WO2020135439A1 - Composé dihydropyrimidine deutéré et son utilisation en tant que médicament - Google Patents

Composé dihydropyrimidine deutéré et son utilisation en tant que médicament Download PDF

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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
hooc
group
methyl
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PCT/CN2019/128015
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English (en)
Chinese (zh)
Inventor
任青云
刘辛昌
张英俊
S•戈尔德曼
王猛
丘荣茂
颜光华
雷斗兴
李凤
邹致富
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广东东阳光药业有限公司
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Priority to CN201980070730.XA priority Critical patent/CN113166154B/zh
Publication of WO2020135439A1 publication Critical patent/WO2020135439A1/fr

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    • 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

La présente invention concerne un composé dihydropyrimidine deutéré et une utilisation correspondante en tant que médicament, en particulier en tant que médicament pour le traitement et/ou la prévention de l'hépatite B. Plus particulièrement, l'invention concerne un composé représenté par la formule générale (I) ou (Ia) ou un stéréoisomère, un tautomère, un oxynitrure, un solvate, un métabolite, un sel pharmaceutiquement acceptable ou un promédicament de celui-ci, chaque variant étant tel que défini dans la description. La présente invention concerne également l'utilisation du composé représenté par la formule générale (I) ou (Ia) ou un stéréoisomère, un tautomère, un oxynitrure, un solvate, un métabolite, ou un sel pharmaceutiquement acceptable de celui-ci en tant que médicament, en particulier en tant que médicament pour le traitement et la prévention de l'hépatite B. (I), (IA)
PCT/CN2019/128015 2018-12-25 2019-12-24 Composé dihydropyrimidine deutéré et son utilisation en tant que médicament WO2020135439A1 (fr)

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WO2021078221A1 (fr) * 2019-10-24 2021-04-29 广东东阳光药业有限公司 Composé dihydropyrimidine et son utilisation en tant que médicament
WO2022111719A1 (fr) * 2020-11-30 2022-06-02 Sunshine Lake Pharma Co., Ltd. Sels de dérivés de dihydropyrimidine, complexes et leurs utilisations en médecine
CN114573589A (zh) * 2020-11-30 2022-06-03 广东东阳光药业有限公司 二氢嘧啶衍生物的盐、复合物以及它们在药物中的应用
CN114573589B (zh) * 2020-11-30 2023-10-20 广东东阳光药业股份有限公司 二氢嘧啶衍生物的盐、复合物以及它们在药物中的应用
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CN115003673B (zh) * 2020-12-09 2023-08-11 上海维申医药有限公司 一种二氢嘧啶类化合物、其制备方法及应用
CN114853761A (zh) * 2021-02-05 2022-08-05 刘沛 一种含有二氢嘧啶的双功能衍生物及其用途
WO2022171072A1 (fr) * 2021-02-09 2022-08-18 上海维申医药有限公司 Composé de dihydropyrimidine, son procédé de préparation et son utilisation

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