WO2022253294A1 - 具有整合酶抑制活性的吡啶酮化合物及其药用用途 - Google Patents

具有整合酶抑制活性的吡啶酮化合物及其药用用途 Download PDF

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WO2022253294A1
WO2022253294A1 PCT/CN2022/096750 CN2022096750W WO2022253294A1 WO 2022253294 A1 WO2022253294 A1 WO 2022253294A1 CN 2022096750 W CN2022096750 W CN 2022096750W WO 2022253294 A1 WO2022253294 A1 WO 2022253294A1
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compound
cycloalkyl
pharmaceutically acceptable
halogen
alkyl
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French (fr)
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祝令建
洪敏�
陶伟峰
吴岱泽
潘小玉
高璐
黄建
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江苏恒瑞医药股份有限公司
上海森辉医药有限公司
瑞可迪（上海）生物医药有限公司
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Priority to CN202280050796.4A priority Critical patent/CN117715908A/zh
Publication of WO2022253294A1 publication Critical patent/WO2022253294A1/zh

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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
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms

Definitions

  • the disclosure belongs to the field of medicine, and relates to a pyridone compound with integrase inhibitory activity and its medicinal use.
  • HIV Human Immunodeficiency Virus
  • AIDS AIDS virus
  • HIV-1 Human immunodeficiency virus type 1 (HIV-1) encodes three enzymes required for viral replication: reverse transcriptase, protease, and integrase. Although drugs targeting reverse transcriptase and protease are widely used and have been shown to be effective, especially when used in combination, the development of toxic and resistant strains has limited their usefulness.
  • HIV integrase inhibitors have attracted attention as anti-HIV drugs with novel mechanisms of action (WO2006116764A1 and WO2013054862A1). HIV integrase inhibitors (integrase inhibitors) are anti-HIV/AIDS drugs with a new mechanism of action. They can be used in combination with other antiretroviral drugs to effectively treat HIV infection, and clinical drug resistance is not easy to develop.
  • the cocktail therapy consisting of HIV integrase inhibitors and marketed reverse transcriptase inhibitors, protease inhibitors, and fusion inhibitors may solve the problem of single-drug resistance and cross-drug resistance, and will significantly improve the existing HIV Therapeutic effects of drugs and become new treatment approaches and options.
  • HIV integrase inhibitors that have been approved for marketing and entered into clinical application include: raltegravir, elvitegravir, dolutegravir, bictegravir, cabotegravir, and fixed-dose compound preparations Stribild.
  • the present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, hydroxyl; the C 1-6 alkyl, C 3-6 cycloalkyl, 3- 6-membered heterocyclyl is optionally substituted by 1-3 R 5a ;
  • R 2 is selected from hydrogen, halogen, C 1-6 alkyl substituted by 1-3 halogens, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, hydroxyl, methylene cyclopropyl, oxo;
  • the C 3-6 cycloalkyl, 3-6 membered heterocyclic group, and methylene cyclopropyl are optionally substituted by 1-3 R 5b ;
  • R3 is independently selected from halogen, cyano, amino, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, hydroxyl; said C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl are optionally substituted by 1-3 R 5c ;
  • n is an integer selected from 0-4;
  • R 4 is independently selected from halogen, cyano, amino, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, hydroxyl, oxo; said C 1-6 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl are optionally substituted by 1-3 R 5d ;
  • n is an integer of 0-2;
  • R 5a , R 5b , R 5c , and R 5d are each independently selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, hydroxyl, cyano, amino, nitro .
  • the compound shown in formula I can be:
  • R is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, hydroxyl;
  • the C 1-6 alkyl and C 3-6 cycloalkyl are optionally substituted by 1-3 R 5a ;
  • R 5a is selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, hydroxyl, cyano, amino, nitro;
  • R 1 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, hydroxyl; said C 1-6 alkyl, C 3-6 cycloalkyl are optionally replaced by 1-3 R 5a Substitution; R 5a is selected from halogen, methyl, ethyl, isopropyl, cyclopropyl, n-propyl, hydroxyl, cyano, amino, nitro.
  • R is independently selected from halogen, cyano, amino, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, hydroxyl, oxo; the C 1-6 alkyl, C 3-6 cycloalkyl are optionally substituted by 1-3 R 5d ;
  • R 5d are each independently selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, hydroxyl, cyano, amino, nitro;
  • R 4 is independently selected from halogen, cyano, amino, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, hydroxyl, oxo.
  • n is an integer of 0-2; preferably m is an integer of 0-1; more preferably m is 0.
  • R is independently selected from halogen, cyano, amino, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, hydroxyl; said C 1-6 alkyl, C 3-6 cycloalkyl is optionally substituted by 1-3 R 5c ;
  • n is an integer selected from 0-4;
  • R 5c are each independently selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, hydroxyl, cyano, amino, nitro;
  • R is independently selected from halogen, cyano, amino, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, hydroxyl; said C 1-6 alkyl, C 3-6 cycloalkyl Optionally replaced by 1-3 R 5c ;
  • n is an integer selected from 0-2;
  • R 5c are each independently selected from halogen, methyl, ethyl, cyclopropyl, isopropyl, hydroxyl, cyano, amino, nitro;
  • R is independently selected from halogen, cyano, amino, nitro, methyl, ethyl, cyclopropyl, isopropyl, hydroxy; any of said methyl, ethyl, cyclopropyl, isopropyl Optionally replaced by 1-3 R 5c ;
  • n is an integer selected from 0-2;
  • R 5c are each independently selected from halogen, methyl, ethyl, cyclopropyl, isopropyl, hydroxyl, cyano, amino, nitro;
  • the present disclosure also provides a compound represented by formula IV or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , R 3 , R 4 , and m are as defined in formula I.
  • the present disclosure also provides a compound represented by formula V or a pharmaceutically acceptable salt thereof,
  • R 2 is as defined in formula I.
  • R 2 is selected from hydrogen, halogen, C 1 substituted by 1-3 halogens -6 alkyl, C 3-6 cycloalkyl, hydroxyl, methylene cyclopropyl, oxo; said C 3-6 cycloalkyl, methylene cyclopropyl is optionally replaced by 1-3 R 5b replaced by
  • R 2 is selected from hydrogen, halogen, C 1-6 alkyl substituted by 1-3 halogens, C 3-6 cycloalkyl; said C 3-6 cycloalkyl is optionally replaced by 1-3 R 5b replace;
  • R is selected from 1-3 fluorine-substituted methyl, cyclopropyl; the cyclopropyl is optionally substituted by 1-3 halogen;
  • R2 is selected from monofluoromethyl, cyclopropyl.
  • R 5b is selected from halogen, C 1-6 alkyl, C 3-6 Cycloalkyl, hydroxyl, cyano, amino, nitro;
  • R is selected from halogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, hydroxyl, cyano, amino, nitro; more
  • R 5b is selected from fluoro, methyl, hydroxy, cyano, amino, nitro.
  • the present disclosure also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof,
  • the present disclosure also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof,
  • the present disclosure also provides an isotopic substitution of a compound shown in Formula I, Formula II, Formula III, Formula IV, Formula V, the second aspect or the third aspect or a pharmaceutically acceptable salt thereof matter, preferably, the isotopic substitution is deuterium atom substitution.
  • the present disclosure also provides a pharmaceutical composition, including the compound shown in formula I, formula II, formula III, formula IV, formula V, second aspect, third aspect, fourth aspect or pharmaceutically acceptable salts and pharmaceutically acceptable excipients.
  • the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.
  • the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 1%-99% of the compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 2%-98% of the compound or a pharmaceutically acceptable salt thereof.
  • the present disclosure also provides a method for treating or preventing HIV infection in humans, by administering to humans a therapeutically effective amount such as formula I, formula II, formula III, formula IV, formula V, the second aspect, the third aspect, the third aspect
  • a therapeutically effective amount such as formula I, formula II, formula III, formula IV, formula V, the second aspect, the third aspect, the third aspect
  • the present disclosure also provides a compound as shown in Formula I, Formula II, Formula III, Formula IV, Formula V, the second aspect, the third aspect, the fourth aspect or its pharmaceutical preparation for treating or preventing human HIV infection
  • a salt or the pharmaceutical composition of the fifth aspect the compound or its pharmaceutically acceptable salt or pharmaceutical composition is used in combination with one or more additional therapeutic agents.
  • the additional therapeutic agent is selected from HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase one or more of the agents.
  • said additional therapeutic agent is selected from the group consisting of Raltegravir, Lamivudine, Abacavir, Ritonavir, Dolugravir, Darunavir, Atazana One or more of Wei, Emtricitabine, Tenofovir, Evitagravir, Rilpivirine or Lopinavir.
  • the present invention may include all isomers such as tautomers, rotamers, geometric isomers, diastereoisomers body, racemate and enantiomer.
  • Tautomers are structural isomers of organic compounds that are readily interconvertible through a chemical reaction known as tautomerization. This reaction often results in the formal transfer of hydrogen atoms or protons, accompanied by the conversion of single bonds and adjacent double bonds. Some common tautomeric pairs are: keto-enol, lactam-lactim. An example of a lactam-lactim equilibrium is between A and B as shown below.
  • the bond Indicates unassigned configuration, i.e. if chiral isomers exist in the chemical structure, the bond can be or or both and Two configurations.
  • the bond If the configuration is not specified, it can be the Z configuration or the E configuration, or both configurations.
  • Atoms capable of being isotopically labeled include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, iodine, and the like. They can be replaced by isotopes 2 H(D), 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I, respectively. Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium (i.e., at least 45% % deuterium incorporation).
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiologically acceptable carriers and excipients. Forming agent.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • “Pharmaceutically acceptable excipients” include, but are not limited to, any adjuvants, carriers, excipients, glidants, sweeteners, diluents, agent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier.
  • Alkyl refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms. An alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and various branched isomers, etc.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, Deuterium, hydroxyl, oxo, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkane Base, 3 to 6 membered heterocycloalkyl, C 5-8 cycloalkenyl, C 3-6 cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 5-8 cycloalkenyloxy, C 6- 10 aryl or 5 to 6-membered heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 ring Alkyl, 3-6 membered heterocycloalkyl, C
  • Cycloalkyl or “cyclic hydrocarbon” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 8 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.; multicyclic cycloalkyls include spiro Cycloalkyl rings, fused rings and bridged rings.
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring where the ring bonded to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc.
  • cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from deuterium, alkyl, alkenyl, alkyne radical, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkane Oxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • Heterocyclyl or “heterocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group containing from 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen or S (O) heteroatoms of m (where m is an integer from 0 to 2), excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • m is an integer from 0 to 2
  • ring portions of -OO-, -OS- or -SS- the remaining ring atoms being carbon.
  • it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably it contains 3 to 7 ring atoms.
  • Non-limiting examples of monocyclic heterocycloalkyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperrolyl, Pyridyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc.
  • Multicyclic heterocycloalkyls include spiro, fused and bridged heterocycloalkyls.
  • Non-limiting examples of "heterocycloalkyl" include:
  • Heterocycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from, for example, halogen, deuterium, hydroxyl, oxo, nitro, cyano radical, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, C 5-8 cycloalkenyl, C 3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C 5-8 cycloalkenyloxy, C 6-10 aryl or 5-6 membered heteroaryl , the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl , C 5-8
  • the heterocyclyl ring may be fused to an aromatic ring, a heteroaromatic ring, or a cyclic hydrocarbon, wherein the ring bonded to the parent structure is a heterocyclyl, non-limiting examples of which include:
  • Substituted by one or more A, B means that it can be substituted by single or multiple substituents. When substituted by a plurality of substituents, it may be a plurality of the same substituents, or one or a combination of a plurality of different substituents.
  • RAL represents raltegravir (raltegravir,); CAB represents cabotegravir, and CAB is set to 1 for the antiviral activity EC50 of each mutant virus strain, **: have significant difference with CAB and p-value is less than 0.05, N shows the number of repeated detections.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • HPLC HP pressure liquid chromatography
  • ACQUITY UPLC BEH C18 1.7UM 2.1X50MM column, Ultimate XB-C180 3.0*15 Column or Xtimate C18 2.1*30mm column Waters ACQUITY ultra high performance LC, Shimadzu LC-20A systems, Shimadzu LC-2010HT series or Agilent Agilent 1200LC high pressure liquid chromatography (ACQUITY UPLC BEH C18 1.7UM 2.1X50MM column, Ultimate XB-C180 3.0*15 Column or Xtimate C18 2.1*30mm column).
  • MS uses a Waters SQD2 mass spectrometer to scan in positive/negative ion mode, and the mass scanning range is 100-1200.
  • Chiralpak IC-3 100 ⁇ 4.6mm I.D., 3um, Chiralpak AD-3 150 ⁇ 4.6mm I.D., 3um, Chiralpak AD-3 50 ⁇ 4.6mm I.D., 3um, Chiralpak AS-3 150 ⁇ 4.6mm for chiral HPLC analysis and determination I.D., 3um, Chiralpak AS-3 100 ⁇ 4.6mm I.D., 3 ⁇ m, ChiralCel OD-3 150 ⁇ 4.6mm I.D., 3um, Chiralcel OD-3 100 ⁇ 4.6mm I.D., 3 ⁇ m, ChiralCel OJ-H 150 ⁇ 4.6mm I.D., 5um, Chiralcel OJ-3 150 ⁇ 4.6mm I.D., 3um column;
  • the thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. ⁇ 0.5mm.
  • the flash column purification system uses Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage).
  • Forward column chromatography generally uses Yantai Huanghai silica gel 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel as the carrier, or Changzhou Santai pre-packed pre-packed ultra-pure normal-phase silica gel column (40-63 ⁇ m, 60, 12g ,, 25g, 40g, 80g or other specifications).
  • Reversed-phase column chromatography generally uses Changzhou Santai pre-packed ultra-pure C18 silica gel column (20-45 ⁇ m, 40g, 80g, 120g, 220g or other specifications).
  • the high-pressure column purification system uses Waters AutoP, together with Waters XBridge BEH C18 OBD Prep Column, 5 ⁇ m, 19mm X 150mm or Atlantis T3 OBD Prep Column, 5 ⁇ m, 19mm X 150mm.
  • the chiral preparative column uses DAICEL CHIRALPAK IC (250mm*30mm, 10um) or Phenomenex-Amylose-1 (250mm*30mm, 5um).
  • the known starting materials in this disclosure can be adopted or synthesized according to methods known in the art, or can be purchased from Shanghai Titan Technology, ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui Chemicals and other companies.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.
  • the pressurized hydrogenation reaction uses Parr 3916EKX hydrogenation instrument and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation instrument.
  • the hydrogenation reaction is usually vacuumized and filled with hydrogen, and the operation is repeated 3 times.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the embodiment adopts thin-layer chromatography (TLC), the developing agent used in reaction, the eluent system of the eluent system of the column chromatography that purification compound adopts and the developing agent system of thin-layer chromatography, the volume of solvent
  • TLC thin-layer chromatography
  • the ratio is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
  • Test compounds were dissolved in DMSO at a concentration of 10 mM and stored at -20°C.
  • test compound was evaluated using an initial concentration of 100 nM and five serial semi-logarithmic dilutions. The concentration of each compound in the assay medium was 2 times the final desired test concentration. Compounds were diluted to 1 mM in DMSO. Compounds were then diluted to 200 nM in drug dilution tubes containing 998 ⁇ L of assay medium (add 2 ⁇ L of 1 mM stock). 320 microliters (320 ⁇ L) of the 200 nM solution were transferred into 680 ⁇ L of assay medium (semi-log dilution) for a total of five serial dilutions. One hundred microliters (100 ⁇ L) of each concentration was added to duplicate wells for cytotoxicity assessment, and each concentration was added to one well for colorimetric assessment.
  • MT-4 cells were passaged in T-75 flasks prior to use in antiviral assays. The day before the assay, cells were passaged in a 1:2 split to ensure they were in exponential growth phase at the time of infection. Total and viable cell quantification was performed using a hemocytometer and trypan blue dye. The proportion of viable cells used for the assay was greater than 95%. Resuspend cells in tissue culture medium at 5 x 104 cells per mL and add to drug-containing microtiter plates in a volume of 50 ⁇ L.
  • the virus used for this assay is the lymphotropic virus strain HIV-1IIIB. Amplified in CEM-SS cells for preparation of virus stocks. Remove pre-titrated viral aliquots from the freezer (-80 °C) and slowly thaw to room temperature in a biosafety cabinet. Diluted virus into tissue culture medium, 50ul of diluted virus produced 85% to 95% cell killing rate at 6 days after infection. Immediately add 50 ⁇ L of diluted virus to the microtiter plate containing cells and drug.
  • XTT/PMS stock solutions by adding a ratio of 40 ⁇ l PMS per ml XTT solution before use. Add 50 microliters of XTT/PMS to each well of the plate and re-incubate the plate at 37°C for 4 hours. Seal the plate with adhesive plate sealant and shake gently or invert several times to mix the soluble formazan product and read absorbance at 450/650 nm.
  • Preparation of Pseudovirus Using the lentiviral plasmid pNL4-3-Luc-R - E- (Heigie Hog) as the backbone, construct an integrase point mutation plasmid.
  • HEK293T cells ATCC were seeded in 6-well plates at a cell number of 5 ⁇ 10 5 per well. After 24 hours, transfection was performed when the cell density reached 60%-80%.
  • transfection reagent add pNL4-3-Luc-R - E - or pNL4-3-Luc-R - E - -IN-mutant plasmid and lentiviral packaging plasmid pMD2.G (Beijing Zhuangmeng) according to a certain ratio.
  • Cell transfection was carried out according to the instructions of the transfection reagent PEI25K (Mao Kang Biology). After 48 hours, the supernatant was collected, centrifuged at 3000 rpm for 5 minutes, filtered through a 0.45 ⁇ m microporous membrane, aliquoted, and stored at -80°C until use.
  • the pseudovirus titer was detected according to the luciferase activity.
  • Detection of compound antiviral activity In a 96-well V-bottom plate, half-logarithmic dilution of the compound to be tested was performed with DMSO, and a compound solution 4 times the final concentration was prepared for use. Dilute the virus with complete medium according to the results of different virus titrations. Trypsinize HEK293T cells to make 2X10 5 /mL cell suspension. In a 96-well flat-bottom plate, 50ul compound dilution, 50ul virus dilution, and 100ul cell suspension were sequentially added. The final compound concentration was 1000 nM-0.1 nM. Place the 96-well assay plate in a 37°C, 5% CO2 incubator for incubation.
  • Test Example 3 Inhibitor activity test against clinical HIV-1 strains.
  • the clinical HIV-1 virus strains (Table 3) were obtained from the American NIH AIDS Research and Reference Reagent Library. PBMC were extracted from three HIV and HBV seronegative fresh blood, mixed cultured, and PHA-P (phytohemagglutinin) was added to stimulate activation. Cells were incubated with virus at 37°C/5% CO2 , and post-infection cell culture supernatants were collected and stored frozen at -80°C. Each virus titer was titrated in three donor pooled PBMCs.
  • HIV-1 subtype virus strain A RW/92/009 C MW/93/959 D. UG/92/001
  • the CC 50 of the compound is greater than 100nM, for different subtypes of HIV-1 clinical isolates (RW/92/009, MW/93/959, UG/92/001), in human PBMC Among them, compound 2 was more active than cabotegravir.

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Abstract

本公开提供具有整合酶抑制活性的吡啶酮化合物及其药用用途。具体而言，本公开提供式I所示的化合物结构或其可药用盐，可用于治疗人类免疫缺陷(HIV)感染。

Description

具有整合酶抑制活性的吡啶酮化合物及其药用用途 技术领域
本公开属于医药领域，涉及一种具有整合酶抑制活性的吡啶酮化合物及其药用用途。
背景技术
人体免疫缺陷病毒(HIV)，又称人体免疫缺损病毒。是已知结构最复杂的一种反转录病毒，包括艾滋病病毒(AIDS)。进入艾滋病期，艾滋病病毒感染会引起各种机会性感染和肿瘤的发生，这些并发症会对人的健康生活带来影响，甚至可能会威胁生命，因此艾滋病病毒会引发人们的恐慌情绪。
1型人类免疫缺陷性病毒(HIV-1)编码三种病毒复制所需的酶：逆转录酶、蛋白酶和整合酶。虽然靶向逆转录酶和蛋白酶的药物广泛使用且已经显示有效，特别是当组合应用时，但是毒性和抗性株的发展限制了它们的有用性。
另一方面，由于耐药病毒的频繁出现，多药联合治疗在AIDS的治疗中有效。在临床上将逆转录酶抑制剂和蛋白酶抑制剂中的两种用作抗HIV药，但是具有相同作用机制的药物常呈现交叉耐药性或仅呈现附加的效能。因此，要求开发具有不同作用机制的抗HIV药。
在这种情况下，作为具有新的作用机制的抗HIV药，整合酶抑制剂备受关注(WO2006116764A1和WO2013054862A1)。HIV整合酶抑制剂(integrase inhibitors)是一种全新作用机制的抗HIV/AIDS药物，可与其他抗逆转录病毒药物联合用药有效治疗HIV感染，且临床不易产生耐药性。
HIV整合酶抑制剂与已上市的逆转录酶抑制剂、蛋白酶抑制剂、融合抑制剂组成的鸡尾酒疗法，可能解决单一用药的耐药性及易产生的交叉耐药问题，将显著改善现有HIV药物的治疗效果，并成为新的治疗途径和选择。
目前已批准上市并进入临床应用的HIV整合酶抑制剂药物有：拉替拉韦(raltegravir)、埃替拉韦(elvitegravir)、dolutegravir、比克替拉韦、卡博特韦以及固定剂量复方制剂Stribild。
发明内容
本公开提供一种式I所示的化合物或其可药用盐，
Figure PCTCN2022096750-appb-000001
其中，
R 1选自氢、C 1-6烷基、C 3-6环烷基、3-6元杂环基、羟基；所述C 1-6烷基、C 3-6环烷基、3-6元杂环基任选被1-3个R 5a所取代；
R 2选自氢、卤素、1-3个卤素取代的C 1-6烷基、C 3-6环烷基、3-6元杂环基、羟基、亚甲基环丙基、氧代；所述C 3-6环烷基、3-6元杂环基、亚甲基环丙基任选被1-3个R 5b所取代；
R 3独立地选自卤素、氰基、氨基、硝基、C 1-6烷基、C 3-6环烷基、3-6元杂环基、羟基；所述C 1-6烷基、C 3-6环烷基、3-6元杂环基任选被1-3个R 5c所取代；
n选自0-4的整数；
R 4独立地选自卤素、氰基、氨基、硝基、C 1-6烷基、C 3-6环烷基、3-6元杂环基、羟基、氧代；所述C 1-6烷基、C 3-6环烷基、3-6元杂环基任选被1-3个R 5d所取代；
m为0-2的整数；
R 5a、R 5b、R 5c、R 5d各自独立地选自卤素、C 1-6烷基、C 3-6环烷基、3-6元杂环基、羟基、氰基、氨基、硝基。
在某些实施方案中，式I所示的化合物可以为：
Figure PCTCN2022096750-appb-000002
在某些实施方案中，式I、式II或式III所示的化合物或其可药用盐中，R 1选自氢、C 1-6烷基、C 3-6环烷基、羟基；所述C 1-6烷基、C 3-6环烷基任选被1-3个R 5a所取代；
R 5a选自卤素、C 1-6烷基、C 3-6环烷基、羟基、氰基、氨基、硝基；
优选R 1选自氢、C 1-6烷基、C 3-6环烷基、羟基；所述C 1-6烷基、C 3-6环烷基任选被1-3个R 5a所取代；R 5a选自卤素、甲基、乙基、异丙基、环丙基、正丙基、羟基、氰基、氨基、硝基。
在某些实施方案中，式I、式II或式III所示的化合物或其可药用盐中，R 4独立地选自卤素、氰基、氨基、硝基、C 1-6烷基、C 3-6环烷基、羟基、氧代；所述C 1-6烷基、C 3-6环烷基任 选被1-3个R 5d所取代；
R 5d各自独立地选自卤素、C 1-6烷基、C 3-6环烷基、羟基、氰基、氨基、硝基；
优选R 4独立地选自卤素、氰基、氨基、硝基、C 1-6烷基、C 3-6环烷基、羟基、氧代。
在某些实施方案中，式I、式II或式III所示的化合物或其可药用盐中，m为0-2的整数；优选m为0-1的整数；更优选m为0。
在某些实施方案中，式I、式II或式III所示的化合物或其可药用盐中，R 3独立地选自卤素、氰基、氨基、硝基、C 1-6烷基、C 3-6环烷基、羟基；所述C 1-6烷基、C 3-6环烷基任选被1-3个R 5c所取代；
n选自0-4的整数；
R 5c各自独立地选自卤素、C 1-6烷基、C 3-6环烷基、羟基、氰基、氨基、硝基；
优选R 3独立地选自卤素、氰基、氨基、硝基、C 1-6烷基、C 3-6环烷基、羟基；所述C 1-6烷基、C 3-6环烷基任选被1-3个R 5c所取代；
n选自0-2的整数；
R 5c各自独立地选自卤素、甲基、乙基、环丙基、异丙基、羟基、氰基、氨基、硝基；
更优选R 3独立地选自卤素、氰基、氨基、硝基、甲基、乙基、环丙基、异丙基、羟基；所述甲基、乙基、环丙基、异丙基任选被1-3个R 5c所取代；
n选自0-2的整数；
R 5c各自独立地选自卤素、甲基、乙基、环丙基、异丙基、羟基、氰基、氨基、硝基；
最优选R 3独立地选自卤素；n选自0-2的整数。
本公开还提供了一种式IV所示的化合物或其可药用盐，
Figure PCTCN2022096750-appb-000003
R 1、R 2、R 3、R 4、m如式I中定义。
本公开还提供了一种式V所示的化合物或其可药用盐，
Figure PCTCN2022096750-appb-000004
R 2如式I中定义。
在某些实施方案中，式I、式II、式III、式IV或式V所示的化合物或其可药用盐中，R 2选自氢、卤素、1-3个卤素取代的C 1-6烷基、C 3-6环烷基、羟基、亚甲基环丙基、氧代；所述C 3-6环烷基、亚甲基环丙基任选被1-3个R 5b所取代；
优选R 2选自氢、卤素、1-3个卤素取代的C 1-6烷基、C 3-6环烷基；所述C 3-6环烷基任选被1-3个R 5b所取代；
更优选R 2选自1-3个氟取代的甲基、环丙基；所述环丙基任选被1-3个卤素所取代；
最优选R 2选自单氟甲基、环丙基。
在某些实施方案中，式I、式II、式III、式IV或式V所示的化合物或其可药用盐中，R 5b选自卤素、C 1-6烷基、C 3-6环烷基、羟基、氰基、氨基、硝基；优选R 5b选自卤素、甲基、乙基、正丙基、异丙基、环丙基、羟基、氰基、氨基、硝基；更优选R 5b选自氟、甲基、羟基、氰基、氨基、硝基。
第二方面，本公开还提供了一种下式所示的化合物或其可药用盐，
Figure PCTCN2022096750-appb-000005
第三方面，本公开还提供了一种下式所示的化合物或其可药用盐，
Figure PCTCN2022096750-appb-000006
第四方面，本公开还提供一种如式I、式II、式III、式IV、式V、第二方面或第三方面所示的化合物或其可药用盐所示的化合物的同位素取代物，优选地，所述的同位素取代为氘原子 取代。
第五方面，本公开还提供一种药物组合物，包括式I、式II、式III、式IV、式V、第二方面、第三方面、第四方面所示的化合物或其可药用盐和可药用赋形剂。
在一些实施方案中，所述的药物组合物的单位剂量为0.001mg-1000mg。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01-99.99％的前述化合物或其可药用的盐。在某些实施方案中，所述的药物组合物含有0.1-99.9％的前述化合物或其可药用的盐。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的化合物或其可药用的盐。在某些实施方案中，所述的药物组合物含有1％-99％的化合物或其可药用的盐。在某些实施方案中，所述的药物组合物含有2％-98％的化合物或其可药用的盐。本公开还提供一种治疗或预防人类HIV感染的的方法，其通过向人类施用治疗有效量的如式I、式II、式III、式IV、式V、第二方面、第三方面、第四方面所示的化合物或其可药用盐或第五方面所述的药物组合物。
本公开还提供一种用于治疗或预防人类HIV感染的如式I、式II、式III、式IV、式V、第二方面、第三方面、第四方面所示的化合物或其可药用盐或第五方面所述的药物组合物，所述的化合物或其可药用盐或药物组合物与一种或多种另外的治疗剂联用。
在某些实施方案中，所述的另外的治疗剂选自HIV蛋白酶抑制剂、逆转录酶的HIV非核苷抑制剂、逆转录酶的HIV核苷抑制剂、逆转录酶的HIV核苷酸抑制剂中的一个或几个。
在某些实施方案中，其中所述的另外的治疗剂选自雷特格韦、拉米夫定、阿巴卡韦、利托那韦、度鲁格韦、达芦那韦、阿扎那韦、恩曲他滨、替诺福韦、埃替格韦、利匹韦林或洛匹那韦中的一种或几种。
虽然为简便起见将全部上述结构式画成某些异构体形式，但是本发明可以包括所有的异构体，如互变异构体、旋转异构体、几何异构体、非对映异构体、外消旋体和对映异构体。
互变异构体是有机化合物的结构异构体，通过被称为互变异构化的化学反应容易相互转化。这种反应常导致氢原子或质子的形式迁移，伴随着单键和邻近的双键的转换。一些常见的互变异构对为：酮-烯醇、内酰胺-内酰亚胺。内酰胺-内酰亚胺平衡实例是在如下所示的A和B之间。
Figure PCTCN2022096750-appb-000007
本发明中的所有化合物可以被画成A型或B型。所有的互变异构形式在本发明的范围内。化合物的命名不排除任何互变异构体。
“任选地”或“任选”是指意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如“任选的被卤素或者氰基取代的C 1-C 6烷基”是指卤素或者氰基可以但不必须存在，该说明包括烷基被卤素或者氰基取代的情形和烷基不被卤素和氰基取代的情形。
本发明所述化合物的化学结构中，键
Figure PCTCN2022096750-appb-000008
表示未指定构型，即如果化学结构中存在手性异构体，键
Figure PCTCN2022096750-appb-000009
可以为
Figure PCTCN2022096750-appb-000010
或
Figure PCTCN2022096750-appb-000011
或者同时包含
Figure PCTCN2022096750-appb-000012
和
Figure PCTCN2022096750-appb-000013
两种构型。本公开所述化合物的化学结构中，键
Figure PCTCN2022096750-appb-000014
并未指定构型，即可以为Z构型或E构型，或者同时包含两种构型。
本公开所述化合物或其可药用盐、或其异构体的任何同位素标记的衍生物都被本公开所覆盖。能够被同位素标记的原子包括但不限于氢、碳、氮、氧、磷、氟、氯、碘等。它们可分别被同位素 2H(D)、 3H、 11C、 13C、 14C、 15N、 18F、 31P、 32P、 35S、 36Cl和 125I等代替。除另有说明，当一个位置被特别地指定为氘(D)时，该位置应理解为具有大于氘的天然丰度(其为0.015％)至少3000倍的丰度的氘(即，至少45％的氘掺入)。
术语解释：
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用赋形剂”包括但不限于任何已经被美国食品和药物管理局批准对于人类或家畜动物使用可接受的任何助剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增香剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
“烷基”指饱和的脂族烃基团，包括1至20个碳原子的直链和支链基团。含有1至6个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基及其各种支链异构体等。如无特殊说明，烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选一个或多个以下基团，独立地选自卤素、氘、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷基、3至6元杂环烷基、C 5-8环烯基、C 3-6环烷氧基、3至6元杂环烷氧基、C 5-8环烯氧基、C 6-10芳基或5至6元杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷基、3至6元杂环烷基、C 5-8环烯基、C 3-6环烷氧基、3至6元杂环烷氧基、C 5-8环烯氧基、C 6-10芳基或5至6元杂芳基任选被一个 或多个选自卤素、氘、羟基、氧代、硝基、氰基所取代。
“环烷基”或“环烃”指饱和或部分不饱和的单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至8个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基等；多环环烷基包括螺环、稠环和桥环的环烷基。
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。如无特殊说明，环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自氘、烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
“杂环基”或“杂环”指饱和或部分不饱和单环或多环环状烃基团，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至7个环原子。单环杂环烷基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环烷基包括螺环、稠环和桥环的杂环烷基。“杂环烷基”非限制性实例包括：
Figure PCTCN2022096750-appb-000015
Figure PCTCN2022096750-appb-000016
等等。
杂环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团， 其独立地选自如卤素、氘、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷基、3至6元杂环烷基、C 5-8环烯基、C 3-6环烷氧基、3至6元杂环烷氧基、C 5-8环烯氧基、C 6-10芳基或5至6元杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷基、3至6元杂环烷基、C 5-8环烯基、C 3-6环烷氧基、3至6元杂环烷氧基、C 5-8环烯氧基、C 6-10芳基或5至6元杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基所取代。
所述杂环基环可以稠合于芳环、杂芳环或环烃上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2022096750-appb-000017
等。
“被一个或多个A、B……取代”是指可以被单个或多个取代基取代。当被多个取代基取代时，可以是复数个相同取代基，也可以是一个或复数个不同取代基的组合。
附图说明
图1化合物1和化合物2针对WT(野生型)毒株的抗病毒活性EC50。
图2化合物1和化合物2针对G140S/Q148R毒株的抗病毒活性EC50。
图3化合物1和化合物2针对Q148R/N155H毒株的抗病毒活性EC50。
图4化合物1和化合物2针对E138K毒株的抗病毒活性EC50。
图5化合物1和化合物2针对R263K毒株的抗病毒活性EC50。
图6化合物1和化合物2针对Y143R/Q148H毒株的抗病毒活性EC50。
图7化合物1和化合物2针对Q148H毒株的抗病毒活性EC50。
上述附图中，RAL代表拉替拉韦(raltegravir,)；CAB代表cabotegravir，CAB对于每个突变病毒株的抗病毒活性EC50设定为1，**:与CAB有显著差异且p-value小于0.05，N显示重复检测次数。
具体实施方式
以下结合实施例进一步描述本公开中，但这些实施例并非限制本公开中的范围。
本公开中实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。化合物的光学异构体(异构体)空间构型可进一步通过测量单晶参数的方式确认。
HPLC的测定使用Waters ACQUITY ultra high performance LC、Shimadzu LC-20A systems、Shimadzu LC-2010HT series或安捷伦Agilent 1200LC高压液相色谱仪(ACQUITY UPLC BEH C18 1.7UM 2.1X50MM色谱柱、Ultimate XB-C18 3.0*150mm色谱柱或Xtimate C18 2.1*30mm色谱柱)。
MS的测定用Waters SQD2质谱仪，以正/负离子模式扫描，质量扫描范围为100～1200。
手性HPLC分析测定使用Chiralpak IC-3 100×4.6mm I.D.，3um、Chiralpak AD-3 150×4.6mm I.D.，3um、Chiralpak AD-3 50×4.6mm I.D.，3um、Chiralpak AS-3 150×4.6mm I.D.，3um、Chiralpak AS-3 100×4.6mm I.D.，3μm、ChiralCel OD-3 150×4.6mm I.D.，3um、Chiralcel OD-3 100×4.6mm I.D.，3μm、ChiralCel OJ-H 150×4.6mm I.D.，5um、Chiralcel OJ-3 150×4.6mm I.D.，3um色谱柱；
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
快速柱纯化系统使用Combiflash Rf150(TELEDYNE ISCO)或者Isolara one(Biotage)。
正向柱层析一般使用烟台黄海硅胶100～200目、200～300目或300～400目硅胶为载体，或者使用常州三泰预填预填超纯正相硅胶柱(40-63μm，60，12g,，25g，40g，80g或其他规格)。
反相柱层析一般使用常州三泰预填超纯C18硅胶柱(20-45μm，
Figure PCTCN2022096750-appb-000018
40g，80g，120g，220g或其他规格)。
高压柱纯化系统使用Waters AutoP，配合使用Waters XBridge BEH C18 OBD Prep Column，
Figure PCTCN2022096750-appb-000019
5μm，19mm X 150mm或者Atlantis T3 OBD Prep Column，
Figure PCTCN2022096750-appb-000020
5μm，19mm X 150mm。
手性制备柱使用DAICEL CHIRALPAK IC(250mm*30mm,10um)或Phenomenex-Amylose-1(250mm*30mm,5um)。
本公开中的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自上海泰坦科技，ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
Figure PCTCN2022096750-appb-000021
1、化合物1b的合成
Figure PCTCN2022096750-appb-000022
氮气保护，将1a(250.4mg,0.794mmol，1.0eq)加入到10mL反应瓶中，加入2.5mL的乙腈，再加入AcOH(227μL)，MsOH(16μL)，加完移入66℃油浴中搅拌约20h，取样LCMS检测，加入(S)-2-氨基-2-环丙基乙醇盐酸盐(153.3mg,1.114mmol，1.4eq)，约5min后加入碳酸钾(158.3mg,1.145mmol，1.4eq)，MeCN(2.1mL)，66℃油浴中继续搅拌20h。取样LCMS检测，反应完成，停止反应，反应液冷却，减压浓缩干，残余物加1N HCl和DCM稀释，分液，水相用DCM提取，合并有机相，用无水硫酸钠干燥。过滤，浓缩，得到粗品产物1b(240mg)。直接用于下一步反应。Ms(ESI):m/z 321.1[M+1] +。
2、化合物1d的合成
Figure PCTCN2022096750-appb-000023
室温下，将1b(300mg,0.94mmol，1.0eq)，1c(158.4mg,1.1mmol，1.2eq)加入到25mL茄形瓶中，加入5mL的DCM，搅拌下，加入DIEA(302mg,2.34mmol，2.5eq)，HATU(448.3mg,1.18mmol，1.3eq)，然后氮气球保护在室温下搅拌2-3小时，取样LCMS检测，反应完成，停止反应，反应液直接加入硅胶拌样，经柱层析后得到油状物粗品1d(786mg)，收率188％，直接用于下一步反应。Ms(ESI):m/z 446.1[M+1] +。
3、化合物1的合成
Figure PCTCN2022096750-appb-000024
室温下，在50mL茄形瓶中，加入粗品1d(739.2mg，1.0eq)，LiBr(368mg，4.24mmol，2.5eq)，THF(10mL)，加完移入62-65℃油浴中搅拌约24h，取样LCMS检测，反应完成，停 止反应，反应液冷却，浓缩除去THF，残余物冰浴下加入3N HCl(3mL)，再用DCM(3mL)稀释，分液，水相用DCM提取，合并有机相，用饱和碳酸氢钠水溶液(1.5mL)洗一次，无水硫酸钠干燥，过滤，滤液减压蒸干，经制备HPLC纯化，冻干后得到化合物1(270mg)。Ms(ESI):m/z 432.1[M+1] +。 1H-NMR(400MHz,CDCl 3)δ10.32-10.29(t,1H),8.35(s,1H),7.39-7.33(q,1H),6.84-6.77(m,2H),5.44-5.41(m,1H),4.69-4.59(m,2H),4.44-4.40(q,1H),4.32-4.28(q,1H),4.02-3.98(q,1H),3.92-3.86(m,2H),1.07-1.03(m,1H),0.79-0.62(m,3H),0.37-0.30(m,1H)。
实施例2
Figure PCTCN2022096750-appb-000025
1、化合物2b的合成
Figure PCTCN2022096750-appb-000026
室温下(20℃)，将2e(503mg,2.6mmol)(根据文献WO2020167628制备得到)，HCl/dioxane(4M，2.6ml,10.4mmol)加入到25mL茄形瓶中，室温下(20℃)搅拌16小时，LCMS监控反应完全。将反应液浓缩，得到化合物2b(320mg)，收率95％，直接用于下一步反 应。
2、化合物2c的合成
Figure PCTCN2022096750-appb-000027
氮气保护，将2a(399mg,1.266mmol，1.0eq)加入到25mL反应瓶中，加入4mL的乙腈，再加入AcOH(364μL)，MsOH(28.8μL)，加完移入66℃油浴中搅拌约24h，取样LCMS检测，原料剩余小于1％，加入2c(234mg,1.806mmol，1.4eq)，约10min后加入碳酸钾(284.6mg,2.059mmol，1.6eq)，66℃油浴中继续搅拌21h。取样LCMS检测，反应完成，停止反应，反应液冷却，减压浓缩干，残余物加1N HCl和DCM稀释，分液，水相用DCM提取，合并有机相，用无水硫酸钠干燥。过滤，浓缩，得到粗品产物2c(420mg)。直接用于下一步反应。Ms(ESI):m/z313.0[M+1] +。
3、化合物2d的合成
Figure PCTCN2022096750-appb-000028
室温下，将2c(450mg,1.44mmol，1.0eq)，2f(222.6mg,1.56mmol，1.1eq)加入到50mL茄形瓶中，加入8mL的DCM，搅拌下，加入DIEA(385mg,2.98mmol，2.1eq)，HATU(641.5mg,1.68mmol，1.2eq)，然后氮气球保护在室温下搅拌2-3小时，取样LCMS检测，反应完成，停止反应，反应液直接加入硅胶拌样，经柱层析得到油状物粗品2d(877mg)，收率139％，直接用于下一步反应。Ms(ESI):m/z438.1[M+1] +。
4、化合物2的合成
Figure PCTCN2022096750-appb-000029
室温下，在50mL茄形瓶中，加入粗品2d(754mg)，LiBr(386.3mg，4.448mmol)，THF(10mL)，加完移入62-65℃油浴中搅拌约24h，取样LCMS检测，反应完成，停止反应，反应液冷却，浓缩除去THF，残余物冰浴下加入3N HCl(3mL)，再用DCM(3mL)稀释，分液，水相用DCM提取，合并有机相，用饱和碳酸氢钠水溶液(1.5mL)洗一次，无水硫酸钠干燥，过滤，滤液减压蒸干得到粗品506mg，经制备HPLC纯化，冻干后得到化合物2(44mg)，Ms(ESI):m/z 424.1[M+1] +。 1H-NMR(400MHz,CDCl 3)δ10.26-10.20(m,1H),8.35(s,1H),7.39-7.31(m,1H),6.84-6.78(m,2H),5.33-5.30(m,1H),5.10-5.07(q,0.5H),4.98-4.95(q,0.5H),4.65-4.41(m,6H),4.25-4.21(m,1H),3.97-3.91(m,1H)。
测试例1：
评估测试化合物在不同浓度下对人类免疫缺陷病毒一型IIIB毒株(HIV-1IIIB)感染MT-4细胞的保护效果。
材料和方法
测试化合物溶解在DMSO中，浓度为10mM，并储存在-20℃。
1)化合物细胞毒性的测试,使用100nM起始浓度和五次连续半对数稀释液评估测试化合物。每种化合物在测定培养基中浓度为最终所需测试浓度的2倍。将化合物在DMSO中稀释至1mM。然后在含有998μL测定培养基的药物稀释管中将化合物稀释至200nM(加入2μL的1mM原液)。将320微升(320μL)的200nM溶液转移到680μL的测定培养基(半对数稀释)中，总共进行五次系列稀释。将100微升(100μL)的每种浓度添加到两复孔用于细胞毒性的评估，每个浓度加入一个孔用于比色评估。
2)化合物抗HIV-1IIIB感染活性的测试,使用10nM起始浓度和五次连续五倍稀释化合物。每种化合物在测定培养基中浓度为最终所需测试浓度的2倍。将100微升(100μL)的每种浓度添加到三次重复孔中以用于效力评估,每个浓度加入一个孔用于比色评估。AZT购自Sigma Aldrich(美国密苏里州圣路易斯)，并在抗病毒测定中作为对照化合物进行了评估。
抗HIV感染的细胞保护检测方法
细胞培养：MT-4细胞在用于抗病毒试验之前在T-75瓶中传代。在测定前一天，细胞以1:2的比例分瓶传代,以确保它们在感染时处于指数生长期。使用血细胞计数器和台盼蓝染料进行总细胞和活细胞定量。用于测定的活细胞比例大于95％。将细胞以每毫升5x 10 4个细胞重悬于组织培养基中，并以50μL的体积加入含药物的微量滴定板中。
病毒制备：用于该测定的病毒是嗜淋巴细胞病毒株HIV-1IIIB。在CEM-SS细胞中扩增，用于制备病毒储液。从冰箱(-80℃)中取出预先滴定的病毒分装管，并在生物安全柜中缓慢解冻至室温。将病毒稀释到组织培养基中，50ul的稀释后的病毒会在感染后6天产生85％至95％的细胞杀伤率。在含有细胞和药物的微量滴定板中,立即加入50μL稀释好的病毒。
利用XTT评估化合物功效和毒性：在37℃,5％CO 2培养箱中培养六天后，将细胞培养板加入四唑染料XTT(2,3-双(2-甲氧基-4-硝基-5-磺苯基)染色-5-[(苯基氨基)羰基]-2H-氢氧化四唑)进行测试。XTT溶液为当天制备1mg/ml的RPMI1640储备液。在PBS中制备浓度为0.15mg/ml的吩嗪硫酸甲酯(PMS)溶液，并在-20℃下避光保存。在使用前通过每毫升XTT溶液添加40μl PMS的比例来制备XTT/PMS储备液。将50微升XTT/PMS添加到板的每个孔中，并将板在37℃下重新孵育4小时。将板用粘性板密封剂密封并轻轻摇动或倒转数次以混合可溶性甲臜产物,读取450/650nm吸光值。
表1 抗病毒功效和细胞毒性数据。
  EC 50(nM) CC 50(nM) CC 50/EC 50
AZT(对照化合物) 2 >500 >250
cabotegravir 2.40 >100 >41.7
化合物1 3.12 >100 >32.1
化合物2 0.89 >100 >112
测试例2：
针对含有HIV-1整合酶常见临床突变位点的假病毒(G140S/Q148R，Q148R/N155H，E138K,Q148H,R263K及Y143R/Q148H)抑制剂活性测试。
基于假病毒的化合物抗HIV-1活性检测方法
假病毒的制备：以慢病毒质粒pNL4-3-Luc-R -E -(海吉浩格)为骨架，构建整合酶点突变质粒。将HEK293T细胞(ATCC)按每孔细胞数5X10 5接种于6孔板中。24小时后，待细胞密度 达到60％～80％时，进行转染。在转染试剂中，按照一定比例加入pNL4-3-Luc-R -E -或pNL4-3-Luc-R -E --IN-mutant质粒和慢病毒包装质粒pMD2.G(北京庄盟)。根据转染试剂PEI25K(懋康生物)说明书进行细胞转染。48小时后，收集上清液，3000rpm离心5分钟，用0.45μm微孔滤膜过滤，分装，于-80℃保存待用。在HEK293T细胞中，根据萤光素酶活性，检测假病毒滴度。
化合物抗病毒活性的检测：在96孔V型底板中，用DMSO对待测化合物进行半对数稀释，准备4倍于终浓度的化合物溶液备用。根据不同病毒滴定的结果用完全培养基稀释病毒待用。胰酶消化HEK293T细胞，制成2X10 5/mL的细胞悬液。在96孔平底板中，依次加入50ul化合物稀释液，50ul病毒稀释液，和100ul细胞悬液。化合物终浓度为1000nM-0.1nM。将96孔检测板置于37℃，5％CO 2培养箱孵育。72小时后，从96孔板每孔小心吸出100uL培养上清液，每孔避光加入25uL Steady-Glo检测试剂(Promega,Cat#E2550)，上机检测(Tecan,Type#Spark)。
表2 化合物1、化合物2、cabotegravir针对不同突变毒株EC 50、EC 90数据
Figure PCTCN2022096750-appb-000030
对于整合酶常见临床突变毒株(G140S/Q148R，Q148R/N155H，E138K,Q148H,R263K及Y143R/Q148H)，化合物2的活性优于cabotegravir，并具有显著差异。
测试例3：针对临床HIV-1毒株的抑制剂活性测试。
病毒的制备：临床HIV-1病毒株(表三)来源于美国NIH艾滋病研究和参考试剂库。从三份HIV和HBV血清阴性的新鲜血液中提取PBMC，混合培养，同时加入PHA-P(植物血球凝集素)刺激活化。将细胞与病毒在37℃/5％CO 2下孵育，收集感染后细胞培养物上清液，冷冻储存在-80℃。在三个供体混合的PBMCs中滴定每个病毒滴度。
化合物抗病毒活性的检测：
HIV-1亚型 病毒毒株
A RW/92/009
C MW/93/959
D UG/92/001
化合物抗病毒活性的检测：将冻存的PBMCs重悬于新鲜培养基中(1 x 10 6细胞/mL)，加入到圆底96孔板(50μL/孔)。每孔加入100ul含有2倍化合物终浓度的培养基，之后加入50μL病毒液(最终感染剂量为MOI＝0.002)。培养7天之后检测上清中逆转录酶活性评估HIV-1的复制。同时准备仅有化合物和细胞的96孔培养板，用于化合物细胞毒性的检测。
在人原代PBMC中，化合物的CC 50均大于100nM，对于不同亚型的HIV-1临床分离毒株(RW/92/009，MW/93/959，UG/92/001)，在人PBMC中，化合物2的活性优于cabotegravir。
表3：抗病毒活性数据
Figure PCTCN2022096750-appb-000031

Claims (13)

  1. 一种式I所示的化合物或其可药用盐
    Figure PCTCN2022096750-appb-100001
    其中，
    R 1选自氢、C 1-6烷基、C 3-6环烷基、羟基；所述C 1-6烷基、C 3-6环烷基任选被1-3个R 5a所取代；
    R 5a选自卤素、C 1-6烷基、C 3-6环烷基、羟基、氰基、氨基、硝基；
    R 2选自氢、卤素、1-3个卤素取代的C 1-6烷基、C 3-6环烷基、3-6元杂环基、羟基、亚甲基环丙基、氧代；所述C 3-6环烷基、3-6元杂环基、亚甲基环丙基任选被1-3个R 5b所取代；
    R 5b选自卤素、C 1-6烷基、C 3-6环烷基、羟基、氰基、氨基、硝基；
    R 3独立地选自卤素、氰基、氨基、硝基、C 1-6烷基、C 3-6环烷基、羟基；所述C 1-6烷基、C 3-6环烷基任选被1-3个R 5c所取代；
    n选自0-4的整数；
    R 5c各自独立地选自卤素、C 1-6烷基、C 3-6环烷基、羟基、氰基、氨基、硝基；
    R 4独立地选自卤素、氰基、氨基、硝基、C 1-6烷基、C 3-6环烷基、羟基、氧代；
    m为0-2的整数，优选m为0-1的整数，更优选m为0。
  2. 如权利要求1所述的化合物或其可药用盐，其中
    R 3独立地选自卤素、氰基、氨基、硝基、甲基、乙基、环丙基、异丙基、羟基；所述甲基、乙基、环丙基、异丙基任选被1-3个R 5c所取代；
    n选自0-2的整数；
    R 5c各自独立地选自卤素、甲基、乙基、环丙基、异丙基、羟基、氰基、氨基、硝基；
    最优选R 3独立地选自卤素；n选自0-2的整数。
  3. 如权利要求1所述的化合物或其可药用盐，其中式I所示的化合物选自
    Figure PCTCN2022096750-appb-100002
    其中
    R 1、R 2、R 3、R 4、m如权利要求1中定义。
  4. 如权利要求1所述的化合物或其可药用盐，其中式I所示的化合物选自
    Figure PCTCN2022096750-appb-100003
    R 2如权利要求1中定义。
  5. 如权利要求1-4中任一项所述的化合物或其可药用盐，其中
    R 2选自氢、卤素、1-3个卤素取代的C 1-6烷基、C 3-6环烷基、羟基、亚甲基环丙基、氧代；所述C 3-6环烷基、亚甲基环丙基任选被1-3个R 5b所取代，R 5b如权利要求1中定义；
    优选R 2选自氢、卤素、1-3个卤素取代的C 1-6烷基、C 3-6环烷基；所述C 3-6环烷基任选被1-3个R 5b所取代，R 5b如权利要求1中定义；
    更优选R 2选自1-3个氟取代的甲基、环丙基；所述环丙基任选被1-3个卤素所取代；
    最优选R 2选自单氟甲基、环丙基。
  6. 如权利要求1所述的化合物或其可药用盐，其中式I所示的化合物选自
    Figure PCTCN2022096750-appb-100004
  7. 如权利要求1所述的化合物或其可药用盐，其中式I所示的化合物选自
    Figure PCTCN2022096750-appb-100005
  8. 一种如权利要求1-7中任一项所示的化合物的同位素取代物，优选地，所述的同位素取代为氘原子取代。
  9. 一种药物组合物，包括权利要求1-8中任一项的所述的化合物或其可药用盐和可药用赋形剂。
  10. 一种治疗或预防人类HIV感染的方法，其通过向人类施用治疗有效量的如权利要求1-8中任一项所述的化合物或其可药用盐或权利要求9所述的药物组合物。
  11. 一种用于治疗或预防人类HIV感染的如权利要求1-8中任一项所述的化合物或其可药用盐或权利要求9所述的药物组合物，所述的化合物或其可药用盐或药物组合物与一种或多种另外的治疗剂联用。
  12. 如权利要求11所述的化合物或其可药用盐或药物组合物，其中所述的另外的治疗剂选自HIV蛋白酶抑制剂、逆转录酶的HIV非核苷抑制剂、逆转录酶的HIV核苷抑制剂、逆转录酶的HIV核苷酸抑制剂中的一个或几个。
  13. 如权利要求12所述的化合物或其可药用盐或药物组合物，其中所述的另外的治疗剂选自雷特格韦、拉米夫定、阿巴卡韦、利托那韦、度鲁格韦、达芦那韦、阿扎那韦、恩曲他滨、替诺福韦、埃替格韦、利匹韦林或洛匹那韦中的一种或几种。
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