CN108947952A - 2- substituted-amino -5- trifluoromethyl -8- nitro benzo (thio) pyrans -4- ketone compounds and its preparation method and application - Google Patents

2- substituted-amino -5- trifluoromethyl -8- nitro benzo (thio) pyrans -4- ketone compounds and its preparation method and application Download PDF

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CN108947952A
CN108947952A CN201710371152.6A CN201710371152A CN108947952A CN 108947952 A CN108947952 A CN 108947952A CN 201710371152 A CN201710371152 A CN 201710371152A CN 108947952 A CN108947952 A CN 108947952A
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substituted
unsubstituted
compound
pharmaceutically acceptable
trifluoromethyl
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CN108947952B (en
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黄海洪
李鹏
李刚
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Institute of Materia Medica of CAMS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention discloses formula (I) 2- substituted-amino -5- trifluoromethyl -8- nitro benzo (thio) pyrans -4- ketone compounds, preparation method and treating and/or preventing the application in infectious disease medicament caused by mycobacterium tuberculosis.Specifically, the present invention relates to compound shown in formula (I) and its pharmaceutically acceptable salt and comprising the pharmaceutical composition of the compounds of this invention, wherein X, R1、R2, n as used in the description.The present invention is directed to prepare with the active noval chemical compound of Killing Mycobacterium Tuberculosis, it is as potential novel drugs, it can be used for the infectious diseases as caused by bacterium, the especially treatment or prevention treatment of the pulmonary tuberculosis as caused by mycobacteria (TB) disease, while can be used for overcoming the problems, such as related to drug resistance of Mycobacterium tuberculosis.

Description

2- substituted-amino -5- trifluoromethyl -8- nitro benzo (thio) pyrans -4- ketone Close object and its preparation method and application
Technical field
The invention belongs to pharmaceutical technology fields.In particular to 2- substituted-amino -5- trifluoromethyl -8- shown in logical formula (I) Nitro benzo (thio) pyrans -4- ketone compounds, preparation method, using the compound as the pharmaceutical composition of active constituent, And they are treating and/or are preventing the application in the infectious diseases as caused by mycobacterium tuberculosis.
Background technique
Tuberculosis (tuberculosis, TB) is a kind of chronic lethal disease as caused by mycobacterium tuberculosis, is danger Evil human health and the great communicable disease for leading to human death, according to the World Health Organization's global tuberculosis report in 2016 It has been shown that, the new hair cases of tuberculosis more than 1,000 ten thousand, dead 1,500,000 in the whole world in 2015.Tuberculosis as AIDS, becomes complete now One of world's major causes of death.Chemotherapy is the main means of tuberculotherapy.With isoniazid, rifampin, pyrazine acyl The successive appearance of amine, so that the treatment tuberculosis course for the treatment of enters " short-term chemotherapy epoch ".It is controlled nevertheless, long-term agents are combined It treats, patient is made to generate adverse reaction, it is difficult to adhere to regular medication, in addition multi-drug resistant tuberculosis (MDR-TB) and extensive drug resistance in recent years The disease incidence of tuberculosis (XDR-TB) is in rising trend, seriously threatens whole world prevention and control lungy.Therefore, novel resistive connection is researched and developed For nuclear pharmaceuticals to treat and control tuberculosis, especially drug resistance tuberculosis is especially urgent.In addition, being also required to for new antituberculotic Have the characteristics that efficient, treatment time can be shortened and there is high security etc..
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of structure novel and there is the active 2- of Killing Mycobacterium Tuberculosis Substituted-amino -5- trifluoromethyl -8- nitro benzo (thio) pyrans -4- ketone compounds.The inventors discovered that 2- replaces ammonia Base -5- trifluoromethyl -8- nitro benzo (thio) pyrans -4- ketone compounds have preferable Killing Mycobacterium Tuberculosis effect, It can be used for the infectious diseases as caused by bacterium, the especially treatment or prevention of the pulmonary tuberculosis as caused by mycobacteria (TB) disease Property treatment, while can be used for overcoming the problems, such as related with drug resistance.It is accomplished the present invention is based on the above discovery.
Summary of the invention
For this purpose, first aspect present invention provides logical formula (I) compound represented and its pharmaceutically acceptable salt,
Wherein,
X is O or S；
N is 0,1,2 or 3；
R1For H, substituted or unsubstituted C1-C3Alkyl, substituted or unsubstituted C3-C6Naphthenic base；
R2For substituted or unsubstituted C3-C6Naphthenic base, substituted or unsubstituted C3-C6It is heterocycle, substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted C2-C9Heteroaryl；
The C3-C6Heterocycle, C2-C9Heteroaryl at least contains a hetero atom in N, O, S；
The R1And R2In substituted or unsubstituted substituent group can be optionally from following group: F, Cl, Br, hydroxyl, amino, nitre Base, cyano, trifluoromethyl, trifluoromethoxy, C1-C3Alkyl, benzyl, cyclohexyl methyl, halogenated C1-C3Alkyl, C1-C3Alkoxy Or C1-C3Alkylamino radical.
In a preferred example, the structural formula of compound such as (II) is shown:
Wherein, R1、R2It defines with n with described in first aspect present invention.
In another preferred example, the structural formula of compound such as (III) is shown:
Wherein, R1、R2It defines with n with described in first aspect present invention.
In another preferred example, as shown in formula (II) or (III), wherein
N is 0 or 1；
R1For H, CH3Or cyclopropyl；
R2For substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl group, substitution Or unsubstituted quinolines base, substituted or unsubstituted furyl, substituted or unsubstituted pyrrole radicals, substituted or unsubstituted thiophene Base and substituted or unsubstituted thiazolyl；
The R2In substituted or unsubstituted substituent group can be optionally from following group: F, Cl, Br, hydroxyl, amino, nitro, Cyano, trifluoromethyl, trifluoromethoxy, C1-C3Alkyl, benzyl, cyclohexyl methyl, halogenated C1-C3Alkyl, C1-C3Alkoxy or C1-C3Alkylamino radical.
Heretofore described pharmaceutically acceptable salt is the compounds of this invention and the salt selected from following acid formation: salt Acid, p-methyl benzenesulfonic acid, tartaric acid, maleic acid, lactic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid or trifluoroacetic acid.It is preferred that For hydrochloric acid, p-methyl benzenesulfonic acid or trifluoroacetic acid.
The compound of any one according to a first aspect of the present invention, the target compound of the present invention prepared for embodiment (with It is that structural formula indicates or with systematic naming method description) and its pharmaceutically acceptable salt.
Any one compound according to a first aspect of the present invention, for selected from following compound:
Second aspect of the present invention provides the method for any one of the preparation first aspect present invention compound comprising with Lower step:
Compound A is in suitable solvent (such as methylene chloride, tetrahydrofuran, acetonitrile, preferably methylene chloride), with amine Class compound N HR1(CH2)nR2, under the action of condensation reagent (such as CDI, DCC, EDCI HOBT, HATU, preferably DCC), In air or inert gas (Ar or N2) under protection, be placed in -10 DEG C -20 DEG C or room temperature and react 1-24 hours, wherein it is preferred that room Temperature reaction 8-15 hours, obtains compound shown in formula B；
Compound shown in formula B is in solvent appropriate (such as DMF, DMSO, preferably DMF), in alkaline condition (such as carbonic acid Sodium, potassium carbonate or cesium carbonate, preferably potassium carbonate) under, in inert gas (Ar or N2) under protection, at room temperature or 20-110 DEG C Reaction is reacted 1-5 hours under the conditions of 0.5-12 hours, preferably 110 DEG C, obtains formula (II) compound.
Compound A in the present invention can be easy to be made with reference to known method in existing publication, such as (J. Med.Chem.2007,50,3369-3379)。
Compound C and carbon disulfide suitable solvent (such as toluene, acetone, tetrahydrofuran, DMF, DMSO, preferably DMSO in), in alkaline condition (such as NaH, sodium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, preferably hydrogen-oxygen Change sodium) under, in air or inert gas (Ar or N2) under protection, reacted 10-60 minutes, preferably 15-25 DEG C at -10-30 DEG C Lower 15-30 minutes, MeI is then added at 15-25 DEG C, reacts 30-60 minutes, obtains compound D；
Compound D and aminated compounds NHR1(CH2)nR2, suitable solvent (such as the tert-butyl alcohol, isopropanol, ethylene glycol, Glycol dimethyl ether, DMF, DMSO, preferably isopropanol) in, in air or inert gas (Ar or N2) under protection, in 80-160 React 1-48 hours at DEG C, preferably 120-140 DEG C reaction 20-25 hours, obtain formula (III) compound.
Third aspect present invention provides a kind of Pharmaceutical composition comprising the first aspect present invention of therapeutically effective amount is appointed One compound and its pharmaceutically acceptable salt, and optional one or more pharmaceutically acceptable auxiliary materials.
Fourth aspect present invention provides any one of first aspect present invention compound and its pharmaceutically acceptable salt, Or any one of third aspect present invention described pharmaceutical composition in preparation treatment and/or prevents to feel caused by mycobacterium tuberculosis Application in infectious diseases drug.
Content noted earlier only outlines certain aspects of the invention, but is not limited to this respect.These aspect and other Aspect content will do more specific complete description below.
Detailed description of the invention
It is further described to various aspects of the present invention with feature below.
All documents recited in the present invention, their full content are incorporated herein by reference, and if these are literary When offering expressed meaning and the inconsistent present invention, it is subject to statement of the invention.In addition, the various terms that use of the present invention and Phrase has that well known to a person skilled in the art general senses, nonetheless, the present invention remain desirable at this to these terms and Phrase is described in more detail and explains, the term and phrase referred to is if any inconsistent with common art-recognized meanings, with institute's table of the present invention Subject to the meaning stated.Here is the definition of a variety of terms used in the present invention, these definition are suitable for the application the whole instruction Term used, unless otherwise indicated in concrete condition.
In general, term it is " substituted or unsubstituted " indicate specifically taken to one or more hydrogen atoms in structure Replaced Dai Ji.Unless otherwise indicated, an optional substituent group can carry out at various substitutable position of that group Replace.When only one position can not be taken given structure by one or more substituent groups are obtained selected from specific group always Generation, then substituent group can replace at various locations identical or differently.
Ci-CjIndicate have integer " i " (including i) to the part of integer " j " (including j) a carbon atom.Thus, for example C1- C3Alkyl refers to the alkyl with 1 to 3 (comprising 1 and 3) carbon atom.Such as C2-C9Heteroaryl refers to 2 to 9 (comprising 2 and 9) The heteroaryl of carbon atom includes tetrazole base, triazol radical, thienyl, pyridyl group, pyrimidine radicals, quinolyl.
As described herein, term " alkyl " refers to the alkyl for specifying number carbon atom number, is linear chain or branched chain Alkyl, and it may include its subbase group, such as refer to " C1-C3It can also include C when alkyl "1-C2What alkyl indicated The group of subrange, and specific group such as methyl, ethyl, n-propyl, isopropyl.
As described herein, term " alkoxy " and " alkylamino radical " belong to idiomatic expression, refer to respectively through an oxygen original Son or amido are connected to the alkyl group of the rest part of molecule, and alkyl therein is as described herein.
As described herein, term " halogenated alkyl " indicates that the hydrogen on alkyl group is taken by one or more halogen atoms In generation, such example includes, but is not limited to, single methyl fluoride, single fluorine methoxyl group etc..
As described herein, term " naphthenic base " refers to the cyclic alkyl for specifying number ring carbon atom number, and its It may include its subbase group, such as refer to " C3-C6It can also include C when naphthenic base "3-C5Naphthenic base, C4-C6The tables such as naphthenic base The group of the subrange shown, and specific group such as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl.
As described herein, term " C3-C6Heterocyclylalkyl ", unless otherwise indicated or restriction is outer, refers to comprising 3-6 ring carbon The unsaturated monocyclic, bicyclic or tricyclic system of the saturation of atom or part, it is former that wherein at least one annular atom is selected from nitrogen, sulphur and oxygen Son.Unless otherwise stated, heterocycle can be carbon-based or nitrogen base, and-CH2Group can be substituted optionally by carbonyl.The sulphur of ring Atom can optionally be oxidized to S- oxide.Heterocycle alkane includes but is not limited to oxetanyl, azetidinyl, four Hydrogen furyl, nafoxidine base, tetrahydro-thiazoles base, piperidyl, piperazinyl, morpholinyl, thiomorpholine, high piperazine base etc..
As described herein, term " C6-C10Aryl " indicate the monocycle containing 6 annular atoms or 6-10 annular atom and pair The carbocyclic ring system of ring, wherein at least one ring be it is aromatic, wherein each ring includes the 3-6 molecular ring of original, and There are one or more attachment points to be connected in ring system with the rest part of molecule.Aromatic group may include phenyl and naphthalene.
As described herein, term " C2-C9Heteroaryl " refers to there is 1 to 3 hetero atom as annular atom herein, Remaining annular atom is the aromatic group of carbon, and hetero atom includes oxygen, sulphur and nitrogen.The example of heteroaryl include but is not limited to pyridyl group, Pyridazinyl, triazol radical, tetrazole base, oxazolyl, isoxazolyl, pyrimidine radicals, imidazole radicals, furyl, thienyl, pyrazinyl Deng.
As described herein, term " ring " indicates substituted or unsubstituted naphthenic base, substituted or unsubstituted Heterocycle, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.So-called ring includes condensed ring.On ring The number of atom is generally defined as first number of ring, such as " C3-C6Ring " refers to around 3-6 atom of arrangement.
As described herein, term " hetero atom " refers to O, S, N, the form of any oxidation state including N, S；Primary, secondary, uncle The form of amine and quaternary ammonium salt；Or the substituted form of hydrogen in heterocycle on nitrogen-atoms.
As described herein, term " halogen ", " halogenated " etc. indicate fluorine (F), chlorine (Cl) or bromine (Br).
" room temperature " refers to temperature by 10 DEG C to 40 DEG C in the present invention.In some embodiments, " room temperature " refers to temperature By 20 DEG C to 30 DEG C；In further embodiments, room temperature refers to 25 DEG C.
As described herein, term " effective quantity " refers to can realize desired treatment disease of the present invention in subject The drug dose of disease or illness.
As described herein, term " pharmaceutically acceptable " indicates the salt for example at description " pharmaceutically acceptable salt " It is not subjected in subject physiologic still, but also can refer to the synthetic for pharmaceutically having use value.
As described herein, term " pharmaceutical composition " can also refer to " composition ", can be used in subject spy It is not to realize to treat disease or illness of the present invention in mammal.
" treatment " of disease include:
(1) prevent the disease, that is, make to be exposed to or the easy infection disease but the lactation for not undergoing or showing the disease symptoms The clinical symptoms of the disease do not occur for animal,
(2) inhibit the disease, that is, the disease or the progress of its clinical symptoms are prevented or reduce,
(3) mitigate the disease, that is, cause the disease or the recovery of its clinical symptoms.
" therapeutically effective amount " refers to treat when disease is applied to mammal and be enough to realize the change of the treatment to the disease Close the amount of object.Therapeutically effective amount will be according to age, the body of compound, disease to be treated and its seriousness and mammal The factors such as weight, gender and change.Therapeutically effective amount also can refer to any amount for the compound for being enough to realize required beneficial effect, should Beneficial effect includes prevention disease, inhibition disease or the mitigation disease as described in above (1)-(3).Such as the amount of compound can be with Between 0.1-250mg/kg, or preferably, 0.5-100mg/kg, or it is highly preferred that 1-50mg/kg, or even further preferably, 2- 20mg/kg.Preferably, the compound of the amount is applied to mammal twice daily.It is highly preferred that the compound of the amount is every It is once applied to mammal.
As described herein, term " disease and/or illness " refers to a kind of physical condition of the subject, the body shape State is related with disease of the present invention and/or illness.For example, disease of the present invention and/or illness refer to it is tuberculosis bacillus infectious Disease.
As described herein, term " subject " can refer to patient or other receive formula Compound I or its medicine Compositions are to treat the animal of disease or illness of the present invention, especially mammal, such as people, dog, monkey, ox, horse etc..
Further aspect of the present invention further relates to the pharmaceutical composition using the compound in the present invention as active ingredient.The drug Composition can be prepared according to method well known in the art.Can by by the compounds of this invention with it is one or more pharmaceutically acceptable Solid or liquid excipient and/or adjuvant combine, any dosage form used suitable for human or animal is made.
Compound in the present invention can be administered in a unit containing its pharmaceutical composition, and administration route can be Enteron aisle or non-bowel, such as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin Skin, vagina, rectum etc..
Form of administration can be liquid dosage form, solid dosage forms or semisolid dosage form.Liquid dosage form can be solution (packet Include true solution and colloidal solution), emulsion (including o/w type, w/o type and emulsion), suspension, injection (including liquid drugs injection, powder Injection and infusion), eye drops, nasal drop, lotion and liniment etc.；Solid dosage forms can be tablet (including ordinary tablet, enteric coatel tablets, Lozenge, dispersible tablet, chewable tablets, effervescent tablet, oral disnitegration tablet), capsule (including hard capsule, soft capsule, capsulae enterosolubilis), particle Agent, powder, pellet, dripping pill, suppository, film, patch, the agent of gas (powder) mist, spray etc.；Semisolid dosage form can be ointment, Gelling agent, paste etc..
The compounds of this invention can be made ordinary preparation or sustained release preparation, controlled release preparation, targeting preparation and each is made Kind particulate delivery system.
In order to which tablet is made in the compounds of this invention, various excipient well known in the art can be widely used, including dilute Release agent, binder, wetting agent, disintegrating agent, lubricant, cosolvent.Diluent can be starch, dextrin, sucrose, glucose, cream Sugar, mannitol, sorbierite, xylitol, microcrystalline cellulose, calcium sulfate, calcium monohydrogen phosphate, calcium carbonate etc.；Wetting agent can be water, second Alcohol, isopropanol etc.；Adhesive can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, Arabic gum Slurry, gelatine size, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, card Wave nurse, polyvinylpyrrolidone, polyethylene glycol etc.；Disintegrating agent can be dried starch, microcrystalline cellulose, low substituted hydroxy-propyl fiber Element, crosslinked polyvinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxy second Alkene sorbitan fatty acid ester, dodecyl sodium sulfate etc.；Lubricant and cosolvent can be talcum powder, silica, tristearin Hydrochlorate, tartaric acid, atoleine, polyethylene glycol etc..
Tablet can also be further made to coating tablet, such as sugar coated tablet, thin membrane coated tablet, enteric coated tablets or double Synusia and multilayer tablet.
In order to which capsule is made in administration unit, effective component the compounds of this invention and diluent, cosolvent can be mixed It closes, mixture is placed directly in hard capsule or soft capsule.It can also effective component the compounds of this invention is first and diluent, bonding Particle or pellet is made in agent, disintegrating agent, then is placed in hard capsule or soft capsule.It is used to prepare each dilute of the compounds of this invention tablet Release agent, binder, wetting agent, disintegrating agent, cosolvent kind can also be used for preparing the capsule of the compounds of this invention.
For injection is made in the compounds of this invention, water, ethyl alcohol, isopropanol, propylene glycol or their mixture can be used Make solvent and appropriate solubilizer commonly used in the art, cosolvent, pH adjusting agent, osmotic pressure regulator is added.Solubilizer or hydrotropy Agent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin etc.；PH adjusting agent can be phosphate, acetate, hydrochloric acid, hydrogen Sodium oxide molybdena etc.；Osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate etc..Such as prepare freeze-dried powder Mannitol, glucose etc. can be also added as proppant in injection.
In addition, if desired, colorant, preservative, fragrance, corrigent or other additions can also be added into pharmaceutical preparation Agent.
To reach medication purpose, enhance therapeutic effect, drug of the invention or pharmaceutical composition well known can be given with any The administration of prescription method.
The compound of the present invention or composition can individually be taken, or merge use with other treatment drug or symptomatic drugs. When the compound of the present invention and other therapeutic agents, which exist, to act synergistically, its dosage should be adjusted according to the actual situation.
Advantageous effects
Present inventor has synthesized a series of compounds, and pass through MABA by extensive research (Microplate alamar blue assay) method is with M.tuberculosis H37Rv bacterial strain carries out minimum inhibitory concentration MIC (Minimum inhibitory concentration) measurement shows preferable anti-mycobacteria activity, wherein most The minimum inhibitory concentration (MIC) of compound reaches micromolar levels, wherein obtaining compound 6,3 of the μ of MIC < 0.5 g/mL The MIC of compound reaches 10-8G/mL, furthermore to Vero cytotoxicity low (IC suitable with treating tuberculosis first-line drug isoniazid50Greatly In 64 μ g/mL) show good safety.The present invention provides a kind of structure novel, internal anti-tuberculars by force, medicine is for property The good noval chemical compound of matter, mother nucleus structure are benzopyrone or benzimidazole thiophanate for pyranone structure, can be used for being caused by bacterium Infectious diseases, the especially treatment of the treatment or prevention property lungy as caused by mycobacteria simultaneously can be used for overcoming The problem related with drug resistance.
Specific embodiment
Can be with the present invention will be described in detail by the following examples, but be not meant to of the invention any unfavorable Limitation.The present invention is described in detail herein, wherein its specific embodiment is also disclosed, to those skilled in the art Speech, carrying out various changes and modifications for the specific embodiment of the invention without departing from the spirit and scope of the present invention is Obviously.
For following whole embodiments, standard operation well known by persons skilled in the art and purification process can be used.Unless It is otherwise noted, all temperature are indicated with DEG C (degree Celsius).The structure of compound is by nuclear magnetic resoance spectrum (NMR) come what is determined.
Prepare embodiment part
The structure of compound be by nuclear magnetic resonance spectroscopy (1H NMR) come what is determined.Nuclear magnetic resonance spectroscopy and carbon spectral displacement (δ) is provided with the unit of hundred a ten thousandths (ppm).Coupling constant (J) is with hertz (Hz) for unit.Nuclear magnetic resoance spectrum is used Mercury-400 type nmr determination, deuterated chloroform (CDCl3) or deuterated dimethyl sulfoxide (DMSO-d6) make solvent, four Methyl-monosilane (TMS) is internal standard.
High resolution mass spectrum is measured using Thermo Exactive Plus spectrometer LC-MS instrument.
Electronic balance uses Japan Yanaco LY-300 type electronic balance.
Column chromatography is generally carrier using 200~300 mesh silica gel.
Anhydrous solvent is handled by standard method.Other reagents are that commercially available analysis is pure.
The present invention uses following initialisms:
CDI is carbonyl dimidazoles.
DCC is dicyclohexylcarbodiimide.
DMF is N,N-dimethylformamide.
DMSO is dimethyl sulfoxide.
EDCI is 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride.
HOBT is I-hydroxybenzotriazole.
HATU is 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester.
Embodiment
Embodiment 1
2- ((phenyl) amido) -6- trifluoromethyl -8- nitro-benzopyran-4-one
Route:
Experimental procedure:
The preparation of first step 3- (chloro- 3- nitro -5- (trifluoromethyl) phenyl of 2-) -3- oxo-N-phenyl propionamide B-1
In 25mL reaction flask, by compound 3- (chloro- 3- nitro -5- (trifluoromethyl) phenyl of 2-) -3- oxopropanoic acid A (311mg, 1.0mmol), DCC (201mg, 1.0mmol) are dissolved in dry methylene chloride (5mL), Ar gas shielded, and aniline is added (93mg, 1.0mmol) is stirred 12 hours at room temperature.Insoluble solids are filtered out, are concentrated, silica gel (200-300 mesh) column chromatography point From ethyl acetate-light petrol (V:V=5~15:100) mixed liquor is eluant, eluent.Intermediate B -1, light yellow solid 218mg, Yield 56.5%.
1H NMR(400MHz,CDCl3) δ: 14.19 (s, 1H), 8.05 (d, J=8.4Hz, 2H), 7.54 (d, J= 7.6Hz, 2H), 7.38 (t, J=7.6Hz, 2H), 7.18 (t, J=7.6Hz, 1H), 7.11 (brs, 1H), 5.57 (s, 1H)
Second step 2- ((phenyl) amido) -6- trifluoromethyl -8- nitro-benzopyran-4-one II-1 (compound 1) system It is standby
In 10mL reaction flask, by compound 3- (chloro- 3- nitro -5- (trifluoromethyl) phenyl of 2-) -3- oxo-N-phenyl Propionamide B-1 (77mg, 0.2mmol), potassium carbonate (28mg, 0.2mmol) are dissolved in DMF (2mL), and Ar gas shielded is warming up to 110 DEG C are reacted 1 hour.25mL methylene chloride is added in solvent evaporated, is successively washed with water and salt, and anhydrous sodium sulfate is dry, mistake Filter, concentration, silica gel (200-300 mesh) pillar layer separation, methanol-methylene chloride (V:V=1:100) mixed liquor are eluant, eluent.? Compound II-1 (compound 1), 23 mg of light yellow solid, yield 32.9%.
1H NMR(400MHz,CDCl3) δ: 8.75 (s, 1H), 8.48 (d, J=1.6Hz, 1H), 7.48-7.45 (m, 2H), 7.35-7.31 (m, 3H), 5.83 (s, 1H) .HR-MS (ESI): m/z [M+H]+Calculated value: C16H10F3N2O4S:351.0587；It is real Measured value: 351.0580.
Embodiment 2
2- (((2,3- dihydrobenzo [b] [1,4] dioxine -6- base) methyl) (methyl) amino) -6- fluoroform Base -8- nitro-benzopyran-4-one
Route:
Experimental procedure:
First step 3- (the chloro- 3- nitro -5- trifluoromethyl of 2-)-N- ((2,3- dihydrobenzo [b] [1,4] dioxane Hexene -6- base) methyl)-N- methyl -3- oxopropanamide B-2 preparation
With 1- (2,3- dihydrobenzos [b] [Isosorbide-5-Nitrae] dioxine -6- base)-N- methyl methylamine (179mg, 1.0mmol) Intermediate B -2,285 mg of light yellow solid, yield are obtained using first step similar operations step in embodiment 1 for raw material 60.3%.
1H NMR(400MHz,CDCl3)δ:15.57(m,1H),8.02(m,2H),6.86(m,1H),6.81(m, 1H), 6.70(m,1H),5.71(m,1H),4.50(m,2H),4.26(m,4H),3.02(m,3H).
Second step 2- (((2,3- dihydrobenzo [b] [1,4] dioxine -6- base) methyl) (methyl) amino) -6- Trifluoromethyl -8- nitro-benzopyran-4-one II-2 (compound 2) preparation
With 3- (the chloro- 3- nitro -5- trifluoromethyl of 2-)-N- ((2,3- dihydrobenzo [b] [1,4] dioxa hexamethylene Alkene -6- base) methyl)-N- methyl -3- oxopropanamide (94mg, 0.2mmol) be raw material, using second step phase in embodiment 1 Like operating procedure, compound II-2 (compound 2), light yellow solid 47mg, yield 54.0% are obtained.
1H NMR(400MHz,CDCl3) δ: 8.76 (d, J=2.4Hz, 1H), 8.51 (d, J=2.4Hz, 1H), 6.86- 6.84(m,1H),6.76-6.72(m,2H),5.61(s,1H),4.66(s,2H),4.25(s,4H),3.13(s, 3H).HR-MS (ESI): m/z [M+H]+Calculated value: C20H16F3N2O6S:437.0955；Measured value: 437.0946.
Embodiment 3
2- ((cyclohexyl) amido) -6- trifluoromethyl -8- nitro-benzo thio-pyrylium -4- ketone
Route
Experimental procedure:
The preparation of the thio chromene -4- ketone D of first step 2- methyl mercapto -8- nitro -6- (trifluoromethyl) -4H-
In 50mL reaction flask, NaOH (800mg, 20mmol) is dissolved in DMSO (5mL), carbon disulfide is added at 20 DEG C The chloro- 3- nitro -5- trifluoromethyl acetophenone of 2- (2.67g, 10 mmol) is added thereto, 15 points by (2.34g, 30mmol) by several times Zhong Hou, 20 DEG C at a temperature of be added iodomethane (10mmol), react 30 minutes.100mL ethyl acetate is added, successively uses 100mL water and salt washing, anhydrous sodium sulfate dry, filter, and are concentrated, silica gel (200-300 mesh) pillar layer separation, ethyl acetate- Petroleum ether (V:V=7:100) mixed liquor is eluant, eluent.Obtain intermediate D, light yellow solid 1.83g, yield 60.0%.
1H NMR(400MHz,CDCl3) δ: 9.12 (d, J=2.0Hz, 1H), 8.84 (d, J=2.0Hz, 1H), 6.91 (s, 1H),2.70(s,3H).
Second step 2- ((cyclohexyl) amido) -6- trifluoromethyl -8- nitro-benzo thio-pyrylium -4- ketone III-1 (chemical combination Object 3) preparation
In 25mL reaction flask, by the thio chromene -4- ketone of (methyl mercapto) -8- nitro -6- (trifluoromethyl) -4H- (64mg, 0.2mmol), cyclohexylamine (198mg, 1.0mmol) is dissolved in isopropanol (5mL), under Ar protection, is reacted 24 hours, is obtained in 140 DEG C Compound III-1 (compound 3), light yellow solid 54mg, yield 72.3%.
1H NMR(400MHz,CDCl3) δ: 9.15 (d, J=2.0Hz, 1H), 8.78 (d, J=2.0Hz, 1H), 6.37 (s, 1H),3.59(s,1H),2.14-2.11(m,2H),1.86-1.82(m,2H),1.72-1.68(m,1H), 1.45-1.38(m, 5H) .HR-MS (ESI): m/z [M+H]+Calculated value: C16H16F3N2O3S:373.0828；Measured value: 373.0824.
Embodiment 4
2- ((phenyl) amido) -6- trifluoromethyl -8- nitro-benzo thio-pyrylium -4- ketone
It is that raw material obtains compound using second step similar operations step in embodiment 3 with aniline (93mg, 1.0mmol) III-2 (compound 4), light yellow solid 50mg, yield 68.3%.
1H NMR(400MHz,CDCl3) δ: 9.15 (d, J=1.6Hz, 1H), 8.82-8.81 (m, 1H), 7.49-7.44 (m, 2H), 7.38-7.34 (m, 3H), 6.86 (s, 1H) .HR-MS (ESI): m/z [M+H]+Calculated value: C16H10F3N2O3S: 367.0359；Measured value: 367.0371.
Embodiment 5
2- ((cyclohexyl methyl) amido) -6- trifluoromethyl -8- nitro-benzo thio-pyrylium -4- ketone
It is that raw material is obtained using second step similar operations step in embodiment 3 with cyclohexylmethylamine (113mg, 1.0mmol) To compound III-3 (compound 5), light yellow solid 55mg, yield 71.2%.
1H NMR(400MHz,CDCl3) δ: 9.14 (d, J=1.6Hz, 1H), 8.77 (d, J=1.6Hz, 1H), 6.14 (s, 1H), 5.39 (brs, 1H), 3.20 (t, J=6.4Hz, 2H), 1.84-1.68 (m, 6H), 1.30-1.21 (m, 5H) .HR-MS (ESI): m/z [M+H]+Calculated value: C17H18F3N2O3S:387.0985；Measured value: 387.0974.
Embodiment 6
2- ((benzyl) amido) -6- trifluoromethyl -8- nitro-benzo thio-pyrylium -4- ketone
It is that raw material obtains chemical combination using second step similar operations step in embodiment 3 with benzylamine (107mg, 1.0mmol) Object III-4 (compound 6), light yellow solid 51mg, yield 67.1%.
1H NMR(400MHz,CDCl3) δ: 9.13 (d, J=2.0Hz, 1H), 8.77 (d, J=2.0Hz, 1H), 7.40- 7.34 (m, 5H), 6.17 (s, 1H), 4.50 (d, J=5.2Hz, 2H) .HR-MS (ESI): m/z [M+H]+Calculated value: C17H12F3N2O3S:381.0515；Measured value: 381.0522.
Embodiment 7
2- ((furans -2- base-methyl) amino) -6- trifluoromethyl -8- nitro-benzo thio-pyrylium -4- ketone
It is that raw material is obtained using second step similar operations step in embodiment 3 with furans -2- methylamine (97mg, 1.0mmol) To compound III-5 (compound 7), light yellow solid 60mg, yield 81.0%.
1H NMR(400MHz,CDCl3) δ: 9.14 (d, J=2.0Hz, 1H), 8.79 (d, J=2.0Hz, 1H), 7.42 (m, 1H),6.41(m,1H),6.39-6.37(m,1H),6.34(m,1H),4.54(s,2H).HR-MS (ESI):m/z[M+H]+Meter Calculation value: C15H10F3N2O4S:371.0308；Measured value: 371.0304.
Embodiment 8
2- (((2,3- dihydrobenzo [b] [1,4] dioxine -6- base) methyl) amino) -6- trifluoromethyl -8- nitre Base-benzo thio-pyrylium -4- ketone
With (2,3- dihydrobenzos [b] [Isosorbide-5-Nitrae] dioxine -6- base) methylamine (165mg, 1.0mmol) for raw material, adopt With second step similar operations step in embodiment 3, compound III-6 (compound 8), light yellow solid 70mg, yield are obtained 79.9%.
1H NMR(400MHz,CDCl3) δ: 9.14 (d, J=1.6Hz, 1H), 8.79 (d, J=1.6Hz, 1H), 6.89- 6.86(m,3H),6.50(s,1H),6.50(brs,1H),4.46(s,2H),4.25(m,4H).HR-MS (ESI):m/z[M+H ]+Calculated value: C19H14F3N2O5S:439.0570；Measured value: 439.0583.
Embodiment 9
2- ((N- methyl-N-benzyl) amido) -6- trifluoromethyl -8- nitro-benzo thio-pyrylium -4- ketone
It is that raw material is obtained using second step similar operations step in embodiment 3 with N- methylbenzylamine (121mg, 1.0mmol) To compound III-7 (compound 9), light yellow solid 59mg, yield 74.9%.
1H NMR(400MHz,CDCl3) δ: 9.17 (d, J=2.4Hz, 1H), 8.77-8.62 (m, 1H), 7.40-7.34 (m,3H),7.26–7.24(m,2H),6.26(s,1H),4.85(s,2H),3.26(s,3H).HR-MS (ESI):m/z[M+H]+ Calculated value: C18H14F3N2O3S:395.0672；Measured value: 395.0671.
Embodiment 10
2- ((pyridine -3- methyl) amido) -6- trifluoromethyl -8- nitro-benzo thio-pyrylium -4- ketone
It is that raw material is obtained using second step similar operations step in embodiment 3 with pyridine -3- methylamine (108mg, 1.0mmol) To compound III-8 (compound 10), light yellow solid 42mg, yield 55.3%.
1H NMR(400MHz,DMSO-d6) δ: 9.01 (t, J=5.6Hz, 1H), 8.82 (m, 2H), 8.63 (s, 1H), 8.53 (m, 1H), 7.81 (d, J=6.0Hz, 1H), 7.44 (d, J=6.0Hz, 1H), 6.03 (brs, 1H), 4.60 (d, J= 5.6Hz,2H).HR-MS(ESI):m/z[M+H]+Calculated value: C16H11F3N3O3S:382.0468；Measured value: 382.0480.
Embodiment 11
2- (3,4- dimethoxy-benzyl) -6- trifluoromethyl -8- nitro-benzo thio-pyrylium -4- ketone
With 3,4- dimethoxybenzylamine (167mg, 1.0mmol) for raw material, walked using second step similar operations in embodiment 3 Suddenly, compound III-9 (compound 11), light yellow solid 63mg, yield 71.6% are obtained.
1H NMR(400MHz,CDCl3) δ: 9.14 (d, J=1.6Hz, 1H), 8.79 (d, J=2.0Hz, 1H), 6.95 (d, J=8.0Hz, 1H), 6.91 (d, J=1.6Hz, 1H), 6.86 (d, J=8.0Hz, 1H), 6.45 (s, 1H), 4.50 (s, 2H), 3.90(s,3H),3.88(s,3H).
Embodiment 12
2- (3- fluorin benzyl amine base) -6- trifluoromethyl -8- nitro-benzo thio-pyrylium -4- ketone
It is that raw material is obtained using second step similar operations step in embodiment 3 with a fluorin benzyl amine (108mg, 1.0mmol) Compound III-10 (compound 12), light yellow solid 62mg, yield 77.8%.
1H NMR(400MHz,CDCl3) δ: 9.13 (d, J=2.0Hz, 1H), 8.80 (d, J=2.0Hz, 1H), 7.37 (m, 1H), 7.14 (d, J=8.0Hz, 1H), 7.06 (d, J=8.0Hz, 2H), 6.16 (s, 1H), 4.53 (d, J=4.4Hz, 2H) .HR-MS(ESI):m/z[M+H]+Calculated value: C17H11F4N2O3S:399.0421；Measured value: 399.0375.
Embodiment 13
2- ((N- methyl-N-4- pyridyl group) amido) -6- trifluoromethyl -8- nitro-benzo thio-pyrylium -4- ketone
With N- picoline -4- amine (108mg, 1.0mmol) for raw material, walked using second step similar operations in embodiment 3 Suddenly, compound III-11 (compound 13), light yellow solid 58mg, yield 76.3% are obtained.
1H NMR(400MHz,DMSO-d6)δ:8.75(s,1H),8.14(s,1H),7.94(s,2H),7.46(m,2H), 6.88(s,1H),2.69(s,3H).
Embodiment 14
2- (4- fluorin benzyl amine base) -6- trifluoromethyl -8- nitro-benzo thio-pyrylium -4- ketone
It is that raw material is obtained using second step similar operations step in embodiment 3 with 4-Fluorobenzylamine (108mg, 1.0mmol) Compound III-12 (compound 14), light yellow solid 65mg, yield 81.6%.
1H NMR(400MHz,CDCl3) δ: 9.14 (s, 1H), 8.79 (s, 1H), 7.35 (t, J=6.4Hz, 2H), 7.10 (t, J=6.8Hz, 2H), 6.21 (s, 1H), 5.51 (brs, 1H), 4.50 (d, J=2.8Hz, 2H) .HR-MS (ESI): m/z [M +H]+Calculated value: C17H11F4N2O3S:399.0421；Measured value: 399.0372.
Biological activity test
1, Tuberculosis in vitro nuclear activity is tested
Measuring method: Microplate Alamar Blue Assay (MABA) method measures Tuberculosis in vitro nuclear activity.
Experimental principle: culture medium, which is added, in Alamar Blue can be used as oxidation-reduction indicator, and color is turned from blue to red Become, reflects consumption of the studied microorganism to oxygen molecule.The color change of Alamar Blue can use photometric determination, hair The a length of 590nm of ejected wave.
Experimental method: sterile 96 orifice plate (Falcon3072；Becton Dickinson, Lincoln Park, N.J.), it is real It tests compound to dissolve with DMSO, the first solution that concentration is 5mg/mL is made, 199 μ L 7H9 culture mediums, 1 μ is added in maximum concentration hole L compound just solution, after mixing, to remaining each hole successively 2 times dilution, final compound concentration are as follows: 25,12.5,6.25, 3.125,1.56,0.78,0.39,0.2,0.1,0.05,0.025μg/mL.Choose mycobacterium tuberculosis H37RvCulture 2~3 weeks Bacteria suspension is made in culture, be inoculated into containing 0.05% Tween 80,10%ADC 7H9 culture medium in, 37 DEG C of static gas wave refrigerators 1~2 In week, growing to turbidity is that McFarland 1 (is equivalent to 107When CFU/mL), after 1:20 dilution, each 100 μ L of hole is added, bacterium solution Final concentration of 106CFU/mL.2 growth control holes for being free of antimicrobial are all provided on every plate, 96 orifice plates are incubated in 37 DEG C.After 7 days Be added growth control hole 20 μ 10 × Alamar of L Blue and 5%T,wee,n80 50 μ L mixed liquor, 37 DEG C be incubated for 24 hours, such as Fruit color becomes pink colour from blue, then the Alamar Blue and Tween 80 that above-mentioned amount is added in the hole of each experimental drug is mixed Liquid, the color in 37 DEG C of incubation each holes of 24 hour records are closed, and application microplate reader measures 590nm fluorescent value, calculates MIC.
Table 1, part of compounds Killing Mycobacterium Tuberculosis in vitro of the present invention activity
From the data in table 1, it can be seen that part of compounds of the invention has good Killing Mycobacterium Tuberculosis in vitro activity.
2, cytotoxicity test
Measuring method: mtt assay
Experimental principle: cell activity is by dehydrogenase (such as succinate dehydrogenase) in mitochondria by the 3- (4,5- of oxidation state Dimethylthiazole -2- base) -2,5- diphenyltetrazolium bromide bromide (trade name: thiazolyl blue)/MTT [3- (4,5- Dimethylthiazo-2-yl) -2,5-diphenyl tetrazolium bromide] it is reduced to the blue formazan of indissoluble (formazan) compound, to measure, inversion quantity is related in positivity to living cells quantity for colour developing after DMSO dissolves.
Experimental method: the preparation of 1. cell suspensions.It will cultivate to 0.25% pancreatin of the Vero cell of logarithmic growth phase 2~3min is digested, inhales and abandons digestive juice, appropriate culture solution is added, 20 μ L is taken to be counted under the microscope after mixing with blood counting instrument, It is configured to the cell suspension of suitable concentration, it is spare.5g/L is prepared with PBS (phosphate buffered solution) simultaneously MTT solution, filtration sterilization is spare.It is detected 2. drug is prepared with cytotoxicity.
Test medicine is dissolved in DMSO, 50 times is diluted with culture medium, tested maximum concentration is made, then uses culture medium It is serially diluted on 96 orifice plates by 1: 3, each compound sets 6 concentration, 64 μ g/mL of maximum concentration, and each concentration sets 6 A parallel hole, 50 holes μ L/.By the cell suspension inoculation prepared in 96 orifice plates, 50 holes μ L/, cell concentration 4 × 105A/ mL..The not cell control well of drug containing and culture medium blank control wells are set simultaneously.After culture 48 hours, 10 hole μ L/ MTT is added, Continue culture 4 hours.Culture plate is taken out, culture medium in hole is carefully discarded, every hole adds DMSO100 μ L, vibrates complete Zhi formazan particle After fully dissolved, its OD value (OD is measured at 570nm wavelength with enzyme-linked immunosorbent assay instrument570).3. data processing.Cell suppression Percentage (%)=[(cell controls OD processed570Value-dosing group OD570Value)/(cell controls OD570Value-blank OD570Value)] × 100%.Dose-response relationship curve matching is carried out with Origin7.0 software, calculates various compound on intracellular inhibiting rates Concentration (IC when 50%50)。
Table 2, part of compounds cytotoxicity of the present invention
From the data in table 2, it can be seen that the cytotoxicity of compound is very low in the present invention, very high safety is shown.
Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is example Property, it is not considered as limiting the invention, those skilled in the art within the scope of the invention can be to above-mentioned Embodiment is changed, modifies, replacement and variant.

Claims (9)

1. such as formula (I) compound represented and its pharmaceutically acceptable salt:
Wherein,
X is O or S；
N is 0,1,2 or 3；
R1For H, substituted or unsubstituted C1-C3Alkyl, substituted or unsubstituted C3-C6Naphthenic base；
R2For substituted or unsubstituted C3-C6Naphthenic base, substituted or unsubstituted C3-C6Heterocycle, substituted or unsubstituted C6-C10 Aryl, substituted or unsubstituted C2-C9Heteroaryl；
The C3-C6Heterocycle, C2-C9Heteroaryl at least contains a hetero atom in N, O, S；
The R1And R2In substituted or unsubstituted substituent group can be optionally from following group: F, Cl, Br, hydroxyl, amino, nitro, cyanogen Base, trifluoromethyl, trifluoromethoxy, C1-C3Alkyl, benzyl, cyclohexylmethylene, halogenated C1-C3Alkyl, C1-C3Alkoxy or C1-C3Alkylamino radical.
2. compound according to claim 1 and its pharmaceutically acceptable salt, the compound is by leading to formula (II) institute Show；
Wherein,
R1、R2It defines with n with claim 1.
3. compound according to claim 1 and its pharmaceutically acceptable salt, the compound is by leading to formula (III) institute Show；
Wherein,
R1、R2It defines with n with claim 1.
4. compound according to claim 2 and its pharmaceutically acceptable salt,
Wherein,
N is 0 or 1；
R1For H, CH3Or cyclopropyl；
R2For substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl group, substitution or not Substituted quinolyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrole radicals, substituted or unsubstituted thienyl and Substituted or unsubstituted thiazolyl；
The R2In substituted or unsubstituted substituent group can be optionally from following group: F, Cl, Br, hydroxyl, amino, nitro, cyano, Trifluoromethyl, trifluoromethoxy, C1-C3Alkyl, benzyl, cyclohexylmethylene, halogenated C1-C3Alkyl, C1-C3Alkoxy or C1-C3 Alkylamino radical.
5. compound according to claim 3 and its pharmaceutically acceptable salt,
Wherein,
N is 0 or 1；
R1For H, CH3Or cyclopropyl；
R2For substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl group, substitution or not Substituted quinolyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrole radicals, substituted or unsubstituted thienyl and Substituted or unsubstituted thiazolyl；
The R2In substituted or unsubstituted substituent group can be optionally from following group: F, Cl, Br, hydroxyl, amino, nitro, cyano, Trifluoromethyl, trifluoromethoxy, C1-C3Alkyl, benzyl, cyclohexylmethylene, halogenated C1-C3Alkyl, C1-C3Alkoxy or C1-C3 Alkylamino radical.
6. being selected from following compounds to the compound and its pharmaceutically acceptable salt of 5 any one according to claim 1:
7. the method for preparing any one of claim 1 to 6 compound comprising following steps:
(1)
Compound A and side chain NHR1(CH2)nR2It is condensed to yield compound shown in formula B, finally cyclization obtains formula under alkaline condition (II) compound shown in；
Or (2)
Compound C is first reacted with carbon disulfide under alkaline condition, then obtains compound D through methylating, then with side chain NHR1 (CH2)nR2Substitution reaction occurs and obtains compound shown in formula (III)；
R1、R2It defines with n with any one of claim 1-5.
8. a kind of pharmaceutical composition comprising the chemical combination as claimed in any one of claims 1 to 6 for the treatment of and/or prevention effective dose It is object and its pharmaceutically acceptable salt and optional one or more pharmaceutically acceptable carriers, excipient, diluent, auxiliary Material and medium.
9. composition described in any one of the claim 1-6 compound and its pharmaceutically acceptable salt or claim 8, Application in the drug of preparation treatment and/or the prevention infectious diseases as caused by mycobacterium tuberculosis.
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