CN103709115A - Pleuromutilin antibiotic derivatives - Google Patents

Pleuromutilin antibiotic derivatives Download PDF

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CN103709115A
CN103709115A CN201310452240.0A CN201310452240A CN103709115A CN 103709115 A CN103709115 A CN 103709115A CN 201310452240 A CN201310452240 A CN 201310452240A CN 103709115 A CN103709115 A CN 103709115A
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罗浩贤
王爱臣
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SHANDONG HENRY MEDICAL SCIENCE AND TECHNOLOGY Co Ltd
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SHANDONG HENRY MEDICAL SCIENCE AND TECHNOLOGY Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • 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
    • C07D413/06—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 carbon chain containing only aliphatic carbon atoms

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Abstract

The present invention relates to pleuromutilin antibiotic derivatives represented by a general formula (I), pharmaceutically acceptable salts, prodrugs, solvates or stereoisomers thereof, wherein R<2>, Q<1>, Q<2>, m and X are defined in an instruction. The present invention further relates to preparation methods of the compounds, drug compositions containing the compounds, drug preparations containing the compounds, and applications of the compounds in preparation of drugs for treatment and/or prevention of diseases caused by microorganisms.

Description

Pleuromutilin antibiotic derivatives
1. Field of the invention
The invention belongs to the technical field of medicines, and relates to pleuromutilin antibiotic derivatives, pharmaceutically acceptable salts, prodrugs, solvates, deuterons or stereoisomers thereof, preparation methods of the compounds, pharmaceutical compositions and pharmaceutical preparations containing the compounds, and application of the compounds in preparation of medicines for treating and/or preventing diseases caused by microorganisms.
2. Background of the invention
Pleuromutilin antibiotics (Pleurothelin antibiotics) are diterpene antibiotics, which are fused by five-membered ring, six-membered ring and eight-membered ring to form a 5-6-8 tricyclic diterpene structure, and are separated from two basidiomycetes (basidiomycetes species), Pleurotus mutilis (Pleurothelius) and P.paseckerianus in 1951.
Pleuromutilin antibiotics exert antibacterial activity by inhibiting bacterial protein synthesis, and based on the unique action mechanism, cross drug resistance is not found clinically at present, and excellent clinical application characteristics are shown. However, few studies to date have found that veterinary drug Tiamulin (Tiamulin) is used to treat swine dysentery, swine epidemic pneumonia and chronic respiratory disease in poultry, and Retapamulin (Retapamulin) is successfully applied as an ointment to human skin pustular dermatitis infection.
Figure BDA0000389361860000011
In addition, other pleuromutilin derivatives are still under investigation, as disclosed in patents EP1972618, WO0222580 for example as antibacterial agents.
Based on the current clinical needs, researches and developments of pleuromutilin antibiotic medicines which have good antibacterial activity and stable metabolism and are used for treating human skin soft tissue infection and pneumonia infection are urgently needed.
3. Summary of the invention
In order to meet clinical requirements, the invention provides pleuromutilin antibiotic medicaments which have good antibacterial activity and less metabolic elimination and are used for treating human skin soft tissue infection and pneumonia infection, and the specific technical scheme is as follows:
a compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof:
Figure BDA0000389361860000021
wherein Q is1、Q2independently-O-, -S-, -SO-、-SO2-、-NR1-；
R1Is hydrogen, C1-6Alkyl, halo C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, hydroxy C1-6Alkyl, carboxyl C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl radical, C1-6Alkoxycarbonyl group, C1-6Alkylsulfinyl radical, C1-6Alkylsulfonyl, sulfonic acid, sulfonyl C1-6Alkyl, sulfonamide C1-6Alkyl, aminosulfonyl, C1-6Alkylaminosulfonyl, di (C)1-6Alkyl) aminosulfonyl, aminosulfonyl C1-6Alkyl radical, C1-6Alkylaminocarbonyl, di (C)1-6Alkyl) carbamoyl, carbamoyl C1-6Alkyl, 3-14 membered cycloalkyl, 6-14 membered aryl C1-6Alkyl, 3-14 membered heterocyclic group C1-6An alkyl group, a carboxyl group,
or a group of the formula
Figure BDA0000389361860000022
R3And R4Independently are:
(1) hydrogen, amino, hydroxyl, mercapto, carboxyl, guanidino,
(2) unsubstituted or substituted by 1 to 3 identical or different R5Substituted: c1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkylamino radical, C1-6Alkylthio, carboxyl C1-6Alkyl, hydroxy C1-6Alkyl, carbamoyl C1-6An alkyl group, a carboxyl group,
(3) unsubstituted or substituted by 1 to 3 identical or different R5Substituted: a 3-14 membered cycloalkyl group, a 3-14 membered heterocyclyl group or a 6-14 membered aryl group,
or R3And R4Taken together with the C atom to which they are attached to form unsubstituted or 1-3 identical or different R6A substituted 3-14 membered cyclic group,
R5、R6independently selected from halogen, hydroxy, amino, carboxyl, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, hydroxy C1-6Alkyl, amino C1-6Alkyl, carboxyl C1-6Alkyl radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, aminosulfonyl C1-6Alkyl, carbamoyl C1-6Alkyl radical, C1-6Alkylcarbonyl group, C1-6Alkyl carbonyl oxy, C1-6Alkoxycarbonyl, phenyl, 3-14 membered cycloalkyl or 3-14 membered heterocyclyl;
R2represents 1-3 substituents selected from hydrogen, halogen, C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino, C1-6Alkylamino radical, di (C)1-6Alkyl) amino or C1-6An alkylaminocarbonyl group;
x is-O-, -S-, -SO2-、-COO-、-NR7R7’、-CONR7R7’-NHCONH-or a bond;
R7、R7’is hydrogen or C1-6An alkyl group;
m and n are each independently 0, 1,2,3 or 4.
A compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof, preferably:
wherein Q is1、Q2Independently is-O-, -NR1-；
R1Is hydrogen, C1-6Alkyl, or a group of the formula
R3And R4Are respectively and independently
(1) Hydrogen, amino, hydroxyl, mercapto, carboxyl, guanidino,
(2) unsubstituted or substituted by 1 to 3 identical or different R5Substituted: c1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkylamino radical, C1-6Alkylthio, carboxyl C1-6Alkyl, hydroxy C1-6Alkyl, carbamoyl C1-6An alkyl group, a carboxyl group,
(3) unsubstituted or substituted by 1 to 3 identical or different R5Substituted: a 3-14 membered cycloalkyl group, a 3-14 membered heterocyclyl group or a 6-14 membered aryl group,
or R3And R4Taken together with the C atom to which they are attached to form unsubstituted or 1-3 identical or different R6A substituted 3-14 membered cyclic group,
R5、R6independently selected from halogen, hydroxy, amino, carboxyl, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, hydroxy C1-6Alkyl, amino C1-6Alkyl, carboxyl C1-6Alkyl radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, aminosulfonyl C1-6Alkyl, carbamoyl C1-6Alkyl radical, C1-6Alkylcarbonyl group, C1-6Alkyl carbonyl oxy, C1-6Alkoxycarbonyl, phenyl, 3-to 14-membered cycloalkyl or 3-to 14-membered heterocyclyl,
R2represents 1-3 substituents selected from hydrogen, halogen, C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino, C1-6Alkylamino radical, di (C)1-6Alkyl) amino or C1-6An alkylaminocarbonyl group;
m and n are each independently 0, 1 or 2.
A compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof, preferably:
wherein Q is1、Q2Independently is-O-, -NR1-；
R1Is hydrogen, C1-4Alkyl, or a group of the formula
Figure BDA0000389361860000032
R3And R4Are respectively and independently
(1) Hydrogen, amino, hydroxyl, mercapto, carboxyl, guanidino,
(2) unsubstituted or substituted by 1-2 identical or different R5Substituted: c1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Alkylamino radical, C1-4Alkylthio, carboxyl C1-4Alkyl, hydroxy C1-4Alkyl, carbamoyl C1-4An alkyl group, a carboxyl group,
(3) unsubstituted or substituted by 1-2 identical or different R5Substituted: a 3-8 membered cycloalkyl group, a 3-8 membered heterocyclyl group or a 6-14 membered aryl group,
or R3And R4Taken together with the C atom to which they are attached to form unsubstituted or 1-2 identical or different R6A substituted 3-6 membered cyclic group,
R5、R6independently selected from halogen, hydroxy, amino, carboxyl, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl, halo C1-4Alkoxy, hydroxy C1-4Alkyl, amino C1-4Alkyl, carboxyl C1-4Alkyl radical, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, aminosulfonyl C1-4Alkyl, carbamoyl C1-4Alkyl radical, C1-4Alkylcarbonyl group, C1-4Alkyl carbonyl oxy, C1-4Alkoxycarbonyl, phenyl, 3-8 membered cycloalkyl or 3-8 membered heterocyclyl;
R2selected from hydrogen, halogen, C1-4Alkyl, halo C1-4Alkyl, hydroxy C1-4Alkyl, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino or C1-4An alkylaminocarbonyl group;
m is 0 or 1; n is 0, 1 or 2.
A compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof, preferably:
wherein Q is1、Q2Independently is-O-, -NR1-；
R1Is hydrogen, C1-4Alkyl, or a group of the formula
Figure BDA0000389361860000041
R3And R4Are respectively and independently
(1) Hydrogen, amino, hydroxyl, mercapto, carboxyl, guanidino,
(2) unsubstituted or substituted by R5Substituted: c1-4Alkyl radical, C1-4Alkylamino radical, C1-4Alkylthio, carbamoyl C1-4An alkyl group, a carboxyl group,
(3) unsubstituted or substituted by R5Substituted: cyclopentane, cyclohexane, cyclopentene, cyclohexene, 1, 3-cyclohexadiene, tetrahydropyrrole, 2, 3-dihydropyrrole, dihydropyrrole,2, 5-dihydropyrrole, pyrrole, imidazole, 4, 5-dihydroimidazole, pyrazole, 4, 5-dihydropyrazole, 1,2, 3-triazole, tetrahydrothiophene, thiophene, 2, 3-dihydrothiophene, thiazole, 4, 5-dihydrothiazole, isothiazole, tetrahydrofuran, 2, 3-dihydrofuran, furan, 4, 5-dihydrooxazole, oxazole, 4, 5-dihydroisoxazole, isoxazole, benzene ring, 1,4,5, 6-tetrahydropyrimidine, 1, 6-dihydropyrimidine, 4, 5-dihydropyrimidine, pyrimidine, 3, 6-dihydro-2H-pyran, piperidine, 1,2,3, 4-tetrahydropyridine, 1,2,3, 6-tetrahydropyridine, 2, 3-dihydropyridine, pyridine, Piperazine, 1,2,3, 4-tetrahydropyrazine, 2, 3-dihydropyrazine or pyrazine,
or R3And R4Taken together with the C atom to which they are attached to form an unsubstituted or substituted R6Substituted: cyclopentane, cyclohexane, cyclopentene, cyclohexene, 1, 3-cyclohexadiene, tetrahydropyrrole, 2, 3-dihydropyrrole, 2, 5-dihydropyrrole, pyrrole, imidazole, 4, 5-dihydroimidazole, pyrazole, 4, 5-dihydropyrazole, 1,2, 3-triazole, tetrahydrothiophene, thiophene, 2, 3-dihydrothiophene, thiazole, 4, 5-dihydrothiazole, isothiazole, tetrahydrofuran, 2, 3-dihydrofuran, furan, 4, 5-dihydrooxazole, oxazole, 4, 5-dihydroisoxazole, isoxazole, benzene rings, 1,4,5, 6-tetrahydropyrimidine, 1, 6-dihydropyrimidine, 4, 5-dihydropyrimidine, pyrimidine, 3, 6-dihydro-2H-pyran, piperidine, 1,2,3, 4-tetrahydropyridine, 1,2,3, 6-tetrahydropyridine, 2, 3-dihydropyridine, pyridine, piperazine, 1,2,3, 4-tetrahydropyrazine, 2, 3-dihydropyrazine or pyrazine,
R5、R6independently selected from hydrogen, fluoro, chloro, carboxy, methyl, trifluoromethyl, hydroxy, hydroxymethyl, amino, methylamino, ethylamino, methylaminoformyl or ethylaminoformyl;
R2is hydrogen; m is 0 or 1; n is 0, 1 or 2.
The compound represented by the general formula (i), a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof is more preferably:
wherein Q is1、Q2Independently is-O-, -NR1-；
R1Is hydrogen, methyl, ethyl, or a group of the formula
R3And R4Are respectively and independently
(1) Hydrogen, amino, hydroxyl, mercapto, carboxyl, guanidino,
(2) unsubstituted or substituted by R5Substituted: methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, methylmercapto, methylamino, ethylamino,
(3) unsubstituted or substituted by R6Substituted: cyclopropane, cyclopentane, cyclohexane, tetrahydropyrrole, pyrrole, thiazole, thiophene, imidazole, isothiazole, tetrahydrofuran, furan, oxazole, benzene ring, pyridine,
or R3And R4Taken together with the C atom to which they are attached to form an unsubstituted or substituted R6Substituted cyclopentane, cyclohexane, tetrahydropyrrole, piperidine or piperazine,
R5、R6independently selected from hydrogen, fluoro, chloro, amino, carboxy, hydroxy, methyl, trifluoromethyl, hydroxymethyl, methylamino, ethylamino, methylaminoformyl or ethylaminoformyl;
R2is hydrogen; m is 0 or 1; n is 0, 1 or 2.
The other technical scheme of the invention is as follows:
a compound represented by the general formula (II), a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof:
Figure BDA0000389361860000052
wherein Q is1、Q2independently-O-, -S-, -SO2-、-NR1-；
R1Is hydrogen, C1-6Alkyl, halo C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, hydroxy C1-6Alkyl, carboxyl C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl radical, C1-6Alkoxycarbonyl group, C1-6Alkylsulfinyl radical, C1-6Alkylsulfonyl, sulfonic acid, sulfonyl C1-6Alkyl, sulfonamide C1-6Alkyl, aminosulfonyl, C1-6Alkylaminosulfonyl, di (C)1-6Alkyl) aminosulfonyl, aminosulfonyl C1-6Alkyl radical, C1-6Alkylaminocarbonyl, di (C)1-6Alkyl) carbamoyl, carbamoyl C1-6Alkyl, 3-14 membered cycloalkyl, 6-14 membered aryl C1-6Alkyl, 3-14 membered heterocyclic group C1-6An alkyl group, a carboxyl group,
or a group of the formula
Figure BDA0000389361860000061
R3And R4Independently are:
(1) hydrogen, amino, hydroxyl, mercapto, carboxyl, guanidino,
(2) unsubstituted or substituted by 1 to 3 identical or different R5Substituted: c1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkylamino radical, C1-6Alkylthio, carboxyl C1-6Alkyl, hydroxy C1-6Alkyl, carbamoyl C1-6An alkyl group, a carboxyl group,
(3) unsubstituted or substituted by 1 to 3 identical or differentSame R5Substituted: a 3-14 membered cycloalkyl group, a 3-14 membered heterocyclyl group or a 6-14 membered aryl group,
or R3And R4Taken together with the C atom to which they are attached to form unsubstituted or 1-3 identical or different R6A substituted 3-14 membered cyclic group,
R5、R6independently selected from halogen, hydroxy, amino, carboxyl, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, hydroxy C1-6Alkyl, amino C1-6Alkyl, carboxyl C1-6Alkyl radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, aminosulfonyl C1-6Alkyl, carbamoyl C1-6Alkyl radical, C1-6Alkylcarbonyl group, C1-6Alkyl carbonyl oxy, C1-6Alkoxycarbonyl, phenyl, 3-14 membered cycloalkyl or 3-14 membered heterocyclyl;
R2represents 1-3 substituents selected from hydrogen, halogen, C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino, C1-6Alkylamino radical, di (C)1-6Alkyl) amino or C1-6An alkylaminocarbonyl group;
R7、R7’is hydrogen or C1-6An alkyl group;
m and n are each independently 0, 1,2,3 or 4.
A compound represented by the general formula (ii), a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof, preferably:
wherein Q is1、Q2Independently is-O-, -NR1-；
R1Is hydrogen, C1-6Alkyl, or a group of the formula
Figure BDA0000389361860000062
R3And R4Are respectively and independently
(1) Hydrogen, amino, hydroxyl, mercapto, carboxyl, guanidino,
(2) unsubstituted or substituted by 1 to 3 identical or different R5Substituted: c1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkylamino radical, C1-6Alkylthio, carboxyl C1-6Alkyl, hydroxy C1-6Alkyl, carbamoyl C1-6An alkyl group, a carboxyl group,
(3) unsubstituted or substituted by 1 to 3 identical or different R5Substituted: a 3-14 membered cycloalkyl group, a 3-14 membered heterocyclyl group or a 6-14 membered aryl group,
or R3And R4Taken together with the C atom to which they are attached to form unsubstituted or 1-3 identical or different R6A substituted 3-14 membered cyclic group,
R5、R6independently selected from halogen, hydroxy, amino, carboxyl, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, hydroxy C1-6Alkyl, amino C1-6Alkyl, carboxyl C1-6Alkyl radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, aminosulfonyl C1-6Alkyl, carbamoyl C1-6Alkyl radical, C1-6Alkylcarbonyl group, C1-6Alkyl carbonyl oxy, C1-6Alkoxycarbonyl, phenyl, 3-to 14-membered cycloalkyl or 3-to 14-membered heterocyclyl,
R2represents 1-3 substituents selected from hydrogen, halogen, C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino, C1-6Alkylamino radical, di (C)1-6Alkyl) amino or C1-6An alkylaminocarbonyl group;
m and n are each independently 0, 1 or 2.
A compound represented by the general formula (ii), a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof, preferably:
wherein Q is1、Q2Independently is-O-, -NR1-；
R1Is hydrogen, C1-4Alkyl, or a group of the formula
Figure BDA0000389361860000071
R3And R4Are respectively and independently
(1) Hydrogen, amino, hydroxyl, mercapto, carboxyl, guanidino,
(2) unsubstituted or substituted by 1-2 identical or different R5Substituted: c1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Alkylamino radical, C1-4Alkylthio, carboxyl C1-4Alkyl, hydroxy C1-4Alkyl, carbamoyl C1-4An alkyl group, a carboxyl group,
(3) unsubstituted or substituted by 1-2 identical or different R5Substituted: a 3-8 membered cycloalkyl group, a 3-8 membered heterocyclyl group or a 6-14 membered aryl group,
or R3And R4Taken together with the C atom to which they are attached to form unsubstituted or 1-2 identical or different R6A substituted 3-6 membered cyclic group,
R5、R6independently selected from halogen, hydroxy, amino, carboxyl, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl, halo C1-4Alkoxy, hydroxy C1-4Alkyl, amino C1-4Alkyl, carboxyl C1-4Alkyl radical, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, aminosulfonyl C1-4Alkyl, carbamoyl C1-4Alkyl radical, C1-4Alkylcarbonyl group, C1-4Alkyl carbonyl oxy, C1-4Alkoxycarbonyl, phenyl, 3-8 membered cycloalkyl or 3-8 membered heterocyclyl;
R2selected from hydrogen, halogen, C1-4Alkyl, halo C1-4Alkyl, hydroxy C1-4Alkyl, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino or C1-4An alkylaminocarbonyl group;
m is 0 or 1; n is 0, 1 or 2.
A compound represented by the general formula (ii), a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof, preferably:
wherein Q is1、Q2Independently is-O-, -NR1-；
R1Is hydrogen, C1-4Alkyl, or a group of the formula
Figure BDA0000389361860000081
R3And R4Are respectively and independently
(1) Hydrogen, amino, hydroxyl, mercapto, carboxyl, guanidino,
(2) unsubstituted or substituted by R5Substituted: c1-4Alkyl radical, C1-4Alkylamino radical, C1-4Alkylthio, carbamoyl C1-4An alkyl group, a carboxyl group,
(3) unsubstituted or substituted by R5Substituted: cyclopentane, cyclohexane, cyclopentene, cyclohexene, 1, 3-cyclohexadiene, tetrahydropyrrole, 2, 3-dihydropyrrole, 2, 5-dihydropyrrole, pyrrole, imidazole, 4, 5-dihydropyrroleImidazole, pyrazole, 4, 5-dihydropyrazole, 1,2, 3-triazole, tetrahydrothiophene, thiophene, 2, 3-dihydrothiophene, thiazole, 4, 5-dihydrothiazole, isothiazole, tetrahydrofuran, 2, 3-dihydrofuran, furan, 4, 5-dihydrooxazole, oxazole, 4, 5-dihydroisoxazole, isoxazole, benzene ring, 1,4,5, 6-tetrahydropyrimidine, 1, 6-dihydropyrimidine, 4, 5-dihydropyrimidine, pyrimidine, 3, 6-dihydro-2H-pyran, piperidine, 1,2,3, 4-tetrahydropyridine, 1,2,3, 6-tetrahydropyridine, 2, 3-dihydropyridine, pyridine, piperazine, 1,2,3, 4-tetrahydropyrazine, 2, 3-dihydropyrazine or pyrazine,
or R3And R4Taken together with the C atom to which they are attached to form an unsubstituted or substituted R6Substituted: cyclopentane, cyclohexane, cyclopentene, cyclohexene, 1, 3-cyclohexadiene, tetrahydropyrrole, 2, 3-dihydropyrrole, 2, 5-dihydropyrrole, pyrrole, imidazole, 4, 5-dihydroimidazole, pyrazole, 4, 5-dihydropyrazole, 1,2, 3-triazole, tetrahydrothiophene, thiophene, 2, 3-dihydrothiophene, thiazole, 4, 5-dihydrothiazole, isothiazole, tetrahydrofuran, 2, 3-dihydrofuran, furan, 4, 5-dihydrooxazole, oxazole, 4, 5-dihydroisoxazole, isoxazole, benzene rings, 1,4,5, 6-tetrahydropyrimidine, 1, 6-dihydropyrimidine, 4, 5-dihydropyrimidine, pyrimidine, 3, 6-dihydro-2H-pyran, piperidine, 1,2,3, 4-tetrahydropyridine, 1,2,3, 6-tetrahydropyridine, 2, 3-dihydropyridine, pyridine, piperazine, 1,2,3, 4-tetrahydropyrazine, 2, 3-dihydropyrazine or pyrazine,
R5、R6independently selected from hydrogen, fluoro, chloro, carboxy, methyl, trifluoromethyl, hydroxy, hydroxymethyl, amino, methylamino, ethylamino, methylaminoformyl or ethylaminoformyl;
R2is hydrogen; m is 0 or 1; n is 0, 1 or 2.
The compound represented by the general formula (ii), a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof is more preferably:
wherein Q is1、Q2Independently is-O-, -NR1-；
R1Is hydrogen, methyl, ethyl, or a group of the formula
R3And R4Are respectively and independently
(1) Hydrogen, amino, hydroxyl, mercapto, carboxyl, guanidino,
(2) unsubstituted or substituted by R5Substituted: methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, methylmercapto, methylamino, ethylamino,
(3) unsubstituted or substituted by R6Substituted: cyclopropane, cyclopentane, cyclohexane, tetrahydropyrrole, pyrrole, thiazole, thiophene, imidazole, isothiazole, tetrahydrofuran, furan, oxazole, benzene ring, pyridine,
or R3And R4Taken together with the C atom to which they are attached to form an unsubstituted or substituted R6Substituted cyclopentane, cyclohexane, tetrahydropyrrole, piperidine or piperazine,
R5、R6independently selected from hydrogen, fluoro, chloro, amino, carboxy, hydroxy, methyl, trifluoromethyl, hydroxymethyl, methylamino, ethylamino, methylaminoformyl or ethylaminoformyl;
R2is hydrogen; m is 0 or 1; n is 0, 1 or 2.
Detailed Description
The "halogen" as referred to herein means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like. Fluorine atom and chlorine atom are preferred.
The term "halo" as used herein means that any atom in the group which can be substituted is substituted by halogen, and can be perhalogenated, i.e., the halogen atom is substituted at all positions in the group which can be substituted.
Said "C" of the present invention1-6Alkyl "means a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like. Preferably C1-3An alkyl group. Said "C" of the present invention1-3Alkyl "refers to the above examples containing 1 to 3 carbon atoms.
Said "C" of the present invention2-6The "alkenyl group" means a straight-chain or branched alkenyl group having 2 to 6 carbon atoms and having a double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-methyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1-dimethyl-2-propenyl, 1, 2-dimethyl-1-propenyl, 1, 2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 2-methyl-3-pentenyl, 3-methyl-1-pentenyl, 3-methyl-2-pentenyl, 1-methyl-pentenyl, 2-methyl-2-pentenyl, 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-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1-dimethyl-2-butenyl, 1-dimethyl-3-butenyl, 1, 2-dimethyl-1-butenyl, 2-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-4-pentenyl, 1-dimethyl-2-butenyl, 1,1, 2-dimethyl-2-butenyl, 1, 2-dimethyl-3-butenyl, 1, 3-dimethyl-1-butenyl, 1, 3-dimethyl-2-butenyl, 1, 3-dimethylPhenyl-2-butenyl, 2-dimethyl-3-butenyl, 2, 3-dimethyl-1-butenyl, 2, 3-dimethyl-2-butenyl, 2, 3-dimethyl-3-butenyl, 3-dimethyl-1-butenyl, 3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1, 2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-2-butenyl, 2, 1-ethyl-2-methyl-1-propenyl group, 1-ethyl-2-methyl-2-propenyl group, 1, 3-butadienyl group, 1, 3-pentadienyl group, 1, 4-pentadienyl group, 2, 4-pentadienyl group, 1, 4-hexadienyl group, 2, 4-hexadienyl group and the like. The double bond may optionally be cis and trans.
Said "C" of the present invention2-6Alkynyl "means a straight-chain or branched alkynyl group having 2 to 6 carbon atoms and having a triple bond, such as ethynyl, 1-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 4-methyl-2-pentynyl, etc, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 1-dimethyl-2-butynyl, 1-dimethyl-3-butynyl, 1, 2-dimethyl-3-butynyl, 2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl and the like.
Said "C" of the present invention1-6Alkoxy "means" C1-6Alkyl "radicals attached to other structures via an oxygen atom, such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1-dimethylethoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1-dimethylpropyloxy, 1, 2-dimethylpropyloxy, 2-dimethylpropyloxy, 1-ethylpropyloxy, hexyloxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, 1-dimethylpropyloxy, 2-methylpentyloxy, 1-ethylpropyloxy, hexyloxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy-dimethylbutoxy, 1, 2-dimethylbutoxy, 1, 3-dimethylbutoxy, 2, 2-dimethylbutoxy, 2, 3-dimethylbutoxy, 3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1, 2-trimethylpropoxy, 1,2, 2-trimethylpropoxy, 1-ethyl-1-methylpropoxy and 1-ethyl-2-methylpropoxy. The term "C1-3The "alkoxy group" refers to a specific example containing 1 to 3 carbon atoms among the above examples.
Said "C" of the present invention1-6Alkylcarbonyl "refers to the term" C1-6Alkyl "a group attached to another structure through a carbonyl group, such as methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, neopentylcarbonyl, hexylcarbonyl, and the like.
Said "C" of the present invention1-6Alkoxycarbonyl "is the term" C1-6Alkoxy "a group bonded to another structure through a carbonyl group, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, pentyloxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl, etc.
The "3-to 14-membered cycloalkyl group" as referred to herein means a cyclic alkyl group derived from an alkane moiety of 3 to 14 carbon atoms by removing one hydrogen atom, and includes a 3-to 8-membered monocyclic cycloalkyl group, a 6-to 14-membered carbocyclic fused cycloalkyl group, a 7-to 12-membered carbocyclic bridged cyclic group and a 5-to 14-membered carbocyclic spiro cyclic group. Preferably C3-8Cycloalkyl radical, C3-6Cycloalkyl and C5-6A cycloalkyl group. The term "C3-8Cycloalkyl group "," C3-6Cycloalkyl group "," C5-6Cycloalkyl "is a specific example containing 3 to 8, 3 to 6, and 5 to 6 carbon atoms in the following examples, respectively.
3-8 membered monocyclic cycloalkyl groups, including 3-8 membered saturated monocyclic cycloalkyl groups and 3-8 membered partially saturated monocyclic cycloalkyl groups. 3-8 membered saturated monocyclic cycloalkyl, meaning that the monocyclic ring is fully saturated carbocyclic, examples of which include, but are not limited to: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, methylcyclopropane, dimethylcyclopropane, methylcyclobutane, dimethylcyclobutane, methylcyclopentane, dimethylcyclopentane, methylcyclohexane, dimethylcyclohexane, etc. 3-8 membered partially saturated monocyclic cycloalkyl, meaning that the monocyclic ring is a partially saturated carbocyclic ring, examples of which include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1, 4-cyclohexadienyl, cycloheptenyl, 1, 4-cycloheptadienyl, cyclooctenyl, 1, 5-cyclooctadienyl, and the like;
the 6-14-membered carbocyclic fused ring group means a 6-14-membered cyclic group formed by two or more cyclic structures sharing two adjacent carbon atoms with each other, and includes a 6-14-membered saturated fused ring group and a 6-14-membered partially saturated fused ring group. 6-to 12-membered fused ring group, 6-to 10-membered fused ring group are preferred. 6-14 membered saturated fused cycloalkyl, meaning that the fused ring group is a fully saturated carbocyclic ring, examples of which include, but are not limited to: bicyclo [3.1.0] hexanyl, bicyclo [4.1.0] heptanyl, bicyclo [2.2.0] hexanyl, bicyclo [3.2.0] heptanyl, bicyclo [4.2.0] octanyl, octahydropentalenyl, octahydro-1H-indenyl, decahydronaphthyl, tetradecahydrophenanthryl and the like. A 6-14 membered partially saturated fused cycloalkyl group, meaning that at least one ring in the fused ring is a partially saturated carbocyclic ring, examples of which include, but are not limited to: bicyclo [3.1.0] hex-2-enyl, bicyclo [4.1.0] hept-3-enyl, bicyclo [3.2.0] hept-3-enyl, bicyclo [4.2.0] oct-3-enyl, 1,2,3,3 a-tetrahydropentalenyl, 2,3,3a,4,7,7 a-hexahydro-1H-indenyl, 1,2,3,4,4a,5,6,8 a-octahydronaphthyl, 1,2,4a,5,6,8 a-hexahydronaphthyl, 1,2,3,4,5,6,7,8,9, 10-decahydrophenanthryl and the like;
5-14 membered carbocyclic bridged ring groups are structures containing 5-14 carbon atoms formed by any two rings sharing two atoms not directly connected, and "5-14 membered bridged ring" includes 5-14 membered saturated bridged ring groups, 5-14 membered partially saturated bridged ring groups. 5-14 membered saturated bridged ring group, preferably 6-10 membered saturated bridged ring group, including but not limited to bicyclo [2.1.1] hexanyl, bicyclo [2.2.1] heptanyl, bicyclo [3.2.1] heptanyl, bicyclo [2.2.2] octanyl, bicyclo [3.2.1] octanyl, bicyclo [3.3.1] nonanyl, bicyclo [4.3.1] nonanyl, 4-azabicyclo [5.3.1] decanyl and the like. 7-12 membered partially saturated bridged ring group means a cyclic group in which at least one ring in the bridged ring is unsaturated, preferably 6-10 membered partially saturated bridged ring group, and specific examples include, but are not limited to, bicyclo [2.2.1] hept-5-enyl, bicyclo [3.2.1] oct-6-enyl, bicyclo [4.3.1] non-5-enyl, biscyclopentadienyl and the like;
5-14 membered carbocyclic spiro ring groups are a class of 5-14 membered carbocyclic fused ring structures formed by at least two rings sharing an atom. 5-14 membered saturated spiro ring group means that all rings in the spiro ring group are saturated cyclic groups, specific examples include but are not limited to:
Figure BDA0000389361860000111
and a group formed by substituting an optionally substituted hydrogen atom with an isocyclic structure. 5-14 membered partially saturated spiro ring group means a cyclic group in which at least one ring of the spiro ring group is unsaturated, and specific examples include, but are not limited to:
Figure BDA0000389361860000122
and a group formed by substituting an optionally substituted hydrogen atom with an isocyclic structure. Preferred are 7-to 10-membered spiro ring groups, including "7-to 10-membered saturated spiro ring groups" and "7-to 10-membered unsaturated spiro ring groups".
"C" according to the invention3-8Cycloalkoxy "refers to the term" C3-8Cycloalkyl "a group attached to another structure through an oxygen atom, such as cyclopropyloxy, cyclobutyloxy, 1-methylcyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, and the like.
The "6-14 membered aryl" as referred to herein means a cyclic aromatic group having 6-14 membered carbon atoms as ring atoms, and includes 6-8 membered monocyclic aryl and 8-14 membered fused ring aryl. The 6-8 membered monocyclic aryl group means an all unsaturated aryl group such as phenyl, cyclooctatetraenyl and the like. The 8-to 14-membered fused ring aryl group means a cyclic group formed by two or more cyclic structures sharing two adjacent carbon atoms with each other and having at least one ring being an all unsaturated aromatic ring, and includes 8-to 14-membered all unsaturated fused ring aryl, naphthyl, anthryl, phenanthryl and the like, and also includes 8-to 14-membered partially saturated fused ring aryl groups such as benzo 3-to 8-membered saturated monocyclic cycloalkyl, benzo 3-to 8-membered partially saturated monocyclic cycloalkyl, and specific examples thereof are 2, 3-dihydro-1H-indenyl, 1,2,3, 4-tetrahydronaphthyl, 1, 4-dihydronaphthyl and the like. Preferably 6-to 10-membered aryl, more preferably benzene or a benzo 3-to 8-membered saturated monocyclic cycloalkyl, a benzo 3-to 8-membered partially saturated monocyclic cycloalkyl. The term "6-to 10-membered aryl" refers to a specific example of the above-mentioned "aryl" having 6 to 10 ring atoms.
The "5-to 14-membered heteroaryl" includes one or more heteroatoms in addition to carbon atoms in the ring, including but not limited to oxygen, nitrogen, and sulfur atoms. Heteroaryl groups may be bonded through carbon or a heterocyclic atom. Including 5-8 membered monocyclic heteroaryl and 8-14 membered fused heterocyclic aryl. 5-8 membered monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, pyridyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 3-triazinyl, 1,2, 4-triazinyl, tetrazolyl, oxadiazolyl, 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-oxazinyl, 4H-1, 4-oxazinyl, isooxazinyl, pyridazinyl, pyrimidinyl, pyrazinyl and the like; 8-14 membered fused heterocyclic aryl groups include, but are not limited to, benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, indolizinyl, indazolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzisoxazolyl, benzoxazinyl, benzimidazolyl, pyridopyridyl, pyrazolo [3,4-b ] pyridyl, purinyl, acridinyl, xanthenyl, and the like.
The term "3-14 membered heterocyclic group" as used herein means a heterocyclic group containing one or more hetero atomsA 3-14 membered cyclic group of atoms, said "heteroatom" being N, S, O, SO and/or SO2And the like. Including saturated, partially saturated, unsaturated having 1-4 substituents selected from N, S, O, SO and/or SO23-8 membered heteromonocyclic group and 5-14 membered heteromonocyclic group of the hetero atom of (a). Also included are the heteroaryl groups mentioned above and their dihydro and tetrahydro analogs. 5-14 membered diheterocyclyl includes saturated, partially saturated, unsaturated having 1-4 substituents selected from N, S, O, SO and/or SO2Fused, spiro, bridged rings of heteroatoms of (a). Preferred is a 3-to 8-membered heterocyclic group, and further preferred is a saturated, partially saturated, unsaturated 3-to 8-membered heteromonocyclic group. More preferred is a 5-8-membered, 5-7-membered, 5-6-membered heterocyclic group, and further preferred is a saturated, partially saturated, unsaturated 5-8-membered, 5-7-membered, 5-6-membered heteromonocyclic group.
3-8 membered heteromonocyclic group means a monocyclic heterocyclic group containing 3 to 8 ring atoms (wherein at least one hetero atom is contained), and includes 3-8 membered unsaturated heteromonocyclic group, 3-8 membered partially saturated heteromonocyclic group, 3-8 membered saturated heteromonocyclic group. Preference is given to 5-7-membered unsaturated heteromonocyclic groups, 5-7-membered partially saturated heteromonocyclic groups, 5-7-membered saturated heteromonocyclic groups. 3-8 membered unsaturated Monoheterocyclyl, which means an aromatic heteroatom-containing cyclic group, specific examples include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, 1, 4-dioxadienyl, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, 6H-1, 2-oxazinyl, 4H-1, 3-oxazinyl, 6H-1, 3-oxazinyl, 4H-1, 4-oxazinyl, pyridazinyl, pyrazinyl, 1,2, 3-triazinyl, 1,2, 4-triazinyl, 1,3, 5-triazinyl, 1,2,4, 5-tetrazinyl, oxepitrienyl, oxacycloheptatrienyl, oxa-yl, oxacycloheptatrienyl, and the like, Thiepinatrienyl, azepinatrienyl, 1, 3-diazacycloheptatrienyl, azepintetraenyl, and the like. 3-8 membered partially saturated monoheterocyclyl means a cyclic group containing a double bond, a heteroatom, and specific examples include, but are not limited to, 2, 5-dihydrothienyl, 4, 5-dihydropyrazolyl, 3, 4-dihydro-2H-pyranyl, 5, 6-dihydro-4H-1, 3-oxazinyl, and the like. 3-8 membered saturated monoheterocyclyl, refers to heteroatom-containing cyclic groups that are all saturated bonds, specific examples include, but are not limited to: aziridinyl, azetidinyl, thietanyl, tetrahydrofuranyl, tetrahydropyrrolyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, 1, 4-dioxanyl, 1, 3-dithianyl, morpholinyl, piperazinyl, and the like.
Said has 1-4 selected from N, S, O and/or SO2Is a fused, spiro or bridged ring of a heteroatom, in particular a fused, spiro or bridged ring in which one of the carbon atoms not shared by it is N, S, O and/or SO2The heteroatom(s) in place of the 6-to 14-membered heterocyclic group, 5-to 14-membered spiroheterocyclic group, 5-to 14-membered bridged heterocyclic group formed.
The 6-to 14-membered heterocyclic group means a heterocyclic ring structure having 6 to 14 ring atoms (wherein at least one hetero atom is contained) and formed by two or more ring structures sharing two adjacent atoms to each other, and includes a 6-to 14-membered unsaturated heterocyclic group, a 6-to 14-membered partially saturated heterocyclic group, and a 6-to 10-membered saturated heterocyclic group. 6-14 membered unsaturated heterocyclo means that all rings are unsaturated fused ring structures such as structures formed by benzo 3-8 membered unsaturated heteromonocyclic group, structures formed by 3-8 membered unsaturated heteromonocyclic group and 3-8 membered unsaturated heteromonocyclic group, and the like, and specific examples include, but are not limited to: benzofuranyl, benzisofuranyl, benzothienyl, indolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, isoquinolyl, acridinyl, phenanthridinyl, pyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, phenazinyl, pteridinyl, purinyl, naphthyridinyl, indolyl, and mixtures thereof,
Figure BDA0000389361860000131
And a group formed by substituting an optionally substituted hydrogen atom with an isocyclic structure. The 6-14 membered partially saturated and heterocyclic group means a condensed ring structure containing at least one partially saturated ring, such as a structure formed by a benzo 3-8 membered partially saturated heteromonocyclic group, a structure formed by a 3-8 membered partially saturated heteromonocyclic group and a 3-8 membered partially saturated heteromonocyclic group, and the like, and specific examples include, but are not limited to: 1, 3-dihydrobenzofuranyl, benzo [ d ]][1.3]Dioxolyl, isoindolinyl, chromanyl, 1,2,3, 4-tetrahydropyrrolo [3,4-c]Pyrrole, pyrrole,
Figure BDA0000389361860000142
And a group formed by substituting an optionally substituted hydrogen atom with an isocyclic structure. 6-to 10-membered saturated and heterocyclic group means a fused ring structure in which all rings are saturated, such as a structure formed by a 3-to 8-membered saturated heteromonocyclic group and a 3-to 8-membered saturated heteromonocyclic group, and specific examples include, but are not limited to: cyclobutane tetrahydropyrrole, cyclopentane tetrahydropyrrole, azetidine imidazolidine radical,
Figure BDA0000389361860000143
And a group formed by substituting an optionally substituted hydrogen atom with an isocyclic structure.
The 5-14 membered bridged heterocyclic group means a bridged ring structure formed by 5 to 14 ring atoms (containing at least one hetero atom therein). "5-14 membered bridged heterocyclic group" includes 5-14 membered saturated bridged heterocyclic group, 5-14 membered partially saturated bridged heterocyclic group.
5-14 membered saturated bridged heterocyclyl, meaning that all rings in the bridged heterocyclyl are saturated cyclic groups, preferably 7-8 membered saturated bridged heterocyclyl, specific examples include but are not limited to:
Figure BDA0000389361860000144
Figure BDA0000389361860000145
and a group formed by substituting an optionally substituted hydrogen atom with an isocyclic structure.
5-14 membered partially saturated bridged heterocyclyl means that there is a cyclic group in the bridged heterocyclyl in which at least one ring is unsaturated, preferably 7-8 membered partially saturated bridged heterocyclyl, specific examples include, but are not limited to:
Figure BDA0000389361860000146
equicyclic knotA group formed by substituting an optionally substitutable hydrogen atom, and the like.
5-14 membered spiroheterocyclyl means a spirocyclic structure formed by 5-14 ring atoms containing at least one heteroatom. The 5-14 membered spiroheterocyclic group includes a 5-14 membered saturated spiroheterocyclic group, a 5-14 membered partially saturated spiroheterocyclic group.
5-14 membered saturated spiroheterocyclyl, meaning that all rings in the spiroheterocyclyl are saturated cyclic groups, specific examples include, but are not limited to:
Figure BDA0000389361860000148
and a group formed by substituting an optionally substituted hydrogen atom with an isocyclic structure.
5-14 membered partially saturated spiroheterocyclic group means a cyclic group in which at least one ring of the spiroheterocyclic group is unsaturated, and specific examples include, but are not limited to:
Figure BDA0000389361860000152
a group formed by substituting an optionally substitutable hydrogen atom, and the like.
The terms 3-8 membered heterocyclic group, 5-7 membered heterocyclic group, 5-6 membered heterocyclic group mean specific examples in which the number of ring atoms in the above-mentioned "3-14 membered heterocyclic group" is 3-8, 5-7, 5-6 membered.
In the present invention, the term "3-14-membered cyclic group" means a 3-14-membered saturated or unsaturated carbocyclic group or a saturated or unsaturated heterocyclic group containing a heteroatom selected from N, O and S, and includes a 3-6-membered cyclic group, a 3-14-membered cycloalkyl group, a 6-14-membered aryl group, a 5-14-membered aryl group and a 3-14-membered heterocyclic group, wherein:
"3-6 membered cyclic group" includes, but is not limited to, for example, the following groups: cyclopropane, cyclobutane, cyclopentane, cyclohexane, aziridine, azetidine, 1, 2-diazetidine, pyrrolidine, imidazolidine, pyrazolidine, hydropyridone, piperidine, piperazine, ethylene oxide, thietane, oxetane, 1, 2-dioxetane, thietane, tetrahydrofuran, tetrahydrothiophene, 1, 3-dioxolane, 1, 3-dithiolane, tetrahydropyran, 1, 4-dioxane, 1, 3-oxathiane, oxazolidine, morpholine, azetidine, 1, 2-diazacyclobutene, pyrrole, 4, 5-dihydropyrrole, 2, 5-dihydropyrrole, imidazole, 4, 5-dihydroimidazole, pyrazole, 4, 5-dihydropyrazole, 1,2, 3-triazole, 1,2, 4-triazole, pyridine, 2-pyridone, 4-pyridone, pyridazine, pyrimidine, pyrazine, 1,2, 3-triazine, 1,2, 4-triazine, 1, 2-dithiocyclobutene, furan, 4, 5-dihydrofuran, 2, 5-dihydrofuran, thiophene, 2, 5-dihydrothiophene, 4, 5-dihydrothiophene, 1, 2-dithiole, 1, 3-dithiole, 2H-pyran-2-one, 3, 4-dihydro-2H-pyran, 4H-pyran-4-one, 1, 4-dioxadiene, 1, 4-dithiine, 1, 4-oxathiahexadiene, oxazole, 4, 5-dihydrooxazole, 2, 3-dihydrooxazole, isoxazole, 4, 5-dihydroisoxazole, 2, 3-dihydroisoxazole, 1,2, 3-oxadiazole, 1,2, 5-oxadiazole, thiazole, 4, 5-dihydrothiazole, 2, 3-dihydrothiazole, isothiazole, 1,2, 3-thiadiazole, 2H-1, 2-oxazine, 4H-1, 2-oxazine, 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, benzene ring, pyridine group and the like.
The "1 to 3" described in the present invention specifically means 1,2 or 3.
Particularly preferred compounds include:
Figure BDA0000389361860000161
Figure BDA0000389361860000171
a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride, or a stereoisomer thereof.
In one embodiment, the present invention provides a process for the preparation of the above-described compounds of the present invention.
In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the invention as described above.
In one embodiment, the present invention provides a method for treating and/or preventing a disease caused by a microorganism using the above-described compound of the present invention.
In one embodiment, the present invention provides the use of a compound of the invention as described above for the preparation of a medicament for the treatment and/or prevention of a disease caused by a microorganism.
The above compounds of the present invention can be synthesized using the methods described in the schemes below and/or other techniques known to those of ordinary skill in the art, but are not limited to the methods below.
The reaction equation is as follows:
Figure BDA0000389361860000172
the reaction steps are as follows:
step 1: dissolving raw materials 1 and 2, inorganic base (such as NaOH, KOH, etc.) aqueous solution and phase transfer catalyst (such as triethyl benzyl ammonium chloride) in organic solvent (such as DMF, dioxane, THF), heating under nitrogen protection for reaction, concentrating, adding water, extracting with organic solvent, drying, concentrating, and separating with silica gel column to obtain intermediate 1.
Step 2: intermediate 1, starting material 3, HATU and DIEA are dissolved in an organic solvent (e.g., DCM, THF) and reacted to completion at room temperature. Or dissolving the intermediate 1 in methanol, adding the raw material 3 in ice water bath, reacting for 1-2h, adding a reducing agent (such as sodium triacetoxyborohydride), reacting at room temperature, adding water, extracting with an organic solvent, drying, concentrating, and separating with a silica gel column to obtain the compound of formula 1.
The raw materials 1 and 2 in the above reaction equation are prepared by converting easily available raw materials through simple functional groups. R in the above reaction equation2、m、X、Q1Or Q2As defined hereinbefore.
The compounds of the present invention include compounds in any form, such as free forms, salt forms, solvate forms, and salt and solvate forms.
According to another aspect, the present invention provides a compound of the invention in the form of a salt and/or solvate.
The salts preferably include pharmaceutically acceptable salts, although pharmaceutically unacceptable salts are included, for example, for purposes of preparation, isolation, purification.
Salts of the compounds of the present invention include base or acid addition salts. Pharmaceutically acceptable base salts include ammonium salts such as the tri ylammonium salt, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts with organic bases including primary, secondary and tertiary amines such as isopropylamine, diethylamine, ethanolamine, tri amine, dicyclohexylamine and N-methyl-D-glucamine, preferably the sodium salt.
The acid addition salts may be pharmaceutically or non-pharmaceutically acceptable salts. When a non-pharmaceutically acceptable salt, it can be used to isolate and purify the compound of the invention or an intermediate thereof, and then converted into a pharmaceutically acceptable salt or a free base. Pharmaceutically acceptable acid addition salts include those described in journal of pharmaceutical sciences (j.pharm.sci), 1977, 66, 1-19. Such as hydrogen fumarate (hydrogen fumarate), fumaric acid, tartaric acid, ethane-1, 2-disulfonic acid, maleic acid, naphthalene-1, 5-sulfonic acid, acetic acid, maleic acid, succinic acid, salicylic acid, azelaic acid, 2- [ (2, 6-dichlorophenyl) amino ] phenylacetic acid, hydrochloric acid, deuterochloric acid (deuterochloric aid); hydrochloric acid is preferred.
"pharmaceutically acceptable salts" of the compounds of the present invention refers to base addition salts or acid addition salts of the compounds of the present invention with pharmaceutically acceptable, non-toxic bases or acids, including organic acid salts, inorganic acid salts, organic base salts, inorganic base salts. The organic acid salt includes formate, acetate, propionate, benzenesulfonate, benzoate, p-toluenesulfonate, 2, 3-dihydroxysuccinate, camphorsulfonate, citrate, methanesulfonate, ethanesulfonate, propanesulfonate, fumarate, gluconate, glutamate, isethionate, lactate, maleate, malate, mandelate, mucate, pamoate, pantothenate, succinate, tartrate and the like, and benzoate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, citrate, maleate, fumarate, tartrate are particularly preferable. The inorganic acid salt includes hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate and the like, and the hydrochloride, hydrobromide, sulfate, phosphate are particularly preferable. Organic base salts include amine salts, including salts with primary, secondary and tertiary amines, cyclic amines and basic ion exchange resins, and may be selected from salts with the following organic bases: such as arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, meglumine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. The inorganic base salt includes salts with ammonia, alkali metals and alkaline earth metals, such as ammonium salts and lithium, sodium, potassium, calcium, magnesium, zinc, barium, aluminum, iron, copper, ferrous, manganese and manganous salts, with ammonium salts and sodium, potassium, calcium and magnesium salts being particularly preferred.
The compounds of the invention in free form can be converted to the corresponding compounds in salt form and vice versa. The compounds of the invention in free form or in salt form and/or solvate form can be converted into the corresponding compounds in non-solvate form, in free form or in salt form; and vice versa.
The term "solvate" is used herein to describe a molecular complex comprising a compound of the invention and a stoichiometric amount (stoichiometric amount) of one or more molecules of a pharmaceutically acceptable solvent, such as ethanol. When the solvent is water, the term "hydrate" is used.
The structures described herein also include compounds in which one or more isotopically enriched atoms are present. For example, structures having the invention but including replacement of hydrogen by deuterium or tritium or enrichment of carbon13C or14Carbon-substituted compounds of C are within the scope of the present invention.
The use of prodrugs, such as esters, of the compounds to which the invention relates is also part of the invention. By "prodrug" is meant a compound which can be converted in vivo by metabolic means (e.g., by hydrolysis, reduction or oxidation) to a compound of formula (I). For example, ester prodrugs of compounds of formula (I) may be converted in vivo to the parent molecule by hydrolysis. Examples of ester prodrugs are those described in f.j.leinweber, Drug metab.res, 1987, 18, 379. As used herein, reference to the meaning of the compounds of formula (I) also includes prodrug forms.
The compounds of the present invention may exist as isomers and mixtures thereof, such as optical isomers, diastereomers, cis/trans conformers. The compounds of the invention may, for example, contain asymmetric carbon atoms and may therefore exist as enantiomers (enatiomers) or diastereomers and mixtures thereof, e.g., racemates or diastereomeric mixtures. Any asymmetric carbon atom may be present in the (R) -, (S) -or (R, S) -configuration, preferably in the (R) -or (S) -configuration.
The compounds of the present invention contain one or more asymmetric centers and are thus useful as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The compounds of the present invention have asymmetric centers that each independently produce two optical isomers, and the scope of the present invention includes all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds. The present invention includes all stereoisomeric forms of these compounds.
The compounds of the present invention, if they contain an olefinic double bond, include both cis-and trans-isomers, unless otherwise specified.
The compounds of the present invention may exist in tautomeric forms having different points of attachment of hydrogen through one or more double bond shifts. Each tautomer and mixtures thereof are included in the compounds of the invention.
The configuration of the substituent attached to the asymmetric carbon atom of the tiamulin-tricycles (tricyclus) is preferably the same as the configuration of the natural pleuromutilins.
The isomer mixtures can be separated as desired, for example, in analogy to conventional methods, to give the pure isomers. The present invention includes compounds of the present invention in any isomeric form and any isomeric mixture thereof. The present invention also includes tautomers of the compounds of the present invention, as long as tautomers can exist.
The compounds of the present invention exhibit pharmacological activity and are therefore useful as pharmaceuticals.
For example, the compounds of the present invention exhibit antimicrobial activity, such as the following: against gram-positive bacteria, for example coagulase-positive Staphylococci (Staphylocci) such as Staphylococcus aureus (Staphyloccus aureus), coagulase-negative Staphylococci such as Staphylococcus epidermidis (Staphyloccus epidermidis), Staphylococcus haemolyticus (Staphyloccus haemolyticus), and Streptococcus (Streptococcus) such as Streptococcus pyogenes (Streptococcus pyogenes), Streptococcus agalactiae (Streptococcus agalactiae), Streptococcus pneumoniae (Streptococcus pneumoniae), Enterococci (Enterococci) such as Enterococcus faecalis (Enterococcus faecalis), and Listeria monocytogenes (Listeria monocytogenes); and gram-negative bacteria such as Moraxella (Moraxella) such as Moraxella catarrhalis (Moraxella catarrhalis), Haemophilus such as Haemophilus influenzae (Haemophilus influenzae), Legionella such as Lung and Legionella (Legionella pneumochia), Neisseriaceae such as Neisseria gonorrhoeae (Neisseria gonorrhoeae), and anti-mycoplasmas (Mycoplasma), Chlamydia (Chlamydia), and obligate anaerobes such as Bacteroides fragilis (Bacteroides agilis), Clostridium difficile (Clostridium difficile), Clostridium (Fusobacterium spp.) and Propionibacterium (Propionibacterium spp.).
The compounds of the invention are therefore suitable for the treatment and prophylaxis of diseases which are mediated by microorganisms, for example bacteria. Diseases that can be treated also include, for example, Helicobacter (Helicobacter pylori) mediated diseases and Mycobacterium tuberculosis (Mycobacterium tuberculosis) mediated diseases. Diseases that can be treated also include inflammatory diseases in general, where the inflammation, including acne for example, is mediated by microorganisms.
In another aspect, the present invention provides a compound of the invention for use as a medicament, preferably as an antimicrobial such as an antibiotic and e.g. an anti-hypoxic medicament.
In another aspect, the invention provides a compound of the invention for use in the treatment of acne.
In a further aspect, the present invention provides a compound of the invention for use in the preparation of a medicament for the treatment of a disease mediated by a microorganism such as a bacterium, for example:
diseases mediated by bacteria, for example selected from staphylococci, streptococci, enterococci;
diseases mediated by bacteria, for example selected from the group consisting of moraxella, haemophilus, legionella, neisseriaceae;
diseases mediated by helicobacter;
diseases mediated by mycobacterium tuberculosis; such as diseases mediated by mycoplasma, chlamydia and obligate anaerobes.
In a further aspect, the present invention provides a method of treating a disease mediated by a microorganism, which comprises administering to a subject in need of such treatment an effective amount of a compound of the present invention, e.g., in the form of a pharmaceutical composition.
In a further aspect, the present invention provides a method for treating acne comprising administering to a subject in need of such treatment an effective amount of a compound of the invention, e.g. in the form of a pharmaceutical composition.
Treatment includes both treatment and prevention.
For antimicrobial and acne treatment, the appropriate dosage will, of course, vary depending upon, for example, the chemical nature and pharmacokinetic data of the compound of the invention employed, the host individual, the mode of administration, and the nature and severity of the condition being treated. In general, however, in order to achieve satisfactory results in most mammals, e.g. humans, a recommended daily dose is from about 0.5mg to 3g of a compound of the invention, suitably administered, e.g. in divided doses up to four times a day.
The compounds of the invention may be administered, for example, in the form of coated or uncoated tablets, capsules, injectable solutions or suspensions, for example in the form of ampoules, vials, emulsions, gels, pastes, inhalation powders, foams, tinctures, lipsticks, drops, sprays, or in the form of suppositories, for example in a form analogous to that of macrocyclic lactones, for example erythromycin, such as clarithromycin and azithromycin, by any conventional route, for example enterally, including, for example, nasal, buccal, rectal, oral administration; parenteral administration, including, for example, intravenous, intramuscular, subcutaneous administration; or topical administration, including, for example, transdermal, intranasal, intratracheal administration.
The compounds of the invention may be administered in the following forms: in the form of a pharmaceutically acceptable salt, for example an acid addition salt or a base addition salt such as a metal salt; or administered in free form; optionally in the form of a solvate. The compounds of the invention in salt form exhibit the same degree of activity as the compounds of the invention in free form, optionally in solvate form.
According to the present invention, the compounds of the present invention may be used in pharmaceutical therapy, either alone or in combination with one or more other pharmaceutically active agents. Such other pharmaceutically active agents include, for example, other antibiotics and anti-inflammatory agents, and if the compounds of the present invention are used to treat acne, other pharmaceutical agents include additional drugs effective against acne.
Said combination comprises a fixed combination wherein the two or more pharmaceutically active agents are in the same formulation; kits in which two or more pharmaceutically active ingredients are sold in separate formulations and in the same package, e.g., with instructions for co-administration; and free combinations, wherein the pharmaceutically active agents are packaged separately, but instructions for simultaneous or sequential administration are given.
In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention in free form or in pharmaceutically acceptable salt form and/or solvate form; and at least one pharmaceutically acceptable excipient, such as a carrier or diluent, including, for example, fillers, binders, disintegrants, flow regulators, lubricants, sugars and sweeteners, fragrances, preservatives, stabilizers, wetting and/or emulsifying agents, solubilizers, salts for regulating osmotic pressure and/or buffering agents.
In another aspect, the invention provides a pharmaceutical composition according to the invention, further comprising another pharmaceutically active agent.
The pharmaceutical compositions may be manufactured, for example, in a manner similar to conventional methods, e.g., by mixing, granulating, coating, dissolving or lyophilizing processes. The unit dosage form may contain, for example, from about 0.5mg to about 2000mg, such as from 10mg to about 500mg, of the active ingredient.
The compounds of the invention are also suitable for use as veterinary, e.g. veterinary active compounds, e.g. for the prevention and treatment of microbial, e.g. bacterial, diseases in animals, e.g. poultry, pigs and cattle; and dilution liquids such as are used in artificial insemination and egg soaking techniques.
In another aspect, the present invention provides a compound of the invention for use as a veterinary drug.
In a further aspect, the present invention provides a compound of the invention for use in the preparation of a veterinary composition for use as a veterinary drug.
In another aspect, the present invention provides a veterinary method of prevention and treatment of microbial, e.g. bacterial, diseases, which comprises administering to a subject in need of such treatment an effective amount of a compound of the present invention, e.g. in the form of a veterinary composition.
The present invention also provides a method of treating a microbial infection in an animal, particularly a human and domestic mammal, comprising administering to a patient in need of treatment a compound of the present invention, or a pharmaceutically acceptable salt or derivative or solvate thereof, or a composition of the present invention.
The invention also provides the use of a compound of the invention or a pharmaceutically acceptable salt or derivative or solvate thereof in the manufacture of a medicament for the treatment of a microbial infection.
In another aspect, the present invention also provides a use of the compound of formula (I), a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deutero-compound thereof, or a stereoisomer thereof in the preparation of a medicament for treating and/or preventing a disease caused by a microorganism.
In a further aspect, the present invention also provides a method for the treatment and/or prevention of a disease caused by microorganisms, which comprises administering a compound of the general formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to the present invention to a mammal, such as a human, in need of such treatment or prevention.
The invention also provides a pharmaceutical preparation, such as oral preparation, injection, inhalation, nasal preparation, ophthalmic preparation, percutaneous absorption preparation, rectal administration preparation, ointment or gel, containing the compound of the general formula (I), pharmaceutically acceptable salt thereof, prodrug thereof, solvate thereof, deuteron or stereoisomer thereof. In another aspect, the pharmaceutical formulation of the present invention is in a spray form starting from nasal administration. The spray is an aqueous spray.
The invention also provides the use of a compound of formula (I) of the invention, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteron or a stereoisomer thereof, in the manufacture of a medicament suitable for nasal administration to reduce or eliminate nasal infection by pathogenic organisms.
The invention also provides the use of a compound of formula (I), a pharmaceutically acceptable salt, a prodrug, a solvate, a deutero-isomer or a stereoisomer thereof, for the manufacture of a medicament suitable for nasal administration for the prevention of recurrent otitis media or recurrent acute bacterial sinusitis.
The invention also provides the application of the compound of the general formula (I), the pharmaceutically acceptable salt, the prodrug, the solvate, the deuteron or the stereoisomer thereof in preparing the medicine for treating skin and soft tissue infection and acne.
Experiments prove that the pleuromutilin antibiotic compound has good antibacterial activity and can be used for treating and/or preventing diseases caused by microorganisms.
The beneficial effects of the compounds of the present invention are further illustrated below by antibacterial activity experiments, but this should not be understood as the only beneficial effects of the compounds of the present invention.
Experimental examples in vitro antibacterial Activity of the Compounds of the invention
Test strains: the following clinical isolates were purchased at public institutions.
Methicillin-resistant staphylococcus aureus (MRSA), methicillin-resistant staphylococcus epidermidis (MRSE), streptococcus pneumoniae, viridans streptococcus, and the like.
And (3) testing the sample: the chemical names and preparation methods of some compounds of the invention are shown in the preparation examples of each compound. Linezolid, commercially available.
The experimental method comprises the following steps: agar Dilution method, see National Committee for Clinical Laboratory standards, 2006.methods for Dilution of analytical chemistry Tests for bacterial That Grow Aerobically, Approved Standard- -Seventh Edition M7-A7Vol26, No.2, 2006. MIC represents the minimum inhibitory concentration.
Experimental results and conclusions:
TABLE 1 antibacterial Activity of some of the compounds of the invention
Figure BDA0000389361860000231
TABLE 2 antibacterial Activity of some of the compounds of the invention
Figure BDA0000389361860000232
TABLE 3 antibacterial Activity of some of the Compounds of the invention
Figure BDA0000389361860000233
Figure BDA0000389361860000241
TABLE 4 antibacterial Activity of some of the Compounds of the invention
Figure BDA0000389361860000242
TABLE 5 antibacterial Activity of some of the Compounds of the invention
Figure BDA0000389361860000243
TABLE 6 antibacterial Activity of some of the Compounds of the invention against MRSA
Figure BDA0000389361860000244
The experimental results show that the compound has better antibacterial activity on gram-positive strains and fastidious strains, and has better clinical application potential.
4. Detailed description of the preferred embodiments
The present invention will be described in further detail with reference to the following examples. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
The generic name "tiamulin" refers to the IUPAC systematic name (1S,2R,3S,4S,6R,7R,8R,14R) -3, 6-dihydroxy-2, 4,7, 14-tetramethyl-4-vinyl-tricyclo [5.4.3.0 ]1,8]Tetradecan-9-one. In the examples, the tiamulin derivatives were coded using a tiamulin numbering system similar to that described in H.Berner (Berner, H.; Schulz, G.; Schneider H.tetrahedron1982,36,1807-1811.)Numbering is performed.
Example 14 preparation of O- (p-toluenesulfonylacetyl) tiamulin (intermediate M1)
Figure BDA0000389361860000251
Tiamulin (SM1,37.8g,0.1mol) was dissolved in 60ml of dichloromethane, and triethylamine (15.15g,0.15mol) was added under nitrogen protection. After stirring for 30 min, the temperature was reduced to-15 ℃ and a solution of TosCl (13.75g,0.12mol) in dichloromethane was added dropwise. The mixture was stirred for 2 hours and 1.15L of water was added slowly. The organic phase was separated, dried and spin dried to give intermediate M1(44g, 96%).
With reference to the above preparation method, the following compounds can also be prepared:
Figure BDA0000389361860000252
example 114 preparation of O- (4-methylmorpholin-2-yl) methylthio) tiamulin (Compound 1)
Figure BDA0000389361860000253
(1) Preparation of 14-O- ((N-Boc-4-methylmorpholin-2-yl) methylthio) tiamulin
Figure BDA0000389361860000254
22-O-methylsulfonyl tiamulin (3g,6.369mmol), N-Boc-2-mercaptomethylmorpholine (3.0g,12.2mmol), aqueous NaOH (1N,1.12g) and triethylbenzylammonium chloride (300mg, 1.4mmol) were dissolved in 100mL of MTBE and reacted overnight at 90 ℃ under nitrogen protection, after concentration, water was added, extraction was performed with ethyl acetate, drying was performed, and after concentration, separation was performed by silica gel column (petroleum ether: ethyl acetate = 5: 1) to obtain 3.0g of a product with a yield of 79%.
(2) Preparation of 14-O- ((4-methylmorpholin-2-yl) methylthio) tiamulin trifluoroacetate
Figure BDA0000389361860000255
14-O- ((N-Boc-4-methylmorpholin-2-yl) thio) tiamulin (3.0g, 5.0mmol) was dissolved in 100mL DCM, 20mL trifluoroacetic acid was added, reaction was carried out at room temperature for 3h and concentrated to give an oil, which was used in the next reaction without purification.
(3) Preparation of 14-O- (4-methylmorpholin-2-yl) methylthio) tiamulin
Figure BDA0000389361860000261
Dissolving the product 14-O- ((4-methylmorpholin-2-yl) methylthio) tiamulin (400mg, 0.67mmol) in the last step in 10mL of methanol, adding formaldehyde (0.27g, 3.35mmol) in an ice-water bath, continuing to react for 2h, adding sodium triacetoxyborohydride (710mg, 3.35mmol), reacting for 15h at room temperature, adding water, extracting with ethyl acetate, drying, concentrating, and separating by a silica gel column (dichloromethane: methanol = 30: 1) to obtain the product 150mg with the yield of 44%.
The molecular formula is as follows: c28H45NO5S molecular weight: 507.3 Mass Spectrometry (m/e): 508.4(M +1)
1H-NMR(400MHz,CDCl3,δppm)δ:0.73(d,3H),0.88(d,3H),1.14-1.20(m,4H),1.22-1.48(m,8H),1.55-1.79(m,3H),1.79-1.95(m,1H),2.08-2.19(m,3H),2.21-2.35(m,6H),2.61-2.80(m,4H),3.18-3.27(m,3H),3.65-3.69(m,2H),3.86-3.87(m,1H),5.18-5.23(d,1H),5.34-5.37(d,1H),5.74-5.76(d,1H),6.45-6.49(m,1H).
Example 214 preparation of O- (1-methyl-4- ((2R) -2-amino-3-methylbutyryl) piperazin-2-yl) methylthio) tiamulin (Compound 2)
Figure BDA0000389361860000262
(1) Preparation of 14-O- ((N-Boc-1-methyl-4- ((2R) -2-amino-3-methylbutyryl) piperazin-2-yl) methylthio) tiamulin
Figure BDA0000389361860000263
22-O-methylsulfonyl tiamulin (1.0g,2.2mmol), N-Boc-3-mercaptomethyl-4-methylpiperazine (1.23g,5mmol),5mL of 1N aqueous NaOH solution and triethylbenzylammonium chloride (0.1g, 0.44mmol) were dissolved in 000mL of dioxane, reacted overnight at 90 ℃ under nitrogen protection, concentrated, added with water, extracted with ethyl acetate, dried, concentrated and separated by a silica gel column (petroleum ether: ethyl acetate = 10: 1) to give 2g of product in 60% yield.
(2) Preparation of 14-O- ((1-methyl-4- ((2R) -2-amino-3-methylbutyryl) piperazine-2-yl) methylthio) tiamulin trifluoroacetate
14-O- ((N-Boc-1-methyl-4- ((2R) -2-amino-3-methylbutyryl) piperazin-2-yl) methylthio) tiamulin (1.0g, 1.6mmol) was dissolved in 100mL DCM, 5mL trifluoroacetic acid was added, reaction was carried out at room temperature for 1h and concentration gave an oil which was used in the next reaction without purification.
(3) Preparation of 14-O- ((2R) -N-Boc-2-amino-2-cyclopropyl-acetyl- (1-methyl-4- ((2R) -2-amino-3-methylbutyryl) piperazin-2-yl) methylthio) tiamulin
Figure BDA0000389361860000272
The product of the previous step (300mg,0.59mmol), (R) -N-Boc-cyclopropylglycine (500mg, 2.3mmol), HATU (400mg, 1.1mmol) and 0.5mL DIEA were dissolved in 20mL THF, reacted at room temperature for 1h, added water, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated to give a yellow oil which was used in the next reaction without purification.
(4) Preparation of 14-O- (1-methyl-4- ((2R) -2-amino-3-methylbutyryl) piperazin-2-yl) methylthio) tiamulin
Figure BDA0000389361860000273
Dissolving the product of the last step in 20mL of dichloromethane, adding 5mL of trifluoroacetic acid, reacting at room temperature for 2h, evaporating the solvent to dryness, adding water, adjusting the pH with sodium bicarbonate to =8, extracting with dichloromethane, drying, concentrating, and separating with a silica gel column (dichloromethane: methanol = 50: 1) to obtain 100mg of the product, wherein the yield of the two steps is 28%.
The molecular formula is as follows: c33H55N3O5S molecular weight: 605.4 Mass Spectrometry (m/e): 606.4(M +1)
1H-NMR(400MHz,CDCl3,δppm)δ:6.55(m,1H),5.75(t,1H),5.33(d,1H),5.22(d,1H),5.18(d,1H),4.15-4.4(m,1H),3.55-3.85(m,1H),3.5(m,1H),3.2-3.3(m,2H),3.1-3.2(m,3H),2.55-3.0(m,4H),2.4-2.5(m,4H),2.3-2.35(m,4H),2.15(t,1H),1.8-1.9(t,2H),1.5.9(m,7H),1.4(d,3H),1.3(m,4H),1.2(m,5H),0.9(m,3H).0.8(m,2H),0.7(m,3H).
With reference to the above preparation method, the following compounds can also be prepared:
example 314 preparation of O- (4- ((2R) -2-amino-3-hydroxypropionyl) morpholin-2-yl) methylthio) tiamulin (Compound 3)
Figure BDA0000389361860000281
The molecular formula is as follows: c30H48N2O7S molecular weight: 580.8
1H-NMR(400MHz,CDCl3,δppm)δ:0.65-0.80(m,3H),0.80-0.90(m,3H),1.05-1.20(m,4H),1.20-1.30(m,3H),1.40-1.50(m,4H),1.55-1.80(m,3H),2.05-2.40(m,5H),2.60-2.80(m,2H),3.20-3.40(m,5H),3.40-3.55(m,1H),3.55-3.70(m,2H),3.70-4.10(m,5H),4.20-4.30(d,1H),4.35-4.45(d,1H),4.50-4.60(s,1H),4.67-4.75(s,1H),5.20(d,1H),5.30-5.40(m,1H),5.70(m,1H),6.35-6.50(m,1H)
Example 414 preparation of O- (4- ((2R) -2-amino-2-cyclopropylacetyl) morpholin-2-yl) methylthio) tiamulin (Compound 4)
Figure BDA0000389361860000282
The molecular formula is as follows: c32H50N2O6S molecular weight: 590.3 Mass Spectrometry (m/e): 591.5(M +1)
1H-NMR(400MHz,CDCl3,δppm)δ:0.45(m,2H),0.588(m,2H),0.725(m,3H),0.872-0.885(d,3H),1.04-1.16(m,4H),1.24-1.37(m,4H),1.53-1.56(m,6H),1.64-1.75(m,3H),2.00-2.23(m,4H),2.68-2.72(m,2H),2.98-3.08(t,1H),3.1-3.67(m,4H),3.48-3.77(m,3H),3.83-3.89(d,1H),3.92(t,2H),4.34-4.56(m,2H),5.17-5.35(m,2H),5.73-5.75(d,1H),6.43-6.50(m,1H)
Example 514 preparation of O- (4- ((2R) -2-amino-3, 3-dimethylbutyryl) morpholin-2-yl) methylthio) tiamulin (Compound 5)
Figure BDA0000389361860000283
The molecular formula is as follows: c33H54N2O6S molecular weight: 606.4 Mass Spectrometry (m/e): 607.3(M +1)
1H-NMR(400MHz,CDCl3,δppm)δ:0.70-0.75(m,3H),0.85-0.90(m,3H),0.95-1.05(d,9H), 1.10-1.20(m,4H),1.20-1.43(m,4H),1.43-1.52(m,5H),1.52-1.60(d,1H),1.60-1.80(m,4H),2.02-2.16(m,2H),2.16-2.40(m,3H),2.52-2.88(m,3H),2.95-3.32(m,2H),3.32-3.42(s,1H),3.42-3.68(m,3H),3.80-4.05(m,2H),4.38-4.65(m,1H),5.20(d,1H),5.30-5.40(m,1H),5.75(d,1H),6.43-6.53(m,1H)
Example 614 preparation of O- (4- ((2R) -2, 3-Diaminopropionyl) morpholin-2-yl) methylthio) tiamulin (Compound 6)
Figure BDA0000389361860000291
The molecular formula is as follows: c30H49N3O6S molecular weight: 579.3 Mass Spectrometry (m/e): 580.4(M +1)
1H-NMR(400MHz,CDCl3,δppm)δ:6.47(q,1H),5.75(d,1H),5.34(d,1H),5.20(d,1H),4.33-4.49(m,1H),3.56-3.95(m,5H),3.22-3.37(m,3H),2.68-2.76(m,3H),2.03-2.34(m,13H),1.54-1.79(m,5H),1.45(s,3H),1.25(s,3H),1.17(s,3H),0.88(d,3H),0.73(d,3H).
Example 714 preparation of O- ((2R) -4-prolylmorpholin-2-yl) methylthio) tiamulin (Compound 7)
Figure BDA0000389361860000292
The molecular formula is as follows: c32H50N2O6S molecular weight: 590.8 Mass Spectrometry (m/e): 591.4(M +1)
1H-NMR(400MHz,CDCl3,δppm)δ:0.70-0.75(m,3H),0.80-0.90(m,3H),1.10-1.20(m,4H),1.20-1.35(m,2H),1.35-1.42(m,3H),1.42-1.50(m,4H),1.50-1.70(m,2H),1.70-1.90(m,3H),1.90-2.02(m,1H),2.02-2.13(m,2H),2.13-2.40(m,4H),2.60-2.95(m,3H),2.95-3.42(m,5H),3.42-4.02(m,5H),4.15-4.50(m,2H),5.20(d,1H),5.30-5.35(m,1H),5.73(d,1H),6.43-6.53(m,1H).
Example 814 preparation of O- ((2R, 4S) -4-Hydroxyprolylmorpholin-2-yl) methylthio) tiamulin (Compound 8)
Figure BDA0000389361860000293
The molecular formula is as follows: c32H50N2O7S molecular weight: 606.3 Mass Spectrometry (m/e): 607.4(M +1)
1H-NMR(400MHz,CDCl3,δppm)δ:0.73(d,3H),0.88(d,3H),1.04-1.20(m,4H),1.22-1.47(m,7H),1.57-1.79(m,3H),1.79-1.95(m,2H),2.08-2.47(m,6H),2.51-2.87(m,4H),2.87-3.36(m,7H),3.37(m,1H),3.47-3.50(m,1H),3.6(s,1H),3.92(m,2H),4.2-4.51(m,2H),5.18-5.22(d,1H),5.32-5.35(d,1H),5.73-5.75(d,1H),6.43-6.48(m,1H).
Example 914-O- (4- ((2R) -2-amino)Preparation of (E) -2- (4-fluorophenyl) acetyl) morpholin-2-yl) methylthio) tiamulin (Compound 9)
Figure BDA0000389361860000301
The molecular formula is as follows: c35H49FN2O6S molecular weight: 644.8 Mass Spectrometry (m/e): 645.0(M +1)
1H-NMR(400MHz,CDCl3,δppm)δ:0.65-0.75(m,3H),0.80-0.90(m,3H),1.10-1.20(m,4H),1.20-1.40(m,3H),1.40-1.55(m,4H),1.55-1.70(m,2H),1.70-1.80(d,1H),1.80-2.00(m,4H),2.00-2.12(m,3H),2.12-2.25(m,2H),2.25-2.55(m,1H),2.55-3.00(m,4H),3.10-3.20(m,1H),3.20-3.40(m,2H),3.50-3.65(m,1H),3.70-3.90(m,1H),4.35-4.50(m,1H),4.50-4.70(m,1H),5.15-5.25(d,1H),5.25-5.35(m,1H),5.65-5.75(t,1H),6.40-6.50(m,1H),7.00-7.10(m,2H),7.20-7.35(m,2H).
Example 1014 preparation of O- (1- ((2R) -2-amino-3-methylbutyryl)) morpholin-2-yl) methylthio) tiamulin (Compound 10)
Figure BDA0000389361860000302
Mass Spectrum (m/e): 593(M + H)+
1H-NMR(400MHz,MeOD,δppm)δ:6.32(m,1H),5.76(m,1H),5.17(m,2H),4.14(m,1H),3.92(m,2H),3.63(m,2H),3.47(m,3H),3.08(m,4H),1.99-2.42(m,7H),1.54-1.89(m,4H),1.44(s,3H),0.97-1.40(m,12H),0.93(s,3H),0.74(s,3H).
Example 1114 preparation of O- (4- ((2R) -2-amino-3-methylbutyryl)) morpholin-2-yl) methylthio) tiamulin (Compound 11)
Figure BDA0000389361860000311
Mass Spectrum (m/e): 593(M + H)+
1H-NMR(400MHz,DMSO,δppm)δ:6.13(m,1H),5.55(m,1H),5.03(m,2H),4.32(m,1H),4.15(m,1H),3.85(m,3H),3.31(m,4H),3.17(m,1H),2.96(m,1H),2.71(m,3H),2.38(s,1H),1.95-2.23(m,6H),1.40-1.70(m,4H).1.16-1.33(m,10H).1.05(m,3H),0.70-1.12(m,6H),0.60(m,3H).
Example 1214-preparation of O- (4- ((2R) -2-amino-2- (thien-2-yl) acetyl) morpholin-2-yl) methylthio) tiamulin (Compound 12)
Figure BDA0000389361860000312
The molecular formula is as follows: c33H48N2O6S2Molecular weight: 632.3 Mass Spectrometry (m/e): 632.9(M +1)
1H-NMR(400MHz,CDCl3,δppm)δ:7.26(s,2H),6.90-7.00(m,2H),6.44-6.52(m,1H),5.75(d,1H),5.33-5.36(m,1H),4.97-5.20(m,2H),4.40-4.56(m,1H),3.82-3.95(m,1H),3.42-3.74(m,2H),3.36(d,1H),3.22-3.27(m,2H),2.79-3.11(m,2H),2.50-2.79(m,2H),1.84-2.50(m,9H),1.48-1.84(m,5H),1.21-1.41(m,4H),1.09-1.21(m,4H),0.88(d,3H),0.74(d,3H).
Example 1314 preparation of O- (4- ((2R) -2-amino-2- (4-chlorophenyl) acetyl) morpholin-2-yl) methylthio) tiamulin (Compound 13)
Figure BDA0000389361860000313
Mass Spectrum (m/e): 661(M +1)
1H-NMR(400MHz,CDCl3,δppm)δ:7.33-7.23(m,4H),6.49-6.45(m,1H),5.74(d,1H),5.30-5.18(m,2H),4.69-4.66(m,2H),3.95-3.79(m,1H),3.61-3.51(m,2H),3.42-3.37(m,2H),3.20-3.15(m,2H),2.88-2.72(m,4H),2.41-2.01(m,4H),1.99-1.60(m,9H),1.63-1.50(m,4H),1.48-1.31(m,7H),1.22-1.31(m,4H),1.11-1.02(m,3H),0.81(d,3H),0.62(d,3H).
Example 1414 preparation of O- (4- ((2R) -2-amino-2- (4-hydroxyphenyl) acetyl) morpholin-2-yl) methylthio) tiamulin (Compound 14)
Figure BDA0000389361860000321
Mass Spectrum (m/e): 643(M +1)
1H-NMR(400MHz,CDCl3,δppm)δ:7.13-7.11(m,2H),6.73-6.71(m,2H),6.49-6.45(m,1H),5.74(d,1H),5.30-5.18(m,2H),4.69-4.66(m,2H),3.95-3.79(m,1H),3.61-3.51(m,2H),3.42-3.37(m,2H),3.20-3.15(m,2H),2.88-2.72(m,4H),2.41-2.01(m,4H),1.99-1.60(m,9H),1.63-1.50(m,4H),1.48-1.31(m,7H),1.22-1.31(m,4H),1.11-1.02(m,3H),0.81(d,3H),0.62(d,3H).
Example 1414 preparation of O- (4- ((2R) -2-amino-2- (4-hydroxyphenyl) acetyl) morpholin-2-yl) methylthio) tiamulin (Compound 14)
Figure BDA0000389361860000322
Mass Spectrum (m/e): 643(M +1)
1H-NMR(400MHz,CDCl3,δppm)δ:7.13-7.11(m,2H),6.73-6.71(m,2H),6.49-6.45(m,1H),5.74(d,1H),5.30-5.18(m,2H),4.69-4.66(m,2H),3.95-3.79(m,1H),3.61-3.51(m,2H),3.42-3.37(m,2H),3.20-3.15(m,2H),2.88-2.72(m,4H),2.41-2.01(m,4H),1.99-1.60(m,9H),1.63-1.50(m,4H),1.48-1.31(m,7H),1.22-1.31(m,4H),1.11-1.02(m,3H),0.81(d,3H),0.62(d,3H).
Example 1514 preparation of O- (4- ((2R) -2-amino-2- (pyridin-3-yl) acetyl) morpholin-2-yl) methylthio) tiamulin (Compound 15)
Mass Spectrum (m/e): 628(M +1)
1H-NMR(400MHz,CDCl3,δppm)δ:8.50-8.60(m,2H),7.59-7.73(m,1H),7.28-7.34(m,1H),6.40-6.50(m,1H),5.69-5.74(m,1H),5.29-5.34(m,1H),5.19(d,1H),4.73-4.80(m,1H),4.41-4.53(m,1H),3.45-3.96(m,3H),3.07-3.42(m,3H),2.49-3.01(m,5H),2.14-2.41(m,4H),1.83-2.14(m,5H),1.48～-1.82(m,5H),1.21-1.41(m,4H),1.09-1.21(m,4H),0.88(d,3H),0.74(d,3H)。

Claims (10)

1. A compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof:
Figure FDA0000389361850000011
wherein,
Q1、Q2independently-O-, -S-, -SO2-、-NR1-；
R1Is hydrogen, C1-6Alkyl, halo C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, hydroxy C1-6Alkyl, carboxyl C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl radical, C1-6Alkoxycarbonyl group, C1-6Alkylsulfinyl radical, C1-6Alkylsulfonyl, sulfonic acid, sulfonyl C1-6Alkyl, sulfonamide C1-6Alkyl, aminosulfonyl, C1-6Alkylaminosulfonyl, di (C)1-6Alkyl) aminosulfonyl, aminosulfonyl C1-6Alkyl radical, C1-6Alkylaminocarbonyl, di (C)1-6Alkyl) carbamoyl, carbamoyl C1-6Alkyl, 3-14 membered cycloalkyl, 6-14 membered aryl C1-6Alkyl, 3-14 membered heterocyclic group C1-6An alkyl group, a carboxyl group,
or a group of the formula
Figure FDA0000389361850000012
R3And R4Independently are:
(1) hydrogen, amino, hydroxyl, mercapto, carboxyl, guanidino,
(2) unsubstituted or substituted by 1 to 3 identical or different R5Substituted: c1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkylamino radical, C1-6Alkylthio, carboxyl C1-6Alkyl, hydroxy C1-6Alkyl, carbamoyl C1-6An alkyl group, a carboxyl group,
(3) unsubstituted or substituted by 1 to 3 identical or different R5Substituted: a 3-14 membered cycloalkyl group, a 3-14 membered heterocyclyl group or a 6-14 membered aryl group,
or R3And R4Taken together with the C atom to which they are attached to form unsubstituted or 1-3 identical or different R6A substituted 3-14 membered cyclic group,
R5、R6is independently selected fromHalogen, hydroxy, amino, carboxy, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, hydroxy C1-6Alkyl, amino C1-6Alkyl, carboxyl C1-6Alkyl radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, aminosulfonyl C1-6Alkyl, carbamoyl C1-6Alkyl radical, C1-6Alkylcarbonyl group, C1-6Alkyl carbonyl oxy, C1-6Alkoxycarbonyl, phenyl, 3-14 membered cycloalkyl or 3-14 membered heterocyclyl;
R2represents 1-3 substituents selected from hydrogen, halogen, C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino, C1-6Alkylamino radical, di (C)1-6Alkyl) amino or C1-6An alkylaminocarbonyl group;
x is-O-, -S-, -SO2-、-COO-、-NR7R7’、-CONR7R7’-NHCONH-or a bond;
R7、R7’is hydrogen or C1-6An alkyl group;
m and n are each independently 0, 1,2,3 or 4.
2. The compound of claim 1, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride, or a stereoisomer thereof:
wherein X is-S-.
3. The compound of claim 1 or 2, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof:
wherein,
Q1、Q2independently is-O-, -NR1-；
R1Is hydrogen, C1-6Alkyl, or a group of the formula
Figure FDA0000389361850000021
R3And R4Are respectively and independently
(1) Hydrogen, amino, hydroxyl, mercapto, carboxyl, guanidino,
(2) unsubstituted or substituted by 1 to 3 identical or different R5Substituted: c1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkylamino radical, C1-6Alkylthio, carboxyl C1-6Alkyl, hydroxy C1-6Alkyl, carbamoyl C1-6An alkyl group, a carboxyl group,
(3) unsubstituted or substituted by 1 to 3 identical or different R5Substituted: a 3-14 membered cycloalkyl group, a 3-14 membered heterocyclyl group or a 6-14 membered aryl group,
or R3And R4Taken together with the C atom to which they are attached to form unsubstituted or 1-3 identical or different R6A substituted 3-14 membered cyclic group,
R5、R6independently selected from halogen, hydroxy, amino, carboxyl, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, hydroxy C1-6Alkyl, amino C1-6Alkyl, carboxyl C1-6Alkyl radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, aminosulfonyl C1-6Alkyl, carbamoyl C1-6Alkyl radical, C1-6Alkylcarbonyl group, C1-6Alkyl carbonyl oxy, C1-6Alkoxycarbonyl, phenyl, 3-to 14-membered cycloalkyl or 3-to 14-membered heterocyclyl,
R2represents 1-3 substituents selected from hydrogen, halogen, C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino, C1-6Alkylamino radical, di (C)1-6Alkyl) amino or C1-6An alkylaminocarbonyl group;
m and n are each independently 0, 1 or 2.
4. The compound of claim 3, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride, or a stereoisomer thereof:
wherein,
Q1、Q2independently is-O-, -NR1-；
R1Is hydrogen, C1-4Alkyl, or a group of the formula
Figure FDA0000389361850000031
R3And R4Are respectively and independently
(1) Hydrogen, amino, hydroxyl, mercapto, carboxyl, guanidino,
(2) unsubstituted or substituted by 1-2 identical or different R5Substituted: c1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Alkylamino radical, C1-4Alkylthio, carboxyl C1-4Alkyl, hydroxy C1-4Alkyl, carbamoyl C1-4An alkyl group, a carboxyl group,
(3) unsubstituted or substituted by 1-2 identical or different R5Substituted: a 3-8 membered cycloalkyl group, a 3-8 membered heterocyclyl group or a 6-14 membered aryl group,
or R3And R4Taken together with the C atom to which they are attached to form unsubstituted or 1-2 identical or different R6A substituted 3-6 membered cyclic group,
R5、R6independently selected from halogen, hydroxy, amino, carboxyl, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl, halo C1-4Alkoxy, hydroxy C1-4Alkyl, amino C1-4Alkyl, carboxyl C1-4Alkyl radical, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, aminosulfonyl C1-4Alkyl, carbamoyl C1-4Alkyl radical, C1-4Alkylcarbonyl group, C1-4Alkyl carbonyl oxy, C1-4Alkoxycarbonyl, phenyl, 3-to 8-membered cycloalkyl or 3-to 8-membered heteroA cyclic group;
R2selected from hydrogen, halogen, C1-4Alkyl, halo C1-4Alkyl, hydroxy C1-4Alkyl, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino or C1-4An alkylaminocarbonyl group;
m is 0 or 1;
n is 0, 1 or 2.
5. The compound of claim 4, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride, or a stereoisomer thereof:
wherein,
Q1、Q2independently is-O-, -NR1-；
R1Is hydrogen, C1-4Alkyl, or a group of the formula
Figure FDA0000389361850000032
R3And R4Are respectively and independently
(1) Hydrogen, amino, hydroxyl, mercapto, carboxyl, guanidino,
(2) unsubstituted or substituted by R5Substituted: c1-4Alkyl radical, C1-4Alkylamino radical, C1-4Alkylthio, carbamoyl C1-4An alkyl group, a carboxyl group,
(3) unsubstituted or substituted by R5Substituted: cyclopentane, cyclohexane, cyclopentene, cyclohexene, 1, 3-cyclohexadiene, tetrahydropyrrole, 2, 3-dihydropyrrole, 2, 5-dihydropyrrole, pyrrole, imidazole, 4, 5-dihydroimidazole, pyrazole, 4, 5-dihydropyrazole, 1,2, 3-triazole, tetrahydrothiophene, thiophene, 2, 3-dihydrothiophene, thiazole, 4, 5-dihydrothiazole, isothiazole, tetrahydrofuran, 2, 3-dihydrofuran, furan, 4, 5-dihydrooxazole, oxazole, 4, 5-dihydroisoxazole, isoxazole, benzene rings, 1,4,5, 6-tetrahydropyrimidine, 1, 6-dihydropyrimidine, 4, 5-dihydropyrimidine, pyrimidine, 3, 6-dihydro-2H-pyran, piperidine, 1,2,3, 4-tetrahydropyridine, 1,2,3, 6-tetrahydropyridine, 2, 3-dihydropyridine, pyridine, and their use,Pyridine, piperazine, 1,2,3, 4-tetrahydropyrazine, 2, 3-dihydropyrazine or pyrazine,
or R3And R4Taken together with the C atom to which they are attached to form an unsubstituted or substituted R6Substituted: cyclopentane, cyclohexane, cyclopentene, cyclohexene, 1, 3-cyclohexadiene, tetrahydropyrrole, 2, 3-dihydropyrrole, 2, 5-dihydropyrrole, pyrrole, imidazole, 4, 5-dihydroimidazole, pyrazole, 4, 5-dihydropyrazole, 1,2, 3-triazole, tetrahydrothiophene, thiophene, 2, 3-dihydrothiophene, thiazole, 4, 5-dihydrothiazole, isothiazole, tetrahydrofuran, 2, 3-dihydrofuran, furan, 4, 5-dihydrooxazole, oxazole, 4, 5-dihydroisoxazole, isoxazole, benzene rings, 1,4,5, 6-tetrahydropyrimidine, 1, 6-dihydropyrimidine, 4, 5-dihydropyrimidine, pyrimidine, 3, 6-dihydro-2H-pyran, piperidine, 1,2,3, 4-tetrahydropyridine, 1,2,3, 6-tetrahydropyridine, 2, 3-dihydropyridine, pyridine, piperazine, 1,2,3, 4-tetrahydropyrazine, 2, 3-dihydropyrazine or pyrazine,
R5、R6independently selected from hydrogen, fluoro, chloro, carboxy, methyl, trifluoromethyl, hydroxy, hydroxymethyl, amino, methylamino, ethylamino, methylaminoformyl or ethylaminoformyl;
R2is hydrogen;
m is 0 or 1;
n is 0, 1 or 2.
6. The compound of claim 5, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride, or a stereoisomer thereof:
wherein,
Q1、Q2independently is-O-, -NR1-；
R1Is hydrogen, methyl, ethyl, or a group of the formula
Figure FDA0000389361850000041
R3And R4Are respectively and independently
(1) Hydrogen, amino, hydroxyl, mercapto, carboxyl, guanidino,
(2) unsubstituted or substituted by R5Substituted: methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, methylmercapto, methylamino, ethylamino,
(3) unsubstituted or substituted by R6Substituted: cyclopropane, cyclopentane, cyclohexane, tetrahydropyrrole, pyrrole, thiazole, thiophene, imidazole, isothiazole, tetrahydrofuran, furan, oxazole, benzene ring, pyridine,
or R3And R4Taken together with the C atom to which they are attached to form an unsubstituted or substituted R6Substituted cyclopentane, cyclohexane, tetrahydropyrrole, piperidine or piperazine,
R5、R6independently selected from hydrogen, fluoro, chloro, amino, carboxy, hydroxy, methyl, trifluoromethyl, hydroxymethyl, methylamino, ethylamino, methylaminoformyl or ethylaminoformyl;
R2is hydrogen;
m is 0 or 1;
n is 0, 1 or 2.
7. The compound of claim 1, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride, or a stereoisomer thereof, selected from:
Figure FDA0000389361850000051
Figure FDA0000389361850000061
a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride, or a stereoisomer thereof.
8. A pharmaceutical formulation comprising a compound as claimed in any one of claims 1 to 7, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteron or a stereoisomer thereof, and one or more pharmaceutically acceptable carriers and/or diluents, in any pharmaceutically acceptable dosage form.
9. A pharmaceutical composition comprising a compound of any one of claims 1-7, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride, or a stereoisomer thereof, and further comprising an additional pharmaceutically active ingredient.
10. Use of a compound of any one of claims 1-7, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteron, or a stereoisomer thereof, for the manufacture of a medicament for the treatment and/or prevention of a disease caused by a microorganism.
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CN104803926A (en) * 2015-03-25 2015-07-29 中国农业科学院兰州畜牧与兽药研究所 Pleuromutilin derivative with pyrimidine side chain and application of pleuromutilin derivative
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Publication number Priority date Publication date Assignee Title
US10849895B2 (en) 2014-10-24 2020-12-01 Landos Biopharma, Inc. Lanthionine synthetase C-like 2-based therapeutics
US11571419B2 (en) 2014-10-24 2023-02-07 Landos Biopharma, Inc. Lanthionine synthetase C-like 2-based therapeutics
CN104803926A (en) * 2015-03-25 2015-07-29 中国农业科学院兰州畜牧与兽药研究所 Pleuromutilin derivative with pyrimidine side chain and application of pleuromutilin derivative
CN104803926B (en) * 2015-03-25 2017-05-03 中国农业科学院兰州畜牧与兽药研究所 Pleuromutilin derivative with pyrimidine side chain and application of pleuromutilin derivative
CN105399684A (en) * 2015-11-03 2016-03-16 中国农业科学院兰州畜牧与兽药研究所 Pleuromutilin compound, preparation method of pleuromutilin compound, polymorphism and preparation method of polymorphism
CN105949146A (en) * 2016-05-06 2016-09-21 武汉工程大学 Pleuromutilin-tizoxanide hybrid drug and preparation method thereof
US11117881B2 (en) 2019-12-20 2021-09-14 Landos Biopharma, Inc. Lanthionine c-like protein 2 ligands, cells prepared therewith, and therapies using same
US11377437B2 (en) 2019-12-20 2022-07-05 Landos Biopharma, Inc. Lanthionine C-like protein 2 ligands, cells prepared therewith, and therapies using same

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