CN109134481A - A kind of substituted azole chromogen ketone compounds or its pharmaceutically acceptable salt and its preparation method and application - Google Patents

A kind of substituted azole chromogen ketone compounds or its pharmaceutically acceptable salt and its preparation method and application Download PDF

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CN109134481A
CN109134481A CN201810890337.2A CN201810890337A CN109134481A CN 109134481 A CN109134481 A CN 109134481A CN 201810890337 A CN201810890337 A CN 201810890337A CN 109134481 A CN109134481 A CN 109134481A
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ketone compounds
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CN109134481B (en
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罗海彬
吴德燕
黄雅丹
陈仪萍
于艳发
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Sun Yat Sen University
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Abstract

The invention discloses a kind of substituted azole chromogen ketone compounds or its pharmaceutically acceptable salts and its preparation method and application.The structure of the compound or its pharmaceutically acceptable salt is such as shown in (I).Substituted azole chromogen ketone compounds of the present invention or its pharmaceutically acceptable salt structure novel, excellent inhibiting effect is shown for 5 type phosphodiesterases, and optionally inhibit 5 type phosphodiesterases, and to other hypotype phosphodiesterases without or with extremely faint inhibiting effect, compound i.e. of the present invention can be used as 5 type phosphodiesterase inhibitors carry out using, it is prepared into drug, the related disease that treatment and/or prevention are caused by 5 type phosphodiesterases, such as male sexual disfunction, pulmonary hypertension, the diseases such as pulmonary fibrosis and tumor drug resistance reversal.

Description

A kind of substituted azole chromogen ketone compounds or its pharmaceutically acceptable salt and its system Preparation Method and application
Technical field
The present invention relates to field of medicinal chemistry, and in particular, to a kind of new substituted pyrroles chromogen ketone compounds or its Pharmaceutically acceptable salt and its preparation method and application.
Background technique
Cyclic nucleotide phosphodiesterase (Cyclic nucleotide phosphodiesterases, PDEs) is a kind of weight The super enzyme family wanted effectively controls intracellular cAMP and cGMP concentration, to adjust by the hydrolysis to cAMP and cGMP The biochemical action that internal second messenger is conducted.PDEs (PDE1-PDE11) is widely distributed in mammalian tissues, multiplicity Property causes different PDE enzymes to have specific distribution in cell and subcellsular level, and optionally adjustable various kinds of cell function is Good drug design and therapy target.
5 type phosphodiesterases (PDE5) are separated in the blood platelet of mouse at first as the PDE family special to cGMP And confirms, be also found in the lung of mouse later and purify to obtain.Mankind PDE5A is mainly distributed on aorta vessel smooth muscle Also there are minute quantity distribution in cell, heart, placenta, Skeletal Muscle Cell, pancreas, blood platelet, brain, liver, lung.Male penis sea PDE5 content in continuous body far exceeds other PDE families.
Developing in PDEs inhibitor most successful is PDE5A inhibitor.Silaenafil (Sildenafil, Viagra) is cut down Ground that non-(Vardenafil, Levitra), tadalafil (Tadalafil, Cialis) are treatment erectile dysfunction drug, More it is proved to have effects that clinical treatment pulmonary hypertension after silaenafil.In addition, it has also been found that PDE5 inhibitor It can be used for improving memory capability, antitumor, treatment pulmonary disease, treatment heart disease.Nevertheless, existing PDE5A inhibits Agent has very important side effect: such as headache eye-blurred, is blushed, nasal decongestion, the disorders of digestion, myalgia Deng.On the other hand, existing drug may also cause more serious adverse reaction to serious hepatic and kidney function obstacle person.Exploitation a new generation The PDE5 selective depressant that curative effect is strong, side effect is weak is of great significance.Currently, substituted azole chromogen ketone compounds are multi-purpose In preparing blood lipid-lowering medicine, research there is no for the application as PDE5 inhibitor.
Summary of the invention
The purpose of the present invention is to provide a kind of new substituted pyrroles chromogen ketone compounds.Compound knot of the present invention Structure is novel, shows excellent inhibiting effect for 5 type phosphodiesterases, can be used as 5 type phosphodiesterase inhibitors into It exercises and uses, and then be prepared into drug, the related disease that treatment and/or prevention are caused by 5 type phosphodiesterases, such as male's property The diseases such as dysfunction, pulmonary hypertension, pulmonary fibrosis and tumor drug resistance reversal.
Another object of the present invention is to provide the preparation methods of the substituted azole chromogen ketone compounds.
A further object of the present invention is to provide the applications of the substituted azole chromogen ketone compounds.
Above-mentioned purpose of the invention is achieved by following scheme:
A kind of substituted azole chromogen ketone compounds have structure or its pharmaceutically acceptable salt shown in formula (I):
Wherein, Y is oxygen or sulphur；X is selected from hydrogen, halogen, C1-5Substituted or non-substituted cycloalkane, substituted or non-substituted aromatic rings, Substituted or non-substituted aromatic heterocycle, C1-5Substituted or non-substituted acyl group, C1-5Substituted or non-substituted amide groups, C1-5Replace or non-takes For carboxylic acid group, C1-5Replace and contains carboxylate group；
R1、R2And R4It is respectively selected from hydrogen, halogen, hydroxyl, C1-6Substituted or non-substituted alkyl, C1-6Substituted or non-substituted alcoxyl Base, C1-6Substituted or non-substituted alkylamino radical, C1-5Substituted or non-substituted acyl group, C1-5Substituted or non-substituted amide groups, C1-5Replace or Non-substituted carboxylic acid group, C1-5Replace and contains carboxylate group, nitrogen-containing group, phosphorus-containing groups or sulfur-containing group；
R3Selected from hydrogen, halogen, hydroxyl, C1-6Substituted or non-substituted alkyl, C1-6Substituted or non-substituted alkoxy, C1-6.Replace Or non-substituted alkylamino radical, C1-5Substituted or non-substituted acyl group, C1-5Substituted or non-substituted amide groups, takes substituted or non-substituted piperazine Generation or non-substituted piperidines, substituted or non-substituted morpholine, C1-5Substituted or non-substituted acyl group, C1-5Substituted or non-substituted amide groups, C1-5 Substituted or non-substituted carboxylic acid group, C1-5Replace and contains carboxylate group, nitrogen-containing group, phosphorus-containing groups or sulfur-containing group；
R5Selected from hydrogen, halogen, C1-5Substituted or non-substituted alkyl, C1-5It is substituted or non-substituted alkoxy, substituted or non-substituted Phenyl, substituted or non-substituted benzyl, substituted or non-substituted (3,4- methylene-dioxy) benzyl；Substituted or non-substituted anilino- takes Generation or non-substituted benzamido group, C1-5Substituted or non-substituted alkoxyl-methyl, C1-5It is substituted or non-substituted alkanamine methyl, substituted or non-substituted Phenoxymethyl, substituted or non-substituted benzyloxymethyl, substituted or non-substituted anilinomethyl, substituted or non-substituted benzylamine methyl, C1-5It takes Generation or non-substituted acyl group, C1-5Substituted or non-substituted amide groups, C1-5Substituted or non-substituted amide methyl, C1-5It is substituted or non-substituted Carboxylic acid group, C1-5Substituted or non-substituted carboxylic acid methyl, C1-5Replace containing carboxylate group, nitrogen-containing group, phosphorus-containing groups, contain sulfenyl Group, substituted or non-substituted benzyl group, substituted or non-substituted aromatic group, amino acid side chain structure.
Preferably, the X is selected from hydrogen, halogen, C1-5Substituted or non-substituted cycloalkane, substituted or non-substituted aromatic rings, substitution Or non-substituted aromatic heterocycle；
The R1、R2And R4It is respectively selected from hydrogen, halogen, hydroxyl, C1-6Substituted or non-substituted alkyl, C1-6It is substituted or non-substituted Alkoxy, C1-6Substituted or non-substituted alkylamino radical；
The R3Selected from hydrogen, halogen, hydroxyl, C1-6Substituted or non-substituted alkyl, C1-6Substituted or non-substituted alkoxy, C1-6. Substituted or non-substituted alkylamino radical, C1-5Substituted or non-substituted acyl group, C1-5Substituted or non-substituted amide groups, substituted or non-substituted piperazine Piperazine, substituted or non-substituted piperidines, substituted or non-substituted morpholine；
The R5Selected from hydrogen, halogen, C1-5Substituted or non-substituted alkyl, C1-5Substituted or non-substituted alkoxy, substitution or non- It is substituted-phenyl, substituted or non-substituted benzyl, substituted or non-substituted
Preferably, the X is selected from C5-6Substituted or non-substituted aromatic rings, C5-6Substituted or non-substituted aromatic heterocycle；
The R1、R2And R4It is respectively selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, chloromethyl, bromomethyl, two Methyl fluoride, trifluoromethyl, methoxyl group, ethyoxyl；
The R3In substituent group be C1-4Alkyl, C1-4Alkoxy, piperazine, piperidines or morpholine；
The R5In substituent group be carboxylic acid group, C1-4Alkyl, C1-4Alkoxy, C1-5Aliphatic radical, acyl group or substituted amide.
Preferably, the X is selected from 2- thiazole or 2- oxazole；
The R3Selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, methoxyl group, ethyoxyl, -NHCH3、-NHCH2CH2OCH3、-NHCH2CH2N(CH3)2、N(CH3) CH2CH2OCH3Or-N (CH3)CH2CH2N(CH3)2；
The R5Selected from-CH2OC(CH3)3、-CH2COOH、-CH2COOC(CH3)3、CH2CONHCH3、
Preferably, pyrroles's chromogen ketone compounds of structure shown in formula (I) have structure shown in formula (II) or (III):
Wherein, R6Selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, chloromethyl, trifluoromethyl, methoxyl group, ethyoxyl, acetyl group, Isopropyl, cyano, nitro, amino, N, TMSDMA N dimethylamine base, carboxylic acid group, substituted-amino, substituted or non-substituted guanidine radicals, take benzyloxy Generation or non-substituted phosphate, substituted or non-substituted phosphoryl, substituted or non-substituted sulfonic group, in substituted or non-substituted sulfonyl It is one or more.
Preferably, the R6Selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, chloromethyl, trifluoromethyl, methoxyl group, ethyoxyl, second Acyl group, isopropyl, cyano, nitro, amino, N, one of TMSDMA N dimethylamine base, benzyloxy, carboxylic acid group or substituted-amino or more Kind.
It is highly preferred that R6Selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, chloromethyl, trifluoromethyl, methoxyl group, ethyoxyl, cyano Or one of nitro or a variety of.
Preferably, the structure of the substituted azole chromogen ketone compounds or its pharmaceutically acceptable salt is selected from following It is a kind of:
Preferably, the compound pharmaceutically acceptable salt is the product that formula (I) compound is reacted with acid.Formula (I) there are thiazole, secondary amine or tertiary amines in compound shown in, salt-forming reaction can occur with acid, obtain equally having bioactivity To learn acceptable salt.
Preferably, the acid includes but is not limited to hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, methylsulphur Acid, salicylic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, naphthalene sulfonic acids, maleic acid, fumaric acid, citric acid, acetic acid, tartaric acid, succinic acid, Malic acid or glutamic acid.
The present invention also protects the preparation method of the substituted azole chromogen ketone compounds simultaneously, includes the following steps:
S1. compound 1 mixes in -30~25 DEG C of the solvent dissolved with alkaline matter with compound 2, and is gradually warming up to 25~120 DEG C of reactions, can be obtained compound 3；
S2. compound 4 and compound 3 under condensing agent effect, heat up in the solvent dissolved with alkaline matter after first room temperature It is reacted to 40~90 DEG C, compound 4 can be obtained；
Wherein, the Z is sulphur or oxygen；The R is the R in claims 1 to 31~R4One of or it is a variety of；The R ' For the R in claims 1 to 35。
Preferably, the condensing agent in the step S2 is selected from 2- (7- azo benzotriazole)-N, N, N', N'- tetramethyl Urea hexafluorophosphoric acid ester (HATU), benzotriazole-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HBTU), 1- (3- diformazan ammonia Base propyl) -3- ethyl-carbodiimide hydrochloride (EDCI), 2- (1H- benzo trisazo- L-1- yl) -1,1,3,3- tetramethylurea four Fluoboric acid ester (TBTU), N, N '-dicyclohexylcarbodiimide (DCC) or N, N'- carbonyl dimidazoles (CDI).
Preferably, temperature when compound 1 and compound 2 mix in step S1 is 0 DEG C.
Preferably, the alkaline matter in step S1 is including but not limited to potassium tert-butoxide, sodium tert-butoxide, sodium hydride, double front threes One of silicon substrate lithium amide, double trimethylsilyl Sodamides, lithium diisopropylamine are a variety of.
Preferably, the alkaline matter in step S2 is selected from diisopropyl ethyl amine, three second including but not limited to alkaline matter Or mixtures thereof one of amine, 4-dimethylaminopyridine, piperidines, sodium bicarbonate, sodium carbonate, potassium carbonate.
Preferably, the solvent in step S1 is selected from tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide, dichloromethane One of alkane, chloroform, 1,4- dioxane, benzene, toluene or dimethylbenzene are a variety of.
Preferably, the solvent in step S2 is selected from dimethylformamide, dimethyl sulfoxide, pyridine, tetrahydrofuran, Isosorbide-5-Nitrae-two One of six ring of oxygen, toluene or dimethylbenzene are a variety of.
Preferably, when the Z in compound 2 is sulphur, compound 2 is prepared by following procedure: thiazole or 2- halogen-thiophene Azoles reacts at -80~10 DEG C under alkaline condition, with trimethyl halogenated silanes, then is gradually warming up to 0~30 DEG C of reaction, obtains To intermediate 1, i.e. 2- (trimethylsilyl)-thiazole；Then intermediate 1 is anti-with halogen formate ethyl ester under the conditions of 0~30 DEG C Compound 2 should can be obtained.Reaction process is as follows:
Wherein R6For hydrogen or halogen.
It is highly preferred that the initial reaction temperature of compound 2 and trimethyl halogenated silanes is -78 DEG C.
Preferably, working as R ' isWhen, 4 structure of compound isIt is obtained by following preparation process:
S41. compound 6 mixes under the conditions of -30~10 DEG C with acidic materials, is then gradually warming up to 25~100 DEG C instead It answers, obtains compound 7；
S42. compound 7 first and alkaline matter mixing, is then gradually then gradually adding di-tert-butyl dicarbonate, and 10~40 DEG C reaction obtains compound 8；
S43. in a solvent, compound 8, methylene halide are mixed with alkaline matter, is then gradually warming up to 60~120 DEG C, reaction obtains compound 9；
S44. in a solvent, compound 9 is mixed with alkaline matter, then heats to 25~100 DEG C of reactions and obtains chemical combination Object 10；
S45. in a solvent, compound 10 is mixed with acidic materials, 0~30 DEG C is stirred to react, and obtains compound 11；
S46. in a solvent, compound 11 and alkaline matter are mixed in -20~20 DEG C, is then gradually adding chloro-carbonic acid - 9- fluorenyl methyl ester (FmocCl) reaction, then 25~40 DEG C of reactions are gradually warming up to, target product (i.e. compound 12) can be obtained；
Wherein, R " is C1-5Alkyl or benzyl.
Preferably, the initial reaction temperature in step S41 and step S46 is 0 DEG C.
Preferably, acidic materials described in step S41 are selected from one of thionyl chloride, oxalyl chloride or concentrated sulfuric acid or more Kind；The reaction is in C1-5It is carried out in one of alkylol or benzylalcohol or multi-solvents.
Preferably, alkaline matter described in step S42 is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, lithium hydroxide, hydrogen-oxygen Change one of sodium, triethylamine, diisopropyl ethyl amine, piperidines or pyridine or a variety of；The reaction is in tetrahydrofuran, 1,4- bis- It is carried out in one of six ring of oxygen, N,N-dimethylformamide, dimethyl sulfoxide or water or multi-solvents.
Preferably, methylene halide described in step S43 is mixed selected from one or both of methylene bromide or diiodomethane It closes；The alkaline matter is selected from one of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide or potassium hydroxide or a variety of；It is described Reaction is in one of acetone, dimethylformamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran or 1,4- dioxane or a variety of It is carried out in solvent.
Preferably, alkaline matter described in step S44 is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide or hydroxide One of potassium is a variety of；The reaction is in acetone, dimethylformamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran or 1,4- bis- It is carried out in one of six ring of oxygen or multi-solvents.
Preferably, acidic materials described in step S45 are selected from trifluoroacetic acid, concentrated hydrochloric acid, hydrogen chloride, hydrogen chloride methanol solution Or one of 1,4- dioxane solution of hydrogen chloride or a variety of；The reaction is in methylene chloride, chloroform, toluene, tetrahydro furan It mutters, carried out in one of ethyl acetate or ether or multi-solvents.
Preferably, alkaline matter described in step S46 is selected from sodium bicarbonate, sodium carbonate, saleratus, potassium carbonate, carbonic acid One of caesium, pyridine, triethylamine or diisopropyl ethyl amine are a variety of；It is described reaction tetrahydrofuran, 1,4- dioxane, It is carried out in one of N,N-dimethylformamide, dimethyl sulfoxide or water or multi-solvents.
Preferably, step S42 after reaction, reaction solution is extracted with ethyl acetate, water and saturated salt solution are washed respectively It washs, anhydrous sodium sulfate drying, compound 8 is obtained after concentration.
Preferably, step S43 after reaction, reaction solution is extracted with ethyl acetate, water and saturated salt solution are washed respectively It washs, anhydrous sodium sulfate drying, the residual solution that acquisition is concentrated obtains compound 9 through column chromatography for separation.
Preferably, step S44 after reaction, reaction solution is concentrated and removes most of solvent, with dilute hydrochloric acid regulation system To acidity, then be extracted with ethyl acetate, water and saturated salt solution wash respectively, anhydrous sodium sulfate is dry, concentration obtains compound 10。
Preferably, step S45 after reaction, reaction solution is diluted with methylene chloride, saturated sodium bicarbonate, water are washed respectively It washs, anhydrous sodium sulfate is dry, and concentration obtains compound 11.
Preferably, step S46 after reaction, reaction solution is diluted with water, ether washing, water layer with salt acid for adjusting pH extremely 2~4, then be extracted with ethyl acetate, water and saturated salt solution wash respectively, anhydrous sodium sulfate is dry, target is obtained after concentration and is produced Object (i.e. compound 12).
Preferably, step S1 after the reaction was completed, reaction solution is imported in mixture of ice and water, reaction solution is then adjusted to acid Property, it is subsequently extracted with ethyl acetate, water washs respectively with saturated salt solution, and anhydrous sodium sulfate is dry, can be obtained after concentration Compound 3.
Preferably, in step S2 after the reaction was completed, reaction solution is cooled to room temperature, and concentration removes solvent, is extracted with ethyl acetate Take, water and saturated salt solution wash respectively, anhydrous sodium sulfate is dry, and the residual solution that acquisition is concentrated obtains chemical combination through column chromatography for separation Object 5.
The substituted azole chromogen ketone compounds or its pharmaceutically acceptable salt are as 5 type phosphodiesterase inhibitors Application it is also within the scope of the present invention.
The present invention equally also protects the substituted azole chromogen ketone compounds or its pharmaceutically acceptable salt preparing Treat the application in the drug of 5 type phosphodiesterase related diseases.
Preferably, the 5 type phosphodiesterase related disease is male sexual disfunction, pulmonary hypertension, pulmonary fibrosis Or tumor drug resistance reversal.
Preferably, the dosage form that clinical receiving is made in customary adjuvant can be added in the drug according to common process.
It is highly preferred that the dosage form of the drug be oral type tablet, it is pill, capsule, injection injection, powder needle, percutaneous Or the dosage form of subcutaneous absorption.
Compared with prior art, the invention has the following advantages:
Substituted azole chromogen ketone compounds of the present invention or its pharmaceutically acceptable salt structure novel, for 5 types Phosphodiesterase shows excellent inhibiting effect, and optionally inhibits 5 type phosphodiesterases, and to other hypotypes Phosphodiesterase can be used as 5 type di-phosphate esters without or with extremely faint inhibiting effect, i.e., compound of the present invention Enzyme inhibitor carry out using, be prepared into drug, the related disease that treatment and/or prevention are caused by 5 type phosphodiesterases, such as The diseases such as male sexual disfunction, pulmonary hypertension, pulmonary fibrosis and tumor drug resistance reversal.
Specific embodiment
The present invention is made combined with specific embodiments below and further being elaborated, the embodiment is served only for explaining this Invention, is not intended to limit the scope of the present invention.Test method as used in the following examples is normal unless otherwise specified Rule method；Used material, reagent etc., unless otherwise specified, for the reagent and material commercially obtained.
Embodiment 1
In compound shown in formula (II), work as R5ForWhen, specific synthetic route is as follows:
Wherein, in compound 15, compound 14, compound 16 and compound 13 respectively summary of the invention in preparation method Compound 1, compound 2, compound 3 and intermediate 1；
When X is 2- oxazole, R5When for other substituent groups, above-mentioned preparation method is equally used, raw material therein is replaced Target compound can be obtained in generation.
The specific preparation step of the above process is as follows:
(1) synthesis of compound 7
Under the conditions of 0 DEG C, thionyl chloride (134mL, 1.8mol) is slowly added dropwise into dissolved with levodopa (compound 6) In the 500mL methanol solution of (59.2g, 0.3mol), after being added dropwise, gradually it is warmed to room temperature and is stirred to react 12 hours.After concentration Obtain product (S) -2- amino -3- (3,4- methylenedioxyphenyl) propionate hydrochloride (74.3g), i.e. compound 7, white Solid, yield 100%.1H NMR(400MHz,DMSO–d6)δ8.94(s,1H),8.91(s,1H),8.52(br s,3H),6.68 (d, J=8.0Hz, 1H), 6.60 (d, J=2.1Hz, 1H), 6.45 (dd, J=8.0,2.1Hz, 1H), 4.12 (t, J=6.4Hz, 1H), 3.70 (s, 3H), 3.00 (dd, J=14.1,5.9Hz, 1H), 2.92 (dd, J=14.1,6.9Hz, 1H)
(2) synthesis of compound 8
Under the conditions of 0 DEG C, sodium bicarbonate (50.4g, 0.6mol) is slowly added to (S) -2- amino -3- (3,4- methylenes two Phenyl) propionate hydrochloride (74.3g, 0.3mol) 300mL aqueous solution in, be then slowly added dropwise into system Boc2Tetrahydrofuran (150mL) solution of O (74.3g, 0.3mol) after being added dropwise, is gradually warmed to room temperature that be stirred to react 16 small When.Concentration removes most of solvent, is then extracted with ethyl acetate, and water washs respectively with saturated salt solution, anhydrous sodium sulfate is dry Dry, concentration obtains product (S) -2- (tertiary butyloxycarbonyl acylamino-) -3- (3,4- methylenedioxyphenyl) methyl propionate (i.e. compound 8) (89.6g), white solid, yield 96%.1H NMR(400MHz,DMSO–d6) δ 8.69 (s, 2H), 7.12 (d, J=7.9Hz, 1H), 6.61 (dd, J=9.8,4.9Hz, 2H), 6.51-6.41 (m, 1H), 4.12-4.00 (m, 1H), 3.60 (s, 3H), 2.79 (dd, J=13.8,5.3Hz, 1H), 2.68 (dd, J=13.6,9.5Hz, 1H), 1.35 (s, 9H)
(3) synthesis of compound 9
(S) -2-Boc- amino -3- (3,4- dihydroxy phenyl) methyl propionate is added in potassium carbonate (79.6g, 576mmol) In the 500mL acetonitrile solution of (89.6g, 288mmol), diiodomethane (46.4mL, 576mmol) then is added, is warming up to reflux It is stirred to react 16 hours.After fully reacting, it is cooled to room temperature, concentration removes most of solvent, and residue is diluted with ethyl acetate, Be filtered to remove insoluble matter, filter cake is washed with ethyl acetate, filtrate water washs three times, then dry with anhydrous sodium sulfate, concentration, Column chromatographs (petroleum ether: ethyl acetate=5:1) and obtains product (S) -2- (tertiary butyloxycarbonyl acylamino-) -3- (3,4- methylene-dioxy Phenyl) methyl propionate (i.e. compound 9) (58.7g), white solid, yield 63%.1H NMR(400MHz,CDCl3)δ6.75(d, J=7.9Hz, 1H), 6.63 (d, J=1.5Hz, 1H), 6.59 (dd, J=7.9,1.6Hz, 1H), 5.95 (d, J=1.3Hz, 2H), 5.00 (d, J=6.3Hz, 1H), 4.54 (dd, J=12.1,5.4Hz, 1H), 3.74 (s, 3H), 3.02 (qd, J=13.8, 5.7Hz,2H),1.45(s,9H).
(4) synthesis of compound 10
(S) -2- (tertiary butyloxycarbonyl acylamino-) -3- (3,4- methylene-dioxy is added in sodium hydroxide (7.24g, 181mmol) Phenyl) methyl propionate (58.7g, 181mmol) methanol/water=3/1 (400mL) in the mixed solvent, it is 3 small that reaction is stirred at room temperature When.It after fully reacting, is diluted with water, concentration removes methanol, then uses 3N hydrochloric acid regulation system pH=3.0, then use ethyl acetate Extraction, water, saturated salt solution wash respectively, and anhydrous sodium sulfate is dry, and concentration obtains product (S) -2- (tertiary butyloxycarbonyl acylamino-) - 3- (3,4- methylenedioxyphenyl) propionic acid (compound 10) (55.4), white solid, yield 99%.1H NMR(400MHz, CDCl3) δ 6.76 (d, J=7.9Hz, 1H), 6.69 (s, 1H), 6.65 (d, J=7.9Hz, 1H), 5.95 (d, J=1.8Hz, 2H), 5.01 (d, J=7.0Hz, 1H), 4.57 (dd, J=11.4,5.6Hz, 1H), 3.20-2.96 (m, 2H), 1.45 (s, 9H)
(5) synthesis of compound 11
Trifluoroacetic acid (40mL) is slowly added to (S) -2-Boc- amino -3- (3,4- methylenedioxyphenyl) propionic acid In the 120mL dichloromethane solution of (55.4g, 179mmol), reaction 3 hours is stirred at room temperature.After TLC monitors raw material fully reacting, Concentration removes solvent and trifluoroacetic acid, is then beaten debris with petroleum ether, and pale solid is precipitated, is filtered and is dried Product (S) -2- amino -3- (3,4- methylenedioxyphenyl) propionic acid trifluoroacetate (i.e. compound 11) (52.1g) is obtained afterwards, Yield 95%.1HNMR(400MHz,DMSO–d6) δ 8.22 (s, 2H), 6.88 (d, J=7.9Hz, 1H), 6.84 (d, J=1.5Hz, 1H), 6.78-6.67 (m, 1H), 6.00 (d, J=1.1Hz, 2H), 4.20-4.09 (m, 1H), 3.02 (ddd, J=27.4, 14.3,6.5Hz,2H).
(6) synthesis of compound 4
Under the conditions of 0 DEG C, washing soda (121.6g, 425mmol) is slowly added to (S) -2- amino -3-, and (3,4- is sub- Methylenedioxy group phenyl) propionic acid trifluoroacetate (52.1g, 170mmol) 1,4- dioxane/water=1/1 (400mL) solution In, Isosorbide-5-Nitrae-dioxane (200mL) solution of FmocCl (44.0g, 170mol) is then slowly added dropwise into system, is added dropwise Afterwards, continue to be stirred to react 1 hour for 0 DEG C, be then gradually warmed to room temperature reaction 1 hour.After fully reacting, system is diluted with water, so It is washed three times with ether afterwards, water layer adjusts pH=3.0 with concentrated hydrochloric acid, then is extracted with ethyl acetate, organic layer anhydrous sodium sulfate Dry, concentration obtains product (S) -2- (9- fluorenes methoxycarbonyl amido) -3- (3,4- methylenedioxyphenyl) propionic acid (i.e. compound 4) (63.0g), pale solid, yield 86%.1H NMR(400MHz,CDCl3) δ 7.67 (d, J=7.5Hz, 2H), 7.39 (dd, J=15.7,7.9Hz, 2H), 7.35-7.27 (m, 2H), 7.16 (dd, J=12.3,6.9Hz, 2H), 6.68-6.56 (m, 2H), 6.52 (s, 1H), 6.50-6.39 (m, 1H), 5.71 (s, 2H), 5.63 (s, 1H), 4.47 (d, J=5.0Hz, 1H), 4.40-4.24 (m, 1H), 4.08-3.99 (m, 1H), 3.04 (dd, J=18.3,8.8Hz, 1H), 2.88 (dd, J=13.5, 7.4Hz,1H).
(7) synthesis of compound 13
Under -78 DEG C, argon gas protection, 2- bromo thiazole (compound 13) (49.2g, 300mmol) is slowly added dropwise into positive fourth In the 500mL diethyl ether solution of base lithium (2.5M hexane solution, 122mL, 305mmol), after being added dropwise, continue to be stirred to react 30 Minute, trim,ethylchlorosilane (32.6g, 300mmol) is then slowly added into system, the reaction was continued 1 hour, then gradually heats up To room temperature reaction 1 hour.Then saturated sodium bicarbonate solution quenching reaction, ethyl acetate extraction, water and saturated common salt moisture are used It not washing, organic layer is dry, and vacuum distillation obtains product 2- trimethylsilyl thiazole (i.e. compound 13) (38.5g), colourless liquid, Yield 82%.1H NMR(400MHz,CDCl3) δ 8.13 (d, J=2.9Hz, 1H), 7.54 (d, J=2.7Hz, 1H), 0.43 (s, 9H).
(8) synthesis of compound 14
Ethyl chloroformate (24.5mL, 257mmol) is slowly added dropwise into 2- trimethylsilyl thiazole (38.5g, 245mmol) In 500mL toluene solution, reaction 3 hours is stirred at room temperature.Reaction solution is poured slowly into quenching reaction in the aqueous solution of sodium carbonate, so It stirs 30 minutes afterwards.Organic layer is separated, aqueous layer with ethyl acetate extraction merges organic layer, and it is dry with anhydrous sodium sulfate, after concentration It obtains product thiazole -2- Ethyl formate (i.e. compound 14) (37.7g), yield 98%.1H NMR(400MHz,CDCl3)δ8.03 (d, J=3.1Hz, 1H), 7.64 (d, J=3.1Hz, 1H), 4.49 (q, J=7.1Hz, 2H), 1.45 (t, J=7.1Hz, 3H)
(9) synthesis of compound 16
The compound 15 with different substituents is dissolved in the solvent of alkalinity under the conditions of 0 DEG C, is stirred to react 15 minutes, It is then slowly added into compound 14,25-120 DEG C is gradually warming up to until raw material fully reacting, reaction solution is then imported into ice water In mixture, with dilute hydrochloric acid regulation system to acidity, then it is extracted with ethyl acetate, water and saturated salt solution wash respectively, nothing Aqueous sodium persulfate is dry, and the compound 16 with different substituents is obtained after concentration.
(10) synthesis of target compound
In a solvent, it is small to be stirred into 2-5 under alkaline matter and condensing agent effect for compound 12 and compound 17 in room temperature When, it then proceedes to be warming up to 40-90 DEG C until raw material fully reacting, then cools to room temperature, concentration removes most of solvent, uses Ethyl acetate extraction, water and saturated salt solution wash respectively, anhydrous sodium sulfate is dry, and the residual solution of acquisition is concentrated through column chromatography point From acquisition target compound, i.e. compound 18.
The synthesis of 2 compound P1 of embodiment
(1) synthesis of compound 16a
Under the conditions of 0 DEG C, sodium hydride (60% is scattered in mineral oil, 2.0g, 50mmol) is slowly added to the fluoro- 6- hydroxyl of 2- In the 50mL anhydrous toluene solution of benzoylformaldoxime (1.54g, 10mmol), it is stirred to react 15 minutes, is then slowly added into thiazole -2- The 20mL anhydrous toluene solution of Ethyl formate (2.36g, 15mmol) is gradually warming up to 60 DEG C and reacts 2 hours.After fully reacting, It is cooled to room temperature, reaction solution is poured into quenching reaction in the beaker for fill mixture of ice and water, then with 3M hydrochloric acid regulation system PH=4.0, then be extracted with ethyl acetate, water washs respectively with saturated salt solution, and anhydrous sodium sulfate is dry, and the remnants of acquisition are concentrated Object obtains product 1- (the fluoro- 6- hydroxy phenyl of 2-) -3- (thiophene after the mashing washing of the mixed solvent of petrol ether/ethyl acetate=5/1 Azoles -2- base) propane -1,3- diketone (i.e. compound 16a) (1.62g), yellow solid, yield 61%.1H NMR(400MHz, DMSO–d6) δ 10.87 (s, 1H), 8.24 (d, J=3.0Hz, 1H), 8.16 (d, J=2.6Hz, 1H), 7.83 (s, 1H), 7.38 (d, J=6.8Hz, 1H), 6.95 (s, 1H), 6.86-6.79 (m, 1H), 6.77 (d, J=3.3Hz, 1H)
(2) synthesis of compound P1
By 1- (the fluoro- 6- hydroxy phenyl of 2-) -3- (thiazol-2-yl) propane -1,3- diketone (477mg, 1.8mmol) and (S) - 2- (9- fluorenes methoxycarbonyl amido) -3- (3,4- methylenedioxyphenyl) propionic acid (1165mg, 2.7mmol) is dissolved in 10mL pyridine In, N, N- dicyclohexyl diimine (742mg, 3.6mmol) and N, N- lutidines (88mg, 0.72mmol) is then added, After reaction being stirred at room temperature 3 hours, it is warming up to 50 DEG C of reaction 6h.It is cooling, be concentrated with Rotary Evaporators and remove solvent pyridine, then plus Enter the dilution of 80mL ethyl acetate, filters except the N generated in dereaction, N- dicyclohexylurea (DCU), chromatograph (petroleum through column after filtrate concentration Ether: ethyl acetate=3:1) isolated 288mg product P1, i.e. the 3- fluoro- 1- of (3,4- methylenedioxy benzyl) -8- (thiazole -2- Base) chromone [2,3-c] and pyrroles -9 (2H) -one, yellow solid, yield 38%, purity > 99%.1H NMR(400MHz, CDCl3) δ 11.23 (br, 1H), 7.76 (d, 0.J=3.1Hz, 1H), 7.57 (td, J=8.3,5.7Hz, 1H), 7.39 (d, J= 3.2Hz, 1H), 7.21 (d, J=8.5Hz, 1H), 7.00 (dd, J=10.9,8.3Hz, 1H), 6.58 (d, J=7.9Hz, 1H), 6.50 (s, 1H), 6.43 (d, J=7.9Hz, 1H), 5.80 (s, 2H), 3.99 (s, 2H)；13C NMR(101MHz,CDCl3)δ 174.19,163.78,161.15,158.25,157.80,147.83,146.33,141.54,133.84,133.73,131.36, 121.41,120.91,120.10,114.51,113.51,110.52,110.30,108.46,108.25,101.00,29.52； HRMS(ESI)m/z calcd C22H14FN2O4S+[M+H]+ 421.0653,found 421.0657.
The synthesis of 3 compound P2 of embodiment
Compound P1 (84mg, 0.2mmol) is dissolved in 2mL toluene, then be added lawesson reagent (162mg, 0.4mmol), argon gas is protected, and temperature rising reflux is stirred to react 3 hours.It then cools to room temperature, concentration removes solvent, column chromatography point From product P2 (71mg) is obtained, i.e. 3- (3,4- methylenedioxy benzyl) -8- fluoro- 1- (thiazol-2-yl) chromone [2,3-c] is simultaneously Pyrroles -9 (2H)-thioketones, red brown solid, yield 81%.1H NMR(500MHz,DMSO–d6)δ13.24(br s,1H),8.00 (d, J=3.1Hz, 1H), 7.83-7.76 (m, 1H), 7.68 (d, J=3.1Hz, 1H), 7.58-7.50 (m, 1H), 7.39 (t, J =7.6Hz, 1H), 7.01 (d, J=2.7Hz, 1H), 7.00 (d, J=2.7Hz, 1H), 6.97 (s, 1H), 5.95 (s, 2H), 4.16(s,2H).
The synthesis of 4 compound P3 of embodiment
1.0mmol 1- (the fluoro- 6- hydroxy phenyl of 2-) -3- (thiazol-2-yl) propane -1,3- diketone, 1.5mmol (S) -2- (9- fluorenes methoxycarbonyl amido) -3- (4- fluorophenyl) propionic acid, 2.0mmol N, N- dicyclohexyl diimine, 0.4mmol N, N- bis- Picoline obtains 134mg product P3, i.e. the 3- fluoro- 1- of (4- luorobenzyl) -8- (thiazol-2-yl) according to the method for embodiment 10 Chromone [2,3-c] and pyrroles -9 (2H)-thioketones, yellow solid, yield 34%.1H NMR(400MHz,CDCl3)δ10.80(br S, 1H), 7.74 (d, J=9.7Hz, 1H), 7.66-7.49 (m, 1H), 7.38 (d, J=9.7Hz, 1H), 7.25-7.15 (m, 1H), 7.12-6.98 (m, 3H), 6.92 (dt, J=16.5,8.4Hz, 2H), 4.08 (s, 2H)
The synthesis of 5 compound P4 of embodiment
1.0mmol 1- (the fluoro- 6- hydroxy phenyl of 2-) -3- (thiazol-2-yl) propane -1,3- diketone, 1.5mmol (S) -2- (9- fluorenes methoxycarbonyl amido) -3- (3,4- difluorophenyl) propionic acid, 2.0mmol N, N- dicyclohexyl diimine, 0.4mmol N, N- lutidines obtains 153mg product P4, the i.e. fluoro- 1- (thiophene of 3- (3,4- difluorobenzyl) -8- according to the method for embodiment 10 Azoles -2- base) chromone [2,3-c] and pyrroles -9 (2H)-thioketones, yellow solid, yield 37%.1H NMR(400MHz,CDCl3)δ 11.14 (s, 1H), 7.73 (d, J=3.1Hz, 1H), 7.62-7.50 (m, 1H), 7.39 (d, J=3.1Hz, 1H), 7.18 (d, J =8.5Hz, 1H), 7.04-6.94 (m, 2H), 6.90-6.80 (m, 1H), 6.75 (d, J=8.0Hz, 1H), 4.03 (s, 2H)
The synthesis of 6 compound P5 of embodiment
(1) synthesis of compound 16b
Raw material is replaced with 2- hydroxyl -6- methoxyacetophenone to react with thiazole -2- Ethyl formate (compound 14), according to The method of (1) step in embodiment 1 obtains product to get 1- (2- hydroxyl -6- methoxyphenyl) -3- (thiazol-2-yl) is arrived Propane -1,3- diketone, yellow solid, yield 39%.1H NMR(400MHz,CDCl3) δ 12.92 (s, 1H), 8.06 (d, J= 3.0Hz, 1H), 7.74 (d, J=3.0Hz, 1H), 7.38 (t, J=8.4Hz, 1H), 6.62 (d, J=8.4Hz, 1H), 6.34 (d, J=8.3Hz, 1H), 4.80 (s, 2H), 3.58 (s, 3H)
(2) synthesis of compound P5
Raw material is replaced with 16b to react with compound 4, obtains product according to the method for embodiment 2 to get 3- (3,4- is arrived Methylenedioxy benzyl) -8- methoxyl group -1- (thiazol-2-yl) chromone [2,3-c] and pyrroles -9 (2H) -one, yellow solid, Yield 21%.1H NMR(400MHz,CDCl3) δ 10.48 (br, 1H), 7.72 (d, J=2.4Hz, 1H), 7.52 (t, J= 8.2Hz, 1H), 7.32 (d, J=2.3Hz, 1H), 6.98 (d, J=8.3Hz, 1H), 6.76 (d, J=8.1Hz, 1H), 6.65 (d, J=7.9Hz, 1H), 6.60 (s, 1H), 6.57 (d, J=7.4Hz, 1H), 5.84 (s, 2H), 4.04 (s, 3H), 4.02 (s, 2H) ；13C NMR(101MHz,CDCl3)δ175.88,161.53,159.35,157.86,147.91,146.38,141.59, 141.34,133.94,131.58,121.17,121.14,119.79,113.83,112.92,110.70,110.03,108.74, 108.33,105.04,100.98,56.47,29.70；HRMS(ESI)m/z calcd C23H17N2O5S+[M+H]+ 433.0853, found 433.0858.
The synthesis of 7 compound P6 of embodiment
(1) synthesis of compound 16c
Raw material is replaced with into 2- hydroxyl -6- tertiary butyl dimethyl Si benzoylformaldoxime and thiazole -2- Ethyl formate (compound 14) it reacts, obtains product according to the method for embodiment 2 to get 1- (2- hydroxyl -6- tertiary butyl dimethyl Si base phenyl)-is arrived 3- (thiazol-2-yl) propane -1,3- diketone, yellow solid, yield 71%.1H NMR(400MHz,CDCl3)δ15.37(br, 1H), 11.64 (s, 1H), 7.99 (d, J=3.0Hz, 1H), 7.72 (s, 1H), 7.63 (d, J=3.0Hz, 1H), 7.25 (t, J= 8.2Hz, 1H), 6.61 (dd, J=8.3,0.8Hz, 1H), 6.42 (dd, J=8.1,0.8Hz, 1H), 1.00 (s, 9H), 0.32 (s,6H).
(2) synthesis of compound P6
Raw material is replaced with 16c to react with compound 4, obtains product P6 according to the method for embodiment 10, i.e. (3,4- is sub- by 3- Methylenedioxy group benzyl) -8- hydroxyl -1- (thiazol-2-yl) chromone [2,3-c] and pyrroles -9 (2H) -one, yellow solid, yield 38%.1H NMR(400MHz,CDCl3) δ 12.97 (s, 1H), 11.00 (br, 1H), 7.76 (d, J=2.8Hz, 1H), 7.49 (t, J=8.3Hz, 1H), 7.40 (d, J=2.9Hz, 1H), 6.83 (d, J=8.3Hz, 1H), 6.74 (d, J=8.2Hz, 1H), 6.61 (d, J=7.8Hz, 1H), 6.51 (s, 1H), 6.47 (d, J=7.7Hz, 1H), 5.77 (s, 2H), 3.99 (s, 2H)；13C NMR (101MHz,CDCl3)δ180.95,167.82,162.65,157.56,157.45,147.89,146.40,142.22, 141.83,135.72,131.27,121.03,120.24,117.91,114.77,110.25,108.55,108.39,106.88, 101.04,99.99,29.53；HRMS(ESI)m/z calcd C22H15N2O5S+[M+H]+ 419.0696,found 419.0693.
The synthesis of 8 compound P7 of embodiment
(1) synthesis of compound 16d
Raw material is replaced with 2- hydroxyl-5-fluorine acetophenone to react with thiazole -2- Ethyl formate (compound 14), according to implementation The method of example 2 obtains product to get 1- (2- hydroxyl-5-fluorine phenyl) -3- (thiazol-2-yl) propane -1,3- diketone is arrived, and yellow is solid Body, yield 68%.1H NMR(400MHz,CDCl3) δ 15.13 (br, 1H), 11.65 (s, 1H), 8.07 (d, J=3.1Hz, 1H), 7.71 (d, J=3.0Hz, 1H), 7.56 (dd, J=9.1,3.1Hz, 1H), 7.27 (s, 1H), 7.26-7.21 (m, 1H), 7.00 (dd, J=9.1,4.6Hz, 1H)
(2) synthesis of compound P7
Raw material is replaced with 16d to react with compound 4, obtains product P7 according to the method for embodiment 2, i.e. (3,4- is sub- by 3- Methylenedioxy group benzyl) -7- fluoro- 1- (thiazol-2-yl) chromone [2,3-c] and pyrroles -9 (2H) -one, yellow solid, yield 37%.1H NMR(400MHz,DMSO–d6) δ 13.12 (br, 1H), 7.93 (d, J=2.9Hz, 1H), 7.85 (d, J=7.9Hz, 1H), 7.75 (d, J=2.9Hz, 1H), 7.70-7.57 (m, 2H), 6.94 (s, 1H), 6.90-6.76 (m, 2H), 5.95 (s, 2H),4.10(s,2H)；13C NMR(101MHz,DMSO–d6)δ173.79,159.34,157.19,153.11,147.74, 146.11,142.86,141.75,133.39,122.77,122.52,121.59,121.04,120.59,120.34,116.48, 111.38,111.14,109.22,108.69,101.22,29.37；HRMS(ESI)m/z calcd C22H14FN2O4S+[M+H]+ 421.0653,found 421.0658.
The synthesis of 9 compound P8 of embodiment
(1) synthesis of compound 16e
Raw material is replaced with 2- hydroxyl -5- chloro-acetophenone to react with thiazole -2- Ethyl formate (compound 15), according to implementation The method of example 2 obtains product to get 1- (2- hydroxyl -5- chlorphenyl) -3- (thiazol-2-yl) propane -1,3- diketone is arrived, and yellow is solid Body, yield 71%.1H NMR(400MHz,CDCl3) δ 15.08 (br, 1H), 11.83 (s, 1H), 8.08 (d, J=3.1Hz, 1H), 7.86 (d, J=2.5Hz, 1H), 7.72 (d, J=3.0Hz, 1H), 7.45 (dd, J=8.9,2.5Hz, 1H), 7.30 (s, 1H), 6.99 (d, J=8.9Hz, 1H)
(2) synthesis of compound P8
Raw material is replaced with 16e to react with compound 4, obtains product P8 according to the method for embodiment 2, i.e. (3,4- is sub- by 3- Methylenedioxy group benzyl) -7- chloro- 1- (thiazol-2-yl) chromone [2,3-c] and pyrroles -9 (2H) -one, yellow solid, yield 41%.1H NMR(400MHz,DMSO–d6) δ 13.13 (br, 1H), 8.09 (d, J=2.7Hz, 1H), 7.94 (d, J=3.2Hz, 1H), 7.81-7.73 (m, 2H), 7.58 (d, J=8.9Hz, 1H), 6.94 (s, 1H), 6.86-6.78 (m, 2H), 5.94 (s, 2H),4.10(s,2H)；13C NMR(101MHz,DMSO–d6)δ173.40,157.12,155.33,147.74,146.12, 142.87,141.55,134.56,133.33,127.89,125.61,123.39,121.61,121.13,120.65,120.63, 116.64,109.23,108.68,108.65,101.22,29.36；HRMS(ESI)m/z calcd C22H14ClN2O4S+[M+H]+ 437.0357,found 437.0364.
The synthesis of 10 compound P9 of embodiment
(1) synthesis of compound 16f:
Raw material is replaced with 2- hydroxyl -5- bromoacetophenone to react with thiazole -2- Ethyl formate (compound 14), according to implementation The method of example 2 obtains product to get 1- (2- hydroxyl -5- bromophenyl) -3- (thiazol-2-yl) propane -1,3- diketone is arrived, and yellow is solid Body, yield 67%.1H NMR(400MHz,CDCl3) δ 15.06 (br, 1H), 11.83 (s, 1H), 8.06 (d, J=3.0Hz, 1H), 7.97 (d, J=2.3Hz, 1H), 7.70 (d, J=3.0Hz, 1H), 7.56 (dd, J=8.9,2.3Hz, 1H), 7.27 (s, 1H), 6.91 (d, J=8.9Hz, 1H)
(2) synthesis of compound P9
Raw material is replaced with 16f to react with compound 4, obtains product P9 according to the method for embodiment 2, i.e. (3,4- is sub- by 3- Methylenedioxy group benzyl) -7- bromo- 1- (thiazol-2-yl) chromone [2,3-c] and pyrroles -9 (2H) -one, yellow solid, yield 37%.1H NMR(400MHz,DMSO–d6) δ 13.15 (br, 1H), 8.23 (d, J=1.2Hz, 1H), 7.94 (d, J=1.7Hz, 1H), 7.88 (d, J=7.9Hz, 1H), 7.76 (d, J=1.9Hz, 1H), 7.53 (d, J=8.8Hz, 1H), 6.94 (s, 1H), 6.84–6.79(m,2H),5.95(s,2H),4.09(s,2H)；13C NMR(101MHz,DMSO–d6)δ173.32,157.14, 155.77,147.76,146.14,142.91,141.52,137.32,133.34,128.74,123.86,121.63,121.18, 120.94,120.71,116.69,115.62,109.25,108.71,108.67,101.24,29.37；HRMS(ESI)m/z calcd C22H14BrN2O4S+[M+H]+ 480.9852,found 480.9852.
The synthesis of 11 compound P10 of embodiment
(1) synthesis of compound 16g
Raw material is replaced with 2- hydroxy-5-methyl oxygroup acetophenone to react with thiazole -2- Ethyl formate (compound 14), according to The method of embodiment 2 obtains product to get 1- (2- hydroxy-5-methyl phenyl) -3- (thiazol-2-yl) propane -1,3- bis- is arrived Ketone, yellow solid, yield 38%.1H NMR(400MHz,CDCl3) δ 15.33 (br, 1H), 11.51 (s, 1H), 8.06 (d, J= 3.0Hz, 1H), 7.69 (d, J=3.1Hz, 1H), 7.31 (s, 1H), 7.30 (d, J=3.1Hz, 1H), 7.15 (d, J=3.0Hz, 1H), 6.98 (d, J=9.1Hz, 1H), 3.86 (s, 3H)
(2) synthesis of compound P10
Raw material is replaced with 16g to react with compound 4, obtains product P10, i.e. 3- (3,4- according to the method for embodiment 10 Methylenedioxy benzyl) -7- methoxyl group -1- (thiazol-2-yl) chromone [2,3-c] and pyrroles -9 (2H) -one, yellow solid, Yield 34%.1H NMR(400MHz,CDCl3) δ 11.53 (br, 1H), 7.79 (d, J=3.0Hz, 1H), 7.73 (d, J= 3.1Hz, 1H), 7.36 (d, J=3.1Hz, 1H), 7.33 (d, J=9.1Hz, 1H), 7.26-7.22 (m, 1H), 6.52 (d, J= 7.9Hz, 1H), 6.42 (s, 1H), 6.35 (d, J=7.7Hz, 1H), 5.67 (s, 2H), 3.95 (s, 2H), 3.92 (s, 3H)；13C NMR(101MHz,CDCl3)δ175.39,158.27,155.38,151.74,147.67,146.16,142.69,141.44, 131.61,123.68,122.62,120.88,120.60,119.72,118.91,114.81,109.36,108.43,108.21, 106.45,100.90,55.88,29.52；HRMS(ESI)m/z calcd C23H17N2O5S+[M+H]+ 433.0853,found 433.0857.
The synthesis of 12 compound P11 of embodiment
(1) synthesis of compound 16h
Raw material is replaced with 2- hydroxy-5-methyl benzoylformaldoxime to react with thiazole -2- Ethyl formate (compound 14), according to reality The method for applying example 2 obtains product to get 1- (2- hydroxy-5-methyl base phenyl) -3- (thiazol-2-yl) propane -1,3- diketone, Huang is arrived Color solid, yield 74%.1H NMR(400MHz,CDCl3) δ 15.24 (br, 1H), 11.70 (s, 1H), 8.06 (d, J=2.9Hz, 1H), 7.68 (d, J=2.9Hz, 1H), 7.66 (s, 1H), 7.36-7.30 (m, 2H), 6.93 (d, J=8.5Hz, 1H), 2.34 (s,3H).
(2) synthesis of compound P111
Raw material is replaced with 16h to react with compound 4, obtains product P11 according to the method for embodiment 2, i.e. (3,4- is sub- by 3- Methylenedioxy group benzyl)-7- methyl-1-(thiazol-2-yl) chromone [2,3-c] and pyrroles-9 (2H) -one, yellow solid, yield 38%.1H NMR(400MHz,CDCl3) δ 11.36 (br, 1H), 8.18 (s, 1H), 7.75 (d, J=3.2Hz, 1H), 7.47 (dd, J=8.5,1.9Hz, 1H), 7.38 (d, J=3.2Hz, 1H), 7.31 (d, J=8.5Hz, 1H), 6.56 (d, J=7.9Hz, 1H), 6.48 (s, 1H), 6.41 (d, J=7.8Hz, 1H), 5.72 (s, 2H), 3.99 (s, 2H), 2.48 (s, 3H)；13C NMR (101MHz,CDCl3)δ175.61,158.20,155.23,147.72,146.21,142.56,141.43,135.11, 132.62,131.60,126.29,122.08,120.91,120.85,119.74,117.35,114.76,109.72,108.47, 108.21,100.90,29.56,20.78；HRMS(ESI)m/z calcd C23H17N2O4S+[M+H]+ 417.0904,found 417.0902.
The synthesis of 13 compound P12 of embodiment
(1) synthesis of compound 16i
Raw material is replaced with Paeonolum to react with thiazole -2- Ethyl formate (compound 14), according to The method of embodiment 2 obtains product to get 1- (2- hydroxyl -4- methoxyphenyl) -3- (thiazol-2-yl) propane -1,3- bis- is arrived Ketone, yellow solid, yield 46%.1H NMR(400MHz,CDCl3) δ 15.04 (br, 1H), 12.41 (s, 1H), 8.03 (d, J= 3.0Hz, 1H), 7.80 (d, J=9.0Hz, 1H), 7.66 (d, J=2.9Hz, 1H), 7.24 (s, 1H), 6.53-6.45 (m, 2H), 3.88(s,3H).
(2) synthesis of compound P12
Raw material is replaced with 16i to react with compound 4, obtains product P12 according to the method for embodiment 2, i.e. (3,4- is sub- by 3- Methylenedioxy group benzyl) simultaneously pyrroles -9 (2H) -one, yellow solid produce -6- methoxyl group -1- (thiazol-2-yl) chromone [2,3-c] Rate 35%.1H NMR(400MHz,CDCl3) δ 10.29 (br, 1H), 8.30 (d, J=8.9Hz, 1H), 7.77 (d, J=3.2Hz, 1H), 7.37 (d, J=3.2Hz, 1H), 6.91 (dd, J=8.9,2.3Hz, 1H), 6.85 (d, J=2.3Hz, 1H), 6.71 (d, J =7.8Hz, 1H), 6.67 (s, 1H), 6.64 (d, J=7.9Hz, 1H), 5.88 (s, 2H), 4.09 (s, 2H), 3.95 (s, 3H)；13C NMR(101MHz,CDCl3)δ175.02,167.81,164.55,158.93,157.78,148.02,146.49,142.50, 141.77,131.48,128.28,121.23,120.96,119.78,116.40,114.43,111.87,108.78,108.43, 101.03,100.45,55.75,29.76；HRMS(ESI)m/z calcd C23H17N2O5S+[M+H]+ 433.0853,found 433.0858.
The synthesis of 14 compound P13 of embodiment
(1) synthesis of compound 16j
Raw material is replaced with 2- hydroxyl -4- fluoro acetophenone to react with thiazole -2- Ethyl formate (compound 14), according to implementation The method of example 2 obtains product to get 1- (2- hydroxyl -4- fluorophenyl) -3- (thiazol-2-yl) propane -1,3- diketone is arrived, and yellow is solid Body, yield 67%.1H NMR(400MHz,CDCl3)δ14.93(br,1H),12.26(s,1H),8.11–7.92(m,1H), 7.92–7.78(m,1H),7.70–7.52(m,1H),7.20(s,1H),6.74–6.53(m,2H).
(2) synthesis of compound P13
Raw material is replaced with 16j to react with compound 4, obtains product P13 according to the method for embodiment 2, i.e. (3,4- is sub- by 3- Methylenedioxy group benzyl) -6- fluoro- 1- (thiazol-2-yl) chromone [2,3-c] and pyrroles -9 (2H) -one, yellow solid, yield 36%.1H NMR(400MHz,CDCl3) δ 10.42 (br, 1H), 8.40 (dd, J=8.7,6.6Hz, 1H), 7.78 (d, J= 3.2Hz, 1H), 7.40 (d, J=3.1Hz, 1H), 7.15-7.02 (m, 2H), 6.71 (d, J=7.8Hz, 1H), 6.65 (s, 1H), 6.64 (d, J=7.9Hz, 1H), 5.88 (s, 2H), 4.09 (s, 2H)；13C NMR(101MHz,CDCl3)δ174.49,167.32, 164.78,157.90,147.78,146.29,141.56,131.35,129.16,121.16,120.94,119.98,119.39, 115.02,111.69,111.46,108.46,108.25,104.43,104.18,100.94,29.53；HRMS(ESI)m/z calcd C22H14FN2O4S+[M+H]+ 421.0653,found 421.0647.
The synthesis of 15 compound P14 of embodiment
(1) synthesis of compound 16k
Raw material is replaced with 2- hydroxyl -4- chloro-acetophenone to react with thiazole -2- Ethyl formate (compound 14), according to implementation The method of example 2 obtains product to get 1- (2- hydroxyl -4- chlorphenyl) -3- (thiazol-2-yl) propane -1,3- diketone is arrived, and yellow is solid Body, yield 61%.1H NMR(400MHz,CDCl3) δ 15.01 (br, 1H), 12.07 (s, 1H), 8.03 (d, J=3.0Hz, 1H), 7.80 (d, J=8.7Hz, 1H), 7.68 (d, J=3.1Hz, 1H), 7.28 (s, 1H), 7.03 (d, J=2.0Hz, 1H), 6.92 (dd, J=8.7,2.0Hz, 1H)
(2) synthesis of compound P14
Raw material is replaced with 16k to react with compound 4, obtains product P14 according to the method for embodiment 2, i.e. (3,4- is sub- by 3- Methylenedioxy group benzyl) -6- chloro- 1- (thiazol-2-yl) chromone [2,3-c] and pyrroles -9 (2H) -one, yellow solid, yield 39%.1H NMR(400MHz,CDCl3) δ 11.22 (br, 1H), 8.32 (d, J=8.5Hz, 1H), 7.76 (d, J=3.2Hz, 1H), 7.44 (d, J=1.8Hz, 1H), 7.40 (d, J=3.2Hz, 1H), 7.31 (dd, J=8.5,1.9Hz, 1H), 6.59 (d, J =7.9Hz, 1H), 6.51 (s, 1H), 6.46 (d, J=7.9Hz, 1H), 5.78 (s, 2H), 4.00 (s, 2H)；13C NMR (101MHz,CDCl3)δ174.57,157.78,157.17,147.82,146.34,142.17,141.63,139.88, 131.30,128.12,123.83,121.21,121.11,120.99,120.01,117.69,115.09,109.38,108.50, 108.29,100.97,29.58；HRMS(ESI)m/z calcd C22H14ClN2O4S+[M+H]+ 437.0357,found 437.0358.
The synthesis of 16 compound P15 of embodiment
(1) synthesis of compound 16l
Raw material is replaced with 2- hydroxyl -4- bromoacetophenone to react with thiazole -2- Ethyl formate (compound 14), according to implementation The method of example 9 obtains product to get 1- (2- hydroxyl -4- bromophenyl) -3- (thiazol-2-yl) propane -1,3- diketone is arrived, and yellow is solid Body, yield 65%.1H NMR(400MHz,CDCl3) δ 15.00 (br, 1H), 12.01 (s, 1H), 8.03 (d, J=3.0Hz, 1H), 7.71 (d, J=8.6Hz, 1H), 7.68 (d, J=3.0Hz, 1H), 7.28 (s, 1H), 7.21 (d, J=1.7Hz, 1H), 7.07 (dd, J=8.6,1.7Hz, 1H)
(2) synthesis of compound P15
Raw material is replaced with 16l to react with compound 4, obtains product P15 according to the method for embodiment 2, i.e. (3,4- is sub- by 3- Methylenedioxy group benzyl) -6- bromo- 1- (thiazol-2-yl) chromone [2,3-c] and pyrroles -9 (2H) -one, yellow solid, yield 36%.1H NMR(400MHz,CDCl3) δ 11.19 (br, 1H), 8.24 (d, J=8.5Hz, 1H), 7.77 (d, J=3.2Hz, 1H), 7.62 (d, J=1.5Hz, 1H), 7.46 (dd, J=8.5,1.5Hz, 1H), 7.40 (d, J=3.2Hz, 1H), 6.59 (d, J =7.9Hz, 1H), 6.50 (s, 1H), 6.45 (d, J=7.9Hz, 1H), 5.77 (s, 2H), 3.99 (s, 2H)；13C NMR (101MHz,CDCl3)δ174.69,157.76,157.11,147.85,146.37,142.10,141.66,131.28,128.20 ×2,126.67,121.49,121.25,120.99,120.75,120.04,115.09,109.39,108.50,108.31, 100.99,29.58；HRMS(ESI)m/z calcd C22H14BrN2O4S+[M+H]+ 480.9852,found 480.9848.
The synthesis of 17 compound P16 of embodiment
Compound P15 (241mg, 0.5mmol) is dissolved in 5.0mL dimethyl sulfoxide, morpholine is then respectively adding (131mg,1.5mmol)、BINAP(62mg,0.1mmol)、Pd(dppf)2Cl2(41mg, 0.05mmol) and sodium tert-butoxide (96mg, 1.0mmol) under argon gas protection, is warming up to 120 DEG C and reacts 6 hours.It after fully reacting, is cooled to room temperature, with acetic acid second Ester dilution, water wash respectively with saturated salt solution, and anhydrous sodium sulfate is dry, and the residue that acquisition is concentrated is obtained through column chromatography for separation Product P16 (76mg), i.e. 3- (3,4- methylenedioxy benzyl) -6- morpholinyl -1- (thiazol-2-yl) chromone [2,3-c] are simultaneously Pyrroles -9 (2H) -one, yellow solid, yield 31%.1H NMR(400MHz,CDCl3) δ 11.28 (s, 1H), 8.22 (d, J= 9.0Hz, 1H), 7.71 (d, J=3.2Hz, 1H), 7.34 (d, J=3.2Hz, 1H), 6.86 (dd, J=9.0,2.3Hz, 1H), 6.68 (d, J=2.3Hz, 1H), 6.53 (d, J=7.9Hz, 1H), 6.45 (s, 1H), 6.38 (d, J=7.9Hz, 1H), 5.72 (s,2H),3.93(s,2H),3.91–3.80(m,4H),3.43–3.29(m,4H)；13C NMR(101MHz,CDCl3)δ 174.85,158.94,158.40,155.27,147.70,146.18,142.61,141.37,131.74,127.91,120.87, 120.67,119.69,114.70,114.55,110.55,109.85,108.45,108.20,100.95,100.23,66.56× 2,47.59×2,29.53；HRMS(ESI)m/z calcd C26H22N3O5S+[M+H]+ 488.1275,found 488.1263.
The synthesis of 18 compound P17 of embodiment
Raw material is replaced with compound P15 to react with N methyl piperazine, obtains product P17 according to the method for embodiment 17, That is 3- (3,4- methylenedioxy benzyl) -6- (4- methylpiperazine-1-yl) -1- (thiazol-2-yl) chromone [2,3-c] and pyrrole Cough up -9 (2H) -one, yellow-brown solid, yield 33%.1H NMR(400MHz,CDCl3) δ 10.92 (s, 1H), 8.22 (d, J= 9.0Hz, 1H), 7.73 (d, J=3.2Hz, 1H), 7.35 (d, J=3.2Hz, 1H), 6.89 (dd, J=9.1,2.3Hz, 1H), 6.71 (d, J=2.2Hz, 1H), 6.60 (d, J=7.9Hz, 1H), 6.54 (d, J=1.3Hz, 1H), 6.48 (d, J=7.9Hz, 1H),5.79(s,2H),3.99(s,2H),3.52–3.35(m,4H),2.63–2.50(m,4H),2.38(s,3H)；13C NMR (101MHz,CDCl3)δ174.87,159.03,158.35,155.14,147.76,146.22,142.59,141.41, 131.76,127.84,120.95,120.63,119.65,114.59,114.09,110.83,109.91,108.54,108.25, 100.96,100.22,54.71,47.32,46.12,29.58；HRMS(ESI)m/z calcd C27H25N4O4S+[M+H]+ 501.1591,found 501.1584.
The synthesis of 19 compound P18 of embodiment
Raw material is replaced with compound P15 to react with 2- (4- methylpiperazine-1-yl) ethamine, according to the method for embodiment 17 Obtain product P18, i.e. 3- (3,4- methylenedioxy benzyl) -6- (2- (4- methylpiperazine-1-yl) ethylamino-) -1- (thiazole -2- Base) chromone [2,3-c] and pyrroles -9 (2H) -one, yellow-brown solid, yield 46%.1H NMR(400MHz,CD3OD–d4)δ 7.95 (d, J=8.8Hz, 1H), 7.83 (d, J=3.2Hz, 1H), 7.52 (d, J=3.2Hz, 1H), 6.82 (s, 1H), 6.79 (d, J=8.1Hz, 1H), 6.75 (d, J=8.0Hz, 1H), 6.66 (d, J=8.9Hz, 1H), 6.50 (s, 1H), 5.90 (s, 2H), 4.59 (s, 1H), 4.13 (s, 2H), 3.40 (t, J=6.2Hz, 2H), 3.37 (br s, 4H), 3.15 (br s, 4H), 2.79 (t, J=6.5Hz, 2H), 2.77 (s, 3H)
The synthesis of 20 compound P19 of embodiment
Raw material is replaced with compound P15 to react with 2- methoxyethyl amine, obtains product according to the method for embodiment 17 - 1- (thiazol-2-yl) chromone [2,3-c] is simultaneously by P29, i.e. 3- (3,4- methylenedioxy benzyl) -6- (2- methoxyethyl amine base) Pyrroles -9 (2H) -one, yellow-brown solid, yield 48%.1H NMR(400MHz,CDCl3) δ 10.29 (s, 2H), 8.15 (d, J= 8.7Hz, 1H), 7.74 (d, J=3.2Hz, 1H), 7.34 (d, J=3.2Hz, 1H), 6.70 (d, J=7.9Hz, 1H), 6.65 (s, 1H), 6.62 (d, J=7.9Hz, 1H), 6.58 (dd, J=8.8,2.2Hz, 1H), 6.45 (d, J=2.1Hz, 1H), 5.87 (s, 2H), 4.70 (t, J=5.3Hz, 1H), 4.06 (s, 2H), 3.68 (t, J=5.2Hz, 2H), 3.44 (s, 3H), 3.44-3.39 (m,2H)；13C NMR(101MHz,CDCl3)δ174.86,159.51,158.32,153.21,147.82,146.28,142.50, 141.46,131.77,128.05,121.05,120.57,119.61,114.42,113.48,110.67,109.91,108.64, 108.30,100.97,97.02,70.51,58.87,42.93,29.65；HRMS(ESI)m/z calcd C25H22N3O5S+[M+ H]+ 476.1275,found 476.1263.
The synthesis of 21 compound P20 of embodiment
Raw material is replaced with compound P15 to react with 2- dimethylaminoethylamine, obtains product according to the method for embodiment 17 P20, i.e. 3- (3,4- methylenedioxy benzyl) -6- (2- dimethylaminoethylamine base) -1- (thiazol-2-yl) chromone [2,3-c] And pyrroles -9 (2H) -one, yellow-brown solid, 3- (3,4- methylenedioxy benzyl) -6- (2- dimethylaminoethylamine base) -1- (thiophene Azoles -2- base) chromone [2,3-c] and pyrroles -9 (2H) -one, yield 44%.1H NMR(400MHz,DMSO–d6)δ12.69(s, 1H), 7.88 (d, J=3.2Hz, 1H), 7.84 (d, J=8.8Hz, 1H), 7.68 (d, J=3.2Hz, 1H), 6.93 (s, 1H), 6.83 (d, J=7.9Hz, 1H), 6.79 (d, J=8.0Hz, 1H), 6.71-6.61 (m, 2H), 6.43 (d, J=1.8Hz, 1H), 5.95 (s, 2H), 4.06 (s, 2H), 3.24 (dd, J=11.9,6.3Hz, 2H), 2.50-2.47 (m, 2H), 2.22 (s, 6H)；13C NMR(101MHz,CDCl3)δ178.48,164.15,162.51,159.23,152.46,150.80,147.26,146.48, 138.49,132.25,126.27,125.39,124.49,120.74,119.86,116.47,114.26,113.94,113.43, 105.96,99.96,62.71,50.41×2,45.67,34.17.
The synthesis of 22 compound P21 of embodiment
Raw material is replaced with compound P15 to react, produced according to the method for embodiment 17 with 2- (pyrroles -1- base) ethamine Object P21, i.e. 3- (3,4- methylenedioxy benzyl) -6- (2- (pyrroles -1- base) ethylamino-) -1- (thiazol-2-yl) chromone [2, 3-c] and pyrroles -9 (2H) -one, yellow-brown solid, yield 46%.1H NMR(400MHz,CDCl3)δ10.46(s,1H),8.14 (d, J=8.7Hz, 1H), 7.73 (d, J=3.2Hz, 1H), 7.34 (d, J=3.2Hz, 1H), 6.67 (d, J=7.9Hz, 1H), 6.62 (s, 1H), 6.61-6.55 (m, 2H), 6.43 (d, J=1.8Hz, 1H), 5.85 (s, 2H), 5.18 (s, 1H), 4.04 (s, 2H), 3.33 (dd, J=11.1,5.3Hz, 2H), 2.84 (t, J=5.9Hz, 2H), 2.64 (s, 4H), 1.85 (s, 4H)；13C NMR(101MHz,CDCl3)δ174.85,159.58,158.22,153.40,147.87,146.32,142.46,141.51, 131.77,127.96,121.13,120.55,119.55,114.31,113.16,110.60,109.95,108.72,108.32, 100.97,96.78,54.26,53.88×2,41.55,29.72,23.49×2.
The synthesis of 23 compound P22 of embodiment
Raw material is replaced with into compound P15 and (2- dimethylamino) ethylmethylamine, is obtained according to the method for embodiment 17 Product P22, i.e. 3- (3,4- methylenedioxy benzyl) -6- ((2- dimethylamino) ethyl-methyl amido) -1- (thiazol-2-yl) color Former ketone [2,3-c] and pyrroles -9 (2H) -one, yellow-brown solid, yield 41%.1H NMR(400MHz,CDCl3)δ10.78(s, 1H), 8.19 (d, J=9.0Hz, 1H), 7.72 (d, J=3.2Hz, 1H), 7.34 (d, J=3.2Hz, 1H), 6.69 (dd, J= 9.1,2.2Hz, 1H), 6.63 (d, J=7.9Hz, 1H), 6.57 (s, 1H), 6.52 (d, J=7.9Hz, 1H), 6.48 (d, J= 2.2Hz,1H),5.81(s,2H),4.02(s,2H),3.63–3.54(m,2H),3.11(s,3H),2.60–2.53(m,2H), 2.35(s,6H)；13C NMR(126MHz,CDCl3)δ174.84,159.30,158.42,153.50,147.77,146.22, 142.58,141.38,131.84,128.04,121.00,120.54,119.55,114.44,112.37,109.98,108.60, 108.41,108.25,100.96,97.05,56.04,50.85,45.87×2,38.85,29.60.
The synthesis of 24 compound P23 of embodiment
Raw material is replaced with into compound P15 and (2- methoxyl group) ethylmethylamine, is produced according to the method for embodiment 17 Object P23, i.e. 3- (3,4- methylenedioxy benzyl) -6- ((2- methoxyl group) ethyl-methyl amido) -1- (thiazol-2-yl) chromone [2,3-c] and pyrroles -9 (2H) -one, yellow-brown solid, yield 43%.1H NMR(400MHz,CDCl3)δ10.66(s,1H), 8.20 (d, J=9.0Hz, 1H), 7.73 (d, J=3.2Hz, 1H), 7.34 (d, J=3.2Hz, 1H), 6.72 (dd, J=9.1, 2.4Hz, 1H), 6.64 (d, J=7.9Hz, 1H), 6.59 (d, J=1.3Hz, 1H), 6.54 (d, J=7.9Hz, 1H), 6.51 (d, J=2.3Hz, 1H), 5.83 (s, 2H), 4.03 (s, 2H), 3.70-3.60 (m, 4H), 3.40 (s, 3H), 3.14 (s, 3H)；13C NMR(126MHz,CDCl3)δ174.87,159.27,158.35,153.64,147.79,146.24,142.57,141.42, 131.80,127.97,121.02,120.55,119.56,114.37,112.41,109.98,108.62,108.55,108.27, 100.96,97.21,70.14,59.16,52.17,39.31,29.61.
The synthesis of 25 compound P24 of embodiment
(1) synthesis of compound 16m
Raw material is replaced with 2- hydroxyl -3- chloro-acetophenone to react with thiazole -2- Ethyl formate (compound 14), according to implementation The method of example 2 obtains product to get 1- (2- hydroxyl -3- chlorphenyl) -3- (thiazol-2-yl) propane -1,3- diketone is arrived, and yellow is solid Body, yield 54%.1H NMR(400MHz,CDCl3) δ 14.93 (br, 1H), 12.46 (s, 1H), 8.04 (d, J=3.0Hz, 1H), 7.81 (d, J=8.1Hz, 1H), 7.69 (d, J=3.0Hz, 1H), 7.59 (d, J=7.8Hz, 1H), 7.35 (s, 1H), 6.90 (t, J=8.0Hz, 1H)
(2) synthesis of compound P24
Raw material is replaced with 17m to react with compound 4, obtains product P24 according to the method for embodiment 2, i.e. (3,4- is sub- by 3- Methylenedioxy group benzyl) -5- chloro- 1- (thiazol-2-yl) chromone [2,3-c] and pyrroles -9 (2H) -one, yellow solid, yield 35%.1H NMR(400MHz,DMSO–d6) δ 13.16 (br, 1H), 8.12 (d, J=7.9Hz, 1H), 7.94 (d, J=3.1Hz, 1H), 7.90 (d, J=7.7Hz, 1H), 7.75 (d, J=3.1Hz, 1H), 7.35 (t, J=7.9Hz, 1H), 7.00 (s, 1H), 6.87 (d, J=7.8Hz, 1H), 6.83 (d, J=7.9Hz, 1H), 5.94 (s, 2H), 4.10 (s, 2H)；13C NMR(101MHz, DMSO–d6)δ173.81,157.11,152.04,147.74,146.17,142.88,141.03,134.80,133.15, 125.71,123.92,123.77,121.79,121.75,121.13,120.54,117.10,109.37,108.72,108.56, 101.23,29.71；HRMS(ESI)m/z calcd C22H14ClN2O4S+[M+H]+ 437.0357,found 437.0354.
The synthesis of 26 compound P25 of embodiment
(1) synthesis of compound 16n
Raw material is replaced with the bromo- 6- hydroxy acetophenone of the fluoro- 4- of 2- to react with thiazole -2- Ethyl formate (compound 14), is pressed Product is obtained according to the method for embodiment 2 to get to 1- (the bromo- 6- hydroxy phenyl of the fluoro- 4- of 2-) -3- (thiazol-2-yl) propane -1,3- Diketone, yellow solid, yield 68%.1H NMR(400MHz,CDCl3)δ15.10(br s,1H),12.39(s,1H),8.05(d, J=2.9Hz, 1H), 7.68 (d, J=3.0Hz, 1H), 7.44 (s, 1H), 7.02 (s, 1H), 6.86 (d, J=11.6Hz, 1H)
(2) synthesis of compound P25
Raw material is replaced with 17n to react with compound 4, obtains product P25 according to the method for embodiment 2, i.e. (3,4- is sub- by 3- Methylenedioxy group benzyl) simultaneously pyrroles -9 (2H) -one, yellow solid produce the bromo- 8- of -6- fluoro- 1- (thiazol-2-yl) chromone [2,3-c] Rate 56%.1H NMR(400MHz,DMSO–d6) δ 13.16 (s, 1H), 7.94 (d, J=2.0Hz, 1H), 7.78 (d, J=1.9Hz, 1H),7.17(s,1H),6.93(s,1H),6.90(s,1H),6.86–6.74(m,2H),5.94(s,2H),4.04(s,2H)；13C NMR(101MHz,DMSO–d6)δ180.22,162.74,157.37,156.73,147.76,146.17,143.11,141.13, 133.14,129.29,121.70×2,120.96,116.77,113.42,110.84,109.29,108.73,107.63, 107.40,101.26,29.26；HRMS(ESI)m/z calcd C22H13BrFN2O4S+[M+H]+ 498.9758,found 498.9745.
The synthesis of 27 compound P26 of embodiment
Raw material is replaced with compound P25 to react with 2- methoxyethyl amine, obtains product according to the method for embodiment 17 P26, i.e. 3- (3,4- methylenedioxy benzyl) -6- (2- methoxyethyl amine base) -8- hydroxyl -1- (thiazol-2-yl) chromone [2, 3-c] and pyrroles -9 (2H) -one, yellow solid, yield 37%.1HNMR(500M,Acetone–d6)δ13.25(s,1H),7.82 (d, J=3.1Hz, 1H), 7.59 (d, J=3.1Hz, 1H), 6.89 (s, 1H), 6.83 (d, J=8.0Hz, 1H), 6.76 (d, J= 7.9Hz, 1H), 6.17 (s, 1H), 6.01 (s, 1H), 5.94 (s, 2H), 4.18 (s, 2H), 3.60 (t, J=5.3Hz, 2H), 3.43 (dd, J=10.2,5.1Hz, 2H), 3.35 (s, 3H)；13C NMR(101MHz,DMSO–d6)δ178.23,163.32, 159.06,157.56,155.90,147.73,146.11,141.75,141.50,133.35,121.56,121.20,119.26, 116.83,109.20,108.70,108.10,101.26,99.81,93.76,89.75,70.80,58.52,42.49,29.32； HRMS(ESI)m/z calcd C25H22N3O6S+[M+H]+ 492.1224,found 492.1223.
The synthesis of 28 compound P27 of embodiment
Raw material is replaced with compound P25 to react with methylamine hydrochloride, obtains product P27 according to the method for embodiment 17, That is 3- (3,4- methylenedioxy benzyl) -6- methylamino -8- hydroxyl -1- (thiazol-2-yl) chromone [2,3-c] and pyrroles -9 (2H) -one, yellow solid, yield 32%.1H NMR(500MHz,DMSO–d6)δ13.20(s,1H),12.86(s,1H),7.91 (d, J=3.2Hz, 1H), 7.73 (d, J=3.2Hz, 1H), 6.91 (d, J=1.5Hz, 1H), 6.84 (d, J=8.0Hz, 1H), 6.77 (dd, J=8.0,1.6Hz, 1H), 6.00 (d, J=2.0Hz, 1H), 5.95 (s, 2H), 5.86 (d, J=2.0Hz, 1H), 4.03(s,2H),2.77(s,3H)；13C NMR(101MHz,DMSO–d6)178.49,163.41,159.09,157.37, 156.64,147.73,146.09,142.73,141.33,133.54,121.53,121.12,119.95,116.11,109.19, 108.70,107.74,101.24,99.75,93.39,89.46,29.60,29.31；HRMS(ESI)m/z calcd C23H18N3O5S+[M+H]+ 448.0962,found 448.0960.
The synthesis of 29 compound P28 of embodiment
Raw material is replaced with compound P25 to react with morpholine, obtains product P28 according to the method for embodiment 17, i.e. 3- (3, 4- methylenedioxy benzyl) -6- morpholinyl -8- hydroxyl -1- (thiazol-2-yl) chromone [2,3-c] and pyrroles -9 (2H) -one, Brown solid, yield 31%.1H NMR(400MHz,CDCl3) δ 13.05 (s, 1H), 10.74 (s, 1H), 7.73 (d, J= 3.1Hz, 1H), 7.36 (d, J=3.1Hz, 1H), 6.62 (d, J=7.8Hz, 1H), 6.53 (s, 1H), 6.48 (d, J=7.7Hz, 1H), 6.25 (d, J=1.9Hz, 1H), 6.21 (s, 1H), 5.81 (s, 2H), 3.96 (s, 2H), 3.91-3.76 (m, 4H), 3.44–3.26(m,4H)；13C NMR(101MHz,CDCl3)δ179.13,163.65,159.04,157.78,156.14, 147.89,146.38,142.22,141.71,131.44,121.02,120.01,114.53,108.57,108.37×2, 102.04,101.08,100.00,95.41,91.69,66.51×2,47.13×2,29.55；HRMS(ESI)m/z calcd C26H22N3O6S+[M+H]+ 504.1224,found 504.1223.
The synthesis of 30 compound P29 of embodiment
Raw material is replaced with compound P25 to react with N methyl piperazine, obtains product P29 according to the method for embodiment 17, That is 3- (3,4- methylenedioxy benzyl) -6- (4- methylpiperazine-1-yl) -8- hydroxyl -1- (thiazol-2-yl) chromone [2,3- C] and pyrroles -9 (2H) -one, brown solid, yield 33%.1H NMR(400MHz,CDCl3)δ13.05(s,1H),7.71(d,J =2.9Hz, 1H), 7.35 (d, J=2.9Hz, 1H), 6.56 (d, J=7.6Hz, 1H), 6.46 (s, 1H), 6.41 (s, 1H), 6.23 (d, J=1.9Hz, 1H), 6.20 (s, 1H), 5.76 (s, 2H), 3.91 (s, 2H), 3.53-3.31 (m, 4H), 2.60- 2.44(m,4H),2.35(s,3H)；13C NMR(101MHz,CDCl3)δ178.99,163.62,159.07,158.06, 155.86,147.78,146.28,145.48,142.28,141.54,131.56,120.89,120.52,119.92,114.65, 108.46,108.28,101.69,101.04,95.51,91.76,54.63×2,46.86×2,46.07,29.71；HRMS (ESI)m/z calcd C27H25N4O5S+[M+H]+ 517.1540,found 517.1535.
The synthesis of 31 compound P30 of embodiment
Raw material is replaced with compound P25 to react, produced according to the method for embodiment 17 with 2- (morpholine -1- base) ethamine Object P30, i.e. 3- (3,4- methylenedioxy benzyl) -6- (2- (morpholine -1- base) ethylamino-) -8- hydroxyl -1- (thiazol-2-yl) color Former ketone [2,3-c] and pyrroles -9 (2H) -one, brown solid, yield 34%.1HNMR(500M,Acetone–d6)δ13.25(s, 1H), 7.80 (s, 1H), 7.58 (s, 1H), 6.88 (s, 1H), 6.82 (d, J=6.9Hz, 1H), 6.75 (d, J=7.6Hz, 1H), 6.14(s,1H),5.96(s,1H),5.93(s,2H),4.17(s,2H),3.70(s,4H),3.40(s,2H),2.75(s,2H), 2.60(s,4H)；13C NMR(101MHz,Acetone–d6)δ178.74,159.30,157.21,156.68,155.36, 147.85,146.22,142.26,141.70,133.06,129.68,121.24,120.40,120.00,115.31,108.74, 108.06,100.99,100.33,93.47,89.69,66.10×2,56.67,53.26×3,29.27；HRMS(ESI)m/z calcd C28H27N4O6S+[M+H]+ 547.1646,found 547.1644.
The synthesis of 32 compound P31 of embodiment
Raw material is replaced with compound P25 to react with 2- (4- methylpiperazine-1-yl) ethamine, according to the method for embodiment 17 Obtain product P31, i.e. 3- (3,4- methylenedioxy benzyl) -6- (2- (4- methylpiperazine-1-yl) ethylamino-) -8- hydroxyl -1- (thiazol-2-yl) chromone [2,3-c] and pyrroles -9 (2H) -one, brown solid, yield 36%.1H NMR(400MHz,CDCl3) δ 13.19 (s, 1H), 7.75 (d, J=3.2Hz, 1H), 7.36 (d, J=3.2Hz, 1H), 6.70 (d, J=7.9Hz, 1H), 6.65 (s, 1H), 6.62 (d, J=7.9Hz, 1H), 6.02 (d, J=2.0Hz, 1H), 5.96 (d, J=2.0Hz, 1H), 5.89 (s, 2H), 5.07 (s, 1H), 4.03 (s, 2H), 3.27 (dd, J=10.3,5.4Hz, 2H), 2.75-2.68 (m, 2H), 2.60 (s, 6H),2.38(s,3H),2.13(s,4H)；13C NMR(101MHz,CDCl3)δ175.26,163.93,159.30,154.50, 151.25,147.90,144.86,141.67,134.19,131.58,130.34,121.11,119.90,114.47,108.67, 108.37,101.32,101.06,99.99,94.09,90.14,55.84,54.73×2,52.12×2,45.58,39.27, 29.61；HRMS(ESI)m/z calcd C29H30N5O5S+[M+H]+ 560.1962,found 560.1957.
The synthesis of 33 compound P31 hydrochloride of embodiment
Compound P31 (280mg, 0.5mmol) is dissolved in 20mL methylene chloride, is then added 4M HCl's into system Isosorbide-5-Nitrae-dioxane solution (1.5mL, 6.0mmol), is stirred at room temperature reaction 1 hour, and the solid of precipitation is washed through filtering, methylene chloride Product is obtained after washing, raw material replaces with compound P25 and reacts with 2- (4- methylpiperazine-1-yl) ethamine, according to embodiment 17 Method obtains product P31 hydrochloride (286mg), brown solid, yield 96%.1H NMR(400MHz,CDCl3)δ13.21(s, 1H), 7.76 (d, J=3.2Hz, 1H), 7.38 (d, J=3.2Hz, 1H), 6.71 (d, J=7.9Hz, 1H), 6.67 (s, 1H), 6.64 (d, J=7.9Hz, 1H), 6.03 (d, J=2.0Hz, 1H), 5.97 (d, J=2.0Hz, 1H), 5.89 (s, 2H), 5.08 (s, 1H), 4.05 (s, 2H), 3.28 (dd, J=10.3,5.4Hz, 2H), 2.75-2.68 (m, 2H), 2.60 (s, 6H), 2.38 (s,3H),2.14(s,4H).
The synthesis of 34 compound 32 of embodiment
Raw material is replaced with into 1- (the fluoro- 4- bromophenyl of 2-) -3- (oxazole -2- base) propane -1,3- diketone and (S) -2- (9- fluorenes Methoxycarbonyl amido) reaction of -3- (4- fluorophenyl) propionic acid, product P32, i.e. 3- (4- fluorine benzyl are obtained according to the method for embodiment 2 Base) the bromo- 1- of -6- (oxazole -2- base) chromone [2,3-c] and pyrroles -9 (2H) -one, yellow solid, yield 37%.1H NMR (400MHz,CDCl3) δ 11.29 (brs, 1H), 8.26 (d, J=8.5Hz, 1H), 7.84 (s, 1H), 7.63 (d, J=1.6Hz, 1H), 7.47 (dd, J=8.5,1.6Hz, 1H), 7.10 (s, 1H), 7.04 (dd, J=8.4,5.4Hz, 2H), 6.89 (t, J= 8.6Hz,2H),4.11(s,2H).
The synthesis of 35 compound P33 of embodiment
Raw material is replaced with and reacts compound P32 with 2- (4- methylpiperazine-1-yl) ethamine, according to the side of embodiment 17 Method obtains product P33, i.e. 3- (4- luorobenzyl) -6- (2- (4- methylpiperazine-1-yl) ethylamino-) -8- hydroxyl -1- (oxazole -2- Base) chromone [2,3-c] and pyrroles -9 (2H) -one, brown solid, yield 33%.1H NMR(500MHz,DMSO–d6)δ12.85 (br s, 1H), 8.21 (s, 1H), 7.81 (d, J=8.8Hz, 1H), 7.40 (s, 1H), 7.34 (dd, J=8.6,5.6Hz, 2H), 7.13 (dd, J=12.3,5.5Hz, 2H), 6.66 (t, J=5.2Hz, 1H), 6.63 (dd, J=8.8,2.1Hz, 1H), 6.41 (d, J=1.9Hz, 1H), 4.13 (s, 2H), 3.24 (dd, J=12.2,6.4Hz, 4H), 3.17 (s, 3H), 2.53 (d, J= 6.7Hz,2H),2.46(s,2H),2.37(s,4H).
The synthesis of 36 compound P34 of embodiment
Raw material is replaced with into 1- (2- hydroxy phenyl) -3- (thiazol-2-yl) propane -1,3- diketone and FMOC-O- tert-butyl - Serine reaction, obtains product P34, i.e. tertiary fourth oxygen methyl-1-(thiazol-2-yl) chromone of 3- according to the method for embodiment 2 [2,3-c] and pyrroles -9 (2H) -one, yellow solid, yield 35%.1H NMR(400MHz,CDCl3)δ10.34(s,1H),8.35 (dd, J=7.9,1.6Hz, 1H), 7.84 (d, J=3.2Hz, 1H), 7.63 (ddd, J=8.7,7.1,1.7Hz, 1H), 7.42- 7.36 (m, 2H), 7.31 (t, J=7.5Hz, 1H), 4.69 (s, 2H), 1.33 (s, 9H)
The synthesis of 37 compound P35 of embodiment
Raw material is replaced with into 1- (2- hydroxy phenyl) -3- (thiazol-2-yl) propane -1,3- diketone and Fmoc-L- asparagus fern ammonia The reaction of the acid -4- tert-butyl ester, obtains product P35, i.e. 2- [9- oxo -1- (thiazol-2-yl) -2,9- bis- according to the method for embodiment 2 Hydrogen chromone [2,3-c] and pyrroles -3- base] tert-butyl acetate, yellow solid, yield 39%.1H NMR(500MHz,CDCl3)δ 10.71 (br s, 1H), 8.35 (dd, J=7.9,1.6Hz, 1H), 7.84 (d, J=3.2Hz, 1H), 7.68-7.60 (m, 1H), 7.42-7.36 (m, 2H), 7.31 (t, J=7.5Hz, 1H), 3.86 (s, 2H), 1.52 (s, 9H)
The synthesis of 38 compound P36 of embodiment
Compound P35 (382mg, 1.0mmol) is dissolved in 3.0mL methylene chloride, is then slowly added into system Reaction 1 hour is stirred at room temperature in 1.0mL trifluoroacetic acid.Concentration removes most of solvent, is then diluted with ethyl acetate, water and full It is washed respectively with sodium bicarbonate solution, anhydrous sodium sulfate drying, concentration obtains product P36 (320mg), i.e. 2- [9- oxo -1- (thiazol-2-yl) -2,9- chromanone [2,3-c] and pyrroles -3- base] acetic acid, yellow solid, yield 98%.1H NMR (400MHz,DMSO–d6) δ 13.00 (s, 1H), 12.68 (br s, 1H), 8.21 (dd, J=7.9,1.7Hz, 1H), 7.95 (d, J =3.2Hz, 1H), 7.83-7.73 (m, 2H), 7.54 (d, J=8.3Hz, 1H), 7.40 (t, J=7.4Hz, 1H), 3.87 (s, 2H).
The synthesis of 39 compound P37 of embodiment
Compound P36 (81mg, 0.25mmol) is dissolved in 2.0mL methylene chloride, methylamine salt is then added into system Hydrochlorate (24mg, 0.35mmol), triethylamine (70 μ L, 0.5mmol) and HATU (143mg, 0.38mmol), are stirred at room temperature reaction 4 Hour.After fully reacting, column chromatography for separation obtains product P37 (57mg), i.e. N- methyl -2- [9- oxo -1- (thiazol-2-yl) - 2,9- chromanones [2,3-c] and pyrroles -3- base] acetamide, yellow solid, yield 67%.1H NMR(400MHz,DMSO– d6) δ 12.86 (s, 1H), 8.21 (dd, J=7.9,1.6Hz, 1H), 7.94 (d, J=3.2Hz, 1H), 7.87 (d, J=4.5Hz, 1H), 7.82-7.70 (m, 2H), 7.52 (d, J=8.1Hz, 1H), 7.39 (dd, J=11.0,4.0Hz, 1H), 3.72 (s, 2H), 2.62 (d, J=4.6Hz, 3H)
40 compound of embodiment tests the inhibitory activity of PDE5 enzyme
(preparation method of the recombinant protein is referring to document: Bioorganic& with recombination PDE5A1 albumen is contained for testing molecule Medicinal Chemistry Letters, 2012, volume 22, the page number: 3261-3264), 20mM Tris-HCl, pH 7.5, 2mM dithiothreitol (DTT) (dithiothreitol), 10mM MgCl2And 20,000-30,000cpm3H-cGMP is at room temperature It is incubated for 15 minutes, then uses 0.2M ZnSO respectively4With Ba (OH)2Then stopped reaction is counted using PerkinElmer 2910 Instrument measures unreacted in supernatant3H-cGMP, each molecule at least measure three times.The IC that PDE5A1 protein active is inhibited50 Value is calculated and is obtained by concentration determination and nonlinear regression.The expression and purification method of other hypotypes PDEs is similar with PDE5.
The compounds of this invention to the inhibitory activity test data of PDE5 enzyme as shown in table 1 (under equal conditions, positive control Inhibitory activity IC of the silaenafil Sildenafil to PDE5 enzyme50For 5.1nM).
Inhibitory activity test result of 1 compound of table to PDE5 enzyme
As can be known from Table 1, majority of compounds shows inhibiting effect for PDE5 enzyme, wherein except compound P2, P3, Outside P4, P8, P32, P33~P37, other compounds are superior to positive control silaenafil for the inhibiting effect of PDE5 enzyme；And Compound P16, P19, P20, P23, P26, P27, P28, P30 and P31 are more excellent to the inhibiting effect of PDE5 enzyme, IC50It is worth small In 1nM, to PDE5 enzyme inhibition it is still further preferred that compound P26.
Using the optimal compound P26 of activity as representative, its selectivity index to PDEs family is tested, result such as table 2 is measured It is shown.
Selectivity index test result of the 2 representative compound P26 of table to PDEs family
It can be seen that by the above results, substituted azole chromogen ketone compounds of the present invention have phosphodiesterase 5 type There is good inhibitory activity, and is better than positive drug silaenafil；And other are sub- to di-phosphate ester enzyme family for the compound Type has good selectivity, and has similar subtype-selective with silaenafil, shows to 5 type phosphodiesterases excellent Inhibiting effect, but there is no inhibiting effect or inhibiting effect extremely faint the phosphodiesterase of other hypotypes.As it can be seen that of the invention The substituted azole chromogen ketone compounds have wide application space as phosphodiesterase 5 type inhibitor.
Finally, it should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention rather than protects to the present invention The limitation of shield range can also be made on the basis of above description and thinking for those of ordinary skill in the art Other various forms of variations or variation, there is no necessity and possibility to exhaust all the enbodiments.It is all of the invention Made any modifications, equivalent replacements, and improvements etc., should be included in the protection of the claims in the present invention within spirit and principle Within the scope of.

Claims (10)

1. a kind of substituted azole chromogen ketone compounds, which is characterized in that have formula (I) shown in structure or its can pharmaceutically connect The salt received:
；
Wherein, Y is oxygen or sulphur；X is selected from hydrogen, halogen, C1-5Substituted or non-substituted cycloalkane, substituted or non-substituted aromatic rings, substitution Or non-substituted aromatic heterocycle, C1-5Substituted or non-substituted acyl group, C1-5Substituted or non-substituted amide groups, C1-5Substituted or non-substituted carboxylic Acidic group, C1-5Replace and contains carboxylate group；
R1、R2And R4It is respectively selected from hydrogen, halogen, hydroxyl, C1-6Substituted or non-substituted alkyl, C1-6Substituted or non-substituted alkoxy, C1-6Substituted or non-substituted alkylamino radical, C1-5Substituted or non-substituted acyl group, C1-5Substituted or non-substituted amide groups, C1-5Replace or non-takes For carboxylic acid group, C1-5Replace and contains carboxylate group, nitrogen-containing group, phosphorus-containing groups or sulfur-containing group；
R3Selected from hydrogen, halogen, hydroxyl, C1-6Substituted or non-substituted alkyl, C1-6Substituted or non-substituted alkoxy, C1-6.Replace or non- Replace alkylamino radical, C1-5Substituted or non-substituted acyl group, C1-5Substituted or non-substituted amide groups, substituted or non-substituted piperazine, substitution or Non-substituted piperidines, substituted or non-substituted morpholine, C1-5Substituted or non-substituted acyl group, C1-5Substituted or non-substituted amide groups, C1-5Replace Or non-substituted carboxylic acid group, C1-5Replace and contains carboxylate group, nitrogen-containing group, phosphorus-containing groups or sulfur-containing group；
R5Selected from hydrogen, halogen, C1-5Substituted or non-substituted alkyl, C1-5Substituted or non-substituted alkoxy, substituted or non-substituted phenyl, Substituted or non-substituted benzyl, substituted or non-substituted (3,4- methylene-dioxy) benzyl；Substituted or non-substituted anilino-, substitution or non- Alpha substituted benzylamine base, C1-5Substituted or non-substituted alkoxyl-methyl, C1-5Substituted or non-substituted alkanamine methyl, substituted or non-substituted benzene oxygen first Base, substituted or non-substituted benzyloxymethyl, substituted or non-substituted anilinomethyl, substituted or non-substituted benzylamine methyl, C1-5Replace or non- Substituted acyl, C1-5Substituted or non-substituted amide groups, C1-5Substituted or non-substituted amide methyl, C1-5Substituted or non-substituted carboxylic acid group, C1-5Substituted or non-substituted carboxylic acid methyl, C1-5Replace containing carboxylate group, nitrogen-containing group, phosphorus-containing groups, sulfur-containing group, substitution or Non-substituted benzyl group, substituted or non-substituted aromatic group or amino acid side chain structure.
2. substituted azole chromogen ketone compounds according to claim 1, which is characterized in that the X is selected from hydrogen, halogen, C1-5 Substituted or non-substituted cycloalkane, substituted or non-substituted aromatic rings, substituted or non-substituted aromatic heterocycle；
The R1、R2And R4It is respectively selected from hydrogen, halogen, hydroxyl, C1-6Substituted or non-substituted alkyl, C1-6Substituted or non-substituted alcoxyl Base, C1-6Substituted or non-substituted alkylamino radical；
The R3Selected from hydrogen, halogen, hydroxyl, C1-6Substituted or non-substituted alkyl, C1-6Substituted or non-substituted alkoxy, C1-6.Replace Or non-substituted alkylamino radical, C1-5Substituted or non-substituted acyl group, C1-5Substituted or non-substituted amide groups, takes substituted or non-substituted piperazine Generation or non-substituted piperidines, substituted or non-substituted morpholine；
The R5Selected from hydrogen, halogen, C1-5Substituted or non-substituted alkyl, C1-5Substituted or non-substituted alkoxy, substituted or non-substituted benzene It is base, substituted or non-substituted benzyl, substituted or non-substituted。
3. substituted azole chromogen ketone compounds according to claim 1, which is characterized in that the X is selected from C5-6Replace or non- Substituted aroma ring, C5-6Substituted or non-substituted aromatic heterocycle；
The R1、R2And R4It is respectively selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, chloromethyl, bromomethyl, difluoro first Base, trifluoromethyl, methoxyl group, ethyoxyl；
The R3In substituent group be C1-4Alkyl, C1-4Alkoxy, piperazine, piperidines or morpholine；
The R5In substituent group be carboxylic acid group, C1-4Alkyl, C1-4Alkoxy, C1-5Aliphatic radical, acyl group or substituted amide.
4. substituted azole chromogen ketone compounds according to claim 1 or claim 2, which is characterized in that the X be selected from 2- thiazole or 2- oxazole；The R3Selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, methoxyl group, ethyoxyl,、、、、、、-NHCH3、-NHCH2CH2OCH3、-NHCH2CH2N(CH3)2、N (CH3)CH2CH2OCH3Or-N (CH3)CH2CH2N(CH3)2；
The R5Selected from-CH2OC(CH3)3、-CH2COOH、-CH2COOC(CH3)3、CH2CONHCH3、、Or。
5. any substituted azole chromogen ketone compounds according to claim 1~4, which is characterized in that the compound medicine Acceptable salt is the product that formula (I) compound is reacted with acid on；It is described acid include but is not limited to hydrofluoric acid, hydrochloric acid, Hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, methanesulfonic acid, salicylic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, naphthalene sulfonic acids, maleic acid, richness Horse acid, citric acid, acetic acid, tartaric acid, succinic acid, malic acid or glutamic acid.
6. the preparation method of any substituted azole chromogen ketone compounds of Claims 1 to 4, which is characterized in that including such as Lower step:；
S1. compound 1 mixes in -30~25 DEG C of the solvent dissolved with alkaline matter with compound 2, and is gradually warming up to 25 ~120 DEG C of reactions, can be obtained compound 3；
S2. compound 3 and compound 4 under condensing agent effect, are warming up in the solvent dissolved with alkaline matter after first room temperature 40~90 DEG C of reactions, can be obtained compound 4；
Wherein, the Z is sulphur or oxygen；The R is the R in claims 1 to 31~R4One of or it is a variety of；The R ' is power Benefit requires the R in 1~35。
7. the preparation method of substituted azole chromogen ketone compounds according to claim 6, which is characterized in that the step S2 In condensing agent be 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester, benzotriazole-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester, 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, 2- (1H- benzo three Azo L-1- yl) -1,1,3,3- tetramethylurea tetrafluoro boric acid ester, N, two miaow of N '-dicyclohexylcarbodiimide or N, N'- carbonyl Azoles；
Alkaline matter in step S1 including but not limited to potassium tert-butoxide, sodium tert-butoxide, sodium hydride, double trimethylsilyl lithium amides, One of double trimethylsilyl Sodamides, lithium diisopropylamine are a variety of；
Alkaline matter in step S2 is selected from diisopropyl ethyl amine, triethylamine, 4- diformazan ammonia including but not limited to alkaline matter Or mixtures thereof one of yl pyridines, piperidines, sodium bicarbonate, sodium carbonate, potassium carbonate.
8. the preparation method of substituted azole chromogen ketone compounds according to claim 6, which is characterized in that when compound 2 In Z be sulphur when, compound 2 is prepared by following procedure: thiazole or 2- halogen-thiazole under alkaline condition, with trimethyl Halogenated silanes reacts at -80~-10 DEG C, then is gradually warming up to 0~30 DEG C of reaction, obtains intermediate 1；Then intermediate 1 Reacting under the conditions of 0~30 DEG C with halogen formate ethyl ester can be obtained compound 2；
Working as R ' isWhen, 4 structure of compound is, it is obtained by following preparation process:
；
S41. compound 6 mixes under the conditions of -30~10 DEG C with acidic materials, is then gradually warming up to 25~100 DEG C of reactions, Obtain compound 7；
S42. compound 7 first and alkaline matter mixing, is then gradually then gradually adding di-tert-butyl dicarbonate, and 10~40 DEG C Reaction obtains compound 8；
S43. in a solvent, compound 8, methylene halide are mixed with alkaline matter, are then gradually warming up to 60~120 DEG C, Reaction obtains compound 9；
S44. in a solvent, compound 9 is mixed with alkaline matter, then heats to 25~100 DEG C of reactions and obtains compound 10；
S45. in a solvent, compound 10 is mixed with acidic materials, 0~30 DEG C is stirred to react, and obtains compound 11；
S46. in a solvent, compound 11 and alkaline matter are mixed in -20~20 DEG C, is then gradually adding chloro-carbonic acid -9- fluorenes The reaction of base methyl esters, then 25~40 DEG C of reactions are gradually warming up to, target product can be obtained；
Wherein, R ' ' is C1-5Alkyl or benzyl.
9. any substituted azole chromogen ketone compounds of claim 1 to 5 or its pharmaceutically acceptable salt are as 5 type phosphorus The application of acid diesters enzyme inhibitor.
10. any substituted azole chromogen ketone compounds of claim 1 to 5 or its pharmaceutically acceptable salt are controlled in preparation Treat the application in the drug of 5 type phosphodiesterase related diseases.
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