CN107987072A - Benzazole compounds as CRTH2 inhibitor - Google Patents

Benzazole compounds as CRTH2 inhibitor Download PDF

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Publication number
CN107987072A
CN107987072A CN201711238122.4A CN201711238122A CN107987072A CN 107987072 A CN107987072 A CN 107987072A CN 201711238122 A CN201711238122 A CN 201711238122A CN 107987072 A CN107987072 A CN 107987072A
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compound
alkyl
cycloalkyl
400mhz
solution
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CN107987072B (en
Inventor
姚元山
陈斌
陈远
李敖
徐然
黄振昇
田东东
李宏伟
杨成帅
黎健
陈曙辉
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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NANJING MINGDE NEW DRUG RESEARCH AND DEVELOPMENT Co Ltd
Chia Tai Tianqing Pharmaceutical Group Co Ltd
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    • 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
    • C07D417/06—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 carbon chain containing only aliphatic carbon atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

This application discloses the Benzazole compounds or its pharmaceutically acceptable salt as CRTH2 inhibitor as shown in formula (I), and it is being treated and the application in the relevant disease of CRTH2 acceptors.

Description

Benzazole compounds as CRTH2 inhibitor
Technical field
This application involves as the Benzazole compounds of CRTH2 inhibitor, its preparation method, the medicine containing the compound Composition and its purposes in CRTH2 receptor associated diseases are treated.
Background technology
CRTH2 (DP2 or GPR44) is g protein coupled receptor, and prostaglandin (Prostaglandin) (PGD2) combines The activation and chemotaxis of Th2 lymphocytes, eosinophil and basophilic granulocyte can be participated in afterwards, and it is thin to suppress Th2 lymphs The apoptosis of born of the same parents, stimulates and produces IL4, IL5 and IL13.These interleukins participate in important biological respinse, including acidophil granules The recruitment and survival of cell, the generation of mucous secretion, airway hyperreactivity and immunoglobulin E (IgE).
Leimaquban (Ramatroban) is TP (thromboxane-type prostanoid receptor) acceptor Antagonist, has extremely strong blood vessel, bronchial smooth muscle contraction and platelet activation effect.Leimaquban is weaker CRTH2 receptor antagonists.Leimaquban ratifies treatment allergic rhinitis in Japan.
WO2005044260 reports compound OC459, WO2005123731 and reports compound Q AW-039.
The content of the invention
This application involves formula (I) compound or its pharmaceutically acceptable salt,
Wherein,
A is selected from
Represent singly-bound or double bond；
R1、R2、R3、R4、R5、R6Independently selected from H, halogen, hydroxyl, amino, C1-3Alkyl, C1-3Alkoxy and C3-6Cycloalkanes Base, the amino, C1-3Alkyl, C1-3Alkoxy and C3-6Cycloalkyl is optionally by F, Cl, Br, cyano group, hydroxyl, C1-3Alkyl and C3-6Cycloalkyl substitutes；
X is selected from CR9R10、CR9、NR9, N and covalent bond；
R7、R8、R9、R10Independently selected from H, halogen, hydroxyl, amino, cyano group, C1-3Alkyl, C1-3Alkoxy, C3-6Cycloalkanes Base, phenyl and 5-6 unit's heteroaryls, the C1-3Alkyl, C1-3Alkoxy, C3-6Cycloalkyl, phenyl and 5-6 unit's heteroaryls are optionally By F, Cl, Br, cyano group, hydroxyl, C1-3Alkyl and C3-6Cycloalkyl substitutes.
In some embodiments, R1、R2、R3、R4Independently selected from H, halogen, hydroxyl, amino, C1-3Alkyl, C1-3Alcoxyl Base and C3-6Cycloalkyl.
In some embodiments, R1、R2、R3、R4Independently selected from H, halogen, C1-3Alkyl and C3-6Cycloalkyl.
In some embodiments, R1、R3、R4For H.
In some embodiments, R2Selected from H and halogen.In some embodiments, R2For F.
In some embodiments, R5For H.
In some embodiments, R6Selected from H, halogen, C1-3Alkyl and C3-6Cycloalkyl, the C1-3Alkyl and C3-6Cycloalkanes Base is optionally substituted by F, Cl and Br.
In some embodiments, R6Selected from H, F, Cl, Br, C1-3Alkyl, the C1-3Alkyl is optionally substituted by F.
In some embodiments, R6Selected from H, F and CF3。
In some embodiments, X is selected from CR9R10、NR9, N and covalent bond.
In some embodiments, R7、R8、R9、R10Independently selected from H, halogen, C1-3Alkyl and C3-6Cycloalkyl, it is described C1-3Alkyl and C3-6Cycloalkyl is optionally substituted by F, Cl, Br, cyano group and hydroxyl.
In some embodiments, R7、R8、R9、R10Independently selected from H, halogen, C1-3Alkyl and C3-6Cycloalkyl, it is described C1-3Alkyl and C3-6Cycloalkyl is optionally substituted by F and Cl.
In some embodiments, R7Selected from H, methyl and cyclopropyl.
In some embodiments, R8Selected from H and methyl.
In some embodiments, R9、R10Independently selected from F and methyl.
In some embodiments, formula (I) compound of the application is selected from formula (II) compound,
WhereinR1、R2、R3、R4、R6、R7、R8It is as defined above with X.
In some embodiments, formula (I) compound of the application is selected from following compound：
On the other hand, this application involves pharmaceutical composition, it includes formula (I) compound of the application or its can pharmaceutically connect The salt received.In some embodiments, the pharmaceutical composition of the application further includes pharmaceutically acceptable auxiliary material.
On the other hand, the method this application involves treatment mammal by the CRTH2 diseases mediated, including to needing this to control The mammal for the treatment of, the preferably mankind, give formula (I) compound or its pharmaceutically acceptable salt or its medicine of therapeutically effective amount Compositions.
On the other hand, this application involves formula (I) compound or its pharmaceutically acceptable salt or its pharmaceutical composition to make Purposes in the medicine of the standby disease prevented or treat CRTH2 mediations.
On the other hand, this application involves prevent or treatment CRTH2 mediation disease formula (I) compound or its pharmaceutically Acceptable salt.
Definition
Unless otherwise indicated, following term use herein has following meanings.One specific term is not having It especially should not be considered as uncertain or unclear in the case of definition, and should be gone according to the common implication in this area Understand.When herein presented trade name, it is intended that refer to its corresponding commodity or its active ingredient.
Term " substituted " refers to that any one or more hydrogen atoms in specific atoms are substituted with a substituent, as long as specific The valence state of atom be it is normal and substitute after compound be stable.
The event or situation that term " optional " or " optionally " refer to then describes may or may not occur, the description bag Include and the event or situation occurs and the event or situation does not occur.For example, ethyl " optional " is optionally substituted by halogen, referring to ethyl can To be unsubstituted (CH2CH3), mono-substituted (such as CH2CH2F), polysubstituted (such as CHFCH2F、CH2CHF2Deng) or completely Substituted (CF2CF3).Those skilled in the art, will not it is understood that for any group comprising one or more substituents Introducing any can not possibly spatially exist and/or the substitution that cannot be synthesized or substitute mode.
C hereinm-n, be the part have given range in integer carbon atom.Such as " C1-6" refer to the group Can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
When any variable (such as R) the once above occurs in the composition of compound or structure, it is in each situation Under definition be all independent.If thus, for example, a group is substituted by 2 R, each R has independent option.
When one of variable is selected from covalent bond, represent that two groups of its connection are connected directly, such as L in A-L-Z It is actually A-Z that the structure is represented when representing singly-bound.
Term " halogen " or " halogen " refer to fluorine, chlorine, bromine and iodine.
Term " hydroxyl " refers to-OH groups.
Term " cyano group " refers to-CN groups.
Term " amino " refers to-NH2Group.
Term " alkyl " refers to that general formula is CnH2n+1Alkyl.The alkyl can be straight or branched.For example, term “C1-6Alkyl " refer to containing 1 to 6 carbon atom alkyl (such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, Sec-butyl, the tert-butyl group, n-pentyl, 1- methyl butyls, 2- methyl butyls, 3- methyl butyls, neopentyl, hexyl, 2- methyl amyls Deng).Similarly, moieties (i.e. alkyl) tool of alkoxy, alkyl amino, dialkyl amido, alkyl sulphonyl and alkylthio group There is above-mentioned identical definition.
Term " alkoxy " refers to-O- alkyl.
Term " cycloalkyl " refers to fully saturated and can be with carbocyclic ring existing for monocyclic, condensed ring, bridged ring or loop coil.Remove Non- indicated otherwise, which is usually 3 to 10 yuan of rings.Cycloalkyl non-limiting examples include but not limited to cyclopropyl, cyclobutyl, Cyclopenta, cyclohexyl, norborny (bicyclic [2.2.1] heptyl), bicyclic [2.2.2] octyl group, adamantyl etc..
Term " heteroaryl " refers to monocyclic or fused polycycle system, wherein containing at least one annular atom selected from N, O, S, Remaining annular atom is C, and has at least one aromatic rings.The non-limiting examples of heteroaryl include but not limited to pyrrole radicals, Furyl, thienyl, imidazole radicals, oxazolyls, pyrazolyl, pyridine radicals, pyrimidine radicals, pyrazinyl, tetrazole radical, triazolyl, triazine radical Deng.
Term " treatment " mean herein described compound or preparation are administered to prevent, improve or eliminate a disease or With the relevant one or more symptoms of the disease, and including：
(i) prevention disease or morbid state occur in mammal, particularly when this kind of mammal is susceptible to the disease Diseased state, but when being not yet diagnosed as suffering from the morbid state；
(ii) suppress disease or morbid state, that is, contain its development；
(iii) disease or morbid state are alleviated, even if the disease or morbid state disappear.
Term " therapeutically effective amount " means that (i) treats or prevents specified disease, the patient's condition or obstacle, (ii) mitigate, improve or One or more symptoms of specified disease, the patient's condition or obstacle are eliminated, or (iii) prevents or postpone specific disease specifically described herein The dosage of the application compound of one or more paresthesia epilepsies of disease, the patient's condition or obstacle.Form this Shen of " therapeutically effective amount " Please the amount of compound depend on the compound, morbid state and its seriousness, administering mode and mammal to be treated Age and change, but can be determined by those skilled in the art according to its own knowledge and present disclosure to routine.
Term " pharmaceutically acceptable ", be for those compounds, material, composition and/or formulation, they Within the scope of reliable medical judgment, use is contacted suitable for the tissue with human and animal, without excessive toxicity, thorn Swash property, allergic reaction or other problems or complication, match with rational interests/Hazard ratio.
As pharmaceutically acceptable salt, for example, it can be mentioned that metal salt, ammonium salt, with organic base formed salt, with it is inorganic Salt and alkalescence that the salt and organic acid that acid is formed are formed or the salt that acidic amino acid is formed etc..
Term " pharmaceutical composition " refer to the compound or its salt of one or more the application with it is pharmaceutically acceptable auxiliary Expect the mixture of composition.The purpose of pharmaceutical composition is the compound for being conducive to give organism the application.
Term " pharmaceutically acceptable auxiliary material " refers to act on organism without obvious stimulation, and will not damage the activity The bioactivity of compound and those auxiliary materials of performance.Suitably auxiliary material is well known to those skilled in the art, such as carbon aquation Compound, wax, water solubility and/or the expandable polymer of water, hydrophily or hydrophobic material, gelatin, oil, solvent, water etc..
Word " including (comprise) " or " including (comprise) " and its English variation such as comprises or Comprising is interpreted as opening, nonexcludability meaning, i.e., " includes but not limited to ".
The compound and intermediate of the application can also exist with different tautomeric forms, and all such Form is contained in scope of the present application.Term " dynamic isomer " or " tautomeric forms " refer to can be mutual via low energy barrier The constitutional isomer of the different-energy of change.For example, proton tautomer (also referred to as Prototropic tautomers) includes warp By the change of proton transfer, such as keto-enol and imine-enamine isomerizations.The instantiation of proton tautomer is imidazoles portion Point, wherein proton can migrate between two ring nitrogen.Valence tautomerism body includes the change of the restructuring by some bonding electrons.
The application further include with it is described herein those are identical, but one or more atoms are by atomic weight or mass number Different from the atomic weight or the application compound of the isotope marks of the atomic substitutions of mass number being generally found in nature.It can tie Closing the example of the isotope of the application compound includes the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, iodine and chlorine, such as divides It is not2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、123I、125I and36Cl etc..
Some isotope marks the application compound (such as with3H and14Those of C flag) can be used for compound and/or In substrate tissue distributional analysis.It is tritiated (i.e.3H) and carbon-14 (i.e.14C) isotope is for since they are easily prepared and detectable Property is especially preferred.Positron emitting isotopes, such as15O、13N、11C and18F can be used for positron emission computerized tomography (PET) study to measure substrate occupation rate.Those classes with being disclosed in scheme and/or embodiment hereafter can usually be passed through As following procedure, substitute the reagent without isotope marks to prepare this Shen of isotope marks by isotope labeling reagent Please compound.
In addition, with higher isotope, (such as deuterium is (i.e.2H)) substitution can provide some metabolic stabilities by higher and produce Treatment advantages (such as increased Half-life in vivo or volume requirements of reduction), and be therefore probably excellent in some cases Choosing, wherein deuterium substitution can be that partially or completely, deuterium substitution in part refers to that at least one hydrogen is substituted by least one deuterium.
The application compound can be asymmetric, for example, with one or more stereoisomers.Unless otherwise saying Bright, all stereoisomers all include, such as enantiomter and diastereoisomer.The application containing asymmetric carbon atom Compound can be in the form of optical activity be pure or racemic form is separated.The pure form of optical activity can disappear from outside Revolve mixture to split, or synthesized by using chiral raw material or chiral reagent.
The pharmaceutical composition of the application can be by by the compound of the application and suitable pharmaceutically acceptable auxiliary material group Close and prepare, such as solid-state, semisolid, liquid or gaseous state preparation can be configured to, such as tablet, pill, capsule, pulvis, particle Agent, paste, emulsion, suspending agent, suppository, injection, inhalant, gelling agent, microballoon and aerosol etc..
Give the application compound or its pharmaceutically acceptable salt or the classical pathway of its pharmaceutical composition is included but not Be limited to take orally, rectum, part, suction, parenteral, sublingual, intravaginal, intranasal, intraocular, peritonaeum it is interior, intramuscular, subcutaneous, intravenous Administration.
The pharmaceutical composition of the application can use method well-known in the art to manufacture, such as conventional mixing method, molten Solution, granulation, dragee method processed, levigate method, emulsion process, freeze-drying etc..
In some embodiments, pharmaceutical composition is oral form., can be by by active ingredient for being administered orally Thing is mixed with pharmaceutically acceptable auxiliary material well known in the art, to prepare the pharmaceutical composition.These auxiliary materials can make the application Compound be formulated into tablet, pill, lozenge, sugar-coat agent, capsule, liquid, gelling agent, slurry agent, suspending agent etc., for pair The oral administration of patient.
Solid oral composition can be prepared by conventional mixing, filling or tabletting method.For example, can be by following Method obtains：The reactive compound is mixed with solid adjuvant material, the mixture for gained of optionally milling, adds if necessary Enter other suitable auxiliary materials, the mixture is then processed into particle, obtain the core of tablet or sugar-coat agent.Suitable auxiliary material Including but not limited to：Adhesive, diluent, disintegrant, lubricant, glidant, sweetener or flavouring etc..
Pharmaceutical composition could be applicable to parenteral administration, such as the sterile solution agent of suitable unit dosage forms, supensoid agent or Freeze-drying prods.
In all application processes of generalformulaⅰcompound as described herein, the dosage of daily administration arrives 200mg/kg for 0.01 Weight, preferably 0.02 arrives 100mg/kg weight, more preferably 0.1 arrives 20mg/kg weight, in the form of independent or separate doses.
The compound of the application can be prepared by a variety of synthetic methods well-known to those skilled in the art, including under The embodiment and art technology that the combination of embodiment that face is enumerated, itself and other chemical synthesis process is formed Equivalent substitution mode known to upper personnel, preferred embodiment include but not limited to embodiments herein.
The chemical reaction of the application embodiment is completed in a suitable solvent, and the solvent must be suitable for The chemical change of the application and its required reagent and material.In order to obtain the compound of the application, it is sometimes desirable to this area skill Art personnel modify or select to synthesis step or reaction process on the basis of existing embodiment.
An important consideration factor in the synthetic route planning of this area is for the reactive functional groups (ammonia in such as the application Base) the suitable protection group of selection, for example, referring to Greene's Protective Groups in Organic Synthesis(4th Ed).Hoboken,New Jersey:All references that John Wiley＆Sons, Inc. the application quote Document is incorporated herein on the whole.
The application uses following initialisms：Aq represents water；HATU represents O- (7- azepine benzos triazol-1-yl)-N, N, N ', N '-tetramethylurea hexafluorophosphate；EDC represents N- (3- dimethylaminopropyls)-N '-ethyl-carbodiimide hydrochloride；m- CPBA represents 3- chloroperoxybenzoic acids；Eq represents equivalent, equivalent；CDI represents carbonyl dimidazoles；DCM represents dichloromethane；PE generations Table petroleum ether；DIAD represents diisopropyl azo-2-carboxylic acid；DMF represents N,N-dimethylformamide；DMSO represents dimethyl sulfoxide； EtOAc represents ethyl acetate；EtOH represents ethanol；MeOH represents methanol；CBz represents benzyloxycarbonyl group, is a kind of amino protecting group Group；BOC represents tert-butyl carbonyl, is a kind of amido protecting group；HOAc represents acetic acid；NaCNBH3Represent sodium cyanoborohydride； R.t. room temperature is represented；O/N is represented overnight；THF represents tetrahydrofuran；Boc2O represents two carbonic ester of di-t-butyl；TFA represents three Fluoroacetic acid；DIPEA represents diisopropylethylamine；SOCl2Represent thionyl chloride；CS2Represent carbon disulfide；TsOH is represented to toluene Sulfonic acid；NFSI represents N- fluoro- N- (benzenesulfonyl) benzsulfamide；NCS represents 1- chlorine pyrrolidine-2,5-diones；n-Bu4NF is represented Tetrabutylammonium；IPrOH represents 2- propyl alcohol；Mp represents fusing point；LDA represents lithium diisopropylamine.
For clarity, further the present invention is illustrated with embodiment, but embodiment not limits scope of the present application. All reagents used in this application are commercially available, and can be used without being further purified.
Embodiment
Embodiment 1
The first step
Compound 1a (18.60g, 80.85mmol) is dissolved in concentrated hydrochloric acid (200mL, 12N), at -10~0 DEG C, slowly Be added dropwise sodium nitrite (6.69g, 97.02mmol) aqueous solution, reaction solution stirred at 0 DEG C 1 it is small when.This is reacted at 0 DEG C Drop is added in the mixture of stannous chloride (800mg, 8.09mmol) and sulfur dioxide (15.54g, 242.55mmol).Gained Reaction solution stirred at 0 DEG C 1 it is small when, then be warming up to 20 DEG C stirring 3 it is small when, after completion of the reaction, with ethyl acetate (200mL × 3) Extraction.Organic phase merges, dry, is concentrated under reduced pressure after doing, and it is pure to analyse (petrol ether/ethyl acetate=100-0%) separation through silicagel column Change obtains compound 1b (4.10g).1H NMR(400MHz,CDCl3) δ 8.03 (d, J=8.4Hz, 1H), 7.83-7.91 (m, 2H), 4.01 (s, 3H) .MS-ESI calculated values [M+H]+314, measured value 314.
Second step
At 20 DEG C by diisopropylethylamine (1.28g, 9.89mmol) be added drop-wise to compound 1b (3.10g, 9.89mmol) and In the 30mL dichloromethane solutions of compound 1c (1.74g, 10.38mmol).Gained reaction solution continue stirring 1 it is small when.React Finish, the crude product obtained after solvent is removed, separating (petrol ether/ethyl acetate=100-0%) with silica gel column chromatography purifies, and obtains To compound 1d (2.80g).1H NMR(400MHz,CDCl3) δ 7.81 (d, J=2.0Hz, 1H), 7.65 (d, J=8.0Hz, 1H), 7.54 (dd, J=8.4, J=2.0Hz, 1H) 6.96 (d, J=8.0Hz, 1H), 6.61 (t, J=6.4Hz, 1H), 6.25 (dd, J=8.0, J=2.0Hz, 1H), 6.14 (d, J=2.0Hz, 1H), 4.19 (d, J=6.4Hz, 2H), 3.95 (s, 3H), 3.75 (s, 3H), 3.62 (s, 3H) .MS-ESI calculated values [M+H]+445, measured value 445.
3rd step
Compound 1d (2.70g, 6.08mmol) is dissolved in tetrahydrofuran (50mL), it is different to be then slowly dropped into two in 0 DEG C Butyl aluminum hydride (1M, 18.2mL).Gained reaction solution stirred at 0 DEG C 3 it is small when reaction solutions saturation aqueous sodium potassium tartrate 70mL is quenched, and is extracted with ethyl acetate (50mL × 3).Organic phase merges, dry, is concentrated under reduced pressure after doing through silica gel plate layer chromatography (stone Oily ether/ethyl acetate=1/1) isolate and purify to obtain compound 1e (1.85g).1HNMR(400MHz,CDCl3) δ 7.69 (d, J= 8.4Hz, 1H), 7.57 (s, 1H) 7.45 (dd, J=8.4, J=2.0Hz, 1H), 6.89 (d, J=8.0Hz, 1H), 6.25-6.33 (m, 2H), 5.55 (t, J=5.6Hz, 1H), 4.83 (d, J=6.8Hz, 2H), 4.07-4.12 (m, 2H), 3.78 (s, 3H), 3.71 (s, 3H), 2.63-2.72 (m, 1H) .MS-ESI calculated values [M+H]+417, measured value 417.
4th step
Compound 1e (1.85g, 4.44mmol) is dissolved in tetrahydrofuran (300mL), under nitrogen protection, adds triphen Base phosphine (2.33g, 8.88mmol) and diisopropyl azodiformate (1.80g, 8.88mmol), 20 DEG C of stirrings 16 of reaction solution are small When.After completion of the reaction plus water (30mL) is quenched, after the most of tetrahydrofuran of the removing that is concentrated under reduced pressure, with ethyl acetate (200mL × 3) Extraction.Organic phase merges, dry, is concentrated under reduced pressure after doing, and is separated through silica gel column chromatography (petrol ether/ethyl acetate=100-0%) Purifying obtains compound 1f (2.80g).1H NMR(400MHz,CDCl3)δ7.62-7.71(m,2H),7.48(brs,1H),7.32 (d, J=8.8Hz, 1H), 6.47-6.52 (m, 2H), 4.44 (s, 2H), 4.23 (s, 2H), 3.85 (s, 3H), 3.82 (s, 3H) .MS-ESI calculated value [M+H]+399, measured value 399.
5th step
Compound 1f (2.70g, 6.78mmol) is dissolved in methanol (42mL), then adds n,N-Dimethylformamide (14mL), triethylamine (14mL) and [1,1- double (diphenylphosphino) ferrocene] palladium chloride (1.11g, 1.36mmol).Reaction After liquid is when stirring 16 is small under 80 DEG C and carbon monoxide atmosphere (50psi), reacting liquid filtering, is concentrated under reduced pressure, and is diluted with 50mL water, Extracted with ethyl acetate (50mL × 3).Organic phase merges, dry, is concentrated under reduced pressure after doing, through silica gel column chromatography (petroleum ether/acetic acid Ethyl ester=100-0%) it is purified to compound 1g (2.11g).1H NMR(400MHz,CDCl3) δ 8.18 (d, J=8.0Hz, 1H), 8.14-8.21 (m, 1H), 8.01 (s, 1H), 7.89 (d, J=8.0Hz, 1H), 7.34 (d, J=8.8Hz, 1H), 6.48-6.53 (m, 2H), 4.48 (s, 2H), 4.30 (s, 2H), 3.96 (s, 3H), 3.87 (s, 3H), 3.82 (s, 3H) .MS-ESI calculated values [M+ H]+378, measured value 378.
6th step
Compound 1g (2.0g, 5.30mmol) is dissolved in dichloromethane (40mL), is then slowly dropped into two isobutyls in 0 DEG C Base aluminum hydride (1M, 21.1mL).Gained reaction solution stirred at 0 DEG C 2 it is small when, be quenched with saturation aqueous sodium potassium tartrate 80mL Reaction, is extracted with dichloromethane (50mL × 3).Organic phase merges, dry, be concentrated under reduced pressure it is dry after through chromatography silica gel column (petroleum ether/ Ethyl acetate=100-0%) isolate and purify to obtain compound 1h (810mg).1H NMR(400MHz,CDCl3) δ 7.75 (d, J= 8.0Hz, 1H), 7.45 (d, J=8.0Hz, 1H), 7.31-7.36 (m, 2H), 6.47-6.53 (m, 2H), 5.31 (s, 1H), 4.77 (brs, 2H), 4.44 (s, 2H), 4.23 (s, 2H), 3.86 (s, 3H), 3.82 (s, 3H) .MS-ESI calculated values [M+H]+350, it is real Measured value 350.
7th step
Compound 1h (810mg, 2.32mmol) is dissolved in dichloromethane (20mL), addition manganese dioxide (1.61g, 18.55mmol), reaction solution be stirred at room temperature 16 it is small when after filter, filtrate directly concentrates dry silica gel plate layer chromatography (petroleum ether/second Acetoacetic ester=1/1) obtain compound 1i (640mg).1H NMR(400MHz,CDCl3)δ10.09(s,1H),7.98-8.05(m, 2H), 7.85 (s, 1H), 7.34 (d, J=9.2Hz, 1H), 6.48-6.53 (m, 2H), 4.49 (s, 2H), 4.34 (s, 2H), 3.87 (s, 3H), 3.83 (s, 3H) .MS-ESI calculated values [M+H]+348, measured value 348.
8th step
At ambient temperature, to the fluoro- 2- Methyl-1H-indoles (10.00g, 67.04mmol) of compound 5- and cesium carbonate In the solution of the N,N-dimethylformamide of the 100mL of (32.77g, 100.56mmol) be added dropwise bromoacetate (13.44g, 80.45mmol).Reaction solution reacted at 60 DEG C 3 it is small when.Reaction finishes, and 200mL saturated sodium bicarbonate solutions are added to reaction In liquid, ethyl acetate extraction (100mL × 3), organic phase is washed with saturated sodium-chloride water solution, anhydrous sodium sulfate drying, filtering, Concentration, with silica gel chromatograph column purification (petrol ether/ethyl acetate 100-50%), obtain target compound 1k (15.00g, it is faint yellow Oily, yield：95%).1H NMR(400MHz,CDCl3)δ7.19-7.17(m,1H),7.07-7.05(m,1H),6.89-6.87 (m,1H),6.26(s,1H),4.75(s,2H),4.23(m,2H),2.38(s,3H),1.25(m,3H).
Compound 1i (40mg, 0.12mmol) and compound 1k (27mg, 0.12mmol) are dissolved in 1,2- dichloroethanes In (3mL), trifluoroacetic acid (79mg, 0.69mmol) and triethylsilane (134mg, 1.15mmol) are added.Reaction solution is at 60 DEG C It is lower stirring 2 it is small when.Reaction solution is gone out with 5mL water quenchings, ethyl acetate (10ml × 2) extraction.Organic phase merges, and is done with anhydrous sodium sulfate Dry, filtering, is concentrated under reduced pressure to give crude Compound 1j (40mg).MS-ESI calculated values [M+H]+417, measured value 417.
9th step
Compound 1j (58mg, 0.14mmol) is dissolved in the in the mixed solvent of tetrahydrofuran (5mL) and water (1mL), is added One hydronium(ion) lithia (29mg, 0.70mmol) reaction solutions when 50 DEG C of stirrings 2 are small is added dropwise 1N hydrochloric acid and is neutralized to pH 2-3, uses Ethyl acetate (10mL × 3) extracts.Organic phase is dried over anhydrous sodium sulfate, and is filtered, and concentration, crude product is through high performance liquid chromatography Purifying, obtains compound 1 (9mg).1H NMR(400MHz,DMSO-d6) δ 7.67 (d, J=8.0Hz, 2H), 7.39 (brs, J= 8.8Hz, 1H), 7.34 (s, 1H), 7.16 (dd, J=9.6, J=2.4Hz, 1H), 6.87 (td, J=9.6, J=2.4Hz, 1H), 4.96 (s, 2H), 4.32 (d, J=4.8Hz, 2H), 4.12 (s, 2H), 2.35-2.35 (m, 1H), 2.32 (s, 2H), 2.07 (s, 1H) .MS-ESI calculated values [M+H]+389, measured value 389.
Embodiment 2
The first step
Compound 2a (5.80g, 19.25mmol) is dissolved in tetrahydrofuran (150mL), at 0 DEG C, hydrogenation is added portionwise Sodium (1.54g, 38.50mmol, 60%).Gained reaction solution adds saturated ammonium chloride solution after completion of the reaction when 20 DEG C of stirrings 3 are small It is quenched, adjusts pH to 6~7, after the most of tetrahydrofuran of the removing that is concentrated under reduced pressure, is extracted with ethyl acetate (100mL × 3).It is organic Mutually merge, it is dry, it is concentrated under reduced pressure after doing and obtains compound 2b (5.00g).1H NMR(400MHz,CDCl3) δ 8.21 (d, J= 8.4Hz, 1H), 8.06-8.12 (m, 1H), 7.89 (d, J=8.0Hz, 1H), 4.39 (s, 2H), 3.95-4.01 (m, 3H), 3.00 (s, 3H) .MS-ESI calculated values [M+H]+270, measured value 270.
Second step
Compound 2b (3.00g, 11.14mmol) is dissolved in tetrahydrofuran (30mL), at 0 DEG C, boron hydrogen is added portionwise Change sodium (506mg, 13.37mmol).Gained reaction solution after completion of the reaction, adds saturated ammonium chloride solution when 20 DEG C of stirrings 0.5 are small It is quenched, adjusts pH to 6~7, after the most of tetrahydrofuran of the removing that is concentrated under reduced pressure, is extracted with ethyl acetate (50mL × 2).It is associated with Machine phase, it is dry, it is concentrated under reduced pressure after doing, isolates and purifies to obtain chemical combination through silica gel column chromatography (petrol ether/ethyl acetate=100-0%) Thing 2c (2.70g).MS-ESI calculated values [M+H]+272, measured value 272.
3rd step
At -10 DEG C by methane sulfonyl chloride (1.70g, 14.84mmol) be slowly dropped to compound 2c (1.30g, 4.79mmol) and in the 30mL dichloromethane solutions of triethylamine (2.42g, 23.96mmol).Gained reaction solution is warming up to 20 DEG C simultaneously Continue stirring 1 it is small when.Then 1,8- diazabicylos [5.4.0] 11 carbon -7- alkene (3.65g, 23.96mmol) is added.Gained Reaction solution 20 DEG C continue stirring 1 it is small when.After completion of the reaction at 0 DEG C, saturated ammonium chloride solution is added to be quenched, adjusting pH to 6~ 7, extracted with dichloromethane (30mL × 2).Organic phase merges, dry, is concentrated under reduced pressure after doing, through silica gel column chromatography (petroleum ether/second Acetoacetic ester=100-0%) isolate and purify to obtain compound 2d (1.13g).1H NMR(400MHz,CDCl3)δ7.75-7.91(m, 2H), 7.51 (d, J=8.0Hz, 1H), 7.33 (d, J=10.0Hz, 1H), 6.88 (d, J=10Hz, 1H), 3.98 (s, 3H), 3.58 (s, 3H) .MS-ESI calculated values [M+H]+254, measured value 254.
4th step
Compound 2d reacts to obtain compound 2e (90mg) with reference to the synthetic method in embodiment 1.1H NMR(400MHz, CDCl3) δ 7.42 (d, J=8.0Hz, 1H), 7.21 (s, 1H), 7.13-7.18 (m, 1H), 6.99-7.06 (m, 1H), 6.75 (d, J=10.0Hz, 1H), 4.81 (d, J=6.0Hz, 2H), 4.70 (d, J=6.0Hz, 1H), 3.52 (s, 3H) .MS-ESI calculated values [M+H]+226, measured value 226.
5th step
Compound 2e reacts to obtain compound 2f (40mg) according to the synthetic method in embodiment 1.1H NMR(400MHz, CDCl3) δ 10.4 (s, 1H), 7.67-7.72 (m, 2H), 7.60-7.66 (m, 1H), 7.35 (d, J=10.4Hz, 1H), 6.93 (d, J=10.4Hz, 1H), 3.60 (s, 3H) .MS-ESI calculated values [M+H]+224, measured value 224.
6th step
Compound 2f and compound 1k reacts to obtain compound 2g with reference to the synthetic method of compound 1j in embodiment 1 (23mg).MS-ESI calculated values [M+H]+443, measured value 443.
7th step
Compound 2g reacts to obtain compound 2 (9mg) with reference to the synthetic method of embodiment 1.1HNMR(400MHz,DMSO- d6) δ 7.44-7.54 (m, 2H), 7.36 (dd, J=9.2, J=4.4Hz, 1H), 7.19-7.26 (m, 2H), 7.15 (d, J= 10.0Hz, 1H), 7.01 (d, J=8.2Hz, 1H), 6.81-6.91 (m, 1H), 4.97 (s, 2H), 4.12 (s, 2H), 2.35 (s, 3H) .MS-ESI calculated values [M+H]+415, measured value 415.
Embodiment 3
The first step
At 0 DEG C, 150mL methanol from the mixing to compound 3a (19.00g, 92.62mmol) and 150mL dichloromethane Trimethyl silicane base diazomethane (55.57mL, 2M, 111.15mmol) is slowly added dropwise in solution.Gained reaction solution stirs 1 at 0 DEG C After hour, into reaction solution adding 10mL water quenchings goes out reaction, is directly concentrated under reduced pressure to give compound 3b (20.30g).1H NMR (400MHz,CDCl3) δ 7.78-7.76 (d, J=8.8Hz, 1H), 6.99-6.98 (d, J=2.0Hz, 1H), 6.78-6.75 (dd, J=8.4Hz, J=2.4Hz, 1H), 4.21 (s, 2H), 3.88 (s, 3H)
Second step
At 0 DEG C, bromine is slowly added dropwise into the 200mL methanol solutions of compound 3b (20.30g, 92.63mmol) The 200mL methanol solutions of (15.54g, 97.26mmol).Gained reaction solution stirred at 0 DEG C 1 it is small when, be concentrated under reduced pressure to give remnants Thing.Residue is diluted with 200mL ethyl acetate and 200mL saturated sodium bicarbonate solutions, then with ethyl acetate (100mL × 3) Extraction, organic phase are dried after merging with anhydrous sodium sulfate, are filtered, are concentrated under reduced pressure to give compound 3c (27.00g).MS-ESI is counted Calculation value [M+H]+298, measured value 298.
3rd step
Be slowly added dropwise into acetic acid (100mL) solution of compound 3c (19.0g, 63.75mmol) concentrated hydrochloric acid (100mL, 36%) after when, stirring 0.5 is small, sodium nitrite (8.80g, 127.49mmol) is slowly added dropwise into reaction system at 0 DEG C 5mL aqueous solutions, continue after being added dropwise stirring 0.5 it is small when.At 0 DEG C by previous reaction drop be added to stannous chloride (1.89g, 19.12mmol) with the mixture of sulfur dioxide liquid (200g, 3.12mol), then proceed to stirring 0.5 it is small when.Reaction solution is used 500mL water dilutes, and is extracted with ethyl acetate (200mL × 4).Organic phase uses saturated nacl aqueous solution (150mL × 4) after merging Washing, anhydrous sodium sulfate drying, filtering, is concentrated under reduced pressure to give crude Compound 3d (24.32g).
4th step
Compound 3d is slowly added dropwise into the 160mL tetrahydrofuran solutions of methylamine (319.98mmol, 2M) at 0 DEG C Acetonitrile (200mL) solution of (24.32g, 63.74mmol).After when gained reaction solution stirring 1 is small, residue is concentrated under reduced pressure to give. Residue obtains compound 3e (15.00g) through (the mixed solvent 50mL of ethyl acetate/petroleum ether=10/1) mashing.1H NMR (400MHz,CDCl3) δ 8.48 (s, 1H), 8.14 (s, 1H), 5.10-5.09 (d, J=5.2Hz, 1H), 3.99 (s, 3H), 2.71-2.70 (d, J=5.2Hz, 3H)
5th step
Under nitrogen protection copper is added into the 150mL dimethyl sulphoxide solutions of compound 3e (10.0g, 26.59mmol) Powder (13.52g, 212.68mmol) and Bromodifluoroacetic acid ethyl ester (21.59g, 106.34mmol).Gained reaction solution stirs at 35 DEG C Mix 3 it is small when, reaction solution is cooled to room temperature.Diluted with saturated nacl aqueous solution (500mL), and with ethyl acetate (200mL × 3) Extraction, organic phase are washed after merging with saturated nacl aqueous solution (200mL × 3), and anhydrous sodium sulfate drying, filtering, is concentrated under reduced pressure Obtain residue.Residue isolates and purifies to obtain compound 3f through column chromatography (petrol ether/ethyl acetate=100-0%) (8.00g)。
6th step
At -10 DEG C, lithium aluminium hydride is added into the 150mL tetrahydrofuran solutions of compound 3f (7.0g, 16.69mmol) (634mg,16.69mmol).Gained reaction solution continue at this temperature stirring 0.5 it is small when.At -10 DEG C into reaction system according to Secondary addition water (0.6mL) and 15% sodium hydroxide solution (0.6mL) and water (0.6mL), continue to stir 0.5 it is small when.Filtering, subtracts Pressure is concentrated to give residue.Residue isolates and purifies to obtain compound 3g through column chromatography (petrol ether/ethyl acetate=100-0%) (630mg)。
7th step
Compound 3g reacts to obtain compound 3h (15mg) according to the synthetic method of embodiment 1.1H NMR(400MHz, CD3OD)δ8.14(s,1H),7.45(s,1H),7.31-7.29(m,1H),6.85-6.83(m,2H),4.99(s,2H),4.36 (s, 2H), 4.23 (t, J=12.4Hz, 2H), 2.97 (s, 3H), 2.32 (s, 3H) .MS-ESI calculated values [M+H]+521, actual measurement Value 521.
8th step
Method according to embodiment 1 is reacted by compound 3h after the conversion of two steps with compound 1k synthesizes compound 3 (15mg)。1H NMR(400MHz,CD3OD)8.14(s,1H),7.45(s,1H),7.31-7.29(m,1H),6.85-6.83(m, 2H), 4.99 (s, 2H), 4.36 (s, 2H), 4.23 (t, J=12.4,2H), 2.97 (s, 3H), 2.32 (s, 3H) .MS-ESI are calculated It is worth [M+H]+521, measured value 521.
Embodiment 4
The first step
Vulcanized sodium is added into dimethylformamide (200mL) solution of compound 4a (25.00g, 115.96mmol) (10.86g, 139.15mmol), reaction solution stirred at 20 DEG C 16 it is small when.Reaction finishes, and reaction solution is poured into water (500mL) In, pH to 5 is adjusted with 1N aqueous hydrochloric acid solutions, there is solid precipitation.Solid, then the mixing with petroleum ether and ethyl acetate is obtained by filtration Solvent (200mL, v/v=3/1) mashing obtains compound 4b (16.70g).1H NMR(400MHz,CDCl3) δ 8.89 (d, J= 1.6Hz, 1H), 8.05 (dd, J=1.6, J=8.4Hz, 1H), 7.52 (d, J=8.4Hz, 1H), 4.21 (s, 1H), 3.96 (s, 3H).
Second step
Chlorosuccinimide (52.29g, 391.63mmol) is added portionwise in compound 4b (16.7g, 78.33mmol) In acetonitrile (500mL) solution of hydrochloric acid (2M, 83.42mL), temperature is kept to be less than 20 DEG C by ice bath during charging.Add Afterwards by reaction solution be warming up to 20 DEG C stirring 16 it is small when.Reaction finishes, and reaction solution adds water (200mL) dilution, by most of acetonitrile Evaporate, extracted with ethyl acetate (200mL × 2).Merge organic phase, successively with saturated sodium bicarbonate solution (500mL × 2) and Saturated salt solution (500mL × 2) washs, and is dried over anhydrous sodium sulfate, filters, being concentrated to give compound 4c (25.00g).1H NMR(400MHz,CDCl3)δ8.49-8.43(m,2H),8.33(m,1H),4.03(m,3H).
3rd step
The acetonitrile solution (6M, 44.70mL) of ammonia is added into acetonitrile (250mL) solution of 4c (15g, 53.64mmol). Gained reaction solution stirred at 25 DEG C 1 it is small when.Reaction finishes, and reaction solution adds water (500mL) to dilute, and most of acetonitrile is evaporated Fall, extracted with ethyl acetate (300mL × 2).Merge organic phase, washed with saturated salt solution (500mL × 2), through anhydrous slufuric acid Sodium is dry, filters, is concentrated to give compound 4d (9.60g).1H NMR(400MHz,DMSO-d6)δ8.46-8.34(m,2H), (8.20 d, J=8.4Hz, 1H), 8.06 (s, 2H), 3.92 (s, 3H)
4th step
The methanol (100mL) and tetrahydrofuran of compound 4d (9.60g, 36.89mmol) and Raney's nickel (316mg) (100mL) solution stirred at hydrogen (50PSI) atmosphere and 20 DEG C 5 it is small when.Reaction finishes, reacting liquid filtering, being concentrated to give Compound 4e (8.45g).1H NMR(400MHz,DMSO-d6) δ 7.64 (d, J=8.4Hz, 1H), 7.45 (d, J=1.6Hz, 1H), 7.42(s,2H),7.13(m,1H),6.09(s,2H),3.83(s,3H).
5th step
By formic acid (50mL) solution of compound 4e (1.00g, 4.34mmol) be heated to 100 DEG C stirring 0.5 it is small when.Reaction Finishing, reaction solution concentration is dry, mixed solvent (20mL, the v/v=5/1) mashing of residue petroleum ether and ethyl acetate, filtering, Obtain compound 4f (800mg).1H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.97-7.89(m,3H),3.91(s, 3H) .MS-ESI calculated values [M+H]+241, measured value 241.
6th step
Compound 4f reacts to obtain compound 4g (0.35g) according to the synthetic method of compound 3g in embodiment 3.MS-ESI Calculated value [M+H]+213, measured value 213.
7th step
Compound 4g reacts to obtain compound 4h (0.08g) according to the synthetic method of compound 2f in embodiment 2.
8th step
Synthesized by compound 4h and compound 1k to obtain compound 4 (61mg) according to the method for embodiment 1.1H NMR (400MHz,DMSO-d6) δ 7.88 (s, 1H), 7.70 (d, J=8.4Hz, 1H), 7.37 (m, 1H), 7.33 (d, J=9.2Hz, 1H),7.16(m,1H),7.09(s,1H),6.92-6.84(m,1H),4.96(s,2H),4.11(s,2H),2.31(s,3H) .MS-ESI calculated value [M+H]+402, measured value 402.
Embodiment 5
The first step
Into dimethylformamide (10mL) solution of compound 4h (0.08g, 0.38mmol) add cesium carbonate (248mg, 0.76mmol) and iodomethane (81mg, 0.57mmol).Gained reaction solution stirred at 50 DEG C 2 it is small when.Reaction finishes, and directly will Reacting liquid filtering, filtrate are concentrated to give compound 5a (0.09g).
Second step
Synthesized by compound 5a and compound 1k to obtain compound 5 (13mg) according to the method for embodiment 1.1H NMR (400MHz,DMSO-d6) δ 8.03 (s, 1H), 7.74 (d, J=8.0Hz, 1H), 7.39 (s, 1H), 7.38-7.34 (m, 1H), 7.28 (d, J=8.4Hz, 1H), 7.22 (m, 1H), 6.87 (m, 1H), 4.97 (s, 2H), 4.17 (s, 2H), 3.57 (s, 3H), 2.34 (s, 3H) .MS-ESI calculated values [M+H]+416, measured value 416.
Embodiment 6
The first step
Into dimethylformamide (15mL) solution of compound 4f (520mg, 2.16mmol) add cesium carbonate (1.76g, 5.41mmol) and iodomethane (461mg, 3.25mmol).Gained reaction solution stirred at 50 DEG C 2 it is small when.Reaction finishes, and will react Liquid is poured into water (100mL), ethyl acetate (20mL × 2) extraction.Merge organic phase, washed with saturated salt solution (50mL × 2), It is dried over anhydrous sodium sulfate, filters, concentrates, then is washed with methyl tertiary butyl ether(MTBE) (5mL × 1) to obtain compound 6a (330mg). MS-ESI calculated values [M+H]+255, measured value 255.
Second step
At 0 DEG C sodium borohydride is added into tetrahydrofuran (50mL) solution of compound 6a (330mg, 0.91mmol) (34mg,0.91mmol).Gained reaction solution be warming up to 25 DEG C and continue stirring 1 it is small when.Reaction finishes, and reaction solution adds water (20mL) It is quenched, is extracted with ethyl acetate (30mL × 2).Merge organic phase, be dried over anhydrous sodium sulfate, filter, concentrate, through chromatographic column layer Analysis (petrol ether/ethyl acetate=100-0%) isolates and purifies to obtain compound 6b (214mg).1H NMR(400MHz,DMSO-d6) δ 8.24-8.22 (m, 1H), 7.68 (d, J=8.4Hz, 1H), 7.32 (m, 2H), 4.73 (d, J=8.0Hz, 2H), 3.87 (s, 3H), 3 (s, 3H) .MS-ESI calculated values [M+H]+257, measured value 257.
3rd step
At 0 DEG C sodium hydride is added into dimethylformamide (10mL) solution of compound 6b (214mg, 0.84mmol) (33mg, 0.84mmol, purity：60%).Gained reaction solution continue stirring 0.5 it is small when.Addition iodomethane (178mg, 1.25mmol), reaction solution stirred at 20 DEG C 1 it is small when.Reaction finishes, and reaction solution is poured into water (100mL), uses ethyl acetate (20mL × 2) extract.Merge organic phase, washed with saturated salt solution (50mL × 2), be dried over anhydrous sodium sulfate, filter, concentrate Obtain compound 6c (200mg).MS-ESI calculated values [M+H]+271, measured value 271.
4th step
Compound 6c reacts to obtain compound 6d (161mg) according to the synthetic method in embodiment 2.MS-ESI calculated values [M +H]+241, measured value 241.
6th step
Synthesized by compound 6d and compound 1k to obtain compound 6 (63mg) according to the method for embodiment 1.1H NMR (400MHz,DMSO-d6) δ 7.40 (d, J=8.0Hz, 1H), 7.36 (m, 1H), 7.20 (m, 1H), 6.86 (m, 1H), 6.77 (s, 1H), 6.62 (d, J=8.0Hz, 1H), 4.97 (s, 2H), 4.82 (s, 2H), 4.01 (s, 2H), 2.93 (s, 3H), 2.63 (s, 3H), 2.33 (s, 3H) .MS-ESI calculated values [M+H]+432, measured value 432.
Embodiment 7
The first step
When acetic anhydride (50mL) solution of compound 4e (1.20g, 5.21mmol) is heated to 120 DEG C and small stirring 2.Reaction Finish, reaction solution is washed with saturated sodium bicarbonate solution (200mL), ethyl acetate (50mL × 2) extraction.Merge organic phase, use Saturated salt solution (100mL × 2) washs, and is dried over anhydrous sodium sulfate, filters, concentrates, then is washed with methyl tertiary butyl ether(MTBE) (10mL) Wash, obtain compound 7a (370mg).MS-ESI calculated values [M+H]+255, measured value 255.
Second step
Compound 7a reacts to obtain compound 7b (200mg) according to the synthetic method in embodiment 4.MS-ESI calculated values [M +H]+225, measured value 225.
3rd step
Synthesized by compound 7b and compound 1k to obtain compound 7 (13mg) according to the method for embodiment 1.1H NMR (400MHz,DMSO-d6) δ 11.87 (brs, 1H), 7.68 (d, J=8.4Hz, 1H), 7.38 (m, 1H), 7.34 (d, J= 8.0Hz,1H),7.16(m,1H),7(s,1H),6.89(m,1H),4.97(s,2H),4.11(s,2H),2.31(s,3H),2.22 (s, 3H) .MS-ESI calculated values [M+H]+416, measured value 416.
Embodiment 8
The first step
Cyclopropylamine (2.55g, 44.70mmol) is added into acetonitrile (50mL) solution of 4c (2.50g, 8.94mmol).Institute Reaction solution stirred at 25 DEG C 2 it is small when.Reaction finishes, and reaction solution adds water (100mL) to dilute, and most of acetonitrile is evaporated and is removed Go, extracted with ethyl acetate (50mL × 3).Merge organic phase, washed with saturated salt solution (250mL × 2), through anhydrous sodium sulfate Dry, filter, being concentrated to give compound 8a (2.40g).1H NMR(400MHz,CDCl3) δ 8.46 (d, J=1.6Hz, 1H), 8.40-8.35(m,1H),8.31-8.27(m,1H),5.60(s,1H),4.01(s,3H),2.43-2.32(m,1H),0.77- 0.68(m,4H).
Second step
The method of reference implementation example 4 is synthesized to obtain compound 8b (1.80g) by compound 8a.1H NMR(400MHz, DMSO-d6) δ 8.02 (brs, 1H), 7.63 (d, J=8.4Hz, 1H), 7.47 (d, J=1.6Hz, 1H), 7.15 (m, 1H), 6.15 (s, 2H), 3.84 (s, 3H), 2.08 (m, 1H), 0.48-0.41 (m, 2H), 0.40-0.33 (m, 2H) .MS-ESI calculated values [M+ H]+271, measured value 271.
3rd step
Formic acid (50mL) solution of compound 8b (1.80g, 6.66mmol) be heated to 100 DEG C stirring 12 it is small when.React Finish, reaction solution is concentrated to dryness, and by silica gel chromatography column (petrol ether/ethyl acetate=100-0%) isolates and purifies to obtain compound 8c (1.25g)。1H NMR(400MHz,DMSO-d6)δ9.55(brs,1H),8.88(s,1H),8.49(s,1H),8.40(br s, 1H), 7.99 (d, J=8.4Hz, 1H), 7.87 (m, 1H), 3.90 (s, 3H), 2.22-2.12 (m, 1H), 0.53-0.46 (m, 2H), 0.39-0.32 (m, 2H) .MS-ESI calculated values [M+H]+299, measured value 299.
4th step
Into methanol (50mL) solution of compound 8c (1.00g, 3.35mmol) add sodium hydroxide (1.07g, Water (10mL) solution 26.82mmol).Gained is when stirring 16 is small at 80 DEG C of reaction solution.Reaction finishes, and reaction solution adds water (30mL) dilutes, and most of methanol evaporates, and adjusts pH to 5 with dilute hydrochloric acid, is extracted with ethyl acetate (100mL × 2).It is associated with Machine phase, is dried over anhydrous sodium sulfate, filters, being concentrated to give compound 8d (850mg).MS-ESI calculated values [M+H]+257, actual measurement Value 257.
5th step
Triethyl orthoformate (40mL) solution of compound 8d (850mg, 3.32mmol) is heated to 140 DEG C and stirring 8 is small When.Reaction finishes, and reaction solution concentration is dry, adds ethyl acetate (100mL) to dissolve, is washed with saturated sodium bicarbonate solution (100mL × 1) Wash.Organic phase is dried over anhydrous sodium sulfate, filters, being concentrated to give compound 8e (950mg).1H NMR(400MHz,CDCl3)δ 8.20 (d, J=1.2Hz, 1H), 8.10 (m, 1H), 7.99 (d, J=8.4Hz, 1H), 7.67 (s, 1H), 4.42 (m, 2H), 3.20 (m, 1H), 1.42 (m, 3H), 1.20-1.14 (m, 4H) .MS-ESI calculated values [M+H]+295, measured value 295.
6th step
The method of reference implementation example 6 is synthesized to obtain compound 8f (85mg) by compound 8e through four steps.1H NMR (400MHz,CDCl3) δ 10 (s, 1H), 7.92 (d, J=8.0Hz, 1H), 7.33 (m, 1H), 7.24 (s, 1H), 4.91 (s, 2H), 3.14(s,3H),2.30(m,1H),0.91(m,2H),0.79(m,2H).
7th step
Synthesized by compound 8f and compound 1k to obtain compound 8 (42mg) according to the method for embodiment 1.1H NMR (400MHz,DMSO-d6) δ 7.42 (d, J=8.0Hz, 1H), 7.25 (m, 1H), 7.20-7.08 (m, 1H), 6.80 (m, 2H), 6.65 (d, J=8.0Hz, 1H), 4.79 (s, 2H), 4.65 (brs, 2H), 3.99 (s, 2H), 2.97 (s, 3H), 2.31 (brs, 3H), 2.19-2.10 (m, 1H), 0.76-0.61 (m, 4H) .MS-ESI calculated values [M+H]+458, measured value 458.
Embodiment 9
The first step
Into acetonitrile (50mL) solution of 4c (5g, 17.88mmol) add methylamine ethanol solution (9.26g, 89.40mmol purity：30%).Gained reaction solution stirred at 25 DEG C 1 it is small when.Reaction finishes, and reaction solution adds water (100mL) dilute Release, most of acetonitrile is evaporated, extracted with ethyl acetate (100mL × 2).Merge organic phase, with saturated salt solution (100mL × 2) wash, be dried over anhydrous sodium sulfate, filter, concentrate, column (petrol ether/ethyl acetate=100- is chromatographed through Flash silica 0%) isolate and purify to obtain compound 9a (2.30g).1H NMR(400MHz,CDCl3) δ 8.47 (d, J=1.6Hz, 1H), 8.37 (m, 1H), 8.21 (d, J=8.0Hz, 1H), 5.28-5.26 (m, 1H), 4.01 (s, 3H), 2.82-2.81 (m, 3H)
Second step
The method of reference implementation example 4 is synthesized to obtain compound 9b (2.00g) by compound 9a.MS-ESI calculated values [M+H]+ 245, measured value 245.
3rd step
Triethly orthoacetate (50mL) solution of compound 9b (1.95g, 7.98mmol) is heated to 130 DEG C and stirring 16 is small When.Reaction finishes, and reaction solution concentration is dry, by silica gel chromatography column (petrol ether/ethyl acetate=100-0%) isolating and purifying Compound 9c (1.50g).1H NMR(400MHz,DMSO-d6)δ8.08-8.04(m,1H),8.02-7.98(m,1H),7.94(d,J =1.2Hz, 1H), 3.91 (s, 3H), 3.47 (s, 3H), 2.51 (s, 3H) .MS-ESI calculated values [M+H]+269, measured value 269.
4th step
The method of reference implementation example 4 is synthesized to obtain compound 9d (300mg) by compound 9c.1H NMR(400MHz, CDCl3) δ 10.10 (s, 1H), 8.12-7.83 (m, 3H), 3.51 (s, 3H), 2.52 (s, 3H) .MS-ESI calculated values [M+H]+ 239, measured value 239.
6th step
Synthesized by compound 9d and compound 1k to obtain compound 9 (198mg) according to the method for embodiment 1.1H NMR (400MHz,DMSO-d6)δ9.24(s,1H),8.09(brs,1H),7.68-7.59(m,2H),7.35(m,1H),7.18-7.08 (m,2H),6.91-6.81(m,1H),4.96(s,2H),4.05(s,2H),2.39-2.37(m,3H),2.33(s,3H),2.09 (s, 3H) .MS-ESI calculated values [M+MeCN]+430, measured value 430.
Embodiment 10
The first step
Compound 3d (2.00g, 5.32mmol) is dissolved in methanol (40mL), addition methylamine (ethanol solution, 10.01g, 106.34mmol, 30%), reaction solution stirred at 65 DEG C 13 it is small when.Reaction solution is cooled to room temperature, water (30mL) is added and is quenched Reaction, is extracted with dichloromethane (120mL × 2).Merge organic phase, saturated common salt water washing (100mL), anhydrous sodium sulfate is done Dry, filtering, is concentrated under reduced pressure, residue isolates and purifies (petrol ether/ethyl acetate=100-0%) with silica gel column chromatography, obtains Compound 10a (950mg).1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.04(s,1H),6.41(brs,1H),4.58 (brs, 1H), 3.96 (s, 3H), 2.97 (d, J=5.2Hz, 3H), 2.63 (d, J=5.6Hz, 3H)
Second step
Compound 10a (950mg, 2.91mmol) is dissolved in ethanol (15mL) and 1,2- dichloroethanes (8mL), is added more Polyformaldehyde (600mg, 2.91mmol) and the concentrated sulfuric acid (0.2mL).Gained reaction solution stirred at 80 DEG C 3 it is small when.Reaction solution is cold But to room temperature, add saturated sodium bicarbonate aqueous solution (20mL) and reaction is quenched, extracted with dichloromethane (30mL × 2).It is associated with Machine phase, saturated common salt water washing (50mL), anhydrous sodium sulfate drying, filtering, is concentrated under reduced pressure, residue silica gel column chromatography point From purifying (petrol ether/ethyl acetate=100-0%), compound 10b (820mg) is obtained.1H NMR(400MHz,CDCl3)δ 8.05(s,1H),7.06(s,1H),4.93(s,2H),3.96(s,3H),3.12(s,3H),2.82(s,3H).
3rd step
According to the method for embodiment 2 compound 10c (350mg) is obtained through two-step reaction by compound 10b.1H NMR (400MHz,CDCl3)δ10.35(s,1H),8.10(s,1H),7.43(s,1H),4.95(s,2H),3.17(s,3H),2.83 (s,3H).
4th step
Reacted by compound 10c and compound 1k to obtain compound 10 (58mg) according to the method for embodiment 1.1H NMR (400MHz,CD3OD)δ7.86(s,1H),7.32-7.28(m,1H),6.91-6.86(m,2H),6.43(s,1H),5.04(s, 2H), 4.84 (s, 2H), 4.22 (s, 2H), 2.69-2.67 (m, 6H), 2.33 (s, 3H) .MS-ESI calculated values [M+H]+500, it is real Measured value 500.
Embodiment 11
The first step
At 0 DEG C, compound 11a (15.00g, 90.81mmol) is dissolved in absolute methanol (200mL), is protected in nitrogen Lower methanol (100mL) solution that bromine (13.06g, 81.72mmol) is added dropwise.Gained reaction solution reacted at 20 DEG C 2 it is small when.Instead Directly being concentrated after answering, add water (100mL), extracted with ethyl acetate (200mL × 3), organic phase is dried with anhydrous sodium sulfate, Filtering, concentration, isolates and purifies to obtain compound 11b through Flash silica column chromatography (petrol ether/ethyl acetate=100-0%) (11.8g)。1H NMR(400MHz,CD3OD) δ 7.99 (d, J=1.6Hz, 1H), 7.72-7.70 (m, 1H), 6.78 (d, J= 8.4Hz,1H),4.32-4.26(m,2H),1.37-1.33(m,3H).
Second step
At -10 DEG C, compound 11b (11.8g, 48.34mmol) is dissolved in concentrated hydrochloric acid (60.43mL, 12N), then Water (300mL) solution of sodium nitrite (4.00g, 58.01mmol) is added dropwise.Gained reaction solution reacted at 0 DEG C 0.5 it is small when after, Be added portionwise at -10 DEG C it is another equipped with stannous chloride (1.44g, 14.50mmol) and liquid sulfur dioxide (9.29g, 145.03mmol) reaction bulb in.Gained reaction solution reacted at 0 DEG C 0.5 it is small when.Ethyl acetate (100mL × 3) extracts, and has Machine is mutually washed with saturated salt solution (100mL × 3), and anhydrous sodium sulfate drying, is filtered, concentration, obtains compound 11c (14.00g)。1H NMR(400MHz,CDCl3) δ 8.48 (d, J=1.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 8.18- 8.16(m,1H),4.48-4.43(m,2H),1.46-1.41(m,3H).
3rd step
At 20 DEG C, compound 11c (14.00g, 42.74mmol) is dissolved in acetonitrile (200mL), under nitrogen protection Methylamine solution (427mmol, 213.69mL) is added dropwise.Gained reaction solution is when 20 DEG C of reactions 12 are small.Water (100mL) is added to be quenched, second Acetoacetic ester (100mL × 3) extracts, and organic phase is dried with anhydrous sodium sulfate, filters, concentration, through Flash silica column chromatography (oil Ether/ethyl acetate=100-0%) isolate and purify to obtain compound 11d (10.8g).1H NMR(400MHz,CDCl3)δ8.39(d, J=1.6Hz, 1H), 8.22 (d, J=8.4Hz, 1H), 8.13-8.11 (m, 1H), 5.13-5.09 (m, 1H), 4.44 (q, J= 7.2Hz, 2H), 2.65-2.64 (m, 3H), 1.43 (t, J=7.2Hz, 3H)
4th step
Synthetic method according to compound 3f in embodiment 3 reacts to obtain compound 11e (11.10g).1H NMR (400MHz,CDCl3) δ 8.55 (d, J=1.6Hz, 1H), 8.32 (dd, J=1.6,8.4Hz, 1H), 8.15 (d, J=8.4Hz, 1H), 4.71-4.70 (m, 1H), 4.46 (q, J=7.2Hz, 2H), 4.34 (q, J=7.2Hz, 2H), 2.75-2.69 (m, 3H), 1.44 (t, J=7.2Hz, 3H)
5th step
At 0 DEG C, compound 11e (11.00g, 30.11mmol) is dissolved in tetrahydrofuran (200mL), then adds four Hydrogen aluminium lithium (5.71g, 150.54mmol).Gained reaction solution is under nitrogen protection when 20 DEG C of reactions 2 are small.Slowly add at 0 DEG C Water (150mL) is quenched, and ethyl acetate (50mL × 3) extraction, organic phase is dried with anhydrous sodium sulfate, is filtered, concentration, through quick silicon Plastic column chromatography (petrol ether/ethyl acetate=100-0%) isolates and purifies to obtain compound 11f (3.90g).1H NMR(400MHz, CD3OD) δ 8.06 (d, J=8.0Hz, 1H), 7.75 (s, 1H), 7.64 (d, J=8.0Hz, 1H), 4.73 (s, 2H), 4.18 (t, J =14.4Hz, 2H), 2.59 (s, 3H)
6th step
Synthesized by compound 11f to obtain compound 11g (1.15g) according to the synthetic method of compound 2f in embodiment 2.1H NMR(400MHz,CDCl3) δ 10.15 (s, 1H), 8.37 (d, J=8.0Hz, 1H), 8.23 (d, J=1.6Hz, 1H), 8.12 (dd, J=1.6,8.0Hz, 1H), 4.72 (brs, 1H), 4.35-4.26 (m, 2H), 2.72 (d, J=5.2Hz, 3H), 2.51 (t, J=7.2Hz, 1H).
7th step
Synthesized by compound 1k and 11g to obtain compound 11h (535mg) according to the method for embodiment 1.MS-ESI calculated values [M+H]+499, measured value 499.
8th step
At 25 DEG C, compound 11h (535mg, 1.07mmol) is dissolved in dichloromethane (10mL), is then added to first Benzene sulfonyl chloride (225mg, 1.18mmol) and triethylamine (326mg, 3.22mmol).Gained reaction solution is under nitrogen protection in 25 DEG C React 16 it is small when.Directly concentrate after reaction.Crude product is through Flash silica column chromatography (petrol ether/ethyl acetate=100- 0%) isolate and purify to obtain compound 11i (440mg).MS-ESI calculated values [M+H]+654, measured value 654.
9th step
At 0 DEG C, compound 11i (440mg, 0.67mmol) is dissolved in tetrahydrofuran (10mL), then adds hydrogenation Sodium (54mg, 1.35mmol, 60%).Gained reaction solution under nitrogen protection in 20 DEG C reaction 2 it is small when after plus water (5mL).Reaction After directly concentrate, crude product is through the isolated compound 11 (48mg) of performance liquid chromatographic column.1H NMR(400MHz, CDCl3) δ 7.71 (d, J=7.6Hz, 1H), 7.60 (s, 1H), 7.41 (d, J=8.4Hz, 1H), 7.13 (dd, J=4.0, J= 8.8Hz,1H),7.01-6.98(m,1H),6.94-6.93(m,1H),4.88(s,2H),4.20-4.17(m,2H),4.16- 4.14(m,2H),3.03(s,3H),2.34(s,3H).MS-ESI calculated values [M+H]+453, measured value 453.
Embodiment 12
The first step
At 25 DEG C, compound 12a (24g, 154.71mmol) is dissolved in methanol (300mL), then adds chlorine at 0 DEG C Change sulfoxide (27.61g, 232.07mmol), under nitrogen protection when 50 DEG C of reactions 16 are small.Directly concentrate, add after reaction Water (300mL) dilutes, and ethyl acetate (100 × 3) extraction, organic phase is dried with anhydrous sodium sulfate, is filtered, is concentrated to give compound 12b(23.8g)。1H NMR(400MHz,CDCl3) δ 7.77 (t, J=8.4Hz, 1H), 6.42 (dd, J=2.0,8.8Hz, 1H), 6.34 (dd, J=2.4,12.8Hz, 1H), 4.81 (s, 2H), 3.87 (s, 3H).
Second step
Synthesized by compound 12b to obtain compound 12 (2mg) according to the method for embodiment 11.1H NMR(400MHz, CD3OD) δ 7.58 (d, J=8.8Hz, 1H), 7.53 (d, J=6.8Hz, 1H), 7.25 (dd, J=4.4,8.8Hz, 1H), 7.02- 7.01(m,1H),6.90-6.83(m,1H),4.95(s,2H),4.24-4.18(m,4H),2.96(s,3H),2.37(s,3H)。 MS-ESI calculated values [M+H]+471, measured value 471.
Experimental example 1
WillCHO-K1CRTH2 β-arrestin cells (DiscoverX, catalog number (Cat.No.) 93-0291C2) exist Grow under standard conditions, and be inoculated with 384 microwell plates of white wall with 5000 cells/wells, per hole with 20 microlitres of Cell Cell is in 37 DEG C/5%CO before Plating Reagent 1. are tested2Lower overnight incubation.Compound will be tested in DMSO with 3 times The coefficient of dilution carry out a series of dilutions, obtain the test compound of 8 concentration of serial dilution.Test not long ago, to foregoing The test compound of serial dilution is further diluted to 5 times of test concentrations with assay buffer again.By 5 microlitres of further dilutions Test compound afterwards is added in cell and is incubated 30 minutes at 37 DEG C.Solvent concentration is 1%.Again by 5 microlitres of 6X EC80The buffer solution of activator (PGD2) is added in cell and is incubated 90 minutes at 37 DEG C.By disposably adding 15 microlitres What (50%v/v) PathHunter detected mixed liquor reagent and then carried out is incubated to generate measure signal for one hour.Pass through PerkinElmer EnvisionTMThe chemiluminescence signal of instrument reads microwell plate.The bioactivity for testing compound is logical CBIS data analyses external member (ChemInnovation, CA) analysis is crossed, with IC50Value display.Experimental result is as shown in table 1.
Table 1
Compound IC50
Embodiment 1 +++
Embodiment 2 ++
Embodiment 3 ++
Embodiment 4 +++
Embodiment 5 +++
Embodiment 6 +++
Embodiment 7 +++
Embodiment 8 +++
Embodiment 10 +++
Embodiment 11 +++
Embodiment 12 ++
Note：1.0 μM of+＞；++ 0.1~1.0 μM；+++ 0.1 μM of ＜；
Conclusion：The application compound has CRTH2 acceptors strong antagonism.
Experimental example 2
Plasma pharmacokinetics experiment uses 12 female C57BL/6 mouse, is randomly divided into two groups, every group of 6 animals.The One group of animal gives intravenous injection tested medicine 1mg/kg, gives gavage for second group and is tested medicine 5mg/kg.Preparation solvent uses Contain HPbCD and cosolventFormula, the vein or gavage preparation of acquisition are settled solution.Vein group with And gavage group animal in 0.0833 after administration, 0.25,0.5,1,2,4,8 and 24 it is small when, using saphena, blood was collected, often A time point is 3 samples.The plasma sample of collection is frozen in -80 DEG C, and is thawed before LC-MS/MS sample analysis.Solution Plasma sample after jelly, adds acetonitrile containging interior traget and carries out albumen precipitation according to a certain percentage, and obtains supernatant after centrifuging Liquid carries out LC-MS/MS sample introductions.Analytical instrument uses API4000 or 5500, and chromatographic column is ACQUITY UPLC BEH C18 (2.1 × 50mm, 1.7 μm), using ESI just or anion source is detected the ionization of compound.In each analysis batch, contain There is the standard specimen of 8 concentration, with the peak area of test compound to the ratio between internal standard (IS) peak area for Y, test compound is in blood plasma Concentration in sample is X, and with 1/x2Linear regression is carried out for weighting coefficient, tries to achieve measure response and the regression equation of concentration. In each analysis batch, also containing corresponding quality-control sample.Use Phoenix 6.3Data processing is carried out, and is obtained Obtain corresponding PK parameters.Result of the test is as shown in table 2.
Table 2
NA：IV administrations are not tested.

Claims (10)

1. formula (I) compound or its pharmaceutically acceptable salt,
Wherein,
A is selected from
Represent singly-bound or double bond；
R1、R2、R3、R4、R5、R6Independently selected from H, halogen, hydroxyl, amino, C1-3Alkyl, C1-3Alkoxy and C3-6Cycloalkyl, institute State amino, C1-3Alkyl, C1-3Alkoxy and C3-6Cycloalkyl is optionally by F, Cl, Br, cyano group, hydroxyl, C1-3Alkyl and C3-6Cycloalkanes Base substitutes；
X is selected from CR9R10、CR9、NR9, N and covalent bond；
R7、R8、R9、R10Independently selected from H, halogen, hydroxyl, amino, cyano group, C1-3Alkyl, C1-3Alkoxy, C3-6Cycloalkyl, benzene Base and 5-6 unit's heteroaryls, the C1-3Alkyl, C1-3Alkoxy, C3-6Cycloalkyl, phenyl and 5-6 unit's heteroaryls optionally by F, Cl, Br, cyano group, hydroxyl, C1-3Alkyl and C3-6Cycloalkyl substitutes.
2. the compound of claim 1, wherein, R1、R2、R3、R4Independently selected from H, halogen, hydroxyl, amino, C1-3Alkyl, C1-3 Alkoxy and C3-6Cycloalkyl.
3. the compound of claim 1, wherein, R5For H.
4. the compound of claim 1, wherein, R6Selected from H, halogen, C1-3Alkyl and C3-6Cycloalkyl, the C1-3Alkyl and C3-6 Cycloalkyl is optionally substituted by F, Cl and Br.
5. the compound of claim 1, wherein, X is selected from CR9R10、NR9, N and covalent bond.
6. the compound of claim 1, wherein, R7、R8、R9、R10Independently selected from H, halogen, C1-3Alkyl and C3-6Cycloalkyl, institute State C1-3Alkyl and C3-6Cycloalkyl is optionally substituted by F, Cl, Br, cyano group and hydroxyl.
7. the compound of claim 1, selected from formula (II) compound,
WhereinR1、R2、R3、R4、R6、R7、R8Defined with X such as any one of claim 1-6.
8. the compound of claim 1, selected from following compound：
9. pharmaceutical composition, it includes formula (I) compound of claim 1 or its pharmaceutically acceptable salt.
10. formula (I) compound or the pharmaceutical composition of its pharmaceutically acceptable salt or claim 9 of claim 1 are being made Purposes in the medicine of the standby disease prevented or treat CRTH2 mediations.
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Cited By (4)

* Cited by examiner, † Cited by third party
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CN108658896A (en) * 2018-06-20 2018-10-16 常州制药厂有限公司 A kind of synthetic method of Hydrochioro
CN108863980A (en) * 2018-07-05 2018-11-23 浙江工业大学 A method of synthesis 1- (5- benzothiazolyl) ethyl ketone
CN111574414A (en) * 2020-05-20 2020-08-25 上海毕得医药科技有限公司 Synthesis method of 4-bromo-2-methoxybenzenesulfonyl chloride
CN116836130A (en) * 2023-08-31 2023-10-03 嘉实（湖南）医药科技有限公司 Synthesis method of 3, 4-dihydrobenzothiadiazine compound

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US20110124683A1 (en) * 2007-11-13 2011-05-26 Oxagen Limited Use of CRTH2 Antagonist Compounds
CN104114169A (en) * 2011-12-16 2014-10-22 阿托佩斯治疗有限公司 Combination of CRTH2 antagonist and a proton pump inhibitor for the treatment of eosinophilic esophagitis

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US20110124683A1 (en) * 2007-11-13 2011-05-26 Oxagen Limited Use of CRTH2 Antagonist Compounds
CN104114169A (en) * 2011-12-16 2014-10-22 阿托佩斯治疗有限公司 Combination of CRTH2 antagonist and a proton pump inhibitor for the treatment of eosinophilic esophagitis

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108658896A (en) * 2018-06-20 2018-10-16 常州制药厂有限公司 A kind of synthetic method of Hydrochioro
CN108658896B (en) * 2018-06-20 2022-03-08 常州制药厂有限公司 Synthesis method of hydrochlorothiazide
CN108863980A (en) * 2018-07-05 2018-11-23 浙江工业大学 A method of synthesis 1- (5- benzothiazolyl) ethyl ketone
CN111574414A (en) * 2020-05-20 2020-08-25 上海毕得医药科技有限公司 Synthesis method of 4-bromo-2-methoxybenzenesulfonyl chloride
CN116836130A (en) * 2023-08-31 2023-10-03 嘉实（湖南）医药科技有限公司 Synthesis method of 3, 4-dihydrobenzothiadiazine compound
CN116836130B (en) * 2023-08-31 2023-11-21 嘉实（湖南）医药科技有限公司 Synthesis method of 3, 4-dihydrobenzothiadiazine compound

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