CN107849014A - A kind of biphenyl derivatives and preparation method thereof and purposes in medicine - Google Patents

A kind of biphenyl derivatives and preparation method thereof and purposes in medicine Download PDF

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Publication number
CN107849014A
CN107849014A CN201680042175.6A CN201680042175A CN107849014A CN 107849014 A CN107849014 A CN 107849014A CN 201680042175 A CN201680042175 A CN 201680042175A CN 107849014 A CN107849014 A CN 107849014A
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ethyl
alkyl
oxo
cyano
phenyl
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CN107849014B (en
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郑苏欣
张国彪
张晓波
李航
魏用刚
邱关鹏
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Sichuan Haisco Pharmaceutical Co Ltd
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Sichuan Haisco Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Abstract

Compound or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug shown in a kind of logical formula (I), and preparation method and the application in preparation is used to treat airway obstructive disease medicine, its formula of (I) compound are

Description

A kind of biphenyl derivatives and preparation method thereof and purposes in medicine Technical field
Application the present invention relates to a kind of biphenyl derivatives and preparation method thereof and in medicine, it is specifically a kind of that there is muscarinic receptor antagonism and β2The novel biphenyl derivatives or its stereoisomer, hydrate, solvate, metabolite, pharmaceutically acceptable salt, eutectic or prodrug of the dynamic double activity of adrenergic receptor kinase 1, its pharmaceutical composition and its application in medicine.
Background technique
Bronchodilator plays an important role for the treatment of respiratory disorder such as Chronic Obstructive Pulmonary Disease (COPD) and asthma etc..Widely used bronchodilator includes muscarinic receptor antagonists and beta 2-adrenergic agonist in clinic.Muscarinic receptor antagonists play bronchiectasic effect by reducing the vagal cholinergic tone of airway smooth muscle.Sucking muscarinic receptor antagonists used at present include Ipratropium Bromide, oxitropium bromide, glycopyrronium bromide, Tiotropium Bromide, Ah 's bromo-amine and overgrown with weeds ground bromo-amine.Beta 2-adrenergic agonist reverses reaction of the bronchoconstriction agent to various media such as acetylcholine by stimulating the adrenergic receptor of airway smooth muscle to make bronchiectasis.Beta 2-adrenergic agonist used at present includes salbutamol, salmeterol, Afromoterol, formoterol, Vilantro and datro.These drugs in addition to improve lung function, can also improve patients ' life quality and reduce sb.'s illness took a turn for the worse.
As more clinical researches are found, it is more more effective than one of therapeutic agent is used alone that muscarinic receptor antagonists and beta 2-adrenergic agonist is used in combination in proof, muscarinic receptor antagonists and beta 2-adrenergic agonist are clinically prepared into compound preparation at present, for the treatment of asthma and middle severe COPD, this kind of compound preparation mainly includes Anoro Ellipta (overgrown with weeds ground bromo-amine/Vilantro), Ultibro Breezhaler (glycopyrronium bromide/datro) and SCH 1000/salbutamol etc..Although compound preparation has better therapeutic effect than wherein single formulation, there is higher requirement in preparation preparation.
Accordingly it is desirable to develop while having the drug of muscarinic receptor antagonism and beta 2-adrenergic excitement double action, this difunctional drug tool is provided simultaneously with single molecule pharmacokinetics there are two types of the pharmaceutical advantages at subassembly.These compounds are administered in the form of single therapy agent, by two kinds of differences and the binding mode to work can may be cooperateed with to provide bronchiectatic activity.In addition, compound with muscarinic receptor antagonism and beta 2-adrenergic excitement double action (MABA) can also be combined with corticosteroid (ICS) anti-inflammatory agent pharmaceutical, formed two kinds of therapeutic agents (MABA/ICS) and provided the therapeutic effect (Expert Opin.Investig.Drugs (2014) 23 (4): 453-456) of triple role.
Therefore, it is necessary to double activity while developing novelty with muscarinic receptor antagonism and beta 2-adrenergic excitement Drug provides more clinical application selections to provide more effective single therapy dosage or compound preparation for patient.
Summary of the invention
The present invention provides a kind of logical formula (I) compound represented or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug,
Wherein:
R1、R2It is independently selected from F, Cl, Br, I, CF3、C1-4Alkyl, cyano ,-OR1a,-C (=O) OR1b、-SR1c、-S(O)R1d、-S(O)2R1eOr-NR1fR1g；
R1a、R1b、R1c、R1d、R1e、R1fAnd R1gIt is independently selected from H or C1-4Alkyl；
Alternatively, R1f、R1gNitrogen-atoms connected to it forms one 5 to 6 yuan of heterocycle, and the heterocycle contains 1,2 or 3 hetero atom for being selected from N, O or S；
W is-O- ,-NH- or-NC1-4Alkyl-；
R3Each it is independently selected from F, Cl, Br, I, CF3, OH, cyano, C1-4Alkyl or C1-4Alkoxy；
R4Selected from C1-6Alkylidene, C2-6Alkenylene or C2-6Alkynylene, the alkylidene, alkenylene or alkynylene are optionally further selected from F, Cl, Br, I, OH, cyano, C by 0,1,2,3,4 or 51-4Alkyl, C1-4Alkoxy, phenyl or phenyl-C1-4Replaced the substituent group of alkylidene；
R5Each it is independently selected from F, Cl, Br, I, OH, NH2, carboxyl, cyano, nitro, C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-4Alkoxy ,-OC3-6Naphthenic base, C1-4Alkylthio group ,-S (O)-C1-4Alkyl ,-S (O)2-C1-4Alkyl ,-C (=O)-C1-4Alkyl ,-C (=O) O-C1-4Alkyl ,-OC (=O)-C1-4Alkyl, 5 to 6 unit's heteroaryls or-C (=O) NH2, the alkyl, alkoxy, naphthenic base, alkenyl, alkynyl, 5 to 6 unit's heteroaryls, NH2With-C (=O) NH2Optionally F, Cl, Br, I, CF further are selected from by 0,1,2,3 or 43、C1-4Alkyl, C1-4Alkoxy or-C (=O)-C1-4Replaced the substituent group of alkyl, and the heteroaryl contains 1,2,3 or 4 hetero atom for being selected from N, O or S；
Y is selected from key ,-CYaYb-、-CYaYbCYaYb-、-NYa-、-CYaYbNYa-、-NYaCYaYb,-O- ,-C=O- ,-CYaYbO-、-OCYaYb-、-S-、-CYaYbS-、-SCYaYb,-S (O)-or-S (O)2-；
Ya、YbIt is independently selected from H or C1-4Alkyl；Or Ya、YbCoupled carbon atom is formed together 3 to 6 yuan of carbocyclic rings；
R6Each it is independently selected from F, Cl, Br, I, C=O, cyano, C1-4Alkyl or C1-4Alkoxy, the alkyl or alkoxy are optionally further selected from F, Cl, Br, I, CH by 0,1,2,3 or 42F、CHF2、CF3Or replaced the substituent group of cyano；
Alternatively, two R6The atom that can be connected with them is formed together 3 to 6 yuan of carbocyclic rings, and the carbocyclic ring is optionally further selected from F, Cl, Br, I, cyano, OH, C by 0,1,2,3,4 or 51-4Alkyl or C1-4Replaced the substituent group of alkoxy；
R7Selected from C1-6Alkylidene, the alkylidene are optionally further selected from R by 0,1,2,3,4 or 57aSubstituent group replaced；
R7aSelected from F, Cl, Br, I, cyano, OH, C1-4Alkyl, C1-4Alkoxy, phenyl or phenyl-C1-4Alkylidene；
Alternatively, two R7aThe atom that can be connected with them is formed together 3 to 6 yuan of carbocyclic rings, and the carbocyclic ring is optionally further selected from F, Cl, Br, I, cyano, OH, C by 0,1,2,3,4 or 51-4Alkyl or C1-4Replaced the substituent group of alkoxy；
R8、R9It is independently selected from H or C1-4Alkyl；
R10Selected from H or hydroxyl；
Expression can be with receptor,β conjugated group；
A is selected from 0,1,2,3,4 or 5；
B is selected from 0,1,2,3 or 4；
C is selected from 0,1,2,3 or 4；
D is selected from 0,1,2 or 3；
E is selected from 0,1,2,3 or 4.
A preferred embodiment of the present invention, a kind of logical formula (I) compound represented or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug, in which:
B is selected fromWherein R11、R12、R13、R14、R15、R16、R17、R18Or R19It is independently selected from H, F, Cl, Br, I, CF3、OH、-CH2OH, cyano, carboxyl, C1-4Alkyl, C1-4Alkoxy ,-C (=O) C1-4Alkyl ,-C (=O) OC1-4Alkyl ,-NHC (=O) H ,-NHS (=O)2-C1-4Alkyl ,-NHS (=O)2-NH2Or-NHS (=O)2-NHC1-4Alkyl, Q are selected from-CRq1Rq2CRq3Rq4-、-O-、-S-、 -OCRq1Rq2-、-CRq1Rq2O-、-SCRq1Rq2-、-CRq1Rq2S-, the Rq1、Rq2、Rq3Or Rq4It is independently selected from selected from H, F, Cl, Br, I or C1-4Alkyl；
B is preferred Q is selected from-CH2CH2,-CH=CH- ,-O- ,-S- ,-CH2O-、-OCH2-、-C(CH3)2O- or-OC (CH3)2-；
B is more preferable
R1、R2It is independently selected from F, Cl, Br, I, CF3、C1-4Alkyl, cyano ,-OR1a,-C (=O) OR1b、-SR1c、-S(O)R1d、-S(O)2R1eOr-NR1fR1g；
R1a、R1b、R1c、R1d、R1e、R1fAnd R1gIt is independently selected from H or C1-4Alkyl；
Alternatively, R1f、R1gNitrogen-atoms connected to it forms one 5 to 6 yuan of heterocycle, and the heterocycle contains 1 to 3 hetero atom for being selected from N, O or S；
W is-O- ,-NH- or-NC1-4Alkyl-；
R3Each it is independently selected from F, Cl, Br, I, CF3, OH, cyano, C1-4Alkyl or C1-4Alkoxy；
R4Selected from C1-6Alkylidene, C2-6Alkenylene or C2-6Alkynylene, preferably C1-6Alkylidene, more preferable C1-4Alkylidene, the alkylidene, alkenylene or alkynylene optionally further by 0,1,2,3,4 or 5 selected from F, Cl, Br, I, OH, cyano, C1-4Alkyl, C1-4Alkoxy, phenyl or phenyl-C1-4Replaced the substituent group of alkylidene；
R5Each it is independently selected from F, Cl, Br, I, OH, NH2, carboxyl, cyano, nitro, C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-4Alkoxy ,-OC3-6Naphthenic base, C1-4Alkylthio group ,-S (O)-C1-4Alkyl ,-S (O)2-C1-4Alkyl ,-C (=O)-C1-4Alkyl ,-C (=O) O-C1-4Alkyl ,-OC (=O)-C1-4Alkyl, 5 to 6 unit's heteroaryls or-C (=O) NH2, preferably F, Cl, Br, I, OH, NH2, carboxyl, cyano, nitro, C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-4Alkoxy ,-OC3-6Naphthenic base or 5 to 6 unit's heteroaryls, the alkyl, alkoxy, naphthenic base, alkenyl, alkynyl, 5 to 6 unit's heteroaryls, NH2With-C (=O) NH2Optionally F, Cl, Br, I, CF further are selected from by 0,1,2,3 or 43、C1-4Alkyl, C1-4Alkoxy or-C (=O)-C1-4Replaced the substituent group of alkyl, and the heteroaryl contains 1,2,3 or 4 hetero atom for being selected from N, O or S；
Y is selected from key ,-CYaYb-、-CYaYbCYaYb-、-NYa-、-CYaYbNYa-、-NYaCYaYb,-O- ,-C=O- ,-CYaYbO-、-OCYaYb-、-S-、-CYaYbS-、-SCYaYb,-S (=O)-or-S (=O)2-；
Ya、YbIt is independently selected from H or C1-4Alkyl, preferably H, methyl or ethyl；Or Ya、YbCoupled carbon atom is formed together 3 to 6 yuan of carbocyclic rings；
R6Each it is independently selected from F, Cl, Br, I, C=O, cyano, C1-4Alkyl or C1-4Alkoxy, the alkyl or alkoxy are optionally further selected from F, Cl, Br, I, CH by 0,1,2,3 or 42F、CHF2、CF3Or replaced the substituent group of cyano；
Alternatively, two R6The atom that can be connected with them is formed together 3 to 6 yuan of carbocyclic rings, and the carbocyclic ring is optionally further selected from F, Cl, Br, I, cyano, OH, C by 0,1,2,3,4 or 51-4Alkyl or C1-4Replaced the substituent group of alkoxy；
R7Selected from C1-6Alkylidene, preferably C1-4Alkylidene, the alkylidene are optionally further selected from R by 0,1,2,3,4 or 57aSubstituent group replaced；
R7aSelected from F, Cl, Br, I, cyano, OH, C1-4Alkyl, C1-4Alkoxy, phenyl or phenyl-C1-4Alkylidene；
Alternatively, two R7aThe atom that can be connected with them is formed together 3 to 6 yuan of carbocyclic rings, and the carbocyclic ring is optionally further selected from F, Cl, Br, I, cyano, OH, C by 0,1,2,3,4 or 51-4Alkyl or C1-4Replaced the substituent group of alkoxy；
R8、R9It is independently selected from H or C1-4Alkyl, preferably H, methyl or ethyl；
R10Selected from H or hydroxyl；
A is selected from 0,1,2,3,4 or 5；
B is selected from 0,1,2,3 or 4；
C is selected from 0,1,2,3 or 4；
D is selected from 0,1,2 or 3；
E is selected from 0,1,2,3 or 4.
A preferred embodiment of the present invention, a kind of logical formula (I) compound represented or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug, in which:
B is selected from Q is selected from-CH2CH2,-CH=CH- ,-O- ,-S- ,-CH2O-、-OCH2-、-C(CH3)2O- or-OC (CH3)2-；
B is preferred
R1And R2It is each independently selected from F, Cl, Br, I, CF3、NH2, OH, cyano, C1-4Alkyl, C1-4Alkoxy, C1-4Alkylthio group ,-NHC1-4Alkyl or-N (C1-4Alkyl)2, preferably F, Cl, Br, I, CF3、NH2, OH, cyano, methyl, ethyl, methoxyl group, ethyoxyl ,-NHCH3Or-N (CH3)2；
W is-O- ,-NH- or-NC1-4Alkyl-, preferably-O- ,-NH- or-NCH3-；
R3Each it is independently selected from F, Cl, Br, I, CF3, OH, cyano, methyl, ethyl, methoxy or ethoxy, preferably F, Cl, Br, I, OH, cyano, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl or propoxyl group；
R4Selected from C1-4Alkylidene, preferably methylene, ethylidene, propylidene or butylidene, the alkylidene, methylene, ethylidene, propylidene or butylidene are optionally further selected from F, Cl, Br, I, OH, cyano, C by 0,1,2,3,4 or 51-4Alkyl, C1-4Alkoxy, phenyl or phenyl-C1-4Replaced the substituent group of alkylidene；
R5Each it is independently selected from F, Cl, Br, I, OH, NH2, carboxyl, cyano, nitro, C1-4Alkyl, C2-4Alkynyl, C1-4Alkoxy ,-OC3-6Naphthenic base, C1-4Alkylthio group ,-S (=O)-C1-4Alkyl ,-S (=O)2-C1-4Alkyl ,-C (=O)-C1-4Alkyl, 5 to 6 unit's heteroaryls or-C (=O) O-C1-4Alkyl, preferably F, Cl, Br, I, OH, NH2, carboxyl, cyano, C1-4Alkyl, C2-4Alkynyl, C1-4Alkoxy ,-OC3-6Naphthenic base or 5 to 6 unit's heteroaryls, more preferable F, Cl, Br, cyano, methyl, ethyl, propyl, isopropyl, CHF2、CF3, methoxyl group, ethyoxyl ,-OCHF2、-OCF3, acetenyl, propinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, thiazolyl or oxazolyl, the alkyl, alkynyl, alkoxy, naphthenic base, heteroaryl, NH2, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, acetenyl, propinyl, pyrrole radicals, imidazole radicals, pyrazolyl, thienyl, furyl, thiazolyl or oxazolyl be optionally further selected from F, Cl, Br, I, CF by 0,1,2,3 or 43、C1-4Alkyl, C1-4Alkoxy or-C (=O)-C1-4Replaced the substituent group of alkyl, and the heteroaryl contains 1,2,3 or 4 hetero atom for being selected from N, O or S；
Y is selected from key ,-CYaYb-、-CYaYbCYaYb-、-NYa-、-CYaYbNYa-、-NYaCYaYb,-O- ,-C=O- ,-CYaYbO-、-OCYaYb-、-S-、-CYaYbS-、-SCYaYb,-S (O)-or-S (O)2-；
Ya、YbIt is independently selected from H or C1-4Alkyl, preferably H, methyl or ethyl；Or Ya、YbCoupled carbon atom is formed together 3 to 6 yuan of carbocyclic rings；
R6Each it is independently selected from F, Cl, Br, I, C=O, cyano, C1-4Alkyl or C1-4Alkoxy, preferably F, Cl, Br, I, C=O, cyano, methyl, ethyl, methoxy or ethoxy, the alkyl or alkoxy are optionally further selected from F, Cl, Br, I, CH by 0,1,2,3 or 42F、CHF2、CF3Or replaced the substituent group of cyano；
R7Selected from C1-4Alkylidene, preferably methylene, ethylidene, propylidene or butylidene, the alkylidene, methylene, ethylidene, propylidene or butylidene are optionally further selected from R by 0,1,2,3,4 or 57aSubstituent group replaced；
R7aSelected from F, Cl, Br, I, cyano, OH, C1-4Alkyl, C1-4Alkoxy or phenyl, preferably F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxyl group, ethyoxyl or phenyl；
Alternatively, two R7aThe atom that can be connected with them is formed together 3 to 6 yuan of carbocyclic rings, and the carbocyclic ring is optionally further selected from F, Cl, Br, I, cyano, OH, C by 0,1,2,3,4 or 51-4Alkyl or C1-4Replaced the substituent group of alkoxy；
R8、R9It is independently selected from H or C1-4Alkyl, preferably H, methyl or ethyl；
R10Selected from H or hydroxyl；
A is selected from 0,1 or 2；
B is selected from 0,1 or 2；
C is selected from 0,1 or 2；
D is selected from 0,1,2 or 3；
E is selected from 0,1,2,3 or 4.
A preferred embodiment of the present invention, a kind of logical formula (I) compound represented or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug, in which:
B is selected from Q is selected from-CH2CH2,-CH=CH- ,-O- ,-S- ,-CH2O-、-OCH2-、-C(CH3)2O- or-OC (CH3)2-；
B is preferred
R1And R2It is each independently selected from F, Cl, Br, I, CF3、NH2, OH, cyano, methyl, ethyl, methoxyl group, ethyoxyl ,-NHCH3Or-N (CH3)2；
W is selected from-O- ,-NH- or-NCH3-；
R3Each it is independently selected from F, Cl, Br, I, OH, cyano, methyl, ethyl, propyl, isopropyl, first Oxygroup, ethyoxyl or propoxyl group；
R4Selected from methylene, ethylidene, propylidene or butylidene；
R5Each it is independently selected from F, Cl, Br, cyano, methyl, ethyl, propyl, isopropyl, CHF2、CF3, methoxyl group, ethyoxyl ,-OCHF2、-OCF3, cyclopropyl oxygroup, acetenyl or propinyl；
Y is selected from key ,-CYaYb-、-CYaYbCYaYb-、-NYa-、-CYaYbNYa-、-NYaCYaYb,-O- ,-C=O- ,-CYaYbO-、-OCYaYb-、-S-、-CYaYbS-、-SCYaYb,-S (O)-or-S (O)2-；
Ya、YbIt is independently selected from H or C1-4Alkyl, preferably H, methyl or ethyl；Or Ya、YbCoupled carbon atom is formed together 3 to 6 yuan of carbocyclic rings；
R6Each F, Cl independent, Br, I, C=O, cyano, methyl, ethyl, methoxy or ethoxy；
Alternatively, two R6The atom that can be connected with them is formed together 3 to 6 yuan of carbocyclic rings, and the carbocyclic ring is optionally further selected from replaced the substituent group of F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy by 0,1,2,3,4 or 5；
R7Selected from methylene, ethylidene, propylidene ,-CH2CH(CH3)-、-CH(CH3)CH2-、-C(CH3)2CH2-、-CH2C(CH3)2, butylidene ,-CH (CH3)CH2CH2-、-CH2CH(CH3)CH2-、-CH2CH(CH3)CH2Or
R8、R9It is independently selected from H or C1-4Alkyl, preferably H, methyl or ethyl；
R10Selected from H or hydroxyl；
A is selected from 0,1 or 2；
B is selected from 0,1 or 2；
C is selected from 0,1 or 2；
D is selected from 0,1,2 or 3；
E is selected from 0,1,2,3 or 4.
The preferred solution of the invention, a kind of logical formula (II) compound represented or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug,
Wherein shown in the numerical value of p1, p2 of each chemical combination and the following table of the substituent group of B:
The preferred solution of the invention, a kind of logical formula (III) compound represented or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug,
Wherein shown in the numerical value of the p2 of each chemical combination and the following table of the substituent group of Z, B:
The preferred solution of the invention, a kind of logical formula (IV) compound represented or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug,
Wherein shown in the numerical value of the p2 of each chemical combination and the following table of the substituent group of Z, B:
The present invention relates to compounds, including but not limited to:
The invention further relates to provide a kind of pharmaceutical composition, the pharmaceutical composition contains logical formula (I), (II), (III) or (IV) described in any item compounds or one of its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug and pharmaceutically acceptable carrier, diluent, adjuvant, medium and excipient or a variety of for the treatment of effective dose；The composition can also further comprise one or more other therapeutic agents；Preferably, wherein the other therapeutic agents, which are selected from PDE4 inhibitor, muscarinic receptor antagonists, corticosteroid and beta-adrenergic receptor kinase 1, moves one of agent or a variety of.
The invention further relates to provide logical formula (I), (II), compound or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug described in (III) or (IV), or pharmaceutical composition described above is preparing the application in the drug for treating airway obstructive disease, preferably, in preparation for treating the application in asthma, Chronic Obstructive Pulmonary Disease or the drug of bronchitis.
The present invention also provides a kind of methods for treating airway obstructive disease, the method includes above-mentioned logical formula (I), (II), (III) or (IV) described in any item compounds or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug is administered, or above-mentioned pharmaceutical composition, the preferred asthma of the airway obstructive disease, Chronic Obstructive Pulmonary Disease or bronchitis.
Unless there are opposite statement, the term used in the specification and in the claims has following meanings.
Carbon, hydrogen, oxygen, sulphur, nitrogen or halogen involved in group and compound of the present invention include their isotope, and optionally further by one or more, their corresponding isotopes are substituted for carbon involved in group of the present invention and compound, hydrogen, oxygen, sulphur, nitrogen or halogen, wherein the isotope of carbon includes12C、13C and14C, the isotope of hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as superheavy hydrogen), and the isotope of oxygen includes16O、17O and18The isotope of O, sulphur includes32S、33S、34S and36The isotope of S, nitrogen includes14N and15N, the isotope of fluorine19The isotope of F, chlorine includes35Cl and37The isotope of Cl, bromine includes79Br and81Br。
" alkyl " refers to the univalent saturated hydrocarbon radical of straight chain and branch, and main chain includes 1 to 10 carbon atom, preferably 1 to 8 carbon atom, further preferably 1 to 6 carbon atom, the straight chain and branched group of more preferably 1 to 4 carbon atom, Most preferably 1 to 2 carbon atom, the example of alkyl include but is not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl, 2- amyl, 3- amyl, 2- methyl -2- butyl, 3- methyl -2- butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and positive decyl etc.；The alkyl optionally further can be selected from F, Cl, Br, I ,=O ,-CH by 0,1,2,3,4 or 52F、-CHF2、-CF3、-OCH2F、-OCHF2、-OCF3, hydroxyl ,-SR18, nitro, cyano, isocyano group, alkyl, hydroxy alkyl, alkoxy, carbocylic radical, heterocycle, C2-8Alkenyl, C2-8Alkynyl ,-(CH2)q- C (=O)-R18、-(CH2)q- C (=O)-O-R18、-(CH2)q- C (=O)-NR18R18a、-(CH2)q- S (=O)k-R18,-O-C (=O)-O-R18Or-NR18R18aSubstituent group replaced, wherein R18And R18aIt is each independently selected from H, hydroxyl, amino, carboxyl, C1-8Alkyl, C1-8Alkoxy, C2-8Alkenyl, C2-8Alkynyl, 3 to 10 yuan of carbocylic radicals, 4 to 10 circle heterocyclic ring bases, 3 to 10 yuan of carbocylic radical oxygroups perhaps 4 to 10 circle heterocyclic ring base oxygroup q be selected from 0,1,2,3,4 perhaps 5 k be selected from 0,1 or 2.Herein presented alkyl, k, q, R18And R18a, as defined above.
" alkylidene " refers to the divalent saturated hydrocarbon base of straight chain and branch, including-(CH2)v(v is integer of 1 to 10), alkylidene embodiment include but is not limited to methylene, ethylidene, propylidene and butylidene etc.；The alkylidene optionally further can be selected from F, Cl, Br, I ,=O ,-CH by 0,1,2,3,4 or 52F、-CHF2、-CF3、-OCH2F、-OCHF2、-OCF3, hydroxyl ,-SR18, nitro, cyano, isocyano group, alkyl, hydroxy alkyl, alkoxy, carbocylic radical, heterocycle, C2-8Alkenyl, C2-8Alkynyl ,-(CH2)q- C (=O)-R18、-(CH2)q- C (=O)-O-R18、-(CH2)q- C (=O)-NR18R18a、-(CH2)q- S (=O)k-R18,-O-C (=O)-O-R18Or-NR18R18aSubstituent group replaced.Herein presented alkylidene, it is as defined above.
" alkoxy " refers to the univalent perssad of O- alkyl, wherein, alkyl is as defined herein, and alkylidene embodiment includes but is not limited to methoxyl group, ethyoxyl, 1- propoxyl group, 2- propoxyl group, 1- butoxy, 2- methyl-1-propoxyl group, 2- butoxy, 2- methyl-2- propoxyl group, 1- amoxy, 2- amoxy, 3- amoxy, 2- methyl-2- butoxy, 3- methyl-2- butoxy, 3- methyl-1-butoxy and 2-methyl-1-butene oxygroup etc..
" alkenyl " refers to the univalent unsaturated hydrocarbon radical of straight chain and branch, it is at least one, usually have 1, 2 or 3 carbon-carbon double bonds, main chain includes 2 to 10 carbon atoms, further preferred 2 to 6 carbon atoms, more preferably there are 2 to 4 carbon atoms on main chain, alkenyl embodiment includes but is not limited to vinyl, allyl, 1- acrylic, 2- acrylic, 1- cyclobutenyl, 2- cyclobutenyl, 3- cyclobutenyl, 1- pentenyl, 2- pentenyl, 3- pentenyl, 4- pentenyl, 1- methyl-1-cyclobutenyl, 2-methyl-1-butene alkenyl, 2- methyl -3- cyclobutenyl, 1- hexenyl, 2- hexenyl, 3- hexenyl, 4- hexenyl, 5- hexenyl, 1- methyl-1-pentene alkenyl, 2- methyl-1-pentene alkenyl, 1- heptenyl, 2- heptenyl, 3- Heptenyl, 4- heptenyl, 1- octenyl, 3- octenyl, 1- nonenyl, 3- nonenyl, 1- decene base, 4- decene base, 1,3- butadiene, 1,3- pentadiene, 1,4- pentadiene and 1,4- hexadiene etc.；The alkylidene can be optionally further selected from by 0,1,2,3,4 or 5 F, Cl, Br, I ,=O ,-CH2F、-CHF2、-CF3、-OCH2F、-OCHF2、-OCF3, hydroxyl ,-SR18, nitro, cyano, isocyano group, alkyl, hydroxy alkyl, alkoxy, carbocylic radical, heterocycle, C2-8Alkenyl, C2-8Alkynyl ,-(CH2)q- C (=O)-R18、-(CH2)q- C (=O)-O-R18、-(CH2)q- C (=O)-NR18R18a、-(CH2)q- S (=O)k-R18,-O-C (=O)-O-R18Or-NR18R18aSubstituent group replaced.Herein presented alkenyl, it is as defined above.
" alkenylene " refers to that the divalent alkenyl of straight chain and branch, alkenyl are as defined above.
" alkynyl " refers to the univalent unsaturated hydrocarbon radical of straight chain and branch, it is at least one, usually have 1, 2 or 3 triple carbon-carbon bonds, main chain includes 2 to 10 carbon atoms, further preferred 2 to 6 carbon atoms, more preferably there are 2 to 4 carbon atoms on main chain, alkynyl embodiment includes but is not limited to acetenyl, 1- propinyl, 2-propynyl, butynyl, 2- butynyl, 3- butynyl, 1- methyl -2-propynyl, 4- pentynyl, 3- pentynyl, 1- methyl -2- butynyl, 2- hexin base, 3- hexin base, 2- heptynyl, 3- heptynyl, 4- heptynyl, 3- octynyl, 3- n-heptylacetylene base and 4- decynyl etc.；The alkylidene optionally further can be selected from F, Cl, Br, I ,=O ,-CH by 0,1,2,3,4 or 52F、-CHF2、-CF3、-OCH2F、-OCHF2、-OCF3, hydroxyl ,-SR18, nitro, cyano, isocyano group, alkyl, hydroxy alkyl, alkoxy, carbocylic radical, heterocycle, C2-8Alkenyl, C2-8Alkynyl ,-(CH2)q- C (=O)-R18、-(CH2)q- C (=O)-O-R18、-(CH2)q- C (=O)-NR18R18a、-(CH2)q- S (=O)k-R18,-O-C (=O)-O-R18Or-NR18R18aSubstituent group replaced.Herein presented alkynyl, it is as defined above.
" alkynylene " refers to that the divalent alkynyl radical of straight chain and branch, alkynyl are as defined above.
" naphthenic base " refers to the carbocyclic hydrocarbon radicals of monovalence saturation, usually has 3 to 10 carbon atoms, non-limiting embodiment includes cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl or suberyl etc..The naphthenic base optionally further can be selected from F, Cl, Br, I ,=O ,-CH by 0 to 52F、-CHF2、-CF3、-OCH2F、-OCHF2、-OCF3, hydroxyl ,-SR19, nitro, cyano, isocyano group, alkyl, hydroxy alkyl, alkoxy, carbocylic radical, heterocycle, C2-8Alkenyl, C2-8Alkynyl ,-(CH2)a- C (=O)-R19、-(CH2)k- C (=O)-O-R19、-(CH2)k- C (=O)-NR19R19a、-(CH2)k- S (=O)j-R19,-O-C (=O)-O-R19Or-NR19R19aSubstituent group replaced.Herein presented naphthenic base, it is as defined above.
" cycloalkylidene " refers to divalent cycloalkyl, and wherein naphthenic base is as defined above.
" aryl " refers to the monovalence aromatic hydrocarbyl with monocycle or fused rings, usually there is 6 to 10 carbon atoms, and non-limiting embodiment includes phenyl, naphthalene -1- base or naphthalene -2- base.The aryl optionally further can be selected from F, Cl, Br, I ,=O ,-CH by 0,1,2,3,4 or 52F、-CHF2、-CF3、-OCH2F、-OCHF2、-OCF3, hydroxyl ,-SR19, nitro, cyano, isocyano group, alkyl, hydroxy alkyl, alkoxy, carbocylic radical, heterocycle, C2-8Alkenyl, C2-8Alkynyl ,-(CH2)a- C (=O)-R19、-(CH2)k- C (=O)-O-R19、-(CH2)k- C (=O)-NR19R19a、-(CH2)q- S (=O)k-R18,-O-C (=O)-O-R19Or-NR19R19aSubstituent group replaced.Herein presented aryl, it is as defined above.
" arlydene " refers to divalent aryl, and wherein aryl is as defined above.
" carbocyclic ring " or " carbocylic radical " refers to saturation or unsaturated 3 to 10 yuan of monocycle or 4 to 12 membered bicyclic systems, carbocyclic ring can connect bridged ring or loop coil, non-limiting embodiment include cyclopropyl, cyclobutyl, cyclopenta, 1- cyclopenta -1- alkenyl, 1- cyclopenta -2- alkenyl, 1- cyclopenta -3- alkenyl, cyclohexyl, 1- cyclohexyl -2- alkenyl, 1- cyclohexyl -3- alkenyl, cyclohexenyl group, suberyl, cyclooctyl, cyclononyl, cyclodecyl andThe carbocylic radical optionally further can be selected from F, Cl, Br, I ,=O ,-CH by 0,1,2,3,4 or 52F、-CHF2、-CF3、-OCH2F、-OCHF2、-OCF3, hydroxyl ,-SR18, nitro, cyano, isocyano group, alkyl, hydroxy alkyl, alkoxy, carbocylic radical, heterocycle, C2-8Alkenyl, C2-8Alkynyl ,-(CH2)q- C (=O)-R18、-(CH2)q- C (=O)-O-R18、-(CH2)q- C (=O)-NR18R18a、-(CH2)q- S (=O)k-R18,-O-C (=O)-O-R18Or-NR18R18aSubstituent group replaced.Herein presented carbocyclic ring, it is as defined above.
" heterocycle " or " heterocycle " refers to saturated or unsaturated non-aromatic ring, non-aromatic ring can be 3 to 10 yuan of monocycle or 4 to 12 membered bicyclics, it and include 1 to 4 hetero atom for being selected from N, O or S, it is preferred that 4 to 8 circle heterocyclic ring bases, N, the S selectively replaced in the ring of heterocycle can be oxidized to various oxidation state.Heterocycle can connect on hetero atom or carbon atom, heterocycle can connect bridged ring or loop coil, non-limiting embodiment includes epoxy ethyl, glycidyl, aziridinyl, oxetanylmethoxy, azelidinyl, thietanyl, 1, 3- dioxolanyl, 1, 4- dioxolanyl, 1, 3- dioxane, azacycloheptyl, oxetane, thiocycloheptyl, oxygen azatropylidene base, sulphur azatropylidene base, piperidyl, homopiperidinyl, furyl, pyranose, N- alkyl pyrrole radicals, pyrimidine radicals, piperazinyl, high piperazine base, piperidyl, piperazine stings base, morpholinyl, thio-morpholinyl, thiophene oxane base, 1, bis- thiophene base of 3-, dihydrofuryl, dihydro pyranyl, two thiophenes, penta ring group, tetrahydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, tetrahydro thiapyran base, nafoxidine base, tetrahydro miaow Oxazolyl, tetrahydro-thiazoles base, THP trtrahydropyranyl, benzimidazolyl, benzo pyridyl group, pyrrolopyridinyl, 2- pyrrolinyl, 3- pyrrolinyl, indolinyl, 2H- pyranose, 4H- pyranose, dioxacyclohexyl, 1,3- dioxymyl, pyrazolinyl, dithianyl, dithienyl group, dihydrothiophene, pyrazolidinyl imidazolinyl and imidazolidinyl.The heterocycle optionally further can be selected from F, Cl, Br, I ,=O ,-CH by 0,1,2,3,4 or 52F、-CHF2、-CF3、-OCH2F、-OCHF2、-OCF3, hydroxyl ,-SR18, nitro, cyano, isocyano group, alkyl, hydroxy alkyl, alkoxy, carbocylic radical, heterocycle, C2-8Alkenyl ,-(CH2)q- C (=O)-R18、-(CH2)q- C (=O)-O-R18、-(CH2)q- C (=O)-NR18R18a、-(CH2)q- S (=O)k-R18,-O-C (=O)-O-R18Or-NR18R18aSubstituent group replaced.Herein presented heterocycle, it is as defined above.
" heteroaryl " refers to the heteroatomic monovalence aryl for being selected from N, O or S comprising at least one with monocycle or two fused rings and in ring, it is usually made of 5 to 10 yuan of atom, non-limiting embodiment includes pyrrole radicals, imidazole radicals, thiazolyl, thienyl, furyl, pyrazolyl, isoxazolyl, oxazolyl, pyridyl group or pyrazinyl.The heteroaryl Base optionally further can be selected from F, Cl, Br, I ,=O ,-CH by 0,1,2,3,4 or 52F、-CHF2、-CF3、-OCH2F、-OCHF2、-OCF3, hydroxyl ,-SR19, nitro, cyano, isocyano group, alkyl, hydroxy alkyl, alkoxy, carbocylic radical, heterocycle, C2-8Alkenyl, C2-8Alkynyl ,-(CH2)a- C (=O)-R19、-(CH2)k- C (=O)-O-R19、-(CH2)k- C (=O)-NR19R19a、-(CH2)k- S (=O)j-R19,-O-C (=O)-O-R19Or-NR19R19aSubstituent group replaced.Herein presented heteroaryl, it is as defined above.
" inferior heteroaryl " refers to divalent heteroaryl radical, and wherein heteroaryl is as defined above.
" receptor,β conjugated group " is the group referred in conjunction with B-adrenergic receptor；Such as referring to survey article " β-adrenergic receptors in Comprehensive Medicinal Chemistry, 1990, B.E.Main, p187 (Pergamon Press) ".Above-mentioned group is referring also to such as WO/2005092841, US/20050215542, WO/2005070872, WO/2006023460, WO/2006051373, WO/2006087315 and WO/2006032627.Non-limiting embodiment includesB is selected fromR10Selected from H or hydroxyl, R11、R12、R13、R14、R15、R16、R17、R18Or R19It is independently selected from H, F, Cl, Br, I, CF3、OH、-CH2OH, cyano, carboxyl, C1-4Alkyl, C1-4Alkoxy ,-C (O) C1-4Alkyl ,-C (O) OC1-4Alkyl ,-NHC (O) H, NHS (O)2-C1-4Alkyl, NHS (O)2-NH2Or NHS (O)2-NHC1-4Alkyl, Q are selected from-CRq1=CRq2-、-CRq1Rq2CRq3Rq4, O, S or-CRq1Rq2O-, the Rq1、Rq2、Rq3Or Rq4It is independently selected from selected from H, F, Cl, Br, I or C1-4Alkyl.
" optional " or " optionally " refer to event or environment described later can with but necessarily occur, which includes the occasion that the event or environment occur or do not occur.Such as: " alkyl optionally replaced by F " refer to alkyl can with but necessarily replaced by F, illustrate to include situation that alkyl is not replaced by the F situation replaced and alkyl by F.
" pharmaceutical composition " indicates compound described in one or more texts or the mixture of its physiology/pharmaceutically acceptable salt and other constituents, wherein other components include physiology/pharmaceutically acceptable carrier and excipient.
" carrier " refers to that organism will not be generated obvious stimulation and will not eliminate the bioactivity of given compound and the carrier or diluent of characteristic.
" excipient " refers to being added to the inert substance that compound administration is further relied in pharmaceutical composition.The example of excipient includes but is not limited to calcium carbonate, calcium phosphate, various sugar and different types of starch, cellulose derivative (packet Include microcrystalline cellulose), gelatin, vegetable oil, polyethylene glycols, diluent, granulating agent, lubricant, adhesive, disintegrating agent etc..
" prodrug " refers to the compound that biologically active the compounds of this invention can be converted into physiological conditions or by solvolysis.Prodrug of the invention is prepared by the functional group in modification the compounds of this invention, which can be removed by conventional operation or in vivo, and obtain parent compound.
" eutectic " or " eutectic " refers to active pharmaceutical ingredient (active pharmaceutical ingredient,) and eutectic formation (cocrystal former API, CCF) the crystal being combined under the action of hydrogen bond or other non-covalent bonds, wherein the pure state of API and CCF is solid at room temperature, and there is fixed stoichiometric ratio between each component.Eutectic is a kind of multicomponent crystal, both comprising the binary eutectic formed between two kinds of neutral solids, the multi-element eutectic also formed comprising neutral solid and salt or solvate.
" stereoisomer " refers to the isomers as caused by the spatially arrangement mode difference of atom in molecule, including cis-trans-isomer, enantiomter and conformer.
" effective dose " has guided the amount of the compound of tissue, system or subject physiologic or medical response, this amount be it is sought, the one or more of symptoms for being enough to prevent treated illness or illness with subject when including applying occur or mitigate it to the amount of compound to a certain degree.
" solvate " refers to the compounds of this invention or its salt, they further include the stoichiometry combined with non-covalent intermolecular forces or non-stoichiometric solvent.
Specific embodiment
The technical solution that the present invention will be described in detail with reference to the accompanying drawings and embodiments, but protection scope of the present invention includes but is not limited to this.
The structure of compound be by nuclear magnetic resonance (NMR) or (and) mass spectrum (MS) is come what is determined.NMR is displaced (δ) with 10-6(ppm) unit provides.The measurement of NMR is to use (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic resonance spectrometer, and measurement solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), inside it is designated as tetramethylsilane (TMS).
(Agilent 6120B (ESI) and Agilent 6120B (APCI)) is used in the measurement of MS.
The measurement of HPLC uses Agilent 1260DAD high pressure liquid chromatograph (100 × 4.6mm of Zorbax SB-C18).
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate, and the specification that the silica gel plate that thin-layered chromatography (TLC) uses uses is 0.15mm~0.20mm, and the specification that thin-layer chromatography isolates and purifies product use is 0.4 Mm~0.5mm.
Column chromatography is generally carrier using 200~300 mesh silica gel of Yantai Huanghai Sea silica gel.
Known starting material of the invention can be used or be synthesized according to methods known in the art, or be can purchase in safe smooth science and technology, pacified the companies such as silent resistance to Jilin Chemical, Shanghai moral, Chengdu section Long Huagong, splendid remote chemical science and technology, lark prestige science and technology.
Nitrogen atmosphere refers to that reaction flask connects the nitrogen balloon of an about 1L volume.
Nitrogen atmosphere refers to that reaction flask connects the hydrogen balloon of an about 1L volume.
Hydrogenation usually vacuumizes, and is filled with hydrogen, operates 3 times repeatedly.
Without specified otherwise in embodiment, reaction carries out under nitrogen atmosphere.
Without specified otherwise in embodiment, solution refers to aqueous solution.
Without specified otherwise in embodiment, the temperature of reaction is room temperature.
Without specified otherwise in embodiment, M is mole every liter.
Room temperature is optimum reaction temperature, is 20 DEG C~30 DEG C.
CHO: refer to formoxyl.
TBS: refer to t-Butyldimethylsilyl.
Boc: refer to t-butyloxycarbonyl.
Intermediate 1
Dimethyl 2- (bromomethyl) phenyl -1,4- dicarboxylic ester
dimethyl 2-(bromomethyl)benzene-1,4-dicarboxylate
2- methyl-1 is weighed, 4- rutgers (1a, 6.24g, 30.0mmol) are placed in 250mL round-bottomed flask, and chlorobenzene (150mL) is added into reaction flask.It is sequentially added into reaction flask N- bromo-succinimide (5.6g, 31.5mmol), benzoyl peroxide (0.07,0.3mmol), reaction, which is warming up at 85 DEG C, stirs 4 hours.It is cooled to room temperature wait react, it is concentrated under reduced pressure and removes most of reaction dissolvent, saturated sodium bicarbonate aqueous solution (100mL) is added into residue, ethyl acetate (200mL × 2) extraction, organic phase after merging washes (100mL) with saturated common salt, after anhydrous sodium sulfate is dry, column chromatography for separation [(petrol ether/ethyl acetate (v/v)=15:1)] is concentrated under reduced pressure and obtains dimethyl 2- (bromomethyl) phenyl -1 of white solid, 4- dicarboxylic ester (intermediate 1) (4.8g, yield 56%).
1H NMR(400MHz,CDCl3)δ8.11(s,1H),7.99-7.98(d,2H),4.94(s,2H),3.95(s,3H),3.93(s,3H)。
Intermediate 2
7- [(1R) -2- amino -1- [tert-butyl (dimethyl) silicon substrate] oxygroup ethyl] -4- [tert-butyl (dimethyl) silicon substrate] oxygroup -3H-1,3- benzothiazole -2- ketone
7-[(1R)-2-amino-1-[tert-butyl(dimethyl)silyl]oxy-ethyl]-4-[tert-butyl(dimethyl)silyl]oxy-3H-1,3-benzothiazol-2-one
Step 1: 7- [(1R) -2- azido -1- [tert-butyl (dimethyl) silicon substrate] oxygroup ethyl] -4- [tert-butyl (dimethyl) silicon substrate] oxygroup -3H-1,3- benzothiazole -2- ketone (2b)
7-[(1R)-2-azido-1-[tert-butyl(dimethyl)silyl]oxy-ethyl]-4-[tert-butyl(dimethyl)silyl]oxy-3H-1,3-benzothiazol-2-one
7- [(1R) -2- azido -1- hydroxy-ethyl] -4- hydroxyl -3H-1, (0.56g (is prepared) in 3- benzothiazole -2- ketone (2a) with reference to WO2009098448A1,2.2mmol) it is dissolved in N, in dinethylformamide (20mL), then imidazoles (0.6g is added, 8.9mmol), tert-butyl chloro-silicane (1.3g is added portionwise, 8.9mmol), the 4-dimethylaminopyridine of catalytic amount is added, temperature rises to 40 DEG C and stirs 7 hours.Reaction solution is poured into water (100mL), it is extracted with ethyl acetate (100mL × 1), organic phase is washed with saturated sodium-chloride water solution (100mL × 2), it is dry with anhydrous sodium sulfate, filtering, filtrate decompression concentration, residue silica gel column chromatography (eluant, eluent is ethyl acetate/petroleum ether (v/v)=0/1~5/95), obtain title compound 7- [(1R) -2- azido -1- [tert-butyl (dimethyl) silicon substrate] oxygroup ethyl] -4- [tert-butyl (dimethyl) silicon substrate] oxygroup -3H-1, 3- benzothiazole -2- ketone (2b), white solid (0.85g, yield 80%).
1H NMR(400MHz,CDCl3)δ8.25(s,1H),6.92(d,1H),6.71(d,1H),4.78(dd,1H),3.41(dd,1H),3.25(dd,1H),1.05-0.98(m,9H),0.92-0.88(m,9H),0.28(t,6H),0.12(d,3H),-0.04(d,3H)。
Step 2: 7- [(1R) -2- amino -1- [tert-butyl (dimethyl) silicon substrate] oxygroup ethyl] -4- [tert-butyl (dimethyl) silicon substrate] oxygroup -3H-1,3- benzothiazole -2- ketone (intermediate 2)
7-[(1R)-2-amino-1-[tert-butyl(dimethyl)silyl]oxy-ethyl]-4-[tert-butyl(dimethyl)silyl]oxy-3H-1,3-benzothiazol-2-one
By 7- [(1R) -2- azido -1- [tert-butyl (dimethyl) silicon substrate] oxygroup ethyl] -4- [tert-butyl (dimethyl) silicon substrate] oxygroup -3H-1,3- benzothiazole -2- ketone (2b) (0.85g, it 1.8mmol) is dissolved in ethyl acetate (20mL), the palladium carbon (0.085g) of 10% (w/w) is added, is stirred overnight under atmospheric hydrogen ball.Pad diatomite filtering, it is concentrated to give title compound 7- [(1R) -2- amino -1- [tert-butyl (dimethyl) silicon substrate] oxygroup ethyl] -4- [tert-butyl (dimethyl) silicon substrate] oxygroup -3H-1,3- benzothiazole -2- ketone (intermediate 2), light/dark balance solid (0.7g, yield 90%).
1H NMR(400MHz,CDCl3)δ6.89(d,1H),6.68(t,1H),4.64(dd,1H),2.88(ddd,2H),1.04-0.96(m,9H),0.95-0.87(m,9H),0.33-0.23(m,6H),0.12-0.06(m,3H),-0.04--0.11(m,3H)。
Embodiment 1
[1- [2- [6- [[[(2R) -2- hydroxyl -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amido] methyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (compound 1)
[1-[2-[6-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
Step 1: the bromo- 3,4- dihydro -2H- isoquinoline-1-ketone (1B) of 6-
6-bromo-3,4-dihydro-2H-isoquinolin-1-one
Bromo- 1- print ketone (1A) (1.08g, 5.1mmol) of 5- is weighed, is placed in 100mL round-bottomed flask.At 0 DEG C, methylene chloride (30mL), methanesulfonic acid (15mL) and sodium azide (0.5g, 7.7mmol) are sequentially added into reaction flask, temperature is warmed to room temperature stirring 3 hours.1.0M sodium hydrate aqueous solution (50mL) quenching reaction is added dropwise into reaction solution, water phase is extracted with methylene chloride (100mL × 1), merge organic phase, successively washed with saturated common salt washing (40mL × 1), anhydrous sodium sulfate is dry, filtering, filtrate decompression concentration, residue is with silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=3:1), obtain title product 6- bromo- 3,4- dihydro -2H- isoquinoline-1-ketone (1B), gray solid (0.45g, yield 39%).
1H NMR(400MHz,CDCl3)δ7.91-7.89(m,1H),7.48-7.46(m,1H),7.38(s,1H),7.15(br,1H),3.58-3.54(m,2H),2.98-2.94(m,2H)。
Step 2: the bromo- 3,4- dihydro-isoquinoline -1- ketone (1C) of 2- allyl -6-
2-allyl-6-bromo-3,4-dihydroisoquinolin-1-one
N,N-dimethylformamide (25mL) is added in 250mL round-bottomed flask.At 0 DEG C, sodium hydride (1.8g is added into reaction flask, 33.0mmol, 60% (w/w)), 6- bromo- 3 is then added dropwise, 4- dihydro -2H- isoquinoline-1-ketone (9B) (5.0g, n,N-Dimethylformamide (20mL) solution 22.0mmol), stirring is after twenty minutes, it is added dropwise 3- bromopropene (4.0g, 33mmol).Temperature is warmed to room temperature stirring 4 hours.Water (100mL) quenching reaction is added dropwise into reaction solution, ethyl acetate (200mL × 2) extraction, merge organic phase to use, successively washed with saturated salt solution (100mL × 2), anhydrous sodium sulfate is dry, filtering, filtrate decompression concentration, residue silica gel column chromatography separates (petrol ether/ethyl acetate (v/v)=10:1) purification, obtain title product 2- allyl -6- bromo- 3,4- dihydro-isoquinoline -1- ketone (1C), yellow liquid (4.80g, yield 82%).
1H NMR(400MHz,CDCl3)δ7.94-7.92(m,1H),7.45-7.43(m,1H),7.32(s,1H),5.84-5.78(m,1H),5.25-5.19(m,2H),4.17-4.16(m,2H),3.49-3.48(m,2H),2.96-2.93(m,2H)。
Step 3: 2- allyl -1- carbonyl -3,4- dihydro-isoquinoline -6- formaldehyde (1D)
2-allyl-1-oxo-3,4-dihydroisoquinoline-6-carbaldehyde
The bromo- 3,4- dihydro-isoquinoline -1- ketone (2c) (0.80g, 3.0mmol) of 2- allyl -6- is weighed to be placed in 50mL round-bottomed flask.At -78 DEG C, tetrahydrofuran (20mL) and n,N-Dimethylformamide (0.33g, 4.5mmol) are sequentially added into reaction flask, are added dropwise tert-butyl lithium (4.5mL, 6.0mmol, 1.3M hexane solution).After being stirred 1 hour at -78 DEG C, acetic acid (5mL) quenching reaction is added dropwise, ethyl acetate (100mL) and saturated salt solution (50mL) is added, extraction, water phase is extracted with ethyl acetate (100mL × 1), merge organic phase, anhydrous sodium sulfate is dry, filtering, filtrate decompression concentration, residue use column chromatography (petrol ether/ethyl acetate (v/v)=2:1) purification, obtain title product 2- allyl -1- carbonyl -3,4- dihydro-isoquinoline -6- formaldehyde (1D), yellow liquid (0.28g, 43%).
1H NMR(400MHz,CDCl3)δ10.05(s,1H),8.27-8.25(d,1H),7.84-7.82(d,1H),7.72-7.71(m,1H),5.90-5.81(m,1H),5.29-5.23(m,2H),4.23-4.21(m,2H),3.57-3.55(m,2H),3.09-3.06(m,2H)。
Step 4: 2- allyl -6- (hydroxymethyl) -3,4- dihydro-isoquinoline -1- ketone (1E)
2-allyl-6-(hydroxymethyl)-3,4-dihydroisoquinolin-1-one
2- allyl -1- carbonyl -3,4- dihydro-isoquinoline -6- formaldehyde (1D) (0.28g, 1.3mmol) is weighed, is placed in 50mL round-bottomed flask.Methanol (10mL) is added into reaction flask, sodium borohydride (0.1g, 2.0mmol) is added portionwise, stirs 2 hours at room temperature.Water (5mL) quenching reaction is added dropwise, with ethyl acetate (50mL × 2) extraction merging organic phase, successively washed with saturated salt solution (50mL × 1), anhydrous sodium sulfate is dry, filtering obtains title product 2- allyl -6- (hydroxymethyl) -3,4- dihydro-isoquinoline -1- ketone (1E) after filtrate decompression concentration, yellow liquid (0.26g, 92%).
1H NMR(400MHz,CDCl3)δ8.05-8.04(d,1H),7.29-7.27(d,1H),7.20(s,1H),5.88-5.80(m,1H),5.26-5.19(m,2H),4.72(s,2H),4.20-4.18(m,2H),3.52-3.49(m,2H),2.99-2.95(m,2H)。
Step 5: 2- allyl -6- [[tert-butyl (dimethyl) silicon substrate] oxygroup methyl] -3,4- dihydro-isoquinoline -1- ketone (1F)
2-allyl-6-[[tert-butyl(dimethyl)silyl]oxymethyl]-3,4-dihydroisoquinolin-1-one
2- allyl -6- (hydroxymethyl) -3,4- dihydro-isoquinoline -1- ketone (1E) (0.26g, 1.2mmol) is dissolved in methylene chloride (15mL).Sequentially add triethylamine (0.48mL, 3.6mmol), tert-butyl chloro-silicane (0.27g, 1.8mmol) and 4- dimethylamino pyridine (0.015g, 0.12mmol).After stirring 2 hours at room temperature.Reaction solution is directly concentrated under reduced pressure, residue is with silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=2:1), obtain title product 2- allyl -6- (hydroxymethyl) -3,4- dihydro-isoquinoline -1- ketone (1F), yellow liquid (0.4g, 100%).
1H NMR(400MHz,CDCl3)δ8.05-8.03(d,1H),7.27-7.25(d,1H),7.15(s,1H),5.89-5.81(m,1H),5.26-5.19(m,2H),4.75(s,2H),4.20-4.19(m,2H),3.52-3.49(m,2H),2.99-2.96(m,2H),0.95(s,9H),0.11(s,6H)。
Step 6: 2- [6- [[tert-butyl (dimethyl) silicon substrate] oxygroup methyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] acetaldehyde (1G)
2-[6-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]acetaldehyde
By 2- allyl -6- [[tert-butyl (dimethyl) silicon substrate] oxygroup methyl] -3,4- dihydro-isoquinoline -1- ketone (1F) (0.33g, 1.0mmol) is dissolved in the in the mixed solvent of tetrahydrofuran (12mL) Yu water (3mL).At 0 DEG C, two hydration potassium osmates (0.07g, 0.2mmol) and sodium metaperiodate (1.05g, 5.0mmol) are sequentially added.Reaction temperature is warmed to room temperature lower stirring 2 hours.Saturated aqueous sodium thiosulfate (30mL) quenching reaction is added dropwise, ethyl acetate (50mL × 2) extraction, merge organic phase, successively washed with saturated salt solution (50mL × 1), anhydrous sodium sulfate is dry, filtering, filtrate decompression concentration, residue is with silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=1:1), obtain title product 2- [6- [[tert-butyl (dimethyl) silicon substrate] oxygroup methyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] acetaldehyde (1G), yellow liquid (0.21g, 64%).
1H NMR(400MHz,CDCl3)δ9.69(s,1H),8.04-8.02(d,1H),7.29-7.27(d,1H),7.18(s,1H),4.77(s,2H),4.39(s,2H),3.64-3.60(m,2H),3.09-3.06(m,2H),0.95(s,9H),0.11(s,6H)。
Step 7: [1- [2- [6- [[tert-butyl (dimethyl) silicon substrate] oxygroup methyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (1H)
[1-[2-[6-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
2- [6- [[tert-butyl (dimethyl) silicon substrate] oxygroup methyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] acetaldehyde (1G) (0.33g, 1.0mmol) is dissolved in methylene chloride (10mL).4- piperidyl N- (2- phenyl) carbamate is added thereto and (obtains) (0.3g, 1.0mmol) with reference to WO2012009166 preparation example 1.It after being stirred at room temperature 1 hour, is added sodium triacetoxy borohydride (0.63g, 3.0mmol), continues stirring 2 hours.Saturated sodium bicarbonate aqueous solution (40mL) quenching reaction is added dropwise, methylene chloride (50mL × 2) extraction merges organic phase, successively uses saturated salt solution (50 ML × 1) washing, anhydrous sodium sulfate is dry, filtering, filtrate decompression concentration, residue obtains [1- [2- [6- [[tert-butyl (dimethyl) silicon substrate] oxygroup methyl] -1- oxo -3 with silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=15:1), 4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (1H) (0.41g, 67%).
1H NMR(400MHz,CDCl3)δ8.10-8.08(d,1H),8.02-8.00(d,1H),7.43-7.37(m,6H),7.20-7.10(m,4H),6.59(s,1H),4.76-4.74(m,3H),3.68-3.58(m,4H),2.98-2.95(m,2H),2.76-2.74(m,2H),2.60-2.58(m,2H),2.32-2.30(m,2H),1.93-1.91(m,2H),1.68-1.64(m,2H),0.95(s,9H),0.11(s,6H)。
LCMS m/z=614.4 [M+1].
Step 8: [1- [2- (6- hydroxymethyl) -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) ammonium carbonate (1I)
[1-[2-[6-(hydroxymethyl)-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
By [1- [2- [6- [[tert-butyl (dimethyl) silicon substrate] oxygroup methyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (1H) (0.31g, it 0.5mmol) is dissolved in tetrahydrofuran (10mL), tetrabutyl ammonium fluoride (0.26g is added, 1.0mmol), after being stirred at room temperature 2 hours.After reaction solution is directly concentrated under reduced pressure, residue is with silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=15:1), obtain title product [1- [2- (6- hydroxymethyl) -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) ammonium carbonate (1I) (0.20g, 80%).
LCMS m/z=500.3 [M+1].
Step 9: [1- [2- (6- carboxaldehyde radicals -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (1J)
[1-[2-(6-formyl-1-oxo-3,4-dihydroisoquinolin-2-yl)ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
By [1- [2- (6- hydroxymethyl) -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) ammonium carbonate (1I) (0.20g, 0.4mmol) is dissolved in methylene chloride (10mL).At 0 DEG C, Dai Si-Martin's oxidant (0.4g, 1.0mmol) is added.Temperature is warmed to room temperature lower stirring 2 hours.Saturated sodium bicarbonate aqueous solution (40mL) quenching reaction is added dropwise, residue is extracted with methylene chloride (50mL × 2), merge organic phase, successively washed with saturated salt solution (50mL × 1), anhydrous sodium sulfate is dry, filtering, filtrate decompression concentration, residue is with silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=15:1), obtain title product [1- [2- (6- carboxaldehyde radicals -1- oxo -3, 4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (1J) (0.15g, 75%).
LCMS m/z=498.3 [M+1].
Step 10: [1- [2- [6- [[[(2R) -2- [tert-butyl (dimethyl) silicon substrate] oxygroup -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amido] methyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (1L)
[1-[2-[6-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
Take [1- [2- (6- carboxaldehyde radicals -1- oxo -3, 4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (1J) (0.34g, 0.68mmol) and 5- [(1R) -2- amino -1- [tert-butyl (dimethyl) silicon substrate] oxygroup-ethyl] -8- hydroxyl -1H- quinoline-2-one (1K) (prepares and refers to WO2007102771A1) (0.24g, it 0.82mmol) is placed in 50mL round-bottomed flask, it is added methanol (10mL), it is added methylene chloride (10mL), after being stirred at room temperature 1 hour, sodium triacetoxy borohydride (0.44g is added, 2.1mmol), the reaction was continued 3 hours.Saturated sodium bicarbonate solution (30mL) quenching reaction is added after reaction, methylene chloride extracts (30mL × 2) extraction, merge organic phase, anhydrous sodium sulfate is dry, filtering, filtrate decompression concentration, after residue is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=1:12), obtain title compound [1- [2- [6- [[[(2R) -2- [tert-butyl (dimethyl) silicon substrate] oxygroup -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amido] methyl] -1- oxo -3, 4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (1L), yellow solid (0.32g, yield: 55%).
LCMS m/z=816.5 [M+1].
Step 11: [1- [2- [6- [[[(2R) -2- hydroxyl -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amido] methyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (compound 1)
[1-[2-[6-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
By [1- [2- [6- [[[(2R) -2- [tert-butyl (dimethyl) silicon substrate] oxygroup -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amido] methyl] -1- oxo -3, 4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (1L) (0.32g, it 0.38mmol) is placed in 25mL round-bottomed flask, it is added tetrahydrofuran (10mL), after mixing evenly, triethylamine trihydrofluoride (0.33mL is added to system, 2.0mmol), room temperature reaction 16 hours.Saturated sodium bicarbonate solution (30mL) quenching reaction after reaction, methylene chloride (30mL × 2) extraction, merge organic phase, anhydrous sodium sulfate is dry, filtering, filtrate decompression concentration, residue is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=1:10), obtain title compound [1- [2- [6- [[[(2R) -2- hydroxyl -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amido] methyl] -1- oxo -3, 4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (compound 1), yellow solid (0.27g, 97%).
1H NMR(400MHz,DMSO-d6)δ10.29(s,1H)8.59(s,1H),8.15-8.12(d,1H),7.80-7.78(d,1H),7.42-7.28(m,9H),7.20(s,1H),7.09-7.07(d,1H),6.94-6.92(d,1H),6.48-6.46(d,1H),5.12-5.09(m,1H),4.45-4.43(m,1H),3.81(s,2H),3.55-3.51(m,5H),2.90-2.87(m,2H),2.72-2.67(m,5H),2.50-2.45(m,2H),2.20-2.16(m,2H),1.69(m,2H),1.40-1.38(m,2H)。
LCMS m/z=702.3 [M+1].
Embodiment 2
[1- [2- [6- [[[(2R) -2- hydroxyl -2- (5- hydroxyl -3- oxo -4H-1,4- benzoxazine -8- base) ethyl] amido] methyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (compound 2)
[1-[2-[6-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]methyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
Step 1: [1- [2- [6- [[[(2R) -2- [tert-butyl (dimethyl) silicon substrate] oxygen -2- (5- hydroxyl -3- oxo -4H-1,4- benzoxazine -8- base) ethyl] amido] methyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (2B)
[1-[2-[6-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]methyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
By [1- [2- (6- formoxyl -1- oxo -3; 4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (1J) (0.497g, 1.0mmol) is dissolved in the in the mixed solvent of methylene chloride (20mL) and methanol (6mL).8- [(1R) -2- amino -1- [tert-butyl (dimethyl) silicon substrate] oxygen-ethyl] -5- hydroxyl -4H-1 is added thereto, 4- benzoxazine -3- ketone (2A) (preparation refers to WO2008149110A1) (0.338g, 1.0mmol), sodium triacetoxy borohydride (0.63g is added after stirring 30 minutes at room temperature, 3.0mmol), it stirs 3 hours at room temperature.Saturated sodium bicarbonate aqueous solution (50mL) quenching reaction is added thereto, it is extracted with methylene chloride (100mL × 2), organic phase after merging is dry with anhydrous sodium sulfate, silica gel column chromatography separation (methylene chloride: methanol (v/v)=1:0~8:1) obtains [1- [2- [6- [[[(2R) -2- [tert-butyl (dimethyl) silicon substrate] oxygroup -2- (5- hydroxyl -3- oxo -4H-1 of yellow solid after reduced pressure, 4- benzoxazine -8- base) ethyl] amido] methyl] -1- oxo -3, 4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (2B) (0.41g, yield 50%).
LCMS m/z=410.9 [M/2+1].
Step 2: [1- [2- [6- [[[(2R) -2- hydroxyl -2- (5- hydroxyl -3- oxo -4H-1,4- benzoxazine -8- base) ethyl] amido] methyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (compound 2)
[1-[2-[6-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]methyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
By [1- [2- [6- [[[(2R) -2- [tert-butyl (dimethyl) silicon substrate] oxygroup -2- (5- hydroxyl -3- oxo -4H-1,4- benzoxazine -8- base) ethyl] amido] methyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (2B) (0.41g, it 0.5mmol) is dissolved in tetrahydrofuran (10mL), three hydrofluoric acid (0.98g of triethylamine is added into reaction flask, 6.1mmol), it is stirred at room temperature 12 hours.Saturated sodium bicarbonate aqueous solution (50mL) successively is added dropwise thereto, methanol (5mL) quenching reaction, it is extracted with methylene chloride (100mL × 2), organic phase after merging is dry with anhydrous sodium sulfate, column chromatography for separation (methylene chloride: methanol (v/v)=1:0~8:1) obtains [1- [2- [6- [[[(2R) -2- hydroxyl -2- (5- hydroxyl -3- oxo -4H-1 of yellow solid after reduced pressure, 4- benzoxazine -8- base) ethyl] amido] methyl] -1- oxo -3, 4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (compound 2) (0.19g, yield 54%).
1H NMR (400MHz, DMSO-d6) δ 9.81 (br, 1H), 8.58 (s, 1H), 7.78 (d, J=7.9Hz, 1H), 7.44-7.25 (m, 11H), 7.20 (s, 1H), 6.86 (d, J=8.5Hz, 1H), 6.49 (d, J=8.4Hz, 1H), 4.88 (dd, J=8.2,3.4Hz, 1H), 4.47-4.39 (m, 3H), 3.75 (d, J=2.9Hz, 2H), 3.51-3.56 (m, 5H), 2.91 (t, J=6.4Hz, 2H), 2.60-2.64 (m, 7H), 2.14-2.21 (m, 2H) 1.66-1.73 (m, 2H).
LCMS m/z=706.3 [M+1].
Embodiment 3
[1- [2- [6- [[2- (5- hydroxyl -3- oxo -4H-1,4- benzoxazine -8- base) ethylamino] methyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (compound 3)
[1-[2-[6-[[2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethylamino]methyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
By [1- [2- (6- formoxyl -1- oxo -3; 4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (1J) (0.34g; it 0.68mmol) is dissolved in N-Methyl pyrrolidone (15mL); 8- (2- amine ethyl) -5- hydroxyl -4H-1 is successively added thereto; acetate (being prepared with reference to WO2008075025) (3A) (0.167g of 4- benzoxazine -3- ketone 0.68mmol), acetic acid (0.06g, 0.1mmol).After stirring 30 minutes at room temperature, sodium triacetoxy borohydride (0.43g, 2.0mmol) is added thereto, reaction is terminated after 5 hours.It is concentrated under reduced pressure and removes most of reaction dissolvent, saturated sodium bicarbonate aqueous solution (50mL) is slowly added dropwise into residue, (100mL × 2) are extracted with dichloromethane in water phase, organic phase after merging washes (50mL) with saturated common salt, after anhydrous sodium sulfate is dry, it is concentrated under reduced pressure, column chromatography for separation [(methylene chloride/methanol (v/v)=15:1)] obtains [1- [2- [6- [[2- (5- hydroxyl -3- oxo -4H-1 of white solid, 4- benzoxazine -8- base) ethylamino] methyl] -1- oxo -3, 4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (compound 3) (0.072g, yield 15%).
1H NMR (400MHz, DMSO-d6) δ 9.81 (s, 1H), 8.59 (s, 1H), 7.79 (d, J=7.9Hz, 1H), (7.22-7.43 m, 12H), 6.62 (d, J=8.3Hz, 1H), 6.44 (d, J=8.3Hz, 1H), (3.79 s, 2H), 3.54 (t, J=6.4Hz, 4H), 2.91 (t, J=6.5Hz, 2H), 2.78 (m, 6H), 2.70-2.63 (m, 5H), 2.18 (t, J=9.4Hz, 2H), 1.68 (m, 2H), 1.38-1.40 (m, 2H).
LCMS m/z=690.2 [M+1].
Embodiment 4
[1- [2- [5- [[[(2R) -2- hydroxyl -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amino] methyl] -1- oxo-isoindoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (compound 4)
[1-[2-[5-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-1-oxo-isoindolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
Step 1: [1- [2- (tert-butoxycarbonylamino) ethyl] -4- piperidines] N- (2- phenyl) carbamate (4B)
[1-[2-(tert-butoxycarbonylamino)ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
4- piperidyl N- (2- phenyl) carbamate (is prepared) (4A) (2.96g, 10.0mmol) to be dissolved in acetonitrile (60mL) with reference to WO2012009166A1.N- tertbutyloxycarbonyl-bromine ethamine (2.24g, 10.0mmol), n,N-diisopropylethylamine (3.56mL, 20.0mmol) are sequentially added thereto.Reaction is stirred 24 hours at 50 DEG C.It is concentrated under reduced pressure and removes reaction dissolvent, saturated sodium bicarbonate aqueous solution (100mL) is added into residue, it is extracted with methylene chloride (150mL × 2), organic phase after merging is washed with saturated salt solution (100mL), anhydrous sodium sulfate is dry, [1- [2- (tert-butoxycarbonylamino) ethyl] -4- piperidines] N- (2- phenyl) carbamate (4B) (4.4g, 100%) of yellow liquid is obtained after reduced pressure.
LCMS m/z=440.3 [M+1].
Step 2: [1- (2- amido ethyl) -4- piperidines] N- (2- phenyl) carbamate (4C)
[1-(2-aminoethyl)-4-piperidyl]N-(2-phenylphenyl)carbamate
By [1- [2- (tert-butoxycarbonylamino) ethyl] -4- piperidines] N- (2- phenyl) carbamate (4B) (4.4g, it 10.0mmol) is dissolved in methylene chloride (50mL), trifluoroacetic acid (10mL) is added thereto, is stirred at room temperature 3 hours.It is concentrated under reduced pressure and removes reaction dissolvent, methylene chloride (200mL) is added into residue, saturated sodium bicarbonate aqueous solution (100mL), extraction, water phase is extracted with methylene chloride (100mL), organic phase after merging is dry with anhydrous sodium sulfate, column chromatography for separation (methylene chloride/methanol (v/v)=10:1) obtains [1- (2- amido ethyl) -4- piperidines] N- (2- phenyl) carbamate (4C) (2.1g, 62.0%) of yellow solid after reduced pressure.
LCMS m/z=340.1 [M+1].
Step 3: 1- oxo -2- [2- [4- [(2- phenyl) amido formacyl oxygen] -1- piperidyl] ethyl] isoindoline -5- carboxylate methyl ester (4D)
methyl 1-oxo-2-[2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl]isoindoline-5-carboxylate
By [1- (2- amido ethyl) -4- piperidines] N- (2- phenyl) carbamate (4C) (3.4g, it 10.0mmol) is dissolved in tetrahydrofuran (50mL), dimethyl 2- (bromomethyl) phenyl -1 is sequentially added thereto, 4- dicarboxylic ester (intermediate 1) (2.9g, 10.0mmol), triethylamine (2.1mL, 15.0mmol).Reaction is rear after stirring 12 hours at 50 DEG C to be terminated.It is cooled to room temperature wait react, it is concentrated under reduced pressure and removes reaction dissolvent, methylene chloride (200mL) is added into residue, saturated sodium bicarbonate aqueous solution (100mL), extraction, water phase is extracted with methylene chloride (100mL), organic phase after merging is dry with anhydrous sodium sulfate, column chromatography for separation (methylene chloride/methanol (v/v)=15:1) obtains 1- oxo -2- [2- [4- [(2- phenyl) amido formacyl oxygen] -1- piperidyl] ethyl] isoindoline -5- carboxylate methyl ester (4D) (4.0g of white solid after reduced pressure, 77.8%).
Step 4: [1- [2- [5- (hydroxymethyl) -1- oxo-isoindoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (4E)
[1-[2-[5-(hydroxymethyl)-1-oxo-isoindolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
By 1- oxo -2- [2- [4- [(2- phenyl) amido formacyl oxygen] -1- piperidyl] ethyl] isoindoline -5- carboxylate methyl ester (4D) (0.85g; it 1.7mmol) is dissolved in methylene chloride (30mL); at -78 DEG C; toluene solution (the 2M of diisobutyl aluminium hydride is added dropwise; 1.7mL; 3.4mmol), after being added dropwise, -78 DEG C are stirred 3 hours.10% aqueous sodium potassium tartrate (30mL) quenching reaction is added dropwise, after reacting and being warmed to room temperature, liquid separation, water phase is extracted with methylene chloride (50mL), organic phase after merging is dry with anhydrous sodium sulfate, column chromatography for separation (methylene chloride/methanol (v/v)=15:1) obtains [1- [2- [5- (hydroxymethyl) -1- oxo-isoindoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (4E) [(0.6g, 75%) of yellow solid after reduced pressure.
LCMS m/z=486.3 [M+1].
Step 5: [1- [2- (5- formoxyl -1- oxo-isoindoline -2- base) ethyl] -4- piperidyl] N- (2- phenyl) carbamate (4F)
[1-[2-(5-formyl-1-oxo-isoindolin-2-yl)ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
By [1- [2- [5- (hydroxymethyl) -1- oxo-isoindoline -2- base] ethyl] -4- piperidyl]-N- (2- phenyl) amino first Acid esters (4E) (0.6g, 1.2mmol) is dissolved in methylene chloride (20mL), at 0 DEG C, Dai Si-Martin's oxidant (0.79g, 1.9mmol) is added dropwise thereto, 0 DEG C is stirred 2 hours.Saturated sodium bicarbonate aqueous solution (30mL) quenching reaction is added dropwise; it is extracted with methylene chloride (50mL × 2); organic phase after merging is dry with anhydrous sodium sulfate; column chromatography for separation (methylene chloride/methanol (v/v)=15:1) obtains [1- [2- (5- formoxyl -1- oxo-isoindoline -2- base) ethyl] -4- piperidyl]-N- (2- phenyl) carbamate (4F) [(0.45g, 75%) of yellow solid after reduced pressure.
LCMS m/z=484.3 [M+1].
Step 6: [1- [2- [5- [[[(2R) -2- [tert-butyl (dimethyl) silicon substrate] oxygen -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amino] methyl] -1- oxo-isoindoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (4G)
[1-[2-[5-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-1-oxo-isoindolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
[1- [2- (5- carboxaldehyde radicals -1- oxo-isoindoline -2- base) ethyl] -4- piperidyl] N- (2- phenyl) carbamate (4F) (0.32g, 0.66mmol) is dissolved in the in the mixed solvent of methylene chloride (20mL) and methanol (6mL).5- [(1R) -2- amino -1- [tert-butyl (dimethyl) silicon substrate] oxygroup-ethyl] -8- hydroxyl -1H- quinoline-2-one (1K) (0.22g is added thereto, 0.66mmol), sodium triacetoxy borohydride (0.42g is added after stirring 30 minutes at room temperature, 2.0mmol), it stirs 3 hours at room temperature.Saturated sodium bicarbonate aqueous solution (50mL) quenching reaction is added thereto, it is extracted with methylene chloride (100mL × 2), organic phase after merging is dry with anhydrous sodium sulfate, column chromatography for separation (methylene chloride: methanol (v/v)=1:0~8:1) obtains [1- [2- [5- [[[(2R) -2- [tert-butyl (dimethyl) silicon substrate] oxygen -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amino] methyl] -1- oxo-isoindoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (4G) (0.50g of yellow solid after reduced pressure, yield 94%).
Step 7: [1- [2- [5- [[[(2R) -2- hydroxyl -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amino] methyl] -1- oxo-isoindoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (compound 4)
[1-[2-[5-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-1-oxo-isoindolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
By [1- [2- [5- [[[(2R) -2- [tert-butyl (dimethyl) silicon substrate] oxygen -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amino] methyl] -1- oxo-isoindoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (4G) (0.50g, it 0.62mmol) is dissolved in tetrahydrofuran (10mL), three hydrofluoric acid (0.98g of triethylamine is added into reaction flask, 6.1mmol), reaction terminates after being stirred at room temperature 12 hours.Saturated sodium bicarbonate aqueous solution (50mL) quenching reaction is successively added dropwise thereto, it is extracted with methylene chloride (100mL × 2), organic phase after merging is dry with anhydrous sodium sulfate, column chromatography for separation (methylene chloride: methanol (v/v)=1:0~8:1) obtains [1- [2- [5- [[[(2R) -2- hydroxyl -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amino] methyl] -1- oxo-isoindoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (compound 4) (0.22g of yellow solid after reduced pressure, yield 51%).
1H NMR (400MHz, DMSO-d6) δ 8.58 (s, 1H), 8.13 (d, J=9.9Hz, 1H), 7.58 (d, J=7.7Hz, 1H), 7.49 (s, 1H), 7.42-7.27 (m, 10H), 7.06 (d, J=8.1Hz, 1H), 6.91 (d, J=8.1Hz, 1H), 6.45 (d, J=9.9Hz, 1H), 5.07 (dd, J=7.7,4.3Hz, 1H), 4.45-4.47 (m, 3H), 3.84 (s, 2H), 3.59 (t, J=6.0Hz, 2H), 2.63-2.75 (m, 4H), (2.51 m, 3H), 2.1 8 (t, J=9.1Hz, 2H), 1.69 (m, 2H), 1.38-1.40 (m, 2H).
LCMS m/z=688.4 [M+1].
Embodiment 5
[1- [2- [6- [[[(2R) -2- hydroxyl -2- [4- hydroxyl -2- oxo -3H-1,3- benzothiazole -7- base] ethyl] amino] methyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (compound 5)
[1-[2-[6-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]methyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
Step 1: [1- [2- [6- [[[(2R) -2- [tert-butyl (dimethyl) silicon substrate] oxygroup -2- [4- [tert-butyl (dimethyl) silicon substrate] oxygroup -2- oxo -3H-1,3- benzothiazole -7- base] ethyl] amino] methyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (5B)
[1-[2-[6-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-2-oxo -3H-1,3-benzothiazol-7-yl]ethyl]amino]methyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
By [1- [2- (6- formoxyl -1- oxo -3; 4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (1J) (0.17g, 0.34mmol) is dissolved in the in the mixed solvent of methylene chloride (20mL) and methanol (6mL).7- [(1R) -2- amino -1- [tert-butyl (dimethyl) silicon substrate] oxygen-ethyl] -4- [tert-butyl (dimethyl) silicon substrate] oxygen -3H-1 is added thereto, 3- benzothiazole -2- ketone (intermediate 2) (0.16g, 0.34mmol), sodium triacetoxy borohydride (0.22g is added after stirring 30 minutes at room temperature, 1.0mmol), reaction terminates after being stirred at room temperature 3 hours.Saturated sodium bicarbonate aqueous solution (50mL) quenching reaction is added thereto, it is extracted with methylene chloride (100mL × 2), organic phase after merging is dry with anhydrous sodium sulfate, column chromatography for separation (methylene chloride: methanol (v/v)=1:0~8:1) obtains [1- [2- [6- [[[(2R) -2- [tert-butyl (dimethyl) silicon substrate] oxygroup -2- [4- [tert-butyl (dimethyl) silicon substrate] oxygroup -2- oxo -3H-1 of brown solid after reduced pressure, 3- benzothiazole -7- base] ethyl] amino] methyl] -1- oxo -3, 4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (5B) (0.08g, yield 30%).
LCMS m/z=469.0 [M/2+1].
Step 2: [1- [2- [6- [[[(2R) -2- hydroxyl -2- [4- hydroxyl -2- oxo -3H-1,3- benzothiazole -7- base] ethyl] amino] methyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (compound 5)
[1-[2-[6-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]methyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
By [1- [2- [6- [[[(2R) -2- [tert-butyl (dimethyl) silicon substrate] oxygroup -2- [4- [tert-butyl (dimethyl) silicon substrate] oxygroup -2- oxo -3H-1, 3- benzothiazole -7- base] ethyl] amino] methyl] -1- oxo -3, 4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (5B) (0.08g, it 0.09mmol) is dissolved in tetrahydrofuran (10mL), three hydrofluoric acid (0.98g of triethylamine is added into reaction flask, 6.1mmol), reaction terminates after being stirred at room temperature 12 hours.Saturated sodium bicarbonate aqueous solution (50mL) quenching reaction is successively added dropwise thereto, it is extracted with methylene chloride (100mL × 2), organic phase after merging is dry with anhydrous sodium sulfate, and column chromatography for separation (methylene chloride: methanol (v/v)=1:0~8:1) obtains after reduced pressure [1- [2- [6- [[[(2R) -2- hydroxyl -2- [4- hydroxyl -2- oxo -3H-1 of brown solid, 3- benzothiazole -7- base] ethyl] amino] methyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (compound 5) (0.01g, yield 20%).
1H NMR(400MHz,CDCl3)δ8.13–7.95(m,1H),7.64-7.90(m,1H),7.61–7.28(m,6H),7.21–7.03(m,3H),7.00–6.56(m,3H),5.56-5.13(m,2H),5.11–4.59(m,4H),4.57-4.26(m,2H),4.02-3.86(m,1H),3.69–3.39(m,4H),2.96–2.70(m,4H),2.68-2.51(m,2H),2.39-2.29(m,1H),1.98-1.82(m,2H),1.69–1.58(m,2H)。
LCMS m/z=708.3 [M+1].
Embodiment 6
[1- [2- [7- [[[(2R) -2- hydroxyl -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amino] methyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (compound 6)
[1-[2-[7-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
Step 1: the bromo- 3,4- dihydro-isoquinoline -1- ketone (6B) of 2- allyl -7-
2-allyl-7-bromo-3,4-dihydroisoquinolin-1-one
N,N-Dimethylformamide (200mL) is placed in 1000mL round-bottomed flask.At 0 DEG C, add into reaction flask Enter sodium hydride (12g, 300mmol, 60%) bromo- 3,4- dihydro -2H- isoquinoline-1-ketone (the 6A) (33.9g of 7-, is added dropwise into reaction flask by constant pressure funnel, N 150mmol), dinethylformamide (150mL) solution, stirring after twenty minutes, 3- bromopropene (27.2g are added dropwise into reaction flask, 225mmol), reaction, which is warming up to, is stirred at room temperature 4 hours.Water (100mL) quenching reaction is added dropwise into reaction solution, (200mL × 5) are extracted with ethyl acetate, organic phase after merging washes (100mL × 2) with saturated common salt, anhydrous sodium sulfate is dry, column chromatography for separation (petrol ether/ethyl acetate (v/v)=10:1) obtains the 2- allyl -7- bromo- 3 of yellow liquid after reduced pressure, 4- dihydro-isoquinoline -1- ketone (6B) (29.0g, yield 73%).
Step 2: 2- allyl -1- oxo -3,4- dihydro-isoquinoline -7- formonitrile HCN (6C)
2-allyl-1-oxo-3,4-dihydroisoquinoline-7-carbonitrile
By 2- allyl -7- bromo- 3,4- dihydro-isoquinoline -1- ketone (6B) (29.0g, 108.9mmol) is placed in 1000mL round-bottomed flask, and N is added, dinethylformamide (250mL), cuprous cyanide (20.1g, 244.8mmol).Reaction terminates after rising to 160 DEG C of stirrings 10 hours.Water (300mL) is added into reaction solution, (200mL × 3) are extracted with ethyl acetate, organic phase after merging washes (100mL × 2) with saturated common salt, anhydrous sodium sulfate is dry, column chromatography for separation (petrol ether/ethyl acetate (v/v)=10:1) obtains the 2- allyl -1- oxo -3 of yellow solid after reduced pressure, 4- dihydro-isoquinoline -7- formonitrile HCN (6C) (15.6g, yield 68%).
LCMS m/z=213.1 [M+1].
Step 3: 2- allyl -1- carbonyl -3,4- dihydro-isoquinoline -6- benzaldehyde (6D)
2-allyl-1-oxo-3,4-dihydroisoquinoline-7-carbaldehyde
2- allyl -1- oxo -3,4- dihydro-isoquinoline -7- formonitrile HCN (6C) (15.6g, 73.5mmol) is placed in 1000mL round-bottomed flask, it is added ethyl alcohol (250mL), nickel (5.0g, 85mmol), formic acid (10.0g, 217mmol).Reaction rises to 160 DEG C and stirs 10 hours.Reaction solution is cooled to room temperature, is filtered with diatomite, obtains 2- allyl -1- carbonyl -3,4- dihydro-isoquinoline -6- benzaldehyde (6D) (8.5g, yield 54%) of yellow liquid after filtrate decompression concentration.
LCMS m/z=216.1 [M+1].
Step 4: 2- allyl -7- (hydroxymethyl) -3,4- dihydro-isoquinoline -1- ketone (6E)
2-allyl-7-(hydroxymethyl)-3,4-dihydroisoquinolin-1-one
2- allyl -1- carbonyl -3,4- dihydro-isoquinoline -6- benzaldehyde (6D) (8.5g, 39mmol) is placed in 500mL round-bottomed flask.Methanol (100mL) is added into reaction flask, sodium borohydride (1.9g, 51mmol) is added portionwise, stirs 2 hours at room temperature.Water (15mL) quenching reaction is added dropwise, it is extracted with ethyl acetate (200mL), water phase is extracted with ethyl acetate (150mL × 1), organic phase after merging is washed with saturated salt solution (50mL), anhydrous sodium sulfate is dry, 2- allyl -7- (hydroxymethyl) -3,4- dihydro-isoquinoline -1- ketone (6E) (3.8g, 44%) of yellow liquid is obtained after reduced pressure.
LCMS m/z=218.1 [M+1].
Step 5: 2- allyl -7- [[tert-butyl (dimethyl) silicon substrate] Oxymethylene] -3,4- dihydro-isoquinoline -1- ketone (6F)
2-allyl-7-[[tert-butyl(dimethyl)silyl]oxymethyl]-3,4-dihydroisoquinolin-1-one
2- allyl -7- (hydroxymethyl) -3,4- dihydro-isoquinoline -1- ketone (6E) (3.8g, 17.5mmol) is dissolved in methylene chloride (50mL).Triethylamine (7.5g, 74mmol) successively is added thereto, tert-butyl chloro-silicane (4.35g, 28.9mmol), 4- dimethylamino pyridine (0.8g, 7mmol) stirs 1 hour at room temperature.Column chromatography for separation (petrol ether/ethyl acetate (v/v)=10:1) obtains the 2- allyl -7- [[tert-butyl (dimethyl) silicon substrate] Oxymethylene] -3 of yellow liquid after reaction solution is concentrated under reduced pressure, 4- dihydro-isoquinoline -1- ketone (6F) (5.8g, 100%).
Step 6: 2- [7- [[tert-butyl (dimethyl) silicon substrate] oxygroup methyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] acetaldehyde (6G)
2-[7-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]acetaldehyde
By 2- allyl -7- [[tert-butyl (dimethyl) silicon substrate] Oxymethylene] -3,4- dihydro-isoquinoline -1- ketone (6F) (2.9g, it 8.7mmol) is dissolved in tetrahydrofuran (28mL), in water (7mL).At 0 DEG C, two hydrations potassium osmate (0.5g, 1.0mmol), sodium metaperiodate (9.24g, 43.2mmol) are successively added thereto.Reaction is warmed to room temperature stirring 6 hours.Saturated aqueous sodium thiosulfate (80mL) quenching reaction is added dropwise, residue is extracted with ethyl acetate (150mL × 2), organic phase after merging is washed with saturated salt solution (50mL), anhydrous sodium sulfate is dry, column chromatography for separation (petrol ether/ethyl acetate (v/v)=1:1) obtains 2- [7- [[tert-butyl (dimethyl) silicon substrate] oxygroup methyl] -1- oxo -3 of yellow liquid after reduced pressure, 4- dihydro-isoquinoline -2- base] acetaldehyde (6G) (2.2g, 75%).
LCMS m/z=334.1 [M+1].
Step 7: [1- [2- [7- [[tert-butyl (dimethyl) silicon substrate] Oxymethylene] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (6H)
[1-[2-[7-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
2- [7- [[tert-butyl (dimethyl) silicon substrate] oxygroup methyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] acetaldehyde (6G) (2.2g, 6.6mmol) is dissolved in methylene chloride (100mL).4- piperidyl N- (2- phenyl) carbamate (2.0g, 6.75mmol) is added thereto.Sodium triacetoxy borohydride (3.5g, 17mmol) is added after being stirred at room temperature 1 hour in reaction, continues stirring 2 hours.Saturated sodium bicarbonate aqueous solution (80mL) quenching reaction is added dropwise, it is extracted with methylene chloride (150mL × 2), organic phase after merging is washed with saturated salt solution (50mL), anhydrous sodium sulfate is dry, column chromatography for separation (methylene chloride/methanol (v/v)=15:1) obtains [1- [2- [7- [[tert-butyl (dimethyl) silicon substrate] oxygroup methyl] -1- oxo -3 after reduced pressure, 4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (6H) (0.92g, 23%).
Step 8: [1- [2- (7- hydroxy methylene) -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (6I)
[1-[2-[7-(hydroxymethyl)-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
By [1- [2- [7- [[tert-butyl (dimethyl) silicon substrate] oxygroup methyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (6H) (0.92g, 1.5mmol) is dissolved in tetrahydrofuran (20mL).Tetrabutyl ammonium fluoride (0.65g, 2.5mmol) is added thereto, is stirred at room temperature 2 hours.Column chromatography for separation (methylene chloride/methanol (v/v)=15:1) obtains [1- [2- (7- hydroxy methylene) -1- oxo -3 after reaction solution is concentrated under reduced pressure, 4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (6I) (0.67g, 89%).
LCMS m/z=500.3 [M+1].
Step 9: [1- [2- (7- carboxaldehyde radicals -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (26J)
[1-[2-(7-formyl-1-oxo-3,4-dihydroisoquinolin-2-yl)ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
By [1- [2- (7- hydroxy methylene) -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (6I) (0.67g, 1.33mmol) is dissolved in methylene chloride (10mL).At 0 DEG C, Dai Si-Martin's oxidant (0.68g, 1.6mmol) is added thereto.Reaction is rear after being stirred at room temperature 2 hours to be terminated.Saturated sodium bicarbonate aqueous solution (40mL) quenching reaction is added dropwise; it is extracted with methylene chloride (50mL × 2); organic phase after merging is washed with saturated salt solution (50mL); anhydrous sodium sulfate is dry; column chromatography for separation (methylene chloride/methanol (v/v)=15:1) obtains [1- [2- (7- formoxyl -1- oxo -3 of yellow liquid after reduced pressure; 4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (6J) (0.58g, 87%).
Step 10: [1- [2- [7- [[[(2R) -2- [tert-butyl (dimethyl) silicon substrate] oxygroup -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amino] methyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (6K)
[1-[2-[7-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
By [1- [2- (7- formoxyl -1- oxo -3; 4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (6J) (0.29g, 0.58mmol) is dissolved in the in the mixed solvent of methylene chloride (20mL) and methanol (6mL).5- [(1R) -2- amino -1- [tert-butyl (dimethyl) silicon substrate] oxygroup-ethyl] -8- hydroxyl -1H- quinoline-2-one (1K) (0.20g is added thereto, 0.60mmol), sodium borohydride (0.065g is added after stirring 3 hours at room temperature, 1.7mmol), reaction is stirred at room temperature 0.5 hour.Water (5mL) quenching reaction is added thereto, it is extracted with methylene chloride (100mL × 2), organic phase after merging is dry with anhydrous sodium sulfate, column chromatography for separation (methylene chloride: methanol (v/v)=1:0~8:1) obtains [1- [2- [7- [[[(2R) -2- [tert-butyl (dimethyl) silicon substrate] oxygen -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amino] methyl] -1- oxo -3 of yellow solid after reduced pressure, 4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (6K) (0.24g, yield 51%).
Step 11: [1- [2- [7- [[[(2R) -2- hydroxyl -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amino] methyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (compound 6)
[1-[2-[7-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
By [1- [2- [7- [[[(2R) -2- [tert-butyl (dimethyl) silicon substrate] oxygen -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amino] methyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (6K) (0.24g, it 0.29mmol) is dissolved in tetrahydrofuran (10mL), three hydrofluoric acid (0.8g of triethylamine is added into reaction flask, 5.0mmol), reaction is stirred at room temperature 12 hours.Saturated sodium bicarbonate aqueous solution (50mL) quenching reaction is successively added dropwise thereto, it is extracted with methylene chloride (100mL × 2), organic phase after merging is dry with anhydrous sodium sulfate, column chromatography for separation (methylene chloride: methanol (v/v)=1:0~8:1) obtains [1- [2- [7- [[[(2R) -2- hydroxyl -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amino] methyl] -1- oxo -3 of yellow solid after reduced pressure, 4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (compound 6) (0.19g, yield 90%).
1H NMR (400MHz, DMSO-d6) δ 10.29 (br, 1H), 8.58 (s, 1H), 8.12 (d, J=10.0Hz, 1H), 7.88 (s, 1H), 7.44-7.27 (m, 11H), 7.22 (d, J=7.8Hz, 1H), 7.07 (d, J=8.2Hz, 1H), 6.93 (d, J=8.1Hz, 1H), 6.47 (d, J=9.9Hz, 1H), 5.17-5.11 (m, 1H), 4.47-4.41 (m, 1H), 3.86 (s, 2H), 3.58-3.52 (m, 4H), 3.14-3.48 (m, 2H), 2.91 (t, J=6. 3Hz, 2H), 2.84 (d, J=6.8Hz, 1H), 2.73 (t, J=3.9Hz, 2H), 2.62-2.68 (m, 2H), 2.19 (t, J=9.1Hz, 2H), 1.65-1.73 (m, 2H), 1.45-1.36 (m, 2H).
LCMS m/z=703.3 [M+2].
Embodiment 7:[1- [2- [9- [2- [[(2R) -2- hydroxyl -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amido] ethyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl]-N- (2- phenyl) carbamate (compound 7)
[1-[2-[6-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
Step 1: [1- oxo -2- [2- [4- (2- biphenyl) carbamoyl oxygroup] -1- piperidyl] ethyl] -3,4- dihydro-isoquinoline -6- base] methyl-methanesulfonate ester (7A)
[1-oxo-2-[2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl]-3,4-dihydroisoquinolin-6-yl]methyl methanesulfonate
By [1- [2- (6- hydroxy methylene) -1- oxygen -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) ammonium carbonate (1I) (1.20g, 2.4mmol) is dissolved in methylene chloride (20mL).It at 0 DEG C, sequentially adds thereto triethylamine (0.73g, 7.2mmol), 4-dimethylaminopyridine (0.03g, 0.24mmol), methane sulfonyl chloride (0.41g, 3.6mmol).Reaction is stirred 2 hours at 0 DEG C.Saturated sodium bicarbonate aqueous solution (40mL) quenching reaction is added dropwise, it is extracted with methylene chloride (100mL × 2), organic phase after merging is washed with saturated salt solution (50mL), anhydrous sodium sulfate is dry, [1- carbonyl -2- [2- [4- (2- biphenyl) carbamoyl the oxygroup] -1- piperidyl] ethyl] -3 of yellow solid is obtained after reduced pressure, 4- dihydro-isoquinoline -6- base] methyl-methanesulfonate ester (7A) (1.20g, 86.5%).
Step 2: [1- [2- (6- cyano methyl) -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl Phenyl) carbamate (7B)
[1-[2-[6-(cyanomethyl)-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
By [1- oxo -2- [2- [4- (2- biphenyl) carbamoyl oxygroup] -1- piperidyl] ethyl] -3,4- dihydro-isoquinoline -6- base] methyl-methanesulfonate ester (7A) (1.20g, 2.1mmol) it is dissolved in N, in dinethylformamide (20mL), potassium cyanide (0.16g is added, 2.5mmol), after stirring 8 hours at room temperature.It is added water (50mL), it is extracted with methylene chloride (100mL × 2), organic phase after merging is washed with saturated salt solution (50mL × 2), anhydrous sodium sulfate is dry, [1- [2- (6- cyano methyl) -1- oxo -3 of yellow solid is obtained after reduced pressure, 4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (7B) (1.1g, 100%).
LCMS m/z=509.7 [M+1].
Step 3: 2- [1- oxo -2- [2- [4- (2- biphenyl) carbamoyl oxygroup] -1- piperidyl] ethyl] -3,4- dihydro-isoquinoline -6- base] ethyl acetate (7C)
ethyl 2-[1-oxo-2-[2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl]-3,4-dihydroisoquinolin-6-yl]acetate
By [1- [2- (6- cyano methyl) -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (7B) (0.4g, 0.8mmol) is dissolved in ethyl alcohol (20mL).At room temperature, be passed through HCl gas thereto, stop being passed through HCl gas after 30 minutes, reaction is warming up to stirred 8 hours at 60 DEG C after terminate.It is concentrated under reduced pressure and removes most of reaction dissolvent, methylene chloride (100mL) and saturated sodium bicarbonate aqueous solution (50mL) are added into residue, extraction, water phase is extracted with methylene chloride (100mL × 1), organic phase after merging is washed with saturated salt solution (50mL), anhydrous sodium sulfate is dry, the 2- [1- oxo -2- [2- [4- (2- biphenyl) carbamoyl oxygroup] -1- piperidyl] ethyl] -3 of yellow solid is obtained after reduced pressure, 4- dihydro-isoquinoline -6- base] ethyl acetate (7C) (0.44g, 100%).
LCMS m/z=556.4 [M+1].
Step 4: [1- [2- [6- (2- hydroxyethyl) -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl Phenyl) carbamate (7D)
[1-[2-[6-(2-hydroxyethyl)-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
By 2- [1- oxo -2- [2- [4- (2- biphenyl) carbamoyl oxygroup] -1- piperidyl] ethyl] -3,4- dihydro-isoquinoline -6- base] ethyl acetate (7C) (0.44g, 0.8mmol) is dissolved in the in the mixed solvent of tetrahydrofuran (9mL) and methanol (1mL).At room temperature, lithium borohydride (0.05g, 2.4mmol) is added thereto, stirs 4 hours.It is added water (30mL), it is extracted with methylene chloride (100mL × 2), organic phase after merging is washed with saturated salt solution (50mL), anhydrous sodium sulfate is dry, column chromatography for separation (methylene chloride/methanol (v/v)=10:1) obtains [[1- [2- [6- (2- hydroxyethyl) -1- oxo -3 of yellow solid after reduced pressure, 4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (7D) (0.1g, 25%).
LCMS m/z=514.3 [M+1]
Step 5: [1- [2- [6- (2- bromoethyl) -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (7E)
[1-[2-[6-(2-bromoethyl)-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
By [[1- [2- [6- (2- hydroxyethyl) -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (7D) (0.48g, 0.93mmol) is dissolved in methylene chloride (10mL).At room temperature, triphenylphosphine (0.37g, 1.4mmol) successively is added thereto, carbon tetrabromide (0.46g, 1.4mmol), imidazoles (0.13g, 1.9mmol) stirs 4 hours.It is added saturated sodium bicarbonate aqueous solution (50mL), it is extracted with methylene chloride (100mL × 2), organic phase after merging is washed with saturated salt solution (50mL), anhydrous sodium sulfate is dry, column chromatography for separation (methylene chloride/methanol (v/v)=10:1) obtains [1- [2- [6- (2- bromoethyl) -1- oxo -3 of yellow solid after reduced pressure, 4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (7E) (0.4g, 74%).
LCMS m/z=576.2 [M+1].
Step 6: [1- [2- [6-2- [[(2R) -2- [tert-butyl (dimethyl) silicon substrate] oxygroup -2- (8- hydroxyl -2- oxo -1H- quinoline -5- Base) ethyl] amido] ethyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (7F)
[1-[2-[6-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
By [1- [2- [6- (2- bromoethyl) -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (7E) (0.40g, it 0.69mmol) is dissolved in N,N-dimethylformamide (10mL).At room temperature, 5- [(1R) -2- amino -1- [tert-butyl (dimethyl) silicon substrate] oxygroup-ethyl] -8- hydroxyl -1H- quinoline-2-one (1K) (0.26g is added, 0.76mmol), diisopropyl ethyl amine (0.18g, 1.4mmol), reaction be warming up to stirred 4 hours at 50 DEG C after reaction terminating.Reaction is cooled to room temperature, it is added saturated sodium bicarbonate aqueous solution (50mL), it is extracted with methylene chloride (100mL × 2), organic phase after merging is washed with saturated salt solution (50mL × 2), anhydrous sodium sulfate is dry, column chromatography for separation (methylene chloride/methanol (v/v)=10:1) obtains [1- [2- [6-2- [[(2R) -2- [tert-butyl (dimethyl) silicon substrate] oxygroup -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amido] ethyl] -1- oxo -3 of yellow solid after reduced pressure, 4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (7F) (0.4g, 69%).
LCMS m/z=415.8 [M/2+1].
Step 7: [1- [2- [9- [2- [[(2R) -2- hydroxyl -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amido] ethyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl]-N- (2- phenyl) carbamate (compound 7)
[1-[2-[6-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
By [1- [2- [6-2- [[(2R) -2- [tert-butyl (dimethyl) silicon substrate] oxygroup -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) second Base] amido] ethyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (7F) (0.40g, it 0.48mmol) is dissolved in tetrahydrofuran (10mL), three hydrofluoric acid (0.39g of triethylamine is added into reaction flask, 2.4mmol), reaction is stirred at room temperature 12 hours.Saturated sodium bicarbonate aqueous solution (50mL) and methanol (5mL) quenching reaction is added thereto, it is extracted with methylene chloride (100mL × 2), organic phase after merging is dry with anhydrous sodium sulfate, column chromatography for separation (methylene chloride: methanol (v/v)=1:0~8:1) obtains [1- [2- [9- [2- [[(2R) -2- hydroxyl -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amido] ethyl] -1- oxygen -3 of yellow solid after reduced pressure, 4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) ammonium carbonate (compound 7) (0.3g, yield 90%).
LCMS m/z=717.3 [M+1].
1H NMR(400MHz,Methanol-D4)δ8.33-8.31(d,1H),7.83-7.81(d,1H),7.56-7.54(m,1H),7.36-7.28(m,9H),7.21-7.19(d,1H),7.10-7.09(m,1H),6.92-6.90(d,1H),6.92-6.90(d,1H),5.21-5.18(m,1H),4.59-4.53(m,1H),3.68-3.65(m,2H),3.60-3.57(m,2H),2.93-2.86(m,8H),2.75-2.70(m,2H),2.59-2.46(m,2H),2.37-2.32(m,2H),1.83-1.80(m,2H),1.60-1.57(m,2H)。
Embodiment 8:1- [2- [5- [2- [[(2R) -2- hydroxyl -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amido] ethyl] -1- oxo-isoindoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (compound 8)
[1-[2-[5-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]-1-oxo-isoindolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
Step 1: [1- oxo -2- [2- [4- (2- phenyl) carbamoyloxy] -1- piperidyl] ethyl] isoindoline -5- base] methylmethanesulfonate ester (8A)
[1-oxo-2-[2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl]isoindolin-5-yl]methylmethanesulfonate
[1- [2- [5- (hydroxymethyl) -1- oxygen-isoindoline -2- base] ethyl] -4- piperidyl]-N- (2- phenyl) carbamate (4E) (0.80g, 1.6mmol) is dissolved in methylene chloride (20mL).At 0 DEG C, it is added triethylamine (0.50g, 4.9mmol), 4-dimethylaminopyridine (0.02g, 0.16mmol), methane sulfonyl chloride (0.28g, 2.5mmol).Reaction is stirred 2 hours at 0 DEG C.It is added saturated sodium bicarbonate aqueous solution (40mL), it is extracted with methylene chloride (100mL × 2), organic phase after merging is washed with saturated salt solution (50mL), anhydrous sodium sulfate is dry, filtering, [1- oxo -2- [2- [4- (2- phenyl) carbamoyl oxygroup] -1- piperidyl] ethyl] isoindoline -5- base of yellow solid is obtained after filtrate decompression concentration] methylmethanesulfonate ester (8A) (0.9g, 100%).
Step 2: [1- [2- [5- (cyano methyl) -1- oxo-isoindoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (8B)
[1-[2-[5-(cyanomethyl)-1-oxo-isoindolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
By [1- oxo -2- [2- [4- (2- phenyl) carbamoyl oxygroup] -1- piperidyl] ethyl] isoindoline -5- base] methyl Methanesulfonates (8A) (0.90g, 1.6mmol) is dissolved in N,N-dimethylformamide (20mL).Potassium cyanide (0.21g, 3.2mmol) is added thereto, stirs 8 hours at room temperature.It is added water (50mL), it is extracted with methylene chloride (100mL × 2), organic phase after merging is washed with saturated salt solution (50mL × 2), anhydrous sodium sulfate is dry, filtering, [1- [2- [5- (cyano methyl) -1- oxo-isoindoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (8B) (0.80g, 100%) of yellow solid is obtained after filtrate decompression concentration.
LCMS m/z=496.4 [M+1].
Step 3: 2- [1- oxo -2- [2- [4- [(2- phenyl) carbamoyl oxygroup] -1- piperidyl] ethyl] isoindoline -5- base] ethyl acetate (8C)
ethyl 2-[1-oxo-2-[2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl]isoindolin-5-yl]acetate
[1- [2- [5- (cyano methyl) -1- oxo-isoindoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (8B) (0.8g, 1.6mmol) is dissolved in ethyl alcohol (20mL).At room temperature, it is passed through HCl gas thereto, stops being passed through HCl gas after 30 minutes, reaction, which is warming up at 60 DEG C, stirs 8 hours.It is concentrated under reduced pressure and removes most of reaction dissolvent, methylene chloride (100mL) and saturated sodium bicarbonate aqueous solution (50mL) is added, extraction, water phase is extracted with methylene chloride (100mL × 1), organic phase after merging is washed with saturated salt solution (50mL), anhydrous sodium sulfate is dry, filtering, column chromatography for separation (methylene chloride/methanol (v/v)=10:1) obtains 2- [1- oxo -2- [2- [4- [(2- phenyl) carbamoyl oxygroup] -1- piperidyl] ethyl] isoindoline -5- base] ethyl acetate (8C) (0.30g of yellow solid after filtrate decompression concentration, 34%).
LCMS m/z=542.3 [M+1].
Step 4: [1- [2- [5- (2- hydroxyethyl) -1- oxo-isoindoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (8D)
[1-[2-[5-(2-hydroxyethyl)-1-oxo-isoindolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
2- [1- oxo -2- [2- [4- [(2- phenyl) carbamoyl oxygroup] -1- piperidyl] ethyl] isoindoline -5- base] ethyl acetate (8C) (0.30g, 0.55mmol) is dissolved in the in the mixed solvent of tetrahydrofuran (9mL) and methanol (1mL).At room temperature, lithium borohydride (0.05g, 2.2mmol) is added thereto, after stirring 4 hours.It is added water (30mL), it is extracted with methylene chloride (100mL × 2), organic phase after merging is washed with saturated salt solution (50mL), anhydrous sodium sulfate is dry, filtering, column chromatography for separation (methylene chloride/methanol (v/v)=10:1) obtains [1- [2- [5- (2- hydroxyethyl) -1- oxo-isoindoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (8D) (0.28g, 100%) of yellow solid after filtrate decompression concentration.
LCMS m/z=500.3 [M+1].
Step 5: [1- [2- [5- (2- bromoethyl) -1- oxo-isoindoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (8E)
[1-[2-[5-(2-bromoethyl)-1-oxo-isoindolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
[1- [2- [5- (2- hydroxyethyl) -1- oxo-isoindoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (8D) (0.28g, 0.56mmol) is dissolved in methylene chloride (10mL).At room temperature, triphenylphosphine (0.22g, 0.84mmol) successively is added thereto, carbon tetrabromide (0.28g, 0.84mmol), imidazoles (0.11g, 1.7mmol) stirs 4 hours.It is added saturated sodium bicarbonate aqueous solution (50mL), it is extracted with methylene chloride (100mL × 2), organic phase after merging is washed with saturated salt solution (50mL), anhydrous sodium sulfate is dry, filtering, column chromatography for separation (methylene chloride/methanol (v/v)=10:1) obtains [1- [2- [5- (2- bromoethyl) -1- oxo-isoindoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (8E) (0.18g, 57%) of yellow solid after filtrate decompression concentration.
LCMS m/z=562.2 [M+1].
Step 6: [1- [2- [5- [2- [[(2R) -2- [tert-butyl (dimethyl) silicon substrate] oxygroup -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amido] ethyl] -1- oxo-isoindoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (8F)
[1-[2-[5-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]-1-oxo-isoindolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
By [1- [2- [5- (2- bromoethyl) -1- oxo-isoindoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (8E) (0.18g, it 0.32mmol) is dissolved in N,N-dimethylformamide (10mL).At room temperature, 5- [(1R) -2- amino -1- [tert-butyl (dimethyl) silicon substrate] oxygroup-ethyl] -8- hydroxyl -1H- quinoline-2-one (1K) (0.11g is added, 0.32mmol), diisopropyl ethyl amine (0.08g, 0.64mmol), reaction, which is warming up at 50 DEG C, stirs 4 hours.It is cooled to room temperature wait react, it is added saturated sodium bicarbonate aqueous solution (50mL), it is extracted with methylene chloride (100mL × 2), organic phase after merging is washed with saturated salt solution (50mL × 2), anhydrous sodium sulfate is dry, filtering, column chromatography for separation (methylene chloride/methanol (v/v)=10:1) obtains [1- [2- [5- [2- [[(2R) -2- [tert-butyl (dimethyl) silicon substrate] oxygroup -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amido] ethyl] -1- oxo-isoindoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (8F) (0.15g of yellow solid after filtrate decompression concentration, 57%).
LCMS m/z=408.8 [M/2+1].
Step 7: 1- [2- [5- [2- [[(2R) -2- hydroxyl -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amido] ethyl] -1- oxo-isoindoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (compound 8)
[1-[2-[5-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]-1-oxo-isoindolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
By [1- [2- [5- [2- [[(2R) -2- [tert-butyl (dimethyl) silicon substrate] oxygroup -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amido] ethyl] -1- oxo-isoindoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (8F) (0.15g, it 0.18mmol) is dissolved in tetrahydrofuran (10mL), three hydrofluoric acid (0.30g of triethylamine is added into reaction flask, 1.8mmol), it is stirred at room temperature 12 hours.Saturated sodium bicarbonate aqueous solution (50mL) and methanol (5mL) quenching reaction is added thereto, it is extracted with methylene chloride (100mL × 2), organic phase after merging is dry with anhydrous sodium sulfate, filtering, column chromatography for separation (methylene chloride: methanol (v/v)=1:0~8:1) obtains 1- [2- [5- [2- [[(2R) -2- hydroxyl -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amido] ethyl] -1- oxo-isoindoline -2- base] ethyl] -4- piperidyl of yellow solid after filtrate decompression concentration] N- (2- phenyl) carbamate (compound 8) (0.1g, yield 78%).
LCMS m/z=703.3 [M+1].
1H NMR(400MHz,Methanol-D4)δ8.36-8.36(d,1H),7.75-7.73(d,1H),7.56-7.54(m,2H),7.36-7.26(m,12H),7.04-7.02(d,1H),6.71-6.69(d,1H),5.44-5.40(m,1H),4.65-4.61(m,1H),3.87-3.84(m,2H),3.31-3.16(m,6H),2.93-2.86(m,5H),2.79-2.75(m,2H),1.92-1.90(m,2H),1.72-1.70(m,2H)。
Embodiment 9:[1- [2- [6-2- [[(2R) -2- hydroxyl -2- (5- hydroxyl -3- oxo -4H-1,4- benzoxazine -8- base) ethyl] amido] ethyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (compound 9)
[1-[2-[6-[2-[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]ethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
Step 1: [1- [2- [6-2- [[(2R) -2- [tert-butyl (dimethyl) silicon substrate] oxo -2- (5- hydroxyl -3- oxo -4H-1,4- benzoxazine -8- base) ethyl] amido] ethyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (9A)
[1-[2-[6-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]ethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
By [1- [2- [6- (2- bromoethyl) -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (7E) (0.40g, it 0.69mmol) is dissolved in N,N-dimethylformamide (10mL).At room temperature, -4 hydrogen -1 of 8- [(1R) -2- amido -1- [tert-butyl (dimethyl) silicon substrate] oxygen - ethyl] -5- hydroxyl is added, 4- benzoxazine -3- ketone (2A) (0.26g, 0.76mmol), diisopropyl ethyl amine (0.18g, 1.4mmol), reaction, which is warming up at 50 DEG C, stirs 4 hours.It is cooled to room temperature wait react, it is added saturated sodium bicarbonate aqueous solution (50mL), it is extracted with methylene chloride (100mL × 2), organic phase after merging is washed with saturated salt solution (50mL × 2), anhydrous sodium sulfate is dry, column chromatography for separation (methylene chloride/methanol (v/v)=10:1) obtains [1- [2- [6-2- [[(2R) -2- [tert-butyl (dimethyl) silicon substrate] oxo -2- (5- hydroxyl -3- oxo -4H-1 of yellow solid after reduced pressure, 4- benzoxazine -8- base) ethyl] amido] ethyl] -1- oxo -3, 4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (9A) (0.3g, 52%).
LCMS m/z=835.4 [M+1].
Step 2: [1- [2- [6-2- [[(2R) -2- hydroxyl -2- (5- hydroxyl -3- oxo -4H-1,4- benzoxazine -8- base) ethyl] amido] ethyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (compound 9)
[1-[2-[6-[2-[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]ethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
By [1- [2- [6-2- [[(2R) -2- [tert-butyl (dimethyl) silicon substrate] oxo -2- (5- hydroxyl -3- oxo -4H-1,4- benzoxazine -8- base) ethyl] amido] ethyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (9A) (0.30g, it 0.36mmol) is dissolved in tetrahydrofuran (10mL), three hydrofluoric acid (0.58g of triethylamine is added, 3.6mmol), reaction is stirred at room temperature 12 hours.Saturated sodium bicarbonate aqueous solution (50mL) and methanol (5mL) quenching reaction is added thereto, it is extracted with methylene chloride (100mL × 2), organic phase after merging is dry with anhydrous sodium sulfate, column chromatography for separation (methylene chloride: methanol (v/v)=1:0~8:1) obtains [1- [2- [6-2- [[(2R) -2- hydroxyl -2- (5- hydroxyl -3- oxo -4H-1 of yellow solid after reduced pressure, 4- benzoxazine -8- base) ethyl] amido] ethyl] -1- oxo -3, 4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (compound 9) (0.1g, yield 39%).
LCMS m/z=720.3 [M+1].
1H NMR(400MHz,Methanol-D4)δ7.84-7.82(d,1H),7.56-7.54(m,1H),7.37-7.18(m,9H),7.11-7.10(m,1H),6.91-6.89(d,1H),6.50-6.48(m,1H),5.03-5.01(m,1H),4.60-4.45(m,1H),3.69-3.61(m,4H),2.90-2.71(m,10H),2.63-2.60(m,2H),2.39-2.37(m,2H),1.84-1.80 (m,2H),1.61-1.59(m,2H)。
Embodiment 10:[1- [2- [6- [2- [2- (5- hydroxyl -3- oxo -4H-1,4- benzoxazine -8- base) ethyl] amido] ethyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] two trifluoroacetate (compound 10) of N- (2- phenyl) carbamate
[1-[2-[6-[2-[2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethylamino]ethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate ditrifluoroacetic acid
By [1- [2- [6- (2- bromoethyl) -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (7E) (0.35g, it 0.61mmol) is dissolved in N,N-dimethylformamide (10mL).At room temperature, 8- (2- amido ethyl) -5- hydroxyl -4H-1 is added, (0.18g (is prepared) in 4- benzoxazine -3- ketone diacetin with reference to WO2008075025A1,0.67mmol), diisopropyl ethyl amine (0.16g, 1.2mmol), reaction, which is warming up at 50 DEG C, stirs 4 hours.It is cooled to room temperature wait react, saturated sodium bicarbonate aqueous solution (50mL) is added thereto, methylene chloride (100mL × 2) extraction, organic phase after merging is washed with saturated salt solution (50mL × 2), anhydrous sodium sulfate is dry, filtering, after filtrate decompression concentration, residue liquid phase prepares post separation and purifies (liquid phase preparation condition: C18 reverse phase preparative column, mobile phase is the deionized water (A) containing 0.1% trifluoroacetic acid, acetonitrile (B) containing 0.1% trifluoroacetic acid, gradient elution, B content=5%~50%, elution time 15min, flow velocity 12mL/min, column temperature: 30 DEG C) obtain [1- [2- [6- [2- [2- (5- hydroxyl -3- oxo -4H-1 of yellow solid, 4- benzoxazine -8- base) ethyl] amido] second Base] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] two trifluoroacetate (compound 10) (0.15g, 35%) of N- (2- phenyl) carbamate.
LCMS m/z=705.4 [M+1].
1H NMR(400MHz,Methanol-D4)δ7.96-7.94(d,1H),7.43-7.22(m,10H),6.75-6.73(d,1H),6.52-6.50(m,1H),3.94-3.91(m,2H),3.80-3.65(m,5H),3.40-3.38(m,2H),3.20-3.04(m,11H),2.94-2.91(m,2H),2.04-2.02(m,2H)。
Embodiment 11:[1- [2- [6-2- [[(2R) -2- hydroxyl -2- (4- hydroxyl -2- oxo -3H-1,3- benzothiazole -7- base) ethyl] amido] ethyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (chemical combination Object 11)
[1-[2-[6-[2-[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]ethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
Step 1: [1- [2- [6- [2- [[(2R) -2- [tert-butyl (dimethyl) silicon substrate] oxygroup -2- (4- hydroxyl -2- oxo -3H-1,3- benzothiazole -7- base) ethyl] amido] ethyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (11A)
[1-[2-[6-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]ethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
By [1- [2- [6- (2- bromoethyl) -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (7E) (0.35g, it 0.61mmol) is dissolved in N,N-dimethylformamide (10mL).At room temperature, 7- [(1R) -2- amido -1- [tert-butyl (dimethyl) silicon substrate] oxygroup-ethyl] -4- [tert-butyl (dimethyl) silicon substrate] oxygroup -3H-1 is added, 3- benzoxazoles -2- ketone (intermediate 2) (0.30g, 0.67mmol), diisopropyl ethyl amine (0.16g, 1.2mmol), reaction, which is warming up at 50 DEG C, stirs 4 hours.It is cooled to room temperature wait react, is added saturated sodium bicarbonate aqueous solution (50mL), uses dichloro Methane (100mL × 2) extraction, organic phase after merging is washed with saturated salt solution (50mL × 2), anhydrous sodium sulfate is dry, filtering, column chromatography for separation (methylene chloride/methanol (v/v)=10:1) obtains [1- [2- [6- [2- [[(2R) -2- [tert-butyl (dimethyl) silicon substrate] oxygroup -2- (4- hydroxyl -2- oxo -3H-1 of yellow solid after filtrate decompression concentration, 3- benzothiazole -7- base) ethyl] amido] ethyl] -1- oxo -3, 4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (11A) (0.15g, 26%).
Step 2: [1- [2- [6-2- [[(2R) -2- hydroxyl -2- (4- hydroxyl -2- oxo -3H-1,3- benzothiazole -7- base) ethyl] amido] ethyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (compound 11)
[1-[2-[6-[2-[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]ethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
By [1- [2- [6- [2- [[(2R) -2- [tert-butyl (dimethyl) silicon substrate] oxygroup -2- (4- hydroxyl -2- oxo -3H-1,3- benzothiazole -7- base) ethyl] amido] ethyl] -1- oxo -3,4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (11A) (0.15g, it 0.16mmol) is dissolved in tetrahydrofuran (10mL), three hydrofluoric acid (0.25g of triethylamine is added into reaction flask, 1.6mmol), it is stirred at room temperature 12 hours.It is added dropwise saturated sodium bicarbonate aqueous solution (50mL), methanol (5mL) quenching reaction, it is extracted with methylene chloride (100mL × 2), organic phase after merging is dry with anhydrous sodium sulfate, column chromatography for separation (methylene chloride: methanol (v/v)=1:0~8:1) obtains [1- [2- [6-2- [[(2R) -2- hydroxyl -2- (4- hydroxyl -2- oxo -3H-1 of yellow solid after reduced pressure, 3- benzothiazole -7- base) ethyl] amido] ethyl] -1- oxo -3, 4- dihydro-isoquinoline -2- base] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (compound 11) (0.05g, yield 40%).
1H NMR(400MHz,Methanol-D4)δ7.84-7.82(d,1H),7.56-7.54(m,1H),7.42-7.18(m,9H),7.11-7.10(m,1H),6.91-6.89(d,1H),6.70-6.68(m,1H),4.60-4.53(m,3H),3.70-3.61(m,4H),2.94-2.68(m,10H),2.65-2.61(m,2H),2.39-2.37(m,2H),1.84-1.80(m,2H),1.61-1.59(m,2H)。
LCMS m/z=723.3 [M+1].
Embodiment 12:[1- [2- [6- [2- [[[(2R) -2- hydroxyl -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amido] methyl] -4,4- dimethyl -1- oxo -3H- isoquinolin-2-yl] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (compound 12)
[1-[2-[6-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-4, 4-dimethyl-1-oxo-3H-isoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
Step 1: the bromo- 4,4- dimethyl -3H- isoquinoline-1-ketone (12B) of 2- allyl -6-
2-allyl-6-bromo-4,4-dimethyl-3H-isoquinolin-1-one
N,N-dimethylformamide (50mL) is placed in 250mL round-bottomed flask.At 0 DEG C, sodium hydride (1.3g, 31.0mmol, 60%) is added into reaction flask, 6- bromo- 4 is added dropwise, 4- dimethyl -3,4- dihydro-isoquinolin -1 (2 hydrogen) -one (12A) (4.0g, 16.0mmol, US20120225857A1), after twenty minutes, 3- bromopropene (2.9g, 24.0mmol) is added dropwise into reaction flask in stirring.Reaction terminates after being warmed to room temperature stirring 4 hours.Water (100mL) quenching reaction is added dropwise into reaction solution, (200mL × 2) are extracted with ethyl acetate in residue, organic phase after merging washes (100mL × 2) with saturated common salt, anhydrous sodium sulfate is dry, and column chromatography for separation (petrol ether/ethyl acetate (v/v)=10:1) obtains yellow liquid after reduced pressure The bromo- 4,4- dimethyl -3H- isoquinoline-1-ketone (12B) (4.65g, yield 100%) of 2- allyl -6-.
Step 2: 2- allyl -4,4- dimethyl -1- oxo -3H- isoquinolin -6- nitrile (12C)
2-allyl-4,4-dimethyl-1-oxo-3H-isoquinoline-6-carbonitrile
By 2- allyl -6- bromo- 4,4- dimethyl -3H- isoquinoline-1-ketone (12B) (4.65g, 15.8mmol) it is dissolved in N, in dinethylformamide (50mL), cuprous cyanide (2.83g is added thereto, 31.6mol), reaction is stirred 24 hours at 160 DEG C.After reacting and being cooled to room temperature, water (100mL) and ethyl acetate (200mL) are sequentially added thereto, filtering, filter cake washes (20mL × 3) with ethyl acetate, by filtrate liquid separation, water phase is extracted with ethyl acetate (100mL × 3), organic phase after merging washes (50mL) with saturated common salt, anhydrous sodium sulfate is dry, column chromatography for separation (petrol ether/ethyl acetate (v/v)=4:1) obtains the 2- allyl -4 of white solid after reduced pressure, 4- dimethyl -1- oxo -3H- isoquinolin -6- nitrile (12C) (3.8g, yield 100%).
LCMS m/z=241.1 [M+1].
Step 3: 2- allyl -4,4- dimethyl -1- oxo -3H- isoquinolin -6- aldehyde (12D)
2-allyl-4,4-dimethyl-1-oxo-3H-isoquinoline-6-carbaldehyde
2- allyl -4,4- dimethyl -1- oxo -3H- isoquinolin -6- nitrile (12C) (3.8g, 16.0mmol) is weighed, is placed in 50mL round-bottomed flask.It is sequentially added into reaction flask formic acid (32mL), water (8mL), alumel (1.36g, 16.0mmol), reaction is stirred 2 hours at 90 DEG C.After reacting and being cooled to room temperature, filtering, filter cake washes (20mL × 2) with ethyl acetate, after filtrate decompression is concentrated, it is added in ethyl acetate (150mL) and water (50mL), liquid separation, water phase is extracted with ethyl acetate (150mL), organic phase after merging is dry with anhydrous sodium sulfate, column chromatography for separation (petrol ether/ethyl acetate (v/v)=2:1) obtains the 2- allyl -4 of yellow liquid after reduced pressure, 4- dimethyl -1- oxo -3H- isoquinolin -6- aldehyde (12D) (2.0g, 52%).
LCMS m/z=244.1 [M+1].
Step 4: 2- allyl -6- (hydroxymethyl) -4,4- dimethyl -3H- isoquinoline-1-ketone (12E)
2-allyl-6-(hydroxymethyl)-4,4-dimethyl-3H-isoquinolin-1-one
2- allyl -4,4- dimethyl -1- oxo -3H- isoquinolin -6- aldehyde (12D) (2.0g, 8.2mmol) is weighed, is placed in 50mL round-bottomed flask.Methanol (10mL) is added into reaction flask, sodium borohydride (0.62g, 16.4mmol) is added portionwise, is stirred at room temperature 2 hours.Water (5mL) quenching reaction is added dropwise, it is extracted with ethyl acetate (50mL × 2), organic phase after merging is washed with saturated salt solution (50mL), anhydrous sodium sulfate is dry, 2- allyl-the 6- (hydroxymethyl) -4 of yellow liquid is obtained after reduced pressure, 4- dimethyl -3H- isoquinoline-1-ketone (12E) (1.2g, 60%).
Step 5: 2- allyl -6- [[tert-butyl (dimethyl) silicon substrate] oxygroup methyl] -4,4- dimethyl -3H- isoquinoline-1-ketone (12F)
2-allyl-6-[[tert-butyl(dimethyl)silyl]oxymethyl]-4,4-dimethyl-3H-isoquinolin-1-one
2- allyl -6- (hydroxymethyl) -4,4- dimethyl -3H- isoquinoline-1-ketone (12E) (1.2g, 4.9mmol) is dissolved in methylene chloride (15mL).Triethylamine (1.24g, 12.2mmol) successively is added thereto, tert-butyl chloro-silicane (1.1g, 7.34mmol), 4- dimethylamino pyridine (0.06g, 0.5mmol) is stirred at room temperature 2 hours.Column chromatography for separation (petrol ether/ethyl acetate (v/v)=2:1) obtains the 2- allyl -6- [[tert-butyl (dimethyl) silicon substrate] oxygroup methyl] -4 of yellow liquid after reaction solution is concentrated under reduced pressure, 4- dimethyl -3H- isoquinoline-1-ketone (12F) (1.6g, 91%).
1H NMR(400MHz,CDCl3)δ8.07-8.05(d,1H),7.29-7.22(m,2H),5.87-5.79(m,1H),5.24-5.21(m,2H),4.77(s,2H),4.19-4.09(m,2H),3.26(s,2H),1.32(s,6H),0.95(s,9H),0.11(s,6H)
Step 6: 2- [6- [[tert-butyl (dimethyl) silicon substrate] oxygroup methyl] -4,4- dimethyl -1- oxo -3H- isoquinolin-2-yl] acetaldehyde (12G)
2-[6-[[tert-butyl(dimethyl)silyl]oxymethyl]-4,4-dimethyl-1-oxo-3H-isoquinolin-2-yl]acetaldehyde
By 2- allyl -6- [[tert-butyl (dimethyl) silicon substrate] oxygroup methyl] -4,4- dimethyl -3H- isoquinoline-1-ketone (12F) (1.6g, it 4.45mmol) is dissolved in tetrahydrofuran (40mL), in water (10mL).At 0 DEG C, two hydrations potassium osmate (0.33g, 0.9mmol) are successively added thereto, sodium metaperiodate (4.76g, 22.2mmol) is warmed to room temperature stirring 2 hours.Saturated aqueous sodium thiosulfate (30mL) quenching reaction is added dropwise, it is extracted with ethyl acetate (50mL × 2), organic phase after merging is washed with saturated salt solution (50mL), anhydrous sodium sulfate is dry, 2- [the 6- [[tert-butyl (dimethyl) silicon substrate] oxygroup methyl] -4 of yellow liquid is obtained after reduced pressure, 4- dimethyl -1- oxo -3H- isoquinolin-2-yl] acetaldehyde (12G) (1.61g 100%).
Step 7: [1- [2- [6- [[tert-butyl (dimethyl) silicon substrate] oxygroup methyl] -4,4- dimethyl -1- oxo -3H- isoquinolin-2-yl] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (12H)
[1-[2-[6-[[tert-butyl(dimethyl)silyl]oxymethyl]-4,4-dimethyl-1-oxo-3H-isoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
By 2- [6- [[tert-butyl (dimethyl) silicon substrate] oxygroup methyl] -4,4- dimethyl -1- oxo -3H- isoquinolin-2-yl] acetaldehyde (12G) (1.61g, 4.45mmol) is dissolved in methylene chloride (50mL).Piperidin-4-yl [1,1 '-diphenyl] -2- aminocarbamic acid ester (preparation refers to WO2012009166) (1.32g, 4.45mmol) is added thereto.Sodium triacetoxy borohydride (2.83g, 13.4mmol) is added after being stirred at room temperature 1 hour in reaction, continues stirring 2 hours.Saturated sodium bicarbonate aqueous solution (40mL) quenching reaction is added, it is extracted with methylene chloride (50mL × 2), organic phase after merging is washed with saturated salt solution (50mL), anhydrous sodium sulfate is dry, column chromatography for separation (methylene chloride/methanol (v/v)=15:1) obtains [1- [2- [6- [[tert-butyl (dimethyl) silicon substrate] Oxymethylene] -4 after reduced pressure, 4- dimethyl -1- oxo -3H- isoquinolin-2-yl] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (12H) (1.2g, 42%).
LCMS m/z=642.4 [M+1].
Step 8: [1- [2- (6- hydroxymethyl) -4,4- dimethyl -1- oxo -3H- isoquinolin-2-yl] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (12I)
[1-[2-[6-(hydroxymethyl)-4,4-dimethyl-1-oxo-3H-isoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
By [1- [2- [6- [[tert-butyl (dimethyl) silicon substrate] oxygroup methyl] -4,4- dimethyl -1- oxo -3H- isoquinolin-2-yl] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (12H) (1.2g, 1.87mmol) is dissolved in tetrahydrofuran (30mL).Tetrabutyl ammonium fluoride (1.0g, 3.74mmol) is added thereto, is stirred at room temperature 2 hours.Column chromatography for separation (methylene chloride/methanol (v/v)=15:1) obtains [1- [2- (6- hydroxy methylene) -4 after reaction solution is concentrated under reduced pressure, 4- dimethyl -1- oxo -3H- isoquinolin-2-yl] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (12I) (0.80g, 81%).
LCMS m/z=528.3 [M+1].
Step 9: [1- [2- (6- formoxyl -4,4- dimethyl -1- oxo -3H- isoquinolin-2-yl] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (12J)
[1-[2-(6-formyl-4,4-dimethyl-1-oxo-3H-isoquinolin-2-yl)ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
By [1- [2- (6- hydroxymethyl) -4,4- dimethyl -1- oxo -3H- isoquinolin-2-yl] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (12I) (0.80g, 1.5mmol) is dissolved in methylene chloride (30mL).At 0 DEG C, Dai Si-Martin's oxidant (1.30g, 3.0mmol) is added thereto.Reaction is rear after being stirred at room temperature 2 hours to be terminated.Saturated sodium bicarbonate aqueous solution (40mL) quenching reaction is added; it is extracted with methylene chloride (50mL × 2); organic phase after merging is washed with saturated salt solution (50mL); anhydrous sodium sulfate is dry; column chromatography for separation (methylene chloride/methanol (v/v)=15:1) obtains [1- [2- (6- formoxyl -4 after reduced pressure; 4- dimethyl -1- oxo -3H- isoquinolin-2-yl] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (12J) (0.60g, 75%).
LCMS m/z=526.2 [M+1]
Step 10: [1- [2- [6- [[[(2R) -2- [tert-butyl (dimethyl) silicon substrate] oxygroup -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amido] -4,4- dimethyl -1- oxo -3H- isoquinolin-2-yl] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (12K)
[1-[2-[6-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]-4,4-dimethyl-1-oxo-3H-isoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
By [1- [2- (6- formoxyl -4; 4- dimethyl -1- oxo -3H- isoquinolin-2-yl] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (12J) (0.3g, 0.57mmol) is dissolved in the in the mixed solvent of methylene chloride (20mL) and methanol (6mL).5- [(1R) -2- amino -1- [tert-butyl (dimethyl) silicon substrate] oxygroup-ethyl] -8- hydroxyl -1H- quinoline-2-one (1K) is added thereto (0.19g, 0.57mmol), anhydrous sodium sulfate (2g), stirs filter after sixty minutes at room temperature, and sodium borohydride (0.03g, 0.86mmol) is added into filtrate, is stirred at room temperature 30 minutes.Saturated sodium bicarbonate aqueous solution (50mL) quenching reaction is added thereto, it is extracted with methylene chloride (100mL × 2), organic phase after merging is dry with anhydrous sodium sulfate, column chromatography for separation (methylene chloride: methanol (v/v)=1:0~8:1) obtains [1- [2- [6- [[[(2R) -2- [tert-butyl (dimethyl) silicon substrate] oxygroup -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amido] -4 of yellow solid after reduced pressure, 4- dimethyl -1- oxo -3H- isoquinolin-2-yl] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (12K) (0.48g, yield 100%).
LCMS m/z=422.9 [M/2+1].
Step 11: [1- [2- [6- [2- [[[(2R) -2- hydroxyl -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amido] methyl] -4,4- dimethyl -1- oxo -3H- isoquinolin-2-yl] ethyl] -4- piperidyl]-N- (2- phenyl) carbamate (compound 12)
[1-[2-[6-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-4,4-dimethyl-1-oxo-3H-isoquinolin-2-yl]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
By [1- [2- [6- [[[(2R) -2- [tert-butyl (dimethyl) silicon substrate] oxygroup -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amido] -4,4- dimethyl -1- oxo -3H- isoquinolin-2-yl] ethyl] -4- piperidyl] N- (2- phenyl) carbamate (12K) (0.48g, it 0.57mmol) is dissolved in tetrahydrofuran (10mL), three hydrofluoric acid of triethylamine (0.5mL) is added into reaction flask, reaction terminates after being stirred at room temperature 12 hours.Saturated sodium bicarbonate aqueous solution (50mL) and methanol (5mL) quenching reaction is added thereto, it is extracted with methylene chloride (100mL × 2), organic phase after merging is dry with anhydrous sodium sulfate, column chromatography for separation (methylene chloride: methanol (v/v)=1:0~8:1) obtains [1- [2- [6- [2- [[[(2R) -2- hydroxyl -2- (8- hydroxyl -2- oxo -1H- quinoline -5- base) ethyl] amido] methyl] -4 of yellow solid after reduced pressure, 4- dimethyl -1- oxo -3H- isoquinolin-2-yl] ethyl] -4- piperidyl]-N- (2- phenyl) carbamate (compound 12) (0.1g, yield 24%).
LCMS m/z=731.3 [M+1].
Biological test example
Test case 1: to the inhibitory activity of people's muscarine M3 receptor
Stablize the Chinese hamster ovary celI (PerkinElmer of expression people's M-ChR 3 (hM3) and apo-Aequorin, ES-212-AF it) is incubated at containing 10% fetal calf serum (FBS) (Gibico 10099-141), 400 μ g/mL G418 (sigma G5013) and in Ham ' the S F12 culture medium (Invitrogen 12500-062) of 250ug/mL Zeocin (invivogen ant-zn-5p), at 37 DEG C, 5%CO2Under the conditions of cultivate, reach 90-100% fusion.Separation cell is rinsed with PBS/5mM EDTA, it is collected by centrifugation, cell is resuspended without phenol red Ham ' s F12 culture medium (Invitrogen 11039-021) containing 0.1%BSA (BOVOGEN BSAS 100) and counts, adjustment cell concentration to 1x106cells/mL.50mL centrifuge tube is added in 15ml cell suspension, Coelenterazine-h (promega S2011) is added to final concentration of 5 μM.It is protected from light with tinfoil package, is incubated for 4 hours at 20 DEG C of rotary shaker.Again with 0.1%BSA/ without phenol red Ham ' s F12 culture medium diluting cells to final concentration of 5.0 × 105Cells/mL, cell is placed on rotary shaker and is slowly run, and is incubated at room temperature at least 1 hour.The inhibitor of embodiment is formulated as 10mM mother liquor with DMSO, and without phenol red Ham ' s F12 culture medium gradient dilution (log (M): -7, -8, -9, -10, -11), 96 orifice plates, every 50 μ L of hole is added in 0.1%BSA/.Every hole adds 50 μ L cell suspensions (25000 cells/well), is incubated at room temperature 15 minutes.96 orifice plates are put into microplate reader (Perkin Elmer, Envision), acecoline (Sigma A6625) solution is added with microplate reader sample injector, concentration is 112.92nM (hM3), record shines 20 seconds, and IC is calculated and analyzed using origin7.550.The inhibitory activity of the compounds of this invention people's M-ChR is measured by above experiment, the IC measured50Value see the table below 1.
Table 1 tests compound to the inhibitory activity result of people's muscarine M3 receptor
Embodiment number HM3 receptor IC50(nM)
Compound 1 0.52
Compound 2 3.55
Compound 3 0.61
Compound 4 1.89
Compound 6 1.05
Compound 7 0.76
Compound 8 2.09
Compound 9 0.66
Compound 10 0.24
Compound 11 2.27
Compound 12 2.28
Conclusion: the compounds of this invention has remarkable inhibiting activity to people's muscarine M3 receptor.
Test case 2: to the agonist activity of human adrenal gland element energy beta 2 receptor
Embodiment compound measures the agonist activity of human adrenal gland element energy receptor by LANCE Ultra cAMP Assay.
Stablize the Chinese hamster ovary celI (PerkinElmer of expression human adrenal gland element energy receptor (h β 2), ES-034-CF) it is incubated at the MEM-alpha culture medium (Invitrogen 12561-056) containing 10% fetal calf serum (FBS) (Gibico 10099-141) and 250 μ g/mL Zeocin (InvivoGen ant-zn-5p), at 37 DEG C, 5%CO2Under the conditions of cultivate, reach after 90-100% fusion with LANCE Ultra cAMP Assay kit (PerkinElmer TRF0263) detection embodiment to the agonism of cAMP.Cell is separated with PBS/5mM EDTA, is collected by centrifugation, cell, adjustment cell concentration to 6x10 is resuspended with Stimulation Buffer (1x HBSS, 5mM HEPES, 0.5mM IBMX, 0.1%BSA, PH7.4)5cells/ml.The inhibitor of embodiment is formulated as 10mM mother liquor with DMSO, 384 orifice plates are added with every 5 μ l of hole after Stimulation Buffer gradient dilution.Every hole adds 5 μ L cell suspensions (3000 cells/well), after incubation at room temperature 30 minutes, 5 μ l 4x Eu-cAMP tracer working solutions are added in every hole, and then 5 μ l 4x Ulight-anti-cAMP working solutions are added in every hole, and are incubated at room temperature 1 hour.384 orifice plates detect TR-FRET with microplate reader (Perkin Elmer, Envision), and EC is calculated and analyzed using origin7.550.The compounds of this invention is measured the agonist activity of human adrenal gland element energy receptor by above experiment, the EC measured50Value is shown in Table 2:
Table 2 tests compound to the agonist activity result of human adrenal gland element energy beta 2 receptor
Embodiment number EC50(nM) h beta 2 receptor
Compound 1 13.35
Compound 2 7.64
Compound 3 15.98
Compound 4 4.37
Compound 7 0.99
Compound 8 0.21
Compound 9 0.44
Compound 11 0.52
Compound 12 11.33
Conclusion: the compounds of this invention has significant agonist activity to beta 2-adrenergic receptor.
Test case 3: the guinea pig bronchial of methacholine induction shrinks inhibiting effect
8 week old all-male cavys are purchased in dimension tonneau China, start to test after adapting to 3 days.Untested compound is configured to 0.6mM stock solution with+17% Tween 80 of 83% dehydrated alcohol.Required concentration is diluted with water to before administration.Before administration, toy Anesthesia machine (Matrx is used；VME2 5% isoflurane anesthetized animal) is given, anesthesia duration is 1.5~2 minutes.After cavy anesthesia, cavy is fixed on trachea cannula operating platform, is set with (penn-century using rat liquid aerosol administration；MSA-250-R) intrarterial, every 250 μ l of cavy administered volume.After administration, in 4 hours, 24 hours, use Full volumetric retouches meter instrument (DSI；GS220A12-R7B) measurement cavy enhancing expiration interval (enhanced pause；PenH) value.Atomization is given 3mg/ml methacholine (Mch), nebulisation time 36 seconds, records the time 7 minutes.Calculate PenH average value.(bibliography J Pharmacol Exp Ther 345:260-270.).Experimental result is shown in Table 3.
PenH calculation formula: PenH=PEP/PIP*Pause；Pause=(Te-Tr)/Tr
Te: expiratory phase time (s)
Tr: relaxation phase time (s)
PEP: End--tidal PCO_2 (ml/s)
PIP: air-breathing peak flow velocity (ml/s)
3 compound of table shrinks inhibiting effect result to the guinea pig bronchial that methacholine induces
Conclusion: the compounds of this invention, which shrinks the guinea pig bronchial that methacholine induces, has strong inhibiting effect, and after administration 24 hours, still has good bronchoconstriction inhibitory effect.

Claims (11)

  1. A kind of logical formula (I) compound represented or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug,
    Wherein:
    R1、R2It is independently selected from F, Cl, Br, I, CF3、C1-4Alkyl, cyano ,-OR1a,-C (=O) OR1b、-SR1c、-S(O)R1d、-S(O)2R1eOr-NR1fR1g；
    R1a、R1b、R1c、R1d、R1e、R1fAnd R1gIt is independently selected from H or C1-4Alkyl；
    Alternatively, R1f、R1gNitrogen-atoms connected to it forms one 5 to 6 yuan of heterocycle, and the heterocycle contains 1 to 3 hetero atom for being selected from N, O or S；
    W is-O- ,-NH- or-NC1-4Alkyl-；
    R3Each it is independently selected from F, Cl, Br, I, CF3, OH, cyano, C1-4Alkyl or C1-4Alkoxy；
    R4Selected from C1-6Alkylidene, C2-6Alkenylene or C2-6Alkynylene, the alkylidene, alkenylene or alkynylene are optionally further selected from F, Cl, Br, I, OH, cyano, C by 0 to 51-4Alkyl, C1-4Alkoxy, phenyl or phenyl-C1-4Replaced the substituent group of alkylidene；
    R5Each it is independently selected from F, Cl, Br, I, OH, NH2, carboxyl, cyano, nitro, C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-4Alkoxy ,-OC3-6Naphthenic base, C1-4Alkylthio group ,-S (=O)-C1-4Alkyl ,-S (=O)2-C1-4Alkyl ,-C (=O)-C1-4Alkyl ,-C (=O) O-C1-4Alkyl ,-OC (=O)-C1-4Alkyl, 5 to 6 unit's heteroaryls or-C (=O) NH2, the alkyl, alkoxy, naphthenic base, alkenyl, alkynyl, NH2With-C (=O) NH2Optionally F, Cl, Br, I, CF further are selected from by 0 to 43、C1-4Alkyl, C1-4Alkoxy or-C (=O)-C1-4Replaced the substituent group of alkyl, and the heteroaryl contains 1 to 4 hetero atom for being selected from N, O or S；
    Y is selected from key ,-CYaYb-、-CYaYbCYaYb-、-NYa-、-CYaYbNYa-、-NYaCYaYb,-O- ,-C=O- ,-CYaYbO-、-OCYaYb-、-S-、-CYaYbS-、-SCYaYb,-S (=O)-or-S (=O)2-；
    Ya、YbIt is independently selected from H or C1-4Alkyl；Or Ya、YbCoupled carbon atom is formed together 3 to 6 yuan of carbocyclic rings；
    R6Each it is independently selected from F, Cl, Br, I, C=O, cyano, C1-4Alkyl or C1-4Alkoxy, it is described Alkyl or alkoxy are optionally further selected from F, Cl, Br, I, CH by 0 to 42F、CHF2、CF3Or replaced the substituent group of cyano；
    Alternatively, two R6The atom that can be connected with them is formed together 3 to 6 yuan of carbocyclic rings, and the carbocyclic ring is optionally further selected from F, Cl, Br, I, cyano, OH, C by 0 to 51-4Alkyl or C1-4Replaced the substituent group of alkoxy；
    R7Selected from C1-6Alkylidene, the alkylidene are optionally further selected from R by 0 to 57aSubstituent group replaced；
    R7aSelected from F, Cl, Br, I, cyano, OH, C1-4Alkyl, C1-4Alkoxy, phenyl or phenyl-C1-4Alkylidene；
    Alternatively, two R7aThe atom that can be connected with them is formed together 3 to 6 yuan of carbocyclic rings, and the carbocyclic ring is optionally further selected from F, Cl, Br, I, cyano, OH, C by 0 to 51-4Alkyl or C1-4Replaced the substituent group of alkoxy；
    R8、R9It is independently selected from H or C1-4Alkyl；
    R10Selected from H or hydroxyl；
    Expression can be with receptor,β conjugated group；
    A is selected from 0,1,2,3,4 or 5；
    B is selected from 0,1,2,3 or 4；
    C is selected from 0,1,2,3 or 4；
    D is selected from 0,1,2 or 3；
    E is selected from 0,1,2,3 or 4.
  2. Compound according to claim 1 or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug, in which:
    B is selected from
    Q is selected from-CH=CH- ,-CH2CH2-、-O-、-S-、-CH2O-、-OCH2-、-C(CH3)2O- or-OC (CH3)2-。
  3. Compound according to claim 2 or its stereoisomer, hydrate, metabolite, solvate, Pharmaceutically acceptable salt, eutectic or prodrug, in which:
    R1And R2It is each independently selected from F, Cl, Br, I, CF3、NH2, OH, cyano, C1-4Alkyl, C1-4Alkoxy, C1-4Alkylthio group ,-NHC1-4Alkyl or-N (C1-4Alkyl)2；
    R3Each it is independently selected from F, Cl, Br, I, CF3, OH, cyano, methyl, ethyl, methoxy or ethoxy；
    R4Selected from C1-4Alkylidene, the alkylidene are optionally further selected from F, Cl, Br, I, OH, cyano, C by 0 to 51-4Alkyl, C1-4Alkoxy, phenyl or phenyl-C1-4Replaced the substituent group of alkylidene；
    R5Each it is independently selected from F, Cl, Br, I, OH, NH2, carboxyl, cyano, nitro, C1-4Alkyl, C2-4Alkynyl, C1-4Alkoxy ,-OC3-6Naphthenic base, C1-4Alkylthio group ,-S (=O)-C1-4Alkyl ,-S (=O)2-C1-4Alkyl ,-C (=O)-C1-4Alkyl ,-C (=O) O-C1-4Alkyl or 5 to 6 unit's heteroaryls, the alkyl, alkoxy, naphthenic base, alkynyl and NH2Optionally F, Cl, Br, I, CF further are selected from by 0 to 43、C1-4Alkyl, C1-4Alkoxy or-C (O)-C1-4Replaced the substituent group of alkyl；
    R7Selected from C1-4Alkylidene, the alkylidene are optionally further selected from R by 0 to 57aSubstituent group replaced；
    R7aSelected from F, Cl, Br, I, cyano, OH, C1-4Alkyl, C1-4Alkoxy or phenyl；
    Alternatively, two R7aThe atom that can be connected with them is formed together 3 to 6 yuan of carbocyclic rings, and the carbocyclic ring is optionally further selected from F, Cl, Br, I, cyano, OH, C by 0 to 51-4Alkyl or C1-4Replaced the substituent group of alkoxy；
    A is selected from 0,1 or 2；
    B is selected from 0,1 or 2；
    C is selected from 0,1 or 2.
  4. Compound according to claim 3 or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug, wherein compound is selected from logical formula (II) compound represented:
    R1And R2It is each independently selected from F, Cl, Br, I, CF3、NH2, OH, cyano, methyl, ethyl, methoxyl group, ethyoxyl ,-NHCH3Or-N (CH3)2；
    W is selected from-O- ,-NH- or-NCH3-；
    R3Each it is independently selected from F, Cl, Br, I, OH, cyano, methyl, ethyl, methoxy or ethoxy
    R4Selected from methylene, ethylidene, propylidene or butylidene；
    R5Each it is independently selected from F, Cl, Br, cyano, methyl, ethyl, propyl, isopropyl, CHF2、CF3, methoxyl group, ethyoxyl ,-OCHF2、-OCF3, cyclopropyl oxygroup, acetenyl or propinyl；
    R6Each it is independently selected from F, Cl, Br, I, C=O, cyano, methyl, ethyl, methoxy or ethoxy；
    Alternatively, two R6The atom that can be connected with them is formed together 3 to 6 yuan of carbocyclic rings, and the carbocyclic ring is optionally further selected from replaced the substituent group of F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy by 0 to 5；
    Ya、YbIt is independently selected from H, methyl or ethyl；Or Ya、YbCoupled carbon atom is formed together 3 to 6 yuan of carbocyclic rings；
    R7Selected from methylene, ethylidene, propylidene ,-CH2CH(CH3)-、-CH(CH3)CH2-、-C(CH3)2CH2-、-CH2C(CH3)2, butylidene ,-CH (CH3)CH2CH2-、-CH2CH(CH3)CH2-、-CH2CH(CH3)CH2Or
    R8、R9It is independently selected from H, methyl or ethyl；
    B is selected from
  5. Compound according to any one of claims 1 to 4 or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug, wherein the compound is selected from such as one of flowering structure:
  6. A kind of pharmaceutical composition, the pharmaceutical composition contain treatment effective dose according to benefit require any one of 1~5 described in compound or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug, and one of selected from pharmaceutically acceptable carrier, diluent, adjuvant, medium and excipient Or a variety of combination；The composition can also further comprise one or more other therapeutic agents.
  7. Pharmaceutical composition according to claim 6, wherein the other therapeutic agents, which are selected from PDE4 inhibitor, muscarinic receptor antagonists, corticosteroid and beta-adrenergic receptor kinase 1, moves one of agent or a variety of.
  8. Pharmaceutical composition described in the described in any item compounds of Claims 1 to 5 or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug or claim 6 or 7 is preparing the application in the drug for treating airway obstructive disease.
  9. Application according to claim 8, the airway obstructive disease are selected from asthma, Chronic Obstructive Pulmonary Disease or bronchitis.
  10. A method for the treatment of airway obstructive disease, the method includes pharmaceutical composition described in compound according to any one of claims 1 to 5 or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug or claim 6 or 7 is administered.
  11. According to the method described in claim 10, the airway obstructive disease is selected from asthma, Chronic Obstructive Pulmonary Disease or bronchitis.
CN201680042175.6A 2015-12-25 2016-12-19 Biphenyl derivative, preparation method and medical application thereof Expired - Fee Related CN107849014B (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999064043A1 (en) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. Muscarinic receptor antagonists
US20060205946A1 (en) * 2005-03-10 2006-09-14 Theravance, Inc. Biphenyl compounds useful as muscarinic receptor antagonists
US20080161343A1 (en) * 2006-07-11 2008-07-03 Washington University Sigma 2 Receptor Ligands and Therapeutic Uses Therefor

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999064043A1 (en) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. Muscarinic receptor antagonists
US20060205946A1 (en) * 2005-03-10 2006-09-14 Theravance, Inc. Biphenyl compounds useful as muscarinic receptor antagonists
US20080161343A1 (en) * 2006-07-11 2008-07-03 Washington University Sigma 2 Receptor Ligands and Therapeutic Uses Therefor

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