WO2018045911A1 - Dihydropyrimidines, leur procédé de préparation et leur utilisation - Google Patents

Dihydropyrimidines, leur procédé de préparation et leur utilisation Download PDF

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Publication number
WO2018045911A1
WO2018045911A1 PCT/CN2017/100103 CN2017100103W WO2018045911A1 WO 2018045911 A1 WO2018045911 A1 WO 2018045911A1 CN 2017100103 W CN2017100103 W CN 2017100103W WO 2018045911 A1 WO2018045911 A1 WO 2018045911A1
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methyl
fluorophenyl
alkyl
chloro
group
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PCT/CN2017/100103
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English (en)
Chinese (zh)
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季明哲
白骅
刘礼飞
龚永祥
李译
曹启雄
邓永先
柴健
骆红英
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浙江海正药业股份有限公司
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Priority to CN201780053025.XA priority Critical patent/CN109803967B/zh
Publication of WO2018045911A1 publication Critical patent/WO2018045911A1/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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a dihydropyrimidine compound and its use as a medicament.
  • Such compounds have the effect of treating and preventing hepatitis B, particularly as a hepatitis B virus (HBV) inhibitor, by treating HBV capsids for the treatment of HBV infection.
  • HBV hepatitis B virus
  • the invention also relates to a process for the preparation of such compounds.
  • Hepatitis B is a disease caused by hepatitis B virus (HBV), which is mainly caused by inflammatory lesions of the liver and can cause damage to multiple organs.
  • HBV hepatitis B virus
  • Hepatitis B virus referred to as hepatitis B virus
  • hepatitis B virus is a DNA virus belonging to the Hepadnavividae family. It can cause acute or persistent/progressive chronic diseases.
  • Hepatitis B is widely prevalent in countries around the world, with more than 400 million people sick, especially in the Asia- Pacific region. A few of these patients can be converted to cirrhosis or liver cancer.
  • anti-hepatitis B virus nucleoside (acid) drugs on the market include lamivudine, telbivudine, entecavir, tenofovir, clafidine and the like.
  • the shortcomings of these drugs are: the treatment is not fixed, prone to virus resistance, and easy to relapse after stopping the drug. These shortcomings prevent patients from being cured.
  • heteroaryl ring-substituted dihydropyrimidine (HAP) compounds represented by Bay41-4109 and Bay3905493, which can inhibit HBV replication by preventing the formation of normal nucleocapsids.
  • Bay41-4109 showed better drug metabolism parameters in clinical studies (Deres K. et al., Science, 299 (2003), 893-896).
  • Studies on its mechanism of action have revealed that the heteroaryl ring-substituted dihydropyrimidine compounds change the angle between the dimers forming the nucleocapsid by acting on the 113-143 amino acid residues of the core protein, resulting in the formation of no Stable expanded nucleocapsid accelerates degradation of core proteins (Biochem. Pharmacol. 66 (2003), 2273-2279).
  • the present invention provides a compound represented by the formula (I), or a pharmaceutically acceptable salt or tautomer or enantiomer or diastereomer thereof:
  • R 1 is phenyl, wherein the phenyl group is optionally further substituted with one or more substituents selected from halogen, C 1-6 alkyl;
  • R 2 is selected from hydrogen or C 1-4 alkyl
  • A is a bond, -O-, -S- or -N(R 5 )-;
  • R 5 is hydrogen or C 1-4 alkyl
  • R is a group shown below:
  • R 9 is alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclyl or arylalkyl;
  • R 10 and R 10a are each independently hydrogen, haloalkyl, cycloalkyl, alkyl or hydroxyalkyl, or R 10 and R 10a together with a nitrogen atom attached thereto form a heterocyclic group;
  • n are each independently 1, 2, 3, 4;
  • n are each independently 0, 1, 2, 3, 4;
  • p is each independently 1 or 2.
  • R is preferably a substructure of the formula:
  • R is preferably selected from:
  • R 1 is preferably selected from phenyl, optionally further substituted by one or more halo.
  • R 2 is preferably methyl or ethyl.
  • A is preferably -O-.
  • R 3 is preferably thiazolyl, imidazolyl or pyridyl, wherein said thiazolyl, imidazolyl or pyridyl group is further optionally further selected from one or more selected from the group consisting of halogen, alkyl, Substituted by alkoxy, haloalkyl, alkylsulfonyl or cycloalkyl substituents.
  • R 1 is preferably 2 halogen-substituted phenyl;
  • R 2 is preferably methyl or ethyl;
  • A is preferably -O-;
  • n are each independently 0, 1, 2, 3, 4, preferably 0;
  • p is each independently 1 or 2.
  • the compound of formula (I) according to the invention is selected from the group consisting of:
  • a pharmaceutical composition comprising an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or tautomer or enantiomer or non-correspondence thereof isomer.
  • a further aspect of the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or tautomer or enantiomer or diastereomer thereof, or a pharmaceutical composition thereof, for use in therapy or Application in medicines for preventing diseases of hepatitis B virus infection.
  • a further aspect of the invention provides a process for the preparation of a compound of formula (I).
  • the method comprises reacting a compound of formula d with an R-H compound or a salt thereof in the presence of a base to give a compound of formula (I):
  • R 1 , R 2 , R 3 , R and A are as defined above; wherein the base is preferably an organic base, more preferably triethylamine.
  • the compound of the formula d is prepared by the following methods, including:
  • Step (1) a compound of the formula a is reacted with a compound of the formula b to give a compound of the formula c.
  • Step (2) The compound of formula c is reacted with a brominating reagent to give a compound of formula d:
  • the brominating agent in step (2) is preferably N-bromosuccinimide.
  • patient may include humans (including adults and children) or other animals. In some embodiments, “patient” refers to a human.
  • Alkyl means a straight or branched saturated aliphatic hydrocarbon group.
  • the alkyl group in the present application is preferably a C 1-6 alkyl group, that is, a saturated straight or branched alkyl group having 1 to 6 carbon atoms; a particularly preferred alkyl group in the present application is a C 1-4 alkyl group. That is, a saturated linear or branched alkyl group of 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, 1-butyl, 2-butyl and t-butyl groups and the like.
  • Alkoxy means a group of (alkyl-O-). Wherein alkyl is as defined above.
  • a preferred alkoxy group is a C 1-6 alkoxy group, and a particularly preferred alkoxy group is a C 1-4 alkoxy group.
  • the term C 1-6 alkoxy includes methoxy, ethoxy, n-propoxy and isopropoxy and the like.
  • cycloalkyl denotes a saturated carbocyclic ring containing from 3 to 12 carbon atoms, especially from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • cycloalkyl is cyclopropyl, cyclopentyl or cyclohexyl.
  • Haloalkyl or haloalkoxy means that the alkyl or alkoxy group is substituted by one or more of the same or different halogen atoms.
  • Preferred alkyl or alkoxy groups are as defined above. Examples include, but are not limited to, trifluoromethyl, trifluoroethyl, trifluoromethoxy.
  • Cycloalkylalkyl means that the alkyl group is substituted by one or more cycloalkyl groups. Examples include, but are not limited to, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, and the like.
  • Aryl means a monocyclic, bicyclic and tricyclic carbocyclic ring system containing from 6 to 14 ring atoms, wherein at least one ring system is aromatic, wherein each ring system comprises from 3 to 7 atoms A ring with one or more attachment points attached to the rest of the molecule. Examples include, but are not limited to, phenyl, naphthyl, anthracene, and the like. Preferably, the aryl group is a carbocyclic ring system of 6-10 or 6-7 ring atoms.
  • Heteroaryl means a monocyclic, bicyclic and tricyclic ring system containing from 5 to 14 ring atoms, wherein at least one ring system is aromatic and at least one ring system comprises one or more selected from the group consisting of nitrogen, oxygen, A sulfur heteroatom in which each ring system contains a ring of 5-7 atoms and has one or more attachment points attached to the remainder of the molecule.
  • the term “heteroaryl” can be used interchangeably with the terms “heteroaryl ring” or “heteroaromatic compound”. Examples include, but are not limited to, furyl, imidazolyl, 2-pyridyl, 3-pyridyl, thiazolyl, indolyl, quinolyl.
  • the heteroaryl is a ring system of 5 to 10 ring atoms.
  • Heteroarylalkyl means that a heteroaryl group is attached to the remainder of the molecule through an alkyl group. Examples include, but are not limited to, pyridin-2-ethyl, thiazol-2-methyl, pyrimidine-2-propyl, and the like.
  • amino refers to primary (-NH 2 ), secondary (-NH-) or tertiary amino
  • halogen means fluoro, chloro, bromo and iodo. In particular, halogen means fluorine, chlorine or bromine.
  • cyano refers to the group -CN.
  • hydroxy refers to the group -OH.
  • sulfonyl refers to the group -S(O) 2- .
  • C1-6 alkoxycarbonyl refers to the group C1-6 alkoxy-C(O)-, wherein said " C1-6 alkoxy” is as defined above.
  • aminocarbonyl refers to the group amino-C(O)-, wherein the “amino” is as defined above.
  • C1-6 alkylsulfonyl refers to the group C1-6 alkyl-S(O) 2- wherein the " C1-6 alkyl” is as defined above.
  • aminosulfonyl refers to the group amino-S(O) 2- wherein the “amino” is as defined above.
  • heterocyclyl refers to a non-aromatic saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system comprising from 3 to 12 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms.
  • the heterocyclyl group may be optionally substituted by one or more substituents described herein.
  • the sulfur atom of the ring can be optionally oxidized to an S-oxide.
  • the heterocyclic group is a 3-10, 3-6 ring atom, non-aromatic saturated or partially unsaturated monocyclic, bicyclic or tricyclic system wherein at least one ring atom is selected from nitrogen, Sulfur and oxygen atoms.
  • hydroxyalkyl means that the hydroxyalkyl group is attached to the remainder of the molecule through a carbon atom, wherein the alkyl group is as defined above.
  • the hydroxyalkyl group is preferably a linear or branched alkyl group having from 1 to 10 carbon atoms and substituted by one or more hydroxyl groups. More preferred hydroxyalkyl groups are lower hydroxyalkyl groups having from 1 to 6 carbon atoms or from 1 to 4 carbon atoms and one or more hydroxyl groups, such as hydroxymethyl (-CH 2 OH), hydroxyethyl (-CH) 2 CH 2 OH) and hydroxypropyl (-CH 2 CH 2 CH 2 OH) and the like.
  • tautomer refers to a structural isomer of an organic compound that is readily converted into each other by a chemical reaction known as tautomerization. This reaction usually results in the migration of a hydrogen atom or a proton, accompanied by the conversion of a single bond and an adjacent double bond, such as a compound of formula (I)
  • chiral refers to a molecule that has properties that are incapable of overlapping with its mirror image; and “achiral” refers to a molecule that can overlap with its mirror image.
  • enantiomer refers to two isomers of a compound that are not superimposable but are mirror images of one another.
  • diastereomer refers to a stereoisomer that has two or more centers of chirality and whose molecules are not mirror images of each other. Diastereomers generally have different physical properties such as melting point, boiling point, spectral properties, and reactivity. The mixture of diastereomers can be separated by high resolution analytical procedures such as electrophoresis and chromatography, such as HPLC.
  • the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the above formula, specific compounds of the invention, or particular examples, subclasses, as in the examples, And a class of compounds encompassed by the present invention.
  • substituents such as the compounds of the above formula, specific compounds of the invention, or particular examples, subclasses, as in the examples, And a class of compounds encompassed by the present invention.
  • substituents such as the compounds of the above formula, specific compounds of the invention, or particular examples, subclasses, as in the examples, And a class of compounds encompassed by the present invention.
  • substituents such as the compounds of the above formula, specific compounds of the invention, or particular examples, subclasses, as in the examples, And a class of compounds encompassed by the present invention.
  • substituents such as the compounds of the above formula, specific compounds of the invention, or particular examples, subclasses, as in the examples, And a class of compounds encompassed by the present invention
  • substituents may be substituted at the respective positions in the same or different manner.
  • pharmaceutically acceptable salt refers to certain salts of the above compounds which retain their original biological activity and are suitable for pharmaceutical use.
  • the pharmaceutically acceptable salt of the compound represented by the formula (I) may be a salt formed with a suitable acid, and the suitable acid includes an inorganic acid and an organic acid such as acetic acid, benzenesulfonic acid, and benzoic acid.
  • Acid camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionethane, lactic acid, malic acid, maleic acid, mandelic acid, methylsulfonate Acid, nitric acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like. Particularly preferred is hydrochloric acid, phosphoric acid or sulfuric acid.
  • the following reactions are generally operated under a positive pressure of nitrogen.
  • a suitable rubber stopper is placed on the reaction bottle, and the substrate can be driven through a syringe.
  • the glassware is dried.
  • the column is a silica gel column.
  • Nuclear magnetic resonance data was determined by a Bruker Advance 400 NMR spectrometer using CDCl 3 , d 6 -DMSO or CD 3 OD as a solvent (reported in ppm) with TMS (0 ppm) or chloroform (7.25 ppm) as a reference standard.
  • MS mass spectrometry
  • the starting materials and reagents of the present invention are all commercially available, and their suppliers are Aldrich Chemical Company, Alfa Chemical Company, Sinopharm Group, Linan Qingshan Chemical Reagent Factory, Jiangsu Huada Chemical Group and Hangzhou Chemical Reagent Co., Ltd. Commercially available starting materials and reagents were used without further purification unless otherwise indicated. For the described embodiments of the invention, all temperatures are in degrees Celsius (° C.) unless otherwise indicated.
  • Example 1 4-(2-Chloro-4-fluorophenyl)-6-(((S)-6-((methylsulfonyl)carbamoyl)-5-azaspiro[2.4]heptane Preparation of methyl 5-amino)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate
  • Step 1) Synthesis of the compound methyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate
  • Step 2 Compound 4-(2-chloro-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid methyl ester synthesis
  • Step 5 Compound 4-(2-chloro-4-fluorophenyl)-6-(((S)-6-((methylsulfonyl)carbamoyl)-5-azaspiro[2.4]heptane Synthesis of methyl 5-(5-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate
  • Example 5 4-(2-Chloro-4-fluorophenyl)-2-(3,5-fluoropyridin-2-yl)-6-(((S)-6-((methylsulfonyl)) Preparation of methyl carbamoyl)-5-azaspiro[2.4]heptane-5-yl)methyl)-1,4-dihydropyrimidine-5-carboxylate
  • Example 7 4-(2-Chloro-4-fluorophenyl)-6-(((S)-6-((methylsulfonyl)carbamoyl)-5-azaspiro[2.4]heptane Preparation of ethyl 5-amino)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate
  • Example 8 4-(2-Chloro-4-fluorophenyl)-6-(((S)-6-((cyclopropylsulfonyl)carbamoyl)-5-azaspiro[2.4]g Preparation of ethyl alk-5-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate
  • Example 9 4-(2-Chloro-4-fluorophenyl)-6-(((S)-6-(isopropylcarbamoyl)-5-azaspiro[2.4]heptane-5- Preparation of methyl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate
  • Example 19 (1S,2S,5R)-3-(((R)-6-(2-chloro-3-fluorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yl) Preparation of -3,6-dihydropyrimidin-4-yl)methyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid.
  • Example 29 (S)-((isopropoxycarbonyl)oxy)methyl 5-((6-(2-chloro-4-fluorophenyl)-5-(methoxycarbonyl)-(thiazole) Preparation of methyl-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)-5-azaspiro[2.4]heptane-6-carboxylate
  • qPCR detects the viral DNA content of the cell culture medium and calculates the concentration (EC 50 ) of the compound when the virus is inhibited by half.
  • concentration EC 50
  • HepG2.2.15 cells were inoculated into 24-well cell culture plates (200,000 cells/well), and cells were treated with cell culture medium containing different concentrations of test compounds on the next day (the highest concentration of compound was 5 ⁇ M, 5 times gradient dilution, 6 Dilution point). On the fifth day, the culture solution containing the drug to be tested was replaced, and on the eighth day, the culture supernatant was collected and centrifuged.
  • Quantitative PCR Refer to the Hepatitis B Virus Nucleic Acid Quantification Kit (PCR-Fluorescence Probe Method).
  • the nucleic acid release agent was added to the PCR reaction tube, and the diluted standard template was added to each tube (the highest concentration of the standard template was 4 ⁇ 10 7 IU/mL, and the 10-fold dilution was 4 points, and the lowest concentration was 4 ⁇ 10 4 IU/ mL);
  • Add the sample template configure the reaction mixture according to the PCR system, add to the reaction tube; cover the PCR reaction tube cover; run the quantitative PCR instrument according to the setting procedure.
  • %Inh. [1 - Total amount of compound treated HBV DNA / total amount of control treated HBV DNA] X100.
  • EC 50 values calculated for the compound of HBV replication GraphPad Prism5 application software, using the "four parameter logistic equation" calculate EC 50 values.
  • Example EC 50 ( ⁇ mol) Example EC 50 ( ⁇ mol) 1 a 11 a 2 a 12 a 4 a 17 a 5 a 19 a 6 a twenty two a 7 a twenty three a 10 a 28 a
  • Active interval a (0.001 ⁇ a ⁇ 0.20 ⁇ mol).
  • the experimental results show that the compound of the present invention has a strong anti-HBV virus action and is therefore suitable for treating various diseases caused by HBV virus infection.
  • the luminescence cell viability assay kit detects the HepG2 cell viability and calculates the concentration (CC 50 ) of the compound to inhibit the HepG2 cell viability by half.
  • the specific experimental methods are as follows:
  • %Inh. [1-Add compound treatment HepG2 cell viability/control treatment HepG2 cell viability] X100.
  • the CC 50 value of the compound for HepG2 cell viability was calculated: using the GraphPad Prism 5 analysis software, the "four-parameter logistic equation" was used to calculate the CC 50 value.
  • Example 7 90
  • Example 8 110
  • Example 10 115
  • Example 19 108
  • Example 22 70
  • Example 23 96
  • Example 28 79
  • control compound The structural formula of the control compound is shown in the following formula, and the preparation method thereof is described in Example 2 of WO2014037480.
  • the toxicity test results show that the compounds of the present invention are less toxic.
  • Compound compared to the control (murine LD 50> 600 mg)
  • some of the compounds, e.g., compounds of Example 4 (murine LD 50> 1000 mg) embodiment exhibits less toxicity than the control compound, better security.
  • Beagle dogs were injected intravenously with 2 mg/kg of test compound through the forelimb.
  • Beagle dogs were orally administered with 10 mg/kg of test compound.
  • the compounds of the present invention have a strong anti-HBV virus effect; and the compounds of the present invention have more favorable pharmacokinetic test results and good toxicity test results, which will make them more likely to be effective and safe. drug.
  • the compound of Example 4 had moderate clearance (4.99 mL/kg/min) and good bioavailability (48%), good toxicity test results (CC 50 of 132 ⁇ mol), which indicates that the compound of Example 4 is The application prospects for anti-HBV viruses are very good.

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Abstract

L'invention concerne un composé de dihydropyrimidine de formule (I) ou un sel pharmaceutiquement acceptable ou un tautomère ou un énantiomère ou un diastéréomère de celui-ci, où R 1 , R 2 , R 3 , R et A sont tels que définis dans la description et les revendications. L'invention concerne en outre un procédé de préparation du composé de formule (I) et son utilisation dans la préparation d'un médicament pour le traitement ou la prophylaxie de maladies infectieuses du virus de l'hépatite B.
PCT/CN2017/100103 2016-09-09 2017-09-01 Dihydropyrimidines, leur procédé de préparation et leur utilisation WO2018045911A1 (fr)

Priority Applications (1)

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CN201780053025.XA CN109803967B (zh) 2016-09-09 2017-09-01 二氢嘧啶类化合物及其制备方法和用途

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WO2019195181A1 (fr) 2018-04-05 2019-10-10 Gilead Sciences, Inc. Anticorps et leurs fragments qui se lient à la protéine x du virus de l'hépatite b
WO2019193533A1 (fr) 2018-04-06 2019-10-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Dinucléotides 2'2'-cycliques
WO2019193543A1 (fr) 2018-04-06 2019-10-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Dinucléotides 3'3'-cycliques
WO2019193542A1 (fr) 2018-04-06 2019-10-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Dinucléotides 2'3'-cycliques
WO2019200247A1 (fr) 2018-04-12 2019-10-17 Precision Biosciences, Inc. Méganucléases modifiées optimisées ayant une spécificité pour une séquence de reconnaissance dans un génome du virus de l'hépatite b
WO2019211799A1 (fr) 2018-05-03 2019-11-07 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Analogue de dinucléotide 2'3'-cyclique comprenant un nucléotide modifié par cyclopentanyle
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WO2020092621A1 (fr) 2018-10-31 2020-05-07 Gilead Sciences, Inc. Composés de 6-azabenzimidazole substitués en tant qu'inhibiteurs de hpk1
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US11261190B2 (en) 2017-10-18 2022-03-01 Sunshine Lake Pharma Co., Ltd. Dihydropyrimidine compounds and uses thereof in medicine
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WO2019211799A1 (fr) 2018-05-03 2019-11-07 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Analogue de dinucléotide 2'3'-cyclique comprenant un nucléotide modifié par cyclopentanyle
WO2020028097A1 (fr) 2018-08-01 2020-02-06 Gilead Sciences, Inc. Formes solides d'acide (r)-11-(méthoxyméthyl)-12-(3-méthoxypropoxy)-3,3-diméthyl-8-0 x0-2,3,8,13b-tétrahydro-1h-pyrido[2,1-a] pyrrolo[1,2-c]phtalazine-7-carboxylique
EP4371987A1 (fr) 2018-10-31 2024-05-22 Gilead Sciences, Inc. Composés de 6-azabenzimidazole substitués utilisés en tant qu'inhibiteurs de hpk1
WO2020092621A1 (fr) 2018-10-31 2020-05-07 Gilead Sciences, Inc. Composés de 6-azabenzimidazole substitués en tant qu'inhibiteurs de hpk1
WO2020092528A1 (fr) 2018-10-31 2020-05-07 Gilead Sciences, Inc. Composés 6-azabenzimidazole substitués ayant une activité inhibitrice de hpk1
US11766447B2 (en) 2019-03-07 2023-09-26 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3′3′-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide as sting modulator
WO2020178768A1 (fr) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Analogue du dinucléotide 3'3'-cyclique comprenant un nucléotide modifié par cyclopentanyle utilisé en tant que modulateur de sting
WO2020178770A1 (fr) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Dinucléotides 3'3'-cycliques et leurs promédicaments
WO2020178769A1 (fr) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Dinucléotides cycliques en 2'3' et leurs promédicaments
WO2020214652A1 (fr) 2019-04-17 2020-10-22 Gilead Sciences, Inc. Formes solides d'un modulateur de récepteur de type toll
WO2020214663A1 (fr) 2019-04-17 2020-10-22 Gilead Sciences, Inc. Formes solides d'un modulateur de récepteur de type toll
WO2020237025A1 (fr) 2019-05-23 2020-11-26 Gilead Sciences, Inc. Exo-méthylène-oxindoles substitués qui sont des inhibiteurs de hpk1/map4k1
WO2020263830A1 (fr) 2019-06-25 2020-12-30 Gilead Sciences, Inc. Protéines de fusion flt3l-fc et procédés d'utilisation
WO2021034804A1 (fr) 2019-08-19 2021-02-25 Gilead Sciences, Inc. Formulations pharmaceutiques de ténofovir alafénamide
WO2021067181A1 (fr) 2019-09-30 2021-04-08 Gilead Sciences, Inc. Vaccins contre le virus de l'hépatite b et méthodes de traitement du vhb
WO2021113765A1 (fr) 2019-12-06 2021-06-10 Precision Biosciences, Inc. Méganucléases modifiées optimisées ayant une spécificité pour une séquence de reconnaissance dans un génome du virus de l'hépatite b
WO2021188959A1 (fr) 2020-03-20 2021-09-23 Gilead Sciences, Inc. Promédicaments de nucléosides de 4'-c-substitué-2-halo-2'-désoxyadénosine et leurs procédés de fabrication et d'utilisation
WO2022031894A1 (fr) 2020-08-07 2022-02-10 Gilead Sciences, Inc. Promédicaments d'analogues nucléotidiques de phosphonamide et leur utilisation pharmaceutique
WO2022087149A2 (fr) 2020-10-22 2022-04-28 Gilead Sciences, Inc. Protéines de fusion d'interleukine-2-fc et méthodes d'utilisation
WO2022241134A1 (fr) 2021-05-13 2022-11-17 Gilead Sciences, Inc. Combinaison d'un composé de modulation de tlr8 et agent thérapeutique anti-arnsi de vhb
WO2022271650A1 (fr) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Composés de modulation de la diacylglycérol kinase
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