CN103709093B

CN103709093B - The pleuromulins antibiotic containing and encircle

Info

Publication number: CN103709093B
Application number: CN201310471450.4A
Authority: CN
Inventors: 张蕙; 王爱臣
Original assignee: SHANDONG HENRY MEDICAL SCIENCE AND TECHNOLOGY Co Ltd
Current assignee: SHANDONG HENRY MEDICAL SCIENCE AND TECHNOLOGY Co Ltd
Priority date: 2012-09-28
Filing date: 2013-09-28
Publication date: 2016-06-08
Anticipated expiration: 2033-09-28
Also published as: CN103709093A

Abstract

The present invention relates to the pleuromulins antibiotic that contains and encircle, its pharmaceutically acceptable salt, its pro-drug, its solvate or its stereoisomer, the wherein R shown in general formula (I)¹、R²、R³, m, A, B and X definition define with the specification above; The invention still further relates to the preparation method of these compounds, the pharmaceutical composition that contains these compounds and pharmaceutical preparation, and these compounds treat and/or prevent the application in the medicine of the disease being caused by microorganism in preparation.

Description

The pleuromulins antibiotic containing and encircle

1, technical field

The invention belongs to medical technical field, relate to the pleuromulins antibiotic that contains and encircle, it pharmaceutically can connectThe salt, its pro-drug, its solvate, deuterated thing or its stereoisomer that are subject to, the preparation method of these compounds, contains thisPharmaceutical composition and the pharmaceutical preparation of a little compounds, and these compounds treat and/or prevent by microorganism and cause in preparationThe medicine of disease in application.

2, background technology

Pleuromulins antibiotic (Pleuromutilinantibiotics) is a kind of diterpene antibiotic, byFive yuan, hexa-atomic, octatomic ring three rings merge the structure that forms 5-6-8 tricyclic diterpenes, in nineteen fifty-one from two kinds of basidiomycetes(basidiomycetespecies) Pleurotusmutilis (bacterium of picking up the ears) obtains with separating in P.passeckerianus.

Pleuromulins antibiotic is by the synthetic performance of anti-bacteria protein antibacterial activity, based on the effect of its uniquenessMechanism, does not find crossing drug resistant at present clinically, shows excellent clinical practice speciality. But, research up to nowFind lessly, be only used for treating the safe wonderful mycin of veterinary medicine of swine dysentery, the popular pneumonia of pig and poultry chronic respiratory disease(Tiamulin), and as ointment be successfully applied the Retapamulin that human skin dermatitis impetiginosa infects(Retapamulin)。

In addition, other pleuromutilin analog derivatives still under study for action, as open at patent EP1972618, WO0222580As the pleuromulins compound of antiseptic.

Based on current clinical needs, urgently research and develop have good antibacterial activity and metabolic stability, for controllingTreat the pleuromulins antibiotic medicine of human skin soft tissue infection, pneumonia.

3, summary of the invention

For meeting clinical demand, the invention provides a class have good antibacterial activity and metabolism eliminate few, for controllingTreat the pleuromulins antibiotic medicine of human skin soft tissue infection, pneumonia, concrete technical scheme is as follows:

Compound shown in general formula (I), its pharmaceutically acceptable salt, its pro-drug, its solvate, deuterated thing orIts stereoisomer:

Wherein, R¹For hydrogen, C_1-6Alkyl, halo C_1-6Alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, C_1-6Alkoxyl, halo C_1-6AlcoxylBase, C_1-6Alkylthio group, hydroxyl C_1-6Alkyl, carboxyl C_1-6Alkyl, amino C_1-6Alkyl, C_1-6Alkyl amine group C_1-6Alkyl, C_1-6AlkoxylCarbonyl, C_1-6Alkyl sulphinyl, C_1-6Alkyl sulphonyl, sulfonic group, sulfonyl C_1-6Alkyl, sulfoamido C_1-6Alkyl, aminoSulfonyl, C_1-6Alkyl amine group sulfonyl, two (C_1-6Alkyl) amido sulfonyl, amino-sulfonyl C_1-6Alkyl, C_1-6Alkyl amine groupFormoxyl, two (C_1-6Alkyl) amido formacyl, carbamoyl, carbamoyl C_1-6Alkyl, 3-14 unit cycloalkyl, 6-14 unitAryl, the aryl C of 6-14 unit_1-6Alkyl, 3-14 unit heterocyclic radical, the heterocyclic radical C of 3-14 unit_1-6Alkyl,

Or the group shown in following formula

R⁴And R⁵Be independently respectively:

(1) hydrogen, amino, hydroxyl, sulfydryl, carboxyl, guanidine radicals,

(2) be not substituted or by 1-3 identical or different R⁶Replace: C_1-6Alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, C_1-6Alkyl amine group, C_1-6Alkylthio group, carboxyl C_1-6Alkyl, hydroxyl C_1-6Alkyl, carbamoyl, carbamoyl C_1-6Alkyl,

(3) be not substituted or by 1-3 identical or different R⁶Replace: 3-14 unit cycloalkyl, 3-14 unit's heterocyclic radical or6-14 unit aryl,

Or R⁴And R⁵The C atom being connected with them is combined together to form and is not substituted or identical or different by 1-3R⁷The 3-14 unit cyclic group replacing,

R⁶、R⁷Respectively independently selected from halogen, hydroxyl, amino, carboxyl, C_1-6Alkyl, C_1-6Alkoxyl, halo C_1-6Alkyl,Halo C_1-6Alkoxyl, hydroxyl C_1-6Alkyl, amino C_1-6Alkyl, carboxyl C_1-6Alkyl, C_1-6Alkyl amine group, two (C_1-6Alkyl) amineBase, amino-sulfonyl, amino-sulfonyl C_1-6Alkyl, carbamoyl, carbamoyl C_1-6Alkyl, C_1-6Alkyl-carbonyl, C_1-6Alkyl carbonyl oxy, C_1-6Alkoxy carbonyl, phenyl, 3-14 unit's cycloalkyl or 3-14 unit heterocyclic radical;

For the condensed-bicyclic system in parallel of A ring and shared two carbon atoms composition of B ring,

Wherein A ring is selected from unsubstituted or by 1-3 R²The 3-14 unit's heterocyclic radical replacing or 6-14 unit aryl, Qi ZhongsuoState R²Independently selected from hydrogen, halogen, 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_1-6Alkyl amine group formoxyl,

It is unsubstituted or by 1-3 R that B ring is selected from³The 3-14 unit cycloalkyl, 3-14 unit's heterocyclic radical or the 6-14 unit virtue that replaceBase, wherein said R³Independently selected from hydrogen, halogen, 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_1-6Alkyl amine group formoxyl;

X is-O-,-S-,-SO-,-SO₂-、-COO-、NR^8’、CONR^8’,-NHCONH-or a key;

R⁸And R^8’For hydrogen or C_1-6Alkyl;

M and n are 0,1,2,3 or 4.

Compound shown in general formula (I), its pharmaceutically acceptable salt, its pro-drug, its solvate, deuterated thing orIts stereoisomer, is preferably:

Wherein, R¹For hydrogen, C_1-6Alkyl, or the group shown in following formula

R⁴And R⁵Be independently respectively:

(1) hydrogen, amino, hydroxyl, sulfydryl, carboxyl, guanidine radicals,

R⁶、R⁷Respectively independently selected from halogen, hydroxyl, amino, carboxyl, C_1-6Alkyl, C_1-6Alkoxyl, halo C_1-6Alkyl,Halo C_1-6Alkoxyl, hydroxyl C_1-6Alkyl, amino C_1-6Alkyl, carboxyl C_1-6Alkyl, C_1-6Alkyl amine group, two (C_1-6Alkyl) amineBase, amino-sulfonyl, amino-sulfonyl C_1-6Alkyl, carbamoyl, carbamoyl C_1-6Alkyl, C_1-6Alkyl-carbonyl, C_1-6Alkyl carbonyl oxy, C_1-6Alkoxy carbonyl, phenyl, 3-14 unit's cycloalkyl or 3-14 unit heterocyclic radical,

Y is S, O or NR⁸；

R⁸For hydrogen or C_1-6Alkyl;

M and n are 0,1 or 2.

Wherein, R¹For hydrogen, C_1-4Alkyl, or the group shown in following formula

R⁴And R⁵Be independently respectively:

(1) hydrogen, amino, hydroxyl, sulfydryl, carboxyl, guanidine radicals,

(2) be not substituted or by 1-2 identical or different R⁶Replace: C_1-4Alkyl, C_2-4Thiazolinyl, C_2-4Alkynyl, C_1-4Alkyl amine group, C_1-4Alkylthio group, carboxyl C_1-4Alkyl, hydroxyl C_1-4Alkyl, carbamoyl, carbamoyl C_1-4Alkyl,

(3) be not substituted or by 1-2 identical or different R⁶Replace: 3-8 unit cycloalkyl, 3-8 unit's heterocyclic radical or 6-14 yuan of aryl,

Or R⁴And R⁵The C atom being connected with them is combined together to form and is not substituted or identical or different by 1-2R⁷The 3-6 unit cyclic group replacing,

R⁶、R⁷Respectively independently selected from halogen, hydroxyl, amino, carboxyl, C_1-4Alkyl, C_1-4Alkoxyl, halo C_1-4Alkyl,Halo C_1-4Alkoxyl, hydroxyl C_1-4Alkyl, amino C_1-4Alkyl, carboxyl C_1-4Alkyl, C_1-4Alkyl amine group, two (C_1-4Alkyl) amineBase, amino-sulfonyl, amino-sulfonyl C_1-4Alkyl, carbamoyl, carbamoyl C_1-4Alkyl, C_1-4Alkyl-carbonyl, C_1-4Alkyl carbonyl oxy, C_1-4Alkoxy carbonyl, phenyl, 3-8 unit's cycloalkyl or 3-8 unit heterocyclic radical;

Y is S, O or NR⁸；

Wherein A ring is selected from unsubstituted or by 1-2 R²The 3-8 unit heterocyclic radical replacing, wherein said R²Independently selected fromHydrogen, halogen, C_1-4Alkyl, halo C_1-4Alkyl, hydroxyl, hydroxyl C_1-4Alkyl, amino, C_1-4Alkyl amine group, two (C_1-4Alkyl) amidoOr C_1-4Alkyl amine group formoxyl;

It is unsubstituted or by 1-2 R that B ring is selected from³The 3-8 unit's cycloalkyl replacing or 3-8 unit heterocyclic radical, wherein said R³Independently selected from hydrogen, halogen, 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_1-4Alkyl amine group formoxyl;

R⁸For hydrogen or C_1-4Alkyl; M is 0 or 1; N is 0,1 or 2.

Wherein, R¹For hydrogen, C_1-4Alkyl, or the group shown in following formula

R⁴And R⁵Be independently respectively:

(1) hydrogen, amino, hydroxyl, sulfydryl, carboxyl, guanidine radicals,

(2) be not substituted or by R⁶Replace: C_1-4Alkyl, C_1-4Alkyl amine group, C_1-4Alkylthio group, carbamoyl, aminoFormoxyl C_1-4Alkyl,

(3) be not substituted or by R⁶Replace: pentamethylene, cyclohexane, cyclopentene, cyclohexene, 1,3-cyclohexadiene, tetrahydrochysenePyrroles, 2,3-pyrrolin, 2,5-pyrrolin, pyrroles, imidazoles, 4,5-glyoxalidine, pyrazoles, 4,5-pyrazoline, 1,2,3-triazole, thiophane, thiophene, 2,3-dihydro-thiophene, thiazole, 4,5-thiazoline, isothiazole, oxolane, 2,3-bis-Hydrogen furans, furans, 4,5-dihydro-oxazole, oxazole, 4,5-dihydro-isoxazole, isoxazole, phenyl ring, Isosorbide-5-Nitrae, 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,1,2,3,6-tetrahydropyridine, 2,3-dihydropyridine, pyridine, piperazine, 1,2,3,4-tetrahydrochysene pyrazine, 2,3-dihydro pyrazine or pyrazine,

Or R⁴And R⁵The C atom being connected with them is combined together to form and is not substituted or by R⁷Replace: pentamethylene,Cyclohexane, cyclopentene, cyclohexene, 1,3-cyclohexadiene, nafoxidine, 2,3-pyrrolin, 2,5-pyrrolin, pyrroles, miaowAzoles, 4,5-glyoxalidine, pyrazoles, 4,5-pyrazoline, 1,2,3-triazole, thiophane, thiophene, 2,3-dihydro-thiophene, thiopheneAzoles, 4,5-thiazoline, isothiazole, oxolane, DHF, furans, 4,5-dihydro-oxazole, oxazole, 4,5-dihydroIsoxazole, isoxazole, phenyl ring, Isosorbide-5-Nitrae, 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, 1,2,3,6-tetrahydropyridine, 2,3-dihydropyridine, pyridine, piperazinePiperazine, 1,2,3,4-tetrahydrochysene pyrazine, 2,3-dihydro pyrazine or pyrazine,

Wherein said R⁶And R⁷For hydrogen, fluorine, chlorine, carboxyl, methyl, trifluoromethyl, hydroxyl, methylol, amino, methylamino,Ethylamino-, methylamino formoxyl or ethylamino-formoxyl;

Wherein A ring is selected from unsubstituted or by R²The nafoxidine, 2 replacing, 3-pyrrolin, 2,5-pyrrolin,Pyrroles, imidazoles, 4,5-glyoxalidine, pyrazoles, 4,5-pyrazoline, 1,2,3-triazole, thiophane, thiophene, 2,3-dihydroThiophene, thiazole, 4,5-thiazoline, isothiazole, oxolane, DHF, furans, 4,5-dihydro-oxazole, oxazole, 4,5-dihydro-isoxazole, isoxazole, phenyl ring, Isosorbide-5-Nitrae, 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, 1,2,3,6-tetrahydropyridine, 2,3-dihydropyridine, pyrrolePyridine, piperazine, 1,2,3,4-tetrahydrochysene pyrazine, 2,3-dihydro pyrazine or pyrazine,

B ring is selected from unsubstituted by R³The pentamethylene, cyclohexane, cyclopentene, the cyclohexene, 1 that replace, 3-cyclohexadiene,Nafoxidine, 2,3-pyrrolin, 2,5-pyrrolin, pyrroles, imidazoles, 4,5-glyoxalidine, pyrazoles, 4,5-pyrazoline,1,2,3-triazole, thiophane, thiophene, 2,3-dihydro-thiophene, thiazole, 4,5-thiazoline, isothiazole, oxolane, 2,3-dihydrofuran, furans, 4,5-dihydro-oxazole, oxazole, 4,5-dihydro-isoxazole, isoxazole, phenyl ring, Isosorbide-5-Nitrae, 5,6-tetrahydrochysene is phoneticPyridine, 1,6-dihydro-pyrimidin, 4,5-dihydro-pyrimidin, pyrimidine, 3,6-dihydro-2H-pyrans, 2H-pyrans, piperidines, 1,2,3,4-tetrahydrochysenePyridine, 1,2,3,6-tetrahydropyridine, 2,3-dihydropyridine, pyridine, piperazine, 1,2,3,4-tetrahydrochysene pyrazine, 2,3-dihydro pyrazine orPyrazine,

Wherein said R²And R³Independently selected from hydrogen, fluorine, methyl, trifluoromethyl, hydroxyl, methylol, amino, methylamino, secondAmido, methylamino formoxyl or ethylamino-formoxyl;

M is 0 or 1; N is 0,1 or 2.

Wherein, R¹For hydrogen, methyl, ethyl, or the group shown in following formula

R⁴And R⁵Be independently respectively:

(1) hydrogen, amino, hydroxyl, sulfydryl, carboxyl, guanidine radicals,

(2) be not substituted or by R⁶Replace: methyl, ethyl, propyl group, isopropyl, isobutyl group, methyl mercapto, methylamino,Ethylamino-,

(3) be not substituted or by R⁶Replace: cyclopropane, pentamethylene, cyclohexane, nafoxidine, pyrroles, thiazole, thiophene,Imidazoles, isothiazole, oxolane, furans, oxazole, phenyl ring, pyridine,

Or R⁴And R⁵The C atom being connected with them is combined together to form and is not substituted or by R⁷The pentamethylene, the ring that replaceHexane, nafoxidine, piperidines or piperazine,

Described R⁶And R⁷For hydrogen, fluorine, chlorine, amino, carboxyl, hydroxyl, methyl, trifluoromethyl, methylol, methylamino, ethamineBase, methylamino formoxyl or ethylamino-formoxyl;

Wherein, A ring is selected from nafoxidine, piperidines,

B ring is selected from pentamethylene, cyclohexane, nafoxidine, pyrroles, imidazoles, pyrazoles, thiophene, thiazole, isothiazole, tetrahydrochysene furanMutter, furans, oxazole, isoxazole, piperidines, piperazine;

M is 0 or 1; N is 0,1 or 2.

Another technical scheme of the present invention is as follows: the compound shown in general formula (II), its pharmaceutically acceptable salt, before itBody medicine, its solvate, deuterated thing or its stereoisomer:

Or the group shown in following formula

R⁴And R⁵Be independently respectively:

(1) hydrogen, amino, hydroxyl, sulfydryl, carboxyl, guanidine radicals,

R⁸And R^8’For hydrogen or C_1-6Alkyl; M and n are 0,1,2,3 or 4.

Compound shown in general formula (II), its pharmaceutically acceptable salt, its pro-drug, its solvate, deuterated thingOr its stereoisomer, be preferably:

Wherein, R¹For hydrogen, C_1-6Alkyl, or the group shown in following formula

R⁴And R⁵Be independently respectively:

(1) hydrogen, amino, hydroxyl, sulfydryl, carboxyl, guanidine radicals,

Y is S, O or NR⁸；

R⁸For hydrogen or C_1-6Alkyl; M and n are 0,1 or 2.

Wherein, R¹For hydrogen, C_1-4Alkyl, or the group shown in following formula

R⁴And R⁵Be independently respectively:

(1) hydrogen, amino, hydroxyl, sulfydryl, carboxyl, guanidine radicals,

Y is S, O or NR⁸；

R⁸For hydrogen or C_1-4Alkyl; M is 0 or 1; N is 0,1 or 2.

Compound shown in general formula (II), its pharmaceutically acceptable salt, its pro-drug, its solvate, deuterated thingOr its stereoisomer, more preferably:

Wherein, R¹For hydrogen, C_1-4Alkyl, or the group shown in following formula

R⁴And R⁵Be independently respectively:

(1) hydrogen, amino, hydroxyl, sulfydryl, carboxyl, guanidine radicals,

M is 0 or 1; N is 0,1 or 2.

R⁴And R⁵Be independently respectively:

(1) hydrogen, amino, hydroxyl, sulfydryl, carboxyl, guanidine radicals,

Wherein, A ring is selected from nafoxidine, piperidines,

M is 0 or 1; N is 0,1 or 2.

Detailed Description Of The Invention

" halogen " of the present invention refers to fluorine atom, chlorine atom, bromine atoms, iodine atom etc. Preferably fluorine atom and chlorine atom.

" halo " of the present invention refers to that in described group, any one can be replaced by halogen by substituted atom, can be completeHalo, the i.e. substituted position of all energy in halogen atom substituted radical.

" C of the present invention_1-6Alkyl " represent the alkyl that contains 1-6 carbon atom of straight or branched, as methyl, ethyl,N-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, isopentyl, 2-methyl butyl, neopentyl, 1-Ethyl propyl, n-hexyl, isohesyl, 3-methyl amyl, 2-methyl amyl, 1-methyl amyl, 3,3-dimethylbutyl, 2,2-bis-Methyl butyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethyl fourthBase, 1,2-dimethyl propyl etc. Preferably C_1-3Alkyl. " C of the present invention_1-3Alkyl " refer to contain 1-3 the above-mentioned enforcement of carbon atomExample.

" C of the present invention_2-6Thiazolinyl " refer to the thiazolinyl of the straight or branched that the carbon number that contains two keys is 2-6, as secondThiazolinyl, 1-acrylic, 2-acrylic, 1-methyl ethylene, 1-cyclobutenyl, 2-cyclobutenyl, 3-cyclobutenyl, 1-methyl-1-propyleneBase, 2-methyl-1-propylene base, 1-methyl-2-acrylic, 2-methyl-2-acrylic, 1-pentenyl, 2-pentenyl, 3-amyleneBase, 4-pentenyl, 1-methyl isophthalic acid-cyclobutenyl, 2-methyl-1-butene thiazolinyl, 3-methyl-1-butene base, 1-methyl-2-butene base,2-methyl-2-butene base, 3-methyl-2-butene base, 1-methyl-3-cyclobutenyl, 2-methyl-3-cyclobutenyl, 3-methyl-3-butyleneBase, 1,1-dimethyl-2-acrylic, 1,2-dimethyl-1-acrylic, 1,2-dimethyl-2-acrylic, 1-ethyl-1-propyleneBase, 1-ethyl-2-acrylic, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-Methyl-1-penteneBase, 2-methyl-1-pentene thiazolinyl, 3-methyl-1-pentene thiazolinyl, 4-methyl-1-pentene base, 1-methyl-2-pentenyl, 2-methyl-2-Pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-firstBase-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl,4-methyl-4-pentenyl, 1,1-dimethyl-2-cyclobutenyl, 1,1-dimethyl-3-cyclobutenyl, 1,2-dimethyl-1-cyclobutenyl,1,2-dimethyl-2-cyclobutenyl, 1,2-dimethyl-3-cyclobutenyl, 1,3-dimethyl-1-cyclobutenyl, 1,3-dimethyl-2-butyleneBase, 1,3-dimethyl-2-cyclobutenyl, 2,2-dimethyl-3-cyclobutenyl, 2,3-dimethyl-1-cyclobutenyl, 2,3-dimethyl-2-Cyclobutenyl, 2,3-dimethyl-3-cyclobutenyl, 3,3-dimethyl-1-cyclobutenyl, 3,3-dimethyl-2-cyclobutenyl, 1-ethyl-1-Cyclobutenyl, 1-ethyl-2-cyclobutenyl, 1-ethyl-3-cyclobutenyl, 2-ethyl-1-cyclobutenyl, 2-ethyl-2-cyclobutenyl, 2-secondBase-3-cyclobutenyl, 1,1,2-trimethyl-2-acrylic, 1-ethyl-1-methyl-2-acrylic, 1-Ethyl-2-Methyl-1-propyleneBase, 1-Ethyl-2-Methyl-2-acrylic, 1,3-butadiene base, 1,3-pentadiene base, Isosorbide-5-Nitrae-pentadienyl, 2,4-pentadieneBase, Isosorbide-5-Nitrae-hexadienyl, 2,4-hexadienyl etc. Two keys are optionally cis and trans.

" C of the present invention_2-6Alkynyl " refer to the alkynyl of the straight or branched that the carbon number that contains triple bond is 2-6, as secondAlkynyl, 1-propinyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, valerylene base, 3-pentynyl, 4-Pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1-Ethyl-2-propynyl, 2-hexin base, 3-hexin base, 4-hexin base, 5-hexin base, 1-methyl-valerylene base, 4-methyl-2-pentaAlkynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-diformazanBase-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-Propinyl etc.

" C of the present invention_1-6Alkoxyl " refer to " C_1-6Alkyl " group that is connected with other structures by oxygen atom, as firstOxygen base, ethyoxyl, propoxyl group, 1-methyl ethoxy, butoxy, 1-methyl propoxyl group, 2-methyl propoxyl group, 1,1-dimethyl secondOxygen base, amoxy, 1-methyl butoxy, 2-methyl butoxy, 3-methyl butoxy, 1,1-dimethyl propoxyl group, 1,2-diformazanBase propoxyl group, 2,2-dimethyl propoxyl group, 1-ethyl propoxyl group, own oxygen base, 1-methyl amoxy, 2-methyl amoxy, 3-firstBase amoxy, 4-methyl amoxy, 1,1-dimethyl butoxy, 1,2-dimethyl butoxy, 1,3-dimethyl butoxy, 2,2-Dimethyl butoxy, 2,3-dimethyl butoxy, 3,3-dimethyl butoxy, 1-ethyl butoxy, 2-ethyl butoxy, 1,1,2-trimethyl propoxyl group, 1,2,2-trimethyl propoxyl group, 1-ethyl-1-methyl propoxyl group and 1-Ethyl-2-Methyl propoxyl group. ArtLanguage " C_1-3Alkoxyl " refer to the instantiation that contains 1-3 carbon atom in above-mentioned example.

" C of the present invention_1-6Alkyl-carbonyl " refer to term " C_1-6Alkyl " group that is connected with other structures by carbonyl,As methyl carbonyl, ethyl carbonyl, propyl group carbonyl, isopropyl carbonyl, butyl carbonyl, isobutyl group carbonyl, tert-butyl group carbonyl, sec-butylCarbonyl, amyl group carbonyl, neopentyl carbonyl, hexyl carbonyl etc.

" C of the present invention_1-6Alkoxy carbonyl group " be term " C_1-6Alkoxyl " base that is connected with other structures by carbonylGroup, as methoxycarbonyl group, carbethoxyl group, the third oxygen carbonyl, isopropyl oxygen carbonyl, butoxy carbonyl, isobutyl boc, tertbutyloxycarbonyl, the second month in a seasonButoxy carbonyl, penta oxygen carbonyl, new penta oxygen carbonyl, own oxygen carbonyl etc.

" 3-14 unit cycloalkyl " of the present invention refers to that a hydrogen atom of paraffin section removal of 3-14 carbon atom spreads outRaw cyclic alkyl, comprises 3-8 unit monocyclic cycloalkyl, 6-14 unit and encircles cycloalkyl, 7-12 unit's bridged ring base and 7-12 unit volution base.Preferably C_3-8Cycloalkyl, C_3-6Cycloalkyl and C_5-6Cycloalkyl. Term " C_3-8Cycloalkyl ", " C_3-6Cycloalkyl ", " C_5-6Cycloalkyl " pointIn Wei following example, contain the instantiation of 3-8,3-6, a 5-6 carbon atom.

3-8 unit monocyclic cycloalkyl, comprises the 3-8 saturated monocyclic cycloalkyl of unit and 3-8 unit fractional saturation monocyclic cycloalkyl. 3-8The saturated monocyclic cycloalkyl of unit, refers to that this monocycle is whole saturated carbocyclic rings, and the example includes but not limited to: cyclopropane base, ring fourthAlkyl, pentamethylene base, cyclohexyl, cycloheptane base, cyclooctane base, methyl cyclopropane base, dimethylcyclopropane base, methyl ring fourthAlkyl, dimethyl cyclobutane base, methyl cyclopentane base, dimethylcyclopentane base, methyl cyclohexane alkyl, dimethyl cyclohexane baseDeng. 3-8 unit fractional saturation monocyclic cycloalkyl, refers to that this monocycle is the carbocyclic ring of fractional saturation, and the example includes but are not limited to ringAcrylic, cyclobutane base, cyclopentenyl, cyclohexenyl group, Isosorbide-5-Nitrae-cyclohexadienyl, cycloheptenyl, Isosorbide-5-Nitrae-cycloheptadiene base, encircle pungentThiazolinyl, 1,5-cyclo-octadiene base etc.;

6-14 unit cyclic group, refer to by two or more circuluses and share each other two adjacent carbon atom institute shapesThe 6-14 unit cyclic group becoming, comprises 6-14 first saturated and cyclic group and 6-14 unit's fractional saturation cyclic group. Preferably 6-12 unit ringBase, 6-10 unit cyclic group. 6-14 unit is saturated and encircle cycloalkyl, refers to that this and cyclic group are whole saturated carbocyclic rings, and the example comprisesBut be not limited to: two ring [3.1.0] hexyls, two ring [4.1.0] heptane bases, two ring [2.2.0] hexyls, two encircle [3.2.0] heptanAlkyl, two ring [4.2.0] octyls, octahydro pentalene base, octahydro-1H-indenyl, decahydronaphthalenes base, ten tetrahydrochysene phenanthryl etc.6-14 unit fractional saturation is also encircled cycloalkyl, refers to the carbocyclic ring that in this and ring, at least one ring is fractional saturation, the example comprise butBe not limited to: dicyclo [3.1.0] oneself-2-thiazolinyl, dicyclo [4.1.0] heptan-3-thiazolinyl, dicyclo [3.2.0] heptan-3-thiazolinyl, dicyclo[4.2.0] pungent-3-thiazolinyl, 1,2,3, and 3a-tetrahydrochysene pentalene base, 2,3,3a, 4,7,7a-, six hydrogen-1H-indenyl, 1,2,3,4,4a, 5,6,8a-octahydro-naphthalene base, 1,2,4a, 5,6,8a-hexahydro naphthyl, 1,2,3,4,5,6,7,8,9,10-decahydro phenanthrylDeng;

7-12 unit bridged ring base, refer to that any two rings share neither that directly connected atom forms to contain 5-14 carbon formerThe structure of son, " 5-14 unit bridged ring " comprises the saturated bridged ring base of 5-14 unit, 5-14 unit fractional saturation bridged ring base. The saturated bridged ring of 5-14 unitBase, preferably the saturated bridged ring base of 6-10 unit, includes but are not limited to dicyclo [2.1.1] hexyl, dicyclo [2.2.1] heptane base, twoRing [3.2.1] heptane base, dicyclo [2.2.2] octyl, dicyclo [3.2.1] octyl, dicyclo [3.3.1] octyl, dicyclo[3.3.1] nonyl, dicyclo [4.3.1] nonyl, 4-azabicyclo [5.3.1] decyl etc. 7-12 unit fractional saturation bridged ringBase, referring to has in this bridged ring that to have a ring at least be undersaturated cyclic group, is preferably 6-10 unit fractional saturation bridged ring base, toolBody example includes but not limited to dicyclo [2.2.1] heptan-5-thiazolinyl, dicyclo [3.2.1] oct-6-ene base, dicyclo [4.3.1] ninth of the ten Heavenly Stems-5-Thiazolinyl, bicyclic pentadiene etc.;

7-12 unit volution base, refers to that a class has at least two rings to share the 5-14 unit condensed ring structure that an atom forms. 5-14 yuan of saturated volution bases, refer to that all rings in this volution base are saturated cyclic group, instantiation comprise but not only forIn:Etc. ring-typeThe group that any commutable hydrogen atom of structure replacement forms etc. 5-14 unit fractional saturation volution base, refers in this volution baseHaving a ring at least is undersaturated cyclic group, and instantiation includes but are not limited to: Replace arbitrarily etc. circulusThe group that commutable hydrogen atom forms etc. Preferably 7-10 unit volution base, comprises " the saturated volution base of 7-10 unit " and " 7-10 unitUnsaturated volution base ".

" C of the present invention_3-8Cycloalkyloxy " refer to term " C_3-8Cycloalkyl " be connected with other structures by oxygen atomThe group connecing, as encircled propoxyl group, cyclobutoxy group, 1-methyl cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, ring oxygen in heptan base, encircling pungent oxygenBase etc.

" 6-14 unit aryl " of the present invention refers to that annular atoms is the ring-type aromatic group of 6-14 unit carbon atom, comprises 6-8 yuan of monocyclic aryl and 8-14 unit fused ring aryl. 6-8 unit monocyclic aryl refers to whole undersaturated aryl, for example phenyl, encircle pungent fourThiazolinyl etc. 8-14 unit fused ring aryl refers to by two or more circuluses and shares each other two adjacent carbon atom institute shapesBecome, have the cyclic group that a ring is whole undersaturated aromatic rings at least, comprise the whole unsaturated fused ring aryl of 8-14 unit,Naphthyl, anthryl and phenanthryl etc., also comprise 8-14 unit fractional saturation fused ring aryl, for example the saturated monocyclic cycloalkyl of benzo 3-8 unit, benzeneAnd 3-8 unit fractional saturation monocyclic cycloalkyl, instantiation is as 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-naphthaneBase, Isosorbide-5-Nitrae-dihydro naphthyl etc. Preferably 6-10 unit aryl, the saturated monocyclic cycloalkyl of further preferred benzene or benzo 3-8 unit, benzo 3-8 yuan of fractional saturation monocyclic cycloalkyls. The concrete reality that in the finger above-mentioned " aryl " of term " 6-10 unit aryl ", annular atoms number is 6-10Example.

Described " 5-14 unit heteroaryl ", its annular atoms, except carbon atom, also comprises one or more hetero atoms, described in" hetero atom " includes but not limited to oxygen atom, nitrogen-atoms and sulphur atom. Heteroaryl can pass through carbon or heteroatom bonding. Comprise 5-8 yuan of bicyclic heteroaryls and 8-14 unit condensed hetero ring aryl. 5-8 unit bicyclic heteroaryl includes but not limited to pyrrole radicals, imidazole radicals, pyrazolesBase, 1,2,3-triazoles base, 1,2,4-triazolyl, pyridine radicals, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, different thiopheneAzoles base, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,3-oxadiazolyl, 1,2,4-oxadiazoleBase, 1,2,5-oxadiazolyl, 1,2,3-triazine radical, 1,2,4-triazine radical, tetrazole radical, oxatriazole base, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 2H-1,3-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 2H-1,4-EvilPiperazine base, 4H-1,4-oxazinyl, Yi oxazinyl, pyridazinyl, pyrimidine radicals and pyrazinyl etc.; 8-14 unit condensed hetero ring aryl comprises but notBe limited to benzofuranyl, isobenzofuran-base, benzothienyl, indyl, isoindolyl, quinolyl, isoquinolyl, indolizineBase, indazolyl, phthalazinyl, quinoxalinyl, quinazolyl, benzodiazine base, benzoisoxazole base, benzoxazinyl, benzo miaowAzoles base, pyridopyridine base, pyrazolo [3,4-b] pyridine radicals, purine radicals, acridinyl and xanthyl etc.

" 3-14 unit heterocyclic radical " of the present invention refer to and contain one or more heteroatomic 3-14 unit cyclic group, described in" hetero atom " refers to N, S, O, SO and/or SO₂Deng. Comprise saturated, fractional saturation, a undersaturated 1-4 of having be selected from N, S, O,SO and/or SO₂The two heterocyclic radicals of the heteroatomic 3-8 single heterocyclic radical of unit and 5-14 unit. Also comprise above mentioned heteroaryl andDihydro and tetrahydro analog. That the two heterocyclic radicals of 5-14 unit comprise is saturated, fractional saturation, a undersaturated 1-4 of having are selected from N,S, O, SO and/or SO₂Heteroatomic and ring, volution, bridged ring. Preferably 3-8 unit heterocyclic radical, further preferably saturated, part is satisfiedWith the single heterocyclic radical of, undersaturated 3-8 unit. More preferably 5-8 unit, 5-7 unit, 5-6 unit heterocyclic radical, further preferably saturated, part is satisfiedWith, undersaturated 5-8 unit, 5-7 unit, the single heterocyclic radical of 5-6 unit.

The single heterocyclic radical of 3-8 unit, refers to and contains 3-8 the annular atoms monocyclic heterocycles of (wherein at least containing a hetero atom)Base, comprises the unsaturated single heterocyclic radical of 3-8 unit, 3-8 unit fractional saturation list heterocyclic radical, 3-8 unit saturated mono heterocyclic radical. Preferably 5-7 unitUnsaturated single heterocyclic radical, 5-7 unit fractional saturation list heterocyclic radical, 5-7 unit saturated mono heterocyclic radical. The unsaturated single heterocyclic radical of 3-8 unit, isThe heteroatomic cyclic group that contains that refers to armaticity, instantiation includes but are not limited to furyl, thienyl, pyrrole radicals, thiopheneAzoles base, thiadiazolyl group, oxazolyl, oxadiazolyl, imidazole radicals, pyrazolyl, pyridine radicals, pyrimidine radicals, Isosorbide-5-Nitrae-DioxinBase, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 4H-Isosorbide-5-Nitrae-oxazinyls, pyridazinyl, pyrazinyl, 1,2,3-triazine radical, 1,2,4-triazine radical, 1,3,5-triazines base, 1,2,4,5-tetrazineBase, oxepin base, thia cycloheptatriene base, azacyclo-heptantriene base, 1,3-diazacyclo heptantriene base, azacyclo-are pungentApos etc. 3-8 unit fractional saturation list heterocyclic radical, refers to and contains two keys, heteroatomic cyclic group, and instantiation comprises but notOnly limit to 2,5-dihydro-thiophene base, 4,5-pyrazoline base, 3,4-dihydro-2H-pyranose, 5,6-dihydro-4H-1,3-oxazinylDeng. 3-8 unit saturated mono heterocyclic radical, refers to be all heteroatomic cyclic group of containing of saturated bond, and instantiation comprises but notOnly limit to: aziridine base, azetidinyl, Thietane base, tetrahydrofuran base, nafoxidine base, imidazolidinyl,Pyrazolidinyl, tetrahydrofuran base, Isosorbide-5-Nitrae-dioxane base, 1,3-dioxane base, 1,3-dithian base,Morpholinyl, piperazinyl etc.

The described 1-4 of having is selected from N, S, O and/or SO₂Heteroatomic and ring, volution, bridged ring, specifically refer to and encircle,A non-shared carbon atom in volution, bridged ring is by N, S, O and/or SO₂Hetero atom substitute the 6-14 unit the heterocycle that formBase, 5-14 unit spiro heterocyclic radical, 5-14 unit bridge heterocyclic radical.

6-14 unit heterocyclic radical refer to and contain 6-14 annular atoms (wherein at least containing a hetero atom) by two or twoIndividual above circulus share each other two adjacent atoms couple together form and ring structure, comprise that 6-14 unit is also unsaturatedHeterocyclic radical, 6-14 unit's fractional saturation heterocyclic radical, the saturated and heterocyclic radical of 6-10 unit. Unsaturated and the heterocyclic radical of 6-14 unit, refers to completeThe ring of portion is undersaturated condensed ring structure, the structure that single heterocyclic radical as unsaturated in benzo 3-8 unit forms, the unsaturated list of 3-8 unitThe structures that the unsaturated single heterocyclic radical of heterocyclic radical 3-8 unit forms etc., instantiation includes but not limited to: benzofuranyl, benzoDifferent furyl, benzothienyl, indyl, benzoxazolyl, benzimidazolyl, indazolyl, BTA base, quinolyl, differentQuinolyl, acridinyl, phenanthridinyl, benzo pyridazinyl, phthalazinyl, quinazolyl, quinoxalinyl, phenol piperazine base, pteridine radicals, purineBase, naphthyridines base,Replace any commutable hydrogen atom institute shape etc. circulusThe group becoming etc. 6-14 unit's fractional saturation heterocyclic radical, refer to the condensed ring structure that at least contains a fractional saturation ring, as benzoThe structure that 3-8 unit fractional saturation list heterocyclic radical forms, 3-8 unit's fractional saturation list heterocyclic radical 3-8 unit fractional saturation list heterocyclic radicalThe structures that form etc., instantiation includes but not limited to: 1,3-dihydro benzo furyl, benzo [d] [1.3] dioxoleBase, isoindoline base, Chromanyl, 1,2,3,4-nafoxidine also [3,4-c] pyrroles, On ringThe group that any commutable hydrogen atom of shape structure replacement forms etc. Saturated and the heterocyclic radical of 6-10 unit, refers to that whole rings is equalFor saturated condensed ring structure, the structure that saturated mono heterocyclic radical as first in 3-8 3-8 unit saturated mono heterocyclic radical are formed, instantiationInclude but are not limited to: cyclobutane nafoxidine base, pentamethylene nafoxidine base, azetidine imidazolidinyl,The group forming etc. any commutable hydrogen atom of circulus replacement etc.

5-14 unit bridge heterocyclic radical refers to the bridged ring knot being formed by 5-14 annular atoms (wherein at least containing a hetero atom)Structure. " 5-14 unit bridge heterocyclic radical " comprises the saturated bridge heterocyclic radical of 5-14 unit, 5-14 unit fractional saturation bridge heterocyclic radical.

The saturated bridge heterocyclic radical of 5-14 unit, refers to that all rings in this bridge heterocycle are saturated cyclic group, is preferably 7-8The saturated bridge heterocyclic radical of unit, instantiation includes but not limited to: Etc. circulusReplace group that any commutable hydrogen atom forms etc.

5-14 unit fractional saturation bridge heterocyclic radical, referring to has in this bridge heterocycle that to have a ring at least be undersaturated cyclic groupGroup, is preferably 7-8 unit fractional saturation bridge heterocyclic radical, and instantiation includes but not limited to: The group forming etc. any commutable hydrogen atom of circulus replacement etc.

5-14 unit spiro heterocyclic radical refers to the volution knot being formed by 5-14 annular atoms (wherein at least containing a hetero atom)Structure. 5-14 unit spiro heterocyclic radical comprises the saturated spiro heterocyclic radical of 5-14 unit, 5-14 unit fractional saturation spiro heterocyclic radical.

The saturated spiro heterocyclic radical of 5-14 unit, refers to that all rings in this spiroheterocyclic are saturated cyclic group, instantiationInclude but are not limited to: The group forming etc. any commutable hydrogen atom of circulus replacement etc.

5-14 unit fractional saturation spiro heterocyclic radical, refers to that in this spiroheterocyclic, having a ring at least is undersaturated cyclic group,Instantiation includes but are not limited to:The group forming etc. any commutable hydrogen atom of circulus replacement etc.

Term 3-8 unit heterocyclic radical, 5-7 unit heterocyclic radical, 5-6 unit heterocyclic radical refer to annular atoms number in above-mentioned " 3-14 unit heterocyclic radical "For the instantiation of 3-8 unit, 5-8 unit, 5-7 unit, 5-6 unit.

In the present invention, term " 3-14 unit cyclic group " refers to the saturated or unsaturated carbon cyclic group of 3-14 unit or contains choosingFrom the heteroatomic saturated or unsaturated heterocycle group of N, O and S, comprise 3-6 unit cyclic group, 3-14 unit cycloalkyl, 6-14 unitAryl, 5-14 unit's aryl and 3-14 unit heterocyclic radical, wherein:

" 3-6 unit cyclic group " includes, but not limited to for example following groups: cyclopropane, cyclobutane, pentamethylene, hexamethyleneAlkane, aziridine, azetidine, 1,2-diazetidine, pyrrolidines, imidazolidine, pyrazolidine, hydrogenated pyridine ketone, piperazinePyridine, piperazine, oxirane, thiirane, oxetanes, 1,2-dioxetane, Thietane, oxolane,Thiophane, 1,3-dioxolane, 1,3-dithiolane, oxinane, Isosorbide-5-Nitrae-dioxane, 1,3-dioxyHeterocycle hexane, 1,3-thioxane, oxazolidine, morpholine, diazete, 1,2-diazetine, pyrroles, 4,5-Pyrrolin, 2,5-pyrrolin, imidazoles, 4,5-glyoxalidine, pyrazoles, 4,5-pyrazoline, 1,2,3-triazoles, 1,2,4-tri-Azoles, pyridine, 2-pyridone, 4-pyridone, pyridazine, pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,2-dithia ring fourthAlkene, furans, 4,5-dihydrofuran, DHF, thiophene, 2,5-dihydro-thiophene, 4,5-dihydro-thiophene, 1,2-dithia ringAmylene, 1,3-dithiole, 2H-pyrans, 2H-pyran-2-one, 3,4-dihydro-2H-pyrans, 4H-pyrans, 4H-pyrans-4-ketone, Isosorbide-5-Nitrae-Dioxin, Isosorbide-5-Nitrae-dithia cyclohexadiene, Isosorbide-5-Nitrae-oxathiin, oxazole, 4,5-bis-Qing EvilAzoles, 2,3-dihydro-oxazole, isoxazole, 4,5-dihydro-isoxazole, 2,3-dihydro-isoxazole, 1,2,3-oxadiazole, 1,2,5-Evil bis-Azoles, thiazole, 4,5-thiazoline, 2,3-thiazoline, isothiazole, 1,2,3-thiadiazoles, 2H-1,2-oxazine, 4H-1,2-EvilPiperazine, 6H-1,2-oxazine, 2H-1,3-oxazine, 4H-1,3-oxazine, 5,6-dihydro-4H-1,3-oxazine, 6H-1,3-oxazine, 2H-1,4-oxazine, 4H-1,4-oxazine, 2H-1,3-thiazine, 4H-1,3-thiazine, 5,6-dihydro-4H-1,3-thiazine, 6H-1,3-thiazine,2H-1,4-thiazine, 4H-1,4-thiazine, phenyl ring, pyridine groups etc.

In general formula of the present invention (I) compound,Represent A ring and the common condensed-bicyclic in parallel forming of B ringSystem, and A encircles and two shared atoms of B ring are carbon atom, and this parallel connection condensed-bicyclic system includes, but not limited to, 2,3-dihydro-1H-indenyl, indoline base, naphthyl, 1,2,3,4-tetrahydrochysene-quinolyl, 1,2,3,4-tetrahydro-isoquinoline base, isoindoline base, indyl, isoindolyl, benzimidazolyl, benzeneAnd pyrazolyl, BTA base, 2,3-dihydro-benzothienyl, benzothienyl, benzothiazolyl, 2,3-dihydro-benzo furanMutter base, benzofuranyl, benzoxazolyl, 1,2,3,4-tetrahydrochysene-naphthyl, quinolyl, 1,2,3,4-tetrahydrochysene-quinoxalinyl, quinolineQuinoline base, quinazolyl, 3,4-dihydro-chinazoline base, 2H-benzopyranyl, 6,7-dihydro-5H-pentamethylene [b] pyridine radicals,3H-imidazoles [4,5-b] pyridine radicals, thiazole [4,5-b] pyridine radicals, 5,6,7,8-tetrahydrochysene-quinolyl, isoquinolyl etc., preferably 2,3-dihydro-1H-indenyl, indoline base, naphthyl, 1,2,3,4-tetrahydrochysene-quinolyl, 1,2,3,4-tetrahydro-isoquinoline base, iso-indolesQuinoline base etc.

" 1-3 " of the present invention specifically refers to 1,2 or 3.

Particularly preferred compound comprises:

Its pharmaceutically acceptable salt, its pro-drug, its solvate, deuterated thing or its stereoisomer.

In one embodiment, the invention provides the preparation method of the invention described above compound.

In one embodiment, the invention provides the pharmaceutical composition that contains the invention described above compound.

In one embodiment, the invention provides use the preparation of the invention described above compound treat and/or prevent byThe method of the disease that microorganism causes.

In one embodiment, the invention provides the invention described above compound treats and/or prevents by micro-in preparationApplication in the medicine of the disease that biology causes.

Above-claimed cpd of the present invention can adopt the method described in following flow process and/or those of ordinary skill in the artOther technology of knowing is synthesized, but is not limited only to following methods.

Reaction equation:

Reactions steps:

Step 1: by raw material 1 and raw material 2, inorganic base (as NaOH, the KOH etc.) aqueous solution and phase transfer catalyst are (as three secondBase benzyl ammonium chloride) be dissolved in organic solvent (as DMF, dioxane, THF), under nitrogen protection, add thermal response, after concentrating, addWater, with organic solvent extraction, dry, after concentrating, separate to obtain intermediate 1 through silicagel column.

Step 2: by intermediate 1, raw material 3, HATU and DIEA are dissolved in organic solvent (as DCM, THF), under room temperature, reactTo finishing. Or intermediate 1 is dissolved in methyl alcohol, under ice-water bath, add raw material 3, continue, after reaction 1-2h, to add reducing agent (as threeAcetoxyl group sodium borohydride), under room temperature, reaction, to finishing, adds water, with organic solvent extraction, dry, after concentrating, divides through silicagel columnFrom obtaining formula 1 compound.

Raw material 1, raw material 2 in above reaction equation transform and make through simple functional group by the raw material that is easy to get. Anti-aboveAnswer the R in equation¹、R²、R³, m, X, A or B be as defined above.

Compound of the present invention comprises any form for example free form, salt form, solvate forms and salt and moltenThe compound of agent compound form.

Root Ju on the other hand, the invention provides the compounds of this invention of salt and/or solvate forms.

Described salt preferably includes pharmaceutically acceptable salt, although for example in order to prepare, the object of separation, purifying also comprisesPharmaceutically unacceptable salt.

The salt of the compounds of this invention comprises alkali salt or acid-addition salts. Pharmaceutically acceptable alkali salt comprises that ammonium salt is such as three YueThe salt of base ammonium salt, alkali metal salt such as sodium and potassium, alkali salt be such as the salt of calcium and magnesium and the salt of organic base, comprise primary,The salt of the second month in a season, tertiary amine such as isopropylamine, diethylamine, monoethanolamine, three Yue amine, dicyclohexyl amine and N-methyl D-gucosamine, preferably sodiumSalt.

Acid-addition salts can be officinal salt or non-officinal salt. In the time being non-officinal salt, it can be used for separating and is pureChange the compounds of this invention or its intermediate, and then change into officinal salt or free alkali. Pharmaceutically acceptable acid addition salts comprises " medicineScientific Magazine " (J.Pharm.Sci), the salt of describing in 1977,66,1-19. Described acid is for example hydrogen fumaric acid (hydrogenFumaricacid), fumaric acid, tartaric acid, ethane-1,2-disulfonic acid, maleic acid, how 1,5-sulfonic acid, acetic acid, maleic acid, amberAmber acid, salicylic acid, azelaic acid, 2-[(2,6-dichlorophenyl) amino] phenylacetic acid, hydrochloric acid, deuterium chloric acid (deuterochloricAid); Preferably hydrochloric acid.

" pharmaceutically acceptable salt " of the compounds of this invention refers to the compounds of this invention and pharmaceutically acceptable, non-poisonProperty alkali or acid form base addition salts or acid-addition salts, comprise acylate, inorganic acid salt, organic alkali salt, inorganic base salts. OrganicHydrochlorate comprises formates, acetate, propionate, benzene sulfonate, benzoate, tosilate, 2,3-dyhydrobutanedioic acidSalt, camsilate, citrate, mesylate, esilate, propane sulfonic acid salt, fumarate, gluconate, glutamate,Isethionate, lactate, maleate, malate, mandelate, mucate, embonate, pantothenate, butanedioic acidSalt, tartrate etc., particularly preferably benzoate, benzene sulfonate, tosilate, mesylate, citrate, maleic acidSalt, fumarate, tartrate. Inorganic acid salt comprises hydrogen chlorate, hydrobromate, hydriodate, sulfate, phosphate, nitreHydrochlorate etc., particularly preferably hydrogen chlorate, hydrobromate, sulfate, phosphate. Organic alkali salt comprises amine salt, comprise with primary, secondary andThe salt that tertiary amine, cyclammonium and basic ion exchanger resin form, can be selected from the salt forming with following organic base: for example arginine, sweetDish alkali, caffeine, choline, N, N '-dibenzyl-ethylenediamin, diethylamine, 2-diethylaminoethanol, DMAE, ethanolAmine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, meglumine, Glucosamine, histidine, Hai Baming, isopropylamine, badPropylhomoserin, methylglucosamine, morpholine, piperazine, piperidines, procaine, purine, theobromine, triethylamine, trimethylamine, tripropyl amine (TPA) and ammoniaButantriol etc. Inorganic base salts comprises the salt forming with ammonia, alkali metal, alkaline-earth metal, for example 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, particularly preferably ammonium salt and sodium salt,Sylvite, calcium salt, magnesium salts.

The respective compound that the compounds of this invention of free form can be changed into salt form, vice versa. Can be by freeThe compounds of this invention of form or salt form and/or solvate forms changes into free form or the salt of non-solvent compound formThe respective compound of form; Vice versa.

Term " solvate " comprises compound of the present invention and stoichiometry in order to describe in this article(stoichiometricamount) molecular complex of one or more acceptable solvent molecules, described solvent has, for exampleEthanol. In the time that described solvent is water, use term " hydrate ".

Structure as herein described also comprises the compound of the atom that has one or more isotope enrichments. Come for exampleSay, there is structure of the present invention but comprise hydrogen through the displacement of deuterium or tritium or carbon through enrichment¹³C or¹⁴The compound of the carbon displacement of C is at thisIn scope of invention.

The prodrug of the compound the present invention relates to, if the purposes of ester is also a part of the present invention. The implication of " prodrug " isCan pass through in vivo the compound that metabolic way (for example,, by hydrolysis, reduction or oxidation) is converted into formula (I) compound. For exampleThe ester prodrugs of formula (I) compound can be converted into parent molecule in vivo by hydrolysis. The example of ester prodrugs hasF.J.Leinweber, DrugMetab.Res., those that record in 1987,18,379. As used herein, mention formula (I)The implication of compound also comprises prodrug forms.

The compounds of this invention can be with isomers and composition thereof for example optical isomer, diastereoisomer, cis/trans structureThe form that resembles isomers exists. Compound of the present invention can for example contain asymmetric carbon atom, and therefore can be with enantiomer(enatiomer) or the form of for example racemic modification of diastereoisomer and composition thereof or non-enantiomer mixture exist. AppointWhat asymmetric carbon atom can with (R)-, (S)-or (R, S)-configuration, preferably with (R)-or (S)-configuration exist.

The compounds of this invention contains one or more asymmetric centers, thereby can be used as racemic modification and racemic mixingThing, single enantiomter, non-enantiomer mixture and single diastereoisomer. The compounds of this invention have asymmetric inThe heart, this class asymmetric center respectively will produce two optical isomers independently, and scope of the present invention comprises all possible lightLearn isomers and non-enantiomer mixture and pure or partial-purified compound. The present invention includes all of these compoundsStereoisomeric forms in any ratio.

If compound of the present invention contains olefinic double bonds, unless stated otherwise, the present invention includes cis-isomer andTransisomer.

Compound of the present invention can exist with tautomeric forms, and it is by one or more double-bond shiftsThere is the tie point of different hydrogen. Each dynamic isomer and composition thereof is all included in compound of the present invention.

The substituent configuration being connected with Tiamulin-tri-ring (tricyclus) asymmetric carbon atom preferably with natural sectionThe configuration of short pleurin is identical.

Isomer mixture can for example separate according to being for example similar to conventional method as required, pure to obtainIsomers. The present invention includes the compounds of this invention of any isomeric forms and any isomer mixture thereof. The present invention also wrapsDraw together the dynamic isomer of the compounds of this invention, as long as dynamic isomer can exist.

The compounds of this invention shows pharmacologically active, therefore can be used as medicine.

For example, the compounds of this invention shows antimicrobial acivity, routine antibacterial activity described as follows: resisting gram-positiveBacterium, for example coagulase-positive staphylococci (Staphylococci) is as staphylococcus aureus (StaphylococcusAureus), CN-S is as MRSE (Staphylococcusepidermidis), hemolytic PortugalGrape coccus (Staphylococcushaemolyticus), and streptococcus (Streptococci) is as streptococcus pyogenes(Streptococcuspyogenes), Streptococcusagalactiae (Streptococcusagalactiae), streptococcus pneumonia(Streptococcuspneumoniae), enterococcus (Enterococci) is as enterococcus faecalis (Enterococcus, and listeria monocytogenes (Listeriamonocytogenes) faecalis); With anti-Gram-negative bacteriaHave a liking for as influenza as Moraxella catarrhalis (Moraxellacatarrhalis), Haemophilus spp such as Moraxella (Moraxella)Blood bacterium (Haemophilusinfluenzae), Legionnella are as having a liking for lung and Legionella (LegionellaPneumophila), Neisseriaceae is as Neisseria gonorrhoeae (Neisseriagonorrhoeae); And mycoplasma(Mycoplasms), Chlamydia (Chlamydia), and obligate anaerobe is as bacteroides fragilis (BacteroidesFragilis), clostridium difficile (Clostridiumdifficile), fusobacterium (Fusobacteriumspp.) and propionic acid barPseudomonas (Propionibacteriumspp.).

Therefore the compounds of this invention is applicable to treatment and for example disease of thin mattress mediation of pre-preventing microorganism. Treatable diseaseAlso comprise for example Helicobacterium (Helicobacter) as the disease of helicobacter pylori (Helicobacterpylori) mediation andThe disease of Much's bacillus (Mycobacteriumtuberculosis) mediation. Treatable disease also comprises general inflammationProperty disease, wherein said inflammation for example comprises that acne are by microbe-mediated.

On the other hand, the invention provides as medicine, be preferably used as antimicrobial such as antibiotic and for example anti-anti-oxygenThe compounds of this invention of medicine.

On the other hand, the invention provides the compounds of this invention for acne treatment.

Another aspect, the invention provides for the preparation of the chemical combination of the present invention for the treatment of the perverse medicine of disease and treatment powderThing, described disease by microorganism such as bacteria mediated, for example:

The disease being mediated by thin mattress, described bacterium is for example selected from staphylococcus, streptococcus, enterococcus;

The disease being mediated by thin mattress, described bacterium is for example selected from Moraxella, Haemophilus spp, Legionnella, neisser's coccusSection;

The disease being mediated by Helicobacterium;

By the disease of tuberculosis branch bar mattress mediation; For example, by mycoplasma, the disease of Chlamydia and the mediation of obligate anaerobic mattress.

Again on the one hand, the invention provides the method for the treatment of by the disease of microbe-mediated, it comprises to needs are this controlsThe experimenter who treats use effective dose for example with the compounds of this invention of pharmaceutical compositions.

Again on the one hand, the invention provides be used for the treatment of powder perverse method, it comprises tested to this treatment of needsPerson use effective dose for example with the compounds of this invention of pharmaceutical compositions.

Treatment comprises treatment and prevention.

For antimicrobial and acne treatment, suitable dosage will rely on for example change of the compounds of this invention used certainlyThe character of the illness of learning character and pharmacokinetic data available, host's individuality, administering mode and treat and the order of severity and change.But generally, in order for example to obtain satisfied result in people most mammals, the daily dose of recommendation is for approximatelyThe compounds of this invention of 0.5mg-3g, for example uses to be up to four broken doses every day aptly.

Compound of the present invention can be for example with dressing or the shape of tablet, glue Nang, Injectable solution or the suspension of dressing notFormula, for example, with the form of ampoule, phial, with emulsion, gel, paste, inhalation of dust, foaming agent, tincture, lipstick agent, drops,The form of spray, or with the form of suppository, for example be similar to macrolide for example erythromycin series as CLA and ArchieThe form of mycin, by the administration of any routine, for example intestinal canal administration, for example, comprise nose, cheek, rectum, oral administration; StomachIntestines external administration, for example, comprise in intravenous, muscle, subcutaneous administration; Or topical, for example comprise in epidermis administration, nose toAdministration in medicine, tracheae.

Compound of the present invention can be with following form administration: for example, with the form of pharmaceutically-acceptable salts, acid-addition saltsOr base addition salts is as the form administration of slaine; Or with free form administration; Optionally with the form administration of solvate. Salt shapeThe compounds of this invention of formula shows with the same degree of the compounds of this invention of free form, optional solvate formsActive.

According to the present invention, compound of the present invention can be separately or with the combined use of one or more other medicines activating agentsTreat in medicine. Described other medicines activating agent comprises for example other antibiotic and antiinflammatory, and if the compounds of this inventionBe used for the treatment of acne, other medicinal agent comprises effectively other medicine of acne.

Described combination comprises fixed combination, and wherein two or more pharmaceutically active agents are in same preparation; Medicine box, whereinTwo or more active constituents of medicine are sold in the preparation separating and in same packaging, for example, and with saying of co-administeredBright; And independent assortment, wherein, pharmaceutically active agents is packaging separately, but has provided the explanation for while or sequential administration.

On the other hand, the invention provides pharmaceutical composition, it comprises free form or pharmaceutically acceptable salt formAnd/or the compounds of this invention of solvate forms; And at least one pharmaceutical excipient, for example carrier or diluent, for exampleComprise filler, adhesive, disintegrant, flowing regulator, lubricant, sugar and sweetener, aromatic, anticorrisive agent, stabilizing agent, profitHumectant and/or emulsifying agent, solubilizer, for regulating salt and/or the Huan Red agent of osmotic pressure.

On the other hand, the invention provides according to pharmaceutical composition of the present invention, it also comprises another kind of pharmaceutically active agents.

Described pharmaceutical composition can be according to being for example similar to conventional method for example by mixing, granulation, dressing, moltenSolution or freezing dry process are produced. Unit dosage forms can contain for example extremely about 2000mg of about 0.5mg, such as extremely about 500mg of 10mgActive component.

Compound of the present invention is also suitable to veterinary drug, and for example reactive compound for animals is for example moving for prevention and treatmentMicroorganism in thing for example poultry, pig and ox is thin mattress disease for example; For example soak technology for artificial insemination and ovumDiluent liquid.

On the other hand, the invention provides the compounds of this invention as veterinary drug.

Another aspect, the invention provides the compounds of this invention for the preparation of the veterinary composition as veterinary drug.

On the other hand, the invention provides animal doctor's method of prevention and for example bacteriosis for the treatment of microorganism, it comprisesGive need the experimenter of this treatment use effective dose for example with the compounds of this invention of animal medicinal composition form.

The present invention also provides the method for the treatment of infected by microbes in animal, especially people and the mammal raised and train,Comprise the compounds of this invention or its officinal salt or derivative or solvate or the trouble of the present composition to needs treatmentPerson's administration.

The present invention also provides the compounds of this invention or its officinal salt or derivative or solvate for the preparation of controllingApplication in the medicine for the treatment of infected by microbes.

On the other hand, the present invention also provides general formula of the present invention (I) compound, its pharmaceutically acceptable salt, its precursor medicineThing, its solvate, deuterated thing or its stereoisomer treat and/or prevent the medicine of the disease being caused by microorganism in preparationIn application.

On the one hand, the present invention also provides the method that treats and/or prevents the disease being caused by microorganism, comprises this againBright general formula (I) compound or its pharmaceutically acceptable salt or their stereoisomer need the food in one's mouth of this treatment or preventionBreast animal, for example people.

The present invention also provide contain general formula of the present invention (I) compound, its pharmaceutically acceptable salt, its pro-drug,The pharmaceutical preparation of its solvate, deuterated thing or its stereoisomer, for example oral formulations, injection, inhalant, system for noseAgent, eye-drops preparations, transdermal formulation, rectally preparation, ointment or gel etc. On the other hand, of the present inventionPharmaceutical preparation is the spray formulation starting from nasal-cavity administration. Described spray is aqueous sprays.

The present invention also provides general formula of the present invention (I) compound, its pharmaceutically acceptable salt, its pro-drug, its solventCompound, deuterated thing or its stereoisomer are suitable for nasal-cavity administration to alleviate or to eliminate the intranasal infection of pathogenic organisms body in preparationMedicine in application.

The present invention also provides general formula of the present invention (I) compound, its pharmaceutically acceptable salt, its pro-drug, its solventCompound, deuterated thing or its stereoisomer are suitable for nasal-cavity administration acute thin with prevention recurrent tympanitis or recurrent in preparationApplication in the medicine of bacterium sinusitis.

The present invention also provides general formula of the present invention (I) compound, its pharmaceutically acceptable salt, its pro-drug, its solventCompound, deuterated thing or its stereoisomer answering in the medicine for the preparation for the treatment of Skin and soft tissue infection and acneWith.

Experiment showed, that the present invention contains and the pleuromulins Antibiotique composition that encircles has good antibacterial activity,Can be used for treating and/or preventing the disease being caused by microorganism.

Further set forth the compounds of this invention beneficial effect by antibacterial activity test below, but this should be interpreted as to thisInvention compound 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 MRSE (MRSE), pneumonia streptococcusBacterium, Streptococcus viridans etc.

Test sample: part of compounds of the present invention, its chemical name and preparation method are shown in the Preparation Example of each compound. ProfitHow azoles amine, commercially available.

Experimental technique: agar dilution, with reference to NationalCommitteeforClinicalLaboratoryStandards.2006.MethodsforDilutionAntimicrobialSusceptibilityTestsforBacteriaThatGrowAerobically，ApprovedStandard--SeventhEditionM7-A7Vol26, No.2,2006. MIC represents minimum inhibitory concentration.

Experimental result and conclusion:

The antibacterial activity of table 1 part of compounds of the present invention

The antibacterial activity of table 2 part of compounds of the present invention

The antibacterial activity of table 3 part of compounds of the present invention

The antibacterial activity of table 4 part of compounds of the present invention

The antibacterial activity of table 5 part of compounds of the present invention

The antibacterial activity of table 6 part of compounds of the present invention

The antibacterial activity of table 7 part of compounds of the present invention

The antibacterial activity of table 8 part of compounds of the present invention to MRSA

From above experimental result, the compounds of this invention has anti-preferably to Grain-positive bacteria strain and severe bacteria strainBacterium activity, the compounds of this invention has good clinical practice potentiality.

4, detailed description of the invention

The detailed description of the invention of form by the following examples, does further to say in detail to foregoing of the present inventionBright. But this should be interpreted as to the scope of the above-mentioned theme of the present invention only limits to following examples. All based on foregoing of the present inventionThe technology realizing all belongs to scope of the present invention.

Common name " Tiamulin " refers to IUPAC systematic naming method (1S, 2R, 3S, 4S, 6R, 7R, 8R, 14R)-3,6-bis-Hydroxyl-2,4,7,14-tetramethyl-4-vinyl-tri-encircle [5.4.3.0^1,8] tetradecane-9-ketone. In an embodiment, adopt similarIn H.Berner (Berner, H.; Schulz, G.; SchneiderH.Tetrahedron1982,36,1807-1811.) described inTiamulin numbering system pleuromutilin derivative is numbered.

The preparation of embodiment 14-O-(p-toluenesulfonyl acetyl group) Tiamulin (intermediate M1)

Tiamulin (SM1,37.8g, 0.1mol) is dissolved in carrene 60ml, under nitrogen protection, adds triethylamine(15.15g, 0.15mol). Stir 30 minutes, be cooled to-15 DEG C, the carrene that drips TosCl (13.75g, 0.12mol) is moltenIn liquid. Mixture stirs 2 hours, slowly adds water 1.15L. Separate organic phase, dry, be spin-dried for product intermediate M1 (44g,96%)。

With reference to above-mentioned preparation method, can also prepare following compound:

Embodiment 114-O-((2-methyl octahydro cyclopenta [c] pyrroles-5-yl) methyl mercapto) Tiamulin (is changed Compound 1) preparation

(1) system of 5-((methyl sulphonyl oxygen base) methyl) six hydrogen cyclopenta [c] pyrroles-2 (1H)-carboxylic acid tert-butyl estersStandby

The tert-butyl group-5-(hydroxymethyl) six hydrogen cyclopenta [c] pyrroles-2 (1H)-carboxylic acid tert-butyl esters (SM2,3.75g,15.56mmol) and triethylamine (2.36g, 23.34mmol) add in 100mL carrene, be cooled to 0 DEG C, drip sulfonyloxy methylChlorine (3.56g, 31.12mol), vigorous stirring 2h, adds water to stir 15 minutes, separates organic phase, dry, is spin-dried for to obtain product 5-((methyl sulphonyl oxygen base) methyl) six hydrogen cyclopenta [c] pyrroles-2 (1H)-carboxylic acid tert-butyl esters (4.53g, 81.1%).

(2) preparation of 5-(acetyl mercapto methyl) six hydrogen cyclopenta [c] pyrroles-2 (1H)-carboxylic acid tert-butyl esters

By 5-((methyl sulphonyl oxygen base) methyl) six hydrogen cyclopenta [c] pyrroles-2 (1H)-carboxylic acid tert-butyl esters(3.2g, 0.1mol) joins in 50mL acetonitrile, is warming up to 50 DEG C, adds thioacetic acid potassium (2.56g) to be warming up to backflow, stirs2 hours. compound of reaction adds ethyl acetate and water and mixed liquor, removes water, and organic phase was dried post purifying and obtains 5-(acetylMercapto methyl) six hydrogen cyclopenta [c] pyrroles-2 (1H)-carboxylic acid tert-butyl esters (2.1g, 70.1%)..

(3) preparation of S-(2-methyl octahydro cyclopenta [c] pyrroles-5-yl) methyl acetyl thioester

By 5-(acetyl mercapto methyl) six hydrogen cyclopenta [c] pyrroles-2 (1H)-carboxylic acid tert-butyl esters (2.09g, 7mmol)Be dissolved in formic acid (20ml), add formaldehyde (10ml), solution is warming up to 100 DEG C and stirs 3 hours. Be cooled to room temperature, regulate PH extremely7, the compound of water and ethyl acetate is washed, and separates organic phase, is dried to obtain product S-(2-methyl octahydro cyclopenta[c] pyrroles-5-yl) methyl acetyl thioester (0.76g, 51.0%).

(4) preparation of (2-methyl octahydro cyclopenta [c] pyrroles-5-yl) methyl mercapto

S-(2-methyl octahydro cyclopenta [c] pyrroles-5-yl) methyl acetyl thioester (0.64g, 3mmol) is dissolved in to firstIn alcohol (34mL), add sodium methoxide (0.32g, 6mmol), stir 4 hours, add salt acid for adjusting pH to 2.6-3 tert-butyl group firstEther extraction, is dried to obtain (2-methyl octahydro cyclopenta [c] pyrroles-5-yl) methyl mercapto (0.49g, 95.5%).

(5) preparation of 14-O-((2-methyl octahydro cyclopenta [c] pyrroles-5-yl) methyl mercapto) Tiamulin

M1 (4.56g, 10mmol) is dissolved in 100mL oxolane, adds 1NNaOH (10mL) and benzyl tributyl chlorineChange ammonium (1.2g), mixture control temperature, at 15 DEG C, adds (2-methyl octahydro cyclopenta [c] pyrroles-5-yl) methyl mercaptoBase (0.34g, 2mmol), stirring at room temperature 20 hours, adds the mixture of water and ethyl acetate, separates organic phase, be driedProduct compound 1 (79mg, 7.5%).

Molecular formula: C₃₁H₄₉NO₄S molecular weight: 531.3 mass spectrums (m/e): 532 (M+H)⁺

¹H-NMR(400MHz,CDCl₃)δ_ppm:6.45(m,1H),5.72(m,1H),5.32(m,1H),5.19(m,1H),3.35(m,1H),3.11(s,2H),3.01(m,1H),2.68(m,7H),2.43(m,6H),2.34(m,2H),2.21(m,8H),1.97(m,1H),1.76(m,1H),1.46(m,5H),1.30(m,15H),0.81(m,4H),0.72(m,3H).

Embodiment 214-O-((2R)-2-amino-2-cyclopropyl-acetyl group-(six hydrogen pentamethylene are [c] pyrroles-5-yl also) Sulfo-) preparation of Tiamulin (compound 2)

(1) preparation of 14-O-((N-Boc-six hydrogen pentamethylene are [c] pyrroles-5-yl also) sulfo-) Tiamulin

By 22-O-mesyl Tiamulin (10g, 22mmol), also [c] pyrroles of N-Boc-5-sulfydryl six hydrogen pentamethylene(5.3g, 22mmol), the 22mL1NNaOH aqueous solution and triethyl benzyl ammonia chloride (1g, 4.4mmol) are dissolved in 200mL dioxy sixIn ring, under nitrogen protection, 90 degree reactions are spent the night, and after concentrating, add water, and are extracted with ethyl acetate, dry, after concentrating, separate through silicagel column(benzinum: ethyl acetate=10:1) obtains product 6.6g, productive rate 50%.

(2) preparation of 14-O-((six hydrogen pentamethylene are [c] pyrroles-5-yl also) sulfo-) Tiamulin trifluoroacetate

By 14-O-((N-Boc-six hydrogen pentamethylene are [c] pyrroles-5-yl also) sulfo-) Tiamulin (6.6g, 10.9mmol)Be dissolved in 300mLDCM, add 10mL trifluoroacetic acid, react the concentrated grease that to obtain after 1h under room temperature, this product is without purifying directlyFor next step reaction.

(3) 14-O-((2R)-N-Boc-2-amino-2-cyclopropyl-acetyl group-(six hydrogen pentamethylene are [c] pyrroles-5-yl also)Sulfo-) preparation of Tiamulin

By previous step product (300mg, 0.60mmol), (R)-N-Boc-cyclopropyl glycine (500mg, 2.3mmol),HATU (400mg, 1.1mmol) and 0.5mLDIEA are dissolved in 20mLTHF, under room temperature, react 1h, add water, and extract with ethyl acetateGet, anhydrous sodium sulfate drying, concentrates to obtain yellow oil, and this product is directly used in next step reaction without purification.

(4) 14-O-((2R)-2-amino-2-cyclopropyl-acetyl group-(six hydrogen pentamethylene are [c] pyrroles-2-yl also) sulfo-)The preparation of Tiamulin

Previous step product is dissolved in 20mL carrene, adds 5mL trifluoroacetic acid, under room temperature, react 2h, solvent is steamedDry, add water, adjust PH=8 with sodium acid carbonate, dichloromethane extraction, dry, concentrated after through silicagel column separate (carrene: methyl alcohol=50:1) obtain product 100mg, two step productive rates 28%.

Molecular formula: C₃₄H₅₂N₂O₅S molecular weight: 600.3 mass spectrums (m/e): 601.4 (M+H)

¹H-NMR(400MHz,CDCl₃)δ_ppm:6.55(m,1H),5.75(t,1H),5.33(d,1H),5.22(d,1H),5.18(d,1H),3.75(m,2H),3.45(m,7H),2.90(m,2H),2.34(m,3H),2.24(m,3H),1.89(m,4H),1.55(m,8H),1.26(m,1H),2.34(s,1H),1.24(t,6H),0.9(d,3H),0.74(d,3H),0.51(m,2H),0.3(m,1H),0.2(m,1H).

Embodiment 314-O-((2R)-2-amino-3-methyl-bytyry-(six hydrogen pentamethylene are [c] pyrroles-5-yl also) sulphur Generation) preparation of Tiamulin (compound 3)

Molecular formula: C₃₄H₅₄N₂O₅S molecular weight: 602.4 mass spectrums (m/e): 603 (M+1)

¹H-NMR(400MHz,MeOD)δ_ppm:6.35(m,1H),5.74(m,1H),5.16(m,2H),3.55-3.88(m,2H),3.50(m,4H),3.22(m,2H),2.92(m,2H),2.33(m,2H),2.16(m,2H),1.95(m,4H),1.64(m,3H),1.45(s,3H),1.33(m,6H),1.16(m,5H).1.04(m,6H),0.93(m,3H),0.74(m,3H).

Embodiment 414-O-((2R)-2-amino-3-hydroxyl-propiono-(six hydrogen pentamethylene are [c] pyrroles-5-yl also) sulphur Generation) preparation of Tiamulin (compound 4)

Molecular formula: C₃₂H₅₀N₂O₆S molecular weight: 590.8 mass spectrums (m/e): 591.4 (M+1)

¹H-NMR(400MHz,CDCl₃)δ_ppm:6.48(m,1H),5.76(m,1H),5.35(m,1H),5.18(d,1H),3.33(m,2H),3.33(m,4H),3.15(d,2H),2.96(s,1H),2.85(s,1H),2.21(m,6H),1.90(m,5H),1.78(d,1H),1.66(m,3H),1.55(d,1H),1.28(m,14H),0.88(t,3H),0.72(d,3H).

Embodiment 514-O-((2R)-prolyl-(six hydrogen pentamethylene are [c] pyrroles-5-yl also) sulfo-) Tiamulin The preparation of (compound 5)

Molecular formula: C₃₄H₅₂N₂O₅S molecular weight: 600.8 mass spectrums (m/e): 601.4 (M+1)

¹H-NMR(400MHz,CDCl₃)δ_ppm:6.47(m,1H),5.73(m,1H),5.34(m,1H),5.18(d,1H),4.03(s,1H),3.75(t,1H)3.59(m,1H),3.37(m,3H),3.24(d,2H),3.15(d,2H),3.06(s,1H),2.78(d,7H),2.34(s,1H),2.22(t,3H),2.08(t,2H),1.79(m,3H),1.40(m,5H),1.14(d,10H),0.88(d,3H),0.71(d,3H).

((2R)-2-amino-3,3-dimethyl-bytyry-(six hydrogen pentamethylene are [c] pyrroles-5-also for embodiment 614-O- Base) sulfo-) preparation of Tiamulin (compound 6)

Molecular formula: C₃₅H₅₆N₂O₅S molecular weight: 616.4 mass spectrums (m/e): 617.4 (M+1)

¹H-NMR(400MHz,CDCl₃)δ_ppm:6.47(m,1H),5.74(m,1H),5.34(m,1H),5.17(d,1H),3.79(m,1H),3.65(m,1H),3.39(m,3H),3.24(m,2H),3.14(s,2H),2.82(m,2H),2.34(m,1H),2.21(m,2H),2.05(m,3H),1.88(m,4H),1.66(m,6H),1.41(m,3H),1.26(m,3H),1.14(m,4H),0.98(t,9H),0.89(t,3H),0.68(d,3H).

(acetyl group-(six hydrogen pentamethylene are [c] pyrroles-5-also for (2R)-2-amino-2-(4-fluorophenyl) for embodiment 714-O- Base) sulfo-) preparation of Tiamulin (compound 7)

Molecular formula: C₃₇H₅₁FN₂O₅S molecular weight: 654.8 mass spectrums (m/e): 655.4 (M+1)

¹HNMR(400MHz,CDCl₃)δ_ppm:7.32(t,2H),7.03(m,2H),6.46(m,1H),5.71(m,1H),5.34(m,1H),5.18(d,1H),4.51(s,1H),3.05(s,1H),2.82(m,2H),2.20(m,6H),1.52-1.80(m,14H),1.11-1.52(m13H)0.88(t3H)0.73(m3H).

Embodiment 814-O-((2R, 4S)-4-hydroxyl prolyl-(six hydrogen pentamethylene are [c] pyrroles-5-yl also) sulfo-) The preparation of Tiamulin (compound 8)

Molecular formula: C₃₄H₅₂N₂O₅S molecular weight: 469.2 mass spectrums (m/e): 470.2 (M+1)

¹H-NMR(400MHz,CDCl₃)δ_ppm:6.46(t,1H),5.75(d,1H),5.33(d,1H),5.22(d,1H),5.18(d,1H),4.03(s,1H),3.75(t,1H)，3.59(m,1H),3.37(m,3H),3.24(d,2H),3.15(d,2H),3.06(s,1H),2.78(d,7H),2.34(s,1H),2.22(t,3H),2.08(t,2H),1.79(m,3H),1.40(m,5H),1.14(m,9H),0.88(d,3H),0.71(d,3H).

The preparation of embodiment 914-O-(six hydrogen pentamethylene are [c] pyrroles-5-yl also) sulfo-Tiamulin (compound 9)

Molecular formula: C₂₉H₄₅NO₄S molecular weight: 503.3 mass spectrums (m/e): 504 (M+1)

¹H-NMR(400MHz,MeOD)δ_ppm:6.33(m,1H),5.75(m,1H),5.15-5.19(m,2H),3.31-3.51(m,4H),3.04(s,2H),2.93-2.97(m,2H),2.31-2.38(m,3H),2.13-2.19(m,2H),1.89(m,1H),1.62(m,3H),1.30-1.45(m,10H),1.16(s,3H),0.92(m,6H),0.74(m,3H).

Embodiment 1014-O-((2R)-2,3-bis-amido propionos-(six hydrogen pentamethylene are [c] pyrroles-5-yl also) sulfo-) The preparation of Tiamulin (compound 10)

Molecular formula: C₃₂H₅₁N₃O₅S molecular weight: 589.3 mass spectrums (m/e): 590.4 (M+1)

¹H-NMR(400MHz,CDCl₃)δ_ppm:6.45(m,1H),5.75(m,1H),5.32(m,1H),5.18(d,1H),3.60-3.87(m,3H),3.16-3.43(m,7H)2.80-2.95(m,4H),2.11-2.34(m,7H),1.87(m,4H),1.50-1.80(m,5H),1.45(m,5H),1.13-1.40(m,6H),0.88(d,3H),0.71(d,3H).

Embodiment 1114-O-(5,6-dihydro-4H-pyrroles [3,4-d] oxazole) methyl mercapto) Tiamulin (compound 11) preparation

Molecular formula: C₂₈H₄₀N₂O₅S molecular weight: 516.3 mass spectrums (m/e): 517.6 (M+1)

¹H-NMR(400MHz,CDCl₃)δ_ppm:6.48(m,1H),5.77(d,1H),5.34(d,1H),5.20(d,1H),4.03(s,1H),3.91(m,3H),3.36(d,1H),3.30(s,2H),2.10-2.36(m,4H),1.88(m,4H),1.80(d,4H),1.75(m,3H),1.48(m,3H),1.37(m,2H),1.34(m,2H),1.25(s,3H),1.13(m,1H),0.88(d,3H),0.75(d,3H).

Embodiment 1214-O-(5,6-dihydro-4H-pyrroles [3,4-d] thiazole) methyl mercapto) Tiamulin (compound 12) preparation

Molecular formula: C₂₈H₄₀N₂O₄S₂Molecular weight: 532.2 mass spectrums (m/e): 533.4 (M+1)

¹H-NMR(400MHz,CDCl₃)δ_ppm:6.45-6.53(m,1H),5.78(d,1H),5.35-5.38(m,1H),5.22(d,1H),4.27(s,1H),4.09-4.18(m,4H),3.44-3.52(m,1H),3.37(d,1H),3.24(s,1H),1.96-2.39(m,8H),1.46(s,2H),1.31-1.41(m,2H),1.11-1.28(m,10H),0.89(d,3H),0.74(d,3H).

Embodiment 1414-O-((2R)-2-amido-3-methylbutyryl base-(six hydrogen pentamethylene are [c] pyrroles-4-yl also) first Sulfo-) preparation of Tiamulin (compound 14)

(1) preparation of 14-O-((N-Boc-six hydrogen pentamethylene are [c] pyrroles-4-yl also) first sulfo-) Tiamulin

Operation is with embodiment 2(1), productive rate 48.8%.

(2) preparation of 14-O-((six hydrogen pentamethylene are [c] pyrroles-4-yl also) first sulfo-) Tiamulin trifluoroacetate

Operation is with embodiment 2(2), this product is directly used in next step reaction without purification.

(3) 14-O-((2R)-N-Boc-2-amido-3-methylbutyryl base-(six hydrogen pentamethylene are [c] pyrroles-4-yl also) firstSulfo-) preparation of Tiamulin

Operation is with embodiment 2(3), this product is directly used in next step reaction without purification.

(4) 14-O-((2R)-2-amido-3-methylbutyryl base-(six hydrogen pentamethylene are [c] pyrroles-4-yl also) first sulfo-) ThailandThe preparation of wonderful rhzomorph

Operation is with embodiment 2(4), productive rate 37.8%.

Molecular formula: C₃₅H₅₆N₂O₅S molecular weight: 616.4 mass spectrums (m/e): 617.5 (M+1)

¹H-NMR(400MHz,CDCl₃,δ_ppm)δ:6.51(m,1H),5.74(d,1H),5.34(m,1H),5.20(d,1H),3.31-3.74(m,6H),3.11-3.12(m,2H),2.60-2.71(m,3H),2.04-2.43(m,10H),1.11-1.79(m,19H),0.91-1.03(m,6H),0.83(d,3H),0.74(d,3H).

(acetyl group-(six hydrogen pentamethylene are [c] pyrroles-5-also for (2R)-2-amino-2-(4-chlorphenyl) for embodiment 1514-O- Base) sulfo-) preparation of Tiamulin (compound 15)

Molecular formula: C₃₇H₅₁ClN₂O₅S molecular weight: 670.3 mass spectrums (m/e): 670.7 (M+).

¹H-NMR(400MHz,CDCl₃)δ_ppm:0.65-0.75(m,3H),0.80-0.90(d,3H),1.08-1.20(d,4H),1.20-1.30(m,2H),1.30-1.50(m,6H),1.50-1.60(m,1H),1.60-1.70(m,2H),1.70-1.80(m,2H),1.80-1.90(m,2H),1.90-2.10(m,5H),2.20-2.30(m,2H),2.30-2.40(m,1H),2.70-2.80(m,2H),3.00-3.30(m,4H),3.30-3.50(m,2H),3.55-3.70(m,1H),4.50(d,1H),5.10-5.35(m,2H),5.72(m,1H),6.40-6.50(m,1H),7.22-7.35(m,4H).

Embodiment 1614-O-((2R)-2-amino-2-(4-hydroxy phenyl) acetyl group-(also [c] pyrroles of six hydrogen pentamethylene- 5-yl) sulfo-) preparation of Tiamulin (compound 16)

Molecular formula: C₃₇H₅₂N₂O₆S molecular weight: 652.3 mass spectrums (m/e): 652.7 (M+).

¹H-NMR(400MHz,CDCl₃)δ_ppm:0.65-0.75(m,3H),0.85-0.95(d,3H),1.08-1.20(d,4H),1.20-1.32(m,5H),1.32-1.50(m,6H),1.50-1.90(m,7H),1.90-2.08(m,1H),2.08-2.15(m,1H),2.15-2.40(m,3H),2.70-2.85(m,2H),3.00-3.35(m,4H),3.35-3.45(m,2H),3.55-3.75(m,2H),4.50(s,1H),5.15-5.35(m,2H),5.70-5.80(m,1H),6.45-6.80(m,1H),6.65-6.70(m,2H),7.05-7.15(m,2H).

(acetyl group-(six hydrogen pentamethylene are [c] pyrroles-5-also for (2R)-2-amino-2-(2-chlorphenyl) for embodiment 1714-O- Base) sulfo-) safe wonderful bacteriumElementThe preparation of (compound 17)

Molecular formula: C₃₇H₅₁ClN₂O₅S molecular weight: 670.3 mass spectrums (m/e): 670.7 (M+)

¹H-NMR(400MHz,CDCl₃)δ_ppm:0.65-0.75(m,3H),0.80-0.90(d,3H),1.08-1.20(d,4H),1.20-1.40(m,4H),1.40-1.45(m,2H),1.45-1.50(m,2H),1.50-1.57(m,1H),1.57-1.70(m,3H),1.70-1.80(m,2H),1.80-2.00(m,5H),2.00-2.15(m,2H),2.15-2.25(m,2H),2.25-2.38(m,1H),2.65-2.85(m,2H),3.00-3.10(m,2H),3.10-3.15(m,1H),3.15-3.38(m,2H),3.38-3.50(m,1H),3.50-3.68(m,1H),5.00-5.08(d,1H),5.12-5.25(m,1H),5.25-5.35(m,1H),5.70-5.77(m,1H),7.20-7.28(m,2H),7.28-7.36(m,1H),7.36-7.43(m,1H).

Embodiment 1814-O-(2-amino-2-(2-thiophene) acetyl group-(six hydrogen pentamethylene are [c] pyrroles-5-yl also) sulphur Generation) preparation of Tiamulin (compound 18)

Molecular formula: C₃₅H₅₀N₂O₅S₂Molecular weight: 642.3 mass spectrums (m/e): 643.0 (M+1).

¹H-NMR(400MHz,CDCl₃)δ_ppm:0.65-0.75(m,3H),0.80-0.90(d,3H),1.08-1.20(d,4H),1.20-1.40(m,4H),1.40-1.50(m,4H),1.50-1.60(m,1H),1.60-1.70(m,2H),1.70-1.90(m,5H),1.90-2.12(m,4H),2.12-2.30(m,2H),2.30-2.40(m,1H),2.75-2.90(s,2H),3.05-3.15(m,2H),3.15-3.30(m,1H),3.30-3.50(m,3H),3.60-3.70(m,1H),4.80(m,1H),5.15-5.25(m,1H),5.25-5.35(m,1H),5.72(m,1H),6.40-6.50(m,1H),6.90-6.95(m,2H),7.22-7.30(m,1H).

The preparation of embodiment 1914-O-(3-anilinic piperidines-2-oxo-6-first sulfo-) Tiamulin (compound 19)

Operation is with embodiment 2(4), productive rate 35%.

Molecular formula: C₃₄H₅₀N₄O₅S₂Molecular weight: 658.3 mass spectrums (m/e): 658.9 (M+1)

¹H-NMR(400MHz,d₆-DMSO,δ_ppm)δ:6.86(d,2H),6.34(d,1H),6.09-6.18(m,1H),5.44-5.56(m,1H),5.01-5.08(m,2H),4.43-4.45(m,2H),3.36-3.68(m,4H),3.06-3.28(m,5H),2.68-2.81(m,3H),2.40(s,1H),1.98-2.22(m,4H),1.57-1.88(m,6H),1.16-1.48(m,9H),0.97-1.08(m,3H),0.81(d,3H),0.62(t,3H).

Embodiment 2014-O-((2S)-2-amino-2-(pyridin-3-yl) acetyl group-(also [c] pyrroles of six hydrogen pentamethylene- 5-yl) sulfo-) preparation of Tiamulin (compound 21)

Molecular formula: C₃₆H₅₁N₃O₅S₂Molecular weight: 637.3 mass spectrums (m/e): 638.0 (M+1)

¹H-NMR(400MHz,CDCl3,δ_ppm)δ:8.57(s,2H),7.77(s,1H),7.28-7.36(m,1H),6.35-6.54(m,1H),5.74(s,1H),5.13-5.39(m,3H),4.73(s,1H),3.54-3.88(m,2H),2.99-3.54(m,7H),2.63-2.98(m,3H),1.93-2.42(m,8H),1.50-1.92(m,10H),1.07-1.20(m,5H),0.88(d,3H),0.74(d,3H).

(acetyl group-(six hydrogen pentamethylene are [c] pyrroles-5-also for (2S)-2-amino-2-(4-fluorophenyl) for embodiment 2114-O- Base) sulfo-) preparation of Tiamulin (compound 21)

Molecular formula: C₃₇H₅₁FN₂O₅S molecular weight: 654.3 mass spectrums (m/e): 655.0 (M+1).

¹H-NMR(400MHz,CDCl₃)δ_ppm:0.65-0.75(m,3H),0.80-0.90(d,3H),1.08-1.20(d,4H),1.20-1.60(m,9H),1.60-1.70(m,3H),1.70-1.90(m,4H),1.90-2.12(m,5H),2.12-2.38(m,3H),2.70-2.85(m,2H),2.85-3.08(s,1H)3.08-3.45(m,4H),3.55-3.65(m,1H),4.50(s,1H),5.10-5.35(m,2H),5.65-5.75(m,1H),6.35-6.45(m,1H),6.90-7.10(m,2H),7.25-7.35(m,2H).

Claims

1. the compound shown in general formula (I) or its pharmaceutically acceptable salt:

Wherein, R¹For hydrogen, C_1-4Alkyl, or the group shown in following formula

R⁴And R⁵Be independently respectively:

(1) amino,

(2) be not substituted or by 1 R⁶The C replacing_1-4Alkyl,

(3) be not substituted or by 1 R⁶The 3-6 unit cycloalkyl, the undersaturated 5-6 single heterocyclic radical of unit or the phenyl ring that replace,

Or R⁴And R⁵The C atom being connected with them is combined together to form and is not substituted or by 1 R⁷Replace nafoxidine,Piperidines or piperazine,

R⁶、R⁷Respectively independently selected from halogen, hydroxyl, amino, C_1-4Alkyl;

Wherein A ring is selected from unsubstituted or by 1 R²The 5-6 that the contains N atom unit saturated mono heterocyclic radical replacing, wherein saidR²Independently selected from hydrogen;

It is unsubstituted or by 1 R that B ring is selected from³The single heterocyclic radical of the 5-6 unit's cycloalkyl replacing or saturated, undersaturated 5-6 unit, itsDescribed in R³Independently selected from hydrogen;

X is-S-;

M is 0 or 1;

N is 0 or 1.

2. compound as claimed in claim 1 or its pharmaceutically acceptable salt:

Wherein, R¹For hydrogen, C_1-4Alkyl, or the group shown in following formula

R⁴And R⁵Be independently respectively:

(1) amino,

(2) be not substituted or by 1 R⁶The C replacing_1-4Alkyl,

(3) be not substituted or by 1 R⁶Replace: pentamethylene, cyclohexane, pyrroles, imidazoles, pyrazoles, 1,2,3-triazole, thiophene,Thiazole, isothiazole, furans, oxazole, isoxazole, phenyl ring, pyrimidine, pyridine or pyrazine,

Or R⁴And R⁵The C atom being connected with them is combined together to form and is not substituted or by 1 R⁷Replace: nafoxidine,Piperidines, piperazine,

Wherein said R⁶And R⁷For hydrogen, fluorine, chlorine, methyl, hydroxyl, amino;

Wherein A ring is selected from nafoxidine or piperidines,

B ring is selected from pentamethylene, cyclohexane, nafoxidine, pyrroles, imidazoles, pyrazoles, 1,2,3-triazole, thiophene, thiazole, different thiopheneAzoles, oxolane, furans, oxazole, isoxazole, phenyl ring, pyrimidine, piperidines, pyridine, piperazine or pyrazine,

M is 0 or 1;

N is 0 or 1.

3. compound as claimed in claim 1 or its pharmaceutically acceptable salt:

R⁴And R⁵Be independently respectively:

(1) amino,

(2) be not substituted or by 1 R⁶Replace: methyl, ethyl, propyl group, isobutyl group,

(3) be not substituted or by 1 R⁶Replace: cyclopropane, pentamethylene, cyclohexane, pyrroles, thiazole, thiophene, imidazoles, different thiopheneAzoles, furans, oxazole, phenyl ring, pyridine,

Described R⁶And R⁷For fluorine, chlorine, amino, hydroxyl;

Wherein, A ring is selected from nafoxidine, piperidines,

B ring is selected from pentamethylene, cyclohexane, nafoxidine, pyrroles, imidazoles, pyrazoles, thiophene, thiazole, isothiazole, oxolane, furanNan, oxazole, isoxazole, piperidines, piperazine;

M is 0 or 1;

N is 0 or 1.

4. compound as claimed in claim 1 or its pharmaceutically acceptable salt, described compound is selected from:

5. contain compound described in claim 1-4 any one or its pharmaceutically acceptable salt and one or more medicinal yearThe pharmaceutical preparation of body and/or diluent is pharmaceutically acceptable arbitrary formulation.

6. pharmaceutical composition, contains compound or its pharmaceutically acceptable salt described in claim 1-4 any one, also comprisesOther medicines active component.

7. compound or its pharmaceutically acceptable salt as described in claim 1-4 any one treats and/or prevents in preparationApplication in the medicine of the disease being caused by microorganism.