CN107709325B - Double cyclics, preparation method and medical usage as Lp-PLA2 inhibitor - Google Patents

Double cyclics, preparation method and medical usage as Lp-PLA2 inhibitor Download PDF

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CN107709325B
CN107709325B CN201680016991.XA CN201680016991A CN107709325B CN 107709325 B CN107709325 B CN 107709325B CN 201680016991 A CN201680016991 A CN 201680016991A CN 107709325 B CN107709325 B CN 107709325B
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compound
alkyl
group
formula
phenyl
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CN107709325A (en
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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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    • 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 be used as Lp-PLA2Double cyclics, preparation method and the medical usage of inhibitor, and the pharmaceutical composition comprising the compound, the structure of double cyclics is as shown in general formula I, R1、R2、R3, X, Y, Z, Ar, n definition as shown in specification and claims.Compound of Formula I of the invention can be used as Lp-PLA2Inhibitor, prevention and/or treatment and/or improvement and Lp-PLA2The related disease of enzymatic activity.

Description

As Lp-PLA2Double cyclics, preparation method and the medical usage of inhibitor
Technical field
The present invention relates to field of medicinal chemistry more particularly to novel double cyclics and preparation method thereof, with such Compound be active constituent pharmaceutical composition and they preparation treatment and Lp-PLA2Enzymatic activity has the drug of related disorders In application.
Background technique
The relevant phospholipase A of lipoprotein2(Lp-PLA2) it is also referred to as platelet-activating factor acetylhydrolase (PAF-AH), the enzyme Contain 441 amino acid, relative molecular mass 45kD.70% Lp-PLA in human plasma2It is tied with low-density lipoprotein (LDL) It closes, 30% Lp-PLA2It is combined with high-density lipoprotein (HDL).Lp-PLA2It can be promptly by the hydrolysis of phosphatidlycholine of oxidation As lysophosphatidylcholine (lyso-PC) and oxidation non-esterified fatty acid (ox-NEFA), and lyso-PC and ox-NEFA have There is very strong rush inflammatory effect, can start including endothelial cell, smooth muscle cell, Monocytes/Macrophages, T cell, neutrophilia Inflammation/immune response of various kinds of cell including granulocyte.
Lp-PLA2Inhibitor may be generally applicable to any lipid for being related to oxidation in Lp-PLA2Participation under be hydrolyzed into For the illness of two inflammatory properties substance this processes.It among these include atherosclerosis, diabetes, care of patients with diabetic ocular disease After disease, diabetes brain diseases, hypertension, angina pectoris, rheumatoid arthritis, apoplexy, myocardial infarction, ischemia and reperfusion, Psoriasis, brain inflammation disease (such as: Alzheimer's disease), all kinds of neuropsychiatric diseases (such as: schizophrenia), Ischemia Reperfusion Infuse damage, septicemia, acute and chronic inflammation disease.
Atherosclerosis is more than and blood lipid level is extremely related and a kind of inflammation-related diseases, inhibits artery The inflammatory factor of atherosis is to treat the new way of the disease.Some researches show that lyso-PC can promote atherosclerosis Plaque progression, and ultimately form necrotic cores.The experiment carried out on diabetes high cholesterol pig model confirms Lp-PLA2Inhibit Agent can influence the case where arteriosclerosis plaque volume, composition and gene expression of diabetes high cholesterol pig, and effectively press down The continued growth of atherosclerotic plaque processed.
Some studies pointed out that in all neurodegenerative diseases, such as: multiple sclerosis, Parkinson's disease, A Er Ci Haimo disease etc., shows neuroinflamation.Lyso-PC can induce release various kinds of cell as an anticusp inflammation factor Toxicity inflammatory cytokine, and Lp-PLA2Inhibitor can weaken inflammatory reaction by inhibiting the generation of lyso-PC.
The experiment carried out on diabetes high cholesterol pig model shows Lp-PLA2Inhibitor can improve blood-brain barrier (blood brain barrier, BBB) function reduces blood-brain barrier (BBB) permeability, and can alleviate β sample albumen in brain Precipitating.These results of study show Lp-PLA2Inhibitor may can be applied to disease associated with Blood Brain Barrier (BBB) permeability Treatment, such as diabetes mellitus encephalopathy, Alzheimer's disease.
Since lyso-PC participates in leukocyte activation, induces cell apoptosis and inner skin cell function can be mediated to lack of proper care, and Diabetes can cause lasting vascular inflammation and increase the generation of active oxygen, therefore generally believe Lp-PLA2Inhibitor can To pass through the generation for inhibiting lyso-PC, for the relevant tissue damage for the treatment of diabetes.In view of the inflammatory reaction of part It plays an important role during the occurrence and development of diabetic retinopathy, therefore speculates Lp-PLA2Inhibitor can be applied In the treatment of diabetic oculopathy.
In addition, the destruction of blood retina barrier (BRB) is the common pathological characters of diabetic macular edema (DME) patient. Under normal circumstances, BRB can prevent blood plasma components from being freely accessible to retina by actively and passively transporting, and maintain retina enteroception The self stability of device cell.Once BRB is destroyed, it is impossible to which albumen and moisture enter retina reality in strict control blood plasma Matter layer causes retina cell's external series gap obviously to be expanded, and will appear as macular edema in macular area.At streptozotocin (STZ) The zoopery carried out on the SD rat of induction and brown Norway Rat model shows, Lp-PLA2Inhibitor can reduce BRB Permeability, result of study show Lp-PLA2Inhibitor may can be applied to the treatment of diabetic macular edema.
Glaucoma and age-dependent macular degeneration (AMD) are retina neural degenerative disease, and researches show that inflammation Disease reaction, comprising: TNF-α signal path may play an important role in both diseases.In view of Lp-PLA2Inhibit Agent can block the release of inflammatory cytokine, therefore speculate Lp-PLA2Inhibitor can be applied to controlling for glaucoma and AMD It treats.
GlaxoSmithKline PLC develops a kind of 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.), to contain in structure There is bicyclic or pyridone group to be characterized, representation compound darapladib and rilapladib are currently under clinical research Stage.
GlaxoSmithKline PLC also developed a kind of 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), for structure also characterized by bicyclic radicals, the difference with a kind of reversible inhibitor before is that the class formation is Linear structure, molecular weight are also relatively small.
It is still necessary to Lp-PLA for this field2Inhibitor carries out in-depth study and exploitation.
Summary of the invention
The purpose of the present invention is to provide one kind to be used as Lp-PLA2The double cyclics and its pharmaceutical composition of inhibitor Object.
The first aspect of the present invention provides a kind of compound of Formula I or its pharmaceutically acceptable salt:
In formula, R1For C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C8Naphthenic base, 3-8 circle heterocyclic ring base, C3-C8Cyclenes Base ,-(CH2)m-NR4R5、C6-C10Aryl ,-(CH2)m(3-8 unit's heteroaryl) or halogen, wherein the C1-C6Alkyl, C2-C6 Alkenyl, C2-C6Alkynyl, C3-C8Naphthenic base, C3-C8Cycloalkenyl, 3-8 unit's heteroaryl, 3-8 circle heterocyclic ring base, C6-C10Aryl is nonessential Ground is replaced by 1-4 groups selected from the group below :-OH ,-CN ,=O, C1-C6Alkyl, C6-C10Aryl, C1-C6Alkoxy, C1-C6Alkane Oxygen acyl group, C1-C6Alkanoyl, C1-C6Alkanoyloxy, C3-C8Naphthenic base, carboxyl, halogen, halogenated C1-C6Alkyl ,-S (O) R1’、- SO2R2’、-NO2、-NR3’R4'；
Preferably, R1For C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C3-C6Naphthenic base, 3-6 circle heterocyclic ring base ,-(CH2)m- NR4R5, phenyl ,-(CH2)m(3-8 unit's heteroaryl) or halogen, wherein the C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C3- C6Naphthenic base, 3-8 unit's heteroaryl, 3-6 circle heterocyclic ring base, phenyl are not necessarily replaced 1-4 groups selected from the group below :-CN, C1-C6Alkyl, C1-C6Alkoxy, halogen, hydroxyl, halogenated C1-C6Alkyl；
It is highly preferred that R1For-(CH2)m-NR4R5, phenyl ,-(CH2)m(3-6 unit's heteroaryl), wherein the 3-6 member is miscellaneous Aryl, phenyl are not necessarily replaced 1-3 groups selected from the group below :-CN, fluorine, chlorine, bromine, methoxyl group, trifluoromethyl, first Base, ethyl or propyl；
It is highly preferred that R1For-(CH2)-N(CH3)2, phenyl ,-(CH2)-pyrazolyl, pyrimidine radicals, pyridyl group, wherein described Pyrazolyl, pyrimidine radicals, pyridyl group, phenyl are not necessarily replaced 1-3 groups selected from the group below :-CN, fluorine, chlorine, bromine, first Oxygroup, trifluoromethyl, methyl, ethyl or propyl；
R2、R3Independently selected from H, C1-C6Alkyl, C3-C8Naphthenic base, C1-C6Alkoxy or-NR6R7, wherein the C1-C6 Alkyl, C3-C8Naphthenic base, C1-C6Alkoxy is not necessarily replaced by 1-4 groups selected from the group below :-OH ,-CN ,=O, C1-C6 Alkyl, C6-C10Aryl, C1-C6Alkoxy, C1-C6Alkoxy acyl, C1-C6Alkanoyl, C1-C6Alkanoyloxy, C3-C8Naphthenic base, Carboxyl, halogen, halogenated C1-C6Alkyl ,-S (O) R1’、-SO2R2’、-NO2、-NR3’R4'；
It is preferred that R2For H or C1-C6Alkyl, wherein the C1-C6Alkyl is not necessarily by 1-4 bases selected from the group below Group replaces :-CN, C1-C6Alkyl, C1-C6Alkoxy, halogen, hydroxyl, halogenated C1-C6Alkyl；More preferable R2For H or C1-C4Alkyl, Wherein, the C1-C4Alkyl is not necessarily replaced by 1-3 groups selected from the group below :-CN, fluorine, chlorine, bromine, methoxyl group, three Methyl fluoride, methyl, ethyl or propyl；More preferable R2For H or methyl；
It is preferred that R3For H or C1-C6Alkyl, wherein the C1-C6Alkyl is not necessarily by 1-4 bases selected from the group below Group replaces :-CN, C1-C6Alkyl, C1-C6Alkoxy, halogen, hydroxyl, halogenated C1-C6Alkyl；More preferable R3For H or C1-C4Alkyl, Wherein, the C1-C4Alkyl is not necessarily replaced by 1-3 groups selected from the group below :-CN, fluorine, chlorine, bromine, methoxyl group, three Methyl fluoride, methyl, ethyl or propyl；More preferable R3For H；
X is O, S ,-(CH2)qOr-N (R8)-；It is preferred that X is O or S；
N is 0,1,2,3 or 4；It is preferred that n is 0,1,2 or 3；More preferable n is 0,1 or 2；
Ar is C6-C10Aryl or 3-8 unit's heteroaryl, wherein the C6-C10Aryl or 3-8 unit's heteroaryl not necessarily by 1-4 groups selected from the group below replace :-CN, C1-C6Alkyl, C1-C6Alkoxy, halogen, hydroxyl, halogenated C1-C6It is alkyl, halogenated C1-C6Alkoxy；
It is preferred that Ar is phenyl, naphthalene or 5-6 unit's heteroaryl, wherein the phenyl, naphthalene, 5-6 unit's heteroaryl are not necessarily Replaced by 1-4 groups selected from the group below :-CN, C1-C6Alkyl, C1-C6Alkoxy, halogen, hydroxyl, halogenated C1-C6Alkyl, halogen For C1-C6Alkoxy；
More preferable Ar is phenyl or 5-6 unit's heteroaryl, wherein the phenyl, 5-6 unit's heteroaryl are not necessarily by 1-3 Group selected from the group below replaces :-CN, C1-C4Alkyl, C1-C4Alkoxy, halogen, hydroxyl, halogenated C1-C4Alkyl, halogenated C1-C4Alkane Oxygroup；
More preferable Ar is phenyl, wherein the phenyl is not necessarily replaced by 1-3 groups selected from the group below :-CN, fluorine, Chlorine, bromine, trifluoromethyl, methyl, ethyl, propyl；
Y is hydrogen ,-A- (C6-C10) aryl) or-A- (3-8 unit's heteroaryl), wherein A O, S ,-(CH2)oOr-N (R9)-, The C6-C10Aryl, 3-8 unit's heteroaryl are not necessarily replaced by 1-3 groups selected from the group below :-CN, C1-C6Alkyl, C1-C6 Alkoxy, halogen, halogenated C1-C6Alkyl；
Preferably, Y is-A- (C6-C10Aryl) or-A- (5-6 unit's heteroaryl), wherein A O, the C6-C10Aryl, 5- 6 unit's heteroaryls are not necessarily replaced by 1-3 groups selected from the group below :-CN, fluorine, chlorine, bromine, trifluoromethyl, methyl, ethyl, third Base；
Z is CH or N；
The R4To R9And R1' to R4' it is each independently selected from H, C1-C6Alkyl, C1-C6Alkanoyl ,-(CH2)p-(C1- C6Alkoxy), C3-C8Naphthenic base, C2-C6Alkenyl, C2-C6Alkynyl and C3-C8Cycloalkenyl；Preferably, R4To R9And R1' extremely 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 preferred example, the compound of Formula I has one or two following feature:
(1)R2For H or C1-C6Alkyl, preferably, R2For H or C1-C4Alkyl；Most preferably, R2For H or methyl；
(2)R3For H or C1-C6Alkyl；Preferably, R3For H or C1-C4Alkyl；Most preferably, R3For H；
(3) n is 0,1,2 or 3；
(4) X is O, S；
In another preferred example, R1For C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C3-C6Naphthenic base, 3-6 circle heterocyclic ring Base ,-(CH2)m-NR4R5, phenyl ,-(CH2)m(3-8 unit's heteroaryl) or halogen, wherein
The C1-C4Alkyl, 3-6 circle heterocyclic ring base, phenyl ,-(CH2)m(3-8 unit's heteroaryl) is not necessarily selected by 1-4 Replace from the group of the following group :=O, C1-C6Alkyl, C6-C10Aryl, C1-C6Alkoxy, C3-C8Naphthenic base, halogen, halogenated C1-C6 Alkyl or-NR3’R4'；
R4、R5、R3' and R4' it is each independently selected from H, C1-C6Alkyl ,-(CH2)p-(C1-C6Alkoxy), C3-C8Cycloalkanes Base；
M and p is each independently 0,1,2 or 3.
In another preferred example, R1For C1-C4Alkyl, C2-C4Alkenyl, C3-C6Naphthenic base, 3-6 circle heterocyclic ring base ,-(CH2)m- NR4R5, phenyl ,-(CH2)m(3-6 unit's heteroaryl) or halogen, wherein the C1-C4Alkyl, 3-6 circle heterocyclic ring base, phenyl ,- (CH2)m(3-6 unit's heteroaryl) is not necessarily by substitution selected from the group below :=O, C1-C4Alkyl, C6-C10Aryl, C1-C4Alcoxyl Base, C3-C6Naphthenic base, halogen, halogenated C1-C4Alkyl or-NR3’R4'；R4、R5、R3' and R4' it is each independently selected from H, C1-C4Alkane Base ,-(CH2)p-(C1-C4Alkoxy), C3-C6Naphthenic base；M and p is each independently 0 or 1.
In another preferred example, R1For-(CH2)m-NR4R5, phenyl ,-(CH2)m(3-6 unit's heteroaryl), wherein the benzene Base ,-(CH2)m(3-6 unit's heteroaryl) is not necessarily replaced by group selected from the group below :=O, C1-C4Alkyl, phenyl, C1-C4Alkane Oxygroup, C3-C6Naphthenic base, halogen, fluoro C1-C4Alkyl or-NR3’R4'；R4、R5、R3' and R4' be each independently selected from methyl, Ethyl, propyl ,-(CH2)2OCH3Or cyclopropyl；M is 0 or 1.
In another preferred example, R1For-(CH2)-N(CH3)2, phenyl ,-(CH2)-pyrazolyl, pyrazolyl, pyrimidine radicals, pyridine Base, wherein the phenyl, pyrazolyl, pyrimidine radicals are not necessarily selected from following group of substitution :=O, methyl, ethyl, phenyl, Methoxyl group, ethyoxyl, cyclopropyl, fluorine, chlorine, bromine, trifluoromethyl；
In another preferred example, the compound of Formula I has one or two following feature:
(1) Ar is substituted or unsubstituted phenyl, substituted or unsubstituted naphthalene, substituted or unsubstituted 5-6 member heteroaryl Base, the substitution, which refers in phenyl, naphthalene or 5-6 unit's heteroaryl, has 1-4 substituent groups selected from the group below :-CN, C1-C6Alkane Base, C1-C6Alkoxy, halogen, hydroxyl, halogenated C1-C6Alkyl, halogenated C1-C6Alkoxy；
(2) Y is hydrogen ,-A- (C6-C10Aryl) or-A- (5-6 unit's heteroaryl), wherein A is O or S；The C6-C10Aryl, Not necessarily there are 1-3 substituent groups selected from the group below: C in the 5-6 unit's heteroaryl1-C4Alkyl ,-CN, halogen, halogenated C1- C6Alkyl.
In another preferred example, Ar is substituted or unsubstituted phenyl, and substituted or unsubstituted 5-6 unit's heteroaryl is described Substitution, which refers in phenyl or 5-6 unit's heteroaryl, has 1-3 substituent groups selected from the group below :-CN, C1-C4Alkyl, C1-C4Alcoxyl Base, halogen, hydroxyl, halogenated C1-C4Alkyl, halogenated C1-C4Alkoxy.
In another preferred example, Ar is substituted or unsubstituted phenyl, and the substitution refers on phenyl, and there are 1-3 to be selected from The substituent group of the following group :-CN, fluorine, chlorine, bromine, trifluoromethyl, methyl, ethyl or propyl.
In another preferred example, A O.In another preferred example, the C6-C10It is nonessential on aryl, 5-6 unit's heteroaryl Ground has 1-3 substituent groups selected from the group below :-CN, F, Cl, CF3。
In another preferred example, the compound has 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, pyridyl group, wherein the benzene Base, pyrazolyl, pyrimidine radicals are not necessarily selected from following group of substitution :-CN ,=O, methyl, ethyl, phenyl, methoxyl group, ethoxy Base, cyclopropyl, fluorine, chlorine, bromine, trifluoromethyl；
R2For hydrogen or methyl；
Ar ' is phenyl, pyridyl group, pyrimidine radicals, wherein the phenyl, pyridyl group, pyrimidine radicals are not necessarily selected by 1-3 Replace from the group of the following group: trifluoromethyl, fluorine, chlorine, cyano, methyl.
In another preferred example, the compound of Formula I is any compound as shown in the table.
In another preferred example, the pharmaceutically acceptable salt be hydrochloride, hydrobromate, sulfate, nitrate, Phosphate, citrate, mesylate, trifluoroacetate, acetate, oxalates, succinate, malate, toluenesulfonic acid Salt, tartrate, fumarate, glutamate, glucuronate, lactate, glutarate, arginine salt or maleate.
The second aspect of the present invention provides compound of Formula I described in first aspect or its pharmaceutically acceptable salt Preparation method, comprising the following steps:
When Z is CH in general formula I, as Compounds of formula II, by Formulas I c compound and R1W reacts to obtain, wherein W is Cl, Br or I；
Or the preparation method comprises the following steps:
When Z is CH in general formula I, as Compounds of formula II, by Formulas I d compound with Reaction obtains；
Or the preparation method comprises the following steps:
When Z is CH in general formula I, as Compounds of formula II, by Formula II d compound and Y-Ar- (CH2)nXH exists in alkali Lower reaction obtains；
Or the preparation method comprises the following steps:
When Z is N in general formula I, as compound of formula III, by formula III e compound with Reaction obtains；
Wherein, the R1、R2、R3, Y, Ar, n, X definition as described in relation to the first aspect.
The third aspect of the present invention provides a kind of pharmaceutical composition, comprising compound of Formula I described in first aspect or its Pharmaceutically acceptable salt；And pharmaceutically acceptable carrier.
The fourth aspect of the present invention provides compound of Formula I described in first aspect or its pharmaceutically acceptable salt Or the purposes of pharmaceutical composition described in the third aspect, the purposes are to be used for:
(1) preparation inhibits Lp-PLA2Drug；
(2) preparation prevention and/or treatment and/or improvement and Lp-PLA2The drug of the related disease of enzymatic activity.
In another preferred example, described and Lp-PLA2The related disease of enzymatic activity is atherosclerosis, apoplexy, cardiac muscle Infarct, ischemical reperfusion injury, care of patients with diabetic ocular disease, diabetes mellitus encephalopathy, diabetic macular edema, all kinds of nervus retrogression diseases Disease, Alzheimer's disease, acute inflammatory diseases, chronic inflammatory diseases, psoriasis or glaucoma macular degeneration.
In another preferred example, described and Lp-PLA2The related disease of enzymatic activity is atherosclerosis, diabetic macular Oedema, diabetes mellitus encephalopathy or Alzheimer's disease.
The fifth aspect of the present invention provides the intermediate of compound of Formula I, structure are as follows:
Wherein, the R2、R3, Y, Ar, n, X definition as described in relation to the first aspect.
The sixth aspect of the present invention provides the intermediate of compound of Formula I, structure are as follows:
Wherein, the R2、R3, Y, Ar, n, X definition as described in relation to the first aspect.
The seventh aspect of the present invention provides the intermediate of compound of Formula I, structure are as follows:
Wherein, the R2、R3, Y, Ar, n, X definition as described in relation to the first aspect.
The eighth aspect of the present invention provides the intermediate of compound of Formula I, structure are as follows:
Wherein, the R1、R2、R3Definition as described in relation to the first aspect.
The ninth aspect of the present invention provides the intermediate of compound of Formula I, structure are as follows:
Wherein, the R2、R3, Y, Ar, n, X definition as described in relation to the first aspect.
The tenth aspect of the present invention provides a kind of inhibition Lp-PLA2Method, applied to required object or into environment With the compound of Formula I of safe and effective amount.
The eleventh aspect of the present invention provides a kind for the treatment of and Lp-PLA2The method that enzymatic activity has related disorders, to required Object application safe and effective amount compound of Formula I.
In another preferred example, the object of the needs includes cell, people or the non-human mammal of in vitro culture, preferably Ground is people, mouse or rat.
In the present invention, " safe and effective amount " is referred to: the amount of active constituent (compound of Formula I) is enough to be obviously improved disease Feelings, and be unlikely to generate serious side effect.
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist This no longer tires out one by one states.
Detailed description of the invention
Fig. 1 is after giving the compound and positive reference compound darapladib of embodiment 1 and 11 to SD Oral Administration in Rats Rat blood serum Lp-PLA2Activity figure.
Fig. 2 is after giving the compound and positive reference compound darapladib of embodiment 44 and 47 to SD Oral Administration in Rats Rat blood serum Lp-PLA2Activity figure.
Specific embodiment
Present inventor develops a kind of bicyclic class chemical combination of structure novel by depth studying extensively for the first time Object can be used as Lp-PLA2Inhibitor, prevention and/or treatment and/or improvement and Lp-PLA2The related disease of enzymatic activity.In this base On plinth, the present invention is completed.
Term
In the present invention, term " C1-C6Alkyl " refers to the linear or branched alkyl group with 1 to 6 carbon atom, unrestricted Property include methyl, ethyl, propyl, isopropyl and butyl etc.；Term " C1-C4Alkyl " has similar meaning.Term " C2-C6 Alkenyl " refers to the linear chain or branched chain alkenyl containing a double bond with 2 to 6 carbon atoms, include without limitation vinyl, Acrylic, cyclobutenyl, isobutenyl, pentynyl and hexin base.Term " halogenated C1-C6Alkyl " refers to former by one or more halogen The alkyl that son replaces, such as-CH2F、-CF3、-CH2CHF3Deng.
In the present invention, term " C1-C6Alkoxy " refers to the straight or branched alkoxyl with 1 to 6 carbon atom, non- It restrictively include methoxyl group, ethyoxyl, propoxyl group, isopropoxy and butoxy etc.；Term " C1-C4Alkoxy " has similar Meaning.
In the present invention, term " C3-C8Naphthenic base " refers to the cyclic alkyl on ring with 3 to 8 carbon atoms, non-limit It include property processed cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl etc.；Term " C3-C6Naphthenic base " has class As meaning.Term " C3-C8Cycloalkenyl " is the cyclic alkenyl radical on finger ring with 3 to 8 carbon atoms, without limitation includes ring Acrylic, cyclobutane base, cyclopentenyl, cyclohexenyl group etc..
In the present invention, term " aryl " indicates the alkyl comprising one or more aromatic rings, such as phenyl or naphthyl.
Term " heteroaryl " indicates the heteroatomic aromatic ring group that N, O, S are selected from comprising 1-4, without limitation includes pyrrole Oxazolyl, thienyl, pyridyl group, pyrimidine radicals, pyrazinyl, pyridazinyl, furyl, pyrrole radicals, oxazolyl, isoxazolyl, imidazole radicals, Thiazolyl, isothiazolyl, quinazolyl, quinolyl, isoquinolyl and indyl.
In the present invention, term " heterocycle " indicates the heteroatomic naphthenic base that N, O, S are selected from comprising 1-4, non-limiting Ground includes pyrrolidinyl, morpholinyl, piperidyl, thio-morpholinyl, piperazinyl, tetrahydrofuran base, THP trtrahydropyranyl, thiophane Base, tetrahydro-thiazoles base.
Preparation method
Compound of Formula I of the invention, its stereoisomer or its pharmaceutically acceptable salt can pass through such as lower section Method preparation:
Route 1:
(a) Formulas I a-1 or Ia-2 compound and Y-Ar- (CH2)nXH reacts in the presence of a base obtains Formulas I b compound；
(b) ring closure reaction production Ic occurs for bromoacetaldehyde and Formulas I b compound；
(c) Ib compound withRing closure reaction production II occurs；
(d) Formulas I c compound reacts to obtain Formulas I d compound with N- bromo-succinimide；
(e) Formulas I d compound and R1Boric acid or boron ester occur Suzuki react to obtain Formula II compound；
(f) Formulas I c compound and R1W reacts to obtain Formula II compound, wherein the W is Cl, Br or I；
Route 2:
(g) Formulas I a-1 or Ia-2 compound react to obtain Formula II a compound with benzyl mercaptan in the presence of a base；
(h) ring closure reaction production IIb occurs for bromoacetaldehyde and Formula II a compound；
(i) Formula II b compound and R1W reacts under acetic acid palladium chtalyst obtains Formula II c compound, wherein W Cl, Br or I；
(j) Formula II c compound is aoxidized to obtain Formula II d compound by metachloroperbenzoic acid；
(k) Formula II d compound and Y-Ar- (CH2)nXH reacts in the presence of a base obtains Formula II compound；
Route 3:
(l) formula III a compound and Y-Ar- (CH2)nXH reacts in the presence of a base obtains formula III b compound；
(o) nucleophilic displacement of fluorine production IIIc occurs for formula III b compound and hydrazine hydrate；
(p) formula III c compound and triethyl orthoformate generation ring closure reaction obtain formula III d compound；
(q) formula III d compound reacts to obtain formula III e compound with N- bromo-succinimide；
(r) formula III e compound and R1Boric acid or boron ester occur Suzuki react to obtain formula III compound；
In another preferred example, the R1Boric acid or boron ester be selected from
The step (a), (g), (k) or (l) in alkali be selected from inorganic base, organic base and a combination thereof；Preferably, the nothing Machine alkali is selected from sodium hydroxide, potassium hydroxide, strontium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, cesium hydroxide, bicarbonate Sodium, saleratus, potassium carbonate, sodium carbonate, strontium carbonate, cesium carbonate, vulcanized sodium, sodium hydrogen and a combination thereof；The organic base is selected from alcohol Sodium, potassium alcoholate, butyl lithium, 1,8- diazacyclo [5,4,0] hendecene -7, pyridine, piperidines, pyrrolidines, morpholine, N-methylmorpholine, Quinoline, 4-dimethylaminopyridine, triethylamine, diethylamine, tri-n-butylamine, tripropylamine, diisopropylamine, diisopropylethylamine and A combination thereof；It is highly preferred that the alkali is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, saleratus, carbonic acid Potassium, sodium carbonate, cesium carbonate, sodium hydrogen, sodium methoxide, sodium ethoxide, potassium tert-butoxide, pyridine, piperidines, pyrrolidines, morpholine, N- methyl Quinoline, triethylamine, diethylamine, diisopropylamine, diisopropylethylamine and a combination thereof；The reaction dissolvent of the reaction is selected from aromatic hydrocarbons Solvent, ether solvent, halogenated hydrocarbon solvent and other solvents；Preferably, the aromatic hydrocarbon solvent be selected from benzene,toluene,xylene, Chlorobenzene, nitrobenzene and a combination thereof；The ether solvent is selected from tetrahydrofuran, ether, glycol dimethyl ether, diethylene glycol diformazan Ether, glycol monoethyl ether, dioxane and a combination thereof；The halogenated hydrocarbon solvent be selected from methylene chloride, chloroform, carbon tetrachloride, Dichloroethanes and a combination thereof；Other described solvents be selected from n,N-Dimethylformamide, n,N-dimethylacetamide, dimethyl sulfoxide, N-Methyl pyrrolidone, hexamethyl phosphoramide, acetone, acetonitrile, ethyl acetate and a combination thereof；Preferably, the reaction of the reaction Temperature is -30 DEG C~300 DEG C, more preferably -10 DEG C~150 DEG C；Preferably, the reaction time of the reaction is 0.5~12 hour.
Purposes
The compounds of this invention is Lp-PLA2Inhibitor.Therefore these compounds can be used for treating, such as treatment and Lp-PLA2 The related illness of activity.Therefore, another aspect of the present invention relates to treatment and Lp-PLA2The related illness of activity.Ability Field technique personnel are appreciated that specific illness or its treatment can be related to and Lp-PLA2The related one or more bases of activity Plinth mechanism, including one or more mechanism described herein.
In a specific embodiment, the compounds of this invention, which can be used for treating, is related to any disease of endothelial dysfunction, example Such as, the illness after atherosclerosis, diabetes, hypertension, angina pectoris and local ischemia and reperfusion.
In a specific embodiment, the compounds of this invention can be used for treating and be related to and the related lipid oxidation of enzymatic activity Any disease, for example, the other illnesss other than such as atherosclerosis and diabetes and other diseases, such as rheumatoid joint Inflammation, apoplexy, brain inflammatory conditions such as Alzheimer disease, various Neuropsychiatric disorders such as schizophrenia, myocardial infarction, office Portion's ischemic, reperfusion injury, septicemia and acute and chronic inflammation.
In a specific embodiment, the compounds of this invention can be used for treat be related to activation monocyte, macrophage or The disease of lymphocyte, because all these cell categories express Lp-PLA2, the disease of the macrophage including being related to activation, Typical illness includes but is not limited to psoriasis, rheumatoid arthritis, wound healing, chronic obstructive pulmonary disease, cirrhosis, spy Answering property dermatitis, pulmonary emphysema, chronic pancreatitis, chronic gastritis, aortic aneurysm, atherosclerosis, multiple sclerosis, alzheimer ' Silent disease and autoimmune disease such as lupus.
In a specific embodiment, the present invention provides treatment and Lp-PLA2The method of the related disease of activity comprising use A effective amount of Lp-PLA2Inhibitor for treating subject in need for the treatment of.The disease can be with monocyte, macrophage or leaching The participation of bar cell increases related；It is related with the formation of lysophosphatidyl choline and the free fatty acid of oxidation；With it is associated Lp-PLA2Active lipid oxidation is related；Or it is related with endothelial dysfunction.
In other embodiments, the compounds of this invention can be used for the primary or secondary pre- of Acute coronary event It is anti-, the combination therapy of pre- anti-restenosis or the development of delay diabetes or hypertensive cerebral renal insufficiency.Prevention and treatment have The subject of the risk of illness in this way.
In some embodiments, the compounds of this invention can be used for and lipidemia agent, antiatherosclerotic, anti-sugar Urinate sick agent, antianginal agent or rescinnamine or for reducing lipoprotein a medicament in conjunction with treating the disease that the present invention describes Disease.The example of above-mentioned medicament includes but is not limited to inhibitors of cholesterol synthesis, such as Statins；Antioxidant, such as the third fourth Phenol；Insulin sensitizers；Calcium-channel antagonists and anti-inflammatory agent, such as non-steroidal anti-inflammatory drugs.
In one embodiment, the compounds of this invention can be used for treating the neurodegenerative disease of subject.The side Method includes will be containing inhibition Lp-PLA2The pharmaceutical composition of active drug delivers medicine to subject in need for the treatment of.Illustratively Neurodegenerative disease includes but is not limited to Alzheimer disease, vascular dementia, Parkinson's disease and Huntington chorea.? In one specific embodiment, neurodegenerative disease of the present invention is related with abnormal blood-brain barrier.In an embodiment party In formula, administration inhibits Lp-PLA2The subject of active medicament is people.
In one embodiment, the present invention provide treatment with vascular dementia or with vascular dementia risk by The method of examination person.The method includes the pharmaceutical composition for containing a effective amount of the compounds of this invention is delivered medicine to subject.? In one specific embodiment, the vascular dementia Ahl tribulus sea silent sickness is related.
In a specific embodiment, the present invention provide treat in subject in need for the treatment of with abnormal blood brain barrier function, The method of inflammation or the related neurological conditions of glial activation.The method includes by a effective amount of chemical combination of the present invention Object delivers medicine to subject.In another embodiment, the abnormal blood brain barrier is permeability blood-brain barrier.In another reality It applies in mode, the disease is neurodegenerative disease.This kind of neurodegenerative disease is such as, but not limited to, vascular dementia, Alzheimer disease, Parkinson's disease and Huntington's chorea.In one embodiment, the present invention provide treatment subject with The method that blood-brain barrier reveals related disease.Illustrative disease includes but is not limited to cerebral hemorrhage, cerebral amyloid angiopathy. In one embodiment, the neurodegenerative disease is Alzheimer disease.In one embodiment, the nerve moves back Row disease is vascular dementia.In one embodiment, the neurodegenerative disease is multiple sclerosis.
In a specific embodiment, the present invention provides the method for reducing amyloid beta accumulation in subject's brain.The side Method includes that the pharmaceutical composition containing a effective amount of the compounds of this invention is delivered medicine to subject in need for the treatment of.In another reality It applies in mode, the amyloid beta is A β -42.
In a specific embodiment, when the compounds of this invention a effective amount of to snibject, the method can be with Including by can be used for treating the neurodegenerative disease of subject being treated or may be complication another therapeutic agent to Medicine is in subject, or can also include while use other therapies.For example, when the neurodegenerative disease is similar to A Erci When extra large silent disease, subject can use other medicaments or the treatment of other therapies, the medicament or therapy example of targeting Alzheimer disease As donepezil, Tacrine, rivastigmine, galanthamine, anti-amyloid vaccine, A β reduce therapy, thinking practice or Stimulation.
In a specific embodiment, the present invention relates in need for the treatment of by delivering medicine to a effective amount of the compounds of this invention The method of subject's metabolic bone disease.Illustrative metabolic bone disease includes disease related with sclerotin and loss of bone density Disease, including but not limited to osteoporosis and sclerotin reduce related disease.Illustrative osteoporosis is related to sclerotin reduction Disease includes but is not limited to that marrow exception, dyslipidemia, Pa Jiteshi disease, type-2 diabetes mellitus, metabolic syndrome, insulin support Resist, parathyroid gland is hyperfunction and related disease.In another embodiment, subject in need for the treatment of is people.
It has been generally acknowledged that preventing the method for osteoporosis described herein and/or sclerotin reduction disease may be suppressed Lp-PLA2Expression and/or inhibit Lp-PLA2Protein active influence.Therefore, some embodiments of the present invention provide resistance Disconnected enzymatic activity inhibits Lp-PLA2Method.In another embodiment, it provides by reducing and/or lowering Lp- PLA2The expression of RNA is to inhibit Lp-PLA2Method.In another embodiment, prevent and/or reduce bone mass loss and/ Or loss of bone density, so that prevention or reduction are related with metabolic bone disease such as osteoporosis and/or sclerotin reduction disease Symptom.
In a specific embodiment, the method also includes delivering medicine to the other therapeutic agents for being used to treat metabolic bone disease Subject in need for the treatment of.For example, other therapeutic agents can be used when the metabolic bone disease is osteoporosis, such as Bis phosphoric acid salt therapeutic agent.
An aspect of of the present present invention provides the method for treating eye disease by the way that a effective amount of the compounds of this invention is administered.The present invention is suitable Eye disease can be related with the destruction of barrier in blood retina.Illustrative eye disease is related to diabetic oculopathy and including macula lutea The illness of oedema, diabetic retinopathy etc..In addition, in one embodiment, the present invention relates to pass through the administration present invention Compound is to inhibit Lp-PLA2The method for treating eye disease.Illustrative eye disease includes but is not limited to central vein of retina resistance Plug, branch retinal vein occlusion, Yi-plus syndrome, retinitis pigmentosa, flat part inflammation, birdshot retina train of thought Film lesion, ectoretina film, choroidal tumor, capsule macular edema, parafovea telangiectasis, traction property macula lutea Disease, Vitreomacular traction syndrome, detached retina, neuroretinitis, idiopathic macular oedema etc..
In addition, some embodiments of the present invention provide the method for treating the diabetic macular edema of subject.Institute The method of stating includes that a effective amount of the compounds of this invention is delivered medicine to subject in need for the treatment of.In a specific embodiment, this hair It is bright to provide for treating the method with macular edema or the subject with macular edema risk.The method includes will be effective The compounds of this invention of amount delivers medicine to subject.In another embodiment, the macular edema and diabetic oculopathy example As diabetic retinopathy is related.In another embodiment, the macular edema is related with posterior uveitis.
In a specific embodiment, the present invention provides the method for the treatment of glaucoma or macular degeneration.The method includes will A effective amount of the compounds of this invention delivers medicine to subject.
In one embodiment, the present invention provide treat subject in need for the treatment of with barrier breakdown in blood retina The method of related disease.The method includes a effective amount of the compounds of this invention is delivered medicine to subject.
In one embodiment, systemic inflammatory disease such as juvenile rheumatoid arthritis, inflammatory bowel disease, Kawasaki Disease, multiple sclerosis, sarcoidosis, panarteritis, arthritic psoriasis, adjuvant arthritis, systemic loupus erythematosus, volt- Vogt-Koyanagi-Harada syndrome, Lyme disease, behcet disease, ankylosing spondylitis, inflammatory granuloma disease etc..The present invention relates to The method for treating any one of posterior uveitis or these systemic inflammatory diseases by the way that a effective amount of the compounds of this invention is administered.
Application method
Compound provided by the present invention and pharmaceutical composition can be diversified forms, such as tablet, capsule, powder, sugar Agent, solution, suspension and aerosol etc. are starched, and can reside in suitable solid or liquid-carrier or dilution.This hair Bright pharmaceutical composition can also be stored in the disinfector of suitable injection or instillation.Also may include in the pharmaceutical composition Odorant agent, flavouring agent etc..
In the present invention, the pharmaceutical composition contains safe and effective amount (such as 0.1-99.9 parts by weight, preferably 1-90 weight Measure part) formula (I) compound represented or its pharmaceutically acceptable salt；And the pharmaceutically acceptable auxiliary material of surplus, The total weight of middle composition is 100 parts by weight.Alternatively, pharmaceutical composition of the present invention, which contains, accounts for total weight 0.1-99.9 weight % is measured, formula (I) compound represented or its pharmaceutically acceptable salt of total weight 1-90 weight % are preferably accounted for；And surplus Pharmaceutically acceptable auxiliary material, wherein the total weight of composition is 100 weight %.
Formula (I) compound and the preferred proportion of pharmaceutically acceptable carrier, excipient or sustained release agent are formula (I) conducts Active constituent accounts for 60% or more total weight, and rest part accounts for total weight 0-40%, and the amount of rest part is preferably 1-20%, optimal It is selected as 1-10%.
Formula (I) compound represented of the present invention or pharmaceutical composition comprising formula (I) compound can be to mammal clinics Use, including humans and animals, administration route may include take orally, nasal cavity sucking, Transdermal absorption, pulmonary administration or gastrointestinal tract etc.. Preferred administration route is oral.Preferably unit dosage forms, and every dose includes effective component 0.01mg-200mg, preferably 0.5mg- 100mg, primary or part vic.Which kind of ineffective instructions of taking, personal optimal dose should be depending on specific treatments.Usually In the case of be to gradually increase dosage until find most suitable dosage since low dose.
Pharmaceutical composition of the invention can be administered by the approach such as oral and intravenous, intramuscular or subcutaneous.From being easy to make Standby and administration position sees that preferred pharmaceutical composition is solid-state composition, especially tablet and solid-filling or liquid filling Capsule.The oral administration of pharmaceutical composition is preferred.
The feature that the features described above or embodiment that the present invention mentions are mentioned can be in any combination.Disclosed in this case specification All features can be used in combination with any composition form, each feature disclosed in specification, can by it is any provide it is identical, The alternative characteristics of impartial or similar purpose replace.Therefore except there is special instruction, revealed feature is only impartial or similar spy The general example of sign.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip Part such as Sambrook et al., molecular cloning: laboratory manual (New York:Cold Spring Harbor Laboratory Press, 1989) condition described in, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and Number is calculated by weight.
Unless otherwise defined, it anticipates known to all professional and scientific terms as used herein and one skilled in the art Justice is identical.In addition, any method similar to or equal to what is recorded and material can be applied to the method for the present invention.Wen Zhong The preferred implementation method is for illustrative purposes only with material.
Prepare embodiment
The present invention will be further illustrated below in an example.These embodiments are merely to illustrate the present invention, but It does not limit the invention in any way.The starting material used in the present invention is purchased from lark prestige, Tai Tanke without illustrating Skill, splendid remote chemistry, up to auspicious chemistry, traditional Chinese medicines etc..
Intermediate 1 --- (4- (4- chloro- 3- (trifluoromethyl) phenoxy group) phenyl) methanol
By 4- chloro- 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 n,N-Dimethylformamide, nitrogen protection, 120 DEG C of stirring 2h, cooling, adds water, acetic acid Ethyl ester is extracted twice, and saturated common salt is washed three times, and anhydrous magnesium sulfate dries, filters, and solvent evaporated obtains 11g intermediate 1a.MS (ESI): 301 (M+H).
Intermediate 1a (4.0g, 1 equivalent) is dissolved in 50ml dehydrated alcohol, sodium borohydride is added under ice bath, and (493mg, 1 works as Amount), 1h is then stirred at room temperature.Aqueous ammonium chloride solution quenching reaction is added, water is added in solvent evaporated, and ethyl acetate extracts twice, Saturated common salt washing is primary, and anhydrous sodium sulfate dries, filters, solvent evaporated, and column chromatography for separation obtains 4g intermediate 1.MS (ESI): 285(M-17)。
Intermediate 2 --- (4- (4- chloro- 3- (trifluoromethyl) phenoxy group) phenyl) methyl mercaptan
Intermediate 1 (1.0g, 1 equivalent) is dissolved in and is steamed in methylene chloride again, thionyl chloride is added dropwise under ice bath, and (480 μ l, 2 work as Amount), 2h is stirred at room temperature after being added dropwise to complete, then solvent evaporated and thionyl chloride, obtains 1.05g intermediate 2a, it is direct to be not required to purifying For in next step.
Intermediate 2a (210mg, 1 equivalent) and thiocarbamide (70mg, 1.4 equivalents) is mixed in 2ml dehydrated alcohol, flow back 4h, It is cooled to room temperature, is added 10N sodium hydrate aqueous solution (2ml), flow back 3h, is cooled to room temperature, and 4N aqueous hydrochloric acid solution is added to adjust PH To 5, ethyl acetate is extracted 3 times, and saturated common salt is washed 1 time, and anhydrous magnesium sulfate dries, filters, solvent evaporated, direct without purifying For in next step.MS (ESI): 285 (M-33).
Intermediate 3 --- (4- (4- chloro- 3- (trifluoromethyl) phenoxy group)-3,5- difluorophenyl) methanol
By 4- chloro- 3- (trifluoromethyl) phenol (4.67g, 1 equivalent), 3,4,5- trifluro benzaldehydes (4.0g, 1.05 equivalents) And Anhydrous potassium carbonate (4.27g, 1.3 equivalents) is dissolved in n,N-Dimethylformamide, nitrogen protection, 120 DEG C of stirring 2h, it is cold But, add water, ethyl acetate is extracted twice, and saturated common salt is washed three times, and magnesium sulfate dries, filters, and solvent evaporated obtains among 8.0g Body 3a.MS (ESI): 337 (M+H).
Intermediate 3a (4.0g, 1 equivalent) is dissolved in 50ml dehydrated alcohol, and sodium borohydride (440mg, 1 equivalent) is added under ice bath, Then 1h is stirred at room temperature.Aqueous ammonium chloride solution quenching reaction is added, water is added in solvent evaporated, and ethyl acetate extracts twice, saturation Salt washing is primary, and anhydrous sodium sulfate is dry, 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, sequentially adds super dry tetrahydrofuran, methyl triphen Then base phosphonium bromide (2.54g, 1.2 equivalents), 0 DEG C of stirring 1h are added intermediate 3a (2g, 1 equivalent), 2h are stirred at room temperature.Reaction After the completion, column chromatography for separation obtains 730mg intermediate 4a.
Intermediate 4a (730mg, 1 equivalent) is dissolved in super dry tetrahydrofuran, 1N borine tetrahydro is added under ice bath in nitrogen protection Tetrahydrofuran solution (2.2ml, 1.2 equivalents), is stirred at room temperature 1h, 2ml methanol is then slowly added dropwise under ice bath, extra borine is quenched, in batches It is added sodium hydroxide (350mg, 4 equivalents), hydrogen peroxide (3.1ml, 30% aqueous solution, 14 equivalents) then is added, charging is completed 60 DEG C of reaction 2h afterwards, sodium sulfite aqueous solution quenching reaction, ethyl acetate extract three times, and saturated common salt washing is primary, anhydrous sulphur Sour sodium dries, filters, solvent evaporated, and 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, and under ice Lip river, metachloroperbenzoic acid is added, and (246mg, 1.5 work as Amount, 70%), it is stirred at room temperature for 24 hours, sodium bicarbonate aqueous solution is added, is vigorously stirred a period of time, separates chloroform layer, anhydrous slufuric acid Sodium dries, filters, solvent evaporated, and 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), cuprous iodide (19mg, 0.1 equivalent) and tetrabutylammonium bromide (33mg, 0.1 equivalent) are mixed in N, N- bis- In methylformamide, 150 DEG C of reaction 22h.Add water, ethyl acetate extraction, anhydrous sodium sulfate dries, filters, solvent evaporated, column layer Analysis separates to obtain 150mg intermediate 6a.
Intermediate 6a (150mg, 1 equivalent), propenyl (33mg, 1.5 equivalents), sodium bicarbonate (79mg, 2.5 equivalents), four Butyl ammonium chloride (105mg, 1 equivalent) and palladium acetate (2mg, 0.02 equivalent) are mixed in n,N-Dimethylformamide, and 60 DEG C are stirred Mix 5h.Add water, ethyl acetate extraction, anhydrous sodium sulfate dries, filters, and solvent evaporated, column chromatography for separation obtains 65mg intermediate 6b.
Intermediate 6b (65mg, 1 equivalent) is dissolved in dehydrated alcohol, under ice Lip river, is added sodium borohydride (7.6mg, 1 equivalent), React at room temperature 30min.Solvent evaporated adds water, and ethyl acetate extracts twice, and saturated common salt washing is primary, and anhydrous sodium sulfate is dry, Filtering, solvent evaporated, column chromatography for separation obtain 60mg intermediate 6.
Intermediate 7 --- (the fluoro- 4- of 3- ((5- (trifluoromethyl) pyridine-2- base) oxygroup) phenyl) methanol
In addition to using the chloro- 5- of 2- (trifluoromethyl) pyridine and fluoro- 4 hydroxy benzaldehyde of 3-, other than initial feed, reference is intermediate The preparation method of body 1 prepares intermediate 7.
Intermediate 8 --- (4- ((4- (trifluoromethyl) thiazol-2-yl) oxygroup) phenyl) methanol
Bromo- 1,1,1- trifluoro propane -2- ketone (5g, 1 equivalent) of 3- and thiocarbamide (2.98g, 1.5 equivalents) are dissolved in dehydrated alcohol In, 55 DEG C of reaction 3h.Solvent evaporated adds water, adjusts PH ≈ 10 with sodium hydrate aqueous solution, methylene chloride extracts four times, saturation Salt washing, anhydrous sodium sulfate dry, filter, and solvent evaporated, column chromatography for separation obtains 3.9g intermediate 8a.
Intermediate 8a (1.5g, 1 equivalent) and copper chloride (1.78g, 1.5 equivalents) are dissolved in acetonitrile, are slowly added dropwise into nitrous Tert-butyl acrylate (1.6mL, 1.5 equivalents) after being added dropwise to complete, reacts 0.5h, then evaporates most of acetonitrile, dilute hydrochloric acid, second is added Ether extracts, and saturated common salt washing, anhydrous sodium sulfate dries, filters, and solvent evaporated obtains 1.0g intermediate 8b.
Intermediate 8b (1g, 1 equivalent), parahydroxyben-zaldehyde (0.65g, 1.3 equivalents) and potassium carbonate (0.96g, 1.3 equivalents) It is mixed in n,N-Dimethylformamide, 85 DEG C of reaction 6h.After the reaction was completed, adding water, ethyl acetate extraction, saturated common salt is washed, Anhydrous sodium sulfate dries, filters, solvent evaporated, and column chromatography for separation obtains 0.65g intermediate 8c.
Other than intermediate 1a is substituted for intermediate 8c, come referring to from intermediate 1a to intermediate 1 preparation method Prepare intermediate 8.
Intermediate 9 --- (1- (3,4- dichloro benzyl)-1H- pyrazoles-4- base) methanol
Sodium hydride (0.6g, 1.5 equivalents) is suspended in tetrahydrofuran, ice bath, is slowly added to pyrazoles under nitrogen protection (760mg, 1.1 equivalents) 1,2- bis- chloro- 4- (chloromethyl) benzene (1.38mL, 1 equivalent) is added after 5min, and 50 DEG C of reactions are overnight.Chlorine Change aqueous ammonium quenching reaction, ethyl acetate extraction, saturated common salt is washed, and anhydrous sodium sulfate dries, filters, solvent evaporated, column Chromatography obtains 2.08g intermediate 9a.
Intermediate 9a (1.0g, 1 equivalent) is dissolved in dry n,N-Dimethylformamide, at 90 DEG C~100 DEG C, is added dropwise Phosphorus oxychloride (0.45mL, 1.1 equivalents) is further continued for reaction 2h after being added dropwise to complete.After cooling, water quenching reaction is added under ice bath, 10% sodium hydrate aqueous solution adjusts PH ≈ 9, ethyl acetate extraction, and saturated common salt is washed 3 times, and anhydrous sodium sulfate dries, filters, Solvent evaporated obtains 1.0g intermediate 9b.
Other than intermediate 1a is substituted for intermediate 9b, referring to from intermediate 1a to intermediate 1 preparation method system Standby intermediate 9.
Intermediate 10 --- (2- (4- chloro- 3- (trifluoromethyl) phenoxy group) oxazole-5- base) methanol
Ethyl bromide acetone (5mL, 1 equivalent) and urea (3.22g, 1.5 equivalents) are dissolved in dehydrated alcohol, back flow reaction 5h, solvent evaporated add water, and aqueous sodium carbonate adjusts PH ≈ 9, has white solid precipitation, precipitating is collected by filtration, and wash, ethyl alcohol It washes, dry 2.8g intermediate 10a.
Nitrite tert-butyl (3.22mL, 1.5 equivalents) and copper chloride (3.58g, 1.5 equivalents) are dissolved in acetonitrile, at 60 DEG C Intermediate 10a (2.8g, 1 equivalent) is added portionwise, 80 DEG C of reaction 1.5h are warming up to after adding, evaporates most of acetonitrile, water is added, Methylene chloride extracts, and saturated common salt washing, anhydrous sodium sulfate is dried, filtered, is evaporated, and column chromatography for separation obtains 2.13g intermediate 10b。
Other than initial feed is intermediate 10b and chloro- 3 trifloro methyl phenol of 4-, referring to the preparation side of intermediate 1a Method prepares intermediate 10c.
Other than intermediate 1a is substituted for intermediate 10c, referring to from intermediate 1a to intermediate 1 preparation method system Standby intermediate 10.
Intermediate 11 --- (6- (4- chloro- 3- (trifluoromethyl) phenoxy group)-5 fluorine pyridin-3-yls) methanol
The fluoro- 5- picoline of the chloro- 3- of 2- (200mg, 1 equivalent), N- bromo-succinimide (734mg, 3 equivalents) and mistake Benzoyl Oxide (67mg, 0.2 equivalent) is mixed in carbon tetrachloride, 85 DEG C of reaction 8.5h.Solvent evaporated adds water, ethyl acetate extraction It takes, saturated common salt is washed 3 times, and anhydrous sodium sulfate dries, filters, and solvent evaporated obtains the crude product of 240mg intermediate 11a.
Intermediate 11a (240mg, 1 equivalent) and silver nitrate (538mg, 4 equivalents) are mixed in mixing for ethyl alcohol (2ml) and water (2ml) Solution, 100 DEG C of reaction 1h are closed, filtering evaporates partial solvent, ethyl acetate extraction, and saturated common salt is washed, and anhydrous sodium sulfate is dry Dry, filtering, solvent evaporated, column chromatography for separation obtains 60mg intermediate 11b.
Other than 4-Fluorobenzaldehyde is substituted for intermediate 11b, intermediate is prepared referring to the preparation method of intermediate 1a 11c。
Other than intermediate 1a is substituted for intermediate 11c, referring to from intermediate 1a to intermediate 1 preparation method system Standby intermediate 11.MS (ESI): 322 (M+1).
Intermediate 12 --- 2- (4- (4- chloro- 3- (trifluoromethyl) phenoxy group) phenyl) ethane-1- alcohol
In addition to using intermediate 1a as raw material other than, prepare intermediate 12 referring to the preparation method of intermediate 4.
With reference to following table, other than substituting corresponding raw material using raw material described in " raw material " column, referring to intermediate 1 Preparation method prepares following intermediate 13-27.
Intermediate 28 --- 7- ((4- (4- chloro- 3- (trifluoromethyl) phenoxy group) benzyl) oxygroup) imidazoles [1,2-a] pyrimidine
Intermediate 1 (3.0g, 1.5 equivalents) is dissolved in tetrahydrofuran, and sodium hydride (0.8g, 60%, 3 equivalent) is added under ice bath, 30min is stirred under ice bath, is added chloro- 2 aminopyrimidine of 4- (0.85g, 1 equivalent), and room temperature reaction is overnight.After the reaction was completed, ice Lip river Lower addition aqueous ammonium chloride solution quenching reaction, ethyl acetate extract 3 times, and anhydrous sodium sulfate dries, filters, solvent evaporated, column layer Analysis separates to obtain 2.4g intermediate 28a.
Bromoacetaldehyde dimethyl-acetal (2.4mL, 8 equivalents) and aqueous solution of hydrogen bromide (850 μ L, 3 equivalents, 48%) are dissolved in In 95% ethyl alcohol, 80 DEG C of hydrolysis 6h are cooling, and carbonic acid chlorine sodium (1.0g, 5 equivalents) are added portionwise, and intermediate 28a is then added (1.0g, 1 equivalent) is placed in 70 DEG C of reaction 2h.After the reaction was completed, methylene chloride is added in solvent evaporated, and anhydrous sodium sulfate is dry, Filtering, solvent evaporated, column chromatography for separation obtain 310mg product intermediate 28.MS (ESI): 420 (M+H).
With reference to following table, other than substituting corresponding raw material using raw material described in " raw material " column, referring to intermediate 28 Preparation method prepare 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) and vinegar Sour palladium (64mg, 0.1 equivalent) is mixed in n,N-dimethylacetamide, nitrogen displacement, 140 DEG C of reaction 2h.It is cooling, filtering, acetic acid Ethyl ester extraction, saturated common salt washing, anhydrous sodium sulfate dry, filter, and 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 steams methylene chloride again, under ice Lip river be added metachloroperbenzoic acid (715mg, 2.5 equivalents, 70%), 3h is reacted under ice bath.Sodium bicarbonate aqueous solution quenching reaction, methylene chloride extract, saturated sodium bicarbonate water Solution is washed, and saturated common salt washing, anhydrous magnesium sulfate dries, filters, and solvent evaporated obtains 240mg intermediate 53.MS (ESI): 352 (M +1)。
Intermediate 54 --- the bromo- 7- of 3- ((4- (4- chloro- 3- (trifluoromethyl) phenoxy group) benzyl) oxygroup) imidazoles [1,2-a] Pyrimidine
Intermediate 28 (560mg, 1 equivalent) is dissolved in tetrahydrofuran, under ice bath be added N- bromo-succinimide (262mg, 1.1 equivalents), then react at room temperature 1h.After the reaction was completed, direct column chromatography for separation obtains 240mg intermediate 54.MS (ESI): 498 (M+1)。
Intermediate 55 --- the bromo- 7- of 3- ((4- (4- chloro- 3- (trifluoromethyl) phenoxy group)-3,5- difluorobenzyl) oxygroup) miaow Azoles [1,2-a] pyrimidine
Other than being raw material with intermediate 29, intermediate 55 is prepared referring to the preparation method of intermediate 54.MS (ESI): 534(M+1)。
Intermediate 56 --- the bromo- 7- of 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%) are mixed in n,N-Dimethylformamide, ice Bath is lower to stir 10min, is added 2,4 ,-dichloro pyrimidine reacts at room temperature 30min.Aqueous ammonium chloride solution quenching reaction, ethyl acetate extraction It takes, saturated common salt washing, anhydrous sodium sulfate dries, filters, and 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.Solvent evaporated obtains in 1.3g Mesosome 56b is not required to purify, and is directly used in and reacts in next step.
Intermediate 56b (1.3g, 1 equivalent) is dissolved in triethyl orthoformate (10mL), 120 DEG C of reaction 3h.Solvent evaporated, column Chromatography obtains 1.14g intermediate 56c.
Intermediate 56c (1.14g, 1 equivalent) is dissolved in be steamed in methylene chloride again, addition N- bromo-succinimide (1027mg, 2.2 equivalents), overnight, direct column chromatography for separation obtains 1.2g intermediate 56 for 40 DEG C of reactions.MS (ESI): 513 (M+1).
Intermediate 57 --- the bromo- 7- of 3- ((4- (4- chloro- 3- (trifluoromethyl) phenoxy group)-3,5- difluorobenzyl) oxygroup)- [1,2,4] triazole [4,3-a] pyrimidine
Other than being raw material with intermediate 3, intermediate 57 is prepared referring to the preparation method of intermediate 56.MS (ESI): 535(M+1)。
Intermediate 58 --- the bromo- 7- of 3- ((4- (4- chloro- 3- (trifluoromethyl) phenoxy group) benzyl) oxygroup)-5- methylimidazole [1,2-a] pyrimidine
Other than being raw material with intermediate 50, intermediate 58 is prepared referring to the preparation method of intermediate 54.MS (ESI): 498(M+1).MS (ESI): 512 (M+1).
Intermediate 59 --- the bromo- 7- of 3- ((4- (4- chloro- 3- (trifluoromethyl) phenoxy group)-3,5 difluorobenzyls) oxygroup)-5- Methylimidazole [1,2-a] pyrimidine
Other than being raw material with intermediate 51, intermediate 59 is prepared referring to the preparation method of intermediate 54.MS (ESI): 548(M+1)。
Intermediate 60 --- the bromo- 3- of 2- (1- methyl-1 H- pyrazoles-4- base) propane
N- methylpyrazole (1.0g, 1 equivalent) is dissolved in n,N-Dimethylformamide (2.8ml, 3 equivalents), is added dropwise three at 90 DEG C Chlorethoxyfos (1.3ml, 1.2 equivalents), about 1h is added dropwise to complete, and is further continued for reaction 2h.Cooling, reaction solution pours into ice water, and 10% Sodium hydrate aqueous solution adjusts PH to 4~5, and methylene chloride extracts 4 times, and twice, anhydrous sodium sulfate dries, filters, and is evaporated for washing Solvent, column chromatography for separation obtain 600mg intermediate 60a.
Intermediate 60a (600mg, 1 equivalent) is dissolved in dioxane (16mL), at room temperature, sequentially adds cesium carbonate (4.0g, 2 equivalents), phosphoric acid 3-acetic acid methyl ester (1.1g, 2 equivalents), dimethyl sulfoxide (4mL) are placed in 100 DEG C of reactions overnight.Add Water, ethyl acetate extraction, saturated common salt washing, anhydrous sodium sulfate dry, filter, and solvent evaporated, column chromatography for separation obtains in 650mg Mesosome 60b.
Intermediate 60b (650mg, 1 equivalent) is dissolved in dehydrated alcohol, is added 10%Pd/C (65mg), under hydrogen environment, 40 DEG C reaction overnight.Cooling, filtering, solvent evaporated obtains 500mg intermediate 60c.
Intermediate 60c (500mg, 1 equivalent) is dissolved in tetrahydrofuran, and lithium aluminium hydride is slowly added under ice bath, and (113mg, 1 works as Amount), react at room temperature 1h.After the reaction was completed, a certain amount of ethyl acetate is sequentially added, sodium bicarbonate aqueous solution, water, then mistake Filter, tetrahydrofuran filter wash cake, filtrate are evaporated to obtain 435mg intermediate 60d.
Oxalyl chloride (428 μ L, 1.5 equivalents) is dissolved in methylene chloride, and nitrogen protection is slowly added to diformazan as -60 DEG C of cold hydrazines Methylene chloride (2mL) solution of base sulfoxide (0.64mL, 3 equivalents), about 5min are added, and 5min is stirred after adding, then in addition The dichloromethane solution of mesosome 60d, about 10min add, and 5min is stirred after adding, and triethylamine is then added, and (1.67mL, 4 work as Amount), about 3min is added, and reaction flask is taken out from cold hydrazine after stirring 5min after adding, and is placed in room temperature reaction 5min.Water quenching is added to go out instead It answers, separates dichloromethane layer, saturated common salt washing, anhydrous sodium sulfate dries, filters, and solvent evaporated, column chromatography for separation obtains 100mg Intermediate 60e.
Intermediate 60e (70mg, 1 equivalent), N- bromo-succinimide (99mg, 1.1 equivalents) and L-PROLINE (11.5mg, 0.2 equivalent) is dissolved in methylene chloride, reacts at room temperature 2h, saturated common salt washing, and anhydrous magnesium sulfate is dried, filtered, steamed Dry solvent, column chromatography for separation obtain 60mg intermediate 60.
Intermediate 61 --- the bromo- 7- of 3- ((4- (4- chloro- 3- (trifluoromethyl) phenoxy group) benzyl) oxygroup)-[1,2,4] three Nitrogen azoles [4,3-a] pyrimidine
It is raw material with intermediate 1, referring to the preparation method of intermediate 56.MS (ESI): 499 (M+1).
Intermediate 62 --- the bromo- 7- of 3- ((4- (4- chloro- 3- (trifluoromethyl) phenoxy group)-3- methylbenzyl) oxygroup)-[1, 2,4] triazole [4,3-a] pyrimidine
It is raw material with intermediate 25, referring to the preparation method of intermediate 56.MS (ESI): 513 (M+1).
Intermediate 63 --- 5- (((bromo- [1,2,4] triazole [4, the 3-a] pyrimidin-7-yl of 3-) oxygroup) methyl)-2- (4- Chloro- 3- (trifluoromethyl) phenoxy group) benzonitrile
It is raw material with intermediate 14, referring to the preparation method of intermediate 56.MS (ESI): 524 (M+1).
Intermediate 64 --- the bromo- 7- of 3- ((4- (4- chloro- 3- (trifluoromethyl) phenoxy group)-3- luorobenzyl) oxygroup)-[1,2, 4] triazole [4,3-a] pyrimidine
It is raw material with intermediate 13, referring to the preparation method of intermediate 56.MS (ESI): 517 (M+1).
Intermediate 65 --- the bromo- 7- of 3- ((the chloro- 4- of 3- (4- chloro- 3- (trifluoromethyl) phenoxy group) benzyl) oxygroup)-[1,2, 4] triazole [4,3-a] pyrimidine
It is raw material with intermediate 26, referring to the preparation method of intermediate 56.MS (ESI): 533 (M+1).
Intermediate 66 --- the bromo- 7- of 3- ((4- (4- chloro- 3- (trifluoromethyl) phenoxy group)-3- (trifluoromethyl) benzyl) oxygen Base)-[1,2,4] triazole [4,3-a] pyrimidine
It is raw material with intermediate 27, referring to the preparation method of intermediate 56.MS (ESI): 567 (M+1).
Intermediate 67 --- 7- ((4- (4- chloro- 3- (trifluoromethyl) phenoxy group) benzyl) oxygroup)-6- methylimidazole [1,2- A] pyrimidine
Using intermediate 1 and the chloro- 5- methylpyrimidine -2- amine of 4- as raw material, referring to the preparation method of intermediate 28.MS (ESI): 434(M+1)。
Embodiment 1 --- 7- ((4- (4- chloro- 3- (trifluoromethyl) phenoxy group) benzyl) oxygroup)-3- (pyrimidine-5- base) miaow Azoles [1,2-a] pyrimidine
Intermediate 28 (100mg, 1 equivalent), 4- Bromopyrimidine (42mg, 1.1 equivalents), potassium acetate (44mg, 2 equivalents) and acetic acid Palladium (6mg, 0.1 equivalent) is mixed in n,N-dimethylacetamide, and nitrogen displacement, 140 DEG C of reaction 2h are cooling, filtering, ethyl acetate Extraction, saturated common salt washing, anhydrous sodium sulfate dry, filter, and solvent evaporated, column chromatography for separation obtains the implementation of 60mg white solid 1 compound of example.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).
Embodiment 2 --- 7- ((4- (4- chloro- 3- (trifluoromethyl) phenoxy group) benzyl) oxygroup)-3- (2- methoxy pyrimidine- 5- yl) imidazoles [1,2-a] pyrimidine
It other than raw material, is prepared referring to the preparation method of embodiment 1 in addition to using intermediate 28 and -4 Bromopyrimidine of 2- methoxyl group 2 compound of embodiment.1H NMR (300MHz, Chloroform-d) δ 8.65 (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) imidazoles [1,2-a] pyrimidine
Other than raw material, change referring to the preparation method preparation embodiment 3 of embodiment 1 in addition to using intermediate 33 and 4- Bromopyrimidine Close object.1H NMR (400MHz, Chloroform-d) δ 9.26 (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).
Embodiment 4 --- 1- (7- (4- (4- chloro- 3- (trifluoromethyl) phenoxy group) benzene ethyoxyl) imidazoles [1,2-a] pyrimidine- 3- yl)-N, N- dimethyl methylamine
By intermediate 33 (30mg, 1 equivalent), N, N- dimethyl iodine alkene imines (15mg, 1.2 equivalents) is dissolved in acetonitrile, is returned Stream reaction 1.5h, solvent evaporated, column chromatography for separation obtain 20mg product, the i.e. compound of embodiment 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) oxygroup)-3- ((1- methyl-1 H- pyrrole Azoles -4- base) methyl) imidazoles [1,2-a] pyrimidine
Intermediate 60 (16mg, 1 equivalent) is dissolved in the in the mixed solvent of ethyl alcohol (1mL) and water (1mL), and intermediate 28a is added, 70 DEG C of reaction 7h.Solvent evaporated, column chromatography for separation obtain 3mg product, i.e. 5 compound of embodiment.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 oxygroup)-3- (pyrimidine-5- base) imidazoles [1,2-a] pyrimidine
Intermediate 53 is added in 0 DEG C of stirring 30min in benzyl alcohol (23mg, 1.5 equivalents) and sodium hydride (17mg, 3 equivalents) (50mg, 1 equivalent), room temperature reaction is overnight.Aqueous ammonium chloride solution quenching reaction, ethyl acetate extraction is added, saturated common salt is washed, Anhydrous sodium sulfate dries, filters, solvent evaporated, and column chromatography for separation obtains 40mg product, i.e. 6 compound of embodiment.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) oxygroup) methyl) benzonitrile
Other than raw material, change referring to the preparation method preparation embodiment 7 of embodiment 1 in addition to using intermediate 35 and 4- Bromopyrimidine Close object.1H NMR (300MHz, Chloroform-d) δ 9.28 (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) oxygroup)-3- (4- fluorophenyl) imidazoles [1,2-a] pyrimidine
Intermediate 54 (37mg, 1 equivalent), to fluorobenzoic boric acid (12mg, 1.1 equivalents), two (triphenyl phosphorus) palladium chlorides (2.6mg, 0.05 equivalent) and sodium carbonate (23.5mg, 3 equivalents) is mixed in the mixed solution of dioxane (5mL) and water (1mL), 150 DEG C of microwave reaction 30min.Partial solvent is evaporated, water, ethyl acetate extraction are added, anhydrous sodium sulfate is dried, filtered, is evaporated molten Agent, column chromatography for separation obtain 15mg product, i.e. 8 compound of embodiment.1H NMR (300MHz, Chloroform-d) δ 8.30 (d, J =7.4Hz, 1H), 7.48 (dd, J=28.2,8.5Hz, 6H), 7.33 (s, 1H), 7.21 (t, J=8.5Hz, 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) oxygroup)-3- (4- methoxyphenyl) Imidazoles [1,2-a] pyrimidine
It other than raw material, is prepared in fact referring to the preparation method of embodiment 8 in addition to using intermediate 54 and to methoxyphenylboronic acid Apply 9 compound of example.1H NMR (300MHz, Chloroform-d) δ 8.30 (d, J=7.3Hz, 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) oxygroup)-3- is (phonetic Pyridine -5- base) imidazoles [1,2-a] pyrimidine
In addition to other than raw material, preparing embodiment 10 referring to the preparation method of embodiment 1 using intermediate 29 and 4- Bromopyrimidine Compound.1H NMR (300MHz, Chloroform-d) δ 9.28 (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) oxygroup)-3- (pyrimidine-5- Base) imidazoles [1,2-a] pyrimidine
In addition to other than raw material, preparing embodiment 11 referring to the preparation method of embodiment 1 using intermediate 34 and 4- Bromopyrimidine Compound.1H NMR (300MHz, Chloroform-d) δ 9.27 (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 oxygroup)-3- luorobenzyl) oxygroup)-3- (pyrimidine-5- base) imidazoles [1,2-a] pyrimidine
In addition to other than raw material, preparing embodiment 12 referring to the preparation method of embodiment 1 using intermediate 36 and 4- Bromopyrimidine Compound.1H NMR (300MHz, Chloroform-d) δ 9.27 (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) oxygroup)-5- methyl-3- (pyrimidine- 5- yl) imidazoles [1,2-a] pyrimidine
In addition to other than raw material, preparing embodiment referring to the preparation method of embodiment 8 using intermediate 58 and 4- pyrimidine boronic acid 13 compounds.1H NMR (400MHz, Chloroform-d) δ 9.28 (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) oxygroup)-3- (pyridin-4-yl) miaow Azoles [1,2-a] pyrimidine
In addition to other than raw material, preparing embodiment referring to the preparation method of embodiment 8 using intermediate 54 and 4- pyridine boronic acid 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) oxygroup)-3- (pyridin-3-yl) miaow Azoles [1,2-a] pyrimidine
In addition to other than raw material, preparing embodiment 15 referring to the preparation method of embodiment 1 using intermediate 28 and 3- bromopyridine Compound.1H NMR (400MHz, Chloroform-d) δ 8.80 (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) oxygroup)-5- first Base -3- (pyrimidine -5- base) imidazoles [1,2-a] pyrimidine
In addition to other than raw material, preparing embodiment referring to the preparation method of embodiment 8 using intermediate 59 and 4- pyrimidine boronic acid 16 compounds.1H NMR (300MHz, Chloroform-d) δ 9.29 (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- ((3,5- bis- fluoro- 4- (4- fluoro- 3- (trifluoromethyl) phenoxy group) benzyl) oxygroup)-3- is (phonetic Pyridine -5- base) imidazoles [1,2-a] pyrimidine
In addition to other than raw material, preparing embodiment 17 referring to the preparation method of embodiment 1 using intermediate 37 and 4- Bromopyrimidine Compound.1H NMR (300MHz, Chloroform-d) δ 9.31 (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- ((3,5- bis- fluoro- 4- (3- (trifluoromethyl) phenoxy group) benzyl) oxygroup)-3- (pyrimidine-5- Base) imidazoles [1,2-a] pyrimidine
In addition to other than raw material, preparing embodiment 18 referring to the preparation method of embodiment 1 using intermediate 38 and 4- Bromopyrimidine Compound.1H NMR (300MHz, Chloroform-d) δ 9.30 (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- ((3,5- bis- fluoro- 4- ((6- picoline-3- base) oxygroup) benzyl) oxygroup)-3- (pyrimidine- 5- yl) imidazoles [1,2-a] pyrimidine
In addition to other than raw material, preparing embodiment 19 referring to the preparation method of embodiment 1 using intermediate 39 and 4- Bromopyrimidine Compound.1H NMR (300MHz, Chloroform-d) δ 9.28 (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) oxygroup)-3,5- difluorobenzyl) oxygroup)-3- (pyrimidine-5- Base) imidazoles [1,2-a] pyrimidine
In addition to other than raw material, preparing embodiment 20 referring to the preparation method of embodiment 1 using intermediate 40 and 4- Bromopyrimidine Compound.1H NMR (400MHz, Chloroform-d) δ 9.28 (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- (the chloro- 4- methylphenoxy of 3-)-3,5- difluorobenzyl) oxygroup)-3- (pyrimidine-5- Base) imidazoles [1,2-a] pyrimidine
In addition to other than raw material, preparing embodiment 21 referring to the preparation method of embodiment 1 using intermediate 41 and 4- Bromopyrimidine Compound.1H NMR (400MHz, Chloroform-d) δ 9.27 (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- (2,6- bis- fluoro- 4- (((3- (pyrimidine-5- base) imidazoles [1,2-a] pyrimidin-7-yl) oxygroup) Methyl) phenoxy group) -2- fluorobenzonitrile
In addition to other than raw material, preparing embodiment 22 referring to the preparation method of embodiment 1 using intermediate 42 and 4- Bromopyrimidine Compound.1H NMR (300MHz, Chloroform-d) δ 9.28 (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- ((3,5- bis- fluoro- 4- (4- (trifluoromethyl) phenoxy group) benzyl) oxygroup)-3- (pyrimidine-5- Base) imidazoles [1,2-a] pyrimidine
In addition to other than raw material, preparing embodiment 23 referring to the preparation method of embodiment 1 using intermediate 43 and 4- Bromopyrimidine Compound.1H NMR (400MHz, Chloroform-d) δ 9.28 (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) oxygroup)-3- (pyrimidine-5- base) miaow Azoles [1,2-a] pyrimidine
In addition to other than raw material, preparing embodiment 24 referring to the preparation method of embodiment 1 using intermediate 44 and 4- Bromopyrimidine Compound.1H NMR (400MHz, Chloroform-d) δ 9.28 (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) oxygroup) benzyl) oxygroup)-3- is (phonetic Pyridine -5- base) imidazoles [1,2-a] pyrimidine
In addition to other than raw material, preparing embodiment 25 referring to the preparation method of embodiment 1 using intermediate 31 and 4- Bromopyrimidine Compound.1H NMR (300MHz, Chloroform-d) δ 9.27 (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) oxygroup) methyl) benzene oxygen Base) -4- (trifluoromethyl) thiazole
Other than being raw material with intermediate 8 and intermediate 53, change referring to the preparation method preparation embodiment 26 of embodiment 6 Close object.1H NMR (300MHz, Chloroform-d) δ 9.27 (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) miaow Azoles [1,2-a] pyrimidine
Other than being raw material with intermediate 9 and intermediate 53, change referring to the preparation method preparation embodiment 27 of embodiment 6 Close object.1H NMR (400MHz, Chloroform-d) δ 9.26 (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) oxygroup) methyl) oxazole
Other than being raw material with intermediate 10 and intermediate 53, embodiment 28 is prepared referring to the preparation method of embodiment 6 Compound.1H NMR (400MHz, Chloroform-d) δ 9.26 (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) oxygroup)-3- (1- methyl-1 H- pyrrole Azoles -4- base) imidazoles [1,2-a] pyrimidine
In addition to being with intermediate 28 and 1- methyl -4- (4,4,5,5- tetramethyls -1,3, penta ring -2- base of 2- dioxy boron) pyrazoles Other than raw material, 29 compound of embodiment is prepared referring to the preparation method of embodiment 8.1H NMR (400MHz, 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) oxygroup)-3- (1- Methyl-1 H- pyrazoles -4- base) imidazoles [1,2-a] pyrimidine
In addition to being with intermediate 29 and 1- methyl -4- (4,4,5,5- tetramethyls -1,3, penta ring -2- base of 2- dioxy boron) pyrazoles Other than raw material, 30 compound of embodiment is prepared referring to the preparation method of embodiment 8.1H NMR (300MHz, 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=31.3Hz, 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) oxygroup)-3- (2- Methoxy pyrimidine -5- base) -5- methylimidazole [1,2-a] pyrimidine
In addition to using intermediate 59 and 2- methoxyl group -4- pyrimidine boronic acid other than raw material, referring to embodiment 8 preparation method system Standby 31 compound of embodiment.1H NMR (300MHz, Chloroform-d) δ 8.59 (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) oxygroup)-3- (4- Picoline -3- base) imidazoles [1,2-a] pyrimidine
It other than raw material, is prepared in fact referring to the preparation method of embodiment 1 in addition to using intermediate 29 and the bromo- 4- picoline of 3- Apply 32 compound of example.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=8.7Hz, 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) methoxyl group)-3- (pyrimidine -5- base) imidazoles [1,2-a] pyrimidine
In addition to other than raw material, preparing embodiment 33 referring to the preparation method of embodiment 1 using intermediate 32 and 4- Bromopyrimidine Compound.1H NMR (300MHz, Chloroform-d) δ 9.28 (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 ethyoxyl)-3- is (phonetic Pyridine -5- base) imidazoles [1,2-a] pyrimidine
In addition to other than raw material, preparing embodiment 34 referring to the preparation method of embodiment 1 using intermediate 30 and 4- Bromopyrimidine Compound.1H NMR (300MHz, Chloroform-d) δ 9.27 (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) oxygroup)-3- is (phonetic Pyridine -5- base)-[1,2,4] triazole [4,3-a] pyrimidine
In addition to other than raw material, preparing embodiment referring to the preparation method of embodiment 8 using intermediate 57 and 4- pyrimidine boronic acid 35 compounds.1H NMR (400MHz, Chloroform-d) δ 9.56 (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- ((3,5- bis- fluoro- 4- ((6- (trifluoromethyl) pyridin-3-yl) oxygroup) benzyl) oxygroup)-3- (pyrimidine -5- base) imidazoles [1,2-a] pyrimidine
In addition to other than raw material, preparing embodiment 36 referring to the preparation method of embodiment 1 using intermediate 45 and 4- Bromopyrimidine Compound.1H NMR (400MHz, Chloroform-d) δ 9.28 (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- methylbenzyl) oxygroup)-3- (pyrimidine- 5- yl) imidazoles [1,2-a] pyrimidine
In addition to other than raw material, preparing embodiment 37 referring to the preparation method of embodiment 1 using intermediate 46 and 4- Bromopyrimidine Compound.1H NMR (400MHz, Methanol-d4) δ 9.19 (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) miaow Azoles [1,2-a] pyrimidine
Other than being raw material with intermediate 2 and intermediate 53, change referring to the preparation method preparation embodiment 38 of embodiment 6 Close object.1H NMR (400MHz, Chloroform-d) δ 9.28 (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) oxygroup)-3- (pyrimidine-5- Base) imidazoles [1,2-a] pyrimidine
In addition to other than raw material, preparing embodiment 39 referring to the preparation method of embodiment 1 using intermediate 47 and 4- Bromopyrimidine Compound.1H NMR (400MHz, Chloroform-d) δ 9.27 (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 other than raw material, preparing embodiment referring to the preparation method of embodiment 8 using intermediate 56 and 4- pyrimidine boronic acid 40 compounds.1H NMR (400MHz, Chloroform-d) δ 9.41 (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
Other than being raw material with intermediate 5 and intermediate 53, change referring to the preparation method preparation embodiment 41 of embodiment 6 Close object.1H NMR (400MHz, Chloroform-d) δ 9.31 (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
Other than being raw material with intermediate 6 and intermediate 53, change referring to the preparation method preparation embodiment 42 of embodiment 6 Close object.1H NMR (400MHz, Chloroform-d) δ 9.26 (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) oxygroup)-3- (pyrimidine -5- base) imidazoles [1,2-a] pyrimidine
In addition to other than raw material, preparing embodiment 43 referring to the preparation method of embodiment 1 using intermediate 48 and 4- Bromopyrimidine Compound.1H NMR (400MHz, Chloroform-d) δ 9.27 (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).
Embodiment 44 --- 7- ((4- (4- chloro- 3- (trifluoromethyl) phenoxy group) benzyl) oxygroup)-3- (pyrimidine-5- base)- [1,2,4] triazole [4,3-a] pyrimidine
Other than using intermediate 61 and 4- pyrimidine boronic acid as raw material, referring to the preparation method of embodiment 8.1H NMR (400MHz, Chloroform-d) δ 9.25 (s, 1H), 9.03 (s, 2H), 7.77 (d, J=6.6Hz, 1H), 7.50 (d, J=8.8Hz, 1H), 7.43 (d, J=6.6Hz, 1H), 7.39 (d, J=2.7Hz, 1H), 7.33 (d, J=8.5Hz, 2H), 7.16 (dd, J=8.7, 2.6Hz, 1H), 7.02 (d, J=8.5Hz, 2H), 5.56 (s, 2H) .MS (ESI): m/z499 (M+H).
Embodiment 45 --- 7- ((4- (4- chloro- 3- (trifluoromethyl) phenoxy group)-3- methylbenzyl) oxygroup)-3- (pyrimidine- 5- yl)-[1,2,4] triazole [4,3-a] pyrimidine
Other than using intermediate 62 and 4- pyrimidine boronic acid as raw material, referring to the preparation method of embodiment 8.1H NMR (400MHz, Chloroform-d) δ 9.39 (s, 1H), 9.23 (s, 2H), 8.35 (d, J=7.5Hz, 1H), 7.45-7.43 (m, 1H), 7.41 (d, J=8.8Hz, 1H), 7.36 (dd, J=8.3,2.0Hz, 1H), 7.26 (s, 1H), 6.98 (dd, J=8.8,2.9Hz, 1H), 6.94 (d, J=8.2Hz, 1H), 5.57 (s, 2H), 2.25 (s, 3H) .MS (ESI): m/z 513 (M+H).
(((3- (pyrimidine-5- base)-[1,2,4] three embodiment 46 --- 2- (4- chloro- 3- (trifluoromethyl) phenoxy group)-5- Nitrogen azoles [4,3-a] pyrimidin-7-yl) oxygroup) methyl) benzonitrile
Other than using intermediate 63 and 4- pyrimidine boronic acid as raw material, referring to the preparation method of embodiment 8.1H NMR (400MHz, Chloroform-d) δ 9.41 (s, 1H), 9.23 (s, 2H), 8.37 (d, J=7.5Hz, 1H), 7.86 (d, J=2.0Hz, 1H), 7.72 (dd, J=8.6,2.1Hz, 1H), 7.55 (d, J=8.7Hz, 1H), 7.42 (d, J=2.7Hz, 1H), 7.21 (dd, J= 8.6,2.8Hz, 1H), 6.95 (d, J=8.6Hz, 1H), 6.69 (d, J=7.5Hz, 1H), 5.60 (s, 2H) .MS (ESI): m/z 524(M+H)。
Embodiment 47 --- 7- ((4- (4- chloro- 3- (trifluoromethyl) phenoxy group)-3- luorobenzyl) oxygroup)-3- (pyrimidine-5- Base)-[1,2,4] triazole [4,3-a] pyrimidine
Other than using intermediate 64 and 4- pyrimidine boronic acid as raw material, referring to the preparation method of embodiment 8.1H NMR (400MHz, Chloroform-d) δ 9.43 (s, 1H), 9.25 (s, 2H), 8.38 (d, J=7.5Hz, 1H), 7.46 (d, J=8.9Hz, 1H), 7.42 (dd, J=10.9,1.8Hz, 1H), 7.33 (d, J=3.1Hz, 2H), 7.16 (t, J=8.2Hz, 1H), 7.08 (dd, J= 8.8,2.9Hz, 1H), 6.71 (d, J=7.5Hz, 1H), 5.62 (s, 2H) .MS (ESI): m/z 517 (M+H).
Embodiment 48 --- 7- ((the chloro- 4- of 3- (4- chloro- 3- (trifluoromethyl) phenoxy group) benzyl) oxygroup)-3- (pyrimidine-5- Base)-[1,2,4] triazole [4,3-a] pyrimidine
Other than using intermediate 65 and 4- pyrimidine boronic acid as raw material, referring to the preparation method of embodiment 8.1H NMR (400MHz, Chloroform-d) δ 9.40 (s, 1H), 9.23 (s, 2H), 8.35 (d, J=7.5Hz, 1H), 7.66 (d, J=2.0Hz, 1H), 7.45 (d, J=8.8Hz, 2H), 7.29 (d, J=2.9Hz, 1H), 7.07 (d, J=8.3Hz, 1H), 7.02 (dd, J=8.8, 2.9Hz, 1H), 6.69 (d, J=7.5Hz, 1H), 5.59 (s, 2H) .MS (ESI): m/z 533 (M+H).
Embodiment 49 --- 7- ((4- (4- chloro- 3- (trifluoromethyl) phenoxy group)-3- (trifluoromethyl) benzyl) oxygroup)-3- (pyrimidine -5- base)-[1,2,4] triazole [4,3-a] pyrimidine
Other than using intermediate 66 and 4- pyrimidine boronic acid as raw material, referring to the preparation method of embodiment 8.1H NMR (400MHz, Chloroform-d) δ 9.40 (s, 1H), 9.23 (s, 2H), 8.36 (d, J=7.5Hz, 1H), 7.86 (d, J=1.7Hz, 1H), 7.70 (dd, J=8.4,1.7Hz, 1H), 7.49 (d, J=8.8Hz, 1H), 7.37 (d, J=2.9Hz, 1H), 7.12 (dd, J= 8.7,2.9Hz, 1H), 7.00 (d, J=8.4Hz, 1H), 6.69 (d, J=7.5Hz, 1H), 5.63 (s, 2H) .MS (ESI): m/z 567(M+H)。
Embodiment 50 --- 7- ((4- (4- chloro- 3- (trifluoromethyl) phenoxy group) benzyl) oxygroup)-6- methyl-3- (pyrimidine- 5- yl) imidazoles [1,2-a] pyrimidine
It is other than raw material, referring to the preparation method of embodiment 1 with intermediate 67.1H NMR (400MHz, chloroform- D) δ 9.28 (s, 1H), 8.93 (s, 2H), 8.15 (s, 1H), 7.73 (s, 1H), 7.56 (d, J=8.5Hz, 2H), 7.45 (d, J= 8.8Hz, 1H), 7.35 (d, J=2.6Hz, 1H), 7.10 (dd, J=8.6,2.8Hz, 1H), 7.04 (d, J=7.3Hz, 2H), 5.58 (s, 2H), 2.26 (s, 3H) .MS (ESI): m/z 512 (M+H).
Pharmacological Examples
Pharmacological Examples 1: external inhibitory activity experiment
Reagent
1) reaction buffer
Reaction buffer is 0.1M Tris-HCl, 1mM EGTA, PH 7.2.
2) the thioesters analog (2- sulphur-PAF, 2-thio-PAF, Cayman, Lot 60945) of phosphatidyl choline
It is dissolved with dehydrated alcohol, configures 25mg/ml mother liquor, and dispense, be stored in -80 DEG C.It is used after 900 times of dilution (dense About 50 μM of degree).
3) DTNB (5,5 '-two sulphur-bis--(2- nitrobenzoic acid), 5,5 '-dithio-bis- (2-nitrobenzoic Acid), Sigma, Lot D8130)
It is just prepared when use.Being configured to concentration with tri-distilled water is 1.1mg/ml, and appropriate 0.1M NaOH to DTNB is added just Dissolution.
4) compound is dissolved to suitable concentration with DMSO.
Experimental principle
Lp-PLA is measured by substrate of 2- sulphur-PAF2Activity.The sulfydryl generated after 2- sulphur-PAF hydrolysis can be reacted with DTNB, Yellow substance is generated, OD value can be detected in 414nm, to reflect Lp-PLA2Activity.
1.1 compounds are the Lp-PLA in enzyme source to rabbit anteserum2The measurement (external) of inhibitory activity
1.1.1 experimental method
1) corresponding reagent is added by table 1, and vibrates and is uniformly mixed
Table 1: reaction system list
2) 10 μ L DTNB are added in every hole.
3) 150 μ L 2- sulphur-PAF are added in every hole, and 15s is vibrated in microplate reader, makes liquid blending in hole.414nM detection 10 Minute, detection is primary per minute, measures slope.Inhibiting rate is calculated according to the following formula
Inhibiting rate=1- (slope sample well-slope blank well)/(slope control wells-slope blank well) × 100%
1.1.2 experimental result is shown in the following table 2.
Table 2: part of compounds is the Lp-PLA in enzyme source to rabbit anteserum under each concentration conditions2Inhibitory activity
" NT " expression is not tested.
Listed compound is under 1 μM of concentration to Lp-PLA in table 22Inhibiting rate is all larger than 50%, and part of compounds is in 100nM To Lp-PLA under concentration2Inhibiting rate is greater than 50%, wherein and embodiment 16 shows best external activity in rabbit anteserum, To Lp-PLA under 100nM concentration2Inhibiting rate can reach 70% or more.
1.2 compounds are the Lp-PLA in enzyme source to source of people recombinase2The measurement (external) of inhibitory activity
1.2.1 experimental method
1) corresponding reagent is added by table 3, and vibrates and is uniformly mixed
Table 3: reaction system list
2) 10 μ L DTNB are added in every hole.
3) 150 μ L 2- sulphur-PAF are added in every hole, and 15s is vibrated in microplate reader, makes liquid blending in hole.414nM detection 10 Minute, detection is primary per minute, measures slope.Inhibiting rate is calculated according to the following formula
Inhibiting rate=1- (slope sample well-slope blank well)/(slope control wells-slope blank well) × 100%
1.2.2 experimental result is shown in the following table 4.
Table 4: part of compounds is the Lp-PLA in enzyme source to source of people recombinase2Inhibitory activity
Listed compound is under 10nM concentration to Lp-PLA in table 42Inhibiting rate is all larger than 50%, wherein embodiment 16, reality It applies example 31 and shows best external activity in source of people recombinase, to Lp-PLA under 10nM concentration2Inhibiting rate reaches about 90%.
1.3 compounds are the Lp-PLA in enzyme source to rat blood serum2The measurement (external) of inhibitory activity
1.3.1 experimental method
1) corresponding reagent is added by table 5, and vibrates and is uniformly mixed
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 dissolution) 10L
2) 10 μ L DTNB are added in every hole.
3) 150 μ L 2- sulphur-PAF are added in every hole, and 15s is vibrated in microplate reader, makes liquid blending in hole.414nM detection 10 Minute, detection is primary per minute, measures slope.Inhibiting rate is calculated according to the following formula
Inhibiting rate=1- (slope sample well-slope blank well)/(slope control wells-slope blank well) × 100%
1.3.2 experimental result is shown in the following table 6.
Table 6: part of compounds is the Lp-PLA in enzyme source to rat blood serum2Inhibitory activity
" NT " expression is not tested.
Listed compound in table 6, the good external activity shown in rat blood serum, all compounds exist To Lp-PLA under 100nM concentration2Inhibiting rate is all larger than 50%.
The experiment of Pharmacological Examples 2:S9 metabolic stability in vitro
2.1. reagent
2.1.1 Tris/HCl (0.1M, pH 7.4) buffer
It weighs 12.12g TRIS (trishydroxymethylaminomethane, tris-hydroxymethyl aminomethane), it is molten Solution adjusts pH to 7.4 in 800mL water, with HCl (2M), is then settled to 1000mL with water.
2.1.2 MgCl2It prepares
MgCl is made into 0.1M Tris/HCl buffer2(100mM) solution, deposits in -20 DEG C after packing.MgCl2Incubate Educating concentration is 5.0mM.
2.1.3 NADPH is prepared
It is made into NADPH (10mM) solution with 0.1M Tris/HCl buffer, deposits in -20 DEG C after packing.NADPH's incubates Educating concentration is 1.0mM.
2.1.4 S9 is prepared
With 0.1M Tris/HCl by people S9 (being purchased from Ruide Liver Disease Inst. (Shanghai) Co., Ltd.) 10 times of dilution, greatly Mouse S9 (being purchased from Ruide Liver Disease Inst. (Shanghai) Co., Ltd.) 5 times of dilution.So that the incubation concentration of people, rat S9 are equivalent to Corresponding kind hepatomicrosome incubation concentration (people, rat liver microsomes incubation concentration be 0.33mg/mL).
2.1.5 untested compound is prepared
The stock solution that concentration is 10mM is obtained with DMSO dissolved compound.It is diluted to after 1mM with DMSO again with 0.1%BSA- Water dilution obtains the working solution that concentration is 2 μM.In incubation system, 2 μM of working solution dilutes 20 times, final concentration of 0.1 μM. DMSO concentration≤0.01% in incubation system.
2.1.6 positive reference compound is prepared
Using 2 μM of determinand working solutions by 2mM VIVID stock solution (be purchased from Shanghai Bai Li Biotechnology Co., Ltd) 50 times of dilution.In incubation system, the hybrid working solution of VIVID and determinand dilutes 20 times.
2.2 experimental method
S9 incubation carried out in 96 orifice plates, each incubation system volume be 450 μ L, 0.1M Tris buffers (pH 7.4), MgCl2, S9 and+NADPH/-NADPH incubated in advance at 37 DEG C after 10min (revolving speed 600rpm), it is anti-that test medicine starting is added It answers, the ice methanol that same volume is added after 0,7,17,30,60min respectively terminates reaction.
2.3 experimental result is shown in the following table 7.
Table 7: metabolic stability of the part of compounds in people, rat S9
It indicates that compound is stablized in test system, half-life period can not be measured.
Listed compound in table 7, experimental result show metabolic stability compared to the change for being currently in clinical investigation phase Closing object darapladib has advantage, and people and metabolism of rat property show preferable kind consistency.
Inhibit Lp-PLA in Pharmacological Examples 3:SD rat body2Activity experiment
2.1 experimental method
25mg/kg is administered orally in every group of 5 SD rats, and Darapladib is dissolved with ddH2O, embodiment compound solvent For 0.5% sodium carboxymethylcellulose (CMC sodium).Before being administered 1h, 3h after 0h, administration, 5h, 7h, eye socket is taken a blood sample for 24 hours, room temperature is put It is centrifuged after setting 30 minutes, takes serum, measure Lp-PLA in serum2Activity.
2.2 experimental result
According to the test result of external activity, has chosen part of compounds and carried out the intracorporal Lp-PLA of SD rat2Inhibit Active testing, experimental result are as depicted in figs. 1 and 2.
The result shows that after single-dose, it is big can to significantly inhibit SD for the embodiment compound 1,11,44 and 47 of selection Lp-PLA in mouse serum2Activity, and show and the comparable internal inhibitory activity of positive reference compound darapladib. Experiment in vivo has shown pretty good Lp-PLA the results show that oral embodiment compound in rat body2Inhibit to live Property, show that embodiment compound has good development prospect.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims It encloses.

Claims (8)

1. a kind of compound of Formula I or its pharmaceutically acceptable salt:
In formula, R1For C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C3-C6Naphthenic base, 3-6 circle heterocyclic ring base ,-(CH2)m-NR4R5、 Phenyl ,-(CH2)m(3-8 unit's heteroaryl) or halogen, wherein the C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C3-C6Ring Alkyl, 3-8 unit's heteroaryl, 3-6 circle heterocyclic ring base, phenyl are optionally replaced group selected from the group below :-CN, C1-C6Alkyl, C1-C6Alkoxy, halogen, hydroxyl, halogenated C1-C6Alkyl；
R2For H or C1-C6Alkyl, wherein the C1-C6Alkyl is optionally replaced by group selected from the group below :-CN, C1-C6Alkyl, C1-C6Alkoxy, halogen, hydroxyl, halogenated C1-C6Alkyl；
R3For H or C1-C6Alkyl, wherein the C1-C6Alkyl is optionally replaced by group selected from the group below :-CN, C1-C6Alkyl, C1-C6Alkoxy, halogen, hydroxyl, halogenated C1-C6Alkyl；
X is O or S；
N is 0,1,2 or 3；
Ar is phenyl, naphthalene or 5-6 unit's heteroaryl, wherein the phenyl, naphthalene, 5-6 unit's heteroaryl are optionally selected by 1-4 Replace from the group of the following group :-CN, C1-C6Alkyl, C1-C6Alkoxy, halogen, hydroxyl, halogenated C1-C6Alkyl, halogenated C1-C6Alcoxyl Base；
Y is-A- (C6-C10Aryl) or-A- (5-6 unit's heteroaryl), wherein A O, the C6-C10Aryl, 5-6 unit's heteroaryl are appointed Selection of land is replaced by 1-3 groups selected from the group below :-CN, fluorine, chlorine, bromine, trifluoromethyl, methyl, ethyl, propyl；
Z is CH or N；
The R4And R5It is each independently selected from H, C1-C6Alkyl, C1-C6Alkanoyl ,-(CH2)p-(C1-C6Alkoxy), C3-C8Ring Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 3-8 circle heterocyclic ring base, C3-C8Cycloalkenyl and C6-C10Aryl；
The m and p is each independently 0,1,2 or 3.
2. compound according to claim 1 or its pharmaceutically acceptable salt,
In formula, R1For-(CH2)m-NR4R5, phenyl or-(CH2)m(3-6 unit's heteroaryl)；
R2For H or methyl；
R3For H；
X is O or S；
N is 0,1 or 2；
Ar is phenyl, and the phenyl is optionally replaced by 1-3 groups selected from the group below :-CN, fluorine, chlorine, bromine, trifluoromethyl, first Base, ethyl or propyl；
Y is-A- (C6-C10Aryl) or-A- (5-6 unit's heteroaryl), wherein A O, the C6-C10Aryl, 5-6 unit's heteroaryl are appointed Selection of land is replaced by 1-3 groups selected from the group below :-CN, fluorine, chlorine, bromine, trifluoromethyl, methyl, ethyl, propyl；
Z is CH or N；
The R4And R5It is each independently selected from H, C1-C3Alkyl；
The m is 0,1,2 or 3.
3. a kind of compound as described in following general formula (IA) or its pharmaceutically acceptable salt,
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, pyridyl group, wherein the phenyl, pyrrole Oxazolyl, pyrimidine radicals are optionally selected from following group of substitution :-CN ,=O, methyl, ethyl, phenyl, methoxyl group, ethyoxyl, cyclopropyl Base, fluorine, chlorine, bromine, trifluoromethyl；
R2For hydrogen or methyl；
Ar ' is phenyl, pyridyl group, pyrimidine radicals, wherein the phenyl, pyridyl group, pyrimidine radicals are optionally by 1-3 selected from following The group of group replaces: trifluoromethyl, fluorine, chlorine, cyano, methyl.
4. a kind of compound or its pharmaceutically acceptable salt, the compound are any compound as shown in the table:
5. compound according to claim 1 or its pharmaceutically acceptable salt, wherein described pharmaceutically to receive Salt be hydrochloride, hydrobromate, sulfate, nitrate, phosphate, citrate, mesylate, trifluoroacetate, acetic acid Salt, oxalates, succinate, malate, toluene fulfonate, tartrate, fumarate, glutamate, glucuronate, Lactate, glutarate, arginine salt or maleate.
6. the preparation method of compound of Formula I according to claim 1 or its pharmaceutically acceptable salt, including it is following Step:
When Z is CH in general formula I, as Compounds of formula II, by Formulas I c compound and R1W reacts to obtain, wherein W Cl, Br Or I；
Or the preparation method comprises the following steps:
When Z is CH in general formula I, as Compounds of formula II, by Formulas I d compound with Reaction It obtains；
Or the preparation method comprises the following steps:
When Z is CH in general formula I, as Compounds of formula II, by Formula II d compound and Y-Ar- (CH2)nXH is anti-in the presence of a base It should obtain；
Or the preparation method comprises the following steps:
When Z is N in general formula I, as compound of formula III, by formula III e compound with Instead It should obtain；
Wherein, the R1、R2、R3, the definition of Y, Ar, n, X it is identical as the definition in claim 1.
7. a kind of pharmaceutical composition, include compound of Formula I according to claim 1 or its pharmaceutically acceptable Salt；And pharmaceutically acceptable carrier.
8. compound of Formula I according to claim 1 or its pharmaceutically acceptable salt or as claimed in claim 7 The purposes of pharmaceutical composition, the purposes are to be used for:
(1) preparation inhibits Lp-PLA2Drug；Or
(2) preparation prevention and/or treatment and/or improvement and Lp-PLA2The drug of the related disease of enzymatic activity.
CN201680016991.XA 2015-05-08 2016-04-29 Double cyclics, preparation method and medical usage as Lp-PLA2 inhibitor Expired - Fee Related CN107709325B (en)

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