WO2020057604A1 - Tlr8激动剂 - Google Patents

Tlr8激动剂 Download PDF

Info

Publication number
WO2020057604A1
WO2020057604A1 PCT/CN2019/106687 CN2019106687W WO2020057604A1 WO 2020057604 A1 WO2020057604 A1 WO 2020057604A1 CN 2019106687 W CN2019106687 W CN 2019106687W WO 2020057604 A1 WO2020057604 A1 WO 2020057604A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
isomer
pharmaceutically acceptable
acceptable salt
tlr8
Prior art date
Application number
PCT/CN2019/106687
Other languages
English (en)
French (fr)
Inventor
蔡哲
孙飞
丁照中
陈曙辉
Original Assignee
正大天晴药业集团股份有限公司
南京明德新药研发有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 正大天晴药业集团股份有限公司, 南京明德新药研发有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to KR1020217011377A priority Critical patent/KR20210060567A/ko
Priority to AU2019344868A priority patent/AU2019344868A1/en
Priority to CA3112953A priority patent/CA3112953A1/en
Priority to JP2021515104A priority patent/JP2022501350A/ja
Priority to US17/276,920 priority patent/US20210371414A1/en
Priority to CN201980052513.8A priority patent/CN112805283B/zh
Priority to EP19862693.9A priority patent/EP3854794A4/en
Priority to SG11202102641RA priority patent/SG11202102641RA/en
Priority to CN202211301510.3A priority patent/CN115650979A/zh
Publication of WO2020057604A1 publication Critical patent/WO2020057604A1/zh
Priority to PH12021550601A priority patent/PH12021550601A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • the present application relates to a novel structural TLR8 (Toll-like receptor 8) agonist, and particularly to a compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof, and a compound containing the indicated compound or a pharmaceutically acceptable compound thereof.
  • TLR8 Toll-like receptor 8
  • TLRs Toll-like receptors
  • TLR is an important class of protein molecules involved in non-specific immunity (native immunity), and they are also the bridge connecting non-specific immunity and specific immunity.
  • TLR is a single transmembrane non-catalytic protein, which is mainly expressed in a series of immune cells, such as dendritic cells, macrophages, monocytes, T cells, B cells, and NK cells.
  • Toll-like receptors can recognize molecules with conserved structures derived from microorganisms. When microorganisms break through the physical barriers of the body, such as the skin and mucous membranes, TLRs can recognize them and activate the body to produce immune cell responses.
  • TLR1, TLR2, TLR4, TLR5, and TLR6 mainly recognize extracellular stimuli, such as bacterial lipopolysaccharides, lipopeptides, flagellins, etc., while TLR3, TLR7, TLR8, and TLR9 play a role in cell endosomes, engulfing and encapsulating After the membrane is lysed, they bind to their ligands and can recognize the nucleic acids of microorganisms.
  • TLR8 has a unique function: TLR8 is mainly expressed in monocytes, macrophages and myeloid dendritic cells.
  • the TLR8 signaling pathway can be activated by bacterial single-stranded RNA, small molecule agonists, and microRNAs. Activation of TLR8 results in the production of Th1 polar cytokines, such as IL-12, IL-18, TNF-a and IFN- ⁇ , and various co-stimulatory factors such as CD80, CD86.
  • Th1 polar cytokines such as IL-12, IL-18, TNF-a and IFN- ⁇
  • co-stimulatory factors such as CD80, CD86.
  • activating TLR8 on antigen presenting cells and other immune cells in the liver can activate cytokines such as IL-12, which can activate specific T cells and NK cells that are depleted by the virus, thereby reconstructing the liver.
  • cytokines such as IL-12
  • VentiRX Pharmaceuticals' selective TLR8 agonist, VTX-2337 is used clinically for the evaluation of different tumors for the first time. VTX-2337 is administered subcutaneously. Gilead Sciences reported that the TLR8 agonist, which can be taken orally, is currently in Phase 2 clinical use for the treatment of chronic hepatitis B infection, but its structure has not been disclosed.
  • the application provides a compound represented by formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof,
  • Carbon atoms with “*” may be chiral carbon atoms and exist in the form of a single enantiomer (R) or (S) or are rich in one enantiomer;
  • X is selected from N and CH;
  • R 1 is selected from H, F, Cl, Br, I, CN, C 1-6 alkyl, C 3-6 cycloalkyl, -N (R a ) (R b ), and -O (R c ), so Said C 1-6 alkyl and C 3-6 cycloalkyl are optionally substituted with 1, 2 or 3 Rd ;
  • R 2 is selected from C 1-6 alkyl, said C 1-6 alkyl optionally substituted with 1, 2, or 3 R e;
  • R a, R b, R c , R d and R e are each independently selected from H, F, Cl, Br, I, OH, CN, NH 2, CH 3, Said CH 3 , Optionally substituted by 1, 2 or 3 R;
  • Each R is independently selected from F, Cl, Br, I, OH, CN, NH 2 , CH 3 ,
  • the application provides a compound represented by formula (I '), an isomer thereof, or a pharmaceutically acceptable salt thereof,
  • X is selected from N and CH;
  • R 1 is selected from H, F, Cl, Br, I, CN, C 1-6 alkyl, C 3-6 cycloalkyl, -N (R a ) (R b ), and -O (R c ), so Said C 1-6 alkyl and C 3-6 cycloalkyl are optionally substituted with 1, 2 or 3 Rd ;
  • R 2 is selected from C 1-6 alkyl, said C 1-6 alkyl optionally substituted with 1, 2, or 3 R e;
  • R a, R b, R c , R d and R e are each independently selected from H, F, Cl, Br, I, OH, CN, NH 2, CH 3, Said CH 3 , Optionally substituted by 1, 2 or 3 R;
  • Each R is independently selected from F, Cl, Br, I, OH, CN, NH 2 , CH 3 ,
  • R a, R b, R c , R d and R e are each independently selected from H, F, Cl, Br, I, OH, CN, NH 2, CH 3,
  • the R 1 is selected from the group consisting of H, F, Cl, Br, I, CN, CH 3 , Cyclopentyl, cyclobutyl, NH 2 , Said CH 3 , Cyclopentyl and cyclobutyl are optionally substituted with 1, 2 or 3 Rd .
  • R 1 is selected from H, F, Cl, Br, I, CH 3 and
  • R 2 is selected from Said Optionally substituted with 1, 2, or 3 R e.
  • R 2 is selected from
  • the application also provides a compound of the formula, an isomer thereof, or a pharmaceutically acceptable salt thereof,
  • the aforementioned compound, an isomer thereof, or a pharmaceutically acceptable salt thereof is selected from
  • R a, R b, R c , R d and R e are each independently selected from H, F, Cl, Br, I, OH, CN, NH 2, CH 3, Other variables are as defined above.
  • the R 1 is selected from the group consisting of H, F, Cl, Br, I, CN, CH 3 , Cyclopentyl, cyclobutyl, NH 2 , Said CH 3 , Cyclopentyl and cyclobutyl are optionally substituted with 1, 2 or 3 Rd .
  • R 1 is selected from H, F, Cl, Br, I, CH 3 and Other variables are as defined above.
  • R 2 is selected from Said Optionally substituted with 1, 2, or 3 R e, the other variables are as defined above.
  • R 2 is selected from Other variables are as defined above.
  • the present application provides a pharmaceutical composition comprising a compound of the present application, an isomer thereof, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical compositions of the present application further include a pharmaceutically acceptable excipient.
  • the present application provides a method for agonizing TLR8, comprising administering to a subject in need thereof, preferably a human, a therapeutically effective amount of a compound of the present application, an isomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof .
  • the present application provides a method of treating or preventing a disease responsive to TLR8 agonism, comprising administering to a subject in need thereof, preferably a human, a therapeutically effective amount of a compound of the present application, an isomer thereof, a pharmaceutically acceptable A salt, or a pharmaceutical composition thereof.
  • the present application provides the use of a compound of the present application, an isomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for treating or preventing a disease responsive to TLR8 agonism.
  • the present application provides the use of a compound of the present application, an isomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating or preventing a disease responsive to TLR8 agonism.
  • the present application provides a compound of the present application, an isomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in treating or preventing a disease responsive to TLR8 agonism.
  • the disease responsive to TLR8 agonism is selected from a viral infection.
  • the viral infection is selected from a hepatitis B virus (HBV) infection.
  • HBV hepatitis B virus
  • the compounds of the present application have significant agonistic activity on TLR8.
  • the compounds of the present application exhibit ideal TLR8 agonistic activity and specific selectivity.
  • the compounds of the present application exhibit ideal TLR8 pathway-specific cytokine (IL-12p40, IFN- ⁇ ) inducing activity.
  • Pharmacokinetic studies in mice have shown that the compounds of the present application have moderate oral bioavailability and drug exposure and support oral administration.
  • TLR8 agonists are immune modulators. Excessive exposure may lead to excessive activation of the body's immune system, resulting in unforeseen side effects.
  • pharmaceutically acceptable refers to 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 excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit / risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present application, prepared from a compound having a specific substituent and a relatively non-toxic acid or base found herein.
  • base addition salts can be obtained by contacting a sufficient amount of a base with a neutral form of such compounds in a pure solution or a suitable inert solvent.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts, or organic acid salts
  • the pharmaceutically acceptable salts of the present application can be synthesized from the parent compound containing an acid group or a base by a conventional chemical method. Generally, such salts are prepared by reacting these compounds in the form of a free acid or base with a stoichiometric appropriate base or acid in water or an organic solvent or a mixture of the two.
  • an ethyl group is "optionally” substituted with a halogen, meaning that the ethyl group may be unsubstituted (CH 2 CH 3 ), mono-substituted (such as CH 2 CH 2 F), poly-substituted (such as CHFCH 2 F, CH 2 CHF 2 etc.) or completely substituted (CF 2 CF 3 ).
  • C mn in this document means that the part has an integer number of carbon atoms in a given range.
  • C 1-6 means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
  • the compounds of the present application may exist in specific geometric or stereoisomeric forms.
  • This application contemplates all such compounds, including cis and trans isomers, (-)-and (+)-enantiomers, (R)-and (S) -enantiomers, diastereomers Isomers, (D) -isomers, (L) -isomers, and racemic and other mixtures thereof, such as enantiomeric or diastereomeric enriched mixtures, all of which belong to the present invention
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All these isomers and their mixtures are included within the scope of this application.
  • enantiomers or “optical isomers” refer to stereoisomers in mirror image relationship to each other.
  • cis-trans isomer or “geometric isomer” are caused by the inability of a double bond or a single bond of a ring-forming carbon atom to rotate freely.
  • diastereomer refers to a stereoisomer in which a molecule has two or more centers of chirality and is in a non-mirror relationship between molecules.
  • wedge solid line key And wedge dashed keys Represents the absolute configuration of a solid center, using straight solid line keys And straight dashed keys Represents the relative configuration of the solid center, with wavy lines Represents a wedge solid line key Or wedge-shaped dotted key Or with wavy lines Represents a straight solid line key And straight dashed keys
  • tautomer or “tautomeric form” means that at room temperature, the isomers of different functional groups are in dynamic equilibrium and can be quickly converted to each other. If tautomers are possible (eg in solution), the chemical equilibrium of the tautomers can be reached.
  • proton tautomers also known as prototropic tautomers
  • proton migration such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence tautomers include recombination of some bonding electrons for mutual conversion.
  • a specific example of the keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the "isomers” described herein include stereoisomers, cis-trans isomers, and tautomers.
  • the terms “rich in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enantiomerically enriched” refer to one of the isomers or the The enantiomeric content is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or more 99.9%.
  • the terms “isomer excess” or “enantiomeric excess” refer to the difference between the two isomers or the relative percentages of the two enantiomers. For example, if the content of one isomer or enantiomer is 90%, and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80% .
  • Optically active (R)-and (S) -isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the present application is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, and then by a conventional method known in the art Diastereomeric resolution is performed and the pure enantiomer is recovered.
  • Diastereomeric resolution is performed and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereoisomers is usually accomplished by using chromatography that employs a chiral stationary phase and optionally is combined with chemical derivatization (such as the generation of amino groups from amines) Formate).
  • the compounds of the present application may contain atomic isotopes in unnatural proportions on one or more of the atoms constituting the compound.
  • compounds such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C) can be labeled with radioisotopes.
  • deuterated drugs can be replaced by heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have reduced side effects and increased drug stability. , Enhance efficacy, extend the biological half-life of drugs and other advantages. Transformations of all isotopic compositions of the compounds of this application, whether radioactive or not, are included within the scope of this application. "Optional” or “optionally” refers to events or conditions described later that may, but need not, occur, and that the description includes situations in which the events or conditions occur and situations in which the events or conditions do not occur.
  • substituted refers to the replacement of any one or more hydrogen atoms on a specific atom with a substituent, and can include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
  • O oxygen
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable such as R
  • its definition in each case is independent.
  • the group may be optionally substituted with at most two R, and R in each case has independent options.
  • combinations of substituents and / or variants are only permitted if such combinations result in stable compounds.
  • C 1-6 alkyl is used to indicate a straight or branched chain saturated hydrocarbon group containing 1 to 6 carbon atoms.
  • the C 1- 6 alkyl includes C 1-4, C 1-3, C 1-2 , C 2-6, C 2-4, C 6 and C 5 alkyl groups like; which may be monovalent (e.g. Methyl), divalent (such as methylene) or polyvalent (such as methine).
  • C 1-6 alkyl examples include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl and the like.
  • C 3-6 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic and bicyclic system.
  • the C 3-6 cycloalkyl includes C 3-5 , C 4-5 and C 5-6 cycloalkyl and the like; it may be monovalent, divalent or polyvalent.
  • Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • composition refers to a mixture of one or more compounds of the present application or a salt thereof and a pharmaceutically acceptable excipient.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application to an organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no significant stimulating effect on the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
  • treating means administering a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • terapéuticaally effective amount means the amount of a compound of the present application that (i) treats a particular disease, condition, or disorder, and (ii) reduces, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder.
  • the amount of the compound of the present application that constitutes a “therapeutically effective amount” varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on Determined by its own knowledge and this disclosure.
  • prevention means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, and includes: preventing the occurrence of a disease or disease state in a mammal, particularly when Such mammals are susceptible to the disease state but have not yet been diagnosed as having the disease state.
  • the solvents used in this application are commercially available and require no further purification.
  • the reaction is generally carried out under an inert nitrogen in an anhydrous solvent.
  • Proton nuclear magnetic resonance data were recorded on a Bruker Avance III 400 (400 MHz) spectrometer, and the chemical shift was expressed in the high field (ppm) of tetramethylsilane.
  • Mass spectra were measured on an Agilent 1200 Series plus 6110 (& 1956A).
  • LC / MS or Shimadzu MS includes a DAD: SPD-M20A (LC) and Shimadzu Micromass 2020 detector.
  • the mass spectrometer is equipped with an electrospray ion source (ESI) that operates in positive or negative mode.
  • ESI electrospray ion source
  • a Shimadzu LC20AB system equipped with a Shimadzu SIL-20A autosampler and a Shimadzu DAD: SPD-M20A detector was used for HPLC analysis, and a Xtimate C18 (3m packing, 2.1 ⁇ 300mm) column was used.
  • Step A Dissolve compound 1-1 (50 g, 412.54 mmol) and tetraethyl titanate (94.10 g, 412.54 mmol, 85.55 ml) in THF (500 ml) at 20-30 degrees Celsius, then add 2-hexane Ketone (41.32 g, 41.54 mmol, 51.01 ml). The reaction solution was heated to 65 degrees Celsius and stirred for 48 hours, and the obtained reaction solution was directly used in the next step.
  • Step B The reaction solution in Step A was cooled to room temperature, and THF (1000 ml) was added, and then allyl bromide (196.33 g, 1.62 mol) was added, and then zinc powder (53.06 g, 811.43 mmol) was added slowly in batches to react The liquid was stirred at 20-30 degrees Celsius for 12 hours under the protection of nitrogen.
  • the reaction solution was filtered through diatomaceous earth, and the filtrate was added with 100 ml of saturated saline solution. After stirring, it was filtered through celite again, and the filtrate was spin-dried.
  • Step C Dissolve compound 1-3 (15 g, 61.12 mmol) in methanol (150 ml) and cool to 0 degrees Celsius. Slowly add dioxane hydrochloride solution (4M, 91.68 ml) at 0 to 20 degrees Celsius. The reaction solution was stirred at 25 degrees Celsius for 2 hours. The reaction solution was directly concentrated under reduced pressure to obtain compound 1-4.
  • Step D Dissolve compound 1-4 (hydrochloride, 13 g, 73.15 mmol) and sodium bicarbonate (55.31 g, 658.36 mmol) in dioxane (90 mL) and H 2 O (60 mL) After cooling to 0 ° C, CbzCl (74.87 g, 438.91 mmol, 62.40 ml) was slowly added dropwise. The reaction solution was heated to 20 to 30 degrees Celsius and stirred for 2 hours, and extracted twice with 100 ml of ethyl acetate each time. The organic phases were combined and washed once with saturated brine (150 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure Get rough.
  • Step E Dissolve compound 1-5 (20.8 g, 75.53 mmol) in acetonitrile (100 ml), H 2 O (150 ml) and carbon tetrachloride (100 ml), cool to 0 ° C and slowly add high iodine Sodium (64.62 g, 302.12 mmol), ruthenium trichloride trihydrate (394.99 mg, 1.51 mmol) was added, and the reaction solution was raised to 25 ° C and stirred for 2 hours. The reaction solution was filtered through diatomaceous earth, and then extracted once with DCM (200 ml).
  • the organic phase was washed once with a saturated aqueous sodium sulfite solution (200 ml), and once with saturated brine (200 ml), dried over anhydrous sodium sulfate, and filtered.
  • the crude compound 1-6 was concentrated under reduced pressure and used directly in the next step.
  • Step F Dissolve compound 1-6 (20 g, 68.18 mmol) and triethylamine (10.35 g, 102.26 mmol, 14.23 ml) in THF (250 ml), and add chloroformic acid dropwise at -10 ° C under nitrogen. Isobutyl ester (9.78 g, 71.59 mmol, 9.40 ml), stirred at minus 10 to 0 degrees Celsius for 30 minutes. Aqueous ammonia (63.70 g, 454.41 mmol, 70 ml, 25%) was then added slowly, and the reaction was stirred at 0 to 5 degrees Celsius for 30 minutes.
  • reaction solution was concentrated under reduced pressure, and then extracted once with ethyl acetate (200 ml), and the organic phase was washed twice with saturated brine, 100 ml each time, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product.
  • Step G Compound 1-7 (15.34 g, 52.47 mmol) and N, N-dimethylformamide dimethyl acetal (134.55 g, 1.13 mol, 150 ml) were stirred at 120 degrees Celsius for 2 hours, minus After concentration under pressure, it was redissolved in acetic acid (250 ml), and hydrazine hydrate (25.75 g, 504.09 mmol, 25 ml, 98%) was slowly added, and stirred at 90 ° C for 2 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure. After adding H 2 O (400 ml), it was extracted twice with DCM, 200 ml each time.
  • H 2 O 400 ml
  • Step H Compound 1-8 (15.20 g, 48.04 mmol) and DIPEA (12.42 g, 96.08 mmol, 16.74 ml) were dissolved in DCM (160 ml), and triphenylchloromethane (20.09 g, 72.06 mmol) was slowly added ), The reaction solution was stirred at 25 degrees Celsius for 2 hours. Add H 2 O (100 ml) to the reaction solution and adjust the pH (7-8) with 2N dilute hydrochloric acid, and extract once with 100 ml of DCM. Wash the organic phase twice with saturated brine, 100 ml each time, and dry. It was dried over sodium sulfate and concentrated under reduced pressure to obtain a crude product.
  • Step I Compound 1-9 (12.75 g, 22.82 mmol) was dissolved in isopropanol (300 ml), and Pd / C (6 g) was added under the protection of nitrogen. The suspension was degassed under vacuum and replaced with hydrogen three times. Stir at 25 degrees Celsius for 16 hours under an atmosphere (15 psi). The reaction solution was filtered through celite and washed with 300 ml of DCM, and the filtrate was concentrated under reduced pressure to obtain the compound 1-10.
  • Step A Compound 1-10 (1.91 g, 4.50 mmol) and compound 1-11 (900 mg, 4.50 mmol) were dissolved in THF (9 ml), and then DIPEA (9.00 mmol, 1.57 ml) was added, and the mixture The reaction was stirred at 70 degrees Celsius for 3 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure to obtain crude compound 1-12.
  • Step B Crude compound 1-12 (3.60 g, 6.12 mmol) and 2,4-dimethoxybenzylamine ((3.01 mg, 18.00 mmol, 2.71 ml) were dissolved in 1,4-dioxane ( 30 ml) and nitrogen protection, and then added DIPEA (8.99 mmol, 1.57 ml), the mixture was stirred at 100 degrees Celsius for 12 hours.
  • the reaction solution was separated by adding water (20 ml) and ethyl acetate (50 ml), and the organic phase was used for separation. It was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product.
  • Step C Compound 1-13 (2.00 g, 2.78 mmol), triethylsilane (970.50 mg, 8.35 mmol, 1.33 ml) were dissolved in TFA (41.81 ml), and the reaction was stirred at 28 degrees Celsius for 12 hours.
  • the reaction solution was directly concentrated under reduced pressure and then subjected to p-HPLC (column: Phenomenex luna C18 250 * 50mm * 10 ⁇ m; flowability: [water (0.05% HCl) -acetonitrile]; acetonitrile%: 10% -40%, 28min, 50% min) to obtain the hydrochloride salt of Example 1.
  • the HEK-Blue TM hTLR7 (article number: hkb-htlr7) and HEK-Blue TM hTLR8 (article number: hkb-htlr8) cell lines used in this experiment were purchased from InvivoGen. These two cell lines were constructed from human embryonic kidney 293 cell line stably co-transfected with hTLR7 or hTLR8 and induced expression of secretory alkaline phosphatase (SEAP) reporter genes, of which secretory embryonic alkaline phosphatase (SEAP) reporter genes Regulated by the IFN- ⁇ promoter.
  • SEAP secretory alkaline phosphatase
  • hTLR7 or hTLR8 agonists activate NF- ⁇ B and AP-1 and induce the expression and secretion of secreted alkaline phosphatase (SEAP).
  • SEAP secreted alkaline phosphatase
  • Compound activity detection Take 20 microliters of the cell supernatant from each well after induction, add it to a cell culture plate containing 180 ⁇ L QUANTI-Blue TM reagent, incubate at 37 ° C for 1 hour, and then test with a multifunctional microplate reader Optical density absorption (OD 650 ) at 650 nm per well.
  • the compounds of the present application exhibit ideal TLR8 agonist activity and have specific selectivity for TLR8 between TLR8 and TLR7.
  • TLR8 is a type of receptor that the innate immune system senses exogenous pathogens. It can recognize foreign virus single-stranded RNA and cause a series of cytokines, such as TNF- ⁇ , IL-12, IFN- ⁇ , to release resistance. Viral immune response; TLR7 is another type of receptor that the innate immune system senses exogenous pathogens. After being activated, it mainly produces antiviral cytokines such as IFN- ⁇ .
  • potential compounds of TLR8 agonists were used to stimulate human peripheral blood mononuclear cells (hPBMC). The levels of TNF- ⁇ , IL-12p40, IFN- ⁇ , and IFN- ⁇ were measured to reflect the activation of TLR8 receptors by the compounds. And TLR8 / TLR7 selectivity.
  • Flow cytometry microarray (CBA) was used to detect IL-12p40, TNF- ⁇ , and IFN- ⁇ in the supernatant; ELISA was used to detect IFN- ⁇ in the cell supernatant.
  • the compounds of the present application have ideal TLR8 pathway-specific cytokines IL-12p40, TNF- ⁇ , and IFN- ⁇ -inducing activity, and relatively low inductive activity on TLR7 pathway-specific cytokine IFN- ⁇ , showing an ideal pair.
  • TLR8 pathway is specifically selective for activation.
  • Intravenous administration The test compound is formulated as a clear solution of 0.5 mg / ml in a vehicle of 5% DMSO / 5% polyethylene glycol-15 hydroxystearate / 90% water; intragastric administration: test compound Formulated as a 2 mg / ml suspension in 0.5% sodium carboxymethyl cellulose / 0.2% Tween 80 / 99.3% water.
  • the concentration of the test compound in plasma was determined by high performance liquid chromatography-tandem mass spectrometry (LC-MS / MS).
  • LC-MS / MS high performance liquid chromatography-tandem mass spectrometry
  • the retention times of compounds and internal standards, chromatogram acquisition, and integration of chromatograms were processed using the software Analyst (Applied BioSystems), and the statistics of the data were processed by software Watson LIMS (Thermo Fisher Scientific) or Analyst (Applied BioSystems).

Abstract

一种TLR8(Toll样受体8)激动剂，结构为式(I)所示化合物、其异构体或其药学上可接受的盐。

Description

TLR8激动剂
本申请要求于2018年09月19日向中华人民共和国国家知识产权局提交的第201811094969.4号中国发明专利申请的权益和优先权，在此将其全部内容以援引的方式整体并入本文中。
技术领域
本申请涉及结构新颖的TLR8(Toll样受体8)激动剂，具体涉及式(I)所示化合物，其异构体或其药学上可接受的盐以及包含所示化合物或其药学上可接受的盐的药用组合物，以及式(I)所示化合物或其药学上可接受的盐和药用组合物在治疗或预防响应于TLR8激动的疾病中的应用。
背景技术
Toll样受体(Toll-like receptors，TLR)是参与非特异性免疫(天然免疫)的一类重要蛋白质分子，也是连接非特异性免疫和特异性免疫的桥梁。TLR是单个的跨膜非催化性蛋白质，主要表达于一系列免疫细胞，如树突细胞、巨噬细胞、单核细胞、T细胞、B细胞、NK细胞等。Toll样受体可以识别来源于微生物的具有保守结构的分子，当微生物突破机体的物理屏障，如皮肤、粘膜等时，TLR可以识别它们并激活机体产生免疫细胞应答。如TLR1、TLR2、TLR4、TLR5和TLR6主要识别胞外的刺激，如细菌的脂多糖，脂肽、鞭毛蛋白等，而TLR3、TLR7、TLR8、和TLR9在细胞内涵体中起作用，吞噬和包膜溶解后结合它们的配体，可识别微生物的核酸等。
在TLR不同亚型中，TLR8具有独特的功能：TLR8主要表达于单核细胞，巨噬细胞和髓样树突细胞中。TLR8的信号通路可以被细菌单链RNA、小分子激动剂和microRNAs活化。激活TLR8后导致产生Th1极性细胞因子，如IL-12、IL-18、TNF-a和IFN-γ和各种共刺激因子如CD80、CD86。这些细胞因子能激活和放大先天免疫和适应性免疫应答，并在涉及抗病毒、抗感染、自身免疫、肿瘤等疾病方面提供有益的治疗方案。例如，关于乙型肝炎，活化肝内抗原呈递细胞和其它免疫细胞上的TLR8可以激活IL-12等细胞因子，从而能激活被病毒耗尽的特异性T细胞和NK细胞，从而重建肝内的抗病毒免疫。
VentiRX制药公司的选择性TLR8激动剂VTX-2337首次在临床上用于不同肿瘤的评价，VTX-2337给药方式为皮下注射。吉利德科学公司报道了可以口服的TLR8激动剂，目前处于临床2期，用于慢性乙肝感染的治疗，但其结构没有公布。
Figure PCTCN2019106687-appb-000001
吉利德科学公司专利WO2016141092报道了一系列TLR8激动剂，如式1，激动TLR8诱导产生特异性细胞因子IL-12p40的AC 50分别为0.02μM(数据引用自WO2016141092表1)，其中AC 50代表半数最大激动效应对应的化合物浓度。专利WO2016141092还报道了含有五元氮杂环的化合物，如式2和式3，但是，式2和式3激动TLR8诱导产生特异性细胞因子IL-12p40的活性不佳，AC 50分别为21.5μM和3.4μM(数据引用自WO2016141092表1)。式1、式2和式3分别为WO2016141092中披露的实施例61、55和56。
Figure PCTCN2019106687-appb-000002
发明内容
本申请提供式(I)所示化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2019106687-appb-000003
其中，
带“*”碳原子可为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；
X选自N和CH；
R 1选自H、F、Cl、Br、I、CN、C 1-6烷基、C 3-6环烷基、-N(R a)(R b)和-O(R c)，所述C 1-6烷基和C 3-6环烷基任选被1、2或3个R d取代；
R 2选自C 1-6烷基，所述C 1-6烷基任选被1、2或3个R e取代；
R a、R b、R c、R d和R e分别独立地选自H、F、Cl、Br、I、OH、CN、NH 2、CH 3、
Figure PCTCN2019106687-appb-000004
Figure PCTCN2019106687-appb-000005
所述CH 3、
Figure PCTCN2019106687-appb-000006
Figure PCTCN2019106687-appb-000007
任选被1、2或3个R取代；
各R独立地选自F、Cl、Br、I、OH、CN、NH 2、CH 3、
Figure PCTCN2019106687-appb-000008
Figure PCTCN2019106687-appb-000009
本申请提供式(I’)所示化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2019106687-appb-000010
其中，
X选自N和CH；
R 1选自H、F、Cl、Br、I、CN、C 1-6烷基、C 3-6环烷基、-N(R a)(R b)和-O(R c)，所述C 1-6烷基和C 3-6环烷基任选被1、2或3个R d取代；
R 2选自C 1-6烷基，所述C 1-6烷基任选被1、2或3个R e取代；
R a、R b、R c、R d和R e分别独立地选自H、F、Cl、Br、I、OH、CN、NH 2、CH 3、
Figure PCTCN2019106687-appb-000011
Figure PCTCN2019106687-appb-000012
所述CH 3、
Figure PCTCN2019106687-appb-000013
Figure PCTCN2019106687-appb-000014
任选被1、2或3个R取代；
各R独立地选自F、Cl、Br、I、OH、CN、NH 2、CH 3、
Figure PCTCN2019106687-appb-000015
Figure PCTCN2019106687-appb-000016
在本申请的一些方案中，上述R a、R b、R c、R d和R e分别独立地选自H、F、Cl、Br、I、OH、CN、NH 2、CH 3、
Figure PCTCN2019106687-appb-000017
Figure PCTCN2019106687-appb-000018
在本申请的一些方案中，上述R 1选自H、F、Cl、Br、I、CN、CH 3、
Figure PCTCN2019106687-appb-000019
环戊基、环丁基、
Figure PCTCN2019106687-appb-000020
NH 2、
Figure PCTCN2019106687-appb-000021
所述CH 3、
Figure PCTCN2019106687-appb-000022
环戊基和环丁基任选被1、2或3个R d取代。
在本申请的一些方案中，上述R 1选自H、F、Cl、Br、I、CH 3和
Figure PCTCN2019106687-appb-000023
在本申请的一些方案中，上述R 2选自
Figure PCTCN2019106687-appb-000024
所述
Figure PCTCN2019106687-appb-000025
Figure PCTCN2019106687-appb-000026
任选被1、2或3个R e取代。
在本申请的一些方案中，上述R 2选自
Figure PCTCN2019106687-appb-000027
本申请还提供下式化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2019106687-appb-000028
在本申请的一些方案中，上述化合物、其异构体或其药学上可接受的盐，选自
Figure PCTCN2019106687-appb-000029
在本申请的一些方案中，上述R a、R b、R c、R d和R e分别独立地选自H、F、Cl、Br、I、OH、CN、NH 2、CH 3、
Figure PCTCN2019106687-appb-000030
Figure PCTCN2019106687-appb-000031
其他变量如上述所定义。
在本申请的一些方案中，上述R 1选自H、F、Cl、Br、I、CN、CH 3、
Figure PCTCN2019106687-appb-000032
环戊基、环丁基、
Figure PCTCN2019106687-appb-000033
NH 2、
Figure PCTCN2019106687-appb-000034
所述CH 3、
Figure PCTCN2019106687-appb-000035
环戊基和环丁基任选被1、2或3个R d取代。
在本申请的一些方案中，上述R 1选自H、F、Cl、Br、I、CH 3和
Figure PCTCN2019106687-appb-000036
其他变量如上述所定义。
在本申请的一些方案中，上述R 2选自
Figure PCTCN2019106687-appb-000037
所述
Figure PCTCN2019106687-appb-000038
Figure PCTCN2019106687-appb-000039
任选被1、2或3个R e取代，其他变量如上述所定义。
在本申请的一些方案中，上述R 2选自
Figure PCTCN2019106687-appb-000040
其他变量如上述所定义。
本申请还有一些方案是由上述各变量任意组合而来。
另一方面，本申请提供药物组合物，其包含本申请的化合物、其异构体或其药学上可接受的盐。在一些实施方案中，本申请的药物组合物还包括药学上可接受的辅料。
另一方面，本申请提供激动TLR8的方法，包括对需要的个体施用(优选人类)给予治疗有效量的本申请的化合物、其异构体、其药学上可接受的盐、或其药物组合物。
另一方面，本申请提供治疗或预防响应于TLR8激动的疾病的方法，包括对需要的个体施用(优选人类)给予治疗有效量的本申请的化合物、其异构体、其药学上可接受的盐、或其药物组合物。
另一方面，本申请提供本申请的化合物、其异构体、其药学上可接受的盐、或其药物组合物在制备治疗或预防响应于TLR8激动的疾病的药物中的用途。
另一方面，本申请提供本申请的化合物、其异构体、其药学上可接受的盐、或其药物组合物在治疗或预防响应于TLR8激动的疾病中的用途。
另一方面，本申请提供用于治疗或预防响应于TLR8激动的疾病的本申请的化合物、其异构体、其药学上可接受的盐、或其药物组合物。
在本申请的一些方案中，所述响应于TLR8激动的疾病选自病毒感染。
在本申请的一些方案中，所述病毒感染选自乙型肝炎病毒(HBV)感染。
技术效果
本申请化合物对TLR8有显著的激动活性。本申请的化合物展示出理想的TLR8激动活性和特异选择性。本申请化合物展示出理想的TLR8通路特异性细胞因子(IL-12p40、IFN-γ)诱导活性。小鼠药代动力学研究显示，本申请的化合物具有中等的口服生物利用度和药物曝露量，支持口服给药。TLR8激动剂属于免疫调节剂，过高的曝露量可能会导致机体免疫过度激活，从而产生不可预见的副作用。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。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。
这里所采用的术语“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“药学上可接受的盐”是指本申请化合物的盐，由本申请发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本申请的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。当本申请的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐、或有机酸盐
本申请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。
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，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，指乙基可以是未被取代的(CH 2CH 3)、单取代的(如CH 2CH 2F)、多取代的(如CHFCH 2F、CH 2CHF 2等)或完全被取代的(CF 2CF 3)。本领域技术人员可理解，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。本领域技术人员可理解，当被多个取代基取代时，所述取代基的个数可以是2、3、4、5或更多个，直到可发生取代的位点全被取代，例如，当乙基被多个F原子取代时，可发生2个、3个、4个或5个F原子取代。
本文中的“C m-n”，是该部分具有给定范围中的整数个碳原子。例如“C 1-6”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子。
本申请的化合物可以存在特定的几何或立体异构体形式。本申请设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本申请的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本申请的范围之内。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(D)”或者“(+)”表示右旋，“(L)”或者“(-)”表示左旋，“(DL)”或者“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2019106687-appb-000041
和楔形虚线键
Figure PCTCN2019106687-appb-000042
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2019106687-appb-000043
和直形虚线键
Figure PCTCN2019106687-appb-000044
表示立体中心的相对构型，用波浪线
Figure PCTCN2019106687-appb-000045
表示楔形实线键
Figure PCTCN2019106687-appb-000046
或楔形虚线键
Figure PCTCN2019106687-appb-000047
或用波浪线
Figure PCTCN2019106687-appb-000048
表示直形实线键
Figure PCTCN2019106687-appb-000049
和直形虚线键
Figure PCTCN2019106687-appb-000050
本申请的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
本申请所述“异构体”包括立体异构体、顺反异构体、互变异构体。
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本申请某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然 后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本申请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)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本申请的化合物的所有同位素组成的变换，无论放射性与否，都包括在本申请的范围之内。“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，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。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
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“C 1-6烷基”用于表示直链或支链的包含1至6个碳原子的饱和碳氢基团。所述C 1- 6烷基包括C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6和C 5烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-6烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)、戊基(包括n-戊基，异戊基和新戊基)、己基等。
除非另有规定，“C 3-6环烷基”表示由3至6个碳原子组成的饱和环状碳氢基团，其为单环和双环体系，所述C 3-6环烷基包括C 3-5、C 4-5和C 5-6环烷基等；其可以是一价、二价或者多价。C 3-6环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基等。
术语“药物组合物”是指一种或多种本申请的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。
术语“药学上可接受的辅料”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辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
术语“治疗”意为将本申请所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)抑制疾病或疾病状态，即遏制其发展；
(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“治疗有效量”意指(i)治疗特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状 态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“预防”意为将本申请所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，且包括：预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。
本申请采用下述缩略词：
Pd/C Pd/C催化剂，钯含量10w％
DCM 二氯甲烷
THF 四氢呋喃
Boc 叔丁氧羰基，是一种胺保护基团
Cbz 苄氧羰基，是一种胺保护基团
DMF N,N-二甲基甲酰胺
TFA 三氟乙酸
PE 石油醚
DMSO 二甲亚砜
EtOH 乙醇
MeOH 甲醇
HOAc 乙酸
Trt 三苯甲基
CbzCl 氯甲酸苄酯
DIPEA 二异丙基乙基胺
SiO 2 100-200目硅胶粉，用于柱层析
psi 磅力/平方英寸，压力单位
p-HPLC 制备高效液相色谱，用于化合物的纯化
本申请所使用的溶剂可经市售获得且不需要进一步纯化。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高场处的(ppm)表示。质谱是在安捷伦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)。
用配有Shimadzu SIL-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2.1×300mm)色谱柱。
具体实施方式
下面通过实施例对本申请进行详细描述，但并不意味着对本申请任何不利限制。本文已经详细地描述了本申请，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本申请精神和范围的情况下针对本申请具体实施方式进行各种变化和改进将是显而易见的。
实施例1
Figure PCTCN2019106687-appb-000051
中间体化合物1-10的制备：
Figure PCTCN2019106687-appb-000052
步骤A:20-30摄氏度将化合物1-1(50克，412.54毫摩尔)和钛酸四乙酯(94.10克，412.54毫摩尔，85.55毫升)溶于THF(500毫升)，再加入2-己酮(41.32克，412.54毫摩尔，51.01毫升)。将反应液升温至65摄氏度搅拌48小时，所得反应液直接用于下一步。
步骤B:将步骤A反应液冷却至室温补加THF(1000毫升)，再加入烯丙基溴(196.33克，1.62摩尔)，然后分批缓慢加入锌粉(53.06克，811.43毫摩尔)，反应液在氮气保护下于20-30摄氏度搅拌12小时。反应液通过硅藻土过滤，滤液加饱和食盐水100毫升，搅拌后再次通过硅藻土过滤，滤液旋干。残余物用乙酸乙酯(100毫升)溶解，分出的有机相用饱和食盐水(300毫升)洗涤一次，无水硫酸钠干燥，过滤减压浓缩得粗品。粗品经柱层析(SiO 2，PE/EtOAc＝15/1至5/1)纯化后得化合物1-3。 1H NMR(400MHz，CDCl 3)δ5.96-5.75(m，1H)，5.23-5.08(m，2H)，3.20(s，1H)，2.39-2.20(m，2H)，1.74(br s，1H)，1.56-1.42(m，2H)，1.40-1.15(m，14H)，0.96-0.86(m，3H)。
步骤C:将化合物1-3(15克，61.12毫摩尔)溶于甲醇(150毫升)并冷却至0摄氏度，将盐酸二氧六环溶液(4M，91.68毫升)在0至20摄氏度下缓慢加入，反应液在25摄氏度搅拌2小时。将反应液直接 减压浓缩得化合物1-4。
步骤D:将化合物1-4(盐酸盐，13克，73.15毫摩尔)和碳酸氢钠(55.31克，658.36毫摩尔)溶于二氧六环(90毫升)和H 2O(60毫升)，冷却至0摄氏度后缓慢滴加CbzCl(74.87克，438.91毫摩尔，62.40毫升)。反应液升温到20至30摄氏度搅拌2小时，用乙酸乙酯萃取两次，每次100毫升，合并有机相，并用饱和食盐水(150毫升)洗涤一次，无水硫酸钠干燥，过滤减压浓缩得粗品。粗品经柱层析(SiO 2，PE/EtOAc＝1/0至100/1)纯化后得化合物1-5。 1H NMR(400MHz，CDCl 3)δ7.30-7.26(m，5H)，5.76-5.62(m，1H)，5.08-4.91(m，4H)，2.47-2.34(m，1H)，2.32-2.20(m，1H)，1.72-1.57(m，1H)，1.50-1.42(m，1H)，1.30-1.10(m，7H)，0.76-0.76(m，1H)，0.76-0.76(m，1H)，0.82(t，J＝7.0Hz，2H)。
步骤E:将化合物1-5(20.8克，75.53毫摩尔)溶于乙腈(100毫升)，H 2O(150毫升)和四氯化碳(100毫升)中，冷却至0摄氏度缓慢加入高碘酸钠(64.62克，302.12毫摩尔)，再加入三水合三氯化钌(394.99毫克，1.51毫摩尔)，反应液升至25摄氏度搅拌2小时。反应液通过硅藻土过滤，然后用DCM(200毫升)萃取一次，有机相用饱和亚硫酸钠水溶液(200毫升)洗涤一次，再用饱和食盐水(200毫升)洗涤一次，无水硫酸钠干燥，过滤减压浓缩得粗品化合物1-6直接用于下一步。 1H NMR(400MHz，CDCl 3)δ7.40-7.35(m，5H)，5.19(s，1H)，5.08(s，2H)，2.89(br d，J＝14.5Hz，1H)，2.69(br d，J＝14.4Hz，1H)，1.90-1.77(m，1H)，1.74-1.62(m，1H)，1.43-1.20(m，7H)，0.90(t，J＝6.9Hz，3H)。
步骤F:将化合物1-6(20克，68.18毫摩尔)和三乙胺(10.35克，102.26毫摩尔，14.23毫升)溶于THF(250毫升)，氮气保护下于零下10摄氏度滴加氯甲酸异丁酯(9.78克，71.59毫摩尔，9.40毫升)，零下10至0摄氏度搅拌30分钟。随后将氨水(63.70克，454.41毫摩尔，70毫升，25％)缓慢加入，反应在0至5摄氏度下搅拌30分钟。反应液减压浓缩，然后用乙酸乙酯(200毫升)萃取一次，有机相用饱和食盐水洗涤两次，每次100毫升，无水硫酸钠干燥，过滤减压浓缩得粗品。粗品经柱层析(SiO 2，PE/EtOAc＝10/1至1/1)纯化后得化合物1-7。 1H NMR(400MHz，CDCl 3)δ7.41-7.28(m，5H)，5.62(br s，1H)，5.30-5.12(m，2H)，5.11-5.01(m，2H)，2.76(d，J＝13.2Hz，1H)，2.44(d，J＝13.3Hz，1H)，1.85-1.74(m，1H)，1.73-1.62(m，3H)，1.39-1.29(m，5H)，0.90(t，J＝7.0Hz，3H)。LCMS(ESI)m/z:293.3[M+H] +。
步骤G:将化合物1-7(15.34克，52.47毫摩尔)和N,N-二甲基甲酰胺二甲基缩醛(134.55克，1.13摩尔，150毫升)在120摄氏度下搅拌2小时，减压浓缩后再溶于乙酸(250毫升)中，缓慢加入水合肼(25.75克，504.09毫摩尔，25毫升，98％)，氮气保护下90摄氏度搅拌2小时。反应液减压浓缩，加H 2O(400毫升)后用DCM萃取两次，每次200毫升，合并有机相用饱和食盐水洗涤两次，每次200毫升，无水硫酸钠干燥，过滤减压浓缩得粗品化合物1-8。 1H NMR(400MHz，CDCl 3)δ7.95(s，1H)，7.43-7.29(m，5H)，5.08(s，2H)，4.90(br s，1H)，3.42(br d，J＝13.9Hz，1H)，3.12(d，J＝14.3Hz，1H)，1.87-1.77(m，1H)，1.68-1.58(m，1H)，1.41-1.17(m，7H)，0.90(br t，J＝6.5Hz，3H)。LCMS(ESI)m/z:317.2[M+H] +。
步骤H:化合物1-8(15.20克，48.04毫摩尔)和DIPEA(12.42克，96.08毫摩尔，16.74毫升)溶于DCM(160毫升)，缓慢加入三苯基氯甲烷(20.09克，72.06毫摩尔)，反应液在25摄氏度搅拌2小时。向反应液中加H 2O(100毫升)并用2N的稀盐酸调节pH(7～8)，再用100毫升DCM萃取一次，有机相 用饱和食盐水洗涤两次，每次100毫升，无水硫酸钠干燥，过滤减压浓缩得粗品。粗品经柱层析(SiO 2，PE/EtOAc＝20/1至5/1)纯化后得化合物1-9。 1H NMR(400MHz，CDCl 3)δ7.89(s，1H)，7.37-7.27(m，14H)，7.18-7.07(m，6H)，5.72(br s，1H)，5.16-4.93(m，2H)，3.07(d，J＝14.2Hz，1H)，2.90(d，J＝14.2Hz，1H)，1.80-1.61(m，4H)，1.33(s，3H)，0.90-0.84(m，3H)。LCMS(ESI)m/z:559.3[M+H] +。
步骤I:将化合物1-9(12.75克，22.82毫摩尔)溶于异丙醇(300毫升)，氮气保护下加入Pd/C(6克)，悬浮液经真空脱气并用氢气置换三次，氢气氛围(15psi)下于25摄氏度搅拌16小时。反应液经硅藻土过滤，并用300毫升DCM洗涤，滤液减压浓缩所得化合物1-10。 1H NMR(400MHz，CDCl 3)δ7.91(s，1H)，7.37-7.28(m，9H)，7.17-7.11(m，6H)，2.87(s，2H)，1.45-1.24(m，6H)，1.12(s，3H)，0.92-0.84(m，3H)。LCMS(ESI)m/z:425.2[M+H] +。
实施例1的合成：
Figure PCTCN2019106687-appb-000053
步骤A:将化合物1-10(1.91克,4.50毫摩尔)和化合物1-11(900毫克,4.50毫摩尔)溶于THF(9毫升)，再加入DIPEA(9.00毫摩尔,1.57毫升)，混合物在氮气保护下于70摄氏度搅拌反应3小时。反应液减压浓缩得到粗品化合物1-12。LCMS(ESI)m/z:588.42[M+H] +。
步骤B：粗品化合物1-12(3.60克,6.12毫摩尔)和2,4-二甲氧基苄胺((3.01毫克,18.00毫摩尔,2.71毫升)溶于1,4-二氧六环(30毫升)并氮气保护，再加入DIPEA(8.99毫摩尔,1.57毫升)，混合物在100摄氏度下搅拌反应12小时。反应液加水(20毫升)和乙酸乙酯(50毫升)分液，有机相用饱和食盐水(20毫升)洗涤，无水硫酸钠干燥，过滤后减压浓缩得粗品。粗品经硅胶柱色谱(SiO 2，DCM/MeOH＝100/1至15/1)纯化后得化合物1-13。LCMS(ESI)m/z:719.7[M+H] +。
步骤C:化合物化合物1-13(2.00克,2.78毫摩尔)、三乙基硅烷(970.50毫克,8.35毫摩尔,1.33毫升)溶于TFA(41.81毫升)中后在28摄氏度搅拌反应12小时。反应液直接减压浓缩后经p-HPLC(柱子:Phenomenex luna C18 250*50mm*10μm；流动性:[水(0.05％HCl)-乙腈]；乙腈％:10％-40％,28min,50％min)纯化，得到实施例1的盐酸盐。 1H NMR(400MHz,CD 3OD)δ9.15(s,1H),8.90(s,1H),8.59(d,J＝5.6Hz,1H),8.26(d,J＝5.5Hz,1H),4.11(d,J＝14.8Hz,1H),3.53(d,J＝14.9Hz,1H),2.60(dt,J＝4.1,12.8Hz,1H),1.79(dt,J＝4.2,12.8Hz,1H),1.58(s,3H),1.52-1.19(m,4H),0.92(t,J＝7.2Hz,3H)。LCMS(ESI)m/z:327.1 [M+H] +。
实验例1：人Toll样受体7(TLR7)和人Toll样受体8(TLR8)体外受体结合活性筛选实验
本实验所用的HEK-Blue TM hTLR7(货号：hkb-htlr7)和HEK-Blue TM hTLR8(货号：hkb-htlr8)细胞株购于InvivoGen公司。这两个细胞株由人胚肾293细胞系稳定共转染hTLR7或hTLR8和诱导表达分泌型碱性磷酸酶(SEAP)报告基因所构建的，其中分泌型胚胎碱性磷酸酶(SEAP)报告基因由IFN-β启动子调控。该启动子与NF-κB和AP-1结合位点融合，hTLR7或hTLR8激动剂会激活NF-κB和AP-1，并诱导分泌型碱性磷酸酶(SEAP)的表达和分泌。用QUANTI-Blue TM试剂检测SEAP表达量，以此来鉴定化合物对hTLR7和hTLR8受体的激动活性。
实验步骤：
1.化合物按3倍梯度加入到细胞板中，终浓度依次为5000nM，1667nM，556nM，185nM，62nM，21nM，6.9nM，2.3nM，0.76nM，0.25nM，每个浓度双复孔。阴性对照孔每孔加入1微升DMSO。
2.从CO 2培养箱取出T150培养的细胞，弃去细胞培养上清，用杜氏磷酸盐缓冲液(DPBS)清洗细胞一次，加入约10mL培养液，然后轻拍细胞培养瓶使细胞脱壁，然后用移液器将细胞团轻轻吹打均匀。细胞计数，并将细胞悬液用培养液调整到500000细胞/毫升。然后在含有化合物的96孔板中每孔加入100微升稀释后的细胞(50000细胞/孔)。
3.将化合物和细胞在37℃、5％CO 2培养箱共孵育24小时。
4.化合物活性检测：取20微升诱导后每个孔的细胞上清液，加入到含有180μL QUANTI-Blue TM试剂的细胞培养板中，37℃孵育1小时之后，用多功能酶标仪检测每孔在650纳米的光密度吸收值(OD 650)。
5.细胞活性检测：按照ATPlite 1Step说明书方法操作，荧光素酶信号(RLU)用多功能酶标仪检测。
6.数据分析：化合物活性：OD 650值用GraphPad Prism软件分析，并拟合化合物剂量效应曲线，计算化合物的EC 50值(半数最大效应浓度)。
实验结果：如表1所示。
表1
受试化合物 人TLR8 EC 50(μM) 人TLR7 EC 50(μM)
实施例1的盐酸盐 0.003 33.33
结论：本申请化合物展示出理想的TLR8激动剂活性，且在TLR8和TLR7之间的具有TLR8的特异选择性。
实验例2：外周血单个核细胞实验方案
TLR8是固有免疫系统感受外源性的病原体的一类受体，能够识别外源的病毒单链RNA，引起一系列细胞因子，如TNF-α，IL-12，IFN-γ的释放以引起抗病毒免疫反应；TLR7是另外一类固有免疫系统感受外源性的病原体的一类受体，被激活后主要产生IFN-α等抗病毒细胞因子。本实验使用TLR8激动剂的潜在化合物刺激人外周血单个核细胞(hPBMC)，通过检测上述TNF-α，IL-12p40，IFN-γ和IFN-α的水平来 反映化合物对TLR8受体的活化作用和TLR8/TLR7的选择性。
实验步骤：
1.采集健康志愿者新鲜血液，EDTA-K2抗凝管(货号：BD-8516542)抗凝；
2.Ficoll密度梯度离心，分离中间云雾层的hPBMC细胞，含10％血清的RPMI1640(来源：Gibco，货号：224400-089)培养液洗2次，培养液重悬至10mL，Vi-cell细胞计数仪计数，调整细胞悬液浓度至2×10 6/mL；
3.用DMSO将化合物溶解至100mM，并分别用DMSO稀释至50mM,2mM，分别作为初始浓度，依次做3倍稀释，即取前一浓度样本5μL+10μLDMSO；稀释8个梯度；再分别用培养基稀释500倍，配成化合物工作液；
4.U底96孔板中，每孔加入hPBMC悬液100μL，以及化合物工作液100μL，终浓度依次为2000nM，666.7nM，222.2nM，74.1nM，24.7nM，8.2nM，2.7nM，0.9nM，孵育24小时，收上清-20℃冻存，待检测TNF-α，IFN-gamma，IL-12p40细胞因子；另一组化合物样本终浓度依次为50μM，16.7μM，5.6μM，1.9μM，0.6μM，0.2μM，0.1μM，0.02μM，孵育24小时，收上清-20℃冻存，待检测IFN-alpha细胞因子；
5.流式细胞小球微阵列术(CBA)检测上清中IL-12p40，TNF-α，IFN-γ；酶联免疫法(ELISA)检测细胞上清中IFN-α。
6.数据分析：化合物活性：EC 50值(半数最大效应浓度)用GraphPad Prism软件分析，并拟合化合物剂量效应曲线，计算化合物的EC 50值。
实验结果：如表2所示。
表2
Figure PCTCN2019106687-appb-000054
结论：本申请化合物具有理想的TLR8通路特异性细胞因子IL-12p40，TNF-α和IFN-γ诱导活性，对TLR7通路特异性细胞因子IFN-α的诱导活性相对较低，展示出理想的对TLR8通路激动特异选择性。
实验例3：小鼠药物代谢动力学研究
本实验旨在评价化合物在小鼠体内单次静脉注射或灌胃给药后的药代动力学行为。静脉注射给药：受试化合物配制成0.5毫克/毫升的澄清溶液，溶媒为5％DMSO/5％聚乙二醇-15羟基硬脂酸酯/90％水；灌胃给药：受试化合物配制成2毫克/毫升的混悬液，溶媒为0.5％羧甲基纤维素钠/0.2％吐温80/99.3％水。
受试化合物在血浆中的浓度由高效液相色谱-串联质谱(LC-MS/MS)进行测定。化合物和内标的保留时间、色谱图采集和色谱图的积分采用软件Analyst(Applied Biosystems)进行处理，数据的统计采用软件Watson LIMS(Thermo Fisher Scientific)或Analyst(Applied Biosystems)进行处理。
采用WinNonlin TM Version 6.3(Pharsight，Mountain View，CA)药动学软件的非房室模型处理血浆浓度，使用线性对数梯形法方法计算药动学参数。
实施例1的盐酸盐分别在静脉注射给药1mg/Kg和口服灌胃给药5mg/Kg剂量下的小鼠药代动力学相关参数如下表3所示。
表3 小鼠药代动力学相关参数
Figure PCTCN2019106687-appb-000055

Claims (13)

  1. 式(I)所示化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2019106687-appb-100001
    其中，
    带“*”碳原子可为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；
    X选自N和CH；
    R 1选自H、F、Cl、Br、I、CN、C 1-6烷基、C 3-6环烷基、-N(R a)(R b)和-O(R c)，所述C 1-6烷基和C 3-6环烷基任选被1、2或3个R d取代；
    R 2选自C 1-6烷基，所述C 1-6烷基任选被1、2或3个R e取代；
    R a、R b、R c、R d和R e分别独立地选自H、F、Cl、Br、I、OH、CN、NH 2、CH 3、
    Figure PCTCN2019106687-appb-100002
    Figure PCTCN2019106687-appb-100003
    所述CH 3、
    Figure PCTCN2019106687-appb-100004
    Figure PCTCN2019106687-appb-100005
    任选被1、2或3个R取代；
    各R独立地选自F、Cl、Br、I、OH、CN、NH 2、CH 3、
    Figure PCTCN2019106687-appb-100006
    Figure PCTCN2019106687-appb-100007
  2. 根据权利要求1所述的化合物、其异构体或其药学上可接受的盐，其中R a、R b、R c、R d和R e分别独立地选自H、F、Cl、Br、I、OH、CN、NH 2、CH 3、
    Figure PCTCN2019106687-appb-100008
    Figure PCTCN2019106687-appb-100009
  3. 根据权利要求1或2所述的化合物、其异构体或其药学上可接受的盐，其中，R 1选自H、F、Cl、Br、I、CN、CH 3、
    Figure PCTCN2019106687-appb-100010
    环戊基、环丁基、
    Figure PCTCN2019106687-appb-100011
    NH 2、
    Figure PCTCN2019106687-appb-100012
    所述CH 3、
    Figure PCTCN2019106687-appb-100013
    环戊基和环丁基任选被1、2或3个R d取代。
  4. 根据权利要求1或2所述的化合物、其异构体或其药学上可接受的盐，其中，R 1选自H、F、Cl、Br、 I、CH 3和
    Figure PCTCN2019106687-appb-100014
  5. 根据权利要求1或2所述的化合物、其异构体或其药学上可接受的盐，其中，R 2选自
    Figure PCTCN2019106687-appb-100015
    Figure PCTCN2019106687-appb-100016
    所述
    Figure PCTCN2019106687-appb-100017
    任选被1、2或3个R e取代。
  6. 根据权利要求5所述的化合物、其异构体或其药学上可接受的盐，其中，R 2选自
    Figure PCTCN2019106687-appb-100018
  7. 下式化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2019106687-appb-100019
  8. 根据权利要求7所述的化合物、其异构体或其药学上可接受的盐，选自
    Figure PCTCN2019106687-appb-100020
  9. 药物组合物，其包含如权利要求1-8任一项所述的化合物、其异构体或其药学上可接受的盐。
  10. 激动TLR8的方法，包括对需要的个体施用给予治疗有效量的如权利要求1-8任一项所述的化合物、其异构体、其药学上可接受的盐、或其药物组合物。
  11. 治疗响应于TLR8激动的疾病的方法，包括对需要的个体施用给予治疗有效量的如权利要求1-8任一项所述的化合物、其异构体、其药学上可接受的盐、或其药物组合物。
  12. 根据权利要求11所述的方法，其中所述响应于TLR8激动的疾病选自病毒感染。
  13. 根据权利要求12所述的方法，其中所述病毒感染选自乙型肝炎病毒感染。
PCT/CN2019/106687 2018-09-19 2019-09-19 Tlr8激动剂 WO2020057604A1 (zh)

Priority Applications (10)

Application Number Priority Date Filing Date Title
KR1020217011377A KR20210060567A (ko) 2018-09-19 2019-09-19 Tlr8 아고니스트
AU2019344868A AU2019344868A1 (en) 2018-09-19 2019-09-19 TLR8 agonist
CA3112953A CA3112953A1 (en) 2018-09-19 2019-09-19 Tlr8 agonist
JP2021515104A JP2022501350A (ja) 2018-09-19 2019-09-19 Ｔｌｒ８アゴニスト
US17/276,920 US20210371414A1 (en) 2018-09-19 2019-09-19 Tlr8 agonist
CN201980052513.8A CN112805283B (zh) 2018-09-19 2019-09-19 Tlr8激动剂
EP19862693.9A EP3854794A4 (en) 2018-09-19 2019-09-19 TLR8 AGONIST
SG11202102641RA SG11202102641RA (en) 2018-09-19 2019-09-19 Tlr8 agonist
CN202211301510.3A CN115650979A (zh) 2018-09-19 2019-09-19 Tlr8激动剂
PH12021550601A PH12021550601A1 (en) 2018-09-19 2021-03-17 Tlr8 agonist

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201811094969.4 2018-09-19
CN201811094969 2018-09-19

Publications (1)

Publication Number Publication Date
WO2020057604A1 true WO2020057604A1 (zh) 2020-03-26

Family

ID=69888288

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/106687 WO2020057604A1 (zh) 2018-09-19 2019-09-19 Tlr8激动剂

Country Status (10)

Country Link
US (1) US20210371414A1 (zh)
EP (1) EP3854794A4 (zh)
JP (1) JP2022501350A (zh)
KR (1) KR20210060567A (zh)
CN (2) CN115650979A (zh)
AU (1) AU2019344868A1 (zh)
CA (1) CA3112953A1 (zh)
PH (1) PH12021550601A1 (zh)
SG (1) SG11202102641RA (zh)
WO (1) WO2020057604A1 (zh)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021185312A1 (zh) * 2020-03-18 2021-09-23 正大天晴药业集团股份有限公司 一种tlr8激动剂晶型
WO2023078241A1 (zh) * 2021-11-05 2023-05-11 中国医药研究开发中心有限公司 芳胺类衍生物及其制备方法和医药用途

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102015651A (zh) * 2008-03-03 2011-04-13 Irm责任有限公司 作为tlr活性调节剂的化合物和组合物
CN103748081A (zh) * 2011-05-18 2014-04-23 爱尔兰詹森研发公司 用于治疗病毒感染和另外的疾病的喹唑啉衍生物
WO2016141092A1 (en) 2015-03-04 2016-09-09 Gilead Sciences, Inc. Toll-like receptor modulating 4,6-diamino-pyrido[3,2-d]pyrimidine compounds
WO2018045150A1 (en) * 2016-09-02 2018-03-08 Gilead Sciences, Inc. 4,6-diamino-pyrido[3,2-d]pyrimidine derivaties as toll like receptor modulators

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT3507276T (pt) * 2016-09-02 2022-01-11 Gilead Sciences Inc Compostos moduladores do recetor de tipo toll

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102015651A (zh) * 2008-03-03 2011-04-13 Irm责任有限公司 作为tlr活性调节剂的化合物和组合物
CN103748081A (zh) * 2011-05-18 2014-04-23 爱尔兰詹森研发公司 用于治疗病毒感染和另外的疾病的喹唑啉衍生物
WO2016141092A1 (en) 2015-03-04 2016-09-09 Gilead Sciences, Inc. Toll-like receptor modulating 4,6-diamino-pyrido[3,2-d]pyrimidine compounds
CN107108615A (zh) * 2015-03-04 2017-08-29 吉利德科学公司 Toll样受体调节性4,6‑二氨基‑吡啶并[3,2‑D]嘧啶化合物
WO2018045150A1 (en) * 2016-09-02 2018-03-08 Gilead Sciences, Inc. 4,6-diamino-pyrido[3,2-d]pyrimidine derivaties as toll like receptor modulators

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3854794A4

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021185312A1 (zh) * 2020-03-18 2021-09-23 正大天晴药业集团股份有限公司 一种tlr8激动剂晶型
WO2023078241A1 (zh) * 2021-11-05 2023-05-11 中国医药研究开发中心有限公司 芳胺类衍生物及其制备方法和医药用途

Also Published As

Publication number Publication date
EP3854794A4 (en) 2022-06-15
KR20210060567A (ko) 2021-05-26
SG11202102641RA (en) 2021-04-29
JP2022501350A (ja) 2022-01-06
CA3112953A1 (en) 2020-03-26
CN112805283A (zh) 2021-05-14
PH12021550601A1 (en) 2021-11-29
AU2019344868A1 (en) 2021-04-15
EP3854794A1 (en) 2021-07-28
CN115650979A (zh) 2023-01-31
US20210371414A1 (en) 2021-12-02
CN112805283B (zh) 2022-09-20

Similar Documents

Publication Publication Date Title
US10370338B2 (en) Benzazepine dicarboxamide compounds with tertiary amide function
CN111225896B (zh) 免疫调节剂化合物
CN109311851B (zh) 二氢嘧啶基苯并氮杂䓬甲酰胺化合物
CN109369640B (zh) 一种二氢异喹啉类化合物的制备方法
JP6367366B2 (ja) ４−アミノ−イミダゾキノリン化合物
JP2020531448A (ja) 新規なスルホンアミドカルボキサミド化合物
CN111225665A (zh) 大环免疫调节剂
TW202014400A (zh) 多環型胺甲醯基吡啶酮化合物之合成
CN108250121A (zh) 磺酰胺-芳基酰胺类化合物及其治疗乙型肝炎的药物用途
CN114555080A (zh) 用于治疗pd-l1疾病的杂芳基联苯胺
KR102354082B1 (ko) 기생충 질환, 예컨대 리슈마니아증을 치료하기 위한 원충 프로테아솜 억제제로서의 [1,2,4]트리아졸로[1,5-a]피리미딘 유도체
CN112805283B (zh) Tlr8激动剂
WO2022213980A1 (zh) Tyk2抑制剂及其用途
WO2019096241A1 (zh) 抗HBV的四氢异噁唑并[4,3-c]吡啶类化合物
JP2023145644A (ja) ジヒドロイソキノリン系化合物
CN112839929B (zh) Tlr8激动剂
WO2023160572A1 (zh) 吡唑类衍生物、药物组合物及应用
KR20170048596A (ko) 거대고리 rip2 키나아제 억제제
RU2800877C2 (ru) Агонист tlr8
CN111971285A (zh) 咪唑并吡咯酮化合物及其应用
CN114790164B (zh) 一种取代的异吲哚啉-1,3-二酮类pde4抑制剂及其药物用途
WO2021185312A1 (zh) 一种tlr8激动剂晶型
CN111747927B (zh) 作为免疫调节剂的化合物及其应用
WO2023051749A1 (zh) Aak1抑制剂及其用途
TW202413366A (zh) 含氮雜環化合物作為泛素－特異性蛋白酶１抑制劑的製備方法、應用及其用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19862693

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3112953

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2021515104

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2019344868

Country of ref document: AU

Date of ref document: 20190919

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 20217011377

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2019862693

Country of ref document: EP

Effective date: 20210419