WO2019057158A1 - 稠合杂芳基衍生物、其制备方法及其在医药上的应用 - Google Patents

稠合杂芳基衍生物、其制备方法及其在医药上的应用 Download PDF

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WO2019057158A1
WO2019057158A1 PCT/CN2018/106983 CN2018106983W WO2019057158A1 WO 2019057158 A1 WO2019057158 A1 WO 2019057158A1 CN 2018106983 W CN2018106983 W CN 2018106983W WO 2019057158 A1 WO2019057158 A1 WO 2019057158A1
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group
compound
formula
alkyl
cycloalkyl
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PCT/CN2018/106983
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English (en)
French (fr)
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张国宝
马殿强
贺峰
陶维康
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CN201880058416.5A priority Critical patent/CN111065636B/zh
Publication of WO2019057158A1 publication Critical patent/WO2019057158A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • 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 present invention belongs to the field of medicine, and relates to a novel fused heteroaryl derivative represented by the general formula (I), a preparation method thereof, and a pharmaceutical composition containing the same, and as a therapeutic agent, particularly as a TLR7 Use of the agent.
  • TLRs Toll-like receptors
  • TLRs are important protein molecules involved in innate immunity.
  • TLRs are non-catalytic receptors for monomeric transmembranes, usually expressed in sentinel cells such as macrophages and dendritic cells, and can recognize structurally conserved molecules produced by microorganisms. Once these microorganisms break through physical barriers such as the skin or intestinal mucosa, they are recognized by TLRs, which in turn activate immune cell responses (Mahla, R S. et al., Front Immunol. 4:248 (2013)). The ability of the immune system to broadly recognize pathogenic microorganisms is due in part to the widespread presence of Toll-like immunoreceptors.
  • TLR7 is a member of a subset of TLRs (TLRs 3, 7, 8, and 9) and is restricted to the endosomal compartment of cells that specifically detect non-hexucleic acids. TLR7 plays a key role in recognizing ssRNA antiviral defense (Diebold S.S. et al, Science, 2004: 303, 1529-1531; and Lund J. M. et al, PNAS, 2004: 101, 5598-5603).
  • TLR7 has a limited expression profile in humans and is expressed primarily by B cells and plasmacytoid dendritic cells (pDC), but to a lesser extent by monocytes.
  • Plasmacytoid DCs are the only population of lymphoid-derived dendritic cells (0.2-0.8% of peripheral blood mononuclear cells (PBMCs)) that secrete high levels of interferon- ⁇ (IFN ⁇ ) and interferon in response to viral infections.
  • PBMCs peripheral blood mononuclear cells
  • IFN ⁇ interferon- ⁇
  • the first type I interferon-producing cell of ⁇ (IFN ⁇ ) Liu YJ, Annu. Rev. Immunol., 2005: 23, 275-306).
  • TLRs diseases and disorders are associated with abnormalities in TLRs such as melanoma, non-small cell lung cancer, hepatocellular carcinoma, basal cell carcinoma, renal cell carcinoma, myeloma, allergic rhinitis, asthma, chronic obstructive pneumonia (COPD). ), ulcerative colitis, liver fibrosis, HBV, Flaviviridae virus, HCV, HPV, RSV, SARS, HIV or influenza virus infection. Therefore, the use of agonists for TLRs to treat related diseases is promising.
  • TLR7 and TLR8 are highly homologous, the TLR7 ligand, in most cases, is also a TLR8 ligand.
  • TLR8 stimulation primarily induces the production of cytokines such as tumor necrosis factor alpha (TNF-alpha) and chemokines.
  • TNF-alpha tumor necrosis factor alpha
  • Interferon alpha is one of the main drugs for the treatment of chronic hepatitis B or hepatitis C
  • TNF- ⁇ is a pro-inflammatory cytokine, and excessive secretion may cause serious side effects. Therefore, selectivity for TLR7 and TLR8 is critical for the development of TLR7 agonists for the treatment of viral infectious diseases.
  • TLR7 agonist patent applications such as WO2005025583, WO2007093901, WO2008011406, WO2009091032, WO2010077613, WO2010133882, WO2011031965, WO2012080730.
  • TLR7 agonists there are currently related TLR7 agonist patent applications, such as WO2005025583, WO2007093901, WO2008011406, WO2009091032, WO2010077613, WO2010133882, WO2011031965, WO2012080730.
  • TLR7 agonists such as WO2005025583, WO2007093901, WO2008011406, WO2009091032, WO2010077613, WO2010133882, WO2011031965, WO2012080730.
  • the present invention is directed to the above technical problem, and provides a pharmaceutical compound having lower onset concentration, better selectivity and more obvious activation effect, and at the same time, it has no inhibition or inhibition effect on CYP and hERG, and is safer and more effective.
  • TLR7 agonist TLR7 agonist.
  • G 1 is CR 3 or N
  • L 1 is selected from -O-, -S-, -NR 4 -, -C(O)-, -S(O) m -, -N(R 4 )C(O)-, -C(O)N (R 4 )-, -N(R 4 )S(O) 2 -, -S(O) 2 N(R 4 )- and a covalent bond;
  • X 1 is an alkylene group, wherein the alkylene group is optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and hetero Substituting one or more substituents in the ring group;
  • R 1 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, the alkenyl group, the alkynyl group, and the cycloalkyl group are selected.
  • a heterocyclic group, an aryl group and a heteroaryl group are each independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero Substituting one or more substituents of a cyclic group, an aryl group, and a heteroaryl group;
  • R 2 is selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group.
  • cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitrate , cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, -C(O)R 5 , -C(O)OR 5 , -S(O) m R 5 , -NR Substituting one or more substituents of 6 R 7 , -C(O)NR 6 R 7 and -X 2 -NR 6 R 7 ;
  • R 3 is selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 4 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R 5 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an amino group, a hydroxyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group,
  • the heterocyclic group, the aryl group and the heteroaryl group are each independently selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aromatic Substituted with one or more substituents in the heteroaryl group;
  • the R 6 and R 7 together with the nitrogen atom to which they are bonded form a heterocyclic group, wherein the heterocyclic group optionally contains 1 to 2 identical or different ones in addition to one nitrogen atom.
  • a hetero atom of N, O and S and said heterocyclic group is optionally selected from the group consisting of alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkane Substituted by one or more substituents in the group, heterocyclic group, aryl group and heteroaryl group;
  • X 2 is an alkylene group, wherein the alkylene group is optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and hetero Substituting one or more substituents in the ring group;
  • n 0, 1, or 2.
  • the compound of the formula (I) is a compound of the formula (II):
  • G 1 , L 1 , X 1 , R 1 and R 2 are as defined in the formula (I).
  • the compound of the formula (I) is a compound of the formula (IIaa):
  • G 1 , L 1 , X 1 , R 1 and R 2 are as defined in the formula (I).
  • X 2 , R 6 and R 7 are as defined in the formula (I).
  • the phenyl, pyridyl and pyrrolidinyl groups are each independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, heterocycle. Substituting one or more substituents in the alkyl group and -X 2 -NR 6 R 7 , preferably a pyrrolidinyl methylene group;
  • X 2 , R 6 and R 7 are as defined in the formula (I).
  • the compound of the formula (I) is a compound of the formula (III) or (IV):
  • Ring A is a phenyl or pyridyl group
  • R 8 are the same or different and are each independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro and heterocyclylalkyl;
  • R 6 and R 7 together with the nitrogen atom to which they are bonded form a heterocyclic group, wherein the heterocyclic group optionally contains 1 to 2 identical or different selected from N, O and in addition to 1 nitrogen atom.
  • a hetero atom of S and said heterocyclic group is optionally selected from the group consisting of alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocycle Substituted by one or more substituents in the aryl, aryl and heteroaryl;
  • s 0, 1, 2 or 3;
  • G 1 , L 1 , X 1 , X 2 , R 1 and R 5 are as defined in the formula (I).
  • the compound of the formula (I), wherein the X 1 is an alkylene group is an alkylene group.
  • the compound of the formula (I), wherein the G 1 is N is N.
  • the compound represented by the formula (I) is a compound represented by the formula (V) or the formula (VI):
  • Ring A is a phenyl or pyridyl group
  • n is an integer from 1 to 9;
  • L 1 , X 2 , R 1 , R 6 and R 7 are as defined in the formula (III).
  • the compound of the formula (I) is a compound of the formula (VII):
  • L 1 , X 2 , R 1 , R 6 and R 7 are as defined in the formula (III).
  • the compound of the formula (I), wherein the R 1 is an alkyl group is an alkyl group.
  • Typical compounds of the invention include, but are not limited to:
  • a tautomer a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention relates to a compound of the formula (IA),
  • G 1 is CR 3 or N
  • W is an amino protecting group selected from the group consisting of t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl, preferably p-methoxybenzyl;
  • R a is an amino protecting group or a hydrogen atom, and the amino protecting group is selected from the group consisting of t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl, preferably p-methoxybenzyl;
  • L 1 is selected from -O-, -S-, -NR 4 -, -C(O)-, -S(O) m -, -N(R 4 )C(O)-, -C(O)N (R 4 )-, -N(R 4 )S(O) 2 -, -S(O) 2 N(R 4 )- and a covalent bond;
  • X 1 is an alkylene group, wherein the alkylene group is optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and hetero Substituting one or more substituents in the ring group;
  • R 1 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, the alkenyl group, the alkynyl group, and the cycloalkyl group are selected.
  • a heterocyclic group, an aryl group and a heteroaryl group are each independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero Substituting one or more substituents of a cyclic group, an aryl group, and a heteroaryl group;
  • R 2 is selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group.
  • cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitrate , cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, -C(O)R 5 , -C(O)OR 5 , -S(O) m R 5 , -NR Substituting one or more substituents of 6 R 7 , -C(O)NR 6 R 7 and -X 2 -NR 6 R 7 ;
  • R 3 is selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 4 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R 5 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an amino group, a hydroxyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group,
  • the heterocyclic group, the aryl group and the heteroaryl group are each independently selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aromatic Substituted with one or more substituents in the heteroaryl group;
  • the R 6 and R 7 together with the nitrogen atom to which they are bonded form a heterocyclic group, wherein the heterocyclic group optionally contains 1 to 2 identical or different ones in addition to one nitrogen atom.
  • a hetero atom of N, O and S and said heterocyclic group is optionally selected from the group consisting of alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkane Substituted by one or more substituents in the group, heterocyclic group, aryl group and heteroaryl group;
  • X 2 is an alkylene group, wherein the alkylene group is optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and hetero Substituting one or more substituents in the ring group;
  • n 0, 1, or 2.
  • the compound represented by the formula (IA) includes, but is not limited to:
  • Another aspect of the invention relates to a compound of the formula (IIA),
  • W is an amino protecting group selected from the group consisting of t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl, preferably p-methoxybenzyl;
  • R a is an amino protecting group or a hydrogen atom, and the amino protecting group is selected from the group consisting of t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl, preferably p-methoxybenzyl;
  • G 1 , L 1 , X 1 , R 1 and R 2 are as defined in the formula (IA).
  • Another aspect of the invention relates to a compound of the formula (IIB),
  • W is an amino protecting group selected from the group consisting of t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl, preferably p-methoxybenzyl;
  • R a is an amino protecting group or a hydrogen atom, and the amino protecting group is selected from the group consisting of t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl, preferably p-methoxybenzyl;
  • G 1 , L 1 , X 1 , R 1 and R 2 are as defined in the formula (IA).
  • the compound represented by the formula (IIB) includes, but is not limited to:
  • Another aspect of the invention relates to a process for the preparation of a compound of formula (I), which process comprises:
  • W is an amino protecting group selected from the group consisting of t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl, preferably p-methoxybenzyl;
  • R a is an amino protecting group or a hydrogen atom, and the amino protecting group is selected from the group consisting of t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl, preferably p-methoxybenzyl;
  • G 1 , L 1 , X 1 , R 1 and R 2 are as defined in the formula (I).
  • Another aspect of the invention relates to a process for the preparation of a compound of the formula (IIA), which process comprises:
  • W is an amino protecting group selected from the group consisting of t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl, preferably p-methoxybenzyl;
  • R a is an amino protecting group or a hydrogen atom, and the amino protecting group is selected from the group consisting of t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl, preferably p-methoxybenzyl;
  • G 1 , L 1 , X 1 , R 1 and R 2 are as defined in the general formula (II A).
  • Another aspect of the invention relates to a process for the preparation of a compound of formula (II), the process comprising:
  • W is an amino protecting group selected from the group consisting of t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl, preferably p-methoxybenzyl;
  • R a is an amino protecting group or a hydrogen atom, and the amino protecting group is selected from the group consisting of t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl, preferably p-methoxybenzyl;
  • G 1 , L 1 , X 1 , R 1 and R 2 are as defined in the formula (II).
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a tautomer, a mesogen, a racemate thereof, Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or Use of a pharmaceutically acceptable salt or a pharmaceutical composition comprising the same for the preparation of a medicament for stimulating TLR7.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or Use of a pharmaceutically acceptable salt or a pharmaceutical composition comprising the same for the preparation of a medicament for the treatment of an infection caused by a virus.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or Use of a pharmaceutically acceptable salt or a pharmaceutical composition comprising the same for the preparation of a medicament for the treatment or prevention of a tumor.
  • the invention further relates to a method of agonizing TLR7 comprising the compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer
  • a method of agonizing TLR7 comprising the compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer
  • the invention further relates to a method of treating an infection caused by a virus, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, a mesogen, and an external Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same.
  • the invention further relates to a method of treating or preventing a tumor comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula (I) or a tautomer, a mesogen, a racemate thereof, An enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof Or a pharmaceutically acceptable salt thereof or a medicament comprising the same, which is used as a medicament.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof Or a pharmaceutically acceptable salt thereof or a medicament comprising the same for use in stimulating TLR7.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof Or a pharmaceutically acceptable salt thereof or a medicament comprising the same for use in the treatment or prevention of an infection caused by a virus.
  • the virus described in the present invention is selected from the group consisting of: dengue virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, Kunjin virus, Murray Valley encephalitis virus, St. Louis encephalitis virus, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Zika virus, HIV, HBV, HCV, HPV, RSV, SARS and influenza viruses.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof Or a pharmaceutically acceptable salt thereof or a medicament comprising the same for use in the treatment or prevention of a tumor.
  • the tumor described in the present invention is selected from the group consisting of melanoma, non-small cell lung cancer, hepatocellular carcinoma, basal cell carcinoma, renal cell carcinoma, and myeloma.
  • the active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture.
  • Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives, To provide a pleasing and tasty pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of a tablet for admixture.
  • excipients can be inert excipients, granulating agents, disintegrating agents, binders, and lubricants. These tablets may be uncoated or may be coated by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract, thus providing a sustained release effect over a longer period of time.
  • Oral formulations can also be provided in soft gelatine capsules in which the active ingredient is mixed with an inert solid diluent or the active ingredient in admixture with a water-soluble vehicle or an oil vehicle.
  • the aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing. Such excipients are suspending, dispersing or wetting agents.
  • the aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
  • the oil suspension can be formulated by suspending the active ingredient in vegetable oil, or mineral oil.
  • the oil suspension may contain a thickening agent.
  • the above sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of an antioxidant.
  • compositions of the invention may also be in the form of an oil-in-water emulsion.
  • the oil phase can be a vegetable oil, or a mineral oil or a mixture thereof.
  • Suitable emulsifiers can be naturally occurring phospholipids, and emulsions can also contain sweeteners, flavoring agents, preservatives, and antioxidants.
  • Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • the pharmaceutical compositions of the invention may be in the form of a sterile injectable aqueous solution.
  • acceptable vehicles or solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase.
  • the injection or microemulsion is injected into the bloodstream of the patient by topical injection.
  • the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the invention.
  • a continuous intravenous delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration.
  • the suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent.
  • sterile fixed oils may conveniently be employed as a solvent or suspension medium.
  • the compounds of the invention may be administered in the form of a suppository for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug.
  • suitable non-irritating excipient include a mixture of cocoa butter, glycerin gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.
  • the dosage of the drug to be administered depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient. , the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment modality such as the mode of treatment, the daily dosage of the compound of formula (I) or the pharmaceutically acceptable salt
  • the type can be verified according to traditional treatment options.
  • alkyl refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbons.
  • the alkyl group of the atom is a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbons.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -methylhexyl, 3-methylhexyl, 4-methylhexyl,
  • lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of an alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, naphthenic An oxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • an alkane Base alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, hetero
  • alkylene refers to a saturated straight or branched aliphatic hydrocarbon radical having two residues derived from the removal of two hydrogen atoms from the same carbon atom of the parent alkane or two different carbon atoms.
  • Non-limiting examples of alkylene include, but are not limited to, methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 ) CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -) and 1,5-butylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -) Wait.
  • the alkylene group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably independently selected from alkyl, alkenyl, alkynyl groups. , alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy , cycloalkylthio, heterocycloalkylthio, oxo, -C(O)R 5 , -C(O)OR 5 , -S(O) m R 5 , -NR 6 R 7 and -C( O) Substituted by one or more substituents in NR 6 R 7 .
  • alkenyl refers to an alkyl compound containing a carbon-carbon double bond in the molecule, wherein the alkyl group is as defined above.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a halogenated alkyl group, a hydroxyl group, Hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 5 , -C(O)OR 5 , -S(O) m R Substituting one or more substituents of 5 , -NR 6 R 7 and -C(O)NR 6 R 7 .
  • alkynyl refers to an alkyl compound containing a carbon-carbon triple bond in the molecule, wherein the alkyl group is as defined above.
  • the alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a halogenated alkyl group, a hydroxyl group, Hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 5 , -C(O)OR 5 , -S(O) m R Substituting one or more substituents of 5 , -NR 6 R 7 and -C(O)NR 6 R 7 .
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. One carbon atom, most preferably from 5 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • a polycycloalkyl group includes a spiro ring, a fused ring, and a cycloalkyl group.
  • spirocycloalkyl refers to a polycyclic group that shares a carbon atom (referred to as a spiro atom) between 5 to 20 members of a single ring, which may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the rings.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to 5 to 20 members, and each ring in the system shares an all-carbon polycyclic group of an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have complete Conjugate ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, more preferably a bicyclic ring or a tricyclic ring.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene A benzocycloheptyl group or the like; preferably a phenylcyclopentyl group or a tetrahydronaphthyl group.
  • the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from nitrogen, oxygen or S(O).
  • a hetero atom of m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, Hydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like are preferably tetrahydropyranyl, piperidinyl or pyrrolidinyl.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • spiroheterocyclyl refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5 to 20 members of a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O). ) m (where m is an integer 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of shared spiro atoms between the ring and the ring, and is preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group.
  • Non-limiting examples of spiroheterocyclyl groups include:
  • fused heterocyclyl refers to 5 to 20 members, and each ring in the system shares an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more Double bond, but none of the rings have a fully conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining rings
  • the atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • fused heterocyclic groups include:
  • bridge heterocyclyl refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have a total A ⁇ -electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • bridge heterocyclic groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples of which include:
  • the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene. Base and naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle An alkylthio group, a carboxyl group or a carboxylate group.
  • heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 5 to 10 members, and has 1 to 3 hetero atoms; more preferably 5 or 6 members, and 1 to 2 hetero atoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyridyl
  • the oxazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like are preferably an imidazolyl group, a pyrazolyl or pyrimidinyl group, or a thiazolyl group; more preferably a pyrazolyl group.
  • the heteroaryl ring may be fused to an aryl
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group.
  • a hydroxyl group substituted by one or more substituents of a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group.
  • amino protecting group is intended to keep the amino group unchanged during the reaction of other parts of the molecule, and to protect the amino group with a group which is easily removed.
  • Non-limiting examples include t-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with from 1 to 3 substituents selected from halogen, alkoxy or nitro.
  • the amino protecting group is preferably p-methoxybenzyl.
  • heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl group, wherein alkyl and heterocyclyl are as defined above.
  • haloalkyl refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.
  • hydroxy refers to an -OH group.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
  • halogen means fluoro, chloro, bromo or iodo.
  • amino means -NH 2.
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but is not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.
  • a method for preparing a medicinal salt comprising the steps of:
  • W is an amino protecting group selected from the group consisting of t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl, preferably p-methoxybenzyl;
  • R a is an amino protecting group or a hydrogen atom, and the amino protecting group is selected from the group consisting of t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl, preferably p-methoxybenzyl;
  • G 1 , L 1 , X 1 , R 1 and R 2 are as defined in the formula (I).
  • Agents providing acidic conditions include, but are not limited to, hydrogen chloride, hydrogen chloride in 1,4-dioxane solution, ammonium chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-benzene. Methanesulfonic acid and TMSOTf.
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, water, N,N-dimethylformamide and mixtures thereof.
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, water, N,N-dimethylformamide and mixtures thereof.
  • a method for preparing a medicinal salt comprising the steps of:
  • the compound of the formula (II-1) is reacted under acidic conditions in the presence of a reducing agent to obtain a compound of the formula (IIB);
  • the compound of the formula (IIB) is subjected to elimination reaction under basic conditions to obtain a compound of the formula (IIA);
  • the compound of the formula (IIA) is deprotected under acidic conditions to give a compound of the formula (II);
  • W is an amino protecting group selected from the group consisting of t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl, preferably p-methoxybenzyl;
  • R a is an amino protecting group or a hydrogen atom, and the amino protecting group is selected from the group consisting of t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl, preferably p-methoxybenzyl;
  • R b is an alkyl group, preferably an ethyl group or a methyl group
  • G 1 , L 1 , X 1 , R 1 and R 2 are as defined in the formula (II).
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, pyridine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, 1, and the like. 8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicycloindole-5-ene (DBN), n-butyllithium, diisopropylamino Lithium, bistrimethylsilylamide lithium, potassium acetate, sodium t-butoxide, potassium t-butoxide and sodium n-butoxide, the inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate , potassium acetate, cesium carbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide.
  • organic bases including, but not limited to, triethylamine, pyridine, 4-dimethylaminopyridine, N,N-di
  • Agents providing acidic conditions include, but are not limited to, hydrogen chloride, hydrogen chloride in 1,4-dioxane solution, ammonium chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-benzene. Methanesulfonic acid and TMSOTf.
  • Reducing reagents include, but are not limited to, iron powder, zinc powder, sodium sulfide, sodium thiosulfate, sodium disulfide, stannous chloride, Pd/C/H 2 , Pt/C/H 2 , Raney nickel/H 2 Lithium aluminum hydride, sodium borohydride, DIBAL-H, NaAlH(Ot-Bu) 3 , AlH 3 , NaCNBH 3 , Na(AcO) 3 BH and Li(Et) 3 BH.
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, water, N,N-dimethylformamide and mixtures thereof.
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, water, N,N-dimethylformamide and mixtures thereof.
  • a method for preparing a medicinal salt comprising the steps of:
  • the compound of the formula (IIaa-1) is heated under acidic conditions to obtain a compound of the formula (IIaa-2);
  • the compound of the formula (IIaa-2) is deprotected under acidic conditions to give a compound of the formula (IIaa);
  • W is an amino protecting group selected from the group consisting of t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl, preferably p-methoxybenzyl;
  • R a is an amino protecting group or a hydrogen atom, and the amino protecting group is selected from the group consisting of t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl, preferably p-methoxybenzyl;
  • R b is an alkyl group, preferably an ethyl group or a methyl group
  • G 1 , L 1 , X 1 , R 1 and R 2 are as defined in the formula (IIaa).
  • Agents that provide acidic conditions include, but are not limited to, hydrogen chloride, hydrogen chloride in 1,4-dioxane solution, ammonium chloride, trifluoroacetic acid, formic acid, acetic acid, concentrated hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, and the like. Benzyl methanesulfonic acid and TMSOTf.
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, water, N,N-dimethylformamide and mixtures thereof.
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, water, N,N-dimethylformamide and mixtures thereof.
  • W is an amino protecting group selected from the group consisting of t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl, preferably p-methoxybenzyl;
  • R a is an amino protecting group or a hydrogen atom, and the amino protecting group is selected from the group consisting of t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl, preferably p-methoxybenzyl;
  • Ring A, G 1 , L 1 , X 1 , X 2 , R 1 , R 6 to R 8 and s are as defined in the formula (III).
  • Agents providing acidic conditions include, but are not limited to, hydrogen chloride, hydrogen chloride in 1,4-dioxane solution, ammonium chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-benzene. Methanesulfonic acid, Me 3 SiCl and TMSOTf.
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, water, N,N-dimethylformamide and mixtures thereof.
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, water, N,N-dimethylformamide and mixtures thereof.
  • a method for preparing a medicinal salt comprising the steps of:
  • the compound of the formula (V-1) is reacted under acidic conditions in the presence of a reducing agent to obtain a compound of the formula (V-2);
  • the compound of the formula (V-2) is subjected to elimination reaction under basic conditions to obtain a compound of the formula (VA);
  • the compound of the formula (VA) is deprotected under acidic conditions to give a compound of the formula (V);
  • W is an amino protecting group selected from the group consisting of t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl, preferably p-methoxybenzyl;
  • R a is an amino protecting group or a hydrogen atom, and the amino protecting group is selected from the group consisting of t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl, preferably p-methoxybenzyl;
  • R b is an alkyl group, preferably an ethyl group or a methyl group
  • Rings A, L 1 , X 2 , R 1 , R 6 and R 7 are as defined in the formula (V).
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, pyridine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, 1, and the like. 8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicycloindole-5-ene (DBN), n-butyllithium, diisopropylamino Lithium, bistrimethylsilylamide lithium, potassium acetate, sodium t-butoxide, potassium t-butoxide and sodium n-butoxide, the inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate , potassium acetate, cesium carbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide.
  • organic bases including, but not limited to, triethylamine, pyridine, 4-dimethylaminopyridine, N,N-di
  • Agents providing acidic conditions include, but are not limited to, hydrogen chloride, hydrogen chloride in 1,4-dioxane solution, ammonium chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-benzene. Methanesulfonic acid and TMSOTf.
  • Reducing reagents include, but are not limited to, iron powder, zinc powder, sodium sulfide, sodium thiosulfate, sodium disulfide, stannous chloride, Pd/C/H 2 , Pt/C/H 2 , Raney nickel/H 2 Lithium aluminum hydride, sodium borohydride, DIBAL-H, NaAlH(Ot-Bu) 3 , AlH 3 , NaCNBH 3 , Na(AcO) 3 BH and Li(Et) 3 BH.
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, water, N,N-dimethylformamide and mixtures thereof.
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, water, N,N-dimethylformamide and mixtures thereof.
  • a method for preparing a medicinal salt comprising the steps of:
  • the compound of the formula (VI-1) is reacted under acidic conditions in the presence of a reducing agent to obtain a compound of the formula (V-2);
  • the compound of the formula (VI-2) is subjected to elimination reaction under basic conditions to obtain a compound of the formula (VIA);
  • the compound of the formula (VIA) is deprotected under acidic conditions to give a compound of the formula (VI);
  • W is an amino protecting group selected from the group consisting of t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl, preferably p-methoxybenzyl;
  • R a is an amino protecting group or a hydrogen atom, and the amino protecting group is selected from the group consisting of t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl, preferably p-methoxybenzyl;
  • R b is an alkyl group, preferably an ethyl group or a methyl group
  • L 1 , R 1 , n, R 6 and R 7 are as defined in the formula (VI).
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, pyridine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, 1, and the like. 8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicycloindole-5-ene (DBN), n-butyllithium, diisopropylamino Lithium, bistrimethylsilylamide lithium, potassium acetate, sodium t-butoxide, potassium t-butoxide and sodium n-butoxide, the inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate , potassium acetate, cesium carbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide.
  • organic bases including, but not limited to, triethylamine, pyridine, 4-dimethylaminopyridine, N,N-di
  • Agents providing acidic conditions include, but are not limited to, hydrogen chloride, hydrogen chloride in 1,4-dioxane solution, ammonium chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-benzene. Methanesulfonic acid and TMSOTf.
  • Reducing reagents include, but are not limited to, iron powder, zinc powder, sodium sulfide, sodium thiosulfate, sodium disulfide, stannous chloride, Pd/C/H 2 , Pt/C/H 2 , Raney nickel/H 2 Lithium aluminum hydride, sodium borohydride, DIBAL-H, NaAlH(Ot-Bu) 3 , AlH 3 , NaCNBH 3 , Na(AcO) 3 BH and Li(Et) 3 BH.
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, water, N,N-dimethylformamide and mixtures thereof.
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, water, N,N-dimethylformamide and mixtures thereof.
  • a method for preparing a medicinal salt comprising the steps of:
  • the compound of the formula (VII-1) is reacted under acidic conditions in the presence of a reducing agent to obtain a compound of the formula (VII-2);
  • the compound of the formula (VII-2) is subjected to elimination reaction under basic conditions to obtain a compound of the formula (VIIA);
  • W is an amino protecting group selected from the group consisting of t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl, preferably p-methoxybenzyl;
  • R a is an amino protecting group or a hydrogen atom, and the amino protecting group is selected from the group consisting of t-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl, preferably p-methoxybenzyl;
  • R b is an alkyl group, preferably an ethyl group or a methyl group
  • L 1 , X 2 , R 1 , R 6 and R 7 are as defined in the formula (VII).
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, pyridine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, 1, and the like. 8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicycloindole-5-ene (DBN), n-butyllithium, diisopropylamino Lithium, bistrimethylsilylamide lithium, potassium acetate, sodium t-butoxide, potassium t-butoxide and sodium n-butoxide, the inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate , potassium acetate, cesium carbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide.
  • organic bases including, but not limited to, triethylamine, pyridine, 4-dimethylaminopyridine, N,N-di
  • Agents providing acidic conditions include, but are not limited to, hydrogen chloride, hydrogen chloride in 1,4-dioxane solution, ammonium chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-benzene. Methanesulfonic acid and TMSOTf.
  • Reducing reagents include, but are not limited to, iron powder, zinc powder, sodium sulfide, sodium thiosulfate, sodium disulfide, stannous chloride, Pd/C/H 2 , Pt/C/H 2 , Raney nickel/H 2 Lithium aluminum hydride, sodium borohydride, DIBAL-H, NaAlH(Ot-Bu) 3 , AlH 3 , NaCNBH 3 , Na(AcO) 3 BH and Li(Et) 3 BH.
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, water, N,N-dimethylformamide and mixtures thereof.
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, water, N,N-dimethylformamide and mixtures thereof.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • the NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four.
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS Methyl silane
  • the measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • ESI FINNIGAN LCQAd
  • HPLC High performance liquid chromatography
  • Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.
  • the CombiFlash Rapid Preparer uses the Combiflash Rf200 (TELEDYNE ISCO).
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Dari Companies such as chemicals.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • the microwave reaction used a CEM Discover-S Model 908860 microwave reactor.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature and is 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC), the developing agent used for the reaction, the column chromatography eluent system used for the purification of the compound, and the thin layer chromatography developing solvent system including: A: Methylene chloride/methanol system, B: n-hexane/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and may be adjusted by adding a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid.
  • TLC thin layer chromatography
  • A Methylene chloride/methanol system
  • B n-hexane/ethyl acetate system
  • the volume ratio of the solvent is adjusted according to the polarity of the compound, and may be adjusted by adding a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid.
  • the crude compound 1i (220 mg, 0.34 mmol) was dissolved in 5 mL of acetonitrile, and 1,8-diazabicyclo[5.4.0]undec-7-ene (155 mg, 1.02 mmol) was added, and the reaction was stirred at 80 ° C. hour. The reaction mixture was cooled to room temperature, and then evaporated, evaporated, evaporated.
  • the crude compound 2d (250 mg, 0.36 mmol) was dissolved in 5 mL of acetic acid, and zinc powder (234 mg, 3.6 mmol) was added and reacted for 0.5 hour. The reaction mixture was filtered, and the filtrate was evaporated, evaporated, evaporated, evaporated, evaporated. The crude title compound 2e (220 mg) was used for the next step without purification.
  • Methyl 7-bromoheptanoate 3a (1.12 g, 5 mmol, prepared by the well-known method "Journal of Natural Products, 79 (1), 244-247; 2016"), pyrrolidine (710 mg, 10 mmol) and three Ethylamine (1.01 mg, 10 mmol) was dissolved in 15 mL of N,N-dimethylformamide, and the mixture was stirred at 80 ° C for 1 hour. The reaction mixture was cooled to room temperature, then added with aq. EtOAc (30 mL) The resulting residue was purified with EtOAc EtOAc (EtOAc).
  • Test Example 1 Determination of agonistic activity of human TLR7 by the compound of the present invention
  • Determination of the compounds of the present invention adopts the following experimental method hTLR7 activation HEK-Blue TM hTLR7 expression in stably transfected cell lines of:
  • PBS Phosphate buffer pH 7.4 (Shanghai Yuanpei Biotechnology Co., Ltd., B320).
  • HEK-Blue assay medium Take a bag of HEK-Blue dry powder, add 50ml to endotoxin water to dissolve, then put it into the 37 °C incubator, and then sterile filtration after 10 minutes.
  • the compound was first formulated into a 20 mM stock solution; it was diluted with pure DMSO to a maximum concentration of 6 x 10 6 nM and diluted by a 3-fold gradient for a total of 10 points.
  • the above-prepared compound was diluted 20-fold with a medium, and then 20 ⁇ l of the diluted compound was added to each well.
  • HEK-Blue TM hTLR7 cells Take HEK-Blue TM hTLR7 cells, first remove the supernatant, then add 2-5 ml of pre-warmed PBS, put into the incubator for 1-2 minutes, gently pipe the cells, and trypan blue staining. The cells were resuspended in HEK-Blue assay medium to a concentration of 2.2 x 10 5 cells/ml, and 180 ⁇ l of the cells were added to the above 96-well cell culture plate to which 20 ⁇ l of the drug had been added, and cultured at 37 ° C for 6-16 hours.
  • the microplate reader reads at a wavelength of 620 nm.
  • the corresponding OD value can be obtained, and the EC 50 value of the drug is calculated by Graphpad Prism.
  • the activation of human TLR7 by the compounds of the present invention can be determined by the above test, and the measured EC 50 values are shown in Table 1.
  • Table 1 Compound of the present invention to the human EC TLR7 50.
  • the compounds of the present invention have a good activation effect on human TLR7.
  • Test Example 2 Determination of agonistic activity of human TLR8 by the compound of the present invention
  • Determination of the compounds of the present invention adopts the following experimental method hTLR8 activation HEK-Blue TM hTLR8 expression in stably transfected cell lines of:
  • HEK-Blue TM hTLR8 cell line (InvivoGen, hkb-hTLR8)
  • PBS Phosphate buffer pH 7.4 (Shanghai Yuanpei Biotechnology Co., Ltd., B320).
  • HEK-Blue assay medium Take a bag of HEK-Blue dry powder, add 50ml to endotoxin water to dissolve, then put it into the 37 °C incubator, and then sterile filtration after 10 minutes.
  • the compound was first formulated into a 20 mM stock solution; it was diluted with pure DMSO to a maximum concentration of 6 x 10 6 nM, and then diluted 3 times in a total of 10 points; the compound was diluted 20-fold with the medium, and then 20 ⁇ l of each well was added after dilution. compound of.
  • HEK-Blue TM hTLR8 cells Take HEK-Blue TM hTLR8 cells, first remove the supernatant, add 2-5 ml of pre-warmed PBS, put into the incubator for 1-2 minutes, gently pipe the cells, and trypan blue staining. The cells were resuspended in HEK-Blue assay medium to a concentration of 2.2 x 10 5 cells/ml, and 180 ⁇ l of the cells were added to the above 96-well cell culture plate to which 20 ⁇ l of the drug had been added, and cultured at 37 ° C for 6-16 hours.
  • the microplate reader reads at a wavelength of 620 nm.
  • the corresponding OD value can be obtained, and the EC 50 value of the drug is calculated by Graphpad Prism.
  • the activation of human TLR8 by the compounds of the present invention can be determined by the above test, and the measured EC 50 values are shown in Table 2.
  • Table Compound 2 of the present invention to human TLR8, EC 50.
  • the compounds of the present invention have weak activation on human TLR8, indicating that the compounds of the present invention are selective for TLR7.
  • Test Example 3 Determination of the ability of the compound of the present invention to stimulate peripheral blood mononuclear cells (PBMC) to secrete IFN- ⁇
  • PHERAStar multi-function microplate reader BMG, PHERAStar.
  • RMPI 1640 medium containing 10% FBS Resuspend and count with RMPI 1640 medium containing 10% FBS, adjust the amount of PBMC to 3.33 ⁇ 10 6 cells/ml, take 150 ⁇ l to the cell culture plate to which the compound has been added, and incubate at 37 ° C, 5.0% CO 2 The medium was cultured for 24 hours.
  • the cell culture plate was placed in a centrifuge, centrifuged at 1200 rpm for 10 minutes at room temperature. 150 ⁇ l of the supernatant was taken out per well.
  • the reagent in the human IFN- ⁇ kit is firstly equilibrated to room temperature, and anti-IFN- ⁇ -Eu 3+ - Cryptate conjugate and anti-IFN- ⁇ - are prepared according to the kit instructions in the dark.
  • the d2-conjugate both mixed in a 1:40 ratio with a conjugate buffer. Then, 16 ⁇ l of the supernatant obtained by centrifugation was added to each well.
  • the HTRF mode is read on the PHERAStar.
  • MEC Minimum Effective Concentration
  • Test Example 4 Inhibition of the Enzymatic Activity of the Compound of the Invention on the Metabolite of the Metabolite of CYP3A4 Midazolam in Human Liver Microsomes
  • PBS Phosphate buffer
  • CYP probe substrate (15 ⁇ M midazolam, SIGMA UC429) and positive control inhibitor (ketoconazole, SIGMA K1003).
  • the compound of the present invention has no inhibitory effect on the midazolam metabolic site of human liver microsome CYP3A4, and shows better safety, suggesting that metabolites based on CYP3A4 metabolism of midazolam metabolite sites do not occur. effect.
  • Test Example 5 Inhibition of human liver microsomal CYP2D6 enzyme activity by the compound of the present invention
  • the activity of the compound of the present invention on human liver microsome CYP2D6 enzyme activity was determined by the following experimental method:
  • PBS Phosphate buffer
  • CYP probe substrate (20 ⁇ M dextromethorphan, SIGMA Q0750) and positive control inhibitor (Quinidine, SIGMA D9684).
  • the compound of the present invention has no inhibitory effect on the enzymatic activity of human liver microsome CYP2D6, and shows better safety, suggesting that no metabolic drug interaction based on CYP2D6 occurs.
  • Test Example 6 Inhibition of Enzyme Activity of Testosterone Metabolism Site of Human Liver Microsome CYP3A4 by Human Compound Microsomes
  • the enzymatic activity of the compound of the present invention on the testosterone metabolism site of human liver microsome CYP3A4 was determined by the following experimental method:
  • PBS Phosphate buffer
  • CYP probe substrate testosterone / 100 ⁇ M, SIGMA K1003
  • positive control inhibitor ketoconazole, Dr. Ehrenstorfer GmbH, C17322500
  • the compound of the present invention has no inhibitory effect on the testosterone metabolism site of human liver microsome CYP3A4, and shows better safety, suggesting that metabolic drug interaction based on CYP3A4-based testosterone metabolism site does not occur.
  • Test Example 7 Blocking Effect of Compounds of the Invention on hERG Potassium Current
  • the blocking effect of the compounds of the invention on hERG potassium current was tested using a fully automated patch clamp on a stable cell line transfected with hERG potassium channels.
  • the HEK293-hERG stable cell line was passaged at a density of 1:4 in MEM/EBSS medium (10% FBS, 400 ⁇ g/ml G418, 1% MEM non-essential amino acid solution (100 ⁇ ), 1% sodium pyruvate solution). Culture, culture within 48-72 hours for automated patch-clamp experiments.
  • the cells were digested with 0.25% trypsin, and the cells were collected by centrifugation and resuspended with extracellular fluid (140 mM NaCl, 4 mM KCl, 1 mM MgCl 2 , 2 mM CaCl 2 , 5 mM MD-water glucose, 10 mM Hepes, pH 7.4, 298 mOsmol).
  • extracellular fluid 140 mM NaCl, 4 mM KCl, 1 mM MgCl 2 , 2 mM CaCl 2 , 5 mM MD-water glucose, 10 mM Hepes, pH 7.4, 298 mOsmol.
  • the cells are made into a cell suspension.
  • the cell suspension was placed on the cell bank of the Patchliner instrument.
  • the Patchliner instrument used a negative pressure controller to apply the cells to the chip (NPC-16), and the negative pressure attracted individual cells to the wells of the chip.
  • the instrument When the whole cell mode is formed, the instrument will get the hERG current according to the set hERG current voltage program, and then the instrument will automatically perfuse the compound from low to high concentration.
  • the currents at each concentration of the compounds and the blank control current were analyzed by HEAK Patchmaster, HEAK EPC10 patch clamp amplifiers (Nanion) and Pathlinersoftware and data analysis software provided by Pathcontrol HTsoftware.
  • the compounds of the present invention have a weak inhibitory effect on hERG, and the side effects caused by the hERG pathway are small.

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Abstract

提供一类稠合杂芳基衍生物、其制备方法及其在医药上的应用。具体而言，提供一种通式（I）所示的稠合杂芳基衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂，特别是作为TLR7激动剂的用途，其中通式的各取代基与说明书中的定义相同。

Description

稠合杂芳基衍生物、其制备方法及其在医药上的应用 技术领域
本发明属于医药领域，涉及一种通式(I)所示的新的稠合杂芳基衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂，特别是作为TLR7激动剂的用途。
背景技术
Toll样受体(toll-like receptors；TLRs)是参与先天免疫的一类重要蛋白质分子。TLRs是单体跨膜的非催化性受体，通常在岗哨细胞如巨噬细胞和树突状细胞中表达，可以识别由微生物产生的结构保守的分子。一旦这些微生物突破如皮肤或肠道粘膜的物理屏障，就会被TLRs识别，继而激活免疫细胞应答(Mahla,R S.等人,Front Immunol.4:248(2013))。免疫系统之所以具有广泛识别病原微生物的能力，某种程度上是由于Toll样免疫受体的广泛存在。
在哺乳动物中至少有10种不同的TLRs。一些此类受体的配体和相应的信号级联放大已经被鉴定出。TLR7是TLRs(TLRs 3、7、8和9)亚组的成员，局限于专门检测非己核酸的细胞的内涵体隔室。TLR7在通过识别ssRNA抗病毒防御方面起关键作用(Diebold S.S.等,Science,2004:303,1529-1531；和Lund J.M.等,PNAS,2004:101,5598-5603)。TLR7在人身上具有有限的表达分布，并主要通过B细胞和浆细胞样树突细胞(pDC)表达，而较低程度地通过单核细胞表达。浆细胞样DCs是淋巴衍生的树突细胞的唯一群体(0.2-0.8％的外周血单核细胞(PBMCs))，它是响应病毒感染而分泌高水平干扰素-α(IFNα)和干扰素-β(IFNβ)的最初的I型干扰素生成细胞(Liu Y-J,Annu.Rev.Immunol.,2005:23,275-306)。
很多疾病、障碍与TLRs的异常有关，比如黑色素瘤、非小细胞肺癌、肝细胞癌、基底细胞癌(basalcellcarcinoma)、肾细胞癌、骨髓瘤、变应性鼻炎、哮喘、慢性阻塞性肺炎(COPD)、溃疡性结肠炎、肝纤维化，HBV、黄病毒科(Flaviviridae)病毒、HCV、HPV、RSV、SARS、HIV或流行性感冒的病毒感染等。因此运用TLRs的激动剂治疗相关疾病是很有前景的。
由于TLR7和TLR8高度同源，因此TLR7配体，在大多数情况下也是TLR8配体。TLR8刺激主要诱导产生细胞因子如肿瘤坏死因子α(TNF-α)和趋化因子。干扰素α是治疗慢性乙型肝炎或丙型肝炎的主要药物之一，而TNF-α是一种促炎细胞因子，过多分泌可能导致严重的副作用。所以对TLR7和TLR8的选择性对于开发TLR7激动剂用于治疗病毒感染性疾病至关重要。
目前已有相关的TLR7激动剂专利申请，如WO2005025583、WO2007093901、WO2008011406、WO2009091032、WO2010077613、WO2010133882、 WO2011031965、WO2012080730。但是仍有必要继续研发安全的和治疗上更有效的TLR7激动剂。
本发明针对上述技术问题，提供一种起效浓度更低，选择性更好，激活效果更明显的药物化合物，同时，其对CYP和hERG没有抑制作用或抑制作用弱，是更安全和更有效的TLR7激动剂。
发明内容
本发明的目的在于提供一种通式(I)所示的化合物：
Figure PCTCN2018106983-appb-000001
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，
其中：
G 1为CR 3或N；
L 1选自-O-、-S-、-NR 4-、-C(O)-、-S(O) m-、-N(R 4)C(O)-、-C(O)N(R 4)-、-N(R 4)S(O) 2-、-S(O) 2N(R 4)-和共价键；
X 1为亚烷基，其中所述的亚烷基任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基和杂环基中的一个或多个取代基所取代；
R 1选自氢原子、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 2选自氢原子、烷基、烷氧基、卤素、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基、-C(O)R 5、-C(O)OR 5、-S(O) mR 5、-NR 6R 7和-C(O)NR 6R 7，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、杂环基烷基、芳基、杂芳基、-C(O)R 5、-C(O)OR 5、-S(O) mR 5、-NR 6R 7、-C(O)NR 6R 7和-X 2-NR 6R 7中的一个或多个取代基所取代；
R 3选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；
R 4选自氢原子、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基；
R 5选自氢原子、烷基、卤代烷基、氨基、羟基、环烷基、杂环基、芳基和杂芳基；
R 6和R 7相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自烷基、烷氧基、卤素、氨基、氰基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
或者，所述R 6和R 7与相连接的氮原子一起形成杂环基，其中所述的杂环基除含有1个氮原子之外，还任选含有1～2个相同或不同选自N、O和S的杂原子，并且所述的杂环基任选被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
X 2为亚烷基，其中所述的亚烷基任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基和杂环基中的一个或多个取代基所取代；且
m为0、1或2。
在本发明一个优选的实施方案中，所述的通式(I)所示的化合物，其为通式(II)所示的化合物：
Figure PCTCN2018106983-appb-000002
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，
其中：
G 1、L 1、X 1、R 1和R 2如通式(I)中所定义。
在本发明一个优选的实施方案中，所述的通式(I)所示的化合物，其为通式(IIaa)所示的化合物：
Figure PCTCN2018106983-appb-000003
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，
其中：
G 1、L 1、X 1、R 1和R 2如通式(I)中所定义。
在本发明一个优选的实施方案中，所述的通式(I)所示的化合物，其中所述的R 2选自芳基、杂芳基、杂环基和-NR 6R 7，其中所述的芳基、杂芳基和杂环基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、杂环基烷基和-X 2-NR 6R 7中的一个或多个取代基所取代；
X 2、R 6和R 7如通式(I)中所定义。
在本发明一个优选的实施方案中，所述的通式(I)所示的化合物，其中所述的R 2选自苯基、吡啶基、吡咯烷基和-NR 6R 7，其中所述的苯基、吡啶基和吡咯烷基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、杂环基烷基和-X 2-NR 6R 7中的一个或多个取代基所取代，所述杂环基烷基优选吡咯烷基亚甲基；
X 2、R 6和R 7如通式(I)中所定义。
在本发明一个优选的实施方案中，所述的通式(I)所示的化合物，其为通式(III)或通式(IV)所示的化合物：
Figure PCTCN2018106983-appb-000004
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，
其中：
环A为苯基或吡啶基；
R 8相同或不同，且各自独立地选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基和杂环基烷基；
R 6和R 7与相连接的氮原子一起形成杂环基，其中所述的杂环基除含有1个氮原子之外，还任选含有1～2个相同或不同选自N、O和S的杂原子，并且所述的杂环基任选被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
s为0、1、2或3；且
G 1、L 1、X 1、X 2、R 1和R 5如通式(I)中所定义。
在本发明一个优选的实施方案中，所述的通式(I)所示的化合物，其中所述的X 1为亚烷基。
在本发明一个优选的实施方案中，所述的通式(I)所示的化合物，其中所述的 G 1为N。
在本发明一个优选的实施方案中，所述的通式(I)所示的化合物，其为通式(V)或通式(VI)所示的化合物：
Figure PCTCN2018106983-appb-000005
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，
其中：
环A为苯基或吡啶基；
n为1到9的整数；
L 1、X 2、R 1、R 6和R 7如通式(III)中所定义。
在本发明一个优选的实施方案中，所述的通式(I)所示的化合物，其为通式(VII)所示的化合物：
Figure PCTCN2018106983-appb-000006
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，
其中：
L 1、X 2、R 1、R 6和R 7如通式(III)中所定义。
在本发明一个优选的实施方案中，所述的通式(I)所示的化合物，其中所述的L 1为-O-。
在本发明一个优选的实施方案中，所述的通式(I)所示的化合物，其中所述的R 1为烷基。
本发明的典型化合物包括但不限于：
Figure PCTCN2018106983-appb-000007
Figure PCTCN2018106983-appb-000008
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐。
本发明的另一方面涉及一种通式(IA)所示的化合物，
Figure PCTCN2018106983-appb-000009
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，
其中：
G 1为CR 3或N；
W为氨基保护基，选自叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基， 优选为对甲氧苄基；
R a为氨基保护基或氢原子，所述氨基保护基选自叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基，优选为对甲氧苄基；
L 1选自-O-、-S-、-NR 4-、-C(O)-、-S(O) m-、-N(R 4)C(O)-、-C(O)N(R 4)-、-N(R 4)S(O) 2-、-S(O) 2N(R 4)-和共价键；
X 1为亚烷基，其中所述的亚烷基任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基和杂环基中的一个或多个取代基所取代；
R 1选自氢原子、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 2选自氢原子、烷基、烷氧基、卤素、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基、-C(O)R 5、-C(O)OR 5、-S(O) mR 5、-NR 6R 7和-C(O)NR 6R 7，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、杂环基烷基、芳基、杂芳基、-C(O)R 5、-C(O)OR 5、-S(O) mR 5、-NR 6R 7、-C(O)NR 6R 7和-X 2-NR 6R 7中的一个或多个取代基所取代；
R 3选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；
R 4选自氢原子、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基；
R 5选自氢原子、烷基、卤代烷基、氨基、羟基、环烷基、杂环基、芳基和杂芳基；
R 6和R 7相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自烷基、烷氧基、卤素、氨基、氰基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
或者，所述R 6和R 7与相连接的氮原子一起形成杂环基，其中所述的杂环基除含有1个氮原子之外，还任选含有1～2个相同或不同选自N、O和S的杂原子，并且所述的杂环基任选被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
X 2为亚烷基，其中所述的亚烷基任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基和杂环基中的一个或多个取代基所取代；且
m为0、1或2。
通式(IA)所示的化合物包括，但不限于：
Figure PCTCN2018106983-appb-000010
本发明的另一方面涉及一种通式(IIA)所示的化合物，
Figure PCTCN2018106983-appb-000011
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，
其中：
W为氨基保护基，选自叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基，优选为对甲氧苄基；
R a为氨基保护基或氢原子，所述氨基保护基选自叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基，优选为对甲氧苄基；
G 1、L 1、X 1、R 1和R 2如通式(IA)中所定义。
本发明的另一方面涉及一种通式(IIB)所示的化合物，
Figure PCTCN2018106983-appb-000012
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，
其中：
W为氨基保护基，选自叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基，优选为对甲氧苄基；
R a为氨基保护基或氢原子，所述氨基保护基选自叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基，优选为对甲氧苄基；
G 1、L 1、X 1、R 1和R 2如通式(IA)中所定义。
通式(IIB)所示的化合物包括，但不限于：
Figure PCTCN2018106983-appb-000013
Figure PCTCN2018106983-appb-000014
本发明的另一方面涉及一种制备通式(I)所示的化合物的方法，该方法包括：
Figure PCTCN2018106983-appb-000015
通式(IA)的化合物脱去保护基得到通式(I)的化合物；
其中：
W为氨基保护基，选自叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基，优选为对甲氧苄基；
R a为氨基保护基或氢原子，所述氨基保护基选自叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基，优选为对甲氧苄基；
G 1、L 1、X 1、R 1和R 2如通式(I)中所定义。
本发明的另一方面涉及一种制备通式(IIA)所示的化合物的方法，该方法包括：
Figure PCTCN2018106983-appb-000016
通式(IIB)的化合物在碱性条件下，发生消除反应得到通式(IIA)的化合物；
其中：
W为氨基保护基，选自叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基，优选为对甲氧苄基；
R a为氨基保护基或氢原子，所述氨基保护基选自叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基，优选为对甲氧苄基；
G 1、L 1、X 1、R 1和R 2如通式(II A)中所定义。
本发明的另一方面涉及一种制备通式(II)所示的化合物的方法，该方法包括：
Figure PCTCN2018106983-appb-000017
通式(IIA)的化合物在酸性条件下脱去保护基得到通式(II)的化合物；
其中：
W为氨基保护基，选自叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基，优选为对甲氧苄基；
R a为氨基保护基或氢原子，所述氨基保护基选自叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基，优选为对甲氧苄基；
G 1、L 1、X 1、R 1和R 2如通式(II)中所定义。
本发明的另一方面涉及一种药物组合物，所述药物组合物含有治疗有效量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本发明进一步涉及通式(I)所示化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或包含其的药物组合物在制备用于激动TLR7的药物中的用途。
本发明进一步涉及通式(I)所示化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或包含其的药物组合物在制备用于治疗由病毒引起的感染的药物中的用途。
本发明进一步涉及通式(I)所示化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或包含其的药物组合物在制备用于治疗或预防肿瘤的药物中的用途。
本发明进一步涉及一种激动TLR7的方法，其包括将通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或包含其的药物组合物与TLR7接触的步骤。
本发明进一步涉及一种治疗由病毒引起的感染的方法，所述方法包括给予所需患者治疗有效量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或包含其的药物组合物。
本发明进一步涉及一种治疗或预防肿瘤的方法，其包括给予所需患者治疗有效量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或包含其的药物组合物。
本发明进一步涉及一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或包含其的药物，其用作药物。
本发明进一步涉及一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或包含其的药物，其用于激动TLR7。
本发明进一步涉及一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或包含其的药物，其用于治疗或预防由病毒引起的感染。
本发明中所述的病毒选自：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、HIV、HBV、HCV、HPV、RSV、SARS和流感病毒。
本发明进一步涉及一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或包含其的药物，其用于治疗或预防肿瘤。
本发明中所述的肿瘤选自：黑色素瘤、非小细胞肺癌、肝细胞癌、基底细胞癌、肾细胞癌和骨髓瘤。
含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。 可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂，造粒剂、崩解剂，粘合剂，和润滑剂。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。
也可用其中活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒混合的软明胶胶囊提供口服制剂。
水悬浮液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。此类赋形剂是悬浮剂，分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。
油混悬液可通过使活性成分悬浮于植物油，或矿物油配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。
本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油，或矿物油或其混合物。适宜的乳化剂可以是天然产生的磷脂，乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
本发明的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本发明化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。
药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。
可按用于直肠给药的栓剂形式给予本发明化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。此类物质包括可可脂、甘油明胶、氢化植物油、各种分子量的聚乙二醇和聚乙二醇的脂肪酸酯的混合物。
如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、排泄的速率、药物的组合等；另外，最佳的治疗方式如治疗的模式、通式化合物(I)的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
发明的详细说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“亚烷基”指饱和的直链或支链脂肪族烃基，其具有2个从母体烷的相同碳原子或两个不同的碳原子上除去两个氢原子所衍生的残基，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子，更优选含有1至6个碳原子的亚烷基。亚烷基的非限制性实例包括但不限于亚甲基(-CH 2-)、1,1-亚乙基(-CH(CH 3)-)、1,2-亚乙基(-CH 2CH 2)-、1,1-亚丙基(-CH(CH 2CH 3)-)、1,2-亚丙基(-CH 2CH(CH 3)-)、1,3-亚丙基(-CH 2CH 2CH 2-)、1,4-亚丁基(-CH 2CH 2CH 2CH 2-)和1,5-亚丁基(-CH 2CH 2CH 2CH 2CH 2-)等。亚烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、-C(O)R 5、-C(O)OR 5、-S(O) mR 5、-NR 6R 7和-C(O)NR 6R 7中的一个或多 个取代基所取代。
术语“烯基”指分子中含有碳碳双键的烷基化合物，其中烷基的定义如上所述。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自氢原子、烷基、烷氧基、卤素、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基、-C(O)R 5、-C(O)OR 5、-S(O) mR 5、-NR 6R 7和-C(O)NR 6R 7中的一个或多个取代基所取代。
术语“炔基”指分子中含有碳碳三键的烷基化合物，其中烷基的定义如上所述。炔基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自氢原子、烷基、烷氧基、卤素、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基、-C(O)R 5、-C(O)OR 5、-S(O) mR 5、-NR 6R 7和-C(O)NR 6R 7中的一个或多个取代基所取代。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至6个碳原子，最优选包含5至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：
Figure PCTCN2018106983-appb-000018
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：
Figure PCTCN2018106983-appb-000019
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更优选为双环或三环。桥环烷基的非限制性实例包括：
Figure PCTCN2018106983-appb-000020
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等；优选苯基并环戊基、四氢萘基。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；最优选包含3至8个环原子，其中1～3个是杂原子；最优选包含5至6个环原子，其中1～2或1～3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢吡喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等，优选四氢吡喃基、哌啶基、吡咯烷基。多环杂环基包括螺环、稠环和桥环的杂环基。
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括：
Figure PCTCN2018106983-appb-000021
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括：
Figure PCTCN2018106983-appb-000022
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更优选为双环或三环。桥杂环基的非限制性实例包括：
Figure PCTCN2018106983-appb-000023
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2018106983-appb-000024
等。
杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2018106983-appb-000025
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，含1至3个杂原子；更优选为5元或6元，含1至2个杂原子；优选例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选为咪唑基、吡唑基或嘧啶基、噻唑基；更优选吡唑基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2018106983-appb-000026
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基和环烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、 环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基所取代。
术语“氨基保护基”是为了使分子其它部位进行反应时氨基保持不变，用易于脱去的基团对氨基进行保护。非限制性实施例包含叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基等。这些基团可任选地被选自卤素、烷氧基或硝基中的1-3个取代基所取代。所述氨基保护基优选为对甲氧苄基。
术语“杂环基烷基”指被杂环基取代的烷基，其中烷基和杂环基如上所定义。
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。
术语“羟基”指-OH基团。
术语“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“氧代基”指＝O。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。
m和R 5～R 7如通式(I)化合物中所定义。
本发明化合物的合成方法
为了完成本发明的目的，本发明采用如下技术方案：
方案一
本发明通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2018106983-appb-000027
通式(IA)的化合物在酸性条件下，脱去保护基得到通式(I)的化合物；
其中：
W为氨基保护基，选自叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基，优选为对甲氧苄基；
R a为氨基保护基或氢原子，所述氨基保护基选自叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基，优选为对甲氧苄基；
G 1、L 1、X 1、R 1和R 2如通式(I)中所定义。
提供酸性的条件的试剂包括但不限于氯化氢、氯化氢的1,4-二氧六环溶液、氯化铵、三氟乙酸、甲酸、乙酸、盐酸、硫酸、甲磺酸、硝酸、磷酸、对苯甲磺酸和TMSOTf。
上述反应优选在溶剂中进行，所用溶剂包括但不限于：醋酸、甲醇、乙醇、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺及其混合物。
方案二
本发明通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2018106983-appb-000028
第一步，通式(II-1)的化合物在还原剂存在下，在酸性条件下，反应得到通式(IIB)的化合物；
第二步，通式(IIB)的化合物在碱性条件下，发生消除反应得到通式(IIA)的化合物；
第三步，通式(IIA)的化合物在酸性条件下，脱去保护基得到通式(II)的化合物；
其中：
W为氨基保护基，选自叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基，优选为对甲氧苄基；
R a为氨基保护基或氢原子，所述氨基保护基选自叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基，优选为对甲氧苄基；
R b为烷基，优选为乙基或甲基；
G 1、L 1、X 1、R 1和R 2如通式(II)中所定义。
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、吡啶、4-二甲氨基吡啶、N,N-二异丙基乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、1,5-二氮杂双环壬-5-烯(DBN)、正丁基锂、二异丙基氨基锂、双三甲基硅基胺基锂、醋酸钾、叔丁醇钠、叔丁醇钾和正丁醇钠，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、醋酸钾、碳酸铯、氢氧化钠、氢氧化钾和氢氧化锂。
提供酸性的条件的试剂包括但不限于氯化氢、氯化氢的1,4-二氧六环溶液、氯化铵、三氟乙酸、甲酸、乙酸、盐酸、硫酸、甲磺酸、硝酸、磷酸、对苯甲磺酸和TMSOTf。
还原试剂包括但不限于：铁粉、锌粉、硫化钠、硫代硫酸钠、二硫化钠、氯化亚锡、Pd/C/H 2、Pt/C/H 2、雷尼镍/H 2、氢化铝锂、硼氢化钠、DIBAL-H、NaAlH(O-t-Bu) 3、AlH 3、NaCNBH 3、Na(AcO) 3BH和Li(Et) 3BH。
上述反应优选在溶剂中进行，所用溶剂包括但不限于：醋酸、甲醇、乙醇、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺及其混合物。
方案三
本发明通式(IIaa)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2018106983-appb-000029
第一步，通式(IIaa-1)的化合物在酸性条件下，加热反应得到通式(IIaa-2)的化合物；
第二步，通式(IIaa-2)的化合物在酸性条件下，脱去保护基得到通式(IIaa)的化合物；
其中：
W为氨基保护基，选自叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基，优选为对甲氧苄基；
R a为氨基保护基或氢原子，所述氨基保护基选自叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基，优选为对甲氧苄基；
R b为烷基，优选为乙基或甲基；
G 1、L 1、X 1、R 1和R 2如通式(IIaa)中所定义。
提供酸性的条件的试剂包括但不限于氯化氢、氯化氢的1,4-二氧六环溶液、氯化铵、三氟乙酸、甲酸、乙酸、浓盐酸、硫酸、甲磺酸、硝酸、磷酸、对苯甲磺酸和TMSOTf。
上述反应优选在溶剂中进行，所用溶剂包括但不限于：醋酸、甲醇、乙醇、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺及其混合物。
方案四
本发明通式(III)或通式(IV)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2018106983-appb-000030
Figure PCTCN2018106983-appb-000031
通式(IIIA)的化合物在酸性条件下，脱去保护基得到通式(III)的化合物；
或通式(IVA)的化合物在酸性条件下，脱去保护基得到通式(IV)的化合物；
其中：
W为氨基保护基，选自叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基，优选为对甲氧苄基；
R a为氨基保护基或氢原子，所述氨基保护基选自叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基，优选为对甲氧苄基；
环A、G 1、L 1、X 1、X 2、R 1、R 6～R 8和s如通式(III)中所定义。
提供酸性的条件的试剂包括但不限于氯化氢、氯化氢的1,4-二氧六环溶液、氯化铵、三氟乙酸、甲酸、乙酸、盐酸、硫酸、甲磺酸、硝酸、磷酸、对苯甲磺酸、Me 3SiCl和TMSOTf。
上述反应优选在溶剂中进行，所用溶剂包括但不限于：醋酸、甲醇、乙醇、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺及其混合物。
方案五
本发明通式(V)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2018106983-appb-000032
第一步，通式(V-1)的化合物在还原剂存在下，在酸性条件下，反应得到通式(V-2)的化合物；
第二步，通式(V-2)的化合物在碱性条件下，发生消除反应得到通式(VA)的化合物；
第三步，通式(VA)的化合物在酸性条件下，脱去保护基得到通式(V)的化合物；
其中：
W为氨基保护基，选自叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基，优选为对甲氧苄基；
R a为氨基保护基或氢原子，所述氨基保护基选自叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基，优选为对甲氧苄基；
R b为烷基，优选为乙基或甲基；
环A、L 1、X 2、R 1、R 6和R 7如通式(V)中所定义。
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、吡啶、4-二甲氨基吡啶、N,N-二异丙基乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、1,5-二氮杂双环壬-5-烯(DBN)、正丁基锂、二异丙基氨基锂、双三甲基硅基胺基锂、醋酸钾、叔丁醇钠、叔丁醇钾和正丁醇钠，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、醋酸钾、碳酸铯、氢氧化钠、氢氧化钾和氢氧化锂。
提供酸性的条件的试剂包括但不限于氯化氢、氯化氢的1,4-二氧六环溶液、氯化铵、三氟乙酸、甲酸、乙酸、盐酸、硫酸、甲磺酸、硝酸、磷酸、对苯甲磺酸和TMSOTf。
还原试剂包括但不限于：铁粉、锌粉、硫化钠、硫代硫酸钠、二硫化钠、氯化亚锡、Pd/C/H 2、Pt/C/H 2、雷尼镍/H 2、氢化铝锂、硼氢化钠、DIBAL-H、NaAlH(O-t-Bu) 3、AlH 3、NaCNBH 3、Na(AcO) 3BH和Li(Et) 3BH。
上述反应优选在溶剂中进行，所用溶剂包括但不限于：醋酸、甲醇、乙醇、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺及其混合物。
方案六
本发明通式(VI)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2018106983-appb-000033
第一步，通式(VI-1)的化合物在还原剂存在下，在酸性条件下，反应得到通式(V-2)的化合物；
第二步，通式(VI-2)的化合物在碱性条件下，发生消除反应得到通式(VIA)的化合物；
第三步，通式(VIA)的化合物在酸性条件下，脱去保护基得到通式(VI)的化合物；
其中：
W为氨基保护基，选自叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基，优选为对甲氧苄基；
R a为氨基保护基或氢原子，所述氨基保护基选自叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基，优选为对甲氧苄基；
R b为烷基，优选为乙基或甲基；
L 1、R 1、n、R 6和R 7如通式(VI)中所定义。
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、吡啶、4-二甲氨基吡啶、N,N-二异丙基乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、1,5-二氮杂双环壬-5-烯(DBN)、正丁基锂、二异丙基氨基锂、双三甲基硅基胺基锂、醋酸钾、叔丁醇钠、叔丁醇钾和正丁醇钠，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、醋酸钾、碳酸铯、氢氧化钠、氢氧化钾和氢氧化锂。
提供酸性的条件的试剂包括但不限于氯化氢、氯化氢的1,4-二氧六环溶液、氯化铵、三氟乙酸、甲酸、乙酸、盐酸、硫酸、甲磺酸、硝酸、磷酸、对苯甲磺酸和TMSOTf。
还原试剂包括但不限于：铁粉、锌粉、硫化钠、硫代硫酸钠、二硫化钠、氯化亚锡、Pd/C/H 2、Pt/C/H 2、雷尼镍/H 2、氢化铝锂、硼氢化钠、DIBAL-H、NaAlH(O-t-Bu) 3、AlH 3、NaCNBH 3、Na(AcO) 3BH和Li(Et) 3BH。
上述反应优选在溶剂中进行，所用溶剂包括但不限于：醋酸、甲醇、乙醇、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺及其混合物。
方案七
本发明通式(VII)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2018106983-appb-000034
第一步，通式(VII-1)的化合物在还原剂存在下，在酸性条件下，反应得到通式(VII-2)的化合物；
第二步，通式(VII-2)的化合物在碱性条件下，发生消除反应得到通式(VIIA)的化合物；
第三步，通式(VIIA)的化合物在酸性条件下，脱去保护基得到通式(VII)的化合物；
其中：
W为氨基保护基，选自叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基，优选为对甲氧苄基；
R a为氨基保护基或氢原子，所述氨基保护基选自叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基，优选为对甲氧苄基；
R b为烷基，优选为乙基或甲基；
L 1、X 2、R 1、R 6和R 7如通式(VII)中所定义。
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、吡啶、4-二甲氨基吡啶、N,N-二异丙基乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、1,5-二氮杂双环壬-5-烯(DBN)、正丁基锂、二异丙基氨基锂、双三 甲基硅基胺基锂、醋酸钾、叔丁醇钠、叔丁醇钾和正丁醇钠，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、醋酸钾、碳酸铯、氢氧化钠、氢氧化钾和氢氧化锂。
提供酸性的条件的试剂包括但不限于氯化氢、氯化氢的1,4-二氧六环溶液、氯化铵、三氟乙酸、甲酸、乙酸、盐酸、硫酸、甲磺酸、硝酸、磷酸、对苯甲磺酸和TMSOTf。
还原试剂包括但不限于：铁粉、锌粉、硫化钠、硫代硫酸钠、二硫化钠、氯化亚锡、Pd/C/H 2、Pt/C/H 2、雷尼镍/H 2、氢化铝锂、硼氢化钠、DIBAL-H、NaAlH(O-t-Bu) 3、AlH 3、NaCNBH 3、Na(AcO) 3BH和Li(Et) 3BH。
上述反应优选在溶剂中进行，所用溶剂包括但不限于：醋酸、甲醇、乙醇、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺及其混合物。
具体实施方式
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商：Thermo，型号：Finnigan LCQ advantage MAX)。
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高压液相色谱仪。
手性HPLC分析测定使用Agilent 1260DAD高效液相色谱仪。
高效液相制备使用Waters 2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson-281制备型色谱仪。
手性制备使用Shimadzu LC-20AP制备型色谱仪。
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。
激酶平均抑制率及IC 50值的测定用NovoStar酶标仪(德国BMG公司)。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
4-氨基-2-丁氧基-8-(4-(吡咯烷-1-基甲基)苄基)吡啶并[3,2-d]嘧啶-6(5H)-酮1
Figure PCTCN2018106983-appb-000035
第一步
2-丁氧基-6-氯-N,N-二(4-甲氧基苄基)-5-硝基嘧啶-4-胺1b
将2-丁氧基-4,6-二氯-5-硝基嘧啶1a(4.62g，17.43mmol，采用公知的方法“Journal of Medicinal Chemistry,2012,55(23),10387-10404”制备而得)溶于50mL四氢呋喃溶剂中，加入三乙胺(2.64g，26.14mmol)和N,N-双(4-甲氧基苄基)胺(4.49g，17.43mmol)，搅拌反应4小时。反应液减压浓缩，用CombiFlash快速制备仪以洗脱剂体系B纯化残余物，得到标题化合物1b(6.20g，产率：73.8％)。
MS m/z(ESI):487.5[M+1]
第二步
2-(6-(二(4-甲氧基苄基)氨基)-2-丁氧基-5-硝基嘧啶-4-基)乙酸乙酯1c
将乙酸乙酯(1.09g，12.32mmol)溶于40mL四氢呋喃中，冷却至-70℃，滴加入1M双(三甲基硅基)氨基锂的四氢呋喃溶液(12.3mL，12.3mmol)，-70℃下搅拌反应0.5小时，加入化合物1b(4g，8.21mmol)，-70℃下搅拌反应5小时。反应液中加入50mL饱和氯化铵溶液，用乙酸乙酯萃取(300mL×1)，有机相用水洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用CombiFlash快速制备仪以洗脱剂体系B纯化所得残余物，得到标题化合物1c(2.1g，产率：47％)。
MS m/z(ESI):539.5[M+1]
第三步
2-(6-(二(4-甲氧基苄基)氨基)-2-丁氧基-5-硝基嘧啶-4-基)-3-(4-(吡咯烷-1-基甲基)苯基)丙酸乙酯1e
将化合物1c(355mg，0.65mmol)溶于5mL N,N-二甲基甲酰胺中，加入1-(4-(氯甲基)苄基)-吡咯烷盐酸盐1d(240mg，0.97mmol，采用专利申请“WO2002012224”公开的方法制备而得)和碳酸铯(1.06g，3.25mmol)，50℃下搅拌反应5小时。反应液冷却至室温，加入20mL饱和氯化钠溶液，用二氯甲烷萃取(100mL×1)，有机相用水洗涤(30mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用CombiFlash快速制备仪以洗脱剂体系A纯化所得残余物，得到标题化合物1e(270mg，产率：58％)。
MS m/z(ESI):712.4[M+1]
第四步
2-丁氧基-N,N-二(4-甲氧基苄基)-5-硝基-6-(4-(吡咯烷-1-基甲基)苯乙基)嘧啶-4-胺1f
将化合物1e(270mg，0.38mmol)和氢氧化锂一水合物(159.5mg，3.8mmol)溶于10mL四氢呋喃和5mL水的混合溶剂中，70℃搅拌反应16小时。反应液冷却至室温，加入20mL饱和氯化钠溶液，用二氯甲烷萃取(50mL×1)，有机相用饱和氯化钠溶液洗涤(20mL×1)，用无水硫酸钠干燥，过滤，滤液减压浓缩，用CombiFlash快速制备仪以洗脱剂体系A纯化所得残余物，得到标题化合物1f(220mg，产率：90％)。
MS m/z(ESI):640.6[M+1]
第五步
3-(6-(二(4-甲氧基苄基)氨基)-2-丁氧基-5-硝基嘧啶-4-基)-2-羟基-4-(4-(吡咯烷-1-基甲基)苯基)丁酸乙酯1h
将化合物1f(220mg，0.34mmol)溶于5mL N,N-二甲基甲酰胺中，加入叔丁醇钾(116mg，1.03mmol)，再加入50％乙醛酸乙酯的甲苯溶液1g(210mg，1.03mmol)，搅拌反应0.5小时。反应中加入20mL饱和氯化铵溶液，用二氯甲烷萃取(50mL×1)，有机相用水洗涤(20mL×1)，用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题化合物1h(250mg)，产品不经纯化直接用于下一步反应。
MS m/z(ESI):742.7[M+1]
第六步
4-(二(4-甲氧基苄基)氨基)-2-丁氧基-7-羟基-8-(4-(吡咯烷-1-基甲基)苄基)-7,8-二氢吡啶并[3,2-d]嘧啶-6(5H)-酮1i
将粗品化合物1h(250mg，0.34mmol)溶于5mL醋酸中，加入锌粉(219mg，3.4mmol)，搅拌反应0.5小时。反应液过滤，滤液减压浓缩，用饱和碳酸钾溶液调节所得残余物的pH为7后，用二氯甲烷萃取(50mL×1)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题化合物1i(220mg)，产品不经纯化直接用于下一步反应。
MS m/z(ESI):666.2[M+1]
第七步
4-(二(4-甲氧基苄基)氨基)-2-丁氧基-8-(4-(吡咯烷-1-基甲基)苄基)吡啶并[3,2-d]嘧啶-6(5H)-酮1j
将粗品化合物1i(220mg，0.34mmol)溶于5mL乙腈中，加入1,8-二氮杂二环[5.4.0]十一碳-7-烯(155mg，1.02mmol)，80℃搅拌反应0.5小时。反应液冷却至室温，减压浓缩，用CombiFlash快速制备仪以洗脱剂体系A纯化所得残余物，得到标题化合物1j(100mg，产率：45％)。
MS m/z(ESI):648.7[M+1]
第八步
4-氨基-2-丁氧基-8-(4-(吡咯烷-1-基甲基)苄基)吡啶并[3,2-d]嘧啶-6(5H)-酮1
将化合物1j(100mg，0.15mmol)溶于10mL三氟乙酸中，密闭加热至100℃搅拌反应16小时。反应液冷却至室温，减压浓缩，用高效液相色谱法(Waters-2767，洗脱体系：10mmol/L碳酸氢铵，水，乙腈)纯化所得残余物，得到标题化合物1(20mg，产率：32％)。
MS m/z(ESI):408.5[M+1]
1H NMR(400MHz,DMSO-d 6)δ11.18(s,1H),7.40(s,2H),7.25(d,2H),7.20(d,2H),6.58(s,1H),4.21(t,2H),4.09(s,2H),3.51(s,2H),2.39(s,4H),1.66(s,6H),1.41-1.36(m,2H),0.91(t,3H)。
实施例2
4-氨基-2-丁氧基-8-(5-(吡咯烷-1-基)戊基)吡啶并[3,2-d]嘧啶-6(5H)-酮2
Figure PCTCN2018106983-appb-000036
第一步
2-(6-(二(4-甲氧基苄基)氨基)-2-丁氧基-5-硝基嘧啶-4-基)-7-溴代庚酸乙酯2a
将化合物1c(2.10g，3.90mmol)和1,5-二溴戊烷(2.67g，11.70mmol)溶于30mL N,N-二甲基甲酰胺中，加入碳酸铯(3.80g，11.70mmol)，搅拌反应6小时。反应液中加入60mL饱和氯化铵溶液，用乙酸乙酯萃取(100mL×1)，有机相用水洗涤(50mL×1)，用无水硫酸钠干燥，过滤，滤液减压浓缩，用CombiFlash快速制备仪以
洗脱剂体系B纯化所得残余物，得到标题化合物2a(1.16g，产率：43％)。
MS m/z(ESI):687.5[M+1]
第二步
2-(6-(二(4-甲氧基苄基)氨基)-2-丁氧基-5-硝基嘧啶-4-基)-7-(吡咯烷-1-基)庚酸乙酯2b
将化合物2a(1.16g，1.69mmol)、吡咯烷(360mg，5.06mmol)和三乙胺(511mg，5.06mmol)溶于15mL N,N-二甲基甲酰胺中，80℃搅拌反应1小时。反应液冷却至室温，加入30mL饱和氯化铵溶液，用二氯甲烷萃取(100mL×1)，有机相用水洗涤(50mL×1)，用无水硫酸钠干燥，过滤，滤液减压浓缩，用CombiFlash快速制备仪以洗脱剂体系A纯化所得残余物，得到标题化合物2b(1.01g，产率：87％)。
MS m/z(ESI):678.4[M+1]
第三步
2-丁氧基-N,N-二(4-甲氧基苄基)-5-硝基-6-(6-(吡咯烷-1-基)己基)嘧啶-4-胺2c
将化合物2b(900mg，1.33mmol)和氢氧化锂一水合物(167.3mg，3.98mmol)溶于20mL四氢呋喃和10mL水的混合溶剂中，70℃搅拌反应16小时。反应液冷却至室温，加入40mL饱和氯化钠水溶液，用二氯甲烷萃取(100mL×1)，有机相用饱和氯化钠溶液洗涤(30mL×1)，用无水硫酸钠干燥，过滤，滤液减压浓缩，用CombiFlash快速制备仪以洗脱剂体系A纯化所得残余物，得到标题化合物2c(700mg，产率：87％)。
MS m/z(ESI):606.4[M+1]
第四步
ethyl 3-(6-(二(4-甲氧基苄基)氨基)-2-丁氧基-5-硝基嘧啶-4-基)-2-羟基-8-(吡咯烷-1-基)辛酸乙酯2d
将化合物2c(220mg，0.36mmol)溶于5mL N,N-二甲基甲酰胺中，加入叔丁醇钾(122mg，1.09mmol)，再加入50％乙醛酸乙酯的甲苯溶液1g(223mg，1.09mmol)，搅拌反应0.5小时。反应液中加入20mL饱和氯化铵溶液，用二氯甲烷萃取(50mL×1)，有机相用水洗涤(20mL×1)，用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题化合物2d(250mg)，产品不经纯化直接用于下一步反应。MS m/z(ESI):708.3[M+1]
第五步
4-(二(4-甲氧基苄基)氨基)-2-丁氧基-7-羟基-8-(5-(吡咯烷-1-基)戊基)-7,8-二氢吡啶并[3,2-d]嘧啶-6(5H)-酮2e
将粗品化合物2d(250mg，0.36mmol)溶于5mL醋酸中，加入锌粉(234mg，3.6mmol)，反应0.5小时。反应液过滤，滤液减压浓缩，用饱和碳酸钾溶液调节所得残余物pH为7，用二氯甲烷萃取(50mL×1)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题化合物2e(220mg)，产品不经纯化直接用于下一步反应。
MS m/z(ESI):632.3[M+1]
第六步
4-(二(4-甲氧基苄基)氨基)-2-丁氧基-8-(5-(吡咯烷-1-基)戊基)吡啶并[3,2-d]嘧啶-6(5H)-酮2f
将粗品化合物2e(220mg，0.36mmol)溶于5mL乙腈中，加入1,8-二氮杂二环[5.4.0]十一碳-7-烯(164mg，1.08mmol)，80℃搅拌反应0.5小时。反应液冷却至室温，减压浓缩，用CombiFlash快速制备仪以洗脱剂体系A纯化所得残余物，得到标题化合物2f(100mg，产率：45％)。
MS m/z(ESI):614.4[M+1]
第七步
4-氨基-2-丁氧基-8-(5-(吡咯烷-1-基)戊基)吡啶并[3,2-d]嘧啶-6(5H)-酮2
将化合物2f(100mg，0.16mmol)溶于10mL三氟乙酸中，密闭加热至100℃搅拌反应16小时。反应液冷却至室温，减压浓缩，用高效液相色谱法(Waters-2767， 洗脱体系：10mmol/L碳酸氢铵，水，乙腈)纯化所得残余物，得到标题化合物2(30mg，产率：50％)。
MS m/z(ESI):374.3[M+1]
1H NMR(400MHz,CD 3OD):δ6.76(s,1H),4.33(t,2H),2.88(t,2H),2.71(t,4H),2.63(t,2H),1.90-1.86(m,4H),1.82-1.74(m,4H),1.70-1.62(m,2H),1.55-1.45(m,4H),0.99(t,3H)。
实施例3
4-氨基-2-丁氧基-7-(5-(吡咯烷-1-基)戊基)吡啶并[3,2-d]嘧啶-6(5H)-酮3
Figure PCTCN2018106983-appb-000037
第一步
7-(吡咯烷-1-基)庚酸甲酯3b
将7-溴庚酸甲酯3a(1.12g，5mmol，采用公知的方法“Journal of Natural Products,79(1),244-247；2016”制备而得)、吡咯烷(710mg，10mmol)和三乙胺(1.01mg，10mmol)溶于15mL N,N-二甲基甲酰胺中，80℃搅拌反应1小时。反应液冷却至室温，加入30mL饱和氯化铵溶液，用二氯甲烷萃取(100mL×1)，有机相用水洗涤(50mL×1)，用无水硫酸钠干燥，过滤，滤液减压浓缩，用CombiFlash快速制备仪以洗脱剂体系A纯化所得残余物，得到标题化合物3b(920mg，产率：86％)。
第二步
2-丁氧基-6-氯-N 4,N 4-二(4-甲氧基苄基)嘧啶-4,5-二胺3c
将化合物1b(4g，8.21mmol)溶于30mL乙醇、30mL四氢呋喃和15mL水 的混合溶剂中，加入锌粉(2.67g，41.07mmol)和氯化铵(2.18g，41.07mmol)，搅拌反应2小时。反应液中加入100mL饱和氯化钠溶液，用乙酸乙酯萃取(200mL×1)，有机相用水洗涤(60mL×1)，用无水硫酸钠干燥，过滤，滤液减压浓缩，用CombiFlash快速制备仪以洗脱剂体系B纯化所得残余物，得到标题化合物3c(2g，产率：53％)。
MS m/z(ESI):457.5[M+1]
第三步
5-氨基-6-(二(4-甲氧基苄基)氨基)-2-丁氧基嘧啶-4-甲酸甲酯3d
将化合物3c(1g，2.19mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(160mg，0.22mmol)和三乙胺(442mg，4.38mmol)溶于20mL甲醇和10mL N,N-二甲基甲酰胺的混合溶剂中，用氮气置换空气，再用一氧化碳置换氮气后，密闭加热至70℃搅拌反应7小时。反应液冷却至室温，减压浓缩，用CombiFlash快速制备仪以洗脱剂体系B纯化所得残余物，得到标题化合物3d(1g，产率：95％)。
MS m/z(ESI):481.2[M+1]
第四步
5-氨基-6-(二(4-甲氧基苄基)氨基)-2-丁氧基嘧啶-4-甲醛3e
将化合物3d(760mg，1.58mmol)溶于10mL二氯甲烷中，冷却至-70℃，加入1M二异丁基氢化铝的正己烷溶液(5.54mL，5.54mmol)，在-70℃氮气保护下搅拌反应3小时。反应液升温至0℃，加入20mL饱和氯化铵溶液淬灭反应，用二氯甲烷萃取(50mL×1)，有机相用水洗涤(30mL×1)，用无水硫酸钠干燥，过滤，滤液减压浓缩，用CombiFlash快速制备仪以洗脱剂体系B纯化所得残余物，得到标题化合物3e(200mg，产率：28％)。
MS m/z(ESI):451.5[M+1]
第五步
2-((5-氨基-6-(二(4-甲氧基苄基)氨基)-2-丁氧基嘧啶-4-基)(羟基)甲基)-7-(吡咯烷-1-基)庚酸甲酯3f
将化合物3b(142mg，0.67mmol)溶于5mL四氢呋喃中，冷却至-70℃，加入2M二异丙氨基锂的四氢呋喃/乙苯/庚烷溶液(0.45mL，0.9mmol)，在-70℃氮气保护下搅拌反应0.5小时，加入化合物3e(200mg，0.45mmol)，将反应液温度缓缓升至室温，搅拌反应1小时。反应液用10mL饱和氯化铵溶液淬灭，用二氯甲烷萃取(50mL×1)，有机相用饱和氯化钠溶液洗涤(20mL×1)后，用无水硫酸钠干燥，过滤，滤液减压浓缩，用CombiFlash快速制备仪以洗脱剂体系A纯化所得残余物，得到标题化合物3f(40mg，产率：14％)。
MS m/z(ESI):664.4[M+1]
第六步
2-丁氧基-4-((4-甲氧基苄基)氨基)-7-(5-(吡咯烷-1-基)戊基)吡啶并[3,2-d]嘧啶-6(5H)-酮3g
将化合物3f(40mg，0.06mmol)溶于5mL1,4-二氧六环中，加入0.5mL浓盐酸和0.5mL水，加热至85℃搅拌反应2小时。反应液冷却至室温，用饱和碳酸氢钠溶液调节pH为7，减压浓缩，得到粗品标题化合物3g(31mg)，产品不经纯化直接用于下一步反应。
MS m/z(ESI):494.3[M+1]
第七步
4-氨基-2-丁氧基-7-(5-(吡咯烷-1-基)戊基)吡啶并[3,2-d]嘧啶-6(5H)-酮3
将粗品化合物3g(31mg，0.06mmol)溶于5mL三氟乙酸中，密闭加热至100℃搅拌反应16小时。反应液冷却至室温，减压浓缩，用高效液相色谱法(Gilson-281，洗脱体系：水，乙腈)纯化所得残余物，得到标题化合物3(3mg，产率：13％)。MS m/z(ESI):374.3[M+1]
1H NMR(400MHz,CD 3OD)δ7.62(s,1H),4.52(s,2H),3.65(s,2H),3.20(t,2H),3.08(s,2H),2.75(s,2H),2.15(s,2H),2.03(s,2H),1.83-1.74(m,6H),1.54-1.49(m,4H),1.00(t,3H)。
测试例：
生物学评价
测试例1、本发明化合物对人源TLR7激动活性的测定
本发明化合物对HEK-Blue TM hTLR7稳转株细胞表达的hTLR7激活作用采用如下实验方法测定：
一、实验材料及仪器
1.DMEM(Gibco，10564-029),
2.胎牛血清(GIBCO,10099),
3.台盼蓝溶液(Sigma,T8154-100ML),
4.Flexstation 3多功能酶标仪(Molecμlar Devices),
5.HEK-Blue TM hTLR7细胞系(InvivoGen,hkb-hTLR7),
6.HEK-Blue检测试剂(InvivoGen,hb-det3),
7.磷酸盐缓冲液(PBS)pH7.4(上海源培生物科技股份有限公司，B320)。
二、实验步骤
配置HEK-Blue检测培养基，取HEK-Blue检测干粉一袋，加入50ml去内毒素水溶解，再放入37℃培养箱，10分钟后无菌过滤。化合物先配制成20mM的原液；再用纯DMSO稀释至最高浓度为6x 10 6nM，经3倍梯度稀释，共10个点。用培养基先把上述配制好的化合物稀释20倍，然后每孔加入20μl稀释后的化合物。
取HEK-Blue TM hTLR7细胞，先去掉上清，再加入2-5ml预热的PBS，放入培养箱1-2分钟，轻轻吹打细胞，台盼蓝染色计数。用HEK-Blue检测培养基重悬细胞调整浓度为2.2x 10 5个细胞/ml，加180μl细胞至上述已加入20μl药物的96孔细胞培养板中，37℃，培养6-16h。
酶标仪读数，波长为620nm。可获得相应的OD值，经Graphpad Prism计算得到药物的EC 50值。
本发明化合物对人源TLR7激活作用可通过以上的试验进行测定，测得的EC 50值见表1。
表1本发明化合物对人源TLR7的EC 50。
实施例编号 EC 50(nM) Emax(％)
1 62 94
2 356 88
结论：本发明化合物对人源TLR7具有较好的激活作用。
测试例2、本发明化合物对人源TLR8激动活性的测定
本发明化合物对HEK-Blue TM hTLR8稳转株细胞表达的hTLR8激活作用采用如下实验方法测定：
一、实验材料及仪器
1.DMEM(Gibco，10564-029),
2.胎牛血清(GIBCO,10099),
3.台盼蓝溶液(Sigma,T8154-100ML),
4.Flexstation 3多功能酶标仪(Molecμlar Devices),
5.HEK-Blue TM hTLR8细胞系(InvivoGen,hkb-hTLR8),
6.HEK-Blue检测试剂(InvivoGen,hb-det3),
7.磷酸盐缓冲液(PBS)pH7.4(上海源培生物科技股份有限公司，B320)。
二、实验步骤
配置HEK-Blue检测培养基，取HEK-Blue检测干粉一袋，加入50ml去内毒素水溶解，再放入37℃培养箱，10分钟后无菌过滤。化合物先配制成20mM的原液；再用纯DMSO稀释至最高浓度为6x 10 6nM，然后3倍梯度稀释，共10个点；用培养基先把化合物稀释20倍，然后每孔加入20μl稀释后的化合物。
取HEK-Blue TM hTLR8细胞，先去掉上清，加入2-5ml预热的PBS，放入培养箱1-2分钟,轻轻吹打细胞，台盼蓝染色计数。用HEK-Blue检测培养基重悬细胞调整浓度为2.2x 10 5个细胞/ml，加180μl细胞至上述已加入20μl药物的96孔细胞培养板中，37℃，培养6-16h。
酶标仪读数，波长为620nm。可获得相应的OD值，经Graphpad Prism计算得到药物的EC 50值。
本发明化合物对人源TLR8激活作用可通过以上的试验进行测定，测得的EC 50值见表2。
表2本发明化合物对人源TLR8的EC 50。
实施例编号 EC 50(nM) Emax(％)
1 6.7×10 3 76
2 4.4×10 3 93
结论：本发明化合物对人源TLR8激活作用较弱，说明本发明化合物对TLR7具有选择性。
测试例3、本发明中化合物刺激外周血单个核细胞(PBMC)分泌IFN-α能力的测定
本发明中化合物刺激PBMC分泌IFN-α能力采用如下实验方法测定：
一、实验材料及仪器
1.RPMI 1640(Invitrogen,11875),
2.FBS(Gibco,10099-141),
3.Ficoll-Paque PREMIUM(GE,17-5442-02),
4.台盼蓝溶液(Sigma,T8154-100ML),
5.SepMateTM-50(Stemcell,15460),
6.Bright-Line TM血细胞计数仪(Sigma,Z359629-1EA),
7.96孔平底板(Corning,3599),
8.96孔v底板(Corning,3894),
9.人源IFN-α试剂盒(cisbio,6FHIFPEB),
10.PHERAStar多功能酶标仪(BMG，PHERAStar)。
二、实验步骤
化合物用纯DMSO稀释，最高浓度为5mM，4倍梯度稀释，共9个点。然后取4μl化合物，加入到196μl含10％FBS的RMPI 1640培养基中，混匀。每孔取50μl至新的96孔细胞培养板。
所有试剂平衡到室温，取250ml培养瓶，将60ml血液和PBS+2％FBS加入其中，轻轻吹打混匀稀释。取50ml PBMC分离管SepMateTM-50，加入15ml淋巴细胞分离液Ficoll-Paque PREMIUM，然后加入30ml稀释后血液。1200g离心10分钟,室温。取上清，然后300g，离心8分钟。用含10％FBS的RMPI 1640培养基重悬并计数，调整PBMC数量至3.33×10 6个细胞/ml，取150μl至已加入化合物的细胞培养板中，37℃，5.0％CO 2的培养箱中培养24h。
将细胞培养板放入离心机中，1200rpm，室温离心10分钟。每孔取出150μl上清。先平衡人源IFN-α试剂盒中的试剂至常温，在避光条件下根据试剂盒说明书配制抗-IFN-α-Eu 3+-穴状结合物(Cryptate conjugate)和抗-IFN-α-d2-结合物，两者均以1：40的比例与结合缓冲液(conjugate Buffer)混匀。然后每孔加入16μl的离心取得的上清液。再每孔加入2μl刚配好的抗-IFN-α-Eu 3+-穴状结合物和抗-IFN-α-d2-结合物，震荡混匀，室温避光孵育3h。
在PHERAStar上用HTRF模式读数。我们将刺激产生最低检测限至少3倍以上细胞因子水平的最低药物浓度，定义为该化合物在该细胞因子刺激实验上的 MEC(最小有效浓度Minimal Effective Concentration)值。
本发明化合物刺激PBMC分泌IFN-α的能力通过以上的试验进行测定，测得的MEC值见表3。
表3本发明化合物刺激PBMC分泌IFN-α的MEC
实施例编号 MEC(nM)
1 0.6
结论：从刺激PBMC分泌IFN-α的活性的数据上看，本发明化合物能够较好的引起IFN-α释放。
测试例4、本发明化合物对人肝微粒体CYP3A4咪达唑仑代谢位点的酶活性的抑制作用
本发明化合物对人肝微粒体CYP3A4咪达唑仑代谢位点的酶活性采用如下实验方法测定：
一、实验材料及仪器
1.磷酸缓冲液(PBS),
2.NADPH(Sigma N-1630),
3.人肝微粒体(Corning Gentest),
4.ABI QTrap 4000液质两用仪(AB Sciex),
5.Inertsil C8-3柱,4.6×50mm,5μm(美国迪马公司),
6.CYP探针底物(15μM的咪达唑仑，SIGMA UC429)和阳性对照抑制剂(酮康唑，SIGMA K1003)。
二、实验步骤
配置100mM的PBS缓冲液，用该缓冲液配制2.5mg/ml的微粒体溶液和5mM的NADPH溶液，用PBS梯度稀释5X浓度的化合物工作液(150、50、15、5、1.5、0.15、0.015、0μM)。用PBS梯度稀释5X浓度的酮康唑工作液(150、50、15、5、1.5、0.15、0.015、0μM)。用PBS稀释至15μM浓度的咪达唑仑工作液。
分别取2.5mg/ml的微粒体溶液、15μM的咪达唑仑工作液、MgCl 2溶液和化合物工作液(150、50、15、5、1.5、0.15、0.015、0μM，每个浓度设置不同的反应体系)各20μl，混合均匀。阳性对照组用相同浓度的酮康唑代替化合物。同时将5mM的NADPH溶液一起在37℃预孵育5分钟。5分钟之后取20μl NADPH加入到个孔中，启动反应，孵育30分钟。所有孵育样品设双样本。30分钟后向所有样本中加入250μl含内标的乙腈，混匀，800rpm摇10分钟，然后3700rpm离心10分钟。取80μl的上清液，转移至LC-MS/MS分析。
数值经Graphpad Prism计算得到药物对CYP3A4咪达唑仑代谢位点的IC 50值见表4。
表4本发明化合物对CYP3A4咪达唑仑代谢位点的IC 50值
实施例编号 IC 50(μM)
1 >30
2 >30
结论：本发明化合物对人肝微粒体CYP3A4的咪达唑仑代谢位点没有抑制作用，表现出更好的安全性，提示不会发生基于CYP3A4代谢咪达唑仑代谢位点的代谢性药物相互作用。
测试例5、本发明化合物对人肝微粒体CYP2D6酶活性的抑制作用
本发明化合物对人肝微粒体CYP2D6酶活性采用如下实验方法测定：
一、实验材料及仪器
1.磷酸缓冲液(PBS),
2.NADPH(Sigma N-1630),
3.人肝微粒体(Corning Gentest),
4.ABI QTrap 4000液质两用仪(AB Sciex),
5.Inertsil C8-3柱,4.6×50mm,5μm(美国迪马公司),
6.CYP探针底物(20μM的右美沙芬，SIGMA Q0750)和阳性对照抑制剂(奎尼丁，SIGMA D9684)。
二、实验步骤
配置100mM的PBS缓冲液，用该缓冲液配制2.5mg/ml的微粒体溶液和5mM的NADPH溶液，用PBS梯度稀释5X浓度的化合物工作液(150、50、15、5、1.5、0.15、0.015、0μM)。用PBS梯度稀释5X浓度的奎尼丁工作液(150、50、15、5、1.5、0.15、0.015、0μM)。用PBS稀释至20μM浓度的右美沙芬工作液。
分别取2.5mg/ml的微粒体溶液、20μM的右美沙芬工作液、MgCl 2溶液和化合物工作液(150、50、15、5、1.5、0.15、0.015、0μM，每个浓度设置不同的反应体系)各20μl，混合均匀。阳性对照组用相同浓度的奎尼丁代替化合物。同时将5mM的NADPH溶液一起在37℃预孵育5分钟，5分钟之后取20μl NADPH加入到个孔中，启动反应，孵育30分钟。所有孵育样品设双样本。30分钟后向所有样本中加入250μl含内标的乙腈，混匀，800rpm摇10分钟。3700rpm离心10分钟。取80μl的上清液，转移至LC-MS/MS分析。
数值经Graphpad Prism计算得到药物对CYP2D6代谢位点的IC 50值见表5。
表5本发明化合物对CYP2D6代谢位点的IC 50值
实施例编号 IC 50(μM)
1 10
2 4.4
结论：本发明化合物对人肝微粒体CYP2D6的酶活性没有抑制作用，表现出更好的安全性，提示不会发生基于CYP2D6发生代谢性药物相互作用。
测试例6、本发明化合物对人肝微粒体CYP3A4睾酮代谢位点的酶活性的抑制作用
本发明化合物对人肝微粒体CYP3A4睾酮代谢位点的酶活性采用如下实验方法测定：
一、实验材料及仪器
1.磷酸缓冲液(PBS),
2.NADPH(Sigma N-1630),
3.人肝微粒体(Corning Gentest),
4.ABI QTrap 4000液质两用仪(AB Sciex),
5.Inertsil C8-3柱,4.6×50mm,5μm(美国迪马公司),
6.CYP探针底物(睾酮/100μM，SIGMA K1003)和阳性对照抑制剂(酮康唑，Dr.Ehrenstorfer GmbH,C17322500)。
二、实验步骤
配置100mM的PBS缓冲液，用该缓冲液配制2.5mg/ml的微粒体溶液和5mM的NADPH溶液，用PBS梯度稀释5X浓度的化合物工作液(150、50、15、5、1.5、0.15、0.015、0μM)。用PBS梯度稀释5X浓度的酮康唑工作液(150、50、15、5、1.5、0.15、0.015、0μM)。用PBS稀释至50μM浓度的右美沙芬工作液。
分别取2.5mg/ml的微粒体溶液、50μM的睾酮工作液、MgCl 2溶液和化合物工作液(150、50、15、5、1.5、0.15、0.015、0μM，每个浓度设置不同的反应体系)各20μl，混合均匀。阳性对照组用相同浓度的酮康唑代替化合物。同时将5mM的NADPH溶液一起在37℃预孵育5分钟。5分钟之后取20μl NADPH加入到个孔中，启动反应，孵育30分钟。所有孵育样品设双样本。30分钟后向所有样本中加入250μl含内标的乙腈，混匀，800rpm摇10分钟。3700rpm离心10分钟。取80μl的上清液，转移至LC-MS/MS分析。
数值经Graphpad Prism计算得到药物对CYP3A4睾酮代谢位点的IC 50值见表6。
表6本发明化合物对CYP3A4睾酮代谢位点的IC 50值
实施例编号 IC 50(μM)
1 >30
2 >30
结论：本发明化合物对对人肝微粒体CYP3A4的睾酮代谢位点没有抑制作用，表现出更好的安全性，提示不会发生基于CYP3A4的睾酮代谢位点的代谢性药物相互作用。
测试例7、本发明化合物对hERG钾电流的阻断作用
1、实验目的
应用全自动膜片钳在转染hERG钾通道的稳定细胞株上测试本发明化合物对hERG钾电流的阻断作用。
2、实验方法
2.1实验材料与仪器
2.1.1实验材料：
试剂名称 供货公司 货号
FBS GIBCO 10099
丙酮酸钠溶液 sigma S8636-100ML
MEM非必需氨基酸溶液(100×) sigma M7145-100ML
G418硫酸盐 Enzo ALX-380-013-G005
MEM Hyclone SH30024.01B
hERG cDNA Origene -
2.1.2实验仪器：
Figure PCTCN2018106983-appb-000038
2.2全自动膜片钳实验步骤
HEK293-hERG稳定细胞株按照1:4的密度在MEM/EBSS培养基(10％FBS，400μg/ml G418,1％MEM非必需氨基酸溶液(100×),1％丙酮酸钠溶液)中进行传代培养，培养48-72小时之内进行全自动膜片钳实验。实验当天将细胞用0.25％胰酶消化后，离心收集细胞，用细胞外液(140mM NaCl，4mM KCl，1mM MgCl 2，2mM CaCl 2，5mMD一水葡萄糖，10mM Hepes,pH7.4,298mOsmol)重悬细胞制成细胞悬液。将细胞悬液放置在Patchliner仪器的细胞库上，Patchliner仪器利用负压控制器将细胞加到芯片(NPC-16)上，负压将单个细胞吸引在芯片的小孔上。当形成全细胞模式后，仪器将按照设定的hERG电流电压程序得到hERG电流，然后仪器自动的由低浓度到高浓度，进行化合物灌流。通过HEAK Patchmaster,HEAK EPC10膜片钳放大器(Nanion)和Pathlinersoftware以及Pathcontrol HTsoftware提供的数据分析软件，对化合物各浓度下的电流以及空白对照电流进行分析。
2.3测试结果
本发明化合物对hERG钾电流的阻断作用通过以上的试验进行测定，测得的IC 50值见表7。
表7本发明化合物对hERG钾电流的阻断作用的IC 50
实施例编号 IC 50(μM)
1 9.1
2 11
结论：本发明化合物对hERG的抑制作用弱，由hERG通路引起的副作用可能性小。

Claims (26)

  1. 一种通式(I)所示的化合物：
    Figure PCTCN2018106983-appb-100001
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，
    其中：
    G 1为CR 3或N；
    L 1选自-O-、-S-、-NR 4-、-C(O)-、-S(O) m-、-N(R 4)C(O)-、-C(O)N(R 4)-、-N(R 4)S(O) 2-、-S(O) 2N(R 4)-和共价键；
    X 1为亚烷基，其中所述的亚烷基任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基和杂环基中的一个或多个取代基所取代；
    R 1选自氢原子、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 2选自氢原子、烷基、烷氧基、卤素、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基、-C(O)R 5、-C(O)OR 5、-S(O) mR 5、-NR 6R 7和-C(O)NR 6R 7，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、杂环基烷基、芳基、杂芳基、-C(O)R 5、-C(O)OR 5、-S(O) mR 5、-NR 6R 7、-C(O)NR 6R 7和-X 2-NR 6R 7中的一个或多个取代基所取代；
    R 3选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；
    R 4选自氢原子、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基；
    R 5选自氢原子、烷基、卤代烷基、氨基、羟基、环烷基、杂环基、芳基和杂芳基；
    R 6和R 7相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自 独立地任选被选自烷基、烷氧基、卤素、氨基、氰基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    或者，所述R 6和R 7与相连接的氮原子一起形成杂环基，其中所述的杂环基除含有1个氮原子之外，还任选含有1～2个相同或不同选自N、O和S的杂原子，并且所述的杂环基任选被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    X 2为亚烷基，其中所述的亚烷基任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基和杂环基中的一个或多个取代基所取代；且
    m为0、1或2。
  2. 根据权利要求1所述的通式(I)所示的化合物，其为通式(II)所示的化合物：
    Figure PCTCN2018106983-appb-100002
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，
    其中：
    G 1、L 1、X 1、R 1和R 2如权利要求1中所定义。
  3. 根据权利要求1或2中所述的通式(I)所示的化合物，其中所述的R 2选自芳基、杂芳基、杂环基和-NR 6R 7，其中所述的芳基、杂芳基和杂环基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、杂环基烷基和-X 2-NR 6R 7中的一个或多个取代基所取代；
    X 2、R 6和R 7如权利要求1中所定义。
  4. 根据权利要求1～3中任一项所述的通式(I)所示的化合物，其中所述的R 2选自苯基、吡啶基、吡咯烷基和-NR 6R 7，其中所述的苯基、吡啶基和吡咯烷基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、杂环基烷基和-X 2-NR 6R 7中的一个或多个取代基所取代；
    X 2、R 6和R 7如权利要求1中所定义。
  5. 根据权利要求1～4中任一项所述的通式(I)所示的化合物，其为通式(III) 或通式(IV)所示的化合物：
    Figure PCTCN2018106983-appb-100003
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，
    其中：
    环A为苯基或吡啶基；
    R 8相同或不同，且各自独立地选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基和杂环基烷基；
    R 6和R 7与相连接的氮原子一起形成杂环基，其中所述的杂环基除含有1个氮原子之外，还任选含有1～2个相同或不同选自N、O和S的杂原子，并且所述的杂环基任选被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    s为0、1、2或3；且
    G 1、L 1、X 1、X 2和R 1如权利要求1中所定义。
  6. 根据权利要求1～5中任一项所述的通式(I)所示的化合物，其中所述的X 1为亚烷基。
  7. 根据权利要求1～6中任一项所述的通式(I)所示的化合物，其中所述的G 1为N。
  8. 根据权利要求1～7中任一项所述的通式(I)所示的化合物，其为通式(V)或通式(VI)所示的化合物：
    Figure PCTCN2018106983-appb-100004
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，
    其中：
    环A为苯基或吡啶基；
    n为1到9的整数；
    R 6和R 7与相连接的氮原子一起形成杂环基，其中所述的杂环基除含有1个氮原子之外，还任选含有1～2个相同或不同选自N、O和S的杂原子，并且所述的杂环基任选被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    L 1、X 2和R 1如权利要求1中所定义。
  9. 根据权利要求1～8中任一项所述的通式(I)所示的化合物，其为通式(VII)所示的化合物：
    Figure PCTCN2018106983-appb-100005
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，
    其中：
    R 6和R 7与相连接的氮原子一起形成杂环基，其中所述的杂环基除含有1个氮原子之外，还任选含有1～2个相同或不同选自N、O和S的杂原子，并且所述的杂环基任选被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    L 1、X 2和R 1如权利要求1中所定义。
  10. 根据权利要求1～9中任一项所述的通式(I)所示的化合物，其中所述的L 1为-O-。
  11. 根据权利要求1～10中任一项所述的通式(I)所示的化合物，其中所述的R 1为烷基。
  12. 根据权利要求1～11中任一项所述的通式(I)所示的化合物，其选自：
    Figure PCTCN2018106983-appb-100006
  13. 一种通式(IA)所示的化合物：
    Figure PCTCN2018106983-appb-100007
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，
    其中：
    G 1为CR 3或N；
    W为氨基保护基；
    R a为氨基保护基或氢原子；
    L 1选自-O-、-S-、-NR 4-、-C(O)-、-S(O) m-、-N(R 4)C(O)-、-C(O)N(R 4)-、-N(R 4)S(O) 2-、-S(O) 2N(R 4)-和共价键；
    X 1为亚烷基，其中所述的亚烷基任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基和杂环基中的一个或多个取代基所取代；
    R 1选自氢原子、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 2选自氢原子、烷基、烷氧基、卤素、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基、-C(O)R 5、-C(O)OR 5、-S(O) mR 5、-NR 6R 7和-C(O)NR 6R 7，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、杂环基烷基、芳基、杂芳基、-C(O)R 5、-C(O)OR 5、-S(O) mR 5、-NR 6R 7、-C(O)NR 6R 7和-X 2-NR 6R 7中的一个或多个取代基所取代；
    R 3选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；
    R 4选自氢原子、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基；
    R 5选自氢原子、烷基、卤代烷基、氨基、羟基、环烷基、杂环基、芳基和杂芳基；
    R 6和R 7相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自烷基、烷氧基、卤素、氨基、氰基、硝基、羟基、羟烷基、环 烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    或者，所述R 6和R 7与相连接的氮原子一起形成杂环基，其中所述的杂环基除含有1个氮原子之外，还任选含有1～2个相同或不同选自N、O和S的杂原子，并且所述的杂环基任选被选自烷基、烷氧基、氧代基、卤素、氨基、氰基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    X 2为亚烷基，其中所述的亚烷基任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基和杂环基中的一个或多个取代基所取代；且
    m为0、1或2。
  14. 根据权利要求13所述的通式(IA)所示的化合物，其选自：
    Figure PCTCN2018106983-appb-100008
  15. 一种通式(IIA)所示的化合物：
    Figure PCTCN2018106983-appb-100009
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，
    其中：
    W为氨基保护基；
    R a为氨基保护基或氢原子；
    G 1、L 1、X 1、R 1和R 2如权利要求13中所定义。
  16. 一种通式(IIB)所示的化合物：
    Figure PCTCN2018106983-appb-100010
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，
    其中：
    W为氨基保护基；
    R a为氨基保护基或氢原子；
    G 1、L 1、X 1、R 1和R 2如权利要求13中所定义。
  17. 根据权利要求16所述的通式(IIB)所示的化合物，其选自：
    Figure PCTCN2018106983-appb-100011
  18. 一种制备根据权利要求1所述的通式(I)所示的化合物的方法，该方法包括：
    Figure PCTCN2018106983-appb-100012
    通式(IA)的化合物脱去保护基得到通式(I)的化合物；
    其中：
    W为氨基保护基；
    R a为氨基保护基或氢原子；
    G 1、L 1、X 1、R 1和R 2如权利要求1中所定义。
  19. 一种制备根据权利要求15所述的通式(IIA)所示的化合物的方法，该方法 包括：
    Figure PCTCN2018106983-appb-100013
    通式(IIB)的化合物在碱性条件下，发生消除反应得到通式(IIA)的化合物；
    其中：
    W为氨基保护基；
    R a为氨基保护基或氢原子；
    G 1、L 1、X 1、R 1和R 2如权利要求15中所定义。
  20. 一种制备根据权利要求2所述的通式(II)所示的化合物的方法，该方法包括：
    Figure PCTCN2018106983-appb-100014
    通式(IIA)的化合物在酸性条件下脱去保护基得到通式(II)的化合物；
    其中：
    W为氨基保护基；
    R a为氨基保护基或氢原子；
    G 1、L 1、X 1、R 1和R 2如权利要求2中所定义。
  21. 一种药物组合物，所述药物组合物含有治疗有效量的根据权利要求1～12中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  22. 根据权利要求1～12中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或根据权利要求21所述的药物组合物在制备用于激动TLR7的药物中的用途。
  23. 根据权利要求1～12中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或根据权利要求21所述的药物组合物在制备用于治疗由病毒引起的感染的药物中的用途。
  24. 根据权利要求23所述的用途，其中病毒选自：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、HIV、HBV、HCV、HPV、RSV、SARS和流感病毒。
  25. 根据权利要求1～12中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或根据权利要求21所述的药物组合物在制备用于治疗或预防肿瘤的药物中的用途。
  26. 根据权利要求25所述的用途，其中肿瘤选自：黑色素瘤、非小细胞肺癌、肝细胞癌、基底细胞癌、肾细胞癌和骨髓瘤。
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