CN102153547A - Oxazolidinone antibiotic containing parallel rings - Google Patents

Oxazolidinone antibiotic containing parallel rings Download PDF

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Publication number
CN102153547A
CN102153547A CN2010102017403A CN201010201740A CN102153547A CN 102153547 A CN102153547 A CN 102153547A CN 2010102017403 A CN2010102017403 A CN 2010102017403A CN 201010201740 A CN201010201740 A CN 201010201740A CN 102153547 A CN102153547 A CN 102153547A
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ring
alkyl
methyl
dihydro
triazole
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黄振华
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Shandong Xuanzhu Pharma Co Ltd
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Shandong Xuanzhu Pharma Co Ltd
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Priority to CN2010102017403A priority Critical patent/CN102153547A/en
Priority to PCT/CN2011/000159 priority patent/WO2011097946A1/en
Priority to CN201180004791.XA priority patent/CN102762553B/en
Publication of CN102153547A publication Critical patent/CN102153547A/en
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    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Abstract

The invention belongs to technical field of medicaments, in particular to relates to an oxazolidinone antibiotic containing parallel rings as shown in a general formula (I) and a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1,R2, R3, R4, R5, R6, an A ring, a B ring and -Y- are defined in the specification. The invention also relates to a preparation method of the compounds, a pharmaceutical composition containing the compounds and application of the compounds in preparing medicaments for treating and/or preventing infectious diseases.

Description

Contain and Huan De oxazolidone antibiotic
1, technical field
The invention belongs to medical technical field, be specifically related to contain and Huan De oxazolidone antibiotic, its pharmacy acceptable salt or its steric isomer, the preparation method of these compounds, the pharmaceutical composition that contains these compounds, and these compounds treat and/or prevent purposes in the medicine of infectious diseases in preparation.
2, background technology
Oxazolidine ketone antimicrobial drug is the complete synthesis antimicrobial drug of developing after sulfamido and fluoroquinolones of a class new chemical, has the effect that suppresses the multidrug resistant gram-positive microorganism.
Linezolid is first listing De oxazolidone antibiotics, and gram-positive microorganism is had stronger restraining effect, does not have cross resistance with other antimicrobial drugs.The mechanism of action uniqueness suppresses bacterioprotein synthetic commitment.Be mainly used in the infectious diseases that treatment is caused by the resistance gram-positive microorganism, good to the characteristics of pharmacokinetics of the perviousness of bone, lung, cerebrospinal fluid etc. and tissue concentration, also can be used for the surgical infection treatment of diseases.
Yet the clinical application kind of the more and more serious ， oxazolidone antibiotics of the resistance situation of gram-positive microorganism is very single again clinically, can not satisfy clinical application, and the resistance situation of linwzolid occurs constantly also.Therefore, be badly in need of research and development to the effective antibacterials of drug tolerant bacteria height.
3, summary of the invention
The invention provides a class anti-infective compounds, have better antibacterial activity, concrete technical scheme is as follows:
Compound shown in the general formula (I):
Figure BSA00000144719800011
Wherein, R 1Be acetamido, hydroxyl, amino, C 1-6Alkyl amine group, 1,2,3-triazol radical Huo isoxazole oxygen base;
R 2, R 3Be hydrogen atom independently, halogen atom or C 1-6Alkyl;
Figure BSA00000144719800012
Be common form and the cyclic group of A ring and B ring,
Wherein the A ring is 3-8 unit cyclic group;
The A ring can be further by 1-3 R 5Replace R 5Be independently selected from hydrogen atom, halogen atom, C 1-6Alkyl, halo C 1-6Alkyl, hydroxyl, hydroxyl C 1-6Alkyl, amino, C 1-6Alkyl amine group, two (C 1-6Alkyl) amido or C 1-6The alkyl amine group formyl radical;
The B ring is phenyl ring, pyridine or pyrazine;
The B ring can be further by 1-3 R 4Replace R 4Be independently selected from hydrogen atom, halogen atom, C 1-6Alkyl, halo C 1-6Alkyl, hydroxyl, hydroxyl C 1-6Alkyl, amino, C 1-6Alkyl amine group, two (C 1-6Alkyl) amido or C 1-6The alkyl amine group formyl radical;
-Y-is-(CH 2) n-,-CH (R 7)-,-NH-,-(CH 2) n-NH-,-(CH 2) n-NH-CH 2-,-(CH 2) n-N (R 7)-CH 2-,-(CH 2) n-(CO)-,-O-,-S-,-C (O)-,-SO-or-SO 2-,
R wherein 7Be C 1-6Alkyl, hydroxyl or amino, n are 1～4 integer;
R 6Be the saturated or undersaturated nitrogen heterocyclic of 5-6 unit, R 6Also can be further by R 7Replace R 7Be selected from by halogen atom and replace or unsubstituted C 1-6Alkyl.
Be preferably:
Wherein, R 1Be acetamido, hydroxyl, 1,2,3-triazol radical Huo isoxazole oxygen base;
R 2, R 3Be hydrogen atom or halogen atom independently;
Figure BSA00000144719800021
Be common form and the cyclic group of A ring and B ring,
Wherein the A ring is 5-6 unit cyclic group;
The A ring can be further by 1-2 R 5Replace R 5Be independently selected from hydrogen atom, halogen atom, C 1-4Alkyl, halo C 1-4Alkyl, hydroxyl, hydroxyl C 1-4Alkyl, amino, C 1-4Alkyl amine group, two (C 1-4Alkyl) amido or C 1-4The alkyl amine group formyl radical;
The B ring is phenyl ring or pyridine;
The B ring can be further by 1-2 R 4Replace R 4Be independently selected from hydrogen atom, halogen atom, C 1-4Alkyl, halo C 1-4Alkyl, hydroxyl, hydroxyl C 1-4Alkyl, amino, C 1-4Alkyl amine group, two (C 1-4Alkyl) amido or C 1-4The alkyl amine group formyl radical;
-Y-is-(CH 2) n-,-NH-,-(CH 2) n-NH-,-(CH 2) n-(CO)-,-O-or-S-, wherein n is 1,2 or 3;
R 6Be the saturated or undersaturated nitrogen heterocyclic of 5-6 unit, R 6Also can be further by R 7Replace R 7Be selected from by fluorine atom and replace or unsubstituted C 1-4Alkyl.
More preferably:
Wherein, R 1Be acetamido;
R 2, R 3Be hydrogen atom or fluorine atom independently;
Be common form and the cyclic group of A ring and B ring,
Wherein the A ring is pentamethylene, hexanaphthene, cyclopentenes, tetrahydrobenzene, 1, Pyrrolidine, 2,3-pyrrolin, 2,5-pyrrolin, pyrroles, imidazoles, 4,5-glyoxalidine, pyrazoles, 4,5-pyrazoline, 1,2,3-triazole, tetramethylene sulfide, thiophene, 2, the 3-dihydro-thiophene, thiazole, 4,5-thiazoline, isothiazole, tetrahydrofuran (THF), 2,3 dihydro furan, furans, 4,5-dihydro-oxazole ， oxazole, 4,5-dihydro-isoxazole ， isoxazole, phenyl ring, 1,4,5,6-tetrahydropyrimidine, 1,6-dihydro-pyrimidin, 4,5-dihydro-pyrimidin, pyrimidine, 3,6-dihydro-2H-pyrans, 2H-pyrans, piperidines, 1,2,3,4-tetrahydropyridine, 1,2,3, the 6-tetrahydropyridine, 2,3-dihydropyridine, pyridine, piperazine, 1,2,3,4-tetrahydrochysene pyrazine, 2,3-dihydro pyrazine or pyrazine;
The A ring can be further by 1-2 R 5Replace R 5Be independently selected from hydrogen atom, fluorine atom, methyl, trifluoromethyl, hydroxyl, methylol, amino, methylamino, ethylamino-, methylamino formyl radical or ethylamino-formyl radical;
The B ring is phenyl ring or pyridine;
The B ring can be further by 1-2 R 4Replace R 4Be independently selected from hydrogen atom, fluorine atom, methyl, methyl fluoride, trifluoromethyl, hydroxyl, methylol, amino, methylamino, ethylamino-, methylamino formyl radical or ethylamino-formyl radical;
-Y-is-(CH 2) n-,-NH-,-(CH 2) n-NH-or-(CH 2) n-(CO)-, wherein n is 1,2 or 3;
R 6Be the pyrroles, imidazoles, 1,2,3-triazole, 1,2,4-triazole, pyrrotriazole, pyridine or pyrazine, R 6Also can be further by R 7Replace R 7Be selected from methyl, ethyl, propyl group or trifluoromethyl.
More preferably:
Wherein, R 1Be acetamido;
R 2, R 3Be hydrogen atom or fluorine atom independently;
Be common form and the cyclic group of A ring and B ring,
Wherein the A ring is pentamethylene, hexanaphthene, cyclopentenes, tetrahydrobenzene, 1, Pyrrolidine, 2,3-pyrrolin, 2,5-pyrrolin, pyrroles, imidazoles, 4, the 5-glyoxalidine, pyrazoles, 4,5-pyrazoline, 1,2,3-triazole, tetramethylene sulfide, thiophene, 2,3-dihydro-thiophene, thiazole, 4,5-thiazoline, tetrahydrofuran (THF), 2,3 dihydro furan, furans ， oxazole, phenyl ring, 1,4,5,6-tetrahydropyrimidine, 1,6-dihydro-pyrimidin, 4, the 5-dihydro-pyrimidin, pyrimidine, 3,6-dihydro-2H-pyrans, 2H-pyrans, piperidines, 1,2,3,4-tetrahydropyridine, 1,2,3,6-tetrahydropyridine, 2,3-dihydropyridine, pyridine, piperazine, 1,2,3,4-tetrahydrochysene pyrazine, 2,3-dihydro pyrazine or pyrazine;
The A ring can be further by 1 R 5Replace R 5Be selected from hydrogen atom, fluorine atom, methyl or methylamino formyl radical;
The B ring is phenyl ring or pyridine;
The B ring can be further by 1 R 4Replace R 4Be selected from hydrogen atom, fluorine atom, methyl or methyl fluoride;
-Y-is-(CH 2) n-,-NH-,-(CH 2) n-NH-or-(CH 2) n-(CO)-, wherein n is 1 or 2;
R 6Be 1,2,3-triazole, 1,2,4-triazole or pyrrotriazole, R 6Also can be further by R 7Replace R 7Be selected from methyl or ethyl.
More preferably:
Wherein, R 1Be acetamido;
R 2, R 3Be hydrogen atom or fluorine atom independently;
Be common form and the cyclic group of A ring and B ring,
Wherein the A ring is pentamethylene, cyclopentenes, 1, Pyrrolidine, 2,3-pyrrolin, pyrroles, phenyl ring, piperidines, 1,2,3,4-tetrahydropyridine, 1,2,3,6-tetrahydropyridine, 2,3-dihydropyridine or pyridine;
The B ring is phenyl ring;
R 4, R 5Be hydrogen atom;
-Y-is-(CH 2) n-,-NH-or-(CH 2) n-NH-, wherein n is 1 or 2;
R 6Be 1,2, the 3-triazole.
Another technical scheme of the present invention is:
Figure BSA00000144719800041
Wherein, R 1Be acetamido, hydroxyl, amino, C 1-6Alkyl amine group, 1,2,3-triazol radical Huo isoxazole oxygen base;
R 2, R 3Be hydrogen atom independently, halogen atom or C 1-6Alkyl;
Figure BSA00000144719800042
Be common form and the cyclic group of A ring and B ring,
Wherein the A ring is 3-8 unit cyclic group;
The A ring can be further by 1-3 R 5Replace R 5Be independently selected from hydrogen atom, halogen atom, C 1-6Alkyl, halo C 1-6Alkyl, hydroxyl, hydroxyl C 1-6Alkyl, amino, C 1-6Alkyl amine group, two (C 1-6Alkyl) amido or C 1-6The alkyl amine group formyl radical;
The B ring is phenyl ring, pyridine or pyrazine;
The B ring can be further by 1-3 R 4Replace R 4Be independently selected from hydrogen atom, halogen atom, C 1-6Alkyl, halo C 1-6Alkyl, hydroxyl, hydroxyl C 1-6Alkyl, amino, C 1-6Alkyl amine group, two (C 1-6Alkyl) amido or C 1-6The alkyl amine group formyl radical;
-Y-is-(CH 2) n-,-CH (R 7)-,-NH-,-(CH 2) n-NH-,-(CH 2) n-NH-CH 2-,-(CH 2) n-N (R 7)-CH 2-,-(CH 2) n-(CO)-,-O-,-S-,-C (O)-,-SO-or-SO 2-,
R wherein 7Be C 1-6Alkyl, hydroxyl or amino, n are 1～4 integer;
R 6Be the saturated or undersaturated nitrogen heterocyclic of 5-6 unit, R 6Also can be further by R 7Replace R 7Be selected from by halogen atom and replace or unsubstituted C 1-6Alkyl.
Be preferably:
Wherein, R 1Be acetamido, hydroxyl, 1,2,3-triazol radical Huo isoxazole oxygen base;
R 2, R 3Be hydrogen atom or halogen atom independently;
Figure BSA00000144719800043
Be common form and the cyclic group of A ring and B ring,
Wherein the A ring is 5-6 unit cyclic group;
The A ring can be further by 1-2 R 5Replace R 5Be independently selected from hydrogen atom, halogen atom, C 1-4Alkyl, halo C 1-4Alkyl, hydroxyl, hydroxyl C 1-4Alkyl, amino, C 1-4Alkyl amine group, two (C 1-4Alkyl) amido or C 1-4The alkyl amine group formyl radical;
The B ring is phenyl ring or pyridine;
The B ring can be further by 1-2 R 4Replace R 4Be independently selected from hydrogen atom, halogen atom, C 1-4Alkyl, halo C 1-4Alkyl, hydroxyl, hydroxyl C 1-4Alkyl, amino, C 1-4Alkyl amine group, two (C 1-4Alkyl) amido or C 1-4The alkyl amine group formyl radical;
-Y-is-(CH 2) n-,-NH-,-(CH 2) n-NH-,-(CH 2) n-(CO)-,-O-or-S-, wherein n is 1,2 or 3;
R 6Be the saturated or undersaturated nitrogen heterocyclic of 5-6 unit, R 6Also can be further by R 7Replace R 7Be selected from by fluorine atom and replace or unsubstituted C 1-4Alkyl.
More preferably:
Wherein, R 1Be acetamido;
R 2, R 3Be hydrogen atom or fluorine atom independently;
Figure BSA00000144719800051
Be common form and the cyclic group of A ring and B ring,
Wherein the A ring is pentamethylene, hexanaphthene, cyclopentenes, tetrahydrobenzene, 1, Pyrrolidine, 2,3-pyrrolin, 2,5-pyrrolin, pyrroles, imidazoles, 4,5-glyoxalidine, pyrazoles, 4,5-pyrazoline, 1,2,3-triazole, tetramethylene sulfide, thiophene, 2, the 3-dihydro-thiophene, thiazole, 4,5-thiazoline, isothiazole, tetrahydrofuran (THF), 2,3 dihydro furan, furans, 4,5-dihydro-oxazole ， oxazole, 4,5-dihydro-isoxazole ， isoxazole, phenyl ring, 1,4,5,6-tetrahydropyrimidine, 1,6-dihydro-pyrimidin, 4,5-dihydro-pyrimidin, pyrimidine, 3,6-dihydro-2H-pyrans, 2H-pyrans, piperidines, 1,2,3,4-tetrahydropyridine, 1,2,3, the 6-tetrahydropyridine, 2,3-dihydropyridine, pyridine, piperazine, 1,2,3,4-tetrahydrochysene pyrazine, 2,3-dihydro pyrazine or pyrazine;
The A ring can be further by 1-2 R 5Replace R 5Be independently selected from hydrogen atom, fluorine atom, methyl, trifluoromethyl, hydroxyl, methylol, amino, methylamino, ethylamino-, methylamino formyl radical or ethylamino-formyl radical;
The B ring is phenyl ring or pyridine;
The B ring can be further by 1-2 R 4Replace R 4Be independently selected from hydrogen atom, fluorine atom, methyl, methyl fluoride, trifluoromethyl, hydroxyl, methylol, amino, methylamino, ethylamino-, methylamino formyl radical or ethylamino-formyl radical;
-Y-is-(CH 2) n-,-NH-,-(CH 2) n-NH-or-(CH 2) n-(CO)-, wherein n is 1,2 or 3;
R 6Be the pyrroles, imidazoles, 1,2,3-triazole, 1,2,4-triazole, pyrrotriazole, pyridine or pyrazine, R 6Also can be further by R 7Replace R 7Be selected from methyl, ethyl, propyl group or trifluoromethyl.
More preferably:
Wherein, R 1Be acetamido;
R 2, R 3Be hydrogen atom or fluorine atom independently;
Figure BSA00000144719800061
Be common form and the cyclic group of A ring and B ring,
Wherein the A ring is pentamethylene, hexanaphthene, cyclopentenes, tetrahydrobenzene, 1, Pyrrolidine, 2,3-pyrrolin, 2,5-pyrrolin, pyrroles, imidazoles, 4, the 5-glyoxalidine, pyrazoles, 4,5-pyrazoline, 1,2,3-triazole, tetramethylene sulfide, thiophene, 2,3-dihydro-thiophene, thiazole, 4,5-thiazoline, tetrahydrofuran (THF), 2,3 dihydro furan, furans ， oxazole, phenyl ring, 1,4,5,6-tetrahydropyrimidine, 1,6-dihydro-pyrimidin, 4, the 5-dihydro-pyrimidin, pyrimidine, 3,6-dihydro-2H-pyrans, 2H-pyrans, piperidines, 1,2,3,4-tetrahydropyridine, 1,2,3,6-tetrahydropyridine, 2,3-dihydropyridine, pyridine, piperazine, 1,2,3,4-tetrahydrochysene pyrazine, 2,3-dihydro pyrazine or pyrazine;
The A ring can be further by 1 R 5Replace R 5Be selected from hydrogen atom, fluorine atom, methyl or methylamino formyl radical;
The B ring is phenyl ring or pyridine;
The B ring can be further by 1 R 4Replace R 4Be selected from hydrogen atom, fluorine atom, methyl or methyl fluoride;
-Y-is-(CH 2) n-,-NH-,-(CH 2) n-NH-or-(CH 2) n-(CO)-, wherein n is 1 or 2;
R 6Be 1,2,3-triazole, 1,2,4-triazole or pyrrotriazole, R 6Also can be further by R 7Replace R 7Be selected from methyl or ethyl.
More preferably:
Wherein, R 1Be acetamido;
R 2, R 3Be hydrogen atom or fluorine atom independently;
Figure BSA00000144719800062
Be common form and the cyclic group of A ring and B ring,
Wherein the A ring is pentamethylene, cyclopentenes, 1, Pyrrolidine, 2,3-pyrrolin, pyrroles, phenyl ring, piperidines, 1,2,3,4-tetrahydropyridine, 1,2,3,6-tetrahydropyridine, 2,3-dihydropyridine or pyridine;
The B ring is phenyl ring;
R 4, R 5Be hydrogen atom;
-Y-is-(CH 2) n-,-NH-or-(CH 2) n-NH-, wherein n is 1 or 2;
R 6Be 1,2, the 3-triazole.
" halogen atom " of the present invention is meant fluorine atom, chlorine atom, bromine atoms, iodine atom etc.
" C of the present invention 1-6Alkyl, C 1-6Alkyl amine group, hydroxyl C 1-6Alkyl, C 1-6Alkyl amine group, C 1-6Alkyl amine group formyl radical, halo C 1-6Alkyl " in " C 1-6Alkyl " expression straight or branched the alkyl that contains 1-6 carbon atom; as methyl; ethyl; n-propyl; sec.-propyl; normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, the 2-methyl butyl, neo-pentyl, the 1-ethyl propyl, n-hexyl, isohexyl, the 4-methyl amyl, the 3-methyl amyl, the 2-methyl amyl, the 1-methyl amyl, 3, the 3-dimethylbutyl, 2, the 2-dimethylbutyl, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, 2, the 3-dimethylbutyl, the 2-ethyl-butyl, 1-methyl-2-methyl-propyl etc.
" 3-8 unit cyclic group " of the present invention comprises (1) and do not contain the first saturated cyclic group of heteroatomic 3-8; (2) do not contain the first unsaturated cyclic group of heteroatomic 3-8; (3) contain the first saturated cyclic group of heteroatomic 3-8; (4) contain the first unsaturated cyclic group of heteroatomic 3-8.
(1) " do not contain heteroatomic 3-8 unit saturated cyclic group " finger ring alkyl is selected from cyclopropane, tetramethylene, pentamethylene, hexanaphthene, suberane, cyclooctane etc.Wherein, preferred cyclopropyl, cyclopentyl, cyclohexyl etc., more preferably cyclopropyl, cyclohexyl.
(2) the finger ring thiazolinyl that " do not contain heteroatomic 3-8 unit unsaturated cyclic group " is selected from cyclobutene, cyclopentenes, tetrahydrobenzene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene etc.Wherein, cyclopentene, tetrahydrobenzene, cyclopentadiene, cyclohexadiene etc., more preferably cyclopentenes, cyclopentadiene.
(3) there is not the 3-8 unit cyclic group of unsaturated link(age) in " contain heteroatomic 3-8 unit saturated cyclic group " finger ring, for example, ethylenimine, the 2H-ethylenimine, diazacyclo propane, azetidine, 1, the 2-diazetidine, tetramethyleneimine, imidazolidine, pyrazolidine, hydrogenated pyridine ketone, piperidines, piperazine, oxyethane, dioxirane, thiirane, trimethylene oxide, 1, the 2-dioxetane, Thietane, tetrahydrofuran (THF), tetramethylene sulfide, 1, the 3-dioxolane, 1, the 3-dithiolane, tetrahydropyrans, 1, the 4-dioxane, 1, the 3-dioxane, 1, the 3-oxathiane, oxaza propane oxazole, morpholine etc.Wherein, preferred ethylenimine, azetidine, tetramethyleneimine, imidazolidine, pyrazolidine, hydrogenated pyridine ketone, piperidines, piperazine, oxyethane, tetrahydrofuran (THF), tetramethylene sulfide, 1,3-dioxolane, 1,3-dithiolane, tetrahydropyrans, 1,4-dioxane, 1,3-dioxane, 1,3-oxathiane, oxaza Bing Wan, oxazole, morpholine etc.
(4) there is the 3-8 unit cyclic group of unsaturated link(age) in the finger ring that " contains heteroatomic 3-8 unit unsaturated cyclic group ", 3H-diazacyclo propylene for example, azete, 1, the 2-diazetine, the pyrroles, pyrrolin, imidazoles, 4, the 5-glyoxalidine, pyrazoles, 4, the 5-pyrazoline, 1,2, the 3-triazole, 1,2, the 4-triazole, tetrazolium, pyridine, the 2-pyridone, the 4-pyridone, pyridazine, pyrimidine, pyrazine, 1,2, the 3-triazine, 1,2, the 4-triazine, 1,3, the 5-triazine, 1,2,4, the 5-tetrazine, the nitrogen heterocyclic heptantriene, 1,2-diazacyclo heptantriene, 1,3-diazacyclo heptantriene, 1,4-diazacyclo heptantriene, the nitrogen heterocyclic octatetraene, 1,4-dihydro-1,4-diazacyclo sarohornene, 1,2-dithia cyclobutene, furans, thiophene, 2, the 5-dihydro-thiophene, 1,2-dithia cyclopentenes, the 2H-pyrans, the 2H-pyran-2-one, 3,4-dihydro-2H-pyrans, the 4H-pyrans, 4H-pyrans-4-ketone, 1, the 4-Dioxin, 1,4-dithia cyclohexadiene, 1, the 4-oxathiin, oxepin, the thia cycloheptatriene, 1,4-dioxane sarohornene oxazole, 4,5-dihydro-oxazole isoxazole, 4, the 5-dihydro-isoxazole, 2, the 3-dihydro-isoxazole, 1,2, the 3-oxadiazole, 1,2, the 5-oxadiazole, thiazole, 4, the 5-thiazoline, isothiazole, 1,2, the 3-thiadiazoles, 1,2, the 4-thiadiazoles, 1,3, the 4-thiadiazoles, 2H-1, the 2-oxazine, 4H-1, the 2-oxazine, 6H-1, the 2-oxazine, 2H-1, the 3-oxazine, 4H-1, the 3-oxazine, 5,6-dihydro-4H-1, the 3-oxazine, 6H-1, the 3-oxazine, 2H-1, the 4-oxazine, 4H-1, the 4-oxazine, 2H-1, the 3-thiazine, 4H-1, the 3-thiazine, 5,6-dihydro-4H-1, the 3-thiazine, 6H-1, the 3-thiazine, 2H-1, the 4-thiazine, 4H-1, the 4-thiazine, morpholine etc.Wherein preferred azete, 1, the 2-diazetine, the pyrroles, pyrrolin, imidazoles, 4, the 5-glyoxalidine, pyrazoles, 4, the 5-pyrazoline, pyridine, the 2-pyridone, the 4-pyridone, pyridazine, pyrimidine, pyrazine, the nitrogen heterocyclic heptantriene, 1,2-dithia cyclobutene, furans, thiophene, 2, the 5-dihydro-thiophene, 1,2-dithia cyclopentenes, the 2H-pyrans, the 2H-pyran-2-one, 3,4-dihydro-2H-pyrans, the 4H-pyrans, 4H-pyrans-4-ketone, 1, the 4-Dioxin, 1,4-dithia cyclohexadiene, 1, the 4-oxathiin, oxepin, 1,4-dioxane sarohornene oxazole, 4,5-dihydro-oxazole isoxazole, 4, the 5-dihydro-isoxazole, 2, the 3-dihydro-isoxazole, 1,2, the 3-oxadiazole, 1,2, the 5-oxadiazole, thiazole, 4, the 5-thiazoline, isothiazole, 1,2, the 3-thiadiazoles, 1,2, the 4-thiadiazoles, 1,3, the 4-thiadiazoles, 2H-1, the 2-oxazine, 4H-1, the 2-oxazine, 6H-1, the 2-oxazine, 2H-1, the 3-oxazine, 4H-1, the 3-oxazine, 5,6-dihydro-4H-1, the 3-oxazine, 6H-1, the 3-oxazine, 2H-1, the 4-oxazine, 4H-1, the 4-oxazine, 2H-1, the 3-thiazine, 4H-1, the 3-thiazine, 5,6-dihydro-4H-1, the 3-thiazine, 6H-1, the 3-thiazine, 2H-1, the 4-thiazine, 4H-1, the 4-thiazine, morpholine, 1,3, the 4-thiadiazoles.More preferably pyrroles, pyrrolin, imidazoles, 4, the 5-glyoxalidine, pyrazoles, 4, the 5-pyrazoline, pyridine, pyridazine, pyrimidine, pyrazine, furans, thiophene, 2, the 5-dihydro-thiophene, the 2H-pyrans, the 2H-pyran-2-one, 3,4-dihydro-2H-pyrans, the 4H-pyrans, 4H-pyrans-4-ketone, 1, the 4-Dioxin, 1,4-dithia cyclohexadiene, 1,4-oxathiin oxazole, 4,5-dihydro-oxazole isoxazole, 4, the 5-dihydro-isoxazole, 2, the 3-dihydro-isoxazole, 1,2, the 3-oxadiazole, 1,2, the 5-oxadiazole, thiazole, 4, the 5-thiazoline, isothiazole, 1,2, the 3-thiadiazoles, 1,2, the 4-thiadiazoles, 1,3,4-thiadiazoles etc.
" the saturated or undersaturated nitrogen heterocyclic of 5-6 unit " of the present invention comprises pyrryl, Pyrrolidine base, imidazolidyl, pyrazolidine, imidazolyl, pyrazolyl, 4,5-pyrazoline, 1,2,3-triazol radical, 1,2,4-triazol radical, 1,2,3,4-tetrazyl, 1,2,3,5-tetrazyl, pyridyl, piperidyl, pyridazinyl, pyrimidyl, pyrazinyl, piperazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazines base, 1,2,4,5-tetrazine base etc.
Particularly preferred compound comprises:
Figure BSA00000144719800081
Figure BSA00000144719800091
Invention also provides the preparation method of The compounds of this invention:
Reaction equation:
Reactions steps:
The preparation of step 1 intermediate 1
Add 1 in the exsiccant reaction flask, 4-dioxane alkane, raw material 1, raw material 2, Potassium ethanoate feed argon gas in reaction flask, add bi triphenyl phosphorus palladium chloride (Pd (PPh then 3) 2Cl 2), continuing in reaction solution, to feed argon gas, the high-temperature stirring reaction is spent the night, and be cooled to room temperature, and use diatomite filtration, ethyl acetate and salt solution extraction, organic layer concentrates with anhydrous sodium sulfate drying, separates out gray solid, gets intermediate 1.
The preparation of step 2 formula (I) compound
In the exsiccant reaction flask, add mixed solvent (dioxane/EtOH/H 2O), add intermediate 1, raw material 3, solid CS then 2CO 3, after the dissolving, under nitrogen protection, add Pd (PPh 3) 2Cl 2, the reaction solution reacting by heating reclaims solvent, washing, and column chromatography purification gets the off-white color solid.
The off-white color solid is dissolved in methyl alcohol, and room temperature adds Pd (OH) 2/ C, heating, reaction is spent the night, and is cooled to room temperature, filters.By preparation HPLC purifying, get formula (I) compound.Or off-white color is dissolved among the DCM, add trifluoroacetic acid and stir, concentrate, through column chromatographic isolation and purification, formula (I) compound.
R in the above reaction equation 1, R 2, R 3, R 4, R 5, R 6, A ring, B ring and-Y-such as preamble define.
Wherein raw material 3
Figure BSA00000144719800101
Middle R 4, R 5, R 6, A ring, B ring with-Y-is different, adopts different material to be prepared from, and sees specific embodiment for details.
The compounds of this invention " pharmacy acceptable salt " is meant by the salt of pharmaceutically acceptable, non-toxic bases or acid preparation, comprises organic acid salt, inorganic acid salt, organic alkali salt, inorganic base salts.Organic acid salt comprises formate, acetate, propionic salt, benzene sulfonate, benzoate, tosilate, 2,3-dyhydrobutanedioic acid salt, camsilate, Citrate trianion, mesylate, esilate, propanesulfonic acid salt, fumarate, gluconate, glutaminate, isethionate, lactic acid salt, maleate, malate, mandelate, mucate, embonate, pantothenate, succinate, tartrate etc., preferred especially benzoate, benzene sulfonate, tosilate, mesylate, Citrate trianion, maleate, fumarate, tartrate.Inorganic acid salt comprises hydrogen chlorate, hydrobromate, hydriodate, vitriol, phosphoric acid salt, nitrate etc., preferred especially hydrogen chlorate, hydrobromate, vitriol, phosphoric acid salt.Organic alkali salt comprises primary, the second month in a season and tertiary amine, be substituted amine and comprise naturally occurring replacement amine, cyclammonium and basic ion exchange resin, be selected from arginine, trimethyl-glycine, caffeine, choline, N, N '-dibenzyl-ethylenediamin, diethylamine, 2-diethylin ethanol, the 2-dimethylamino-ethanol, thanomin, quadrol, N-ethyl-morpholine, N-ethylpiperidine, meglumine, glucosamine, Histidine, Hai Baming, isopropylamine, Methionin, methylglucosamine, morpholine, piperazine, piperidines, the polyamides resin, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, the salt that Trometamol etc. form.Inorganic base salts comprises the basic cpd of ammonium salt and lithium salts, sodium salt, sylvite, calcium salt, magnesium salts, zinc salt, barium salt, aluminium salt, molysite, mantoquita, ferrous salt, manganese salt, manganous salt etc., preferred especially ammonium salt and sodium salt, sylvite, calcium salt, magnesium salts.
The compounds of this invention contains one or more asymmetric centers, thereby can be used as racemic modification and racemic mixture, single enantiomer, non-enantiomer mixture and single diastereomer.The compounds of this invention has asymmetric center, and each will independently produce two optical isomers this class asymmetric center, and scope of the present invention comprises all possible optical isomer and non-enantiomer mixture and pure or partial-purified compound.The present invention includes all stereoisomeric forms in any ratio of these compounds.
Compound of the present invention unless stated otherwise, the present invention includes cis-isomeride and trans-isomer(ide) if contain olefinic double bonds.
Compound of the present invention can exist with tautomeric forms, and it has the tie point of different hydrogen by one or more double-bond shifts.Each tautomer and composition thereof all is included in the compound of the present invention.
Compound and the intermediate in preparation process thereof shown in the formula for example of the present invention (I), R 6Representative
Figure BSA00000144719800111
The time, change can take place, when having prepared one of them, be equivalent to prepare its tautomer.The compounds of this invention and preparation intermediate thereof that all relate to above-mentioned situation are considered as being equal to, and all are included in the scope of the invention.
Figure BSA00000144719800112
That is:
Figure BSA00000144719800113
For example prepare compound 1, be equivalent to prepare compound 1 '.
Figure BSA00000144719800114
Compound 1 '
The present invention is the claimed pharmaceutical composition that comprises arbitrary compound recited above, its pharmacy acceptable salt or its steric isomer and one or more pharmaceutical carriers and/or thinner further.Described composition can be made clinically or pharmaceutically acceptable arbitrary formulation, is preferably oral preparations, injection.
The compounds of this invention, its pharmacy acceptable salt or its steric isomer can be oral or mode such as administered parenterally be applied to the patient who needs this treatment.
When being used for administered parenterally, can be made into injection.Injection means the intravital solution of confession injection, emulsion or the suspension that medicine is made and supplies to face with preceding preparation or be diluted to solution or the sterile preparation of the powder of suspension or strong solution that injection can be divided into injection liquid, injectable sterile powder and concentrated solution for injection.Injection liquid means that the confession that medicine is made is injected into sterile solution type injection liquid, emulsion-type injection liquid or the suspension type injection liquid of using in the body, can be used for intramuscularly, intravenous injection, intravenous drip etc.; Its specification has 1mL, 2mL, 5mL, 10mL, 20mL, 50mL, 100mL, 200mL, 250mL, 500mL etc., and wherein large volume (generally the being not less than 100mL) injection liquid of using for intravenous drip also claims intravenous infusion.Injectable sterile powder means that confession that medicine is made is faced with the suitable sterile solution of preceding usefulness and is mixed with settled solution or the evenly sterilized powder or the aseptic block of suspension, available suitable solvent for injection preparation back injection, also available intravenous infusion preparation posterior vein instils; Sterilized powder makes with solvent crystallization, spray-drying process or freeze-drying etc.Concentrated solution for injection means that confession that medicine is made faces the aseptic strong solution of using for intravenous drip with preceding dilution.
When making injection, can adopt the ordinary method production in the existing pharmacy field, optional use solvent or non-aqueous solvent.The most frequently used aqueous solvent is a water for injection, also available 0.9% sodium chloride solution or other suitable aqueous solution; Non-aqueous solvent commonly used is a vegetables oil, is mainly the injection soybean oil, and other also have the aqueous solution of ethanol, propylene glycol, polyoxyethylene glycol etc.During the preparation injection, can not add additives, also can add suitable additives, as osmotic pressure regulator, pH value conditioning agent, solubilizing agent, weighting agent, oxidation inhibitor, fungistat, emulsifying agent, suspending agent etc. according to the character of medicine.Osmotic pressure regulator commonly used comprises sodium-chlor, glucose, Repone K, magnesium chloride, calcium chloride, sorbyl alcohol etc., preferred sodium-chlor or glucose; PH value conditioning agent commonly used comprises acetic acid-sodium-acetate, lactic acid, Citric Acid-Sodium Citrate, sodium bicarbonate-yellow soda ash etc.; Solubilizing agent commonly used comprises Polysorbate 80, propylene glycol, Yelkin TTS, polyoxyethylenated castor oil etc.; Weighting agent commonly used comprises lactose, N.F,USP MANNITOL, sorbyl alcohol, dextran etc.; Oxidation inhibitor commonly used has S-WAT, sodium bisulfite, Sodium Pyrosulfite etc.; Fungistat commonly used is phenol, cresols, trichloro-butyl alcohol etc.Injection container commonly used has glass ampoule, vial, plastic ampoule, Plastic Bottle etc.
Be used for when oral, can be made into conventional solid preparation, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.Tablet means disk shape or the special-shaped flaky solid preparation that medicine and the auxiliary materials and mixing compacting that suits form, based on oral ordinary tablet, other has lozenge, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet and enteric coated tablet etc.Capsule means medicine or is added with the auxiliary material filling in Capsules or be sealed in solid preparation in the soft capsule material, according to its dissolving and release characteristics, can be divided into hard capsule (being commonly referred to as capsule), soft capsule (capsule and pill), slow releasing capsule, controlled release capsule and enteric coated capsule etc.Pill means medicine and suitable auxiliary material uniform mixing, and the spherical or near-spherical solid preparation so that proper method is made comprises dripping pill, sugar-pill, piller etc.Granule means that medicine and suitable auxiliary material make the dried particles shape preparation with certain particle size, can be divided into soluble particles (being commonly referred to as particle), mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules and controlled release granule etc.Oral solution means that medicine dissolution makes for oral clarified liq preparation in suitable solvent.Oral suspensions means the insoluble solid pharmaceutical, is dispersed in the liquid medium, makes for oral suspension body preparation, also comprises dry suspensoid or dense suspension.Syrup means the dense aqueous sucrose solution that contains medicine.
When making oral preparations, can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc.Weighting agent commonly used comprises starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, Microcrystalline Cellulose, lactose, pregelatinized Starch, N.F,USP MANNITOL etc.; Typical binders comprises Xylo-Mucine, PVP-K30, hydroxypropylcellulose, starch slurry, methylcellulose gum, ethyl cellulose, hypromellose, gelling starch etc.; Disintegrating agent commonly used comprises dry starch, polyvinylpolypyrrolidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose etc.; Conventional lubricants comprises Magnesium Stearate, talcum powder, sodium lauryl sulphate, micropowder silica gel etc.
The present invention also provides and has contained the purposes that phenyl ring De oxazolidone antibiotic is used for preparing the medicine that treats and/or prevents infectious diseases.De oxazolidone antibiotic of the present invention has good antibacterial activity to gram-positive microorganism, and the Gram-positive resistant organism is also had good antibacterial activity, can be used for treating and/or preventing the various diseases that is caused by gram-positive microorganism.
Below further set forth the The compounds of this invention beneficial effect by antibacterial activity test, but this should be interpreted as that The compounds of this invention only has following beneficial effect.
The antibacterial activity in vitro of experimental example The compounds of this invention
For trying bacterial classification: following clinical isolates strain is all bought in public institution.
Methicillin-resistant staphylococcus aureus (MRSA), methicillin-resistant staphylococcus epidermidis (MRSE), vancomycin-resistant enterococcus (VRE), penicillin resistant streptococcus pneumoniae (PRSP)
Trial-product: part of compounds of the present invention, its chemical name and preparation method are seen the preparation embodiment of each compound.
Experimental technique: agar dilution, with reference to National Committee for Clinical LaboratoryStandards.2006.Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria ThatGrow Aerobically; Approved Standard--Seventh Edition M7-A7.
Experimental result and conclusion:
The anti-microbial activity of table 1 The compounds of this invention
Figure BSA00000144719800131
The anti-microbial activity of table 2 The compounds of this invention
Figure BSA00000144719800132
By above experimental result as seen, The compounds of this invention all has better antibacterial activity to above strains tested, compares with Linezolid, and The compounds of this invention has better anti-microbial activity.The compounds of this invention has clinical application potentiality preferably.
4, embodiment
The embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following examples.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.The auxiliary material of each formulation can be replaced with acceptable accessories in following examples, perhaps reduces, increases.
Embodiment 1 (S)-N-[[3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-yl) phenyl]-2-oxo-5-oxazole Alkyl] methyl] preparation of ethanamide
Figure BSA00000144719800141
In the exsiccant reaction flask, add 1,4-dioxane alkane 30mL, (S) N-[[3-(3-fluoro-4-bromophenyl)-2-oxo-5-oxazolidinyl] methyl] ethanamide 3.31g (10mmol), two valeryl diboron hexahydride 2.54g (10mmol), Potassium ethanoate 0.98g (10mmol), in reaction flask, feed argon gas, add Pd (PPh then 3) 2Cl 20.3g, continue in reaction solution, to feed argon gas, spend the night in 90 ℃ of stirring reactions, be cooled to room temperature, and use diatomite filtration, ethyl acetate and salt solution extraction, organic layer concentrates with anhydrous sodium sulfate drying, separates out gray solid, gets product 3.22g, yield 85.2%.((S)-N-[[3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-yl) phenyl that following examples are used]-2-oxo-5-oxazolidinyl] methyl] ethanamide preparation all adopt among the embodiment 1 the method preparation)
Embodiment 2N-[[(5S)-and 3-[4-[1-[(1H-1,2,3-triazole-5-yl) methylamine]-2,3-two Hydrogen-1H-indenes-5-yl]-the 3-fluorophenyl]-2- Oxo-5-oxazolidinyl] methyl] preparation of acetamide hydrochloride (compound 1 hydrochloride)
(1) 5-bromine N-(2-propynyl)-2, the preparation of 3-dihydro-1H-indenes-1-amine
Figure BSA00000144719800143
(6.6g, 0.12mol) (22.9g 0.109mmol) is dissolved in 1, in the 2-ethylene dichloride (300mL), under ice-water bath, to wherein adding NaBH (OAc) with 5-bromo-1-indone with propargyl amine 3(43.3g 203mmol), finishes back mixture stirring reaction 40 hours at room temperature, and organic phase water (50mL * 2) and NaCl (150mL * 2) is successively washed, anhydrous magnesium sulfate drying, and organic phase is not purified to be directly used in next step.
(2) the 5-bromo-2, the preparation of 3-dihydro-1H-indenes-1-base (2-propynyl) amido formic acid tertiary butyl ester
Figure BSA00000144719800151
With 5-bromo-N-(2-propynyl)-2,3-dihydro-1H-indenes-1-amine (8.9g, 0.036mol) be dissolved in the 50mL methyl alcohol, add triethylamine (7.2g, 0.071mmol) and tert-Butyl dicarbonate (9.3g, 0.043mol), the mixture stirred overnight at room temperature, reaction solution is poured in the 200mL frozen water, and water dichloromethane extraction behind the separatory washs and use anhydrous sodium sulfate drying with NaCl (50mL * 2) after the merging organic phase, solvent is after decompression removes, (PET: EA=25: 1) purifying obtains brown oil to resistates, and promptly the 5-bromo-2,3-dihydro-1H-indenes-1-base (2-propynyl) amido formic acid tertiary butyl ester 8.8g through column chromatography.
(3) (1H-1,2,3-triazole-5-yl) methyl-5-bromo-2, the preparation of 3-dihydro-1H-indenes-1-amido formic acid tertiary butyl ester
Figure BSA00000144719800152
With 5-bromo-2,3-dihydro-1H-indenes-(14.4g 40mmol) is dissolved in (9: 1) in DMF and the methyl alcohol to 1-base (2-propynyl) amido formic acid tertiary butyl ester, adds TMSN under nitrogen protection 3(7.1g, 0.06mol) and CuI (0.4g, 0.002mol), reaction solution reacted 12 hours down at 100 ℃, be cooled to room temperature, add the entry ethyl acetate extraction, organic layer is washed with saturated common salt, anhydrous sodium sulfate drying, filter, obtain oily matter (1H-1,2 behind the concentrating under reduced pressure, 3-triazole-5-yl) methyl-5-bromo-2,3-dihydro-1H-indenes-1-amido formic acid tertiary butyl ester 10.2g.
(4) the 5-bromo-2, the preparation of 3-dihydro-1H-indenes-1-base-(1-trityl-1H-1,2,3-triazole-5-yl) toluic acid tertiary butyl ester
Figure BSA00000144719800153
With (1H-1,2,3-triazole-5-yl) methyl-5-bromo-2, (16.1g 0.04mol) is dissolved among the DCM (115mL) 3-dihydro-1H-indenes-1-amido formic acid tertiary butyl ester, adds triethylamine (12.4g, 0.123mol) and trityl chloride (22.9g, 0.08mol), stirred 2 hours under the room temperature, add the entry ethyl acetate extraction, organic layer is washed with saturated common salt, anhydrous sodium sulfate drying filters, and solvent is transferred, thick product is through column chromatography (PET: EA=15: 1) get white solid 5-bromo-2,3-dihydro-1H-indenes-1-base-(1-trityl-1H-1,2,3-triazole-5-yl) toluic acid tertiary butyl ester 22g.
(5) N-[[(5S)-and 3-[4-[1-[N-[(1-trityl-1H-1,2,3-triazole-5-yl) methyl]-N-tertbutyloxycarbonyl amido]-2,3-dihydro-1H-indenes-5-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] preparation of ethanamide
Figure BSA00000144719800154
In the exsiccant reaction flask, add mixed solvent (dioxane/EtOH/H 2O=36mL/12mL/12mL), add (S) N-[[3-[3-fluoro-4-(4,4 then, 5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide (1.53g, 0.004mol), 5-bromo-2,3-dihydro-1H-indenes-1-base-(1-trityl-1H-1,2,3-triazole-5-yl) the toluic acid tertiary butyl ester (2.32g, 0.004mol), solid Cs 2CO 3(6.59g 0.02mmol), after the dissolving, under nitrogen protection, adds PddppfCl 2(0.46g), reaction solution is heated to 80 ℃ of reactions and spends the night, filter, remove dioxy hexane and ethanol, filter cake 200mL water and ethyl acetate extraction (100mL), organic layer water and saturated sodium-chloride washing, anhydrous magnesium sulfate drying, column chromatography (pure EA) obtains yellow solid N-[[(5S after removing solvent under reduced pressure)-3-[4-[1-[N-[(1-trityl-1H-1,2,3-triazole-5-yl) methyl] N-tertbutyloxycarbonyl amido]-2,3-dihydro-1H-indenes-5-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide 1.90g.
(6) N-[[(5S)-and 3-[4-[1-(1H-1,2,3-triazole-5-yl) methylamino]-2,3-dihydro-1H-indenes-5-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] preparation of acetamide hydrochloride
Figure BSA00000144719800161
Under the room temperature to N-[[(5S)-3-[4-[1-[N-[(1-trityl-1H-1,2,3-triazole-5-yl) methyl]-N-tertbutyloxycarbonyl amido]-2,3-dihydro-1H-indenes-5-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide (5g, 0.06mmol) be dissolved among the 50mL DCM, add 5mL trifluoroacetic acid and 5mL water, stirred overnight at room temperature, will solvent decompression transfer down, slightly product through column chromatography for separation (EA: MeOH=100: 1) separate white solid.Solid is dissolved in the methanol solution of HCl, stirred 2 hours, the solvent evaporated under reduced pressure got N-[[(5S)-3-[4-[1-(1H-1,2,3-triazole-5-yl) methylamino]-2,3-dihydro-1H-indenes-5-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide hydrochloride 660mg.
Molecular formula: C 24H 26FClN 6O 3Molecular weight: 500.95 mass spectrums (M+H): 465
1H-NMR(DMSO，300MHz)：δ1.84(3H，s)，2.434(1H，m)，2.90(1H，m)，3.25-3.45(6H，m)，3.781(1H，t)，4.16(1H，t)，4.32(2H，s)，4.79(2H，br)，7.41-7.63(5H，m)，7.86(1H，d)，，8.33(1H，t)，10.0(1H，br)。
Embodiment 3N-[[(5S)-and 3-[4-[1-[2-(1H-1,2,3-triazole-5-yl) ethyl] indoline-5-yl]-the 3-fluorophenyl]-the 2-oxo -5-oxazolidinyl] methyl] preparation of ethanamide (compound 2)
Figure BSA00000144719800162
(1) preparation of 3-butynyl methanesulfonates
Figure BSA00000144719800171
In the 250mL reaction flask, with 90mL methylene dichloride dissolving 3-butine-1-alcohol 0.500g (7.13mmol) and triethylamine 2.17g (21.4mmol), ice-water bath cooling back is to wherein slowly dripping methylsulfonyl chloride 1.06g (9.23mmol), approximately dripped 30 minutes, remove stirred overnight at room temperature (16 hours) after the cryostat, organic phase is used 1M HCl (aqueous solution) and sodium-chlor washing successively, use anhydrous magnesium sulfate drying then, filter and obtain oily matter 3-butynyl methanesulfonates 1.02g, yield 96% after the back decompression removes solvent.
(2) preparation of 5-bromo-1-(3-butynyl) indoline
Figure BSA00000144719800172
In the toluene solution (40mL) of 5-bromo indole quinoline 4.95g (25mmol), add Na 2CO 32.42g (22.8mmol) and 3-butynyl methanesulfonates 2.53g (17.1mmol); mixture stirring at room 20 hours under nitrogen protection; filtration removes inorganic salt; the mother liquor decompression gets thick product after steaming solvent; this thick product column chromatography purification (EtOAc/PE=1: 19) get product 5-bromo-1-(3-butynyl) indoline 2.91g, yield 68%.
(3) 1-[2-(1-benzyl-1H-1,2,3-triazole-5-yl) ethyl]-preparation of 5-bromo indole quinoline
In the 100mL reaction flask, dissolve benzyl azide 2.70g (20.3mmol) and 5-bromo-1-(3-butynyl) indoline 5.07g (20.3mmol) with the 30mL propyl carbinol.Simultaneously in the another one reaction flask with 30mL deionized water dissolving sodium ascorbate 1.20g (6.07mmol) and copper sulfate 0.162g (1.01mmol).After the dissolving aqueous solution is once joined in the butanol solution, room temperature vigorous stirring 16 hours, (3 * 30mL), the merging organic phase is also used anhydrous MgSO with dichloromethane extraction behind the reaction mixture concentrating under reduced pressure 4Drying obtains oily matter 1-[2-(1-benzyl-1H-1,2,3-triazole-5-yl) ethyl after decompression removes solvent]-5-bromo indole quinoline 6.2g, yield 80%.
(4) N-[[(5S)-and 3-[4-[1-[2-(1-benzyl-1H-1,2,3-triazole-5-yl) ethyl] indoline-5-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] preparation of ethanamide
Figure BSA00000144719800174
In the exsiccant reaction flask, add mixed solvent (dioxane/EtOH/H 2O=60mL/20mL/20mL), add (S) N-[[3-(3-fluoro-4-(4 then, 4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide 3.78g (10mmol), 1-[2-(1-benzyl-1H-1,2,3-triazole-5-yl) ethyl]-5-bromo indole quinoline 3.83g (10mmol), Cs 2CO 316g (50mmol), the dissolving back adds Pd (dppf) Cl under nitrogen protection 2100mg (0.14mmol), be heated to back flow reaction 2 hours, TLC checks that reaction finishes, reaction solution is cooled to room temperature, water 200mL and ethyl acetate (2 * 100mL) extractions, water layer ethyl acetate extraction (2 * 50mL), merge organic layer, (2 * 50mL) and saturated sodium-chloride (50mL) washing, anhydrous magnesium sulfate drying separates (0-5%MeOH-CH with flash column chromatography after removing solvent under reduced pressure to water 2Cl 2Gradient) obtain gray solid N-[[(5S)-3-[4-[1-[2-(1-benzyl-1H-1,2,3-triazole-5-yl) ethyl] indoline-5-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide 3.3g, yield 60%.
(5) N-[[(5S)-and 3-[4-[1-[2-(1H-1,2,3-triazole-5-yl) ethyl] indoline-5-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] preparation of ethanamide
Figure BSA00000144719800181
Under the room temperature to N-[[(5S)-3-[4-[1-[2-(1-benzyl-1H-1,2,3-triazole-5-yl) ethyl] indoline-5-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] add Pd (OH) in MeOH (50mL) solution of ethanamide 1.5g (2.7mmol) 2/ C, mixture stirs under 50 ℃ of nitrogen atmosphere and spends the night, TLC detection reaction to raw material all disappears, be chilled to filtration catalizer after the room temperature, mother liquor preparative chromatography purifying after removing solvent under reduced pressure gets white solid N-[[(5S)-3-[4-[1-[2-(1H-1,2,3-triazole-5-yl) ethyl] indoline-5-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide 440mg, yield 35%.
Molecular formula: C 24H 25FN 6O 3Molecular weight: 464.49 mass spectrums (M+H): 465
1H-NMR(DMSO，300MHz)：δ1.85(3H，s)，2.92-2.97(4H，m)，3.37-3.44(6H，m)，3.76(1H，m)，4.15(1H，t)，4.75(1H，m)，6.59(1H，d)，7.16-7.21(2H，m)，7.34(1H，d)，7.44-7.54(2H，m)，7.73(1H，s)，8.28(1H，t).
Embodiment 4N-[[(5S)-3-[4-[2-(1H-1,2,3-triazole-5-base amine) naphthalene-6-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] Methyl] preparation of acetamide hydrochloride (compound 3 hydrochlorides)
Figure BSA00000144719800182
(1) preparation of 1-(2-bromonaphthalene-6-yl)-3-(nitrile methyl) triazene
Figure BSA00000144719800183
With 6-bromo-2-amino naphthalenes (13.4g, 0.06mol) be dissolved among the HCl (30mL), frozen water cooling drips Sodium Nitrite down, and (4.14g, aqueous solution 0.06mmol) are stirred to reaction soln under 0 ℃ and become clarification, then to wherein adding 2-aminoacetonitriles hydrochloride (3.4g, 0.06mol), be reflected at 0 ℃ and stirred 30 minutes, in reaction mixture, add excessive acetic acid sodium, continue to stir 3 hours, filter and collect crude product.Crude product is dissolved among the DCM, and drying, evaporated in vacuo get dark red solid 1-(2-bromonaphthalene-6-yl)-3-(nitrile methyl) triazene 8g.
(2) N-(2-bromonaphthalene-6-yl)-1H-1,2, the preparation of 3-triazolyl-5-amine
Figure BSA00000144719800191
With 1-(2-bromonaphthalene-6-yl)-3-(nitrile methyl) triazene (8g, 27.7mmol) be dissolved in the 100mL dehydrated alcohol, 80 ℃ down reaction spend the night to the TLC detection reaction and finish, get thick product after removing solvent under reduced pressure, thick product uses column chromatography (EA: PE=1: 4) obtain red solid N-(2-bromonaphthalene-6-yl)-1H-1,2,3-triazolyl-5-amine 2.2g, first two steps total recovery 11.7%.
(3) N-(2-bromonaphthalene-6-yl)-3-trityl-1H-1,2, the preparation of 3-triazole-5-amine
Figure BSA00000144719800192
With N-(2-bromonaphthalene-6-yl)-1H-1,2,3-triazolyl-5-amine (2.2g, 0.007mol) be dissolved among the DCM, drip triethylamine (2.8g, 0.028mol) and trityl chloride (7.8g, 0.028mol), stirring reaction to TLC detection reaction finishes under the room temperature, adds entry in solution, with DCM extraction (3 * 20mL), organic layer anhydrous sodium sulfate drying, solvent evaporated in vacuo get N-(2-bromonaphthalene-6-yl)-3-trityl-1H-1,2,3-triazole-5-amine 1.8g, productive rate 45%.
(4) N-[[(5S)-3-[4-[2-(1-trityl-1H-1,2,3-triazolyl-5-amido) naphthalene-6-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] preparation of ethanamide
Figure BSA00000144719800193
In the exsiccant reaction flask, add mixed solvent (dioxane/EtOH/H 2O=60mL/20mL/20mL), add (S)-N-[[3-[3-fluoro-4-(4,4 then, 5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide (0.9g, 0.003mol), N-(2-bromonaphthalene-6-yl)-3-trityl-1H-1,2,3-triazole-5-amine (1.5g, 0.003mol), solid Cs 2CO 3(2.2g 0.009mol), under nitrogen protection, adds PddppfCl 2(0.1g, 0.01mmol), reaction solution is heated to 90 ℃ of reactions 2.5 hours, filters, and removes dioxy hexane and ethanol, and filter cake washs with 200mL water and ethyl acetate extraction (100mL), organic layer water and saturated sodium-chloride, anhydrous magnesium sulfate drying.Column chromatography obtains gray solid N-[[(5S after removing solvent under reduced pressure)-3-[4-[2-(1-trityl-1H-1,2,3-triazolyl-5-amido) naphthalene-6-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide 0.9g, yield 47%.
(5) N-[[(5S)-3-[4-[2-(1H-1,2,3-triazolyl-5-amido) naphthalene-6-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] preparation of acetamide hydrochloride
Figure BSA00000144719800201
With N-[[(5S)-3-[4-[2-(1-trityl-1H-1,2,3-triazolyl-5-amido) naphthalene-6-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide (0.9g, 0.001mol) be dissolved among the 5mL THF, drip TFA (2g, 0.02mol), stirred 1 hour under the solution room temperature, dissolving is removed, transfer to alkalescence with saturated sodium bicarbonate, the DCM solution for continuous of product being poured into HCl stirred 30 minutes, solvent was transferred obtaining white powder N-[[(5S)-3-[4-[2-(1H-1,2,3-triazolyl-5-amido) naphthalene-6-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide hydrochloride 0.3g.
Molecular formula: C 24H 22FClN 6O 3Molecular weight: 496.1 mass spectrums (M+H): 461
1H-NMR(DMSO，300MHz)：δ1.85(3H，s)，3.44(2H，t)，3.78(1H，m)，4.20(1H，t)，4.77(1H，m)，7.437-7.93(10H，m)，8.329(1H，m)，9.11(1H，br)。
Embodiment 3N-[[(5S)-and 3-[4-[2-[(1H-1,2,3-triazole-5-yl) methyl]-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-the 3-fluorobenzene Base]-2-oxo-5-oxazolidinyl] methyl] preparation of acetamide hydrochloride (compound 4 hydrochlorides)
(1) preparation of 2-toluquinoline
Figure BSA00000144719800203
Aniline 10.0g (107mmol) is dissolved in the 20mL acetic acid and the 100mL vitriol oil, at room temperature drips crotonic aldehyde 7.5g (107mmol), dropwised the post-heating back flow reaction 5 hours, concentrate the back and add 300mL water, use Na then 2CO 3Neutralization, (2 * 300mL), the merging organic layer is used the saturated common salt water washing, and anhydrous sodium sulfate drying concentrates with ethyl acetate extraction.Thick product uses column chromatography (PE: EA=12: 1～10: 1) obtain yellow oil 2-toluquinoline 3.5g, yield 22.7%.
(2) 2-(quinoline-2-yl) ethyl acetate
Figure BSA00000144719800204
2-toluquinoline 3.5g (24.4mmol) and diethyl carbonate 10.7g (90.4mmol) are dissolved in the 35mL tetrahydrofuran (THF); under-78 ℃ and nitrogen protection, drip LDA2M (34mL) then; dropwise and continue reaction 1.5 hours; add 10mL water then and rise to room temperature; add 200mL water, (2 * 150mL), organic layer is washed with saturated common salt with ethyl acetate extraction; anhydrous sodium sulfate drying concentrates.Crude product uses column chromatography (PE: EA=5: 1～3: 1) obtain yellow oil 2-(quinoline-2-yl) ethyl acetate 4.7g, yield 88.8%.
(3) 2-(1,2,3,4-tetrahydroquinoline-2-yl) ethyl acetate
Figure BSA00000144719800211
2-(quinoline-2-yl) ethyl acetate 2.7g (12.5mmol) is dissolved in 16mL acetic acid, add sodium cyanoborohydride 2.7g (43mmol) in batches, continue under the room temperature to stir to spend the night, add 100mL water then, with ethyl acetate extraction (2 * 40mL), organic layer is dissolved in sodium bicarbonate water to be washed, and anhydrous sodium sulfate drying concentrates.Crude product uses column chromatography (PE: EA=20: 1) obtain light yellow oil 2-(1,2,3,4-tetrahydroquinoline-2-yl) ethyl acetate 1.8g, yield 65.5%.
(4) 2-(6-bromo-1,2,3,4-tetrahydroquinoline-2-yl) ethyl acetate
Figure BSA00000144719800212
With 2-(1,2,3,4-tetrahydroquinoline-2-yl) ethyl acetate 1.2g (5.47mmol) is dissolved among the 10mL DMF, drips the 5mLDMF solution of NBS 0.97g (5.47mmol) under ice-water bath, and ice-water bath continued stirring reaction 2 hours down, add 80mL water, (2 * 30mL), organic layer is washed with salt with ethyl acetate extraction, anhydrous sodium sulfate drying, concentrate yellow oil 2-(6-bromo-1,2,3,4-tetrahydroquinoline-2-yl) ethyl acetate 1.56g, yield 95.7%.
(5) the 6-bromo-1,2,3,4-tetrahydrochysene-2-propargyl quinoline
Figure BSA00000144719800213
With 2-(6-bromo-1; 2; 3; 4-tetrahydroquinoline-2-yl) ethyl acetate 1.3g (4.36mmol) is dissolved in the 26mL methylene dichloride; under-78 ℃ and nitrogen protection, drip the toluene solution of DIBAL 1M (10.9mL); low temperature continues reaction 3 hours down; add 6.5mL methyl alcohol then, make reaction solution rise to 0 ℃, in reaction solution, drip the methanol solution (9mL) of (1-diazo-2-oxopropyl) dimethyl phosphonate 1.26g (6.54mmol); and then adding salt of wormwood 2.41g (17.4mmol); rise to room temperature reaction and spend the night, add 100mL water, with dichloromethane extraction (2 * 60mL); the organic layer anhydrous sodium sulfate drying; vacuum drain light yellow oil 6-bromo-1,2,3; 4-tetrahydrochysene-2-propargyl quinoline 1.31g, yield 100%.This crude product need not purified and is directly used in next step reaction.
(6) 2-[(1-benzyl-1H-1,2,3-triazole-5-yl) methyl]-6-bromo-1,2,3, the preparation of 4-tetrahydroquinoline
Figure BSA00000144719800221
With 6-bromo-1,2,3,4-tetrahydrochysene-2-propargyl quinoline 1.271g (5.1mmol), benzyl azide 0.812g (6.1mmol), sodium ascorbate (0.3g) and copper sulfate (0.3g) are dissolved in 5mL ethanol and the 5mL water, being reflected at 50 ℃ reacted 30 minutes down, add 50mL water then, and the usefulness ethyl acetate extraction (2 * 30mL), the organic layer anhydrous sodium sulfate drying, concentrate, thick product is through column chromatography for separation (PE: EA=3: 1～2: 1) obtain yellow oil 2-[(1-benzyl-1H-1,2,3-triazole-5-yl) methyl]-6-bromo-1,2,3,4-tetrahydroquinoline 1.29g, yield 66.2%.
(7) N-[[(5S)-and 3-[4-[2-[(1-benzyl-1H-1,2,3-triazole-5-yl) methyl]-1,2,3,4-tetrahydroquinoline-6-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] preparation of ethanamide
In the exsiccant reaction flask, add mixed solvent (dioxane/H 2O=10mL/5mL), under nitrogen protection, add 2-[(1-benzyl-1H-1,2 then; 3-triazole-5-yl) methyl]-6-bromo-1,2,3; 4-tetrahydroquinoline 0.82g (2.14mmol); (S) N-[[3-[3-fluorine 4-(4,4,5; 5-tetramethyl--1; 3,2-dioxy boron penta ring-2-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide 0.97g (2.58mmol), yellow soda ash 0.54g (5.13mmol) and Pd (PPh 3) 4(100mg), reaction solution is heated to 90 ℃ of reactions 5 hours, filter, column chromatography obtains pale solid N-[[(5S after removing solvent under reduced pressure)-3-[4-[2-[(1-benzyl-1H-1,2,3-triazole-5-yl) methyl]-1,2,3,4-tetrahydroquinoline-6-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide 0.52g, yield 43.7%.
(8) N-[[(5S)-and 3-[4-[2-[(1H-1,2,3-triazole-5-yl) methyl]-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] preparation of acetamide hydrochloride
Figure BSA00000144719800223
Under the room temperature to N-[[(5S)-3-[4-[2-[2-(1-benzyl-1H-1,2,3-triazole-5-yl) methyl]-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] add Pd (OH) in acetate (10mL) solution of ethanamide 0.52g (0.94mmol) 2/ C 50mg (20%), mixture stirs under 40 ℃ of nitrogen atmosphere and spends the night, filter, mother liquor through removing solvent under reduced pressure after column chromatography for separation (PE: EA=1: 1～0: 1) white solid, solid is dissolved among the DCM/MeOH (5mL/2mL), in 5 hours, drip the dioxane solution (20mL) of HCl, after dripping off solvent is taken away, solid successively with EC wash gray solid N-[[(5S)-3-[4-[2-[(1H-1,2,3-triazole-5-yl) methyl]-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide hydrochloride 260mg, yield 55.3%.
Molecular formula: C 24H 26FClN 6O 3Molecular weight: 500.95 mass spectrums (M+H): 465
1H-NMR(DMSO)：δ1.58(1H，m)，1.89(4H，m)，2.76(2H，m)，2.88(1H，m)，3.01(1H，m)，3.42(2H，m)，3.61(1H，m)，3.77(1H，m)，4.14(1H，t)，4.74(1H，m)，6.79(1H，d)，7.18(2H，m)，7.34(1H，d)，7.49(2H，m)，7.76(1H，s)，8.25(1H，m).
1H-NMR(DMSO+D 2O)：δ1.52(1H，m)，1.87(4H，m)，2.73(2H，m)，2.91(2H，m)，3.41(2H，m)，3.57(1H，m)，3.72(1H，m)，4.10(1H，t)，4.72(1H，m)，6.75(1H，d)，7.16(2H，m)，7.28(1H，d)，7.45(2H，m)，7.73(1H，s).
Embodiment 4N-[[(5S)-and 3-[4-[2-(1H-1,2,3-triazole-5-yl) methyl]-1,2,3,4-tetrahydroisoquinoline-6-yl]-the 3-fluorobenzene Base]-2-oxo-5-oxazolidinyl] methyl] preparation of acetamide hydrochloride (compound 5 hydrochlorides)
(1) preparation of 2-(3-bromophenyl) ethanamide
Figure BSA00000144719800231
2-(3-bromophenyl) acetate 50g (0.23mol) is dissolved in the methyl alcohol, drips SOCl 2(34mL), after the TLC detection reaction finishes, reaction solution is poured in the frozen water with ethyl acetate extraction (2 * 200mL), the organic layer drying, evaporate to dryness gets the 48g colorless oil, and oily matter is dissolved in the 100mL methyl alcohol, adds to stir under the ammoniacal liquor room temperature to spend the night, the methyl alcohol evaporate to dryness is got white solid 2-(3-bromophenyl) ethanamide 24.9g, yield 50%.
(2) preparation of 2-(3-bromophenyl) ethamine
2-(3-bromophenyl) ethanamide 24g (0.11mol) and sodium borohydride 14.4g (0.33mol) are dissolved among the THF, drip boron trifluoride ether solution down at 0 ℃, after the TLC detection reaction is complete, in system, add entry ethyl acetate extraction (3 * 100mL), the organic layer drying, evaporate to dryness obtains white solid 2-(3-bromophenyl) ethamine 11.2g, yield 48%.
(3) preparation of 2-(3-bromophenyl)-N-toluol sulfonamide
Figure BSA00000144719800233
2-(3-bromophenyl) ethamine 11.2g (0.056mol) and triethylamine 6.07g (0.06mol) are dissolved among the 100mL DCM, at 0 ℃ of 50mL dichloromethane solution that drips TsCl 11.4g (0.06mol) down, after TLC detects complete reaction, in system, add water, with DCM extraction (2 * 100mL), organic anhydrous sodium sulfate drying that embraces, evaporate to dryness get white solid 2-(3-bromophenyl)-N-toluol sulfonamide 15.2g, yield 76.7%.
(4) 6-bromo-N-tosyl group-1,2,3, the preparation of 4-tetrahydroisoquinoline
Figure BSA00000144719800241
2-(3-bromophenyl)-N-toluol sulfonamide 15g (0.04mol) and Paraformaldehyde 96 3.6g (0.12mol) are dissolved in 20mL sulfuric acid and the 30mL acetum; stirring reaction spends the night; add entry; filter white solid 6-bromo-N-tosyl group-1; 2; 3,4-tetrahydroisoquinoline 13.3g, yield 86%.
(5) 6-bromine N-(2-propargyl)-1,2,3, the preparation of 4-tetrahydroisoquinoline
Figure BSA00000144719800242
With 6-bromo-N-tosyl group-1,2,3; 4-tetrahydroisoquinoline 13g (0.036mol) is dissolved in sulfuric acid: in water=3: 1 solution, 110 ℃ of reactions are spent the night, and mixture is poured in the frozen water filtered; solid uses column chromatography and obtains 6-bromo-1,2,3; 4-tetrahydroisoquinoline 6.2g; with product and 2-propynyl methanesulfonates 4.3g (0.032mol), yellow soda ash 3.4g (0.032mol) is dissolved in the acetonitrile, and 80 ℃ of following reactions are spent the night; solvent is drained, and residuum adds entry and extracts (2 * 100mL) with DCM.Organic layer drying, evaporate to dryness get 6-bromine N-(2-propargyl)-1,2,3,4-tetrahydroisoquinoline 5.1g, yield 57%.
(6) 2-(1H-1,2,3-triazole-5-yl)-6-bromo-1,2,3, the preparation of 4-tetrahydroisoquinoline
Figure BSA00000144719800243
With 6-bromine N-(2-propargyl)-1; 2; 3; 4-tetrahydroisoquinoline 5g (0.02mol) and trimethyl silicane nitrine 3.45g (0.03mol) are dissolved among the 30mL DMF; under nitrogen protection, add cuprous iodide 0.76g (0.004mol); be reacted to TLC under 100 ℃ and detect the raw material complete reaction, remove solvent under the vacuum, add entry ethyl acetate extraction (2 * 100mL); the organic layer drying; evaporate to dryness obtains yellow solid 2-(1H-1,2,3-triazole-5-yl)-6-bromo-1; 2; 3,4-tetrahydroisoquinoline 2.3g, yield 40%.This product need can not be used for the next step through purifying.
(7) (5S)-and N-[[3-[3-fluoro-4-[2-[(1-trityl-1H-1,2,3-triazole-5-yl) methyl]-1,2,3,4-tetrahydroisoquinoline-6-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl] preparation of ethanamide
Figure BSA00000144719800244
With 2-(1H-1,2,3-triazole-5-yl)-6-bromo-1,2,3,4-tetrahydroisoquinoline 2.3g (0.007mol) and triethylamine 1.2g (0.01mol) are dissolved among the 15mLDCM, add trityl chloride then, react after 3 hours, solvent is drained, residuum is through column chromatography for separation (EA: PE=1: 2) obtain 6-bromo-2-[(1-trityl-1H-1,2,3-triazole-5-yl) methyl]-1,2,3, the 4-tetrahydroisoquinoline is dissolved in dioxane/EtOH/H with this product 2O=3: in 1: 1 mixed solvent, add 3eq cesium carbonate and 1eq (S) N-[[3-[3-fluoro-4-(4,4; 5,5-tetramethyl--1,3; 2-dioxy boron penta ring-2-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide, under nitrogen protection, add 0.05eq Pd (dppf) Cl 2Be reacted to TLC under 90 ℃ and detect the raw material complete reaction, remove solvent under the vacuum, residuum is through column chromatography for separation (EA: PE=1: 1) obtain 1.2g yellow solid (5S)-N-[[3-[3-fluoro-4-[2-[(1-trityl-1H-1,2,3-triazole-5-yl) methyl]-1,2,3,4-tetrahydroisoquinoline-6-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide, yield 22%.
(8) (5S)-and N-[[3-[3-fluoro-4-[2-[(1H-1,2,3-triazole-5-yl) methyl]-1,2,3,4-tetrahydroisoquinoline-6-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl] preparation of acetamide hydrochloride
Figure BSA00000144719800251
With (5S) N-[[3-[3-fluoro-4-[2-[(1-trityl-1H-1,2,3-triazole-5-yl) methyl]-1,2,3,4-tetrahydroisoquinoline-6-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide 1.2g (0.02mol) is dissolved in the dioxane solution of HCl, behind the stirring reaction 2 hours, the solvent vacuum is removed, and residuum obtains white powder (5S)-N-[[3-[3-fluoro-4-[2-[(1H-1,2 with the ether washing, 3-triazole-5-yl) methyl]-1,2,3,4-tetrahydroisoquinoline-6-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide hydrochloride 400mg.
Molecular formula: C 24H 26ClFN 6O 3Molecular weight: 500.95 mass spectrums (M+H): 465
1H-NMR(DMSO)：δ＝1.84(m，3H)，3.06(m，1H)，3.30(m，4H)，3.68(m，1H)，3.80(m，1H)，4.16(m，1H)，4.20(s，2H)，4.60(s，2H)，4.76(br，1H)，7.29-7.41(m，4H)，7.60(t，2H)，8.30(d，2H)，12.01(br，1H).
1H-NMR(DMSO+D 2O)：δ＝1.85(s，3H)，3.16(s，2H)，3.43(m，3H)，3.80(m，2H)，4.17(t，1H)，4.45(s，2H)，4.64(s，2H)，4.77(m，1H)，7.30-7.42(m，4H)，7.60(t，2H)，8.23(br，1H).
Embodiment 3N-[[(5S)-and 3-[4-[1-[2-(1H-1,2,3-triazole-5-yl) ethyl]-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-the 3-fluorobenzene Base]-2-oxo-5-oxazolidinyl] methyl] preparation of acetamide hydrochloride (compound 6 hydrochlorides)
Figure BSA00000144719800252
(1) 6-bromo-1-(3-butynyl)-1,2,3, the preparation of 4-tetrahydrochysene-quinoline
Figure BSA00000144719800253
To 6-bromo-1,2,3, add Na in acetonitrile (60mL) solution of 4-4H-quinoline 6.8g (32mmol) 2CO 36.8g (64mmol) and 3-butynyl methanesulfonates 7.2g (48mmol), the mixture back flow reaction is spent the night, be chilled to the room temperature filtration and remove inorganic salt, mother liquor removes column chromatography purification (EtOAc/PE=1: 20) obtain compound 6-bromo-1-(3-butynyl)-1 behind the solvent under reduced pressure, 2,3,4-tetrahydrochysene-quinoline 2.2g, yield 26.1%.
(2) 1-[2-(1H-1,2,3-triazole-5-yl) ethyl]-6-bromo-1,2,3, the preparation of 4-tetrahydrochysene-quinoline
Figure BSA00000144719800261
In the 100mL reaction flask, use 9mL DMF and 1mL dissolve with methanol 6-bromo-1-(3-butynyl)-1; 2; 3; 4-tetrahydrochysene-quinoline 2.1g (8.0mmol) and trimethyl silicane nitrine 1.4g (12.0mmol) add CuI 0.3g (1.6mmol) fast in system under nitrogen protection, be heated to 100 ℃ of reactions 10 hours then; the TLC detection reaction finishes; add 50mL methyl alcohol, filter, filtrate is with the solvent evaporate to dryness; thick product is through column chromatography for separation (EA: PE=1: 1); obtain yellow oil 1-[2-(1H-1,2,3-triazole-5-yl) ethyl]-6-bromo-1; 2; 3,4-tetrahydrochysene-quinoline 1.1g, yield 45.1%.
(3) the 6-bromo-1,2,3,4-tetrahydrochysene-1-[2-(1-trityl-1H-1,2,3-triazole-5-yl) ethyl] quinoline
Figure BSA00000144719800262
With 1-[2-(1H-1,2,3-triazole-5-yl) ethyl]-6-bromo-1,2,3,4-tetrahydrochysene-quinoline 1.1g (3.6mmol) and triethylamine 0.6g (5.4mmol) are dissolved in the 8mL methylene dichloride, and frozen water drips triphenylmethyl chloride 1.2g (4.3mmol) down, keep temperature of reaction to be lower than 5 ℃, rise to room temperature after dripping off and continue reaction 2 hours, reaction solution washes with water, and anhydrous sodium sulfate drying filters, evaporate to dryness, thick product obtains white solid 6-bromo-1,2,3 through column chromatography for separation, 4-tetrahydrochysene-1-[2-(1-trityl-1H-1,2,3-triazole-5-yl) ethyl] quinoline 1.3g, yield 58.4%.
(4) N-[[(5S)-and 3-[3-fluoro-4-[1,2,3,4-tetrahydrochysene-1-[2-(1-trityl-1H-1,2,3-triazole-5-yl) ethyl] quinoline-6-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide
Figure BSA00000144719800271
In the exsiccant reaction flask, add mixed solvent (dioxane/EtOH/H 2O=9mL/3mL/3mL), add 6-bromo-1,2 then; 3,4-tetrahydrochysene-1-[2-(1-trityl-1H-1,2; 3-triazole-5-yl) ethyl] quinoline 1.3g (2.1mmol); (S)-N-[[3-[3-fluoro-4-(4,4,5; 5-tetramethyl--1; 3,2-dioxy boron penta ring-2-yl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide 1.0g (2.7mmol) and cesium carbonate 2.0g (6.2mmol), under nitrogen protection, add Pd (dppf) Cl 20.30g (0.40mmol), be heated to 90 ℃ of reactions 2 hours, LC-MS detects explanation raw material complete reaction, is cooled to room temperature, filter, the solvent vacuum is removed in the filtrate, residuum is poured in the frozen water, with DCM extraction (4 * 20mL), the organic layer anhydrous sodium sulfate drying filters evaporate to dryness.Crude product uses column chromatography (EA: PE=4: 1) obtain white solid N-[[(5S)-3-[3-fluoro-4-[1,2,3,4-tetrahydrochysene-1-[2-(1-trityl-1H-1,2,3-triazole-5-yl) ethyl] quinoline-6-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide 810mg, yield 54.6%.
(5) N-[[(5S)-and 3-[4-[1-[2-(1H-1,2,3-triazole-5-yl) ethyl]-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] preparation of acetamide hydrochloride
Figure BSA00000144719800272
Under the room temperature to N-[[(5S)-3-[3-fluoro-4-[1,2,3,4-tetrahydrochysene-1-[2-(1-trityl-1H-1,2,3-triazole-5-yl) ethyl] quinoline-6-yl] phenyl]-2-oxo-5-oxazolidinyl] methyl] add trifluoroacetic acid 1mL and water 0.5mL in DCM (8mL) solution of ethanamide 810mg (1.13mmol), reaction is at room temperature stirred and is spent the night, LC-MS detects explanation raw material complete reaction, reaction solution is transferred to pH=9 with saturated sodium carbonate, filter, filter cake washs with ether, and vacuum-drying obtains white solid.Product is dissolved among methyl alcohol 0.5mL and the DCM1mL, drip the saturated dioxane solution of 1mL hydrogenchloride in 1 hour, the solvent vacuum moved down away obtains N-[[(5S)-3-[4-[1-[2-(1H-1,2,3-triazole-5-yl) ethyl]-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide hydrochloride 220mg, yield 35.3%.
Molecular formula: C 25H 28FClN 6O 3Molecular weight: 514.98 mass spectrums (M+H): 479
1H-NMR(DMSO)：δ1.84(5H，m)，2.72(2H，t)，2.91(2H，t)，3.25(2H，m)，3.42(2H，t)，3.56(2H，t)，3.76(1H，m)，4.14(1H，t)，4.74(1H，m)，6.71(1H，d)，7.10(1H，s)，7.20(1H，d)，7.32(1H，m)，7.50(2H，m)，7.72(1H，s)，8.28(1H，t).
1H-NMR(DMSO+D 2O)：δ1.74(2H，s)，1.84(3H，s)，2.63(2H，m)，2.89(2H，m)，3.15(2H，m)，3.52(2H，m)，3.70(1H，m)，4.05(1H，m)，4.71(1H，m)，6.62(1H，m)，7.04(1H，s)，7.13(1H，d)，7.21-7.44(4H，m)，7.66(1H，s).
With reference to above-mentioned preparation method, also prepared following compound.
Figure BSA00000144719800291
Figure BSA00000144719800311

Claims (9)

1. the compound shown in the general formula (I), its pharmacy acceptable salt or its steric isomer:
Figure FSA00000144719700011
Wherein, R 1Be acetamido, hydroxyl, amino, C 1-6Alkyl amine group, 1,2,3-triazol radical Huo isoxazole oxygen base;
R 2, R 3Be hydrogen atom independently, halogen atom or C 1-6Alkyl;
Figure FSA00000144719700012
Be common form and the cyclic group of A ring and B ring,
Wherein the A ring is 3-8 unit cyclic group;
The A ring can be further by 1-3 R 5Replace R 5Be independently selected from hydrogen atom, halogen atom, C 1-6Alkyl, halo C 1-6Alkyl, hydroxyl, hydroxyl C 1-6Alkyl, amino, C 1-6Alkyl amine group, two (C 1-6Alkyl) amido or C 1-6The alkyl amine group formyl radical;
The B ring is phenyl ring, pyridine or pyrazine;
The B ring can be further by 1-3 R 4Replace R 4Be independently selected from hydrogen atom, halogen atom, C 1-6Alkyl, halo C 1-6Alkyl, hydroxyl, hydroxyl C 1-6Alkyl, amino, C 1-6Alkyl amine group, two (C 1-6Alkyl) amido or C 1-6The alkyl amine group formyl radical;
-Y-is-(CH 2) n-,-CH (R 7)-,-NH-,-(CH 2) n-NH-,-(CH 2) n-NH-CH 2-,-(CH 2) n-N (R 7)-CH 2-,-(CH 2) n-(CO)-,-O-,-S-,-C (O)-,-SO-or-SO 2-,
R wherein 7Be C 1-6Alkyl, hydroxyl or amino, n are 1～4 integer;
R 6Be the saturated or undersaturated nitrogen heterocyclic of 5-6 unit, R 6Also can be further by R 7Replace R 7Be selected from by halogen atom and replace or unsubstituted C 1-6Alkyl.
2. compound as claimed in claim 1, its pharmacy acceptable salt or its steric isomer:
Wherein, R 1Be acetamido, hydroxyl, 1,2,3-triazol radical Huo isoxazole oxygen base;
R 2, R 3Be hydrogen atom or halogen atom independently;
Figure FSA00000144719700013
Be common form and the cyclic group of A ring and B ring,
Wherein the A ring is 5-6 unit cyclic group;
The A ring can be further by 1-2 R 5Replace R 5Be independently selected from hydrogen atom, halogen atom, C 1-4Alkyl, halo C 1-4Alkyl, hydroxyl, hydroxyl C 1-4Alkyl, amino, C 1-4Alkyl amine group, two (C 1-4Alkyl) amido or C 1-4The alkyl amine group formyl radical;
The B ring is phenyl ring or pyridine;
The B ring can be further by 1-2 R 4Replace R 4Be independently selected from hydrogen atom, halogen atom, C 1-4Alkyl, halo C 1-4Alkyl, hydroxyl, hydroxyl C 1-4Alkyl, amino, C 1-4Alkyl amine group, two (C 1-4Alkyl) amido or C 1-4The alkyl amine group formyl radical;
-Y-is-(CH 2) n-,-NH-,-(CH 2) n-NH-,-(CH 2) n-(CO)-,-O-or-S-, wherein n is 1,2 or 3;
R 6Be the saturated or undersaturated nitrogen heterocyclic of 5-6 unit, R 6Also can be further by R 7Replace R 7Be selected from by fluorine atom and replace or unsubstituted C 1-4Alkyl.
3. compound as claimed in claim 2, its pharmacy acceptable salt or its steric isomer:
Wherein, R 1Be acetamido;
R 2, R 3Be hydrogen atom or fluorine atom independently;
Figure FSA00000144719700021
Be common form and the cyclic group of A ring and B ring,
Wherein the A ring is pentamethylene, hexanaphthene, cyclopentenes, tetrahydrobenzene, 1, Pyrrolidine, 2,3-pyrrolin, 2,5-pyrrolin, pyrroles, imidazoles, 4,5-glyoxalidine, pyrazoles, 4,5-pyrazoline, 1,2,3-triazole, tetramethylene sulfide, thiophene, 2, the 3-dihydro-thiophene, thiazole, 4,5-thiazoline, isothiazole, tetrahydrofuran (THF), 2,3 dihydro furan, furans, 4,5-dihydro-oxazole ， oxazole, 4,5-dihydro-isoxazole ， isoxazole, phenyl ring, 1,4,5,6-tetrahydropyrimidine, 1,6-dihydro-pyrimidin, 4,5-dihydro-pyrimidin, pyrimidine, 3,6-dihydro-2H-pyrans, 2H-pyrans, piperidines, 1,2,3,4-tetrahydropyridine, 1,2,3, the 6-tetrahydropyridine, 2,3-dihydropyridine, pyridine, piperazine, 1,2,3,4-tetrahydrochysene pyrazine, 2,3-dihydro pyrazine or pyrazine;
The A ring can be further by 1-2 R 5Replace R 5Be independently selected from hydrogen atom, fluorine atom, methyl, trifluoromethyl, hydroxyl, methylol, amino, methylamino, ethylamino-, methylamino formyl radical or ethylamino-formyl radical;
The B ring is phenyl ring or pyridine;
The B ring can be further by 1-2 R 4Replace R 4Be independently selected from hydrogen atom, fluorine atom, methyl, methyl fluoride, trifluoromethyl, hydroxyl, methylol, amino, methylamino, ethylamino-, methylamino formyl radical or ethylamino-formyl radical;
-Y-is-(CH 2) n-,-NH-,-(CH 2) n-NH-or-(CH 2) n-(CO)-, wherein n is 1,2 or 3;
R 6Be the pyrroles, imidazoles, 1,2,3-triazole, 1,2,4-triazole, pyrrotriazole, pyridine or pyrazine, R 6Also can be further by R 7Replace R 7Be selected from methyl, ethyl, propyl group or trifluoromethyl.
4. compound as claimed in claim 3, its pharmacy acceptable salt or its steric isomer:
Wherein, R 1Be acetamido;
R 2, R 3Be hydrogen atom or fluorine atom independently;
Figure FSA00000144719700022
Be common form and the cyclic group of A ring and B ring,
Wherein the A ring is pentamethylene, hexanaphthene, cyclopentenes, tetrahydrobenzene, 1, Pyrrolidine, 2,3-pyrrolin, 2,5-pyrrolin, pyrroles, imidazoles, 4, the 5-glyoxalidine, pyrazoles, 4,5-pyrazoline, 1,2,3-triazole, tetramethylene sulfide, thiophene, 2,3-dihydro-thiophene, thiazole, 4,5-thiazoline, tetrahydrofuran (THF), 2,3 dihydro furan, furans ， oxazole, phenyl ring, 1,4,5,6-tetrahydropyrimidine, 1,6-dihydro-pyrimidin, 4, the 5-dihydro-pyrimidin, pyrimidine, 3,6-dihydro-2H-pyrans, 2H-pyrans, piperidines, 1,2,3,4-tetrahydropyridine, 1,2,3,6-tetrahydropyridine, 2,3-dihydropyridine, pyridine, piperazine, 1,2,3,4-tetrahydrochysene pyrazine, 2,3-dihydro pyrazine or pyrazine;
The A ring can be further by 1 R 5Replace R 5Be selected from hydrogen atom, fluorine atom, methyl or methylamino formyl radical;
The B ring is phenyl ring or pyridine;
The B ring can be further by 1 R 4Replace R 4Be selected from hydrogen atom, fluorine atom, methyl or methyl fluoride;
-Y-is-(CH 2) n-,-NH-,-(CH 2) n-NH-or-(CH 2) n-(CO)-, wherein n is 1 or 2;
R 6Be 1,2,3-triazole, 1,2,4-triazole or pyrrotriazole, R 6Also can be further by R 7Replace R 7Be selected from methyl or ethyl.
5. compound as claimed in claim 4, its pharmacy acceptable salt or its steric isomer:
Wherein, R 1Be acetamido;
R 2, R 3Be hydrogen atom or fluorine atom independently;
Figure FSA00000144719700031
Be common form and the cyclic group of A ring and B ring,
Wherein the A ring is pentamethylene, cyclopentenes, 1, Pyrrolidine, 2,3-pyrrolin, pyrroles, phenyl ring, piperidines, 1,2,3,4-tetrahydropyridine, 1,2,3,6-tetrahydropyridine, 2,3-dihydropyridine or pyridine;
The B ring is phenyl ring;
R 4, R 5Be hydrogen atom;
-Y-is-(CH 2) n-,-NH-or-(CH 2) n-NH-, wherein n is 1 or 2;
R 6Be 1,2, the 3-triazole.
6. compound as claimed in claim 5, its pharmacy acceptable salt or its steric isomer, its compound is selected from:
N-[[(5S)-and 3-[4-[1-[(1H-1,2,3-triazole-5-yl) methylamine]-2,3-dihydro-1H-indenes-5-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide,
N-[[(5S)-and 3-[4-[1-[2-(1H-1,2,3-triazole-5-yl) ethyl] indoline-5-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide,
N-[[(5S)-3-[4-[2-(1H-1,2,3-triazolyl-5-amido) naphthalene-6-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide,
N-[[(5S)-and 3-[4-[2-[(1H-1,2,3-triazole-5-yl) methyl]-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide,
N-[[(5S)-3-[4-[2-(1H-1,2,3-triazole-5-yl) methyl]-1,2,3,4-tetrahydroisoquinoline-6-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide and
N-[[(5S)-and 3-[4-[1-[2-(1H-1,2,3-triazole-5-yl) ethyl]-1,2,3,4-tetrahydrochysene-quinoline-6-yl]-the 3-fluorophenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide.
7. as each described compound of claim 1～6, its pharmacy acceptable salt is benzoate, benzene sulfonate, tosilate, mesylate, Citrate trianion, maleate, fumarate, tartrate, hydrogen chlorate, hydrobromate, vitriol, phosphoric acid salt, ammonium salt, sodium salt, sylvite, calcium salt, magnesium salts.
8. the pharmaceutical composition that comprises each described compound of claim 1～6, its pharmacy acceptable salt or its steric isomer and one or more pharmaceutical carriers and/or thinner is characterized in that described pharmaceutical composition is for clinically or pharmaceutically acceptable arbitrary formulation.
9. each described compound of claim 1～6, its pharmacy acceptable salt or its steric isomer treat and/or prevent application in the medicine of infectious diseases in preparation.
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