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WO2018196677A1 - 氟代烯丙胺衍生物及其用途 - Google Patents

氟代烯丙胺衍生物及其用途 Download PDF

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Publication number
WO2018196677A1
WO2018196677A1 PCT/CN2018/083792 CN2018083792W WO2018196677A1 WO 2018196677 A1 WO2018196677 A1 WO 2018196677A1 CN 2018083792 W CN2018083792 W CN 2018083792W WO 2018196677 A1 WO2018196677 A1 WO 2018196677A1
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membered
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ring
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compound
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PCT/CN2018/083792
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English (en)
French (fr)
Inventor
朱加望
宋智泉
杨龙
李睿
张帅
周林
赵明亮
唐祖建
钟维
曾宏
宋宏梅
周信
谭玉婷
胡晓
王利春
王晶翼
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Application filed by Sichuan Kelun Biotech Biopharmaceutical Co Ltd filed Critical Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Priority to US16/489,474 priority Critical patent/US20200087248A1/en
Priority to CN201880014600.XA priority patent/CN110352188B/zh
Priority to EP18790399.2A priority patent/EP3617186A1/en
Publication of WO2018196677A1 publication Critical patent/WO2018196677A1/zh
Anticipated expiration legal-status Critical
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    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
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    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C07D277/66—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 with aromatic rings or ring systems directly attached in position 2
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/14—Nitrogen atoms not forming part of a nitro radical
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    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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    • C07C2601/00—Systems containing only non-condensed rings
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/12—One of the condensed rings being a six-membered aromatic ring the other ring being at least seven-membered

Definitions

  • the invention relates to the field of medicine, in particular to a fluoroallylamine derivative and its inhibition as vascular adhesion protein-1 (VAP-1)/semicarbazide-sensitive amine oxidase (SSAO) Use of the agent.
  • VAP-1 vascular adhesion protein-1
  • SSAO semiconductor amine oxidase
  • Vascular adhesion protein-1 is a dimeric glycoprotein with a relative molecular mass (MW) of 170,000 to 180,000, a multifunctional protein widely present in mammals.
  • Vascular adhesion protein 1 is both an endothelial adhesion molecule and a semicarbazide-sensitive amine oxidase (SSAO) activity. It has a wide range of tissue distribution, mainly from endothelial cells, smooth muscle cells, and fat cells, and is most commonly found in two forms in the body: tissue-bound forms and soluble forms. Circulating in the plasma of humans and some animals is its soluble form, which is a cleavage product of membrane-bound vascular adhesion protein 1/semicarbazide-sensitive amine oxidase.
  • SSAO semicarbazide-sensitive amine oxidase
  • vascular adhesion protein 1 / semicarbazide-sensitive amine oxidase is induced in the process of adipogenesis (Fontana, E., et. al., Biochem. J., 2001, 356, 769; Moldes, M., Et.al., J. Biol. Chem., 1999, 274, 9515); vascular adhesion protein 1/semicarbazide-sensitive amine oxidase also in leukocyte exudation, adhesion cascade, regulation of glucose metabolism, vascular injury, etc.
  • vascular adhesion protein 1 plays an important role; in the inflammatory disease, tissue damage fibrosis, glucose metabolism-related diseases, tumors, strokes and many other clinical diseases, the expression and function of vascular adhesion protein 1 / semicarbazide-sensitive amine oxidase Important role; high levels of vascular adhesion protein 1/semicarbazide-sensitive amine oxidase positive cells were found in the skin of patients with atopic eczema or psoriasis.
  • vascular adhesion protein 1/semicarbazide-sensitive amine oxidase is an effective drug in diabetes, pneumonia, hepatitis, pulmonary fibrosis, liver fibrosis, fatty liver, stroke, and other inflammatory or fibrotic-related diseases.
  • Biological target In a nutshell, vascular adhesion protein 1/semicarbazide-sensitive amine oxidase is an effective drug in diabetes, pneumonia, hepatitis, pulmonary fibrosis, liver fibrosis, fatty liver, stroke, and other inflammatory or fibrotic-related diseases.
  • Biological target In a nutshell, vascular adhesion protein 1/semicarbazide-sensitive amine oxidase is an effective drug in diabetes, pneumonia, hepatitis, pulmonary fibrosis, liver fibrosis, fatty liver, stroke, and other inflammatory or fibrotic-related diseases.
  • Biological target In a nutshell, vascular adhesion protein 1/semic
  • vascular adhesion protein 1/semicarbazide-sensitive amine oxidase such as deuterated compounds, benzomethenone, decyl alcohol, deuterated indan, aromatic cycloalkylamine, propylene , propargylamine, oxazolidinone, haloalkylamine, 1,3,4-oxazolidinone, oxadiazine, thioamide, thiazole derivatives, and other organic compounds (Dunke1, P. et.al., Curr. Med. Chem., 2008, 15, 1827; Tetra. Letters, 1977, 36, 3155).
  • Propargylamine family compounds have also been reported to be useful for inhibiting vascular adhesion protein 1/semicarbazide-sensitive amine oxidase (O'Connell, K.M., et. al., Biochemistry, 2004, 43, 10965). These compounds, like semicarbazide, rely on the hydrazine functional group to form a covalent imine bond with the TPQ cofactor to inhibit.
  • the present inventors have surprisingly discovered an effective compound having vascular adhesion protein 1/semicarbazide-sensitive amine oxidase inhibitory activity, which can be used for preventing or treating susceptibility to vascular adhesion protein 1/semicarbazide.
  • the present invention provides a fluoroallylamine derivative of the formula I which has a high inhibitory activity against vascular adhesion protein 1/semicarbazide-sensitive amine oxidase, and has a higher affinity for monoamine oxidase and diamine oxidase. Good selectivity, improved metabolic stability in the body.
  • a first aspect of the invention provides a compound of formula I, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, isotopically labeled compound thereof, or any crystalline form or racemate thereof, or metabolism thereof Forms of matter, and mixtures thereof,
  • R 1 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, 3-10 membered cycloalkyl-CH 2 NHC(O)-, 3-8 membered heteroheterocyclyl-CH 2 NHC(O)-, 6- 20-membered aryl-CH 2 NHC(O)-, 5-20 membered heteroaryl-CH 2 NHC(O)-, 5-20 membered heteroaryl-CH 2 NHC(O)-, benzo-3- 10-membered cycloalkyl-NHC(O)-, 3-8 membered alicyclic-NHC(O)-, 6-20 membered aryl-NHC(O)-, 5-20 membered heteroaryl-NHC ( O)-, 5-20 membered heteroaryl-NHC(O)-; and, the C 1-6 alkyl group, 3-10 membered cycloalkyl-CH 2 NHC(O)-, 3-8 member Aliphatic-CH 2 NHC(O)
  • R 2 is each independently selected from the group consisting of hydrogen, cyano, nitro, hydroxy, halogen, C 1-6 alkyl, 3-10 membered cycloalkyl, 3-8 membered heteroheterocyclyl, halogenated C 1-6 alkane a group, a C 1-6 alkoxy group, a halogenated C 1-6 alkoxy group;
  • n 1, 2 or 3;
  • R 3 and R 4 are selected from:
  • R 3 is selected from 3-10 membered cycloalkyl-CH 2 , 3-8 membered heteroheterocyclyl-CH 2 , 6-20 membered aryl-CH 2 , 5-20 membered heteroaryl-CH 2 5-20 membered heteroaryl-CH 2 , benzo 3-10 membered cycloalkyl, benzo 3-8 membered heterocyclic group, phenyl-3-10 membered cycloalkyl group, 5-20 membered hetero Aryl-phenyl, 5-20 membered fused heteroarylphenyl, 3-8 membered heteroheterocyclyl, 6-20 membered aryl, 5-20 membered heteroaryl, 5-20 membered heteroaryl; Further, the 3-10 membered cycloalkyl-CH 2 , 3-8 membered heteroheterocyclyl-CH 2 , 6-20 membered aryl-CH 2 , 5-20 membered heteroaryl-CH 2 , 5- 20-membere
  • R 3 is bonded to R 4 to form a ring Y, which is a 5-8 membered heterocyclic ring or a 5-8 membered alicyclic ring; and, the 5-8 membered alicyclic or 5-8 membered lipid Rings which are unsubstituted or each independently are one or more (for example 1, 2, 3 or 4) selected from the group consisting of halogen, cyano, -NRR', nitro, hydroxy, C 1-6 alkyl, C 1- Substituents for 6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, 6-20 membered aryl, 5-20 membered heteroaryl and 5-20 membered heteroaryl And wherein the C 1-6 alkyl group, C 1-6 alkoxy group, halogenated C 1-6 alkyl group, halogenated C 1-6 alkoxy group, 6-20 membered aryl group, 5-20 The heteroheteroaryl group and the
  • R 3 is bonded to M to form a ring Z, which is a 3-10 membered heterocyclic ring, a 6-20 membered aromatic ring or a 5-20 membered heteroaryl ring; and, the 3-10 membered aliphatic
  • R 5 is selected from halogen
  • R 6 is selected from the group consisting of hydrogen, C 1-6 alkyl and -COOR; wherein the C 1-6 alkyl group is unsubstituted or one or more (for example 1, 2, 3 or 4) is selected from halogen, a substituent of a hydroxyl group, an amino group, and a cyano group;
  • a atom is selected from C, N, O and S;
  • R and R' are each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, 3-8 membered cycloalkyl, 3-8 membered heteroheterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl or 5-10 membered fused heteroaryl;
  • R 1 is not hydrogen, Independently, the whole is hydrogen.
  • the compound is a mixture of cis and trans configuration compounds in any ratio.
  • the compound is in the cis (Z) configuration.
  • the compound is in the trans (E) configuration.
  • the compound has the structure of Formula II,
  • R 3 is selected from the group consisting of 3-10 membered cycloalkyl-CH 2 , 3-8 membered heteroheterocyclyl-CH 2 , 6-20 membered aryl-CH 2 , 5-20 member.
  • R 3 is selected from the group consisting of 3-10 membered cycloalkyl-CH 2 , 3-8 membered heteroheterocyclyl-CH 2 , 6-20 membered aryl -CH 2 , 5-20 membered heteroaryl-CH 2 , 5-20 membered heteroaryl-CH 2 , benzo 3-10 membered cycloalkyl, benzo 3-8 aliphatic heterocyclyl, phenyl -3-10 membered cycloalkyl, 5-20 membered heteroaryl-phenyl, 5-20 membered heteroaryl-phenyl, 3-8 membered heterocyclic group, 6-20 membered aryl, 5- a 20-membered heteroaryl group, a 5-20 membered heteroaryl group; and, the 3-10 membered cycloalkyl-CH 2 , 3-8 membered heteroheterocyclyl-CH 2 , 6-20 membered
  • R 4 is selected from H or methyl
  • R 1 is selected from H, halogen, C 1-3 alkyl
  • R 5 , R 6 , R and R′ are substituents selected from halo, hydroxy, -NRR ', C 1-3 alkyl, C 1- 3 alkoxy, cyano, 3-10 cycloalkyl, 3-8 membered heteroheterocyclyl, 6-20 membered aryl, 5-20 membered heteroaryl, 5-20 membered heteroaryl, halogenated C 1-3 alkyl, halo C 1-3 alkoxy, C 1-3 alkoxy-C 1-3 alkyl, C 1-3 alkoxy-C 1-3 alkoxy, C 1- Substituted by a substituent of 3 alkoxy-C 1-3 alkoxy-C 1-3 alky
  • R 3 is selected from the group consisting of phenyl, quinazolinyl, quinoxalinyl, naphthyl, benzo[1,4]dioxane, Benzimidazolyl, fluorenyl, [1,3,4]oxadiazolyl, [1,3,4]oxadiazolyl-phenyl, imidazolyl-phenyl, phenyl-cyclohexyl, benzo Cyclohexyl, tetrahydropyranyl, thienyl, benzothiazolyl, oxazolyl, tetrahydropyranyl-CH 2 -, cyclopropyl-CH 2 -, pyridyl-CH 2 -, quinolinyl, The phenyl, quinazolinyl, naphthyl, benzo[1,4]dioxanyl, benzimidazolyl, in
  • R 1 is selected from the group consisting of H, halogen, and C 1-3 alkyl.
  • R 2 is selected from the group consisting of H, halogen, and C 1-3 alkyl.
  • n 1.
  • R 5 is F
  • R 6 is H.
  • R 3 is selected from the group consisting of 6-15 membered aryl, benzo 3-8 membered cycloalkyl, benzo 3-8 membered heterocyclic, 3 -8-membered alicyclic heterocyclic group, 5-10 membered heteroaryl-CH 2 , 5-10 membered fused heteroaryl-CH 2 , 3-8 membered cycloalkyl-CH 2 , 3-8 membered aliphatic heterocyclic group -CH 2 , 6-10 membered aryl-CH 2 , 5-10 membered heteroaryl, 5-10 membered heteroaryl; and, 6-15 membered aryl, benzo 3-8 membered naphthenic Base, benzo 3-8 membered heteroheterocyclyl, 3-8 membered heteroheterocyclyl, 5-10 membered heteroaryl-CH 2 , 5-10 membered heteroaryl-CH 2 , 3-8 membered ring
  • R 1 is selected from H, halogen
  • R 5 and R 6 are as defined in formula I.
  • R 3 is selected from the group consisting of phenyl, naphthyl, benzocyclohexyl, tetrahydropyranyl, pyridyl-CH 2 -, benzo[1, 4] dioxolyl, said phenyl, naphthyl, benzocyclohexyl, tetrahydropyranyl, pyridyl-CH 2 -, benzo[1,4]dioxane, unsubstituted Or independently substituted by one or more (for example 1 or 2) substituents selected from methyl, halogen, -N(CH 3 ) 2 , methoxy-ethoxy; R 4 is selected from H or A base.
  • R 3 is selected from the group consisting of 3-7 membered cycloalkyl-CH 2 , 3-7 membered alicyclic-CH 2 , 6-10 membered aryl-CH 2 , 5-6 a heteroaryl-CH 2 -, a benzo 3-7 membered cycloalkyl group, a 3-7 membered alicyclic group, a 6-10 membered aryl group, a 5-10 membered heteroaryl group, a 5-10 membered heteroaryl group Base;
  • R 4 is H;
  • R 3 is selected from the group consisting of 6-10 membered aryl, 3-7 membered alicyclic group; and R 4 is H.
  • R 3 is selected from phenyl, tetrahydropyranyl; and R 4 is H.
  • the compound is a mixture of cis and trans configuration compounds in any ratio.
  • the compound of formula II is in the cis (Z) configuration.
  • the compound of formula II is in the trans (E) configuration.
  • the compound has the structure shown in Formula III,
  • R 4 is selected from the group consisting of hydrogen, C 1-6 alkyl, 3-8 membered cycloalkyl, 3-8 membered heteroheterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, and 5-10 membered thick.
  • heteroaryl group and, the C 1-6 alkyl group, a 3-8 membered cycloalkyl group, a 3-8 membered heterocyclic group, a 6-10 membered aryl group, a 5-10 membered heteroaryl group or 5-10
  • the fused heteroaryl group is optionally selected from one or more (e.g., 1, 2, 3 or 4) selected from the group consisting of halogen, cyano, -NRR', hydroxy, C 1-4 alkyl, C 1-4 alkoxy Substituent substitution of a 3-8 membered cycloalkyl group, a 3-8 membered alicyclic group, a 6-10 membered aryl group, a 5-10 membered heteroaryl group or a 5-10 membered fused heteroaryl group;
  • R 2 , R 5 , R 6 , R, R′ and A are as defined in formula I.
  • A is selected from the group consisting of N and C.
  • R 2 is selected from the group consisting of hydrogen and halogen.
  • R 4 is selected from the group consisting of hydrogen and C 1-3 alkyl.
  • R 5 is selected from halogen.
  • R 6 is H.
  • ring X is a 5-7 membered alicyclic or 5-7 alicyclic ring; and, said 5-7 membered alicyclic or 5-7 membered fat
  • Ring X is a 5-membered alicyclic or a 6-membered nitrogen-containing heterocyclic ring.
  • the 6-membered nitrogen-containing heteroalicyclic ring is a piperidine ring.
  • the compound is a mixture of cis and trans configuration compounds in any ratio.
  • the compound of formula III is in the cis (Z) configuration.
  • the compound of formula III is in the trans (E) configuration.
  • the compound has the structure shown in Formula IV,
  • R 4 is selected from the group consisting of hydrogen, C 1-6 alkyl, 3-8 membered cycloalkyl, 3-8 membered heteroheterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 5-10 member thick a heteroaryl group; and, the C 1-6 alkyl group, a 3-8 membered cycloalkyl group, a 3-8 membered heterocyclic group, a 6-10 membered aryl group, a 5-10 membered heteroaryl group or 5-10
  • the fused heteroaryl group is optionally selected from one or more (e.g., 1, 2, 3 or 4) selected from the group consisting of halogen, cyano, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, 3- a substituent substituted with an 8-membered cycloalkyl group, a 3-8 membered alicyclic group, a 6-10 membered aryl group, a 5-10 membered heteroary
  • R 2 , R 5 , R 6 , R, R′, A and n are as defined in formula I.
  • Ring X is selected from the group consisting of a 5-7 membered alicyclic ring or a 5-7 membered heterocyclic ring containing a nitrogen atom or an oxygen atom (eg, pyrrolidine ring, piperidine).
  • a ring, a tetrahydropyran ring and the 5-7 membered alicyclic ring or a 5-7 membered heterocyclic ring containing a nitrogen atom or an oxygen atom is unsubstituted or independently one or more (for example 1, 2, 3 or 4) substituents selected from halogen, C 1-4 alkyl (for example methyl); or, the 5-7 membered alicyclic or 5-7 membered heteroalicyclic ring containing a nitrogen atom
  • a spiro ring structure is formed with a cyclopropyl group.
  • R 4 is selected from the group consisting of hydrogen, phenyl, diaza naphthyl, halobenzyl, tetrahydropyranyl-CH 2 -, C 1- alkyl (e.g. methyl, ethyl), cyclopentyl, benzyl, tetrahydropyranyl.
  • R 2 is selected from the group consisting of hydrogen and halogen.
  • R 5 is selected from halogen.
  • R 6 is H.
  • A is selected from the group consisting of N and C.
  • Ring X is a 5-7 membered alicyclic or 5-7 membered alicyclic ring; and, said 5-7 membered alicyclic or 5-7 membered
  • A is selected from N and C;
  • R 4 is selected from H, C 1-4 alkyl, benzyl or halobenzyl;
  • R 5 is selected from F;
  • R 6 From H.
  • Ring X is a 5-6 membered alicyclic ring or a 5-6 membered alicyclic ring; and, the 5-6 membered alicyclic ring or 5-6 membered member
  • Ring X is selected from the group consisting of a pyrrolidine ring, a piperidine ring, and the pyrrolidine ring or piperidine ring is unsubstituted or substituted with one or more methyl groups. .
  • R 4 is selected from the group consisting of H, halobenzyl, methyl.
  • A is N;
  • R 4 is selected from H, CH 3 , CH 2 CH 3 ;
  • R 5 is selected from F; and
  • R 6 is selected from H.
  • the compound is a mixture of cis and trans configuration compounds in any ratio.
  • the compound of formula IV is in the cis (Z) configuration.
  • the compound of formula IV is in the trans (E) configuration.
  • the compound has the structure shown in Formula V,
  • the ring Y is a 5-8 membered alicyclic ring or a 5-8 membered alicyclic ring; and the 5-8 membered alicyclic or 5-8 membered alicyclic ring is unsubstituted or independently substituted by one or A plurality (for example 1, 2, 3 or 4) are selected from the group consisting of halogen, cyano, -NRR', nitro, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 a substituent substituted with an alkyl group, a halogenated C 1-6 alkoxy group, a 6-20 membered aryl group, a 5-20 membered heteroaryl group, and a 5-20 membered fused heteroaryl group, wherein the C 1-6 alkane a group, a C 1-6 alkoxy group, a halogenated C 1-6 alkyl group, a halogenated C 1-6 alkoxy group, a 6
  • the aryl groups are unsubstituted or each independently one or more (eg 1, 2, 3 or 4) selected from the group consisting of halogen, cyano, -NRR', C 1-6 alkyl, 6-20 membered aryl, Substituting a 5-20 membered heteroaryl group and a 5-20 membered fused heteroaryl group; or, the 5-8 membered alicyclic or 5-8 membered alicyclic ring and 6-20 membered aromatic ring or 5-20
  • the heteroaromatic ring forms a fused ring system wherein the fused ring system is unsubstituted or independently one or more (eg 1, 2, 3 or 4) selected from the group consisting of halogen, cyano, -NRR ', C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1- Substituted by 6 alkoxy, 6-20 membered aryl, 5-20 membere
  • Ring Y is a 5-7 membered heteroalicyclic; and wherein the 5-7 membered Aliphatic is unsubstituted or substituted by one or more (eg, 1, 2, 3 or 4) are selected from the group consisting of halogen, cyano, -NRR', 6-15 membered aryl and C 1-4 alkyl substituent, wherein the 6-15 membered aryl group, C 1 -4 alkyl is unsubstituted or each independently one or more (e.g.
  • 1, 2, 3 or 4 is selected from the group consisting of halogen, C 1-4 alkyl, halo C 1-4 alkyl and 6-10 Substituting a substituent of a aryl group; or, the 5-7 membered alicyclic ring forms a fused ring system with a 6-10 membered aromatic ring or a 5-10 membered heteroaryl ring, and the fused ring system is not Substituted or independently of one or more (for example 1, 2, 3 or 4) substituents selected from halogen, C 1-4 alkyl, halo C 1-4 alkyl and 6-10 membered aryl Replace
  • R 1 , R 2 , R 5 , R 6 , R and R′ are as defined in formula I; A is N.
  • R 1 is H
  • the compound of the formula V, R 2 is selected from halo.
  • R 5 is selected from halogen.
  • R 6 is H.
  • the ring Y is a 5-7 membered nitrogen-containing aliphatic heterocyclic ring; and the 5-7 membered nitrogen-containing aliphatic heterocyclic ring is unsubstituted or substituted by one or Substituting a plurality of substituents selected from the group consisting of phenyl and diphenylmethyl; or the 5- to 7-membered nitrogen-containing heterocyclic ring forms a fused ring system with a benzene ring or a thiophene ring, and the fused ring system is not Substituted or independently substituted with one or more substituents selected from halogen, phenyl, trifluoromethyl.
  • Ring Y is a 5-7 membered heteroalicyclic; and wherein the 5-7 membered Aliphatic is unsubstituted or substituted by one or more (eg, 1, 2, 3 or 4) substituents selected from 6-10 membered aryl; A is N, R 1 is H; R 2 is selected from H or F; R 5 is F; and R 6 is H.
  • the ring Y is a 5- to 10-membered heterocyclic ring containing a nitrogen atom; and the 5-7 member contains an aliphatic heterocyclic ring containing a nitrogen atom. Unsubstituted or substituted by a phenyl group; or, the 5-7 membered alicyclic ring containing a nitrogen atom forms a fused ring system with a benzene ring, the fused ring system being unsubstituted or one or more Substituted with a substituent selected from the group consisting of halogen, phenyl, and trifluoromethyl.
  • the compound is a mixture of cis and trans configuration compounds in any ratio.
  • the compound of formula V is in the cis (Z) configuration.
  • the compound of formula V is in the trans (E) configuration.
  • the compound has the structure of formula VI,
  • the ring Z is a 3-10 membered alicyclic ring, a 6-20 membered aromatic ring or a 5-20 membered heteroaryl ring; and the 3-10 membered alicyclic ring, 6-20 membered aromatic ring or 5 -20 membered heteroaryl ring is unsubstituted or independently substituted with one or more (e.g.
  • ring forms a fused ring system wherein the fused ring system is unsubstituted or independently independently one or more (eg 1, 2, 3 or 4) selected from the group consisting of halogen, cyano, -NRR', C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, 6-20 membered aryl, 5-20 membered heteroaryl and 5-20 Substituted by a substituent of a fused heteroaryl group; or, the 3-10 membered alicyclic ring, 6-20 membered aromatic ring or 5-20 membered heteroaryl ring and 6-20 membered aromatic ring or 5-20 membered heteroaryl
  • the ring forms a fused ring system wherein the fused ring system is unsubstituted or independently independently one or more (eg 1, 2, 3 or 4) selected from the group consisting of halogen, cyano, -NRR', C 1-6
  • R 4 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, absent or valence bond;
  • R 1 , R 2 , R 5 , R 6 , R, R′, A, M and n are as defined in formula I.
  • R 1 is selected from H or halogen.
  • R 2 is selected from H or halogen.
  • R 5 is selected from halogen.
  • R 6 is selected from H or C 1-6 alkyl.
  • A is selected from S or N.
  • M is selected from C or N.
  • n 1 or 2.
  • the ring Z is a 5-7 membered heterocyclic ring, a 6-10 membered aromatic ring or a 5-10 membered heteroaryl ring, and the 5-7
  • the monoaliphatic heterocyclic ring, the 6-10 membered aromatic ring or the 5-10 membered heteroaryl ring is unsubstituted or independently independently one or more (for example 1, 2, 3 or 4) selected from the group consisting of halogen, cyano, -NRR Substituent substitution of ', nitro, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkyl, halo C 1-6 alkoxy; or, 5 a -7 membered aliphatic heterocyclic ring, a 6-10 membered aromatic ring or a 5-10 membered heteroaryl ring forms a fused ring system with a 6-10 membered aromatic ring or a 5-10 member
  • R 4 is selected from hydrogen, C 1-6 alkyl, absent or forms a valence bond
  • R 1 is selected from hydrogen, halogen;
  • R 5 is selected from F or Cl; and
  • R 6 is selected from hydrogen, C 1-6 alkyl;
  • A is selected from N and S;
  • M is selected from N;
  • R and R' are as defined in formula I.
  • the ring Z is a 5-7 membered heterocyclic ring, a 6-10 membered aromatic ring or a 5-10 membered heteroaryl ring; and, the 5-7
  • the monoaliphatic heterocyclic ring, the 6-10 membered aromatic ring or the 5-10 membered heteroaryl ring is unsubstituted or each independently one or more (eg 1, 2 or 3) selected from the group consisting of halogen, cyano, -NRR', Substituent substitution of nitro, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkyl, halo C 1-6 alkoxy; wherein R and R' are each Independently selected from hydrogen and C 1-3 alkyl; or, the 5-7 membered alicyclic, 6-10 membered aromatic or 5-10 membered heteroaryl ring and 6-10 membered aromatic ring or 5-10
  • R 4 is selected from hydrogen, C 1-6 alkyl, absent or forms a valence bond
  • R 1 is selected from H, halogen;
  • R 5 is selected from F or Cl
  • R 6 is selected from the group consisting of H, C 1-6 alkyl
  • A is selected from N;
  • M is selected from N.
  • Ring Z is a 5-7 membered heteroaryl ring containing one or more heteroatoms selected from N or S.
  • the 5-7 membered heteroaryl ring is substituted with a C1-3 alkyl group.
  • ring Z is selected from the group consisting of a pyrimidine ring, an imidazole ring, a thiazole ring, a [1,2,4]triazine ring.
  • the 5-7 membered heteroaryl ring forms a fused ring with a 6-10 membered aromatic ring (e.g., a benzene ring) or a 5-10 membered nitrogen-containing heteroaryl ring (e.g., an imidazole ring).
  • a 6-10 membered aromatic ring e.g., a benzene ring
  • a 5-10 membered nitrogen-containing heteroaryl ring e.g., an imidazole ring
  • the fused ring system is substituted with a halogen.
  • Ring Z is a pyrimidine ring, an imidazole ring or a thiazole ring optionally substituted with a methyl group; or, the pyrimidine ring, the imidazole ring or the thiazole ring and benzene
  • the ring forms a fused ring system which is optionally substituted by a halogen.
  • Ring Z is a pyrimidine ring or an imidazole ring; alternatively, the pyrimidine ring or the imidazole ring forms a fused ring system with the phenyl ring.
  • the compound is a mixture of cis and trans configuration compounds in any ratio.
  • the compound of formula VI is in the cis (Z) configuration.
  • the compound of formula VI is in the trans (E) configuration.
  • the compound is selected from the group consisting of
  • the pharmaceutically acceptable salt of the compound is a hydrochloride or a trifluoroacetate; preferably, the pharmaceutically acceptable salt is the hydrochloride salt.
  • the pharmaceutically acceptable salt of the compound is:
  • the pharmaceutically acceptable salt of the compound is:
  • the compounds of the present invention include the compounds encompassed by Formulas I-VI, pharmaceutically acceptable salts, esters, hydrates, solvates, isomers, isotopically labeled compounds thereof, any crystal or racemate thereof, or Their metabolite forms, and or mixtures thereof.
  • a second aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the first aspect of the invention, a pharmaceutically acceptable salt, ester, hydrate, solvate, isomer thereof, isotopically labeled compound thereof, Any crystal or racemate, or a metabolite form thereof, and or mixtures thereof, and one or more pharmaceutical excipients.
  • the medicinal excipients described herein refer to the excipients and auxiliaries used in the production of pharmaceuticals and formulation formulations, which refer to the reasonable evaluation of safety in addition to the active ingredients, and are included in the pharmaceutical preparations. Substance. Pharmaceutical excipients can be used for prototyping, acting as a carrier, improving stability, and also having important functions such as solubilization, solubilization, slow release and release, and are important ingredients that may affect the quality, safety and effectiveness of drugs. According to its source, it can be divided into natural materials, semi-synthetic materials and total synthetic materials.
  • solvent propellant
  • solubilizer cosolvent
  • emulsifier colorant
  • binder disintegrant
  • filler filler
  • lubricant wetting agent
  • osmotic pressure regulator stabilizer
  • Glidants flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, antioxidants, chelating agents, penetration enhancers, pH adjusters, buffers, plasticizers, surface active agents Agent, foaming agent, antifoaming agent, thickener, inclusion agent, moisturizer, absorbent, diluent, flocculant and deflocculant, filter aid, release retardant, etc.
  • solvent propellant
  • solubilizer cosolvent
  • emulsifier colorant
  • binder disintegrant
  • filler filler
  • lubricant wetting agent
  • osmotic pressure regulator stabilizer
  • Glidants osmotic pressure regulator
  • flavoring agents preservatives
  • suspending agents coating materials
  • fragrances anti
  • Specific pharmaceutical excipients include water, lactose, glucose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, rubber, gel, alginate, calcium silicate, calcium phosphate, cellulose. , aqueous syrup, methyl cellulose, polyvinyl pyrrolidone, alkyl p-hydroxybenzoate, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, soybean oil, and the like.
  • the pharmaceutical composition may be administered in any form as long as it achieves prevention, alleviation, prevention or cure of symptoms of a human or animal patient.
  • various suitable dosage forms can be prepared depending on the route of administration.
  • the pharmaceutical composition can be formulated into any orally acceptable preparation including, but not limited to, tablets, capsules, granules, pills, syrups, oral solutions, oral suspensions, and oral emulsions. Wait.
  • the carrier used for the tablet generally includes lactose and corn starch, and a lubricant such as magnesium stearate may also be added.
  • the diluent used in the capsules generally includes lactose and dried corn starch.
  • Oral suspensions are usually prepared by admixing the active ingredient with suitable emulsifying and suspending agents.
  • suitable emulsifying and suspending agents may also be added to the above oral formulation forms.
  • the pharmaceutical compositions When administered transdermally or topically, the pharmaceutical compositions may be in the form of a suitable ointment, lotion or lozenge, wherein the active ingredient is suspended or dissolved in one or more carriers.
  • Carriers which can be used in ointment preparations include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; and carriers which can be used for lotions or elixirs include, but are not limited to, minerals Oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical composition can also be administered in the form of an injection, including an injection, a sterile powder for injection, and a concentrated solution for injection.
  • carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils may also be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.
  • the amount of administration and the administration regimen of the pharmaceutical composition can be readily determined by one of ordinary skill in the clinical arts.
  • the composition or compound of the present invention is generally administered once a day to once every three days, preferably once a day, and the total amount of administration is from 0.01 to 1000 mg per time.
  • the dosage of the treatment varies, depending on the considerations, such as the age, sex and general health of the patient to be treated; the frequency of treatment and the nature of the desired effect; the extent of tissue damage; the symptoms Duration; and other variables that can be adjusted by each physician.
  • the desired dose can be administered one or more times to achieve the desired result.
  • the pharmaceutical composition according to the invention may also be provided in unit dosage form.
  • the invention also provides a process for the preparation of a compound according to the first aspect, wherein, when R 6 in formula I is hydrogen, the process is selected from the following schemes:
  • the compound SM-1 is subjected to nucleophilic substitution reaction with the compound INT-1 to form the compound INT-2; the compound INT-2 is deprotected to obtain the target product;
  • the compound SM-2 is subjected to nucleophilic substitution reaction with the compound INT-1 to form the compound INT-4; the compound INT-4 is coupled to obtain the compound INT-2; and the compound INT-2 is deprotected to obtain the target product;
  • the compound SM-2 is reacted with the compound INT-3 by Mitsunobu to obtain the compound INT-4; the compound INT-4 is subjected to a coupling reaction to obtain the compound INT-2; and the compound INT-2 is deprotected to obtain the target product;
  • the compound SM-3 is subjected to nucleophilic substitution reaction with the compound INT-1 to form the compound INT-5; the compound INT-5 is deprotected to obtain the target product;
  • the compound SM-3 is reacted with the compound INT-3 by Mitsunobu to form the compound INT-5; the compound INT-2 is deprotected to obtain the target product;
  • Lg represents a leaving group such as halogen, -OTs, etc.
  • P represents an amino protecting group such as Boc, Cbz, Fmoc, benzyl, etc.; and the remaining atoms and groups are as defined above.
  • the intermediates INT-1 and INT-3 are commercially available or can be obtained by the preparation methods described in the specific examples of the present invention.
  • the invention also provides the compound, a pharmaceutically acceptable salt, ester, hydrate, solvate, isomer, isotopically labeled compound thereof, any crystal or racemate thereof, or a metabolite thereof, and or Use of their mixtures in the preparation of VAP-1/SSAO inhibitors.
  • the invention also provides the compound, a pharmaceutically acceptable salt, ester, hydrate, solvate, isomer, isotopically labeled compound thereof, any crystal or racemate thereof, or a metabolite thereof, and or Use of a mixture thereof, or a pharmaceutical composition of the invention, for the manufacture of a medicament for the treatment of a disease or condition associated with VAP-1/SSAO overactivity.
  • the invention also provides a method of treating a disease or condition associated with VAP-1/SSAO overactivity comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined above, a pharmaceutically acceptable salt, ester thereof And hydrates, solvates, isomers, isotopically labeled compounds, any crystals or racemates thereof, or metabolite forms thereof, or mixtures thereof, or pharmaceutical compositions of the invention.
  • an effective amount as used herein is meant an amount sufficient to achieve, or at least partially achieve, the desired effect.
  • a “therapeutically effective amount” refers to an amount sufficient to cure or at least partially arrest a disease and a complication thereof in a patient already suffering from a disease. Determination of such an effective amount is well within the capabilities of those skilled in the art. For example, the amount effective for therapeutic use will depend on the severity of the condition to be treated, the overall condition of the patient's own immune system, the general condition of the patient such as age, weight and sex, the mode of administration of the drug, and other treatments administered simultaneously. and many more.
  • the disease or condition associated with VAP-1/SSAO overactivity is selected from an inflammatory disease (such as an inflammatory disease associated with the liver such as hepatitis, hepatomegaly, liver fibrosis, cirrhosis or liver) Ascites; such as inflammatory diseases associated with the respiratory tract, such as bronchitis, pneumonia, pulmonary fibrosis, asthma, acute lung injury, acute respiratory distress syndrome, bronchitis or chronic obstructive pulmonary disease; such as inflammatory diseases associated with the eye, For example, uveitis; such as other inflammations, such as synovitis or peritonitis), organ and / or tissue transplant rejection, autoimmune diseases (such as rheumatoid arthritis or multiple sclerosis (such as chronic multiple sclerosis), skin diseases (eg eczema or psoriasis), diabetes (eg type I or type 2 diabetes) and stroke.
  • an inflammatory disease such as an inflammatory disease associated with the liver such as hepatitis,
  • the subject is selected from any animal, preferably a mammal, such as a bovine, equine, ovine, porcine, canine, feline, rodent, spiritual. Long-lived animals. Among them, a particularly preferred subject is a human.
  • the invention also provides a method of inhibiting VAP-1/SSAO activity in a cell comprising administering to a cell in need thereof an effective amount of a compound as defined above, a pharmaceutically acceptable salt, ester, hydrate, solvate, or different Constructs, isotopically labeled compounds, any crystals or racemates thereof, or their metabolite forms, and or mixtures thereof.
  • the method is for use in vivo, eg, the cell is a subject (eg, a mammal; eg, a bovine, an equine, a sheep, a porcine, a canine, a cell of a feline, a rodent, a primate; for example, a human; or the method is for use in vitro, for example, the cell is an in vitro cell (eg, a cell line or a cell from a subject) .
  • a subject eg, a mammal; eg, a bovine, an equine, a sheep, a porcine, a canine, a cell of a feline, a rodent, a primate; for example, a human
  • the method is for use in vitro, for example, the cell is an in vitro cell (eg, a cell line or a cell from a subject) .
  • the invention also provides a kit for reducing or inhibiting VAP-1/SSAO activity in a cell, the kit comprising a compound of the invention, a pharmaceutically acceptable salt, ester, hydrate, solvate thereof, Isomers, isotopically labeled compounds, any crystals or racemates thereof, or their metabolite forms, and or mixtures thereof, and optionally also instructions for use.
  • hydrogen and hydrogen in each of the groups include hydrazine (H), hydrazine (D), and hydrazine (T).
  • halogen includes fluorine, chlorine, bromine and iodine.
  • C 1-6 alkyl means a straight-chain or branched alkyl group having 1 to 6 carbon atoms, for example C 1-4 alkyl, C 1 - 3 alkyl, C 1 - 2 alkoxy A group, a C 1 alkyl group, a C 2 alkyl group, a C 3 alkyl group, a C 4 alkyl group, a C 5 alkyl group or a C 6 alkyl group.
  • Specific examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.
  • halogenated C 1-6 alkyl group means a group formed by substituting a C 1-6 alkyl group as described above with one or more halogens as described above.
  • a halogenated C 1-4 alkyl group a halogenated C 1-2 alkyl group, a fluoro C 1 -C 4 alkyl group, a fluorinated C 1 -C 2 alkyl group or the like.
  • Specific examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, pentafluoroethyl, and the like.
  • the "C 1-6 alkoxy group” means a group formed by a C 1-6 alkyl-O- group, wherein the "C 1-6 alkyl group” is as defined above.
  • C 1 -C 4 alkoxy, C 1 -C 2 alkoxy Specific examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentane Oxyl, hexyloxy, and the like.
  • halogenated C 1-6 alkoxy means a group formed by substituting a C 1-6 alkoxy group as described above with one or more halogens as described above.
  • a halogenated C 1-4 alkoxy group a halogenated C 1-2 alkoxy group, a fluorinated C 1 -C 4 alkoxy group, a fluorinated C 1 -C 2 alkoxy group or the like.
  • Specific examples include, but are not limited to, trifluoromethoxy, difluoromethoxy, and the like.
  • the "3-10 membered cycloalkyl group” means a saturated or partially saturated monocyclic hydrocarbon group having 3 to 10 carbon atoms, for example, a 3-6 membered cycloalkyl group. Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.
  • the "3-8 membered aliphatic heterocyclic group” means a saturated or partially saturated non-aromatic group having 3 to 8 ring members and at least one ring member being a hetero atom selected from N, O and S.
  • the cyclic group preferably, the number of the hetero atoms is 1, 2, 3 or 4.
  • a 3-6 membered aliphatic heterocyclic group is especially preferred.
  • a 3-8 membered nitrogen-containing heterocyclic group for example, a 3-8 membered nitrogen-containing heterocyclic group, a 3-8 membered oxyaliphatic heterocyclic group, a 3-8 membered sulfur-containing heterocyclic group, a 3-6 membered nitrogen-containing aliphatic heterocyclic group, and a 3-6 member-containing Oxygen heterocyclic group, 3-6 membered sulfur-containing heterocyclic group.
  • Specific examples include, but are not limited to, oxiranyl, oxocyclobutane, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, homopiperazinyl and the like.
  • the "6-20 membered aryl group” means an aromatic monocyclic or polycyclic hydrocarbon group having 6 to 20 ring members, for example, a 6-10 membered aryl group or the like. Specific examples include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, and the like.
  • 5-20 membered heteroaryl means an aromatic monocyclic group in which at least one ring member is a hetero atom selected from N, O and S, preferably, the number of said hetero atom It is 1, 2, 3 or 4, for example 5-10 membered heteroaryl, 5-6 membered heteroaryl.
  • the "3-8 membered alicyclic ring” means a saturated or partially saturated carbocyclic ring having no aromatic character.
  • it includes a 5-6-membered alicyclic ring, a 5-membered alicyclic ring, a 6-membered alicyclic ring, a 7-membered alicyclic ring, and an 8-membered alicyclic ring.
  • the "3-10 membered aliphatic heterocyclic ring” means an aliphatic saturated or partially saturated ring having no aromatic character in which at least one ring member is a hetero atom selected from N, O and S, preferably, said The number of heteroatoms is 1, 2, 3 or 4.
  • a 5-6-membered alicyclic ring For example, a 5-6-membered alicyclic ring, a 5-membered alicyclic ring, a 6-membered alicyclic ring, a 7-membered alicyclic ring, and an 8-membered alicyclic ring.
  • the "6-20 membered aromatic ring” means an aromatic ring having 6 to 20 carbon atoms, for example, a 6-20 membered aromatic ring, a 6-10 membered aromatic ring or the like. Specific examples include, but are not limited to, a benzene ring, a naphthalene ring, an anthracene ring, a phenanthrene ring, and the like.
  • the "5-20 membered heteroaryl ring” means an aromatic ring in which at least one ring member is a hetero atom selected from N, O and S, and preferably, the number of the hetero atom is 1. 2, 3 or 4.
  • a heteroaryl ring containing 1 or 2 N atoms for example, a heteroaryl ring containing only one O atom, for example, a heteroaryl ring containing only one S atom, or the like.
  • Specific examples include, but are not limited to, an imidazole ring, a thiazole ring, a pyrimidine ring, and the like.
  • the "fused ring system (fused ring)" means a polycyclic structure formed by two or more (for example, 3, 4 or 5) carbocyclic or heterocyclic rings in a shared ring edge,
  • the carbocyclic ring includes an alicyclic ring and an aromatic ring, and the heterocyclic ring includes a heteroaromatic ring and an aliphatic heterocyclic ring.
  • the fused ring system includes, but is not limited to, a fused ring system formed by an alicyclic ring and an alicyclic ring, a fused ring system formed by an alicyclic ring and an aliphatic heterocyclic ring, a fused ring system formed by an alicyclic ring and an aromatic ring, and an alicyclic ring.
  • a fused ring system formed with a heteroaromatic ring a fused ring system formed by an aliphatic heterocyclic ring and an aliphatic heterocyclic ring, a fused ring system formed by an aliphatic heterocyclic ring and a heteroaromatic ring, a fused ring formed by an alicyclic ring and an aromatic ring a fused ring system formed by a heteroaromatic ring and a heteroaromatic ring, a fused ring system formed by a heteroaromatic ring and an aromatic ring; for example, a 5-7 membered alicyclic ring, a 6-10 membered aromatic ring or 5-10 members a fused ring system formed by a heteroaryl ring with a 6-10 membered aromatic ring or a 5-10 membered heteroaryl ring, or a 5-8 membered alicyclic or 5-8 membered alicyclic ring and a 6-20 membered aromatic ring
  • heteroaryl means an aromatic ring-containing fused ring group containing one or more (for example, 1, 2, 3 or 4) hetero atoms (for example, O, N, S), which may It is formed by an aryl group and a heteroaryl group, or a heteroaryl group and a heteroaryl group with a shared ring edge.
  • metabolite form means a compound of the present invention or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer thereof, isotopically labeled compound or any crystal form or racemate thereof.
  • salts denote those salts which retain the biological effectiveness and properties of the parent compound, for example, by the protonation of the proton accepting moiety of the compound and/or the proton donation of the proton.
  • Chemical It should be noted that proton accepting partial protonation results in the formation of a cationic species in which the charge is balanced by the presence of physiological anions, while deprotonation of the proton donor moiety results in the formation of an anionic species, wherein the charge is balanced by the presence of physiological cations.
  • Specific examples include, but are not limited to, sodium salts, potassium salts, calcium salts, ammonium salts, aluminum salt propionates, tyrosinates, formates, salts with cysteine, hydroiodides, nicotinates , oxalate, hydrochloride or trifluoroacetate.
  • the atoms in the group include their isotopes.
  • H or hydrogen includes 1 H, 2 H, 3 H.
  • formulation or “dosage form” shall include both solid and liquid preparations of the compounds of the present invention, and those skilled in the art will appreciate that the ingredients of the compounds of the present invention may be present in different formulations depending on the desired dosage and pharmacokinetic parameters. in.
  • the compound or a salt thereof may exist in the form of a solvate selected from an organic solvent (e.g., ethanol, acetone).
  • an organic solvent e.g., ethanol, acetone
  • the compound or a salt thereof may exist in the form of a hydrate.
  • the invention includes isomers formed based on any stereo configuration of the chiral carbon, for example including racemates or any of the mirror image isomers. . Moreover, the invention includes all other stereoisomers that may be present. That is, the compounds of the present invention include all enantiomers, diastereomers, cis and trans isomers, racemates and the like.
  • vascular adhesion proteins 1/Semicarbazide-sensitive amine oxidase has high inhibitory activity, has good selectivity for monoamine oxidase and diamine oxidase, and has improved metabolic stability in vivo.
  • 1 H NMR spectra were recorded at ambient temperature using a Bruker instrument (400 MHz) using TMS as an internal standard. The chemical shift ( ⁇ ) is given in ppm and the coupling constant (J) is given in hertz (Hz).
  • the fractional weights of the 1 H NMR spectrum peaks are abbreviated as follows: s (single peak), d (doublet), t (triplet), q (quadruple), m (multiplet), br (broad).
  • the solvent was determined to be deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ) or hexamethyl dimethyl sulfoxide (DMSO-d6).
  • LC-MS was detected on an Aglient 1200 liquid chromatograph using an Aglient 6120 Quadrupole mass spectrometer at 214 nm and 254 nm.
  • the MS was measured using an Agilent (ESI) mass spectrometer, manufacturer: Agilent.
  • a high performance liquid phase was prepared using Shimadzu LC-8A preparative liquid chromatograph (YMC, ODS, 250 x 20 mml column).
  • the thin-layer chromatography silica gel plate was prepared by thin-layer chromatography using an aluminum plate (20 ⁇ 20 cm) manufactured by Merck.
  • the silica gel specification was GF 254 (0.4-0.5 nm) produced by Yantai.
  • reaction was monitored by thin layer chromatography (TLC) or LCMS using the developing solvent system: dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system, solvent volume ratio according to compound
  • TLC thin layer chromatography
  • LCMS LCMS using the developing solvent system: dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system, solvent volume ratio according to compound
  • the polarity is adjusted differently, and triethylamine or the like may be added for adjustment.
  • reaction solvents were either commercially available anhydrous solvents or HPLC grade solvents without further purification.
  • the microwave reaction was carried out using a Biotage Initiator + (400 W, RT ⁇ 300 ° C) microwave reactor.
  • reaction temperature is room temperature (20 ° C ⁇ 30 ° C)
  • the reagents used in the present invention were purchased from companies such as Acros Organics, Aldrich Chemical Company, and Tebe Chemical.
  • DMF N,N-dimethylformamide
  • DMA N,N-dimethylacetamide
  • DMSO dimethyl sulfoxide
  • NMP N-methylpyrrolidone
  • DIBAL-H diisobutylaluminum hydride
  • DIEA N,N-diisopropylethylamine
  • THF tetrahydrofuran
  • Boc tert-butoxycarbonyl
  • NBS N-bromosuccinimide
  • Cbz-Cl benzyl chloroformate
  • m-CPBA m-chloroperoxybenzoic acid
  • TFA trifluoroacetic acid
  • Dioxane 1,4-dioxane
  • TLC thin layer chromatography
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • EA ethyl acetate
  • DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
  • PE petroleum ether
  • MTBE methyl tert-butyl ether
  • ACN acetonitrile
  • the second step preparation of fluoromethyltriphenyltetrafluoroborate (2).
  • Step 5 Preparation of tert-butyl (3-tert-butyldimethylsilyloxy-2-oxopropyl)carbamate (5)
  • Step 7 Preparation of tert-butyl (3-fluoro-2-hydroxymethylallyl)carbamate (7).
  • Second step Preparation of (2-(4-(naphthyl-2-carbamoyl)phenoxy)methyl-3-fluoroallyl)carbamic acid tert-butyl ester (1-2)
  • the chemical shifts of 4.82 and 3.58 may be characteristic peaks of the Z configuration, and 4.70 and 3.66 may be characteristic peaks of the E configuration.
  • the title compound was prepared in a similar manner to that described in Example 1 except that N-methyl-p-methylaniline was used in the first step of this example instead of 2-naphthylamine in the first step of Example 1.
  • the rate is 19%.
  • the chemical shifts of 4.64 and 3.51 may be characteristic peaks of the Z configuration, and 4.52 and 3.57 may be characteristic peaks of the E configuration.
  • the title compound was prepared in a similar manner to that described in the second step of Example 1 except that in the next step, methyl hydroxybenzoate was substituted for the intermediate 1-1 of the second step of Example 1.
  • the crude product obtained was used directly in the next step.
  • the chemical shift of 4.89, 3.71 can be the characteristic peak of the Z configuration
  • 4.69, 3.83 can be the characteristic peak of the E configuration.
  • Example 3 The p-fluoroaniline of the third step of Example 3 was replaced by 1,2,3,4-tetrahydro-6-trifluoromethylisoquinoline in the first step of this example, and was used in Example 3.
  • the title compound was prepared in a similar manner as described in the third and fourth steps, with a total yield of 16%.
  • the chemical shift of 4.87, 3.70 can be the characteristic peak of the Z configuration
  • 4.67, 3.83 can be the characteristic peak of the E configuration.
  • the chemical shift of 4.90, 3.71 can be the characteristic peak of the Z configuration
  • 4.70, 3.84 can be the characteristic peak of the E configuration.
  • the chemical shifts of 4.86 and 3.69 may be characteristic peaks of the Z configuration, and 4.65 and 3.82 may be characteristic peaks of the E configuration.
  • the title compound was prepared in a similar manner to that described in the second step of Example 1 except that the 4-hydroxyphenylboronic acid pinacol ester was used in the next step.
  • the yield was 83%.
  • Second step Preparation of (3-fluoro-2-(4-(4-methylthiazole-2-phenoxy)methyl)allyl)carbamic acid tert-butyl ester (7-2)
  • the chemical shifts of 7.12, 4.88, 3.70 can be characteristic peaks of the Z configuration, and 7.24, 4.68, 3.84 can be characteristic peaks of the E configuration.
  • the second step preparation of 5-chloro-2-p-toluenesulfonyl isoindoline (8-2)
  • the third step preparation of 5-chloroisoindoline (8-3)
  • Step 6 Preparation of (2-(4-(5-chloroisoindoline-2-carbonyl)phenoxymethyl)-3-fluoroallyl)carbamic acid tert-butyl ester (8-6)
  • Step 7 (4-(2-Aminomethyl-3-fluoroallyloxy)phenyl)-(5-chloroisoindol-2-yl)-methanone trifluoroacetate (TM71 Preparation
  • the chemical shifts of 4.80 and 3.55 may be characteristic peaks of the Z configuration, and 4.65 and 3.64 may be characteristic peaks of the E configuration.
  • the title compound was prepared in a similar manner to that described in Example 1 except that aniline was used in the first step of this example to replace 2-naphthylamine in the first step of Example 1.
  • the total yield was 35%.
  • the effluent was collected in the interval of 5.6-6.7 min and lyophilized to obtain TM1-E.
  • the effluent was collected in the interval of 7.0-8.0 min and lyophilized to obtain TM1-Z.
  • Example 2 In place of the 2-naphthylamine of the first step of Example 1 with (S)-1,2,3,4-tetrahydro-1-naphthylamine in the first step of this example, the same as in Example 1 was employed. A similar procedure was described to prepare the title compound with a total yield of 46%.
  • the isomer was resolved in a manner similar to that described in Example 9, and the retention time of TM63-E was shorter than that of TM63-Z.
  • Example 2 The title compound was prepared in a similar manner to that described in Example 1 except that 4-phenylpiperidine was used instead of 2-naphthylamine in Example 1 in the first step of this.
  • the title compound was prepared in a similar manner to that described in Example 1 except that tetrahydroisoquinoline was used in the first step of this example to replace 2-naphthylamine in the first step of Example 1.
  • the total yield was 31%.
  • the isomer was resolved in a manner similar to that described in Example 9, and the retention time of TM72-E was shorter than that of TM72-Z.
  • the title compound was prepared in a similar manner to that described in Example 1 except that 5-chlorotetrahydroisoquinoline was replaced by 5-chlorotetrahydroisoquinoline in the first step of this example. 32%.
  • the isomer was resolved in a manner similar to that described in Example 9, and the retention time of TM73-E was shorter than that of TM73-Z.
  • the title compound was prepared in a similar manner to that described in the third and fourth steps of Example 3, except that in the first step of this example, tetrahydroisoquinoline was substituted for the p-fluoroaniline of the third step of Example 3.
  • the total yield was 81%.
  • Example 16 (4-((2-Aminomethyl-3-fluoroallyl)oxy)phenyl)-(4-phenylpiperidin-1-yl)methanone trifluoroacetate (TM44 Preparation of).
  • the title compound was prepared in a similar manner to that described in the third and fourth steps of Example 3 except that 4-phenylpiperidine was replaced by 4-phenylpiperidine in the first step of this example.
  • the total yield was 42%.
  • the isomer was resolved in a similar manner to that described in Example 9, and the retention time of TM44-E was shorter than that of TM44-Z.
  • Second step Preparation of 2-(4-(2-pyrimidinyl)phenoxymethyl)-3-fluoroallylamine (17-2).
  • the effluent was collected in the interval of 6.8-7.7 min and lyophilized to obtain TM39-E.
  • the effluent was collected in the interval of 8.2-8.8 min and lyophilized to obtain TM39-Z.
  • Second step Preparation of tert-butyl 2-(4-(1H-benzimidazol-2-yl)phenoxymethyl)-3-fluoroallylcarbamate (18-2)
  • the isomer was resolved in a manner similar to that described in Example 9, and the retention time of TM41-E was shorter than that of TM41-Z.
  • the title compound was prepared in a similar manner to that described in Example 19 except that 3-fluoro-4-hydroxybenzaldehyde was used in the second step of this example to replace the p-hydroxybenzaldehyde of the second step of Example 19.
  • the rate is 9%.
  • the third step 2-(2-(4-chlorobenzyl)-1-oxoisoindoline-5-oxymethyl)-3-fluoroallylcarbamic acid tert-butyl ester (21-3) Preparation.
  • the title compound was prepared in a similar manner to that described in the third step of Example 1 except that Intermediate 21-3 was used instead of Intermediate 1-2 in the first step of Example 1 in a yield of about 100%.
  • the isomer was resolved in a manner similar to that described in Example 9, and the retention time of TM33-E was shorter than that of TM33-Z.
  • the fourth step preparation of 6-hydroxy-4,4-dimethyl-3,4-dihydroisoquinolin-1-(2H)-one (23-4)
  • Step 5 (2-(4,4-Dimethyl-1,2,3,4-tetrahydroisoquinolin-1-one-6-oxymethyl)-3-fluoroallyl)amino Preparation of tert-butyl formate (23-5)
  • the isomer was resolved in a manner similar to that described in Example 9, and the retention time of TM27-E was shorter than that of TM27-Z.
  • Example 1 In place of the intermediate 1-1 of the second step of Example 1 with 5-hydroxy-isoindolin-1-one in the first step of this example, the second and third steps of Example 1 were employed. A similar procedure was described to prepare the title compound with a total yield of 63%.
  • the isomer was resolved in a similar manner to that described in Example 9, and the retention time of TM77-E was shorter than that of TM77-Z.
  • the total yield of the second and third steps was 77%.
  • Example 9 A separation method similar to that in Example 9 was employed, and the elution gradient was: 0-9 min: 10%-26.8% B, flow rate 16 mL/min; 9.1-11 min: 95% B, flow rate 20 mL/min; 11.1-13 min: 10 %B, flow rate 20 mL/min.
  • the effluent was collected in the interval of 6.6-7.6 min and lyophilized to obtain TM7-E.
  • the effluent was collected in the interval of 7.8-8.7 min and lyophilized to obtain TM7-Z.
  • Second step Preparation of 6-methoxy-3,3-dimethyl-3,4-dihydroisoquinolin-1(2H)-one (26-2) except in this step as intermediate 26 -1
  • the title compound was prepared in a similar manner to that described in the third step of Example 23.
  • the third step preparation of 6-hydroxy-3,3-dimethyl-3,4-dihydroisoquinolin-1(2H)-one (26-3)
  • the total yield of the third step to the fifth step was 46%.
  • Example 9 A separation similar to that of Example 9 was employed, and the elution gradient: 0-7.4 min: 10% - 28.5% B, flow rate 16 mL/min; 7.5-9 min: 95% B, flow rate 20 mL/min; 9.1-11 min: 10 %B, flow rate 20 mL/min.
  • the effluent was collected in the interval of 5.6-6.2 min and lyophilized to obtain TM38-E.
  • the effluent was collected in the interval of 6.4-6.9 min and lyophilized to obtain TM38-Z.
  • the title compound was prepared in a similar manner to that described in the third step of Example 23, except that 5-methoxy-1-indolone was used in this step to replace the intermediate 23-2 of the third step of Example 23.
  • the yield was 48%.
  • the compound 27-1 (250 mg, 1.41 mmol) was dissolved in DMF (10 mL), and NaH (EtOAc, <RTIgt; Slowly warm to room temperature and react for 2 hours. The reaction was completed by EtOAc. EtOAc (EtOAc)EtOAc.
  • the third step preparation of 6-hydroxy-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (27-3)
  • the total yield of the third step to the fifth step was 77%.
  • Example 9 A separation similar to that of Example 9 was employed, and the elution gradient was: 0-7.8 min: 10% - 24.6% B, flow rate 16 mL/min; 7.9-10 min: 95% B, flow rate 20 mL/min; 10.1-12 min: 10 %B, flow rate 20 mL/min.
  • the effluent was collected in the interval of 5.6-6.2 min and lyophilized to obtain TM66-E.
  • the effluent was collected in the interval of 6.8-7.3 min and lyophilized to obtain TM66-Z.
  • the title compound was prepared in a similar manner to that described in the third step of Example 23, except that 6-methoxy-1-indolone was used in this step to replace the intermediate 23-2 of the third step of Example 23.
  • the yield was 49%.
  • 29-1 (225 mg, 0.86 mmol) was dissolved in 10 mL of anhydrous methanol, and 1 mL of water and potassium carbonate (354 mg, 2.58 mmol) were added and allowed to react at room temperature for 1 hour. After 1 h, the reaction mixture was evaporated.
  • the isomer was resolved in a similar manner to that described in Example 9, and the retention time of TM76-E was shorter than that of TM76-Z.
  • the isomer was resolved in a manner similar to that described in Example 9, and the retention time of TM112-E was shorter than that of TM112-Z.
  • the 2-aminomethylpyridine of the first step of Example 30 was replaced by a 6-amino-1,4-benzodioxane in the first step of this example, using a procedure similar to that described in Example 30. Method The title compound was prepared in a total yield of 9%.
  • the isomer was resolved in a manner similar to that described in Example 9, and the retention time of TM114-E was shorter than that of TM114-Z.
  • the third step preparation of 3-(2-methoxyethoxy)aniline (32-3)
  • Step 6 4-((2-tert-Butoxycarbonylaminomethyl-3-fluoroallyl)oxy)-N-(3-(2-methoxyethoxy)phenyl)benzamide Preparation of (32-6)
  • Step 7 4-((2-Aminomethyl-3-fluoroallyl)oxy)-N-(3-(2-methoxyethoxy)phenyl)benzamide trifluoroacetic acid Preparation of salt (TM106)
  • the isomer was resolved in a manner similar to that described in Example 9, and the retention time of TM106-E was shorter than that of TM106-Z.
  • Test Example 1 Inhibition of in vitro enzymatic activity of VAP-1 (Vascular adhesion protein 1)
  • Reaction buffer 50 mM PBS, pH 7.4
  • TM1-E 1.6 ⁇ 0.2 TM42-Z 1.5 ⁇ 0.1 TM42-E 2.0 ⁇ 0.3 TM26-Z 3.7 ⁇ 0.8 TM26-E 9.9 ⁇ 1.2 TM44-Z 9.7 ⁇ 0.9 TM44-E 12.9 ⁇ 4.4 TM74-Z 5.3 ⁇ 0.2 TM74-E 3.2 ⁇ 0.2 TM39-Z 0.7 ⁇ 0.1 TM39-E 1.2 ⁇ 0.2 TM7-Z 3.8 ⁇ 0.4 TM7-E 3.0 ⁇ 0.7 TM38-Z 2.9 ⁇ 0.3 TM38-E 4.7 ⁇ 1.1 TM66-Z 1.6 ⁇ 0.2 TM66-E 2.0 ⁇ 0.4 TM75-Z 1.3 ⁇ 0.2 TM75-E 23.4 ⁇ 2.2 TM76-Z 1.8 ⁇ 0.2 TM76-E 4.3 ⁇ 0.6 TM112-Z 6.5 ⁇ 1.8 TM112-E 3.2 ⁇ 0.4 TM114-Z 0.8 ⁇ 0.1 TM114-E 1.1 ⁇ 0.2 HC38-E 2.85 ⁇ 0.30
  • test results indicate that the compounds of the present invention have a strong inhibition of VAP-1 activity.
  • Test Example 2 In vivo enzyme activity inhibition test
  • Tissue homogenization buffer (20 mM HEPES, pH 7.2, 1 mM EDTA, 250 mM sucrose, PMSF 0.2 mM)
  • Reaction buffer 50 mM PBS, pH 7.4
  • BALBc mice were orally administered with different doses of the test compound, and the vehicle was used as a control.
  • the abdominal fat was collected after 6 hours, and homogenized with 1:20 (w/v) with pre-cooled homogenization buffer. After centrifugation at 10,000 g for 10 min at 4 ° C, the supernatant was collected and stored at -80 ° C until use.
  • the sample to be tested was diluted with the reaction buffer, and the inhibitor solution A was separately added: 1 ⁇ M chlorgilin +1 ⁇ M eugenin to inhibit MAO-A, MAO-B activity; inhibitor solution B: 1 ⁇ M chlorgilin +1 ⁇ M was added. ⁇ +1 ⁇ M ⁇ as a blank control, after incubation for 20min at room temperature, 500 ⁇ M benzylamine hydrochloride, 1U/mL HRP and 200 ⁇ M Amplex Red reagent were added to start the reaction, refer to the “VAP-1 Enzymatic Activity Inhibition Test” method, The fluorescence signal-reaction time ratio in the linear range was the reaction rate, and the relative activity of each dose group was calculated in the vehicle group as a positive control. The inhibition of VAP-1 enzyme activity in the abdominal fat of mice was examined.
  • VAP-1 enzyme activity in the abdominal fat of mice was determined by the above method as shown in Tables 2 and 3.
  • the compound of the present invention has a strong inhibitory effect on VAP-1 in vivo at a low dose of 0.5 mg/kg.
  • the compound of the present invention has a strong inhibitory effect on VAP-1 in vivo.
  • Test Example 3 MAO-A (Monoamine oxidase type A) inhibition test for enzymatic activity
  • Test kit Monoamine Oxidase Assay, manufacturer: ThermoFisher
  • Reaction buffer 50 mM PBS, pH 7.4
  • Protein MAO-A, manufacturer: Sigma Aldrich
  • DMSO solvent group
  • Percent inhibition rate (1 - (each compound concentration group rate - blank group rate) / (solvent group rate - blank group rate)) * 100
  • the inhibition of MAO-A activity by the compounds was determined according to the above method, and the range of IC 50 was obtained according to the inhibition rates of 100 ⁇ M and 10 ⁇ M, and the results are shown in Table 4.
  • Test Example 4 MAO-B (Monoamine oxidase type B) enzymatic activity inhibition test
  • Test kit Monoamine Oxidase Assay, manufacturer: ThermoFisher
  • Protein MAO-B, manufacturer: Sigma Aldrich
  • the MAO-B protein (5 ⁇ g/ml) was pre-incubated with different concentrations of compound for 10 min at room temperature according to the kit instructions. The reaction was initiated by the addition of 150 ⁇ M benzylamine hydrochloride, 1 U/mL HRP and 200 ⁇ M Amplex Red reagent. The inhibition rate of each concentration group was calculated by referring to the MAO-A test method.
  • the inhibition of MAO-B activity by the compounds was determined according to the above method, and the IC 50 range was obtained according to the inhibition rates of 10 ⁇ M, 1 ⁇ M and 0.1 ⁇ M, and the results are shown in Table 5.
  • Test Example 5 DAO (Diamine oxidase) enzymatic activity inhibition test
  • Test kit Monoamine Oxidase Assay, manufacturer: ThermoFisher protein: DAO, manufacturer: R&D Systems
  • DAO protein (15 ⁇ g/ml) was pre-incubated with different concentrations of compound for 20 min at room temperature, and then reacted by adding 100 ⁇ M histamine dihydrochloride, 1 U/mL HRP and 200 ⁇ M Amplex Red reagent. The inhibition rate of each concentration group was calculated by referring to the MAO-A test method.
  • the potential of the compound to induce cardiac QT interval prolongation was assessed using the kits described above.
  • the test compound, the positive control (E4031) and the negative control (experimental buffer) in the kit were added to the microplate containing the hERG cell membrane according to the method provided in the kit, and then the high hERG affinity tracer was added. Tracer, after incubating the microplate at 25 ° C for 2 hours, the change of fluorescence polarization value was detected by BMG PHAREStar multi-plate reader, and the percentage inhibition rate (%) at different concentrations was calculated to determine the half inhibitory concentration (IC 50 ) of the compound.
  • the scope The test compound, the positive control (E4031) and the negative control (experimental buffer) in the kit were added to the microplate containing the hERG cell membrane according to the method provided in the kit, and then the high hERG affinity tracer was added. Tracer, after incubating the microplate at 25 ° C for 2 hours, the change of fluorescence polarization value
  • Percent inhibition rate (%) (1 - mP-30 ⁇ M of test compound mP1 of E4031 / (mP-30 ⁇ M of experimental buffer mP of E4031)) *100
  • test results indicate that the compounds of the present invention have low affinity with hERG and compete with the affinity tracer Tracer for an IC50 of more than 10 ⁇ M.
  • Test Example 7 In vivo enzyme activity inhibition test in different doses and time conditions
  • Tissue homogenization buffer (20 mM HEPES, pH 7.2, 1 mM EDTA, 250 mM sucrose, PMSF 0.2 mM)
  • Reaction buffer 50 mM PBS, pH 7.4
  • BALBc mice were orally administered with different doses (0.5 mg/kg, 3 mg/kg) of the test compound, and the vehicle group was used as a control.
  • the abdominal fat was collected after 6, 10, and 24 hours, and buffered with pre-cooled homogenate. After the liquid is homogenized, the supernatant is collected and stored for use.
  • the sample to be tested was diluted with the reaction buffer, and the inhibitor solution A was separately added: 1 ⁇ M chlorgilin +1 ⁇ M eugenin to inhibit MAO-A, MAO-B activity; inhibitor solution B: 1 ⁇ M chlorgilin +1 ⁇ M was added. ⁇ +1 ⁇ M ⁇ as a blank control, after incubation at room temperature, 500 ⁇ M benzylamine hydrochloride, 1U/mL HRP and 200 ⁇ M Amplex Red reagent were added to start the reaction, refer to the “VAP-1 Enzymatic Activity Inhibition Test” method, linear The fluorescence signal-reaction time ratio in the range was the reaction rate, and the relative activity of each dose group was calculated in the solvent group. The inhibition of the compound on the VAP-1 enzyme activity in the abdominal fat of mice was investigated.
  • VAP-1 enzyme activity in the abdominal fat of mice was determined according to the above method, as shown in Table 8 below.
  • Test Example 8 Model test of liver injury induced by carbon tetrachloride in mice
  • mice were randomly divided into a model group (0.5% methylcellulose) by weight, a compound HC38-E 3 mg/kg group, and a compound HC38-E 10 mg/kg group, 10 animals per group.
  • the administration was started at the same time as the administration, and the administration volume was 10 mL/kg, and a single intragastric administration was performed every day for 6 weeks.
  • liver tissues were taken, and 10% formalin was fixed, and liver tissue sections were prepared, and Sirius red staining was performed. Sectioning was performed using a semi-automated digital image analysis system and measurement software (OsteoMetrics, Inc., Atlanta, GA) and an Olympus optical microscope.
  • 10nM CYP1A2, 5nMCYP2D6, 1nM CYP3A4 protein was pre-incubated with the corresponding substrate (100 ⁇ M, 30 ⁇ M, 3 ⁇ M) and compound for 10min at room temperature, then added to the G6PDH-G6P-NADP regeneration system to initiate the reaction. After a period of reaction The detection reagent was added and the chemiluminescence signal was detected after 20 min. The inhibition rate was calculated using a vehicle control group (DMSO) as a negative control and a Membrance (inactive enzyme) as a blank control.
  • DMSO vehicle control group
  • Membrance active enzyme
  • Percent inhibition rate (%) (1 - (each compound concentration group signal - blank group signal) / (negative control signal - blank group signal)) * 100
  • IC 50 X * (1-percent inhibition (%)) / percent inhibition (%), where X is the compound test concentration.
  • the compounds of the present invention have no significant inhibitory effect on the three major CYP subtypes, indicating that the potential drug interaction potential is relatively low, and has a good drug preparation. nature.
  • Formulation of compound stock solution Weigh the test compound, diclofenac, testosterone and propafenone in an appropriate amount, and calibrate to a concentration of 10 mM stock solution with about 1 mL of DMSO, and store in a refrigerator at 4 °C;
  • Compound working solution preparation 10 ⁇ L of the stock solution was added to 990 ⁇ L of acetonitrile-water (1:1) to obtain an intermediate solution with a concentration of 100 ⁇ M, 120 ⁇ L of the intermediate solution was taken, and further diluted with 2880 ⁇ L of PBS to obtain a working solution of 4 ⁇ M;
  • NADPH working solution weigh the appropriate amount of NADPH, and correct it to a concentration of 4 mM NADPH working solution with 33 mM MgCl 2 ;
  • liver microsome working solution 100 ⁇ L of human, monkey, canine, rat, and mouse liver microsomes were separately diluted with 1900 ⁇ L PBS to prepare 1 mg/mL liver microsome working solution.
  • the reaction was stopped by adding an equal volume of ice-cold acetonitrile (4 ° C), and the concentration of the compound in various liver microsomes after incubation for different time was determined by LC-MS/MS, and the incubation time was plotted on the abscissa, at each time point.
  • the natural logarithm of the percentage of the remaining amount of the compound is plotted on the ordinate, the slope of which is the velocity constant (Ke), and the half-life (T 1/2 ) and the clearance rate (CL liver ) are calculated according to the following formula. Stability in liver microsomes.
  • Liver clearance (CL liver ) Ke / amount of microsomal protein per milliliter of reaction solution (mg) ⁇ amount of microsomal protein per gram of liver ⁇ liver weight per kilogram of body weight (g)
  • the compound of the present invention for example, compound HC38-E
  • T 1/2 half-life
  • Compound stock solution Weigh a certain amount of the test compound, and add a certain amount of DMSO to prepare a 10 mM stock solution.
  • the cells were seeded into a Transwell chamber at 6*10 4 /cm 2 , 200 ⁇ L of the medium was added to the A side (base top side), and 1000 ⁇ L of the medium was added to the B side (base side). The solution was changed every two days after inoculation and cultured for 21 to 28 days.
  • dCr/dt is the integral of the concentration of the base side compound with respect to time
  • Vr is the reaction volume on the basal side
  • A is the area of the monolayer cell
  • the area is 0.33 cm 2
  • C 0 is the concentration of the compound on the apical side.
  • the compound of the present invention e.g., HC38-E
  • Test Example 12 Rat PK test
  • Test compounds were prepared according to the method of Table 17
  • the plasma concentrations of the compounds were determined by LC-MS/MS.
  • the main pharmacokinetic parameters were calculated by WinNonlin 6.3 software.
  • test design grouping is shown in Table 18 below.
  • the compounds of the present invention have good pharmacokinetic parameters by intravenous (iv) or intragastric (po), and the average bioavailability (F%) of the compounds of the present invention (for example, compound HC38-E reaches 89.9). %) has good oral bioavailability.

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Abstract

本发明涉及氟代烯丙胺衍生物及其用途，具体的，本发明涉及式I所示化合物、其前药、异构体、同位素标记的化合物、溶剂化物或药学上可接受的盐，其具有VAP-1/SSAO抑制活性，可用于与VAP-1/SSAO过度活性相关的疾病的治疗。

Description

氟代烯丙胺衍生物及其用途 技术领域
本发明涉及医药领域，具体涉及氟代烯丙胺衍生物及其作为血管黏附蛋白1(vascular adhesion protein-1，VAP-1)/氨基脲敏感性胺氧化酶(semicarbazide-sensitive amine oxidase，SSAO)抑制剂的用途。
背景技术
血管黏附蛋白1(vascular adhesion protein-1，VAP-1)是一个相对分子质量(MW)为170,000～180,000的二聚体糖蛋白，是一种在哺乳动物体内广泛存在的多功能蛋白。血管黏附蛋白1既是一种内皮黏附分子，同时还具有氨基脲敏感性胺氧化酶(semicarbazide-sensitive amine oxidase，SSAO)活性。其具有广泛的组织分布，主要来源是内皮细胞、平滑肌细胞、脂肪细胞，在体内最常见于两种形式：组织结合的形式以及可溶形式。在人体和一些动物的血浆中循环的是其可溶形式，这种形式是膜结合的血管黏附蛋白1/氨基脲敏感性胺氧化酶的裂开产物。
研究发现，血管黏附蛋白1/氨基脲敏感性胺氧化酶在脂肪生成过程中会有诱导地表达(Fontana,E.,et.al.,Biochem.J.,2001,356,769；Moldes,M.,et.al.,J.Biol.Chem.,1999,274,9515)；血管黏附蛋白1/氨基脲敏感性胺氧化酶在白细胞渗出、黏附级联反应、糖代谢调节、血管损伤等方面也发挥了重要的作用；在炎症性疾病、组织损伤纤维化、糖代谢相关疾病、肿瘤、脑卒中等众多临床疾病中，血管黏附蛋白1/氨基脲敏感性胺氧化酶的表达及功能都起着重要的作用；在特应性湿疹或牛皮癣患者的皮肤中发现了具有高水平的血管黏附蛋白1/氨基脲敏感性胺氧化酶阳性细胞(positive cell)。
概括地说，血管黏附蛋白1/氨基脲敏感性胺氧化酶在糖尿病、肺炎、肝炎、肺纤维化、肝纤维化、脂肪肝、脑卒中以及其它炎症或纤维化相关疾病中是有效的药物作用生物靶点。
一些有机小分子被发现有血管黏附蛋白1/氨基脲敏感性胺氧化酶的抑制作用，例如肼代物、苯代烯甲肼、肼醇、肼代二氢化茚、芳香环烷基胺、丙烯基、丙炔胺，噁唑烷酮、卤代烷基胺、1,3,4-噁唑烷酮、噁二嗪、硫酰胺、噻唑衍生物，和其它有机化合物(Dunke1,P.et.al.,Curr.Med.Chem.,2008,15,1827；Tetra.Letters,1977,36,3155)。炔丙胺家族化合物也被报道可用于抑制血管黏附蛋白1/氨基脲敏感性胺氧化酶(O’Connell，K.M.,et.al.,Biochemistry,2004，43，10965)。这些化合物，像氨基脲是依赖于肼官能团以形 成与TPQ辅因子的共价亚胺键而起到抑制效果的。
发明内容
经过深入研究，本发明令人意外地发现了一种有效的具有血管黏附蛋白1/氨基脲敏感性胺氧化酶抑制活性的化合物，其可用于预防或治疗与血管黏附蛋白1/氨基脲敏感性胺氧化酶过度活性相关的疾病。更详细地说，本发明提供了式I所示氟代烯丙胺衍生物，其对血管黏附蛋白1/氨基脲敏感性胺氧化酶具有较高的抑制活性，对单胺氧化酶和双胺氧化酶具有较好的选择性，体内代谢稳定性得到了提高。
本发明第一方面提供式I所示化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，同位素标记的化合物或它们的任意晶型或消旋物，或它们的代谢物形式，以及它们的混合物,
Figure PCTCN2018083792-appb-000001
其中，
R 1选自氢、卤素、C 1-6烷基、3-10元环烷基-CH 2NHC(O)-、3-8元脂杂环基-CH 2NHC(O)-、6-20元芳基-CH 2NHC(O)-、5-20元杂芳基-CH 2NHC(O)-、5-20元稠杂芳基-CH 2NHC(O)-、苯并3-10元环烷基-NHC(O)-、3-8元脂杂环基-NHC(O)-、6-20元芳基-NHC(O)-、5-20元杂芳基-NHC(O)-、5-20元稠杂芳基-NHC(O)-；并且，所述C 1-6烷基、3-10元环烷基-CH 2NHC(O)-、3-8元脂杂环基-CH 2NHC(O)-、6-20元芳基-CH 2NHC(O)-、5-20元杂芳基-CH 2NHC(O)-、5-20元稠杂芳基-CH 2NHC(O)-、苯并3-10元环烷基-NHC(O)-、3-8元脂杂环基-NHC(O)-、6-20元芳基-NHC(O)-、5-20元杂芳基-NHC(O)-、5-20元稠杂芳基-NHC(O)-未被取代或独立地被一个或多个(例如1、2、3或4个)选自卤素、羟基、-NRR’、C 1-3烷基、C 1-3烷氧基和氰基的取代基取代；
R 2各自独立地选自氢、氰基、硝基、羟基、卤素、C 1-6烷基、3-10元环烷基、3-8元脂杂环基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基；
n＝1，2或3；
R 3和R 4选自：
(a)R 3选自3-10元环烷基-CH 2、3-8元脂杂环基-CH 2、6-20元芳基-CH 2、5-20元 杂芳基-CH 2、5-20元稠杂芳基-CH 2、苯并3-10元环烷基、苯并3-8元脂杂环基、苯基-3-10元环烷基、5-20元杂芳基-苯基、5-20元稠杂芳基苯基、3-8元脂杂环基、6-20元芳基、5-20元杂芳基、5-20元稠杂芳基；并且，所述3-10元环烷基-CH 2、3-8元脂杂环基-CH 2、6-20元芳基-CH 2、5-20元杂芳基-CH 2、5-20元稠杂芳基-CH 2、苯并3-10元环烷基、苯并3-8元脂杂环基、苯基-3-10元环烷基、5-20元杂芳基-苯基、5-20元稠杂芳基苯基、3-8元脂杂环基、6-20元芳基、5-20元杂芳基、5-20元稠杂芳基未被取代或独立地被一个或多个(例如1、2、3或4个)选自卤素、羟基、-NRR’、C 1-3烷基、C 1-3烷氧基、氰基、3-10环烷基、3-8元脂杂环基、6-20元芳基、5-20元杂芳基、5-20元稠杂芳基、卤代C 1-3烷基、卤代C 1-3烷氧基、C 1-3烷氧基-C 1-3烷基、C 1-3烷氧基-C 1-3烷氧基、C 1-3烷氧基-C 1-3烷氧基-C 1-3烷基的取代基取代；R 4选自氢、C 1-6烷基、卤代C 1-6烷基；
(b)R 3与R 1相连形成环X，所述环X为5-8元脂环或5-8元脂杂环；并且，所述5-8元脂环或5-8元脂杂环未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自O＝、卤素、氰基、-NRR’、硝基、羟基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、6-20元芳基、5-20元杂芳基和5-20元稠杂芳基的取代基取代；或者，所述5-8元脂环或5-8元脂杂环与3-8元脂环形成螺环结构；R 4选自氢、C 1-6烷基、3-8元环烷基、3-8元脂杂环基、6-10元芳基、5-10元杂芳基、5-10元稠杂芳基；并且，所述C 1-6烷基、3-8元环烷基、3-8元脂杂环基、6-10元芳基5-10元杂芳基或5-10元稠杂芳基任选地被一个或多个(例如1、2、3或4个)选自卤素、-NRR’、氰基、羟基、C 1-4烷基、C 1-4烷氧基、3-8元环烷基、3-8元脂杂环基、6-10元芳基、5-10元杂芳基或5-10元稠杂芳基的取代基取代；其中，所述的C 1-4烷基、3-8元环烷基、3-8元脂杂环基、6-10元芳基、5-10元杂芳基或5-10元稠杂芳基-任选地被一个或多个(例如1、2、3或4)选自卤素、-NRR’、C 1-3烷基、C 1-3烷氧基的取代基取代；
(c)R 3与R 4相连形成环Y，所述环Y为5-8元脂杂环或5-8元脂环；并且，所述5-8元脂杂环或5-8元脂环未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自卤素、氰基、-NRR’、硝基、羟基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、6-20元芳基、5-20元杂芳基和5-20元稠杂芳基的取代基取代，其中，所述C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、6-20元芳基、5-20元杂芳基和5-20元稠杂芳基未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自卤素、氰基、-NRR’、C 1-6烷基、C 1-6烷氧基、6-20元芳基、5-20元杂芳基和5-20元稠杂芳基的取代基取代；或者，所述5-8元脂杂环或5-8元脂环与6-20元芳环或5-20元杂芳环形成稠合环系，其中，所述稠合环系未被取代或各自独立地被一个或多个(例如1、2、 3或4个)选自卤素、氰基、-NRR’、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、6-20元芳基、5-20元杂芳基或5-20元稠杂芳基的取代基取代；
(d)R 3与M相连形成环Z，所述环Z为3-10元脂杂环、6-20元芳环或5-20元杂芳环；并且，所述3-10元脂杂环、6-20元芳环或5-20元杂芳环未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自卤素、氰基、-NRR’、硝基、羟基、＝O、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、6-20元芳基、5-20元杂芳基和5-20元稠杂芳基的取代基取代；或者，所述3-10元脂杂环、6-20元芳环或5-20元杂芳环与6-20元芳环或5-20元杂芳环形成稠合环系，其中，所述稠合环系未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自卤素、氰基、-NRR’、C 1-6烷基、卤代C 1-6烷基、卤代C 1-6烷氧基、6-20元芳基、5-20元杂芳基和5-20元稠杂芳基的取代基取代；R 4选自氢、C 1-6烷基、C 1-6烷氧基、不存在或形成价键；
R 5选自卤素；
R 6选自氢、C 1-6烷基和-COOR；其中，所述C 1-6烷基未被取代或被一个或多个(例如1、2、3或4个)选自卤素、羟基、氨基和氰基的取代基取代；
A原子选自C、N、O和S；
M选自C、N、O、H 2和＝NR；
R和R’各自独立地选自氢、卤素、氰基、羟基、C 1-3烷基、C 1-3烷氧基、3-8元环烷基、3-8元脂杂环基、6-10元芳基、5-10元杂芳基或5-10元稠杂芳基；
在本发明的部分优选实施方案中，R 1不为氢，
Figure PCTCN2018083792-appb-000002
独立地整体为氢。
在本发明的部分实施方案中，所述化合物为任意比例的顺式构型和反式构型化合物的混合物。
在本发明的部分优选实施方案中，所述化合物为顺式(Z)构型。
在本发明的部分优选实施方案中，所述化合物为反式(E)构型。
在本发明的部分优选实施方案中，所述化合物具有式II所示结构，
Figure PCTCN2018083792-appb-000003
其中，所述式II化合物中，R 3选自3-10元环烷基-CH 2、3-8元脂杂环基-CH 2、6-20 元芳基-CH 2、5-20元杂芳基-CH 2、5-20元稠杂芳基-CH 2、苯并3-10元环烷基、苯并3-8元脂杂环基、苯基-3-10元环烷基、5-20元杂芳基-苯基、5-20元稠杂芳基-苯基、3-8元脂杂环基、6-20元芳基、5-20元杂芳基、5-20元稠杂芳基；并且，所述3-10元环烷基-CH 2、3-8元脂杂环基-CH 2、6-20元芳基-CH 2、5-20元杂芳基-CH 2、5-20元稠杂芳基-CH 2、苯并3-10元环烷基、苯并3-8元脂杂环基、苯基-3-10元环烷基、5-20元杂芳基-苯基、5-20元稠杂芳基-苯基、3-8元脂杂环基、6-20元芳基、5-20元杂芳基、5-20元稠杂芳基未被取代或独立地被一个或多个(例如1、2、3或4个)选自卤素、羟基、-NRR’、C 1-3烷基、C 1-3烷氧基、氰基、3-10环烷基、3-8元脂杂环基、6-20元芳基、5-20元杂芳基、5-20元稠杂芳基、卤代C 1-3烷基、卤代C 1-3烷氧基、C 1-3烷氧基-C 1-3烷基、C 1-3烷氧基-C 1-3烷氧基、C 1-3烷氧基-C 1-3烷氧基-C 1-3烷基的取代基取代；R 4选自氢、C 1-6烷基、卤代C 1-6烷基；R 1、R 2、R 5、R 6、R、R’和n的定义如式I所定义。
在本发明的部分优选实施方案中，所述式II化合物中，R 3选自3-10元环烷基-CH 2、3-8元脂杂环基-CH 2、6-20元芳基-CH 2、5-20元杂芳基-CH 2、5-20元稠杂芳基-CH 2、苯并3-10元环烷基、苯并3-8元脂杂环基、苯基-3-10元环烷基、5-20元杂芳基-苯基、5-20元稠杂芳基-苯基、3-8元脂杂环基、6-20元芳基、5-20元杂芳基、5-20元稠杂芳基；并且，所述3-10元环烷基-CH 2、3-8元脂杂环基-CH 2、6-20元芳基-CH 2、5-20元杂芳基-CH 2、5-20元稠杂芳基-CH 2、苯并3-10元环烷基、苯并3-8元脂杂环基、苯基-3-10元环烷基、5-20元杂芳基-苯基、5-20元稠杂芳基-苯基、3-8元脂杂环基、6-20元芳基、5-20元杂芳基、5-20元稠杂芳基未被取代或独立地被一个或多个(例如1或2个)选自卤素、羟基、-NRR’、C 1-3烷基、C 1-3烷氧基、氰基、3-10环烷基、3-8元脂杂环基、6-20元芳基、5-20元杂芳基、5-20元稠杂芳基、卤代C 1-3烷基、卤代C 1-3烷氧基、C 1-3烷氧基-C 1-3烷基、C 1-3烷氧基-C 1-3烷氧基、C 1-3烷氧基-C 1-3烷氧基-C 1-3烷基的取代基取代；R 4选自H或甲基；R 1选自H、卤素、C 1-3烷基；R 2选自氢、氰基、硝基、卤素、C 1-3烷基、C 1-3烷氧基，且n＝1；R 5、R 6、R和R’的定义如式I所定义。
在本发明的部分优选实施方案中，所述式II化合物中，R 3选自苯基、喹唑啉基、喹喔啉基、萘基、苯并[1,4]二氧六环基、苯并咪唑基、吲哚基、[1,3,4]噁二唑基、[1,3,4]噁二唑基-苯基、咪唑基-苯基、苯基-环己基、苯并环己基、四氢吡喃基、噻吩基、苯并噻唑基、吲唑基、四氢吡喃基-CH 2-、环丙基-CH 2-、吡啶基-CH 2-、喹啉基，所述苯基、喹唑啉基、萘基、苯并[1,4]二氧六环基、苯并咪唑基、吲哚基、咪唑基-苯基、苯基-环己基、苯并环己基、四氢吡喃基、噻吩基、苯并噻唑基、吲唑基、四氢吡喃基-CH 2-、环丙基-CH 2-、吡啶基-CH 2-、喹啉基，未被取代或独立地被一个或多个(例如1或2个)选自甲氧基- 甲基、异丙基、三氟甲氧基、甲基、卤素、甲氧基-乙氧基-甲基、三氟甲基、苯基、-N(CH 3) 2、二氟甲氧基、吡咯啉基、吗啉基的取代基取代；R 4选自H或甲基。
在本发明的部分优选实施方案中，所述式II化合物中，R 1选自H、卤素、C 1-3烷基。
在本发明的部分优选实施方案中，所述式II化合物中，R 2选自H、卤素、C 1-3烷基。
在本发明的部分优选实施方案中，所述式II化合物中，n＝1。
在本发明的部分优选实施方案中，所述式II化合物中，R 5为F。
在本发明的部分优选实施方案中，所述式II化合物中，R 6为H。
在本发明的部分优选实施方案中，所述式II化合物中，R 3选自6-15元芳基、苯并3-8元环烷基、苯并3-8元脂杂环基、3-8元脂杂环基、5-10元杂芳基-CH 2、5-10元稠杂芳基-CH 2、3-8元环烷基-CH 2、3-8元脂杂环基-CH 2、6-10元芳基-CH 2、5-10元杂芳基、5-10元稠杂芳基；并且，所述6-15元芳基、苯并3-8元环烷基、苯并3-8元脂杂环基、3-8元脂杂环基、5-10元杂芳基-CH 2、5-10元稠杂芳基-CH 2、3-8元环烷基-CH 2、3-8元脂杂环基-CH 2、6-10元芳基-CH 2、5-10元杂芳基、5-10元稠杂芳基未被取代或独立地被一个或多个(例如1或2)选自卤素、C 1-3烷基、C 1-3烷氧基-C 1-3烷氧基和NRR’的取代基取代；其中，R和R’各自独立地选自H和C 1-3烷基；R 4选自H或甲基；
R 1选自H、卤素；R 2选自H、卤素、C 1-3烷基、C 1-3烷氧基，且n＝1；
R 5和R 6的定义如式I所定义。
在本发明的部分优选实施方案中，所述式II化合物中，R 3选自苯基、萘基、苯并环己基、四氢吡喃基、吡啶基-CH 2-、苯并[1,4]二氧六环基，所述苯基、萘基、苯并环己基、四氢吡喃基、吡啶基-CH 2-、苯并[1,4]二氧六环基，未被取代或被独立地被一个或多个(例如1或2个)选自甲基、卤素、-N(CH 3) 2、甲氧基-乙氧基的取代基取代；R 4选自H或甲基。
在本发明的部分优选实施方案中，R 3选自3-7元环烷基-CH 2、3-7元脂杂环基-CH 2、6-10元芳基-CH 2、5-6元杂芳基-CH 2-、苯并3-7元环烷基、3-7元脂杂环基、6-10元芳基、5-10元杂芳基、5-10元稠杂芳基；R 4为H；
R 1选自H；R 2选自H或卤素，且n＝1；R 5为F；R 6为H。
在本发明的部分优选实施方案中，所述式II化合物中，R 3选自6-10元芳基、3-7元脂杂环基；R 4为H。
在本发明的部分优选实施方案中，所述式II化合物中，R 3选自苯基、四氢吡喃基；R 4为H。
在本发明的部分实施方案中，所述化合物为任意比例的顺式构型和反式构型化合物的 混合物。
在本发明的部分优选实施方案中，所述式II化合物为顺式(Z)构型。
在本发明的部分优选实施方案中，所述式II化合物为反式(E)构型。
在本发明的部分优选实施方案中，所述化合物具有式III所示结构，
Figure PCTCN2018083792-appb-000004
其中，所述环X为5-8元脂环或5-8元脂杂环；并且，所述5-8元脂环或5-8元脂杂环未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自＝O、卤素、氰基、-NRR’、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、6-10元芳基、5-10元杂芳基和5-10元稠杂芳基的取代基取代；或者，所述5-8元脂环或5-8元脂杂环与3-8元脂环形成螺环结构；
R 4选自氢、C 1-6烷基、3-8元环烷基、3-8元脂杂环基、6-10元芳基、5-10元杂芳基和5-10元稠杂芳基；并且，所述C 1-6烷基、3-8元环烷基、3-8元脂杂环基、6-10元芳基、5-10元杂芳基或5-10元稠杂芳基任选地被一个或多个(例如1、2、3或4个)选自卤素、氰基、-NRR’、羟基、C 1-4烷基、C 1-4烷氧基、3-8元环烷基、3-8元脂杂环基、6-10元芳基、5-10元杂芳基或5-10元稠杂芳基的取代基取代；
R 2、R 5、R 6、R、R'和A的定义如式I所定义。
在本发明的部分优选实施方案中，所述式III化合物中，A选自N和C。
在本发明的部分优选实施方案中，所述式III化合物中，R 2选自氢、卤素。在本发明的部分优选实施方案中，所述式III化合物中，R 4选自氢、C 1-3烷基。
在本发明的部分优选实施方案中，所述式III化合物中，R 5选自卤素。
在本发明的部分优选实施方案中，所述式III化合物中，R 6为H。
在本发明的部分优选实施方案中，所述式III化合物中，环X为5-7元脂环或5-7脂杂环；并且，所述5-7元脂环或5-7元脂杂环未被取代或被一个或多个(例如1、2、3或4个)选自＝O、卤素、C 1-4烷基、6-10元芳基、5-10元杂芳基和5-10元稠杂芳基的取代基取代；或者，所述5-7元脂环或5-7元脂杂环与3-6元脂环形成螺环结构；A选自N和C；R 2选自F、Cl、H；R 4选自H、CH 3、CH 2CH 3；R 5为F；R 6为H。
在本发明的部分优选实施方案中，所述式III化合物中，环X为5-6元脂环或5-6元 脂杂环；并且，所述5-6元脂环或5-6元脂杂环未被取代或被一个或多个(例如1、2或3)选自O＝、卤素、C 1-3烷基的取代基取代；其中A选自N和C；R 2选自F、H；R 4选自H、CH 3、CH 2CH 3；R 5选自F；R 6为H。
在本发明的部分优选实施方案中，所述式III化合物中，环X为5元脂环或6元含氮脂杂环。
在本发明的部分优选实施方案中，所述式III化合物中，所述6元含氮脂杂环为哌啶环。
在本发明的部分实施方案中，所述化合物为任意比例的顺式构型和反式构型化合物的混合物。
在本发明的部分优选实施方案中，所述式III化合物为顺式(Z)构型。
在本发明的部分优选实施方案中，所述式III化合物为反式(E)构型。
在本发明的部分优选实施方案中，所述化合物具有式IV所示结构，
Figure PCTCN2018083792-appb-000005
其中，所述环X为5-8元脂环或5-8元脂杂环；并且，所述5-8元脂环或5-8元脂杂环未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自＝O、卤素、氰基、-NRR’、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、6-10元芳基、5-10元杂芳基和5-10元稠杂芳基的取代基取代；或者，所述5-8元脂环或5-8元脂杂环与3-8元脂环形成螺环结构；
R 4选自氢、C 1-6烷基、3-8元环烷基、3-8元脂杂环基、6-10元芳基、5-10元杂芳基、5-10元稠杂芳基；并且，所述C 1-6烷基、3-8元环烷基、3-8元脂杂环基、6-10元芳基、5-10元杂芳基或5-10元稠杂芳基任选地被一个或多个(例如1、2、3或4个)选自卤素、氰基、羟基、C 1-4烷基、C 1-4烷氧基、3-8元环烷基、3-8元脂杂环基、6-10元芳基、5-10元杂芳基或5-10元稠杂芳基的取代基取代；其中，所述的C 1-4烷基、3-8元环烷基、3-8元脂杂环基、6-10元芳基、5-10元杂芳基或5-10元稠杂芳基任选地被一个或多个(例如1、2或3)选自卤素、-NRR’、C 1-3烷基的取代基取代；
R 2、R 5、R 6、R、R’、A和n的定义如式I所定义。
在本发明的部分优选实施方案中，所述式IV化合物中，环X选自5-7元脂环或5-7元含氮原子或氧原子的脂杂环(例如吡咯烷环、哌啶环、四氢吡喃环)；并且，所述5-7元脂环或5-7元含氮原子或氧原子的脂杂环未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自卤素、C 1-4烷基(例如甲基)的取代基取代；或者，所述5-7元脂环或5-7元含一个氮原子的脂杂环与环丙基形成螺环结构。
在本发明的部分优选实施方案中，所述式IV化合物中，R 4选自氢、苯基、二氮杂萘基、卤代苄基、四氢吡喃基-CH 2-、C 1-3烷基(例如甲基、乙基)、环戊基、苄基、四氢吡喃基。
在本发明的部分优选实施方案中，所述式IV化合物中，R 2选自氢、卤素。
在本发明的部分优选实施方案中，所述式IV化合物中，R 5选自卤素。
在本发明的部分优选实施方案中，所述式IV化合物中，R 6为H。在本发明的部分优选实施方案中，所述式IV化合物中，A选自N和C。
在本发明的部分优选实施方案中，所述式IV化合物中，环X为5-7元脂环或5-7元脂杂环；并且，所述5-7元脂环或5-7元脂杂环未被取代或被一个或多个(例如1、2、3或4个)选自＝O、卤素、C 1-4烷基、6-10元芳基、5-10元杂芳基和5-10元稠杂芳基的取代基取代；或者，所述5-7元脂环或5-7元脂杂环与3-6元脂环形成螺环结构；A选自N和C；R 2独立地选自F、Cl、H，且n＝1或2；R 4选自H、C 1-4烷基、苄基或卤代苄基；R 5选自F；R 6选自H。
在本发明的部分优选实施方案中，所述式IV化合物中，环X为5-6元脂环或5-6元脂杂环；并且，所述5-6元脂环或5-6元脂杂环未被取代或被一个或多个(例如1、2、3或4个)选自＝O、卤素、C 1-4烷基的取代基取代；A选自N和C；R 2独立地选自F、Cl、H，且n＝1；R 4选自H、C 1-4烷基、苄基或氯代苄基；R 5选自F；R 6选自H。
在本发明的部分优选实施方案中，所述式IV化合物中，环X选自吡咯烷环、哌啶环，所述吡咯烷环或哌啶环未被取代或被一个或多个甲基取代。
在本发明的部分优选实施方案中，所述式IV化合物中，R 4选自H、卤代苄基、甲基。
在本发明的部分优选实施方案中，所述式IV化合物中，环X为6元脂杂环(例如6元含氮脂杂环，例如哌啶环)；并且，所述6元脂杂环未被取代或被一个或多个(例如1、2或3)选自＝O、卤素、C 1-3烷基的取代基取代；A为N；R 2独立地选自F、H，且n＝1；R 4选自H、CH 3、CH 2CH 3；R 5选自F；R 6选自H。
在本发明的部分实施方案中，所述化合物为任意比例的顺式构型和反式构型化合物的混合物。
在本发明的部分优选实施方案中，所述式IV化合物为顺式(Z)构型。
在本发明的部分优选实施方案中，所述式IV化合物为反式(E)构型。
在本发明的部分优选实施方案中，所述化合物具有式V所示结构，
Figure PCTCN2018083792-appb-000006
其中，所述环Y为5-8元脂杂环或5-8元脂环；并且，所述5-8元脂杂环或5-8元脂环未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自卤素、氰基、-NRR’、硝基、羟基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、6-20元芳基、5-20元杂芳基和5-20元稠杂芳基的取代基取代，其中，所述C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、6-20元芳基、5-20元杂芳基和5-20元稠杂芳基未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自卤素、氰基、-NRR’、C 1-6烷基、6-20元芳基、5-20元杂芳基和5-20元稠杂芳基的取代基取代；或者，所述5-8元脂杂环或5-8元脂环与6-20元芳环或5-20元杂芳环形成稠合环系，其中，所述稠合环系未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自卤素、氰基、-NRR’、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、6-20元芳基、5-20元杂芳基或5-20元稠杂芳基的取代基取代；R 1、R 2、R 5、R 6、R和R’的定义如式I所定义；A选自N或C。
在本发明的部分优选实施方案中，所述式V化合物中，环Y为5-7元脂杂环；并且，所述5-7元脂杂环未被取代或被一个或多个(例如1、2、3或4个)选自卤素、氰基、-NRR’、6-15元芳基和C 1-4烷基取代基取代，其中，所述6-15元芳基、C 1-4烷基未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自卤素、C 1-4烷基、卤代C 1-4烷基和6-10元芳基的取代基取代；或者，所述5-7元脂杂环与6-10元芳环或5-10元杂芳环形成稠合环系，并且，所述稠合环系未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自卤素、C 1-4烷基、卤代C 1-4烷基和6-10元芳基的取代基取代；
R 1、R 2、R 5、R 6、R和R’的定义如式I所定义；A为N。
在本发明的部分优选实施方案中，所述式V化合物中，R 1为H。
在本发明的部分优选实施方案中，所述式V化合物中，R 2选自卤素。
在本发明的部分优选实施方案中，所述式V化合物中，R 5选自卤素。
在本发明的部分优选实施方案中，所述式V化合物中，R 6为H。
在本发明的部分优选实施方案中，所述式V化合物中，A为N。
在本发明的部分优选实施方案中，所述式V化合物中，环Y为5-7元含氮脂杂环；并且，所述5-7元含氮脂杂环未被取代或被一个或多个选自苯基、二苯基甲基的取代基所取代；或者，所述5-7元含氮脂杂环与苯环或噻吩环形成稠合环系，所述稠合环系未被取代或各自独立地被一个或多个选自卤素、苯基、三氟甲基的取代基取代。
在本发明的部分优选实施方案中，所述式V化合物中，环Y为5-7元脂杂环；并且，所述5-7元脂杂环未被取代或被一个或多个(例如1、2、3或4个)选自6-10元芳基的取代基取代；A为N，R 1为H；R 2选自H或F；R 5为F；R 6为H。
在本发明的部分优选实施方案中，所述式IV化合物中，环Y为5-7元含一个氮原子的脂杂环；并且，所述5-7元含含一个氮原子的脂杂环未被取代或被苯基所取代；或者，所述5-7元含一个氮原子的脂杂环与苯环形成稠合环系，所述稠合环系未被取代或被一个或多个选自卤素、苯基、三氟甲基的取代基取代。
在本发明的部分实施方案中，所述化合物为任意比例的顺式构型和反式构型化合物的混合物。
在本发明的部分优选实施方案中，所述式V化合物为顺式(Z)构型。
在本发明的部分优选实施方案中，所述式V化合物为反式(E)构型。
在本发明的部分优选实施方案中，所述化合物具有式VI所示结构，
Figure PCTCN2018083792-appb-000007
其中，所述环Z为3-10元脂杂环、6-20元芳环或5-20元杂芳环；并且，所述3-10元脂杂环、6-20元芳环或5-20元杂芳环未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自卤素、氰基、-NRR’、硝基、羟基、＝O、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、6-20元芳基、5-20元杂芳基和5-20元稠杂芳基的取代基取代；或者，所述3-10元脂杂环、6-20元芳环或5-20元杂芳环与6-20元芳环或5-20元杂 芳环形成稠合环系，其中，所述稠合环系未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自卤素、氰基、-NRR’、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、6-20元芳基、5-20元杂芳基和5-20元稠杂芳基的取代基取代；
R 4选自氢、C 1-6烷基、C 1-6烷氧基、不存在或形成价键；
R 1、R 2、R 5、R 6、R、R’、A、M和n的定义如式I所定义。
在本发明的部分优选实施方案中，所述式VI化合物中，R 1选自H或卤素。
在本发明的部分优选实施方案中，所述式VI化合物中，R 2选自H或卤素。
在本发明的部分优选实施方案中，所述式VI化合物中，R 5选自卤素。
在本发明的部分优选实施方案中，所述式VI化合物中，R 6选自H或C 1-6烷基。
在本发明的部分优选实施方案中，所述式VI化合物中，A选自S或N。
在本发明的部分优选实施方案中，所述式VI化合物中，M选自C或N。
在本发明的部分优选实施方案中，所述式VI化合物中，n＝1或2。
在本发明的部分优选实施方案中，所述式VI化合物中，环Z为5-7元脂杂环、6-10元芳环或5-10元杂芳环，并且，所述5-7元脂杂环、6-10元芳环或5-10元杂芳环未被取代或各自独立地被一个或多个(例如1、2、3或4)选自卤素、氰基、-NRR’、硝基、羟基、C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷基、卤代C 1-6烷氧基的取代基取代；或者，所述5-7元脂杂环、6-10元芳环或5-10元杂芳环与6-10元芳环或5-10元杂芳环形成稠合环系，其中，所述稠合环系未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自卤素、氰基、-NRR’、C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷基、卤代C 1-3烷氧基、6-10元芳基、5-10元杂芳基和5-10元稠杂芳基的取代基取代；
R 4选自氢、C 1-6烷基、不存在或形成价键；
R 1选自氢、卤素；R 2各自独立地选自氢、卤素或氰基，且n＝1或2；R 5选自F或Cl；R 6选自氢、C 1-6烷基；A选自N和S；M选自N；
R和R’的定义如式I所定义。
在本发明的部分优选实施方案中，所述式VI化合物中，环Z为5-7元脂杂环、6-10元芳环或5-10元杂芳环；并且，所述5-7元脂杂环、6-10元芳环或5-10元杂芳环未被取代或各自独立地被一个或多个(例如1、2或3)选自卤素、氰基、-NRR’、硝基、羟基、C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷基、卤代C 1-6烷氧基的取代基取代；其中，R和R’各自独立地选自氢和C 1-3烷基；或者，所述5-7元脂杂环、6-10元芳环或5-10元杂芳环与6-10元芳环或5-10元杂芳环形成稠合环系，其中，所述稠合环系未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自卤素、氰基、-NRR’、C 1-3烷基、C 1-3烷氧 基、卤代C 1-3烷基、卤代C 1-3烷氧基的取代基取代；其中，R和R’各自独立地选自氢和C 1-3烷基；
R 4选自氢、C 1-6烷基、不存在或形成价键；
R 1选自H、卤素；R 2各自独立地选自H或F，且n＝1或2；
R 5选自F或Cl；
R 6选自H、C 1-6烷基；
A选自N；
M选自N。
在本发明的部分优选实施方案中，所述式VI化合物中，环Z为5-7元杂芳环，所述5-7元杂芳环含有一个或多个选自N或S的杂原子；任选地，所述5-7元杂芳环被C 1-3烷基取代。在本发明的部分优选实施方案中，环Z选自嘧啶环、咪唑环、噻唑环、[1，2，4]三嗪环。在本发明的部分优选实施方案中，所述5-7元杂芳环与6-10元芳环(例如苯环)或5-10元含氮杂芳环(例如咪唑环)形成稠合环系，任选地，所述稠合环系被卤素取代。
在本发明的部分优选实施方案中，所述式VI化合物中，环Z为任选被甲基取代的嘧啶环、咪唑环或噻唑环；或者，所述嘧啶环、咪唑环或噻唑环与苯环形成稠合环系，所述稠合环系任选被卤素取代。
在本发明的部分优选实施方案中，所述式VI化合物中，环Z为嘧啶环或咪唑环；或者，所述嘧啶环或咪唑环与苯环形成稠合环系。
在本发明的部分实施方案中，所述化合物为任意比例的顺式构型和反式构型化合物的混合物。
在本发明的部分优选实施方案中，所述式VI化合物为顺式(Z)构型。
在本发明的部分优选实施方案中，所述式VI化合物为反式(E)构型。
本发明的上述式I至式VI中，所有优选实施方案的基团可以适宜地选择任意组合，从而得到不同的通式范围或具体方案。这些范围和方案均属于本发明。
在本发明的部分优选实施方案中，所述化合物选自：
Figure PCTCN2018083792-appb-000008
Figure PCTCN2018083792-appb-000009
Figure PCTCN2018083792-appb-000010
Figure PCTCN2018083792-appb-000011
Figure PCTCN2018083792-appb-000012
Figure PCTCN2018083792-appb-000013
Figure PCTCN2018083792-appb-000014
在本发明的部分优选实施方案中，所述化合物其药学可接受的盐为盐酸盐或三氟乙酸盐；优选地，所述药学可接受的盐为盐酸盐。
在本发明的部分优选实施方案中，所述化合物其药学可接受的盐为：
Figure PCTCN2018083792-appb-000015
在本发明的部分优选实施方案中，所述化合物其药学可接受的盐为：
Figure PCTCN2018083792-appb-000016
本发明所述化合物包括指式I-VI所涵盖的化合物，其药学可接受的盐、酯、水合物、 溶剂化物、异构体、同位素标记的化合物，它们的任意晶体或消旋物，或它们的代谢物形式，以及或它们的混合物。
本发明第二方面提供一种药物组合物，其含有本发明第一方面所述的化合物，其药学可接受的盐、酯、水合物、溶剂化物、异构体、同位素标记的化合物，它们的任意晶体或消旋物，或它们的代谢物形式，以及或它们的混合物，以及一种或多种药用辅料。
本文中所述药用辅料是指生产药品和调配处方时，使用的的赋形剂和附加剂，是指除活性成分外，在安全性方面已进行了合理的评估，并且包含在药物制剂中的物质。药用辅料可用于赋型、充当载体、提高稳定性，还可具有增溶、助溶、缓控释等重要功能，是可能会影响到药品的质量、安全性和有效性的重要成分。根据其来源可分为天然物、半合成物和全合成物。根据其作用与用途可分为：溶剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、湿润剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏着剂、抗氧剂、螯合剂、渗透促进剂、pH调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、助滤剂、释放阻滞剂等；根据其给药途径可分为口服、注射、黏膜、经皮或局部给药、经鼻或口腔吸入给药和眼部给药等。具体的药用辅料包含水、乳糖、葡萄糖、果糖、蔗糖、山梨糖醇、甘露醇、聚乙二醇、丙二醇、淀粉、橡胶、凝胶、藻酸盐、硅酸钙、磷酸钙、纤维素、水性糖浆、甲基纤维素、聚乙烯基吡咯烷酮、对羟基苯并山梨酸烷基酯、滑石、硬脂酸镁、硬脂酸、甘油、芝麻油、橄榄油、大豆油等。
所述药物组合物可以以任意形式施用，只要其实现预防、减轻、防止或者治愈人类或动物患者的症状。例如，可根据给药途径制成各种适宜的剂型。
当口服用药时，所述药物组合物可制成任意口服可接受的制剂形式，包括但不限于片剂、胶囊剂、颗粒剂、丸剂、糖浆剂、口服溶液剂、口服混悬剂和口服乳剂等。其中，片剂使用的载体一般包括乳糖和玉米淀粉，另外也可加入润滑剂如硬脂酸镁。胶囊剂使用的稀释剂一般包括乳糖和干燥玉米淀粉。口服混悬剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合使用。任选地，以上口服制剂形式中还可加入一些甜味剂、芳香剂或着色剂。
当经皮或局部施用时，所述药物组合物可制成适当的软膏、洗剂或搽剂形式，其中将活性成分悬浮或溶解于一种或多种载体中。软膏制剂可使用的载体包括但不限于：矿物油、液体凡士林、白凡士林、丙二醇、聚氧化乙烯、聚氧化丙烯、乳化蜡和水；洗剂 或搽剂可使用的载体包括但不限于：矿物油、脱水山梨糖醇单硬脂酸酯、吐温60、十六烷酯蜡、十六碳烯芳醇、2-辛基十二烷醇、苄醇和水。
所述药物组合物还可以注射剂形式用药，包括注射液、注射用无菌粉末与注射用浓溶液。其中，可使用的载体和溶剂包括水、林格氏溶液和等渗氯化钠溶液。另外，灭菌的非挥发油也可用作溶剂或悬浮介质，如单甘油酯或二甘油酯。
可以通过临床领域的普通技术人员容易地确定所述药物组合物的施用量和施用方案。本发明的组合物或化合物一般为每天两次至每3天给药1次，优选每天给药1次，并且给药总量0.01～1000mg/次。一般地，治疗的剂量是变化的，这取决于所考虑的事项，例如：待治疗患者的年龄、性别和一般健康状况；治疗的频率和想要的效果的性质；组织损伤的程度；症状的持续时间；以及可由各个医师调整的其它变量。可以以一次或多次施用想要的剂量，以获得想要的结果。也可以以单位剂量形式提供根据本发明的药物组合物。
本发明还提供第一方面所述化合物的制备方法，其中，式I中R 6为氢时，所述方法选自以下方案：
方案一：
将化合物SM-1与化合物INT-1进行亲核取代反应生成化合物INT-2；化合物INT-2脱保护基得到目标产物；
Figure PCTCN2018083792-appb-000017
方案二：
将化合物SM-1与化合物INT-3进行Mitsunobu反应生成化合物INT-2；化合物INT-2脱保护基得到目标产物；
Figure PCTCN2018083792-appb-000018
方案三：
将化合物SM-2与化合物INT-1进行亲核取代反应生成化合物INT-4；化合物INT-4发生偶联反应得到化合物INT-2；化合物INT-2脱保护基得到目标产物；
Figure PCTCN2018083792-appb-000019
方案四：
将化合物SM-2与化合物INT-3进行Mitsunobu反应得到化合物INT-4；化合物INT-4进行偶联反应得到化合物INT-2；化合物INT-2脱保护基得到目标产物；
Figure PCTCN2018083792-appb-000020
方案五：
将化合物SM-3与化合物INT-1进行亲核取代反应生成化合物INT-5；化合物INT-5脱保护基得到目标产物；
Figure PCTCN2018083792-appb-000021
方案六：
将化合物SM-3与化合物INT-3进行Mitsunobu反应生成化合物INT-5；化合物INT-2脱保护基得到目标产物；
Figure PCTCN2018083792-appb-000022
其中，Lg表示离去基团，如卤素、-OTs等；P表示氨基保护基，如Boc、Cbz、Fmoc、苄基等；其余原子和基团的定义如前文所述。
中间体INT-1和INT-3为市售可得或者通过本发明具体实施例中所述制备方法得到。
本发明还提供所述化合物，其药学可接受的盐、酯、水合物、溶剂化物、异构体、同位素标记的化合物，它们的任意晶体或消旋物，或它们的代谢物形式，以及或它们的混合物在制备VAP-1/SSAO抑制剂中的用途。
本发明还提供所述化合物，其药学可接受的盐、酯、水合物、溶剂化物、异构体、同位素标记的化合物，它们的任意晶体或消旋物，或它们的代谢物形式，以及或它们的混合物，或本发明的药物组合物在制备治疗与VAP-1/SSAO过度活性相关的疾病或病症的药物中的用途。
本发明还提供一种治疗与VAP-1/SSAO过度活性相关的疾病或病症的方法，包括给有此需要的受试者施用治疗有效量的如上定义的化合物，其药学可接受的盐、酯、水合物、溶剂化物、异构体、同位素标记的化合物，它们的任意晶体或消旋物，或它们的代谢物形式，以及或它们的混合物，或本发明的药物组合物。
本发明所述的“有效量”是指足以获得或至少部分获得期望的效果的量。例如，“治疗有效量”是指，足以治愈或至少部分阻止已患有疾病的患者的疾病和其并发症的量。测定这样的有效量完全在本领域技术人员的能力范围之内。例如，对于治疗用途有效的量将取决于待治疗的疾病的严重度、患者自己的免疫系统的总体状态、患者的一般情况例如年龄、体重和性别，药物的施用方式，以及同时施用的其他治疗等等。
在本发明中，所述与VAP-1/SSAO过度活性相关的疾病或病症选自炎症性疾病(如与肝脏相关的炎症性疾病，例如肝炎、肝肿大、肝纤维化、肝硬化或肝腹水；如与呼吸道相关的炎症性疾病，例如气管炎、肺炎、肺纤维化、哮喘、急性肺损伤、急性呼吸窘迫综合征、支气管炎或慢性阻塞性肺病；如与眼相关的炎症性疾病，例如葡萄膜炎；如其它炎症，例如滑膜炎或腹膜炎)、器官和/或组织移植排斥、自身免疫性疾病(例如风湿性关节炎或多发性硬化(例如慢性多发性硬化))、皮肤病(例如湿疹或牛皮癣)、糖尿病(例如I型或II型糖尿病)和中风。
在本发明中，所述受试者选自任何动物，优选地哺乳动物，例如牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物。其中，特别优选的受试者为人。
本发明还提供一种抑制细胞中VAP-1/SSAO活性的方法，包括给有此需要的细胞施用有效量的如上定义的化合物，其药学可接受的盐、酯、水合物、溶剂化物、异构体、同位素标记的化合物，它们的任意晶体或消旋物，或它们的代谢物形式，以及或它们的混合物。
在本发明的部分实施方案中，所述方法用于体内，例如所述细胞是受试者(例如哺乳 动物；例如牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物；例如，人)体内的细胞；或者，所述方法用于体外，例如所述细胞是体外的细胞(例如细胞系或者来自受试者的细胞)。
本发明还提供了一种用于降低或抑制细胞中VAP-1/SSAO活性的试剂盒，所述的试剂盒包括本发明的化合物，其药学可接受的盐、酯、水合物、溶剂化物、异构体、同位素标记的化合物，它们的任意晶体或消旋物，或它们的代谢物形式，以及或它们的混合物，且任选地还包括使用说明。
在本发明中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。为了更好地理解本发明，下面提供相关术语的定义和解释。
本发明中，“氢”及所述各基团中的氢包括氕(H)，氘(D)，氚(T)。
本发明中，“卤素”包括氟、氯、溴和碘。
本发明中，“C 1-6烷基”是指具有1-6个碳原子的直链或支链烷基，例如C 1-4烷基、C 1- 3烷基、C 1- 2烷基、C 1烷基、C 2烷基、C 3烷基、C 4烷基、C 5烷基或C 6烷基。具体的实例包括但不限于甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基等。
本发明中，“卤代C 1-6烷基”是指如前文所述的C 1-6烷基被一个或多个如前文所述的卤素取代后形成的基团。例如卤代C 1-4烷基、卤代C 1-2烷基、氟代C 1-C 4烷基、氟代C 1-C 2烷基等。具体的实例包括但不限于氟代甲基、二氟甲基、三氟甲基、三氟乙基、五氟乙基等。
本发明中，“C 1-6烷氧基”是指以C 1-6烷基-O-方式形成的基团，其中“C 1-6烷基”的定义如前文所述。例如C 1-C 4烷氧基、C 1-C 2烷氧基。具体的实例包括但不限于甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、2-丁氧基、异丁氧基、仲丁氧基、叔丁氧基、戊氧基、己氧基等。
本发明中，“卤代C 1-6烷氧基”是指如前文所述的C 1-6烷氧基被一个或多个如前文所述的卤素取代后形成的基团。例如卤代C 1-4烷氧基、卤代C 1-2烷氧基、氟代C 1-C 4烷氧基、氟代C 1-C 2烷氧基等。具体的实例包括但不限于三氟甲氧基、二氟甲氧基等。
本发明中，“3-10元环烷基”是指含有3-10个碳原子的饱和或部分饱和的单环烃基，例如3-6元环烷基。具体的实例包括但不限于环丙基、环丁基、环戊基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等。
本发明中，“3-8元脂杂环基”是指含有3-8个环成员的且至少一个环成员为选自N、O和S的杂原子的饱和或部分饱和的不具有芳香性的环状基团，优选地，所述杂原子的 个数为1、2、3或4个。例如3-6元脂杂环基。例如3-8元含氮脂杂环基、3-8元含氧脂杂环基、3-8元含硫脂杂环基、3-6元含氮脂杂环基、3-6元含氧脂杂环基、3-6元含硫脂杂环基。具体的实例包括但不限于环氧乙烷基、氧代环丁烷基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、四氢吡喃基、高哌嗪基等。
本发明中，“6-20元芳基”是指含有6-20个环成员的具有芳香性的单环或多环烃基，例如6-10元芳基等。具体的实例包括但不限于苯基、萘基、蒽基、菲基等。
本发明中，“5-20元杂芳基”是指至少一个环成员为选自N、O和S的杂原子的具有芳香性的单环基团，优选地，所述杂原子的个数为1、2、3或4个，例如5-10元杂芳基、5-6元杂芳基。例如5-20元含氧杂芳基、5-20元含硫杂芳基、5-20元含氮杂芳基、5-10元含氧杂芳基、5-10元含硫杂芳基、5-10元含氮杂芳基、5-6元含氧杂芳基、5-6元含硫杂芳基、5-6元含氮杂芳基。具体的实例包括但不限于呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、吡啶基、2-吡啶酮基、4-吡啶酮基、嘧啶基、2H-1,2-噁嗪基、4H-1,2-噁嗪基、6H-1,2-噁嗪基、4H-1,3-噁嗪基、6H-1,3-噁嗪基、4H-1,4-噁嗪基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基、1,2,4,5-四嗪基、氮杂环庚三烯基、1,3-二氮杂环庚三烯基等。
本发明中，“3-8元脂环”是指饱和或部分饱和的不具有芳香特性的碳环。例如包括5-6元脂环、5元脂环、6元脂环、7元脂环、8元脂环等。
本发明中，“3-10元脂杂环”是指至少一个环成员为选自N、O和S的杂原子的脂肪族饱和或部分饱和的不具有芳香特性的环，优选地，所述杂原子的个数为1、2、3或4个。例如3-10元含氮脂杂环、3-10元含氧脂杂环、3-10元含硫脂杂环、5-8元含氮脂杂环、5-8元含氧脂杂环、5-8元含硫脂杂环、5-6元含氮脂杂环、5-6元含氧脂杂环、5-6元含硫脂杂环。例如5-6元脂杂环、5元脂杂环、6元脂杂环、7元脂杂环、8元脂杂环等。
本发明中，“6-20元芳环”是指含有6-20个碳原子的芳香环，例如6-20元芳环、6-10元芳环等。具体的实例包括但不限于苯环、萘环、蒽环、菲环等。
本发明中，“5-20元杂芳环”是指至少一个环成员为选自N、O和S的杂原子的具有芳香性的环，优选地，所述杂原子的个数为1、2、3或4个。例如含有1个或2个N原子的杂芳环、例如只含一个O原子的杂芳环、例如只含一个S原子的杂芳环等。例如5-20元杂芳环、5-14元杂芳环、5-10元杂芳环、5-6元杂芳环等。例如5-20元含氮杂芳环、5-20元含氧杂芳环、5-20元含硫杂芳环、5-14元含氮杂芳环、5-14元含氧杂芳 环、5-14元含硫杂芳环、5-10元含氮杂芳环、5-10元含氧杂芳环、5-10元含硫杂芳环、5-6元含氮杂芳环、5-6元含氧杂芳环、5-6元含硫杂芳环。具体的实例包括但不限于咪唑环、噻唑环、嘧啶环等。
本发明中，“稠合环系(稠环)”是指由两个或两个以上(例如3、4或5个)碳环或杂环以共有环边而形成的多环结构，所述所述碳环包括脂环和芳环，所述杂环包括杂芳环和脂杂环。所述稠合环系包括但不限于：脂环与脂环形成的稠合环系、脂环与脂杂环形成的稠合环系、脂环与芳环形成的稠合环系、脂环与杂芳环形成的稠合环系、脂杂环与脂杂环形成的稠合环系、脂杂环与杂芳环形成的稠合环系、脂杂环与芳环形成的稠合环系、杂芳环与杂芳环形成的稠合环系、杂芳环与芳环形成的稠合环系；例如：5-7元脂杂环、6-10元芳环或5-10元杂芳环与6-10元芳环或5-10元杂芳环形成的稠合环系，或者，5-8元脂杂环或5-8元脂环与6-20元芳环或5-20元杂芳环形成稠合环系；例如：苯并呋喃、苯并异呋喃、苯并噻吩、吲哚、异吲哚、苯并噁唑、苯并咪唑、吲唑、苯并三唑、喹啉、2-喹啉酮、4-喹啉酮、1-异喹啉酮、异喹啉、吖啶、菲啶、苯并哒嗪、酞嗪、喹唑啉、喹喔啉、酚嗪、喋啶、嘌呤、萘啶、吩嗪、吩噻嗪、苯并咪唑环、苯并噻唑环、喹唑啉环、吡咯并[2,1-f][1,2,4]三嗪环。
本发明中，“稠杂芳基”是指具有芳香性的含一个或多个(例如1、2、3或4个)杂原子(例如O、N、S)的稠环基团，其可以通过芳基与杂芳基，或杂芳基与杂芳基以共有环边而形成。
本发明中，“代谢物形式”是指本发明的化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，同位素标记的化合物或它们的任意晶型或消旋物在施用至需要的受试者后，在受试者体内产生的化合物。
本发明中，“药学可接受的盐”表示保留母体化合物的生物有效性和性质的那些盐，例如，通过下列方式制备：使化合物的质子接受部分质子化和/或使质子供给部分去质子化。应该注意，质子接受部分质子化导致形成阳离子类物质，其中该电荷通过生理阴离子的存在而平衡，而质子供给部分去质子化导致形成阴离子类物质，其中该电荷通过生理阳离子的存在而平衡。具体的实例包括但不限于钠盐、钾盐、钙盐、铵盐、铝盐丙酸盐、酪酸盐、甲酸盐、与半胱氨酸形成的盐、氢碘酸盐、烟酸盐、草酸盐、盐酸盐或三氟乙酸盐等。
本发明的式I-VI化合物中，基团中的原子包括其同位素。例如，H或氢包括 1H、 2H、 3H。
本发明中，“制剂”或“剂型”应包括本发明化合物的固体和液体制剂，本领域技术人员会理解，根据所需剂量和药代动力学参数，本发明化合物成分可存在于不同的制剂中。
在本发明的实施方案中，所述化合物或其盐可以以溶剂化物的形式存在，所述溶剂选自有机溶剂(例如乙醇、丙酮)。
在本发明的实施方案中，所述化合物或其盐可以以水合物的形式存在。
在本发明的实施方案中，如果所述化合物存在手性碳，则本发明包括基于该手性碳的任何立体构型形成的异构体，例如包括消旋体或任何一种镜像异构体。而且，本发明包括全部可能出现的其他立体异构体。也就是说，本发明的化合物包括所有对映异构体、非对映异构体、顺反异构体、消旋体等。
发明的有益效果
经过深入研究，本发明令人意外地发现一类式I所示化合物，其具有VAP-1/SSAO抑制活性，可用于与VAP-1/SSAO过度活性相关的疾病的治疗，其对血管黏附蛋白1/氨基脲敏感性胺氧化酶具有较高的抑制活性，对单胺氧化酶和双胺氧化酶具有较好的选择性，体内代谢稳定性得到了提高。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
用Bruker仪器(400MHz)在环境温度下记录 1H NMR光谱，使用TMS为内标。化学位移(δ)以ppm为单位给出，耦合常数(J)以赫兹(Hz)为单位给出。 1H NMR波谱峰的裂分重数缩写如下：s(单峰)、d(双峰)、t(三重峰)、q(四重峰)、m(多重峰)、br(宽峰)。测定溶剂为氘代甲醇(CD 3OD)、氘代氯仿(CDCl 3)或六氘代二甲基亚砜(DMSO-d6)。
LC-MS采用Aglient 1200液相色谱仪联用Aglient 6120 Quadrupole型质谱仪，在214nm及254nm下检测。
制备液相色谱法使用SHIMADZU CBM-20A及Aglient 1260型制备液相仪，C18OBD 19×150mm 5μM制备柱，检测波长214nm，流动相A为水，流动相B为乙腈(添加0.5‰甲酸)，按下表进行线性梯度洗脱：
时间(min) A％ B％
0 90 10
15 40 60
30 10 90
MS的测定用Agilent(ESI)质谱仪，生产商:Agilent。
制备高效液相使用岛津LC-8A制备液相色谱仪(YMC，ODS,250×20mml色谱柱)。
薄层色谱硅胶板(TLC)使用Merck产的铝板(20×20cm)，薄层层析分离纯化采用的硅胶规格是烟台产GF 254(0.4～0.5nm)。
反应的监测采用薄层色谱法(TLC)或LCMS，使用的展开剂体系有：二氯甲烷和甲醇体系，正己烷和乙酸乙酯体系，石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可加入三乙胺等进行调节。
除非另外说明，反应溶剂均为市售的无水溶剂或HPLC级溶剂而不经进一步的纯化。
微波反应使用BiotageInitiator+(400W,RT～300℃)微波反应器。
实施例中无特殊说明，反应的温度为室温(20℃～30℃)
本发明所使用的试剂购自Acros Organics,Aldrich Chemical Company,特伯化学等公司。
如无特别说明，在常规的合成方法以及实施例和中间体合成例中所用的各缩写具有下述含义。
DMF：N，N-二甲基甲酰胺；    DMA：N，N-二甲基乙酰胺；
DMSO：二甲基亚砜；          NMP：N-甲基吡咯烷酮；
DIBAL-H：二异丁基氢化铝；   DIEA：N，N-二异丙基乙胺；
THF：四氢呋喃；             Boc：叔丁氧基羰基；
NBS：N-溴琥珀酰亚胺；       Cbz-Cl：氯甲酸苄酯；
m-CPBA：间氯过氧苯甲酸；    TFA：三氟醋酸；
Et 2O：二乙基醚；             EtOH：乙醇；
Dioxane：1，4-二氧六环；     TLC：薄层色谱；
HATU：O-(7-氮杂苯并三唑-1-基)-N，N，N’，N’-四甲基脲六氟磷酸盐；
Me：甲基；                   DCM：二氯甲烷；
EA：乙酸乙酯；              DDQ：2,3-二氯-5,6-二氰-1,4-苯醌；
XPhos：2-双环己基膦-2',4',6'-三异丙基联苯；
PE：石油醚；           MTBE：甲基叔丁基醚；
ACN：乙腈。
(2-溴甲基-3-氟烯丙基)氨基甲酸叔丁酯(Int-1)的制备
Figure PCTCN2018083792-appb-000023
第一步：羟甲基三苯基四氟硼酸鏻(1)的制备。
将多聚甲醛(30g,1.00mol)和三苯基磷(250g,0.95mol)置于反应瓶中，加入乙醚(2L)。向搅拌的反应器中缓慢加入氟硼酸水溶液(525g,2.38mol)。室温反应5天。将反应液里的乙醚浓缩后过滤得到固体。固体经乙醚(500mL)、水(500mL)和乙醚(500mL)依次洗涤。固体经过干燥箱烘干(50℃)过夜得到产品羟甲基三苯基四氟硼酸鏻(240g,67％)。
第二步：氟甲基三苯基四氟硼酸鏻(2)的制备。
将化合物1(150g,0.396mol)溶于二氯甲烷(1.5L)，冷却至0℃。向反应体系中缓慢滴加DAST(191g,1.187mol)。滴加完后升至室温反应过夜。将反应液加入到冰水中淬灭。二氯甲烷萃取，合并有机相。有机相分别用水(500mL)和饱和食盐水(500mL)各洗一次，无水硫酸钠干燥浓缩。粗品用二氯甲烷(350mL)加热溶解后往搅拌的石油醚缓慢滴加。过程中伴有固体析出。将固体过滤后烘箱干燥(50℃)过夜得到产 品氟甲基三苯基四氟硼酸鏻(110g,73％)。
第三步：(2,3-二羟基丙基)氨基甲酸叔丁酯(3)的制备
将3-氨基-1,2丙二醇(10g,110mmol)加入无水甲醇(200mL)中，搅拌下加入三乙胺(23mL,170mL)和(Boc) 2O(26.4g,120mmol)，室温下搅拌过夜。浓缩反应液，加水、乙酸乙酯萃取2次，有机相干燥浓缩，得到黄色油状液体(12.7g,4％)。
第四步：(3-叔丁基二甲基硅氧基-2-羟基丙基)氨基甲酸叔丁酯(4)的制备
将化合物3(12.7g,66.5mmol)溶于二氯甲烷(100mL)中，加入三乙胺(11.6mL,113.0mmol)和咪唑(410mg,6.0mmol)，冰浴下搅拌加入TBSCl(11g,72.0mmol)，缓慢升温至室温反应过夜。加二氯甲烷、饱和食盐水萃取2次，有机相干燥浓缩得到淡黄色油状液体，柱层析分离提纯，得到化合物4(15g,75％)。
第五步：(3-叔丁基二甲基硅氧基-2-氧代丙基)氨基甲酸叔丁酯(5)的制备
将化合物4(120g,400mmol)溶于二氯甲烷(1L)中，冰浴下加入Des-Martin氧化剂(250g,600mmol)、NaHCO 3(100g,1190mmol)，升至室温反应过夜。抽滤反应液，母液加饱和Na 2SO 3、二氯甲烷萃取4次，得到有机相，干燥浓缩，柱层析分离得到无色油状液体(50g,42％)。
第六步：(2-(叔丁基二甲基硅氧基甲基)-3-氟烯丙基)氨基甲酸叔丁酯(6)的制备。
将化合物2(158g,0.416mol)溶于THF(200mL)，降温至-20℃。在氮气保护下将NaHMDS(208mL,0.417mol,2N in THF)于30min内缓慢滴加到反应液中。-20℃反应30分钟后将化合物5(42g,0.139mol)溶解在THF(100mL)中缓慢滴加到反应液中。移去冷浴，自然升至室温后反应2小时。待反应完全后，将反应液加入到冰水中淬灭。低温浓缩掉有机溶剂，乙酸乙酯萃取，合并有机相。有机相依次用水，饱和食盐水洗一次，无水硫酸钠干燥浓缩。粗品经硅胶柱层析纯化(石油醚：乙酸乙酯＝97：3)得到产品(2-(叔丁基二甲基硅氧基甲基)-3-氟烯丙基)氨基甲酸叔丁酯(18g,41％)。
第七步：(3-氟-2-羟甲基烯丙基)氨基甲酸叔丁酯(7)的制备。
将化合物6(18.0g,56.4mmol)溶于THF(200mL)，加入TBAF(21.4g,67.7mmol)，室温反应3小时。待反应完全后加水淬灭，乙酸乙酯萃取、合并有机相。有机相经饱和食盐水洗一遍，硫酸镁干燥浓缩。粗品直接用于下一步反应。
第八步：(2-溴甲基-3-氟烯丙基)氨基甲酸叔丁酯(Int-1)的制备。
将化合物7(56.4mmol)和三乙胺(19.3g,169.3mmol)溶于丙酮(200mL)中。降温至0℃，缓慢滴加甲烷磺酰氯(7.7g,67.7mmol)(析出大量固体)，滴加完毕后室温反应2小时。待反应完全后，过滤，向滤液中加入溴化锂(24.5g,282.0mmol)。 室温反应过夜，反应完全后，将固体过滤。滤液浓缩，加水和乙酸乙酯分层后萃取水相，合并有机相。有机相经水和饱和食盐水洗涤后无水硫酸钠干燥浓缩。将粗品经硅胶柱层析纯化(石油醚：乙酸乙酯＝97:3)得到目标产品(2-溴甲基-3-氟烯丙基)氨基甲酸叔丁酯(6.0g,40％)。
实施例1:4-((2-(氨甲基)-3-氟烯丙基)氧基)-N-(萘基)苯甲酰胺三氟乙酸盐(TM8)的制备
Figure PCTCN2018083792-appb-000024
第一步：N-萘基-4-羟基苯甲酰胺(1-1)的制备
将对羟基苯甲酸(200mg,1.45mmol)溶于DMF(10mL)中，在冰浴下依次加入HOBT(294mg,2.17mmol)、DIEA(374mg,2.90mmol)和EDCI(417mg,2.17mmol)，搅拌30分钟。然后加入2-萘胺(248mg,1.74mmol)，升至室温搅拌过夜。反应液用水淬灭，乙酸乙酯萃取，合并有机相。有机相用饱和食盐水溶液洗涤2次，无水硫酸镁干燥，过滤浓缩后的粗产品经柱层析纯化得到白色固体(240mg,65％)。
MS m/z(ESI):264[M+H] +
第二步：(2-(4-(萘基-2-氨甲酰基)苯氧基)甲基-3-氟烯丙基)氨基甲酸叔丁酯(1-2)的制备
将化合物1-1(240mg,0.91mmol)溶于DMF(10mL)，加入Int-1(293mg,1.09mmol)和碳酸钾(450mg,3.27mmol)，室温搅拌过夜后加水淬灭，乙酸乙酯萃取，合并有机相。有机相用饱和食盐水溶液洗涤3次，硫酸镁干燥，过滤浓缩，经制备TLC纯化得到目标产物(206mg,50％)。
MS m/z(ESI):451[M+H] +
第三步：N-萘基-4-(2-氨甲基-3-氟烯丙基氧基)-苯甲酰胺三氟乙酸盐(TM8)的制备
将化合物1-2(206mg,0.5mmol)溶于二氯甲烷(6mL)中，加入TFA(2mL)，室温并搅拌30min。LC-MS监测反应完毕后在真空下浓缩，然后冷冻干燥得到目标产物 TM8(60mg,39％)。
MS m/z(ESI):351[M+H] +
1HNMR(400MHz,DMSO-d 6)δ:10.31(s,1H),8.44(s,1H),8.07-7.99(m,4H),7.89-7.82(m,4H),7.49-7.42(m,2H),7.18-7.14(m,2H),4.82(s,2H),4.70(d,J＝2.8Hz,2H),3.66(s,2H),3.58(d,J＝2.0Hz,2H).
根据一般地经验分析推测，其中的化学位移4.82，3.58可以是Z构型的特征峰，4.70,3.66可以是E构型的特征峰。
实施例2:N-甲基-N-对甲基苯基-4-((2-氨甲基-3-氟烯丙基)氧基)-苯甲酰胺三氟乙酸盐(TM67)的制备
Figure PCTCN2018083792-appb-000025
除在本实施例的第一步中以N-甲基-对甲基苯胺代替实施例1中第一步的2-萘胺，采用与实施例1所描述类似的方法制备标题化合物，总收率19％。
MS m/z(ESI):329[M+H] +
1HNMR(400MHz,DMSO-d 6)δ:7.97(s,2H),7.38-7.18(m,3H),7.09-7.01(m,4H),6.84-6.82(m,2H),4.64(d,J＝2.0Hz,2H),4.52(d,J＝3.6Hz,2H),3.57(d,J＝7.6Hz,2H),3.51(s,2H),3.32(s,3H),2.23(s,3H)。
根据一般经验分析推测，其中的化学位移4.64，3.51可以是Z构型的特征峰，4.52,3.57可以是E构型的特征峰。
实施例3:N-(4-氟苯基)-4-((2-氨甲基-3-氟烯丙基)氧基)-苯甲酰胺三氟乙酸盐(TM61)的制备
Figure PCTCN2018083792-appb-000026
第一步：4-(2-(叔丁氧羰基氨基甲基)-3-氟烯丙基氧基)苯甲酸甲酯(3-1)的制备
除在本步中以对羟基苯甲酸甲酯代替实施例1中第二步的中间体1-1，采用与实施例1中的第二步所描述类似的方法制备标题化合物。所得粗品直接用于下一步。
MS m/z(ESI):340[M+H] +
第二步：4-(2-(叔丁氧羰基氨基甲基)-3-氟烯丙基氧基)苯甲酸(3-2)的制备
将化合物3-1(2.71g,7.99mmol)溶于四氢呋喃(18mL)和水(9mL)中，加氢氧化锂(2.02g,48.08mmol)，于45℃反应过夜。加稀盐酸水溶液至pH＝2-3，乙酸乙酯萃取两次，饱和食盐水洗，无水硫酸钠干燥，真空下浓缩，得产品(1.78g,69％)。
MS m/z(ESI):326[M+H] +
第三步：(2-(4-(4-氟苯基氨基甲酰基)苯氧基)甲基-3-氟烯丙基)氨基甲酸叔丁酯(3-3)的制备
将化合物3-2(150mg,0.44mmol)溶于DMF(4mL)中，加入DIEA(114mg,0.88mmol)和HATU(252mg,0.66mmol)，在氮气保护和冰浴下搅拌半小时。然后，在相同温度下加入对氟苯胺(49mg,0.44mmol)。15分钟后撤去冰浴，在室温下反应2小时。反应结束后，加饱和碳酸氢钠淬灭，乙酸乙酯萃取两次。收集有机相，用饱和食盐水洗两次，无水硫酸钠干燥，真空下浓缩，制备TLC纯化，得产品(168mg,87％)。
MS m/z(ESI):419[M+H] +
第四步：N-(4-氟苯基)-4-((2-氨甲基-3-氟烯丙基)氧基)-苯甲酰胺三氟乙酸盐(TM61)的制备
除在本步中以中间体3-3代替实施例1中第三步的中间体1-2，采用与实施例1中的第三步所描述类似的方法制备标题化合物，收率约100％。
MS m/z(ESI):319[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.97-7.94(m,2H),7.68-7.65(m,2H),7.35-7.02(m, 5H),4.89(d,J＝2.4Hz,2H),4.69(d,J＝3.2Hz,2H),3.83(d,J＝2.0Hz,2H),3.71(d,J＝2.4Hz,2H,)。
根据一般经验分析推测，其中化学位移4.89，3.71可以是Z构型的特征峰，4.69,3.83可以是E构型的特征峰。
实施例4:(4-(2-氨甲基-3-氟烯丙基氧基)苯基)-(6-三氟甲基-3,4-二氢异喹啉-2(1H)-基)-甲酮三氟乙酸盐(TM68)的制备
Figure PCTCN2018083792-appb-000027
除在本实施例的第一步中以1,2,3,4-四氢-6-三氟甲基异喹啉代替实施例3中第三步的对氟苯胺，采用与实施例3中的第三和第四步所描述类似的方法制备标题化合物，总收率16％。
MS m/z(ESI):409[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.76-7.47(m,4H),7.40-6.92(m,4H),5.06-4.67(m,2H),4.87(d,J＝2.4Hz,2H),4.67(d,J＝3.2Hz,2H),3.83(d,J＝1.6Hz,2H),3.83-3.70(m,2H),3.70(d,J＝2.4Hz,2H),3.01(s,2H).
根据一般经验推测，其中化学位移4.87，3.70可以是Z构型的特征峰，4.67,3.83可以是E构型的特征峰。
实施例5:N-(3-二甲氨基苯基)-4-(2-氨甲基-3-氟烯丙基氧基)-苯甲酰胺三氟乙酸盐(TM62)的制备
Figure PCTCN2018083792-appb-000028
除在本实施例的第一步中以N,N-二甲基间苯二胺代替实施例3中第三步的对氟苯胺，采用与实施例3中的第三和第四步所描述类似的方法制备标题化合物，总收率49％。
MS m/z(ESI):344[M+H] +
1HNMR(400MHz,CD 3OD)δ:8.04-7.96(m,3H),7.54-7.45(m,2H),7.36-7.00(m,4H),4.90(d,J＝2.4Hz,2H),4.70(d,J＝3.2Hz,2H),3.84(d,J＝1.6Hz,2H),3.71(d,J＝ 1.6Hz,2H),3.23(s,6H)。
根据一般经验推测，其中化学位移4.90，3.71可以是Z构型的特征峰，4.70,3.84可以是E构型的特征峰。
实施例6:(S)-(4-(2-氨甲基)-3-氟烯丙基氧基)苯基)-(1-苯基-3,4-二氢异喹啉-2(1H)-基)-甲酮三氟乙酸盐(TM69)的制备
Figure PCTCN2018083792-appb-000029
除在本实施例的第一步中以(S)-1-苯基-1,2,3,4-四氢异喹啉代替实施例3中第三步的对氟苯胺，采用与实施例3中的第三和第四步所描述类似的方法制备标题化合物，总收率52％。
MS m/z(ESI):417[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.38(dd,J＝8.8Hz,2.4Hz,2H),7.33-7.20(m,8H),7.13-7.00(m,4H),4.86(d,J＝2.8Hz,2H),4.65(d,J＝3.2Hz,2H),3.82(d,J＝1.2Hz,2H),3.75(br,1H),3.69(d,J＝2.4Hz,2H),3.40(m,1H),3.08-3.00(m,1H),2.85-2.76(m,1H)。
根据一般经验分析推测，其中化学位移4.86，3.69可以是Z构型的特征峰，4.65，3.82可以是E构型的特征峰。
实施例7:2-(4-(4-甲基噻唑-2-苯氧基)甲基)-3-氟烯丙基胺三氟乙酸盐(TM70)的制备
Figure PCTCN2018083792-appb-000030
第一步：(3-氟-2-(4-频哪醇硼酸酯基苯氧基甲基)烯丙基)氨基甲酸叔丁酯(7-1)的制备
除在本步中以4-羟基苯硼酸频哪醇酯代替实施例中第二步的中间体1-1，采用与实施例1中的第二步所描述类似的方法制备标题化合物。收率83％。
MS m/z(ESI):408[M+H] +
第二步：(3-氟-2-(4-(4-甲基噻唑-2-苯氧基)甲基)烯丙基)氨基甲酸叔丁酯(7-2)的制备
将化合物7-1(100mg,0.25mmol)溶于1,4-二氧六环(3mL)中，加入2-溴-4-甲基噻唑(52mg,0.30mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(20mg,0.03mmol)和1mmol/L的碳酸钾水溶液(1.3mL)，在氮气保护下于90℃反应过夜。反应完成后，加水淬灭，水相加乙酸乙酯萃取两次，收集有机相，有机相加饱和食盐水洗，无水硫酸钠干燥，真空下浓缩，制备TLC纯化，得到目标产品(62mg,67％)。
MS m/z(ESI):379[M+H] +
第三步：2-(4-(4-甲基噻唑-2-苯氧基)甲基)-3-氟烯丙基胺三氟乙酸盐(TM70)的制备
除在本步中以中间体7-2代替实施例1中第三步的中间体1-2，采用与实施例1中的第三步所描述类似的方法制备标题化合物。收率约100％。
MS m/z(ESI):279[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.89(dd,J＝8.8Hz,2.4Hz,2H),7.24(d,J＝81.2Hz,1H),7.12(d,J＝80.8Hz,1H),7.14-7.11(m,3H),4.88(d,J＝2.4Hz,2H),4.68(d,J＝3.2Hz,2H),3.84(d,J＝2.6Hz,2H),3.70(d,J＝2.0Hz,2H),2.47(s,3H).
根据一般经验分析推测，其中化学位移7.12,4.88，3.70可以是Z构型的特征峰，7.24，4.68，3.84可以是E构型的特征峰。
实施例8:(4-(2-氨甲基-3-氟烯丙基氧基)苯基)-(5-氯异吲哚啉-2-基)-甲酮三氟乙酸盐(TM71)的制备
Figure PCTCN2018083792-appb-000031
第一步：1,2-二(溴甲基)-4-氯苯(8-1)的制备
将化合物4-氯-1,2-二甲基苯(0.2mL,1.5mmol)溶于乙腈(26mL)中，加入NBS(0.55g,3.0mmol)和AIBN(0.14g,0.8mmol)，75℃反应2小时。加水淬灭，乙酸乙酯萃取两次。有机相用饱和食盐水洗涤，无水硫酸钠干燥，真空下浓缩，柱层析，得目标产物(0.20g,47％)。
第二步：5-氯-2-对甲苯磺酰基异吲哚啉(8-2)的制备
氢化钠(1.60g,40.00mmol)溶于DMF(20mL)中，滴加4-甲基苯磺酰胺(2.64g,15.40mmol)的DMF(10mL)溶液，90℃反应2小时。滴加化合物8-1(2.00g,6.76mmol)的DMF(10mL)溶液，90℃反应4小时。将反应液倒入冰水中，搅拌后抽滤，滤饼加稀盐酸洗，乙酸乙酯溶解，再加5％碳酸钠溶液洗涤。收集有机相，用饱和食盐水洗涤，无水硫酸钠干燥，真空下浓缩，得目标产物(1.40g,68％)。
MS m/z(ESI):308[M+H] +
第三步：5-氯异吲哚啉(8-3)的制备
将化合物8-2(1g,3.26mmol)，苯酚(1g,10.60mmol)，氢溴酸(8mL)和异丙醇(1.4mL)在126℃反应4小时。加水淬灭，乙酸乙酯萃取三次，水相加稀氢氧化钠水溶液至pH＝8-9，乙酸乙酯萃取两次。合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，真空下浓缩。粗品加HCl/1,4-二氧六环溶液，搅拌后真空下浓缩，得目标产物(489mg,98％)。
MS m/z(ESI):155[M+H] +
第四步：4-(5-氯异吲哚啉-2-羰基)苯基-4-羟基苯甲酸酯(8-4)的制备
将对羟基苯甲酸(270mg,1.95mmol)溶于DMF(6mL)中，冰浴下依次加入DIEA(503mg,3.90mmol)和HATU(1.11g,2.93mmol)，氮气保护反应1小时。然后加入化合物8-3(300mg,1.95mmol)的DMF(2mL)溶液，在氮气保护下冰浴反应15分 钟后，升至室温反应过夜。反应完毕后，加入碳酸氢钠水溶液淬灭，乙酸乙酯萃取水相，合并有机相。有机相水洗后干燥，浓缩得粗品400mg。
MS m/z(ESI):394[M+H] +
第五步：(5-氯异吲哚啉-2-基)-(4-羟苯基)甲酮(8-5)的制备
将化合物8-4(300mg,0.76mmol)溶于甲醇(8mL)中，加碳酸钾固体(300mg,2.17mmol)和水(2mL)，室温反应4小时。反应完毕后，加水稀释，用稀盐酸调至pH＝3-4。水溶液用二氯甲烷萃取两次，有机相依次用用水和饱和食盐水洗涤，无水硫酸钠干燥，浓缩后用制备TLC纯化，得目标产物(94mg,45％)。
MS m/z(ESI):274[M+H] +
第六步：(2-(4-(5-氯异吲哚啉-2-羰基)苯氧基甲基)-3-氟烯丙基)氨基甲酸叔丁酯(8-6)的制备
除在本步中以中间体8-5代替实施例1中第二步的中间体1-1，采用与实施例1中的第二步所描述类似的方法制备标题化合物。收率90％。
MS m/z(ESI):461[M+H] +
第七步：(4-(2-氨甲基-3-氟烯丙基氧基)苯基)-(5-氯异吲哚啉-2-基)-甲酮三氟乙酸盐(TM71)的制备
除在本步中以中间体8-6代替实施例1中第三步的中间体1-2，采用与实施例1中的第三步所描述类似的方法制备标题化合物。收率72％。
MS m/z(ESI):361[M+H] +
1HNMR(400MHz,DMSO-d 6)δ:7.79(br,2H),7.62(d,J＝8.0Hz,2H),7.50-7.24(m,4H),7.11-7.06(m,2H),4.85-4.78(m,4H),4.80(s,2H)),4.65(d,J＝3.2Hz,2H),3.64(s,2H),3.55(s,2H)。
根据一般经验分析推测，其中化学位移4.80,3.55可以是Z构型的特征峰，4.65，3.64可以是E构型的特征峰。
实施例9:N-苯基-4-((2-氨甲基-3-氟烯丙基)氧基)-苯甲酰胺三氟乙酸盐(TM1)的制备及异构体拆分
Figure PCTCN2018083792-appb-000032
除在本实施例的第一步中以苯胺代替实施例1中第一步的2-萘胺，采用与实施例1所描述类似的方法制备标题化合物，总收率35％。
N-苯基-4-((2-氨甲基-3-氟烯丙基)氧基)-苯甲酰胺三氟乙酸盐异构体的拆分方法。
仪器：Agilent 1260，Sunfire C18；流动相：A：0.1％TFA，B：ACN；
洗脱梯度：0-8min：20％-30％B，流速16mL/min；8.1-10min：95％B，流速20mL/min；10.1-12min：20％B，流速20mL/min。
收集保留时间为5.6～6.7min区间内流出液并冻干得到TM1-E，收集保留时间为7.0～8.0min区间内流出液并冻干得到TM1-Z。
(Z)-N-苯基-4-((2-氨甲基-3-氟烯丙基)氧基)-苯甲酰胺三氟乙酸盐(TM1-Z)。
MS m/z(ESI):301[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.97(d,J＝8.8Hz,2H),7.66(dd,J＝7.6Hz,2H),7.37-7.33(m,2H),7.16-7.12(m,3H),7.12(d,J＝80.4Hz,1H),4.90(d,J＝2.0Hz,2H),3.71(d,J＝2.4Hz,2H).
(E)-N-苯基-4-((2-氨甲基-3-氟烯丙基)氧基)-苯甲酰胺三氟乙酸盐(TM1-E)。
MS m/z(ESI):301[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.97(d,J＝9.2Hz,2H),7.66(dd,J＝7.6Hz,2H),7.37-7.33(m,2H),7.33-7.11(m,4H),4.70(d,J＝2.8Hz,2H),3.84(d,J＝2.0Hz,2H).
实施例10：(S)-N-(1,2,3,4-四氢-1-萘基)-4-((2-氨甲基-3-氟烯丙基)氧基)-苯甲酰胺三氟乙酸盐(TM63)的制备及异构体拆分
Figure PCTCN2018083792-appb-000033
除在本实施例的第一步中以(S)-1,2,3,4-四氢-1-萘胺代替实施例1中第一步的2-萘胺，采用与实施例1所描述类似的方法制备标题化合物，总收率46％。
采用与实施例9所描述类似的方法拆分异构体，TM63-E的保留时间较TM63-Z保留时间短。
(Z)-(S)-N-(1,2,3,4-四氢-1-萘基)-4-((2-氨甲基-3-氟烯丙基)氧基)-苯甲酰胺三氟乙酸盐(TM63-Z)。
MS m/z(ESI):355[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.80(d,J＝8.8Hz,2H),7.30-7.23(m,4H),7.10(d,J＝8.8Hz,2H),7.05(d,J＝80.4Hz,1H),5.20(t,J＝5.6Hz,1H),4.92(d,J＝1.6Hz,2H),3.75(s,2H),2.89-2.72(m,2H),2.14-1.86(m,4H).
(E)-(S)-N-(1,2,3,4-四氢-1-萘基)-4-((2-氨甲基-3-氟烯丙基)氧基)-苯甲酰胺三氟乙酸盐(TM63-E)。
MS m/z(ESI):355[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.80(dd,J＝22.8Hz,8.8Hz,2H),7.30-7.23(m,4H),7.10-7.05(m,2H),5.20(t,J＝6.0Hz,1H),4.70(d,J＝3.2Hz,2H),3.90(s,2H),2.91-2.72(m,2H),2.14-1.84(m,4H).
实施例11:(4-((2-氨甲基-3-氟烯丙基)氧基)-3-氟苯基)-(4-苯基哌啶-1-基)甲酮三氟乙酸盐(TM48)的制备
Figure PCTCN2018083792-appb-000034
除在本实施例的第一步中以4-苯基哌啶代替实施例1中的2-萘胺，采用与实施例1所描述类似的方法制备标题化合物，总收率57％。
采用与实施例9所描述类似的方法拆分异构体，TM48-E的保留时间较TM48-Z保留时间短。
(Z)-(4-((2-氨甲基-3-氟烯丙基)氧基)-3-氟苯基)-(4-苯基哌啶-1-基)甲酮三氟乙酸盐(TM48-Z)。
MS m/z(ESI):387[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.48-7.02(m,9H),4.93(d,J＝2.4Hz,2H),4.78-4.48(m,1H),3.91-3.82(m,1H),3.72(d,J＝2.0Hz,2H),3.29-3.23(m,1H),2.98-2.93(m,1H),2.87-2.83(m,1H),1.93-1.71(m,4H).
(E)-(4-((2-氨甲基-3-氟烯丙基)氧基)-3-氟苯基)-(4-苯基哌啶-1-基)甲酮三氟乙酸盐(TM48-E)。
MS m/z(ESI):387[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.34-7.14(m,9H),4.78-4.73(m,1H),4.73(d,J＝3.2Hz,2H),3.90-3.84(m,1H),3.84(s,2H),3.29-3.23(m,1H),2.98-2.93(m,1H),2.87-2.83(m,1H),1.93-1.71(m,4H).
实施例12:(4-((2-氨甲基-3-氟烯丙基)氧基)-3-氟苯基)-(3,4-四氢异喹啉-2(1H))甲酮三氟乙酸盐(TM72)的制备
Figure PCTCN2018083792-appb-000035
除在本实施例的第一步中以四氢异喹啉代替实施例1中第一步的2-萘胺，采用与实施例1所描述类似的方法制备标题化合物，总收率31％。
采用与实施例9所描述类似的方法拆分异构体，TM72-E的保留时间较TM72-Z保留时间短。
(Z)-(4-((2-氨甲基-3-氟烯丙基)氧基)-3-氟苯基)-(3,4-四氢异喹啉-2(1H))甲酮三氟乙酸盐(TM72-Z)。
MS m/z(ESI):359[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.41-6.94(m,8H),4.94(d,J＝2.4Hz,2H),4.85-4.75(m,1H),4.70-4.65(m,1H),3.95-3.93(m,1H),3.72(s,2H),3.72-3.70(m,1H),2.95-2.93(m,2H).
(E)-(4-((2-氨甲基-3-氟烯丙基)氧基)-3-氟苯基)-(3,4-四氢异喹啉-2(1H))甲酮三氟乙酸盐(TM72-E)。
MS m/z(ESI):359[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.39-6.94(m,8H),4.85-4.82(m,1H),4.75(d,J＝3.2Hz,2H),4.68-4.65(m,1H),3.95-3.93(m,1H),3.84(s,2H),3.72-3.69(m,1H),2.99-2.93(m,2H).
实施例13:(4-((2-氨甲基-3-氟烯丙基)氧基)-3-氟苯基)-(5-氯-3,4-二氢异喹啉-2(1H))甲酮三氟乙酸盐(TM73)的制备
Figure PCTCN2018083792-appb-000036
除在本实施例的第一步中以5-氯四氢异喹啉代替实施例1中第一步的2-萘胺，采用与实施例1所描述类似的方法制备标题化合物，总收率32％。
采用与实施例9所描述类似的方法拆分异构体，TM73-E的保留时间较TM73-Z保留时间短。
(Z)-(4-((2-氨甲基-3-氟烯丙基)氧基)-3-氟苯基)-(5-氯-3,4-二氢异喹啉-2(1H))甲酮三氟乙酸盐(TM73-Z)。
MS m/z(ESI):393[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.35-7.20(m,6H),7.13(d,J＝80.0Hz,1H),4.95(d,J＝2.4Hz,2H),4.81-4.64(m,2H),4.13-3.79(m,2H),3.73(d,J＝2.0Hz,2H),3.00-2.92(m,2H).
(E)-(4-((2-氨甲基-3-氟烯丙基)氧基)-3-氟苯基)-(5-氯-3,4-二氢异喹啉-2(1H))甲酮三氟乙酸盐(TM73-E)。
MS m/z(ESI):393[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.44-7.15(m,7H),4.75(d,J＝3.2Hz,2H),4.85-4.62(m,2H),4.11-3.65(m,2H),3.85(s,2H),3.01-2.89(m,2H).
实施例14:N-(4-氟苯基)-4-((2-氨甲基-3-氟烯丙基)氧基)-3-氯-苯甲酰胺三氟乙酸盐(TM65)的制备
Figure PCTCN2018083792-appb-000037
除在本实施例的第一步中以对氟苯胺代替实施例1中第一步的2-萘胺和以3-氯-4-羟基苯甲酸代替实施例1中第一步的对羟基苯甲酸，采用与实施例1所描述类似的方法制备标题化合物，总收率8％。
采用与实施例9所描述类似的方法拆分异构体，TM65-E的保留时间较TM65-Z保留时间短。
(Z)-N-(4-氟苯基)-4-((2-氨甲基-3-氟烯丙基)氧基)-3-氯-苯甲酰胺三氟乙酸盐(TM65-Z)。
MS m/z(ESI):353[M+H] +
1HNMR(400MHz,CD 3OD)δ:8.06(d,J＝2.4Hz,1H),7.95(dd,J＝8.4Hz,2.0Hz,1H),7.68-7.65(m,2H),7.30(d,J＝8.4Hz,1H),7.15(d,J＝80.8Hz,1H),7.10(t,J＝8.8Hz,2H),4.99(d,J＝2.4Hz,2H),3.76(d,J＝2.4Hz,2H).
(E)-N-(4-氟苯基)-4-((2-氨甲基-3-氟烯丙基)氧基)-3-氯-苯甲酰胺三氟乙酸盐(TM65-E)。
MS m/z(ESI):353[M+H] +
1HNMR(400MHz,CD 3OD)δ:8.06(d,J＝2.4Hz,1H),7.94(dd,J＝8.4Hz,2.0Hz,1H),7.68-7.65(m,2H),7.28(d,J＝80.8Hz,1H),7.27(d,J＝8.4Hz,1H),7.10(t,J＝8.8Hz,2H),4.78(d,J＝3.2Hz,2H),3.88(d,J＝3.2Hz,2H).
实施例15:(4-((2-氨甲基-3-氟烯丙基)氧基)苯基)-(3,4-二氢异喹啉-2(1H)-基)甲酮三氟乙酸盐(TM45)的制备
Figure PCTCN2018083792-appb-000038
除在本实施例的第一步中以四氢异喹啉代替实施例3中第三步的对氟苯胺，采用与实施例3中的第三和第四步所描述类似的方法制备标题化合物，总收率81％。
采用与实施例9所描述类似的方法拆分异构体，TM45-E的保留时间较TM45-Z保留时间短。
(Z)-(4-((2-氨甲基-3-氟烯丙基)氧基)苯基)-(3,4-二氢异喹啉-2(1H)-基)甲酮三氟乙酸盐(TM45Z)。
MS m/z(ESI):341[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.47(d,J＝8.4Hz,2H),7.21-7.11(m,6H),7.11(d,J＝80.8Hz,1H,1H),4.89(d,J＝2.4Hz,2H),4.83-4.67(m,2H),3.94-3.70(m,2H),3.70(d,J＝2.0Hz,2H),2.93(s,2H).
(E)-(4-((2-氨甲基-3-氟烯丙基)氧基)苯基)-(3,4-二氢异喹啉-2(1H)-基)甲酮三氟乙酸盐(TM45-E)。
MS m/z(ESI):341[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.46(d,J＝8.8Hz,2H),7.24(d,J＝81.2Hz,1H),7.19-6.92(m,6H),4.82-4.67(m,2H),4.67(d,J＝2.8Hz,2H),3.94(br,1H),3.83(s,2H),3.70(br,1H),2.92(s,2H).
实施例16:(4-((2-氨甲基-3-氟烯丙基)氧基)苯基)-(4-苯基哌啶-1-基)甲酮三氟乙酸盐(TM44)的制备。
Figure PCTCN2018083792-appb-000039
除在本实施例的第一步中以4-苯基哌啶代替实施例3中第三步的对氟苯胺，采用与实施例3的第三和第四步所描述类似的方法制备标题化合物，总收率42％。
采用与实施例9所描述类似的方法拆分异构体，TM44-E的保留时间较TM44-Z保留时间短。
(Z)-(4-((2-氨甲基-3-氟烯丙基)氧基)苯基)-(4-苯基哌啶-1-基)甲酮三氟乙酸盐(TM44-Z)
MS m/z(ESI):369[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.46(d,J＝8.8Hz,2H),7.22-7.00(m,8H),4.84(d,J＝2.4Hz,2H),4.81-4.56(m,1H),4.01-3.83(m,1H),3.69(d,J＝2.4Hz,2H),3.23-2.82(m,3H),2.10-1.54(m,4H).
(E)-(4-((2-氨甲基-3-氟烯丙基)氧基)苯基)-(4-苯基哌啶-1-基)甲酮三氟乙酸盐(TM44-E)
MS m/z(ESI):369[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.45(d,J＝8.4Hz,2H),7.34-7.24(m,6H),7.09(d,J＝8.8Hz,2H),4.84-4.70(m,1H),4.66(d,J＝3.2Hz,2H),4.01-3.86(m,1H),3.82(d,J＝2.0Hz,2H),3.27-2.93(m,2H),2.90-2.82(m,1H),2.04-1.55(m,4H).
实施例17：2-(4-(2-嘧啶基)苯氧基甲基)-3-氟烯丙基胺三氟乙酸盐(TM39)的制备
Figure PCTCN2018083792-appb-000040
第一步：4-(2-嘧啶基)苯酚(17-1)的制备。
将2-氯嘧啶(1.0g,8.77mmol)，4-羟基苯硼酸(2.3g,10.53mmol)，饱和碳酸氢钠水溶液(2mL)和二氧六环(8mL)置于反应瓶中，用氮气鼓泡5分钟，加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(320mg,0.44mmol)，继续用氮气鼓泡3分钟，然后升温至100℃搅拌8小时。加入水乙酸乙酯萃取，合并有机相。有机相经水、饱和食盐水洗涤。无水硫酸钠干燥后浓缩得到粗产品。粗产品经硅胶柱层析纯化得到产品(150mg,9％)。
MS m/z(ESI):173[M+H] +
第二步：2-(4-(2-嘧啶基)苯氧基甲基)-3-氟烯丙基胺(17-2)的制备。
将化合物17-1(110mg,0.636mmol)、化合物Int-1(204mg,0.763mmol)和碳酸钾(132mg,0.954mmol)溶于DMF(10mL)中，室温反应过夜。反应液加水和乙酸乙酯萃取，合并有机相。有机相经水，饱和食盐水洗涤。无水硫酸钠干燥后浓缩。粗品经TLC板纯化得到产品(100mg,37％)。
第三步：2-(4-(2-嘧啶基)苯氧基甲基)-3-氟烯丙胺三氟乙酸盐(TM39)的制备。
除在本步中以中间体17-2代替实施例1中第三步的中间体1-2，采用与实施例1中的第三步所描述类似的方法制备标题化合物，收率约100％。
2-(4-(2-嘧啶基)苯氧基甲基)-3-氟烯丙胺三氟乙酸盐异构体的拆分方法。
仪器：Agilent 1260，Sunfire C18,OBD TM 5μm，19*150mm column；流动相：A：0.1％TFA，B：ACN；
洗脱梯度：流速16mL/min；0-9.6min：10％-28％B，9.7-12min：95％B；12.1-15min：10％B。
收集保留时间为6.8～7.7min区间内流出液并冻干得到TM39-E，收集保留时间为8.2～8.8min区间内流出液并冻干得到TM39-Z。
(Z)-2-(4-(2-嘧啶基)苯氧基甲基)-3-氟烯丙胺三氟乙酸盐(TM39-Z)
MS m/z(ESI):260[M+H] +
1HNMR(400MHz,CD 3OD)δ:8.80(d,J＝4.8Hz,2H),8.37(d,J＝8.8Hz,2H),7.31(t,J＝4.8Hz,1H),7.14(d,J＝7.2Hz,2H),7.12(d,J＝80.8Hz,1H),4.90(d,J＝2.4Hz,2H),3.71(d,J＝2.0Hz,2H).
(E)-2-(4-(2-嘧啶基)苯氧基甲基)-3-氟烯丙胺三氟乙酸盐(TM39-E)
MS m/z(ESI):260[M+H] +
1HNMR(400MHz,CD 3OD)δ:8.80(d,J＝4.8Hz,2H),8.37(d,J＝8.8Hz,2H),7.31(t,J＝4.8Hz,1H),7.24(d,J＝81.2Hz,1H),7.14-7.11(m,2H),4.70(d,J＝3.2Hz,2H),3.85(d,J＝1.2Hz,2H).
实施例18:2-(4-(1H-苯并咪唑-2-基)苯氧基甲基)-3-氟烯丙基胺三氟乙酸盐(TM42)的制备
Figure PCTCN2018083792-appb-000041
第一步：4-(1H-苯并咪唑-2-基)苯酚(18-1)的制备
将化合物邻二苯胺(300mg,2.78mmol)和对羟基苯甲醛(430mg,3.52mmol)溶于DMF(10mL)中，滴加冰乙酸(20滴)，145℃回流反应5小时，加水淬灭，用乙酸乙酯萃取，合并有机相。有机相加入饱和食盐水后析出黄色固体，过滤干燥得目标产物(220mg,38％)。
MS m/z(ESI):211[M+H] +
第二步：2-(4-(1H-苯并咪唑-2-基)苯氧基甲基)-3-氟烯丙基氨基甲酸叔丁酯(18-2)的制备
除在本步中以中间体18-1代替实施例1中第二步的中间体1-1，采用与实施例1中的第二步所描述类似的方法制备标题化合物。粗品直接投下一步。
MS m/z(ESI):398[M+H] +
第三步：2-(4-(1H-苯并咪唑-2-基)苯氧基甲基)-3-氟烯丙基胺三氟乙酸盐(TM42)的制备
除在本步中以中间体18-2代替实施例1中第三步的中间体1-2，采用与实施例1中的第三步所描述类似的方法制备标题化合物，收率90％。
2-(4-(1H-苯并咪唑-2-基)苯氧基甲基)-3-氟烯丙基胺三氟乙酸盐异构体的拆分方法。
采用类似实施例9中的分离方式，洗脱梯度：0-6min：10％-28.7％B，流速16mL/min；6.1-9min：95％B，流速16mL/min；9.1-12min：10％B，流速16mL/min。收集保留时间为5.1～5.3min区间内流出液并冻干得到TM42-E，收集保留时间为5.5～5.7min区间内流出液并冻干得到TM42-Z。
(Z)-2-(4-(1H-苯并咪唑-2-基)苯氧基甲基)-3-氟烯丙基胺三氟乙酸盐(TM42-Z)
MS m/z(ESI):298[M+H] +
1HNMR(400MHz,CD 3OD)δ:8.12(d,J＝8.8Hz,2H),7.77-7.75(m,2H),7.55-7.54(m,2H),7.34(d,J＝9.2Hz,2H),7.16(d,J＝80.4Hz,1H),4.96(d,J＝2.0Hz,2H),3.73(d,J＝2.0Hz,2H).
(E)-2-(4-(1H-苯并咪唑-2-基)苯氧基甲基)-3-氟烯丙基胺三氟乙酸盐(TM20-E)
MS m/z(ESI):298[M+H] +
1HNMR(400MHz,CD 3OD)δ:8.13(d,J＝8.0Hz,2H),7.79-7.77(m,2H),7.59-7.57(m,2H),7.34(d,J＝8.8Hz,2H),7.29(d,J＝80.8Hz,1H),4.77(d,J＝3.2Hz,2H),3.86(d,J＝2.0Hz,2H).
实施例19:2-(4-(6-氯-苯并噻唑-2-基)苯氧基甲基)-3氟烯丙基胺三氟乙酸盐(TM41)的制备
Figure PCTCN2018083792-appb-000042
第一步：双(2-氨基-5-氯苯基)二硫醚(19-1)的制备
将2-氨基-6-氯-苯并噻唑(2g,5.4mmol)溶于水(50mL)中，加入氢氧化钾(10g,89mmol)，100℃回流反应5小时。反应完成后，将反应液降至室温，加4N HCl调至pH＝6-7，加水搅拌1小时后，抽滤得到黄色固体，用乙醇/水重结晶后得到黄色固体(710mg,32％)。
第二步：4-(6-氯-苯并噻唑-2-基)-苯酚(19-2)的制备
将化合物19-1(710mg,2.3mmol)、对羟基苯甲醛(280mg,4.6mmol)、三苯基磷(600mg,2.3mmol)和对甲基苯磺酸(90mg,0.46mmol)混合溶于甲苯(100mL)中，搅拌加热至回流，反应24小时。反应完毕后，冷却反应液至室温，浓缩反应液，加二氯甲烷溶解，不溶解部分抽滤，母液浓缩，制备板分离提纯，得到白色固体(120mg,27％)。
MS m/z(ESI):262[M+H] +
第三步：2-(4-(6-氯-苯并噻唑-2-基)苯氧基甲基)-3-氟烯丙基氨基甲酸叔丁酯(19-3)的制备
除在本步中以中间体19-2代替实施例1中第二步的中间体1-1，采用与实施例1中的第二步所描述类似的方法制备标题化合物，收率32％。
MS m/z(ESI):449[M+H] +
第四步：2-(4-(6-氯-苯并噻唑-2-基)苯氧基甲基)-3氟烯丙基胺三氟乙酸盐(TM41)的制备
除在本步中以中间体19-3代替实施例1中第三步的中间体1-2，采用与实施例1中 的第三步所描述类似的方法制备标题化合物，收率90％。
采用与实施例9所描述类似的方法拆分异构体，TM41-E的保留时间较TM41-Z保留时间短。
(Z)-2-(4-(6-氯-苯并噻唑-2-基)苯氧基甲基)-3氟烯丙基胺三氟乙酸盐(TM41-Z)。
MS m/z(ESI):349[M+H] +
1HNMR(400MHz,CD 3OD)δ:8.07(d,J＝8.8Hz,2H),8.03(d,J＝2.0Hz,1H),7.93(d,J＝8.4Hz,1H),7.51(dd,J＝8.8Hz,2.0Hz,1H),7.19(d,J＝9.2Hz,2H),7.12(d,J＝80.8Hz,1H),4.91(d,J＝2.4Hz,2H),3.71(d,J＝2.4Hz,2H).
(E)-2-(4-(6-氯-苯并噻唑-2-基)苯氧基甲基)-3氟烯丙基胺三氟乙酸盐(TM41-E)。
MS m/z(ESI):349[M+H] +
1HNMR(400MHz,CD 3OD)δ:8.06(d,J＝8.8Hz,2H),8.03(d,J＝2.0Hz,1H),7.93(d,J＝8.8Hz,1H),7.51(dd,J＝8.8Hz,2.0Hz,1H),7.27(d,1H),7.17(d,J＝8.8Hz,2H),4.71(d,J＝3.2Hz,2H),3.84(d,J＝2.0Hz,2H).
实施例20:2-(4-(6-氯-苯并噻唑-2-基)-2-氟苯氧基甲基)-3-氟烯丙基胺三氟乙酸盐三氟乙酸盐(TM74)的制备
Figure PCTCN2018083792-appb-000043
除在本实施例的第二步中以3-氟-4-羟基苯甲醛代替实施例19中第二步的对羟基苯甲醛，采用与实施例19所描述类似的方法制备标题化合物，总收率9％。
采用与实施例9所描述类似的方法拆分异构体，TM74-E的保留时间较TM74-Z保留时间短。
(Z)-2-(4-(6-氯-苯并噻唑-2-基)-2-氟苯氧基甲基)-3-氟烯丙基胺三氟乙酸盐三氟乙酸 盐(TM74-Z)。
MS m/z(ESI):367[M+H] +
1HNMR(400MHz,CD 3OD)δ:8.05(d,J＝2.0Hz,1H),7.97-7.87(m,3H),7.52(dd,J＝8.8Hz,2.0Hz,1H),7.36(t,J＝8.4Hz,1H),7.15(d,J＝80.4Hz,1H),4.98(d,J＝2.4Hz,2H),3.74(d,J＝2.8Hz,2H).
(E)-2-(4-(6-氯-苯并噻唑-2-基)-2-氟苯氧基甲基)-3-氟烯丙基胺三氟乙酸盐三氟乙酸盐(TM74-E)。
MS m/z(ESI):367[M+H] +
1HNMR(400MHz,CD 3OD)δ:8.05(d,J＝2Hz,1H),7.97-7.87(m,3H),7.53(dd,J＝8.8Hz,2.0Hz,1H),7.34(t,J＝8.4Hz,1H),7.28(d,J＝80.8Hz,1H),4.79(d,J＝3.2Hz,2H),3.86(d,J＝2.0Hz,2H).
实施例21：5-((2-氨甲基-3-氟烯丙基)氧基)-2-(4-氯苄基)异吲哚啉-1-酮(TM33)的制备
Figure PCTCN2018083792-appb-000044
第一步：2-(4-氯苄基)-5-甲氧基异吲哚啉-1-酮(21-1)的制备。
将反应物2-溴甲基-4-甲氧基苯甲酸乙酯(500mg,1.93mmol)，对氯苄胺(272mg,1.93mmol)与三乙胺(585mg,5.79mmol)溶于甲苯(3mL)，密封110℃加热4小时。反应完后将反应液浓缩掉，加水乙酸乙酯萃取，合并有机相。有机相经过水、饱和食盐水洗，无水硫酸钠干燥，浓缩。粗品经硅胶柱层析纯化得到产品21-1(275mg,50％)。
第二步：2-(4-氯苄基)-5-羟基异吲哚啉-1-酮(21-2)的制备
将化合物21-1(150mg,0.52mmol)溶于二氯甲烷(20mL)中，在-78℃加入BBr 3(392mg,1.57mmol)，然后升至室温反应1小时。反应完毕后，将反应液加入到冰水中淬灭，用二氯甲烷萃取，合并有机相。有机相经水、饱和食盐水洗涤，无水硫酸钠干燥，浓缩。粗品经硅胶柱层析纯化得到产品21-2(110mg,96％)。
第三步：2-(2-(4-氯苄基)-1-氧代异吲哚啉-5-氧基甲基)-3-氟烯丙基氨基甲酸叔丁酯(21-3)的制备。
将化合物21-2(80mg,0.293mmol)，化合物Int-1(81mg,0.322mmol)与碳酸钾(61mg,0.439mmol)溶于DMF(10mL)。室温反应过夜。加水和乙酸乙酯萃取，合并有机相，有机相经水、饱和食盐水洗涤。无水硫酸钠干燥后浓缩得到粗产品。粗产品经过制备TLC纯化后得到产品21-3(80mg,48％)。
第四步：5-((2-氨甲基-3-氟烯丙基)氧基)-2-(4-氯苄基)异吲哚啉-1-酮(TM33)的制备
除在本步中以中间体21-3代替实施例1中第三步的中间体1-2，采用与实施例1第三步所描述类似的方法制备标题化合物，收率约100％。
采用与实施例9所描述类似的方法拆分异构体，TM33-E的保留时间较TM33-Z保留时间短。
(Z)-5-((2-氨甲基-3-氟烯丙基)氧基)-2-(4-氯苄基)异吲哚啉-1-酮(TM33-Z)
MS m/z(ESI):361[M+H] +
1HNMR(400MHz,DMSO-d 6)δ:8.08(br,2H),7.66(d,J＝8.4Hz,1H),7.41(d,J＝8.4Hz,2H),7.32-7.07(m,5H),4.78(d,J＝1.6Hz,2H),4.69(s,2H),4.32(s,2H),3.56(s,2H).
(E)-5-((2-氨甲基-3-氟烯丙基)氧基)-2-(4-氯苄基)异吲哚啉-1-酮(TM33-E)
MS m/z(ESI):361[M+H] +
1HNMR(400MHz,DMSO-d 6)δ:8.17(br,2H),7.66(d,J＝8.4Hz,1H),7.45-7.24(m,5H),7.18(d,J＝1.6Hz,1H),7.11(dd,J＝8.4Hz,2.0Hz,1H),4.69(s,2H),4.67(s,2H),4.32(s,2H),3.64(s,2H).
实施例22:6-((2-氨甲基-3-氟烯丙基)氧基)-3,4-二氢异喹啉-1(2H)-酮三氟乙酸盐(TM26)的制备
Figure PCTCN2018083792-appb-000045
第一步：6-羟基-3,4-二氢异喹啉-1(2H)-酮(22-1)的制备
将5-羟基-1-茚酮(300mg,2.03mmol)溶于三氟乙酸(10mL)中，缓慢加入叠氮钠(200mg,3.08mmol)，74℃回流反应5小时，然后加入水，真空下旋转蒸发除去大部分三氟乙酸。向剩余溶液中加入碳酸氢钠水溶液调至弱碱性，乙酸乙酯萃取，合并有机相。有机相用饱和食盐水洗，无水硫酸钠干燥，真空下浓缩，得目标产物(240mg,73％)。
MS m/z(ESI):164[M+H] +
第二步：(2-(1-氧代-1,2,3,4-四氢异喹啉-6-氧基甲基)-3-氟烯丙基)氨基甲酸叔丁酯(22-2)的制备
除在本步中以中间体22-1代替实施例1中第二步的中间体1-1，采用与实施例1中的第二步所描述类似的方法制备标题化合物，收率58％。
MS m/z(ESI):351[M+H] +
第三步：6-((2-氨甲基-3-氟烯丙基)氧基)-3,4-二氢异喹啉-1(2H)-酮三氟乙酸盐(TM26)的制备
除在本步中以中间体22-2代替实施例1中第三步的中间体1-2，采用与实施例1中的第三步所描述类似的方法制备标题化合物，收率90％。
采用与实施例9所描述类似的方法拆分异构体，TM26-E的保留时间较TM26-Z保留时间短。
(Z)-6-((2-氨甲基-3-氟烯丙基)氧基)-3,4-二氢异喹啉-1(2H)-酮三氟乙酸盐(TM26-Z)
MS m/z(ESI):251[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.89(dd,J＝8.8Hz,2.0Hz,1H),7.11(d,J＝80.8Hz,1H),6.98(dd,J＝8.4Hz,2.4Hz,1H),6.93(d,J＝2.4Hz,1H),4.87(d,J＝2.4Hz,2H),3.69(d,J＝2.4Hz,2H),3.48(t,J＝6.8Hz,2H),2.97(t,J＝6.8Hz,2H).
(E)-6-((2-氨甲基-3-氟烯丙基)氧基)-3,4-二氢异喹啉-1(2H)-酮三氟乙酸盐(TM26-E)
MS m/z(ESI):251[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.88(dd,J＝8.8Hz,2.0Hz,1H),7.23(d,J＝80.8Hz,1H),6.97(dd,J＝8.4Hz,2.4Hz,1H),6.91(d,J＝2.0Hz,1H),4.67(d,J＝2.4Hz,2H),3.82(d,J＝1.2Hz,2H),3.48(t,J＝6.8Hz,2H),2.96(t,J＝6.8Hz,2H).
实施例23:6-((2-氨甲基-3-氟烯丙基)氧基)-4,4-二甲基-3,4-二氢异喹啉-1(2H)-酮三氟乙酸盐(TM27)的制备
Figure PCTCN2018083792-appb-000046
第一步：6-甲氧基-1,1-二甲基-2,3-二氢-1H-茚(23-1)的制备
将TiCl 4(2.2mL,0.02mmol)溶于20mL无水二氯甲烷中，在N 2保护下于-40℃下搅拌加入Me 2Zn(80mL,0.08mmol)。保持该温度搅拌30分钟后，加入用5mL二氯甲烷溶解的6-甲氧基-1-茚酮(1.76g,0.01mmol)，缓慢升温至室温反应过夜。向反应液中缓慢滴加10mL无水甲醇淬灭反应，再加入二氯甲烷、饱和NH 4Cl溶液稀释萃取分液。有机相用饱和NH 4Cl溶液洗2次，水相用二氯甲烷萃取2次，合并有机相，干燥浓缩后得到油状液体(2.10g,72％)。
第二步：5-甲氧基-3,3-二甲基-2,3-二氢-1H-茚-1-酮(23-2)的制备
将化合物23-1(1.65g,9.4mmol)用冰乙酸20mL溶解，0℃下搅拌加入用8mL冰乙酸和7mL水溶解的CrO 3，缓慢升至室温反应过夜。将反应液用水稀释再用乙酸乙酯萃取2次。有机相用饱和碳酸氢钠溶液洗至中性，干燥浓缩，得到黄色油状液体(1.50g,83％)。
第三步：6-甲氧基-4,4-二甲基-3,4-二氢异喹啉-1-(2H)-酮(23-3)的制备
将化合物23-2(1.1g,5.8mmol)、NaN 3(0.65g,10mmol)混合置于三口瓶中，加 入三氟乙酸(20mL)，回流反应4小时。反应完毕后冷却至室温，加入水稀释，用饱和碳酸氢钠调至pH＝7-8。二氯甲烷萃取2次，合并有机相。有机相干燥浓缩得到棕色固体，加石油醚-乙酸乙酯混合溶液(石油醚：乙酸乙酯＝20：1)重结晶，得到棕色固体(600mg,62％)。
第四步：6-羟基-4,4-二甲基-3,4-二氢异喹啉-1-(2H)-酮(23-4)的制备
向化合物23-3(168mg,0.82mmol)中加入17％BBr 3的二氯甲烷溶液(10mL)，室温反应过夜。反应完毕后，加入甲醇淬灭反应，浓缩反应液，加少量二氯甲烷溶解，制备TLC分离得到白色固体(82mg,52％)。
第五步：(2-(4,4-二甲基-1,2,3,4-四氢异喹啉-1-酮-6-氧基甲基)-3-氟烯丙基)氨基甲酸叔丁酯(23-5)的制备
除在本步中以中间体23-4代替实施例1中第二步的中间体1-1，采用与实施例1中的第二步所描述类似的方法制备标题化合物，收率32％
第六步：6-((2-氨甲基-3-氟烯丙基)氧基)-4,4-二甲基-3,4-二氢异喹啉-1(2H)-酮三氟乙酸盐(TM27)的制备
除在本步中以中间体23-5代替实施例1中第三步的中间体1-2，采用与实施例1中的第三步所描述类似的方法制备标题化合物，收率约100％
采用与实施例9所描述类似的方法拆分异构体，TM27-E的保留时间较TM27-Z保留时间短。
(Z)-6-((2-氨甲基-3-氟烯丙基)氧基)-4,4-二甲基-3,4-二氢异喹啉-1(2H)-酮三氟乙酸盐(TM27-Z)。
MS m/z(ESI):279[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.93(d,J＝8.4Hz,1H),7.22-6.95(m,3H),4.90(d,J＝2.4Hz,2H),3.69(d,J＝2.4Hz,2H),3.27(s,2H),1.33(s,6H).
(E)-6-((2-氨甲基-3-氟烯丙基)氧基)-4,4-二甲基-3,4-二氢异喹啉-1(2H)-酮三氟乙酸盐(TM27-E)。
MS m/z(ESI):279[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.93(d,J＝8.4Hz,1H),7.35-6.96(m,3H),4.69(d,J＝3.6Hz,2H),3.83(s,2H),3.27(s,2H),1.33(s,6H).
实施例24:5-((2-氨甲基-3-氟烯丙基)氧基)异吲哚啉-1-酮三氟乙酸盐(TM77)的制备
Figure PCTCN2018083792-appb-000047
除在本实施例的第一步中以5-羟基-异吲哚啉-1-酮代替实施例1中第二步的中间体1-1，采用与实施例1第二和第三步所描述类似的方法制备标题化合物，总收率63％。
采用与实施例9所描述类似的方法拆分异构体，TM77-E的保留时间较TM77-Z保留时间短。
(Z)-5-((2-氨甲基-3-氟烯丙基)氧基)异吲哚啉-1-酮三氟乙酸盐(TM77-Z)。
MS m/z(ESI):226[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.73(d,J＝8.4Hz,1H),7.22(s,1H),7.15(dd,J＝8.4Hz,2.0Hz,1H),7.12(d,J＝80.8Hz,1H),4.90(d,J＝2.4Hz,2H),4.43(s,2H),3.71(d,J＝2.0Hz,2H).
(E)-5-((2-氨甲基-3-氟烯丙基)氧基)异吲哚啉-1-酮三氟乙酸盐(TM77-E)。
MS m/z(ESI):226[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.72(d,J＝8.4Hz,1H),7.35-7.12(m,3H),4.70(d,J＝2.8Hz,2H),4.42(s,2H),3.84(d,J＝2.0Hz,2H).
实施例25:6-((2-氨甲基-3-氟烯丙基)氧基)-2,3-二氢-1-茚酮三氟乙酸盐(TM7)的制备
Figure PCTCN2018083792-appb-000048
第一步：6-羟基-2,3-二氢-1-茚酮(25-1)的制备
将化合物6-甲氧基-2,3-二氢-1-茚酮(1.0g,6.17mmol)置于反应瓶中，加入溶剂甲苯 (20mL)。向搅拌的反应器中加入固体三氯化铝(2.4g,18.50mmol)，105℃反应2小时。TLC监测反应完全后，浓缩除去溶剂，加入水用乙酸乙酯萃取后合并有机相。有机相经饱和食盐水洗涤后干燥浓缩得到粗品。粗品经柱层析纯化得到产品25-1(420mg,46％)。
第二步：6-(2-叔丁氧羰基氨基甲基-3-氟烯丙基氧基)-2,3-二氢-1-茚酮(25-2)的制备
除在本步中以中间体25-1代替实施例1中第二步的中间体1-1，采用与实施例1中的第二步所描述类似的方法制备标题化合物。
第三步：6-((2-氨甲基-3-氟烯丙基)氧基)-2,3-二氢-1-茚酮三氟乙酸盐(TM7)的制备
除在本步中以中间体25-2代替实施例1中第三步的中间体1-2，采用与实施例1中的第三步所描述类似的方法制备标题化合物。
第二步和第三步反应总收率77％。
6-((2-氨甲基-3-氟烯丙基)氧基)-2,3-二氢-1-茚酮三氟乙酸盐异构体的拆分方法。
采用类似于实施例9中的分离方法，并且洗脱梯度：0-9min：10％-26.8％B，流速16mL/min；9.1-11min：95％B，流速20mL/min；11.1-13min：10％B，流速20mL/min。收集保留时间为6.6～7.6min区间内流出液并冻干得到TM7-E，收集保留时间为7.8～8.7min区间内流出液并冻干得到TM7-Z。
(Z)-6-((2-氨甲基-3-氟烯丙基)氧基)-2,3-二氢-1-茚酮三氟乙酸盐(TM7-Z)
MS m/z(ESI):236[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.49(d,J＝8.4Hz,1H),7.35(dd,J＝8.4Hz,2.8Hz,1H),7.26(d,J＝2.8Hz,1H),7.10(d,J＝80.8Hz,1H),4.85(d,J＝2.4Hz,2H),3.70(d,J＝2.4Hz,2H),3.11-3.09(m,2H),2.73-2.70(m,2H).
(E)-6-((2-氨甲基-3-氟烯丙基)氧基)-2,3-二氢-1-茚酮三氟乙酸盐(TM7-E)
MS m/z(ESI):236[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.48(d,J＝8.4Hz,1H),7.35-7.32(m,1H),7.25(s,1H),7.23(d,J＝81.2Hz,1H),4.65(d,J＝3.6Hz,2H),3.83(d,J＝1.6Hz,2H),3.10-3.18(m,2H),2.72-2.70(m,2H).
实施例26:6-((2-氨甲基-3-氟烯丙基)氧基)-3,3-二甲基-3,4-二氢异喹啉-1(2H)-酮三氟乙酸盐(TM38)的制备
Figure PCTCN2018083792-appb-000049
第一步：5-甲氧基-2,2-二甲基-2,3-二氢-1H-茚-1-酮(26-1)的制备
将化合物5-甲氧基-2,3-二氢-1-茚酮(1.5g,9.3mmol)溶于乙醚(40mL)中，冰浴下滴加碘甲烷(2.9mL,46.2mmol)。于冰浴下加入叔丁醇钾(3.4g,30.4mmol)的叔丁醇(20mL)溶液，回流反应6h。加水淬灭反应，乙醚萃取两次，饱和食盐水洗有机相，收集有机相，无水硫酸钠干燥，浓缩柱层析，得目标分子(1.2g，68％)。
第二步：6-甲氧基-3,3-二甲基-3,4-二氢异喹啉-1(2H)-酮(26-2)的制备除在本步中以中间体26-1代替实施例23中第三步的中间体23-2，采用与实施例23中的第三步所描述类似的方法制备标题化合物，收率15％。
第三步：6-羟基-3,3-二甲基-3,4-二氢异喹啉-1(2H)-酮(26-3)的制备
除在本步中以中间体26-2代替实施例25中第一步的6-甲氧基-2,3-二氢-1-茚酮，采用与实施例25中的第一步所描述类似的方法制备标题化合物。
第四步：6-(2-叔丁氧羰基氨基甲基-3-氟烯丙基氧基)-3,3-二甲基-3,4-二氢异喹啉-1(2H)-酮(26-4)的制备
除在本步中以中间体26-3代替实施例1中第二步的中间体1-1，采用与实施例1中的第二步所描述类似的方法制备标题化合物。
第五步：6-(2-氨甲基-3-氟烯丙基氧基)-3,3-二甲基-3,4-二氢异喹啉-1(2H)-酮三氟乙酸盐(TM38)的制备
除在本步中以中间体26-4代替实施例1中第三步的中间体1-2，采用与实施例1中的第三步所描述类似的方法制备标题化合物。
第三步到第五步的总收率46％。
6-((2-氨甲基-3-氟烯丙基)氧基)-3,3-二甲基-3,4-二氢异喹啉-1(2H)-酮三氟乙酸盐异构 体的拆分方法。
采用类似于实施例9的分离方式，并且洗脱梯度：0-7.4min：10％-28.5％B，流速16mL/min；7.5-9min：95％B，流速20mL/min；9.1-11min：10％B，流速20mL/min。收集保留时间为5.6～6.2min区间内流出液并冻干得到TM38-E，收集保留时间为6.4～6.9min区间内流出液并冻干得到TM38-Z。
(Z)-6-((2-(甲氨基)-3-氟烯丙基)氧代)-3,3-二甲基-3,4-二氢异喹啉-1(2H)-酮三氟乙酸盐(TM38-Z)。
MS m/z(ESI):279[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.89(d,J＝8.4Hz,1H),7.11(d,J＝80.8Hz,1H),7.01-6.98(m,1H),6.92-6.91(m,1H),4.87(s,2H),3.69(d,J＝2.4Hz,2H),2.92(s,2H),1.29(s,6H).
(E)-6-((2-(甲氨基)-3-氟烯丙基)氧代)-3,3-二甲基-3,4-二氢异喹啉-1(2H)-酮三氟乙酸盐(TM38-E)。
MS m/z(ESI):279[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.89(d,J＝8.8Hz,1H),7.24(d,J＝81.2Hz,1H),6.98(dd,J＝8.8Hz,2.4Hz,1H),6.90-6.89(m,1H),4.67(d,J＝2.8Hz,2H),3.82(s,2H),2.92(s,2H),1.29(s,6H).
实施例27:6-((2-氨甲基-3-氟烯丙基)氧基)-2-甲基-3,4-二氢异喹啉-1(2H)-酮三氟乙酸盐(TM66)的制备
Figure PCTCN2018083792-appb-000050
第一步：6-甲氧基-3,4-二氢异喹啉-1(2H)-酮(27-1)的制备
除在本步中以5-甲氧基-1-茚酮代替实施例23中第三步的中间体23-2，采用与实施例23中的第三步所描述类似的方法制备标题化合物，收率48％。
第二步：6-甲氧基-2-甲基-3,4-二氢异喹啉-1(2H)-酮(27-2)的制备
将化合物27-1(250mg,1.41mmol)溶于DMF(10mL)中，冰浴下加入NaH(84mg,2.11mmol,60％)，反应10分钟后，滴加碘甲烷(300mg,2.11mmol)，缓慢升至室温，反应2小时。LCMS监测反应完全，加入饱和食盐水、乙酸乙酯萃取，有机相用饱和食盐水洗2次，合并有机相干燥浓缩至干，得到棕色液体产品27-2(225mg,83％)。
第三步：6-羟基-2-甲基-3,4-二氢异喹啉-1(2H)-酮(27-3)的制备
除在本步中以中间体27-2代替实施例25中第一步的6-甲氧基-2,3-二氢-1-茚酮，采用与实施例25中的第一步所描述类似的方法制备标题化合物。
第四步：6-(2-叔丁氧羰基氨基甲基-3-氟烯丙基氧基)-2-甲基-3,4-二氢异喹啉-1(2H)-酮(27-4)的制备
除在本步中以中间体27-3代替实施例1中第二步的中间体1-1，采用与实施例1中的第二步所描述类似的方法制备标题化合物。
第五步：6-((2-氨甲基-3-氟烯丙基)氧基)-2-甲基-3,4-二氢异喹啉-1(2H)-酮三氟乙酸盐(TM66)的制备
除在本步中以中间体27-4代替实施例1中第三步的中间体1-2，采用与实施例1中的第三步所描述类似的方法制备标题化合物。
第三步到第五步的总收率77％。
6-((2-氨甲基-3-氟烯丙基)氧基)-2-甲基-3,4-二氢异喹啉-1(2H)-酮三氟乙酸盐异构体的拆分方法。
采用类似于实施例9的分离方式，并且洗脱梯度：0-7.8min：10％-24.6％B，流速16mL/min；7.9-10min：95％B，流速20mL/min；10.1-12min：10％B，流速20mL/min。收集保留时间为5.6～6.2min区间内流出液并冻干得到TM66-E，收集保留时间为6.8～7.3min区间内流出液并冻干得到TM66-Z。
(Z)-6-((2-(甲氨基)-3-氟烯丙基)氧代)-2-甲基-3,4-二氢异喹啉-1(2H)-酮三氟乙酸盐(TM66-Z)。
MS m/z(ESI):265[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.89(d,J＝8.8Hz,1H),7.10(d,J＝80.8Hz,1H),6.98-6.96(m,1H),6.90(d,J＝2.4Hz,1H),4.86(d,J＝2.4Hz,2H),3.69(d,J＝2.0Hz,2H), 3.60(t,J＝6.8Hz,2H),3.12(s,3H),3.01(t,J＝6.8Hz,2H).
(E)-6-((2-(甲氨基)-3-氟烯丙基)氧代)-2-甲基-3,4-二氢异喹啉-1(2H)-酮三氟乙酸盐(TM66-E)。
MS m/z(ESI):265[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.89(d,J＝8.4Hz,1H),7.24(d,J＝81.2Hz,1H),6.96(dd,J＝8.8Hz,2.4Hz,1H),6.88(d,J＝2.4Hz,1H),4.66(d,J＝2.8Hz,2H),3.82(s,2H),3.60(t,J＝6.8Hz,2H),3.12(s,3H),3.01(t,J＝6.8Hz,2H).
实施例28:7-((2-氨甲基-3-氟烯丙基)氧基)-3,4-二氢异喹啉-1(2H)-酮三氟乙酸盐(TM75)的制备
Figure PCTCN2018083792-appb-000051
第一步：7-甲氧基-3,4-二氢异喹啉-1(2H)-酮(28-1)的制备
除在本步中以6-甲氧基-1-茚酮代替实施例23中第三步的中间体23-2，采用与实施例23中的第三步所描述类似的方法制备标题化合物，收率49％。
第二步：7-羟基-3,4-二氢异喹啉-1(2H)-酮(28-2)的制备
除在本步中以中间体28-1代替实施例25中第一步的6-甲氧基-2,3-二氢-1-茚酮，采用与实施例25中的第一步所描述类似的方法制备标题化合物，收率67％。
第三步：(2-(1-氧代-1,2,3,4-四氢异喹啉-7-氧基甲基)-3-氟烯丙基)氨基甲酸叔丁酯(28-3)的制备
除在本步中以中间体28-2代替实施例1中第二步的中间体1-1，采用与实施例1中的第二步所描述类似的方法制备标题化合物，收率53％。
第四步：7-((2-氨甲基-3-氟烯丙基)氧基)-3,4-二氢异喹啉-1(2H)-酮三氟乙酸盐(TM75)的制备
除在本步中以中间体28-3代替实施例1中第三步的中间体1-2，采用与实施例1中的第三步所描述类似的方法制备标题化合物，收率约100％。
采用与实施例9所描述类似的方法拆分异构体，TM75-E的保留时间较TM75-Z保留时间短。
(Z)-7-((2-氨甲基-3-氟烯丙基)氧基)-3,4-二氢异喹啉-1(2H)-酮三氟乙酸盐(TM75-Z)
MS m/z(ESI):251[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.07(d,J＝81.2Hz,1H),7.11(d,J＝8.0Hz,1H),6.64(dd,J＝8.4Hz,2.8Hz,1H)6.53(d,J＝2.8Hz,1H),4.77(d,J＝2.0Hz,2H),3.67(d,J＝2.4Hz,2H),2.88(t,J＝7.6Hz,2H),2.53(t,J＝7.6Hz,2H).
(E)-7-((2-氨甲基-3-氟烯丙基)氧基)-3,4-二氢异喹啉-1(2H)-酮三氟乙酸盐(TM75-E)
MS m/z(ESI):251[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.18(d,J＝81.8Hz,1H),7.09(d,J＝8.4Hz,1H),6.63(dd,J＝8.4Hz,2.4Hz,1H),6.52(d,J＝2.4Hz,1H),4.56(d,J＝3.6Hz,2H),3.81(s,2H),2.86(t,J＝7.6Hz 2H),2.51(t,J＝7.6Hz,2H).
实施例29:N-(四氢-2H-吡喃-4-基)-4-((2-氨甲基-3-氟烯丙基)氧基)-苯甲酰胺三氟乙酸盐(TM76)的制备
Figure PCTCN2018083792-appb-000052
第一步：4-((四氢-2H-吡喃-4-基)氨基甲酰)苯基乙酸酯(29-1)的制备
将4-乙酰氧基苯甲酸(500mg,2.78mmol)溶于无水二氯甲烷(10mL)和DMF(10mL)中，冰浴下加入草酰氯(1.06g,8.34mmol)，反应半小时，半小时后将反应液浓缩待用。将4-氨基四氢-2H-吡喃(336mg,3.33mmol)溶于DMF中，加入待用的酰氯溶液，室温反应，LCMS监测反应进程。5小时后，加入水用乙酸乙酯萃取，有机相干燥浓缩，柱层析分离得到标题化合物为棕色液体(225mg,31％)。
第二步：4-羟基-N-(四氢-2H-吡喃-4-基)苯甲酰胺(29-2)的制备
将29-1(225mg,0.86mmol)溶于10mL无水甲醇中，加入1mL水、碳酸钾(354mg,2.58mmol)，室温反应1小时。1小时后浓缩反应液，加入水用乙酸乙酯萃取，有机相浓缩至干，得到标题化合物为油状液体(125mg,66％)。
第三步：N-(四氢-2H-吡喃-4-基)-4-((2-叔丁氧羰基氨甲基-3-氟烯丙基)氧基)-苯甲酰胺(29-3)的制备
除在本步中以中间体29-2代替实施例1中第二步的中间体1-1，采用与实施例1中的第二步所描述类似的方法制备标题化合物，收率42％。
第四步：N-(四氢-2H-吡喃-4-基)-4-((2-氨甲基-3-氟烯丙基)氧基)-苯甲酰胺三氟乙酸盐(TM76)的制备
除在本步中以中间体29-3代替实施例1中第三步的中间体1-2，采用与实施例1中的第三步所描述类似的方法制备标题化合物，收率99％。
采用与实施例9所描述类似的方法拆分异构体，TM76-E的保留时间较TM76-Z保留时间短。
(Z)-N-(四氢-2H-吡喃-4-基)-4-((2-氨甲基-3-氟烯丙基)氧基)-苯甲酰胺三氟乙酸盐(TM76-Z)
MS m/z(ESI):309[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.83(d,J＝9.2Hz,2H),7.10(d,J＝80.8Hz,1H),7.08(d,J＝8.8Hz,2H),4.86(d,J＝2.4Hz,2H),4.12-4.06(m,1H),3.98(dd,J＝8.0Hz,2.4Hz,2H),3.69(s,2H),3.52(td,J＝12.0Hz,2.0Hz,2H),1.89-1.86(m,2H),1.71-1.61(m,2H).
(E)-N-(四氢-2H-吡喃-4-基)-4-((2-氨甲基-3-氟烯丙基)氧基)-苯甲酰胺三氟乙酸盐(TM76-E)
MS m/z(ESI):309[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.83(d,J＝8.8Hz,2H),7.24(d,J＝80.8Hz,1H),7.06(d,J＝8.8Hz,2H),4.66(d,J＝3.6Hz,2H),4.12-4.06(m,1H),3.98(dd,J＝12.0Hz,2.4Hz,2H),3.82(s,2H),3.52(td,12.0Hz,2.0Hz,2H),1.90-1.86(m,2H),1.71-.61(m,2H).
实施例30:4-((2-氨甲基-3-氟烯丙基)氧基)-N-(吡啶-2-基甲基)苯甲酰胺三氟乙酸盐(TM112)的制备
Figure PCTCN2018083792-appb-000053
第一步：4-((吡啶-2-基甲基)氨基甲酰基)苯基乙酸酯(30-1)的制备
将化合物4-乙酰氧基苯甲酸(2.00g,11.1mmol)溶于二氯甲烷(24mL)中，滴加草酰氯(2.11g,16.65mmol)，DMF(5滴)，室温反应3小时。补加草酰氯(1.50g,11.81mmol)，室温反应3小时，旋蒸至干待用。将化合物2-氨甲基吡啶(0.5g,4.62mmol)溶于二氯甲烷(10mL)中，加入DIPEA(1.79g,13.86mmol)和待用的酰氯(0.92g,4.62mmol)，室温反应6小时。加水淬灭反应，二氯甲烷萃取两次，饱和食盐水洗有机相，收集有机相，无水硫酸钠干燥，浓缩柱层析，所得粗品直接投下一步。
第二步：4-羟基-N-(吡啶-2-甲基)苯甲酰胺(30-2)的制备
将化合物30-1粗品溶于甲醇(20mL)中，加水(20mL)和碳酸钾(2.50g,18.10mmol)，室温反应过夜。加水稀释，滴加稀盐酸至pH＝3左右，再加饱和碳酸氢钠溶液至pH＝8左右，乙酸乙酯萃取两次，饱和食盐水洗有机相，收集有机相，无水硫酸钠干燥，浓缩柱层析，得到标题化合物(0.20g，两步收率19％)。
第三步:4-((2-叔丁氧羰基氨甲基-3-氟烯丙基)氧基)-N-(吡啶-2-基甲基)苯甲酰胺(30-3)的制备
除在本步中以中间体30-2代替实施例1中第二步的中间体1-1，采用与实施例1中的第二步所描述类似的方法制备标题化合物，收率56％。
第四步：4-((2-氨甲基-3-氟烯丙基)氧基)-N-(吡啶-2-基甲基)苯甲酰胺三氟乙酸盐(TM112)的制备
除在本步中以中间体30-3代替实施例1中第三步的中间体1-2，采用与实施例1中的第三步所描述类似的方法制备标题化合物，收率99％。
采用与实施例9所描述类似的方法拆分异构体，TM112-E的保留时间较TM112-Z保留时间短。
(Z)-4-((2-氨甲基-3-氟烯丙基)氧基)-N-(吡啶-2-基甲基)苯甲酰胺三氟乙酸盐(TM112-Z)
MS m/z(ESI):316[M+H] +
1HNMR(400MHz,CD 3OD)δ:8.72(d,J＝4.8Hz,1H),8.42(td,J＝8.0Hz,1.6Hz,1H),7.93-7.91(m,3H),7.85-7.82(m,1H),7.11(d,J＝80.8Hz,1H),7.14-7.12(m,2H),4.88(d,J＝2.4Hz,2H),4,84(s,2H),3.70(d,J＝2.0Hz,2H).
(E)-4-((2-氨甲基-3-氟烯丙基)氧基)-N-(吡啶-2-基甲基)苯甲酰胺三氟乙酸盐(TM112-E)
MS m/z(ESI):316[M+H] +
1HNMR(400MHz,CD 3OD)δ:8.72(d,J＝5.6Hz,1H),8.42(td,J＝8.0Hz,1.6Hz,1H),7.93-7.90(m,3H),7.86-7.82(m,1H),7.24(d,J＝80.8Hz,1H),7.13-7.09(m,2H),4.84(s,2H),4.68(d,J＝3.2Hz,2H),3.83(d,J＝1.2Hz,2H).
实施例31:4-((2-氨甲基-3-氟烯丙基)氧基)-N-(2,3-二氢苯并[b][1,4]二氧杂-6-基)苯甲酰胺三氟乙酸盐(TM114)的制备
Figure PCTCN2018083792-appb-000054
除在本实施例的第一步中以6-氨基-1,4-苯并二氧杂环代替实施例30中第一步的2-氨甲基吡啶，采用与实施例30所描述类似的方法制备标题化合物，总收率9％。
采用与实施例9所描述类似的方法拆分异构体，TM114-E的保留时间较TM114-Z保留时间短。
(Z)-4-((2-氨甲基-3-氟烯丙基)氧基)-N-(2,3-二氢苯并[b][1,4]二氧杂-6-基)苯甲酰胺三氟乙酸盐(TM114-Z)
MS m/z(ESI):359[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.92(d,J＝8.8Hz,2H),7.26-7.25(m,1H),7.12(d,J＝8.8Hz,2H),7.11(d,J＝80.8Hz,1H),7.05-7.03(m,1H),6.79(d,J＝8.8Hz,1H),4.88(s,2H),4.25-4.22(m,4H),3.70(d,J＝2.4Hz,2H).
(E)-4-((2-氨甲基-3-氟烯丙基)氧基)-N-(2,3-二氢苯并[b][1,4]二氧杂-6-基)苯甲酰胺三氟乙酸盐(TM114-E)
MS m/z(ESI):359[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.91(d,J＝8.8Hz,2H),7.25(d,J＝80.8Hz,1H),7.26-7.25(m,1H),7.10(d,J＝8.8Hz,2H),7.04(dd,J＝8.8Hz,2.4Hz,1H),6.80(d,J＝8.8Hz,1H),4.68(d,J＝3.2Hz,2H),4.25-4.22(m,4H),3.83(s,2H).
实施例32:4-((2-氨甲基-3-氟烯丙基)氧基)-N-(3-(2-甲氧基乙氧基)苯基)苯甲酰胺三氟乙酸盐(TM106)的制备
Figure PCTCN2018083792-appb-000055
第一步：N-叔丁氧羰基-3-氨基苯酚(32-1)的制备
将化合物3-氨基苯酚(10.0g,91.7mmol)置于反应瓶中，依次加入DCM(100mL)、TEA(27.8g,275.1mmol)和Boc 2O(21.8g,100.0mmol)，室温反应3小时。低温浓缩后 加入水，用乙酸乙酯萃取然后后合并有机相。有机相经饱和食盐水洗涤后干燥浓缩得到粗品。粗品经柱层析纯化得到标题化合物(3.8g,20％)。
第二步：N-叔丁氧羰基-3-(2-甲氧基乙氧基)苯胺(32-2)的制备
将化合物32-1(3.8g,18.2mmol)溶于DMF(10mL)中，加入K 2CO 3(7.5g,54.6mmol)和2-溴乙基甲基醚(2.8g,20.0mmol)，室温反应10小时。反应液加水稀释后用乙酸乙酯萃取，有机相水洗后用饱和食盐水溶液洗涤3次，硫酸钠干燥，过滤浓缩，粗品经柱层析纯化得到标题化合物(2.9g,60％)。
第三步：3-(2-甲氧基乙氧基)苯胺(32-3)的制备
将化合物32-2(2.9g,10.8mmol)溶于DCM(10mL)中，低温下加入TFA(3mL)。室温反应1小时。TLC监测反应完全后，低温浓缩。粗品用水溶解后加入饱和碳酸钠碱化，然后用乙酸乙酯萃取。合并有机相，用饱和食盐水洗涤3次，硫酸钠干燥，过滤浓缩，得到标题化合物，未进一步纯化直接用于下一步。
第四步：4-((3-(2-甲氧基乙氧基)苯基)氨甲酰基)苯基乙酸酯(32-4)的制备
除在本步中以中间体32-3代替实施例30中第一步的2-氨甲基吡啶，采用与实施例30中的第一步所描述类似的方法制备标题化合物，收率49％。
第五步：4-羟基-N-(3-(2-甲氧基乙氧基)苯基)苯甲酰胺(32-5)的制备
除在本步中以中间体32-4代替实施例30中第二步的中间体30-1，采用与实施例30中的第二步所描述类似的方法制备标题化合物，收率91％。
第六步：4-((2-叔丁氧羰基氨甲基-3-氟烯丙基)氧基)-N-(3-(2-甲氧基乙氧基)苯基)苯甲酰胺(32-6)的制备
除在本步中以中间体32-5代替实施例1中第二步的中间体1-1，采用与实施例1中的第二步所描述类似的方法制备标题化合物，收率37％。
第七步：4-((2-氨甲基-3-氟烯丙基)氧基)-N-(3-(2-甲氧基乙氧基)苯基)苯甲酰胺三氟乙酸盐(TM106)的制备
除在本步中以中间体32-6代替实施例1中第三步的中间体1-2，采用与实施例1中的第三步所描述类似的方法制备标题化合物，收率99％。
采用与实施例9所描述类似的方法拆分异构体，TM106-E的保留时间较TM106-Z保留时间短。
(Z)-4-((2-氨甲基-3-氟烯丙基)氧基)-N-(3-(2-甲氧基乙氧基)苯基)苯甲酰胺三氟乙酸盐(TM106-Z)
MS m/z(ESI):375[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.94(d,J＝8.8Hz,2H),7.40(s,1H),7.25-7.23(m,2H),7.12(d,J＝8.8Hz,2H),7.11(d,J＝80.8Hz,1H),6.75-6.72(m,1H),4.89(s,2H),4.13-4.11(m,2H),3.76-3.74(m,2H),3.70(d,J＝2.0Hz,2H),3.43(s,3H).
(E)-4-((2-氨甲基-3-氟烯丙基)氧基)-N-(3-(2-甲氧基乙氧基)苯基)苯甲酰胺三氟乙酸盐(TM106-E)
MS m/z(ESI):375[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.93(d,J＝8.8Hz,2H),7.40(s,1H),7.23(d,J＝81.2Hz,1H),7.25-7.23(m,2H),7.10(d,J＝8.8Hz,2H),6.75-6.72(m,1H),4.68(d,J＝3.6Hz,2H),4.13-4.11(m,2H),3.83(s,2H),3.76-3.74(m,2H),3.43(s,3H).
实施例33：(E)-6-((2-氨甲基-3-氟烯丙基)氧基)-3,3-二甲基-3,4-二氢异喹啉-1(2H)-酮盐酸盐(HC38-E)的制备
Figure PCTCN2018083792-appb-000056
将化合物TM-38-E(1.74g,5.8mmol)制备溶液中加入2mol/L氢氧化钠溶液至pH＝9-10，DCM萃取两次，然后合并有机相。有机相经饱和食盐水洗涤后干燥，向有机相中加入2mol/L氯化氢的乙酸乙酯溶液10mL，浓缩得到标题化合物(1.44g,98％)。
(E)-6-((2-氨甲基-3-氟烯丙基)氧基)-3,3-二甲基-3,4-二氢异喹啉-1(2H)-酮盐酸盐(HC38-E)
MS m/z(ESI):279[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.88(d,J＝8.4Hz,1H),7.24(d,J＝81.2Hz,1H),6.97(dd,J＝8.4Hz,2.4Hz,1H),6.91-6.90(m,1H),4.68(d,J＝2.8Hz,2H),3.83(d,J＝2.0Hz,2H),2.92(s,2H),1.29(s,6H).
实施例34：(E)-6-((2-氨甲基-3-氟烯丙基)氧基)-2-甲基-3,4-二氢异喹啉-1(2H)-酮盐酸盐(HC66-E)的制备
Figure PCTCN2018083792-appb-000057
将化合物TM-66-E(4.2g,11.6mmol)制备溶液中加入2mol/L氢氧化钠溶液至pH＝9-10，DCM萃取两次，然后合并有机相。有机相经饱和食盐水洗涤后干燥，向有机相中加入2mol/L氯化氢的乙酸乙酯溶液30mL，浓缩得到标题化合物(2.8g,80％)。
(E)-6-((2-氨甲基-3-氟烯丙基)氧基)-2-甲基-3,4-二氢异喹啉-1(2H)-酮盐酸盐(HC66-E)
MS m/z(ESI):265[M+H] +
1HNMR(400MHz,CD 3OD)δ:7.88(d,J＝8.4Hz,1H),7.24(d,J＝81.2Hz,1H),6.97(dd,J＝8.4Hz,2.4Hz,1H),6.90(s,1H),4.67(s,2H),3.82(s,2H),3.60(t,J＝6.8Hz,2H),3.12(s,3H),3.00(t,J＝6.8Hz,2H).
试验例1：VAP-1(Vascular adhesion protein 1)体外酶学活性抑制试验
试剂：
检测试剂盒：
Figure PCTCN2018083792-appb-000058
Monoamine Oxidase Assay，生产厂家：ThermoFisher
反应缓冲液：50mM PBS,pH7.4
酶：VAP-1，生产厂家：R&D Systems
将VAP-1蛋白(～20nM)与不同浓度的待测化合物室温预孵育10min后,按照试剂盒说明加入500μM苄胺盐酸盐、1U/mL HRP及200μM Amplex Red reagent启动反应。将反应板放入酶标仪中，在动力学模式下，于Ex/Em＝540/590nm测定荧光信号。以线性范围内荧光信号-反应时间比值(斜率)为反应速度，以溶媒组(DMSO)为阴性对照、反应缓冲液组(不含酶和化合物)为空白对照，计算各浓度组相对抑制活性，按照四参数模型拟合曲线，计算化合物的半数抑制浓度(IC 50)。
试验结果
按照上述方法测定化合物对VAP-1活性的抑制，结果如表1中所示。
表1.VAP-1酶活抑制试验结果
化合物编号 IC 50(nM)
TM70 0.2±0.0
TM1 0.5±0.0
TM68 9.9±1.8
TM67 11.5±1.3
TM8 2.2±0.1
TM62 1.8±0.2
TM26 5.8±1.0
TM42 1.6±0.2
TM41 4.8±0.7
TM39 1.0±0.1
TM33 3.3±0.2
TM48 6.5±0.5
TM61 0.5±0.0
TM72 3.4±0.5
TM71 2.4±0.2
TM44 3.4±0.4
TM45 0.9±0.1
TM69 10.4±1.4
TM45-Z 1.1±0.1
TM45-E 2.4±0.7
TM33-Z 6.3±1.2
TM33-E 4.9±0.5
TM41-Z 3.5±0.4
TM41-E 3.1±0.5
TM48-Z 10.6±1.4
TM48-E 9.2±1.1
TM63-Z 4.4±0.8
TM63-E 5.7±0.8
TM65-Z 1.7±0.3
TM65-E 4.1±0.7
TM73-Z 3.7±0.3
TM73-E 4.2±0.3
TM1-Z 0.7±0.1
TM1-E 1.6±0.2
TM42-Z 1.5±0.1
TM42-E 2.0±0.3
TM26-Z 3.7±0.8
TM26-E 9.9±1.2
TM44-Z 9.7±0.9
TM44-E 12.9±4.4
TM74-Z 5.3±0.2
TM74-E 3.2±0.2
TM39-Z 0.7±0.1
TM39-E 1.2±0.2
TM7-Z 3.8±0.4
TM7-E 3.0±0.7
TM38-Z 2.9±0.3
TM38-E 4.7±1.1
TM66-Z 1.6±0.2
TM66-E 2.0±0.4
TM75-Z 1.3±0.2
TM75-E 23.4±2.2
TM76-Z 1.8±0.2
TM76-E 4.3±0.6
TM112-Z 6.5±1.8
TM112-E 3.2±0.4
TM114-Z 0.8±0.1
TM114-E 1.1±0.2
HC38-E 2.85±0.30
测试结果表明，本发明的化合物对VAP-1活性的抑制较强。
试验例2：体内酶活抑制试验
试剂：
组织匀浆缓冲液(20mM HEPES,pH7.2,1mM EDTA,250mM sucrose,PMSF 0.2mM)
反应缓冲液:50mM PBS,pH 7.4
检测试剂盒：
Figure PCTCN2018083792-appb-000059
Monoamine Oxidase Assay，生产厂家：ThermoFisher
试验方法
1样品采集、处理
BALBc小鼠以不同剂量的待测化合物口服给药，以溶媒组为对照，于6小时后采集腹部脂肪，用预冷的匀浆缓冲液按照1:20(w/v)匀浆后，以10,000g，4℃离心10min后收集上清，保存于-80℃待用。
2酶活检测
将待测样品用反应缓冲液稀释，分别加入抑制剂溶液A：1μM氯吉灵+1μM优降宁以抑制MAO-A，MAO-B活性；加入抑制剂溶液B：1μM氯吉灵+1μM优降宁+1μM莫非吉兰作为空白对照，室温孵育20min后，加入500μM苄胺盐酸盐、1U/mL HRP及200μM Amplex Red reagent启动反应，参照“VAP-1酶学活性抑制试验”方法，以线性范围内荧光信号-反应时间比值为反应速度，溶媒组为阳性对照计算各剂量组的相对活性，考察化合物对小鼠腹部脂肪中VAP-1酶活的抑制。
试验结果
按照上述方法测定化合物对小鼠腹部脂肪中VAP-1酶活的抑制，如表2,3中所示。
表2.VAP-1体内酶活抑制试验结果
Figure PCTCN2018083792-appb-000060
表3.VAP-1体内酶活抑制试验结果
Figure PCTCN2018083792-appb-000061
结果表明，本发明化合物TM26、TM33、TM42在口服给药2mg/kg 6小时后，体内VAP-1被完全抑制，本发明的其它化合物在2mg/kg给药剂量下对体内VAP-1均有完全或较强抑制作用。本发明的化合物在低给药剂量0.5mg/kg下，对体内VAP-1也具有较强的抑制作用。
可见，本发明化合物对体内VAP-1有较强抑制作用。
试验例3：MAO-A(Monoamine oxidase type A)酶学活性抑制试验
1.检测试剂盒：
Figure PCTCN2018083792-appb-000062
Monoamine Oxidase Assay，生产厂家：ThermoFisher
2.反应缓冲液:50mM PBS,pH7.4
蛋白：MAO-A，生产厂家：Sigma Aldrich
3.MAO-A酶活抑制检测方法
参照试剂盒说明书方法，将MAO-A蛋白(15μg/ml)与不同浓度的化合物室温预孵育30min后加入200μM p-盐酸酪胺、1U/mL HRP及200μM Amplex Red reagent启动反应。在动力学模式下，于Ex/Em＝540/590nm测定荧光信号。以线性范围内荧光信号-反应时间比值为反应速度，以溶媒组(DMSO)为阴性对照、反应缓冲液组(不含酶和化合物)为空白对照，计算各浓度组抑制率。
百分比抑制率(％)＝(1-(各化合物浓度组速率-空白组速率)/(溶媒组速率-空白组速率))*100
3.试验结果
按照上述方法测定化合物对MAO-A活性的抑制，根据100μM和10μM的抑制率得到了IC 50的范围，结果如表4中所示。
表4.MAO-A酶活抑制试验结果
化合物编号 IC 50(μM)
TM26-Z >100
TM39-E >10
TM77-Z >100
TM7-E >100
TM38-E >100
TM66-E >10
TM75-Z >100
TM76-Z >100
TM76-E >100
TM112-Z >100
TM112-E >100
TM114-Z >10
TM114-E >10
结果表明，本发明化合物对MAO-A活性的抑制均弱于对VAP-1活性的抑制。
试验例4：MAO-B(Monoamine oxidase type B)酶学活性抑制试验
1.检测试剂盒：
Figure PCTCN2018083792-appb-000063
Monoamine Oxidase Assay，生产厂家：ThermoFisher
蛋白：MAO-B，生产厂家：Sigma Aldrich
2.MAO-B酶活抑制检测方法
参照试剂盒说明书方法，将MAO-B蛋白(5μg/ml)与不同浓度的化合物室温预孵育10min后加入150μM苄胺盐酸盐、1U/mL HRP及200μM Amplex Red reagent启动反应。参照MAO-A试验方法计算各浓度组抑制率。
3.试验结果
按照上述方法测定化合物对MAO-B活性的抑制，根据10μM、1μM和0.1μM的抑制率得到IC 50范围，结果如表5中所示。
表5.MAO-B酶活抑制试验结果
化合物编号 IC 50(μM)
TM26-Z >1
TM7-Z >10
TM7-E >10
TM38-Z >10
TM38-E >10
TM66-Z >10
TM66-E >10
TM75-Z >10
TM76-Z >0.1
TM76-E >1
TM112-Z >0.1
TM112-E >0.1
结果表明，本发明化合物对MAO-B活性的抑制均弱于对VAP-1活性的抑制。
试验例5：DAO(Diamine oxidase)酶学活性抑制试验
1.检测试剂盒：
Figure PCTCN2018083792-appb-000064
Monoamine Oxidase Assay，生产厂家：ThermoFisher蛋白：DAO，生产厂家：R&D Systems
2.DAO酶活抑制检测方法
将DAO蛋白(15μg/ml)与不同浓度的化合物室温预孵育20min后加入100μM组胺二盐酸盐、1U/mL HRP及200μM Amplex Red reagent启动反应。参照MAO-A试验方法计算各浓度组抑制率。
3.试验结果
按照上述方法测定化合物对DAO活性的抑制作用，结果如表6中所示。
表6.DAO酶活抑制试验结果
化合物编号 IC 50(μM)
TM1-E >0.1
TM7-Z >0.1
TM7-E >1
TM38-Z >0.1
TM38-E >1
TM66-E >0.1
TM76-E >0.1
TM112-Z >0.1
结果表明，本发明化合物对DAO活性的抑制均弱于对VAP-1活性的抑制。
试验例6.hERG(Ether-a-go-go-related gene potassium channel)抑制试验
试剂：Predictor TM hERG Fluorescence Polarization Assay Kit，生产厂家：ThermoFisher
试验方法
使用上述试剂盒对化合物诱导心脏QT间期延长的潜力进行评估。按照试剂盒提供的方法，将测试化合物，试剂盒中的阳性对照(E4031)和阴性对照(实验缓冲液)加入到含有hERG细胞膜的微孔板中，再加入具有高hERG亲和性示踪剂Tracer，将微孔板在25℃孵育2小时后，使用BMG PHAREStar多功能酶标仪检测荧光偏振值的变化，计算不同浓度下百分比抑制率(％)，判断化合物的半数抑制浓度(IC 50)的范围。
百分比抑制率(％)＝(1-(测试化合物的mP-30μM E4031的mP)/(实验缓冲液的mP-30μM E4031的mP))*100
试验结果
采用上述方法测定化合物对hERG的抑制，结果如表7中所示。
表7.hERG抑制试验结果
化合物编号 hERG(μM)
TM70 >30
TM1 >10
TM67 >30
TM62 >30
TM26 >30
TM42 >10
TM39 >30
TM61 >10
TM44 >10
TM45 >10
TM45-Z >10
TM45-E >10
TM33-E >10
TM63-Z >10
TM63-E >10
TM1-Z >10
TM1-E >10
TM42-Z >10
TM42-E >10
TM26-Z >10
TM26-E >10
TM39-Z >10
TM39-E >10
TM77-Z >10
TM7-E >10
TM38-E >10
TM66-E >10
TM76-E >10
TM112-Z >10
测试结果表明，本发明化合物与hERG亲和性低，与亲和性示踪剂Tracer竞争的IC 50均大于10μM。
试验例7：不同剂量和时间条件体内酶活抑制试验
试剂：
组织匀浆缓冲液(20mM HEPES,pH7.2,1mM EDTA,250mM sucrose,PMSF 0.2mM)
反应缓冲液:50mM PBS,pH 7.4
检测试剂盒：
Figure PCTCN2018083792-appb-000065
Monoamine Oxidase Assay，生产厂家：ThermoFisher
试验方法
1 样品采集、处理
BALBc小鼠以不同剂量(0.5mg/kg，3mg/kg)的待测化合物口服给药，以溶媒组为对 照，分别于6、10、24小时后采集腹部脂肪，用预冷的匀浆缓冲液匀浆后，收集上清，保存待用。
2 酶活检测
将待测样品用反应缓冲液稀释，分别加入抑制剂溶液A：1μM氯吉灵+1μM优降宁以抑制MAO-A，MAO-B活性；加入抑制剂溶液B：1μM氯吉灵+1μM优降宁+1μM莫非吉兰作为空白对照，室温孵育后，加入500μM苄胺盐酸盐、1U/mL HRP及200μM Amplex Red reagent启动反应，参照“VAP-1酶学活性抑制试验”方法，以线性范围内荧光信号-反应时间比值为反应速度，溶媒组为阳性对照计算各剂量组的相对活性，考察化合物对小鼠腹部脂肪中VAP-1酶活的抑制。
试验结果
按照上述方法测定化合物对小鼠腹部脂肪中VAP-1酶活的抑制，如下表8所示。
表8.化合物HC38-E在不同时间和剂量条件下对小鼠腹部脂肪中VAP-1酶活的抑制率
剂量/时间 6小时 10小时 24小时
0.5mg/kg 95.8±3.6％ 90.3±3.2％ 68.1±7.4％
3.0mg/kg 96.4±5.6％ 95.3±1.9％ 78.0±9.3％
结果表明，给药剂量为0.5mg/kg给药6小时，化合物HC38-E对脂肪组织中VAP-1活性平均抑制率高达95％以上，给药24小时，仍有明显抑制；给药剂量为3.0mg/kg给药10小时，化合物HC38-E对脂肪组织中VAP-1活性平均抑制率仍高达95％以上，给药24小时，仍有明显抑制。
试验例8：四氯化碳诱导的小鼠肝损伤模型试验
试剂：
橄榄油：国药集团化学试剂有限公司
四氯化碳：国药集团化学试剂有限公司
试验方法
1 造模方法
雌性BALB/c小鼠腹腔注射25％四氯化碳溶液(四氯化碳：橄榄油＝1:4，体积比)，注射体积为4ml/kg，每周2次，连续6周。
2 分组及给药
小鼠按体重随机分为模型组(0.5％甲基纤维素)，给药化合物HC38-E 3mg/kg组，化合物HC38-E 10mg/kg组，每组10只动物。
造模的同时开始给药，给药体积为10mL/kg，每天单次灌胃给药，连续给药6周。
3 纤维化定量分析
给药结束后安乐死动物，取肝组织，10％福尔马林固定后，制肝组织切片，天狼星红染色。切片采用半自动数字化图像分析系统和测量软件(OsteoMetrics,Inc.,Atlanta,GA)和Olympus光学显微镜进行纤维化面积计算。
试验结果
按照上述方法测定化合物对小鼠肝脏纤维化的影响，如下表9所示。
表9.化合物HC38-E对四氯化碳诱导的小鼠肝纤维化面积的影响
剂量 纤维化面积
溶媒组 1.05±0.27％
10mg/kg 0.56±0.23％
3mg/kg 0.73±0.21％
结果显示，给药6周后，化合物HC38-E在10mg/kg、3mg/kg剂量下均可降低肝部纤维化程度，其中10mg/kg具有显著抗纤维化效果。
试验例9：细胞色素P450同工酶(CYP)抑制试验
试剂：
P450-Glo TM CYP1A2 Screening System，生产厂家：Promega
P450-Glo TM CYP2D6 Screening System，生产厂家：Promega
P450-Glo TM CYP3A4 Screening System，生产厂家：Promega
试验方法：
按照试剂盒说明，分别将10nM CYP1A2，5nMCYP2D6，1nM CYP3A4蛋白与对应的底物(100μM、30μM、3μM)及化合物室温预孵育10min后，加入G6PDH-G6P-NADP再生系统启动反应，反应一段时间后加入检测试剂，于20min后检测化学发光信号。以溶媒组(DMSO)为阴性对照、Membrance(无活性的酶)为空白对照计算抑制率。
百分比抑制率(％)＝(1-(各化合物浓度组信号-空白组信号)/(阴性对照信号-空白组信号))*100
根据不同浓度下化合物对P450酶的抑制率，估算化合物的半数抑制浓度(IC 50)或范围。
IC 50＝X*(1-百分比抑制率(％))/百分比抑制率(％),其中X为化合物测试浓度。
试验结果
按照上述方法测定化合物在10μM、1μM浓度时对三种CYPs的抑制，结果下表10-12中所示。
表10.CYP1A2抑制试验结果
化合物编号 IC 50(μM)
TM38-E 6.73±0.39
表11.CYP2D6抑制试验结果
化合物编号 IC 50(μM)
TM38-E >10
TM66-E >10
表12.CYP3A4抑制试验结果
化合物编号 IC 50(μM)
TM38-E >10
TM66-E >10
上述结果表明，本发明的化合物(例如化合物TM38-E,TM66-E)对3种主要CYP亚型均无明显抑制作用，表明其潜在的药物相互作用可能性相对较低，具有较好的成药性质。
试验例10：肝微粒体稳定性
试剂：
化合物储备液配制：称取测试化合物、双氯芬酸、睾酮和普罗帕酮适量，用1mL左右DMSO校正成浓度分别为10mM储备液，4℃冰箱中保存；
化合物工作液配制：分别取10μL储备液加入到990μL乙腈-水(1:1)中得浓度为100μM的中间溶液，取120μL中间溶液，用2880μL PBS进一步稀释得4μM的工作液；
NADPH工作液配制：称取适量NADPH，用33mM MgCl 2校正成浓度为4mM的 NADPH工作液；
肝微粒体工作液配制：分别取人、猴、犬、大鼠、小鼠肝微粒体100μL，用1900μL PBS稀释成1mg/mL的肝微粒体工作液。
试验方法：
按照下表13试验条件配制测试化合物的反应液
表13.试验条件
Figure PCTCN2018083792-appb-000066
孵育一定时间后，加入等体积冰冷乙腈(4℃)终止反应，采用LC-MS/MS测定化合物在各种属肝微粒体中孵育不同时间后的浓度，以孵育时间为横坐标，各时间点化合物的剩余量百分比的自然对数为纵坐标作图，其斜率为速度常数(Ke)，并根据下述公式计算其半衰期(T 1/2)与清除率(CL liver)，以此来评价在肝微粒体中的稳定性。
T 1/2＝ln(2)/Ke
肝脏清除率(CL liver)＝Ke/每毫升反应液中所含的微粒体蛋白量(mg)×每克肝脏所含的微粒体蛋白量(mg)×每公斤体重对应的肝脏重量(g)
试验结果
化合物在不同种属动物肝微粒体中的稳定性测试结果见下表14。
表14.肝微粒体稳定性测试结果
Figure PCTCN2018083792-appb-000067
上述结果表明，本发明的化合物(例如化合物HC38-E)在人、猴、犬、大鼠、小鼠肝微粒体中半衰期(T 1/2)均较长，体内清除率均较低，具有良好的稳定性。
试验例11：Caco-2渗透性试验
试剂：
培养基：10％FBS+1％非必须氨基酸+90％DMEM(高糖)
渗透液(pH 7.4)：HBSS(Ca +，Mg +)+10mM Hepes
化合物储备液：称取一定量的待测化合物，加入一定量DMSO配制成10mM储备液。
试验方法：
将细胞按6*10 4个/cm 2接种到Transwell小室中，A侧(基顶侧)加入培养基200μL，B侧(基底侧)加入培养基1000μL。接种后每两天换液一次，培养至21～28天。
在Caco-2细胞接种21～28天后，测定跨膜电阻值。
渗透性实验：测定细胞跨膜电阻值后，将两侧缓冲液吸除，按以下体系加入溶液。
按照下表15试验条件分别配制各实验组反应液
表15.试验条件及分组表
Figure PCTCN2018083792-appb-000068
其中“-”表示不存在。
荧光黄：孵育两小时后，分别取A侧和B侧100μL，通过酶标仪在Ex＝485nm，Em＝530nm波长处测定荧光值，计算透过量(小于1％)。
样品处理：孵育两小时后，分别吸取A侧和B侧50μL，加入等体积冰冷乙腈终止反应，采用LC-MS/MS方法检测AB两侧化合物的浓度，以下述公式计算表观渗透性(Papp)与外排率(Efflux Ratio)。
Papp＝(dCr/dt)x Vr/(A x C 0)
Efflux Ratio＝Papp(BA)/Papp(AB)
其中，dCr/dt为基底侧化合物浓度对时间的积分，Vr为基底侧反应体积，A为单层细胞的面积，面积为0.33cm 2,C 0为基顶侧化合物的浓度。
试验结果
化合物在Caco-2细胞渗透性试验结果见下表16
表16.Caco-2渗透性结果
Figure PCTCN2018083792-appb-000069
Figure PCTCN2018083792-appb-000070
上述结果表明，本发明的化合物(例如HC38-E)具有高的渗透性，经主动转运外排可能性较小。
试验例12：大鼠PK试验
供试品配制：
测试化合物按下表17方法配制
表17.待测化合物配制表
Figure PCTCN2018083792-appb-000071
试验方法：
雄性大鼠分别静脉(iv)与灌胃(po)给予待测化合物，采用LC-MS/MS测定大鼠体内化合物的血浆浓度，利用WinNonlin 6.3软件计算主要药代动力学参数。
试验设计分组见下表18。
表18.试验设计分组表
Figure PCTCN2018083792-appb-000072
试验结果
待测化合物在大鼠血浆中的PK测试结果见下表19。
表19 待测化合物在大鼠血浆中的PK数据
Figure PCTCN2018083792-appb-000073
Figure PCTCN2018083792-appb-000074
“/”表示不存在
结果表明，本发明的化合物通过静脉(iv)或灌胃(po)均具有良好的药代动力学参数，本发明的化合物(例如：化合物HC38-E的平均生物利用度(F％)达到89.9％)具有良好的口服生物利用度。
上述实施例不以任何方式限制本发明。尽管本发明的具体实施方式已经得到详细的描述，根据已经公开的所有教导，本领域技术人员可以对本发明技术方案的细节进行各种修改和替换，这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。

Claims (15)

  1. 式I所示化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体、同位素标记的化合物，或它们的任意晶型或消旋物，或它们的代谢物形式，以及它们的混合物,
    Figure PCTCN2018083792-appb-100001
    其中，
    R 1选自氢、卤素、C 1-6烷基、3-10元环烷基-CH 2NHC(O)-、3-8元脂杂环基-CH 2NHC(O)-、6-20元芳基-CH 2NHC(O)-、5-20元杂芳基-CH 2NHC(O)-、5-20元稠杂芳基-CH 2NHC(O)-、苯并3-10元环烷基-NHC(O)-、3-8元脂杂环基-NHC(O)-、6-20元芳基-NHC(O)-、5-20元杂芳基-NHC(O)-、5-20元稠杂芳基-NHC(O)-；并且，所述C 1-6烷基、3-10元环烷基-CH 2NHC(O)-、3-8元脂杂环基-CH 2NHC(O)-、6-20元芳基-CH 2NHC(O)-、5-20元杂芳基-CH 2NHC(O)-、5-20元稠杂芳基-CH 2NHC(O)-、苯并3-10元环烷基-NHC(O)-、3-8元脂杂环基-NHC(O)-、6-20元芳基-NHC(O)-、5-20元杂芳基-NHC(O)-、5-20元稠杂芳基-NHC(O)-未被取代或独立地被一个或多个(例如1、2、3或4个)选自卤素、羟基、-NRR’、C 1-3烷基、C 1-3烷氧基和氰基的取代基取代；
    R 2各自独立地选自氢、氰基、硝基、羟基、卤素、C 1-6烷基、3-10元环烷基、3-8元脂杂环基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基；
    n＝1，2或3；
    R 3和R 4选自：
    (a)R 3选自3-10元环烷基-CH 2、3-8元脂杂环基-CH 2、6-20元芳基-CH 2、5-20元杂芳基-CH 2、5-20元稠杂芳基-CH 2、苯并3-10元环烷基、苯并3-8元脂杂环基、苯基-3-10元环烷基、5-20元杂芳基-苯基、5-20元稠杂芳基-苯基、3-8元脂杂环基、6-20元芳基、5-20元杂芳基、5-20元稠杂芳基；并且，所述3-10元环烷基-CH 2、3-8元脂杂环基-CH 2、6-20元芳基-CH 2、5-20元杂芳基-CH 2、5-20元稠杂芳基-CH 2、苯并3-10元环烷基、苯并3-8元脂杂环基、苯基-3-10元环烷基、5-20元杂芳基-苯基、5-20元稠杂芳基-苯基、3-8元脂杂环基、6-20元芳基、5-20元杂芳基、5-20元稠杂芳基未被取代或独立地被一 个或多个(例如1、2、3或4个)选自卤素、羟基、-NRR’、C 1-3烷基、C 1-3烷氧基、氰基、3-10环烷基、3-8元脂杂环基、6-20元芳基、5-20元杂芳基、5-20元稠杂芳基、卤代C 1-3烷基、卤代C 1-3烷氧基、C 1-3烷氧基-C 1-3烷基、C 1-3烷氧基-C 1-3烷氧基、C 1-3烷氧基-C 1-3烷氧基-C 1-3烷基的取代基取代；R 4选自氢、C 1-6烷基、卤代C 1-6烷基；
    (b)R 3与R 1相连形成环X，所述环X为5-8元脂环或5-8元脂杂环；并且，所述5-8元脂环或5-8元脂杂环未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自O＝、卤素、氰基、-NRR’、硝基、羟基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、6-20元芳基、5-20元杂芳基和5-20元稠杂芳基的取代基取代；或者，所述5-8元脂环或5-8元脂杂环与3-8元脂环形成螺环结构；R 4选自氢、C 1-6烷基、3-8元环烷基、3-8元脂杂环基、6-10元芳基、5-10元杂芳基、5-10元稠杂芳基；并且，所述C 1-6烷基、3-8元环烷基、3-8元脂杂环基、6-10元芳基、5-10元杂芳基、5-10元稠杂芳基-任选地被一个或多个(例如1、2、3或4个)选自卤素、-NRR’、氰基、羟基、C 1-4烷基、C 1-4烷氧基、3-8元环烷基、3-8元脂杂环基、6-10元芳基、5-10元杂芳基或5-10元稠杂芳基的取代基取代；其中，所述的C 1-4烷基、3-8元环烷基、3-8元脂杂环基、6-10元芳基、5-10元杂芳基或5-10元稠杂芳基-任选地被一个或多个(例如1、2、3或4)选自卤素、-NRR’、C 1-3烷基、C 1-3烷氧基的取代基取代；
    (c)R 3与R 4相连形成环Y，所述环Y为5-8元脂杂环或5-8元脂环；并且，所述5-8元脂杂环或5-8元脂环未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自卤素、氰基、-NRR’、硝基、羟基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、6-20元芳基、5-20元杂芳基和5-20元稠杂芳基的取代基取代，其中，所述C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、6-20元芳基、5-20元杂芳基和5-20元稠杂芳基未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自卤素、氰基、-NRR’、C 1-6烷基、C 1-6烷氧基、6-20元芳基、5-20元杂芳基和5-20元稠杂芳基的取代基取代；或者，所述5-8元脂杂环或5-8元脂环与6-20元芳环或5-20元杂芳环形成稠合环系，其中，所述稠合环系未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自卤素、氰基、-NRR’、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、6-20元芳基、5-20元杂芳基和5-20元稠杂芳基的取代基取代；
    (d)R 3与M相连形成环Z，所述环Z为3-10元脂杂环、6-20元芳环或5-20元杂芳环；并且，所述3-10元脂杂环、6-20元芳环或5-20元杂芳环未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自卤素、氰基、-NRR’、硝基、羟基、＝O、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、6-20元芳基、5-20元杂芳基和5-20 元稠杂芳基的取代基取代；或者，所述3-10元脂杂环、6-20元芳环或5-20元杂芳环与6-20元芳环或5-20元杂芳环形成稠合环系，其中，所述稠合环系未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自卤素、氰基、-NRR’、C 1-6烷基、卤代C 1-6烷基、卤代C 1-6烷氧基、6-20元芳基、5-20元杂芳基和5-20元稠杂芳基的取代基取代；R 4选自氢、C 1-6烷基、C 1-6烷氧基、不存在或形成价键；
    R 5选自卤素；
    R 6选自氢、C 1-6烷基和-COOR；其中，所述C 1-6烷基未被取代或被一个或多个(例如1、2、3或4个)选自卤素、羟基、氨基和氰基的取代基取代；
    A原子选自C、N、O和S；
    M选自C、N、O、H 2和＝NR；
    R和R’各自独立地选自氢、卤素、氰基、羟基、C 1-3烷基、C 1-3烷氧基、3-8元环烷基、3-8元脂杂环基、6-10元芳基、5-10元杂芳基和5-10元稠杂芳基；
    优选地R 1不为氢，
    Figure PCTCN2018083792-appb-100002
    独立地整体为氢；
    优选地，所述化合物为任意比例的顺式构型和反式构型化合物的混合物；
    优选地，所述化合物为顺式(Z)构型；
    优选地，所述化合物为反式(E)构型。
  2. 权利要求1的化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体、同位素标记的化合物，或它们的任意晶型或消旋物，或它们的代谢物形式，以及它们的混合物，其中，所述化合物具有式II所示结构，
    Figure PCTCN2018083792-appb-100003
    其中，所述式II化合物中，R 3选自3-10元环烷基-CH 2、3-8元脂杂环基-CH 2、6-20元芳基-CH 2、5-20元杂芳基-CH 2、5-20元稠杂芳基-CH 2、苯并3-10元环烷基、苯并3-8元脂杂环基、苯基-3-10元环烷基、5-20元杂芳基-苯基、5-20元稠杂芳基-苯基、3-8元脂杂环基、6-20元芳基、5-20元杂芳基、5-20元稠杂芳基；并且，所述3-10元环烷基-CH 2、3-8元脂杂环基-CH 2、6-20元芳基-CH 2、5-20元杂芳基-CH 2、5-20元稠杂芳基-CH 2、苯并3-10元环烷基、苯并3-8元脂杂环基、苯基-3-10元环烷基、5-20元杂芳基-苯基、5-20 元稠杂芳基-苯基、3-8元脂杂环基、6-20元芳基、5-20元杂芳基、5-20元稠杂芳基未被取代或独立地被一个或多个(例如1、2、3或4个)选自卤素、羟基、-NRR’、C 1-3烷基、C 1-3烷氧基、氰基、3-10环烷基、3-8元脂杂环基、6-20元芳基、5-20元杂芳基、5-20元稠杂芳基、卤代C 1-3烷基、卤代C 1-3烷氧基、C 1-3烷氧基-C 1-3烷基、C 1-3烷氧基-C 1-3烷氧基、C 1-3烷氧基-C 1-3烷氧基-C 1-3烷基的取代基取代；R 4选自氢、C 1-6烷基、卤代C 1-6烷基；
    R 1、R 2、R 5、R 6、R、R’和n的定义如式I所定义；
    优选地，所述式II化合物中，R 3选自3-10元环烷基-CH 2、3-8元脂杂环基-CH 2、6-20元芳基-CH 2、5-20元杂芳基-CH 2、5-20元稠杂芳基-CH 2、苯并3-10元环烷基、苯并3-8元脂杂环基、苯基-3-10元环烷基、5-20元杂芳基-苯基、5-20元稠杂芳基-苯基、3-8元脂杂环基、6-20元芳基、5-20元杂芳基、5-20元稠杂芳基；并且，所述3-10元环烷基-CH 2、3-8元脂杂环基-CH 2、6-20元芳基-CH 2、5-20元杂芳基-CH 2、5-20元稠杂芳基-CH 2、苯并3-10元环烷基、苯并3-8元脂杂环基、苯基-3-10元环烷基、5-20元杂芳基-苯基、5-20元稠杂芳基-苯基、3-8元脂杂环基、6-20元芳基、5-20元杂芳基、5-20元稠杂芳基未被取代或独立地被一个或多个(例如1或2个)选自卤素、羟基、-NRR’、C 1-3烷基、C 1-3烷氧基、氰基、3-10环烷基、3-8元脂杂环基、6-20元芳基、5-20元杂芳基、5-20元稠杂芳基、卤代C 1-3烷基、卤代C 1-3烷氧基、C 1-3烷氧基-C 1-3烷基、C 1-3烷氧基-C 1-3烷氧基、C 1-3烷氧基-C 1-3烷氧基-C 1-3烷基的取代基取代；R 4选自H或甲基；
    R 1选自H、卤素、C 1-3烷基；R 2选自氢、氰基、硝基、卤素、C 1-3烷基、C 1-3烷氧基，且n＝1；
    R 5、R 6、R和R’的定义如式I所定义；
    优选地，所述式II化合物中，R 3选自6-15元芳基、苯并3-8元环烷基、苯并3-8元脂杂环基、3-8元脂杂环基、5-10元杂芳基-CH 2、5-10元稠杂芳基-CH 2、3-8元环烷基-CH 2、3-8元脂杂环基-CH 2、6-10元芳基-CH 2、5-10元杂芳基、5-10元稠杂芳基；并且，所述6-15元芳基、苯并3-8元环烷基、苯并3-8元脂杂环基、3-8元脂杂环基、5-10元杂芳基-CH 2、5-10元稠杂芳基-CH 2、3-8元环烷基-CH 2、3-8元脂杂环基-CH 2未被取代或独立地被一个或多个(例如1或2)选自卤素、C 1-3烷基、C 1-3烷氧基-C 1-3烷氧基和NRR’的取代基取代；其中，R和R’各自独立地选自H和C 1-3烷基；R 4选自H或甲基；
    R 1选自H、卤素；R 2选自H、卤素、C 1-3烷基、C 1-3烷氧基，且n＝1；
    R 5和R 6的定义如式I所定义；
    优选地，R 3选自3-7元环烷基-CH 2、3-7元脂杂环基-CH 2、6-10元芳基-CH 2、5-6 元杂芳基-CH 2、苯并3-7元环烷基、3-7元脂杂环基、6-10元芳基、5-10元杂芳基、5-10元稠杂芳基-CH 2；R 4为H；
    R 1选自H；R 2选自H或卤素，且n＝1；R 5为F；R 6为H。
  3. 权利要求1的化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体、同位素标记的化合物，或它们的任意晶型或消旋物，或它们的代谢物形式，以及它们的混合物，其中，所述化合物具有式III所示结构，
    Figure PCTCN2018083792-appb-100004
    其中，所述环X为5-8元脂环或5-8元脂杂环；并且，所述5-8元脂环或5-8元脂杂环未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自＝O、卤素、氰基、-NRR’、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、6-10元芳基、5-10元杂芳基和5-10元稠杂芳基的取代基取代；或者，所述5-8元脂环或5-8元脂杂环与3-8元脂环形成螺环结构；
    R 4选自氢、C 1-6烷基、3-8元环烷基、3-8元脂杂环基、6-10元芳基、5-10元杂芳基、5-10元稠杂芳基；并且，所述C 1-6烷基、3-8元环烷基、3-8元脂杂环基、6-10元芳基、5-10元杂芳基或5-10元稠杂芳基任选地被一个或多个(例如1、2、3或4个)选自卤素、氰基、-NRR’、羟基、C 1-4烷基、C 1-4烷氧基、3-8元环烷基、3-8元脂杂环基、6-10元芳基、5-10元杂芳基或5-10元稠杂芳基的取代基取代；
    R 2、R 5、R 6、R、R'和A的定义如式I所定义；
    优选地，所述式III化合物中，环X为5-7元脂环或5-7脂杂环；并且，所述5-7元脂环或5-7元脂杂环未被取代或被一个或多个(例如1、2、3或4个)选自＝O、卤素、C 1-4烷基、6-10元芳基、5-10元杂芳基或5-10元稠杂芳基的取代基取代；或者，所述5-7元脂环或5-7元脂杂环与3-6元脂环形成螺环结构；A选自N和C；R 2选自F、Cl、H；R 4选自H、CH 3、CH 2CH 3；R 5为F；R 6为H；
    优选地，所述式III化合物中，环X为5-6元脂环或5-6元脂杂环；并且，所述5-6元脂环或5-6元脂杂环未被取代或被一个或多个(例如1、2或3)选自O＝、卤素、C 1-3烷基的取代基取代；其中A选自N和C；R 2选自F、H；R 4选自H、CH 3、CH 2CH 3；R 5选自F；R 6为H。
  4. 权利要求1的化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体、同位素标记的化合物，或它们的任意晶型或消旋物，或它们的代谢物形式，以及它们的混合物，其中，所述化合物具有式IV所示结构，
    Figure PCTCN2018083792-appb-100005
    其中，所述环X为5-8元脂环或5-8元脂杂环；并且，所述5-8元脂环或5-8元脂杂环未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自＝O、卤素、氰基、-NRR’、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、6-10元芳基、5-10元杂芳基和5-10元稠杂芳基的取代基取代；或者，所述5-8元脂环或5-8元脂杂环与3-8元脂环形成螺环结构；
    R 4选自氢、C 1-6烷基、3-8元环烷基、3-8元脂杂环基、6-10元芳基、5-10元杂芳基、5-10元稠杂芳基；并且，所述C 1-6烷基、3-8元环烷基、3-8元脂杂环基、6-10元芳基、5-10元杂芳基、5-10元稠杂芳基任选地被一个或多个(例如1、2、3或4个)选自卤素、氰基、羟基、C 1-4烷基、C 1-4烷氧基、3-8元环烷基、3-8元脂杂环基、6-10元芳基、5-10元杂芳基或5-10元稠杂芳基的取代基取代；其中，所述的C 1-4烷基、3-8元环烷基、3-8元脂杂环基、6-10元芳基、5-10元杂芳基或5-10元稠杂芳基任选地被一个或多个(例如1、2或3)选自卤素、-NRR’、C 1-3烷基的取代基取代；
    R 2、R 5、R 6、R、R’、A和n的定义如式I所定义；
    优选地，所述式IV化合物中，环X为5-7元脂环或5-7元脂杂环；并且，所述5-7元脂环或5-7元脂杂环未被取代或被一个或多个(例如1、2、3或4个)选自＝O、卤素、C 1-4烷基、6-10元芳基、5-10元杂芳基和5-10元稠杂芳基的取代基取代；或者，所述5-7元脂环或5-7元脂杂环与3-6元脂环形成螺环结构；A选自N和C；R 2独立地选自F、Cl、H，且n＝1或2；R 4选自H、C 1-4烷基、苄基或卤代苄基；R 5选自F；R 6选自H；
    优选地，所述式IV化合物中，环X为5-6元脂环或5-6元脂杂环；并且，所述5-6元脂环或5-6元脂杂环未被取代或被一个或多个(例如1、2、3或4个)选自＝O、卤素、C 1-4烷基的取代基取代；A选自N和C；R 2独立地选自F、Cl、H，且n＝1；R 4选自H、C 1-4烷基、苄基或氯代苄基；R 5选自F；R 6选自H。
    优选地，所述式IV化合物中，环X为6元脂杂环(例如6元含氮脂杂环，例如哌 啶环)；并且，所述6元脂杂环未被取代或被一个或多个(例如1、2或3)选自＝O、卤素、C 1-3烷基的取代基取代；A为N；R 2独立地选自F、H，且n＝1；R 4选自H、CH 3、CH 2CH 3；R 5选自F；R 6选自H。
  5. 权利要求1的化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体、同位素标记的化合物，或它们的任意晶型或消旋物，或它们的代谢物形式，以及它们的混合物，其中，所述化合物具有式V所示结构，
    Figure PCTCN2018083792-appb-100006
    其中，所述环Y为5-8元脂杂环或5-8元脂环；并且，所述5-8元脂杂环或5-8元脂环未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自卤素、氰基、-NRR’、硝基、羟基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、6-20元芳基、5-20元杂芳基和5-20元稠杂芳基的取代基取代，其中，所述C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、6-20元芳基、5-20元杂芳基和5-20元稠杂芳基未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自卤素、氰基、-NRR’、C 1-6烷基、6-20元芳基、5-20元杂芳基、5-20元稠杂芳基的取代基取代；或者，所述5-8元脂杂环或5-8元脂环与6-20元芳环或5-20元杂芳环形成稠合环系，其中，所述稠合环系未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自卤素、氰基、-NRR’、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、6-20元芳基、5-20元杂芳基或5-20元稠杂芳基的取代基取代；
    R 1、R 2、R 5、R 6、R和R’的定义如式I所定义；A选自N或C；
    优选地，所述式V化合物中，环Y为5-7元脂杂环；并且，所述5-7元脂杂环未被取代或被一个或多个(例如1、2、3或4个)选自卤素、氰基、-NRR’、6-15元芳基和C 1-4烷基取代基取代，其中，所述6-15元芳基、C 1-4烷基未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自卤素、C 1-4烷基、卤代C 1-4烷基和6-10元芳基的取代基取代；或者，所述5-7元脂杂环与6-10元芳环或5-10元杂芳环形成稠合环系，并且，所述稠合环系未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自卤素、 C 1-4烷基、卤代C 1-4烷基和6-10元芳基的取代基取代；
    R 1、R 2、R 5、R 6、R和R’的定义如式I所定义；A为N。
    优选地，所述式V化合物中，环Y为5-7元脂杂环；并且，所述5-7元脂杂环未被取代或被一个或多个(例如1、2、3或4个)选自6-10元芳基的取代基取代；A为N，R 1为H；R 2选自H或F；R 5为F；R 6为H。
  6. 权利要求1的化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体、同位素标记的化合物，或它们的任意晶型或消旋物，或它们的代谢物形式，以及它们的混合物，其中，所述化合物具有式VI所示结构，
    Figure PCTCN2018083792-appb-100007
    其中，所述环Z为3-10元脂杂环、6-20元芳环或5-20元杂芳环；并且，所述3-10元脂杂环、6-20元芳环或5-20元杂芳环未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自卤素、氰基、-NRR’、硝基、羟基、＝O、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、6-20元芳基、5-20元杂芳基和5-20元稠杂芳基的取代基取代；或者，所述3-10元脂杂环、6-20元芳环或5-20元杂芳环与6-20元芳环或5-20元杂芳环形成稠合环系，其中，所述稠合环系未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自卤素、氰基、-NRR’、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、6-20元芳基、5-20元杂芳基和5-20元稠杂芳基的取代基取代；
    R 4选自氢、C 1-6烷基、C 1-6烷氧基、不存在或形成价键；
    R 1、R 2、R 5、R 6、R、R’、A、M和n的定义如式I所定义；
    优选地，所述式VI化合物中，环Z为5-7元脂杂环、6-10元芳环或5-10元杂芳环，并且，所述5-7元脂杂环、6-10元芳环或5-10元杂芳环未被取代或各自独立地被一个或多个(例如1、2、3或4)选自卤素、氰基、-NRR’、硝基、羟基、C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷基、卤代C 1-6烷氧基的取代基取代；或者，所述5-7元脂杂环、6-10元芳环或5-10元杂芳环与6-10元芳环或5-10元杂芳环形成稠合环系，其中，所述稠合环系未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自卤素、氰基、-NRR’、 C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷基、卤代C 1-3烷氧基、6-10元芳基、5-10元杂芳基和5-10元稠杂芳基的取代基取代；
    R 4选自氢、C 1-6烷基、不存在或形成价键；
    R 1选自氢、卤素；R 2各自独立地选自氢、卤素或氰基，且n＝1或2；R 5选自F或Cl；R 6选自氢、C 1-6烷基；A选自N和S；M选自N；
    R和R’的定义如式I所定义；
    优选地，所述式VI化合物中，环Z为5-7元脂杂环、6-10元芳环或5-10元杂芳环；并且，所述5-7元脂杂环、6-10元芳环或5-10元杂芳环未被取代或各自独立地被一个或多个(例如1、2或3)选自卤素、氰基、-NRR’、硝基、羟基、C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷基、卤代C 1-6烷氧基的取代基取代；其中，R和R’各自独立地选自氢和C 1-3烷基；或者，所述5-7元脂杂环、6-10元芳环或5-10元杂芳环与6-10元芳环或5-10元杂芳环形成稠合环系，其中，所述稠合环系未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自卤素、氰基、-NRR’、C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷基、卤代C 1-3烷氧基的取代基取代；其中，R和R’各自独立地选自氢和C 1-3烷基；
    R 4选自氢、C 1-6烷基、不存在或形成价键；
    R 1选自H、卤素；R 2各自独立地选自H或F，且n＝1或2；
    R 5选自F或Cl；
    R 6选自H、C 1-6烷基；
    A选自N；
    M选自N。
  7. 权利要求1-6任一项的化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体、同位素标记的化合物，或它们的任意晶型或消旋物，或它们的代谢物形式，以及它们的混合物，其中，所述化合物选自：
    Figure PCTCN2018083792-appb-100008
    Figure PCTCN2018083792-appb-100009
    Figure PCTCN2018083792-appb-100010
    Figure PCTCN2018083792-appb-100011
    Figure PCTCN2018083792-appb-100012
    Figure PCTCN2018083792-appb-100013
    Figure PCTCN2018083792-appb-100014
  8. 权利要求1-7任一项的化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体、同位素标记的化合物，或它们的任意晶型或消旋物，或它们的代谢物形式，以及它们的混合物，其中，所述药学可接受的盐为盐酸盐或三氟乙酸盐，优选地，所述药学可接受的盐为盐酸盐。
  9. 权利要求1-8任一项的化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体、同位素标记的化合物，或它们的任意晶型或消旋物，或它们的代谢物形式，以及它们的混合物，其中，所述药学可接受的盐为：
    Figure PCTCN2018083792-appb-100015
  10. 权利要求1-9任一项的化合物或其药学可接受的盐、酯、溶剂化物、水合物、 异构体、同位素标记的化合物，或它们的任意晶型或消旋物，或它们的代谢物形式，以及它们的混合物，其中，所述药学可接受的盐为：
    Figure PCTCN2018083792-appb-100016
  11. 药物组合物，其含有权利要求1-10任一项的化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体、同位素标记的化合物，或它们的任意晶型或消旋物，或它们的代谢物形式，以及或它们的混合物，以及一种或多种药用辅料。
  12. 一种制备权利要求1-7任一项的化合物的方法，其中，式I中R 6为氢时，所述方法选自以下方案：
    方案一：
    将化合物SM-1与化合物INT-1进行亲核取代反应生成化合物INT-2；化合物INT-2脱保护基得到目标产物；
    Figure PCTCN2018083792-appb-100017
    方案二：
    将化合物SM-1与化合物INT-3进行Mitsunobu反应生成化合物INT-2；化合物INT-2脱保护基得到目标产物；
    Figure PCTCN2018083792-appb-100018
    方案三：
    将化合物SM-2与化合物INT-1进行亲核取代反应生成化合物INT-4；化合物INT-4发生偶联反应得到化合物INT-2；化合物INT-2脱保护基得到目标产物；
    Figure PCTCN2018083792-appb-100019
    方案四：
    将化合物SM-2与化合物INT-3进行Mitsunobu反应得到化合物INT-4；化合物INT-4进行偶联反应得到化合物INT-2；化合物INT-2脱保护基得到目标产物；
    Figure PCTCN2018083792-appb-100020
    方案五：
    将化合物SM-3与化合物INT-1进行亲核取代反应生成化合物INT-5；化合物INT-5脱保护基得到目标产物；
    Figure PCTCN2018083792-appb-100021
    方案六：
    将化合物SM-3与化合物INT-3进行Mitsunobu反应生成化合物INT-5；化合物INT-2脱保护基得到目标产物；
    Figure PCTCN2018083792-appb-100022
    其中，Lg表示离去基团，如卤素、-OTs等；P表示氨基保护基，如Boc、Cbz、Fmoc、苄基等；其余原子和基团如权利要求1-7所定义。
  13. 权利要求1-10任一项的化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体、同位素标记的化合物，或它们的任意晶型或消旋物，或它们的代谢物形式，以及它们的混合物，或者如权利要求11所述的药物组合物在制备治疗与VAP-1/SSAO过度活性相关的疾病或病症的药物中的用途。
  14. 权利要求13的用途，其中所述与VAP-1/SSAO过度活性相关的疾病或病症选自炎症性疾病(如与肝脏相关的炎症性疾病，例如肝炎、肝肿大、肝纤维化、肝硬化或肝腹水；如与呼吸道相关的炎症性疾病，例如气管炎、肺炎、肺纤维化、哮喘、急性肺损伤、急性呼吸窘迫综合征、支气管炎或慢性阻塞性肺病；如与眼相关的炎症性疾病，例如葡萄膜炎；如其它炎症，例如滑膜炎或腹膜炎)、器官和/或组织移植排斥、自身免疫性疾病(例如风湿性关节炎或多发性硬化(例如慢性多发性硬化))、皮肤病(例如湿疹或牛皮癣)、糖尿病和中风。
  15. 一种治疗与VAP-1/SSAO过度活性相关的疾病或病症的方法，包括给有此需要的受试者施用治疗有效量权利要求1-10任一项的化合物，其药学可接受的盐、酯、水合物、溶剂化物、异构体、同位素标记的化合物，它们的任意晶体或消旋物，或它们的代谢物形式，以及或它们的混合物，或者如权利要求11所述的药物组合物。
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