WO2024259934A9 - 核苷类似物及其医药用途 - Google Patents

核苷类似物及其医药用途 Download PDF

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Publication number
WO2024259934A9
WO2024259934A9 PCT/CN2023/141230 CN2023141230W WO2024259934A9 WO 2024259934 A9 WO2024259934 A9 WO 2024259934A9 CN 2023141230 W CN2023141230 W CN 2023141230W WO 2024259934 A9 WO2024259934 A9 WO 2024259934A9
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Prior art keywords
virus
compound
substituted
carbonyl
unsubstituted
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French (fr)
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WO2024259934A1 (zh
Inventor
吕佳声
张启国
周天伦
孔宪起
陈大为
张文宏
万延民
陈刚
叶祥胜
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Risen Shanghai Pharma Engineering Co Ltd
Risen Suzhou Pharma Tech Co Ltd
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Risen Shanghai Pharma Engineering Co Ltd
Risen Suzhou Pharma Tech Co Ltd
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Publication of WO2024259934A1 publication Critical patent/WO2024259934A1/zh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a nucleoside analog or a pharmaceutically acceptable salt or ester thereof, and use thereof in preparing a drug for treating, inhibiting or preventing a viral infection disease or a cell proliferation disease.
  • viruses can be divided into DNA viruses, RNA viruses, etc.
  • the design and discovery of new antiviral drugs are generally directed against viral or cellular targets. Drugs that inhibit viral proteins may be virus-specific and more susceptible to resistance.
  • the 2022 monkeypox outbreak was first discovered in the UK on May 7, 2022, local time. On May 20, local time, with more than 100 confirmed and suspected cases of monkeypox in Europe.
  • Monkeypox is a viral zoonosis that causes symptoms in humans similar to those seen in smallpox patients in the past. However, since smallpox was eradicated from the world in 1980, smallpox no longer exists, while monkeypox is still sporadic in parts of Africa. Monkeypox occurs in monkeys in the rainforests of central and western Africa, and can also infect other animals and occasionally humans. The clinical manifestations are similar to smallpox, but the condition is milder.
  • the disease is caused by the monkeypox virus, a double-stranded DNA virus with a relatively stable structure and a low mutation rate.
  • the virus can be transmitted from animals to humans through direct close contact, and can also be transmitted from person to person.
  • the main technical problem solved by the present application is to provide a nucleoside analog compound, which can have at least one or more of the following effects:
  • the present invention provides a nucleoside analogue represented by formula (I) or a pharmaceutically acceptable salt or ester thereof:
  • X is selected from -OR 4 , or X and R 3 are combined to form a chemical bond;
  • R1 is selected from H or C4-C30 carbonyl
  • the C4-C30 carbonyl includes substituted or unsubstituted hydrocarbon carbonyl, substituted or unsubstituted aryl carbonyl or heterocyclic carbonyl, and substituted or unsubstituted hydrocarbon oxycarbonyl
  • the carbonyl has a carbon number of 4 to 30, which can be 4 to 10, 10 to 30 or 20 to 30, and specifically can be 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30;
  • R 1 , R 2 , R 3 , and R 4 are not H at the same time; when X and R 3 are combined to form a chemical bond, R 1 and R 2 are not H at the same time.
  • R 1 , R 3 , and R 4 are not H at the same time; when X and R 3 are combined to form a chemical bond, R 1 is not H.
  • the present invention provides compounds represented by formula (IIIa) and formula (IIIb):
  • R 1 , R 3 , and R 4 are not H at the same time; when X and R 3 are combined to form a chemical bond, R 1 is not H.
  • the present invention provides a compound represented by formula (IVa) or (IVb):
  • R 1 or R 3 is as defined above.
  • R 1 and R 3 are independently selected from formyl, C1-C3 alkylcarbonyl, (CH 3 ) 2 CHCOOCH(CH 3 )C(O)-, CH 3 COOCH(CH 3 )C(O)-; and X is H.
  • R 1 and R 3 are independently selected from C1-C3 alkylcarbonyl, and X is H.
  • R1 is selected from substituted or unsubstituted arylcarbonyl or heterocyclic carbonyl, including the groups shown below:
  • Y is selected from H, F, Cl, Br, Me, -OMe, -OEt, -CF3 or -CN.
  • R1 is selected from substituted or unsubstituted alkyloxycarbonyl groups, including the groups shown below:
  • R 5 includes the following groups:
  • R 3 includes the following groups:
  • the compounds of the present invention include the compounds shown in the following Table 1a and Table 1b:
  • viral infections include hepatitis B virus (HBV), new coronavirus (SARS-COV-2), human immunodeficiency virus (HIV), varicella zoster virus (VZV), cytomegalovirus (CMV), herpes simplex virus (HSV), BK virus, JC virus, Epstein-Barr virus (EBV), Ebola virus, polyomavirus, papillomavirus, orthopoxvirus, hepatitis C virus (HCV), respiratory syncytial virus (RSV), dengue virus, influenza virus, adenovirus, parainfluenza virus and/or infection caused by rhinovirus.
  • HBV hepatitis B virus
  • SARS-COV-2 new coronavirus
  • HCV human immunodeficiency virus
  • VZV varicella zoster virus
  • CMV herpes simplex virus
  • BK virus BK virus
  • JC virus herpes simplex virus
  • EBV Epstein-Barr virus
  • orthopoxviruses include severe and mild smallpox viruses, monkeypox virus, cowpox virus, camelpox virus, molluscum contagiosum, sheeppox virus, aractuba virus (ARAV), BeAn58058 virus (BAV), cantagalo orthopoxvirus (CTGV), mousepox virus, elephantpox virus, vaccinia virus (VV), rabbitpox virus, raccoonpox virus, skunkpox virus, gerbilpox virus and volepox virus.
  • the compounds disclosed in the present application can be used to prepare drugs for treating, inhibiting or preventing diseases caused by monkeypox virus or smallpox virus infection in mammals.
  • the compounds provided in the present application can be used to prepare drugs for treating, inhibiting or preventing diseases caused by viral infection.
  • diseases caused by viral infection include diseases caused by DNA virus infection, specifically, the diseases are selected from retinitis, pneumonia, cystitis, proteinopathy, etc.
  • the cells provided herein can also be used to prepare drugs for treating, inhibiting or preventing cell proliferation-induced diseases.
  • the cell proliferation-induced disease is a tumor or cancer, specifically, the tumor or cancer is selected from multiple myeloma (MM), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), solid tumors, refractory solid tumors, non-Hodgkin's lymphoma, hematological tumors, neuroblastoma, colorectal cancer, cervical cancer, lung cancer, leukemia, breast cancer, pancreatic cancer, B-cell malignancies, metastatic tumors and colon cancer.
  • MM myeloma
  • CLL chronic lymphocytic leukemia
  • MCL mantle cell lymphoma
  • solid tumors refractory solid tumors
  • non-Hodgkin's lymphoma hematological tumors
  • neuroblastoma colorectal cancer
  • cervical cancer lung cancer
  • leukemia breast cancer
  • the present application also provides a pharmaceutical composition, comprising one or more of the above compounds and at least one pharmaceutically acceptable carrier or excipient.
  • the pharmaceutically acceptable carrier includes one or more of creams, emulsions, gels, liposomes and nanoparticles;
  • the pharmaceutically acceptable excipient includes one or more of binders, fillers, disintegrants, lubricants and glidants.
  • the above pharmaceutical composition is suitable for oral administration or injection administration.
  • the present application also provides a kit, which includes any one or more of the above-mentioned compounds or pharmaceutically acceptable salts or esters or any one or more of the pharmaceutical compositions.
  • the specific compounds provided in the present application can effectively treat, inhibit or prevent viral infections and/or cell proliferation diseases in mammals, especially smallpox and monkeypox, and have at least one or more of the effects of changing the pharmacokinetic properties in the body, adjusting the absorption and distribution of the drug in the body, improving the stability and solubility of the drug, reducing toxicity and adverse reactions, improving the transport and distribution to specific parts, improving the sustained release effect, and prolonging the duration of action.
  • FIG1 is a graph showing the inhibitory activity-drug concentration curve of the test compound.
  • FIG. 2 shows a death curve diagram of a surrogate endpoint of mouse death, wherein FIG. 2a is a graph of body weight change, and FIG. 2b is a surrogate endpoint death curve.
  • FIG. 3 shows a graph of the actual mortality of mice, wherein FIG. 3a is a graph of weight changes, and FIG. 3b is an actual mortality curve.
  • the words “comprising”, “having” and synonyms are inclusive and open-ended and do not exclude additional unlisted elements or processing steps.
  • the term “about” or “approximately” is used to indicate that the value includes the error caused by the instruments and methods used in determining the value.
  • pharmaceutically acceptable refers to drugs, medicines, inert ingredients, etc. described by the term, which are suitable for contact with the tissues of humans and lower animals without abnormal toxicity, incompatibility, instability, irritation, allergic reaction, etc., commensurate with a reasonable benefit/risk ratio. It preferably refers to compounds, compositions and preparations, etc. listed in the pharmacopoeia or other recognized pharmacopoeias for use in animals, more particularly in humans.
  • a "pharmaceutically acceptable salt” of a compound refers to a salt of a compound that is pharmaceutically acceptable. Desirable salts of compounds (basic, acidic or charged functional groups) can retain or improve the biological activity and properties of the parent compound as defined herein and are not biologically undesirable.
  • esters refers to esters derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in free acid or alcohol form).
  • physiologically hydrolyzable esters which can be hydrolyzed under physiological conditions to release the compounds of the present invention in free acid or alcohol form.
  • the compounds of the present invention themselves may also be esters.
  • the compounds disclosed herein exist as a prodrug.
  • prodrug refers to a pharmaceutical agent that is directly or indirectly converted into an active form in vitro or in vivo (see, for example, R.B. Silverman, 1992, “The Organic Chemistry of Drug Design and Drug Action,” Academic Press, Chap. 8; Bundgaard, Hans; Editor. Neth. (1985), “Design of Prodrugs”. 360pp. Elsevier, Amsterdam; Stella, V.; Borchardt, R.; Hageman, M.; Oliyai, R.; Maag, H.; Tilley, J. (Eds.)(2007), “Prodrugs: Challenges and Rewards, XVIII, 1470p. Springer).
  • Prodrugs can be used to alter the biodistribution (e.g., so that the agent does not normally enter the protease reaction site) or pharmacokinetics of a particular drug.
  • a variety of groups such as esters, ethers, phosphates/salts, etc. have been used to modify compounds to form prodrugs.
  • prodrug When the prodrug is administered to a subject, the group is cleaved off enzymatically or non-enzymatically, reduced, oxidatively or hydrolytically, or otherwise releases the active compound.
  • prodrug includes pharmaceutically acceptable salts, or pharmaceutically acceptable solvates, and any crystalline forms of the above. Prodrugs are generally (although not necessarily) pharmaceutically inactive until they are converted to an active form.
  • substituted or “substituted” as used in the present invention includes the implicit condition that such substitution changes with the valence of the substituted atom and the substituent, and the substitution produces a stable compound (for example, the compound cannot spontaneously undergo rearrangement, cyclization, elimination, etc.).
  • substituted includes all permissible substituents of organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. The substituent can be one or more.
  • substituted means that when the above groups are substituted at one or more positions, the substituents include acylamino (including carbamoyl and ureido), alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, alkoxycarbonyl, carboxyl, carboxyl, aminocarbonyl, mono- and dialkylaminocarbonyl, cyano, azido, halogen, hydroxy, nitro, trifluoromethyl, thio, alkylthio, arylthio, alkylthiocarbonyl, thiocarboxylate, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, lower alkoxy, aryloxy, aryloxycarbonyloxy, benzyloxy, benzyl, sulfinyl, alkylsulfinyl, sulfony
  • hydrocarbyloxy refers to -OR b , where R b is a hydrocarbyl.
  • C15-C30 hydrocarbon group means having 15 to 30 carbon atoms in the hydrocarbon structure, specifically, the number of carbon atoms can be 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, and the term "C1-C16 hydrocarbon group” means having 1 to 16 carbon atoms in the hydrocarbon structure, specifically, the number of carbon atoms can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16.
  • aryl or “aryl ring” used in the present invention refers to an aromatic group having "4n+2" ( ⁇ ) electrons in a conjugated monocyclic or polycyclic system (condensed or non-condensed), and having 6 to 14 ring atoms, wherein n is an integer from 1 to 3.
  • the polycyclic system includes at least one aromatic ring.
  • the aryl group can be directly connected or connected through a C1-C3 alkyl group (also referred to as an arylalkyl group or an aralkyl group).
  • aryl groups include, but are not limited to, phenyl, benzyl, phenethyl, 1-phenylethyl, tolyl, naphthyl, biphenyl, terphenyl, indenyl, benzocyclooctenyl, benzocycloheptenyl, azulenyl, acenaphthenyl, fluorenyl, phenanthrenyl, anthracenyl, etc.
  • aryl includes unsubstituted aryl and substituted aryl.
  • heteroaryl or “heteroaryl ring” as used herein refers to an aromatic group having "4n+2" ( ⁇ ) electrons in a conjugated monocyclic or polycyclic system (fused or non-fused), wherein n is an integer from 1 to 3 and includes one to six heteroatoms (e.g., N, O, S, P) or a group including heteroatoms (e.g., NH, NRx (Rx is alkyl, acyl, aryl, heteroaryl or cycloalkyl), PO2 , SO, SO2 , etc.).
  • the polycyclic system includes at least one heteroaromatic ring.
  • the heteroaryl group can be directly attached or attached through a C1-C3 alkyl group (also called heteroarylalkyl or heteroaralkyl).
  • the heteroaryl group can be attached to carbon or to a heteroatom (e.g., through a nitrogen atom).
  • heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolidinyl, quinolyl, isoquinolyl, indolyl, isoindolyl, chromenyl, isochromenyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl , pyrazinyl, triazine, isoindolyl, pteridinyl, furanyl, benzofuranyl, benzothiazolyl, benzothienyl, benzothiazolyl, benzoxazolyl, quin
  • heteroaryl includes unsubstituted heteroaryl and substituted heteroaryl.
  • C5-Cn heteroaryl wherein n is an integer from 6 to 15, means a heteroaryl having from 5 to "n" atoms in the ring structure, including at least one heterocyclic group or atom as defined above.
  • the present invention provides a phosphonate compound, or a pharmaceutically acceptable salt or ester thereof, for use in the preparation of a medicament for treating, inhibiting or preventing a viral infection or a cell proliferation disease, wherein the phosphonate compound is selected from but not limited to the compounds listed in Table 1.
  • amino acid residue refers to the major portion of an amino acid after removal of the carboxyl group.
  • amino acid generally refers to an organic compound that contains both a carboxylic acid group and an amine group.
  • amino acid includes “natural” and “unnatural” amino acids.
  • amino acid includes O-alkylated or N-alkylated amino acids, as well as amino acids with nitrogen-, sulfur- or oxygen-containing side chains (e.g., Lys, Cys or Ser), wherein the nitrogen, sulfur or oxygen atom may or may not be acylated or alkylated.
  • the amino acid may be an L-amino acid, a D-amino acid or a mixed L- and D-amino acid, including (but not limited to) a racemic mixture.
  • natural amino acid and equivalent expressions used in the present invention refer to L-amino acids that are usually found in naturally occurring proteins.
  • natural amino acids include, but are not limited to, alanine (Ala), cysteine (Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr), ⁇ -alanine ( ⁇ -Ala) and ⁇ -aminobutyric acid (GABA), etc.
  • non-natural amino acid refers to any derivative of a natural amino acid, including D-amino acids and their derivatives, as well as ⁇ - and ⁇ -amino acid derivatives. It should be noted that certain non-natural amino acids (e.g., hydroxyproline) in the present invention may exist in certain biological tissues or specific proteins in nature. Amino acids with many different protecting groups suitable for direct use in solid phase peptide synthesis are commercially available.
  • unnatural amino acids and amino acid derivatives can be used according to the present invention (common abbreviations are in parentheses): 2-aminoadipic acid (Aad), 3-aminoadipic acid ( ⁇ -Aad), 2-aminobutyric acid (2-Abu), ⁇ , ⁇ -dehydro-2-aminobutyric acid (8-AU), 1-aminocyclopropane-1-carboxylic acid (ACPC), aminoisobutyric acid (Aib), 3-aminoisobutyric acid ( ⁇ -Aib), 2-amino-thiazoline-4-carboxylic acid, 5-aminopentanoic acid (5-Ava), 6-aminohexanoic acid (6-Ahx), 2-aminoheptanoic acid (Ahe), 8-aminooctanoic acid (8-Aoc), 11-aminoundecanoic acid (11-Aun), 12-amino
  • the present invention provides methods for treating mammalian diseases associated with viral infection, inappropriate cell proliferation, etc. These methods specifically comprise administering to a human or other mammal in need of treatment a therapeutically effective amount of a compound of the present invention.
  • the compounds provided herein can be used to prepare a drug that can be used to treat, inhibit or prevent viral infection or viral infection-induced diseases.
  • the compounds provided herein and their pharmaceutically acceptable salts or esters are used to prepare drugs for treating smallpox virus infection or diseases caused by smallpox virus.
  • the compounds provided herein and their pharmaceutically acceptable salts or esters are used to prepare drugs for treating monkeypox virus infection or diseases caused by monkeypox virus.
  • the compounds provided herein have good effects in treating, inhibiting or preventing viral infections and diseases caused by viral infections. At the same time, the applicant has found that the compounds provided herein also have good effects in treating cancer or tumors.
  • the compounds provided herein and their pharmaceutically acceptable salts or esters can be used to prepare drugs, which can be used to treat, inhibit or prevent tumors or cancers caused by cell proliferation.
  • the drug provided herein further comprises at least one pharmaceutically acceptable carrier or diluent.
  • the pharmaceutically acceptable carrier or diluent is selected from creams, emulsions, gels, liposomes or nanoparticles.
  • the compound or medicine provided by the present invention can be applied to the subject in any appropriate manner known in the art.
  • Suitable routes of administration include, but are not limited to, oral; parenteral, such as intramuscular, intravenous, subcutaneous (such as injection or implantation), intraperitoneal, intracisternal, intraarticular, intracerebral (intracerebral parenchyma and intraventricular); nasal; vaginal; sublingual; intraocular; rectal; topical (such as transdermal); oral and inhaled.
  • the accumulation injection method generally administered subcutaneously or intramuscularly can also be used to release the compound or medicine disclosed in the present application within a limited time period.
  • the medicine is an injectable preparation.
  • the medicine is formulated for oral administration to the subject.
  • the present invention also provides a kit comprising an antiviral infection compound or drug.
  • the kit is generally in the form of a physical structure that accommodates various components, and can be used, for example, to implement the method provided herein.
  • the kit may include one or more compounds or drugs disclosed in the present invention (e.g., provided in a sterile container), which may be in the form of a pharmaceutical composition suitable for administration to a subject.
  • the compound may be provided in a ready-to-use form (e.g., tablet or capsule) or in a form that requires, for example, reconstruction or dilution (e.g., powder) before administration.
  • the kit may also include a diluent (e.g., sterile water), a buffer, a pharmaceutically acceptable excipient, etc. that is packaged together with the compound or packaged separately.
  • a diluent e.g., sterile water
  • the kit may contain several therapeutic agents independently, or they may have been combined in the kit.
  • Each component of the kit may be encapsulated in a separate container, and all the various containers may be in a single package.
  • the kit of the present invention may be designed to appropriately maintain the conditions required for the components contained therein (e.g., refrigeration or freezing).
  • the medicaments or pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology.
  • the method of such preparation comprises the steps of combining a compound described herein ("active ingredient") with a carrier and/or one or more other auxiliary ingredients, and then, if necessary and/or desired, forming and/or packaging the product into a desired single-dose unit or multiple-dose units.
  • a "unit dose" is a discrete amount of a pharmaceutical composition containing a predetermined amount of an active ingredient.
  • the amount of the active ingredient is generally equal to the dose of the active ingredient to be administered to a subject and/or a convenient fraction of such a dose, such as half or one-third of such a dose.
  • the compounds provided by the present invention can be synthesized according to the following general formula, wherein all reagents used to prepare the compounds of the present invention are commercially available or prepared according to preparation methods disclosed in the literature.
  • Compound A is used as a starting material, and under the action of a condensation agent 1H-benzotriazole-1-yloxytripyrrolidino hexafluorophosphate (PYBOP), it undergoes cyclization and condensation reaction with different alcohols to obtain compound B; under the action of a base such as potassium carbonate, the amino group on compound B reacts with an acyl chloride to obtain compound C, which is then hydrolyzed with a sodium hydroxide solution and acidified to obtain compound D;
  • a condensation agent 1H-benzotriazole-1-yloxytripyrrolidino hexafluorophosphate PYBOP
  • PYBOP condensation agent 1H-benzotriazole-1-yloxytripyrrolidino hexafluorophosphate
  • Step A Add diethoxymethanol phosphate (20 g, 118.96 mmol, 1.0 eq.), dichloromethane (400 mL) and triethylamine (14.44 g, 142.75 mmol, 1.2 eq.) to the reaction flask. After cooling to -60 °C, slowly drop trifluoromethanesulfonic anhydride (38.6 g, 136.80 mmol, 23.02 mL, 1.15 eq.) into the reaction system and stir for half an hour. Slowly warm to room temperature and stir for 1 hour.
  • Step C Add compound b (5 g, 11.07 mmol, 1.0 eq.) and tetrahydrofuran (100 mL) to the reaction flask. Cool to -60 °C, slowly add LiHMDs (1.0 M, 33.22 mL, 3.0 eq.). After stirring at -60 °C for 15 minutes, slowly add diethoxy methyl trifluoromethanesulfonate solution (8.30 g dissolved in 20 mL tetrahydrofuran, 28.79 mmol, 2.6 eq.). Warm to room temperature and stir for 16 hours.
  • LiHMDs 1.0 M, 33.22 mL, 3.0 eq.
  • Step E Add d (0.8 g, 2.23 mmol, 1 eq.), acetonitrile (10 mL) and TMSBr (1.36 g, 8.91 mmol, 1.18 mL, 4.0 eq.) to a reaction flask, stir at room temperature for 16 hours, concentrate to remove the reaction solvent, add water to the residue, and freeze-dry to obtain product e (675 mg, yield: 99.10%).
  • Step F Add e (0.2 g, 0.66 mmol, 1 eq.), DMF (10 mL), and DIPEA (1 mL) to the reaction flask. Stir the reaction at 45°C for 2 hours. Concentrate and remove the solvent to obtain a residue, add DMF (10 mL), 2-(octadecyloxy)ethane-1-ol (0.31 g, 0.99 mmol, 1.5 eq.), DIPEA (0.51 g, 3.96 mmol, 0.69 mL, 6.0 eq.) and pyBOP (1.03 g, 1.98 mmol, 3.0 eq.).
  • Step G Add f (70 mg, 0.12 mmol, 1 eq.) and sodium hydroxide aqueous solution (0.5 M, 1.2 mmol, 5.0 eq.) to the reaction flask. Stir the reaction at room temperature for 48 hours. The reaction system becomes clear. In an ice-water bath, slowly add 1N HCl solution dropwise to adjust the pH to about 1. A large amount of solid precipitates, which is filtered and dried in vacuo to obtain intermediate 1 (65 mg, yield 84.56%).
  • Step A Add intermediate 1 (50 mg, 0.083 mmol, 1.0 eq.), DMF (3 mL) and NaH (33.35 mg, 0.833 mmol, 60% purity, 10.0 eq.) to the reaction flask. Stir at room temperature for 20 minutes. 4-nitrophenylbutyrate (34.22 mg, 0.208 mmol, 2.5 eq.) DMF (0.5 mL) solution was added dropwise to the reaction. Stir at room temperature for 3 hours, then heated to 50 ° C for 2 hours.
  • Step A 4-nitrophenol (2.0 g, 14.38 mmol, 1 eq.) and Py (4 mL) were added to the reaction flask, acetic anhydride (2.20 g, 21.57 mmol, 1.5 eq.) was added dropwise under ice bath conditions, and the reaction was stirred at room temperature for 16 hours.
  • the intermediate 1 (100 mg, 166.74 ⁇ mol, 1 eq.) and DMF (2 mL) were added to the reaction flask, and NaH (53.36 mg, 1.33 mmol, 60% purity, 8 eq.) was added under ice bath, and the reaction was stirred at 0°C for 20 min, and then a DMF (1 mL) solution of 4-nitrophenyl acetate (120.82 mg, 666.96 ⁇ mol, 4 eq.) was added dropwise, and the reaction was stirred at 50°C for 2 hours after the addition.
  • Step A 2-(octadecyloxy)ethyl hydrogen (((S)-1-(6-amino-9H-purin-9-yl)-3-hydroxypropyl-2-yl)oxy)methyl)phosphonate (30 mg, 0.05 mmol, 1 eq.) and formic acid (4 mL) were added to a reaction flask. The mixture was stirred at 60°C for 16 hours, and the formic acid was removed by concentration. Methanol (5 mL) was added to the residual crude product, and the mixture was stirred for 30 minutes. The solid was filtered to obtain a solid. After the solid was dispersed in water, it was lyophilized to obtain compound 3b (20 mg, yield 59.88%).
  • Step A Add intermediate 1 (80 mg, 133.39 ⁇ mol, 1 eq.), DIPEA (68.96 mg, 533.56 ⁇ mol, 4 eq.) and DMF (2 mL) into a reaction flask, and then add dropwise a solution of ethyl 1-(((4-nitrophenoxy)carbonyl)oxy)isobutyrate (79.30 mg, 266.78 ⁇ mol, 2 eq.) in DMF (1 mL). After the addition is completed, stir the reaction at 80°C for 6 hours. LC-MS monitoring showed that the reaction raw materials were basically consumed.
  • reaction system was adjusted to pH 2 with 1 mol/L hydrochloric acid aqueous solution, water (50 mL) was added, and ethyl acetate was extracted and washed (20 mL*4). The organic layer was washed once with saturated brine (60 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by reverse phase preparative column (acetonitrile, water, ammonium acetate system) and lyophilized to obtain compound 4b (20 mg, yield 18.83%).
  • Step A Intermediate 1 (100 mg, 166.74 ⁇ mol, 1 eq.), DIPEA (86.20 mg, 666.96 ⁇ mol, 4 eq.) and DMF (4 mL) were added to a reaction flask, and then a solution of ethyl 1-(((4-nitrophenoxy)carbonyl)oxy)acetate (67.33 mg, 250.11 ⁇ mol, 1.5 eq.) in DMF (1 mL) was added dropwise. The mixture was stirred at 80°C for 5 hours. LC-MS monitoring showed that the reaction raw materials were basically consumed. The reaction system was adjusted to pH 2 with 1 mol/L hydrochloric acid aqueous solution under ice-water bath conditions.
  • Step A Add intermediate 1 (200 mg, 0.34 mmol, 1 eq.) and formic acid (10 mL) to the reaction flask. Stir the reaction at 60°C for 16 hours, concentrate to remove formic acid, add methanol (5 mL) and acetonitrile (5 mL) to the residual crude product, stir for 10 minutes, filter to obtain a solid, disperse the solid in methanol (15 mL), continue stirring for 10 minutes, and filter to obtain a solid. After the solid is dispersed in water, freeze-dried to obtain compound 6b (150 mg, yield 69.87%).
  • Step C Add 1-1 (5 g, 11.07 mmol, 1.0 eq.) and tetrahydrofuran (100 mL) to the reaction flask. Cool to -60 °C, slowly add LiHMDs (1.0 M, 33.22 mL, 3.0 eq.). After stirring at -60 °C for 15 minutes, slowly add diethoxy methyl trifluoromethanesulfonate solution (8.30 g dissolved in 20 mL tetrahydrofuran, 28.79 mmol, 2.6 eq.). Warm to room temperature and stir for 16 hours.
  • LiHMDs 1.0 M, 33.22 mL, 3.0 eq.
  • Step E 1-3 (0.8 g, 2.23 mmol, 1 eq.), acetonitrile (10 mL) and TMSBr (1.36 g, 8.91 mmol, 1.18 mL, 4.0 eq.) were added to a reaction flask, stirred at room temperature for 16 hours, concentrated to remove the reaction solvent, added water to the residue, and freeze-dried to obtain product 1-4 (675 mg, yield: 99.10%).
  • Step F 1-4 (0.2 g, 0.66 mmol, 1 eq.), DMF (10 mL), and DIPEA (1 mL) were added to the reaction flask. The reaction was stirred at 45°C for 2 hours. The solvent was removed by concentration to obtain a residue, and DMF (10 mL), 2-(octadecyloxy)ethane-1-ol (0.31 g, 0.99 mmol, 1.5 eq.), DIPEA (0.51 g, 3.96 mmol, 0.69 mL, 6.0 eq.) and pyBOP (1.03 g, 1.98 mmol, 3.0 eq.) were added.
  • Step G Add 1-5 (70 mg, 0.12 mmol, 1 eq.) and sodium hydroxide aqueous solution (0.5 M, 1.2 mmol, 5.0 eq.) to the reaction flask. Stir the reaction for 48 hours at room temperature. The reaction system becomes clear. In an ice-water bath, slowly add 1N HCl solution dropwise to adjust the pH to about 1. A large amount of solid precipitates, which is filtered and dried in vacuo to obtain Comparative Example 1 (65 mg, yield 84.56%).
  • Steps A-E are the same as those of Comparative Example 1
  • Step F Add 2-1 (0.675 g, 2.23 mmol, 1 eq.), DMF (25 mL), and DIPEA (3 mL) to the reaction flask. Stir the reaction at 45°C for 2 hours. Concentrate and remove the solvent to obtain a residue, add DMF (25 mL), 3-(hexadecyloxy)propanol (1 g, 3.34 mmol, 1.5 eq.), DIPEA (1.73 g, 13.36 mmol, 2.33 mL, 6.0 eq.) and pyBOP (3.48 g, 6.68 mmol, 3.0 eq.).
  • Step G Add 2-2 (150 mg, 0.26 mmol, 1 eq.) and sodium hydroxide aqueous solution (0.5 M, 2.64 mmol, 5.0 eq.) to the reaction flask. Stir the reaction for 4 hours at room temperature. The reaction system becomes clear. In an ice-water bath, slowly add 1N HCl solution dropwise to adjust the pH to about 1. A large amount of solid precipitates, which is filtered and dried in vacuo to obtain the product comparative example 2 (80 mg, yield 51.29%).
  • the animal is administered a measured volume of dosing solution by oral administration.
  • blood samples are collected at specific time points (e.g., 0.5, 1, 2, 4, 8, 24, 32, and 48 hours).
  • the blood samples are converted into plasma samples using standard techniques.
  • LC-MS/MS analysis is performed to obtain the concentration of the test compound and the parent drug in the comparative example in plasma.
  • Vero cells (ATCC CRL-1587) were inoculated in 96-well plates in a medium containing 10% fetal bovine serum, 100 U/mL penicillin, and 100 ⁇ g/mL streptomycin in MEM (Gibco Cat#41500034), and 0.05 PFU/cell of vaccinia virus, Tiantan strain was added.
  • Virus inhibition activity (%) (number of virus plaques in the drug group/number of virus plaques in the control group) ⁇ 100.
  • the results of the in vitro test are shown in FIG1 .
  • the inhibitory activities of BCV and BCV prodrug 15b are similar, while the inhibitory activities of the present compound 3b and compound 6b are similar, about 10-30 times that of BCV, with EC50 values of 0.068 ⁇ M and 0.165 ⁇ M, respectively.
  • mice 60 male Balb/c nude mice were randomly divided into 5 groups, namely blank control group, BCV administration group, BCV prodrug 15b administration group, compound 3b administration group and compound 6b administration group.
  • the experimental mice were inoculated with vaccinia virus on D1 of the experiment, and then gavaged with the corresponding drugs on D2, D4 and D6 of the experiment (the blank control group was only given the same volume of solvent), and the three administration doses were 20 mg/kg, 5 mg/kg and 5 mg/kg respectively.
  • the weight changes of the animals before and after administration were recorded during the experiment to evaluate the protective effect of the test substance on the animals, and blood and tissues were taken for standby use.
  • mice in the blank control group gradually reached the surrogate endpoint from D3, a large number of mice reached the surrogate endpoint on D6 and D7, and all mice reached the surrogate endpoint on D8; the BCV administration group failed to improve the situation of mice reaching the surrogate endpoint, and all mice in this group also reached the surrogate endpoint on D8; while the situation of the compound 3b and compound 6b administration groups was significantly improved, among which compound 3b had the best effect, and only one mouse reached the surrogate endpoint on D14.
  • the therapeutic effects of compound 3b and compound 6b are better than BCV. They can delay the virus-induced weight loss in mice, and even restore the weight growth of mice, and can also reduce the death of mice caused by the virus.

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Abstract

一种核苷类似物，或其药学上可接受的盐或酯，在制备用于治疗、抑制或预防病毒感染或细胞增殖所引发疾病的药物中的用途，尤其可用于治疗、抑制或预防包括人类在内的哺乳动物所受的猴痘病毒感染或由猴痘病毒感染引起的疾病。

Description

核苷类似物及其医药用途
相关申请的交叉引用
本申请基于申请号为202310741316.5、申请日为2023年06月21日的中国专利申请提出，并要求该中国专利申请的优先权，该中国专利申请的全部内容在此引入本申请作为参考。
技术领域
本发明涉及一种核苷类似物或其药学上可接受的盐或酯，及其在制备用于治疗、抑制或预防病毒感染疾病或细胞增殖疾病的药物中的用途。
 背景技术
基于病毒携带的核酸的类型和表达模式，病毒可以被分成DNA病毒、RNA病毒等。新抗病毒药物的设计和发现一般是针对病毒或细胞靶标，抑制病毒蛋白的药物可能是病毒特异性的，并且更容易产生抗性。
2022年猴痘疫情最先被英国在当地时间2022年5月7日发现。当地时间5月20日，随着欧洲确诊和疑似猴痘病例超过100例。猴痘是一种病毒性人畜共患病，人类感染后出现的症状与过去在天花患者身上所看到的症状相似。但是自1980年世界上消灭天花以后，天花已不复存在，而猴痘仍然在非洲部分地区散发。猴痘发生于非洲中西部雨林中的猴类，也可感染其他动物，偶可使人类受感染。临床表现类似天花，但病情较轻。这种疾病由猴痘病毒造成，猴痘病毒式结构较稳定、突变率较低的双链DNA病毒，这种病毒可以通过直接密切接触由动物传染给人，也可以在人与人之间传播。
自从发现(S)-羟基膦酰甲氧基丙基腺嘌呤((S)-HPMPA)对DNA病毒表现出广谱抗病毒作用后，人们对于膦酸核苷的抗病毒作用进行了广泛的研究，但由于膦酸基团带有负电荷使其细胞通透性和口服生物利用度较低，目前市面上已公开的抑制病毒的药物，仍然不足以应对频发的病毒感染疾病的传播，因此需要开发和生产更有效的广谱抗病毒药。
发明内容
本申请主要解决的技术问题是提供一种核苷类似物的化合物，该化合物能够具有至少以下效果中的一种或多种：
1)较好的体内的药代动力学性质；
2)较高的药物的稳定性和溶解性；
3)较低的毒性和不良反应；
4)较高的向特定部位的转运和分布能力；以及
5)较好的缓释效果和较长的作用时间。
一方面，本发明提供一种式(I)所示的核苷类似物或其药学上可接受的盐或酯：
其中，X选自-OR4,或者X与R3组合成一个化学键；
R1选自H或C4-C30羰基，所述C4-C30羰基包括取代或未取代的烃基羰基、取代或未取代的芳基羰基或杂环羰基,以及取代或未取代的烃氧基羰基，且所述羰基的碳数为4～30，可以是4～10、10～30或20～30，具体地可以是10、12、14、16、18、20、22、24、26、28、30；
R2、R4独立地选自H、其中R5选自取代或未取代的C15-C30烃基，且所述烃基可以是直链烃基或支链烃基；
R3选自：H；甲酰基、C4-C30羰基，其中所述C4-C30羰基包括取代或未取代的烃基羰基、取代或未取代的芳基羰基或杂环羰基，以及取代或未取代的烃氧基羰基，且所述羰基的碳数不大于30；或氨基酸残基。
作为限制的，当X为-OR4时，所述R1、R2、R3、R4不同时为H，当X与R3组合成一个化学键时，所述R1、R2不同时为H。
进一步地，本申请提供式(II)所示的化合物；
进一步地，本申请提供式(III)所示的化合物：
作为限制的，当X为-OR4时，所述R1、R3、R4不同时为H；当X与R3组合成一个化学键时，所述R1不为H。
在一些实施方式，本发明提供了式(IIIa)和式(IIIb)所示的化合物：
其中所涉及的R1或R3如上文所限定。在一些实施方式中，在式(IIIa)和(IIIb)中，R1和R3分别独立地选自甲酰基、C1-C3烷羰基、(CH3)2CHCOOCH(CH3)C(O)-、CH3COOCH(CH3)C(O)-；且X为H。在一些优选实施方式中，在式(IIIa)和(IIIb)中，R1和R3分别独立地选自C1-C3烷羰基且X为H。
进一步地，本申请提供式(IV)所示的化合物：
作为限制的，当X为-OR4时，所述R1、R3、R4不同时为H；当X与R3组合成一个化学键时，所述R1不为H。
在一些实施方式，本发明提供了式(IVa)或(IVb)所示的化合物：
其中所涉及的R1或R3如上文所限定。在一些优选实施方式中，在式(IVa)和(IVb)中，R1和R3分别独立地选自甲酰基、C1-C3烷羰基、(CH3)2CHCOOCH(CH3)C(O)-、CH3COOCH(CH3)C(O)-；且X为H。在一些优选实施方式中，在式(IVa)和(IVb)中，R1和R3分别独立地选自C1-C3烷羰基，且X为H。
更优选地，R3选自甲酰基。进一步地，R1选自取代或未取代的烃基羰基，包括以下所示的基团：
进一步地，R1选自取代或未取代的芳基羰基或杂环羰基，包括以下所示的基团：
其中，Y选自H、F、Cl、Br、Me、-OMe、-OEt、-CF3或-CN。
进一步地，R1选自取代或未取代的烃氧基羰基，包括以下所示的基团：
进一步地，R5包括以下基团：
进一步地，R3包括以下基团：
本发明的化合物包括以下表1a和表1b所示的化合物：
表1a
[根据细则26改正 08.01.2025]
表1b
本申请提供的化合物，可用于制备治疗、抑制或预防病毒感染或病毒感染所致疾病的药物。在一些实施方式中，病毒感染包括乙肝病毒(HBV)、新冠病毒(SARS-COV-2)、人类免疫缺陷病毒(HIV)、水痘带状疱疹病毒(VZV)、巨细胞病毒(CMV)、单纯疱疹病毒(HSV)、BK病毒、JC病毒、爱泼斯坦-巴尔病毒(EBV)、埃博拉病毒、多瘤病毒、乳头瘤病毒、正痘病毒、丙肝病毒(HCV)、呼吸道合胞体病毒(RSV)、登革热病毒、流感病毒、腺病毒、副流感病毒和/或鼻病毒引起的感染。
进一步地，上述正痘病毒包括重型和轻型天花病毒、猴痘病毒、牛痘病毒、骆驼痘病毒、传染性软疣、羊痘病毒、aractuba病毒(ARAV)、BeAn58058病毒(BAV)、cantagalo正痘病毒(CTGV)、小鼠痘病毒、象痘病毒、牛痘苗病毒(VV)、兔痘病毒、浣熊痘病毒、臭鼬痘病毒、沙鼠痘病毒和田鼠痘病毒。优选地，本申请公开的化合物可用于制备治疗、抑制或预防哺乳动物的猴痘病毒或天花病毒感染所致疾病的药物。
本申请提供的化合物，可用于制备治疗、抑制或预防病毒感染引发疾病的药物。进一步地，病毒感染引发的疾病包括DNA病毒感染所引起的疾病，具体地，疾病选自视网膜炎、肺炎、膀胱炎、蛋白质病变等。
本申请提供的化合物，还可用于制备治疗、抑制或预防细胞增殖引发疾病的药物。进一步地，细胞增殖引发疾病为肿瘤或癌症，具体地，肿瘤或癌症选自多发性骨髓瘤(MM)、慢性淋巴细胞白血病(CLL)、套细胞淋巴瘤(MCL)、实体瘤、难治性实体瘤、非霍奇金淋巴瘤、血液瘤、神经母细胞瘤、结直肠癌、宫颈癌、肺癌、白血病、乳腺癌、胰腺癌、B-细胞恶性肿瘤、转移性肿瘤和结肠癌。
本申请还提供一种药物组合物，包括上述化合物中的一种或多种，以及至少一种药学上可接受的载体或赋形剂。具体地，药学上可接受的载体包括乳膏、乳剂、凝胶、脂质体和纳米颗粒中的一种或多种；药学上可接受的赋形剂包括粘合剂，填充剂，崩解剂，润滑剂和助流剂中的一种或多种。
进一步地，上述药物组合物适用于口服施用或者注射施用。
本申请还提供一种试剂盒，该试剂盒包括上述任意一种或多种化合物或药学上可接受的盐或酯或者任意一种或多种所述的药物组合物。
本申请提供的特定化合物，或其药学上可接受的盐或酯，或者含有其的药物组合物，能够有效地治疗、抑制或预防哺乳动物的病毒感染和/或细胞增殖疾病，尤其是天花和猴痘，且至少具有改变体内的药代动力学性质、调整药物在体内的吸收和分布、改善药物的稳定性和溶解性、减低毒性和不良反应、提高向特定部位的转运和分布、提高缓释效果、延长作用时间等效果中的一种或多种。
 附图说明
图1为试验化合物的抑制活性-药物浓度曲线图。
图2示出了小鼠死亡替代终点的死亡曲线图，其中图2a为体重变化图，图2b为替代终点死亡曲线。
图3示出了小鼠实际死亡曲线图，其中图3a为体重变化图，图3b为实际死亡曲线。
 具体实施方式
为了对本发明的说明书中所使用的术语提供清楚且一致的理解，在下文中提供一些定义。此外，除了特殊说明，本发明所用的全部技术和科学术语具有同本发明所属领域中普通技术人员通常所理解的相同的含义。
当在权利要求和/或说明书中与术语“包括”结合使用时，词语“一”的使用可以表示“一个/种”，但它也与“一个/种或多个/种”，“至少一个/种”和“一个/种或多于一个/种”的含义一致。类似地，词语“另一个/种”可以表示至少第二个/种或者很多个/种。
如在本说明书和权利要求中所使用的词语“包括”、“具有”以及同义词是包括性的和开放式的，并且不排除另外的未列出的要素或处理步骤。术语“约”或“大约”用于表示该值包括在确定该值中所用的仪器和方法带来的误差。
本发明所用术语“药学上可接受的”是指该术语描述的药物、药品、惰性成分等，适合用于与人和低等动物的组织相接触，而没有异常毒性、不相容性、不稳定性、刺激性、过敏反应等，与合理的利益/风险比率相称。它优选的是指药典或其它公认的药典中列出的用于动物，更特别是用于人的化合物、组合物以及制剂等。
化合物的“药学上可接受的盐”是指药学上可接受的化合物的盐。理想的化合物的盐(碱性、酸性或带电官能团)可以保留或改善如本发明所定义的母体化合物的生物活性和性质，并且不是生物学上不需要的。
术语“酯”意指衍生自本申请中各个通式化合物的酯，其包括生理上可水解的酯(可在生理条件下水解以释放游离酸或醇形式的本发明的化合物)。本发明的化合物本身也可以是酯。
在一些实施方式中，本发明公开的化合物以一种前药的方式存在。
术语“前药”或其等同表述是指在体外或体内直接或间接转化成活性形式的药剂(例如参见R.B.Silverman,1992,"The Organic Chemistry of Drug Design and Drug Action,"Academic Press,Chap.8；Bundgaard,Hans；Editor.Neth.(1985),"Design of Prodrugs".360pp.Elsevier,Amsterdam；Stella,V.；Borchardt,R.；Hageman,M.；Oliyai,R.；Maag,H.；Tilley,J.(Eds.)(2007),"Prodrugs:Challenges and Rewards,XVIII,1470p.Springer)。前药可用于改变具体药物的生物分布(例如，使药剂通常不会进入蛋白酶反应位点)或药代动力学。已经使用多种基团例如酯、醚、磷酸酯/盐等来修饰化合物以形成前药。当将前药施用至受试者时，该基团通过酶促或非酶促、还原、氧化或水解地裂解掉，或者以其它方式释放出活性化合物。如本文中所使用的，“前药”包括药学上可接受的盐，或药学上可接受的溶剂化物，以及上文的任何结晶形式。前药通常(尽管不一定)是药学上无活性的，直至其转化为活性形成。
应当理解的是本发明所用术语“取代”或“被取代”包括隐含的条件，即这种取代随着取代原子化合价和取代基的变化，取代产生稳定的化合物(例如化合物不能自发进行重排、环化、消除等过程)。如本发明所用术语“取代的”包括有机化合物所有允许的取代基。在广义上，允许的取代基包括无环和环状，支链化和非支链化，碳环和杂环，芳香族和非芳香族的有机化合物。取代基可以是一个或多个。术语“取代的”是指当上述基团与在一个或多个位置被取代时，取代基包括酰基氨基(包括氨基甲酰基和脲基)、烷基羰基氧基、芳基羰基氧基、烷氧基羰基氧基、烷氧基羰基、羧基、羧基、氨基羰基、单和二烷基氨基羰基、氰基、叠氮基、卤素、羟基、硝基、三氟甲基、硫基、烷硫基、芳硫基、烷硫基羰基、硫代羧酸酯、低烷基、低链烯基、低炔基、环烷基、杂环烷基、芳基、杂芳基、低烷氧基、芳氧基、芳氧基羰氧基、苄氧基、苄基、亚磺酰基、烷基亚磺酰基、磺酰基、硫酸盐、磺酸盐、磺酰胺、磷酸盐、膦酸盐、亚氨基、甲酰基等。如果允许，任何上述取代基可以进一步被取代，例如被烷基、芳基或其它基团取代。
术语“烃基羰基”、“芳基羰基”、“杂环羰基”或“烃氧基羰基”指-C(＝O)Ra，Ra为烃基、芳基、杂芳基、杂环基或烃氧基。术语“烃氧基”指-ORb，Rb为烃基。例如，表述“C4-C30羰基”是指其中Ra具有3至29个碳原子的“-C(＝O)Ra”，具体地，碳原子数可以是3、9、11、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29，并且Ra可为取代或未取代的烃基、取代或未取代的芳基、取代或未取代的三元环、四元环、五元环、取代或未取代的烃氧基。
术语“C15-C30烃基”表示在烃基结构中具有15至30个碳原子，具体地，碳原子数可以是15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30，术语“C1-C16烃基”表示在烃基结构中具有1至16个碳原子，具体地，碳原子数可以是1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16。
本发明所用术语“芳基”或“芳基环”是指在共轭单环或多环体系(稠和或非稠和的)中具有“4n+2”个(π)电子，并具有6至14个环原子的芳族基团，其中n是1至3的整数。多环系统包括至少一个芳环。芳基可以直接连接或通过C1-C3烷基(也称为芳基烷基或芳烷基)连接。芳基的实例包括但不限于苯基、苄基、苯乙基、1-苯基乙基、甲苯基、萘基、联苯基、三联苯基、茚基、苯并环辛烯基、苯并环庚烯基、薁基、苊基、芴基、菲基、蒽基等。术语“芳基”包括未取代的芳基和取代的芳基。
本发明所用术语“杂芳基”或“杂芳基环”是指在共轭单环或多环体系(稠和或非稠和的)中具有“4n+2”个(π)电子的芳族基团，其中n是1至3的整数，并包括一个至六个杂原子(例如N、O、S、P)或者包括杂原子(例如NH、NRx(Rx是烷基、酰基、芳基、杂芳基或环烷基)、PO2、SO、SO2等)的基团。多环系统包括至少一个杂芳环。杂芳基可以直接连接或通过C1-C3烷基(也称为杂芳基烷基或杂芳烷基)连接。杂芳基可以与碳连接的或者与杂原子连接的(例如，通过氮原子)。杂芳基的实例包括但不限于吡啶基、咪唑基、嘧啶基、吡唑基、三唑基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基、异噻唑基、吡咯烷基、喹啉基、异喹啉基、吲哚基、异吲哚基、色烯基、异色烯基、苯并咪唑基、苯并呋喃基、噌啉基、吲唑基、吲嗪基、酞嗪基、哒嗪基、吡嗪基、三嗪基、异吲哚基、喋啶基、呋喃基、苯并呋喃基、苯并噻唑基、苯并噻吩基、苯并噻唑基、苯并恶唑基、喹唑啉基、喹啉酮基、异喹啉酮基、喹喔啉基、萘啶基、呋喃并吡啶基、咔唑基、菲啶基、吖啶基、苝基、菲咯啉基、吩嗪基、吩噻嗪基、吩恶嗪基、二苯并呋喃基等。术语“杂芳基”包括未取代的杂芳基和取代的杂芳基。术语“C5-Cn杂芳基”，其中n是6至15的整数，表示在环结构中具有从5至所示“n”个原子的杂芳基，包括至少一个如上所定义的杂环基团或原子。
在一些实施方式中，本发明提供了一种膦酸酯类化合物，或其药学上可接受的盐或酯，在制备用于治疗、抑制或预防病毒感染疾病或细胞增殖疾病的药物中的用途，该膦酸酯化合物选自但不限于表1所列化合物。
术语“氨基酸残基”是指氨基酸上的羧基脱羟基基团后的主要部分。
本发明所用术语“氨基酸”通常是指同时包含羧酸基团和胺基基团的有机化合物。术语“氨基酸”包括“天然”和“非天然”的氨基酸。另外，术语“氨基酸”包括O-烷基化或N-烷基化的氨基酸，以及具有含氮、硫或氧的侧链(例如Lys，Cys或Ser)的氨基酸，其中氮、硫或氧原子可以被或不被酰基化或烷基化。氨基酸可以是L-氨基酸，D-氨基酸或L-和D-混合的氨基酸，包括(但不限于)外消旋混合物。
本发明所用术语“天然氨基酸”和等同表达是指通常在天然存在的蛋白质中发现的L-氨基酸。天然氨基酸的实例包括但不限于丙氨酸(Ala)，半胱氨酸(Cys)，天冬氨酸(Asp)，谷氨酸(Glu)，苯丙氨酸(Phe)，甘氨酸(Gly)，组氨酸(His)，异亮氨酸(Ile)，赖氨酸(Lys)，亮氨酸(Leu)，甲硫氨酸(Met)，天冬酰胺(Asn)，脯氨酸(Pro)，谷氨酰胺(Gln)，精氨酸(Arg)，丝氨酸(Ser)，苏氨酸(Thr)，色氨酸(Trp)，酪氨酸(Tyr)，β-丙氨酸(β-Ala)和γ-氨基丁酸(GABA)等。
本发明所用术语“非天然氨基酸”是指天然氨基酸的任何衍生物，包括D-型氨基酸及其衍生物，以及α-和β-氨基酸衍生物。应注意的是，在本发明中某些非天然氨基酸的(例如羟脯氨酸)可在自然界中存在于某些生物组织或特定蛋白质中。具有许多不同保护基团、适于固相肽合成中直接应用的氨基酸是可以通过购买得到的。除了二十个最常见的天然氨基酸，可以根据本发明使用如下实例的非天然氨基酸和氨基酸衍生物(括号中为常见的缩写)：2-氨基己二酸(Aad)，3-氨基己二酸(β-Aad)，2-氨基丁酸(2-Abu)，α，β-脱氢-2-氨基丁酸(8-AU)，1-氨基环丙烷-1-羧酸(ACPC)，氨基异丁酸(Aib)，3-氨基异丁酸(β-Aib)，2-氨基-噻唑啉-4-羧酸，5-氨基戊酸(5-Ava)，6-氨基己酸(6-Ahx)，2-氨基庚酸(Ahe)，8-氨基辛酸(8-Aoc)，11-氨基十一烷酸(11-Aun)，12-氨基十二烷酸(12-Ado)，2-氨基苯甲酸(2-Abz)，3-氨基苯甲酸(3-Abz)，4-氨基苯甲酸(4-Abz)，4-氨基-3-羟基-6-甲基庚酸(Statine，Sta)，氨基氧基乙酸(Aoa)，2-氨基四氢化萘-2-羧酸(ATC)，4-氨基-5-环己基-3-羟基戊酸(ACHPA)，对氨基苯丙氨酸(4-NH2-Phe)，2-氨基庚二酸(Apm)，联苯基丙氨酸(Bip)，对溴苯丙氨酸(4-Br-Phe)，邻氯苯丙氨酸(2-Cl-Phe)，间氯苯丙氨酸(3-Cl-Phe)，对氯苯丙氨酸(3-Cl-Phe)，间-氯酪氨酸(3-Cl-Tyr)，对苯甲酰基苯丙氨酸(Bpa)，叔丁基甘氨酸(TLG)，环己基丙氨酸(Cha)，环己基甘氨酸(Chg)，锁链素(Des)，2,2-二氨基庚二酸(Dpm)，2,3-二氨基丙酸(Dpr)，2,4-二氨基丁酸(Dbu)，3,4-二氯苯丙氨酸(3,4-Cl2-Phe)，3,4-二氟苯丙氨酸(3,4-F2-Phe)，3,5-二碘酪氨酸(3,5-I2-Tyr)，N-乙基甘氨酸(EtGly)，N-乙基天冬酰胺(EtAsn)，邻氟苯丙氨酸(2-F-Phe)，间氟苯丙氨酸(3-F-Phe)，对氟苯丙氨酸(4-F-Phe)，间-氟酪氨酸(3-F-Tyr)，高丝氨酸(Hse)，高苯丙氨酸(Hfe)，高酪氨酸羟基赖氨酸(Hyl)，异羟基赖氨酸(aHyl)，5-羟色氨酸(5-OH-Trp)，3-或4-羟基脯氨酸(3-或4-Hyp)，对碘苯丙氨酸-异酪氨酸(3-I-Tyr)，二氢吲哚-2-羧酸(Idc)，异艾杜霉素(Ide)，异亮氨酸(α-Ile)，异哌啶酸(Inp)，N-甲基异亮氨酸(MeLys)，间甲基酪氨酸(3-Me-Tyr)，N-甲基缬氨酸(MeVal)，1-萘基丙氨酸(1-Nal)，2-萘基丙氨酸(2-Nal)，对硝基苯丙氨酸(4-NO2-Phe)，3-硝基酪氨酸(3-NO2-Tyr)，正亮氨酸(Nle)，正缬氨酸(Nva)，鸟氨酸(Orn)，邻磷酸酪氨酸(H2PO3-Tyr)，八氢吲哚-2-羧酸(Penicillamine)，五氟苯丙氨酸(F5-Phe)，苯基甘氨酸(Phg)，哌啶酸(Pip)，炔丙基甘氨酸(Pra)，焦谷氨酸(PGLU)，肌氨酸(Sar)，四氢异喹啉-3-羧酸(Tic)，噻唑烷-4-羧酸(硫代脯氨酸，Th)。
本发明提供了治疗病毒感染、不适当的细胞增殖等有关的哺乳动物疾病的方法。这些方法具体包括给予需要治疗的人或其它哺乳动物治疗学有效量的本发明的化合物。
在一些实施方式中，本申请提供的化合物可用于制备一种药物，该药物可用于治疗、抑制或预防病毒感染或病毒感染引发疾病。在一些实施方式中，本申请提供的化合物及其药学上可接受的盐或酯用于制备治疗天花病毒感染或由天花病毒引发疾病的药物。在一些实施方式中，本申请提供的化合物及其药学上可接受的盐或酯用于制备治疗猴痘病毒感染或由猴痘病毒引发疾病的药物。
本申请提供的化合物，在治疗、抑制或预防病毒感染以及病毒感染所致疾病上具有很好的效果。同时，申请人发现本申请提供的化合物在治疗癌症或肿瘤上也有很好的效果。在一些实施方式中，本申请提供的化合物及其药学上可接受的盐或酯可用于制备药物，该药物可用于治疗、抑制或预防细胞增殖引发的肿瘤或癌症。
在一些实施方式中，本申请提供的药物还包括至少一种可药用的载体或稀释剂。在一些实施方式中，可药用的载体或稀释剂选自乳膏、乳剂、凝胶、脂质体或纳米颗粒。
本发明提供的化合物或药物可以以本领域已知的任何适当方式施用于受试者。合适的给药途径包括但不限于口服；肠胃外，例如肌内、静脉内、皮下(例如注射或植入)、腹腔内、脑池内、关节内、脑内(脑实质内和脑室内)；鼻腔；阴道；舌下；眼内；直肠；局部(例如透皮)；口腔和吸入。一般通过皮下或肌肉内给药的积存注射法也可用于在限定的时间段内释放本申请公开的化合物或药物。在一些实施方式中，药物是可注射的制剂。在其它实施方式中，药物被配制为用于口服施用至受试者。
本发明还提供了包含抗病毒感染化合物或药物的试剂盒。试剂盒通常为容纳各种组分的物理结构的形式，并且可用于例如实施本文提供的方法。例如，试剂盒可以包括本发明公开的一种或多种化合物或药物(例如提供在无菌容器中)，其可为适合施用至受试者的药物组合物的形式。化合物可以以即用型(例如片剂或胶囊)形式或以需要例如在施用前重构或稀释(例如粉末)的形式提供。当化合物为需要使用者被重构或稀释的形式时，该试剂盒还可包括与化合物一起包装或者分别包装的稀释剂(例如无菌水)、缓冲液、药学上可接受的赋形剂等。当采用组合疗法时，试剂盒可独立地含有几种治疗剂，或者它们可已经在试剂盒中组合。试剂盒的每个组分可以被封装在单独的容器内，并且所有的各种容器可以在单个包装内。本发明的试剂盒可被设计用于适当地保持容纳在其中的组分所需的条件(例如，冷藏或冷冻)。
本文描述的药物或药物组合物可以通过药理学领域中已知的任何方法来制备。通常，此类准备的方法包括以下步骤：使在此描述的一种化合物(“活性成分”)与一种载体和/或一种或多种其他辅助成分结合，并且然后如果必要和/或希望，使产品成形和/或包装成希望的单剂量单位或多剂量单位。
其中药物或药物组合物可以呈一个单一单位剂量和/或呈多个单一单位剂量进行制备、包装和/或批量出售。如在此所使用，“单位剂量”是包含预定量的活性成分的药物组合物的离散量。该活性成分的量通常等于将要向受试者给予的该活性成分的剂量和/或这样一种剂量的一个合宜部分，例如像这样一种剂量的一半或三分之一。
为了更好地理解本发明并更清楚地展示出如何实现本发明，现通过示例的方式，并阐述了根据本发明的实施方式的特征。
实施例
通过参考以下实施例将更容易理解本发明，所述实施例用于说明本发明，而不应被解释为以任何方式限制本发明的范围。
本发明提供的化合物可以通过以下通式进行合成，其中，用于制备本发明的化合物的所有试剂都是市售的或根据文献中已经公开的制备方法进行制备。
以化合物A为起始原料，在缩合剂1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐(PYBOP)作用下，与不同的醇进行环化和缩合反应得到化合物B；在碱如碳酸钾作用下，化合物B上的氨基与酰氯反应得到化合物C，再经过氢氧化钠溶液水解并酸化可以得到化合物D；
将上述中间体化合物B上的氨基经过Boc酸酐保护得到化合物E，经过氢氧化钠溶液水解得到开环化合物F，化合物F与酰氯缩合得到化合物G，最后进过脱保护得到化合物H。
通式中所有的R1、R2、R3、R4等R基团均如说明书和权利要求书所定义。
除非另有定义或上下文另有明确规定，本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同的含义。应当理解，与本文所述类似或等同的任何方法和材料可用于本发明的实践或测试。
中间体的合成
中间体1的合成
步骤A：反应瓶中加入二乙氧基磷酸甲醇(20g，118.96mmol，1.0eq.)、二氯甲烷(400mL)和三乙胺(14.44g，142.75mmol，1.2eq.)。降温至-60℃后，将三氟甲磺酸酐(38.6g，136.80mmol，23.02mL，1.15eq.)缓慢滴加入反应体系并搅拌反应半个小后。缓慢升温至室温后，搅拌反应1小时。浓缩除去二氯甲烷后，加入乙酸乙酯(500mL)，有机相水洗，1N稀盐酸洗，浓盐水洗。无水硫酸钠干燥，过滤浓缩得产物二乙氧基磷酸甲基三氟甲磺酸酯(28g，收率：78.41％)。
步骤B：反应瓶中加入化合物a(4.9g，36.26mmol，1.0eq.)、DMF(100mL)、DBU(1.1g，7.25mmol，1.08mL，0.2eq.)和(S)-2-((三苯氧基)甲基)环氧乙烷(10.33g，36.26mmol，0.9eq.)。100℃搅拌反应6小时，浓缩除去反应溶剂，残留物过硅胶柱(二氯甲烷：甲醇＝100：0-94：6)得产物b(7g，收率：42.75％)。
步骤C：反应瓶中加入化合物b(5g，11.07mmol，1.0eq.)和四氢呋喃(100mL)。降温至-60℃，缓慢滴加LiHMDs(1.0M，33.22mL,，3.0eq.)。在-60℃温度下搅拌15分钟后，缓慢滴加二乙氧基磷酸甲基三氟甲磺酸酯溶液(8.30g溶于20mL四氢呋喃，28.79mmol，2.6eq.)。升温至室温，搅拌反应16小时。浓缩除去大部分反应溶剂后，加入乙酸乙酯(300mL)，有机相水洗、浓盐水洗，无水硫酸钠干燥，过滤浓缩，残留物过硅胶柱(二氯甲烷：甲醇＝100：0-92：8)得产物c(3.5g，收率：52.53％)。
步骤D：反应瓶中加入c(3.5g，5.82mmol，1eq.)、醋酸(50mL)和水(12mL)。在90℃温度下搅拌反应3小时，过滤浓缩，残留物过硅胶柱(二氯甲烷：甲醇＝100：0-90：10)得产物d(1.6g，收率：76.54％)。
步骤E：反应瓶中加入d(0.8g，2.23mmol，1eq.)、乙腈(10mL)和TMSBr(1.36g，8.91mmol，1.18mL，4.0eq.)。室温搅拌反应16小时，浓缩除去反应溶剂，残留物加入水，冷冻干燥得产物e(675mg，收率：99.10％)。
步骤F：反应瓶中加入e(0.2g，0.66mmol，1eq.)、DMF(10mL)、和DIPEA(1mL)。45℃反应搅拌反应2小时。浓缩除去溶剂得残留物，加入DMF(10mL)、2-(十八烷氧基)乙烷-1-醇(0.31g，0.99mmol，1.5eq.)、DIPEA(0.51g，3.96mmol，0.69mL，6.0eq.)和pyBOP(1.03g，1.98mmol，3.0eq.)。45℃搅拌反应16小时，浓缩除去反应溶剂，残留物用硅胶柱分离纯化(二氯甲烷：甲醇＝100：0-90：10)，得产物f(0.22g，收率56.08％)。1H NMR(500MHz,CDCl3)δppm:0.87(t,J＝6.8Hz,3H),1.24(s,30H),1.54(s,2H),3.43(dt,J＝13.6,6.7Hz,2H),3.54-3.70(m,2H),3.89(dd,J＝13.1,6.2Hz,1H),4.04-4.66(m,8H),6.02(d,J＝34.8Hz,2H),7.87(d,J＝3.0Hz,1H),8.34(d,J＝3.8Hz,1H)；m/z(ESI+):582.5(M+H).
步骤G：反应瓶中加入f(70mg，0.12mmol，1eq.)和氢氧化钠水溶液(0.5M，1.2mmol，5.0eq.)。室温条件下，搅拌反应48小时。反应体系变澄清。冰水浴下，缓慢滴加1N HCl溶液，调节pH至1左右，大量固体析出，过滤，真空干燥得中间体1(65mg，收率84.56％)。1H NMR(500MHz,CDCl3)δppm:0.84(t,J＝6.8Hz,3H),1.21(s,30H),1.51(d,J＝6.7Hz,2H),3.42(t,J＝7.0Hz,2H),3.49(d,J＝8.9Hz,1H),3.57(t,J＝4.5Hz,2H),3.70(dd,J＝21.7,8.8Hz,2H),3.84(d,J＝8.7Hz,2H),4.07(d,J＝6.1Hz,2H),4.34(dd,J＝14.2,7.3Hz,1H),4.47(d,J＝11.7Hz,1H),8.15(s,1H),8.30(s,1H)；m/z(ESI+):600.6(M+H).
化合物的合成
实施例1：化合物1b的合成
步骤A：反应瓶中加入中间体1(50mg，0.083mmol，1.0eq.)、DMF(3mL)和NaH(33.35mg，0.833mmol，60％纯度，10.0eq.)。室温搅拌20分钟。4-硝基苯基丁酸酯(34.22mg，0.208mmol，2.5eq.)DMF(0.5mL)溶液滴加入反应。室温搅拌反应3小时，后加热至50℃反应2小时。加入乙酸乙酯(25mL)稀释，低温环境，滴加50％醋酸水溶液，后滴加1N HCl淬灭反应，确保水相pH为1-2。有机层浓盐水洗2次，干燥浓缩后，残留物用硅胶柱分离纯化(二氯甲烷：甲醇＝100：0-80：20)，得产物化合物1b(22mg，收率32.30％)。1H NMR(500MHz,CDCl3)δppm:0.84(t,J＝6.8Hz,3H),0.91(t,J＝7.4Hz,3H),0.97(t,J＝7.3Hz,3H),1.20(d,J＝11.6Hz,30H),1.44(s,2H),1.60(dq,J＝14.5,7.2Hz,2H),1.74(dd,J＝14.6,7.2Hz,2H),2.27(t,J＝7.3Hz,2H),2.67(t,J＝7.1Hz,2H),3.31(t,J＝6.9Hz,2H),3.37(s,2H),3.47(t,J＝11.8Hz,1H),3.83(dd,J＝25.5,18.8Hz,4H),4.04(d,J＝7.5Hz,1H),4.14(d,J＝6.6Hz,1H),4.29(dd,J＝14.5,7.4Hz,1H),4.58(d,J＝13.1Hz,1H),8.65(d,J＝12.2Hz,2H)；m/z(ESI+):740.
实施例2：化合物2b的合成
步骤A：反应瓶中加入4-硝基苯酚(2.0g，14.38mmol，1eq.)和Py(4mL)，冰浴条件下滴加乙酐(2.20g，21.57mmol，1.5eq.)，滴毕室温下搅拌反应16小时。TLC监测反应原料消耗完毕，冰水浴条件下用1mol/L的盐酸水溶液调至反应体系为弱酸性，加入水(80mL)二氯甲烷萃洗(30mL*2)，有机层饱和食盐水洗一次(60mL)，分出有机层，无水硫酸钠干燥过滤，经浓缩后，残留物用硅胶柱分离纯化(二氯甲烷)得产物4-硝基苯基乙酸酯(2.2g，收率84.47％)。反应瓶中加入中间体1(100mg，166.74μmol，1eq.)和DMF(2mL)，冰浴下加入NaH(53.36mg，1.33mmol，60％纯度，8eq.)，0℃下搅拌反应20min，然后滴加4-硝基苯基乙酸酯(120.82mg，666.96μmol，4eq.)的DMF(1mL)溶液，滴毕50℃下搅拌反应2小时。LC-MS监测反应原料消耗完毕，冰水浴条件下用1mol/L的盐酸水溶液调至反应体系PH为2，加入水(50mL)，乙酸乙酯萃洗(20mL*4)，有机层饱和食盐水洗一次(60mL)，分出有机层，无水硫酸钠干燥过滤，经浓缩后，残留物用制备板分离纯化得化合物2b(42mg，收率46.27％)。1H NMR(500MHz,MeOD)δ0.91-0.96(m,3H),1.31(s,30H),1.51(s,2H),2.03(s,2H),2.40(s,2H),3.42(s,2H),3.55(s,2H),3.64-3.73(m,1H),3.84-3.99(m,2H),4.09-4.21(m,3H),4.51-4.58(m,1H),4.62-4.69(m,2H),8.61-8.80(m,2H)；m/z(ESI+):684.7(M+H).
实施例3：化合物3b的合成
步骤A：反应瓶中加入2-(十八烷氧基)乙基氢(((S)-1-(6-氨基-9H-嘌呤-9-基)-3-羟丙基-2-基)氧基)甲基)膦酸酯(30mg，0.05mmol，1eq.)和甲酸(4mL)。60℃搅拌反应16小时，浓缩除去甲酸，残留粗产品加入甲醇(5mL)，搅拌30分钟，过滤得固体，固体分散于水后，冻干得化合物3b(20mg,收率59.88％)。1H NMR(500MHz,CD3OD)δppm:0.88(d,J＝6.9Hz,3H),1.27(s,30H),1.51(s,2H),3.42(d,J＝6.6Hz,2H),3.55(s,2H),3.72(s,1H),3.82-3.90(m,1H),3.97(s,2H),4.13(d,J＝11.4Hz,2H),4.31(d,J＝7.7Hz,1H),4.45(d,J＝8.1Hz,1H),4.60(d,J＝13.5Hz,1H),8.12(s,1H),8.30(s,1H),8.45(s,1H)；m/z(ESI+):628.39(M+H).
实施例4：化合物4b的合成
步骤A：反应瓶中加入中间体1(80mg，133.39μmol，1eq.)，DIPEA(68.96mg，533.56μmol，4eq.)和DMF(2mL)，然后滴加1-(((4-硝基苯氧基)羰基)氧基)异丁酸乙酯(79.30mg，266.78μmol，2eq.)的DMF(1mL)溶液，滴毕80℃下搅拌反应6小时。LC-MS监测反应原料基本消耗完毕，冰水浴条件下用1mol/L的盐酸水溶液调至反应体系PH为2，加入水(50mL)，乙酸乙酯萃洗(20mL*4)，有机层饱和食盐水洗一次(60mL)，分出有机层，无水硫酸钠干燥过滤，经浓缩后，粗品经反相制备柱(乙腈，水，醋酸铵体系)分离纯化，冻干得化合物4b(20mg，收率18.83％)。
1H NMR(500MHz,MeOD)δ0.93(t,J＝6.7Hz,3H),1.16-1.21(m,6H),1.30(d,J＝10.7Hz,30H),1.50-1.58(m,5H),2.60(dt,J＝13.8,6.9Hz,1H),3.47(t,J＝6.3Hz,2H),3.60(d,J＝3.5Hz,2H),3.77-3.85(m,1H),3.88-3.95(m,1H),4.03(s,2H),4.09-4.18(m,1H),4.22(s,1H),4.36(ddd,J＝28.4,11.5,4.2Hz,1H),4.47(dd,J＝14.5,5.6Hz,1H),4.61(d,J＝14.7Hz,1H),6.70-6.75(m,1H),8.29(d,J＝6.4Hz,1H),8.46(s,1H)；m/z(ESI+):758.5(M+H).
实施例5：化合物5b的合成
步骤A：反应瓶中加入中间体1(100mg，166.74μmol，1eq.)，DIPEA(86.20mg，666.96μmol，4eq.)和DMF(4mL)，然后滴加1-(((4-硝基苯氧基)羰基)氧基)乙酸乙酯(67.33mg，250.11μmol，1.5eq.)的DMF(1mL)溶液，滴毕80℃下搅拌反应5小时。LC-MS监测反应原料基本消耗完毕，冰水浴条件下用1mol/L的盐酸水溶液调至反应体系PH为2，加入水(50mL)，乙酸乙酯萃洗(20mL*4)，有机层饱和食盐水洗一次(60mL)，分出有机层，无水硫酸钠干燥过滤，经浓缩后，粗品经反相制备柱(乙腈，水，醋酸铵体系)分离纯化，冻干得化合物5b(40mg，收率31.08％)。1H NMR(500MHz,MeOD)δ0.93(t,J＝6.6Hz,3H),1.32(s,30H),1.48-1.56(m,5H),2.10(s,3H),3.45(t,J＝6.0Hz,2H),3.55-3.61(m,2H),3.74(q,J＝11.2Hz,1H),3.86-3.93(m,1H),3.96-4.04(m,2H),4.13-4.19(m,2H),4.26-4.39(m,1H),4.45-4.51(m,1H),4.56-4.63(m,1H),6.71(q,J＝5.1Hz,1H),8.28(d,J＝4.8Hz,1H),8.44(d,J＝3.0Hz,1H)；m/z(ESI+):730.5(M+H).
实施例6：化合物6b的合成
步骤A：反应瓶中加入中间体1(200mg，0.34mmol，1eq.)和甲酸(10mL)。60℃搅拌反应16小时，浓缩除去甲酸，残留粗产品加入甲醇(5mL)和乙腈(5mL)，搅拌10分钟，过滤得固体，固体分散于甲醇(15mL)继续搅拌10分钟，过滤得固体。固体分散于水后，冷冻干燥得化合物6b(150mg,收率69.87％)。1H NMR(500MHz,CD3OD)δppm:0.89(t,J＝6.7Hz,3H),1.27(s,26H),1.51(d,J＝6.8Hz,2H),1.82(p,J＝6.4Hz,2H),3.39(t,J＝6.6Hz,2H),3.48(t,J＝6.3Hz,2H),3.67(dd,J＝13.1,8.9Hz,1H),3.85(dd,J＝13.2,8.9Hz,1H),3.92(q,J＝6.4Hz,2H),4.09-4.21(m,2H),4.33(d,J＝7.0Hz,1H),4.46(dd,J＝14.6,6.3Hz,1H),4.59(d,J＝14.6Hz,1H),8.13(s,1H),8.31(s,1H),8.42(s,1H)；m/z(ESI+):614.72(M+H).
对比例1(ODE-(S)-HPMPA)的合成
步骤A：反应瓶中加入二乙氧基磷酸甲醇(20g，118.96mmol，1.0eq.)、二氯甲烷(400mL)和三乙胺(14.44g，142.75mmol，1.2eq.)。降温至-60℃后，将三氟甲磺酸酐(38.6g，136.80mmol，23.02mL，1.15eq.)缓慢滴加入反应体系并搅拌反应半个小后。缓慢升温至室温后，搅拌反应1小时。浓缩除去二氯甲烷后，加入乙酸乙酯(500mL)，有机相水洗，1N稀盐酸洗，浓盐水洗。无水硫酸钠干燥，过滤浓缩得产物二乙氧基磷酸甲基三氟甲磺酸酯(28g，收率：78.41％)。
步骤B：反应瓶中加入9H-嘌呤-6-胺(4.9g，36.26mmol，1.0eq.)、DMF(100mL)、DBU(1.1g，7.25mmol，1.08mL，0.2eq.)和(S)-2-((三苯氧基)甲基)环氧乙烷(10.33g，36.26mmol，0.9eq.)。100℃搅拌反应6小时，浓缩除去反应溶剂，残留物过硅胶柱(二氯甲烷：甲醇＝100：0-94：6)得产物1-1(7g，收率：42.75％)。
步骤C：反应瓶中加入1-1(5g，11.07mmol，1.0eq.)和四氢呋喃(100mL)。降温至-60℃，缓慢滴加LiHMDs(1.0M，33.22mL,，3.0eq.)。在-60℃温度下搅拌15分钟后，缓慢滴加二乙氧基磷酸甲基三氟甲磺酸酯溶液(8.30g溶于20mL四氢呋喃，28.79mmol，2.6eq.)。升温至室温，搅拌反应16小时。浓缩除去大部分反应溶剂后，加入乙酸乙酯(300mL)，有机相水洗、浓盐水洗，无水硫酸钠干燥，过滤浓缩，残留物过硅胶柱(二氯甲烷：甲醇＝100：0-92：8)得产物1-2(3.5g，收率：52.53％)。
步骤D：反应瓶中加入1-2(3.5g，5.82mmol，1eq.)、醋酸(50mL)和水(12mL)。在90℃温度下搅拌反应3小时，过滤浓缩，残留物过硅胶柱(二氯甲烷：甲醇＝100：0-90：10)得产物1-3(1.6g，收率：76.54％)。
步骤E：反应瓶中加入1-3(0.8g，2.23mmol，1eq.)、乙腈(10mL)和TMSBr(1.36g，8.91mmol，1.18mL，4.0eq.)。室温搅拌反应16小时，浓缩除去反应溶剂，残留物加入水，冷冻干燥得产物1-4(675mg，收率：99.10％)。
步骤F：反应瓶中加入1-4(0.2g，0.66mmol，1eq.)、DMF(10mL)、和DIPEA(1mL)。45℃反应搅拌反应2小时。浓缩除去溶剂得残留物，加入DMF(10mL)、2-(十八烷氧基)乙烷-1-醇(0.31g，0.99mmol，1.5eq.)、DIPEA(0.51g，3.96mmol，0.69mL，6.0eq.)和pyBOP(1.03g，1.98mmol，3.0eq.)。45℃搅拌反应16小时，浓缩除去反应溶剂，残留物用硅胶柱分离纯化(二氯甲烷：甲醇＝100：0-90：10)，得1-5(0.22g，收率56.08％)。1H NMR(500MHz,CDCl3)δppm:0.87(t,J＝6.8Hz,3H),1.24(s,30H),1.54(s,2H),3.43(dt,J＝13.6,6.7Hz,2H),3.54-3.70(m,2H),3.89(dd,J＝13.1,6.2Hz,1H),4.04-4.66(m,8H),6.02(d,J＝34.8Hz,2H),7.87(d,J＝3.0Hz,1H),8.34(d,J＝3.8Hz,1H)；m/z(ESI+):582.5(M+H).
步骤G：反应瓶中加入1-5(70mg，0.12mmol，1eq.)和氢氧化钠水溶液(0.5M，1.2mmol，5.0eq.)。室温条件下，搅拌反应48小时。反应体系变澄清。冰水浴下，缓慢滴加1N HCl溶液，调节pH至1左右，大量固体析出，过滤，真空干燥得对比例1(65mg，收率84.56％)。1H NMR(500MHz,CDCl3)δppm:0.84(t,J＝6.8Hz,3H),1.21(s,30H),1.51(d,J＝6.7Hz,2H),3.42(t,J＝7.0Hz,2H),3.49(d,J＝8.9Hz,1H),3.57(t,J＝4.5Hz,2H),3.70(dd,J＝21.7,8.8Hz,2H),3.84(d,J＝8.7Hz,2H),4.07(d,J＝6.1Hz,2H),4.34(dd,J＝14.2,7.3Hz,1H),4.47(d,J＝11.7Hz,1H),8.15(s,1H),8.30(s,1H)；m/z(ESI+):600.6(M+H).
对比例2：
步骤A-E同对比例1的合成步骤A-E
步骤F：反应瓶中加入2-1(0.675g，2.23mmol，1eq.)、DMF(25mL)、和DIPEA(3mL)。45℃反应搅拌反应2小时。浓缩除去溶剂得残留物，加入DMF(25mL)、3-(十六烷氧基)丙醇(1g，3.34mmol，1.5eq.)、DIPEA(1.73g，13.36mmol，2.33mL，6.0eq.)和pyBOP(3.48g，6.68mmol，3.0eq.)。45℃搅拌反应4小时，浓缩除去反应溶剂，残留物用硅胶柱分离纯化(二氯甲烷：甲醇＝100：0-90：10)，得产物2-2(0.6g，收率47.48％)。
步骤G：反应瓶中加入2-2(150mg，0.26mmol，1eq.)和氢氧化钠水溶液(0.5M，2.64mmol，5.0eq.)。室温条件下，搅拌反应4小时。反应体系变澄清。冰水浴下，缓慢滴加1N HCl溶液，调节pH至1左右，大量固体析出，过滤，真空干燥得产物对比例2(80mg，收率51.29％)。1H NMR(500MHz,CD3OD)δppm:0.92(t,J＝5.9Hz,3H),1.31(s,26H),1.55(d,J＝5.9Hz,2H),1.80-1.93(m,2H),3.41(dd,J＝17.7,12.4Hz,2H),3.52(t,J＝5.5Hz,2H),3.59(d,J＝12.3Hz,1H),3.70(t,J＝10.9Hz,2H),3.84(dd,J＝28.7,17.4Hz,2H),3.93-3.99(m,2H),4.47(dd,J＝14.1,7.0Hz,1H),4.58(d,J＝14.4Hz,1H),8.34(s,1H),8.41(s,1H)；m/z(ESI+):586.5(M+H).
效果实施例
1、生物学测定
药代动力学研究的一般方法：
将待测化合物溶解在PBS(pH＝8)中，其浓度由化合物所施用的特定动物的期望剂量和给药体积确定。向动物以口服给药的方式施用经计量的给药溶液体积。给予待测化合物之后，在特定时间点(例如0.5、1、2、4、8、24、32和48小时)收集血液样品。使用标准技术将血液样品转化为血浆样品。LC-MS/MS分析后以获得待测化合物及对比例中母药在血浆中的浓度。
1.1、小鼠中本发明化合物的药代动力学研究
在将化合物与对比例分别单次静脉注射/口服施用至禁食的ICR雄性小鼠后，在施用后的0.083h(IV)、0.25h(IV)、0.5h、1h、2h、4h、8h、24h、32h和48h时收集血液样品。通过离心(3200rpm,10min,4℃)来分离血浆，并且将其冷冻(-80℃)直至用于分析。通过UPLC-MS/MS来确定小鼠血浆中化合物的浓度。将血浆分配至含内标和沉淀剂的适当的管中，使管剧烈震荡1分钟，以实现脱蛋白，随后以12000rmp离心5分钟。取上清液转移至96孔板中进行稀释后，震荡混匀再次离心(4100rpm,5min,4℃)后，用LC-MS/MS进行定量分析。利用DAS 3.2.8软件来计算药代动力学参数，如AUC0-t，AUC0-∞，Cmax，tmax，t1/2，MRT，CL和Vd。如下计算绝对生物利用度：F＝[AUC(i.g.)×剂量(i.v.)]/[AUC(i.v.)×剂量(i.g.)]×100％。
化合物2b和3b和对比例1化合物均以等摩尔量42.7mg/kg口服施用至ICR雄性小鼠中，实验方法如上所述，所得药代动力学参数见表2。
表2
化合物6b和对比例2化合物均以等摩尔量41.7mg/kg口服施用至ICR雄性小鼠中，实验方法如上所述，所得药代动力学参数见表3。
表3
2、药效试验
2.1、体外药效试验
接种非洲绿猴肾细胞(Vero cell,ATCC CRL-1587)于96孔板内，培养基为含10％胎牛血清、100U/mL青霉素、100μg/mL链霉素的MEM(Gibco Cat#41500034)，同时加入感染剂量为0.05PFU/cell的痘苗病毒天坛株(Vaccinia virus,Tiantan strain)。在5％CO2培养箱中37℃孵育2小时后，加入10系列对半稀释的药物BCV(布林西多福韦，Brincidofovir)、BCV前药15b、化合物3b或化合物6b(10μM、5μM、2.5μM、1.25μM、0.63μM、0.32μM、0.16μM、0.08μM、0.04μM、0.02μM)，每种浓度有3个重复孔。连续培养细胞3天，存留的细胞用4％的中性多聚甲醛固定后用0.1％结晶紫染色,计数病毒噬斑数量。未感染病毒的Vero细胞作为对照。病毒抑制活性(％)＝(用药组病毒噬斑数/对照组病毒噬斑数)×100。
体外试验结果如图1所示，BCV和BCV前药15b的抑制活性接近，而本发明化合物3b和化合物6b的抑制活性接近，约为BCV的10-30倍，EC50分别为0.068μM和0.165μM。
2.2、体内药效试验
60只雄性Balb/c裸鼠随机分为5组，分别为空白对照组、BCV给药组、BCV前药15b给药组、化合物3b给药组和化合物6b给药组。试验小鼠均于试验D1接种痘苗病毒，后在试验D2、D4、D6灌胃给予对应的药物(空白对照组仅给予相同体积的溶剂)，3次给药剂量分别为20mg/kg、5mg/kg、5mg/kg，试验过程中记录动物给药前后的体重变化，以评估受试物对动物的保护效果，另取血液和组织备用。
记录各组小鼠试验过程中的体重，以D0小鼠体重作为基准，以小鼠体重下降＞初始体重的30％作为死亡替代终点。结果如图2a和图2b所示，可以明显观察到，空白对照组小鼠从D3开始陆续达到替代终点，D6和D7大量小鼠达到替代终点，D8小鼠全部达到替代终点；BCV给药组未能改善小鼠达到替代终点的情况，该组小鼠也在D8全部达到替代终点；而化合物3b和化合物6b给药组的情况明显改善，其中以化合物3b效果最佳，D14仅有1只小鼠达到替代终点。
记录各组小鼠试验过程中的体重，以D0小鼠体重作为基准，得到体重变化图和实际死亡曲线，结果如图3a和图3b所示。从体重变化图可以明显观察到，空白对照组小鼠体重下降明显，D14仅有D0体重的70％-80％，BCV给药组小鼠体重初期下降明显，后期有所回升，D14接近D0的水平；化合物3b和化合物6b给药组小鼠的体重始终高于BCV给药组，其中化合物3b给药组小鼠体重最低点为D0的80％，D14达到D0的110％，与空白对照组有显著性差异。从实际死亡曲线可以观察到，空白对照组在D14仅有2只小鼠存活，BCV给药组在D14有10只小鼠存活，化合物3b给药组在D14全部小鼠都存活，化合物6b给药组在D14有11只小鼠存活。
无论是体重变化、替代终点死亡曲线还是实际死亡曲线，化合物3b和化合物6b的疗效均优于BCV，可以延缓病毒导致的小鼠体重减少，甚至使小鼠体重恢复增长，也可以减少小鼠因病毒造成的死亡。
尽管参照本发明的实施例详细描述了本发明，但提供这些实施例是为了说明而不是限制本发明。根据本发明原理能够得到的其它实施例均属于本发明权利要求所界定的范畴。

Claims (21)

  1. 一种式(I)所示的化合物或其药学上可接受的盐或酯：
    其中，X选自-OR4，或者X与R3组合成一个化学键；
    R1选自H或C4-C30羰基，所述C4-C30羰基包括取代或未取代的烃基羰基、取代或未取代的芳基羰基或杂环羰基，以及取代或未取代的烃氧基羰基，且所述羰基的碳数不大于30；
    R2、R4独立地选自H、其中R5选自取代或未取代的C15-C30烃基，且所述烃基可以是直链烃基或支链烃基；
    R3选自H；甲酰基，C4-C30羰基，其中所述C4-C30羰基包括取代或未取代的烃基羰基、取代或未取代的芳基羰基或杂环羰基，以及取代或未取代的烃氧基羰基，且所述羰基的碳数不大于30，或氨基酸残基；
    作为限制，当X为-OR4时，R1、R2、R3、R4不同时为H，当X与R3组合成一个化学键时，R1、R2不同时为H。
  2. 根据权利要求1所述的化合物，其中，所述化合物为式(III)所示的化合物；
    作为限制，当X为-OR4时，所述R1、R3、R4不同时为H；当X与R3组合成一个化学键时，所述R1不为H。
  3. 根据权利要求2所述的化合物，其中，所述化合物为式(IIIa)所示的化合物；
  4. 根据权利要求1所述的化合物，其中，所述化合物为式(IV)所示的化合物；
    作为限制，当X为-OR4时，所述R1、R3、R4不同时为H；当X与R3组合成一个化学键时，所述R1不为H。
  5. 根据权利要求4所述的化合物，其中，所述化合物为式(IVa)所示的化合物；
  6. 根据权利要求1至权利要求5任一项所述的化合物，其中，所述R1为取代或未取代的烃基羰基，所述取代或未取代的烃基羰基包括以下所示的基团：
  7. 根据权利要求1至权利要求6任一项所述的化合物，其中，所述R1为取代或未取代的芳基羰基或杂环羰基，所述取代或未取代的芳基羰基或杂环羰基包括以下所示的基团：
    其中，Y选自H、F、Cl、Br、Me、-OMe、-OEt、-CF3或-CN。
  8. 根据权利要求1至权利要求6中任一项所述的化合物，其中，所述R1为取代或未取代的烃氧基羰基，所述取代或未取代的烃氧基羰基包括以下所示的基团：
  9. 根据权利要求1至权利要求6中任一项所述的化合物，其中，所述R5包括以下基团：
  10. 根据权利要求1至权利要求6任意所述的化合物，其中，所述R3包括以下基团：
    优选地，R3选自
  11. [根据细则26改正 08.01.2025]
    选自以下的化合物及其药学上可接受的盐：
  12. 一种药物组合物，其中，包括至少一种根据权利要求1至权利要求11中任一项所述的化合物，以及至少一种药学上可接受的载体或赋形剂。
  13. 根据权利要求12所述的药物组合物，其中，所述药学上可接受的载体包括乳膏、乳剂、凝胶、脂质体和纳米颗粒中的一种或多种；所述药学上可接受的赋形剂包括粘合剂、填充剂、崩解剂、润滑剂和助流剂中的一种或多种。
  14. 根据权利要求12或13所述的药物组合物，其中，所述药物组合物适用于口服施用或者注射施用。
  15. 权利要求1至权利要求11中任一项所述的化合物或根据权利要求12至14中任一项所述的药物组合物在制备用于治疗、抑制或预防病毒感染或病毒感染所致疾病的药物中的用途。
  16. 根据权利要求15所述的用途，其中，所述病毒感染包括乙肝病毒(HBV)、新冠病毒(SARS-COV-2)、人类免疫缺陷病毒(HIV)、水痘带状疱疹病毒(VZV)、巨细胞病毒(CMV)、单纯疱疹病毒(HSV)、BK病毒、JC病毒、爱泼斯坦-巴尔病毒(EBV)、埃博拉病毒、多瘤病毒、乳头瘤病毒、正痘病毒、丙肝病毒(HCV)、呼吸道合胞体病毒(RSV)、登革热病毒、流感病毒、腺病毒、副流感病毒和/或鼻病毒引起的感染。
  17. 根据权利要求16所述的用途，其中，所述正痘病毒包括重型和轻型天花病毒、猴痘病毒、牛痘病毒、骆驼痘病毒、传染性软疣、羊痘病毒、aractuba病毒、BeAn 58058病毒、cantagalo正痘病毒、小鼠痘病毒、象痘病毒、牛痘苗病毒(VV)、兔痘病毒、浣熊痘病毒、臭鼬痘病毒、沙鼠痘病毒和田鼠痘病毒。
  18. 根据权利要求16所述的用途，其中，所述病毒感染包括由天花病毒、猴痘病毒引起的感染。
  19. 权利要求1至11中任一项所述的化合物或根据权利要求12至14中任一项所述的药物组合物在制备用于治疗、抑制或预防细胞增殖引发疾病的药物上的用途。
  20. 根据权利要求19所述的用途，其中，所述细胞增殖引发疾病包括肿瘤、癌症或其他病毒感染疾病，所述肿瘤或癌症选自多发性骨髓瘤(MM)、慢性淋巴细胞白血病(CLL)、套细胞淋巴瘤(MCL)、实体瘤、难治性实体瘤、非霍奇金淋巴瘤、血液瘤、神经母细胞瘤、结直肠癌、宫颈癌、肺癌、白血病、乳腺癌、胰腺癌、B-细胞恶性肿瘤、肿瘤、转移性肿瘤、结肠癌；所述病毒感染引起的疾病选自DNA病毒感染所引起的疾病，其中包括视网膜炎、肺炎、膀胱炎、蛋白质病变等。
  21. 一种试剂盒，所述试剂盒包括根据权利要求1至11中任一项所述的化合物或药学上可接受的盐或酯或者根据权利要求12至14中任一项所述的药物组合物。
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