CN106188063A - As Lp-PLA2dicyclo compounds, its preparation method and the medical usage of inhibitor - Google Patents

As Lp-PLA2dicyclo compounds, its preparation method and the medical usage of inhibitor Download PDF

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Publication number
CN106188063A
CN106188063A CN201510233237.9A CN201510233237A CN106188063A CN 106188063 A CN106188063 A CN 106188063A CN 201510233237 A CN201510233237 A CN 201510233237A CN 106188063 A CN106188063 A CN 106188063A
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alkyl
group
compound
formula
phenyl
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沈建华
王逸平
陈鑫德
徐文伟
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Shanghai Institute of Materia Medica of CAS
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Shanghai Institute of Materia Medica of CAS
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Priority to CN201510233237.9A priority Critical patent/CN106188063A/en
Priority to CN201680016991.XA priority patent/CN107709325B/en
Priority to PCT/CN2016/080725 priority patent/WO2016180247A1/en
Publication of CN106188063A publication Critical patent/CN106188063A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

The present invention relates to as Lp-PLA2Dicyclo compounds, its preparation method and the medical usage of inhibitor, and comprise the pharmaceutical composition of this compound, the structure of described dicyclo compounds as shown in formula I, R1、R2、R3, X, Y, Z, Ar, n definition as shown in specification and claims.The compound of Formula I of the present invention can be used as Lp-PLA2Inhibitor, prevents and/or treats and/or improve and Lp-PLA2The disease that enzymatic activity is relevant.

Description

As Lp-PLA2Dicyclo compounds, its preparation method and the medical usage of inhibitor
Technical field
The present invention relates to medicinal chemistry art, particularly relate to dicyclo compounds of novelty and preparation method thereof, Pharmaceutical composition with this compounds as active component, and they are at preparation treatment and Lp-PLA2Enzyme Activity has the application in the medicine of related disorders.
Background technology
The phospholipase A that lipoprotein is relevant2(Lp-PLA2) it is also referred to as platelet-activating factor acetylhydrolase (PAF-AH), this enzyme contains 441 aminoacid, and relative molecular mass is 45kD.In human plasma 70% Lp-PLA2Combine with low density lipoprotein, LDL (LDL), the Lp-PLA of 30%2With high density lipoprotein (HDL) combine.Lp-PLA2Promptly the hydrolysis of phosphatidlycholine of oxidation can be become lysophosphatidylcholine (lyso-PC) and oxidation non-esterified fatty acid (ox-NEFA), and lyso-PC and ox-NEFA is There is the strongest rush inflammatory effect, it is possible to start that to include that endotheliocyte, smooth muscle cell, monokaryon/huge are bitten thin Born of the same parents, T cell, neutrophil cell are in the inflammation/immunoreation of interior various kinds of cell.
Lp-PLA2Inhibitor may be generally applicable to any lipid of oxidation that relates at Lp-PLA2Ginseng With the disease that lower hydrolysis becomes two inflammatory properties these processes of material.Include among these atherosclerosis, Diabetes, care of patients with diabetic ocular disease, diabetes brain diseases, hypertension, angina pectoris, rheumatoid close Joint inflammation, apoplexy, myocardial infarction, ischemia and reperfusion after, psoriasis, brain inflammation disease (such as: Ah Er Cihaimo disease), all kinds of neuropsychiatric disease (such as: schizophrenia), ischemical reperfusion injury, lose Mass formed by blood stasis, acute and chronic inflammation disease.
Atherosclerosis is more than relevant with blood lipid level exception, is also a kind of inflammation-related diseases, Suppressing atherosclerotic inflammatory factor is the new way treating this disease.There are some researches show, lyso-PC Can promote that atheromatous plaque develops, and ultimately form necrotic cores.At diabetes hypercholesterolemia The experiment carried out on pig model confirms Lp-PLA2Inhibitor can affect the tremulous pulse of diabetes hypercholesterolemia pig The situation of plaque volume, composition and gene expression, and effectively suppress atheromatous plaque Continued growth.
Research is had to point out in the middle of all of neurodegenerative diseases, such as: multiple sclerosis, handkerchief gold Gloomy disease, Alzheimer's disease etc., all show neuroinflamation.Lyso-PC as a proinflammatory because of Son, it is possible to induction release various kinds of cell toxicity inflammatory cytokine, and Lp-PLA2Inhibitor can pass through The generation of suppression lyso-PC weakens inflammatory reaction.
The experiment carried out on diabetes hypercholesterolemia pig model shows, Lp-PLA2Inhibitor can improve Blood brain barrier (blood brain barrier, BBB) function, reduces blood brain barrier (BBB) permeability, And β sample albumen precipitation in brain can be alleviated.These results of study show Lp-PLA2Inhibitor is possible can To be applied to the treatment of the disease being associated with Blood Brain Barrier (BBB) permeability, such as diabetes mellitus encephalopathy, alzheimer ' Silent disease.
Owing to lyso-PC participates in leukocyte activation, inducing cell apoptosis and can mediate endotheliocyte merit Can lack of proper care, and diabetes can cause lasting vascular inflammation and increase the generation of active oxygen, the most general All over thinking Lp-PLA2Inhibitor can by suppressing the generation of lyso-PC, thus be used for treating diabetes Relevant tissue injury.Inflammatory reaction in view of local developed at diabetic retinopathy Journey plays an important role, therefore speculates Lp-PLA2Inhibitor can apply to controlling of diabetic oculopathy Treat.
It addition, the destruction of blood retina barrier (BRB) is diabetic macular edema (DME) patient Common pathological characters.Under normal circumstances, BRB can stop blood plasma components freely by actively and passively transhipment Enter retina, maintain the self stability of retina interoceptor cell.Once BRB is destroyed, Can not strictly control albumen and moisture entrance retina essential layer in blood plasma, cause retina cell outer room Gap is substantially expanded, and will appear as macular edema at macular area.At the SD that streptozotocin (STZ) is induced The zoopery carried out on rat and brown Norway Rat model shows, Lp-PLA2Inhibitor can drop Low BRB permeability, result of study display Lp-PLA2Inhibitor may can apply to diabetic macular The treatment of edema.
The degeneration of macula (AMD) that glaucoma and age are correlated with is retina neural degenerative disease, Research display inflammatory reaction, including: TNF-α signal path may play important in the middle of both diseases Effect.In view of Lp-PLA2Inhibitor can block the release of inflammatory cytokine, therefore speculates Lp-PLA2Inhibitor can apply to the treatment of glaucoma and AMD.
GlaxoSmithKline PLC develops class Lp-PLA2Potent reversible inhibitor (WO 99/24420, WO 01/60805, WO 02/30911, WO 03/016287, WO 03/042179, WO 03/042206, WO 08/048867 etc.), so that structure to be characterized containing dicyclo or pyridone group, representation compound Darapladib and rilapladib is currently under clinical investigation phase.
GlaxoSmithKline PLC also developed class Lp-PLA2Inhibitor (US 2012/0142717, WO 2012/075917, WO 2012/037782, WO 2013/013503, WO 2013/014185, WO 2014/114248, WO 2014/114249, WO 2014/114694), structure is also with bicyclic radicals as spy Levying, the difference of the most previous class reversible inhibitor is that this class formation is linear structure, and molecular weight is the most relative Less.
Still need to Lp-PLA in this area2Inhibitor carries out in-depth study and exploitation.
Summary of the invention
It is an object of the invention to provide a kind of as Lp-PLA2The dicyclo compounds of inhibitor and medicine thereof Compositions.
A first aspect of the present invention, it is provided that a kind of compound of Formula I or its pharmaceutically acceptable salt:
In formula, R1For C1-C6Alkyl, C2-C6Thiazolinyl, C2-C6Alkynyl, C3-C8Cycloalkyl, 3-8 unit Heterocyclic radical, C3-C8Cycloalkenyl group ,-(CH2)m-NR4R5、C6-C10Aryl ,-(CH2)m-(3-8 unit heteroaryl), Or halogen, wherein, described C1-C6Alkyl, C2-C6Thiazolinyl, C2-C6Alkynyl, C3-C8Cycloalkyl, C3-C8 Cycloalkenyl group, 3-8 unit heteroaryl, 3-8 unit heterocyclic radical, C6-C10Aryl is not necessarily selected from down by 1-4 The group of group replaces :-OH ,-CN ,=O, C1-C6Alkyl, C6-C10Aryl, C1-C6Alkoxyl, C1-C6Alkoxy acyl, C1-C6Alkanoyl, C1-C6Alkanoyloxy, C3-C8Cycloalkyl, carboxyl, halogen, Halo C1-C6Alkyl ,-S (O) R1’、-SO2R2’、-NO2、-NR3’R4’；
Preferably, R1For C1-C4Alkyl, C2-C4Thiazolinyl, C2-C4Alkynyl, C3-C6Cycloalkyl, 3-6 Unit heterocyclic radical ,-(CH2)m-NR4R5, phenyl ,-(CH2)m-(3-8 unit heteroaryl) or halogen, wherein, institute State C1-C4Alkyl, C2-C4Thiazolinyl, C2-C4Alkynyl, C3-C6Cycloalkyl, 3-8 unit heteroaryl, 3-6 unit Heterocyclic radical, phenyl are not necessarily replaced selected from the group of lower group by 1-4 :-CN, C1-C6Alkyl, C1-C6Alkoxyl, halogen, hydroxyl, halo C1-C6Alkyl；
It is highly preferred that R1For-(CH2)m-NR4R5, phenyl ,-(CH2)m-(3-6 unit heteroaryl), wherein, Described 3-6 unit heteroaryl, phenyl are not necessarily replaced selected from the group of lower group by 1-3 :-CN, fluorine, Chlorine, bromine, methoxyl group, trifluoromethyl, methyl, ethyl or propyl group；
It is highly preferred that R1For-(CH2)-N(CH3)2, phenyl ,-(CH2)-pyrazolyl, pyrimidine radicals, pyridine Base, wherein, described pyrazolyl, pyrimidine radicals, pyridine radicals, phenyl are not necessarily selected from lower group by 1-3 Group replaced :-CN, fluorine, chlorine, bromine, methoxyl group, trifluoromethyl, methyl, ethyl or propyl group；
R2、R3Independently selected from H, C1-C6Alkyl, C3-C8Cycloalkyl, C1-C6Alkoxyl or-NR6R7, Wherein, described C1-C6Alkyl, C3-C8Cycloalkyl, C1-C6Alkoxyl is not necessarily selected from down by 1-4 The group of group replaces :-OH ,-CN ,=O, C1-C6Alkyl, C6-C10Aryl, C1-C6Alkoxyl, C1-C6Alkoxy acyl, C1-C6Alkanoyl, C1-C6Alkanoyloxy, C3-C8Cycloalkyl, carboxyl, halogen, Halo C1-C6Alkyl ,-S (O) R1’、-SO2R2’、-NO2、-NR3’R4’；
Preferably R2For H or C1-C6Alkyl, wherein, described C1-C6Alkyl is not necessarily by 1-4 The individual group selected from lower group replaces :-CN, C1-C6Alkyl, C1-C6Alkoxyl, halogen, hydroxyl, halogen For C1-C6Alkyl；More preferably R2For H or C1-C4Alkyl, wherein, described C1-C4Alkyl is non- Necessarily replaced selected from the group of lower group by 1-3 :-CN, fluorine, chlorine, bromine, methoxyl group, fluoroform Base, methyl, ethyl or propyl group；More preferably R2For H or methyl；
Preferably R3For H or C1-C6Alkyl, wherein, described C1-C6Alkyl is not necessarily by 1-4 The individual group selected from lower group replaces :-CN, C1-C6Alkyl, C1-C6Alkoxyl, halogen, hydroxyl, halogen For C1-C6Alkyl；More preferably R3For H or C1-C4Alkyl, wherein, described C1-C4Alkyl is non- Necessarily replaced selected from the group of lower group by 1-3 :-CN, fluorine, chlorine, bromine, methoxyl group, fluoroform Base, methyl, ethyl or propyl group；More preferably R3For H；
X is O, S ,-(CH2)q-or-N (R8)-；Preferably X is O or S；
N is 0,1,2,3 or 4；Preferably n is 0,1,2 or 3；More preferably n is 0,1 or 2；
Ar is C6-C10Aryl or 3-8 unit heteroaryl, wherein, described C6-C10Aryl or 3-8 unit heteroaryl Base is not necessarily replaced selected from the group of lower group by 1-4 :-CN, C1-C6Alkyl, C1-C6Alkoxyl, Halogen, hydroxyl, halo C1-C6Alkyl, halo C1-C6Alkoxyl；
Preferably Ar is phenyl, naphthyl or 5-6 unit heteroaryl, wherein, and described phenyl, naphthyl, 5-6 unit Heteroaryl is not necessarily replaced selected from the group of lower group by 1-4 :-CN, C1-C6Alkyl, C1-C6Alcoxyl Base, halogen, hydroxyl, halo C1-C6Alkyl, halo C1-C6Alkoxyl；
More preferably Ar is phenyl or 5-6 unit heteroaryl, and wherein, described phenyl, 5-6 unit heteroaryl is non-must Must be replaced selected from the group of lower group by 1-3 on ground :-CN, C1-C4Alkyl, C1-C4Alkoxyl, halogen, Hydroxyl, halo C1-C4Alkyl, halo C1-C4Alkoxyl；
More preferably Ar is phenyl, and wherein, described phenyl is not necessarily taken selected from the group of lower group by 1-3 Generation :-CN, fluorine, chlorine, bromine, trifluoromethyl, methyl, ethyl, propyl group；
Y is hydrogen ,-A-(C6-C10Aryl) or-A-(3-8 unit heteroaryl), wherein, A is O, S ,-(CH2)o- Or-N (R9The described C of)-,6-C10The group that aryl, 3-8 unit heteroaryl are not necessarily selected from lower group by 1-3 Replace :-CN, C1-C6Alkyl, C1-C6Alkoxyl, halogen, halo C1-C6Alkyl；
Preferably, Y is-A-(C6-C10Aryl) or-A-(5-6 unit heteroaryl), wherein, A is O, described C6-C10Aryl, 5-6 unit heteroaryl are not necessarily replaced selected from the group of lower group by 1-3 :-CN, fluorine, Chlorine, bromine, trifluoromethyl, methyl, ethyl, propyl group；
Z is CH or N；
Described R4To R9, and R1' to R4' it is each independently selected from H, C1-C6Alkyl, C1-C6Alkane Acyl group ,-(CH2)p-(C1-C6Alkoxyl), C3-C8Cycloalkyl, C2-C6Thiazolinyl, C2-C6Alkynyl and C3-C8 Cycloalkenyl group；Preferably, R4To R9, and R1' to R4' it is each independently selected from H, C1-C3Alkyl；
Described m, q, o and p are each independently 0,1,2 or 3.
In another preference, described compound of Formula I has one or two feature following:
(1)R2For H or C1-C6Alkyl, it is preferred that R2For H or C1-C4Alkyl；Most preferably, R2 For H or methyl；
(2)R3For H or C1-C6Alkyl；It is preferred that R3For H or C1-C4Alkyl；Most preferably, R3 For H；
(3) n is 0,1,2 or 3；
(4) X is O, S；
In another preference, R1For C1-C4Alkyl, C2-C4Thiazolinyl, C2-C4Alkynyl, C3-C6Cycloalkanes Base, 3-6 unit heterocyclic radical ,-(CH2)m-NR4R5, phenyl ,-(CH2)m-(3-8 unit heteroaryl) or halogen, Wherein,
Described C1-C4Alkyl, 3-6 unit heterocyclic radical, phenyl ,-(CH2)m-(3-8 unit heteroaryl) is not necessarily Replaced selected from the group of lower group by 1-4 :=O, C1-C6Alkyl, C6-C10Aryl, C1-C6Alkoxyl, C3-C8Cycloalkyl, halogen, halo C1-C6Alkyl or-NR3’R4’；
R4、R5、R3' and R4' it is each independently selected from H, C1-C6Alkyl ,-(CH2)p-(C1-C6Alkoxyl), C3-C8Cycloalkyl；
M and p is each independently 0,1,2 or 3.
In another preference, R1For C1-C4Alkyl, C2-C4Thiazolinyl, C3-C6Cycloalkyl, 3-6 unit are miscellaneous Ring group ,-(CH2)m-NR4R5, phenyl ,-(CH2)m-(3-6 unit heteroaryl) or halogen, wherein, described C1-C4 Alkyl, 3-6 unit heterocyclic radical, phenyl ,-(CH2)m-(3-6 unit heteroaryl) is not necessarily selected from lower group take Generation :=O, C1-C4Alkyl, C6-C10Aryl, C1-C4Alkoxyl, C3-C6Cycloalkyl, halogen, halo C1-C4Alkyl or-NR3’R4’；R4、R5、R3' and R4' it is each independently selected from H, C1-C4Alkyl, -(CH2)p-(C1-C4Alkoxyl), C3-C6Cycloalkyl；M and p is each independently 0 or 1.
In another preference, R1For-(CH2)m-NR4R5, phenyl ,-(CH2)m-(3-6 unit heteroaryl), Wherein, described phenyl ,-(CH2)m-(3-6 unit heteroaryl) is not necessarily selected from the group of lower group and replaces: =O, C1-C4Alkyl, phenyl, C1-C4Alkoxyl, C3-C6Cycloalkyl, halogen, fluoro C1-C4Alkyl Or-NR3’R4’；R4、R5、R3' and R4' it is each independently selected from methyl, ethyl, propyl group ,-(CH2)2OCH3 Or cyclopropyl；M is 0 or 1.
In another preference, R1For-(CH2)-N(CH3)2, phenyl ,-(CH2)-pyrazolyl, pyrazolyl, Pyrimidine radicals, pyridine radicals, wherein, described phenyl, pyrazolyl, pyrimidine radicals are not necessarily selected from following group Replacement :=O, methyl, ethyl, phenyl, methoxyl group, ethyoxyl, cyclopropyl, fluorine, chlorine, bromine, Trifluoromethyl；
In another preference, described compound of Formula I has one or two feature following:
(1) Ar is substituted or unsubstituted phenyl, and substituted or unsubstituted naphthyl is substituted or unsubstituted 5-6 unit heteroaryl, described replacement refers to that having 1-4 on phenyl, naphthyl or 5-6 unit heteroaryl is selected from down The substituent group of group :-CN, C1-C6Alkyl, C1-C6Alkoxyl, halogen, hydroxyl, halo C1-C6Alkyl, Halo C1-C6Alkoxyl；
(2) Y is hydrogen ,-A-(C6-C10Aryl) or-A-(5-6 unit heteroaryl), wherein, A is O or S； Described C6-C10Not necessarily there is on aryl, described 5-6 unit heteroaryl the replacement that 1-3 selected from lower group Base: C1-C4Alkyl ,-CN, halogen, halo C1-C6Alkyl.
In another preference, Ar is substituted or unsubstituted phenyl, and substituted or unsubstituted 5-6 unit is miscellaneous Aryl, described replacement refers to have the substituent group that 1-3 selected from lower group on phenyl or 5-6 unit heteroaryl: -CN、C1-C4Alkyl, C1-C4Alkoxyl, halogen, hydroxyl, halo C1-C4Alkyl, halo C1-C4 Alkoxyl.
In another preference, Ar is substituted or unsubstituted phenyl, and described replacement refers to have on phenyl 1-3 the substituent group being selected from lower group :-CN, fluorine, chlorine, bromine, trifluoromethyl, methyl, ethyl or propyl group.
In another preference, A is O.In another preference, described C6-C10Aryl, 5-6 unit Not necessarily there is the substituent group that 1-3 is selected from lower group :-CN, F, Cl, CF on heteroaryl3。
In another preference, described compound has a structure shown in formula (IA):
Wherein, Ra and Rb is each independently H, halogen ,-CN, trifluoromethyl or methyl；
Z is CH or N；
N is 0,1,2 or 3；
R1For-(CH2)-N(CH3)2, phenyl ,-(CH2)-pyrazolyl, pyrazolyl, pyrimidine radicals, pyridine radicals, Wherein, described phenyl, pyrazolyl, pyrimidine radicals be not necessarily selected from the replacement of following group :-CN ,=O, Methyl, ethyl, phenyl, methoxyl group, ethyoxyl, cyclopropyl, fluorine, chlorine, bromine, trifluoromethyl；
R2For hydrogen or methyl；
Ar ' is phenyl, pyridine radicals, pyrimidine radicals, and wherein, described phenyl, pyridine radicals, pyrimidine radicals are nonessential Ground is replaced selected from the group of following group by 1-3: trifluoromethyl, fluorine, chlorine, cyano group, methyl.
In another preference, described compound of Formula I is arbitrary compound as shown in the table.
In another preference, described pharmaceutically acceptable salt is hydrochlorate, hydrobromate, sulphuric acid Salt, nitrate, phosphate, citrate, mesylate, trifluoroacetate, acetate, oxalates, Succinate, malate, toluene fulfonate, tartrate, fumarate, glutamate, Glu, glucose Aldehydic acid salt, lactate, glutarate, arginine salt or maleate.
A second aspect of the present invention, it is provided that compound of Formula I described in first aspect or it is the most permissible The preparation method of the salt accepted, comprises the following steps:
When Z is CH in formula I, it is Compounds of formula II, by Formulas I c compound and R1W is anti- Should obtain, wherein, W is Cl, Br or I；
Or described preparation method comprises the following steps:
When Z is CH in formula I, be Compounds of formula II, by Formulas I d compound with Reaction obtains；
Or described preparation method comprises the following steps:
When Z is CH in formula I, be Compounds of formula II, by Formula II d compound with Y-Ar-(CH2)nXH reacts in the presence of a base and obtains；
Or described preparation method comprises the following steps:
When Z is N in formula I, be compound of formula III, by formula III e compound with Reaction obtains；
Wherein, described R1、R2、R3, Y, Ar, n, X definition as described in relation to the first aspect.
A third aspect of the present invention, it is provided that a kind of pharmaceutical composition, comprises the formula I described in first aspect Compound or its pharmaceutically acceptable salt；With pharmaceutically acceptable carrier.
A fourth aspect of the present invention, it is provided that compound of Formula I described in first aspect or it is the most permissible The purposes of pharmaceutical composition described in the salt accepted or the third aspect, described purposes be for:
(1) preparation suppression Lp-PLA2Medicine；
(2) preparation prevents and/or treats and/or improve and Lp-PLA2The medicine of the disease that enzymatic activity is relevant.
In another preference, described and Lp-PLA2The relevant disease of enzymatic activity be atherosclerosis, Apoplexy, myocardial infarction, ischemical reperfusion injury, care of patients with diabetic ocular disease, diabetes mellitus encephalopathy, diabetes Macular edema, all kinds of neurodegenerative diseases, Alzheimer's disease, acute inflammatory diseases, chronic inflammatory disease Disease, psoriasis or glaucoma degeneration of macula.
In another preference, described and Lp-PLA2The relevant disease of enzymatic activity be atherosclerosis, Diabetic macular edema, diabetes mellitus encephalopathy or Alzheimer's disease.
A fifth aspect of the present invention, it is provided that the intermediate of compound of Formula I, structure is:
Wherein, described R2、R3, Y, Ar, n, X definition as described in relation to the first aspect.
A sixth aspect of the present invention, it is provided that the intermediate of compound of Formula I, structure is:
Wherein, described R2、R3, Y, Ar, n, X definition as described in relation to the first aspect.
A seventh aspect of the present invention, it is provided that the intermediate of compound of Formula I, structure is:
Wherein, described R2、R3, Y, Ar, n, X definition as described in relation to the first aspect.
A eighth aspect of the present invention, it is provided that the intermediate of compound of Formula I, structure is:
Wherein, described R1、R2、R3Definition as described in relation to the first aspect.
A ninth aspect of the present invention, it is provided that the intermediate of compound of Formula I, structure is:
Wherein, described R2、R3, Y, Ar, n, X definition as described in relation to the first aspect.
A tenth aspect of the present invention, it is provided that a kind of suppression Lp-PLA2Method, to required object or The compound of Formula I of safe and effective amount is used in environment.
A eleventh aspect of the present invention, it is provided that a kind for the treatment of and Lp-PLA2Enzymatic activity has the method for related disorders, The compound of Formula I of safe and effective amount is used to required object.
In another preference, the object of described needs includes the cell of In vitro culture, people or inhuman suckling Animal, it is preferred that be people, mice or rat.
In the present invention, " safe and effective amount " refers to: the amount of active component (compound of Formula I) be enough to substantially Improve the state of an illness, and be unlikely to produce serious side effect.
In should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and below (as implemented Example) in can be combined with each other between each technical characteristic of specifically describing, thus constitute new or preferred skill Art scheme.As space is limited, the most tired at this state.
Detailed description of the invention
Present inventor, through extensively and in depth studying, develops the double of a kind of novel structure first Cyclics, can be used as Lp-PLA2Inhibitor, prevents and/or treats and/or improve and Lp-PLA2 The disease that enzymatic activity is relevant.On this basis, the present invention is completed.
Term
In the present invention, term " C1-C6Alkyl " refer to the straight or branched alkane with 1 to 6 carbon atom Base, includes methyl, ethyl, propyl group, isopropyl and butyl etc. without limitation；Term " C1-C4Alkyl " There is similar implication.Term " C2-C6Thiazolinyl " refer to have 2 to 6 carbon atoms containing a double bond Straight or branched thiazolinyl, include without limitation vinyl, acrylic, cyclobutenyl, isobutenyl, Pentenyl and hexenyl.Term " C2-C6Alkynyl " refer to have 2 to 6 carbon atoms containing three keys Straight or branched alkynyl, include without limitation acetenyl, propinyl, butynyl, butynyl, Pentynyl and hexin base.Term " halo C1-C6Alkyl " refer to the alkane that is optionally substituted with one or more halogen atoms Base, such as-CH2F、-CF3、-CH2CHF3Deng.
In the present invention, term " C1-C6Alkoxyl " refer to the straight or branched with 1 to 6 carbon atom Alkoxyl, includes methoxyl group, ethyoxyl, propoxyl group, isopropoxy and butoxy etc. without limitation； Term " C1-C4Alkoxyl " there is similar implication.
In the present invention, term " C3-C8Cycloalkyl " refer to that there is on ring the ring-type of 3 to 8 carbon atoms Alkyl, includes cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, ring octyl group without limitation Deng；Term " C3-C6Cycloalkyl " there is similar implication.Term " C3-C8Cycloalkenyl group " it is on finger ring, to have 3 To the cyclic alkenyl radical of 8 carbon atoms, include without limitation cyclopropanyl, cyclobutane base, cyclopentenyl, Cyclohexenyl group etc..
In the present invention, term " aryl " represents the alkyl comprising one or more aromatic ring, such as phenyl or naphthyl Deng.
Term " heteroaryl " expression comprises 1-4 the heteroatomic aromatic ring group selected from N, O, S, non-limit Include to property processed pyrazolyl, thienyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, furyl, Pyrrole radicals, oxazolyl, isoxazolyl, imidazole radicals, thiazolyl, isothiazolyl, quinazolyl, quinoline Base, isoquinolyl and indyl.
In the present invention, term " heterocyclic radical " expression comprises 1-4 the heteroatomic cycloalkanes selected from N, O, S Base, include without limitation pyrrolidinyl, morpholinyl, piperidyl, thio-morpholinyl, piperazinyl, four Hydrogen furyl, THP trtrahydropyranyl, tetrahydro-thienyl, tetrahydro-thiazoles base.
Preparation method
The present invention compound of Formula I, its stereoisomer or its pharmaceutically acceptable salt can lead to Cross following method to prepare:
Route 1:
(a) Formulas I a-1 or Ia-2 compound and Y-Ar-(CH2)nXH reacts in the presence of a base and obtains Formulas I bization Compound；
(b) bromoacetaldehyde and Formulas I b compound generation ring closure reaction production Ic；
(c) Ib compound withRing closure reaction is occurred to generate Formula II；
D () Formulas I c compound reacts with N-bromo-succinimide and obtains Formulas I d compound；
(e) Formulas I d compound and R1Boric acid or boron ester occur Suzuki reaction obtain Formula II compound；
(f) Formulas I c compound and R1W reaction obtains Formula II compound, and wherein, described W is Cl, Br Or I；
Route 2:
G () Formulas I a-1 or Ia-2 compound react in the presence of a base with benzyl mercaptan and obtain Formula II a compound；
(h) bromoacetaldehyde and Formula II a compound generation ring closure reaction production IIb；
(i) Formula II b compound and R1W reacts under palladium is catalyzed and obtains Formula II c compound, wherein, W is Cl, Br or I；
J () Formula II c compound is obtained Formula II d compound by metachloroperbenzoic acid oxidation；
(k) Formula II d compound and Y-Ar-(CH2)nXH reacts in the presence of a base and obtains Formula II compound；
Route 3:
(l) formula III a compound and Y-Ar-(CH2)nXH reacts in the presence of a base and obtains formula III b compound；
(o) formula III b compound and hydrazine hydrate generation nucleophilic displacement of fluorine production IIIc；
P () formula III c compound and triethyl orthoformate generation ring closure reaction obtain formula III d compound；
Q () formula III d compound and N-bromo-succinimide react and obtain formula III e compound；
(r) formula III e compound and R1Boric acid or boron ester occur Suzuki reaction obtain formula III compound；
In another preference, described R1Boric acid or boron ester be selected from
Alkali in described step (a), (g), (k) or (l) is selected from inorganic base, organic base and a combination thereof；Preferably, Described inorganic base is selected from sodium hydroxide, potassium hydroxide, Strontium hydrate., Lithium hydrate, barium hydroxide, hydrogen Calcium oxide, Cesium hydrate., sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, strontium carbonate, carbonic acid Caesium, sodium sulfide, sodium hydrogen and a combination thereof；Described organic base is selected from sodium alkoxide, potassium alcoholate, butyl lithium, 1,8-bis- Azacyclo-[5,4,0] hendecene-7, pyridine, piperidines, pyrrolidine, morpholine, N-methylmorpholine, quinoline, DMAP, triethylamine, diethylamine, tri-n-butylamine, tripropylamine, diisopropylamine, two Wopropyl ethyl amine and a combination thereof；It is highly preferred that described alkali is selected from sodium hydroxide, potassium hydroxide, hydroxide Lithium, sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogen, Feldalat NM, ethanol Sodium, potassium tert-butoxide, pyridine, piperidines, pyrrolidine, morpholine, N-methylmorpholine, triethylamine, diethylamine, Diisopropylamine, diisopropylethylamine and a combination thereof；The reaction dissolvent of described reaction selected from aromatic hydrocarbon solvent, Ether solvent, halogenated hydrocarbon solvent and other solvents；Preferably, described aromatic hydrocarbon solvent is selected from benzene, first Benzene, dimethylbenzene, chlorobenzene, Nitrobenzol and a combination thereof；Described ether solvent selected from oxolane, ether, Glycol dimethyl ether, diethylene glycol dimethyl ether, glycol monoethyl ether, dioxane and a combination thereof；Described Halogenated hydrocarbon solvent is selected from dichloromethane, chloroform, carbon tetrachloride, dichloroethanes and a combination thereof；Described its He is selected from N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, dimethyl sulfoxide, N-methylpyrrole by solvent Alkanone, hexamethyl phosphoramide, acetone, acetonitrile, ethyl acetate and a combination thereof；Preferably, described reaction Reaction temperature be-30 DEG C～300 DEG C, more preferably-10 DEG C～150 DEG C；Preferably, the reaction of described reaction Time is 0.5～12 hour.
Purposes
The compounds of this invention is Lp-PLA2Inhibitor.Therefore these compounds can be used for treating, such as, control Treat and Lp-PLA2The relevant disease of activity.Therefore, another aspect of the present invention relate to treatment with Lp-PLA2The relevant disease of activity.It will be understood by those skilled in the art that specific disease or its control Treatment can relate to and Lp-PLA2One or more base mechanisms that activity is relevant, including one or more originally Mechanism described in literary composition.
In a specific embodiment, the compounds of this invention can be used for treating and relates to any of endothelial dysfunction Disease, such as, atherosclerosis, diabetes, hypertension, angina pectoris and local ischemia and reperfusion After disease.
In a specific embodiment, the compounds of this invention can be used for treatment and relates to fat related with enzymatic activity Any disease of matter oxidation, such as, other in addition to such as atherosclerosis and diabetes and other diseases Disease, such as rheumatoid arthritis, apoplexy, the inflammatory disease such as Alzheimer of brain, various Neuropsychiatric disorders such as schizophrenia, myocardial infarction, ischemia, reperfusion injury, septicemia with And acute and chronic inflammation.
In a specific embodiment, the compounds of this invention can be used for treating and relates to the mononuclear cell of activation, huge Phagocyte or the disease of lymphocyte, because all these cell category expresses Lp-PLA2, including relating to The disease of macrophage of activation, typical disease include but not limited to psoriasis, rheumatoid arthritis, Wound healing, chronic obstructive pulmonary disease, liver cirrhosis, atopic dermatitis, emphysema, chronic pancreatitis, Chronic gastritis, aortic aneurysm, atherosclerosis, multiple sclerosis, Alzheimer and self exempt from Epidemic is sick such as lupus.
In a specific embodiment, the present invention provides treatment and Lp-PLA2The method of the disease that activity is relevant, It includes with the Lp-PLA of effective dose2Inhibitor for treating needs the experimenter for the treatment of.Described disease can be with The participation of mononuclear cell, macrophage or lymphocyte increases relevant；With LYSO-PHOSPHATIDYLCHOLINE LYSOPC and oxidation The formation of free fatty relevant；With the Lp-PLA being associated2The lipid oxidation of activity is relevant；Or with Endothelial dysfunction is relevant.
In other embodiments, the compounds of this invention may be used for Acute coronary event primary or Sending out of secondary prevention, the therapeutic alliance of prevention of restenosis or delay diabetes or hypertensive cerebral renal insufficiency Exhibition.Prevention and treatment have the experimenter of the risk of such disease.
In some embodiments, the compounds of this invention can be used for hard with lipidemia agent, anti-atherogenic Agent, antidiabetic, antianginal agent or hypotensive agent or for reduce LP(a) medicament knot The disease that the incompatible treatment present invention describes.The example of above-mentioned medicament includes but not limited to, cholesterol biosynthesis presses down Preparation, such as Statins；Antioxidant, such as probacol；Insulin sensitizers；Calcium-channel antagonists And anti-inflammatory agent, such as NSAID (non-steroidal anti-inflammatory drug).
In one embodiment, the compounds of this invention can be used for treating the neurodegenerative diseases of experimenter. Described method includes containing suppression Lp-PLA2The pharmaceutical composition of the medicine of activity delivers medicine to need treatment Experimenter.Exemplary neurodegenerative diseases includes but not limited to, Alzheimer, vascular Dementia, parkinson disease and Huntington chorea.In a detailed description of the invention, nerve of the present invention Degenerative disease is relevant with abnormal blood brain barrier.In one embodiment, suppression Lp-PLA it is administered2 The experimenter of the medicament of activity is people.
In one embodiment, the present invention provides treatment suffer from vascular dementia or have vascular dementia The method of the experimenter of risk.Described method includes the medicine group of the compounds of this invention containing effective dose Compound delivers medicine to experimenter.In a detailed description of the invention, described vascular dementia Ahl tribulus sea silent sickness Relevant.
In a specific embodiment, with abnormal blood brain screen during the present invention provides the treatment experimenter that needs are treated The method of the neurological conditions that barrier function, inflammation or glial activation are relevant.Described method includes The compounds of this invention of effective dose is delivered medicine to experimenter.In another embodiment, described abnormal blood Brain barrier is permeability blood brain barrier.In another embodiment, described disease is nervus retrogression disease Sick.This kind of neurodegenerative diseases such as but not limited to, vascular dementia, Alzheimer, handkerchief gold Gloomy disease and Huntington Chorea.In one embodiment, the present invention provide treatment experimenter with blood brain Barrier reveals the method for relevant disease.Exemplary disease includes but not limited to, cerebral hemorrhage, brain starch Angiopathy.In one embodiment, described neurodegenerative diseases is Alzheimer.One In individual embodiment, described neurodegenerative diseases is vascular dementia.In one embodiment, institute Stating neurodegenerative diseases is multiple sclerosis.
In a specific embodiment, the present invention provides and reduces the side of amyloid beta accumulation in experimenter's brain Method.Described method includes that the pharmaceutical composition of the compounds of this invention containing effective dose is delivered medicine to needs controls The experimenter treated.In another embodiment, described amyloid beta is A β-42.
In a specific embodiment, when to the compounds of this invention of snibject's effective dose, described side Method can also include treating the neurodegenerative disease of the experimenter treated by can be used for or being probably merging The another kind of Therapeutic Administration of disease is in experimenter, or can also include using other therapies simultaneously.Such as, When described neurodegenerative disease is similar to Alzheimer's disease, experimenter can use targeting Alzheimer Other medicaments or other therapy for treating, described medicament or therapy such as donepezil, tacrine, profit all This bright, galantamine, anti-amyloid vaccine, A β reduces therapy, thinking exercise or stimulates.
In a specific embodiment, the present invention relates to by the compounds of this invention of effective dose being delivered medicine to need The method of subject's metabolic osteopathy to be treated.Exemplary metabolic osteopathy include with sclerotin and The disease that loss of bone density is relevant, includes but not limited to osteoporosis and osteopenia relevant disease.Show Osteoporosis and the osteopenia relevant disease of example include but not limited to, bone marrow exception, dyslipidemia, Pa Jiteshi disease, type ii diabetes, metabolism syndrome, insulin resistant, parathyroid gland are hyperfunction and relevant Disease.In another embodiment, the experimenter needing treatment is people.
It has been generally acknowledged that the method preventing osteoporosis described herein and/or osteopenia disease may be subject to To suppression Lp-PLA2Expression and/or suppression Lp-PLA2The impact of protein active.Therefore, the present invention Some embodiments provide block enzymatic activity suppress Lp-PLA2Method.At another embodiment In, it is provided that by reducing and/or lowering Lp-PLA2The expression of RNA thus suppress Lp-PLA2Side Method.In another embodiment, prevent and/or reduce bone mass loss and/or loss of bone density, thus Prevent or reduce the symptom relevant with metabolic osteopathy such as osteoporosis and/or osteopenia disease.
In a specific embodiment, described method also includes the other treatment by being used for treating metabolic osteopathy Agent delivers medicine to need the experimenter for the treatment of.Such as, when described metabolic osteopathy is osteoporosis, can To use other therapeutic agents, such as bis phosphoric acid salt therapeutic agent.
An aspect of of the present present invention provides the method treating oculopathy by the compounds of this invention of effective dosage. The oculopathy that the present invention is suitable for can be relevant with the destruction of barrier in blood retina.Exemplary oculopathy relates to sugar Urine characteristic of disease oculopathy and the disease including macular edema, diabetic retinopathy etc..Additionally, a reality Execute in mode, the present invention relates to by being administered the compounds of this invention to suppress Lp-PLA2The side for the treatment of oculopathy Method.Exemplary oculopathy includes but not limited to, central retinal vein occlusion, branch retinal vein hinder Plug, Yi-add syndrome, retinitis pigmentosa, par inflammation, birdshot chorioretinopathy, Ectoretina film, choroidal tumor, capsule macular edema, parafovea telangiectasis, traction Property maculopathy, Vitreomacular traction syndrome, detachment of retina, neuroretinitis, idiopathic Macular edema etc..
Additionally, some embodiments of the present invention provide the diabetic macular edema for treating experimenter Method.Described method includes the experimenter that the compounds of this invention of effective dose delivers medicine to needs treatment.? In detailed description of the invention, the present invention is provided to treat and suffer from macular edema or there is macular edema risk The method of experimenter.Described method includes the compounds of this invention of effective dose is delivered medicine to experimenter.Separately In one embodiment, described macular edema is relevant with diabetic oculopathy such as diabetic retinopathy. In another embodiment, described macular edema is relevant with posterior uveitis.
In a specific embodiment, the present invention provides treatment glaucoma or the method for degeneration of macula.Described side Method includes the compounds of this invention of effective dose is delivered medicine to experimenter.
In one embodiment, the present invention provide treatment need treatment experimenter with in blood retina The method of the disease that barrier breakdown is relevant.Described method includes delivering medicine to the compounds of this invention of effective dose Experimenter.
In one embodiment, SIDA such as juvenile rheumatoid arthritis, inflammatory Enteropathy, mucocutaneous lymphnode syndrome, multiple sclerosis, sarcoidosis, polyarteritis, arthritic psoriasis, reactivity Arthritis, systemic lupus erythematosus (sle), volt-Vogt-Koyanagi-Harada syndrome, Lyme disease, behcet disease, strong Straightforward spondylitis, inflammatory granuloma disease etc..The present invention relates to of the present inventionization by effective dosage The method of any one in compound treatment posterior uveitis or these systemic inflammatory disease.
Using method
Compound provided by the present invention and pharmaceutical composition can be various ways, as tablet, capsule, Powder, syrup, solution, suspensoid and aerosol etc., it is possible to be present in suitable solid or liquid In body carrier or diluent.The pharmaceutical composition of the present invention can also be stored in suitable injection or instil In disinfector.This pharmaceutical composition also can comprise odorant agent, flavouring agent etc..
In the present invention, it is (such as 0.1-99.9 weight portion, excellent that described pharmaceutical composition contains safe and effective amount Select 1-90 weight portion) the compound shown in formula (I) or its pharmaceutically acceptable salt；And the medicine of surplus Acceptable adjuvant on, wherein the gross weight of compositions is 100 weight portions.Or, of the present invention Pharmaceutical composition contain and account for gross weight 0.1-99.9 weight %, preferably comprise the formula of gross weight 1-90 weight % (I) compound shown in or its pharmaceutically acceptable salt；And the pharmaceutically acceptable adjuvant of surplus, Wherein the gross weight of compositions is 100 weight %.
Formula (I) compound with the preferred proportion of pharmaceutically acceptable carrier, excipient or slow releasing agent is, formula (I) accounting for gross weight more than 60% as active component, remainder accounts for gross weight 0-40%, remainder Amount is preferably 1-20%, most preferably 1-10%.
Compound shown in formula (I) of the present invention or comprise the pharmaceutical composition of formula (I) compound can be to mammal Clinical practice, including humans and animals, route of administration can include being administered orally, nasal cavity suction, Transdermal absorption, Pulmonary administration or gastrointestinal tract etc..Preferably route of administration is oral.It is preferably unit dosage forms, and every dose of bag Containing effective ingredient 0.01mg-200mg, preferably 0.5mg-100mg, once or part vic.The most effective what Plant instructions of taking, depending on the optimal dose of individual should be according to concrete treatment.It is from low dose under normal circumstances Starting, being gradually increased dosage until finding most suitable dosage.
The pharmaceutical composition of the present invention can be by oral and intravenous, intramuscular or the administration such as subcutaneous. In terms of position that is easily prepared and that be administered, preferred pharmaceutical composition is solid-state composition, especially tablet The capsule filled with solid-filling or liquid.The oral administration of pharmaceutical composition is preferred.
The features described above that the present invention mentions, or the feature that embodiment is mentioned can be in any combination.This case explanation All features disclosed in book can be with any composition forms use, each feature disclosed in description, Can identical by any offer, impartial or similar purpose alternative characteristics replace.Therefore say especially except having Bright, disclosed feature is only the impartial or general example of similar features.
Below in conjunction with specific embodiment, the present invention is expanded on further.Should be understood that these embodiments are only used for The present invention is described rather than limits the scope of the present invention.The reality of unreceipted actual conditions in the following example Proved recipe method, generally according to normal condition such as Sambrook et al., molecular cloning: laboratory manual (New York:Cold Spring Harbor Laboratory Press, 1989) condition described in, or according to maker Condition proposed by business.Unless otherwise indicated, otherwise percentage ratio and number are calculated by weight.
Unless otherwise defined, all specialties used in literary composition and scientific words and one skilled in the art institute The same meaning being familiar with.Additionally, any method similar or impartial to described content and material all can be answered In the inventive method.The method that is preferable to carry out described in literary composition only presents a demonstration with material and is used.
Preparation embodiment
The present invention be will be further illustrated below in an example.These embodiments are merely to illustrate this Invention, but limit the present invention never in any form.The initiation material used in the present invention without special instruction, It is purchased from lark prestige, safe smooth science and technology, splendid remote chemistry, reaches auspicious chemistry, traditional Chinese medicines etc..
Intermediate 1 (4-(4-chloro-3-(trifluoromethyl) phenoxy group) phenyl) methanol
By chloro-for 4-3-(trifluoromethyl) phenol (6.5g, 1 equivalent), 4-Fluorobenzaldehyde (3.9ml, 1.1 equivalents) And Anhydrous potassium carbonate (6g, 1.3 equivalents) is dissolved in DMF, nitrogen is protected, 120 DEG C Stirring 2h, cooling, add water, ethyl acetate is extracted twice, and saturated common salt is washed three times, anhydrous magnesium sulfate Being dried, filter, solvent evaporated obtains 11g intermediate 1a.MS(ESI):301(M+H).
Intermediate 1a (4.0g, 1 equivalent) is dissolved in 50ml dehydrated alcohol, under ice bath, adds sodium borohydride (493mg, 1 equivalent), is then stirred at room temperature 1h.Add aqueous ammonium chloride solution cancellation reaction, be evaporated molten Agent, adds water, and ethyl acetate is extracted twice, and saturated common salt is washed once, and anhydrous sodium sulfate is dried, mistake Filter, solvent evaporated, column chromatography for separation obtains 4g intermediate 1.MS(ESI):285(M-17).
Intermediate 2 (4-(4-chloro-3-(trifluoromethyl) phenoxy group) phenyl) methanthiol
Intermediate 1 (1.0g, 1 equivalent) is dissolved in and heavily steams in dichloromethane, under ice bath, drip thionyl chloride (480 μ l, 2 equivalents), are stirred at room temperature 2h, then solvent evaporated and thionyl chloride after being added dropwise to complete, 1.05g intermediate 2a, is not required to purification and is directly used in next step.
Intermediate 2a (210mg, 1 equivalent) is mixed in the anhydrous second of 2ml with thiourea (70mg, 1.4 equivalents) In alcohol, reflux 4h, is cooled to room temperature, adds 10N sodium hydrate aqueous solution (2ml), and reflux 3h, Being cooled to room temperature, add 4N aqueous hydrochloric acid solution regulation PH to 5, ethyl acetate extracts 3 times, saturated common salt Washing 1 time, anhydrous magnesium sulfate is dried, and filters, solvent evaporated, it is not necessary to purification is directly used in next step. MS(ESI):285(M-33)。
Intermediate 3 (4-(4-chloro-3-(trifluoromethyl) phenoxy group)-3,5-difluorophenyl) methanol
By chloro-for 4-3-(trifluoromethyl) phenol (4.67g, 1 equivalent), and 3,4,5-trifluro benzaldehydes (4.0g, 1.05 Equivalent) and Anhydrous potassium carbonate (4.27g, 1.3 equivalents) be dissolved in DMF, nitrogen Protection, 120 DEG C of stirring 2h, cooling, add water, ethyl acetate is extracted twice, and saturated common salt is washed three times, Magnesium sulfate is dried, and filters, and solvent evaporated obtains 8.0g intermediate 3a.MS(ESI):337(M+H).
Intermediate 3a (4.0g, 1 equivalent) is dissolved in 50ml dehydrated alcohol, under ice bath add sodium borohydride (440mg, 1 equivalent), 1h is then stirred at room temperature.Add aqueous ammonium chloride solution cancellation reaction, solvent evaporated, add water, Ethyl acetate is extracted twice, and saturated common salt is washed once, and anhydrous sodium sulfate is dried, and column chromatography for separation obtains 4g Intermediate 3.MS(ESI):321(M-17).
Intermediate 4 2-(4-(4-chloro-3-(trifluoromethyl) phenoxy group)-3,5-difluorophenyl) ethane-1-alcohol
Sodium hydride (950mg, 4 equivalents) is placed in flask, under ice bath, is sequentially added into super dry tetrahydrochysene Furan, methyltriphenylphospbromide bromide phosphorus (2.54g, 1.2 equivalents), 0 DEG C of stirring 1h, it is subsequently adding intermediate 3a (2g, 1 equivalent), is stirred at room temperature 2h.After having reacted, column chromatography for separation obtains 730mg intermediate 4a.
Intermediate 4a (730mg, 1 equivalent) is dissolved in super dry tetrahydrofuran, and nitrogen is protected, and adds under ice bath 1N borine tetrahydrofuran solution (2.2ml, 1.2 equivalents), is stirred at room temperature 1h, then slowly drips under ice bath Add the 2ml unnecessary borine of methanol cancellation, be dividedly in some parts sodium hydroxide (350mg, 4 equivalents), then add Hydrogen peroxide (3.1ml, 30% aqueous solution, 14 equivalents), fed rear 60 DEG C of reaction 2h, sulfurous acid Sodium water solution cancellation is reacted, and ethyl acetate extracts three times, and saturated common salt is washed once, and anhydrous sodium sulfate is done Dry, filter, solvent evaporated, column chromatography for separation obtains 600mg intermediate 4.MS(ESI):348(M-17).
Intermediate 5 4-(4-chloro-3-(trifluoromethyl) phenoxy group) phenol
Intermediate 1a (200mg, 1 equivalent) is dissolved in chloroform, under ice bath, adds metachloroperbenzoic acid (246mg, 1.5 equivalents, 70%), 24h is stirred at room temperature, adds sodium bicarbonate aqueous solution, be stirred vigorously A period of time, separating chloroform layer, anhydrous sodium sulfate is dried, and filters, and solvent evaporated, column chromatography for separation obtains 150mg intermediate 5.MS(ESI):289(M+1).
Intermediate 6 3-(4-(4-chloro-3-(trifluoromethyl) phenoxy group) phenyl) propane-1-alcohol
4-chloro-3-(trifluoromethyl) phenol (200mg, 1 equivalent), paradiiodobenzene (336mg, 1 equivalent), Potassium phosphate (432mg, 2 equivalents), Hydro-Giene (Water Science). (19mg, 0.1 equivalent) and tetrabutyl ammonium bromide (33mg, 0.1 equivalent) is mixed in DMF, 150 DEG C of reaction 22h.Add water, acetic acid Ethyl ester extracts, and anhydrous sodium sulfate is dried, and filters, and solvent evaporated, column chromatography for separation obtains 150mg intermediate 6a。
Intermediate 6a (150mg, 1 equivalent), propenyl (33mg, 1.5 equivalents), sodium bicarbonate (79mg, 2.5 equivalents), tetrabutylammonium chloride (105mg, 1 equivalent) and palladium (2mg, 0.02 equivalent) It is mixed in DMF, 60 DEG C of stirring 5h.Adding water, ethyl acetate extracts, anhydrous slufuric acid Sodium is dried, and filters, and solvent evaporated, column chromatography for separation obtains 65mg intermediate 6b.
Intermediate 6b (65mg, 1 equivalent) is dissolved in dehydrated alcohol, under ice bath, adds sodium borohydride (7.6mg, 1 equivalent), room temperature reaction 30min.Solvent evaporated, adds water, and ethyl acetate is extracted twice, Saturated common salt is washed once, and anhydrous sodium sulfate is dried, and filters, and solvent evaporated, column chromatography for separation obtains 60mg Intermediate 6.
Intermediate 7 (the fluoro-4-of 3-((5-(trifluoromethyl) pyridine-2-base) epoxide) phenyl) methanol
In addition to 2-chloro-5-(trifluoromethyl) pyridine and fluoro-4 hydroxy benzaldehydes of 3-as initial feed, ginseng Preparation method according to intermediate 1 prepares intermediate 7.
Intermediate 8 (4-((4-(trifluoromethyl) thiazol-2-yl) epoxide) phenyl) methanol
Bromo-1,1, the 1-trifluoro propane-2-ketone (5g, 1 equivalent) of 3-and thiourea (2.98g, 1.5 equivalents) are dissolved in In dehydrated alcohol, 55 DEG C of reaction 3h.Solvent evaporated, adds water, and regulates PH ≈ 10 with sodium hydrate aqueous solution, Dichloromethane extraction four times, saturated common salt washing, anhydrous sodium sulfate is dried, and filters, solvent evaporated, post Chromatography obtains 3.9g intermediate 8a.
Intermediate 8a (1.5g, 1 equivalent) and copper chloride (1.78g, 1.5 equivalents) are dissolved in acetonitrile, slow Slowly it is added dropwise to nitrite tert-butyl (1.6mL, 1.5 equivalents), after being added dropwise to complete, reacts 0.5h, then Evaporating major part acetonitrile, add dilute hydrochloric acid, ether extraction, saturated common salt is washed, and anhydrous sodium sulfate is dried, Filtering, solvent evaporated obtains 1.0g intermediate 8b.
Intermediate 8b (1g, 1 equivalent), hydroxy benzaldehyde (0.65g, 1.3 equivalents) and potassium carbonate (0.96g, 1.3 equivalents) it is mixed in DMF, 85 DEG C of reaction 6h.After having reacted, add water, second Acetoacetic ester extracts, and saturated common salt is washed, and anhydrous sodium sulfate is dried, and filters, and solvent evaporated, column chromatography divides From obtaining 0.65g intermediate 8c.
In addition to intermediate 1a is replaced to intermediate 8c, with reference to from intermediate 1a to intermediate 1 Preparation method prepares intermediate 8.
Intermediate 9 (1-(3,4-dichloro benzyl)-1H-pyrazoles-4-base) methanol
Sodium hydride (0.6g, 1.5 equivalents) is suspended in oxolane, ice bath, slowly adds under nitrogen protection Enter pyrazoles (760mg, 1.1 equivalents), addition 1 after 5min, 2-bis-chloro-4-(chloromethyl) benzene (1.38mL, 1 Equivalent), 50 DEG C of reactions are overnight.Aqueous ammonium chloride solution cancellation is reacted, and ethyl acetate extracts, saturated aqueous common salt Washing, anhydrous sodium sulfate is dried, and filters, and solvent evaporated, column chromatography for separation obtains 2.08g intermediate 9a.
Intermediate 9a (1.0g, 1 equivalent) is dissolved in dry DMF, 90 DEG C～100 DEG C Under, it is added dropwise over phosphorus oxychloride (0.45mL, 1.1 equivalents), is further continued for after being added dropwise to complete reacting 2h.Cold But, after, add shrend under ice bath and go out reaction, 10% sodium hydrate aqueous solution regulation PH ≈ 9, ethyl acetate extraction Taking, saturated common salt is washed 3 times, and anhydrous sodium sulfate is dried, and filters, and solvent evaporated obtains 1.0g intermediate 9b.
In addition to intermediate 1a is replaced to intermediate 9b, with reference to from intermediate 1a to intermediate 1 Preparation method prepare intermediate 9.
Intermediate 10 (2-(4-chloro-3-(trifluoromethyl) phenoxy group) oxazole-5-base) methanol
Ethyl bromide acetone (5mL, 1 equivalent) and carbamide (3.22g, 1.5 equivalents) are dissolved in dehydrated alcohol In, back flow reaction 5h, solvent evaporated, add water, aqueous sodium carbonate regulation PH ≈ 9, there is white solid Separating out, precipitation is collected by filtration, washing, ethanol is washed, and is dried to obtain 2.8g intermediate 10a.
Nitrite tert-butyl (3.22mL, 1.5 equivalents) and copper chloride (3.58g, 1.5 equivalents) are dissolved in second In nitrile, at 60 DEG C, it is dividedly in some parts intermediate 10a (2.8g, 1 equivalent), after adding, is warming up to 80 DEG C of reaction 1.5h, Evaporating major part acetonitrile, add water, dichloromethane extraction, saturated common salt is washed, and anhydrous sodium sulfate is dried, Filtering, be evaporated, column chromatography for separation obtains 2.13g intermediate 10b.
In addition to initial feed is chloro-3 trifloro methyl phenols of intermediate 10b Yu 4-, with reference to intermediate 1a Preparation method prepare intermediate 10c.
In addition to intermediate 1a is replaced to intermediate 10c, with reference to from intermediate 1a to intermediate 1 Preparation method prepare intermediate 10.
Intermediate 11 (6-(4-chloro-3-(trifluoromethyl) phenoxy group)-5 fluorine pyridin-3-yls) methanol
The chloro-3-of 2-fluoro-5-picoline (200mg, 1 equivalent), N-bromo-succinimide (734mg, 3 equivalents) and benzoyl peroxide (67mg, 0.2 equivalent) be mixed in carbon tetrachloride, 85 DEG C of reactions 8.5h.Solvent evaporated, adds water, and ethyl acetate extracts, and saturated common salt is washed 3 times, and anhydrous sodium sulfate is done Dry, filter, solvent evaporated obtains the crude product of 240mg intermediate 11a.
Intermediate 11a (240mg, 1 equivalent) and silver nitrate (538mg, 4 equivalents) are mixed in ethanol (2ml) With the mixed solution of water (2ml), 100 DEG C of reaction 1h, filtering, evaporate partial solvent, ethyl acetate extracts Taking, saturated common salt is washed, and anhydrous sodium sulfate is dried, and filters, and solvent evaporated, column chromatography for separation obtains 60mg Intermediate 11b.
In addition to 4-Fluorobenzaldehyde is replaced to intermediate 11b, with reference to the preparation method system of intermediate 1a Standby intermediate 11c.
In addition to intermediate 1a is replaced to intermediate 11c, with reference to from intermediate 1a to intermediate 1 Preparation method prepare intermediate 11.MS(ESI):322(M+1).
Intermediate 12 2-(4-(4-chloro-3-(trifluoromethyl) phenoxy group) phenyl) ethane-1-alcohol
In addition to intermediate 1a as raw material, the preparation method with reference to intermediate 4 prepares intermediate 12.
With reference to following table, in addition to using the corresponding raw material of raw material substitution described in " raw material " hurdle, reference The preparation method of intermediate 1 prepares following intermediate 13-27.
Intermediate 28 7-((4-(4-chloro-3-(trifluoromethyl) phenoxy group) benzyl) epoxide) imidazoles [1,2-a] is phonetic Pyridine
Intermediate 1 (3.0g, 1.5 equivalents) is dissolved in oxolane, under ice bath add sodium hydride (0.8g, 60%, 3 equivalents), stir 30min under ice bath, add chloro-2 aminopyrimidines of 4-(0.85g, 1 equivalent), room temperature Reaction is overnight.After having reacted, adding aqueous ammonium chloride solution cancellation reaction under ice bath, ethyl acetate extracts 3 times, anhydrous sodium sulfate is dried, and filters, and solvent evaporated, column chromatography for separation obtains 2.4g intermediate 28a.
Bromoacetaldehyde dimethyl-acetal (2.4mL, 8 equivalents) and aqueous solution of hydrogen bromide (850 μ L, 3 Equivalent, 48%) be dissolved in 95% ethanol, 80 DEG C of hydrolysis 6h, cooling, be dividedly in some parts sodium bicarbonate (1.0g, 5 equivalents), it is subsequently adding intermediate 28a (1.0g, 1 equivalent), is placed in 70 DEG C of reaction 2h.Reaction completes After, solvent evaporated, add dichloromethane, anhydrous sodium sulfate is dried, and filters, solvent evaporated, column chromatography Separate to obtain 310mg product intermediate 28.MS(ESI):420(M+H).
With reference to following table, in addition to using the corresponding raw material of raw material substitution described in " raw material " hurdle, reference The preparation method of intermediate 28 prepares following intermediate 29-51.
Intermediate 52 7-(benzyl sulfenyl)-3-(pyrimidine-5-base) imidazoles [1,2-a] pyrimidine
Intermediate 49 (685mg, 1 equivalent), 4-Bromopyrimidine (496mg, 1.1 equivalents), potassium acetate (556mg, 2 equivalents) it is mixed in N,N-dimethylacetamide with palladium (64mg, 0.1 equivalent), nitrogen is replaced, 140 DEG C of reaction 2h.Cooling, filters, and ethyl acetate extracts, and saturated common salt is washed, and anhydrous sodium sulfate is done Dry, filter, solvent evaporated, column chromatography for separation obtains 370mg intermediate 52.MS(ESI):320(M+1).
Intermediate 53 7-(benzylsulphonyl)-3-(pyrimidine-5-base) imidazoles [1,2-a] pyrimidine
Intermediate 52 (370mg, 1 equivalent) is dissolved in and heavily steams dichloromethane, adds m-chloro peroxide under ice bath Benzoic acid (715mg, 2.5 equivalents, 70%), under ice bath, react 3h.Sodium bicarbonate aqueous solution cancellation is anti- Answering, dichloromethane extraction, saturated sodium bicarbonate aqueous solution is washed, and saturated common salt is washed, and anhydrous magnesium sulfate is done Dry, filter, solvent evaporated obtains 240mg intermediate 53.MS(ESI):352(M+1).
The bromo-7-of intermediate 54 3-((4-(4-chloro-3-(trifluoromethyl) phenoxy group) benzyl) epoxide) imidazoles [1,2-a] pyrimidine
Intermediate 28 (560mg, 1 equivalent) is dissolved in oxolane, adds N-bromo fourth two under ice bath Acid imide (262mg, 1.1 equivalents), then room temperature reaction 1h.After having reacted, direct column chromatography divides From obtaining 240mg intermediate 54.MS(ESI):498(M+1).
The bromo-7-of intermediate 55 3-((4-(4-chloro-3-(trifluoromethyl) phenoxy group)-3,5-difluorobenzyl) epoxide) Imidazoles [1,2-a] pyrimidine
In addition to intermediate 29 as raw material, the preparation method with reference to intermediate 54 prepares intermediate 55. MS(ESI):534(M+1)。
The bromo-7-of intermediate 56 3-(4-(4-chloro-3-(trifluoromethyl) phenoxy group) benzene ethyoxyl)-[1,2,4] three Nitrogen azoles [4,3-a] pyrimidine
Intermediate 12 (1g, 1 equivalent) and sodium hydride (506mg, 4 equivalents, 60%) it is mixed in N, N- In dimethylformamide, under ice bath, stir 10min, addition 2,4 ,-dichloro pyrimidine, room temperature reaction 30min. Aqueous ammonium chloride solution cancellation is reacted, and ethyl acetate extracts, and saturated common salt is washed, and anhydrous sodium sulfate is dried, Filtering, solvent evaporated, column chromatography for separation obtains 1.22g intermediate 56a.
Intermediate 56a (1.22g, 1 equivalent) is dissolved in hydrazine hydrate (7mL), back flow reaction 1h.Steam Dry solvent, obtains 1.3g intermediate 56b, is not required to purification, is directly used in next step reaction.
Intermediate 56b (1.3g, 1 equivalent) is dissolved in triethyl orthoformate (10mL), 120 DEG C of reactions 3h.Solvent evaporated, column chromatography for separation obtains 1.14g intermediate 56c.
Intermediate 56c (1.14g, 1 equivalent) is dissolved in and heavily steams in dichloromethane, adds N-bromo succinyl Imines (1027mg, 2.2 equivalents), overnight, direct column chromatography for separation obtains 1.2g intermediate in 40 DEG C of reactions 56。MS(ESI):513(M+1)。
The bromo-7-of intermediate 57 3-((4-(4-chloro-3-(trifluoromethyl) phenoxy group)-3,5-difluorobenzyl) oxygen Base)-[1,2,4] triazole [4,3-a] pyrimidine
In addition to intermediate 3 as raw material, the preparation method with reference to intermediate 56 prepares intermediate 57. MS(ESI):535(M+1)。
The bromo-7-of intermediate 58 3-((4-(4-chloro-3-(trifluoromethyl) phenoxy group) benzyl) epoxide)-5-methyl miaow Azoles [1,2-a] pyrimidine
In addition to intermediate 50 as raw material, the preparation method with reference to intermediate 54 prepares intermediate 58. MS(ESI):498(M+1)。MS(ESI):512(M+1)。
The bromo-7-of intermediate 59 3-((4-(4-chloro-3-(trifluoromethyl) phenoxy group)-3,5 difluorobenzyls) oxygen Base)-5-Methylimidazole. [1,2-a] pyrimidine
In addition to intermediate 51 as raw material, the preparation method with reference to intermediate 54 prepares intermediate 59. MS(ESI):548(M+1)。
The bromo-3-of intermediate 60 2-(1-methyl isophthalic acid H-pyrazoles-4-base) propane
N-methylpyrazole (1.0g, 1 equivalent) is dissolved in DMF (2.8ml, 3 equivalents), Dripping phosphorus oxychloride (1.3ml, 1.2 equivalents) at 90 DEG C, about 1h is added dropwise to complete, and is further continued for reacting 2h. Cooling, reactant liquor pours in frozen water, 10% sodium hydrate aqueous solution regulation PH to 4～5, dichloromethane Extracting 4 times, wash twice, anhydrous sodium sulfate is dried, and filters, and solvent evaporated, column chromatography for separation obtains 600mg Intermediate 60a.
Intermediate 60a (600mg, 1 equivalent) is dissolved in dioxane (16mL), under room temperature, depends on Secondary addition cesium carbonate (4.0g, 2 equivalents), phosphoric acid 3-acetic acid methyl ester (1.1g, 2 equivalents), dimethyl is sub- Sulfone (4mL), is placed in 100 DEG C of reactions overnight.Adding water, ethyl acetate extracts, and saturated common salt is washed, nothing Aqueous sodium persulfate is dried, and filters, and solvent evaporated, column chromatography for separation obtains 650mg intermediate 60b.
Intermediate 60b (650mg, 1 equivalent) is dissolved in dehydrated alcohol, adds 10%Pd/C (65mg), Under hydrogen environment, 40 DEG C of reactions are overnight.Cooling, filters, and solvent evaporated obtains 500mg intermediate 60c.
Intermediate 60c (500mg, 1 equivalent) is dissolved in oxolane, is slowly added to lithium hydride under ice bath Aluminum (113mg, 1 equivalent), room temperature reaction 1h.After having reacted, it is sequentially added into a certain amount of acetic acid second Ester, sodium bicarbonate aqueous solution, water, then to filter, oxolane filter wash cake, filtrate is evaporated to obtain 435mg Intermediate 60d.
Oxalyl chloride (428 μ L, 1.5 equivalents) is dissolved in dichloromethane, and nitrogen is protected, as-60 DEG C of cold hydrazines, It is slowly added to dichloromethane (2mL) solution of dimethyl sulfoxide (0.64mL, 3 equivalents), about 5min Add, stir 5min after adding, be subsequently adding the dichloromethane solution of intermediate 60d, about 10min and add Complete, stir 5min after adding, be subsequently adding triethylamine (1.67mL, 4 equivalents), about 3min adds, From cold hydrazine, take out reaction bulb after stirring 5min after adding, be placed in room temperature reaction 5min.The cancellation that adds water is anti- Should, separating dichloromethane layer, saturated common salt is washed, and anhydrous sodium sulfate is dried, and filters, solvent evaporated, Column chromatography for separation obtains 100mg intermediate 60e.
Intermediate 60e (70mg, 1 equivalent), N-bromo-succinimide (99mg, 1.1 equivalents) with L-PROLINE (11.5mg, 0.2 equivalent) is dissolved in dichloromethane, room temperature reaction 2h, saturated aqueous common salt Washing, anhydrous magnesium sulfate is dried, and filters, and solvent evaporated, column chromatography for separation obtains 60mg intermediate 60.
Embodiment 1 7-((4-(4-chloro-3-(trifluoromethyl) phenoxy group) benzyl) epoxide)-3-(pyrimidine-5-base) Imidazoles [1,2-a] pyrimidine
Intermediate 28 (100mg, 1 equivalent), 4-Bromopyrimidine (42mg, 1.1 equivalents), potassium acetate (44mg, 2 equivalents) it is mixed in N,N-dimethylacetamide with palladium (6mg, 0.1 equivalent), nitrogen is replaced, 140 DEG C of reaction 2h, cooling, filter, ethyl acetate extracts, and saturated common salt is washed, and anhydrous sodium sulfate is done Dry, filter, solvent evaporated, column chromatography for separation obtains embodiment 1 compound of 60mg white solid.1H NMR (400MHz, Chloroform-d) δ 9.27 (s, 1H), 8.93 (s, 2H), 8.33 (d, J=7.4Hz, 1H), 7.76 (s, 1H), 7.54 (d, J=8.6Hz, 2H), 7.45 (d, J=8.8Hz, 1H), 7.34 (d, J=2.9Hz, 1H), 7.10 (dd, J=8.8,2.8Hz, 1H), 7.04 (d, J=8.6Hz, 2H), 6.61 (d, J=7.4Hz, 1H),5.55(s,2H).MS(ESI):498(M+H)。
(2-methoxyl group is phonetic for-3-for embodiment 2 7-((4-(4-chloro-3-(trifluoromethyl) phenoxy group) benzyl) epoxide) Pyridine-5-base) imidazoles [1,2-a] pyrimidine
In addition to intermediate 28 and 2-methoxyl group-4 Bromopyrimidine as raw material, with reference to the system of embodiment 1 Preparation Method prepares embodiment 2 compound.1H NMR(300MHz,Chloroform-d)δ8.65(s,2H), 8.19 (d, J=7.4Hz, 1H), 7.63 (d, J=10.0Hz, 1H), 7.54 (d, J=8.5Hz, 2H), 7.44 (d, J=8.7Hz, 1H), 7.34 (d, J=2.8Hz, 1H), 7.09 (dd, J=8.7,2.8Hz, 1H), 7.02 (d, J=8.2Hz, 2H), 6.57 (d, J=7.1Hz, 1H), 5.53 (s, 2H), 4.10 (s, 3H) .MS (ESI): 528(M+H)。
Embodiment 3 7-(4-(4-chloro-3-(trifluoromethyl) phenoxy group) benzene ethyoxyl)-3-(pyrimidine-5-base) miaow Azoles [1,2-a] pyrimidine
In addition to intermediate 33 and 4-Bromopyrimidine as raw material, with reference to the preparation method system of embodiment 1 Standby embodiment 3 compound.1H NMR(400MHz,Chloroform-d)δ9.26(s,1H),8.92(s, 2H), 8.30 (d, J=7.4Hz, 1H), 7.72 (s, 1H), 7.42 (d, J=8.8Hz, 1H), 7.32 (m, 3H), 7.06 (d, J=9.0Hz, 1H), 6.98 (d, J=8.0Hz, 2H), 6.54 (d, J=8.3Hz, 1H), 4.74 (t, J=6.5Hz, 2H), 3.16 (t, J=6.4Hz, 2H) .MS (ESI): 512 (M+H).
(7-(4-(4-chloro-3-(trifluoromethyl) phenoxy group) benzene ethyoxyl) imidazoles [1,2-a] is phonetic for embodiment 4 1- Pyridine-3-base)-N, N-dimethyl methylamine
By intermediate 33 (30mg, 1 equivalent), N, N-dimethyl iodine alkene imines (15mg, 1.2 equivalents) Being dissolved in acetonitrile, back flow reaction 1.5h, solvent evaporated, column chromatography for separation obtains 20mg product, i.e. implements The compound of example 4.1H NMR (400MHz, Chloroform-d) δ 8.43 (d, J=7.3Hz, 1H), 7.41 (d, J=8.7Hz, 1H), 7.32 (m, 4H), 7.05 (dd, J=8.8,2.9Hz, 1H), 6.96 (d, J= 8.6Hz, 2H), 6.38 (d, J=7.3Hz, 1H), 4.68 (t, J=6.9Hz, 2H), 3.62 (s, 2H), 3.12 (t, J=6.8Hz, 2H), 2.21 (s, 6H) .MS (ESI): 491 (M+H).
Embodiment 5 7-((4-(4-chloro-3-(trifluoromethyl) phenoxy group) benzyl) epoxide)-3-((1-methyl isophthalic acid H- Pyrazoles-4-base) methyl) imidazoles [1,2-a] pyrimidine
Intermediate 60 (16mg, 1 equivalent) is dissolved in ethanol (1mL) and the mixed solvent of water (1mL) In, add intermediate 28a, 70 DEG C of reaction 7h.Solvent evaporated, column chromatography for separation obtains 3mg product, i.e. Embodiment 5 compound.1H NMR (400MHz, Chloroform-d) δ 7.91 (d, J=7.4Hz, 1H), 7.51 (d, J=8.6Hz, 2H), 7.43 (d, J=8.6Hz, 1H), 7.35 (s, 1H), 7.34 (d, J=2.1Hz, 2H), 7.10 (s, 1H), 7.08 (dd, J=8.9,2.9Hz, 1H), 7.02 (d, J=8.5Hz, 2H), 6.41 (d, J=7.3Hz, 1H), 5.49 (s, 2H), 4.01 (s, 2H), 3.84 (s, 3H) .MS (ESI): 514 (M+H).
Embodiment 6 7-(benzyl epoxide)-3-(pyrimidine-5-base) imidazoles [1,2-a] pyrimidine
Benzyl alcohol (23mg, 1.5 equivalents) stirs 30min with sodium hydride (17mg, 3 equivalents) in 0 DEG C, Adding intermediate 53 (50mg, 1 equivalent), room temperature reaction is overnight.Add aqueous ammonium chloride solution cancellation anti- Should, ethyl acetate extracts, and saturated common salt is washed, and anhydrous sodium sulfate is dried, and filters, solvent evaporated, post Chromatography obtains 40mg product, i.e. embodiment 6 compound.1H NMR(300MHz,Chloroform-d) δ 9.25 (s, 1H), 8.92 (s, 2H), 8.31 (d, J=7.4Hz, 1H), 7.73 (s, 1H), 7.51 (dd, J= 7.9,1.6Hz, 2H), 7.44 7.35 (m, 3H), 6.59 (d, J=7.4Hz, 1H), 5.55 (s, 2H) .MS (ESI):304(M+H)。
Embodiment 7 2-(4-chloro-3-(trifluoromethyl) phenoxy group)-5-(((3-(pyrimidine-5-base) imidazoles [1,2-a] Pyrimidin-7-yl) epoxide) methyl) benzonitrile
In addition to intermediate 35 and 4-Bromopyrimidine as raw material, with reference to the preparation method system of embodiment 1 Standby embodiment 7 compound.1H NMR(300MHz,Chloroform-d)δ9.28(s,1H),8.93(s, 2H), 8.36 (d, J=7.4Hz, 1H), 7.85 (d, J=1.8Hz, 1H), 7.75 (s, 1H), 7.71 (dd, J= 8.6,2.0Hz, 1H), 7.54 (d, J=8.8Hz, 1H), 7.42 (d, J=2.8Hz, 1H), 7.20 (dd, J= 8.7,2.7Hz, 1H), 6.94 (d, J=8.6Hz, 1H), 6.63 (d, J=7.4Hz, 1H), 5.56 (s, 2H). MS(ESI):523(M+H)。
Embodiment 8 7-((4-(4-chloro-3-(trifluoromethyl) phenoxy group) benzyl) epoxide)-3-(4-fluorophenyl) miaow Azoles [1,2-a] pyrimidine
Intermediate 54 (37mg, 1 equivalent), to fluorobenzoic boric acid (12mg, 1.1 equivalents), two (triphens Base phosphorus) palladium chloride (2.6mg, 0.05 equivalent) and sodium carbonate (23.5mg, 3 equivalents) be mixed in dioxy In the mixed solution of six rings (5mL) and water (1mL), 150 DEG C of microwave reaction 30min.Evaporate part Solvent, adds water, and ethyl acetate extracts, and anhydrous sodium sulfate is dried, and filters, and solvent evaporated, column chromatography divides From obtaining 15mg product, i.e. embodiment 8 compound.1H NMR(300MHz,Chloroform-d)δ8.30 (d, J=7.4Hz, 1H), 7.48 (dd, J=28.2,8.5Hz, 6H), 7.33 (s, 1H), 7.21 (t, J=8.5 Hz, 2H), 7.13 6.93 (m, 3H), 6.51 (d, J=6.6Hz, 1H), 5.51 (s, 2H) .MS (ESI): 514(M+H)。
Embodiment 9 7-((4-(4-chloro-3-(trifluoromethyl) phenoxy group) benzyl) epoxide)-3-(4-methoxybenzene Base) imidazoles [1,2-a] pyrimidine
Except with intermediate 54 and to methoxyphenylboronic acid as raw material in addition to, with reference to the preparation side of embodiment 8 Method prepares embodiment 9 compound.1H NMR (300MHz, Chloroform-d) δ 8.30 (d, J=7.3 Hz, 1H), 7.63 7.28 (m, 7H), 7.04 (m, 5H), 6.49 (d, J=6.8Hz, 1H), 5.49 (s, 2H), 3.86(s,3H).MS(ESI):526(M+H)。
Embodiment 10 7-((4-(4-chloro-3-(trifluoromethyl) phenoxy group)-3,5-difluorobenzyl) epoxide)-3-is (phonetic Pyridine-5-base) imidazoles [1,2-a] pyrimidine
In addition to intermediate 29 and 4-Bromopyrimidine as raw material, with reference to the preparation method system of embodiment 1 Standby embodiment 10 compound.1H NMR(300MHz,Chloroform-d)δ9.28(s,1H),8.94(s, 2H), 8.37 (d, J=7.4Hz, 1H), 7.76 (s, 1H), 7.42 (d, J=8.8Hz, 1H), 7.30 (d, J= 2.9Hz, 1H), 7.20 (d, J=8.1Hz, 2H), 7.03 (dd, J=8.7,2.7Hz, 1H), 6.65 (d, J= 7.4Hz,1H),5.56(s,2H).MS(ESI):534(M+H)。
Embodiment 11 7-((4-(4-chloro-3-(trifluoromethyl) phenoxy group)-3-luorobenzyl) epoxide)-3-(pyrimidine -5-base) imidazoles [1,2-a] pyrimidine
In addition to intermediate 34 and 4-Bromopyrimidine as raw material, with reference to the preparation method system of embodiment 1 Standby embodiment 11 compound.1H NMR(300MHz,Chloroform-d)δ9.27(s,1H),8.93(s, 2H), 8.35 (d, J=7.4Hz, 1H), 7.75 (s, 1H), 7.48 7.35 (m, 2H), 7.34 7.29 (m, 2H), 7.13 (t, J=8.2Hz, 1H), 7.05 (dd, J=8.8,2.5Hz, 1H), 6.63 (d, J=7.4Hz, 1H),5.56(s,2H).MS(ESI):516(M+H)。
Embodiment 12 7-((4-(3,4-difluorophenyl epoxide)-3-luorobenzyl) epoxide)-3-(pyrimidine-5-base) miaow Azoles [1,2-a] pyrimidine
In addition to intermediate 36 and 4-Bromopyrimidine as raw material, with reference to the preparation method system of embodiment 1 Standby embodiment 12 compound.1H NMR(300MHz,Chloroform-d)δ9.27(s,1H),8.92(s, 2H), 8.33 (d, J=7.5Hz, 1H), 7.77 (s, 1H), 7.35 (d, J=11.0Hz, 1H), 7.29 (s, 1H), 7.08 (td, J=8.7,5.5Hz, 2H), 6.80 (ddd, J=10.0,6.5,3.2Hz, 1H), 6.74 6.66 (m, 1H), 6.62 (d, J=7.5Hz, 1H), 5.54 (s, 2H) .MS (ESI): 450 (M+H).
Embodiment 13 7-((4-(4-chloro-3-(trifluoromethyl) phenoxy group) benzyl) epoxide)-5-methyl-3-is (phonetic Pyridine-5-base) imidazoles [1,2-a] pyrimidine
In addition to intermediate 58 and 4-pyrimidine boronic acid as raw material, with reference to the preparation method of embodiment 8 Preparation embodiment 13 compound.1H NMR(400MHz,Chloroform-d)δ9.28(s,1H),8.84 (s, 2H), 7.57 7.48 (m, 3H), 7.44 (d, J=8.8Hz, 1H), 7.34 (d, J=2.8Hz, 1H), 7.09 (dd, J=8.7,2.8Hz, 1H), 7.03 (d, J=8.6Hz, 2H), 6.31 (s, 1H), 5.53 (s, 2H), 2.20(s,3H).MS(ESI):512(M+H)。
Embodiment 14 7-((4-(4-chloro-3-(trifluoromethyl) phenoxy group) benzyl) epoxide)-3-(pyridin-4-yl) Imidazoles [1,2-a] pyrimidine
In addition to intermediate 54 and 4-pyridine boronic acid as raw material, with reference to the preparation method of embodiment 8 Preparation embodiment 14.1H NMR (400MHz, Chloroform-d) δ 8.75 (d, J=5.1Hz, 2H), 8.55 (d, J=4.4Hz, 1H), 7.87 (s, 1H), 7.57 7.47 (m, 4H), 7.44 (d, J=8.7Hz, 1H), 7.33 (d, J=2.6Hz, 1H), 7.09 (dd, J=8.6,2.7Hz, 1H), 7.03 (d, J=8.3Hz, 2H), 6.63 (d, J=7.4Hz, 1H), 5.55 (s, 2H) .MS (ESI): 497 (M+H).
Embodiment 15 7-((4-(4-chloro-3-(trifluoromethyl) phenoxy group) benzyl) epoxide)-3-(pyridin-3-yl) Imidazoles [1,2-a] pyrimidine
In addition to intermediate 28 and 3-bromopyridine as raw material, with reference to the preparation method system of embodiment 1 Standby embodiment 15 compound.1H NMR(400MHz,Chloroform-d)δ8.80(s,1H),8.69(d, J=4.2Hz, 1H), 8.35 (d, J=7.4Hz, 1H), 7.82 (d, J=8.1Hz, 1H), 7.70 (s, 1H), 7.54 (d, J=8.5Hz, 2H), 7.49 7.42 (m, 2H), 7.34 (d, J=2.8Hz, 1H), 7.09 (dd, J =8.8,3.0Hz, 1H), 7.03 (d, J=8.6Hz, 2H), 6.56 (d, J=7.4Hz, 1H), 5.53 (s, 2H). MS(ESI):497(M+H)。
Embodiment 16 7-((4-(4-chloro-3-(trifluoromethyl) phenoxy group)-3,5-difluorobenzyl) epoxide)-5-first Base-3-(pyrimidine-5-base) imidazoles [1,2-a] pyrimidine
In addition to intermediate 59 and 4-pyrimidine boronic acid as raw material, with reference to the preparation method of embodiment 8 Preparation embodiment 16 compound.1H NMR(300MHz,Chloroform-d)δ9.29(s,1H),8.84 (s, 2H), 7.56 (s, 1H), 7.41 (d, J=8.7Hz, 1H), 7.29 (s, 1H), 7.18 (d, J=8.1Hz, 2H), 7.01 (d, J=8.4Hz, 1H), 6.36 (s, 1H), 5.54 (s, 2H), 2.23 (s, 3H) .MS (ESI): 548(M+H)。
Embodiment 17 7-((the fluoro-4-of 3,5-bis-(4-fluoro-3-(trifluoromethyl) phenoxy group) benzyl) epoxide)-3-is (phonetic Pyridine-5-base) imidazoles [1,2-a] pyrimidine
In addition to intermediate 37 and 4-Bromopyrimidine as raw material, with reference to the preparation method system of embodiment 1 Standby embodiment 17 compound.1H NMR(300MHz,Chloroform-d)δ9.31(s,1H),8.96(s, 2H), 8.39 (d, J=7.2Hz, 1H), 7.81 (s, 1H), 7.17 (m, 5H), 6.73 (d, J=7.3Hz, 1H), 5.58(s,2H).MS(ESI):518(M+H)。MS(ESI):518(M+H)。
Embodiment 18 7-((the fluoro-4-of 3,5-bis-(3-(trifluoromethyl) phenoxy group) benzyl) epoxide)-3-(pyrimidine-5- Base) imidazoles [1,2-a] pyrimidine
In addition to intermediate 38 and 4-Bromopyrimidine as raw material, with reference to the preparation method system of embodiment 1 Standby embodiment 18 compound.1H NMR(300MHz,Chloroform-d)δ9.30(s,1H),8.95(s, 2H), 8.39 (d, J=6.1Hz, 1H), 7.80 (s, 1H), 7.38 (m, 2H), 7.21 (m, 3H), 7.12 (d, J =8.0Hz, 1H), 6.71 (d, J=6.0Hz, 1H), 5.58 (s, 2H) .MS (ESI): 500 (M+H).
Embodiment 19 7-((the fluoro-4-of 3,5-bis-((6-picoline-3-base) epoxide) benzyl) epoxide)-3-(pyrimidine -5-base) imidazoles [1,2-a] pyrimidine
In addition to intermediate 39 and 4-Bromopyrimidine as raw material, with reference to the preparation method system of embodiment 1 Standby embodiment 19 compound.1H NMR(300MHz,Chloroform-d)δ9.28(s,1H),8.94(s, 2H), 8.38 (d, J=7.4Hz, 1H), 8.23 (d, J=2.6Hz, 1H), 7.77 (s, 1H), 7.34 (d, J= 7.1Hz, 1H), 7.21 (d, J=8.2Hz, 3H), 6.66 (d, J=7.4Hz, 1H), 5.55 (s, 2H), 2.62 (s,3H).MS(ESI):447(M+H)。
Embodiment 20 7-((4-((6-chloropyridine-3-base) epoxide)-3,5-difluorobenzyl) epoxide)-3-(pyrimidine -5-base) imidazoles [1,2-a] pyrimidine
In addition to intermediate 40 and 4-Bromopyrimidine as raw material, with reference to the preparation method system of embodiment 1 Standby embodiment 20 compound.1H NMR(400MHz,Chloroform-d)δ9.28(s,1H),8.94(s, 2H), 8.37 (d, J=7.4Hz, 1H), 8.14 (d, J=2.8Hz, 1H), 7.76 (s, 1H), 7.25 (m, 2H), 7.20 (d, J=8.1Hz, 2H), 6.65 (d, J=7.4Hz, 1H), 5.56 (s, 2H) .MS (ESI): 467 (M+H)。
Embodiment 21 7-((4-(3-chloro-4-methylphenoxy)-3,5-difluorobenzyl) epoxide)-3-(pyrimidine-5- Base) imidazoles [1,2-a] pyrimidine
In addition to intermediate 41 and 4-Bromopyrimidine as raw material, with reference to the preparation method system of embodiment 1 Standby embodiment 21 compound.1H NMR(400MHz,Chloroform-d)δ9.27(s,1H),8.93(s, 2H), 8.36 (d, J=7.3Hz, 1H), 7.75 (s, 1H), 7.16 (d, J=7.9Hz, 2H), 7.13 (d, J= 8.5Hz, 1H), 6.96 6.90 (m, 1H), 6.80 6.74 (m, 1H), 6.64 (d, J=7.4Hz, 1H), 5.54(s,2H),2.31(s,3H).MS(ESI):480(M+H)。
Embodiment 22 4-(the fluoro-4-of 2,6-bis-(((3-(pyrimidine-5-base) imidazoles [1,2-a] pyrimidin-7-yl) epoxide) Methyl) phenoxy group)-2-fluorobenzonitrile
In addition to intermediate 42 and 4-Bromopyrimidine as raw material, with reference to the preparation method system of embodiment 1 Standby embodiment 22 compound.1H NMR(300MHz,Chloroform-d)δ9.28(s,1H),8.94(s, 2H), 8.38 (d, J=7.2Hz, 1H), 7.77 (s, 1H), 7.58 (t, J=7.6Hz, 1H), 7.23 (d, J= 8.2Hz, 2H), 6.81 (dd, J=21.1,9.7Hz, 2H), 6.66 (d, J=7.2Hz, 1H), 5.57 (s, 2H). MS(ESI):475(M+H)。
Embodiment 23 7-((the fluoro-4-of 3,5-bis-(4-(trifluoromethyl) phenoxy group) benzyl) epoxide)-3-(pyrimidine-5- Base) imidazoles [1,2-a] pyrimidine
In addition to intermediate 43 and 4-Bromopyrimidine as raw material, with reference to the preparation method system of embodiment 1 Standby embodiment 23 compound.1H NMR(400MHz,Chloroform-d)δ9.28(s,1H),8.94(s, 2H), 8.38 (d, J=7.4Hz, 1H), 7.77 (s, 1H), 7.57 (d, J=8.6Hz, 2H), 7.24 7.17 (m, 2H), 7.02 (d, J=8.6Hz, 2H), 6.66 (d, J=7.4Hz, 1H), 5.56 (s, 2H) .MS (ESI): 500(M+H)。
Embodiment 24 7-((4-(3,4-dichlorophenoxy)-3,5-difluorobenzyl) epoxide)-3-(pyrimidine-5-base) Imidazoles [1,2-a] pyrimidine
In addition to intermediate 44 and 4-Bromopyrimidine as raw material, with reference to the preparation method system of embodiment 1 Standby embodiment 24 compound.1H NMR(400MHz,Chloroform-d)δ9.28(s,1H),8.94(s, 2H), 8.37 (d, J=7.4Hz, 1H), 7.76 (s, 1H), 7.36 (d, J=8.9Hz, 1H), 7.19 (d, J= 8.0Hz, 2H), 7.04 (d, J=3.2Hz, 1H), 6.84 (dd, J=9.0,2.8Hz, 1H), 6.65 (d, J= 7.5Hz,1H),5.56(s,2H).MS(ESI):500(M+H)。
Embodiment 25 7-((the fluoro-4-of 3-((5-(trifluoromethyl) pyridine-2-base) epoxide) benzyl) epoxide)-3-is (phonetic Pyridine-5-base) imidazoles [1,2-a] pyrimidine
In addition to intermediate 31 and 4-Bromopyrimidine as raw material, with reference to the preparation method system of embodiment 1 Standby embodiment 25 compound.1H NMR(300MHz,Chloroform-d)δ9.27(s,1H),8.93(s, 2H), 8.39 (s, 1H), 8.34 (d, J=7.4Hz, 1H), 7.94 (dd, J=8.5,2.0Hz, 1H), 7.75 (s, 1H), 7.37 (t, J=8.2Hz, 2H), 7.30 7.21 (m, 1H), 7.12 (d, J=8.7Hz, 1H), 6.62 (d, J=7.4Hz, 1H), 5.57 (s, 2H) .MS (ESI): 483 (M+H).
Embodiment 26 2-(4-(((3-(pyrimidine-5-base) imidazoles [1,2-a] pyrimidin-7-yl) epoxide) methyl) benzene oxygen Base)-4-(trifluoromethyl) thiazole
In addition to intermediate 8 and intermediate 53 as raw material, prepared by the preparation method with reference to embodiment 6 Embodiment 26 compound.1H NMR(300MHz,Chloroform-d)δ9.27(s,1H),8.93(s, 2H), 8.34 (d, J=7.4Hz, 1H), 7.75 (s, 1H), 7.60 (d, J=8.5Hz, 2H), 7.36 (d, J= 8.6Hz, 2H), 7.29 (s, 1H), 6.61 (d, J=7.4Hz, 1H), 5.58 (s, 2H) .MS (ESI): 455 (M+H)。
Embodiment 27 7-((1-(3,4-dichloro benzyl)-1H-pyrazoles-4-base) methoxyl group)-3-(pyrimidine-5-base) Imidazoles [1,2-a] pyrimidine
In addition to intermediate 9 and intermediate 53 as raw material, prepared by the preparation method with reference to embodiment 6 Embodiment 27 compound.1H NMR(400MHz,Chloroform-d)δ9.26(s,1H),8.92(s, 2H), 8.30 (d, J=7.4Hz, 1H), 7.73 (s, 1H), 7.70 (s, 1H), 7.68 (s, 1H), 7.41 (d, J= 8.2Hz, 1H), 7.30 (d, J=1.9Hz, 1H), 7.07 (dd, J=8.3,1.9Hz, 1H), 6.53 (d, J= 7.4Hz,1H),5.46(s,2H).MS(ESI):452(M+H)。
Embodiment 28 2-(4-chloro-3-(trifluoromethyl) phenoxy group)-4-(((3-(pyrimidine-5-yl) imidazoles [1,2-a] Pyrimidin-7-yl) epoxide) methyl) oxazole
In addition to intermediate 10 and intermediate 53 as raw material, with reference to the preparation method system of embodiment 6 Standby embodiment 28 compound.1H NMR(400MHz,Chloroform-d)δ9.26(s,1H),8.92(s, 2H), 8.32 (d, J=7.4Hz, 1H), 7.74 (d, J=3.8Hz, 2H), 7.59 7.55 (m, 3H), 6.59 (d, J=7.4Hz, 1H), 5.39 (s, 2H) .MS (ESI): 489 (M+H).
Embodiment 29 7-((4-(4-chloro-3-(trifluoromethyl) phenoxy group) benzyl) epoxide)-3-(1-methyl isophthalic acid H- Pyrazoles-4-base) imidazoles [1,2-a] pyrimidine
Except with intermediate 28 and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxy boron penta ring-2-base) pyrazoles Beyond raw material, the preparation method with reference to embodiment 8 prepares embodiment 29 compound.1H NMR(400 MHz, Chloroform-d) δ 8.21 (d, J=7.4Hz, 1H), 7.67 (s, 1H), 7.58 (s, 1H), 7.53 (d, J=8.4Hz, 2H), 7.49 (s, 1H), 7.44 (d, J=8.8Hz, 1H), 7.37 7.31 (m, 1H), 7.08 (dd, J=8.4,2.1Hz, 1H), 7.03 (d, J=8.2Hz, 2H), 6.50 (d, J=7.4Hz, 1H), 5.52 (s, 2H),4.01(s,3H).MS(ESI):500(M+H)。
Embodiment 30 7-((4-(4-chloro-3-(trifluoromethyl) phenoxy group)-3,5-difluorobenzyl) epoxide)-3-(1- Methyl isophthalic acid H-pyrazoles-4-base) imidazoles [1,2-a] pyrimidine
Except with intermediate 29 and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxy boron penta ring-2-base) pyrazoles Beyond raw material, the preparation method with reference to embodiment 8 prepares embodiment 30 compound.1H NMR(300 MHz, Chloroform-d) δ 8.25 (d, J=7.4Hz, 1H), 7.88 7.46 (m, 3H), 7.40 (d, J= 8.6Hz, 1H), 7.28 (s, 1H), 7.18 (d, J=8.5Hz, 2H), 6.99 (s, 1H), 6.60 (d, J=31.3 Hz,1H),5.51(s,2H),4.00(s,3H).MS(ESI):536(M+H)。
Embodiment 31 7-((4-(4-chloro-3-(trifluoromethyl) phenoxy group)-3,5-difluorobenzyl) epoxide)-3-(2- Methoxy pyrimidine-5-base)-5-Methylimidazole. [1,2-a] pyrimidine
In addition to intermediate 59 and 2-methoxyl group-4-pyrimidine boronic acid as raw material, with reference to embodiment 8 Preparation method prepares embodiment 31 compound.1H NMR(300MHz,Chloroform-d)δ8.59(s, 2H), 7.41 (d, J=8.8Hz, 1H), 7.35 7.26 (m, 2H), 7.18 (d, J=7.5Hz, 2H), 7.01 (d, J=10.1Hz, 1H), 6.38 (d, J=35.6Hz, 1H), 5.54 (s, 2H), 4.10 (s, 3H), 2.24 (s, 3H).MS(ESI):578(M+H)。
Embodiment 32 7-((4-(4-chloro-3-(trifluoromethyl) phenoxy group)-3,5-difluorobenzyl) epoxide)-3-(4- Picoline-3-base) imidazoles [1,2-a] pyrimidine
In addition to the bromo-4-picoline of intermediate 29 and 3-as raw material, with reference to the preparation of embodiment 1 Method prepares embodiment 32 compound.1H NMR (400MHz, Chloroform-d) δ 8.61 (d, J= 5.1Hz, 1H), 8.58 (s, 1H), 7.95 (d, J=7.3Hz, 1H), 7.61 (s, 1H), 7.44 (d, J=8.7 Hz, 1H), 7.35 (d, J=5.2Hz, 1H), 7.33 (d, J=2.9Hz, 1H), 7.25 7.19 (m, 2H), 7.05 (dd, J=9.1,2.9Hz, 1H), 6.57 (d, J=7.4Hz, 1H), 5.58 (s, 2H), 2.28 (s, 3H). MS(ESI):547(M+H)。
Embodiment 33 7-((6-(4-chloro-3-(trifluoromethyl) phenoxy group)-5-fluorine pyridin-3-yl) methoxy Base)-3-(pyrimidine-5-base) imidazoles [1,2-a] pyrimidine
In addition to intermediate 32 and 4-Bromopyrimidine as raw material, with reference to the preparation method system of embodiment 1 Standby embodiment 33 compound.1H NMR(300MHz,Chloroform-d)δ9.28(s,1H),8.93(s, 2H), 8.35 (d, J=7.4Hz, 1H), 8.06 (s, 1H), 7.74 (m, 2H), 7.54 (m, 2H), 7.33 (dd, J =8.7,2.6Hz, 1H), 6.60 (d, J=7.4Hz, 1H), 5.55 (s, 2H) .MS (ESI): 517 (M+H).
Embodiment 34 7-(4-(4-chloro-3-(trifluoromethyl) phenoxy group)-3,5-difluorophenyl ethoxy Base)-3-(pyrimidine-5-base) imidazoles [1,2-a] pyrimidine
In addition to intermediate 30 and 4-Bromopyrimidine as raw material, with reference to the preparation method system of embodiment 1 Standby embodiment 34 compound.1H NMR(300MHz,Chloroform-d)δ9.27(s,1H),8.92(s, 2H), 8.31 (d, J=7.4Hz, 1H), 7.74 (s, 1H), 7.41 (d, J=8.8Hz, 1H), 7.27 (d, J= 3.0Hz, 1H), 7.05 6.95 (m, 3H), 6.55 (d, J=7.4Hz, 1H), 4.76 (t, J=6.5Hz, 2H), 3.16 (t, J=6.4Hz, 2H) .MS (ESI): 548 (M+H).
Embodiment 35 7-((4-(4-chloro-3-(trifluoromethyl) phenoxy group)-3,5-difluorobenzyl) epoxide)-3-is (phonetic Pyridine-5-base)-[1,2,4] triazole [4,3-a] pyrimidine
In addition to intermediate 57 and 4-pyrimidine boronic acid as raw material, with reference to the preparation method of embodiment 8 Preparation embodiment 35 compound.1H NMR(400MHz,Chloroform-d)δ9.56(s,2H),9.33 (s, 1H), 8.67 (d, J=7.2Hz, 1H), 7.43 (d, J=8.7Hz, 1H), 7.29 (d, J=2.7Hz, 1H), 7.20 (d, J=8.0Hz, 2H), 7.04 (dd, J=8.7,3.1Hz, 1H), 6.75 (d, J=7.3Hz, 1H), 5.59(s,2H).MS(ESI):535(M+H)。
Embodiment 36 7-((the fluoro-4-of 3,5-bis-((6-(trifluoromethyl) pyridin-3-yl) epoxide) benzyl) oxygen Base)-3-(pyrimidine-5-base) imidazoles [1,2-a] pyrimidine
In addition to intermediate 45 and 4-Bromopyrimidine as raw material, with reference to the preparation method system of embodiment 1 Standby embodiment 36 compound.1H NMR(400MHz,Chloroform-d)δ9.28(s,1H),8.93(s, 2H), 8.49 (d, J=2.7Hz, 1H), 8.37 (d, J=7.4Hz, 1H), 7.76 (s, 1H), 7.64 (d, J= 8.7Hz, 1H), 7.32 (dd, J=8.6,2.8Hz, 1H), 7.23 (d, J=8.0Hz, 2H), 6.65 (d, J= 7.4Hz,1H),5.57(s,2H).MS(ESI):501(M+H)。
Embodiment 37 7-((4-(4-chloro-3-(trifluoromethyl) phenoxy group)-3-methyl-benzyl) epoxide)-3-is (phonetic Pyridine-5-base) imidazoles [1,2-a] pyrimidine
In addition to intermediate 46 and 4-Bromopyrimidine as raw material, with reference to the preparation method system of embodiment 1 Standby embodiment 37 compound.1H NMR(400MHz,Methanol-d4)δ9.19(s,1H),9.09(s, 2H), 8.79 (d, J=7.4Hz, 1H), 7.78 (s, 1H), 7.53 (m, 2H), 7.42 (dd, J=8.2,1.8Hz, 1H), 7.25 (d, J=2.9Hz, 1H), 7.06 (dd, J=8.8,2.9Hz, 1H), 6.99 (d, J=8.3Hz, 1H), 6.72 (d, J=7.4Hz, 1H), 5.52 (s, 2H), 2.21 (s, 3H) .MS (ESI): 512 (M+H).
Embodiment 38 7-((4-(4-chloro-3-(trifluoromethyl) phenoxy group) benzyl) sulfenyl)-3-(pyrimidine-5-base) Imidazoles [1,2-a] pyrimidine
In addition to intermediate 2 and intermediate 53 as raw material, prepared by the preparation method with reference to embodiment 6 Embodiment 38 compound.1H NMR(400MHz,Chloroform-d)δ9.28(s,1H),8.93(s, 2H), 8.24 (d, J=7.2Hz, 1H), 7.83 (s, 1H), 7.51 (d, J=8.6Hz, 2H), 7.42 (d, J= 8.8Hz, 1H), 7.32 (d, J=2.9Hz, 1H), 7.06 (dd, J=8.8,2.8Hz, 1H), 6.96 (d, J= 8.6Hz, 2H), 6.80 (d, J=7.2Hz, 1H), 4.61 (s, 2H) .MS (ESI): 514 (M+H).
Embodiment 39 7-((the chloro-4-of 3-(4-chloro-3-(trifluoromethyl) phenoxy group) benzyl) epoxide)-3-(pyrimidine -5-base) imidazoles [1,2-a] pyrimidine
In addition to intermediate 47 and 4-Bromopyrimidine as raw material, with reference to the preparation method system of embodiment 1 Standby embodiment 39 compound.1H NMR(400MHz,Chloroform-d)δ9.27(s,1H),8.94(s, 2H), 8.37 (d, J=7.4Hz, 1H), 7.77 (s, 1H), 7.65 (d, J=1.8Hz, 1H), 7.44 (m, 2H), 7.29 (d, J=2.9Hz, 1H), 7.07 (d, J=8.3Hz, 1H), 7.01 (dd, J=8.8,2.8Hz, 1H), 6.65 (d, J=7.4Hz, 1H), 5.55 (s, 2H) .MS (ESI): 532 (M+H).
Embodiment 40 7-(4-(4-chloro-3-(trifluoromethyl) phenoxy group) phenyl ethoxy)-3-(pyrimidine-5- Base)-[1,2,4] triazole [4,3-a] pyrimidine
In addition to intermediate 56 and 4-pyrimidine boronic acid as raw material, with reference to the preparation method of embodiment 8 Preparation embodiment 40 compound.1H NMR(400MHz,Chloroform-d)δ9.41(s,1H),9.24 (s, 2H), 8.33 (d, J=7.5Hz, 1H), 7.45 (d, J=8.7Hz, 1H), 7.35 7.31 (m, 3H), 7.09 (dd, J=8.7,2.7Hz, 1H), 7.01 (d, J=8.5Hz, 2H), 6.62 (d, J=7.5Hz, 1H), 4.81 (t, J=6.9Hz, 2H), 3.19 (t, J=6.8Hz, 2H) .MS (ESI): 513 (M+H).
Embodiment 41 7-(4-(4-chloro-3-(trifluoromethyl) phenoxy group) phenoxy group)-3-(pyrimidine-5-base) imidazoles [1,2-a] pyrimidine
In addition to intermediate 5 and intermediate 53 as raw material, prepared by the preparation method with reference to embodiment 6 Embodiment 41 compound.1H NMR(400MHz,Chloroform-d)δ9.31(s,1H),8.97(s, 2H), 8.48 (d, J=7.4Hz, 1H), 7.78 (s, 1H), 7.49 (d, J=8.8Hz, 1H), 7.43 (d, J= 2.7Hz, 1H), 7.31 (d, J=8.9Hz, 2H), 7.16 (dd, J=8.8,2.7Hz, 1H), 7.10 (d, J= 8.9Hz, 2H), 6.83 (d, J=7.3Hz, 1H) .MS (ESI): 484 (M+H).
Embodiment 42 7-(3-(4-(4-chloro-3-(trifluoromethyl) phenoxy group) phenyl) propoxyl group)-3-(pyrimidine -5-base) imidazoles [1,2-a] pyrimidine
In addition to intermediate 6 and intermediate 53 as raw material, prepared by the preparation method with reference to embodiment 6 Embodiment 42 compound.1H NMR(400MHz,Chloroform-d)δ9.26(s,1H),8.92(s, 2H), 8.30 (d, J=7.4Hz, 1H), 7.72 (s, 1H), 7.42 (d, J=8.8Hz, 1H), 7.31 (d, J= 2.9Hz, 1H), 7.23 (d, J=8.5Hz, 2H), 7.05 (dd, J=8.7,2.9Hz, 1H), 6.95 (d, J= 8.5Hz, 2H), 6.55 (d, J=7.4Hz, 1H), 4.54 (t, J=6.5Hz, 2H), 2.85 2.78 (m, 2H), 2.25–2.20(m,2H).MS(ESI):526(M+H)。
Embodiment 43 7-((4-(4-chloro-3-(trifluoromethyl) phenoxy group)-3-(trifluoromethyl) benzyl) oxygen Base)-3-(pyrimidine-5-base) imidazoles [1,2-a] pyrimidine
In addition to intermediate 48 and 4-Bromopyrimidine as raw material, with reference to the preparation method system of embodiment 1 Standby embodiment 43 compound.1H NMR(400MHz,Chloroform-d)δ9.27(s,1H),8.93(s, 2H), 8.36 (d, J=7.4Hz, 1H), 7.85 (d, J=1.7Hz, 1H), 7.75 (s, 1H), 7.69 (dd, J= 8.5,1.8Hz, 1H), 7.48 (d, J=8.8Hz, 1H), 7.37 (d, J=2.9Hz, 1H), 7.11 (dd, J= 8.8,2.8Hz, 1H), 6.99 (d, J=8.5Hz, 1H), 6.63 (d, J=7.4Hz, 1H), 5.59 (s, 2H). MS(ESI):566(M+H)。
Pharmacological Examples
Pharmacological Examples 1: vitro inhibition activity experiment
Reagent
1) reaction buffer
Reaction buffer is 0.1M Tris-HCl, 1mM EGTA, PH 7.2.
2) the thioesters analog (2-sulfur-PAF, 2-thio-PAF, Cayman, Lot 60945) of phosphatidylcholine
With anhydrous alcohol solution, configure 25mg/ml mother solution, and subpackage, be stored in-80 DEG C.Dilution 900 (concentration is about 50 μMs) is used after times.
3) DTNB (5,5 '-two sulfur-bis--(2-nitrobenzoic acid), 5,5 '-dithio-bis-(2-nitrobenzoic acid),Sigma,Lot D8130)
Just preparation during use.Being configured to concentration with tri-distilled water is 1.1mg/ml, adds appropriate 0.1M NaOH Just dissolve to DTNB.
4) compound DMSO is dissolved to suitable concentration.
Experimental principle
Lp-PLA is measured for substrate with 2-sulfur-PAF2Activity.The sulfydryl produced after 2-sulfur-PAF hydrolysis can React with DTNB, generate yellow substance, optical density value can be detected at 414nm, thus reflect Lp-PLA2 Activity.
1.1 compounds are to the Lp-PLA that rabbit anteserum is enzyme source2The mensuration (external) of inhibitory activity
1.1.1 experimental technique
1) corresponding reagent, and the mix homogeneously that vibrates are added by table 1
Table 1: reaction system list
2) every hole adds 10 μ L DTNB.
3) every hole adds 150 μ L 2-sulfur-PAF, and vibrate in microplate reader 15s, makes liquid blending in hole. 414nM detects 10 minutes, and detection per minute once, measures slope.Suppression ratio is calculated by following equation
Suppression ratio=1-(slope sample well-slope blank well)/(slope control wells-slope is blank Hole) × 100%
1.1.2 experimental result see table 2.
Table 2: part of compounds under each concentration conditions to the Lp-PLA that rabbit anteserum is enzyme source2Inhibitory activity
" NT " expression is not tested.
In table 2 listed compound under 1 μM of concentration to Lp-PLA2Suppression ratio is all higher than 50%, part Compound under 100nM concentration to Lp-PLA2Suppression ratio is more than 50%, and wherein, embodiment 16 is rabbit Serum shows best external activity, to Lp-PLA under 100nM concentration2Suppression ratio can reach More than 70%.
1.2 compounds are to the Lp-PLA that people source recombinase is enzyme source2The mensuration (external) of inhibitory activity
1.2.1 experimental technique
1) corresponding reagent, and the mix homogeneously that vibrates are added by table 3
Table 3: reaction system list
2) every hole adds 10 μ L DTNB.
3) every hole adds 150 μ L 2-sulfur-PAF, and vibrate in microplate reader 15s, makes liquid blending in hole. 414nM detects 10 minutes, and detection per minute once, measures slope.Suppression ratio is calculated by following equation
Suppression ratio=1-(slope sample well-slope blank well)/(slope control wells-slope is blank Hole) × 100%
1.2.2 experimental result see table 4.
Table 4: part of compounds is to the Lp-PLA that people source recombinase is enzyme source2Inhibitory activity
In table 4 listed compound under 10nM concentration to Lp-PLA2Suppression ratio is all higher than 50%, wherein, Embodiment 16, embodiment 31 show best external activity, at 10nM in the recombinase of people source To Lp-PLA under concentration2Suppression ratio reaches about 90%.
1.3 compounds are to the Lp-PLA that rat blood serum is enzyme source2The mensuration (external) of inhibitory activity
1.3.1 experimental technique
1) corresponding reagent, and the mix homogeneously that vibrates are added by table 5
Table 5: reaction system list
Blank well Sample well Control wells
Reaction buffer 30μL 20μL 20μL
Rat blood serum (enzyme source) 10μL 10μL
DMSO 10μL 10μL
Sample (DMSO dissolving) 10L
2) every hole adds 10 μ L DTNB.
3) every hole adds 150 μ L 2-sulfur-PAF, and vibrate in microplate reader 15s, makes liquid blending in hole. 414nM detects 10 minutes, and detection per minute once, measures slope.Suppression ratio is calculated by following equation
Suppression ratio=1-(slope sample well-slope blank well)/(slope control wells-slope is blank Hole) × 100%
1.3.2 experimental result see table 6.
Table 6: part of compounds is to the Lp-PLA that rat blood serum is enzyme source2Inhibitory activity
" NT " expression is not tested.
Listed compound, the good external activity shown in rat blood serum, allization in table 6 Compound under 100nM concentration to Lp-PLA2Suppression ratio is all higher than 50%.
Pharmacological Examples 2:S9 metabolic stability in vitro is tested
2.1. reagent
2.1.1 Tris/HCl (0.1M, pH 7.4) buffer
Weigh 12.12g TRIS (trishydroxymethylaminomethane, tris-hydroxymethyl Aminomethane), it is dissolved in 800mL water, regulates pH to 7.4 with HCl (2M), then use Water is settled to 1000mL.
2.1.2MgCl2Preparation
It is made into MgCl with 0.1M Tris/HCl buffer2(100mM) solution, deposits in-20 DEG C after subpackage. MgCl2Concentration of hatching be 5.0mM.
2.1.3 NADPH preparation
It is made into NADPH (10mM) solution with 0.1M Tris/HCl buffer, deposits in after subpackage -20℃.The concentration of hatching of NADPH is 1.0mM.
2.1.4 S9 preparation
With 0.1M Tris/HCl by people S9 (purchased from Ruide Liver Disease Inst. (Shanghai) Co., Ltd.) Diluting 10 times, rat S9 (purchased from Ruide Liver Disease Inst. (Shanghai) Co., Ltd.) dilutes 5 times. Make people, rat S9 hatch concentration be equivalent to corresponding kind hepatomicrosome to hatch concentration (people, big The concentration of hatching of rat hepatic microsome is 0.33mg/mL).
2.1.5 testing compound preparation
Obtaining concentration with DMSO dissolved compound is the storing solution of 10mM.It is diluted to 1 with DMSO Obtain, with the dilution of 0.1%BSA-water, the working solution that concentration is 2 μMs again after mM.In incubation system, 2 μM working solution dilute 20 times, final concentration of 0.1 μM.DMSO concentration in incubation system≤ 0.01%.
2.1.6 positive reference compound preparation
2mM VIVID storing solution (is visitd power purchased from Shanghai biological by the determinand working solution using 2 μMs Science and Technology Ltd.) dilute 50 times.In incubation system, the hybrid working solution of VIVID and determinand Dilute 20 times.
2.2 experimental technique
S9 is hatched and is carried out in 96 orifice plates, and each incubation system volume is 450 μ L, and 0.1M Tris buffers Liquid (pH 7.4), MgCl2, S9 and+NADPH/-NADPH at 37 DEG C, incubate 10min in advance after (turn Speed is 600rpm), add test medicine initial action, respectively 0,7,17,30, add after 60min The ice methanol entering same volume terminates reaction.
2.3 experimental result see table 7.
Table 7: part of compounds metabolic stability in people, rat S9
" " represents that compound is stable in test system, it is impossible to measure the half-life.
Listed compound in table 7, experimental result display metabolic stability is compared to being currently in clinical research The compound darapladib in stage has advantage, and people demonstrates preferable kind with metabolism of rat character Concordance.
The all documents mentioned in the present invention are incorporated as reference the most in this application, just as each literary composition Offer and be individually recited as with reference to like that.In addition, it is to be understood that reading the above-mentioned teachings of the present invention Afterwards, the present invention can be made various changes or modifications by those skilled in the art, and these equivalent form of values are same Fall within the application appended claims limited range.

Claims (10)

1. a compound of Formula I or its pharmaceutically acceptable salt:
In formula, R1For C1-C6Alkyl, C2-C6Thiazolinyl, C2-C6Alkynyl, C3-C8Cycloalkyl, 3-8 unit Heterocyclic radical, C3-C8Cycloalkenyl group ,-(CH2)m-NR4R5、C6-C10Aryl ,-(CH2)m-(3-8 unit heteroaryl), Or halogen, wherein, described C1-C6Alkyl, C2-C6Thiazolinyl, C2-C6Alkynyl, C3-C8Cycloalkyl, C3-C8 Cycloalkenyl group, 3-8 unit heteroaryl, 3-8 unit heterocyclic radical, C6-C10Aryl is not necessarily selected from the base of lower group Group replaces :-OH ,-CN ,=O, C1-C6Alkyl, C6-C10Aryl, C1-C6Alkoxyl, C1-C6Alkane Oxygen acyl group, C1-C6Alkanoyl, C1-C6Alkanoyloxy, C3-C8Cycloalkyl, carboxyl, halogen, halo C1-C6Alkyl ,-S (O) R1’、-SO2R2’、-NO2、-NR3’R4’；
R2、R3Independently selected from H, C1-C6Alkyl, C3-C8Cycloalkyl, C1-C6Alkoxyl or-NR6R7, Wherein, described C1-C6Alkyl, C3-C8Cycloalkyl, C1-C6Alkoxyl is not necessarily selected from lower group Group replaces :-OH ,-CN ,=O, C1-C6Alkyl, C6-C10Aryl, C1-C6Alkoxyl, C1-C6 Alkoxy acyl, C1-C6Alkanoyl, C1-C6Alkanoyloxy, C3-C8Cycloalkyl, carboxyl, halogen, halo C1-C6Alkyl ,-S (O) R1’、-SO2R2’、-NO2、-NR3’R4’；
X is O, S ,-(CH2)q-or-N (R8)-；
N is 0,1,2,3 or 4；
Ar is C6-C10Aryl or 3-8 unit heteroaryl, wherein, described C6-C10Aryl or 3-8 unit heteroaryl Base is not necessarily replaced selected from the group of lower group by 1-4 :-CN, C1-C6Alkyl, C1-C6Alkoxyl, Halogen, hydroxyl, halo C1-C6Alkyl, halo C1-C6Alkoxyl；
Y is hydrogen ,-A-(C6-C10Aryl) or-A-(3-8 unit heteroaryl), wherein, A is O, S ,-(CH2)o- Or-N (R9The described C of)-,6-C10The group that aryl, 3-8 unit heteroaryl are not necessarily selected from lower group by 1-3 Replace :-CN, C1-C6Alkyl, C1-C6Alkoxyl, halogen, halo C1-C6Alkyl；
Z is CH or N；
Described R4To R9, and R1' to R4' it is each independently selected from H, C1-C6Alkyl, C1-C6Alkane Acyl group ,-(CH2)p-(C1-C6Alkoxyl), C3-C8Cycloalkyl, C2-C6Thiazolinyl, C2-C6Alkynyl, 3-8 Unit heterocyclic radical, C3-C8Cycloalkenyl group and C6-C10Aryl；
Described m, q, o and p are each independently 0,1,2 or 3.
Compound the most according to claim 1 or its pharmaceutically acceptable salt,
In formula, R1For C1-C4Alkyl, C2-C4Thiazolinyl, C2-C4Alkynyl, C3-C6Cycloalkyl, 3-6 unit Heterocyclic radical ,-(CH2)m-NR4R5, phenyl ,-(CH2)m-(3-8 unit heteroaryl) or halogen, wherein, described C1-C4Alkyl, C2-C4Thiazolinyl, C2-C4Alkynyl, C3-C6Cycloalkyl, 3-8 unit heteroaryl, 3-6 unit are miscellaneous Ring group, phenyl are not necessarily selected from the group of lower group and are replaced :-CN, C1-C6Alkyl, C1-C6Alkane Epoxide, halogen, hydroxyl, halo C1-C6Alkyl；
R2For H or C1-C6Alkyl, wherein, described C1-C6Alkyl is not necessarily selected from lower group Group replace :-CN, C1-C6Alkyl, C1-C6Alkoxyl, halogen, hydroxyl, halo C1-C6Alkyl；
R3For H or C1-C6Alkyl, wherein, described C1-C6Alkyl is not necessarily selected from lower group Group replace :-CN, C1-C6Alkyl, C1-C6Alkoxyl, halogen, hydroxyl, halo C1-C6Alkyl；
X is O or S；
N is 0,1,2 or 3；
Ar is phenyl, naphthyl or 5-6 unit heteroaryl, wherein, and described phenyl, naphthyl, 5-6 unit heteroaryl Base is not necessarily replaced selected from the group of lower group by 1-4 :-CN, C1-C6Alkyl, C1-C6Alkoxyl, Halogen, hydroxyl, halo C1-C6Alkyl, halo C1-C6Alkoxyl；
Y is-A-(C6-C10Aryl) or-A-(5-6 unit heteroaryl), wherein, A is O, described C6-C10 Aryl, 5-6 unit heteroaryl are not necessarily replaced selected from the group of lower group by 1-3 :-CN, fluorine, chlorine, Bromine, trifluoromethyl, methyl, ethyl, propyl group；
Z is CH or N；
Described R4And R5It is each independently selected from H, C1-C6Alkyl, C1-C6Alkanoyl ,-(CH2)p-(C1-C6 Alkoxyl), C3-C8Cycloalkyl, C2-C6Thiazolinyl, C2-C6Alkynyl, 3-8 unit heterocyclic radical, C3-C8Cyclenes Base and C6-C10Aryl；
Described m and p is each independently 0,1,2 or 3.
Compound the most according to claim 1 or its pharmaceutically acceptable salt,
In formula, R1For-(CH2)m-NR4R5, phenyl or-(CH2)m-(3-6 unit heteroaryl)；
R2For H or methyl；
R3For H；
X is O or S；
N is 0,1 or 2；
Ar is phenyl, and described phenyl is not necessarily replaced selected from the group of lower group by 1-3 :-CN, fluorine, Chlorine, bromine, trifluoromethyl, methyl, ethyl or propyl group；
Y is-A-(C6-C10Aryl) or-A-(5-6 unit heteroaryl), wherein, A is O, described C6-C10 Aryl, 5-6 unit heteroaryl are not necessarily replaced selected from the group of lower group by 1-3 :-CN, fluorine, chlorine, Bromine, trifluoromethyl, methyl, ethyl, propyl group；
Z is CH or N；
Described R4And R5It is each independently selected from H, C1-C3Alkyl；
Described m is 0,1,2 or 3.
Compound the most according to claim 1 or its pharmaceutically acceptable salt, wherein, described Compound has a structure shown in formula (IA):
Wherein, Ra and Rb is each independently H, halogen ,-CN, trifluoromethyl or methyl；
Z is CH or N；
N is 0,1,2 or 3；
R1For-(CH2)-N(CH3)2, phenyl ,-(CH2)-pyrazolyl, pyrazolyl, pyrimidine radicals, pyridine radicals, Wherein, described phenyl, pyrazolyl, pyrimidine radicals be not necessarily selected from the replacement of following group :-CN ,=O, Methyl, ethyl, phenyl, methoxyl group, ethyoxyl, cyclopropyl, fluorine, chlorine, bromine, trifluoromethyl；
R2For hydrogen or methyl；
Ar ' is phenyl, pyridine radicals, pyrimidine radicals, and wherein, described phenyl, pyridine radicals, pyrimidine radicals are nonessential Ground is replaced selected from the group of following group by 1-3: trifluoromethyl, fluorine, chlorine, cyano group, methyl.
Compound the most according to claim 1 or its pharmaceutically acceptable salt, wherein, described Compound of Formula I is arbitrary compound as shown in the table:
Compound the most according to claim 1 or its pharmaceutically acceptable salt, wherein, described Pharmaceutically acceptable salt is hydrochlorate, hydrobromate, sulfate, nitrate, phosphate, Fructus Citri Limoniae Hydrochlorate, mesylate, trifluoroacetate, acetate, oxalates, succinate, malate, first Benzene sulfonate, tartrate, fumarate, glutamate, Glu, glucuronate, lactate, 1,3-propanedicarboxylic acid Salt, arginine salt or maleate.
Compound of Formula I the most according to claim 1 or the preparation of its pharmaceutically acceptable salt Method, comprises the following steps:
When Z is CH in formula I, it is Compounds of formula II, by Formulas I c compound and R1W is anti- Should obtain, wherein, W is Cl, Br or I；
Or described preparation method comprises the following steps:
When Z is CH in formula I, be Compounds of formula II, by Formulas I d compound withOrReaction obtains；
Or described preparation method comprises the following steps:
When Z is CH in formula I, be Compounds of formula II, by Formula II d compound with Y-Ar-(CH2)nXH reacts in the presence of a base and obtains；
Or described preparation method comprises the following steps:
When Z is N in formula I, be compound of formula III, by formula III e compound with OrReaction obtains；
Wherein, described R1、R2、R3, definition and the definition phase in claim 1 of Y, Ar, n, X With.
8. a pharmaceutical composition, comprises compound of Formula I according to claim 1 or its pharmacy Upper acceptable salt；With pharmaceutically acceptable carrier.
Compound of Formula I the most according to claim 1 or its pharmaceutically acceptable salt or power Profit require the purposes of the pharmaceutical composition described in 8, described purposes be for:
(1) preparation suppression Lp-PLA2Medicine；Or
(2) preparation prevents and/or treats and/or improve and Lp-PLA2The medicine of the disease that enzymatic activity is relevant.
10. an intermediate for compound of Formula I according to claim 1, its structure is:
Or
Or
Or
Or
Wherein, described R1、R2、R3, definition and the phase described in claim 1 of Y, Ar, n, X With.
CN201510233237.9A 2015-05-08 2015-05-08 As Lp-PLA2dicyclo compounds, its preparation method and the medical usage of inhibitor Pending CN106188063A (en)

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