CN104662020B - For treating the imidazopyridine derivatives of diabetes - Google Patents

For treating the imidazopyridine derivatives of diabetes Download PDF

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CN104662020B
CN104662020B CN201380046094.XA CN201380046094A CN104662020B CN 104662020 B CN104662020 B CN 104662020B CN 201380046094 A CN201380046094 A CN 201380046094A CN 104662020 B CN104662020 B CN 104662020B
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base
pyridine
imidazo
acetenyl
phenyl
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CN104662020A (en
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弗兰克·F·莱皮弗里
格萨恩德·R·莉娜
瓦莱里·奥捷
米舍利娜·R·凯尔格特
克里斯汀·G·沙龙
索菲·N·雷纳尔
安尼克·M·奥代
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Meng Taboruien Research Co
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Meng Taboruien Research Co
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Abstract

The present invention relates to the imidazopyridine derivatives of below general formula I and it is as especially for treatment and/or the purposes of the medicine of prevention diabetes, its complication and/or associated conditions.

Description

For treating the imidazopyridine derivatives of diabetes
Invention describes
The present invention relates to the imidazopyridine derivatives for treating the disease relevant to metabolism syndrome, particularly treat Or prevention diabetes.
Diabetes are the heterogeneous group of diseases being generally of some feature: hyperglycemia, pancreatic beta cell functional and quantitative Extremely, insulin-resistant tissues and the risk increase of long-term complications development, particularly cardiovascular complication.
Type ii diabetes has become the subject matter of public health.In most industryization country, its prevalence drastically increases Add, especially in the country that economy is fully developed.At present, this disease can be referred to as a kind of epidemic diseases, causes a large amount of concurrent Disease, it is in particular possible to become the very ineffective treatment caused because of renal failure, myocardial infarction or cardiovascular apoplexy or even cause Life.
Several groups of numerals (WHO data) about diabetes:
The whole world has more than 2.2 hundred million people and suffers from diabetes.
Diabetes make stroke risk high 3 times.
In western countries, diabetes are the first reasons of blind and renal failure.
According to estimates, diabetes had resulted in 1,100,000 people's death in 2005.
Predicting according to WHO, the death toll that diabetes cause will be doubled between 2005 to the year two thousand thirty.
In France, the nursing of diabetes and treatment are the significant burden of national healthcare insurance budget.In view of sugar in the world Urine patient's quantity is from the numeral surprising now to the year two thousand thirty, and many pharmacy and biotech company are in the R&D side in metabolism field Face is invested strongly, particularly type ii diabetes, commercially to throw in novel drugs succedaneum.
At present, not treating of type ii diabetes can re-establish normal blood glucose balance in 24 hours, and is not There is no secondary effect.Do not account for the complete disease of disease, be only conceived to correct a kind of or other deficiency.Recently, The antidiabetic drug put on market does not demonstrate any compared with arriving with the Ureteral Calculus being pre-existing in terms of glycemic control Bigger improvement, and cause undesirable secondary effect, this makes new potential treatment is still suffered from space.
Accordingly, it would be desirable to a kind of for treat or prevent diabetes or its complication and/or associated conditions novel molecular, Advantageously type ii diabetes.
Surprisingly, it was found that some imidazopyridine derivatives has inhibitory activity to the liver production of glucose, Active in the secretion of glucose to insulin response, especially can be used as the product of medicinal usage in patient in need Product, especially for preventing and/or treat diabetes and its complication and/or associated conditions (obesity, hypertension etc.), favourable It it is type ii diabetes.
Detailed description of the Invention
Therefore, the present invention relates to the imidazopyridine derivatives of below general formula I:
Wherein:
Y represents oxygen or sulphur atom, group SO, SO2Or-NR19, wherein R19Represent hydrogen atom or C1-C6Alkyl, it is advantageous that Methyl (Me)；Advantageously Y represents oxygen, sulphur atom or group-NR19, particularly oxygen atom or group-NR19；
R1, Ra, RbAnd RcRepresent hydrogen atom independently of one another；Halogen atom, it is advantageous that Cl；C1-C6Alkyl, it is advantageous that first Base, optionally replaces with-OH group；-OH group；-O(C1-C6Alkyl), such as-OMe ,-O (C1-C6Alkyl) O (C1-C6Alkyl)；- CN group；-NR4R5Group, wherein R4And R5Represent hydrogen atom or C independently of one another1-C6Alkyl；Or-(C1-C6Alkyl) NR6R7 Group, wherein R6And R7Represent hydrogen atom or C independently of one another1-C6Alkyl；
R2Represent
-hydrogen atom；
-use the substituted C of-OH group1-C6Alkyl, particularly-(CH2)2OH；
--(C1-C6Alkyl) COOR8Group, it is advantageous that-CH2COOR8, wherein R8Represent hydrogen atom or C1-C6Alkyl, special Not being methyl (Me), ethyl (Et) or isopropyl (iPr), described alkyl can use-NH2Or (advantageously ,-OH group replaces Described alkyl is unsubstituted) ,-(C1-C6Alkyl) COOR8The example of group is-CH2COOH、-CH2COOMe、-CH2COOEt、- CH2CH(NH2) COOEt and-CH2COOiPr；
--(C1-C6Alkyl) CONHR9Group, it is advantageous that-CH2CONHR9, wherein R9Represent-OH group；C1-C6Alkyl, Advantageously ethyl；-O(C1-C6Alkyl), it is advantageous that-OEt；Aryl, it is advantageous that phenyl；Heteroaryl, it is advantageous that pyridine Base；-(C=NH) NHCOO (C1-C6Alkyl), it is advantageous that-(C=NH) the NHCOO tert-butyl group；-(C=NH) NH2Group；Or- (C1-C6Alkyl) NR10R11Group, it is advantageous that-(CH2)2NR10R11, wherein R10And R11Represent C independently of one another1-C6Alkyl, Advantageously methyl；-(C1-C6Alkyl) CONHR9The example of group is-CH2CONHOH、-CH2CONHOEt and-CH2CONH (CH2)2NMe2；
--(C1-C6Alkyl) CO morpholine group, it is advantageous that-CH2CO morpholine；
--C (=O) R12Group, wherein R12Represent-O (C1-C6Alkyl), it is advantageous that-O isobutyl group (OiBu)；C1-C6Alkane Base, it is advantageous that ethyl or isopropyl, optionally replaces with-OH group, such as-(CH2)2OH；Morpholine group；NH-aryl, favorably Be-NH phenyl, wherein said aryl-COOH or-COO (C1-C6Alkyl) optionally replace, it is advantageous that-COOMe；Or base Group-NR13R14, wherein R13And R14Represent C independently of one another1-C6Alkyl, it is advantageous that ethyl；Group-C (=O) R12Example It is-C (=O) OiBu ,-C (=O) (CH2)2OH ,-C (=O) NEt2,-C (=O) morpholine ,-C (=O) iPr ,-C (=O) NH-3- HO2C-Ph and-C (=O) NH-3-MeO2C-Ph；
-(C1-C6Alkyl) aryl, it is advantageous that benzyl, wherein said aryl-CN ,-COOH or-COO (C1-C6Alkyl) Optionally replace；Substituted (C1-C6Alkyl) example of aryl is-CH2-3-NC-Ph；
-(C1-C6Alkyl) heteroaryl, it is advantageous that (C1-C6Alkyl) thiophene, particularly methylthiophene group；
-aryl, it is advantageous that phenyl, wherein said aryl optionally replaces with selected from following one or more groups :- COOH ,-COO (C1-C6Alkyl), it is advantageous that-COOMe, with the substituted C of-OH group1-C6Alkyl, it is advantageous that-CH2OH ,- CN ,-CONHOH ,-NHSO2(C1-C6Alkyl), it is advantageous that-NHSO2Me or-CONH-(C1-C6Alkyl) NR15R16, favourable It is-CONH-(ethyl) NR15R16, wherein R15And R16Represent C independently of one another1-C6Alkyl, it is advantageous that methyl；Optionally take The example of the aryl in generation is-Ph ,-2-MeO2C-Ph、-2-HO2C-Ph、-3-MeO2C-Ph、-3-HO2C-Ph、-4-MeO2C-Ph、- 4-HO2C-Ph；-2-HO2HC-Ph、-3-MeSO2HN-Ph ,-3-NC-Ph ,-2-HONHOC-Ph and-2-Me2N(CH2)2HNOC- Ph；
-heteroaryl, it is advantageous that pyridine radicals；
-heterocyclic group, it is advantageous that oxolane, especially with one or two hetero atom, it is advantageous that selected from N, S And O, described heterocyclic group can optionally comprise degree of unsaturation, such as thiazoline；
The lactone groups of-3～6 yuan, particularly oxolane ketone, use one or more C1-C6Alkyl optionally replaces, special It not to replace, such as two methyl with two groups；
-or-SO2(C1-C6Alkyl), it is advantageous that-SO2(isopropyl)；
R3Represent aryl, it is advantageous that phenyl, or heteroaryl, it is advantageous that pyridine radicals or thienyl, wherein said aryl Optionally replace with selected from following one or more groups :-(C1-C6Alkyl), it is advantageous that methyl, wherein said alkyl is used One or more halogen atoms optionally replace, it is advantageous that F, such as-CF3, or replace with-CN, such as-CH2CN；Halogen atom, has Profit is F ,-O (C1-C6Alkyl), it is advantageous that-OMe, wherein said alkyl optionally replaces with one or more halogen atoms, has Profit is F, such as-OCF3Or-OCH2F；-CN；-OH；-NO2；-COOH；-NR17R18, wherein R17And R18Represent independently of one another C1-C6Alkyl, it is advantageous that methyl；Or-NHCO-(C1-C6Alkyl), it is advantageous that-NHCOMe；Optionally substituted aryl Example is-Ph ,-2-F3C-Ph、-3-F3C-Ph、-4-F3C-Ph、-2-F-Ph、-3-F-Ph、-4-F-Ph、-3,4-(F)2-Ph、- 3-F-4-F3CO-Ph、-3-F3CO-Ph、-4-F3CO-Ph、-3-F2HCO-Ph、-3-NC-Ph、-3-HO-Ph、-2-MeO-Ph、- 3-MeO-Ph、-4-MeO-Ph、-3,4-(MeO)2-Ph、-4-Me-Ph、-4-Me2N-Ph、-4-O2N-Ph、-3-HO2C-Ph、-3- MeCOHN-Ph and-4-NCH2C-Ph；
Or its enantiomer, diastereomer, hydrate, solvate, tautomer, racemic mixture or medicine Acceptable salt on.
In the particular of the present invention, Y represents oxygen atom or group-NH or-NMe, it is advantageous that oxygen atom.
In another particular of the present invention, R1, Ra, RbAnd RcRepresenting hydrogen atom independently of one another, halogen is former Son, particularly Cl, or-O (C1-C6Alkyl), such as OMe, particularly hydrogen atom or halogen atom.Advantageously at R1, Ra, RbAnd RcIn Three Represents hydrogen atom, the 4th represents hydrogen atom, halogen atom, particularly Cl, or-O (C1-C6Alkyl), such as OMe, favourable It is hydrogen atom or halogen atom.It should further be appreciated that R1, Ra, RbAnd RcRepresent hydrogen atom.
In another particular of the present invention, R2Represent
-(C1-C6Alkyl) COOR8Group, it is advantageous that-CH2COOR8, wherein R8Represent hydrogen atom or C1-C6Alkyl, especially It is methyl (Me), ethyl (Et) or isopropyl (iPr) ,-(C1-C6Alkyl) COOR8The example of group is-CH2COOH、- CH2COOMe、-CH2COOEt and-CH2COOiPr；
-(C1-C6Alkyl) CONHR9Group, it is advantageous that-CH2CONHR9, wherein R9Represent-OH group；-O(C1-C6Alkane Base), it is advantageous that-OEt, or-(C1-C6Alkyl) NR10R11Group, wherein R10And R11Represent C independently of one another1-C6Alkyl, has Profit is methyl；-(C1-C6Alkyl) CONHR9The example of group is-CH2CONHOH、-CH2CONHOEt and-CH2CONH(CH2)2NMe2；
-aryl, it is advantageous that phenyl, wherein said aryl optionally replaces with selected from following one or more groups :- COOH ,-COO (C1-C6Alkyl), it is advantageous that-COOMe ,-CONHOH, or-CONH-(C1-C6Alkyl) NR15R16, it is advantageous that- CONH-(ethyl) NR15R16, wherein R15And R16Represent C independently of one another1-C6Alkyl, it is advantageous that methyl；Optionally substituted The example of aryl is-Ph ,-2-MeO2C-Ph、-2-HO2C-Ph、-3-MeO2C-Ph、-3-HO2C-Ph、-4-MeO2C-Ph、-4- HO2C-Ph；-2-HONHOC-Ph, and-2-Me2N(CH2)2HNOC-Ph；Or
--CONH aryl, it is advantageous that-CONH phenyl, with-COOH or-COO (C1-C6Alkyl) optionally replace, favourable It is-COOMe.
Advantageously, R2Representative-(C1-C6Alkyl) COOR8Group, wherein R8Represent hydrogen atom or C1-C6Alkyl, particularly Methyl (Me), ethyl (Et) or isopropyl (iPr), or aryl, it is advantageous to described aryl is with one or more groups optionally Replace, be especially selected from following group :-COOH ,-COO (C1-C6Alkyl), it is advantageous that-COOMe.It should further be appreciated that R2Generation Table group-(C1-C6Alkyl) COOH, it is advantageous that-CH2COOH。
In another particular of the present invention, R3Represent aryl, it is advantageous that phenyl, with selected from following one Individual or multiple groups optionally replace :-(C1-C6Alkyl), it is advantageous that methyl, wherein said alkyl is former with one or more halogen Son optionally replaces, it is advantageous that F, such as-CF3；Halogen atom, it is advantageous that F ,-O (C1-C6Alkyl), it is advantageous that-OMe, its Described in alkyl optionally replace with one or more halogen atoms, it is advantageous that F, such as-OCF3Or-OCH2F；-CN；Or-NO2； The example of optionally substituted aryl is-Ph ,-2-F3C-Ph、-3-F3C-Ph、-4-F3C-Ph、-2-F-Ph、-3-F-Ph、-4- F-Ph、-3,4-(F)2-Ph、-3-F-4-F3CO-Ph、-3-F3CO-Ph、-4-F3CO-Ph、-3-F2HCO-Ph、-3-NC-Ph、-2- MeO-Ph、-3-MeO-Ph、-4-MeO-Ph、-3,4-(MeO)2-Ph ,-4-Me-Ph and-4-O2N-Ph。
Advantageously, R3Represent with selected from the following substituted phenyl of one or more groups :-(C1-C6Alkyl), favorably Be methyl, with one or more halogen atoms replace, it is advantageous that F, such as-CF3；Halogen atom, it is advantageous that F ,-O (C1-C6Alkane Base), it is advantageous that-OMe, wherein said alkyl replaces with one or more halogen atoms, it is advantageous that F, such as-OCF3；Or- CN。
Within the scope of the invention, " aryl " refers to the aromatic ring with 5～8 carbon atoms or has 5～14 carbon atoms Several fused aromatic rings.Especially, aryl can be monocycle or bicyclic radicals, preferably phenyl or naphthyl.Advantageously, it is benzene Base (Ph).
Within the scope of the invention, " heteroaryl " refers to have 3～9 atoms (containing one or more hetero atoms, such as Sulfur, nitrogen or oxygen atom) any hydrocarbon aryl.Heteroaryl according to the present invention can be formed by one or more condensed ring.Heteroaryl Example be furyl, isoxazolyl, pyridine radicals, thiazolyl, pyrimidine radicals, benzimidazole, benzothiazole, thienyl, thiophenyl, Benzotriazole group.Advantageously, heteroaryl is selected from furyl, pyridine radicals, thiazolyl, thiophenyl and thienyl, it is advantageous to It is pyridine radicals, thiophenyl and thienyl.
Within the scope of the invention, " heterocyclic group " refers to have 3～9 atoms (containing one or more hetero atoms, example Such as sulfur, nitrogen or oxygen atom) any saturated cyclic hydrocarbon group.Heterocyclic group according to the present invention can be by one or more condensed ring Formed.The example of heterocyclic group be oxolane, pyrrolidinyl, piperidyl, tiacyclopentane, oxirane, alkane, thiophene alkane, Thiazolidine, morpholine group.Advantageously, heterocyclic group is selected from oxolane, Thiazolidine and morpholine group.
Within the scope of the invention, " halogen atom " refers to any halogen atom, it is advantageous that selected from Cl, Br, I or F, particularly Selected from F, Cl or Br, particularly Cl or F.
Within the scope of the invention, " C1-C6Alkyl " refer to any alkyl with 1～6 carbon atom, straight or branched, Particularly methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, n-hexyl.Favorably , it is methyl, ethyl, isopropyl or the tert-butyl group, particularly methyl or ethyl, more particularly methyl.
Within the scope of the invention, by " (C1-C6Alkyl) aryl " refer to via C defined above1-C6Alkyl linked Any aryl defined above.Especially, (C1-C6Alkyl) example of aryl is benzyl.
Within the scope of the invention, by " C1-C6Alkyl) heteroaryl " refer to via C defined above1-C6Alkyl linked Any heteroaryl defined above.Especially, (C1-C6Alkyl) example of heteroaryl is methylthiophene group.
Within the scope of the invention, " pharmaceutically acceptable " refers to be applicable to prepare pharmaceutical composition, it is common that peace Entirely, nontoxic and be desired in biology or other aspects, and be acceptable for veterinary purpose and human pharmaceutical.
Within the scope of the invention, " pharmaceutically acceptable salt of compound " refers to defined above pharmaceutically acceptable And the salt of the required pharmacologically active with parent compound.This salt includes:
(1) acid-addition salts formed with mineral acid, example hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid etc.；Or with organic acid shape The acid-addition salts become, such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethyl sulfonic acid, fumaric acid, glucoheptonic acid, glucose Acid, glutamic acid, glycolic, hydroxynaphthoic acid, 2-ethylenehydrinsulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, viscous Health acid, 2-LOMAR PWA EINECS 246-676-2, propanoic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric, tartaric acid, p-methyl benzenesulfonic acid, trimethyl Acetic acid, trifluoroacetic acid etc.；Or
(2) when proton sour present in parent compound is by metal ion displacement (such as, alkali metal ion, alkaline earth gold Belong to ion or aluminium ion) time the salt that formed；Or the salt formed when being coordinated with organic or inorganic alkali.Acceptable organic base includes two Ethanolamine, ethanolamine, N-methylethanolamine, triethanolamine, trometamol etc..Acceptable inorganic base includes aluminium hydroxide, hydrogen Calcium oxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
Within the scope of the invention, " solvate of compound " refers to by being added to inert solvent molecules according to this Any compound obtained on bright compound, because their mutual attractive force forms solvate.Solvate is e.g. The alcoholates of compound.Hydrate is solvate, and the atent solvent used in it is water.It can be mono-, di-or three water Compound.
Within the scope of the invention, " tautomer " refers to that composition is anti-by being referred to as the reversible chemical of tautomerization Should any isomer of the compound according to the present invention of inversion of phases mutually.In most of the cases, by being attended by Double bond location The hydrogen atom of change migrates and reacts.Can tautomerization compound solution in, produce 2 kinds of tautomers Between balance.Ratio between tautomer depends on solvent, temperature and pH value.Therefore, tautomerism is a kind of official's energy Group, to the transformation of another kind of functional group, is most commonly changed by the adjoint displacement of hydrogen atom and π key (double or triple bonds).Often See tautomer e.g. aldehyde/ketone-ol, or more specifically enol pair；Amide-imide acid；Lactams-interior acyl is sub- Amine；Imine-enamine；Enamine-enamine pair.Especially, it can include movement the turning along with open architecture to ring when proton The ring-chain tautomerism occurred during change.
In the particularly interesting embodiment of the present invention, imidazopyridine derivatives formula 1 shown in the table 1 below～ The compound of 138.
In the embodiment that another is more interesting, imidazopyridine derivatives is selected from the numbered 1-shown in table 1 below 3、5、7、10-12、14、17、18、20、23、25-27、29、30、32、35、38-40、42、44、45、46、47、48、51、54、 55,84 compounds of 57-59,68,72-79,81,83,87-90,92,93,95,96,101-126,129-131 and 135.
It should further be appreciated that they be compound shown in table 1 below 3,7,14,25,26,29,44,51,54,58,59, 72,76-79,81,87-90,92,93,101,102,104,110-112,114-120 and 135.
The invention still further relates to a kind of imidazopyridine derivatives containing the with good grounds present invention and pharmaceutically acceptable figuration The pharmaceutical composition of agent.
These compositionss can be configured to for giving in mammal, including the mankind.Dosage is according to treatment and according to phase Close disease and change.These pharmaceutical compositions are suitable to give via any suitable approach, such as, be administered orally and (include cheek and Sublingual Approach), per rectum, nose, locally (include percutaneous), vagina, ophthalmic or parenteral (including subcutaneous, intramuscular or intravenous) on the way Footpath.Advantageously, pharmaceutical composition is suitable to be orally administered to.These preparations can well known to a person skilled in the art institute by use The pharmaceutically acceptable excipient having method to be suitable for by combination is prepared with active component.
Suitable oral dosage unit form includes tablet, gelatine capsule, powder, granule and at aqueous or non-aqueous liquid Oral administration solution in body, edible or food foam or oil-in-water or water-in-oil liquid emulsion or suspension.When solid composite system During standby piece agent, main active component is advantageously mixed into powder with applicable drug excipient, as gelatin, starch, Lactose, magnesium stearate, Talcum, Radix Acaciae senegalis etc..Therefore, it can with sucrose or with other be suitable for material coated tablet, or Person, they can be further processed so that they have the activity extending or postponing, and they discharge the work of scheduled volume continuously Property composition.
Preparation in gelatine capsule is by mixing active component (advantageously as powder) and by system with diluent Mixture be poured in soft or hard gelatin capsule and obtain, especially gelatine capsule.Such as Talcum, magnesium stearate, calcium stearate Or the lubricant of the solid form such as Polyethylene Glycol can be added in compositions before being put in gelatine capsule.Such as calcium carbonate or The disintegrating agents such as sodium carbonate or solubilizing agent can also add, in order to improve the availability of medicine after taking gelatine capsule.
Additionally, if necessary, binding agent, lubricant and applicable disintegrating agent and coloring agent may be added in mixture. Be suitable for binding agent can be such as starch, gelatin, natural saccharide (such as glucose or beta lactose), by Semen Maydis make sweetened Agent, synthesis or natural rubber (such as arabic gum or sodium alginate), carboxymethyl cellulose, Polyethylene Glycol, wax etc..Can be at these The lubricant used in dosage form includes enuatrol, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride etc..Disintegrate Agent includes starch, methylcellulose, agar, bentonite, xanthan gum etc..Tablet is such as by following preparation: prepare the mixed of powder Compound, the granulation of mixture or the addition of dry-pressing, lubricant and disintegrating agent, pressing mixt are to obtain tablet.The mixing of powder Thing by by be properly added the active component of diluent or alkali and optional binding agent (such as carboxymethyl cellulose, alginate, Gelatin or polyvinylpyrrolidone), dissolution delayed-action activator (such as paraffin), absorption enhancer (such as quaternary ammonium salt) and/or absorbent Prepared by (such as bentonite, Kaolin or dicalcium phosphate) mixing.The mixture of powder can be by using such as syrup, starch Paste, arabic gum rubber cement or the binding agent moistening such as cellulose solution or polymeric material also suppress pelletize by sieve.Granule Can lubricate by adding stearic acid, stearate, Talcum or mineral oil, to avoid it to adhere on mould, thus allow The manufacture of tablet.Then, the mixture of lubrication is pressed, thus obtains tablet.It is made up of or polymeric material Lac layer, sugar layer Opaque or protective clear layer be optionally present.Coloring agent may be added in these coatings, in order to it is distinguished with other tablets Come.
Preparation as syrup or elixir can contain active component and sweeting agent, preservative and taste imparting agent and fit Suitable coloring agent.In general, syrup preparation by by compound dissolution containing be suitable for taste imparting agent aqueous solution in Obtain, and elixir is by using nontoxic alcohol carrier to prepare.
The powder being dispersed in water or granule can contain and dispersant, wetting agent or suspending agent (such as ethoxylation Isooctadecanol and polyoxyethylene sorbitol ether) and flavour enhancer or sweetener mixing active component.
For rectal administration, having of enumerating uses binding agent (the such as cocoa butter or poly-second two of fusing under rectal temperature Alcohol) suppository prepared.
Parenteral, intranasal or ophthalmic are given, uses containing pharmaceutically-compatible dispersant and/or the water of wetting agent Property suspension, isotonic saline solution or aseptic and Injectable solution.
Active component optionally can also be configured to the form of microcapsule together with one or more additive carriers.
Be suitable to via the pharmaceutical composition that topic route gives can be configured to emulsifiable paste, ointment, suspension, lotion, powder, Solution, paste, gel, spray, aerosol or oil preparation.
The pharmaceutical composition being suitable to be in solid-state via the wherein support excipient that nose approach gives contains particle diameter for example, The powder of 20～500 microns, gives by sucking from the container containing powder being positioned near nose.
The pharmaceutical preparation being suitable to give via vaginal approach can be as buffer, emulsifiable paste, gel, paste, foam or spray Mist agent gives.
In favourable embodiment, according to the pharmaceutical composition of the present invention possibly together with another kind of activating agent, it is advantageous that There is complementation or cooperative effect.Especially, described activating agent is another kind of antidiabetic, it is advantageous that selected from insulin, sulphur Ureide derivative, arrange how class, biguanides, thiazolidinediones, GLP-1R agonist, DPP-IV inhibitor, SGLT-2 inhibitor, favorably Be double selected from insulin, glibenclamide, gliclazide, glipizide, glimepiride, repaglinide, Nateglinide, diformazan Guanidine, troglitazone, rosiglitazone, pioglitazone, Exenatide, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], sitagliptin, vildagliptin, BMS-477118, Ah Ge Lieting, Da Gelie are clean.More particularly, it is metformin.The second activating agent can be at the thiophene derivant with the present invention Identical pharmaceutical composition gives.It can also be given individually, i.e. at synchronization or in the separately moment.Favorably , the second activating agent is given orally.
The invention still further relates to a kind of imidazopyridine derivatives according to the present invention as medicine.
The invention still further relates to the imidazopyridine derivatives according to the present invention for preparing the purposes of medicine.
According to the present invention, the compound of formula (I) has reducing hyperglycaemia activity.They can reduce hyperglycemia, more particularly The hyperglycemia of type ii diabetes.It should be noted that the compound of the present invention has reducing hyperglycaemia activity, therefore can be used for treating And/or prevention diabetes, its complication and/or its relevant disease, such as relevant to metabolism syndrome disease, it is advantageous that Type ii diabetes or hyperglycemia.These medicines are especially effective in old people." old people " refers to the people of over-65s, no matter Men and women.
Term " insulin resistance " used in the scope of the present invention refers to a kind of state, wherein the normal amount of insulin without Method produces physiology or normal molecule reaction.
Therefore, the present invention relates to be used as to be intended for treatment and/or prevention diabetes, its complication and/or associated conditions The imidazopyridine derivatives according to the present invention of medicine, it is advantageous that type ii diabetes and hyperglycemia.
It has been found by the present inventors that the derivant according to the present invention provides stimulation INS1 in the rat hepatocytes separated The insulin secretion of cell and the liver manufacturing feasibility of suppression glucose.
Advantageously, diabetes are selected from early stage, later stage, juvenile-onset diabetes, old people and gravidic people, especially old age People.Advantageously, the deficiency of diabetes and the complication relevant with diabetes and/or disease is selected from hyperglycemia, endocrine pancreas Functional and the quantitation of abnormal of glandular cell, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic view Film disease, inflammation, obesity, hypertension, cardiovascular, blood capillary, neurological problem and the problem of wound healing.Advantageously, It is hyperglycemia, the function of endocrine pancreas cell and quantitation of abnormal, insulin resistance and inflammation.
Advantageously, the patient through treatment has the risk factor relevant with diabetes, i.e. the generation with diabetes is direct Or the morbidity rate of indirect correlation.Especially, it include family history, gestational diabetes, body weight excess, fat, physical exercise not enough, Hypertension, the high level of triglyceride, inflammation and hyperlipemia.
The invention still further relates to the imidazopyridine derivatives according to the present invention for preparation for treating and/or preventing glycosuria The purposes of the medicine of disease, its complication and/or associated conditions, particularly type ii diabetes and hyperglycemia.
Finally, the present invention relates to a kind of diabetes, its complication and/or the treatment of associated conditions and/or prevention and/or pre- Anti-property Therapeutic Method and/or delay it to occur, it is advantageous that type ii diabetes and hyperglycemia, including giving patient in need The imidazopyridine derivatives according to the present invention of effective dose.
Effective dose according to character and the order of severity of the disease that will treat, give approach and the body weight of patient and age It is adjusted.Generally, dosage unit is every day 0.5～2,000mg, and one or many gives, it is advantageous that 1～1,000mg.
Imidazopyridine derivatives according to the present invention by well known to a person skilled in the art method and partly by Prepared by method as described below.
The present invention be may be better understood by reading description and the following embodiment provided as non-limiting instruction.
Synthesis and the explanation of general scheme
The compound of logical formula (I) can be by applying or use those skilled in the art known per se and/or this area Prepared by any method that technical staff is capable of, particularly by Larock at Comprehensive Organic Transformations, VCH Pub., those described in 1989, or retouch by applying or adopting in postpose program The method stated.
The synthesis of the molecule of logical formula (I) is close to those described in (being identical sometimes) document [1]～[8], document List is not considered as exhaustive.
Different group R in scheme 1～41～R3With Y with reference to the definition be above given；" GP " refers to protection group；" Hal " refers to halogen Atom.
Scheme 1: the derivant of Formulas I can be prepared according to known method, from the beginning of PA, in one step With 1,3-dichloro acrylate-2-reactive ketone, form heterocycle 1.2.The chlorine of the derivant of Class1 .2 is particularly suitable for participating in and alcoholates, phenol Various O-, S-or N-alkylated reactions that salt and secondary amine are carried out in alkaline medium.Once chain is introduced into, and selective halogenation reacts (preferably iodination reaction) provides the probability of the derivant receiving Class1 .4, then carries out Sonogashira type reaction, it is thus achieved that The derivant of Class1 .5.
Scheme 2: when under the particular case of Y=NH, it is advantageous to use the derivant of another kind of method synthesis type I.
From the beginning of chlorinated substance 1.2, carry out the amine synthesis of Gabriel method.Phthalimide derivative 2.1 halogenation (preferably iodate), then carries out Sonogashira type reaction, thus obtains the derivant of type 2.3, discharge in the basic conditions Primary amine.Then, the derivant of type 2.4 can advantageously participate in reductive amination reaction, acylation reaction or further with isocyanide Acid esters reacts, thus obtains the secondary amine of type 2.5, amide, carbamate or urea.
Scheme 3: evaluate the another kind of method of the synthesis of the Formulas I derivant of wherein Y=O, from imidazo [1,2-a] pyridine- 2-base methanol 2.1 starts, and protects (such as triisopropylsilyl) by suitable protection group, thus it is (excellent to carry out halogenation Select iodination reaction), then carry out Sonogashira type reaction.Then, protection group cracks under suitable conditions (with three different In the case of propylsilyl protection, tetrabutyl ammonium fluoride), then, primary alconol alkali deprotonation, it is alkylated reaction, or Acylation reaction, thus obtain the derivant of type 3.6.
Scheme 4: evaluate the second method of the synthesis of the Formulas I derivant of wherein Y=O.This method includes building heterocycle The most different strategies, owing to PA reacts with ethyl bromide acetone, thus form ester derivant 4.1, then enter Row halogenation (preferably iodination reaction), then carries out Sonogashira type reaction.Ester functional group is reduced into by standard method Alcohol (reacts with aluminum hydride), so that the derivant of type 3.5 is alkylated or acylation reaction.
Embodiment:
Equipment and method
Proton (1H) nuclear magnetic resonance, NMR (NMR) spectrum obtains on Bruker Avance DPX300 (300.16MHz) instrument. Chemical shift (δ) measures with a few millionths (ppm).Spectrum is calibrated by the chemical shift of deuterated solvent used.Even Close constant (J) to represent with hertz (Hz), and represent multiplicity in the following manner: unimodal (s), bimodal (d), doublet-two Weight peak (dd), triplet (t), triplet-doublet (td), quartet (q), multiplet (m).Mass spectrum (MS) uses spectrogrph Agilent Technologies MSD, model G1946A obtains, and sample is carried out by " Atmosphere Pressure Chemical Ionization (APCI) " (APCI) source Ionization.
Abbreviation
AIBN azodiisobutyronitrile
Dba dibenzalacetone
DIAD diisopropyl azodiformate
DME 1,2-dimethoxy-ethane
EDC N-(3-dimethylaminopropyl)-N '-ethyl carbodiimide
HOBt I-hydroxybenzotriazole
LAH lithium aluminium hydride reduction
Double (2-methoxy ethoxy) sodium aluminate of RED-Al dihydro
TIPS triisopropylsilyl
CDCl3Deuterochloroform
DMSO deuterated dimethyl sulfoxide
PyBOP (hexafluorophosphoric acid benzotriazole-1-base-epoxide tripyrrole alkyl)
DMPU 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2 (1H)-pyrimidone
DMF dimethylformamide
Boc tert-butoxycarbonyl
Mmol mM
μM micromole
Ml milliliter
G gram
M mol/l
N equivalent
Nm nanometer
Min minute
H hour
D days
R.t. room temperature
UV ultraviolet
Ctrl compares
HGP liver glucose generates
The following examples are used for the present invention being described rather than being used for limiting its application.
Table 1: the list of the molecule that synthesis is illustrated
Embodiment 1: preparation derivant No.1:2-((3-(phenylene-ethynylene) imidazo [1,2-a] pyridine-2-base) methoxy Base) ethyl acetate
Step 1: preparation 2-(chloromethyl) imidazo [1,2-a] pyridine
7.09g (54.1mmol) 1,3-DCA is dissolved in 13ml DME, adds in solution under magnetic agitation 5g (52.1mmol) PA.Mixture stirs 16h under r.t..Filter and separate the solid formed, use 30ml diisopropyl Base ether washs.Yellow solid is suspended in 125ml dehydrated alcohol, mixture return stirring 2h.Vacuum concentrated mixture, then To product put in the 150ml mixture that is made up of water and ice.The pH of aqueous phase is by adding saturated NaHCO3Water-soluble liquid caustic soda Change to pH 8-9.Aqueous phase extracts with 3 x 100ml dichloromethane.Merge organic facies, wash with NaCl aqueous solution saturated for 200ml Wash, use Na2SO4It is dried, is filtered to remove.The filtrate that obtains is concentrated in vacuo.Crude product (is washed by the purification by flash chromatography of silicagel column De-agent: heptane/ethyl acetate gradient, the heptane of 50%～40%, v/v).Obtain 4.77g (productivity=55%) 2-(chloromethyl) Imidazo [1,2-a] pyridine, white solid.LC-MS:m/z=167 (MH+)；UV purity=99% under 254nm.1H NMR (300MHz, DMSO) δ 8.52 (d, J=6.8Hz, 1H), 7.99 (s, 1H), 7.51 (d, J=9.1Hz, 1H), 7.32-7.16 (m, 1H), 6.89 (t, J=6.8Hz, 1H), 4.84 (s, 2H).
Step 2: preparation 2-(imidazo [1,2-a] pyridine-2-ylmethoxy) acetic acid
By 4.24g (25.4mmol) 2-(chloromethyl) imidazo [1,2-a] pyridinium dissolution at 150ml tetrahydrochysene under magnetic agitation In furan, it is subsequently adding 4.2g (28mmol) sodium iodide.Mixture stirs 3h under r.t..In another flask, magnetic force stirs Mixing and lower be dissolved in 100ml oxolane by 9.84ml (101.8mmol) 2-hydroxyl ethyl acetate, then mixture is cooled to 0 DEG C, it is dividedly in some parts 4.072g (101.8mmol) sodium hydride.Mixture stirs 15min at 0 DEG C, then drips 2-in 15min The solution of (iodomethyl) imidazo [1,2-a] pyridine brand-new in oxolane.Mixture stirs 24h under r.t., then Silica gel filters (eluant: oxolane 100%).Filtrate is concentrated in vacuo, by the flash chromatography direct purification of silicagel column (eluant: methylene chloride/methanol gradient, the dichloromethane of 100%～70%, v/v；Then with 100% methanol washing pillar). Obtain 3.62g (productivity=69%) 2-(imidazo [1,2-a] pyridine-2-ylmethoxy) acetic acid, brown solid.LC-MS:m/z =207 (MH+)；UV purity=98% under 254nm.
Step 3: preparation 2-(imidazo [1,2-a] pyridine-2-ylmethoxy) ethyl acetate
By 3.62g (15.58mmol) 2-(imidazo [1,2-a] pyridine-2-ylmethoxy) acetic acid under magnetic agitation In 100ml ethanol, add 0.094ml (1.758mmol) sulphuric acid.Mixture return stirring 5d.Reaction medium is concentrated in vacuo, logical Cross the flash chromatography direct purification (eluant: ethyl acetate 100%, then methylene chloride/methanol, 9/1, v/v) of silicagel column.Instead Medium is answered to wash with 2 x 10ml water, then with 2 x 30ml ethyl acetate extractions.Merge organic facies, with the NaCl that 30ml is saturated Solution washing, uses Na2SO4It is dried, is filtered to remove.The filtrate that obtains is concentrated in vacuo.Obtain 0.162mg (productivity=91%) 2- ((3-((4-fluorophenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) isopropyl acetate, brown oil.MS:m/z =235 (MH+)。1H NMR (300MHz, DMSO) δ 8.52 (d, J=7.9Hz, 1H), 7.91 (s, 1H), 7.50 (d, J=9.1Hz, 1H), 7.30-7.13 (m, 1H), 6.87 (t, J=6.7Hz, 1H), 4.65 (s, 2H), 4.20 (s, 2H), 4.12 (q, J= 7.1Hz, 2H), 1.19 (t, J=7.2Hz, 3H).
Step 4: preparation 2-((3-iodine imidazo [1,2-a] pyridine-2-base) methoxyl group) ethyl acetate
By 0.45g (1.921mmol) 2-(imidazo [1,2-a] pyridine-2-ylmethoxy) ethyl acetate under magnetic agitation It is dissolved in 6ml acetonitrile, in solution, adds 0.475g (2.113mmol) N-iodosuccinimide.Mixture is under r.t. Stirring 16h.Solids removed by filtration, is concentrated in vacuo the filtrate obtained.Product 10ml Di Iso Propyl Ether grinds, and it is heavy to filter to isolate Form sediment.Obtain 0.465g (productivity=67%) 2-((3-iodine imidazo [1,2-a] pyridine-2-base) methoxyl group) ethyl acetate, yellow Solid.LC-MS:m/z=361 (MH+)；UV purity=75% under 254nm.1H NMR (300MHz, DMSO) δ 8.34 (d, J= 6.9Hz, 1H), 7.59 (d, J=8.1Hz, 1H), 7.47-7.28 (m, 1H), 7.07 (d, J=5.7Hz, 1H), 4.67 (s, 2H), 4.14 (t, J=10.7Hz, 4H), 1.22 (d, J=1.9Hz, 3H).
Step 5: preparation 2-((3-(phenylene-ethynylene) imidazo [1,2-a] pyridine-2-base) methoxyl group) ethyl acetate (is spread out Biological No.1)
In being placed in the flask that argon flows down, by 0.1g (0.278mmol) 2-((3-iodine imidazo [1,2-under magnetic agitation A] pyridine-2-base) methoxyl group) acetic acid ethyl dissolution is in 0.3ml dimethylformamide.Add in solution: 0.005g (0.028mmol) Copper diiodide, 0.037ml (0.333mmol) phenylacetylene and 0.3ml (2.152mmol) triethylamine.Reaction medium is used Argon-degassed 10min, is subsequently adding 0.025g (0.028mmol) Pd2(dba)3.Mixture stirs 16h under r.t., then exists Filtered over Celite.Kieselguhr 20ml ethyl acetate is washed, and then filtrate is washed with 2 x 50ml water.After separation, aqueous phase is used 30ml ethyl acetate extracts, and merges organic facies, with NaCl solution washing saturated for 30ml, uses Na2SO4It is dried, is filtered to remove. The filtrate that obtains is concentrated in vacuo.Crude product by the purification by flash chromatography of silicagel column (eluant: heptane/ethyl acetate, 1/1, v/ v).Obtain 0.038g (productivity=41%) 2-((3-(phenylene-ethynylene) imidazo [1,2-a] pyridine-2-base) methoxyl group) acetic acid Ethyl ester, light yellow solid.LC-MS:m/z=335 (MH+)；UV purity=99% under 254nm.1H NMR (300MHz, DMSO) δ 8.63 (d, J=5.6Hz, 1H), 7.68 (d, J=8.0Hz, 3H), 7.54-7.39 (m, 4H), 7.14 (t, J=6.8Hz, 1H), 4.79 (s, 2H), 4.24 (s, 2H), 4.09 (q, J=7.1Hz, 2H), 1.15 (t, J=7.1Hz, 3H).
Derived from 2-((3-iodine imidazo [1,2-a] pyridine-2-base) methoxyl group) ethyl acetate according to same program Thing No.2～26,98 and 99:
Embodiment 2: preparation derivant No.27:2-((3-((3-cyano-phenyl) acetenyl) imidazo [1,2-a] pyridine- 2-yl) methoxyl group) acetic acid
By 0.05g (0.139mmol) 2-((3-((3-cyano-phenyl) acetenyl) imidazo [1,2-a] pyrrole under magnetic agitation Pyridine-2-base) methoxyl group) acetic acid ethyl dissolution in 4ml ethanol/oxolane (1/1, v/v) mixture, be subsequently adding 0.167ml (0.167mmol) 1N NaOH aqueous solution.Mixture stirs 16h under r.t., is subsequently adding 20ml water, is subsequently adding 0.016ml (0.278mmol) acetic acid.Aqueous phase extracts by 3 x 20ml ethyl acetate.Merge organic facies, use Na2SO4It is dried, filters Remove.The filtrate that obtains is concentrated in vacuo.Obtain 0.042g (productivity=91%) 2-((3-((3-cyano-phenyl) acetenyl) imidazoles And [1,2-a] pyridine-2-base) methoxyl group) acetic acid, light yellow solid.LC-MS:m/z=332 (MH+)；UV purity under 254nm =99%.1H NMR (300MHz, DMSO) δ 12.70 (s, 1H), 8.73 (d, J=6.7Hz, 1H), 8.22 (t, J=1.3Hz, 1H), 8.07-7.94 (m, 1H), 7.94-7.78 (m, 1H), 7.78-7.55 (m, 2H), 7.54-7.38 (m, 1H), 7.15 (td, J =6.8,0.9Hz, 1H), 4.79 (s, 2H), 4.15 (s, 2H).
Derivant No.28～44 is prepared according to same program:
Embodiment 3: preparation derivant No.45:2-((3-(phenylene-ethynylene) imidazo [1,2-a] pyridine-2-base) methoxy Base) sodium acetate
0.061g (0.182mmol) 2-((3-(phenylene-ethynylene) imidazo [1,2-a] pyridine-2-base) under magnetic agitation Methoxyl group) ethyl acetate is dissolved in the mixture (1/1, v/v) that 3ml is made up of methanol and oxolane, is subsequently adding 0.173ml (0.173mmol) 1N NaOH aqueous solution.Mixture stirs 2d under r.t., is then concentrated in vacuo.Crude product is at 3ml In Di Iso Propyl Ether grind, filter isolated solid, in vacuum bell jar be dried, thus obtain 0.027g (productivity= 45%) 2-((3-(phenylene-ethynylene) imidazo [1,2-a] pyridine-2-base) methoxyl group) sodium acetate.LC-MS:m/z=307 (MH+)；UV purity=99% under 254nm.1H NMR (300MHz, DMSO) δ 8.62 (d, J=6.7Hz, 1H), 7.79-7.58 (m, 3H), 7.45 (dd, J=8.8,7.2Hz, 4H), 7.13 (t, J=6.5Hz, 1H), 4.74 (s, 2H), 3.70 (s, 2H).
Derivant No.46～53 is prepared according to same program:
Embodiment 4: preparation derivant No.54:2-((3-((4-fluorophenyl) acetenyl) imidazo [1,2-a] pyridine-2- Base) methoxyl group) isopropyl acetate
By 0.155g (0.478mmol) 2-((3-((4-fluorophenyl) acetenyl) imidazo [1,2-a] pyrrole under magnetic agitation Pyridine-2-base) methoxyl group) acetic acid in 5ml isopropanol, add 1 sulphuric acid.Mixture stirs 3h at 60 DEG C.Reaction is situated between Matter is washed with 2 x 10ml water, then with 2 x 30ml ethyl acetate extractions.Merging organic facies, the NaCl saturated with 30ml is water-soluble Liquid washs, and uses Na2SO4It is dried, is filtered to remove.The filtrate that obtains is concentrated in vacuo.Obtain 0.162mg (productivity=91%) 2-((3- ((4-fluorophenyl) acetenyl) imidazo [1,2-a] pyridine-2-base)-methoxyl group) isopropyl acetate, brown oil.LC-MS:m/z =367 (MH+)；UV purity=98% under 254nm.1H NMR (300MHz, DMSO) δ 8.62 (d, J=6.8Hz, 1H), 7.74 (dd, J=8.7,5.5Hz, 2H), 7.67 (d, J=9.0Hz, 1H), 7.45 (d, J=7.0Hz, 1H), 7.33 (t, J=8.9Hz, 2H), 7.12 (t, J=6.5Hz, 1H), 4.93 (dt, J=12.5,6.3Hz, 1H), 4.78 (s, 2H), 4.19 (s, 2H), 1.15 (d, J=6.3Hz, 6H).
Embodiment 5: preparation derivant No.55:N-(2-(dimethylamino) ethyl)-2-((3-((3-(trifluoromethyl) benzene Base) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) acetamide
Under magnetic agitation by 0.15g (0.373mmol) 2-((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1, 2-a] pyridine-2-base) methoxyl group) and acetic acid ethyl dissolution in 2ml pyridine, in solution add 0.409ml (3.73mmol) N, N-dimethyl ethane-1,2-diamidogen and 0.249mg (1.864mmol) aluminum chloride.Mixture stirs 18h under r.t., then uses NaCl aqueous solution saturated for 30ml processes.Aqueous phase extracts by 3 x 30ml ethyl acetate.Merge organic facies, use Na2SO4It is dried, mistake Filter.The filtrate that obtains is concentrated in vacuo.Obtain 0.056g (productivity=34%) N-(2-(dimethylamino) ethyl)-2-((3- ((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) acetamide, brown solid.LC- MS:m/z=445 (MH+)；UV purity=96% under 254nm.1H NMR (300MHz, CDCl3) δ 7.85 (s, 1H), 7.78 (d, J=7.7Hz, 2H), 7.70 (s, 2H), 7.58 (t, J=7.8Hz, 2H), 7.23 (s, 1H), 5.11 (s, 2H), 4.31 (dd, J= 26.6,11.2Hz, 2H), 3.83 (s, 2H), 3.33 (s, 2H), 2.89 (s, 6H).
Embodiment 6: preparation derivant No.56:2-((3-((4-fluorophenyl) acetenyl) imidazo [1,2-a] pyridine-2- Base) methoxyl group)-1-morpholinyl ethyl ketone
Step 1: preparation 2-((3-((4-fluorophenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) acetyl Chlorine
Under magnetic agitation by 1.5g (4.63mmol) 2-((3-((4-fluorophenyl) acetenyl) imidazo [1,2-a] pyridine- 2-yl) methoxyl group) acetic acid is suspended in 40ml dichloromethane, and mixture is placed in the bath of 0 DEG C, then drips 1.215ml (13.88mmol) oxalyl chloride, finally, adds several dimethylformamides.Removing cryostat, then mixture stirs under r.t. 1h.Reaction medium is concentrated in vacuo, is used in immediately in next step.
Step 2: preparation 2-((3-((4-fluorophenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group)-1- Quinoline base ethyl ketone (derivant No.56)
Under magnetic agitation, 0.806ml (9.25mmol) morpholine is dissolved in 4ml dichloromethane, adds 2-((3-((4-fluorine Phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) chloroacetic chloride solution in 4ml dichloromethane, then mixes Compound adds 1h under r.t., then processes with 10ml water.Aqueous phase extracts with 2 x 5ml dichloromethane.Merge organic facies, use NaCl solution washing saturated for 5ml, uses Na2SO4It is dried, is filtered to remove.The filtrate that obtains is concentrated in vacuo.Crude product passes through silicon The purification by flash chromatography (eluant: ethyl acetate 100%) of glue post.Obtain 0.211g (productivity=58%) 2-((3-((4-fluorobenzene Base) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group)-1-morpholinyl ethyl ketone, light yellow solid.LC-MS:m/z= 394(MH+)；UV purity=99% under 254nm.1H NMR (300MHz, DMSO) δ 8.62 (d, J=6.8Hz, 1H), 7.74 (dd, J=8.7,5.5Hz, 2H), 7.67 (d, J=9.0Hz, 1H), 7.50-7.39 (m, 1H), 7.33 (t, J=8.9Hz, 2H), 7.12 (t, J=6.8Hz, 1H), 4.75 (s, 2H), 4.27 (s, 2H), 3.55-3.46 (m, 4H), 3.39 (s, 4H).
According to same program from 2-((3-((4-fluorophenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) Chloroacetic chloride obtains derivant No.57～59:
Embodiment 7: preparation derivant No.60:2-((3-((4-fluorophenyl) acetenyl) imidazo [1,2-a] pyridine-2- Base) methoxyl group)-1-morpholinyl ethyl ketone
Step 1: preparation 2-(((triisopropylsilyl) epoxide) methyl) imidazo [1,2-a] pyridine
Under magnetic agitation, 1g (6.55mmol) imidazo [1,2-a] pyridine-2-base methanol is dissolved in 25ml dichloromethane In, it is then slowly added into 2.145ml (9.82mmol) triisopropylsilyl chlorine.Mixture stirs 1h under r.t., then Process with 100ml water.Aqueous phase extracts with 3 x 50ml dichloromethane.Merge organic facies, wash with NaCl aqueous solution saturated for 100ml Wash, use Na2SO4It is dried, is filtered to remove.The filtrate that obtains is concentrated in vacuo.Crude product (is washed by the purification by flash chromatography of silicagel column De-agent: dichloromethane 100%, then ethyl acetate 100%).Obtain 1.85g (productivity=92%) 2-(((triisopropyl first silicon Alkyl) epoxide) methyl) imidazo [1,2-a] pyridine, water white oil.LC-MS:m/z=305 (MH+)；UV purity under 254nm= 99%.1H NMR (300MHz, DMSO) δ 8.57-8.50 (m, 1H), 7.81 (s, 1H), 7.46 (dd, J=9.1,0.6Hz, 1H), 7.19 (ddd, J=9.1,6.7,1.3Hz, 1H), 6.84 (td, J=6.8,1.1Hz, 1H), 4.88 (d, J=0.6Hz, 2H), 1.23-1.11 (m, 3H), 1.11-1.02 (m, 18H).
Step 2: the preparation iodo-2-of 3-(((triisopropylsilyl) epoxide) methyl) imidazo [1,2-a] pyridine
Under magnetic agitation by 1.85g (6.08mmol) 2-(((triisopropylsilyl) epoxide) methyl) imidazo [1, 2-a] pyridinium dissolution in 25ml acetonitrile, in solution add 1.409g (6.08mmol) N-iodosuccinimide.Mixture Under r.t., stir 16h, then process with 100ml water.Aqueous phase extracts with 3 x 50ml dichloromethane.Merge organic facies, use NaCl solution washing saturated for 100ml, uses Na2SO4It is dried, is filtered to remove.The filtrate that obtains is concentrated in vacuo.Obtain 2.29g The iodo-2-of (productivity=83%) 3-(((triisopropylsilyl) epoxide) methyl) imidazo [1,2-a] pyridine, light yellow solid Body.LC-MS:m/z=431 (MH+)；UV purity=95% under 254nm.1H NMR (300MHz, DMSO) δ 8.30 (dd, J= 5.6,2.2Hz, 1H), 7.59 (dd, J=14.3,9.1Hz, 1H), 7.33 (tt, J=6.8,4.1Hz, 1H), 7.14-6.96 (m, 1H), 4.80 (s, 2H), 1.27-0.90 (m, 21H).
Step 3: preparation 3-(phenylene-ethynylene)-2-(((triisopropylsilyl) oxy) methyl) imidazo [1,2-a] Pyridine
In being placed in the flask that argon flows down, by 2.29g (5.32mmol) 3-iodo-2-(((triisopropyl under magnetic agitation Silicyl) epoxide) methyl) imidazo [1,2-a] pyridinium dissolution is in 11ml dimethylformamide.Add in solution: 0.103g (0.532mmol) Copper diiodide, 0.715ml (6.38mmol) phenylacetylene and 11.12ml (80mmol) triethylamine.Reaction is situated between Matter argon-degassed 10min, is subsequently adding 0.487g (0.532mmol) Pd2(dba)3.Mixture stirs 16h under r.t., so After filter over celite.Kieselguhr 200ml ethyl acetate is washed.Filtrate is with the saturated NaCl of 2 x 100ml water and 100ml Solution washing, then uses Na2SO4It is dried, is filtered to remove.The filtrate that obtains is concentrated in vacuo.Crude product is quick by silicagel column Chromatogram purification (eluant: heptane/ethyl acetate gradient, the heptane of 90%～80%, v/v).Obtain 1.56g (productivity=72%) 3-(phenylene-ethynylene)-2-(((triisopropylsilyl) epoxide) methyl) imidazo [1,2-a] pyridine, brown solid.LC- MS:m/z=405 (MH+)；UV purity=99% under 254nm.1H NMR (300MHz, DMSO) δ 8.60 (d, J=6.7Hz, 1H), 7.72-7.55 (m, 3H), 7.52-7.36 (m, 4H), 7.17-7.06 (m, 1H), 4.94 (s, 2H), 1.14 (m, 3H), 1.04 (d, J=6.5Hz, 18H).
Step 4: preparation (3-(phenylene-ethynylene) imidazo [1,2-a] pyridine-2-base) methanol (derivant No.60)
Under magnetic agitation by 1.56g (3.86mmol) 2-(((triisopropylsilyl) epoxide) methyl) imidazo [1, 2-a] pyridinium dissolution is in 30ml oxolane, and in solution, addition 4.24ml (4.24mmol) 1M tetrabutylammonium chloride is at tetrahydrochysene Solution in furan.Mixture stirs 1h under r.t., is then concentrated in vacuo.Crude product is direct by the flash chromatography of silicagel column Purification (eluant: ethyl acetate 100%).Obtain 0.83g (productivity=86%) (3-(phenylene-ethynylene) imidazo [1,2-a] Pyridine-2-base) methanol, orange solids.LC-MS:m/z=249 (MH+)；UV purity=99% under 254nm.1H NMR (300MHz, DMSO) δ 8.59 (dt, J=6.7,1.1Hz, 1H), 7.77-7.56 (m, 3H), 7.56-7.32 (m, 4H), 7.11 (td, J=6.8,1.1Hz, 1H), 5.33 (t, J=5.9Hz, 1H), 4.67 (d, J=5.9Hz, 2H).
Derivant No.100 is obtained according to same program:
Embodiment 8: preparation derivant No.61:((3-(phenylene-ethynylene) imidazo [1,2-a] pyridine-2-base) methyl) Isobutyl carbonate butyl ester
By 0.1g (0.403mmol) (3-(phenylene-ethynylene) imidazo [1,2-a] pyridine-2-base) methanol under magnetic agitation It is dissolved in 3ml dichloromethane.Add 0.084ml (0.604mmol) triethylamine and 0.059ml (0.443mmol) chloro-carbonic acid is different Butyl ester.Mixture stirs 15min under r.t., is then concentrated in vacuo.Product puts in 10ml Di Iso Propyl Ether, filters and separates admittedly Body.Solid passes through preparative HPLC purification, obtains 0.084g (productivity=59%) ((3-(phenylene-ethynylene) imidazo [1,2-a] Pyridine-2-base) methyl) isobutyl carbonate butyl ester, light yellow solid.LC-MS:m/z=349 (MH+)；UV purity under 254nm= 99%.1H NMR (300MHz, DMSO) δ 8.70 (d, J=6.8Hz, 1H), 7.79-7.65 (m, 3H), 7.60-7.45 (m, 4H), 7.23 (td, J=6.8,1.1Hz, 1H), 5.42 (s, 2H), 3.91 (d, J=6.6Hz, 2H), 1.95-1.80 (m, 1H), 0.86 (d, J=6.7Hz, 6H).
Embodiment 9: preparation derivant No.62: morpholine-4-formic acid (3-(phenylene-ethynylene) imidazo [1,2-a] pyridine- 2-yl) methyl ester
By 0.117g (0.467mmol) (3-(phenylene-ethynylene) imidazo [1,2-a] pyridine-2-base) first under magnetic agitation Alcohol is dissolved in 4ml oxolane.Add 0.228g (0.7mmol) cesium carbonate and 0.61ml (0.513mmol) morpholine-4-phosphinylidyne Chlorine.Mixture stirs 16h under r.t..Adding 1.22ml (1.026mmol) morpholine-4-phosgene, mixture is under r.t. Stirring 2d, then processes with NaCl aqueous solution saturated for 10ml.Aqueous phase extracts by 3 x 10ml ethyl acetate.Merge organic facies, Use Na2SO4It is dried, is filtered to remove.Crude product passes through preparative HPLC purification, obtains 0.078g (productivity=46%) morpholine-4-first Acid (3-(phenylene-ethynylene) imidazo [1,2-a] pyridine-2-base) methyl ester, brown solid.LC-MS:m/z=362 (MH+)； UV purity=99% under 254nm.1H NMR (300MHz, DMSO) δ 8.60 (d, J=6.7Hz, 1H), 7.66 (dd, J= 11.0,5.4Hz, 3H), 7.47 (dd, J=4.1,1.3Hz, 4H), 7.14 (t, J=6.4Hz, 1H), 5.33 (s, 2H), 3.48 (s, 4H), 3.34 (s, 4H).
Embodiment 10: preparation derivant No.63: diethylamino formic acid (3-(phenylene-ethynylene) imidazo [1,2-a] pyrrole Pyridine-2-base) methyl ester
By 0.1g (0.403mmol) (3-(phenylene-ethynylene) imidazo [1,2-a] pyridine-2-base) methanol under magnetic agitation It is dissolved in 3ml dimethylformamide.Mixture is cooled to 0 DEG C, is dividedly in some parts 0.048g (1.208mmol) sodium hydride (60 matter Amount %).Mixture stirs 10min at 0 DEG C, is subsequently adding 0.204ml (1.611mmol) diethylamino formyl chloride.Remove Cryostat, mixture stirs 2h under r.t., then processes with NaCl aqueous solution saturated for 30ml.Aqueous phase is by 3 x 10ml acetic acid second Ester extracts.Merge organic facies, use Na2SO4It is dried, is filtered to remove.Crude product by the purification by flash chromatography of silicagel column (eluant: Heptane/ethyl acetate, 6/4, v/v).Obtain 0.101g (productivity=72%) diethylamino formic acid (3-(phenylene-ethynylene) miaow Azoles also [1,2-a] pyridine-2-base) methyl ester, light yellow solid.LC-MS:m/z=348 (MH+)；UV purity under 254nm= 99%.1H NMR (300MHz, DMSO) δ 8.61 (d, J=6.8Hz, 1H), 7.74-7.59 (m, 3H), 7.53-7.38 (m, 4H), 7.13 (td, J=6.8,1.1Hz, 1H), 5.30 (s, 2H), 3.22 (q, J=7.1Hz, 4H), 1.01 (t, J=7.1Hz, 6H).
Embodiment 11: preparation derivant No.64:3-((2-((2-hydroxyl-oxethyl) methyl) imidazo [1,2-a] pyridine- 3-yl) acetenyl) benzonitrile
Step 1: preparation 2-(chloromethyl)-3-iodine imidazo [1,2-a] pyridine
Under magnetic agitation, 5g (30mmol) 2-(chloromethyl) imidazo [1,2-a] pyridinium dissolution, in 60ml acetonitrile, is added Entering 7.31g (31.5mmol) N-iodosuccinimide, mixture stirs 15min under r.t..Filter and separate the solid formed, Wash with 30ml water, be dried in vacuum bell jar.Obtain 8.46g (productivity=95%) 2-(chloromethyl)-3-iodine imidazo [1,2- A] pyridine, white solid.LC-MS:m/z=293 (MH+)；UV purity=99% under 254nm.1H NMR (300MHz, DMSO) δ 8.31 (d, J=6.9Hz, 1H), 7.58 (d, J=9.1Hz, 1H), 7.46-7.29 (m, 1H), 7.07 (td, J=6.8,1.0Hz, 1H), 4.81 (s, 2H).
Step 2: preparation 3-hydracrylic acid (3-iodine imidazo [1,2-a] pyridine-2-base) methyl ester
In being placed in the flask that argon flows down, by 0.515ml (3.42mmol) 2-(chloromethyl)-3-iodine miaow under magnetic agitation Azoles also [1,2-a] pyridinium dissolution, in 8ml oxolane, is subsequently adding 0.06g (1.504mmol) sodium hydride (60 mass %), Mixture stirs 30min under r.t., is subsequently adding 0.4g (1.368mmol) 2-(chloromethyl)-3-iodine imidazo [1,2-a] pyrrole Pyridine and 0.05ml (0.137mmol) tetrabutylammonium iodide.Mixture return stirring 2d.The ammonium chloride that reaction medium 30ml is saturated Aqueous solution processes.Aqueous phase extracts by 2 x 30ml ethyl acetate.Merge organic facies, with NaCl solution washing saturated for 30ml, Use Na2SO4It is dried, is filtered to remove.The filtrate that obtains is concentrated in vacuo.Crude product purification by flash chromatography (the eluting by silicagel column Agent: heptane/ethyl acetate gradient, 1/1, v/v).Obtain 0.17g (productivity=36%) 3-hydracrylic acid (3-iodine imidazo [1,2- A] pyridine-2-base) methyl ester, brown solid.LC-MS:m/z=347 (MH+)；UV purity=99% under 254nm.1H NMR (300MHz, DMSO) δ 8.32 (d, J=6.9Hz, 1H), 7.57 (d, J=9.1Hz, 1H), 7.42-7.24 (m, 1H), 7.07 (t, J=6.4Hz, 1H), 5.16 (s, 2H), 4.73 (t, J=5.3Hz, 1H), 3.64 (dd, J=11.6,6.0Hz, 2H), 2.46 (m, 2H)。
Step 3: preparation 3-hydracrylic acid (3-((3-cyano-phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) first Ester (derivant No.64)
In being placed in the flask that argon flows down, by 0.138g (0.397mmol) 3-hydracrylic acid (3-iodine miaow under magnetic agitation Azoles also [1,2-a] pyridine-2-base) methyl ester is dissolved in 4ml dimethylformamide.Add in solution: 0.008g (0.04mmol) Copper diiodide, 0.06g (0.477mmol) 3-acetylenylbenzene formonitrile HCN and 0.831ml (5.96mmol) triethylamine.Reaction Medium argon-degassed 10min, is subsequently adding 0.036g (0.04mmol) Pd2(dba)3.Mixture stirs 1h under r.t., so Processing with NaCl aqueous solution saturated for 50ml afterwards, aqueous phase extracts by 2 x 50ml ethyl acetate.Merge organic facies, saturated with 0ml NaCl solution washing 5, then use Na2SO4It is dried, is filtered to remove.The filtrate that obtains is concentrated in vacuo.Crude product passes through silica gel The purification by flash chromatography (eluant: heptane/ethyl acetate, 2/8, v/v) of post.Obtain 0.12g (productivity=82%) 3-hydroxyl third Acid (3-((3-cyano-phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methyl ester, yellow solid.LC-MS:m/z=346 (MH+)；UV purity=93% under 254nm.1H NMR (300MHz, DMSO) δ 8.74 (d, J=6.8Hz, 1H), 8.26 (s, 1H), 7.98 (dd, J=5.3,3.9Hz, 1H), 7.90 (dd, J=5.2,3.8Hz, 1H), 7.76-7.63 (m, 2H), 7.57- 7.41 (m, 1H), 7.18 (td, J=6.8,1.0Hz, 1H), 5.35 (s, 2H), 4.76 (t, J=5.3Hz, 1H), 3.67 (dd, J =11.6,6.2Hz, 2H), 2.54-2.49 (m, 2H).
Same sequence according to step 1～4 prepares derivant No.65～67:
Embodiment 12: preparation derivant No.68:2-(((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2- A] pyridine-2-base) methyl) amino) acetic acid
Step 1: preparation 2-(imidazo [1,2-a] pyridine-2-ylmethyl) isoindoline-1,3-diketone
By 1.5g (9mmol) 2-(chloromethyl) imidazo [1,2-a] pyridinium dissolution at 55ml dimethyl methyl under magnetic agitation In amide, being dividedly in some parts 1.834g (9.9mmol) potassium phthalimide, then mixture stirs 2h at 60 DEG C.Filter The solid of isolated, with 30ml Di Iso Propyl Ether wash, in vacuum bell jar be dried, thus obtain 1.81g (productivity= 67%) 2-(imidazo [1,2-a] pyridine-2-ylmethyl) isoindoline-1,3-diketone, white solid.LC-MS:m/z=278 (MH+)；UV purity=93% under 254nm.1H NMR (300MHz, DMSO) δ 8.45 (d, J=6.8Hz, 1H), 7.96-7.67 (m, 5H), 7.45 (dd, J=9.1,0.5Hz, 1H), 7.33-7.14 (m, 1H), 6.84 (td, J=6.8,1.1Hz, 1H), 4.88 (s, 2H).
Step 2: preparation 2-((3-iodine imidazo [1,2-a] pyridine-2-base) methyl) isoindoline-1,3-diketone
Under magnetic agitation by 1.7g (5.7mmol) 2-(chloromethyl) imidazo [1,2-a] pyridinium dissolution in 65ml acetonitrile, Adding 1.389g (5.99mmol) N-iodosuccinimide, mixture stirs 1h under r.t..Filter and separate the solid formed, Wash with 20ml Di Iso Propyl Ether, be dried in vacuum bell jar.Obtain 0.105g (productivity=87%) 2-((3-iodine imidazo [1, 2-a] pyridine-2-base) methyl) isoindoline-1,3-diketone, white solid.LC-MS:m/z=404 (MH+)；UV under 254nm Purity=78%.1H NMR (300MHz, DMSO) δ 8.29 (d, J=6.8Hz, 1H), 7.89 (d, J=5.6Hz, 4H), 7.48 (d, J=9.0Hz, 1H), 7.36-7.24 (m, 1H), 7.03 (t, J=6.4Hz, 1H), 4.89 (s, 2H).
Step 3: preparation 2-((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) first Base) isoindoline-1,3-diketone
In being placed in the flask that argon flows down, by 2.1g (5.21mmol) 2-((3-iodine imidazo [1,2-under magnetic agitation A] pyridine-2-base) methyl) isoindoline-1,3-diketone is dissolved in 11ml dimethylformamide.Add in solution: 0.008g (0.04mmol) Copper diiodide, 0.921ml (6.25mmol) 3-trifluoromethyl acetyl group ene and 10.89ml (78mmol) triethylamine.Reaction medium argon-degassed 10min, is subsequently adding 0.477g (0.521mmol) Pd2(dba)3.Mixing Thing stirs 16h under r.t., filters the most on a silica gel column, then uses 300ml ethyl acetate rinse.Organic facies 3 x NaCl solution washing saturated for 150ml, then uses Na2SO4It is dried, is filtered to remove.The filtrate that obtains is concentrated in vacuo.Crude product By the purification by flash chromatography (eluant: heptane/ethyl acetate gradient, the heptane of 50%～40%, v/v) of silicagel column.Obtain 1.41g (productivity=59%) 2-((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methyl) Isoindoline-1,3-diketone, brown solid.LC-MS:m/z=446 (MH+)；UV purity=97% under 254nm.1H NMR (300MHz, DMSO) δ 8.67 (d, J=6.7Hz, 1H), 7.91 (dd, J=5.6,3.0Hz, 2H), 7.82 (dd, J=5.5, 3.1Hz, 2H), 7.69 (dd, J=12.5,8.5Hz, 2H), 7.63-7.52 (m, 2H), 7.52-7.42 (m, 2H), 7.13 (td, J =6.8,1.1Hz, 1H), 5.09 (s, 2H).
Step 4: preparation (3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methylamine
Under magnetic agitation by 1.41g (3.08mmol) 2-((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1, 2-a] pyridine-2-base) methyl) isoindoline-1,3-diketone is dissolved in 30ml ethanol, adds 0.978ml (30.8mmol) water Close hydrazine.Mixture gradually becomes emulsus, stirs 1.5h under r.t..Filter and separate the solid suspended, wash with 2 x 25ml ethanol Wash.Filtrate is concentrated in vacuo.Product grinds in 20ml ethanol, filters to isolate solid, filtrate is concentrated in vacuo, thus obtains 0.715g (productivity=69%) (3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methylamine is shallow Yellow solid.LC-MS:m/z=316 (MH+)；UV purity=94% under 254nm.1H NMR (300MHz, DMSO) δ 8.73 (d, J=6.7Hz, 1H), 8.12 (s, 1H), 7.98 (d, J=7.7Hz, 1H), 7.82-7.63 (m, 3H), 7.49-7.40 (m, 1H), 7.13 (td, J=6.8,1.1Hz, 1H), 3.96 (s, 2H).
Step 5: preparation 2-(((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) first Base) amino) acetic acid (derivant No.68)
Filter is being installed and in reactor that emptying system is placed on vortex, putting into 0.33g (0.656mmol) cyanogen Base boron hydride resin.Resin is swelling in 3ml dichloromethane, and mixture stirs 10min under r.t., is then filtered to remove two Chloromethanes.Operation is repeated twice, and is subsequently adding 0.2g (3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyrrole Pyridine-2-base) methylamine and the mixture of 0.055g (0.596mmol) 2-Oxoacetic Acid hydrate that is dissolved in 3ml methanol.Mixing Thing stirs 24h under slow vortex under r.t..It is filtered to remove resin, with 15ml methanol, 15ml dichloromethane, the most again 15ml Methanol washs.The filtrate that obtains is concentrated in vacuo, the product purification by flash chromatography (eluant: dichloromethane/first by silicagel column Alcohol/ammonia (20 mass %), 80/20/2, v/v/v).Obtain 0.049g (productivity=22%) 2-(((3-((3-(trifluoromethyl) Phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methyl) amino) acetic acid, white solid.LC-MS:m/z=374 (MH+)；UV purity=98% under 254nm.1H NMR (300MHz, DMSO) δ 8.76 (d, J=6.7Hz, 1H), 8.13 (s, 1H), 8.01 (d, J=7.6Hz, 1H), 7.78 (d, J=7.9Hz, 1H), 7.69 (dd, J=8.3,7.1Hz, 2H), 7.53-7.42 (m, 1H), 7.16 (td, J=6.8,1.0Hz, 1H), 4.17 (s, 2H), 3.31 (s, 6H).
Embodiment 13: preparation derivant No.69:N-((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2- A] pyridine-2-base) methyl) propane-2-sulfonamide
By 0.08g (0.239mmol) (3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-under magnetic agitation A] pyridine-2-base) methylamine (according to the step 1 of embodiment 11～4 preparations) is dissolved in 2ml dichloromethane, adds 0.208ml (1.193mmol) diisopropyl ethyl amine and 0.083ml (0.716mmol) isopropyl sulphonyl chloride.Mixture stirs under r.t. 16h.Supplementing and add 0.083ml (0.716mmol) isopropyl sulphonyl chloride, mixture stirs 1h under r.t., is then concentrated in vacuo. The crude product flash chromatography direct purification (eluant: methylene chloride/methanol 95/5, v/v) by silicagel column.Obtain 0.048g (productivity=22%) N-((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methyl) propane- 2-sulfonamide, white solid.LC-MS:m/z=422 (MH+)；UV purity=98% under 254nm.1H NMR (300MHz, DMSO) δ 8.75 (d, J=6.8Hz, 1H), 8.13 (s, 1H), 7.99 (d, J=7.5Hz, 1H), 7.85-7.61 (m, 4H), 7.53-7.38 (m, 1H), 7.15 (t, J=6.8Hz, 1H), 4.44 (d, J=5.9Hz, 2H), 3.25 (dd, J=13.6, 6.8Hz, 1H), 1.21 (d, J=6.8Hz, 6H).
Derivant No.70 and 71 is prepared according to same program:
Embodiment 14: preparation derivant No.72:2-(methyl ((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methyl) amino) methyl acetate
Step 1: preparation 2-((imidazo [1,2-a] pyridine-2-ylmethyl) (methyl) amino) methyl acetate
By 0.303g (1.773mmol) 2-(chloromethyl) imidazo [1,2-a] pyridinium dissolution at 15ml bis-under magnetic agitation In methylformamide, it is subsequently adding 0.253g (1.773mmol) hydrochloride methyl sarcosnate and 0.741ml (5.32mmol) three second Amine.Mixture stirs 16h under r.t., then processes with NaCl aqueous solution saturated for 30ml.Aqueous phase is concentrated in vacuo.Product exists 75ml isopropanol grinds, is filtered to remove salt, filtrate is concentrated in vacuo.Crude product purification by flash chromatography (the eluting by silicagel column Agent: methylene chloride/methanol, 95/5, v/v).Obtain 0.107g (productivity=26%) 2-((imidazo [1,2-a] pyridine-2-Ji Jia Base) (methyl) amino) methyl acetate, light yellow oil.LC-MS:m/z=234 (MH+)；UV purity=99% under 254nm.1H NMR (300MHz, DMSO) δ 8.49 (d, J=6.8Hz, 1H), 7.79 (s, 1H), 7.47 (d, J=9.0Hz, 1H), 7.18 (ddd, J=9.0,6.7,1.2Hz, 1H), 6.84 (td, J=6.7,1.1Hz, 1H), 3.76 (s, 2H), 3.61 (s, 3H), 2.32 (s, 3H)。
Step 2: preparation 2-(((3-iodine imidazo [1,2-a] pyridine-2-base) methyl) (methyl) amino) methyl acetate
By 0.107g (0.459mmol) 2-((imidazo [1,2-a] pyridine-2-ylmethyl) (methyl) ammonia under magnetic agitation Base) methyl acetate is dissolved in 4ml acetonitrile, adds 0.112g (0.482mmol) N-iodosuccinimide in solution.Mixing Thing stirs 16h under r.t..Reactant mixture 10ml water processes, then with 3 x 10ml ethyl acetate extractions.Merge organic Phase, with NaCl solution washing saturated for 20ml, then uses Na2SO4It is dried, is filtered to remove.The filtrate that obtains is concentrated in vacuo.Slightly The product purification by flash chromatography (eluant: ethyl acetate 100%) by silicagel column.Obtain 0.093g (productivity=46%) 2- (((3-iodine imidazo [1,2-a] pyridine-2-base) methyl) (methyl) amino) methyl acetate, yellow oil.LC-MS:m/z=360 (MH+)；UV purity=82% under 254nm.1H NMR (300MHz, DMSO) δ 8.30 (d, J=6.8Hz, 1H), 7.54 (d, J= 9.0Hz, 1H), 7.41-7.23 (m, 1H), 7.03 (t, J=6.7Hz, 1H), 3.79 (s, 2H), 3.62 (s, 3H), 3.37 (s, 2H), 2.34 (s, 3H).
Step 3: preparation 2-(methyl ((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2- Base) methyl) amino) methyl acetate (derivant No.72)
In being placed in the flask that argon flows down, by 0.093g (0.212mmol) 2-(((3-iodine imidazo under magnetic agitation [1,2-a] pyridine-2-base) methyl) (methyl) amino) methyl acetate is dissolved in 0.5ml dimethylformamide.Add in solution Enter: 0.004g (0.021mmol) Copper diiodide, 0.037ml (0.255mmol) 3-trifluoromethylbenzene ethyl-acetylene and 0.444ml (3.18mmol) triethylamine.Reaction medium argon-degassed 10min, is subsequently adding 0.019g (0.021mmol) Pd2(dba)3.Mixed Compound stirs 16h under r.t., then processes, uses 15ml diluted ethyl acetate, washes with 2 NaCl aqueous solutions saturated for x 15ml Wash.Aqueous phase 20ml ethyl acetate extracts.Merge organic facies, use Na2SO4It is dried, is filtered to remove.The filtrate that obtains is concentrated in vacuo. The crude product purification by flash chromatography (eluant: ethyl acetate 100%) by silicagel column.Obtain 0.05g (productivity=57%) 2- (methyl ((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methyl) amino) methyl acetate, Light tan solid.LC-MS:m/z=402 (MH+)；UV purity=96% under 254nm.1H NMR (300MHz, DMSO) δ 8.75 (d, J=6.7Hz, 1H), 8.11 (s, 1H), 7.97 (d, J=7.6Hz, 1H), 7.83-7.59 (m, 3H), 7.55-7.37 (m, 1H), 7.14 (td, J=6.8,0.9Hz, 1H), 3.97 (s, 2H), 3.58 (s, 3H), 3.43 (s, 2H), 2.39 (s, 3H).
Derivant No.101～104 is prepared according to same program:
Embodiment 15: preparation derivant No.73:2-(methyl ((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methyl) amino) acetic acid
By 0.22g (0.543mmol) 2-(methyl ((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazoles under magnetic agitation And [1,2-a] pyridine-2-base) methyl) amino) methyl acetate is dissolved in the mixture that 6ml is made up of methanol and oxolane, It is subsequently adding 0.543ml (0.543mmol) 1M NaOH aqueous solution.Mixture stirs 16h under r.t..Add 0.163ml (0.163mmol) 1M NaOH aqueous solution.Mixture is stirred for 24h under r.t., then with 0.04ml (0.705mmol) acetic acid Solution in 10ml water processes.Mixture stirs 30min under r.t..Filter and separate the solid formed, wash with 5ml water, Vacuum bell jar is dried, thus obtains 0.155g (productivity=73%) 2-(methyl ((3-((3-(trifluoromethyl) phenyl) acetylene Base) imidazo [1,2-a] pyridine-2-base) methyl) amino) acetic acid, brown solid.LC-MS:m/z=388 (MH+)；Under 254nm UV purity=99%.1H NMR (300MHz, DMSO) δ 8.74 (d, J=6.7Hz, 1H), 8.10 (s, 1H), 7.97 (d, J= 7.6Hz, 1H), 7.77 (d, J=7.8Hz, 1H), 7.74-7.64 (m, 2H), 7.49-7.39 (m, 1H), 7.13 (t, J= 6.4Hz, 1H), 4.02 (s, 2H), 3.59 (s, 1H), 3.33 (s, 2H), 2.41 (s, 3H).
Derivant No.105～107 is prepared according to same program:
Embodiment 16: preparation derivant No.74:3-(3-((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1, 2-a] pyridine-2-base) methyl) urea groups) essence of Niobe
By 0.15g (0.477mmol) (3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-under magnetic agitation A] pyridine-2-base) methylamine (according to the step 1 of embodiment 11～4 preparations) is dissolved in 4ml dichloromethane, is subsequently adding 0.09g (0.492mmol) essence of Niobe-3-isocyanates.Mixture stirs 15min under r.t..Filter and separate the solid formed, Wash with 10ml dichloromethane.Then, by preparative HPLC pure solid, thus obtain 0.057g (productivity=25%) 3- (3-((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methyl) urea groups) essence of Niobe, White powder.LC-MS:m/z=493 (MH+)；UV purity=98% under 254nm.1H NMR (300MHz, DMSO) δ), 8.74 (d, J=6.7Hz, 1H), 8.11 (t, J=1.8Hz, 1H), 8.04 (s, 1H), 7.91 (d, J=7.8Hz, 1H), 7.70 (dd, J =13.0,8.5Hz, 2H), 7.58 (t, J=7.9Hz, 2H), 7.53-7.42 (m, 2H), 7.34 (t, J=7.9Hz, 1H), 7.15 (td, J=6.8,1.1Hz, 1H), 6.81 (t, J=5.7Hz, 1H), 4.64 (d, J=5.7Hz, 2H), 3.83 (s, 3H).
Embodiment 17: preparation derivant No.75:3-(3-((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1, 2-a] pyridine-2-base) methyl) urea groups) benzoic acid
By 0.038g (0.078mmol) 3-(3-((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazoles under magnetic agitation And [1,2-a] pyridine-2-base) methyl) urea groups) essence of Niobe is dissolved in 2ml methanol/tetrahydrofuran compound (1/1, v/v) In, it being subsequently adding 0.931ml (0.931mmol) (1M) NaOH aqueous solution, mixture stirs 16h under r.t., then uses 0.053ml (0.931mmol) acetic acid solution in 10ml water processes.Mixture stirs 30min under r.t..Filter and separate shape The solid become, washs with 5ml water, is dried, thus obtains 0.026g (productivity=70%) 3-(3-((3-((3-in vacuum bell jar (trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methyl) urea groups) benzoic acid, white solid.LC-MS: M/z=479 (MH+)；UV purity=99% under 254nm.1H NMR (300MHz, DMSO) δ 12.83 (s, 1H), 8.96 (s, 1H), 8.73 (d, J=6.7Hz, 1H), 8.04 (s, 2H), 7.90 (d, J=7.5Hz, 1H), 7.69 (dd, J=13.0,8.4Hz, 2H), 7.58 (d, J=7.7Hz, 2H), 7.45 (d, J=7.5Hz, 2H), 7.29 (t, J=7.9Hz, 1H), 7.13 (t, J= 6.8Hz, 1H), 6.80 (t, J=5.4Hz, 1H), 4.62 (d, J=5.6Hz, 2H).
Embodiment 18: preparation derivant No.76:2-((3-((4-fluorophenyl) acetenyl) imidazo [1,2-a] pyridine-2- Base) methoxyl group) essence of Niobe
Step 1: preparation 2-((3-iodine imidazo [1,2-a] pyridine-2-base) methoxyl group) essence of Niobe
By 4g (13.68mmol) 2-(chloromethyl)-3-iodine imidazo [1,2-a] pyridinium dissolution at dimethyl under magnetic agitation In Methanamide, it is subsequently adding 2.71ml (20.51mmol) 2 hydroxybenzoic acid methyl ester and 6.68g (20.51mmol) cesium carbonate.Mixed Compound stirs 2h at 60 DEG C, is subsequently poured in 200ml water.Aqueous phase extracts by 2 x 100ml ethyl acetate.Merge organic facies, With the NaHCO that 100ml is saturated3The NaCl solution washing that aqueous solution, 100ml are saturated, uses Na2SO4It is dried, is filtered to remove.Vacuum The filtrate being concentrated to give.Crude product grinds in 50ml Di Iso Propyl Ether, filters the solid of isolated.Isolate 2.55g mesh Mark product.On the other hand, filter to isolate suspension liquid of aqueous phase, with 2 x 30ml water washings.Being analyzed to identify, it is also that target is produced Thing.Therefore, collect two batches, obtain 5.58g (productivity=76%) 2-((3-iodine imidazo [1,2-a] pyridine-2-base) methoxyl group) Essence of Niobe, white powder.LC-MS:m/z=409 (MH+)；UV purity=98% under 254nm.1H NMR (300MHz, DMSO) δ 8.33 (d, J=6.9Hz, 1H), 7.69-7.44 (m, 3H), 7.45-7.28 (m, 2H), 7.16-6.93 (m, 2H), 5.23 (s, 2H), 3.73 (s, 3H).
Step 2: preparation 2-((3-((4-fluorophenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) benzene first Acid methyl ester (derivant No.76)
In being placed in the flask that argon flows down, by 2g (3.82mmol) 2-((3-iodine imidazo [1,2-a] under magnetic agitation Pyridine-2-base) methoxyl group) essence of Niobe is dissolved in 8ml dimethylformamide.Add in solution: 0.074g (0.382mmol) Copper diiodide, 0.551g (4.59mmol) 1-acetenyl-4-fluorobenzene and 8ml (57.3mmol) triethylamine.Reaction is situated between Matter argon-degassed 10min, is subsequently adding 0.35g (0.382mmol) Pd2(dba)3.Mixture stirs 16h under r.t., then Process with NaCl aqueous solution saturated for 100ml.Aqueous phase extracts by 2 x 100ml ethyl acetate.Merge organic facies, satisfy with 100ml The NaCl solution washing of sum, uses Na2SO4It is dried, is filtered to remove.The filtrate that obtains is concentrated in vacuo.Crude product is by silicagel column Purification by flash chromatography (eluant: heptane/ethyl acetate, 1/1, v/v).Obtain 1.36g (productivity=84%) 2-((3-((4-fluorine Phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) essence of Niobe, light tan solid.LC-MS:m/z= 401(MH+)；UV purity=98% under 254nm.1H NMR (300MHz, DMSO) δ 8.63 (d, J=6.7Hz, 1H), 7.75- 7.59 (m, 4H), 7.48 (ddd, J=15.9,11.5,4.8Hz, 2H), 7.40-7.26 (m, 3H), 7.13 (t, J=6.8Hz, 1H), 7.01 (t, J=7.4Hz, 1H), 5.40 (s, 2H), 3.68 (s, 3H).
Same sequence according to step 1 and 2 prepares derivant No.77～86:
Embodiment 19: preparation derivant No.87:3-((3-(phenylene-ethynylene) imidazo [1,2-a] pyridine-2-base) first Epoxide) essence of Niobe
Step 1: prepare imidazo [1,2-a] pyridine-2-Ethyl formate
Under magnetic agitation, 3g (31.9mmol) PA is dissolved in 65ml oxolane.Add 4.44ml (31.9mmol) ethyl bromide acetone, causes separating out solid.Impurity phase mixture return stirring 4h.After returning to r.t., filter Isolate solid, put in 65ml ethanol, return stirring 16h in 65ml ethanol.After returning to r.t., filter to isolate solid Body.Filtrate is placed on ice, thus promotes the crystallization of product, is collected by filtration, until liquid phase is transparent.Solid 30ml Di Iso Propyl Ether Rinse, be dried in vacuum bell jar, thus obtain 5.14g (productivity=84%) imidazo [1,2-a] pyridine-2-Ethyl formate, White powder.LC-MS:m/z=191 (MH+)；UV purity=99% under 254nm.1H NMR (300MHz, DMSO) δ 8.95 (s, 1H), 8.84 (d, J=6.8Hz, 1H), 7.98-7.80 (m, 2H), 7.46 (t, J=7.2Hz, 1H), 4.43 (q, J=7.1Hz, 2H), 1.35 (d, J=7.1Hz, 3H).
Step 2: preparation 3-iodine imidazo [1,2-a] pyridine-2-Ethyl formate
Under magnetic agitation, 2.405g (12.16mmol) imidazo [1,2-a] pyridine-2-Ethyl formate is dissolved in 60ml second In nitrile, in solution, add 3.01g (13.38mmol) N-iodosuccinimide.Mixture stirs 1h under r.t..Reaction is mixed Compound 50ml 100mg/ml Na2S2O5Aqueous solution processes.Aqueous phase extracts by 2 x 100ml ethyl acetate.Aqueous phase is by batches Add NaHCO3Neutralize, then with 3 x 100ml ethyl acetate extractions.Merge whole organic facies, then saturated with 200ml NaCl solution washing, then uses Na2SO4It is dried, is filtered to remove.The filtrate that obtains is concentrated in vacuo, thus obtains 1.59g (productivity =41%) 3-iodine imidazo [1,2-a] pyridine-2-Ethyl formate, light yellow solid.LC-MS:m/z=317 (MH+)；254nm Under UV purity=99%.1H NMR (300MHz, DMSO) δ 8.45 (d, J=6.9Hz, 1H), 7.66 (d, J=9.1Hz, 1H), 7.46 (d, J=7.0Hz, 1H), 7.15 (d, J=6.6Hz, 1H), 4.30 (d, J=7.1Hz, 2H), 1.36 (d, J=7.1Hz, 3H)。
Step 3: preparation 3-(phenylene-ethynylene) imidazo [1,2-a] pyridine-2-Ethyl formate
In being placed in the flask that argon flows down, by 1.82g (5.77mmol) 3-iodine imidazo [1,2-a] pyrrole under magnetic agitation Pyridine-2-Ethyl formate is dissolved in 6ml dimethylformamide.Add in solution: 0.11g (0.577mmol) Copper diiodide, 0.776ml (6.93mmol) phenylacetylene and 6ml (43mmol) triethylamine.Reaction medium argon-degassed 10min, is subsequently adding 0.529g(0.577mmol)Pd2(dba)3.Mixture stirs 16h under r.t., filters the most over celite.Kieselguhr is used 50ml ethyl acetate is washed, and then filtrate is washed with 2 x 50ml water.After separation, aqueous phase extracts by 2 x 50ml ethyl acetate； Merge organic facies, with NaCl solution washing saturated for 70ml, use Na2SO4It is dried, is filtered to remove.The filter that obtain is concentrated in vacuo Liquid.The crude product purification by flash chromatography (eluant: heptane/ethyl acetate, 6/4, v/v) by silicagel column.Obtain 1.28g (to produce Rate=57%) 3-(phenylene-ethynylene) imidazo [1,2-a] pyridine-2-Ethyl formate, light yellow solid.LC-MS:m/z=291 (MH+)；UV purity=93% under 254nm.1H NMR (300MHz, DMSO) δ 8.70 (d, J=6.8Hz, 1H), 7.74 (dd, J =22.1,6.2Hz, 3H), 7.53 (dd, J=17.6,6.9Hz, 4H), 7.23 (t, J=6.3Hz, 1H), 4.36 (d, J= 4.7Hz, 2H), 1.36 (d, J=7.1Hz, 3H).
Step 4: preparation (3-(phenylene-ethynylene) imidazo [1,2-a] pyridine-2-base) methanol
In being placed in the flask that argon flows down, 0.078g (1.984mmol) LAH is dissolved in 1.4ml oxolane, so 0.3g (0.992mmol) 3-(phenylene-ethynylene) imidazo [1,2-a] pyridine-2-Ethyl formate is dripped under the stirring of rear vigorous magnetic Solution in 3.3ml oxolane.Mixture stirs 15min under r.t., is then carefully added into 0.2ml water, is subsequently adding 0.2ml sulphuric acid solution in 1.5ml water.After separation, organic facies 50ml water washs.Aqueous phase extracts by 3 x 50ml ethyl acetate Take, be then combined with organic facies, with NaCl solution washing saturated for 100ml, then use Na2SO4It is dried, is filtered to remove.Vacuum is dense The filtrate that contracting obtains.Crude product by the purification by flash chromatography of silicagel column (eluant: heptane/ethyl acetate gradient, 40%～ The heptane of 30%, v/v).Obtain 0.076g (productivity=30%) (3-(phenylene-ethynylene) imidazo [1,2-a] pyridine-2-base) Methanol, light yellow solid.LC-MS:m/z=249 (MH+)；UV purity=97% under 254nm.1H NMR (300MHz, DMSO) δ 8.59 (dt, J=6.7,1.1Hz, 1H), 7.77-7.56 (m, 3H), 7.56-7.32 (m, 4H), 7.11 (td, J=6.8, 1.1Hz, 1H), 5.33 (t, J=5.9Hz, 1H), 4.67 (d, J=5.9Hz, 2H).
Step 5: preparation 3-((3-(phenylene-ethynylene) imidazo [1,2-a] pyridine-2-base) methoxyl group) essence of Niobe (derivant No.87)
Under magnetic agitation, 0.09g (0.594mmol) 3-methyl hydroxybenzoate is dissolved in 1ml oxolane, then Add 0.312g (1.188mmol) triphenylphosphine and 0.231ml (1.188mmol) DIAD.Mixture stirs under r.t. 15min, is subsequently adding 0.076g (0.297mmol) (3-(phenylene-ethynylene) imidazo [1.2-a] pyridine-2-base) methanol and exists Solution in 4ml oxolane, mixture stirs 16h under r.t..Add 0.09g (0.594mmol) 3-hydroxy benzoic acid first Ester, 0.312g (1.188mmol) triphenylphosphine are mixed with 0.231ml (1.188mmol) DIAD's being dissolved in 1ml oxolane Compound, reaction medium is stirred for 2h under r.t..Reaction medium 10ml water processes.Aqueous phase extracts by 3 x 10ml ethyl acetate Take, be then combined with organic facies, with NaCl solution washing saturated for 10ml, then use Na2SO4It is dried, is filtered to remove.It is concentrated in vacuo The filtrate obtained.Crude product purification by flash chromatography (eluant: heptane/ethyl acetate, 70%～40% heptan by silicagel column Alkane, v/v).Obtain 0.048g (productivity=42%) 3-((3-(phenylene-ethynylene) imidazo [1.2-a] pyridine-2-base) methoxy Base) essence of Niobe, light yellow solid.LC-MS:m/z=383 (MH+)；UV purity=99% under 254nm.1H NMR (300MHz.DMSO)δ8.64(d.J=6.8Hz.1H).7.68(dd.J=17.0.7.2Hz.4H).7.55(d.J=8.7Hz. 1H).7.52-7.34(m.6H).7.15(t.J=7.3Hz.1H).5.42(s.2H).3.80(s.3H).
Embodiment 20: preparation derivant No.88:2-((3-((4-fluorophenyl) acetenyl) imidazo [1.2-a] pyridine-2- Base) methoxyl group) benzoic acid
By 0.65g (1.542mmol) 2-((3-((4-fluorophenyl) acetenyl) imidazo [1,2-a] pyrrole under magnetic agitation Pyridine-2-base) methoxyl group) essence of Niobe is dissolved in the mixture (1/1, v/v) that 30ml is made up of ethanol and oxolane, so Rear addition 15.42ml (15.42mmol) 1N NaOH aqueous solution.Mixture stirs 16h under r.t., is subsequently adding 20ml water, so Rear addition 0.883ml (15.42mmol) acetic acid.Filter and separate the precipitation formed, wash with 10ml water, dry in vacuum bell jar Dry, thus obtain 0.518g (productivity=81%) 2-((3-((4-fluoro-phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) Methoxyl group) benzoic acid, light yellow solid.LC-MS:m/z=387 (MH+)；UV purity=99% under 254nm.1H NMR (300MHz, DMSO) δ 12.72 (s, 1H), 8.64 (d, J=5.5Hz, 1H), 7.78-7.59 (m, 4H), 7.45 (d, J= 6.2Hz, 2H), 7.41-7.24 (m, 3H), 7.14 (t, J=6.8Hz, 1H), 7.00 (t, J=7.3Hz, 1H), 5.42 (s, 2H).
Derivant No.89～93 is prepared according to same program:
Embodiment 21: preparation derivant No.94:(2-((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2- A] pyridine-2-base) methoxyl group) phenyl) methanol
In being placed in the flask that argon flows down, by 0.16g (0.352mmol) 2-((3-((3-(fluoroform under magnetic agitation Base)-phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) essence of Niobe is dissolved in 4ml oxolane, Mixture is cooled to 0 DEG C, is subsequently adding 0.148ml (0.492mmol) RED-Al.Mixture stirs 15min at 0 DEG C, then Use 15ml diluted ethyl acetate, pour in 20ml water.It is stirred vigorously down, is slowly added to 1ml NaOH aqueous solution (32 mass %). After separation, organic facies is washed with 2 x 10ml water.Aqueous phase extracts by 2 x 5ml ethyl acetate.Merge organic facies, saturated with 20ml NaCl solution washing, then use Na2SO4It is dried, is filtered to remove.The filtrate that obtains is concentrated in vacuo.Crude product is by 10ml Di Iso Propyl Ether grinds purification.Filter to isolate solid, vacuum drying.Obtain 0.091g (productivity=58%) (2-((3- ((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) phenyl) methanol, light tan solid. LC-MS:m/z=425 (M+2H+)；UV purity=94% under 254nm.1H NMR (300MHz, DMSO) δ 8.77 (d, J= 6.8Hz, 1H), 8.05 (s, 1H), 7.92 (d, J=7.6Hz, 1H), 7.73 (dt, J=14.3,7.8Hz, 3H), 7.55-7.43 (m, 1H), 7.38 (d, J=7.4Hz, 1H), 7.20 (d, J=3.6Hz, 3H), 7.03-6.86 (m, 1H), 5.39 (s, 2H), 4.98 (t, J=5.7Hz, 1H), 4.55 (d, J=5.6Hz, 2H).
Embodiment 22: preparation derivant No.95:N-(2-(dimethylamino) ethyl)-2-((3-((4-fluorophenyl) acetylene Base) imidazo [1,2-a] pyridine-2-base) methoxyl group) Benzoylamide
Step 1: preparation 2-((3-((4-fluorophenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) benzene first Acyl chlorides
Under magnetic agitation by 0.6g (1.553mmol) 2-((3-((4-fluorophenyl) acetenyl) imidazo [1,2-a] pyridine- 2-yl) methoxyl group) benzoic acid is suspended in 20ml dichloromethane, and mixture is placed in the bath of 0 DEG C, then drips 0.408ml (4.66mmol) oxalyl chloride, finally, adds several dimethylformamides.Removing cryostat, then mixture stirs 2h under r.t.. Reaction medium is concentrated in vacuo, is used in immediately in next step.
Step 2: preparation N-(2-(dimethylamino) ethyl)-2-((3-((4-fluorophenyl) acetenyl) imidazo [1,2- A] pyridine-2-base) methoxyl group) Benzoylamide (derivant No.95)
Under magnetic agitation, 0.896ml (7.76mmol) N, N-dimethyl ethane-1,2-diamidogen is dissolved in 8ml dichloromethane In, add 0.449g (0.776mmol) 2-((3-((4-fluorophenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxy Base) Benzenecarbonyl chloride., mixture stirs 16h under r.t., is then concentrated in vacuo.Crude product is by grinding in 20ml Di Iso Propyl Ether Mill purification.Filter to isolate solid, wash with 10ml water, vacuum drying.Obtain 0.178g (productivity=50%) N-(2-(diformazan Base amino) ethyl)-2-((3-((4-fluorophenyl) acetenyl) imidazo [1,2-a]-pyridine-2-base) methoxyl group) Benzoylamide, Light yellow solid.LC-MS:m/z=457 (MH+)；UV purity=98% under 254nm.1H NMR (300MHz, DMSO) δ 8.68 (d, J=6.7Hz, 1H), 8.47 (d, J=4.8Hz, 1H), 7.91 (dd, J=7.7,1.5Hz, 1H), 7.72 (dd, J=8.6, 5.2Hz, 3H), 7.57-7.39 (m, 3H), 7.32 (t, J=8.9Hz, 2H), 7.17 (t, J=6.6Hz, 1H), 7.09 (t, J= 7.3Hz, 1H), 5.51 (s, 2H), 2,5 (1H hides under solvent peak), 2.25 (t, J=6.5Hz, 2H), 1.92 (s, 6H).
Derivant No.96 is prepared according to same program:
Embodiment 23: preparation derivant No.97:N-(3-((3-(phenylene-ethynylene) imidazo [1,2-a] pyridine-2-base) Methoxyl group) phenyl) amsacrine
Step 1: preparation 2-(chloromethyl)-3-(phenylene-ethynylene) imidazo [1,2-a] pyridine
By 0.238g (0.949mmol) (3-(phenyl-ethynyl) imidazo [1,2-a] pyridine-2-base) under magnetic agitation Methanol is dissolved in 5ml dichloromethane, is subsequently adding 0.346ml (4.75mmol) thionyl chloride.Mixture stirs under r.t. 2h, is then concentrated in vacuo.Product puts into 20ml by ethyl acetate and saturated NaHCO3The mixture (1/1, v/ of aqueous solution composition V) in.After separation, aqueous phase 10ml ethyl acetate extracts.Merge organic facies, with NaCl solution washing saturated for 10ml, then Use Na2SO4It is dried, is filtered to remove.The filtrate that obtains is concentrated in vacuo.Obtain 0.246g (productivity=96%) 2-(chloromethyl)-3- (phenylene-ethynylene) imidazo [1,2-a] pyridine, brown solid.LC-MS:m/z=267 (MH+)；UV purity under 254nm= 98%.
Step 2: preparation N-(3-hydroxy phenyl) amsacrine
Being dissolved in 6ml pyridine by 2g (18.33mmol) 3-amino-phenol under magnetic agitation, mixture is cooled to 10 DEG C, It is subsequently adding 1.8ml (23.26mmol) methane sulfonyl chloride.Removing cryostat, mixture stirs 18h under r.t., then uses 100ml Saturated NaCl aqueous solution dilution.Aqueous phase 100ml ethyl acetate extracts.The NaHCO that organic facies 50ml is saturated3Aqueous solution is washed Wash, with 50ml NaOH (0.5N) aqueous solution extraction.Alkalescence aqueous phase washs by 2 x 100ml ethyl acetate, then by adding 1N HCl/water solution is acidified to pH 2-3.The aqueous phase of acidifying extracts by 2 x 100ml ethyl acetate.Merge organic facies, satisfy with 100ml The NaCl solution washing of sum, then uses Na2SO4It is dried, is filtered to remove.The filtrate that obtains is concentrated in vacuo.Obtain 3.3g (productivity =80%) N-(3-hydroxy phenyl) amsacrine, oil.LC-MS:m/z=186 (M-H+)；UV purity under 254nm= 81%.
Step 3: preparation N-(3-((3-(phenylene-ethynylene) imidazo [1,2-a] pyridine-2-base) methoxyl group) phenyl) first Alkyl sulfonamide (derivant No.97)
By 0.094g (0.352mmol) 2-(chloromethyl)-3-(phenylene-ethynylene) imidazo [1,2-a] pyrrole under magnetic agitation Pyridine is dissolved in 2ml dimethylformamide, add 121mg (0.529mmol) N-(3-hydroxy phenyl) amsacrine and 0.172g (0.529mmol) cesium carbonate.Mixture stirs 3h at 60 DEG C, is then poured on NaCl aqueous solution saturated for 15ml. Aqueous phase extracts by 2 x 20ml ethyl acetate.Merge organic facies, use Na2SO4It is dried, is filtered to remove.The filter that obtain is concentrated in vacuo Liquid.Crude product passes through preparative HPLC purification, obtains 0.028g (productivity=18%) N-(3-((3-(phenylene-ethynylene) imidazo [1,2-a] pyridine-2-base)-methoxyl group) phenyl) amsacrine, white solid.LC-MS:m/z=418 (MH+)；Under 254nm UV purity=95%.1H NMR (300MHz, DMSO) δ 9.53 (s, 1H), 8.55 (d, J=6.8Hz, 1H), 7.76-7.57 (m, 3H), 7.54-7.33 (m, 4H), 7.17-7.02 (m, 2H), 6.89 (dd, J=8.0,1.1Hz, 1H), 6.79 (t, J= 2.1Hz, 1H), 6.69-6.54 (m, 1H), 5.07 (s, 2H), 3.14 (s, 3H).
Embodiment 24: preparation derivant No.111:2-((the chloro-3-of 6-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methyl mercapto) ethyl acetate
Step 1: preparation 2-((6-chlorine imidazo [1,2-a] pyridine-2-base) methyl mercapto) ethyl acetate
By 20g (99mmol) 6-chloro-2-(chloromethyl) imidazo [1,2-a] pyridine, 0.746g (4.97mmol) sodium iodide Put in 500ml acetonitrile with 64.8g (199mmol) cesium carbonate.Solution stirs 3h under room temperature (r.t.).Filter the salt separated out, Vacuum evaporating solvent.The brown solid obtained is dissolved in 300ml ethyl acetate, with 3 x 100ml water washings, at silicon oxide cake Upper direct purification, uses ethyl acetate eluting.Obtain 28.74g (productivity=100%) 2-((6-chlorine imidazo [1,2-a] pyridine-2- Base) methyl mercapto) ethyl acetate, orange solids.LC-MS:m/z=285 (MH+), UV purity=99% under 254nm.1H NMR (300MHz, DMSO) δ 8.79 (dd, J=2.1,0.8Hz, 1H), 7.82 (s, 1H), 7.52 (d, J=9.6Hz, 1H), 7.25 (dd, J=9.6,2.1Hz, 1H), 4.06 (q, J=7.1Hz, 2H), 3.90 (s, 2H), 3.36 (s, 2H), 1.16 (t, J= 7.1Hz, 3H).
Step 2: preparation 3-iodo-2-(iodomethyl) imidazo [1,2-a] pyridine
24.5g (86mmol) 2-((6-chlorine imidazo [1,2-a] pyridine-2-base) methyl mercapto) ethyl acetate is added to In 400ml acetonitrile, it is subsequently adding 20.32g (90mmol) N-iodosuccinimide.Solvent stirs 1h under r.t..Vacuum is steamed Sending out solvent, the product obtained is stirred vigorously in 250ml water and 200ml Di Iso Propyl Ether.Filter the solid separated out, use 2 x 30ml water and the washing of 2 x 30ml Di Iso Propyl Ethers.Obtain 33.93g (productivity=88%) 3-iodo-2-(iodomethyl) imidazo [1, 2-a] pyridine, brown solid.LC-MS:m/z=411 (MH+), UV purity=91.3% under 254nm.1H NMR 300MHz, DMSO) δ 8.40 (dd, J=1.9,0.7Hz, 1H), 7.61 (dd, J=9.5,0.6Hz, 1H), 7.38 (dd, J=9.5,2.0Hz, 1H), 4.07 (q, J=7.1Hz, 2H), 3.92 (s, 2H), 3.39 (s, 2H), 1.18 (t, J=7.1Hz, 3H).
Step 3: preparation 2-((the chloro-3-of 6-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2- Base) methyl mercapto) ethyl acetate
In argon gas atmosphere, by 27g (59.8mmol) 2-((6-chloro-3-iodine imidazo [1,2-a]-pyridine-2-base) first sulfur Base) ethyl acetate, 9.51ml (65.8mmol) 1-acetenyl-3-(trifluoromethyl) benzene, 1.139g (5.98mmol) Copper diiodide and 125ml (897mmol) triethylamine puts in 100ml DMF.Argon bubbling 10min in the solution, is subsequently adding 2.74g (2.99mmol)Pd2(dba)3.Mixture stirs 1h under r.t..Filtering catalyst on fan-fold paper, solution is poured on 300ml water In, with 2 x 200ml ethyl acetate extractions, collect organic facies, with 3 x 150ml water washings, washed once with 150ml saline, Use Na2SO4It is dried, is filtered to remove, the filtrate that obtains is concentrated in vacuo.Product is purification on silicon oxide cake, by heptane/ethyl acetate Mixture eluting.Obtain 23.21g (productivity=85%) 2-((the chloro-3-of 6-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methyl mercapto) ethyl acetate, yellow solid.LC-MS:m/z=453 (MH+), the UV purity under 254nm =99%.1H NMR (300MHz, DMSO) δ 8.91 (dd, J=1.9,0.6Hz, 1H), 8.14 (s, 1H), 8.01 (d, J= 7.6Hz, 1H), 7.71 (ddd, J=14.3,9.4,4.3Hz, 3H), 7.47 (dd, J=9.5,2.0Hz, 1H), 4.18-3.93 (m, 4H), 3.46 (s, 2H), 1.11 (t, J=7.1Hz, 3H).
Derivant 108～110 and 112～114 is prepared according to same program:
Embodiment 25: preparation derivant No.118:2-((the chloro-3-of 6-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methyl mercapto) acetic acid
By 16g (35.3mmol) 2-((the chloro-3-of 6-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyrrole Pyridine-2-base) methyl mercapto) ethyl acetate is added in 75ml ethanol and 75ml oxolane, is subsequently adding 4.24ml (42.4mmol) 32% sodium hydrate aqueous solution.Mixture stirs 2h under r.t., then after the solid separated out dissolves 30min, adds 50ml Water.Vacuum evaporating solvent, the product obtained dilutes in 250ml water and 50ml Di Iso Propyl Ether, and then solution is by adding 2.53ml (44.2mmol) acetic acid becomes acid pH.Filter the solid separated out, then with water and Di Iso Propyl Ether washing.Obtain 12.45g (productivity=83%) 2-((the chloro-3-of 6-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2- Base) methyl mercapto) acetic acid, yellow solid.LC-MS:m/z=425 (MH+), UV purity=99% under 254nm.1H NMR (300MHz, DMSO) δ 12.65 (s, 1H), 8.96 (s, 1H), 8.19 (s, 1H), 8.03 (d, J=7.6Hz, 1H), 7.84-7.63 (m, 3H), 7.50 (dd, J=9.5,1.8Hz, 1H), 4.07 (s, 2H), 3.40 (s, 2H).
Derivant 115～117,119 and 120 is prepared according to same program:
Embodiment 26: preparation derivant No.121:2-((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2- A] pyridine-2-base) methyl sulphonyl) ethyl acetate
By 40mg (0.096mmol) 2-((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a]-pyridine- 2-yl) methyl mercapto) acetic acid ethyl dissolution in 1ml acetone, be subsequently adding 8.03mg (0.096mmol) sodium bicarbonate.Solution is cold But to 0 DEG C, it is subsequently adding 118mg (0.096mmol) potassium hydrogen persulfate solution in 1ml water.Mixture stirs under r.t. 4h.Solution 5ml water washs, the solid being filtrated to get, and washs with 5ml water and 2ml Di Iso Propyl Ether.Obtain 29mg (productivity= 64%) 2-((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methyl sulphonyl) acetic acid second Ester, light yellow solid.LC-MS:m/z=451 (MH+), UV purity=94.6% under 254nm.1H NMR (300MHz, DMSO) δ 8.80 (d, J=6.8Hz, 1H), 8.17 (s, 1H), 8.03 (d, J=7.6Hz, 1H), 7.76 (dt, J=13.6,7.8Hz, 3H), 7.62-7.45 (m, 1H), 7.21 (t, J=6.6Hz, 1H), 4.98 (s, 2H), 4.62 (s, 2H), 4.19 (dd, J=14.1, 7.0Hz, 2H), 1.21 (t, J=7.1Hz, 3H).
Derivant 122 is prepared according to same program:
Embodiment 27: preparation derivant No.123:2-((the chloro-3-of 6-((3-(trifluoromethoxy) phenyl) acetenyl) imidazoles And [1,2-a] pyridine-2-base) methyl sulphonyl) acetic acid
By 100mg (0.200mmol) 2-((the chloro-3-of 6-((3-(trifluoromethoxy) phenyl)-acetenyl) imidazo [1,2- A] pyridine-2-base) methyl sulphonyl) and acetic acid ethyl dissolution in 2ml ethanol, be subsequently adding 0.060ml (0.599mmol) 32% Sodium hydrate aqueous solution.Mixture stirs 16h under r.t..Solution is poured in 10ml water, is acidified with acetic acid to acid pH, with 2 X 5ml dichloromethane extracts, and merges organic facies, uses Na2SO4It is dried, is filtered to remove, the filtrate that obtains is concentrated in vacuo.Obtain 76mg (productivity=80%) 2-((the chloro-3-of 6-((3-(trifluoromethoxy) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) first Base sulfonyl) acetic acid, yellow solid.LC-MS:m/z=473 (MH+), UV purity=99% under 254nm.1H NMR (300MHz, DMSO) δ 14.72-12.20 (m, 1H), 9.00 (d, J=1.2Hz, 1H), 7.88-7.76 (m, 3H), 7.62-7.45 (m, 3H), 4.96 (s, 2H), 4.42 (s, 2H).
Embodiment 28: preparation derivant No.124:N-(pyridin-3-yl)-2-((3-((3-(trifluoromethyl) phenyl) acetylene Base) imidazo [1,2-a] pyridine-2-base) methyl mercapto) acetamide
By 141mg (0.358mmol) 2-((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a]-pyridine- 2-yl) methyl mercapto) acetic acid in 5ml dichloromethane, be subsequently adding 0.094ml (1.073mmol) oxalyl chloride and 1 DMF. Solvent stirs 2h, then vacuum evaporating solvent under r.t..The product obtained puts in 5ml oxolane, adds 99mg (0.715mmol) sodium carbonate, is subsequently adding 40.4mg (0.429mmol) 3-aminopyridine.Solution stirs 16h under r.t..So After, mixture is poured in 15ml water, extracts 3 times by 15ml ethyl acetate, merges organic facies, washs with 20ml saline, then uses Na2SO4It is dried, is filtered to remove, the filtrate that obtains is concentrated in vacuo.Crude product by the purification by flash chromatography of silicagel column (eluant: Methylene chloride/methanol gradient, the dichloromethane of 100%～90%, v/v).Obtain 89mg N-(pyridin-3-yl)-2-((3- ((3-(trifluoromethyl)-phenyl)-acetenyl) imidazo [1,2-a] pyridine-2-base) methyl mercapto) acetamide, light yellow solid. LC-MS:m/z=467 (MH+), UV purity=95% under 254nm.1H NMR (300MHz, DMSO) δ 10.13 (s, 1H), 8.76 (dd, J=16.4,4.5Hz, 2H), 8.24 (dd, J=4.7,1.5Hz, 1H), 8.07 (ddd, J=8.3,2.5,1.5Hz, 1H), 7.79-7.60 (m, 3H), 7.60-7.35 (m, 3H), 7.30 (dd, J=8.3,4.7Hz, 1H), 7.16 (td, J=6.8, 1.1Hz, 1H), 4.90 (s, 2H), 4.26 (s, 2H).
Derivant 125～128 is prepared according to same program:
Embodiment 29: preparation derivant No.129:4-hydroxyl-3,3-dimethyl-2-((3-((3-(trifluoromethyl) phenyl) Acetenyl) imidazo [1,2-a] pyridine-2-base) methyl mercapto) butanoic acid
By 130mg (0.303mmol) 4,4-dimethyl-3-((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methyl mercapto) dihydrofuran-2 (3H)-one is dissolved in 2ml methanol and 2ml oxolane, then adds Enter 0.334ml (0.334mmol) 1N sodium hydrate aqueous solution.Solution stirring 16h.It is acidified with acetic acid to acid pH, dilute with water, Until separating out solid, then filtering, washing with water.Obtain 115mg 4-hydroxyl-3,3-dimethyl-2-((3-((3-(fluoroform Base) phenyl)-acetenyl) imidazo [1,2-a] pyridine-2-base) methyl mercapto) butanoic acid, light tan solid.LC-MS:m/z=447 (MH+), UV purity=99% under 254nm.1H NMR (300MHz, DMSO) δ 12.69 (s, 1H), 8.77 (d, J=6.7Hz, 1H), 8.11 (s, 1H), 7.97 (d, J=7.5Hz, 1H), 7.79 (d, J=7.7Hz, 1H), 7.70 (t, J=8.2Hz, 2H), 7.54-7.41 (m, 1H), 7.16 (t, J=6.6Hz, 1H), 4.81 (d, J=12.3Hz, 1H), 4.70 (sl, 1H), 4.58 (d, J =12.3Hz, 1H), 3.92 (s, 1H), 3.40 (s, 1H), 3.10 (d, J=10.4Hz, 1H), 0.86 (s, 3H), 0.82 (s, 3H)。
Embodiment 30: preparation derivant No.130:2-((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2- A] pyridine-2-base) methyl mercapto) ethanol
In argon gas atmosphere, by 200mg (0.446mmol) 2-((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methyl mercapto) acetic acid ethyl dissolution in 4ml oxolane, add 33.9mg (0.892mmol) LiAlH4.Solution is heated to 50 DEG C and keeps 1h.It is slowly added to 0.030ml water, is subsequently adding 0.030ml 6N sodium hydroxide, then Add 0.1ml water.After stirring 30min, filter precipitation, wash by ethyl acetate.Collect organic facies, wash with saline, then use Na2SO4It is dried, is filtered to remove, the filtrate that obtains is concentrated in vacuo.In ethyl acetate, grind the solid obtained, filter, then use Ethyl acetate is washed.Obtain 50mg (productivity=28%) 2-((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2- A] pyridine-2-base)-methyl mercapto) ethanol, white solid.LC-MS:m/z=407 (MH+), UV purity=89% under 254nm.1H NMR (300MHz, DMSO) δ 8.30 (d, 1H), 8.12 (s, 1H), 7.99 (m, 1H), 7.75 (m, 2H), 7.03 (m, 1H), 6.88 (d, 1H), 4.84 (t, 1H), 3.96 (s, 5H), 3.60 (m, 2H), 2.67 (t, 2H).
Derivant 131 is prepared according to same program:
Embodiment 31: preparation derivant No.132:N-(N-(tert-butoxycarbonyl) amidino groups)-2-((3-((4-fluorophenyl) Acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) acetamide
By 200mg 2-((3-((4-fluorophenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) acetic acid, 200mg (0.617mmol) PyBOP and 118mg (0.740mmol) guanidine-Boc puts in 2ml DMF.Then, 0.258ml is poured into (1.850mmol) triethylamine, 4h is stirred in reaction under r.t..Pour the mixture under stirring in 10ml water and 5ml heptane.Filter The solid obtained, then by 2ml water and 1ml heptane wash.Obtain 220mg (productivity=77%) N-(N-(tert-butoxycarbonyl) Amidino groups)-2-((3-((4-fluorophenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) acetamide, gray solid. LC-MS:m/z=466 (MH+), UV purity=99% under 254nm.1H NMR (300MHz, DMSO) δ 11.10 (s, 1H), 8.71 (t, J=37.0Hz, 3H), 7.86-7.62 (m, 3H), 7.51-7.37 (m, 1H), 7.30 (t, J=8.9Hz, 2H), 7.13 (dd, J=6.7,6.0Hz, 1H), 4.81 (s, 2H), 4.18 (s, 2H), 1.38 (s, 9H).
Derivant 133 is prepared according to same program:
Embodiment 32: preparation derivant No.134:N-amidino groups-2-((3-((4-fluorophenyl) acetenyl) imidazo [1,2- A] pyridine-2-base)-methoxyl group) acetamide hydrochloride
By 190mg (0.408mmol) N-(N-(tert-butoxycarbonyl) amidino groups)-2-((3-((4-fluorophenyl) acetenyl) miaow Azoles also [1,2-a] pyridine-2-base) methoxyl group) acetamide is dissolved in 2ml ethanol, is subsequently adding 1.020ml (4.08mmol) 4N The dioxane solution of hydrochloric acid.Solution is heated to 60 DEG C and keeps 2h.Vacuum evaporating solvent.After cooling, the solid of filtering for crystallizing, use second Alcohol washs.Obtain 85mg (productivity=52%) N-amidino groups-2-((3-((4-fluorophenyl) acetenyl) imidazo [1,2-a] pyridine- 2-yl) methoxyl group) acetamide hydrochloride, yellow solid.LC-MS:m/z=366 (MH+), UV purity=99% under 254nm.1H NMR (300MHz, DMSO) δ 11.36 (s, 1H), 8.86 (d, J=6.7Hz, 1H), 8.55 (d, J=28.4Hz, 4H), 7.92- 7.71 (m, 4H), 7.44-7.31 (m, 3H), 4.99 (s, 2H), 4.40 (s, 2H).
Derivant 135 is prepared according to same program:
Embodiment 33: preparation derivant No.138:2-((pyridine-2-base sulfenyl) methyl)-3-((3-(trifluoromethyl) benzene Base) acetenyl) imidazo [1,2-a] pyridine
By 150mg (0.421mmol) 2-(chloromethyl)-3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2- A] pyridinium dissolution in 5ml acetonitrile, be subsequently adding 96mg (0.842mmol) pyridine-2-mercaptan and 274mg (0.842mmol) carbon Acid caesium.Solvent stirs 2h 30min under r.t..Then, mixture is poured in 40ml water, then extracts 3 by 15ml ethyl acetate Secondary.Collect organic facies, with sodium bicarbonate solution saturated for 30ml, the washing of 30ml saline, then use Na2SO4It is dried, is filtered to remove, The filtrate that obtains is concentrated in vacuo.Crude product by the purification by flash chromatography of silicagel column (eluant: heptane/ethyl acetate gradient, The heptane of 80%～70%, v/v).Obtain 129mg (productivity=74%) 2-((pyridine-2-base sulfenyl) methyl)-3-((3-(three Methyl fluoride) phenyl) acetenyl) imidazo [1,2-a] pyridine, brown solid.LC-MS:m/z=410 (MH+), the UV under 254nm Purity=99%.1H NMR (300MHz, DMSO) δ 8.70 (d, J=6.7Hz, 1H), 8.52-8.37 (m, 1H), 8.02 (s, 1H), 7.91 (d, J=7.6Hz, 1H), 7.71 (dd, J=41.7,4.5Hz, 4H), 7.43 (s, 2H), 7.13 (d, J=1.1Hz, 2H), 4.73 (s, 2H).
Derivant 136 and 137 is prepared according to same program:
The stimulation test of the insulin secretion of INS-1 cell
INS-1 β-pancreas system is carried out the test of different compound, strengthens the insulin in response to glucose with evaluation and divide The ability secreted.Briefly, cultivating cell in the medium, RPMI 1640, containing 1mM Sodium Pyruvate, 50 μMs of 2-sulfydryl second The hyclone of alcohol, 2mM glutamine, 10mM HEPES, 100IU/mL penicillin, 100 μ g/mL streptomycins and 10% inactivation 10mM glucose, as by [9] described in Asfari et al..Insulin secretion is tested, 96 orifice plates are inoculated INS-1 cell And cultivate.At moist atmosphere (95% air/5%CO2), cultivate 3 days at 37 DEG C after, remove culture medium, and cell contained Have in the culture medium of 5mM glucose and 1% hyclone inactivated and hatch 16h.On the same day of test, cell is with containing 0.1% Krebs buffer (pH 7.4) washing of bovine serum albumin, then 37 in the same buffer containing 2.8mM glucose Preincubate 30min at DEG C.Finally, cell uses Krebs buffer solution again, then secretion test buffer (Krebs, PH 7.4, containing 0.1% bovine serum albumin and 3.5mM glucose and molecule to be evaluated) in hatch 1h.At the end of test, Reclaim cell supernatant, with ELISA kit (the ELISA Alpco Cat no.80-by utilizing rat anti-insulin antibody INSRTH-E10) insulin of secretion is measured.Each condition is tested in triplicate.3.5mM glucose, 10-7M GLP-1 and Forskoline 10-7/IBMX 10-5M mixture is used as the positive control of test.For given glucose dose, if the factor More than or equal to the 130% of comparison, then compound stimulates the secretion of insulin.
Therefore, the insulin secretion in response to glucose strengthening INS-1 β pancreatic cell is had by the test derivant of Formulas I There is remarkable result.These values activate, regardless of relevant dose between more than 450% 131%.
Study the effect that the liver to glucose produces
Equipment and method:
From the Wistar rat liver isolating hepatocytes of fasting 24h after portal vein perfusion collagenase.Fresh separated Hepatocyte is seeded in and scribbles collagen protein and containing in 6 orifice plates of adhesive culture base (Williams Medium).After bonding, Culture medium is replaced with RPMI 1640 culture medium without any glucose, containing hydrocortisone (7.10-5M), persistent period 16 ～18h.Second day, Krebs culture medium carries out glucose liver production test 3h.Basic condition is only to cultivate with Krebs Cell, incentive condition is placed in the cell in Krebs+ lactate+pyruvate, is that working condition is exposed at Krebs+ lactic acid The cell of the chemical compound in salt+acetone acid culture medium.In the case of when compound dissolution in DMSO, 0.1% The all conditions of test is met in the presence of the ultimate density of DMSO.The positive control of test is known via phosphoenolpyruvate The carboxylic kinases mercaptopyridine formic acid esters to the inhibitory action that glucose liver produces.Short-term is processed, compound incubation 3h.For Long-term disposal, when culture hepatocyte, then addition during the 3h of liver production test in RPMI when, compound incubation 20h.At the end of the hatching of 3h, reclaim supernatant, to use the colorimetric method for determining glucose utilizing glucoseoxidase.Will be thin Born of the same parents use 0.1%NaOH aqueous dissolution, to utilize Lowry method to measure the amount of albumen.Result is with mmol glucose/mg albumen table Show.If the factor is less than or equal to the 75% of comparison, then the liver of compound suppression glucose produces.
3h is hatched
The test derivant of Formulas I has remarkable result for the liver production of suppression glucose.The derivant 7 of two dosage, 78,87,92,93,110 and 117 obtain the strongest suppression, the derivant of 100 μMs of dosage 29,51,59,76,77,81,88,89, 90,111,112 and 115 the strongest suppression is obtained.
20h is hatched
Therefore, the test derivant of Formulas I has remarkable result for the liver production of suppression glucose.The dosage of derivant 58 Obtain the strongest suppression.
Study the compound effect to the secretion in response to glucose in perfusion pancreas separated at N0STZ diabetes rat Really
Equipment and method:
From by birth sky injection streptozotocin and suffer from diabetes [10] and with pentobarbital (: 45mg/kg；Intraperitoneal routes) rat anaesthetized obtains pancreas.These rats have the specific shortage [11] in response to glucose, As observed in human type II diabetes.The program that the separation of pancreas and perfusion describe according to Sussman et al. [13] Deformation [12] realizes.The effect of compound or reference material is carried out 35min test (from t=in Krebs buffer 20min to t=55min), then in the presence of glucose 16.5mM, carry out 20min test (from t=55min to t= 75min).Measured by enzyme-linked immunosorbent assay (ELISA Alpco Cat no.80-INSRTH-E10) and be secreted into culture medium In the concentration of insulin.Result is expressed as mean+/-SEM (standard error of mean) many experiments.
Result table:
N0STZ diabetes rat separate through perfusion pancreas in, the test derivant of Formulas I for recover in response to Fructus Vitis viniferae The insulin secretion of sugar has remarkable result.
Research anti-diabetic activity in GK (Goto-Kakisaki) rat
The anti-diabetic activity of compound 118 is evaluated in GK rat (the non-obese model of type ii diabetes).Pass through base This model [14] is obtained in the cross breeding slightly not tolerating the Wistar rat that glucose is selected.These rats have the mankind Type ii diabetes in most of dysfunctions [15] of observing: hyperglycemia, do not tolerate glucose, insulin resistance and sound Should be in the insulin of glucose deterioration.These animal feedings are in Metabrain and are positioned in Animal Shelter facility, scalable Temperature (22 ± 2 DEG C), constant humidity (50 ± 20%), 12h day/night cycle (light of 7h-19h), and ad lib and drinking-water. Residence and experiment condition meet the health about laboratory animal and Europe instruction (ETS123) of morals agreement.Study at this In, rat used is the female 16 week old GK rats of fasting 2h (postabsorptive state) before beginning one's study.To 2 groups of rat prisons Survey blood glucose: one group processes with the compound 118 of oral single dose 50mg/kg, and matched group oral carrier processes.Just giving T0 before compound 118 or carrier and T1h, T2h, T4h and the T6h after giving gathers blood sample.By from blood glucose Bleed and realize the determination of blood glucose in the 1 of the tail bleeds taken that instrument Accu-Check Performa measures.For processing with compound 118 Group, the result being illustrated below is expressed as the blood glucose of T1h, T2h, T4h and T6h reduction percentage ratio compared with matched group.
These results indicate that the compound 118 giving single dose 50mg/kg can reduce the height of type ii diabetes rat Blood glucose.
Document
[1]WO 2010089292；
[2]WO 2010070008；
[3]WO 2010034500；
[4]EP 2168965；
[5]WO 2009080291；
[6]WO 2009023179；
[7] Helvetica Chimica Acta (2007), 90 (12), 2349-2367；
[8] Letters in Organic Chemistry (2005), 2 (2), 184-187；
[9] Asfari et al., Endocrinology 130:167-178,1992；
[10] Portha et al., Diabetes, 23, (1974), 889-895；
[11] Giroix et al., Diabetes, 32, (1983), 445-451
[12] Assan et al., Nature, 239, (1972), 125-126；
[13] Sussman et al., Diabetes, 15, (1966), 466-472；
[14] Goto et al., Proc.Jpn.Acad.51,80-85,1975；
[15] Portha et al., Mol.Cell.Endocrinol., 297:73-85,2009.

Claims (12)

1. the imidazopyridine derivatives of below general formula I:
Wherein:
Y represents oxygen or sulphur atom, group SO, SO2Or-NR19, wherein R19Represent hydrogen atom or C1-C6Alkyl；
R1, Ra, RbAnd RcRepresent hydrogen atom independently of one another；Halogen atom；With the optionally substituted C of-OH group1-C6Alkyl；-OH Group；-O(C1-C6Alkyl)；-O(C1-C6Alkyl) O (C1-C6Alkyl)；-CN group；-NR4R5Group, wherein R4And R5The most only On the spot represent hydrogen atom or C1-C6Alkyl；Or-(C1-C6Alkyl) NR6R7Group, wherein R6And R7Represent hydrogen atom independently of one another Or C1-C6Alkyl；
R2Represent
-hydrogen atom；
-use the substituted C of-OH group1-C6Alkyl；
-(C1-C6Alkyl) COOR8Group, wherein R8Represent hydrogen atom or C1-C6Alkyl, described alkyl can use-NH2Or-OH base Group replaces；
-(C1-C6Alkyl) CONHR9Group, wherein R9Represent-OH group；C1-C6Alkyl；-O(C1-C6Alkyl)；Phenyl；Pyridine Base；-(C=NH) NHCOO (C1-C6Alkyl)；-(C=NH) NH2Group or-(C1-C6Alkyl) NR10R11Group, wherein R10And R11 Represent C independently of one another1-C6Alkyl；
-(C1-C6Alkyl) CO morpholine group；
-C (=O) R12Group, wherein R12Represent-O (C1-C6Alkyl)；With the optionally substituted C of-OH group1-C6Alkyl；Morpholine Group；NH-phenyl, wherein said phenyl-COOH or-COO (C1-C6Alkyl) optionally replace；Or-NR13R14Group, its Middle R13And R14Represent C independently of one another1-C6Alkyl；
-(C1-C6Alkyl) phenyl, wherein said phenyl-CN, COOH or-COO (C1-C6Alkyl) optionally replace；
-(C1-C6Alkyl) thienyl；
-phenyl, wherein said phenyl optionally replaces with selected from following one or more groups :-COOH ,-COO (C1-C6Alkane Base), with the substituted C of-OH1-C6Alkyl ,-CN ,-CONHOH ,-NHSO2(C1-C6Alkyl) or-CONH-(C1-C6Alkyl) NR15R16, Wherein R15And R16Represent C independently of one another1-C6Alkyl；
-pyridine radicals；
-can optionally comprise the heterocyclic group of degree of unsaturation；
The lactone groups of-3～6 yuan, uses one or more C1-C6Alkyl is optionally substituted；
-or-SO2(C1-C6Alkyl)；
R3Represent phenyl, or pyridine radicals or thienyl, wherein said phenyl optionally takes with selected from following one or more groups Generation :-C1-C6Alkyl, wherein said alkyl optionally replaces with one or more halogen atoms, or replaces with-CN；Halogen atom ,-O (C1-C6Alkyl), wherein said alkyl optionally replaces with one or more halogen atoms；-CN；-OH；-NO2；-COOH； NR17R18, wherein R17And R18Represent C independently of one another1-C6Alkyl；Or-NHCO-(C1-C6Alkyl)；
Or its enantiomer, diastereomer, tautomer, racemic mixture or pharmaceutically acceptable salt.
Imidazopyridine derivatives the most according to claim 1, it is characterised in that Y represent oxygen or sulphur atom or-NH or- NMe group.
Imidazopyridine derivatives the most according to claim 1, it is characterised in that R1, Ra, RbAnd RcRepresent hydrogen atom.
Imidazopyridine derivatives the most according to claim 1, it is characterised in that R2Represent
-(C1-C6Alkyl) COOR8Group, wherein R8Represent hydrogen atom or C1-C6Alkyl；
-(C1-C6Alkyl) CONHR9Group, wherein R9Represent-OH group；-O(C1-C6Alkyl)；Or-(C1-C6Alkyl) NR10R11 Group, wherein R10And R11Represent C independently of one another1-C6Alkyl；
-phenyl, wherein said phenyl optionally replaces with selected from following one or more groups :-COOH ,-COO (C1-C6Alkane Base) ,-CONHOH, or-CONH-(C1-C6Alkyl) NR15R16, wherein R15And R16Represent C independently of one another1-C6Alkyl；Or
--CONH phenyl, with-COOH or-COO (C1-C6Alkyl) optionally replace.
Imidazopyridine derivatives the most according to claim 4, it is characterised in that R2Representative-(C1-C6Alkyl) COOH base Group.
Imidazopyridine derivatives the most according to claim 1, it is characterised in that R3Represent phenyl, with selected from following one Individual or multiple groups optionally replace :-(C1-C6Alkyl), wherein said alkyl optionally replaces with one or more halogen atoms； Halogen atom ,-O (C1-C6Alkyl), wherein said alkyl optionally replaces with one or more halogen atoms；-CN；Or-NO2。
Imidazopyridine derivatives the most according to claim 6, it is characterised in that R3Represent with selected from following one or The substituted phenyl of multiple groups: with one or more halogen atoms substituted-(C1-C6Alkyl)；Halogen atom ,-O (C1-C6Alkyl), Wherein said alkyl replaces with one or more halogen atoms；Or-CN.
Imidazopyridine derivatives the most according to claim 1, it is characterised in that it is selected from following compound:
2-(((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methyl) amino) acetic acid (68)；
2-((3-((2-fluorophenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) acetic acid (42)；
2-((3-((3-(difluoro-methoxy) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) acetic acid (35)；
2-((3-((3-(trifluoromethoxy) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) acetic acid (29)；
2-((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) benzoic acid (89)；
2-((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) sodium acetate (51)；
2-((3-((3,4-difluorophenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) acetic acid (38)；
2-((3-((3-cyano-phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) acetic acid (27)；
2-((3-((3-fluoro-4-(trifluoromethoxy) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) acetic acid (39)；
2-((3-((3-fluorophenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) acetic acid (40)；
2-((3-((3-methoxyphenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) acetic acid (30)；
2-((3-((4-(trifluoromethoxy) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) acetic acid (32)；
2-((3-((4-fluorophenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) acetic acid (44)；
2-((3-((4-fluorophenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) benzoic acid (88)；
2-((3-((4-fluorophenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group)-N-hydroxyl acetamide (59)；
2-((3-((4-fluorophenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group)-N-hydroxybenzamide (96)；
2-((3-((4-nitrobenzophenone) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) sodium acetate (48)；
2-((3-(phenylene-ethynylene) imidazo [1,2-a] pyridine-2-base) methoxyl group) sodium acetate (45)；
2-((3-(phenylene-ethynylene) imidazo [1,2-a] pyridine-2-base) methoxyl group) sodium benzoate (92)；
2-((3-(p-tolylethynyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) sodium acetate (47)；
2-(methyl ((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methyl) amino) second Acid (73)；
3-((3-(phenylene-ethynylene) imidazo [1,2-a] pyridine-2-base) methoxyl group) benzoic acid (93)；
3-(3-((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methyl) urea groups) benzene first Acid (75)；
4-((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) benzoic acid (90)；
2-((3-((2-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) ethyl acetate (26)；
2-((3-((2-fluorophenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) ethyl acetate (25)；
2-((3-((3-(difluoro-methoxy) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) ethyl acetate (20)；
2-((3-((3-(trifluoromethoxy) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) ethyl acetate (18)；
2-((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) ethyl acetate (7)；
2-((3-((3,4-difluorophenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) ethyl acetate (10)；
2-((3-((3-cyano-phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) ethyl acetate (14)；
2-((3-((3-fluoro-4-(trifluoromethoxy) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) acetic acid Ethyl ester (11)；
2-((3-((3-fluorophenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) ethyl acetate (23)；
2-((3-((3-methoxyphenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) ethyl acetate (12)；
2-((3-((4-(trifluoromethoxy) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) ethyl acetate (17)；
2-((3-((4-fluorophenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) ethyl acetate (3)；
2-((3-((4-nitrobenzophenone) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) ethyl acetate (5)；
2-((3-(phenylene-ethynylene) imidazo [1,2-a] pyridine-2-base) methoxyl group) ethyl acetate (1)；
2-((3-(p-tolylethynyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) ethyl acetate (2)；
2-((3-((4-fluorophenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) isopropyl acetate (54)；
2-((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) essence of Niobe (77)；
2-((3-((3-cyano-phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) essence of Niobe (79)；
2-((3-((4-fluorophenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) essence of Niobe (76)；
2-((3-(phenylene-ethynylene) imidazo [1,2-a] pyridine-2-base) methoxyl group) essence of Niobe (78)；
2-(methyl ((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methyl) amino) second Acetoacetic ester (72)；
3-((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) essence of Niobe (81)；
3-((3-(phenylene-ethynylene) imidazo [1,2-a] pyridine-2-base) methoxyl group) essence of Niobe (87)；
3-(3-((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methyl) urea groups) benzene first Acid methyl ester (74)；
4-((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) essence of Niobe (83)；
N-(2-(dimethylamino) ethyl)-2-((3-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine- 2-yl) methoxyl group) acetamide (55)；
N-(2-(dimethylamino) ethyl)-2-((3-((4-fluorophenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) first Epoxide) acetamide (57)；
N-(2-(dimethylamino) ethyl)-2-((3-((4-fluorophenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) first Epoxide) Benzoylamide (95)；
N-ethyoxyl-2-((3-((4-fluorophenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) acetamide (58)；
2-((3-((4-fluorophenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methoxyl group) sodium acetate (46)；
2-[methyl-[[3-[2-[3-(trifluoromethyl) phenyl] acetenyl] imidazo [1,2-a] pyridine-2-base] methyl] amino] Ethyl acetate hydrochloride (101)；
2-[[the chloro-3-of 6-[2-[3-(trifluoromethyl) phenyl] acetenyl] imidazo [1,2-a] pyridine-2-base] methyl-methyl- Amino] ethyl acetate (102)；
2-(methyl ((3-((3-(trifluoromethoxy) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methyl) amino) Ethyl acetate (103)；
2-(((the chloro-3-of 6-((3-(trifluoromethoxy) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methyl) (first Base) amino) ethyl acetate hydrochloride (104)；
2-(((the chloro-3-of 6-((3-(trifluoromethoxy) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methyl) (first Base) amino) acetic acid (105)；
2-(methyl ((3-((3-(trifluoromethoxy) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methyl) amino) Acetic acid (106)；
2-(((the chloro-3-of 6-((3-(trifluoromethyl) phenyl) acetenyl) imidazo [1,2-a] pyridine-2-base) methyl) (methyl) Amino) acetic acid (107)；
2-[[3-[2-[3-(trifluoromethyl) phenyl] acetenyl] imidazo [1,2-a] pyridine-2-base] methyl-sulfanyl] acetic acid second Ester (108)；
2-[[3-[2-[3-(trifluoromethoxy) phenyl] acetenyl] imidazo [1,2-a] pyridine-2-base] methyl-sulfanyl] acetic acid Ethyl ester (109)；
2-[[the chloro-3-of 6-[2-[4-(fluorine) phenyl] acetenyl] imidazo [1,2-a] pyridine-2-base] methyl-sulfanyl] acetic acid second Ester (110)；
2-[[the chloro-3-of 6-[2-[3-(trifluoromethyl) phenyl] acetenyl] imidazo [1,2-a] pyridine-2-base] methyl-sulfanyl] Ethyl acetate (111)；
2-[[the chloro-3-of 6-[2-[3-(trifluoromethoxy) phenyl] acetenyl] imidazo [1,2-a] pyridine-2-base] methyl-sulfur Base] ethyl acetate (112)；
(2R)-2-amino-3-[[3-[2-[3-(trifluoromethyl) phenyl] acetenyl] imidazo [1,2-a] pyridine-2-base] first Base-sulfenyl] ethyl propionate (113)；
2-[[8-methoxyl group-3-[2-[3-(trifluoromethyl) phenyl] acetenyl] imidazo [1,2-a] pyridine-2-base] methyl-sulfur Base] ethyl acetate (114)；
2-[[3-[2-[3-(trifluoromethyl) phenyl] acetenyl] imidazo [1,2-a] pyridine-2-base] methyl-sulfanyl] acetic acid (115)；
2-[[3-[2-[3-(trifluoromethoxy) phenyl] acetenyl] imidazo [1,2-a] pyridine-2-base] methyl-sulfanyl] acetic acid (116)；
2-[[the chloro-3-of 6-[2-(4-fluorophenyl) acetenyl] imidazo [1,2-a] pyridine-2-base] methyl-sulfanyl] acetic acid (117)；
2-[[the chloro-3-of 6-[2-[3-(trifluoromethyl) phenyl] acetenyl] imidazo [1,2-a] pyridine-2-base] methyl-sulfanyl] Acetic acid (118)；
2-[[the chloro-3-of 6-[2-[3-(trifluoromethoxy) phenyl] acetenyl] imidazo [1,2-a] pyridine-2-base] methyl-sulfur Base] acetic acid (119)；
2-[[8-methoxyl group-3-[2-[3-(trifluoromethyl) phenyl] acetenyl] imidazo [1,2-a] pyridine-2-base] methyl-sulfur Base] acetic acid (120)；
2-[[3-[2-[3-(trifluoromethyl) phenyl] acetenyl] imidazo [1,2-a] pyridine-2-base] methyl sulphonyl] acetic acid Ethyl ester (121)；
2-[[the chloro-3-of 6-[2-[3-(trifluoromethoxy) phenyl] acetenyl] imidazo [1,2-a] pyridine-2-base] sulfonyloxy methyl Base] ethyl acetate (122)；
2-[[the chloro-3-of 6-[2-[3-(trifluoromethoxy) phenyl] acetenyl] imidazo [1,2-a] pyridine-2-base] sulfonyloxy methyl Base] acetic acid (123)；
N-(3-pyridine radicals)-2-[[3-[2-[3-(trifluoromethyl) phenyl] acetenyl] imidazo [1,2-a] pyridine-2-base] first Base-sulfenyl] acetamide (124)；
N-(3-pyridine radicals)-2-[[3-[2-[3-(trifluoromethoxy) phenyl] acetenyl] imidazo [1,2-a] pyridine-2-base] Methoxyl group] acetamide (125)；
N-(3-pyridine radicals)-2-[[3-[2-[3-(trifluoromethoxy) phenyl] acetenyl] imidazo [1,2-a] pyridine-2-base] Methyl-sulfanyl] acetamide (126)；
4-hydroxyl-3,3-dimethyl-2-[[3-[2-[3-(trifluoromethyl) phenyl] acetenyl] imidazo [1,2-a] pyridine-2- Base] methoxyl group] butanoic acid (129)；
2-[[8-methoxyl group-3-[2-[3-(trifluoromethyl) phenyl] acetenyl] imidazo [1,2-a] pyridine-2-base] methyl-sulfur Base] ethanol (130)；
2-[[the chloro-3-of 6-[2-[3-(trifluoromethyl) phenyl] acetenyl] imidazo [1,2-a] pyridine-2-base] methyl-sulfanyl] Ethanol (131)；
N-amidino groups-2-[[3-[2-[3-(trifluoromethyl) phenyl] acetenyl] imidazo [1,2-a] pyridine-2-base] methyl-sulfur Base] acetamide hydrochloride (135).
9. the derivant contained according to any one of with good grounds claim 1～8 and the medicine of pharmaceutically acceptable excipient Compositions.
Pharmaceutical composition the most according to claim 9, possibly together with another kind of antidiabetic.
11. are intended for treatment and/or prevention glycosuria according to the derivant according to any one of claim 1～8 for preparation The purposes of the medicine of disease, its complication and/or associated conditions.
12. are intended for treatment and/or prevention II type according to the derivant according to any one of claim 1～8 for preparation The purposes of the medicine of diabetes and hyperglycemia.
CN201380046094.XA 2012-07-20 2013-07-16 For treating the imidazopyridine derivatives of diabetes Active CN104662020B (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR1257082 2012-07-20
FR1257082A FR2993564B1 (en) 2012-07-20 2012-07-20 IMIDAZOPYRIDINE DERIVATIVES USEFUL IN THE TREATMENT OF DIABETES
PCT/FR2013/051703 WO2014013182A1 (en) 2012-07-20 2013-07-16 Imidazopyridine derivative used in the treatment of diabetes

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CN104662020A CN104662020A (en) 2015-05-27
CN104662020B true CN104662020B (en) 2016-11-30

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