WO2017097217A1 - 呔嗪类衍生物、其制备方法、药物组合物和用途 - Google Patents

呔嗪类衍生物、其制备方法、药物组合物和用途 Download PDF

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WO2017097217A1
WO2017097217A1 PCT/CN2016/108975 CN2016108975W WO2017097217A1 WO 2017097217 A1 WO2017097217 A1 WO 2017097217A1 CN 2016108975 W CN2016108975 W CN 2016108975W WO 2017097217 A1 WO2017097217 A1 WO 2017097217A1
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alkyl
group
substituted
substituents
alkoxy
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PCT/CN2016/108975
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French (fr)
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李帅
孙勇
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上海赛默罗生物科技有限公司
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Priority to JP2018530763A priority Critical patent/JP6669868B2/ja
Priority to EP16872406.0A priority patent/EP3388433B1/en
Priority to US16/060,256 priority patent/US11220503B2/en
Publication of WO2017097217A1 publication Critical patent/WO2017097217A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol

Definitions

  • the present invention relates to oxazine derivatives having a regulatory function to ⁇ 5-GABA A receptors, their preparation, pharmaceutical compositions containing them and their use as medicaments.
  • GABA ⁇ -aminobutyric acid
  • GABA A receptor which is a ligand gate.
  • GABA B receptor which is a member of the G-protein coupled receptor superfamily.
  • the GABA A receptor subunits in mammals are found to have subunits such as ⁇ 1 ⁇ 6, ⁇ 1 ⁇ 4, ⁇ 1 ⁇ 3, ⁇ , ⁇ , ⁇ , and ⁇ 1 ⁇ 2, among which ⁇ subunit, ⁇ subunit, and ⁇ subunit.
  • the base pair is essential for the formation of a complete functional GABA A receptor, and the alpha subunit is critical for the binding of benzodiazepine to the GABA A receptor.
  • the ⁇ 5-containing GABA A receptor accounts for less than 5% of the GABA A receptor in the mammalian brain, and has a very low expression level in the cerebral cortex, but GABA in the hippocampus of the brain.
  • the proportion of A receptors is greater than 20%, and other brain regions are hardly expressed.
  • ⁇ 5-GABA a receptor inverse agonists by selective binding to a receptor ⁇ 5-GABA a peripheral nervous system, the effect of suppressing action of various types of pain, animal model data, inverse agonist
  • Another object of the present invention is to provide a process for the preparation of a compound of the formula (I), (II), (III) or (IV).
  • Another object of the present invention is to provide a use of a compound of the formula (I), (II), (III) or (IV) as a modulator of ⁇ 5-GABA A receptor, thereby preparing for prevention, treatment or improvement Use in drugs for diseases associated with the ⁇ 5-GABA A receptor, such as cognitive diseases, Alzheimer's disease, memory disorders, Down's syndrome, amyotrophic lateral sclerosis (ALS), drugs Addiction, restless legs syndrome, cognitive deficits, multi-infarct dementia, pain, stroke and attention deficits, or use in the preparation of pain-relieving drugs.
  • diseases associated with the ⁇ 5-GABA A receptor such as cognitive diseases, Alzheimer's disease, memory disorders, Down's syndrome, amyotrophic lateral sclerosis (ALS), drugs Addiction, restless legs syndrome, cognitive deficits, multi-infarct dementia, pain, stroke and attention deficits, or use in the preparation of pain-relieving drugs.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising one or more effective therapeutic doses of a compound of the formula (I), (II), (III) or (IV) or a pharmaceutically acceptable compound thereof Accepted salts, as well as pharmaceutically acceptable carriers and/or adjuvants.
  • Another object of the present invention is to provide a method for preventing, treating or ameliorating a disease associated with the ⁇ 5-GABA A receptor, comprising administering the general formula (I), (II), (III) or (present) according to the present invention.
  • a compound of formula I a cis-trans isomer, an enantiomer, a diastereomer, a racemate, a solvate, a hydrate, or Pharmaceutically acceptable salts and esters,
  • T represents C3-7 cycloalkyl, C4-7 cycloalkenyl, C6-8 bicycloalkyl, C6-10 aryl, C3-7 heterocycloalkyl; preferably T represents phenyl;
  • Z represents a 5-membered heteroaryl ring containing 1, 2 or 3 hetero atoms independently selected from the group consisting of oxygen, nitrogen and sulfur; the 5-membered heteroaryl ring is optionally substituted by one or more substituents selected from the group consisting of: , halogen, -R1, -OR1, -OC(O)R1, -NR2R3, CN, cyano(C1-6)alkyl- or R2; preferably, Z represents 1, 2 or 3 independently selected from oxygen a 5-membered heteroaryl ring of a hetero atom of nitrogen and sulfur, wherein at most one hetero atom is oxygen or sulfur, and when one hetero atom is a nitrogen atom, at least one oxygen or sulfur atom is also present.
  • the heteroaromatic ring is optionally substituted by one or more substituents selected from C1 to C4 alkyl, hydroxy, halogen, hydroxy or amino substituted C1 - C4 alkyl, C2 - C4 alkenyl, C2 - C4 Alkynyl, C1-C4 alkoxy; more preferably Z represents a 5-membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, and at most one heteroatom is oxygen or sulfur, Further, when one hetero atom is a nitrogen atom, one oxygen atom or one sulfur atom is also present; preferably Z represents a 5-membered heteroaryl ring containing two hetero atoms independently selected from oxygen, nitrogen and sulfur, and one Hetero atom is oxygen Sulfur, the other is a nitrogen atom; a 5-membered heteroaryl ring is a Or a plurality of substituents selected from the group consisting of C1-6 alkyl or hydroxy C1-6
  • R1 represents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkyl (C1-6) alkyl, cyano (C1-6) alkane a C1-6 alkyl group substituted with a hydroxy group or an amino group, and R1 is optionally mono-, di- or trifluoro;
  • R2 or R3 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl or CF3, or R2 and R3 together with the nitrogen atom to which they are attached 4 a 7-membered heteroalicyclic ring containing the nitrogen atom and one additional heteroatom optionally selected from O, N and S, optionally substituted by one or more R1 groups;
  • A is -NR2 -; or A is a 5-membered heteroarylene containing 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur and at most one of the heteroatoms is oxygen or sulfur; Is a 6-membered heteroarylene containing 1, 2 or 3 nitrogen atoms, or the 5 or 6-membered heteroarylene is optionally fused to a benzene or pyridine ring, said 5 or 6-membered
  • the arylene group is optionally substituted by Rx and/or Ry and/or Rz, wherein Rx is halogen, -R1, -OR1, -OC(O)R1, -C(O)OR1, -NR2R3, -NR2C(O) R3, ⁇ OH, ⁇ CN, Ry is halogen, —R1, —OR1, —OC(O)R1, —NR2R3, —NR2C(O)R3, or CN, and Rz is —R1, —OR1, or
  • Y is ⁇ NY1Y2 or ⁇ NH ⁇ NY3Y4;
  • Y1 is selected from the group consisting of: H; C1-6 alkyl; C1-6 alkyl substituted with 1 to 5 substituents independently selected from the group consisting of amino, halogen, halo-C1-6 alkoxy, Hydroxy, C1-6 alkoxy, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N-, nitro and C1-6 alkyl-S(O) 2-;
  • Y2 is selected from the group consisting of: H; C1-6-6 alkyl; C1-6 alkyl substituted by 1 to 5 substituents, said substituent alone Site selected from: amino, halogen, halo-C1-6 alkoxy, hydroxy, C1-6 alkoxy, cycloalkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1 ⁇ 6 alkyl, H) N-, nitro and C1-6 alkyl-S(O)2-; heteroaryl, or heteroaryl substituted by 1 to 4 substituents, substituted by said heteroaryl
  • the group is independently selected from the group consisting of: acetamido, acetyl, acetylamino, amido, amino, carboxyl, cyano, halogen, halo-C1-6 alkoxy, halo-C1-6 alkyl, hydroxy, Hydroxy-C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, C1-6 alkyl,
  • Y2 is preferably a C1-6 alkyl group; a C1-6 alkyl group substituted by 1 to 5 substituents, which are individually selected from the group consisting of amino, halogen, halo-C1-6 alkoxy, hydroxy, C1-6 alkoxy, C3 ⁇ C6 cycloalkyl, (C1 ⁇ 6 alkyl, C1-6-6 alkyl) N ⁇ , (C1 ⁇ 6 alkyl, H) N ⁇ , nitro and C1-6 alkyl ⁇ S(O)2 ⁇ ;
  • a C3 ⁇ 67 cycloalkyl group a C3-7 cycloalkyl group substituted by 1 to 4 substituents, which are individually selected from the group consisting of acetamido, acetyl, acetylamino, amido, amino, carboxy, Cyano, halogen, halo-C1-6 alkoxy, halo-C1-6 alkyl, hydroxy, hydroxy-C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1- 6 alkyl, C1-6 alkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N-, nitro and C1-6 alkyl-S (O )2-;
  • Y2 is C1-6 alkyl; C1-6 alkyl substituted by hydroxy or halo or C1-6 alkoxy; morpholinyl; C3-6 cycloalkyl; hydroxy substituted C3-6 cycloalkyl; Pyrazolyl optionally substituted by C1-6 alkyl; tetrahydrofuranyl, tetrahydropyranyl;
  • Y1, Y2 together with the N atom to which they are attached form a 4-6-membered heterocycloalkyl group which, in addition to the nitrogen atom, contains zero, one or more impurities selected from O and S An atom, and the S atom may be in the form of its oxide;
  • Y1, Y2 together with the N atom to which they are attached form azetidinyl, morpholinyl, piperidinyl, pyrrolidinyl, dioxythiomorpholinyl, monooxythiomorpholinyl;
  • Y1; Y2 together with the N atom to which they are attached form a group selected from azetidine-1-yl, morpholine-4-yl, piperidinyl-1, pyrrolidine-1-yl, 1-oxo-thio Porphyrin-4-yl and 1,1-dioxo-thiomorpholine-4-yl;
  • Y3, Y4 are independently selected from the group consisting of: hydrogen, C1-C6 alkyl, SO2-C1-C6 alkyl, cycloalkyl and heterocyclic, optionally substituted by 1 to 4 substituents independently selected from the group consisting of: Halogen, cyano, hydroxy, C1-C6 alkyl and C1-C6 alkoxy, or wherein Y3, Y4 together with the nitrogen atom to which they are attached form a heterocyclic group which is optionally 1-4 independent Substituted with a substituent selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C6 alkyl and C1-C6 alkoxy;
  • Y3, Y4 are independently selected from the group consisting of: hydrogen, C1-C6 alkyl, SO2-C1-C6 alkyl, C3-7 cycloalkyl and C3-7 heterocyclic, optionally selected from 1 to 4 independently selected Substituted by a substituent of the following groups: halogen, cyano, hydroxy, C1-C6 alkyl and C1-C6 alkoxy, or wherein Y3, Y4 together with the nitrogen atom to which they are attached form a C3-C7 heterocyclic group,
  • the C3 to C7 heterocyclic group is piperidinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, monooxathiomorpholinyl and pyrrolidinyl, the piperidine
  • the base morpholinyl, thiomorpholinyl, dioxythiomorpholinylmonooxathiomorpholinyl and pyrrolidiny
  • the invention also provides a compound having the following general formula II:
  • Z represents a 5-membered heteroaryl ring containing 1, 2 or 3 hetero atoms independently selected from the group consisting of oxygen, nitrogen and sulfur, wherein at most one hetero atom is oxygen or sulfur, and when one hetero atom is a nitrogen atom, At least one oxygen or sulfur atom is also present, and the 5-membered heteroaryl ring is optionally substituted with one or more substituents selected from C1 to C4 alkyl, hydroxy, halogen, hydroxy or amino substituted C1-C4 Alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy;
  • A is a 5-membered heteroarylene containing 1, 2 or 3 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur and at most one of the heteroatoms is oxygen or sulfur, or contains 1, 2 or 3 nitrogen atoms a 6-membered heteroarylene or phenylene group; the 5-membered heteroarylene, 6-membered heteroarylene, and phenylene are optionally substituted with a substituent selected from the group consisting of halogen, cyano, C1 ⁇ 6 alkyl;
  • Y is ⁇ NY1Y2 or ⁇ NH ⁇ NY3Y4;
  • Y1 is H, C1-6 alkyl or C1-6 alkyl substituted with 1 to 5 substituents; the substituents are individually selected from the group consisting of: amino, hydroxy, C1-6 alkoxy, (C1-6 alkane) Base, C1-6 alkyl) N ⁇ , (C1 ⁇ 6 alkyl, H)N ⁇ and C1 ⁇ 6 alkyl-S(O)2 ⁇ ;
  • Y2 is selected from C1-6-6 alkyl; C1-6-6 alkyl substituted by 1 to 5 substituents, which are independently selected from the group consisting of: amino, hydroxy, C1-6 alkoxy, cycloalkyl, (C1) -6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N- and C1-6 alkyl-S(O)2 ⁇ ;
  • C5-C6 heteroaryl group containing 1 - 3 hetero atoms selected from N, O or S C5-C6 substituted by C1-6 alkyl group containing 1 - 3 hetero atoms selected from N, O or S Heteroaryl,
  • a C3-6 cycloalkyl group a C3-6 cycloalkyl group substituted by 1 to 4 substituents, which are individually selected from the group consisting of: an amino group, a hydroxyl group, a hydroxy-C1-6 alkyl group, and a C1-6 alkoxy group. , C1-6 alkoxy-C1-6 alkyl, C1-6 alkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N- and C1- 6 alkyl-S(O)2 ⁇ ;
  • Y1, Y2 together with the N atom to which they are attached form a 4-6-membered heterocycloalkyl group which, in addition to the nitrogen atom, contains zero, one or more impurities selected from O and S An atom, and the S atom may be in the form of its oxide;
  • Y3, Y4 are independently selected from each other: hydrogen, C1-C6 alkyl, SO2-C1-C6 alkyl, or Y3 and Y4 together with the nitrogen atom to which they are attached form a heterocyclic group selected from piperidine Base, morpholinyl, dioxythiomorpholinyl and monooxathiomorpholinyl.
  • Z in the formula I or II represents a 5-membered heteroaryl ring containing 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, and one hetero atom is oxygen or sulfur, and the other atom Is a nitrogen; the 5-membered heteroaryl ring is optionally substituted with one or more substituents selected from C1-6 alkyl or hydroxy C1-6 alkyl.
  • Z in the formula I or II represents oxadiazolyl, furyl, thienyl or isoxazolyl, which is substituted by one or more selected from the group consisting of The base is optionally substituted: H, C1-6 alkyl or hydroxy C1-6 alkyl.
  • a in formula I or II represents a phenylene, pyridylene, or isoxazolyl group; optionally substituted by 1, 2 or 3 substituents independently selected from: Halogen, cyano, C1-6 alkyl.
  • Z in the formula I or II represents oxadiazolyl, furyl, thienyl or isoxazolyl, which is substituted by one or more selected from the group consisting of Optionally substituted: H, C1-6 alkyl or hydroxy C1-6 alkyl; A represents phenylene, pyridylene, isoxazolyl; optionally 1, 2 or 3 independently selected from Substituent substitution: halogen, cyano, C1-6 alkyl.
  • Z in the formula I or II represents oxadiazole, furyl, thiophene Or an isoxazolyl group optionally substituted by one or more substituents selected from the group consisting of H, C1-6 alkyl or hydroxy C1-6 alkyl;
  • A represents phenylene, arylene Pyridyl, isoxazolyl; optionally substituted by 1, 2 or 3 substituents independently selected from halogen, cyano, C1-6 alkyl;
  • Y is ⁇ NY1Y2 or ⁇ NH ⁇ NY3Y4; Y1 Is H or C1-6 alkyl;
  • Y2 is selected from C1-6-6 alkyl; C1-6-6 alkyl substituted by 1 to 5 substituents, which are independently selected from the group consisting of: amino, hydroxy, C1-6 alkoxy;
  • C5-C6 heteroaryl group containing 1 - 3 hetero atoms selected from N, O or S C5-C6 substituted by C1-6 alkyl group containing 1 - 3 hetero atoms selected from N, O or S Heteroaryl,
  • a C4-6 cycloalkyl group a C3-6 cycloalkyl group substituted by 1 to 4 substituents, the substituents being individually selected from: a hydroxyl group;
  • a C4-C6-heterocycloalkyl group having 1 to 3 hetero atoms selected from N, O or S, substituted by 1 to 4 substituents, having 1 to 3 hetero atoms selected from N, O or S C4 ⁇ C6 heterocycloalkyl;
  • Y1 and Y2 together with the nitrogen atom to which they are attached form morpholinyl, piperidinyl, monooxo-thiomorpholinyl and dioxo-thiomorpholinyl;
  • Y3 and Y4 are independently selected from the group consisting of hydrogen, methyl and SO2-methyl, and Y3 and Y4 together with the nitrogen atom to which they are attached form a heterocyclic group selected from the group consisting of morpholinyl, piperidinyl and dioxo-thio Morpholine-based.
  • Z in the formula I or II represents oxadiazolyl, furyl, thienyl or isoxazolyl, which is substituted by one or more selected from the group consisting of Optionally substituted: H, C1-6 alkyl or hydroxy C1-6 alkyl;
  • A represents a phenylene group, a pyridylene group, an isoxazolyl group; optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, C1-6 alkyl;
  • Y is ⁇ NY1Y2 or ⁇ NH ⁇ NY3Y4;
  • Y1 is H or C1-6 alkyl
  • Y2 is selected from C1-6-6 alkyl; C1-6-6 alkyl substituted by 1 to 5 substituents, which are individually selected from the group consisting of: hydroxy, C1-6 alkoxy;
  • C5-C6 heteroaryl group containing 1 - 3 hetero atoms selected from N, O or S C5-C6 substituted by C1-6 alkyl group containing 1 - 3 hetero atoms selected from N, O or S Heteroaryl,
  • a C4-6 cycloalkyl group a C3-6 cycloalkyl group substituted by 1 to 4 substituents, the substituents being individually selected from: a hydroxyl group;
  • a C4-C6-heterocycloalkyl group having 1 to 3 hetero atoms selected from N, O or S, substituted by 1 to 4 substituents, having 1 to 3 hetero atoms selected from N, O or S C4 ⁇ C6 heterocycloalkyl;
  • Y3 and Y4 are independently selected from the group consisting of hydrogen, methyl and SO2-methyl, and Y3 and Y4 together with the nitrogen atom to which they are attached form a heterocyclic group selected from the group consisting of morpholine-4-yl, piperidinyl-l-yl and 1,1-dioxo-thiomorpholine-4-yl.
  • Z in the formula I or II represents oxadiazolyl, furyl, thienyl or isoxazolyl, which is substituted by one or more selected from the group consisting of The base is optionally substituted: H, C1-6 alkyl or hydroxy C1-6 alkyl.
  • A represents a phenylene group, a pyridylene group, or an isoxazolyl group; and is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, and C1-6 alkyl.
  • Y is ⁇ NY1Y2 or ⁇ NH ⁇ NY3Y4;
  • Y1 is H or methyl
  • Y2 is selected from C1-6-6 alkyl; C1-6-6 alkyl substituted by 1 to 5 substituents, which are individually selected from the group consisting of: hydroxy, C1-6 alkoxy;
  • Y3 and Y4 are independently selected from the group consisting of hydrogen and methyl, and Y3 and Y4 together with the nitrogen atom to which they are attached form a heterocyclic group selected from the group consisting of morpholine-4-yl, piperidinyl-1-yl and 1,1-di Oxo-thiomorpholine-4-yl.
  • Z represents oxadiazolyl, furyl, thienyl or isoxazolyl, and the isoxazolyl is substituted by one or more selected from the group consisting of Optionally substituted: H, C1-6 alkyl or hydroxy C1-6 alkyl;
  • A represents a phenylene group, a pyridylene group, an isoxazolyl group; optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, C1-6 alkyl;
  • Y is ⁇ NY1Y2 or ⁇ NH ⁇ NY3Y4;
  • Y1 is H or methyl
  • Y2 is selected from the group consisting of methyl, ethyl, methoxyethyl or hydroxypropyl;
  • Y3 and Y4 are independently selected from the group consisting of hydrogen and methyl, and Y3 and Y4 together with the nitrogen atom to which they are attached form a heterocyclic group selected from the group consisting of morpholine-4-yl, piperidinyl-1-yl and 1,1-di Oxo-thiomorpholine-4-yl.
  • the invention also provides a compound having the following general formula III:
  • R4 is a C1-C4 alkyl group, a hydroxy-substituted C1-C4 alkyl group
  • Y is ⁇ NY1Y2 or ⁇ NH ⁇ NY3Y4;
  • Y1 is H, C1-6 alkyl or C1-6 alkyl substituted with 1 to 5 substituents; the substituents are individually selected from the group consisting of: amino, hydroxy, C1-6 alkoxy, (C1-6 alkane) Base, C1-6 alkyl) N ⁇ , (C1 ⁇ 6 alkyl, H)N ⁇ and C1 ⁇ 6 alkyl-S(O)2 ⁇ ;
  • Y2 is selected from C1-6-6 alkyl; C1-6-6 alkyl substituted by 1 to 5 substituents, which are independently selected from the group consisting of: amino, hydroxy, C1-6 alkoxy, cycloalkyl, (C1) -6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N- and C1-6 alkyl-S(O)2 ⁇ ;
  • C5-C6 heteroaryl group containing 1 - 3 hetero atoms selected from N, O or S C5-C6 substituted by C1-6 alkyl group containing 1 - 3 hetero atoms selected from N, O or S a heteroaryl C3-6 cycloalkyl group, a C3-6 cycloalkyl group substituted by 1 to 4 substituents, which are individually selected from the group consisting of amino, hydroxy, hydroxy-C1-6 alkyl, C1 ⁇ 6 Alkoxy, C1-6 alkoxy-C1-6 alkyl, C1-6 alkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N- And C1-6 alkyl-S(O)2 ⁇ ;
  • Y1, Y2 together with the N atom to which they are attached form a 4-6-membered heterocycloalkyl group which, in addition to the nitrogen atom, contains zero, one or more impurities selected from O and S An atom, and the S atom may be in the form of its oxide.
  • Y3, Y4 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, SO2-C1-C6 alkyl, or Y3 and Y4
  • the nitrogen atoms to which they are attached together form a heterocyclic group selected from the group consisting of piperidinyl, morpholinyl, dioxythiomorpholinyl and monooxathiomorpholinyl.
  • the present invention also provides a compound having the following formula IV
  • Y is ⁇ NY1Y2 or ⁇ NH ⁇ NY3Y4;
  • Y1 is H, C1-6 alkyl or C1-6 alkyl substituted with 1 to 5 substituents; the substituents are independently selected from the group consisting of: amino, hydroxy, C1-6 alkoxy, (C1-6 alkane) Base, C1-6 alkyl) N ⁇ , (C1 ⁇ 6 alkyl, H)N ⁇ and C1 ⁇ 6 alkyl-S(O)2 ⁇ ;
  • Y2 is selected from C1-6-6 alkyl; C1-6-6 alkyl substituted by 1 to 5 substituents independently selected from the group consisting of amino, hydroxy, C1-6 alkoxy, cycloalkyl, (C1) -6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N- and C1-6 alkyl-S(O)2 ⁇ ;
  • C5-C6 heteroaryl group containing 1 - 3 hetero atoms selected from N, O or S C5-C6 substituted by C1-6 alkyl group containing 1 - 3 hetero atoms selected from N, O or S Heteroaryl,
  • a C3-6 cycloalkyl group a C3-6 cycloalkyl group substituted by 1 to 4 substituents independently selected from the group consisting of amino, hydroxy, hydroxy-C1-6 alkyl, C1-6 alkoxy , C1-6 alkoxy-C1-6 alkyl, C1-6 alkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N- and C1- 6 alkyl-S(O)2 ⁇ ;
  • Y1, Y2 together with the N atom to which they are attached form a 4-6-membered heterocycloalkyl group which, in addition to the nitrogen atom, contains zero, one or more impurities selected from O and S An atom, and the S atom may be in the form of its oxide;
  • Y3, Y4 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, SO2-C1-C6 alkyl, or Y3 and Y4 together with the nitrogen atom to which they are attached form a heterocyclic group selected from piperidinyl and morpholinyl. , dioxythiomorpholinyl and monooxathiomorpholinyl.
  • Y is ⁇ NY1Y2 or ⁇ NH ⁇ NY3Y4;
  • Y1 is H, C1-6 alkyl or C1-6 alkyl substituted with 1 to 5 substituents; the substituents are independently selected from the group consisting of: amino, hydroxy, C1-6 alkoxy, (C1-6 alkane) Base, C1-6 alkyl) N ⁇ , (C1 ⁇ 6 alkyl, H)N ⁇ and C1 ⁇ 6 alkyl-S(O)2 ⁇ ;
  • Y2 is selected from C1-6-6 alkyl; C1-6-6 alkyl substituted by 1 to 5 substituents independently selected from the group consisting of: amino, hydroxy, C1-6 alkoxy;
  • C5-C6 heteroaryl group containing 1 - 3 hetero atoms selected from N, O or S C5-C6 substituted by C1-6 alkyl group containing 1 - 3 hetero atoms selected from N, O or S Heteroaryl,
  • a C4-6 cycloalkyl group a C3-6 cycloalkyl group substituted by 1 to 4 substituents, the substituents being independently selected from: a hydroxyl group;
  • a C4-C6-heterocycloalkyl group having 1 to 3 hetero atoms selected from N, O or S, substituted by 1 to 4 substituents, having 1 to 3 hetero atoms selected from N, O or S C4 ⁇ C6 heterocycloalkyl;
  • Y1 and Y2 together with the nitrogen atom to which they are attached form morpholinyl, piperidinyl, monooxo-thiomorpholinyl and dioxo-thiomorpholinyl;
  • Y3 and Y4 are independently selected from the group consisting of hydrogen, methyl and SO2-methyl, and Y3 and Y4 together with the nitrogen atom to which they are attached form a heterocyclic group selected from the group consisting of morpholinyl, piperidinyl and dioxo-thio Morpholinyl.
  • the compound has the following general formula IV:
  • Y is ⁇ NY1Y2 or ⁇ NH ⁇ NY3Y4;
  • Y1 is H or C1-6 alkyl
  • Y2 is selected from C1-6-6 alkyl; C1-6-6 alkyl substituted by 1 to 5 substituents, which are individually selected from the group consisting of: hydroxy, C1-6 alkoxy;
  • C5-C6 heteroaryl group containing 1 - 3 hetero atoms selected from N, O or S C5-C6 substituted by C1-6 alkyl group containing 1 - 3 hetero atoms selected from N, O or S Heteroaryl,
  • a C4-6 cycloalkyl group a C3-6 cycloalkyl group substituted by 1 to 4 substituents, the substituents being individually selected from: a hydroxyl group;
  • a C4-C6-heterocycloalkyl group having 1 to 3 hetero atoms selected from N, O or S, substituted by 1 to 4 substituents, having 1 to 3 hetero atoms selected from N, O or S C4 ⁇ C6 heterocycloalkyl;
  • Y3 and Y4 are independently selected from the group consisting of hydrogen, methyl and SO2-methyl, and Y3 and Y4 together with the nitrogen atom to which they are attached form a heterocyclic group selected from the group consisting of morpholine-4-yl, piperidinyl-l-yl and 1,1-dioxo-thiomorpholine-4-yl.
  • the compound has the following general formula IV:
  • Y is ⁇ NY1Y2 or ⁇ NH ⁇ NY3Y4;
  • Y1 is H or methyl
  • Y2 is selected from C1-6-6 alkyl; C1-6-6 alkyl substituted by 1 to 5 substituents, which are individually selected from the group consisting of: hydroxy, C1-6 alkoxy;
  • Y3 and Y4 are independently selected from the group consisting of hydrogen and methyl, and Y3 and Y4 together with the nitrogen atom to which they are attached form a heterocyclic group selected from the group consisting of morpholine-4-yl, piperidinyl-1-yl and 1,1-di Oxo-thiomorpholine-4-yl.
  • the compound has the following general formula IV:
  • Y is ⁇ NY1Y2 or ⁇ NH ⁇ NY3Y4;
  • Y1 is H or methyl
  • Y2 is selected from the group consisting of methyl, ethyl, 2-methoxyethyl or hydroxypropyl;
  • Y3 and Y4 are independently selected from the group consisting of hydrogen and methyl, together with the nitrogen atom to which they are attached, form a heterocyclic group selected from the group consisting of morpholine-4-yl, piperidinyl-1-yl and 1,1-dioxo - thiomorpholine-4-yl.
  • the compound of formula I is selected from the group consisting of:
  • the compound of formula I is selected from the group consisting of:
  • the invention provides a compound of formula I, which is a cis-trans isomer, an enantiomer, a diastereomer, a racemate, a solvate, hydrated Or its pharmaceutically acceptable salts and esters,
  • T represents C3-7 cycloalkyl, C4-7 cycloalkenyl, C6-8 dicycloalkyl, C6-10 aryl, C3-7 heterocycloalkyl; preferably T represents phenyl;
  • Z represents a 5-membered heteroaryl ring containing 1, 2 or 3 hetero atoms independently selected from the group consisting of oxygen, nitrogen and sulfur; the 5-membered heteroaryl ring is optionally substituted by one or more substituents selected from the group consisting of: , halogen, -R1, -OR1, -OC(O)R1, -NR2R3, CN, cyano(C1-6)alkyl- or R2; preferably, Z represents 1, 2 or 3 independently selected from oxygen a 5-membered heteroaryl ring of a hetero atom of nitrogen and sulfur, wherein at most one hetero atom is oxygen or sulfur, and when one hetero atom is a nitrogen atom, at least one oxygen or sulfur atom is also present.
  • the heteroaromatic ring is optionally substituted by one or more substituents selected from C1 to C4 alkyl, hydroxy, halogen, hydroxy or amino substituted C1 - C4 alkyl, C2 - C4 alkenyl, C2 - C4 Alkynyl, C1-C4 alkoxy; more preferably, Z represents a 5-membered heteroaryl ring containing 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, and one hetero atom is oxygen or sulfur and the other atom is Nitrogen; the 5-membered heteroaryl ring is optionally substituted with one or more substituents selected from C1-6 alkyl or hydroxy C1-6 alkyl;
  • R1 represents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkyl (C1-6) alkyl, cyano (C1-6) alkane a C1-6 alkyl group substituted with a hydroxy group or an amino group, and R1 is optionally mono-, di- or trifluoro;
  • R2 or R3 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl or CF3, or R2 and R3 together with the nitrogen atom to which they are attached form 4 a -7 membered heteroalicyclic ring containing the nitrogen atom and one additional heteroatom selected from O, N and S, optionally substituted by one or more R1 groups;
  • A is -NR2-; or A is a 5-membered heteroarylene containing 1, 2, 3 or 4 heteroatoms independently selected from oxygen, nitrogen and sulfur and at most one of the heteroatoms is oxygen or sulfur; Is a 6-membered heteroarylene containing 1, 2 or 3 nitrogen atoms, or the 5 or 6-membered heteroarylene is optionally fused to a benzene or pyridine ring, said 5 or 6-membered
  • the arylene group is optionally substituted by Rx and/or Ry and/or Rz, wherein Rx is Halogen, -R1, -OR1, -OC(O)R1, -C(O)OR1, -NR2R3, -NR2C(O)R3, -OH, -CN, Ry are halogen, -R1, -OR1, -OC (O) R1, -NR2R3, -NR2C(O)R3, or CN, Rz is -R1, -OR1 or -OC(O)R1, provided
  • Y is -NY1Y2 or -NH-NY3Y4;
  • Y1 is selected from the group consisting of: H; C1-6 alkyl; C1-6 alkyl substituted by 1 to 5 substituents independently selected from the group consisting of amino, halogen, halo-C1-6 alkoxy, Hydroxy, C1-6 alkoxy, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N-, nitro and C1-6 alkyl-S(O) 2-;
  • Y2 is selected from the group consisting of: H; C1-6 alkyl-S(O)2-; amino; NH-S(O)2-; C1-6 alkoxy; C1-6 alkyl, or substituted by 1-5 a substituted C1-6 alkyl group, said substituent being independently selected from the group consisting of: amino, substituted amino, halogen, halo-C1-6 alkoxy, hydroxy, C1-6 alkoxy, carboxy, cycloalkyl , (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N-, nitro, C1-6 alkyl-S(O)2-, heterocycloalkyl, Or a heterocycloalkyl group substituted by 1 to 4 substituents, which are independently selected from the group consisting of acetamido, acetyl, acetylamino, amido, amino, carboxyl, cyano, halogen, halo- C1-6 alkoxy, halo-C1-6 al
  • Alkyl (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N- and C1-6 alkyl-S(O)2-, heterocycloalkyl, or a heterocycloalkyl group substituted by 1 to 4 substituents, which are independently selected from the group consisting of: acetamido, acetyl, C1-6 alkoxy, C1-6 alkyl;
  • C5-C6 heteroaryl group containing 1 - 3 hetero atoms selected from N, O or S C5-C6 substituted by C1-6 alkyl group containing 1 - 3 hetero atoms selected from N, O or S Heteroaryl
  • a C3-6 cycloalkyl group a C3-6 cycloalkyl group substituted by 1 to 4 substituents, which are individually selected from the group consisting of: an amino group, a hydroxyl group, a hydroxy-C1-6 alkyl group, and a C1-6 alkoxy group. , C1-6 alkoxy-C1-6 alkyl, C1-6 alkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N- and C1- 6 alkyl-S(O)2 ⁇ ;
  • Y1, Y2 together with the N atom to which they are attached form a 4-6 membered heterocycloalkyl group which, in addition to the nitrogen atom, contains zero, one or more impurities selected from O and S An atom, and the S atom may be in the form of its oxide;
  • Y1, Y2 together with the N atom to which they are attached form a 4-6 membered heterocycloalkyl group having 1-3 heteroatoms selected from N, O or S, substituted with from 1 to 4 substituents, and said
  • Y1 and Y2 together with the nitrogen atom to which they are attached form morpholinyl, piperidinyl, piperazinyl, azetidinyl, oxazabicycloheptane; morpholinyl, piperidinyl
  • Y3, Y4 each independently selected from: hydrogen, C1-C6 alkyl, SO 2 -C1-C6 alkyl, cycloalkyl and heterocyclyl optionally substituted with 1-4 groups independently selected from the group of substituents Halogen, cyano, hydroxy, C1-C6 alkyl and C1-C6 alkoxy,
  • Y3, Y4 together with the nitrogen atom to which they are attached form a heterocyclic group which is optionally substituted with from 1 to 4 substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C6 alkyl and C1-C6 alkoxy;
  • Y3, Y4 each independently selected from: hydrogen, C1-C6 alkyl, SO 2 -C1-C6 alkyl, C3-7 cycloalkyl and C3-7 heterocyclyl, optionally substituted with 1-4 substituents independently selected from Substituted from a substituent of the following groups: halogen, cyano, hydroxy, C1-C6 alkyl and C1-C6 alkoxy, or wherein Y3, Y4 together with the nitrogen atom to which they are attached form a C3-C7 heterocyclic group, More preferably, the C3 to C7 heterocyclic group is piperidinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinyl, monooxathiomorpholinyl and pyrrolidinyl, said Pyridyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinylmonooxathiomorpholinyl and pyrrolidin
  • the compound has the following formula II,
  • Z represents a 5-membered heteroaryl ring containing 1, 2 or 3 hetero atoms independently selected from the group consisting of oxygen, nitrogen and sulfur, wherein At most one hetero atom is oxygen or sulfur, and when one hetero atom is a nitrogen atom, at least one oxygen or sulfur atom is also present, and the 5-membered heteroaryl ring is one or more substituents selected from the group consisting of Optionally substituted: C1 - C4 alkyl, hydroxy, halogen, hydroxy or amino substituted C1 - C4 alkyl, C2 - C4 alkenyl, C2 - C4 alkynyl, C1 - C4 alkoxy;
  • A is a 5-membered heteroarylene containing 1, 2 or 3 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur and at most one of the heteroatoms is oxygen or sulfur, or contains 1, 2 or 3 nitrogen atoms a 6-membered heteroarylene or phenylene group; the 5-membered heteroarylene, 6-membered heteroarylene, and phenylene are optionally substituted with a substituent selected from the group consisting of halogen, cyano, C1 ⁇ 6 alkyl;
  • Y is ⁇ NY1Y2 or ⁇ NH ⁇ NY3Y4;
  • Y1 is H, C1-6 alkyl or C1-6 alkyl substituted with 1 to 5 substituents; the substituents are individually selected from the group consisting of: amino, hydroxy, C1-6 alkoxy, (C1-6 alkane) Base, C1-6 alkyl) N ⁇ , (C1 ⁇ 6 alkyl, H)N ⁇ and C1 ⁇ 6 alkyl-S(O)2 ⁇ ;
  • Y2 is selected from C1-6-6 alkyl; C1-6-6 alkyl substituted by 1 to 5 substituents, which are individually selected from the group consisting of amino, substituted amino, hydroxy, C1-6 alkoxy, carboxy, Halogen, cycloalkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N- and C1-6 alkyl-S(O)2-, heterocycloalkane a heterocyclic alkyl group substituted with 1 to 4 substituents, the substituent being independently selected from the group consisting of: acetamido, acetyl, C1-6 alkoxy, C1-6 alkyl;
  • C5-C6 heteroaryl group containing 1 - 3 hetero atoms selected from N, O or S C5-C6 substituted by C1-6 alkyl group containing 1 - 3 hetero atoms selected from N, O or S Heteroaryl
  • a C3-6 cycloalkyl group a C3-6 cycloalkyl group substituted by 1 to 4 substituents, which are individually selected from the group consisting of: an amino group, a hydroxyl group, a hydroxy-C1-6 alkyl group, and a C1-6 alkoxy group. , C1-6 alkoxy-C1-6 alkyl, C1-6 alkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N- and C1- 6 alkyl-S(O)2 ⁇ ;
  • Y1, Y2 together with the N atom to which they are attached form a 4-6-membered heterocycloalkyl group which, in addition to the nitrogen atom, contains zero, one or more impurities selected from O and S An atom, and the S atom may be in the form of its oxide;
  • Y1, Y2 together with the N atom to which they are attached form a 4-6 membered heterocycloalkyl group having 1-3 heteroatoms selected from N, O or S, substituted with from 1 to 4 substituents, and said
  • Y3, Y4 each independently selected from: hydrogen, C1-C6 alkyl, SO 2 -C1-C6 alkyl, or Y3 and Y4 nitrogen atom to which they are attached form a heterocyclic group
  • a heterocyclyl group is selected from piperidine Pyridyl, morpholinyl, dioxythiomorpholinyl and monooxathiomorpholinyl.
  • Z in the formula I or II represents a 5-membered heteroaryl ring containing 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, and one hetero atom is oxygen or sulfur, and the other atom Is a nitrogen; the 5-membered heteroaryl ring is optionally substituted with one or more substituents selected from C1-6 alkyl or hydroxy C1-6 alkyl.
  • Z in the formula I or II represents oxadiazolyl, furyl, thienyl or isoxazolyl, which is substituted by one or more selected from the group consisting of The base is optionally substituted: H, C1-6 alkyl or hydroxy C1-6 alkyl.
  • a in formula I or II represents a phenylene, pyridylene, or isoxazolyl group; optionally substituted by 1, 2 or 3 substituents independently selected from: Halogen, cyano, C1-6 alkyl.
  • Z in the formula I or II represents oxadiazolyl, furyl, thienyl or isoxazolyl, which is substituted by one or more selected from the group consisting of Optionally substituted: H, C1-6 alkyl or hydroxy C1-6 alkyl;
  • A represents a phenylene group, a pyridylene group, or an isoxazolyl group; and is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, and C1-6 alkyl.
  • Z in the formula I or II represents oxadiazolyl, furyl, thienyl or isoxazolyl, which is substituted by one or more selected from the group consisting of Base optional replacement: H, C1-6 alkyl or hydroxy C1-6 alkyl;
  • A represents a phenylene group, a pyridylene group, an isoxazolyl group; optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, C1-6 alkyl;
  • Y is ⁇ NY1Y2 or ⁇ NH ⁇ NY3Y4;
  • Y1 is H or C1-6 alkyl
  • Y2 is selected from C1-6-6 alkyl; C1-6-6 alkyl substituted by 1 to 5 substituents, which are individually selected from the group consisting of amino, substituted amino, hydroxy, C1-6 alkoxy, carboxy, Halogen, C1-6 alkyl-S(O)2-; cycloalkyl, heterocycloalkyl, or heterocycloalkyl substituted by 1-4 substituents, individually selected from acetamide Base, acetyl, C1-6 alkoxy, C1-6 alkyl;
  • a C5-C6 heteroaryl group having 1 to 3 hetero atoms selected from N, O or S a C5-C6 heteroaryl group substituted with an alkyl group and having 1 to 3 hetero atoms selected from N, O or S ;
  • Y1, Y2 together with the N atom to which they are attached form a 4-6-membered heterocycloalkyl group which, in addition to the nitrogen atom, contains zero, one or more impurities selected from O and S An atom, and the S atom may be in the form of its oxide;
  • Y1, Y2 together with the N atom to which they are attached form a 4-6 membered heterocycloalkyl group having 1-3 heteroatoms selected from N, O or S, substituted with from 1 to 4 substituents, and said
  • Y3 and Y4 are independently selected from the group consisting of hydrogen, methyl and ⁇ SO2-methyl, and Y3 and Y4 together with the nitrogen atom to which they are attached form a heterocyclic group selected from the group consisting of morpholinyl, piperidinyl and dioxo-sulfur Dimorpholine-based.
  • Z in the formula I or II represents oxadiazolyl, furyl, thienyl or isoxazolyl, the isoxazolyl being substituted by one or more substituents selected from Optional substitution: H, C1-6 alkyl or hydroxy C1-6 alkyl;
  • A represents a phenylene group, a pyridylene group, an isoxazolyl group; optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, C1-6 alkyl;
  • Y is ⁇ NY1Y2 or ⁇ NH ⁇ NY3Y4;
  • Y1 is H or C1-6 alkyl
  • Y2 is selected from C1-6 alkyl; C1-6 alkyl substituted by 1 to 5 substituents, which are individually selected from the group consisting of: hydroxy, C1-6 alkoxy, acylamino, halogen, carboxyl, C3 a -6 cycloalkyl group, a C4-C6-heterocycloalkyl group containing from 1 to 3 hetero atoms selected from N, O or S, C1-6 alkyl-S(O)2-;
  • a C5-C6 heteroaryl group having 1-3 hetero atoms selected from N, O or S a C5-C6 heteroaryl group substituted with an alkyl group and containing 1 to 3 hetero atoms selected from N, O or S ,
  • Y1 and Y2 together with the nitrogen atom to which they are attached form morpholinyl, piperidinyl, piperazinyl, azetidinyl, oxazabicycloheptane; morpholinyl, piperidinyl, piperidine
  • Y3 and Y4 are independently selected from the group consisting of hydrogen, methyl and SO2-methyl, and Y3 and Y4 together with the nitrogen atom to which they are attached form a heterocyclic group selected from the group consisting of morpholin-4-yl, piperidin-1-yl and 1,1-dioxo-thiomorpholine-4-yl.
  • Z in the formula I or II represents oxadiazolyl, furyl, thienyl or isoxazolyl, which is substituted by one or more selected from the group consisting of Optionally substituted: H, C1-6 alkyl or hydroxy C1-6 alkyl;
  • A represents a phenylene group, a pyridylene group, an isoxazolyl group; optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, C1-6 alkyl;
  • Y is ⁇ NY1Y2 or ⁇ NH ⁇ NY3Y4;
  • Y1 is H or methyl
  • Y2 is selected from C1-6-6 alkyl; C1-6-6 alkyl substituted by 1 to 5 substituents, which are individually selected from the group consisting of: hydroxy, C1-6 alkoxy, acetylamino, fluoro, carboxy, Morpholinyl, cyclopropyl, tetrahydrofuran;
  • a C5-C6 heteroaryl group having 1-3 hetero atoms selected from N, O or S, a C5-C6 heteroaryl group substituted with an alkyl group and containing 1 to 3 hetero atoms selected from N, O or S ;
  • a C3-6 cycloalkyl group a C3-6 cycloalkyl group substituted by 1 to 4 substituents, the substituents being individually selected from the group consisting of: a hydroxyl group, a methoxy group, a methyl group;
  • a C4-C6 heterocycloalkyl group having 1 to 3 hetero atoms selected from N, O or S; a heterocyclic atom containing 1 to 3 hetero atoms selected from N, O or S substituted by 1 to 4 substituents a cycloalkyl group, the substituent being individually selected from the group consisting of: methyl, acetyl;
  • Y1 and Y2 together with the nitrogen atom to which they are attached form morpholinyl, piperidinyl, piperazinyl, azetidinyl, oxazabicycloheptane; morpholinyl, piperidinyl, piperidine
  • the S atom in the morpholinyl group may also be in the form of its oxide;
  • Y3 and Y4 are independently selected from the group consisting of hydrogen and methyl, and Y3 and Y4 together with the nitrogen atom to which they are attached form a heterocyclic group selected from the group consisting of morpholine-4-yl, piperidinyl-1-yl and 1,1-di Oxo-thiomorpholine-4-yl.
  • Z in the formula I or II represents oxadiazolyl, furyl, thienyl or isoxazolyl, which is substituted by one or more selected from the group consisting of Optionally substituted: H, C1-6 alkyl or hydroxy C1-6 alkyl;
  • A represents a phenylene group, a pyridylene group, an isoxazolyl group; optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, C1-6 alkyl;
  • Y is ⁇ NY1Y2 or ⁇ NH ⁇ NY3Y4;
  • Y1 is H or methyl
  • Y2 is selected from the group consisting of methyl, ethyl, methoxyethyl, hydroxypropyl, acetylaminoethyl, H, -CH 2 COOH, hydroxycyclopentyl, cyclopropane, methylpyrazolyl, morphinolinyl, Hydroxyethyl, butyl, methylpiperidinyl, morphinolylethyl, tetrahydrofuranyl, methoxycyclopentyl, acetylpyrrolidinyl, tetrahydrofuranylmethylene, difluoroethyl, cyclopropyl , methanesulfonylethyl, trifluoroethyl, isopropyl, tetrahydropyran, cyclobutyl, amino, piperidinyl, methylsulfonyl, dioxythiomorpholinyl, hydroxymethylethyl;
  • Y1 and Y2 together with the nitrogen atom to which they are attached form methylpiperazinyl, carboxamidopiperidinyl, methoxypiperidinyl, difluoropiperidinyl, oxazabicycloheptane, dioxo Dimorpholinyl, morpholinyl, azetidinyl, monooxathiomorpholinyl;
  • Y3 and Y4 are independently selected from the group consisting of hydrogen and methyl, and Y3 and Y4 together with the nitrogen atom to which they are attached form a heterocyclic group selected from the group consisting of morpholine-4-yl, piperidinyl-1-yl and 1,1-di Oxo-thiomorpholine-4-yl.
  • the compound has the following formula III:
  • R4 is a C1-C4 alkyl group, a hydroxy-substituted C1-C4 alkyl group
  • Y is ⁇ NY1Y2 or ⁇ NH ⁇ NY3Y4;
  • Y1 is H, C1-6 alkyl or C1-6 alkyl substituted with 1 to 5 substituents; the substituents are individually selected from the group consisting of: amino, hydroxy, C1-6 alkoxy, (C1-6 alkane) Base, C1-6 alkyl) N ⁇ , (C1 ⁇ 6 alkyl, H)N ⁇ and C1 ⁇ 6 alkyl-S(O)2 ⁇ ;
  • Y2 is selected from C1-6-6 alkyl; C1-6-6 alkyl substituted by 1 to 5 substituents, which are individually selected from the group consisting of amino, substituted amino, hydroxy, C1-6 alkoxy, carboxy, Halogen, cycloalkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N-, C1-6 alkyl-S(O)2-, heterocycloalkane a heterocyclic alkyl group substituted with 1 to 4 substituents, the substituent being independently selected from the group consisting of: acetamido, acetyl, C1-6 alkoxy, C1-6 alkyl;
  • a C5-C6 heteroaryl group having 1 to 3 hetero atoms selected from N, O or S a C1-6 alkyl group substituted a C5-C6 heteroaryl group having 1 to 3 hetero atoms selected from N, O or S;
  • C3-6 cycloalkyl C3-6 cycloalkyl; C3-6 cycloalkyl substituted by 1 to 4 substituents, which are individually selected from the group consisting of amino, hydroxy, hydroxy-C1-6 alkyl, C1-6 alkoxy , C1-6 alkoxy-C1-6 alkyl, C1-6 alkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N- and C1- 6 alkyl-S(O)2 ⁇ ;
  • a C4-C6-heterocycloalkyl group having 1 to 3 hetero atoms selected from N, O or S; and 1 to 3 hetero atoms selected from N, O or S substituted by 1 to 4 substituents a C4-C6 heterocycloalkyl group, said substituent being independently selected from the group consisting of: an amino group, a hydroxyl group, a hydroxy-C1-6 alkyl group, a C1-6 alkoxy group, an acetyl group, a dioxythio group, a C1-6 alkoxy group Base-C1-6 alkyl, C1-6 alkyl and C1-6 alkyl-S(O)2-;
  • Y1, Y2 together with the N atom to which they are attached form a 4-6-membered heterocycloalkyl group which, in addition to the nitrogen atom, contains zero, one or more impurities selected from O and S An atom, and the S atom may be in the form of its oxide;
  • Y1, Y2 together with the N atom to which they are attached form a 4-6-membered heterocycloalkyl group having 1 to 3 hetero atoms selected from N, O or S, substituted by 1 to 4 substituents, and said The S atom may be in the form of its oxide.
  • Y3, Y4 each independently selected from: hydrogen, C1-C6 alkyl, SO 2 -C1-C6 alkyl, or Y3 and Y4 nitrogen atom to which they are attached form a heterocyclic group selected from piperidinyl, morpholinyl Base, dioxythiomorpholinyl and monooxathiomorpholinyl.
  • the compound has the following general formula IV:
  • Y is ⁇ NY1Y2 or ⁇ NH ⁇ NY3Y4;
  • Y1 is H, C1-6 alkyl or C1-6 alkyl substituted with 1 to 5 substituents independently selected from the group consisting of: amino, hydroxy, C1-6 alkoxy, (C1-6 alkane) Base, C1-6 alkyl) N ⁇ , (C1 ⁇ 6 alkyl, H) N ⁇ And C1-6 alkyl-S(O)2 ⁇ ;
  • Y2 is selected from C1-6-6 alkyl; C1-6-6 alkyl substituted by 1 to 5 substituents independently selected from the group consisting of amino, substituted amino, hydroxy, C1-6 alkoxy, carboxy, Halogen, cycloalkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N-, C1-6 alkyl-S(O)2, heterocycloalkyl Or a heterocycloalkyl group substituted by 1 to 4 substituents, which are independently selected from the group consisting of: acetamido, acetyl, C1-6 alkoxy, C1-6 alkyl;
  • C3-6 cycloalkyl C3-6 cycloalkyl; C3-6 cycloalkyl substituted by 1 to 4 substituents independently selected from the group consisting of amino, hydroxy, hydroxy-C1-6 alkyl, C1-6 alkoxy , C1-6 alkoxy-C1-6 alkyl, C1-6 alkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N- and C1- 6 alkyl-S(O)2 ⁇ ;
  • Y1, Y2 together with the N atom to which they are attached form a 4-6-membered heterocycloalkyl group which, in addition to the nitrogen atom, contains zero, one or more impurities selected from O and S An atom, and the S atom may be in the form of its oxide;
  • Y1, Y2 together with the N atom to which they are attached form a 4-6-membered heterocycloalkyl group having 1 to 3 hetero atoms selected from N, O or S, substituted by 1 to 4 substituents, and said
  • Y3, Y4 each independently selected from: hydrogen, C1-C6 alkyl, SO 2 -C1-C6 alkyl, or Y3 and Y4 nitrogen atom to which they are attached form a heterocyclic group selected from piperidinyl, morpholinyl Base, dioxythiomorpholinyl and monooxathiomorpholinyl.
  • the compound has the following general formula IV:
  • Y is ⁇ NY1Y2 or ⁇ NH ⁇ NY3Y4;
  • Y1 is H, C1-6 alkyl or C1-6 alkyl substituted with 1 to 5 substituents independently selected from the group consisting of: amino, hydroxy, C1-6 alkoxy, (C1-6 alkane) Base, C1-6 alkyl) N ⁇ , (C1 ⁇ 6 alkyl, H)N ⁇ and C1 ⁇ 6 alkyl-S(O)2 ⁇ ;
  • Y2 is selected from a C1-6 alkyl group; a C1-6 alkyl group substituted by 1 to 5 substituents independently selected from the group consisting of an amino group, a substituted amino group, a hydroxyl group, a C1-6 alkoxy group, a halogen, a carboxyl group, a C3-6 cycloalkyl group, a C4-C6-heterocycloalkyl group having 1 to 3 hetero atoms selected from N, O or S;
  • a C4-C6-heterocycloalkyl group having 1 to 3 hetero atoms selected from N, O or S; and 1 to 3 hetero atoms selected from N, O or S substituted by 1 to 4 substituents a C4-C6 heterocycloalkyl group, said substituent being individually selected from the group consisting of: C1-6 alkyl, acetyl, dioxythio;
  • Y1 and Y2 together with the nitrogen atom to which they are attached form morpholinyl, piperidinyl, piperazinyl, azetidinyl, oxazabicycloheptane; morpholinyl, piperidinyl, piperazine
  • Y3 and Y4 are independently selected from the group consisting of hydrogen, methyl and SO2-methyl, and Y3 and Y4 together with the nitrogen atom to which they are attached form a heterocyclic group selected from the group consisting of morpholinyl, piperidinyl and dioxo-thio Morpholinyl.
  • the compound has the following general formula IV:
  • Y is ⁇ NY1Y2 or ⁇ NH ⁇ NY3Y4;
  • Y1 is H or C1-6 alkyl
  • Y2 is selected from C1-6 alkyl; C1-6 alkyl substituted by 1-5 substituents, which are individually selected from the group consisting of: hydroxy, C1-6 alkoxy, acetylamino, fluoro, carboxy, a C3-6 cycloalkyl group having from 1 to 3 C4-C6-heterocycloalkyl groups selected from hetero atoms of N, O or S;
  • a C5-C6 heteroaryl group having 1-3 hetero atoms selected from N, O or S a C5-C6 heteroaryl group substituted with a methyl group and containing 1-3 hetero atoms selected from N, O or S base;
  • a C4-C6-heterocycloalkyl group having 1 to 3 hetero atoms selected from N, O or S; and 1 to 3 substituents selected from N, O or S substituted by 1 to 4 substituents a C4-C6 heterocycloalkyl group, said substituent being individually selected from the group consisting of: C1-6 alkyl, acetyl, dioxothio;
  • Y1 and Y2 together with the nitrogen atom to which they are attached form morpholinyl, piperidinyl, piperazinyl, azetidinyl, oxazabicycloheptane; morpholinyl, piperidinyl, piperazine
  • Y3 and Y4 are independently selected from the group consisting of hydrogen, methyl and SO2-methyl, and Y3 and Y4 together with the nitrogen atom to which they are attached form a heterocyclic group selected from the group consisting of morpholin-4-yl, piperidin-1-yl and 1,1-dioxo-thiomorpholine-4-yl.
  • the compound has the following general formula IV:
  • Y is ⁇ NY1Y2 or ⁇ NH ⁇ NY3Y4;
  • Y1 is H or methyl
  • Y2 is selected from C1-6 alkyl; C1-6 alkyl substituted by 1-5 substituents, which are individually selected from the group consisting of: hydroxy, C1-6 alkoxy, acetylamino, fluoro, carboxy, Morpholinyl, cyclopropyl, tetrahydrofuran;
  • a C3-6 cycloalkyl group a C3-6 cycloalkyl group substituted by 1 to 4 substituents, the substituents being individually selected from the group consisting of: a hydroxyl group, a methoxy group, a methyl group;
  • a C5-C6 heteroaryl group having 1-3 hetero atoms selected from N, O or S a C5-C6 heteroaryl group substituted with a methyl group and containing 1-3 hetero atoms selected from N, O or S base;
  • a C4-C6 heterocycloalkyl group having 1 to 3 hetero atoms selected from N, O or S; a heterocyclic group containing 1 to 3 substituents selected from N, O or S, substituted by 1 to 4 substituents a cycloalkyl group, said substituent being individually selected from the group consisting of: methyl, acetyl, dioxothio;
  • Y1 and Y2 together with the nitrogen atom to which they are attached form morpholinyl, piperidinyl, piperazinyl, azetidinyl, oxazabicycloheptane; morpholinyl, piperidinyl, piperazine
  • Y3 and Y4 are independently selected from the group consisting of hydrogen and methyl, and Y3 and Y4 together with the nitrogen atom to which they are attached form a heterocyclic group selected from the group consisting of morpholine-4-yl, piperidinyl-1-yl and 1,1-di Oxo-thiomorpholine-4-yl.
  • the compound has the following general formula IV:
  • Y is ⁇ NY1Y2 or ⁇ NH ⁇ NY3Y4;
  • Y1 is H or methyl
  • Y2 is selected from the group consisting of methyl, ethyl, 2-methoxyethyl, hydroxypropyl, acetylaminoethyl, H, -CH2COOH, hydroxycyclopentyl, cyclopropane, methylpyrazolyl, morphinolinyl, Hydroxyethyl, butyl, methylpiperidinyl, morphinolylethyl, tetrahydrofuranyl, methoxycyclopentyl, acetylpyrrolidinyl, tetrahydrofuranylmethylene, difluoroethyl, cyclopropyl , methanesulfonylethyl, trifluoroethyl, isopropyl, tetrahydropyran, cyclobutyl, amino, piperidinyl, methylsulfonyl, dioxythiomorpholinyl, hydroxymethylethyl;
  • Y1 and Y2 together with the nitrogen atom to which they are attached form methylpiperazinyl, carboxamidopiperidinyl, methoxypiperidinyl, difluoropiperidinyl, oxazabicycloheptane, dioxo Dimorpholinyl, morpholinyl, azetidinyl, monooxathiomorpholinyl;
  • Y3 and Y4 are independently selected from the group consisting of hydrogen and methyl, together with the nitrogen atom to which they are attached, form a heterocyclic group selected from the group consisting of morpholine-4-yl, piperidinyl-1-yl and 1,1-dioxo- Thiomorpholine-4-yl.
  • the compound has the following general formula IV:
  • Y is ⁇ NY1Y2;
  • Y1 is an H group
  • Y2 is selected from the group consisting of methyl, ethyl, methoxyethyl, hydroxypropyl, acetylaminoethyl, H, -CH2COOH, hydroxycyclopentyl, cyclopropane, methylpyrazolyl, morphinolyl, hydroxyethyl , butyl, methyl piperidinyl, morphinolylethyl, tetrahydrofuranyl, methoxycyclopentyl, acetylpyrrolidinyl, tetrahydrofuranylmethylene, difluoroethyl, cyclopropylmethyl, Methanesulfonylethyl, trifluoroethyl;
  • Y1 and Y2 together with the nitrogen atom to which they are attached form methylpiperazinyl, carboxamidopiperidinyl, methoxypiperidinyl, difluoropiperidinyl, oxazabicycloheptane.
  • the compound has the following Formula II:
  • Z represents a methyl isoxazolyl group
  • A is selected from the group consisting of cyanophenylene and pyridylene;
  • Y is ⁇ NY1Y2;
  • Y1 is an H group
  • Y2 is selected from C1-6-6 alkyl; C1-6 alkyl substituted by 1-3 C3-6 cycloalkyl or C1-6 alkoxy; C1-6 alkoxy.
  • the invention also provides a composition comprising a compound as described above or a pharmaceutically acceptable salt thereof.
  • the invention also provides the use of a compound or composition as described above for the preparation of a medicament.
  • the present invention also provides a method of treating or preventing a disease, comprising An effective amount of a compound or composition as described above is administered to the patient.
  • the invention also provides the use of a compound or composition as described herein for the manufacture of a medicament for the treatment or prevention of a disease associated with the ⁇ 5-GABA A receptor.
  • the invention provides a method of treating or preventing a disease associated with an ⁇ 5-GABA A receptor, characterized by administering to a patient an effective amount of a compound described herein or a combination as described herein Things.
  • the invention further provides the use of a compound or composition as described herein for the manufacture of a medicament for the treatment or prevention of pain, Alzheimer's disease, multi-infarct dementia and stroke.
  • the pain is neuropathic pain, inflammatory pain, and cancer pain.
  • the pain is selected from the group consisting of: headache, facial pain, neck pain, shoulder pain, back pain, chest pain, abdominal pain, back pain, back pain, lower limb pain, musculoskeletal pain, vascular pain, gout , arthritis pain, visceral pain, pain caused by infectious diseases (such as AIDS and post-herpetic neuralgia), bone pain, sickle cell anemia, autoimmune disease, multiple sclerosis or inflammation-related pain, injury or Chronic pain caused by surgery, nociceptive pain, painful diabetes, trigeminal neuralgia, lumbar or cervical radiculopathy, glossopharyngeal neuralgia, autonomic reflex pain, reflex sympathetic dystrophy, nerve root avulsion, cancer , chemical damage, toxins, nutritional deficiencies, viral or bacterial infections, and pain associated with degenerative osteoarthrosis.
  • infectious diseases such as AIDS and post-herpetic neuralgia
  • bone pain such as AIDS and post-herpetic neuralgia
  • autoimmune disease such as AIDS and post-her
  • the invention also provides a method of treating or preventing pain, Alzheimer's disease, multi-infarct dementia and stroke, characterized in that an effective amount of a compound or composition as described herein is administered to a patient.
  • the pain is neuropathic pain, inflammatory pain, and cancer pain.
  • the pain is selected from the group consisting of: headache, facial pain, neck pain, shoulder pain, back pain, chest pain, abdominal pain, back pain, back pain, lower limb pain, musculoskeletal pain, vascular pain, Gout, arthritic pain, visceral pain, pain caused by infectious diseases (such as AIDS and post-herpetic neuralgia), bone pain, sickle cell anemia, autoimmune disease, multiple sclerosis or inflammation-related pain, injury Or chronic pain caused by surgery, nociceptive pain, painful diabetes, trigeminal neuralgia, lumbar or cervical radiculopathy, glossopharyngeal neuralgia, autonomic reflex pain, reflex sympathetic dystrophy, nerve root avulsion, Cancer, chemical damage, toxins, nutritional deficiencies, viral or bacterial infections, pain associated with degenerative osteoarthrosis.
  • infectious diseases such as AIDS and post-herpetic neuralgia
  • bone pain such as AIDS and post-herpetic neuralgia
  • autoimmune disease such as AIDS and post-herp
  • the invention further relates to a process for the production of a compound of formula (II) as defined above, which process comprises:
  • T represents a C3-7 cycloalkyl group, a C4-7 cycloalkenyl group, a C6-8 cycloalkylene group, a C6-10 aryl group, a C3-7 heterocycloalkyl group;
  • T represents a phenyl group.
  • Z represents a 5-membered heteroaryl ring containing 1, 2 or 3 hetero atoms independently selected from oxygen, nitrogen and sulfur; the 5-membered heteroaryl ring is a Or a plurality of substituents selected from the group consisting of: hydroxy, halogen, -R1, -OR1, -OC(O)R1, -NR2R3, CN, cyano(C1-6)alkyl- or R2; wherein R1 Represents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkyl (C1-6) alkyl, cyano (C1-6) alkyl a hydroxy or amino substituted C1-6 alkyl group, and R1 is optionally mono-, di- or trifluoro; R2 or R3 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 An alkynyl group,
  • Z represents a 5 membered heteroatom containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur An aromatic ring, and at most one hetero atom is oxygen or sulfur, and when one hetero atom is a nitrogen atom, one oxygen atom or one sulfur atom is also present; preferably Z represents two independently selected from oxygen, Nitrogen and sulfur heteroatoms 5 a heteroaromatic ring, and one hetero atom is oxygen or sulfur, and the other atom is nitrogen; the 5-membered heteroaryl ring is optionally substituted by one or more substituents selected from C1-6 alkyl or hydroxy C1 1-6 alkyl; preferably Z represents oxadiazole, furyl, thienyl or isoxazolyl, one or more selected from the oxadiazole, furyl, thienyl or isoxazolyl group
  • oxadiazole furyl, thienyl or isoxazolyl
  • A is -NR2 -; or A is a 5-membered heteroarylene containing 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur. And at most one of the heteroatoms is oxygen or sulfur, or a 6-membered heteroarylene containing 1, 2 or 3 nitrogen atoms, or the 5 or 6-membered heteroarylene is optionally fused to On the phenyl or pyridine ring, the 5 or 6 membered heteroarylene is optionally substituted by Rx and/or Ry and/or Rz, wherein Rx is halogen, -R1, -OR1, -OC(O)R1, - C(O)OR1, ⁇ NR2R3, ⁇ NR2C(O)R3, ⁇ OH, ⁇ CN, Ry is halogen, —R1, —OR1, —OC(O)R1, —NR2R3, —NR2C(O)R3, or CN, Rz is
  • Y is ⁇ NY1Y2 or ⁇ NH ⁇ NY3Y4;
  • Y1 is selected from the group consisting of: H; C1-6 alkyl; C1-6 alkyl substituted with 1 to 5 substituents independently selected from the group consisting of amino, halogen, halo-C1-6 alkoxy, Hydroxy, C1-6 alkoxy, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N-, nitro and C1-6 alkyl-S(O)
  • Y1 is H, C1-6 alkyl or C1-6 alkyl substituted with 1 to 5 substituents; said substituents being individually selected from the group consisting of: amino, hydroxy, C1-6 alkoxy , (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N- and C1-6-6 alkyl-S(O)2-; more preferably, Y1 is H or C1-6-6 alkyl; more preferably, Y1 is H or methyl;
  • Y2 is selected from the group consisting of: H; C1-6-6 alkyl; C1-6-6 alkyl substituted by 1 to 5 substituents independently selected from the group consisting of amino, halogen, halo-C1-6 alkoxy, Hydroxy, C1-6 alkoxy, cycloalkyl, (C1 ⁇ 6) Alkyl, C1-6 alkyl)N ⁇ , (C1 ⁇ 6 alkyl, H)N ⁇ , nitro and C1-6 alkyl-S(O)2 ⁇ ; heteroaryl, or 1-4 a substituent-substituted heteroaryl group, the substituent of which is independently selected from the group consisting of: acetamido, acetyl, acetylamino, amido, amino, carboxyl, cyano, halogen, halo-C1 ⁇ 6 Alkoxy, halo-C1-6 alkyl, hydroxy, hydroxy-C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, C1-6 al
  • Y2 is preferably a C1-6 alkyl group; a C1-6 alkyl group substituted by 1 to 5 substituents, which are individually selected from the group consisting of amino, halogen, halo-C1-6 alkoxy, hydroxy, C1-6 alkoxy, C3 ⁇ C6 cycloalkyl, (C1 ⁇ 6 alkyl, C1-6-6 alkyl) N ⁇ , (C1 ⁇ 6 alkyl, H) N ⁇ , nitro and C1-6 alkyl ⁇ S(O)2 ⁇ ;
  • a C3 ⁇ 67 cycloalkyl group a C3-7 cycloalkyl group substituted by 1 to 4 substituents, which are individually selected from the group consisting of acetamido, acetyl, acetylamino, amido, amino, carboxy, Cyano, halogen, halo-C1-6 alkoxy, halo-C1-6 alkyl, hydroxy, hydroxy-C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1- 6 alkyl, C1-6 alkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N-, nitro and C1-6 alkyl-S (O )2-;
  • Y2 is selected from C1-6-6 alkyl; C1-6-6 alkyl substituted by 1 to 5 substituents, which are individually selected from the group consisting of: amino, hydroxy, C1-6 alkoxy, cycloalkyl , (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N- and C1-6 alkyl-S(O)2-;
  • C5-C6 heteroaryl group containing 1 - 3 hetero atoms selected from N, O or S C5-C6 substituted by C1-6 alkyl group containing 1 - 3 hetero atoms selected from N, O or S Heteroaryl,
  • a C3-6 cycloalkyl group a C3-6 cycloalkyl group substituted by 1 to 4 substituents, which are individually selected from the group consisting of: an amino group, a hydroxyl group, a hydroxy-C1-6 alkyl group, and a C1-6 alkoxy group. , C1-6 alkoxy-C1-6 alkyl, C1-6 alkyl, (C1-6 alkyl, C1-6 alkyl) N-, (C1-6 alkyl, H) N- and C1- 6 alkyl-S(O)2 ⁇ ;
  • Y2 is selected from C1-6-6 alkyl; C1-6-6 alkyl substituted by 1 to 5 substituents, which are individually selected from the group consisting of: amino, hydroxy, C1-6 alkoxy;
  • a C5-C6 heteroaryl group having 1 to 3 hetero atoms selected from N, O or S a C5-C6 heteroaryl group substituted with an alkyl group and having 1 to 3 hetero atoms selected from N, O or S ,
  • a C4-6 cycloalkyl group a C3-6 cycloalkyl group substituted by 1 to 4 substituents, the substituents being individually selected from: a hydroxyl group;
  • a C4-C6-heterocycloalkyl group having 1 to 3 hetero atoms selected from N, O or S, substituted by 1 to 4 substituents, having 1 to 3 hetero atoms selected from N, O or S C4 ⁇ C6 heterocycloalkyl;
  • Y2 is C1-6 alkyl; C1-6 alkyl substituted by hydroxy or halo or C1-6 alkoxy; morpholinyl; C3-6 cycloalkyl; hydroxy substituted C3-6 cycloalkyl; Pyrazolyl optionally substituted by C1-6 alkyl; tetrahydrofuranyl, tetrahydropyranyl;
  • Y2 is selected from C1-6-6 alkyl; C1-6-6 alkyl substituted by 1 to 5 substituents, which are individually selected from the group consisting of: hydroxy, C1-6 alkoxy;
  • Y2 is selected from the group consisting of methyl, ethyl, methoxyethyl or hydroxypropyl.
  • Y1, Y2 together with the N atom to which they are attached form a 4-6-membered heterocycloalkyl group which, in addition to the nitrogen atom, contains zero, one or more impurities selected from O and S An atom, and the S atom may be in the form of its oxide;
  • Y1, Y2 together with the N atom to which they are attached form azetidinyl, morpholinyl, piperidinyl, pyrrolidinyl, dioxythiomorpholinyl, monooxythiomorpholinyl;
  • Y1; Y2 together with the N atom to which they are attached form a group selected from azetidine-1-yl, morpholine-4-yl, piperidinyl-1, pyrrolidine-1-yl, 1-oxo-thio Porphyrin-4-yl and 1,1-dioxo-thiomorpholine-4-yl;
  • Y3, Y4 are independently selected from the group consisting of: hydrogen, C1-C6 alkyl, SO2-C1-C6 alkyl, cycloalkyl and heterocyclic, optionally substituted by 1 to 4 substituents independently selected from the group consisting of: Halogen, cyano, hydroxy, C1-C6 alkyl and C1-C6 alkoxy, or wherein Y3, Y4 together with the nitrogen atom to which they are attached form a heterocyclic group which is optionally 1-4 independent Substituted with a substituent selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C6 alkyl and C1-C6 alkoxy;
  • Y3, Y4 are independently selected from the group consisting of: hydrogen, C1-C6 alkyl, SO2-C1-C6 alkyl, C3-7 cycloalkyl and C3-7 heterocyclic, optionally selected from 1 to 4 independently selected
  • the substituents of the following groups are substituted: halogen, cyano, hydroxy, C1-C6 alkyl and C1-C6 alkoxy.
  • Y3, Y4 are independently selected from the group consisting of: hydrogen, C1-C6 alkyl, SO2-C1 ⁇ C6 alkyl.
  • the C3-C7 heterocyclic group is piperidinyl, morpholinyl, thiomorpholinyl, dioxane Thiormorpholinyl, monooxathiomorpholinyl and pyrrolidinyl, the piperidinyl, morpholinyl, thiomorpholinyl, dioxythiomorpholinylmonooxathiomorpholinyl and pyrrole
  • the alkyl group is optionally substituted with from 1 to 4 substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-6 alkyl and C1-6 alkoxy.
  • Y3, Y4 are independently selected from the group consisting of hydrogen, C1-C6 alkyl and SO2-C1-C6 alkyl, and Y3 and Y4 together with the nitrogen atom to which they are attached form morpholine-4-yl, piperidine- 1 -yl, pyrrolidine-1 -yl and 1,1 -dioxo-thiomorpholine-4-yl.
  • Y3 and Y4 are independently selected from each other: hydrogen, methyl and SO2-methyl, and Y3 and Y4 together with the nitrogen atom to which they are attached form a heterocyclic group selected from morpholinyl, piperidinyl and dioxane. Generation - thiomorpholine-based.
  • Y3 and Y4 are independently selected from each other: hydrogen, methyl and SO2-methyl, and Y3 and Y4 together with the nitrogen atom to which they are attached form a heterocyclic group selected from morpholine-4-yl, piperidine-1 -Base and 1,1 -dioxo-thiomorpholine-4-yl.
  • Y3 and Y4 are independently selected from each other: hydrogen and methyl, and Y3 and Y4 together with the nitrogen atom to which they are attached form a heterocyclic group selected from the group consisting of morpholine-4-yl, piperidine-1-yl and , 1 -dioxo-thiomorpholine-4-yl.
  • substituted means that the specified group or moiety may have 1, 2, 3, 4, 5 or 6 substituents.
  • substituents are independently selected and are not necessarily the same.
  • substituents When the number of substituents is indicated, the term "one or more" refers to the most likely number of substitutions to substitutions, i.e., substitution of one hydrogen to all hydrogens is replaced by a substituent. Unless otherwise specified, 1, 2, 3, 4 or 5 substituents are preferred.
  • halogen means fluoro, chloro, bromo and iodo, preferably fluoro.
  • lower alkyl refers to a straight or branched alkyl group containing from 1 to 6 carbon atoms, which may be interchangeable with the C1-6 alkyl group described herein, and an example of a C1-6 alkyl group.
  • Particularly preferred "lower alkyl” are methyl and n-butyl.
  • lower alkoxy refers to the group -O-R, wherein R is lower alkyl as defined above.
  • cycloalkyl refers to a monovalent saturated cyclic hydrocarbon group, preferably a monovalent saturated cyclic hydrocarbon group having 3 to 7 ring carbon atoms, more preferably 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, Cyclopentyl or cyclohexyl, as well as those groups specifically exemplified below.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic group having a hetero atom, preferably containing one, two or three ring heteroatoms selected from N, O or S. - 7-membered saturated or partially unsaturated monocyclic ring. It preferably contains one or two ring heteroatoms. Preferably, it contains 1 or 2 selected from A 4-6-membered heterocyclic group of a ring hetero atom of N, O or S. S can be optionally substituted with two oxo groups.
  • heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydropyridyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidin Pyridyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, piperazinyl, azepanyl, diazepanyl, oxygen Azepanyl or dihydrooxazolyl, and those groups specifically exemplified below.
  • Preferred heterocyclic groups are morpholine-4-yl, piperidinyl-1, pyrrolidine-1-yl, thiomorpholine-4-yl and 1,1 dioxo-thiomorpholine-4
  • Particularly preferred heterocyclic groups are morpholine-4-yl, pyrrolidin-1-yl and 1,1 dioxo-thiomorpholine-4-yl.
  • aryl refers to a monovalent aromatic carbocyclic ring system containing from 6 to 14, preferably from 6 to 10 carbon atoms and having at least one aromatic ring or a polyfused ring wherein at least one ring is an aromatic ring.
  • aryl groups are phenyl, naphthyl, biphenyl or indanyl, as well as those groups specifically exemplified below.
  • Preferred aryl groups are phenyl groups, and aryl groups can also be substituted, as defined below and in the claims.
  • heteroaryl is an aromatic group containing a hetero atom, preferably an aromatic 5-6-membered monocyclic ring or 9- 10 member containing one, two or three atoms selected from nitrogen, oxygen and/or sulfur.
  • Bicyclic rings such as furyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetra Azyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, fluorenyl, oxazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, Quinolinyl or isoquinolyl, as well as those groups specifically exemplified below.
  • lower alkyl substituted by halogen means a lower alkyl group which is mono- or polysubstituted by halogen.
  • Examples of lower alkyl substituted by halogen are, for example, CFH 2 , CF 2 H, CF 3 , CF 3 CH 2 , CF 3 (CH 2 ) 2 , (CF 3 ) 2 CH or CF 2 H-CF 2 , and Those groups specifically exemplified herein.
  • lower alkyl substituted by hydroxy means a lower alkyl group as defined above wherein a hydrogen atom in at least one alkyl group is substituted by a hydroxy group.
  • Examples of lower alkyl substituted by hydroxy include, but are not limited to, methyl, ethyl, propyl, isopropyl substituted by one or more hydroxyl groups, particularly one, two or three hydroxyl groups, preferably one or two hydroxyl groups.
  • Base isobutyl, sec-butyl, tert-butyl, pentyl or n-hexyl.
  • the compounds of formula (I), (II), (III) and IV) can form pharmaceutically acceptable acid addition salts.
  • pharmaceutically acceptable salts are those of the compounds of formula (I), (II), (III) and IV) which are formed with physiologically compatible inorganic or organic acids, such as hydrochloric acid, sulfuric acid, Sulfuric acid or phosphoric acid;
  • the organic acid is, for example, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.
  • pharmaceutically acceptable salt refers to such salts.
  • the compound of formula (I) containing an acidic group such as COOH can also form a salt with a base.
  • salts are alkali metal, alkaline earth metal and ammonium salts, such as Na-, K-, Ca- and trimethylammonium salts.
  • pharmaceutically acceptable salt also refers to such salts.
  • esters includes derivatives of the compounds of formula (I), (II), (III) and IV) wherein the carboxyl group is converted to an ester.
  • esters Preference is given to methyl, ethyl, propyl, butyl and benzyl esters.
  • pharmaceutically acceptable ester also includes derivatives of the compounds of formula (I) wherein the hydroxy group is converted to the corresponding ester by an inorganic or organic acid such as nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, Maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid, etc., these acids are not toxic to organisms.
  • an inorganic or organic acid such as nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, Maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid, etc.
  • the invention further relates to a process for the production of a compound of formula (II) as defined above, which process comprises:
  • the invention further relates to a process for the production of a compound of formula (II) as defined above, which process comprises:
  • G and W are optionally Cl, Br, I, OH, OTs, OTf and OMs, etc.;
  • R5 is alkyl, methyl, ethyl, tert-butyl and benzyl, and then
  • G and W are optional substituents such as Cl, Br, I, OH, OTs, OTf and OMs.
  • the reaction can be carried out under the conditions described in the examples or under conditions known to those skilled in the art.
  • the reaction can be carried out under LDA, NaH, potassium or sodium t-butoxide, in a suitable solvent such as dioxane at room temperature (e.g., 20 ° C).
  • a suitable solvent such as dioxane at room temperature (e.g., 20 ° C).
  • it is a production condition for producing an ether using Mitsunobu conditions (PPh3, DEAD), a phase transfer catalyst (TBAB, crown ether), or the like.
  • reaction of the compound with Y to give a compound of formula (I) can be carried out under the conditions described in the examples or under conditions known to those skilled in the art.
  • the reaction can be carried out in the presence of trimethylaluminum in a suitable solvent such as dioxane at elevated temperatures (e.g., 85-95 ° C).
  • the reaction of the compound with Y to give a compound of formula (II) can be carried out under the conditions described in the examples or under conditions known to those skilled in the art.
  • the reaction can be carried out in Hünigs base (N,N-diisopropylethylamine) and O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea
  • the reaction is carried out in the presence of tetrafluoroborate in a suitable solvent such as dimethylformamide at room temperature.
  • the reaction can be carried out in the presence of 1,1'-carbonyldiimidazole in a suitable solvent such as dimethylformamide at elevated temperature (e.g., 80 ° C).
  • reaction can also be carried out in 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N1-hydroxybenzotriazole and Hünigs base (N,N-diisopropyl)
  • a base ethylamine in a suitable solvent such as dichloromethane at room temperature.
  • the saponification of the compound to the compound of formula (1-4) can be carried out under the conditions described in the examples or under conditions known to those skilled in the art.
  • the reaction can be carried out in the presence of sodium hydroxide in a suitable solvent such as water at room temperature.
  • the reaction can be carried out in the presence of sodium hydroxide or lithium hydroxide in a suitable solvent such as tetrahydrofuran or water at room temperature.
  • it may be carried out under other conditions as described or under conditions known to those skilled in the art, such as hydrogenation of the benzyl group, hydrolysis of the t-butyl group under acidic conditions and the like.
  • reaction of the compound to give the compound of formula (II) can be carried out under the conditions described in the examples or under conditions known to those skilled in the art.
  • the reaction can be carried out under LDA, NaH, potassium or sodium t-butoxide, in a suitable solvent (such as dioxane, THF, DMF, etc.) at room temperature (eg, 20 ° C).
  • a suitable solvent such as dioxane, THF, DMF, etc.
  • it is a production condition for producing an ether using Mitsunobu conditions (PPh3, DEAD), a phase transfer catalyst (TBAB, crown ether, etc.).
  • the product is formed under appropriate base or catalyst conditions in a suitable solvent such as dioxane, THF and DMF, at elevated temperature (e.g., 80 ° C).
  • the invention further relates to compounds of formula (II) as described above, which are prepared by the methods described above.
  • the compound of the formula (II) of the present invention and a pharmaceutically acceptable salt thereof can be produced by the following methods.
  • the compound of the formula (II) and its intermediate product can be produced according to a similar method or according to the aforementioned method.
  • Starting materials known in the art may be obtained commercially or may be prepared according to methods known in the art or analogous methods known in the art.
  • the compound of the formula (II) and its intermediate product can be produced according to a similar method or according to the aforementioned method.
  • Starting materials known in the art may be obtained commercially or may be prepared according to methods known in the art or analogous methods known in the art.
  • novel compounds of the present invention and pharmaceutically acceptable salts and esters thereof have important pharmacological properties and are ⁇ 5GABA A receptor inverse agonists.
  • the compounds of the invention may be used alone or in combination with other drugs for the treatment or prevention of diseases mediated by GABA A receptor ligands containing the alpha 5 subunit. These diseases include, but are not limited to, pain, Alzheimer's disease, multiple infarct dementia, and stroke.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant.
  • the present invention includes the compounds as described above for use in the preparation of a medicament for the treatment or prevention of a disease associated with the ⁇ 5GABA A receptor, in particular for the treatment or prevention of the following diseases: pain, Alzheimer's disease, multi-infarct dementia And stroke.
  • cancer pain refers to the pain that occurs during the development of a malignant tumor.
  • the occurrence of cancer pain is currently believed to have three mechanisms: pain directly caused by cancer development, pain caused by cancer treatment, and cancer patients. Complicated with painful diseases.
  • neuroopathic pain is pain that is caused or caused by primary damage and dysfunction of the nervous system.
  • inflammatory pain is pain caused by local acute inflammation or chronic inflammation stimulating nerves.
  • treatment also includes prophylactic administration to alleviate or eliminate the condition once the condition is established.
  • patient is defined as any warm-blooded animal, such as, but not limited to, a mouse, a guinea pig, a dog, a horse, or a human, preferably a human.
  • acute pain is defined as pain caused by damage to the skin, body structure or internal organs and/or harmful irritation of the disease, or pain caused by abnormal function of the muscle or viscera that does not cause actual tissue damage. .
  • chronic pain is defined as a reasonable period of time beyond the usual course of the acute disease or the healing of the injury, or associated with a chronic pathological process that causes persistent pain, or pain that recurs at intervals of months or years, if It is considered to be chronic pain after pain has been reached or after the usual treatment process.
  • the length of time required for pain depends on the nature of the pain and the course of the pain-related treatment, and if the pain exceeds the usual course of treatment, the pain is chronic.
  • Chronic pain includes, but is not limited to, headache, facial pain, neck pain, shoulder pain, chest pain, abdominal pain, back pain, back pain, lower limb pain, musculoskeletal pain, pain associated with somatic-like mental disorders, visceral pain, painful diabetes sexual neuropathy, vascular pain, gout, arthritic pain, cancer pain, Autonomic reflex pain, pain caused by infectious diseases (such as AIDS and herpes zoster), pain caused by autoimmune diseases (rheumatoid), pain caused by acute and chronic inflammation, post-operative pain, and post-burn pain.
  • infectious diseases such as AIDS and herpes zoster
  • autoimmune diseases rheumatoid
  • the medicament disclosed in the present invention can effectively treat chronic pain as defined above, and the medicament disclosed in the present invention can be used for treating pain sensitivity accompanying other disorders, including hyperalgesia, allodynia, pain enhancement and pain memory enhancement, and the invention will improve Treatment of its pain.
  • headache can be divided into primary headaches and secondary headaches.
  • Primary headaches include tension headaches, migraine headaches, and cluster headaches, while secondary headaches are caused by other diseases. Pain-sensitive tissue of the head and face can cause various headaches when it is damaged or stimulated. These pain-sensitive tissues include the scalp, face, mouth and throat. Because they are mainly the muscles or blood vessels of the head, they are rich in nerves. Fiber, which is sensitive to pain, can cause headaches when these tissues are damaged.
  • facial pain includes, but is not limited to, trigeminal neuralgia, atypical facial pain, facial paralysis, and hemifacial spasm.
  • trigeminal neuralgia is a unique chronic painful condition, also known as painful convulsion, which refers to the appearance of transient, paroxysmal and recurrent electric shock-like severe pain in the area of the trigeminal nerve. Or accompanied by the same side tendon. Trigeminal neuralgia is divided into two types: primary and secondary. Primary trigeminal neuralgia refers to no clinical signs of the nervous system. No organic lesions are found. Secondary trigeminal neuralgia refers to clinical There are signs of the nervous system, and organic diseases such as tumors and inflammation are found.
  • typical facial pain refers to pain caused by a variety of causes. It is characterized by persistent burning pain, no intermittentness, and no special action or triggering stimulation. The pain is mostly bilateral, and the pain often exceeds the distribution of the trigeminal nerve and even the skin of the neck. The cause can be caused by sinusitis, malignant tumor, jaw and skull base infection or other causes of stimulation or damage to the trigeminal nerve.
  • neck pain, back pain, shoulder pain refers to pain caused by acute and chronic muscle strain and degenerative changes and trauma of bones and joints.
  • Common diseases that cause neck, shoulder and upper limb pain include neck and shoulder muscle fasciitis, ligament inflammation, cervical spondylosis, frozen shoulder, thoracic outlet syndrome, external humeral epicondylitis, or pain caused by autoimmune diseases.
  • rheumatoid arthritis, ankylosing spondylitis and rheumatoid arthritis other diseases that may cause neck pain, back pain, shoulder pain, neck and shoulder tumors, neuritis, arteriovenous diseases and Infection and pain involved in chest and abdominal organ diseases Wait.
  • chest, abdomen and back pain refers to pain caused by diseases of the visceral and thoracic and abdominal tissues of the chest and abdomen, including but not limited to intercostal neuralgia, intercostal chondritis, angina pectoris, abdominal pain (acute abdominal visceral pain). And lumbar back myofascial syndrome.
  • Waist, lower limb pain refers to lower back, lumbosacral, sacral, hip, hip, and lower extremity pain. Waist and lower extremity pain is often not an independent disease, but a common feature of a variety of diseases, clinical manifestations are diverse, the cause is very complex, with degenerative and injury, including but not limited to lumbar disc herniation, acute lumbar sprain, sciatica Osteoporosis, third lumbar transverse process syndrome, piriformis syndrome, knee osteoarthritis, tail pain and heel pain.
  • muscle and bone pain includes, but is not limited to, myofascial pain, wound-induced pain, and chronic regional pain syndrome.
  • painful diabetes refers to pain caused by a neurological injury associated with diabetes, which is at least in part due to reduced blood flow and hyperglycemia. Some diabetic patients do not develop neuropathy, and other patients develop the disease early. Diabetic neuropathic pain can be divided into single neuropathy and systemic polyneuropathy involving one or more lesion sites, which may be diffusion and symmetry. Often, it mainly involves the way of feeling (Merrit's Textbook of Neurology, 9th edition, edited by LPRowland LP). The manifestations of diabetic neuropathy can include autonomic dysfunction, leading to dysregulation including the heart, smooth muscles, and glands, causing hypotension, diarrhea, constipation, and sexual incompetence.
  • Diabetic neuropathy often develops in stages, early in the nerve ending area, autonomic or sensory neuropathy occurs in the foot, cranial neuropathy occurs around the face and around the eyes, intermittent pain and tingling, in the subsequent stages, Pain is stronger and more frequent. Finally, when pain loss occurs in a certain area, it occurs as a painless neuropathy. Since there is no pain as an indication of injury, the risk of serious tissue damage is greatly increased.
  • visceral pain includes, but is not limited to, irritable bowel syndrome (IBS) with or without chronic fatigue syndrome (CFS), inflammatory bowel disease (IBD), and interstitial cystitis. .
  • IBS irritable bowel syndrome
  • CFS chronic fatigue syndrome
  • IBD inflammatory bowel disease
  • interstitial cystitis interstitial cystitis
  • vascular pain is pain that results from one or more of the following factors.
  • Examples include, but are not limited to, occlusive arteriosclerosis, occlusive thromboangiitis, acute arterial occlusion, embolism, congenital arteriovenous vascular disease, vasospasm disease, Rayaud disease, hand and foot cyanosis, acute venous closure, thrombophlebitis, varicose veins And lymphedema.
  • autonomic reflex pain refers to pain caused by "reflex sympathetic atrophy.”
  • Reflex sympathetic atrophy sign refers to the body's acute and chronic pain, severe spontaneous pain, allergies to touch and pain, may be accompanied by edema and blood disorder, followed by skin and musculoskeletal nutrition disorders and atrophy.
  • postoperative pain refers to a complex physiological response of the body to the disease itself and tissue damage caused by surgery, which manifests itself as an unpleasant experience in psychology and behavior.
  • arthritic pain includes, but is not limited to, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, psoriasis joint disease, gout, pseudogout, infectious arthritis, tendonitis, bursa Pain caused by diseases such as inflammation, bone damage and joint soft tissue inflammation.
  • herbalgia after herpes zoster refers to the severe pain that persists under the skin of the original rash area after healing of the rash of herpes zoster.
  • nociceptive pain is pain caused by a process of tissue damage induced by stimulation of nociceptors, or by excitability prolonged by nociceptors.
  • the pain caused by the excitability of the nociceptors may be caused by the persistent noxious stimuli of the nociceptors or their sensitization or both, or they may be caused by these factors, and by their persistence, various reflex mechanisms and other factors And extended.
  • the invention provides the use of a pharmaceutical composition comprising a therapeutically effective amount of an ⁇ 5-GABA A inverse agonist.
  • a pharmaceutical composition comprising a therapeutically effective amount of an ⁇ 5-GABA A inverse agonist.
  • the ⁇ 5-GABA A inverse agonist for use in the treatment of the present invention may be administered as a starting compound, it is preferred to have the active ingredient, optionally in the form of a physiologically acceptable salt, with one or more additives, Excipients, carriers, buffers, diluents and/or other conventional pharmaceutical excipients are combined together to form a pharmaceutical composition.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an ⁇ 5-GABA A inverse agonist, wherein the ⁇ 5-GABA A inverse agonist is combined with one or more pharmaceutically acceptable carriers, and optionally Mix with other therapeutic and/or prophylactic components known or used in the art.
  • the carrier must be "acceptable”, i.e., compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • compositions for use in the present invention may be those suitable for oral, rectal, bronchial, nasal, pulmonary, topical (including buccal and sublingual), transdermal, vaginal or parenteral (including skin, subcutaneous, intramuscular, Compositions for intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion, or those in a form suitable for inhalation or spray administration, including powders and liquid aerosols, or A pharmaceutical composition for sustained release system administration.
  • suitable sustained release systems include semipermeable matrices of solid hydrophobic polymers containing the compounds of the invention, wherein the matrices can be in the form of shaped articles, such as films or microcapsules.
  • the compound for use in the present invention can thus be formulated into a pharmaceutical composition and unit dosage form thereof together with conventional additives, or diluents.
  • forms such as these include solids (especially in the form of tablets, filled capsules, powders and pills), and liquids (especially aqueous or non-aqueous solutions, suspensions, emulsions, elixirs), and capsules filled with the above forms, all orally Forms for administration, suppositories for rectal administration, and sterile injectable solutions for parenteral administration.
  • Such pharmaceutical compositions and unit dosage forms thereof may include conventional ingredients in conventional proportions, with or without additional active compounds or ingredients, and such unit dosage forms may contain any suitable, effective, equivalent Amount of active ingredient.
  • the compounds used in the present invention can be administered in a variety of oral and parenteral dosage forms.
  • the dosage form described below may contain, as an active ingredient, a compound of the invention or a pharmaceutically acceptable salt thereof, to those skilled in the art.
  • the pharmaceutically acceptable carrier can be either solid or liquid.
  • Solid form preparations include powders, tablets, nine doses, capsules, cachets, suppositories, and dispersible granules.
  • the solid carrier can be one or more substances which may also act as a diluent, a flavoring agent, a solubilizer, a lubricant, a suspension, a binder, a preservative, a tablet disintegrating agent, or a encapsulated material.
  • the carrier is a finely divided solid which is admixed with the finely divided active ingredient.
  • the active ingredient is mixed with a carrier having the necessary adhesive properties in an appropriate ratio and compressed into a desired shape and size.
  • the powders and tablets preferably contain from 5% or 10% to about 70% of the active compound.
  • a suitable carrier is Magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter, etc. Wait.
  • the term "formulation” includes active compounds formulated with a encapsulating material as a carrier, the encapsulating material providing a capsule in which the active ingredient with or without the carrier is surrounded by the carrier so as to be bound thereto.
  • the formulations include cachets and lozenges. Tablets, powders, capsules, pills, cachets and lozenges can be used as solid forms suitable for oral administration.
  • a low melting wax such as a fatty acid glyceride or a cocoa butter mash is first melted, and then the active ingredient is uniformly dispersed therein by stirring. The molten homogeneous mixture is then poured into a suitably sized mold which is allowed to cool and thereby solidify.
  • compositions suitable for vaginal administration may be presented in the form of pessaries, tampons, creams, gels, pastes, foams or sprays.
  • compositions comprise suitable carriers known in the art. .
  • Liquid preparations include solutions, suspensions and emulsions, for example, aqueous solutions or water-propylene glycol solutions.
  • a parenteral injection liquid preparation can be formulated as a solution of water-polyethylene glycol.
  • the compounds for use in the present invention may be formulated for parenteral administration (e.g., by injection, such as bolus injection or continuous infusion), and may be presented in unit dosage form in ampules, together with the added preservatives. Filled syringes, small volume infusion bags or multi-dose containers.
  • the compositions may take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain such ingredients such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in the form of a powder, which may be obtained in the form of a sterile solid or a lyophilized solution for reconstitution with a suitable vehicle such as sterile, pyrogen-free water.
  • Aqueous solutions suitable for oral administration can be prepared by dissolving the active ingredient in water and adding the desired coloring, flavoring, stabilizing and thickening agents.
  • Aqueous suspensions suitable for oral administration can be prepared by dispersing the finely divided active ingredient in a viscous material such as a natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, or other known suspensions Prepared in water.
  • a viscous material such as a natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, or other known suspensions Prepared in water.
  • liquid preparations designed to be converted to liquid formulations for oral administration shortly before use.
  • liquid preparations include solutions, suspensions and emulsions.
  • Such preparations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersant thickeners, solubilizing agents, and the like.
  • the compounds of the invention may be formulated as ointments, creams or lotions or as a transdermal patch.
  • ointments and creams may be formulated with aqueous or oily bases in admixture with suitable thickening agents and/or gels.
  • Lotions may be formulated with aqueous or oily bases and usually contain one or more emulsifying, stabilizing, dispersing, suspending, thickening or coloring agents.
  • compositions suitable for topical oral administration include lozenges containing the active ingredient in a flavoring base, typically sucrose and acacia or tragacanth; in inert matrices such as gelatin and glycerin or sucrose and acacia An active ingredient-containing tablet (pastiIles); and a mouthwash containing the active ingredient in a suitable liquid carrier.
  • a flavoring base typically sucrose and acacia or tragacanth
  • inert matrices such as gelatin and glycerin or sucrose and acacia
  • An active ingredient-containing tablet pastiIles
  • a mouthwash containing the active ingredient in a suitable liquid carrier.
  • the solution or suspension can be applied directly to the nasal cavity by conventional means such as with a dropper, pipette or spray.
  • the composition may be in the form of a single dose or multiple doses.
  • Respiratory administration can also be achieved by aerosols in which the active ingredient is packaged in a pressurized package together with a suitable propellant, including a chlorofluorocarbon (CFC) such as dichlorodifluoromethane or trichlorofluoride. Methane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. Aerosols may also suitably contain a surfactant such as lecithin. The dose of the drug can be controlled by a metering valve.
  • CFC chlorofluorocarbon
  • the active ingredient may be in the form of a dry powder, for example a powder mix of the compound with a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP).
  • a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP).
  • the powder carrier conveniently forms a gel in the nasal cavity.
  • the powder composition may be presented in unit dosage form, for example, in a capsule or cartridge (such as a gelatin capsule or cartridge), or in a blister pack in which the powder can be administered via an inhaler.
  • compositions for respiratory administration typically the compound has a small particle size, such as a particle size on the order of 5 microns or less.
  • a particle size on the order of 5 microns or less.
  • Such particle size can be obtained by methods known in the art, such as by micronization.
  • a composition suitable for sustained release of the active ingredient can be applied as needed.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses of the appropriate amount of active ingredient.
  • the unit dosage form can be a packaged preparation wherein the sealed package contains discrete quantities of the preparation, such as encapsulated tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form may be a capsule, a tablet, a sputum or a lozenge itself, or may be an appropriate amount of the above capsules, tablets or the like in any package.
  • Tablets or capsules for oral administration and liquids for intravenous administration as well as continuous infusion are preferred compositions.
  • the amount of active ingredient in a unit dosage formulation can vary depending on the particular application and the effectiveness of the active ingredient, and can be adjusted from 0.01 mg to about 0.1 g.
  • the drug may be administered three times a day in capsules of from 0.01 to about 100 mg, and if desired, the composition may also contain other compatible therapeutic agents.
  • the compounds used in the present invention are administered at a starting dose of from 0.001 mg/kg to 10 mg/kg body weight per day.
  • these dosages may vary depending on the needs of the patient, the severity of the condition being treated, and the compound to be employed.
  • treatment with a smaller dose that is less than the optimal dose of the compound is initially initiated, after which a small increase in dose is achieved.
  • the total daily dose can be subdivided into divided doses within one day if needed.
  • compositions of the present invention may also be used in combination with other drugs for the treatment of pain, Alzheimer's disease, multi-infarct dementia and stroke, including but not limited to morphine, gabapentin and the like. Accordingly, the present invention provides a medicament for treating a pain, Alzheimer's disease, multi-infarct dementia and stroke, which is not only effective but has no obvious side effects, and another object of the present invention is to provide A highly safe drug for a particular patient population, such as the elderly, patients with liver or kidney failure, or cardiovascular disease.
  • Feed A2 was added to 150 mL of DMF (preparation of the starting material by reference to Leslie J. Street, Francine Sternfeld, et al. J. Med. Chem. 2004, 47, 3642-3657) (1.75 g, 10.5 mmol), argon gas protection down temperature To 0 degrees Celsius, sodium hydride (400 mg, 1.9 eq) was then added and stirred at this temperature for 15 minutes.
  • Compound A1 (preparation reference Sternfeld, Francine; Carling, Robert W, et al. J. Med. Chem., 2004, 47, 2176-2179) (1.5 g, 5.2 mmol) was then added to the reaction mixture and stirred at room temperature 1.5. hour.
  • Example 1 The experimental procedure was as described in Example 1: The starting material was compound A4 and trans-(1S,2S)-2-amino-cyclopentanol hydrochloride (CAS: 68327-04-8) to give the product (75 mg, 65.8%). The appearance is a white solid.
  • trans-(1S,2S)-2-amino-cyclopentanol hydrochloride 15-1 (CAS: 68327-04-8) (1.37 g, 10 mmol) and Et3N (3 g, 30 mmol) to toluene ( After stirring for 4 minutes at room temperature, 40 mL), phthalic anhydride (1.48 g, 10 mmol) was added with stirring, and the mixture was stirred under reflux for 4 hours. After TLC showed the reaction was completed, 40 ml of water was added, and the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness.
  • Example 2 The experimental procedure was as described in Example 1: the starting material was compound A4 and glycine tert-butyl ester (CAS: 6456-74-2) to obtain the product, and then trifluoroacetic acid was stirred at room temperature to obtain a final product (100 mg, total yield 60%). White solid.
  • Acetyl chloride (18 g) was added to acetic acid (10.5 g) and stirred at room temperature to give acetic anhydride, which was used.
  • Hydroxylamine hydrochloride (8.6 g), acetic acid (48 ml) and ethyl cyanoacetate B7 (10 g) were separately added to a 100 ml reaction flask, stirred at room temperature, and then added sodium acetate (10.1 g) in portions for about 15 minutes. After the addition, the reaction mixture was stirred at 18-28 degrees for 2 hours, and the reaction mixture was cooled to 15 degrees. The acetic anhydride was slowly added dropwise to the above reaction solution, and the addition was completed in about 20 minutes.
  • Example 1 The experimental procedure is as described in Example 1: The saponification reaction of B13 (see A3 for the preparation of B13 from B12) is condensed with D-aminopropanol (CAS: 35320-23-1) to obtain a product white solid 40 mg. 33%.
  • reaction solution was washed with 40 mL of water, and then washed with 40 mL of 10% aqueous sodium hydrogencarbonate, and the organic layer was dried over anhydrous sodium sulfate and evaporated to give 5.3 g of crude product. It is a yellow liquid.
  • the crude C2 (crude, 5.3 g, 14.6 mmol) from the previous step was added to 20 mL of methanol, and anhydrous sodium carbonate (7.7 g, 73 mmol) was added and stirred at room temperature for 1 hour.
  • the crude product was purified by column chromatography to afford (l,g, 41%).
  • the product C4 (crude, 268 mg, 0.55 mmol) from the previous step was added to 20 mL of ethanol, and then a 10% aqueous sodium hydroxide solution (5 mL) was added and stirred at room temperature for 0.5 hour.
  • the reaction solution was concentrated to remove ethanol.
  • the residue was added to 20 mL of water and the mixture was extracted with ethyl acetate (30mL ⁇ 2).
  • the aqueous phase was adjusted to pH 4 with citric acid, concentrated to dryness and then purified by column chromatography to afford product 120 mg, yield 46.1%.
  • the reaction solution was poured into 500 mL of water, stirred, and then separated, and the organic layer was washed twice with water, and water was added 500 mL each time. The organic layer was dried over anhydrous sodium sulfate and concentrated to give a crude material.
  • the crude product of the previous step was directly added to 30 mL of ethanol, and then 8 mL of a 10% aqueous sodium hydroxide solution was added thereto, and the mixture was stirred at room temperature for 0.5 hour.
  • the reaction solution was concentrated to remove ethanol, and the residue was added to 20 mL of water, and ethyl acetate (30mL ⁇ 2) was used to extract the impurities.
  • the aqueous phase was adjusted to pH 4 with dilute hydrochloric acid, and a large amount of solid precipitated. After suction filtration, the filter cake was washed once with 5 mL of ice water. The filter cake was dried to give D7 (1.5 g, yield: 46.1%).
  • Example 12 1-methoxythiazoline-4-aminoq starting material (Synthesis Reference Biodegradation, 1998, 9, (6) 433-442) and D7 condensation reaction to give the product 75 mg, yield 90 %, the appearance is a white solid.
  • Example 31 The starting material was compound E3 and D-aminopropanol (CAS: 35320-23-1) to give the product 42 mg, yield 81.8%.
  • Example 35 Starting material is compound E3 and trans-(1S,2S)-2-amino-cyclopentanol hydrochloride (CAS: 68327-04-8) to give product 44 mg, yield 78.5%, appearance It is a white solid.
  • Acetyl chloride (18 g) was added to acetic acid (10.5 g) and stirred at room temperature to give acetic anhydride, which was used.
  • Hydroxylamine hydrochloride (8.6 g), acetic acid (48 ml), ethyl cyanoformate F1 (10 g) were separately added to a 100 ml reaction flask, stirred at room temperature, and sodium acetate (10.1 g) was added portionwise for about 15 minutes. After the addition, the reaction mixture was stirred at 18-28 degrees for 2 hours, and the reaction mixture was cooled to 15 degrees. The acetic anhydride was slowly added dropwise to the above reaction solution, and the addition was completed in about 20 minutes.
  • step H2 was dissolved in ethanol (10 ml), followed by a 10% aqueous sodium hydroxide solution (4.8 ml) at room temperature.
  • the reaction solution was stirred at room temperature for half an hour.
  • the reaction mixture was concentrated, taken up in water (20 mL)
  • the aqueous phase was quenched with saturated ammonium chloride solution. A large amount of solid was precipitated, filtered, and the filter cake was washed with 5 ml of water and dried in vacuo to give a white solid H3 (500 mg, 43%).
  • HOBt (18 mg, 0.13 mmol), EDCI (26 mg, 0.13 mmol), K6 (50 mg, 0.1 mmol) and DMF (3 mL) were added to a 25 mL vial, stirred and dissolved, and R-2-aminopropanol was added under argon atmosphere. The mixture was stirred at room temperature overnight. TLC showed that the reaction was completed, diluted with 25 ml of dichloromethane, washed three times with water, dried over anhydrous sodium sulfate and evaporated to dryness.
  • Example 1 The starting material was compound L3 and ethylamine hydrochloride (CAS: 557-66-4) afforded product 32mg, yield 86%, appearance as white solid.
  • GABA A receptors mediate at least two modes of inhibition, tonic inhibition and phasic inhibition.
  • GABA is increased in millimolar concentrations, the GABA A receptor is rapidly desensitized, with low affinity for GABA, forming a phase-type inhibition.
  • GABA activates the GABA A receptor at concentrations ranging from a few hundred nanomolar to tens of micromolar, the high affinity synaptic GABA A receptor mediates tone-type inhibition, regulating neural excitability and signaling.
  • Yeung JY et al disclosed that low concentrations of GABA are more likely to activate ⁇ 5-GABA A receptors (Yeung JY et al (2003). Tonically activated GABA A receptors in hippocampal neurons are high-affinity, low-conductance sensors for extracellular GABA. Mol Pharmacol; 63:2–8).
  • KYLEE reported a low-concentration GABA-activated sustained high-affinity GABA A current on isolated DRG cells cultured for 24 hours, with 20 ⁇ M GABA-activated high-affinity GABA A currents reaching approximately 100 pA/pF. (Lee KY et al. Upregulation of high-affinity GABA (A) receptors in cultured rat dorsal root ganglion neurons.
  • ⁇ 5IA (US6200975B1) is a representative inverse agonist of the 5- ⁇ GABA A receptor.
  • the inventors detected the reverse activation efficiency of the substance to be tested by an electrophysiological method.
  • the specific method is as follows:
  • the GABA A receptor Different subunits of the GABA A receptor are expressed in the human renal epithelial cell line HEK-293 cell line.
  • the cells were cultured in a medium, and the cells were used as a cell model for screening drugs for inhibiting pain.
  • the alpha subunit, beta subunit and gamma subunit are essential for the formation of a complete functional GABA A receptor.
  • the inventors established the following cell models: (a) the ⁇ 5 subunit (see GenBank accession number: NP_001158509 for the protein sequence), the ⁇ 3 subunit (see GenBank accession number: NP_068712 for the protein sequence), and the ⁇ 2 subunit. (The protein sequence is shown in GenBank accession number: NP_944494) is simultaneously expressed in the HEK-293 cell line to constitute a fully functional receptor containing the ⁇ 5 subunit.
  • the cells are green fluorescent protein (GFP)-labeled HEK-293 cells stably expressing ⁇ 5 ⁇ 2 ⁇ 3-receptor.
  • 293 cells were cultured on 10 cm culture dishes, and cells were passaged to 80%-90% for passage.
  • the first medium is aspirated, then 3mL DMEM medium (Gibco TM) added to the culture dish, the dish slightly shaken, and then aspirated DMEM.
  • 3mL trypsin Trpsin-EDTA 0.05%, Gibco TM
  • the cell suspension is diluted 1:5 or 1:10.
  • the cell suspension is diluted in a ratio of 1:12, and a 24-well plate placed with a slide previously treated with Poly-D-Lysine is added. In the experiment, the cells were tested after adhering to the cells.
  • the cell culture time for electrophysiology is not more than 24 hours.
  • Drug concentration setting The final concentration of the drug used for drug screening is 100 nM, and the concentration of GABA is 0.05-0.1 ⁇ M.
  • the dose-reverse activation efficiency (%) test used a final concentration of 1 nM, 10 nM, 50 nM, 100 nM and 1000 nM.
  • the electrophysiological test uses whole-cell patch clamp technique, and the electrophysiological extracellular fluid components are as follows: 150 mM NaCl, 5 mM KCl, 2.5 mM CaCl 2 , 1 mM MgCl 2 , 10 mM HEPES and 10 mM glucose (pH 7.4); electrophysiological electrode solution
  • the formulation was as follows: 140 mM KCl, 5 mM EGTA, 10 mM HEPES (pH adjusted to 7.4 with KOH, osmotic pressure 320-330 mOsm).
  • the electrophysiology electrode solution was as follows: 140 mM KCl, 5 mM EGTA, 10 mM HEPES (pH adjusted to 7.4 with KOH, osmotic pressure 285-295 mOsm).
  • Signal acquisition uses the EPC 10 amplifier and the PatchMaster software (HEKA).
  • the recording electrode was drawn using borosilicate glass (Sutter) and the electrode resistance was 5 to 6 M ⁇ .
  • Extracellular administration employed OCTAFLOW II TM system. At the time of recording, GFP-positive and single independently growing cells were selected. During recording, the cell membrane potential was clamped at -60 mV. At the time of the test, an extracellular fluid was applied extracellularly for about 20 seconds. After the baseline is stabilized, the extracellular fluid is switched to GABA.
  • the current caused by GABA can be detected.
  • the extracellular fluid is switched to the corresponding drug solution to detect the effect of the drug.
  • the solution was switched to the extracellular fluid and the test was terminated until the baseline returned to the pre-dose level. Only the data that the baseline can reply to will be analyzed later.
  • GABA was diluted in the extracellular fluid at a final concentration of 0.05 to 0.1 ⁇ M. The drug is then diluted to the extracellular fluid containing GABA at the desired concentration.
  • the blood brain tissue distribution ratio was calculated by comparing the concentration levels of the compounds in rat plasma and brain tissue.
  • the experimental group animals were divided into 2 groups, plasma group and brain tissue group, 3 in each group.
  • the test compound was dissolved in 50% PEG400 at a drug dose of 10 mg/kg, and the animals were orally administered.
  • One hour after the administration, serum and brain samples were taken and detected by LC-MS/MS-AJ (Triple Quad 5500).
  • LC-MS/MS-AJ Multiple Quad 5500
  • the inventors have again verified the reverse activation efficiency of some substances to be tested by a new electrophysiological method.
  • the inventors refer to (I. Lecker, Y. Yin, DS Wang and BA Orser, (2013) Potentiation of GABA A receptor activity by volatile anaesthetics is reduced by ⁇ 5-GABA A receptor-preferring inverse agonists, British Journal of Anaesthesia 110(S1): i73–i81) reported method for electrophysiological extracellular fluid components as in the previous method: 150 mM NaCl, 5 mM KCl, 2.5 mM CaCl 2 , 1 mM MgCl 2 , 10 mM HEPES and 10 mM glucose (adjusted with NaOH) pH to 7.4, osmotic pressure is 320 mOsm).
  • the electrophysiological electrode solution was adjusted as follows: 140 mM CsCl, 10 mM HEPES, 11 mM EGTA, 2 mM MgCl 2 , 1 mM CaCl 2 , 4 mM MgATP, 2 mM TEA, (pH adjusted to 7.4 with CsOH, osmotic pressure 285-295 mOsm).
  • the GABA concentration range was adjusted to 0.1 to 0.3 ⁇ M.
  • the reverse agonistic efficiency of the test compound was taken as ⁇ 5IA as a reference compound, and the two batches of experimental data are as follows:
  • the blood brain tissue distribution ratio was calculated by comparing the concentration levels of the compounds in rat plasma and brain tissue.
  • the experimental group animals were divided into 2 groups, plasma group and brain tissue group, 3 in each group.
  • the test compound was dissolved in 50% PEG400 at a drug dose of 10 mg/kg, and the animals were orally administered.
  • One hour after the administration, serum and brain samples were taken and detected by LC-MS/MS-AJ (Triple Quad 5500).
  • LC-MS/MS-AJ Multiple Quad 5500

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Abstract

本发明提供一种通式（I）所示的化合物、其顺反异构体、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、或其药学上可以接受的盐和酯，其制备方法，含有该化合物的药物组合物以及所述化合物作为α5‐GABAA受体调节剂的用途，其中T、Z、A、Y如说明书中所定义。

Description

呔嗪类衍生物、其制备方法、药物组合物和用途 技术领域:
本发明涉及对α5‐GABAA受体具有调节功能的呔嗪类衍生物、它们的制备、含有它们的药物组合物和它们作为药物的应用。
背景技术:
γ‐氨基丁酸(GABA)是哺乳动物中枢神经系统中重要的抑制性神经递质，有两类GABA受体存在于自然界中，一类是GABAA受体，该类受体为配体门控离子通道超家族的成员，另一类是GABAB受体，该类受体是为G蛋白偶联受体超家族的成员。哺乳动物中的GABAA受体亚基被发现的有α1‐6、β1‐4、γ1‐3、δ、ε、θ和ρ1‐2等亚基，其中α亚基、β亚基和γ亚基对形成一个完整的功能型GABAA受体是必不可少的，而α亚基对苯二氮与GABAA受体的结合是至关重要的。
含α5的GABAA受体(α5‐GABAA受体)在哺乳动物大脑的GABAA受体中所占的比例小于5％，在大脑皮层中表达水平非常低，但在大脑海马组织中的GABAA受体中所占比例大于20％，其他大脑区域几乎不表达。考虑到α5‐GABAA受体的在大脑海马组织中特异性分布和功能研究，包括罗氏在内的许多制药公司从事于α5‐GABAA受体配体的研究，陆续有大量的化合物合成出来，特别是针对大脑海马组织的含α5亚基的GABAA受体的反向激动剂，其中α5IA和MRK‐016在动物疾病模型和人体试验中显示出良好的治疗认知类疾病的效果，特别是治疗阿尔茨海默氏病。普遍认为α5亚基的GABAA受体的反向激动剂可以用来治疗认知类疾病，特别是治疗阿尔茨海默氏病。专利申请US 2011 0224278 A1披露含α5亚基的GABAA受体的反向激动剂可用于治疗多梗塞性痴呆和中风相关疾病。
近十年的研究证明(Zlokovic et al.Nat Rev Neurosci.；12(12):723–738)在许多疾病状态下，尤其是神经退行性疾病、阿尔茨海默氏病和中风等，血脑屏障被破坏，即使那些原本无法进入大脑的物质也可以发挥相应的药理作用，因此原本无法跨过血脑屏障的α5亚基的GABAA受体的反向激动剂也可用于治疗阿尔茨海默氏病和中风。
2002年张旭实验室报道α5‐GABAA受体也主要表达在小神经元，并且在神经切断模型中表达升高(Xiao HS et al.,Identification of gene expression profile of dorsal root ganglion in the rat peripheral axotomy model of neuropathic pain.”Proc Natl Acad Sci U S A.2002年6月11日；99(12),专利申请CN103239720A披露α5‐GABAA受体在外周神经系统表达,在神经部分损伤模型中表达升高非常明显，并且α5‐GABAA受体的反向激动剂通过选择性地结合于外周神经系统的α5‐GABAA受体，发挥抑制各类疼痛的作用，动物实验模型数据显示，反向激动剂的反向激动效果越强，其抑制疼痛的效果越好。
检测一个化合物是否是针对包含α5亚基的GABAA受体的反向激动剂或者拮抗剂，这方面的研究工作已经做了很多，例如在国际申请专利WO 92/22652和WO 94/13799中，用GABAA受体的α5、β3和γ2组合来检测某一个化合物是否与该受体相结合；在进行药物筛选的过程中，通常用Goeders等(Goeders N E and Kuhar M J(1985)Benzodiazepine binding in vivo with[.sup.3H]Ro 15‐1788.Life Sci 37:345‐355)所述的方法。检测一个能与GABAA受体α5亚基结合的配体是拮抗剂、激动剂还是反向激动剂，在这一方面的研究也很多，可以参照Wafford等(Wafford K A，Whiting P J and Kemp J A(1993)Differences in affinity and efficacy of benzodiazepine receptor ligands on recombinantGABA.sub.A receptor subtypes.Mol.Pharmacol 43:240‐244)所述的方法。
筛选药物是否进入血脑屏障的办法比较广泛，在文献(Jones et al.,Pharmacokinetics and metabolism studies on(3‐tert‐butyl‐7‐(5‐methylisoxazol‐3‐yl)‐2‐(1‐methyl‐1H‐1,2,4‐triazol‐5‐ylmethoxy)pyrazolo[1,5‐d][1,2,4]triazine,a functionally selective GABAAα5inverse agonist for cognitive dysfunction.Bioorg Med Chem Lett.2006Feb 15；16(4):872‐5)中报道可以检测化合物抑制(3H)R0‐15‐1788(α5GABAA受体标记的特异性反向激动剂)在大脑中的结合，MRK016可以有效地抑制(3H)R0‐15‐1788在中枢的结合，而MRK016‐M3却几乎不能显著的抑制(3H)R0‐15‐1788在中枢的结合。也可以通过检测药物在不同组织的方法检测，例如检测药物在大脑和血浆中的分布比例来确定药物是否可以有效进入血脑屏障。
以往的研究发现使用药物或基因方法抑制或者降低α5GABAA受体介导的突出外抑制效果可以改善认知和学习能力，但同时会导致轻微焦虑样行为。 (Brickley,S.G.&Mody,I.Extrasynaptic GABAA receptors:their function in the CNS and implications for disease.Neuron 73,23–34(2012).；Harris,D.et al.Selective influence on contextual memory:physiochemical properties associated with selectivity of benzodiazepine ligands at GABAA receptors containing the alpha5subunit.J.Med.Chem.51,3788–3803(2008).；Savic′,M.M.et al.PWZ‐029,a compound with moderate inverse agonist functional selectivity at GABAA receptors containingα5subunits,improves passive,but not active,avoidance learning in rats.Brain Res.1208,150–159(2008)；Clément,Y.et al.Gabra5‐gene haplotype block associated with behavioral properties of the full agonist benzodiazepine chlordiazepoxide.Behav.Brain Res.233,474–482(2012)).。研究发现恐惧和焦虑特质与Gabra5mRNA的降低相关。(Heldt,S.A.&Ressler,K.J.Training‐induced changes in the expression of GABAAassociated genes in the amygdala after the acquisition and extinction of Pavlovian fear.Eur.J.Neurosci.26,3631–3644(2007).；Tasan,R.O.et al.Altered GABA transmission in a mouse model of increased trait anxiety.Neuroscience 183,71–80(2011).)。Paolo Botta等披露了α5GABAA受体参与焦虑和恐惧的机制。在脑区域特异性的敲除α5GABAA受体表达会导致动物产生恐惧和焦虑行为。由此，过往披露的α5GABAA反向激动剂进入大脑会产生恐惧和焦虑的副作用，不可能直接应用于医药领域，必须对其进行改造。
发明内容
本发明的一个目的在于提供通式(I)，(II)、(III)或(IV)所示的化合物、其顺反异构体、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、或其药学上可以接受的盐和酯。
本发明的另一个目的在于提供通式(I)，(II)、(III)或(IV)所示化合物的制备方法。
本发明的另一个目的在于提供通式(I)，(II)、(III)或(IV)所示化合物作为α5‐GABAA受体调节剂的用途，从而在制备用于预防、治疗或改善与α5‐GABAA受体有关的疾病的药物中的应用，所述疾病如认知疾病、阿尔茨海默氏病、记忆障碍、唐氏综合征、肌萎缩侧索硬化症(ALS)、药物成瘾、下肢不宁综合征、认知不足、多梗塞性痴呆、疼痛、中风和注意缺陷，或者在制备缓解疼痛药物中的用途。
本发明的另一个目的在于提供一种药物组合物，其包含一种或多种有效治疗剂量的通式(I),(II)、(III)或(IV)所示化合物或其药学上可以接受的盐，以及药学上可以接受的载体和/或辅助剂。
本发明的另一个目的在于提供一种预防、治疗或改善与α5‐GABAA受体有关的疾病的方法，包括给予本发明所述的通式(I),(II)、(III)或(IV)所示化合物或其药学上可以接受的盐或本发明所述的组合物。
在本发明的第一方面，提供式I所示的化合物，其顺反异构体、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、或其药学上可以接受的盐和酯，
Figure PCTCN2016108975-appb-000001
T表示C3‐7环烷基，C4‐7环烯基，C6‐8二环烷基，C6‐10芳基，C3‐7杂环烷基；优选地T表示苯基；
Z表示含有1、2或3个独立选自氧、氮和硫的杂原子的5元杂芳环；所述5元杂芳环被一个或多个选自以下的取代基任选取代：羟基，卤素，‐R1，‐OR1，‐OC(O)R1，‐NR2R3，CN，氰基(C1‐6)烷基‐或R2；优选地，Z表示含有1、2或3个独立选自氧、氮和硫的杂原子的5元杂芳环，其中最多有1个杂原子为氧或硫，并且当1个杂原子为氮原子时，至少也存在1个氧或硫原子，所述5元杂芳环被一个或多个选自以下的取代基任选取代：C1‐C4烷基、羟基、卤素、羟基或氨基取代的C1‐C4烷基、C2‐C4链烯基、C2‐C4炔基、C1‐C4烷氧基；更优选地Z表示含有1或2个独立选自氧、氮和硫的杂原子的5元杂芳环，并且最多有1个杂原子为氧或硫，而且当1个杂原子为氮原子时，也存在1个氧原子或1个硫原子；优选地Z表示含有2个独立选自氧、氮和硫的杂原子的5元杂芳环，并且一个杂原子为氧或硫，另一个原子为氮；所述5元杂芳环被一个 或多个选自以下的取代基任选取代：C1‐6烷基或羟基C1‐6烷基；优选地Z表示氧杂二氮唑、呋喃基、噻吩基或异噁唑基，所述氧杂二氮唑、呋喃基、噻吩基或异噁唑基被一个或多个选自以下的取代基任选取代：C1‐6烷基或羟基C1‐6烷基；
R1表示C1‐6烷基，C2‐6链烯基，C2‐6炔基，C3‐6环烷基，C3‐6环烷基(C1‐6)烷基，氰基(C1‐6)烷基，羟基或氨基取代的C1‐6烷基，且R1任选为一、二或三氟代的；
R2或R3独立地为氢，C1‐6烷基，C2‐6链烯基，C2‐6炔基，C3‐6环烷基或CF3，或R2和R3与它们共同连接的氮原子一起形成4‐7元杂脂肪环，该杂脂肪环含有所述氮原子和一个任选自O、N和S的其它杂原子，所述杂脂肪环任选被一个或多个R1基团任选取代；
A为‐NR2‐；或A为含有1、2、3或4个独立选自氧、氮和硫的杂原子的5元杂亚芳基且杂原子中最多有1个为氧或硫；或为含有1、2或3个氮原子的6元杂亚芳基，或所述5或6元杂亚芳基还任选地稠合于苯环或吡啶环上，所述5或6元杂亚芳基任选被Rx和/或Ry和/或Rz取代，其中Rx为卤素、‐R1、‐OR1、‐OC(O)R1、‐C(O)OR1、‐NR2R3、‐NR2C(O)R3、‐OH、‐CN，Ry为卤素、‐R1、‐OR1、‐OC(O)R1、‐NR2R3、‐NR2C(O)R3、或CN，Rz为‐R1、‐OR1或‐OC(O)R1，前提是当A为吡啶衍生物时，该吡啶环任选为N‐氧化物形式；或A为被1、2或3个独立选自以下的基团任选取代的亚苯基：卤素、氰基、C1‐6烷基、C2‐6链烯基、C2‐6炔基和C3‐6环烷基；优选地A表示含有1、2或3个独立选自氧、氮和硫的杂原子的5元杂亚芳基且杂原子中最多有1个为氧或硫，或含有1、2或3个氮原子的6元杂亚芳基或亚苯基；所述5元杂亚芳基、6元杂亚芳基和亚苯基任选地被选自以下的取代基取代：卤素、氰基、C1‐6烷基；优选地A表示亚苯基、亚吡啶基、亚异噁唑基；任选地被1、2或3个独立选自以下的取代基取代：卤素、氰基、C1‐6烷基；
Y为‐NY1Y2或‐NH‐NY3Y4；
Y1选自：H；C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基独立地选自：氨基，卤素，卤代‐C1‐6烷氧基，羟基，C1‐6烷氧基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐，硝基和C1‐6烷基‐S(O)2‐；
Y2选自：H；C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基独 立地选自：氨基，卤素，卤代‐C1‐6烷氧基，羟基，C1‐6烷氧基，环烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐，硝基和C1‐6烷基‐S(O)2‐；杂芳基，或被1‐4个取代基取代的杂芳基，所述杂芳基的取代基独立地选自：乙酰胺基，乙酰基，乙酰基氨基，酰氨基，氨基，羧基，氰基，卤素，卤代‐C1‐6烷氧基，卤代‐C1‐6烷基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐，硝基和C1‐6烷基‐S(O)2‐；环烷基，或被1‐4个取代基取代的环烷基，所述的取代基单独地选自：乙酰胺基，乙酰基，乙酰基氨基，酰氨基，氨基，羧基，氰基，卤素，卤代‐C1‐6烷氧基，卤代‐C1‐6烷基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐，硝基和C1‐6烷基‐S(O)2‐；杂环烷基，或被1‐4个取代基取代的杂环烷基，所述取代基单独地选自：乙酰胺基，乙酰基，乙酰基氨基，酰氨基，氨基，羧基，氰基，卤素，卤代‐C1‐6烷氧基，卤代‐C1‐6烷基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐，硝基和C1‐6烷基‐S(O)2‐；
Y2优选地为C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基单独地选自：氨基，卤素，卤代‐C1‐6烷氧基，羟基，C1‐6烷氧基，C3‐C6环烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐，硝基和C1‐6烷基‐S(O)2‐；
含有1‐3个选自N、O或S的杂原子的C3‐C7杂芳基，被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的C3‐C7杂芳基，所述C3‐C7杂芳基的取代基独立地选自：乙酰胺基，乙酰基，乙酰基氨基，酰氨基，氨基，羧基，氰基，卤素，卤代‐C1‐6烷氧基，卤代‐C1‐6烷基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐，硝基和C1‐6烷基‐S(O)2‐；
C3‐67环烷基，被1‐4个取代基取代的C3‐7环烷基，所述取代基单独地选自：乙酰胺基，乙酰基，乙酰基氨基，酰氨基，氨基，羧基，氰基，卤素，卤代‐C1‐6烷氧基，卤代‐C1‐6烷基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐，硝基和C1‐6烷基‐S(O)2‐；
含有1‐3个选自N、O或S的杂原子的C3‐C7‐杂环烷基，被1‐4个取代基取 代的含有1‐3个选自N、O或S的杂原子的C3‐C7杂环烷基，所述取代基单独地选自：乙酰胺基，乙酰基，乙酰基氨基，酰氨基，氨基，羧基，氰基，卤素，卤代‐C1‐6烷氧基，卤代‐C1‐6烷基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基，硝基和C1‐6烷基‐S(O)2‐；
优选地Y2为C1‐6烷基；被羟基或卤素或C1‐6烷氧基取代的C1‐6烷基；吗啉基；C3‐6环烷基；羟基取代的C3‐6环烷基；被C1‐6烷基任选取代的吡唑基；四氢呋喃基、四氢吡喃基；
或者Y1、Y2与它们所连接的N原子一起形成4‐6元杂环烷基，所述杂环烷基除了含有氮原子外，还含有零个、一个或多个选自O和S的杂原子，并且所述S原子可以为其氧化物形式；
优选地Y1、Y2与它们所连接的N原子一起形成氮杂环丁基、吗啉基、哌啶基、吡咯烷基、二氧硫代吗啉基、一氧硫代吗啉基；Y1、Y2与它们所连接的N原子一起形成选自氮杂环丁‐1‐基、吗啉‐4‐基、哌啶‐1‐基、吡咯烷‐1‐基、1‐氧代‐硫代吗啉‐4‐基和1，1‐二氧代‐硫代吗啉‐4‐基；
Y3，Y4相互独立选自：氢、C1‐C6烷基、SO2‐C1‐C6烷基、环烷基和杂环基，任选被1‐4个独立选自下列基团的取代基取代：卤素、氰基、羟基、C1‐C6烷基和C1‐C6烷氧基，或者其中Y3，Y4与它们所连接的氮原子一起形成杂环基，该杂环基任选被1‐4个独立选自下列基团的取代基取代：卤素、氰基、羟基、氧代、C1‐C6烷基和C1‐C6烷氧基；
优选地Y3，Y4相互独立选自：氢、C1‐C6烷基、SO2‐C1‐C6烷基、C3‐7环烷基和C3‐7杂环基，任选被1‐4个独立选自下列基团的取代基取代：卤素、氰基、羟基、C1‐C6烷基和C1‐C6烷氧基，或者其中Y3，Y4与它们所连接的氮原子一起形成C3‐C7杂环基,更优选地，所述C3‐C7杂环基为哌啶基、吗啉基、硫代吗啉基、二氧硫代吗啉基、一氧硫代吗啉基和吡咯烷基，所述哌啶基、吗啉基、硫代吗啉基、二氧硫代吗啉基一氧硫代吗啉基和吡咯烷基任选被1‐4个独立选自下列基团的取代基取代：卤素、氰基、羟基、氧代、C1‐6烷基和C1‐6烷氧基，更优选地Y3，Y4相互独立选自：氢、C1‐C6烷基和SO2‐C1‐C6烷基，Y3和Y4与它们所连接的氮原子一起形成吗啉‐4‐基、哌啶‐1‐基、吡咯烷‐1‐基和1，1‐二氧代‐硫代吗啉‐4‐基。
本发明还提供具有以下通式II的化合物：
Figure PCTCN2016108975-appb-000002
其中
Z表示含有1、2或3个独立选自氧、氮和硫的杂原子的5元杂芳环，其中最多有1个杂原子为氧或硫，并且当1个杂原子为氮原子时，至少也存在1个氧或硫原子，所述5元杂芳环被一个或多个选自以下的取代基任选取代：C1‐C4烷基、羟基、卤素、羟基或氨基取代的C1‐C4烷基、C2‐C4链烯基、C2‐C4炔基、C1‐C4烷氧基；
A为含有1、2或3个独立选自氧、氮和硫的杂原子的5元杂亚芳基且杂原子中最多有1个为氧或硫，或含有1、2或3个氮原子的6元杂亚芳基或亚苯基；所述5元杂亚芳基、6元杂亚芳基和亚苯基任选地被选自以下的取代基取代：卤素、氰基、C1‐6烷基；
Y为‐NY1Y2或‐NH‐NY3Y4；
Y1是H，C1‐6烷基或被1‐5个取代基取代的C1‐6烷基；所述取代基单独地选自：氨基，羟基，C1‐6烷氧基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基单独地选自：氨基，羟基，C1‐6烷氧基，环烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，被C1‐6烷基取代的含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，
C3‐6环烷基，被1‐4个取代基取代的C3‐6环烷基，所述取代基单独地选自：氨基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
含有1‐3个选自N、O或S的杂原子的C4‐C6‐杂环烷基，被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的C4‐C6杂环烷基，所述取代基单独地选自：氨基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基和C1‐6烷基‐S(O)2‐；
或者Y1、Y2与它们所连接的N原子一起形成4‐6元杂环烷基，所述杂环烷基除了含有氮原子外，还含有零个、一个或多个选自O和S的杂原子，并且所述S原子可以为其氧化物形式；
Y3，Y4相互独立选自：氢、C1‐C6烷基、SO2‐C1‐C6烷基，或者Y3和Y4与它们所连接的氮原子一起形成杂环基，所述杂环基选自哌啶基、吗啉基、二氧硫代吗啉基和一氧硫代吗啉基。
在一优选的实施方式中，通式I或II中的Z表示含有2个独立选自氧、氮和硫的杂原子的5元杂芳环，并且一个杂原子为氧或硫，另一个原子为氮；所述5元杂芳环被一个或多个选自以下的取代基任选取代：C1‐6烷基或羟基C1‐6烷基。
在一优选的实施方式中，通式I或II中的Z表示氧杂二氮唑、呋喃基、噻吩基或异噁唑基，所述异噁唑基被一个或多个选自以下的取代基任选取代：H，C1‐6烷基或羟基C1‐6烷基。
在一优选的实施方式中，通式I或II中的A表示亚苯基、亚吡啶基、亚异噁唑基；任选地被1、2或3个独立选自以下的取代基取代：卤素、氰基、C1‐6烷基。
在一优选的实施方式中，通式I或II中的Z表示氧杂二氮唑、呋喃基、噻吩基或异噁唑基，所述异噁唑基被一个或多个选自以下的取代基任选取代：H，C1‐6烷基或羟基C1‐6烷基；A表示亚苯基、亚吡啶基、亚异噁唑基；任选地被1、2或3个独立选自以下的取代基取代：卤素、氰基、C1‐6烷基。
在一优选的实施方式中，通式I或II中的Z表示氧杂二氮唑、呋喃基、噻吩 基或异噁唑基，所述异噁唑基被一个或多个选自以下的取代基任选取代：H，C1‐6烷基或羟基C1‐6烷基；A表示亚苯基、亚吡啶基、亚异噁唑基；任选地被1、2或3个独立选自以下的取代基取代：卤素、氰基、C1‐6烷基；Y为‐NY1Y2或‐NH‐NY3Y4；Y1是H或C1‐6烷基；
Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基单独地选自：氨基，羟基，C1‐6烷氧基；
含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，被C1‐6烷基取代的含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，
C4‐6环烷基，被1‐4个取代基取代的C3‐6环烷基，所述取代基单独地选自：羟基；
含有1‐3个选自N、O或S的杂原子的C4‐C6‐杂环烷基，被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的C4‐C6杂环烷基；
或Y1和Y2与它们所连接的氮原子一起形成吗啉基、哌啶基、一氧代‐硫代吗啉基和二氧代‐硫代吗啉基；
Y3和Y4相互独立选自：氢、甲基和SO2‐甲基,Y3和Y4与它们所连接的氮原子一起形成杂环基,选自吗啉基、哌啶基和二氧代‐硫代吗啉‐基。
在一优选的实施方式中，通式I或II中的Z表示氧杂二氮唑、呋喃基、噻吩基或异噁唑基，所述异噁唑基被一个或多个选自以下的取代基任选取代：H，C1‐6烷基或羟基C1‐6烷基；
A表示亚苯基、亚吡啶基、亚异噁唑基；任选地被1、2或3个独立选自以下的取代基取代：卤素、氰基、C1‐6烷基；
Y为‐NY1Y2或‐NH‐NY3Y4；
Y1是H或C1‐6烷基；
Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基单独地选自：羟基，C1‐6烷氧基；
含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，被C1‐6烷基取代的含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，
C4‐6环烷基，被1‐4个取代基取代的C3‐6环烷基，所述取代基单独地选自：羟基；
含有1‐3个选自N、O或S的杂原子的C4‐C6‐杂环烷基，被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的C4‐C6杂环烷基；
或Y1和Y2与它们所连接的氮原子一起形成吗啉基和哌啶基；
Y3和Y4相互独立选自：氢、甲基和SO2‐甲基,Y3和Y4与它们所连接的氮原子一起形成杂环基,选自吗啉‐4‐基、哌啶‐1‐基和1，1‐二氧代‐硫代吗啉‐4‐基。
在一优选的实施方式中，通式I或II中的Z表示氧杂二氮唑、呋喃基、噻吩基或异噁唑基，所述异噁唑基被一个或多个选自以下的取代基任选取代：H，C1‐6烷基或羟基C1‐6烷基。
A表示亚苯基、亚吡啶基、亚异噁唑基；任选地被1、2或3个独立选自以下的取代基取代：卤素、氰基、C1‐6烷基。
Y为‐NY1Y2或‐NH‐NY3Y4；
Y1是H或甲基；
Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基单独地选自：羟基，C1‐6烷氧基；
Y3和Y4相互独立选自：氢和甲基,Y3和Y4与它们所连接的氮原子一起形成杂环基,选自吗啉‐4‐基、哌啶‐1‐基和1，1‐二氧代‐硫代吗啉‐4‐基。
在一优选的实施方式中，通式I或II中，Z表示氧杂二氮唑、呋喃基、噻吩基或异噁唑基，所述异噁唑基被一个或多个选自以下的取代基任选取代：H，C1‐6烷基或羟基C1‐6烷基；
A表示亚苯基、亚吡啶基、亚异噁唑基；任选地被1、2或3个独立选自以下的取代基取代：卤素、氰基、C1‐6烷基；
Y为‐NY1Y2或‐NH‐NY3Y4；
Y1是H或甲基；
Y2选自甲基、乙基、甲氧基乙基或羟基丙基；
Y3和Y4相互独立选自：氢和甲基,Y3和Y4与它们所连接的氮原子一起形成杂环基,选自吗啉‐4‐基、哌啶‐1‐基和1，1‐二氧代‐硫代吗啉‐4‐基。
本发明还提供具有以下通式III的化合物:
Figure PCTCN2016108975-appb-000003
其中
R4为C1‐C4烷基、羟基取代的C1‐C4烷基；
Y为‐NY1Y2或‐NH‐NY3Y4；
Y1是H，C1‐6烷基或被1‐5个取代基取代的C1‐6烷基；所述取代基单独地选自：氨基，羟基，C1‐6烷氧基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基单独地选自：氨基，羟基，C1‐6烷氧基，环烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，被C1‐6烷基取代的含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基C3‐6环烷基，被1‐4个取代基取代的C3‐6环烷基，所述取代基单独地选自：氨基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
含有1‐3个选自N、O或S的杂原子的C4‐C6‐杂环烷基，被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的C4‐C6杂环烷基，所述取代基单独地选自：氨基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基和C1‐6烷基‐S(O)2‐；
或者Y1、Y2与它们所连接的N原子一起形成4‐6元杂环烷基，所述杂环烷基除了含有氮原子外，还含有零个、一个或多个选自O和S的杂原子，并且所述S原子可以为其氧化物形式。
Y3，Y4相互独立选自：氢、C1‐C6烷基、SO2‐C1‐C6烷基，或者Y3和Y4与 它们所连接的氮原子一起形成杂环基，选自哌啶基、吗啉基、二氧硫代吗啉基和一氧硫代吗啉基。
本发明还提供具有以下通式IV的化合物
Figure PCTCN2016108975-appb-000004
Y为‐NY1Y2或‐NH‐NY3Y4；
Y1是H，C1‐6烷基或被1‐5个取代基取代的C1‐6烷基；所述取代基独立地选自：氨基，羟基，C1‐6烷氧基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基独立地选自：氨基，羟基，C1‐6烷氧基，环烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，被C1‐6烷基取代的含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，
C3‐6环烷基，被1‐4个取代基取代的C3‐6环烷基，所述取代基独立地选自：氨基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
含有1‐3个选自N、O或S的杂原子的C4‐C6‐杂环烷基，被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的C4‐C6杂环烷基，所述取代基独立地选自：氨基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基和C1‐6烷基‐S(O)2‐；
或者Y1、Y2与它们所连接的N原子一起形成4‐6元杂环烷基，所述杂环烷基除了含有氮原子外，还含有零个、一个或多个选自O和S的杂原子，并且所述S原子可以为其氧化物形式；
Y3，Y4相互独立选自：氢、C1‐C6烷基、SO2‐C1‐C6烷基，或者Y3和Y4与它们所连接的氮原子一起形成杂环基，选自哌啶基、吗啉基、二氧硫代吗啉基和一氧硫代吗啉基。
在一优选的实施方式中，通式IV的化合物中，Y为‐NY1Y2或‐NH‐NY3Y4；
Y1是H，C1‐6烷基或被1‐5个取代基取代的C1‐6烷基；所述取代基独立地选自：氨基，羟基，C1‐6烷氧基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基独立地选自：氨基，羟基，C1‐6烷氧基；
含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，被C1‐6烷基取代的含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，
C4‐6环烷基，被1‐4个取代基取代的C3‐6环烷基，所述取代基独立地选自：羟基；
含有1‐3个选自N、O或S的杂原子的C4‐C6‐杂环烷基，被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的C4‐C6杂环烷基；
或Y1和Y2与它们所连接的氮原子一起形成吗啉基、哌啶基、一氧代‐硫代吗啉基和二氧代‐硫代吗啉基；
Y3和Y4相互独立选自：氢、甲基和SO2‐甲基,Y3和Y4与它们所连接的氮原子一起形成杂环基,选自吗啉基、哌啶基和二氧代‐硫代吗啉基。
在一优选的实施方式中，所述化合物具有以下通式IV:
Figure PCTCN2016108975-appb-000005
Y为‐NY1Y2或‐NH‐NY3Y4；
Y1是H或C1‐6烷基；
Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基单独地选自：羟基，C1‐6烷氧基；
含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，被C1‐6烷基取代的含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，
C4‐6环烷基，被1‐4个取代基取代的C3‐6环烷基，所述取代基单独地选自：羟基；
含有1‐3个选自N、O或S的杂原子的C4‐C6‐杂环烷基，被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的C4‐C6杂环烷基；
或Y1和Y2与它们所连接的氮原子一起形成吗啉基和哌啶基；
Y3和Y4相互独立选自：氢、甲基和SO2‐甲基,Y3和Y4与它们所连接的氮原子一起形成杂环基,选自吗啉‐4‐基、哌啶‐1‐基和1，1‐二氧代‐硫代吗啉‐4‐基。
在一优选的实施方式中，所述化合物具有以下通式IV:
Figure PCTCN2016108975-appb-000006
Y为‐NY1Y2或‐NH‐NY3Y4；
Y1是H或甲基；
Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基单独地选自：羟基，C1‐6烷氧基；
Y3和Y4相互独立选自：氢和甲基,Y3和Y4与它们所连接的氮原子一起形成杂环基,选自吗啉‐4‐基、哌啶‐1‐基和1，1‐二氧代‐硫代吗啉‐4‐基。
在一优选的实施方式中，所述化合物具有以下通式IV:
Figure PCTCN2016108975-appb-000007
Y为‐NY1Y2或‐NH‐NY3Y4；
Y1是H或甲基；
Y2选自选自甲基、乙基、2‐甲氧基乙基或羟基丙基；
Y3和Y4相互独立选自：氢和甲基,与它们所连接的氮原子一起形成杂环基,,选自吗啉‐4‐基、哌啶‐1‐基和1，1‐二氧代‐硫代吗啉‐4‐基。
在一优选的实施方式中，所述通式I的化合物选自以下化合物：
Figure PCTCN2016108975-appb-000008
Figure PCTCN2016108975-appb-000009
Figure PCTCN2016108975-appb-000010
Figure PCTCN2016108975-appb-000011
Figure PCTCN2016108975-appb-000012
Figure PCTCN2016108975-appb-000013
Figure PCTCN2016108975-appb-000014
Figure PCTCN2016108975-appb-000015
Figure PCTCN2016108975-appb-000016
在一优选的实施方式中，所述通式I的化合物选自以下化合物：
Figure PCTCN2016108975-appb-000017
在本发明的第二方面，本发明提供一种式I所示的化合物，其顺反异构体、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、或其药学上可以接受的盐和酯，
Figure PCTCN2016108975-appb-000018
T表示C3-7环烷基，C4-7环烯基，C6-8二环烷基，C6-10芳基，C3-7杂环烷基；优选地T表示苯基；
Z表示含有1、2或3个独立选自氧、氮和硫的杂原子的5元杂芳环；所述5元杂芳环被一个或多个选自以下的取代基任选取代：羟基，卤素，-R1，-OR1，-OC(O)R1，-NR2R3，CN，氰基(C1-6)烷基-或R2；优选地，Z表示含有1、2或3个独立选自氧、氮和硫的杂原子的5元杂芳环，其中最多有1个杂原子为氧或硫，并且当1个杂原子为氮原子时，至少也存在1个氧或硫原子，所述5元杂芳环被一个或多个选自以下的取代基任选取代：C1‐C4烷基、羟基、卤素、羟基或氨基取代的C1‐C4烷基、C2‐C4链烯基、C2‐C4炔基、C1‐C4烷氧基；更优选地，Z表示含有2个独立选自氧、氮和硫的杂原子的5元杂芳环，并且一个杂原子为氧或硫，另一个原子为氮；所述5元杂芳环被一个或多个选自以下的取代基任选取代：C1-6烷基或羟基C1-6烷基；
R1表示C1-6烷基，C2-6链烯基，C2-6炔基，C3-6环烷基，C3-6环烷基(C1-6)烷基，氰基(C1-6)烷基，羟基或氨基取代的C1-6烷基，且R1任选为一、二或三氟代的；
R2或R3独立地为氢，C1-6烷基，C2-6链烯基，C2-6炔基，C3-6环烷基或CF3，或R2和R3与它们共同连接的氮原子一起形成4-7元杂脂肪环，该杂脂肪环含有所述氮原子和一个任选自O、N和S的其它杂原子，所述杂脂肪环任选被一个或多个R1基团任选取代；
A为-NR2-；或A为含有1、2、3或4个独立选自氧、氮和硫的杂原子的5元杂亚芳基且杂原子中最多有1个为氧或硫；或为含有1、2或3个氮原子的6元杂亚芳基，或所述5或6元杂亚芳基还任选地稠合于苯环或吡啶环上，所述5或6元杂亚芳基任选被Rx和/或Ry和/或Rz取代，其中Rx为 卤素、-R1、-OR1、-OC(O)R1、-C(O)OR1、-NR2R3、-NR2C(O)R3、-OH、-CN，Ry为卤素、-R1、-OR1、-OC(O)R1、-NR2R3、-NR2C(O)R3、或CN，Rz为-R1、-OR1或-OC(O)R1，前提是当A为吡啶衍生物时，该吡啶环任选为N-氧化物形式；或A为被1、2或3个独立选自以下的基团任选取代的亚苯基：卤素、氰基、C1-6烷基、C2-6链烯基、C2-6炔基和C3-6环烷基；优选地，A为含有1、2或3个独立选自氧、氮和硫的杂原子的5元杂亚芳基且杂原子中最多有1个为氧或硫，或含有1、2或3个氮原子的6元杂亚芳基或亚苯基；所述5元杂亚芳基、6元杂亚芳基和亚苯基任选地被选自以下的取代基取代：卤素、氰基、C1‐6烷基；
Y为-NY1Y2或-NH-NY3Y4；
Y1选自：H；C1-6烷基；被1-5个取代基取代的C1-6烷基，所述取代基独立地选自：氨基，卤素，卤代-C1-6烷氧基，羟基，C1-6烷氧基，(C1-6烷基，C1-6烷基)N-，(C1-6烷基，H)N-，硝基和C1-6烷基-S(O)2-；
Y2选自：H；C1-6烷基-S(O)2-；氨基；NH-S(O)2-；C1-6烷氧基；C1-6烷基，或被1-5个取代基取代的C1-6烷基，所述取代基独立地选自：氨基，取代的氨基，卤素，卤代-C1-6烷氧基，羟基，C1-6烷氧基，羧基，环烷基，(C1-6烷基，C1-6烷基)N-，(C1-6烷基，H)N-，硝基，C1-6烷基-S(O)2-，杂环烷基，或被1-4个取代基取代的杂环烷基，所述取代基单独地选自：乙酰胺基，乙酰基，乙酰基氨基，酰氨基，氨基，羧基，氰基，卤素，卤代-C1-6烷氧基，卤代-C1-6烷基，羟基，羟基-C1-6烷基，C1-6烷氧基，C1-6烷氧基-C1-6烷基，C1-6烷基，(C1-6烷基，C1-6烷基)N-，(C1-6烷基，H)N-，硝基和C1-6烷基-S(O)2-；杂芳基，或被1-4个取代基取代的杂芳基，所述杂芳基的取代基独立地选自：乙酰胺基，乙酰基，乙酰基氨基，酰氨基，氨基，羧基，氰基，卤素，卤代-C1-6烷氧基，卤代-C1-6烷基，羟基，羟基-C1-6烷基，C1-6烷氧基，C1-6烷氧基-C1-6烷基，C1-6烷基，(C1-6烷基，C1-6烷基)N-，(C1-6烷基，H)N-，硝基和C1-6烷基-S(O)2-；环烷基，或被1-4个取代基取代的环烷基，所述的取代基单独地选自：乙酰胺基，乙酰基，乙酰基氨基，酰氨基，氨基，羧基，氰基，卤素，卤代-C1-6烷氧基，卤代-C1-6烷基，羟基，羟基-C1-6烷基，C1-6烷氧基，C1-6烷氧基-C1-6烷基，C1-6烷基，(C1-6烷基，C1-6烷基)N-，(C1-6烷基，H)N-，硝基和C1-6烷基-S(O)2-；杂环烷基，或被 1-4个取代基取代的杂环烷基，所述取代基单独地选自：乙酰胺基，乙酰基，乙酰基氨基，酰氨基，氨基，羧基，氰基，卤素，卤代-C1-6烷氧基，卤代-C1-6烷基，羟基，羟基-C1-6烷基，C1-6烷氧基，C1-6烷氧基-C1-6烷基，C1-6烷基，(C1-6烷基，C1-6烷基)N-，(C1-6烷基，H)N-，硝基和C1-6烷基-S(O)2-；优选地，Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基单独地选自：氨基，取代的氨基，羟基，C1‐6烷氧基，羧基，卤素，环烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐，杂环烷基，或被1-4个取代基取代的杂环烷基，所述取代基单独地选自：乙酰胺基，乙酰基，C1-6烷氧基，C1-6烷基；
H；C1-6烷基-S(O)2-；氨基；NH-S(O)2-；C1-6烷氧基；
含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，被C1‐6烷基取代的含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基；
C3‐6环烷基，被1‐4个取代基取代的C3‐6环烷基，所述取代基单独地选自：氨基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
含有1‐3个选自N、O或S的杂原子的C4‐C6‐杂环烷基，被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的C4‐C6杂环烷基，所述取代基单独地选自：氨基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，乙酰基，二氧硫代基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基和C1‐6烷基‐S(O)2‐；
或者Y1、Y2与它们所连接的N原子一起形成4-6元杂环烷基，所述杂环烷基除了含有氮原子外，还含有零个、一个或多个选自O和S的杂原子，并且所述S原子可以为其氧化物形式；
或者Y1、Y2与它们所连接的N原子一起形成被1-4个取代基取代的含有1-3个选自N、O或S的杂原子的4-6元杂环烷基，并且所述S原子可以为其氧化物形式；所述取代基单独地选自：C1-6烷基，C1-6烷基-S(O)2-，C1-6烷氧基，卤代C1-6烷基，NH2C(＝O)-，卤素；
或者Y1和Y2与它们所连接的氮原子一起形成C5-10氧杂氮杂双环烷基；
优选地，Y1和Y2与它们所连接的氮原子一起形成吗啉基、哌啶基、哌嗪基、氮杂环丁基、氧杂氮杂双环庚烷；所述吗啉基、哌啶基、哌嗪基、氮杂环丁基、氧杂氮杂双环庚烷任选地被1-4个选自下组的取代基取代：C1-6烷基，C1-6 烷基-S(O)2-，C1-6烷氧基，卤素，NH2C(＝O)-；所述吗啉基中的S原子还可以为其氧化物形式；
Y3，Y4相互独立选自：氢、C1-C6烷基、SO2-C1-C6烷基、环烷基和杂环基，任选被1-4个独立选自下列基团的取代基取代：卤素、氰基、羟基、C1-C6烷基和C1-C6烷氧基，
或者其中Y3，Y4与它们所连接的氮原子一起形成杂环基，该杂环基任选被1-4个独立选自下列基团的取代基取代：卤素、氰基、羟基、氧代、C1-C6烷基和C1-C6烷氧基；
优选地Y3，Y4相互独立选自：氢、C1‐C6烷基、SO2‐C1‐C6烷基、C3‐7环烷基和C3‐7杂环基，任选被1‐4个独立选自下列基团的取代基取代：卤素、氰基、羟基、C1‐C6烷基和C1‐C6烷氧基，或者其中Y3，Y4与它们所连接的氮原子一起形成C3‐C7杂环基,更优选地，所述C3‐C7杂环基为哌啶基、吗啉基、硫代吗啉基、二氧硫代吗啉基、一氧硫代吗啉基和吡咯烷基，所述哌啶基、吗啉基、硫代吗啉基、二氧硫代吗啉基一氧硫代吗啉基和吡咯烷基任选被1‐4个独立选自下列基团的取代基取代：卤素、氰基、羟基、氧代、C1‐6烷基和C1‐6烷氧基，更优选地Y3，Y4相互独立选自：氢、C1‐C6烷基和SO2-C1‐C6烷基，Y3和Y4与它们所连接的氮原子一起形成吗啉-4-基、哌啶-1-基、吡咯烷-1-基和1，1-二氧代-硫代吗啉-4-基。
以上所有选自取代基团中氢原子可以被氘取代。
在一优选的实施方式中，所述化合物具有以下通式II，
Figure PCTCN2016108975-appb-000019
其中
Z表示含有1、2或3个独立选自氧、氮和硫的杂原子的5元杂芳环，其中 最多有1个杂原子为氧或硫，并且当1个杂原子为氮原子时，至少也存在1个氧或硫原子，所述5元杂芳环被一个或多个选自以下的取代基任选取代：C1‐C4烷基、羟基、卤素、羟基或氨基取代的C1‐C4烷基、C2‐C4链烯基、C2‐C4炔基、C1‐C4烷氧基；
A为含有1、2或3个独立选自氧、氮和硫的杂原子的5元杂亚芳基且杂原子中最多有1个为氧或硫，或含有1、2或3个氮原子的6元杂亚芳基或亚苯基；所述5元杂亚芳基、6元杂亚芳基和亚苯基任选地被选自以下的取代基取代：卤素、氰基、C1‐6烷基；
Y为‐NY1Y2或‐NH‐NY3Y4；
Y1是H，C1‐6烷基或被1‐5个取代基取代的C1‐6烷基；所述取代基单独地选自：氨基，羟基，C1‐6烷氧基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基单独地选自：氨基，取代的氨基，羟基，C1‐6烷氧基，羧基，卤素，环烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐，杂环烷基，或被1-4个取代基取代的杂环烷基，所述取代基单独地选自：乙酰胺基，乙酰基，C1-6烷氧基，C1-6烷基；
H；C1-6烷基-S(O)2-；氨基；NH-S(O)2-；C1-6烷氧基；
含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，被C1‐6烷基取代的含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基；
C3‐6环烷基，被1‐4个取代基取代的C3‐6环烷基，所述取代基单独地选自：氨基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
含有1‐3个选自N、O或S的杂原子的C4‐C6‐杂环烷基，被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的C4‐C6杂环烷基，所述取代基单独地选自：氨基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，乙酰基，二氧硫代基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基和C1‐6烷基‐S(O)2‐；
或者Y1、Y2与它们所连接的N原子一起形成4‐6元杂环烷基，所述杂环烷基除了含有氮原子外，还含有零个、一个或多个选自O和S的杂原子，并且所述S原子可以为其氧化物形式；
或者Y1、Y2与它们所连接的N原子一起形成被1-4个取代基取代的含有1-3个选自N、O或S的杂原子的4-6元杂环烷基，并且所述S原子可以为其氧化物形式，所述取代基单独地选自：C1-6烷基，C1-6烷基-S(O)2-，C1-6烷氧基，卤代C1-6烷基，NH2C(＝O)-，卤素；
或者Y1和Y2与它们所连接的氮原子一起形成C5-10氧杂氮杂双环烷基；
Y3，Y4相互独立选自：氢、C1‐C6烷基、SO2‐C1‐C6烷基，或者Y3和Y4与它们所连接的氮原子一起形成杂环基，所述杂环基选自哌啶基、吗啉基、二氧硫代吗啉基和一氧硫代吗啉基。
在一优选的实施方式中，通式I或II中的Z表示含有2个独立选自氧、氮和硫的杂原子的5元杂芳环，并且一个杂原子为氧或硫，另一个原子为氮；所述5元杂芳环被一个或多个选自以下的取代基任选取代：C1-6烷基或羟基C1-6烷基。
在一优选的实施方式中，通式I或II中的Z表示氧杂二氮唑、呋喃基、噻吩基或异噁唑基，所述异噁唑基被一个或多个选自以下的取代基任选取代：H，C1‐6烷基或羟基C1‐6烷基。
在一优选的实施方式中，通式I或II中的A表示亚苯基、亚吡啶基、亚异噁唑基；任选地被1、2或3个独立选自以下的取代基取代：卤素、氰基、C1‐6烷基。
在一优选的实施方式中，通式I或II中的Z表示氧杂二氮唑、呋喃基、噻吩基或异噁唑基，所述异噁唑基被一个或多个选自以下的取代基任选取代：H，C1‐6烷基或羟基C1‐6烷基；
A表示亚苯基、亚吡啶基、亚异噁唑基；任选地被1、2或3个独立选自以下的取代基取代：卤素、氰基、C1‐6烷基。
在一优选的实施方式中，通式I或II中的Z表示氧杂二氮唑、呋喃基、噻吩基或异噁唑基，所述异噁唑基被一个或多个选自以下的取代基任选取代： H，C1‐6烷基或羟基C1‐6烷基；
A表示亚苯基、亚吡啶基、亚异噁唑基；任选地被1、2或3个独立选自以下的取代基取代：卤素、氰基、C1‐6烷基；
Y为‐NY1Y2或‐NH‐NY3Y4；
Y1是H或C1‐6烷基；
Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基单独地选自：氨基，取代的氨基，羟基，C1‐6烷氧基，羧基，卤素，C1-6烷基-S(O)2-；环烷基，杂环烷基，或被1-4个取代基取代的杂环烷基，所述取代基单独地选自：乙酰胺基，乙酰基，C1-6烷氧基，C1-6烷基；
H；C1-6烷基-S(O)2-；氨基；NH-S(O)2-；C1-6烷氧基；
含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，被烷基取代的含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基；
C4‐6环烷基，环丙基，被1‐4个取代基取代的C3‐6环烷基，所述取代基单独地选自：羟基，C1‐6烷基，C1‐6烷氧基；
含有1‐3个选自N、O或S的杂原子的C4‐C6‐杂环烷基，被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的C4‐C6杂环烷基，所述取代基单独地选自：C1‐6烷基，乙酰基，二氧硫代基；
或者Y1、Y2与它们所连接的N原子一起形成4‐6元杂环烷基，所述杂环烷基除了含有氮原子外，还含有零个、一个或多个选自O和S的杂原子，并且所述S原子可以为其氧化物形式；
或者Y1、Y2与它们所连接的N原子一起形成被1-4个取代基取代的含有1-3个选自N、O或S的杂原子的4-6元杂环烷基，并且所述S原子可以为其氧化物形式；所述取代基单独地选自：C1-6烷基，C1-6烷基-S(O)2-，C1-6烷氧基，卤代C1-6烷基，NH2C(＝O)-，卤素；
或者Y1和Y2与它们所连接的氮原子一起形成C5-10氧杂氮杂双环烷基；
Y3和Y4相互独立选自：氢、甲基和‐SO2‐甲基,Y3和Y4与它们所连接的氮原子一起形成杂环基,选自吗啉基、哌啶基和二氧代‐硫代吗啉‐基。
在一优选的实施方式中，通式I或II中Z表示氧杂二氮唑、呋喃基、噻吩基或异噁唑基，所述异噁唑基被一个或多个选自以下的取代基任选取代：H， C1‐6烷基或羟基C1‐6烷基；
A表示亚苯基、亚吡啶基、亚异噁唑基；任选地被1、2或3个独立选自以下的取代基取代：卤素、氰基、C1‐6烷基；
Y为‐NY1Y2或‐NH‐NY3Y4；
Y1是H或C1‐6烷基；
Y2选自C1-6烷基；被1-5个取代基取代的C1-6烷基，所述取代基单独地选自：羟基，C1-6烷氧基，酰氨基，卤素，羧基，C3-6环烷基，含有1-3个选自N、O或S的杂原子的C4-C6-杂环烷基，C1-6烷基-S(O)2-；
H基；C1-6烷基-S(O)2-；氨基；NH-S(O)2-；C1-6烷氧基；
含有1-3个选自N、O或S的杂原子的C5-C6杂芳基，被烷基取代的含有1-3个选自N、O或S的杂原子的C5-C6杂芳基，
C4-6环烷基，环丙基，被1-4个取代基取代的C3-6环烷基，所述取代基单独地选自：羟基，C1‐6烷基，C1‐6烷氧基；
含有1-3个选自N、O或S的杂原子的C4-C6-杂环烷基，被1-4个取代基取代的含有1-3个选自N、O或S的杂原子的C4-C6杂环烷基，所述取代基单独地选自：C1‐6烷基，乙酰基，二氧硫代基；
或Y1和Y2与它们所连接的氮原子一起形成吗啉基、哌啶基、哌嗪基、氮杂环丁基、氧杂氮杂双环庚烷；所述吗啉基、哌啶基、哌嗪基、氮杂环丁基、氧杂氮杂双环庚烷任选地被1-4个选自下组的取代基取代：C1-6烷基，C1-6烷基-S(O)2-，C1-6烷氧基，卤素，NH2C(＝O)-；所述吗啉基中的S原子还可以为其氧化物形式；
Y3和Y4相互独立选自：氢、甲基和SO2-甲基,Y3和Y4与它们所连接的氮原子一起形成杂环基,选自吗啉-4-基、哌啶-1-基和1，1‐二氧代‐硫代吗啉‐4‐基。
在一优选的实施方式中，通式I或II中的Z表示氧杂二氮唑、呋喃基、噻吩基或异噁唑基，所述异噁唑基被一个或多个选自以下的取代基任选取代：H，C1‐6烷基或羟基C1‐6烷基；
A表示亚苯基、亚吡啶基、亚异噁唑基；任选地被1、2或3个独立选自以下的取代基取代：卤素、氰基、C1‐6烷基；
Y为‐NY1Y2或‐NH‐NY3Y4；
Y1是H或甲基；
Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基单独地选自：羟基，C1‐6烷氧基，乙酰氨基，氟基，羧基，吗啉基，环丙基，四氢呋喃；
H基；C1‐6烷基‐S(O)2‐；氨基；NH‐S(O)2‐；C1‐6烷氧基；
含有1-3个选自N、O或S的杂原子的C5-C6杂芳基，被烷基取代的含有1-3个选自N、O或S的杂原子的C5-C6杂芳基；
C3‐6环烷基；被1‐4个取代基取代的C3‐6环烷基，所述的取代基单独地选自：羟基，甲氧基，甲基；
含有1‐3个选自N、O或S的杂原子的C4‐C6杂环烷基；被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的杂环烷基，所述取代基单独地选自：甲基，乙酰基；
或Y1和Y2与它们所连接的氮原子一起形成吗啉基、哌啶基、哌嗪基、氮杂环丁基、氧杂氮杂双环庚烷；所述吗啉基、哌啶基、哌嗪基、氮杂环丁基、氧杂氮杂双环庚烷任选地被1-4个选自下组的取代基取代：甲基，甲氧基，氟，NH2C(＝O)-；所述吗啉基中的S原子还可以为其氧化物形式；
Y3和Y4相互独立选自：氢和甲基,Y3和Y4与它们所连接的氮原子一起形成杂环基,选自吗啉‐4‐基、哌啶‐1‐基和1，1‐二氧代‐硫代吗啉‐4‐基。
在一优选的实施方式中，通式I或II中的Z表示氧杂二氮唑、呋喃基、噻吩基或异噁唑基，所述异噁唑基被一个或多个选自以下的取代基任选取代：H，C1‐6烷基或羟基C1‐6烷基；
A表示亚苯基、亚吡啶基、亚异噁唑基；任选地被1、2或3个独立选自以下的取代基取代：卤素、氰基、C1‐6烷基；
Y为‐NY1Y2或‐NH‐NY3Y4；
Y1是H或甲基；
Y2选自甲基、乙基、甲氧基乙基，羟基丙基，乙酰氨乙基，H，‐CH2COOH，羟基环戊基，环丙烷基，甲基吡唑基，吗啡啉基，羟乙基，丁基，甲基哌啶基，吗啡啉基乙基，四氢呋喃基，甲氧基环戊基，乙酰基吡咯烷基，四氢 呋喃基亚甲基，二氟乙基，环丙基甲基，甲磺酰基乙基，三氟乙基，异丙基，四氢吡喃，环丁基，氨基，哌啶基，甲磺酰基，二氧硫代吗啉基，羟基甲基乙基；
或者Y1和Y2与它们所连接的氮原子一起形成甲基哌嗪基，甲酰胺基哌啶基，甲氧基哌啶基，二氟哌啶基，氧杂氮杂双环庚烷，二氧硫代吗啉基，吗啉基，氮杂环丁基，一氧硫代吗啉基；
Y3和Y4相互独立选自：氢和甲基,Y3和Y4与它们所连接的氮原子一起形成杂环基,选自吗啉‐4‐基、哌啶‐1‐基和1，1‐二氧代‐硫代吗啉‐4‐基。
在一优选的实施方式中，化合物具有以下通式III:
Figure PCTCN2016108975-appb-000020
其中
R4为C1‐C4烷基、羟基取代的C1‐C4烷基；
Y为‐NY1Y2或‐NH‐NY3Y4；
Y1是H，C1‐6烷基或被1‐5个取代基取代的C1‐6烷基；所述取代基单独地选自：氨基，羟基，C1‐6烷氧基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基单独地选自：氨基，取代的氨基，羟基，C1‐6烷氧基，羧基，卤素，环烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐，C1‐6烷基‐S(O)2‐，杂环烷基，或被1-4个取代基取代的杂环烷基，所述取代基单独地选自：乙酰胺基，乙酰基，C1-6烷氧基，C1-6烷基；
H；C1-6烷基-S(O)2-；氨基；NH-S(O)2-；C1-6烷氧基；
含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基；被C1‐6烷基取代的含 有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基；
C3‐6环烷基；被1‐4个取代基取代的C3‐6环烷基，所述取代基单独地选自：氨基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
含有1‐3个选自N、O或S的杂原子的C4‐C6‐杂环烷基；被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的C4‐C6杂环烷基，所述取代基单独地选自：氨基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，乙酰基，二氧硫代基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基和C1‐6烷基‐S(O)2‐；
或者Y1、Y2与它们所连接的N原子一起形成4‐6元杂环烷基，所述杂环烷基除了含有氮原子外，还含有零个、一个或多个选自O和S的杂原子，并且所述S原子可以为其氧化物形式；
或者Y1、Y2与它们所连接的N原子一起形成被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的4‐6元杂环烷基，并且所述S原子可以为其氧化物形式所述取代基单独地选自：C1‐6烷基，C1‐6烷基‐S(O)2‐，C1‐6烷氧基，卤代C1‐6烷基，NH2C(＝O)‐，卤素；
或者Y1和Y2与它们所连接的氮原子一起形成C5‐10氧杂氮杂双环烷基；
Y3，Y4相互独立选自：氢、C1‐C6烷基、SO2‐C1‐C6烷基，或者Y3和Y4与它们所连接的氮原子一起形成杂环基，选自哌啶基、吗啉基、二氧硫代吗啉基和一氧硫代吗啉基。
在一优选的实施方式中，化合物具有以下通式IV:
Figure PCTCN2016108975-appb-000021
Y为‐NY1Y2或‐NH‐NY3Y4；
Y1是H，C1‐6烷基或被1‐5个取代基取代的C1‐6烷基，所述取代基独立地选自：氨基，羟基，C1‐6烷氧基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐ 和C1‐6烷基‐S(O)2‐；
Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基独立地选自：氨基，取代的氨基，羟基，C1‐6烷氧基，羧基，卤素，环烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐，C1‐6烷基‐S(O)2，杂环烷基，或被1-4个取代基取代的杂环烷基，所述取代基单独地选自：乙酰胺基，乙酰基，C1-6烷氧基，C1-6烷基；
H；C1‐6烷基‐S(O)2‐；氨基；NH‐S(O)2‐；C1‐6烷氧基；
含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基；被C1‐6烷基取代的含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基；
C3‐6环烷基；被1‐4个取代基取代的C3‐6环烷基，所述取代基独立地选自：氨基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
含有1‐3个选自N、O或S的杂原子的C4‐C6‐杂环烷基，被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的C4‐C6杂环烷基，所述取代基独立地选自：氨基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，乙酰基，二氧硫代基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基和C1‐6烷基‐S(O)2‐；
或者Y1、Y2与它们所连接的N原子一起形成4‐6元杂环烷基，所述杂环烷基除了含有氮原子外，还含有零个、一个或多个选自O和S的杂原子，并且所述S原子可以为其氧化物形式；
或者Y1、Y2与它们所连接的N原子一起形成被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的4‐6元杂环烷基，并且所述S原子可以为其氧化物形式，所述取代基单独地选自：C1‐6烷基，C1‐6烷基‐S(O)2‐，C1‐6烷氧基，卤代C1‐6烷基，NH2C(＝O)‐，卤素；
或者Y1和Y2与它们所连接的氮原子一起形成C5‐10氧杂氮杂双环烷基；
Y3，Y4相互独立选自：氢、C1‐C6烷基、SO2‐C1‐C6烷基，或者Y3和Y4与它们所连接的氮原子一起形成杂环基，选自哌啶基、吗啉基、二氧硫代吗啉基和一氧硫代吗啉基。
在一优选的实施方式中，化合物具有以下通式IV:
Figure PCTCN2016108975-appb-000022
Y为‐NY1Y2或‐NH‐NY3Y4；
Y1是H，C1‐6烷基或被1‐5个取代基取代的C1‐6烷基，所述取代基独立地选自：氨基，羟基，C1‐6烷氧基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基独立地选自：氨基，取代的氨基，羟基，C1-6烷氧基，卤素，羧基，C3-6环烷基，含有1-3个选自N、O或S的杂原子的C4-C6-杂环烷基；
H；C1-6烷基-S(O)2-；氨基；NH-S(O)2-；C1-6烷氧基；
含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基；被C1‐6烷基取代的含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基；
C4‐6环烷基；环丙基；被1‐4个取代基取代的C3‐6环烷基，所述取代基独立地选自：羟基，C1‐6烷基，C1‐6烷氧基；
含有1‐3个选自N、O或S的杂原子的C4‐C6‐杂环烷基；被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的C4‐C6杂环烷基，所述取代基单独地选自：C1‐6烷基，乙酰基，二氧硫代基；
Y1和Y2与它们所连接的氮原子一起形成吗啉基、哌啶基、哌嗪基、氮杂环丁基、氧杂氮杂双环庚烷；所述吗啉基、哌啶基、哌嗪基、氮杂环丁基、氧杂氮杂双环庚烷任选地被1-4个选自下组的取代基取代：C1-6烷基，C1-6烷基-S(O)2-，C1-6烷氧基，卤素，NH2C(＝O)-；所述吗啉基中的S原子还可以为其氧化物形式；
Y3和Y4相互独立选自：氢、甲基和SO2‐甲基,Y3和Y4与它们所连接的氮原子一起形成杂环基,选自吗啉基、哌啶基和二氧代‐硫代吗啉基。
在一优选的实施方式中，化合物具有以下通式IV:
Figure PCTCN2016108975-appb-000023
Y为‐NY1Y2或‐NH‐NY3Y4；
Y1是H或C1‐6烷基；
Y2选自C1-6烷基；被1-5个取代基取代的C1-6烷基，所述取代基单独地选自：羟基，C1-6烷氧基，乙酰氨基，氟基，羧基，C3-6环烷基，含有1-3个选自N、O或S的杂原子的C4-C6-杂环烷基；
H；C1-6烷基-S(O)2-；氨基；NH-S(O)2-；C1-6烷氧基；
含有1-3个选自N、O或S的杂原子的C5-C6杂芳基；被甲基基取代的含有1-3个选自N、O或S的杂原子的C5-C6杂芳基；
C4-6环烷基；环丙基；被1-4个取代基取代的C3-6环烷基，所述取代基单独地选自：羟基，C1-6烷基，C1-6烷氧基；
含有1-3个选自N、O或S的杂原子的C4-C6-杂环烷基；被1-4个取代基取代的含有1-3个选自N、O或S的杂原子的C4-C6杂环烷基，所述取代基单独地选自：C1-6烷基，乙酰基，二氧硫代基；；
Y1和Y2与它们所连接的氮原子一起形成吗啉基、哌啶基、哌嗪基、氮杂环丁基、氧杂氮杂双环庚烷；所述吗啉基、哌啶基、哌嗪基、氮杂环丁基、氧杂氮杂双环庚烷任选地被1-4个选自下组的取代基取代：C1-6烷基，C1-6烷基-S(O)2-，C1-6烷氧基，卤素，NH2C(＝O)-；所述吗啉基中的S原子还可以为其氧化物形式；
Y3和Y4相互独立选自：氢、甲基和SO2-甲基,Y3和Y4与它们所连接的氮原子一起形成杂环基,选自吗啉-4-基、哌啶-1-基和1，1‐二氧代‐硫代吗啉‐4‐基。
在一优选的实施方式中，化合物具有以下通式IV:
Figure PCTCN2016108975-appb-000024
Y为‐NY1Y2或‐NH‐NY3Y4；
Y1是H或甲基；
Y2选自C1-6烷基；被1-5个取代基取代的C1-6烷基，所述取代基单独地选自：羟基，C1-6烷氧基，乙酰氨基，氟基，羧基，吗啉基，环丙基，四氢呋喃；
H；C1-6烷基-S(O)2-；氨基；NH-S(O)2-；C1-6烷氧基；
C3-6环烷基；被1-4个取代基取代的C3-6环烷基，所述的取代基单独地选自：羟基，甲氧基，甲基；
含有1-3个选自N、O或S的杂原子的C5-C6杂芳基；被甲基基取代的含有1-3个选自N、O或S的杂原子的C5-C6杂芳基；
含有1-3个选自N、O或S的杂原子的C4-C6杂环烷基；被1-4个取代基取代的含有1-3个选自N、O或S的杂原子的杂环烷基，所述取代基单独地选自：甲基，乙酰基，二氧硫代基；
Y1和Y2与它们所连接的氮原子一起形成吗啉基、哌啶基、哌嗪基、氮杂环丁基、氧杂氮杂双环庚烷；所述吗啉基、哌啶基、哌嗪基、氮杂环丁基、氧杂氮杂双环庚烷任选地被1-4个选自下组的取代基取代：C1-6烷基，C1-6烷基-S(O)2-，C1-6烷氧基，卤素，NH2C(＝O)-；所述吗啉基中的S原子还可以为其氧化物形式；
Y3和Y4相互独立选自：氢和甲基,Y3和Y4与它们所连接的氮原子一起形成杂环基,选自吗啉‐4‐基、哌啶‐1‐基和1，1‐二氧代‐硫代吗啉‐4‐基。
在一优选的实施方式中，化合物具有以下通式IV:
Figure PCTCN2016108975-appb-000025
Y为‐NY1Y2或‐NH‐NY3Y4；
Y1是H或甲基；
Y2选自甲基，乙基，2‐甲氧基乙基，羟基丙基，乙酰氨乙基，H，‐CH2COOH，羟基环戊基，环丙烷基，甲基吡唑基，吗啡啉基，羟乙基，丁基，甲基哌啶基，吗啡啉基乙基，四氢呋喃基，甲氧基环戊基，乙酰基吡咯烷基，四氢呋喃基亚甲基，二氟乙基，环丙基甲基，甲磺酰基乙基，三氟乙基，异丙基，四氢吡喃，环丁基，氨基，哌啶基，甲磺酰基，二氧硫代吗啉基，羟基甲基乙基；
或者Y1和Y2与它们所连接的氮原子一起形成甲基哌嗪基，甲酰胺基哌啶基，甲氧基哌啶基，二氟哌啶基，氧杂氮杂双环庚烷，二氧硫代吗啉基，吗啉基，氮杂环丁基，一氧硫代吗啉基；
Y3和Y4相互独立选自：氢和甲基,与它们所连接的氮原子一起形成杂环基,选自吗啉‐4‐基、哌啶‐1‐基和1，1‐二氧代‐硫代吗啉‐4‐基。
在一优选的实施方式中，化合物具有以下通式IV:
Figure PCTCN2016108975-appb-000026
Y为‐NY1Y2；
Y1是H基；
Y2选自甲基，乙基、甲氧基乙基，羟基丙基，乙酰氨乙基，H，‐CH2COOH，羟基环戊基，环丙烷基，甲基吡唑基，吗啡啉基，羟乙基，丁基，甲基哌啶基，吗啡啉基乙基，四氢呋喃基，甲氧基环戊基，乙酰基吡咯烷基，四氢呋喃基亚甲基，二氟乙基，环丙基甲基，甲磺酰基乙基，三氟乙基；
或者Y1和Y2与它们所连接的氮原子一起形成甲基哌嗪基，甲酰胺基哌啶基，甲氧基哌啶基，二氟哌啶基，氧杂氮杂双环庚烷。
在一优选的实施方式中，化合物具有以下通式II:
Figure PCTCN2016108975-appb-000027
其中
Z表示甲基异噁唑基；
A选自氰基亚苯基、亚吡啶基；
Y为‐NY1Y2；
Y1是H基；
Y2选自C1‐6烷基；被1‐3个C3‐6环烷基或C1‐6烷氧基取代的C1‐6烷基；C1‐6烷氧基。
在本发明的第三方面，本发明还提供一种组合物，其包含如上文所述的化合物或其药学上可以接受的盐。
在本发明的第四方面，本发明还提供如上所述的化合物或组合物在制备药物中的用途。
在本发明的第五方面，本发明还提供一种治疗或预防疾病的方法，包括 向患者施用有效剂量的如上所述的化合物或组合物。
在本发明的第六方面，本发明还提供本文所述的化合物或组合物在制备治疗或预防与α5‐GABAA受体有关的疾病的药物中的用途。
在本发明的第七方面，本发明还提供一种治疗或预防与α5‐GABAA受体有关的疾病的方法，其特征在于向患者施用有效剂量的本文所述的化合物或本文所述的组合物。
在本发明的第八方面，本发明还提供本文所述的化合物或组合物在制备治疗或预防下列疾病的药物中的用途：疼痛、阿尔茨海默氏病、多梗塞性痴呆和中风。
在一优选的实施方式中，所述的疼痛是神经病理性疼痛、炎性疼痛和癌性痛。
在一优选的实施方式中，所述的疼痛选自：头痛，面部痛，颈痛，肩痛，背痛，胸痛，腹痛，背部痛，腰痛，下肢痛，肌肉与骨骼疼痛，血管疼痛，痛风，关节炎疼痛，内脏疼痛，感染性疾病(如AIDS和带状疱疹后神经痛)导致的疼痛，多骨疼痛，镰刀细胞贫血、自身免疫性疾病、多发性硬化或炎症有关的疼痛，损伤或手术引起的慢性疼痛，伤害感受性疼痛，疼痛性糖尿病，三叉神经痛，腰部或子宫颈神经根病痛，舌咽神经痛，自主神经反射性疼痛，反射性交感神经营养不良、神经根撕脱、癌症、化学损伤、毒素、营养缺乏、病毒或细菌感染、退行性骨关节病有关的疼痛。
本发明还提供一种治疗或预防疼痛、阿尔茨海默氏病、多梗塞性痴呆和中风的方法，其特征在于向患者施用有效剂量的如本文所述的化合物或组合物。
在一优选的实施方式中，所述的疼痛是神经病理性疼痛、炎性疼痛和癌性痛。
在一优选的实施方式中，所述的疼痛选自：头痛，面部痛，颈痛，肩痛，背痛，胸痛，腹痛，背部痛，腰痛，下肢痛，肌肉与骨骼疼痛，血管疼痛， 痛风，关节炎疼痛，内脏疼痛，感染性疾病(如AIDS和带状疱疹后神经痛)导致的疼痛，多骨疼痛，镰刀细胞贫血、自身免疫性疾病、多发性硬化或炎症有关的疼痛，损伤或手术引起的慢性疼痛，伤害感受性疼痛，疼痛性糖尿病，三叉神经痛，腰部或子宫颈神经根病痛，舌咽神经痛，自主神经反射性疼痛，反射性交感神经营养不良、神经根撕脱、癌症、化学损伤、毒素、营养缺乏、病毒或细菌感染、退行性骨关节病有关的疼痛。
本发明还涉及生产上文定义的式(II)化合物的方法，该方法包括：
Figure PCTCN2016108975-appb-000028
a)使式(IV)化合物
Figure PCTCN2016108975-appb-000029
与
Figure PCTCN2016108975-appb-000030
反应得到式(1‐3)化合物，其中G和W选自Cl，Br，I，OH，OTs，OTf和OMs，R5是烷基，甲基，乙基，叔丁基和苄基；其中Z、Y、A如上文所定义；
然后使式(1‐3)化合物
Figure PCTCN2016108975-appb-000031
与Y反应，其中Z、Y、A如上文所定义；或者
b)使式(1‐4)的化合物：
Figure PCTCN2016108975-appb-000032
与Y反应，其中Z、Y、A如上文所定义；
c)将式(1‐3)的化合物皂化为式(1‐4)化合物，随后与Y反应，
其中，其中Z、Y、A如上文所定义；或
d)式
Figure PCTCN2016108975-appb-000033
化合物与式
Figure PCTCN2016108975-appb-000034
化合物的反应。
在本发明中的通式I的化合物中，T表示C3‐7环烷基，C4‐7环烯基，C6‐8二环烷基，C6‐10芳基，C3‐7杂环烷基；优选地T表示苯基。
在本发明中的通式I、II的化合物中，Z表示含有1、2或3个独立选自氧、氮和硫的杂原子的5元杂芳环；所述5元杂芳环被一个或多个选自以下的取代基任选取代：羟基，卤素，‐R1，‐OR1，‐OC(O)R1，‐NR2R3，CN，氰基(C1‐6)烷基‐或R2；其中R1表示C1‐6烷基，C2‐6链烯基，C2‐6炔基，C3‐6环烷基，C3‐6环烷基(C1‐6)烷基，氰基(C1‐6)烷基，羟基或氨基取代的C1‐6烷基，且R1任选为一、二或三氟代的；R2或R3独立地为氢，C1‐6烷基，C2‐6链烯基，C2‐6炔基，C3‐6环烷基或CF3，或R2和R3与它们共同连接的氮原子一起形成4‐7元杂脂肪环，该脂肪环含有所述氮原子和一个任选自O、N和S的其它杂原子，所述环任选被一个或多个R1基团任选取代；优选地，Z表示含有1、2或3个独立选自氧、氮和硫的杂原子的5元杂芳环，其中最多有1个杂原子为氧或硫，并且当1个杂原子为氮原子时，至少也存在1个氧或硫原子，所述5元杂芳环被一个或多个选自以下的取代基任选取代：C1‐C4烷基、羟基、卤素、羟基或氨基取代的C1‐C4烷基、C2‐C4链烯基、C2‐C4炔基、C1‐C4烷氧基；更优选地Z表示含有1或2个独立选自氧、氮和硫的杂原子的5元杂芳环，并且最多有1个杂原子为氧或硫，而且当1个杂原子为氮原子时，也存在1个氧原子或1个硫原子；优选地Z表示含有2个独立选自氧、氮和硫的杂原子的5 元杂芳环，并且一个杂原子为氧或硫，另一个原子为氮；所述5元杂芳环被一个或多个选自以下的取代基任选取代：C1‐6烷基或羟基C1‐6烷基；优选地Z表示氧杂二氮唑、呋喃基、噻吩基或异噁唑基，所述氧杂二氮唑、呋喃基、噻吩基或异噁唑基被一个或多个选自以下的取代基任选取代：C1‐6烷基或羟基C1‐6烷基；更优选地，Z表示氧杂二氮唑、呋喃基、噻吩基或异噁唑基，所述氧杂二氮唑、呋喃基、噻吩基或异噁唑基被一个或多个选自以下的取代基任选取代：甲基或羟基甲基。
在本发明中的通式I、II的化合物中，A为‐NR2‐；或A为含有1、2、3或4个独立选自氧、氮和硫的杂原子的5元杂亚芳基且杂原子中最多有1个为氧或硫，或为含有1、2或3个氮原子的6元杂亚芳基，或所述5或6元杂亚芳基还任选地稠合于苯环或吡啶环上，所述5或6元杂亚芳基任选被Rx和/或Ry和/或Rz取代，其中Rx为卤素、‐R1、‐OR1、‐OC(O)R1、‐C(O)OR1、‐NR2R3、‐NR2C(O)R3、‐OH、‐CN，Ry为卤素、‐R1、‐OR1、‐OC(O)R1、‐NR2R3、‐NR2C(O)R3、或CN，Rz为‐R1、‐OR1或‐OC(O)R1，前提是当A为吡啶衍生物时，该吡啶环任选为N‐氧化物形式；或A为被1、2或3个独立选自以下的基团任选取代的亚苯基：卤素、氰基、C1‐6烷基、C2‐6链烯基、C2‐6炔基和C3‐6环烷基；优选地A表示含有1、2或3个独立选自氧、氮和硫的杂原子的5元杂亚芳基且杂原子中最多有1个为氧或硫，或含有1、2或3个氮原子的6元杂亚芳基或亚苯基；所述5元杂亚芳基、6元杂亚芳基和亚苯基任选地被选自以下的取代基取代：卤素、氰基、C1‐6烷基；更优选地A表示亚苯基、亚吡啶基、亚异噁唑基；任选地被1、2或3个独立选自以下的取代基取代：卤素、氰基、C1‐6烷基；
在本发明中的通式I、II、III和IV的化合物中，Y为‐NY1Y2或‐NH‐NY3Y4；
Y1选自：H；C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基独立地选自：氨基，卤素，卤代‐C1‐6烷氧基，羟基，C1‐6烷氧基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐，硝基和C1‐6烷基‐S(O)2‐；优选地，Y1是H，C1‐6烷基或被1‐5个取代基取代的C1‐6烷基；所述取代基单独地选自：氨基，羟基，C1‐6烷氧基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；更优选地，Y1是H或C1‐6烷基；更优选地，Y1是H或甲基；
Y2选自：H；C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基独立地选自：氨基，卤素，卤代‐C1‐6烷氧基，羟基，C1‐6烷氧基，环烷基，(C1‐6 烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐，硝基和C1‐6烷基‐S(O)2‐；杂芳基，或被1‐4个取代基取代的杂芳基，所述杂芳基的取代基独立地选自：乙酰胺基，乙酰基，乙酰基氨基，酰氨基，氨基，羧基，氰基，卤素，卤代‐C1‐6烷氧基，卤代‐C1‐6烷基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐，硝基和C1‐6烷基‐S(O)2‐；环烷基，或被1‐4个取代基取代的环烷基，所述的取代基单独地选自：乙酰胺基，乙酰基，乙酰基氨基，酰氨基，氨基，羧基，氰基，卤素，卤代‐C1‐6烷氧基，卤代‐C1‐6烷基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐，硝基和C1‐6烷基‐S(O)2‐；杂环烷基，或被1‐4个取代基取代的杂环烷基，所述取代基单独地选自：乙酰胺基，乙酰基，乙酰基氨基，酰氨基，氨基，羧基，氰基，卤素，卤代‐C1‐6烷氧基，卤代‐C1‐6烷基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐，硝基和C1‐6烷基‐S(O)2‐；
Y2优选地为C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基单独地选自：氨基，卤素，卤代‐C1‐6烷氧基，羟基，C1‐6烷氧基，C3‐C6环烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐，硝基和C1‐6烷基‐S(O)2‐；
含有1‐3个选自N、O或S的杂原子的C3‐C7杂芳基，被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的C3‐C7杂芳基，所述C3‐C7杂芳基的取代基独立地选自：乙酰胺基，乙酰基，乙酰基氨基，酰氨基，氨基，羧基，氰基，卤素，卤代‐C1‐6烷氧基，卤代‐C1‐6烷基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐，硝基和C1‐6烷基‐S(O)2‐；
C3‐67环烷基，被1‐4个取代基取代的C3‐7环烷基，所述取代基单独地选自：乙酰胺基，乙酰基，乙酰基氨基，酰氨基，氨基，羧基，氰基，卤素，卤代‐C1‐6烷氧基，卤代‐C1‐6烷基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐，硝基和C1‐6烷基‐S(O)2‐；
含有1‐3个选自N、O或S的杂原子的C3‐C7‐杂环烷基，被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的C3‐C7杂环烷基，所述取代基单独地选自：乙酰胺基，乙酰基，乙酰基氨基，酰氨基，氨基，羧基，氰基，卤素，卤代‐C1‐6烷氧基，卤代‐C1‐6烷基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6 烷基，C1‐6烷基，硝基和C1‐6烷基‐S(O)2‐；
优选地，Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基单独地选自：氨基，羟基，C1‐6烷氧基，环烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，被C1‐6烷基取代的含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，
C3‐6环烷基，被1‐4个取代基取代的C3‐6环烷基，所述取代基单独地选自：氨基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
含有1‐3个选自N、O或S的杂原子的C4‐C6‐杂环烷基，被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的C4‐C6杂环烷基，所述取代基单独地选自：氨基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基和C1‐6烷基‐S(O)2‐；
更优选地，Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基单独地选自：氨基，羟基，C1‐6烷氧基；
含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，被烷基取代的含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，
C4‐6环烷基，被1‐4个取代基取代的C3‐6环烷基，所述取代基单独地选自：羟基；
含有1‐3个选自N、O或S的杂原子的C4‐C6‐杂环烷基，被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的C4‐C6杂环烷基；
优选地Y2为C1‐6烷基；被羟基或卤素或C1‐6烷氧基取代的C1‐6烷基；吗啉基；C3‐6环烷基；羟基取代的C3‐6环烷基；被C1‐6烷基任选取代的吡唑基；四氢呋喃基、四氢吡喃基；
优选地，Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基单独地选自：羟基，C1‐6烷氧基；
最优选地，Y2选自甲基、乙基、甲氧基乙基或羟基丙基。
或者Y1、Y2与它们所连接的N原子一起形成4‐6元杂环烷基，所述杂环烷基除了含有氮原子外，还含有零个、一个或多个选自O和S的杂原子，并且所述S原子可以为其氧化物形式；
优选地Y1、Y2与它们所连接的N原子一起形成氮杂环丁基、吗啉基、哌啶基、吡咯烷基、二氧硫代吗啉基、一氧硫代吗啉基；Y1、Y2与它们所连接的N原子一起形成选自氮杂环丁‐1‐基、吗啉‐4‐基、哌啶‐1‐基、吡咯烷‐1‐基、1‐氧代‐硫代吗啉‐4‐基和1，1‐二氧代‐硫代吗啉‐4‐基；
Y3，Y4相互独立选自：氢、C1‐C6烷基、SO2‐C1‐C6烷基、环烷基和杂环基，任选被1‐4个独立选自下列基团的取代基取代：卤素、氰基、羟基、C1‐C6烷基和C1‐C6烷氧基，或者其中Y3，Y4与它们所连接的氮原子一起形成杂环基，该杂环基任选被1‐4个独立选自下列基团的取代基取代：卤素、氰基、羟基、氧代、C1‐C6烷基和C1‐C6烷氧基；
优选地Y3，Y4相互独立选自：氢、C1‐C6烷基、SO2‐C1‐C6烷基、C3‐7环烷基和C3‐7杂环基，任选被1‐4个独立选自下列基团的取代基取代：卤素、氰基、羟基、C1‐C6烷基和C1‐C6烷氧基，优选地，Y3，Y4相互独立选自：氢、C1‐C6烷基、SO2‐C1‐C6烷基。
或者其中Y3，Y4与它们所连接的氮原子一起形成C3‐C7杂环基,更优选地，所述C3‐C7杂环基为哌啶基、吗啉基、硫代吗啉基、二氧硫代吗啉基、一氧硫代吗啉基和吡咯烷基，所述哌啶基、吗啉基、硫代吗啉基、二氧硫代吗啉基一氧硫代吗啉基和吡咯烷基任选被1‐4个独立选自下列基团的取代基取代：卤素、氰基、羟基、氧代、C1‐6烷基和C1‐6烷氧基，
更优选地，Y3，Y4相互独立选自：氢、C1‐C6烷基和SO2‐C1‐C6烷基，Y3和Y4与它们所连接的氮原子一起形成吗啉‐4‐基、哌啶‐1‐基、吡咯烷‐1‐基和1，1‐二氧代‐硫代吗啉‐4‐基。
更优选地，Y3和Y4相互独立选自：氢、甲基和SO2‐甲基,Y3和Y4与它们所连接的氮原子一起形成杂环基,选自吗啉基、哌啶基和二氧代‐硫代吗啉‐基。
优选地，Y3和Y4相互独立选自：氢、甲基和SO2‐甲基,Y3和Y4与它们所连接的氮原子一起形成杂环基,选自吗啉‐4‐基、哌啶‐1‐基和1，1‐二氧代‐硫代吗啉‐4‐基。
更优选地，Y3和Y4相互独立选自：氢和甲基,Y3和Y4与它们所连接的氮原子一起形成杂环基,选自吗啉‐4‐基、哌啶‐1‐基和1，1‐二氧代‐硫代吗啉‐4‐基。
具体实施方式
除特别指明外，下列定义用于说明和定义在本文中用于描述本发明时使用的各种术语的意义和范围。
无论是单独出现还是组合出现，一般术语的下列定义均适用。
本申请中使用的命名规则是基于AutoNomTM 2000，用于产生IUPAC系统命名的Beilstein Institute计算机化的系统。在本文中给出的化学结构是采用ChemDraw版本12得到的。在本文中给出的结构中的碳、氧、硫或氮原子上出现的任何开放价键表明存在氢原子。
除特别说明外，术语“取代的”是指指定的基团或部分可以具有1、2、3、4、5或6个取代基。当基团上可以具有多个取代基并且给出了多种可能的取代基时，所述取代基独立选择，不必是相同的。
术语“未取代的”是指指定的基团上不具有取代基。
术语“任选取代的”是指指定的基团是未取代的或者是被一个或多个独立选自可能的取代基的取代基所取代的。
当指明取代基的数目时，术语“一个或多个”是指一个取代至取代的最多可能的数目，即取代一个氢至所有的氢均被取代基取代。除特别指明外，优选1、2、3、4或5个取代基。
术语“卤素”是指氟、氯、溴和碘，优选氟。
本文所用的术语“低级烷基”是指含有1‐6个碳原子的直链或支链烷基，可以与本文中所述的C1‐6烷基互换，的C1‐6烷基的例子例如甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基以及下文中特别示例的那些基团。特别优选的“低级烷基”为甲基和正丁基。
术语“低级烷氧基”指基团‐O‐R，其中R为如上文所定义的低级烷基。
术语“环烷基”是指单价饱和的环状烃基，优选具有3‐7个环碳原子、更优选3‐6个碳原子的单价饱和的环状烃基，例如环丙基、环丁基、环戊基或环己基，以及下文中特别示例的那些基团。
术语“杂环基”是指具有杂原子的饱和或部分不饱和的单环或多环基团，优选含有1个、2个或3个选自N、O或S的环杂原子的单价3‐7元饱和或部分不饱和的单环环。优选含有1个或2个环杂原子。优选含有1个或2个选自 N、O或S的环杂原子的4‐6元杂环基。S可任选被两个氧代基团取代。杂环基的示例为吡咯烷基、四氢呋喃基、四氢吡喃基、四氢噻吩基、四氢吡啶基、四氢吡咯基、氮杂环丁烷基、噻唑烷基、唑烷基、哌啶基、吗啉基、硫代吗啉基、1，1‐二氧代‐硫代吗啉‐4‐基、哌嗪基、氮杂环庚烷基、二氮杂环庚烷基、氧氮杂环庚烷基或二氢‐唑基、以及下文中特别示例的那些基团。优选的杂环基为吗啉‐4‐基、哌啶‐1‐基、吡咯烷‐1‐基、硫代吗啉‐4‐基和1，1‐二氧代‐硫代吗啉‐4‐基，特别优选的杂环基为吗啉‐4‐基、吡咯烷‐1‐基和1，1‐二氧代‐硫代吗啉‐4‐基。
术语“芳基”是指含有6‐14个、优选6‐10碳原子并具有至少一个芳环或其中至少一个环为芳环的多稠合环的单价芳族碳环环系。芳基的示例为苯基、萘基、联苯基或茚满基，以及下文中特别示例的那些基团。优选的芳基为苯基，芳基也可以被取代，如下文和权利要求中所定义。
术语“杂芳基”是含有杂原子的芳香基团，优选含有1个、2个或3个选自氮、氧和/或硫的原子的芳族5‐6元单环或9‐10元双环，例如呋喃基、吡啶基、哒嗪基、嘧啶基、吡嗪基、噻吩基、异唑基、噁唑基、二唑基、咪唑基、吡咯基、吡唑基、三唑基、四唑基、噻唑基、异噻唑基、噻二唑基、苯并咪唑基、吲哚基、吲唑基、苯并噻唑基、苯并异噻唑基、苯并唑基、苯并异唑基、喹啉基或异喹啉基，以及下文中特别示例的那些基团。杂芳基也可以为取代的，如下文和权利要求中所定义。优选的杂芳基为5‐氟‐吡啶‐2‐基。
术语“被卤素取代的低级烷基”是指被卤素单或多取代的低级烷基。被卤素取代的低级烷基的示例为例如CFH2、CF2H、CF3、CF3CH2、CF3(CH2)2、(CF3)2CH或CF2H‐CF2，以及下文中特别示例的那些基团。
术语“被羟基取代的低级烷基”是指其中至少一个烷基中的氢原子被羟基取代的如上文所定义的低级烷基。被羟基取代的低级烷基的示例包括但不限于被一或多个羟基、特别是一个、两个或三个羟基、优选一个或两个羟基取代的甲基、乙基、丙基、异丙基、异丁基、仲‐丁基、叔‐丁基、戊基或正己基。
式(I)、(II)、(III)和IV)的化合物可以形成药学上可接受的酸加成盐。此类药学上可接受的盐的示例为式(I)、(II)、(III)和IV)化合物与生理学上相容的无机酸或有机酸形成的盐，无机酸为例如盐酸、硫酸、亚硫酸或磷酸； 有机酸为例如甲烷磺酸、p‐甲苯磺酸、乙酸、乳酸、三氟乙酸、柠檬酸、富马酸、马来酸、酒石酸、琥珀酸或水杨酸。术语“药学上可接受的盐”是指此类盐。含有酸性基团例如COOH的式(I)化合物还可以与碱形成盐。此类盐的示例为碱金属、碱土金属和铵盐，例如Na‐、K‐、Ca‐和三甲基铵盐。术语“药学上可接受的盐”也指此类盐。
术语“药学上可接受的酯”包括式(I)、(II)、(III)和IV)化合物的衍生物，其中羧基被转化为酯。低级烷基、被羟基取代的低级烷基、被低级烷氧基取代的低级烷基、氨基‐低级烷基、单‐或二低级烷基‐氨基‐低级烷基、吗啉代‐低级烷基、吡咯烷子基‐低级烷基、哌啶子基‐低级烷基、哌嗪子基‐低级烷基、低级烷基‐哌嗪子基‐低级烷基和芳基‐低级‐烷基酯是适当的酯的示例。优选甲基、乙基、丙基、丁基和苄基酯。术语“药学上可接受的酯”还包括式(I)化合物的衍生物，其中羟基被无机或有机酸转化为相应的酯，无机或有机酸为例如硝酸、硫酸、磷酸、柠檬酸、甲酸、马来酸、乙酸、琥珀酸、酒石酸、甲磺酸、p‐甲苯磺酸等，这些酸对生物体是无毒的。
制备方法
本发明还涉及生产上文定义的式(II)化合物的方法，该方法包括：
Figure PCTCN2016108975-appb-000035
本发明还涉及生产上文定义的式(II)化合物的方法，该方法包括：
a)使式(IV)化合物
Figure PCTCN2016108975-appb-000036
与
Figure PCTCN2016108975-appb-000037
反应，其中G和W为任选的Cl，Br，I，OH，OTs，OTf和OMs等；R5是烷基，甲基，乙基，叔丁基和苄基，然后
使式(1‐3)化合物
Figure PCTCN2016108975-appb-000038
与Y反应或者
b)使式(1‐4)的化合物：
Figure PCTCN2016108975-appb-000039
与Y反应；或
c)将式(1‐3)的化合物皂化为式(1‐4)化合物，随后与Y反应；或
d)式
Figure PCTCN2016108975-appb-000040
化合物与式
Figure PCTCN2016108975-appb-000041
化合物的反应，
其中Z、Y、A如上文所定义。
使式
Figure PCTCN2016108975-appb-000042
与
Figure PCTCN2016108975-appb-000043
反应，其中G和W是Cl，Br，I，OH，OTs，OTf和OMs等任选的取代基。反应可以在实例中所述的条件下或者在本领域技术人员已知的条件下进行。例如，所述反应可以在LDA，NaH，叔丁醇钾或钠等下、在适当的溶剂(如二氧六环)中、在室温下(如20℃)下进行。或者是利用Mitsunobu条件(PPh3，DEAD)、相转移催化剂(TBAB，冠醚)等生成醚的生产条件。
式
Figure PCTCN2016108975-appb-000044
化合物与Y反应得到式(I)化合物的反应可以在实例中所述的条件下或者在本领域技术人员已知的条件下进行。例如，所述反应可以在三甲基铝存在下、在适当的溶剂(如二氧六环)中、在升高的温度(如85‐95℃)下进行。
式
Figure PCTCN2016108975-appb-000045
化合物与Y反应得到式(II)化合物的反应可以在实例中所述的条件下或者在本领域技术人员已知的条件下进行。例如，所述反应可以在Hünigs碱(N，N‐二异丙基乙基胺)和O‐(苯并三唑‐1‐基)‐N，N，N′，N′‐四甲基脲四氟硼酸盐存在下、在适当的溶剂(如二甲基甲酰胺)中、在室温下进行。或者，该反应可以在1，1′‐羰基二咪唑存在下、在适当的溶剂(如二甲基甲酰胺)中、在升高的温度(如80℃)下进行。此外，该反应还可以在1‐乙基‐3‐(3‐二甲基氨基丙基)碳二亚胺盐酸盐、N1‐羟基苯并三唑和Hünigs碱(N，N‐二异丙基乙基胺)存在下、在适当的溶剂(如二氯甲烷)中、于室温下进行。
式
Figure PCTCN2016108975-appb-000046
化合物皂化为式(1‐4)化合物的反应可以在实例中所述的条件下或者在本领域技术人员已知的条件下进行。例如，所述反应可以在氢 氧化钠存在下、在适当的溶剂(如水)中、在室温下进行。或者，所述反应可以在氢氧化钠或氢氧化锂存在下、在适当的溶剂(如四氢呋喃或水)中、在室温下进行。或者是其它所述的条件下或者在本领域技术人员已知的条件下进行，比如氢化脱掉苄基类的，酸性条件水解叔丁基等等条件。
式
Figure PCTCN2016108975-appb-000047
化合物与式
Figure PCTCN2016108975-appb-000048
化合物的反应得到式(II)化合物的反应可以在实例中所述的条件下或者在本领域技术人员已知的条件下进行。例如，例如，所述反应可以在LDA，NaH，叔丁醇钾或钠等下、在适当的溶剂(如二氧六环、THF和DMF等)中、在室温下(如20℃)下进行。或者是利用Mitsunobu条件(PPh3，DEAD)、相转移催化剂(TBAB，冠醚等)等生成醚的生产条件。在适当的溶剂(如二氧六环、THF和DMF等)中、在升高的温度(如80℃)下进行，在相应的碱或催化剂条件下生成产物。
本发明还涉及如上所述的式(II)化合物，是通过如上所述的方法制备的。
本发明的式(II)化合物及其药学上可接受的盐可以通过下列方法制备。
如果没有在实施例中描述其制备方法，那么式(II)化合物及其中间体产物可以根据类似的方法或者根据前述方法制备。本领域已知的原料可以得自商业，或者可以根据本领域已知的方法或已知方法的类似方法制备。
可以理解，本发明的通式(II)化合物可以在官能团上衍生，从而得到能够在体内再转化为母体化合物的衍生物。
如果没有在实施例中描述其制备方法，那么式(II)化合物及其中间体产物可以根据类似的方法或者根据前述方法制备。本领域已知的原料可以得自商业，或者可以根据本领域已知的方法或已知方法的类似方法制备。
可以理解，本发明的通式(II)化合物可以在官能团上衍生，从而得到能够在体内再转化为母体化合物的衍生物。
如上所述，本发明的新化合物及其药学上可接受的盐和酯具有重要的药理学性质，为α5GABAA受体反向激动剂。因此，本发明化合物可以单独使用或与其他药物组合使用，用于治疗或预防由含有α5亚单位的GABAA受体配体介导的疾病。这些疾病包括但不限于疼痛、阿尔茨海默氏病、多梗塞性痴呆和中 风。
因此，本发明还涉及药用组合物，该药用组合物包括如上文所定义的化合物和药学上可接受的载体和/或辅助剂。
同样，本发明还包括如上所述的化合物，用作制备治疗或预防与α5GABAA受体有关的疾病的药物，尤其是治疗或预防下列疾病：疼痛、阿尔茨海默氏病、多梗塞性痴呆和中风。
优选治疗或预防疼痛。
特别优选治疗或预防神经病理性痛、炎性疼痛和癌性痛。
如本文所用，“癌性痛”是指恶性肿瘤在其发展过程中出现的疼痛，癌性痛发生目前认为有三种机制，即：癌症发展直接造成的疼痛、癌症治疗后造成的疼痛和癌症患者并发疼痛性疾病。
如本文所用，“神经病理性痛”是为由神经系统原发性损害和功能障碍所激发或引起的疼痛。
如本文所用，“炎性疼痛”是局部急性炎症或是慢性炎症刺激神经所致的疼痛。
如本文所用，“治疗”也包括预防性给药，一旦所述病症建立后缓解或消除所述病症。
如本文所用，“患者”定义为任何温血动物，例如不限于小鼠、豚鼠、狗、马或人，所述患者最好是人。
如本文所用，“急性疼痛”定义为由皮肤、身体结构或内脏的损伤和/或疾病发生的有害刺激而引起的疼痛，或由不产生实际组织损害的肌肉或内脏的异常功能而引起的疼痛。
如本文所用，“慢性疼痛”定义为持续超出急性疾病通常的病程或损伤治愈的合理时间，或与引起持续疼痛的慢性病理过程有关，或疼痛以一定间隔复发数月或数年，如果在应该已经达到治愈后或超过通常的治疗过程后仍存在疼痛，则认为是慢性疼痛。在疼痛需要经过的时间长度取决于疼痛的性质和与疼痛有关的治疗过程，如果疼痛超过通常的治疗过程，则疼痛是慢性的。慢性疼痛包括但不限于头痛、面部痛、颈痛、肩痛、胸痛、腹痛、背部痛、腰痛、下肢痛、肌与骨骼疼痛、与躯体病样精神障碍有关的疼痛、内脏痛、疼痛性糖尿病性神经病、血管疼痛、痛风、关节炎性疼痛、癌症疼痛、 自主神经反射性疼痛、感染性疾病(如艾滋病和带状疱疹)导致的疼痛、自身免疫性疾病(风湿)导致的疼痛、急慢性炎症导致的疼痛、手术后疼痛和烧伤后疼痛。
本发明揭示的药物能有效地治疗如上定义的慢性疼痛，而且本发明揭示的药物可用于治疗伴随其他病症的痛敏，包括痛觉过敏、异常性疼痛、痛觉增强和疼痛记忆增强，该发明将改善对其疼痛的治疗。
如本文所用，“头痛”可分为原发性头痛和继发性头痛，原发性头痛包括紧张性头痛、偏头痛和丛集性头痛，而继发性头痛是由于其他疾病引起的。头面部的痛敏感组织发生病变或受到刺激时，可引起各种头痛，这些痛敏感组织包括分布于头皮、面部、口腔及咽喉等，由于它们主要是头部的肌肉或血管，含有丰富的神经纤维，对疼痛比较敏感，所以当这些组织受到伤害时可引起头痛。
如本文所用，“面部痛”包括但不限于三叉神经痛、非典型面痛、面神经麻痹和面肌痉挛。
如本文所用，“三叉神经痛”是一种独特的慢性疼痛性疾病，又称痛性抽搐，是指在三叉神经分布区域出现短暂的、阵发性的和反复发作的电击样剧烈性疼痛，或伴有同侧面肌痉挛。三叉神经痛分为原发性和继发性两种类型，原发性三叉神经痛是指临床上未发现神经系统体征，检查未发现器质性病变；继发性三叉神经痛是指在临床上有神经系统体征，检查发现有器质性病变，如肿瘤和炎症等。
如本文所用，“非典型面痛”是指由多种病因引起的疼痛。表现为持续性烧灼样疼痛、无间歇性、与特殊的动作或触发刺激无关，疼痛多为双侧、疼痛常常超出三叉神经的分布范围甚至累及颈部皮肤。病因可由鼻窦炎、恶性肿瘤、颌及颅底感染等原因刺激或损伤三叉神经而引起疼痛。
如本文所用，“颈痛、背痛、肩痛”是指由于急慢性肌肉劳损及骨关节的退行性变和外伤等导致的疼痛。引起颈、肩及上肢疼痛的常见疾病有颈肩肌筋膜炎、项韧带炎、颈椎病、肩周炎、胸廓出口综合症、肱骨外上髁炎等，或由自身免疫性疾病引起的疼痛常见于类风湿性关节炎、强直性脊柱炎和风湿性关节炎等疾病，其他可能引起颈痛、背痛、肩痛的疾病还有颈、肩部的肿瘤、神经炎、动静脉疾病和各种感染以及胸、腹腔脏器病变引起的牵涉痛 等。
如本文所用，“胸、腹及背部痛”指由于胸腹部内脏、胸腹壁组织的疾病导致的疼痛，包括但不限于肋间神经痛、肋间软骨炎、心绞痛、腹痛(急性腹部内脏痛)和腰背部肌筋膜综合征。
如本文所用，“腰、下肢痛”是指下腰、腰骶、骶髂、髋、臀及下肢痛。腰和下肢痛往往并不是独立的疾病，而是多种疾病的共有特征，临床表现多样，病因十分复杂，以退行性和损伤为多，包括但不限于腰椎间盘突出、急性腰扭伤、坐骨神经痛、骨质疏松症、第三腰椎横突综合症、梨状肌综合症、膝关节骨性关节炎、尾痛症和足跟痛等涉及的疼痛。
如本文所用，“肌与骨骼疼痛”包括但不限于肌筋膜疼痛、创伤引发的疼痛和慢性区域性疼痛综合症。
如本文所用，“疼痛性糖尿病”是指糖尿病并发的神经损伤而引起的疼痛，糖尿病中的神经损伤至少部分是由于血流减少和高血糖引起的。某些糖尿病患者不发生神经病变，而其他患者早期就发生该疾病，糖尿病性神经病痛可以分为涉及一个或者多个病灶部位的单神经病和全身性多神经病，所述多神经病可以是扩散和对称的，通常主要涉及感觉方式(Merrit’s Textbook of Neurology，第9版，LPRowland LP编辑)。糖尿病性神经病的表现可以包括植物神经功能障碍，导致包括心脏、平滑肌和腺体在内的调节障碍，引起低血压、腹泻、便秘和性无能。糖尿病神经病往往分阶段发展，早期在神经末梢区，植物神经病或感觉神经病的时发生在足部，脑神经病时发生在面部和眼周围，出现间歇性疼痛和麻刺感，在随后的阶段中，疼痛更强和经常发生，最后，当某一区域痛觉丧失时，发生为无痛性神经病，由于没有疼痛作为损伤的指示，大大增加了发生严重组织损伤的风险。
如本文所用，“内脏疼痛”包括但不限于刺激性肠综合征(IBS)，伴有或不伴有慢性疲劳综合征(CFS)、炎性肠病(IBD)和间质性膀胱炎的疼痛。
如本文所用，“血管疼痛”是由以下一种或多种因素产生的疼痛。第一，组织的灌注不当。引起暂时或连续的局部缺血，诸如在运动期间发生肢体肌肉中的局部缺血；第二，迟发性变化。例如在皮肤或腹部内脏中的溃疡或坏疽；第三，大血管口径的突然或加速变化。例如动脉瘤发生的变化；第四，主动脉破裂。结果是血液溢出，刺激腹膜或胸膜壁层中的伤害感受纤维；第 五，由于动脉内注射严重刺激动脉内皮而引起的强痉挛；第六，静脉血回流的损害，结果是迅速扩张筋膜隔室的大量水肿(Bonica等，The Management of Pain，第一卷(第二版)，Philadelphia；Lea&Feboger，1990)。实例包括但不限于闭塞性动脉硬化、闭塞性血栓脉管炎、急性动脉闭合、栓塞、先天性动静脉瘤、血管痉挛性疾病、Rayaud病、手足发绀、急性静脉闭合、血栓静脉炎、静脉曲张和淋巴水肿。
如本文所用，“自主神经反射性疼痛”是指由“反射性交感神经萎缩征”导致的疼痛。反射性交感神经萎缩征是指机体遭受急慢性损伤后，有剧烈的自发疼痛，对触觉和痛觉过敏，可伴有浮肿和血行障碍，随后可出现皮肤及肌肉骨骼的营养障碍和萎缩等症状。
如本文所用，“术后疼痛”是指机体对疾病本身和手术造成的组织损伤的一种复杂的生理反应，它表现为心理和行为上的一种不愉快的经历。
如本文所用，“关节炎性疼痛”包括但不限于骨关节炎、类风湿性关节炎、关节强直性脊椎炎、牛皮癣性关节病、痛风、假痛风、传染性关节炎、腱炎、粘液囊炎、骨损害和关节软组织炎症等疾病导致的疼痛。
如本文所用，“带状疱疹后的神经痛”是指带状疱疹的皮疹愈合后，在原来皮疹区的皮下长期存在的剧烈疼痛。
如本文所用，“伤害感受性疼痛”是由刺激伤害性感受器传入的组织损害过程引起的疼痛，或是由伤害性感受器延长的兴奋引起的疼痛。由伤害感受器延长的兴奋引起的疼痛可以是由于伤害感受器的持久有害刺激或其敏化或这两者共同引起，或它们可以由这些因素引起，并由其持久性、各种反射机制和其他因素而延长。
药物组合物
本发明提供含治疗有效量的α5‐GABAA反向激动剂的药物合物的用途。尽管用于本发明治疗的α5‐GABAA反向激动剂可以原料化合物的形式给药，但优选将活性成分，任选地以生理上可接受的盐的形式，与一种或多种添加剂、赋形剂、载体、缓冲剂、稀释剂和/或其它常规的药物辅料一起混合成药物组合物。
在优选的实施方案中，本发明提供含α5‐GABAA反向激动剂的药物组合 物，其中α5‐GABAA反向激动剂与一种或多种药学上可接受的载体、和任选地与其它本领域已知的或使用的治疗性的和/或预防性的组份混合。该载体必须是“可接受的”，即与制剂中的其它成分相容且不会对其接受者有害。
用于本发明的药物组合物可以是那些适合于经口、直肠、支气管、鼻腔、肺、局部(包括颊内和舌下)、经皮、阴道或肠胃外(包括皮肤、皮下、肌内、腹腔内的、静脉内、动脉内、脑内、眼内注射或输注)给药的组合物，或那些以适合于吸入或喷洒给药的形式，包括粉末和液体气雾剂给药、或缓释系统给药的药物组合物。合适的缓释系统的例子包括含本发明化合物的固体疏水性聚合物的半渗透基质，其中基质可以是成形的制品形式，例如膜或微囊。
因此可将用于本发明的化合物与常规的添加剂、或稀释剂一起制成药物组合物及其单位剂量的形式。诸如此类的形式包括固体(尤其是片剂、填充胶囊、粉末以及丸剂的形式)、和液体(尤其是水溶液或非水溶液、混悬液、乳剂、酏剂)、和填充上述形式的胶囊、所有口服给药的形式、直肠给药的栓剂、以及肠胃外给药的无菌可注射的溶液。诸如此类药物组合物及其单位剂量形式可包括常规比例的常规成分、含或不含另外的活性化合物或成分，这类单位剂量形式可含与所需的每日应用剂量范围相当的任何合适的有效量的活性成分。
用于本发明的化合物可以各种的口服的和胃肠外的剂型给药。对本说领域的技术人员来说下述的剂型可含作为活性成分的本发明的化合物或其药学上可接受的盐。
为将用于本发明的化合物制成药物组合物，药学上可接受的载体可以是固体或者液体。固体形式的制剂包括粉末、片剂、九剂、胶囊、扁囊剂、栓剂、以及可分散的颗粒剂。固体载体可以是一种或多种还起稀释剂、调味剂、增溶剂、润滑剂、悬浮剂、粘合剂、防腐剂、片剂崩解剂、或囊化材料作用的物质。
粉末中，载体为细分的固体，它与细分的活性成分混合。
片剂中，活性成分与具有必要的粘合性能的载体以适当的比例混合并压缩成所需的形状和大小。
粉末和片剂优选地含5％或10％到约7 0％的活性化合物。合适的载体为 碳酸镁、硬脂酸镁、滑石粉、糖、乳糖、果胶、糊精、淀粉、明胶、西黄蓍胶、甲基纤维素、羧甲基纤维素钠、低熔点的蜡、可可脂等等。术语“制剂”包括含与作为载体的囊化材料配制的活性化合物，囊化材料提供囊，其中含或不含载体的活性成分被载体包围，这样与其结合在一起。同样地，制剂包括扁囊剂和锭剂(lozenges)。片剂、散剂、胶囊、丸剂、扁囊剂和锭剂可以用作适合于口服给药的固体形式。
为制备栓剂，首先将低熔点的蜡，如脂肪酸甘油酯或可可脂的泥合物熔化，然后通过搅拌将活性成分均匀地分散于其中。然后将该熔化的均匀混合物倒入适当大小模具中，让其冷却并由此固化。
适合于阴道给药的组合物可以阴道栓剂、棉塞、乳膏剂、凝胶剂、糊剂、泡沫或喷雾剂的形式存在，组合物除含活性成分外还含本领域已知的合适的载体。
液体制剂包括溶液、混悬液和乳剂，例如，水溶液或水‐丙二醇溶液。例如，肠胃外注射液体制剂可以配制成水‐聚乙二醇的溶液。
因此用于本发明的化合物可配制成用于肠胃外给药(例如注射，如快速浓注或连续输注)的制剂，和可以与添加的防腐剂一起以单位剂量的形式存在于安瓿、预填充的注射器、小体积的输液袋中或多剂量容器中。该组合物可采取油性或水性载体的混悬液、溶液或乳剂的形式，并可含制剂成分，如悬浮剂、稳定剂和/或分散剂。另外，活性成分可以是粉末的形式，可由灭菌的固体无菌分离或由溶液冻干获得，用于临用前与合适的载体如无菌的、无热原的水重建。
适合于口服给药的水溶液可通过将活性成分溶解于水中和加入所需的着色剂、调味剂、稳定剂和增稠剂来制备。
适合于口服给药的水悬浮液可通过将细分的活性成分分散于含粘性物质，如天然的或合成的树胶、树脂、甲基纤维素、羧甲基纤维素钠、或其它公知的悬浮剂的水中而制备。
还包括为在临用前不久转化为用于口服给药的液态制剂而设计的固体制剂。这类液体制剂包括溶液、混悬液和乳剂。除活性成分之外，这类制剂可含着色剂、调味剂、稳定剂、缓冲剂、人造的和天然的甜味剂、分散剂增稠剂、增溶剂等。
为了局部施用到表皮，可将本发明的化合物配制成软膏剂、乳膏剂或洗剂或透皮贴剂。例如，软膏剂和乳膏剂可用水性或油性基质外加合适的增稠剂和/或胶凝剂配制而成。洗剂可用水性或油性基质配制而成，且通常还含一种或多种乳化剂、稳定剂、分散剂、悬浮剂、增稠剂或着色剂。
适合于口腔局部给药的组合物包括在调味基质通常为蔗糖和金合欢胶或西黄蓍胶中含有活性成分的锭剂(lozenges)；在惰性的基质如明胶和甘油或蔗糖和金合欢胶中含活性成分的锭剂(pastiIles)；以及在合适的液体载体中含活性成分的漱口药。
可将溶液或混悬液用常规方法例如用滴管、吸管或喷雾器直接应用到鼻腔。该组合物可以是单剂量或多剂量的形式。
呼吸道给药也可以通过气雾剂实现，其中活性成分与合适的推进剂一起装在加压的包装中，合适的推进剂包括氟氯化碳(CFC)例如二氯二氟甲烷、三氯氟甲烷或二氯四氟乙烷，二氧化碳或其它合适的气体。气雾剂还可适当地含表面活性剂，如卵磷脂。药物的剂量可通过量阀控制。
另外活性成分可以是干粉的形式，例如化合物与合适粉末基质如乳糖、淀粉、淀粉衍生物如羟丙基甲基纤维素和聚乙烯吡咯烷酮(PVP)的粉末混合物。粉末载体可方便地在鼻腔内形成凝胶。粉末组合物可以单位剂量的形式存在，例如存在于胶囊或药筒(如明胶的胶裘或药筒)中，或存在于粉末可经吸入器给药的泡罩包装中。
在用于呼吸道给药的组合物(包括鼻内用的组合物)中，通常化合物具有小的粒度，例如为5微米或更小数量级的粒度。这样的粒度可以用本领域已知的方法，例如通过微粉化获得。
需要时，可以应用适于活性成分缓释的组合物。
药物制剂优选为单位剂量形式。这类形式中，制剂被细分成合适量活性成分的单位剂量。单位剂量形式可以是封装的制剂，其中密封包装中含分离的大量制剂，如封装的片剂、胶囊和装入小瓶或安瓿中的粉末。此外，单位剂量形式可以是胶囊、片剂、扁裘剂或锭剂(lozenge)本身，或可以是任何封装形式的适量上述胶囊、片剂等。
用于口服给药的片剂或胶囊和用于静脉给药的液体以及连续的输液为优选的组合物。
关于制剂和给药技术的更详细的资料可以在Remington's Pharmaceutical Sciences(雷明顿药物科学)(Maack Publishing Co.,Easton,PA)的最新的版本上见到。
单位剂量制剂中活性组份的量可根据具体的应用和活性组份的效力而变化，可调节自0.01mg至约0.1g。例如，在医药用途中，该药物可以0.01至约100mg的胶囊每天给药三次，必要时该组合物还可以含其他相容的治疗剂。
治疗方法
在治疗用途中，用于本发明的化合物以起始剂量每天0.001mg/kg至10mg/kg体重。但是，这些剂量可以根据患者的需要、被治疗病症的严重性以及使用的化合物而变化，一般来说，开始以小于该化合物最佳剂量的较小剂量治疗，此后，小量增加此剂量达到最佳效果，方便起见，如果需要可将总日剂量再细分为一天内分次给药。
本发明的药物组合物还可同时与其它治疗疼痛、阿尔茨海默氏病、多梗塞性痴呆和中风的药物联合使用，包括但不限于吗啡、加巴喷丁等。因此，本发明提供了一种用于治疗疼痛、阿尔茨海默氏病、多梗塞性痴呆和中风的药物的药物，该药物不仅有效，而且没有明显的副作用，本发明的另一个目的是提供一种对于特殊病人群体，如老人、患有肝或肾功能衰退、或心脏血管性疾病的病人，具有高度安全性的药物。
实施例:
Figure PCTCN2016108975-appb-000049
合成路线1
Figure PCTCN2016108975-appb-000050
实验操作:
步骤1
6-[3-(5-甲基-异噁唑-3-基)-[1,2,4]三氮唑[3，4-a]酞嗪-6-氧)亚甲基]-烟酸甲酯(A3)
在150mL的DMF中加入原料A2(原料的制备参考Leslie J.Street，Francine Sternfeld，etal。J.Med.Chem.2004,47,3642-3657)(1.75g，10.5mmol)，氩气保护下降温至0摄氏度，然后再加入氢化钠(400mg，1.9eq)，并在此温度下搅拌15分钟。然后把化合物A1(制备参考Sternfeld,Francine；Carling,Robert W，etal。J.Med.Chem.,2004,47,2176-2179)(1.5g，5.2mmol)加入到反应液中，室温下搅拌1.5小时。TLC(展开剂为二氯甲烷：甲醇＝20：1，Rf＝0.3)显示原料反应完全。在反应混合物中加入30mL的冰水，并用2N的柠檬酸调节pH值为5～6，浓缩掉大部分的溶剂DMF，残余物分散在300mL乙酸乙酯和300mL水中。分出有机层用水(200mL×3次)洗。最后用盐水(50mL)洗，用无水硫酸钠干燥和浓缩。残余物经柱层析(淋洗剂为二氯甲烷)得到产物1.19g，产率54.2％。
1H NMR(400MHz,CDCl3)δ:9.24(d,1H),8.71～8.69(d,1H),8.36～8.32(m,2H),7.98(t,1H),7.87～7.85(t,2H),6.79(s,1H),5.82(s,2H),3.96(s,3H),2.58(s,3H).
步骤2
6-[3-(5-甲基-异噁唑-3-基)-[1,2,4]三氮唑[3，4-a]酞嗪-6-氧)亚甲基]-烟酸(A4)
在室温下将化合物A3 1.8g，4.3mmol)溶在乙醇(20mL)中，加入氢氧化钠水溶液(2.5N，2.5mL)后搅拌1小时。TLC(展开剂为二氯甲烷：甲醇＝10：1，Rf＝0.2)显示原料反应完全。用柠檬酸(2N)调节pH值为5～6，过滤，滤液用乙醇(5mL)洗一次，再用二氯甲烷(8mL)洗一次。然后将滤饼加入到10mL二氯甲烷中搅拌1小时，抽滤，滤饼用二氯甲烷2mL洗一次。干燥，得到产物粗品(550mg，31.6％)。
步骤3
实施例1
6-((3-(5-甲基异噁唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧)亚甲基)-N-吗啡啉烟酰胺(01)
将化合物A4(100mg，0.248mmol)、HOBt(68mg，0.496mmol)和EDCI(95mg，0.496mmol)依次加入到5mL的DMF中，于室温和氩气保护下搅拌10分钟。4-氨基吗啉(CAS:4319-49-7)(30.6mg，0.3mmol)和N,N-二异丙基乙胺(130mg，0.992mmol)依次加入到混合物中，然后室温搅拌12小时。TLC(展开剂为二氯甲烷：甲醇＝10：1，Rf＝0.4)显示原料反应完全。加入25mL二氯甲烷到反应液中，然后将反应液倒入30mL水中，用2N的柠檬酸调节pH值为5～6。分出有机层，再用水(20mL×2)洗，有机层用无水硫酸钠干燥，浓缩，残余物经制备板纯化得到产物(36mg，29.7％)外观为白色固体。1H NMR(400MHz,DMSO-d6)δ:9.76(s,1H),8.99(s,1H),8.61～8.60(d,1H),8.59(d,1H),8.38～8.36(m,2H),8.23～7.85(m,2H),6.93(s,1H),5.78(s,2H),3.68(s,4H),2.90(s,4H),2.58(s,3H)；LC-MS:m/z(ES+)for C24H22N8O4487.15[M+1]+。
实施例2
(R)-N-(1-羟基正丙醇-2-基)-6-((3-(5-甲基异噁唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧)亚甲基)烟酰胺(02)
实验操作如实施例1所述：原料是化合物A4和D-氨基丙醇(CAS:35320-23-1) 得到产物(02)(35mg，20.5％)外观为白色固体。1H NMR(400MHz,DMSO-d6)δ:9.06～9.05(d,1H),8.60～8.58(d,1H),8.37～8.35(d,2H),8.27(d,1H),8.13(t,1H),8.00(t,1H),7.87～7.85(d,1H),6.93(s,1H),5.77(s,2H),4.77～4.74(t,1H),4.05～4.02(m,1H),3.45(m,1H),3.37(m,1H),3.33(s,1H),2.58(s,3H),2.01～1.99(m,1H),1.15～1.13(d,3H)；LC-MS:m/z(ES+)for C23H21N7O4 460.14[M+1]+。
实施例3
N-((1S，2S)-2-羟基环戊基)-6-((3-(5-甲基异噁唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧)亚甲基)烟酰胺(03)
实验操作如实施例1所述：原料是化合物A4和反式-(1S,2S)-2-氨基-环戊醇盐酸盐(CAS:68327-04-8)得到产物(75mg，65.8％)外观为白色固体。1H NMR(400MHz,DMSO-d6)δ:9.04(d,1H),8.60～8.58(d,1H),8.48～8.46(d,1H),8.38～8.36(d,1H),8.28～8.25(d,1H),8.15～8.12(t,1H),8.02～8.00(t,1H),7.87～7.85(d,1H),6.93(s,1H),5.78(s,2H),4.81～4.80(d,1H),4.02～3.99(m,2H),2.58(s,3H),2.02～1.99(m,2H),1.87～1.46(m,4H)；LC-MS:m/z(ES+)for C25H23N7O4 486.19[M+1]+。
实施例4
N-环丙基-6-((3-(5-甲基异噁唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧)亚甲基)烟酰胺(04)
实验操作如实施例1所述：原料是化合物A4和环丙胺(CAS:765-30-0)得到产物(54mg，50％)外观为白色固体。1H NMR(400MHz,DMSO-d6)δ:9.02～9.01(d,1H),8.69～8.68(d,1H),8.59～8.57(d,1H),8.37～8.35(d,1H),8.25～8.23(d,1H),8.13～8.11(t,1H),8.01～7.99(t,1H),7.86～7.84(d,1H),6.93(d,1H),5.76(d,2H),2.87～2.86(m,1H),2.57(s,3H),0.73～0.71(m,2H),0.59～0.58(m,2H)；LC-MS:m/z(ES+)for C23H19N7O3 442.15[M+1]+。
实施例5
N-(1-甲基-1H-吡唑-4-基)-6-((3-(5-甲基异噁唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧)亚甲基)烟酰胺(05)
实验操作如实施例1所述：原料是化合物A4和1-甲基-4-氨基吡唑(CAS: 69843-13-6)得到产物(53mg，44.3％)外观为白色固体。1H NMR(400MHz,DMSO-d6)δ:10.67(s,1H),9.15(s,1H),8.61～8.59(d,1H),8.40～8.36(t,2H),8.16～8.12(t,1H),8.04～8.01(m,2H),7.93～7.91(d,1H),7.58(d,1H),6.95(s,1H),5.80(s,2H),3.83(s,3H),2.59(s,3H)；LC-MS:m/z(ES+)for C24H19N9O3 482.13[M+1]+。
实施例6
N，N-(二甲基)-6-((3-(5-甲基异噁唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧)亚甲基)烟酰胺(06)
实验操作如实施例1所述：原料是化合物A4和二甲胺盐酸盐,(CAS:506-59-2)得到产物(60mg，70％)外观为白色固体。1H NMR(400MHz,DMSO-d6)δ:8.67(s,1H),8.57(d,1H J＝8.0),8.35(d,1H J＝8.0),8.11(t,1H J＝7.6),7.99～7.93(m,2H),7.81(d,1H J＝8.0),6.91(s,1H),5.74(s,2H),3.00(s,3H),2.92(s,3H),2.57(s,3H)。LC-MS:m/z(ES+)for C22H19N7O3 430.12[M+1]+。
实施例7 N-乙基-6-((3-(5-甲基异噁唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧)亚甲基)烟酰胺(07)
实验操作如实施例1所述：原料是化合物A4和乙胺盐酸盐(CAS:557-66-4)得到产物(105mg，75％)外观为白色固体。1H NMR(400MHz,DMSO-d6)δ:9.03(d,1H J＝1.6),8.72(t,1H J＝5.2),8.58(d,1H J＝8.0),8.37(d,1H J＝8.0),8.26～8.24(m,1H),8.12(t,1H J＝7.2),7.99(t,1H J＝7.2),7.86(d,1H J＝8.0),6.91(s,1H),5.75(s,2H),3.38～3.25(m,2H),2.56(s,3H),1.13(t,3H J＝7.2)。LC-MS:m/z(ES+)for C22H19N7O3 430.0[M+1]+。
实施例8
N-(2-甲氧基乙基)-6-((3-(5-甲基异噁唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧)亚甲基)烟酰胺(08)
实验操作如实施例1所述：原料是化合物A4和2-甲氧基乙胺(CAS:109-85-3)得到产物(42mg，63％)外观为白色固体。1H NMR(400MHz,DMSO-d6)δ:9.03(s,1H),8.80(t,1H J＝4.4),8.55(d,1H J＝8.0),8.34(d,1H J＝8.0),8.28～8.25(m,1H),8.10(t,1H J＝7.2),7.97(t,1H J＝7.6),7.84(d,1H  J＝8.4),6.87(s,1H),5.73(s,2H),3.50～3.30(m,4H)，3.26(s,3H),2.55(s,3H)。LC-MS:m/z(ES+)for C23H21N7O4 460.11[M+1]+。
实施例9
N-(2-羟乙基)-6-((3-(5-甲基异噁唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧)亚甲基)烟酰胺(09)
实验操作如实施例1所述：原料是化合物A4和乙醇胺(CAS:141-43-5)得到产物(42mg，63％)外观为白色固体。1H NMR(400MHz,DMSO-d6)δ:9.04(s,1H),8.72(t,1H J＝5.2),8.57(d,1H J＝7.6),8.36(d,1H J＝7.6),8.28～8.24(m,1H),8.11(t,1H J＝7.6),7.96(t,1H J＝7.6),7.85(d,1H J＝8.4),6.90(s,1H),5.75(s,2H),4.80(t,1H J＝5.2),3.55～3.48(m,2H),3.31～3.38(m,2H),2.56(s,3H)。LC-MS:m/z(ES+)for C22H19N7O4 446.02[M+1]+。
实施例10
6-[3-(5-甲基异恶唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧亚甲基]-N-(2-丁基)-烟酰胺(10)
实验操作如实施例1所述：原料是化合物A4和异丁胺(CAS:78-81-9)得到产物(01)(10mg，16％)外观为类白色固体。1H NMR(400MHz,DMSO-d6)δ9.01(d,J＝1.6Hz,1H),8.55(d,J＝7.8Hz,1H),8.34(dd,J＝13.9,8.1Hz,2H),8.23(dd,J＝8.2,2.2Hz,1H),8.13–8.06(m,1H),7.99–7.93(m,1H),7.81(d,J＝8.0Hz,1H),6.88(d,J＝0.9Hz,1H),5.73(s,2H),3.90(dt,J＝14.0,7.1Hz,1H),2.54(d,J＝0.6Hz,3H),1.48(td,J＝13.5,6.7Hz,2H),1.11(d,J＝6.6Hz,3H),0.84(t,J＝7.4Hz,3H).LC-MS:m/z(ES+)for C24H23N7O3 458[M+1]+。
实施例11
6-[3-(5-甲基异恶唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧亚甲基]-N-(1-甲基-哌啶-4-基)-烟酰胺(11)
实验操作如实施例1所述：原料是化合物A4和4-氨基-1-甲基哌啶(CAS:41838-46-4)得到产物(75mg，65.8％)外观为灰白色固体。1H NMR(400MHz,DMSO-d6)δ9.01(d,J＝1.9Hz,1H),8.60–8.47(m,2H),8.30(d,J ＝8.1Hz,1H),8.24(dd,J＝8.2,2.0Hz,1H),8.08(s,1H),7.95(s,1H),7.81(d,J＝8.2Hz,1H),6.87(s,1H),5.72(s,2H),3.86-3.80(m,1H),3.01-2.96(m,2H),2.53(s,3H),2.38-2.31(m,5H),1.85-1.80(m,2H),1.64-1.68(m,2H).LC-MS:m/z(ES+)for C26H26N8O3 499[M+1]+。
实施例12
6-[3-(5-甲基异恶唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧亚甲基]-N-(2-吗啡啉-4-基-乙基)-烟酰胺(12)
实验操作如实施例1所述：原料是化合物A4和N-(2-氨基乙基)吗啉(CAS:2038-03-1)得到产物(54mg，50％)外观为白色固体。1H NMR(400MHz,DMSO-d6)δ9.01(s,1H),8.69(s,1H),8.53(s,1H),8.27(d,J＝35.0Hz,2H),8.08(s,1H),7.95(s,1H),7.82(s,1H),6.87(s,1H),5.72(s,2H),4.02-3.95(m,1H),3.58-3.51(m,3H),3.24–3.01(m,4H),2.53(s,3H),2.43–2.28(m,3H),1.98-1.92(m,1H).LC-MS:m/z(ES+)for C26H26N8O4515[M+1]+。
实施例13
6-[3-(5-甲基异恶唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧亚甲基]-N-(四氢呋喃-3-基)-烟酰胺(13)
实验操作如实施例1所述：原料是化合物A4和3-氨基四氢呋喃(CAS:88675-24-5)得到产物(53mg，60％)外观为类白色固体。1H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.75(d,J＝6.2Hz,1H),8.52(d,J＝7.9Hz,1H),8.34–8.20(m,2H),8.08(t,J＝7.4Hz,1H),7.94(t,J＝7.7Hz,1H),7.82(d,J＝8.1Hz,1H),6.88(s,1H),5.72(s,2H),4.44(s,1H),3.88–3.76(m,2H),3.68(dd,J＝14.1,8.1Hz,1H),3.57(dd,J＝8.9,4.1Hz,1H),2.53(s,3H),2.13(dt,J＝14.9,8.0Hz,1H),1.96–1.83(m,1H).LC-MS:m/z(ES+)for C24H21N7O4 472[M+1]+。
实施例14
N-(2-乙酰氨乙基)-6-[3-(5-甲基异恶唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧亚甲基]-N-(1S，2S-2-羟基-环戊烷基)-烟酰胺(14)
实验操作如实施例1所述：原料是化合物A4和N-乙酰基乙二胺(CAS： 1001-53-2)得到产物(58mg)外观为白色固体，产率80％。1H NMR(400MHz,DMSO-d6)δ9.00(d,J＝1.6Hz,1H),8.73(t,J＝5.6Hz,1H),8.54(d,J＝7.6Hz,1H),8.33(d,J＝8.1Hz,1H),8.22(dd,J＝8.1,2.3Hz,1H),8.09(t,J＝7.7Hz,1H),7.96(t,J＝7.2Hz,2H),7.83(d,J＝8.3Hz,1H),6.89(s,1H),5.73(s,2H),3.29–3.24(m,2H),3.18(t,J＝5.8Hz,2H),2.54(s,3H),1.76(s,3H).LC-MS:m/z(ES+)for C24H22N8O4 487[M+1]+。
实施例15
6-[3-(5-甲基异恶唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧亚甲基]-N-(1S-2-羟甲基-环戊烷基)-烟酰胺(15)
Figure PCTCN2016108975-appb-000051
15-4的合成如下：
1S,2S-2-(2-羟基-环戊基)-异吲哚-1,3-二酮(15-2)
将反式-(1S,2S)-2-氨基-环戊醇盐酸盐15-1(CAS:68327-04-8)(1.37g,10mmol)和Et3N(3g,30mmol)分别加入到甲苯(40mL)中室温搅拌5分钟，搅拌下加入邻苯二甲酸酐(1.48g,10mmol)，搅拌回流4小时。TLC显示反应完毕，加40毫升水洗，有机相无水硫酸钠干燥，减压蒸干过柱得1.7克白色固体，收率73.5％。
(S)-2-(2-甲氧基-环戊基)-异吲哚-1,3-二酮(15-3)
将15-2(850mg,3.68mmol)溶解在DMF(3mL)中，降温到0oC,分批加入NaH(177mg，4.4mmol)搅拌至无气泡，在加入MeI(624mg，4.4mmol)约20分钟加毕，自然升至室温反应2h，TLC(PE:EA＝2:1,Rf＝0.8)显示反应完毕，加水，EA萃取，干燥有机相。过硅胶柱纯化得600毫克白色固体，收率66％。
(S)-2-甲氧基-环戊胺(15-4)
将15-3(700mg,2.85mmol)和水合肼(500mg，8.49mmol)分别加入到乙醇(15毫升)中，搅拌下升温回流3小时，TLC(PE:EA＝1:1)原料反应完全，加入1N的氢氧化钠溶液，用DCM(6*20mL)萃取，合并有机相，干燥旋干得油状物200mg，收率61％。
6-[3-(5-甲基异恶唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧亚甲基]-N-(1S-2-羟甲基-环戊烷基)-烟酰胺(15)
实验操作如实施例1所述：原料是化合物A4和中间体(15-4)得到产物(190mg，63％)外观为白色固体。1H NMR(400MHz,DMSO-d6)δ:9.03(d,J＝1.6Hz,1H),8.56(t,J＝8.0Hz,2H),8.34-8.24(m,2H),8.10(t,J＝7.6Hz,1H),7.97(t,J＝7.6Hz,1H),7.86(d,J＝8.0Hz,1H),6.89(s,1H),5.75(s,2H),4.22-4.15(m,1H),3.72-3.67(m,1H),3.25(s,3H),2.56(s,3H),2.04-1.83(m,2H),1.75-1.48(m,4H)。LC-MS:m/z(ES+)for C26H25N7O4500.0[M+1]+。
实施例16
N-甲基-6-[3-(5-甲基异恶唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧亚甲基]-N-(2-吗啡啉-4-基-乙基)-烟酰胺(16)
实验操作如实施例1所述：原料是化合物A4和N-甲基-2-吗啉乙胺(CAS:41239-40-1)得到产物(45mg，71％)外观为白色固体。1H NMR(400MHz,DMSO-d6)δ:δ8.62(d,J＝1.1Hz,1H),8.53(d,J＝8.1Hz,1H),8.31(d,J＝8.1Hz,1H),8.08(t,J＝7.7Hz,1H),7.94(t,J＝7.7Hz,1H),7.88(dd,J＝7.9,1.7Hz,1H),7.77(d,J＝7.4Hz,1H),6.88(s,1H),5.71(s,2H),3.54(s,3H),3.29–3.18(m,3H),2.92(d,J＝23.7Hz,3H),2.54(s,4H),2.37(d,J＝43.8Hz,3H),2.01(s,2H)。LC-MS:m/z(ES+)for C27H28N8O4 529[M+1]+。
实施例17
(6-(((3-(5-甲基异恶唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-基)氧基)亚甲基)吡啶-3-基)(4-甲基哌嗪-1-基)甲酮(17)
实验操作如实施例1所述：原料是化合物A4和N-甲基哌嗪(CAS:109-01-3) 得到产物(100mg，88％)外观为白色固体。1H NMR(400MHz,DMSO-d6)δ8.62(d,J＝1.5Hz,1H),8.55(d,J＝8.0Hz,1H),8.33(d,J＝7.9Hz,1H),8.09(t,J＝7.1Hz,1H),7.96(t,J＝7.2Hz,1H),7.88(dd,J＝8.0,2.1Hz,1H),7.78(d,J＝8.0Hz,1H),6.90(d,J＝0.8Hz,1H),5.72(s,2H),3.62-3.58(m,2H),3.35-3.30(s,2H),2.54(s,3H),2.37-2.33(m,2H),2.26-2.22(m,2H),2.17(s,3H).LC-MS:m/z(ES+)for C25H24N8O3 485[M+1]+。
实施例18
N-(1-乙酰基吡咯烷-3-基)-6-(((3-(5-甲基异恶唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-基)氧基)亚甲基)-烟酰胺(18)
实验操作如实施例1所述：原料是化合物A4和1-乙酰基-3-氨基吡咯烷(CAS:833483-45-7)得到产物(100mg，87％)外观为白色固体。1H NMR(400MHz,DMSO-d6)δ9.04–8.98(m,1H),8.75(dd,J＝17.7,6.6Hz,1H),8.53(d,J＝7.9Hz,1H),8.30(d,J＝7.9Hz,1H),8.24(dd,J＝8.2,2.2Hz,1H),8.07(dd,J＝11.2,4.0Hz,1H),7.95(t,J＝7.5Hz,1H),7.83(dd,J＝8.2,3.1Hz,1H),6.88(d,J＝0.7Hz,1H),5.72(s,2H),4.44(ddd,J＝30.1,11.5,5.9Hz,1H),3.76–3.53(m,1H),3.53–3.31(m,3H),2.53(s,3H),2.14-2.08(m,1H),2.00–1.83(m,4H).LC-MS:m/z(ES+)for C26H24N8O4 513[M+1]+。
实施例19
1-(6-(((3-(5-甲基异恶唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-基)氧基)亚甲基)烟酰基)哌啶-3-甲酰胺(19)
实验操作如实施例1所述：原料是化合物A4和3-哌啶甲酰胺(CAS:4138-26-5)得到产物(75mg，60％)外观为白色固体。1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),8.55(d,J＝8.2Hz,1H),8.33(d,J＝8.0Hz,1H),8.09(t,J＝7.6Hz,1H),7.96(t,J＝7.8Hz,1H),7.88(s,1H),7.79(d,J＝8.2Hz,1H),7.39-7.25(m,1H),6.90-6.81(m,2H),5.72(s,2H),4.41-4.22(m,1H),3.49-3.45(m,1H),3.25–3.11(m,1H),3.04-2.99(s,1H),2.87-2.82(m,1H),2.54(s,3H),2.31-2.27(m,1H),1.92-1.87(m, 1H),1.58-1.52(m,2H),1.43-1.38(m,1H).LC-MS:m/z(ES+)for C26H24N8O4513[M+1]+。
实施例20
6-[3-(5-甲基异恶唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧亚甲基]-N-(四氢呋喃-3-基)亚甲基)-烟酰胺(20)
实验操作如实施例1所述：原料是化合物A4和3-氨基甲基-四氢呋喃(CAS:165253-31-6)得到产物(50mg，63％)外观为白色固体。1H NMR(400MHz,DMSO-d6)δ9.01(d,J＝2.1Hz,1H),8.77(s,1H),8.55(d,J＝7.7Hz,1H),8.33(d,J＝8.0Hz,1H),8.23(dd,J＝8.0,2.1Hz,1H),8.10(t,J＝7.1Hz,1H),7.96(t,J＝7.6Hz,1H),7.83(d,J＝8.2Hz,1H),6.88(s,1H),5.74(s,2H),3.75–3.54(m,3H),3.46-3.42(m,1H),3.25-3.21(m,2H),2.54(s,3H),1.93-1.89(m,2H),1.59-1.55(m,1H).LC-MS:m/z(ES+)for C25H23N7O4 486[M+1]+。
实施例21
N-(2,2-二氟乙基)-6-[3-(5-甲基异恶唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧亚甲基]烟酰胺(21)
实验操作如实施例1所述：原料是化合物A4和2,2-二氟乙胺(CAS:430-67-1)得到产物(100mg，80％)外观为白色固体。1H NMR(400MHz,DMSO-d6)δ9.08-9.04(m,2H),8.55(d,J＝7.5Hz,1H),8.34(d,J＝8.3Hz,1H),8.27(dd,J＝8.2,2.3Hz,1H),8.12–8.07(m,1H),7.97(t,J＝7.2Hz,1H),7.85(d,J＝8.1Hz,1H),6.88(d,J＝0.9Hz,1H),6.11(tt,J＝55.4,4.1Hz,1H),5.73(s,2H),3.75–3.61(m,2H),2.54(d,J＝0.8Hz,3H).LC-MS:m/z(ES+)for C22H17F2N7O3 466[M+1]+。
实施例22
(4-甲氧基哌啶-1-基)(6-(((3-(5-甲基异恶唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-基)氧基)亚甲基)吡啶-3-基)甲酮(22)
实验操作如实施例1所述：原料是化合物A4和4-甲氧基哌啶(CAS: 4045-24-3)得到产物(50mg，56％)外观为白色固体。1H NMR(400MHz,DMSO-d6)δ8.66(d,J＝1.5Hz,1H),8.59(d,J＝8.0Hz,1H),8.37(d,J＝8.0Hz,1H),8.12(dd,J＝11.2,4.2Hz,1H),8.02–7.97(m,1H),7.92(dd,J＝8.0,2.2Hz,1H),7.81(d,J＝8.1Hz,1H),6.94(d,J＝0.8Hz,1H),5.76(s,2H),3.96–3.87(m,1H),3.49–3.39(m,2H),3.26(s,3H),3.22–3.09(m,2H),2.58(d,J＝0.6Hz,3H),1.92–1.75(m,2H),1.53–1.39(m,2H).LC-MS:m/z(ES+)for C26H25N7O4 500[M+1]+。
实施例23
(4，4二氟哌啶-1-基)(6-(((3-(5-甲基异恶唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-基)氧基)亚甲基)吡啶-3-基)甲酮(23)
实验操作如实施例1所述：原料是化合物A4和4,4-二氟哌啶盐酸盐(CAS:144230-52-4)得到产物(60mg，58％)外观为白色固体。1H NMR(400MHz,DMSO-d6)δ8.69(d,J＝1.5Hz,1H),8.55(d,J＝7.8Hz,1H),8.33(d,J＝8.0Hz,1H),8.09(t,J＝7.6Hz,1H),7.95(dd,J＝12.9,4.8Hz,2H),7.81(d,J＝8.0Hz,1H),6.91(s,1H),5.73(s,2H),3.80–3.59(m,2H),3.47–3.33(m,2H),2.55(s,3H),2.12–1.93(m,4H).LC-MS:m/z(ES+)for C25H21F2N7O3 506[M+1]+。
实施例24
N-(环丙胺亚甲基)-6-[3-(5-甲基异恶唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧亚甲基]烟酰胺(24)
实验操作如实施例1所述：原料是化合物A4和环丙基甲胺(CAS:2516-47-4)得到产物(65mg，41％)外观为白色固体。1H NMR(400MHz,DMSO-d6)δ9.07(d,J＝1.8Hz,1H),8.83(t,J＝5.6Hz,1H),8.60(d,J＝8.0Hz,1H),8.38(d,J＝8.0Hz,1H),8.29(dd,J＝8.2,2.2Hz,1H),8.14(t,J＝7.6Hz,1H),8.01(t,J＝7.7Hz,1H),7.87(d,J＝8.1Hz,1H),6.93(s,1H),5.78(s,2H),3.18(t,J＝6.2Hz,2H),2.59(s,3H),1.09–0.96(m,1H),0.53–0.35(m,2H),0.24(q,J＝4.9Hz,2H).LC-MS:m/z(ES+)for C24H21N7O3 456[M+1]+。
实施例25
(1R，4R)-2-氧杂-5-氮杂双环[2.2.1]庚-5-基(6-(((3-(5-甲基异恶唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-基)氧基)亚甲基)吡啶-3-基)甲酮(25)
实验操作如实施例1所述：原料是化合物A4和2-噁-5-氮杂双环[2.2.1]庚烷(CAS:909186-56-7)得到产物(87mg，67％)外观为白色固体。1H NMR(400MHz,DMSO-d6)δ8.62(d,J＝1.5Hz,1H),8.55(d,J＝8.0Hz,1H),8.33(d,J＝7.9Hz,1H),8.09(t,J＝7.1Hz,1H),7.96(t,J＝7.2Hz NMR(400MHz,dmso)δ8.74(dd,J＝21.3,1.5Hz,1H),8.55(d,J＝7.7Hz,1H),8.33(d,J＝8.1Hz,1H),8.09(t,J＝7.2Hz,1H),8.05–7.93(m,2H),7.79(dd,J＝11.2,8.2Hz,1H),6.89(d,J＝14.0Hz,1H),5.73(d,J＝4.6Hz,2H),4.83-4.31(m,2H),3.85(dd,J＝40.0,7.4Hz,1H),3.68(dd,J＝40.0,6.3Hz,1H),3.50(t,J＝10.0Hz,1H),3.24(d,J＝9.6Hz,1H),2.54(s,3H),1.91–1.69(m,2H).LC-MS:m/z(ES+)for C25H21N7O4484[M+1]+。
实施例26
6-[3-(5-甲基异恶唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧亚甲基]-N-((四氢呋喃-2-基)亚甲基)烟酰胺(26)
实验操作如实施例1所述：原料是化合物A4和糠胺(CAS:617-89-0)得到产物(60mg，63％)外观为白色固体。1H NMR(400MHz,DMSO)δ9.02(d,J＝1.7Hz,1H),8.77(t,J＝5.8Hz,1H),8.55(d,J＝7.9Hz,1H),8.33(d,J＝8.3Hz,1H),8.24(dd,J＝8.2,2.2Hz,1H),8.09(t,J＝7.6Hz,1H),7.96(t,J＝7.6Hz,1H),7.82(d,J＝8.1Hz,1H),6.88(s,1H),5.73(s,2H),4.02–3.89(m,1H),3.67(ddd,J＝58.7,14.5,7.4Hz,2H),3.36–3.31(m,2H),2.54(s,3H),1.94–1.73(m,3H),1.59–1.48(m,1H)，LC-MS:m/z(ES+)for C25H23N7O4 486[M+1]+。
实施例27
6-[3-(5-甲基异恶唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧亚甲基]-N-(2-(甲磺酰基)乙基)烟酰胺(27)
实验操作如实施例1所述：原料是化合物A4和2-(甲磺酰基)乙胺(CAS:49773-20-8)得到产物(100mg，80％)外观为白色固体。1H NMR(400MHz,DMSO)δ9.05(d,J＝1.8Hz,1H),9.01(t,J＝5.6Hz,1H),8.59(d,J＝7.8Hz,1H),8.38(d,J＝8.1Hz,1H),8.27(dd,J＝8.2,2.2Hz,1H),8.14(t,J＝7.2Hz,1H),8.01(t,J＝7.2Hz,1H),7.89(d,J＝8.2Hz,1H),6.93(d,J＝0.7Hz,1H),5.78(s,2H),3.71(dd,J＝12.6,6.5Hz,2H),3.41(t,J＝6.8Hz,2H),3.06(s,3H),2.58(s,3H).LC-MS:m/z(ES+)for C23H21N7O5S 508[M+1]+。
实施例28
6-[3-(5-甲基异恶唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧亚甲基]烟酰胺(28)
Figure PCTCN2016108975-appb-000052
在20mL的DMF中加入原料A1(100mg，0.35mmol)、6-(羟基甲基)-3-吡啶羧酰胺(A5)(CAS:119646-49-0)(40mg,0.35mmol)和Cs2CO3(227mg,0.70mmol)，氩气保护下室温搅拌过夜黄色悬浊液。TLC(展开剂为二氯甲烷：甲醇＝20：1，Rf＝0.3)显示原料反应完全。蒸干DMF，柱层析得白色固体77mg，产率55％。1H NMR(400MHz,DMSO)δ9.04(d,J＝2.0Hz,1H),8.54(d,J＝8.0Hz,1H),8.33(d,J＝8.1Hz,1H),8.26(dd,J＝8.2,2.2Hz,1H),8.17(s,1H),8.08(d,J＝7.9Hz,1H),7.95(t,J＝7.7Hz,1H),7.81(d,J＝8.2Hz,1H),7.60(s,1H),6.87(s,1H),5.73(s,2H),2.54(s,3H).LC-MS:m/z(ES+)for C20H15N7O3 402[M+1]+。
实施例29
2-(6-[3-(5-甲基异恶唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧亚甲基]烟酰胺)乙酸(29)
实验操作如实施例1所述：原料是化合物A4和甘氨酸叔丁酯(CAS:6456-74-2)得到产物然后三氟乙酸室温搅拌得到最终产品(100mg，总收率60％)，外观为 白色固体。1H NMR(400MHz,DMSO)δ12.66(s,1H),9.07(dd,J＝12.8,6.8Hz,2H),8.54(d,J＝7.7Hz,1H),8.34(d,J＝7.9Hz,1H),8.27(dd,J＝8.3,2.0Hz,1H),8.09(t,J＝7.7Hz,1H),7.96(t,J＝7.7Hz,1H),7.85(d,J＝8.1Hz,1H),6.86(s,1H),5.74(s,2H),3.93(d,J＝5.8Hz,2H),2.53(s,3H).LC-MS:m/z(ES+)for C22H17N7O5 460[M+1]+。
实施例30
6-[3-(5-甲基异恶唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧亚甲基]-N-(2，2，2--三氟乙基)烟酰胺(30)
实验操作如实施例1所述：原料是化合物A4和2,2,2-三氟乙基胺(CAS:753-90-2)得到产物(56mg，48％)外观为白色固体。1H H NMR(400MHz,dmso)δ9.32(t,J＝6.2Hz,1H),9.06(d,J＝2.0Hz,1H),8.55(d,J＝7.9Hz,1H),8.35(d,J＝8.0Hz,1H),8.29(dd,J＝8.2,2.3Hz,1H),8.09(dd,J＝11.2,4.2Hz,1H),7.97(t,J＝7.8Hz,1H),7.86(d,J＝8.3Hz,1H),6.87(d,J＝0.8Hz,1H),5.75(s,2H),4.18–4.02(m,2H),2.53(s,3H).LC-MS:m/z(ES+)for C22H16F3N7O3 484[M+1]+。
Figure PCTCN2016108975-appb-000053
合成路线2
Figure PCTCN2016108975-appb-000054
Figure PCTCN2016108975-appb-000055
实验过程:
步骤1
3-溴-4-甲基苯甲酸甲酯(B2)
将4.5g的3-溴-4甲基苯甲酸(B1)溶解在50毫升的甲醇中冰浴搅拌的条件下滴加7.47g的氯化亚砜，滴加完毕，自然升到室温，再回流1小时，TLC板(石油醚：乙酸乙酯＝2：1，Rf＝0.9)显示原料反应完全，减压蒸干溶剂，得到黄色的液体(4.6g,产率96％)，不用纯化直接投下一步反应。
步骤2
3-氰基-4-甲基苯甲酸甲酯(B3)
室温下将化合物B2(2.4g)和氰化亚铜(3.0g)分别加入到50毫升的DMF中氩气保护，混合物被升温到140度反应16小时。TLC板(石油醚：乙酸乙酯＝2：1，Rf＝0.5)显示原料反应完全，反应混合物被倒入150毫升的水中，用150毫升的二氯甲烷萃取，有机相用100毫升的水洗三次，再用100毫升盐水洗，无水硫酸钠干燥浓缩溶剂，用层析柱分离纯化得到目标物B3 1.4g，产率76.3％。
步骤3
4-溴甲基-3-氰基苯甲酸甲酯(B4)
常温下将溴代丁二酰亚胺(1.56g)和过氧化苯酰甲(40mg)分别加入到化 合物B3(1.4g)的四氯化碳(35毫升)溶液中，反应混合物被加热回流3天，TLC板(石油醚：乙酸乙酯＝5：1，Rf＝0.7)显示原料反应完全，反应液降至室温，加40毫升水淬灭反应，接着加入40毫升10％的碳酸氢钠水溶液，分液，有机相无水硫酸钠干燥，减压旋干溶剂得黄色液体，粗品1.5g，产率95％。
步骤4&5
3-氰基-4-羟甲基苯甲酸甲酯(B6)
室温下将乙酸钠(3.3g)加入到化合物B4(2.03g)的乙酸溶液中，反应混合物被加热回流16小时，TLC板(石油醚：乙酸乙酯＝3：1，Rf＝0.4)显示原料反应完全，反应液冷却到室温加入100毫升水和80毫升的乙酸乙酯淬灭反应，分液，有机相用10％的碳酸氢钠水溶液洗，无水硫酸钠干燥，减压蒸干，得到粗品B5为黄色液体，将粗品溶解在60毫升的甲醇中，加入4.24g的碳酸钠室温搅拌1小时，TLC板(石油醚：乙酸乙酯＝3：1，Rf＝0.01)显示原料反应完全，反应混合物被过滤，滤饼用少量的甲醇洗，滤液减压蒸干，用层析柱分离用(石油醚：乙酸乙酯＝2：1)淋洗得到白色固体B6 0.6g，产率39％。
步骤6
5-甲基-[1，2，4]氧杂二氮唑-3-甲酸乙酯(B8)
将乙酰氯(18g)加入到乙酸(10.5g)中室温搅拌，得到乙酸酐，备用。将盐酸羟胺(8.6g)，乙酸(48毫升)，氰基甲酸乙酯B7(10g)分别被加入到100毫升的反应瓶中，室温搅拌，再分批加入乙酸钠(10.1g)约15分钟加完，反应混合物在18～28度搅拌2小时，反应混合物被冷却到15度，将乙酸酐缓慢滴加到上述反应液中，约20分钟加完，加完是温度升到约26度，反应混合物被继续搅拌15分钟，再升温到99度，反应12小时，反应液被冷却到室温，减压蒸干乙酸，加入100毫升乙酸乙酯和20毫升的水，再加入37毫升的30％的碳酸钾水溶液，调pH值为7，分液，水相在用30毫升*2的乙酸乙酯萃取，合并有机相用20毫升的水洗，无水硫酸钠干燥，旋干得到白色固体B8 15g,产率95％。
步骤7
5-甲基-[1，2，4]氧杂二氮唑-3-甲酸(B9)
室温下将62毫升2摩尔/升的氢氧化钠溶液滴加到B8(20g)的100毫升乙 醇溶液中，室温搅拌1小时，TLC板(石油醚：乙酸乙酯＝2：1，Rf＝0.5)显示原料反应完全，反应混合物用饱和氯化铵淬灭，减压蒸干溶剂，加甲醇搅拌溶解，过滤，再减压蒸干甲醇，得到白色固体B9 8g，产率49％。
步骤8
5-甲基-(1，2，4)-氧杂二氮唑-3-羧酸-N’-(4-氯-1，2-二氢-酞嗪-1-基)-肼(B11)
将B9(789mg)和三乙胺(1.56g)溶解在100毫升的二氯甲烷中，降温至零度，加入双(2-氧代-3-噁唑烷基)次磷酰氯(1.57g)，氩气保护下搅拌，零度下搅拌20分钟，加入(4-氯-1，2-二氢-酞嗪-1-基)-肼B10(制备参考文献J.Med.Chem.,2004,47,2176-2179)(1g)，反应混合物保持零度搅拌1小时，自然升至室温搅拌过夜，TLC板(二氯甲烷：甲醇＝10：1，Rf＝0.5)显示原料反应完全，反应混合物被过滤，滤液用15毫升的水洗，无水硫酸钠干燥，旋干，柱层析得到产物300毫克，产率19％。
步骤9
6-氯-3-(5-甲基-[1，2，4]氧杂二氮唑-3-基)-[]1，2，4]三氮唑[3，4-a]酞嗪(B12)
化合物B11(800毫克)和三乙胺盐酸盐(69毫克)被加入到100毫升的二甲苯中搅拌加热回流30分钟，TLC板(二氯甲烷：甲醇＝20：1，Rf＝0.7)显示原料反应完全，冷却到室温，反应混合物用10毫升的水洗，水相用20毫升的乙酸乙酯萃取两次，合并有机相，无水硫酸钠干燥，浓缩后柱层析分离(石油醚：乙酸乙酯＝2：1)淋洗得到黄色固体B12 580毫克。1H NMR(400MHz,DMSO-d6)δ:8.82(d,1H J＝8.0),8.35(d,1H J＝8.4),8.13～8.06(m,1H),8.02～7.94(m,1H),2.79(s,3H)。
实施例31
(R)-3-氰基-N(1-羟基丙烷-2-基)-4-[3-(5-甲基-[1,2，4]氧杂二氮唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧杂甲基]-苯甲酰胺(31)
实验操作如实施例1所述：将B13(由B12制备B13的方法参见A3)皂化反应后与D-氨基丙醇(CAS:35320-23-1)缩合反应得到产物白色固体40毫克，产率33％。1H NMR(400MHz,DMSO-d6)δ:8.57(d,1H J＝8.0),8.42～8.33(m,2H),8.28 (d,2H J＝8.0),8.19～7.98(m,4H),5.83(s,2H),4.80～4.70(m,1H),4.06～3.96(m,1H),3.48～3.41(m,1H),3.37～3.31(m,1H),2.80(s,3H),1.11(d,3H J＝6.4)；LC-MS:m/z(ES+)for C24H20N8O4 485.27[M+1]+。
Figure PCTCN2016108975-appb-000056
合成路线3
Figure PCTCN2016108975-appb-000057
实验步骤:
3-溴-4-(溴甲基)苯甲酸甲酯(C1)
将原料B2(3.6g，15.7mmol)(制备见合成路线2)溶解在四氯化碳(40mL)中，室温下加入NBS(3.2g，18mmol)和催化量AIBN。加完后升温至回流反应14小时。TLC板(展开剂为石油醚：乙酸乙酯＝10：1，Rf＝0.5)显示原料反应了 大约2/3。补加0.2当量的NBS，然后再回流3小时。反应没有变化。冷至室温，用40mL水洗涤反应液，接着用40mL的10％的碳酸氢钠水溶液洗涤，最后用无水硫酸钠干燥有机层，蒸干，得到5.3g的粗品产物，产率125％，外观为黄色液体。
4-(乙酰氧甲基)-3-溴-苯甲酸甲酯(C2)
室温下，将C1(4.5g，14.6mmol)加入到乙酸(20mL)中，再加入无水乙酸钠(6g，73mmol)，反应混合物加热至回流，反应14小时。TLC板(展开剂为石油醚：乙酸乙酯＝10：1，Rf＝0.3)显示原料反应完全。反应液冷至室温，加入200mL水和150mL的乙酸乙酯，有机层用10％的碳酸氢钠水溶液洗一次。用无水硫酸钠干燥，蒸干得到C2(粗品，5.3g，产率为125％)，外观为黄色液体。粗品不做纯化，直接投下一步反应。
3-溴-4-(羟甲基)苯甲酸甲酯(C3)
将上步的粗品C2(粗品，5.3g，14.6mmol)加入到20mL的甲醇中，加入无水碳酸钠(7.7g，73mmol)，室温搅拌1小时。TLC板(展开剂为石油醚：乙酸乙酯＝10：1，Rf＝0.1)显示原料反应完全。过滤，滤饼用甲醇洗。合并滤液，浓缩，得到产物的粗品。将粗品过柱层析纯化得到产物(1.5g，41.9％)，外观为白色固体。
3-溴-4-((3-(5-甲基异噁唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧基)亚甲基)苯甲酸甲酯(C4)
将原料A1(155mg，0.55mmol)和C3(200mg，0.82mmol)加入到四氢呋喃(60mL)中，0摄氏度和氮气保护下在10分钟里分批加入叔丁醇钾(92mg，0.82mmol)。加完后，反应液在0摄氏度下反应0.5小时，然后升至室温反应1小时。TLC板(展开剂为二氯甲烷：甲醇＝20：1，Rf＝0.4)显示原料反应完全。反应也直接蒸干得到产物粗品。不做纯化，直接投下一步反应。
3-溴-4-((3-(5-甲基异噁唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧基)亚甲基)苯甲酸(C5)
将上一步的产物C4(粗品，268mg，0.55mmol)加入到20mL的乙醇中，再加入10％的氢氧化钠水溶液(5mL)，室温下搅拌0.5小时。TLC板(展开剂为二氯甲烷：甲醇＝20：1，Rf＝0.2)显示原料反应完全。将反应液浓缩以除去乙醇。 残余物加入20mL的水，用乙酸乙酯(30mL×2)萃取杂质。将水相用柠檬酸调节pH值至4，浓缩干后经柱层析纯化得到产物120mg，产率46.1％，外观为黄色固体。
实施例32
(R)-3-溴-N-(1-羟基丙烷-2-基)-4-((3-(5-甲基异噁唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧)亚甲基)苯甲酰胺(32)
在3mL的DMF中依次加入原料C5(50mg，0.1mmol)、HOBt(18mg，0.13mmol)和EDCI(26mg，0.13mmol)，室温和氮气保护下搅拌10分钟。将(R)-2-氨基正丙醇(10mg，0.13mmol)和N，N-二异丙基乙胺(40mg，0.3mmol)加到反应液中。混合物室温搅拌12小时。TLC板(展开剂：二氯甲烷：甲醇＝10：1，Rf＝0.4)显示原料反应完全。蒸除反应液中的大部分DMF，残余物加入二氯甲烷(10mL)和水(10mL)，并用盐酸调节pH值＝5～6，有机层用水(5mL×2次)洗涤。用无水硫酸钠干燥有机层，浓缩，残余物通过制备板纯化得到产物(10mg，产率：17.8％)，外观为黄色固体。
1H NMR(400MHz,DMSO-d6)δ:8.59～8.57(d,1H),8.31～8.26(m,2H),8.21(s,1H),8.14～8.10(t,1H),7.99～7.95(t,1H),7.90～7.87(t,2H),6.99(s,1H),5.74(s,2H),4.75～4.72(t,1H),4.04～3.97(m,1H),3.46～3.42(m,1H),3.37～3.30(m,1H),2.58(s,3H),1.13～1.11(d,3H)；LC-MS:m/z(ES+)for C24H21BrN6O4 537.12[M+1]+。
Figure PCTCN2016108975-appb-000058
合成路线4
Figure PCTCN2016108975-appb-000059
实验步骤:
5-(羟甲基)异噁唑-3-羧酸(D2)
D1(1g，6.4mmol)加入到10mL的1N的氢氧化钠水溶液中，室温下搅拌1.5小时。TLC板(展开剂：石油醚：乙酸乙酯＝2：1，Rf＝0.01)显示原料反应完全。加入饱和食盐水20mL，用稀盐酸调节pH值为2，每次用60mL的乙酸乙酯萃取水相，共萃取8次。合并有机相，用无水硫酸钠干燥有机相，浓缩蒸干，得到产物D2(0.8g，产率：90％)，外观为白色固体。
5-((四氢化-2H-吡喃-2-氧基)甲基)异噁唑-3-羧酸(D3)
将原料D2(14g，98mmol)和3，4-二氢-2H-吡喃(DHP，9g，107mmol)加入到200mL的乙腈中，再加入五水硫酸铜(1.2g，4.9mmol)，室温下搅拌1h。TLC板(展开剂：二氯甲烷：甲醇＝10：1，Rf＝0.4)显示原料反应完全。将混合物过滤，滤液用无水硫酸钠干燥，浓缩得到粗产品。粗品不做纯化，直接投下一步。
N’-(4-氯代酞嗪-1-基)-5-((四氢-2H-吡喃-2-氧)甲基)异噁唑-3-碳酰肼(D4)
将上一步的粗品(9.1g，40mmol)和三乙胺(12.4g，123mmol)先后加入到900mL的二氯甲烷中，氮气保护下，于0度下再加入双(2-氧-3-噁唑烷基) 磷酰氯(BOP-Cl，10.2g，40mmol)。混合物在0度下搅拌20分钟后，将B10(6g，30.8mmol)加入反应液中。混合物在0度搅拌1小时后，让其自然升至室温，继续搅拌过夜。TLC板(展开剂：二氯甲烷：甲醇＝20：1，Rf＝0.5)显示原料反应完全。将反应液倒入500mL的水中，搅拌后分液，有机层用水洗两次，每次加水500mL。用无水硫酸钠干燥有机层，浓缩得到粗品，不需要做进一步纯化，将粗品直接投下一步反应。
3-(6-氯-[1,2,4]三氮唑[3,4-a]酞嗪-3-基)-5-((四氢-2H-吡喃-2-氧基)甲基)异噁唑(D5)
将上一步的粗品D4(20g，49mmol)和三乙胺盐酸盐(2g，15mmol)加入到750mL的二甲苯中，搅拌加热回流0.5小时。TLC板(展开剂：二氯甲烷：甲醇＝20：1，Rf＝0.7)显示原料反应完全。冷至室温，反应液用500mL的水洗一次。水层用乙酸乙酯(200mL×2次)萃取。合并有机层，用无水硫酸钠干燥，浓缩后将粗品过层析柱纯化得到纯产物8g，外观为黄色固体。还有粗品4g，外观为红色固体。
6-((3-(5((四氢-2H-吡喃-2-氧)甲基)异噁唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧)甲基)烟酸甲酯(D6)
将原料D5(2g，5.2mmol)和6-羟甲基烟酸甲酯(1.73g，10.4mmol)加入到四氢呋喃(400mL)中，氮气保护下，降温至0度，在10分钟内分批加入叔丁醇钾(1.16g，10.4mmol)，反应混合物在0度下搅拌半小时，然后升至室温，再搅拌1小时。TLC板(展开剂：二氯甲烷：甲醇＝20：1，Rf＝0.3)显示原料反应完全。蒸除溶剂，残余物不做进一步纯化，直接投下一步。
6-((3-(5((四氢-2H-吡喃-2-氧)甲基)异噁唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧)甲基)烟酸(D7)
将上一步的粗品直接加入30mL的乙醇，再加入10％的氢氧化钠水溶液8mL，室温下搅拌0.5小时。TLC板(展开剂：二氯甲烷：甲醇＝20：1，Rf＝0.1)显示原料反应完全。将反应液浓缩除去乙醇，残余物加入20mL的水，用乙酸乙酯(30mL×2次)萃取杂质。水相用稀盐酸调pH值＝4，有大量固体析出。抽滤，滤饼用5mL冰水洗一次。抽干滤饼得到D7(1.5g，产率：46.1％)，外观为黄色固体。
实施例33
Figure PCTCN2016108975-appb-000060
6-[3-(5-羟甲基-异噁唑-3-)-[1,2，4]三氮唑[3,4-a]酞嗪-6-氧)亚甲基]-N-吗啉-4-烟酰胺(33)
在5mL的DMF中依次加入原料D7(105mg)、1-羟基苯并三唑(54mg)和1-乙基(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(76.7mg)，室温和氮气保护下搅拌10分钟。将4-氨基吗啡啉(49mg)(CAS：4319-49-7)和N，N-二异丙基乙胺(130mg)加到反应液中。混合物室温搅拌60小时。TLC板(展开剂：二氯甲烷：甲醇＝20：1，Rf＝0.3)显示原料反应完全。反应混合物加入二氯甲烷(25mL)和水(30mL)，有机层用水(20mL×2次)洗涤。用无水硫酸钠干燥有机层，浓缩，残余物通过硅胶柱层析纯化得到产物(76.4mg，产率：65％)，外观为白色固体N-吗啡啉-4-基-6-{3-[5(四氢吡喃-2-氧杂甲基)异噁唑-3-基]-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧甲基}烟酰胺(Da)。
将Da(76.4mg)加入到5mLDCM中，加入一滴盐酸，然后混合物在室温下搅拌16小时。TLC板(展开剂：二氯甲烷：甲醇＝10：1，Rf＝0.3)显示原料反应完全。将反应液过滤，滤饼用DCM(5mL×2次)洗。到产物12 48mg，产率73.3％，外观为白色固体。
1H NMR(400MHz,DMSO-d6)δ:9.73(s,1H),8.96(d,1H J＝1.6),8.58(d,1H J＝8.0),8.35(d,1H J＝8.0),8.22～8.19(m,1H),8.16～8.11(m,1H),8.03～7.98(m,1H),7.86(d,1H J＝8.0),7.11(s,1H),5.85(t,1H J＝6.0),5.76(s,2H),4.72(d,2H J＝6.0),3.8～3.65(m,4H),2.94～2.87(m,4H)；LC-MS:m/z(ES+)for C24H22N8O5 503.25[M+1]+。
实施例34
Figure PCTCN2016108975-appb-000061
N-[(R)-1-羟基丙醇-2-基]-6-{3-[5(羟甲基)异噁唑-3-基]-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧)亚甲基}烟酰胺(34)
实验操作参见实施例12，中间体D7和(R)-2-氨基正丙醇缩合反应得到Db，然后THP脱保护后得到目标化合物78mg，产率100％，外观为淡黄色固体。1H NMR(400MHz,DMSO-d6)δ:9.07(d,1H J＝1.6),8.61～8.53(m,2H),8.40～8.30(m,2H),8.16～8.10(m,1H),8.05～7.95(m,1H),7.84(d,1H J＝8.4),7.13(s,1H),5.76(s,2H),4.73(s,2H),4.05～3.97(m,1H),3.50～3.42(m,2H),1.12(d,3H J＝6.4)；LC-MS:m/z(ES+)for C23H21N7O5 476.17[M+1]+。
实施例35
Figure PCTCN2016108975-appb-000062
N-((1S，2S)-2-羟基环戊基)-6-((3-(5-(羟甲基)异噁唑-3-基)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧)亚甲基)烟酰胺(35)
实验操作参见实施例12，中间体D7和反式-(1S,2S)-2-氨基-环戊醇盐酸盐(CAS：68327-04-8)缩合反应得到Dc,然后THP脱保护后得到目标产物20mg，产率46.9％，外观为黄色固体。1H NMR(400MHz,DMSO-d6)δ:9.02(d,1H),8.60～8.58(d,1H),8.47～8.45(d,1H),8.37～8.35(d,1H),8.27～8.24(m,1H),8.15～8.11(t,1H),8.02～7.98(t,1H),7.87～7.85(d,1H),7.13(s,1H)5.76(s,2H),4.73(s,2H),4.01～3.97(m,2H),2.01～1.82(m,3H),1.68～1.62(m,2H),1.49～1.45(m,2H)；LC-MS:m/z(ES+)for C25H23N7O5 502.19[M+1]+。
实施例36
Figure PCTCN2016108975-appb-000063
N-环丙基-6-{3-[5(羟甲基)异噁唑-3-基]-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧)亚甲基}烟酰胺(36)
实验操作参见实施例12，中间体D7和环丙胺(CAS：765-30-0)缩合反应得Dd然后THP脱保护后得到目标产物38mg，产率50.8％，外观为白色固体。1H NMR(400MHz,DMSO-d6)δ:9.00(d,1H J＝1.2),8.65(d,1H J＝4.0),8.57(d,1H J＝8.0),8.35(d,1H J＝8.0),8.25～8.22(m,1H),8.15～8.10(m,1H),8.02～7.97(m,1H),7.85(d,1H J＝8.0),7.11(s,1H),5.85(t,1H J＝6.0),5.76(s,2H),4.72(d,2H J＝6.0),2.90～2.80(m,1H),0.75～0.69(m,2H),0.61～0.56(m,2H)；LC-MS:m/z(ES+)for C23H19N7O4 458.21[M+1]+。
实施例37
Figure PCTCN2016108975-appb-000064
N-(1-甲基-1H-吡唑-4-基)-6-{3-[5(羟甲基)异噁唑-3-基]-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧)亚甲基}烟酰胺(37)
实验操作参见实施例12，中间体D7和1-甲基-1H-吡唑-4-胺(CAS：69843-13-6)缩合反应得De然后THP脱保护后得到目标产物41mg，产率88％，外观为类白色固体。
1H NMR(400MHz,DMSO-d6)δ:10.70(s,1H),9.14(s,1H),8.58(d,1H J＝7.6),8.37(d,2H J＝6.8),8.13(t,1H J＝6.4),8.06～7.91(m,3H),7.58(s,1H),7.13(s,1H),5.88(t,1H J＝6.0),5.79(s,2H),4.73(d,2H J＝6.0),3.82(s,3H)；LC-MS:m/z(ES+)for C24H19N9O4 498.27[M+1]+。
实施例38
Figure PCTCN2016108975-appb-000065
6-{3-[5(羟甲基)异噁唑-3-基]-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧甲基}N-异丙基烟酰胺(38)
实验操作参见实施例12，中间体D7和异丙胺(CAS：75-31-0)缩合反应得Df然后THP脱保护后得到目标产物66mg，产率90％，外观为白色固体。1H NMR(400MHz,DMSO-d6)δ:9.03(d,1H J＝1.6),8.60(d,1H J＝7.6),8.45(d,1H J＝7.6),8.35(d,1H J＝8.0),8.28～8.24(m,1H),8.16～8.10(m,1H),8.03～7.98(m,1H),7.85(d,1H J＝8.0),7.13(s,1H),5.88(s,1H),5.76(s,2H),4.73(s,2H),4.16～4.05(m,1H),1.16(d,6H J＝6.4)；LC-MS:m/z(ES+)for C23H21N7O4 460.27[M+1]+。
实施例39
Figure PCTCN2016108975-appb-000066
N-(2-羟乙基)-6-{3-[5(羟甲基)异噁唑-3-基]-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧)亚甲基}烟酰胺(39)
实验操作参见实施例12，中间体D7和乙醇胺(CAS：141-43-5)缩合反应得Dg然后THP脱保护后得到目标产物66mg，产率90％，外观为白色固体。1H NMR(400MHz,DMSO-d6)δ:9.04(d,1H J＝1.6),8.70(t,1H J＝5.6),8.58(d,1H J＝8.0),8.37(d,1H J＝7.6),8.30～8.26(m,1H),8.16～8.10(m,1H),8.03～7.98(m,1H),7.86(d,1H J＝8.4),7.13(s,1H),5.86(t,1H J＝6.4),5.76(s,2H),4.78～4.72(m,3H),3.55～3.45(m,2H),3.38～3.32(m, 2H)；LC-MS:m/z(ES+)for C22H19N7O5 462.25[M+1]+。
实施例40
Figure PCTCN2016108975-appb-000067
(6-{3-[5(羟甲基)异噁唑-3-基]-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧)亚甲基)N-(1，1-二氧硫代吗啉-4-基)烟酰胺(40)
实验操作参见实施例12，中间体D7和硫代吗啉1,1-二氧化物盐酸盐(CAS:59801-62-6)缩合反应得Dh然后THP脱保护后得到目标产物58mg，产率83.9％，外观为白色固体。1H NMR(400MHz,DMSO-d6)δ:8.75(d,1H J＝1.2),8.58(d,1H J＝8.0),8.36(d,1H J＝8.4),8.13(t,1H J＝7.6),8.05～7.97(m,2H),7.85(d,1H J＝8.0),7.12(s,1H),5.85(t,1H J＝6.0),5.75(s,2H),4.73(d,2H J＝6.0),4.12～3.95(m,2H),3.82～3.65(m,2H),3.22～3.35(m,4H)；LC-MS:m/z(ES+)for C24H21N7O6S 536.24[M+1]+。
实施例41
Figure PCTCN2016108975-appb-000068
(6-{3-[5(羟甲基)异噁唑-3-基]-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧)亚甲基)N-吗啉烟酰胺(41)
实验操作参见实施例12，中间体D7和吗啉(CAS:110-91-8)缩合反应得Di然后THP脱保护后得到目标产物70mg，产率90.5％，外观为白色固体。
1H NMR(400MHz,DMSO-d6)δ:8.67(d,1H J＝1.6),8.60(d,1H J＝3.6),8.36 (d,1H J＝8.0),8.13(t,1H J＝7.2),8.02～7.92(m,2H),7.82(d,1H J＝8.0),7.11(s,1H),5.85(t,1H J＝6.0),5.75(s,2H),4.72(d,2H J＝6.0),3.70～3.5(m,6H),3.35～3.25(m,2H)；LC-MS:m/z(ES+)for C24H21N7O5488.26[M+1]+。
实施例42
Figure PCTCN2016108975-appb-000069
6-{3-[5(羟甲基)异噁唑-3-基]-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧)亚甲基}-N-(2，2，2-三氟乙基)烟酰胺(42)
实验操作参见实施例12，中间体D7和2,2,2-三氟乙胺盐酸盐(CAS:373-88-6)缩合反应得Dj然后THP脱保护后得到目标产物57mg，产率88％，外观为白色固体。1H NMR(400MHz,DMSO-d6)δ:9.34(t,1H J＝6.0),9.08(d,1H J＝1.6),8.56(d,1H J＝8.0),8.38～8.30(m,2H),8.12(t,1H,J＝7.6),7.99(t,1H J＝8.0),7.92(d,2H,J＝8),7.11(s,1H),5.86(t,1H J＝6.0),5.77(s,2H),4.72(d,2H J＝6.0),4.20～4.08(m,2H)；LC-MS:m/z(ES+)for C22H16F3N7O4 500.20[M+1]+。
实施例43
Figure PCTCN2016108975-appb-000070
N-(2-甲氧基乙基)-6-{3-[5(羟甲基)异噁唑-3-基]-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧)亚甲基}烟酰胺(43)
实验操作参见实施例12，中间体D7和2-甲氧基乙胺(CAS:109-85-3)缩合反应得Dk然后THP脱保护后得到目标产物57mg，产率85％，外观为白色固体。
1H NMR(400MHz,DMSO-d6)δ:9.04(d,1H J＝1.6),8.78(t,1H J＝4.8),8.58(d,1H J＝8.0),8.36(d,1H J＝8.0),8.30～8.26(m,1H),8.16～8.10(m,1H),8.03～7.98(m,1H),7.86(d,1H J＝8.0),7.12(s,1H),5.86(t,1H J＝6.4),5.76(s,2H),4.72(d,2H J＝6.0),3.50～3.40(m,4H),3.26(s,3H)；LC-MS:m/z(ES+)for C23H21N7O5 476.26[M+1]+。
实施例44
Figure PCTCN2016108975-appb-000071
N-(四氢吡喃-4-基)-6-{3-[5(羟甲基)异噁唑-3-基]-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧)亚甲基}烟酰胺(44)
实验操作参见实施例12，中间体D7和4-氨基四氢吡喃盐酸(CAS:33024-60-1)缩合反应得Dl然后THP脱保护后得到目标产物51.7mg，产率63.8％，外观为白色固体。1H NMR(400MHz,DMSO-d6)δ:9.03(s,1H),8.58(d,1H J＝7.6),8.53(d,1H J＝7.6),8.35(d,1H J＝8.0),8.28～8.25(m,1H),8.16～8.10(m,1H),8.03～7.98(m,1H),7.85(d,1H J＝8.0),7.12(s,1H),5.86(t,1H J＝5.6),5.76(s,2H),4.72(d,2H J＝6.0),4.07～3.83(m,4H),1.82～1.75(m,2H),1.62～1.52(m,2H)；LC-MS:m/z(ES+)for C25H23N7O5 502.26[M+1]+。
实施例45
Figure PCTCN2016108975-appb-000072
N，N-二甲基-6-{3-[5(羟甲基)异噁唑-3-基]-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧)亚甲基}烟酰胺(45)
实验操作参见实施例12，中间体D7和盐酸二甲胺(CAS:506-59-2)缩合反应得Dm然后THP脱保护后得到目标产物74mg，产率96％，外观为白色固体。1HNMR(400MHz,DMSO-d6)δ:8.67(d,1H J＝1.6),8.58(d,1H J＝8.0),8.36(d,1H J＝8.0),8.16～8.11(m,1H),8.02～7.92(m,2H),7.81(d,1H J＝8.0),
7.12(s,1H),5.85(t,1H J＝6.0),5.75(s,2H),4.72(d,2H J＝6.0),3.00(s,3H),2.92(s,3H)；LC-MS:m/z(ES+)for C22H19N7O4 446.28[M+1]+。
实施例46
Figure PCTCN2016108975-appb-000073
N-乙基-6-{3-[5(羟甲基)异噁唑-3-基]-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧)亚甲基}烟酰胺(46)
实验操作参见实施例12，中间体D7和乙胺盐酸盐(CAS:557-66-4)缩合反应得Dn然后THP脱保护后得到目标产物80mg，产率92％，外观为白色固体。1HNMR(400MHz,DMSO-d6)δ:9.03(d,1H J＝1.6),8.70(t,1H J＝5.2),8.59(d,1H J＝8.0),8.38(d,1H J＝8.4),8.27～8.24(m,1H),8.13(t,1H J＝7.6),7.99(t,1H J＝7.6),7.87(d,1H J＝8.4),7.12(s,1H),5.86(t,1H J＝6.0),5.76(s,2H),4.74(d,2H J＝6.0),3.38～3.25(m,2H),1.13(t,3H J＝7.2)。LC-MS:m/z(ES+)for C22H19N7O4 446.00[M+1]+。
实施例47
Figure PCTCN2016108975-appb-000074
N-(四氢呋喃-3-基)-6-{3-[5(羟甲基)异噁唑-3-基]-[1,2,4]三氮唑[3,4-a] 酞嗪-6-氧)亚甲基}烟酰胺(47)
实验操作参见实施例12，中间体D7和3-氨基四氢呋喃盐酸盐(CAS:204512-94-7)缩合反应得Do然后THP脱保护后得到目标产物79mg，产率92％，外观为灰白色固体。
1H NMR(400MHz,DMSO-d6)δ:9.04(d,1H J＝1.6),8.76(d,1H J＝6.4),8.57(d,1H J＝8.0),8.35(d,1H J＝8.0),8.30～8.26(m,1H),8.16～8.10(m,1H),8.02～7.97(m,1H),7.86(d,1H J＝8.4),7.12(s,1H),5.86(t,1H J＝6.4),5.76(s,2H),4.72(d,2H J＝6.0),4.50～4.30(m,1H),3.90～3.80(m,2H),3.76～3.68(m,1H),3.62～3.57(m,1H),2.22～2.12(m,1H),1.95～1.90(m,1H)；LC-MS:m/z(ES+)for C24H21N7O5 488.32[M+1]+。
实施例48
Figure PCTCN2016108975-appb-000075
N-环丁基-6-{3-[5(羟甲基)异噁唑-3-基]-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧)亚甲基}烟酰胺(48)
实验操作参见实施例12，中间体D7和环丁基胺(CAS:2516-34-9)缩合反应得Dp然后THP脱保护后得到目标产物61mg，产率90％，外观为灰白色固体。1H NMR(400MHz,DMSO-d6)δ:9.02(d,1H J＝1.6),8.82(d,1H J＝6.4),8.58(d,1H J＝7.6),8.36(d,1H J＝8.0),8.28～8.24(m,1H),8.16～8.10(m,1H),8.02～7.98(m,1H),7.86(d,1H J＝8.4),7.12(s,1H),5.86(t,1H J＝6.4),5.76(s,2H),4.72(d,2H J＝6.0),4.46～4.38(m,1H),2.27～2.18(m,2H),2.10～2.03(m,2H),1.73～1.65(m,2H)；LC-MS:m/z(ES+)for C24H21N7O4472.33[M+1]+。
实施例49
Figure PCTCN2016108975-appb-000076
氮杂环丁基-1-基-(6-{3-[5(羟甲基)异噁唑-3-基]-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧)亚甲基}-3-烟酰胺(49)
实验操作参见实施例12，中间体D7和杂氮环丁烷(CAS:503-29-7)缩合反应得Dq然后THP脱保护后得到产物54mg，产率88％，外观为白色固体。
1H NMR(400MHz,DMSO-d6)δ:8.84(d,1H J＝1.6),8.58(d,1H J＝7.6),8.36(d,1H J＝8.0),8.16～8.05(m,2H),8.02～7.98(m,1H),7.83(d,1H J＝8.0),7.11(s,1H),5.86(t,1H J＝6.4),5.76(s,2H),4.72(d,2H J＝6.0),4.33(t,2H J＝7.6),4.07(t,2H J＝7.6),2.32～2.23(m,2H)；LC-MS:m/z(ES+)for C23H19N7O4458.29[M+1]+。
实施例50
Figure PCTCN2016108975-appb-000077
(6-{3-[5(羟甲基)异噁唑-3-基]-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧)亚甲基}N-(1-一氧硫代吗啉-4-基)烟酰胺(50)
实验操作参见实施例12：1-一氧硫代吗啉-4-氨基q的原料(合成参考文献Biodegradation,1998,9,(6)433-442)与D7缩合反应得到产物75mg，产率90％，外观为白色固体。
1H NMR(400MHz,DMSO-d6)δ:8.71(d,1H J＝1.6),8.55(d,1H J＝8.0),8.33(d,1H J＝8.0),8.13～8.08(m,1H),8.00～7.95(m,2H),7.85(d,1H J＝8.0),7.11(s,1H),5.89(t,1H J＝6.0),5.74(s,2H),4.74(d,2H,J＝5.6)4.45～4.33(m,1H),3.95～3.45(m,3H),3.08～2.93(m,2H),2.92～2.62(m,2H)； LC-MS:m/z(ES+)for C24H21N7O5S 520.21[M+1]+。
实施例51
6-{3-[5(羟甲基)异噁唑-3-基]-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧)亚甲基}烟酰肼(51)
Figure PCTCN2016108975-appb-000078
N'-(6-{3-[5(四氢-2H-吡喃-2-氧甲基)异噁唑-3-基]-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧甲基}-吡啶-3-羰基)-烟酰肼(Ds)
3mL的水合肼的15mL的乙醇溶液中加入原料D6(375mg)室温搅拌5h。反应液过滤。乙醇和少量水洗涤滤饼，滤饼干燥后得到白色固体。直接进行下一步反应没有经过进一步纯化。
6-{3-[5(羟甲基)异噁唑-3-基]-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧甲基}烟酰肼(51)
将Ds(280mg)加入到25mL的二氯甲烷中，加入浓盐酸(100mg)，然后混合物在室温下搅拌16小时。TLC板(展开剂：二氯甲烷：甲醇＝10：1，Rf＝0.4)显示原料反应完全。将反应液过滤，滤饼柱层析纯化得到产物180mg，产率91.7％，外观为白色固体。
1H NMR(400MHz,DMSO-d6)δ:11.86(m,1H),9.11(s,1H),8.59(d,1H J＝7.6),8.42～8.35(m,2H),8.14(t,1H J＝7.6),8.01(t,1H J＝7.6),7.94(d,1H J＝8.4),7.10(s,1H),5.80(s,2H),4.73(s,2H)；LC-MS:m/z(ES+)for C20H16N8O4 433.24[M+1]+。
实施例52
Figure PCTCN2016108975-appb-000079
N-哌啶-1-基-6-{3-[5(羟甲基)异噁唑-3-基]-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧)亚甲基}烟酰胺(52)
实验操作参见实施例12，中间体D7和N-氨基哌啶盐酸盐(CAS:63234-70-8)缩合反应得Dt然后THP脱保护后得到产物42mg，产率70％，外观为白色固体。1H NMR(400MHz,DMSO-d6)δ:9.59(s,1H)8.95(d,1H J＝1.6),8.58(d,1H J＝7.6),8.35(d,1H J＝8.0),8.21～8.10(m,2H),8.03～7.97(m,1H),7.84(d,1H J＝8.0),7.11(s,1H),5.76(s,2H),4.73(s,2H),2.83(t,4H J＝5.2),1.63～1.56(m,4H),1.40～1.33(m,2H)；LC-MS:m/z(ES+)for C25H24N8O4 501.36[M+1]+。
实施例53
Figure PCTCN2016108975-appb-000080
6-{3-[5(羟甲基)异噁唑-3-基]-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧)亚甲基}烟酸甲磺酰肼(53)
将30(60mg)加入到2mL吡啶中，滴加甲黄酰氯(21.3mg)，然后混合物在室温下搅拌16小时。TLC板(展开剂：二氯甲烷：甲醇＝10：1，Rf＝0.4)显示原料反应完全。将反应液浓缩，柱层析纯化得到产物4mg，产率5.6％，外观为白色固体。1H NMR(400MHz,DMSO-d6)δ:10.98(s,1H)9.72(s,1H)9.07(d,1H J＝1.6),8.57(d,1H J＝8.0),8.37(d,1H J＝8.0),8.33～8.30(m,1H), 8.16～8.11(m,1H),8.03～7.98(m,1H),7.90(d,1H J＝8.4),7.12(s,1H),5.87(t,1H J＝6.0),5.78(s,2H),4.72(d,2H J＝5.6),3.03(s,3H)；LC-MS:m/z(ES+)for C21H18N8O6S 511.26[M+1]+。
实施例54
Figure PCTCN2016108975-appb-000081
N-(1，1-二氧硫代吗啉-4-基)-6-{3-[5(羟甲基)异噁唑-3-基]-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧甲基}烟酰胺(54)
实验操作参见实施例12，中间体D7和4-氨基硫代吗啉-1,1-二氧化物(CAS:26494-76-8)缩合反应得Dv然后THP脱保护后得到产物30mg，产率69％，外观为白色固体。
1H NMR(400MHz,DMSO-d6)δ:10.08(s,1H)8.99(s,1H)8.58(d,1H J＝8.0),8.37-8.35(d,1H J＝8.0),8.22(d,1H J＝8.0),8.16～8.10(m,1H),8.03～7.98(m,1H),7.86(d,1H J＝8.4),7.11(s,1H),5.88(t,1H J＝6.0),5.76(s,2H),4.72(d,2H J＝5.6),3.44～3.39(m,4H),3.30～3.25(m,4H)；LC-MS:m/z(ES+)for C24H22N8O6S 551.33[M+1]+。
Figure PCTCN2016108975-appb-000082
合成路线5
Figure PCTCN2016108975-appb-000083
实验过程:
3-氰基-4-{3-[5-(四氢-2H-吡喃-2-氧甲基)-异噁唑-3-基]-[1,2,4]三氮唑[3，4-a]酞嗪-6-氧甲基}-苯甲酸甲酯(E1)
氩气保护下，D5(400毫克)和B6(400毫克)的无水四氢呋喃溶液被分批加入叔丁醇钠(200毫克)保持零度，约10分钟加完。反应混合物零度搅拌30分钟，自然升到室温再搅拌1小时，TLC板(二氯甲烷：甲醇＝20：1，Rf＝0.5)显示原料反应完全，反应混合物被浓缩干，直接投下一步反应。
3-氰基-4-{3-[5-(四氢-2H-吡喃-2-氧甲基)-异噁唑-3-基]-[1,2,4]三氮唑[3，4-a]酞嗪-6-氧甲基}-苯甲酸(E2)
向上一步的旋干得残渣中加入10毫升的乙醇，在加入10％的氢氧化钠约4毫升，室温搅拌30分钟，TLC板(二氯甲烷：甲醇＝20：1，Rf＝0.1)显示原料反应完全，反应混合物中乙醇被浓缩干，加入20毫升水，乙酸乙酯30毫升萃取两次，水相加入饱和氯化铵，有固体析出，过滤，滤饼用水洗，干燥得到白色固体140毫克，产率25.7％。
实施例55
3-氰基-N-(R)(2-羟基-1-甲基-乙基)-4-{3-[5-(羟甲基)-异噁唑-3-基]-[1,2,4]三氮唑[3，4-a]酞嗪-6-氧甲基}-苯甲酰胺(55)
实验操作参见实施例31：原料是化合物E3和D-氨基丙醇(CAS:35320-23-1)得到产物42mg，产率81.8％，外观为白色固体。
1H NMR(400MHz,DMSO-d6)δ:8.58(d,1H J＝7.6),8.42～8.36(m,2H),8.27(d,1H J＝8.0),8.18(m,1H),8.01～7.96(m,1H),7.19(s,1H),5.90～5.80(m,3H),4.80～4.70(m,3H),4.05～3.97(t,1H),3.49～3.42(m,1H),3.39～3.32(m,1H),1.12(d,3H J＝6.8)；LC-MS:m/z(ES+)for C25H21N7O5 500.31[M+1]+。
实施例56
3-氰基-N-((1S，2S)-2-羟基环戊基2-羟基-环戊基)-4-{3-[5-(羟甲基)-异噁唑-3-基]-[1,2,4]三氮唑[3，4-a]酞嗪-6-氧)亚甲基}-苯甲酰胺(56)
实验操作参见实施例35：原料是化合物E3和反式-(1S,2S)-2-氨基-环戊醇盐酸盐(CAS:68327-04-8)得到产物44mg，产率78.5％，外观为白色固体。
1H NMR(400MHz,DMSO-d6)δ:8.58(d,1H J＝8.0),8.45(d,1H J＝6.4),8.39(d,1H J＝1.6),8.27(d,1H J＝8.0),8.17(m,1H),8.04(d,1H J＝8.0),8.01～7.96(m,1H)7.19(s,1H),5.90～5.80(m,3H),4.81～4.73(m,3H),4.03～3.96(t,2H),2.04～1.96(m,1H),1.89～1.81(m,1H),1.70～1.62(m,2H),1.52～1.44(m,2H)；LC-MS:m/z(ES+)for C27H23N7O5 526.31[M+1]+。
Figure PCTCN2016108975-appb-000084
合成路线6
Figure PCTCN2016108975-appb-000085
实验过程:
步骤1
5-甲基-[1，2，4]氧杂二氮唑-3-甲酸乙酯(F2)
将乙酰氯(18g)加入到乙酸(10.5g)中室温搅拌，得到乙酸酐，备用。将盐酸羟胺(8.6g)，乙酸(48毫升)，氰基甲酸乙酯F1(10g)分别被加入到100毫升的反应瓶中，室温搅拌，再分批加入乙酸钠(10.1g)约15分钟加完，反应混合物在18～28度搅拌2小时，反应混合物被冷却到15度，将乙酸酐缓慢滴加到上述反应液中，约20分钟加完，加完是温度升到约26度，反应混合物被继续搅拌15分钟，再升温到99度，反应12小时，反应液被冷却到室温，减压蒸干乙酸，加入100毫升乙酸乙酯和20毫升的水，再加入37毫升的30％的碳酸钾水溶液，调pH值为7，分液，水相在用30毫升*2的乙酸乙酯萃取，合并有机相用20毫升的水洗，无水硫酸钠干燥，旋干得到白色固体F2约15g,产率95％。
步骤2
5-甲基-[1，2，4]氧杂二氮唑-3-甲酸(F3)
室温下将62毫升2摩尔/升的氢氧化钠溶液滴加到F2(20g)的100毫升乙醇溶液中，室温搅拌1小时，TLC板(石油醚：乙酸乙酯＝2：1，Rf＝0.5)显示原料反应完全，反应混合物用饱和氯化铵淬灭，减压蒸干溶剂，加甲醇搅拌溶解，过滤，再减压蒸干甲醇，得到白色固体F3约8g)，产率49％。
步骤3
5-甲基-(1，2，4)-氧杂二氮唑-3-羧酸-N’-(4-氯-1，2-二氢-酞嗪-1-基)-肼(F4)
将F3(789mg)和三乙胺(1.56g)溶解在100毫升的二氯甲烷中，降温至零度，加入双(2-氧代-3-噁唑烷基)次磷酰氯(1.57g)，氩气保护下搅拌，零度下搅拌20分钟，加入(4-氯-1，2-二氢-酞嗪-1-基)-肼(1g)，反应混合物保持零度搅拌1小时，自然升至室温搅拌过夜，TLC板(二氯甲烷：甲醇＝10：1，Rf＝0.5)显示原料反应完全，反应混合物被过滤，滤液用15毫升的水洗，无水硫酸钠干燥，旋干，过柱得到产物300毫克，产率19％。
步骤4
6-氯-3-(5-甲基-[1，2，4]氧杂二氮唑-3-基)-[]1，2，4]三氮唑[3，4-a]酞嗪(F5)
F4(800毫克)和三乙胺盐酸盐(69毫克)被加入到100毫升的二甲苯中搅拌加热回流30分钟，TLC板(二氯甲烷：甲醇＝20：1，Rf＝0.7)显示原料反应完全，冷却到室温，反应混合物用10毫升的水洗，水相用20毫升的乙酸乙酯萃取两次，合并有机相，无水硫酸钠干燥，浓缩过柱用(石油醚：乙酸乙酯＝2：1)淋洗得到黄色固体F5约580毫克。
1H NMR(400MHz,DMSO-d6)δ:8.82(d,1H J＝8.0),8.35(d,1H J＝8.4),8.13～8.06(m,1H),8.02～7.94(m,1H),2.79(s,3H)。
步骤5
6-{3-[5-甲基-异噁唑-3-基]-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧甲基}烟酸甲酯(F6)
氩气保护下，F5(286毫克)和6-羟甲基烟酸甲酯A2(334毫克)的无水四氢呋喃溶液被分批加入叔丁醇钠(192毫克)保持零度，约10分钟加完。反应混合物零度搅拌30分钟，自然升到室温再搅拌1小时，TLC板(二氯甲烷：甲 醇＝20：1，Rf＝0.5)显示原料反应完全，反应混合物被浓缩干，直接投下一步反应。
步骤6
6-{3-[5-甲基-异噁唑-3-基]-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧甲基}烟酸(F7)
向上一步的旋干得残渣中加入10毫升的乙醇，在加入10％的氢氧化钠约1.6毫升，室温搅拌30分钟，TLC板(二氯甲烷：甲醇＝20：1，Rf＝0.01)显示原料反应完全，反应混合物中乙醇被浓缩干，加入饱和氯化铵，有固体析出，过滤，滤饼用水洗，干燥得到类白色固体240毫克，产率60％。
步骤7
实施例57
(R)-N-(1-羟基-2-丙基)-(6-{3-[5-甲基-1,2,4-氧杂二氮唑-3-)-[1,2,4]三氮唑[3,4-a]酞嗪-6-氧)亚甲基}烟酰胺(57)
将1-羟基苯并三唑(81mg)，1-乙基(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(115mg),F7(120mg)分别溶解到5毫升的DMF中氩气保护下室温搅拌10分钟，(R)-2-氨基丙醇(45mg)和N,N’-二异丙基乙胺(155mg)被加入到反应混合物中，室温搅拌过夜，TLC板(二氯甲烷：甲醇＝20：1，Rf＝0.3)显示原料反应完全，反应混合物被加入25毫升的二氯甲烷和30毫升的水，分液，有机相水洗二次，无数硫酸钠干燥，浓缩过柱，得到白色固体54毫克，产率44.9％。1H NMR(400MHz,DMSO-d6)δ:9.01(d,1H J＝1.2),8.63～8.56(m,1H),8.38～8.33(m,2H),8.24～8.28(m,1H),8.17～8.11(m,1H),8.05～7.95(m,1H),7.89(d,1H J＝8.0),5.72(s,2H),4.74(t,2H J＝6.0),4.08～3.98(m,1H),3.49～3.42(m,1H),3.38～3.32(m,1H),2.78(s,3H),1.12(d,3H J＝6.8)；LC-MS:m/z(ES+)for C22H20N8O4 461.30[M+1]+。
Figure PCTCN2016108975-appb-000086
合成路线7
Figure PCTCN2016108975-appb-000087
实验步骤:
Step 1
3-羟甲基异噁唑-5-羧酸(2-羟基-1-甲乙基)-酰胺(G1)
在50mL单口瓶中加入HOBt(878mg,6.5mmol),EDCI(500mg,6.5mmol),D2(715mg,5mmol)和DMF(30mL)，搅拌溶解，氩气保护下加入R-2-氨基丙醇和DIPEA，常温搅拌过夜，TLC显示反应完毕，加入THF溶解，饱和氯化钠水溶液洗涤两次，无水硫酸钠干燥，减压蒸干得600毫克黄色油状物，收率60％。
Step2
实施例58
(R)-N-(1-羟基-2-丙基)-3-(((3-(5-甲基异噁唑-3)-[1,2,4]三唑并[3,4]酞嗪-6-氧)亚甲基]-异噁唑-5-酰胺(58)
在100mL三口瓶中加入G1(105mg,0.53mmol),A1(100mg,0.35mmol)和THF(50mL)，氩气保护下搅拌溶解，冰浴冷却至0度，加入t-BuONa(51mg,1.5eq)，加毕搅拌自然升温反应1.5小时，TLC(DCM:MeOH＝20:1,Rf＝0.4)显示反应完毕。反应混合液倒到30毫升水溶液中，二氯甲烷萃取(50mLX2)，有机层合并，水洗，饱和食盐水洗，无水硫酸钠干燥，减压浓缩后过硅胶柱纯化得32毫克白色固体，收率22％。
1H NMR(400MHz,DMSO-d6)δ:8.58(d,J＝7.6Hz,1H),8.46(d,J＝8.0Hz,1H),8.27(d,J＝8.0Hz,1H),8.12(t,J＝7.2Hz,1H),7.98(t,1H),7.20(s,1H),7.12(s,1H),5.87(s,2H),4.78(t,J＝5.6Hz,1H),4.02～3.98(m,1H),3.44-3.41(m,1H),2.61(s,3H),1.12(d,J＝6.8Hz,3H)；LC-MS:m/z(ES+)for C21H19N7O5 450.24[M+1]+。
Figure PCTCN2016108975-appb-000088
合成路线8
Figure PCTCN2016108975-appb-000089
实验过程:
6-(3-呋喃-3-基-[1,2,4]三唑并[3,4-a]酞嗪-6-基氧亚甲基)-烟酸甲酯(H2)
将H1(812毫克)(制备参考US6313125)和6-羟甲基烟酸甲酯(812毫克)溶于无水四氢呋喃，随后在0℃氩气保护下十分钟内分批加入叔丁醇钠(576毫克)。反应液在0℃下搅拌半小时，然后升至室温搅拌1小时。TLC(二氯甲烷:甲醇＝20:1，Rf＝0.5)显示原料反应完全。反应液浓缩干燥，并直接用于下一步反应。
6-(3-呋喃-3-基-[1,2,4]三唑并[3,4-a]酞嗪-6-基氧亚甲基)-烟酸(H3)
将上步H2溶于乙醇(10毫升)，随后在室温下加入10％氢氧化钠水溶液(4.8毫升)。反应液室温下搅拌半小时。TLC(二氯甲烷:甲醇＝20:1，Rf＝0.1)显示原料反应完全。反应液浓缩，加入20毫升水溶解，并用乙酸乙酯洗涤(30毫升×2)。水相用饱和氯化铵溶液淬灭。有大量固体析出，过滤，滤饼用5毫升水洗涤，真空干燥得到灰白色固体H3(500毫克，43％)。
实施例59
R-6-(((3-呋喃-3-基-[1,2,4]三唑并[3,4-a]酞嗪-6-基氧)亚甲基)-N-(1-羟基丙基-2-)-烟酰胺(59)
将1-羟基苯并三唑(81毫克，0.6毫摩尔)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(115毫克，0.6毫摩尔)，和H3(116毫克，0.3毫摩尔)溶于N，N-二甲基甲酰胺(5毫升)，在室温、氩气保护下搅拌10分钟。(R)-2-氨基丙醇(45毫克)和N，N-二异丙基乙胺(155毫克)依次加入。反应液室温下搅拌16小时。TLC(二氯甲烷:甲醇＝20:1，Rf＝0.3)显示原料反应完全。反应液中加入二氯甲烷(25毫升)和水(30毫升)。有机相用水洗涤(20毫升*2)，无水硫酸钠干燥，浓缩，柱层析得到白色固体(23.8毫克，17.8％)。
1H NMR(400MHz,DMSO-d6)δ:9.04(d,1H J＝1.6),8.61(s,1H),8.52(d,1H J＝8.0),8.34(d,2H J＝8.0),8.28～8.24(m,1H),8.09(t,1H J＝7.6),7.99～7.92(m,2H),7.79(d,1H J＝8.0),7.19(d,1H J＝1.2),5.83(s,2H),4.74(t,1H J＝5.6),4.06～3.98(m,1H),3.49～3.42(m,1H),3.38～3.35(m,1H)1.12(d,3H J＝6.8)；LC-MS:m/z(ES+)for C23H20N6O4 445.30[M+1]+。
Figure PCTCN2016108975-appb-000090
合成路线9
Figure PCTCN2016108975-appb-000091
合成步骤:
噻吩-3-羧酸N'-(4-氯-酞嗪-1-基)-肼(J2)
将B10(640毫克，5毫摩尔)和三乙胺(1.58克，15毫摩尔)溶于40毫升二氯甲烷，随后在0℃氩气保护下一次性加入双(2-氧-3噁唑烷基)磷酸氯 (BOP-Cl，1.53克，6毫摩尔)。混合物室温下搅拌20分钟。然后再加入J1(970毫克，4.98毫摩尔)，反应液在0℃下搅拌1小时，随后室温下过夜。TLC(二氯甲烷：甲醇＝10：1，Rf＝0.5)显示原料反应完全。过滤，并用15毫升水洗涤，干燥得到产物(0.9克，59％)。
6-氯-3-噻吩-3-基-[1,2,4]三唑并[3,4-a]酞嗪(J3)
将J2(900毫克，2.95毫摩尔)和三乙胺盐酸盐(69毫克，0.5毫摩尔)置于100毫升二甲苯中，搅拌，加热回流0.5小时。TLC(二氯甲烷：甲醇＝20：1，Rf＝0.7)显示大部分原料反应完全。冷却至室温，加10毫升水稀释，水相用乙酸乙酯萃取(20毫升*2)。合并有机相，无水硫酸钠干燥。浓缩得到粗产品，柱层析得到800毫克黄色固体。
6-(3-噻吩-3-基-[1,2,4]三唑并[3,4-a]酞嗪-6-基氧亚甲基)-烟酸甲酯(J4)
将J3(717毫克)和6-羟甲基烟酸甲酯溶于无水四氢呋喃(100毫升)，在0℃氩气保护下，10分钟内分批加入t-NaOBu(576毫克)。混合物在0℃下继续搅拌0.5小时，然后升至室温反应1小时。TLC(二氯甲烷：甲醇＝20：1，Rf＝0.5)显示原料反应完全。除去溶剂得到粗产品直接用于下一步反应。
6-(3-噻吩-3-基-[1,2,4]三唑并[3,4-a]酞嗪-6-基氧亚甲基)-烟酸(J5)
将上一步产物J4溶于10毫升乙醇中，随后加入4毫升10％氢氧化钠水溶液，室温下搅拌0.5小时。TLC(二氯甲烷：甲醇＝20：1，Rf＝0.1)显示原料反应完全。除去溶剂乙醇，加入20毫升水，并用乙酸乙酯萃取(30毫升*2)。水层用饱和氯化铵水溶液淬灭。有大量固体析出，过滤，滤饼用5毫升水洗涤，真空干燥得到灰白色固体J5(500毫克，51.7％)。
实施例60
R-6-(((3-噻吩-3-基-[1,2,4]三唑并[3,4-a]酞嗪-6-基氧)亚甲基)-N-(1-羟基丙基-2-)-烟酰胺(60)
将1-羟基苯并三唑(81毫克，0.6毫摩尔)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(115毫克，0.6毫摩尔)，和J5(121毫克，0.3毫摩尔)溶于N，N-二甲基甲酰胺(5毫升)，在室温、氩气保护下搅拌10分钟。(R)-2-氨基丙醇(45毫克)和N，N-二异丙基乙胺(155毫克)依次加入。反应液室温下搅拌16小时。TLC(二氯甲烷:甲醇＝20:1，Rf＝0.3)显示原料反应完全。反应液中加入二氯甲 烷(25毫升)和水(30毫升)。有机相用水洗涤(20毫升*2)，无水硫酸钠干燥，浓缩，柱层析得到白色固体(36毫克，26％)。
1H NMR(400MHz,DMSO-d6)δ:9.04(d,1H J＝1.6),8.55～8.52(m,2H),8.37～8.33(m,2H),8.29～8.25(m,1H),8.12～8.06(m,1H),7.98～7.93(m,1H),7.93～7.87(m,1H),7.84～7.77(m,2H),5.82(s,2H),4.75(t,1H J＝5.6),4.06～3.99(m,1H),3.49～3.42(m,1H),3.38～3.35(m,1H)1.12(d,3H J＝6.8)；LC-MS:m/z(ES+)for C23H20N6O3S 461.30[M+1]+。
Figure PCTCN2016108975-appb-000092
合成路线10
Figure PCTCN2016108975-appb-000093
实验过程:
4-乙氧基-2-氧代-3-丁烯酸乙酯(K2)
室温下，在乙烯基乙醚(14.4g,200mmol)、TEA(12g,120mmol)和 Pd(AcO)2(3mL)的混合物中滴加草酰氯单乙酯(5.5g,40mmol)，滴毕搅拌过夜，TLC检测反应完毕，反应混合物过滤，滤饼用MTBE(50mL)洗涤，滤液减压浓缩得产物7.3黄色油状物，收率100％。
6-甲基吡啶-2,5-二羧酸二乙酯(K3)
在反应瓶中加入K2(1.7g,10mmol)，丙酮酸乙酯(1.2g,10mmol),AcONH4(1.2g,15mmol)和AcOH，搅拌均匀后回流反应过夜，TLC检测反应完毕，反应混合物减压浓缩，残留物过硅胶柱纯化(PE:EA＝100:1-2:1)得1.0克黑色油状物，收率42％。
6-羟甲基-2-甲基烟酸乙酯(K4)
0度下，在K3(1g,4mmol)，CaCl2(0.88g,6mmol),EtOH(50mL)和THF(50mL)的混合物中分批加入NaBH4(0.228g,8mmol)，加毕常温搅拌过夜，TLC检测反应完毕，反应混合物倒入冰水中，乙酸乙酯萃取(100mLX3)，有机层合并，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，过硅胶柱纯化得300毫克淡黄色固体，收率38％。
2-甲基-6-{3-[5-(四氢吡喃-2-氧甲基)-3-异噁唑]-[1,2,4]三氮唑并[3,4]酞嗪-6-氧甲基}-烟酸甲酯(K5)
把D4(193mg,0.5mmol)和K4(98mg,0.5mmol)溶于THF(20mL)中，氮气保护，室温下加入t-BuONa(70mg,0.75mmol)，搅拌反应1.5小时，TLC(DCM:MeOH＝20:1,Rf＝0.4)显示反应完毕，反应液直接用于下一步。
2-甲基-6-{3-[5-(四氢吡喃-2-氧甲基)-3-异噁唑]-[1,2,4]三氮唑并[3,4]酞嗪-6-氧甲基}-烟酸(K6)
室温下，在上一步反应液中加入10％NaOH(0.5mL)，搅拌半小时，TLC(PE:EtOAc＝2:1,Rf＝0.01)显示反应完毕，减压蒸去四氢呋喃，加入2mL水溶解，乙酸乙酯洗涤，水层用柠檬酸调pH＝4，析出固体，过滤，水洗，干燥得50毫克黄色固体，收率19％。
N-(2-羟基-1-甲乙基)-2-甲基-6-{3-[5-(四氢吡喃-2-氧甲基)-3-异噁唑]-[1,2,4]三氮唑并[3,4]酞嗪-6-氧甲基}-烟酰胺(K7)
在25mL单口瓶中加入HOBt(18mg,0.13mmol),EDCI(26mg,0.13mmol),K6(50mg,0.1mmol)和DMF(3mL)，搅拌溶解，氩气保护下加入R-2-氨基丙醇 和DIPEA，常温搅拌过夜，TLC显示反应完毕，加入25毫升二氯甲烷稀释，水洗三次，无水硫酸钠干燥，减压蒸干，制备硅胶板纯化得25毫克黄色固体，收率42％。
实施例61
R-6-(((3-(5-羟甲基-3-异噁唑)-[1,2,4]三氮唑并[3,4]酞嗪-6-氧)亚甲基}-N-(1-羟基丙基-2-)-2-甲基烟酰胺(61)
在K7(25mg,0.04mmol)的DCM(5mL)溶液中加入con.HCl(0.1mL)，常温搅拌3小时，TLC显示反应完毕，反应混合液调pH＝8-9，减压浓缩，制备硅胶板纯化得8毫克白色固体，收率42％。
1H NMR(400MHz,DMSO-d6)δ:8.60(d,J＝8.0Hz,1H),8.34(d,J＝8.0Hz,1H),8.21(d,J＝8.0Hz,2H),8.15(d,J＝8.0Hz,1H),8.01(d,J＝8.0Hz,1H),7.78(d,J＝8.0Hz,1H),7.16(s,1H),5.87(t,J＝6.4Hz,1H),5.69(s,2H),4.76-4.73(m,3H),4.02-3.95(m,1H),3.46-3.36(m,1H),2.56(s,3H),2.01-2.00(m,1H),1.11(d,J＝6.4Hz,3H)；LC-MS:m/z(ES+)for C24H23N7O5 490.29[M+1]+。
Figure PCTCN2016108975-appb-000094
合成路线11
Figure PCTCN2016108975-appb-000095
实验过程:
3-氰基-4-{异噁唑-3-甲基]-[1,2,4]三氮唑[3，4-a]酞嗪-6-氧甲基}-苯甲酸甲酯(L2)
氩气保护下，A1(300毫克)和B6(300毫克)的无水四氢呋喃溶液被分批加入叔丁醇钠(180毫克)保持零度，约10分钟加完。反应混合物零度搅拌30分钟，自然升到室温再搅拌1小时，TLC板(二氯甲烷：甲醇＝20：1，Rf＝0.4)显示原料反应完全，反应混合物被浓缩干，直接投下一步反应。
3-氰基-4-{异噁唑-3-甲基]-[1,2,4]三氮唑[3，4-a]酞嗪-6-氧甲基}-苯甲酸(L2)
向上一步的旋干得残渣中加入8毫升的乙醇，在加入10％的氢氧化钠约3毫升，室温搅拌30分钟，TLC板(二氯甲烷：甲醇＝20：1，Rf＝0.1)显示原料反应完全，反应混合物中乙醇被浓缩干，加入20毫升水，乙酸乙酯30毫升萃取两次，水相加入饱和氯化铵，有固体析出，过滤，滤饼用水洗，干燥得到白色固体100毫克，产率27％。
实施例62
3-氰基-N-乙基-4-{3-[5-甲基-异噁唑-3-基]-[1,2,4]三氮唑[3，4-a]酞嗪-6-氧甲基}-苯甲酰胺(62)
实验操作参见实施例1：原料是化合物L3和乙胺盐酸盐(CAS:557-66-4)得到产物32mg，产率86％，外观为白色固体。
1H NMR(400MHz,DMSO-d6)δ:1H NMR(400MHz,dmso)δ8.68(s,1H),8.55(d,J＝7.9Hz,1H),8.34(d,J＝1.4Hz,1H),8.26(d,J＝8.1Hz,1H),8.18–8.12(m,1H),8.09(t,J＝7.6Hz,1H),8.01(d,J＝8.1Hz,1H),7.95(t,J＝7.2Hz,1H),7.01(s,1H),5.85(s,2H),3.26(d,J＝7.5Hz,2H),2.56(s,3H),1.10(t,J＝7.2Hz,3H)；LC-MS:m/z(ES+)for C24H19N7O3454[M+1]+。
生物学实验方法：
近期的研究结果表明，GABAA受体介导了至少2种抑制模式，时相型(tonic inhibition)和紧张型抑制(phasic inhibition)。当GABA以毫摩尔级浓度增 加时，GABAA受体迅速去敏化，对GABA低亲和力，形成时相型抑制。当GABA以几百纳摩尔至几十微摩尔的浓度激活GABAA受体时，高亲和力突触外的GABAA受体介导了紧张型抑制，调节神经兴奋性和信号传递。(Farrant M et al.(2005)Variations on an inhibitory theme:phasic and tonic activation of GABA(A)receptors.Nat Rev Neurosci 6:215–229Y)。Yeung JY et al披露低浓度的GABA更易激活α5‐GABAA受体(Yeung JY et al(2003).Tonically activated GABAA receptors in hippocampal neurons are high-affinity,low-conductance sensors for extracellular GABA.Mol Pharmacol；63:2–8)。K.Y.LEE,报道在培养24小时的分离的DRG细胞上检测到了低浓度GABA激活的持续的高亲和力的GABAA电流，20μM GABA激活的高亲和力的GABAA电流达约100pA/pF。(Lee KY et al.Upregulation of high-affinity GABA(A)receptors in cultured rat dorsal root ganglion neurons.Neuroscience 208(2012)133–142)。2013年I.Lecker等披露α5‐GABAA受体反向激动剂L-655,708剂量依赖性的抑制低浓度GABA(5,50和500nM)引起的电流，当GABA浓度增至1μM时，最高浓度的L-655,708仅能抑制15％的电流，当GABA浓度继续增加时，L-655,708对GABA引起的电流没有抑制作用。(I.Lecker et al(2013).Potentiation of GABAA receptor activity by volatile anaesthetics is reduced byα5‐GABAA receptor-preferring inverse agonists.British Journal of Anaesthesia 110(S1):i73–i81)。
α5IA(US6200975B1)是具有代表性的5‐GABAA受体的反向激动剂。
Figure PCTCN2016108975-appb-000096
1.细胞水平筛选
本发明人通过电生理的方法检测待测物质的反向激动效率。具体方法如下所示:
1)将GABAA受体的不同亚基表达在人肾上皮细胞系HEK-293细胞系中。将所 述细胞培养于培养基中，将该种细胞作为用于筛选抑制疼痛的药物的细胞模型。α亚基、β亚基和γ亚基对形成一个完整的功能型GABAA受体是必不可少的。在该实施例中，本发明人建立了以下细胞模型：(a)将α5亚基(蛋白序列见GenBank登录号：NP_001158509)、β3亚基(蛋白序列见GenBank登录号：NP_068712)和γ2亚基(蛋白序列见GenBank登录号：NP_944494)同时表达在HEK-293细胞系中，组成含α5亚基的具有完整功能的受体。
2)细胞为绿色荧光蛋白(GFP)标记的表达α5β2γ3-受体的HEK-293细胞稳转株。293细胞培养在10cm培养皿上，待细胞长到80％-90％进行传代。传代时，先吸走培养基，然后将3mL DMEM培养基(GibcoTM)加入培养皿中，将培养皿轻微摇晃，再吸去DMEM。加入3mL胰酶(Trypsin-EDTA 0.05％，GibcoTM)，在37℃消化3分钟。然后加入3mL完全培养基(DMEM+10％horseserum(GibcoTM))将培养皿底面的细胞吹散，转移至15mL离心管
Figure PCTCN2016108975-appb-000097
200g离心3分钟。弃上清，加入4mL完全培养基，轻轻吹打，将细胞重悬起来备用。如进行细胞传代，将细胞悬液按1:5或1:10的比例稀释。如制备电生理用细胞，将细胞悬液按照1:12的比例稀释后，加入放置有预先用Poly-D-Lysine处理过的玻片的24孔盘
Figure PCTCN2016108975-appb-000098
中，待细胞贴壁后进行试验。电生理用细胞培养时间不超过24小时。
3)药物浓度设定：药物筛选使用的药物终浓度均为100nM，GABA浓度范围为0.05～0.1μM。剂量-反向激动效率(％)试验使用的药物终浓度为1nM，10nM，50nM，100nM和1000nM。电生理试验采用全细胞膜片钳技术,电生理用细胞外液成分如下：150mM NaCl，5mM KCl，2.5mM CaCl2，1mM MgCl2，10mM HEPES和10mM glucose(pH 7.4)；电生理用电极内液配方如下：140mM KCl，5mM EGTA，10mM HEPES(用KOH调节pH至7.4，渗透压为320–330mOsm)。；电生理用电极内液配方如下：140mM KCl，5mM EGTA，10mM HEPES(用KOH调节pH至7.4，渗透压为285–295mOsm)。信号采集使用EPC 10放大器以及PatchMaster软件(HEKA)。记录电极使用硼硅酸盐(borosilicate)玻璃(Sutter)拉制，电极电阻为5～6MΩ。胞外给药采用OCTAFLOW IITM系统。记录时，选取GFP阳性且单个独立生长的细胞。记录过程中，细胞膜电位被钳制在-60mV。试验时，先在胞外施加约20秒的细胞外液。待基线稳定后，将胞外液切换至GABA。此时，可以检测到GABA 引起的电流。大约20～40秒，待电流稳定后，将胞外液切换至相应的药物溶液，检测药物的效果。最后，将溶液切换至细胞外液，待基线回复到给药前水平终止试验。只有基线能够回复的数据才会做后续分析。将GABA按照0.05～0.1μM的终浓度稀释在细胞外液中。然后，将药物按照所需浓度稀释到含有GABA的细胞外液中。
4)实验结果的分析采用PatchMaster软件。分析时，分别测量加药前GABA电流(Ipre)和加药后GABA电流(Ipost)，药物效果由以下公式计算得到：反向激动效率(％)＝(Ipost–Ipre)*100/Ipre。N为试验次数。
5)化合物的筛选结果:
Figure PCTCN2016108975-appb-000099
Figure PCTCN2016108975-appb-000100
6)化合物α5IA，06和07的剂量-反向激动效率(％)结果：
Figure PCTCN2016108975-appb-000101
2.药物组织分布:
通过比较大鼠血浆和脑组织中的化合物浓度水平来计算血脑组织分布比。实验组动物被分成2组，血浆组和脑组织组，每组各3只。检测化合物以10mg/kg的药物剂量分别溶解于50％PEG400，动物口服给药。服药后1小时，取血清和脑样品，并用LC-MS/MS-AJ(Triple Quad 5500)检测。用程序Phoenix WinNonlin处理数据获得结果如下：
化合物 大脑/血清ratio
07 <1％
08 <1％
3.细胞水平筛选补充结果：
本发明人通过新的电生理方法又重新验证了部分待测物质的反向激动效率。在本次试验中，发明人参考(I.Lecker,Y.Yin,D.S.Wang and B.A.Orser,(2013)Potentiation of GABAA receptor activity by volatile anaesthetics is reduced byα5-GABAA receptor-preferring inverse agonists,British Journal of Anaesthesia 110(S1):i73–i81)报道的方法，电生理用细胞外液的成分如之前的方法：150mM NaCl，5mM KCl，2.5mM CaCl2，1mM MgCl2，10mM HEPES和10mM glucose(用NaOH调节pH至7.4，渗透压为320mOsm)。电生理用电极内液配方调整如下：140mM CsCl，10mM HEPES,11mM EGTA，2mM MgCl2,1mM CaCl2,4mM MgATP，2mM TEA，(用CsOH调节pH至7.4，渗透压为285–295mOsm)。GABA浓度范围调整为0.1～0.3μM。其他操作方法参考上述的实验要求。在每组实验中,待测化合物的反向激动效率以以α5IA作为参考化合物,2批实验数据如下所示:
化合物的筛选补充结果如下所示:
Figure PCTCN2016108975-appb-000102
Figure PCTCN2016108975-appb-000103
Figure PCTCN2016108975-appb-000104
4.药物组织分布:
通过比较大鼠血浆和脑组织中的化合物浓度水平来计算血脑组织分布比。实验组动物被分成2组，血浆组和脑组织组，每组各3只。检测化合物以10mg/kg的药物剂量分别溶解于50％PEG400，动物口服给药。服药后1小时，取血清和脑样品，并用LC-MS/MS-AJ(Triple Quad 5500)检测。用程序Phoenix WinNonlin处理数据获得结果如下：
化合物 大脑/血清ratio
07 <1％
08 <1％
我们也检测了24号化合物大鼠血浆和脑组织中的化合物浓度水平。实验组动物被分成2组，血浆组和脑组织组，每组各3只。检测化合物以1mg/kg的药物剂量溶解于5％DMSO+70％PEG400+25％H2O，动物口服给药。服药后1小时，取血清和脑样品，并用LC-MS/MS-AJ(Triple Quad 5500)检测。用程序Phoenix WinNonlin处理数据获得结果如下：
化合物 大脑/血清ratio
24 4.4％
由以上结果可以发现，本发明的化合物生物学效果明显优于以往的α5-GABAA受体反向激动剂，且由于本发明的化合物不进入大脑，不会产生以往α5-GABAA受体反向激动剂可能产生的恐惧和焦虑的副作用。

Claims (48)

  1. 一种式I所示的化合物，其顺反异构体、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、或其药学上可以接受的盐和酯，
    Figure PCTCN2016108975-appb-100001
    T表示C3-7环烷基，C4-7环烯基，C6-8二环烷基，C6-10芳基，C3-7杂环烷基；
    Z表示含有1、2或3个独立选自氧、氮和硫的杂原子的5元杂芳环；所述5元杂芳环被一个或多个选自以下的取代基任选取代：羟基，卤素，-R1，-OR1，-OC(O)R1，-NR2R3，CN，氰基(C1-6)烷基-或R2；
    R1表示C1-6烷基，C2-6链烯基，C2-6炔基，C3-6环烷基，C3-6环烷基(C1-6)烷基，氰基(C1-6)烷基，羟基或氨基取代的C1-6烷基，且R1任选为一、二或三氟代的；
    R2或R3独立地为氢，C1-6烷基，C2-6链烯基，C2-6炔基，C3-6环烷基或CF3，或R2和R3与它们共同连接的氮原子一起形成4-7元杂脂肪环，该杂脂肪环含有所述氮原子和一个任选自O、N和S的其它杂原子，所述杂脂肪环任选被一个或多个R1基团任选取代；
    A为-NR2-；或A为含有1、2、3或4个独立选自氧、氮和硫的杂原子的5元杂亚芳基且杂原子中最多有1个为氧或硫；或为含有1、2或3个氮原子的6元杂亚芳基，或所述5或6元杂亚芳基还任选地稠合于苯环或吡啶环上，所述5或6元杂亚芳基任选被Rx和/或Ry和/或Rz取代，其中Rx为卤素、-R1、-OR1、-OC(O)R1、-C(O)OR1、-NR2R3、-NR2C(O)R3、-OH、-CN，Ry为卤素、-R1、-OR1、-OC(O)R1、-NR2R3、-NR2C(O)R3、或CN， Rz为-R1、-OR1或-OC(O)R1，前提是当A为吡啶衍生物时，该吡啶环任选为N-氧化物形式；或A为被1、2或3个独立选自以下的基团任选取代的亚苯基：卤素、氰基、C1-6烷基、C2-6链烯基、C2-6炔基和C3-6环烷基；
    Y为-NY1Y2或-NH-NY3Y4；
    Y1选自：H；C1-6烷基；被1-5个取代基取代的C1-6烷基，所述取代基独立地选自：氨基，卤素，卤代-C1-6烷氧基，羟基，C1-6烷氧基，(C1-6烷基，C1-6烷基)N-，(C1-6烷基，H)N-，硝基和C1-6烷基-S(O)2-；
    Y2选自：H；C1-6烷基-S(O)2-；氨基；NH-S(O)2-；C1-6烷氧基；C1-6烷基，或被1-5个取代基取代的C1-6烷基，所述取代基独立地选自：氨基，取代的氨基，卤素，卤代-C1-6烷氧基，羟基，C1-6烷氧基，羧基，环烷基，(C1-6烷基，C1-6烷基)N-，(C1-6烷基，H)N-，硝基，C1-6烷基-S(O)2-，杂环烷基，或被1-4个取代基取代的杂环烷基，所述取代基单独地选自：乙酰胺基，乙酰基，乙酰基氨基，酰氨基，氨基，羧基，氰基，卤素，卤代-C1-6烷氧基，卤代-C1-6烷基，羟基，羟基-C1-6烷基，C1-6烷氧基，C1-6烷氧基-C1-6烷基，C1-6烷基，(C1-6烷基，C1-6烷基)N-，(C1-6烷基，H)N-，硝基和C1-6烷基-S(O)2-；杂芳基，或被1-4个取代基取代的杂芳基，所述杂芳基的取代基独立地选自：乙酰胺基，乙酰基，乙酰基氨基，酰氨基，氨基，羧基，氰基，卤素，卤代-C1-6烷氧基，卤代-C1-6烷基，羟基，羟基-C1-6烷基，C1-6烷氧基，C1-6烷氧基-C1-6烷基，C1-6烷基，(C1-6烷基，C1-6烷基)N-，(C1-6烷基，H)N-，硝基和C1-6烷基-S(O)2-；环烷基，或被1-4个取代基取代的环烷基，所述的取代基单独地选自：乙酰胺基，乙酰基，乙酰基氨基，酰氨基，氨基，羧基，氰基，卤素，卤代-C1-6烷氧基，卤代-C1-6烷基，羟基，羟基-C1-6烷基，C1-6烷氧基，C1-6烷氧基-C1-6烷基，C1-6烷基，(C1-6烷基，C1-6烷基)N-，(C1-6烷基，H)N-，硝基和C1-6烷基-S(O)2-；杂环烷基，或被1-4个取代基取代的杂环烷基，所述取代基单独地选自：乙酰胺基，乙酰基，乙酰基氨基，酰氨基，氨基，羧基，氰基，卤素，卤代-C1-6烷氧基，卤代-C1-6烷基，羟基，羟基-C1-6烷基，C1-6烷氧基，C1-6烷氧基-C1-6烷基，C1-6烷基，(C1-6烷基，C1-6烷基)N-，(C1-6烷基，H)N-，硝基和C1-6烷基-S(O)2-；
    或者Y1、Y2与它们所连接的N原子一起形成4-6元杂环烷基，所述杂环烷基除了含有氮原子外，还含有零个、一个或多个选自O和S的杂原子， 并且所述S原子可以为其氧化物形式；
    或者Y1、Y2与它们所连接的N原子一起形成被1-4个取代基取代的含有1-3个选自N、O或S的杂原子的4-6元杂环烷基，并且所述S原子可以为其氧化物形式；所述取代基单独地选自：C1-6烷基，C1-6烷基-S(O)2-，C1-6烷氧基，卤代C1-6烷基，NH2C(＝O)-，卤素；
    或者Y1和Y2与它们所连接的氮原子一起形成C5-10氧杂氮杂双环烷基；
    Y3，Y4相互独立选自：氢、C1-C6烷基、SO2-C1-C6烷基、环烷基和杂环基，任选被1-4个独立选自下列基团的取代基取代：卤素、氰基、羟基、C1-C6烷基和C1-C6烷氧基，
    或者其中Y3，Y4与它们所连接的氮原子一起形成杂环基，该杂环基任选被1-4个独立选自下列基团的取代基取代：卤素、氰基、羟基、氧代、C1-C6烷基和C1-C6烷氧基；
    以上所有选自取代基团中氢原子可以被氘取代。
  2. 如权利要求1所述的化合物，其具有以下通式II，
    Figure PCTCN2016108975-appb-100002
    其中
    Z表示含有1、2或3个独立选自氧、氮和硫的杂原子的5元杂芳环，其中最多有1个杂原子为氧或硫，并且当1个杂原子为氮原子时，至少也存在1个氧或硫原子，所述5元杂芳环被一个或多个选自以下的取代基任选取代：C1‐C4烷基、羟基、卤素、羟基或氨基取代的C1‐C4烷基、C2‐C4链烯基、C2‐C4炔基、C1‐C4烷氧基；
    A为含有1、2或3个独立选自氧、氮和硫的杂原子的5元杂亚芳基且杂原子中最多有1个为氧或硫，或含有1、2或3个氮原子的6元杂亚芳基或亚苯基； 所述5元杂亚芳基、6元杂亚芳基和亚苯基任选地被选自以下的取代基取代：卤素、氰基、C1‐6烷基；
    Y为‐NY1Y2或‐NH‐NY3Y4；
    Y1是H，C1‐6烷基或被1‐5个取代基取代的C1‐6烷基；所述取代基单独地选自：氨基，羟基，C1‐6烷氧基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
    Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基单独地选自：氨基，取代的氨基，羟基，C1‐6烷氧基，羧基，卤素，环烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐，杂环烷基，或被1-4个取代基取代的杂环烷基，所述取代基单独地选自：乙酰胺基，乙酰基，C1-6烷氧基，C1-6烷基；
    H；C1‐6烷基‐S(O)2‐；氨基；NH‐S(O)2‐；C1‐6烷氧基；
    含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，被C1‐6烷基取代的含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基；
    C3‐6环烷基，被1‐4个取代基取代的C3‐6环烷基，所述取代基单独地选自：氨基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
    含有1‐3个选自N、O或S的杂原子的C4‐C6‐杂环烷基，被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的C4‐C6杂环烷基，所述取代基单独地选自：氨基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，乙酰基，二氧硫代基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基和C1‐6烷基‐S(O)2‐；
    或者Y1、Y2与它们所连接的N原子一起形成4‐6元杂环烷基，所述杂环烷基除了含有氮原子外，还含有零个、一个或多个选自O和S的杂原子，并且所述S原子可以为其氧化物形式；
    或者Y1、Y2与它们所连接的N原子一起形成被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的4‐6元杂环烷基，并且所述S原子可以为其氧化物形式，所述取代基单独地选自：C1‐6烷基，C1‐6烷基‐S(O)2‐，C1‐6烷氧基，卤代C1‐6烷基，NH2C(＝O)‐，卤素；
    或者Y1和Y2与它们所连接的氮原子一起形成C5‐10氧杂氮杂双环烷基；
    Y3，Y4相互独立选自：氢、C1‐C6烷基、SO2‐C1‐C6烷基，或者Y3和Y4与 它们所连接的氮原子一起形成杂环基，所述杂环基选自哌啶基、吗啉基、二氧硫代吗啉基和一氧硫代吗啉基。
  3. 如权利要求1或2所述的化合物，其特征在于，Z表示含有2个独立选自氧、氮和硫的杂原子的5元杂芳环，并且一个杂原子为氧或硫，另一个原子为氮；所述5元杂芳环被一个或多个选自以下的取代基任选取代：C1-6烷基或羟基C1-6烷基。
  4. 如权利要求1或2所述的化合物，其特征在于，Z表示氧杂二氮唑、呋喃基、噻吩基或异噁唑基，所述异噁唑基被一个或多个选自以下的取代基任选取代：H，C1‐6烷基或羟基C1‐6烷基。
  5. 如权利要求1或2所述的化合物，其特征在于，A表示亚苯基、亚吡啶基、亚异噁唑基；任选地被1、2或3个独立选自以下的取代基取代：卤素、氰基、C1‐6烷基。
  6. 如权利要求1或2所述的化合物，其特征在于，
    Z表示氧杂二氮唑、呋喃基、噻吩基或异噁唑基，所述异噁唑基被一个或多个选自以下的取代基任选取代：H，C1‐6烷基或羟基C1‐6烷基；
    A表示亚苯基、亚吡啶基、亚异噁唑基；任选地被1、2或3个独立选自以下的取代基取代：卤素、氰基、C1‐6烷基。
  7. 如权利要求1或2所述的化合物，其特征在于，
    Z表示氧杂二氮唑、呋喃基、噻吩基或异噁唑基，所述异噁唑基被一个或多个选自以下的取代基任选取代：H，C1‐6烷基或羟基C1‐6烷基；
    A表示亚苯基、亚吡啶基、亚异噁唑基；任选地被1、2或3个独立选自以下的取代基取代：卤素、氰基、C1‐6烷基；
    Y为‐NY1Y2或‐NH‐NY3Y4；
    Y1是H或C1‐6烷基；
    Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基单独 地选自：氨基，取代的氨基，羟基，C1‐6烷氧基，羧基，卤素，C1-6烷基-S(O)2-；环烷基，杂环烷基，或被1-4个取代基取代的杂环烷基，所述取代基单独地选自：乙酰胺基，乙酰基，C1-6烷氧基，C1-6烷基；
    H；C1-6烷基-S(O)2-；氨基；NH-S(O)2-；C1-6烷氧基；
    含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，被烷基取代的含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基；
    C4‐6环烷基，环丙基，被1‐4个取代基取代的C3‐6环烷基，所述取代基单独地选自：羟基，C1‐6烷基，C1‐6烷氧基；
    含有1‐3个选自N、O或S的杂原子的C4‐C6‐杂环烷基，被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的C4‐C6杂环烷基，所述取代基单独地选自：C1‐6烷基，乙酰基，二氧硫代基；
    或者Y1、Y2与它们所连接的N原子一起形成4‐6元杂环烷基，所述杂环烷基除了含有氮原子外，还含有零个、一个或多个选自O和S的杂原子，并且所述S原子可以为其氧化物形式；
    或者Y1、Y2与它们所连接的N原子一起形成被1-4个取代基取代的含有1-3个选自N、O或S的杂原子的4-6元杂环烷基，并且所述S原子可以为其氧化物形式；所述取代基单独地选自：C1-6烷基，C1-6烷基-S(O)2-，C1-6烷氧基，卤代C1-6烷基，NH2C(＝O)-，卤素；
    或者Y1和Y2与它们所连接的氮原子一起形成C5-10氧杂氮杂双环烷基；
    Y3和Y4相互独立选自：氢、甲基和‐SO2‐甲基,Y3和Y4与它们所连接的氮原子一起形成杂环基,选自吗啉基、哌啶基和二氧代‐硫代吗啉‐基。
  8. 如权利要求1或2所述的化合物，其特征在于，
    Z表示氧杂二氮唑、呋喃基、噻吩基或异噁唑基，所述异噁唑基被一个或多个选自以下的取代基任选取代：H，C1‐6烷基或羟基C1‐6烷基；
    A表示亚苯基、亚吡啶基、亚异噁唑基；任选地被1、2或3个独立选自以下的取代基取代：卤素、氰基、C1‐6烷基；
    Y为‐NY1Y2或‐NH‐NY3Y4；
    Y1是H或C1‐6烷基；
    Y2选自C1-6烷基；被1-5个取代基取代的C1-6烷基，所述取代基单独地选 自：羟基，C1-6烷氧基，酰氨基，卤素，羧基，C3-6环烷基，含有1-3个选自N、O或S的杂原子的C4-C6-杂环烷基，C1-6烷基-S(O)2-；
    H基；C1-6烷基-S(O)2-；氨基；NH-S(O)2-；C1-6烷氧基；
    含有1-3个选自N、O或S的杂原子的C5-C6杂芳基，被烷基取代的含有1-3个选自N、O或S的杂原子的C5-C6杂芳基，
    C4-6环烷基，环丙基，被1-4个取代基取代的C3-6环烷基，所述取代基单独地选自：羟基，C1‐6烷基，C1‐6烷氧基；
    含有1-3个选自N、O或S的杂原子的C4-C6-杂环烷基，被1-4个取代基取代的含有1-3个选自N、O或S的杂原子的C4-C6杂环烷基，所述取代基单独地选自：C1‐6烷基，乙酰基，二氧硫代基；
    或Y1和Y2与它们所连接的氮原子一起形成吗啉基、哌啶基、哌嗪基、氮杂环丁基、氧杂氮杂双环庚烷；所述吗啉基、哌啶基、哌嗪基、氮杂环丁基、氧杂氮杂双环庚烷任选地被1-4个选自下组的取代基取代：C1-6烷基，C1-6烷基-S(O)2-，C1-6烷氧基，卤素，NH2C(＝O)-；所述吗啉基中的S原子还可以为其氧化物形式；
    Y3和Y4相互独立选自：氢、甲基和SO2-甲基,Y3和Y4与它们所连接的氮原子一起形成杂环基,选自吗啉-4-基、哌啶-1-基和1，1‐二氧代‐硫代吗啉‐4‐基。
  9. 如权利要求1或2所述的化合物，其特征在于，
    Z表示氧杂二氮唑、呋喃基、噻吩基或异噁唑基，所述异噁唑基被一个或多个选自以下的取代基任选取代：H，C1‐6烷基或羟基C1‐6烷基；
    A表示亚苯基、亚吡啶基、亚异噁唑基；任选地被1、2或3个独立选自以下的取代基取代：卤素、氰基、C1‐6烷基；
    Y为‐NY1Y2或‐NH‐NY3Y4；
    Y1是H或甲基；
    Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基单独地选自：羟基，C1‐6烷氧基，乙酰氨基，氟基，羧基，吗啉基，环丙基，四氢呋喃；
    H基；C1‐6烷基‐S(O)2‐；氨基；NH‐S(O)2‐；C1‐6烷氧基；
    含有1-3个选自N、O或S的杂原子的C5-C6杂芳基，被烷基取代的含有1-3个选自N、O或S的杂原子的C5-C6杂芳基；
    C3‐6环烷基；被1‐4个取代基取代的C3‐6环烷基，所述的取代基单独地选自：羟基，甲氧基，甲基；
    含有1‐3个选自N、O或S的杂原子的C4‐C6杂环烷基；被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的杂环烷基，所述取代基单独地选自：甲基，乙酰基；
    或Y1和Y2与它们所连接的氮原子一起形成吗啉基、哌啶基、哌嗪基、氮杂环丁基、氧杂氮杂双环庚烷；所述吗啉基、哌啶基、哌嗪基、氮杂环丁基、氧杂氮杂双环庚烷任选地被1-4个选自下组的取代基取代：甲基，甲氧基，氟，NH2C(＝O)-；所述吗啉基中的S原子还可以为其氧化物形式；
    Y3和Y4相互独立选自：氢和甲基,Y3和Y4与它们所连接的氮原子一起形成杂环基,选自吗啉‐4‐基、哌啶‐1‐基和1，1‐二氧代‐硫代吗啉‐4‐基。
  10. 如权利要求1或2所述的化合物，其特征在于，
    Z表示氧杂二氮唑、呋喃基、噻吩基或异噁唑基，所述异噁唑基被一个或多个选自以下的取代基任选取代：H，C1‐6烷基或羟基C1‐6烷基；
    A表示亚苯基、亚吡啶基、亚异噁唑基；任选地被1、2或3个独立选自以下的取代基取代：卤素、氰基、C1‐6烷基；
    Y为‐NY1Y2或‐NH‐NY3Y4；
    Y1是H或甲基；
    Y2选自甲基、乙基、甲氧基乙基，羟基丙基，乙酰氨乙基，H，‐CH2COOH，羟基环戊基，环丙烷基，甲基吡唑基，吗啡啉基，羟乙基，丁基，甲基哌啶基，吗啡啉基乙基，四氢呋喃基，甲氧基环戊基，乙酰基吡咯烷基，四氢呋喃基亚甲基，二氟乙基，环丙基甲基，甲磺酰基乙基，三氟乙基，异丙基，四氢吡喃，环丁基，氨基，哌啶基，甲磺酰基，二氧硫代吗啉基，羟基甲基乙基；
    或者Y1和Y2与它们所连接的氮原子一起形成甲基哌嗪基，甲酰胺基哌啶基，甲氧基哌啶基，二氟哌啶基，氧杂氮杂双环庚烷，二氧硫代吗啉基，吗啉基，氮杂环丁基，一氧硫代吗啉基；
    Y3和Y4相互独立选自：氢和甲基,Y3和Y4与它们所连接的氮原子一起形成杂环基,选自吗啉‐4‐基、哌啶‐1‐基和1，1‐二氧代‐硫代吗啉‐4‐基。
  11. 如权利要求1或2所述的化合物，其具有以下通式III:
    Figure PCTCN2016108975-appb-100003
    其中
    R4为C1‐C4烷基、羟基取代的C1‐C4烷基；
    Y为‐NY1Y2或‐NH‐NY3Y4；
    Y1是H，C1‐6烷基或被1‐5个取代基取代的C1‐6烷基；所述取代基单独地选自：氨基，羟基，C1‐6烷氧基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
    Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基单独地选自：氨基，取代的氨基，羟基，C1‐6烷氧基，羧基，卤素，环烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐，C1‐6烷基‐S(O)2‐，杂环烷基，或被1-4个取代基取代的杂环烷基，所述取代基单独地选自：乙酰胺基，乙酰基，C1-6烷氧基，C1-6烷基；
    H；C1-6烷基-S(O)2-；氨基；NH-S(O)2-；C1-6烷氧基；
    含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基；被C1‐6烷基取代的含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基；
    C3‐6环烷基；被1‐4个取代基取代的C3‐6环烷基，所述取代基单独地选自：氨基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
    含有1‐3个选自N、O或S的杂原子的C4‐C6‐杂环烷基；被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的C4‐C6杂环烷基，所述取代基单独地 选自：氨基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，乙酰基，二氧硫代基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基和C1‐6烷基‐S(O)2‐；
    或者Y1、Y2与它们所连接的N原子一起形成4‐6元杂环烷基，所述杂环烷基除了含有氮原子外，还含有零个、一个或多个选自O和S的杂原子，并且所述S原子可以为其氧化物形式；
    或者Y1、Y2与它们所连接的N原子一起形成被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的4‐6元杂环烷基，并且所述S原子可以为其氧化物形式所述取代基单独地选自：C1‐6烷基，C1‐6烷基‐S(O)2‐，C1‐6烷氧基，卤代C1‐6烷基，NH2C(＝O)‐，卤素；
    或者Y1和Y2与它们所连接的氮原子一起形成C5‐10氧杂氮杂双环烷基；
    Y3，Y4相互独立选自：氢、C1‐C6烷基、SO2‐C1‐C6烷基，或者Y3和Y4与它们所连接的氮原子一起形成杂环基，选自哌啶基、吗啉基、二氧硫代吗啉基和一氧硫代吗啉基。
  12. 如权利要求1或2所述的化合物，其具有以下通式IV:
    Figure PCTCN2016108975-appb-100004
    Y为‐NY1Y2或‐NH‐NY3Y4；
    Y1是H，C1‐6烷基或被1‐5个取代基取代的C1‐6烷基，所述取代基独立地选自：氨基，羟基，C1‐6烷氧基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
    Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基独立地选自：氨基，取代的氨基，羟基，C1‐6烷氧基，羧基，卤素，环烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐，C1‐6烷基‐S(O)2，杂环烷基，或被1‐4个取代基取代的杂环烷基，所述取代基单独地选自：乙酰胺基，乙 酰基，C1‐6烷氧基，C1‐6烷基；
    H；C1‐6烷基‐S(O)2‐；氨基；NH‐S(O)2‐；C1‐6烷氧基；
    含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基；被C1‐6烷基取代的含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基；
    C3‐6环烷基；被1‐4个取代基取代的C3‐6环烷基，所述取代基独立地选自：氨基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
    含有1‐3个选自N、O或S的杂原子的C4‐C6‐杂环烷基，被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的C4‐C6杂环烷基，所述取代基独立地选自：氨基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，乙酰基，二氧硫代基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基和C1‐6烷基‐S(O)2‐；
    或者Y1、Y2与它们所连接的N原子一起形成4‐6元杂环烷基，所述杂环烷基除了含有氮原子外，还含有零个、一个或多个选自O和S的杂原子，并且所述S原子可以为其氧化物形式；
    或者Y1、Y2与它们所连接的N原子一起形成被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的4‐6元杂环烷基，并且所述S原子可以为其氧化物形式，所述取代基单独地选自：C1‐6烷基，C1‐6烷基‐S(O)2‐，C1‐6烷氧基，卤代C1‐6烷基，NH2C(＝O)‐，卤素；
    或者Y1和Y2与它们所连接的氮原子一起形成C5‐10氧杂氮杂双环烷基；
    Y3，Y4相互独立选自：氢、C1‐C6烷基、SO2‐C1‐C6烷基，或者Y3和Y4与它们所连接的氮原子一起形成杂环基，选自哌啶基、吗啉基、二氧硫代吗啉基和一氧硫代吗啉基。
  13. 如权利要求1或2所述的化合物，其具有以下通式IV:
    Figure PCTCN2016108975-appb-100005
    Y为‐NY1Y2或‐NH‐NY3Y4；
    Y1是H，C1‐6烷基或被1‐5个取代基取代的C1‐6烷基，所述取代基独立地选自：氨基，羟基，C1‐6烷氧基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
    Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基独立地选自：氨基，取代的氨基，羟基，C1‐6烷氧基，卤素，羧基，C3‐6环烷基，含有1‐3个选自N、O或S的杂原子的C4‐C6‐杂环烷基；
    H；C1‐6烷基‐S(O)2‐；氨基；NH‐S(O)2‐；C1‐6烷氧基；
    含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基；被C1‐6烷基取代的含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基；
    C4‐6环烷基；环丙基；被1‐4个取代基取代的C3‐6环烷基，所述取代基独立地选自：羟基，C1‐6烷基，C1‐6烷氧基；
    含有1‐3个选自N、O或S的杂原子的C4‐C6‐杂环烷基；被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的C4‐C6杂环烷基，所述取代基单独地选自：C1‐6烷基，乙酰基，二氧硫代基；
    Y1和Y2与它们所连接的氮原子一起形成吗啉基、哌啶基、哌嗪基、氮杂环丁基、氧杂氮杂双环庚烷；所述吗啉基、哌啶基、哌嗪基、氮杂环丁基、氧杂氮杂双环庚烷任选地被1‐4个选自下组的取代基取代：C1‐6烷基，C1‐6烷基‐S(O)2‐，C1‐6烷氧基，卤素，NH2C(＝O)‐；所述吗啉基中的S原子还可以为其氧化物形式；
    Y3和Y4相互独立选自：氢、甲基和SO2‐甲基,Y3和Y4与它们所连接的氮原子一起形成杂环基,选自吗啉基、哌啶基和二氧代‐硫代吗啉基。
  14. 如权利要求1或2所述的化合物，其具有以下通式IV:
    Figure PCTCN2016108975-appb-100006
    Y为‐NY1Y2或‐NH‐NY3Y4；
    Y1是H或C1‐6烷基；
    Y2选自C1-6烷基；被1-5个取代基取代的C1-6烷基，所述取代基单独地选自：羟基，C1-6烷氧基，乙酰氨基，氟基，羧基，C3-6环烷基，含有1-3个选自N、O或S的杂原子的C4-C6-杂环烷基；
    H；C1‐6烷基‐S(O)2‐；氨基；NH‐S(O)2‐；C1‐6烷氧基；
    含有1-3个选自N、O或S的杂原子的C5-C6杂芳基；被甲基基取代的含有1-3个选自N、O或S的杂原子的C5-C6杂芳基；
    C4-6环烷基；环丙基；被1-4个取代基取代的C3-6环烷基，所述取代基单独地选自：羟基，C1-6烷基，C1-6烷氧基；
    含有1-3个选自N、O或S的杂原子的C4-C6-杂环烷基；被1-4个取代基取代的含有1-3个选自N、O或S的杂原子的C4-C6杂环烷基，所述取代基单独地选自：C1-6烷基，乙酰基，二氧硫代基；；
    Y1和Y2与它们所连接的氮原子一起形成吗啉基、哌啶基、哌嗪基、氮杂环丁基、氧杂氮杂双环庚烷；所述吗啉基、哌啶基、哌嗪基、氮杂环丁基、氧杂氮杂双环庚烷任选地被1-4个选自下组的取代基取代：C1-6烷基，C1-6烷基-S(O)2-，C1-6烷氧基，卤素，NH2C(＝O)-；所述吗啉基中的S原子还可以为其氧化物形式；
    Y3和Y4相互独立选自：氢、甲基和SO2-甲基,Y3和Y4与它们所连接的氮原子一起形成杂环基,选自吗啉-4-基、哌啶-1-基和1，1‐二氧代‐硫代吗啉‐4‐基。
  15. 如权利要求1或2所述的化合物，其具有以下通式IV:
    Figure PCTCN2016108975-appb-100007
    Y为‐NY1Y2或‐NH‐NY3Y4；
    Y1是H或甲基；
    Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基单独地选自：羟基，C1‐6烷氧基，乙酰氨基，氟基，羧基，吗啉基，环丙基，四氢呋喃；
    H；C1‐6烷基‐S(O)2‐；氨基；NH‐S(O)2‐；C1‐6烷氧基；
    C3‐6环烷基；被1‐4个取代基取代的C3‐6环烷基，所述的取代基单独地选自：羟基，甲氧基，甲基；
    含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基；被甲基基取代的含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基；
    含有1‐3个选自N、O或S的杂原子的C4‐C6杂环烷基；被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的杂环烷基，所述取代基单独地选自：甲基，乙酰基，二氧硫代基；
    Y1和Y2与它们所连接的氮原子一起形成吗啉基、哌啶基、哌嗪基、氮杂环丁基、氧杂氮杂双环庚烷；所述吗啉基、哌啶基、哌嗪基、氮杂环丁基、氧杂氮杂双环庚烷任选地被1‐4个选自下组的取代基取代：C1‐6烷基，C1‐6烷基‐S(O)2‐，C1‐6烷氧基，卤素，NH2C(＝O)‐；所述吗啉基中的S原子还可以为其氧化物形式；
    Y3和Y4相互独立选自：氢和甲基,Y3和Y4与它们所连接的氮原子一起形成杂环基,选自吗啉‐4‐基、哌啶‐1‐基和1，1‐二氧代‐硫代吗啉‐4‐基。
  16. 如权利要求1或2所述的化合物，其具有以下通式IV:
    Figure PCTCN2016108975-appb-100008
    Y为‐NY1Y2或‐NH‐NY3Y4；
    Y1是H或甲基；
    Y2选自甲基，乙基，2‐甲氧基乙基，羟基丙基，乙酰氨乙基，H，‐CH2COOH，羟基环戊基，环丙烷基，甲基吡唑基，吗啡啉基，羟乙基，丁基，甲基哌啶基，吗啡啉基乙基，四氢呋喃基，甲氧基环戊基，乙酰基吡咯烷基，四氢呋喃基亚甲基，二氟乙基，环丙基甲基，甲磺酰基乙基，三氟乙基，异丙基，四氢吡喃，环丁基，氨基，哌啶基，甲磺酰基，二氧硫代吗啉基，羟基甲基乙基；
    或者Y1和Y2与它们所连接的氮原子一起形成甲基哌嗪基，甲酰胺基哌啶基，甲氧基哌啶基，二氟哌啶基，氧杂氮杂双环庚烷，二氧硫代吗啉基，吗啉基，氮杂环丁基，一氧硫代吗啉基；
    Y3和Y4相互独立选自：氢和甲基,与它们所连接的氮原子一起形成杂环基,选自吗啉‐4‐基、哌啶‐1‐基和1，1‐二氧代‐硫代吗啉‐4‐基。
  17. 如权利要求1或2所述的化合物，其具有以下通式IV:
    Figure PCTCN2016108975-appb-100009
    Y为‐NY1Y2；
    Y1是H基；
    Y2选自甲基，乙基、甲氧基乙基，羟基丙基，乙酰氨乙基，H，‐CH2COOH，羟基环戊基，环丙烷基，甲基吡唑基，吗啡啉基，羟乙基，丁基，甲基哌啶基，吗啡啉基乙基，四氢呋喃基，甲氧基环戊基，乙酰基吡咯烷基，四氢呋喃基亚甲基，二氟乙基，环丙基甲基，甲磺酰基乙基，三氟乙基；
    或者Y1和Y2与它们所连接的氮原子一起形成甲基哌嗪基，甲酰胺基哌啶基，甲氧基哌啶基，二氟哌啶基，氧杂氮杂双环庚烷。
  18. 如权利要求1或2所述的化合物，其具有以下通式II，
    Figure PCTCN2016108975-appb-100010
    其中
    Z表示甲基异噁唑基；
    A选自氰基亚苯基、亚吡啶基；
    Y为‐NY1Y2；
    Y1是H基；
    Y2选自C1‐6烷基；被1‐3个C3‐6环烷基或C1‐6烷氧基取代的C1‐6烷基；C1‐6烷氧基。
  19. 如权利要求1所述化合物，其为以下式I所示的化合物，其顺反异构体、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、或其药学上可以接受的盐和酯，
    Figure PCTCN2016108975-appb-100011
    T表示C3-7环烷基，C4-7环烯基，C6-8二环烷基，C6-10芳基，C3-7杂环烷基；
    Z表示含有1、2或3个独立选自氧、氮和硫的杂原子的5元杂芳环；所述5元杂芳环被一个或多个选自以下的取代基任选取代：羟基，卤素，-R1，-OR1，-OC(O)R1，-NR2R3，CN，氰基(C1-6)烷基-或R2；
    R1表示C1-6烷基，C2-6链烯基，C2-6炔基，C3-6环烷基，C3-6环烷基(C1-6)烷基，氰基(C1-6)烷基，羟基或氨基取代的C1-6烷基，且R1任选为一、二或三氟代的；
    R2或R3独立地为氢，C1-6烷基，C2-6链烯基，C2-6炔基，C3-6环烷基或CF3，或R2和R3与它们共同连接的氮原子一起形成4-7元杂脂肪环，该杂脂肪环含有所述氮原子和一个任选自O、N和S的其它杂原子，所述杂脂肪环任选被一个或多个R1基团任选取代；
    A为-NR2-；或A为含有1、2、3或4个独立选自氧、氮和硫的杂原子的5元杂亚芳基且杂原子中最多有1个为氧或硫；或为含有1、2或3个氮原子的6元杂亚芳基，或所述5或6元杂亚芳基还任选地稠合于苯环或吡啶环上，所述5或6元杂亚芳基任选被Rx和/或Ry和/或Rz取代，其中Rx为卤素、-R1、-OR1、-OC(O)R1、-C(O)OR1、-NR2R3、-NR2C(O)R3、-OH、-CN，Ry为卤素、-R1、-OR1、-OC(O)R1、-NR2R3、-NR2C(O)R3、或CN，Rz为-R1、-OR1或-OC(O)R1，前提是当A为吡啶衍生物时，该吡啶环任选为N-氧化物形式；或A为被1、2或3个独立选自以下的基团任选取代的亚苯基：卤素、氰基、C1-6烷基、C2-6链烯基、C2-6炔基和C3-6环烷基；
    Y为-NY1Y2或-NH-NY3Y4；
    Y1选自：H；C1-6烷基；被1-5个取代基取代的C1-6烷基，所述取代基独立地选自：氨基，卤素，卤代-C1-6烷氧基，羟基，C1-6烷氧基，(C1-6烷基，C1-6烷基)N-，(C1-6烷基，H)N-，硝基和C1-6烷基-S(O)2-；
    Y2选自：H；C1-6烷基；被1-5个取代基取代的C1-6烷基，所述取代基独立地选自：氨基，卤素，卤代-C1-6烷氧基，羟基，C1-6烷氧基，环烷基，(C1-6烷基，C1-6烷基)N-，(C1-6烷基，H)N-，硝基和C1-6烷基-S(O)2-；杂芳基，或被1-4个取代基取代的杂芳基，所述杂芳基的取代基独立地选自：乙酰胺基，乙酰基，乙酰基氨基，酰氨基，氨基，羧基，氰基，卤素，卤代-C1-6烷氧基，卤代-C1-6烷基，羟基，羟基-C1-6烷基，C1-6烷氧基，C1-6烷氧基-C1-6烷基，C1-6烷基，(C1-6烷基，C1-6烷基)N-，(C1-6烷基，H)N-，硝基和C1-6烷基-S(O)2-；环烷基，或被1-4个取代基取代的环烷基，所述的取代基单独地选自：乙酰胺基，乙酰基，乙酰基氨基，酰氨基，氨基，羧基，氰基，卤素，卤代-C1-6烷氧基，卤代-C1-6烷基，羟基，羟基-C1-6烷基，C1-6 烷氧基，C1-6烷氧基-C1-6烷基，C1-6烷基，(C1-6烷基，C1-6烷基)N-，(C1-6烷基，H)N-，硝基和C1-6烷基-S(O)2-；杂环烷基，或被1-4个取代基取代的杂环烷基，所述取代基单独地选自：乙酰胺基，乙酰基，乙酰基氨基，酰氨基，氨基，羧基，氰基，卤素，卤代-C1-6烷氧基，卤代-C1-6烷基，羟基，羟基-C1-6烷基，C1-6烷氧基，C1-6烷氧基-C1-6烷基，C1-6烷基，(C1-6烷基，C1-6烷基)N-，(C1-6烷基，H)N-，硝基和C1-6烷基-S(O)2-；
    或者Y1、Y2与它们所连接的N原子一起形成4-6元杂环烷基，所述杂环烷基除了含有氮原子外，还含有零个、一个或多个选自O和S的杂原子，并且所述S原子可以为其氧化物形式；
    Y3，Y4相互独立选自：氢、C1-C6烷基、SO2-C1-C6烷基、环烷基和杂环基，任选被1-4个独立选自下列基团的取代基取代：卤素、氰基、羟基、C1-C6烷基和C1-C6烷氧基，
    或者其中Y3，Y4与它们所连接的氮原子一起形成杂环基，该杂环基任选被1-4个独立选自下列基团的取代基取代：卤素、氰基、羟基、氧代、C1-C6烷基和C1-C6烷氧基。
  20. 如权利要求19所述的化合物，其具有以下通式II，
    Figure PCTCN2016108975-appb-100012
    其中
    Z表示含有1、2或3个独立选自氧、氮和硫的杂原子的5元杂芳环，其中最多有1个杂原子为氧或硫，并且当1个杂原子为氮原子时，至少也存在1个氧或硫原子，所述5元杂芳环被一个或多个选自以下的取代基任选取代：C1‐C4烷基、羟基、卤素、羟基或氨基取代的C1‐C4烷基、C2‐C4链烯基、C2‐C4炔基、C1‐C4烷氧基；
    A为含有1、2或3个独立选自氧、氮和硫的杂原子的5元杂亚芳基且杂原子中最多有1个为氧或硫，或含有1、2或3个氮原子的6元杂亚芳基或亚苯基；所述5元杂亚芳基、6元杂亚芳基和亚苯基任选地被选自以下的取代基取代：卤素、氰基、C1‐6烷基；
    Y为‐NY1Y2或‐NH‐NY3Y4；
    Y1是H，C1‐6烷基或被1‐5个取代基取代的C1‐6烷基；所述取代基单独地选自：氨基，羟基，C1‐6烷氧基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
    Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基单独地选自：氨基，羟基，C1‐6烷氧基，环烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
    含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，被C1‐6烷基取代的含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基；
    C3‐6环烷基，被1‐4个取代基取代的C3‐6环烷基，所述取代基单独地选自：氨基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
    含有1‐3个选自N、O或S的杂原子的C4‐C6‐杂环烷基，被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的C4‐C6杂环烷基，所述取代基单独地选自：氨基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基和C1‐6烷基‐S(O)2‐；
    或者Y1、Y2与它们所连接的N原子一起形成4‐6元杂环烷基，所述杂环烷基除了含有氮原子外，还含有零个、一个或多个选自O和S的杂原子，并且所述S原子可以为其氧化物形式；
    Y3，Y4相互独立选自：氢、C1‐C6烷基、SO2‐C1‐C6烷基，或者Y3和Y4与它们所连接的氮原子一起形成杂环基，所述杂环基选自哌啶基、吗啉基、二氧硫代吗啉基和一氧硫代吗啉基。
  21. 如权利要求19或20所述的化合物，其特征在于，Z表示含有2个独立选自氧、氮和硫的杂原子的5元杂芳环，并且一个杂原子为氧或硫，另一个原子为氮；所述5元杂芳环被一个或多个选自以下的取代基任选取代：C1‐6 烷基或羟基C1‐6烷基。
  22. 如权利要求19或20所述的化合物，其特征在于，Z表示氧杂二氮唑、呋喃基、噻吩基或异噁唑基，所述异噁唑基被一个或多个选自以下的取代基任选取代：H，C1‐6烷基或羟基C1‐6烷基。
  23. 如权利要求19或20所述的化合物，其特征在于，A表示亚苯基、亚吡啶基、亚异噁唑基；任选地被1、2或3个独立选自以下的取代基取代：卤素、氰基、C1‐6烷基。
  24. 如权利要求19或20所述的化合物，其特征在于，
    Z表示氧杂二氮唑、呋喃基、噻吩基或异噁唑基，所述异噁唑基被一个或多个选自以下的取代基任选取代：H，C1‐6烷基或羟基C1‐6烷基；
    A表示亚苯基、亚吡啶基、亚异噁唑基；任选地被1、2或3个独立选自以下的取代基取代：卤素、氰基、C1‐6烷基。
  25. 如权利要求19或20所述的化合物，其特征在于，
    Z表示氧杂二氮唑、呋喃基、噻吩基或异噁唑基，所述异噁唑基被一个或多个选自以下的取代基任选取代：H，C1‐6烷基或羟基C1‐6烷基。
    A表示亚苯基、亚吡啶基、亚异噁唑基；任选地被1、2或3个独立选自以下的取代基取代：卤素、氰基、C1‐6烷基；
    Y为‐NY1Y2或‐NH‐NY3Y4；
    Y1是H或C1‐6烷基；
    Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基单独地选自：氨基，羟基，C1‐6烷氧基；
    含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，被烷基取代的含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，
    C4‐6环烷基，被1‐4个取代基取代的C3‐6环烷基，所述取代基单独地选自：羟基；
    含有1‐3个选自N、O或S的杂原子的C4‐C6‐杂环烷基，被1‐4个取代 基取代的含有1‐3个选自N、O或S的杂原子的C4‐C6杂环烷基；
    或Y1和Y2与它们所连接的氮原子一起形成吗啉基、哌啶基、一氧代‐硫代吗啉基和二氧代‐硫代吗啉基；
    Y3和Y4相互独立选自：氢、甲基和‐SO2‐甲基,Y3和Y4与它们所连接的氮原子一起形成杂环基,选自吗啉基、哌啶基和二氧代‐硫代吗啉‐基。
  26. 如权利要求19或20所述的化合物，其特征在于，
    Z表示氧杂二氮唑、呋喃基、噻吩基或异噁唑基，所述异噁唑基被一个或多个选自以下的取代基任选取代：H，C1‐6烷基或羟基C1‐6烷基；
    A表示亚苯基、亚吡啶基、亚异噁唑基；任选地被1、2或3个独立选自以下的取代基取代：卤素、氰基、C1‐6烷基；
    Y为‐NY1Y2或‐NH‐NY3Y4；
    Y1是H或C1‐6烷基；
    Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基单独地选自：羟基，C1‐6烷氧基；
    含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，被烷基取代的含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，
    C4‐6环烷基，被1‐4个取代基取代的C3‐6环烷基，所述取代基单独地选自：羟基；
    含有1‐3个选自N、O或S的杂原子的C4‐C6‐杂环烷基，被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的C4‐C6杂环烷基；
    或Y1和Y2与它们所连接的氮原子一起形成吗啉基和哌啶基；
    Y3和Y4相互独立选自：氢、甲基和SO2‐甲基,Y3和Y4与它们所连接的氮原子一起形成杂环基,选自吗啉‐4‐基、哌啶‐1‐基和1，1‐二氧代‐硫代吗啉‐4‐基。
  27. 如权利要求19或20所述的化合物，其特征在于，
    Z表示氧杂二氮唑、呋喃基、噻吩基或异噁唑基，所述异噁唑基被一个或多个选自以下的取代基任选取代：H，C1‐6烷基或羟基C1‐6烷基；
    A表示亚苯基、亚吡啶基、亚异噁唑基；任选地被1、2或3个独立选自以下的取代基取代：卤素、氰基、C1‐6烷基；
    Y为‐NY1Y2或‐NH‐NY3Y4；
    Y1是H或甲基；
    Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基单独地选自：羟基，C1‐6烷氧基；
    Y3和Y4相互独立选自：氢和甲基,Y3和Y4与它们所连接的氮原子一起形成杂环基,选自吗啉‐4‐基、哌啶‐1‐基和1，1‐二氧代‐硫代吗啉‐4‐基。
  28. 如权利要求19或20所述的化合物，其特征在于，
    Z表示氧杂二氮唑、呋喃基、噻吩基或异噁唑基，所述异噁唑基被一个或多个选自以下的取代基任选取代：H，C1‐6烷基或羟基C1‐6烷基。
    A表示亚苯基、亚吡啶基、亚异噁唑基；任选地被1、2或3个独立选自以下的取代基取代：卤素、氰基、C1‐6烷基。
    Y为‐NY1Y2或‐NH‐NY3Y4；
    Y1是H或甲基；
    Y2选自甲基、乙基、甲氧基乙基或羟基丙基；
    Y3和Y4相互独立选自：氢和甲基,Y3和Y4与它们所连接的氮原子一起形成杂环基,选自吗啉‐4‐基、哌啶‐1‐基和1，1‐二氧代‐硫代吗啉‐4‐基。
  29. 如权利要求19所述的化合物，其具有以下通式III:
    Figure PCTCN2016108975-appb-100013
    其中
    R4为C1‐C4烷基、羟基取代的C1‐C4烷基；
    Y为‐NY1Y2或‐NH‐NY3Y4；
    Y1是H，C1‐6烷基或被1‐5个取代基取代的C1‐6烷基；所述取代基单独地 选自：氨基，羟基，C1‐6烷氧基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
    Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基单独地选自：氨基，羟基，C1‐6烷氧基，环烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
    含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，被C1‐6烷基取代的含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，
    C3‐6环烷基，被1‐4个取代基取代的C3‐6环烷基，所述取代基单独地选自：氨基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
    含有1‐3个选自N、O或S的杂原子的C4‐C6‐杂环烷基，被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的C4‐C6杂环烷基，所述取代基单独地选自：氨基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基和C1‐6烷基‐S(O)2‐；
    或者Y1、Y2与它们所连接的N原子一起形成4‐6元杂环烷基，所述杂环烷基除了含有氮原子外，还含有零个、一个或多个选自O和S的杂原子，并且所述S原子可以为其氧化物形式；
    Y3，Y4相互独立选自：氢、C1‐C6烷基、SO2‐C1‐C6烷基，或者Y3和Y4与它们所连接的氮原子一起形成杂环基，选自哌啶基、吗啉基、二氧硫代吗啉基和一氧硫代吗啉基。
  30. 如权利要求19所述的化合物，其具有以下通式IV:
    Figure PCTCN2016108975-appb-100014
    Y为‐NY1Y2或‐NH‐NY3Y4；
    Y1是H，C1‐6烷基或被1‐5个取代基取代的C1‐6烷基；所述取代基独立地 选自：氨基，羟基，C1‐6烷氧基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
    Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基独立地选自：氨基，羟基，C1‐6烷氧基，环烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
    含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，被C1‐6烷基取代的含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，
    C3‐6环烷基，被1‐4个取代基取代的C3‐6环烷基，所述取代基独立地选自：氨基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
    含有1‐3个选自N、O或S的杂原子的C4‐C6‐杂环烷基，被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的C4‐C6杂环烷基，所述取代基独立地选自：氨基，羟基，羟基‐C1‐6烷基，C1‐6烷氧基，C1‐6烷氧基‐C1‐6烷基，C1‐6烷基和C1‐6烷基‐S(O)2‐；
    或者Y1、Y2与它们所连接的N原子一起形成4‐6元杂环烷基，所述杂环烷基除了含有氮原子外，还含有零个、一个或多个选自O和S的杂原子，并且所述S原子可以为其氧化物形式；
    Y3，Y4相互独立选自：氢、C1‐C6烷基、SO2‐C1‐C6烷基，或者Y3和Y4与它们所连接的氮原子一起形成杂环基，选自哌啶基、吗啉基、二氧硫代吗啉基和一氧硫代吗啉基。
  31. 如权利要求19所述的化合物，其具有以下通式IV:
    Figure PCTCN2016108975-appb-100015
    Y为‐NY1Y2或‐NH‐NY3Y4；
    Y1是H，C1‐6烷基或被1‐5个取代基取代的C1‐6烷基；所述取代基独立地 选自：氨基，羟基，C1‐6烷氧基，(C1‐6烷基，C1‐6烷基)N‐，(C1‐6烷基，H)N‐和C1‐6烷基‐S(O)2‐；
    Y2选自C1‐6烷基；被1‐5个取代基取代的C1‐6烷基，所述取代基独立地选自：氨基，羟基，C1‐6烷氧基；
    含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，被C1‐6烷基取代的含有1‐3个选自N、O或S的杂原子的C5‐C6杂芳基，
    C4‐6环烷基，被1‐4个取代基取代的C3‐6环烷基，所述取代基独立地选自：羟基；
    含有1‐3个选自N、O或S的杂原子的C4‐C6‐杂环烷基，被1‐4个取代基取代的含有1‐3个选自N、O或S的杂原子的C4‐C6杂环烷基；
    或Y1和Y2与它们所连接的氮原子一起形成吗啉基、哌啶基、一氧代‐硫代吗啉基和二氧代‐硫代吗啉基；
    Y3和Y4相互独立选自：氢、甲基和SO2‐甲基,Y3和Y4与它们所连接的氮原子一起形成杂环基,选自吗啉基、哌啶基和二氧代‐硫代吗啉基。
  32. 如权利要求19所述的化合物，其具有以下通式IV:
    Figure PCTCN2016108975-appb-100016
    Y为‐NY1Y2或‐NH‐NY3Y4；
    Y1是H或C1‐6烷基；
    Y2选自C1-6烷基；被1-5个取代基取代的C1-6烷基，所述取代基单独地选自：羟基，C1-6烷氧基；
    含有1-3个选自N、O或S的杂原子的C5-C6杂芳基，被C1‐6烷基取代的含有1-3个选自N、O或S的杂原子的C5-C6杂芳基，
    C4-6环烷基，被1-4个取代基取代的C3-6环烷基，所述取代基单独地选自：羟基；
    含有1-3个选自N、O或S的杂原子的C4-C6-杂环烷基，被1-4个取代基取代的含有1-3个选自N、O或S的杂原子的C4-C6杂环烷基；
    或Y1和Y2与它们所连接的氮原子一起形成吗啉基和哌啶基；
    Y3和Y4相互独立选自：氢、甲基和SO2-甲基,Y3和Y4与它们所连接的氮原子一起形成杂环基,选自吗啉-4-基、哌啶-1-基和1，1‐二氧代‐硫代吗啉‐4‐基。
  33. 如权利要求19所述的化合物，其具有以下通式IV:
    Figure PCTCN2016108975-appb-100017
    Y为‐NY1Y2或‐NH‐NY3Y4；
    Y1是H或甲基；
    Y2选自C1-6烷基；被1-5个取代基取代的C1-6烷基，所述取代基单独地选自：羟基，C1-6烷氧基；
    Y3和Y4相互独立选自：氢和甲基,Y3和Y4与它们所连接的氮原子一起形成杂环基,选自吗啉‐4‐基、哌啶‐1‐基和1，1‐二氧代‐硫代吗啉‐4‐基。
  34. 如权利要求19所述的化合物，其具有以下通式IV:
    Figure PCTCN2016108975-appb-100018
    Y为‐NY1Y2或‐NH‐NY3Y4；
    Y1是H或甲基；
    Y2选自选自甲基、乙基、2‐甲氧基乙基或羟基丙基；
    Y3和Y4相互独立选自：氢和甲基,与它们所连接的氮原子一起形成杂环基,,选自吗啉‐4‐基、哌啶‐1‐基和1，1‐二氧代‐硫代吗啉‐4‐基。
  35. 权利要求1‐18中任一项所述的化合物，其独立地选自:
    Figure PCTCN2016108975-appb-100019
    Figure PCTCN2016108975-appb-100020
    Figure PCTCN2016108975-appb-100021
    Figure PCTCN2016108975-appb-100022
    Figure PCTCN2016108975-appb-100023
    Figure PCTCN2016108975-appb-100024
    Figure PCTCN2016108975-appb-100025
    Figure PCTCN2016108975-appb-100026
  36. 权利要求1‐18中任一项所述的化合物，其独立地选自:
    Figure PCTCN2016108975-appb-100027
    Figure PCTCN2016108975-appb-100028
  37. 一种组合物，其包含如权利要求1-36中任一项所述的化合物或其药学上可以接受的盐。
  38. 如权利要求1-36中任一项所述的化合物或权利要求37所述的组合物在制备药物中的用途。
  39. 一种治疗或预防疾病的方法，其特征在于向患者施用有效剂量的如权利要求1-36中任一项所述的化合物或权利要求37所述的组合物。
  40. 如权利要求1-36中任一项所述的化合物或如权利要求37所述的组合物在制备治疗或预防与α5‐GABAA受体有关的疾病的药物中的用途。
  41. 一种治疗或预防与α5‐GABAA受体有关的疾病的方法，其特征在于向患者施用有效剂量的如权利要求1-36中任一项所述的化合物或如权利要求37所述的组合物。
  42. 如权利要求1‐36中任一项所述的化合物或如权利要求37所述的组合物在制备治疗或预防下列疾病的药物中的用途：疼痛、阿尔茨海默氏病、多 梗塞性痴呆和中风。
  43. 一种治疗或预防疼痛、阿尔茨海默氏病、多梗塞性痴呆和中风的方法，其特征在于向患者施用有效剂量的如权利要求1-36中任一项所述的化合物或如权利要求37所述的组合物。
  44. 如权利要求42所述的用途，其特征在于，所述的疼痛是神经病理性疼痛、炎性疼痛和癌性痛。
  45. 如权利要求43所述的方法，其特征在于，所述的疼痛是神经病理性疼痛、炎性疼痛和癌性痛。
  46. 如权利要求42所述的用途，其特征在于，所述的疼痛选自：头痛，面部痛，颈痛，肩痛，背痛，胸痛，腹痛，背部痛，腰痛，下肢痛，肌肉与骨骼疼痛，血管疼痛，痛风，关节炎疼痛，内脏疼痛，感染性疾病(如AIDS和带状疱疹后神经痛)导致的疼痛，多骨疼痛，镰刀细胞贫血、自身免疫性疾病、多发性硬化或炎症有关的疼痛，损伤或手术引起的慢性疼痛，伤害感受性疼痛，疼痛性糖尿病，三叉神经痛，腰部或子宫颈神经根病痛，舌咽神经痛，自主神经反射性疼痛，反射性交感神经营养不良、神经根撕脱、癌症、化学损伤、毒素、营养缺乏、病毒或细菌感染、退行性骨关节病有关的疼痛。
  47. 如权利要求43所述的方法，其特征在于，所述的疼痛选自：头痛，面部痛，颈痛，肩痛，背痛，胸痛，腹痛，背部痛，腰痛，下肢痛，肌肉与骨骼疼痛，血管疼痛，痛风，关节炎疼痛，内脏疼痛，感染性疾病(如AIDS和带状疱疹后神经痛)导致的疼痛，多骨疼痛，镰刀细胞贫血、自身免疫性疾病、多发性硬化或炎症有关的疼痛，损伤或手术引起的慢性疼痛，伤害感受性疼痛，疼痛性糖尿病，三叉神经痛，腰部或子宫颈神经根病痛，舌咽神经痛，自主神经反射性疼痛，反射性交感神经营养不良、神经根撕脱、癌症、化学损伤、毒素、营养缺乏、病毒或细菌感染、退行性骨关节病有关的疼痛。
  48. 如权利要求1‐36中任一项所述的化合物的制备方法，该方法选自以下中的任一种：
    Figure PCTCN2016108975-appb-100029
    a)使式(IV)化合物
    Figure PCTCN2016108975-appb-100030
    与
    Figure PCTCN2016108975-appb-100031
    反应得到式(1‐3)化合物，其中G和W选自Cl，Br，I，OH，OTs，OTf和OMs，R5是烷基，甲基，乙基，叔丁基和苄基，其中Z、Y、A如权利要求1‐36中所定义；
    然后使式(1‐3)化合物
    Figure PCTCN2016108975-appb-100032
    与Y反应，其中Z、Y、A如权利要求1‐36中所定义；或者
    b)使式(1‐4)的化合物：
    Figure PCTCN2016108975-appb-100033
    与Y反应，其中Z、Y、A如权利要求1‐36中所定义；
    c)将式(1‐3)的化合物皂化为式(1‐4)化合物，随后与Y反应，其中，其中Z、Y、A如权利要求1‐36中所定义；或
    d)式
    Figure PCTCN2016108975-appb-100034
    化合物与式
    Figure PCTCN2016108975-appb-100035
    化合物的反应。
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JP2021518425A (ja) * 2018-03-12 2021-08-02 シャンハイ エスアイエムアール バイオテクノロジー カンパニー リミテッド フタラジンイソオキサゾールアルコキシ誘導体、その製造方法、薬物組成物および使用
US11512089B2 (en) * 2018-03-12 2022-11-29 Shanghai SIMR Biotechnology Co., Ltd Substituted [1,2,4]triazolo[3,4-a]phthalazines as modulators of GABAA receptor activity
JP7351590B2 (ja) 2018-03-12 2023-09-27 シャンハイ エスアイエムアール バイオテクノロジー カンパニー リミテッド フタラジンイソオキサゾールアルコキシ誘導体、その製造方法、薬物組成物および使用

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