPRGKRZSA-N CC(C)(C)OC(N(CC1)C[C@@H](CN2c3ccc(C(O)=O)c(F)c3)N1C2=O)=O Chemical compound CC(C)(C)OC(N(CC1)C[C@@H](CN2c3ccc(C(O)=O)c(F)c3)N1C2=O)=O BGULEIXYTQYDLE-LBPRGKRZSA-N 0.000 description 1
- UHADKPBFSATCPX-ZDUSSCGKSA-N CC(C)(C)OC(N(CC1)C[C@@H](CN2c3ccc(C=O)cc3F)N1C2=O)=O Chemical compound CC(C)(C)OC(N(CC1)C[C@@H](CN2c3ccc(C=O)cc3F)N1C2=O)=O UHADKPBFSATCPX-ZDUSSCGKSA-N 0.000 description 1
- BKRLZMVYEDUWIT-INIZCTEOSA-N CC(C)(C)OC(N(CC1)C[C@@H](CN2c3ccc(CCC(O)=O)cc3)N1C2=O)=O Chemical compound CC(C)(C)OC(N(CC1)C[C@@H](CN2c3ccc(CCC(O)=O)cc3)N1C2=O)=O BKRLZMVYEDUWIT-INIZCTEOSA-N 0.000 description 1
- UYKCUDSWZOPOHY-AWEZNQCLSA-N CC(C)(C)OC(N(CC1)C[C@@H](CN2c3ccc(CCC(O)=O)cc3F)N1C2=O)=O Chemical compound CC(C)(C)OC(N(CC1)C[C@@H](CN2c3ccc(CCC(O)=O)cc3F)N1C2=O)=O UYKCUDSWZOPOHY-AWEZNQCLSA-N 0.000 description 1
- XEGIBPQIQPRNJQ-KRWDZBQOSA-N CC(C)(C)OC(N(CC1)C[C@@H](CN2c3ccc(CCC(OC)=O)cc3)N1C2=O)=O Chemical compound CC(C)(C)OC(N(CC1)C[C@@H](CN2c3ccc(CCC(OC)=O)cc3)N1C2=O)=O XEGIBPQIQPRNJQ-KRWDZBQOSA-N 0.000 description 1
- QNLHDLWXANXWTC-HNNXBMFYSA-N CC(C)(C)OC(N(CC1)C[C@@H](CN2c3ccc(CCC(OC)=O)cc3F)N1C2=O)=O Chemical compound CC(C)(C)OC(N(CC1)C[C@@H](CN2c3ccc(CCC(OC)=O)cc3F)N1C2=O)=O QNLHDLWXANXWTC-HNNXBMFYSA-N 0.000 description 1
- WZCVQEPQYRZMHO-LESKNEHBSA-N CC(C)(C)OC(N(CC1)C[C@](C2)(C2N2)N1C2=O)=O Chemical compound CC(C)(C)OC(N(CC1)C[C@](C2)(C2N2)N1C2=O)=O WZCVQEPQYRZMHO-LESKNEHBSA-N 0.000 description 1
- JNUHBVDBJBVQMS-IAXJKZSUSA-N CC(CC(O)=O)c(cc1)ccc1N(C[C@H]1N2CCNC1)C2=O Chemical compound CC(CC(O)=O)c(cc1)ccc1N(C[C@H]1N2CCNC1)C2=O JNUHBVDBJBVQMS-IAXJKZSUSA-N 0.000 description 1
- NTNUDYROPUKXNA-UHFFFAOYSA-N COC(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)=O Chemical compound COC(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)=O NTNUDYROPUKXNA-UHFFFAOYSA-N 0.000 description 1
- DLILIUSWDLJMCE-UHFFFAOYSA-N COC(c(c(F)c1)ccc1Br)=O Chemical compound COC(c(c(F)c1)ccc1Br)=O DLILIUSWDLJMCE-UHFFFAOYSA-N 0.000 description 1
- LDYGRLNSOKABMM-UHFFFAOYSA-N Cc1ccc(CCC(O)=O)cc1 Chemical compound Cc1ccc(CCC(O)=O)cc1 LDYGRLNSOKABMM-UHFFFAOYSA-N 0.000 description 1
- ZYODXRYBYZMUNL-UHFFFAOYSA-N Cc1ccc(CCC(OC)=O)cc1 Chemical compound Cc1ccc(CCC(OC)=O)cc1 ZYODXRYBYZMUNL-UHFFFAOYSA-N 0.000 description 1
- QSNCNDFGKLTQNI-ZDUSSCGKSA-N OC(CCc(cc1)ccc1N(C[C@H]1N2CCNC1)C2=O)=O Chemical compound OC(CCc(cc1)ccc1N(C[C@H]1N2CCNC1)C2=O)=O QSNCNDFGKLTQNI-ZDUSSCGKSA-N 0.000 description 1
- OKZFKJXETJLFML-NSHDSACASA-N OC(CCc(cc1F)ccc1N(C[C@H]1N2CCNC1)C2=O)=O Chemical compound OC(CCc(cc1F)ccc1N(C[C@H]1N2CCNC1)C2=O)=O OKZFKJXETJLFML-NSHDSACASA-N 0.000 description 1
- ZQQSRVPOAHYHEL-UHFFFAOYSA-N OC(c(c(F)c1)ccc1Br)=O Chemical compound OC(c(c(F)c1)ccc1Br)=O ZQQSRVPOAHYHEL-UHFFFAOYSA-N 0.000 description 1
- DKVPZVXUKCQDRA-VIFPVBQESA-N OC(c(c(F)c1)ccc1N(C[C@H]1N2CCNC1)C2=O)=O Chemical compound OC(c(c(F)c1)ccc1N(C[C@H]1N2CCNC1)C2=O)=O DKVPZVXUKCQDRA-VIFPVBQESA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Definitions
- the invention belongs to the field of medicine. Specifically, the present invention relates to a deuterated dihydropyrimidine compound and its use as a medicine, especially as a medicine for treating and preventing hepatitis B. The invention also relates to a composition composed of these deuterated dihydropyrimidine compounds and other antiviral agents, and its application for treating and preventing hepatitis B virus (HBV) infection.
- HBV hepatitis B virus
- Hepatitis B virus belongs to the family of hepadnaviruses. It can cause acute and/or progressive chronic diseases. Hepatitis B virus can also cause many other clinical features in pathological morphology-especially chronic inflammation of the liver, liver cirrhosis and canceration of liver cells. In addition, co-infection with hepatitis D will have an adverse effect during the development of the disease.
- interferon is only moderately active and has high toxicity; although lamivudine has good activity, its drug resistance increases rapidly during treatment and often after stopping treatment A rebound effect occurs, and the IC 50 value of lamivudine (3-TC) is 300 nM (Science, 299 (2003), 893-896).
- heteroaromatic ring-substituted dihydropyrimidines represented by Bay41-4109 and Bay39-5493 can inhibit HBV replication by preventing normal nucleocapsid formation.
- Bay41-4109 showed good drug metabolic properties in clinical studies (Science, 299 (2003), 893-896).
- the heteroaromatic ring-substituted dihydropyrimidine compounds pass through the core
- the 113-143 amino acid residues of the protein change the angle between the dimers that form the nucleocapsid, resulting in the formation of an unstable swollen nucleocapsid and accelerating the degradation of the core protein (Biochem. Pharmacol. 66 (2003) , 2273-2279).
- the invention relates to a novel deuterated dihydropyrimidine compound and its use in the preparation of a medicine for treating and preventing HBV infection.
- the present invention relates to a novel deuterated dihydropyrimidine compound and its pharmaceutically acceptable composition.
- the compound has good pharmacokinetic properties, good solubility, good stability, and Liver drug enzymes basically have no advantages such as induction and less toxicity, and can effectively inhibit HBV infection, and they have good application prospects in anti-HBV.
- the present invention relates to a deuterated compound which is a deuterated compound represented by formula (I) or (Ia) or a stereoisomer of a deuterated compound represented by formula (I) or (I) , Tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or its prodrugs,
- each R 1 is independently hydrogen, deuterium, F, Cl, Br, I, cyano, methyl, ethyl, methoxy, ethoxy, or nitro;
- R 2 is methyl, ethyl, n-propyl or isopropyl, wherein the methyl, ethyl, n-propyl and isopropyl are each independently unsubstituted or substituted by 1, 2, 3, 4 or 5 Replaced by deuterium;
- W is CH or N
- R 4 is a C 1-6 alkyl group, a heteroaryl group consisting of 5-6 ring atoms, Wherein the C 1-6 alkyl group is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from deuterium, F, Cl, Br, HO, methyl or HOOC-, Heteroaryl groups consisting of 5-6 ring atoms are unsubstituted or substituted with 1, 2, 3, 4 or 5 R 13 substituents;
- Each R 9 , R 11 and R 12 is independently deuterium, F, Cl, Br, amino, C 1-6 alkyl, NH 2 C( ⁇ O)-, C 1-6 alkyl-OC( ⁇ O) -, carboxyl, carboxyl C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-4 alkoxy C 1-4 alkyl or C 1-6 haloalkyl;
- Each R 11a is independently deuterium, F, Cl, Br, amino, C 1-6 alkyl, NH 2 C( ⁇ O)-, C 1-6 alkyl-OC( ⁇ O)-, hydroxyl C 1- 6 alkyl, C 1-4 alkoxy C 1-4 alkyl or C 1-6 haloalkyl, or two adjacent R 11a and the carbon atom to which they are attached together to form a 5-atom heterocyclic group Wherein the heterocyclic group consisting of 5 atoms is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from deuterium, F, Cl, Br, amino or C 1-6 alkyl ;
- R 14 is a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a phenyl group, or a heteroaryl group composed of 5-6 ring atoms, wherein the C 1-6 alkyl group, C 3-6 cycloalkyl group , Phenyl and heteroaryl groups consisting of 5-6 ring atoms are unsubstituted or 1, 2, 3, 4 or 5 selected from deuterium, F, Cl, Br, HO, C 1-4 alkyl or HOOC -Substituted by a substituent;
- Each R a , R b and R c is independently hydrogen, deuterium or C 1-4 alkyl, wherein the C 1-4 alkyl is unsubstituted or substituted by 1, 2, 3, 4 or 5 selected from deuterium , F, Cl, Br, HO, methyl, ethyl or HOOC- substituents;
- Each f, n, t, g, j, and m is independently 0, 1, 2, 3, or 4;
- Each k and q are independently 1, 2, or 3.
- R 2 is CDH 2 , CD 2 H, CD 3 , CD 3 CD 2 or CD 3 CH 2 ;
- R 3 is phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazole Group, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein the phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, Oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, and pyrimidinyl are each independently unsubstituted or selected by 1, 2, 3, 4, or 5 From deuterium, F, Cl, Br, HO, CN, C 1-4
- Each R 11a is independently deuterium, F, Cl, Br, amino, methyl, ethyl, n-propyl, isopropyl, NH 2 C( ⁇ O)-, C 1-4 alkyl-OC( ⁇ O )-, hydroxy C 1-4 alkyl, ethoxyethyl, methoxyethyl, isopropoxymethyl, ethoxyethyl, methoxymethyl or C 1-4 haloalkyl, or Two adjacent R 11a and the carbon atom to which they are attached together form 1,3-dioxolane Wherein the 1,3-dioxolane is unsubstituted or substituted with 1 or 2 substituents selected from deuterium, F, Cl, Br, amino, methyl, ethyl, n-propyl or isopropyl .
- the deuterated compounds involved in the present invention have the structure represented by formula (II) or formula (IIa):
- R 1 and R 1a are independently hydrogen, deuterium, F, Cl, Br, I, cyano, methyl, ethyl, methoxy, ethoxy or nitro;
- each of R 3 , R 4 , R 9 , X 1 and m has the meaning described in the present invention.
- R 4 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl , Triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, Wherein, the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl groups are unsubstituted or 1, 2, 3, 4 or 5 are selected from deuterium, F, Substituted by a substituent of Cl, Br, HO, methyl or HOOC-, the furanyl,
- each of R 11a , R 11 , R 10 , R 10b , R 12 , R 13 , n, and k has the meaning described in the present invention.
- each R 13 is independently deuterium, F, Cl, Br, HOOC-(CR a R b ) g -, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, sec-butyl, tert-butyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, phenyl, benzyl, CH 3 OCH 2 -, CH 3 OCH 2 CH 2- , CH 3 OCH(CH 3 )-, CH 3 OCH 2 CH 2 CH 2 -, CH 3 CH 2 OCH 2 -, CH 3 CH 2 OCH 2 CH 2 -, CH 3 CH 2 OCH(CH 3 )-, CH 3 CH 2 OCH 2 CH 2 CH 2 -, HOCH 2 -, HOCH 2 CH 2 -, HOCH(CH 3 )-, HOCH 2 CH 2 CH 2 -, furyl
- each of R a , R b , g and j has the meaning described in the present invention.
- Each R a , R b and R c is independently hydrogen, deuterium, methyl, ethyl, n-propyl or isopropyl, wherein the methyl, ethyl, n-propyl and isopropyl are unsubstituted or Substituted by 1, 2, 3, 4 or 5 substituents selected from deuterium, F, Cl, Br, HO, methyl, ethyl or HOOC-;
- each R 14 , q, and t have the meanings described in the present invention.
- R 14 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, pyrrolyl, pyridine Group, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or Pyrimidinyl, wherein the methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl , Imidazolyl, triazo
- the present invention relates to one of the following compounds or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or its Prodrugs, but by no means limited to these compounds:
- the present invention also provides a pharmaceutical composition comprising the deuterated compound described in the present invention, and pharmaceutically acceptable excipients.
- the pharmaceutical composition of the present invention further comprises other anti-HBV drugs.
- the pharmaceutical composition of the present invention wherein the other anti-HBV drugs are HBV polymerase inhibitors, immunomodulators, or interferons.
- the pharmaceutical composition of the present invention wherein the other anti-HBV drugs are lamivudine, telbivudine, tenofovir dipivoxil, entecavir, adefovir dipivoxil, Alfaferone, Alloferon , Simor interleukin, Kravudine, emtricitabine, famciclovir, interferon, proganpine CP, intefen, interferon ⁇ -1b, interferon ⁇ , interferon ⁇ -2a, interferon ⁇ -1a, interferon alpha-2, interleukin-2, mivoritate, nitazoxanide, pegylated interferon alpha-2a, ribavirin, rotavirin-A, cezoran, Eufravac, Amphetamine, Phosphazid, Heplisav, interferon alpha-2b, levamisole or propargium.
- the invention also provides the use of the deuterated compound or the pharmaceutical composition in the preparation of a medicament for the prevention, treatment or alleviation of viral diseases in patients.
- the use according to the present invention wherein the viral disease refers to a disease caused by a hepatitis B virus infection or a hepatitis B virus infection.
- the use according to the present invention, wherein the disease caused by hepatitis B virus infection refers to cirrhosis or hepatocellular carcinoma.
- the present invention relates to the use of the deuterated compound or pharmaceutical composition for the preparation of a medicament for the prevention, treatment or alleviation of hepatitis B disease in patients, including administration of the compound as described in the present invention or the present invention The effective therapeutic dose of the pharmaceutical composition.
- Another aspect of the invention relates to a method of preventing, treating or alleviating HBV disorders in a patient, the method comprising administering to the patient a pharmaceutically acceptable effective dose of a compound of the invention.
- Another aspect of the invention relates to a method of preventing, treating or alleviating HBV disorders in a patient, the method comprising administering to the patient a pharmaceutically acceptable effective dose of a pharmaceutical composition containing a compound of the invention.
- Another aspect of the present invention relates to the use of a deuterated compound of the present invention to produce a medicament for preventing or treating HBV disorders in a patient and reducing its severity.
- Another aspect of the present invention relates to the use of a pharmaceutical composition comprising the deuterated compound of the present invention for the production of a medicament for preventing or treating HBV disorders in a patient and reducing its severity.
- Another aspect of the invention relates to a method of inhibiting HBV infection, the method comprising contacting the cells with a compound or pharmaceutical composition of the invention in an amount effective to inhibit HBV.
- the method further includes contacting the cells with other anti-HBV therapeutic agents.
- Another aspect of the invention relates to a method of treating HBV disease in a patient, the method comprising administering to a patient in need of treatment an effective therapeutic dose of a compound of the invention or a pharmaceutical composition thereof.
- the method further includes administering to the patient in need of treatment an effective therapeutic dose of other anti-HBV drugs.
- Another aspect of the invention relates to a method of inhibiting HBV infection in a patient, the method comprising administering to a patient in need of treatment an effective therapeutic dose of a compound of the invention or a pharmaceutical composition thereof.
- the method further includes administering to the patient in need of treatment an effective therapeutic dose of other anti-HBV drugs.
- Another aspect of the present invention relates to a method for the preparation, isolation, and purification of the deuterated compounds contained in Formula (I) or, (Ia), (II), or (IIa).
- the present invention also relates to the use of the compound of the present invention and its pharmaceutically acceptable salt for the production of pharmaceutical products to effectively inhibit HBV infection.
- the compound of the present invention is also used to produce a medicinal product for reducing, preventing, controlling or treating hepatitis B in patients.
- the salt is a pharmaceutically acceptable salt.
- pharmaceutically acceptable includes that the substance or composition must be chemically or toxicologically related to the other components that make up the formulation and the mammal used for treatment.
- the salt of the compound of the present invention also includes an intermediate or formula (I) or, formula (Ia) for preparing or purifying a compound represented by formula (I) or, formula (Ia), formula (II), or formula (IIa) ,
- the salt of the enantiomer isolated from the compound represented by formula (II) or formula (IIa) but not necessarily a pharmaceutically acceptable salt.
- the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the general formula above, or like the specific examples, subclasses, and inclusions of the present invention in the examples.
- substituents such as the compounds of the general formula above, or like the specific examples, subclasses, and inclusions of the present invention in the examples.
- a class of compounds such as the compounds of the general formula above, or like the specific examples, subclasses, and inclusions of the present invention in the examples.
- substituted means that one or more hydrogen atoms in a given structure are replaced by specific substituents. Unless otherwise indicated, an optional substituent may have a substituent at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from specific groups, the substituents may be substituted at the same positions or differently.
- C 1-6 alkyl particularly refers to independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
- alkyl used in the present invention includes a monovalent hydrocarbon group saturated with a linear or branched chain of 1 to 20 carbon atoms, wherein the alkyl group may be independently optionally substituted with one or more substituents described in the present invention. Some of these embodiments have an alkyl group containing 1-12 carbon atoms, other embodiments have an alkyl group containing 1-10 carbon atoms, and other embodiments have an alkyl group containing 1-8 Carbon atoms, in some other embodiments, the alkyl group contains 1-6 carbon atoms, in other embodiments, the alkyl group contains 1-4 carbon atoms, in other embodiments, the alkyl group Contains 1-3 carbon atoms.
- alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), 2-methylpropyl or isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), 1-methylpropyl or sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu , -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-
- deuterated compound means that any compound of the present invention contains at least one deuterium atom (D).
- the compound of formula (I) or formula (Ia) according to the present invention contains at least one deuterium atom, ie, R 1 , at least one of R 2 , R 3 , R 4 , R 9 and X 1 is a group containing one or more deuterium atoms; for another example, the compound of the present invention Contains 3 deuterium atoms, like a compound Contains 9 deuterium atoms.
- the deuterated compounds of the present invention contain 1 deuterium atom; in some embodiments, the deuterated compounds of the present invention contain 2 deuterium atoms; in some embodiments, the deuterated compounds of the present invention The deuterated compound contains 3 deuterium atoms; in some embodiments, the deuterated compound according to the present invention contains 4 deuterium atoms; in some embodiments, the deuterated compound according to the present invention contains 5 deuterium atoms; In some embodiments, the deuterated compounds of the present invention contain 6 deuterium atoms; in some embodiments, the deuterated compounds of the present invention contain 7 deuterium atoms; in some embodiments, the deuterated compounds of the present invention The deuterated compound contains 8 deuterium atoms; in some embodiments, the deuterated compound described in the present invention contains 9 deuterium atoms.
- alkylene means a saturated divalent or polyvalent hydrocarbon group obtained by removing two or more hydrogen atoms from a saturated linear or branched hydrocarbon group. Unless otherwise specified, alkylene groups contain 1-12 carbon atoms. In some embodiments, the alkylene group contains 1-6 carbon atoms; in other embodiments, the alkylene group contains 1-4 carbon atoms; in some embodiments, the alkylene group The group contains 1-3 carbon atoms; in still other embodiments, the alkylene group contains 1-2 carbon atoms. Examples of alkylene groups include, but are not limited to, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), isopropylidene (-CH(CH 3 )CH 2 -), and the like.
- hydroxyalkyl and “hydroxyalkoxy” mean alkyl or alkoxy, as the case may be, substituted by one or more hydroxy groups, where "hydroxyalkyl", “hydroxyalkylene”""And”hydroxyalkyl” can be used interchangeably, such examples include, but are not limited to, hydroxymethyl (-CH 2 OH), hydroxyethyl (-CH 2 CH 2 OH, -CHOHCH 3 ), Hydroxypropyl (-CH 2 CH 2 CH 2 OH, -CH 2 CHOHCH 3 , -CHOHCH 2 CH 3 ), hydroxymethoxy (-OCH 2 OH), etc.
- haloalkyl refers to an alkyl group, the alkenyl or alkoxy group is replaced by one or more halogen atoms, wherein, alkyl, alkenyl and alkoxy
- the radical has the meaning described in the present invention.
- alkoxy means that the alkyl group is connected to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described in the present invention. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In some embodiments, the alkoxy group contains 1-8 carbon atoms; in other embodiments, the alkoxy group contains 1-6 carbon atoms; in other embodiments, the alkoxy group The group contains 1-4 carbon atoms; in still other embodiments, the alkoxy group contains 1-3 carbon atoms. The alkoxy group can be optionally substituted with one or more substituents described herein.
- alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n- Propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n- Butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butan Oxygen (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH 3 ) 3 ), 1-pentoxy (n-pentoxy, -OCH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentoxy (
- cycloalkyl denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3-12 carbon atoms.
- the cycloalkyl group contains 3-12 carbon atoms; in another embodiment, the cycloalkyl group contains 3-8 carbon atoms; in another embodiment, the cycloalkyl group contains 3-7 carbon atoms Carbon atoms; in still other embodiments, the cycloalkyl group contains 3-6 carbon atoms.
- the cycloalkyl group may independently be unsubstituted or substituted with one or more substituents described in the present invention.
- heterocyclic group refers to a monocyclic, bicyclic or tricyclic system containing 3-12 ring atoms, non-aromatic, saturated or partially unsaturated, monovalent or polyvalent, wherein at least one ring atom is selected from Atoms of nitrogen, sulfur or oxygen.
- the heterocyclic group may be optionally substituted with one or more substituents described in the present invention.
- the sulfur atom of the ring can optionally be oxidized to an S-oxide.
- the heterocyclic group is a monocyclic heterocyclic group composed of 5-7 atoms. In some embodiments, the heterocyclic group is a monocyclic heterocyclic group composed of 5-6 atoms. In some embodiments, the heterocyclic group is a bicyclic heterocyclic group consisting of 7-12 ring atoms. In some embodiments, the heterocyclic group is a bicyclic heterocyclic group consisting of 8-10 ring atoms.
- the heterocyclic group is a 4-atom heterocyclic group, which means a monovalent or polyvalent, saturated or partially unsaturated, non-aromatic monocyclic ring containing 4 ring atoms, at least one of which The ring atoms are selected from nitrogen, sulfur and oxygen atoms.
- the heterocyclic group is a 5-membered heterocyclic group, which means a monovalent or polyvalent, saturated or partially unsaturated, non-aromatic monocyclic ring containing 5 ring atoms, wherein at least One ring atom is selected from nitrogen, sulfur and oxygen atoms.
- the heterocyclic group is a 6-membered heterocyclic group, which refers to a monovalent or polyvalent, saturated or partially unsaturated, non-aromatic monocyclic ring containing 6 ring atoms, wherein at least One ring atom is selected from nitrogen, sulfur and oxygen atoms.
- heterocyclic groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piper Pyridinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, Epoxypropyl, azacycloheptyl, oxetanyl, thiaheptyl, oxazepinyl, diazepinyl, thiozepine, 2-pyrrolyl, 3-pyrrole Porphyrinyl, indoline, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-
- examples include, but are not limited to pyrimidinedione, 1,2 ,4-thiadiazole-5(4H)-keto, 1,2,4-oxadiazole-5(4H)-keto, 1H-1,2,4-triazole-5(4H)-one
- heteroatom means one or more of O, S, N, P and Si, including N, S and P in any oxidation state; primary, secondary, tertiary amine and quaternary ammonium salt forms; or heterocyclic nitrogen Atom-substituted form of hydrogen, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like N-substituted pyrrolidine NR and R in the group are the substituents described in the present invention).
- halogen or "halogen atom” refers to F, Cl, Br or I.
- unsaturated means that the portion contains one or more degrees of unsaturation.
- aryl refers to monocyclic, bicyclic and tricyclic carbocyclic systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic Family, where each ring system contains a ring of 3-7 atoms, and there are one or more points of attachment to the rest of the molecule.
- aryl may be used interchangeably with the term “aromatic ring”. Examples of aryl groups may include phenyl, naphthyl and anthracenyl. The aryl group may be independently optionally substituted with one or more substituents described in the present invention.
- heteroaryl refers to monocyclic, bicyclic and tricyclic systems containing 5-12 ring atoms, wherein at least one ring is an aromatic ring, and at least one aromatic ring contains one or more heteroatoms, wherein each ring system It contains a ring composed of 5-7 ring atoms, and one or more connection points are connected to the rest of the molecule.
- heteroaryl may be used interchangeably with the terms “aromatic heterocycle”, “heteroaromatic ring” or “heteroaromatic compound”.
- the heteroaryl group is a monocyclic heteroaryl group consisting of 5-7 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl group is a monocyclic heteroaryl group consisting of 5-6 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl group is a bicyclic heteroaryl group composed of 7-12 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen.
- the heteroaryl group is a bicyclic heteroaryl group consisting of 8-10 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl group is a bicyclic heteroaryl group consisting of 9-10 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen.
- heteroaryl group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, deuterium, F, Cl, Br, OH, C 1-8 alkyl, C 1-8 alkoxy, HOOC -(CR 7 R 8 ) q -or C 1-8 alkoxy-(CR 7 R 8 ) k -O- substituted, wherein q, k, R 7 and R 8 have the meaning.
- heteroaromatic rings include the following monocyclic rings, but are not limited to these monocyclic rings: 1,2,4-oxadiazole-5(4H)-thione, 1,2,4-thiadiazole-5( 4H)-keto, 1,2,4-oxadiazole-5(4H)-keto, 1,3,4-oxadiazole-2(3H)-thione, 1H-1,2,4 -Triazole-5(4H)-keto, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4 -Isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl , 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimi
- MM consists of 1 ring atom
- the cyclic group is composed of 1 ring atom of MM, and the ring atom includes carbon atoms and/or heteroatoms such as O, N, S, and P.
- heteroaryl consisting of 6-10 ring atoms represents a heteroaryl consisting of 6, 7, 8, 9 or 10 ring atoms.
- alkoxyalkyl and “alkoxyalkylene” are used interchangeably, meaning that the alkyl group can be replaced by one or more alkoxy groups that are the same or different, where alkoxy and alkyl
- the radical group has the meaning as described in the present invention. Such examples include, but are not limited to methoxyethyl, ethoxymethyl, and the like.
- a ring system formed by a substituent connecting a bond to the central ring represents that the substituent can be substituted at any substitutable position on the ring, and can include enantiomers.
- the substitution of isomers is represented by the formulas b, c, d, e, f, g and h.
- connection points in the system that are connected to the rest of the molecule, for example, as shown in formula q, it can be either E-terminal or E′-terminal connected to the rest of the molecule, that is, the molecular structure is reasonable
- connection methods at both ends can be interchanged.
- the structural formula described in the present invention includes all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers): for example, R containing an asymmetric center , S configuration, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Therefore, the single stereochemical isomer of the compound of the present invention or its enantiomer Isomers, diastereomers, or mixtures of geometric isomers (or conformers) are within the scope of the present invention.
- prodrug used in the present invention means that a compound is converted into a compound represented by formula (I), formula (Ia), formula (II) or formula (IIa) in vivo. Such conversion is affected by prodrug hydrolysis in the blood or enzymatic conversion into the parent structure in the blood or tissue.
- the prodrug compounds of the present invention may be esters.
- esters may be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, and carbonates. , Carbamates and amino acid esters.
- a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug.
- prodrug forms include phosphate esters, as these phosphate ester compounds are obtained by phosphorylation of hydroxyl groups on the parent.
- prodrugs please refer to the following documents: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJHecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008 , 51, 2328-2345.
- Metal refers to a product obtained by metabolizing a specific compound or its salt in the body.
- the metabolite of a compound can be identified by techniques well known in the art, and its activity can be characterized by an experimental method as described in the present invention.
- Such products can be obtained by administering compounds through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc.
- the present invention includes metabolites of the compound, including metabolites produced by fully contacting the compound of the present invention with a mammal for a period of time.
- stereochemistry in the present invention generally refer to the following documents: SPParker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S ., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.
- the compound of the present invention may contain an asymmetric center or a chiral center, so different stereoisomers exist. All stereoisomeric forms of the compounds of the present invention, including but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute the present invention Part.
- optically active compounds that is, they have the ability to rotate the plane of plane polarized light.
- the prefixes D, L or R, S are used to indicate the absolute configuration of the molecular chiral center.
- the prefixes d, l, or (+), (-) are used to designate the symbol for the rotation of the plane polarized light of the compound, (-) or l means that the compound is left-handed, and the prefix (+) or d means that the compound is right-handed.
- the chemical structures of these stereoisomers are the same, but their stereostructures are different.
- the specific stereoisomer may be an enantiomer, and a mixture of isomers is usually called a mixture of enantiomers.
- a 50:50 mixture of enantiomers is called a racemic mixture or a racemate, which may result in no stereoselectivity or stereospecificity during the chemical reaction.
- racemic mixture and racemate refer to an equimolar mixture of two enantiomers, lacking optical activity.
- tautomer or "tautomeric form” means that structural isomers of different energies can be converted to each other by a low energy barrier.
- proton tautomers i.e., proton shift tautomers
- the atomic valence (valence) tautomers include the interconversion of reorganized bond electrons. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
- salts formed by pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups include hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods described in books and literature such as ion exchange These salts.
- salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate , Borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate Acid salt, glucoheptonic salt, glycerol phosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactic acid Salt, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, paraben ,
- Salts obtained by suitable bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
- the present invention also contemplates the formation of quaternary ammonium salts of any compound containing N groups. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
- the alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
- Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter-ions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C 1 -8 sulfonate and aromatic sulfonate.
- solvate of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention.
- Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
- hydrate refers to an association formed by the solvent molecule being water.
- protecting group or “Pg” means that when a substituent reacts with another functional group, it is usually used to block or protect a particular functionality.
- amino protecting group refers to a substituent attached to an amino group to block or protect the functionality of the amino group in the compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc).
- hydroxyl protecting group refers to the functionality of a hydroxyl group's substituent used to block or protect the hydroxyl group.
- Suitable protecting groups include acetyl and silyl.
- Carboxyl protecting group refers to the substituent of carboxyl group used to block or protect the functionality of carboxyl group
- general carboxyl protecting group includes -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilane Group) ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl Phosphino) ethyl, nitroethyl, etc.
- protecting groups reference can be made to: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
- compositions compositions, formulations, administration of compounds of the present invention and use of compounds and compositions
- the characteristics of the pharmaceutical composition of the present invention include a deuterated compound of formula (I), formula (Ia), formula (II), or formula (IIa), a compound listed in the present invention, or an example compound , And pharmaceutically acceptable excipients.
- the compound in the composition of the present invention can effectively inhibit hepatitis B virus, and is suitable for the treatment of virus-induced diseases, especially acute and chronic persistent HBV infection. Chronic viral diseases caused by HBV may lead to serious morbidity, chronic hepatitis B Viral infections can cause cirrhosis and/or hepatocellular carcinoma in many cases.
- areas of disease treatment that may be mentioned are, for example, the treatment of acute and chronic viral infections that may lead to infectious hepatitis, for example, hepatitis B virus infection.
- the compounds of the present invention are particularly suitable for the treatment of chronic hepatitis B infections and acute and chronic hepatitis B virus infections.
- the present invention includes pharmaceutical preparations, in addition to non-toxic and inert pharmaceutically suitable auxiliary materials, it also contains one or more deuteriums of formula (I), formula (Ia), formula (II) or formula (IIa) of the present invention
- Substitute compounds or pharmaceutical compositions thereof contain one or more active ingredients of the compound of formula (I), formula (Ia), formula (II) or formula (IIa) or the pharmaceutical composition of the present invention.
- the above-mentioned pharmaceutical preparation may also contain other active pharmaceutical ingredients other than the deuterated compound represented by formula (I), formula (Ia), formula (II) or formula (IIa).
- pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, ester salts, or any other that can be administered directly or indirectly according to the needs of the patient Adducts or derivatives, compounds described in other aspects of the invention, their metabolites or their residues.
- the pharmaceutical composition of the present invention comprises any one of the deuterated compounds of formula (I), formula (Ia), formula (II), or formula (IIa) of the present invention, further comprising pharmaceutically acceptable Accepted excipients, such as those used in the present invention, include any solvent, solid excipient, diluent, binder, disintegrant, or other liquid excipient, dispersant, flavor, or suspension Agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., suitable for the specific target dosage form. As described in the following documents: In Remington: The Science and Practice Pharmacy, 21st edition, 2005, ed.
- Substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins such as human serum proteins; buffer substances such as phosphates; glycine; sorbic acid; sorbic acid Potassium acid; partial glyceride mixture of saturated vegetable fatty acids; water; salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt; colloidal silicon; magnesium trisilicate; polyethylene Pyrrolidone; polyacrylate; wax; polyethylene-polyoxypropylene-blocking polymer; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl Sodium cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; auxiliary materials such as cocoa
- the pharmaceutical composition of the compound of the present invention can be administered in any of the following ways: oral administration, spray inhalation, local administration, rectal administration, nasal administration, local administration, vaginal administration, parenteral administration Medicines such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, or intracranial injection or infusion, or use an explanted reservoir.
- oral administration intramuscular injection, intraperitoneal administration or intravenous injection.
- the compound of the present invention or the pharmaceutical composition thereof can be administered in unit dosage form.
- the dosage form for administration may be a liquid dosage form or a solid dosage form.
- the liquid dosage form may be a true solution type, a colloid type, a particulate dosage form, or a suspension dosage form.
- Other dosage forms such as tablets, capsules, pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, lyophilized powder injections, clathrates, implants, patches, rubs Agent.
- Oral tablets and capsules may contain excipients such as binders, such as syrup, gum arabic, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, amino Acetic acid; lubricants, such as magnesium stearate, talc, polyethylene glycol, silica; disintegrating agents, such as potato starch; or acceptable moisturizers, such as sodium lauryl sulfate.
- binders such as syrup, gum arabic, sorbitol, tragacanth, or polyvinylpyrrolidone
- fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, amino Acetic acid
- lubricants such as magnesium stearate, talc, polyethylene glycol, silica
- disintegrating agents such as potato starch
- acceptable moisturizers such as sodium lauryl s
- Oral liquids can be prepared as suspensions, solutions, emulsions, syrups or elixirs of hydrated oils, or as dry products, supplemented with water or other suitable medium before use.
- Such liquid preparations may contain conventional additives such as suspending agents, sorbitol, cellulose methyl ether, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated food Fats, emulsifiers such as lecithin, sorbitan monooleate, gum arabic; or non-aqueous excipients (which may contain edible oils), such as almond oil, fats such as glycerin, ethylene glycol, or ethanol; preservatives, Such as methyl or propyl paraben, sorbic acid. If necessary, flavoring agents or coloring agents can be added.
- Suppositories may contain conventional suppository bases such as cocoa butter or other glycerides.
- the liquid dosage form is usually made of a compound and a sterilized auxiliary material.
- the auxiliary material is preferably water.
- the compound can be either dissolved in the excipient or made into a suspension solution.
- the compound is first dissolved in water, filtered and sterilized and then put into a sealed bottle or ampoule.
- the compounds of the present invention can be prepared in the form of suitable ointments, lotions, or creams, in which the active ingredient is suspended or dissolved in one or more excipients, where the excipients that can be used in ointment formulations include but Not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; auxiliary materials that can be used in lotions and creams include but are not limited to: mineral oil, sorbitan mono Stearate, Tween 60, cetyl ester wax, hexadecenyl aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
- the total amount of active compound of the present invention is about 0.5-500 mg, preferably 1-100 mg/kg body weight every 24 hours, whether in human medicine or veterinary medicine, if appropriate Single dose administration multiple times to achieve the desired effect.
- the amount of the active compound contained in a single dose is preferably about 1-80 mg, more preferably 1-50 mg/kg body weight, but it may not be in accordance with the above dose, that is, it depends on the type and weight of the subject to be treated, the nature and severity of the disease , The type of preparation and the mode of administration of the drug, as well as the administration cycle or time interval.
- the pharmaceutical composition provided by the present invention also includes anti-HBV drugs.
- the anti-HBV drugs are HBV polymerase inhibitors, immunomodulators or interferons.
- the anti-HBV drugs are lamivudine, telbivudine, tenofovir dipivoxil, entecavir, adefovir dipivoxil, Alfaferone, Alloferon, simo interleukin, clavudine, emtricitabine, famciclovir Wei, Interferon, Baoganling CP, Intefen, Interferon ⁇ -1b, Interferon ⁇ , Interferon ⁇ -2a, Interferon ⁇ -1a, Interferon ⁇ -2, Interleukin-2, Mifu Titrate, nitazoxanide, pegylated interferon ⁇ -2a, ribavirin, rapamycin-A, cezolan, Euforavac, April, Phosphazid, Heplisav, interferon ⁇ -2b, levamisole Or propargium germanium.
- Hepatitis B disease refers to liver disease caused by hepatitis B virus infection or hepatitis B infection, including acute hepatitis, chronic hepatitis, liver cirrhosis and stem cell cancer.
- Acute hepatitis B virus infection can be asymptomatic or present as symptoms of acute hepatitis.
- Patients with chronic viral infections have active diseases that can progress to cirrhosis and liver cancer.
- Anti-HBV drugs can be administered separately from the composition containing the compound of the present invention as part of a multiple dosing regimen. Alternatively, those drugs may be part of a single dosage form, mixed with the compound of the invention to form a single composition. If the drug is administered as part of a multiple dosing regimen, the two active agents can be delivered to each other continuously or over a period of time to obtain the target agent activity.
- the amount of compound and composition that can be combined with the excipient materials to produce a single dosage form varies depending on the indication and the particular mode of administration. Normally, the amount of the composition of the present invention will not exceed the amount of the composition normally administered as the sole active agent. On the other hand, the amount of the presently disclosed composition ranges from about 50% to 100% of the normal amount of the existing composition, and contains the agent as the only active therapeutic agent. Among those contained compositions, the composition will act synergistically with the compounds of the present invention.
- the compounds of the present invention show strong antiviral effects. Such compounds have unexpected antiviral activity against HBV and are therefore suitable for the treatment of various diseases caused by viruses, especially those caused by acute and chronic persistent HBV infection. Chronic viral diseases caused by HBV can cause various symptoms of various severity. It is well known that chronic hepatitis B virus infection can lead to cirrhosis and/or hepatocellular carcinoma.
- indications that can be treated with the compounds of the present invention are: acute and chronic viral infections that can cause infectious hepatitis, such as heterosexual hepatitis virus infection. Particularly preferred are chronic hepatitis B infection and acute hepatitis B virus infection.
- the present invention also relates to the use of the compounds and compositions of the present invention for the preparation of medicaments for the treatment and prevention of viral diseases, especially hepatitis B.
- the compound of the present invention can be prepared by the method described in the present invention, unless otherwise specified, wherein the definition of the substituent is as formula (I), formula (Ia), formula (II) or formula (IIa) Show.
- the following synthesis schemes and examples are used to further illustrate the content of the present invention.
- the chromatography column used silica gel column, silica gel (200-300 mesh) was purchased from Qingdao Ocean Chemical Factory. Nuclear magnetic resonance spectroscopy uses CDC1 3 , DMSO-d 6 , CD 3 OD or acetone-d 6 as the solvent (reported in ppm), and uses TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard.
- MS data was measured by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30°C).
- the G1329A automatic sampler and G1315B DAD detector were used for analysis , ESI source is applied to LC-MS spectrometer.
- MS data was also measured by an Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and G1316A TCC (column temperature maintained at 30°C).
- the G1329A automatic sampler and G1315D DAD detector were used for analysis , ESI source is applied to LC-MS spectrometer.
- Compound (2a) can be prepared by the method described in Synthesis Scheme 1.
- Compound (1a) (compound (1a) can be obtained by referring to Synthesis Scheme 1 in WO2015074546 and the specific examples thereof) and compound (a) are basic Under conditions (such as potassium carbonate, etc.) and a suitable solvent (such as ethanol, etc.), the compound (2a) is obtained.
- F6-0 400mg, 1.97mmol
- (R)-3-oxohexahydroimidazo[1,5-a]pyrazine-7(1H)-carboxylic acid tert-butyl ester were added to the dry reaction bottle in sequence. 522mg, 2.16mmol), Pd(OAc) 2 (23mg, 0.10mmol), Xantphos (117mg, 0.20mmol) and Cs 2 CO 3 (1.16g, 3.56mmol), add 1,4-dioxane under the protection of nitrogen (25mL). The reaction was carried out at 80°C for 2h. Stop the reaction.
- F8-0 500 mg, 1.22 mmol was dissolved in methanol (10 mL), to which was added a solution of lithium hydroxide monohydrate (250 mg, 6.10 mmol) in water (5 mL), and the reaction was carried out at 50° C. for 12 h. Concentrate to remove methanol, cool to 0°C, adjust the pH of the solution to 2 with 1M hydrochloric acid, filter, and dry the filter cake to obtain the title compound as a brown solid (480 mg, 99%).
- Fragment F10 (F10 can be obtained according to the synthesis method of Steps 1-3 of Example 27 in WO2019001396) replaces F1 of Step 1 of Example 1, and the rest of the operations are performed according to the method of Step 6 of Example 1, to obtain the title compound as a yellow solid (170 mg, 50.95%).
- Fragment F11 (F11 can be obtained according to the synthesis method of Step 19 of Example 19 in WO2019076310) replaces F1 of Step 1 of Example 1, and the rest of the operations are performed according to the method of Step 6 of Example 1, to obtain the title compound as a yellow solid (180 mg, 56%).
- Fragment F12 (F12 can be obtained according to the synthesis method of Steps 1-5 of Example 18 in WO 2019076310) replaces F1 of Step 1 of Example 1, and the rest of the operations are carried out according to the method of Step 6 of Example 1, to obtain the title compound as a yellow solid (180 mg , 49%).
- Fragment F13 (F13 can be obtained according to the synthesis method of Steps 1-5 of Example 20 in WO 2019076310) replaces F1 of Step 1 of Example 1, and the rest of the operations are carried out according to the method of Step 6 of Example 1, to obtain the title compound as a yellow solid (160 mg , 54%).
- Test 1 Anti-HBV EC 50 test method
- HepG2.2.15 cells The chromosome of HepG2.2.15 cells (SELLS, PNAS, 1987 and SELLS, JV, 1988) integrates the complete HBV genome and stably expresses viral RNA and viral proteins. HepG2.2.15 cells can secrete mature HBV particles, HBsAg and HBeAg into the culture medium. HepG2.2.15 was cultured in DMEM medium containing 10% fetal bovine serum, 100 U/mL penicillin, 100 U/mL streptomycin, 1% non-essential amino acids, and 1 mM sodium pyruvate 300 ⁇ g/mL G418.
- Virion DNA secreted by HepG2.2.15 cells can be quantified by qPCR, and the effect of compounds on virus replication can be detected from this.
- Table 2 EC 50 values of compounds of the present invention for HBV replication
- cytotoxicity (%) 100-(detection value/average value of DMSO control well ⁇ 100).
- concentration-cytotoxicity (%) data was processed with Graphpad Prism 5 software, and CC 50 was calculated by a four-parameter nonlinear regression model. A CC 50 greater than 50 indicates that the toxicity is relatively low.
- the experimental results of the compound of the present invention are shown in Table 3.
- Table 3 CC 50 values of cytotoxicity of the compounds of the invention
- the cytotoxicity experiment data shows that the compound of the present invention has low toxicity to cells.
- Test 3 Pharmacokinetic experiments of the compounds of the present invention in beagle dogs, mice and rats
- Beagle dogs were given 2.5 mg/kg or 5 mg/kg by oral gavage or 1 mg/kg or 2 mg/kg of test compound intravenously.
- mice purchased from Hunan Slake Jingda Experimental Animal Co., Ltd., body weight 20-25g, male, age 45-60 days, 3 orally per group, 3 intravenously per group
- ICR mice were given 10 mg/kg orally or 2 mg/kg or 10 mg/kg of test compound via the tail vein.
- the rats were given 2.5 mg/kg or 5 mg/kg orally or intravenously 1 mg/kg of the test compound.
- Test 4 Stability test of the compound of the present invention in liver microsomes of different species
- the compounds of the present invention have better stability in liver microsomes of different species.
- Very soluble means that 1g (mL) of solute can be dissolved in less than 1mL of solvent;
- Dissolution means that 1g (mL) of solute can be dissolved in the solvent from 10 to less than 30mL;
- Slightly soluble means that 1g (mL) of solute can be dissolved in the solvent from 30 to less than 100mL;
- Slightly soluble means that the solute lg (mL) can be dissolved in the solvent from 100 to less than 1000 mL;
- Very slight dissolution means that 1g (mL) of solute can be dissolved in solvent from 1000 to less than 10000mL;
- Test 7 Liver drug enzyme induction test
- hepatocytes After cryopreserved human hepatocytes (Baltimore, MD, USA) were recovered, trypan blue staining and cell counter were used to determine the cell number and cell viability. After counting, the hepatocytes were diluted with preheated seed plate culture fluid to contain 700,000 viable cells per ml. Inoculate the diluted hepatocyte suspension at a rate of 0.2mL/well onto a 48-well plate pre-plated with collagen, and incubate for at least 4 hours in the incubator. When the cells are adherent, incubate with 2% Matrigel The culture medium replaces the seed plate culture medium.
- the remaining drug solution in the plate was discarded, and the cell wells were washed twice with 0.5 mL of HBSS solution preheated to 37°C, and 100 ⁇ L of preheated to 37°C was added to each well.
- the enzyme-labeled substrate working solution was incubated for 30 minutes. After incubating for 30 minutes, 75 ⁇ L of supernatant sample was taken from each well and added to a 96-well deep well plate containing 150 ⁇ L of stop solution.
- the potential toxicity of the test article is evaluated by the amount of lactate dehydrogenase (LDH) released in the liver cells.
- LDH lactate dehydrogenase
- the liquid chromatography tandem mass spectrometry (LC/MS/MS) method was used to determine the metabolites of three CYP enzyme substrates (Acetaminophen, Hydroxybupropion) and 1 in liver cells after protein precipitation. -The concentration of 1'-Hydroxymidazolam). The analysis method is shown in Table 5.
- This project uses the relative quantitative method of ⁇ Ct to compare the difference in gene expression between different treatment groups, and uses 18S rRNA as the internal reference gene to correct the gene expression of each sample.
- the experimental data shows the amount of enzyme metabolites produced by CYP3A4.
- the change in enzyme activity is shown by comparing the fold induction of the corresponding cytochrome enzyme in the presence or absence of the compound.
- the calculation method of the induction multiple and the calculation method of the induction ratio with the control compound are as follows:
- Induction factor enzyme activity in the sample treated for the test article/enzyme activity in the sample treated with the matrix control
- Induction ratio with control compound (induction factor of sample treated with test article-1)/(induction factor of sample treated with control compound-1) ⁇ 100%.
- liver drug enzyme induction test The experimental results of liver drug enzyme induction test are shown in Table 6:
- Test 8 Experiment on the effect of human serum on the anti-HBV efficacy of the compound
- HepG2.2.15 cell integrates the complete HBV genome and stably expresses viral RNA and viral protein.
- HepG2.2.15 cells can secrete mature HBV particles, HBsAg and HBeAg into the culture medium.
- Viral DNA secreted by HepG2.2.15 cells can be quantified by qPCR method, while adding different concentrations of human serum at the same time as the test compound treatment, and thus detecting the effect of human serum on the antiviral efficacy of the compound.
- Step 1 Spread 15,000 HepG2.2.15 cells per well in a 96-well cell culture plate and 200 ⁇ L of cell culture medium per well.
- Step 2 Incubate at 37°C in a 5% CO 2 cell incubator for 3 days until the cells grow to full pores.
- Step: 3 On day 0 of the test, discard the old medium and add 200 ⁇ L of fresh detection medium containing 2% FBS and different human serum (HS) concentrations, including 0% HS, 5% HS, 10% HS , 20% HS, 40% HS and 50% HS.
- HS human serum
- Step 4 Compound preparation and cell treatment in antiviral experiments: Dissolve the compound with DMSO to 30 mM, further dilute the compound with DMSO to 800 ⁇ M, and then perform 4 dilutions of 8 dilutions, with a maximum concentration of 800 ⁇ M. Add 1 ⁇ L of serially diluted compound to each cell plate prepared in step 3. The maximum final concentration of the experiment is 4 ⁇ M (200-fold dilution).
- Step 5 Experiment setting TDF (tenofovir disoproxil fumarate, Selleck, Cat S1400) under 2% FBS as the positive control compound, the highest concentration is 4 ⁇ M. Add 1 ⁇ LDMSO to the negative control well, and the final concentration of the experiment is 0.5%.
- TDF tenofovir disoproxil fumarate, Selleck, Cat S1400
- Step 6 Incubate the 96-well cell test plate in a 37°C CO 2 incubator for 11 days, change the fluid every other day (days 2, 4, 6, 8, and 10), and add 1 ⁇ L of freshly prepared test compound , See steps 3 to 5.
- Step 7 On day 11, 150 ⁇ L of supernatant was taken for qPCR detection of viral DNA.
- Step 8 Compound preparation and cell treatment in cytotoxicity experiments: Bravo liquid handling system was used to prepare serially diluted compounds, 11 dilutions, 3 times dilution, and the highest concentration was 30 mM. Add 0.25 ⁇ L of compound diluted serially with Echo550 to a 384-well cytotoxic cell plate (Greiner 781098). Prepare HepG2.2.15 cells and resuspend in different concentrations of human serum concentrations (50%, 40%, 20%, 10%, 5%, and 0%). Add 50 ⁇ L (4000 cells) of HepG2.2.15 cells prepared above each well to a 384-well cytotoxic cell plate, and the maximum final concentration of the experiment is 150 ⁇ M (200-fold dilution). The cytotoxicity test was carried out after incubating in a 37°C CO 2 incubator for 4 days.
- Step 1 Dilute the supernatant under 20% HS experiment conditions with DPBS, dilute the supernatant under 40% HS experiment conditions with DPBS, and use DPBS with the supernatant under 50% HS conditions Make a 5-fold dilution. After mixing, take 1 ⁇ L for qPCR detection.
- Step 2 Take 1 ⁇ L of the supernatant under the experimental conditions of 0% HS, 5% HS and 10% HS directly for qPCR detection.
- Step 3 Prepare the qPCR reaction system according to the following ingredients:
- Step 4 Set up the ABI ViiA7 qPCR instrument according to the following conditions
- Step 1 Equilibrate PromegaCelltiter-Glo reagent to room temperature.
- Step 2 Discard the cytotoxicity assay plate medium and add 50 ⁇ L of DPBS to each well.
- Step 3 Add 10 ⁇ L CellTiter-Glo reagent to each well.
- Step 4 Shake the instrument for 2 minutes.
- Step 5 Equilibrate in the dark at room temperature for 10 minutes.
- Step 6 Reading on the Envision plate reader (0.1 sec/well)
- a plasmid containing the HBV genome (virus copy number: 2 ⁇ 10E6, 2 ⁇ 10E5, 2 ⁇ 10E4, 2 ⁇ 10E3) was used as the standard curve, and the virus copy number was calculated with the standard curve.
- the cytotoxicity% data was processed and graphed with Graphpad Prism 5 software, and CC 50 was calculated by a four-parameter nonlinear regression model.
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Abstract
A deuterated dihydropyrimidine compound and use thereof as a drug, especially as a drug for treating and preventing hepatitis B. In particular, the present invention relates to a compound represented by general formula (I) or (Ia) or a stereoisomer, a tautomer, an oxynitride, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, wherein each variate is as defined in the description. The present invention also relates to use of the compound represented by general formula (I) or (Ia) or a stereoisomer, a tautomer, an oxynitride, a solvate, a metabolite, or a pharmaceutically acceptable salt thereof as a drug, in particular as a drug for treating and preventing hepatitis B. (I), (IA)
Description
本发明属于医药领域。具体地，本发明涉及一种氘代二氢嘧啶类化合物及其作为药物的用途，尤其是作为用于治疗和预防乙型肝炎的药物的用途。本发明还涉及这些氘代二氢嘧啶类化合物同其他抗病毒剂组成的组合物，及其用于治疗和预防乙型肝炎病毒(HBV)感染的应用。The invention belongs to the field of medicine. Specifically, the present invention relates to a deuterated dihydropyrimidine compound and its use as a medicine, especially as a medicine for treating and preventing hepatitis B. The invention also relates to a composition composed of these deuterated dihydropyrimidine compounds and other antiviral agents, and its application for treating and preventing hepatitis B virus (HBV) infection.
乙型肝炎病毒属于肝病毒科。它可引起急性的和/或持续渐进的慢性病。乙型肝炎病毒还可引起病理形态中的许多其他的临床表征——尤其是肝脏的慢性炎症、肝硬化和肝细胞的癌变。另外，与丁型肝炎的共同感染在疾病的发展过程中会产生不利影响。Hepatitis B virus belongs to the family of hepadnaviruses. It can cause acute and/or progressive chronic diseases. Hepatitis B virus can also cause many other clinical features in pathological morphology-especially chronic inflammation of the liver, liver cirrhosis and canceration of liver cells. In addition, co-infection with hepatitis D will have an adverse effect during the development of the disease.
被许可用于治疗慢性肝炎的常规药物是干扰素和拉米夫定(lamivudine)。然而，干扰素只具有中等的活性，并具有较高的毒副反应；虽然拉米夫定(lamivudine)具有良好的活性，但其耐药性在治疗过程中增幅迅速，并在停止治疗之后常常出现反弹效应，拉米夫定(3-TC)的IC
50值为300nM(Science,299(2003),893-896)。
The conventional drugs approved for the treatment of chronic hepatitis are interferon and lamivudine. However, interferon is only moderately active and has high toxicity; although lamivudine has good activity, its drug resistance increases rapidly during treatment and often after stopping treatment A rebound effect occurs, and the IC 50 value of lamivudine (3-TC) is 300 nM (Science, 299 (2003), 893-896).
Deres等报道了以Bay41-4109、Bay39-5493为代表的杂芳环取代的二氢嘧啶类(HAP)化合物，该类化合物能够通过阻止正常核衣壳的形成起到抑制HBV复制的作用。Bay41-4109在临床研究中表现出较好的药物代谢性质(Science,299(2003),893-896)，通过对其作用机制的研究发现，杂芳环取代的二氢嘧啶类化合物通过与核心蛋白的113-143氨基酸残基作用，改变了形成核衣壳的二聚体之间的夹角，导致形成不稳定的膨胀核衣壳，加速核心蛋白的降解(Biochem.Pharmacol.66(2003),2273-2279)。Deres et al. reported that heteroaromatic ring-substituted dihydropyrimidines (HAP) compounds represented by Bay41-4109 and Bay39-5493 can inhibit HBV replication by preventing normal nucleocapsid formation. Bay41-4109 showed good drug metabolic properties in clinical studies (Science, 299 (2003), 893-896). Through the study of its mechanism of action, it was found that the heteroaromatic ring-substituted dihydropyrimidine compounds pass through the core The 113-143 amino acid residues of the protein change the angle between the dimers that form the nucleocapsid, resulting in the formation of an unstable swollen nucleocapsid and accelerating the degradation of the core protein (Biochem. Pharmacol. 66 (2003) , 2273-2279).
目前仍然需要有新的能够有效地用作抗病毒药物的化合物，尤其是用作治疗和/或预防乙型肝炎的药物。There is still a need for new compounds that can be effectively used as antiviral drugs, especially for the treatment and/or prevention of hepatitis B.
发明内容Summary of the invention
本发明涉及新型氘代二氢嘧啶类化合物和其在制备治疗与预防HBV感染的药物中的用途。特别地，本发明所涉及一种新型的氘代二氢嘧啶类化合物的化合物，及其药学上可接受的组合物，该化合物具有药代动力学性质好、溶解性好、稳定性好、对肝药酶基本无诱导作用和较小的毒性等优点，可以有效抑制HBV感染，其在抗HBV方面有很好的应用前景。The invention relates to a novel deuterated dihydropyrimidine compound and its use in the preparation of a medicine for treating and preventing HBV infection. In particular, the present invention relates to a novel deuterated dihydropyrimidine compound and its pharmaceutically acceptable composition. The compound has good pharmacokinetic properties, good solubility, good stability, and Liver drug enzymes basically have no advantages such as induction and less toxicity, and can effectively inhibit HBV infection, and they have good application prospects in anti-HBV.
一方面，本发明涉及一种氘代化合物，其为如式(I)或(Ia)所示的氘代化合物或如式(I)或(I)所示的氘代化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，In one aspect, the present invention relates to a deuterated compound which is a deuterated compound represented by formula (I) or (Ia) or a stereoisomer of a deuterated compound represented by formula (I) or (I) , Tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or its prodrugs,
其中，各R
1独立地为氢、氘、F、Cl、Br、I、氰基、甲基、乙基、甲氧基、乙氧基或硝基；
Wherein, each R 1 is independently hydrogen, deuterium, F, Cl, Br, I, cyano, methyl, ethyl, methoxy, ethoxy, or nitro;
R
2为甲基、乙基、正丙基或异丙基，其中所述甲基、乙基、正丙基和异丙基各自独立地未被取代或被1、2、3、4或5个氘所取代；
R 2 is methyl, ethyl, n-propyl or isopropyl, wherein the methyl, ethyl, n-propyl and isopropyl are each independently unsubstituted or substituted by 1, 2, 3, 4 or 5 Replaced by deuterium;
R
3为苯基或者5-6个环原子组成的杂芳基，其中所述苯基和5-6个环原子组成的杂芳基各自独立地未被取代或被1、2、3、4或5个选自氘、F、Cl、Br、HO、CN、C
1-4烷基、羟基C
1-4烷基、C
1-4烷基-OC(＝O)-、C
1-4烷基-OC(＝O)-C
1-3亚烷基、HOOC-C
1-3亚烷基、C
1-4烷氧基-C
1-3亚烷基和C
1-4烷基-S(＝O)
2-的取代基所取代；
R 3 is a phenyl group or a heteroaryl group composed of 5-6 ring atoms, wherein the phenyl group and a heteroaryl group composed of 5-6 ring atoms are each independently unsubstituted or substituted by 1, 2, 3, 4 Or 5 selected from deuterium, F, Cl, Br, HO, CN, C 1-4 alkyl, hydroxy C 1-4 alkyl, C 1-4 alkyl-OC(=O)-, C 1-4 Alkyl-OC(=O)-C 1-3 alkylene, HOOC-C 1-3 alkylene, C 1-4 alkoxy-C 1-3 alkylene and C 1-4 alkyl- S(=O) 2 -substituted by a substituent;
其中，W为CH或N；Among them, W is CH or N;
X
1为-C(＝O)-、-S(＝O)
2-或-(CR
7R
8)
j-；
X 1 is -C(=O)-, -S(=O) 2 -or -(CR 7 R 8 ) j -;
各R
7和R
8独立地为氢、氘、F、Cl、Br、氨基、C
1-6烷基、NH
2C(＝O)-、C
1-6烷基-OC(＝O)-、羧基、羧基C
1-6烷基、羟基C
1-6烷基、C
1-4烷氧基C
1-4烷基或C
1-6卤代烷基，或R
7、R
8和与它们相连的碳原子一起形成C
3-6环烷基或羰基；
Each R 7 and R 8 is independently hydrogen, deuterium, F, Cl, Br, amino, C 1-6 alkyl, NH 2 C(=O)-, C 1-6 alkyl-OC(=O)- , Carboxyl, carboxyl C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-4 alkoxy C 1-4 alkyl or C 1-6 haloalkyl, or R 7 , R 8 and connected to them The carbon atoms of together form C 3-6 cycloalkyl or carbonyl;
R
4为C
1-6烷基、5-6个环原子组成的杂芳基、
其中，所述C
1-6烷基未被取代或被1、2、3、4或5个选自氘、F、Cl、Br、HO、甲基或HOOC-的取代基所取代，所述5-6个环原子组成的杂芳基未被取代或被1、2、3、4或5个R
13取代基所取代；
R 4 is a C 1-6 alkyl group, a heteroaryl group consisting of 5-6 ring atoms, Wherein the C 1-6 alkyl group is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from deuterium, F, Cl, Br, HO, methyl or HOOC-, Heteroaryl groups consisting of 5-6 ring atoms are unsubstituted or substituted with 1, 2, 3, 4 or 5 R 13 substituents;
各R
9、R
11和R
12独立地为氘、F、Cl、Br、氨基、C
1-6烷基、NH
2C(＝O)-、C
1-6烷基-OC(＝O)-、羧基、羧基C
1-6烷基、羟基C
1-6烷基、C
1-4烷氧基C
1-4烷基或C
1-6卤代烷基；
Each R 9 , R 11 and R 12 is independently deuterium, F, Cl, Br, amino, C 1-6 alkyl, NH 2 C(═O)-, C 1-6 alkyl-OC(═O) -, carboxyl, carboxyl C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-4 alkoxy C 1-4 alkyl or C 1-6 haloalkyl;
各R
13独立地为氘、F、Cl、Br、HOOC-(CR
aR
b)
g-、C
1-6烷基、C
1-6卤代烷基、苯基、苄基、C
1-6烷氧基C
1-4烷基、羟基C
1-6烷基或5-6个环原子组成的杂芳基；其中所述C
1-6烷基、C
1-6卤代烷基、苯基、苄基、C
1-6烷氧基C
1-4烷基、羟基C
1-6烷基和5-6个环原子组成的杂芳基未被取代或被1、2、3、4或5个选自氘、F、Cl、Br、HO、HOOC-(CR
aR
b)
j-、HOOC-C
2-6烯基或C
1-6烷基-NHC(＝O)-的取代基所取代；
Each R 13 is independently deuterium, F, Cl, Br, HOOC-(CR a R b ) g -, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, benzyl, C 1-6 alkyl Oxygen C 1-4 alkyl, hydroxy C 1-6 alkyl or heteroaryl consisting of 5-6 ring atoms; wherein the C 1-6 alkyl, C 1-6 haloalkyl, phenyl, benzyl Group, C 1-6 alkoxy C 1-4 alkyl, hydroxy C 1-6 alkyl and 5-6 ring atoms composed of heteroaryl groups are not substituted or are 1, 2, 3, 4 or 5 Substituted by a substituent selected from deuterium, F, Cl, Br, HO, HOOC-(CR a R b ) j -, HOOC-C 2-6 alkenyl or C 1-6 alkyl-NHC(=O)- ;
各R
11a独立地为氘、F、Cl、Br、氨基、C
1-6烷基、NH
2C(＝O)-、C
1-6烷基-OC(＝O)-、羟基C
1-6烷基、C
1-4烷氧基C
1-4烷基或C
1-6卤代烷基，或相邻的两个R
11a和与它们相连的碳原子一起形成5个原子组成的杂环基，其中所述5个原子组成的杂环基未被取代或被1、2、3、4或5个选自氘、F、Cl、Br、氨基或C
1-6烷基的取代基所取代；
Each R 11a is independently deuterium, F, Cl, Br, amino, C 1-6 alkyl, NH 2 C(═O)-, C 1-6 alkyl-OC(═O)-, hydroxyl C 1- 6 alkyl, C 1-4 alkoxy C 1-4 alkyl or C 1-6 haloalkyl, or two adjacent R 11a and the carbon atom to which they are attached together to form a 5-atom heterocyclic group Wherein the heterocyclic group consisting of 5 atoms is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from deuterium, F, Cl, Br, amino or C 1-6 alkyl ;
R
10为HO、5-6个环原子组成的杂芳基、苯基、C
3-6环烷基、HO-S(＝O)
2-、(HO)
2P(＝O)-、R
14-S(＝O)
2-NR
cC(＝O)-、HOOC-(CR
aR
b)
q-或C
1-6烷基-NR
cC(＝O)-，其中所述5-6个环原子组成的杂芳基、苯基、C
3-6环烷基和C
1-6烷基-NR
cC(＝O)-中的C
1-6烷基未被取代或被1、2、3、4或5个选自氘、F、Cl、Br、HO、C
1-6烷基或HOOC-的取代基所取代；
R 10 is HO, heteroaryl consisting of 5-6 ring atoms, phenyl, C 3-6 cycloalkyl, HO-S(=O) 2 -, (HO) 2 P(=O)-, R 14 -S(=O) 2 -NR c C(=O)-, HOOC-(CR a R b ) q -or C 1-6 alkyl-NR c C(=O)-, wherein the 5- The heteroaryl group consisting of 6 ring atoms, phenyl group, C 3-6 cycloalkyl group and C 1-6 alkyl group-NR c C 1-6 alkyl group is unsubstituted or substituted by 1 , 2, 3, 4 or 5 substituents selected from deuterium, F, Cl, Br, HO, C 1-6 alkyl or HOOC-;
R
14为C
1-6烷基、C
3-6环烷基、苯基或5-6个环原子组成的杂芳基，其中所述C
1-6烷基、C
3-6环烷基、苯基和5-6个环原子组成的杂芳基未被取代或被1、2、3、4或5个选自氘、F、Cl、Br、HO、C
1-4烷基或HOOC-的取代基所取代；
R 14 is a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a phenyl group, or a heteroaryl group composed of 5-6 ring atoms, wherein the C 1-6 alkyl group, C 3-6 cycloalkyl group , Phenyl and heteroaryl groups consisting of 5-6 ring atoms are unsubstituted or 1, 2, 3, 4 or 5 selected from deuterium, F, Cl, Br, HO, C 1-4 alkyl or HOOC -Substituted by a substituent;
R
10b为HOOC-(CR
aR
b)
t-或C
1-6烷基-NHC(＝O)-，其中所述C
1-6烷基-NHC(＝O)-中的C
1-6烷基未被取代或被1、2、3、4或5个选自氘、F、Cl、Br、HO、甲基、乙基、异丙基或HOOC-的取代基所取代；
R 10b is HOOC- (CR a R b) t - C 1-6 alkyl or -NHC (= O) -, wherein said C 1-6 alkyl group -NHC (= O) - C 1-6 of The alkyl group is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from deuterium, F, Cl, Br, HO, methyl, ethyl, isopropyl or HOOC-;
各R
a、R
b和R
c独立地为氢、氘或C
1-4烷基，其中所述C
1-4烷基未被取代或被1、2、3、4或5个选自氘、F、Cl、Br、HO、甲基、乙基或HOOC-的取代基所取代；
Each R a , R b and R c is independently hydrogen, deuterium or C 1-4 alkyl, wherein the C 1-4 alkyl is unsubstituted or substituted by 1, 2, 3, 4 or 5 selected from deuterium , F, Cl, Br, HO, methyl, ethyl or HOOC- substituents;
各f、n、t、g、j和m独立地为0、1、2、3或4；Each f, n, t, g, j, and m is independently 0, 1, 2, 3, or 4;
各k和q独立地为1、2或3。Each k and q are independently 1, 2, or 3.
在一些实施例中，其中，R
2为CDH
2、CD
2H、CD
3、CD
3CD
2或CD
3CH
2；
In some embodiments, wherein R 2 is CDH 2 , CD 2 H, CD 3 , CD 3 CD 2 or CD 3 CH 2 ;
R
3为苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、***基、四唑基、噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中所述苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、***基、四唑基、噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基各自独立地未被取代或被1、2、3、4或5个选自氘、F、Cl、Br、HO、CN、C
1-4烷基、羟基C
1-4烷基、C
1-4烷基-OC(＝O)-、C
1-4烷基-OC(＝O)-C
1-3 亚烷基-、HOOC-C
1-3亚烷基-、C
1-4烷氧基-C
1-3亚烷基-或C
1-4烷基-S(＝O)
2-的取代基所取代；
R 3 is phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazole Group, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein the phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, Oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, and pyrimidinyl are each independently unsubstituted or selected by 1, 2, 3, 4, or 5 From deuterium, F, Cl, Br, HO, CN, C 1-4 alkyl, hydroxy C 1-4 alkyl, C 1-4 alkyl-OC (=O)-, C 1-4 alkyl-OC (=O)-C 1-3 alkylene-, HOOC-C 1-3 alkylene-, C 1-4 alkoxy-C 1-3 alkylene- or C 1-4 alkyl-S (=O) 2 -substituted by a substituent;
各R
7和R
8独立地为氢、氘、F、Cl、Br、氨基、甲基、乙基、正丙基、异丙基、NH
2C(＝O)-、C
1-4烷基-OC(＝O)-、羧基、羧基C
1-3烷基、羟基C
1-4烷基、乙氧基乙基、甲氧基乙基、异丙氧基甲基、乙氧基乙基、甲氧基甲基或C
1-4卤代烷基，或R
7、R
8和与它们相连的碳原子一起形成环丙基、环丁基、环戊基、环己基或羰基；
Each R 7 and R 8 is independently hydrogen, deuterium, F, Cl, Br, amino, methyl, ethyl, n-propyl, isopropyl, NH 2 C(═O)-, C 1-4 alkyl -OC(=O)-, carboxyl, carboxyl C 1-3 alkyl, hydroxy C 1-4 alkyl, ethoxyethyl, methoxyethyl, isopropoxymethyl, ethoxyethyl , Methoxymethyl or C 1-4 haloalkyl, or R 7 and R 8 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or carbonyl;
各R
9、R
11和R
12独立地为氘、F、Cl、Br、氨基、甲基、乙基、正丙基、异丙基、NH
2C(＝O)-、C
1-4烷基-OC(＝O)-、羧基、羧基C
1-3烷基、羟基C
1-4烷基、乙氧基乙基、甲氧基乙基、异丙氧基甲基、乙氧基乙基、甲氧基甲基或C
1-4卤代烷基；
Each R 9 , R 11 and R 12 are independently deuterium, F, Cl, Br, amino, methyl, ethyl, n-propyl, isopropyl, NH 2 C(═O)-, C 1-4 alkane -OC(=O)-, carboxyl, carboxyl C 1-3 alkyl, hydroxy C 1-4 alkyl, ethoxyethyl, methoxyethyl, isopropoxymethyl, ethoxyethyl Group, methoxymethyl or C 1-4 haloalkyl;
各R
11a独立地为氘、F、Cl、Br、氨基、甲基、乙基、正丙基、异丙基、NH
2C(＝O)-、C
1-4烷基-OC(＝O)-、羟基C
1-4烷基、乙氧基乙基、甲氧基乙基、异丙氧基甲基、乙氧基乙基、甲氧基甲基或C
1-4卤代烷基，或相邻的两个R
11a和与它们相连的碳原子一起形成1,3–二氧戊环
其中所述1,3–二氧戊环未被取代或被1或2个选自氘、F、Cl、Br、氨基、甲基、乙基、正丙基或异丙基的取代基所取代。
Each R 11a is independently deuterium, F, Cl, Br, amino, methyl, ethyl, n-propyl, isopropyl, NH 2 C(═O)-, C 1-4 alkyl-OC(═O )-, hydroxy C 1-4 alkyl, ethoxyethyl, methoxyethyl, isopropoxymethyl, ethoxyethyl, methoxymethyl or C 1-4 haloalkyl, or Two adjacent R 11a and the carbon atom to which they are attached together form 1,3-dioxolane Wherein the 1,3-dioxolane is unsubstituted or substituted with 1 or 2 substituents selected from deuterium, F, Cl, Br, amino, methyl, ethyl, n-propyl or isopropyl .
在一些实施例中，本发明涉及的氘代化合物具有式(II)或式(IIa)所示结构：In some embodiments, the deuterated compounds involved in the present invention have the structure represented by formula (II) or formula (IIa):
其中，各R
1和R
1a独立地为氢、氘、F、Cl、Br、I、氰基、甲基、乙基、甲氧基、乙氧基或硝基；
Wherein R 1 and R 1a are independently hydrogen, deuterium, F, Cl, Br, I, cyano, methyl, ethyl, methoxy, ethoxy or nitro;
其中，各R
3、R
4、R
9、X
1和m具有本发明所述的含义。
Among them, each of R 3 , R 4 , R 9 , X 1 and m has the meaning described in the present invention.
在一些实施例中，R
4为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、***基、四唑基、噁唑基、噁二唑基、1,3,5-三嗪基、 噻唑基、噻吩基、吡嗪基、哒嗪基、嘧啶基、
其中，所述甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基未被取代或被1、2、3、4或5个选自氘、F、Cl、Br、HO、甲基或HOOC-的取代基所取代，所述呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、***基、四唑基、噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基未被取代或被1、2、3、4或5个R
13取代基所取代；
In some embodiments, R 4 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl , Triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, Wherein, the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl groups are unsubstituted or 1, 2, 3, 4 or 5 are selected from deuterium, F, Substituted by a substituent of Cl, Br, HO, methyl or HOOC-, the furanyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazole Radicals, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are unsubstituted or substituted with 1, 2, 3, 4 or 5 R 13 substituents;
其中，各R
11a、R
11、R
10、R
10b、R
12、R
13、n和k具有本发明所述的含义。
Among them, each of R 11a , R 11 , R 10 , R 10b , R 12 , R 13 , n, and k has the meaning described in the present invention.
在一些实施例中，各R
13独立地为氘、F、Cl、Br、HOOC-(CR
aR
b)
g-、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、苯基、苄基、CH
3OCH
2-、CH
3OCH
2CH
2-、CH
3OCH(CH
3)-、CH
3OCH
2CH
2CH
2-、CH
3CH
2OCH
2-、CH
3CH
2OCH
2CH
2-、CH
3CH
2OCH(CH
3)-、CH
3CH
2OCH
2CH
2CH
2-、HOCH
2-、HOCH
2CH
2-、HOCH(CH
3)-、HOCH
2CH
2CH
2-、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、***基、四唑基、噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中所述甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、二氟甲基、二氟乙基、三氟乙基、苯基、苄基、CH
3OCH
2-、CH
3OCH
2CH
2-、CH
3OCH(CH
3)-、CH
3OCH
2CH
2CH
2-、CH
3CH
2OCH
2-、CH
3CH
2OCH
2CH
2-、CH
3CH
2OCH(CH
3)-、CH
3CH
2OCH
2CH
2CH
2-、HOCH
2-、HOCH
2CH
2-、HOCH(CH
3)-、HOCH
2CH
2CH
2-、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、***基、四唑基、噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基未被取代或被1、2、3、4或5个选自氘、F、Cl、Br、HO、HOOC-(CR
aR
b)
j-、HOOC-CH＝CH-、HOOC-CH
2-CH＝CH-、HOOC-CH＝CH-CH
2-或C
1-4烷基-NHC(＝O)-的取代基所取代；
In some embodiments, each R 13 is independently deuterium, F, Cl, Br, HOOC-(CR a R b ) g -, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, sec-butyl, tert-butyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, phenyl, benzyl, CH 3 OCH 2 -, CH 3 OCH 2 CH 2- , CH 3 OCH(CH 3 )-, CH 3 OCH 2 CH 2 CH 2 -, CH 3 CH 2 OCH 2 -, CH 3 CH 2 OCH 2 CH 2 -, CH 3 CH 2 OCH(CH 3 )-, CH 3 CH 2 OCH 2 CH 2 CH 2 -, HOCH 2 -, HOCH 2 CH 2 -, HOCH(CH 3 )-, HOCH 2 CH 2 CH 2 -, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazole Group, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein the Group, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoroethyl, phenyl, benzyl, CH 3 OCH 2 -, CH 3 OCH 2 CH 2 -, CH 3 OCH(CH 3 )-, CH 3 OCH 2 CH 2 CH 2 -, CH 3 CH 2 OCH 2 -, CH 3 CH 2 OCH 2 CH 2- , CH 3 CH 2 OCH(CH 3 )-, CH 3 CH 2 OCH 2 CH 2 CH 2 -, HOCH 2 -, HOCH 2 CH 2 -, HOCH(CH 3 )-, HOCH 2 CH 2 CH 2 -, furan Group, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazine Radical, pyridazinyl and pyrimidinyl are unsubstituted or 1, 2, 3, 4 or 5 selected from deuterium, F, Cl, Br, HO, HOOC-(CR a R b ) j -, HOOC-CH = CH-, HOOC-CH 2 -CH=CH-, HOOC-CH=CH-CH 2 -or C 1-4 alkyl-NHC(=O)- substituents;
其中，各R
a、R
b、g和j具有本发明所述的含义。
Among them, each of R a , R b , g and j has the meaning described in the present invention.
在一些实施例中，其中，R
10为HO、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、***基、四唑基、噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基、嘧啶基、苯基、环丙基、环丁基、环戊基、环己基、HO-S(＝O)
2-、(HO)
2P(＝O)-、R
14-S(＝O)
2-NR
cC(＝O)-、HOOC-(CR
aR
b)
q-或C
1-4烷基-NR
cC(＝O)-，其中所述呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、***基、四唑基、噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基、 嘧啶基、苯基、环丙基、环丁基、环戊基、环己基和C
1-4烷基-NR
cC(＝O)-中的C
1-4烷基未被取代或被1、2、3、4或5个选自氘、F、Cl、Br、HO、C
1-4烷基或HOOC-的取代基所取代；
In some embodiments, wherein R 10 is HO, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, HO-S(=O) 2- , (HO) 2 P(=O)-, R 14 -S(=O) 2 -NR c C(=O)-, HOOC-(CR a R b ) q -or C 1-4 alkyl-NR c C(=O)-, wherein the furanyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5- Triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and C 1-4 alkyl-NR c C( =O)- C 1-4 alkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 selected from deuterium, F, Cl, Br, HO, C 1-4 alkyl or HOOC- Substituted by radicals;
R
10b为HOOC-(CR
aR
b)
t-或C
1-4烷基-NHC(＝O)-，其中所述C
1-4烷基-NHC(＝O)-中的C
1-4烷基未被取代或被1、2、3、4或5个选自氘、F、Cl、Br、HO、甲基、乙基、异丙基或HOOC-的取代基所取代；
R 10b is HOOC- (CR a R b) t - C 1-4 alkyl or -NHC (= O) -, wherein said C 1-4 alkyl group -NHC (= O) - C 1-4 of The alkyl group is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from deuterium, F, Cl, Br, HO, methyl, ethyl, isopropyl or HOOC-;
各R
a、R
b和R
c独立地为氢、氘、甲基、乙基、正丙基或异丙基，其中所述甲基、乙基、正丙基和异丙基未被取代或被1、2、3、4或5个选自氘、F、Cl、Br、HO、甲基、乙基或HOOC-的取代基所取代；
Each R a , R b and R c is independently hydrogen, deuterium, methyl, ethyl, n-propyl or isopropyl, wherein the methyl, ethyl, n-propyl and isopropyl are unsubstituted or Substituted by 1, 2, 3, 4 or 5 substituents selected from deuterium, F, Cl, Br, HO, methyl, ethyl or HOOC-;
其中，各R
14、q和t具有本发明所述的含义。
Here, each R 14 , q, and t have the meanings described in the present invention.
在一些实施例中，其中，R
14为甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、***基、四唑基、噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中所述甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、***基、四唑基、噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基未被取代或被1、2、3、4或5个选自氘、F、Cl、Br、HO、甲基、乙基、正丙基、异丙基或HOOC-的取代基所取代。
In some embodiments, wherein R 14 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, pyrrolyl, pyridine Group, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or Pyrimidinyl, wherein the methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl , Imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, and pyrimidinyl unsubstituted Or it is substituted with 1, 2, 3, 4 or 5 substituents selected from deuterium, F, Cl, Br, HO, methyl, ethyl, n-propyl, isopropyl or HOOC-.
还在一些实施方案中，本发明涉及到以下其中之一的化合物或它们的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，但绝不限于这些化合物：In still other embodiments, the present invention relates to one of the following compounds or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or its Prodrugs, but by no means limited to these compounds:
另一方面，本发明还提供了一种药物组合物，包含本发明所述的氘代化合物，及药学上可接受的辅料。On the other hand, the present invention also provides a pharmaceutical composition comprising the deuterated compound described in the present invention, and pharmaceutically acceptable excipients.
在一些实施方案中，本发明所述的药物组合物，其进一步地包含其它抗HBV药物。In some embodiments, the pharmaceutical composition of the present invention further comprises other anti-HBV drugs.
在一些实施方案中，本发明所述的药物组合物，其中所述其它抗HBV药物为HBV聚合酶抑制剂、免疫调节剂或干扰素。In some embodiments, the pharmaceutical composition of the present invention, wherein the other anti-HBV drugs are HBV polymerase inhibitors, immunomodulators, or interferons.
在一些实施方案中，本发明所述的药物组合物，其中所述其它抗HBV药物为拉米夫定、替比夫定、替诺福韦酯，恩替卡韦、阿德福韦酯、Alfaferone、Alloferon、西莫白介素、克拉夫定、恩曲他滨、法昔洛韦、干扰素、宝甘灵CP、因特芬、干扰素α-1b、干扰素α、干扰素α-2a、干扰素β-1a、干扰素α-2、白细胞介素-2、米伏替酯、硝唑尼特、聚乙二醇干扰素α-2a、病毒唑、罗扰素-A、西佐喃、Euforavac、安普利近、Phosphazid，Heplisav、干扰素α-2b、左旋咪唑或丙帕锗。In some embodiments, the pharmaceutical composition of the present invention, wherein the other anti-HBV drugs are lamivudine, telbivudine, tenofovir dipivoxil, entecavir, adefovir dipivoxil, Alfaferone, Alloferon , Simor interleukin, Kravudine, emtricitabine, famciclovir, interferon, proganpine CP, intefen, interferon α-1b, interferon α, interferon α-2a, interferon β -1a, interferon alpha-2, interleukin-2, mivoritate, nitazoxanide, pegylated interferon alpha-2a, ribavirin, rotavirin-A, cezoran, Eufravac, Amphetamine, Phosphazid, Heplisav, interferon alpha-2b, levamisole or propargium.
另一方面，本发明还提供了所述氘代化合物或所述药物组合物在制备用于预防、治疗或减轻患者病毒性疾病的药物中的用途。In another aspect, the invention also provides the use of the deuterated compound or the pharmaceutical composition in the preparation of a medicament for the prevention, treatment or alleviation of viral diseases in patients.
在一些实施方案中，本发明所述的用途，其中所述病毒性疾病是指乙型肝炎病毒感染或乙型肝炎病毒感染引起的疾病。In some embodiments, the use according to the present invention, wherein the viral disease refers to a disease caused by a hepatitis B virus infection or a hepatitis B virus infection.
在另外一些实施方案中，本发明所述的用途，其中所述乙型肝炎病毒感染引起的疾病是指肝硬化或肝细胞癌变。In some other embodiments, the use according to the present invention, wherein the disease caused by hepatitis B virus infection refers to cirrhosis or hepatocellular carcinoma.
另一方面，本发明涉及所述的氘代化合物或药物组合物来制备用于预防、治疗或减轻患者乙型肝炎疾病的药物中的用途，包括给予患者如本发明所述的化合物或本发明所述的药物组合物的有效治疗剂量。In another aspect, the present invention relates to the use of the deuterated compound or pharmaceutical composition for the preparation of a medicament for the prevention, treatment or alleviation of hepatitis B disease in patients, including administration of the compound as described in the present invention or the present invention The effective therapeutic dose of the pharmaceutical composition.
本发明另一方面涉及预防、治疗或减轻患者HBV病症的方法，所述方法包含使用本发明的化合物药学上可接受的有效剂量对患者进行给药。Another aspect of the invention relates to a method of preventing, treating or alleviating HBV disorders in a patient, the method comprising administering to the patient a pharmaceutically acceptable effective dose of a compound of the invention.
本发明另一方面涉及预防、治疗或减轻患者HBV病症的方法，所述方法包含使用含有本发明的化合物的药物组合物的药学上可接受的有效剂量对患者进行给药。Another aspect of the invention relates to a method of preventing, treating or alleviating HBV disorders in a patient, the method comprising administering to the patient a pharmaceutically acceptable effective dose of a pharmaceutical composition containing a compound of the invention.
本发明另一方面涉及使用一种本发明的氘代化合物来生产用于预防或治疗患者HBV病症，并减轻其严重程度的药物的用途。Another aspect of the present invention relates to the use of a deuterated compound of the present invention to produce a medicament for preventing or treating HBV disorders in a patient and reducing its severity.
本发明另一方面涉及使用一种包含本发明的氘代化合物的药物组合物来生产用于预防或治疗患者HBV病症，并减轻其严重程度的药物的用途。Another aspect of the present invention relates to the use of a pharmaceutical composition comprising the deuterated compound of the present invention for the production of a medicament for preventing or treating HBV disorders in a patient and reducing its severity.
本发明另一方面涉及一种抑制HBV感染的方法，该方法包含将细胞与能有效抑制HBV的剂量的本发明的化合物或药物组合物接触。另外一些实施例是，所述方法更进一步地包含将细胞与其它抗HBV治疗剂接触。Another aspect of the invention relates to a method of inhibiting HBV infection, the method comprising contacting the cells with a compound or pharmaceutical composition of the invention in an amount effective to inhibit HBV. In other embodiments, the method further includes contacting the cells with other anti-HBV therapeutic agents.
本发明另一方面涉及对患者HBV疾病的治疗方法，该方法包含向需要治疗的患者施用有效治疗剂量的本发明的化合物或其药物组合物。另外一些实施例是，所述方法更进一步地包含向需要治疗的患者施用有效治疗剂量的其它抗HBV药物。Another aspect of the invention relates to a method of treating HBV disease in a patient, the method comprising administering to a patient in need of treatment an effective therapeutic dose of a compound of the invention or a pharmaceutical composition thereof. In still other embodiments, the method further includes administering to the patient in need of treatment an effective therapeutic dose of other anti-HBV drugs.
本发明另一方面涉及一种抑制患者HBV感染的方法，该方法包含向需要治疗的患者施用有效治疗剂量的本发明的化合物或其药物组合物。另外一些实施例是，所述方法更进一步地包含向需要治疗的患者施用有效治疗剂量的其它抗HBV药物。Another aspect of the invention relates to a method of inhibiting HBV infection in a patient, the method comprising administering to a patient in need of treatment an effective therapeutic dose of a compound of the invention or a pharmaceutical composition thereof. In still other embodiments, the method further includes administering to the patient in need of treatment an effective therapeutic dose of other anti-HBV drugs.
本发明另一方面涉及式(I)或、式(Ia)、式(II)或式(IIa)所包含的氘代化合物的制备、分离和纯化的方法。Another aspect of the present invention relates to a method for the preparation, isolation, and purification of the deuterated compounds contained in Formula (I) or, (Ia), (II), or (IIa).
本发明还涉及本发明的化合物及其药学上可接受的盐用于生产医药产品来有效抑制HBV感染的应用,本发明的化合物在生产有效抑制HBV感染的药物中的应用。本发明的化合物还用于生产一种医药品用来减轻、阻止、控制或治疗患者乙型肝炎的病症。The present invention also relates to the use of the compound of the present invention and its pharmaceutically acceptable salt for the production of pharmaceutical products to effectively inhibit HBV infection. The use of the compound of the present invention in the production of a medicament for effectively inhibiting HBV infection. The compound of the present invention is also used to produce a medicinal product for reducing, preventing, controlling or treating hepatitis B in patients.
除非其他方面表明，本发明的化合物所有的立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，盐和药学上可接受的前药都属于本发明的范围。Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are It belongs to the scope of the present invention.
具体地说，盐是药学上可接受的盐。术语“药学上可接受的”包括物质或组合物必须是适合化学或毒理学地，与组成制剂的其他组分和用于治疗的哺乳动物有关。Specifically, the salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" includes that the substance or composition must be chemically or toxicologically related to the other components that make up the formulation and the mammal used for treatment.
本发明的化合物的盐还包括用于制备或纯化式(I)或、式(Ia)、式(II)或式(IIa)所示化合物的中间体或式(I)或、式(Ia)、式(II)或式(IIa)所示化合物分离的对映异构体的盐，但不一定是药学上可接受的盐。前面所述内容只概述了本发明的某些方面，但并不限于这些方面。这些方面及其他的方面的内容将在下面作更加具体完整的描述。The salt of the compound of the present invention also includes an intermediate or formula (I) or, formula (Ia) for preparing or purifying a compound represented by formula (I) or, formula (Ia), formula (II), or formula (IIa) , The salt of the enantiomer isolated from the compound represented by formula (II) or formula (IIa), but not necessarily a pharmaceutically acceptable salt. The foregoing describes only certain aspects of the invention, but is not limited to these aspects. The contents of these and other aspects will be described more specifically and completely below.
本发明的详细说明书Detailed description of the invention
定义和一般术语Definitions and general terms
本发明将会把确定的具体化的内容所对应的文献详细列出，实施例都伴随有结构式和化学式的图解。本发明有预期地涵盖所有的选择余地、变体和同等物，这些可能像权利要求所定义的那样包含在现有发明领域。所属领域的技术人员将识别许多类似或等同于在此所描述的方法和物质，这些可以应用于本发明的实践中去。本发明绝非限于方法和物质的描述。有很多文献和相似的物质与本发明相区别或抵触，其中包括但绝不限于术语的定义，术语的用法，描述的技术，或像本发明所控制的范围。The present invention will list the documents corresponding to the determined specific content in detail, and the embodiments are accompanied by illustrations of structural formulas and chemical formulas. The invention is intended to cover all options, variants and equivalents, which may be included in the existing field of invention as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be applied in the practice of the present invention. The invention is by no means limited to the description of methods and materials. There are many documents and similar substances that differ or contradict the present invention, including but not limited to the definition of terms, the usage of terms, the techniques described, or the scope as controlled by the present invention.
本发明将应用以下定义除非其他方面表明。根据本发明的目的，化学元素根据元素周期表，CAS版本和化学药品手册，75，
thEd，1994来定义。另外，有机化学一般原理见"Organic Chemistry,"Thomas Sorrell,University Science Books,Sausalito:1999,and"March's Advanced Organic Chemistry,"by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007，因此所有的内容都融合了参考文献。
The present invention will apply the following definitions unless otherwise indicated. For the purposes of the present invention, chemical elements are defined according to the periodic table of elements, the CAS version and the Handbook of Chemicals, 75, th Ed, 1994. In addition, for general principles of organic chemistry, see "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, so all The contents are integrated with references.
像本发明所描述的，本发明的化合物可以任选地被一个或多个取代基所取代，如上面的通式化合物，或者像实施例里面特殊的例子，子类，和本发明所包含的一类化合物。As described in the present invention, the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the general formula above, or like the specific examples, subclasses, and inclusions of the present invention in the examples. A class of compounds.
一般而言，术语“取代的”，表示所给结构中的一个或多个氢原子被具体取代基所取代。除非其他方面表明，一个任选的取代基团可以有一个取代基在基团各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by specific substituents. Unless otherwise indicated, an optional substituent may have a substituent at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from specific groups, the substituents may be substituted at the same positions or differently.
在本说明书的各部分，本发明化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C
1-6烷基”特别指独立公开的甲基、乙基、C
3烷基、C
4烷基、C
5烷基和C
6烷基。
In each part of this specification, the substituents of the compounds of the present invention are disclosed according to the type or range of groups. In particular, the present invention includes each independent sub-combination of each member of these group types and ranges. For example, the term "C 1-6 alkyl" particularly refers to independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
本发明使用的术语“烷基”包括1-20个碳原子饱和直链或支链的单价烃基，其中烷基可以 独立任选地被一个或多个本发明所描述的取代基所取代。其中一些实施例是，烷基基团含有1-12个碳原子，另外一些实施例是，烷基基团含有1-10个碳原子，另外一些实施例是，烷基基团含有1-8个碳原子，另外一些实施例是，烷基基团含有1-6个碳原子，另外一些实施例是，烷基基团含有1-4个碳原子，另外一些实施例是，烷基基团含有1-3个碳原子。烷基基团更进一步的实例包括，但并不限于，甲基(Me，-CH
3)、乙基(Et，-CH
2CH
3)、正丙基(n-Pr，-CH
2CH
2CH
3)、异丙基(i-Pr，-CH(CH
3)
2)、正丁基(n-Bu，-CH
2CH
2CH
2CH
3)、2-甲基丙基或异丁基(i-Bu，-CH
2CH(CH
3)
2)、1-甲基丙基或仲丁基(s-Bu，-CH(CH
3)CH
2CH
3)、叔丁基(t-Bu，-C(CH
3)
3)、正戊基(-CH
2CH
2CH
2CH
2CH
3)、2-戊基(-CH(CH
3)CH
2CH
2CH
3)、3-戊基(-CH(CH
2CH
3)
2)、2-甲基-2-丁基(-C(CH
3)
2CH
2CH
3)、3-甲基-2-丁基(-CH(CH
3)CH(CH
3)
2)、3-甲基-1-丁基(-CH
2CH
2CH(CH
3)
2)、2-甲基-1-丁基(-CH
2CH(CH
3)CH
2CH
3)、正己基(-CH
2CH
2CH
2CH
2CH
2CH
3)、2-己基(-CH(CH
3)CH
2CH
2CH
2CH
3)、3-己基(-CH(CH
2CH
3)(CH
2CH
2CH
3))、2-甲基-2-戊基(-C(CH
3)
2CH
2CH
2CH
3)、3-甲基-2-戊基(-CH(CH
3)CH(CH
3)CH
2CH
3)、4-甲基-2-戊基(-CH(CH
3)CH
2CH(CH
3)
2)、3-甲基-3-戊基(-C(CH
3)(CH
2CH
3)
2)、2-甲基-3-戊基(-CH(CH
2CH
3)CH(CH
3)
2)、2,3-二甲基-2-丁基(-C(CH
3)
2CH(CH
3)
2)、3,3-二甲基-2-丁基(-CH(CH
3)C(CH
3)
3)、正庚基、正辛基，等等。
The term "alkyl" used in the present invention includes a monovalent hydrocarbon group saturated with a linear or branched chain of 1 to 20 carbon atoms, wherein the alkyl group may be independently optionally substituted with one or more substituents described in the present invention. Some of these embodiments have an alkyl group containing 1-12 carbon atoms, other embodiments have an alkyl group containing 1-10 carbon atoms, and other embodiments have an alkyl group containing 1-8 Carbon atoms, in some other embodiments, the alkyl group contains 1-6 carbon atoms, in other embodiments, the alkyl group contains 1-4 carbon atoms, in other embodiments, the alkyl group Contains 1-3 carbon atoms. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), 2-methylpropyl or isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), 1-methylpropyl or sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu , -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 ) CH 2 CH 3 ), n-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH (CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3 -Pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-di Methyl-2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2 ), 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 ), N-heptyl, n-octyl, etc.
术语“氘代化合物”表示本发明的任何一个化合物至少含有一个氘原子(D)，比如，本发明所述的式(I)或式(Ia)所示化合物至少含有一个氘原子，即，R
1、R
2、R
3、R
4、R
9和X
1中至少一个是含有一个或多个氘原子的基团；又如，本发明化合物
含有3个氘 原子，再如化合物
含有9个氘原子。在一些实施例中，本发明所述的氘代化合物包含1个氘原子；在一些实施例中，本发明所述的氘代化合物包含2个氘原子；在一些实施例中，本发明所述氘代化合物包含3个氘原子；在一些实施例中，本发明所述的氘代化合物包含4个氘原子；在一些实施例中，本发明所述的氘代化合物包含5个氘原子；在一些实施例中，本发明所述的氘代化合物包含6个氘原子；在一些实施例中，本发明所述的氘代化合物包含7个氘原子；在一些实施例中，本发明所述的氘代化合物包含8个氘原子；在一些实施例中，本发明所述的氘代化合物包含9个氘原子。
The term "deuterated compound" means that any compound of the present invention contains at least one deuterium atom (D). For example, the compound of formula (I) or formula (Ia) according to the present invention contains at least one deuterium atom, ie, R 1 , at least one of R 2 , R 3 , R 4 , R 9 and X 1 is a group containing one or more deuterium atoms; for another example, the compound of the present invention Contains 3 deuterium atoms, like a compound Contains 9 deuterium atoms. In some embodiments, the deuterated compounds of the present invention contain 1 deuterium atom; in some embodiments, the deuterated compounds of the present invention contain 2 deuterium atoms; in some embodiments, the deuterated compounds of the present invention The deuterated compound contains 3 deuterium atoms; in some embodiments, the deuterated compound according to the present invention contains 4 deuterium atoms; in some embodiments, the deuterated compound according to the present invention contains 5 deuterium atoms; In some embodiments, the deuterated compounds of the present invention contain 6 deuterium atoms; in some embodiments, the deuterated compounds of the present invention contain 7 deuterium atoms; in some embodiments, the deuterated compounds of the present invention The deuterated compound contains 8 deuterium atoms; in some embodiments, the deuterated compound described in the present invention contains 9 deuterium atoms.
术语“亚烷基”表示从饱和的直链或支链烃基中去掉两个或多个氢原子所得到的饱和的二价或多价烃基基团。除非另外详细说明，亚烷基基团含有1-12个碳原子。在一些实施方案中，亚烷基基团含有1-6个碳原子；在另一些实施方案中，亚烷基基团含有1-4个碳原子；还在一些实施方案中，亚烷基基团含有1-3个碳原子；还在另一些实施方案中，亚烷基基团含有1-2个碳原子。亚烷基的实例包括，但不限于亚甲基(-CH
2-)，亚乙基(-CH
2CH
2-)，亚异丙基(-CH(CH
3)CH
2-)等等。
The term "alkylene" means a saturated divalent or polyvalent hydrocarbon group obtained by removing two or more hydrogen atoms from a saturated linear or branched hydrocarbon group. Unless otherwise specified, alkylene groups contain 1-12 carbon atoms. In some embodiments, the alkylene group contains 1-6 carbon atoms; in other embodiments, the alkylene group contains 1-4 carbon atoms; in some embodiments, the alkylene group The group contains 1-3 carbon atoms; in still other embodiments, the alkylene group contains 1-2 carbon atoms. Examples of alkylene groups include, but are not limited to, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), isopropylidene (-CH(CH 3 )CH 2 -), and the like.
术语“羟基烷基”和“羟基烷氧基”表示烷基或烷氧基，视情况而定，被一个或多个羟基基团所取代，其中，“羟基烷基”、“羟基亚烷基”与“羟烷基”相互之间可以交换使用，这样的实例包含，但并不限于，羟基甲基(-CH
2OH)、羟基乙基(-CH
2CH
2OH,-CHOHCH
3)、羟基丙基(-CH
2CH
2CH
2OH,-CH
2CHOHCH
3,-CHOHCH
2CH
3)、羟基甲氧基(-OCH
2OH)等。
The terms "hydroxyalkyl" and "hydroxyalkoxy" mean alkyl or alkoxy, as the case may be, substituted by one or more hydroxy groups, where "hydroxyalkyl", "hydroxyalkylene""And"hydroxyalkyl" can be used interchangeably, such examples include, but are not limited to, hydroxymethyl (-CH 2 OH), hydroxyethyl (-CH 2 CH 2 OH, -CHOHCH 3 ), Hydroxypropyl (-CH 2 CH 2 CH 2 OH, -CH 2 CHOHCH 3 , -CHOHCH 2 CH 3 ), hydroxymethoxy (-OCH 2 OH), etc.
术语“卤代烷基”、“卤代烯基”或“卤代烷氧基”表示烷基，烯基或烷氧基基团被一个或多个卤素原子所取代，其中，烷基、烯基和烷氧基具有本发明所述的含义。这样的实例包含，但并不限于，二氟甲基(-CHF
2)、二氟乙基(-CH
2CHF
2,-CF
2CH
3,-CHFCH
2F)、三氟乙基(-CH
2CF
3,-CF
2CH
2F,-CFHCHF
2)、三氟甲基(-CF
3)、三氟甲氧基(-OCF
3)、氟乙烯基(-CH＝CHF,-CF＝CH
2)等。
The term "haloalkyl", "haloalkenyl" or "haloalkoxy" refers to an alkyl group, the alkenyl or alkoxy group is replaced by one or more halogen atoms, wherein, alkyl, alkenyl and alkoxy The radical has the meaning described in the present invention. Examples include, but are not limited to, difluoromethyl (-CHF 2 ), difluoroethyl (-CH 2 CHF 2 , -CF 2 CH 3 , -CHFCH 2 F), trifluoroethyl (-CH 2 CF 3 , -CF 2 CH 2 F, -CFHCHF 2 ), trifluoromethyl (-CF 3 ), trifluoromethoxy (-OCF 3 ), fluorovinyl (-CH=CHF, -CF=CH 2 ) Wait.
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中烷基基团具有如本发明所述的含义。除非另外详细说明，所述烷氧基基团含有1-12个碳原子。在一些实施方案中， 烷氧基基团含有1-8个碳原子；在另一些实施方案中，烷氧基基团含有1-6个碳原子；在另一些实施方案中，烷氧基基团含有1-4个碳原子；在又一些实施方案中，烷氧基基团含有1-3个碳原子。所述烷氧基基团可以任选地被一个或多个本发明描述的取代基所取代。The term "alkoxy" means that the alkyl group is connected to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described in the present invention. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In some embodiments, the alkoxy group contains 1-8 carbon atoms; in other embodiments, the alkoxy group contains 1-6 carbon atoms; in other embodiments, the alkoxy group The group contains 1-4 carbon atoms; in still other embodiments, the alkoxy group contains 1-3 carbon atoms. The alkoxy group can be optionally substituted with one or more substituents described herein.
烷氧基基团的实例包括，但并不限于，甲氧基(MeO、-OCH
3)，乙氧基(EtO、-OCH
2CH
3)，1-丙氧基(n-PrO、n-丙氧基、-OCH
2CH
2CH
3)，2-丙氧基(i-PrO、i-丙氧基、-OCH(CH
3)
2)，1-丁氧基(n-BuO、n-丁氧基、-OCH
2CH
2CH
2CH
3)，2-甲基-l-丙氧基(i-BuO、i-丁氧基、-OCH
2CH(CH
3)
2)，2-丁氧基(s-BuO、s-丁氧基、-OCH(CH
3)CH
2CH
3)，2-甲基-2-丙氧基(t-BuO、t-丁氧基、-OC(CH
3)
3)，1-戊氧基(n-戊氧基、-OCH
2CH
2CH
2CH
2CH
3)，2-戊氧基(-OCH(CH
3)CH
2CH
2CH
3)，3-戊氧基(-OCH(CH
2CH
3)
2)，2-甲基-2-丁氧基(-OC(CH
3)
2CH
2CH
3)，3-甲基-2-丁氧基(-OCH(CH
3)CH(CH
3)
2)，3-甲基-l-丁氧基(-OCH
2CH
2CH(CH
3)
2)，2-甲基-l-丁氧基(-OCH
2CH(CH
3)CH
2CH
3)，等等。
Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n- Propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n- Butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butan Oxygen (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH 3 ) 3 ), 1-pentoxy (n-pentoxy, -OCH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentoxy (-OCH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyloxy (-OCH(CH 2 CH 3 ) 2 ), 2-methyl-2-butoxy (-OC(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butoxy Group (-OCH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-l-butoxy (-OCH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-l-butoxy (-OCH 2 CH(CH 3 )CH 2 CH 3 ), and so on.
术语“环烷基”表示含有3-12个碳原子的，单价或多价的饱和单环，双环或三环体系。在一实施方案中，环烷基包含3-12个碳原子；在另一实施方案中，环烷基包含3-8个碳原子；在另一实施方案中，环烷基包含3-7个碳原子；在又一些实施方案中，环烷基包含3-6个碳原子。所述环烷基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3-12 carbon atoms. In one embodiment, the cycloalkyl group contains 3-12 carbon atoms; in another embodiment, the cycloalkyl group contains 3-8 carbon atoms; in another embodiment, the cycloalkyl group contains 3-7 carbon atoms Carbon atoms; in still other embodiments, the cycloalkyl group contains 3-6 carbon atoms. The cycloalkyl group may independently be unsubstituted or substituted with one or more substituents described in the present invention.
术语“杂环基”是指包含3-12个环原子的，非芳香族的，饱和或部分不饱和的，单价或多价的单环、双环或三环体系，其中至少一个环原子选自氮、硫或氧原子。其中，所述杂环基基团可以任选地被一个或多个本发明描述的取代基所取代。除非另外说明，杂环基可以是碳基或氮基，且-CH
2-基团可以任选地被-C(＝O)-或-C(＝S)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化物。在一些实施方案中，杂环基为5-7个原子组成的单环杂环基。在一些实施方案中，杂环基为5-6个原子组成的单环杂环基。在一些实施方案中，杂环基为7-12个环原子组成的双环杂环基。在一些实施方案中，杂环基为8-10个环原子组成的双环杂环基。在一些实施方案中，杂环基为4个原子组成的杂环基，是指包含4个环原子的单价或多价的，饱和或部分不饱和的，非芳香性的单环，其中至少一个环原子选自氮、硫和氧原子。在另一些实施方案中，杂环基为5个原子组成的杂环基，是指包含5个环原子的单价或多价的，饱和或部分不饱和的，非芳香性的单环，其中至少一个环原子选自氮、硫和氧原子。在另一些实施方案中，杂环基为6个原子组成的杂环基，是指包含6个环原子的单价或多价的，饱和或部分不饱和的，非芳香性的单环，其中至少一个环原子选自氮、硫和氧原子。
The term "heterocyclic group" refers to a monocyclic, bicyclic or tricyclic system containing 3-12 ring atoms, non-aromatic, saturated or partially unsaturated, monovalent or polyvalent, wherein at least one ring atom is selected from Atoms of nitrogen, sulfur or oxygen. Wherein, the heterocyclic group may be optionally substituted with one or more substituents described in the present invention. Unless otherwise specified, the heterocyclic group may be a carbon group or a nitrogen group, and the -CH 2 -group may be optionally replaced by -C(=O)- or -C(=S)-. The sulfur atom of the ring can optionally be oxidized to an S-oxide. The nitrogen atom of the ring can optionally be oxidized to an N-oxide. In some embodiments, the heterocyclic group is a monocyclic heterocyclic group composed of 5-7 atoms. In some embodiments, the heterocyclic group is a monocyclic heterocyclic group composed of 5-6 atoms. In some embodiments, the heterocyclic group is a bicyclic heterocyclic group consisting of 7-12 ring atoms. In some embodiments, the heterocyclic group is a bicyclic heterocyclic group consisting of 8-10 ring atoms. In some embodiments, the heterocyclic group is a 4-atom heterocyclic group, which means a monovalent or polyvalent, saturated or partially unsaturated, non-aromatic monocyclic ring containing 4 ring atoms, at least one of which The ring atoms are selected from nitrogen, sulfur and oxygen atoms. In other embodiments, the heterocyclic group is a 5-membered heterocyclic group, which means a monovalent or polyvalent, saturated or partially unsaturated, non-aromatic monocyclic ring containing 5 ring atoms, wherein at least One ring atom is selected from nitrogen, sulfur and oxygen atoms. In other embodiments, the heterocyclic group is a 6-membered heterocyclic group, which refers to a monovalent or polyvalent, saturated or partially unsaturated, non-aromatic monocyclic ring containing 6 ring atoms, wherein at least One ring atom is selected from nitrogen, sulfur and oxygen atoms.
“杂环基”的实例包括，但并不限于，吡咯烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、四氢吡喃基、二氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、噻噁烷基、哌嗪基、 高哌嗪基、氮杂环丁基、氧杂环丁基、硫杂环丁基、高哌啶基、环氧丙基、氮杂环庚基、氧杂环庚基、硫杂环庚基、氧氮杂卓基、二氮杂卓基、硫氮杂卓基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己基、1,3-二氧戊基、吡唑啉基、二噻烷基、二噻茂烷基、二氢噻吩基、吡唑烷基咪唑啉基、咪唑烷基、1,2,3,4-四氢异喹啉基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、氮杂双环[2.2.2]己基、3H-吲哚基喹嗪基和N-吡啶基尿素。杂环基团的实例还包括，1,1-二氧硫代吗啉基，其中环上碳原子被氧代(＝O)取代的实例实例包括，但不限于嘧啶二酮基、1,2,4-噻二唑-5(4H)-酮基，1,2,4-噁二唑-5(4H)-酮基，1H-1,2,4-***-5(4H)-酮基等，其中环上碳原子被基团＝S所取代的实例包括，但不限于1,2,4-噁二唑-5(4H)-硫酮基，1,3,4-噁二唑-2(3H)-硫酮基等。Examples of "heterocyclic groups" include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piper Pyridinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, Epoxypropyl, azacycloheptyl, oxetanyl, thiaheptyl, oxazepinyl, diazepinyl, thiozepine, 2-pyrrolyl, 3-pyrrole Porphyrinyl, indoline, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolyl, pyrazolinyl, dithianyl, dithialkane , Dihydrothienyl, pyrazolidinyl imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3.1.0]hexyl, 3-aza Bicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinazinyl and N-pyridylurea. Examples of heterocyclic groups also include 1,1-dioxothiomorpholinyl, in which carbon atoms on the ring are substituted with oxo (=O). Examples include, but are not limited to pyrimidinedione, 1,2 ,4-thiadiazole-5(4H)-keto, 1,2,4-oxadiazole-5(4H)-keto, 1H-1,2,4-triazole-5(4H)-one Examples where carbon atoms on the ring are replaced by the group =S include, but are not limited to 1,2,4-oxadiazole-5(4H)-thione, 1,3,4-oxadiazole -2(3H)-thione and so on.
术语“杂原子”表示一个或多个O、S、N、P和Si，包括N、S和P任何氧化态的形式；伯、仲、叔胺和季铵盐的形式；或者杂环中氮原子上的氢被取代的形式，例如，N(像3,4-二氢-2H-吡咯基中的N)，NH(像吡咯烷基中的NH)或NR(像N-取代的吡咯烷基中的NR，R为本发明所描述的取代基)。The term "heteroatom" means one or more of O, S, N, P and Si, including N, S and P in any oxidation state; primary, secondary, tertiary amine and quaternary ammonium salt forms; or heterocyclic nitrogen Atom-substituted form of hydrogen, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like N-substituted pyrrolidine NR and R in the group are the substituents described in the present invention).
术语“卤素”或“卤原子”是指F、Cl、Br或I。The term "halogen" or "halogen atom" refers to F, Cl, Br or I.
本发明所使用的术语“不饱和的”表示部分含有一个或多个不饱和度。As used herein, the term "unsaturated" means that the portion contains one or more degrees of unsaturation.
术语“芳基”表示含有6-14个环原子，或6-12个环原子，或6-10个环原子的单环、双环和三环的碳环体系，其中，至少一个环体系是芳香族的，其中每一个环体系包含3-7个原子组成的环，且有一个或多个连接点与分子的其余部分相连。术语“芳基”可以和术语“芳香环”交换使用。芳基基团的实例可以包括苯基、萘基和蒽基。所述芳基基团可以独立任选地被一个或多个本发明所描述的取代基所取代。The term "aryl" refers to monocyclic, bicyclic and tricyclic carbocyclic systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic Family, where each ring system contains a ring of 3-7 atoms, and there are one or more points of attachment to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring". Examples of aryl groups may include phenyl, naphthyl and anthracenyl. The aryl group may be independently optionally substituted with one or more substituents described in the present invention.
术语“杂芳基”表示含有5-12个环原子的单环、双环和三环体系，其中至少一个环是芳香环，且至少一个芳香环包含一个或多个杂原子，其中每一个环体系包含5-7个环原子组成的环，且有一个或多个连接点与分子其余部分相连。术语“杂芳基”可以与术语“芳杂环”、“杂芳环”或“杂芳族化合物”交换使用。在一些实施方案中，杂芳基为包含1，2，3或4个独立选自氮、硫和氧的杂原子的5-7个环原子组成的单环杂芳基。一些实施方案中，杂芳基为包含1，2，3或4个独立选自氮、硫和氧的杂原子的5-6个环原子组成的单环杂芳基。在一些实施案中，杂芳基为包含1，2，3或4个独立选自氮、硫和氧的杂原子的7-12个环原子组成的双环杂芳基。在一些实施案中，杂芳基为包含1，2，3或4个独立选自氮、硫和氧的杂原子的8-10个环原子组成的双环杂芳基。在一些实施案中，杂芳基为包含1，2，3或4个独立选自氮、硫和氧的杂原子的9-10个环原子组成的双环杂芳基。并且所述杂芳基可以是取代或非取代的，其中取代基可以是，但并不限于氘、F、Cl、Br、OH、C
1-8烷基、C
1-8烷氧基、HOOC-(CR
7R
8)
q- 或C
1-8烷氧基-(CR
7R
8)
k-O-的取代基所取代,其中q、k、R
7和R
8具有本发明所述的含义。
The term "heteroaryl" refers to monocyclic, bicyclic and tricyclic systems containing 5-12 ring atoms, wherein at least one ring is an aromatic ring, and at least one aromatic ring contains one or more heteroatoms, wherein each ring system It contains a ring composed of 5-7 ring atoms, and one or more connection points are connected to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "aromatic heterocycle", "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, the heteroaryl group is a monocyclic heteroaryl group consisting of 5-7 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl group is a monocyclic heteroaryl group consisting of 5-6 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl group is a bicyclic heteroaryl group composed of 7-12 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl group is a bicyclic heteroaryl group consisting of 8-10 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl group is a bicyclic heteroaryl group consisting of 9-10 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. And the heteroaryl group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, deuterium, F, Cl, Br, OH, C 1-8 alkyl, C 1-8 alkoxy, HOOC -(CR 7 R 8 ) q -or C 1-8 alkoxy-(CR 7 R 8 ) k -O- substituted, wherein q, k, R 7 and R 8 have the meaning.
杂芳环的实例包括以下的单环，但并不限于这些单环：1,2,4-噁二唑-5(4H)-硫酮基、1,2,4-噻二唑-5(4H)-酮基、1,2,4-噁二唑-5(4H)-酮基、1,3,4-噁二唑-2(3H)-硫酮基、1H-1,2,4-***-5(4H)-酮基、2-呋喃基、3-呋喃基、N-咪唑基、2-咪唑基、4-咪唑基、5-咪唑基、3-异噁唑基、4-异噁唑基、5-异噁唑基、2-噁唑基、4-噁唑基、5-噁唑基、N-吡咯基、2-吡咯基、3-吡咯基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基、哒嗪基(如3-哒嗪基)、2-噻唑基、4-噻唑基、5-噻唑基、四唑基(如5-四唑基)、***基(如2-***基和5-***基)、2-噻吩基、3-噻吩基、吡喃基、吡唑基(如2-吡唑基)、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-***基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基、二唑基、噻二唑基、三嗪基等；也包括以下的双环，但绝不限于这些双环：苯并噻唑基、苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基(如2-吲哚基)、嘌呤基、喹啉基(如2-喹啉基、3-喹啉基、4-喹啉基)、异喹啉基(如1-异喹啉基、3-异喹啉基或4-异喹啉基)等。Examples of heteroaromatic rings include the following monocyclic rings, but are not limited to these monocyclic rings: 1,2,4-oxadiazole-5(4H)-thione, 1,2,4-thiadiazole-5( 4H)-keto, 1,2,4-oxadiazole-5(4H)-keto, 1,3,4-oxadiazole-2(3H)-thione, 1H-1,2,4 -Triazole-5(4H)-keto, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4 -Isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl , 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5- Thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyranyl, pyrazolyl (Such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2, 3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3, 5-triazinyl, diazolyl, thiadiazolyl, triazinyl, etc.; also includes the following bicyclic rings, but by no means limited to these bicyclic rings: benzothiazolyl, benzimidazolyl, benzofuranyl, benzo Thienyl, indolyl (such as 2-indolyl), purinyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (such as 1- Isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), etc.
术语“M-M
1个环原子组成的”表示所述环状基团由M-M
1个环原子所组成，所述的环原子包括碳原子和/或O、N、S、P等杂原子。例如，“6-10个环原子组成的杂芳基”代表其包括6、7、8、9或10个环原子组成的杂芳基。
The term "MM consists of 1 ring atom" means that the cyclic group is composed of 1 ring atom of MM, and the ring atom includes carbon atoms and/or heteroatoms such as O, N, S, and P. For example, "heteroaryl consisting of 6-10 ring atoms" represents a heteroaryl consisting of 6, 7, 8, 9 or 10 ring atoms.
术语“烷氧基烷基”“烷氧基亚烷基”可相互交换使用，表示烷基基团可以被一个或多个相同或不同的烷氧基基团所取代，其中烷氧基和烷基基团具有如本发明所述的含义。这样的实例包括，但并不限于甲氧基乙基，乙氧基甲基等。The terms "alkoxyalkyl" and "alkoxyalkylene" are used interchangeably, meaning that the alkyl group can be replaced by one or more alkoxy groups that are the same or different, where alkoxy and alkyl The radical group has the meaning as described in the present invention. Such examples include, but are not limited to methoxyethyl, ethoxymethyl, and the like.
像本发明所描述的，取代基画一个键连接到中心的环上形成的环体系(如式a所示)代表取代基在环上任何可取代的位置都可以取代，并且可以是包含对映异构体的取代，如式b、c、d、e、f、g和h所示。As described in the present invention, a ring system formed by a substituent connecting a bond to the central ring (as shown in formula a) represents that the substituent can be substituted at any substitutable position on the ring, and can include enantiomers. The substitution of isomers is represented by the formulas b, c, d, e, f, g and h.
另外，需要说明的是，除非以其他方式明确指出，在本文中通篇采用的描述方式“各…和…独立地为”、“…和…各自独立地为”和“…和…分别独立地为”可以互换，应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以 表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。例如，如式p所示，多个R
9的具体选项互相之间不受影响。
In addition, it should be noted that, unless explicitly stated otherwise, the descriptions used throughout this article are "each... and... independently", "... and... each independently"and"... and... independently To be interchangeable, it should be understood in a broad sense. It can mean that in different groups, the specific options expressed between the same symbols do not affect each other, or it can mean that in the same group, the same symbol The specific options expressed between do not affect each other. For example, as shown in formula p, the specific options of multiple R 9 are not affected by each other.
像本发明所描述的，体系中有两个连接点与分子其余部分相连，例如，式q所示，表示既可以是E端也可以是E’端与分子其余部分相连，即在分子结构合理的情况下，两端的连接方式可以互换。As described in the present invention, there are two connection points in the system that are connected to the rest of the molecule, for example, as shown in formula q, it can be either E-terminal or E′-terminal connected to the rest of the molecule, that is, the molecular structure is reasonable In the case of, the connection methods at both ends can be interchanged.
除非其他方面表明，本发明所描述的结构式包括所有的同分异构形式(如对映异构，非对映异构，和几何异构(或构象异构)：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体，和(Z)、(E)的构象异构体。因此，本发明的化合物的单个立体化学异构体或其对映异构体，非对映异构体，或几何异构体(或构象异构体)的混合物都属于本发明的范围。Unless otherwise indicated, the structural formula described in the present invention includes all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers): for example, R containing an asymmetric center , S configuration, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Therefore, the single stereochemical isomer of the compound of the present invention or its enantiomer Isomers, diastereomers, or mixtures of geometric isomers (or conformers) are within the scope of the present invention.
本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)、式(Ia)、式(II)或式(IIa)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C
1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14 of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51，2328-2345。
The term "prodrug" used in the present invention means that a compound is converted into a compound represented by formula (I), formula (Ia), formula (II) or formula (IIa) in vivo. Such conversion is affected by prodrug hydrolysis in the blood or enzymatic conversion into the parent structure in the blood or tissue. The prodrug compounds of the present invention may be esters. In the present invention, esters may be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, and carbonates. , Carbamates and amino acid esters. For example, a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug. Other prodrug forms include phosphate esters, as these phosphate ester compounds are obtained by phosphorylation of hydroxyl groups on the parent. For a complete discussion of prodrugs, please refer to the following documents: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJHecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008 , 51, 2328-2345.
除非其他方面表明，本发明的化合物的所有互变异构形式都包含在本发明的范围之内。另外，除非其他方面表明，本发明所描述的化合物的结构式包括一个或多个不同的原子的富集同位素。Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention. In addition, unless otherwise indicated, the structural formula of the compounds described in this invention includes one or more different atom-enriched isotopes.
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的 代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化、还原、水解、酰氨化，脱酰氨作用、酯化、脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。"Metabolite" refers to a product obtained by metabolizing a specific compound or its salt in the body. The metabolite of a compound can be identified by techniques well known in the art, and its activity can be characterized by an experimental method as described in the present invention. Such products can be obtained by administering compounds through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. Accordingly, the present invention includes metabolites of the compound, including metabolites produced by fully contacting the compound of the present invention with a mammal for a period of time.
本发明中立体化学的定义和惯例的使用通常参考以下文献：S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons,Inc.,New York,1994.本发明的化合物可以包含不对称中心或手性中心，因此存在不同的立体异构体。本发明的化合物所有的立体异构形式，包括但绝不限于，非对映体，对映异构体，阻转异构体，和它们的混合物，如外消旋混合物，组成了本发明的一部分。很多有机化合物都以光学活性形式存在，即它们有能力旋转平面偏振光的平面。在描述光学活性化合物时，前缀D、L或R、S用来表示分子手性中心的绝对构型。前缀d、l或(+)、(-)用来命名化合物平面偏振光旋转的符号，(-)或l是指化合物是左旋的，前缀(+)或d是指化合物是右旋的。这些立体异构体的化学结构是相同的，但是它们的立体结构不一样。特定的立体异构体可以是对映体，异构体的混合物通常称为对映异构体混合物。50：50的对映体混合物被称为外消旋混合物或外消旋体，这可能导致化学反应过程中没有立体选择性或立体定向性。术语“外消旋混合物”和“外消旋体”是指等摩尔的两个对映异构体的混合物，缺乏光学活性。The definition and usage of stereochemistry in the present invention generally refer to the following documents: SPParker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S ., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compound of the present invention may contain an asymmetric center or a chiral center, so different stereoisomers exist. All stereoisomeric forms of the compounds of the present invention, including but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute the present invention Part. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefixes D, L or R, S are used to indicate the absolute configuration of the molecular chiral center. The prefixes d, l, or (+), (-) are used to designate the symbol for the rotation of the plane polarized light of the compound, (-) or l means that the compound is left-handed, and the prefix (+) or d means that the compound is right-handed. The chemical structures of these stereoisomers are the same, but their stereostructures are different. The specific stereoisomer may be an enantiomer, and a mixture of isomers is usually called a mixture of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or a racemate, which may result in no stereoselectivity or stereospecificity during the chemical reaction. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers, lacking optical activity.
术语“互变异构体”或“互变异构的形式”是指不同能量的结构的同分异构体可以通过低能垒互相转化。例如质子互变异构体(即质子移变的互变异构体)包括通过质子迁移的互变，如酮式-烯醇式和亚胺-烯胺的同分异构化作用。原子价(化合价)互变异构体包括重组成键电子的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。The term "tautomer" or "tautomeric form" means that structural isomers of different energies can be converted to each other by a low energy barrier. For example, proton tautomers (i.e., proton shift tautomers) include interconversion through proton migration, such as the isomerization of keto-enol and imine-enamine. The atomic valence (valence) tautomers include the interconversion of reorganized bond electrons. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,66:1-19,1977.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、高氯酸盐、和有机酸盐如乙酸盐、草酸盐、马来酸盐、酒石酸盐、柠檬酸盐、琥珀酸盐、丙二酸盐、或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐、苹果酸盐、2-羟基丙酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、环戊基丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、反丁烯二酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、 乳糖醛酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐，等等。通过适当的碱得到的盐包括碱金属，碱土金属，铵和N
+(C
1-4烷基)
4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠、锂、钾、钙、镁，等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物、氢氧化物、羧化物、硫酸化物、磷酸化物、硝酸化物、C
1-8磺酸化物和芳香磺酸化物。
As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19, 1977. Salts formed by pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups include hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods described in books and literature such as ion exchange These salts. Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate , Borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate Acid salt, glucoheptonic salt, glycerol phosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactic acid Salt, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, paraben , Pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoic acid Salt, valerate, etc. Salts obtained by suitable bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts. The present invention also contemplates the formation of quaternary ammonium salts of any compound containing N groups. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. The alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter-ions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C 1 -8 sulfonate and aromatic sulfonate.
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水、异丙醇、乙醇、甲醇、二甲亚砜、乙酸乙酯、乙酸、氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。The "solvate" of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed by the solvent molecule being water.
术语“保护基团”或“Pg”是指一个取代基与别的官能团起反应的时候，通常用来阻断或保护特殊的功能性。例如，“氨基的保护基团”是指一个取代基与氨基基团相连来阻断或保护化合物中氨基的功能性，合适的氨基保护基团包括乙酰基、三氟乙酰基、叔丁氧羰基(BOC)、苄氧羰基(CBZ)和9-芴亚甲氧羰基(Fmoc)。相似地，“羟基保护基团”是指羟基的取代基用来阻断或保护羟基的功能性，合适的保护基团包括乙酰基和甲硅烷基。“羧基保护基团”是指羧基的取代基用来阻断或保护羧基的功能性，一般的羧基保护基包括-CH
2CH
2SO
2Ph、氰基乙基、2-(三甲基硅烷基)乙基、2-(三甲基硅烷基)乙氧基甲基、2-(对甲苯磺酰基)乙基、2-(对硝基苯磺酰基)乙基、2-(二苯基膦基)乙基、硝基乙基，等等。对于保护基团一般的描述可参考文献：T W.Greene,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005。
The term "protecting group" or "Pg" means that when a substituent reacts with another functional group, it is usually used to block or protect a particular functionality. For example, "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in the compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to the functionality of a hydroxyl group's substituent used to block or protect the hydroxyl group. Suitable protecting groups include acetyl and silyl. "Carboxyl protecting group" refers to the substituent of carboxyl group used to block or protect the functionality of carboxyl group, general carboxyl protecting group includes -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilane Group) ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl Phosphino) ethyl, nitroethyl, etc. For a general description of protecting groups, reference can be made to: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
本发明的化合物的组合物，制剂，给药和化合物及组合物的用途Compositions, formulations, administration of compounds of the present invention and use of compounds and compositions
根据另一方面，本发明的药物组合物的特点包括式(I)、式(Ia)、式(II)或式(IIa)的氘代化合物，本发明所列出的化合物，或实施例化合物，和药学上可接受的辅料。本发明的组合物中化合物能有效的抑制乙型肝炎病毒，适用于病毒引起的疾病尤其是急性和慢性持续的HBV感染的治疗，HBV引发的慢性病毒病可能导致病态变严重，慢性乙型肝炎病毒感染在许多情况下可导致肝硬化和/或肝细胞癌变。According to another aspect, the characteristics of the pharmaceutical composition of the present invention include a deuterated compound of formula (I), formula (Ia), formula (II), or formula (IIa), a compound listed in the present invention, or an example compound , And pharmaceutically acceptable excipients. The compound in the composition of the present invention can effectively inhibit hepatitis B virus, and is suitable for the treatment of virus-induced diseases, especially acute and chronic persistent HBV infection. Chronic viral diseases caused by HBV may lead to serious morbidity, chronic hepatitis B Viral infections can cause cirrhosis and/or hepatocellular carcinoma in many cases.
对本发明的化合物来说，可能被提及的疾病治疗的区域是，例如：可能导致传染性肝炎的急性和慢性病毒感染的治疗，例如，乙肝病毒感染。本发明的化合物尤其适合治疗慢性乙肝感染和急性和慢性乙肝病毒感染。For the compounds of the present invention, areas of disease treatment that may be mentioned are, for example, the treatment of acute and chronic viral infections that may lead to infectious hepatitis, for example, hepatitis B virus infection. The compounds of the present invention are particularly suitable for the treatment of chronic hepatitis B infections and acute and chronic hepatitis B virus infections.
本发明包括药物制剂，除了无毒，惰性的制药学上合适的辅料外，还含有一种或多种本发明的式(I)、式(Ia)、式(II)或式(IIa)氘代化合物或其药物组合物或含有一种或多种活性成分式(I)、式(Ia)、式(II)或式(IIa)化合物或本发明的药物组合物。The present invention includes pharmaceutical preparations, in addition to non-toxic and inert pharmaceutically suitable auxiliary materials, it also contains one or more deuteriums of formula (I), formula (Ia), formula (II) or formula (IIa) of the present invention Substitute compounds or pharmaceutical compositions thereof contain one or more active ingredients of the compound of formula (I), formula (Ia), formula (II) or formula (IIa) or the pharmaceutical composition of the present invention.
上述药物制剂也可以包含式(I)、式(Ia)、式(II)或式(IIa)所示氘代化合物以外的其他活性药物成分。The above-mentioned pharmaceutical preparation may also contain other active pharmaceutical ingredients other than the deuterated compound represented by formula (I), formula (Ia), formula (II) or formula (IIa).
本发明的化合物存在自由形态，或合适的、作为药学上可接受的衍生物。根据本发明，药学上可接受的衍生物包括，但并不限于，药学上可接受的前药，盐，酯，酯类的盐，或能直接或间接地根据患者的需要给药的其他任何加合物或衍生物，本发明其他方面所描述的化合物，其代谢产物或他的残留物。The compounds of the present invention exist in free form or are suitable as pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, ester salts, or any other that can be administered directly or indirectly according to the needs of the patient Adducts or derivatives, compounds described in other aspects of the invention, their metabolites or their residues.
像本发明所描述的，本发明药物组合物包含任何一种本发明的式(I)、式(Ia)、式(II)或式(IIa)所示的氘代化合物，进一步包含药学上可接受的辅料，这些辅料，例如像本发明所应用的，包括任何溶剂、固体赋形剂、稀释剂、粘合剂、崩解剂、或其他液体赋形剂、分散剂、矫味剂或悬浮剂、表面活性剂、等渗剂、增稠剂、乳化剂、防腐剂，固体粘合剂或润滑剂，等等，适合于特有的目标剂型。如以下文献所描述的：In Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York,综合此处文献的内容，表明不同的辅料可应用于药学上可接受的组合物的制剂和它们公知的制备方法。除了任何常规的辅料与本发明的化合物不相容的范围，例如所产生的任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式产生的相互作用，它们的用途也是本发明所考虑的范围。As described in the present invention, the pharmaceutical composition of the present invention comprises any one of the deuterated compounds of formula (I), formula (Ia), formula (II), or formula (IIa) of the present invention, further comprising pharmaceutically acceptable Accepted excipients, such as those used in the present invention, include any solvent, solid excipient, diluent, binder, disintegrant, or other liquid excipient, dispersant, flavor, or suspension Agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., suitable for the specific target dosage form. As described in the following documents: In Remington: The Science and Practice Pharmacy, 21st edition, 2005, ed. DBTroy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Science, Technology, eds. J. Swarbrick 1988 JCBoylan , Marcel Dekker, New York, synthesizing the contents of the literature here, shows that different excipients can be applied to the preparation of pharmaceutically acceptable compositions and their well-known preparation methods. In addition to the extent that any conventional excipients are incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions with any other components of the pharmaceutically acceptable composition in a harmful manner, their The application is also within the scope of the present invention.
可作为药学上可接受辅料的物质包括，但并不限于，离子交换剂；铝；硬脂酸铝；卵磷脂；血清蛋白，如人血清蛋白；缓冲物质如磷酸盐；甘氨酸；山梨酸；山梨酸钾；饱和植物脂肪酸的部分甘油酯混合物；水；盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐；胶体硅；三硅酸镁；聚乙烯吡咯烷酮；聚丙烯酸脂；蜡；聚乙烯-聚氧丙烯-阻断聚合体；羊毛脂；糖，如乳糖，葡萄糖和蔗糖；淀粉如玉米淀粉和土豆淀粉；纤维素和它的衍生物如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；树胶粉；麦芽；明胶；滑石粉；辅料如可可豆脂和栓剂蜡状物；油如花生油，棉子油，红花油，麻油，橄榄油，玉米油和豆油；二醇类化合物，如丙二醇和聚乙二醇；酯类如乙基油酸酯和乙基月桂酸酯；琼脂；缓冲剂如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等渗盐；林格(氏)溶液；乙醇；磷酸缓冲溶液；和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁；着色剂；释放剂；包衣衣料；甜味剂；调味剂；香料；防腐剂和抗氧化剂。Substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins such as human serum proteins; buffer substances such as phosphates; glycine; sorbic acid; sorbic acid Potassium acid; partial glyceride mixture of saturated vegetable fatty acids; water; salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt; colloidal silicon; magnesium trisilicate; polyethylene Pyrrolidone; polyacrylate; wax; polyethylene-polyoxypropylene-blocking polymer; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl Sodium cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; auxiliary materials such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, Olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; seaweed Acid; pyrogen-free water; isotonic salt; Ringer's solution; ethanol; phosphate buffer solution; and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; colorant; release agent; Coating materials; sweeteners; flavoring agents; spices; preservatives and antioxidants.
本发明化合物的药物组合物，可以以下面的任意方式施用：口服给药，喷雾吸入法，局部给药，经直肠给药，经鼻给药，局部给药，***给药，非肠道给药如皮下，静脉，肌内，腹腔内，鞘内，心室内，胸骨内，或颅内注射或输液，或借助一种外植的储器用药。优选的方式为口服给药，肌注，向腹膜内给药或静脉注射。The pharmaceutical composition of the compound of the present invention can be administered in any of the following ways: oral administration, spray inhalation, local administration, rectal administration, nasal administration, local administration, vaginal administration, parenteral administration Medicines such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, or intracranial injection or infusion, or use an explanted reservoir. The preferred mode is oral administration, intramuscular injection, intraperitoneal administration or intravenous injection.
本发明化合物或其药物组合物可以是以单位剂量形式给药。给药剂型可以是液体剂型、固体剂型。液体剂型可以是真溶液类、胶体类、微粒剂型、混悬剂型。其他剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉针剂、包合物、埋植剂、贴剂、擦剂等。The compound of the present invention or the pharmaceutical composition thereof can be administered in unit dosage form. The dosage form for administration may be a liquid dosage form or a solid dosage form. The liquid dosage form may be a true solution type, a colloid type, a particulate dosage form, or a suspension dosage form. Other dosage forms such as tablets, capsules, pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, lyophilized powder injections, clathrates, implants, patches, rubs Agent.
口服片剂和胶囊可以含有赋形剂如粘合剂，如糖浆，***胶，山梨醇，黄芪胶，或聚乙烯吡咯烷酮；填充剂，如乳糖，蔗糖，玉米淀粉，磷酸钙，山梨醇，氨基乙酸；润滑剂，如硬脂酸镁，滑石，聚乙二醇，硅土；崩解剂，如马铃薯淀粉；或可接受的增润剂如月桂醇钠硫酸盐。片剂可以用制药学上公知的方法包衣。Oral tablets and capsules may contain excipients such as binders, such as syrup, gum arabic, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, amino Acetic acid; lubricants, such as magnesium stearate, talc, polyethylene glycol, silica; disintegrating agents, such as potato starch; or acceptable moisturizers, such as sodium lauryl sulfate. The tablets can be coated by methods well known in pharmacy.
口服液可以制成水合油的悬浮液，溶液，乳浊液，糖浆或酏剂，也可以制成干品，用前补充水或其它合适的媒质。这种液体制剂可以包含常规的添加剂，如悬浮剂，山梨醇，纤维素甲醚，葡萄糖糖浆，凝胶，羟乙基纤维素，羧甲基纤维素，硬脂酸铝凝胶，氢化的食用油脂，乳化剂，如卵磷脂，山梨聚醣单油酸盐，***胶；或非水辅料(可能包含可食用油)，如杏仁油，油脂如甘油，乙二醇，或乙醇；防腐剂，如对羟基苯甲酸甲酯或丙酯，山梨酸。如需要可添加调味剂或着色剂。Oral liquids can be prepared as suspensions, solutions, emulsions, syrups or elixirs of hydrated oils, or as dry products, supplemented with water or other suitable medium before use. Such liquid preparations may contain conventional additives such as suspending agents, sorbitol, cellulose methyl ether, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated food Fats, emulsifiers such as lecithin, sorbitan monooleate, gum arabic; or non-aqueous excipients (which may contain edible oils), such as almond oil, fats such as glycerin, ethylene glycol, or ethanol; preservatives, Such as methyl or propyl paraben, sorbic acid. If necessary, flavoring agents or coloring agents can be added.
栓剂可包含常规的栓剂基质，如可可黄油或其他甘油酯。Suppositories may contain conventional suppository bases such as cocoa butter or other glycerides.
对胃外投药，液态剂型通常由化合物和一种消毒的辅料制成。辅料首选水。依照所选辅料和药物浓度的不同，化合物既可溶于辅料中也可制成悬浮溶液，在制成注射用溶液时先将化合物溶于水中，过滤消毒后装入封口瓶或安瓿中。For parenteral administration, the liquid dosage form is usually made of a compound and a sterilized auxiliary material. The auxiliary material is preferably water. Depending on the concentration of the selected excipient and drug, the compound can be either dissolved in the excipient or made into a suspension solution. When making the solution for injection, the compound is first dissolved in water, filtered and sterilized and then put into a sealed bottle or ampoule.
当皮肤局部施用时，本发明化合物可以制成适当的软膏，洗剂，或霜剂的形式，其中活性成分悬浮或溶解于一种或多种的辅料中，其中软膏制剂可以使用的辅料包括但不局限于：矿物油，液体凡士林，白凡士林，丙二醇，聚氧化乙烯，聚氧化丙烯，乳化蜡和水；洗剂和霜剂可使用的辅料包括但不限于：矿物油，脱水山梨糖醇单硬脂酸酯，吐温60，十六烷酯蜡，十六碳烯芳醇，2-辛基十二烷醇，苄醇和水。When applied topically to the skin, the compounds of the present invention can be prepared in the form of suitable ointments, lotions, or creams, in which the active ingredient is suspended or dissolved in one or more excipients, where the excipients that can be used in ointment formulations include but Not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; auxiliary materials that can be used in lotions and creams include but are not limited to: mineral oil, sorbitan mono Stearate, Tween 60, cetyl ester wax, hexadecenyl aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
一般而言，已经证明有利的是无论在人体医药还是在兽医药中，本发明活性化合物的给药总量每24小时为约0.5-500mg，优选1-100mg/kg体重，如果合适的话，分多次单剂量给药，以达到所要求的效果。单剂量中含活性化合物的量优选为约1-80mg，更优选为1-50mg/kg体重，但也可以不按照上述的剂量，即取决于治疗对象的种类和体重、疾病的性质和严重程 度、制剂的类型和药物的给药方式，以及给药周期或时间间隔。In general, it has proven to be advantageous whether the total amount of active compound of the present invention is about 0.5-500 mg, preferably 1-100 mg/kg body weight every 24 hours, whether in human medicine or veterinary medicine, if appropriate Single dose administration multiple times to achieve the desired effect. The amount of the active compound contained in a single dose is preferably about 1-80 mg, more preferably 1-50 mg/kg body weight, but it may not be in accordance with the above dose, that is, it depends on the type and weight of the subject to be treated, the nature and severity of the disease , The type of preparation and the mode of administration of the drug, as well as the administration cycle or time interval.
本发明提供的药物组合物中还包含抗HBV药物。其中抗HBV药物为HBV聚合酶抑制剂、免疫调节剂或干扰素。The pharmaceutical composition provided by the present invention also includes anti-HBV drugs. The anti-HBV drugs are HBV polymerase inhibitors, immunomodulators or interferons.
所述抗HBV药物有拉米夫定、替比夫定、替诺福韦酯，恩替卡韦、阿德福韦酯、Alfaferone、Alloferon、西莫白介素、克拉夫定、恩曲他滨、法昔洛韦、干扰素、宝甘灵CP、因特芬、干扰素α-1b、干扰素α、干扰素α-2a、干扰素β-1a、干扰素α-2、白细胞介素-2、米伏替酯、硝唑尼特、聚乙二醇干扰素α-2a、病毒唑、罗扰素-A、西佐喃、Euforavac、安普利近、Phosphazid，Heplisav、干扰素α-2b、左旋咪唑或丙帕锗等。The anti-HBV drugs are lamivudine, telbivudine, tenofovir dipivoxil, entecavir, adefovir dipivoxil, Alfaferone, Alloferon, simo interleukin, clavudine, emtricitabine, famciclovir Wei, Interferon, Baoganling CP, Intefen, Interferon α-1b, Interferon α, Interferon α-2a, Interferon β-1a, Interferon α-2, Interleukin-2, Mifu Titrate, nitazoxanide, pegylated interferon α-2a, ribavirin, rapamycin-A, cezolan, Euforavac, April, Phosphazid, Heplisav, interferon α-2b, levamisole Or propargium germanium.
本发明另一方面涉及一种本发明的氘代化合物或药物组合物来制备用于预防、治疗或减轻患者乙型肝炎疾病的药品的用途，包括给予患者药学上可接受的有效剂量对患者进行给药。乙型肝炎疾病是指由乙肝病毒感染或乙型肝炎感染导致引起的肝脏疾病，包括急性肝炎、慢性肝炎，肝硬化和干细胞癌。急性乙型肝炎病毒感染可以是无症状或表现为急性肝炎症状。慢性病毒感染患者患有活动性疾病，可发展为肝硬化和肝癌。Another aspect of the present invention relates to the use of a deuterated compound or pharmaceutical composition of the present invention to prepare a medicament for preventing, treating or alleviating hepatitis B disease in a patient, including administering to the patient a pharmaceutically acceptable effective dose Administration. Hepatitis B disease refers to liver disease caused by hepatitis B virus infection or hepatitis B infection, including acute hepatitis, chronic hepatitis, liver cirrhosis and stem cell cancer. Acute hepatitis B virus infection can be asymptomatic or present as symptoms of acute hepatitis. Patients with chronic viral infections have active diseases that can progress to cirrhosis and liver cancer.
抗HBV药物可以与包含本发明的化合物的组合物分开给药，作为多给药方案的一部分。或者，那些药物可以是单剂型的一部分，与本发明的化合物混合在一起形成单个组合物。如果给药作为多给药方案的一部分，两个活性剂可以同时连续地或在一段时间内互相传递，从而得到目标试剂活性。Anti-HBV drugs can be administered separately from the composition containing the compound of the present invention as part of a multiple dosing regimen. Alternatively, those drugs may be part of a single dosage form, mixed with the compound of the invention to form a single composition. If the drug is administered as part of a multiple dosing regimen, the two active agents can be delivered to each other continuously or over a period of time to obtain the target agent activity.
可以结合辅料物质产生单剂型的化合物和组合物的用量(那些包含一个组合物像本发明所描述的)的改变取决于主治和特殊给药模式。正常地，本发明的组合物的量将不超过组合物包含作为唯一的活性剂的正常给药的量。另一方面，现公开的组合物的量的范围大约是现有组合物正常量的50％-100％，包含的试剂作为唯一活性治疗剂。在那些包含的组合物中，组合物将与本发明的化合物起协同作用。The amount of compound and composition that can be combined with the excipient materials to produce a single dosage form (those containing a composition as described in the present invention) varies depending on the indication and the particular mode of administration. Normally, the amount of the composition of the present invention will not exceed the amount of the composition normally administered as the sole active agent. On the other hand, the amount of the presently disclosed composition ranges from about 50% to 100% of the normal amount of the existing composition, and contains the agent as the only active therapeutic agent. Among those contained compositions, the composition will act synergistically with the compounds of the present invention.
本发明的化合物显示出较强的抗病毒作用。这类化合物对HBV具有出乎预料的抗病毒活性，因此适于用来治疗病毒引起的各种疾病，尤其是急性和慢性持久性HBV感染引起的疾病。由HBV引起的慢性病毒性疾病可以导致各种不同严重程度的综合症状，众所周知，慢性乙肝病毒感染可导致肝硬化和/或肝细胞癌。The compounds of the present invention show strong antiviral effects. Such compounds have unexpected antiviral activity against HBV and are therefore suitable for the treatment of various diseases caused by viruses, especially those caused by acute and chronic persistent HBV infection. Chronic viral diseases caused by HBV can cause various symptoms of various severity. It is well known that chronic hepatitis B virus infection can lead to cirrhosis and/or hepatocellular carcinoma.
可用本发明化合物治疗的适应症的实例有：可导致感染性肝炎的急性和慢性病毒感染，例如异性肝炎病毒感染。特别优选的是慢性乙型肝炎感染和急性乙型肝炎病毒感染。Examples of indications that can be treated with the compounds of the present invention are: acute and chronic viral infections that can cause infectious hepatitis, such as heterosexual hepatitis virus infection. Particularly preferred are chronic hepatitis B infection and acute hepatitis B virus infection.
本发明还涉及，本发明的化合物和组合物用于制备治疗和预防病毒性疾病特别是乙型肝炎的药物的用途。The present invention also relates to the use of the compounds and compositions of the present invention for the preparation of medicaments for the treatment and prevention of viral diseases, especially hepatitis B.
一般合成方法General synthesis method
一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如式(I)、式(Ia)、式(II)或式(IIa)所示。下面的合成方案和实施例用于进一步举例说明本发明的内容。Generally, the compound of the present invention can be prepared by the method described in the present invention, unless otherwise specified, wherein the definition of the substituent is as formula (I), formula (Ia), formula (II) or formula (IIa) Show. The following synthesis schemes and examples are used to further illustrate the content of the present invention.
所属领域的技术人员将认识到：本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的试剂除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。Those skilled in the art will recognize that the chemical reactions described in the present invention can be used to properly prepare many other compounds of the present invention, and other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention Inside. For example, the synthesis of non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by using other known reagents in addition to the description of the present invention, or The reaction conditions should be modified routinely. In addition, the reactions disclosed in the present invention or known reaction conditions are also generally applicable to the preparation of other compounds of the present invention.
下面所描述的实施例，除非其他方面表明所有的温度定为摄氏度(℃)。试剂购买于商品供应商如Aldrich Chemical Company,Arco Chemical Company and Alfa Chemical Company，使用时都没有经过进一步纯化，除非其他方面表明。一般的试剂从汕头西陇化工厂，广东光华化学试剂厂，广州化学试剂厂，天津好寓宇化学品有限公司，青岛腾龙化学试剂有限公司，和青岛海洋化工厂购买得到。The examples described below, unless otherwise indicated, all temperatures are set in degrees Celsius (°C). Reagents were purchased from commodity suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, and were not further purified when used, unless otherwise indicated. General reagents are purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.
色谱柱使用硅胶柱，硅胶(200-300目)购于青岛海洋化工厂。核磁共振光谱以CDC1
3,DMSO-d
6,CD
3OD或丙酮-d
6为溶剂(报导以ppm为单位)，用TMS(0ppm)或氯仿(7.25ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰),d(doublet，双峰),t(triplet，三重峰),m(multiplet，多重峰),br(broadened，宽峰),dd(doublet of doublets，双二重峰),dt(doublet of triplets，双三重峰),br.s(broadened singlet，宽单峰)。偶合常数J，单位用赫兹(Hz)表示。
The chromatography column used silica gel column, silica gel (200-300 mesh) was purchased from Qingdao Ocean Chemical Factory. Nuclear magnetic resonance spectroscopy uses CDC1 3 , DMSO-d 6 , CD 3 OD or acetone-d 6 as the solvent (reported in ppm), and uses TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard. When multiple peaks appear, the following abbreviations will be used: s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), m (multiplet, multiplet), br (broadened, wide Peak), dd (doublet of doublets, double doublet), dt (doublet of triplets, double triplet), br.s (broadened singlet, wide singlet). The coupling constant J is expressed in hertz (Hz).
低分辨率质谱(MS)数据通过配备G1312A二元泵和a G1316A TCC(柱温保持在30℃)的Agilent 6320系列LC-MS的光谱仪来测定，G1329A自动采样器和G1315B DAD检测器应用于分析，ESI源应用于LC-MS光谱仪。Low-resolution mass spectrometry (MS) data was measured by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30°C). The G1329A automatic sampler and G1315B DAD detector were used for analysis , ESI source is applied to LC-MS spectrometer.
低分辨率质谱(MS)数据还通过配备G1311A四元泵和G1316A TCC(柱温保持在30℃)的Agilent 6120系列LC-MS的光谱仪来测定，G1329A自动采样器和G1315D DAD检测器应用于分析，ESI源应用于LC-MS光谱仪。Low-resolution mass spectrometry (MS) data was also measured by an Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and G1316A TCC (column temperature maintained at 30°C). The G1329A automatic sampler and G1315D DAD detector were used for analysis , ESI source is applied to LC-MS spectrometer.
以上两种光谱仪都配备了Agilent Zorbax SB-C18柱，规格为2.1×30mm，5μm。注射体积是通过样品浓度来确定；流速为0.6mL/min；HPLC的峰值是通过在210nm和254nm处的UV-Vis波长来记录读取的。流动相为0.1％的甲酸乙腈溶液(相A)和0.1％的甲酸超纯水溶液(相B)。梯度洗脱条件如表1所示：Both of the above spectrometers are equipped with Agilent Zorbax SB-C18 columns with specifications of 2.1×30mm and 5μm. The injection volume is determined by the sample concentration; the flow rate is 0.6 mL/min; the peak of HPLC is recorded by the UV-Vis wavelength at 210 nm and 254 nm. The mobile phase was 0.1% formic acid in acetonitrile (phase A) and 0.1% formic acid in ultrapure water (phase B). The gradient elution conditions are shown in Table 1:
表1：梯度洗脱条件Table 1: Gradient elution conditions
化合物纯化是通过Agilent 1100系列高效液相色谱(HPLC)来评价的，其中UV检测在210nm和254nm处，Zorbax SB-C18柱，规格为2.1×30mm，4μm，10分钟，流速为0.6mL/min，5-95％的(0.1％甲酸乙腈溶液)的(0.1％甲酸水溶液)，柱温保持在40℃。Compound purification was evaluated by Agilent 1100 series high performance liquid chromatography (HPLC), where UV detection was at 210nm and 254nm, Zorbax SB-C18 column, specification was 2.1×30mm, 4μm, 10 minutes, flow rate was 0.6mL/min , 5-95% (0.1% formic acid in acetonitrile) (0.1% formic acid in water), the column temperature was maintained at 40 ℃.
下面简写词的使用贯穿本发明：The following abbreviations are used throughout the present invention:
合成方法resolve resolution
以下合成方案列出了制备本发明中公开化合物的实验步骤。其中，各R
1、R
2、R
4、R
9、X
1、m和f具有如本发明所述的含义。
The following synthetic scheme lists the experimental procedures for preparing the compounds disclosed in the present invention. Here, each of R 1 , R 2 , R 4 , R 9 , X 1 , m, and f has the meaning as described in the present invention.
合成方案1Synthesis Scheme 1
化合物(2a)可以通过合成方案1描述的方法制备得到，化合物(1a)(化合物(1a)可参考WO2015074546中的合成方案1和其中的具体实施例方法制备得到)与化合物(a)在碱性条件下(如碳酸钾等)和合适的溶剂(如乙醇等)中反应得到化合物(2a)。Compound (2a) can be prepared by the method described in Synthesis Scheme 1. Compound (1a) (compound (1a) can be obtained by referring to Synthesis Scheme 1 in WO2015074546 and the specific examples thereof) and compound (a) are basic Under conditions (such as potassium carbonate, etc.) and a suitable solvent (such as ethanol, etc.), the compound (2a) is obtained.
片段F1的合成：Synthesis of fragment F1:
步骤1：化合物F1-1的合成Step 1: Synthesis of compound F1-1
于100mL单口瓶中加入化合物F1-0(0.50g,2.2mmol)、乙腈(20mL)、碳酸钾(0.60g,4.3mmol)和碘甲烷(0.16mL,2.6mmol)，混合物在25℃下搅拌2h，然后过滤，浓缩滤液。所得残留物经硅胶柱层析(PE/EtOAc(V/V)＝15/1)纯化，得标题化合物为无色油状物(0.43g，81％)。
1H NMR(400MHz,CDCl
3)δ(ppm)7.42(d,J＝8.3Hz,2H),7.09(d,J＝8.3Hz,2H),3.68(s,3H),2.92(t,J＝7.7Hz,2H),2.63(t,J＝7.7Hz,2H)。
In a 100 mL single-necked flask, compound F1-0 (0.50 g, 2.2 mmol), acetonitrile (20 mL), potassium carbonate (0.60 g, 4.3 mmol) and methyl iodide (0.16 mL, 2.6 mmol) were added, and the mixture was stirred at 25°C for 2 h , Then filtered and concentrated the filtrate. The obtained residue was purified by silica gel column chromatography (PE/EtOAc (V/V)=15/1) to obtain the title compound as a colorless oil (0.43 g, 81%). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 7.42 (d, J=8.3 Hz, 2H), 7.09 (d, J=8.3 Hz, 2H), 3.68 (s, 3H), 2.92 (t, J= 7.7 Hz, 2H), 2.63 (t, J=7.7 Hz, 2H).
步骤2：化合物F1-2的合成Step 2: Synthesis of compound F1-2
于100mL两口瓶中加入(R)-3-氧代六氢咪唑并[1,5-a]吡嗪-7(1H)-甲酸叔丁酯(228mg,0.95mmol)、化合物F1-1(230mg,0.95mmol)、三(二亚苄基丙酮)二钯(87mg,0.095mmol)、2-二叔丁基膦-2′,4′,6′-三异丙基联苯(80mg,0.19mmol)、碳酸铯(0.62g,1.89mmol)和1,4-二氧六环(10mL)。反应混合物在90℃下搅拌2h，然后减压浓缩，所得残留物经硅胶柱层析(PE/EtOAc(V/V)＝1/1)纯化，得标题化合物为白色固体(171mg,45％)。MS(ESI,pos.ion)m/z:426.1[M+Na]
+。
(R)-3-oxohexahydroimidazo[1,5-a]pyrazine-7(1H)-carboxylic acid tert-butyl ester (228 mg, 0.95 mmol), compound F1-1 (230 mg , 0.95mmol), tris(dibenzylideneacetone) dipalladium (87mg, 0.095mmol), 2-di-tert-butylphosphine-2', 4', 6'-triisopropylbiphenyl (80mg, 0.19mmol) ), cesium carbonate (0.62g, 1.89mmol) and 1,4-dioxane (10mL). The reaction mixture was stirred at 90°C for 2h, then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EtOAc (V/V) = 1/1) to give the title compound as a white solid (171mg, 45%) . MS (ESI, pos.ion) m/z: 426.1 [M+Na] + .
步骤3：化合物F1-3的合成Step 3: Synthesis of compound F1-3
于50mL单口瓶中加化合物F1-2(161.5mg,0.40mmol)、甲醇(2mL)、水(2mL)和一水氢氧化锂(83mg,2.0mmol)。反应混合物在25℃下搅拌反应6h，然后减压浓缩，浓缩残留物加入水(5mL)和乙酸乙酯(10mL)稀释，静止分层，水层用稀盐酸(1M)调pH至5左右，再用乙酸乙酯(10mL)萃取，然后合并所有有机相，合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓缩，得标题化合物为白色固体(0.12g,77％)。MS(ESI,pos.ion)m/z: 412.1[M+Na]
+。
In a 50 mL single-necked bottle, add compound F1-2 (161.5 mg, 0.40 mmol), methanol (2 mL), water (2 mL), and lithium hydroxide monohydrate (83 mg, 2.0 mmol). The reaction mixture was stirred at 25°C for 6 h, and then concentrated under reduced pressure. The concentrated residue was diluted with water (5 mL) and ethyl acetate (10 mL), and the layers were separated at rest. The aqueous layer was adjusted to pH 5 with dilute hydrochloric acid (1M). After extraction with ethyl acetate (10 mL), all organic phases were combined. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound as a white solid (0.12 g, 77%). MS (ESI, pos.ion) m/z: 412.1[M+Na] + .
步骤4：化合物F1的合成Step 4: Synthesis of compound F1
于25mL单口瓶中加入化合物F1-3(0.12g,0.31mmol)和氯化氢的1,4-二氧六环溶液(4mol/L,20mL)。反应混合物在25℃下搅拌反应16h，然后减压浓缩，得标题化合物为白色固体(0.10g,100％)。MS:(ESI,pos.ion)m/z:290.1[M+H]
+。
In a 25 mL single-necked bottle, compound F1-3 (0.12 g, 0.31 mmol) and hydrogen chloride in 1,4-dioxane (4 mol/L, 20 mL) were added. The reaction mixture was stirred at 25°C for 16 h, and then concentrated under reduced pressure to obtain the title compound as a white solid (0.10 g, 100%). MS: (ESI, pos.ion) m/z: 290.1[M+H] + .
片段F2的合成：Synthesis of fragment F2:
步骤1：化合物F2-1的合成Step 1: Synthesis of compound F2-1
将化合物F2-0(1.00g,4.37mmol)溶于无水DMF(12.5mL)中，反应液在N
2保护下，于0℃下加入NaH(700mg,17.5mmol,60％)，搅拌15分钟左右，再缓慢加入CH
3I(1.62mL)。滴加完毕，反应液于0℃下继续搅拌15分钟，然后转移至室温下反应12h。反应完后，用饱和氯化铵(20mL)淬灭反应，用EA(20mL)萃取，有机层用饱和食盐水(30mL)洗涤，然后减压浓缩，得标题化合物为黄色油状物(1.12g,99.8％)。
1H NMR(400MHz,CDCl
3)δ(ppm)7.44(d,J＝8.7Hz,2H),7.21(d,J＝8.7Hz,2H),3.65(s,3H),1.56(s,3H),1.55(s,3H)。
Compound F2-0 (1.00 g, 4.37 mmol) was dissolved in anhydrous DMF (12.5 mL). Under the protection of N 2 , NaH (700 mg, 17.5 mmol, 60%) was added at 0°C and stirred for 15 minutes. Around, add CH 3 I (1.62 mL) slowly again. After the dropwise addition was completed, the reaction solution was further stirred at 0°C for 15 minutes, and then transferred to room temperature and reacted for 12 hours. After the reaction was completed, the reaction was quenched with saturated ammonium chloride (20 mL), extracted with EA (20 mL), the organic layer was washed with saturated brine (30 mL), and then concentrated under reduced pressure to give the title compound as a yellow oil (1.12 g, 99.8%). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 7.44 (d, J = 8.7 Hz, 2H), 7.21 (d, J = 8.7 Hz, 2H), 3.65 (s, 3H), 1.56 (s, 3H) , 1.55 (s, 3H).
步骤2：化合物F2-2的合成Step 2: Synthesis of compound F2-2
依次将化合物F2-1(689mg,2.68mmol)、(R)-3-氧代六氢咪唑并[1,5-a]吡嗪-7(1H)-甲酸叔丁酯(630mg,2.61mmol)、Pd
2(dba)
3(180mg,0.19mmol)、2-二-叔丁膦基-2',4',6'-三异丙基联苯(550mg,1.26mmol)、Cs
2CO
3(173mg,0.53mmol)和1,4-二氧六环(25mL)加入到50mL的两口瓶中,反应混合物在氮气保护下并于90℃下反应12h。反应完后，反应体系冷却至室 温，过滤，滤饼用EtOAc(25mL)洗涤。向滤液加入EtOAc(75mL)和水(50mL)，所得混合物振摇分层。水相用EtOAc(50mL)反萃，合并的有机层用无水硫酸钠干燥，过滤，并减压浓缩滤液，所得残留物经硅胶柱层析(PE/EA(V/V)＝1.2/1)纯化，得标题化合物为白色固体(200mg,17.88％)。MS(ESI,pos.ion)m/z:440.1[M+23]
+。
Compound F2-1 (689mg, 2.68mmol), (R)-3-oxohexahydroimidazo[1,5-a]pyrazine-7(1H)-carboxylic acid tert-butyl ester (630mg, 2.61mmol) , Pd 2 (dba) 3 (180mg, 0.19mmol), 2-di-tert-butylphosphino-2', 4', 6'-triisopropylbiphenyl (550mg, 1.26mmol), Cs 2 CO 3 (173mg, 0.53mmol) and 1,4-dioxane (25mL) were added to a 50mL two-necked flask, the reaction mixture was under nitrogen protection and reacted at 90 ℃ for 12h. After the reaction was completed, the reaction system was cooled to room temperature, filtered, and the filter cake was washed with EtOAc (25 mL). EtOAc (75 mL) and water (50 mL) were added to the filtrate, and the resulting mixture was shaken to separate layers. The aqueous phase was back-extracted with EtOAc (50 mL), the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (PE/EA(V/V)=1.2/1 ) Purification to give the title compound as a white solid (200 mg, 17.88%). MS (ESI, pos.ion) m/z: 440.1 [M+23] + .
步骤3：化合物F2-3的合成Step 3: Synthesis of compound F2-3
将化合物F2-2(200mg,0.48mmol)溶于THF(6mL)中，并向其中依次加入MeOH(2mL)和LiOH.H
2O(85mg)的H
2O(2mL)溶液。反应混合物于50℃下反应12h。反应完后，反应体系减压浓缩，所得残留物加入水(30mL)稀释，再用EA(20mL)萃取，弃去有机相。水相用1M稀盐酸调节PH＝5-6，然后用EA(30mL)萃取，水层再用EA(10mL)反萃，合并有机相，合并的有机相用无水硫酸钠干燥后，过滤，并减压浓缩，得标题化合物为黄色固体(155mg,80.19％)。MS(ESI,pos.ion)m/z:426.3[M+Na]
+。
Compound F2-2 (200 mg, 0.48 mmol) was dissolved in THF (6 mL), and a solution of MeOH (2 mL) and LiOH.H 2 O (85 mg) in H 2 O (2 mL) was sequentially added thereto. The reaction mixture was reacted at 50°C for 12h. After the reaction was completed, the reaction system was concentrated under reduced pressure, the resulting residue was diluted with water (30 mL), and then extracted with EA (20 mL), and the organic phase was discarded. The aqueous phase was adjusted to PH=5-6 with 1M dilute hydrochloric acid, and then extracted with EA (30 mL). The aqueous layer was back-extracted with EA (10 mL). The organic phases were combined. The combined organic phases were dried over anhydrous sodium sulfate and filtered. And concentrated under reduced pressure to give the title compound as a yellow solid (155mg, 80.19%). MS (ESI, pos.ion) m/z: 426.3 [M+Na] + .
步骤4：化合物F2的合成Step 4: Synthesis of compound F2
将化合物F2-3(155mg,0.38mmol)溶于DCM(8mL)，然后向其中加入TFA(4mL)。反应液于室温下反应2h。然后减压浓缩，得标题化合物为黄色油状物质(160mg,99.79％)。Compound F2-3 (155 mg, 0.38 mmol) was dissolved in DCM (8 mL), and TFA (4 mL) was added thereto. The reaction solution was reacted at room temperature for 2h. It was then concentrated under reduced pressure to give the title compound as a yellow oily substance (160 mg, 99.79%).
片段F3的合成：Synthesis of fragment F3:
将CD
3I替换片段F2合成步骤1的碘甲烷，其余操作按照片段F2的合成方法，得到标题化合物为白色固体。
Substitute CD 3 I for the methyl iodide of Step 1 in the synthesis of fragment F2. For the rest, follow the synthesis method of fragment F2 to obtain the title compound as a white solid.
片段F4的合成：Synthesis of fragment F4:
分别将片段F1合成方法中步骤1的化合物F1-0和步骤2的2-二-叔丁膦基-2',4',6'-三异丙基联苯替换成化合物F4-0和Xantphos，其余操作按照F1的合成方法，得标题化合物白色固体。MS(ESI,pos.ion)m/z：280.0[M+H]
+。
Replace compound F1-0 of step 1 and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl of step 2 with compound F4-0 and Xantphos, respectively, in the synthesis method of fragment F1 Operation According to the synthesis method of F1, the title compound was obtained as a white solid. MS (ESI, pos.ion) m/z: 280.0 [M+H] + .
片段F5的合成：Synthesis of fragment F5:
分别将片段F1合成方法中步骤1的F1-0和步骤2的2-二-叔丁膦基-2',4',6'-三异丙基联苯替换成F5-0和Xantphos，其余操作按照片段F1的合成方法，得标题化合物为白色固体。MS (ESI,pos.ion)m/z：280.0[M+H]
+。
Replace F1-0 of Step 1 and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl of Step 2 in the synthesis method of fragment F1 with F5-0 and Xantphos, and follow the rest According to the synthesis method of fragment F1, the title compound was obtained as a white solid. MS (ESI, pos.ion) m/z: 280.0 [M+H] + .
片段F6的合成：Synthesis of fragment F6:
:步骤1：F6-1的合成: Step 1: Synthesis of F6-1
于干燥反应瓶中依次加入F6-0(400mg,1.97mmol)、(R)-3-氧代六氢咪唑并[1,5-a]吡嗪-7(1H)-羧酸叔丁酯(522mg,2.16mmol)、Pd(OAc)
2(23mg,0.10mmol)、Xantphos(117mg,0.20mmol)和Cs
2CO
3(1.16g,3.56mmol)，氮气保护下加入1,4-二氧六环(25mL)。80℃下反应2h。停止反应。加入水(30mL)和EA(50mL)，分液萃取，收集有机相，无水硫酸钠干燥，旋干，残留物经硅胶柱层析(PE/EA(V/V)＝1/1)纯化，得到标题化合物为淡红色固体(560mg,78.21％)。MS(ESI,pos.ion)m/z：308.1[M+H-56]
+。
F6-0 (400mg, 1.97mmol) and (R)-3-oxohexahydroimidazo[1,5-a]pyrazine-7(1H)-carboxylic acid tert-butyl ester were added to the dry reaction bottle in sequence. 522mg, 2.16mmol), Pd(OAc) 2 (23mg, 0.10mmol), Xantphos (117mg, 0.20mmol) and Cs 2 CO 3 (1.16g, 3.56mmol), add 1,4-dioxane under the protection of nitrogen (25mL). The reaction was carried out at 80°C for 2h. Stop the reaction. Water (30 mL) and EA (50 mL) were added, liquid extraction was performed, the organic phase was collected, dried over anhydrous sodium sulfate, and spin-dried. The residue was purified by silica gel column chromatography (PE/EA(V/V)=1/1) The title compound was obtained as a light red solid (560mg, 78.21%). MS (ESI, pos.ion) m/z: 308.1 [M+H-56] + .
步骤2：F6-2的合成:Step 2: Synthesis of F6-2:
于干燥反应瓶中依次加入F6-1(560mg,1.54mmol)和DCM(20mL)，冰浴下分批加入甲氧甲酰基亚甲基三苯基膦(566mg,1.69mmol)，加毕，移至室温下反应12h。旋干反应液，所得残留物经硅胶柱层析分离纯化(PE/EA(V/V)＝2/1)，得标题化合物为白色固体(450mg,69.63％)。MS(ESI,pos.ion)m/z:364.1[M+H-56]
+。
F6-1 (560mg, 1.54mmol) and DCM (20mL) were added to the dry reaction bottle in sequence, and methoxyformylmethylenetriphenylphosphine (566mg, 1.69mmol) was added in portions under ice bath. Reaction to room temperature for 12h. The reaction solution was spin-dried, and the resulting residue was separated and purified by silica gel column chromatography (PE/EA (V/V) = 2/1) to obtain the title compound as a white solid (450 mg, 69.63%). MS (ESI, pos.ion) m/z: 364.1 [M+H-56] + .
步骤3：F6-3的合成Step 3: Synthesis of F6-3
于干燥反应瓶中依次加入F6-2(450mg,1.07mmol)、THF(25mL)、MeOH(10mL)和Pd/C(135mg)，氢气氛围下反应12h。硅藻土过滤，直接旋干得标题化合物为白色固体(440mg,97.29％)。MS(ESI,pos.ion)m/z:366.3[M+H-56]
+。
F6-2 (450 mg, 1.07 mmol), THF (25 mL), MeOH (10 mL), and Pd/C (135 mg) were added to the dry reaction bottle in sequence, and the reaction was performed under a hydrogen atmosphere for 12 h. Filter through diatomaceous earth and spin-dry to give the title compound as a white solid (440 mg, 97.29%). MS (ESI, pos.ion) m/z: 366.3 [M+H-56] + .
步骤4：F6-4的合成Step 4: Synthesis of F6-4
将F6-3(440mg,1.04mmol)溶于THF(8mL)中后，然后加入水合氢氧化锂(200mg, 8.33mmol)的H
2O(8mL)溶液，室温下搅拌1h。反应完后，用1M稀盐酸调节PH至5-6，EA萃取(2×30mL)后，收集有机相，无水硫酸钠干燥后，旋干得到标题化合物为白色固体(425mg,99.93％)。MS(ESI,pos.ion)m/z：352.1[M+H-56]
+。
After dissolving F6-3 (440 mg, 1.04 mmol) in THF (8 mL), a solution of lithium hydroxide hydrate (200 mg, 8.33 mmol) in H 2 O (8 mL) was added and stirred at room temperature for 1 h. After the reaction was completed, the pH was adjusted to 5-6 with 1 M dilute hydrochloric acid, and after extraction with EA (2×30 mL), the organic phase was collected, dried over anhydrous sodium sulfate, and spin-dried to give the title compound as a white solid (425 mg, 99.93%). MS (ESI, pos.ion) m/z: 352.1 [M+H-56] + .
步骤5：F6的合成Step 5: Synthesis of F6
将F-4(425mg,1.04mmol)溶于DCM(8mL)中，然后加入TFA(4mL)，室温下搅拌1h。旋干，得到标题化合物为黄色油状物(437mg,99.82％)。MS(ESI,pos.ion)m/z：308.1M+H]
+。
F-4 (425 mg, 1.04 mmol) was dissolved in DCM (8 mL), then TFA (4 mL) was added, and stirred at room temperature for 1 h. Spin dry to give the title compound as a yellow oil (437 mg, 99.82%). MS (ESI, pos.ion) m/z: 308.1M+H] + .
片段F7的合成Synthesis of Fragment F7
步骤1：F7-2的合成Step 1: Synthesis of F7-2
于干燥反应瓶中依次加入(R)-3-氧代六氢咪唑并[1,5-a]吡嗪-7(1H)-羧酸叔丁酯(300mg,1.24mmol)、F7-1(354mg,1.36mmol)、醋酸钯(15mg,0.06mmol)、tBuXPHOS(56mg,0.12mmol)、碳酸铯(608mg,1.87mmol)和1,4-二氧六环(10mL)，氮气保护下，加热至100℃下反应12h。旋干，所得残留物经硅胶柱层析分离纯化(PE/EA(V/V)＝2/1)，得标题化合物为白色固体(320mg,62％)。MS(ESI,pos.ion)m/z:366.2[M+H-56]
+。
(R)-3-oxohexahydroimidazo[1,5-a]pyrazine-7(1H)-carboxylic acid tert-butyl ester (300mg, 1.24mmol), F7-1( 354mg, 1.36mmol), palladium acetate (15mg, 0.06mmol), tBuXPHOS (56mg, 0.12mmol), cesium carbonate (608mg, 1.87mmol) and 1,4-dioxane (10mL), under nitrogen protection, heated to Reaction at 100°C for 12h. Spin dry, and the resulting residue was separated and purified by silica gel column chromatography (PE/EA (V/V) = 2/1) to give the title compound as a white solid (320 mg, 62%). MS (ESI, pos.ion) m/z: 366.2 [M+H-56] + .
步骤2：F7-3的合成Step 2: Synthesis of F7-3
将F7-2(300mg,0.71mmol)溶于甲醇(10mL)中，向其中加入一水合氢氧化锂(57mg,1.42mmol)的水(1mL)溶液，50℃下搅拌2h，旋干，向其中加入水(10mL)和DCM(20mL)溶剂残留物，再用1M盐酸将其pH调至4，有机层减压蒸除溶剂，得白色固体(280mg,97％)。MS(ESI,pos.ion)m/z:430.2[M+Na]
+。
F7-2 (300mg, 0.71mmol) was dissolved in methanol (10mL), to which was added a solution of lithium hydroxide monohydrate (57mg, 1.42mmol) in water (1mL), stirred at 50°C for 2h, vortexed, into which Water (10 mL) and DCM (20 mL) solvent residues were added, and then the pH was adjusted to 4 with 1M hydrochloric acid, and the solvent was distilled off under reduced pressure in the organic layer to obtain a white solid (280 mg, 97%). MS (ESI, pos.ion) m/z: 430.2 [M+Na] + .
步骤3：F7的合成Step 3: Synthesis of F7
将F7-3(200mg,0.49mmol)溶于DCM(5mL)中，向其中加入三氟乙酸(5mL)，室温下搅拌1h。直接旋干，得标题化合物为棕色固体(200mg,97％)。MS(ESI,pos.ion)m/z:308.1[M+H]
+；
F7-3 (200 mg, 0.49 mmol) was dissolved in DCM (5 mL), trifluoroacetic acid (5 mL) was added thereto, and stirred at room temperature for 1 h. Spin dry directly to give the title compound as a brown solid (200mg, 97%). MS(ESI,pos.ion)m/z:308.1[M+H] + ;
片段F8的合成：Synthesis of fragment F8:
步骤1：F8-1的合成Step 1: Synthesis of F8-1
将F8-0(500mg,1.22mmol)溶于甲醇(10mL)中，向其中加入一水合氢氧化锂(250mg,6.10mmol)的水(5mL)溶液，50℃下反应12h。浓缩除去甲醇，降温至0℃，用1M盐酸将溶液pH调至2，过滤，滤饼干燥得标题化合物为棕色固体(480mg,99％)。F8-0 (500 mg, 1.22 mmol) was dissolved in methanol (10 mL), to which was added a solution of lithium hydroxide monohydrate (250 mg, 6.10 mmol) in water (5 mL), and the reaction was carried out at 50° C. for 12 h. Concentrate to remove methanol, cool to 0°C, adjust the pH of the solution to 2 with 1M hydrochloric acid, filter, and dry the filter cake to obtain the title compound as a brown solid (480 mg, 99%).
步骤2：F8的合成Step 2: Synthesis of F8
于干燥反应瓶中依次加入F8-1(480mg,1.2mmol)、DCM(2mL)和TFA(2mL)，25℃下搅拌12h，减压浓缩溶剂，得标题化合物为白色固体(485mg,99％)。F8-1 (480mg, 1.2mmol), DCM (2mL) and TFA (2mL) were added to the dry reaction bottle in turn, stirred at 25°C for 12h, and the solvent was concentrated under reduced pressure to obtain the title compound as a white solid (485mg, 99%) .
片段F9的合成：Synthesis of fragment F9:
将F9-0替换F1合成方法中的F1-0，其余操作按F1的合成方法进行，得F9为白色固体。MS(ESI,pos.ion)m/z:276.10[M+H]
+。
Replace F9-0 with F1-0 in the synthesis method of F1. The rest of the operations are carried out according to the synthesis method of F1. F9 is obtained as white solid. MS(ESI,pos.ion)m/z:276.10[M+H] + .
实施例1的合成Synthesis of Example 1
步骤1：化合物1-1的合成Step 1: Synthesis of compound 1-1
于反应瓶中加入化合物1-0(25g,55.3mmol)、THF(400mL)、(Boc)
2O(25mL,110mmol)和DMAP(6.75g,55.3mmol)，混合物于室温搅拌12h，减压蒸除溶剂，向残余物中加入EA(500mL)稀释，有机层依次用5％盐酸水溶液(200mL×2)和饱和食盐水(200mL×2)洗涤，无水硫酸钠干燥。过滤，滤液减压蒸除溶剂，残留物经硅胶柱层析(PE/EtOAc(V/V)＝3/1)分离纯化，得标题化合物为黄色固体(19g,62.2％)。
Compound 1-0 (25g, 55.3mmol), THF (400mL), (Boc) 2 O (25mL, 110mmol) and DMAP (6.75g, 55.3mmol) were added to the reaction flask, the mixture was stirred at room temperature for 12h, and evaporated under reduced pressure The solvent was removed, and EA (500 mL) was added to the residue for dilution. The organic layer was washed successively with 5% aqueous hydrochloric acid (200 mL×2) and saturated brine (200 mL×2), and dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (PE/EtOAc (V/V) = 3/1) to obtain the title compound as a yellow solid (19 g, 62.2%).
MS(ESI,pos.ion)m/z：552.1[M+H]
+。
MS (ESI, pos.ion) m/z: 552.1 [M+H] + .
步骤2：化合物1-2的合成Step 2: Synthesis of compound 1-2
向反应瓶中依次加入化合物1-1(15.0g,27.2mmol)、甲醇(400mL)、氢氧化钠(21.7g,543.5mmol)的水(75mL)溶液，25℃搅拌2h。减压蒸除甲醇，向残余物中加入乙酸乙酯(300mL)和水(75mL)稀释，加浓盐酸调pH至5左右，饱和食盐水(100mL)洗涤有机相，合并有机相，合并的有机相用无水硫酸钠干燥，过滤，浓缩滤液得标题化合物为黄色油状物，直接投下一步反应。To the reaction flask were sequentially added a solution of compound 1-1 (15.0 g, 27.2 mmol), methanol (400 mL), and sodium hydroxide (21.7 g, 543.5 mmol) in water (75 mL), and stirred at 25° C. for 2 h. Methanol was distilled off under reduced pressure, and ethyl acetate (300 mL) and water (75 mL) were added to the residue for dilution. The pH was adjusted to about 5 with concentrated hydrochloric acid. The organic phase was washed with saturated brine (100 mL), the organic phases were combined, and the combined organic The phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound as a yellow oil, which was directly poured into the next reaction.
MS(ESI,pos.ion)m/z：452.1[M+H]
+。
MS (ESI, pos.ion) m/z: 452.1 [M+H] + .
步骤3：化合物1-3的合成Step 3: Synthesis of compounds 1-3
往上述步骤2得到的黄色油状物中加入氯化氢的1,4-二氧六环溶液(4mol/L,40mL)，混合物于室温搅拌反应16h，浓缩溶剂，向残余物中加入水(100mL)和乙酸乙酯(200mL)稀释，萃取分层，有机层饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，所得残留物经硅胶柱层析(PE/EtOAc(V/V)＝1/1)纯化，得标题化合物为黄色固体(6.4g,67％)。MS(ESI,pos.ion)m/z：352.1[M+H]
+。
To the yellow oil obtained in the above step 2 was added a solution of hydrogen chloride in 1,4-dioxane (4mol/L, 40mL), the mixture was stirred at room temperature for 16h, the solvent was concentrated, and water (100mL) was added to the residue. Dilute with ethyl acetate (200 mL), extract the layers, wash the organic layer with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. The resulting residue was subjected to silica gel column chromatography (PE/EtOAc (V/V) = 1/1) purification to give the title compound as a yellow solid (6.4g, 67%). MS (ESI, pos.ion) m/z: 352.1 [M+H] + .
步骤4：化合物1-4的合成Step 4: Synthesis of Compounds 1-4
于干燥反应瓶中加入化合物1-3(5.7g,16mmol)、二氯甲烷(400mL)、DCC(4.0g,19mmol)、氘代甲醇(1.2mL,24mmol)、DMAP(2.0g,16mmol)，室温搅拌4h。加入水(100mL)，室温搅拌30min，过滤，滤液用饱和食盐水(100mL×2)洗涤，浓缩有机相，所得残留物经硅胶柱层析(PE/EtOAc(V/V)＝4/1)分离纯化，得标题化合物为黄色固体(3.9g,65％)。In a dry reaction flask, compound 1-3 (5.7g, 16mmol), dichloromethane (400mL), DCC (4.0g, 19mmol), deuterated methanol (1.2mL, 24mmol), DMAP (2.0g, 16mmol), Stir at room temperature for 4h. Water (100 mL) was added, stirred at room temperature for 30 min, filtered, the filtrate was washed with saturated brine (100 mL×2), the organic phase was concentrated, and the resulting residue was subjected to silica gel column chromatography (PE/EtOAc (V/V) = 4/1) Isolation and purification gave the title compound as a yellow solid (3.9g, 65%).
MS(ESI,pos.ion)m/z：369.1[M+H]
+。
MS (ESI, pos.ion) m/z: 369.1 [M+H] + .
步骤5：化合物1-5的合成Step 5: Synthesis of compounds 1-5
于反应瓶中加入化合物1-4(3.5g,9.49mmol)和二氯甲烷(70mL)。氮气保护下，混合物升温至38℃，然后加入NBS(1.81g,9.97mmol)，再保温搅拌20min，停止反应，浓缩溶剂，所得残留物直接投入下一步反应。MS(ESI,pos.ion)m/z：447.1[M+H]。Compound 1-4 (3.5 g, 9.49 mmol) and dichloromethane (70 mL) were added to the reaction flask. Under nitrogen protection, the mixture was heated to 38°C, and then NBS (1.81 g, 9.97 mmol) was added, and the mixture was kept under stirring for 20 min to stop the reaction, the solvent was concentrated, and the resulting residue was directly put into the next reaction. MS (ESI, pos.ion) m/z: 447.1 [M+H].
步骤6：化合物1的合成Step 6: Synthesis of Compound 1
于反应瓶中加入化合物F1(3.6g,8.9mmol)、化合物1-5(4.4g,8.9mmol)、碳酸钾(2.5g,18mmol)、乙醇(88mL)。反应混合物于40℃搅拌反应3h。抽滤，滤饼用乙醇(20mL)洗涤。滤液减压浓缩，残余物加入水(80mL)和入乙酸乙酯(200mL)稀释，然后用浓盐酸调pH至5-6，有机相饱和食盐水(50mL×3)洗涤，浓缩，所得残留物经硅胶柱层析(DCM/CH
3OH(V/V)＝25/1)分离纯化，得标题化合物为浅黄色固体(3.66g,63％)。MS(ESI,pos.ion)m/z：656.1[M+H]；
1H NMR(400MHz,CDCl
3)δ(ppm)9.65(s,1H),8.04(s,1H),7.87(d,J＝3.1Hz,1H),7.51–7.45(m,3H),7.33–7.28(m,1H),7.20(d,J＝8.5Hz,2H),7.15(dd,J＝8.6,2.4Hz,1H),6.94(td,J＝8.3,2.5Hz,1H),6.22(s,1H),4.15–4.05(m,2H),4.03–3.96(m,1H),3.94–3.86(m,2H),3.42(dd,J＝9.0,4.6Hz,1H),3.29–3.23(m,1H),2.98–2.86(m,4H),2.66(t,J＝7.7Hz,2H),2.55–2.46(m,1H),2.27(t,J＝10.7Hz,1H)。
In the reaction flask, compound F1 (3.6 g, 8.9 mmol), compound 1-5 (4.4 g, 8.9 mmol), potassium carbonate (2.5 g, 18 mmol), and ethanol (88 mL) were added. The reaction mixture was stirred at 40°C for 3h. Filter with suction and wash the filter cake with ethanol (20 mL). The filtrate was concentrated under reduced pressure. The residue was diluted with water (80 mL) and ethyl acetate (200 mL), and then adjusted to pH 5-6 with concentrated hydrochloric acid. The organic phase was washed with saturated brine (50 mL×3) and concentrated. The resulting residue It was separated and purified by silica gel column chromatography (DCM/CH 3 OH (V/V)=25/1) to obtain the title compound as a pale yellow solid (3.66 g, 63%). MS (ESI, pos.ion) m/z: 656.1 [M+H]; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 9.65 (s, 1H), 8.04 (s, 1H), 7.87 (d, J = 3.1 Hz, 1H), 7.51-7.45 (m, 3H), 7.33-7.28 (m, 1H), 7.20 (d, J = 8.5 Hz, 2H), 7.15 (dd, J = 8.6, 2.4 Hz, 1H ), 6.94 (td, J=8.3, 2.5 Hz, 1H), 6.22 (s, 1H), 4.15–4.05 (m, 2H), 4.03–3.96 (m, 1H), 3.94–3.86 (m, 2H), 3.42 (dd, J = 9.0, 4.6 Hz, 1H), 3.29-3.23 (m, 1H), 2.98-2.86 (m, 4H), 2.66 (t, J = 7.7 Hz, 2H), 2.55-2.46 (m, 1H), 2.27 (t, J = 10.7 Hz, 1H).
实施例2的合成Synthesis of Example 2
于反应瓶中加入化合物F2(0.42g,1mmol)、化合物1-5(0.45g,1mmol)、碳酸钾(0.28g,2mmol)和乙醇(20mL)。反应混合物于40℃搅拌反应3h。抽滤，滤饼用乙醇(10mL)洗涤。滤液减压浓缩，残余物加入水(20mL)，和乙酸乙酯(60mL)稀释，再用浓盐酸调pH至5-6，分离的有机相用饱和食盐水(50mL×3)洗涤，浓缩，所得残留物经硅胶柱层析(DCM/CH
3OH(V/V)＝25/1)纯化，得标题化合物为浅黄色固体(0.41g,61％)。MS(ESI,pos.ion)m/z：670.3[M+H]
+；
1H NMR(400MHz,CDCl
3)δ(ppm)9.66(s,1H),7.87(s,1H),7.56–7.46(m,3H),7.38(d,J＝7.1Hz,2H),7.33–7.27(m,1H),7.15(d,J＝7.3Hz,1H),6.94(s,1H),6.23(s,1H),4.16–3.98(m,3H),3.96–3.84(m,2H),3.43(s,1H),3.25(t,J＝10.9Hz,1H),2.88(d,J＝6.9Hz,2H),2.50(t,J＝10.0Hz,1H),2.25(t,J＝9.0Hz,1H),1.59(s,6H)。
In the reaction flask, compound F2 (0.42 g, 1 mmol), compound 1-5 (0.45 g, 1 mmol), potassium carbonate (0.28 g, 2 mmol) and ethanol (20 mL) were added. The reaction mixture was stirred at 40°C for 3h. Filter with suction and wash the filter cake with ethanol (10 mL). The filtrate was concentrated under reduced pressure, and the residue was diluted with water (20 mL) and diluted with ethyl acetate (60 mL), and then adjusted to pH 5-6 with concentrated hydrochloric acid. The separated organic phase was washed with saturated brine (50 mL×3) and concentrated. The obtained residue was purified by silica gel column chromatography (DCM/CH 3 OH (V/V)=25/1) to obtain the title compound as a pale yellow solid (0.41 g, 61%). MS (ESI, pos.ion) m/z: 670.3 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 9.66 (s, 1H), 7.87 (s, 1H), 7.56–7.46 (m, 3H), 7.38 (d, J = 7.1 Hz, 2H), 7.33-7.27 (m, 1H), 7.15 (d, J = 7.3 Hz, 1H), 6.94 (s, 1H), 6.23 (s, 1H), 4.16–3.98 (m, 3H), 3.96–3.84 (m, 2H), 3.43 (s, 1H), 3.25 (t, J = 10.9Hz, 1H), 2.88 (d, J = 6.9Hz, 2H ), 2.50 (t, J = 10.0 Hz, 1H), 2.25 (t, J = 9.0 Hz, 1H), 1.59 (s, 6H).
实施例3的合成Synthesis of Example 3
将化合物F3替换实施例2中的化合物F2，其余操作按实施例2方法操作，得标题化合物为黄色固体(0.33g,49％)。MS(ESI,pos.ion)m/z：676.3[M+H]
+；
1H NMR(400MHz,CDCl
3)δ(ppm)9.65(s,1H),7.87(d,J＝3.0Hz,1H),7.50(dd,J＝14.5,5.9Hz,3H),7.38(d,J＝8.7Hz,2H),7.33–7.29(m,1H),7.15(dd,J＝8.5,2.4Hz,1H),6.94(td,J＝8.4,2.4Hz,1H),6.23(s,1H),4.12–3.96(m,3H),3.95–3.85(m,2H),3.42(dd,J＝8.9,4.5Hz,1H),3.26(t,J＝11.2Hz,1H),2.88(d,J＝10.4Hz,2H),2.50(td,J＝11.0,2.3Hz,1H),2.25(t,J＝10.6Hz,1H)。
The compound F3 was substituted for the compound F2 in Example 2, and the rest of the operations were performed as in Example 2. The title compound was obtained as a yellow solid (0.33 g, 49%). MS (ESI, pos.ion) m/z: 676.3 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 9.65 (s, 1H), 7.87 (d, J=3.0 Hz, 1H ), 7.50 (dd, J = 14.5, 5.9 Hz, 3H), 7.38 (d, J = 8.7 Hz, 2H), 7.33-7.29 (m, 1H), 7.15 (dd, J = 8.5, 2.4 Hz, 1H) , 6.94 (td, J=8.4, 2.4Hz, 1H), 6.23 (s, 1H), 4.12–3.96 (m, 3H), 3.95–3.85 (m, 2H), 3.42 (dd, J=8.9, 4.5Hz , 1H), 3.26 (t, J = 11.2 Hz, 1H), 2.88 (d, J = 10.4 Hz, 2H), 2.50 (td, J = 11.0, 2.3 Hz, 1H), 2.25 (t, J = 10.6 Hz ,1H).
实施例4的合成Synthesis of Example 4
将化合物F4替换实施例1的化合物F1，其余操作按实施例1方法操作，得标题化合物为黄色固体(41mg,43.1％)。MS(ESI,pos.ion)m/z：646.0[M+H]
+；
1H NMR(400MHz,CDCl
3)δ(ppm)9.64(s,1H),7.86(s,4H),7.48(s,1H),7.34–7.24(m,1H),7.23–7.11(m,1H),7.05–6.85(m,1H),6.22(s,1H),4.25–3.88(m,5H),3.65(s,1H),3.42–3.24(m,1H),2.94(s,2H),2.55(s,1H),2.36(s,1H)。
The compound F4 was replaced with the compound F1 of Example 1, and the rest of the operations were performed as in Example 1. The title compound was obtained as a yellow solid (41 mg, 43.1%). MS (ESI, pos.ion) m/z: 646.0 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 9.64 (s, 1H), 7.86 (s, 4H), 7.48 (s ,1H),7.34–7.24(m,1H),7.23–7.11(m,1H),7.05–6.85(m,1H),6.22(s,1H),4.25–3.88(m,5H),3.65(s , 1H), 3.42–3.24 (m, 1H), 2.94 (s, 2H), 2.55 (s, 1H), 2.36 (s, 1H).
实施例5的合成Synthesis of Example 5
将化合物F5替换实施例1的化合物F1，其余操作按实施例1方法操作，得标题化合物为黄色固体(41mg,43.1％)。MS(ESI,pos.ion)m/z：646.0[M+H]
+；
1H NMR(400MHz,CDCl
3)δ(ppm)9.59(s,1H),8.04–7.93(m,1H),7.87(s,1H),7.55(d,J＝13.0Hz,1H),7.48(s,1H),7.34–7.28(m,2H),7.16(d,J＝7.3Hz,1H),6.94(t,J＝7.5Hz,1H),6.23(s,1H),4.20–4.04(m,3H),3.98–3.89(m,2H),3.45(s,1H),3.29(t,J＝12.4Hz,1H),2.95(s,2H),2.59–2.47(m,1H),2.28(t,J＝10.6Hz,1H)。
The compound F5 was replaced with the compound F1 of Example 1, and the rest of the operations were performed as in Example 1. The title compound was obtained as a yellow solid (41 mg, 43.1%). MS (ESI, pos.ion) m/z: 646.0 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 9.59 (s, 1H), 8.04–7.93 (m, 1H), 7.87 (s, 1H), 7.55 (d, J = 13.0 Hz, 1H), 7.48 (s, 1H), 7.34–7.28 (m, 2H), 7.16 (d, J = 7.3 Hz, 1H), 6.94 (t, J = 7.5Hz, 1H), 6.23 (s, 1H), 4.20-4.04 (m, 3H), 3.98-3.89 (m, 2H), 3.45 (s, 1H), 3.29 (t, J = 12.4Hz, 1H) ), 2.95 (s, 2H), 2.59–2.47 (m, 1H), 2.28 (t, J = 10.6 Hz, 1H).
实施例6的合成Synthesis of Example 6
将片段F6替换实施例1步骤6的F1，其余操作按实施例1步骤6方法操作，得标题化合物为黄色固体(251mg,83.35％)。MS(ESI,pos.ion)m/z：674.4[M+H]
+；
1H NMR(400MHz,CDCl
3)δ9.67(s,1H),7.88(s,1H),7.49(s,1H),7.45–7.38(m,1H),7.35–7.25(m,1H),7.20–7.10(m,1H),7.06–6.89(m,3H),6.22(s,1H),4.28–3.82(m,5H),3.48(s,1H),3.38–3.16(m,1H),3.10–2.75(m,4H),2.65(s,2H),2.59–2.47(m,1H),2.44–2.30(m,1H).
The fragment F6 was replaced with F1 in Step 6 of Example 1, and the rest of the operations were carried out according to the method in Step 6 of Example 1, to obtain the title compound as a yellow solid (251 mg, 83.35%). MS (ESI, pos.ion) m/z: 674.4 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 9.67 (s, 1H), 7.88 (s, 1H), 7.49 (s, 1H ), 7.45–7.38(m, 1H), 7.35–7.25(m, 1H), 7.20–7.10(m, 1H), 7.06–6.89(m, 3H), 6.22(s, 1H), 4.28–3.82(m , 5H), 3.48(s, 1H), 3.38–3.16(m, 1H), 3.10–2.75(m, 4H), 2.65(s, 2H), 2.59–2.47(m, 1H), 2.44–2.30(m ,1H).
实施例7的合成Synthesis of Example 7
将片段F7替换实施例1步骤6的F1，其余操作按实施例1步骤6方法操作，得标题化合物为黄色固体(227mg,75.38％)。MS(ESI,pos.ion)m/z：674.4[M+H]
+；
1H NMR(400MHz,CDCl
3)δ9.63(s,1H),7.87(s,1H),7.54–7.38(m,2H),7.29(d,J＝6.0Hz,1H),7.15(s,3H),6.94(s,1H),6.22(s,1H),4.22–3.98(m,3H),3.90(d,J＝16.4Hz,2H),3.40(s,1H),3.27(t,J＝11.5Hz,1H),2.94(d,J＝6.7Hz,4H),2.66(s,2H),2.58–2.44(m,1H),2.35–2.18(m,1H)。
The fragment F7 was replaced with F1 in Step 6 of Example 1, and the rest of the operations were performed according to the method in Step 6 of Example 1, to obtain the title compound as a yellow solid (227 mg, 75.38%). MS (ESI, pos.ion) m/z: 674.4 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 9.63 (s, 1H), 7.87 (s, 1H), 7.54–7.38 (m , 2H), 7.29 (d, J = 6.0 Hz, 1H), 7.15 (s, 3H), 6.94 (s, 1H), 6.22 (s, 1H), 4.22–3.98 (m, 3H), 3.90 (d, J = 16.4 Hz, 2H), 3.40 (s, 1H), 3.27 (t, J = 11.5 Hz, 1H), 2.94 (d, J = 6.7 Hz, 4H), 2.66 (s, 2H), 2.58-2.44 ( m,1H), 2.35–2.18 (m,1H).
实施例8的合成：Synthesis of Example 8:
将片段F8替换实施例1步骤6的F1，其余操作按实施例1步骤6方法操作，得标题化合物为黄色固体(180mg,61％)。MS(ESI,pos.ion)m/z：661.1[M+H]
+；
1H NMR(400MHz,CDCl
3)δ9.60(s,1H),7.88(d,J＝3.1Hz,1H),7.58(d,J＝15.3Hz,1H),7.50(d,J＝3.1Hz,1H),7.33–7.29(m,1H),7.16(dd,J＝8.6,2.5Hz,1H),7.13(s,1H),6.95(td,J＝8.4,2.5Hz,1H),6.63(d,J＝15.3Hz,1H),6.23(s,1H),4.30–4.22(m,1H),4.21–4.12(m,2H),4.09(dd,J＝13.4,1.9Hz,1H),3.97(d,J＝16.9Hz,1H),3.79(dd,J＝10.5,4.5Hz,1H),3.37(t,J＝11.3Hz,1H),3.10–2.88(m,2H),2.55(t,J＝9.7Hz,1H),2.38–2.30(m,1H)。
The fragment F8 was replaced with F1 in Step 6 of Example 1, and the rest of the operations were carried out according to the method in Step 6 of Example 1, to obtain the title compound as a yellow solid (180 mg, 61%). MS (ESI, pos.ion) m/z: 661.1 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 9.60 (s, 1H), 7.88 (d, J=3.1 Hz, 1H), 7.58 (d, J = 15.3 Hz, 1H), 7.50 (d, J = 3.1 Hz, 1H), 7.33-7.29 (m, 1H), 7.16 (dd, J = 8.6, 2.5 Hz, 1H), 7.13 (s , 1H), 6.95 (td, J = 8.4, 2.5 Hz, 1H), 6.63 (d, J = 15.3 Hz, 1H), 6.23 (s, 1H), 4.30–4.22 (m, 1H), 4.21–4.12 ( m, 2H), 4.09 (dd, J = 13.4, 1.9 Hz, 1H), 3.97 (d, J = 16.9 Hz, 1H), 3.79 (dd, J = 10.5, 4.5 Hz, 1H), 3.37 (t, J = 11.3 Hz, 1H), 3.10–2.88 (m, 2H), 2.55 (t, J=9.7 Hz, 1H), 2.38–2.30 (m, 1H).
实施例9的合成Synthesis of Example 9
将片段F9替换实施例1步骤6的F1，其余操作按实施例1步骤6方法操作，得标题化合物为黄色固体(220mg,76.70％)。MS(ESI,pos.ion)m/z：642.4[M+H]
+；
1H NMR(400MHz,CDCl
3)δ9.64(s,1H),7.87(d,J＝2.0Hz,1H),7.59–7.42(m,3H),7.35–7.21(m,3H),7.15(d,J＝7.2Hz,1H),6.93(t,J＝7.1Hz,1H),6.22(s,1H),4.21–3.95(m,3H),3.90(d,J＝13.2Hz,2H),3.60(s,2H),3.47–3.36(m,1H),3.25(t,J＝11.4Hz,1H),2.89(d,J＝9.4Hz,2H),2.50(t,J＝10.1Hz,1H),2.26(t,J＝10.4Hz,1H)。
The fragment F9 was replaced with F1 in Step 6 of Example 1, and the rest of the operations were carried out according to the method in Step 6 of Example 1, to obtain the title compound as a yellow solid (220 mg, 76.70%). MS (ESI, pos.ion) m/z: 642.4 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 9.64 (s, 1H), 7.87 (d, J=2.0 Hz, 1H), 7.59–7.42(m, 3H), 7.35–7.21(m, 3H), 7.15(d, J=7.2Hz, 1H), 6.93(t, J=7.1Hz, 1H), 6.22(s, 1H), 4.21 –3.95(m,3H),3.90(d,J=13.2Hz,2H),3.60(s,2H),3.47–3.36(m,1H),3.25(t,J=11.4Hz,1H),2.89( d, J = 9.4 Hz, 2H), 2.50 (t, J = 10.1 Hz, 1H), 2.26 (t, J = 10.4 Hz, 1H).
实施例10的合成Synthesis of Example 10
将片段F10(F10可根据WO2019001396中实施例27步骤1-3的合成方法得到)替换实施例1步骤6的F1，其余操作按实施例1步骤6方法操作，得标题化合物为黄色固体(170mg，50.95％)。MS(ESI,pos.ion)m/z:668.6[M+H]
+；
1H NMR(400MHz,CDCl
3)δ9.64(s,1H),7.87(d,J＝3.1Hz,1H),7.51(d,J＝8.7Hz,2H),7.48(d,J＝3.1Hz,1H),7.34(d,J＝8.7Hz,2H),7.30(d,J＝2.4Hz,1H),7.16(dd,J＝8.6,2.5Hz,1H),6.94(td,J＝8.4,2.4Hz,1H),6.22(s,1H),4.17–3.97(m,3H),3.95–3.87(m,2H),3.43(dd,J＝9.1,4.4Hz,1H),3.34–3.25(m,1H),2.88(s,2H),2.55–2.47(m,1H),2.29–2.22(m,1H),1.33–1.28(m,2H),0.95–0.87(m,2H)。
Fragment F10 (F10 can be obtained according to the synthesis method of Steps 1-3 of Example 27 in WO2019001396) replaces F1 of Step 1 of Example 1, and the rest of the operations are performed according to the method of Step 6 of Example 1, to obtain the title compound as a yellow solid (170 mg, 50.95%). MS (ESI, pos.ion) m/z: 668.6 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 9.64 (s, 1H), 7.87 (d, J=3.1 Hz, 1H), 7.51 (d, J = 8.7 Hz, 2H), 7.48 (d, J = 3.1 Hz, 1H), 7.34 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 2.4 Hz, 1H), 7.16 ( dd, J=8.6, 2.5 Hz, 1H), 6.94 (td, J=8.4, 2.4 Hz, 1H), 6.22 (s, 1H), 4.17–3.97 (m, 3H), 3.95–3.87 (m, 2H) , 3.43 (dd, J = 9.1, 4.4 Hz, 1H), 3.34–3.25 (m, 1H), 2.88 (s, 2H), 2.55–2.47 (m, 1H), 2.29–2.22 (m, 1H), 1.33 –1.28(m,2H),0.95–0.87(m,2H).
实施例11的合成Synthesis of Example 11
将片段F11(F11可根据WO2019076310中实施例19步骤1-5的合成方法得到)替换实施例1步骤6的F1，其余操作按实施例1步骤6方法操作，得标题化合物为黄色固体(180mg,56％)。MS(ESI,pos.ion)m/z:670.2[M+H]
+；
1H NMR(400MHz,CDCl
3)δ9.65(s,1H),7.87(d,J＝3.1Hz,1H),7.53–7.43(m,3H),7.34–7.29(m,1H),7.21(d,J＝8.5Hz,2H),7.15(dd,J＝8.5,2.4Hz,1H),6.94(td,J＝8.4,2.4Hz,1H),6.22(s,1H),4.15–4.10(m,1H),4.09–3.95(m,2H),3.95–3.85(m,2H),3.42(dd,J＝8.9,4.4Hz,1H),3.26(dd,J＝14.2,7.1Hz,2H),2.89(d,J＝8.7 Hz,2H),2.72–2.55(m,2H),2.55–2.44(m,1H),2.27(t,J＝10.2Hz,1H),1.31(d,J＝6.9Hz,3H)。
Fragment F11 (F11 can be obtained according to the synthesis method of Step 19 of Example 19 in WO2019076310) replaces F1 of Step 1 of Example 1, and the rest of the operations are performed according to the method of Step 6 of Example 1, to obtain the title compound as a yellow solid (180 mg, 56%). MS (ESI, pos.ion) m/z: 670.2 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 9.65 (s, 1H), 7.87 (d, J=3.1 Hz, 1H), 7.53–7.43 (m, 3H), 7.34–7.29 (m, 1H), 7.21 (d, J=8.5 Hz, 2H), 7.15 (dd, J=8.5, 2.4 Hz, 1H), 6.94 (td, J= 8.4, 2.4Hz, 1H), 6.22 (s, 1H), 4.15–4.10 (m, 1H), 4.09–3.95 (m, 2H), 3.95–3.85 (m, 2H), 3.42 (dd, J=8.9, 4.4Hz, 1H), 3.26 (dd, J=14.2, 7.1Hz, 2H), 2.89 (d, J=8.7 Hz, 2H), 2.72–2.55 (m, 2H), 2.55–2.44 (m, 1H), 2.27 (t, J = 10.2 Hz, 1H), 1.31 (d, J = 6.9 Hz, 3H).
实施例12的合成Synthesis of Example 12
将片段F12(F12可根据WO 2019076310中实施例18步骤1-5的合成方法得到)替换实施例1步骤6的F1，其余操作按实施例1步骤6方法操作，得标题化合物为黄色固体(180mg,49％)。MS(ESI,pos.ion)m/z:670.2[M+H]
+；
1H NMR(400MHz,CDCl
3)δ9.65(s,1H),7.87(d,J＝3.1Hz,1H),7.53–7.41(m,3H),7.33–7.29(m,1H),7.16(dd,J＝11.1,5.4Hz,3H),6.94(td,J＝8.4,2.4Hz,1H),6.23(s,1H),4.13(dd,J＝12.6,5.3Hz,1H),4.07(d,J＝14.1Hz,1H),4.00(s,1H),3.95–3.85(m,2H),3.43(dd,J＝8.6,4.3Hz,1H),3.26(t,J＝11.2Hz,1H),3.04(dd,J＝13.4,6.4Hz,1H),2.88(d,J＝10.1Hz,2H),2.75(dt,J＝13.4,6.8Hz,1H),2.66(dd,J＝13.4,7.8Hz,1H),2.51(t,J＝10.1Hz,1H),2.27(t,J＝10.7Hz,1H),1.19(d,J＝6.8Hz,3H)。
Fragment F12 (F12 can be obtained according to the synthesis method of Steps 1-5 of Example 18 in WO 2019076310) replaces F1 of Step 1 of Example 1, and the rest of the operations are carried out according to the method of Step 6 of Example 1, to obtain the title compound as a yellow solid (180 mg , 49%). MS (ESI, pos.ion) m/z: 670.2 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 9.65 (s, 1H), 7.87 (d, J=3.1 Hz, 1H), 7.53–7.41 (m, 3H), 7.33–7.29 (m, 1H), 7.16 (dd, J = 11.1, 5.4 Hz, 3H), 6.94 (td, J = 8.4, 2.4 Hz, 1H), 6.23 (s, 1H), 4.13 (dd, J = 12.6, 5.3 Hz, 1H), 4.07 (d, J = 14.1 Hz, 1H), 4.00 (s, 1H), 3.95–3.85 (m, 2H), 3.43 (dd, J = 8.6, 4.3 Hz, 1H), 3.26 (t, J = 11.2 Hz, 1H), 3.04 (dd, J = 13.4, 6.4 Hz, 1H), 2.88 (d, J = 10.1 Hz, 2H), 2.75 (dt , J = 13.4, 6.8 Hz, 1H), 2.66 (dd, J = 13.4, 7.8 Hz, 1H), 2.51 (t, J = 10.1 Hz, 1H), 2.27 (t, J = 10.7 Hz, 1H), 1.19 (d, J = 6.8 Hz, 3H).
实施例13的合成Synthesis of Example 13
将片段F13(F13可根据WO 2019076310中实施例20步骤1-5的合成方法得到)替换实施例1步骤6的F1，其余操作按实施例1步骤6方法操作，得标题化合物为黄色固体(160mg, 54％)。MS(ESI,pos.ion)m/z:663.1[M+H]
+；
1H NMR(400MHz,CDCl
3)δ9.54(s,1H),7.86(d,J＝3.1Hz,1H),7.49(d,J＝3.1Hz,1H),7.32–7.28(m,1H),7.16(dd,J＝8.6,2.5Hz,1H),6.94(td,J＝8.4,2.5Hz,1H),6.56(s,1H),6.22(s,1H),4.22–4.13(m,3H),4.08(dd,J＝13.8,2.1Hz,1H),3.95(d,J＝17.1Hz,1H),3.72(dd,J＝9.8,4.0Hz,1H),3.35(td,J＝13.0,3.0Hz,1H),3.06–2.89(m,4H),2.78–2.71(m,2H),2.53(td,J＝11.4,2.9Hz,1H),2.30(t,J＝10.5Hz,1H).
Fragment F13 (F13 can be obtained according to the synthesis method of Steps 1-5 of Example 20 in WO 2019076310) replaces F1 of Step 1 of Example 1, and the rest of the operations are carried out according to the method of Step 6 of Example 1, to obtain the title compound as a yellow solid (160 mg , 54%). MS (ESI, pos.ion) m/z: 663.1 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 9.54 (s, 1H), 7.86 (d, J=3.1 Hz, 1H), 7.49 (d, J = 3.1 Hz, 1H), 7.32-7.28 (m, 1H), 7.16 (dd, J = 8.6, 2.5 Hz, 1H), 6.94 (td, J = 8.4, 2.5 Hz, 1H), 6.56 (s,1H),6.22(s,1H),4.22-4.13(m,3H),4.08(dd,J=13.8,2.1Hz,1H),3.95(d,J=17.1Hz,1H),3.72( dd, J=9.8, 4.0 Hz, 1H), 3.35 (td, J=13.0, 3.0 Hz, 1H), 3.06–2.89 (m, 4H), 2.78–2.71 (m, 2H), 2.53 (td, J= 11.4, 2.9Hz, 1H), 2.30 (t, J=10.5Hz, 1H).
生物学测试Biological test
测试1：抗HBV EC
50测试方法
Test 1: Anti-HBV EC 50 test method
HBV细胞系和培养条件HBV cell line and culture conditions
HepG2.2.15细胞(SELLS,PNAS,1987和SELLS,JV,1988)的染色体整合有完整的HBV基因组，并稳定表达病毒RNA和病毒蛋白质。HepG2.2.15细胞能够向培养基中分泌成熟的乙肝病毒颗粒，HBsAg和HBeAg。HepG2.2.15培养于含有10％胎牛血清、100U/mL青霉素、100U/mL链霉素、1％非必需氨基酸、1mM丙酮酸钠300μg/mL G418的DMEM培养基。The chromosome of HepG2.2.15 cells (SELLS, PNAS, 1987 and SELLS, JV, 1988) integrates the complete HBV genome and stably expresses viral RNA and viral proteins. HepG2.2.15 cells can secrete mature HBV particles, HBsAg and HBeAg into the culture medium. HepG2.2.15 was cultured in DMEM medium containing 10% fetal bovine serum, 100 U/mL penicillin, 100 U/mL streptomycin, 1% non-essential amino acids, and 1 mM sodium pyruvate 300 μg/mL G418.
HepG2.2.15细胞分泌的病毒粒子DNA可以通过qPCR的方法来定量，并由此检测化合物对病毒复制的影响。Virion DNA secreted by HepG2.2.15 cells can be quantified by qPCR, and the effect of compounds on virus replication can be detected from this.
体外抗HBV活性测定Determination of anti-HBV activity in vitro
HepG 2.2.15细胞8,000个每孔接种到96孔细胞培养板，37℃，5％CO
2培养3天至细胞长至满孔。在测试第0天，弃掉旧的培养基并加入200μL新鲜的检测培养基(5％FBS)。
8,000 HepG 2.2.15 cells were seeded into 96-well cell culture plates per well, and cultured at 37°C, 5% CO 2 for 3 days until the cells grew to full wells. On day 0 of the test, the old medium was discarded and 200 μL of fresh detection medium (5% FBS) was added.
抗病毒实验中化合物配制和细胞处理：用DMSO溶解化合物至30mM，进一步用DMSO稀释化合物到800μM，然后进行8个稀释度的4倍稀释，最高浓度为800μM。加系列稀释的化合物1μL每孔到上述细胞板中，实验最高终浓度为4μM(200倍稀释)。TDF(富马酸替诺福韦二吡呋酯,Selleck,Cat S1400)作为阳性对照化合物，最高浓度为4μM。阴性对照孔加入1μL DMSO，终浓度为0.5％,阳性对照孔加入TDF，终浓度为1μM。Compound preparation and cell treatment in antiviral experiments: Dissolve the compound with DMSO to 30 mM, further dilute the compound with DMSO to 800 μM, and then perform 4 dilutions of 8 dilutions, with a maximum concentration of 800 μM. Add 1 μL of serially diluted compound to each of the above cell plates. The maximum final concentration of the experiment is 4 μM (200-fold dilution). TDF (tenofovir disoproxil fumarate, Selleck, Cat S1400) was used as a positive control compound with a maximum concentration of 4 μM. Add 1 μL of DMSO to the negative control wells at a final concentration of 0.5%, and add TDF to the positive control wells at a final concentration of 1 μM.
qPCR方法检测病毒基因组DNAqPCR detection of viral genomic DNA
引物：HBV-For-202，CAGGCGGGGTTTTTCTTGTTGA；HBV-Rev-315，GTGATTGGAGGTTGGGGACTGC。使用SYBR Premix Ex Taq II–Takara DRR081S试剂盒，以1μL细胞培养上清作为模板，用包含HBV基因组的质粒做标准曲线，并以标准曲线来计算病毒拷贝数。用Graphpad Prism 5软件处理浓度-病毒拷贝数，通过四参数非线性回归模型计算化合物对病毒复制的EC
50。实验结果见表2。
Primers: HBV-For-202, CAGGCGGGGTTTTTCTTGTTGA; HBV-Rev-315, GTGATTGGAGGTTGGGGACTGC. Using the SYBR Premix Ex Taq II–Takara DRR081S kit, using 1 μL of cell culture supernatant as a template, a plasmid containing the HBV genome was used as a standard curve, and the standard curve was used to calculate the virus copy number. Treatment concentration with Graphpad Prism 5 software - number of viral copies, by a four-parameter non-linear regression model to calculate the compound of viral replication EC 50. The experimental results are shown in Table 2.
表2：本发明化合物对HBV复制的EC
50值
Table 2: EC 50 values of compounds of the present invention for HBV replication
| 实施例Examples | EC 50(nM) EC 50 (nM) |
| 11 | 44 |
| 22 | 77 |
| 33 | 66 |
| 44 | 1818 |
| 55 | 21twenty one |
| 66 | 99 |
| 77 | 33 |
| 88 | 77 |
| 99 | 33 |
| 1010 | 66 |
| 1111 | 33 |
| 1212 | 55 |
| 1313 | 1111 |
结论：实验数据表明，本发明化合物对HBV具有较好的抑制活性，在抗HBV方面有很好的应用前景。Conclusion: The experimental data shows that the compound of the present invention has a good inhibitory activity against HBV and has a good application prospect in anti-HBV.
测试2：细胞毒性和选择性指数Test 2: Cytotoxicity and selectivity index
测试化合物细胞毒性和选择性指数实验方法：Experimental methods for testing compound cytotoxicity and selectivity index:
加系列稀释的化合物到384孔细胞毒性细胞板中，每孔加入50μL HepG2.2.15细胞(3000个细胞/孔)，实验最高终浓度为150μM(200倍稀释)。37℃，CO
2培养箱中孵育4天后用CellTiter Glo试剂检测化合物的细胞毒性作用。
Add serially diluted compounds to the 384-well cytotoxic cell plate, add 50 μL of HepG2.2.15 cells (3000 cells/well) to each well, and the maximum final concentration of the experiment is 150 μM (200-fold dilution). After incubating in a CO 2 incubator at 37°C for 4 days, CellTiter Glo reagent was used to detect the cytotoxic effect of the compound.
化合物细胞毒性用以下公式计算：细胞毒性(％)＝100-(检测值/DMSO对照孔平均值×100)。用Graphpad Prism 5软件处理浓度-细胞毒性(％)数据，通过四参数非线性回归模型计算CC
50。CC
50大于50说明毒性比较低，本发明化合物的实验结果见表3。
The cytotoxicity of the compound is calculated by the following formula: cytotoxicity (%)=100-(detection value/average value of DMSO control well×100). The concentration-cytotoxicity (%) data was processed with Graphpad Prism 5 software, and CC 50 was calculated by a four-parameter nonlinear regression model. A CC 50 greater than 50 indicates that the toxicity is relatively low. The experimental results of the compound of the present invention are shown in Table 3.
表3：本发明化合物细胞毒的CC
50值
Table 3: CC 50 values of cytotoxicity of the compounds of the invention
| 实施例Examples | CC 50(μM) CC 50 (μM) |
| 11 | >150>150 |
| 22 | >150>150 |
| 33 | >150>150 |
| 44 | >150>150 |
| 55 | >150>150 |
结论：细胞毒性实验数据表明，本发明化合物对细胞的毒性小。Conclusion: The cytotoxicity experiment data shows that the compound of the present invention has low toxicity to cells.
测试3：本发明化合物在比格犬、小鼠、大鼠中的药代动力学实验Test 3: Pharmacokinetic experiments of the compounds of the present invention in beagle dogs, mice and rats
(1)比格犬PK测试实验(1) Beagle dog PK test experiment
化合物在比格犬(购自湖南斯莱克景达实验动物有限公司，体重10-12kg，雄性，年龄10-12个月，口服每组3只，静脉注射每组3只)体内的PK测定实验方法：Compound PK determination experiment in Beagle dogs (purchased from Hunan Slake Jingda Experimental Animal Co., Ltd., body weight 10-12kg, male, age 10-12 months, 3 animals per group, 3 mice per group) method:
比格犬经口灌胃给予2.5mg/kg或5mg/kg或经静脉注射1mg/kg或2mg/kg的测试化合物。Beagle dogs were given 2.5 mg/kg or 5 mg/kg by oral gavage or 1 mg/kg or 2 mg/kg of test compound intravenously.
给药后按时间点(0.083、0.25、0.5、1、2、4、6、8和24小时)静脉采血，收集于加EDTA-K
2的抗凝管内。血浆样品经液液萃取后，在三重四极杆串联质谱仪上，以多重反应离子监测(MRM)方式进行定量分析。采用WinNonlin 6.3软件用非房室模型法计算药动学参数。
After administration, blood was collected intravenously at time points (0.083, 0.25, 0.5, 1, 2 , 4, 6, 8, and 24 hours) and collected in anticoagulation tubes with EDTA-K2. After liquid-liquid extraction, the plasma samples were quantitatively analyzed by multiple reactive ion monitoring (MRM) on a triple quadrupole tandem mass spectrometer. The WinNonlin 6.3 software was used to calculate the pharmacokinetic parameters using the non-compartmental model method.
结论：药代实验数据表明，本发明化合物在比格犬体内具有较好的药代动力学性质，在抗HBV方面有很好的应用前景。Conclusion: The pharmacokinetic experimental data show that the compound of the present invention has good pharmacokinetic properties in beagle dogs and has a good application prospect in anti-HBV.
(2)小鼠PK测试实验：(2) Mouse PK test experiment:
化合物在小鼠(购自湖南斯莱克景达实验动物有限公司，体重20-25g，雄性，年龄45-60天，口服每组3只，静脉注射每组3只)体内的PK测定实验方法：Experimental method of PK determination of the compound in mice (purchased from Hunan Slake Jingda Experimental Animal Co., Ltd., body weight 20-25g, male, age 45-60 days, 3 orally per group, 3 intravenously per group):
ICR小鼠经口灌胃给予10mg/kg或经尾静脉注射2mg/kg或10mg/kg的测试化合物。ICR mice were given 10 mg/kg orally or 2 mg/kg or 10 mg/kg of test compound via the tail vein.
给药后按时间点(0.083，0.25，0.5，1，2，4，6，8和24小时)眼眶静脉采血，收集于加EDTA-K
2的抗凝管内。血浆样品经液液萃取后，在三重四极杆串联质谱仪上，以多重反应离子监测(MRM)方式进行定量分析。采用WinNonlin 6.3软件用非房室模型法计算药动学参数。
After administration, blood was collected from the orbital vein at time points (0.083, 0.25, 0.5, 1, 2 , 4, 6, 8, and 24 hours) and collected in anticoagulation tubes with EDTA-K2. After liquid-liquid extraction, the plasma samples were quantitatively analyzed by multiple reactive ion monitoring (MRM) on a triple quadrupole tandem mass spectrometer. The WinNonlin 6.3 software was used to calculate the pharmacokinetic parameters using the non-compartmental model method.
结论：药代实验数据表明，本发明化合物在小鼠体内具有较好的药代动力学性质，在抗HBV方面有很好的应用前景。Conclusion: The data of pharmacokinetic experiments show that the compound of the present invention has good pharmacokinetic properties in mice and has a good application prospect in anti-HBV.
(3)SD大鼠PK测试实验：(3) SD rat PK test experiment:
化合物在SD大鼠(购自湖南斯莱克景达实验动物有限公司，体重200-250g，雄性，年龄2-3个月，口服每组3只，静脉注射每组3只)体内的PK测定实验方法：Compound PK determination experiment in SD rats (purchased from Hunan Slake Jingda Experimental Animal Co., Ltd., body weight 200-250g, male, age 2-3 months, 3 rats per group orally, 3 rats per group) method:
大鼠经口灌胃给予2.5mg/kg或5mg/kg或经静脉注射1mg/kg的测试化合物。The rats were given 2.5 mg/kg or 5 mg/kg orally or intravenously 1 mg/kg of the test compound.
给药后按时间点(0.083、0.25、0.5、1、2、5、7和24小时)静脉采血，收集于加EDTA-K
2的抗凝管内。血浆样品经液液萃取后，在三重四极杆串联质谱仪上，以多重反应离子监测(MRM)方式进行定量分析。采用WinNonlin 6.3软件用非房室模型法计算药动学参数。部分化合物的实验结果见表4。
After administration, blood was collected intravenously at time points (0.083, 0.25, 0.5, 1, 2 , 5, 7, and 24 hours) and collected in anticoagulation tubes with EDTA-K2. After liquid-liquid extraction, the plasma samples were quantitatively analyzed by multiple reactive ion monitoring (MRM) on a triple quadrupole tandem mass spectrometer. The WinNonlin 6.3 software was used to calculate the pharmacokinetic parameters using the non-compartmental model method. The experimental results of some compounds are shown in Table 4.
表4：部分化合物在大鼠体内的PK数据Table 4: PK data of some compounds in rats
N/A表示未测试N/A means not tested
结论：药代实验数据表明，本发明化合物药时曲线下面积AUC
last较大，暴露量较好，说明本发明化合物在SD大鼠体内的吸收好，体内稳定，并且生物利用度高。因此，本发明化合物在SD大鼠体内具有较好的药代动力学性质，在抗HBV方面有很好的应用前景。
Conclusion: The data of the pharmacokinetic experiments show that the area under the drug-time curve of the compound of the present invention is greater in AUC last and the exposure is better, indicating that the compound of the present invention is well absorbed in SD rats, stable in vivo, and has high bioavailability. Therefore, the compound of the present invention has better pharmacokinetic properties in SD rats and has a good application prospect in anti-HBV.
测试4：本发明化合物在不同种属的肝微粒体中的稳定性测试Test 4: Stability test of the compound of the present invention in liver microsomes of different species
测试化合物在不同种属中的肝微粒体稳定性方法：Method for testing the stability of liver microsomes in different species:
向96孔板中加入空白溶液与肝微粒体的混合溶液30μL，在各孔中加入15μL含待测化合物的缓冲液，平行做两份样品。37℃预孵育10min后按时间点加入15μL NADPH溶液(8mM)，待测化合物的终浓度为1μM，肝微粒体的浓度为0.5mg/mL，NADPH终浓度为2mM。分别孵育0、15、30、60min，孵育结束后将150μL乙腈(含内标)加入混合体系中。乙腈稀释后的样品在4000rpm下离心5min，取150μL上清液至LC-MS/MS进行分析。Add 30 μL of the mixed solution of the blank solution and liver microsomes to the 96-well plate, add 15 μL of the buffer containing the test compound to each well, and make two samples in parallel. After pre-incubation at 37°C for 10 min, 15 μL of NADPH solution (8 mM) was added at a time point. The final concentration of the test compound was 1 μM, the concentration of liver microsomes was 0.5 mg/mL, and the final concentration of NADPH was 2 mM. Incubate for 0, 15, 30, and 60 min, and add 150 μL of acetonitrile (including internal standard) to the mixed system after the incubation. The acetonitrile diluted sample was centrifuged at 4000 rpm for 5 min, and 150 μL of supernatant was taken to LC-MS/MS for analysis.
结论：本发明化合物在不同种属的肝微粒体中的稳定性较好。Conclusion: The compounds of the present invention have better stability in liver microsomes of different species.
测试5：溶解度测试方法Test 5: Solubility test method
化合物溶解度的实验测试方法Experimental test method of compound solubility
除另有规定外，称取研成细粉的供试品或量取液体供试品至25℃±2℃、一定容量的溶剂中，每隔5min强力振摇30s，观察30min内的溶解情况，如无目视可见的溶质颗粒或液滴时，即视为完全溶解。根据中国药典2015版的标准：Unless otherwise specified, weigh the test sample into a fine powder or measure the liquid sample to 25℃±2℃, a certain volume of solvent, shake it vigorously every 5min for 30s, and observe the dissolution within 30min If no solute particles or droplets are visible, it is regarded as completely dissolved. According to the standards of the 2015 edition of the Chinese Pharmacopoeia:
极易溶解系指溶质1g(mL)能在溶剂不到1mL中溶解；Very soluble means that 1g (mL) of solute can be dissolved in less than 1mL of solvent;
易溶系指溶质1g(mL)能在溶剂1～不到10mL中溶解；Easily soluble means that 1g (mL) of solute can be dissolved in the solvent from 1 to less than 10mL;
溶解系指溶质1g(mL)能在溶剂10～不到30mL中溶解；Dissolution means that 1g (mL) of solute can be dissolved in the solvent from 10 to less than 30mL;
略溶系指溶质1g(mL)能在溶剂30～不到100mL中溶解；Slightly soluble means that 1g (mL) of solute can be dissolved in the solvent from 30 to less than 100mL;
微溶系指溶质lg(mL)能在溶剂100～不到1000mL中溶解；Slightly soluble means that the solute lg (mL) can be dissolved in the solvent from 100 to less than 1000 mL;
极微溶解系指溶质1g(mL)能在溶剂1000～不到10000mL中溶解；Very slight dissolution means that 1g (mL) of solute can be dissolved in solvent from 1000 to less than 10000mL;
几乎不溶或不溶系指溶质1g(mL)在溶剂10000mL中不能完全溶解。Almost insoluble or insoluble means that 1 g (mL) of solute cannot be completely dissolved in 10000 mL of solvent.
结论：溶解度实验数据表明，本发明化合物溶解性较好。Conclusion: The solubility experiment data shows that the compound of the present invention has good solubility.
测试6：hERG测试方法Test 6: hERG test method
化合物对心脏的实验测试方法Experimental test method of compound on heart
在384孔板中依次加入化合物/阳性对照品/阴性对照品、含有hERG通道的膜片段、与hERG通道具有高度亲和力的示踪物，25℃，250rpm孵育4小时。用多功能酶标仪测量各 孔的荧光偏振值，计算化合物对hERG通道的相对抑制率和50％抑制浓度(IC
50)。
Compound/positive control substance/negative control substance, membrane fragment containing hERG channel, and tracer with high affinity to hERG channel were sequentially added to the 384-well plate, and incubated at 250C and 250 rpm for 4 hours. The fluorescence polarization value of each well was measured with a multifunctional microplate reader to calculate the relative inhibition rate and 50% inhibition concentration (IC 50 ) of the compound on hERG channel.
结论：hERG测试实验数据表明，本发明化合物对心脏的毒性小。Conclusion: The experimental data of hERG test shows that the compound of the present invention has low toxicity to the heart.
测试7：肝药酶诱导测试Test 7: Liver drug enzyme induction test
细胞培养Cell culture
所有孵育均在37℃、5％CO2和95％湿度条件的培养箱中进行。All incubations were conducted in an incubator at 37°C, 5% CO2, and 95% humidity.
冻存人肝细胞(Baltimore,MD,USA)复苏后，采用台盼蓝染色法和细胞计数器确定细胞数量和细胞活率。计数完毕后用预热的种板培养液将肝细胞稀释到每毫升中含70万个活细胞。将稀释好的肝细胞悬液按0.2mL/孔接种到预铺胶原的48孔板上，于培养箱中孵育培养至少4小时，待细胞呈贴壁状态，用含有2％基底基质胶的孵育培养液替换种板培养液。After cryopreserved human hepatocytes (Baltimore, MD, USA) were recovered, trypan blue staining and cell counter were used to determine the cell number and cell viability. After counting, the hepatocytes were diluted with preheated seed plate culture fluid to contain 700,000 viable cells per ml. Inoculate the diluted hepatocyte suspension at a rate of 0.2mL/well onto a 48-well plate pre-plated with collagen, and incubate for at least 4 hours in the incubator. When the cells are adherent, incubate with 2% Matrigel The culture medium replaces the seed plate culture medium.
每天用孵育培养液新鲜配制给药工作液，包括供试品(浓度不低于0.1μM)，CYP1A2，CYP2B6，CYP3A4的阳性诱导剂omeprazole，phenobarbital，rifampicin，稀释1000倍DMSO储备液得到。给药工作液的信息见下表。Prepare the working solution freshly with the incubation medium every day, including the test products (concentration not less than 0.1μM), CYP1A2, CYP2B6, CYP3A4 positive inducer omeprazole, phenobarbital, rifampicin, obtained by diluting 1000-fold DMSO stock solution. See the table below for information on administration of working fluids.
待培养体系建立好后，弃去三明治培养基的上层培养液，于每个细胞培养孔中加入200μL已预热至37℃并新鲜配制的给药工作液(包含供试品、阳性对照，阴性对照和基质对照)，将细胞培养板放置于培养箱中继续培养24小时。培养24小时后，更换新鲜配制的给药工作液并继续培养24小时。整个孵育时间为48小时。每个药物浓度及对照浓度分别做三个平行。After the culture system is established, discard the upper culture medium of the sandwich culture medium and add 200 μL of freshly prepared working solution (including test product, positive control, negative) to each cell culture well, which has been preheated to 37°C. Control and matrix control), place the cell culture plate in the incubator and continue culturing for 24 hours. After 24 hours of incubation, the freshly prepared dosing working solution was replaced and the incubation continued for 24 hours. The entire incubation time is 48 hours. Three parallels were made for each drug concentration and control concentration.
待细胞与给药工作液孵育48小时后，弃去板中剩余的药物溶液，用0.5mL预热至37℃的HBSS溶液清洗细胞孔2次，于每孔加入100μL已预热至37℃的酶活标记底物工作液孵育30分钟。孵育30分钟后，每孔取出75μL上清样品加入到含有150μL终止液的96孔深孔板中。摇板10分钟，于4℃、3220g离心20分钟，然后取上清溶液按1:4的比例用含有0.1％甲酸的水溶液稀释。稀释后的样品摇板10分钟后，用液相色谱串联质谱(LC/MS/MS)方法对代谢产物的生成量进行检测。After incubating the cells with the dosing working solution for 48 hours, the remaining drug solution in the plate was discarded, and the cell wells were washed twice with 0.5 mL of HBSS solution preheated to 37°C, and 100 μL of preheated to 37°C was added to each well. The enzyme-labeled substrate working solution was incubated for 30 minutes. After incubating for 30 minutes, 75 μL of supernatant sample was taken from each well and added to a 96-well deep well plate containing 150 μL of stop solution. Shake the plate for 10 minutes, centrifuge at 3220g at 4°C for 20 minutes, and then take the supernatant solution at a ratio of 1:4 and dilute it with an aqueous solution containing 0.1% formic acid. After the diluted sample was shaken for 10 minutes, the amount of metabolite production was detected by liquid chromatography tandem mass spectrometry (LC/MS/MS).
酶活性检测反应结束之后，弃去上清剩余溶液，并用0.5mL预热的HBSS清洗细胞。于每孔加入280μL含有1％β-巯基乙醇的裂解液RLT，封板，摇板10分钟后，转移至-80℃冰箱内保存。After the enzyme activity detection reaction was completed, the remaining solution of the supernatant was discarded, and the cells were washed with 0.5 mL of pre-warmed HBSS. Add 280 μL of lysis solution RLT containing 1% β-mercaptoethanol to each well, seal the plate, shake the plate for 10 minutes, and transfer to -80°C refrigerator for storage.
细胞毒性实验Cytotoxicity test
供试品的潜在毒性由肝细胞中乳酸脱氢酶(LDH)的释放量来评估。将与肝细胞孵育24 小时和48小时后的给药工作液各自取出100μL，用商品化LDH试剂盒对其乳酸脱氢酶的浓度进行检测。细胞裂解溶液作为实验阳性对照，孵育培养液作为空白对照。The potential toxicity of the test article is evaluated by the amount of lactate dehydrogenase (LDH) released in the liver cells. 100 μL of the administration working solution after incubation with hepatocytes for 24 hours and 48 hours was taken out, and the concentration of lactate dehydrogenase was detected using a commercial LDH kit. The cell lysis solution was used as a positive control for the experiment, and the culture medium was used as a blank control.
RNA分析检测RNA analysis and detection
室温化冻样品板，将所有样品转移至新的48孔细胞培养板中。应用全自动核酸抽提工作站抽提RNA。在样品板的不同位置随机抽取超过样品总量10％的样品，运用ND2000微量分光光度计测定260nM与280nM的OD值，通过计算两者的比值来判断总RNA的纯度。反转录以得到cDNA。用CFX connectTM实时荧光定量PCR仪实时定量分析选择的基因。按如下程序设置反应条件：50℃两分钟；95℃十分钟；以下两步做40个循环：95℃十五秒，60℃一分钟。内源性对照18S rRNA作为内标。Thaw the sample plate at room temperature and transfer all samples to a new 48-well cell culture plate. Extract RNA using a fully automatic nucleic acid extraction workstation. Randomly draw samples exceeding 10% of the total amount of samples at different positions on the sample plate, use the ND2000 micro spectrophotometer to measure the OD values of 260nM and 280nM, and determine the purity of the total RNA by calculating the ratio of the two. Reverse transcription to obtain cDNA. Real-time quantitative analysis of selected genes with CFX connectTM real-time quantitative PCR instrument. Set the reaction conditions according to the following procedures: 50°C for two minutes; 95°C for ten minutes; the following two steps to do 40 cycles: 95°C for fifteen seconds and 60°C for one minute. The endogenous control 18S rRNA was used as an internal standard.
样品分析检测Sample analysis and testing
利用液相色谱串联质谱(LC/MS/MS)方法测定经蛋白沉淀后肝细胞中三个CYP酶底物的代谢产物(对乙酰氨基酚(Acetaminophen)、羟基安非他酮(Hydroxybupropion)以及1-羟基咪达***(1’-Hydroxymidazolam))的浓度。分析方法见表5。The liquid chromatography tandem mass spectrometry (LC/MS/MS) method was used to determine the metabolites of three CYP enzyme substrates (Acetaminophen, Hydroxybupropion) and 1 in liver cells after protein precipitation. -The concentration of 1'-Hydroxymidazolam). The analysis method is shown in Table 5.
表5：诱导试验LCMS分析方法Table 5: LCMS analysis method of induction test
基因表达数据计算Gene expression data calculation
该项目采用ΔCt相对定量的方法来比较不同处理组间基因表达的差异，以18S rRNA为 内参基因来校正每个样品的基因表达量。目的基因的Ct值减去内参基因的Ct值则为ΔCt，即Ct
目的基因–Ct
18S＝ΔCt。用处理组的ΔCt值减去空白对照组的ΔCt值则为ΔΔCt，即ΔCt处理组–ΔCt空白对照组＝ΔΔCt。最后以2
-ΔΔCt的方法进行统计分析，比较处理组与空白对照组间的倍数的变化。
This project uses the relative quantitative method of ΔCt to compare the difference in gene expression between different treatment groups, and uses 18S rRNA as the internal reference gene to correct the gene expression of each sample. The Ct value of the target gene minus the Ct value of the internal reference gene is ΔCt, which is the Ct target gene – Ct 18S = ΔCt. The ΔCt value of the treatment group minus the ΔCt value of the blank control group is ΔΔCt, that is, ΔCt treatment group-ΔCt blank control group = ΔΔCt. Finally, statistical analysis was carried out by the method of 2- ΔΔCt , and the change of fold between the treatment group and the blank control group was compared.
酶活性数据计算Calculation of enzyme activity data
实验数据显示了CYP3A4的酶代谢产物的生成量。酶活性的改变是通过比较在化合物存在或不存在的条件下相应细胞色素酶的诱导倍数来表现的。诱导倍数的计算方法及与对照化合物的诱导比率的计算方法如下：The experimental data shows the amount of enzyme metabolites produced by CYP3A4. The change in enzyme activity is shown by comparing the fold induction of the corresponding cytochrome enzyme in the presence or absence of the compound. The calculation method of the induction multiple and the calculation method of the induction ratio with the control compound are as follows:
诱导倍数＝供试品处理过的样品中的酶活性/基质对照处理过的样品中的酶活性Induction factor = enzyme activity in the sample treated for the test article/enzyme activity in the sample treated with the matrix control
与对照化合物的诱导比率＝(供试品处理过的样品的诱导倍数-1)/(对照化合物处理过的样品的诱导倍数-1)×100％。Induction ratio with control compound = (induction factor of sample treated with test article-1)/(induction factor of sample treated with control compound-1)×100%.
肝药酶诱导测试实验结果见表6：The experimental results of liver drug enzyme induction test are shown in Table 6:
表6：肝药酶诱导测试实验数据Table 6: Experimental data of liver drug enzyme induction test
| 实施例Examples | 与对照化合物(10μmol利福平)的诱导比率Induction ratio with control compound (10 μmol rifampicin) |
| 11 | 6.7％6.7% |
结论：肝药酶诱导测试实验数据表明，本发明化合物对肝药酶基本无诱导作用。Conclusion: Experimental data of liver drug enzyme induction test shows that the compound of the present invention has basically no induction effect on liver drug enzyme.
测试8：人血清对化合物抗HBV药效影响实验Test 8: Experiment on the effect of human serum on the anti-HBV efficacy of the compound
实验原理Experimental principle
HepG2.2.15细胞的染色体整合有完整的HBV基因组，并稳定表达病毒RNA和病毒蛋白质。HepG2.2.15细胞能够向培养基中分泌成熟的乙肝病毒颗粒、HBsAg和HBeAg。HepG2.2.15细胞分泌的病毒DNA可以通过qPCR的方法来定量，在测试化合物处理的同时加入不同浓度的人血清，并由此检测人血清对化合物抗病毒药效的影响。The chromosome of HepG2.2.15 cell integrates the complete HBV genome and stably expresses viral RNA and viral protein. HepG2.2.15 cells can secrete mature HBV particles, HBsAg and HBeAg into the culture medium. Viral DNA secreted by HepG2.2.15 cells can be quantified by qPCR method, while adding different concentrations of human serum at the same time as the test compound treatment, and thus detecting the effect of human serum on the antiviral efficacy of the compound.
实验方法experimental method
HepG2.2.15细胞的化合物处理Compound treatment of HepG2.2.15 cells
步骤1：96孔细胞培养板中铺HepG2.2.15细胞15000个每孔，每孔200μL细胞培养基。Step 1: Spread 15,000 HepG2.2.15 cells per well in a 96-well cell culture plate and 200 μL of cell culture medium per well.
步骤2：在37℃，5％CO
2细胞培养箱中培养3天至细胞长至满孔。
Step 2: Incubate at 37°C in a 5% CO 2 cell incubator for 3 days until the cells grow to full pores.
步骤:3：在测试第0天，弃掉旧的培养基并加入200μL新鲜的含有2％FBS和不同人血清(HS)浓度的检测培养基，包括0％HS、5％HS、10％HS、20％HS、40％HS和50％HS。Step: 3: On day 0 of the test, discard the old medium and add 200 μL of fresh detection medium containing 2% FBS and different human serum (HS) concentrations, including 0% HS, 5% HS, 10% HS , 20% HS, 40% HS and 50% HS.
步骤4：抗病毒实验中化合物配制和细胞处理：用DMSO溶解化合物至30mM，进一步用DMSO稀释化合物到800μM，然后进行8个稀释度的4倍稀释，最高浓度为800μM。加 系列稀释的化合物1μL每孔到步骤3准备的细胞板中，实验最高终浓度为4μM(200倍稀释)。Step 4: Compound preparation and cell treatment in antiviral experiments: Dissolve the compound with DMSO to 30 mM, further dilute the compound with DMSO to 800 μM, and then perform 4 dilutions of 8 dilutions, with a maximum concentration of 800 μM. Add 1 μL of serially diluted compound to each cell plate prepared in step 3. The maximum final concentration of the experiment is 4 μM (200-fold dilution).
步骤5：实验设定在2％FBS条件下TDF(富马酸替诺福韦二吡呋酯,Selleck,Cat S1400)作为阳性对照化合物，最高浓度为4μM。阴性对照孔加入1μLDMSO，其实验终浓度为0.5％。Step 5: Experiment setting TDF (tenofovir disoproxil fumarate, Selleck, Cat S1400) under 2% FBS as the positive control compound, the highest concentration is 4 μM. Add 1μLDMSO to the negative control well, and the final concentration of the experiment is 0.5%.
步骤6：96孔细胞测试板在37℃ CO
2培养箱中孵育11天，每隔一天(第2，4，6，8，10天)换一次液，并加入1μL新鲜配置的化测试合物，方法见步骤3到5。
Step 6: Incubate the 96-well cell test plate in a 37°C CO 2 incubator for 11 days, change the fluid every other day (days 2, 4, 6, 8, and 10), and add 1 μL of freshly prepared test compound , See steps 3 to 5.
步骤7：在第11天每孔取150μL上清作病毒DNA的qPCR检测。Step 7: On day 11, 150 μL of supernatant was taken for qPCR detection of viral DNA.
步骤8：细胞毒实验中化合物配制和细胞处理：用Bravo liquid handling system配制系列稀释的化合物，11个稀释度，3倍稀释，最高浓度为30mM。用Echo550加系列稀释的化合物0.25μL每孔到384孔细胞毒细胞板中(Greiner 781098)。准备HepG2.2.15细胞，并重悬于不同浓度人血清浓度(50％，40％，20％，10％，5％和0％)的培养基中。加入50μL(4000个细胞)每孔以上制备的HepG2.2.15细胞到384孔细胞毒细胞板中，实验最高终浓度为150μM(200倍稀释)。37℃ CO
2培养箱中孵育4天后进行细胞毒测试。
Step 8: Compound preparation and cell treatment in cytotoxicity experiments: Bravo liquid handling system was used to prepare serially diluted compounds, 11 dilutions, 3 times dilution, and the highest concentration was 30 mM. Add 0.25 μL of compound diluted serially with Echo550 to a 384-well cytotoxic cell plate (Greiner 781098). Prepare HepG2.2.15 cells and resuspend in different concentrations of human serum concentrations (50%, 40%, 20%, 10%, 5%, and 0%). Add 50 μL (4000 cells) of HepG2.2.15 cells prepared above each well to a 384-well cytotoxic cell plate, and the maximum final concentration of the experiment is 150 μM (200-fold dilution). The cytotoxicity test was carried out after incubating in a 37°C CO 2 incubator for 4 days.
qPCR方法检测病毒基因组DNAqPCR detection of viral genomic DNA
步骤1：将20％HS实验条件下的上清液用DPBS作2倍稀释，40％HS实验条件下的上清液用DPBS作4倍稀释，50％HS实验条件下的上清液用DPBS作5倍稀释。混匀后取1μL进行qPCR检测。Step 1: Dilute the supernatant under 20% HS experiment conditions with DPBS, dilute the supernatant under 40% HS experiment conditions with DPBS, and use DPBS with the supernatant under 50% HS conditions Make a 5-fold dilution. After mixing, take 1μL for qPCR detection.
步骤2：0％HS，5％HS和10％HS实验条件下的上清液直接取1μL进行qPCR检测。Step 2: Take 1 μL of the supernatant under the experimental conditions of 0% HS, 5% HS and 10% HS directly for qPCR detection.
步骤3：按以下成分配制qPCR反应体系：Step 3: Prepare the qPCR reaction system according to the following ingredients:
| SYBR Premix Ex TaqTM II(2×)SYBR Premix Ex TaqTM II (2×) | 10μL10μL |
| HBV-For-202(10μM)HBV-For-202 (10μM) | 0.8μL0.8μL |
| HBV-Rev-315(10μM)HBV-Rev-315 (10μM) | 0.8μL0.8μL |
| ROX Reference Dye(50×)ROXReferenceDye(50×) | 0.4μL0.4μL |
| 病毒上清Virus supernatant | 1μL1μL |
| 加水至Add water to | 20μL20μL |
步骤4：按以下条件设置ABI ViiA7 qPCR仪Step 4: Set up the ABI ViiA7 qPCR instrument according to the following conditions
阶段1：Phase 1:
Reps：95℃，30s，1个循环Reps: 95℃, 30s, 1 cycle
阶段2：Phase 2:
Reps：95℃，5s和60℃，34s，40个循环Reps: 95°C, 5s and 60°C, 34s, 40 cycles
添加溶解曲线Add dissolution curve
化合物的细胞毒作用检测Compound cytotoxicity detection
步骤1：平衡PromegaCelltiter-Glo试剂至室温。Step 1: Equilibrate PromegaCelltiter-Glo reagent to room temperature.
步骤2：弃去细胞毒实验板培养基，每孔加入50μL DPBS。Step 2: Discard the cytotoxicity assay plate medium and add 50 μL of DPBS to each well.
步骤3：每孔加入10μL CellTiter-Glo试剂。Step 3: Add 10 μL CellTiter-Glo reagent to each well.
步骤4：振板仪上振2分钟。Step 4: Shake the instrument for 2 minutes.
步骤5：室温避光平衡10分钟。Step 5: Equilibrate in the dark at room temperature for 10 minutes.
步骤6：在Envision读板仪上读数(0.1秒/孔)Step 6: Reading on the Envision plate reader (0.1 sec/well)
结果分析Result analysis
用包含HBV基因组的质粒(病毒拷贝数:2×10E6,2×10E5,2×10E4,2×10E3)做标准曲线，并以标准曲线来计算病毒拷贝数。用Graphpad Prism 5软件处理数据并绘制浓度-病毒拷贝数曲线，通过四参数非线性回归模型计算EC
50。细胞毒性％＝100-(检测值/DMSO对照孔平均值×100)。细胞毒性％数据用Graphpad Prism 5软件处理并绘制曲线，通过四参数非线性回归模型计算CC
50。
A plasmid containing the HBV genome (virus copy number: 2×10E6, 2×10E5, 2×10E4, 2×10E3) was used as the standard curve, and the virus copy number was calculated with the standard curve. The data was processed with Graphpad Prism 5 software and the concentration-virus copy number curve was plotted, and the EC 50 was calculated by a four-parameter nonlinear regression model. Cytotoxicity %=100-(detection value/average value of DMSO control well×100). The cytotoxicity% data was processed and graphed with Graphpad Prism 5 software, and CC 50 was calculated by a four-parameter nonlinear regression model.
结论：实验数据表明，人血清对本发明化合物抗病毒药效的影响较小，说明本发明化合物在人体可起到良好的抗病毒效果。Conclusion: Experimental data shows that human serum has little effect on the antiviral efficacy of the compound of the present invention, indicating that the compound of the present invention can play a good antiviral effect in humans.
虽然，上文中已经用一般性说明、具体实施方式及试验，对本发明作了详尽的描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。Although the present invention has been described in detail with general descriptions, specific embodiments and tests, but on the basis of the present invention, some modifications or improvements can be made to it, which is obvious to those skilled in the art . Therefore, these modifications or improvements made on the basis of not deviating from the spirit of the present invention shall fall within the protection scope of the present invention.
Claims (10)
- 一种氘代化合物，其为如式(I)或(Ia)所示的氘代化合物或如式(I)或(Ia)所示的氘代化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，A deuterated compound, which is a stereoisomer or tautomer of a deuterated compound shown by formula (I) or (Ia) or a deuterated compound shown by formula (I) or (Ia) , Nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or its prodrugs,
其中，各R 1独立地为氢、氘、F、Cl、Br、I、氰基、甲基、乙基、甲氧基、乙氧基或硝基； Wherein, each R 1 is independently hydrogen, deuterium, F, Cl, Br, I, cyano, methyl, ethyl, methoxy, ethoxy, or nitro;R 2为CDH 2、CD 2H、CD 3、CD 3CD 2或CD 3CH 2； R 2 is CDH 2 , CD 2 H, CD 3 , CD 3 CD 2 or CD 3 CH 2 ;R 3为苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、***基、四唑基、噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中所述苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、***基、四唑基、噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基各自独立地未被取代或被1、2、3、4或5个选自氘、F、Cl、Br、HO、CN、C 1-4烷基、羟基C 1-4烷基、C 1-4烷基-OC(＝O)-、C 1-4烷基-OC(＝O)-C 1-3亚烷基-、HOOC-C 1-3亚烷基-、C 1-4烷氧基-C 1-3亚烷基-或C 1-4烷基-S(＝O) 2-的取代基所取代； R 3 is phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazole Group, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein the phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, Oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, and pyrimidinyl are each independently unsubstituted or selected by 1, 2, 3, 4, or 5 From deuterium, F, Cl, Br, HO, CN, C 1-4 alkyl, hydroxy C 1-4 alkyl, C 1-4 alkyl-OC (=O)-, C 1-4 alkyl-OC (=O)-C 1-3 alkylene-, HOOC-C 1-3 alkylene-, C 1-4 alkoxy-C 1-3 alkylene- or C 1-4 alkyl-S (=O) 2 -substituted by a substituent;其中，W为CH或N；Among them, W is CH or N;X 1为-C(＝O)-、-S(＝O) 2-或-(CR 7R 8) j-； X 1 is -C(=O)-, -S(=O) 2 -or -(CR 7 R 8 ) j -;各R 7和R 8独立地为氢、氘、F、Cl、Br、氨基、甲基、乙基、正丙基、异丙基、NH 2C(＝O)-、C 1-4烷基-OC(＝O)-、羧基、羧基C 1-3烷基、羟基C 1-4烷基、乙氧基乙基、甲氧基乙基、异丙氧基甲基、乙氧基乙基、甲氧基甲基或C 1-4卤代烷基，或R 7、R 8和与它们相连的碳原子一起形成环丙基、环丁基、环戊基、环己基或羰基； Each R 7 and R 8 is independently hydrogen, deuterium, F, Cl, Br, amino, methyl, ethyl, n-propyl, isopropyl, NH 2 C(═O)-, C 1-4 alkyl -OC(=O)-, carboxyl, carboxyl C 1-3 alkyl, hydroxy C 1-4 alkyl, ethoxyethyl, methoxyethyl, isopropoxymethyl, ethoxyethyl , Methoxymethyl or C 1-4 haloalkyl, or R 7 and R 8 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or carbonyl;R 4为C 1-6烷基、5-6个环原子组成的杂芳基、
其中，所述C 1-6烷基未被取代或被1、2、3、4或5个选自氘、F、Cl、Br、HO、甲基或HOOC-的取代基所取代，所述5-6个环原子组成的杂芳基未被取代或被1、2、3、4或5个R 13取代基所取代； R 4 is a C 1-6 alkyl group, a heteroaryl group consisting of 5-6 ring atoms,
Wherein the C 1-6 alkyl group is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from deuterium, F, Cl, Br, HO, methyl or HOOC-, Heteroaryl groups consisting of 5-6 ring atoms are unsubstituted or substituted with 1, 2, 3, 4 or 5 R 13 substituents;各R 9、R 11和R 12独立地为氘、F、Cl、Br、氨基、甲基、乙基、正丙基、异丙基、NH 2C(＝O)-、C 1-4烷基-OC(＝O)-、羧基、羧基C 1-3烷基、羟基C 1-4烷基、乙氧基乙基、甲氧基乙基、异丙氧基甲基、乙氧基乙基、甲氧基甲基或C 1-4卤代烷基； Each R 9 , R 11 and R 12 are independently deuterium, F, Cl, Br, amino, methyl, ethyl, n-propyl, isopropyl, NH 2 C(═O)-, C 1-4 alkane -OC(=O)-, carboxyl, carboxyl C 1-3 alkyl, hydroxy C 1-4 alkyl, ethoxyethyl, methoxyethyl, isopropoxymethyl, ethoxyethyl Group, methoxymethyl or C 1-4 haloalkyl;各R 13独立地为氘、F、Cl、Br、HOOC-(CR aR b) g-、C 1-6烷基、C 1-6卤代烷基、苯基、苄基、C 1-6烷氧基C 1-4烷基、羟基C 1-6烷基或5-6个环原子组成的杂芳基；其中所述C 1-6烷基、C 1-6卤代烷基、苯基、苄基、C 1-6烷氧基C 1-4烷基、羟基C 1-6烷基和5-6个环原子组成的杂芳基未被取代或被1、2、3、4或5个选自氘、F、Cl、Br、HO、HOOC-(CR aR b) j-、HOOC-C 2-6烯基或C 1-6烷基-NHC(＝O)-的取代基所取代； Each R 13 is independently deuterium, F, Cl, Br, HOOC-(CR a R b ) g -, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, benzyl, C 1-6 alkyl Oxygen C 1-4 alkyl, hydroxy C 1-6 alkyl or heteroaryl consisting of 5-6 ring atoms; wherein the C 1-6 alkyl, C 1-6 haloalkyl, phenyl, benzyl Group, C 1-6 alkoxy C 1-4 alkyl, hydroxy C 1-6 alkyl and 5-6 ring atoms composed of heteroaryl groups are not substituted or are 1, 2, 3, 4 or 5 Substituted by a substituent selected from deuterium, F, Cl, Br, HO, HOOC-(CR a R b ) j -, HOOC-C 2-6 alkenyl or C 1-6 alkyl-NHC(=O)- ;各R 11a独立地为氘、F、Cl、Br、氨基、甲基、乙基、正丙基、异丙基、NH 2C(＝O)-、C 1-4烷基-OC(＝O)-、羟基C 1-4烷基、乙氧基乙基、甲氧基乙基、异丙氧基甲基、乙氧基乙基、甲氧基甲基或C 1-4卤代烷基，或相邻的两个R 11a和与它们相连的碳原子一起形成1,3–二氧戊环，其中所述1,3–二氧戊环未被取代或被1或2个选自氘、F、Cl、Br、氨基、甲基、乙基、正丙基或异丙基的取代基所取代； Each R 11a is independently deuterium, F, Cl, Br, amino, methyl, ethyl, n-propyl, isopropyl, NH 2 C(═O)-, C 1-4 alkyl-OC(═O )-, hydroxy C 1-4 alkyl, ethoxyethyl, methoxyethyl, isopropoxymethyl, ethoxyethyl, methoxymethyl or C 1-4 haloalkyl, or Two adjacent R 11a and the carbon atom to which they are connected together form 1,3-dioxolane, wherein the 1,3-dioxolane is unsubstituted or is selected from deuterium or F by 1 or 2 , Cl, Br, amino, methyl, ethyl, n-propyl or isopropyl substituents;R 10为HO、5-6个环原子组成的杂芳基、苯基、C 3-6环烷基、HO-S(＝O) 2-、(HO) 2P(＝O)-、R 14-S(＝O) 2-NR cC(＝O)-、HOOC-(CR aR b) q-或C 1-6烷基-NR cC(＝O)-，其中所述5-6个环原子组成的杂芳基、苯基、C 3-6环烷基和C 1-6烷基-NR cC(＝O)-中的C 1-6烷基未被取代或被1、2、3、4或5个选自氘、F、Cl、Br、HO、C 1-6烷基或HOOC-的取代基所取代； R 10 is HO, heteroaryl consisting of 5-6 ring atoms, phenyl, C 3-6 cycloalkyl, HO-S(=O) 2 -, (HO) 2 P(=O)-, R 14 -S(=O) 2 -NR c C(=O)-, HOOC-(CR a R b ) q -or C 1-6 alkyl-NR c C(=O)-, wherein the 5- The heteroaryl group consisting of 6 ring atoms, phenyl group, C 3-6 cycloalkyl group and C 1-6 alkyl group-NR c C 1-6 alkyl group is unsubstituted or substituted by 1 , 2, 3, 4 or 5 substituents selected from deuterium, F, Cl, Br, HO, C 1-6 alkyl or HOOC-;R 14为C 1-6烷基、C 3-6环烷基、苯基或5-6个环原子组成的杂芳基，其中所述C 1-6烷基、C 3-6环烷基、苯基和5-6个环原子组成的杂芳基未被取代或被1、2、3、4或5个选自氘、F、Cl、Br、HO、C 1-4烷基或HOOC-的取代基所取代； R 14 is a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a phenyl group, or a heteroaryl group composed of 5-6 ring atoms, wherein the C 1-6 alkyl group, C 3-6 cycloalkyl group , Phenyl and heteroaryl groups consisting of 5-6 ring atoms are unsubstituted or 1, 2, 3, 4 or 5 selected from deuterium, F, Cl, Br, HO, C 1-4 alkyl or HOOC -Substituted by a substituent;R 10b为HOOC-(CR aR b) t-或C 1-6烷基-NHC(＝O)-，其中所述C 1-6烷基-NHC(＝O)-中的C 1-6烷基未被取代或被1、2、3、4或5个选自氘、F、Cl、Br、HO、甲基、乙基、异丙基或HOOC-的取代基所取代； R 10b is HOOC- (CR a R b) t - C 1-6 alkyl or -NHC (= O) -, wherein said C 1-6 alkyl group -NHC (= O) - C 1-6 of The alkyl group is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from deuterium, F, Cl, Br, HO, methyl, ethyl, isopropyl or HOOC-;各R a、R b和R c独立地为氢、氘或C 1-4烷基，其中所述C 1-4烷基未被取代或被1、2、3、4或5个选自氘、F、Cl、Br、HO、甲基、乙基或HOOC-的取代基所取代； Each R a , R b and R c is independently hydrogen, deuterium or C 1-4 alkyl, wherein the C 1-4 alkyl is unsubstituted or substituted by 1, 2, 3, 4 or 5 selected from deuterium , F, Cl, Br, HO, methyl, ethyl or HOOC- substituents;各f、n、t、g、j和m独立地为0、1、2、3或4；Each f, n, t, g, j, and m is independently 0, 1, 2, 3, or 4;各k和q独立地为1、2或3。Each k and q are independently 1, 2, or 3. - 根据权利要求1所述的氘代化合物，其具有式(II)或式(IIa)所示结构：The deuterated compound according to claim 1, which has a structure represented by formula (II) or formula (IIa):
其中，各R 1和R 1a独立地为氢、氘、F、Cl、Br、I、氰基、甲基、乙基、甲氧基、乙氧基或硝基。 Wherein each R 1 and R 1a is independently hydrogen, deuterium, F, Cl, Br, I, cyano, methyl, ethyl, methoxy, ethoxy, or nitro. - 根据权利要求1或2所述的氘代化合物，R 4为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、***基、四唑基、噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基、嘧啶基、
其中，所述甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基未被取代或被1、2、3、4或5个选自氘、F、Cl、Br、HO、甲基或HOOC-的取代基所取代，所述呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、***基、四唑基、噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基未被取代或被1、2、3、4或5个R 13取代基所取代。 The deuterated compound according to claim 1 or 2, R 4 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, furyl, pyrrolyl, pyridyl , Pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidine base,
Wherein, the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl groups are unsubstituted or 1, 2, 3, 4 or 5 are selected from deuterium, F, Substituted by a substituent of Cl, Br, HO, methyl or HOOC-, the furanyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazole The radicals, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are unsubstituted or substituted with 1, 2, 3, 4 or 5 R 13 substituents. - 根据权利要求1-3任意一项所述的氘代化合物，各R 13独立地为氘、F、Cl、Br、HOOC-(CR aR b) g-、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、苯基、苄基、CH 3OCH 2-、CH 3OCH 2CH 2-、CH 3OCH(CH 3)-、CH 3OCH 2CH 2CH 2-、CH 3CH 2OCH 2-、CH 3CH 2OCH 2CH 2-、CH 3CH 2OCH(CH 3)-、CH 3CH 2OCH 2CH 2CH 2-、HOCH 2-、HOCH 2CH 2-、HOCH(CH 3)-、HOCH 2CH 2CH 2-、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、***基、四唑基、噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中所述甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、二氟甲基、二氟乙基、三氟乙基、苯基、苄基、CH 3OCH 2-、CH 3OCH 2CH 2-、CH 3OCH(CH 3)-、CH 3OCH 2CH 2CH 2-、CH 3CH 2OCH 2-、CH 3CH 2OCH 2CH 2-、CH 3CH 2OCH(CH 3)-、CH 3CH 2OCH 2CH 2CH 2-、HOCH 2-、HOCH 2CH 2-、HOCH(CH 3)-、HOCH 2CH 2CH 2-、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、***基、四唑基、噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基未被取代或被1、2、3、4或5个选自氘、F、Cl、Br、HO、HOOC-(CR aR b) j-、HOOC-CH＝CH-、HOOC-CH 2-CH＝CH-、HOOC-CH＝CH-CH 2-或C 1-4烷基-NHC(＝O)-的取代基所取代。 The deuterated compound according to any one of claims 1-3, wherein each R 13 is independently deuterium, F, Cl, Br, HOOC-(CR a R b ) g -, methyl, ethyl, n-propyl , Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, phenyl, benzyl, CH 3 OCH 2 -, CH 3 OCH 2 CH 2 -, CH 3 OCH(CH 3 )-, CH 3 OCH 2 CH 2 CH 2 -, CH 3 CH 2 OCH 2 -, CH 3 CH 2 OCH 2 CH 2 -, CH 3 CH 2 OCH(CH 3 )-, CH 3 CH 2 OCH 2 CH 2 CH 2 -, HOCH 2 -, HOCH 2 CH 2 -, HOCH(CH 3 )-, HOCH 2 CH 2 CH 2 -, furyl, pyrrole Group, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridyl Azinyl or pyrimidinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, difluoromethyl, difluoroethyl, tri Fluoroethyl, phenyl, benzyl, CH 3 OCH 2 -, CH 3 OCH 2 CH 2 -, CH 3 OCH(CH 3 )-, CH 3 OCH 2 CH 2 CH 2 -, CH 3 CH 2 OCH 2- , CH 3 CH 2 OCH 2 CH 2 -, CH 3 CH 2 OCH(CH 3 )-, CH 3 CH 2 OCH 2 CH 2 CH 2 -, HOCH 2 -, HOCH 2 CH 2 -, HOCH(CH 3 )- , HOCH 2 CH 2 CH 2 -, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazine Group, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are unsubstituted or 1, 2, 3, 4 or 5 selected from deuterium, F, Cl, Br, HO, HOOC-(CR a R b ) j -, HOOC-CH=CH-, HOOC-CH 2 -CH=CH-, HOOC-CH=CH-CH 2 -or C 1-4 alkyl-NHC(=O)- replace.
- 根据权利要求1-4任意一项所述的氘代化合物，其中，R 10为HO、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、***基、四唑基、噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基、嘧啶基、苯基、环丙基、环丁基、环戊基、环己基、HO-S(＝O) 2-、(HO) 2P(＝O)-、R 14-S(＝O) 2-NR cC(＝O)-、HOOC-(CR aR b) q-或C 1-4烷基-NR cC(＝O)-，其中所述呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、***基、四唑基、噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基、嘧啶基、苯基、环丙基、环丁基、环戊基、环己基和C 1-4烷基-NR cC(＝O)-中的C 1-4烷基未被取代或被1、2、3、4或5个选自氘、F、Cl、Br、HO、C 1-4烷基或HOOC-的取代基所取代； The deuterated compound according to any one of claims 1 to 4, wherein R 10 is HO, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl , Oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , HO-S(＝O) 2 -, (HO) 2 P(＝O)-, R 14 -S(＝O) 2 -NR c C(＝O)-, HOOC-(CR a R b ) q -Or C 1-4 alkyl-NR c C(=O)-, wherein the furanyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxazolyl Diazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and C 1-4 alkyl -NR c C (= O) - is a substituted or unsubstituted C 1-4 alkyl, 4 or 5 selected from deuterium, F, Cl, Br, HO , C Substituted by 1-4 alkyl or HOOC- substituents;R 10b为HOOC-(CR aR b) t-或C 1-4烷基-NHC(＝O)-，其中所述C 1-4烷基-NHC(＝O)-中的C 1-4 烷基未被取代或被1、2、3、4或5个选自氘、F、Cl、Br、HO、甲基、乙基、异丙基或HOOC-的取代基所取代； R 10b is HOOC- (CR a R b) t - C 1-4 alkyl or -NHC (= O) -, wherein said C 1-4 alkyl group -NHC (= O) - C 1-4 of The alkyl group is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from deuterium, F, Cl, Br, HO, methyl, ethyl, isopropyl or HOOC-;各R a、R b和R c独立地为氢、氘、甲基、乙基、正丙基或异丙基，其中所述甲基、乙基、正丙基和异丙基未被取代或被1、2、3、4或5个选自氘、F、Cl、Br、HO、甲基、乙基或HOOC-的取代基所取代。 Each R a , R b and R c is independently hydrogen, deuterium, methyl, ethyl, n-propyl or isopropyl, wherein the methyl, ethyl, n-propyl and isopropyl are unsubstituted or It is substituted by 1, 2, 3, 4 or 5 substituents selected from deuterium, F, Cl, Br, HO, methyl, ethyl or HOOC-.
- 根据权利要求1-5任意一项所述的氘代化合物，其中，R 14为甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、***基、四唑基、噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中所述甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、***基、四唑基、噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基未被取代或被1、2、3、4或5个选自氘、F、Cl、Br、HO、甲基、乙基、正丙基、异丙基或HOOC-的取代基所取代。 The deuterated compound according to any one of claims 1 to 5, wherein R 14 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Phenyl, furanyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophene Group, pyrazinyl, pyridazinyl or pyrimidinyl, wherein the methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl , Pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl , Pyridazinyl and pyrimidinyl are unsubstituted or 1, 2, 3, 4 or 5 selected from deuterium, F, Cl, Br, HO, methyl, ethyl, n-propyl, isopropyl or HOOC- Is replaced by the substituent.
- 一种氘代化合物，其包含以下其中之一的结构：A deuterated compound that contains one of the following structures:
或其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药。
Or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or its prodrugs. - 一种药物组合物，包含权利要求1-7任意一项所述的氘代化合物，及其药学上可接受的辅料。A pharmaceutical composition comprising the deuterated compound according to any one of claims 1-7 and pharmaceutically acceptable excipients.
- 根据权利要求8所述的药物组合物，其更进一步地包含其它抗HBV药物，其中所述其它抗HBV药物为拉米夫定、替比夫定、替诺福韦酯，恩替卡韦、阿德福韦酯、Alfaferone、Alloferon、西莫白介素、克拉夫定、恩曲他滨、法昔洛韦、干扰素、宝甘灵CP、因特芬、干扰素α-1b、干扰素α、干扰素α-2a、干扰素β-1a、干扰素α-2、白细胞介素-2、米伏替酯、硝唑尼特、聚乙二醇干扰素α-2a、病毒唑、罗扰素-A、西佐喃、Euforavac、安普利近、Phosphazid，Heplisav、干扰素α-2b、左旋咪唑或丙帕锗。The pharmaceutical composition according to claim 8, further comprising other anti-HBV drugs, wherein the other anti-HBV drugs are lamivudine, telbivudine, tenofovir disoproxil, entecavir, adefo Weiwei ester, Alfaferone, Alloferon, simor interleukin, Kravudine, emtricitabine, famciclovir, interferon, Baoganling CP, Intefen, interferon α-1b, interferon α, interferon α -2a, interferon beta-1a, interferon alpha-2, interleukin-2, mivorimate, nitazoxanide, pegylated interferon alpha-2a, ribavirin, rotavirin-A, Sizoran, Euforavac, April, Phosphazid, Heplisav, interferon alpha-2b, levamisole or propargium.
- 权利要求1-7任意一项所述的氘代化合物或权利要求8-9任意一项所述的药物组合物在制备预防、处理、治疗或减轻患者病毒性疾病的药物中的用途，其中所述病毒性疾病是指乙型肝炎病毒感染或乙型肝炎病毒感染引起的疾病，其中所述乙型肝炎病毒感染引起的疾病是指肝硬化或肝细胞癌变。Use of the deuterated compound according to any one of claims 1-7 or the pharmaceutical composition according to any one of claims 8-9 in the preparation of a medicament for preventing, treating, treating or alleviating a viral disease in a patient, wherein The viral disease refers to a disease caused by hepatitis B virus infection or hepatitis B virus infection, wherein the disease caused by hepatitis B virus infection refers to liver cirrhosis or hepatocellular carcinoma.
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| WO2022111719A1 (en) * | 2020-11-30 | 2022-06-02 | Sunshine Lake Pharma Co., Ltd. | Salts of dihydropyrimidine derivatives, complexes and uses thereof in medicine |
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| WO2022171072A1 (en) * | 2021-02-09 | 2022-08-18 | 上海维申医药有限公司 | Dihydropyrimidine compound, preparation method therefor and application thereof |
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| WO2021078221A1 (en) * | 2019-10-24 | 2021-04-29 | 广东东阳光药业有限公司 | Dihydropyrimidine compound and use thereof in drug |
| WO2022111719A1 (en) * | 2020-11-30 | 2022-06-02 | Sunshine Lake Pharma Co., Ltd. | Salts of dihydropyrimidine derivatives, complexes and uses thereof in medicine |
| CN114573589A (en) * | 2020-11-30 | 2022-06-03 | 广东东阳光药业有限公司 | Salts of dihydropyrimidine derivatives, complexes and their use in medicine |
| CN114573589B (en) * | 2020-11-30 | 2023-10-20 | 广东东阳光药业股份有限公司 | Salts, complexes of dihydropyrimidine derivatives and their use in medicine |
| WO2022121844A1 (en) * | 2020-12-09 | 2022-06-16 | 上海维申医药有限公司 | Dihydropyrimidine compound, preparation method therefor, and application thereof |
| CN115003673A (en) * | 2020-12-09 | 2022-09-02 | 上海维申医药有限公司 | Dihydropyrimidine compound, and preparation method and application thereof |
| CN115003673B (en) * | 2020-12-09 | 2023-08-11 | 上海维申医药有限公司 | Dihydropyrimidine compound, preparation method and application thereof |
| CN114853761A (en) * | 2021-02-05 | 2022-08-05 | 刘沛 | Bifunctional derivative containing dihydropyrimidine and application thereof |
| WO2022171072A1 (en) * | 2021-02-09 | 2022-08-18 | 上海维申医药有限公司 | Dihydropyrimidine compound, preparation method therefor and application thereof |
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| Publication number | Publication date |
|---|---|
| CN113166154B (en) | 2022-12-27 |
| CN113166154A (en) | 2021-07-23 |
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