CN109180671A - Imino group thiadiazine dioxide derivative and application thereof - Google Patents

Abstract

The invention discloses imino group thiadiazine dioxide derivatives and application thereof, in particular it relates to a kind of novel imino group thiadiazine dioxide derivative and the pharmaceutical composition comprising such compound, they can be used as BACE-1 inhibitor.The invention further relates to the method for preparing this kind of compound and pharmaceutical composition and they preparation treatment with beta-amyloid protein (" A β ") related disease, the especially purposes in the drug of Alzheimer disease.

Description

Imino group thiadiazine dioxide derivative and application thereof

Technical field

The invention belongs to technical field of pharmaceuticals, and in particular to novel imino group thiadiazine dioxide derivative and comprising The pharmaceutical composition and its application method and purposes of these compounds.Particularly, novel imino group thiophene two of the present invention Piperazine dioxide derivative can be used as BACE-1 inhibitor, have for preventing, treating or mitigating with beta-amyloid protein (" A β ") The disease of pass, especially Alzheimer disease.

Background technique

Beta-amyloid protein (" A β ") is the chief component of beta amyloid fibrinogen and patch, disease related with A β Including but not limited to: dull-witted, senile dementia, alzheimer's disease, Ahl tribulus sea silent sickness, Parkinson's disease and/or Down syndrome Relevant dementia, Down syndrome, attention deficit symptom, Ahl tribulus sea silent sickness, Parkinson's disease and/or Down syndrome phase The attention deficit symptom of pass, the loss of memory, the loss of memory relevant to Parkinson's disease, the relevant memory of Ahl tribulus sea silent sickness It loses, apoplexy, neurodegeneration, amyloidosis, beta amyloid angiosis, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, blood Liquid Complication of dialysis (is derived from β₂Microglobulin, and complication is thus generated in hemodialysis patients), glaucoma, II type glycosuria Disease, the relevant amyloid of diabetes generate, traumatic brain injury (" TBI "), bovine spongiform encephalopathy, and Corticobasal becomes Property, stein-leventhal syndrome, microglia hyperplasia and brain inflammation, smell damage, Ahl tribulus sea silent sickness, Parkinson's disease And/or Down syndrome relevant smell damage, itch, Creutzfeld-Jakob disease, mild cognitive impairment (" MCI ") and Alzheimer disease.

Alzheimer disease (Alzheimer ' s disease, AD) is the main Types of senile dementia, is that the elderly recognizes Know the Etiological with mental deterioration, is the Neuro-degenerative disease for seriously affecting the progress sexual development of life of elderly person quality Disease.Clinically with memory disorders, aphasia, appraxia, agnosia, the damage of visual space technical ability, execution dysfunction and personality and behavior The performance of the generalized dementias such as change is characterized.Alzheimer disease not only deteriorates personal and quality of social life, can also make patient It agonizes with other people of surrounding.Alzheimer disease is that the 4th height after cancer, heart disease and cerebral hemorrhage is dead Die reason.

It is estimated that in worldwide, suffer from AD more than 2 million peoples, and think AD be cause it is dull-witted most common The reason of.AD is the disease by neuronal degeneration and characterized by losing, and also will form neurofibrillary tangles and senile plaques.

According to the multiple epidemiological surveys in China as a result, the illness rate of AD is about 5% in over-65s crowd, disease incidence Generally increase with the increase at age.The Research statistics of developed country are shown with the number of the patient with Alzheimer disease Amount ratio is also the increase with the age and increases.Wherein, in more than 60 years old crowds, more than 70 years old crowds and more than 80 years old crowds Illness rate is respectively 15-20%, 30-40% and 60%.It can be seen that the case where suffering from AD in more than 80 years old crowds, is very serious, often Alzheimer disease is just suffered to a people in spouse.

There are many causes of disease for leading to Alzheimer disease.Firstly, according to existing research, the disease with Alzheimer disease People has the acetylcholine of low concentration, and when acetylcholinesterase is suppressed, the concentration by increasing acetylcholine improves Ah The symptom of Alzheimer's disease；Second, by using estrogen, antioxidant, radical scavenger or anti-inflammatory agent can between take over control The only further deterioration of Alzheimer disease；Third, by preventing gradually controlling with irreversible degeneration for cynapse and neuron Treat Alzheimer disease；4th, postpone the progress of Alzheimer disease, institute by studying the inherent cause of Alzheimer disease State inherent cause be related to the synthesis of beta-amyloid protein, progress, the accumulation of neuron and in cortex beta-amyloid protein it is heavy Product.Similarly, the governing factor of the extracellular concentration of beta-amyloid protein is reduced by discovery, and is selectively removed in intracerebral Beta-amyloid protein deposit, can treat Alzheimer disease.

Currently, the treatment of Alzheimer disease is only limitted to treat its symptom, rather than treat its underlying etiology.In order to The medicament for improving symptom and ratifying includes, for example, N-methyl-D-aspartate receptor antagonist (for example, Memantine), acetyl gallbladder Alkali esterase inhibitor (for example, donepezil, rivastigmine, galanthamine, Tacrine).Clinically there are no can effectively reverse Cognitive impairment improves the drug for the treatment of Alzheimer disease.Acetylcholinesterase inhibitor (donepezil, Rivastigmine, Shi Shan Alkali first, galanthamine) treatment is light-and moderate AD patients have certain curative effect, but are also temporary relief of symptoms, it can not further hinder The only decaying of nerve cell, and it is accompanied by serious adverse reaction.Use in conjunction brain blood flow and cerebral metabolism such as Oxiracetam (oxiracetam) have certain curative effect in terms of improving memory, but more when be as intelligence development agent exist.Therefore, anxious The new drug that can improve or treat Alzheimer disease need to be developed.And the drug development of the target spot around A β, recognized always To be the new approach got a good chance of.

A β peptide is the small peptide generated by the proteolysis cracking for being referred to as the transmembrane protein of amyloid precusor protein (" APP ").APP Fracture generates A β peptide: being broken in the N-terminal neighbouring position of A β by beta-secretase activity, passes through γ-points in the C-terminal neighbouring position of A β Secreting enzymatic activity fracture, (APP can be also broken by alpha-secretase activity, generate secretion, non-starch sample section, referred to as soluble APPα).It is by beta-secretase enzyme activity that the site β APP, which is broken enzyme (Beta site APP Cleaving Enzyme, " BACE-1 "), Property and be responsible for generate A β main aspartyl protease.Research inhibits BACE-1 it has been shown that passing through so as to inhibit A β Generation.

In AD, ternary structural can be formed by the A β peptide that beta-secretase and gamma-secretase activity are formed, assemble shape Amyloidogenic fibrinogen.In addition, A β peptide can form A β oligomer (also known as " A beta-aggregation object " or " Abeta oligomer ").Aβ The small multimeric structure that oligomer is made of 2-12 A β peptide (being different from A β fibrinogen in its structure).Amyloid fibrils Can be deposited on outside neuron to memory and the important brain area domain of cognitive ability with densified form, referred to as neuritis spot, decline Old spot or diffusion spot.When injecting in cell culture or in the brain of rat, A β oligomer is cytotoxin.This A β bites Spot is formed and deposited and/or A β oligomer is formed, and the neuronal death and cognitive impairment that occur as a result, is AD pathology Some marks of physiology.Other marks of AD Pathological Physiology further include: the cell being made of the Protein tau of abnormal Phosphorylation Interior neurofibrillary tangles and neuroinflamation.

Evidence suggests A β, A β plaque block, A β fibrinogen, A β aggregate and/or A β oligomer rise in AD Pathological Physiology To origin cause of formation effect (Ohno, et al.Neurobiology of Disease, 2007, No.26,134-145).It is known that APP and Gene mutation in presenilin (presenilins) 1/2 (PS1/2) can lead to familial AD, and think familial AD's The cause of disease is that the generation of the 42- amino acid form of A β increases.It has been proved that A β can neurotoxic in culture and in vivo.For example, working as When being injected into the brain of old primate, fibrous A β leads to the neuronal death around injection site.And it also reported A Other direct and indirect evidences of effect of the β in the cause of disease of AD.

BACE-1 has become the treatment targeting for the treatment of Alzheimer disease.For example, McConlogue group it is stated that The AD class lesion that the part of BACE-1 enzymatic activity reduces and the adjoint reduction of A β level inhibits A β to motivate in which can dramatically, so that β-points Secrete enzyme become in AD for therapy intervention targeting (McConlogue, et al.J.Bio.Chem., Sep.2007, Vol.282,No.36).Luo group is reported that the mouse for lacking BACE-1 still has normal phenotype, and eliminates β-starch Sample albumen forms (Luo, et al.Nature Neuroscience, March 2001, Vol.4, No.3).Roberds group is Through determination, beta-secretase is active to inhibit or loses the phenotypic defects that not will cause extreme, and the adjoint property for also resulting in A β reduces (Roberds,et al.HumanMol.Genetics,2001,Vol.10,No.12,1317-1324).Ohno group has reported Road, in 5XFAD mouse, the genetic defect of BACE-1 can eliminate A β and be formed, hinder amyloid beta deposition, prevent in brain skin Layer and (the brain area domain for showing most serious amyloidosis in 5XFAD mouse) middle neuron loss found of getting a foothold, and Memory impairment can be saved in 5XFAD mouse.The group also reports that A β is finally responsible to the neuronal death in AD, and Infer BACE-1 inhibit to can be used as treatment AD effective ways (Ohno, et al.Neurobiology of Disease, 2007, No.26,134-145)。

Currently, the treatment potentiality of A β deposition is inhibited to promote many groups to remove characterization BACE-1 and identified that BACE-1 inhibits Agent.People also have carried out some research BACE-1 inhibitor:

2011044181 A1 of WO discloses the imino group thiophene as BACE inhibitor (BACE-1 or BACE-2 inhibitor) Diazine dioxide compound, composition and their purposes are generated for preventing or treating with beta-amyloid protein (" A β ") Relevant various lesions, including Alzheimer disease.

2016172255 A1 of WO discloses imino group tetrahydropyrimidine -4 (1H) -one compound as BACE-1 inhibitor With imino group thiomorpholine dioxide compound and their purposes, for preventing or treating Down Syndrome, β kind of starch proteinemina Pipe lesion, illness relevant to cognitive impairment, Alzheimer disease, the loss of memory, the relevant attention of Ahl tribulus sea silent sickness Insufficient disease, neurodegenerative disorders, early onset dementia, old dementia and with Parkinson's disease, Alzheimer disease and/or Tang The relevant dementia of family name's disease, Age related macular portion lesion, glaucoma, olfactory impairment, traumatic brain injury, gradual muscle wither Contracting disease, type-2 diabetes mellitus base cardiovascular disease (apoplexy).

2014093190 A1 of WO discloses the imino group thiophene as BACE inhibitor (BACE-1 or BACE-2 inhibitor) Diazine dioxide compound, composition and their purposes, for preventing or treating Alzheimer disease.

2017051294 A1 of WO is disclosed as the imino group thiadiazine dioxide compound of BACE-1 inhibitor, group The purposes for closing object and they, for preventing or treating the disease such as Alzheimer disease mediated by BACE-1.

2015094930 A1 of WO discloses the C-6 spiral shell carbocyclic ring as BACE inhibitor (BACE-1 or BACE-2 inhibitor) Substituted imino group thiadiazine dioxide compound, composition and their purposes, for preventing or treating Alzheimer Disease.

2014099768 A1 of WO discloses the C-6 azaspiro as BACE inhibitor (BACE-1 or BACE-2 inhibitor) Cyclosubstituted imino group thiadiazine dioxide compound, composition and their purposes, for preventing or treating alzheimer ' Silent disease.

2014150340 A1 of WO discloses the S- imino group-as BACE inhibitor (BACE-1 or BACE-2 inhibitor) Imino group thiadiazine compound, composition and their purposes of S- oxo, for preventing or treating Alzheimer disease.

2012139425 A1 of WO discloses the 5- substitution as BACE inhibitor (BACE-1 or BACE-2 inhibitor) Imino group thiazide and its single and dioxide compound, composition and their purposes, for preventing or treating alzheimer ' Silent disease.

2013174781 A1 of WO is disclosed as 5- amino [1,4] thiazides compounds of BACE-1 inhibitor, combination The purposes of object and they, for preventing or treating Alzheimer disease.

2018112094 A1 of WO discloses the 1,4- thiazine as BACE inhibitor (BACE-1 or BACE-2 inhibitor) Dioxide and 1,2,4- thiadiazine dioxide compounds, composition and their purposes, for preventing or treating A Erci The silent disease in sea.

Summary of the invention

Novel imino group thiadiazine dioxide derivative the present invention provides one kind as BACE-1 inhibitor, It can be used for treating by beta-amyloid protein (" A β ") mediation by inhibiting BACE-1 to inhibit the generation of A β, therefore Disease, especially for treating Alzheimer disease.And it is shown experimentally that, imino group thiadiazine titanium dioxide of the invention The property of object derivative is stablized, good security, has good pharmacodynamics and a pharmacokinetic property, such as good brain/ Blood plasma ratio (brain plasma ratio), good bioavilability or good metabolic stability etc..Therefore, have good Good potential applicability in clinical practice.

The present invention also provides prepare the method for this kind of compound, the pharmaceutical composition containing this kind of compound and this kind of The purposes of the pharmaceutical composition of compound and this kind of compound in medicine preparation.

On the one hand, the present invention relates to a kind of compound, be formula (I) or formula (I ') compound represented or formula (I) or Stereoisomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, the medicine of compound shown in formula (I ') Acceptable salt or its prodrug on,

Wherein: each R^1a、R^1b、R^1c、R^1d、R^1e、R^2a、R^2b、R^2c、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹, X and Y have such as the present invention The meaning.

In one embodiment, X CR^xOr N.

In one embodiment, Y is CH or N.

In one embodiment, R^1a、R^1b、R^1c、R^1dAnd R^1eIt is each independently H, D, F, Cl, Br, I ,-CN ,-NO₂、- NH₂、-OH、-SH、-COOH、-CONH₂,-C (=O) NHCH₃,-C (=O) N (CH₃)₂,-C (=O)-(C₁-C₆Alkyl) ,-C (= O)-(C₁-C₆Alkoxy), C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆It is halogenated Alkoxy, C₁-C₆Alkylthio group, C₁-C₆The C that alkylamino or hydroxyl replace₁-C₆Alkyl.

In one embodiment, R^2a、R^2b、R^2cAnd R^xIt is each independently H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂、- OH ,-COOH ,-C (=O) NH₂、C₁-C₆Alkyl, C₁-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆Halogenated alkoxy or hydroxyl take The C in generation₁-C₆Alkyl.

In one embodiment, R³And R⁴It is each independently H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂、-OH、- COOH ,-C (=O) NH₂、C₁-C₆Alkyl, C₁-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆What halogenated alkoxy or hydroxyl replaced C₁-C₆Alkyl.

In one embodiment, R⁵For H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂,-OH ,-COOH ,-C (=O) NH₂、C₁- C₆Alkyl, C₁-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆The C that halogenated alkoxy or hydroxyl replace₁-C₆Alkyl.

In one embodiment, R⁶For H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂,-OH ,-COOH ,-C (=O) NH₂、C₁- C₆Alkyl, C₁-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆The C that halogenated alkoxy or hydroxyl replace₁-C₆Alkyl.

In one embodiment, R⁷And R⁸It is each independently H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂、-OH、- COOH ,-C (=O) NH₂、C₁-C₆Alkyl, C₁-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆What halogenated alkoxy or hydroxyl replaced C₁-C₆Alkyl.

In one embodiment, R⁹For H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂,-OH ,-COOH ,-C (=O) NH₂、C₁- C₆Alkyl, C₁-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆The C that halogenated alkoxy or hydroxyl replace₁-C₆Alkyl.

In one embodiment, R^1a、R^1b、R^1c、R^1dAnd R^1eIt is each independently H, D, F, Cl, Br, I ,-CN ,-NO₂、- NH₂、-OH、-SH、-COOH、-CONH₂,-C (=O)-(C₁-C₄Alkyl) ,-C (=O)-(C₁-C₄Alkoxy), C₁-C₄Alkyl, C₂- C₄Alkenyl, C₂-C₄Alkynyl, C₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, C₁-C₄Halogenated alkoxy, C₁-C₄Alkylthio group, C₁-C₄Alkane ammonia The C that base or hydroxyl replace₁-C₄Alkyl.

In another embodiment, R^1a、R^1b、R^1c、R^1dAnd R^1eIt is each independently H, D, F, Cl, Br, I ,-CN ,-NO₂、- NH₂、-OH、-SH、-COOH、-CONH₂,-C (=O) CH₃,-C (=O) OCH₃,-C (=O) OCH₂CH₃,-C (=O) OCH₂CH₂CH₃,-C (=O) OCH (CH₃)₂, methyl, ethyl, n-propyl, isopropyl ,-CF₃、-CH₂CF₃, methoxyl group, ethyoxyl, N-propyl oxygroup or isopropyl oxygroup.

In one embodiment, R^2a、R^2b、R^2cAnd R^xIt is each independently H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂、- OH ,-COOH ,-C (=O) NH₂、C₁-C₄Alkyl, C₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, C₁-C₄Halogenated alkoxy or hydroxyl take The C in generation₁-C₄Alkyl.

In another embodiment, R^2a、R^2b、R^2cAnd R^xIt is each independently H, D, F, Cl, Br, I ,-CN ,-NO₂、- NH₂,-OH ,-COOH ,-C (=O) NH₂, methyl, ethyl, n-propyl, isopropyl ,-CF₃、-CH₂CF₃, methoxyl group, ethyoxyl, just Propyl oxygroup or isopropyl oxygroup.

In one embodiment, R³And R⁴It is each independently H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂、-OH、- COOH ,-C (=O) NH₂、C₁-C₄Alkyl, C₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, C₁-C₄What halogenated alkoxy or hydroxyl replaced C₁-C₄Alkyl.

In another embodiment, R³And R⁴It is each independently H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂、-OH、- COOH ,-C (=O) NH₂, methyl, ethyl, n-propyl, isopropyl ,-CF₃、-CH₂CF₃, methoxyl group, ethyoxyl, n-propyl oxygroup Or isopropyl oxygroup.

In one embodiment, R⁵For H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂,-OH ,-COOH ,-C (=O) NH₂、C₁- C₄Alkyl, C₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, C₁-C₄The C that halogenated alkoxy or hydroxyl replace₁-C₄Alkyl.

In another embodiment, R⁵For H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂,-OH ,-COOH ,-C (=O) NH₂、 Methyl, ethyl, n-propyl, isopropyl ,-CF₃、-CH₂CF₃, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup.

In one embodiment, R⁶For H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂,-OH ,-COOH ,-C (=O) NH₂、C₁- C₄Alkyl, C₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, C₁-C₄The C that halogenated alkoxy or hydroxyl replace₁-C₄Alkyl.

In one embodiment, R⁶For H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂,-OH ,-COOH ,-C (=O) NH₂, first Base, ethyl, n-propyl, isopropyl ,-CF₃、-CH₂CF₃, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup.

In another embodiment, R⁷And R⁸It is each independently H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂、-OH、- COOH ,-C (=O) NH₂、C₁-C₄Alkyl, C₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, C₁-C₄What halogenated alkoxy or hydroxyl replaced C₁-C₄Alkyl.

In one embodiment, R⁷And R⁸It is each independently H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂、-OH、- COOH ,-C (=O) NH₂, methyl, ethyl, n-propyl, isopropyl ,-CF₃、-CH₂CF₃, methoxyl group, ethyoxyl, n-propyl oxygroup Or isopropyl oxygroup.

In one embodiment, R⁹For H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂,-OH ,-COOH ,-C (=O) NH₂、C₁- C₄Alkyl, C₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, C₁-C₄The C that halogenated alkoxy or hydroxyl replace₁-C₄Alkyl.

In another embodiment, R⁹For H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂,-OH ,-COOH ,-C (=O) NH₂、 Methyl, ethyl, n-propyl, isopropyl ,-CF₃、-CH₂CF₃, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup.

On the one hand, the present invention relates to a kind of compounds, are formula (II) or formula (II ') compound represented or formula (II) or the stereoisomer of compound shown in formula (II '), tautomer, nitrogen oxides, hydrate, solvate, metabolism Product, pharmaceutically acceptable salt or its prodrug,

In one embodiment, compound of the present invention for the compound with one of following structure or has The stereoisomer of the compound of one of following structure, tautomer, nitrogen oxides, hydrate, solvate, metabolism produce Object, pharmaceutically acceptable salt or its prodrug:

On the other hand, the present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition includes chemical combination disclosed by the invention Object.

In one embodiment, pharmaceutical composition of the present invention, further include pharmaceutically acceptable excipient, Carrier, adjuvant or their any combination.

In another embodiment, pharmaceutical composition of the present invention further includes additional therapeutic agent, wherein institute Additional therapeutic agent is stated to be nalmefene, Risperidone, Rivastigmine, Memantine, mitzapine, Venlafaxine, desipramine, first is gone to replace Woods, zolpidem, zopiclone, Nicergoline, Piracetam, selegiline, pentoxifylline, Tacrine, donepezil, Garland He is quick, rivastigmine, vitamin e, fibrates, niacin, nicotinic receptor agonist, nicotinic acetylcholine receptor excitement Agent, anticholinesterase, N-methyl-D-aspartate receptor antagonist, the promotor of α secretase activity, glycogen synthetase Kinases beta inhibitor, the inhibitor of amyloid aggregation, gamma-secretase inhibitors, gamma secretase modulators, 3 antagonism of histamine H Agent, histone deacetylase inhibitors, PDE-4 inhibitor, PDE-10 inhibitor, mGluR1 receptor modulators or antagonist, MGluR5 receptor modulators or antagonist, mGluR2/3 antagonist, 5-HT₄Agonist, 5-HT₆Receptor antagonist or GABA_AReversely Agonist.

Another aspect, the present invention relates to the purposes of compound disclosed by the invention or pharmaceutical composition in medicine preparation, The generation that the drug is used to inhibit BACE-1 to inhibit A β.

In another aspect, the purposes the present invention relates to compound disclosed by the invention or pharmaceutical composition in medicine preparation, The drug is for preventing, treating or mitigating disease related with beta-amyloid protein.

In one embodiment, the disease related with beta-amyloid protein is dementia, senile dementia, with alzheimer ' Silent disease, Parkinson's disease and/or the relevant dementia of Down syndrome, Down syndrome, attention deficit symptom, with Alzheimer Disease, Parkinson's disease and/or the relevant attention deficit symptom of Down syndrome, the loss of memory, memory relevant to Parkinson's disease It loses, the relevant loss of memory of Ahl tribulus sea silent sickness, apoplexy, neurodegeneration, amyloidosis, beta amyloid angiosis, greatly Cerebral amyloid angiopathy, hereditary cerebral hemorrhage, complication of hemodialysis, glaucoma, type-2 diabetes mellitus, the relevant starch of diabetes Shape albumen generates, traumatic brain injury, bovine spongiform encephalopathy, mild cognitive impairment or Alzheimer disease.

In another embodiment, the disease related with beta-amyloid protein is Alzheimer disease.

On the other hand, the present invention relates to formula (I), (I '), preparation, separation and the purifying of compound shown in (II) or (II ') Method.

Biological results show that the compounds of this invention passes through and inhibit BACE-1 to inhibit the generation of A β, and can be used as Preferable BACE-1 inhibitor.

Any embodiment in either present invention face can be combined with other embodiments, as long as they are not It will appear contradiction.In addition, any technical characteristic can be adapted for other realities in any embodiment of either side of the present invention The technical characteristic in scheme is applied, as long as they are not in contradiction.

Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its Content in terms of him will make more specific complete description below.All bibliography in this specification pass through whole reference In this.When the disclosure of the specification and citation are variant, it is subject to the disclosure of the specification.

Detailed description of the invention book

Definition and general terms

It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation that are appended.This Invention is intended to cover all replacement, modification and equivalent technical solutions, they are included in the present invention defined such as claim In range.Those skilled in the art will appreciate that many can be used in similar or equivalent method and material of the present invention The practice present invention.The present invention is not limited to method of the present invention and material.In document, patent and the similar material combined One or more or contradict in the case where (including but not limited to defined in term, term application, institutes different from the application Technology of description, etc.), it is subject to the application.

It will further be appreciated that certain features of the invention, be it is clearly visible, carry out in a number of independent embodiments Description, but can also provide in combination in a single embodiment.Conversely, various features of the invention, for brevity, It is described in a single embodiment, but can also be individually or with the offer of any suitable sub-portfolio.

Unless otherwise stated, following definition used in the present invention should be applied.For purposes of the present invention, chemical element With the periodic table of elements CAS editions, and " Handbook of Chemistry and Physics ", the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can With reference to " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito: 1999, and " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry Description in March, John Wiley&Sons, New York:2007, entire contents are incorporated by reference into the present invention.

There is apparent conflict unless otherwise indicated or in context, the article " one " used in the present invention, " one (kind) " and " described " are intended to include "at least one" or " one or more ".Therefore, these articles used in the present invention refer to The article of one or more than one (i.e. at least one) object.For example, " component " refers to one or more components, it is possible to have more It uses or uses in the embodiment that one component is taken into account in the embodiment.

Term " stereoisomer " refers to identical chemical constitution, but spatially arrangement mode is different for atom or group Compound.Stereoisomer includes that enantiomter, diastereoisomer, conformer (rotational isomer), geometry are different Structure body (cis/trans isomers), atropisomer, etc..

Term " chiral molecules " be with its mirror image cannot be overlapped property molecule；And " achiral molecule " refers to and it The molecule that mirror image can be overlapped.

Term " enantiomter " refers to two isomers that cannot be overlapped but be mutually mirror of a compound.

Term " racemate " or " racemic mixture " refer to the equimolar mixture of two enantiomters, the mixing Object lacks optical activity.

Term " diastereoisomer " refer to there are two or multiple chiral centers and its molecule not solid of mirror image each other Isomers.Diastereoisomer has different physical properties, such as fusing point, boiling point, spectral property and reactivity.Diastereo-isomerism Body mixture can be operated such as electrophoresis and chromatography, such as HPLC by high resolution analysis and be separated.

Stereochemical definitions used in the present invention and rule generally follow S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S,“Stereochemistry of Organic Compounds”,John Wiley&Sons, Inc,New York,1994.Many organic compounds exist with optical active forms, i.e., they, which have, makes the flat of linearly polarized light The ability that face rotates.When describing optically active compound, indicate molecule about one using prefix D and L or R and S A or multiple chiral centers absolute configurations.Prefix d and l or (+) and (-) are revolved for linearly polarized light caused by appointed compound The symbol turned, wherein (-) or l indicate that compound is left-handed.Prefix is (+) or the compound of d is dextrorotation.It is a kind of specific Stereoisomer is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50 of enantiomter: 50 mixtures are known as racemic mixture or racemic modification, when in chemical reaction or in the process without stereoselectivity or three-dimensional spy When anisotropic, such case may occur in which.

Any asymmetric atom (for example, carbon etc.) of disclosed compound of present invention can be enriched with racemic or enantiomer Form exist, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration in terms of have at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomer It is excessive.

According to the selection of starting material and method, the compounds of this invention can with one in possible isomers or they Mixture, such as the form of racemic modification and non-enantiomer mixture (this depends on the quantity of asymmetric carbon atom) deposits ?.Chiral synthon or chiral reagent preparation can be used in optically active (R)-or (S)-isomers, or is torn open using routine techniques Point.If compound contains a double bond, substituent group may be E or Z configuration；If containing disubstituted cycloalkanes in compound The substituent group of base, naphthenic base may have cis or trans configuration.

The mixture of resulting any stereoisomer can be separated into according to the difference in component physicochemical properties Pure or substantially pure geometric isomer, enantiomter, diastereoisomer, for example, passing through chromatography and/or fractional crystallization Method.

The racemic modification of any gained final product or intermediate can be passed through into those skilled in the art by known method Known method splits into optical antipode, e.g., is separated by its diastereoisomeric salt to acquisition.Racemic production Object can also be separated by chiral chromatogram, e.g., use the high performance liquid chromatography (HPLC) of chiral sorbent.Particularly, mapping Isomers can be prepared by asymmetric syntheses, for example, can refer to Jacques, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2^ndEd.Robert E.Gawley,Jeffrey Aube,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany, 2007)。

Term " tautomer " or " tautomeric form " refer to that with different energy can be by low energy barrier (low Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can achieve The chemical balance of tautomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) include the mutual inversion of phases carried out by proton transfer, such as keto-enol isomerization and Imine-enamine isomerizations.

" pharmaceutically acceptable " refers to compounds some in this way, raw material, composition and/or dosage form, they are cured rationally Learn judgement in the range of, be suitable for contacted with patient tissue and without excessive toxicity, irritation, allergy or with reasonable benefit The symmetrical other problems of benefit/Hazard ratio and complication, and effective for given application.

Term " optionally by ... replaced " can be used interchangeably, i.e., with term " unsubstituted or by ... replaced .. " The structure is unsubstituted or is replaced by one or more substituent groups of the present invention, substituent group packet of the present invention It includes, but is not limited to D, F, Cl, Br, I, N₃、-CN、-NO₂、-NH₂、-OH、-SH、-COOH、-CONH₂,-C (=O) NHCH₃,-C (= O)N(CH₃)₂,-C (=O)-alkyl ,-C (=O)-alkoxy, alkyl, alkenyl, alkynyl, halogenated alkyl, alkoxy, haloalkoxy Base, alkylthio group, alkylamino, the alkyl of hydroxyl substitution, naphthenic base, heterocycle, aryl, heteroaryl etc..

In general, term it is " substituted " indicate specifically replaced to one or more hydrogen atoms in structure or group Replaced base.Unless otherwise indicated, a substituent group can be replaced in each substitutive reasonable position of group. Replaced the specific substituent group of one or more that more than one position can be selected from given structural formula, then substituent group It can each reasonable position be replaced in structural formula identical or differently.

In addition, it is necessary to explanation, unless otherwise explicitly point out, in the present invention used by describing mode " each ... independently be " and " ... be each independently " and " ... independently be " can be interchanged, and shall be understood in a broad sense, both may be used To refer among the different groups, does not influence mutually, can also indicate in phase between expressed specific option between the same symbol In same group, do not influenced mutually between expressed specific option between the same symbol.

Term " study subject " used in the present invention refers to animal.The typically described animal is mammal.It is tested right As, such as also refer to primate (such as mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, small Mouse, fish, bird etc..In certain embodiments, the study subject is primate.In other embodiments, it is described by Trying object is people.

Term " patient " used in the present invention refers to people (including adult and children) or other animals.In some implementations In scheme, " patient " refers to people.

Term "comprising" is open language, that is, includes content specified by the present invention, but be not precluded otherwise Content.

It is disclosed in the substituent group of each section of this specification, disclosed compound of present invention according to radical species or range.It is special It does not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and range.For example, term “C₁-C₆Alkyl " refers in particular to the methyl being individually disclosed, ethyl, C₃Alkyl, C₄Alkyl, C₅Alkyl and C₆Alkyl.

Term " D " indicates single D-atom.

Term " halogen " and " halogenated " are used interchangeably in the present invention, refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I)。

Terminology used in the present invention " alkyl " or " alkyl group ", indicate contain 1-20 carbon atom, the straight chain of saturation or Branch univalent hydrocarbyl group, wherein the substituent group institute that the alkyl group can be described optionally by one or more present invention Replace.In one embodiment, alkyl group contains 1-6 carbon atom；In another embodiment, alkyl group contains 1-4 A carbon atom；Also in one embodiment, alkyl group contains 1-3 carbon atom.The example of alkyl group includes, but and unlimited In methyl (Me ,-CH₃), ethyl (Et ,-CH₂CH₃), n-propyl (n-Pr ,-CH₂CH₂CH₃), isopropyl (i-Pr ,-CH (CH₃)₂), normal-butyl (n-Bu ,-CH₂CH₂CH₂CH₃), isobutyl group (i-Bu ,-CH₂CH(CH₃)₂), sec-butyl (s-Bu ,-CH (CH₃)CH₂CH₃), tert-butyl (t-Bu ,-C (CH₃)₃), etc..

Term " alkenyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, that is, there is a carbon-to-carbon sp²Double bond, wherein the alkenyl group can be retouched optionally by one or more present invention Replaced the substituent group stated comprising the positioning of " cis " and " trans ", or the positioning of " E " and " Z ".In an embodiment In, alkenyl group includes 2-8 carbon atom；In another embodiment, alkenyl group includes 2-6 carbon atom；In another reality It applies in scheme, alkenyl group includes 2-4 carbon atom.The example of alkenyl group includes, but is not limited to, vinyl (- CH= CH₂), allyl (- CH₂CH=CH₂), 1- acrylic is (that is, acrylic ,-CH=CH-CH₃), etc..

Term " alkynyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, that is, there is tri- key of carbon-to-carbon sp, wherein the alkynyl group can be retouched optionally by one or more present invention Replaced the substituent group stated.In one embodiment, alkynyl group includes 2-8 carbon atom；In another embodiment, alkynyl Group includes 2-6 carbon atom；In yet another embodiment, alkynyl group includes 2-4 carbon atom.The example packet of alkynyl group It includes, but is not limited to, acetenyl (- C ≡ CH), propargyl (- CH₂C ≡ CH), 1- propinyl is (that is, propinyl ,-C ≡ C-CH₃), Etc..

Term " alkoxy " indicates that alkyl group is connected by oxygen atom with molecule rest part, and wherein alkyl group has Meaning as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-12 carbon atom.In an embodiment party In case, alkoxy base contains 1-6 carbon atom；In another embodiment, alkoxy base contains 1-4 carbon atom；? In another embodiment, alkoxy base contains 1-3 carbon atom.The alkoxy base can be optionally one or more Replaced the substituent group that the present invention describes.

The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH₃), ethyoxyl (EtO ,- OCH₂CH₃), 1- propoxyl group (n-PrO, n- propoxyl group ,-OCH₂CH₂CH₃), 2- propoxyl group (i-PrO, i- propoxyl group ,-OCH (CH₃)₂), 1- butoxy (n-BuO, n- butoxy ,-OCH₂CH₂CH₂CH₃), 2- methyl-l- propoxyl group (i-BuO, i- fourth oxygen Base ,-OCH₂CH(CH₃)₂), 2- butoxy (s-BuO, s- butoxy ,-OCH (CH₃)CH₂CH₃), 2- methyl -2- propoxyl group (t- BuO, t- butoxy ,-OC (CH₃)₃), etc..

Term " alkylthio group " indicates that alkyl group is connected by sulphur atom with molecule rest part, and wherein alkyl group has Meaning as described in the present invention.Unless otherwise detailed instructions, the alkylthio radicals contain 1-12 carbon atom.In an embodiment party In case, alkylthio radicals contain 1-6 carbon atom；In another embodiment, alkylthio radicals contain 1-4 carbon atom；? In another embodiment, alkylthio radicals contain 1-3 carbon atom.The alkylthio radicals can be optionally one or more Replaced the substituent group that the present invention describes.

The example of alkylthio radicals includes, but is not limited to, methyl mercapto (MeS ,-SCH₃), ethylmercapto group (EtS ,- SCH₂CH₃), 1- rosickyite base (n-PrS, n- rosickyite base ,-SCH₂CH₂CH₃), 2- rosickyite base (i-PrS, i- rosickyite base ,-SCH (CH₃)₂), 1- butylthio (n-BuS, n- butylthio ,-SCH₂CH₂CH₂CH₃), 2- methyl-l- rosickyite base (i-BuS, i- fourth sulphur Base ,-SCH₂CH(CH₃)₂), 2- butylthio (s-BuS, s- butylthio ,-SCH (CH₃)CH₂CH₃), 2- methyl -2- rosickyite base (t- BuS, t- butylthio ,-SC (CH₃)₃), etc..

Term " alkylamino " or " alkyl amino " include " N- alkyl amino " and " N, N- dialkyl amido ", wherein amino base Group is separately replaced one or two alkyl group, and wherein alkyl group has meaning as described in the present invention.It closes Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example includes, but is not limited to, N- first ammonia Base, N- ethylamino, N, N- dimethylamino, N, N- lignocaine etc..The alkylamino radicals are optionally by one or more sheets It invents replaced described substituent group.

Term " alkyl that hydroxyl replaces " indicates alkyl group replaced one or more hydroxyls, and wherein alkyl group has There is meaning as described in the present invention；Such example includes, but is not limited to, methylol, 2- hydroxyethyl, 2- hydroxyl -1- third Base, 3- hydroxyl -1- propyl, 2,3- dihydroxypropyl etc..

Term " halogenated alkyl " indicates alkyl group replaced one or more halogen atoms, and wherein alkyl group has Meaning as described in the present invention, such example includes, but is not limited to ,-CF₃、-CH₂CF₃、-CHFCH₃、-CH₂CH₂F、- CF₂CH₃Deng.In one embodiment, C₁-C₆Halogenated alkyl includes fluorine-substituted C₁-C₆Alkyl；In another embodiment, C₁- C₄Halogenated alkyl includes fluorine-substituted C₁-C₄Alkyl；In yet another embodiment, C₁-C₂Halogenated alkyl includes fluorine-substituted C₁-C₂ Alkyl.

Term " halogenated alkoxy " indicate alkoxy base replaced one or more halogen atoms, wherein alkoxy base Group has meaning as described in the present invention, and such example includes, but is not limited to ,-OCF₃、-OCH₂CF₃、-OCHFCH₃、- OCH₂CH₂F、-OCF₂CH₃Deng.In one embodiment, C₁-C₆Halogenated alkoxy includes fluorine-substituted C₁-C₆Alkoxy；Another In embodiment, C₁-C₄Halogenated alkoxy includes fluorine-substituted C₁-C₄Alkoxy；In yet another embodiment, C₁-C₂Alkyl halide Oxygroup includes fluorine-substituted C₁-C₂Alkoxy.

When term " blocking group " or " PG " refer to a substituent group and other reacted with functional groups, commonly used to resistance It is disconnected or protect special functionality.For example, " blocking group of amino " refers to that a substituent group is connected to block with amino group Or the functionality of amino in compound is protected, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl Substituent group be used to block or protect the functionality of hydroxyl, suitable blocking group includes trialkylsilkl, acetyl group, benzene Formoxyl and benzyl." carboxy protective group " refers to that the substituent group of carboxyl is used to block or protect the functionality of carboxyl, general Carboxyl-protecting group includes-CH₂CH₂SO₂Ph, cyano ethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxy Ylmethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro second Base, etc..Description general for blocking group can refer to document: Greene et al., Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991 and Kocienski et al., Protecting Groups,Thieme,Stuttgart,2005。

Term " prodrug " used in the present invention represents a compound and is converted into vivo formula (I), (I '), (II) or (II ') compound represented.Such conversion is hydrolyzed in blood by pro-drug or is through enzymatic conversion in blood or tissue The influence of precursor structure.Pro-drug compounds of the present invention can be ester, and ester can be used as precursor medicine in existing invention Object has phenyl ester class, aliphatic (C_1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters. Such as a compound in the present invention includes hydroxyl, it can is acylated to obtain the compound of prodrug form.Other Prodrug form include phosphate, if these phosphate compounds are obtaining through the di on parent.

" metabolite " refers to specific compound or its salt product obtained by metabolic action in the body.One change The metabolite for closing object can be identified that activity can be retouched by such as the present invention by technology well-known in the art It adopts as stating and is experimentally characterized.Such product can be by, by aoxidizing, restoring, water to drug compound Solution, amidated, deamidation, esterification, degreasing, the methods of enzymatic lysis etc. obtain.Correspondingly, the present invention includes compound Metabolite, including the compound of the present invention and mammal are come into full contact with into metabolite caused by a period of time.

" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in fields on, such as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. documented.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by recorded in books, literature Other methods such as ion-exchanges obtain these salt.Other pharmaceutically acceptable salts include adipate, and alginates resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonic acid Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2- naphthalene sulphur Hydrochlorate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, bitter taste Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through The salt that alkali appropriate obtains includes alkali metal, alkaline-earth metal, ammonium and N⁺(C_1-4Alkyl)₄Salt.The present invention is also intended to contemplate any The compound of the group of included N is formed by quaternary ammonium salt.Water-soluble or oil-soluble or dispersion product can be turned by quaternary ammonium With obtaining.Alkali or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises fitting When, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, sulfuric acid Compound, phosphoric acid compound, nitric acid compound, C₁-C₈Sulphonic acid compound and aromatic sulphonic acid compound.

" solvate " of the invention refers to that one or more solvent molecules and the compound of the present invention are formed by association Object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second Or mixtures thereof acid, ethanol amine.Term " hydrate " refers to that solvent molecule is that water is formed by associated matter.

When the solvent is water, term " hydrate " can be used.In one embodiment, a compounds of this invention Molecule can be combined with a hydrone, such as monohydrate；In another embodiment, a compounds of this invention molecule It can be combined with more than one hydrone, such as dihydrate；In yet another embodiment, a compounds of this invention point Son can be combined with the hydrone less than one, such as semihydrate.It should be noted that hydrate of the present invention remain with it is non- The biological effectiveness of the compound of hydrated form.

Any disease of term " treatment " or illness refer to that improving disease or illness (slows down in some of these embodiments Or prevent or mitigate disease or the development of its at least one clinical symptoms).In other embodiments, " treatment " refer to mitigation or Improve at least one body parameter, including the body parameter that may not be discovered by patient.In other embodiments, it " controls Treat " refer in terms of (such as stablizing perceptible symptom) on body or physiologically (such as parameter of stable body) or above-mentioned two Adjust disease or illness.In other embodiments, " treatment " refers to the breaking-out, generation or evil for preventing or delaying disease or illness Change.

Term " preventing " or " prevention " refer to that the reduction for obtaining the risk of disease or obstacle (that is: makes at least one clinical condition of disease Shape stops development in main body, which may face or be inclined in advance in face of this disease, but without undergoing or show The symptom of disease).

Imino group thiadiazine dioxide derivative of the present invention, pharmaceutically acceptable salt, pharmaceutical preparation and Its composition, can by inhibiting BACE-1 to inhibit the generation of A β, to disease related with beta-amyloid protein (" A β "), The treatment of especially Alzheimer disease has potential purposes.

Unless otherwise mentioned, all suitable isotope variations of the compound of the present invention, stereoisomer, tautomerism Body, solvate, metabolite, salt and pharmaceutically acceptable prodrug are intended to be included within the scope of the present invention.

In structure disclosed by the invention, when the spatial chemistry of the chiral atom of any specific does not indicate, then the structure All stereoisomers all consider within the present invention, and be included in the invention as disclosed compound of present invention.When Spatial chemistry is expressed the real wedge-shaped line (solid wedge) of particular configuration or when dotted line indicates, then the alloisomerism of the structure Body is with regard to this clear and definition.

The nitrogen oxides of the compounds of this invention is also contained within the scope of the present invention.It can be by an elevated temperature using normal Corresponding nitrogen-containing basic substance is aoxidized, or pass through in the presence of the acid of such as acetic acid with oxidant (such as hydrogen peroxide) It reacts in suitable solvent with peracid, such as is reacted in methylene chloride, ethyl acetate or methyl acetate with peracetic acid, or It is reacted in chloroform or methylene chloride with 3- chloroperoxybenzoic acid, prepares the nitrogen oxides of the compounds of this invention.

Formula (I), (I '), compound shown in (II) or (II ') can exist in a salt form.In one embodiment, institute It states salt and refers to pharmaceutically acceptable salt.Term " pharmaceutically acceptable " refer to substance or composition must with comprising preparation Other ingredients and/or compatible chemically and/or in toxicology with the mammal of its treatment.In another embodiment, described Salt is not necessarily pharmaceutically acceptable salt, can be and is used to prepare and/or purifies formula (I), (I '), shown in (II) or (II ') Compound and/or for separating this formula (I), (I '), the intermediate of the enantiomer of compound shown in (II) or (II ').

Officinal salt of the invention can be synthesized with conventional chemical processes by parent compound, alkalinity or acidic moiety. In general, such salt can by make these compounds free acid form and stoichiometry suitable alkali (such as Na, Ca, Hydroxide, carbonate, bicarbonate of Mg or K etc.) reaction, or free alkali form and chemistry by making these compounds The suitable acid reaction of metered amount is to be prepared.Such reaction usually carries out in the mixture of water or organic solvent or both. Generally, in appropriate cases, it needs using non-aqueous medium such as ether, ethyl acetate, ethyl alcohol, isopropanol or acetonitrile.? Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton,Pa.,(1985)；" pharmaceutical salts handbook: property, selection and application (Handbook of Pharmaceutical Salts:Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) list that other is suitable for salt can be found in.

Any structural formula that the present invention provides, which is also intended to, indicates these compounds not by the form of isotope enrichment and same The form of position element enrichment.The structure that the general formula that there is the compound of isotope enrichment the present invention to provide is described, in addition to one or more A atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention Isotope including hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such as²H、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、¹⁸F、³¹P、³²P、³⁵S、³⁶Cl and¹²⁵I。

On the other hand, the present invention relates to preparation formula (I), (I '), the intermediates of compound shown in (II) or (II ').

On the other hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition includes the compounds of this invention.One In embodiment, pharmaceutical composition of the present invention further includes pharmaceutically acceptable carrier, excipient, adjuvant, molten Matchmaker or their combination.In another embodiment, pharmaceutical composition can be liquid, solid, semisolid, gel or spray Type.

Pharmaceutical composition, preparation and the administration of the compounds of this invention

The present invention provides a kind of pharmaceutical composition, including formula (I), (I '), compound shown in (II) or (II ') or its individually Stereoisomer, the racemic or non-racemic mixture of isomers or its pharmaceutically acceptable salt or solvate.? In an embodiment of the invention, described pharmaceutical composition further includes at least one pharmaceutically acceptable carrier, auxiliary Agent or excipient, and optionally, others treatment and/or prevention ingredient.

It is that suitable carrier, adjuvant and excipient are well known to those skilled in the art and be described in detail in for example Ansel H.C.et al.,Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems(2004)Lippincott,Williams&Wilkins,Philadelphia；Gennaro A.R.et al., Remington:The Science and Practice of Pharmacy (2000) Lippincott, Williams& Wilkins,Philadelphia；With Rowe R.C., Handbook of Pharmaceutical Excipients (2005) In Pharmaceutical Press, Chicago.

It further comprise that additional control is carried out to patient comprising the treatment method that the compounds of this invention or pharmaceutical composition are administered Treat agent (combination therapy) administration, wherein additional therapeutic agent be nalmefene, Risperidone, Rivastigmine, Memantine, mitzapine, Venlafaxine, desipramine, nortriptyline, zolpidem, zopiclone, Nicergoline, Piracetam, selegiline, pentoxifylline Alkali, Tacrine, donepezil, galanthamine, rivastigmine, vitamin e, fibrates, niacin, nicotinic receptor excitement Agent, nicotinic acetylcholine receptors alpha7, anticholinesterase, N-methyl-D-aspartate receptor antagonist, α secretase Active promotor, glycogen synthase kinase beta inhibitor, the inhibitor of amyloid aggregation, gamma-secretase inhibitors, γ points Secrete enzyme adjustment agent, histamine H 3 antagonists, histone deacetylase inhibitors, PDE-4 inhibitor, PDE-10 inhibitor, MGluR1 receptor modulators or antagonist, mGluR5 receptor modulators or antagonist, mGluR2/3 antagonist, 5-HT₄Agonist, 5-HT₆Receptor antagonist and GABA_AInverse agonist or their any combination.

" pharmaceutically acceptable excipient " used in the present invention means related to form of administration or pharmaceutical composition consistency Pharmaceutically acceptable material, mixture or solvent.Every kind of excipient mixing when must with pharmaceutical composition it is other at Split-phase is held, and interaction the effect of to avoid will be greatly reduced disclosed compound of present invention when administering to a patient and will lead to not It is the interaction of pharmaceutically acceptable pharmaceutical composition.In addition, every kind of excipient must be pharmaceutically acceptable, example Such as, there is sufficiently high purity.

Suitable pharmaceutically acceptable excipient can be different according to selected specific dosage form.In addition, can be according to them in group The specific function in object is closed to select pharmaceutically acceptable excipient.For example, may be selected to can help to produce equal one dosage type low temperature Certain pharmaceutically acceptable excipient.The certain pharmaceutically acceptable figurations that can help to produce stabilizer type may be selected Agent.Facilitate to carry or transport the compounds of this invention when may be selected to administer to a patient from an organ of body or partially to body Another organ or partial certain pharmaceutically acceptable excipient.May be selected enhancing patient compliance it is certain pharmaceutically Acceptable excipient.

Suitable pharmaceutically acceptable excipient includes following kind of excipient: diluent, filler, adhesive, Disintegrating agent, glidant, granulating agent, coating agent, wetting agent, solvent, cosolvent, suspending agent, emulsifier, sweetener, is rectified lubricant Taste agent, odor mask, colorant, anticaking agent, moisturizer, chelating agent, plasticiser, tackifier, antioxidant, preservative, stabilization Agent, surfactant and buffer.Technical staff can be appreciated that certain pharmaceutically acceptable excipient can provide more than one Function, and provide alternative function, this depends in preparation existing in how much excipient and preparation there are which other Excipient.

Technical staff grasps the knowledge and skills of this field, so that they can select for the suitable of appropriate amount of the invention Pharmaceutically acceptable excipient.Additionally, there are resources obtained by a large amount of technical staff, they describe pharmaceutically acceptable Excipient, and for selecting suitable pharmaceutically acceptable excipient.Example includes Remington's Pharmaceutical Sciences(Mack Publishing Company),The Handbook of Pharmaceutical Additives(Gower Publishing Limited),and The Handbook of Pharmaceutical Excipients(the American Pharmaceutical Association and the Pharmaceutical Press)。

In order to prepare pharmaceutical composition with compound described in the invention, pharmaceutically acceptable carrier can be solid Body or liquid-carrier.Solid form preparations include pulvis, tablet, dispersible granule, capsule, cachet and suppository.Powder Agent and tablet may include the active component of about 5 to about 95%.Suitable solid carrier is known in the art, example Such as, magnesium carbonate, magnesium stearate, talcum powder, sugar or lactose.Tablet, pulvis, cachet and capsule may be used as be suitble to it is oral Solid dosage forms.The example of pharmaceutical acceptable carrier and method for preparing various compositions can obtain in following: A.Gennaro (ed.),Remington's Pharmaceutical Sciences,18^th ed.,1990,Mack Publishing Company Co.,Easton,Pennsylvania。

In Remington:The Science and Practice of Pharmacy, 21st edition, 2005, ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel The various carriers for configuring pharmaceutically acceptable composition are disclosed in Dekker, New York, and for its preparation Well-known technique, the respective content of these documents are incorporated by reference into the present invention.Except any such as because generating any undesirable life Object effect, or with interaction occurs for any other ingredient in harmful way and pharmaceutically acceptable composition and with the present invention Outside the incompatible any commonly employed carrier of compound, pays close attention to its application and belong to the scope of the present invention.

Pharmaceutical composition disclosed by the invention is prepared using technology and methods well known by persons skilled in the art.This field The description of some common methods can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company)。

Therefore, on the other hand, the present invention relates to the technique of preparation pharmaceutical composition, described pharmaceutical composition includes the present invention Open compound and pharmaceutically acceptable excipient, carrier, adjuvant, solvent or their combination, the technique include that mixing is each Kind ingredient.Pharmaceutical composition comprising disclosed compound of present invention can mix under such as environment temperature and atmospheric pressure to make It is standby.

Compound disclosed by the invention is usually formulated as the dosage form for being suitable for administering to a patient by required approach.Example Such as, dosage form includes those dosage forms for being suitable for following administration route: (1) being administered orally, such as tablet, capsule, caplet agent, ball Agent contains tablet, pulvis, syrup, elixir, suspension, solution, emulsion, sachet agent and cachet；(2) parenteral, example Such as sterile solution agent, suspension and redissolution powder；(3) cutaneous penetration, such as transdermal patch tablet；(4) rectally, such as bolt Agent；(5) it sucks, such as aerosol, solution and dry powder doses；(6) local administration, for example, it is cream, ointment, lotion, molten Liquor, paste, spray, foaming agent and gelling agent.

It will also be appreciated that certain compounds of the invention can exist for treating in a free form, or if appropriate Can exist in the form of its pharmaceutically acceptable derivates.Some unrestricted implementations of pharmaceutically acceptable derivative Scheme includes pharmaceutically acceptable prodrug, salt, ester, the salt of these esters, or when patient in need is administered can directly or Any other adduct or derivative of compound of the present invention or its metabolite or residue are provided indirectly.

In one embodiment, compound disclosed by the invention can be configured to peroral dosage form.In another embodiment, Compound disclosed by the invention can be configured to inhalant dosage form.In another embodiment, compound disclosed by the invention can be with It is configured to nose administration dosage form.In yet another embodiment, compound disclosed by the invention can be configured to transdermal administration. Also in one embodiment, compound disclosed by the invention can be configured to Topical dosage forms.

Pharmaceutical composition provided by the invention can with compressed tablets, develop piece, chewable pastille, rapidly dissolving tablet, multiple compressed tablet or Enteric coatel tablets, sugar-coat or Film coated tablets provide.Enteric coatel tablets are with the substance packet for being resistant to gastric acid effect but dissolving or being disintegrated in intestines The compressed tablets of clothing, to prevent the acidic environment of active ingredient contacts stomach.Enteric coating includes, but are not limited to fatty acid, rouge Fat, phenyl salicylate, wax, lac, ammonification lac and cellulose acetate phthalate ester.Sugar coated tablet is the compacting that sugar-coat surrounds Piece can be conducive to cover taste or smell beastly and can prevent tablet from aoxidizing.Thin membrane coated tablet is with water-soluble The compressed tablets of thin layer or the film covering of substance.Film coating includes, but are not limited to hydroxyethyl cellulose, carboxymethyl cellulose Sodium, Macrogol 4000 and cellulose acetate phthalate ester.Film coating possesses general characteristic identical with sweet tablet.It is multiple Tabletting is the compressed tablets by preparing more than a press cycles, including multilayer tablet and pressed coated or dry coating tablet.

Tabules can be by one kind that powder, crystallization or granular active constituent are individual or describe with the present invention Or prepared by variety carrier or excipient composition, the carrier and excipient include adhesive, disintegrating agent, controlled release polymer, profit Lubrication prescription, diluent and/or colorant.Fumet and sweetener are particularly useful when forming chewable tablets and pastille.

Pharmaceutical composition provided by the invention can be provided with soft capsule or hard capsule, can be fine by gelatin, methyl Element, starch or calcium alginate are tieed up to prepare.The hard gelatin capsule is also referred to as dry-filled capsules (DFC), is formed by two sections, and one section It fills in another section, therefore encloses active constituent completely.Soft elastic capsules (SEC) are soft, spherical shell, such as gelatin shell, It is by being added glycerol, sorbierite or the plasticizing of similar polyalcohol.It is raw that soft gelatin shell may include the pre- preventing microorganism of preservative It is long.Suitable preservative be as described in the present invention those, including methylparaben and propylben and sorbic acid.This Liquid, semisolid and the solid dosage forms that invention provides can be encapsulated in capsule.Suitable liquid and semisolid dosage form are included in Solution and suspension in propene carbonate, vegetable oil or triglycerides.Capsule comprising such solution can be such as in the U.S. Patent U.S.Pat.Nos.4,328,245；It is prepared described in 4,409,239 and 4,410,545.The capsule can also be adopted With coating as is known to persons skilled in the art, so as to improve or maintain the dissolution of active constituent.

Pharmaceutical composition provided by the invention can be provided with liquid and semisolid dosage form, including emulsion, solution, suspension Agent, elixir and syrup.Emulsion is two-phase system, and one of liquid is thoroughly dispersed in pellet form in another liquid, It can be oil-in-water type or water-in-oil type.Emulsion may include pharmaceutically acceptable on-aqueous liquid and solvent, emulsifier and Preservative.Suspension may include pharmaceutically acceptable suspending agent and preservative.Aqueous alcohol solutions may include pharmaceutically may be used The acetal of receiving, such as two (low alkyl group) acetals of low alkyl group aldehyde, such as acetaldehyde diethyl acetal；And have one or more The water-soluble solvent of a hydroxyl, such as propylene glycol and ethyl alcohol.Elixir is transparent, sweet taste water-alcohol solution.Syrup is dense The aqueous solution of sugared such as sucrose, and can also include preservative.For liquid dosage form, for example, the solution in polyethylene glycol It can be diluted with enough pharmaceutically acceptable liquid-carriers such as water, to be accurately, conveniently administered.

Pharmaceutical composition provided by the invention can be configured to be suitable for any dosage form to patient's inhalation, such as dry powder Agent, aerosol, suspension or liquid composite.In one embodiment, pharmaceutical composition disclosed in this invention can be prepared At be suitable for dry powder doses to the dosage form of patient's inhalation.In yet another embodiment, pharmaceutical composition disclosed in this invention It can be configured to be suitable for the dosage form by sprayer to patient's inhalation.Dry powder composite by inhalation delivery to lung is usual Include fine powdered compound disclosed in this invention and one or more fine powdered pharmaceutically acceptable taxes Shape agent.Pharmaceutically acceptable excipient dawn known to those skilled in the art be especially suitable for dry powder doses comprising cream Sugar, starch, mannitol and mono-, two- and polysaccharide.Fine powder can be for example, by being micronized and grinding is prepared.It is general next It says, (as being micronized) compound that size reduces can be by about 1 to 10 micron of D₅₀Value with laser diffractometry (for example, surveyed Amount) it defines.

The pharmaceutical composition for being suitable for cutaneous penetration can be prepared into discontinuous patch agent, it is intended that keep with the epidermis of patient It is in close contact the time of an elongated segment.For example, the delivering active ingredients from patch agent can be permeated by ion, such as Pharmaceutical Research, 3 (6), the general description in 318 (1986).

Be suitable for local administration pharmaceutical composition can be formulated into ointment, cream, suspension, lotion, pulvis, Solution, paste, gelling agent, spray, aerosol or finish.For example, ointment, cream and gelling agent can use water or oil Matrix, and suitable thickener and/or gelling agent and/or solvent configure.Such matrix may include water, and/or oily example Such as atoleine and vegetable oil (such as peanut oil or castor oil) or solvent such as polyethylene glycol.It is used according to medium property Thickener and gelling agent include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, carbopol and Cellulose derivative and/or single stearic acid glycerine lipoprotein and/or nonionic emulsifier.

The compounds of this invention can also be in conjunction with the soluble polymer as target medicine carrier.Such polymer packet Include polyvinylpyrrolidone, pyran co-polymer, poly- hydroxypropyhnethacrylamide-phenol, polyhydroxyethylaspart or The oxide polylysine that palmitoyl residues replace.In addition, compound disclosed in this invention can with realizing drug Control release used in one kind Biodegradable polymeric combination, for example, polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyrate, Polyorthoester, polyacetals, poly- dihydropyran, polybutylcyanoacrylate and hydrogel crosslinking or amphiphilic block copolymer.

Pharmaceutical composition provided by the invention can be by injection, infusion or implantation parenteral administration, for part or entirely Body administration.As the parenteral administration that uses of the present invention includes in intravenous, intra-arterial, peritonaeum, in intrathecal, intra-ventricle, urethra, chest In bone, encephalic, intramuscular, intrasynovial and subcutaneous administration.

Pharmaceutical composition provided by the invention can be configured to any dosage form suitable for parenteral administration, including solution, mixed Suspension, emulsion, micella, liposome, microballoon, nanometer system and suitable for consolidating for solution or suspension is made in a liquid before the injection Body form.Such dosage form can be prepared according to conventional method known to the technical staff in pharmaceutical science field (referring to Remington:The Science and Practice of Pharmacy, ibid).

Be intended for parenteral administration pharmaceutical composition may include one or more pharmaceutically acceptable carriers and Excipient includes, but are not limited to containing transporter, water miscibility carrier, non-transporter, antimicrobial or resists micro- life Preservative, stabilizer, dissolution enhancers, isotonic agent, buffer, antioxidant, local anesthetic, suspending agent and the dispersion of object growth Agent, wetting agent or emulsifier, complexing agent, sequestering agent or chelating agent, antifreezing agent, cryoprotector, thickener, pH adjusting agent And inert gas.

Pharmaceutical composition provided by the invention can be administered by rectal suppository, by by drug with it is suitable nonirritant Excipient (such as cupu oil, the glyceride of polyethylene glycol synthesis) mixing, be solid under room temperature, then in rectum intraluminal fluid Change or dissolution discharges drug.Due to individual difference, bigger variation can be presented in the severity of symptom, and every kind of medicine has Its unique treatment characteristic, therefore, for the accurate administration mode of each individual, dosage form and therapeutic scheme all should be by operation Doctor determines.

Pharmaceutical composition provided by the invention can be configured to immediately or Modified release dosage forms, including delay-, sustained release-, arteries and veins Punching-, control-, targeting-and sequencing releasing pattern.

Term as used herein " therapeutically effective amount " refers to each active component for being enough to show beneficial therapeutic effect Total amount.For example, being administered or making the amount for the symptom for being enough to treat, curing or mitigating disease for reaching balance in vivo.Special controls Effective quantity needed for treatment scheme depends on many factors, the disease including treatment, the severity of disease, the certain drug used Activity, administration mode, the clearance rate of certain drug, duration for the treatment of, drug combination, the age, weight, gender, diet and The health etc. of patient.This field description as described in " therapeutically effective amount " other factors in need of consideration can be found in Gilman et al.,eds.,Goodman And Gilman’s:The Pharmacological Bases of Therapeutics,8^th ed.,Pergamon Press,1990；Remington's Pharmaceutical Sciences,17^th ed.,Mack Publishing Company,Easton,Pa.,1990。

Those skilled in the art (for example, attending physician, pharmacists or others skilled in the art) can readily determine that and give The suitable dose of the compounds of this invention of patient, and can according to patient health situation, the age, weight, administration frequency, other Active component using and/or the indication of given compound change.The dosage of the compounds of this invention can be about The range of 0.001-500mg/kg body weight/day.In one embodiment, the compounds of this invention or the compound is pharmaceutically acceptable The dosage of salt or solvate about 0.01-25mg/kg body weight/day.It in another embodiment, can according to concrete application Quantity with the reactive compound being varied or adjusted in the unit dose of preparation, from about 1mg to about 100mg, preferably approximately 1mg to about 50mg, more preferably from about 1mg are to about 25mg.In another embodiment, for oral administration, it is proposed that Typical day dosage regimen preferably 1mg/ days to 200mg/ days, can be given in about 1mg/ days to about 500mg/ days ranges Two to four separate doses.

Term " administration " shows individual and provides the drug of therapeutically effective amount, and administration mode includes oral, sublingual, vein, skin Under, it is percutaneously, intramuscular, it is intradermal, it is intrathecal, on dura mater, intraocularly, and encephalic, sucking, rectum, vagina etc..Form of administration includes paste, is washed Agent, tablet, capsule, pill, dustability powder agent, granule, suppository, sublimed preparation, pastille, injection, sterile solution or non-aqueous Solution, suspending agent, emulsion, patch agent etc..Active component and nontoxic pharmaceutically acceptable carrier (such as glucose, lactose, Gum arabic, gelatin, mannitol, gelatinized corn starch, magnesium trisilicate, talcum powder, cornstarch, keratin, silica gel, potato starch, Urea, dextran etc.) it is compound.

Preferred administration route can change with Clinical symptoms, and the variation of dosage is necessarily dependent upon patient being treated The case where, doctor can determine suitable dosage according to individual patient.The therapeutically effective amount of per unit dose depends on weight, raw Manage the vaccination regimen of function and selection.The weight of compound when the compound of per unit dose refers to each administration does not include carrying The weight (containing carrier in drug) of body.

Pharmaceutical composition provided by the invention can be configured to single dose or multiple dose administration.The single-dose preparations are wrapped In ampulla, bottle or syringe.The multi-dose parenteral administration must comprising it is antibacterial or fungistatic concentrations resist it is micro- Biological agent.All parenteral administrations all must be it is sterile, as known in the art and practice.

Pharmaceutical composition provided by the invention can be common with the other active constituents that will not damage expected therapeutic effect It prepares, or the substance co-formulation with the expected effect of supplement.

In one embodiment, treatment method of the invention includes that this hair of safe and effective amount is given to patient in need Bright compound or pharmaceutical composition comprising the compounds of this invention.Each embodiment of the present invention includes by patient in need It gives the compounds of this invention of safe and effective amount or the pharmaceutical composition comprising the compounds of this invention, is referred to treat the present invention Disease.

In one embodiment, the compounds of this invention or pharmaceutical composition comprising the compounds of this invention can be by any Suitable administration route is administered, including Formulations for systemic administration and local administration.Formulations for systemic administration include oral administration, parenteral, Cutaneous penetration and rectally.Typical parenteral refers to through injection or administered by infusion, including intravenous, intramuscular and skin Lower injection or administered by infusion.Local administration includes being applied to skin and intraocular, ear, intravaginal, sucking and intranasal administration.One In a embodiment, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be oral administration.Another In embodiment, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be inhalation.It is also real one It applies in scheme, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be intranasal administration.

In one embodiment, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can disposably give Medicine, or according to dosage regimen, at the appointed time in section, doses at intervals is several times in different times.For example, daily administration one It is secondary, twice, three times or four times.In one embodiment, it is administered once a day.In yet another embodiment, it is taken twice daily. It can be administered until reaching desired therapeutic effect or indefinitely maintaining desired therapeutic effect.The compounds of this invention or comprising The appropriate dosage regimen of the pharmaceutical composition of the compounds of this invention depends on the pharmacokinetic property of the compound, such as inhales Receipts, distribution and half-life period, these can be by determination of technical staff.In addition, the compounds of this invention or including the compounds of this invention The appropriate dosage regimen of pharmaceutical composition, the duration including implementing the program are treated disease depending on treated disease The severity of disease, the age of patient under consideration and physical condition, the medical history of patient under consideration while the property of therapy are thought The factor within the scope of technical staff's knowledge and experience such as therapeutic effect wanted.Such technical staff should also be understood that for Reaction of the individual patient to dosage regimen, or when individual patient needs to change as time goes by it may require that adjust it is suitable to Prescription case.

The compounds of this invention can be administered simultaneously, or before it or later with one or more other therapeutic agents.This hair Bright compound can be administered with other therapeutic agents by identical or different administration route respectively, or therewith with same pharmaceutical composition Form administration.This is selected by those skilled in the art according to the actual conditions of the bodies such as the health of patient, age, weight.If It is formulated as fixed dosage, this combination product uses the compound of the present invention (within dosage range described herein) and its His forms of pharmacologically active agents (within its dosage range).

Correspondingly, in one aspect, the present invention includes drug combination comprising a certain number of at least one of the invention Compound or pharmaceutically acceptable salt thereof, solvate, ester or pro-drug and a effective amount of one or more above-mentioned additional therapeutic agents.

In addition, the compounds of this invention can be administered with prodrug forms.In the present invention, " prodrug " of the compounds of this invention is When administering to a patient, the functional derivatives of the compounds of this invention can be finally released in vivo.This hair is given with prodrug forms When bright compound, one of implementable following manner of those skilled in the art or more: the internal action of compound (a) is changed Time；(b) the internal acting duration of compound is changed；(c) the internal conveying or distribution of compound are changed；(d) modification Close the internal solubility of object；And the side effect or other difficult points for (e) overcoming compound to be faced.It is used to prepare the typical of prodrug Functional derivatives, comprising in vivo chemically or the variant of compound that cracks of the mode of enzyme.Comprising prepare phosphate, Amide, ester, monothioester, carbonate and carbaminate these variants be well-known to those skilled in the art.

The purposes of the compounds of this invention and pharmaceutical composition

Compound provided by the invention and pharmaceutical composition can be used for preparing by inhibiting BACE-1 to inhibit the production of A β Raw drug can be used for preparation for treating and beta-amyloid protein (" A β ") related disease, especially alzheimer ' The drug for disease of writing from memory.

Specifically, the amount of compound effectively can be selected detectably in the compound of the present invention or pharmaceutical composition Property by inhibiting BACE-1 to inhibit the generation of A β.

The compound of the present invention can be applied to, but be not limited to, and use the compound of the present invention or pharmaceutical composition Effective quantity administers to a patient to prevent, treat or mitigate and beta-amyloid protein (" A β ") related disease.Described and β-starch The related disease of sample albumen (" A β "), further comprises but is not limited to, dull-witted, senile dementia, Ahl tribulus sea silent sickness, pa gold Gloomy disease and/or the relevant dementia of Down syndrome, Down syndrome, attention deficit symptom, Ahl tribulus sea silent sickness, Parkinson Disease and/or the relevant attention deficit symptom of Down syndrome, the loss of memory, the loss of memory relevant to Parkinson's disease, with Ah The relevant loss of memory of Alzheimer's disease, apoplexy, neurodegeneration, amyloidosis, beta amyloid angiosis, Cerebral Amyloid blood Pipe disease, hereditary cerebral hemorrhage, complication of hemodialysis (are derived from β₂Microglobulin, and thus generated simultaneously in hemodialysis patients Send out disease), glaucoma, type-2 diabetes mellitus, the relevant amyloid generation of diabetes, traumatic brain injury (" TBI "), Niu Haimian Shape encephalopathy, corticobasal degeneration, stein-leventhal syndrome, microglia hyperplasia and brain inflammation, alzheimer's disease, smell Damage, Ahl tribulus sea silent sickness, Parkinson's disease and/or the relevant smell damage of Down syndrome, itch, Creutzfeld- Jakob disease, mild cognitive impairment (" MCI ") or Alzheimer disease.

The compound of the present invention and pharmaceutical composition to human treatment in addition to beneficial to other than, applying also for veterinary treatment and doting on Mammal in the animal of object, the animal of introduced variety and farm.The example of other animal includes horse, dog and cat.? This, the compound of the present invention includes its pharmaceutically acceptable derivates.

General synthesis step

For the description present invention, it is listed below embodiment.But it is to be understood that the present invention is not limited to these Examples, only Method of the invention is practiced in offer.

Generally, the compound of the present invention described method can be prepared through the invention, unless there are further Explanation, the wherein definition of substituent group such as formula (I), (I '), shown in (II) or (II ').Following reaction scheme and embodiment are used In the contents of the present invention are further illustrated.

The professional of fields will be appreciated that chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds mostly of the invention, and other methods for the preparation of the compounds of the present invention are considered as in model of the invention Within enclosing.For example, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art according to the present invention It is completed by method of modifying, such as protection interference group appropriate, by utilizing other known reagent in addition to described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is suitable for the preparation of other compounds of the invention.

The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent purchase is in quotient Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all without by not being further purified when use, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, tianjin haoyuyu chemicals co., ltd., Tianjin good fortune morning chemistry Chemical reagent work, Wuhan Xin Huayuan development in science and technology Co., Ltd, Qingdao Tenglong Chemical Reagent Co., Ltd. and Haiyang Chemical Plant, Qingdao's purchase It can buy.

Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by sodium metal reflux.Anhydrous methylene chloride It with chloroform is dried to obtain by calcium hydride reflux.Ethyl acetate, petroleum ether, n-hexane, n,N-dimethylacetamide and N, N- Dimethylformamide is used through anhydrous sodium sulfate is dry in advance.

Reaction is usually to cover a drying tube under positive pressure of nitrogen or argon or on anhydrous solvents (unless other aspects below Show), reaction flask all squeezed by syringe beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.

Chromatographic column is using silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.

¹H H NMR spectroscopy is recorded using Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer.¹H H NMR spectroscopy is with CDC1₃、 DMSO-d₆、CD₃OD or acetone-d₆For solvent (as unit of ppm), use TMS (0ppm) or chloroform (7.26ppm) as referring to mark It is quasi-.When there is multiplet, following abbreviation: s (singlet, unimodal), d (doublet, bimodal), t will be used (triplet, triplet), q (quartet, quartet), m (multiplet, multiplet), br (broadened, broad peak), brs (broadened singlet, wide is unimodal), dd (doublet of doublets, double doublet), ddd (doublet of Doublet of doublets, in pairs doublet), dt (doublet of triplets, double triplets), td (triplet Of doublets, three doublets), tt (triplet of triplets, three triplets).Coupling constant J, with hertz (Hz) table Show.

The determination condition of low resolution mass spectrometry (MS) data is: 6120 level four bars HPLC-M of Agilent (column model: Zorbax SB-C18,2.1x 30mm, 3.5 microns, 6min, flow velocity 0.6mL/min.Mobile phase: 5%-95% (contains 0.1% The CH of formic acid₃CN) in (H containing 0.1% formic acid₂O the ratio in), using electrospray ionisation (ESI), at 210nm/254nm, It is detected with UV.

Pure compound uses 1260 pre-HPLC or Calesep pump of Agilent, 250 pre-HPLC (pillar type Number: NOVASEP 50/80mm DAC), detected in 210nm/254nm with UV.

The use of logogram word below is through the present invention:

CDCl₃Deuterated chloroform ng nanogram

DMSO dimethyl sulfoxide μ g microgram

DMSO-d₆Mg milligrams of deuterated dimethyl sulfoxide

CD₃G grams of OD deuterated methanol

ML, ml milliliters of EtOAc, EA ethyl acetate

Glycerol glycerol μ L, μ l microlitres

KF potassium fluoride nL, nl nanoliter

Min minutes PE petroleum ethers (60-90 DEG C)

H hours RT, rt, r.t. room temperatures

MM, mmol/L mMs of every liter of Boc₂O, Boc acid anhydrides di-tert-butyl dicarbonate

Every liter of two ethanesulfonic acid of PIPES piperazine -1,4- of μM, μm ol/L micromole

Every liter of Tris-HCl of nM, nmol/L nanomole tri- (methylol) aminomethane-hydrochloric acid

M, mol/L moles every liter mmol mMs

HATU 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester

Following synthetic schemes describes the step of preparation disclosed compound of present invention, unless otherwise stated, wherein each R^1a、 R^1b、R^1c、R^1d、R^1eAnd R⁵With definition of the present invention.

Synthetic schemes 1

Wherein, PMB refers to 4- methoxy-benzylPh refers to phenyl

Formula (14) compound represented can be prepared by following process: formula (1) compound represented and formula (2) institute Show compound react, obtain formula (3) compound represented；Then formula (3) compound represented and formula (4) shown in compound it is anti- Answer, obtain formula (5) compound represented.Formula (5) compound represented deprotection base obtain formula (6) compound represented；So Afterwards formula (6) compound represented react to obtain with benzoyl isothiocyanate formula (7) compound represented.Formula (7) shown in change Close object removing benzoyl obtain formula (8) compound represented.Formula (8) compound represented ring closure reaction obtain formula (9) shown in Compound；Formula (9) in compound represented protecting group obtain formula (10) compound represented.Formula (10) in compound represented Nitro be reduced to obtain formula (11) compound represented.Formula (11) compound represented and formula (12) compound represented condensation Obtain formula (13) compound represented；Formula (13) compound represented deprotection base obtain formula (14) shown in target product.

Compound provided by the invention, pharmaceutical composition and its application are further described with reference to embodiments.

Embodiment

Embodiment 1 (R)-N- (the fluoro- 3- of 4- (3- imino group -2,5- dimethyl -1,1- dioxo -1,2,4- thiadiazine -5- Base) phenyl) -5- phenylpyridine amide synthesis

The synthesis of step 1) (R, E)-N- (1- (the fluoro- 5- nitrobenzophenone of 2-) ethylidene) -2- methylpropane -2- sulfenamide

By 1- (the fluoro- 5- nitro-phenyl of 2-) ethyl ketone (5g, 27.3mmol), (R)-(+)-t-butyl sulfonamide (3.8g, 31mmol) it is added in 100mL single necked round bottom flask with anhydrous tetrahydro furan (25mL), addition tetraethyl titanate (13.7g, 60.1mmol), it reacts 12 hours for lower 70 DEG C of nitrogen protection.It is cooled to room temperature after reaction, reaction solution is poured into water (50mL) In, filtering, filter cake is washed (40mL × 2) with methylene chloride, merges organic phase, and decompression is spin-dried for, column chromatographic isolation and purification (petroleum Ether/ethyl acetate (v/v)=20/1~5/1) title compound is obtained as yellow solid (7.1g, 91.0%).

MS(ESI,pos.ion)m/z:287.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃) δ (ppm) 8.59-8.51 (m, 1H), 8.31 (dd, J=14.9,12.1Hz, 1H), 7.30 (dd, J=16.0,6.5Hz, 1H), 2.81 (s, 3H), 1.33 (s, 9H)

Step 2) (R) -2- ((R) -1,1- dimethyl ethyl sulfonamido) -2- (the fluoro- 5- nitrobenzophenone of 2-)-N- (4- Methoxy-benzyl)-N- methylpropane -1- sulfonamide synthesis

N- (4- methoxy-benzyl)-N- methylmethanesulfonamide (1.60g, 6.98mmol) is placed in 100mL two mouth flask, Anhydrous tetrahydro furan (20mL) is added under nitrogen protection, low temperature bathes cooling 10 minutes at -30 DEG C, is then slowly added into n-BuLi (4.5mL, 1.6M), stirring were slowly added to (R, E)-N- (1- (the fluoro- 5- nitrobenzophenone of 2-) ethylidene) -2- methyl after 0.5 hour Propane -2- sulfenamide (1.00g, 3.49mmol are dissolved in 5mL tetrahydrofuran), the reaction was continued 0.5 hour.Saturation chlorination is added Aqueous ammonium (5mL) is quenched, and adds water (50mL), and ethyl acetate extracts (100mL × 2), collects organic phase, and decompression is spin-dried for, Column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=2/1) obtain title compound be yellow oil (0.85g, 47%).

MS(ESI,pos.ion)m/z:516.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 8.59 (dd, J=6.8,2.7Hz, 1H), 8.26 (dt, J=8.4, 3.3Hz, 1H), 7.28 (d, J=6.1Hz, 1H), 7.23 (d, J=8.3Hz, 2H), 6.88 (d, J=8.5Hz, 2H), 6.04 (s, 1H), 4.32-4.18 (m, 2H), 3.99-3.84 (m, 2H), 3.82 (d, J=6.7Hz, 3H), 2.81-2.70 (m, 3H), 1.95 (s,3H),1.38(s,9H).

The synthesis of step 3) (R) -2- amino -2- (the fluoro- 5- nitrobenzophenone of 2-)-N- methylpropane -1- sulfonamide

By (R) -2- ((R) -1,1- dimethyl ethyl sulfonamido) -2- (the fluoro- 5- nitrobenzophenone of 2-)-N- at 25 DEG C (4- methoxy-benzyl)-N- methylpropane -1- sulfonamide (5.85g, 11.3mmol), methylene chloride (90mL) and methanol (30mL) It is added in 500mL single necked round bottom flask, is added concentrated hydrochloric acid (10mL), continues to be stirred to react 1.5 hours；Stop reaction, decompression It is spin-dried for；Then trifluoroacetic acid (15mL) and 1 is added, 3- dimethoxy benzene (10mL) continues to be stirred to react 16 hours；Stop anti- It answers, water (100mL) and ethyl acetate (100mL) is added, water phase is collected in liquid separation, and sodium carbonate solid is added and is adjusted to pH=10, adds Enter methylene chloride (100mL) extraction, organic phase is collected in liquid separation, and decompression is spin-dried for, column chromatographic isolation and purification (methylene chloride/methanol (v/v)=40/1) obtaining title compound is yellow solid (2.28g, 69%).

MS(ESI,pos.ion)m/z:292.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 8.66 (dd, J=6.9,2.7Hz, 1H), 8.27-8.18 (m, 1H), 7.22 (dd, J=10.7,9.2Hz, 1H), 4.18 (t, J=10.9Hz, 1H), 3.89 (d, J=14.4Hz, 1H), 3.46 (d, J =14.4Hz, 1H), 2.72 (d, J=5.2Hz, 3H), 1.67 (s, 3H)

((2- (the fluoro- 5- nitrobenzophenone of 2-) -1- (N- methylaminosulfonyl) propane -2- base) is thio by step 4) (R)-N- Carbamyl) benzamide synthesis

At 25 DEG C by (R) -2- amino -2- (the fluoro- 5- nitrobenzophenone of 2-)-N- methylpropane -1- sulfonamide (0.34g, It 1.17mmol) is added in 100mL single necked round bottom flask with methylene chloride (5mL), benzoyl isothiocyanate is added dropwise (0.300g, 1.84mmol) continues to be stirred to react 10 hours；Organic phase decompression is spin-dried for, column chromatographic isolation and purification (petroleum ether/second Acetoacetic ester (v/v)=2/1) title compound is obtained as yellow solid (0.5g, 94.3%).

MS(ESI,pos.ion)m/z:455.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 11.67 (d, J=37.2Hz, 1H), 9.01 (s, 1H), 8.30 (dd, J= 6.8,2.5Hz, 1H), 8.25-8.16 (m, 1H), 7.88 (d, J=7.7Hz, 2H), 7.64 (t, J=7.4Hz, 1H), 7.52 (t, J=7.6Hz, 2H), 7.21 (dd, J=11.1,9.1Hz, 1H), 4.84 (dd, J=26.0,9.6Hz, 2H), 3.76 (t, J= 17.6Hz, 1H), 2.87 (d, J=5.1Hz, 3H), 2.27 (s, 3H)

The synthesis of step 5) (R) -2- (the fluoro- 5- nitrobenzophenone of 2-)-N- methyl -2- thiocarbamide propane -1- sulfonamide

By (R)-N- ((2- (the fluoro- 5- nitrobenzophenone of 2-) -1- (N- methylaminosulfonyl) propane -2- base) at 25 DEG C Thiocarbamoyl) benzamide (7.8g, 17.2mmol) and methanol (100mL) is added in 500mL single necked round bottom flask, adds Enter sodium carbonate (1.80g, 17.0mmol), continues to be stirred to react 0.5 hour.It is added ammonium chloride (1.00g, 18.7mmol), it is organic Mutually decompression is spin-dried for, and it is yellow solid that column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=1/1), which obtains title compound, (4.3g, 71.5%).

MS(ESI,pos.ion)m/z:351.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)8.25-8.16(m,2H),8.07(s,1H),7.46-7.39(m, 1H), 7.18 (s, 1H), 7.06 (d, J=4.8Hz, 1H), 4.03 (q, J=7.1Hz, 1H), 3.82 (d, J=14.1Hz, 1H), 2.61 (d, J=4.8Hz, 3H), 1.96 (s, 3H)

Step 6) (R) -5- (the fluoro- 5- nitrobenzophenone of 2-) -3- imino group -2,5- dimethyl -1,2,4- thiadiazine 1,1- bis- The synthesis of oxo compound

At 25 DEG C by (R) -2- (the fluoro- 5- nitrobenzophenone of 2-)-N- methyl -2- thiocarbamide propane -1- sulfonamide (0.5g, It 1.43mmol) is added in 100mL single necked round bottom flask, is added iodomethane (0.608g, 4.28mmol) with ethyl alcohol (20mL), after Continuous reaction 12 hours.It then heats to 70 DEG C to react 3 hours, stops reaction, decompression is spin-dried for, and is added water (20mL), ethyl acetate It extracts (50mL), liquid separation, organic phase decompression is spin-dried for, and column chromatographic isolation and purification (methylene chloride/methanol (v/v)=40/1) is marked Topic compound is yellow solid (0.298g, 66%).

MS(ESI,pos.ion)m/z:317.1[M+H]⁺；

¹H NMR(400MHz,CD₃OD) δ (ppm) 8.45 (dt, J=13.3,6.7Hz, 1H), 8.30-8.19 (m, 1H), 7.35 (dd, J=11.2,9.0Hz, 1H), 3.34-3.31 (m, 2H), 3.17 (s, 3H), 1.74 (s, 3H)

Step 7) (R)-tert-butyl (5- (the fluoro- 5- nitrobenzophenone of 2-) -2,5- dimethyl -1,1- dioxo -1,2,4- thiophene two Piperazine -3- subunit) carbamate synthesis

By (R) -5- (the fluoro- 5- nitrobenzophenone of 2-) -3- imino group -2,5- dimethyl -1,2,4- thiadiazine 1 at 25 DEG C, 1- dioxo compound (0.47g, 1.49mmol), triethylamine (0.3g, 2.96mmol) and methylene chloride (10mL) are added to 100mL In single necked round bottom flask, Boc acid anhydrides (0.500g, 2.29mmol) then is added, continues to be stirred to react 12 hours；Stop reaction, Decompression is spin-dried for, and it is white solid that column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=6/1), which obtains title compound, (0.5g, 81%).

MS(ESI,pos.ion)m/z:361.0[M+H-56]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 7.28 (s, 1H), 6.91 (dd, J=11.9,8.5Hz, 1H), 6.61 (dt, J=9.4,2.7Hz, 2H), 4.29 (dd, J=14.1,2.1Hz, 1H), 3.68 (d, J=14.1Hz, 1H), 3.27 (s, 3H),1.88(s,3H),1.57(s,9H).

Step 8) (R)-tert-butyl (5- (5- amino -2- fluorophenyl) -2,5- dimethyl -1,1- dioxo -1,2,4- thiophene two Piperazine -3- subunit) carbamate synthesis

By (R)-tert-butyl (5- (the fluoro- 5- nitrobenzophenone of 2-) -2,5- dimethyl -1,1- dioxo -1,2,4- at 25 DEG C Thiadiazine -3- subunit) carbamate (0.5g, 1.2mmol), palladium carbon (150mg) and methanol (15mL) is added to 100mL single port In round-bottomed flask, it is stirred to react under hydrogen balloon 24 hours.Stop reaction, filtering, filtrate decompression is spin-dried for, column chromatographic isolation and purification It is white solid (0.424g, 91.4%) that (petrol ether/ethyl acetate (v/v)=3/1), which obtains title compound,.

MS(ESI,pos.ion)m/z:387.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 7.28 (s, 1H), 6.91 (dd, J=11.9,8.5Hz, 1H), 6.61 (dt, J=9.4,2.7Hz, 2H), 4.29 (dd, J=14.1,2.1Hz, 1H), 3.68 (d, J=14.1Hz, 1H), 3.27 (s, 3H),1.88(s,3H),1.57(s,9H).

Step 9) (R)-tert-butyl (5- (the fluoro- 5- of 2- (5- phenylpyridine formamido group) phenyl) -2,5- dimethyl -1,1- Dioxo -1,2,4- thiadiazine -3- subunit) carbamate synthesis

5- phenyl picolinic acids (258mg, 1.3mmol) are dissolved in methylene chloride (5mL), N, N- diisopropyl are added at 0 DEG C Base ethamine (251mg, 1.94mmol), anhydrous magnesium sulfate (300mg) and HATU (492mg, 1.23mmol), stirring 0.5 is small at 0 DEG C When.(R)-tert-butyl is added, and (5- (5- amino -2- fluorophenyl) -2,5- dimethyl -1,1- dioxo -1,2,4- thiadiazine -3- is sub- Base) carbamate (250mg, 0.65mmol), under nitrogen protection, continuation is stirred 1 hour at 0 DEG C, is then transferred to room temperature Reaction 3 hours.Stop reaction, water (30mL) is added to wash, methylene chloride extracts (30mL × 2), and organic phase is dry with anhydrous sodium sulfate It is dry, organic phase is concentrated, it is faint yellow that column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=5/1), which obtains title compound, Solid (0.35g, 95%).

¹H NMR(400MHz,CDCl₃) δ (ppm) 10.70 (s, 1H), 10.05 (s, 1H), 8.83 (d, J=1.5Hz, 1H), 8.34 (d, J=8.1Hz, 1H), 8.11 (dd, J=8.1,2.2Hz, 1H), 8.02 (ddd, J=8.7,4.1,2.7Hz, 1H), 7.67-7.65 (m, 2H), 7.62 (dd, J=7.2,2.6Hz, 1H), 7.56 (t, J=7.3Hz, 2H), 7.49 (dd, J=8.4, 6.1Hz, 1H), 7.17 (dd, J=11.6,8.9Hz, 1H), 4.33 (dd, J=14.1,1.5Hz, 1H), 3.75 (d, J= 14.1Hz,1H),3.30(s,3H),1.95(s,3H),1.62(s,9H).

Step 10) (R)-N- (the fluoro- 3- of 4- (3- imino group -2,5- dimethyl -1,1- dioxo -1,2,4- thiadiazine -5- Base) phenyl) -5- phenylpyridine amide synthesis

By (R)-tert-butyl (5- (the fluoro- 5- of 2- (5- phenylpyridine formamido group) phenyl) -2,5- dimethyl -1,1- dioxy - 1,2,4- thiadiazine -3- subunits of generation) carbamate (350mg, 0.62mmol) is dissolved in methylene chloride (10mL), then it is added Hydrochloride/ethyl acetate (10mL) reacts at room temperature 2 hours.Stop reaction, decompression is spin-dried for, and saturated sodium bicarbonate solution is added PH=8~9 are adjusted to, methylene chloride extracts (30mL × 2), and anhydrous sodium sulfate is dry, and organic phase, column chromatographic isolation and purification is concentrated It is faint yellow solid (0.27g, 94%) that (methylene chloride/methanol (v/v)=30/1), which obtains title compound,.

MS(ESI,pos.ion)m/z:468.6[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 9.96 (s, 1H), 8.73 (d, J=1.6Hz, 1H), 8.24 (d, J= 8.1Hz, 1H), 8.05-7.99 (m, 2H), 7.74-7.70 (m, 1H), 7.63-7.61 (m, 2H), 7.53 (t, J=7.3Hz, 2H), 7.49-7.46 (m, 1H), 7.07 (dd, J=11.7,8.8Hz, 1H), 3.96 (d, J=13.7Hz, 1H), 3.71 (d, J= 14.0Hz,1H),3.25(s,3H),1.82(s,3H).

Embodiment 2 (R)-N- (the fluoro- 3- of 4- (3- imino group -2,5- dimethyl -1,1- dioxo -1,2,4- thiadiazine -5- Base) phenyl) -5- (4- fluorophenyl) picolinamide synthesis

Step 1) (R)-tert-butyl (5- (the fluoro- 5- of 2- (5- (4- fluorophenyl) pyridinecarboxylic amino) phenyl) -2,5- diformazan Base -1,1- dioxo -1,2,4- thiadiazine -3- subunit) carbamate synthesis

5- (4- fluorophenyl) pyridine carboxylic acid (281mg, 1.3mmol) is dissolved in methylene chloride (5mL), N, N- is added at 0 DEG C Diisopropylethylamine (251mg, 1.94mmol), anhydrous magnesium sulfate (300mg) and HATU (492mg, 1.23mmol), 0 DEG C of stirring 0.5 hour.(R)-tert-butyl (5- (5- amino -2- fluorophenyl) -2,5- dimethyl -1,1- dioxo -1,2,4- thiophene two is added Piperazine -3- subunit) carbamate (250mg, 0.65mmol), under nitrogen protection, continuation is stirred 1 hour at 0 DEG C, is then shifted To room temperature reaction 3 hours.Stop reaction, water (30mL) is added to wash, methylene chloride extracts (30mL × 2), the anhydrous sulphur of organic phase Sour sodium is dry, and organic phase is concentrated, and column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=5/1) obtains title compound and is Faint yellow solid (0.35g, 92%).

MS(ESI,pos.ion)m/z:586.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 10.70 (s, 1H), 10.02 (s, 1H), 8.78 (d, J=1.6Hz, 1H), 8.33 (d, J=8.1Hz, 1H), 8.06 (dd, J=8.1,2.2Hz, 1H), 8.03-7.99 (m, 1H), 7.65-7.61 (m, 3H), 7.25 (t, J=8.6Hz, 2H), 7.17 (dd, J=11.6,8.9Hz, 1H), 4.34 (dd, J=14.1,1.6Hz, 1H), 3.74 (d, J=14.2Hz, 1H), 3.29 (s, 3H), 1.95 (s, 3H), 1.62 (s, 9H)

Step 2) (R)-N- (the fluoro- 3- of 4- (3- imino group -2,5- dimethyl -1,1- dioxo -1,2,4- thiadiazine -5- Base) phenyl) -5- (4- fluorophenyl) picolinamide synthesis

By (R)-tert-butyl (5- (the fluoro- 5- of 2- (5- (4- fluorophenyl) pyridinecarboxylic amino) phenyl) dimethyl-1-2,5-, 1- dioxo -1,2,4- thiadiazine -3- subunit) carbamate (350mg, 0.6mmol) is dissolved in methylene chloride (10mL), then It is added Hydrochloride/ethyl acetate (10mL), reacts at room temperature 2 hours.Stop reaction, decompression is spin-dried for, and saturated sodium bicarbonate is added Solution is adjusted to pH=8~9, and methylene chloride extracts (30mL × 2), and anhydrous sodium sulfate is dry, and organic phase, column chromatography for separation is concentrated It is faint yellow solid (0.26g, 90%) that purifying (methylene chloride/methanol (v/v)=30/1), which obtains title compound,.

MS(ESI,pos.ion)m/z:486.6[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 9.95 (s, 1H), 8.68 (d, J=1.7Hz, 1H), 8.23 (d, J= 8.1Hz, 1H), 7.99 (dd, J=8.2,2.1Hz, 2H), 7.75-7.71 (m, 1H), 7.60-7.57 (m, 2H), 7.22 (t, J= 8.6Hz, 2H), 7.07 (dd, J=11.6,8.8Hz, 1H), 4.00 (d, J=13.6Hz, 1H), 3.72 (d, J=14.0Hz, 1H),3.25(s,3H),1.82(s,3H).

Embodiment 3 (R) -5- (4- chlorphenyl)-N- (the fluoro- 3- of 4- (dioxo -1 3- imino group -2,5- dimethyl -1,1-, 2,4- thiadiazine -5- base) phenyl) picolinamide synthesis

Step 1) (R)-tert-butyl (5- (5- (5- (4- chlorphenyl) pyridinecarboxylic amino) -2- fluorophenyl) -2,5- diformazan Base -1,1- dioxo -1,2,4- thiadiazine -3- subunit) carbamate synthesis

5- (4- chlorphenyl) pyridine carboxylic acid (302mg, 1.3mmol) is dissolved in methylene chloride (5mL), N, N- is added at 0 DEG C Diisopropylethylamine (251mg, 1.94mmol), anhydrous magnesium sulfate (300mg) and HATU (492mg, 1.23mmol), 0 DEG C of stirring 0.5 hour.(R)-tert-butyl (5- (5- amino -2- fluorophenyl) -2,5- dimethyl -1,1- dioxo -1,2,4- thiophene two is added Piperazine -3- subunit) carbamate (250mg, 0.65mmol), under nitrogen protection, continuation is stirred 1 hour at 0 DEG C, is then shifted To room temperature reaction 3 hours.Stop reaction, water (30mL) is added to wash, methylene chloride extracts (30mL × 2), the anhydrous sulphur of organic phase Sour sodium is dry, and organic phase is concentrated, and column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=5/1) obtains title compound and is Faint yellow solid (0.35g, 89%).

¹H NMR(400MHz,CDCl₃) δ (ppm) 10.70 (s, 1H), 10.02 (s, 1H), 8.79 (d, J=1.6Hz, 1H), 8.34 (d, J=8.1Hz, 1H), 8.07 (dd, J=8.1,2.2Hz, 1H), 8.01 (ddd, J=8.8,4.1,2.7Hz, 1H), 7.62 (dd, J=7.2,2.6Hz, 1H), 7.60-7.58 (m, 2H), 7.52 (d, J=8.6Hz, 2H), 7.17 (dd, J=11.6, 8.9Hz, 1H), 4.33 (dd, J=14.1,1.6Hz, 1H), 3.74 (d, J=14.2Hz, 1H), 3.29 (s, 3H), 1.95 (s, 3H),1.62(s,9H).

Step 2) (R) -5- (4- chlorphenyl)-N- (the fluoro- 3- of 4- (dioxo -1,2 3- imino group -2,5- dimethyl -1,1-, 4- thiadiazine -5- base) phenyl) picolinamide synthesis

By (R)-tert-butyl (5- (5- (5- (4- chlorphenyl) pyridinecarboxylic amino)-2- fluorophenyl) dimethyl-1-2,5-, 1- dioxo -1,2,4- thiadiazine -3- subunit) carbamate (350mg, 0.6mmol) is dissolved in methylene chloride (10mL), then It is added Hydrochloride/ethyl acetate (10mL), reacts at room temperature 2 hours.Stop reaction, decompression is spin-dried for, and saturated sodium bicarbonate is added Solution adjusts pH=8~9, and methylene chloride extracts (30mL × 2), and anhydrous sodium sulfate is dry, and organic phase is concentrated, and column chromatography for separation is pure Changing (methylene chloride/methanol (v/v)=30/1) to obtain title compound is faint yellow solid (0.25g, 86%).

MS(ESI,pos.ion)m/z:502.5[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 9.93 (s, 1H), 8.66 (d, J=1.6Hz, 1H), 8.22 (d, J= 8.1Hz, 1H), 7.99 (dt, J=5.2,2.1Hz, 2H), 7.74-7.70 (m, 1H), 7.52 (q, J=8.7Hz, 4H), 7.07 (dd, J=11.6,8.8Hz, 1H), 3.97 (d, J=13.6Hz, 1H), 3.70 (d, J=14.0Hz, 1H), 3.24 (s, 3H), 1.81(s,3H).

Embodiment 4 (R) -5- (4- cyano-phenyl)-N- (the fluoro- 3- of 4- (3- imino group -2,5- dimethyl -1,1- dioxo - 1,2,4- thiadiazine -5- base) phenyl) picolinamide synthesis

Step 1) (R)-tert-butyl (5- (5- (5- (4- cyano-phenyl) pyridinecarboxylic amino) -2- fluorophenyl) -2,5- diformazan Base -1,1- dioxo -1,2,4- thiadiazine -3- subunit) carbamate synthesis

5- (4- cyano-phenyl) pyridine carboxylic acid (290mg, 1.3mmol) is dissolved in methylene chloride (5mL), N is added at 0 DEG C, N- diisopropylethylamine (251mg, 1.94mmol), anhydrous magnesium sulfate (300mg) and HATU (492mg, 1.23mmol), 0 DEG C is stirred It mixes 0.5 hour.(R)-tert-butyl (5- (5- amino -2- fluorophenyl) -2,5- dimethyl -1,1- dioxo -1,2,4- thiophene two is added Piperazine -3- subunit) carbamate (250mg, 0.65mmol), under nitrogen protection, continuation is stirred 1 hour at 0 DEG C, is then shifted To room temperature reaction 3 hours.Stop reaction, water (30mL) is added to wash, methylene chloride extracts (30mL × 2), the anhydrous sulphur of organic phase Sour sodium is dry, and organic phase is concentrated, and column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=5/1) obtains title compound and is Faint yellow solid (0.35g, 91%).

¹H NMR(400MHz,CDCl₃) δ (ppm) 10.00 (s, 1H), 8.83 (d, J=1.6Hz, 1H), 8.38 (d, J= 8.1Hz, 1H), 8.12 (dd, J=8.1,2.2Hz, 1H), 8.00 (ddd, J=8.7,4.1,2.8Hz, 1H), 7.85 (d, J= 8.4Hz, 2H), 7.77 (d, J=8.5Hz, 2H), 7.63 (dd, J=7.2,2.6Hz, 1H), 7.17 (dd, J=11.6,8.9Hz, 1H), 4.34 (dd, J=14.1,1.7Hz, 1H), 3.73 (d, J=14.2Hz, 1H), 3.29 (s, 3H), 1.95 (s, 3H), 1.61 (s,9H).

Step 2) (R) -5- (4- cyano-phenyl)-N- (the fluoro- 3- of 4- (dioxo -1 3- imino group -2,5- dimethyl -1,1-, 2,4- thiadiazine -5- base) phenyl) picolinamide synthesis

By (R)-tert-butyl (5- (5- (5- (4- cyano-phenyl) pyridinecarboxylic amino) -2- fluorophenyl) -2,5- dimethyl - 1,1- dioxo -1,2,4- thiadiazine -3- subunit) carbamate (350mg, 0.6mmol) is dissolved in methylene chloride (10mL), so Hydrochloride/ethyl acetate (10mL) is added afterwards, reacts at room temperature 2 hours.Stop reaction, decompression is spin-dried for, and unsaturated carbonate hydrogen is added Sodium solution is adjusted to pH=8~9, and methylene chloride extracts (30mL × 2), and anhydrous sodium sulfate is dry, and organic phase, column chromatography point is concentrated Obtaining title compound from purifying (methylene chloride/methanol (v/v)=30/1) is faint yellow solid (0.28g, 96%).

MS(ESI,pos.ion)m/z:493.6[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 9.92 (s, 1H), 8.69 (d, J=1.6Hz, 1H), 8.26 (d, J= 8.1Hz, 1H), 8.04 (dd, J=8.1,2.2Hz, 1H), 8.00 (dd, J=7.2,2.7Hz, 1H), 7.82 (d, J=8.4Hz, 2H), 7.72 (d, J=8.4 Hz, 3H), 7.06 (dd, J=11.6,8.8Hz, 1H), 4.00 (d, J=13.9Hz, 1H), 3.69 (d, J=14.0Hz, 1H), 3.23 (s, 3H), 1.80 (s, 3H)

Embodiment 5 (R)-N- (the fluoro- 3- of 4- (3- imino group -2,5- dimethyl -1,1- dioxo -1,2,4- thiadiazine -5- Base) phenyl) -5- (3- fluorophenyl) picolinamide synthesis

Step 1) (R)-tert-butyl (5- (the fluoro- 5- of 2- (5- (3- fluorophenyl) pyridinecarboxylic amino) phenyl) -2,5- diformazan Base -1,1- dioxo -1,2,4- thiadiazine -3- subunit) carbamate synthesis

5- (3- fluorophenyl) pyridine carboxylic acid (281mg, 1.3mmol) is dissolved in methylene chloride (5mL), N, N- is added at 0 DEG C Diisopropylethylamine (251mg, 1.94mmol), anhydrous magnesium sulfate (300mg) and HATU (492mg, 1.23mmol), 0 DEG C of stirring 0.5 hour.(R)-tert-butyl (5- (5- amino -2- fluorophenyl) -2,5- dimethyl -1,1- dioxo -1,2,4- thiophene two is added Piperazine -3- subunit) carbamate (250mg, 0.65mmol), under nitrogen protection, continuation is stirred 1 hour at 0 DEG C, is then shifted To room temperature reaction 3 hours.Stop reaction, water (30mL) is added to wash, methylene chloride extracts (30mL × 2), the anhydrous sulphur of organic phase Sour sodium is dry, and organic phase is concentrated, and column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=5/1) obtains title compound and is Faint yellow solid (0.35g, 92%).

¹H NMR(400MHz,CDCl₃) δ (ppm) 10.70 (s, 1H), 10.02 (s, 1H), 8.81 (d, J=1.6Hz, 1H), 8.35 (d, J=8.1Hz, 1H), 8.09 (dd, J=8.1,2.2Hz, 1H), 8.01 (ddd, J=8.7,4.1,2.7Hz, 1H), 7.63 (dd, J=7.2,2.6Hz, 1H), 7.52 (td, J=7.9,5.9Hz, 1H), 7.44 (d, J=8.0Hz, 1H), 7.37- 7.34 (m, 1H), 7.18 (ddd, J=16.5,8.8,5.3Hz, 2H), 4.33 (dd, J=14.1,1.5Hz, 1H), 3.74 (d, J =14.1Hz, 1H), 3.29 (s, 3H), 1.95 (s, 3H), 1.62 (s, 9H)

Step 2) (R)-N- (the fluoro- 3- of 4- (3- imino group -2,5- dimethyl -1,1- dioxo -1,2,4- thiadiazine -5- Base) phenyl) -5- (3- fluorophenyl) picolinamide synthesis

By (R)-tert-butyl (5- (the fluoro- 5- of 2- (5- (3- fluorophenyl) pyridinecarboxylic amino) phenyl) dimethyl-1-2,5-, 1- dioxo -1,2,4- thiadiazine -3- subunit) carbamate (350mg, 0.6mmol) is dissolved in methylene chloride (10mL), then It is added Hydrochloride/ethyl acetate (10mL), reacts at room temperature 2 hours.Stop reaction, decompression is spin-dried for, and saturated sodium bicarbonate is added Solution is adjusted to pH=8~9, and methylene chloride extracts (30mL × 2), and anhydrous sodium sulfate is dry, and organic phase, column chromatography for separation is concentrated It is faint yellow solid (0.26g, 90%) that purifying (methylene chloride/methanol (v/v)=30/1), which obtains title compound,.

MS(ESI,pos.ion)m/z:486.6[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 9.95 (s, 1H), 8.69 (d, J=1.6Hz, 1H), 8.23 (d, J= 8.1Hz, 1H), 8.00 (dd, J=8.0,2.2Hz, 2H), 7.72-7.69 (m, 1H), 7.49 (td, J=8.0,6.0Hz, 1H), 7.39 (d, J=8.1Hz, 1H), 7.32-7.29 (m, 1H), 7.17 (td, J=8.3,1.8Hz, 1H), 7.06 (dd, J=11.7, 8.8Hz, 1H), 4.02 (d, J=13.5Hz, 1H), 3.72 (d, J=14.0Hz, 1H), 3.25 (s, 3H), 1.82 (s, 3H)

Embodiment 6 (R)-N- (the fluoro- 3- of 4- (3- imino group -2,5- dimethyl -1,1- dioxo -1,2,4- thiadiazine -5- Base) phenyl) -5- (3- chlorphenyl) picolinamide synthesis

Step 1) (R)-tert-butyl (5- (the fluoro- 5- of 2- (5- (3- chlorphenyl) pyridinecarboxylic amino) phenyl) -2,5- diformazan Base -1,1- dioxo -1,2,4- thiadiazine -3- subunit) carbamate synthesis

5- (3- chlorphenyl) pyridine carboxylic acid (302mg, 1.3mmol) is dissolved in methylene chloride (5mL), N, N- is added at 0 DEG C Diisopropylethylamine (251mg, 1.94mmol), anhydrous magnesium sulfate (300mg) and HATU (492mg, 1.23mmol), 0 DEG C of stirring 0.5 hour.(R)-tert-butyl (5- (5- amino -2- fluorophenyl) -2,5- dimethyl -1,1- dioxo -1,2,4- thiophene two is added Piperazine -3- subunit) carbamate (250mg, 0.65mmol), under nitrogen protection, continuation is stirred 1 hour at 0 DEG C, is then shifted To room temperature reaction 3 hours.Stop reaction, water (30mL) is added to wash, methylene chloride extracts (30mL × 2), the anhydrous sulphur of organic phase Sour sodium is dry, and organic phase is concentrated, and column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=5/1) obtains title compound and is Faint yellow solid (0.35g, 90%).

¹H NMR(400MHz,CDCl₃)δ(ppm)10.69(s,1H),10.02(s,1H),8.82-8.76(m,1H),8.35 (d, J=8.1Hz, 1H), 8.08 (dd, J=8.1,2.2Hz, 1H), 7.99 (ddd, J=8.7,4.1,2.7Hz, 1H), 7.64 (t, J=4.8Hz, 2H), 7.55-7.51 (m, 1H), 7.48 (dd, J=9.4,4.9Hz, 2H), 7.17 (dd, J=11.6, 8.9Hz, 1H), 4.33 (dd, J=14.1,1.5Hz, 1H), 3.74 (d, J=14.1Hz, 1H), 3.29 (s, 3H), 1.95 (s, 3H),1.62(s,9H).

Step 2) (R)-N- (the fluoro- 3- of 4- (3- imino group -2,5- dimethyl -1,1- dioxo -1,2,4- thiadiazine -5- Base) phenyl) -5- (3- chlorphenyl) picolinamide synthesis

By (R)-tert-butyl (5- (the fluoro- 5- of 2- (5- (3- chlorphenyl) pyridinecarboxylic amino) phenyl) dimethyl-1-2,5-, 1- dioxo -1,2,4- thiadiazine -3- subunit) carbamate (360mg, 0.58mmol) is dissolved in methylene chloride (10mL), so Hydrochloride/ethyl acetate (10mL) is added afterwards, reacts at room temperature 2 hours.Stop reaction, decompression is spin-dried for, and unsaturated carbonate hydrogen is added Sodium solution is adjusted to pH=8~9, and methylene chloride extracts (30mL × 2), and anhydrous sodium sulfate is dry, and organic phase, column chromatography point is concentrated Obtaining title compound from purifying (methylene chloride/methanol (v/v)=30/1) is faint yellow solid (0.27g, 93%).

MS(ESI,pos.ion)m/z:502.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 9.98 (s, 1H), 8.72 (d, J=1.6Hz, 1H), 8.27 (d, J= 8.1Hz, 1H), 8.02 (dd, J=8.1,2.2Hz, 1H), 7.98 (dd, J=7.2,2.6Hz, 1H), 7.78-7.75 (m, 1H), 7.60 (s, 1H), 7.52-7.49 (m, 1H), 7.47-7.45 (m, 2H), 7.09 (dd, J=11.7,8.8Hz, 1H), 4.04 (d, J =13.9Hz, 1H), 3.78 (d, J=14.0Hz, 1H), 3.29 (s, 3H), 1.85 (s, 3H)

Biologic test

Embodiment A:BACE-1 inhibitor enzyme level external activity evaluation method

Experimental method

1.1X assay buffer and test-compound are prepared

(1)1X assay buffer(20nM PIPES,pH5.0；0.1%Brij-35；10%Glycerol)

(2) test-compound is prepared

Test-compound is diluted to respectively by 1mM using 100%DMSO, control compound MK-8931 is diluted to 100 μM. 45 μ L, 1mM test-compound solution and 100 μM of MK- are separately added into 384 orifice plate of Echo (Labcyte, P-05525) 8931 solution.Test-compound is diluted 9 times with 3 times of dilution gradient precisions.Pass through (550 sound wave of Labcyte echo of Echo 550 Liquor-transferring system equipment) by 100nL test-compound solution from starting sheet be transferred to test board (PerkinElmer, Cat.No.6008289).Into control wells, 100nL DMSO is added.DMSO final concentration of 1% in all holes.

2.BACE-1 enzyme solutions are prepared

(1) BACE-1 enzyme solutions are prepared using 1X assay buffer, concentration is twice of final concentration of test, and test is dense eventually Degree is 3nM.

(2) using electronic multichannel pipettor, 5 μ L BACE-1 enzyme solutions, solution rapid centrifugation is added in every hole in test board.

(3) it is incubated at room temperature 15min.

3.2X APP substrate solution is prepared

(1) APP substrate solution is prepared using 1X assay buffer, solution concentration is twice of final concentration of test.

Final concentration: Biotin-APP substrate-K 25nM；5 μM of non-biotinylation and unmarked APP substrate.

(2) using electronic multichannel pipettor, 5 μ L APP substrate solutions are added in every hole in test board, start to react.

(3) solution rapid centrifugation.

4. reaction

After sealing test plate, in 28 DEG C of incubation 4h.

5.Homogeneous Time-Resolved Fluorescence (HTRF) detection

(1) prepare 2X detection buffer (25mM Tris-HCl, pH 8.0；0.0005%Brij-35；250mM KF)

(2) Streptavidin-XLent solution is prepared using 2X detection buffer, concentration is test final concentration 2 times of (10 μ g/mL).

(3) use electronic multichannel pipettor that 10 μ L Streptavidin-XLent solution are added with end in the every hole of test board Only react.

(4) after centrifuge quickly mixes, in 25 DEG C of balance 60min.

6. collecting data

Data are collected in EnVison software.

7. data are analyzed

(1) HTRF fluorescence ratio (665nm/615nm*10000) is copied out from EnVison software.

(2) HTRF fluorescence ratio is converted into percentage inhibiting value.Maximum value and minimum value are handled: numerical value is more than Avg ± 3SD is considered as deviation value.The ratio that deviation value is deleted controls within 20%.

A. inhibiting rate=(sample ratio-minimum value)/(maximum value-minimum value) * 100

B. minimum value is the HTRF fluorescence ratio of BACE-1 enzyme and APP substrate, and maximum value is the bottom assay buffer and APP The HTRF ratio of object.

(3) data are fitted with the presentation of Excel form, curve using GraphPad Prism 5.

(4) each compound IC₅₀Value, which calculates, uses 5 four parameter fitting model of GraphPad Prism:

Y=Bottom+ (Top-Bottom)/(1+ (IC₅₀/ X) ^HillSlope), Y is % inhibiting rate, and X is that compound is dense Degree.

It the results are shown in Table A.

Table A the compounds of this invention is to BACE-1 enzyme level In-vitro Inhibitory Effect test result

Example No.	IC50(μM)	Example No.	IC50(μM)
				Embodiment 1	0.13	Embodiment 4	0.64
Embodiment 2	0.50	Embodiment 5	0.10
				Embodiment 3	0.17	Embodiment 6	0.12

Experimental result shows that the compounds of this invention has preferable BACE-1 inhibiting effect.

In the description of this specification, reference term " one embodiment ", " embodiment ", " some embodiments ", " show The description of example ", specific examples or " some examples " etc. means to combine the specific spy of the embodiment, embodiment or example description Sign, structure, material or feature are contained at least one embodiment of the present invention, embodiment or example.In this specification In, schematic expression of the above terms are necessarily directed to identical embodiment, embodiment or example.Moreover, description Particular features, structures, materials, or characteristics can be in any one or more embodiments, embodiment or example with suitable Mode combines.In addition, without conflicting with each other, those skilled in the art can be by difference described in this specification Embodiment, embodiment or example and different embodiments, embodiment or exemplary feature are combined.

Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is example Property, it is not considered as limiting the invention, those skilled in the art within the scope of the invention can be to above-mentioned Embodiment is changed, modifies, replacement and variant.

Claims (10)

1. a kind of compound is compound shown in formula (I) or formula (I ') compound represented or formula (I) or formula (I ') Stereoisomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or it Prodrug,

Wherein:

X is CR^xOr N；

Y is CH or N；

R^1a、R^1b、R^1c、R^1dAnd R^1eIt is each independently H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂、-OH、-SH、-COOH、- CONH₂,-C (=O) NHCH₃,-C (=O) N (CH₃)₂,-C (=O)-(C₁-C₆Alkyl) ,-C (=O)-(C₁-C₆Alkoxy), C₁- C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆Halogenated alkoxy, C₁-C₆Alkylthio group, C₁-C₆The C that alkylamino or hydroxyl replace₁-C₆Alkyl；

R^2a、R^2b、R^2cAnd R^xIt is each independently H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂,-OH ,-COOH ,-C (=O) NH₂、 C₁-C₆Alkyl, C₁-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆The C that halogenated alkoxy or hydroxyl replace₁-C₆Alkyl；

R³And R⁴It is each independently H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂,-OH ,-COOH ,-C (=O) NH₂、C₁-C₆Alkane Base, C₁-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆The C that halogenated alkoxy or hydroxyl replace₁-C₆Alkyl；

R⁵For H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂,-OH ,-COOH ,-C (=O) NH₂、C₁-C₆Alkyl, C₁-C₆Alkyl halide Base, C₁-C₆Alkoxy, C₁-C₆The C that halogenated alkoxy or hydroxyl replace₁-C₆Alkyl；

R⁶For H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂,-OH ,-COOH ,-C (=O) NH₂、C₁-C₆Alkyl, C₁-C₆Alkyl halide Base, C₁-C₆Alkoxy, C₁-C₆The C that halogenated alkoxy or hydroxyl replace₁-C₆Alkyl；

R⁷And R⁸It is each independently H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂,-OH ,-COOH ,-C (=O) NH₂、C₁-C₆Alkane Base, C₁-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆The C that halogenated alkoxy or hydroxyl replace₁-C₆Alkyl；With

R⁹For H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂,-OH ,-COOH ,-C (=O) NH₂、C₁-C₆Alkyl, C₁-C₆Alkyl halide Base, C₁-C₆Alkoxy, C₁-C₆The C that halogenated alkoxy or hydroxyl replace₁-C₆Alkyl.

2. compound according to claim 1, wherein R^1a、R^1b、R^1c、R^1dAnd R^1eBe each independently H, D, F, Cl, Br, I、-CN、-NO₂、-NH₂、-OH、-SH、-COOH、-CONH₂,-C (=O)-(C₁-C₄Alkyl) ,-C (=O)-(C₁-C₄Alkoxy), C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, C₁-C₄Halogenated alkoxy, C₁-C₄Alkane sulphur Base, C₁-C₄The C that alkylamino or hydroxyl replace₁-C₄Alkyl.

3. compound according to claim 1 or 2, wherein R^1a、R^1b、R^1c、R^1dAnd R^1eBe each independently H, D, F, Cl, Br、I、-CN、-NO₂、-NH₂、-OH、-SH、-COOH、-CONH₂,-C (=O) CH₃,-C (=O) OCH₃,-C (=O) OCH₂CH₃、- C (=O) OCH₂CH₂CH₃,-C (=O) OCH (CH₃)₂, methyl, ethyl, n-propyl, isopropyl ,-CF₃、-CH₂CF₃, methoxyl group, second Oxygroup, n-propyl oxygroup or isopropyl oxygroup.

4. compound according to claim 1, wherein R^2a、R^2b、R^2cAnd R^xBe each independently H, D, F, Cl, Br, I ,- CN、-NO₂、-NH₂,-OH ,-COOH ,-C (=O) NH₂、C₁-C₄Alkyl, C₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, C₁-C₄Alkyl halide The C that oxygroup or hydroxyl replace₁-C₄Alkyl；

R³And R⁴It is each independently H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂,-OH ,-COOH ,-C (=O) NH₂、C₁-C₄Alkane Base, C₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, C₁-C₄The C that halogenated alkoxy or hydroxyl replace₁-C₄Alkyl；

R⁵For H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂,-OH ,-COOH ,-C (=O) NH₂、C₁-C₄Alkyl, C₁-C₄Alkyl halide Base, C₁-C₄Alkoxy, C₁-C₄The C that halogenated alkoxy or hydroxyl replace₁-C₄Alkyl；

R⁶For H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂,-OH ,-COOH ,-C (=O) NH₂、C₁-C₄Alkyl, C₁-C₄Alkyl halide Base, C₁-C₄Alkoxy, C₁-C₄The C that halogenated alkoxy or hydroxyl replace₁-C₄Alkyl；

R⁷And R⁸It is each independently H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂,-OH ,-COOH ,-C (=O) NH₂、C₁-C₄Alkane Base, C₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, C₁-C₄The C that halogenated alkoxy or hydroxyl replace₁-C₄Alkyl；

R⁹For H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂,-OH ,-COOH ,-C (=O) NH₂、C₁-C₄Alkyl, C₁-C₄Alkyl halide Base, C₁-C₄Alkoxy, C₁-C₄The C that halogenated alkoxy or hydroxyl replace₁-C₄Alkyl.

5. compound according to claim 1 or 4, wherein R^2a、R^2b、R^2cAnd R^xBe each independently H, D, F, Cl, Br, I、-CN、-NO₂、-NH₂,-OH ,-COOH ,-C (=O) NH₂, methyl, ethyl, n-propyl, isopropyl ,-CF₃、-CH₂CF₃, methoxy Base, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup；

R³And R⁴It is each independently H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂,-OH ,-COOH ,-C (=O) NH₂, methyl, second Base, n-propyl, isopropyl ,-CF₃、-CH₂CF₃, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup；

R⁵For H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂,-OH ,-COOH ,-C (=O) NH₂, methyl, ethyl, n-propyl, isopropyl Base ,-CF₃、-CH₂CF₃, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup；

R⁶For H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂,-OH ,-COOH ,-C (=O) NH₂, methyl, ethyl, n-propyl, isopropyl Base ,-CF₃、-CH₂CF₃, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup；

R⁷And R⁸It is each independently H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂,-OH ,-COOH ,-C (=O) NH₂, methyl, second Base, n-propyl, isopropyl ,-CF₃、-CH₂CF₃, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup；

R⁹For H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂,-OH ,-COOH ,-C (=O) NH₂, methyl, ethyl, n-propyl, isopropyl Base ,-CF₃、-CH₂CF₃, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup.

6. compound according to claim 1, be formula (II) or formula (II ') compound represented or formula (II) or Stereoisomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, the medicine of compound shown in formula (II ') Acceptable salt or its prodrug on,

7. compound according to claim 1 or 6 for the compound with one of following structure or has one of following The stereoisomer of the compound of structure, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically Acceptable salt or its prodrug:

8. a kind of pharmaceutical composition includes compound described in claim 1-7 any one；With

Described pharmaceutical composition optionally further includes pharmaceutically acceptable excipient, carrier, adjuvant or theirs is any Combination.

9. pharmaceutical composition according to claim 8, further includes additional therapeutic agent, wherein the additional therapeutic agent For nalmefene, Risperidone, Rivastigmine, Memantine, mitzapine, Venlafaxine, desipramine, nortriptyline, zolpidem, assistant Clone, Nicergoline, Piracetam, selegiline, pentoxifylline, Tacrine, donepezil, galanthamine, rivastigmine It is bright, vitamin e, fibrates, niacin, nicotinic receptor agonist, nicotinic acetylcholine receptors alpha7, cholinesterase inhibition Agent, N-methyl-D-aspartate receptor antagonist, the promotor of α secretase activity, glycogen synthase kinase beta inhibitor, starch The inhibitor of sample albumen aggregation, gamma-secretase inhibitors, gamma secretase modulators, histamine H 3 antagonists, histone deacetylase Enzyme inhibitor, PDE-4 inhibitor, PDE-10 inhibitor, mGluR1 receptor modulators or antagonist, mGluR5 receptor modulators or Antagonist, mGluR2/3 antagonist, 5-HT₄Agonist, 5-HT₆Receptor antagonist or GABA_AInverse agonist.

10. pharmaceutical composition described in compound described in claim 1-7 any one or claim 8-9 any one exists The purposes in drug is prepared, the drug is for preventing, treating or mitigating disease related with beta-amyloid protein；

Wherein, the disease related with beta-amyloid protein is dementia, senile dementia, Ahl tribulus sea silent sickness, Parkinson's disease And/or the relevant dementia of Down syndrome, Down syndrome, attention deficit symptom, Ahl tribulus sea silent sickness, Parkinson's disease And/or the relevant attention deficit symptom of Down syndrome, the loss of memory, the loss of memory relevant to Parkinson's disease, with A Er The relevant loss of memory of Ci Haimo disease, apoplexy, neurodegeneration, amyloidosis, beta amyloid angiosis, Cerebral Amyloid blood vessel Disease, hereditary cerebral hemorrhage, complication of hemodialysis, glaucoma, type-2 diabetes mellitus, the relevant amyloid of diabetes generate, Traumatic brain injury, bovine spongiform encephalopathy, mild cognitive impairment or Alzheimer disease.