WO2016023511A1 - 作为tlr7激动剂的吡咯并嘧啶化合物 - Google Patents

作为tlr7激动剂的吡咯并嘧啶化合物 Download PDF

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Publication number
WO2016023511A1
WO2016023511A1 PCT/CN2015/086909 CN2015086909W WO2016023511A1 WO 2016023511 A1 WO2016023511 A1 WO 2016023511A1 CN 2015086909 W CN2015086909 W CN 2015086909W WO 2016023511 A1 WO2016023511 A1 WO 2016023511A1
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group
methyl
pyrrolo
butoxy
alkyl
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PCT/CN2015/086909
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English (en)
French (fr)
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丁照中
吴颢
孙飞
吴立方
杨玲
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正大天晴药业集团股份有限公司
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Priority claimed from CN201410405136.0A external-priority patent/CN105367576A/zh
Priority to MX2017002028A priority Critical patent/MX2017002028A/es
Priority to EP15831451.8A priority patent/EP3190113B1/en
Priority to NZ730011A priority patent/NZ730011B2/en
Priority to JP2017527961A priority patent/JP6328341B2/ja
Priority to BR112017002811-5A priority patent/BR112017002811B1/pt
Priority to ES15831451T priority patent/ES2875313T3/es
Priority to LTEP15831451.8T priority patent/LT3190113T/lt
Priority to SI201531613T priority patent/SI3190113T1/sl
Priority to KR1020177007194A priority patent/KR102215609B1/ko
Priority to SG11201701169XA priority patent/SG11201701169XA/en
Priority to EA201790389A priority patent/EA032824B1/ru
Priority to UAA201702350A priority patent/UA117634C2/uk
Priority to AU2015303558A priority patent/AU2015303558B2/en
Application filed by 正大天晴药业集团股份有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to US15/503,977 priority patent/US9962388B2/en
Priority to CN201580041989.3A priority patent/CN106661034B/zh
Priority to MYPI2017700489A priority patent/MY190026A/en
Priority to DK15831451.8T priority patent/DK3190113T3/da
Priority to PL15831451T priority patent/PL3190113T3/pl
Priority to KR1020197024042A priority patent/KR20190098277A/ko
Priority to CA2958097A priority patent/CA2958097C/en
Publication of WO2016023511A1 publication Critical patent/WO2016023511A1/zh
Priority to IL250586A priority patent/IL250586B/en
Priority to PH12017500281A priority patent/PH12017500281B1/en
Priority to US15/955,523 priority patent/US10555949B2/en
Priority to AU2018236899A priority patent/AU2018236899B2/en
Priority to AU2019253788A priority patent/AU2019253788C1/en
Priority to PH12020551089A priority patent/PH12020551089A1/en
Priority to IL276908A priority patent/IL276908A/en
Priority to HRP20210927TT priority patent/HRP20210927T1/hr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • 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 invention relates to a novel pyrrolopyrimidine ring compound as a TLR7 agonist or a pharmaceutically acceptable salt thereof, and in particular to a compound of the formula (I) or a pharmaceutically acceptable salt thereof.
  • Toll-like receptors are expressed in a variety of immune cells. Toll-like receptors recognize highly conserved structural motifs: pathogen-associated microbial patterns (PAMP) expressed by microbial pathogens or damage-associated molecular patterns (DAMP) released by necrotic cells. Stimulation of Toll-like receptors by a corresponding pathogen-associated microbial pattern (PAMP) or damage-associated molecular pattern (DAMP) triggers a signal cascade leading to transcription factors such as AP-1, NF- ⁇ B and interferon regulatory factors (impulse response functions) activation. This results in a variety of cellular responses, including the production of interferons, pro-inflammatory cytokines, and effector cytokines to produce an immune response.
  • PAMP pathogen-associated microbial patterns
  • DAMP damage-associated molecular patterns
  • 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.
  • Toll-like receptor 7 TLR7
  • pDC plasmacytoid dendritic cell
  • TLR8 TLR8 ligand
  • TLR8 stimulation primarily induces the production of cytokines such as tumor necrosis factor alpha (TNF-alpha) and chemokines.
  • Interferon alpha is one of the main drugs for the treatment of chronic hepatitis B or hepatitis C
  • TNF- ⁇ is a pro-inflammatory cytokine, and excessive secretion may cause serious side effects. Therefore, selectivity for TLR7 and TLR8 is critical for the development of TLR7 agonists for the treatment of viral infectious diseases.
  • TLR7 agonists have been reported, such as imiquimod, resiquimod, GS-9620. However, new TLR7 agonists with better selectivity, activity and safety are still in great demand.
  • R 1 is selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, aryl, heteroaryl, wherein The above C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group, C 3-10 cycloalkyl group, 3-10 membered heterocycloalkyl group, aryl group, heteroaryl group may be optionally one or more R 4 substitution;
  • R 2 is selected from the group consisting of hydrogen, halogen, cyano, hydroxy, decyl, amino, COOH, -CONH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl a 3-10 membered heterocycloalkyl, aryl, heteroaryl group, wherein the above hydroxyl group, fluorenyl group, amino group, COOH, -CONH 2 , C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group a C 3-10 cycloalkyl, a 3-10 membered heterocycloalkyl, aryl, heteroaryl optionally substituted with one or more R 4 ;
  • B is selected from C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, aryl, heteroaryl;
  • R 3 is selected from the group consisting of hydrogen, amino, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, aryl, heteroaryl Wherein the above amino group, C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group, C 3-10 cycloalkyl group, 3-10 membered heterocycloalkyl group, aryl group, heteroaryl group are optionally One or more R 4 substitutions,
  • R 3 , L 3 together with an ortho atom on the B ring form a saturated or unsaturated 5-8 membered ring, which is optionally substituted with one or more R 4 ;
  • n 0, 1, 2, 3, 4 or 5;
  • R 3 is not H.
  • L 1 , L 2 are each independently selected from -O-, -CH 2 -, -S-, -NH-, wherein -CH 2 -, -NH- It is optionally substituted with one or more R 4 .
  • L 1 , L 2 are each independently selected from -O-, -CH 2 -, wherein -CH 2 - is optionally substituted with one or more R 4 .
  • R 1 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 a heterocyclic hydrocarbon group, an aryl group, a heteroaryl group, wherein the above C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, aromatic The benzyl or heteroaryl group is optionally substituted with one or more R 4 groups.
  • R 1 is selected from C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more R 4 .
  • R 2 is selected from the group consisting of hydrogen, halogen, cyano, hydroxy, thiol, amino, CHO, COOH, —CONH 2 , C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, aryl, heteroaryl, wherein the above hydroxyl, thiol, amino, CHO, COOH, -CONH 2 , C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, aryl, heteroaryl are optionally substituted by one or more R 4 .
  • R 2 is selected from hydrogen, halo, cyano, hydroxy, amino, -CONH 2, C 1-6 alkyl, wherein said hydroxy, amino, -CONH 2, C 1
  • the -6 alkyl group is optionally substituted with one or more R 4 groups.
  • R 2 is selected from the group consisting of hydrogen, cyano, and —CONH 2 , wherein said —CONH 2 is optionally substituted with one or more R 4 .
  • B is selected from aryl, heteroaryl. In some embodiments of a compound of Formula (I), B is selected from the group consisting of 5-7 membered aryl, 5-7 membered heteroaryl.
  • B is selected from the group consisting of phenyl, pyridylpyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, furyl, oxazolyl, thiadiazolyl, iso Oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, triazolyl.
  • B is selected from the group consisting of phenyl, pyridyl.
  • L 3 is selected from C 0-6 alkylene, wherein said C 0-6 alkylene is optionally substituted with one or more 4 R.
  • R 3 is selected from the group consisting of hydrogen, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3- 8-membered heterocycloalkyl, aryl, heteroaryl, wherein the above amino group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 cycloalkyl group, 3-8 member hetero
  • the cycloalkyl, aryl, heteroaryl is optionally substituted by one or more R 4 ; or R 3 , L 3 together with the ortho atom of the B ring form a saturated or unsaturated 5-8 membered ring, said 5
  • the -8 membered ring is optionally substituted with one or more R 4 groups.
  • R 3 is selected from the group consisting of hydrogen, amino, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, aryl, heteroaryl, wherein The above amino, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, aryl, heteroaryl are optionally substituted by one or more R 4 ; or R 3 , L 3 and The ortho atoms on the B ring together form a saturated or unsaturated 5-8 membered ring, which is optionally substituted with one or more R 4 .
  • the compound of formula (I) is selected from the group consisting of:
  • Another aspect of the invention provides a method of treating a viral infection, the method comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a viral infection.
  • the viral infection is dengue virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, Kunjin virus, Murray Valley encephalitis virus, Saint-Louis Encephalitis virus, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Zika virus, hepatitis virus infection.
  • the viral infection is a hepatitis virus infection.
  • the viral infection is a hepatitis B or hepatitis C virus infection.
  • compositions of the invention comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
  • the pharmaceutical compositions of the invention may further comprise one or more additional therapeutic agents.
  • the pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention or a salt thereof with a suitable pharmaceutically acceptable carrier, for example, it can be formulated into a solid, semi-solid, liquid or gaseous preparation such as a tablet, a pill, or a capsule.
  • a suitable pharmaceutically acceptable carrier for example, it can be formulated into a solid, semi-solid, liquid or gaseous preparation such as a tablet, a pill, or a capsule.
  • Typical routes of administration of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, Parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous.
  • the pharmaceutical composition of the present invention can be produced by a method well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a drag coating method, a grinding method, an emulsification method, a freeze drying method, and the like.
  • the pharmaceutical compositions may be formulated by admixing the active compound withpharmaceutically acceptable carriers such carriers.
  • pharmaceutically acceptable carriers such carriers.
  • These carriers enable the compounds of the present invention to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the active compound with a solid excipient, optionally milling the resulting mixture, adding other suitable adjuvants if necessary, and then processing the mixture into granules. The core of a tablet or dragee.
  • Suitable accessory package include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • microcrystalline cellulose glucose solution, gum arabic, gelatin solution, sucrose and starch paste; talc, starch, magnesium stearate, calcium stearate or stearic acid; lactose, sucrose, starch, mannitol, sorbus Sugar alcohol or dicalcium phosphate; silica; croscarmellose sodium, pre-treated starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methyl cellulose, agar, carboxymethyl fiber Or cross-linked polyvinylpyrrolidone.
  • the core of the dragee may optionally be coated according to methods well known in the ordinary pharmaceutical practice, especially using enteric coatings.
  • compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in a suitable unit dosage form.
  • suitable excipients such as fillers, buffers or surfactants can be used.
  • the compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, can be administered by any suitable route and method, for example by oral or parenteral (e.g., intravenous) administration.
  • a therapeutically effective amount of a compound of formula (I) is from about 0.0001 to 20 mg/kg body weight per day, such as from 0.001 to 10 mg/kg body weight per day.
  • the dosage frequency of the compound of formula (I) is determined by the needs of the individual patient, for example, once or twice daily, or more times per day. Administration can be intermittent, for example, wherein during a period of several days, the patient receives a daily dose of a compound of formula I, followed by a daily dose of the compound of formula (I) for a period of several days or more. dose.
  • an ethyl group “optionally” substituted with halo refers to an ethyl group may be unsubstituted (CH 2 CH 3), monosubstituted (e.g., CH 2 CH 2 F), polysubstituted (e.g. CHFCH 2 F, CH 2 CHF 2, etc.) or completely substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and/or which cannot be synthesized is introduced.
  • C mn means having mn carbon atoms in this moiety.
  • C 3-10 cycloalkyl means that the cycloalkyl group has 3 to 10 carbon atoms.
  • C 0-6 alkylene group means that the alkylene group has 0 to 6 carbon atoms, and when the alkylene group has 0 carbon atoms, the group is a bond.
  • C 1-10 means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 One carbon atom, nine carbon atoms or ten carbon atoms.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent as long as the valence of the particular atom is normal and the substituted compound is stable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • hetero means a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), that is, an atom other than carbon and hydrogen or an atomic group containing the same, and the hetero atom is independently selected from the group consisting of oxygen, nitrogen, sulfur, Phosphorus, silicon, germanium, aluminum, boron.
  • the two or more heteroatoms may be identical to each other, or some or all of the two or more heteroatoms may be different from each other.
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • hydroxy refers to an -OH group.
  • cyano refers to a -CN group.
  • mercapto refers to a -SH group.
  • amino means -NH 2 group.
  • alkyl refers to a straight or branched saturated aliphatic hydrocarbon group consisting of a carbon atom and a hydrogen atom, which is attached to the remainder of the molecule by a single bond.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, Neopentyl, n-hexyl, 2-methylhexyl, -CH 2 -cyclopropyl, and the like.
  • alkylene refers to a saturated straight or branched or cyclic hydrocarbon radical having two residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane.
  • alkylene include, but are not limited to, methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 ) CH 2 -), 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), and the like.
  • amino refers to -NH-.
  • alkenyl refers to a straight or branched unsaturated aliphatic hydrocarbon group having at least one double bond consisting of a carbon atom and a hydrogen atom.
  • alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.
  • alkynyl means a straight or branched unsaturated aliphatic hydrocarbon group having at least one triple bond composed of a carbon atom and a hydrogen atom.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), 2-propynyl (-CH 2 -C ⁇ CH), 1,3-butadiynyl (-C ⁇ CC ⁇ CH) or the like.
  • cycloalkyl refers to a saturated or unsaturated, non-aromatic cyclic hydrocarbon group consisting of carbon atoms and hydrogen atoms, preferably containing 1 or 2 rings.
  • the cyclic hydrocarbon group may be a monocyclic, fused polycyclic, bridged or spiro ring structure.
  • Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl, and spiro[3.3]heptyl, and the like.
  • heterocycloalkyl refers to a non-aromatic monocyclic, fused polycyclic, bridged or spiro ring system wherein some of the ring atoms are selected from N, O, S(O) n (where n is 0) a hetero atom of 1 or 2), the remaining ring atoms being C.
  • Such rings may be saturated or unsaturated (eg, having one or more double bonds), but do not have a fully conjugated ⁇ -electron system.
  • Examples of the 3-membered heterocyclic hydrocarbon group include, but are not limited to, an oxiranyl group, an ethylenethio group, a cycloalkylethane group, and examples of the 4-membered heterocyclic hydrocarbon group include, but are not limited to, azetidinyl, acetobutyl group, and thidium.
  • Examples of the cyclic group, 5-membered heterocycloalkyl group include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, 1,1-dioxo
  • Examples of thiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, pyrrolinyl, dihydrofuranyl, dihydrothienyl, 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyridyl Cyclol, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thiazolidine, 1,4-dioxacyclyl, thiomorpholinyl, 1,2-, 1,4 Examples of -d
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ -electron system.
  • an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms or 6-12 carbon atoms.
  • Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, the remaining ring atoms being C, and having at least one aromatic ring.
  • Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl , tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, fluorenyl, isodecyl and the like.
  • pharmaceutically acceptable is for those compounds, materials, compositions and/or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues without Many toxic, irritating, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, or the like can be mentioned.
  • metal salts include, but are not limited to, salts of alkali metals such as sodium salts, potassium salts, and the like; salts of alkaline earth metals such as calcium salts, magnesium salts, barium salts, and the like; aluminum salts and the like.
  • Non-limiting examples of salts formed with organic bases include, but are not limited to, with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, A salt formed by dicyclohexylamine or the like.
  • Non-limiting examples of salts formed with inorganic acids include, but are not limited to, salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
  • Non-limiting examples of salts formed with organic acids include, but are not limited to, with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, benzene. a salt formed of a sulfonic acid, p-toluenesulfonic acid or the like.
  • Non-limiting examples of salts formed with basic amino acids include, but are not limited to, salts formed with arginine, lysine, ornithine, and the like.
  • Non-limiting examples of salts formed with acidic amino acids include, but are not limited to, salts formed with aspartic acid, glutamic acid, and the like.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention. Certain compounds of the invention may exist in polycrystalline or amorphous form.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a salt of a diastereomer is formed with a suitable optically active acid or base, followed by stepping as is known in the art.
  • the diastereomeric resolution is carried out by crystallization or chromatography, and then the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • pharmaceutically acceptable carrier refers to those carriers which have no significant irritation to the organism and which do not impair the biological activity and properties of the active compound.
  • “Pharmaceutically acceptable carrier” means an inert substance which, together with the active ingredient, which facilitates administration of the active ingredient, including, but not limited to, acceptable for human or animal use as permitted by the State Food and Drug Administration (eg Any of the glidants, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, disintegrating agents, suspending agents, stabilizers, Isotonicity agent, solvent or emulsifier.
  • Non-limiting examples of such carriers include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols, and the like.
  • excipient generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the bromide (1-4) is exchanged for lithium salt under the action of n-butyllithium, and then reacted with an aldehyde (R 5 is selected from a formaldehyde group or optionally a protecting group L 3 -R 3 ) to obtain a secondary alcohol. (1-5).
  • the secondary alcohol (1-5) is converted in steps 0-3, followed by reduction with trifluoroacetic acid, triethylsilane, and removal of the protecting group to give the final product (II).
  • bromide (2-2) is obtained by reaction with NBS.
  • Bromide (2-2) is further passed through a 1 to 3 step reaction (for example, reduction to aldehyde with DIBAL-H, followed by reductive amination with pyrrole in methanol solvent with NaBH 3 CN) to give another bromide (2-3) .
  • the bromide (2-3) is converted to the 2-cyano compound (2-4) under Zn(CN) 2 /Zn/Pd 2 (dba) 3 /dppf/DMF conditions.
  • the SEM was removed with trifluoroacetic acid to give the final product (III).
  • the present invention employs the following abbreviations: aq for aqueous; SEMCl for (2-(chloromethoxy)ethyl)trimethylsilane; eq for equivalent; 1,3-DPPP for 1,3-double (two Phenylphosphino)propane; DCM stands for dichloromethane; PE stands for petroleum ether; DMF stands for N,N-dimethylformamide; NMP stands for N-methylpyrrolidone; EtOAc stands for ethyl acetate; i-PrOH stands for isopropyl Alcohol; EtOH stands for ethanol; MeOH is methanol; THF stands for tetrahydrofuran; BPO stands for benzoyl peroxide; BOC stands for t-butoxycarbonyl; HOAc is acetic acid; NaCNBH 3 is sodium cyanoborohydride; LAH is lithium aluminum hydride; BBN is 9-borobicyclononane; MsCl is methanes
  • High performance liquid chromatography was performed using a Shimadzu LC20AB system equipped with a Shimadzu SIL-20A autosampler and a Shimadzu DAD: SPD-M20A detector, using a Xtimate C18 (3 m packing, size 2.1 x 300 mm) column.
  • 0-60AB_6 min method Apply a linear gradient, start elution with 100% A (A is 0.0675% TFA in water), and end the elution with 60% B (B is 0.0625% TFA in MeCN solution). The whole process is 4.2 minutes, then eluted with 60% B for 1 minute.
  • the column was equilibrated for 0.8 minutes to reach 100:0 with a total run time of 6 minutes.
  • 10-80AB_6 min method Apply a linear gradient, start elution with 90% A (A is 0.0675% TFA in water), and end the elution with 80% B (B in 0.0625% TFA in acetonitrile). 4.2 minutes, then eluted with 80% B for 1 minute.
  • the column was equilibrated for 0.8 minutes to 90:10 with a total run time of 6 minutes.
  • the column temperature was 50 ° C and the flow rate was 0.8 mL/min.
  • the diode array detector has a scanning wavelength of 200-400 nm.
  • TLC Thin layer chromatography
  • a common solvent for flash column chromatography or thin layer chromatography is a mixture of dichloromethane/methanol, ethyl acetate/methanol and hexane/ethyl acetate.
  • Figure 1 Pharmacodynamic test results (plasma) in a mouse model of HDI hepatitis B infection.
  • Figure 2 Pharmacodynamic test results (liver) in a mouse model of HDI hepatitis B infection.
  • Step A 2,4-Dichloro-5H-pyrrolo[3,2-d]pyrimidine (4 g, 21.4 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL) and then added portionwise at 0 ° C. Sodium hydride (1.03 g, 60% mineral oil mixture, 25.6 mmol). The reaction solution was stirred at room temperature for 30 minutes, and (2-(chloromethoxy)ethyl)trimethylsilane (3.9 g, 23.5 mmol) was added dropwise. After stirring at room temperature for further 2 hours, it was diluted with water (120 ml) and extracted with ethyl acetate (100 ml). The combined organic layers were washed with EtOAc EtOAc.
  • Step B 2,4-Dichloro-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2- in a 1000 ml high pressure reactor d] Pyrimidine (5 g, 15.8 mmol), isopropanol (15 ml) and aqueous ammonia (250 ml) were mixed and stirred at 100-110 ° C for 3 hours. After cooling to room temperature, the mixture was diluted with water (250 ml) and filtered to give 2-chloro-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[ 3,2-d]pyrimidine-4-amine (4 g, 85%) without further purification.
  • Step C 2-Chloro-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (4 g, 13.4 mmol) and sodium butoxide (5.15 g, 53.6 mmol) were dissolved in n-butanol (55 mL). The mixture was heated to 100 ° C under a nitrogen atmosphere and stirred for 8 hours. After cooling to room temperature, the mixture was diluted with H.sub.2 (200 mL). The combined organic layers were washed with EtOAc EtOAc.
  • Step D 2-butoxy-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (4 G, 12 mmol) was dissolved in dry tetrahydrofuran (40 mL). NBS (2.2 g, 12.5 mmol) was made into a saturated solution of anhydrous tetrahydrofuran and added to the above solution at less than 0 ° C in 20 minutes. After the addition was completed, the reaction mixture was stirred at 0 ° C for 30 min, then diluted with brine (150 ml) and ethyl acetate (100 ml ⁇ 3).
  • Step E Stirring 7-bromo-2-butoxy-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3, at -78 ° C.
  • 2-d]pyrimidin-4-amine 3 g, 7.25 mmol
  • dry EtOAc 40 mL
  • isophthalic acid 1 g, 9 mmol
  • anhydrous tetrahydrofuran 5 ml
  • the mixture was stirred at -78.degree. C. for a further 30 min.
  • the combined organic layers were concentrated under reduced pressure.
  • Methyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)(hydroxy)methyl) A total of 1.1 grams of benzaldehyde salt.
  • Step F 3-((4-amino-2-butoxy-5-((2-(trimethylsilyl))ethoxy)methyl)-5H- to be stirred at 0 degrees Celsius Pyrrolo[3,2-d]pyrimidin-7-yl)(hydroxy)methyl)benzaldehyde (200 mg, 0.43 mmol) and 1-methylpiperazine (87 mg, 0.87 mmol) in ethanol (2.5 Sodium cyanoborohydride (40 mg, 0.64 mmol) was added portionwise over a solution.
  • Step G To 4-amino-2-butoxy-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d Triethylacetate (2 ml) in a solution of 3-((4-methylpiperazin-1-yl)methyl)phenyl)methanol (100 mg) in trifluoroacetic acid (2 mL) Silane (0.4 ml). The reaction mixture was stirred at 55 ° C under nitrogen for 1 hour and concentrated under reduced pressure. The residue was dissolved in EtOAc (5 mL)EtOAcEtOAc This mixture was stirred at 50 ° C for another 30 minutes and filtered. The filtrate was concentrated under reduced pressure and the residue was purified mjjjjj Pyrrolo[3,2-d]pyrimidin-4-amine trifluoroacetate.
  • Step A According to Example 1, substituting morpholine for 1-methylpiperazine in step F to prepare (4-amino-2-butoxy-5-((2-(trimethylsilyl))) Oxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)(3-(morpholinomethyl)phenyl)methanol.
  • Step B According to Example 1, 2-butoxy-7-(3-(morpholinomethyl)benzyl)-5H-pyrrolo[3,2-d] was obtained by the method used in Step G. Pyrimidine-4-amine formate.
  • Step A According to Example 1, substituting ammonium acetate for 1-methylpiperazine in step F to prepare (4-amino-2-butoxy-5-((2-(trimethylsilyl))) Oxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)(3-(aminomethyl)phenyl)methanol.
  • Step B Preparation of 7-(3-(Aminomethyl)benzyl)-2-butoxy-5H-pyrrolo[3,2-d]pyrimidine-4 according to the procedure used in Step G -amine.
  • Step A According to Example 1, substituting pyrrolidine for 1-methylpiperazine in step F to prepare (4-amino-2-butoxy-5-((2-(trimethylsilyl))) Oxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)(3-(pyrrolidin-1-ylmethyl)phenyl)methanol.
  • Step B According to the procedure used in Step G, 2-butoxy-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2 -d]pyrimidine-4-amine formate.
  • Step A According to Example 1, substituting terephthalaldehyde for isophthalaldehyde in step E to prepare 4-((4-amino-2-) Butoxy-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)(hydroxy)methyl)benzene formaldehyde.
  • Step B According to Example 1, substituting 3,3-difluoropyrrolidine for 1-methylpiperazine in step F to prepare (4-amino-2-butoxy-5-((2-(tri)) Silyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)(4-((3,3-difluoropyrrolidin-1-yl)methyl) Phenyl)methanol.
  • Step C Preparation of 2-butoxy-7-(4-((3,3-difluoropyrrolidin-1-yl)methyl)benzyl)-5H according to the procedure used in Step G - pyrrolo[3,2-d]pyrimidin-4-amine.
  • Step A Preparation of (4-amino-2-butoxy-5-((2-(trimethyl))) was carried out according to Example 5 by substituting 3-fluoropyrrolidine for 3,3-difluoropyrrolidine in Step B. Silyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)(4-((3-fluoropyrrolidin-1-yl)methyl)phenyl) Methanol.
  • Step B According to Example 5, 2-butoxy-7-(4-((3-fluoropyrrolidin-1-yl)methyl)benzyl)-5H-pyrrole was prepared by the method used in Step C. [3,2-d]pyrimidine-4-amine.
  • Step A According to Example 5, in the step B, pyrrolidin-3-ol was used in place of 3,3-difluoropyrrolidine to prepare 1-(4-((4- Amino-2-butoxy-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)(hydroxy) Methyl)benzyl)pyrrolidin-3-ol.
  • Step B According to Example 5, 1-(4-((4-amino-2-butoxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)) was obtained by the method of Step C Benzyl)pyrrolidine-3-ol formate.
  • Step A Preparation of (4-amino-2-butoxy-5-((2-(trimethylsilyl)) by using piperidine instead of 3,3-difluoropyrrolidine in step B according to Example 5. Ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)(4-(piperidin-1-ylmethyl)phenyl)methanol.
  • Step B Preparation of 2-butoxy-7-(4-(piperidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d] according to the procedure of Example 5. Pyrimidine-4-amine.
  • Step A Preparation of (4-amino-2-butoxy-5-((2-(trimethylsilyl))), using morpholine instead of 3,3-difluoropyrrolidine in step B according to Example 5. Ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)(4-(morpholinomethyl)phenyl)methanol.
  • Step B Preparation of 2-butoxy-7-(4-(morpholinomethyl)benzyl)-5H-pyr according to the procedure of Example 5 Butyr[3,2-d]pyrimidine-4-amine.
  • Step A Preparation of (4-amino-2-butoxy-5-((2-(tri-)) by substituting 1-methylpiperazine for 3,3-difluoropyrrolidine according to Example 5 Silyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)(4-((4-methylpiperazin-1-yl)methyl)benzene Base) methanol.
  • Step B Preparation of 2-butoxy-7-(4-((4-methylpiperazin-1-yl)methyl)benzyl)-5H-pyrrole according to the procedure of Example 5 3,2-d]pyrimidine-4-amine.
  • Step A Preparation of (4-amino-2-butoxy-5-((2-(trimethyl))), in step B, substituting dimethylamine for 3,3-difluoropyrrolidine in step B Silyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)(4-((dimethylamino)methyl)phenyl)methanol.
  • Step B Preparation of 2-butoxy-7-(4-((dimethylamino)methyl)benzyl)-5H-pyrrolo[3,2-d] by the method of Step C according to Example 5. Pyrimidine-4-amine formate.
  • Step A Prepared according to Example 5, using 4-ethylamine 3,3-difluoropyrrolidine in Step B to prepare (4-amino-2-butoxy-5-((2-(trimethyl)) Silyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)(4-((diethylamino)methyl)phenyl)methanol.
  • Step B According to Example 5, 2-butoxy-7-(4-((diethylamino)methyl)benzyl)-5H-pyrrolo[3,2-d was obtained by the method of Step C. Pyrimidine-4-amine formate.
  • Step A Preparation of (4-amino-2-butoxy-5-((2-(trimethylsilane)) by substituting dipropylamine for 3,3-difluoropyrrolidine according to Example 5 Ethyl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)(4-((dipropylamino)methyl)phenyl)methanol.
  • Step B Preparation of 2-butoxy-7-(4-((dipropylamino)methyl)benzyl)-5H-pyrrolo[3,2-d] by the method of Step C according to Example 5. Pyrimidine-4-amine.
  • Step A Prepare (4-amino-2-butoxy-5-((2-(tri-)) by substituting azetidine for 3,3-difluoropyrrolidine according to Example 5 Silyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)(4-(azetidin-1-ylmethyl)phenyl)methanol .
  • Step B Preparation of 7-(4-(azetidin-1-ylmethyl)benzyl)-2-butoxy-5H-pyrrolo[3,2 according to the procedure of Example C. -d]pyrimidine-4-amine.
  • Step A Preparation of (4-amino-2-butoxy-5-(2) by substituting 3-methoxyazetidine for 3,3-difluoropyrrolidine according to Example 5 -(Trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)(4-((3-methoxyazetidine-)- 1-yl)methyl)phenyl)methanol.
  • Step B Preparation of 2-butoxy-7-(4-((3-methoxyazetidin-1-yl)methyl)benzyl)-5H according to the procedure of Example 5 - pyrrolo[3,2-d]pyrimidin-4-amine.
  • Step A Preparation of ((4-amino-2-butoxy) according to Example 5, substituting 1-methyl-1,4-diazacycloheptane for 3,3-difluoropyrrolidine in Step B -5-((2-(Trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)(4-((4-methyl-) 1,4-diazepan-1-yl)methyl)phenyl)methanol.
  • Step B According to Example 5, 2-butoxy-7-(4-((4-methyl-1,4-diazepan-1-yl)methyl) was obtained by the method of Step C Benzyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine formate.
  • Step A Preparation of (4-amino-2-butoxy-5-((2-) according to Example 5, substituting 2,6-dimethylmorpholine for 3,3-difluoropyrrolidine in Step B (Trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)(4-((2,6-dimethylmorpholinyl)) Base) phenyl)methanol.
  • Step B Preparation of 2-butoxy-7-(4-((2,6-dimethylmorpholinyl)methyl)benzyl)-5H-pyrrole by the method of Step C according to Example 5. 3,2-d]pyrimidine-4-amine.
  • Step A Preparation of (4-S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane in place of 3,3-difluoropyrrolidine according to Example 5, (4- ((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-ylmethyl)phenyl)(4-amino-2-butoxy-5-(2 -(Trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methanol.
  • Step B According to Example 5, 7-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-ylmethyl) was obtained by the procedure of Step C. Benzyl)-2-butoxy-5H-pyrrolo[3,2-D]pyrimidine-4-amine formate.
  • Step A Preparation of (4-amino-2-butoxy-5-((2-(3))), in step B, substituting 4-methoxypiperidine for 3,3-difluoropyrrolidine in step B Methylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)(4-((4-methoxypiperidin-1-yl)methyl) Phenyl)methanol.
  • Step B According to Example 5, 2-butoxy-7-(4-((4-methoxypiperidin-1-yl)methyl)benzyl)-5H-pyrrole was obtained by the procedure of Step C. And [3,2-d]pyrimidine-4-amine formate.
  • Step A Preparation of (4-amino-2-butoxy-5-((2-(3))), in Example B, substituting 1-isopropylpiperazine for 3,3-difluoropyrrolidine in Step B Methylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)(4-((4-isopropylpiperazin-1-yl)methyl) Phenyl)methanol.
  • Step B According to Example 5, 2-butoxy-7-(4-((4-isopropylpiperazin-1-yl)methyl)benzyl)-5H-pyrrole was obtained by the procedure of Step C. And [3,2-d]pyrimidine-4-amine formate.
  • Step A Preparation of (4-amino-2-butoxy-5-((2-(trimethylsilyl)) was carried out according to Example 5 by substituting pyrrole for 3,3-difluoropyrrolidine in step B. Ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)(4-(pyrrolidin-1-ylmethyl)phenyl)methanol.
  • Step B According to Example 5, 2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d was obtained by the method of Step C. Pyrimidine-4-amine formate.
  • Step A To a solution of methyl 6-methylnicotinate (10 g, 0.0662 mol) in CCl 4 (100 mL) was added NBS (13.0 g, 0.0728 mol) and BPO (1.6 g, 0.0066 mol). . The reaction mixture was heated to 75 ° C and stirred for 12 hours. After cooling, water (80 ml) was added andEtOAc was evaporated. The organic layer was washed with EtOAc EtOAc. The residue was purified with EtOAc EtOAc EtOAc (EtOAc:EtOAc
  • Step B Partial addition of 6-(bromomethyl) to a solution of pyrrolidine (3.09 g, 43.47 mmol) and triethylamine (3 mL, 21.73 mmol) in anhydrous tetrahydrofuran (100 mL) Methyl nicotinate (5.0 g, 21.73 mmol). After the addition was completed, the ⁇ The organic layer was dried with anhydrous sodium sulfate and evaporated. The residue was purified by silica gel chromatography eluting elut elut elut elut elut It is a brown solid.
  • Step C Batching in a solution of 6-(pyrrolidin-1-ylmethyl)nicotinic acid methyl ester (3.0 g, 13.62 mmol) in anhydrous tetrahydrofuran (70 ml) at below 0 °C Lithium aluminum tetrahydride (1.03 g, 27.24 mmol) was added. The reaction was carried out at about 0 ° C for 2 hours and further at room temperature for 30 minutes. TLC showed the disappearance of the reactants. The mixture was then cooled to 0 ° C and water (1 mL) was added very slowly. Then, 15% aqueous sodium hydroxide solution (1 ml) and additional water (3 ml) were separately added and stirred vigorously. The resulting mixture was filtered. The filtrate was dried over anhydrous Mg 2 SO 4 and concentrated to dryness under reduced pressure, to give (6- (pyrrolidin-1-ylmethyl) pyridin-3-yl) methanol (2.5 g).
  • Step D (6-(Pyrrolidin-1-ylmethyl)pyridin-3-yl)methanol (2.5 g, 13 mmol).
  • Manganese dioxide (5.0 g, 58 mmol) was added in portions at 0 °C. The reaction mixture was stirred at room temperature for 24 hours and filtered. The filtrate was concentrated in vacuo and the residue was purifiedjjjjjjjjjjj It is a yellow oil.
  • Step E Prepare (4-amino-2-butoxy-5-(2) by substituting 6-(pyrrolidin-1-ylmethyl)nitroalin for m-dibenzaldehyde in Step E according to Example 1. -(Trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)(6-(pyrrolidin-1-ylmethyl)pyridine-3 -base) methanol.
  • Step F According to the procedure of Example 1, 2-butoxy-7-((6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)methyl)-5H-pyrrole was obtained by the method of Step G. And [3,2-d]pyrimidine-4-amine formate is a white solid.
  • Step A Methyl 3-bromobenzoate (17.0 g, 79.0 mmol), tributyl(vinyl)stannane (33 g, 102 mmol) and Pd(PPh 3 ) 4 (under nitrogen).
  • a solution of 4.5 g, 4 mmoles of dioxane (200 mL) was stirred at 110 ° C for 6 h then quenched with 10% aqueous potassium fluoride (100 mL).
  • the resulting mixture was stirred at room temperature for additional 10 min and extracted with ethyl acetate (150 mL & The combined organic layers were washed with EtOAc EtOAc.
  • the residue was purified with EtOAc EtOAc (EtOAc:EtOAc:
  • Step B 9-BBN (0.5 M, 166 mL, 83 mmol) was added to a stirred solution of methyl 3-vinylbenzoate in anhydrous tetrahydrofuran (100 mL). Keep the temperature below -30 degrees Celsius. After the addition was completed, the reaction mixture was warmed to room temperature and stirred for 16 hr. Then, it was cooled to -30 ° C, and an aqueous solution of H 2 O 2 (mass ratio: 30%, 19 ml) was added dropwise, followed by dropwise addition of a 15% aqueous sodium hydroxide solution (40 ml). After the mixture was stirred at ambient temperature for additional 1 hour, it was diluted with water (200 ml) and extracted with ethyl acetate (200 ml). The combined organic layers were washed with EtOAcq ⁇ step.
  • Step C To a solution of 3-(2-hydroxyethyl)benzoic acid methyl ester (10 g) in anhydrous dichloromethane (90 mL) was added methanesulfonyl chloride (34 g, 299 m). Mole) and triethylamine (12 g, 118 mmol). The reaction was stirred at 0<0>C for 1 h then quenched with EtOAc (EtOAc) The combined organic layers were dried with anhydrous sodium The residue was purified by silica gel column chromatography (EtOAc:EtOAcEtOAc The ester is a colorless oil.
  • Step D Pyrrolidine (2.3 g, 31.3 mmol) and potassium carbonate (2.2 g, 16 mmol) were dissolved in anhydrous acetonitrile (20 mL) and 3-(2-((methyl) A solution of methyl sulfonyl)oxy)ethyl)benzoate (2.7 g, 10.4 mmol) in EtOAc (5 mL). The reaction mixture was stirred at 70 ° C for 16 hr then cooled to EtOAc. The combined organic layers were dried with anhydrous sodium The residue was purified by silica gel column chromatography (eluent: EtOAc / m. Gram, 71%), as a yellow oil.
  • Step E According to Example 22, 3-(2-(pyrrolidin-1-yl)ethyl)benzaldehyde was obtained by the procedure of Steps C and D.
  • Step F According to Example 22, 2-butoxy-7-(3-(2-(pyrrolidin-1-yl)ethyl)benzyl)-5H-pyrrolo[ 3,2-d]pyrimidine-4-amine formate.
  • Step B Add DIBAL to a solution of 4-(1-(pyrrolidin-1-yl)ethyl)benzonitrile (2 g, 10 mmol) in dry toluene (100 mL) from -20 to -10. A solution of H (1 M, 20 mL, 20 mmol) was taken and taken up in 1 hour. The reaction mixture was stirred for additional 3 hr then EtOAc EtOAc m.
  • Step C According to Example 22, 2-butoxy-7-(4-(1-(pyrrolidin-1-yl)ethyl)benzyl)-5H-pyrrole was obtained by the method of steps E and F. [3,2-d]pyrimidine-4-amine formate.
  • Step A 4-bromopyridine (3.0 g, 19.0 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (2.63 g, 14.6 mmol), Pd(PPh 3 ) 2 Cl 2 (0.35 g, A mixture of 0.5 mmol (0.5 mmol) and sodium carbonate (6.91 g, 65.2 mmol) of 1,2-dimethoxyethane (40 ml) was heated to 90 ° C under a nitrogen atmosphere and stirred for 10 hours. The obtained mixture was concentrated under reduced pressure and the residue was purifiedjjjjjjjjjjj (2.7 g, yield: 86.8%) as a white solid.
  • Step B To a solution of methyl 4-(pyridin-4-yl)benzoate (3.8 g, 17.8 mmol) and PtO 2 (0.2 g) in methanol (40 mL) Stir for 16 hours under a hydrogen atmosphere (50 psi). The mixture was filtered, and the ⁇
  • Step C To a stirred solution of methyl 4-(piperidin-4-yl)benzoate (5.0 g, 22.8 mmol) and potassium carbonate (25.0 g, 182.2 mmol) in THF (50 mL) / water (50 Di-tert-butyl dicarbonate (10.0 g, 45.8 mmol) was added portionwise to the mixed solution and kept at a temperature below 10 °C. After the addition was completed, the reaction mixture was stirred at room temperature for additional 0.5 hr, then diluted with water (50 ml) and ethyl acetate (50 ml x 2). The combined organic layers were washed with brine w... The residue was purified by silica gel column chromatography eluting elut elut elut Butyl ester (1.9 g, yield: 26.4%) was obtained as a white solid.
  • Step D According to Example 22, 4-(4-formylphenyl)piperidine-1-carboxylic acid tert-butyl ester was obtained by the procedure of Steps C and D.
  • Step F Preparation of 2-butoxy-7-(4-(piperidin-4-yl)benzyl)-5H-pyrrolo[3,2-d] by the procedure of Steps E and F according to Example 22. Pyrimidine-4-amine.
  • Step G After stirring for 5 minutes, to 2-butoxy-7-(4-(piperidin-4-yl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine ( Sodium cyanoborohydride (50 mg, 0.796 mmol) was added to a solution of EtOAc (EtOAc). The reaction was stirred at room temperature for 0.5 h, diluted with water and EtOAc. The organic layer was concentrated in vacuo and purified EtOAc mjjjjjj [3,2-d]pyrimidine-4-amine.
  • Step A N 2 atmosphere at 0 ° C, was added to the 1-allyl NaH (446 mg, 18.6 mmol) in dry tetrahydrofuran (20 ml) was - pyrrolidin-2-one (1.14 g, 9.11 mmol Moore). A solution of methyl 4-bromobenzoate in anhydrous tetrahydrofuran (10 mL) was then added slowly. The mixture was stirred at 90 ° C for 2 hours, then cooled to room temperature and diluted with 6N hydrochloric acid. The resulting mixture was stirred at 110 ° C for 12 hours, then the aqueous was washed with ethyl acetate (50 mL).
  • Step C To a stirred solution of tert-butyl 2-(4-bromophenyl)pyrrolidine-l-carboxylate (0.6 g, 1.839 mmol) in anhydrous tetrahydrofuran (20 mL). n-BuLi (1.5 mL, 2.76 mmol) was added to the solution. The reaction mixture was stirred at -78 °C for 30 minutes, then N,N-dimethylformamide (192 mg, 2.63 mmol) was slowly added to the mixture. The mixture was warmed to room temperature and stirred for additional 30 min then quenched with EtOAc EtOAc. It was diluted with water (30 ml) and extracted with ethyl acetate (25 ml).
  • Step D Preparation of 2-butoxy-7-(4-(pyrrolidin-2-yl)benzyl)-5H-pyrrolo[3,2-d] by the procedure of Steps E and F according to Example 22. Pyrimidine-4-amine.
  • Step E Preparation of 2-butoxy-7-(4-(1-methylpyrrolidin-2-yl)benzyl)-5H-pyrrolo[3,2- by the method of Step G according to Example 25. d] pyrimidin-4-amine.
  • Step B Preparation of 1-(4-((4-amino-2-butoxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl) by the procedure of Steps E and F according to Example 22. Methyl)phenyl)-4-methylpiperazin-2-one.
  • Step A To a solution of 2-(4-bromophenyl)ethylamine (27 g, 0.13 mol) and triethylamine (16.4 g, 0.16 mol) in dichloromethane (300 mL). Trifluoroacetic anhydride (34 g, 0.16 mol) was added dropwise to the solution. The reaction mixture was stirred at room temperature for 1 hour and then diluted with water. The organic layer was separated and evaporated to dryness crystals crystals crystals crystals
  • Step B To a stirred solution of N-(4-bromophenethyl)-trifluoroacetamide (37 g, 0.12 mmol) in concentrated sulfuric acid (200 mL) / acetic acid (300 mL) Formaldehyde (10.2 g, 0.34 mol). After the addition was completed, the reaction mixture was stirred at room temperature for 12 hr, then poured into ice water (1 liter) and extracted with ethyl acetate (400 ml ⁇ 2). The combined organic layers were washed with EtOAc EtOAc m.
  • Step C To 1-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-trifluoroethanone (30 g, 0.1 mol) of anhydrous methylpyrrolidin-2- To the ketone (300 ml) solution was added cuprous cyanide (18 g, 0.2 mol). The reaction mixture was stirred at 180 ° C for 4 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was slowly poured into ice water (500 ml) and extracted with ethyl acetate (200 ml ⁇ 2). The combined organic layers were washed with EtOAc EtOAc m.
  • Step D 2-Trifluoroacetyl-tetrahydroisoquinolin-7-carbonitrile (25 g, 0.1 mol) and potassium carbonate (25 g, 0.18 mol) were dissolved in methanol (300 ml) and water (60 ml) The mixture was stirred at room temperature for 2 hours. Di-tert-butyl dicarbonate (26 g, 0.12 mol) was then added in portions over 10 minutes. After the reaction mixture was stirred at room temperature for additional 4 hr, then diluted with EtOAc. The combined organic layers were washed with brine w...
  • Step E To a solution of tert-butyl 7-cyano-3,4-dihydroisoquinolin-2(1H)-carboxylate (1 g, 3.9 mmol) in anhydrous tetrahydrofuran at -10 ° C under nitrogen atmosphere. (20 ml) was added dropwise diisobutylaluminum hydride (1 M, 6 mL, 6.0 mmol). After the addition, the reaction mixture was stirred at 0 ° C for 5 hr and then quenched with water (0.24 mL). Then, a 15% aqueous sodium hydroxide solution (0.24 ml) was added, followed by 0.6 ml of water.
  • Step F According to Example 22, 2-butoxy-7-((1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-5H was obtained by the procedure of Steps E and F. Pyrrolo[3,2-d]pyrimidine-4-amine formate.
  • EtOAc EtOAc
  • Step B Under nitrogen, to a stirred suspension of isoquinoline-6-carboxylate (10 g, 53.5 mmol) in methanol (100 mL) was added acetic acid (2 mL) and PtO 2 (200 mg ). The mixture was stirred at 40 ° C for 3 hours under a hydrogen atmosphere, then the catalyst was filtered through celite and concentrated under vacuum to give 1,2,3,4-tetrahydroisoquinoline-6- Methyl carboxylate (9 g, yield: 88%) was obtained without further purification.
  • Step C Methyl N-tert-butoxycarbonyl 1,2,3,4-tetrahydroisoquinoline-6-carboxylate was prepared according to the procedure of Example C.
  • Step D According to Example 22, N-tert-butoxycarbonyl 1,2,3,4-tetrahydroisoquinoline-6-carboxaldehyde was prepared by the procedure of Steps C and D.
  • Step E According to Example 22, 2-butoxy-7-((1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-5H- Pyrrolo[3,2-d]pyrimidin-4-amine.
  • Step A Preparation of (4-amino-2-(2-methoxyethoxy)-5-((2-(trimethylsilyl)ethyl) by the procedure of Steps C, D, E according to Example 1. -5H-pyrrole [3,2-d]pyrimidin-7-yl)(phenyl)methanol.
  • Step B According to Example 1, 7-benzyl-2-(2-methoxyethoxy)-5H-pyrrolo[3,2-d]pyrimidin-4-amine A was obtained by the method of Step G. Acid salt.
  • Example 35 7-((5-chloropyridin-2-yl)methyl)-2-(2-methoxyethoxy)-5H-pyrrolo[3] was obtained by the procedure of Steps A and B. , 2-d]pyrimidine-4-amine formate.
  • Example 35 2-(2-methoxyethoxy)-7-((6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)methyl was obtained by the method of Steps A and B. -5H-pyrrolo[3,2-d]pyrimidine-4-amine formate.
  • Step A 7-Bromo-2-butoxy-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrole in a nitrogen atmosphere at -78 °C
  • 3,2-d]pyrimidin-4-amine (10.00 g, 24.07 mmol) in anhydrous tetrahydrofurane (200 mL) was added n-BuLi (6.17 g, 96.28 mmol). The mixture was stirred at -78 °C for 1 hour. Then a solution of 6-chloronicotinaldehyde (10.22 g, 72.21 mmol) in tetrahydrofuran (200 ml) was added dropwise.
  • Step B to (4-amino-2-butoxy-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2- at room temperature
  • a solution of triethylsilane (6.08 g, 52.30) in a solution of d]pyrimidin-7-yl)(6-chloropyridin-3-yl)methanol (5.00 g, 10.46 mmol) in trifluoroacetic acid (50 ml) Millimoles).
  • EtOAc EtOAc EtOAc
  • the combined organic phases were washed with brine (20 mL ⁇ 2), dried over anhydrous sodium Empty concentration.
  • Step C To 2-butoxy-7-((6-chloropyridin-3-yl)methyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H Add palladium acetate (111.75 mg, 0.5 mmol) to a solution of pyrrolo[3,2-D]pyrimidine-4-amine (2.30 g, 4.98 mmol) in N,N-dimethylformamide (15 mL) , 1,3-bisdiphenylphosphinepropane (205.30 mg, 0.5 mmol), triethylamine (1.51 g, 14.93 mmol) and methanol (797.43 mg, 24.89 mmol). The suspension was evacuated and charged with carbon monoxide several times.
  • Step D to 5-((4-amino-2-butoxy-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrole at less than 0 degrees Celsius And a solution of methyl [3,2-d]pyrimidin-7-yl)methyl)pyridinecarboxylate (800.00 mg, 1.65 mmol) in tetrahydrofuran (10 ml) was added portionwise to bromosuccinamide (293.18 mg, 1.65 Millimoles). The reaction mixture was stirred at 0.degree. C. for 1 h, diluted with water (30 mL) The combined organic phases were dried with MgSO4 and evaporatedEtOAc.
  • Step E 5-((4-amino-6-bromo-2-butoxy-5-((2-(trimethylsilyl)) ethoxy) being stirred under nitrogen atmosphere at -78 °C Methyl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)pyridinecarboxylate (150.00 mg, 0.266 mmol) in anhydrous tetrahydrofuran (8 mL) Diisobutylaluminum hydride (56.28 mg, 0.396 mmol). After the addition was completed, the reaction mixture was stirred at -78 ° C for 1 hour. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc.
  • Step F To 5-((4-Amino-6-bromo-2-butoxy-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3 , a solution of 2-d]pyrimidin-7-yl)methyl)pyridine aldehyde (150.00 mg, 0.281 mmol), pyrrolidine (29.94 mg, 0.421 mmol), acetic acid (0.2 ml) in tetrahydrofuran (5 ml) Sodium borohydride (35.27 mg, 0.561 mmol) was stirred at room temperature for 12 h.
  • Step G 6-Bromo-2-butoxy-7-((6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)methyl)-5-((2-(trimethyl)) Silyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (150.00 mg, 254.39 ⁇ mol), Pd 2 (dba) 3 (23.30 mg, 25.44 ⁇ mol) 1,1'-bis(diphenylphosphino)ferrocene (14.10 mg, 25.44 micromolar), zinc dicyanide (59.74 mg, 508.78 micromolar) and zinc (33.27 mg, 508.78 micromolar) were added to none Nitrogen N,N-dimethylformamide (2 ml) was replaced with nitrogen and then heated to 110 ° C for 3 hours under a nitrogen atmosphere.
  • Step H 4-Amino-2-butoxy-7-((6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)methyl)-5-((2-(trimethyl)) a solution of silyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidine-6-carbonitrile (120 mg, 0.224 mmol) in trifluoroacetic acid (5 mL) at 20 °C After stirring for 12 hours, it was concentrated to dryness in vacuo and purified m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m
  • Step A 4-Amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidine-6-carbonitrile (90 mg, 0.22 mmol) and sodium hydroxide (34 mg, 0.85 mmol) were dissolved in a solvent mixture of methanol (10 ml) and water (10 ml), and stirred at 80 ° C for 12 hours. After cooling, it was diluted with water (10 mL) The combined organic layers were concentrated to dryness in vacuo then purified by preparative HPLC to afford 10 ⁇ RTIgt; -5H-pyrrolo[3,2-d]pyrimidine-6-carboxamide.
  • Preparation of 1.96-well compound plate Start with a liquid workstation POD to start the compound from a concentration of 10 mmol/L, and make a 3-fold gradient dilution with DMSO for a total of 10 points (from column 2 to column 11, each point 2 Repeat).
  • a liquid workstation POD to start the compound from a concentration of 10 mmol/L
  • DMSO for a total of 10 points (from column 2 to column 11, each point 2 Repeat).
  • 1 ⁇ l of 5 mg/ml of the positive compound R848 was added as a positive control
  • 1 ⁇ l of DMSO was added as a negative control.
  • the volume of DMSO contained in each well was 1 microliter.
  • the culture plate containing the cells and the compound was cultured in a CO 2 incubator for 24 hours under the conditions of 37 ° C and 5% CO 2 concentration.
  • the alkaline phosphatase content in 20 ⁇ l of the supernatant was measured using a microplate reader OD650.
  • Example 21 of the present invention exhibited higher in vitro receptor binding activity to Toll-like receptor 7 than the control Toll-like receptor 7 agonist GS-9620, and was more potent than the control Toll-like receptor 7 Agent GS-9620 has lower in vitro receptor binding activity to Toll-like receptor 8.
  • the aim of this protocol was to detect the expression levels of cytokines after stimulation of human peripheral blood mononuclear cells (PBMC) for 24 h using existing compounds.
  • PBMC peripheral blood mononuclear cells
  • the cell supernatant was not diluted at the time of detection, and the levels of IFN- ⁇ and TNF- ⁇ were directly detected.
  • the compound was first formulated into a 20 mM DMSO stock solution, and a 10-fold serial dilution of the cell culture medium was used to dilute a total of 11 points.
  • Example INF- ⁇ MEC Example INF- ⁇ MEC Example INF- ⁇ MEC Example INF- ⁇ MEC 4 C 28 B 31 B twenty one A 29 A 42 A twenty two B 30 B
  • Example 21 of the present invention exhibited better IFN- ⁇ -inducing activity and comparable TNF- ⁇ -inducing activity of PBMC in vitro relative to the control Toll-like receptor 7 agonist GS-9620.
  • a total of 12 male SD rats were tested and divided into four groups of 3 SD rats each.
  • Two groups of animals were administered intravenously, and the control substance Toll-like receptor 7 agonist GS-9620 and the compound of Example 21 were mixed with 10% hydroxypropyl- ⁇ -cyclodextrin aqueous solution (concentration 0.5 mg/mL) 1 mg/kg. .
  • the other two groups were orally administered, and 5 mg/kg of a 0.5% methylcellulose/0.2% Tween 80 pure water suspension (concentration 1 mg/mL) of GS-9620 and the compound of Example 21 was orally administered.
  • Each rat after intravenous injection continuously collected whole blood samples and prepared plasma at 2, 15, 30, and 1, 2, 4, 8, and 24 hours after administration; each rat after oral administration was administered. Continuously collect whole blood samples and prepare blood after 15, 30 minutes and 1, 2, 4, 8, 24 hours Pulp.
  • the plasma concentrations of the compounds of GS-9620 and Example 21 were determined by LC-MS/MS method, respectively. The results are shown in Table
  • Example 21 of the present invention exhibited a longer half-life and higher exposure in rats relative to the control Toll-like Receptor 7 agonist GS-9620 under the same conditions.
  • mice used a day-old Beijing duck intravenous injection of duck hepatitis B virus-positive duck serum, 7 days after the start of group administration, each group of 6 ducks.
  • Control group normal saline.
  • the test samples were GS-9620, the compound of Example 21, and two dose groups per sample: 20 mg/kg and 5 mg/kg.
  • the test samples were administered by intragastric administration. In the 20 mg/kg group, one dose was given every other day (one drug was given every three days), and the 5 mg/kg group was administered continuously every day, once a day. Give a total of 16 days.
  • the positive control drug lamivudine was produced by GlaxoSmithKline Pharmaceutical Co., Ltd., 50 mg/kg, administered intragastrically, twice a day for 16 days.
  • the solvent was substituted for the drug.
  • Blood was taken from the pre-dose (T0), 8 days after the administration (T8), 16 days after the administration (T16), and 3 days after the withdrawal (P3), and the duck serum was isolated. Store frozen.
  • Duck serum was used for the detection of duck-type infected virus DNA (DHBV-DNA), and the efficacy of GS-9620, the compound of Example 21 and the positive control lamivudine against duck hepatitis B virus was compared.
  • DHBV-DNA duck-type infected virus DNA
  • Duck serum DNA (DHBV-DNA) detection method the same batch of different duck serum was determined by real-time fluorescent quantitative PCR method for duck blood DHBV-DNA levels.
  • Statistical analysis The paired and group analysis statistical methods were used to calculate the significance of the drug's inhibition on duck serum DHBV-DNA, and the effect was judged. The results of the drug efficacy are shown in Table 6.
  • Example 21 of the present invention Compared with the control Toll-like receptor 7 agonist GS-9620, the compound of Example 21 of the present invention exhibited superior drug efficacy in the hepatitis B infected duckling model under the same conditions: 20 mg/kg every 2 days Once the drug was administered, the inhibition rate was roughly equivalent; 5 mg/kg was administered once a day for continuous administration, and the inhibition rate of the compound of Example 21 was very obvious; after 3 days of withdrawal, 20 mg/kg of GS-9620 was administered once every 2 days. - DNA replication rebounded, whereas the corresponding compound group of Example 21 did not.
  • Drug administration group first group: Vehicle, 10% HP- ⁇ -CD; second group: GS-9620, 20 mg/kg; Group 3: Example 21, 20 mg/kg.

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Abstract

提供了作为TLR7激动剂的吡咯并嘧啶化合物，具体涉及式（I）化合物或其药学上可接受的盐、其制备方法、含有该类化合物的药物组合物、及其用于制备抗病毒药物的用途。

Description

作为TLR7激动剂的吡咯并嘧啶化合物 技术领域
本发明涉及新的作为TLR7激动剂的吡咯并嘧啶环化合物或其药学上可接受的盐，具体涉及式(I)所示化合物或其药学上可接受的盐。
Figure PCTCN2015086909-appb-000001
背景技术
Toll样受体表达于多种免疫细胞。Toll样受体识别高度保守结构基序：由微生物病原体表达的病原体相关的微生物模式(PAMP)或由坏死细胞释放的损伤相关分子模式(DAMP)。通过相应的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-κB和干扰素调节因子(脉冲响应函数)的激活。这导致多种细胞反应，包括生产干扰素、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。对于Toll样受体7(TLR7)，它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(TLR7)和Toll样受体8(TLR8)高度同源。因此TLR7配体在大多数情况下也是TLR8配体。TLR8刺激主要诱导产生细胞因子如肿瘤坏死因子α(TNF-α)和趋化因子。干扰素α是治疗慢性乙型肝炎或丙型肝炎的主要药物之一，而TNF-α是一种促炎细胞因子，过多分泌可能导致严重的副作用。所以对TLR7和TLR8的选择性对于开发TLR7激动剂用于治疗病毒感染性疾病至关重要。几个TLR7激动剂已有报道，如咪喹莫特、瑞喹莫德、GS-9620。但具备更好的选择性、活性和安全性的新的TLR7激动剂仍然有很大需求。我们发现了一系列的新颖的吡咯并嘧啶衍生物是TLR7的激动剂。背景研发资料参照如下的期刊文章：Hoffmann,J.A.,Nature,2003,426,p33-38；Akira,S.,Takeda,K.,and Kaisho,T.,Annual.Rev.Immunology,2003,21,335-376；Ulevitch,R.J.,Nature Reviews:Immunology,2004,4,512-520；Coffman,R.L.,Nat.Med.2007,13,552-559；Paul A.Roethle,J.Med.Chem.2013,56(18),7324-7333。
发明内容
本发明的目的在于提供式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2015086909-appb-000002
其中，
L1、L2分别独立地选自-O-、-CH2-、-S-、-NH-、-NHC(＝O)-、-C(＝O)-、-C(＝O)NH-、-S(＝O)-、-S(＝O)2-、-NHS(＝O)2-或-S(＝O)2NH-，其中上述-CH2-、-NH-、-NHC(＝O)-、-C(＝O)NH-、-NHS(＝O)2-或-S(＝O)2NH-任选被一种或多种R4取代；
R1选自氢、C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烃基、3-10元杂环烃基、芳基、杂芳基，其中上述C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烃基、3-10元杂环烃基、芳基、杂芳基任选被一种或多种R4取代；
R2选自氢、卤素、氰基、羟基、巯基、氨基、COOH、-CONH2、C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烃基、3-10元杂环烃基、芳基、杂芳基，其中上述羟基、巯基、氨基、COOH、-CONH2、C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烃基、3-10元杂环烃基、芳基、杂芳基任选被一种或多种R4取代；
B选自C3-10环烃基、3-10元杂环烃基、芳基、杂芳基；
L3选自C0-6亚烷基、亚氨基、-O-、-S-、-S(＝O)-或-S(＝O)2-，其中上述C0-6亚烷基、亚氨基任选被一种或多种R4取代；
R3选自氢、氨基、C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烃基、3-10元杂环烃基、芳基、杂芳基，其中上述氨基、C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烃基、3-10元杂环烃基、芳基、杂芳基任选被一种或多种R4取代，
或R3、L3与B环上邻位原子一起形成饱和或不饱和的5-8元环，所述5-8元环任选被一种或多种R4取代；
n为0、1、2、3、4或5；
R4选自卤素、氰基、-R、-OR、＝O、-SR、-NR2、＝NR、-C(卤素)3、-CR(卤素)2、-CR2(卤素)、-OCN、-SCN、-N＝C＝O、-NCS、-NO、-NO2、-NRC(＝O)R、-NRC(＝O)OR、-NRC(＝O)NRR、-C(＝O)NRR、-C(＝O)OR、-OC(＝O)NRR、-OC(＝O)OR、-C(＝O)R、-S(＝O)2OR、-S(＝O)2R、-OS(＝O)2OR、-S(＝O)2NRR、-S(＝O)R、-NRS(＝O)2R、-NRS(＝O)2NRR、-NRS(＝O)2OR、-OP(＝O)(OR)2、-P(＝O)(OR)2、-C(＝O)R、-C(＝S)R、-C(＝O)OR、-C(＝S)OR、-C(＝O)SR、-C(＝S)SR、-C(＝O)NRR、-C(＝S)NRR、-C(＝NR)NRR或-NRC(＝NR)NRR；R独立地选自H、C1-8烷基、C3-8环烃基、3-8元杂环烃基、芳基、杂芳基、芳基烷基、杂芳基烷基；
并且，当L1为-CH2-或-NH-时，R3不为H。
在式(I)化合物的一些实施方案中，L1、L2分别独立地选自-O-、-CH2-、-S-、-NH-、-C(＝O)-、 -S(＝O)-或-S(＝O)2-，其中上述-CH2-、-NH-任选被一种或多种R4取代。在式(I)化合物的一些实施方案中，L1、L2分别独立地选自-O-、-CH2-、-S-、-NH-，其中上述-CH2-、-NH-任选被一种或多种R4取代。在式(I)化合物的一些实施方案中，L1、L2分别独立地选自-O-、-CH2-，其中上述-CH2-任选被一种或多种R4取代。
在式(I)化合物的一些实施方案中，R1选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烃基、3-6元杂环烃基、芳基、杂芳基，其中上述C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烃基、3-6元杂环烃基、芳基、杂芳基任选被一种或多种R4取代。在式(I)化合物的一些实施方案中，R1选自C1-6烷基，其中上述C1-6烷基任选被一种或多种R4取代。
在式(I)化合物的一些实施方案中，R2选自氢、卤素、氰基、羟基、巯基、氨基、CHO、COOH、-CONH2、C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烃基、3-6元杂环烃基、芳基、杂芳基，其中上述羟基、巯基、氨基、CHO、COOH、-CONH2、C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烃基、3-6元杂环烃基、芳基、杂芳基任选被一种或多种R4取代。在式(I)化合物的一些实施方案中，R2选自氢、卤素、氰基、羟基、氨基、-CONH2、C1-6烷基，其中上述羟基、氨基、-CONH2、C1-6烷基任选被一种或多种R4取代。在式(I)化合物的一些实施方案中，R2选自氢、氰基、-CONH2，其中上述-CONH2任选被一种或多种R4取代。
在式(I)化合物的一些实施方案中，B选自芳基、杂芳基。在式(I)化合物的一些实施方案中，B选自5-7元芳基、5-7元杂芳基。在式(I)化合物的一些实施方案中，B选自苯基、吡啶基嘧啶基、哒嗪基、吡嗪基、噻吩基、噻唑基、呋喃基、噁唑基、噻二唑基、异噁唑基、噁二唑基、吡咯基、咪唑基、吡唑基、异噻唑基、三唑基。在式(I)化合物的一些实施方案中，B选自苯基、吡啶基。
在式(I)化合物的一些实施方案中，L3选自C0-6亚烷基，其中上述C0-6亚烷基任选被一种或多种R4取代。
在式(I)化合物的一些实施方案中，R3选自氢、氨基、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烃基、3-8元杂环烃基、芳基、杂芳基，其中上述氨基、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烃基、3-8元杂环烃基、芳基、杂芳基任选被一种或多种R4取代；或R3、L3与B环上邻位原子一起形成饱和或不饱和的5-8元环，所述5-8元环任选被一种或多种R4取代。在式(I)化合物的一些实施方案中，R3选自氢、氨基、C1-6烷基、C3-8环烃基、3-8元杂环烃基、芳基、杂芳基，其中上述氨基、C1-6烷基、C3-8环烃基、3-8元杂环烃基、芳基、杂芳基任选被一种或多种R4取代；或R3、L3与B环上邻位原子一起形成饱和或不饱和的5-8元环，所述5-8元环任选被一种或多种R4取代。
在式(I)化合物的一些实施方案中，R4选自卤素、氰基、-R、-OR、＝O、-SR、-NR2、＝NR、-C(卤素)3、-CR(卤素)2、-CR2(卤素)、-OCN、-SCN、-N＝C＝O、-NCS、-NO、-NO2、-NRC(＝O)R、-C(＝O)NRR、-C(＝O)OR、-OC(＝O)NRR、-C(＝O)R、-S(＝O)2OR、-S(＝O)2R、-OS(＝O)2OR、-S(＝O)2NRR、-S(＝O)R、-NRS(＝O)2R、-C(＝O)R、-C(＝O)OR或-C(＝O)NRR。在式(I)化合物的一些实施方案中，R4选自卤素、氰基、-R、-OR、＝O、-NR2、＝NR、-C(卤素)3、-CR(卤素)2、-CR2(卤素)。在式(I)化合物的一些实施方案中，R4选自卤素、-R、-OR、＝O。
在一些实施方案中，式(I)化合物选自以下化合物：
Figure PCTCN2015086909-appb-000003
Figure PCTCN2015086909-appb-000004
Figure PCTCN2015086909-appb-000005
Figure PCTCN2015086909-appb-000006
或其药学上可接受的盐。
本发明另一方面提供了一种治疗病毒感染的方法，所述方法包括给予治疗有效量的式(I)化合物或其药学上可接受的盐。
本发明的另一个方面提供了式(I)化合物或其药学上可接受的盐在制备治疗病毒感染的药物中的用途。
在本发明的一些实施方案中，所述病毒感染是登革热病毒、黄热病毒、西尼罗病毒、日本脑炎病毒、蜱传脑炎病毒、昆津病毒、墨累山谷脑炎病毒、圣路易脑炎病毒、鄂木斯克出血热病毒、牛病毒性腹泻病毒、济卡病毒、肝炎病毒感染。在本发明的一个实施方案中，所述病毒感染是肝炎病毒感染。在本发明的一个实施方案中，所述病毒感染是乙型或丙型肝炎病毒感染。
本发明的另一方面提供了一种药物组合物，其包含治疗有效量的式(I)化合物或其药学上可接受的盐和一种或多种药学上可接受的载体或赋形剂。本发明的药物组合物可以进一步含有一种或多种额外的治疗剂。
本发明的药物组合物可通过将本发明的化合物或其盐与适宜的药学上可接受的载体组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本发明的化合物或其药物可接受的盐或其立体异构体或其药物组合物的典型途径包括但不限于口服、直肠、透黏膜、经肠给药，或者局部、经皮、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
本发明的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等等。
对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的载体混合来配制该药物组合物。这些载体能使本发明的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体赋形剂混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅剂，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包 括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。如微晶纤维素、葡萄糖溶液、阿拉伯胶浆、明胶溶液、蔗糖和淀粉糊；滑石、淀粉、硬脂酸镁、硬脂酸钙或硬脂酸；乳糖、蔗糖、淀粉、甘露糖醇、山梨糖醇或磷酸二钙；二氧化硅；交联羧甲基纤维素钠、预交化淀粉、淀粉羟乙酸钠、藻酸、玉米淀粉、马铃薯淀粉、甲基纤维素、琼脂、羧甲基纤维素、交联聚乙烯吡咯烷酮等。可以根据通常药物实践中公知的方法任选地对糖衣剂的核心进行包衣，尤其使用肠溶包衣。
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。能够使用适当的赋形剂，例如填充剂、缓冲剂或表面活性剂。
本文所述的式(I)化合物或其药学上可接受的盐可以通过任何适用的途径和方法给药，例如通过口服或肠胃外(例如，静脉内)给药。式(I)化合物的治疗有效量为从约0.0001到20mg/Kg体重/天，例如从0.001到10mg/Kg体重/天。
式(I)化合物的剂量频率由患者个体的需求决定，例如，每天1次或2次，或每天更多次。给药可以是间歇性的，例如，其中在若干天的期间内，患者接受式Ⅰ化合物的每日剂量，接着在若干天或更多天的期间，患者不接受式(I)化合物的每日剂量。
有关定义：
除非另有说明，本文所用的下列术语和短语具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，指乙基可以是未被取代的(CH2CH3)、单取代的(如CH2CH2F)、多取代的(如CHFCH2F、CH2CHF2等)或完全被取代的(CF2CF3)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
本文所用的Cm-n指该部分中具有m-n个碳原子。例如，“C3-10环烷基”指该环烷基具有3-10个碳原子。“C0-6亚烷基”指该亚烷基具有0-6个碳原子，当亚烷基具有0个碳原子时，该基团为键。
本文中的数字范围，是指给定范围中的各个整数。例如“C1-10”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子、7个碳原子、8个碳原子、9个碳原子或10个碳原子。
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即＝O)时，意味着两个氢原子被取代，酮取代不会发生在芳香基上。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，即碳和氢以外的原子或含有这些原子的原子团，杂原子独立地选自氧、氮、硫、磷、硅、锗、铝、 硼。在出现两个或更多杂原子的实施方式中，所述两个或更多杂原子可彼此相同，或者所述两个或更多杂原子中的部分或全部彼此不同。
术语“卤”或“卤素”是指氟、氯、溴和碘。
术语“羟基”指-OH基团。
术语“氰基”指-CN基团。
术语“巯基”指-SH基团。
术语“氨基”指-NH2基团。
术语“烷基”是指由碳原子和氢原子组成的直链或支链的饱和的脂肪烃基团，其通过单键与分子的其余部分连接。烷基的非限制性实例包括但不限于甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔-丁基、正-戊基、2-甲基丁基、新戊基、正己基、2-甲基己基、-CH2-环丙基等。
术语“亚烷基”是指饱和的直链或支链或环状烃基，其具有2个从母体烷的相同碳原子或两个不同的碳原子上除去两个氢原子所衍生出的残基。亚烷基的非限制性实例包括但不限于亚甲基(-CH2-)、1,1-亚乙基(-CH(CH3)-)、1,2-亚乙基(-CH2CH2-)、1,1-亚丙基(-CH(CH2CH3)-)、1,2-亚丙基(-CH2CH(CH3)-)、1,3-亚丙基(-CH2CH2CH2-)、1,4-亚丁基(-CH2CH2CH2CH2-)等。
术语“亚氨基”指-NH-。
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。烯基的非限制性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、异丁烯基、1,3-丁二烯基等。
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。炔基的非限制性实例包括但不限于乙炔基(-C≡CH)、1-丙炔基(-C≡C-CH3)、2-丙炔基(-CH2-C≡CH)、1,3-丁二炔基(-C≡C-C≡CH)等。
术语“环烃基”是指由碳原子和氢原子组成的饱和的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“杂环烃基”是指无芳香性的单环、稠合多环、桥环或螺环体系基团，其中部分环原子是选自N、O、S(O)n(其中n为0、1或2)的杂原子，其余环原子为C。这样的环可以是饱和的或不饱和的(例如具有一个或多个双键)，但是不具有完全共轭的π-电子体系。3元杂环烃基的实例包括但不限于环氧乙烷基、环硫乙烷基、环氮乙烷基，4元杂环烃基的实例包括但不限于吖丁啶基、噁丁环基、噻丁环基，5元杂环烃基的实例包括但不限于四氢呋喃基、四氢噻吩基、吡咯烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、1,1-二氧代异噻唑烷基、噻唑烷基、咪唑烷基、四氢吡唑基、吡咯啉基、二氢呋喃基、二氢噻吩基，6元杂环烃基的实例包括但不限于哌啶基、四氢吡喃基、四氢噻喃基、吗啉基、哌嗪基、1,4-噻噁烷基、1,4-二氧六环基、硫代吗啉基、1,2-、1,4-二噻烷基、二氢吡啶基、四氢吡啶基、二氢吡喃基、四氢吡喃基、二氢噻喃基，7元杂环烃基的实例包括但不限于氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基、氧杂氮杂双环[2.2.1]庚基和氮杂螺[3.3]庚基等。
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个碳原子或6-12个碳原子。芳基的非限制性实例包括但不限于苯基、萘基和蒽基等。
术语“杂芳基”是指单环或稠合多环体系，其中含有至少一个选自N、O、S的环原子，其余环原子为C，并且具有至少一个芳香环。杂芳基的非限制性实例包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、喹啉基、异喹啉基、四唑基、三唑基、三嗪基、苯并呋喃基、苯并噻吩基、吲哚基、异吲哚基等。
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
作为药学上可接受的盐，例如，可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。金属盐的非限制性实例包括但不限于碱金属的盐，例如钠盐、钾盐等；碱土金属的盐，例如钙盐、镁盐、钡盐等；铝盐等。与有机碱形成的盐的非限制性实例包括但不限于与三甲胺、三乙胺、吡啶、甲基吡啶、2,6-二甲基吡啶、乙醇胺、二乙醇胺、三乙醇胺、环己胺、二环己基胺等形成的盐。与无机酸形成的盐的非限制性实例包括但不限于与盐酸、氢溴酸、硝酸、硫酸、磷酸等形成的盐。与有机酸形成的盐的非限制性实例包括但不限于与甲酸、乙酸、三氟乙酸、富马酸、草酸、苹果酸、马来酸、酒石酸、柠檬酸、琥珀酸、甲磺酸、苯磺酸、对甲基苯磺酸等形成的盐。与碱性氨基酸形成的盐的非限制性实例包括但不限于与精氨酸、赖氨酸、鸟氨酸等形成的盐。与酸性氨基酸形成的盐的非限制性实例包括但不限于与天冬氨酸、谷氨酸等形成的盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。本发明的某些化合物可以以多晶或无定形形式存在。
本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。
本文中消旋体、ambiscalemic and scalemic或者对映体纯的化合物的图示法来自Maehr,J.Chem.Ed.1985,62:114-120。除非另有说明，用楔形键和虚线键表示一个立体中心的绝对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。
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。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的分步结晶法或色谱法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)、碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“药学上可接受的载体”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些载体。“药学上可接受的载体”是指与活性成份一同给药的、有利于活性成份给药的惰性物质，包括但不限于国家食品药品监督管理局许可的可接受的用于人或动物(例如家畜)的任何助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味增强剂、表面活性剂、润湿剂、分散剂、崩解剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。所述载体的非限制性实例包括碳酸钙、磷酸钙、各种糖和各类淀粉、纤维素衍生物、明胶、植物油和聚乙二醇等。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
本领域任何合成路线规划中的一个重要考量因素是为反应性官能团(如本发明中的氨基)选择合适的保护基。对于经过训练的从业者来说，Greene and Wuts的Protective Groups In Organic Synthesis,Wiley and Sons,1991是这方面的权威。本发明引用的所有参考文献整体上并入本发明。
本发明通式(II)的化合物可以由有机合成领域技术人员通过下述路线1用本领域的标准方法来制备：
Figure PCTCN2015086909-appb-000007
通用流程1
从2,4-二氯-5H-吡咯并[3,2-d]嘧啶(1-1)(商品化试剂)出发，用SEM保护，然后用NH3取代得到2-氯-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺(1-2)。使用不同种类的醇(通式R1OH)、比如正丁醇，在钠的作用下形成醇钠，然后发生取代反应生成中间体(1-3)。然后与NBS反应，得到溴化物(1-4)。溴化物(1-4)在正丁基锂作用下溴被交换成锂盐，然后与醛(R5选自甲醛基或任选带有保护基的L3-R3)反应，得到仲 醇(1-5)。仲醇(1-5)经过0-3步转化，然后用三氟乙酸、三乙基硅烷还原同时脱除保护基，生成最终产物(II)。
本发明通式(III)的化合物可以由有机合成领域技术人员通过下述路线2用本领域的标准方法来制备：
Figure PCTCN2015086909-appb-000008
通用流程2
从按照路线1制备的中间体(2-1)(R6选自羧酸甲酯)出发，用NBS反应得到溴化物(2-2)。溴化物(2-2)进一步通过1到3步反应(比如用DIBAL-H还原成醛，然后与吡咯在甲醇溶剂中用NaBH3CN还原胺化)得到另一种溴化物(2-3)。溴化物(2-3)在Zn(CN)2/Zn/Pd2(dba)3/dppf/DMF条件下转化成2-氰基化合物(2-4)。用三氟乙酸脱除SEM得到最终产物(III)。
本领域技术人员应该知道，为了制备本发明化合物，反应路线1和2中反应步骤的顺序可以是不同的，这也属于本发明的范围。
为清楚起见，发明进一步用实施例来阐述。但是实施例不局限于定义或者指定发明范围。
本发明所使用的所有溶剂是市售的，无需进一步纯化即可使用。反应一般是在惰性氮气下、无水溶剂中进行的。质子核磁共振数据记录在Bruker Avance III 400(400MHz)分光仪上，化学位移以四甲基硅烷低场处的(ppm)表示。质谱是在安捷伦1200系列加6110(&1956A)上测定。LC/MS或Shimadzu MS包含一个DAD：SPD-M20A(LC)和Shimadzu Micromass2020检测器。质谱仪配备有一个正或负模式下操作的电喷雾离子源(ESI)。
本发明采用下述缩略词：aq代表含水的；SEMCl代表(2-(氯甲氧基)乙基)三甲基硅烷；eq代表当量；1,3-DPPP代表1,3-双(二苯基膦基)丙烷；DCM代表二氯甲烷；PE代表石油醚；DMF代表N,N-二甲基甲酰胺；NMP代表N-甲基吡咯烷酮；EtOAc代表乙酸乙酯；i-PrOH代表异丙醇；EtOH代表乙醇；MeOH是甲醇；THF代表四氢呋喃；BPO代表过氧苯甲酰；BOC代表叔丁氧羰基；HOAc为乙酸；NaCNBH3是氰基硼氢化钠；LAH为氢化铝锂；9-BBN是9-硼二环壬烷；MsCl是甲磺酰氯；RT为室温；O/N为过夜；Boc2O是二叔丁基二碳酸酯；TFA为三氟乙酸；TFAA为三氟乙酸酐；TEA是三乙胺；DIBAL-H为二异丁基氢化铝；NBS为溴代丁二酰胺；DPPF是1,1'-双(二苯基膦基)二茂铁；Ph3P是三苯基膦；Pd(OAc)2是乙酸钯；Pd(PPh3P)2CL2是双(三苯基膦)氯化钯；Pd2(dba)3是三(亚苄基丙酮)二钯；XANTPHOS是4,5-双(二苯基膦基)-9,9-二甲基氧杂蒽；n-BuLi是正丁基锂。
化合物经手工或者
Figure PCTCN2015086909-appb-000009
软件命名，市售化合物采用供应商目录名称。
用配有ShimadzuSIL-20A自动进样器和日本岛津DAD：SPD-M20A探测器的岛津LC20AB系统进行高效液相色谱分析，采用XtimateC18(3m填料，规格为2.1x300mm)色谱柱。0-60AB_6分钟的方法：应用线性梯度，以100％A(A为0.0675％TFA的水溶液)开始洗脱，并以60％B(B为0.0625％TFA的MeCN溶液)结束洗脱，整个过程为4.2分钟，然后以60％B洗脱1分钟。将色谱柱再平衡0.8分钟达到100:0，总运行时间为6分钟。10-80AB_6分钟的方法：应用线性梯度，以90％A(A为0.0675％TFA的水溶液)开始洗脱，并以80％B(B为0.0625％TFA的乙腈溶液)结束洗脱，整个过程为4.2分钟，然后以80％B洗脱1分钟。将色谱柱再平衡0.8分钟达到90:10，总运行时间为6分钟。柱温为50℃，流速为0.8mL/min。二极管阵列检测器扫描波长为200-400nm。
在Sanpont-group的硅胶GF254上进行薄层色谱分析(TLC)，常用紫外光灯照射检出斑点，在某些情况下也采用其他方法检视斑点，在这些情况下，用碘(10g硅胶中加入约1g碘并彻底混合而成)、香草醛(溶解大约1g香草醛于100mL 10％H2SO4中制得)、茚三酮(从Aldrich购得)或特殊显色剂(彻底混合(NH4)6Mo7O24·4H2O、5g(NH4)2Ce(IV)(NO3)6、450mL H2O和50mL浓H2SO4而制得)展开薄层板，检视化合物。采用Still,W.C.；Kahn,M.；and Mitra,M.Journal of Organic Chemistry,1978,43,2923-2925中所公开技术的类似方法，在Silicycle的40-63μm(230-400目)硅胶上进行快速柱色谱。快速柱色谱或薄层色谱的常用溶剂是二氯甲烷/甲醇、乙酸乙酯/甲醇和己烷/乙酸乙酯的混合物。
在Gilson-281Prep LC 322系统上采用吉尔森UV/VIS-156探测器进行制备色谱分析，所采用的色谱柱是Agella Venusil ASB Prep C18,5m、150×21.2mm；Phenomenex Gemini C18、5m、150×30mm；Boston Symmetrix C18,5m、150×30mm；或者Phenomenex Synergi C18、4m、150×30mm。在流速约为25mL/min时，用低梯度的乙腈/水洗脱化合物，其中水中 含有0.05％HCl、0.25％HCOOH或0.5％NH3·H2O，总运行时间为8-15分钟。
附图说明
图1：HDI乙型肝炎感染小鼠模型体内药效学试验药效结果(血浆)。
图2：HDI乙型肝炎感染小鼠模型体内药效学试验药效结果(肝脏)。
具体实施方式
下面的具体实施例，其目的是使本领域的技术人员能更清楚地理解和实施本发明。它们不应该被认为是对本发明范围的限制，而只是本发明的示例性说明和典型代表。
实施例1
2-丁氧基-7-(3-((4-甲基哌嗪-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000010
反应流程：
Figure PCTCN2015086909-appb-000011
实施例1流程
步骤A：将2,4-二氯-5H-吡咯并[3,2-d]嘧啶(4克，21.4毫摩尔)溶解在无水四氢呋喃(30mL)中，然后在0摄氏度向其中分批加入氢化钠(1.03克，60％的矿物油混合物，25.6毫摩尔)。反应液在室温下搅拌30分钟，将(2-(氯甲氧基)乙基)三甲基硅烷(3.9克，23.5毫摩尔)逐滴加入。室温下再搅拌2小时，然后，用水(120毫升)稀释，并用乙酸乙酯(100毫升×2)萃取。将合并的有机层用饱和碳酸钠水溶液和盐水洗涤，用无水硫酸钠干燥，并减压浓缩。残余物用硅胶柱纯化(洗脱剂：乙酸乙酯/石油醚5％至10％)，得到2,4-二氯-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶(5.8克，85％)，为黄色固体。
MS(ESI)M/Z：318[M+H+]。
步骤B：在1000毫升高压反应器中，将2,4-二氯-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶(5克，15.8毫摩尔)、异丙醇(15毫升)和氨水(250毫升)混合，在100-110摄氏度下搅拌3小时。在冷却到室温后，将该混合物用水稀释(250毫升)并过滤，得到2-氯-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺(4克，85％)，无需进一步纯化。
MS(ESI)M/Z：299[M+H+]。
步骤C：将2-氯-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺(4克，13.4毫摩尔)和丁醇钠(5.15克，53.6毫摩尔)溶于正丁醇(55毫升)。混合物在氮气保护下加热到100摄氏度，搅拌8小时。在冷却到室温后，将该混合物用水稀释(200毫升)，用乙酸乙酯(100毫升×3)萃取。将合并的有机层用盐水洗涤，用无水硫酸钠干燥，并减压浓缩。将残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚15％至25％)，得到2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺(4.1克，91％)，为黄色固体。
MS(ESI)M/Z：337[M+H+]。
步骤D：将2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺(4克，12毫摩尔)溶解在无水四氢呋喃(40mL)中。把NBS(2.2克，12.5毫摩尔)配成无水四氢呋喃的饱和溶液，在20分钟内低于0摄氏度下加入到上述溶液中。加完后，该反应混合物在0摄氏度下搅拌30分钟，然后用盐水(150毫升)稀释，并用乙酸乙酯(100毫升×3)萃取。将合并的有机层经无水硫酸钠干燥并减压浓缩。将残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚5％至15％)得到7-溴-2-丁氧基-5-(2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺(3.85克，78％)，为白色固体。
MS(ESI)M/Z：415，417[M+H+]。
步骤E：在-78摄氏度，向搅拌的7-溴-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺(3克，7.25毫摩尔)的无水四氢呋喃(40毫升)溶液中在氮气保护下加入正丁基锂(2.5M，12毫升，30毫摩尔)。将反应混合物在-78摄氏度下搅拌1小时。然后，将间苯二甲醛(1.26克，9毫摩尔)的无水四氢呋喃(5毫升)溶液缓慢加入。此混合物在-78摄氏度下再搅拌30分钟后，倒入饱和氯化铵水溶液(15毫升)中，并用乙酸乙酯(60毫升×2)萃取。将合并的有机层减压浓缩，残余物经制备型HPLC纯化，得到3-((4-氨基-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(羟基)甲基) 苯甲醛盐共1.1克。
MS(ESI)M/Z：471[M+H+]。
步骤F：在0摄氏度下，向正在搅拌的3-((4-氨基-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(羟基)甲基)苯甲醛(200毫克，0.43毫摩尔)和1-甲基哌嗪(87毫克，0.87毫摩尔)的乙醇(2.5毫升)的溶液中分批加入氰基硼氢化钠(40毫克，0.64毫摩尔)。该反应混合物在室温下搅拌2小时，然后用水(10ml)稀释，并用乙酸乙酯(15毫升×2)萃取。将合并的有机层经无水硫酸钠干燥并在减压浓缩，得到粗品(4-氨基-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(3-((4-甲基哌嗪-1-基)甲基)苯基)甲醇，直接用于下一步。
MS(ESI)M/Z：555[M+H+]。
步骤G：向正在搅拌的(4-氨基-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(3-((4-甲基哌嗪-1-基)甲基)苯基)甲醇(100毫克)的三氟乙酸(2毫升)溶液中分批加入三乙基硅烷(0.4毫升)。此反应混合物在55摄氏度在氮气保护下搅拌1小时，并减压浓缩。将残余物溶解在无水碳酸钾(100毫克)的甲醇(5毫升)溶液中。此混合物于50℃再搅拌30分钟并过滤。将滤液在减压下浓缩，残余物经制备HPLC纯化，得到36毫克2-丁氧基-7-(3-((4-甲基哌嗪-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺三氟乙酸盐。
1HNMR(Methanol–d4,400MHz):δ7.33-7.21(m,4H),4.55(t,J＝6.8Hz,2H),4.01(s,2H),3.67(s,2H),3.29-3.24(m,4H),2.87-2.80(m,7H),1.87-1.80(m,2H),1.56-1.49(m,2H),1.02(t,J＝6.8Hz,3H)。
MS(ESI)m/z:409[M+H+]。
实施例2
2-丁氧基-7-(3-(吗啉代甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000012
步骤A：根据实施例1，在步骤F中用吗啉替代1-甲基哌嗪，制备(4-氨基-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(3-(吗啉代甲基)苯基)甲醇。
LCMS(ESI)m/z:542[M+H+]。
步骤B：根据实施例1，用步骤G中所用的方法制得2-丁氧基-7-(3-(吗啉代甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸盐。
1HNMR(Methanol–d4,400MHz):δ8.41(s,2H),7.35-7.24(m,5H),4.49(t,J＝6.8Hz,2H),4.03(s,2H),3.82(s,2H),3.77-3.75(m,4H),2.77-2.73(m,4H),1.83-1.79(m,2H),1.55-1.49(m,2H),1.01(t,J＝6.8H z,3H)。
MS(ESI)m/z:396[M+H+]。
实施例3
7-(3-(氨基甲基)苄基)-2-丁氧基-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000013
步骤A：根据实施例1，在步骤F中用乙酸铵替代1-甲基哌嗪，制备(4-氨基-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(3-(氨基甲基)苯基)甲醇。
LCMS(ESI)m/z:472[M+H+]。
步骤B：根据实施例1，用步骤G中所用的方法制备7-(3-(氨基甲基)苄基)-2-丁氧基-5H-吡咯并[3,2-d]嘧啶-4-胺。
1HNMR(Methanol–d4,400MHz):δ7.31-7.15(m,4H),7.06(s,1H),4.32(t,J＝6.6Hz,2H),4.00(s,2H),3.80(s,2H),1.79-1.73(m,2H),1.56-1.50(m,2H),1.01(t,J＝7.4Hz,3H)。
MS(ESI)m/z:326[M+H+]。
实施例4
2-丁氧基-7-(3-(吡咯烷-1-基甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4胺
Figure PCTCN2015086909-appb-000014
步骤A：根据实施例1，在步骤F中用吡咯烷替代1-甲基哌嗪，制备(4-氨基-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(3-(吡咯烷-1-基甲基)苯基)甲醇。
步骤B：根据实施例1，用步骤G中所用的方法制得2-丁氧基-7-(3-(吡咯烷-1-基甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸盐。
1HNMR(Methanol–d4,400MHz):δ8.50(s,2H),7.41-7.28(m,5H),4.45(t,J＝6.8Hz,2H),4.31(s,2H),4.06(s,2H),3.31-3.29(m,4H),2.10-2.07(m,4H),1.81-1.76(m,2H),1.54-1.49(m,2H),1.01(t,J＝6.8H z,3H)。
MS(ESI)m/z:380[M+H+]。
实施例5
2-丁氧基-7-(4-((3,3-二氟吡咯烷-1-基)甲基)苄基-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000015
步骤A：根据实施例1，在步骤E中用对苯二甲醛替代间苯二甲醛，制备4-((4-氨基-2- 丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(羟基)甲基)苯甲醛。
LCMS(ESI)m/z:471[M+H+]。
步骤B：根据实施例1，在步骤F中用3,3-二氟吡咯烷替代1-甲基哌嗪，制备(4-氨基-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(4-((3,3-二氟吡咯烷-1-基)甲基)苯基)甲醇。
LCMS(ESI)m/z:562[M+H+]。
步骤C：根据实施例1，用步骤G中所用的方法制备2-丁氧基-7-(4-((3,3-二氟吡咯烷-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺。
1HNMR(Methanol–d4,400MHz):δ7.28-7.15(m,4H),7.04(s,1H),4.30(t,J＝6.4Hz,2H),3.97(s,2H),3.59(s,2H),2.88-2.71(m,4H),2.30-2.19(m,2H),1.78-1.71(m,2H),1.55-1.46(m,2H),0.98(t,J＝7.2H z,3H)。
MS(ESI)m/z:416[M+H+]。
实施例6
2-丁氧基-7-(4-((3-氟吡咯烷-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000016
步骤A：根据实施例5，在步骤B中用3-氟吡咯烷替代3,3-二氟吡咯烷，制备(4-氨基-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(4-((3-氟吡咯烷-1-基)甲基)苯基)甲醇。
LCMS(ESI)m/z:544[M+H+]。
步骤B：根据实施例5，用步骤C中所用的方法制备2-丁氧基-7-(4-((3-氟吡咯烷-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺。
1HNMR(Methanol–d4,400MHz):δ7.30-7.24(m,4H),7.06(s,1H),5.24-5.08(m,1H),4.32(t,J＝6.4Hz,2H),3.99(s,2H),3.69-3.57(m,2H),2.88-2.65(m,4H),2.45-2.43(m,1H),2.25-2.11(m,1H),2.02-1.91(m,1H),1.78-1.73(m,2H),1.57-1.50(m,2H),1.01(t,J＝7.2Hz,3H)。
MS(ESI)m/z:398[M+H+]。
实施例7
1-(4-((4-氨基-2-丁氧基-5H-吡咯并[3,2-d]嘧啶-7-基)甲基)苄基)吡咯烷-3-醇
Figure PCTCN2015086909-appb-000017
步骤A：根据实施例5，在步骤B中用吡咯烷-3-醇替代3,3-二氟吡咯烷，制备1-(4-((4- 氨基-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(羟基)甲基)苄基)吡咯烷-3-醇。
LCMS(ESI)m/z:542[M+H+]。
步骤B：根据实施例5，用步骤C的方法制得1-(4-((4-氨基-2-丁氧基-5H-吡咯并[3,2-d]嘧啶-7-基)甲基)苄基)吡咯烷-3-醇甲酸盐。
1HNMR(Methanol–d4,400MHz):δ8.43(s,2H),7.45-7.39(m,4H),7.25(s,1H),4.53(m,1H),4.44-4.27(m,2H),4.04(s,2H),3.54-3.47(m,1H),3.38-3.36(m,4H),3.22-3.19(m,1H),2.28-2.24(m,1H),2.05-2.01(m,1H),1.82-1.76(m,2H),1.56-1.50(m,2H),1.01(t,J＝7.2Hz,3H)。
MS(ESI)m/z:396[M+H+]。
实施例8
2-丁氧基-7-(4-(哌啶-1-基甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000018
步骤A：根据实施例5，在步骤B中用哌啶替代3,3-二氟吡咯烷，制备(4-氨基-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(4-(哌啶-1-基甲基)苯基)甲醇。
LCMS(ESI)m/z:540[M+H+]。
步骤B：根据实施例5，用步骤C的方法制备2-丁氧基-7-(4-(哌啶-1-基甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺。
1HNMR(Methanol–d4,400MHz):δ7.28(d,J＝8.0Hz,2H),7.22(d,J＝8.0Hz,2H),7.04(s,1H),4.30(t,J＝6.6Hz,2H),3.98(s,2H),3.47(s,2H),2.42(s,4H),1.77-1.73(m,2H),1.60-1.57(m,4H),1.52-1.46(m,4H),0.99(t,J＝7.4Hz,3H)。
MS(ESI)m/z:394[M+H+]。
实施例9
2-丁氧基-7-(4-(吗啉代甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000019
步骤A：根据实施例5，在步骤B中用吗啉替代3,3-二氟吡咯烷，制备(4-氨基-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(4-(吗啉代甲基)苯基)甲醇。
LCMS(ESI)m/z:542[M+H+]。
步骤B：根据实施例5，用步骤C的方法制备2-丁氧基-7-(4-(吗啉代甲基)苄基)-5H-吡 咯并[3,2-d]嘧啶-4-胺。
1HNMR(Methanol–d4,400MHz):δ7.28(d,J＝8.0Hz,2H),7.22(d,J＝8.0Hz,2H),7.03(s,1H),4.29(t,J＝6.6Hz,2H),3.96(s,2H),3.67-3.64(m,4H),3.46(s,2H),2.43(s,4H),1.77-1.72(m,2H),1.55-1.45(m,2H),0.98(t,J＝7.4Hz,3H)。
MS(ESI)m/z:396[M+H+]。
实施例10
2-丁氧基-7-(4-((4-甲基哌嗪-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000020
步骤A：根据实施例5，在步骤B中用1-甲基哌嗪替代3,3-二氟吡咯烷，制备(4-氨基-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(4-((4-甲基哌嗪-1-基)甲基)苯基)甲醇。
LCMS(ESI)m/z:555[M+H+]。
步骤B：根据实施例5，用步骤C的方法制备2-丁氧基-7-(4-((4-甲基哌嗪-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺。
1HNMR(Methanol–d4,400MHz):δ7.29(d,J＝8.0Hz,2H),7.22(d,J＝8.0Hz,2H),7.04(s,1H),4.31(t,J＝6.6Hz,2H),3.97(s,2H),3.50(s,2H),2.49-2.26(m,11H),1.79-1.72(m,2H),1.56-1.47(m,2H),0.99(t,J＝7.4Hz,3H)。
MS(ESI)m/z:409[M+H+]。
实施例11
2-丁氧基-7-(4-((二甲基氨基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000021
步骤A：根据实施例5，在步骤B中用二甲基胺替代3,3-二氟代吡咯烷，制备(4-氨基-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(4-((二甲基氨基)甲基)苯基)甲醇。
LCMS(ESI)m/z:500[M+H+]。
步骤B：根据实施例5，用步骤C的方法制备2-丁氧基-7-(4-((二甲基氨基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸盐。
1HNMR(Methanol–d4,400MHz):δ8.48(s,2H),7.41(s,4H),7.26(s,1H),4.43(t,J＝6.8Hz,2H),4.22(s,2H),4.06(s,2H),2.79(s,6H),1.79(m,J＝6.8Hz,2H),1.55-1.49(m,2H),1.01(t,J＝6.8Hz,3H)。
MS(ESI)m/z:354[M+H+]。
实施例12
2-丁氧基-7-(4-((二乙基氨基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000022
步骤A：根据实施例5制备，在步骤B中用二乙胺代3,3-二氟代吡咯烷，制备(4-氨基-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(4-((二乙基氨基)甲基)苯基)甲醇。
LCMS(ESI)m/z:528[M+H+]。
步骤B：根据实施例5，用步骤C的方法制得2-丁氧基-7-(4-((二乙基氨基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸盐。
1HNMR(Methanol–d4,400MHz):δ8.48(s,2H),7.42(s,4H),7.25(s,1H),4.41(t,J＝6.8Hz,2H),4.28(s,2H),4.06(s,2H),3.20-3.15(m,4H),1.82-1.77(m,2H),1.55-1.49(m,2H),1.34(t,J＝6.8Hz,6H),1.01(t,J＝6.8Hz,3H)。
MS(ESI)m/z:382[M+H+]。
实施例13
2-丁氧基-7-(4-((二丙基氨基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000023
步骤A：根据实施例5，在步骤B中用二丙胺替代3,3-二氟代吡咯烷，制备(4-氨基-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(4-((二丙基氨基)甲基)苯基)甲醇。
LCMS(ESI)m/z:556[M+H+].
步骤B：根据实施例5，用步骤C的方法制备2-丁氧基-7-(4-((二丙基氨基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺。
1HNMR(Methanol–d4,400MHz):δ7.29-7.19(m,4H),7.04(s,1H),4.32(t,J＝6.5Hz,1H),3.99(s,2H),3.55(s,2H),2.41-2.37(m,4H),1.78-1.74(m,2H),1.57-1.47(m,6H),1.00(t,J＝7.4Hz,3H),0.87(t,J＝7.4Hz,6H)。
MS(ESI)m/z:410[M+H+]。
实施例14
7-(4-(氮杂环丁烷-1-基甲基)苄基)-2-丁氧基-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000024
步骤A：根据实施例5，在步骤B中用氮杂环丁烷替代3,3-二氟代吡咯烷，制备(4-氨基-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(4-(氮杂环丁烷-1-基甲基)苯基)甲醇。
LCMS(ESI)m/z:512[M+H+]。
步骤B：根据实施例5，用步骤C的方法制备7-(4-(氮杂环丁烷-1-基甲基)苄基)-2-丁氧基-5H-吡咯并[3,2-d]嘧啶-4-胺。
1HNMR(Methanol–d4,400MHz):δ7.28(d,J＝8.0Hz,2H),7.18(d,J＝8.0Hz,2H),7.04(s,1H),4.31(t,J＝6.8Hz,2H),3.98(s,2H),3.59(s,2H),3.30-3.27(m,4H),2.15-2.10(m,2H),1.78-1.73(m,2H),1.56-1.52(m,2H),1.01(t,J＝6.8Hz,3H)。
MS(ESI)m/z:366[M+H+]。
实施例15
2-丁氧基-7-(4-((3-甲氧基氮杂环丁烷-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000025
步骤A：根据实施例5，在步骤B中用3-甲氧基氮杂环丁烷替代3,3-二氟吡咯烷，制备(4-氨基-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(4-((3-甲氧基氮杂环丁烷-1-基)甲基)苯基)甲醇。
LCMS(ESI)m/z:542[M+H+]。
步骤B：根据实施例5，用步骤C的方法制备2-丁氧基-7-(4-((3-甲氧基氮杂环丁烷-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺。
1HNMR(Methanol–d4,400MHz):δ7.28(d,J＝8.0Hz,2H),7.18(d,J＝8.0Hz,2H),7.04(s,1H),4.31(t,J＝6.8Hz,2H),4.06-4.04(m,1H),3.98(s,2H),3.60(s,2H),3.54-3.52(m,2H),3.24(s,3H),3.04-3.02(m,2H),1.78-1.73(m,2H),1.56-1.52(m,2H),1.01(t,J＝6.8Hz,3H)。
MS(ESI)m/z:396[M+H+]。
实施例16
2-丁氧基-7-(4-((4-甲基-1,4-二氮杂环庚烷-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000026
步骤A：根据实施例5，在步骤B中用1-甲基-1,4-二氮杂环庚烷替代3,3-二氟吡咯烷，制备((4-氨基-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(4-((4-甲基-1,4-二氮杂环庚烷-1-基)甲基)苯基)甲醇。
LCMS(ESI)m/z:569[M+H+]。
步骤B：根据实施例5，用步骤C的方法制得2-丁氧基-7-(4-((4-甲基-1,4-二氮杂环庚烷-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸盐。
1HNMR(Methanol–d4,400MHz):δ8.41(s,3H),7.34-7.24(m,5H),4.52(t,J＝6.8Hz,2H),3.99(s,2H),3.76(s,2H),3.38-3.36(m,2H),3.29-3.27(m,2H),2.95(s,2H),2.87-2.84(m,5H),2.07-2.05(m,2H),1.84-1.80(m,2H),1.55-1.49(m,2H),1.03-0.99(t,J＝8.0Hz,3H)。
MS(ESI)m/z:423[M+H+]。
实施例17
2-丁氧基-7-(4-((2,6-二甲基吗啉基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000027
步骤A：根据实施例5，在步骤B中用2,6-二甲基吗啉替代3,3-二氟吡咯烷，制备(4-氨基-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(4-((2,6-二甲基吗啉基)甲基)苯基)甲醇。
LCMS(ESI)m/z:570[M+H+]。
步骤B：根据实施例5，用步骤C的方法制备2-丁氧基-7-(4-((2,6-二甲基吗啉基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺。
1HNMR(Methanol–d4,400MHz):δ7.30-7.28(d,J＝8.0Hz,2H),7.23-7.21(d,J＝8.0Hz,2H),7.06(s,1H),4.34-4.30(t,J＝8.0Hz,2H),3.99(s,2H),3.69-3.64(m,2H),3.47(s,2H),2.73(d,J＝12.0Hz,2H),1.77-1.70(m,4H),1.54-1.51(m,2H),1.11(d,J＝10.4Hz,6H),1.00(t,J＝8.0Hz,3H).
MS(ESI)m/z:424[M+H+]。
实施例18
7-(4-((1S,4S)-2-氧杂-5-氮杂双环[2.2.1]庚烷-5-基甲基)苄基)-2-丁氧基-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000028
步骤A：根据实施例5，在步骤B中用(1S,4S)-2-氧杂-5-氮杂双环[2.2.1]庚烷替代3,3-二氟吡咯烷，制备(4-((1S,4S)-2-氧杂-5-氮杂双环[2.2.1]庚烷-5-基甲基)苯基)(4-氨基-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)甲醇。
LCMS(ESI)m/z:554[M+H+]。
步骤B：根据实施例5，用步骤C的方法制得7-(4-((1S,4S)-2-氧杂-5-氮杂双环[2.2.1]庚烷-5-基甲基)苄基)-2-丁氧基-5H-吡咯并[3,2-D]嘧啶-4-胺甲酸盐。
1HNMR(Methanol–d4,400MHz):δ:8.38(brs,2H),7.45(d,J＝8.4Hz,2H),7.37(d,J＝8.4Hz,2H),7.29(s,1H),4.66(s,1H),4.47(t,J＝6.8Hz,2H),4.36-4.27(m,1H),4.24-4.23(m,2H),4.16-4.13(m,1H),4.04(s,2H),3.82-3.81(m,1H),3.33-3.31(m,2H),2.33-2.29(m,1H),2.14–2.11(m,1H),1.83-1.76(m,2H),1.56-1.48(m,2H),1.01(t,J＝7.2Hz,3H).
MS(ESI)m/z:408[M+H+]。
实施例19
2-丁氧基-7-(4-((4-甲氧基哌啶-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000029
步骤A：根据实施例5，在步骤B中用4-甲氧基哌啶替代3,3-二氟吡咯烷，制备(4-氨基-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(4-((4-甲氧基哌啶-1-基)甲基)苯基)甲醇。
LCMS(ESI)m/z:570[M+H+]。
步骤B：根据实施例5，用步骤C的方法制得2-丁氧基-7-(4-((4-甲氧基哌啶-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸盐。
1HNMR(Methanol–d4,400MHz):δ:8.45(s,2H),7.43-7.38(m,4H),7.28(s,1H),4.45(t,J＝6.4Hz,2H),4.21(s,2H),4.05(s,2H),3.52-3.53(m,1H),3.33-3.39(m,3H),3.26-3.24(m,2H),3.13-3.10(m,2H),1.99-1.92(m,4H),1.84-1.77(m,2H),1.56-1.50(m,2H),1.01(t,J＝7.2Hz,3H)。
MS(ESI)m/z:424[M+H+]。
实施例20
2-丁氧基-7-(4-((4-异丙基哌嗪-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000030
步骤A：根据实施例5，在步骤B中用1-异丙基哌嗪替代3,3-二氟吡咯烷，制备(4-氨基-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(4-((4-异丙基哌嗪-1-基)甲基)苯基)甲醇。
LCMS(ESI)m/z:583[M+H+]。
步骤B：根据实施例5，用步骤C的方法制得2-丁氧基-7-(4-((4-异丙基哌嗪-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸盐。
1HNMR(Methanol–d4,300MHz):δ:8.45(s,2H),7.31-7.25(m,5H),4.49(t,J＝8.4Hz,2H),3.99(s,2H),3.64(s,2H),3.42-3.40(m,1H),3.21-3.25(m,4H),2.66-2.82(m,4H),1.84-1.79(m,2H),1.56-1.51(m,2H),1.35(d,J＝8.8Hz,6H),1.04-0.99(t,J＝10.0Hz,3H)。
MS(ESI)m/z:437[M+H+]。
实施例21
2-丁氧基-7-(4-(吡咯烷-1-基甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000031
步骤A：根据实施例5，在步骤B中用吡咯替代3,3-二氟吡咯烷，制备(4-氨基-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(4-(吡咯烷-1-基甲基)苯基)甲醇。
LCMS(ESI)m/z:526[M+H+]。
步骤B：根据实施例5，用步骤C的方法制得2-丁氧基-7-(4-(吡咯烷-1-基甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸盐。
1HNMR(Methanol–d4,400MHz):δ8.41(s,2H),7.46(d,J＝8.0Hz,2H),7.40(d,J＝8.0Hz,2H),7.30(s,1H),4.48(t,J＝6.8Hz,2H),4.33(s,2H),4.05(s,2H),3.32-3.30(m,4H),2.10-2.06(m,4H),1.83-1.89(m,2H),1.55-1.48(m,2H),1.02(t,J＝7.2Hz,3H)。
MS(ESI)m/z:380[M+H+]。
实施例22
2-丁氧基-7-((6-(吡咯烷-1-基甲基)吡啶-3-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000032
6-(吡咯烷-1-基甲基)烟醛的制备路线：
Figure PCTCN2015086909-appb-000033
步骤A：在室温下，向6-甲基烟酸甲酯(10克，0.0662摩尔)在CCl4(100毫升)溶液中加入NBS(13.0克，0.0728摩尔)和BPO(1.6克，0.0066摩尔)。将反应混合物加热至75℃并搅拌12小时。冷却后，加入水(80毫升)，并用乙酸乙酯(200毫升×2)萃取。将有机层依次用硫代硫酸钠(80毫升)的饱和水溶液洗涤，用无水硫酸钠干燥，并减压浓缩。残余物通过硅胶柱纯化(洗脱剂：石油醚/乙酸乙酯＝20/1)，得到6-(溴甲基)烟酸甲酯(5.2克，产率34％)，为棕色固体。
1HNMR(CDCl3,400MHz):δ9.18(d,J＝1.6Hz,1H),8.32(dd,J1＝8.0Hz,J2＝2.0Hz,1H),7.55(d,J＝8.0Hz,1H),4.60(s,2H),3.97(s,3H)。
MS(ESI)m/z:230,232[M+H+]。
步骤B：在0摄氏度下，向吡咯烷(3.09克，43.47毫摩尔)和三乙胺(3毫升，21.73毫摩尔)的无水四氢呋喃(100毫升)溶液中分批加入6-(溴甲基)烟酸甲酯(5.0克，21.73毫摩尔)。加完后，将该反应混合物在室温下搅拌16小时，然后用水(80毫升)稀释，并用乙酸乙酯(100毫升)萃取。将有机层用无水硫酸钠干燥，并减压浓缩。残余物通过硅胶柱纯化(洗脱剂：石油醚/乙酸乙酯＝10/1)，得到6-(吡咯烷-1-基甲基)烟酸甲酯(4.1克，产率86％)，为棕色固体。
1HNMR(CDCl3,400MHz):δ9.11(d,J＝2.0Hz,1H),8.22(dd,J1＝8.0Hz,J2＝2.0Hz,1H),7.48(d,J＝8.0Hz,1H),3.91(s,3H),3.81(s,2H),2.58-2.53(m,4H),1.81-1.77(m,4H)。
MS(ESI)m/z:221[M+H+]。
步骤C：在低于0℃下，向正在搅拌的6-(吡咯烷-1-基甲基)烟酸甲酯(3.0克，13.62毫摩尔)的无水四氢呋喃(70毫升)溶液中分批加入四氢锂铝(1.03克，27.24毫摩尔)。在大约0摄氏度反应2小时，并在室温下进一步反应30分钟。TLC显示反应物消失。然后将该混合物冷却至0℃，并非常缓慢地滴入水(1毫升)。然后，将15％的氢氧化钠水溶液(1 毫升)和外加水(3毫升)分别加入并剧烈搅拌。将所得混合物过滤。将滤液用无水Mg2SO4干燥并减压浓缩干，得到(6-(吡咯烷-1-基甲基)吡啶-3-基)甲醇(2.5克)。
1HNMR(CDCl3,400MHz):δ8.41(d,J＝1.6Hz,1H),7.67(dd,J1＝8.0Hz,J2＝2.0Hz,1H),7.37(d,J＝8.0Hz,1H),4.67(s,2H),3.75(s,2H),2.57-2.543(m,4H),1.81-1.76(m,4H)。
步骤D：将(6-(吡咯烷-1-基甲基)吡啶-3-基)甲醇(2.5克，13毫摩尔)溶解在无水二氯甲烷(50毫升)中。将二氧化锰(5.0克，58毫摩尔)在0摄氏度下分批加入。将反应混合物在室温下搅拌24小时，过滤。将滤液在真空下浓缩，残余物通过硅胶柱纯化(洗脱剂：15％乙酸乙酯的石油醚溶剂)，得到6-(吡咯烷-1-基甲基)烟醛(2.2克，粗品)，为黄色油状物。
LCMS(ESI)m/z:191[M+H+]。
2-丁氧基-7-((6-(吡咯烷-1-基甲基)吡啶-3-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺的制备流程：
Figure PCTCN2015086909-appb-000034
实施例22流程
步骤E：根据实施例1，在步骤E中用6-(吡咯烷-1-基甲基)烟醛替代间二苯甲醛，制备(4-氨基-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(6-(吡咯烷-1-基甲基)吡啶-3-基)甲醇。
LCMS(ESI)m/z:527[M+H+]。
步骤F：按照实施例1，用步骤G的方法制得2-丁氧基-7-((6-(吡咯烷-1-基甲基)吡啶-3-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸盐，为白色固体。
1HNMR(Methanol–d4,400MHz):δ8.62(s,1H),8.40(brs,1H),7.77(d,J＝8.0Hz,1H),7.40(d,J＝8.0Hz,1H),7.35(s,1H),4.48(s,2H),4.45(t,J＝6.4Hz,2H),4.08(s,2H),3.42-3.38(m,4H),2.13-2.10(m,4H),1.83-1.76(m,2H),1.55-1.49(m,2H),1.01(t,J＝7.2Hz,3H)。
MS(ESI)m/z:381[M+H+]。
实施例23
2-丁氧基-7-(3-(2-(吡咯烷-1-基)乙基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000035
3-(2-(吡咯烷-1-基)乙基)苯甲醛的制备路线：
Figure PCTCN2015086909-appb-000036
步骤A：在氮气保护下，将3-溴苯甲酸甲酯(17.0克，79.0毫摩尔)、三丁基(乙烯基)锡烷(33克，102毫摩尔)和Pd(PPh3)4(4.5克，4毫摩尔)的二噁烷(200毫升)溶液在110摄氏度下搅拌反应6小时，然后加10％的氟化钾水溶液(100毫升)淬灭。将所得混合物在室温下再搅拌10分钟，并用乙酸乙酯(150毫升×3)萃取。将合并的有机层用盐水洗涤，用无水硫酸钠干燥，并减压浓缩。将残余物用硅胶柱纯化(洗脱剂：25％乙酸乙酯的石油醚溶液)，得到约15克粗品3-乙烯基苯甲酸甲酯，为黄色油状物。
MS(ESI)m/z:163[M+H+]。
步骤B：在氮气氛围下，向正在搅拌的3-乙烯基苯甲酸甲酯的无水四氢呋喃(100毫升) 溶液中通过滴液漏斗加入9-BBN(0.5M，166毫升，83毫摩尔)并保持温度低于-30摄氏度。加完后，将反应混合物升温至室温并搅拌16小时。然后冷却至-30摄氏度，滴加H2O2的水溶液(质量比30％，19毫升)，接着慢慢滴加15％氢氧化钠水溶液(40毫升)。将所得混合物在环境温度下再搅拌1小时后，加水(200毫升)稀释，并用乙酸乙酯(200毫升×2)萃取。将合并的有机层用盐水洗涤，用无水硫酸钠干燥，减压浓缩得到约9克粗品3-(2-羟乙基)苯甲酸甲酯，为淡黄色油状物，其直接用于下一步骤。
1HNMR(CDCl3,400MHz):δ7.92-7.90(m,2H),7.45-7.37(m,2H),3.92(s,3H),3.89(t,J＝6.5Hz,2H),2.93(t,J＝6.5Hz,2H)。
MS(ESI)m/z:181[M+H+]。
步骤C：在约0摄氏度下，向正在搅拌的3-(2-羟乙基)苯甲酸甲酯(10克)无水二氯甲烷(90mL)溶液中加入甲磺酰氯(34克，299毫摩尔)和三乙胺(12克，118毫摩尔)。反应物在0摄氏度下搅拌1小时，用水淬灭(50毫升)，并用乙酸乙酯(100毫升×3)萃取。将合并的有机层经无水硫酸钠干燥并减压浓缩。将残余物用硅胶柱层析纯化(洗脱剂：10％乙酸乙酯的石油醚溶液)，得到2.7g的3-(2-((甲基磺酰基)氧基)乙基)苯甲酸甲酯，为无色油状物。
MS(ESI)m/z:259[M+H+]。
步骤D：将吡咯烷(2.3克，31.3毫摩尔)和碳酸钾(2.2克，16毫摩尔)溶于无水乙腈(20毫升)并用10分钟时间向其中加入3-(2-((甲基磺酰基)氧基)乙基)苯甲酸甲酯(2.7克，10.4毫摩尔)的乙腈(5毫升)溶液。将反应液在70℃搅拌16小时，冷却到室温后，用水(20毫升)稀释，并用乙酸乙酯(20毫升×3)萃取。将合并的有机层经无水硫酸钠干燥并减压浓缩。将残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷等于2％至5％)，得到3-(2-(吡咯烷-1-基)乙基)苯甲酸甲酯(1.7克，71％)，为黄色油状物。
MS(ESI)m/z:234[M+H+]。
步骤E：根据实施例22，用步骤C、D方法制备3-(2-(吡咯烷-1-基)乙基)苯甲醛。
MS(ESI)m/z:204[M+H+]。
步骤F：根据实施例22，用步骤E、F方法制得2-丁氧基-7-(3-(2-(吡咯烷-1-基)乙基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸盐。
1HNMR(Methanol–d4,400MHz):δ8.42(s,2H),7.30-7.13(m,5H),4.38(t,J＝6.4Hz,2H),4.01(s,1H),3.41(t,J＝7.6Hz,2H),3.35-3.32(m,4H),3.01(t,J＝7.6Hz,2H),2.09-2.05(m,4H),1.81-1.74(m,2H),1.57-1.48(m,2H),1.01(t,J＝7.6Hz,3H)。
MS(ESI)m/z:394[M+H+]。
实施例24
2-丁氧基-7-(4-(1-(吡咯烷-1-基)乙基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000037
4-(1-(吡咯烷-1-基)乙基)苯甲醛制备路线：
Figure PCTCN2015086909-appb-000038
步骤A：在搅拌下，向4-氰基苯乙酮(4克，27.56毫摩尔)和吡咯烷(2.94克，41.33毫摩尔)的甲醇(100毫升)溶液中加入醋酸(0.5毫升)以及氰基硼氢化钠(5.2克，82.67毫摩尔)，并保持温度低于0摄氏度。将反应物在室温下搅拌16小时，然后减压浓缩。将所得油状物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/3)，得到2.8克4-(1-(吡咯烷-1-基)乙基)苄腈，为无色油状物。
MS(ESI)m/z:201[M+H+]。
步骤B：在-20至-10摄氏度向4-(1-(吡咯烷-1-基)乙基)苄腈(2克，10毫摩尔)的无水甲苯(100毫升)溶液中加入DIBAL-H(1M，20毫升，20毫摩尔)的溶液并控制在1小时加完。将反应液再搅拌3小时，然后用氯化铵饱和水溶液淬灭，并用乙酸乙酯萃取。用盐水洗涤有机层，用无水硫酸钠干燥，并减压浓缩。将所得固体物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝50/1至10/1)，得到4-(1-(吡咯烷-1-基)乙基)苯甲醛(680毫克，33.5％)，为无色油状物。
(ESI)m/z:204[M+H+]。
步骤C：根据实施例22，用步骤E、F的方法制得2-丁氧基-7-(4-(1-(吡咯烷-1-基)乙基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸盐。
1HNMR(Methanol–d4,400MHz):δ8.50(s,2H),7.44-7.38(m,4H),7.27(s,1H),4.45(t,J＝6.4,2H),4.33-4.28(m,1H),4.04(s,2H),3.37-3.33(m,2H),3.14-3.11(m,2H),2.04-2.02(m,4H),1.83-1.78(m,2H),1.72-1.70(m,3H),1.55-1.49(m,2H),1.01(t,J＝7.4,3H)。
MS(ESI)m/z:394[M+H+]。
实施例25
2-丁氧基-7-(4-(1-甲基哌啶-4-基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000039
4-(4-甲酰基苯基)哌啶-1-甲酸叔丁酯的制备路线：
Figure PCTCN2015086909-appb-000040
步骤A：将4-溴吡啶(3.0克，19.0毫摩尔)、(4-(甲氧羰基)苯基)硼酸(2.63克，14.6毫摩尔)、Pd(PPh3)2Cl2(0.35克，0.5毫摩尔)和碳酸钠(6.91克，65.2毫摩尔)的1,2-二甲氧基乙烷(40毫升)混合物在氮气气氛下加热至90℃并搅拌10小时。将所得混合物减压浓缩，残余物通过硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝6/1至2/1)，得到4-(吡啶-4-基)苯甲酸甲酯(2.7克，收率：86.8％)，为白色固体。
MS(ESI)m/z:214[M+H+]。
步骤B：向4-(吡啶-4-基)苯甲酸甲酯(3.8克，17.8毫摩尔)和PtO2(0.2克)的甲醇(40毫升)溶液中加入2毫升盐酸，加热到约50摄氏度，在氢气氛围下(50psi)搅拌16小时。将所得混合物过滤，滤液减压浓缩，得到粗品4-(哌啶-4-基)苯甲酸甲酯(4.0克)，为盐酸盐，无需进一步纯化。
MS(ESI)m/z:220[M+H+]。
步骤C：向正在搅拌的4-(哌啶-4-基)苯甲酸甲酯(5.0克，22.8毫摩尔)和碳酸钾(25.0克，182.2毫摩尔)的四氢呋喃(50毫升)/水(50毫升)混合溶液中分批加入二叔丁基二碳酸酯(10.0克，45.8毫摩尔)并保持温度低于10℃。加完后，将反应混合物在室温下搅拌另外0.5小时，然后用水(50毫升)稀释，并用乙酸乙酯(50毫升×2)萃取。将合并的有机层用盐水洗涤，用无水硫酸钠干燥，并在真空下浓缩。残余物通过硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝6/1至1/1)，得到4-(4-(甲氧羰基)苯基)哌啶-1-甲酸叔丁酯(1.9克，收率：26.4％)，为白色固体。
1HNMR(CDCl3,400MHz):δ7.98(d,J＝8.4Hz,2H),7.28(d,J＝7.6Hz,2H),4.27(s,1H),3.91(s,3H),2.84-2.68(m,3H),1.85(d,J＝12.8Hz,2H),1.66-1.59(m,2H),1.49(s,9H)。
MS(ESI)m/z:320[M+H+]。
步骤D：根据实施例22，用步骤C、D的方法制备4-(4-甲酰基苯基)哌啶-1-甲酸叔丁酯。
MS(ESI)m/z:312.1[M+Na+]。
步骤F：根据实施例22，用步骤E、F的方法制备2-丁氧基-7-(4-(哌啶-4-基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺。
MS(ESI)m/z:380.2[M+H+]。
2-丁氧基-7-(4-(1-甲基哌啶-4-基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺的制备：
Figure PCTCN2015086909-appb-000041
步骤G：在搅拌5分钟后，向2-丁氧基-7-(4-(哌啶-4-基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺(100毫克，0.264毫摩尔)和HCHO(20毫克，0.666毫摩尔)的甲醇(5毫升)溶液中加入氰基硼氢化钠(50毫克，0.796毫摩尔)。此反应物在室温搅拌0.5小时，用水稀释，并用乙酸乙酯萃取。将有机层在真空下浓缩，残余物经制备型HPLC纯化，得到7.48毫克2-丁氧基-7-(4-(1-甲基哌啶-4-基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺。
1HNMR(Methanol,400MHz):δ7.21(d,J＝8.0Hz,2H),7.11(d,J＝8.0Hz,2H),7.00(s,1H),4.32-4.28(m,2H),3.94(s,2H),3.00-2.97(m,2H),2.52–2.47(m,1H),2.32(s,3H),2.19–2.15(m,2H),1.80-1.72(m,6H),1.53-1.48(m,2H),0.98(t,J＝7.4Hz,3H)。
MS(ESI)m/z:394[M+H+]。
实施例26
2-丁氧基-7-(4-(1-甲基吡咯烷-2-基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000042
2-(4-甲酰基苯基)吡咯烷-1-甲酸叔丁酯的制备路线：
Figure PCTCN2015086909-appb-000043
步骤A：在N2氛围、0摄氏度下，向NaH(446毫克，18.6毫摩尔)的无水四氢呋喃(20毫升)混合物中加入1-烯丙基-吡咯-2-酮(1.14克，9.11毫摩尔)。然后缓慢加入4-溴苯甲酸甲酯的无水四氢呋喃(10毫升)溶液。此混合物在90摄氏度下搅拌2小时，然后冷却至室温，用6N盐酸稀释。将所得混合物在110摄氏度下搅拌12小时，然后将水相用乙 酸乙酯(50毫升)洗涤。用1N氢氧化钠溶液碱化，使pH约为9，再用乙酸乙酯(50毫升×2)萃取。将合并的有机层在真空下浓缩至干，得到2.0克5-(4-溴苯基)-3,4-二氢-2H-吡咯，为黄色固体，将其直接用于下一步骤。
步骤B：在0摄氏度下，向正在搅拌的5-(4-溴苯基)-3,4-二氢-2H-吡咯(2.0克，9.0毫摩尔)甲醇(20毫升)溶液中慢慢地加入硼氢化钠(684毫克，18.1毫摩尔)。加完后，将该反应混合物在室温下搅拌1小时。TLC(石油醚/乙酸乙酯＝2:1)显示原料完全消耗。将得到的混合物用水稀释(30毫升)。向上述步骤中的混合物加入碳酸钾(1.51克，10.9毫摩尔)和Boc2O(2.3克，10.5毫摩尔)。将该混合物在20摄氏度下搅拌2小时后，薄层色谱板(展开剂：石油醚/乙酸乙酯＝2/1)显示起始物质被消耗完全。然后用乙酸乙酯(50毫升×2)萃取，萃取液减压浓缩，用硅胶色谱纯化残余物，得到2-(4-溴苯基)吡咯烷-1-甲酸叔丁酯(1.5克，收率：51.1％)，为黄色固体。
步骤C：在氮气氛围、-78摄氏度下，向正在搅拌的2-(4-溴苯基)吡咯烷-1-甲酸叔丁酯(0.6克，1.839毫摩尔)的无水四氢呋喃(20毫升)溶液中加入n-BuLi(1.5毫升，2.76毫摩尔)。将反应混合物在-78摄氏度下搅拌30分钟，然后将N,N-二甲基甲酰胺(192毫克，2.63毫摩尔)缓慢加入到混合物中。将所得混合物升温至室温，搅拌另外30分钟，用3毫升碳酸氢钠水溶液淬灭。用水稀释(30毫升)，并用乙酸乙酯(25毫升×3)萃取。将合并的有机层用盐水洗涤，用硫酸钠干燥，过滤并减压蒸干。将残余物通过硅胶色谱纯化(石油醚：乙酸乙酯＝15:1至10:1)，得到2-(4-甲酰基苯基)吡咯烷-1-甲酸叔丁酯(0.4g，收率：79.1％)，为无色油。
MS(ESI)m/z:276.0[M+1+]。
2-丁氧基-7-(4-(吡咯烷-2-基)苄基)-5H-吡咯并[3,2-d]2嘧啶-4-胺的制备：
步骤D：根据实施例22，用步骤E、F的方法制备2-丁氧基-7-(4-(吡咯烷-2-基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺。
MS(ESI)m/z:366.2[M+1+]。
2-丁氧基-7-(4-(1-甲基吡咯烷-2-基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺的制备：
步骤E：根据实施例25，用步骤G的方法制备2-丁氧基-7-(4-(1-甲基吡咯烷-2-基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺。
1HNMR(Methanol-d4,400MHz):δ7.27(d,J＝8.0Hz,2H),7.22(d,J＝8.0Hz,2H),7.03(s,1H),4.30(t,J＝7.4Hz,2H),3.97(s,2H),3.31-3.19(m,1H),3.07-3.03(m,1H),2.31-2.87(m,1H),2.18-2.15(m,1H),2.13(s,3H),1.89-1.72(m,5H),1.54-1.48(m,2H),0.98(t,J＝7.4Hz,3H)。
MS(ESI)m/z:380[M+1+]。
实施例27
1-(4-((4-氨基-2-丁氧基-5H-吡咯并[3,2-d]嘧啶-7-基)甲基)苯基)-4-甲基哌嗪-2-酮
Figure PCTCN2015086909-appb-000044
4-(4-甲基-2-氧代哌嗪-1-基)苯甲醛的制备：
Figure PCTCN2015086909-appb-000045
步骤A：向4-溴-苯甲醛(1.8克，9.73毫摩尔)、4-甲基哌嗪-2-酮(1.44克，12.6毫摩尔)、Pd2(dba)3(768毫克，0.84毫摩尔)、Xantphos(435毫克，0.75毫摩尔)和碳酸铯(5.48克，16.8毫摩尔)的二噁烷(30mL)溶液中加入水(1滴)。将混合物在氮气气氛、90摄氏度下搅拌1.5小时。冷却后，将该混合物过滤。将滤液在真空下浓缩至干，残余物通过硅胶色谱法纯化，得到4-(4-甲基-2-氧代哌嗪-1-基)苯甲醛(1.8克，84.8％)，为白色固体。
MS(ESI)m/z:219[M+H+]。
1-(4-((4-氨基-2-丁氧基-5H-吡咯并[3,2-d]嘧啶-7-基)甲基)苯基)-4-甲基哌嗪-2-酮的制备：
步骤B：根据实施例22，用步骤E、F的方法制备1-(4-((4-氨基-2-丁氧基-5H-吡咯并[3,2-d]嘧啶-7-基)甲基)苯基)-4-甲基哌嗪-2-酮。
1HNMR(Methanol-d4,400MHz)δ7.36(s,1H),7.30(d,J＝8.4Hz,2H),7.22(d,J＝8.4Hz,2H),4.52(t,J＝6.4Hz,2H),4.02(s,2H),3.72-3.69(m,2H),3.27(s,2H),2.89-2.86(m,2H),2.44(s,3H),1.83-1.79(m,2H),1.54-1.48(m,2H),1.00(t,J＝7.4Hz,3H)。
MS(ESI)m/z:409[M+H+]。
实施例28
2-丁氧基-7-((1,2,3,4-四氢异喹啉-7-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000046
7-甲酰基-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯的制备路线：
Figure PCTCN2015086909-appb-000047
步骤A：在氮气气氛、0摄氏度下，向2-(4-溴苯基)乙胺(27克，0.13摩尔)和三乙胺(16.4克，0.16摩尔)的无水二氯甲烷(300毫升)溶液中滴加入三氟乙酸酐(34克，0.16摩尔)。将反应混合物在室温下搅拌1小时，然后用水稀释。将有机层分离并在真空下浓缩至干，得到N-(4-溴苯乙基)-三氟乙酰胺(37克，96.1％)，为白色固体。
MS(ESI)m/z:296,298[M+H+]。
步骤B：向N-(4-溴苯乙基)-三氟乙酰胺(37克，0.12毫摩尔)的浓硫酸(200毫升)/乙酸(300毫升)搅拌悬浮液溶液中分批加入多聚甲醛(10.2克，0.34摩尔)。加完后，该反应混合物在室温下搅拌12小时，然后倒入冰水(1升)中，用乙酸乙酯(400毫升×2)萃取。将合并的有机层依次用饱和碳酸氢钠水溶液和盐水洗涤，用无水硫酸镁干燥，并减压浓缩。将残余物用硅胶柱色谱法纯化(洗脱剂：5％乙酸乙酯的石油醚溶液)，得到1-(7-溴-3,4-二氢异喹啉-2(1H)-基)-三氟乙酮(33克，89.3％)。
MS(ESI)m/z:308,310[M+H+]。
步骤C：向1-(7-溴-3,4-二氢异喹啉-2(1H)-基)-三氟乙酮(30克，0.1摩尔)的无水甲基吡咯烷-2-酮(300毫升)溶液中加入氰化亚铜(18克，0.2摩尔)。将反应混合物在180摄氏度、氮气气氛下搅拌4小时。在冷却到室温后，将该混合物慢慢地倒入冰水(500毫升)中，并用乙酸乙酯(200毫升×2)萃取。将合并的有机层用水洗涤，经无水硫酸钠干燥并在真空下浓缩，得到25克粗品2-三氟乙酰基-四氢异喹啉-7-甲腈，其直接用于下一步骤。
MS(ESI)m/z:255[M+H+]。
步骤D：将2-三氟乙酰基-四氢异喹啉-7-甲腈(25克，0.1摩尔)和碳酸钾(25克，0.18摩尔)溶解在甲醇(300毫升)和水(60毫升)的混合溶剂中，在室温下搅拌2小时。然后在10分钟内将二叔丁基二碳酸酯(26克，0.12摩尔)分批加入。将反应混合物在室温下再搅拌4小时后，用水(200毫升)稀释，并用乙酸乙酯(200毫升×2)萃取。将合并的有机层用盐水洗涤，用无水硫酸钠干燥，并在真空下浓缩。将残余物用硅胶柱色谱法纯化(洗脱剂：5％乙酸乙酯的石油醚溶液)，得到7-氰基-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯(14克， 54％)，为白色固体。
MS(ESI)m/z:259[M+H+]。
步骤E：在-10摄氏度、氮气气氛下，向7-氰基-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯(1克，3.9毫摩尔)的无水四氢呋喃(20毫升)溶液中滴加二异丁基氢化铝(1M，6毫升，6.0毫摩尔)。加完后，将反应混合物在0摄氏度下搅拌5小时，并用水(0.24毫升)淬灭。然后，将15％的氢氧化钠水溶液(0.24毫升)加入，再加入0.6毫升水。将所得混合物在室温下进一步搅拌15分钟后，用无水硫酸镁干燥并过滤。将滤液在真空下浓缩，残余物用硅胶柱色谱法纯化(洗脱剂10％的乙酸乙酯石油醚溶液)，得到7-甲酰基-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯(700毫克，70％)，为黄色油状物。
MS(ESI)m/z:262[M+H+]。
2-丁氧基-7-((1,2,3,4-四氢异喹啉-7-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺的制备：
步骤F：根据实施例22，用步骤E、F的方法制得2-丁氧基-7-((1,2,3,4-四氢异喹啉-7-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸盐。
1HNMR(Methanol–d4,400MHz):δ8.49(s,2H),7.23-7.15(m,3H),7.10(s,1H),4.44(t,J＝6.5Hz,2H),4.30(s,2H),3.98(s,2H),3.47(t,J＝6.1Hz,2H),3.08(t,J＝6.1Hz,2H),1.83-1.76(m,2H),1.55-1.49(m,2H),1.01(t,J＝7.4Hz,3H)。
MS(ESI)m/z:352[M+H+]。
实施例29
2-丁氧基-7-((2-甲基-1,2,3,4-四氢异喹啉-7-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000048
以2-丁氧基-7-((1,2,3,4-四氢异喹啉-7-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺为原料，根据实施例25，用步骤G的方法制备2-丁氧基-7-((2-甲基-1,2,3,4-四氢异喹啉-7-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺。
1HNMR(Methanol–d4,400MHz):δ7.11-7.09(m,1H),7.03-7.00(m,3H),4.32(t,J＝6.4Hz,2H),3.92(s,2H),3.55(s,2H),2.91-2.88(m,2H),2.73-2.71(m,2H),2.43(s,3H),1.80-1.73(m,2H),1.56-1.52(m,2H),1.01(t,J＝7.6Hz,3H)。
MS(ESI)m/z:366[M+H+]。
实施例30
2-丁氧基-7-((2-乙基-1,2,3,4-四氢异喹啉-7-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000049
以2-丁氧基-7-((1,2,3,4-四氢异喹啉-7-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺为原料，根据实施例25，用步骤G的方法制得2-丁氧基-7-((2-乙基-1,2,3,4-四氢异喹啉-7-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸盐。
1HNMR(Methanol–d4,400MHz):δ8.43(s,2H),7.25-7.18(m,3H),7.10(s,1H),4.45(t,J＝6.4Hz,2H),4.34(s,2H),3.99(s,2H),3.51(t,J＝6.0Hz,2H),3.32-3.26(m,2H),3.15(t,J＝6.0Hz,2H),1.84-1.77(m,2H),1.58-1.48(m,2H),1.42(t,J＝8.0Hz,3H),1.01(t,J＝6.0Hz,3H)。
MS(ESI)m/z:380[M+H+]。
实施例31
2-丁氧基-7-((2-异丙基-1,2,3,4-四氢异喹啉-7-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000050
以2-丁氧基-7-((1,2,3,4-四氢异喹啉-7-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺为原料，根据实施例25，用步骤G的方法制备2-丁氧基-7-((2-异丙基-1,2,3,4-四氢异喹啉-7-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺。
1HNMR(Methanol–d4,400MHz):δ7.10-7.08(m,1H),7.03-7.00(m,3H),4.32(t,J＝6.4Hz,2H),3.93(s,2H),3.70(s,2H),2.90-2.86(m,3H),2.83-2.80(m,2H),1.80-1.73(m,2H),1.56-1.50(m,2H),1.17(d,J＝6.4Hz,6H),1.01(t,J＝7.6Hz,3H)。
MS(ESI)m/z:394[M+H+]。
实施例32
2-丁氧基-7-((1,2,3,4-四氢异喹啉-6-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000051
N-叔丁氧羰基1,2,3,4-四氢异喹啉-6-甲醛的制备路线：
Figure PCTCN2015086909-appb-000052
步骤A：向6-溴异喹啉(10克，48毫摩尔)的N,N-二甲基甲酰胺/甲醇(V/V＝1/1)(200毫升)混合溶液中加入乙酸钠(5.0克，61毫摩尔)、三苯基膦(3.0克，11.4毫摩尔)和醋酸钯(2.8克，12毫摩尔)。混合物处于通入有300千帕一氧化碳的高压釜中，并加热至100摄氏度。搅拌15小时后，通过LC-MS判定反应完成，其反应物通过硅藻土过滤(用乙酸乙酯洗脱)。将所得混合物浓缩，在减压下将残余物通过硅胶柱色谱纯化(洗脱剂：石油醚/乙酸乙酯＝5/1)。得到异喹啉-6-羧酸甲酯(8.9克，收率：98％)。
MS(ESI)m/z:188[M+H+]。
步骤B：在氮气保护下，向正在搅拌的异喹啉-6-羧酸甲酯(10克，53.5毫摩尔)的甲醇(100毫升)溶液中加乙酸(2毫升)和PtO2(200毫克)。在氢气气氛中，将该混合物在40摄氏度下搅拌反应3小时，然后将催化剂通过硅藻土过滤掉，并在真空下浓缩，得到1,2,3,4-四氢异喹啉-6-羧酸甲酯(9克，收率：88％)无需进一步纯化。
MS(ESI)m/z:192[M+H+]。
步骤C：根据实施例25，用步骤C的方法制备N-叔丁氧羰基1,2,3,4-四氢异喹啉-6-羧酸甲酯。
MS(ESI)m/z:292[M+H+]。
步骤D：根据实施例22，用步骤C、D的方法制备N-叔丁氧羰基1,2,3,4-四氢异喹啉-6-甲醛。
MS(ESI)m/z:262[M+H+]。
2-丁氧基-7-((1,2,3,4-四氢异喹啉-6-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺的制备：
步骤E：根据实施例22，用步骤E、F的方法制备2-丁氧基-7-((1,2,3,4-四氢异喹啉-6-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺。
1HNMR(Methanol–d4,400MHz):δ7.12-7.09(m,1H),7.08(s,1H),7.04(s,1H),6.96(d,J＝7.6Hz,1H),4.32(t,J＝7.4Hz,2H),3.98(s,2H),3.93(s,2H),3.13(t,J＝6.2Hz,2H),2.85-2.82(m,2H),1.79-1.73(m,2H),1.58-1.48(m,2H),1.01(s,3H)。
MS(ESI)m/z:352[M+H+]。
实施例33
2-丁氧基-7-((2-甲基-1,2,3,4-四氢异喹啉-6-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000053
以2-丁氧基-7-((1,2,3,4-四氢异喹啉-6-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺为原料，根据实施例25，用步骤G的方法制备2-丁氧基-7-((2-甲基-1,2,3,4-四氢异喹啉-6-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺。
1HNMR(Methanol–d4,400MHz):δ7.10-7.09(m,2H),7.03(s,1H),6.96(d,J＝8.4Hz,1H),4.32(t,J＝6.6Hz,2H),3.93(s,2H),3.60(s,2H),2.92-2.89(m,2H),2.77-2.74(m,2H),2.46(s,3H),1.81-1.73(m,2H),1.58-1.48(m,2H),1.01(t,J＝7.4Hz,3H)。
MS(ESI)m/z:366[M+H+]。
实施例34
2-丁氧基-7-((2-乙基-1,2,3,4-四氢异喹啉-6-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000054
以2-丁氧基-7-((1,2,3,4-四氢异喹啉-6-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺为原料，根据实施例25，用步骤G的方法制备2-丁氧基-7-((2-乙基-1,2,3,4-四氢异喹啉-6-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺。
1HNMR(Methanol–d4,400MHz):δ7.11-7.08(m,2H),7.03(s,1H),6.97(d,J＝8.0Hz,1H),4.32(t,J＝6.6Hz,2H),3.94(s,2H),3.63(s,2H),2.93-2.88(m,2H),2.79-2.76(m,2H),2.65-2.60(m,2H),1.79-1.75(m,2H),1.56-1.52(m,2H),1.21(t,J＝7.2Hz,3H),1.01(t,J＝7.2Hz,3H)。
MS(ESI)m/z:380[M+H+]。
实施例35
7-苄基-2-(2-甲氧基乙氧基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000055
步骤A：根据实施例1，用步骤C、D、E的方法制备(4-氨基-2-(2-甲氧基乙氧基)-5-((2-(三甲基硅基乙基)-5H-吡咯[3,2-d]嘧啶-7-基)(苯基)甲醇。
MS(ESI)m/z:445[M+H+]。
步骤B：根据实施例1，用步骤G的方法制得7-苄基-2-(2-甲氧基乙氧基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸盐。
1HNMR(Methanol–d4,400MHz):δ8.39(s,1H),7.29-7.19(m,6H),4.61-4.58(m,2H),4.00(s,1H),3.79-3.76(m,2H),3.42(s,3H)。
MS(ESI)m/z:299[M+H+]。
实施例36
2-(2-甲氧基乙氧基)-7-((6-甲基吡啶-3-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000056
根据实施例35，用步骤A、B的方法制得2-(2-甲氧基乙氧基)-7-((6-甲基吡啶-3-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸盐。
1HNMR(Methanol–d4,400MHz):δ8.34(s,3H),7.66(dd,J＝2.4Hz/J＝8.0Hz,1H),7.31(s,1H),7.24(d,J＝8.0Hz,1H),4.57-4.55(m,2H),4.01(s,2H),3.77-3.75(m,2H),3.41(s,3H),2.51(s,3H)。
MS(ESI)m/z:314[M+H+]。
实施例37
7-((5-氯吡啶-2-基)甲基)-2-(2-甲氧基乙氧基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000057
根据实施例35，用步骤A、B的方法制得7-((5-氯吡啶-2-基)甲基)-2-(2-甲氧基乙氧基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸盐。
1HNMR(Methanol–d4,400MHz):δ8.45(s,1H),8.40(s,1H),7.77(dd,J＝2.4Hz/J＝8.0Hz,1H),7.38(d,J＝8.0Hz,1H),7.32(s,1H),4.52(t,J＝4.0Hz,2H),4.17(s,2H),3.75(t,J＝4.0Hz,2H),3.42(s,3H)。
MS(ESI)m/z:334[M+H+]。
实施例38
2-(2-甲氧基乙氧基-)-7-((6-(吡咯烷-1-基甲基)吡啶-3-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000058
根据实施例35，用步骤A、B的方法制得2-(2-甲氧基乙氧基)-7-((6-(吡咯烷-1-基甲基)吡啶-3-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸盐。
1HNMR(Methanol–d4,400MHz):δ8.62(s,1H),8.41(s,2H),7.79-7.76(m,1H),7.36(d,J＝8.4Hz, 1H),7.28(s,1H),4.49-4.44(m,4H),4.05(s,2H),3.74-3.72(m,2H),3.39(s,3H),3.33-3.30(m,4H),2.10-2.07(m,4H)。
MS(ESI)m/z:383[M+H+]。
实施例39
1-(4-((4-氨基-2-(2-甲氧基乙氧基)-5H-吡咯并[3,2-d]嘧啶-7-基)甲基)苯基)-4-甲基哌嗪-2-酮
Figure PCTCN2015086909-appb-000059
根据实施例35，用步骤A、B的方法制备1-(4-((4-氨基-2-(2-甲氧基乙氧基)-5H-吡咯并[3,2-d]嘧啶-7-基)甲基)苯基)-4-甲基哌嗪-2-酮。
1HNMR(Methanol–d4,400MHz):δ7.35(s,1H),7.31(d,J＝8.4Hz,2H),7.22(d,J＝8.4Hz,2H),4.65-4.62(m,2H),4.01(s,2H),3.77-3.76(m,2H),3.70-3.67(m,2H),3.35(s,3H),3.32-3.28(m,2H),2.90-2.88(m,2H),2.45(s,3H)。
MS(ESI)m/z:411[M+H+]。
实施例40
2-丁氧基-7-((5-(吡咯烷-1-基甲基)吡啶-2-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2015086909-appb-000060
根据实施例22的流程，制得2-丁氧基-7-((5-(吡咯烷-1-基甲基)吡啶-2-基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺甲酸盐。
1HNMR(Methanol–d4,400MHz):δ8.61(s,1H),8.46(brs,2H),7.91(d,J＝8.0Hz,1H),7.47(d,J＝7.6Hz,1H),7.37(s,1H),4.44(t,J＝6.4Hz,2H),4.35(s,2H),4.22(s,2H),3.33-3.27(m,4H),2.09-2.06(m,4H),1.83-1.76(m,2H),1.57-1.50(m,2H),1.01(t,J＝7.6Hz,3H)。
MS(ESI)m/z:381[M+H+]。
实施例41
4-氨基-2-丁氧基-7-((6-(吡咯烷-1-基甲基)吡啶-3-基)甲基)-5H-吡咯并[3,2-d]嘧啶-6-甲腈
Figure PCTCN2015086909-appb-000061
实施例41流程：
Figure PCTCN2015086909-appb-000062
实施例41流程
步骤A：在氮气氛、-78℃下，向7-溴-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺(10.00克，24.07毫摩尔)的无水四氢呋喃(200毫升)溶液中加入n-BuLi(6.17克，96.28毫摩尔)。将混合物在-78℃下搅拌1小时。然后将6-氯烟醛(10.22克，72.21毫摩尔)的四氢呋喃(200毫升)溶液逐滴加入。将反应混合物在-78℃下再搅拌1小时，慢慢地倒入水(150毫升)中，在室温下搅拌20分钟，然后用乙酸乙酯(100毫升×3)萃取。将合并的有机相用饱和盐水(50毫升×2)洗涤，经无水硫酸钠干燥，过滤并真空浓缩。残余物通过硅胶色谱法纯化(洗脱机：石油醚/乙酸乙酯＝5/1到1/3)，得到(4-氨基-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(6-氯吡啶-3-基)甲醇(5.00克，43.45％)，为黄色固体。
1HNMR(400MHz,CHLOROFORM-d)δ8.52(d,J＝2.3Hz,1H),7.87(dd,J＝2.4,8.2Hz,1H),7.34(d,J＝8.0Hz,1H),6.65(s,1H),6.14(s,1H),5.97(br.s.,2H),5.39-5.26(m,2H),4.31(t,J＝6.7Hz,2H),3.62-3.49(m,2H),1.86-1.71(m,2H),1.51(qd,J＝7.5,14.9Hz,2H),1.28(t,J＝7.2Hz,1H),1.06-0.87(m,5H),0.00(s,9H)。
MS(ESI)m/z:478[M+H+]。
步骤B：在室温下，向(4-氨基-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)(6-氯吡啶吡啶-3-基)甲醇(5.00克，10.46毫摩尔)的三氟乙酸(50毫升)溶液中分批加入三乙基硅烷(6.08克，52.30毫摩尔)。将反应混合物在环境温度下搅拌24小时，倒入碳酸氢钠饱和水溶液(150毫升)，并进一步搅拌20分钟，然后用乙酸乙酯(100毫升×3)萃取。将合并的有机相用盐水(20毫升×2)洗涤，经无水硫酸钠干燥，过滤并真 空浓缩。残余物通过硅胶色谱法(洗脱剂：石油醚/乙酸乙酯＝3/1)纯化，得到2-丁氧基-7-((6-氯吡啶-3-基)甲基)-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺(2.30克，47.59％)，为黄色固体。
1HNMR(300MHz,CHLOROFORM-d)δ8.52(d,J＝2.3Hz,1H),7.88(dd,J＝2.4,8.1Hz,1H),7.35(d,J＝8.3Hz,1H),6.64(s,1H),6.14(s,1H),5.89(br.s.,2H),5.40-5.23(m,2H),4.31(t,J＝6.6Hz,2H),3.66-3.47(m,2H),1.88-1.70(m,2H),1.60-1.46(m,2H),1.07-0.82(m,5H),0.00(s,9H)。
MS(ESI)m/z:462[M+H+]。
步骤C：向2-丁氧基-7-((6-氯吡啶-3-基)甲基)-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-D]嘧啶-4-胺(2.30克，4.98毫摩尔)的N,N-二甲基甲酰胺(15毫升)溶液中加入醋酸钯(111.75毫克，0.5毫摩尔)、1,3-双二苯基膦丙烷(205.30毫克，0.5毫摩尔)、三乙胺(1.51克，14.93毫摩尔)和甲醇(797.43毫克，24.89毫摩尔)。将悬浮液抽真空，充一氧化碳数次。将混合物加热到100摄氏度，在一氧化碳气氛(3兆帕)下搅拌24小时。薄层色谱板(展开剂：石油醚/乙酸乙酯＝1/1)检测显示原料完全消耗。过滤掉不溶物，并浓缩。将粗产物经硅胶色谱法纯化(洗脱剂：用石油醚/乙酸乙酯＝1/1)，得到5-((4-氨基-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)甲基)吡啶甲酸甲酯(1.10克，45.48％)，为黄色固体。
1HNMR(400MHz,CHLOROFORM-d)δ8.76(d,J＝1.8Hz,1H),8.06(d,J＝8.0Hz,1H),7.85(dd,J＝2.0,8.0Hz,1H),6.82(s,1H),5.71(br.s.,2H),5.35(s,2H),4.33(t,J＝6.5Hz,2H),4.19-4.08(m,3H),4.00(s,3H),3.60-3.51(m,2H),1.85-1.74(m,2H),1.53(qd,J＝7.4,15.0Hz,2H),1.28(t,J＝7.2Hz,2H),1.02-0.90(m,5H),0.00(s,9H)。
MS(ESI)m/z:486[M+H+]。
步骤D：在低于0摄氏度下，向5-((4-氨基-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)甲基)吡啶甲酸甲酯(800.00毫克，1.65毫摩尔)的四氢呋喃(10毫升)溶液中分批加入溴代丁二酰胺(293.18毫克，1.65毫摩尔)。将反应混合物在0摄氏度下搅拌1小时，用水(30毫升)稀释并用二氯甲烷(20毫升×2)萃取。将合并的有机相用硫酸镁干燥并在真空下浓缩。残余物通过制备薄层色谱板纯化，得到5-((4-氨基-6-溴-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)甲基)吡啶甲酸甲酯(160.00毫克，17.18％)，为黄色固体。
1HNMR(400MHz,CHLOROFORM-d)δ8.83(s,1H),8.03(d,J＝8.0Hz,1H),7.86(d,J＝8.0Hz,1H),5.85(br.s.,2H),5.55(s,2H),4.34(t,J＝6.5Hz,2H),4.10(s,2H),4.00(s,3H),3.71-3.60(m,2H),1.84-1.72(m,4H),1.59-1.47(m,2H),0.98(q,J＝7.8Hz,5H),0.01(s,9H)。
MS(ESI)m/z:565,567[M+H+]。
步骤E：在氮气氛、-78摄氏度下，向正在搅拌的5-((4-氨基-6-溴-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)甲基)吡啶甲酸甲酯(150.00毫克，0.266毫摩尔)的无水四氢呋喃(8毫升)溶液中滴加入二异丁基氢化铝(56.28毫克，0.396毫摩尔)。加完后，将该反应混合物在-78摄氏度下搅拌1小时。随后将反应混合物用甲醇(5毫升)淬灭，用水稀释(20毫升)，并用乙酸乙酯(30毫升×2)萃取。合并的有机层在真空下浓缩至干，得到约150毫克粗品5-((4-氨基-6-溴-2-丁氧基-5-((2-(三甲基甲硅烷基)乙 氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7-基)甲基)吡啶醛，无需进一步纯化。
1HNMR(400MHz,CHLOROFORM-d)δ10.05(s,1H),8.87(s,1H),7.96-7.80(m,2H),5.72(br.s,2H),5.56(s,2H),4.34(t,J＝6.5Hz,2H),4.12(s,2H),3.71-3.62(m,2H),1.84-1.72(m,2H),1.56-1.48(m,2H),1.06-0.81(m,5H),0.01(s,9H)。
MS(ESI)m/z:535,537[M+H+]。
步骤F：向5-((4-氨基-6-溴-2-丁氧基-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-7基)甲基)吡啶醛(150.00毫克，0.281毫摩尔)、吡咯烷(29.94毫克，0.421毫摩尔)、乙酸(0.2毫升)的四氢呋喃(5毫升)溶液中加入氰基硼氢化钠(35.27毫克，0.561毫摩尔)，并在室温下搅拌12小时。然后倒入冰/水(体积比＝1/1，15毫升)混合物中搅拌20分钟，并用乙酸乙酯(40毫升×3)萃取。用盐水(20毫升×2)洗涤合并的有机相，用无水硫酸钠干燥，过滤并在减压浓缩。残余物通过制备型HPLC纯化，得到150毫克的6-溴-2-丁氧基-7-((6-(吡咯烷-1-基甲基)吡啶-3-基)甲基)-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺，为黄色固体。
MS(ESI)m/z:589,591[M+H+]。
步骤G：将6-溴-2-丁氧基-7-((6-(吡咯烷-1-基甲基)吡啶-3-基)甲基)-5-((2-(三甲基硅基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺(150.00毫克，254.39微摩尔)、Pd2(dba)3(23.30毫克，25.44微摩尔)、1,1’-双(二苯基膦)二茂铁(14.10毫克，25.44微摩尔)、二氰化锌(59.74毫克，508.78微摩尔)和锌(33.27毫克，508.78微摩尔)加到无水N,N-二甲基甲酰胺(2毫升)中，置换氮气，然后在氮气气氛下加热到110摄氏度并保持3小时。冷却后，该混合物用水稀释(30毫升)，并用乙酸乙酯(25毫升×3)萃取。将合并的有机相用盐水(30毫升)洗涤，经无水硫酸钠干燥并在真空下浓缩，残余物用制备TLC纯化，得到4-氨基-2-丁氧基-7-((6-(吡咯烷-1-基甲基)吡啶-3-基)甲基)-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-6-甲腈(120毫克，88.05％)
MS(ESI)m/z：536[M+H+]。
步骤H：将4-氨基-2-丁氧基-7-((6-(吡咯烷-1-基甲基)吡啶-3-基)甲基)-5-((2-(三甲基甲硅烷基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-6-甲腈(120毫克，0.224毫摩尔)的三氟乙酸(5毫升)溶液在20摄氏度下搅拌12小时，然后在真空下浓缩至干，残余物通过制备型HPLC纯化，得到8.7毫克的4-氨基-2-丁氧基-7-((6-(吡咯烷-1-基甲基)吡啶-3-基)甲基)-5H-吡咯并[3,2-d]嘧啶-6-甲腈。
1HNMR(Methanol–d4,400MHz):δ8.52(s,1H),7.79(d,J＝8.0Hz,1H),7.43(d,J＝8.0Hz,1H),4.33(t,J＝6.8Hz,2H),4.17(s,2H),3.76(s,2H),2.61(s,4H),1.82-1.72(m,6H),1.54-1.49(m,2H),1.02-0.99(t,J＝7.2Hz,3H)。
MS(ESI)m/z:406[M+H+]。
实施例42
4-氨基-2-丁氧基-7-(4-(吡咯烷-1-基甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-6-甲腈
Figure PCTCN2015086909-appb-000063
4-氨基-2-丁氧基-7-(4-(吡咯烷-1-基甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-6-甲腈按照实施例41的流程制备，具体步骤见实施例41的步骤A、B、C、D、E、F、G、H。
1HNMR(Methanol–d4,400MHz):δ7.34-7.32(d,J＝8.4Hz,2H),7.26-7.24(d,J＝8.4Hz,2H),4.36-4.33(t,J＝6.8Hz,2H),4.13(s,2H),3.62(s,2H),2.57(brs,4H),1.82-1.77(m,6H),1.52-1.49(m,2H),1.00(t,J＝7.2Hz,3H)。
MS(ESI)m/z:405[M+H+]。
实施例43
4-氨基-2-丁氧基-7-(4-(吗啉代甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-6-甲腈
Figure PCTCN2015086909-appb-000064
4-氨基-2-丁氧基-7-(4-(吗啉代甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-6-甲腈盐酸盐按照实施例41的流程制备，具体步骤见实施例41的步骤A、B、C、D、E、F、G、H。
1HNMR(Methanol–d4,400MHz):δ:7.55(d,J＝7.8Hz,2H),7.43(d,J＝7.8Hz,2H),4.60(t,J＝6.5Hz,2H),4.38(s,2H),4.23(s,2H),4.06-4.02(m,2H),3.80-3.73(m,2H),3.47-3.35(m,2H),3.28-3.14(m,2H),1.89-1.82(m,2H),1.59-1.51(m,2H),1.03(t,J＝7.4Hz,3H)。
LCMS(ESI)m/z:421[M+H+]。
实施例44
4-氨基-2-丁氧基-7-(4-((4-甲基哌嗪-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-6-甲腈
Figure PCTCN2015086909-appb-000065
4-氨基-2-丁氧基-7-(4-((4-甲基哌嗪-1-基)甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-6-甲腈盐酸盐按照实施例41的流程制备，具体步骤见实施例41的步骤A、B、C、D、E、F、G、H。
1HNMR(Methanol–d4,400MHz):δ:7.61(d,J＝7.8Hz,2H),7.42(d,J＝7.8Hz,2H),4.60(t,J＝6.5Hz,2H),4.47(s,2H),4.23(s,2H),3.89-3.45(m,8H),3.02(s,3H),1.92-1.80(m,2H),1.61-1.44(m,2H),1.03(t,J＝7.3Hz,3H)。
LCMS(ESI)m/z:434[M+H+]。
实施例45
4-氨基-2-丁氧基-7-(4-(吡咯烷-1-基甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-6-甲酰胺
Figure PCTCN2015086909-appb-000066
实施例45制备流程：
Figure PCTCN2015086909-appb-000067
步骤A：将4-氨基-2-丁氧基-7-(4-(吡咯烷-1-基甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-6-甲腈(90毫克，0.22毫摩尔)和氢氧化钠(34毫克，0.85毫摩尔)溶于甲醇(10毫升)和水(10毫升)的混合溶剂，在80摄氏度下搅拌12小时。冷却后，用水(10毫升)稀释，并用乙酸乙酯(15毫升×2)萃取。将合并的有机层在真空下浓缩至干，然后通过制备型HPLC纯化，得到10毫克的4-氨基-2-丁氧基-7-(4-(吡咯烷-1-基甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-6-甲酰胺。
1HNMR(Methanol–d4,400MHz):δ7.46(d,J＝8.0Hz,2H),7.32(d,J＝8.0Hz,2H),4.58(t,J＝6.4Hz,2H),4.39(s,2H),4.34(s,2H),3.34-3.32(m,2H),3.18-3.16(m,2H)2.17-2.16(m,2H),2.03-2.00(m,2H),1.86-1.82(m,2H),1.56-1.50(m,2H),1.02(t,J＝7.2Hz,3H)。
MS(ESI)m/z:423[M+H+]。
实验例1：Toll样受体7和Toll样受体8体外受体结合活性筛选方案
试剂：
HEK-blue hTLR7细胞和HEK-blue hTLR8细胞(来源于InvivoGen公司)
DMEM培养基
热灭活胎牛血清
抗支原体试剂NormocinTM
博来霉素
杀稻瘟菌素
方案：
1.96孔化合物板的准备：利用液体工作站POD将化合物从10毫摩尔/升浓度起始，用DMSO做3倍梯度稀释，共稀释10个点(从第2列到第11列，每个点2个重复)。在第12列加入1微升5毫克/毫升的阳性化合物R848作为阳性对照，在第1列加入1微升DMSO作为阴性对照。每孔中含有的DMSO体积都是1微升。
2.收取细胞培养瓶中的细胞，将细胞密度稀释成250,000个细胞/毫升。
3.加入200微升(50,000个细胞/孔)细胞悬液至准备好的化合物板中。每孔中 DMSO终浓度为0.5％。
4.将含有细胞和化合物的培养板放入CO2培养箱中培养24小时，培养条件为37摄氏度，5％CO2浓度。
5.培养24小时后，从细胞培养板中每孔取出20微升上清液转移到一块96孔透明检测板中。然后向检测板中每孔加入180微升Quanti-Blue试剂，并置于37摄氏度，5％CO2培养箱孵育1小时。
6.1小时后，用酶标仪OD650读板检测20微升上清液中碱性磷酸酶的含量。
7.利用Prism软件分析数据，得出各化合物的EC50。
实验结果如表1所示：
表1
Figure PCTCN2015086909-appb-000068
注：1nM≤A≤100nM；100nM＜B≤1000nM；1000nM＜C≤50μM。
实施例21化合物与对照品Toll样受体7激动剂GS-9620头对头测试实验结果如表2所示：
表2
Figure PCTCN2015086909-appb-000069
结论：本发明的实施例21化合物，展现出比对照品Toll样受体7激动剂GS-9620更高的与Toll样受体7体外受体结合活性，和比对照品Toll样受体7激动剂GS-9620更低的与Toll样受体8体外受体结合活性。
实验例2：外周血单个核细胞试验方案
本方案的目的在于检测利用现有化合物物刺激人外周血单核细胞(PBMC)24h后细胞因子的表达水平。检测时细胞上清液不稀释，直接检测IFN-α和TNF-α的水平。实验过程中首先将化合物配制成20mM的DMSO储存液，用细胞培养基做10倍梯度稀释，总共稀释11个点。取其中9个稀释点的化合物(化合物的最高浓度为200微摩/升)加入96孔板中，每孔50微升，然后接种新鲜的人外周血单核细胞，每孔接种150微升体系，其中含有450,000个细胞。将细胞培养板置于37℃和5％CO2培养箱中培养24小时，培养结束后将培养板以1200rpm的速度离心5分钟，随后收集上清并将其储存于-20℃以待检测。细胞因子的检测利用BD公司的流式液相多重蛋白定量技术(CBA)，在流式细胞仪上完成检测。利用上述检测方法，我们将刺激产生最低检测限至少3倍以上细胞因子水平的最低药物浓度，定义为该化合物在该细胞因子刺激实验上的MEC(Minimal Effective Concentration)值。
实验结果如表3所示：
表3
实施例 INF-αMEC 实施例 INF-αMEC 实施例 INF-αMEC
4 C 28 B 31 B
21 A 29 A 42 A
22 B 30 B    
注：0.01nM≤A≤1nM；1nM＜B≤10nM；10nM＜C≤100μM。
实施例21化合物与对照品Toll样受体7激动剂GS-9620头对头测试实验结果如表4所示：
表4
Figure PCTCN2015086909-appb-000070
结论：本发明的实施例21化合物展示出相对于对照品Toll样受体7激动剂GS-9620更好的体外PBMC的IFN-α诱导活性以及相当的TNF-α的诱导活性。
实验例3：大鼠药代动力学实验
试验用雄性SD大鼠共12只，分成四组，每组3只SD大鼠。2组动物静脉注射给药，分别注射对照品Toll样受体7激动剂GS-9620和实施例21化合物的10％羟丙基-β-环糊精水溶液(浓度0.5mg/mL)1mg/kg。另外2组口服给药，分别口服GS-9620和实施例21化合物的0.5％甲基纤维素/0.2％吐温80纯水混悬液(浓度1mg/mL)5mg/kg。静脉注射后的每只大鼠于给药后2、15、30分钟和1、2、4、8、24小时连续采集全血样本并制备血浆；口服给药后的每只大鼠于给药后15、30分钟和1、2、4、8、24小时连续采集全血样本并制备血 浆。应用LC-MS/MS方法，分别测定GS-9620和实施例21化合物血浆浓度。结果如表5所示。
表5
Figure PCTCN2015086909-appb-000071
结论：本发明的实施例21化合物展示出在同等条件下，相对于对照品Toll样受体7激动剂GS-9620在大鼠中有更长的半衰期和更高的曝露量。
实验例4：乙型肝炎感染雏鸭模型体内药效学试验
实验设计和方法：实验采用一日龄北京鸭静脉注射鸭乙型肝炎病毒阳性鸭血清，7天后开始分组给药，每组6只鸭。对照组：生理盐水。供试样品为GS-9620、实施例21化合物，每个样品2个剂量组：20mg/kg和5mg/kg。供试样品均为灌胃给药，20mg/kg组为隔2天给1次药(每3天给1次药)，5mg/kg组为连续每天给药，每天给药1次。共给16天。阳性对照药物拉米夫定由葛兰素史克药业公司生产，50mg/kg，为灌胃给药，每天给药2次，连续给药16天。对于鸭乙型肝炎病毒感染对照组，以溶剂代替药物。于感染后7天给药前(T0)、给药后8天(T8)、给药后16天(T16)和停药后3天(P3)取血，分离鸭血清， 冷冻保存。鸭血清用于鸭乙型感染病毒DNA(DHBV-DNA)的检测，比较GS-9620、实施例21化合物和阳性对照拉米夫定对鸭乙型肝炎病毒的疗效。鸭血清DNA(DHBV-DNA)的检测方法：同批不同鸭血清用实时荧光定量PCR法测定鸭血DHBV-DNA的水平。统计学处理：采用配对和成组分析统计法，计算药物对鸭血清DHBV-DNA抑制作用的显著性，判断效果。药效结果见表6。
表6
Figure PCTCN2015086909-appb-000072
成组t检验，同一时间点同病毒对照组相比。*p<0.05，**p<0.01。
结论：相对于对照品Toll样受体7激动剂GS-9620，本发明的实施例21化合物在同等条件下在乙肝感染雏鸭模型上展示出更优的药效：20mg/kg隔2天给药一次，抑制率大致相当；5mg/kg每天给药一次连续给药，实施例21化合物抑制率优势十分明显；停药3天后，GS-9620的20mg/kg隔2天给药一次组出现HBV-DNA复制反弹，而对应实施例21化合物组没有。
实验例5：HDI(hydrodynamic injection)乙型肝炎感染小鼠模型体内药效学试验
实验设计和方法：
给药途径：灌胃
给药时间：第1天到第7天，实验周期共7天
给药组：第一组：Vehicle，10％HP-β-CD；第二组：GS-9620，20mg/kg；第三组：实施例21，20mg/kg。
实验第1、3、5、7天给药4小时后收集血浆样本，第7天给药4小时后收集肝样本。详情见表7。
表7
Figure PCTCN2015086909-appb-000073
HDI(hydrodynamic injection)乙型肝炎感染小鼠模型体内药效学试验药效结果详情见图1和图2。结论：血浆中的HBV拷贝数和肝脏中的HBV拷贝数检测数据显示，实施例21化合物在同等条件下药效优于对照品Toll样受体7激动剂GS-9620。

Claims (16)

  1. 式(I)所示化合物或其药学上可接受的盐，
    Figure PCTCN2015086909-appb-100001
    其中，
    L1、L2分别独立地选自-O-、-CH2-、-S-、-NH-、-NHC(＝O)-、-C(＝O)-、-C(＝O)NH-、-S(＝O)-、-S(＝O)2-、-NHS(＝O)2-或-S(＝O)2NH-，其中所述基团任选被一种或多种R4取代；
    R1选自氢、C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烃基、3-10元杂环烃基、芳基、杂芳基，其中上述C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烃基、3-10元杂环烃基、芳基、杂芳基任选被一种或多种R4取代；
    R2选自氢、卤素、氰基、羟基、巯基、氨基、COOH、-CONH2、C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烃基、3-10元杂环烃基、芳基、杂芳基，其中上述羟基、巯基、氨基、COOH、-CONH2、C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烃基、3-10元杂环烃基、芳基、杂芳基任选被一种或多种R4取代；
    B选自C3-10环烃基、3-10元杂环烃基、芳基、杂芳基；
    L3选自C0-6亚烷基、亚氨基、-O-、-S-、-S(＝O)-或-S(＝O)2-，其中上述C0-6亚烷基、亚氨基任选被一种或多种R4取代；
    R3选自氢、氨基、C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烃基、3-10元杂环烃基、芳基、杂芳基，其中上述氨基、C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烃基、3-10元杂环烃基、芳基、杂芳基任选被一种或多种R4取代，
    或R3、L3与B环上邻位原子一起形成饱和或不饱和的5-8元环，所述5-8元环任选被一种或多种R4取代；
    n为0、1、2、3、4或5；
    R4选自卤素、氰基、-R、-OR、＝O、-SR、-NR2、＝NR、-C(卤素)3、-CR(卤素)2、-CR2(卤素)、-OCN、-SCN、-N＝C＝O、-NCS、-NO、-NO2、-NRC(＝O)R、-NRC(＝O)OR、-NRC(＝O)NRR、-C(＝O)NRR、-C(＝O)OR、-OC(＝O)NRR、-OC(＝O)OR、-C(＝O)R、-S(＝O)2OR、-S(＝O)2R、-OS(＝O)2OR、-S(＝O)2NRR、-S(＝O)R、-NRS(＝O)2R、-NRS(＝O)2NRR、-NRS(＝O)2OR、-OP(＝O)(OR)2、-P(＝O)(OR)2、-C(＝O)R、-C(＝S)R、-C(＝O)OR、-C(＝S)OR、-C(＝O)SR、-C(＝S)SR、-C(＝O)NRR、-C(＝S)NRR、-C(＝NR)NRR或-NRC(＝NR)NRR；R独立地选自H、C1-8烷基、C3-8环烃基、3-8元杂环烃基、芳基、杂芳基、芳基烷基、杂芳基烷基；
    并且，当L1为-CH2-或-NH-时，R3不为H。
  2. 如权利要求1所述的化合物，其特征是，L1、L2分别独立地选自-O-、-CH2-、-S-、-NH-、-C(＝O)-、-S(＝O)-或-S(＝O)2-，其中上述-CH2-、-NH-任选被一种或多种R4取代。
  3. 如权利要求2所述的化合物，其特征是，L1、L2分别独立地选自-O-、-CH2-，其中上述-CH2-任选被一种或多种R4取代。
  4. 如权利要求1所述的化合物，其特征是，R1选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烃基、3-6元杂环烃基、芳基、杂芳基，其中上述C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烃基、3-6元杂环烃基、芳基、杂芳基任选被一种或多种R4取代。
  5. 如权利要求4所述的化合物，其特征是，R1选自C1-6烷基，其中上述C1-6烷基任选被一种或多种R4取代。
  6. 如权利要求1所述的化合物，其特征是，R2选自氢、卤素、氰基、羟基、氨基、-CONH2、C1-6烷基，其中上述羟基、氨基、-CONH2、C1-6烷基任选被一种或多种R4取代。
  7. 如权利要求6所述的化合物，其特征是，R2选自氢、氰基、-CONH2，其中上述-CONH2任选被一种或多种R4取代。
  8. 如权利要求1所述的化合物，其特征是，B选自芳基、杂芳基。
  9. 如权利要求8所述的化合物，其特征是，B选自苯基、吡啶基。
  10. 如权利要求1所述的化合物，其特征是，L3选自C0-6亚烷基，其中上述C0-6亚烷基任选被一种或多种R4取代。
  11. 如权利要求1所述的化合物，其特征是，R3选自氢、氨基、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烃基、3-8元杂环烃基、芳基、杂芳基，其中上述氨基、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烃基、3-8元杂环烃基、芳基、杂芳基任选被一种或多种R4取代；或R3、L3与B环上邻位原子一起形成饱和或不饱和的5-8元环，所述5-8元环任选被一种或多种R4取代。
  12. 如权利要求1所述的化合物，其特征是，R4选自卤素、氰基、-R、-OR、＝O、-SR、-NR2、＝NR、-C(卤素)3、-CR(卤素)2、-CR2(卤素)、-OCN、-SCN、-N＝C＝O、-NCS、-NO、-NO2、-NRC(＝O)R、-C(＝O)NRR、-C(＝O)OR、-OC(＝O)NRR、-C(＝O)R、-S(＝O)2OR、-S(＝O)2R、-OS(＝O)2OR、-S(＝O)2NRR、-S(＝O)R、-NRS(＝O)2R、-C(＝O)R、-C(＝O)OR或-C(＝O)NRR。
  13. 如权利要求12所述的化合物，其特征是，R4选自卤素、氰基、-R、-OR、＝O、-NR2、＝NR、-C(卤素)3、-CR(卤素)2、-CR2(卤素)。
  14. 下式表示的化合物：
    Figure PCTCN2015086909-appb-100002
    Figure PCTCN2015086909-appb-100003
    Figure PCTCN2015086909-appb-100004
    Figure PCTCN2015086909-appb-100005
    Figure PCTCN2015086909-appb-100006
    或其药学上可接受的盐。
  15. 权利要求1-14任一项所述的化合物或其药学上可接受的盐在制备治疗病毒感染的药物中的用途。
  16. 药物组合物，其包含治疗有效量的权利要求1-14任一项所述的化合物或其药学上可接受的盐和一种或多种药学上可接受的载体或赋形剂。
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