WO2020083089A1 - 五元或六元杂环并嘧啶类化合物及其用途 - Google Patents

五元或六元杂环并嘧啶类化合物及其用途 Download PDF

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WO2020083089A1
WO2020083089A1 PCT/CN2019/111625 CN2019111625W WO2020083089A1 WO 2020083089 A1 WO2020083089 A1 WO 2020083089A1 CN 2019111625 W CN2019111625 W CN 2019111625W WO 2020083089 A1 WO2020083089 A1 WO 2020083089A1
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alkyl
optionally substituted
compound
alkenyl
alkynyl
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French (fr)
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胡允金
刘乐
魏国平
游志先
李小龙
吴国胜
冯加权
董加强
王铁林
阳华
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罗欣药业(上海)有限公司
山东罗欣药业集团股份有限公司
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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
    • A61K31/495—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
    • A61K31/52—Purines, e.g. adenine
    • 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
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
    • 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

Definitions

  • the present application relates to five-membered or six-membered heteropyrimidine compounds as TLR 7 agonists, pharmaceutical compositions containing such compounds, and the use of such compounds and pharmaceutical compositions.
  • TLRs Toll-like receptors
  • innate immunity non-specific immunity
  • TLR is a single transmembrane non-catalytic protein, expressed in a variety of immune cells.
  • TLR can recognize them and activate the body's immune cell response.
  • Toll-like receptors recognize highly conserved structural motifs: pathogen-associated molecular patterns (PAMP) expressed by microbial pathogens or damage-associated molecular patterns (DAMP) released by necrotic cells.
  • PAMP pathogen-associated molecular patterns
  • DAMP damage-associated molecular patterns
  • Toll-like receptor signaling cascade By respective pathogen-associated microbial patterns (PAMPs), or damage associated molecular patterns (DAMPs) stimulate Toll-like receptor signaling cascade leads to initiation of transcription factors such as AP-1, NF- k B activation and interferon regulatory factors. This leads to a variety of cellular responses, including the production of interferons, proinflammatory cytokines, and effector cytokines, which produce an immune response. So far, 13 Toll-like receptors have been discovered in mammals. Toll-like receptors 1, 2, 4, 5 and 6 are mainly expressed on the cell surface, and Toll-like receptors 3, 7, 8 and 9 are expressed in endosomes. Different Toll-like receptors recognize ligands derived from different pathogens.
  • PAMPs pathogen-associated microbial patterns
  • DAMPs damage associated molecular patterns
  • Toll-like receptor 7 (TLR 7 ) is mainly induced by plasma cell-like dendritic cell (pDC) expression and ligand recognition to induce the secretion of interferon alpha (IFN- ⁇ ).
  • Toll-like receptor 7 (TLR 7 ) and Toll-like receptor 8 (TLR 8 ) are highly homologous, so TLR 7 ligands are also TLR 8 ligands in most cases.
  • TLR 8 stimulation mainly induces the production of cytokines such as tumor necrosis factor alpha (TNF- ⁇ ) and chemokines.
  • TLR 7 agonists have been reported in clinical research and development results, such as imiquimod, remiquimod, GS-9620.
  • Gilead has advanced the TLR 7 agonist GS-9620 to clinical phase II for the treatment of chronic hepatitis B patients (D. Allen, et al, Allen, D. et al, WO2016 / 044183).
  • TLR 7 agonists with higher selectivity, better activity and safety.
  • the present invention provides a five-membered or six-membered heteropyrimidine compound, which can be used as a TLR 7 agonist.
  • the present invention relates to compounds of formula (I):
  • X is selected from O, S and NR x;
  • R x is selected from H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl and C 2 -C 8 alkynyl; wherein said alkyl, alkenyl and alkynyl groups group each optionally substituted with one or more R a;
  • Y is selected from O, S, N, or Y does not exist;
  • Z is selected from N, O, S, C and CH;
  • Q is selected from O, S and NH
  • R 1 is selected from H, hydroxyl, mercapto, amino, halogen, nitro, cyano, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 6 -C 10 aryl and five- to ten-membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, aryl or heteroaryl is optionally substituted with one or more R B ;
  • R 2 is selected from H, hydroxyl, mercapto, amino, halogen, nitro, cyano, C 1 -C 8 alkyl, C 2 -C 8 alkenyl and C 2 -C 8 alkynyl; wherein the alkyl, Alkenyl and alkynyl are each optionally substituted with one or more R C ;
  • L 1 is a C 1 -C 8 hydrocarbon chain
  • Ring A does not exist, or Ring A is selected from: C 3 -C 10 cyclic hydrocarbon groups, C 3 -C 10 heterocyclic groups, C 6 -C 10 aryl groups, and five- to ten-membered heteroaryl groups; wherein the cyclic hydrocarbon group , Heterocyclyl, aryl, heteroaryl are optionally substituted with one or more R D ;
  • L 2 does not exist, or L 2 is a C 1 -C 8 hydrocarbon chain
  • R 3 is H, C 3 -C 10 cyclic hydrocarbon group, C 6 -C 10 aryl group, five- to ten-membered heteroaryl group or -WR 6 R 7 , where W is N or CH, where
  • R 6 and R 7 are each independently selected from H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, and C 2 -C 8 alkynyl; wherein the alkyl, alkenyl, and alkynyl are each optionally substituted with one or more R E; or
  • R 4 is selected from C 1 -C 8 alkyl, C 2 -C 8 alkenyl and C 2 -C 8 alkynyl; wherein the alkyl, alkenyl or alkynyl groups are each optionally substituted by one or more R F replace;
  • Ring B does not exist, or Ring B is selected from C 3 -C 10 cyclic hydrocarbon groups, C 3 -C 10 heterocyclic groups, C 6 -C 10 aryl groups, and five- to ten-membered heteroaryl groups; wherein the ring hydrocarbon group, Heterocyclyl, aryl and heteroaryl are each optionally substituted with one or more R G ;
  • R 5 is selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl and C 2 -C 8 alkynyl; wherein each of the alkyl, alkenyl and alkynyl groups is optionally substituted by one or more Substituent substitution selected from -OR 8 , -SR 8 and -NR 8 R 8 ';
  • R 8 and R 8 ′ are each independently selected from H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl and C 2 -C 8 alkynyl; wherein the alkyl, alkenyl and alkynyl are each Optionally substituted by one or more R H ; or R 8 and R 8 ′ together with the N atom to which they are attached form a three- to ten-membered heterocyclic ring, which is preferably a four- to six-membered heterocyclic ring;
  • R A , R B , R C , R D , R E , R F , R G or R H are each independently -NR a R b , R a , R b are optionally connected to the N atom Together, they form a three- to ten-membered heterocycle, which is preferably a four- to six-membered heterocycle.
  • the present invention also provides compounds of the following formulas (I-1), (I-2), (I-3), (I-4), (I-5), (I-6) and (I-7),
  • R 1 , R 2 , R 3 , R 4 , R F , R 5 , L 1 , L 2 , X, Y, Z, Q, A and B are as defined in formula (I).
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotope Compounds, metabolites or prodrugs, and at least one pharmaceutically acceptable carrier.
  • the invention also provides a compound of the invention or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopic compound, metabolite, or prodrug or
  • a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopic compound, metabolite, or prodrug or The use of the pharmaceutical composition of the present invention in the preparation of a medicament for the treatment of diseases that are responsive to activation of TLR 7 receptors.
  • the invention provides a compound of the invention or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopic compound, metabolite, or prodrug thereof, or
  • the pharmaceutical composition of the present invention is used to treat diseases responsive to activation of TLR 7 receptors.
  • the present invention provides a method of treating a disease responsive to activation of TLR 7 receptors, the method comprising administering to an individual in need thereof a compound of the present invention or a pharmaceutically acceptable salt, stereo Isomers, solvates, polymorphs, tautomers, isotopic compounds, metabolites or prodrugs, or pharmaceutical compositions of the invention.
  • the disease responsive to activation of the TLR 7 receptor is selected from liver-related diseases, tumors, and HIV infection.
  • the tumor type is selected from leukemia, lymphoma, melanoma, or non-small cell lung cancer.
  • the HIV infection is AIDS.
  • the present invention also provides a pharmaceutical combination comprising (1) the compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotope Compounds, metabolites or prodrugs or pharmaceutical compositions of the invention, and (2) PD-1 antibodies, PD-L1 antibodies or PD-1 inhibitors, PD-L1 inhibitors or PD-1 / PD-L1 inhibitors .
  • the pharmaceutical combination is in the form of a pharmaceutical composition or kit.
  • the expression mn refers to the range of m to n and the sub-range consisting of each point value and each point value.
  • C 1 -C 8 covers the range of 1-8 carbon atoms, and should be understood to also cover any sub-range and each point value therein, such as C 2 -C 5 , C 3 -C 4 , C 1 -C 2 , C 1 -C 3 , C 1 -C 4 , C 1 -C 5 , C 1 -C 6 , C 1 -C 7 and so on, as well as C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 etc.
  • C 3 -C 10 should also be understood in a similar manner, for example, it can cover any sub-ranges and point values contained therein, such as C 3 -C 9 , C 6 -C 9 , C 6 -C 8 , C 6 -C 7 , C 7 -C 10 , C 7 -C 9 , C 7 -C 8 , C 8 -C 9, etc. and C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10, etc.
  • the expression "three yuan to ten yuan” should be understood to cover any sub-range and each point value therein, such as 3-5 yuan, 3-6 yuan, 3-7 yuan, 3-8 yuan, 4- 5 yuan, 4-6 yuan, 4-7 yuan, 4-8 yuan, 5-7 yuan, 5-8 yuan, 6-7 yuan, 7-8 yuan, 9-10 yuan, etc., and 3, 4, 5 , 6, 7, 8, 9, 10 yuan, etc.
  • Other similar expressions in this article should be understood in a similar manner.
  • substituted and “substituted” mean that one or more (eg, one, two, three, or four) hydrogens on the designated atom are replaced by the choice of the indicated group, provided that the The normal valence of the designated atom in the current situation and the substitution forms a stable compound. Combinations of substituents and / or variables are only allowed when such combinations form stable compounds. When describing that a certain substituent does not exist, it should be understood that the substituent may be one or more hydrogen atoms, provided that the structure enables the compound to reach a stable state.
  • the point of attachment of a substituent may be from any suitable position of the substituent.
  • a bond of a substituent is shown to pass through a bond connecting two atoms in the ring, then such substituent may be bonded to any ring-forming atom in the substitutable ring.
  • any variable e.g. R
  • marked variables e.g. R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 8 ', R A , R B , R C , R D , R E , R F , R G, etc.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 8 ', R A , R B , R C , R D , R E , R F , R G, etc. appear more than once in the composition or structure of the compound, the definition of which is independent in each case at each occurrence.
  • the group may optionally be substituted with up to four R substituents, and each in each case The options for the R substituents are independent of each other.
  • halo or "halogen” or “halo” is understood to mean a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom, preferably a fluorine, chlorine, bromine or iodine atom.
  • hydroxyl refers to -OH.
  • cyano refers to -CN.
  • mercapto refers to -SH.
  • amino means -NH 2.
  • alkyl refers to a linear or branched saturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms, which is connected to the rest of the molecule by a single bond.
  • Alkyl may have 1-8 carbon atoms, that is, "C 1 -C 8 alkyl", such as C 1 -C 4 alkyl, C 1 -C 3 alkyl, C 1 -C 2 alkyl, C 3 alkyl, C 4 alkyl, C 3 -C 6 alkyl.
  • Non-limiting examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2- Methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-bis Methylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or their isomers body.
  • alkenyl refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one double bond.
  • the alkenyl group may have 2 to 8 carbon atoms, that is, “C 2 -C 8 alkenyl group”, for example, C 2 -C 4 alkenyl group, C 3 -C 4 alkenyl group.
  • alkenyl groups include, but are not limited to, vinyl, allyl, (E) -2-methylvinyl, (Z) -2-methylvinyl, homoallyl, (E) -butyl -2-alkenyl, (Z) -but-2-enyl, (E) -but-1-enyl, (Z) -but-1-enyl, etc.
  • alkynyl refers to a linear or branched unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one triple bond.
  • the alkynyl group may have 2 to 8 carbon atoms, that is, "C 2 -C 8 alkynyl group", for example, C 2 -C 4 alkynyl group, C 3 -C 4 alkynyl group.
  • Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, and the like.
  • cyclic hydrocarbon group refers to a saturated or unsaturated non-aromatic cyclic hydrocarbon group composed of carbon atoms and hydrogen atoms, preferably containing 1 or 2 rings.
  • the cyclic hydrocarbon group may be a monocyclic ring, fused polycyclic ring, bridge ring or spiro ring structure.
  • the cyclic hydrocarbon group may have 3 to 10 carbon atoms, that is, "C 3 -C 10 ring hydrocarbon group", for example, C 3 -C 8 ring hydrocarbon group, C 5 ring hydrocarbon group, C 6 ring hydrocarbon group, C 7 ring hydrocarbon group.
  • Non-limiting examples of cyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.2.1] heptyl, spiro [3.3] heptyl, and the like.
  • heterocyclic group refers to a monocyclic ring having, for example, 3-10 (suitably 3-8, more suitably 3-6, especially 4-6) ring atoms Or a bicyclic non-aromatic ring system (three to ten, three to eight, three to six), where at least one ring atom (eg 1, 2, or 3) is selected from N, O, and S Heteroatom, and the remaining ring atom is C.
  • the ring system may be saturated (also understood as the corresponding "heterocycloalkyl") or unsaturated (ie having one or more double and / or triple bonds within the ring).
  • the heterocyclic group may be, for example, a 4-membered ring, such as azetidine, oxetane; or a 5-membered ring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, imidazolidine Group, pyrazolidinyl, pyrrolinyl, oxopyrrolidinyl, 2-oxoimidazolidin-1-yl, thiazolyl, thiadiazolyl; or 6-membered ring, such as tetrahydropyranyl, piper Pyridinyl, morpholinyl, dithioalkyl, thiomorpholinyl, piperazinyl, 1,1-dioxo-1,2-thiazin-2-yl or trithioalkyl; or 7- Elementary ring, such as diaza Base ring.
  • the heterocyclic group may be benzo-fused.
  • the heterocyclic group may be bicyclic without limitation, for example, a 5,5-membered ring such as hexahydrocyclopentane [c] pyrrole-2 (1H) -yl) ring; or a 5,6-membered bicyclic ring such as Hexahydropyrrolo [1,2-a] pyrazine-2 (1H) -yl ring.
  • the ring containing the nitrogen atom may be partially unsaturated, that is, it may contain one or more double bonds without being restricted, for example, 2,5-dihydro-1H-pyrrolyl, 4H- [1,3,4] thiadiazinyl, 4,5-dihydrooxazolyl, or 4H- [1,4] thiazinyl ring, or it may be benzo-fused and not limited by, for example Dihydroisoquinolinyl ring.
  • aryl refers to an all-carbon monocyclic or fused polycyclic (eg, bicyclic) aromatic ring group having a conjugated pi electron system.
  • an aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, suitably 6-10, more suitably 6 or 10.
  • Examples of aryl groups include but are not limited to phenyl, naphthyl, anthracenyl, and the like.
  • heteroaryl is understood to mean preferably a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9 or 10 ring atoms ("five to ten member hetero Aryl "), especially 5 or 6 or 9 or 10 ring atoms, and the ring atoms contain at least one (suitably 1-4, more suitably 1-3) heteroatoms which may be the same or different
  • the heteroatom is, for example, oxygen, nitrogen, or sulfur, and in addition, the heteroaryl group may be benzo-fused in each case.
  • the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thio Diazolyl, thi-4H-pyrazolyl, etc., and their benzo derivatives such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, Benzotriazolyl, indazolyl, indolyl, isoindolyl, etc .; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives, such as quino Quinolinyl, quinazolinyl, isoquinolinyl, etc .; or azo
  • C 1 -C 8 hydrocarbon chain refers to a group having the group consisting of carbon atoms and hydrogen atoms, which may be linear or branched and contains 1-8 (especially 1-5, e.g. 1, 2, 3, 4 or 5) carbon atoms.
  • the hydrocarbon chain may be saturated (ie, C 1 -C 8 alkylene) or unsaturated, that is, it may contain one or more (preferably one) carbon-carbon double bonds or triple bonds.
  • the alkylene group may have 1-8 carbon atoms, that is, "C 1 -C 8 alkylene group", for example, C 1 -C 5 alkylene group, C 1 -C 4 alkylene group, C 1 -C 3 alkylene group Group, C 1 -C 2 alkylene group, C 3 alkylene group, and C 1 alkylene group, that is, methylene group.
  • C 1 -C 8 alkylene group for example, C 1 -C 5 alkylene group, C 1 -C 4 alkylene group, C 1 -C 3 alkylene group Group, C 1 -C 2 alkylene group, C 3 alkylene group, and C 1 alkylene group, that is, methylene group.
  • 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- ), etc.
  • “Pharmaceutically acceptable” means that it is compatible with other components in the formulation and has no unacceptable toxicity to the person taking it.
  • the compounds of the present invention can be prepared by various synthetic methods well known to those skilled in the art. This includes the specific embodiments listed below, embodiments in combination with other chemical synthesis methods, and equivalent alternatives recognized in the art. Preferred embodiments include but are not limited to the examples of the present invention.
  • Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts.
  • Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include hydrochloride, acetate, aspartate, benzoate, bicarbonate / carbonate, glucoheptonate, gluconate, nitrate, orotate, palmitic acid Salt and other similar salts.
  • Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, choline salts, magnesium salts, and other similar salts.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)-and (+)-enantiomers, (R)-and (S) -enantiomers, diastereomers Isomers, (D) -isomers, (L) -isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of which belong to Within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl. All these isomers and their mixtures are included in the scope of the present invention.
  • preferred compounds are those that exhibit superior biological activity.
  • the purified or partially purified isomers and stereoisomers, or racemic mixtures or diastereoisomeric mixtures of the compounds of the present invention are also included in the scope of the present invention. Purification and separation of such substances can be achieved by standard techniques known in the art.
  • Optically pure enantiomers can be obtained by resolving racemic mixtures according to conventional methods, for example by using optically active acids or bases to form diastereomeric salts, or by forming covalent diastereoisomers .
  • Mixtures of diastereomers can be separated into individual diastereomers based on their physical and / or chemical differences by methods known in the art (eg, by chromatography or fractional crystallization). Then, the optically active enantiomer base or acid is released from the separated diastereomeric salt.
  • Another method for separating racemic enantiomers can use chiral chromatography (for example, chiral HPLC columns).
  • the separated chiral isomers can be subjected to conventional derivatization treatment before separation or not, depending on What method can achieve more effective separation of chiral isomers. Enzymatic methods can also be used to separate derivatized or underivatized chiral isomers. Similarly, optically active materials can be used to obtain the optically pure compounds of the present invention by chiral synthesis.
  • the compounds of the present invention may exist as tautomers.
  • the present invention includes all possible tautomers of the compounds of the present invention, as well as single tautomers or any mixture of said tautomers in any ratio.
  • the compound of the present invention may exist in the form of a solvate (preferably a hydrate), wherein the compound of the present invention contains a polar solvent as a structural element of the crystal lattice of the compound, particularly, for example, water, methanol or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, particularly, for example, water, methanol or ethanol.
  • the amount of polar solvents, especially water, can be present in stoichiometric or non-stoichiometric ratios.
  • the invention also encompasses all possible crystalline forms or polymorphs of the compounds of the invention, which can be a single polymorph or a mixture of more than one polymorph in any ratio.
  • the present invention also includes all pharmaceutically acceptable isotopically-labeled compounds, which are the same as the compounds of the present invention, except that one or more atoms have the same atomic number but the atomic mass or mass number is different from the atomic mass predominant in nature Or the atomic substitution of mass.
  • metabolites of the compounds of the invention ie substances formed in the body when the compounds of the invention are administered.
  • the metabolite of the compound can be identified by techniques well known in the art, and its activity can be characterized by experimental methods. Such products can be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound.
  • the present invention includes metabolites of the compounds of the present invention, including compounds prepared by contacting the compounds of the present invention with mammals for a time sufficient to produce their metabolites.
  • the present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have less or no pharmacological activity when administered into or onto the body It can be converted into the compound of the present invention having a desired activity by, for example, hydrolytic cleavage. Usually such a prodrug will be a functional group derivative of the compound, which is easily converted into the desired therapeutically active compound in vivo.
  • prodrugs of the compounds of the present invention which are certain derivatives of the compounds of the present invention that may themselves have less or no pharmacological activity when administered into or onto the body It can be converted into the compound of the present invention having a desired activity by, for example, hydrolytic cleavage. Usually such a prodrug will be a functional group derivative of the compound, which is easily converted into the desired therapeutically active compound in vivo.
  • prodrugs of the present invention can be used, for example, by those skilled in the art known as "pro-moiety” (eg “Design of Prodrugs", described in H. Bundgaard (Elsevier, 1985)) They are prepared in place of the appropriate functional groups present in the compounds of the invention.
  • the present invention also encompasses compounds of the present invention containing protecting groups.
  • protecting groups In any process for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any relevant molecules, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved with conventional protecting groups, such as those described in T. W. Greene & P. G. M. Wuts, Protective Groups, Organic Synthesis, John Wiley & Sons, 2006, and these references are incorporated herein by reference. Using methods known in the art, the protecting group can be removed at an appropriate subsequent stage.
  • administer or “administer” and the like refer to methods that can enable the delivery of a compound or composition to a desired site of biological action. These methods include, but are not limited to parenteral (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration and the like.
  • treatment includes alleviating, alleviating or ameliorating the disease or symptom, preventing other symptoms, improving or preventing the underlying metabolic factors of the symptom, inhibiting the disease or symptom, for example, preventing the disease or symptom from developing, reducing the disease or symptom, promoting Alleviation of disease or symptom, or cessation of symptoms of disease or symptom, and extension to include prevention.
  • Treatment also includes achieving therapeutic and / or preventive benefits.
  • Therapeutic benefit refers to the eradication or improvement of the condition being treated.
  • the therapeutic benefit is achieved by eradicating or improving one or more physiological symptoms related to the underlying disease. Although the patient may still have the underlying disease, an improvement in the patient's disease can be observed.
  • Prophylactic benefit means that the patient uses the composition to prevent the risk of a certain disease, or the patient takes it when one or more physiological conditions of the disease occur, although the disease has not been diagnosed.
  • ⁇ ективное amount refers to the amount of active ingredient that will achieve the desired effect to a certain extent after administration, such as a One or more symptoms or prevent the appearance of the disorder or its symptoms.
  • “Individual” as used herein includes human or non-human animals.
  • Exemplary human individuals include human individuals (referred to as patients) or normal individuals with a disease (such as the diseases described herein).
  • “non-human animals” include all vertebrates, such as non-mammals (eg birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and / or domesticated animals (eg sheep, dog , Cats, cows, pigs, etc.).
  • the invention provides compounds of formula (I):
  • X is selected from O, S and NR x;
  • R x is selected from H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl and C 2 -C 8 alkynyl; wherein said alkyl, alkenyl and alkynyl groups group each optionally substituted with one or more R a;
  • Y is selected from O, S, N, or Y does not exist;
  • Z is selected from N, O, S, C and CH;
  • Q is selected from O, S and NH
  • R 1 is selected from H, hydroxyl, mercapto, amino, halogen, nitro, cyano, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 6 -C 10 aryl and five- to ten-membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, aryl or heteroaryl is optionally substituted with one or more R B ;
  • R 2 is selected from H, hydroxyl, mercapto, amino, halogen, nitro, cyano, C 1 -C 8 alkyl, C 2 -C 8 alkenyl and C 2 -C 8 alkynyl; wherein the alkyl, Alkenyl and alkynyl are each optionally substituted with one or more R C ;
  • L 1 is a C 1 -C 8 hydrocarbon chain
  • Ring A does not exist, or Ring A is selected from: C 3 -C 10 cyclic hydrocarbon groups, C 3 -C 10 heterocyclic groups, C 6 -C 10 aryl groups, and five- to ten-membered heteroaryl groups; wherein the cyclic hydrocarbon group , Heterocyclyl, aryl, heteroaryl are optionally substituted with one or more R D ;
  • L 2 does not exist, or L 2 is a C 1 -C 8 hydrocarbon chain
  • R 3 is H, C 3 -C 10 cyclic hydrocarbon group, C 6 -C 10 aryl group, five- to ten-membered heteroaryl group or -WR 6 R 7 , where W is N or CH, where
  • R 6 and R 7 are each independently selected from H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, and C 2 -C 8 alkynyl; wherein the alkyl, alkenyl, and alkynyl are each optionally substituted with one or more R E; or
  • R 4 is selected from C 1 -C 8 alkyl, C 2 -C 8 alkenyl and C 2 -C 8 alkynyl; wherein the alkyl, alkenyl or alkynyl groups are each optionally substituted by one or more R F replace;
  • Ring B does not exist, or Ring B is selected from C 3 -C 10 cyclic hydrocarbon groups, C 3 -C 10 heterocyclic groups, C 6 -C 10 aryl groups, and five- to ten-membered heteroaryl groups; wherein the ring hydrocarbon group, Heterocyclyl, aryl and heteroaryl are each optionally substituted with one or more R G ;
  • R 5 is selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl and C 2 -C 8 alkynyl; wherein each of the alkyl, alkenyl and alkynyl groups is optionally substituted by one or more Substituent substitution selected from -OR 8 , -SR 8 and -NR 8 R 8 ';
  • R 8 and R 8 ′ are each independently selected from H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl and C 2 -C 8 alkynyl; wherein the alkyl, alkenyl and alkynyl are each Optionally substituted by one or more R H ; or R 8 and R 8 ′ together with the N atom to which they are attached form a three- to ten-membered heterocyclic ring, which is preferably a four- to six-membered heterocyclic ring;
  • R A , R B , R C , R D , R E , R F , R G or R H are each independently -NR a R b , R a , R b are optionally connected to the N atom Together, they form a three- to ten-membered heterocycle, which is preferably a four- to six-membered heterocycle.
  • a Q bond connected by a double bond to a pyrimidine-5-carbon atom, a pyrimidine-6-carbon atom, a carbon atom between N, Z, N and Z, and optionally a Y heterocyclic ring Since O and S.
  • X is O. In another embodiment, X is S. In yet another embodiment, X is NR x , and R x is selected from H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, and C 2 -C 4 alkynyl; wherein the alkyl, alkenyl and alkynyl each optionally substituted with one or more R a. In another embodiment, X is N, and R x is selected from H and C 1 -C 4 alkyl; wherein said alkyl is optionally substituted with one or more R A.
  • Y is O or S, and R 1 is absent.
  • Y is N and R 1 is selected from H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 6 -C 10 aryl and penta Yuan to ten-membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, aryl, and heteroaryl are each optionally substituted with one or more R B ; wherein the five- to ten-membered heteroaryl Contains 1-3 heteroatoms independently selected from O, N and S.
  • Y is N and R 1 is selected from H, C 1 -C 4 alkyl, C 3 -C 4 alkenyl, C 3 -C 4 alkynyl, C 6 -C 10 aryl And a five- to ten-membered heteroaryl group; wherein the alkyl, alkenyl, alkynyl, aryl, and heteroaryl groups are each optionally substituted with one or more R B ; wherein the five- to ten-membered heteroaryl group
  • the aryl group contains 1-3 heteroatoms independently selected from O, N, and S.
  • R 1 is H or C 1 -C 4 alkyl; preferably H or C 1 -C 3 alkyl; further preferably C 1 -C 2 alkyl; wherein said alkyl is optional Is replaced by one or more R B. More preferably, R 1 is H or C 1 -C 2 alkyl; wherein the alkyl is optionally substituted with one or more halogens. In a further preferred embodiment, R 1 is H, CH 3 , CF 3 or CH 2 CF 3 ; particularly preferably H or CH 3 .
  • Y and R 1 are absent, ie the NY structure is actually N.
  • Z is O or S, and R 2 is absent.
  • Z is N, and R 2 is selected from H, hydroxyl, mercapto, amino, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, and C 2 -C 8 alkynyl; wherein The alkyl, alkenyl and alkynyl groups are each optionally substituted with one or more R C.
  • Z is N, and R 2 is selected from H, hydroxyl, mercapto, amino, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, and C 2 -C 4 alkynyl; wherein The alkyl, alkenyl and alkynyl groups are each optionally substituted with one or more R C.
  • Z is N
  • R 2 is selected from H, hydroxyl, mercapto, C 1 -C 4 alkyl, C 3 -C 4 alkenyl, and C 3 -C 4 alkynyl; wherein The alkyl, alkenyl and alkynyl groups are each optionally substituted with one or more R C.
  • R 2 is H, hydroxyl, mercapto, or C 1 -C 4 alkyl; preferably H, hydroxyl, mercapto, or C 1 -C 3 alkyl; wherein the alkyl is optionally substituted One or more R C substitutions. More preferably, R 2 is H, hydroxyl or methyl; wherein the methyl is optionally substituted with one or more halogens.
  • R 2 is H, hydroxyl or methyl; particularly preferably H or hydroxyl.
  • Z is C or CH
  • R 2 is selected from H, hydroxyl, mercapto, amino, halogen, nitro, cyano, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, and C 2 -C 8 alkynyl; wherein alkyl, alkenyl, and alkynyl are each optionally substituted with one or more R C.
  • Z is C or CH, and R 2 is selected from H, hydroxyl, mercapto, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, and C 2 -C 4 alkynyl; Wherein alkyl, alkenyl and alkynyl are each optionally substituted with one or more R C.
  • Z is CH, and R 2 is selected from H, hydroxyl, mercapto, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, and C 2 -C 4 alkynyl; wherein alkyl The radical, alkenyl and alkynyl are each optionally substituted with one or more R C.
  • Z is CH, and R 2 is H, hydroxyl, mercapto, halogen, or C 1 -C 4 alkyl; preferably H, hydroxyl, mercapto, halogen, or C 1 -C 3 alkyl; wherein The alkyl group is optionally substituted with one or more R C. More preferably, Z is CH and R 2 is H, hydroxy, halogen or methyl; wherein the methyl is optionally substituted with one or more halogens. In a further preferred embodiment, Z is CH and R 2 is H, F, hydroxyl or methyl, particularly preferably H or hydroxyl.
  • L 1 is-(CH 2 ) n- ; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8; preferably 1, 2, 3, 4 or 5, more preferably 1, 2, or 3; 1 is particularly preferred.
  • At least one of ring A, L 2 and R 3 is present in general formula (I).
  • ring A, L 2 and R 3 contain at least one N atom.
  • ring A is absent and L 1 and L 2 are directly connected together.
  • ring A is selected from phenyl, pyridine, furan, thiophene, and pyrrole; and each is optionally substituted with one or more R D.
  • ring A is selected from cyclohexane, cyclopentane, cyclobutane, and cyclopropane; and each is optionally substituted with one or more R D.
  • the A ring is selected from the following groups: bicyclic [2.2.1] heptane, connected to the rest of the molecule with a 1-carbon atom and a 4-carbon atom; 1-carbon and 3-carbon atoms are connected to the rest of the molecule; 7-oxybicyclo [2.2.1] heptane is connected to the rest of the molecule with 1- and 4-carbon atoms; where the bicyclic [2.2. 1] Heptane, bicyclo [1.1.1] pentane and 7-oxybicyclo [2.2.1] heptane; and each is optionally substituted with one or more R D.
  • ring A is selected from phenyl and pyridine; and each is optionally substituted with one or more R D ; wherein R D is preferably halogen, particularly preferably F.
  • R D is preferably halogen, particularly preferably F.
  • the A ring is phenyl and is optionally substituted with one or more R D ; wherein R D is preferably halogen, particularly preferably F.
  • L 2 is selected from-(CH 2 ) n- ; wherein n is 1, 2, 3, 4 or 5, 6, 7 or 8; preferably 1, 2, 3, 4 or 5, more It is preferably 1, 2 or 3; particularly preferably 1.
  • R 3 is H.
  • R 3 is -WR 6 R 7 , where W is CH, ie R 3 is -CH (R 6 ) R 7 ,
  • R 6 and R 7 are each independently selected from H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl and C 2 -C 8 alkynyl; wherein the alkyl, alkenyl and alkynyl are each optionally substituted with one or more R E; or
  • R 6 and R 7 together with the C atom to which they are attached form a three- to ten-membered heterocyclic ring; wherein the heterocyclic ring contains 1-3 heteroatoms independently selected from O, S, and N, and is optionally substituted by one Or multiple R E substitutions;
  • the 3- to 10-membered heterocyclic ring formed by R 6 and R 7 together with the C atom to which they are attached may optionally be fused to the A ring.
  • R 3 is -WR 6 R 7 , where W is N, that is, R 3 is -NR 6 R 7 ,
  • R 6 and R 7 are each independently selected from H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl and C 2 -C 8 alkynyl; wherein the alkyl, alkenyl and alkynyl are each optionally substituted with one or more R E; or
  • R 6 and R 7 together with the N atom to which they are attached form a three- to ten-membered heterocyclic ring; wherein the heterocyclic ring contains 0-2 additional heteroatoms independently selected from O, S, and N, and optionally is substituted with one or more R E;
  • the 3- to 10-membered heterocyclic ring formed by R 6 and R 7 together with the N atom to which they are attached may optionally be fused to the A ring.
  • R 3 is selected from -N (C 1 -C 4 alkyl) (C 1 -C 4 alkyl), pyrrolidine, piperidine, morpholine and piperazine; wherein said alkyl , pyrrolidine, piperidine, morpholine and piperazine, each optionally substituted with one or more R E.
  • R 3 is selected from -N (CH 3 ) 2 , pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl and 4-C 1 -C 3 alkane -Piperazin-1-yl; wherein the CH 3 , pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl and piperazin-1-yl are each optionally substituted by one or more R E replaced.
  • R 3 is pyrrolidin-1-yl or piperidin-1-yl; wherein the pyrrolidin-1-yl and piperidin-1-yl are each optionally substituted by one or more R E replaced.
  • neither L 2 nor A ring is present, and R 3 is directly connected to L 1 .
  • R 4 is C 1 -C 4 alkyl, wherein the alkyl is optionally substituted with one or more R F.
  • R 4 is C 1 -C 3 alkyl, especially C 3 alkyl; wherein said alkyl is optionally substituted with one or more R F.
  • Ring B is absent and R 4 and R 5 are directly linked together.
  • Ring B is selected from phenyl, pyridine, furan, thiophene, pyrrole, thiazole, oxazole, and pyran; and each is optionally substituted with one or more R G.
  • Ring B is selected from pyrrolidine, piperidine, tetrahydrofuran, dihydropyran, tetrahydropyran, and propylene oxide; and each is optionally substituted with one or more R G.
  • Ring B is selected from cyclohexane, cyclopentane, cyclobutane, and cyclopropane; and each is optionally substituted with one or more R G.
  • ring B is phenyl or pyridine; and each is optionally selected from one or more independently selected from halogen, cyano, nitro, -R a , -OR a , -SR a And -NR a R b group substitution.
  • R 5 is H. In another embodiment, R 5 is C 3 -C 6 alkyl, and is optionally substituted with one or more —OR 8 , —SR 8 or —NR 8 R 8 ′; wherein
  • R 8 and R 8 ′ are each independently selected from H and C 1 -C 4 alkyl; preferably C 1 -C 2 alkyl; wherein the alkyl is optionally substituted with one or more R H ;
  • R 8 and R 8 ′ are connected to form -NR 8 R 8 ′ to form a four-membered to eight-membered heterocyclic ring; wherein the heterocyclic ring contains 0-1 additional heteroatoms independently selected from O, S and N And optionally substituted with one or more R H.
  • —NR 8 R 8 ′ forms a four- to six-membered heterocyclic ring; wherein the heterocyclic ring contains 0-1 additional heteroatoms independently selected from O, S, and N, and any It is optionally replaced by one or more R H.
  • ring B is absent and R 5 is directly connected to R 4 .
  • embodiments of the compound of formula (I) may include compounds of formula (I-1) to formula (I-7).
  • the present invention provides a compound of formula (I-1) or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopic compound , Metabolites or prodrugs:
  • R 1 , R 2 , R 3 , R 4 , R 5 , L 1 , L 2 , X, Q, A and B are as defined in formula (I).
  • X and Q are each independently selected from O and S.
  • R 1 is H or C 1 -C 4 alkyl; preferably H or C 1 -C 3 alkyl; further preferably C 1 -C 2 alkyl; wherein the alkyl is optionally Replaced by one or more R B. More preferably, R 1 is H or C 1 -C 2 alkyl; wherein the alkyl is optionally substituted with one or more halogens. In a further preferred embodiment, R 1 is H, CH 3 , CF 3 or CH 2 CF 3 ; particularly preferably H or CH 3 .
  • R 2 is selected from H, hydroxyl, mercapto, amino, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, and C 2 -C 8 alkynyl; wherein the alkyl, The alkenyl and alkynyl groups are each optionally substituted with one or more R C.
  • R 2 is selected from H, hydroxyl, mercapto, amino, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, and C 2 -C 4 alkynyl; wherein said alkyl , Alkenyl and alkynyl are each optionally substituted with one or more R C.
  • R 2 is selected from H, hydroxyl, mercapto, C 1 -C 4 alkyl, C 3 -C 4 alkenyl, and C 3 -C 4 alkynyl; wherein the alkyl, alkenyl The group and the alkynyl group are each optionally substituted with one or more R C.
  • R 2 is H, hydroxyl, mercapto, or C 1 -C 4 alkyl; preferably H, hydroxyl, mercapto, or C 1 -C 3 alkyl; wherein the alkyl is optionally substituted One or more R C substitutions. More preferably, R 2 is H, hydroxyl or methyl; wherein the methyl is optionally substituted with one or more halogens. In a further preferred embodiment, R 2 is H, hydroxyl or methyl; particularly preferably H or hydroxyl.
  • L 1 is-(CH 2 ) n- ; wherein n is 1, 2 or 3; particularly preferably 1.
  • ring A, L 2 and R 3 is present in the general formula (I).
  • ring A, L 2 and R 3 contain at least one N atom.
  • ring A is selected from phenyl, pyridine, furan, thiophene, and pyrrole; and each is optionally substituted with one or more R D.
  • ring A is selected from phenyl and pyridine; and each is optionally substituted with one or more R D ; wherein R D is preferably halogen, particularly preferably F.
  • the A ring is phenyl and is optionally substituted with one or more R D ; wherein R D is preferably halogen, particularly preferably F.
  • L 2 is selected from-(CH 2 ) n- ; wherein n is 1, 2 or 3; particularly preferably 1.
  • R 3 is a five- to ten-membered heteroaryl or -WR 6 R 7 , wherein W is N or CH, wherein
  • R 6 and R 7 are each independently selected from H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, and C 2 -C 8 alkynyl; wherein the alkyl, alkenyl, and alkynyl are each optionally substituted with one or more R E; or
  • R 6 and R 7 together with the N or C atom to which they are attached form a three- to ten-membered heterocyclic ring; the heterocyclic ring contains 1-3 heteroatoms independently selected from O, S, and N, and is optionally substituted by One or more RE substituted.
  • R 3 is -NR 6 R 7 ,
  • R 6 and R 7 are each independently selected from H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl and C 2 -C 8 alkynyl; wherein the alkyl, alkenyl and alkynyl are each optionally substituted with one or more R E; or
  • R 6 and R 7 together with the N atom to which they are attached form a three- to ten-membered heterocyclic ring; wherein the heterocyclic ring contains 0-2 additional heteroatoms independently selected from O, S, and N, and optionally It is substituted with one or more R E.
  • R 3 is selected from -N (C 1 -C 4 alkyl) (C 1 -C 4 alkyl), pyrrolidine, piperidine, morpholine and piperazine, wherein the alkyl , pyrrolidine, piperidine, morpholine and piperazine, each optionally substituted with one or more R E.
  • R 3 is selected from -N (CH 3 ) 2 , pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl and 4-C 1 -C 3 alkane -Piperazin-1-yl; wherein the CH 3 , pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl and piperazin-1-yl are each optionally substituted by one or more R E replaced.
  • R 3 is pyrrolidin-1-yl or piperidin-1-yl; wherein the pyrrolidin-1-yl and piperidin-1-yl are each optionally R E replaced.
  • R 4 is C 1 -C 4 alkyl, especially C 3 alkyl; wherein said alkyl is optionally substituted with one or more R F.
  • ring B is absent and R 4 and R 5 are directly connected together.
  • R 5 is H.
  • the present invention provides a compound of formula (I-2) or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotope Compounds, metabolites or prodrugs:
  • R 1 , R 2 , R 3 , R 4 , R 5 , L 1 , L 2 , X, A and B are as defined in formula (I).
  • X is selected from O and S.
  • R 1 is H or C 1 -C 4 alkyl; preferably H or C 1 -C 3 alkyl; further preferably C 1 -C 2 alkyl; wherein the alkyl is optionally Replaced by one or more R B. More preferably, R 1 is H or C 1 -C 2 alkyl; wherein the alkyl is optionally substituted with one or more halogens. In a further preferred embodiment, R 1 is H, CH 3 , CF 3 or CH 2 CF 3 ; particularly preferably H or CH 3 .
  • R 2 is selected from H, hydroxyl, mercapto, amino, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, and C 2 -C 8 alkynyl; wherein the alkyl, The alkenyl and alkynyl groups are each optionally substituted with one or more R C.
  • R 2 is selected from H, hydroxyl, mercapto, amino, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, and C 2 -C 4 alkynyl; wherein said alkyl , Alkenyl and alkynyl are each optionally substituted with one or more R C.
  • R 2 is selected from H, hydroxyl, mercapto, C 1 -C 4 alkyl, C 3 -C 4 alkenyl, and C 3 -C 4 alkynyl; wherein the alkyl, alkenyl The group and the alkynyl group are each optionally substituted with one or more R C.
  • R 2 is H, hydroxyl, mercapto, or C 1 -C 4 alkyl; preferably H, hydroxyl, mercapto, or C 1 -C 3 alkyl; wherein the alkyl is optionally substituted One or more R C substitutions. More preferably, R 2 is H, hydroxyl or methyl; wherein the methyl is optionally substituted with one or more halogens. In a further preferred embodiment, R 2 is H, hydroxyl or methyl; particularly preferably H or hydroxyl.
  • L 1 is-(CH 2 ) n- ; wherein n is 1, 2 or 3; particularly preferably 1.
  • ring A, L 2 and R 3 is present in the general formula (I).
  • ring A, L 2 and R 3 contain at least one N atom.
  • ring A is selected from phenyl, pyridine, furan, thiophene, and pyrrole; and each is optionally substituted with one or more R D.
  • ring A is selected from phenyl and pyridine; and each is optionally substituted with one or more R D ; wherein R D is preferably halogen, particularly preferably F.
  • the A ring is phenyl and is optionally substituted with one or more R D ; wherein R D is preferably halogen, particularly preferably F.
  • L 2 is selected from-(CH 2 ) n- ; wherein n is 1, 2 or 3; particularly preferably 1.
  • R 3 is a five- to ten-membered heteroaryl or -WR 6 R 7 , wherein W is N or CH, wherein
  • R 6 and R 7 are each independently selected from H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, and C 2 -C 8 alkynyl; wherein the alkyl, alkenyl, and alkynyl are each optionally substituted with one or more R E; or
  • R 6 and R 7 together with the N or C atom to which they are attached form a three- to ten-membered heterocyclic ring; the heterocyclic ring contains 1-3 heteroatoms independently selected from O, S, and N, and is optionally substituted by One or more RE substituted.
  • R 3 is -NR 6 R 7 ,
  • R 6 and R 7 are each independently selected from H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl and C 2 -C 8 alkynyl; wherein the alkyl, alkenyl and alkynyl are each optionally substituted with one or more R E; or
  • R 6 and R 7 together with the N atom to which they are attached form a three- to ten-membered heterocyclic ring; wherein the heterocyclic ring contains 0-2 additional heteroatoms independently selected from O, S, and N, and optionally It is substituted with one or more R E.
  • R 3 is selected from -N (C 1 -C 4 alkyl) (C 1 -C 4 alkyl), pyrrolidine, piperidine, morpholine and piperazine, wherein the alkyl , pyrrolidine, piperidine, morpholine and piperazine, each optionally substituted with one or more R E.
  • R 3 is selected from -N (CH 3 ) 2 , pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl and 4-C 1 -C 3 alkane -Piperazin-1-yl; wherein the CH 3 , pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl and piperazin-1-yl are each optionally substituted by one or more R E replaced.
  • R 3 is pyrrolidin-1-yl or piperidin-1-yl; wherein the pyrrolidin-1-yl and piperidin-1-yl are each optionally substituted by one or more R E replaced.
  • R 4 is C 1 -C 4 alkyl, especially C 3 alkyl; wherein said alkyl is optionally substituted with one or more R F.
  • ring B is absent and R 4 and R 5 are directly connected together.
  • R 5 is H.
  • the present invention provides a compound of formula (I-3) or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotope Compounds, metabolites or prodrugs:
  • R 1 , R 2 , R 3 , R F , R 5 , L 1 , L 2 , X, A and B are as defined in formula (I).
  • X is selected from O and S.
  • R 1 is H or C 1 -C 4 alkyl; preferably H or C 1 -C 3 alkyl; further preferably C 1 -C 2 alkyl; wherein the alkyl is optionally Replaced by one or more R B. More preferably, R 1 is H or C 1 -C 2 alkyl; wherein the alkyl is optionally substituted with one or more halogens. In a further preferred embodiment, R 1 is H, CH 3 , CF 3 or CH 2 CF 3 ; particularly preferably H or CH 3 .
  • R 2 is selected from H, hydroxyl, mercapto, amino, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, and C 2 -C 8 alkynyl; wherein the alkyl, The alkenyl and alkynyl groups are each optionally substituted with one or more R C.
  • R 2 is selected from H, hydroxyl, mercapto, amino, C 1 -C 4 alkyl, C 2 -C 4 alkenyl and C 2 -C 4 alkynyl; wherein said alkyl , Alkenyl and alkynyl are each optionally substituted with one or more R C.
  • R 2 is selected from H, hydroxyl, mercapto, C 1 -C 4 alkyl, C 3 -C 4 alkenyl, and C 3 -C 4 alkynyl; wherein the alkyl, alkenyl The group and the alkynyl group are each optionally substituted with one or more R C.
  • R 2 is H, hydroxyl, mercapto, or C 1 -C 4 alkyl; preferably H, hydroxyl, mercapto, or C 1 -C 3 alkyl; wherein the alkyl is optionally substituted One or more R C substitutions. More preferably, R 2 is H, hydroxyl or methyl; wherein the methyl is optionally substituted with one or more halogens. In a further preferred embodiment, R 2 is H, hydroxyl or methyl; particularly preferably H or hydroxyl.
  • L 1 is-(CH 2 ) n- ; wherein n is 1, 2 or 3; particularly preferably 1.
  • ring A, L 2 and R 3 is present in the general formula (I).
  • ring A, L 2 and R 3 contain at least one N atom.
  • ring A is selected from phenyl, pyridine, furan, thiophene, and pyrrole; and each is optionally substituted with one or more R D.
  • ring A is selected from phenyl and pyridine; and each is optionally substituted with one or more R D ; wherein R D is preferably halogen, particularly preferably F.
  • the A ring is phenyl and is optionally substituted with one or more R D ; wherein R D is preferably halogen, particularly preferably F.
  • L 2 is selected from-(CH 2 ) n- ; wherein n is 1, 2 or 3; particularly preferably 1.
  • R 3 is a five- to ten-membered heteroaryl or -WR 6 R 7 , wherein W is N or CH, wherein
  • R 6 and R 7 are each independently selected from H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, and C 2 -C 8 alkynyl; wherein the alkyl, alkenyl, and alkynyl are each optionally substituted with one or more R E; or
  • R 6 and R 7 together with the N or C atom to which they are attached form a three- to ten-membered heterocyclic ring; the heterocyclic ring contains 1-3 heteroatoms independently selected from O, S, and N, and is optionally substituted by One or more RE substituted.
  • R 3 is -NR 6 R 7 ,
  • R 6 and R 7 are each independently selected from H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl and C 2 -C 8 alkynyl; wherein the alkyl, alkenyl and alkynyl are each optionally substituted with one or more R E; or
  • R 6 and R 7 together with the N atom to which they are attached form a three- to ten-membered heterocyclic ring; wherein the heterocyclic ring contains 0-2 additional heteroatoms independently selected from O, S, and N, and optionally It is substituted with one or more R E.
  • R 3 is selected from -N (C 1 -C 4 alkyl) (C 1 -C 4 alkyl), pyrrolidine, piperidine, morpholine, piperazine, wherein the alkyl , pyrrolidine, piperidine, morpholine and piperazine, each optionally substituted with one or more R E.
  • R 3 is selected from -N (CH 3 ) 2 , pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl and 4-C 1 -C 3 alkane -Piperazin-1-yl; wherein the CH 3 , pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl and piperazin-1-yl are each optionally substituted by one or more R E replaced.
  • R 3 is pyrrolidin-1-yl or piperidin-1-yl; wherein the pyrrolidin-1-yl and piperidin-1-yl are each optionally substituted by one or more R E replaced.
  • ring B is absent and R 4 and R 5 are directly connected together.
  • R 5 is H.
  • the present invention provides a compound of formula (I-4) or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotope Compounds, metabolites or prodrugs:
  • R 2 , R 3 , R 4 , R 5 , L 1 , L 2 , X, Q, A and B are as defined in formula (I).
  • X and Q are each independently selected from O and S.
  • R 2 is selected from H, hydroxyl, mercapto, amino, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, and C 2 -C 8 alkynyl; wherein the alkyl, The alkenyl and alkynyl groups are each optionally substituted with one or more R C.
  • R 2 is selected from the group consisting of hydroxyl, mercapto, amino, C 1 -C 4 alkyl, C 2 -C 4 alkenyl and C 2 -C 4 alkynyl; wherein said alkyl, alkenyl The group and the alkynyl group are each optionally substituted with one or more R C.
  • R 2 is selected from the group consisting of hydroxy, mercapto, C 1 -C 4 alkyl, C 3 -C 4 alkenyl and C 3 -C 4 alkynyl; wherein the alkyl, alkenyl and The alkynyl groups are each optionally substituted with one or more R C.
  • R 2 is hydroxyl, mercapto or C 1 -C 4 alkyl; preferably hydroxyl, mercapto or C 1 -C 3 alkyl; wherein said alkyl is optionally substituted by one or more R C is substituted.
  • R 2 is hydroxyl or methyl; wherein the methyl is optionally substituted with one or more halogens.
  • R 2 is hydroxy or methyl; particularly preferably hydroxy.
  • L 1 is-(CH 2 ) n- ; wherein n is 1, 2 or 3; particularly preferably 1.
  • ring A, L 2 and R 3 is present in the general formula (I).
  • ring A, L 2 and R 3 contain at least one N atom.
  • ring A is selected from phenyl, pyridine, furan, thiophene, and pyrrole; and each is optionally substituted with one or more R D.
  • ring A is selected from phenyl and pyridine; and each is optionally substituted with one or more R D ; wherein R D is preferably halogen, particularly preferably F.
  • the A ring is phenyl and is optionally substituted with one or more R D ; wherein R D is preferably halogen, particularly preferably F.
  • L 2 is selected from-(CH 2 ) n- ; wherein n is 1, 2 or 3; particularly preferably 1.
  • R 3 is a five- to ten-membered heteroaryl or -WR 6 R 7 , wherein W is N or CH, wherein
  • R 6 and R 7 are each independently selected from H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, and C 2 -C 8 alkynyl; wherein the alkyl, alkenyl, and alkynyl are each optionally substituted with one or more R E; or
  • R 6 and R 7 together with the N or C atom to which they are attached form a three- to ten-membered heterocyclic ring; the heterocyclic ring contains 1-3 heteroatoms independently selected from O, S, and N, and is optionally substituted by One or more RE substituted.
  • R 3 is -NR 6 R 7 ,
  • R 6 and R 7 are each independently selected from H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl and C 2 -C 8 alkynyl; wherein the alkyl, alkenyl and alkynyl are each optionally substituted with one or more R E; or
  • R 6 and R 7 together with the N atom to which they are attached form a three- to ten-membered heterocyclic ring; wherein the heterocyclic ring contains 0-2 additional heteroatoms independently selected from O, S, and N, and optionally It is substituted with one or more R E.
  • R 3 is selected from -N (C 1 -C 4 alkyl) (C 1 -C 4 alkyl), pyrrolidine, piperidine, morpholine, piperazine, wherein the alkyl , pyrrolidine, piperidine, morpholine and piperazine, each optionally substituted with one or more R E.
  • R 3 is selected from -N (CH 3 ) 2 , pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl and 4-C 1 -C 3 alkane -Piperazin-1-yl; wherein the CH 3 , pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl and piperazin-1-yl are each optionally substituted by one or more R E replaced.
  • R 3 is pyrrolidin-1-yl or piperidin-1-yl; wherein the pyrrolidin-1-yl and piperidin-1-yl are each optionally substituted by one or more R E replaced.
  • R 4 is C 1 -C 4 alkyl, especially C 3 alkyl; wherein said alkyl is optionally substituted with one or more R F.
  • ring B is absent and R 4 and R 5 are directly connected together.
  • R 5 is H.
  • the present invention provides a compound of formula (I-5) or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotope Compounds, metabolites or prodrugs:
  • R 3 , R 4 , R 5 , L 1 , L 2 , X, Q, A and B are as defined in formula (I).
  • X and Q are each independently selected from O and S.
  • L 1 is-(CH 2 ) n- ; wherein n is 1, 2 or 3; particularly preferably 1.
  • ring A, L 2 and R 3 is present in the general formula (I).
  • ring A, L 2 and R 3 contain at least one N atom.
  • ring A is selected from phenyl, pyridine, furan, thiophene, and pyrrole; and each is optionally substituted with one or more R D.
  • ring A is selected from phenyl and pyridine; and each is optionally substituted with one or more R D ; wherein R D is preferably halogen, particularly preferably F.
  • the A ring is phenyl and is optionally substituted with one or more R D ; wherein R D is preferably halogen, particularly preferably F.
  • L 2 is selected from-(CH 2 ) n- ; wherein n is 1, 2 or 3; particularly preferably 1.
  • R 3 is -NR 6 R 7 , in a preferred embodiment, R 3 is a five- to ten-membered heteroaryl or -WR 6 R 7 , where W is N or CH, among them
  • R 6 and R 7 are each independently selected from H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, and C 2 -C 8 alkynyl; wherein the alkyl, alkenyl, and alkynyl are each optionally substituted with one or more R E; or
  • R 6 and R 7 together with the N or C atom to which they are attached form a three- to ten-membered heterocyclic ring; the heterocyclic ring contains 1-3 heteroatoms independently selected from O, S, and N, and is optionally substituted by One or more RE substituted.
  • R 3 is -NR 6 R 7 ,
  • R 6 and R 7 are each independently selected from H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl and C 2 -C 8 alkynyl; wherein the alkyl, alkenyl and alkynyl are each optionally substituted with one or more R E; or
  • R 6 and R 7 together with the N atom to which they are attached form a three- to ten-membered heterocyclic ring; wherein the heterocyclic ring contains 0-2 additional heteroatoms independently selected from O, S, and N, and optionally It is substituted with one or more R E.
  • R 3 is selected from -N (C 1 -C 4 alkyl) (C 1 -C 4 alkyl), pyrrolidine, piperidine, morpholine, piperazine, wherein the alkyl , pyrrolidine, piperidine, morpholine and piperazine, each optionally substituted with one or more R E.
  • R 3 is selected from -N (CH 3 ) 2 , pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl and 4-C 1 -C 3 alkane -Piperazin-1-yl; wherein the CH 3 , pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl and piperazin-1-yl are each optionally substituted by one or more R E replaced.
  • R 3 is pyrrolidin-1-yl or piperidin-1-yl; wherein the pyrrolidin-1-yl and piperidin-1-yl are each optionally substituted by one or more R E replaced.
  • R 4 is C 1 -C 4 alkyl, especially C 3 alkyl; wherein said alkyl is optionally substituted with one or more R F.
  • ring B is absent and R 4 and R 5 are directly connected together.
  • R 5 is H.
  • the present invention provides a compound of formula (I-6) or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotope Compounds, metabolites or prodrugs:
  • R 3 , R 4 , R 5 , L 1 , L 2 , X, A and B are as defined in formula (I).
  • X is selected from O and S.
  • L 1 is-(CH 2 ) n- ; wherein n is 1, 2 or 3; particularly preferably 1.
  • ring A, L 2 and R 3 is present in the general formula (I).
  • ring A, L 2 and R 3 contain at least one N atom.
  • ring A is selected from phenyl, pyridine, furan, thiophene, and pyrrole; and each is optionally substituted with one or more R D.
  • ring A is selected from phenyl and pyridine; and each is optionally substituted with one or more R D ; wherein R D is preferably halogen, particularly preferably F.
  • the A ring is phenyl and is optionally substituted with one or more R D ; wherein R D is preferably halogen, particularly preferably F.
  • L 2 is selected from-(CH 2 ) n- ; wherein n is 1, 2 or 3; particularly preferably 1.
  • R 3 is a five- to ten-membered heteroaryl or -WR 6 R 7 , wherein W is N or CH, wherein
  • R 6 and R 7 are each independently selected from H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, and C 2 -C 8 alkynyl; wherein the alkyl, alkenyl, and alkynyl are each optionally substituted with one or more R E; or
  • R 6 and R 7 together with the N or C atom to which they are attached form a three- to ten-membered heterocyclic ring; the heterocyclic ring contains 1-3 heteroatoms independently selected from O, S, and N, and is optionally substituted by One or more RE substituted.
  • R 3 is -NR 6 R 7 ,
  • R 6 and R 7 are each independently selected from H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl and C 2 -C 8 alkynyl; wherein the alkyl, alkenyl and alkynyl are each optionally substituted with one or more R E; or
  • R 6 and R 7 together with the N atom to which they are attached form a three- to ten-membered heterocyclic ring; wherein the heterocyclic ring contains 0-2 additional heteroatoms independently selected from O, S, and N, and optionally It is substituted with one or more R E.
  • R 3 is selected from -N (C 1 -C 4 alkyl) (C 1 -C 4 alkyl), pyrrolidine, piperidine, morpholine, piperazine, wherein the alkyl , pyrrolidine, piperidine, morpholine and piperazine, each optionally substituted with one or more R E.
  • R 3 is selected from -N (CH 3 ) 2 , pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl and 4-C 1 -C 3 alkane -Piperazin-1-yl; wherein the CH 3 , pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl and piperazin-1-yl are each optionally substituted by one or more R E replaced.
  • R 3 is pyrrolidin-1-yl or piperidin-1-yl; wherein the pyrrolidin-1-yl and piperidin-1-yl are each optionally substituted by one or more R E replaced.
  • R 4 is C 1 -C 4 alkyl, especially C 3 alkyl; wherein said alkyl is optionally substituted with one or more R F.
  • ring B is absent and R 4 and R 5 are directly connected together.
  • R 5 is H.
  • the present invention provides a compound of formula (I-7) or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotope Compounds, metabolites or prodrugs:
  • R 3 , R F , R 5 , L 1 , L 2 , X, A and B are as defined in formula (I).
  • X is selected from O and S.
  • L 1 is-(CH 2 ) n- ; wherein n is 1, 2 or 3; particularly preferably 1.
  • ring A, L 2 and R 3 is present in the general formula (I).
  • ring A, L 2 and R 3 contain at least one N atom.
  • ring A is selected from phenyl, pyridine, furan, thiophene, and pyrrole; and each is optionally substituted with one or more R D.
  • ring A is selected from phenyl and pyridine; and each is optionally substituted with one or more R D ; wherein R D is preferably halogen, particularly preferably F.
  • the A ring is phenyl and is optionally substituted with one or more R D ; wherein R D is preferably halogen, particularly preferably F.
  • L 2 is selected from-(CH 2 ) n- ; wherein n is 1, 2 or 3; particularly preferably 1.
  • R 3 is a five- to ten-membered heteroaryl or -WR 6 R 7 , wherein W is N or CH, wherein
  • R 6 and R 7 are each independently selected from H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, and C 2 -C 8 alkynyl; wherein the alkyl, alkenyl, and alkynyl are each optionally substituted with one or more R E; or
  • R 6 and R 7 together with the N or C atom to which they are attached form a three- to ten-membered heterocyclic ring; the heterocyclic ring contains 1-3 heteroatoms independently selected from O, S, and N, and is optionally substituted by One or more RE substituted.
  • R 3 is -NR 6 R 7 ,
  • R 6 and R 7 are each independently selected from H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl and C 2 -C 8 alkynyl; wherein the alkyl, alkenyl and alkynyl are each optionally substituted with one or more R E; or
  • R 6 and R 7 together with the N atom to which they are attached form a three- to ten-membered heterocyclic ring; wherein the heterocyclic ring contains 0-2 additional heteroatoms independently selected from O, S, and N, and optionally It is substituted with one or more R E.
  • R 3 is selected from -N (C 1 -C 4 alkyl) (C 1 -C 4 alkyl), pyrrolidine, piperidine, morpholine, piperazine, wherein the alkyl , pyrrolidine, piperidine, morpholine and piperazine, each optionally substituted with one or more R E.
  • R 3 is selected from -N (CH 3 ) 2 , pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl and 4-C 1 -C 3 alkane -Piperazin-1-yl; wherein the CH 3 , pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl and piperazin-1-yl are each optionally substituted by one or more R E replaced.
  • R 3 is pyrrolidin-1-yl or piperidin-1-yl; wherein the pyrrolidin-1-yl and piperidin-1-yl are each optionally substituted by one or more R E replaced.
  • ring B is absent and R 4 and R 5 are directly connected together.
  • R 5 is H.
  • the present invention provides the following compounds or pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, isotopic compounds, metabolites, or prodrugs:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopic compound, metabolite or Prodrug, and at least one pharmaceutically acceptable carrier.
  • the carrier may include excipients, diluents or mixtures thereof.
  • the compounds of the present invention can be administered to patients orally or parenterally in the form of conventional preparations such as capsules, microcapsules, tablets, granules, powders, lozenges, pills, suppositories, injections, and mixtures.
  • Suitable formulations can be prepared by conventional methods using conventional organic or inorganic additives such as excipients (eg, sucrose, starch, mannitol, sorbitol, lactose, glucose, fiber Element, talc, calcium phosphate or calcium carbonate), binder (for example, cellulose, methyl cellulose, hydroxymethyl cellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose Or starch), disintegrants (eg, starch, carboxymethyl cellulose, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, sodium bicarbonate, calcium phosphate, or calcium citrate), lubricants (eg, hard Magnesium fatty acid, light anhydrous silicic acid, talc or sodium lauryl sulfate), flavoring agents (for example, citric acid, menthol, glycine or orange powder), preservatives (for example,
  • the effective amount of the compound in the pharmaceutical composition may be an amount that achieves the desired effect; for example, in a unit dose for oral and parenteral administration, the subject's body weight is about 0.005 mg / kg to about 10 mg / kg of the subject's body weight.
  • the present invention provides a capsule containing the compound of the present invention without an additional carrier.
  • the pharmaceutical composition of the present invention may be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, lozenges, suppositories, suspensions, and the like.
  • the composition may be formulated to contain a daily dose or a suitable portion of a daily dose in a dosage unit, which may be a single tablet or capsule or a suitable volume of liquid.
  • the solution is prepared from a water-soluble salt, such as the hydrochloride salt.
  • Capsules can be prepared by mixing the compound with a suitable carrier or diluent, and filling an appropriate amount of the mixture into capsules.
  • Commonly used carriers and diluents include, but are not limited to inert powdered materials, such as a variety of different starches, powdered cellulose, especially crystalline and microcrystalline cellulose, sugar such as fructose, mannitol and sucrose, grain flour and similar Edible powder.
  • Tablets can be prepared by direct compression, wet granulation or dry granulation.
  • the formulations usually include diluents, binders, lubricants and disintegrants as well as the compound.
  • Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or calcium sulfate, inorganic salts (such as sodium chloride), and powdered sugar. Powdered cellulose derivatives are also useful.
  • Typical tablet binders are substances such as starch, gelatin and sugar (such as lactose, fructose, glucose, etc.). Natural and synthetic gums are also suitable, including gum arabic, alginate, methyl cellulose, polyvinylpyrrolidone, and the like. Polyethylene glycol, ethyl cellulose and wax can also serve as binders.
  • Lubricants may be needed in tablet formulations to prevent tablets and punches from sticking to the mold.
  • Lubricant can choose some solids with lubricating effect, such as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oil.
  • Tablet disintegrants swell when wetted to break up the tablet and release the compound. They include starch, clay, cellulose, alginate and gum. More specifically, for example, corn and potato starch, methyl cellulose, agar, bentonite, wood cellulose, powdered natural sponge, anion exchange resin, alginic acid, guar gum, citrus pomace and carboxymethyl cellulose And sodium lauryl sulfate.
  • Tablets can be coated with sugar as a flavoring agent and sealant, or with a film-forming protective agent to optimize the dissolution properties of the tablet.
  • the composition can also be formulated as a chewable tablet, for example, by adding some substance to the formulation, such as mannitol.
  • Cocoa butter is a traditional suppository base, which can be changed by adding wax to raise its melting point slightly.
  • water-miscible suppository bases including polyethylene glycols of various molecular weights are widely used.
  • the effect of the compound can be delayed or extended by suitable formulations.
  • slowly dissolving pellets of the compound can be prepared and added to tablets or capsules or as a slow-release implantable device.
  • the technique also involves preparing several pellets with different dissolution rates and filling the capsules with a mixture of pellets. Tablets or capsules can be coated with a film that resists dissolution for a predictable period.
  • parenteral preparations can be prepared for growth by dissolving or suspending the compound in an oily or emulsified vehicle that allows it to be slowly dispersed in serum.
  • a further object of the invention is to provide an article, for example in the form of a kit.
  • the product of the invention contains the pharmaceutical composition of the invention, and optionally includes a packaging box and instructions.
  • the invention also provides a compound of the invention or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopic compound, metabolite, or prodrug or Use of the pharmaceutical composition of the present invention in the preparation of a medicament for the treatment of diseases responsive to activation of TLR 7 receptors.
  • the disease responsive to activation of the TLR 7 receptor is selected from liver-related diseases, tumors, or HIV infection.
  • the liver-related disease is selected from viral hepatitis, autoimmune liver disease, drug-toxic liver disease, liver disease-induced liver injury, liver functional failure, chronic severe hepatitis, cirrhosis, liver abscess, fatty liver, and primary One or more of primary liver cancer, preferably the liver-related disease is hepatitis B or C.
  • the tumor is selected from one or more of leukemia, lymphoma, melanoma, and non-small cell lung cancer.
  • the present invention also provides a pharmaceutical combination comprising the compound of component (1) formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, Tautomers, isotopic compounds, metabolites or prodrugs or pharmaceutical compositions, and component (2) PD-1 antibody, PD-L1 antibody or PD-1 inhibitor, PD-L1 inhibitor or PD-1 / PD-L1 inhibitor.
  • the invention also provides the use of the medicine combination in preparing medicine for treating tumor.
  • the tumor type is preferably selected from leukemia, lymphoma, melanoma, or non-small cell lung cancer.
  • the dosage of the compound to be administered to the subject is quite variable and can be subject to the judgment of a health care professional.
  • the compounds of the present invention can be administered orally.
  • the compound when administered orally, is administered with water or with a meal.
  • the compound is dispersed in water or juice (eg, apple juice or orange juice) and administered orally as a suspension.
  • the compounds can also be intradermal, intramuscular, intraperitoneal, transdermal, intravenous, subcutaneous, intranasal, intradural, sublingual, intracerebral, intravaginal, transdermal, rectal, transmucosal, by inhalation or local Give to ear, nose, eye or skin.
  • the mode of administration is determined by a health care professional and may depend in part on the location of the medical condition.
  • the compound of the present invention has higher TLR 7 agonistic activity and excellent TLR 7 selectivity relative to TLR 8 , and the effect is superior to the prior art.
  • the compound of the present invention is active and has good safety. For example, its exposure to the whole blood system is extremely low, and it can induce the expression of IFN- ⁇ in plasma and liver at low concentrations. With lower toxicity, it can achieve better efficacy.
  • Figure 1 Compound 3 and GS-9620 induced IFN- ⁇ and TNF- ⁇ expression in mouse plasma and liver. Among them, the exposure of Compound 3 in mouse plasma and liver is lower than the lower limit of the quantitative analysis of LC / MS / MS, and only the number 0 shows its position.
  • the present invention uses the following abbreviations:
  • CDI N N'-carbonyldiimidazole
  • the compounds are named by hand or ChemDraw software, and the commercially available compounds use the supplier catalog name.
  • the column was re-equilibrated for 0.5 minutes to reach 100: 5, and the total running time was 12.5 minutes.
  • 10-100AB_3.4 minutes method Apply a linear gradient, start elution with 90% A (A is 0.05% TFA in water), and end elution with 100% B (B is acetonitrile), the whole process is 2.2 minutes, Then elute with 100% B for 0.7 minutes.
  • the column was re-equilibrated for 0.2 minutes to reach 90:10, and the total run time was 3.4 minutes.
  • the column temperature was 50 ° C and the flow rate was 0.8 mL / min.
  • the scanning wavelength of the diode array detector is 200-400nm.
  • Thin layer chromatography was performed on Sanpont-group's silica gel GF254. Spots were commonly detected by ultraviolet light irradiation. In some cases, other methods were also used to check the spots. About 1g of iodine and thoroughly mixed), vanillin (dissolved about 1g of vanillin in 100mL of 10% H 2 SO 4 ), ninhydrin (purchased from Aldrich) or a special developer (complete mixing (NH 4 ) 6 Mo 7 O 24 ⁇ 4H 2 O, 5g (NH 4 ) 2 Ce (IV) (NO 3 ) 6 , 450mLH 2 O and 50mL concentrated H 2 SO 4 were prepared) unfold the thin layer plate, inspect the compound.
  • silica gel was used for rapid R.
  • Commonly used solvents for flash column chromatography or thin layer chromatography are methylene chloride / methanol, ethyl acetate / methanol, and hexane / ethyl acetate mixtures.
  • the Gilson UV / VIS-156 detector was used for preparative chromatographic analysis on the Gilson_281Prep LC322 system.
  • the column used was Agella Venusil ASB Prep C18, 150x21.2mm; CHIRALPAKAD-3, 0.46cm * 10cm, 3 ⁇ m; X select C18, 19mm * 150mm; Phenomenex Gemini C18, 5 ⁇ m, 150x30mm; or Phenomenex Synergi C18, 4 ⁇ m, 150x30mm.
  • the compound was eluted with a low gradient of acetonitrile / water, where the water contained 0.05% TFA, 0.25% HCOOH, or 0.5% NH 3 ⁇ H 2 O, with a total run time of 8-15 minutes.
  • the compound of formula I-1 of the present invention can be prepared by the following synthetic route 1.
  • intermediate step 1 is obtained through nucleophilic substitution reaction in reaction step 1. Subsequently, it undergoes a nucleophilic substitution reaction with ammonia through step 2 to obtain a 2-chloro-pyrimidine-6-amine compound (intermediate 2). Then, in step 3, the chlorine at the 2-position of pyrimidine is reacted with sodium or potassium alkoxide or thiol salt or organic amine to obtain intermediate 3. Then, through step 4: 1) reduction of the nitro group with zinc powder, 2) removal of Boc, 3) reaction with an amphiphilic reagent and ring closure to obtain the product, that is, the compound of formula I-1 when R 2 is H.
  • the intermediate 3 can obtain the compound of the formula I-1 when R 2 is H through the same procedure as the synthetic route 1.
  • the compounds of the general formulas I-2 and I-3 of the present invention can be prepared by synthetic routes 1 or 2 by those skilled in the art by selecting appropriate starting materials.
  • the compounds of the general formula I-6 of the present invention can be prepared by synthetic route 3.
  • intermediate compound 1 ' that is, 2-substituted-4,6-dichloro-5-nitropyrimidine or the like (commercial reagent or prepared according to the method of WO2016 / 44183A1)
  • step 1 ′′ and ammonia
  • a nucleophilic substitution reaction occurs to obtain a 6-chloro-pyrimidine-4-amine compound (intermediate 2 ').
  • it reacts with an organic amine through step 2 "to obtain intermediate 3'.
  • step 3 ′′ 1) reduction of the nitro group with zinc powder, 2) the intermediate obtained in 1) undergoes an oxidation reaction with hydrogen peroxide, and the oxidation reaction selectively obtains the 5-position hydroxylamine compound, 3) The 5-position hydroxylamine compound obtained in 2) is reacted with an amphiphile and ring-closed to obtain the product I-6.
  • Step A Preparation of 2- (2-butoxy-6-chloro-5-nitropyrimidin-4-yl) -1-methylhydrazine-1-carboxylic acid tert-butyl ester
  • reaction solution was suction filtered through celite, the filter cake was rinsed with ethyl acetate (50 ml ⁇ 2 times), and the filtrate was collected and concentrated by rotary evaporation under reduced pressure.
  • Step D 2- (6-amino-2-butoxy-5-nitropyrimidin-4-yl) -1-methyl-2- (3- (pyrrolidin-1-ylmethyl) benzyl) Preparation of Hydrazine-1-carboxylic acid tert-butyl ester
  • Step E 2- (5,6-diamino-2-butoxypyrimidin-4-yl) -1-methyl-2- (3- (pyrrolidin-1-ylmethyl) benzyl) hydrazine- 1-carboxylic acid tert-butyl acetate acetate
  • Step F 2-butoxy-6- (2-methyl-1- (3- (pyrrolidin-1-ylmethyl) benzyl) hydrazino) pyrimidine-4,5-diaminetrifluoroacetic acid Preparation of salt
  • Step G 5-amino-7-butoxy-2-methyl-1- (3- (pyrrolidin-1-ylmethyl) benzyl) -1,4-dihydropyrimido [5,4- e]
  • reaction solution was concentrated under reduced pressure to obtain a brown solid (2.10 g) which was dissolved with dimethyl sulfoxide (5.0 mL) until clear, and purified by preparative high performance liquid chromatography. Purification conditions are as follows, chromatography column: Xselect C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia) and acetonitrile; flow rate: 25 ml / min; gradient: within 7 minutes, acetonitrile rises from 10% to 80%; Detection wavelength: 254nm. Collect the product and freeze-dry it under reduced pressure.
  • the reaction product does not produce MS signal, and is directly used in the next reaction.
  • Step BC 2- (2-butoxy-6-chloro-5-nitropyrimidin-4-yl) -2- (4-fluoro-3- (hydroxymethyl) benzyl) -1-methylhydrazine -1- Preparation of tert-butyl carboxylate
  • Post-treatment After the reaction solution is cooled to room temperature, add 100 ml of pure water to dilute. The resulting mixture was concentrated under reduced pressure to remove acetonitrile. The remaining aqueous phase was extracted with ethyl acetate (50 ml ⁇ 3 times), and the organic phases were combined. The organic phase was washed with saturated sodium chloride solution (50 ml x 2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure.
  • Step D 2- (2-butoxy-6-chloro-5-nitropyrimidin-4-yl) -2- (4-fluoro-3-formylbenzyl) -1-methylhydrazine-1- Tert-Butyl carboxylate
  • Step E 2- (6-amino-2-butoxy-5-nitropyrimidin-4-yl) -2- (4-fluoro-3-formylbenzyl) -1-methylhydrazine-1- Tert-Butyl carboxylate
  • Step F 2- (6-amino-2-butoxy-5-nitropyrimidin-4-yl) -2- (4-fluoro-3- (pyrrolidin-1-ylmethyl) benzyl)- Preparation of 1-methylhydrazine-1-carboxylic acid tert-butyl ester
  • Step G 2- (5,6-diamino-2-butoxypyrimidin-4-yl) -2- (4-fluoro-3- (pyrrolidin-1-ylmethyl) benzyl) -1- Preparation of tert-butyl methylhydrazine-1-carboxylate
  • Step H 2-butoxy-6- (1- (4-fluoro-3- (pyrrolidin-1-ylmethyl) benzyl) -2-methylhydrazino) pyrimidine-4,5-diamine
  • Step I 5-amino-7-butoxy-1- (4-fluoro-3- (pyrrolidin-1-ylmethyl) benzyl) -2-methyl-1,4-dihydropyrimido [ Preparation of 5,4-e] [1,2,4] triazine-3 (2H) -one trifluoroacetate
  • the separation conditions are as follows, chromatographic column: X select C18 19mm * 150mm; mobile phase: water and acetonitrile; flow rate: 25 ml / min; gradient: within 7 minutes, acetonitrile rises from 10% to 70%; detection wavelength: 254 nm.
  • the product was collected, lyophilized under reduced pressure to give 0.42 g 2-Butoxy-5- (hydroxyamino) -N 4 - (4- (pyrrolidin-1-ylmethyl) benzyl) -4,6-pyrimidine amine.
  • Step D 6-amino-2-butoxy-7-hydroxy-9- (4- (pyrrolidin-1-ylmethyl) benzyl) -7H-purin-8 (9H) -one trifluoroacetic acid Salt and 2-butoxy-7-hydroxy-6-((4- (pyrrolidin-1-ylmethyl) benzyl) amino) -7H-purin-8 (9H) -one trifluoroacetate preparation
  • Step A Preparation of 6-amino-2-butoxy-7-hydroxy-9- (3- (pyrrolidin-1-ylmethyl) benzyl) -7H-purine-8 (9H) -thione
  • Step A Preparation of 2-butoxy-5-nitro-N 4- (3- (pyrrolidin-1-ylmethyl) benzyl) pyrimidine-4,6-diamine
  • Step B Preparation of 2-butoxy-N 4- (3- (pyrrolidin-1-ylmethyl) benzyl) pyrimidine-4,5,6-triamine
  • Step C Preparation of 2-butoxy-5- (hydroxyamino) -N 4- (3- (pyrrolidin-1-ylmethyl) benzyl) pyrimidine-4,6-diamine
  • the reaction mixture was suction filtered, and the filtrate was purified by preparative high performance liquid chromatography.
  • the separation conditions are as follows. Chromatography column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia) and acetonitrile; flow rate: 25 ml / min; gradient: within 7 minutes, acetonitrile rises from 10% to 70% ; Detection wavelength: 254nm. Lyophilized at low temperature to obtain 0.43 g of 2-butoxy-5- (hydroxyamino) -N 4- (3- (pyrrolidin-1-ylmethyl) benzyl) pyrimidine-4,6-diamine.
  • Step D 6-amino-2-butoxy-7-hydroxy-9- (3- (pyrrolidin-1-ylmethyl) benzyl) -7H-purin-8 (9H) -one
  • Step A Preparation of 2-butoxy-5-nitro-N 4- (3- (piperidin-1-ylmethyl) benzyl) pyrimidine-4,6-diamine
  • Step B Preparation of 2-butoxy-N 4- (3- (piperidin-1-ylmethyl) benzyl) pyrimidine-4,5,6-triamine
  • Step C Preparation of 2-butoxy-5- (hydroxyamino) -N 4- (3- (piperidin-1-ylmethyl) benzyl) pyrimidine-4,6-diamine
  • the separation conditions are as follows, chromatographic column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% ammonia) and acetonitrile; flow rate: 25 ml / min; gradient: within 7 minutes, acetonitrile rises from 10% to 70%; Detection wavelength: 254nm.
  • the product was collected and lyophilized under reduced pressure to obtain 0.51 g of 2-butoxy-5- (hydroxyamino) -N 4- (3- (piperidin-1-ylmethyl) benzyl) pyrimidine-4,6-di amine.
  • Step D 6-amino-2-butoxy-7-hydroxy-9- (3- (piperidin-1-ylmethyl) benzyl) -7H-purin-8 (9H) -one trifluoroacetic acid Preparation of salt
  • 2-Methyl isonicotinic acid (35.0 g, 255.5 mmol) was dissolved in methanol (520 mL). Under ice-water bath, control the temperature of the reaction solution not to exceed 10 degrees Celsius. With stirring, sulfoxide chloride (63.8 g, 536.5 mmol) was slowly added dropwise. After the dropwise addition, the reaction solution was heated to 60 degrees Celsius and reacted for 6 hours.
  • the reaction solution was concentrated under reduced pressure, and the residue was dissolved with water (500 mL), and extracted with ethyl acetate (100 mL ⁇ 1). After adjusting the pH of the aqueous phase to 9 to 10 with potassium carbonate, it was extracted with ethyl acetate (200 ml ⁇ 3). The obtained organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 35.2 g of white solid methyl 2-methylisonicotinate (yield 91.2%).
  • Step B Preparation of 2- (bromomethyl) isonicotinic acid methyl ester
  • Step D 2- (2-butoxy-6-chloro-5-nitropyrimidin-4-yl) -2-((4- (hydroxymethyl) pyridin-2-yl) methyl) -1-
  • Step D 2- (2-butoxy-6-chloro-5-nitropyrimidin-4-yl) -2-((4- (hydroxymethyl) pyridin-2-yl) methyl) -1-
  • Step E 2- (6-amino-2-butoxy-5-nitropyrimidin-4-yl) -2-((4- (hydroxymethyl) pyridin-2-yl) methyl) -1- Preparation of tert-butyl methylhydrazine-1-carboxylate
  • reaction liquid was cooled to room temperature, the reaction liquid was concentrated under reduced pressure to obtain 520 mg of yellow solid 2- (6-amino-2-butoxy-5-nitropyrimidin-4-yl) -2-((4- ( Hydroxymethyl) pyridin-2-yl) methyl) -1-methylhydrazine-1-carboxylic acid tert-butyl ester. Without purification, the crude product is directly used in the next reaction.
  • Step F 2- (6-amino-2-butoxy-5-nitropyrimidin-4-yl) -2-((4-formylpyridin-2-yl) methyl) -1-methylhydrazine Preparation of tert-Butyl-1-carboxylate
  • reaction solution was cooled to room temperature, it was suction filtered with celite under reduced pressure. The filtrate was concentrated under reduced pressure and dissolved with N, N-dimethylformamide (2 ml) until clear. Then purified by preparative high performance liquid chromatography (column: Xselect C18 19mm * 150mm mobile phase: water (0.05% TFA) / acetonitrile; flow rate: 25 ml / min; gradient: within 7 minutes, acetonitrile from 10% 90%; detection wavelength: 254nm.
  • Step G 2- (6-amino-2-butoxy-5-nitropyrimidin-4-yl) -1-methyl-2-((4- (pyrrolidin-1-ylmethyl) pyridine- Preparation of 2-yl) methyl) hydrazine-1-carboxylic acid tert-butyl ester
  • Step H 2- (5,6-diamino-2-butoxypyrimidin-4-yl) -1-methyl-2-((4- (pyrrolidin-1-ylmethyl) pyridine-2- Of methyl) methyl) hydrazine-1-carboxylic acid tert-butyl acetate
  • reaction solution was suction filtered under reduced pressure, and the filtrate was collected.
  • the filter cake was rinsed with ethyl acetate (5 mL ⁇ 2). After combining the filtrates, it was concentrated under reduced pressure to give 80 mg of yellow semi-solid 2- (5,6-diamino-2-butoxypyrimidin-4-yl) -1-methyl-2-((4- (pyrrolidine -1-ylmethyl) pyridin-2-yl) methyl) hydrazine-1-carboxylic acid tert-butyl acetate acetate. Without purification, the crude product is directly used in the next reaction.
  • Step I 2- (5,6-diamino-2-butoxypyrimidin-4-yl) -1-methyl-2-((4- (pyrrolidin-1-ylmethyl) pyridine-2- Of methyl) methyl) hydrazine-1-carboxylic acid tert-butyl ester hydrochloride
  • reaction solution was concentrated under reduced pressure to obtain 83 mg of 2- (5,6-diamino-2-butoxypyrimidin-4-yl) -1-methyl-2-((4- (pyrrolidine-1 -Ylmethyl) pyridin-2-yl) methyl) hydrazine-1-carboxylic acid tert-butyl ester hydrochloride. Without purification, the crude product is directly used in the next reaction.
  • Step J 5-amino-7-butoxy-2-methyl-1-((4- (pyrrolidin-1-ylmethyl) pyridin-2-yl) methyl) -1,2-dihydro
  • the reaction solution was concentrated under reduced pressure.
  • the crude product was dissolved with N, N-dimethylformamide (2.0 ml) until clear, and the crude product was purified by preparative high performance liquid chromatography. Separation conditions are as follows, column: Xselect C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml / min; gradient: within 7 minutes, acetonitrile rose from 10% to 90 %; Detection wavelength: 254nm.
  • Step A 2- (6-amino-2-hydroxy-5-nitropyrimidin-4-yl) -1-methyl-2- (3- (pyrrolidin-1-ylmethyl) benzyl) hydrazine- Preparation of 1-carboxylic acid tert-butyl ester
  • Steps B1 to B2 Preparation of 1- (tetrahydro-2H-pyran-4-yl) ethyl methanesulfonate
  • Step C 2- (6-amino-5-nitro-2- (1- (tetrahydro-2H-pyran-4-yl) ethoxy) pyrimidin-4-yl) -1-methyl-2 -(3- (Pyrrolidine) -1-ylmethyl) benzyl) hydrazine-1-carboxylic acid tert-butyl ester
  • Step D 2- (5,6-diamino-2- (1- (tetrahydro-2H-pyran-4-yl) ethoxy) pyrimidin-4-yl) -1-methyl-2- ( Preparation of tert-butyl 3- (pyrrolidin-1-ylmethyl) benzyl) hydrazine-1-carboxylate acetate
  • Step E 6- (2-methyl-1- (3- (pyrrolidin-1-ylmethyl) benzyl) hydrazino) -2- (1- (tetrahydro-2H-pyran-4-yl ) Ethoxy) pyrimidine-4,5-diamine trifluoroacetate
  • reaction solution was concentrated to dryness under reduced pressure to obtain 350 mg of yellow liquid 6- (2-methyl-1- (3- (pyrrolidin-1-ylmethyl) benzyl) hydrazino) -2- (1- ( Tetrahydro-2H-pyran-4-yl) ethoxy) pyrimidine-4,5-diamine trifluoroacetate.
  • Step F 5-amino-2-methyl-1- (3- (pyrrolidin-1-ylmethyl) benzyl) -7- (1- (tetrahydro-2H-pyran-4-yl) ethyl Oxy) -1,4-dihydropyrimido [5,4-e] [1,2,4] triazin-3 (2H) -one trifluoroacetate
  • reaction solution was concentrated under reduced pressure, and the residue was dissolved with N, N-dimethylformamide (5.0 mL) until clear, and purified by preparative high-performance liquid chromatography. Purification conditions are as follows, column: Xselect C18 19mm * 150mm; mobile phase: water (containing 0.05% TFA) and acetonitrile; flow rate: 20 ml / min; gradient: within 15 minutes, acetonitrile rises from 10% to 60% Detection wavelength: 254nm. Collect the product and freeze-dry it under reduced pressure.
  • Step A 2- (6-amino-2-butoxy-5-nitropyrimidin-4-yl) -1-methyl-2- (3- (2-methylpyrrolidin-1-ylmethyl ) Preparation of benzyl) hydrazine-1-carboxylic acid tert-butyl ester
  • Step B 2- (5,6-diamino-2-butoxypyrimidin-4-yl) -1-methyl-2- (3- (2-methylpyrrolidin-1-ylmethyl) benzyl ) Hydrazine-1-carboxylic acid tert-butyl acetate acetate
  • Step D 5-amino-7-butoxy-2-methyl-1- (3- (2-methylpyrrolidin-1-ylmethyl) benzyl) -1,4-dihydropyrimido [ Preparation of 5,4-e] [1,2,4] triazine-3 (2H) -one trifluoroacetate
  • Step A Preparation of methyl 2- (2-butoxy-6-amino-5-nitropyrimidin-4-yl) hydrazine-1-carboxylate
  • Step B Preparation of methyl 2- (2-butoxy-6-amino-5-nitropyrimidin-4-yl) -2- (3-formylbenzyl) hydrazine-1-carboxylate
  • Step C 2- (2-butoxy-6-amino-5-nitropyrimidin-4-yl) -2- (3- (pyrrolidin-1-ylmethyl) benzyl) hydrazine-1-carboxy Preparation of methyl acid ester
  • Post-treatment Filter and collect the filtrate.
  • the filter residue was washed with ethyl acetate (50 ml ⁇ 3).
  • the filtrates were combined and concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography. Separation conditions are as follows, column: Xselect C18 19mm * 150mm; mobile phase: water (0.05% ammonium bicarbonate) and acetonitrile; flow rate: 25 ml / min; gradient: within 25 minutes, acetonitrile rises from 0% to 90% ; Detection wavelength: 254nm.
  • Step E 5-amino-7-butoxy-1- (3- (pyrrolidin-1-ylmethyl) benzyl) -1,4-dihydropyrimido [5,4-e] [1, 2,4] triazine-3 (2H) -one
  • Post-treatment The reaction solution is filtered and purified by preparative high-performance liquid chromatography. Purification conditions are as follows, chromatography column: Xselect C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml / min; gradient: within 20 minutes, acetonitrile rises from 5% to 80 %; Detection wavelength: 254nm.
  • Step A-B Preparation of (3- (bromomethyl) -4-fluorophenyl) methanol
  • Step D 2- (2-butoxy-6-chloro-5-nitropyrimidin-4-yl) -2- (2-fluoro-5-formylbenzyl) -1-methylhydrazine-1- Preparation of tert-butyl carboxylate
  • Step E 2- (6-amino-2-butoxy-5-nitropyrimidin-4-yl) -2- (2-fluoro-5-formylbenzyl) -1-methylhydrazine-1- Preparation of tert-butyl carboxylate
  • Step F 2- (6-amino-2-butoxy-5-nitropyrimidin-4-yl) -2- (2-fluoro-5- (pyrrolidin-1-ylmethyl) benzyl)- Preparation of 1-methylhydrazine-1-carboxylic acid tert-butyl ester
  • Step G 2- (5,6-diamino-2-butoxypyrimidin-4-yl) -2- (2-fluoro-5- (pyrrolidin-1-ylmethyl) benzyl) -1- Preparation of tert-butyl methylhydrazine-1-carboxylate
  • reaction solution was filtered through celite.
  • the filtrate was collected, the filter cake was rinsed with ethyl acetate (20 ml x 2 times).
  • the combined filtrate was concentrated under low pressure to obtain 240 mg of crude product as a light yellow oil, 2- (5,6-diamino-2-butoxypyrimidin-4-yl) -2- (2-fluoro-5- (pyrrolidine -1-ylmethyl) benzyl) -1-methylhydrazine-1-carboxylic acid tert-butyl ester, used directly in the next reaction without purification.
  • Step H 2-butoxy-6- (1- (2-fluoro-5- (pyrrolidin-1-ylmethyl) benzyl) -2-methylhydrazino) pyrimidine-4,5-diamine
  • reaction solution was concentrated under reduced pressure to obtain 320 mg of light yellow oily 2-butoxy-6- (1- (2-fluoro-5- (pyrrolidin-1-ylmethyl) benzyl) -2-methyl Hydrazino) pyrimidine-4,5-diamine. Without purification, the compound was directly used in the next reaction.
  • Step I 5-amino-7-butoxy-1- (2-fluoro-5- (pyrrolidin-1-ylmethyl) benzyl) -2-methyl-1,4-dihydropyrimido
  • 2-butoxy-6- (1 -(2-fluoro-5- (pyrrolidin-1-ylmethyl) benzyl) -2-methylhydrazino) pyrimidine-4,5-diamine (320 mg, 0.767 mmol), tetrahydrofuran (3.0 ml ) With dichloromethane (3.0 mL).
  • PBS Phosphate Buffered Saline
  • Step 1 Cell plating:
  • Step 2 Drug treatment:
  • test compound was made into 10mM stock solution with DMSO.
  • the control compound GS-9620 has the following structure:
  • Test compound and control compound GS-9620 are identical to Test compound and control compound GS-9620:
  • the maximum concentration is diluted from 10 mM to 2 mM, and then diluted 3 times, 10 gradients, DMSO as a negative control. Take 2 ⁇ L of the diluted compound and add 38 ⁇ L of HEK-Blue TM Detection reagent to make a 20-fold intermediate dilution.
  • the final concentration of the test compound and the control compound was 10000,3333,1111,370,123,41,13,4.6,1.5,0.5,0.0nM.
  • Step 3 Detection
  • Step 1 Human blood collection
  • Step 2 Isolation of human peripheral blood mononuclear cells
  • the separation of PBMC should be separated within 2 hours after blood collection.
  • the seeding cell density is 1.5 ⁇ 10 6 / mL, and the 96-well plate is seeded with 100 ⁇ L of cell suspension, 150,000 cells per well.
  • test compound is made into 10mM stock solution with DMSO.
  • the compound to be tested starts with a 3-fold gradient from 10 mM to prepare 9 concentrations.
  • DMSO is a negative control.
  • Step 4 Compound treatment of cells
  • Step 3 Take 2 ⁇ L of the intermediate diluted compound (Step 3) to the corresponding 96-well plate, the final concentration of DMSO is 0.1%, the final concentration of the test compound is 10000, 3333, 1111, 370, 123, 41, 13, 4.6 1.5, 0.0nM.
  • the final concentration of the control compound was 10000, 3333, 2222, 1481, 987, 658, 219, 146, 98, 65, 43, 29, 19, 13, 0 nM.
  • the compound-added 96-well plate was placed at 37 ° C and incubated in a 5% CO 2 incubator for 20 hours.
  • Standard preparation Add 250 ⁇ L of Diluent 2 to the standard dry powder, mix well, and use it after 5 minutes. Then carry out gradient dilution, 4 times dilution of 7 gradients, Diluent 2 as the zero point.
  • Sample preparation the sample is centrifuged at room temperature for 5 minutes, the centrifugal speed is 1500 rpm, and the supernatant is aspirated for use.
  • Antibody preparation The concentration of antibody stock solution is 50X, and the use concentration is 1X. The antibody was diluted with Diluent 3.
  • test solution the concentration of the stock solution is 4X, the use concentration is 2X, and it is diluted with distilled water.
  • washing solution the stock solution is 20X, the use concentration is 1X, and it is diluted with distilled water.
  • Step 2 Use the MSD kit to detect TNF- ⁇
  • Plate washing Wash the plate 3 times with 300 ⁇ L of 1X washing liquid per well, and clean the last washing liquid.
  • Plate washing Wash the plate 3 times with 300 ⁇ L of 1X washing liquid per well, and clean the last washing liquid.
  • Detection Add 150 ⁇ L of 2X detection solution to each well and use MSD instrument for detection. It should be noted that the test can be performed without incubation after adding the test solution.
  • Standard preparation The standard stock solution is 1 ⁇ g / mL, the initial concentration of the action is 2500pg / mL, and then the gradient is diluted, and the gradient is diluted by 4 times, and Diluent 2 is used as the zero point.
  • Sample preparation the sample is centrifuged at room temperature for 5 minutes, the centrifugal speed is 1500 rpm, and the supernatant is aspirated for use.
  • Antibody preparation The concentration of antibody stock solution is 50X, and the use concentration is 1X. The antibody was diluted with Diluent 3.
  • test solution the concentration of the stock solution is 4X, the use concentration is 2X, and it is diluted with distilled water.
  • washing solution the stock solution is 20X, the use concentration is 1X, and it is diluted with distilled water.
  • Step 2 Use the MSD kit to detect IFN- ⁇
  • Add Diluent 2 Add 25 ⁇ L of Diluent 2 to each well, shake at room temperature for 30 minutes, and the shaking speed is 650 rpm.
  • sample add 25 ⁇ L of sample or standard to each well, seal with plate sealer, place shaker at room temperature and incubate for 2 hours at 650 rpm.
  • Plate washing Wash the plate 3 times with 300 ⁇ L of 1X washing liquid per well, and clean the last washing liquid.
  • Plate washing Wash the plate 3 times with 300 ⁇ L of 1X washing liquid per well, and clean the last washing liquid.
  • Detection Add 150 ⁇ L of 2X detection solution to each well and use MSD instrument for detection. It should be noted that the test can be performed without incubation after adding the test solution.
  • Table 1 and Table 2 show that the compounds of the present invention have high TLR 7 activity and high TLR 7 selectivity relative to TLR 8 . Its high activity has also been confirmed in the hPBMC test.
  • Test object GS-9620 (control compound), compound 3
  • test article was orally administered to three C57 mice by gavage. After administration, blood was collected through the tail vein at 1, 2, and 4 hours. Whole blood was collected in a tube pre-loaded with K 2 EDTA, and the plasma was separated by centrifugation, and stored in a refrigerator at -80 ° C.
  • HPLC High Pressure Liquid Chromatograph
  • Mass spectrometer (MS): AB Sciex Triple Quan 5500LC / MS / MS.
  • Solution A 5% acetonitrile water (0.1% formic acid)
  • Solution B 95% acetonitrile water (0.1% formic acid)
  • Standard preparation 5 ⁇ L of working solution (containing compounds of 1,2,4,10,20,100,200,1000,2000ng / mL, respectively) was added to 10 ⁇ L of blank C57 mouse plasma or liver tissue homogenate to obtain a total volume of 15 ⁇ L of 0.5 ⁇ 1000ng / mL (0.5,1,2,5,10,50,100,500,1000ng / mL) standard.
  • Quality control samples 5 plasma quality control samples with concentrations of 1.5ng / mL, 3ng / mL, 6ng / mL, 50ng / mL and 800ng / mL were prepared independently.
  • Test sample 5 ⁇ L blank solution + 10 ⁇ L test plasma sample.
  • Liver samples (g) were mixed with PBS (mL) at a ratio of 1: 4 and homogenized. Subsequently, 5 ⁇ L of blank solution was added to 10 ⁇ L of homogenized liver sample to obtain a liver sample.
  • FIG. 1 The exposure of the compound, the expression levels of IFN- ⁇ and TNF- ⁇ are shown in FIG. 1. From FIG. 1, it can be seen that the exposure of compound 3 in the plasma and liver of mice is lower than the analytical limit of LC / MS / MS. However, compound 3 can still induce the expression of IFN- ⁇ in plasma and liver, suggesting that compound 3 will greatly reduce the toxic and side effects caused by the compound and its metabolites relative to GS-9620.

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Abstract

本发明涉及式(I)的化合物，或其药学上可接受的盐、立体异构体、溶剂化物、多晶型体、互变异构体、同位素化合物、代谢产物或前药；用于治疗对TLR 7受体的激活响应的疾病。 (I)

Description

五元或六元杂环并嘧啶类化合物及其用途
本申请要求申请日为2018/10/22的中国专利申请201811228693.4的优先权。本申请引用上述中国专利申请的全文。
技术领域
本申请涉及作为TLR 7激动剂的五元或六元杂环并嘧啶类化合物、含有这类化合物的药物组合物、以及使用这类化合物和药物组合物的用途。
背景技术
Toll样受体(Toll-like receptors,TLR)是参与非特异性免疫(天然免疫)的一类重要蛋白质分子，并且在协调针对病原体的非特异性免疫和特异性免疫中发挥着关键作用。TLR是单个的跨膜非催化性蛋白质，表达于多种免疫细胞。当微生物突破机体的物理屏障，如皮肤、粘膜等时，TLR可以识别它们并激活机体产生免疫细胞应答。Toll样受体识别高度保守结构基序：由微生物病原体表达的病原体相关的微生物模式(pathogen-associated molecular pattern，PAMP)或由坏死细胞释放的损伤相关分子模式(damage-associated molecular pattern，DAMP)。通过相应的病原体相关的微生物模式(PAMP)或损伤相关分子模式(DAMP)刺激Toll样受体引发信号级联导致转录因子如AP-1、NF- kB和干扰素调节因子的激活。这导致多种细胞反应，包括生产干扰素、促炎性细胞因子和效应细胞因子，从而产生免疫应答。迄今为止哺乳动物中有13种Toll样受体已被发现。Toll样受体1、2、4、5和6主要表达在细胞表面上，Toll样受体3、7、8和9表达在内体中。不同的Toll样受体识别不同病原体衍生的配体。Toll样受体7(TLR 7)主要是由浆细胞样树突细胞(pDC)表达和配体识别而诱导干扰素α(IFN-α)的分泌。Toll样受体7(TLR 7)和Toll样受体8(TLR 8)高度同源，因此TLR 7配体在大多数情况下也是TLR 8配体。TLR 8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。IFN-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。因此，开发高选择性的TLR 7激动剂用于治疗疾病，包括病毒感染性疾病在临床上具有重要的安全性意义。TLR 7激动剂已有临床研发结果报道，如咪喹莫特、瑞喹莫德、GS-9620。例如，Gilead已将TLR 7激动剂GS-9620推进到临床II期用于治疗慢性乙肝病人(D.Allen,et al,Allen,D.et al,WO2016/044183)。但本领域仍亟需开发新的更高选择性、更好活性和安全性的TLR 7激动剂。
发明内容
在一方面，本发明提供五元或六元杂环并嘧啶类化合物，其可以用作TLR 7激动剂。具体地，本发明涉及式(I)的化合物：
Figure PCTCN2019111625-appb-000001
或其药学上可接受的盐、立体异构体、溶剂化物、多晶型体、互变异构体、同位素化合物、代谢产物或前药；
其中：
X选自O、S和NR x；R x选自H、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R A取代；
Y选自O、S、N，或者Y不存在；
Z选自N、O、S、C和CH；
Q选自O、S和NH；
当Y为N时，R 1选自H、羟基、巯基、氨基、卤素、硝基、氰基、C 1-C 8烷基、C 2-C 8烯基、C 2-C 8炔基、C 6-C 10芳基和五元至十元杂芳基；其中所述烷基、烯基、炔基、芳基或杂芳基任选地被一个或多个R B取代；
R 2选自H、羟基、巯基、氨基、卤素、硝基、氰基、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R C取代；
L 1为C 1-C 8烃链；
A环不存在，或A环选自：C 3-C 10环烃基、C 3-C 10杂环基、C 6-C 10芳基和五元至十元杂芳基；其中所述环烃基、杂环基、芳基、杂芳基任选地被一个或多个R D取代；
L 2不存在，或L 2为C 1-C 8烃链；
R 3为H、C 3-C 10环烃基、C 6-C 10芳基、五元至十元杂芳基或-WR 6R 7，其中W为N或CH，其中
R 6和R 7各自独立地选自H、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R E取代；或
R 6和R 7连同与其相连的N或C原子一起形成三元至十元杂环；所述杂环任选地被一个或多个R E取代；并且任选地，R 6和R 7连同与其相连的N或C原子一起形成的三元 至十元杂环可以任选地与A环稠和；
R 4选自C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基或和炔基各自任选地被一个或多个R F取代；
B环不存在，或B环选自C 3-C 10环烃基、C 3-C 10杂环基、C 6-C 10芳基和五元到十元杂芳基；其中所述环烃基、杂环基、芳基和杂芳基各自任选地被一个或多个R G取代；
R 5选自H、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个选自-OR 8、-SR 8和-NR 8R 8’的取代基取代；
R 8和R 8’各自独立地选自H、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R H取代；或者R 8和R 8’连同与其相连的N原子一起形成三元至十元杂环，所述杂环优选为四元至六元杂环；
R A、R B、R C、R D、R E、R F、R G、R H在每次出现时各自独立地选自卤素、氰基、硝基、-R a、-OR a、＝O、-SR a、-NR aR b、＝NR a、-C(卤素) 3、-CR(卤素) 2、-CR 2(卤素)、-OCN、-SCN、-N＝C＝O、-NCS、-NO、-NO 2、-N(R a)C(＝O)R b、-N(R a)C(＝O)OR b、-N(R a)C(＝O)NR bR c、-C(＝O)NR aR b、-C(＝O)OR a、-OC(＝O)NR aR b、-OC(＝O)R a、-OC(＝O)OR a、-C(＝O)R a、-S(＝O) 2OR a、-S(＝O) 2R a、-OS(＝O) 2R a、-OS(＝O) 2OR a、-S(＝O) 2NR aR b、-S(＝O)R a、-N(R a)S(＝O) 2R b、-N(R a)S(＝O) 2NR bR c、-N(R a)S(＝O) 2OR b、-OP(＝O)(OR a)OR b、-P(＝O)(OR a)OR b、-C(＝O)R a、-C(＝S)R a、-C(＝O)OR a、-C(＝S)OR a、-C(＝O)SR a、-C(＝S)SR a、-C(＝O)NR aR b、-C(＝S)NR aR b、-C(＝NR a)NR bR c、-NR aC(＝NR b)NR cR d；R a、R b、R c和R d每次出现时各自独立地选自H、C 1-C 8烷基、C 3-C 8环烃基、三元到八元杂环基、C 6-C 10芳基、五元到十元杂芳基、C 6-C 10芳基-C 1-C 4烷基和五元到十元杂芳基-C 1-C 4烷基；其中所述烷基、环烃基、杂环基、芳基、杂芳基、芳基-C 1-C 4烷基和杂芳基-C 1-C 4烷基各自任选地被一个或多个卤素、＝O、-OH、-NH 2、-SH取代；
其中当R A、R B、R C、R D、R E、R F、R G或R H各自独立地为-NR aR b时，R a、R b任选地和与其相连的N原子一起形成三元至十元杂环，所述杂环优选为四元至六元杂环。
本发明还提供如下式(I-1)、(I-2)、(I-3)、(I-4)、(I-5)、(I-6)和(I-7)的化合物，
Figure PCTCN2019111625-appb-000002
Figure PCTCN2019111625-appb-000003
或其药学上可接受的盐、立体异构体、溶剂化物、多晶型体、互变异构体、同位素化合物、代谢产物或前药，
其中R 1、R 2、R 3、R 4、R F、R 5、L 1、L 2、X、Y、Z、Q、A和B如式(I)中所定义。
在另一方面，本发明还提供一种药物组合物，其包含本发明的化合物或其药学上可接受的盐、立体异构体、溶剂化物、多晶型体、互变异构体、同位素化合物、代谢产物或前药，以及至少一种药学上可接受的载体。
在又一方面，本发明还提供本发明的化合物或其药学上可接受的盐、立体异构体、溶剂化物、多晶型体、互变异构体、同位素化合物、代谢产物或前药或本发明的药物组合物在制备治疗疾病的药物中的用途，所述疾病为对TLR 7受体的激活响应的疾病。
在另一方面，本发明提供本发明的化合物或其药学上可接受的盐、立体异构体、溶剂化物、多晶型体、互变异构体、同位素化合物、代谢产物或前药，或本发明的药物组合物，用于治疗对TLR 7受体的激活响应的疾病。
在进一步的方面，本发明提供一种治疗对TLR 7受体的激活响应的疾病的方法，所述 方法包括向有此需要的个体给药本发明的化合物或其药学上可接受的盐、立体异构体、溶剂化物、多晶型体、互变异构体、同位素化合物、代谢产物或前药，或本发明的药物组合物。
在一实施方案中，所述对TLR 7受体的激活响应的疾病选自肝脏相关疾病、肿瘤和HIV感染。在一具体实施方案中，所述肿瘤类型选自白血病、淋巴瘤、黑色素瘤或非小细胞肺癌。在一具体实施方案中，所述HIV感染为艾滋病。
本发明还提供一种药物组合，所述药物组合包含(1)本发明的化合物或其药学上可接受的盐、立体异构体、溶剂化物、多晶型体、互变异构体、同位素化合物、代谢产物或前药或本发明的药物组合物，和(2)PD-1抗体、PD-L1抗体或PD-1抑制剂、PD-L1抑制剂或PD-1/PD-L1抑制剂。在一实施方案中，所述药物组合为药物组合物或试剂盒的形式。
一般术语和定义
除非特别地说明，否则本文所使用的术语应当解释为具有本领域普通技术人员通常所理解的所属领域的相同含义。应当进一步理解的是，除非在本文中明确地定义，否则本文所使用的术语应当解释为具有与其在本说明书的上下文中和相关领域中一致的含义。
术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的或开放式的，且不排除其它未列举的元素或方法步骤。本领域技术人员应当理解，上述术语如“包括”涵盖“由…组成”的含义。
术语“一个(种)或多个(种)”或者类似的表述“至少一个(种)”可以表示例如1、2、3、4、5、6、7、8、9、10个(种)或更多个(种)。
当公开了数值范围的下限和上限时，落入该范围中的任何数值和任何包括的范围都被具体公开。特别地，本文公开的值的每个取值范围应理解为表示涵盖于较宽范围中的每个数值和范围。
本文所用的表述m-n指m至n的范围以及由其中的各个点值组成的亚范围以及各个点值。例如，表述“C 1-C 8”涵盖1-8个碳原子的范围，并应理解为还涵盖其中的任意亚范围以及每个点值，例如C 2-C 5、C 3-C 4、C 1-C 2、C 1-C 3、C 1-C 4、C 1-C 5、C 1-C 6、C 1-C 7等，以及C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8等。例如，表述“C 3-C 10”也应当以类似的方式理解，例如可以涵盖包含于其中的任意亚范围和点值，例如C 3-C 9、C 6-C 9、C 6-C 8、C 6-C 7、C 7-C 10、C 7-C 9、C 7-C 8、C 8-C 9等以及C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10等。又例如，表述“三元至十元”应理解为涵盖其中的任意亚范围以及的每个点值，例如3-5元、3-6元、3-7元、3-8元、4-5元、4-6元、4-7元、4-8元、5-7元、5-8元、6-7元、7-8元、9-10 元等，以及3、4、5、6、7、8、9、10元等。本文中其他类似的表述也应当以类似的方式理解。
术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。
术语“取代”和“取代的”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。当描述某取代基不存在时，应当理解该取代基可以为一个或多个氢原子，前提是所述结构能使化合物达到稳定的状态。
如果取代基被描述为“任选地…被取代”，则取代基可以是未被取代的，或者可以是被取代的。如果某个原子或基团被描述为任选地被取代基列表中的一个或多个取代，则该原子或基团上的一个或多个氢可被独立地选择的、任选的取代基替代。当取代基为氧代(即＝O)时，意味着两个氢原子被取代。
除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代的环中的任一成环原子。
当任何变量(例如R)，以及带有标记的变量(例如R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 8’、R A、R B、R C、R D、R E、R F、R G等)在化合物的组成或结构中出现一次以上时，其在每次出现时在每一种情况下的定义都是独立的。例如，如果一个基团被0、1、2、3或4个R取代基所取代，则所述基团可以任选地至多被四个R取代基所取代，并且每种情况下的每个R取代基的选项都是相互独立的。
术语“卤”或“卤素”或“卤代”应理解为表示氟(F)、氯(Cl)、溴(Br)或碘(I)原子，优选氟、氯、溴或碘原子。
术语“羟基”指-OH。
术语“氰基”指-CN。
术语“巯基”指-SH。
术语“氨基”指-NH 2。
术语“烷基”是指由碳原子和氢原子组成的直链或支链的饱和的脂肪烃基团，其通过单键与分子的其余部分连接。“烷基”可以具有1-8个碳原子，即“C 1-C 8烷基”，例如C 1-C 4烷基、C 1-C 3烷基、C 1-C 2烷基、C 3烷基、C 4烷基、C 3-C 6烷基。烷基的非限制性实例包括但不限于甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、 异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基，或者它们的异构体。
术语“烯基”是指由碳原子和氢原子组成的直链或支链的具有至少一个双键的不饱和脂肪族烃基。烯基可以具有2-8个碳原子，即“C 2-C 8烯基”，例如C 2-C 4烯基、C 3-C 4烯基。烯基的非限制性实例包括但不限于乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、高烯丙基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基等。
术语“炔基”是指由碳原子和氢原子组成的直链或支链的具有至少一个三键的不饱和脂肪族烃基。炔基可以具有2-8个碳原子，即“C 2-C 8炔基”，例如C 2-C 4炔基、C 3-C 4炔基。炔基的非限制性实例包括但不限于乙炔基、丙-1-炔基、丙-2-炔基、丁-1-炔基、丁-2-炔基、丁-3-炔基等。
术语“环烃基”是指由碳原子和氢原子组成的饱和或不饱和的非芳香性的环状烃基，优选包含1或2个环。所述环烃基可以是单环、稠合多环、桥环或螺环结构。环烃基可以具有3-10个碳原子，即“C 3-C 10环烃基”，例如C 3-C 8环烃基、C 5环烃基、C 6环烃基、C 7环烃基。环烃基的非限制性实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、双环[2.2.1]庚基和螺[3.3]庚基等。
术语“杂环基”或“杂环烃基”是指具有例如3-10个(适合地具有3-8个，更适合地具有3-6个，特别是4-6个)环原子的单环或双环的非芳香环体系(三元至十元、三元至八元、三元至六元)，其中至少一个环原子(例如1、2或3个)是选自N、O和S的杂原子，且其余环原子是C。该环体系可以是饱和(也可以理解为相应的“杂环烷基”)或不饱和的(即在环内具有一个或多个双键和/或三键)。该术语还涵盖这样的情况，其中的C原子可以被氧代(＝O)取代和/或环上的S原子可以被1个或2个氧代(＝O)取代。
杂环基可以是例如4-元环，如氮杂环丁烷基、氧杂环丁烷基；或者5-元环，如四氢呋喃基、二噁烷基(dioxolinyl)、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基、氧代吡咯烷基、2-氧代咪唑烷-1-基、噻唑基、噻二唑基；或者6-元环，如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基、1,1-二氧代-1,2-噻嗪烷-2-基或三噻烷基；或者7-元环，如二氮杂
Figure PCTCN2019111625-appb-000004
基环。任选地，杂环基可以是苯并稠和的。
杂环基可以是双环的，不受其限制，例如5,5-元环，如六氢环戊烷[c]吡咯-2(1H)-基)环；或者5,6-元双环，如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。
如上文所提到的，包含氮原子的环可以是部分不饱和的，即其可以包含一个或多个 双键，不受其限制，例如2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢噁唑基或4H-[1,4]噻嗪基环，或者其可以是苯并稠和的，不受其限制，例如二氢异喹啉基环。
术语“芳基”是指具有共轭的π电子体系的全碳单环或稠合多环(如双环)的芳香环基团。例如，芳基可以具有6-20个碳原子，6-14个碳原子，适合地具有6-10个，更适合地具有6个或10个。芳基的实例包括但不限于苯基、萘基和蒽基等。
术语“杂芳基”应理解为优选表示一价的单环、双环或三环芳族环系统，其具有5、6、7、8、9或10个环原子(“五元到十元杂芳基”)，特别是5或6或9或10个环原子，并且环原子中包含至少一个(适合地为1-4个，更适合地为1-3个)可以相同或不同的杂原子，所述杂原子是例如氧、氮或硫，此外，在每种情况下杂芳基可以是苯并稠合的。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基、噻-4H-吡唑基等，以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基、异吲哚基等；或者吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及它们的苯并衍生物，例如喹啉基、喹唑啉基、异喹啉基等；或者吖辛因基(azocinyl)、吲嗪基、嘌呤基等，以及它们的苯并衍生物；或者噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、咔唑基、吖啶基等。
本文所用的术语“C 1-C 8烃链”指由碳原子和氢原子构成的链状基团，其可以是直链或支化的，并且包含1-8(特别是1-5、例如1、2、3、4或5)个碳原子。所述烃链可以是饱和的(即C 1-C 8亚烷基)，也可以是不饱和的，即可以包含一个或多个(优选1个)碳碳双键或三键。亚烷基可以具有1-8个碳原子，即"C 1-C 8亚烷基"，例如C 1-C 5亚烷基、C 1-C 4亚烷基、C 1-C 3亚烷基、C 1-C 2亚烷基、C 3亚烷基，以及C 1亚烷基，即亚甲基。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-)等。
“药学可接受”是指与制剂中的其它组分相容，并且对施用对象服用者无不可接受的毒害。
特别地，本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来加以制备。这包括下面列举的具体实施方案，其与其他化学合成方法相结合的实施方案以及本领域所公认的等同替代方式。优选的实施方案包括但不限于本发明的实施例。
本发明的具体的实施方案的化学反应是在合适的溶剂中完成的，所描述的溶剂适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，必要时需要本 领域技术人员在以已有实施的基础上对合成步骤或者反应流程进行修改或者选择。
本发明的化合物的药学上可接受的盐包括其酸加成盐及碱加成盐。适合的酸加成盐由形成药学可接受盐的酸来形成。实例包括盐酸盐、乙酸盐、天冬氨酸盐、苯甲酸盐、碳酸氢盐/碳酸盐、葡庚糖酸盐、葡糖酸盐、硝酸盐、乳清酸盐、棕榈酸盐及其它类似的盐。适合的碱加成盐由形成药学可接受盐的碱来形成。实例包括铝盐、精氨酸盐、胆碱盐、镁盐及其它类似的盐。适合的盐的综述参见例如“Remington′s Pharmaceutical Sciences”，Mack Publishing Company,Easton,Pa.,(2005)；和“药用盐手册：性质、选择和应用”(Handbook of Pharmaceutical Salts：Properties,Selection,and Use)，Stahl and Wermuth(Wiley-VCH,Weinheim,Germany,2002)。用于制备本发明的化合物的药学上可接受的盐的方法为本领域技术人员已知的。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。在某些实施方案中，优选化合物为那些显示更优生物活性的异构体化合物。本发明化合物已纯化的或部分纯化的异构体和立体异构体、或者外消旋混合物或非对映异构体混合物也均包括于本发明范围内。此类物质的纯化和分离可通过本领域已知的标准技术实现。
根据常规方法通过拆分外消旋混合物可获得光学纯对映异构体，例如通过使用具有光学活性的酸或碱形成非对映异构体盐，或者通过形成共价非对映异构体。非对映异构体的混合物可基于它们的物理和/或化学差异，通过本领域已知的方法(例如通过色谱法或分级结晶)分离成单一的非对映异构体。然后，从分离的非对映异构体盐中释放具有光学活性的对映体碱或酸。另一种分离消旋对映异构体的方法可使用手性色谱法(例如手性HPLC柱)，被分离的手性异构体可以在分离前进行常规衍生化处理或不衍生化，取决于何种方法可以实现更有效地分离手性异构体。还可以使用酶法来分离衍生化的或没被衍生化的手性异构体。同样地，可使用具有光学活性的原料，通过手性合成来获得本发明的光学纯化合物。
另外，本发明的化合物可以互变异构体的形式存在。本发明包括本发明的化合物所有可能的互变异构体，也包括单一互变异构体或所述互变异构体的任意比例的任意混合物的形式。
本发明的化合物可以溶剂化物(优选水合物)的形式存在，其中本发明的化合物包含作 为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
本发明还涵盖本发明的化合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。
本发明还包括所有药学上可接受的同位素标记的化合物，其与本发明的化合物相同，除了一个或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子替代。
在本发明的范围内还包括本发明的化合物的代谢产物，即在给药本发明的化合物时体内形成的物质。化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过试验的方法进行表征。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、酶解等产生。因此，本发明包括本发明的化合物的代谢物，包括通过使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。
本发明在其范围内进一步包括本发明的化合物的前药，其为自身可具有较小药理学活性或无药理学活性的本发明的化合物的某些衍生物当被给药至身体中或其上时可通过例如水解裂解转化成具有期望活性的本发明的化合物。通常这样的前药会是所述化合物的官能团衍生物，其易于在体内转化成期望的治疗活性化合物。关于前药的使用的其他信息可参见“Pro-drugs as Novel Delivery Systems”，第14卷，ACS Symposium Series(T.Higuchi及V.Stella)。本发明的前药可例如通过用本领域技术人员已知作为“前-部分(pro-moiety)(例如“Design of Prodrugs”，H.Bundgaard(Elsevier,1985)中所述)”的某些部分替代本发明的化合物中存在的适当官能团来制备。
本发明还涵盖含有保护基的本发明的化合物。在制备本发明的化合物的任何过程中，保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成本发明的化合物的化学保护的形式。这可以通过常规的保护基实现，例如，在T.W.Greene & P.G.M.Wuts,Protective Groups in Organic Synthesis,John Wiley & Sons,2006中所述的那些保护基，这些参考文献通过援引加入本文。使用本领域已知的方法，在适当的后续阶段可以移除保护基。
术语“给药”或“给予”等指可以使化合物或组合物能够递送至期望的生物作用位点的方法。这些方法包括但不限于肠胃外(包括静脉内、皮下、腹膜内、肌内、血管内注射或输注)、局部、直肠给药等。
如本文所用，术语“治疗”包括缓解、减轻或改善疾病或症状，预防其他症状，改善 或预防症状的潜在代谢因素，抑制疾病或症状，例如，阻止疾病或症状发展，减轻疾病或症状，促进疾病或症状缓解，或使疾病或症状的病征停止，和延伸至包括预防。“治疗”还包括实现治疗性获益和/或预防性获益。治疗性获益是指根除或改善所治疗的病症。此外，治疗性获益通过根除或改善一个或多个与潜在疾病相关的生理病征达到，尽管患者可能仍患有潜在疾病，但可观察到患者疾病的改善。预防性获益是指，患者为预防某种疾病风险而使用组合物，或患者出现一个或多个疾病生理病症时服用，尽管尚未诊断此疾病。
如本文中所使用的术语“有效量”(例如“治疗有效量”或“预防有效量”)指给药后会在一定程度上实现预期效果的活性成分的量，例如缓解所治疗病症的一种或多种症状或预防病症或其症状的出现。
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
下述发明详述旨在举例说明非限制性实施方案，使本领域其它技术人员更充分地理解本发明的技术方案、其原理及其实际应用，以便本领域其它技术人员可以以许多形式修改和实施本发明，使其可最佳地适应特定用途的要求。
本发明的化合物
在一个方面，本发明提供式(I)的化合物：
Figure PCTCN2019111625-appb-000005
或其药学上可接受的盐、立体异构体、溶剂化物、多晶型体、互变异构体、同位素化合物、代谢产物或前药；
其中：
X选自O、S和NR x；R x选自H、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R A取代；
Y选自O、S、N，或者Y不存在；
Z选自N、O、S、C和CH；
Q选自O、S和NH；
当Y为N时，R 1选自H、羟基、巯基、氨基、卤素、硝基、氰基、C 1-C 8烷基、C 2-C 8烯基、C 2-C 8炔基、C 6-C 10芳基和五元至十元杂芳基；其中所述烷基、烯基、炔基、芳基或杂芳基任选地被一个或多个R B取代；
R 2选自H、羟基、巯基、氨基、卤素、硝基、氰基、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R C取代；
L 1为C 1-C 8烃链；
A环不存在，或A环选自：C 3-C 10环烃基、C 3-C 10杂环基、C 6-C 10芳基和五元至十元杂芳基；其中所述环烃基、杂环基、芳基、杂芳基任选地被一个或多个R D取代；
L 2不存在，或L 2为C 1-C 8烃链；
R 3为H、C 3-C 10环烃基、C 6-C 10芳基、五元至十元杂芳基或-WR 6R 7，其中W为N或CH，其中
R 6和R 7各自独立地选自H、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R E取代；或
R 6和R 7连同与其相连的N或C原子一起形成三元至十元杂环；所述杂环任选地被一个或多个R E取代；并且任选地，R 6和R 7连同与其相连的N或C原子一起形成的三元至十元杂环可以任选地与A环稠和；
R 4选自C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基或和炔基各自任选地被一个或多个R F取代；
B环不存在，或B环选自C 3-C 10环烃基、C 3-C 10杂环基、C 6-C 10芳基和五元到十元杂芳基；其中所述环烃基、杂环基、芳基和杂芳基各自任选地被一个或多个R G取代；
R 5选自H、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个选自-OR 8、-SR 8和-NR 8R 8’的取代基取代；
R 8和R 8’各自独立地选自H、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R H取代；或者R 8和R 8’连同与其相连的N原子一起形成三元至十元杂环，所述杂环优选为四元至六元杂环；
R A、R B、R C、R D、R E、R F、R G、R H在每次出现时各自独立地选自卤素、氰基、硝基、-R a、-OR a、＝O、-SR a、-NR aR b、＝NR a、-C(卤素) 3、-CR(卤素) 2、-CR 2(卤素)、-OCN、-SCN、-N＝C＝O、-NCS、-NO、-NO 2、-N(R a)C(＝O)R b、-N(R a)C(＝O)OR b、-N(R a)C(＝O)NR bR c、-C(＝O)NR aR b、-C(＝O)OR a、-OC(＝O)NR aR b、-OC(＝O)R a、-OC(＝O)OR a、-C(＝O)R a、-S(＝O) 2OR a、-S(＝O) 2R a、-OS(＝O) 2R a、-OS(＝O) 2OR a、-S(＝O) 2NR aR b、-S(＝O)R a、 -N(R a)S(＝O) 2R b、-N(R a)S(＝O) 2NR bR c、-N(R a)S(＝O) 2OR b、-OP(＝O)(OR a)OR b、-P(＝O)(OR a)OR b、-C(＝O)R a、-C(＝S)R a、-C(＝O)OR a、-C(＝S)OR a、-C(＝O)SR a、-C(＝S)SR a、-C(＝O)NR aR b、-C(＝S)NR aR b、-C(＝NR a)NR bR c和-NR aC(＝NR b)NR cR d；R a、R b、R c和R d每次出现时各自独立地选自H、C 1-C 8烷基、C 3-C 8环烃基、三元到八元杂环基、C 6-C 10芳基、五元到十元杂芳基、C 6-C 10芳基-C 1-C 4烷基和五元到十元杂芳基-C 1-C 4烷基；其中所述烷基、环烃基、杂环基、芳基、杂芳基、芳基-C 1-C 4烷基、杂芳基-C 1-C 4烷基各自任选地被一个或多个卤素、＝O、-OH、-NH 2、-SH取代；
其中当R A、R B、R C、R D、R E、R F、R G或R H各自独立地为-NR aR b时，R a、R b任选地和与其相连的N原子一起形成三元至十元杂环，所述杂环优选为四元至六元杂环。
在一实施方案中，通过双键与嘧啶-5-碳原子、嘧啶-6-碳原子、N、Z、N和Z之间的碳原子、任选存在的Y组成的杂环相连的Q选自O和S。
在一实施方案中，X为O。在另一实施方案中，X为S。在又一实施方案中，X为NR x，并且R x选自H、C 1-C 4烷基、C 2-C 4烯基和C 2-C 4炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R A取代。在另一实施方案中，X为N，并且R x选自H和C 1-C 4烷基；其中所述烷基任选地被一个或多个R A取代。
在一实施方案中，Y为O或S，并且R 1不存在。
在一实施方案中，Y为N，并且R 1选自H、C 1-C 8烷基、C 2-C 8烯基、C 2-C 8炔基、C 6-C 10芳基和五元至十元杂芳基；其中所述烷基、烯基、炔基、芳基和杂芳基各自任选地被一个或多个R B取代；其中所述五元至十元杂芳基含有1-3个各自独立地选自O、N和S的杂原子。在一优选的实施方案中，Y为N，并且R 1选自H、C 1-C 4烷基、C 3-C 4烯基、C 3-C 4炔基、C 6-C 10芳基和五元至十元杂芳基；其中所述烷基、烯基、炔基、芳基和杂芳基各自任选地被一个或多个R B取代；其中所述五元至十元杂芳基含有1-3个各自独立地选自O、N和S的杂原子。在一更优选的实施方案中，R 1为H或C 1-C 4烷基；优选H或C 1-C 3烷基；进一步优选C 1-C 2烷基；其中所述烷基任选地被一个或多个R B取代。更优选地，R 1为H或C 1-C 2烷基；其中所述烷基任选地被一个或多个卤素取代。在进一步优选的实施方案中，R 1为H、CH 3、CF 3或CH 2CF 3；特别优选为H或CH 3。
在另一实施方案中，Y和R 1不存在，即N-Y结构实际为N。
在一实施方案中，Z为O或S，并且R 2不存在。
在一实施方案中，Z为N，并且R 2选自H、羟基、巯基、氨基、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R C取代。在另一实施方案中，Z为N，并且R 2选自H、羟基、巯基、氨基、C 1-C 4烷基、C 2-C 4烯基和 C 2-C 4炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R C取代。在一优选的实施方案中，Z为N，并且R 2选自H、羟基、巯基、C 1-C 4烷基、C 3-C 4烯基和C 3-C 4炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R C取代。在一更优选的实施方案中，R 2为H、羟基、巯基或C 1-C 4烷基；优选H、羟基、巯基或C 1-C 3烷基；其中所述烷基任选地被一个或多个R C取代。更优选地，R 2为H、羟基或甲基；其中所述甲基任选地被一个或多个卤素取代。在进一步优选的实施方案中，R 2为H、羟基或甲基；特别优选为H或羟基。
在一实施方案中，Z为C或CH，并且R 2选自H、羟基、巯基、氨基、卤素、硝基、氰基、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中烷基、烯基和炔基各自任选地被一个或多个R C取代。在又一实施方案中，Z为C或CH，并且R 2选自H、羟基、巯基、卤素、C 1-C 4烷基、C 2-C 4烯基和C 2-C 4炔基；其中烷基、烯基和炔基各自任选地被一个或多个R C取代。在另一实施方案中，Z为CH，并且R 2选自H、羟基、巯基、卤素、C 1-C 4烷基、C 2-C 4烯基和C 2-C 4炔基；其中烷基、烯基和炔基各自任选地被一个或多个R C取代。在一优选的实施方案中，Z为CH，并且R 2为H、羟基、巯基、卤素或C 1-C 4烷基；优选H、羟基、巯基、卤素或C 1-C 3烷基；其中所述烷基任选地被一个或多个R C取代。更优选地，Z为CH，并且R 2为H、羟基、卤素或甲基；其中所述甲基任选地被一个或多个卤素取代。在进一步优选的实施方案中，Z为CH，并且R 2为H、F、羟基或甲基，特别优选为H或羟基。
在一实施方案中，L 1为-(CH 2) n-；其中n为1、2、3、4、5、6、7或8；优选为1、2、3、4或5，更优选为1、2或3；特别优选为1。
在一实施方案中，A环、L 2和R 3中的至少一个存在于通式(I)中。当存在时，A环、L 2和R 3中至少含有一个N原子。
在一实施方案中，A环不存在，L 1和L 2直接连接在一起。在另一实施方案中，A环选自苯基、吡啶、呋喃、噻吩和吡咯；并且各自任选地被一个或多个R D取代。在另一实施方案中，A环选自环己烷、环戊烷、环丁烷和环丙烷；并且各自任选地被一个或多个R D取代。在又一实施方案中，A环选自以下基团：双环[2.2.1]庚烷，以1-碳原子和4-碳原子与分子其他部分相连；双环[1.1.1]戊烷，以1-碳原子和3-碳原子与分子其他部分相连；7-氧双环[2.2.1]庚烷，以1-碳原子和4-碳原子与分子其他部分相连；其中所述双环[2.2.1]庚烷、双环[1.1.1]戊烷和7-氧双环[2.2.1]庚烷；并且各自任选地被一个或多个R D取代。在一优选的实施方案中，A环选自苯基和吡啶；并且各自任选地被一个或多个R D取代；其中R D优选为卤素，特别优选为F。在进一步优选的实施方案中，A环为苯基，并且任 选地被一个或多个R D取代；其中R D优选为卤素，特别优选为F。
在一实施方案中，L 2选自-(CH 2) n-；其中n为1、2、3、4或5、6、7或8；优选为1、2、3、4或5，更优选为1、2或3；特别优选为1。
在一实施方案中，R 3为H。
在又一实施方案中，R 3为-WR 6R 7，其中W为CH，即R 3为-CH(R 6)R 7，
其中，R 6和R 7各自独立地选自H、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R E取代；或
R 6和R 7连同与其相连的C原子一起形成三元至十元杂环；其中所述杂环含有1-3个独立地选自O、S和N的杂原子，并且任选地被一个或多个R E取代；
R 6和R 7连同与其相连的C原子一起形成的三元至十元杂环可任选地与A环稠和。
在另一实施方案中，R 3为-WR 6R 7，其中W为N，即R 3为-NR 6R 7，
其中，R 6和R 7各自独立地选自H、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R E取代；或
R 6和R 7连同与其相连的N原子一起形成三元至十元杂环；其中所述杂环含有0-2个独立地选自O、S和N的额外的杂原子，并且任选地被一个或多个R E取代；
R 6和R 7连同与其相连的N原子一起形成的三元至十元杂环可任选地与A环稠和。
在一优选的实施方案中，R 3选自-N(C 1-C 4烷基)(C 1-C 4烷基)、吡咯烷、哌啶、吗啉和哌嗪；其中所述烷基、吡咯烷、哌啶、吗啉和哌嗪各自任选地被一个或多个R E取代。在又一优选的实施方案中，R 3选自-N(CH 3) 2、吡咯烷-1-基、哌啶-1-基、吗啉-1-基和4-C 1-C 3烷基-哌嗪-1-基；其中所述CH 3、吡咯烷-1-基、哌啶-1-基、吗啉-1-基和哌嗪-1-基各自任选地被一个或多个R E取代。在进一步优选的实施方案中，R 3为吡咯烷-1-基或哌啶-1-基；其中所述吡咯烷-1-基和哌啶-1-基各自任选地被一个或多个R E取代。
在一实施方案中，L 2和A环均不存在，R 3直接与L 1连接。
在一实施方案中，R 4为C 1-C 4烷基，其中所述烷基任选地被一个或多个R F取代。在一优选的实施方案中，R 4为C 1-C 3烷基，特别是C 3烷基；其中所述烷基任选地被一个或多个R F取代。在另一优选的实施方案中，R 4为-CH 2-、-CH(CH 3)-、-CH(C 2H 5)-、-CH(C 3H 7-n)-、-CH(CH 2OR a)-、-CH(CH 2SR a)-、-C(CH 2OR a)(R b)-、-C(CH 2OR a)(OR b)-、-CH(C(＝O)OR a)-、-CH(S(＝O)R a)-、-CH(S(＝O) 2R a)-、-CH(S(＝O) 2OR a)-、-CH(OC(＝O)R a)-、-CH(OS(＝O) 2R a)-、-C(C(＝O)OR a)(R b)-、-C(S(＝O)R a)(R b)-、-C(S(＝O) 2R a)(R b)-、-C(S(＝O) 2OR a)(R b)-、-C(OC(＝O)R a)(R b)-、-C(OS(＝O) 2R a)(R b)-、-C(C(＝O)OR a)(OR b)-、-C(S(＝O)R a)(OR b)-、-C(S(＝O) 2R a)(OR b)-、-C(S(＝O) 2OR a)(OR b)-、-CH(CH 2CH 2OR a)-、-CH(CH 2CH 2SR a)-、 -C(CH 2CH 2OR a)(R b)-、-C(CH 2CH 2OR a)(OR b)-、-CH(CH 2C(＝O)OR a)-、-CH(CH 2S(＝O)R a)-、-CH(CH 2S(＝O) 2R a)-、-CH(CH 2S(＝O) 2OR a)-、-CH(CH 2OC(＝O)R a)-、-CH(CH 2OS(＝O) 2R a)-、-C(CH 2C(＝O)OR a)(R b)-、-C(CH 2S(＝O)R a)(R b)-、-C(CH 2S(＝O) 2R a)(R b)-、-C(CH 2S(＝O) 2OR a)(R b)-、-C(CH 2OC(＝O)R a)(R b)-、-C(CH 2OS(＝O) 2R a)(R b)-、-C(CH 2C(＝O)OR a)(OR b)-、-C(CH 2S(＝O)R a)(OR b)-、-C(CH 2S(＝O) 2R a)(OR b)-、-C(CH 2S(＝O) 2OR a)(OR b)-、-C(CH 2OC(＝O)R a)(OR b)-、-C(CH 2OS(＝O) 2R a)(OR b)-、-CH(CH 2CH 2S(＝O)R a)-、-CH(CH 2CH 2S(＝O) 2R a)-、-CH(CH 2CH 2S(＝O) 2OR a)-、-CH(CH 2CH 2OC(＝O)R a)-、-CH(CH 2CH 2OS(＝O) 2R a)-、-C(CH 2CH 2S(＝O)R a)(R b)-、-C(CH 2CH 2S(＝O) 2R a)(R b)-、-C(CH 2CH 2S(＝O) 2OR a)(R b)-、-C(CH 2CH 2OC(＝O)R a)(R b)-、-C(CH 2CH 2OS(＝O) 2R a)(R b)-、-C(CH 2CH 2S(＝O)R a)(OR b)-、-C(CH 2CH 2S(＝O) 2R a)(OR b)-、-C(CH 2CH 2S(＝O) 2OR a)(OR b)-、-C(CH 2CH 2OC(＝O)R a)(OR b)-、-C(CH 2CH 2OS(＝O) 2R a)(OR b)-、-CH(CH 2NR aR b)-、-C(CH 2NR aR b)(R c)-、-C(CH 2NR aR b)(OR c)-、-CH(CH 2CH 2NR aR b)-、-C(CH 2CH 2NR aR b)(R c)-、-C(CH 2CH 2NR aR b)(OR c)-、-CH(CH 2C(＝O)NR aR b)-、-CH(CH 2S(＝O) 2NR aR b)-、-C(CH 2C(＝O)NR aR b)(R c)-、-C(CH 2S(＝O) 2NR aR b)(R c)-、-C(CH 2C(＝O)NR aR b)(OR c)-、-C(CH 2S(＝O) 2NR aR b)(OR c)-、-CH(CH 2N(R a)C(＝O)R b)-、-CH(CH 2N(R a)S(＝O) 2R b)-、-CH(CH 2CH 2S(＝O) 2NR aR b)-、-CH(CH 2CH 2N(R a)C(＝O)R b)-、-CH(CH 2CH 2N(R a)S(＝O) 2R b)-、-CH(CH 2N(R a)C(＝O)R b)(R c)-、-CH(CH 2N(R a)S(＝O) 2R b)(R c)-、-CH(CH 2CH 2S(＝O) 2NR aR b)(R c)-、-CH(CH 2CH 2N(R a)C(＝O)R b)(R c)-、-CH(CH 2CH 2N(R a)S(＝O) 2R b)(R c)-、-CH(CH 2N(R a)C(＝O)R b)(OR c)-、-CH(CH 2N(R a)S(＝O) 2R b)(OR c)-、-CH(CH 2CH 2S(＝O) 2NR aR b)(OR c)-、-CH(CH 2CH 2N(R a)C(＝O)R b)(OR c)-或-CH(CH 2CH 2N(R a)S(＝O) 2R b)(OR c)-；更优选-CH(C 3H 7-n)-、-CH(CH 2OR a)-、-CH(CH 2SR a)-、-CH(CH 2CH 2OR a)-、-CH(CH 2CH 2SR a)-、-CH(CH 2C(＝O)OR a)-、-CH(CH 2S(＝O) 2R a)-、-CH(CH 2S(＝O) 2OR a)-、-CH(CH 2OC(＝O)R a)-、-CH(CH 2OS(＝O) 2R a)-、-CH(CH 2CH 2OS(＝O) 2R a)-、-CH(CH 2CH 2OC(＝O)R a)-、-CH(CH 2CH 2N(R a)S(＝O) 2R b)-、-CH(CH 2NR aR b)-、-CH(CH 2CH 2NR aR b)-、-CH(CH 2CH 2N(R a)C(＝O)R b)-、-CH(CH 2C(＝O)NR aR b)-或-CH(CH 2S(＝O) 2NR aR b)-；进一步优选-CH(C 3H 7-n)-、-CH(CH 2CH 2OR a)-、-CH(CH 2CH 2SR a)-、-CH(CH 2C(＝O)OR a)-、-CH(CH 2S(＝O) 2R a)-、-CH(CH 2S(＝O) 2OR a)-、-CH(CH 2OC(＝O)R a)-、-CH(CH 2OS(＝O) 2R a)-、-CH(CH 2CH 2OS(＝O) 2R a)-、-CH(CH 2CH 2OC(＝O)R a)-、-CH(CH 2CH 2N(R a)S(＝O) 2R b)-、-CH(CH 2CH 2NR aR b)-、-CH(CH 2CH 2N(R a)C(＝O)R b)-、-CH(CH 2C(＝O)NR aR b)-或-CH(CH 2S(＝O) 2NR aR b)-；特别优选-CH(CH 2CH 2OR a)-、-CH(CH 2CH 2OS(＝O) 2R a)-、 -CH(CH 2CH 2OC(＝O)R a)-、-CH(CH 2CH 2N(R a)S(＝O) 2R b)-、-CH(CH 2C(＝O)OR a)-、-CH(CH 2S(＝O) 2OR a)-、-CH(CH 2CH 2NR aR b)-、-CH(CH 2CH 2N(R a)C(＝O)R b)-、-CH(CH 2C(＝O)NR aR b)-或-CH(CH 2S(＝O) 2NR aR b)-。
在一实施方案中，B环不存在，R 4和R 5直接连接在一起。在另一实施方案中，B环选自苯基、吡啶、呋喃、噻吩、吡咯、噻唑、噁唑和吡喃；并且各自任选地被一个或多个R G取代。在又一实施方案中，B环选自吡咯烷、哌啶、四氢呋喃、二氢吡喃、四氢吡喃和环氧丙烷；并且各自任选地被一个或多个R G取代。在另一实施方案中，B环选自环己烷、环戊烷、环丁烷和环丙烷；并且各自任选地被一个或多个R G取代。在一优选的实施方案中，B环为苯基或吡啶；并且各自任选地被一个或多个各自独立地选自卤素、氰基、硝基、-R a、-OR a、-SR a和-NR aR b的基团取代。
在一实施方案中，R 5为H。在另一实施方案中，R 5为C 3-C 6烷基，并且任选地被一个或多个-OR 8、-SR 8或-NR 8R 8’取代；其中
R 8和R 8’各自独立地选自H和C 1-C 4烷基；优选C 1-C 2烷基；其中所述烷基任选地被一个或多个R H取代；
或R 8和R 8’相连接，使-NR 8R 8’形成四元至八元杂环；其中所述杂环含有0-1个独立地选自O、S和N的额外的杂原子，并且任选地被一个或多个R H取代。在一优选的实施方案中，-NR 8R 8’形成四元至六元杂环；其中所述杂环含有0-1个独立地选自O、S和N的额外的杂原子，并且任选地被一个或多个R H取代。
在一实施方案中，B环不存在，R 5直接与R 4连接。
在本发明的优选实施方案中，式(I)的化合物的实施方案可以包括式(I-1)至式(I-7)的化合物。
在本发明的一实施方案中，本发明提供式(I-1)的化合物或其药学上可接受的盐、立体异构体、溶剂化物、多晶型体、互变异构体、同位素化合物、代谢产物或前药：
Figure PCTCN2019111625-appb-000006
其中R 1、R 2、R 3、R 4、R 5、L 1、L 2、X、Q、A和B如式(I)中所定义。
在一优选的实施方案中，X和Q各自独立地选自O和S。
在一优选的实施方案中，R 1为H或C 1-C 4烷基；优选H或C 1-C 3烷基；进一步优选C 1-C 2烷基；其中所述烷基任选地被一个或多个R B取代。更优选地，R 1为H或C 1-C 2烷 基；其中所述烷基任选地被一个或多个卤素取代。在进一步优选的实施方案中，R 1为H、CH 3、CF 3或CH 2CF 3；特别优选为H或CH 3。
在一优选的实施方案中，R 2选自H、羟基、巯基、氨基、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R C取代。在另一优选的实施方案中，R 2选自H、羟基、巯基、氨基、C 1-C 4烷基、C 2-C 4烯基和C 2-C 4炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R C取代。在又一优选的实施方案中，R 2选自H、羟基、巯基、C 1-C 4烷基、C 3-C 4烯基和C 3-C 4炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R C取代。在一更优选的实施方案中，R 2为H、羟基、巯基或C 1-C 4烷基；优选H、羟基、巯基或C 1-C 3烷基；其中所述烷基任选地被一个或多个R C取代。更优选地，R 2为H、羟基或甲基；其中所述甲基任选地被一个或多个卤素取代。在进一步优选的实施方案中，R 2为H、羟基或甲基；特别优选为H或羟基。
在一优选的实施方案中，L 1为-(CH 2) n-；其中n为1、2或3；特别优选为1。
在一优选的实施方案中，A环、L 2和R 3中的至少一个存在于通式(I)中。当存在时，A环、L 2和R 3中至少含有一个N原子。
在一优选的实施方案中，A环选自苯基、吡啶、呋喃、噻吩和吡咯；并且各自任选地被一个或多个R D取代。在一更优选的实施方案中，A环选自苯基和吡啶；并且各自任选地被一个或多个R D取代；其中R D优选为卤素，特别优选为F。在进一步优选的实施方案中，A环为苯基，并且任选地被一个或多个R D取代；其中R D优选为卤素，特别优选为F。
在一优选的实施方案中，L 2选自-(CH 2) n-；其中n为1、2或3；特别优选为1。
在一优选的实施方案中，R 3为五元至十元杂芳基或-WR 6R 7，其中W为N或CH，其中
R 6和R 7各自独立地选自H、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R E取代；或
R 6和R 7连同与其相连的N或C原子一起形成三元至十元杂环；所述杂环含有1-3个独立地选自O、S和N的杂原子，并且任选地被一个或多个R E取代。
在一更优选的实施方案中，R 3为-NR 6R 7，
其中，R 6和R 7各自独立地选自H、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R E取代；或
R 6和R 7连同与其相连的N原子一起形成三元至十元杂环；其中所述杂环含有0-2个独立地选自O、S和N的额外的杂原子，并且任选地被一个或多个R E取代。
在一优选的实施方案中，R 3选自-N(C 1-C 4烷基)(C 1-C 4烷基)、吡咯烷、哌啶、吗啉和哌嗪，其中所述烷基、吡咯烷、哌啶、吗啉和哌嗪各自任选地被一个或多个R E取代。在又一优选的实施方案中，R 3选自-N(CH 3) 2、吡咯烷-1-基、哌啶-1-基、吗啉-1-基和4-C 1-C 3烷基-哌嗪-1-基；其中所述CH 3、吡咯烷-1-基、哌啶-1-基、吗啉-1-基和哌嗪-1-基各自任选地被一个或多个R E取代。在进一步优选的实施方案中，R 3为吡咯烷-1-基或哌啶-1-基；其中所述吡咯烷-1-基和哌啶-1-基各自任选地被一个或多个R E取代。
在一优选的实施方案中，R 4为C 1-C 4烷基，特别是C 3烷基；其中所述烷基任选地被一个或多个R F取代。在另一优选的实施方案中，R 4为-CH(C 3H 7-n)-、-CH(CH 2OR a)-、-CH(CH 2SR a)-、-CH(CH 2CH 2OR a)-、-CH(CH 2CH 2SR a)-、-CH(CH 2C(＝O)OR a)-、-CH(CH 2S(＝O) 2R a)-、-CH(CH 2S(＝O) 2OR a)-、-CH(CH 2OC(＝O)R a)-、-CH(CH 2OS(＝O) 2R a)-、-CH(CH 2CH 2OS(＝O) 2R a)-、-CH(CH 2CH 2OC(＝O)R a)-、-CH(CH 2CH 2N(R a)S(＝O) 2R b)-、-CH(CH 2NR aR b)-、-CH(CH 2CH 2NR aR b)-、-CH(CH 2CH 2N(R a)C(＝O)R b)-、-CH(CH 2C(＝O)NR aR b)-或-CH(CH 2S(＝O) 2NR aR b)-；特别优选-CH(CH 2CH 2OR a)-、-CH(CH 2CH 2OS(＝O) 2R a)-、-CH(CH 2CH 2OC(＝O)R a)-、-CH(CH 2CH 2N(R a)S(＝O) 2R b)-、-CH(CH 2C(＝O)OR a)-、-CH(CH 2S(＝O) 2OR a)-、-CH(CH 2CH 2NR aR b)-、-CH(CH 2CH 2N(R a)C(＝O)R b)-、-CH(CH 2C(＝O)NR aR b)-或-CH(CH 2S(＝O) 2NR aR b)-。
在一优选的实施方案中，B环不存在，R 4和R 5直接连接在一起。
在一优选的实施方案中，R 5为H。
在本发明的另一实施方案中，本发明提供式(I-2)的化合物或其药学上可接受的盐、立体异构体、溶剂化物、多晶型体、互变异构体、同位素化合物、代谢产物或前药：
Figure PCTCN2019111625-appb-000007
其中R 1、R 2、R 3、R 4、R 5、L 1、L 2、X、A和B如式(I)中所定义。
在一优选的实施方案中，X选自O和S。
在一优选的实施方案中，R 1为H或C 1-C 4烷基；优选H或C 1-C 3烷基；进一步优选C 1-C 2烷基；其中所述烷基任选地被一个或多个R B取代。更优选地，R 1为H或C 1-C 2烷基；其中所述烷基任选地被一个或多个卤素取代。在进一步优选的实施方案中，R 1为H、CH 3、CF 3或CH 2CF 3；特别优选为H或CH 3。
在一优选的实施方案中，R 2选自H、羟基、巯基、氨基、C 1-C 8烷基、C 2-C 8烯基和 C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R C取代。在另一优选的实施方案中，R 2选自H、羟基、巯基、氨基、C 1-C 4烷基、C 2-C 4烯基和C 2-C 4炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R C取代。在又一优选的实施方案中，R 2选自H、羟基、巯基、C 1-C 4烷基、C 3-C 4烯基和C 3-C 4炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R C取代。在一更优选的实施方案中，R 2为H、羟基、巯基或C 1-C 4烷基；优选H、羟基、巯基或C 1-C 3烷基；其中所述烷基任选地被一个或多个R C取代。更优选地，R 2为H、羟基或甲基；其中所述甲基任选地被一个或多个卤素取代。在进一步优选的实施方案中，R 2为H、羟基或甲基；特别优选为H或羟基。
在一优选的实施方案中，L 1为-(CH 2) n-；其中n为1、2或3；特别优选为1。
在一优选的实施方案中，A环、L 2和R 3中的至少一个存在于通式(I)中。当存在时，A环、L 2和R 3中至少含有一个N原子。
在一优选的实施方案中，A环选自苯基、吡啶、呋喃、噻吩和吡咯；并且各自任选地被一个或多个R D取代。在一更优选的实施方案中，A环选自苯基和吡啶；并且各自任选地被一个或多个R D取代；其中R D优选为卤素，特别优选为F。在进一步优选的实施方案中，A环为苯基，并且任选地被一个或多个R D取代；其中R D优选为卤素，特别优选为F。
在一优选的实施方案中，L 2选自-(CH 2) n-；其中n为1、2或3；特别优选为1。
在一优选的实施方案中，R 3为五元至十元杂芳基或-WR 6R 7，其中W为N或CH，其中
R 6和R 7各自独立地选自H、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R E取代；或
R 6和R 7连同与其相连的N或C原子一起形成三元至十元杂环；所述杂环含有1-3个独立地选自O、S和N的杂原子，并且任选地被一个或多个R E取代。
在一更优选的实施方案中，R 3为-NR 6R 7，
其中，R 6和R 7各自独立地选自H、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R E取代；或
R 6和R 7连同与其相连的N原子一起形成三元至十元杂环；其中所述杂环含有0-2个独立地选自O、S和N的额外的杂原子，并且任选地被一个或多个R E取代。
在一优选的实施方案中，R 3选自-N(C 1-C 4烷基)(C 1-C 4烷基)、吡咯烷、哌啶、吗啉和哌嗪，其中所述烷基、吡咯烷、哌啶、吗啉和哌嗪各自任选地被一个或多个R E取代。在又一优选的实施方案中，R 3选自-N(CH 3) 2、吡咯烷-1-基、哌啶-1-基、吗啉-1-基和4-C 1-C 3 烷基-哌嗪-1-基；其中所述CH 3、吡咯烷-1-基、哌啶-1-基、吗啉-1-基和哌嗪-1-基各自任选地被一个或多个R E取代。在进一步优选的实施方案中，R 3为吡咯烷-1-基或哌啶-1-基；其中所述吡咯烷-1-基和哌啶-1-基各自任选地被一个或多个R E取代。
在一优选的实施方案中，R 4为C 1-C 4烷基，特别是C 3烷基；其中所述烷基任选地被一个或多个R F取代。在另一优选的实施方案中，R 4为-CH(C 3H 7-n)-、-CH(CH 2OR a)-、-CH(CH 2SR a)-、-CH(CH 2CH 2OR a)-、-CH(CH 2CH 2SR a)-、-CH(CH 2C(＝O)OR a)-、-CH(CH 2S(＝O) 2R a)-、-CH(CH 2S(＝O) 2OR a)-、-CH(CH 2OC(＝O)R a)-、-CH(CH 2OS(＝O) 2R a)-、-CH(CH 2CH 2OS(＝O) 2R a)-、-CH(CH 2CH 2OC(＝O)R a)-、-CH(CH 2CH 2N(R a)S(＝O) 2R b)-、-CH(CH 2NR aR b)-、-CH(CH 2CH 2NR aR b)-、-CH(CH 2CH 2N(R a)C(＝O)R b)-、-CH(CH 2C(＝O)NR aR b)-或-CH(CH 2S(＝O) 2NR aR b)-；特别优选-CH(CH 2CH 2OR a)-、-CH(CH 2CH 2OS(＝O) 2R a)-、-CH(CH 2CH 2OC(＝O)R a)-、-CH(CH 2CH 2N(R a)S(＝O) 2R b)-、-CH(CH 2C(＝O)OR a)-、-CH(CH 2S(＝O) 2OR a)-、-CH(CH 2CH 2NR aR b)-、-CH(CH 2CH 2N(R a)C(＝O)R b)-、-CH(CH 2C(＝O)NR aR b)-或-CH(CH 2S(＝O) 2NR aR b)-。
在一优选的实施方案中，B环不存在，R 4和R 5直接连接在一起。
在一优选的实施方案中，R 5为H。
在本发明的又一实施方案中，本发明提供式(I-3)的化合物或其药学上可接受的盐、立体异构体、溶剂化物、多晶型体、互变异构体、同位素化合物、代谢产物或前药：
Figure PCTCN2019111625-appb-000008
其中R 1、R 2、R 3、R F、R 5、L 1、L 2、X、A和B如式(I)中所定义。
在一优选的实施方案中，X选自O和S。
在一优选的实施方案中，R 1为H或C 1-C 4烷基；优选H或C 1-C 3烷基；进一步优选C 1-C 2烷基；其中所述烷基任选地被一个或多个R B取代。更优选地，R 1为H或C 1-C 2烷基；其中所述烷基任选地被一个或多个卤素取代。在进一步优选的实施方案中，R 1为H、CH 3、CF 3或CH 2CF 3；特别优选为H或CH 3。
在一优选的实施方案中，R 2选自H、羟基、巯基、氨基、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R C取代。在另一优选的实施方案中，R 2选自H、羟基、巯基、氨基、C 1-C 4烷基、C 2-C 4烯基和C 2-C 4炔基； 其中所述烷基、烯基和炔基各自任选地被一个或多个R C取代。在又一优选的实施方案中，R 2选自H、羟基、巯基、C 1-C 4烷基、C 3-C 4烯基和C 3-C 4炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R C取代。在一更优选的实施方案中，R 2为H、羟基、巯基或C 1-C 4烷基；优选H、羟基、巯基或C 1-C 3烷基；其中所述烷基任选地被一个或多个R C取代。更优选地，R 2为H、羟基或甲基；其中所述甲基任选地被一个或多个卤素取代。在进一步优选的实施方案中，R 2为H、羟基或甲基；特别优选为H或羟基。
在一优选的实施方案中，L 1为-(CH 2) n-；其中n为1、2或3；特别优选为1。
在一优选的实施方案中，A环、L 2和R 3中的至少一个存在于通式(I)中。当存在时，A环、L 2和R 3中至少含有一个N原子。
在一优选的实施方案中，A环选自苯基、吡啶、呋喃、噻吩和吡咯；并且各自任选地被一个或多个R D取代。在一更优选的实施方案中，A环选自苯基和吡啶；并且各自任选地被一个或多个R D取代；其中R D优选为卤素，特别优选为F。在进一步优选的实施方案中，A环为苯基，并且任选地被一个或多个R D取代；其中R D优选为卤素，特别优选为F。
在一优选的实施方案中，L 2选自-(CH 2) n-；其中n为1、2或3；特别优选为1。
在一优选的实施方案中，R 3为五元至十元杂芳基或-WR 6R 7，其中W为N或CH，其中
R 6和R 7各自独立地选自H、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R E取代；或
R 6和R 7连同与其相连的N或C原子一起形成三元至十元杂环；所述杂环含有1-3个独立地选自O、S和N的杂原子，并且任选地被一个或多个R E取代。
在一更优选的实施方案中，R 3为-NR 6R 7，
其中，R 6和R 7各自独立地选自H、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R E取代；或
R 6和R 7连同与其相连的N原子一起形成三元至十元杂环；其中所述杂环含有0-2个独立地选自O、S和N的额外的杂原子，并且任选地被一个或多个R E取代。
在一优选的实施方案中，R 3选自-N(C 1-C 4烷基)(C 1-C 4烷基)、吡咯烷、哌啶、吗啉、哌嗪，其中所述烷基、吡咯烷、哌啶、吗啉和哌嗪各自任选地被一个或多个R E取代。在又一优选的实施方案中，R 3选自-N(CH 3) 2、吡咯烷-1-基、哌啶-1-基、吗啉-1-基和4-C 1-C 3烷基-哌嗪-1-基；其中所述CH 3、吡咯烷-1-基、哌啶-1-基、吗啉-1-基和哌嗪-1-基各自任选地被一个或多个R E取代。在进一步优选的实施方案中，R 3为吡咯烷-1-基或哌啶-1-基； 其中所述吡咯烷-1-基和哌啶-1-基各自任选地被一个或多个R E取代。
在一优选的实施方案中，R F为H、-OR a、-SR a、-C(＝O)OR a、-S(＝O) 2R a、-S(＝O) 2OR a、-OC(＝O)R a、-OS(＝O) 2R a、-N(R a)S(＝O) 2R b、-NR aR b、-N(R a)C(＝O)R b、-C(＝O)NR aR b或-S(＝O) 2NR aR b；特别优选-OR a、-OS(＝O) 2R a、-OC(＝O)R a、-N(R a)S(＝O) 2R b、-C(＝O)OR a、-S(＝O) 2OR a、-NR aR b、-N(R a)C(＝O)R b、-C(＝O)NR aR b或-S(＝O) 2NR aR b。
在一优选的实施方案中，B环不存在，R 4和R 5直接连接在一起。
在一优选的实施方案中，R 5为H。
在本发明的再一实施方案中，本发明提供式(I-4)的化合物或其药学上可接受的盐、立体异构体、溶剂化物、多晶型体、互变异构体、同位素化合物、代谢产物或前药：
Figure PCTCN2019111625-appb-000009
其中R 2、R 3、R 4、R 5、L 1、L 2、X、Q、A和B如式(I)中所定义。
在一优选的实施方案中，X和Q各自独立地选自O和S。
在一优选的实施方案中，R 2选自H、羟基、巯基、氨基、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R C取代。在另一优选的实施方案中，R 2选自羟基、巯基、氨基、C 1-C 4烷基、C 2-C 4烯基和C 2-C 4炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R C取代。在又一优选的实施方案中，R 2选自羟基、巯基、C 1-C 4烷基、C 3-C 4烯基和C 3-C 4炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R C取代。在一更优选的实施方案中，R 2为羟基、巯基或C 1-C 4烷基；优选羟基、巯基或C 1-C 3烷基；其中所述烷基任选地被一个或多个R C取代。更优选地，R 2为羟基或甲基；其中所述甲基任选地被一个或多个卤素取代。在进一步优选的实施方案中，R 2为羟基或甲基；特别优选为羟基。
在一优选的实施方案中，L 1为-(CH 2) n-；其中n为1、2或3；特别优选为1。
在一优选的实施方案中，A环、L 2和R 3中的至少一个存在于通式(I)中。当存在时，A环、L 2和R 3中至少含有一个N原子。
在一优选的实施方案中，A环选自苯基、吡啶、呋喃、噻吩和吡咯；并且各自任选地被一个或多个R D取代。在一更优选的实施方案中，A环选自苯基和吡啶；并且各自任选地被一个或多个R D取代；其中R D优选为卤素，特别优选为F。在进一步优选的实施方案中，A环为苯基，并且任选地被一个或多个R D取代；其中R D优选为卤素，特别优 选为F。
在一优选的实施方案中，L 2选自-(CH 2) n-；其中n为1、2或3；特别优选为1。
在一优选的实施方案中，R 3为五元至十元杂芳基或-WR 6R 7，其中W为N或CH，其中
R 6和R 7各自独立地选自H、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R E取代；或
R 6和R 7连同与其相连的N或C原子一起形成三元至十元杂环；所述杂环含有1-3个独立地选自O、S和N的杂原子，并且任选地被一个或多个R E取代。
在一更优选的实施方案中，R 3为-NR 6R 7，
其中，R 6和R 7各自独立地选自H、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R E取代；或
R 6和R 7连同与其相连的N原子一起形成三元至十元杂环；其中所述杂环含有0-2个独立地选自O、S和N的额外的杂原子，并且任选地被一个或多个R E取代。
在一优选的实施方案中，R 3选自-N(C 1-C 4烷基)(C 1-C 4烷基)、吡咯烷、哌啶、吗啉、哌嗪，其中所述烷基、吡咯烷、哌啶、吗啉和哌嗪各自任选地被一个或多个R E取代。在又一优选的实施方案中，R 3选自-N(CH 3) 2、吡咯烷-1-基、哌啶-1-基、吗啉-1-基和4-C 1-C 3烷基-哌嗪-1-基；其中所述CH 3、吡咯烷-1-基、哌啶-1-基、吗啉-1-基和哌嗪-1-基各自任选地被一个或多个R E取代。在进一步优选的实施方案中，R 3为吡咯烷-1-基或哌啶-1-基；其中所述吡咯烷-1-基和哌啶-1-基各自任选地被一个或多个R E取代。
在一优选的实施方案中，R 4为C 1-C 4烷基，特别是C 3烷基；其中所述烷基任选地被一个或多个R F取代。在另一优选的实施方案中，R 4为-CH(C 3H 7-n)-、-CH(CH 2OR a)-、-CH(CH 2SR a)-、-CH(CH 2CH 2OR a)-、-CH(CH 2CH 2SR a)-、-CH(CH 2C(＝O)OR a)-、-CH(CH 2S(＝O) 2R a)-、-CH(CH 2S(＝O) 2OR a)-、-CH(CH 2OC(＝O)R a)-、-CH(CH 2OS(＝O) 2R a)-、-CH(CH 2CH 2OS(＝O) 2R a)-、-CH(CH 2CH 2OC(＝O)R a)-、-CH(CH 2CH 2N(R a)S(＝O) 2R b)-、-CH(CH 2NR aR b)-、-CH(CH 2CH 2NR aR b)-、-CH(CH 2CH 2N(R a)C(＝O)R b)-、-CH(CH 2C(＝O)NR aR b)-或-CH(CH 2S(＝O) 2NR aR b)-；特别优选-CH(CH 2CH 2OR a)-、-CH(CH 2CH 2OS(＝O) 2R a)-、-CH(CH 2CH 2OC(＝O)R a)-、-CH(CH 2CH 2N(R a)S(＝O) 2R b)-、-CH(CH 2C(＝O)OR a)-、-CH(CH 2S(＝O) 2OR a)-、-CH(CH 2CH 2NR aR b)-、-CH(CH 2CH 2N(R a)C(＝O)R b)-、-CH(CH 2C(＝O)NR aR b)-或-CH(CH 2S(＝O) 2NR aR b)-。
在一优选的实施方案中，B环不存在，R 4和R 5直接连接在一起。
在一优选的实施方案中，R 5为H。
在本发明的又一实施方案中，本发明提供式(I-5)的化合物或其药学上可接受的盐、立体异构体、溶剂化物、多晶型体、互变异构体、同位素化合物、代谢产物或前药：
Figure PCTCN2019111625-appb-000010
其中R 3、R 4、R 5、L 1、L 2、X、Q、A和B如式(I)中所定义。
在一优选的实施方案中，X和Q各自独立地选自O和S。
在一优选的实施方案中，L 1为-(CH 2) n-；其中n为1、2或3；特别优选为1。
在一优选的实施方案中，A环、L 2和R 3中的至少一个存在于通式(I)中。当存在时，A环、L 2和R 3中至少含有一个N原子。
在一优选的实施方案中，A环选自苯基、吡啶、呋喃、噻吩和吡咯；并且各自任选地被一个或多个R D取代。在一更优选的实施方案中，A环选自苯基和吡啶；并且各自任选地被一个或多个R D取代；其中R D优选为卤素，特别优选为F。在进一步优选的实施方案中，A环为苯基，并且任选地被一个或多个R D取代；其中R D优选为卤素，特别优选为F。
在一优选的实施方案中，L 2选自-(CH 2) n-；其中n为1、2或3；特别优选为1。
在一优选的实施方案中，R 3为-NR 6R 7，在一优选的实施方案中，R 3为五元至十元杂芳基或-WR 6R 7，其中W为N或CH，其中
R 6和R 7各自独立地选自H、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R E取代；或
R 6和R 7连同与其相连的N或C原子一起形成三元至十元杂环；所述杂环含有1-3个独立地选自O、S和N的杂原子，并且任选地被一个或多个R E取代。
在一更优选的实施方案中，R 3为-NR 6R 7，
其中，R 6和R 7各自独立地选自H、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R E取代；或
R 6和R 7连同与其相连的N原子一起形成三元至十元杂环；其中所述杂环含有0-2个独立地选自O、S和N的额外的杂原子，并且任选地被一个或多个R E取代。
在一优选的实施方案中，R 3选自-N(C 1-C 4烷基)(C 1-C 4烷基)、吡咯烷、哌啶、吗啉、哌嗪，其中所述烷基、吡咯烷、哌啶、吗啉和哌嗪各自任选地被一个或多个R E取代。在又一优选的实施方案中，R 3选自-N(CH 3) 2、吡咯烷-1-基、哌啶-1-基、吗啉-1-基和4-C 1-C 3 烷基-哌嗪-1-基；其中所述CH 3、吡咯烷-1-基、哌啶-1-基、吗啉-1-基和哌嗪-1-基各自任选地被一个或多个R E取代。在进一步优选的实施方案中，R 3为吡咯烷-1-基或哌啶-1-基；其中所述吡咯烷-1-基和哌啶-1-基各自任选地被一个或多个R E取代。
在一优选的实施方案中，R 4为C 1-C 4烷基，特别是C 3烷基；其中所述烷基任选地被一个或多个R F取代。在另一优选的实施方案中，R 4为-CH(C 3H 7-n)-、-CH(CH 2OR a)-、-CH(CH 2SR a)-、-CH(CH 2CH 2OR a)-、-CH(CH 2CH 2SR a)-、-CH(CH 2C(＝O)OR a)-、-CH(CH 2S(＝O) 2R a)-、-CH(CH 2S(＝O) 2OR a)-、-CH(CH 2OC(＝O)R a)-、-CH(CH 2OS(＝O) 2R a)-、-CH(CH 2CH 2OS(＝O) 2R a)-、-CH(CH 2CH 2OC(＝O)R a)-、-CH(CH 2CH 2N(R a)S(＝O) 2R b)-、-CH(CH 2NR aR b)-、-CH(CH 2CH 2NR aR b)-、-CH(CH 2CH 2N(R a)C(＝O)R b)-、-CH(CH 2C(＝O)NR aR b)-或-CH(CH 2S(＝O) 2NR aR b)-；特别优选-CH(CH 2CH 2OR a)-、-CH(CH 2CH 2OS(＝O) 2R a)-、-CH(CH 2CH 2OC(＝O)R a)-、-CH(CH 2CH 2N(R a)S(＝O) 2R b)-、-CH(CH 2C(＝O)OR a)-、-CH(CH 2S(＝O) 2OR a)-、-CH(CH 2CH 2NR aR b)-、-CH(CH 2CH 2N(R a)C(＝O)R b)-、-CH(CH 2C(＝O)NR aR b)-或-CH(CH 2S(＝O) 2NR aR b)-。
在一优选的实施方案中，B环不存在，R 4和R 5直接连接在一起。
在一优选的实施方案中，R 5为H。
在本发明的又一实施方案中，本发明提供式(I-6)的化合物或其药学上可接受的盐、立体异构体、溶剂化物、多晶型体、互变异构体、同位素化合物、代谢产物或前药：
Figure PCTCN2019111625-appb-000011
其中R 3、R 4、R 5、L 1、L 2、X、A和B如式(I)中所定义。
在一优选的实施方案中，X选自O和S。
在一优选的实施方案中，L 1为-(CH 2) n-；其中n为1、2或3；特别优选为1。
在一优选的实施方案中，A环、L 2和R 3中的至少一个存在于通式(I)中。当存在时，A环、L 2和R 3中至少含有一个N原子。
在一优选的实施方案中，A环选自苯基、吡啶、呋喃、噻吩和吡咯；并且各自任选地被一个或多个R D取代。在一更优选的实施方案中，A环选自苯基和吡啶；并且各自任选地被一个或多个R D取代；其中R D优选为卤素，特别优选为F。在进一步优选的实施方案中，A环为苯基，并且任选地被一个或多个R D取代；其中R D优选为卤素，特别优选为F。
在一优选的实施方案中，L 2选自-(CH 2) n-；其中n为1、2或3；特别优选为1。
在一优选的实施方案中，R 3为五元至十元杂芳基或-WR 6R 7，其中W为N或CH，其中
R 6和R 7各自独立地选自H、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R E取代；或
R 6和R 7连同与其相连的N或C原子一起形成三元至十元杂环；所述杂环含有1-3个独立地选自O、S和N的杂原子，并且任选地被一个或多个R E取代。
在一更优选的实施方案中，R 3为-NR 6R 7，
其中，R 6和R 7各自独立地选自H、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R E取代；或
R 6和R 7连同与其相连的N原子一起形成三元至十元杂环；其中所述杂环含有0-2个独立地选自O、S和N的额外的杂原子，并且任选地被一个或多个R E取代。
在一优选的实施方案中，R 3选自-N(C 1-C 4烷基)(C 1-C 4烷基)、吡咯烷、哌啶、吗啉、哌嗪，其中所述烷基、吡咯烷、哌啶、吗啉和哌嗪各自任选地被一个或多个R E取代。在又一优选的实施方案中，R 3选自-N(CH 3) 2、吡咯烷-1-基、哌啶-1-基、吗啉-1-基和4-C 1-C 3烷基-哌嗪-1-基；其中所述CH 3、吡咯烷-1-基、哌啶-1-基、吗啉-1-基和哌嗪-1-基各自任选地被一个或多个R E取代。在进一步优选的实施方案中，R 3为吡咯烷-1-基或哌啶-1-基；其中所述吡咯烷-1-基和哌啶-1-基各自任选地被一个或多个R E取代。
在一优选的实施方案中，R 4为C 1-C 4烷基，特别是C 3烷基；其中所述烷基任选地被一个或多个R F取代。在另一优选的实施方案中，R 4为-CH(C 3H 7-n)-、-CH(CH 2OR a)-、-CH(CH 2SR a)-、-CH(CH 2CH 2OR a)-、-CH(CH 2CH 2SR a)-、-CH(CH 2C(＝O)OR a)-、-CH(CH 2S(＝O) 2R a)-、-CH(CH 2S(＝O) 2OR a)-、-CH(CH 2OC(＝O)R a)-、-CH(CH 2OS(＝O) 2R a)-、-CH(CH 2CH 2OS(＝O) 2R a)-、-CH(CH 2CH 2OC(＝O)R a)-、-CH(CH 2CH 2N(R a)S(＝O) 2R b)-、-CH(CH 2NR aR b)-、-CH(CH 2CH 2NR aR b)-、-CH(CH 2CH 2N(R a)C(＝O)R b)-、-CH(CH 2C(＝O)NR aR b)-或-CH(CH 2S(＝O) 2NR aR b)-；特别优选-CH(CH 2CH 2OR a)-、-CH(CH 2CH 2OS(＝O) 2R a)-、-CH(CH 2CH 2OC(＝O)R a)-、-CH(CH 2CH 2N(R a)S(＝O) 2R b)-、-CH(CH 2C(＝O)OR a)-、-CH(CH 2S(＝O) 2OR a)-、-CH(CH 2CH 2NR aR b)-、-CH(CH 2CH 2N(R a)C(＝O)R b)-、-CH(CH 2C(＝O)NR aR b)-或-CH(CH 2S(＝O) 2NR aR b)-。
在一优选的实施方案中，B环不存在，R 4和R 5直接连接在一起。
在一优选的实施方案中，R 5为H。
在本发明的又一实施方案中，本发明提供式(I-7)的化合物或其药学上可接受的盐、 立体异构体、溶剂化物、多晶型体、互变异构体、同位素化合物、代谢产物或前药：
Figure PCTCN2019111625-appb-000012
其中R 3、R F、R 5、L 1、L 2、X、A和B如式(I)中所定义。
在一优选的实施方案中，X选自O和S。
在一优选的实施方案中，L 1为-(CH 2) n-；其中n为1、2或3；特别优选为1。
在一优选的实施方案中，A环、L 2和R 3中的至少一个存在于通式(I)中。当存在时，A环、L 2和R 3中至少含有一个N原子。
在一优选的实施方案中，A环选自苯基、吡啶、呋喃、噻吩和吡咯；并且各自任选地被一个或多个R D取代。在一更优选的实施方案中，A环选自苯基和吡啶；并且各自任选地被一个或多个R D取代；其中R D优选为卤素，特别优选为F。在进一步优选的实施方案中，A环为苯基，并且任选地被一个或多个R D取代；其中R D优选为卤素，特别优选为F。
在一优选的实施方案中，L 2选自-(CH 2) n-；其中n为1、2或3；特别优选为1。
在一优选的实施方案中，R 3为五元至十元杂芳基或-WR 6R 7，其中W为N或CH，其中
R 6和R 7各自独立地选自H、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R E取代；或
R 6和R 7连同与其相连的N或C原子一起形成三元至十元杂环；所述杂环含有1-3个独立地选自O、S和N的杂原子，并且任选地被一个或多个R E取代。
在一更优选的实施方案中，R 3为-NR 6R 7，
其中，R 6和R 7各自独立地选自H、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R E取代；或
R 6和R 7连同与其相连的N原子一起形成三元至十元杂环；其中所述杂环含有0-2个独立地选自O、S和N的额外的杂原子，并且任选地被一个或多个R E取代。
在一优选的实施方案中，R 3选自-N(C 1-C 4烷基)(C 1-C 4烷基)、吡咯烷、哌啶、吗啉、哌嗪，其中所述烷基、吡咯烷、哌啶、吗啉和哌嗪各自任选地被一个或多个R E取代。在又一优选的实施方案中，R 3选自-N(CH 3) 2、吡咯烷-1-基、哌啶-1-基、吗啉-1-基和4-C 1-C 3 烷基-哌嗪-1-基；其中所述CH 3、吡咯烷-1-基、哌啶-1-基、吗啉-1-基和哌嗪-1-基各自任选地被一个或多个R E取代。在进一步优选的实施方案中，R 3为吡咯烷-1-基或哌啶-1-基；其中所述吡咯烷-1-基和哌啶-1-基各自任选地被一个或多个R E取代。
在一优选的实施方案中，R F为H、-OR a、-SR a、-C(＝O)OR a、-S(＝O) 2R a、-S(＝O) 2OR a、-OC(＝O)R a、-OS(＝O) 2R a、-N(R a)S(＝O) 2R b、-NR aR b、-N(R a)C(＝O)R b、-C(＝O)NR aR b或-S(＝O) 2NR aR b；特别优选-OR a、-OS(＝O) 2R a、-OC(＝O)R a、-N(R a)S(＝O) 2R b、-C(＝O)OR a、-S(＝O) 2OR a、-NR aR b、-N(R a)C(＝O)R b、-C(＝O)NR aR b或-S(＝O) 2NR aR b。
在一优选的实施方案中，B环不存在，R 4和R 5直接连接在一起。
在一优选的实施方案中，R 5为H。
在某些实施方案中，本发明提供下述化合物或其药学上可接受的盐、立体异构体、溶剂化物、多晶型体、互变异构体、同位素化合物、代谢产物或前药：
Figure PCTCN2019111625-appb-000013
Figure PCTCN2019111625-appb-000014
应当理解，本文所提供化合物上的取代基和取代方式可由本领域普通技术人员进行选择，以提供化学稳定且可通过本领域已知技术以及本文所描述的那些技术合成的化合物。
药物组合物、制剂和试剂盒
本发明还提供一种药物组合物，其包含本发明的化合物或其药学上可接受的盐、立体异构体、溶剂化物、多晶型体、互变异构体、同位素化合物、代谢产物或前药，以及至少一种药学上可接受的载体。所述载体可以包括赋形剂、稀释剂或其混合物。
本发明的化合物可以以常规制剂形式口服或肠胃外给药至患者，所述常规制剂形式为，比如，胶囊、微囊、片剂、颗粒剂、散剂、锭剂、丸剂、栓剂、注射剂、混悬剂、糖浆、贴剂、乳膏剂、洗剂、软膏剂、凝胶、喷雾剂、溶液和乳剂。适合的制剂可以使用常规的有机或无机添加剂，通过通常采用的方法制备，所述有机或无机添加剂为，比如，赋形剂(例如，蔗糖、淀粉、甘露醇、山梨醇、乳糖、葡萄糖、纤维素、滑石、磷酸钙或碳酸钙)、粘合剂(例如，纤维素、甲基纤维素、羟甲基纤维素、聚丙基吡咯烷酮、聚乙烯吡咯烷酮、明胶、阿拉伯胶、聚乙二醇、蔗糖或淀粉)、崩解剂(例如，淀粉、羧甲 基纤维素、羟丙基淀粉、低取代的羟丙基纤维素、碳酸氢钠、磷酸钙或柠檬酸钙)、润滑剂(例如，硬脂酸镁、轻质无水硅酸、滑石或月桂基硫酸钠)、矫味剂(例如，柠檬酸、薄荷醇、甘氨酸或橘子粉)、防腐剂(例如，苯甲酸钠、亚硫酸氢钠、尼泊金甲酯或尼泊金丙酯)、稳定剂(例如，柠檬酸、柠檬酸钠或乙酸)、助悬剂(例如，甲基纤维素、聚乙烯吡咯烷酮或硬脂酸铝)、分散剂(例如，羟丙基甲基纤维素)、稀释剂(例如，水)和底蜡(例如，可可脂、白凡士林或聚乙二醇)。例如，药物组合物中所述化合物的有效量可以是能实现预期效果的量；例如，在用于口服和肠胃外给药的单位剂量中为约0.005mg/kg的受试者体重至约10mg/kg的受试者体重。
在一个实施方案中，本发明提供含有本发明的化合物而不含另外的载体的胶囊。
本发明的药物组合物可以是片剂、咀嚼片、胶囊、溶液、肠胃外溶液、锭剂、栓剂和混悬剂等的形式。组合物可以经配制成在剂量单位中含有每日剂量或每日剂量的适宜部分，所述剂量单位可以是单一片剂或胶囊或适宜体积的液体。在一个实施方案中，溶液由水溶性盐，比如盐酸盐来制备。通常，所有组合物均根据药物化学中的已知方法制备。胶囊可以通过将所述化合物与适合的载体或稀释剂混合，并将适当量的混合物填充到胶囊中来制备。常用的载体和稀释剂包括，但不限于惰性粉状物质，比如多种不同的淀粉、粉状纤维素、尤其是结晶和微晶纤维素、糖比如果糖、甘露醇和蔗糖、谷粉和类似的可食用粉末。
片剂可以通过直接压制、湿法制粒或干法制粒来制备。其制剂通常加入稀释剂、粘合剂、润滑剂和崩解剂以及该化合物。典型的稀释剂包括，例如，多种类型的淀粉、乳糖、甘露醇、高岭土、磷酸钙或硫酸钙、无机盐(比如氯化钠)和糖粉。粉状纤维素衍生物也是有用的。典型的片剂粘合剂为下述物质，比如淀粉、明胶和糖(比如乳糖、果糖、葡萄糖等)。天然和合成树胶也是适宜的，其包括阿拉伯胶、藻酸盐、甲基纤维素、聚乙烯基吡咯烷酮等。聚乙二醇、乙基纤维素和蜡也可以充当粘合剂。
片剂制剂中可能需要润滑剂以防止片剂和冲压机粘在模具中。润滑剂可以选用一些具有润滑作用的固体，如滑石、硬脂酸镁和硬脂酸钙、硬脂酸和氢化植物油。片剂崩解剂是在润湿时膨胀以使片剂破碎并释放化合物。它们包括淀粉、粘土、纤维素、藻胶和树胶。更特别地，可以使用例如玉米和马铃薯淀粉、甲基纤维素、琼脂、膨润土、木纤维素、粉状天然海绵、阴离子交换树脂、藻酸、瓜尔胶、柑桔渣和羧基甲基纤维素以及月桂基硫酸钠。片剂可以涂布作为调味剂和密封剂的糖，或涂布成膜保护剂，以优化片剂的溶解性能。组合物还可以配制成咀嚼片，例如通过在制剂中加入一些物质，比如甘露醇配制。
当希望作为栓剂给药时，可以使用典型的基质。可可脂是传统的栓剂基质，其可以通过加入蜡以稍微升高其熔点而改变。特别地包括各种分子量的聚乙二醇的水可混溶性栓剂基质被广泛使用。
所述化合物的作用可以通过合适的制剂而延迟或延长。例如，所述化合物的缓慢溶解的小丸可以被制备并加入片剂或胶囊剂中或作为缓释可植入装置。该技术还包括制备数种不同溶解速率的小丸，并使用小丸的混合物填充胶囊。片剂或胶囊可以涂布在可预测的期间抵抗溶解的膜。即使是肠胃外制剂也可以通过将所述化合物溶解或悬浮在允许其缓慢分散于血清中的油性或乳化的溶媒中制备成长效的。
本发明的进一步的目的在于提供一种制品，例如以试剂盒形式提供。发明的制品包含本发明的药物组合物，并任选地包括包装盒和说明书。
治疗方法和用途
在另一个方面，本发明还提供本发明的化合物或其药学上可接受的盐、立体异构体、溶剂化物、多晶型体、互变异构体、同位素化合物、代谢产物或前药或本发明的药物组合物在制备治疗对TLR 7受体的激活响应的疾病的药物中的用途。在一实施方案中，所述对TLR 7受体的激活响应的疾病选自肝脏相关疾病、肿瘤或HIV感染。
在一实施方案中，所述肝脏相关疾病选自病毒性肝炎、自身免疫性肝病、药物毒性肝病、肝病性肝损伤、肝功能性衰竭、慢性重型肝炎、肝硬化、肝脓肿、脂肪肝和原发性肝癌中的一种或多种，优选地所述肝脏相关疾病为乙肝或丙肝。在一实施方案中，所述肿瘤选自白血病、淋巴瘤、黑色素瘤和非小细胞肺癌中的一种或多种。
在一实施方案中，本发明还提供一种药物组合，其包含组分(1)式(I)的化合物或其药学上可接受的盐、立体异构体、溶剂化物、多晶型体、互变异构体、同位素化合物、代谢产物或前药或药物组合物，和组分(2)PD-1抗体、PD-L1抗体或PD-1抑制剂、PD-L1抑制剂或PD-1/PD-L1抑制剂。本发明还提供所述药物组合在制备用于治疗肿瘤的药物中的用途。所述肿瘤类型优选地选自白血病、淋巴瘤、黑色素瘤、或非小细胞肺癌。
待给药受试者的所述化合物的剂量在相当程度上是可变的，并且可以服从卫生护理专业人员的判断。
出于方便的原因，本发明的化合物可以口服给药。在一个实施方案中，当口服给药时，所述化合物与水或和膳食一起给予。在另一个实施方案中，化合物分散在水或果汁(例如，苹果汁或橙汁)中，并作为混悬剂口服给药。
所述化合物也可以皮内、肌内、腹膜内、经皮、静脉内、皮下、鼻内、硬膜内、舌下、脑内、阴道内、透皮、直肠、经粘膜、通过吸入或局部给药至耳、鼻、眼或皮肤。 给药方式是由卫生护理专业人员判断，并且可以部分取决于医学病症的部位。
有益效果
本发明的化合物具有较高的TLR 7激动活性，以及优异的相对于TLR 8的TLR 7选择性，效果优于现有技术。并且，本发明的化合物在具备活性的同时，具有良好的安全性，例如其在全身血液系统中的暴露量极低，并且能够在低浓度下诱导IFN-α在血浆及肝脏中的表达，因此具备较低的毒性，能够实现更好的疗效。
附图说明
图1.化合物3和GS-9620诱导的小鼠血浆及肝脏IFN-α及TNF-α表达量。其中化合物3在小鼠血浆及肝脏中暴露量均低于LC/MS/MS的分析定量下限，仅以数字0示出其位置。
具体实施方式
为清楚起见，本发明进一步用实施例来阐述。但是实施例只是作为示例性说明，目的是使本领域的技术人员能够清楚地理解和实施本发明，而不是限制本发明的范围。本领域的技术人员应当了解，为制备本发明中的化合物，可以调整部分反应步骤的次序，或根据期望获得的产物结构省略一个或多个步骤，以及增加或省略保护/脱保护反应步骤，这也落入本发明的范围之内。
本发明所使用的所有溶剂均为市售，无需进一步纯化即可使用。如无特别声明，反应一般是在惰性气体气氛下、无水溶剂中进行的。质子核磁共振数据记录在AVANCE III HD(300MHz)波谱仪上，化学位移以四甲基硅烷低场处的(ppm)表示。质谱是在安捷伦1200系列加6110(G1956A)上测定。LC/MS或Shimadzu MS包含一个DAD:SPD-M20A(LC)和ShimadzuMicromass 2020检测器。质谱仪配备有一个正离子或负离子模式下操作的电喷雾离子源(ESI)。
本发明采用下述缩略词:
aq 含水的；
SEMCl (2-(氯甲氧基)乙基)三甲基硅烷；
eq 当量；
1,3-DPPP 1,3-双(二苯基膦基)丙烷；
DCM 二氯甲烷；
PE 石油醚；
DMA N,N-二甲基乙酰胺；
DMF N,N-二甲基甲酰胺；
NMP N-甲基吡咯烷酮；
EtOAc 乙酸乙酯；
i-PrOH 异丙醇；
EtOH 乙醇；
MeOH 甲醇；
n-BuOH 正丁醇；
THF 四氢呋喃；
Boc 叔丁氧羰基；
HOAc 乙酸；
NaCNBH 3 氰基硼氢化钠；
STAB 醋酸硼氢化钠；
NaBH(OAc) 3 醋酸硼氢化钠；
CDI N,N'-羰基二咪唑；
LAH 氢化铝锂；
9-BBN 9-硼二环壬烷；
MsCl 甲磺酰氯；
RT 室温；
O.N. 过夜；
Boc 2O 二叔丁基二碳酸酯；
TFA 三氟乙酸；
TFAA 三氟乙酸酐；
TEA 三乙胺；
DIBAL-H 二异丁基氢化铝；
NBS 溴代丁二酰胺；
AIBN 偶氮二异丁腈；
DPPF 1,1'-双(二苯基膦基)二茂铁；
Ph 3P 三苯基膦；
Pd(OAc) 2 乙酸钯；
Pd(PPh 3P) 2Cl 2 双(三苯基膦)氯化钯；
Pd 2(dba) 3 三(亚苄基丙酮)二钯；
n-BuLi 正丁基锂。
化合物经手工或者Chem Draw软件命名，市售化合物采用供应商目录名称。
用配有Shimadzu SIL-20A自动进样器和日本岛津DAD:SPD-M20A探测器的岛津LC20AB系统进行高效液相色谱分析，采用Shim-pack XR-ODS(2.2μm填料，规格为2.0x50mm)色谱柱。5-100AB_8分钟的方法:应用线性梯度，以95％A(A为0.05％TFA的水溶液)开始洗脱，并以100％B(B为MeCN)结束洗脱，整个过程为8分钟，然后以100％B洗脱2分钟。将色谱柱再平衡0.5分钟达到100:5，总运行时间为12.5分钟。10-100AB_3.4分钟的方法:应用线性梯度，以90％A(A为0.05％TFA的水溶液)开始洗脱，并以100％B(B为乙腈)结束洗脱，整个过程为2.2分钟，然后以100％B洗脱0.7分钟。将色谱柱再平衡0.2分钟达到90:10，总运行时间为3.4分钟。柱温为50℃，流速0.8mL/min。二极管阵列检测器扫描波长为200-400nm。
在Sanpont-group的硅胶GF254上进行薄层色谱分析(TLC)，常用紫外光灯照射检出斑点，在某些情况下也采用其他方法检视斑点，在这些情况下，用碘(10g硅胶中加入约1g碘并彻底混合而成)、香草醛(溶解大约1g香草醛于100mL10％H 2SO 4中制得)、茚三酮(从Aldrich购得)或特殊显色剂(彻底混合(NH 4) 6Mo 7O 24·4H 2O、5g(NH 4) 2Ce(IV)(NO 3) 6、450mLH 2O和50mL浓H 2SO 4而制得)展开薄层板，检视化合物。采用Still,W.C.；Kahn,M.；and Mitra,M.Jouma1of Organic Chemistry,1978,43,2923-2925中所公开技术的类似方法，在Silicycle的40-63μm(230-400目)硅胶上进行快速柱色谱。快速柱色谱或薄层色谱的常用溶剂是二氯甲烷/甲醇、乙酸乙酯/甲醇和己烷/乙酸乙酯混合物。在Gilson_281Prep LC322系统上釆用吉尔森UV/VIS-156探测器进行制备色谱分析，所采用的色谱柱是Agella Venusil ASB Prep C18，150x21.2mm；CHIRALPAKAD-3，0.46cm*10cm,3μm；X select C18，19mm*150mm；Phenomenex Gemini C18，5μm，150x30mm；或者Phenomenex Synergi C18，4μm，150x30mm。在流速约为25mL/min，用低梯度的乙腈/水洗脱化合物，其中水中含有0.05％TFA、0.25％HCOOH或0.5％NH 3·H 2O，总运行时间为8-15分钟。
合成路线
本发明的式I-1的化合物可以通过下述合成路线1来制备。
Figure PCTCN2019111625-appb-000015
合成路线1
Figure PCTCN2019111625-appb-000016
从2,4,6-三氯-5-硝基嘧啶或者类似物(商品化试剂)出发，经反应步骤1亲核取代反应得到中间体1。随后，经步骤2使其与氨发生亲核取代反应，得到2-氯-嘧啶-6-胺化合物(中间体2)。之后经步骤3，将嘧啶2位上的氯与醇钠或者醇钾或者巯盐或有机胺反应，得到中间体3。然后，经步骤4：1)将硝基用锌粉还原，2)脱除Boc，3)与双亲电试剂反应并关环得到产物，即R 2为H时的式I-1的化合物。
R 2为H时，也可以通过合成路线2，经合成路线1的中间体3来制备式I-1的化合物：
合成路线2
Figure PCTCN2019111625-appb-000017
中间体3通过与合成路线1相同的步骤即可得到R 2为H时的式I-1的化合物。
本发明通式I-2、I-3的化合物可以由本领域技术人员选择合适的原料通过合成路线1或2来制备。
本发明通式I-6的化合物可以通过合成路线3来制备。
Figure PCTCN2019111625-appb-000018
合成路线3
Figure PCTCN2019111625-appb-000019
从中间体化合物1'，即，2-取代-4,6-二氯-5-硝基嘧啶或者类似物(商品化试剂或者根 据WO2016/44183A1的方法制备)出发，经步骤1″，与氨发生亲核取代反应，得到6-氯-嘧啶-4-胺化合物(中间体2')。之后经步骤2″，与有机胺反应，得到中间体3'。然后，经步骤3″：1)将硝基用锌粉还原，2)在1)中得到的中间体与过氧化氢发生氧化反应，该氧化反应选择性地得到5-位羟胺化合物，3)在2)中得到的5-位羟胺化合物与双亲电试剂反应并关环得到产物I-6。
本发明通式I-4、I-5、I-7的化合物可以由本领域技术人员选择合适的原料参照合成路线3来制备。
制备实施例
下面列举的具体实验案例，其目的是使本领域的技术人员能够清楚地理解和实施本发明。它们不应该被认为是对本发明范围的限制，而只是作为本发明的示例性说明和典型代表。
实施例1：5-氨基-7-丁氧基-2-甲基-1-(3-(吡咯烷-1-基甲基)苄基)-1,4-二氢嘧啶并[5,4-e][1,2,4]三嗪-3(2H)-酮
Figure PCTCN2019111625-appb-000020
合成方案
Figure PCTCN2019111625-appb-000021
步骤A：2-(2-丁氧基-6-氯-5-硝基嘧啶-4-基)-1-甲基肼-1-羧酸叔丁酯的制备
取250毫升圆底三口烧瓶，将2-丁氧基-4,6-二氯-5-硝基嘧啶(9.97克,37.6毫摩尔),三乙胺(10.36克，102.6毫摩尔)加入到四氢呋喃(50.0毫升)中。0摄氏度下，缓慢滴加1-甲基肼-1-羧酸叔丁酯(5.00克，34.2毫摩尔)的四氢呋喃(30.0毫升)溶液，滴完后室温下搅拌2小时。
减压旋蒸得到固体残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/1)，得到7.5克黄色油状液体2-(2-丁氧基-6-氯-5-硝基嘧啶-4-基)-1-甲基肼-1-羧酸叔丁酯(收率53％)。
MS(ESI)M/Z：376[M+H +]。
步骤B：2-(2-丁氧基-6-氯-5-硝基嘧啶-4-基)-2-(3-甲酰基苄基)-1-甲基肼-1-羧酸叔丁酯的制备
取500毫升圆底三口瓶，室温下依次加入2-(2-丁氧基-6-氯-5-硝基嘧啶-4-基)-1-甲基肼-1-羧酸叔丁酯(7.50克，19.94毫摩尔)，乙腈(100毫升)，碳酸钾(8.27克，59.84毫摩尔)以及3-(溴甲基)苯甲醛(4.33克，21.94毫摩尔)。搅拌混合均匀后，油浴50摄氏度加热1 小时。
反应液通过硅藻土抽滤，滤饼用乙酸乙酯(50毫升×2次)淋洗，收集滤液并减压旋蒸浓缩。固体残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1)得到8.00克黄色油状液体2-(2-丁氧基-6-氯-5-硝基嘧啶-4-基)-2-(3-甲酰基苄基)-1-甲基肼-1-羧酸叔丁酯为(收率81％)。
MS(ESI)M/Z：494[M+H +]。
步骤C：2-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-2-(3-甲酰基苄基)-1-甲基肼-1-羧酸叔丁酯的制备
取250毫升高压反应器，将2-(2-丁氧基-6-氯-5-硝基嘧啶-4-基)-2-(3-甲酰基苄基)-1-甲基肼-1-羧酸叔丁酯(8.00克，16.19毫摩尔)溶于氨(7.0M,100毫升，700毫摩尔)的甲醇溶液，油浴60摄氏度加热过夜。
减压浓缩脱除溶剂，得到8.50克黄色固体2-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-2-(3-甲酰基苄基)-1-甲基肼-1-羧酸叔丁酯。无需纯化，粗产品直接用于下一步。
MS(ESI)M/Z：475[M+H +]。
步骤D：2-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-1-甲基-2-(3-(吡咯烷-1-基甲基)苄基)肼-1-羧酸叔丁酯的制备
取250毫升圆底三口烧瓶，在氮气气氛下，依次加入2-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-2-(3-甲酰基苄基)-1-甲基肼-1-羧酸叔丁酯(8.50克，17.89毫摩尔)，吡咯烷(15.2克，214.1毫摩尔)，二氯甲烷(50.0毫升)以及
Figure PCTCN2019111625-appb-000022
级分子筛(4.0克)。搅拌30分钟后，零摄氏度下分批次缓慢加入醋酸硼氢化钠(7.58克，35.75毫摩尔)，加完后室温反应过夜。
往反应液中加水(100毫升)稀释。所得混合液通过硅藻土抽滤，滤饼用二氯甲烷洗涤(50毫升×2次)。收集滤液，分液。得到的有机相先用饱和氯化钠溶液(100毫升×1次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。浓缩物通过硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20/1)，得7.01克黄色液体2-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-1-甲基-2-(3-(吡咯烷-1-基甲基)苄基)肼-1-羧酸叔丁酯(收率73.7％)。
MS(ESI)M/Z：530[M+H +]。
步骤E：2-(5,6-二氨基-2-丁氧基嘧啶-4-基)-1-甲基-2-(3-(吡咯烷-1-基甲基)苄基)肼-1-羧酸叔丁酯乙酸盐
取100毫升三口瓶，向2-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-1-甲基-2-(3-(吡咯烷-1-基甲基)苄基)肼-1-羧酸叔丁酯(7.00克，13.2毫摩尔)的醋酸(70.0毫升)溶液中加入锌粉(7.00克，107.6毫摩尔)。室温下搅拌过夜。
将反应液抽滤，收集滤液。滤饼用乙酸乙酯洗涤(20毫升×2次)，合并有机相。有机相减压浓缩，得到7.95克棕色液体2-(5,6-二氨基-2-丁氧基嘧啶-4-基)-1-甲基-2-(3-(吡咯烷-1-基甲基)苄基)肼-1-羧酸叔丁酯乙酸盐。无需纯化，粗产品直接用于下步反应。
MS(ESI)M/Z：500[M+H +]。
步骤F：2-丁氧基-6-(2-甲基-1-(3-(吡咯烷-1-基甲基)苄基)肼基)嘧啶-4,5-二胺三氟乙酸盐的制备
取100毫升三口烧瓶，向2-(5,6-二氨基-2-丁氧基嘧啶-4-基)-1-甲基-2-(3-(吡咯烷-1-基甲基)苄基)肼-1-羧酸叔丁酯(7.90克，15.8毫摩尔)的二氯甲烷溶液(40.0毫升)中缓慢加入三氟乙酸(40.0毫升)，室温下搅拌3小时。
减压浓缩，得到11.6克棕色液体2-丁氧基-6-(2-甲基-1-(3-(吡咯烷-1-基甲基)苄基)肼基)嘧啶-4,5-二胺三氟乙酸盐。无需纯化，粗产品直接用于下步反应。
MS(ESI)M/Z：400[M+H +]。
步骤G：5-氨基-7-丁氧基-2-甲基-1-(3-(吡咯烷-1-基甲基)苄基)-1,4-二氢嘧啶并[5,4-e][1,2,4]三嗪-3(2H)-酮三氟乙酸盐的制备
0摄氏度下，向2-丁氧基-6-(2-甲基-1-(3-(吡咯烷-1-基甲基)苄基)肼基)嘧啶-4,5-二胺(2.00克，5.0毫摩尔)的四氢呋喃(10.0毫升)和二氯甲烷(10.0毫升)的混合溶液中依次加入N,N'-羰基二咪唑(1.62克，10.0毫摩尔)以及三乙胺(1.52克，15.0毫摩尔)。加料完成，将反应液温度维持在0摄氏度下继续搅拌1小时。
将反应液减压浓缩，得棕色固体(2.10克)用二甲基亚砜(5.0毫升)溶解至澄清，制备型高效液相色谱纯化。纯化条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有0.05％氨水)和乙腈；流速:25毫升/分钟；梯度：在7分钟内，乙腈从10％升到80％；检测波长：254nm。收集产品，减压冻干。得到306毫克淡黄色固体5-氨基-7-丁氧基-2-甲基-1-(3-(吡咯烷-1-基甲基)苄基)-1,4-二氢嘧啶并[5,4-e][1,2,4]三嗪-3(2H)-酮三氟乙酸盐(化合物1，收率64％)。
MS(ESI)M/Z：426[M+H +]。
1H NMR(300MHz,DMSO-d 6)δ8.07(s,1H),7.47–7.37(m,2H),7.19–7.16(m,2H),6.58(br,s,2H),4.38–4.29(m,4H),4.01(t,J＝6.6Hz,2H),3.27–3.23(m,2H),3.06(s,3H),2.98–2.86(m,2H),2.07–1.84(m,4H),1.66–1.59(m,2H),1.43–1.38(m,2H),0.93(t,J＝7.2Hz,3H)。
实施例2：5-氨基-7-丁氧基-1-(4-氟-3-(吡咯烷-1-基甲基)苄基)-2-甲基-1,4-二氢嘧啶 并[5,4-e][1,2,4]三嗪-3(2H)-酮
Figure PCTCN2019111625-appb-000023
合成方案
Figure PCTCN2019111625-appb-000024
步骤A：5-(溴甲基)-2-氟苯甲酸的制备
氮气气氛下，向2-氟-5-甲基苯甲酸(25.00克,162毫摩尔)的四氯化碳(1.50升)溶液中依次加入溴代琥珀酰亚胺(31.9克，179毫摩尔)以及偶氮二异丁腈(2.60克，16.2毫摩尔)。搅拌溶解后，将反应液置于油浴中，90摄氏度下加热2小时。
待反应体系冷却至室温，向反应液中加入500毫升饱和碳酸钠溶液稀释。将得到的混合液静置分层。分出有机相，水相用二氯甲烷萃取(500毫升×3次)。将合并后的有机相，先用饱和氯化钠溶液洗涤(500毫升×2次)。然后用无水硫酸钠干燥，最后减压浓缩。所得固体残余物通过硅胶柱纯化(洗脱液：乙酸乙酯/石油醚＝1/3)得到25.6克白色固体5-(溴甲基)-2-氟苯甲酸(收率67.7％)。
该反应物不出MS信号，直接用于下一步反应。
步骤B-C：2-(2-丁氧基-6-氯-5-硝基嘧啶-4-基)-2-(4-氟-3-(羟甲基)苄基)-1-甲基肼-1- 羧酸叔丁酯的制备
将5-(溴甲基)-2-氟苯甲酸(25.60克,110毫摩尔)溶于硼烷的四氢呋喃溶液(2.0摩尔/升，500毫升，1.0摩尔)中,室温搅拌16小时。随后，将所得溶液真空浓缩。所得固体残余物通过硅胶柱纯化(洗脱液：乙酸乙酯/石油醚＝1/3)，得到12.50克棕色液体(5-(溴甲基)-2-氟苯基)甲醇(收率51.9％)。该反应物稳定性不够好，不出MS信号。直接用于下一步反应。
依次将2-(2-丁氧基-6-氯-5-硝基嘧啶-4-基)-1-甲基肼-1-羧酸叔丁酯(2.06克，5.5毫摩尔)，(5-(溴甲基)-2-氟苯基)甲醇(1.75克，8.0毫摩尔)以及无水碳酸钾(2.20克，15.9毫摩尔)溶于乙腈(50毫升)中。搅拌混合均匀后，反应液油浴50摄氏度下加热过夜。
后处理：待反应液冷却至室温，加入100毫升纯水稀释。所得混合液减压浓缩除去乙腈。剩下的水相用乙酸乙酯萃取(50毫升×3次)，合并有机相。有机相先用饱和氯化钠溶液(50毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。残余物通过硅胶柱纯化(洗脱液：乙酸乙酯/石油醚＝1/1)，得1.90克黄色固体2-(2-丁氧基-6-氯-5-硝基嘧啶-4-基)-2-(4-氟-3-(羟甲基)苄基)-1-甲基肼-1-羧酸叔丁酯(收率，68.8％)。
MS(ESI)M/Z：514[M+H +]。
步骤D：2-(2-丁氧基-6-氯-5-硝基嘧啶-4-基)-2-(4-氟-3-甲酰基苄基)-1-甲基肼-1-羧酸叔丁酯
向2-(2-丁氧基-6-氯-5-硝基嘧啶-4-基)-2-(4-氟-3-(羟甲基)苄基)肼-1-羧酸叔丁酯(1.90克,3.70毫摩尔)的二氯甲烷(50毫升)溶液中，加入二氧化锰(1.92克，22.07毫摩尔)。在40摄氏度下搅拌过夜。
将反应混合物通过硅藻土减压抽滤，滤饼用二氯甲烷(30毫升×2次)淋洗。收集滤液，滤液减压浓缩。残余物通过硅胶柱纯化(洗脱液：乙酸乙酯/石油醚＝1/1)，得1.50克黄色固体2-(2-丁氧基-6-氯-5-硝基嘧啶-4-基)-2-(4-氟-3-甲酰基苄基)-1-甲基肼-1-羧酸叔丁酯(收率79.4％)。
MS(ESI)M/Z：514[M+H +]。
步骤E：2-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-2-(4-氟-3-甲酰基苄基)-1-甲基肼-1-羧酸叔丁酯
在100毫升高压反应器中，将2-(2-丁氧基-6-氯-5-硝基嘧啶-4-基)-2-(4-氟-3-甲酰基苄基)-1-甲基肼-1-羧酸叔丁酯(1.50克,3.01毫摩尔)溶于氨的异丙醇溶液(2.0摩尔/升，50.0毫升,100.0毫升)。搅拌混合均匀后，反应液油浴60摄氏度加热16小时。
待反应体系却至室温，将反应液减压浓缩。残余物中加入纯水(20毫升)。减压抽滤， 滤饼用纯水洗涤(20毫升×2次)。收集滤饼并烘干，得1.40克黄色固体2-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-2-(4-氟-3-甲酰基苄基)-1-甲基肼-1-羧酸叔丁酯(收率，97.0％)。
MS(ESI)M/Z：493[M+H +]。
步骤F：2-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-2-(4-氟-3-(吡咯烷-1-基甲基)苄基)-1-甲基肼-1-甲酸叔丁酯的制备
氮气保护下，依次将2-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-2-(4-氟-3-甲酰基苄基)-1-甲基肼-1-羧酸叔丁酯(1.40克,2.84毫摩尔)，吡咯烷(2.42克，34.08毫摩尔)溶于二氯甲烷(50毫升)中。冰水浴下，分批缓慢加入三乙酰氧基硼氢化钠(1.20克，5.66毫摩尔)。加料完成，将反应装置移至室温下，搅拌过夜。
向反应液中加纯水(50毫升)稀释。所得混合液用二氯甲烷(50毫升×2次)萃取，合并有机相。有机相先用饱和食盐水反洗(50毫升×2次)，接着用无水硫酸钠干燥，最后减压浓缩。残余物通过硅胶柱纯化(洗脱液：乙酸乙酯/石油醚＝1/1)，得510毫克固体2-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-2-(4-氟-3-(吡咯烷-1-基甲基)苄基)-1-甲基肼-1-甲酸叔丁酯(收率，32.7％)。
MS(ESI)M/Z：548[M+H +]。
步骤G：2-(5,6-二氨基-2-丁氧基嘧啶-4-基)-2-(4-氟-3-(吡咯烷-1-基甲基)苄基)-1-甲基肼-1-羧酸叔丁酯的制备
将2-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-2-(4-氟-3-(吡咯烷-1-基甲基)苄基)-1-甲基肼-1-甲酸叔丁酯(510毫克,0.96毫摩尔)溶于醋酸(5毫升)中，然后加入锌粉(510毫克)，室温搅拌过夜。
减压抽滤，收集滤液。滤饼用二氯甲烷(10毫升×2)淋洗。合并滤液并减压浓缩，得到450毫克黄色液体2-(5,6-二氨基-2-丁氧基嘧啶-4-基)-2-(4-氟-3-(吡咯烷-1-基甲基)苄基)-1-甲基肼-1-羧酸叔丁酯(收率，93.6％)。
MS(ESI)M/Z：518[M+H +]。
步骤H：2-丁氧基-6-(1-(4-氟-3-(吡咯烷-1-基甲基)苄基)-2-甲基肼基)嘧啶-4,5-二胺三氟乙酸盐的制备
将2-(5,6-二氨基-2-丁氧基嘧啶-4-基)-2-(4-氟-3-(吡咯烷-1-基甲基)苄基)-1-甲基肼-1-羧酸叔丁酯(450毫克，0.89毫摩尔)溶于二氯甲烷(10毫升)中。冰水浴下，缓慢滴加三氟乙酸(3.0毫升)。滴加完毕后，将反应装置移至室温下搅拌1小时。
将反应液减压浓缩，得300毫克棕色液体2-丁氧基-6-(1-(4-氟-3-(吡咯烷-1-基甲基)苄基)-2-甲基肼基)嘧啶-4,5-二胺三氟乙酸盐。无需纯化，直接用于下步反应。
MS(ESI)M/Z：418[M+H +]。
步骤I：5-氨基-7-丁氧基-1-(4-氟-3-(吡咯烷-1-基甲基)苄基)-2-甲基-1,4-二氢嘧啶并[5,4-e][1,2,4]三嗪-3(2H)-酮三氟乙酸盐的制备
将2-丁氧基-6-(1-(4-氟-3-(吡咯烷-1-基甲基)苄基)-2-甲基肼基)嘧啶-4,5-二胺(300毫克,0.718毫摩尔)溶于四氢呋喃(5.0毫升)与二氯甲烷(5.0毫升)的混合溶液中。将冰水浴下，依次加入三乙胺(350毫克,2.16毫摩尔)与N,N'-羰基二咪唑(350毫克,2.16毫摩尔)。随后，将反应液移至室温下搅拌1小时。
将反应液减压浓缩。残留物用N,N-二甲基甲酰胺(4.0毫升)溶至澄清。粗产品用制备型高效液相色谱纯化。分离条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有0.05％的TFA)和乙腈；流速：25毫升/分钟；梯度：在7分钟内，乙腈从10％升到80％；检测波长：254nm。减压冻干，得到88.0毫克棕色半固体5-氨基-7-丁氧基-1-(4-氟-3-(吡咯烷-1-基甲基)苄基)-2-甲基-1,4-二氢嘧啶并[5,4-e][1,2,4]三嗪-3(2H)-酮三氟乙酸盐(化合物2，收率27.7％)。
MS(ESI)M/Z：444[M+H +]。
1H NMR(300MHz,CD 3OD,ppm)δ7.53–7.44(m,1H),7.33–7.18(m,2H),4.50(s,2H),4.44(s,2H),4.42–4.29(m,2H),3.68–3.42(m,2H),3.18(s,5H),2.30–2.04(m,4H),1.81–1.66(m,2H),1.56–1.43(m,2H),1.02–0.90(m,3H)。
19F NMR(300MHz,CD 3OD,ppm),δ-76.82,-117.53。
实施例3：6-氨基-2-丁氧基-7-羟基-9-(4-(吡咯烷-1-基甲基)苄基)-7H-嘌呤-8(9H)-酮
Figure PCTCN2019111625-appb-000025
合成方案
Figure PCTCN2019111625-appb-000026
步骤A：2-丁氧基-5-硝基-N 4-(4-(吡咯烷-1-基甲基)苄基)嘧啶-4,6-二胺的制备
冰水浴下，向500毫升三口圆底烧瓶中，依次加入2-丁氧基-6-氯-5-硝基嘧啶-4-胺(19.18克，77.96毫摩尔)，四氢呋喃(200毫升)以及三乙胺(15.75克，155.92毫摩尔)。搅拌5分钟后，缓慢滴加(4-(吡咯烷-1-基甲基)苯基)甲胺(14.81克，77.96毫摩尔)。滴加完毕，将反应装置移至室温下继续搅拌1小时。有大量白色固体析出。TLC监控发现原料消失。
将反应液抽滤，收集滤液。滤渣用乙酸乙酯洗涤(50毫升×3次)。合并滤液并减压浓缩，得到30.82克2-丁氧基-5-硝基-N 4-(4-(吡咯烷-1-基甲基)苄基)嘧啶-4,6-二胺。无需纯化，粗产品直接用于下一步反应。
MS(ESI)M/Z：401[M+H +]。
步骤B：2-丁氧基-N 4-(4-(吡咯烷-1-基甲基)苄基)嘧啶-4,5,6-三胺的制备
向500毫升的三口圆底烧瓶中依次加入2-丁氧基-5-硝基-N 4-(4-(吡咯烷-1-基甲基)苄基)嘧啶-4,6-二胺(30.82克,粗产品)，乙醇(240毫升)以及水60(毫升)。搅拌溶解后，向混合液中加入铁粉(4.31克，77.05毫摩尔)和氯化铵(4.08克，77.05毫摩尔)。随后，将反应装置油浴60摄氏度下加热。12小时后，LC-MS监控原料消失。
将反应液通过硅藻土抽滤，收集滤液。滤渣用乙酸乙酯洗涤(50毫升×3次)。合并滤液并减压浓缩，得到29.81克2-丁氧基-N 4-(4-(吡咯烷-1-基甲基)苄基)嘧啶-4,5,6-三胺。无需纯化，粗产品直接用于下一步反应。
MS(ESI)M/Z：371[M+H +]。
步骤C：2-丁氧基-5-(羟基氨基)-N 4-(4-(吡咯烷-1-基甲基)苄基)嘧啶-4,6-二胺的制备
向100毫升三口圆底烧瓶中，依次加入2-丁氧基-N 4-(4-(吡咯烷-1-基甲基)苄基)嘧啶-4,5,6-三胺(3.00克,粗产品)以及N-甲基吡咯烷酮(30.0毫升)。然后，冰水浴下依次缓慢滴入30％双氧水(3.00毫升)以及氢氧化钠水溶液(6.0N，0.30毫升，1.8毫摩尔)。滴加完毕，控制反应液温度在0摄氏度。5小时后，LC-MS检测有副产物生成。将反应混合液抽滤，滤液用制备型高效液相色谱纯化。分离条件如下，色谱柱：X select C18 19mm*150mm；流动相：水和乙腈；流速：25毫升/分钟；梯度：在7分钟内，乙腈从10％升到70％；检测波长：254nm。收集产品，减压冻干，得到0.42克2-丁氧基-5-(羟基氨基)-N 4-(4-(吡咯烷-1-基甲基)苄基)嘧啶-4,6-二胺。
MS(ESI)M/Z：387[M+H +]。
步骤D：6-氨基-2-丁氧基-7-羟基-9-(4-(吡咯烷-1-基甲基)苄基)-7H-嘌呤-8(9H)-酮三氟乙酸盐和2-丁氧基-7-羟基-6-((4-(吡咯烷-1-基甲基)苄基)氨基)-7H-嘌呤-8(9H)-酮三氟乙酸盐的制备
取50毫升圆底三口烧瓶，冰水浴下，向2-丁氧基-5-(羟基氨基)-N 4-(4-(吡咯烷-1-基甲基)苄基)嘧啶-4,6-二胺(300毫克，0.78毫摩尔)的二氯甲烷(5.00毫升)溶液中依次加入N,N'-羰基二咪唑(1.26克，7.8毫摩尔)以及三乙胺(1.58克，15.6毫摩尔)。加料完毕后，将反应装置移至室温下搅拌45分钟。
反应液减压浓缩后，得棕色固体用二甲基亚砜(5.0毫升)溶解至澄清。然后，用制备型高效液相色谱纯化。纯化条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有0.05％TFA)和乙腈；流速:25毫升/分钟；梯度：在7分钟内，乙腈从10％升到70％；检测波长：254nm。收集产品，低温减压冻干得到70.8毫克黄色固体6-氨基-2-丁氧基-7-羟基-9-(4-(吡咯烷-1-基甲基)苄基)-7H-嘌呤-8(9H)-酮三氟乙酸盐(化合物3，收率21.9％)以及2.5毫克类白色固体2-丁氧基-7-羟基-6-((4-(吡咯烷-1-基甲基)苄基)氨基)-7H-嘌呤-8(9H)-酮三氟乙酸盐(收率0.8％)。
6-氨基-2-丁氧基-7-羟基-9-(4-(吡咯烷-1-基甲基)苄基)-7H-嘌呤-8(9H)-酮三氟乙酸盐(化合物3)
MS(ESI)M/Z：413[M+H +]。
19F NMR(300MHz,DMSO-d 6)δ-73.72。
1H NMR(300MHz,DMSO-d 6)δ7.63–7.48(m,2H),7.47–7.37(m,2H),6.53(br,s,2H),4.92(s,2H),4.82(s,2H),4.20–4.10(m,2H)3.85-3.67(m,2H),3.67-3.50(m,2H),2.11–2.01(m,4H),1.75–1.54(m,2H),1.47–1.30(m,2H),0.91(t,J＝7.5Hz,3H)。
2-丁氧基-7-羟基-6-((4-(吡咯烷-1-基甲基)苄基)氨基)-7H-嘌呤-8(9H)-酮三氟乙酸盐
MS(ESI)M/Z：413[M+H +]。
19F NMR(300MHz,DMSO-d6):δ-74.18。
1H NMR(300MHz,DMSO-d6)δ11.18(s,1H),9.74(s,1H),7.54–7.38(m,4H),7.18–7.08(m,1H),4.72–4.58(m,2H),4.34(s,2H),4.09(t,J＝6.6Hz,2H),3.70–3.40(m,2H),3.17–2.96(m,2H),2.15–1.74(m,4H),1.68–1.50(m,2H),1.45–1.25(m,2H),0.88(t,J＝7.2Hz,3H)。
实施例4：6-氨基-2-丁氧基-7-羟基-9-(3-(吡咯烷-1-基甲基)苄基)-7H-嘌呤-8(9H)-硫酮
Figure PCTCN2019111625-appb-000027
合成方案
Figure PCTCN2019111625-appb-000028
步骤A：6-氨基-2-丁氧基-7-羟基-9-(3-(吡咯烷-1-基甲基)苄基)-7H-嘌呤-8(9H)-硫酮的制备
取50毫升圆底三口烧瓶，冰水浴下，向2-丁氧基-5-(羟基氨基)-N 4-(3-(吡咯烷-1-基甲基)苄基)嘧啶-4,6-二胺(200毫克，0.52毫摩尔)的二氯甲烷(6.00毫升)溶液中依次加入N,N'-硫羰基二咪唑(0.92克，5.2毫摩尔)以及三乙胺(1.05克，10.4毫摩尔)。加料完毕后，将反应装置移至室温下搅拌1小时。
将反应液减压浓缩。得到的棕色固体用二甲基亚砜(3.0毫升)溶解至澄清。然后，粗产品制备型高效液相色谱纯化。纯化条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有0.05％TFA)和乙腈；流速:25毫升/分钟；梯度：在6分钟内，乙腈从 15％升到65％；检测波长：254nm。收集产品，低温减压冻干得到2.2毫克白色固体6-氨基-2-丁氧基-7-羟基-9-(3-(吡咯烷-1-基甲基)苄基)-7H-嘌呤-8(9H)-硫酮三氟乙酸盐(化合物4，收率1.0％)。
MS(ESI)M/Z：429[M+H +]。
1H NMR(300MHz,CD 3OD)δ7.71–7.50(m,4H),5.46(s,2H),4.82(s,2H),4.31(t,J＝6.6Hz,2H),3.83–3.69(m,4H),2.40–2.18(m,4H),1.79–1.70(m,2H),1.55–1.48(m,2H),0.99(t,J＝7.4Hz,3H)。
19F NMR(300MHz,CD 3OD):δ-76.89。
实施例5：6-氨基-2-丁氧基-7-羟基-9-(3-(吡咯烷-1-基甲基)苄基)-7H-嘌呤-8(9H)-酮
Figure PCTCN2019111625-appb-000029
合成方案
Figure PCTCN2019111625-appb-000030
步骤A：2-丁氧基-5-硝基-N 4-(3-(吡咯烷-1-基甲基)苄基)嘧啶-4,6-二胺的制备
冰水浴下，向500毫升三口圆底烧瓶中，依次加入2-丁氧基-6-氯-5-硝基嘧啶-4-胺(19.16克，77.96毫摩尔)，四氢呋喃(200毫升)以及三乙胺(15.68克，155.92毫摩尔)。搅拌7分钟后，缓慢滴加(3-(吡咯烷-1-基甲基)苯基)甲胺(14.78克，77.96毫摩尔)。滴加完毕，将反应装置移至室温下继续搅拌1.5小时。
将反应液抽滤，收集滤液。滤渣用乙酸乙酯洗涤(50毫升×3次)。合并滤液并减压浓缩，得到30.84克2-丁氧基-5-硝基-N 4-(3-(吡咯烷-1-基甲基)苄基)嘧啶-4,6-二胺。无需纯化，粗产品直接用于下一步反应。
MS(ESI)M/Z：401[M+H +]。
步骤B：2-丁氧基-N 4-(3-(吡咯烷-1-基甲基)苄基)嘧啶-4,5,6-三胺的制备
向500毫升的三口圆底烧瓶中依次加入2-丁氧基-5-硝基-N 4-(3-(吡咯烷-1-基甲基)苄基)嘧啶-4,6-二胺(30.78克,粗产品)，乙醇(240毫升)以及水60(毫升)。搅拌溶解后，向混合液中加入铁粉(4.28克，77.05毫摩尔)和氯化铵(4.06克，77.05毫摩尔)。随后，将反应装置油浴60摄氏度下加热。12小时后，LC-MS监控原料消失。
将反应液通过硅藻土抽滤，收集滤液。滤渣用乙酸乙酯洗涤(50毫升×3次)。合并滤液并减压浓缩，得到29.78克2-丁氧基-N 4-(3-(吡咯烷-1-基甲基)苄基)嘧啶-4,5,6-三胺。无需纯化，粗产品直接用于下一步反应。
MS(ESI)M/Z：371[M+H +]。
步骤C：2-丁氧基-5-(羟基氨基)-N 4-(3-(吡咯烷-1-基甲基)苄基)嘧啶-4,6-二胺的制备
向100毫升三口圆底烧瓶中，依次加入2-丁氧基-N 4-(3-(吡咯烷-1-基甲基)苄基)嘧啶-4,5,6-三胺(3.08克,粗产品)以及N-甲基吡咯烷酮(30.0毫升)。然后，冰水浴下依次缓慢滴入30％双氧水(3.00毫升)以及氢氧化钠水溶液(6.0N，0.30毫升，1.8毫摩尔)。滴加完毕，控制反应液温度在0摄氏度，5小时后，LC-MS检测有副产物生成。将反应混合液抽滤，滤液用制备型高效液相色谱纯化。分离条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含0.05％的氨水)和乙腈；流速：25毫升/分钟；梯度：在7分钟内，乙腈从10％升到70％；检测波长：254nm。低温冻干，得到0.43克2-丁氧基-5-(羟基氨基)-N 4-(3-(吡咯烷-1-基甲基)苄基)嘧啶-4,6-二胺。
MS(ESI)M/Z：387[M+H +]。
步骤D：6-氨基-2-丁氧基-7-羟基-9-(3-(吡咯烷-1-基甲基)苄基)-7H-嘌呤-8(9H)-酮
取50毫升圆底三口烧瓶，冰水浴下，向2-丁氧基-5-(羟基氨基)-N 4-(3-(吡咯烷-1-基甲基)苄基)嘧啶-4,6-二胺(300毫克，0.78毫摩尔)的二氯甲烷(5.00毫升)溶液中依次加入 N,N'-羰基二咪唑(1.26克，7.8毫摩尔)以及三乙胺(1.58克，15.6毫摩尔)。加料完毕后，将反应装置移至室温下搅拌1小时。
反应液减压浓缩后，得棕色固体用二甲基亚砜(5.0毫升)溶解至澄清。然后，用制备型高效液相色谱纯化。纯化条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有0.05％TFA)和乙腈；流速:25毫升/分钟；梯度：在7分钟内，乙腈从10％升到70％；检测波长：254nm。收集产品，低温减压冻干得到27.8毫克黄色半固体6-氨基-2-丁氧基-7-羟基-9-(3-(吡咯烷-1-基甲基)苄基)-7H-嘌呤-8(9H)-酮三氟乙酸盐(化合物5，收率8.7％)。
MS(ESI)M/Z：413[M+H +]。
1H NMR(300MHz,DMSO-d 6)δ11.87(s,1H),7.47–7.43(m,4H),6.55(br,s,2H),4.92(s,2H),4.82(s,2H),4.13(t,J＝7.6Hz,2H),3.81–3.72(m,2H),3.60–3.52(m,2H),2.17–2.05(m,4H),1.65–1.57(m,2H),1.40–1.33(m,2H),0.90(t,J＝7.4Hz,3H)。
19F NMR(300MHz,DMSO-d 6)δ-74.50。
实施例6：6-氨基-2-丁氧基-7-羟基-9-(3-(哌啶-1-基甲基)苄基)-7H-嘌呤-8(9H)-酮
Figure PCTCN2019111625-appb-000031
合成方案
Figure PCTCN2019111625-appb-000032
步骤A：2-丁氧基-5-硝基-N 4-(3-(哌啶-1-基甲基)苄基)嘧啶-4,6-二胺的制备
冰水浴下，向500毫升三口圆底烧瓶中，依次加入2-丁氧基-6-氯-5-硝基嘧啶-4-胺(19.18克，77.96毫摩尔)，四氢呋喃(200毫升)以及三乙胺(15.75克，155.92毫摩尔)。搅拌5分钟后，缓慢滴加((3-(哌啶-1-基甲基)苯基)甲胺(15.98克，77.96毫摩尔)。滴加完毕，将反应装置移至室温下搅拌1小时。有大量白色固体析出。TLC监控发现原料消失。
将反应液抽滤，收集滤液。滤渣用乙酸乙酯洗涤(50毫升×3次)。合并滤液并减压浓缩，得到29.02克2-丁氧基-5-硝基-N 4-(3-(哌啶-1-基甲基)苄基)嘧啶-4,6-二胺。无需纯化，粗产品直接用于下一步反应。
MS(ESI)M/Z：415[M+H +]。
步骤B：2-丁氧基-N 4-(3-(哌啶-1-基甲基)苄基)嘧啶-4,5,6-三胺的制备
向500毫升的三口圆底烧瓶中依次加入2-丁氧基-5-硝基-N 4-(3-(哌啶-1-基甲基)苄基)嘧啶-4,6-二胺(29.02克粗产品)，乙醇(240毫升)以及水(60.0毫升)。搅拌溶解后，向反应液中加入铁粉(4.31克，77.05毫摩尔)和氯化铵(4.08克，77.05毫摩尔)。加料完毕，油浴60摄氏度加热。12小时后，LC-MS监控发现原料消失。
将反应液抽滤，收集滤液，滤渣用乙酸乙酯洗涤(50毫升×3次)。合并滤液并减压浓 缩，得到24.1克2-丁氧基-N 4-(3-(哌啶-1-基甲基)苄基)嘧啶-4,5,6-三胺。无需纯化，粗产品直接用于下一步反应。
MS(ESI)M/Z：385[M+H +]。
步骤C：2-丁氧基-5-(羟基氨基)-N 4-(3-(哌啶-1-基甲基)苄基)嘧啶-4,6-二胺的制备
向100毫升三口圆底烧瓶中，依次加入2-丁氧基-N 4-(3-(哌啶-1-基甲基)苄基)嘧啶-4,5,6-三胺(3.09克，8.05毫摩尔)以及N-甲基吡咯烷酮(30.0毫升)。然后，冰水浴下依次缓慢滴入30％双氧水(3.00毫升)以及氢氧化钠水溶液(6.0N，0.30毫升)。滴加完毕，控制反应液温度在0摄氏度。5小时后，LC-MS检测有副产物生成。将反应混合液抽滤。滤液用制备型高效液相色谱纯化。分离条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含0.05％氨水)和乙腈；流速：25毫升/分钟；梯度：在7分钟内，乙腈从10％升到70％；检测波长：254nm。收集产品，减压冻干，得到0.51克2-丁氧基-5-(羟基氨基)-N 4-(3-(哌啶-1-基甲基)苄基)嘧啶-4,6-二胺。
MS(ESI)M/Z：401[M+H +]。
步骤D：6-氨基-2-丁氧基-7-羟基-9-(3-(哌啶-1-基甲基)苄基)-7H-嘌呤-8(9H)-酮三氟乙酸盐的制备
冰水浴下，向2-丁氧基-5-(羟基氨基)-N 4-(3-(哌啶-1-基甲基)苄基)嘧啶-4,6-二胺(0.30克，0.75毫摩尔)的二氯甲烷(5.00毫升)溶液中依次加入N,N'-羰基二咪唑(1.26克，7.8毫摩尔)以及三乙胺(1.58克，15.6毫摩尔)。加料完成后，将反应装置移至室温下搅拌45分钟。
反应液减压浓缩。得棕色固体用二甲基亚砜(5.0毫升)溶解至澄清，制备型高效液相色谱纯化。纯化条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有0.05％TFA)和乙腈；流速:25毫升/分钟；梯度：在7分钟内，乙腈从10％升到70％；检测波长：254nm。收集产品，低温减压冻干得到得到17.6毫克浅黄色固体6-氨基-2-丁氧基-7-羟基-9-(3-(哌啶-1-基甲基)苄基)-7H-嘌呤-8(9H)-酮三氟乙酸盐(化合物6，收率5.3％).
MS(ESI)M/Z：427[M+H +]。
19F NMR(300MHz,DMSO-d 6)δ-74.25。
1H NMR(300MHz,DMSO-d 6)δ11.75(s,1H),7.58–7.34(m,4H),6.52(br,s,2H),4.92(s,2H),4.74(s,2H),4.12(t,J＝6.6Hz,2H),3.59–3.52(m,2H),3.52–3.40(m,2H),1.87–1.74(m,4H),1.66–1.56(m,3H),1.42–1.30(m,3H),0.90(t,J＝7.5Hz,3H)。
实施例7：5-氨基-7-丁氧基-2-甲基-1-((4-(吡咯烷-1-基甲基)吡啶-2-基)甲基)-1,4-二氢 嘧啶并[5,4-e][1,2,4]三嗪-3(2H)-酮
Figure PCTCN2019111625-appb-000033
合成方案
Figure PCTCN2019111625-appb-000034
步骤A：2-甲基异烟酸甲酯的制备
将2-甲基异烟酸(35.0克，255.5毫摩尔)溶于甲醇(520毫升)中。冰水浴下，控制反应液温度不超过10摄氏度。在搅拌下，缓慢滴加氯化亚砜(63.8克，536.5毫摩尔)。滴加完毕，将反应液加热至60摄氏度下，反应6小时。
将反应液减压浓缩，残余物加水(500毫升)溶解后，用乙酸乙酯(100毫升×1)萃取。水相用碳酸钾调节PH值到9到10后，用乙酸乙酯(200毫升×3)萃取。得到的有机相用无 水硫酸钠干燥，减压浓缩后得到35.2克白色固体2-甲基异烟酸甲酯(收率91.2％)。
MS(ESI)M/Z：152[M+H +]。
步骤B：2-(溴甲基)异烟酸甲酯的制备
在氮气气氛中，向1升三口烧瓶，依次加入2-甲基异烟酸甲酯(35.2克，233.1毫摩尔)，四氯化碳(400.0毫升)，N-溴代丁二酰亚胺(41.5克，233.1毫摩尔)以及偶氮二异丁腈(3.8克，23.2毫摩尔)。随后，将反应液油浴加热至60摄氏度，搅拌过夜。
待反应液冷却到室温，将反应液减压浓缩。得到的固体残余物通过硅胶柱层析纯化(石油醚/乙酸乙酯＝8/1)。收集产品，减压浓缩，得到18.2克紫色固体2-(溴甲基)异烟酸甲酯(收率34.1％)。
MS(ESI)M/Z：230.232[M+H +]。
步骤C：(2-(溴甲基)吡啶-4-基)甲醇的制备
在氮气保护下，将2-(溴甲基)异烟酸甲酯(2.00克，8.7毫摩尔)溶于甲苯(30毫升)。原料搅拌溶解后，将反应装置置于冰盐浴下，并控制反应液温度维持在-10到0摄氏度之间，缓慢滴加二异丁基氢化铝的甲苯溶液(6.9毫升，1.5M，10.4毫摩尔)。滴加完成，在0摄氏度下继续搅拌2小时。
在冰水浴中，向反应液中缓慢滴加饱和的酒石酸钾钠溶液(50毫升)。减压抽滤，水相用乙酸乙酯(20毫升×2次)萃取。合并有机相。有机相先用无水硫酸钠干燥，然后减压浓缩。得到1.27克淡红色固体(2-(溴甲基)吡啶-4-基)甲醇。无需纯化，粗产品直接用于下步反应。
步骤D：2-(2-丁氧基-6-氯-5-硝基嘧啶-4-基)-2-((4-(羟基甲基)吡啶-2-基)甲基)-1-甲基肼-1-羧酸叔丁酯的制备
向100毫升三口烧瓶，室温下依次加入2-(2-丁氧基-6-氯-5-硝基嘧啶-4-基)-1-甲基肼-1-羧酸叔丁酯(1.2克，3.2毫摩尔)，乙腈(50毫升)，2-(溴甲基)吡啶-4-基)甲醇(643毫克，3.2毫摩尔)以及碳酸钾(1.32克，9.6毫摩尔)。在室温下，反应混合物搅拌过夜。
将反应液减压浓缩，得到的固体残余物。然后，粗成品通过硅胶柱层析纯化(石油醚/乙酸乙酯＝8/1)，得到820毫克淡黄色固体2-(2-丁氧基-6-氯-5-硝基嘧啶-4-基)-2-((4-(羟基甲基)吡啶-2-基)甲基)-1-甲基肼-1-羧酸叔丁酯(收率51.5％)。
MS(ESI)M/Z：497[M+H +]。
步骤E：2-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-2-((4-(羟甲基)吡啶-2-基)甲基)-1-甲基肼-1-羧酸叔丁酯的制备
向30毫升高压反应器中，依次加入2-(2-丁氧基-6-氯-5-硝基嘧啶-4-基)-2-((4-(羟基甲 基)吡啶-2-基)甲基)-1-甲基肼-1-羧酸叔丁酯(670毫克，1.35毫摩尔)以及氨的四氢呋喃溶液(20毫升2.0M,40.0毫升)。封口后在50摄氏度下加热2小时。
待反应液冷却到室温后，减压浓缩反应液，得到520毫克黄色固体2-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-2-((4-(羟甲基)吡啶-2-基)甲基)-1-甲基肼-1-羧酸叔丁酯。无需纯化，粗产品直接用于下一步反应。
MS(ESI)M/Z：478[M+H +]。
步骤F：2-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-2-((4-甲酰基吡啶-2-基)甲基)-1-甲基肼-1-羧酸叔丁酯的制备
向100毫升三口烧瓶中，室温下依次加入2-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-2-((4-(羟甲基)吡啶-2-基)甲基)-1-甲基肼-1-羧酸叔丁酯(520毫克，1.09毫摩尔)，二氧化锰(948毫克，10.9毫摩尔)以及三氯甲烷(40.0毫升)。随后，将反应液在50摄氏度下加热5小时。
待反应液冷却到室温后，用硅藻土减压抽滤。将滤液减压浓缩后用N,N-二甲基甲酰胺(2毫升)溶至澄清。然后用制备型高效液相色谱纯化(色谱柱：X select C18 19mm*150mm流动相：水(0.05％TFA)/乙腈；流速:25毫升/分钟；梯度：在7分钟内，乙腈从10％升到90％；检测波长：254nm。收集产品，减压冻干后，得到180毫克黄色固体2-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-2-((4-甲酰基吡啶-2-基)甲基)-1-甲基肼-1-羧酸叔丁酯(34.8％收率)。
MS(ESI)M/Z：496[M+H +]。
步骤G：2-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-1-甲基-2-((4-(吡咯烷-1-基甲基)吡啶-2-基)甲基)肼-1-羧酸叔丁酯的制备
在氮气保护，0摄氏度下，向50毫升三口烧瓶中加入2-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-2-((4-甲酰基吡啶-2-基)甲基)-1-甲基肼-1-羧酸叔丁酯(180毫克，0.38毫摩尔)，二氯甲烷(15毫升)以及吡咯烷(81毫克，1.14毫摩尔)。控制温度在0到10摄氏度，搅拌10分钟后，加入三乙酰氧基硼氢化钠(97毫克，0.46毫摩尔)。随后，将反应装置移至室温下，搅拌过夜。
将反应液减压浓缩，残余物用硅胶柱层析纯化(二氯甲烷/甲醇＝10/1)得到120毫克黄色半固体2-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-1-甲基-2-((4-(吡咯烷-1-基甲基)吡啶-2-基)甲基)肼-1-羧酸叔丁酯(收率59.6％)。
MS(ESI)M/Z：531[M+H +]。
步骤H：2-(5,6-二氨基-2-丁氧基嘧啶-4-基)-1-甲基-2-((4-(吡咯烷-1-基甲基)吡啶-2- 基)甲基)肼-1-羧酸叔丁酯乙酸盐的制备
在室温下，向50毫升三口烧瓶中依次加入2-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-1-甲基-2-((4-(吡咯烷-1-基甲基)吡啶-2-基)甲基)肼-1-羧酸叔丁酯(100毫克，0.19毫摩尔)，醋酸(10毫升)以及锌粉(100毫克，1.53毫摩尔)。随后，反应混合物在室温下搅拌3小时。
将反应液减压抽滤，收集滤液。滤饼用乙酸乙酯(5毫升×2)淋洗。合并滤液后，减压浓缩，得到80毫克黄色半固体2-(5,6-二氨基-2-丁氧基嘧啶-4-基)-1-甲基-2-((4-(吡咯烷-1-基甲基)吡啶-2-基)甲基)肼-1-羧酸叔丁酯乙酸盐。无需纯化，粗产品直接用于下一步反应。
MS(ESI)M/Z：501[M+H +]。
步骤I：2-(5,6-二氨基-2-丁氧基嘧啶-4-基)-1-甲基-2-((4-(吡咯烷-1-基甲基)吡啶-2-基)甲基)肼-1-羧酸叔丁酯盐酸盐的制备
向25毫升三口烧瓶中，加入2-(5,6-二氨基-2-丁氧基嘧啶-4-基)-1-甲基-2-((4-(吡咯烷-1-基甲基)吡啶-2-基)甲基)肼-1-羧酸叔丁酯乙酸盐(87毫克，0.16毫摩尔)和1,4-二氧六环(5.0毫升)。在0摄氏度下，搅拌5分钟。随后，加入1,4-二氧六环的盐酸溶液(5.0毫升，4.0M,20.0毫摩尔)。在0摄氏度下，搅拌1小时。
将反应液减压浓缩，得到83毫克黄色固体2-(5,6-二氨基-2-丁氧基嘧啶-4-基)-1-甲基-2-((4-(吡咯烷-1-基甲基)吡啶-2-基)甲基)肼-1-羧酸叔丁酯盐酸盐。无需纯化，粗产品直接用于下一步反应。
MS(ESI)M/Z：401[M+H +]。
步骤J：5-氨基-7-丁氧基-2-甲基-1-((4-(吡咯烷-1-基甲基)吡啶-2-基)甲基)-1,2-二氢嘧啶并[5,4-e][1,2,4]三嗪-3(4H)-酮三氟乙酸盐的制备
向25毫升三口烧瓶中加入2-(5,6-二氨基-2-丁氧基嘧啶-4-基)-1-甲基-2-((4-(吡咯烷-1-基甲基)吡啶-2-基)甲基)肼-1-羧酸叔丁酯盐酸盐(83毫克，0.21毫摩尔)，二氯甲烷(4.0毫升)与四氢呋喃(4.0毫升)的混合溶液中。在0摄氏度搅拌下，依次加入三乙胺(106毫克，1.05毫摩尔)，N,N'-羰基二咪唑(102毫克，0.63毫摩尔)。随后，控制反应液温度在0摄氏度下，搅拌1小时。
将反应液减压浓缩。粗产品用N,N-二甲基甲酰胺(2.0毫升)溶至澄清，粗产品用制备型高效液相色谱纯化。分离条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有0.05％三氟乙酸)和乙腈；流速：25毫升/分钟；梯度：在7分钟内，乙腈从10％升到90％；检测波长：254nm。收集产品，低温冻干后，得到11.1毫克棕色油状物5-氨基-7-丁氧基-2-甲基-1-((4-(吡咯烷-1-基甲基)吡啶-2-基)甲基)-1,2-二氢嘧啶并[5,4-e][1,2,4]三嗪-3(4H)-酮三氟乙酸盐(化合物7，收率9.8％)。
MS(ESI)M/Z：427[M+H +]。
1H NMR(300MHz,Methanol-d 4)δ8.57(d,J＝2.7Hz,1H),7.55-7.43(m,2H),4.62(s,2H),4.43(s,2H),4.27(t,J＝7.5Hz,2H),3.63–3.30(m,4H),3.18(s,3H),2.25–1.95(m,4H),1.78–1.68(m,2H),1.54-1.42(m,2H),0.98(t,J＝7.5Hz,3H)。
19F NMR(282MHz,Chloroform-d)δ-75.61。
实施例8：5-氨基-2-甲基-1-(3-(吡咯烷-1-基甲基)苄基)-7-(1-(四氢-2H-吡喃-4-基)乙氧基)-1,4-二氢嘧啶并[5,4-e][1,2,4]三嗪-3(2H)-酮
Figure PCTCN2019111625-appb-000035
合成方案
Figure PCTCN2019111625-appb-000036
步骤A：2-(6-氨基-2-羟基-5-硝基嘧啶-4-基)-1-甲基-2-(3-(吡咯烷-1-基甲基)苄基)肼-1-羧酸叔丁酯的制备
将2-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-1-甲基-2-(3-(吡咯烷-1-基甲基)苄基)肼-1-羧酸叔丁酯(2.00克，3.77毫摩尔)溶于50毫升叔丁醇中，再加入4摩尔/升氢氧化钠水溶液(9.4毫升)。70摄氏度反应过夜。LCMS监控原料消失。
将反应减压浓缩除去溶剂，滤渣用10毫升N,N-二甲基甲酰胺溶至澄清。经制备型高效液相色谱纯化。分离条件如下，色谱柱：X select C18 19mm*150mm；流动相：水和乙腈；流速：25毫升/分钟；梯度：在30分钟内，乙腈从0％升到70％；检测波长：254nm。收集产品并冻干，得到1.00克2-(6-氨基-2-羟基-5-硝基嘧啶-4-基)-1-甲基-2-(3-(吡咯烷-1-基甲基)苄基)肼-1-羧酸叔丁酯(收率82％)。
MS(ESI)M/Z:474[M+H +]。
步骤B1至B2：1-(四氢-2H-吡喃-4-基)乙基甲磺酸酯的制备
冰水浴下，将1-(四氢-2H-吡喃-4-基)乙-1-酮(10.00克，78.13毫摩尔)溶于无水甲醇中(100毫升)中。然后，向反应液中分批加入硼氢化钠(1.50克，39.47毫摩尔)。搅拌半小时后，TLC监控发现原料消失。
向反应液中缓慢加入冰水(50毫升)。混合液减压浓缩除去甲醇。水相用乙酸乙酯萃取(50毫升×3次)，合并有机相。有机相先用50毫升饱和氯化钠溶液洗涤一次，然后经无水硫酸钠干燥后减压浓缩。得到10.02克1-(四氢-2H-吡喃-4-基)乙-1-醇。无需纯化，直接用于下步反应。
冰水浴下，将1-(四氢-2H-吡喃-4-基)乙-1-醇(5.00克，38.46毫摩尔)，三乙胺(7.80克，70.08毫摩尔)溶于20毫升二氯甲烷中。然后，逐滴加入甲磺酰氯(5.30克，46.09毫摩尔)。滴加完毕，反应液自然回温至室温，然后在室温下继续搅拌4小时。TLC监控发现原料消失。
向反应液中缓慢加入冰水(20毫升)。混合液用二氯甲烷萃取(20毫升×3次)，合并有机相。有机相先用1摩尔/升的稀盐酸洗涤(20毫升×2次)，再用饱和的碳酸氢钠溶液洗涤(20毫升×2次)，最后用饱和氯化钠溶液洗涤(20毫升×2次)。洗涤后的有机相经无水硫酸钠干燥后，减压浓缩，得到7.50克1-(四氢-2H-吡喃-4-基)乙基甲磺酸酯。该化合物不稳定，无需纯化，粗产品直接用于下步反应。
步骤C：2-(6-氨基-5-硝基-2-(1-(四氢-2H-吡喃-4-基)乙氧基)嘧啶-4-基)-1-甲基-2-(3-(吡咯烷)-1-基甲基)苄基)肼-1-羧酸叔丁酯的制备
将2-(6-氨基-2-羟基-5-硝基嘧啶-4-基)-1-甲基-2-(3-(吡咯烷-1-基甲基)苄基)肼-1-羧酸叔丁酯(1.00克，2.11毫摩尔)和1-(四氢-2H-吡喃-4-基)乙基甲磺酸酯(7.50克，36.06毫摩尔)溶于100毫升乙腈中，随后加入碳酸铯(2.00克，6.13毫摩尔)。搅拌混合均匀后，80 摄氏度反应过夜。
将反应液抽滤，收集滤液。滤渣用二氯甲烷洗涤(20毫升×2次)。合并滤液并减压浓缩。所得残余物经硅胶柱层析法分离纯化(洗脱剂：甲醇/二氯甲烷＝1/20),得到458毫克白色固体2-(6-氨基-5-硝基-2-(1-(四氢-2H-吡喃-4-基)乙氧基)嘧啶-4-基)-1-甲基-2-(3-(吡咯烷)-1-基甲基)苄基)肼-1-羧酸叔丁酯(收率37％)。
MS(ESI)M/Z：586[M+H +]。
步骤D：2-(5,6-二氨基-2-(1-(四氢-2H-吡喃-4-基)乙氧基)嘧啶-4-基)-1-甲基-2-(3-(吡咯烷-1基甲基)苄基)肼-1-羧酸叔丁酯乙酸盐的制备
将2-(6-氨基-5-硝基-2-(1-(四氢-2H-吡喃-4-基)乙氧基)嘧啶-4-基)-1-甲基-2-(3-(吡咯烷)-1-基甲基)苄基)肼-1-羧酸叔丁酯(458毫克，0.78毫摩尔)溶于5.00毫升冰醋酸中。然后，向反应液中加入锌粉(101.4毫克，1.56毫摩尔)。室温下搅拌过夜。
将反应液过滤，收集滤液，滤渣用乙酸乙酯洗涤(20毫升×2次)。合并滤液并减压浓缩，得到400毫克黄色油状物2-(5,6-二氨基-2-(1-(四氢-2H-吡喃-4-基)乙氧基)嘧啶-4-基)-1-甲基-2-(3-(吡咯烷-1基甲基)苄基)肼-1-羧酸叔丁酯乙酸盐。无需纯化，直接用于下步反应。
MS(ESI)M/Z：556[M+H +]。
步骤E：6-(2-甲基-1-(3-(吡咯烷-1-基甲基)苄基)肼基)-2-(1-(四氢-2H-吡喃-4-基)乙氧基)嘧啶-4,5-二胺三氟乙酸盐的制备
冰水浴下，将2-(5,6-二氨基-2-(1-(四氢-2H-吡喃-4-基)乙氧基)嘧啶-4-基)-1-甲基-2-(3-(吡咯烷-1基甲基)苄基)肼-1-羧酸叔丁酯乙酸盐(400毫克，粗产品)溶于二氯甲烷(10.0毫升)中。然后，逐滴加入三氟乙酸(3.0毫升)。滴加完毕，将反应装置移至室温下，搅拌3小时。
将反应液减压浓缩至干，得到350毫克黄色液体6-(2-甲基-1-(3-(吡咯烷-1-基甲基)苄基)肼基)-2-(1-(四氢-2H-吡喃-4-基)乙氧基)嘧啶-4,5-二胺三氟乙酸盐。
MS(ESI)M/Z：456[M+H +]。
步骤F：5-氨基-2-甲基-1-(3-(吡咯烷-1-基甲基)苄基)-7-(1-(四氢-2H-吡喃-4-基)乙氧基)-1,4-二氢嘧啶并[5,4-e][1,2,4]三嗪-3(2H)-酮三氟乙酸盐的制备
冰水浴下，将6-(2-甲基-1-(3-(吡咯烷-1-基甲基)苄基)肼基)-2-(1-(四氢-2H-吡喃-4-基)乙氧基)嘧啶-4,5-二胺三氟乙酸盐(350毫克，粗产品)，三乙胺(775毫克，7.66毫摩尔)以及N,N'-羰基二咪唑(373.4毫克，2.30毫摩尔)依次加入二氯甲烷(5.0毫升)和四氢呋喃(5.0毫升)混合溶剂中。搅拌混合均匀后，将将反应液自然回温至室温，并在室温下继续搅拌1小时。
将反应液减压浓缩，残余用N,N-二甲基甲酰胺(5.0毫升)溶解至澄清，经制备型高效液相色谱纯化。纯化条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有0.05％TFA)和乙腈；流速:20毫升/分钟；梯度：在15分钟内，乙腈从10％升到60％；检测波长：254nm。收集产品，减压冻干。得到11.1毫克黄色固体5-氨基-2-甲基-1-(3-(吡咯烷-1-基甲基)苄基)-7-(1-(四氢-2H-吡喃-4-基)乙氧基)-1,4-二氢嘧啶并[5,4-e][1,2,4]三嗪-3(2H)-酮三氟乙酸盐。(化合物8，三步收率2.4％)
MS(ESI)M/Z：482[M+H +]。
19F NMR(300MHz,Methanol-d 4)δ-76.98。
1H NMR(300MHz,Methanol-d 4)δ7.65–7.48(m,2H),7.41(d,J＝7.8Hz,1H),7.27–7.18(m,1H),5.13–4.97(m,1H),4.51(s,2H),4.37(s,2H),4.09–3.85(m,2H),3.60–3.39(m,4H),3.25–3.08(m,5H),2.30–2.11(m,2H),2.10–1.96(m,2H),1.93–1.73(m,2H),1.73–1.58(m,1H),1.58–1.39(m,2H),1.34(d,J＝6.3Hz,3H)。
实施例9：5-氨基-7-丁氧基-2-甲基-1-(3-((2-甲基吡咯烷-1-基)甲基)苄基)-1,4-二氢嘧啶并[5,4-e][1,2,4]三嗪-3(2H)-酮
Figure PCTCN2019111625-appb-000037
合成方案
Figure PCTCN2019111625-appb-000038
步骤A：2-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-1-甲基-2-(3-(2-甲基吡咯烷-1-基甲基)苄基)肼-1-羧酸叔丁酯的制备
氮气气氛下，向2-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-2-(3-甲酰基苄基)-1-甲基肼-1-羧酸叔丁酯(150毫克,0.316毫摩尔)的1,2-二氯乙烷(2.0毫升)溶液中加入2-甲基吡咯烷(150毫克,0.316毫摩尔)。半小时后，零摄氏度下分批次缓慢加入醋酸硼氢化钠(150毫克,0.316毫摩尔)。室温下搅拌三小时。
后处理：往反应体系中加水(5毫升)稀释，二氯甲烷萃取(10毫升×3次)。合并的有机相用无水硫酸钠干燥，减压浓缩，浓缩物通过硅胶柱纯化(洗脱液：甲醇/二氯甲烷＝1/10)得到淡黄色固体2-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-1-甲基-2-(3-(2-甲基吡咯烷-1-基甲基)苄基)肼-1-羧酸叔丁酯(150毫克收率87％)。
MS(ESI)M/Z：544[M+H +]。
步骤B：2-(5,6-二氨基-2-丁氧基嘧啶-4-基)-1-甲基-2-(3-(2-甲基吡咯烷-1-基甲基)苄基)肼-1-羧酸叔丁酯乙酸盐
向2-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-1-甲基-2-(3-(2-甲基吡咯烷-1-基甲基)苄基)肼-1-羧酸叔丁酯(150毫克,0.276毫摩尔)的醋酸(1.5毫升)溶液中加入锌粉(180毫克,2.81毫摩尔)。室温下搅拌2小时。
后处理：过滤，滤饼用乙酸乙酯(5毫升×3)冲洗，收集滤液并减压浓缩得到淡黄色油状物2-(5,6-二氨基-2-丁氧基嘧啶-4-基)-1-甲基-2-(3-(2-甲基吡咯烷-1-基甲基)苄基)肼-1-羧酸叔丁酯乙酸盐(120毫克)，无需纯化，粗产品直接用于下一步反应。
MS(ESI)M/Z：514[M+H +]。
步骤C：2-丁氧基-6-(2-甲基-1-(3-(2-甲基吡咯烷-1-基甲基)苄基)肼基)嘧啶-4,5-二胺三氟乙酸盐的制备
取100毫升三口烧瓶，向2-(5,6-二氨基-2-丁氧基嘧啶-4-基)-1-甲基-2-(3-(2-甲基吡咯烷-1-基甲基)苄基)肼-1-羧酸叔丁酯乙酸盐(120毫克，0.234毫摩尔)的二氯甲烷溶液(1毫升)中缓慢加入三氟乙酸(0.5毫升)，室温下搅拌3小时。
后处理：减压浓缩，得到淡黄色油状物2-丁氧基-6-(2-甲基-1-(3-(2-甲基吡咯烷-1-基甲基)苄基)肼基)嘧啶-4,5-二胺三氟乙酸盐(160毫克)无需纯化，粗产品直接用于下步反应。
MS(ESI)M/Z：414[M+H +]。
步骤D：5-氨基-7-丁氧基-2-甲基-1-(3-(2-甲基吡咯烷-1-基甲基)苄基)-1,4-二氢嘧啶并[5,4-e][1,2,4]三嗪-3(2H)-酮三氟乙酸盐的制备
0摄氏度下，向2-丁氧基-6-(2-甲基-1-(3-(2-甲基吡咯烷-1-基甲基)苄基)肼基)嘧啶-4,5- 二胺三氟乙酸盐(97毫克,0.233毫摩尔)的四氢呋喃(2毫升)和二氯甲烷(2毫升)的混合溶液中依次加入三乙胺(235毫克,2.33毫摩尔)与N,N'-羰基二咪唑(112毫克,0.70毫摩尔)。加料完成，将反应液温度维持在0摄氏度下继续搅拌1小时。
后处理：将反应液减压浓缩，残留物用N,N-二甲基甲酰胺(2.0毫升)溶至澄清。粗产品通过制备型高效液相色谱纯化。纯化条件如下，色谱柱：X-select C18 19*150；流动相：水(0.05％TFA)和乙腈；流速:25毫升/分钟；梯度：8分钟内，乙腈从10％到80％；检测波长：254nm。低温减压冻干得到5.0毫克淡黄色半固体5-氨基-7-丁氧基-2-甲基-1-(3-(2-甲基吡咯烷-1-基甲基)苄基)-1,4-二氢嘧啶并[5,4-e][1,2,4]三嗪-3(2H)-酮三氟乙酸盐(化合物9，收率5％)。
MS(ESI)M/Z：440[M+H +]。
1H-NMR:(300MHz,Methanol-d 4)：δ7.51–7.35(m,3H),7.22(d,J＝6.9Hz,1H),4.58–4.53(m,1H),4.48(s,2H),4.28(t,J＝6.0Hz,2H),4.15–4.11(m,1H),3.56–3.49(m,1H),3.18–3.09(m,4H),2.41–2.34(m,1H),2.12–1.96(m,2H),1.79–1.70(m,3H),1.56–1.37(m,6H),0.97(t,J＝7.2Hz,3H)。
19F NMR(282MHz，Methanol-d 4)δ-76.88。
实施例10：5-氨基-7-丁氧基-1-(3-(吡咯烷-1-基甲基)苄基)-1,4-二氢嘧啶并[5,4-e][1,2,4]三嗪-3(2H)-酮
Figure PCTCN2019111625-appb-000039
合成方案
Figure PCTCN2019111625-appb-000040
步骤A：2-(2-丁氧基-6-氨基-5-硝基嘧啶-4-基)肼-1-羧酸甲酯的制备
向2-丁氧基-6-氯-5-硝基嘧啶-4-胺(2克，8.1毫摩尔)的四氢呋喃(20毫升)溶液中依次加入三乙胺(1.63克，16.2毫摩尔)，甲氧基羰酰肼(1.02克，15.04毫摩尔)，然后室温搅拌过夜。
后处理：减压浓缩得到固体残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝2/1)，得到黄色固体2-(2-丁氧基-6-氨基-5-硝基嘧啶-4-基)肼-1-羧酸甲酯(1.44克，60％收率)。
MS(ESI)M/Z：301[M+H +]。
步骤B：2-(2-丁氧基-6-氨基-5-硝基嘧啶-4-基)-2-(3-甲酰基苄基)肼-1-羧酸甲酯的制备
向2-(2-丁氧基-6-氨基-5-硝基嘧啶-4-基)肼-1-羧酸甲酯(1.44克，4.80毫摩尔)的乙腈(20毫升)溶液中，加入碳酸钾(746.3毫克，5.4毫摩尔)。然后室温下搅拌8个小时。
后处理：减压浓缩得到固体残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/1)，得到黄色固体2-(2-丁氧基-6-氨基-5-硝基嘧啶-4-基)-2-(3-甲酰基苄基)肼-1-羧酸甲酯(1.18克，60％收率)。
步骤C：2-(2-丁氧基-6-氨基-5-硝基嘧啶-4-基)-2-(3-(吡咯烷-1-基甲基)苄基)肼-1-羧 酸甲酯的制备
向2-(2-丁氧基-6-氨基-5-硝基嘧啶-4-基)-2-(3-甲酰基苄基)肼-1-羧酸甲酯(700毫克，1.68毫摩尔)的二氯甲烷溶液(25毫升)中加入吡咯烷(600毫克，8.36毫摩尔)，将上述溶液在室温下搅拌5分钟。然后加入醋酸硼氢化钠(925毫克，4.37毫摩尔)，室温搅拌5个小时。
后处理：减压浓缩得到固体残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝2/1)，得到黄色固体2-(2-丁氧基-6-氯-5-硝基嘧啶-4-基)-2-(3-甲酰基苄基)肼-1-羧酸甲酯(450毫克，57％收率)。
MS(ESI)M/Z：474[M+H +]。
步骤D：2-(5,6-二氨基-2-丁氧基嘧啶-4-基)-2-(3-(吡咯烷-1-基甲基)苄基)肼-1-羧酸甲酯的制备
向2-(2-丁氧基-6-氨基-5-硝基嘧啶-4-基)-2-(3-甲酰基苄基)肼-1-羧酸甲酯(250毫克，0.53毫摩尔)的乙醇(10毫升)以及水(2.5毫升)溶液中加入铁粉(249.3毫克，4.45毫摩尔)和氯化铵(83毫克，1.5毫摩尔)。随后，将反应装置在60摄氏度下搅拌12个小时。
后处理：过滤，收集滤液。滤渣用乙酸乙酯洗涤(50毫升×3)。合并滤液并减压浓缩，残留物用制备型高效液相色谱纯化。分离条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(0.05％碳酸氢铵)和乙腈；流速：25毫升/分钟；梯度：在25分钟内，乙腈从0％升到90％；检测波长：254nm。收集产品，减压冻干，得到黄色固体2-(5,6-二氨基-2-丁氧基嘧啶-4-基)-2-(3-(吡咯烷-1-基甲基)苄基)肼-1-羧酸甲酯(45毫克，19％收率)。
MS(ESI)M/Z：444[M+H +]。
步骤E：5-氨基-7-丁氧基-1-(3-(吡咯烷-1-基甲基)苄基)-1,4-二氢嘧啶并[5,4-e][1,2,4]三嗪-3(2H)-酮
将2-(5,6-二氨基-2-丁氧基嘧啶-4-基)-2-(3-(吡咯烷-1-基甲基)苄基)肼-1-羧酸甲酯(45毫克，0.1毫摩尔)溶解到N,N-二甲基乙酰胺(2毫升)中，120度反应1个小时。
后处理：反应液过滤后，经过制备型高效液相色谱纯化。纯化条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有0.05％三氟乙酸)和乙腈；流速：25毫升/分钟；梯度：在20分钟内，乙腈从5％升到80％；检测波长：254nm。减压冻干得到8毫克棕色固体5-氨基-7-丁氧基-1-(3-(吡咯烷-1-基甲基)苄基)-1,4-二氢嘧啶并[5,4-e][1,2,4]三嗪-3(2H)-酮三氟乙酸盐(化合物10，1.4％收率)。
MS(ESI)M/Z：412[M+H +]。
1H NMR(300MHz,Methanol-d 4):δ7.69–7.42(m,4H),4.66(s,2H),4.45–4.27(m,4H), 3.50(s,2H),3.16(s,2H),2.17–1.81(m,4H),1.81–1.28(m,4H),0.99–0.94(m,3H)。
19F NMR(282MHz，Methanol-d 4)δ-77.03。
实施例11：5-氨基-7-丁氧基-1-(2-氟-5-(吡咯烷-1-基甲基)苄基)-2-甲基-1,4-二氢嘧啶并[5,4-e][1,2,4]三嗪-3(2H)-酮
Figure PCTCN2019111625-appb-000041
合成方案
Figure PCTCN2019111625-appb-000042
步骤A-B：(3-(溴甲基)-4-氟苯基)甲醇的制备
往1升的单口圆底烧瓶中依次加入4-氟-3-甲基苯甲酸(10.0克，64.9毫摩尔),四氯化碳(300毫升),N-溴代琥珀酰亚胺(11.5克，64.9毫摩尔)和偶氮二异丁腈(200毫克，催化量)。搅拌混合均匀后，90摄氏度下加热3小时。LC-MS监测显示反应完成。
待反应液冷却至室温，往反应体系中加饱和氯化铵水溶液(100毫升)淬灭反应。将反应液抽滤，收集滤液。滤液静置分层，分液得到有机相。水相用二氯甲烷萃取(100毫升×2次)。合并有机相，有机相先用水洗(50毫升×2次)，然后用无水硫酸钠干燥，最后减压浓缩。浓缩物用硅胶柱纯化(洗脱液：乙酸乙酯/石油醚＝3/2)。收集产品，减压浓缩，得到6.80克白色固体3-(溴甲基)-4-氟苯甲酸(收率,45.1％)。粗产品直接用于下一步反应。
往500毫升的单口圆底烧瓶中依次加入3-(溴甲基)-4-氟苯甲酸(6.30克，19.69毫摩尔)和四氢呋喃(100毫升)。冰浴下，缓慢滴加硼烷的四氢呋喃络合物(1.0M，200毫升，200毫摩尔)。加完后移除冰浴，反应液在室温下继续搅拌12小时，TLC监测显示反应原料消失。
把反应液慢慢加入盛有冰水(300毫升)的5升塑料烧杯中。所得混合液用乙酸乙酯萃取(500毫升×3次)，合并有机相。有机相先用无水硫酸钠干燥，然后减压浓缩。得5.0克白色固体(3-(溴甲基)-4-氟苯基)甲醇(收率,84.5％)。无需进一步纯化直接用于下一步反应。
步骤C：2-(2-丁氧基-6-氯-5-硝基嘧啶-4-基)-2-(2-氟-5-(羟甲基)苄基)-1-甲基肼-1-羧酸叔丁酯的制备
往50毫升的单口圆底烧瓶中依次加入(3-(溴甲基)-4-氟苯基)甲醇(630毫克,2.89毫摩尔),乙腈(15.0毫升),2-(2-丁氧基-6-氯-5-硝基嘧啶-4-基)-1-甲基肼-1-羧酸叔丁酯(1.08克,2.89毫摩尔)和无水碳酸钾(1.10克,7.98毫摩尔)。60摄氏度下搅拌3小时。待反应体系冷却至室温，向反应液中加水(20.0毫升)稀释。所得混合液用乙酸乙酯萃取(50毫升×3次)，合并有机相。有机相先用无水硫酸钠干燥，然后减压浓缩得到1.24克淡黄色油状物2-(2-丁氧基-6-氯-5-硝基嘧啶-4-基)-2-(2-氟-5-(羟甲基)苄基)-1-甲基肼-1-羧酸叔丁酯。无需进一步纯化，直接用于下一步反应。
MS(ESI)M/Z：514[M+H +]。
步骤D：2-(2-丁氧基-6-氯-5-硝基嘧啶-4-基)-2-(2-氟-5-甲酰基苄基)-1-甲基肼-1-羧酸叔丁酯的制备
向25毫升的单口瓶中，加入2-(2-丁氧基-6-氯-5-硝基嘧啶-4-基)-2-(2-氟-5-(羟甲基)苄基)-1-甲基肼-1-羧酸叔丁酯(1.24克,2.42毫摩尔)和二氯甲烷(10毫升)。搅拌溶解后,加入二氧化锰(585毫克,6.72毫摩尔)。40摄氏度下搅拌过夜。
将反应液抽滤，收集滤液。滤液减压浓缩。浓缩物用硅胶柱纯化(洗脱液：乙酸乙酯/石油醚＝1/1)。收集产品，减压浓缩，得到580毫克淡黄色固体2-(2-丁氧基-6-氯-5-硝基嘧啶-4-基)-2-(2-氟-5-甲酰基苄基)-1-甲基肼-1-羧酸叔丁酯(收率,43.3％)。
MS(ESI)M/Z：512[M+H +]。
步骤E：2-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-2-(2-氟-5-甲酰基苄基)-1-甲基肼-1-羧酸叔丁酯的制备
往10毫升的高压反应器中依次加入2-(2-丁氧基-6-氯-5-硝基嘧啶-4-基)-2-(2-氟-5-甲酰基苄基)-1-甲基肼-1-羧酸叔丁酯(580毫克,0.978毫摩尔)以及氨的异丙醇溶液(2.0M,3.0毫升，6.0毫摩尔)。搅拌混合均匀后，将反应液油浴60摄氏度加热12小时。LC-MS 监测显示反应完全后，将反应液倒入水(5毫升)中，用乙酸乙酯萃取(10毫升×3次)。合并有机相，无水硫酸钠干燥。减压浓缩得到390毫克淡黄色油状物粗产品2-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-2-(2-氟-5-甲酰基苄基)-1-甲基肼-1-羧酸叔丁酯。无需纯化，化合物直接用于下一步反应。
MS(ESI)M/Z：493[M+H +]。
步骤F：2-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-2-(2-氟-5-(吡咯烷-1-基甲基)苄基)-1-甲基肼-1-羧酸叔丁酯的制备
往25毫升三口瓶中依次加入2-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-2-(2-氟-5-甲酰基苄基)-1-甲基肼-1-羧酸叔丁酯(390毫克,0.793毫摩尔)，二氯甲烷(5.0毫升)以及吡咯烷(750毫克,1.59毫摩尔)。常温下搅拌半小时后，于0摄氏度下分批次缓慢加入三乙酰基硼氢化钠(750毫克,1.58毫摩尔)。加料完成后，将反应液至于室温下，搅拌三小时。LC-MS监测显示反应完全。
往反应体系中加水(10毫升)稀释。所得混合液用二氯甲烷萃取(20毫升×3次)。合并有机相。有机相先用无水硫酸钠干燥，然后减压浓缩，所得残余物通过硅胶柱纯化(洗脱液：甲醇/二氯甲烷＝1/10)得到270毫克2-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-2-(2-氟-5-(吡咯烷-1-基甲基)苄基)-1-甲基肼-1-羧酸叔丁酯淡黄色固体(收率，62.3％)。
MS(ESI)M/Z：548[M+H +]。
步骤G：2-(5,6-二氨基-2-丁氧基嘧啶-4-基)-2-(2-氟-5-(吡咯烷-1-基甲基)苄基)-1-甲基肼-1-羧酸叔丁酯的制备
往25毫升的单口圆底烧瓶中依次加入2-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-2-(2-氟-5-(吡咯烷-1-基甲基)苄基)-1-甲基肼-1-羧酸叔丁酯(270毫克,0.494毫摩尔)，还原锌粉(360毫克,5.62毫摩尔)以及醋酸(3毫升)。室温下搅拌2小时，LC-MS监测显示反应完全。
反应液经硅藻土抽滤。收集滤液，滤饼并用乙酸乙酯(20毫升×2次)淋洗。合并后的滤液低压浓缩，得到240毫克淡黄色油状物粗产品2-(5,6-二氨基-2-丁氧基嘧啶-4-基)-2-(2-氟-5-(吡咯烷-1-基甲基)苄基)-1-甲基肼-1-羧酸叔丁酯，无需纯化直接用于下一步反应。
MS(ESI)M/Z：518[M+H +]。
步骤H：2-丁氧基-6-(1-(2-氟-5-(吡咯烷-1-基甲基)苄基)-2-甲基肼基)嘧啶-4,5-二胺三氟乙酸盐的制备
往25毫升的单口圆底烧瓶中依次加入2-(5,6-二氨基-2-丁氧基嘧啶-4-基)-2-(2-氟-5-(吡咯烷-1-基甲基)苄基)-1-甲基肼-1-羧酸叔丁酯(240毫克,0.464毫摩尔)，二氯甲烷(2.0毫升)以及三氟乙酸(1.0毫升)。室温下搅拌2小时，LC-MS监测显示反应完全。
将反应液减压浓缩，得到320毫克淡黄色油状物2-丁氧基-6-(1-(2-氟-5-(吡咯烷-1-基甲基)苄基)-2-甲基肼基)嘧啶-4,5-二胺。无需纯化，化合物直接用于下一步反应。
MS(ESI)M/Z：418[M+H +]。
步骤I：5-氨基-7-丁氧基-1-(2-氟-5-(吡咯烷-1-基甲基)苄基)-2-甲基-1,4-二氢嘧啶并[5,4-e][1,2,4]三嗪-3(2H)-酮三氟乙酸盐的制备往25毫升的单口圆底烧瓶中依次加入2-丁氧基-6-(1-(2-氟-5-(吡咯烷-1-基甲基)苄基)-2-甲基肼基)嘧啶-4,5-二胺(320毫克,0.767毫摩尔)，四氢呋喃(3.0毫升)与二氯甲烷(3.0毫升)。搅拌溶解后，冰水浴中依次加入三乙胺(773毫克,7.67毫摩尔)以及N,N'-羰基二咪唑(368毫克,2.30毫摩尔)。1小时后，LC-MS监测显示反应完全。
将反应液减压浓缩，所得残留物用N,N-二甲基甲酰胺(3.0毫升)溶至澄清。通过制备型高效液相色谱纯化。纯化条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有0.05％TFA)和乙腈；流速:25毫升/分钟；梯度：在7分钟内，乙腈从10％升到80％；检测波长：254nm。收集产品，减压冻干得到139.8毫克黄色半固体5-氨基-7-丁氧基-1-(2-氟-5-(吡咯烷-1-基甲基)苄基)-2-甲基-1,4-二氢嘧啶并[5,4-e][1,2,4]三嗪-3(2H)-酮三氟乙酸盐(化合物11，收率41.1％)。
MS(ESI)M/Z：444[M+H +]。
1H-NMR(300MHz,CD 3OD,ppm)：δ7.58–7.55(m,1H),7.45(d,J＝6.6Hz,1H),7.19(t,J＝9.0Hz,1H),4.59(s,2H),4.39–4.34(m,4H),3.46(s,2H),3.23(s,3H),3.12(s,2H),2.23–1.92(m,4H),1.81–1.70(m,2H),1.55–1.40(m,2H),0.99(t,J＝7.5Hz,3H)。
19F NMR(300MHz,CD 3OD)：δ-117.77。
效果实施例
实验仪器：Envision(PerkinElmer；型号：2104)；MSD(MSD；型号：MESO SECTOR S 600system)
细胞及试剂：
HEK-Blue hTLR7和HEK-Blue hTLR8细胞(InvivoGen)
HEK-Blue TM Detection(InvivoGen)
DMEM(Gibco)
blasticidin(Invitrogen)
Zeocin TM(InvivoGen)
Normocin TM(InvivoGen)
Penicillin-Streptomycin(Gibco)
Fetal Bovine Serum(Gibco)
Phosphate Buffered Saline(PBS)(Gibco)
缩写：
DMSO：Dimethyl Sulfoxide(Sigma)
MSD:Meso Scale Detection
QC:quality control
IS:Internal Standard
效果实施例1：HEK-Blue hTLR 7和HEK-Blue hTLR 8细胞中药物受体亲和活性实验
实验步骤
步骤一：细胞铺板:
a)提前将HEK-Blue TM Detection检测试剂和PBS放置37℃预热。
b)将培养瓶中的培养基弃掉，用预热的PBS清洗一次。
c)加入适量PBS到培养瓶，在37℃放置5min。
d)轻拍培养瓶使细胞脱落，用含有10％FBS的培养基终止消化反应。
e)细胞悬液转移到15mL无菌离心管中，1000rpm，5min离心。
f)弃去上清，用HEK-Blue TM Detection检测试剂重悬细胞，并计数。
g)在HEK-Blue TM Detection检测试剂中将细胞密度稀释到2.2X10 5/mL。
h)向384孔板中接种45μL稀释好的细胞悬液，即每孔10000个细胞。
步骤二：药物处理:
a)待测化合物用DMSO制成10mM储液。
b)化合物制备
对照化合物GS-9620具有以下结构：
Figure PCTCN2019111625-appb-000043
待测化合物和对照化合物GS-9620：
最大浓度从10mM稀释到2mM，然后3倍稀释，10个梯度，DMSO做阴性对照。取2μL稀释好的化合物加入38μL HEK-Blue TM Detection检测试剂进行20倍中间稀释。
c)化合物对细胞处理
取5μL中间稀释好的化合物加入到已接种45μL细胞的384孔板中，对药物进行10倍稀释，DMSO的终浓度为0.5％。
待测化合物与对照化合物的最终作用浓度为10000,3333,1111,370,123,41,13,4.6,1.5,0.5,0.0nM。
d)将384孔板放入37℃，5％CO 2的培养箱孵育16小时。
步骤三：检测
使用仪器Envision检测分泌型碱性磷酸酶(SEAP)在620nm的光吸收。计算得到各待测化合物和对照化合物GS-9620的受体亲和活性，列于表1中。
效果实施例2：人外周血单核细胞中TLR 7/ 8激动实验
实验步骤:
步骤一：人血采集
1.无菌采集一名捐赠者血液15mL。
2. 15mL血液可进行3个化合物的复孔检测。
步骤二：人外周血单核细胞的分离
1.PBMC的分离应当在血液采集后2小时内分离。
2.向15mL无菌离心管中加入6mL人血分离液，放置室温平衡。
3.将5mL血液贴壁缓慢加入至6mL分离液中，使其自然分层，切忌在分离液液面以下加入。
4.室温离心30分钟，离心转速400g。
5.离心后缓慢取出离心管，小心去除最上层的血浆层。
6.去除血浆后将含单核细胞的白膜层转移到新的无菌15mL离心管。
7.取10mL的PBS到含单核细胞的离心管中，充分混匀。
8.室温离心10分钟，离心转速300g。
9.弃去上清，用10mL PBS重悬细胞，充分混匀。
10.室温离心10分钟，离心转速300g。
11.重复步骤9，10，弃去上清，用1mL培养基重悬细胞计数，培养基为RPMI1640+10％FBS+1％PS。
12.接种细胞密度为1.5X10 6/mL，96孔板接种细胞悬液100μL，每孔15万细胞。
13.将96孔板放置37℃，5％CO 2培养箱。
步骤三：稀释检测化合物
1.待测化合物用DMSO制成10mM储液。
2.待测化合物从10mM起开始3倍梯度稀释，制备9个浓度。
3.对照化合物14个浓度(从储液3倍稀释或者1.5倍稀释)。
4.DMSO为阴性对照。
5.在培养基中进行10倍的中间稀释(5μL梯度稀释化合物到45μL培养基)。
步骤四：化合物对细胞处理
1.每孔补加98μL培养基，使总体积为198μL。
2.取2μL中间稀释好的化合物(步骤三)到对应的96孔板，DMSO的终浓度为0.1％，待测化合物终浓度为10000、3333、1111、370、123、41、13、4.6、1.5、0.0nM。对照化合物终浓度为10000、3333、2222、1481、987、658、219、146、98、65、43、29、19、13、0nM。
步骤五：细胞孵育
将加化合物的96孔板放置37℃，5％CO 2培养箱孵育20小时。
步骤六：MSD实验检测
1.室温离心96孔板5分钟，离心转速1500rpm。
2.吸取上清进行MSD实验。结果列于表2中。
MSD实验中TNF-α检测步骤
步骤一：标准品和样品的制备
1.标准品制备：向标准品干粉中加入250μL Diluent 2，充分混匀，5分钟后即可使用。然后进行梯度稀释，4倍稀释7个梯度，Diluent 2作为零点。
2.样品制备：样品室温离心5分钟，离心转速为1500rpm，吸取上清待用。
3.抗体制备：抗体储液浓度为50X，使用浓度为1X。抗体用Diluent 3稀释。
4.检测液制备：储液浓度为4X，使用浓度为2X，用蒸馏水稀释。
5.洗液制备：储液为20X，使用浓度为1X，用蒸馏水稀释。
步骤二：MSD试剂盒检测TNF-α的使用步骤
1.加样品：每孔中分别加入50μL样品，标准品或对照品，封板膜密封，放置振荡器室温孵育2小时，振荡速度为650rpm。
2.洗板：每孔300μL 1X洗液洗板3次，将最后一次洗液清除干净。
3.加抗体：每孔加入25μL配制好的抗体，封板膜密封，放置振荡器室温孵育2小时，振荡速度为650rpm。
4.洗板：每孔300μL 1X洗液洗板3次，将最后一次洗液清除干净。
5.检测：每孔加入150μL 2X检测液，使用MSD仪器检测。需注意的是，加入检测液后不需孵育即可检测。
MSD实验中IFN-α检测步骤
步骤一：标准品和样品的制备
1.标准品制备：标准品储液为1μg/mL，作用起始浓度为2500pg/mL，然后进行梯度稀释，4倍稀释7个梯度，Diluent 2作为零点。
2.样品制备：样品室温离心5分钟，离心转速为1500rpm，吸取上清待用。
3.抗体制备：抗体储液浓度为50X，使用浓度为1X。抗体用Diluent 3稀释。
4.检测液制备：储液浓度为4X，使用浓度为2X，用蒸馏水稀释。
5.洗液制备：储液为20X，使用浓度为1X，用蒸馏水稀释。
步骤二：MSD试剂盒检测IFN-α的使用步骤
1.加Diluent 2：每孔加入25μL的Diluent 2，室温振荡30分钟，振荡速度为650rpm。
2.加样品：每孔中分别加入25μL样品或标准品，封板膜密封，放置振荡器室温孵育2小时，振荡速度为650rpm。
3.洗板：每孔300μL 1X洗液洗板3次，将最后一次洗液清除干净。
4.加抗体：每孔加入25μL配制好的抗体，封板膜密封，放置振荡器室温孵育2小时，振荡速度为650rpm。
5.洗板：每孔300μL 1X洗液洗板3次，将最后一次洗液清除干净。
6.检测：每孔加入150μL 2X检测液，使用MSD仪器检测。需注意的是，加入检测液后不需孵育即可检测。
表1.受体亲和活性测试结果：
Figure PCTCN2019111625-appb-000044
Figure PCTCN2019111625-appb-000045
表2.hPBMC活性测试结果：
Figure PCTCN2019111625-appb-000046
表1和表2数据显示，本发明的化合物具有高TLR 7活性以及相对于TLR 8的高TLR 7选择性。其高活性也在hPBMC试验中得到了证实。
化合物在小鼠中的PD实验
实验步骤：
a)剂量：10mg/kg
测试物：GS-9620(对照化合物)，化合物3
b)测试物经灌胃口服给三只C57小鼠。给药后，分别于1、2及4小时点经尾静脉采血。全血收集在预先装有K 2EDTA的管子中，并经离心分离得到血浆，保存在-80℃冰箱中。
c)血浆样品经解溶后，用于IFN-α及TNF-α的分析。
IFN-α及TNF-α的分析:参照前述MSD法分析IFN-α及TNF-α的方法测试IFN-α及TNF-α浓度。
d)血浆及肝脏化合物的定量分析
LC-MS/MS设备
高压液相色谱仪(HPLC):Prominence(Degasser DGU-20A5R)；Liquid Chromatograph LC-30AD；Communications Bus Module CBM-20A,Auto Sampler SIL-30AC；Rack changer II。
色谱柱:Eclipse XDB-Phenyl 2.1×50mm 3.5μm。
质谱仪(MS)：AB Sciex Triple Quan 5500LC/MS/MS。
HPLC条件：
流动相
溶液A:5％乙腈水(0.1％甲酸)
溶液B:95％乙腈水(0.1％甲酸)
血浆样品配制：
1)标准品配制：5μL工作液(分别含1,2,4,10,20,100,200,1000,2000ng/mL的化合物)分别加入10μL空白C57小鼠血浆或肝组织匀浆得到总体积为15μL的0.5～1000ng/mL(0.5,1,2,5,10,50,100,500,1000ng/mL)标准品。
2)质控样品(QC)：独立配制5个浓度为1.5ng/mL,3ng/mL,6ng/mL,50ng/mL及800ng/mL的血浆质控样品。
3)测试样品:5μL空白液+10μL测试血浆样品。
肝脏样品配制:
肝脏样品(克)以1:4的比例和PBS(mL)混合匀浆。随后，加5μL空白液于10μL匀浆后的肝脏样品，得到肝脏样品。
上清液配制：
将15μL标准样品、15μL QC样品及15μL未知样品分别加入200μL含有IS的乙腈中，用于沉淀蛋白。随后样品涡旋混合30分钟，然后经过15分钟在4度条件下离心旋转。取10μL上清液用于LC/MS/MS定量分析。
结果和结论：
化合物的暴露量、IFN-α及TNF-α的表达水平如图1所示由图1可知，化合物3在小鼠血浆及肝脏中暴露量均低于LC/MS/MS的分析定量下限。但是，化合物3依然能诱导IFN-α在血浆及肝脏中的表达，提示相对于GS-9620，化合物3将会大大降低由化合物及其代谢物引起的毒副作用。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (21)

  1. 式(I)的化合物，或其药学上可接受的盐、立体异构体、溶剂化物、多晶型互变异构体、同位素化合物、代谢产物或前药：
    Figure PCTCN2019111625-appb-100001
    其中：
    X选自O、S和NR x；R x选自H、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被1、2、3或4个R A取代；
    Y选自O、S、N，或者Y不存在；
    Z选自N、O、S、C和CH；
    Q选自O、S和NH；
    当Y为N时，R 1选自H、羟基、巯基、氨基、卤素、硝基、氰基、C 1-C 8烷基、C 2-C 8烯基、C 2-C 8炔基、C 6-C 10芳基和五元至十元杂芳基；其中所述烷基、烯基、炔基、芳基和杂芳基任选地被1、2、3或4个R B取代；
    R 2选自H、羟基、巯基、氨基、卤素、硝基、氰基、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被1、2、3或4个R C取代；
    L 1为C 1-C 8烃链；
    A环不存在，或A环选自：C 3-C 10环烃基、C 3-C 10杂环基、C 6-C 10芳基和五元至十元杂芳基；其中所述环烃基、杂环基、芳基和杂芳基任选地被1、2、3或4个R D取代；
    L 2不存在，或L 2为C 1-C 8烃链；
    R 3为H、C 3-C 10环烃基、C 6-C 10芳基、五元至十元杂芳基或-WR 6R 7，其中W为N或CH，其中
    R 6和R 7各自独立地选自H、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被1、2、3或4个R E取代；或
    R 6和R 7连同与其相连的N或C原子一起形成三元至十元杂环；所述杂环任选地被1、2、3或4个R E取代；并且任选地，R 6和R 7连同与其相连的N或C原子一起形成的三元至十元杂环可以任选地与A环稠和；
    R 4选自C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基或和炔基各自任 选地被1、2、3或4个R F取代；
    B环不存在，或B环选自C 3-C 10环烃基、C 3-C 10杂环基、C 6-C 10芳基和五元到十元杂芳基；其中所述环烃基、杂环基、芳基和杂芳基各自任选地被1、2、3或4个R G取代；
    R 5选自H、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被1、2、3或4个选自-OR 8、-SR 8和-NR 8R 8’的取代基取代；
    R 8和R 8’各自独立地选自H、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被1、2、3或4个R H取代；或者R 8和R 8’连同与其相连的N原子一起形成三元至十元杂环；
    R A、R B、R C、R D、R E、R F、R G、R H在每次出现时各自独立地选自卤素、氰基、硝基、-R a、-OR a、＝O、-SR a、-NR aR b、＝NR a、-C(卤素) 3、-CR(卤素) 2、-CR 2(卤素)、-OCN、-SCN、-N＝C＝O、-NCS、-NO、-NO 2、-N(R a)C(＝O)R b、-N(R a)C(＝O)OR b、-N(R a)C(＝O)NR bR c、-C(＝O)NR aR b、-C(＝O)OR a、-OC(＝O)NR aR b、-OC(＝O)R a、-OC(＝O)OR a、-C(＝O)R a、-S(＝O) 2OR a、-S(＝O) 2R a、-OS(＝O) 2R a、-OS(＝O) 2OR a、-S(＝O) 2NR aR b、-S(＝O)R a、-N(R a)S(＝O) 2R b、-N(R a)S(＝O) 2NR bR c、-N(R a)S(＝O) 2OR b、-OP(＝O)(OR a)OR b、-P(＝O)(OR a)OR b、-C(＝O)R a、-C(＝S)R a、-C(＝O)OR a、-C(＝S)OR a、-C(＝O)SR a、-C(＝S)SR a、-C(＝O)NR aR b、-C(＝S)NR aR b、-C(＝NR a)NR bR c和-NR aC(＝NR b)NR cR d；R a、R b、R c和R d每次出现时各自独立地选自H、C 1-C 8烷基、C 3-C 8环烃基、三元到八元杂环基、C 6-C 10芳基、五元到十元杂芳基、C 6-C 10芳基-C 1-C 4烷基和五元到十元杂芳基-C 1-C 4烷基；其中所述烷基、环烃基、杂环基、芳基、杂芳基、芳基-C 1-C 4烷基和杂芳基-C 1-C 4烷基各自任选地被1、2、3或4个卤素、＝O、-OH、-NH 2、-SH取代；
    其中当R A、R B、R C、R D、R E、R F、R G或R H各自独立地为-NR aR b时，R a、R b任选地和与其相连的N原子一起形成三元至十元杂环。
  2. 权利要求1的化合物，或其药学上可接受的盐、立体异构体、溶剂化物、多晶型互变异构体、同位素化合物、代谢产物或前药，其中X为O或S，优选为O。
  3. 权利要求1-2中任一项的化合物，或其药学上可接受的盐、立体异构体、溶剂化物、多晶型互变异构体、同位素化合物、代谢产物或前药，其中Y和R 1不存在，或者
    Y为N，并且R 1选自H、C 1-C 8烷基、C 2-C 8烯基、C 2-C 8炔基、C 6-C 10芳基和五元至十元杂芳基；其中所述烷基、烯基、炔基、芳基和杂芳基各自任选地被1、2、3或4个R B取代；其中所述五元至十元杂芳基含有1-3个各自独立地选自O、N和S的杂原子；优选地，Y为N，并且R 1为H或C 1-C 4烷基；优选H或C 1-C 3烷基；进一步优选C 1-C 2烷基；其中所述烷基任选地被1、2、3或4个R B取代；更优选地，Y为N，并且R 1为H 或C 1-C 2烷基；其中所述烷基任选地被1、2、3或4个卤素取代；其中R 1进一步优选为H、CH 3、CF 3或CH 2CF 3，特别优选为H或CH 3。
  4. 权利要求1-3中任一项的化合物，或其药学上可接受的盐、立体异构体、溶剂化物、多晶型互变异构体、同位素化合物、代谢产物或前药，其中Z为N，并且R 2选自H、羟基、巯基、氨基、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被1、2、3或4个R C取代；优选地，Z为N，并且R 2选自H、羟基、巯基、氨基、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被1、2、3或4个R C取代；更优选地，Z为N，并且R 2为H、羟基或甲基，其中所述甲基任选地被1、2或3个卤素取代；其中R 2进一步优选为H、羟基或甲基，特别优选为H或羟基；或者
    Z为CH，并且R 2选自H、羟基、巯基、氨基、卤素、硝基、氰基、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中烷基、烯基和炔基各自任选地被1、2、3或4个R C取代；R 2优选为H、羟基、巯基、卤素或C 1-C 4烷基；优选H、羟基、巯基、卤素或C 1-C 3烷基；其中所述烷基任选地被1、2、3或4个R C取代；R 2更优选为H、羟基、卤素或甲基，其中所述甲基任选地被1、2或3个卤素取代；更优选地，R 2为H、F、羟基或甲基，特别优选为H或羟基。
  5. 权利要求1-4中任一项的化合物，或其药学上可接受的盐、立体异构体、溶剂化物、多晶型互变异构体、同位素化合物、代谢产物或前药，其中L 1为-(CH 2) n-；其中n为1、2、3、4、5、6、7或8；优选为1、2、3、4或5，更优选为1、2或3；特别优选为1。
  6. 权利要求1-5中任一项的化合物，或其药学上可接受的盐、立体异构体、溶剂化物、多晶型互变异构体、同位素化合物、代谢产物或前药，其中A环选自以下基团：苯基；吡啶；呋喃；噻吩；吡咯；环己烷；环戊烷；环丁烷；环丙烷；双环[2.2.1]庚烷，以1-碳原子和4-碳原子与分子其他部分相连；双环[1.1.1]戊烷，以1-碳原子和3-碳原子与分子其他部分相连；7-氧双环[2.2.1]庚烷，以1-碳原子和4-碳原子与分子其他部分相连；其中所述苯基、吡啶、呋喃、噻吩、吡咯、环己烷、环戊烷、环丁烷、环丙烷、双环[2.2.1]庚烷、双环[1.1.1]戊烷和7-氧双环[2.2.1]庚烷各自任选地被1、2、3或4个R D取代；优选地，A环选自苯基和吡啶；并且各自任选地被1、2、3或4个R D取代；其中R D优选为卤素，特别优选为F。
  7. 权利要求1-6中任一项的化合物，或其药学上可接受的盐、立体异构体、溶剂化物、多晶型互变异构体、同位素化合物、代谢产物或前药，其中L 2选自-(CH 2) n-；其中n 为1、2、3、4或5、6、7或8；优选为1、2、3、4或5，更优选为1、2或3；特别优选为1。
  8. 权利要求1-7中任一项的化合物，或其药学上可接受的盐、立体异构体、溶剂化物、多晶型互变异构体、同位素化合物、代谢产物或前药，其中R 3为-NR 6R 7，任选地被1、2、3或4个R E取代；优选地，R 3选自-N(C 1-C 4烷基)(C 1-C 4烷基)、吡咯烷、哌啶、吗啉和哌嗪，其中所述烷基、吡咯烷、哌啶、吗啉和哌嗪各自任选地被1、2、3或4个R E取代；更优选地，R 3选自-N(CH 3) 2、吡咯烷-1-基、哌啶-1-基、吗啉-1-基和4-C 1-C 3烷基-哌嗪-1-基；其中所述CH 3、吡咯烷-1-基、哌啶-1-基、吗啉-1-基和哌嗪-1-基各自任选地被1、2、3或4个R E取代；进一步优选地，R 3选自吡咯烷-1-基和哌啶-1-基；其中所述吡咯烷-1-基和哌啶-1-基各自任选地被1、2、3或4个R E取代。
  9. 权利要求1-8中任一项的化合物，或其药学上可接受的盐、立体异构体、溶剂化物、多晶型互变异构体、同位素化合物、代谢产物或前药，其中R 4为C 1-C 4烷基，其中所述烷基任选地被1、2、3或4个R F取代；优选地，R 4为C 1-C 3烷基，特别是C 3烷基；其中所述烷基任选地被1、2、3或4个R F取代；更优选地，R 4为-CH 2-、-CH(CH 3)-、-CH(C 2H 5)-、-CH(C 3H 7-n)-、-CH(CH 2OR a)-、-CH(CH 2SR a)-、-C(CH 2OR a)(R b)-、-C(CH 2OR a)(OR b)-、-CH(C(＝O)OR a)-、-CH(S(＝O)R a)-、-CH(S(＝O) 2R a)-、-CH(S(＝O) 2OR a)-、-CH(OC(＝O)R a)-、-CH(OS(＝O) 2R a)-、-C(C(＝O)OR a)(R b)-、-C(S(＝O)R a)(R b)-、-C(S(＝O) 2R a)(R b)-、-C(S(＝O) 2OR a)(R b)-、-C(OC(＝O)R a)(R b)-、-C(OS(＝O) 2R a)(R b)-、-C(C(＝O)OR a)(OR b)-、-C(S(＝O)R a)(OR b)-、-C(S(＝O) 2R a)(OR b)-、-C(S(＝O) 2OR a)(OR b)-、-CH(CH 2CH 2OR a)-、-CH(CH 2CH 2SR a)-、-C(CH 2CH 2OR a)(R b)-、-C(CH 2CH 2OR a)(OR b)-、-CH(CH 2C(＝O)OR a)-、-CH(CH 2S(＝O)R a)-、-CH(CH 2S(＝O) 2R a)-、-CH(CH 2S(＝O) 2OR a)-、-CH(CH 2OC(＝O)R a)-、-CH(CH 2OS(＝O) 2R a)-、-C(CH 2C(＝O)OR a)(R b)-、-C(CH 2S(＝O)R a)(R b)-、-C(CH 2S(＝O) 2R a)(R b)-、-C(CH 2S(＝O) 2OR a)(R b)-、-C(CH 2OC(＝O)R a)(R b)-、-C(CH 2OS(＝O) 2R a)(R b)-、-C(CH 2C(＝O)OR a)(OR b)-、-C(CH 2S(＝O)R a)(OR b)-、-C(CH 2S(＝O) 2R a)(OR b)-、-C(CH 2S(＝O) 2OR a)(OR b)-、-C(CH 2OC(＝O)R a)(OR b)-、-C(CH 2OS(＝O) 2R a)(OR b)-、-CH(CH 2CH 2S(＝O)R a)-、-CH(CH 2CH 2S(＝O) 2R a)-、-CH(CH 2CH 2S(＝O) 2OR a)-、-CH(CH 2CH 2OC(＝O)R a)-、-CH(CH 2CH 2OS(＝O) 2R a)-、-C(CH 2CH 2S(＝O)R a)(R b)-、-C(CH 2CH 2S(＝O) 2R a)(R b)-、-C(CH 2CH 2S(＝O) 2OR a)(R b)-、-C(CH 2CH 2OC(＝O)R a)(R b)-、-C(CH 2CH 2OS(＝O) 2R a)(R b)-、-C(CH 2CH 2S(＝O)R a)(OR b)-、-C(CH 2CH 2S(＝O) 2R a)(OR b)-、-C(CH 2CH 2S(＝O) 2OR a)(OR b)-、-C(CH 2CH 2OC(＝O)R a)(OR b)-、-C(CH 2CH 2OS(＝O) 2R a)(OR b)-、-CH(CH 2NR aR b)-、-C(CH 2NR aR b)(R c)-、-C(CH 2NR aR b)(OR c)-、 -CH(CH 2CH 2NR aR b)-、-C(CH 2CH 2NR aR b)(R c)-、-C(CH 2CH 2NR aR b)(OR c)-、-CH(CH 2C(＝O)NR aR b)-、-CH(CH 2S(＝O) 2NR aR b)-、-C(CH 2C(＝O)NR aR b)(R c)-、-C(CH 2S(＝O) 2NR aR b)(R c)-、-C(CH 2C(＝O)NR aR b)(OR c)-、-C(CH 2S(＝O) 2NR aR b)(OR c)-、-CH(CH 2N(R a)C(＝O)R b)-、-CH(CH 2N(R a)S(＝O) 2R b)-、-CH(CH 2CH 2S(＝O) 2NR aR b)-、-CH(CH 2CH 2N(R a)C(＝O)R b)-、-CH(CH 2CH 2N(R a)S(＝O) 2R b)-、-CH(CH 2N(R a)C(＝O)R b)(R c)-、-CH(CH 2N(R a)S(＝O) 2R b)(R c)-、-CH(CH 2CH 2S(＝O) 2NR aR b)(R c)-、-CH(CH 2CH 2N(R a)C(＝O)R b)(R c)-、-CH(CH 2CH 2N(R a)S(＝O) 2R b)(R c)-、-CH(CH 2N(R a)C(＝O)R b)(OR c)-、-CH(CH 2N(R a)S(＝O) 2R b)(OR c)-、-CH(CH 2CH 2S(＝O) 2NR aR b)(OR c)-、-CH(CH 2CH 2N(R a)C(＝O)R b)(OR c)-或-CH(CH 2CH 2N(R a)S(＝O) 2R b)(OR c)-；更优选-CH(C 3H 7-n)-、-CH(CH 2OR a)-、-CH(CH 2SR a)-、-CH(CH 2CH 2OR a)-、-CH(CH 2CH 2SR a)-、-CH(CH 2C(＝O)OR a)-、-CH(CH 2S(＝O) 2R a)-、-CH(CH 2S(＝O) 2OR a)-、-CH(CH 2OC(＝O)R a)-、-CH(CH 2OS(＝O) 2R a)-、-CH(CH 2CH 2OS(＝O) 2R a)-、-CH(CH 2CH 2OC(＝O)R a)-、-CH(CH 2CH 2N(R a)S(＝O) 2R b)-、-CH(CH 2NR aR b)-、-CH(CH 2CH 2NR aR b)-、-CH(CH 2CH 2N(R a)C(＝O)R b)-、-CH(CH 2C(＝O)NR aR b)-或-CH(CH 2S(＝O) 2NR aR b)-；进一步优选-CH(C 3H 7-n)-、-CH(CH 2CH 2OR a)-、-CH(CH 2CH 2SR a)-、-CH(CH 2C(＝O)OR a)-、-CH(CH 2S(＝O) 2R a)-、-CH(CH 2S(＝O) 2OR a)-、-CH(CH 2OC(＝O)R a)-、-CH(CH 2OS(＝O) 2R a)-、-CH(CH 2CH 2OS(＝O) 2R a)-、-CH(CH 2CH 2OC(＝O)R a)-、-CH(CH 2CH 2N(R a)S(＝O) 2R b)-、-CH(CH 2CH 2NR aR b)-、-CH(CH 2CH 2N(R a)C(＝O)R b)-、-CH(CH 2C(＝O)NR aR b)-或-CH(CH 2S(＝O) 2NR aR b)-；特别优选-CH(CH 2CH 2OR a)-、-CH(CH 2CH 2OS(＝O) 2R a)-、-CH(CH 2CH 2OC(＝O)R a)-、-CH(CH 2CH 2N(R a)S(＝O) 2R b)-、-CH(CH 2C(＝O)OR a)-、-CH(CH 2S(＝O) 2OR a)-、-CH(CH 2CH 2NR aR b)-、-CH(CH 2CH 2N(R a)C(＝O)R b)-、-CH(CH 2C(＝O)NR aR b)-或-CH(CH 2S(＝O) 2NR aR b)-。
  10. 权利要求1-9中任一项的化合物，或其药学上可接受的盐、立体异构体、溶剂化物、多晶型互变异构体、同位素化合物、代谢产物或前药，其中B环不存在；或者
    B环选自苯基、吡啶、呋喃、噻吩、吡咯、噻唑、噁唑、吡喃、吡咯烷、哌啶、四氢呋喃、二氢吡喃、四氢吡喃、环氧丙烷、环己烷、环戊烷、环丁烷和环丙烷，并各自任选地被1、2、3或4个R G取代；优选地，B环为苯基或吡啶；并且各自任选地被1、2、3或4个各自独立地选自卤素、氰基、硝基、-R a、-OR a、-SR a和-NR aR b的基团取代。
  11. 权利要求1-10中任一项的化合物，或其药学上可接受的盐、立体异构体、溶剂化物、多晶型互变异构体、同位素化合物、代谢产物或前药，其中R 5选自H和C 3-C 6烷 基，其中所述烷基任选地被1、2、3或4个-OR 8、-SR 8或-NR 8R 8’取代；其中
    R 8和R 8’各自独立地选自H和C 1-C 4烷基；优选C 1-C 2烷基；其中所述烷基任选地被1、2、3或4个R H取代；
    或R 8和R 8’相连接，使-NR 8R 8’形成四元至八元杂环；其中所述杂环含有0-1个独立地选自O、S和N的额外的杂原子，并且任选地被1、2、3或4个R H取代；优选地，-NR 8R 8’形成四元至六元杂环；其中所述杂环含有0-1个独立地选自O、S和N的额外的杂原子，并且任选地被1、2、3或4个R H取代。
  12. 式(I-1)、式(I-2)或式(I-3)的化合物，或其药学上可接受的盐、立体异构体、溶剂化物、多晶型互变异构体、同位素化合物、代谢产物或前药：
    Figure PCTCN2019111625-appb-100002
    其中，X、Q、R 1、R 2、L 1、A、L 2、R 3、R 4、R F、B、R 5如权利要求1-11中任一项所定义。
  13. 式(I-4)的化合物，或其药学上可接受的盐、立体异构体、溶剂化物、多晶型互变异构体、同位素化合物、代谢产物或前药：
    Figure PCTCN2019111625-appb-100003
    其中，X、Q、L 1、A、L 2、R 3、R 4、R F、B、R 5如权利要求1-11中任一项所定义；
    R 2选自H、羟基、巯基、氨基、C 1-C 8烷基、C 2-C 8烯基和C 2-C 8炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R C取代；
    优选地，R 2选自羟基、巯基、氨基、C 1-C 4烷基、C 2-C 4烯基和C 2-C 4炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R C取代；
    更优选地，R 2选自羟基、巯基、C 1-C 4烷基、C 3-C 4烯基和C 3-C 4炔基；其中所述烷基、烯基和炔基各自任选地被一个或多个R C取代；
    进一步优选地，R 2为羟基、巯基或C 1-C 4烷基；优选羟基、巯基或C 1-C 3烷基；其中所述烷基任选地被一个或多个R C取代；
    更优选地，R 2为羟基或甲基；其中所述甲基任选地被一个或多个卤素取代；
    进一步优选地，R 2为羟基或甲基；特别优选为羟基。
  14. 式(I-5)、式(I-6)或式(I-7)的化合物，或其药学上可接受的盐、立体异构体、溶剂化物、多晶型互变异构体、同位素化合物、代谢产物或前药：
    Figure PCTCN2019111625-appb-100004
    其中，X、Q、L 1、A、L 2、R 3、R 4、R F、B、R 5如权利要求1-11中任一项所定义。
  15. 权利要求1-14中任一项的化合物，或其药学上可接受的盐、立体异构体、溶剂化物、多晶型互变异构体、同位素化合物、代谢产物或前药，其中所述化合物选自：
    Figure PCTCN2019111625-appb-100005
    Figure PCTCN2019111625-appb-100006
  16. 一种药物组合物，其包含权利要求1-15中任一项的化合物或其药学上可接受的盐、立体异构体、溶剂化物、多晶型体、互变异构体、同位素化合物、代谢产物或前药，以及至少一种药学上可接受的载体。
  17. 权利要求1-15中任一项的化合物或其药学上可接受的盐、立体异构体、溶剂化物、多晶型体、互变异构体、同位素化合物、代谢产物或前药或权利要求16的药物组合物在制备治疗对TLR 7受体的激活响应的疾病的药物中的用途。
  18. 权利要求1-15中任一项的化合物或其药学上可接受的盐、立体异构体、溶剂化物、多晶型体、互变异构体、同位素化合物、代谢产物或前药或权利要求16的药物组合物在制备用于治疗肝脏相关疾病的药物中的用途，所述肝脏相关疾病选自病毒性肝炎、自身免疫性肝病、药物毒性肝病、肝病性肝损伤、肝功能性衰竭、慢性重型肝炎、肝硬化、肝脓肿、脂肪肝和原发性肝癌中的一种或多种，优选地所述肝脏相关疾病为乙肝或丙肝。
  19. 权利要求1-15中任一项的化合物或其药学上可接受的盐、立体异构体、溶剂化物、多晶型体、互变异构体、同位素化合物、代谢产物或前药或权利要求16的药物组合物在制备用于治疗肿瘤的药物中的用途。
  20. 一种药物组合，其包含
    (1).权利要求1-15中任一项的化合物或其药学上可接受的盐、立体异构体、溶剂化物、多晶型体、互变异构体、同位素化合物、代谢产物或前药或权利要求16的药物组合物，和
    (2).PD-1抗体、PD-L1抗体或PD-1抑制剂、PD-L1抑制剂或PD-1/PD-L1抑制剂。
  21. 权利要求1-15中任一项的化合物或其药学上可接受的盐、立体异构体、溶剂化物、多晶型体、互变异构体、同位素化合物、代谢产物或前药或权利要求16的药物组合物在制备用于治疗HIV感染的药物中的用途，优选地所述HIV感染为艾滋病。
PCT/CN2019/111625 2018-10-22 2019-10-17 五元或六元杂环并嘧啶类化合物及其用途 WO2020083089A1 (zh)

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CN102666541A (zh) * 2009-10-22 2012-09-12 吉里德科学公司 用于治疗特别是病毒感染的嘌呤或脱氮嘌呤的衍生物
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US20090105212A1 (en) * 2005-09-22 2009-04-23 Dainippon Sumitomo Pharma Co., Ltd. a corporation of Japan Novel adenine compound
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