WO2017076346A1 - 作为tlr7激动剂的7-(噻唑-5-基)吡咯并嘧啶化合物 - Google Patents

作为tlr7激动剂的7-(噻唑-5-基)吡咯并嘧啶化合物 Download PDF

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WO2017076346A1
WO2017076346A1 PCT/CN2016/104644 CN2016104644W WO2017076346A1 WO 2017076346 A1 WO2017076346 A1 WO 2017076346A1 CN 2016104644 W CN2016104644 W CN 2016104644W WO 2017076346 A1 WO2017076346 A1 WO 2017076346A1
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Prior art keywords
compound
virus
pharmaceutically acceptable
acceptable salt
group
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PCT/CN2016/104644
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English (en)
French (fr)
Inventor
丁照中
孙飞
吴立方
吴颢
陈曙辉
杨玲
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Priority to ES16861614T priority Critical patent/ES2833927T3/es
Priority to US15/772,995 priority patent/US10676478B2/en
Priority to NZ742453A priority patent/NZ742453A/en
Priority to EP16861614.2A priority patent/EP3381918B1/en
Priority to UAA201806167A priority patent/UA121345C2/uk
Priority to KR1020187015405A priority patent/KR102112192B1/ko
Priority to CN201680064165.2A priority patent/CN108349982B/zh
Priority to EA201891099A priority patent/EA035116B1/ru
Priority to DK16861614.2T priority patent/DK3381918T3/da
Priority to HK18110395.0A priority patent/HK1250983B/zh
Priority to AU2016349080A priority patent/AU2016349080B2/en
Priority to SG11201803699YA priority patent/SG11201803699YA/en
Priority to CA3004173A priority patent/CA3004173C/en
Priority to MYPI2018701754A priority patent/MY189991A/en
Priority to MX2018005708A priority patent/MX375353B/es
Priority to BR112018008880-3A priority patent/BR112018008880B1/pt
Application filed by Chia Tai Tianqing Pharmaceutical Group Co Ltd filed Critical Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority to JP2018541478A priority patent/JP6524355B2/ja
Publication of WO2017076346A1 publication Critical patent/WO2017076346A1/zh
Priority to IL259115A priority patent/IL259115B/en
Priority to PH12018500975A priority patent/PH12018500975A1/en
Anticipated expiration legal-status Critical
Priority to ZA2018/03705A priority patent/ZA201803705B/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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 7-(thiazol-5-yl)pyrrolopyrimidine ring compound as a TLR7 agonist or a pharmaceutically acceptable salt thereof, which is useful for treating or preventing a viral infection, particularly hepatitis B or C Viral infection.
  • Toll-like receptors are expressed by a variety of immune cells. Toll-like receptors recognize highly conserved structural motifs: pathogen-associated microbial patterns (PAMP) expressed by microbial pathogens or damage-associated molecular patterns (DAMP) released by necrotic cells. Activation of the signal cascade by stimulation of Toll-like receptors by the corresponding PAMP or DAMP results in activation of transcription factors such as AP-1, NF- ⁇ B and interferon regulatory factors (impulse response functions). This results in a variety of cellular responses, including the production of interferons, pro-inflammatory cytokines and effector cytokines, thereby eliciting an immune response.
  • PAMP pathogen-associated microbial patterns
  • DAMP damage-associated molecular patterns
  • Toll-like receptors have been found in mammals. Toll-like receptors 1, 2, 4, 5, and 6 are predominantly expressed on the cell surface, while Toll-like receptors 3, 7, 8, and 9 are expressed in endosomes. Different Toll-like receptors can recognize ligands derived from different pathogens. Toll-like receptor 7 (TLR7) is mainly expressed by plasmacytoid dendritic cells (pDC) and induces secretion of interferon alpha (IFN- ⁇ ) by ligand recognition. Toll-like receptor 7 (TLR7) and Toll-like receptor 8 (TLR8) are highly homologous, and thus the TLR7 ligand is in many cases also a TLR8 ligand.
  • pDC plasmacytoid dendritic cells
  • IFN- ⁇ interferon alpha
  • TLR7 and Toll-like receptor 8 (TLR8) are highly homologous, and thus the TLR7 ligand is in many cases also a TLR8 ligand.
  • TLR8 stimulation primarily induces the production of cytokines such as tumor necrosis factor alpha (TNF-alpha) and chemokines.
  • TNF-alpha tumor necrosis factor alpha
  • Interferon alpha is one of the main drugs for the treatment of chronic hepatitis B or hepatitis C, while TNF- ⁇ is a pro-inflammatory cytokine whose excessive secretion may cause serious side effects.
  • TLR7 agonists have been reported to date, such as Imiquimod (British Journal of Dermatology 2003; 149 (Suppl. 66): 5-8), Resiquimod, Antiviral Research 64 (2004) 79–83), GS-9620 (Gastroenterology (2013), 144(7), 1508-1517), but new TLR7 agonists with better selectivity, activity and safety are still in great demand.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof,
  • R 1 and R 2 are each independently selected from H and C 1-4 alkyl, or
  • R 1 and R 2 form with the N atom are attached form 4 to 8-membered heterocycloalkyl, a 4 to 8-membered heterocycloalkyl group optionally substituted with one or more substituents R 3,
  • R 3 is independently selected from From hydroxy, halogen, cyano, C 1-4 alkyl and C 1-4 alkoxy.
  • the 4-8 membered heterocycloalkyl can comprise 0, 1, 2 or 3 additional heteroatoms selected from N, O and S.
  • the 4-8 membered heterocycloalkyl group can be a 4 membered, 5 membered, 6 membered, 7-membered or 8-membered heterocycloalkyl group.
  • R 3 is independently selected from hydroxy, F, Cl, Br, CN , methyl, ethyl, propyl, methoxy, ethoxy and propoxy.
  • the group formed by R 1 , R 2 and the attached N atom is selected from the group consisting of:
  • the compound of formula (I) is a compound of the formula:
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) and/or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and/or excipients .
  • the pharmaceutical composition may also optionally comprise one or more additional therapeutic agents.
  • the invention relates to a method of treating or preventing a viral infection, the method comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or A pharmaceutical composition of the invention.
  • the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention, in the manufacture of a medicament for the treatment or prevention of a viral infection.
  • the invention provides a compound of formula (I) or a pharmaceutical thereof for use in the treatment or prevention of a viral infection
  • An acceptable salt or a pharmaceutical composition of the invention is provided.
  • the viral infection is dengue virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, Kunjin virus, Murray Valley encephalitis virus, Saint-Louis Encephalitis virus, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Zika virus or hepatitis virus infection.
  • the viral infection is a hepatitis virus infection.
  • the viral infection is a hepatitis B or hepatitis C virus infection.
  • Figure 1 Pharmacodynamic results (plasma HBsAg copy levels) in vivo in a mouse model of AAV carrying hepatitis B infection.
  • Figure 2 Pharmacodynamic results (plasma HBV DNA copy levels) in vivo in a mouse model of AAV carrying hepatitis B infection.
  • Figure 3 Pharmacodynamic results (plasma Anti-HBsAb production levels) in a pharmacodynamic test of a mouse model of AAV carrying hepatitis B infection.
  • an ethyl group “optionally” substituted with halo means an ethyl group may be unsubstituted (CH 2 CH 3), monosubstituted (e.g., CH 2 CH 2 F), polysubstituted (e.g. CHFCH 2 F, CH 2 CHF 2, etc.) or completely substituted (CF 2 CF 3). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is not spatially possible and/or synthetic cannot be introduced.
  • C mn refers to having mn carbon atoms in this moiety.
  • C 1-4 alkyl refers to an alkyl group having from 1 to 4 carbon atoms.
  • C 1-4 means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms.
  • C 1-4 alkyl encompasses “C 2-3 alkyl”, “C 1-3 alkyl”, “C 2-4 alkyl”, and C 1 alkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl, and the like.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent as long as the valence of the particular atom is normal and the substituted compound is stable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • hetero denotes a hetero atom or a hetero atomic group (ie, an atomic group containing a hetero atom), that is, an atom other than carbon and hydrogen or an atomic group containing the same.
  • the heteroatoms are independently selected from the group consisting of oxygen, nitrogen, sulfur, and the like.
  • the two or more heteroatoms may be identical to each other, or some or all of the two or more heteroatoms may be different from each other.
  • halo or halogen means fluoro, chloro, bromo or iodo.
  • hydroxy refers to an -OH group.
  • cyano refers to a -CN group.
  • alkyl refers to a straight or branched saturated aliphatic hydrocarbon group consisting of a carbon atom and a hydrogen atom, which is attached to the remainder of the molecule by a single bond.
  • C 1-4 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.
  • C 1-4 alkoxy denotes a “C 1-4 alkyl” group attached to the remainder of the molecule by a “-O-” group, wherein “C 1-4 alkyl” is as defined above.
  • heterocycloalkyl refers to a saturated monocyclic or polycyclic system group wherein a portion of the ring atoms are heteroatoms selected from N, O, S and the remaining ring atoms are C.
  • the term “4- to 8-membered heterocycloalkyl” denotes a heterocycloalkyl group containing from 4 to 8 ring atoms in the system, wherein one or more of the ring atoms is a hetero atom selected from N, O, S.
  • Examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, and examples of 5-membered heterocycloalkyl include, but are not limited to, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazole
  • Examples of alkyl, 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, morpholinyl, piperazinyl, and examples of 7-membered heterocycloalkyl include, but are not limited to, azepanyl, Oxazabicyclo[2.2.1]heptyl and the like.
  • pharmaceutically acceptable is for those compounds, materials, compositions and/or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues without Many toxic, irritating, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • composition refers to an active compound (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof), optionally in association with one or more pharmaceutically acceptable chemical ingredients (eg, but not Limited to carriers and/or excipients) combinations.
  • active compound such as a compound of formula (I) or a pharmaceutically acceptable salt thereof
  • pharmaceutically acceptable chemical ingredients eg, but not Limited to carriers and/or excipients
  • pharmaceutically acceptable carrier refers to those carriers which have no significant irritation to the organism and which do not impair the biological activity and properties of the active compound.
  • “Pharmaceutically acceptable carrier” means an inert substance which, together with the active ingredient, which facilitates administration of the active ingredient, including, but not limited to, acceptable for human or animal use as permitted by the State Food and Drug Administration (eg Any of the glidants, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, disintegrating agents, suspending agents, stabilizers, Isotonicity agent, solvent or emulsifier.
  • Non-limiting examples of such carriers include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols, and the like.
  • excipient generally refers to the vehicle, diluent and/or medium, etc. required to formulate an effective pharmaceutical composition.
  • administering refers to a method by which a compound or composition can be delivered to a desired biological site of action. These methods include, but are not limited to, oral, parenteral (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, and the like.
  • an effective amount refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • the "effective amount” of an active substance in the composition can be the amount required to achieve the desired effect when used in combination with another active substance in the composition.
  • the determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • active ingredient refers to a chemical entity that is effective to treat or prevent a target disorder, disease or condition.
  • Protecting group refers to a class of substituents which are used to react with other functional groups on a compound to block or protect a particular functional group.
  • amino protecting group refers to a substituent attached to an amino group that blocks or protects an amino functional group on a compound.
  • Suitable amino protecting groups include, but are not limited to, acetyl, trifluoro, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), -9-fluorenylmethyl chloroformate (Fmoc), 2-(trimethyl) Silicon) ethoxymethyl (SEM) and the like.
  • the present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof,
  • Part of the group formed examples include, but are not limited to
  • the expression "4 to 8 membered heterocycloalkyl may contain 0, 1, 2 or 3 additional heteroatoms selected from N, O or S" means that in addition to A hetero atom other than the N atom shown in the section.
  • the additional heteroatoms may be selected from N, O and S, and the number may be 0, 1, 2 or 3.
  • the invention relates to a compound of the formula:
  • the compounds of the invention may exist as a pharmaceutically acceptable salt.
  • a pharmaceutically acceptable salt for example, a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, or the like can be mentioned.
  • metal salts include, but are not limited to, salts of alkali metals such as sodium salts, potassium salts, and the like; salts of alkaline earth metals such as calcium salts, magnesium salts, barium salts, and the like; aluminum salts and the like.
  • Non-limiting examples of salts formed with organic bases include, but are not limited to, trimethylamine, triethylamine, pyridine, methyl a salt formed of pyridine, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine or the like.
  • Non-limiting examples of salts formed with inorganic acids include, but are not limited to, salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
  • Non-limiting examples of salts formed with organic acids include, but are not limited to, with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, benzene. a salt formed of a sulfonic acid, p-toluenesulfonic acid or the like.
  • Non-limiting examples of salts formed with basic amino acids include, but are not limited to, salts formed with arginine, lysine, ornithine, and the like.
  • Non-limiting examples of salts formed with acidic amino acids include, but are not limited to, salts formed with aspartic acid, glutamic acid, and the like.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the compounds of the invention may have one or more stereoisomeric centers, and the centers may be present in the R or S configuration or a combination thereof.
  • the compounds of the invention include all individual stereoisomeric forms, positional isomeric forms, diastereomeric forms, enantiomeric forms and epimeric forms, as well as the corresponding mixtures thereof.
  • Techniques for flipping or remaining a particular stereocenter and techniques for dissolving a mixture of stereoisomers are well known in the art, and selection of a suitable method for a particular situation is well within the capabilities of those skilled in the art.
  • the compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.
  • the compounds of the invention may exist in polycrystalline or amorphous form, and such forms are also encompassed within the scope of the invention.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • the invention also encompasses any pharmaceutically acceptable derivative of a compound of formula (I), such as a salt of an ester, an ester, and the like.
  • a particularly preferred derivative is a prodrug.
  • Such derivatives when administered to a recipient, are capable of providing, directly or indirectly, a compound of the invention or a pharmaceutically active metabolite or residue thereof.
  • Particularly preferred derivatives e.g., prodrugs
  • the present invention relates to a method of treating or preventing a viral infection, which comprises administering to a subject in need thereof a therapeutically or prophylactically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical combination of the invention Things.
  • the method can optionally include administering one or more additional active agents to treat or prevent the viral infection.
  • the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention, in the manufacture of a medicament for the treatment or prevention of a viral infection.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof can be used in combination with one or more additional active agents to treat or prevent the viral infection.
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention, for use in the treatment or prevention of a viral infection.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof can be used in combination with one or more additional active agents to treat or prevent the viral infection.
  • the viral infections described above are dengue virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, Kunjin virus, Murray Valley encephalitis virus , St. Louis encephalitis virus, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Zika virus or hepatitis virus infection.
  • the viral infection is a hepatitis virus infection, in particular a hepatitis B or hepatitis C virus infection.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and/or excipients.
  • the pharmaceutical composition may comprise one or more additional active agents.
  • the pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention or a salt thereof with a suitable pharmaceutically acceptable carrier, for example, it can be formulated into a solid, semi-solid, liquid or gaseous preparation such as a tablet, a pill, or a capsule.
  • a suitable pharmaceutically acceptable carrier for example, it can be formulated into a solid, semi-solid, liquid or gaseous preparation such as a tablet, a pill, or a capsule.
  • the pharmaceutical composition of the present invention can be produced by a method well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a drag coating method, a grinding method, an emulsification method, a freeze drying method, and the like.
  • Typical routes of administration of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, Parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous.
  • the pharmaceutical compositions may be formulated by admixing the active compound withpharmaceutically acceptable carriers such carriers.
  • pharmaceutically acceptable carriers such carriers.
  • These carriers enable the compounds of the present invention to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the active compound with a solid excipient, optionally milling the resulting mixture, adding other suitable adjuvants if necessary, and then processing the mixture into granules. The core of a tablet or dragee.
  • Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • microcrystalline cellulose glucose solution, gum arabic, gelatin solution, sucrose and starch paste; talc, starch, magnesium stearate, calcium stearate or stearic acid; lactose, sucrose, starch, mannitol, sorbus Sugar alcohol or dicalcium phosphate; silica; croscarmellose sodium, pre-treated starch, sodium starch glycolate, alginic acid, corn starch, Potato starch, methyl cellulose, agar, carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, and the like.
  • the core of the dragee may optionally be coated according to methods well known in the ordinary pharmaceutical practice, especially using enteric coatings.
  • compositions of the invention may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage form.
  • suitable excipients such as fillers, buffers or surfactants can be used.
  • the compound of formula (I) of the present invention can be administered by any suitable route and method, for example, by oral or parenteral (e.g., intravenous) administration.
  • a therapeutically or prophylactically effective amount of a compound of formula (I) is from about 0.0001 to 20 mg/kg body weight per day, such as from 0.001 to 10 mg/kg body weight per day.
  • the dosage frequency of the compound of formula (I) is determined by the needs of the individual patient, for example, once or twice daily, or more times per day. Administration can be intermittent, for example, wherein during a period of several days, the patient receives a daily dose of a compound of formula I, followed by a daily dose of the compound of formula (I) for a period of several days or more. dose.
  • the invention further relates to a pharmaceutical combination, such as a kit comprising a) a first active substance which is a compound disclosed herein; b) one or more additional active agents.
  • the combination of drugs may also contain instructions for use as needed.
  • the above a) and b) may be provided in the same or different containers as needed.
  • the pharmaceutical combination may also comprise materials for adjuvant administration provided in the same or different containers, such as the pharmaceutically acceptable carriers and/or excipients mentioned above.
  • the kit may further comprise means for diagnosing viral infections such as those described above.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the chemical reaction of a particular embodiment of the invention can be carried out in a suitable solvent which is suitable for the chemical changes of the invention and the reagents and materials required thereof. In order to obtain the compounds of the present invention, it is sometimes necessary for those skilled in the art to modify or select the synthetic steps or reaction schemes based on the prior embodiments.
  • the compounds of formula (I) of the present invention can be prepared by those skilled in the art of organic synthesis by standard procedures in the art by the following routes:
  • a compound of the formula 1 is used as a starting material, and a compound of the formula 2 is condensed to obtain a compound of the formula 3, and the compound of the formula 3 is obtained by the action of n-butyllithium and DMF to give a compound of the formula 4.
  • High performance liquid chromatography was performed using a Shimadzu LC20AB system equipped with a Shimadzu SIL-20A autosampler and a Shimadzu DAD: SPD-M20A detector, using a Xtimate C18 (3 m packing, size 2.1 x 300 mm) column.
  • 0-60AB_6 min method Apply a linear gradient, start elution with 100% A (A is 0.0675% TFA in water), and end the elution with 60% B (B is 0.0625% TFA in MeCN solution). The whole process is 4.2 minutes, then eluted with 60% B for 1 minute.
  • the column was equilibrated for 0.8 minutes to reach 100:0 with a total run time of 6 minutes.
  • 10-80AB_6 minute method Apply a linear gradient to 90% A (A is 0.0675% TFA in water) Elution was started and elution was terminated with 80% B (B in 0.0625% TFA in acetonitrile) for a total of 4.2 minutes and then eluted with 80% B for 1 minute.
  • the column was equilibrated for 0.8 minutes to 90:10 with a total run time of 6 minutes.
  • the column temperature was 50 ° C and the flow rate was 0.8 mL/min.
  • the diode array detector has a scanning wavelength of 200-400 nm.
  • TLC Thin layer chromatography
  • a common solvent for flash column chromatography or thin layer chromatography is a mixture of dichloromethane/methanol, ethyl acetate/methanol and hexane/ethyl acetate.
  • n-BuLi for n-butyllithium
  • THF for tetrahydrofuran
  • SEM for 2-(trimethylsilyl)ethoxymethyl
  • DIPEA for diisopropylethylamine
  • IPA for Propanol
  • TFA stands for trifluoroacetic acid
  • DMF stands for N,N-dimethylformamide
  • n-BuOH stands for n-butanol
  • Et 3 SiH stands for triethylsilane.
  • the compound of the present invention has high binding activity to Toll-like receptor 7 and low binding activity to Toll-like receptor 8, thereby exhibiting better selectivity, activity and safety, and lower side effects, and can be used effectively Treat or prevent viral infections, especially hepatitis B or C infection.
  • 2,4-Dichloro-5H-pyrrolo[3,2-d]pyrimidine (4.00 kg, 21.28 mol) was dissolved in DMF (20.00 L); DIPEA (2.58 kg, 20.00) was added portionwise at room temperature (25 ° C) Mol), followed by stirring for 30 min.
  • the reaction solution was cooled to 0 ° C in an ice bath, and then SEM-Cl (4.00 kg, 24.00 mol) was slowly added dropwise at a dropping rate of 1-2 drops/second over 5 hours. After the dropwise addition, the reaction solution was The reaction was stirred at 0 ° C for 4 hours and the reaction was monitored by HPLC. The reaction solution is terminated with 70L of water.
  • reaction mixture was naturally cooled to 25 ° C, it was slowly poured into 30 L of a saturated aqueous solution of ammonium chloride, and then extracted with ethyl acetate (15 L ⁇ 3), and the combined organic phases were washed with saturated brine (20 L ⁇ 2) aqueous Na 2 SO 4 dried, filtered, and solvent was removed by distillation under reduced pressure, the residue was slurried in n-heptane (4L), the solid was isolated by filtration, recrystallized from ethyl acetate (5L) slurried, to give the title compound as yellow White solid (1.53 kg, 4.55 mol, 69.7%).
  • Step 7 ((4-Amino-2-butoxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-hydroxymethyl)-[2-(pyrrolidin-1-methylene) Thiazol-5-yl]methanol
  • Step 8 2-Butoxy-7-(2-(pyrrolidin-1-ylmethyl)thiazol-5-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine
  • GS-9620 and R848 used are as follows, wherein GS-9620 can be prepared by the method disclosed in US20100143301; R848 is purchased from Baiqi Bio (Cat. No. IMG-2208, specification 0.5 mg).
  • Preparation of 1.96-well compound plate Start with a liquid workstation POD to start the compound from a concentration of 10 mmol/L, and make a 3-fold gradient dilution with DMSO for a total of 10 points (from column 2 to column 11, each point 2 Repeat).
  • a liquid workstation POD to start the compound from a concentration of 10 mmol/L
  • DMSO for a total of 10 points (from column 2 to column 11, each point 2 Repeat).
  • 1 ⁇ l of 5 mg/ml of the positive compound R848 was added as a positive control
  • 1 ⁇ l of DMSO was added as a negative control.
  • the volume of DMSO contained in each well was 1 microliter.
  • the culture plate containing the cells and the compound was cultured in a CO 2 incubator for 24 hours under the conditions of 37 ° C, 5% CO 2 concentration.
  • the alkaline phosphatase content in 20 ⁇ l of the supernatant was measured by a plate reader at OD 650 .
  • the compound of the present invention exhibited higher in vitro receptor binding activity to Toll-like receptor 7 than the control Toll-like receptor 7 agonist GS-9620, and exhibited a Toll-like receptor 7 than the control.
  • the agonist GS-9620 has a lower in vitro receptor binding activity to Toll-like receptor 8.
  • the compounds of the invention have significant selectivity differences for different receptors and are superior to the prior art.
  • a total of 12 male SD rats were tested and divided into four groups of 3 SD rats each.
  • Two groups of animals were administered intravenously (IV), and 1 mg/kg of the control Toll-like receptor 7 agonist GS-9620 and the 10% hydroxypropyl- ⁇ -cyclodextrin aqueous solution of the compound of Example 1 were respectively injected (concentration 0.5). Mg/mL).
  • the other two groups were orally administered (PO), orally administered with 5 mg/kg of GS-9620 and 3 mg/kg of the compound of Example 1 in 0.5% methylcellulose/0.2% Tween 80 pure water suspension (concentration 1 mg/mL). ).
  • Each rat after intravenous injection continuously collected whole blood samples and prepared plasma at 2, 15, 30, and 1, 2, 4, 8, and 24 hours after administration.
  • Each rat after oral administration continuously collected whole blood samples and prepared plasma at 15, 30 minutes and 1, 2, 4, 8, and 24 hours after administration.
  • Plasma concentrations of GS-9620 and Example 1 compounds were determined by LC-MS/MS method, respectively.
  • the compounds of the present invention have a higher exposure in rats relative to the control Toll-like receptor 7 agonist GS-9620.
  • Dosing time every three days from the 26th day after the injection of the virus, for a total of 6 weeks;
  • Administration group the first group, vehicle, 10% HP- ⁇ -CD; the second group, GS-9620, 20 mg/kg; the third group, the compound of Example 1, 20 mg/kg;
  • Blood collection twice a week for the first 8 days after the first administration, for a total of 8 weeks;
  • Liver liver Liver samples were collected on day 64 after the first dose.
  • HBeAg Hepatitis B surface antigen
  • HBeAg Hepatitis B E antigen

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Abstract

本发明涉及作为TLR7激动剂的7-(噻唑-5-基)吡咯并嘧啶化合物，具体涉及式(I)所示化合物或其药学上可接受的盐、其制备方法、含有该类化合物的药物组合物、及其用于制备抗病毒药物的用途。

Description

作为TLR7激动剂的7-(噻唑-5-基)吡咯并嘧啶化合物 技术领域
本发明涉及作为TLR7激动剂的7-(噻唑-5-基)吡咯并嘧啶环化合物或其药学上可接受的盐，其可用于用于治疗或预防病毒感染，特别是乙型或丙型肝炎病毒感染。
背景技术
Toll样受体由多种免疫细胞表达。Toll样受体识别高度保守结构基序：由微生物病原体表达的病原体相关的微生物模式(PAMP)或由坏死细胞释放的损伤相关分子模式(DAMP)。通过相应的PAMP或DAMP刺激Toll样受体引发信号级联导致转录因子如AP-1、NF-κB和干扰素调节因子(脉冲响应函数)的激活。这导致多种细胞反应，包括产生干扰素、促炎性细胞因子和效应细胞因子，从而引发免疫应答。
迄今为在止哺乳动物中已发现13种Toll样受体。Toll样受体1、2、4、5和6主要表达在细胞表面上，而Toll样受体3、7、8和9表达在内体中。不同的Toll样受体可以识别不同病原体衍生的配体。Toll样受体7(TLR7)主要由浆细胞样树突细胞(pDC)表达，并通过配体识别而诱导干扰素α(IFN-α)的分泌。Toll样受体7(TLR7)和Toll样受体8(TLR8)高度同源，因此TLR7配体在很多情况下也是TLR8配体。TLR8刺激主要诱导产生细胞因子，如肿瘤坏死因子α(TNF-α)和趋化因子。干扰素α是治疗慢性乙型肝炎或丙型肝炎的主要药物之一，而TNF-α则是一种促炎细胞因子，其过多的分泌可能导致严重的副作用。
迄今为止已经报道了几种TLR7激动剂，如咪喹莫特(Imiquimod,British Journal of Dermatology 2003；149(Suppl.66):5–8)、瑞喹莫德(Resiquimod,Antiviral Research 64(2004)79–83)、GS-9620(Gastroenterology(2013),144(7),1508-1517)，但具备更好的选择性、活性和安全性的新的TLR7激动剂仍然有很大需求。
发明内容
在一方面，本发明涉及式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2016104644-appb-000001
其中，
R1和R2各自独立地选自H和C1-4烷基，或者
R1和R2与所连的N原子一起形成4～8元杂环烷基，所述4～8元杂环烷基任选地被一个或多个R3取代，R3各自独立地选自羟基、卤素、氰基、C1-4烷基和C1-4烷氧基。
在一实施方案中，所述4～8元杂环烷基可以包含0、1、2或3个额外的选自N、O和S的杂原子。
在另一实施方案中，所述4～8元杂环烷基可以为4元、5元、6元、7元或8元杂环烷基。
在另一实施方案中，R3独立地选自羟基、F、Cl、Br、CN、甲基、乙基、丙基、甲氧基、乙氧基和丙氧基。
在一具体实施方案中，R1、R2与所连的N原子形成的基团选自：
Figure PCTCN2016104644-appb-000002
Figure PCTCN2016104644-appb-000003
优选为
Figure PCTCN2016104644-appb-000004
在一些实施方案中，式(I)所示化合物为下式化合物：
Figure PCTCN2016104644-appb-000005
在另一方面，本发明涉及一种药物组合物，其包含式(I)的化合物和/或其药学上可接受的盐以及一种或多种药学上可接受的载体和/或赋形剂。所述药物组合物还可以任选地包含一种或多种额外的治疗剂。
在又一方面，本发明涉及一种治疗或预防病毒感染的方法，所述方法包括向有此需要的个体给予治疗或预防有效量的式(I)的化合物或其药学上可接受的盐或者本发明的药物组合物。
在进一步的方面，本发明提供式(I)的化合物或其药学上可接受的盐或者本发明的药物组合物在制备用于治疗或预防病毒感染的药物中的用途。
在更进一步的方面，本发明提供用于治疗或预防病毒感染的式(I)的化合物或其药学 上可接受的盐或者本发明的药物组合物。
在本发明的一些实施方案中，所述病毒感染是登革热病毒、黄热病毒、西尼罗病毒、日本脑炎病毒、蜱传脑炎病毒、昆津病毒、墨累山谷脑炎病毒、圣路易脑炎病毒、鄂木斯克出血热病毒、牛病毒性腹泻病毒、济卡病毒或肝炎病毒感染。在优选的实施方案中，所述病毒感染是肝炎病毒感染。在更优选的实施方案中，所述病毒感染是乙型或丙型肝炎病毒感染。
附图说明
图1：AAV携带乙型肝炎感染小鼠模型体内药效学试验药效结果(血浆HBsAg拷贝水平)。
图2：AAV携带乙型肝炎感染小鼠模型体内药效学试验药效结果(血浆HBV DNA拷贝水平)。
图3：AAV携带乙型肝炎感染小鼠模型体内药效学试验药效结果(血浆Anti-HBsAb产生水平)。
具体实施方式
一般定义和术语
除非另有说明，本文所用的术语和短语具有下文所列的含义。特定的术语或短语在没有特别定义的情况下不应该认为是不确定的或不清楚的，而应该按照本领域技术人员通常理解的含义进行解释。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
术语“约”、“大约”当与数值变量并用时，通常指该变量的数值和该变量的所有数值在实验误差内(例如对于平均值95％的置信区间内)或在指定数值的±10％内，或更宽范围内。
表述“包含”或与其同义的类似表述“包括”、“含有”和“具有”等是开放性的，不排除额外的未列举的元素、步骤或成分。表述“由…组成”排除未指明的任何元素、步骤或成分。表述“基本上由…组成”指范围限制在指定的元素、步骤或成分，加上任选存在的不会实质上影响所要求保护的主题的基本和新的特征的元素、步骤或成分。应当理解，表述“包含”涵盖表述“基本上由…组成”和“由…组成”。
术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，指该乙基可以是未被取代的(CH2CH3)、单取代的(如CH2CH2F)、多取代的(如CHFCH2F、 CH2CHF2等)或完全被取代的(CF2CF3)。本领域技术人员应当理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
本文所用的术语“Cm-n”指该部分中具有m-n个碳原子。例如，“C1-4烷基”指具有1-4个碳原子的烷基。
本文中的数字范围涵盖给定范围中的各个整数以及由这些整数形成的亚范围。例如“C1-4”是指该基团可具有1个碳原子、2个碳原子、3个碳原子或4个碳原子。相应地，“C1-4烷基”涵盖“C2-3烷基”、“C1-3烷基”、“C2-4烷基”以及C1烷基、C2烷基、C3烷基、C4烷基等。
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基代替，只要特定原子的价态是正常的并且取代后的化合物是稳定的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，即碳和氢以外的原子或含有这些原子的原子团。优选地，杂原子独立地选自氧、氮、硫等。在出现两个或更多杂原子的实施方案中，所述两个或更多杂原子可彼此相同，或者所述两个或更多杂原子中的部分或全部彼此不同。
术语“卤”或“卤素”是指氟、氯、溴或碘。
术语“羟基”指-OH基团。
术语“氰基”指-CN基团。
术语“烷基”是指由碳原子和氢原子组成的直链或支链的饱和的脂肪烃基团，其通过单键与分子的其余部分连接。C1-4烷基的非限制性实例包括但不限于甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基。
术语“C1-4烷氧基”表示通过“-O-”基团连接至分子的其余部分的“C1-4烷基”，其中“C1-4烷基”如上文所定义。
术语“杂环烷基”是指饱和的单环或多环体系基团，其中部分环原子是选自N、O、S的杂原子，其余环原子为C。相应地，术语“4～8元杂环烷基”表示体系中包含4～8个环原子的杂环烷基，其中一个或多个环原子是选自N、O、S的杂原子。4元杂环烃基的实例包括但不限于吖丁啶基，5元杂环烃基的实例包括但不限于吡咯烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、噻唑烷基、咪唑烷基，6元杂环烃基的实例包括但不限于哌啶基、吗啉基、哌嗪基，7元杂环烃基的实例包括但不限于氮杂环庚烷基、 氧杂氮杂双环[2.2.1]庚基等。
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药物组合物”指活性化合物(如式(I)所示化合物或其药学上可接受的盐)，其任选地与一种或多种药学上可接受的化学成分(例如，但不限于载体和/或赋形剂)组合。
术语“药学上可接受的载体”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些载体。“药学上可接受的载体”是指与活性成份一同给药的、有利于活性成份给药的惰性物质，包括但不限于国家食品药品监督管理局许可的可接受的用于人或动物(例如家畜)的任何助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味增强剂、表面活性剂、润湿剂、分散剂、崩解剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。所述载体的非限制性实例包括碳酸钙、磷酸钙、各种糖和各类淀粉、纤维素衍生物、明胶、植物油和聚乙二醇等。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。术语“赋形剂”通常是指配制有效的药物组合物所需要的媒介物、稀释剂和/或介质等。
术语“给药”或“给予”等指可以使化合物或组合物能够递送至期望的生物作用位点的方法。这些方法包括但不限于口服、肠胃外(包括静脉内、皮下、腹膜内、肌内、血管内注射或输注)、局部、直肠给药等。
针对药物或药理学活性剂而言，术语“有效量”、“治疗有效量”或“预防有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”可以是与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”、“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗或预防目标紊乱、疾病或病症。
“保护基”是指一类用于与化合物上其它官能团反应而阻隔或保护特定官能团的取代基。例如，“氨基保护基”是指联接在氨基上阻隔或保护化合物上氨基官能团的取代基。适合的氨基保护基团包括但不限于乙酰基、三氟基、叔丁氧羰基(BOC)、苄氧羰基(CBZ)、氯甲酸-9-芴基甲酯(Fmoc)、2-(三甲基硅)乙氧基甲基(SEM)等。对于保护基的一般描述和使用说明可以参见Greene and Wuts的Protective Groups In Organic Synthesis,Wiley and Sons,1991。
本发明的化合物
本发明涉及式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2016104644-appb-000006
其中各基团的定义如上文所述。
表述“R1、R2与所连的N原子形成的基团”指的是式(I)的化合物中，
Figure PCTCN2016104644-appb-000007
部分所形成的基团。其实例包括但不限于
Figure PCTCN2016104644-appb-000008
Figure PCTCN2016104644-appb-000009
表述“4～8元杂环烷基可以包含0、1、2或3个额外的选自N、O或S的杂原子”中的额外的杂原子指的是除了
Figure PCTCN2016104644-appb-000010
部分中所示的N原子之外的杂原子。优选地，所述额外的杂原子可以选自N、O和S，数目可以为0、1、2或3个。
在优选的实施方案中，本发明涉及下式的化合物：
Figure PCTCN2016104644-appb-000011
应当理解，本发明的化合物可以作为药物学上可接受的盐的形式存在。作为药学上可接受的盐，例如，可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。金属盐的非限制性实例包括但不限于碱金属的盐，例如钠盐、钾盐等；碱土金属的盐，例如钙盐、镁盐、钡盐等；铝盐等。与有机碱形成的盐的非限制性实例包括但不限于与三甲胺、三乙胺、吡啶、甲基 吡啶、2,6-二甲基吡啶、乙醇胺、二乙醇胺、三乙醇胺、环己胺、二环己基胺等形成的盐。与无机酸形成的盐的非限制性实例包括但不限于与盐酸、氢溴酸、硝酸、硫酸、磷酸等形成的盐。与有机酸形成的盐的非限制性实例包括但不限于与甲酸、乙酸、三氟乙酸、富马酸、草酸、苹果酸、马来酸、酒石酸、柠檬酸、琥珀酸、甲磺酸、苯磺酸、对甲基苯磺酸等形成的盐。与碱性氨基酸形成的盐的非限制性实例包括但不限于与精氨酸、赖氨酸、鸟氨酸等形成的盐。与酸性氨基酸形成的盐的非限制性实例包括但不限于与天冬氨酸、谷氨酸等形成的盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
本发明的化合物可以具有一个或多个立体异构中心，并且各中心可以以R或S构型或它们的组合存在。因此，本发明的化合物包括所有单独的构型立体异构形式、位置异构形式、非对映体形式、对映体形式和差向异构体形式以及它们相应的混合物。使特定立构中心翻转或保持不变的技术以及拆分立体异构体的混合物的技术是本领域公知的，并且针对特定情况选择适当的方法完全在本领域技术人员的能力之内。
本发明的化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。本发明的化合物可以以多晶或无定形形式存在，并且这样的形式也涵盖在本发明的范围之内。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)、碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
本发明还涵盖式(I)的化合物的任何药学可接受的衍生物，如酯、酯的盐等。一种特别优选的衍生物是前药。当向接受者给药时，这样的衍生物能够直接或间接地提供本发明的化合物或其药学活性代谢物或残留物。特别优选的衍生物(如前药)是当向患者给予这样的化合物时，提高本发明的化合物的生物利用度的衍生物，或者改善母体化合物向生物组织或器官递送的衍生物。
给药、药物组合物和试剂盒
本发明涉及一种治疗或预防病毒感染的方法，所述方法包括向有此需要的个体给予治疗或预防有效量的式(I)的化合物或其药学上可接受的盐或者本发明的药物组合物。所述方法可以任选地包括给予一种或多种额外的活性剂来治疗或预防所述病毒感染。
或者，本发明提供式(I)的化合物或其药学上可接受的盐或者本发明的药物组合物在制备用于治疗或预防病毒感染的药物中的用途。在特定的实施方案中，式(I)的化合物或其药学上可接受的盐可以与一种或多种额外的活性剂联合使用来治疗或预防所述病毒感染。
或者，本发明提供用于治疗或预防病毒感染的式(I)的化合物或其药学上可接受的盐或者本发明的药物组合物。在特定的实施方案中，式(I)的化合物或其药学上可接受的盐可以与一种或多种额外的活性剂联合使用来治疗或预防所述病毒感染。
在本发明的一些实施方案中，上文所述的病毒感染是登革热病毒、黄热病毒、西尼罗病毒、日本脑炎病毒、蜱传脑炎病毒、昆津病毒、墨累山谷脑炎病毒、圣路易脑炎病毒、鄂木斯克出血热病毒、牛病毒性腹泻病毒、济卡病毒或肝炎病毒感染。在优选的实施方案中，所述病毒感染是肝炎病毒感染，特别是乙型或丙型肝炎病毒感染。
本发明还涉及一种药物组合物，其包含式(I)的化合物或其药学上可接受的盐以及一种或多种药学上可接受的载体和/或赋形剂。任选地，所述药物组合物可以包含一种或多种额外的活性剂。
本发明的药物组合物可通过将本发明的化合物或其盐与适宜的药学上可接受的载体组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
本发明的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等等。
给予本发明的化合物或其药物可接受的盐或其立体异构体或其药物组合物的典型途径包括但不限于口服、直肠、透黏膜、经肠给药，或者局部、经皮、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的载体混合来配制该药物组合物。这些载体能使本发明的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体赋形剂混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅剂，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。如微晶纤维素、葡萄糖溶液、阿拉伯胶浆、明胶溶液、蔗糖和淀粉糊；滑石、淀粉、硬脂酸镁、硬脂酸钙或硬脂酸；乳糖、蔗糖、淀粉、甘露糖醇、山梨糖醇或磷酸二钙；二氧化硅；交联羧甲基纤维素钠、预交化淀粉、淀粉羟乙酸钠、藻酸、玉米淀粉、 马铃薯淀粉、甲基纤维素、琼脂、羧甲基纤维素、交联聚乙烯吡咯烷酮等。可以根据通常药物实践中公知的方法任选地对糖衣剂的核心进行包衣，尤其使用肠溶包衣。
本发明的药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。能够使用适当的赋形剂，例如填充剂、缓冲剂或表面活性剂。
本发明的式(I)的化合物或其药学上可接受的盐可以通过任何适用的途径和方法给药，例如通过口服或肠胃外(例如，静脉内)给药。式(I)的化合物的治疗或预防有效量为从约0.0001到20mg/Kg体重/天，例如从0.001到10mg/Kg体重/天。
式(I)化合物的剂量频率由患者个体的需求决定，例如，每天1次或2次，或每天更多次。给药可以是间歇性的，例如，其中在若干天的期间内，患者接受式Ⅰ化合物的每日剂量，接着在若干天或更多天的期间，患者不接受式(I)化合物的每日剂量。
本发明还涉及一种药物组合，例如试剂盒，其包含a)第一活性物质，其为本文公开的化合物；b)一种或多种额外的活性剂。所述药物组合还可以根据需要包含使用说明。根据需要，上述a)和b)可以在相同或不同容器中提供。所述药物组合还可以包含在相同或不同容器中提供的用于辅助给药的物质，如上文提及的药学上可接受的载体和/或赋形剂。任选地，所述试剂盒还可以包含用于诊断病毒感染(如上文所述的那些病毒感染)的单元。
合成与制备
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。本发明具体实施方式的化学反应可以在合适的溶剂中完成，所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
本领域任何合成路线规划中的一个重要考量因素是为反应性官能团(如本发明中的氨基)选择合适的保护基。对于经过训练的从业者来说，Greene and Wuts的Protective Groups In Organic Synthesis,Wiley and Sons,1991是这方面的权威。本发明引用的所有参考文献整体上并入本发明。
例如，本发明的式(I)的化合物可以由有机合成领域技术人员通过下述路线用本领域的标准方法来制备：
Figure PCTCN2016104644-appb-000012
式4化合物的制备：以式1化合物为原料，与式2化合物发生缩合反应得式3化合物，式3化合物在正丁基锂和DMF的作用下得到式4化合物。
式(I)化合物的制备：式5化合物用SEM保护得式6化合物，用氨基取代得式7化合物，式7化合物在Na的作用下与正丁醇反应得式8化合物，式8化合物在TFA的作用下脱SEM保护基得式9化合物，式9化合物与式4化合物反应得式10化合物，式10化合物脱去羟基得式(I)化合物。
本发明所使用的所有溶剂是市售的，无需进一步纯化即可使用。反应一般是在惰性氮气下、无水溶剂中进行的。质子核磁共振数据记录在Bruker Avance III 400(400MHz)分光仪上，化学位移以四甲基硅烷低场处的(ppm)表示。质谱在安捷伦1200系列加6110(&1956A)上测定。LC/MS或Shimadzu MS包含一个DAD：SPD-M20A(LC)和Shimadzu Micromass 2020检测器。质谱仪配备有一个正或负模式下操作的电喷雾离子源(ESI)。
化合物经手工或者
Figure PCTCN2016104644-appb-000013
软件命名，市售化合物采用供应商目录名称。
用配有ShimadzuSIL-20A自动进样器和日本岛津DAD：SPD-M20A探测器的岛津LC20AB系统进行高效液相色谱分析，采用Xtimate C18(3m填料，规格为2.1x300mm)色谱柱。0-60AB_6分钟的方法：应用线性梯度，以100％A(A为0.0675％TFA的水溶液)开始洗脱，并以60％B(B为0.0625％TFA的MeCN溶液)结束洗脱，整个过程为4.2分钟，然后以60％B洗脱1分钟。将色谱柱再平衡0.8分钟达到100:0，总运行时间为6分钟。10-80AB_6分钟的方法：应用线性梯度，以90％A(A为0.0675％TFA的水溶液) 开始洗脱，并以80％B(B为0.0625％TFA的乙腈溶液)结束洗脱，整个过程为4.2分钟，然后以80％B洗脱1分钟。将色谱柱再平衡0.8分钟达到90:10，总运行时间为6分钟。柱温为50℃，流速为0.8mL/min。二极管阵列检测器扫描波长为200-400nm。
在Sanpont-group的硅胶GF254上进行薄层色谱分析(TLC)，常用紫外光灯照射检出斑点，在某些情况下也采用其他方法检视斑点，在这些情况下，用碘(10g硅胶中加入约1g碘并彻底混合而成)、香草醛(溶解大约1g香草醛于100mL 10％H2SO4中制得)、茚三酮(从Aldrich购得)或特殊显色剂(彻底混合(NH4)6Mo7O24·4H2O、5g(NH4)2Ce(IV)(NO3)6、450mL H2O和50mL浓H2SO4而制得)展开薄层板，检视化合物。采用Still,W.C.；Kahn,M.；and Mitra,M.Journal of Organic Chemistry,1978,43,2923-2925中所公开技术的类似方法，在Silicycle的40-63μm(230-400目)硅胶上进行快速柱色谱。快速柱色谱或薄层色谱的常用溶剂是二氯甲烷/甲醇、乙酸乙酯/甲醇和己烷/乙酸乙酯的混合物。
在Gilson-281Prep LC 322系统上采用吉尔森UV/VIS-156探测器进行制备色谱分析，所采用的色谱柱是Agella Venusil ASB Prep C18,5m、150×21.2mm；Phenomenex Gemini C18、5m、150×30mm；Boston Symmetrix C18,5m、150×30mm；或者Phenomenex Synergi C18、4m、150×30mm。在流速约为25mL/min时，用低梯度的乙腈/水洗脱化合物，其中水中含有0.05％HCl、0.25％HCOOH或0.5％NH3·H2O，总运行时间为8-15分钟。
本发明采用下述缩略词：n-BuLi代表正丁基锂；THF代表四氢呋喃；SEM代表2-(三甲硅烷基)乙氧基甲基；DIPEA代表二异丙基乙基胺；IPA代表异丙醇；TFA代表三氟乙酸；DMF代表N,N-二甲基甲酰胺；n-BuOH代表正丁醇；Et3SiH代表三乙基硅烷。
有益效果
本发明的化合物具有对Toll样受体7的高结合活性以及对Toll样受体8的低结合活性，从而表现出更好的选择性、活性和安全性以及更低的副作用，可用于有效地治疗或预防病毒感染，特别是乙型或丙型肝炎病毒感染。
实施例
下面的具体实施例的目的是使本领域的技术人员能更清楚地理解和实施本发明。它们不应该被认为是对本发明范围的限制，而只是本发明的示例性说明和典型代表。除非另外专门定义，本文中使用的比例(包括百分比)或份数均按重量计。
实施例1 2-丁氧基-7-(2-(吡咯烷-1-基甲基)噻唑-5-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺(I)
步骤1：2-(吡咯烷-1-基甲基)噻唑
Figure PCTCN2016104644-appb-000014
将噻唑-2-甲醛(25.00g,220.90mmol)和四氢呋喃(300.0mL)投入500mL反应瓶中，搅拌5min，之后加入冰醋酸(39.80g,662.90mmol)，搅拌降温至0-10℃，滴加吡咯烷(13.80g，194.40mmol)，在滴加中保持温度低于10℃。滴毕，分批次加入三乙酰氧基硼氢化钠(56.20g,265.10mmol)，在10-20℃下反应12hr，TLC监控至原料完全消失。反应完全后，向反应液缓慢滴加饱和碳酸氢钠水溶液至pH为9-10，用150mL乙酸乙酯萃取三次，合并有机相并用无水硫酸钠干燥后减压浓缩。残留物经用柱层析法纯化(流动相梯度：乙酸乙酯/石油醚/:3/1/到1/1)得到标题化合物黄色油状物15.00g，收率：40.3％。
1H NMR(400MHz,CHLOROFORM-d)δ7.71(d,J＝3.26Hz,1H),7.26-7.32(m,1H),4.02(s,2H),2.60-2.75(m,4H),1.84(td,J＝3.20,6.65Hz,4H)。
步骤2：2-(吡咯烷-1-基甲基)噻唑-5-甲醛
Figure PCTCN2016104644-appb-000015
将2-(吡咯烷-1-基甲基)噻唑(15.00g,89.10mmol)和四氢呋喃(250.00mL)投入500mL三口瓶中，用干冰丙酮冷却至-78℃。在-78℃下缓慢滴加正丁基锂(2.5M,71.3mL)。滴加完毕后，在-78℃下搅拌半小时后，继续在-78℃下向反应液中滴加DMF(13.00g,178.30mmol)。滴加完毕后，在-78℃下再搅拌半小时后，经TLC检测原料反应完毕。反应液用50mL饱和氯化铵水溶液终止，用150mL乙酸乙酯萃取，合并有机相经饱和硫酸钠干燥，过滤，减压浓缩得到标题化合物黄色油状物15.00g，粗品直接用于下一步。
1H NMR(400MHz,CHLOROFORM-d)δ10.03(s,1H),8.32(s,1H),4.03(s,2H),2.73(t,J＝6.02Hz,4H),1.86(td,J＝3.20,6.65Hz,4H)。
步骤3：2,4-二氯-5-((2-(三甲基硅基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶
Figure PCTCN2016104644-appb-000016
将2,4-二氯-5H-吡咯并[3,2-d]嘧啶(4.00kg，21.28mol)溶解于DMF(20.00L)；室温(25℃)下分批加入DIPEA(2.58kg，20.00mol)，随后搅拌30min。将反应液用冰浴降温至0℃，然后在5小时内，以1～2滴/秒的滴速，缓慢滴加SEM-Cl(4.00kg，24.00mol)，滴完后，将反应液在0℃下搅拌反应4小时，HPLC监测反应完全。反应液用70L水终 止并稀释后，用乙酸乙酯(15L×3)萃取，合并的有机相依次用1M的盐酸水溶液(5L×2)和饱和食盐水(7L×2)洗涤，减压蒸馏除去溶剂后得标题化合物(6.40kg，20.11mol，产率94.50％)。
1H NMR(400MHz,DMSO-d6)δ8.24-8.35(m,1H)，6.70-6.85(m,1H)，5.77(s,2H)，3.45-3.57(m,2H)，0.74-0.86(m,2H)，0.00(s,9H)。
步骤4：2-氯-5-((2-(三甲基硅基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2016104644-appb-000017
在10L高压釜中，将2,4-二氯-5-((2-(三甲基硅基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶(1.60kg，5.03mol)溶于异丙醇(1.60L)，室温(25℃)下一次性加入氨水(4L)。将反应混合物在95℃下搅拌7小时，HPLC监测反应完毕，反应液自然冷却到室温，经布氏漏斗过滤后得到黑褐色固体。该固体依次用乙酸乙酯/正庚烷(1/1,5L×2)打浆，用乙酸乙酯(4L)打浆，得到标题化合物棕色固体(1.25kg,4.18mol，产率83.1％)。
1H NMR(400MHz,DMSO-d6)δ7.61-7.77(m,1H)，6.97-7.19(m,2H)，6.28-6.38(m,1H)，5.54-5.67(m,2H)，3.43-3.53(m,2H)，0.76-0.91(m,2H)，0.07(s,9H)。
步骤5：2-丁氧基-5-((2-(三甲基硅)基乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2016104644-appb-000018
在氮气保护下，将金属钠(525.05g，22.84mol)缓慢分批加入到n-BuOH(17.0L)中；加入完毕后，使体系升温至60℃，并在该温度下持续搅拌，直至金属钠全部溶解。随后，使体系冷却至25℃，将2-氯-5-((2-(三甲基硅基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺(1.95kg，6.53mol)分批加入。搅拌混合均匀后，将反应物在90℃下持续搅拌8小时，HPLC监测反应完全。使反应混合物自然降温至25℃后，缓慢倒入30L饱和氯化铵水溶液中，随后用乙酸乙酯(15L×3)萃取，合并的有机相用饱和食盐水(20L×2)洗涤，经无水Na2SO4干燥、过滤后，减压蒸馏除去溶剂后，将残余物在正庚烷(4L)中打浆，过滤分离得到固体，再在乙酸乙酯(5L)中打浆，得到标题化合物黄白色固体(1.53kg，4.55mol，69.7％)。
1H NMR(400MHz,DMSO-d6)δ7.49-7.54(m,1H)，6.54-6.62(m,2H)，6.15-6.20(m,1H)，5.54(s,2H)，4.10-4.22(m,2H)，3.42-3.55(m,2H)，1.58-1.73(m,2H)，1.35-1.47(m,2H)，0.90-0.96(m,3H)，0.83-0.89(m,2H)，0.05(s,9H)。
步骤6：2-丁氧基-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2016104644-appb-000019
将2-丁氧基-5-((2-(三甲基硅)基乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺(1.10kg,3.27mol)溶于TFA(5.50L)，反应液在25℃下持续搅拌16小时，HPLC监测反应完全，减压蒸馏除去TFA，剩余物溶解在甲醇(1.2L)和冰水(1.2L)中，在均匀搅拌下，用浓氨水调节体系pH至12，然后搅拌2小时。溶液中不断有沉淀析出，过滤后，滤饼为白色固体，依次用15％的氨水(1.2L×3)和乙酸乙酯(4L)打浆，得到标题化合物白色固体(550.00g，2.67mol，81.7％)。
1H NMR(400MHz,METHANOL-d4)δ7.37(d,J＝2.89Hz,1H)，6.29(d,J＝3.01Hz,1H)，4.27(t,J＝6.53Hz,2H)，1.75(d,J＝7.91Hz,2H)，1.44-1.61(m,2H)，1.00(t,J＝7.40Hz,3H)。
步骤7：((4-氨基-2-丁氧基-5H-吡咯并[3,2-d]嘧啶-7-基)-羟基甲基)-[2-(吡咯烷-1-亚甲基)噻唑-5-基]甲醇
Figure PCTCN2016104644-appb-000020
将2-丁氧基-5H-吡咯并[3,2-d]嘧啶-4-胺(10.00g,48.49mmol)、碳酸钾(7.37g,53.34mmol)、水(100mL)和异丙醇(100mL)投入500mL三口瓶中，在搅拌下加入2-(吡咯烷-1-基甲基)噻唑-5-甲醛(14.27g,72.74mmol)，在25℃下反应16hr，LCMS监控至2-(吡咯烷-1-亚甲基)噻唑-5-甲醛反应完全。向反应液加100mL水稀释，用100mL二氯甲烷萃取三遍。合并的有机相用无水硫酸钠干燥，过滤去除固体，减压浓缩得到残留物，用柱层析法纯化(流动相梯度：二氯甲烷/甲醇/氨水/:30/1/0.1到10/1/0.1)得到棕色固体状的标题化合物(5.20g,12.92mmol,收率：26.6％)。MS(ESI)m/z:403.3[M+H+]。
步骤8：2-丁氧基-7-(2-(吡咯烷-1-基甲基)噻唑-5-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2016104644-appb-000021
将((4-氨基-2-丁氧基-5H-吡咯并[3,2-d]嘧啶-7-基)-羟基甲基)-[2-(吡咯烷-1-亚甲基)噻唑-5-基]甲醇(5.10g,12.60mmol)、三乙基硅烷(10.00mL)和三氟乙酸(40.00mL)投入 100mL茄型瓶中，在20℃下搅拌12小时，LCMS监控至原料反应完全。减压浓缩去除溶剂，加入100mL乙酸乙酯，之后加入饱和碳酸钠溶液调节溶液pH＝9-10，用50mL乙酸乙酯萃取三次，合并有机相，用无水硫酸钠干燥，过滤去除固体，有机相减压浓缩得到残留物。残留物通过制备高效液相色谱分离得到2-丁氧基-7-(2-(吡咯烷-1-基甲基)噻唑-5-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺淡黄色油状物4.2g(标题化合物的二甲酸盐)。
1HNMR(400MHz,Methanol-d4)δ8.30(s,2H),7.61(s,1H),7.41(s,1H),4.51(s,2H),4.44(q,J＝6.6Hz,2H),4.24(s,2H),3.33–3.28(m,4H),2.02(s,4H),1.83–1.73(m,2H),1.56–1.46(m,2H),0.99(t,J＝7.2Hz,3H)。
实验例1：Toll样受体7和Toll样受体8体外受体结合活性
试剂：
HEK-blue hTLR7细胞和HEK-blue hTLR8细胞(来源于InvivoGen公司)
DMEM培养基
热灭活胎牛血清
抗支原体试剂NormocinTM
博来霉素
杀稻瘟菌素
所用的GS-9620和R848的结构如下，其中GS-9620可以参考US20100143301中公开的方法制备；R848购自百奇生物(货号IMG-2208，规格0.5mg)。
Figure PCTCN2016104644-appb-000022
方案：
1.96孔化合物板的准备：利用液体工作站POD将化合物从10毫摩尔/升浓度起始，用DMSO做3倍梯度稀释，共稀释10个点(从第2列到第11列，每个点2个重复)。在第12列加入1微升5毫克/毫升的阳性化合物R848作为阳性对照，在第1列加入1微升DMSO作为阴性对照。每孔中含有的DMSO体积都是1微升。
2.收取细胞培养瓶中的细胞，将细胞密度稀释成250,000个细胞/毫升。
3.加入200微升(50,000个细胞/孔)细胞悬液至准备好的化合物板中。每孔中DMSO终浓度为0.5％。
4.将含有细胞和化合物的培养板放入CO2培养箱中培养24小时，培养条件为37℃，5％CO2浓度。
5.培养24小时后，从细胞培养板中每孔取出20微升上清液转移到一块96孔透明检测板中。然后往检测板中每孔加入180微升Quanti-Blue试剂，并置于37℃，5％CO2培养箱孵育1小时。
6.1小时后，用酶标仪在OD650处读板检测20微升上清液中碱性磷酸酶的含量。
7.利用Prism软件分析数据，得出各化合物的EC50。
实验结果如表1所示：
表1
供试样 TLR7EC50(nM) TLR8EC50(nM)
GS-9620 517 7867
实施例1 454.1 29332
从上表可见，本发明的化合物展现出比对照品Toll样受体7激动剂GS-9620更高的与Toll样受体7体外受体结合活性，并且展现出比对照品Toll样受体7激动剂GS-9620更低的与Toll样受体8体外受体结合活性。本发明的化合物对不同受体具有明显的选择性差异，且效果优于现有技术。
实验例2：大鼠药代动力学实验
试验用雄性SD大鼠共12只，分成四组，每组3只SD大鼠。2组动物静脉注射(IV)给药，分别注射1mg/kg的对照品Toll样受体7激动剂GS-9620和实施例1化合物的10％羟丙基-β-环糊精水溶液(浓度0.5mg/mL)。另外2组口服给药(PO)，分别口服5mg/kg的GS-9620和3mg/kg实施例1化合物的0.5％甲基纤维素/0.2％吐温80纯水混悬液(浓度1mg/mL)。静脉注射后的每只大鼠于给药后2、15、30分钟和1、2、4、8、24小时连续采集全血样本并制备血浆。口服给药后的每只大鼠于给药后15、30分钟和1、2、4、8、24小时连续采集全血样本并制备血浆。应用LC-MS/MS方法，分别测定GS-9620和实施例1化合物血浆浓度。
结果如表2所示。
表2
Figure PCTCN2016104644-appb-000023
在同等条件下，无论是静脉注射还是口服给药(折算给药量)，相对于对照品Toll样受体7激动剂GS-9620，本发明的化合物在大鼠中有更高的曝露量。
实验例3：AAV(Adeno Associated Virus，腺伴随病毒)携带乙型肝炎(HBV)感染小鼠模型的体内药效学实验
实验设计和方法：
给药途径：灌胃；
给药时间：自注射病毒后第26天起，每三天给药一次，共6周；
给药组：第一组，媒介物，10％HP-β-CD；第二组，GS-9620，20mg/kg；第三组，实施例1化合物，20mg/kg；
采血：首次给药后第3天起，每周两次，共8周；
取肝：首次给药后第64天收集肝样本。
详情见表3和表4。
表3
Figure PCTCN2016104644-appb-000024
*HBsAg：乙肝表面抗原；HBeAg：乙型肝炎E抗原
表4
Figure PCTCN2016104644-appb-000025
AAV携带乙型肝炎感染小鼠模型体内药效学试验药效结果详情见图1至图3。血浆中的HBV DNA拷贝数、血浆中的HBsAg拷贝数和血浆中的Anti-HBsAb(乙肝表面抗原抗体)产生水平检测数据显示，实施例1化合物在同等条件下药效优于对照品Toll样受体7激动剂GS-9620，从而证实其更优异的效果。
除非另有说明，本说明书(包括权利要求书)中使用的所有表示成分、细胞培养、处理条件等的量的数字应当理解为在所有条件下受到术语“约”的修饰。因此，除非另有相反的说明，数值参数为近似值，并且可以根据通过本发明试图获得的期望特性而变化。除非另有说明，一系列元素之前的术语“至少”应当理解为指该系列中的每个元素。本领域技术人员会认识到或者能够利用不超过常规实验确定本文所述的本发明的具体实施方案的许多等同物。所附权利要求书意图涵盖这类等同物。
本领域技术人员会清楚，可以进行本发明的许多修改和变化而不背离其精神和范围。本文所述的具体实施方案仅通过实例的方式提供，并不意味着以任何方式限制。本发明的真正范围和精神通过所附权利要求书示出，说明书和实施例仅是示例性的。

Claims (12)

  1. 式(I)所示的化合物或其药学上可接受的盐，
    Figure PCTCN2016104644-appb-100001
    其中
    R1和R2各自独立地选自H和C1-4烷基，或者
    R1和R2与所连N原子一起形成4～8元杂环烷基，所述4～8元杂环烷基任选地被一个或多个R3取代，R3各自独立地选自羟基、卤素、氰基、C1-4烷基和C1-4烷氧基。
  2. 如权利要求1所述的化合物或其药学上可接受的盐，其特征在于，
    所述4～8元杂环烷基包含0、1、2或3个额外的选自N、O和S的杂原子。
  3. 如权利要求2所述的化合物或其药学上可接受的盐，其特征在于，
    所述4～8元杂环烷基为4元、5元、6元、7元或8元杂环烷基。
  4. 如权利要求1所述的化合物或其药学上可接受的盐，其特征在于，
    R3独立地选自羟基、F、Cl、Br、CN、甲基、乙基、丙基、甲氧基、乙氧基和丙氧基。
  5. 如权利要求1所述的化合物或其药学上可接受的盐，其特征在于，
    R1、R2与所连的N原子形成的基团选自：
    Figure PCTCN2016104644-appb-100002
    Figure PCTCN2016104644-appb-100003
  6. 如权利要求5所述的化合物或其药学上可接受的盐，其特征在于，
    R1、R2与所连的N原子形成的基团为
    Figure PCTCN2016104644-appb-100004
  7. 下式表示的化合物或其药学上可接受的盐：
    Figure PCTCN2016104644-appb-100005
  8. 一种药物组合物，其包含治疗或预防有效量的权利要求1-7中任一项所述的化合物和/或其药学上可接受的盐以及一种或多种药学上可接受的载体和/或赋形剂。
  9. 权利要求1-7任一项所述的化合物或其药学上可接受的盐或者权利要求8的药物组合物在制备用于治疗或预防病毒感染的药物中的用途。
  10. 如权利要求9所述的用途，其特征在于，所述病毒感染是登革热病毒、黄热病毒、西尼罗病毒、日本脑炎病毒、蜱传脑炎病毒、昆津病毒、墨累山谷脑炎病毒、圣路易脑炎病毒、鄂木斯克出血热病毒、牛病毒性腹泻病毒、济卡病毒或肝炎病毒感染。
  11. 如权利要求10所述的用途，其特征在于，所述病毒感染是肝炎病毒感染。
  12. 如权利要求11所述的用途，其特征在于，所述病毒感染是乙型或丙型肝炎病毒感染。
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