WO2021093779A1 - 咪唑并喹啉取代磷酸酯类激动剂及其制备方法和应用 - Google Patents

咪唑并喹啉取代磷酸酯类激动剂及其制备方法和应用 Download PDF

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WO2021093779A1
WO2021093779A1 PCT/CN2020/128168 CN2020128168W WO2021093779A1 WO 2021093779 A1 WO2021093779 A1 WO 2021093779A1 CN 2020128168 W CN2020128168 W CN 2020128168W WO 2021093779 A1 WO2021093779 A1 WO 2021093779A1
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alkyl
alkoxy
halogenated
deuterated
group
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PCT/CN2020/128168
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English (en)
French (fr)
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吕彬华
崔大为
柴传柯
刘瑞峰
盛泽林
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苏州泽璟生物制药股份有限公司
上海泽璟医药技术有限公司
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Priority to AU2020384162A priority Critical patent/AU2020384162B2/en
Priority to JP2022552995A priority patent/JP7470809B2/ja
Priority to EP20888307.4A priority patent/EP4059938A4/en
Priority to US17/755,877 priority patent/US20230008368A1/en
Priority to CA3157877A priority patent/CA3157877A1/en
Priority to KR1020227019857A priority patent/KR20220098221A/ko
Publication of WO2021093779A1 publication Critical patent/WO2021093779A1/zh

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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • A—HUMAN NECESSITIES
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
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    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/688—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols both hydroxy compounds having nitrogen atoms, e.g. sphingomyelins
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/657163—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom
    • C07F9/657181—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus
    • C07F9/65742—Esters of oxyacids of phosphorus non-condensed with carbocyclic rings or heterocyclic rings or ring 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
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of medicine, and specifically relates to an imidazoquinoline substituted phosphate agonist, and a preparation method and application thereof.
  • TLRs Toll-like receptors
  • innate immunity When microorganisms break through the body's physical barriers (such as skin or mucous membranes, etc.), TLRs can stimulate immune cell responses by recognizing molecules with conserved structures derived from microorganisms.
  • TLRs that have been identified so far contain at least 13 members: TLR1/TLR2 heterodimers recognize triacetyl ester peptides; TLR2/TLR6 heterodimers recognize triacetyl ester peptides; TLR2 and TLR4 can recognize bacteria The surface structure (such as lipoprotein, lipoteichoic acid, peptidoglycan and lipopolysaccharide, etc.); TLR3 recognizes double-stranded RNA; TLR5 recognizes flagellin in bacterial flagella; TLR7 and TLR8 recognize single-stranded RNA; TLR9 recognizes bacteria and CpG-ODN of the virus; TLR11 recognizes inhibitory protein-like molecules from Toxoplasma gondii (Huck, BR.
  • TLR1/TLR2 heterodimers recognize triacetyl ester peptides
  • TLR2/TLR6 heterodimers recognize triacetyl ester peptides
  • TLR2 and TLR4
  • TLR1, 2, 4, 5, and 6 are mainly expressed on the cell surface, while TLR3, 7, 8, and 9 are mainly expressed in endosomes.
  • TLR7 is mainly expressed by plasmacytoid dendritic cells (pDC) and recognized by ligands to induce the secretion of interferon- ⁇ (INF- ⁇ ).
  • TLR8 is mainly expressed by bone marrow immune cells and recognized by ligands to stimulate and induce the production of cytokines, such as tumor necrosis factor ⁇ (TNF ⁇ ), interleukin 18 (IL18), interleukin 12 (IL12) and interferon gamma (INF- ⁇ ).
  • TNF ⁇ tumor necrosis factor ⁇
  • IL18 interleukin 18
  • IL12 interleukin 12
  • IFN- ⁇ interferon gamma
  • TLR8 agonists can also promote the expression of costimulatory molecules such as CD8 + cells, major histocompatibility complex molecules and chemokine receptors (McGowan, D .et al., J. Med. Chem. 2016, 59, 7936-7949).
  • TLR8 agonists are pathologically related to a variety of diseases.
  • TLR8 agonists have the potential to reduce off-target effects, and therefore have more urgent clinical needs.
  • the purpose of the present invention is to provide a new class of compounds that have selective agonism and/or better pharmacodynamic properties on Toll-like receptors 7 and/or 8 (TLR7 and/or TLR8) and uses thereof.
  • an imidazoquinoline substituted phosphate compound having the structure of general formula (I), or a stereoisomer, tautomer, crystal form, or a pharmaceutically acceptable Salt, hydrate, solvate or prodrug:
  • R 1 is selected from the following group of substituted or unsubstituted groups: hydrogen, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, C1-C18 alkoxy, deuterated C1-C18 Alkoxy, halogenated C1-C18 alkoxy, halogen, amino, nitro, hydroxyl, cyano, C3-C18 cycloalkyl, heterocyclic, C6-C10 aryl, heteroaryl, -(CH 2 ) n OR 5 , -(CH 2 ) n O(CH 2 ) m R 5 , -(CH 2 ) n SR 5 , -(CH 2 ) n COR 5 , -(CH 2 ) n C(O)OR 5 , -(CH 2 ) n S(O) m R 5 , -(CH 2 ) n NR 6 R 7 , -(CH
  • R 2 is the same or different, and is independently selected from the following group: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, C1-C18 alkoxy, deuterated C1 -C18 alkoxy, halogenated C1-C18 alkoxy, halogen, amino, nitro, hydroxyl, cyano, C3-C18 cycloalkyl, heterocyclic, C6-C10 aryl, heteroaryl, -( CH 2 ) n OR 5 , -(CH 2 ) n SR 5 , -(CH 2 ) n COR 5 , -(CH 2 ) n C(O)OR 5 , -(CH 2 ) n S(O) m R 5 , -(CH 2 ) n NR 6 R 7 , -(CH 2 ) n C(O)NR 6 R 7 , -(CH
  • Z is selected from the following group of substituted or unsubstituted groups: C1-C18 alkylene, deuterated C1-C18 alkylene, halogenated C1-C18 alkylene, C1-C18 alkyleneoxy, halogenated C1- C18 alkyleneoxy, C3-C18 cycloalkylene, C1-C18 alkylene, C3-C18 cycloalkylene, C3-C18 cycloalkylene, C1-C18 alkylene, C1-C18 alkylene, C3- C18 cycloalkylene C1-C18 alkylene, heterocyclylene, C6-C10 arylene, heteroarylene, wherein the substitution refers to substitution by one or more groups selected from the following group: hydrogen, Deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, C1-C18 alkoxy, deuterated C1-C18
  • Y is selected from O, N or NR 4 ;
  • R 4 is selected from the following group of substituted or unsubstituted groups: hydrogen, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, C1-C18 alkoxy, deuterated C1-C18 Alkoxy, halogenated C1-C18 alkoxy, C3-C18 cycloalkyl, heterocyclyl, C6-C10 aryl, heteroaryl, wherein the substitution refers to one or more groups selected from the following group Group substitution: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, C1-C18 alkoxy, deuterated C1-C18 alkoxy, halogenated C1-C18 Alkoxy, halogen, amino, nitro, hydroxyl, cyano, C3-C18 cycloalkyl, heterocyclic, C6-C10 aryl
  • R 5 is selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, C1-C18 alkoxy, deuterated C1 -C18 alkoxy, halogenated C1-C18 alkoxy, amino, hydroxy, cyano, C3-C18 cycloalkyl, heterocyclyl, C6-C10 aryl, heteroaryl, wherein the substitution means selected Substituting one or more groups from the following group: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, C1-C18 alkoxy, deuterated C1-C18 Alkoxy, halogenated C1-C18 alkoxy, halogen, amino, nitro, hydroxyl, cyano, C3-C18 cyclo
  • R 6 and R 7 are the same or different, and are each independently selected from the following substituted or unsubstituted groups: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl , C1-C18 alkoxy, deuterated C1-C18 alkoxy, halogenated C1-C18 alkoxy, amino, hydroxyl, C3-C18 cycloalkyl, heterocyclic, C6-C10 aryl, heteroaryl ; Wherein the substitution refers to the substitution by one or more groups selected from the following group: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, C1-C18 alkane Oxy, deuterated C1-C18 alkoxy, halogenated C1-C18 alkoxy, halogen, amino, nitro, hydroxyl, cyano,
  • R 8 and R 9 are the same or different, and are each independently selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl , C1-C18 alkoxy, deuterated C1-C18 alkoxy, halogenated C1-C18 alkoxy, amino, hydroxyl, -COOR 16 , C3-C18 cycloalkyl, heterocyclic, C6-C10 aryl , Heteroaryl, wherein the substitution refers to substitution by one or more groups selected from the following group: deuterium, C1-C20 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C4-C10 Heterocyclic group, C6-C10 aryl, C5-C10 heteroaryl, halogen, amino, nitro, -COOR 16 , cyano
  • X 1 and X 2 are independently selected from the following group: oxygen, sulfur, -OCH 2 O-;
  • X 3 is nitrogen
  • R 11 , R 12 , R 13 , R 14 , and R 15 are independently selected from the following group of substituted or unsubstituted groups: hydrogen, C1-C20 alkyl, C1-C20 deuterated alkyl, C3-C10 cycloalkyl , C4-C10 heterocyclic group, C6-C10 aryl group, C5-C10 heteroaryl group, or R 11 and R 12 combine with adjacent X 1 , X 2 and P to form a substituted 5-7 membered heterocyclic group,
  • the substitution refers to substitution by one or more substituents selected from the following group: deuterium, C1-C20 alkyl, halogenated C1-C20 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C4- C10 heterocyclyl, C6-C10 aryl, halogenated C6-C10 aryl, C5-C10 heteroaryl, halogen, amino,
  • R 16 is selected from the following group of substituted or unsubstituted groups: hydrogen, C1-C18 alkyl, C1-C20 deuterated alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, C6-C10 aryl, Amino, heterocyclyl, wherein said substitution refers to substitution by one or more C6-C10 aryl groups;
  • x is an integer of 0, 1, 2, 3 or 4;
  • y is an integer of 1 or 2;
  • n is an integer of 0, 1 or 2;
  • n is an integer of 0, 1, 2, 3, 4 or 5;
  • each heterocyclic group is independently a 5-15 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S;
  • Each heteroaryl group is independently a 5-15 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, and S.
  • it is a compound represented by the general formula (II-1) or (II-2), or a stereoisomer, tautomer, crystal form, or a pharmaceutically acceptable Salt, hydrate, solvate or prodrug:
  • R 1 , R 2 , x, Z, X 1 , X 2 , R 11 , and R 12 are as described in the general formula (I).
  • the compound is a compound represented by the general formula (IV-1) or (IV-2):
  • R 2 , x, Z, X 1 , X 2 , R 11 , and R 12 are as described in the general formula (I).
  • it is a compound represented by the general formula (III-1) or (III-2), or a stereoisomer, tautomer, crystal form, or a pharmaceutically acceptable Salt, hydrate, solvate or prodrug:
  • R 1 , R 2 , x, Z, X 1 , X 3 , R 11 , R 14 , and R 15 are as described in the general formula (I).
  • the compound is a compound represented by the general formula (IV-3) or (IV-4):
  • R 2 , x, Z, X 1 , X 3 , R 11 , R 14 , and R 15 are as described in the general formula (I).
  • Z has an S or R configuration.
  • Z has an S configuration.
  • the P structure has an S or R configuration.
  • the P structure has an S configuration.
  • At least one of R 14 and R 15 has an S configuration.
  • an imidazoquinoline substituted phosphate compound with the structure of the general formula (I), or its stereoisomers, tautomers, crystals as described in the first aspect of the present invention includes the steps:
  • y 1;
  • R 1 , R 2 , x, Z, X 1 , X 2 , X 3 , R 11 , R 12 , R 14 and R 15 are as described in the first aspect of the present invention.
  • Rs is triphenylmethyl or 4,4'-bismethoxytrityl.
  • the third aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more imidazoquinoline substituted phosphoric acid having the structure of the general formula (I) described in the first aspect of the present invention
  • it also contains other drugs or combinations for preventing and/or treating diseases selected from the group consisting of inflammation, cancer, cardiovascular disease, infection, immune disease, and metabolic disease.
  • the infection is a viral infection.
  • the infection is cancer.
  • the pharmaceutical composition further comprises a drug selected from the following group:
  • PD-1 inhibitors nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or biosimilars of the above drugs
  • PD-L1 inhibitors durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 Or biosimilars of the above drugs
  • CD20 antibodies such as rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, 131 I-tositumomab, ibritumo
  • the pharmaceutical composition further comprises a drug selected from the following group:
  • Interferon ⁇ standard INF ⁇ and polyglycolated INF ⁇
  • nucleoside drugs such as Telbivudine, Lamivudine, Clevudine, Adefovir, Tenofovir, Besifovir, Tenofovir Disoproxil Fumarate (TDF), Tenofovir Alafenamide Fumarate (TAF) and HDP-PA ( CMX157) etc.
  • shell protein allosteric modulators such as BAY41-4109, RG-7907, NVR 3-778, ABI-H0731, ABI-H2158, JNJ-56136379, GLS 4JHS, etc.
  • cccDNA inhibitors such as RG-7854, GS9620, etc.
  • hepatitis B virus entry inhibitors such as Myrcludex B, etc.
  • interfering nucleotides such as ARB 1467, ARB 1740, etc.
  • the fourth aspect of the present invention provides an imidazoquinoline substituted phosphate compound with the structure of the general formula (I) described in the first aspect of the present invention, or its stereoisomers, tautomers, Use of the crystal form, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, for use selected from the following group:
  • the use is selected from the following group:
  • the use is selected from the following group:
  • the viral infectious disease is selected from the group consisting of dengue fever 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, viral hepatitis, viral skin diseases.
  • the virus-infected hepatitis is selected from the group consisting of hepatitis B and hepatitis C.
  • the viral skin disease is selected from the group consisting of condyloma acuminata, molluscum contagiosum, genital herpes, and port wine stains.
  • the cancer is selected from the group consisting of lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, gastric cancer, liver cancer, colorectal cancer, melanoma, lymphoma, and blood cancer , Brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.
  • TLR7 and/or TLR8 Toll-like receptors 7 and/or 8
  • TLR7 and/or TLR8 Toll-like receptors 7 and/or 8
  • alkyl refers to a straight or branched chain or cyclic alkane group containing 1-20 carbon atoms, such as 1-18 carbon atoms, especially 1-8 carbon atoms.
  • Typical "alkyl” includes methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, Pentyl, isopentyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and many more.
  • C1-C8 alkyl refers to straight or branched chain or cyclic alkyl, including from 1-8 carbon atoms, such as methyl, ethyl, propyl, isopropyl N-butyl, tert-butyl, isobutyl (e.g. ), n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl.
  • Substituted alkyl means that one or more positions in the alkyl group are substituted, especially 1-4 substituents, which can be substituted at any position.
  • alkylene refers to a group formed by the removal of a hydrogen atom from the “alkyl” group, such as methylene, ethylene, propylene, isopropylene (such as ), butylene (e.g. ), pentylene (e.g. ), hexyl (e.g. ), Heptyl (e.g. )Wait.
  • C1-C18 alkylene C3-C18 cycloalkylene or "C3-C18 cycloalkylene C1-C18 alkylene” have the same meaning and refer to the removal of cycloalkylalkyl or alkylcycloalkyl A group formed by two hydrogen atoms, such as Wait.
  • alkenyl refers to a straight or branched chain hydrocarbon group containing 2-18 carbon atoms and at least one carbon-carbon double bond. Typical groups include vinyl or allyl.
  • (C 2 -C 6 )alkenyl refers to a straight-chain or branched group containing 2-6 carbon atoms and at least one carbon-carbon double bond, such as vinyl, propenyl, and 2-propenyl.
  • alkynyl refers to a straight or branched chain hydrocarbon group containing 2-18 carbon atoms and at least one carbon-carbon triple bond substituent. Typical groups include ethynyl.
  • (C 2 -C 6 )alkynyl refers to a straight-chain or branched group containing 2-6 carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2 -Propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl.
  • cycloalkyl refers to a fully saturated cyclic hydrocarbon compound group, including 1-4 rings, each ring containing 3-8 carbon atoms. "Substituted cycloalkyl” means that one or more positions in the cycloalkyl group are substituted, especially 1-4 substituents, which can be substituted at any position.
  • Typical substituents may be optionally substituted.
  • Typical substitutions also include spirocyclic, bridged or fused ring substituents, especially spirocyclic alkyl, spirocycloalkenyl, spirocyclic heterocycle (excluding heteroaromatic rings), bridged cycloalkyl, bridged cycloalkenyl, Bridged heterocyclic ring (excluding heteroaromatic ring), fused ring alkyl, fused ring alkenyl, fused ring heterocyclic group or fused ring aromatic ring group, the above-mentioned cycloalkyl, cycloalkenyl, heterocyclic group and heterocyclic aromatic The group can be optionally substituted.
  • cycloalkenyl refers to a partially unsaturated cyclic hydrocarbon compound group, including 1-4 rings, each containing 3-8 carbon atoms. Typical cycloalkenyl groups are cyclobutenyl, cyclopentenyl, cyclohexenyl and the like. "Substituted cycloalkenyl” means that one or more positions in the cycloalkyl group are substituted, especially 1-4 substituents, which can be substituted at any position.
  • Typical substituents may be optionally substituted.
  • Typical substitutions also include spirocyclic or fused ring substituents, especially spirocyclic alkyl, spirocycloalkenyl, spirocyclic heterocycle (not including heteroaromatic ring), fused ring alkyl, fused cycloalkenyl, fused ring hetero A cyclic group or a condensed ring aromatic ring group, the above-mentioned cycloalkyl, cycloalkenyl, heterocyclic and heterocyclic aryl groups may be optionally substituted.
  • heterocyclyl refers to a fully saturated or partially unsaturated cyclic group (including but not limited to, for example, 4-7 membered monocyclic ring, 7-11 membered bicyclic ring, or 8-16 membered tricyclic ring system), At least one heteroatom is present in a ring with at least one carbon atom.
  • Each heterocyclic ring containing heteroatoms can have 1, 2, 3 or 4 heteroatoms, these heteroatoms are selected from nitrogen atoms, oxygen atoms or sulfur atoms, wherein nitrogen atoms or sulfur atoms can be oxidized, and nitrogen atoms can also be Is quaternized.
  • the heterocyclic group can be attached to any heteroatom or carbon atom residue of the ring or ring system molecule.
  • Typical monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidine Group, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepine Inyl group, 4-piperidinone group, tetrahydropyranyl group, morpholino group, thiomorpholino group, thiomorpholine sulfoxide group, thiomorpholine sulfone group,
  • Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups involved are optionally connected to other groups through a single bond, or through a ring Any two or more atoms above are further connected to other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups; the heterocyclic group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, Halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxy, and carboxylate.
  • groups are independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, Halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxy, and carboxylate.
  • aryl refers to an aromatic cyclic hydrocarbon compound group with 1-5 rings, especially monocyclic and bicyclic groups, such as phenyl, biphenyl or naphthyl. Where there are two or more aromatic rings (bicyclic, etc.), the aromatic ring of the aryl group can be connected by a single bond (such as biphenyl) or condensed (such as naphthalene, anthracene, etc.). "Substituted aryl” means that one or more positions in the aryl group are substituted, especially 1-3 substituents, which can be substituted at any position.
  • Typical substituents may be optionally substituted.
  • Typical substitutions also include fused ring substituents, especially fused ring alkyl, fused ring alkenyl, fused ring heterocyclic group or fused ring aromatic ring group, the above-mentioned cycloalkyl, cycloalkenyl, heterocyclic group and heterocyclic aromatic The group can be optionally substituted.
  • heteroaryl refers to a heteroaromatic system containing 1-4 heteroatoms and 5-14 ring atoms, where the heteroatoms are selected from oxygen, nitrogen and sulfur.
  • the heteroaryl group is preferably a 5- to 10-membered ring, more preferably 5-membered or 6-membered, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl , Furyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazole and tetrazolyl, etc.
  • Heteroaryl may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy , Haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkane Sulfur group, oxo group, carboxyl group and carboxylate group.
  • R and R can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or Substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle are as defined above.
  • R and R" may be the same or different in the dialkylamine segment.
  • sulfonamido refers to a -SO 2 NRR" group with a structure, wherein R and R" can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, ring Alkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle are as defined above. R and R" may be the same or different in the dialkylamine segment.
  • halogen refers to chlorine, bromine, fluorine, and iodine.
  • halo refers to substitution by halogen.
  • deuterated refers to substitution by deuterium.
  • C1-C18 alkoxy refers to a straight-chain or branched-chain or cyclic alkoxy group having 1 to 18 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropyl Oxy and butoxy, etc. It is preferably a C1-C8 alkoxy group, and more preferably a C1-C6 alkoxy group.
  • C1-C18 alkyleneoxy refers to the group obtained by removing one hydrogen atom from "C1-C18 alkoxy”.
  • C1-C8 alkyleneoxy and "C1-C6 alkyleneoxy” have Similar meaning.
  • substituted means that one or more hydrogen atoms on a specific group are replaced by a specific substituent.
  • the specific substituents are the substituents correspondingly described in the foregoing, or the substituents appearing in each embodiment.
  • a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different in each position.
  • substituents contemplated by the present invention are those that are stable or chemically achievable.
  • the substituents such as (but not limited to): halogen, hydroxyl, carboxy (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-to 12-membered heterocyclic group, aryl group, heteroaryl group, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amino group, C1-C6 alkoxy group, C1-C10 sulfonyl group, etc.
  • the present invention provides imidazoquinoline substituted phosphate compounds with general formula (I) structure, or stereoisomers, tautomers, crystal forms, or pharmaceutically acceptable salts, hydrates thereof, Solvate or prodrug:
  • each group is as defined above.
  • any one of R 1 , R 2 , x, Z, Y, X, and y is the corresponding group in the specific compound described below.
  • the compound is preferably the compound prepared in the embodiment.
  • the compound is selected from the following group:
  • Salts that may be formed by the compounds of the present invention also belong to the scope of the present invention. Unless otherwise specified, the compounds in the present invention are understood to include their salts.
  • the term "salt” as used herein refers to a salt formed into an acid or basic form with an inorganic or organic acid and a base.
  • the compound of the present invention contains a basic fragment, it includes but is not limited to pyridine or imidazole, and when it contains an acidic fragment, including but not limited to carboxylic acid, the zwitterion (“internal salt") that may be formed is contained in Within the scope of the term "salt”.
  • salts are preferred, although other salts are also useful, for example, they can be used in separation or purification steps in the preparation process.
  • the compound of the present invention may form a salt.
  • the compound I can be obtained by reacting with a certain amount of acid or base, such as an equivalent amount of acid or base, and salting out in the medium, or by freeze-drying in an aqueous solution.
  • the basic fragments contained in the compounds of the present invention may form salts with organic or inorganic acids.
  • Typical acids that can form salts include acetate (such as acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, and benzoate.
  • Benzene sulfonate hydrogen sulfate, borate, butyrate, citrate, camphor salt, camphor sulfonate, cyclopentane propionate, diglycolate, dodecyl sulfate, Ethane sulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodide, isethionate (E.g. 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g.
  • 2-naphthalenesulfonate nicotinate, nitrate, oxalic acid Salt, pectinate, persulfate, phenylpropionate (such as 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, Sulfate (such as formed with sulfuric acid), sulfonate, tartrate, thiocyanate, toluenesulfonate such as p-toluenesulfonate, dodecanoate, etc.
  • the acidic fragments that some compounds of the present invention may contain, including but not limited to carboxylic acids, may form salts with various organic or inorganic bases.
  • Typical salts formed by bases include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed by organic bases (such as organic amines) such as benzathine and bicyclohexyl.
  • Hypamine a salt formed with N,N-bis(dehydroabietyl)ethylenediamine
  • N-methyl-D-glucamine N-methyl-D-glucamide
  • tert-butyl Base amines and salts with amino acids such as arginine, lysine, etc.
  • Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (E.g., dimethyl sulfate, diethyl, dibutyl and dipentyl sulfate), long chain halides (such as chlorides and bromides of decyl, dodecyl, tetradecyl and tetradecyl) And iodides), aralkyl halides (such as benzyl and phenyl bromides) and so on.
  • alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides
  • dialkyl sulfates E.g., dimethyl sulfate, diethyl, dibutyl
  • prodrugs and solvates of the compounds of the present invention are also within the scope of coverage.
  • prodrug herein refers to a compound that undergoes metabolic or chemical transformation to produce the compound, salt, or solvate of the present invention when treating related diseases.
  • the compounds of the present invention include solvates, such as hydrates.
  • the compounds, salts or solvates of the present invention may exist in tautomeric forms (such as amides and imine ethers). All these tautomers are part of the invention.
  • All stereoisomers of compounds (for example, those asymmetric carbon atoms that may exist due to various substitutions), including their enantiomeric forms and diastereomeric forms, fall within the scope of the present invention.
  • the independent stereoisomers of the compound in the present invention may not coexist with other isomers (for example, as a pure or substantially pure optical isomer with special activity), or may be a mixture, such as Racemates, or mixtures with all other stereoisomers or part of them.
  • the chiral center of the present invention has two configurations, S or R, defined by the International Union of Theoretical and Applied Chemistry (IUPAC) in 1974.
  • racemic form can be resolved by physical methods, such as fractional crystallization, or separation of crystallization by derivatization into diastereomers, or separation by chiral column chromatography.
  • Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to traditional methods, such as salt formation with an optically active acid and then recrystallization.
  • the weight content of the compound obtained by successive preparation, separation and purification is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compound), as described in the text Listed.
  • very pure compounds of the invention are also part of the invention.
  • All configuration isomers of the compounds of the present invention are within the scope of coverage, whether in mixture, pure or very pure form.
  • the definition of the compound of the present invention includes two olefin isomers, cis (Z) and trans (E), as well as cis and trans isomers of carbocyclic and heterocyclic rings.
  • Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention covers all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, and exogenous Spin mixtures and other mixtures.
  • the asymmetric carbon atom may represent a substituent such as an alkyl group. All isomers and their mixtures are included in the present invention.
  • the ratio of the mixture of isomers containing isomers can be varied.
  • a mixture of only two isomers can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98: 2, 99:1, or 100:0, all ratios of isomers are within the scope of the present invention. Similar ratios, which are easily understood by those skilled in the art, and ratios that are mixtures of more complex isomers are also within the scope of the present invention.
  • the present invention also includes isotopically labeled compounds, which are equivalent to the original compounds disclosed herein. In practice, however, it usually occurs when one or more atoms are replaced by atoms whose atomic weight or mass number is different.
  • isotopes that can be classified as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, and 18 O, respectively. , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • the compounds of the present invention or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the above compounds are all within the scope of the present invention.
  • Certain isotope-labeled compounds of the present invention such as radioisotopes of 3 H and 14 C, are also among them, which are useful in tissue distribution experiments of drugs and substrates.
  • Isotopically-labeled compounds can be prepared by general methods by replacing readily available isotope-labeled reagents with non-isotopic reagents, using the protocol disclosed in the example.
  • a specific enantiomer of the compound of the present invention can be prepared by asymmetric synthesis, or derivatized with a chiral adjuvant, separating the resulting diastereomeric mixture, and then removing the chiral adjuvant. Pure enantiomer.
  • a suitable optically active acid or base can be used to form a diastereomeric salt with it, and then through separation crystallization or chromatography, etc. After separation by conventional means, the pure enantiomers are obtained.
  • the compounds of the present invention can be combined with any number of substituents or functional groups to expand their scope of inclusion.
  • substituents or functional groups Generally, whether the term “substituted” appears before or after the term “optional”, the general formula including substituents in the formula of the present invention means that the substituents of the specified structure are substituted for hydrogen radicals. When a plurality of positions in a specific structure are substituted by a plurality of specific substituents, each position of the substituents may be the same or different.
  • substitution as used herein includes all permissible substitution of organic compounds.
  • the permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds.
  • the heteroatom nitrogen may have a hydrogen substituent or any permitted organic compound as described above to supplement its valence.
  • the present invention is not intended to limit the permitted substitution of organic compounds in any way.
  • the present invention believes that the combination of substituents and variable groups is good in the treatment of diseases in the form of stable compounds, such as infectious diseases or proliferative diseases.
  • stable here refers to a compound that is stable and can be tested for a long enough time to maintain the structural integrity of the compound, preferably for a long enough time to be effective, and is used herein for the above purpose.
  • the preparation process of the compound of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.
  • the compound of the general formula (V-A1) or (V-A2) and the compound of the general formula (V) are coupled to obtain the intermediate (V-B1) or (V-B2), and then the protecting group Rs is removed to obtain the general formula (II) -1) or (III-1) the target compound.
  • R 1 , R 2 , x, Z, X 1 , X 2 , X 3 , R 11 , R 12 , R 14 and R 15 are as described above.
  • Rs is a protecting group for amino.
  • the pharmaceutical composition of the present invention is used to prevent and/or treat the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, and metabolic disease.
  • the compound of general formula (I) can be used in combination with other drugs known to treat or improve similar conditions.
  • the mode of administration and dosage of the original drug can be kept unchanged, while the compound of formula I is administered at the same time or subsequently.
  • a pharmaceutical composition containing one or more known drugs and the compound of formula I can be preferably used.
  • the combination of drugs also includes taking the compound of formula I and one or more other known drugs in overlapping time periods.
  • the dose of the compound of formula I or the known drug may be lower than the dose of the compound used alone.
  • the drugs or active ingredients that can be used in combination with the compound of general formula (I) include but are not limited to: interferon ⁇ (standard INF ⁇ and polyglycolated INF ⁇ ), nucleoside drugs (such as Telbivudine, Lamivudine, Clevudine) , Adefovir, Tenofovir, Besifovir, Tenofovir Disoproxil Fumarate (TDF), Tenofovir Alafenamide Fumarate (TAF) and HDP-PMPA (CMX157), etc.), shell protein allosteric modulators (such as BAY41-4109, RG-7907, NVR 3-778) , ABI-H0731, ABI-H2158, JNJ-56136379, GLS 4JHS, etc.), cccDNA inhibitors, TLR3/7/8/9 agonists (such as RG-7854, GS9620, etc.), hepatitis B virus entry inhibitors (such as Myrcludex
  • the dosage form of the pharmaceutical composition of the present invention includes (but is not limited to): injection, tablet, capsule, aerosol, suppository, film, dripping pill, external liniment, controlled release or sustained release or nano preparation.
  • the pharmaceutical composition of the present invention contains the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/agent, more preferably, 10-1000 mg of the compound of the present invention/agent.
  • the "one dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid).
  • Magnesium stearate calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifiers such as Tween
  • wetting agents such as sodium lauryl sulfate
  • coloring agents such as sodium lauryl sulfate
  • flavoring agents such as pepperminophen, sorbitol, etc.
  • antioxidants
  • the method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited.
  • Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glycty
  • Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into a microcapsule form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the dosage forms of the compound of the present invention for topical administration include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the treatment method of the present invention can be administered alone or in combination with other treatment means or therapeutic drugs.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment.
  • the administered dose is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also consider factors such as the route of administration and the patient's health status, which are all within the skill range of a skilled physician.
  • the present invention also provides a method for preparing a pharmaceutical composition, which comprises the steps of: combining a pharmaceutically acceptable carrier with the compound of general formula (I) of the present invention or its crystal form, pharmaceutically acceptable salt, hydrate or The solvates are mixed to form a pharmaceutical composition.
  • the present invention also provides a treatment method, which comprises the steps of: administering the compound of the general formula (I) of the present invention, or a crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, to a subject in need of treatment , Or administer the pharmaceutical composition of the present invention for selectively agonizing TLR7 and/or TLR8.
  • the present invention has the following main advantages:
  • the compound has a selective agonistic effect on TLR7 and TLR8;
  • the compound has better pharmacodynamic properties and lower toxic and side effects.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) and liquid mass spectrometry (LC-MS).
  • NMR is detected by Bruker AVANCE-400 nuclear magnetic instrument.
  • the solvent for determination includes deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated acetone (CD 3 COCD 3 ), deuterated chloroform (CDCl 3 ) and deuterated methanol ( CD 3 OD), etc.
  • the internal standard uses tetramethylsilane (TMS), and the chemical shift is measured in units of parts per million (ppm).
  • LC-MS Liquid chromatography mass spectrometry
  • Waters SQD2 mass spectrometer Waters SQD2 mass spectrometer.
  • HPLC measurement uses Agilent 1100 high pressure chromatograph (Microsorb 5 micron C18 100 x 3.0mm chromatographic column).
  • the thin layer chromatography silica gel plate uses Qingdao GF254 silica gel plate, the TLC uses 0.15-0.20mm, and the preparative thin layer chromatography uses 0.4mm-0.5mm.
  • Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.
  • the starting materials in the examples of the present invention are all known and commercially available, or can be synthesized by using or according to literature reported in the field.
  • nitric acid 35 mL was slowly added dropwise to a uniformly stirred solution of 2,4-dihydroxyquinoline (23 g, 142.7 mmol) in acetic acid (140 mL). After the addition was completed, the reaction solution was reacted at 105°C for 2 hours and then cooled to room temperature, and then quenched by adding water (30 mL). The obtained mixture was stirred for 15 minutes and then filtered. The filter cake was washed with water and dried under vacuum to obtain the target product (17.5 g, yield 59%).
  • Triethylamine (8.6 g, 84.9 mmol) was slowly added dropwise to a solution of -nitro-2,4-dihydroxyquinoline (17.5 g, 84.9 mmol) in phosphorus oxychloride (60 mL) at room temperature. After the addition was completed, the reaction solution was reacted at 120°C for 2 hours, then cooled to room temperature, and then concentrated under reduced pressure. The obtained residue was poured into ice water (100 mL), adjusted to pH 7-8 with saturated aqueous sodium bicarbonate solution, and extracted with dichloromethane (100 mL ⁇ 3). The combined organic phase was dried with anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by column chromatography to obtain the target product (18 g, yield 87%).
  • the third step the preparation of 1-((2-chloro-3-nitroquinolin-4-yl)amino)-2-propanol
  • N-(2-chloro-4-((2-hydroxy)-propyl)aminoquinolin-3-yl)-2-ethoxyacetamide (2.7g, 8mmol, 1.0eq) ammonia methanol in a closed container
  • the solution (7M, 25 mL, 175 mmol) was reacted at 180°C for 12 hours and then cooled to room temperature.
  • the obtained mixture was concentrated under reduced pressure, and the obtained crude product was purified by column chromatography to obtain the target product (1.5 g, yield 62%).
  • Example 1 two isomers were separated by chiral HPLC (chiral column: Cellulose-SC 4.6*100mm 5 ⁇ m; mobile phase: MeOH (0.2% Methanol Ammonia)).
  • the first step 1-(2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-C]quinolin-1-yl)-2-propanol preparation
  • the second step ((S)-(((R)-1-(2-(ethoxymethyl)-4-(tritylaminoamino)-1H-imidazole[4,5-c]quinoline -1-yl)propyl-2-yl)oxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester and ((S)-(((S)-1-(2-(ethoxy) Methyl)-4-(tritylamino)-1H-imidazole(4,5-c]quinolin-1-yl)propyl-2-yl)oxy)(phenoxy)phosphoryl)-L -Preparation of Alanine Isopropyl Ester
  • reaction solution is reacted at -7°C for 1.5 hours and then ((S)-(perfluorophenoxy)(phenoxy)phosphono)-L-alanine isopropyl ester (230mg, 0.51mmol) ) In tetrahydrofuran (2mL).
  • tetrahydrofuran 2mL
  • the resulting mixture was reacted at -7°C for 7 hours, and then diluted hydrochloric acid (1N) was added dropwise to adjust the pH to 4, and then extracted with ethyl acetate.
  • the combined organic phase was dried with anhydrous magnesium sulfate and filtered.
  • the third step ((S)-(((R)-1-(4-amino-2-(ethoxymethyl)-1H-imidazole[4,5-c]quinolin-1-yl)propane 2-yl)oxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester and ((S)-(((S)-1-(4-amino-2-(ethoxymethyl) (4,5-c]quinolin-1-yl)propyl-2-yl)oxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester
  • Example 2A (Isomer A): LC-MS: m/z 570(M+H) + .
  • Example 2B (Isomer B): LC-MS: m/z 570(M+H) + .
  • Example 3A (Isomer A): LC-MS: m/z 570(M+H) + .
  • Example 3B (Isomer B): LC-MS: m/z 570(M+H) + .
  • 31 P NMR (162MHz,
  • Example 4A (Isomer A): LC-MS: m/z 620(M+H) + .
  • Example 5A (Isomer A): LC-MS: m/z 620(M+H) + .
  • Example 5B (Isomer B): LC-MS: m/z 620(M+H) + .
  • Example 6A (Isomer A): LC-MS: m/z 620(M+H) + .
  • Example 6B (Isomer B): LC-MS: m/z 620(M+H) + .
  • Example 7A (Isomer A): LC-MS: m/z 584(M+H) + .
  • Example 7B (Isomer B): LC-MS: m/z 584(M+H) + .
  • Example 8A (Isomer A): LC-MS: m/z 584(M+H) + .
  • Example 8B (Isomer B): LC-MS: m/z 584(M+H) + .
  • Example 9A (Isomer A): LC-MS: m/z 584(M+H) + .
  • Example 9B (Isomer B): LC-MS: m/z 584(M+H) + .
  • Example 10A (Isomer A): LC-MS: m/z 604 (M+H) + .
  • 31 P NMR (162MHz, CDCl 3 ) ⁇ 1.20 (s).
  • Example 10B (Isomer B): LC-MS: m/z 604(M+H) + .
  • Example 11A (Isomer A): LC-MS: m/z 604 (M+H) + .
  • Example 11B (Isomer B): LC-MS: m/z 604(M+H) + . LCMSm/z 604.59(M+H) +
  • Example 12A (Isomer A): LC-MS: m/z 604 (M+H) + .
  • Example 12B (Isomer B): LC-MS: m/z 604 (M+H) + .
  • Example 13A (Isomer A): LC-MS: m/z 570(M+H) + .
  • Example 13B (Isomer B): LC-MS: m/z 570(M+H) + .
  • Example 14A (Isomer A): LC-MS: m/z 584(M+H) + .
  • Example 14B (Isomer B): LC-MS: m/z 584(M+H) + .
  • Example 15A (Isomer A): LC-MS: m/z 542 (M+H) + .
  • 31 P NMR (162MHz, CDCl 3 ) ⁇ 1.08 (s, 1P).
  • Example 15B (Isomer B): LC-MS: m/z 542 (M+H) + .
  • Example 16A (Isomer A): LC-MS: m/z 618 (M+H) + .
  • Example 17A (Isomer A): LC-MS: m/z 598 (M+H) + .
  • Example 17B (Isomer B): LC-MS: m/z 598 (M+H) + .
  • Example 18A (Isomer A): LC-MS: m/z 614(M+H) + .
  • Example 18B (Isomer B): LC-MS: m/z 614(M+H) + .
  • Example 19A (Isomer A): LC-MS: m/z 618 (M+H) + .
  • Example 19B (Isomer B): LC-MS: m/z 618 (M+H) + .
  • Example 20A (Isomer A): LC-MS: m/z 632(M+H) + .
  • Example 20B (Isomer B): LC-MS: m/z 632(M+H) + .
  • Example 21A (Isomer A): LC-MS: m/z 632(M+H) + .
  • Example 21B (Isomer B): LC-MS: m/z 632(M+H) + .
  • Example 22 LC-MS: m/z 646(M+H) + .
  • Example 23A (Isomer A): LC-MS: m/z 560 (M+H) + .
  • Example 23B (Isomer B): LC-MS: m/z 560 (M+H) + .
  • Example 24A (Isomer A): LC-MS: m/z 552(M+H) + .
  • Example 24B (Isomer B): LC-MS: m/z 552(M+H) + .
  • Example 25A (Isomer A): LC-MS: m/z 528 (M+H) + .
  • Example 25B (Isomer B): LC-MS: m/z 528(M+H) + .
  • the compound was diluted 1:3 serially with 9 concentration points in DMSO, double-replicated, and added to a 96-well plate with Echo.
  • the HEK-Blue TM hTLR cells were suspended in a culture medium, and then seeded into a 96-well plate containing the compound at a density of 50,000 cells/well. The cells were cultured for 1 day under the conditions of 5% CO 2 and 37°C. The final concentration of DMSO in the cell culture medium is 0.5%.
  • the cell viability was determined, and the Luminescence signal value was read with a microplate reader to calculate the cytotoxicity of the compound.
  • the compound of the present invention has very selective TLR7 agonistic activity (relative to TLR8 agonistic activity), or has ultra-high TLR8 selective agonistic activity (relative to TLR7 agonistic activity);

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Abstract

本发明涉及咪唑并喹啉取代磷酸酯类激动剂及其制备方法和应用。具体地，本发明化合物具有式(I)所示结构，其中各基团和取代基的定义如说明书中所述。本发明还公开了所述化合物的制备方法及其作为TLR激动剂的用途。

Description

咪唑并喹啉取代磷酸酯类激动剂及其制备方法和应用 技术领域
本发明属于药物领域，具体涉及一种咪唑并喹啉取代磷酸酯类激动剂及其制备方法和应用。
背景技术
Toll样受体(Toll-like receptors,TLRs)是参与非特异性免疫(天然免疫)的一类重要蛋白质分子。当微生物突破机体的物理屏障(如皮肤或粘膜等)时，TLRs可以通过识别来源于微生物的具有保守结构的分子从而刺激产生免疫细胞应答。到目前为止已经确定的TLR至少含有13个成员：其中TLR1/TLR2异质二聚体识别三乙酰基酯肽；TLR2/TLR6异质二聚体识别三乙酰基酯肽；TLR2和TLR4能够识别细菌的表面结构(如脂蛋白、脂磷壁酸、肽聚糖及脂多糖等)；TLR3识别双链RNA；TLR5识别细菌鞭毛中的鞭毛蛋白；TLR7和TLR8识别单链RNA；TLR9识别来自细菌和病毒的CpG-ODN；TLR11则识别来自弓形虫的抑制蛋白样分子(Huck,BR.et al.,Angew.Chem.Int.Ed.2018,57,4412-4428；Isogawa,M.et al.,J Virology,2005,79(11),7269-7272)。TLR1、2、4、5和6主要表达在细胞表面上，而TLR3、7、8和9主要表达在内体中。
TLR7主要是由浆细胞样树突细胞(pDC)表达和配体识别从而诱导干扰素α(INF-α)分泌。TLR8主要由骨髓免疫细胞表达和配体识别从而刺激诱导产生细胞因子，如肿瘤坏死因子α(TNFα)、白介素18(IL18)、白介素12(IL12)和干扰素γ(INF-γ)。TLR8激动剂除了可以刺激促炎细胞因子和趋化因子分泌之外，还可以促进协同刺激分子如CD8 +细胞、主要组织相容性复合体分子以及趋化因子受体等的表达(McGowan,D.et al.,J.Med.Chem.2016,59,7936-7949)。
现有研究表明，激活先天性和适应性免疫反应可以诱导免疫反应，从而提供针对自身免疫、炎症、过敏、哮喘、移植排斥、移植物抗宿主病(GvHD)、感染、癌症和免疫缺陷等病症的一种治疗方法。比如针对乙型肝炎(HBV)，激活专职性抗原呈递细胞(pAPCs)和其他肝内的免疫细胞上的TLR8会导致促炎细胞因子分泌，从而增加HBV特异性T细胞响应、激活肝内NK细胞以及促进体内抗病毒免疫系统的重建(Wille-Reece,U.et al.,J Exp Med 2006,203,1249-1258；Peng,G.et al.,Science 2005,309,1380-1384；Jo,J.et al.,PLoS Pathogens 2014,10,e1004210；Watashi,K.et al.,J Bioi Chern 2013,288,31715-31727)。
由于Toll样受体在病理学上与多种疾病相关，因此目前还需要新型的Toll样受体调节剂(如TLR8激动剂)用于临床治疗。高选择性高活性的TLR8激动剂具有减少脱靶效应的潜力，因而具有更迫切的临床需求。
发明内容
本发明的目的在于提供一类新型的对Toll样受体7和/或8(TLR7和/或TLR8)有选择性激动作用和/或更好药效学性能的化合物及其用途。
本发明的第一方面，提供了具有通式(I)结构的咪唑并喹啉取代磷酸酯类化合物、或其立体异构体、互变异构体、晶型、或其药学上可接受的盐、水合物、溶剂合物或前药：
Figure PCTCN2020128168-appb-000001
式中：
R 1选自取代或未取代的下组基团：氢、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C18环烷基、杂环基、C6-C10芳基、杂芳基、-(CH 2) nOR 5、-(CH 2) nO(CH 2) mR 5、-(CH 2) nSR 5、-(CH 2) nCOR 5、-(CH 2) nC(O)OR 5、-(CH 2) nS(O) mR 5、-(CH 2) nNR 6R 7、-(CH 2) nC(O)NR 6R 7、-(CH 2) nNR 6C(O)R 5、-(CH 2) nNR 6S(O) mR 5；其中所述取代指被选自下组的一个或多个基团取代：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C18环烷基、杂环基、C6-C10芳基、杂芳基、-(CH 2) nOR 5、-(CH 2) nSR 5、-(CH 2) nCOR 5、-(CH 2) nC(O)OR 5、-(CH 2) nS(O) mR 5、-(CH 2) nNR 6R 7、-(CH 2) nC(O)NR 6R 7、-(CH 2) nC(O)NHR 6、-(CH 2) nNR 6C(O)R 5、-(CH 2) nNR 6S(O) mR 5；
R 2相同或不同，且独立地选自下组：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C18环烷基、杂环基、C6-C10芳基、杂芳基、-(CH 2) nOR 5、-(CH 2) nSR 5、-(CH 2) nCOR 5、-(CH 2) nC(O)OR 5、-(CH 2) nS(O) mR 5、-(CH 2) nNR 6R 7、-(CH 2) nC(O)NR 6R 7、-(CH 2) nC(O)NHR 6、-(CH 2) nNR 6C(O)R 5、-(CH 2) nNR 6S(O) mR 5；
Z选自取代或未取代的下组基团：C1-C18亚烷基、氘代C1-C18亚烷基、卤代C1-C18亚烷基、C1-C18亚烷氧基、卤代C1-C18亚烷氧基、C3-C18亚环烷基、C1-C18亚烷基C3-C18亚环烷基、C3-C18亚环烷基C1-C18亚烷基、C1-C18亚烷基C3-C18 亚环烷基C1-C18亚烷基、亚杂环基、C6-C10亚芳基、亚杂芳基，其中所述取代指被选自下组的一个或多个基团取代：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C18环烷基、杂环基、C6-C10芳基、杂芳基、-(CH 2) nOR 5、-(CH 2) nSR 5、-(CH 2) nCOR 5、-(CH 2) nC(O)OR 5、-(CH 2) nS(O) mR 5、-(CH 2) nNR 6R 7、-(CH 2) nC(O)NR 6R 7、-(CH 2) nC(O)NHR 6、-(CH 2) nNR 6C(O)R 5、-(CH 2) nNR 6S(O) mR 5；
Y选自O、N或NR 4；
R 4选自取代或未取代的下组基团：氢、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、C3-C18环烷基、杂环基、C6-C10芳基、杂芳基，其中所述取代指被选自下组的一个或多个基团取代：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C18环烷基、杂环基、C6-C10芳基、杂芳基、-(CH 2) nOR 5、-(CH 2) nSR 5、-(CH 2) nCOR 5、-(CH 2) nC(O)OR 5、-(CH 2) nS(O) mR 5、-(CH 2) nNR 6R 7、-(CH 2) nC(O)NR 6R 7、-(CH 2) nC(O)NHR 6、-(CH 2) nNR 6C(O)R 5、-(CH 2) nNR 6S(O) mR 5；
R 5选自取代或未取代的下组基团：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、氨基、羟基、氰基、C3-C18环烷基、杂环基、C6-C10芳基、杂芳基，其中所述取代指被选自下组的一个或多个基团取代：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C18环烷基、杂环基、C6-C10芳基、杂芳基、-(CH 2) nOR 8、-(CH 2) nSR 8、-(CH 2) nCOR 8、-(CH 2) nC(O)OR 8、-(CH 2) nS(O) mR 8、-(CH 2) nNR 8R 9、-(CH 2) nC(O)NR 8R 9、-(CH 2) nC(O)NHR 9、-(CH 2) nNR 9C(O)R 8、-(CH 2) nNR 9S(O) mR 8；
R 6和R 7相同或不同，且各自独立地选自取代或未取代的下组基团：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、氨基、羟基、C3-C18环烷基、杂环基、C6-C10芳基、杂芳基；其中所述取代指被选自下组的一个或多个基团取代：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C18环烷基、杂环基、C6-C10芳基、杂芳基、-(CH 2) nOR 8、-(CH 2) nSR 8、-(CH 2) nCOR 8、-(CH 2) nC(O)OR 8、-(CH 2) nS(O) mR 8、-(CH 2) nNR 8R 9、-(CH 2) nC(O)NR 8R 9、-(CH 2) nC(O)NHR 9、-(CH 2) nNR 9C(O)R 8、-(CH 2) nNR 9S(O) mR 8；
R 8和R 9相同或不同，且各自独立地选自取代或未取代的下组基团：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、 卤代C1-C18烷氧基、氨基、羟基、-COOR 16、C3-C18环烷基、杂环基、C6-C10芳基、杂芳基，其中，所述取代指被选自下组的一个或多个基团取代：氘、C1-C20烷基、C1-C6烷氧基、C3-C10环烷基、C4-C10杂环基、C6-C10芳基、C5-C10杂芳基、卤素、氨基、硝基、-COOR 16、氰基、羟基、酰胺基、磺酰胺基；
X选自下组：-P(＝O)(OH) 2、-P(＝O)(OH)OP(＝O)(OH) 2、-P(＝O)(OH)OP(＝O)(OH)OP(＝O)(OH) 2、-P(＝O)(X 1R 11)(X 2R 12)、-P(＝O)(X 1R 11)(X 3R 14R 15)、-P(＝O)(X 3R 14R 15)(X 3R 14R 15)、-CH 2P(＝O)(X 1R 11)(X 2R 12)、-CH 2P(＝O)(X 1R 11)(X 3R 14R 15)、-CH 2P(＝O)(X 3R 14R 15)(X 3R 14R 15)、-P(＝S)(X 1R 11)(X 2R 12)、-P(＝S)(X 1R 11)(X 3R 14R 15)、-P(＝S)(X 3R 14R 15)(X 3R 14R 15)、-CH 2P(＝S)(X 1R 11)(X 2R 12)、-CH 2P(＝S)(X 1R 11)(X 3R 14R 15)、-CH 2P(＝S)(X 3R 14R 15)(X 3R 14R 15)、-P(＝NR 13)(X 1R 11)(X 2R 12)、-P(＝NR 13)(X 1R 11)(X 3R 14R 15)、-P(＝NR 13)(X 3R 14R 15)(X 3R 14R 15)、-CH 2P(＝NR 13)(X 1R 11)(X 2R 12)、-CH 2P(＝NR 13)(X 1R 11)(X 3R 14R 15)、-CH 2P(＝NR 13)(X 3R 14R 15)(X 3R 14R 15)；
X 1、X 2独立地选自下组：氧、硫、-OCH 2O-；
X 3为氮；
R 11、R 12、R 13、R 14、R 15独立地选自取代或未取代的下组基团：氢、C1-C20烷基、C1-C20氘代烷基、C3-C10环烷基、C4-C10杂环基、C6-C10芳基、C5-C10杂芳基，或者R 11和R 12与相邻的X 1、X 2和P结合形成取代的5-7元杂环基，所述取代指被选自下组的一个或多个取代基取代：氘、C1-C20烷基、卤代C1-C20烷基、C1-C6烷氧基、C3-C10环烷基、C4-C10杂环基、C6-C10芳基、卤代C6-C10芳基、C5-C10杂芳基、卤素、氨基、硝基、-COR 16、-COOR 16、-OCOOR 16、氰基、羟基、酰胺基、磺酰胺基；
R 16选自取代或未取代的下组基团：氢、C1-C18烷基、C1-C20氘代烷基、C3-C10环烷基、C3-C10环烯基、C6-C10芳基、氨基、杂环基，其中所述取代指被一个或多个C6-C10芳基取代；
x为0、1、2、3或4的整数；
y为1或2的整数；
m为0、1或2的整数；
且n为0、1、2、3、4或5的整数；
且各杂环基独立为含1-3个选自N、O和S的杂原子的5-15元杂环烷基；
各杂芳基独立为含1-3个选自N、O和S的杂原子的5-15元杂芳基。
在另一优选例中，其为通式(II-1)或(II-2)所示的化合物、或其立体异构体、互变异构体、晶型、或其药学上可接受的盐、水合物、溶剂合物或前药：
Figure PCTCN2020128168-appb-000002
式中：
R 1、R 2、x、Z、X 1、X 2、R 11、R 12如通式(I)所述。
在另一优选例中，所述化合物为通式(IV-1)或(IV-2)所示的化合物：
Figure PCTCN2020128168-appb-000003
式中：
R 2、x、Z、X 1、X 2、R 11、R 12如通式(I)所述。
在另一优选例中，其为通式(III-1)或(III-2)所示的化合物、或其立体异构体、互变异构体、晶型、或其药学上可接受的盐、水合物、溶剂合物或前药：
Figure PCTCN2020128168-appb-000004
R 1、R 2、x、Z、X 1、X 3、R 11、R 14、R 15如通式(I)所述。
在另一优选例中，所述化合物为通式(IV-3)或(IV-4)所示的化合物：
Figure PCTCN2020128168-appb-000005
R 2、x、Z、X 1、X 3、R 11、R 14、R 15如通式(I)所述。
在另一优选例中，Z具有S或R构型。
在另一优选例中，Z具有S构型。
在另一优选例中，P结构具有S或R构型。
在另一优选例中，P结构具有S构型。
在另一优选例中，R 14、R 15中至少一个具有S构型。
本发明的第二方面，提供了一种本发明第一方面所述具有通式(I)结构的咪唑并喹啉取代磷酸酯类化合物、或其立体异构体、互变异构体、晶型、或其药学上可接受的盐、水合物、溶剂合物或前药的制备方法，包括步骤：
1)将
Figure PCTCN2020128168-appb-000006
中－NH 2中的一个H进行保护得到
Figure PCTCN2020128168-appb-000007
其中，Rs为保护基团；
2)将
Figure PCTCN2020128168-appb-000008
与
Figure PCTCN2020128168-appb-000009
反应得到
Figure PCTCN2020128168-appb-000010
3)对
Figure PCTCN2020128168-appb-000011
进行脱保护，得到
Figure PCTCN2020128168-appb-000012
其中，X选自下组：-P(＝O)(X 1R 11)(X 2R 12)、-P(＝O)(X 1R 11)(X 3R 14R 15)；
y为1；
R 1、R 2、x、Z、X 1、X 2、X 3、R 11、R 12、R 14和R 15如本发明第一方面所述。
在另一优选例中，Rs为三苯基甲基或4,4'-双甲氧基三苯甲基。
本发明的第三方面，提供了一种药物组合物，包含药学上可接受的载体和一种或多种本发明第一方面所述的具有通式(I)结构的咪唑并喹啉取代磷酸酯类化合物、或其立体异构体、互变异构体、晶型、或其药学上可接受的盐、水合物、溶剂合物或前药。
在另一优选例中，还包含其它预防和/或治疗选自下组的疾病的药物或联用：炎症、癌症、心血管疾病、感染、免疫性疾病、代谢性疾病。
在另一优选例中，所述感染为病毒性感染。
在另一优选例中，所述感染为癌症。
在另一优选例中，所述药物组合物还包含选自下组的药物：
PD-1抑制剂(nivolumab,pembrolizumab,pidilizumab,cemiplimab，JS-001，SHR-120，BGB-A317，IBI-308，GLS-010，GB-226，STW204，HX008,HLX10,BAT 1306,AK105,LZM 009或上述药物的生物类似药)、PD-L1抑制剂(durvalumab,atezolizumab,avelumab，CS1001，KN035,HLX20,SHR-1316， BGB-A333，JS003,CS1003,KL-A167,F 520,GR1405,MSB2311或上述药物的生物类似药)、CD20抗体(如rituximab,obinutuzumab,ofatumumab,veltuzumab,tositumomab, 131I-tositumomab,ibritumomab, 90Y-ibritumomab, 90In-ibritumomab,ibritumomab tiuxetan)、CD47抗体(Hu5F9-G4，CC-90002，TTI-621，TTI-622,OSE-172，SRF-231，ALX-148，NI-1701，SHR-1603，IBI188，IMM01)、或其组合。
在另一优选例中，所述药物组合物还包含选自下组的药物：
干扰素α(标准INFα和聚乙醇化的INFα)、核苷类药物(如Telbivudine、Lamivudine、Clevudine、Adefovir、Tenofovir、Besifovir、Tenofovir Disoproxil Fumarate(TDF)、Tenofovir Alafenamide Fumarate(TAF)及HDP-PMPA(CMX157)等)、壳蛋白变构调节剂(如BAY41-4109、RG-7907、NVR 3-778、ABI-H0731、ABI-H2158、JNJ-56136379、GLS 4JHS等)、cccDNA抑制剂、TLR3/7/8/9激动剂(如RG-7854、GS9620等)、乙肝病毒进入抑制剂(如Myrcludex B等)、干扰核苷酸(如ARB 1467、ARB 1740等)、HBV表面抗原抑制剂(如RG7834、REP2139、REP2165等)、CRISPER/Cas9、或其组合。
本发明的第四方面，提供了一种本发明第一方面所述的具有通式(I)结构的咪唑并喹啉取代磷酸酯类化合物、或其立体异构体、互变异构体、晶型、或其药学上可接受的盐、水合物、溶剂合物或前药的用途，用于选自下组的用途：
1)用于制备TLR7激动剂；
2)用于制备TLR8激动剂；
3)用于制备TLR7和TLR8双激动剂；
4)用于制备预防和/或治疗病毒感染性疾病的药物；
5)用于制备预防和/或治疗癌症的药物。
在另一优选例中，所述用途选自下组：
1)用于制备TLR7激动剂；
2)用于制备TLR8激动剂。
在另一优选例中，所述用途选自下组：
3)用于制备预防和/或治疗病毒感染性疾病的药物；
4)用于制备预防和/或治疗癌症的药物。
在另一优选例中，所述病毒感染性疾病选自下组：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、病毒感染肝炎、病毒性皮肤病。
在另一优选例中，所述病毒感染肝炎选自下组：乙型肝炎、丙型肝炎。
在另一优选例中，所述病毒性皮肤病选自下组：尖锐湿疣、传染性软疣、生殖器疱疹、鲜红斑痣。
在另一优选例中，所述癌症选自下组：肺癌、乳腺癌、前列腺癌、食道癌、结直肠癌、骨癌、肾癌、胃癌、肝癌、大肠癌、黑色素瘤、淋巴瘤、血癌、脑瘤、骨髓瘤、软组织肉瘤、胰腺癌、皮肤癌。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，意外地制备了一类新型的对Toll样受体7和/或8(TLR7和/或TLR8)有选择性激动作用和/或更好药效学性能的化合物。在此基础上，发明人完成了本发明。
术语
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
术语“烷基”是指直链或支链或环状烷烃基，包含1-20个碳原子，如1-18个碳原子，尤其指1-8个碳原子。典型的“烷基”包括甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基、
Figure PCTCN2020128168-appb-000013
戊基、异戊基、庚基、4,4–二甲基戊基，辛基，2,2,4-三甲基戊基，壬基，癸基、十一烷基，十二烷基等等。
术语“C1-C8烷基”指的是直链或支链或环状烷基，包括从1-8个碳原子，如甲基、乙基、丙基、异丙基
Figure PCTCN2020128168-appb-000014
正丁基、叔丁基、异丁基(如
Figure PCTCN2020128168-appb-000015
)、正戊基、异戊基、正己基、异己基、正庚基、异庚基。“取代烷基”是指烷基中的一个或多个位置 被取代，尤其是1-4个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e,P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基，如烷基、环烷基、烯基、环烯基、炔基、杂环或芳环可以任选取代。
术语“亚烷基”是指“烷基”再脱掉一个氢原子所形成的基团，如亚甲基、亚乙基、亚丙基、亚异丙基(如
Figure PCTCN2020128168-appb-000016
)、亚丁基(如
Figure PCTCN2020128168-appb-000017
)、亚戊基(如
Figure PCTCN2020128168-appb-000018
)、亚己基(如
Figure PCTCN2020128168-appb-000019
)、亚庚基(如
Figure PCTCN2020128168-appb-000020
)等。
术语“C1-C18亚烷基C3-C18亚环烷基”或“C3-C18亚环烷基C1-C18亚烷基”具有相同含义，是指环烷基烷基或烷基环烷基脱掉两个氢原子所形成的基团，如
Figure PCTCN2020128168-appb-000021
Figure PCTCN2020128168-appb-000022
等。
术语“烯基”是指直链或支链烃基含有2-18个碳原子，至少一个碳碳双键的取代基。典型的基团包括乙烯基或烯丙基。术语“(C 2-C 6)烯基”是指直链或支链的含有2-6个碳原子，至少有一个碳碳双键的基团，如乙烯基、丙烯基、2-丙烯基、(E)-2-丁烯基、(Z)-2-丁烯基、(E)-2-甲基-2-丁烯基、(Z)-2-甲基-2-丁烯基、2,3-二甲基-2-丁烯基、(Z)-2-戊烯基、(E)-1-戊烯基、(Z)-1-己烯基、(E)-2-戊烯基、(Z)-2-己烯基、(E)-1-己烯基、(Z)-1- 己烯基、(E)-2-己烯基、(Z)-3-己烯基、(E)-3-己烯基和(E)-1,3-己二烯基。“取代烯基”是指烯基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e,P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基，如烷基、环烷基、烯基、环烯基、炔基、杂环或芳环可以任选取代。
术语“炔基”是指直链或支链烃基含有2-18个碳原子，至少一个碳碳三键的取代基。典型的基团包括乙炔基。术语“(C 2-C 6)炔基”是指直链或支链的含有2-6个碳原子，至少有一个碳碳三键的基团，如乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、1-戊炔基、2-戊炔基、1-己炔基、2-己炔基、3-己炔基。“取代炔基”是指炔基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e,P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。典型的取代基可以任选取代。
术语“环烷基”是指完全饱和的环状烃类化合物基团，包括1-4个环，每个环中含有3-8个碳原子。“取代环烷基”是指环烷基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯 基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e,P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基可以任选取代。典型的取代还包括螺环、桥环或稠环取代基，尤其是螺环烷基、螺环烯基、螺环杂环(不包括杂芳环)、桥环烷基、桥环烯基、桥环杂环(不包括杂芳环)、稠环烷基、稠环烯基、稠环杂环基或稠环芳环基，上述环烷基、环烯基、杂环基和杂环芳基可以任选取代。
术语“环烯基”是指部分不饱和的环状烃类化合物基团，包括1-4个环，每个环中含有3-8个碳原子。典型的环烯基如环丁烯基、环戊烯基、环己烯基等等。“取代环烯基”是指环烷基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e,P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基可以任选取代。典型的取代还包括螺环或稠环取代基，尤其是螺环烷基、螺环烯基、螺环杂环(不包括杂芳环)、稠环烷基、稠环烯基、稠环杂环基或稠环芳环基，上述环烷基、环烯基、杂环基和杂环芳基可以任选取代。
术语“杂环基”是指完全饱和的或部分不饱和的的环状基团(包含但不限于如4-7元单环，7-11元双环，或8-16元三环系统)，其中至少有一个杂原子存在于至少有一个碳原子的环中。每个含有杂原子的杂环可以带有1，2，3或4个杂原子，这些杂原子选自氮原子、氧原子或硫原子，其中氮原子或硫原子可以被氧化，氮原子也可以被季铵化。杂环基团可以连接到环或环系分子的任何杂原子或碳原子的残基上。典型的单环杂环包括但不限于氮杂环丁烷基、吡咯烷基、氧杂环丁烷基、吡唑啉基、咪唑啉基、咪唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、四氢呋喃基、哌 啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、六氢吖庚因基、4-哌啶酮基、四氢吡喃基、吗啡啉基、硫代吗啡啉基、硫代吗啡啉亚砜基、硫代吗啡啉砜基、1,3-二噁烷基和四氢-1,1-二氧噻吩等。多环杂环基包括螺环、稠环和桥环的杂环基；其中涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接，或者通过环上的任意两个或两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接；杂环基团可以是取代的或者未取代的，当被取代时，取代基优选为一个或多个一下基团，其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基。
术语“芳基”是指芳香环状烃类化合物基团，具有1-5个环，尤其指单环和双环基团，如苯基、联苯基或萘基。凡含有两个或两个以上芳香环(双环等)，芳基基团的芳香环可由单键联接(如联苯)，或稠合(如萘、蒽等等)。“取代芳基”是指芳基中的一个或多个位置被取代，尤其是1-3个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e,P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基可以任选取代。典型的取代还包括稠环取代基，尤其是稠环烷基、稠环烯基、稠环杂环基或稠环芳环基，上述环烷基、环烯基、杂环基和杂环芳基可以任选取代。
术语“杂芳基”指包含1-4个杂原子、5-14个环原子的杂芳族体系，其中杂原子选自氧、氮和硫。杂芳基优选5至10元环，更优选为5元或6元，例如吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、异噻唑基、呋喃基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三氮嗪基、三氮唑基及四氮唑基等。“杂芳基”可以是取代的或者未取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基。
术语“酰胺基”是指带有结构的-CONRR"基团，其中R和R"可以独立的代表氢、 烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R"在二烷基胺片段中可以相同或不同。
术语“磺酰胺基”是指带有结构的-SO 2NRR"基团，其中R和R"可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R"在二烷基胺片段中可以相同或不同。
术语“卤素”或“卤”是指氯、溴、氟、碘。
术语“卤代”是指被卤素取代。
术语“氘代”是指被氘取代。
术语“C1-C18烷氧基”是指具有1至18个碳原子的直链或支链或环状烷氧基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。优选为C1-C8烷氧基，更优选C1-C6烷氧基。术语“C1-C18亚烷氧基”是指“C1-C18烷氧基”脱掉一个氢原子所得基团，术语“C1-C8亚烷氧基”、“C1-C6亚烷氧基”具有类似的含义。
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：卤素、羟基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-至12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、氨基、C1-C6烷氧基、C1-C10磺酰基等。
除非另外说明，假定任何不满价态的杂原子有足够的氢原子补充其价态。
化合物
本发明提供了具有通式(I)结构的咪唑并喹啉取代磷酸酯类化合物、或其立体异构体、互变异构体、晶型、或其药学上可接受的盐、水合物、溶剂合物或前药：
Figure PCTCN2020128168-appb-000023
式中，各基团如上文所定义。
在另一优选例中，所述的化合物中，R 1、R 2、x、Z、Y、X和y中任一个分别为以下所述具体化合物中所对应的基团。
在另一优选例中，所述化合物优选为实施例中所制备的化合物。
在另一优选例中，所述化合物选自下组：
Figure PCTCN2020128168-appb-000024
Figure PCTCN2020128168-appb-000025
Figure PCTCN2020128168-appb-000026
Figure PCTCN2020128168-appb-000027
Figure PCTCN2020128168-appb-000028
Figure PCTCN2020128168-appb-000029
Figure PCTCN2020128168-appb-000030
Figure PCTCN2020128168-appb-000031
Figure PCTCN2020128168-appb-000032
Figure PCTCN2020128168-appb-000033
Figure PCTCN2020128168-appb-000034
Figure PCTCN2020128168-appb-000035
Figure PCTCN2020128168-appb-000036
Figure PCTCN2020128168-appb-000037
Figure PCTCN2020128168-appb-000038
Figure PCTCN2020128168-appb-000039
Figure PCTCN2020128168-appb-000040
Figure PCTCN2020128168-appb-000041
Figure PCTCN2020128168-appb-000042
Figure PCTCN2020128168-appb-000043
Figure PCTCN2020128168-appb-000044
Figure PCTCN2020128168-appb-000045
Figure PCTCN2020128168-appb-000046
Figure PCTCN2020128168-appb-000047
Figure PCTCN2020128168-appb-000048
Figure PCTCN2020128168-appb-000049
Figure PCTCN2020128168-appb-000050
Figure PCTCN2020128168-appb-000051
Figure PCTCN2020128168-appb-000052
本发明中的化合物可能形成的盐也是属于本发明的范围。除非另有说明，本发明中的化合物被理解为包括其盐类。在此使用的术语“盐”，指用无机或有机酸和碱形成酸式或碱式的盐。此外，当本发明中的化合物含一个碱性片段时，它包括但不限于吡啶或咪唑，含一个酸性片段时，包括但不限于羧酸，可能形成的两性离子(“内盐”)包含在术语“盐”的范围内。药学上可接受的(即无毒，生理可接受的)盐是首选，虽然其他盐类也有用，例如可以用在制备过程中的分离或纯化步骤。本发明的化合物可能形成盐，例如，化合物I与一定量如等当量的酸或碱反应，在介质中盐析出来，或在水溶液中冷冻干燥得来。
本发明中的化合物含有的碱性片段，包括但不限于胺或吡啶或咪唑环，可能会和 有机或无机酸形成盐。可以成盐的典型的酸包括醋酸盐(如用醋酸或三卤代醋酸，如三氟乙酸)、己二酸盐、藻朊酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑盐、樟脑磺酸盐、环戊烷丙酸盐、二甘醇酸盐、十二烷基硫酸盐、乙烷磺酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟基乙磺酸盐(如，2-羟基乙磺酸盐)、乳酸盐、马来酸盐、甲磺酸盐、萘磺酸盐(如，2-萘磺酸盐)、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、苯丙酸盐(如3-苯丙酸盐)、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐，水杨酸盐、琥珀酸盐、硫酸盐(如与硫酸形成的)、磺酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐如对甲苯磺酸盐、十二烷酸盐等等
本发明的某些化合物可能含有的酸性片段，包括但不限于羧酸，可能会和各种有机或无机碱形成盐。典型的碱形成的盐包括铵盐、碱金属盐如钠、锂、钾盐，碱土金属盐如钙、镁盐，和有机碱形成的盐(如有机胺)，如苄星、二环已基胺、海巴胺(与N,N-二(去氢枞基)乙二胺形成的盐)、N-甲基-D-葡糖胺、N-甲基-D-葡糖酰胺、叔丁基胺，以及和氨基酸如精氨酸、赖氨酸等等形成的盐。碱性含氮基团可以与卤化物季铵盐，如小分子烷基卤化物(如甲基、乙基、丙基和丁基的氯化物、溴化物及碘化物)，二烷基硫酸盐(如，硫酸二甲酯、二乙酯，二丁酯和二戊酯)，长链卤化物(如癸基、十二烷基、十四烷基和十四烷基的氯化物、溴化物及碘化物)，芳烷基卤化物(如苄基和苯基溴化物)等等。
本发明中化合物的前药及溶剂合物也在涵盖的范围之内。此处术语“前药”是指一种化合物，在治疗相关疾病时，经过代谢或化学过程的化学转化而产生本发明中的化合物、盐、或溶剂合物。本发明的化合物包括溶剂合物，如水合物。
本发明中的化合物、盐或溶剂合物，可能存在的互变异构形式(例如酰胺和亚胺醚)。所有这些互变异构体都是本发明的一部分。
所有化合物的立体异构体(例如，那些由于对各种取代可能存在的不对称碳原子)，包括其对映体形式和非对映形式，都属于本发明的设想范围。本发明中的化合物独立的立体异构体可能不与其他异构体同时存在(例如，作为一个纯的或者实质上是纯的光学异构体具有特殊的活性)，或者也可能是混合物，如消旋体，或与所有其他立体异构体或其中的一部分形成的混合物。本发明的手性中心有S或R两种构型，由理论与应用化学国际联合会(IUPAC)1974年建议定义。外消旋形式可通过物理方法解决，例如分步结晶，或通过衍生为非对映异构体分 离结晶，或通过手性柱色谱法分离。单个的光学异构体可通过合适的方法由外消旋体得到，包括但不限于传统的方法，例如与光学活性酸成盐后再结晶。
本发明中的化合物，依次通过制备、分离纯化获得的该化合物其重量含量等于或大于90％，例如，等于或大于95％，等于或大于99％(“非常纯”的化合物)，在正文描述列出。此处这种“非常纯”本发明的化合物也作为本发明的一部分。
本发明的化合物所有的构型异构体都在涵盖的范围之内，无论是混合物、纯的或非常纯的形式。在本发明化合物的定义包含顺式(Z)和返式(E)两种烯烃异构体，以及碳环和杂环的顺式和反式异构体。
在整个说明书中，基团和取代基可以被选择以提供稳定的片段和化合物。
特定官能团和化学术语定义都详细介绍如下。对本发明来说，化学元素与Periodic Table of the Elements,CAS version,Handbook of Chemistry and Physics,75 th Ed.中定义的一致。特定官能团的定义也在其中描述。此外，有机化学的基本原则以及特定官能团和反应性在“Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito:1999,也有说明，其全部内容纳入参考文献之列。
本发明的某些化合物可能存在于特定的几何或立体异构体形式。本发明涵盖所有的化合物，包括其顺式和反式异构体、R和S对映异构体、非对映体、(D)型异构体、(L)型异构体、外消旋混合物和其它混合物。另外不对称碳原子可表示取代基，如烷基。所有异构体以及它们的混合物，都包涵在本发明中。
按照本发明，同分异构体的混合物含有异构体的比率可以是多样的。例如，在只有两个异构体的混合物可以有以下组合：50:50，60:40，70:30，80:20，90:10，95:5，96:4，97:3，98:2，99:1，或100:0，异构体的所有比率都在本发明范围之内。本专业内一般技术人员容易理解的类似的比率，及为更复杂的异构体的混合物的比率也在本发明范围之内。
本发明还包括同位素标记的化合物，等同于原始化合物在此公开。不过实际上对一个或更多的原子被与其原子量或质量序数不同的原子取代通常会出现。可以列为本发明的化合物同位素的例子包括氢，碳，氮，氧，磷，硫，氟和氯同位素，分别如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。本发明中的化合物，或对映体，非对映体，异构体，或药学上可接受的盐或溶剂化物，其中含有上述化合物的同位素或其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物，例如 3H和 14C的放射性同位素也在其中，在药物和底物的组织分布实验中是有用的。氚，即 3H和碳-14，即 14C，它们的制备和 检测比较容易。是同位素中的首选。此外，较重同位素取代如氘，即 2H，由于其很好的代谢稳定性在某些疗法中有优势，例如在体内增加半衰期或减少用量，因此，在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的试剂，用批露在示例中的方案可以制备。
如果要设计一个本发明的化合物特定的对映体的合成，它可以不对称合成制备，或用手性辅剂衍生化，将所产生的非对映混合物分离，再除去手性辅剂而得到纯的对映体。另外，如果分子中含有一个碱性官能团，如氨基酸，或酸性官能团，如羧基，可以用合适的光学活性的酸或碱的与之形成非对映异构体盐，再通过分离结晶或色谱等常规手段分离，然后就得到了纯的对映体。
如本文所述，本发明中的化合物可与任何数量取代基或官能团取而扩大其包涵范围。通常，术语“取代”不论在术语“可选”前面或后面出现，在本发明配方中包括取代基的通式，是指用指定结构取代基，代替氢自由基。当特定结构中的多个在位置被多个特定的取代基取代时，取代基每一个位置可以是相同或不同。本文中所使用的术语“取代”包括所有允许有机化合物取代。从广义上讲，允许的取代基包括非环状的、环状的、支链的非支链的、碳环的和杂环的，芳环的和非芳环的有机化合物。在本发明中，如杂原子氮可以有氢取代基或任何允许的上文所述的有机化合物来补充其价态。此外，本发明是无意以任何方式限制允许取代有机化合物。本发明认为取代基和可变基团的组合在以稳定化合物形式在疾病的治疗上是很好的，例如传染病或增生性疾病。此处术语“稳定”是指具有稳定的化合物，在足够长的时间内检测足以维持化合物结构的完整性，最好是在足够长的时间内都在效，本文在此用于上述目的。
本申请所涉及的化合物及其药学可接受的盐的代谢产物，以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药，也包含在本申请的权利要求中。
制备方法
下面更具体地描述本发明式(I)结构化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得，这样的组合可由本发明所属领域的技术人员容易地进行。
典型地，本发明化合物的制备工艺流程如下，其中所用原料和试剂如无特殊说明，均可通过商业途径购买。
Figure PCTCN2020128168-appb-000053
通式(V-A1)或(V-A2)化合物和通式(V)化合物偶联后得到中间体(V-B1)或(V-B2)，然后脱去保护基Rs得到通式(II-1)或(III-1)的目标化合物。其中，R 1、R 2、x、Z、X 1、X 2、X 3、R 11、R 12、R 14和R 15如上文所述。Rs为氨基的保护基。
药物组合物和施用方法
本发明所述的药物组合物用于预防和/或治疗以下疾病：炎症、癌症、心血管疾病、感染、免疫性疾病、代谢性疾病。
通式(I)所述化合物可以与已知的治疗或改进相似病状的其他药物联用。联合 给药时，原来药物的给药方式和剂量可以保持不变，而同时或随后服用式I的化合物。当式I化合物与其它一种或几种药物同时服用时，可以优选使用同时含有一种或几种已知药物和式I化合物的药用组合物。药物联用也包括在重叠的时间段服用式I化合物与其它一种或几种已知药物。当式I化合物与其它一种或几种药物进行药物联用时，式I化合物或已知药物的剂量可能比它们单独用药的剂量低。
可以与通式(I)所述化合物进行药物联用的药物或活性成分包括但不局限为：干扰素α(标准INFα和聚乙醇化的INFα)、核苷类药物(如Telbivudine、Lamivudine、Clevudine、Adefovir、Tenofovir、Besifovir、Tenofovir Disoproxil Fumarate(TDF)、Tenofovir Alafenamide Fumarate(TAF)及HDP-PMPA(CMX157)等)、壳蛋白变构调节剂(如BAY41-4109、RG-7907、NVR 3-778、ABI-H0731、ABI-H2158、JNJ-56136379、GLS 4JHS等)、cccDNA抑制剂、TLR3/7/8/9激动剂(如RG-7854、GS9620等)、乙肝病毒进入抑制剂(如Myrcludex B等)、干扰核苷酸(如ARB1467、ARB 1740等)、HBV表面抗原抑制剂(如RG7834、REP2139、REP2165等)、CRISPER/Cas9、PD-1抑制剂(nivolumab,pembrolizumab,pidilizumab,cemiplimab，JS-001，SHR-120，BGB-A317，IBI-308，GLS-010，GB-226，STW204，HX008,HLX10,BAT 1306,AK105,LZM 009 or上述药物的生物类似药)、PD-L1抑制剂(durvalumab,atezolizumab,avelumab，CS1001，KN035,HLX20,SHR-1316，BGB-A333，JS003,CS1003,KL-A167,F 520,GR1405,MSB2311 or上述药物的生物类似药)、CD20抗体(如rituximab,obinutuzumab,ofatumumab,veltuzumab,tositumomab, 131I-tositumomab,ibritumomab, 90Y-ibritumomab, 90In-ibritumomab,ibritumomab tiuxetan)、CD47抗体(Hu5F9-G4，CC-90002，TTI-621，TTI-622,OSE-172，SRF-231，ALX-148，NI-1701，SHR-1603，IBI188，IMM01)等。
本发明所述药物组合物的剂型包括(但并不限于)：注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用擦剂、控释型或缓释型或纳米制剂。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-1000mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物 质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2020128168-appb-000054
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明治疗方法可以单独施用，或者与其它治疗手段或者治疗药物联用。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明还提供了一种药物组合物的制备方法，包括步骤：将药学上可接受的载体与本发明所述通式(I)化合物或其晶型、药学上可接受的盐、水合物或溶剂合物进行混合，从而形成药物组合物。
本发明还提供了一种治疗方法，它包括步骤：给需要治疗的对象施用本发明中所述通式(I)化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物，或施用本发明所述的药物组合物，用于选择性地激动TLR7和/或TLR8。
与现有技术相比，本发明具有以下主要优点：
(1)所述化合物对TLR7和TLR8具有选择性激动作用；
(2)所述化合物对TLR8具有很好的选择性激动作用；
(3)所述化合物具有更好的药效学性能和更低的毒副作用。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照 常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
本发明的化合物结构是通过核磁共振(NMR)和液质联用色谱(LC-MS)来确定的。
NMR是使用Bruker AVANCE-400核磁仪检测的，测定溶剂包含氘代二甲亚砜(DMSO-d 6)、氘代丙酮(CD 3COCD 3)、氘代氯仿(CDCl 3)及氘代甲醇(CD 3OD)等，内标采用四甲基硅烷(TMS)，化学位移以百万分之一(ppm)的单位计量。
液质联用色谱(LC-MS)是使用Waters SQD2质谱仪检测的。HPLC的测定使用Agilent 1100高压色谱仪(Microsorb 5 micron C18 100 x 3.0mm色谱柱)。
薄层层析硅胶板使用青岛GF254硅胶板，TLC采用的是0.15-0.20mm，制备薄层色谱采用的是0.4mm-0.5mm。柱层析一般使用青岛硅胶200-300目硅胶作为载体。
本发明实施例中的起始原料都是已知并有市售的，或者可以采用或按照本领域已报道的文献资料合成的。
除特殊说明外，本发明所有反应均在干燥的惰性气体(如氮气或氩气)保护下通过连续磁力搅拌进行，反应温度均为摄氏度。
实施例1
1-(4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-C]喹啉-1-基)-2-丙醇的制备
Figure PCTCN2020128168-appb-000055
第一步：3-硝基-2,4-二羟基喹啉的制备
在室温下将硝酸(35mL)缓慢滴加到均匀搅拌的2,4-二羟基喹啉(23g，142.7mmol)的乙酸(140mL)溶液中。滴加完毕，反应液在105℃反应2小时后冷却至室 温，随后加水(30mL)淬灭。得到的混合物搅拌15min后过滤，滤饼用水洗后真空干燥得到目标产物(17.5g，产率59％)。
LC-MS：m/z 207(M+H) +。
第二步：3-硝基-2,4-二氯喹啉的制备
在室温下将三乙胺(8.6g，84.9mmol)缓慢滴加到-硝基-2,4-二羟基喹啉(17.5g，84.9mmol)的三氯氧磷(60mL)的溶液中。滴加完毕，反应液在120℃反应2小时后冷却至室温，然后减压浓缩。得到的残留物倒入冰水(100mL)中，用饱和碳酸氢钠水溶液调pH至7-8后用二氯甲烷(100mLx3)萃取。合并的有机相用无水硫酸镁干燥后过滤。滤液减压浓缩，得到的粗品经柱层析纯化得到目标产物(18g，产率87％)。
LC-MS：m/z 243(M+H) +。
第三步：1-((2-氯-3-硝基喹啉-4-基)氨基)-2-丙醇的制备
3-硝基-2,4-二氯喹啉(10g，41.14mmol)、三乙胺(5g，49.37mmol)和异丙醇胺(3.79g，50.44mmol)的二氯甲烷(70mL)溶液在46℃反应21小时，然后加入石油醚(60mL)。得到的混合物自然冷却析出固体，然后过滤。滤饼收集得到目标产物(14.3g，定量收率)。
LC-MS：m/z 282(M+H) +。
第四步：制备1-((2-氯-3-氨基喹啉-4-基)氨基)-2-丙醇的制备
在室温下1-((2-氯-3-硝基喹啉-4-基)氨基)-2-丙醇(15g，53.25mmol)和铂碳(10％wt,3.2g)的乙酸乙酯(300mL)和甲醇(100mL)的混合悬浮液在氢气(15psi)氛围下反应4小时，然后通过硅藻土过滤。得到的滤液减压浓缩得到目标产物(14.7g)，无需提纯直接用于下一步反应。
LC-MS：m/z 252(M+H) +。
第五步：N-(2-氯-4-((2-羟基)-丙基)氨基喹啉-3-基)-2-乙氧乙酰胺的制备
在室温下将乙氧基乙酰氯(15g，122.36mmol，2.2eq)的二氯甲烷(30mL)溶液滴加到1-((2-氯-3-氨基喹啉-4-基)氨基)-2-丙醇(14g，55.62mmol，1.0eq)和三乙胺(9g，90mmol，1.6eq)的二氯甲烷(150mL)溶液中。滴加完毕，反应液在25℃反应3小时然后用水(50mL)洗涤。有机相用无水硫酸镁干燥后过滤。滤液减压浓缩，得到的粗品经柱层析纯化得到目标产物(5.3g，收率28.2％)。
LC-MS：m/z 338(M+H) +。
第六步：1-(4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-C]喹啉-1-基)-2-丙醇的制备
在密闭容器里N-(2-氯-4-((2-羟基)-丙基)氨基喹啉-3-基)-2-乙氧乙酰胺(2.7g,8mmol，1.0eq)的氨甲醇溶液(7M，25mL，175mmol)在180℃反应12小时后冷却到室温。得到的混合物减压浓缩，得到的粗品经柱层析纯化得到目标产物(1.5g，收率62％)。
LC-MS：m/z 301(M+H) +。 1H NMR(400MHz,CDCl 3)δ7.82(d,J＝12Hz,1H),7.63(d,J＝12Hz,1H),7.41(t,J＝8Hz,1H),7.25-7.22(m,1H),5.42(s,2H),4.93(d,J＝12Hz,1H),4.68(d,J＝12Hz,1H),4.61-4.57(m,1H),4.52-4.46(m,2H),3.67-3.59(m,2H),1.48(d,J＝8Hz,3H),1.24(t,J＝6Hz,3H)。
实施例1A和1B
(S)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-C]喹啉-1-基)-2-丙醇和(R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-C]喹啉-1-基)-2-丙醇的制备
Figure PCTCN2020128168-appb-000056
实施例1经由手性HPLC(手性柱：Cellulose-SC 4.6*100mm 5μm；流动相：MeOH(0.2％Methanol Ammonia))分离得到两个异构体。
实施例1A(异构体A，(S)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-C]喹啉-1-基)-2-丙醇)：RT(保留时间)＝2.05min。LC-MS：m/z 301(M+H) +。 1H NMR(400MHz,CDCl 3)δ7.82(d,J＝12Hz,1H),7.63(d,J＝12Hz,1H),7.41(t,J＝8Hz,1H),7.25-7.22(m,1H),5.42(s,2H),4.93(d,J＝12Hz,1H),4.68(d,J＝12Hz,1H),4.61-4.57(m,1H),4.52-4.46(m,2H),3.67-3.59(m,2H),1.48(d,J＝8Hz,3H),1.24(t,J＝6Hz,3H)。
实施例1B(异构体B，(R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-C]喹啉-1-基)-2-丙醇)：RT(保留时间)＝3.19min。LC-MS：m/z 301(M+H) +。 1H NMR(400MHz,CDCl 3)δ7.82(d,J＝12Hz,1H),7.63(d,J＝12Hz,1H),7.41(t,J＝8Hz,1H),7.25-7.22(m,1H),5.42(s,2H),4.93(d,J＝12Hz,1H),4.68(d,J＝12Hz,1H),4.61-4.57(m,1H),4.52-4.46(m,2H),3.67-3.59(m,2H),1.48(d,J＝8Hz,3H),1.24(t,J＝6Hz,3H)。
实施例2A和2B
((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(苯氧)磷酰)-L-丙氨酸异丙酯和((S)-(((S)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(苯氧)磷酰)-L-丙氨酸异丙酯的制备
Figure PCTCN2020128168-appb-000057
第一步：1-(2-(乙氧基甲基)-4-(三苯甲氨基)-1H-咪唑并[4,5-C]喹啉-1-基)-2-丙醇的制备
1-(4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-C]喹啉-1-基)-2-丙醇(250mg，0.83mmol)、三苯基氯甲烷(325mg，1.17mmol)和碳酸铯(1g，3.33mmol)的乙腈(20mL)溶液在140℃反应8小时后在100℃反应16小时。得到的混合物冷却至室温后减压浓缩。得到的粗品经柱层析纯化后得到目标产物(340mg，产率75％)。
LC-MS：m/z 543(M+H) +。
第二步：((S)-(((R)-1-(2-(乙氧基甲基)-4-(三苯甲氨基氨基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(苯氧)磷酰)-L-丙氨酸异丙酯和((S)-(((S)-1-(2-(乙氧基甲基)-4-(三苯甲氨基氨基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(苯氧)磷酰)-L-丙氨酸异丙酯的制备
在氮气保护下于-7℃将叔丁基氯化镁的四氢呋喃溶液(1M,0.7mL，0.7mmol) 滴加到1-(2-(乙氧基甲基)-4-(三苯甲氨基)-1H-咪唑并[4,5-C]喹啉-1-基)-2-丙醇(180mg，0.33mmol)的四氢呋喃(6mL，33.3vol)溶液中。滴加完毕，反应液在-7℃反应1.5小时后滴加((S)-(全氟苯氧基)(苯氧基)膦酰)-L-丙氨酸异丙酯(230mg，0.51mmol)的四氢呋喃(2mL)溶液。得到的混合物在-7℃反应7小时后滴加稀盐酸(1N)调pH到4，然后用乙酸乙酯萃取。合并的有机相用无水硫酸镁干燥后过滤。滤液减压浓缩，得到的粗品用柱层析纯化得到((S)-(((R)-1-(2-(乙氧基甲基)-4-(三苯甲氨基氨基)-1H-咪唑[4,5-c]喹啉-1-yl)丙基-2-yl)氧)(苯氧)磷酰)-L-丙氨酸异丙酯和((S)-(((S)-1-(2-(乙氧基甲基)-4-(三苯甲氨基氨基)-1H-咪唑[4,5-c]喹啉-1-yl)丙基-2-yl)氧)(苯氧)磷酰)-L-丙氨酸异丙酯的混合物(1:1,165mg)。
LC-MS：m/z 813(M+H) +。
第三步：((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(苯氧)磷酰)-L-丙氨酸异丙酯和((S)-(((S)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(苯氧)磷酰)-L-丙氨酸异丙酯的制备
在0℃下将三氟乙酸(2mL)滴加到((S)-(((S)-1-(2-(乙氧基甲基)-4-(三苯甲氨基氨基)-1H-咪唑[4,5-c]喹啉-1-yl)丙基-2-yl)氧)(苯氧)磷酰)-L-丙氨酸异丙酯的混合物(1:1,80mg，0.1mmol)的二氯甲烷(6mL，75)溶液中。滴加完毕，反应液在0℃反应1小时后在室温反应3小时，然后减压浓缩。残余物经制备色谱纯化后分别得到两个异构体((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-yl)丙基-2-yl)氧)(苯氧)磷酰)-L-丙氨酸异丙酯和((S)-(((S)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-yl)丙基-2-yl)氧)(苯氧)磷酰)-L-丙氨酸异丙酯的三氟乙酸盐。
实施例2A(异构体A)：LC-MS：m/z 570(M+H) +。 1H NMR(400MHz,CDCl 3)δ11.08(s,1H),8.00(d,J＝8Hz,1H),7.95(d,J＝8Hz,1H),7.62(t,J＝8Hz,1H),7.46(t,J＝8Hz,1H),7.28(s,1H),7.24(s,1H),7.12(t,J＝8Hz,1H),7.00(d,J＝8Hz,2H),6.69(s,1H),5.05(s,1H),4.92-4.85(m,3H),4.76-4.67(m,2H),3.63(q,J＝8Hz,2H),3.54(q,J＝8Hz,1H),3.06(t,J＝12Hz,1H),1.56(d,J＝4Hz,3H),1.27-1.24(m,4H),1.17-1.15(m,6H),0.88(d,J＝8Hz,3H)。 31P NMR(162MHz,CDCl 3)δ1.90(s,1P)。
实施例2B(异构体B)：LC-MS：m/z 570(M+H) +。 1H NMR(400MHz,CDCl 3)δ10.99(s,1H),8.00(d,J＝8Hz,1H),7.93(d,J＝8Hz,1H),7.62(t,J＝8Hz,1H),7.47(t,J＝8Hz,1H),7.07-7.02(m,3H),6.59(d,J＝8Hz,2H),6.55(s,1H),5.15(s,1H),5.03-4.97(m,1H),4.87-4.81(m,2H),4.71-4.62(m,2H),3.73(q,J＝8Hz,1H),3.59(q,J＝8Hz,2H),3.49(t,J＝10Hz,1H),1.61(d,J＝4Hz,3H),1.27-1.22(m,13H). 31P NMR(162MHz,CDCl 3)δ1.33(s,1P).
以同样的方法以不同的起始原料合成了以下实例：
实施例3A和3B
((R)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-yl)氧)(苯氧)磷酰)-L-丙氨酸异丙酯和((R)-(((S)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(苯氧)磷酰)-L-丙氨酸异丙酯
Figure PCTCN2020128168-appb-000058
实施例3A(异构体A)：LC-MS：m/z 570(M+H) +。 1H NMR(400MHz,CDCl 3)δ11.05(s,1H),8.01(d,J＝8Hz,1H),7.96(d,J＝8Hz,1H),7.62(t,J＝8Hz,1H),7.46(t,J＝8Hz,1H),7.28(s,1H),7.24(s,1H),7.12(t,J＝8Hz,1H),7.00(d,J＝8Hz,2H),6.64(s,1H),5.06(s,1H),4.92-4.85(m,3H),4.76-4.68(m,2H),3.63(q,J＝8Hz,2H),3.54(q,J＝8Hz,1H),3.08(t,J＝8Hz,1H),1.57(d,J＝4Hz,3H),1.25(t,J＝6Hz,3H),1.16(m,6H),0.88(d,J＝8Hz,3H)。 31P NMR(162MHz,CDCl 3)δ1.88(s,1P)。
实施例3B(异构体B)：LC-MS：m/z 570(M+H) +。 1H NMR(400MHz,CDCl 3)δ10.71(s,1H),8.01(d,J＝8Hz,1H),7.94(d,J＝8Hz,1H),7.63(t,J＝8Hz,1H),7.48(t,J＝8Hz,1H),7.05(m,3H),6.59(d,J＝8Hz,2H),6.51(s,1H),5.15(s,1H),5.04-4.98(m,1H),4.88-4.81(m,2H),4.72-4.63(m,2H),3.73(q,J＝8Hz,1H),3.60(q,J＝8Hz,2H),3.50(t,J＝8Hz,1H),1.62(d,J＝8Hz,3H),1.25-1.22(m,12H)。 31P NMR(162MHz,CDCl 3)δ1.27(s,1P)。
实施例4A和4B
((S)-(((S)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(萘-1-基氧基)磷酰)-L-丙氨酸异丙酯和((R)-(((S)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(萘-1-基氧基)磷酰)-L-丙氨酸异丙酯
Figure PCTCN2020128168-appb-000059
实施例4A(异构体A)：LC-MS：m/z 620(M+H) +。
实施例4B(异构体B)：LC-MS：m/z 620(M+H) +。
实施例5A和5B
((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(萘-1-基氧基)磷酰)-L-丙氨酸异丙酯和((R)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(萘-1-基氧基)磷酰)-L-丙氨酸异丙酯
Figure PCTCN2020128168-appb-000060
实施例5A(异构体A)：LC-MS：m/z 620(M+H) +。 1H NMR(400MHz,CDCl 3)δ8.67(s,1H),7.91(d,J＝8Hz,1H),7.83(d,J＝8Hz,1H),7.69(d,J＝8Hz,1H),7.52-7.44(m,3H),7.36-7.29(m,3H),7.06(d,J＝8Hz,1H),7.00(t,J＝8Hz,1H),5.24(s,1H),5.07-5.00(m,1H),4.78-4.68(m,2H),4.59-4.53(m,2H),3.98-3.88(m,1H),3.64(t,J＝8Hz,1H),3.58-3.52(m,2H),1.67(d,J＝4Hz,3H),1.36(d,J＝8Hz,3H),1.25-1.22(m,9H)。
实施例5B(异构体B)：LC-MS：m/z 620(M+H) +。 1H NMR(400MHz,CDCl 3)δ8.78(s,1H),8.00(d,J＝8Hz,1H),7.93(d,J＝8Hz,1H),7.83(d,J＝12Hz,1H),7.72(d,J＝8Hz,1H),7.64(d,J＝8Hz,1H),7.55-7.48(m,2H),7.46-7.41(m,2H),7.36-7.29(m,2H),5.15(s,1H),4.88-4.67(m,5H),3.57-3.50(m,2H),3.42(q，J＝8Hz,1H),2.98(t,J＝8Hz,1H),1.60(d,J＝4Hz,3H),1.21(t,J＝8Hz,3H),1.09-1.06(m,6H),0.89(d,J＝8Hz,3H)。
实施例6A和6B
((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(萘-2-基氧基)磷酰)-L-丙氨酸异丙酯和((R)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(萘-2-基氧基)磷酰)-L-丙氨酸异丙酯
Figure PCTCN2020128168-appb-000061
实施例6A(异构体A)：LC-MS：m/z 620(M+H) +。 1H NMR(400MHz,CDCl 3)δ8.73(s,1H),7.95(d,J＝8Hz,1H),7.82(d,J＝8Hz,1H),7.77(d,J＝12Hz,1H),7.55(t,J＝8Hz,1H),7.51(d,J＝8Hz,1H)，7.45-7.43(m,3H),7.39(s,1H),7.30(t,J＝4Hz,1H),7.10(s,1H),6.69(d,J＝12Hz,1H),5.25-5.17(m,1H),5.04-4.98(m,1H),4.84-4.77(m,2H),4.61-4.56(m,1H),3.86-3.77(m,1H),3.63(d,J＝8Hz,1H),3.56(q,J＝8Hz,3H),1.66(d,J＝8Hz,3H),1.29(d,J＝8Hz,3H),1.24(m,9H)。
实施例6B(异构体B)：LC-MS：m/z 620(M+H) +。 1H NMR(400MHz,CDCl 3)δ8.77(s,1H),8.00(d,J＝8Hz,1H),7.94(d,J＝8Hz,1H),7.81(d,J＝8Hz,1H),7.73(t,J＝8Hz,2H),7.56(t,J＝8Hz,1H),7.52-7.42(m,3H),7.34(t,J＝8Hz,1H),7.15(d,J＝12Hz,1H),5.12(s,1H),4.91-4.69(m,5H),3.58(q，J＝8Hz,2H),3.48-3.39(m,1H),3.09(t,J＝8Hz,2H),1.58(d,J＝4Hz,3H),1.23(t,J＝8Hz,3H),1.12-1.08(m,6H),0.98(d,J＝8Hz,3H)。
实施例7A和7B
((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(2-甲基-苯氧)磷酰)-L-丙氨酸异丙酯和((R)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(2-甲基-苯氧)磷酰)-L-丙氨酸异丙酯
Figure PCTCN2020128168-appb-000062
实施例7A(异构体A)：LC-MS：m/z 584(M+H) +。 1H NMR(400MHz,CDCl 3)δ8.77(s,1H),7.98(d,J＝8Hz,1H),7.92(d,J＝12Hz,1H),7.57(t,J＝8Hz,1H),7.40(t,J＝8Hz,1H),6.92-6.77(m,4H),5.15(s,1H),5.06-4.99(m,1H),4.83-4.77(m,2H),4.66-4.57(m,2H),3.87-3.79(m,1H),3.59(q,J＝8Hz,2H),3.51(t,J＝8Hz,1H),1.73(s,3H),1.61(d,J＝4Hz,3H),1.31(d,J＝8Hz,3H),1.27-1.23(m,9H)。 31P NMR(162MHz,CDCl 3)δ1.22(s,1P)。
实施例7B(异构体B)：LC-MS：m/z 584(M+H) +。 1H NMR(400MHz,CDCl 3)δ8.76(s,1H),7.99(d,J＝8Hz,1H),7.90(d,J＝8Hz,1H),7.53(t,J＝8Hz,1H),7.31(t,J＝8Hz,1H),7.23(d,J＝8Hz,1H),7.13-7.07(m,2H),7.02(t,J＝8Hz,1H),5.10(s,1H),4.91-4.67(m,5H),3.59(q,J＝8Hz,2H),3.41-3.31(m,1H),3.08(t,J＝8Hz,1H),2.05(s,3H),1.56(d,J＝8Hz,3H),1.24(t,J＝8Hz,3H),1.12-1.10(m,6H),0.93(d,J＝8Hz,3H)。 31P NMR(162MHz,CDCl 3)δ1.81(s,1P)。
实施例8A和8B
((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(3-甲基-苯氧)磷酰)-L-丙氨酸异丙酯和((R)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(3-甲基-苯氧)磷酰)-L-丙氨酸异丙酯
Figure PCTCN2020128168-appb-000063
实施例8A(异构体A)：LC-MS：m/z 584(M+H) +。 1H NMR(400MHz,CDCl 3)δ8.74(s,1H),7.98(d,J＝12Hz,1H),7.91(d,J＝8Hz,1H),7.58(t,J＝8Hz,1H), 7.41(t,J＝8Hz,1H),6.91(t,J＝8Hz,1H),6.82(d,J＝8Hz,1H),6.42(J＝8Hz,1H),6.35(s,1H),5.13(s,1H),5.04-4.97(m,1H),4.83(t,J＝12Hz,2H),4.71(d,J＝12Hz,1H),4.66-4.60(m,1H),3.77-3.67(m,1H),3.59(q,J＝8Hz,3H),2.15(s,3H),1.62(d,J＝8Hz,3H),1.27-1.22(m,12H)。 31P NMR(162MHz,CDCl 3)δ1.26(s,1P)。
实施例8B(异构体B)：LC-MS：m/z 584(M+H) +。 1H NMR(400MHz,CDCl 3)δ8.78(s,1H),8.01(d,J＝4Hz,1H),7.91(d,J＝8Hz,1H),7.56(t,J＝8Hz,1H),7.36(t,J＝8Hz,1H),7.14(t,J＝8Hz,1H),6.95(d,J＝8Hz,1H),6.81(s,2H),5.09(s,1H),4.92-4.68(m,4H),3.60(q，J＝8Hz,2H),3.43-3.33(m,1H),2.98(t,J＝8Hz,1H),2.30(s,3H),1.56(d,J＝8Hz,3H),1.24(t,J＝8Hz,3H),1.14-1.11(m,6H),0.94(d,J＝8Hz,3H)。 31P NMR(162MHz,CDCl 3)δ1.50(s,1P)。
实施例9A和9B
((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(4-甲基-苯氧)磷酰)-L-丙氨酸异丙酯和((R)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(4-甲基-苯氧)磷酰)-L-丙氨酸异丙酯
Figure PCTCN2020128168-appb-000064
实施例9A(异构体A)：LC-MS：m/z 584(M+H) +。 1H NMR(400MHz,CDCl 3)δ8.74(s,1H),7.99(d,J＝8Hz,1H),7.93(d,J＝12Hz,1H),7.58(t,J＝8Hz,1H),7.41(t,J＝8Hz,1H),6.83(d,J＝8Hz,2H),6.49(d,J＝8Hz,2H),5.13(s,1H),5.03-4.97(m,1H),4.86-4.80(m,2H),4.72(d,J＝12Hz,1H),4.65-4.60(m,1H),3.77-3.71(m,1H),3.59(q,J＝8Hz,2H),3.50(t,J＝8Hz,1H),2.24(s,3H),1.61(d,J＝8Hz,3H),1.27-1.21(m,12H)。 31P NMR(162MHz,CDCl 3)δ1.46(s,1P)。
实施例9B(异构体B)：LC-MS：m/z 584(M+H) +。 1H NMR(400MHz,CDCl 3)δ8.77(s,1H),8.00(d,J＝8Hz,1H),7.90(t,J＝8Hz,1H),7.55(q,J＝8Hz,1H),7.35(t,J＝8Hz,1H),7.06(d,J＝8Hz,2H),6.90(d,J＝4Hz,2H),5.09(s,1H),4.91-4.68(m,4H),3.60(q,J＝8Hz,2H),3.41-3.35(m,1H),3.12-2.99(m,1H),2.29(s,3H),1.55(d,J＝8Hz,3H),1.24(t,J＝8Hz,3H),1.13-1.11(m,6H),0.94(d, J＝8Hz,3H)。 31P NMR(162MHz,CDCl 3)δ1.78(s,1P)。
实施例10A和10B
((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(2-氯-苯氧)磷酰)-L-丙氨酸异丙酯和((R)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(2-氯-苯氧)磷酰)-L-丙氨酸异丙酯
Figure PCTCN2020128168-appb-000065
实施例10A(异构体A)：LC-MS：m/z 604(M+H) +。 1H NMR(400MHz,CDCl 3)δ8.80(s,1H),7.94(d,J＝8Hz,1H),7.85(d,J＝8Hz,1H),7.52(t,J＝8Hz,1H),7.33(t,J＝8Hz,1H),7.18(t,J＝8Hz,1H),7.01-6.87(m,3H),5.21(m,1H),5.50(m,1H),4.90-4.84(m,2H),4.71-4.61(m,2H),3.87(m,1H),3.60(q,J＝8Hz,3H),1.63(d,J＝8Hz,3H),1.28-1.22(m,12H)。 31P NMR(162MHz,CDCl 3)δ1.20(s)。
实施例10B(异构体B)：LC-MS：m/z 604(M+H) +。 1H NMR(400MHz,CDCl 3)δ8.78(s,1H),7.99(d,J＝8Hz,1H),7.89(d,J＝8Hz,1H),7.54(t,1H,J＝8Hz),7.39-7.32(m,3H),7.20(t,J＝8Hz,1H),7.07(t,J＝8Hz,1H),5.15(m,1H),4.96-4.71(m,5H),3.60(q,J＝8Hz,2H),3.49(m,1H),3.19(t,J＝8Hz,1H),1.60(d,J＝8Hz,3H),1.24(t,J＝8Hz,3H),1.13(t,J＝8Hz,6H),0.92(d,J＝8Hz,3H)。 31P NMR(162MHz,CDCl 3)δ1.87(s).
实施例11A和11B
((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(3-氯-苯氧)磷酰)-L-丙氨酸异丙酯和((R)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-yl)丙基-2-yl)氧)(3-氯-苯氧)磷酰)-L-丙氨酸异丙酯
Figure PCTCN2020128168-appb-000066
实施例11A(异构体A)：LC-MS：m/z 604(M+H) +。 1H NMR(400MHz,CDCl 3)δ8.79(s,1H),7.99(d,J＝8Hz,1H),7.88(d,J＝8Hz,1H),7.56(t,J＝8Hz,1H),7.38(t,J＝8Hz,1H),7.00(m,2H),6.70(s,1H),6.49(d,J＝8Hz,1H),5.15(m,1H),5.00(m,1H),4.84(m,2H),4.73-4.62(m,2H),3.68(m,1H),3.62-3.53(m,3H),1.63(d,J＝8Hz,3H),1.25-1.18(m,12H)。 31P NMR(162MHz,CDCl 3)δ1.14(s)。
实施例11B(异构体B)：LC-MS：m/z 604(M+H) +。LCMSm/z 604.59(M+H) +
1H NMR(400MHz,CDCl 3)δ8.78(s,1H),8.01(d,J＝8Hz,1H),7.92(d,J＝8Hz,1H),7.58(t,J＝8Hz,1H),7.37(t,J＝8Hz,1H),7.20(d,J＝8Hz,1H),7.14(d,J＝8Hz,1H),7.03(s,1H),6.96(d,J＝8Hz,1H),5.12(m,1H),4.89-4.70(m,5H),3.65(q,2H,J＝8Hz),3.36(m,1H),3.02(t,J＝8Hz,1H),1.58(d,J＝8Hz,3H),1.26(t,J＝8Hz,3H),1.13(m,J＝8Hz,6H),0.96(d,J＝8Hz,3H)。 31P NMR(162MHz,CDCl 3)δ1.61(s)。
实施例12A和12B
((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(4-氯-苯氧)磷酰)-L-丙氨酸异丙酯和((R)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(4-氯-苯氧)磷酰)-L-丙氨酸异丙酯
Figure PCTCN2020128168-appb-000067
实施例12A(异构体A)：LC-MS：m/z 604(M+H) +。 1H NMR(400MHz,CDCl 3) δ8.78(s,1H),8.00(d,J＝8Hz,1H),7.88(d,J＝8Hz,1H),7.55(t,J＝8Hz,1H),7.35(t,J＝8Hz,1H),7.05(d,J＝8Hz,2H),6.60(d,J＝8Hz,2H),5.15(m,1H),4.98(m,1H),4.90-4.84(m,2H),4.72-4.63(m,2H),3.70-3.64(m,1H),3.59(q,J＝8Hz,2H),3.47(tJ＝8Hz,1H,)1.61(d,J＝4Hz,3H),1.26-1.20(m,9H),1.16(d,J＝8Hz,3H)。 31P NMR(162MHz,CDCl 3)δ1.29(s)。
实施例12B(异构体B)：LC-MS：m/z 604(M+H) +。 1H NMR(400MHz,CDCl 3)δ8.71(s,1H),7.99(d,J＝8Hz,1H),7.88(d,J＝8Hz,1H),7.54(t,J＝8Hz,1H),7.33(t,J＝8Hz,1H),7.22(d,J＝8Hz,2H),6.98(d,J＝8Hz,2H),5.13(m,1H),4.91-4.69(m,5H),3.61(q,J＝8Hz,2H),3.33(m,1H),3.12(t,J＝8Hz,1H),1.57(d,J＝8Hz,3H),1.27(t,J＝8Hz,3H),1.13(t,J＝8Hz,6H),0.93(d,J＝8Hz,3H)。 31P NMR(162MHz,CDCl 3)δ1.72(s)。
实施例13A和13B
((S)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙基-2-基)氧)(苯氧)磷酰)-D-丙氨酸异丙酯和((R)-(((R)-1-(4-氨基-2-(乙氧基甲基)-1H-咪唑[4,5-c]喹啉-1-yl)丙基-2-基)氧)(苯氧)磷酰)-D-丙氨酸异丙酯
Figure PCTCN2020128168-appb-000068
实施例13A(异构体A)：LC-MS：m/z 570(M+H) +。 1H NMR(400MHz,CDCl 3)δ8.72(s,1H),8.03(d,J＝8Hz,1H),7.95(d,J＝8Hz,1H),7.60(t,J＝8Hz,1H),7.44(t,J＝8Hz,1H),7.09-7.03(m,3H),6.64(d,J＝8Hz,2H),5.15(s,1H),4.94-4.82(m,3H),4.72-4.62(m,2H),3.74-3.65(m,1H),3.59(q,J＝8Hz,2H),3.36(t,J＝8Hz,1H),1.64(d,J＝4Hz,3H),1.25(t,J＝8Hz,3H),1.21-1.17(m,9H)。
实施例13B(异构体B)：LC-MS：m/z 570(M+H) +。 1H NMR(400MHz,CDCl 3)δ8.76(s,1H),7.99(d,J＝12Hz,1H),7.94(d,J＝8Hz,1H),7.58(t,J＝8Hz,1H),7.39(t,J＝8Hz,1H),7.29(s,1H),7.26(t,J＝4Hz,1H),7.13(t,J＝8Hz,1H),7.05(d,J＝8Hz,2H),5.03(s,1H),4.91-4.84(m,3H),4.74-4.66(m,2H),3.60(q,J＝8 Hz,2H),3.53(t,J＝8Hz,2H),2.93(t,J＝8Hz,1H),1.56(d,J＝8Hz,3H),1.25(t,J＝8Hz,3H),1.16-1.14(m,6H),0.82(d,J＝8Hz,3H). 31P NMR(162MHz,CDCl 3)δ2.04(s,1P).
实施例14A和14B
((S)-(((R)-1-(4-氨基-2-(乙氧甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧)(苯氧)磷酰)-L-丙氨酸叔丁酯和((R)-(((R)-1-(4-氨基-2-(乙氧甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧)(苯氧)磷酰)-L-丙氨酸叔丁酯
Figure PCTCN2020128168-appb-000069
实施例14A(异构体A)：LC-MS：m/z 584(M+H) +。 1H NMR(400MHz,CDCl 3)δ8.02(d,J＝8Hz,1H),7.87(d,J＝8Hz,1H),7.55(t,J＝8Hz,1H),7.36(t,J＝8Hz,1H),7.08(t,J＝8Hz,2H),7.01(t,J＝8Hz,1H),6.67(d,J＝8Hz,2H),5.14(s,1H),4.90-4.84(m,2H),4.72-4.62(m,2H),3.68-3.63(m,1H),3.6-3.55(q,J＝8Hz,2H),3.43(t,J＝12Hz,1H),1.60(d,J＝4Hz,3H),1.43(s,9H),1.23(t,J＝8Hz,3H),1.16(d,J＝8Hz,3H)。 31P NMR(162MHz,CDCl 3)δ1.34(s,1P).
实施例14B(异构体B)：LC-MS：m/z 584(M+H) +。 1H NMR(400MHz,CDCl 3)δ8.01(d,J＝8Hz,1H),7.88(d,J＝8Hz,1H),7.55(t,J＝8Hz,1H),7.34(t,J＝8Hz,1H),7.30(d,J＝8Hz,2H),7.13(t,J＝8Hz,1H),7.05(d,J＝8Hz,2H),5.11(s,1H),4.91-4.84(m,2H),4.77-4.68(m,2H),3.61-3.56(q,J＝8Hz,2H),3.33-3.23(m,1H),2.97(t,J＝8Hz,1H),1.60(d,J＝4Hz,3H),1.32(s,9H),1.24(t,J＝8Hz,3H),0.89(d,J＝8Hz,3H)。 31P NMR(162MHz,CDCl 3)δ1.65(s,1P).
实施例15A和15B
((S)-(((R)-1-(4-氨基-2-(乙氧甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧)(苯氧)磷酰)-L-丙氨酸甲酯和((R)-(((R)-1-(4-氨基-2-(乙氧甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧)(苯氧)磷酰)-L-丙氨酸甲酯
Figure PCTCN2020128168-appb-000070
实施例15A(异构体A)：LC-MS：m/z 542(M+H) +。 1H NMR(400MHz,CDCl 3)δ8.01(d,J＝8Hz,1H),7.93(d,J＝8Hz,1H),7.63(t,J＝8Hz,1H),7.47(t,J＝8Hz,1H),7.08-7.03(m,3H)，6.60-6.55(m,3H),5.15(s,1H),4.88-4.81(m,2H),4.72-4.63(m,2H),3.77(t,J＝8Hz,1H),3.71(s,3H),3.60(q,J＝8Hz,2H),3.50(t,J＝8Hz,1H),1.63(d,J＝4Hz,3H),1.27-1.23(m,6H)。 31P NMR(162MHz,CDCl 3)δ1.08(s,1P).
实施例15B(异构体B)：LC-MS：m/z 542(M+H) +。 1H NMR(400MHz,CDCl 3)δ8.05(d,J＝8Hz,1H),7.97(d,J＝8Hz,1H),7.62(t,J＝8Hz,2H),7.43(t,J＝8Hz,1H),7.31-7.29(m,1H),7.28(s,1H),7.16(t,J＝8Hz,1H),7.04(d,J＝8Hz,2H),5.10(s,1H),4.93-4.92(d,J＝4Hz,1H),4.88(t,J＝8Hz,1H),4.81-4.71(m,2H),3.64(q，J＝8Hz,2H),3.56(s,3H),3.46(q，J＝4Hz,1H),2.99(t,J＝8Hz,1H),1.60(d,J＝4Hz,3H),1.28(t,J＝8Hz,3H),1.01(d,J＝8Hz,3H)。 31P NMR(162MHz,CDCl 3)δ1.65(s,1P).
实施例16A和16B
((S)-(((R)-1-(4-氨基-2-(乙氧甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧)(苯氧)磷酰)-L-丙氨酸苄酯和((R)-(((R)-1-(4-氨基-2-(乙氧甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧)(苯氧)磷酰)-L-丙氨酸苄酯
Figure PCTCN2020128168-appb-000071
实施例16A(异构体A)：LC-MS：m/z 618(M+H) +。
实施例16B(异构体B)：LC-MS：m/z 618(M+H) +。
实施例17A和17B
((S)-(((R)-1-(4-氨基-2-(乙氧甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧)(4-甲基苯氧)磷酰)-L-丙氨酸叔丁酯和((R)-(((R)-1-(4-氨基-2-(乙氧甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧)(4-甲基苯氧)磷酰)-L-丙氨酸叔丁酯
Figure PCTCN2020128168-appb-000072
实施例17A(异构体A)：LC-MS：m/z 598(M+H) +。 1H NMR(400MHz,CDCl 3)δ8.00(d,J＝8Hz,1H),7.87(d,J＝8Hz,1H),7.54(t,J＝8Hz,1H),7.35(t,J＝8Hz,1H),6.85(d,J＝8Hz,2H),6.54(d,J＝8Hz,2H),5.12(s,1H),4.87(t,J＝12Hz,1H),4.88-4.82(m,1H),4.73(d,J＝12Hz,1H),4.66-4.61(m,1H),3.65(t,J＝8Hz,1H),3.57(q,J＝8Hz,2H),3.43(t,J＝8Hz,1H),2.23(s,3H),1.59(d,J＝8Hz,3H),1.43(s,9H),1.23(t,J＝8Hz,3H),1.17(d,J＝8Hz,3H)。 31P NMR(162MHz,CDCl 3)δ1.53(s,1P)
实施例17B(异构体B)：LC-MS：m/z 598(M+H) +。 1H NMR(400MHz,CDCl 3)δ8.01(d,J＝8Hz,1H),7.89(d,J＝8Hz,1H),7.55(t,J＝8Hz,1H),7.35(t,J＝8Hz,1H),7.07(d,J＝8Hz,2H),6.92(d,J＝8Hz,2H),5.08(s,1H),4.91-4.87(m,1H),4.87(d,J＝12Hz,1H),4.77(d,J＝12Hz,1H),4.73-4.67(m,1H),3.59(t,J＝8Hz,2H),3.34-3.26(m,1H),2.94(t,J＝8Hz,1H),2.30(s,3H),1.54(d,J＝8Hz,3H),1.32(s,9H),1.24(t,J＝8Hz,3H),0.90(d,J＝4Hz,3H)。 31P NMR(162MHz,CDCl 3)δ1.83(s,1P).
实施例18A和18B
((S)-(((R)-1-(4-氨基-2-(乙氧甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧)(4-甲氧基苯氧)磷酰)-L-丙氨酸叔丁酯和((R)-(((R)-1-(4-氨基-2-(乙氧甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧)(4-甲氧基苯氧)磷酰)-L-丙氨酸叔丁酯
Figure PCTCN2020128168-appb-000073
实施例18A(异构体A)：LC-MS：m/z 614(M+H) +。 1H NMR(400MHz,CDCl 3)δ8.01(d,J＝8Hz,1H),7.86(d,J＝8Hz,1H),7.54(t,J＝8Hz,1H),7.35(t,J＝8Hz,1H),6.61-6.56(m,4H)，5.13(s,1H),4.90-4.84(m,2H),4.73(d,J＝12Hz,1H),4.67-4.62(m,1H),3.72(s,3H),3.64(t,J＝8Hz,1H),3.57(q,J＝8Hz,2H),3.37(t,J＝12Hz,1H),1.59(d,J＝8Hz,3H),1.43(s,9H),1.23(t,J＝8Hz,3H),1.16(d,J＝4Hz,3H)。 31P NMR(162MHz,CDCl 3)δ1.82(s,1P)
实施例18B(异构体B)：LC-MS：m/z 614(M+H) +。 1H NMR(400MHz,CDCl 3)δ8.02(d,J＝8Hz,1H),7.90(d,J＝8Hz,1H),7.56(t,J＝8Hz,1H),7.36(t,J＝8Hz,1H),6.96(d,J＝8Hz,2H),6.79(d,J＝8Hz,2H),5.09(s,1H),4.91-4.86(m,2H),4.79(d,J＝12Hz,1H),4.73-4.68(m,1H),3.77(s,3H),3.60(t,J＝8Hz,2H),3.30(q,J＝8Hz,1H),2.89(t,J＝12Hz,1H),1.53(d,J＝8Hz,3H),1.32(s,9H),1.24(t,J＝8Hz,3H),0.90(d,J＝4Hz,3H)。 31P NMR(162MHz,CDCl 3)δ2.18(s,1P)
实施例19A和19B
((S)-(((R)-1-(4-氨基-2-(乙氧甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧)(4-氯苯氧)磷酰)-L-丙氨酸叔丁酯和((R)-(((R)-1-(4-氨基-2-(乙氧甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧)(4-氯苯氧)磷酰)-L-丙氨酸叔丁酯
Figure PCTCN2020128168-appb-000074
实施例19A(异构体A)：LC-MS：m/z 618(M+H) +。 1H NMR(400MHz,CDCl 3)δ7.99(d,J＝8Hz,1H),7.83(d,J＝8Hz,1H),7.52(t,J＝8Hz,1H),7.32(t,J＝8Hz,1H),7.03(d,J＝8Hz,2H),6.59(d,J＝8Hz,2H),5.14(s,1H),4.90-4.84(m,2H),4.72(d,J＝16Hz,1H),4.66-4.62(m,1H),3.62-3.54(m,3H),3.46(t,J＝8Hz,1H), 1.60(d,J＝8Hz,3H),1.42(s,9H),1.23(t,J＝8Hz,3H),1.12(d,J＝8Hz,3H)。 31P NMR(162MHz,CDCl 3)δ1.38(s,1P)
实施例19B(异构体B)：LC-MS：m/z 618(M+H) +。 1H NMR(400MHz,CDCl 3)δ7.99(d,J＝8Hz,1H),7.88(d,J＝8Hz,1H),7.54(t,J＝8Hz,1H),7.33(t,J＝8Hz,1H),7.24(d,J＝8Hz,2H),6.98(d,J＝8Hz,2H),5.10(s,1H),4.91-4.84(m,2H),4.78(d,J＝12Hz,1H),4.73-4.69(m,1H),3.60(q,J＝8Hz,2H),3.32-3.23(m,1H),3.05(s,1H),1.56(d,J＝8Hz,3H),1.31(s,9H),1.24(t,J＝8Hz,3H),0.92(d,J＝4Hz,3H)。 31P NMR(162MHz,CDCl 3)δ1.85(s,1P)
实施例20A和20B
((S)-(((R)-1-(4-氨基-2-(乙氧甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧)(4-氯苯氧)磷酰)-L-丙氨酸新戊酯和((R)-(((R)-1-(4-氨基-2-(乙氧甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧)(4-氯苯氧)磷酰)-L-丙氨酸新戊酯
Figure PCTCN2020128168-appb-000075
实施例20A(异构体A)：LC-MS：m/z 632(M+H) +。
实施例20B(异构体B)：LC-MS：m/z 632(M+H) +。
实施例21A和21B
((S)-(((R)-1-(4-氨基-2-(乙氧甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧)(4-氯苯氧)磷酰)-L-丙氨酸-3-戊酯和((R)-(((R)-1-(4-氨基-2-(乙氧甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧)(4-氯苯氧)磷酰)-L-丙氨酸-3-戊酯
Figure PCTCN2020128168-appb-000076
实施例21A(异构体A)：LC-MS：m/z 632(M+H) +。
实施例21B(异构体B)：LC-MS：m/z 632(M+H) +。
实施例22
(((R)-1-(4-氨基-2-(乙氧甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基)氧)(4-氯苯氧)磷酰)-L-缬氨酸叔丁酯
Figure PCTCN2020128168-appb-000077
实施例22：LC-MS：m/z 646(M+H) +。 1H NMR(400MHz,CDCl 3)δ8.00(d,J＝8Hz,1H),7.90(d,J＝8Hz,1H),7.56(t,J＝8Hz,1H),7.37(t,J＝8Hz,1H),7.02(d,J＝8Hz,2H),6.57(d,J＝8Hz,2H),5.13(s,1H),4.89-4.82(m,2H),4.72-4.69(d,J＝12Hz,1H),4.66-4.61(d,J＝12Hz,1H),3.58(q,J＝8Hz,2H),3.53-3.47(m,1H),3.20(t,J＝8Hz,1H),1.94-1.86(m,1H),1.61(d,J＝8Hz,3H),1.42(s,9H),1.24(t,J＝8Hz,3H),0.84(d,J＝8Hz,3H),0.77(d,J＝8Hz,3H)。
实施例23A和23B
(R)-1-(4-氨基-2-(乙氧甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基(4-氯苯基)(S)-((S)-3-甲基丁烷-2-基)磷酰胺和(R)-1-(4-氨基-2-(乙氧甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基(4-氯苯基)(R)-((S)-3-甲基丁烷-2-基)磷酰胺
Figure PCTCN2020128168-appb-000078
实施例23A(异构体A)：LC-MS：m/z 560(M+H) +。 1H NMR(400MHz,CDCl 3)δ8.05(d,J＝8Hz,1H),7.86(d,J＝8Hz,1H),7.54(t,J＝8Hz,1H),7.33(t,J＝8Hz,1H),7.05(d,J＝8Hz,2H),6.60(d,J＝8Hz,2H),5.12(s,1H),4.91-4.85(m,2H),4.73(d,J＝12Hz,1H),4.68-4.62(m,1H),3.57(q,J＝8Hz,2H),2.87(s,1H),2.18(t,J＝ 8Hz,1H),1.64(d,J＝8Hz,3H),1.49-1.40(m,1H),1.23(t,J＝8Hz,3H),0.85(d,J＝8Hz,3H),0.70(t,J＝8Hz,6H)。
实施例23B(异构体B)：LC-MS：m/z 560(M+H) +。 1H NMR(400MHz,CDCl 3)δ7.99(d,J＝8Hz,1H),7.86(d,J＝8Hz,1H),7.54(t,J＝8Hz,1H),7.31(t,J＝8Hz,1H),7.27(s,1H),7.25(s,1H),7.05(d,J＝4Hz,2H),5.04(s,1H),4.87-4.81(m,2H),4.76-4.67(m,2H),3.60(q,J＝8Hz,2H),2.63(s,2H),1.91(t,J＝8Hz,1H),1.57(d,J＝8Hz,3H),1.25(t,J＝8Hz,3H),1.21-1.13(m,1H),0.62(d,J＝8Hz,3H),0.45-0.42(m,6H)。
实施例24A和24B
(R)-1-(4-氨基-2-(乙氧甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基(4-氯苯基)(S)-((S)-1,1,1-三氟丙烷-2-基)磷酰胺和(R)-1-(4-氨基-2-(乙氧甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基(4-氯苯基)(R)-((S)-1,1,1-三氟丙烷-2-基)磷酰胺
Figure PCTCN2020128168-appb-000079
实施例24A(异构体A)：LC-MS：m/z 552(M+H) +。 1H NMR(400MHz,CDCl 3)δ8.02(d,J＝8Hz,1H),7.85(d,J＝8Hz,1H),7.54(t,J＝8Hz,1H),7.33(t,J＝8Hz,1H),7.05-6.97(m,3H),6.77(s,1H),6.58(d,J＝8Hz,2H),5.13(s,1H),4.89-4.83(m,1H),4.85(d,J＝12Hz,1H),4.71(d,J＝12Hz,1H),4.64-4.60(m,1H),3.59-3.54(m,3H),3.20(s,1H),1.64(d,J＝4Hz,3H),1.23(t,J＝8Hz,3H),1.13(d,J＝4Hz,3H)。 31P NMR(162MHz,CDCl 3)δ0.52(s,1P)
实施例24B(异构体B)：LC-MS：m/z 552(M+H) +。 1H NMR(400MHz,CDCl 3)δ7.98(d,J＝8Hz,1H),7.89(d,J＝8Hz,1H),7.57(t,J＝8Hz,1H),7.36(t,J＝8Hz,1H),7.29(t,J＝8Hz,2H),7.15(t,J＝8Hz,1H),7.05(d,J＝8Hz,2H),5.05(s,1H),4.93(d,J＝16Hz,1H),4.90-4.84(m,1H),4.80(d,J＝16Hz,1H),4.75-4.70(m,1H),3.63(m,3H),3.56(s,1H),1.58(d,J＝4Hz,3H),1.26(t,J＝8Hz,3H),0.92(d,J＝8Hz,3H)。 31P NMR(162MHz,CDCl 3)δ1.87(s,1P)
实施例25A和25B
(R)-1-(4-氨基-2-(乙氧甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基(4-氯苯基)(S)-((S)-1-甲氧基丙烷-2-基)磷酰胺和(R)-1-(4-氨基-2-(乙氧甲基)-1H-咪唑[4,5-c]喹啉-1-基)丙烷-2-基(4-氯苯基)(R)-((S)-1-甲氧基丙烷-2-基)磷酰胺
Figure PCTCN2020128168-appb-000080
实施例25A(异构体A)：LC-MS：m/z 528(M+H) +。 1H NMR(400MHz,CDCl 3)δ8.07(d,J＝8Hz,1H),7.88(d,J＝8Hz,1H),7.57(t,J＝8Hz,1H),7.42(t,J＝8Hz,1H),7.09-7.00(m,4H),6.66(d,J＝8Hz,2H),5.12(s,1H),4.90-4.65(m,4H),3.59(q,J＝8Hz,2H),3.23(s,3H),3.16(s,1H),3.08-3.07(m,2H),2.95(t,J＝8Hz,1H),1.65(d,J＝8Hz,3H),1.24(t,J＝8Hz,3H),0.96(d,J＝8Hz,3H)。 31P NMR(162MHz,CDCl 3)δ2.65(s,1P)
实施例25B(异构体B)：LC-MS：m/z 528(M+H) +。 1H NMR(400MHz,CDCl 3)δ8.10(d,J＝8Hz,1H),7.93(d,J＝8Hz,1H),7.58(t,J＝8Hz,1H),7.45(t,J＝8Hz,1H),7.29(d,J＝8Hz,1H),7.24(s,1H),7.11(t,J＝8Hz,1H),7.05(d,J＝8Hz,2H),5.06(s,1H),4.95-4.89(m,2H),4.78-4.73(m,2H),3.62(q,J＝8Hz,2H),3.11(s,3H),3.04(s,1H),2.89-2.81(m,3H),1.60(d,J＝8Hz,3H),1.25(t,J＝8Hz,3H),0.83(d,J＝8Hz,3H). 31P NMR(162MHz,CDCl 3)δ3.05(s,1P)
生物学测试评价
以下生物学测试例进一步描述解释本发明，但这些实例并非意味着限制本发明的范围
化合物对TLR7和TLR8激活作用的体外实验
实验步骤
对化合物用DMSO进行1:3系列稀释9个浓度点，双复孔，用Echo加入96孔板中。
将HEK-Blue TM hTLR细胞悬浮在培养液中，然后以50,000细胞/孔的密度种到含有化合物的96孔板中。细胞在5％CO 2、37℃条件下培养1天。细胞培养液中的DMSO最终浓度为0.5％。
取20uL细胞培养上清，按照QUANTI-Blue说明书，检测上清中的报告基因SEAP， 用酶标仪读取OD650信号值，用于计算化合物对hTLR7和hTLR8的激动活性。
按照CellTiter-Glo说明书，测定细胞活力，用酶标仪读取Luminescence信号值，用于计算化合物的细胞毒性。
应用GraphPad Prism软件计算化合物的EC 50和CC 50值，并绘出拟合曲线
参照化合物R848结构如下：
Figure PCTCN2020128168-appb-000081
本发明中实施例化合物对TLR7和TLR8激动活性见表1。
表1本发明中实施例化合物酶学活性
Figure PCTCN2020128168-appb-000082
Figure PCTCN2020128168-appb-000083
其中，“/”表示未测定或空。
从表1可以看出：
1)相对于对照化合物R848和实施例1化合物，本发明化合物具有很好择性TLR7激动活性(相对于TLR8激动活性)，或具有超高的TLR8选择性激动活性(相对于TLR7激动活性)；
2)从表1的CC 50数据可以看出，本发明化合物相对于对照化合物R848具有更低的细胞毒性，从而具有更好的安全性。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (12)

  1. 具有通式(I)结构的咪唑并喹啉取代磷酸酯类化合物、或其立体异构体、互变异构体、晶型、或其药学上可接受的盐、水合物、溶剂合物或前药：
    Figure PCTCN2020128168-appb-100001
    式中：
    R 1选自取代或未取代的下组基团：氢、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C18环烷基、杂环基、C6-C10芳基、杂芳基、-(CH 2) nOR 5、-(CH 2) nO(CH 2) mR 5、-(CH 2) nSR 5、-(CH 2) nCOR 5、-(CH 2) nC(O)OR 5、-(CH 2) nS(O) mR 5、-(CH 2) nNR 6R 7、-(CH 2) nC(O)NR 6R 7、-(CH 2) nNR 6C(O)R 5、-(CH 2) nNR 6S(O) mR 5；其中所述取代指被选自下组的一个或多个基团取代：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C18环烷基、杂环基、C6-C10芳基、杂芳基、-(CH 2) nOR 5、-(CH 2) nSR 5、-(CH 2) nCOR 5、-(CH 2) nC(O)OR 5、-(CH 2) nS(O) mR 5、-(CH 2) nNR 6R 7、-(CH 2) nC(O)NR 6R 7、-(CH 2) nC(O)NHR 6、-(CH 2) nNR 6C(O)R 5、-(CH 2) nNR 6S(O) mR 5；
    R 2相同或不同，且独立地选自下组：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C18环烷基、杂环基、C6-C10芳基、杂芳基、-(CH 2) nOR 5、-(CH 2) nSR 5、-(CH 2) nCOR 5、-(CH 2) nC(O)OR 5、-(CH 2) nS(O) mR 5、-(CH 2) nNR 6R 7、-(CH 2) nC(O)NR 6R 7、-(CH 2) nC(O)NHR 6、-(CH 2) nNR 6C(O)R 5、-(CH 2) nNR 6S(O) mR 5；
    Z选自取代或未取代的下组基团：C1-C18亚烷基、氘代C1-C18亚烷基、卤代C1-C18亚烷基、C1-C18亚烷氧基、卤代C1-C18亚烷氧基、C3-C18亚环烷基、C1-C18亚烷基C3-C18亚环烷基、C3-C18亚环烷基C1-C18亚烷基、C1-C18亚烷基C3-C18亚环烷基C1-C18亚烷基、亚杂环基、C6-C10亚芳基、亚杂芳基，其中所述取代指被选自下组的一个或多个基团取代：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C18环烷基、杂环基、C6-C10芳基、杂芳基、-(CH 2) nOR 5、-(CH 2) nSR 5、-(CH 2) nCOR 5、-(CH 2) nC(O)OR 5、-(CH 2) nS(O) mR 5、-(CH 2) nNR 6R 7、-(CH 2) nC(O)NR 6R 7、-(CH 2) nC(O)NHR 6、-(CH 2) nNR 6C(O)R 5、-(CH 2) nNR 6S(O) mR 5；
    Y选自O、N或NR 4；
    R 4选自取代或未取代的下组基团：氢、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、C3-C18环烷基、杂环基、C6-C10芳基、杂芳基，其中所述取代指被选自下组的一个或多个基团取代：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C18环烷基、杂环基、C6-C10芳基、杂芳基、-(CH 2) nOR 5、-(CH 2) nSR 5、-(CH 2) nCOR 5、-(CH 2) nC(O)OR 5、-(CH 2) nS(O) mR 5、-(CH 2) nNR 6R 7、-(CH 2) nC(O)NR 6R 7、-(CH 2) nC(O)NHR 6、-(CH 2) nNR 6C(O)R 5、-(CH 2) nNR 6S(O) mR 5；
    R 5选自取代或未取代的下组基团：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、氨基、羟基、氰基、C3-C18环烷基、杂环基、C6-C10芳基、杂芳基，其中所述取代指被选自下组的一个或多个基团取代：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C18环烷基、杂环基、C6-C10芳基、杂芳基、-(CH 2) nOR 8、-(CH 2) nSR 8、-(CH 2) nCOR 8、-(CH 2) nC(O)OR 8、-(CH 2) nS(O) mR 8、-(CH 2) nNR 8R 9、-(CH 2) nC(O)NR 8R 9、-(CH 2) nC(O)NHR 9、-(CH 2) nNR 9C(O)R 8、-(CH 2) nNR 9S(O) mR 8；
    R 6和R 7相同或不同，且各自独立地选自取代或未取代的下组基团：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、氨基、羟基、C3-C18环烷基、杂环基、C6-C10芳基、杂芳基；其中所述取代指被选自下组的一个或多个基团取代：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C18环烷基、杂环基、C6-C10芳基、杂芳基、-(CH 2) nOR 8、-(CH 2) nSR 8、-(CH 2) nCOR 8、-(CH 2) nC(O)OR 8、-(CH 2) nS(O) mR 8、-(CH 2) nNR 8R 9、-(CH 2) nC(O)NR 8R 9、-(CH 2) nC(O)NHR 9、-(CH 2) nNR 9C(O)R 8、-(CH 2) nNR 9S(O) mR 8；
    R 8和R 9相同或不同，且各自独立地选自取代或未取代的下组基团：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C18烷氧基、氘代C1-C18烷氧基、卤代C1-C18烷氧基、氨基、羟基、-COOR 16、C3-C18环烷基、杂环基、C6-C10芳基、杂芳基，其中，所述取代指被选自下组的一个或多个基团取代：氘、C1-C20烷基、C1-C6烷氧基、C3-C10环烷基、C4-C10杂环基、C6-C10芳基、C5-C10杂芳基、卤素、氨基、硝基、-COOR 16、氰基、羟基、酰胺基、磺酰胺基；
    X选自下组：-P(＝O)(OH) 2、-P(＝O)(OH)OP(＝O)(OH) 2、-P(＝O)(OH)OP(＝O)(OH)OP(＝O)(OH) 2、-P(＝O)(X 1R 11)(X 2R 12)、-P(＝O)(X 1R 11)(X 3R 14R 15)、-P(＝O)(X 3R 14R 15)(X 3R 14R 15)、-CH 2P(＝O)(X 1R 11)(X 2R 12)、-CH 2P(＝O)(X 1R 11)(X 3R 14R 15)、 -CH 2P(＝O)(X 3R 14R 15)(X 3R 14R 15)、-P(＝S)(X 1R 11)(X 2R 12)、-P(＝S)(X 1R 11)(X 3R 14R 15)、-P(＝S)(X 3R 14R 15)(X 3R 14R 15)、-CH 2P(＝S)(X 1R 11)(X 2R 12)、-CH 2P(＝S)(X 1R 11)(X 3R 14R 15)、-CH 2P(＝S)(X 3R 14R 15)(X 3R 14R 15)、-P(＝NR 13)(X 1R 11)(X 2R 12)、-P(＝NR 13)(X 1R 11)(X 3R 14R 15)、-P(＝NR 13)(X 3R 14R 15)(X 3R 14R 15)、-CH 2P(＝NR 13)(X 1R 11)(X 2R 12)、-CH 2P(＝NR 13)(X 1R 11)(X 3R 14R 15)、-CH 2P(＝NR 13)(X 3R 14R 15)(X 3R 14R 15)；
    X 1、X 2独立地选自下组：氧、硫、-OCH 2O-；
    X 3为氮；
    R 11、R 12、R 13、R 14、R 15独立地选自取代或未取代的下组基团：氢、C1-C20烷基、C1-C20氘代烷基、C3-C10环烷基、C4-C10杂环基、C6-C10芳基、C5-C10杂芳基，或者R 11和R 12与相邻的X 1、X 2和P结合形成取代的5-7元杂环基，所述取代指被选自下组的一个或多个取代基取代：氘、C1-C20烷基、卤代C1-C20烷基、C1-C6烷氧基、C3-C10环烷基、C4-C10杂环基、C6-C10芳基、卤代C6-C10芳基、C5-C10杂芳基、卤素、氨基、硝基、-COR 16、-COOR 16、-OCOOR 16、氰基、羟基、酰胺基、磺酰胺基；
    R 16选自取代或未取代的下组基团：氢、C1-C18烷基、C1-C20氘代烷基、C3-C10环烷基、C3-C10环烯基、C6-C10芳基、氨基、杂环基，其中所述取代指被一个或多个C6-C10芳基取代；
    x为0、1、2、3或4的整数；
    y为1或2的整数；
    m为0、1或2的整数；
    且n为0、1、2、3、4或5的整数；
    且各杂环基独立为含1-3个选自N、O和S的杂原子的5-15元杂环烷基；
    各杂芳基独立为含1-3个选自N、O和S的杂原子的5-15元杂芳基。
  2. 根据权利要求1所述的具有通式(I)结构的咪唑并喹啉取代磷酸酯类化合物、或其立体异构体、互变异构体、晶型、或其药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其为通式(II-1)或(II-2)所示的化合物、或其立体异构体、互变异构体、晶型、或其药学上可接受的盐、水合物、溶剂合物或前药：
    Figure PCTCN2020128168-appb-100002
    Figure PCTCN2020128168-appb-100003
    式中：
    R 1、R 2、x、Z、X 1、X 2、R 11、R 12如通式(I)所述。
  3. 根据权利要求1所述的具有通式(I)结构的咪唑并喹啉取代磷酸酯类化合物、或其立体异构体、互变异构体、晶型、或其药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其为通式(III-1)或(III-2)所示的化合物、或其立体异构体、互变异构体、晶型、或其药学上可接受的盐、水合物、溶剂合物或前药：
    Figure PCTCN2020128168-appb-100004
    R 1、R 2、x、Z、X 1、X3、R1 1、R 14、R 15如通式(I)所述。
  4. 根据权利要求1所述的具有通式(I)结构的咪唑并喹啉取代磷酸酯类化合物、或其立体异构体、互变异构体、晶型、或其药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，Z具有S或R构型。
  5. 根据权利要求2或3所述的具有通式(I)结构的咪唑并喹啉取代磷酸酯类化合物、或其立体异构体、互变异构体、晶型、或其药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，P结构具有S或R构型。
  6. 根据权利要求1所述的具有通式(I)结构的咪唑并喹啉取代磷酸酯类化合物、或其立体异构体、互变异构体、晶型、或其药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，所述化合物选自下组：
    Figure PCTCN2020128168-appb-100005
    Figure PCTCN2020128168-appb-100006
    Figure PCTCN2020128168-appb-100007
    Figure PCTCN2020128168-appb-100008
    Figure PCTCN2020128168-appb-100009
    Figure PCTCN2020128168-appb-100010
    Figure PCTCN2020128168-appb-100011
    Figure PCTCN2020128168-appb-100012
    Figure PCTCN2020128168-appb-100013
    Figure PCTCN2020128168-appb-100014
    Figure PCTCN2020128168-appb-100015
    Figure PCTCN2020128168-appb-100016
    Figure PCTCN2020128168-appb-100017
    Figure PCTCN2020128168-appb-100018
    Figure PCTCN2020128168-appb-100019
    Figure PCTCN2020128168-appb-100020
    Figure PCTCN2020128168-appb-100021
    Figure PCTCN2020128168-appb-100022
    Figure PCTCN2020128168-appb-100023
    Figure PCTCN2020128168-appb-100024
    Figure PCTCN2020128168-appb-100025
    Figure PCTCN2020128168-appb-100026
    Figure PCTCN2020128168-appb-100027
    Figure PCTCN2020128168-appb-100028
    Figure PCTCN2020128168-appb-100029
    Figure PCTCN2020128168-appb-100030
    Figure PCTCN2020128168-appb-100031
    Figure PCTCN2020128168-appb-100032
    Figure PCTCN2020128168-appb-100033
  7. 一种权利要求1所述具有通式(I)结构的咪唑并喹啉取代磷酸酯类化合物、或其立体异构体、互变异构体、晶型、或其药学上可接受的盐、水合物、溶剂合物或前药的制备方法，其特征在于，包括步骤：
    1)将
    Figure PCTCN2020128168-appb-100034
    中－NH 2中的一个H进行保护得到
    Figure PCTCN2020128168-appb-100035
    其中，Rs为保护基团；
    2)将
    Figure PCTCN2020128168-appb-100036
    与
    Figure PCTCN2020128168-appb-100037
    反应得到
    Figure PCTCN2020128168-appb-100038
    3)对
    Figure PCTCN2020128168-appb-100039
    进行脱保护，得到
    Figure PCTCN2020128168-appb-100040
    其中，X选自下组：-P(＝O)(X 1R 11)(X 2R 12)、-P(＝O)(X 1R 11)(X3R 14R 15)；
    y为1；
    R 1、R 2、x、Z、X 1、X 2、X 3、R 11、R 12、R 14和R 15如权利要求1所述。
  8. 一种药物组合物，其特征在于，包含药学上可接受的载体和一种或多种权利要求1所述的具有通式(I)结构的咪唑并喹啉取代磷酸酯类化合物、或其立体异构体、互变异构体、晶型、或其药学上可接受的盐、水合物、溶剂合物或前药。
  9. 如权利要求8所述的药物组合物，其特征在于，还包含其它预防和/或治疗选自下组的疾病的药物或联用：炎症、癌症、心血管疾病、感染、免疫性疾病、代谢性疾病。
  10. 一种权利要求1所述的具有通式(I)结构的咪唑并喹啉取代磷酸酯类化合物、或其立体异构体、互变异构体、晶型、或其药学上可接受的盐、水合物、溶剂合物或前药的用途，其特征在于，用于选自下组的用途：
    1)用于制备TLR7激动剂；
    2)用于制备TLR8激动剂；
    3)用于制备TLR7和TLR8双激动剂；
    4)用于制备预防和/或治疗病毒感染性疾病的药物；
    5)用于制备预防和/或治疗癌症的药物。
  11. 如权利要求10所述的用途，其特征在于，所述病毒感染性疾病选自下组：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、病毒感染肝炎、病毒性皮肤病。
  12. 如权利要求10所述的用途，其特征在于，所述癌症选自下组：肺癌、乳腺癌、前列腺癌、食道癌、结直肠癌、骨癌、肾癌、胃癌、肝癌、大肠癌、黑色素瘤、淋巴瘤、血癌、脑瘤、骨髓瘤、软组织肉瘤、胰腺癌、皮肤癌。
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EP4034094A4 (en) * 2019-09-23 2024-01-24 Nanjing Zhengxiang Pharmaceuticals Co., Ltd. PHOSPHODIESTERASE INHIBITORS AND THEIR USE

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