CN107445981A - A kind of reactive compound for anti-treating cervicitis - Google Patents
A kind of reactive compound for anti-treating cervicitis Download PDFInfo
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- CN107445981A CN107445981A CN201710741192.5A CN201710741192A CN107445981A CN 107445981 A CN107445981 A CN 107445981A CN 201710741192 A CN201710741192 A CN 201710741192A CN 107445981 A CN107445981 A CN 107445981A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
- C07D513/14—Ortho-condensed systems
Abstract
The present invention relates to a kind of reactive compound for being used to treat inflammatory disease such as cervicitis, the compound has the structure shown in formula (I).Body outer suppressioning test shows that reactive compound of the present invention has good inhibitory action for Btk, in the preventing and treating that can be consequently used for inflammatory disease such as cervicitis.
Description
Technical field
The invention belongs to medicinal chemistry art, and in particular to a kind of reactive compound for anti-treating cervicitis, the present invention
Further relate to the preparation method of the reactive compound, and the use of medicine of the reactive compound for preparing anti-treating cervicitis
On the way.
Background technology
Cervicitis is one of gynaecology's common disease, often because give a birth, miscarry or surgical injury uterine neck after, pathogen intrusion and
Cause infection.Hygienic bad or estrogen deficiency, local anti-infective ability can also cause.If Cervicitis cannot be thorough in time
The treatment at bottom, genital inflammation can be caused, severe patient's cause is infertile, may also be further development of cervical lesionses.Therefore, actively
Anti- treating cervicitis improves WomanHealth level and promotes family social harmony significant to preventing cervical lesionses.
At present, treatment cervicitis has many methods, can be divided into physical therapy and medicinal treatment, physical therapy is irradiated with laser
Exemplified by use carbon dioxide laser defocus irradiation, 70 watts of power, irradiate 10-15 minutes every time, 10 times are a course for the treatment of.This treatment
The method time is grown, costly.Oral medicine treatment time is grown, and body is adversely affected.Known externally applied drug is although effective in cure, but
It is that some medicine therapeutic effects are not high, easily recurrence.
As can be seen here, there is clearly disadvantageous and defect for treatment method and medicine of the tradition to cervicitis, it would be highly desirable to
Further improve.
Bruton's tyrosine kinase (Bruton ' s tyrosine kinase, Btk), is nonreceptor tyrosine kinase Tec
The member of family.Btk serves the Information Conduction effect of key in hematopoietic cell, especially in autoimmunity and inflammatory disease
The B cell to be played an important role in pathogenesis.Btk inflammatory disease effect by rat basophilic from blood disease cell
(RBL-2H3) model is proven.RBL-2H3 is the common model for studying mast-cell inflammatory condition.Mast cell is rich in thermophilic
Alkali grain, played a leading role in the allergic reaction of immunoglobulin E (IgE)-mediation.Small molecule disturbance ribonucleic acid
(small interfering RNA, siRNA) and LFM-A13 (an effective Btk inhibitor), can be by reducing Btk work
Property reduces inflammatory reaction caused by mast cell：In the RBL-2H3 mast cells handled through siRNA and LFM-A13, discharged
Proinflammatory mediation agent --- the content of histamine reduces 20-25%.
The invention provides a kind of novel B tk inhibitor, and it can be used in the preventing and treating of inflammatory disease such as cervicitis.
The content of the invention
It is an object of the invention to provide a kind of new reactive compound for being used to prevent and treat inflammatory disease such as cervicitis, specifically
Ground, the present invention relates to the compound of formula (I) or its pharmaceutically acceptable salt, dynamic isomer, optical isomer, solvent to close
Thing, pro-drug：
In formula (I),
R、R1、R2It can be represented independently of one another with identical or different：Hydrogen, halogen, C1-4 alkyl, nitro, hydroxyl, amino,
Carboxyl, C4-7 cycloalkyl, C1-4 alkoxies, C1-4 alkyl-carbonyls, C1-4 alkoxy carbonyls, C1-4 alkyl aminos or two (C1-4
Alkyl) amino, wherein, the C1-4 alkyl, C1-4 alkoxies, C1-4 alkyl-carbonyls, C1-4 alkoxy carbonyls, C1-4 alkyl ammonia
Alkyl in base, two (C1-4 alkyl) amino is also optional individual selected from halogen, hydroxyl, amino, C1-4 alkoxies, C6-10 by 1-3
Aryl, the group of C2-10 heterocyclic radicals are substituted；
R3Represent：Hydrogen, C1-4 alkyl or C4-7 cycloalkyl, wherein, the C1-4 alkyl is also optional to be selected from halogen by 1-3
Element, hydroxyl, amino, C1-4 alkoxies, the group of C6-10 aryl are substituted；
L is represented：Singly-bound or C1-6 alkylidenes, wherein, one or more CH in the C1-6 alkylidenes2Can be optional
Ground is substituted by O, S or NH.
In an example of the compounds of this invention, the M is represented：N or CH.
In an example of the compounds of this invention, the R1Represent：Hydrogen, amino, C1-4 alkyl aminos or C1-4 alkoxies.
In an example of the compounds of this invention, the R2Represent：Hydrogen, C1-4 alkyl, C2-10 heterocyclic radicals substitute
C1-4 alkyl or C1-4 alkoxies.
In an example of the compounds of this invention, the L is represented：Singly-bound or-CH2-。
In an example of the compounds of this invention, the R3Represent：C1-4 alkyl or the C1-4 alkyl of C6-10 aryl substitution.
Currently preferred compound is：
Compound provided by the invention is hereinafter referred to as " the compounds of this invention ".The compounds of this invention includes any form
Compound, such as free form, salt form, solvate forms and salt and solvate forms.
On the other hand, the invention provides the compounds of this invention of salt form.
This kind of salt preferably includes pharmaceutically acceptable salt, but also includes pharmaceutically unacceptable salt, for example, for prepare/
The salt of separation/purifying purpose.
The pharmaceutically acceptable salt of the compounds of this invention includes its acid-addition salts, and appropriate acid-addition salts are nontoxic by being formed
The acid formation of salt.The example of the salt includes organic salt, such as acetate, aspartate, benzoate, benzene sulfonate, lemon
Lemon hydrochlorate, ethanedisulphonate, esilate, formates, fumarate, gluconate, glucuronate, lactate, malic acid
Salt, trifluoroacetate, maleate, inorganic salts, such as hydrochloride, hydrobromate, disulfate, nitrate.Appropriate alkali salt
Formed by the alkali for forming nontoxic salts.
The compounds of this invention of free form can be converted into the respective compound of salt form；And vice versa.Trip
From the free shape that form or salt form and the compounds of this invention of solvate forms can be converted into non-solvate form
The respective compound of formula or salt form；And vice versa.
The compounds of this invention can exist in the form of isomers and its mixture；Such as dynamic isomer, optics are different
Structure body, enantiomter, diastereoisomer.The compounds of this invention can be for example comprising asymmetric carbon atom, and therefore can be with
Enantiomter or the form of diastereoisomer and its mixture are present, such as in the form of racemate.Chemical combination of the present invention
Thing can with (R)-, (S)-or (R, S)-configuration are present, be (R)-or (S)-configuration preferably on the ad-hoc location of compound.
The compounds of this invention can be given as prodrug form.Therefore, itself may have seldom pharmacological activity
Or some derivatives without pharmacological activity are converted into when being administered on internal or body for example, by hydrolytic rupture
With required active compound of the invention.This derivative is referred to as " pro-drug ".On using for pro-drug
Details can be found in Pro-drugs as Novel Delivery Systems, Vol.14, ACS Symposium Series
(T.Higuchi and W.Stella) and Bioreversible Carriers in Drug Design, Pergamon
Press, 1987 (editors：E.B.Roche,American Pharmaceutical Association).
Group definition
Terms used herein " halogen " should refer to fluorine, chlorine, bromine and iodine.Halogen is preferably fluorine, chlorine or bromine, more preferably chlorine or
Bromine.
Terms used herein " alkyl " no matter individually or as substituent part using including straight chain and side chain, alkyl
1-6 carbon atom, further preferably 1-4 carbon atom are preferably comprised, the example of alkyl such as C1-4 alkyl includes, for example, first
Base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl and the tert-butyl group.
Terms used herein " alkylidene " refers to that alkyl removes the remaining group after a hydrogen, its no matter individually or as
Using straight chain and side chain is included, alkylidene preferably comprises 1-6 carbon atom, alkylidene such as C1-6 alkyl for the part of substituent
Example include, for example ,-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH(CH3)-、-CH2CH(CH3)CH2-、-
CH2CH2CH2CH2- etc..
No matter terms used herein " cycloalkyl " individually or as the part use of substituent refers both to cyclic saturated hydrocarbon base, ring
Alkyl preferably comprises 4-7 carbon atom, and the example of cycloalkyl such as C4-7 cycloalkyl includes, for example, cyclobutyl, cyclopenta, ring
Hexyl and suberyl.
Terms used herein " aryl " represents isocyclic aryl or biaryl.Isocyclic aryl is preferred containing 6-18 carbon atom
The aromatics of 6-10 carbon atom.It can be monocyclic, bicyclic or tricyclic, such as phenyl or naphthyl etc..
Terms used herein " C2-10 heterocyclic radicals " can enumerate following (1) or (2)：
(1) 1-4 preferably 1,2,3 selected from nitrogen-atoms, oxygen atom and sulphur atom or 4 hetero atoms, simultaneously are contained
It is and former containing the aromatic ring yl or their benzene fused rings of 2-10 preferably 2-8 more preferably 2-5 carbon atoms, described cyclization
When son is nitrogen-atoms or sulphur atom, described nitrogen-atoms, sulphur atom can form oxide.For example, pyrrole radicals, Yin can be enumerated
Diindyl base, furyl, benzofuranyl, thienyl, benzothienyl, thiazolyl, benzothiazolyl, imidazole radicals, benzimidazolyl,
Triazole, pyridine radicals, pyrazolyl, pyrimidine radicals, pyrazinyl, triazine radical.
(2) 1-4 preferably 1,2,3 selected from nitrogen-atoms, oxygen atom and sulphur atom or 4 hetero atoms, simultaneously are contained
And containing the saturation ring group of 2-10 preferably 2-5 carbon atoms, it is described when described ring member nitrogen atoms are nitrogen-atoms or sulphur atom
Nitrogen-atoms, sulphur atom can form oxide.For example, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, pyrroles can be enumerated
Alkyl, tetrahydrofuran base.
The present invention also provides pharmaceutical composition, and described pharmaceutical composition includes the compound of formula as defined above (I)
Or its pharmaceutically acceptable salt, dynamic isomer, optical isomer, solvate, pro-drug with it is pharmaceutically acceptable
The combination of diluent or carrier.
Described pharmaceutical composition can be used as unit dosage forms to there is or can pass through known any method system in pharmaceutical field
It is standby.All methods all include making reactive compound with forming the carrier-bound step of one or more compositions.
Term " pharmaceutically acceptable " used herein refer to the biological activity that does not eliminate compound as described herein or
The material of property, such as carrier or diluent.This kind of material, which is applied to individual, does not cause undesirable biological action or not
With harmful way with being interacted comprising any component in its composition.
Term " pharmaceutically acceptable carrier " as used herein includes any and all solvent, decentralized medium, bag
Clothing material, surfactant, antioxidant, preservative (such as antiseptic, antifungal agent), isotonic agent, absorption delaying agent, salt,
Preservative, drug stabilizing agent, adhesive, excipient, disintegrant, lubricant, dyestuff etc. and its combination, this is people in the art
Member known to (for example, see Remington ' s Pharmaceutical Sciences, 18th Ed.Mack Printing
Company,1990,pp.1289-1329).In addition to the carrier incompatible with active component, in treatment or pharmaceutical composition
Consider to use any conventional carrier.
The medicine of specific embodiments of the present invention can be given by enteral or parenteral approach, including intravenous,
Intramuscular, intraperitoneal, subcutaneous, percutaneous, rectum, vagina and administer locally to.
The method that the present invention also provides preventing and treating inflammatory disease, methods described include the subject's effective dose for giving needs
The compounds of this invention or pharmaceutical composition.
Another example of the present invention is purposes of the compounds of this invention in medicine is prepared, and the medicine is used for need
Subject prevent and treat inflammatory disease.
Inflammatory disease specifically described herein includes but is not limited to cervicitis, colitis, cystitis, oaritis, rectitis, defeated
Oviduct inflammation, vaginitis and vulvitis.
The method that the compound of above-mentioned formula (I) is prepared it is another object of the present invention to provide one kind, it can pass through
Following reaction equations 1 such steps manufactures：
[reaction equation 1]
In above-mentioned reaction equation, M, R1、R2、R3, L is as described above, X1、X2Halogen can be independently represented with identical or different, it is excellent
Select chlorine or bromine.
Beneficial effect
The compounds of this invention has good inhibitory action for Btk, can be consequently used for inflammatory disease such as cervicitis
Preventing and treating in.
Embodiment
The following examples are for the present invention will be described, rather than the limitation present invention.
Those skilled in the art will realize that：Chemical reaction described in the invention can be used for suitably preparing perhaps
Other compounds of more present invention, and other methods of the compound for preparing the present invention are considered as the model in the present invention
Within enclosing.In addition, reaction disclosed in this invention or known reaction condition are also admittedly applied to other compounds of the invention
Preparation.
Embodiment 1：The synthesis of compound 1
In round-bottomed flask, by the bromo- 2- bromomethyls -4- nitrothiazoles of 2- (methylamino) pyridin-3-yl boric acid 15.2g, 5-
31.6g is dissolved in toluene 200ml, adds 150ml K2CO3(2M) and 2.9g Pd (PPh3)4, then carry out return stirring.
Confirm to react by TLC, and add water, then terminating reaction.After organic layer ethyl acetate is extracted and is filtered under diminished pressure, upper prop
It is refined, obtain 24.1g intermediate 1-1, yield 73.2%.
16.5g above-mentioned intermediate 1-1 is dissolved in chlorobenzene 150ml, then adds 100ml P (OEt)3, and returned
Stream stirring.After organic layer dichloromethane is extracted and is filtered under diminished pressure, upper prop refines, and obtains 10.1g intermediate 1-2, yield
67.6%
By 8.9g above-mentioned intermediate 1-2,4.5g KHCO3, 0.57g CuI and 250ml toluene mix, stir
Under be heated to 85 DEG C, then solution of the 3.3g 1- MUs in 30ml toluene is slowly added dropwise into, is added dropwise within 1 hour,
It is being heated to reflux lower stirring 5 hours.Reaction removes solvent under reduced pressure after terminating, residue ethyl alcohol recrystallization, obtain 7.4g whites
The compound 1 of crystal, yield 85.4%.
ESI-MS：291.34[M+H]+
Elementary analysis：Theoretical value/measured value, C (49.64/49.54), H (4.86/4.93), N (28.95/28.82), O
(5.51/5.57), S (11.04/11.14)
1H NMR(400MHz,CDCl3)δ7.99(d,1H),7.87(s,1H),6.95(d,1H),6.72(s,1H),6.41
(s,1H),4.42(s,2H),4.03(s,1H),2.75(s,3H),2.68(s,3H)。
Embodiment 2：The synthesis of compound 2
According to the method for embodiment 1,2- (methylamino) pyridin-3-yl boric acid is replaced with 6- methyl pyridazine -4- ylboronic acids, three
Walk gross production rate 39.2%.
ESI-MS：277.32[M+H]+
Elementary analysis：Theoretical value/measured value, C (47.81/47.74), H (4.38/4.33), N (30.41/30.52), O
(5.79/5.77), S (11.60/11.59)
1H NMR(400MHz,CDCl3)δ9.09(s,1H),7.87(s,1H),6.72(s,1H),6.41(s,1H),4.43
(s,2H),2.73(s,3H),2.38(s,3H)。
Embodiment 3：The synthesis of compound 3
According to the method for embodiment 1, with 6- (pyrrolidines -1- methyl) pyridazine -4- ylboronic acids replace 2- (methylamino) pyridine -
3- ylboronic acids, three step gross production rates 38.4%.
ESI-MS：388.18[M+H]+
Elementary analysis：Theoretical value/measured value, C (55.79/55.74), H (6.50/6.33), N (25.30/25.42), O
(4.13/4.07), S (8.27/8.51)
1H NMR(400MHz,CDCl3)δ7.09(s,1H),6.78(s,1H),6.43(s,1H),6.03(s,1H),4.43
(s,2H),3.63(s,2H),2.58(t,4H),1.68(s,4H),1.63(s,9H),。
Embodiment 4：The synthesis of compound 4
According to the method for embodiment 1,2- (methylamino) pyridin-3-yl is replaced with 2,5- dimethoxy-pyridine -3- ylboronic acids
Boric acid, 1- MUs, three step gross production rates 36.5% are replaced with 1- benzylureas.
ESI-MS：388.45[M+H]+
Elementary analysis：Theoretical value/measured value, C (57.42/57.54), H (4.82/4.73), N (17.62/15.52), O
(12.08/12.17), S (8.07/7.94)
1H NMR(400MHz,CDCl3)δ7.25-7.33(m,6H),6.73(s,1H),6.48(s,1H),6.43(s,1H),
4.43(s,2H),4.23(s,2H),4.08(s,3H),3.88(s,3H)。
Embodiment 5：The synthesis of compound 5
According to the method for embodiment 1,2- (methylamino) pyridin-3-yl boric acid is replaced with PA -3- ylboronic acids, is used
2,5- bis- bromo- 4- nitrothiazoles replace the bromo- 2- bromomethyls -4- nitrothiazoles of 5-, and 1- methyl is replaced with 1- (2- phenylethyls) urea
Urea, three step gross production rates 37.9%.
ESI-MS：353.41[M+H]+
Elementary analysis：Theoretical value/measured value, C (57.94/57.84), H (4.58/4.53), N (23.85/23.77), O
(4.54/4.62), S (9.10/9.32)
1H NMR(400MHz,CDCl3)δ7.93(d,1H),7.28-7.40(m,5H),6.98(d,1H),6.78(s,2H),
6.53(s,1H),6.13(s,1H),6.03(s,1H),3.53(t,2H),2.93(t,2H)。
Test example：Btk external inhibitory activity analysis
In acellular kinase assays, the Btk of the compounds of this invention can be determined with method as described below or the like
IC50。
Usage time resolved fluorescent resonance energy transfer method (TR-FRET) determines Btk kinase activities.Determined using 96 holes
Plate, it is measured in 50 μ L reaction volumes.By kinases, inhibitor, ATP and 1 μM of peptide substrates (biotin-
AVLESEEELYSSARQ-NH2) be incubated 1 hour in the reaction buffer (pH7.4), the reaction buffer by 20mM Tris,
50mM NaCl、MgCl2(5-25mM, depending on kinases), MnCl2 (0-10mM), 1mM DTT, 0.1mM EDTA, 0.01% N
Seralbumin, 0.005% Tween-20 and 10%DMSO compositions.By the 1x Lance buffer solutions (Perkin- for adding 25 μ L
Elmer EDTA (relative to bivalent cation) the quenching reactants of 1.2 equivalents in).It is affine that strepto- is added in 25 μ L volumes
The 1x Lance buffer solutions of the p-Tyr100 antibody (Perkin-Elmer) of element-APC (Perkin-Elmer) and Eu marks, respectively
Final concentration of 100nM and 2.5nM are obtained, the mixture is incubated 1 hour.Use multi-mode plate reader, 330nm excitation wavelength
And TR-FRET signals are measured under 615nm and 665nm Detection wavelength.Activity is determined by the fluorescence ratio under 665nm and 615nm.
To each compound, the enzymatic activity under various concentrations compound is determined.Negative control is reacted in the case of inhibitor is lacked
Carry out and (do six in duplicate), and baseline fluorescence level is determined without enzyme control with two.Use program Batch Ki
(Kuzmic etc. (2000), Anal.Biochem., 286：45-50) fitting obtains IC50。
Table 1：The Btk IC of compound of the embodiment of the present invention50Value
Result of the test shows that the compounds of this invention has good inhibitory action for Btk, can be consequently used for inflammatory disease
In the preventing and treating of case such as cervicitis.
It is understood that embodiment described herein the purpose that illustration is only used for embodiment, and accordingly
Made various modifications change enlightenment can be made to those skilled in the art, and be included in the spirit applied herein with
In the range of scope and appended claims.Herein cited all publications, patents and patent applications all pass through reference
It is fully incorporated herein for all purposes.
Claims (10)
- It is 1. a kind of compound of formula (I) or its pharmaceutically acceptable salt, dynamic isomer, optical isomer, solvate, preceding Body medicine：In formula (I),M is represented：N or CR；R、R1、R2It can be represented independently of one another with identical or different：Hydrogen, halogen, C1-4 alkyl, nitro, hydroxyl, amino, carboxyl, C4-7 cycloalkyl, C1-4 alkoxies, C1-4 alkyl-carbonyls, C1-4 alkoxy carbonyls, C1-4 alkyl aminos or two (C1-4 alkyl) Amino, wherein, the C1-4 alkyl, C1-4 alkoxies, C1-4 alkyl-carbonyls, C1-4 alkoxy carbonyls, C1-4 alkyl aminos, two Alkyl in (C1-4 alkyl) amino it is also optional by 1-3 selected from halogen, hydroxyl, amino, C1-4 alkoxies, C6-10 aryl, The group of C2-10 heterocyclic radicals is substituted；R3Represent：Hydrogen, C1-4 alkyl or C4-7 cycloalkyl, wherein, the C1-4 alkyl is also optional to be selected from halogen, hydroxyl by 1-3 Base, amino, C1-4 alkoxies, the group of C6-10 aryl are substituted；L is represented：Singly-bound or C1-6 alkylidenes, wherein, one or more CH in the C1-6 alkylidenes2Can optionally by O, S or NH is substituted.
- 2. the compound or its pharmaceutically acceptable salt, dynamic isomer, optics of formula (I) according to claim 1 are different Structure body, solvate, pro-drug, it is characterised in that the M is represented：N or CH；The R1Represent：Hydrogen, amino, C1-4 alkyl Amino or C1-4 alkoxies；The R2Represent：Hydrogen, C1-4 alkyl, the C1-4 alkyl or C1-4 alcoxyls of the substitution of C2-10 heterocyclic radicals Base；The L is represented：Singly-bound or-CH2-；The R3Represent：C1-4 alkyl or the C1-4 alkyl of C6-10 aryl substitution.
- 3. the compound or its pharmaceutically acceptable salt, dynamic isomer, optics of formula (I) according to claim 1 or 2 Isomers, solvate, pro-drug, it is characterised in that the C6-10 aryl represents：Phenyl or naphthyl.
- 4. the compound or its pharmaceutically acceptable salt, dynamic isomer, optics of formula (I) according to claim 1 or 2 Isomers, solvate, pro-drug, it is characterised in that the C2-10 heterocycles represent：(1) contain the 1-4 preferably 1,2,3 selected from nitrogen-atoms, oxygen atom and sulphur atom or 4 hetero atoms and contain There are the aromatic ring yl or their benzene fused rings of 2-10 carbon atom, when described ring member nitrogen atoms are nitrogen-atoms or sulphur atom, institute Nitrogen-atoms, the sulphur atom stated can form oxide, can enumerate pyrrole radicals, indyl, furyl, benzofuranyl, thiophene Base, benzothienyl, thiazolyl, benzothiazolyl, imidazole radicals, benzimidazolyl, triazole, pyridine radicals, pyrazolyl, pyrimidine radicals, Pyrazinyl, triazine radical；(2) contain the 1-4 preferably 1,2,3 selected from nitrogen-atoms, oxygen atom and sulphur atom or 4 hetero atoms and contain There is the saturation ring group of 2-10 carbon atom, when described ring member nitrogen atoms are nitrogen-atoms or sulphur atom, described nitrogen-atoms, sulphur atom Oxide can be formed, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, pyrrolidinyl, tetrahydrofuran base can be enumerated.
- 5. the compound or its pharmaceutically acceptable salt, dynamic isomer, optics of formula (I) according to claim 1 are different Structure body, solvate, pro-drug, it is selected from：
- 6. a kind of method for preparing the compound according to the formula (I) described in claim 1, methods described pass through following reaction equations 1 such step manufactures：[reaction equation 1]In above-mentioned reaction equation, M, R1、R2、R3, L as described in the appended claim 1, X1、X2Halogen can be independently represented with identical or different Element, preferably chlorine or bromine.
- 7. a kind of pharmaceutical composition, it include the compound of the formula (I) according to claim any one of 1-5 or its pharmaceutically Acceptable salt, dynamic isomer, optical isomer, solvate, pro-drug and pharmaceutically acceptable diluent or load The combination of body.
- 8. the compound or its pharmaceutically acceptable salt, tautomerism of the formula (I) according to claim any one of 1-5 The application of body, optical isomer, solvate, pro-drug in medicine is prepared, the medicine are used for the subject to need Prevent and treat inflammatory disease.
- 9. application according to claim 8, wherein the inflammatory disease includes but is not limited to cervicitis, colitis, bladder Inflammation, oaritis, rectitis, salpingitis, vaginitis and vulvitis.
- 10. application according to claim 9, wherein the inflammatory disease is cervicitis.
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