CN101627028B

CN101627028B - Substituted diazepan compounds as orexin receptor antagonists

Info

Publication number: CN101627028B
Application number: CN200780050811.0A
Authority: CN
Inventors: J·M·伯格曼; M·J·布雷斯林; P·J·科尔曼; C·D·科克斯; S·P·默瑟; A·J·勒克
Original assignee: Schering Corp
Current assignee: Merck Sharp and Dohme BV
Priority date: 2006-12-01
Filing date: 2007-11-30
Publication date: 2013-03-27
Anticipated expiration: 2027-11-30
Also published as: ZA200903334B; UA106873C2; UA100974C2; CN101627028A; HN2009001067A

Abstract

The present invention is directed to substituted diazepan compounds which are antagonists of orexin receptors, and which are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which orexin receptors are involved.

Description

Diazepan compounds as the replacement of orexin receptor antagonists

Background of invention

Orexin (hypocretins) is included in two kinds of neuropeptides that produce in hypothalamus: orexin-A (OX-A) (a kind of 33 amino acid peptides) and orexin B (OX-B) (a kind of 28 amino acid peptides) (people such as Sakurai, Cell, 1998,92,573-585).It is found that the food consumption of orexin stimulation in rats, shown these peptides as medium, in the maincenter Feedback mechanism of regulating feeding behavior, bring into play physiological action (people such as Sakurai, Cell, 1998,92,573-585).Orexin is regulated sleep and waking state, this may for narcolepsy or insomniac opened a new treatment approach (people such as Chemelli R.M., Cell, 1999,98,437-451).Orexin also be represented as in awakening, remuneration sense (reward), learning and memory and work (Harris, wait the people, Trends Neurosci., 2006,29 (10), 571-577).Two kinds of orexin acceptors have been cloned and have been characterized in Mammals.They belong to the superfamily (people such as Sakurai T. of g protein coupled receptor, Cell, 1998,92,573-585): orexin-1 acceptor (OX or OX1R) is optionally to OX-A, and appetite plain-2 acceptor (OX2 or OX2R) can be in conjunction with OX-A and OX-B.Suppose and have physiological action that orexin participates in to be considered to be expressed by the OX1 acceptor as two hypotypes of orexin acceptor and OX2 acceptor one of them or two simultaneously.

The orexin acceptor finds in mammal brain, and has multiple connotation in pathology, for example depressed; Anxiety; Habituation; Obsession; The emotionality neuropathy; The depressibility neuropathy; The anxiety neuropathy; Dysthymic disorder; Behavioral disorder; Emotionally disturbed; Sexual disorder; Sexual psychology dysfunction, sexual disorder; Schizophrenia; Manic property depression; Psychiatric disorder; Dull-witted; Severe backwardness and dyskinesia be Huntington's disease and tourette's syndrome for example; Eating disorder is apocleisis, Bulimia nerovsa, emaciation and obesity for example; The habituation feeding behavior; Carousing/defaecation feed behavior (binge/purge feeding behaviors); Cardiovascular disorder; Diabetes; Appetite/sense of taste disorder; Vomiting (emesis), vomiting (vomiting), nauseating; Asthma; Cancer; Parkinson's disease; Cushing (Cushing) Cotard/disease; Basophilic adenoma; Prolactinoma; Hyperprolactinemia; Pituitary body knurl/adenoma; Hypothalamic disorder; Inflammatory bowel; Motility disturbances of the stomach; Stomach ulcer; Froehlich ' s syndrome; The adenohypophysis disease; The pituitary gland disease; The adenohypophysis deterioration; The adenohypophysis hyperfunction; The hypothalamic adenasthenia; Kallman ' s syndrome (anosmia, hyposmia); Functional or psychological amenorrhoea; Hypobasophilism; The hypothalamus thyroprivia; The hypothalamus dysadrenalsm; The idiopathic hyperprolactinemia; The hypothalamus obstacle of growth hormone deficiency; The idiopathic growth is not enough; Runt disease; Giant's disease; Acromegaly; Biology and day-night rhythm disorder; With disease neurological disorder for example, sleep disordered relevant with restless leg syndrome of neuropathic pain; Heart and lung diseases, acute and congestive heart failure; Hypopiesia; Hypertension; Urinary retention; Osteoporosis; Stenocardia; Myocardial infarction; Ischemia or congested apoplexy; Subarachnoid hemorrhage; Ulcer; Allergy; Benign prostatauxe; Chronic renal failure; Ephrosis; The sugar dosis tolerata reduces; Migraine; Hyperpathia; Pain; That improve or exaggerate for example hyperpathia of pain sensitivity, causalgia and allodynia; Acute pain; Burn pain; Atypical face ache; Neuropathic pain; Backache; Plyability regional pain syndrome I and II; Arthritis pain; Sport injury pain; The pain relevant to infection is HIV for example, pain after chemotherapy; Pain after apoplexy; Postoperative pain; Neurodynia; Vomiting, feel sick, vomiting; The symptom relevant to visceral pain be irritable bowel syndrome for example, and angina; Migraine; Bladder incontinence is urge incontinence for example; To narcotic tolerance or to narcotic withdrawal; Somnopathy; Sleep apnea; The Narcolepsy; Insomnia; Parasomnia; Jet lag; And the nerve degeneration kind obstacle comprises that the disease on nosonomy for example suppresses the compound disease of releasing-dementia-Parkinson's disease-myatrophy; Grey ball-pons-black substance is degenerated; Epilepsy; Epileptics (seizure disorders) and other disease relevant to general orexin system function obstacle..

Some orexin receptor antagonists is disclosed in PCT patent document: WO 99/09024, WO99/58533, WO 00/47576, WO 00/47577, WO 00/47580, WO 01/68609, WO 01/85693, WO 01/96302, WO 2002/044172, WO 2002/051232, WO 2002/051838, WO 2002/089800, WO 2002/090355, WO2003/002559, WO 2003/002561, WO 2003/032991, WO 2003/037847, WO 2003/041711, WO 2003/051368, WO 2003/051872, WO2003/051873, WO 2004/004733, WO 2004/026866, WO 2004/033418, WO 2004/041807, WO 2004/041816, WO 2004/052876, WO2004/083218, WO 2004/085403, WO 2004/096780, WO 2005/060959, WO 2005/075458, WO2005/118548, WO 2006/067224, WO2006/110626, WO 2006/127550, WO 2007/019234, WO 2007/025069.

Summary of the invention

The present invention relates to diazepan compounds, it is the orexin receptor antagonist, is used for the treatment of or prevents the caused neurological of orexin receptor and psychiatric disturbance and disease.

The invention still further relates to the pharmaceutical composition that contains these compounds, and these compounds and the purposes of composition in prevention or caused this class disease for the treatment of orexin receptor.

Detailed Description Of The Invention

The present invention relates to formula I compound:

Wherein:

R ¹be phenyl, described phenyl is by R ^1a, R ^1band R ^1creplace;

R ²be heteroaryl, described heteroaryl is by R ^2a, R ^2bor R ^2creplace;

R ^1a, R ^1b, R ^1c, R ^2a, R ^2band R ^2cindependently selected from:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4)-(C=0) _m-O _n-C _1-6alkyl, wherein m be 0 or 1, n be 0 or 1 (if wherein m be 0 or n be 0, have a key), adjacent R wherein ^2aand R ^2bperhaps R ^2band R ^2ccan be combined together to form cycloalkyl or cycloalkyloxy ring, and wherein alkyl is unsubstituted or by one or more R of being selected from ¹³substituting group replace,

(5)-(C=O) _m-O _n-C _3-6cycloalkyl, wherein cycloalkyl is unsubstituted or by one or more R of being selected from ¹³substituting group replace,

(6)-(C=O) _m-C _2-4thiazolinyl, wherein thiazolinyl is unsubstituted or by one or more R of being selected from ¹³substituting group replace,

(7)-(C=O) _m-C _2-4alkynyl, wherein alkynyl is unsubstituted or by one or more R of being selected from ¹³substituting group replace,

(8)-(C=O) _m-O _n-phenyl or-(C=O) _m-O _n-naphthyl, wherein phenyl or naphthyl is unsubstituted or by one or more R of being selected from ¹³substituting group replace,

(9)-(C=O) _m-O _n-heterocycle, wherein heterocycle is unsubstituted or by one or more R of being selected from ¹³substituting group replace,

(10)-(C=O) _m-NR ¹⁰r ¹¹, R wherein ¹⁰and R ¹¹independently selected from:

(a) hydrogen,

(b) C _1-6alkyl, described alkyl is unsubstituted or by one or more R of being selected from ¹³substituting group replace

(c) C _3-6thiazolinyl, described thiazolinyl is unsubstituted or by one or more R of being selected from ¹³substituting group replace,

(d) cycloalkyl, described cycloalkyl is unsubstituted or by one or more R of being selected from ¹³substituting group replace,

(e) phenyl, described phenyl is unsubstituted or by one or more R of being selected from ¹³substituting group replace, and

(f) heterocycle, described heterocycle is unsubstituted or by one or more R of being selected from ¹³substituting group replace,

(11)-S (O) ₂-NR ¹⁰r ¹¹,

(12)-S (O) _q-R ¹², wherein q is 0,1 or 2, and R wherein ¹²be selected from R ¹⁰and R ¹¹definition,

(13)-CO ₂h,

(14)-CN,

(15)-NO ₂,

(16)=O, and

(17)-B (OH) ₂,

Condition is R ^2a, R ^2bor R ^2cin one be halogen or C _1-6alkyl, or adjacent R wherein ^2aand R ^2bperhaps R ^2band R ^2cbe joined together to form cycloalkyl or cycloalkyloxy ring, wherein alkyl, cycloalkyl or cycloalkyloxy are unsubstituted or by one or more R of being selected from ¹³substituting group replace;

R ³be-C _1-6alkyl or-C _3-6cycloalkyl, described group is unsubstituted or by one or more R of being selected from ¹³substituting group replace;

R ¹³be selected from:

(1) halogen,

(2) hydroxyl,

(3)-(C=O) _m-O _n-C _1-6alkyl, wherein alkyl unsubstituted or by one or more R that are selected from ¹⁴substituting group replace,

(4)-O _n-(C _1-3) perfluoroalkyl,

(5)-(C=O) _m-O _n-C _3-6cycloalkyl, wherein cycloalkyl is unsubstituted or by one or more R of being selected from ¹⁴substituting group replace,

(6)-(C=O) _m-C _2-4thiazolinyl, wherein thiazolinyl is unsubstituted or by one or more R of being selected from ¹⁴substituting group replace,

(7)-(C=O) _m-O _n-phenyl or-(C=O) _m-O _n-naphthyl, wherein phenyl or naphthyl is unsubstituted or by one or more R of being selected from ¹⁴substituting group replace,

(8)-(C=O) _m-O _n-heterocycle, wherein heterocycle is unsubstituted or by one or more R of being selected from ¹⁴substituting group replace,

(9)-(C=O) _m-NR ¹⁰r ¹¹,

(10)-S (O) ₂-NR ¹⁰r ¹¹,

(11)-S (O) _q-R ¹²,

(12)-CO ₂h,

(13)-CN,

(14)=O, and

(15)-NO ₂;

R ¹⁴be selected from:

(1) hydroxyl,

(2) halogen,

(3) C _1-6alkyl,

(4)-C _3-6cycloalkyl,

(5)-O-C _1-6alkyl,

(6)-O (C=O)-C _1-6alkyl,

(7)-NH-C _1-6alkyl,

(8) phenyl,

(9) heterocycle,

(10)-CO ₂h, and

(11)-CN;

Perhaps its pharmacologically acceptable salt.

One embodiment of the invention comprise formula Ia compound:

R wherein ¹, R ²and R ³as defined herein; ; Perhaps its pharmacologically acceptable salt.

One embodiment of the invention comprise formula Ib compound:

One embodiment of the invention comprise formula Ic compound:

R wherein ^1a, R ^1b, R ^1c, R ²and R ³as defined herein; Perhaps its pharmacologically acceptable salt.

One embodiment of the invention comprise formula Id compound:

R wherein ^1a, R ^1b, R ^1cand R ²as defined herein; Perhaps its pharmacologically acceptable salt.

One embodiment of the invention comprise formula Ie compound:

One embodiment of the invention comprise wherein R ¹be the compound of phenyl, described phenyl is unsubstituted or is selected from following group and replaces by one or more:

(1) halogen,

(2) hydroxyl,

(3)-O _n-C _1-6alkyl, wherein n is 0 or 1 (if wherein n is 0, having a key), and wherein alkyl is unsubstituted or by one or more R of being selected from ¹³substituting group replace,

(4)-O _n-phenyl, wherein phenyl is unsubstituted or by one or more R of being selected from ¹³substituting group replace,

(5)-heterocycle, wherein heterocycle is unsubstituted or by one or more R of being selected from ¹³substituting group replace,

(6)-NR ¹⁰r ¹¹, R wherein ¹⁰and R ¹¹independently selected from:

(a) hydrogen,

(b) C _1-6alkyl, described alkyl is unsubstituted or by one or more R of being selected from ¹³substituting group replace,

(7)-S (O) ₂-NR ¹⁰r ¹¹,

(8)-CO ₂h,

(9)-CN,

(10)-NO ₂, and

(11)-B (OH) ₂.

One embodiment of the invention comprise wherein R ¹be the compound of phenyl, described phenyl is unsubstituted or is replaced by one or more following groups: methyl ,-CF ₃, halogen ,-OCF ₃,-OCH ₃,-OCH ₂cH ₃,-CO ₂cH ₃,-CN ,-N (CH ₃) ,-NH (CH ₂cH ₃) ,-NO ₂,-B (OH) ₂, triazolyl or phenyl.

One embodiment of the invention comprise wherein R ¹be the compound of phenyl, described phenyl is unsubstituted or is replaced by one or more following groups: methyl ,-CF ₃, chlorine, fluorine ,-OCF ₃,-OCH ₃,-OCH ₂cH ₃,-CO ₂cH ₃,-B (OH) ₂, triazolyl or phenyl.

One embodiment of the invention comprise wherein R ¹¹be the compound of phenyl, described phenyl is unsubstituted or is replaced by one or more following groups: methyl ,-CF ₃, fluorine ,-OCF ₃,-OCH ₃,-CO ₂cH ₃,-B (OH) ₂, triazolyl or phenyl.

One embodiment of the invention comprise wherein R ¹¹the compound that is selected from following groups:

(1) phenyl,

(2) xenyl,

(3) 2,6-Dimethoxyphenyls,

(4) 2,4 dichloro benzene base,

(5) 2,6-dichlorophenyls,

(6) 2,3-difluorophenyls,

(7) 2,4 difluorobenzene base,

(8) 2,6-difluorophenyls,

(9) 2-methoxyl group-4-methyl-phenyl,

(10) 3-methoxyl group-xenyl,

(11) 3-methyl-xenyl, and

(12) 5-methyl-2-triazolyl-phenyl.

One embodiment of the invention comprise wherein R ¹be the compound of phenyl, described phenyl is unsubstituted or is replaced by one or more methyl or triazolyl.One embodiment of the invention comprise wherein R ¹it is the compound of triazolyl phenyl or triazolyl (methyl) phenyl.One embodiment of the invention comprise wherein R ¹it is the compound of 5-methyl-2-triazolyl-phenyl.

One embodiment of the invention comprise wherein R ²be the compound of heteroaryl, described heteroaryl is unsubstituted or is replaced by one or more following groups:

(1) halogen,

(2) hydroxyl,

(3)-O _n-C _1-6alkyl, wherein n is that 0 or 1 (if wherein n is 0, having a key) and alkyl are unsubstituted or by one or more R of being selected from ¹³substituting group replace,

(6)-NR ¹⁰r ¹¹, R wherein ¹⁰and R ¹¹independently selected from:

(a) hydrogen,

(7)-S (O) ₂-NR ¹⁰r ¹¹,

(8)-CO ₂h,

(9)-CN, and

(10)-NO ₂,

Condition is at least one substituting group halogen or C _1-6alkyl, or wherein two adjacent substituting groups are joined together to form cycloalkyl ring.

One embodiment of the invention comprise wherein R ²be the compound of heteroaryl, described heteroaryl is by halogen or C _1-6alkyl replaces, and optionally by hydroxyl ,-O-C _1-6alkyl or phenyl replaces.

One embodiment of the invention comprise wherein R ^2a, R ^2band R ^2cin one be halogen or C _1-6alkyl, and R ^2a, R ^2band R ^2cin other two are compounds of hydrogen.Within this embodiment, the present invention includes wherein R ^2a, R ^2band R ^2cin one be chlorine, fluorine or methyl, and R ^2a, R ^2band R ^2cin other two are compounds of hydrogen.One embodiment of the invention comprise wherein R ^2a, R ^2band R ^2cin two be joined together to form C _1-6alkyl ring, and R ^2a, R ^2band R ^2cin other are compounds of hydrogen.Within this embodiment scheme, the present invention includes wherein R ^2a, R ^2band R ^2cbe joined together to form the C replaced by=O _1-6alkyl ring, and R ^2a, R ^2band R ^2cin other are compounds of hydrogen.

One embodiment of the invention comprise wherein R ²be selected from the compound of following group:

(1) benzimidazolyl-,

(2) benzothiazolyl,

(3) benzoxazolyls,

(4) cyclopentyl pyrimidyl,

(5) dihydro cyclopenta pyrimidyl,

(6) dihydroquinoline base,

(7) furo pyrimidyl,

(8) pyrazolopyrimidine base,

(9) pyridyl,

(10) Pyridopyrimidine base,

(11) pyrimidyl,

(12) quinazolyl,

(13) quinolyl,

(14) quinoxalinyl,

(15) tetrahydro quinazoline base,

(16) thiadiazolyl group, and

(17) Thienopyrimidine base,

Described group is by halogen or C _1-6alkyl is obtained, and optionally by hydroxyl ,-O-C _1-6alkyl, ketone group ,-NH ₂or phenyl replaces.

(1) 1,3-benzoxazole-2-base,

(2) 2-(6,7-dihydro-5H-cyclopenta [d] pyrimidine)-Ji,

(3) 2-(7,8-dihydroquinoline-5 (6H)-one)-Ji,

(4) 2-(furo [2,3] pyrimidine)-Ji,

(5) 2-(pyrazolo [3,4] pyrimidine)-Ji,

(6) 2-pyridyl,

(7) 2-(pyrido [2,3-d] pyrimidine-7 (8H)-one)-Ji,

(8) 2-pyrimidyl,

(9) 2-quinazolyl,

(10) 2-quinoxalinyl,

(11) 2-(5,6,7,8-tetrahydro quinazoline)-Ji,

(12) 2-(thieno-[2,3-d] pyrimidine)-Ji, and

(13) 2-(thieno-[2,3] pyrimidine-4-amine)-Ji,

Described group is replaced by methyl, chlorine or fluorine.

(1) 1,3-benzoxazole-2-base,

(2) 2-pyrimidyl,

(3) 2-quinazolyl,

(4) 2-quinoxalinyl, and

(5) 2-(thieno-[2,3] pyrimidine-4-amine)-Ji,

Described group is replaced by methyl, chlorine or fluorine.

One embodiment of the invention comprise wherein R ²be the compound of benzoxazolyl, described benzoxazolyl is replaced by methyl, chlorine or fluorine.

One embodiment of the invention comprise wherein R ²be the compound of pyrimidyl, described pyrimidyl is replaced by methyl, chlorine or fluorine.

One embodiment of the invention comprise wherein R ²the compound of quinazolyl, described quinazolyl is replaced by methyl, chlorine or fluorine.

One embodiment of the invention comprise wherein R ²be the compound of quinoxalinyl, described quinoxalinyl is replaced by methyl, chlorine or fluorine.

One embodiment of the invention comprise wherein R ²be the compound of (thieno-[2,3] pyrimidine-4-amine)-Ji, described (thieno-[2,3] pyrimidine-4-amine)-Ji is replaced by methyl, chlorine or fluorine.

One embodiment of the invention comprise wherein R ²it not the compound of the chloro-benzothiazolyl of 6-.

One embodiment of the invention comprise wherein R ³be-C _1-6the compound of alkyl, described-C _1-6alkyl is unsubstituted or by one or more R of being selected from ¹³substituting group replace.

One embodiment of the invention comprise wherein R ³be-C _1-6the compound of alkyl, described-C _1-6alkyl is unsubstituted or is selected from following group and replaces by one or more:

(1) halogen,

(2) hydroxyl,

(3)-C _1-6alkyl,

(4)-(C _1-3) perfluoroalkyl,

(5)-O-(C _1-3) perfluoroalkyl,

(6)-C _3-6cycloalkyl, and

(7)-C _2-4thiazolinyl.

One embodiment of the invention comprise wherein R ³be-C _1-6the compound of alkyl.Within this embodiment, the present invention includes wherein R ³be selected from the compound of following group: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl and hexyl.In this embodiment, the present invention includes wherein R ³be selected from the compound of methyl.

The specific embodiment of the invention scheme comprises target compound or its pharmacologically acceptable salt that is selected from this paper embodiment.

Therefore compound of the present invention can comprise one or more asymmetric centers and can exist with the form of racemic modification and racemic mixture, single enantiomer, non-enantiomer mixture and independent diastereomer.Also other asymmetric center can occur, this depends on each substituent attribute on molecule.Each such asymmetric center will produce two kinds of optical isomers independently, and all possible optical isomer and non-corresponding isomer mixture and pure or partial-purified compound all will be included within the scope of the present invention.The present invention means all such isomeric form that has comprised these compounds.Formula I has shown the structure of this compounds, does not show concrete stereochemistry.

As known in the art, separately synthetic of these non-corresponding isomer or their chromatographic separation, can be by the disclosed method of the application through suitably improving and realize.Their absolute steric configuration can pass through produced crystallized product or if necessary, the x-ray crystalline diffraction that derives the crystallization of intermediate formed with the reagent that comprises known absolute configuration asymmetric center is determined.If necessary, thus racemic mixture that can separating compound obtains independent enantiomorph.Described separation can be carried out by means commonly known in the art, for example by the racemic mixture of compound and enantiomorphous pure compound coupling to form the mixture of diastereomer, then by standard methods such as fractional crystallization or chromatography, separate independent diastereomer.Coupling reaction is often to use the acid of enantiomer-pure or alkali to form salt.By removing added chirality residue, then the diastereomer derivative can be transformed into pure enantiomorph.The racemic mixture of compound also can directly separate by the chromatographic process of using chiral stationary phase, and the method is known in the field.Or, with the reagent of optically pure starting raw material or configuration known, through method well known in the art, can the synthetic any enantiomorph that obtains compound of stereoselectivity.

As is known to the person skilled in the art, halogen used herein or halo comprise fluorine, chlorine, bromine and iodine.Similarly, C _1-6, as at C _1-6in alkyl, be defined as the straight or branched group of 1,2,3,4,5 or 6 carbon, thus C _1-8alkyl specifically comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, amyl group and hexyl.Being defined as being substituted the group that base replaces independently can be replaced independently by a plurality of such substituting groups.Term as used herein " heterocycle " comprises unsaturated and saturated heterocycle fragment, and wherein unsaturated heterocycle fragment (i.e. " heteroaryl ") comprises benzimidazolyl-, the benzoglyoxaline ketone group, benzofuryl, the benzofuraxan base, the benzopyrazoles base, the benzotriazole base, benzothienyl, benzoxazolyl, carbazyl, carbolinyl, the cinnolines base, furyl, imidazolyl, indolinyl, indyl, indenes piperazine base, indazolyl, isobenzofuran-base, pseudoindoyl, isoquinolyl, isothiazolyl, isoxazolyl, the naphthopyridine base, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyrazinyl, pyrazolyl, pyridazinyl, the pyridopyridine base, pyridazinyl, pyridyl, pyrimidyl, pyrryl, quinazolyl, quinolyl, quinoxalinyl, tetrazyl, the tetrazolium pyridyl, thiadiazolyl group, thiazolyl, thienyl, triazolyl and N-oxygen compound thereof, and wherein saturated heterocycle fragment comprises azetidinyl, Isosorbide-5-Nitrae-dioxane base, six hydrogen azepines

base, piperazinyl, piperidyl, pyridin-2-ones base, pyrrolidyl, morpholinyl, tetrahydrofuran base, thio-morpholinyl and tetrahydro-thienyl and N-oxide compound thereof.

Term " pharmacologically acceptable salt " refers to that described alkali or acid comprise inorganic or organic bases and inorganic or organic acid by pharmaceutically acceptable nontoxic alkali or the salt of acid preparation.The salt that is derived from mineral alkali comprises aluminium, ammonium, calcium, copper, iron, ferrous iron, lithium, magnesium, manganic salt, bivalent manganese, potassium, sodium, zinc etc.Particularly preferably be ammonium, calcium, magnesium, potassium and sodium salt.The salt of solid form can more than one crystalline structure exist, can also be the form of hydrate.The salt that is derived from pharmaceutically acceptable organic nontoxic alkali comprises primary, the second month in a season and tertiary amine, replace amine and comprise naturally occurring replacement amine, cyclammonium and Zeo-karb, arginine for example, trimethyl-glycine, caffeine, choline, N, N '-dibenzyl-ethylenediamin, diethylamine, 2-diethylaminoethanol, DMAE, thanomin, quadrol, N-ethyl-morpholine, N-ethylpiperidine, glycosamine, glucosamine, Histidine, breathe out amine (hydrabamine), Isopropylamine, Methionin, methylglucosamine, , morpholine, piperazine, piperidines, versamid 900, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, trometamol etc.

When compound of the present invention is alkalescence, salt can, by pharmaceutically acceptable non-toxic acid preparation, comprise inorganic and organic acid.Such acid comprises acetic acid, Phenylsulfonic acid, M-nitro benzoic acid, camphorsulfonic acid, citric acid, ethyl sulfonic acid, FUMARIC ACID TECH GRADE, gluconic acid, L-glutamic acid, Hydrogen bromide, hydrochloric acid, hydroxyethylsulfonic acid, lactic acid, toxilic acid, oxysuccinic acid, mandelic acid, methylsulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succsinic acid, sulfuric acid, tartrate, tosic acid etc.Particularly preferably be citric acid, Hydrogen bromide, hydrochloric acid, toxilic acid, phosphoric acid, sulfuric acid, FUMARIC ACID TECH GRADE and tartrate.Should be appreciated that as used in this application, while mentioning the compound of formula I, mean and also comprise pharmacologically acceptable salt.

With embodiment and the present invention of the disclosed compound illustration of the application.Particular compound in the present invention comprises compound and its pharmacy acceptable salt and the independent diastereomer thereof be selected from the disclosed compound of following examples.

Target compound can be for the method for antagonism patient's orexin receptor activity, and described patient for example needs the Mammals suppressed like this, and described method comprises with this compound of significant quantity carries out administration.The present invention relates to the purposes of the disclosed compound of the application as the active antagonist of orexin receptor.Except primate especially people, various other Mammalss also can be treated according to method of the present invention.The present invention relates to the compounds of this invention or the application of its pharmacologically acceptable salt in medicine.The invention still further relates to the compounds of this invention active for the preparation of antagonism orexin receptor in humans and animals or treat the method for the medicine of obstacle described herein and disease.

The individuality for the treatment of in present method is Mammals normally, the mankind for example, sex.Term " treatment significant quantity " refers to the amount of the target compound of induce tissue that the amount of target compound will cause researchist, animal doctor, doctor or other clinician and look for, system, animal or human's biology or medicinal response.Will be appreciated that those skilled in the art treat and suffer from present the patient of this obstacle or prophylactically treat the patient who suffers from this obstacle and can exert an influence to nervosa and spirituality obstacle by the compounds of this invention that uses significant quantity.As used in this application, term " treatment " refers to all methods that can slow down, interrupt, be detained, control or stop the described nervosa of the application and the development of spirituality obstacle, but the symptom that not necessarily means all obstacles all disappears, it also comprises the prophylactic treatment to described symptom, especially in the patient who easily suffers from such disease or obstacle.Term compound " administration " and " giving " compound should be understood to provide to its individuality of needs the prodrug of compound of the present invention or the compounds of this invention.Will be appreciated that those skilled in the art treat and suffer from present the patient of this obstacle or prophylactically treat the patient who suffers from this obstacle and can exert an influence to nervosa and spirituality obstacle by the compounds of this invention that uses significant quantity.As Ben Benwen is used, term " treatment " refers to all progress that can slow down, interrupt, stop, control or stop nervosa described herein and spirituality obstacle, but the symptom that not necessarily means all obstacles all disappears, it also comprises the prophylactic treatment to described symptom, especially in the patient who easily suffers from such disease or obstacle.Term compound " administration " and " giving " compound should be understood to there being this individuality needed that the prodrug of compound of the present invention or the compounds of this invention is provided.

Term " composition " refers to the product that comprises the predetermined component that comprises specified amount as used in this application, and the combination of the predetermined component of specified amount the spawn that produces directly or indirectly.The connotation of this term relevant to pharmaceutical composition comprises the product that comprises activeconstituents (single or a plurality of) and form the inert fraction (single or a plurality of) of carrier, and by any two or more compositions mixing, compound or gathering, perhaps by one or more compositions, decomposed, or the spawn directly or indirectly produced by the reaction of the other types of one or more compositions or interaction.Therefore, pharmaceutical composition of the present invention comprises by the compounds of this invention is mixed to any composition prepared with pharmaceutically acceptable carrier.Term " pharmaceutically acceptable " meaning be carrier, thinner or excipient must with formulation in other composition compatible and be harmless to its recipient.

The compounds of this invention can be easily definite by means commonly known in the art as the effectiveness of orexin receptor OX1R and/or OX2R antagonist, and do not need to carry out excessive test, and method comprises " FLIPR Ca ²⁺flow test " (people such as Okumura, Biochem.Biophys.Res.Comm.280:976-981,2001).In a typical experiment, the OX1 of the compounds of this invention and OX2 receptor antagonist activity are according to following determination of experimental method.Mensuration for intracellular Ca2+, Chinese hamster ovary (CHO) cell of expressing rat orexin-1 acceptor or people's appetite plain-2 acceptor is cultivated in the improved DMEM of Iscove, and described DMEM contains 2mML-glutamine, 0.5g/ml G418,1% xanthoglobulin-thymidine supplement, the penicillin of 100U/ml, Streptomycin sulphate and the 10% heat-killed foetal calf serum (FCS) of 100ug/ml.This cell is seeded in the Becton-bis-ckinson black 384 hole clear bottom sterile plate that scribble poly--D-Lys with the amount of 20,000 cells/well.All reagent all comes from GIBCO-Invitrogen company.The inoculation plate is at 37 ℃ and 5%CO ₂lower hatching is spent the night.Ala-6 as agonist, 12 people's orexin-As are prepared to the 1mM stock solution containing 1% bovine serum albumin (BSA), and be diluted to the ultimate density of the 70pM used in test with test damping fluid (HBSS, the pH7.4 that comprise 20mM HEPES, 0.1%BSA and 2.5mM probenecid).Test compounds is prepared into the 10mM stock solution with DMSO, then in the 384-orifice plate, dilutes, and at first uses DMSO, then with the test damping fluid.Test same day, test the damping fluid washed cell 3 times with 100 μ l, in the test damping fluid that then at 60 μ l, contains 1 μ M Fluo-4AM ester, 0.02%pluronic acid and 1%BSA, hatch 60min (37 ℃, 5%CO ₂).Then sucking-off is loaded with the solution of dyestuff, and tests the damping fluid washed cell 3 times with 100ul.The identical damping fluid of 30 μ l is stayed in each hole.In fluorescence imaging plate reader (FLIPR, MolecularDevices), add test compounds with the volume of 25 μ l in plate, hatch 5 minutes, finally add 25 μ l agonists.With the fluorescence in each hole of interval measurement of 1 second 5 minutes, by the height of each fluorescence peak with replace the 70pM Ala-6 of antagonist with damping fluid, the height of the fluorescence peak that 12 orexin-As cause compares.Determine the IC50 value (concentration that suppresses the needed compound of 50% exciting response) of every kind of antagonist.Can measure the inherent orexin receptor antagonists activity of the compound can be used in the present invention by these tests.

Especially, the compound of following examples has the activity of antagonism rat orexin-1 acceptor and/or people's appetite plain-2 acceptor in above-mentioned test, usually has and is less than the approximately IC of 50 μ M ₅₀.In the present invention, preferred compound has the activity of antagonism rat orexin-1 acceptor and/or people's appetite plain-2 acceptor, the IC had in above-mentioned test ₅₀be less than about 100nM.Such result is the embodiment as the compound intrinsic activity of orexin-1 acceptor and/or orexin-2 receptor antagonist.The present invention also is included in general range of the present invention the compound had as the activity of orexin-1 acceptor and/or orexin-2 receptor stimulant.About other diazepan compounds, the compounds of this invention demonstrates beyond thought characteristic, for example about oral administration biaavailability, metabolic stability, the time-dependent improved, suppresses and/or with respect to the selectivity of other acceptors.

Want plain acceptor and be considered to relevant with the various biological function.This points out these acceptors may play a role in the various diseases process of people or other species.The compounds of this invention has treatment, prevents, improves, controls and reduces the various nervosas relevant to orexin receptor and the effect of spirituality obstacle risk, comprise one or more following symptom or diseases: somnopathy, sleep is chaotic, comprise the raising sleep quality, improve sleep quality, increase Sleep efficiency, increase sleep and continue; The resulting value of Time Calculation of sleep is attempted in increase divided by object by object length of one's sleep; Improving sleep starts; Reduce sleep latent period or initial (entering the time that sleep spends); Reduce the difficulty that enters sleep; Increase the sleep continuity; Reduce the number of times of waking up between sleep period; Reduce intermittent waking up between sleep period; Reduce the awakening at night; Reduce after sleep starts at first the time waken; Increase the total amount of sleep; Reduce the interruption of sleep; Change timing, frequency or the time length of REM sleep cycle; Change time, the frequency of slow wave (i.e. 3 or 4 phases) sleep cycle or continue; Increase the number and percentage of 2 phases sleep; Promote slow wave sleep; Improve EEG-δ activity between sleep period; Reduce night and wake up with a start, especially wake up with a start early morning; Increase vigilance in the daytime; Reduce sleepiness in the daytime; The daytime sleepiness for the treatment of or minimizing transition; The satisfaction of increase to sleep intensity; Increasing sleep maintains; The idiopathic insomnia; Sleeping problems; Insomnia, hypersomnia, idiopathic hypersomnia, reproducibility hypersomnia, intrinsic hypersomnia, narcolepsy, interruptibility sleep, sleep apnea, awakening, nocturnal myoclonus, REM interruptions of sleep, the jet flight jet lag, break tour workman property sleep confusion, somnopathy, sleep terror fright at night, with depression, mood/affective disorder, the insomnia that Alzheimer or cognitive impairment are relevant, and sleep-walking and the enuresis, and astogeny with somnopathy; The Alzheimers sundown syndrome; The symptom relevant with day-night rhythm and with moving through time zone the obstacle of the mind & body relevant with the shift work time, the symptom that the medicine that causes the REM sleep to reduce as side effect produces; Fibromyalgia; Show as expendable sleep and myalgia or the syndrome of the sleep apnea relevant with dyspnoea between sleep period; The symptom that descends and produce by sleep quality; The disturbance of food intake relevant with excessive food intake and complication related to this, the mandatory disturbance of food intake, fat (due to any reason, no matter heredity or environment), fat relevant obstacle comprises hyperphagia and Bulimia nerovsa neurosis, hypertension, diabetes, the plasma insulin concentration and the insulin resistant degree that raise, metabolism disorder of blood lipid, Lipid is too much, uterine endometrium, breast, prostate gland and colorectal carcinoma.Osteoarthritis, obstructive sleep apnea, chololithiasis, cholelithiasis, heart trouble, irregular and the irregular pulse of heart rhythm, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, apoplexy, polycystic ovary disease, craniopharyngioma, Prader-Willi syndrome, hypophyseal syndrome, the main body that GH-lacks, general stature is short and small, Turner's syndrome, and other pathology symptom, its metabolic activity or conduct that shows as reduction always reduces without the rest energy expenditure of lipid amount per-cent, for example, children acute lymphocytoblast leukemia, metabolic syndrome, have another name called X syndrome, insulin resistant syndrome, reproductive hormone is abnormal, property and regenerative function obstacle, the reproductive performance for example weakened, infertile, hypogonadism in the male sex and the hirsutism in the women, the Fetal Defects relevant to maternal obesity, the gastrointestinal peristalsis obstacle, fat relevant stomach oesophagus adverse current for example, dyspnoea, fat hypoventilation syndrome (Pickwickian syndrome) for example, expiratory dyspnea, cardiovascular disorder, inflammation, the system inflammation of vascular structure for example, arteriosclerosis, hypercholesterolemia, hyperuricemia, pain in the back, cholecystopathy, gout, kidney, the anesthetic risks increased, reduce the risk of fat secondary consequence, for example reduce the risk of left ventricular hypertrophy, in brain, the disease of the indefinite activity of abnormal or obstacle, comprise depression, migraine, and neuropathic pain, Parkinson's disease, psychosis and schizophrenia, and disease or obstacle with unusual combining movement, particularly by ganglion cerebral, the cognitive function of strengthening, strengthen memory, increasing memory retains, increase immune response, increase immunologic function, hectic fever, night sweat, prolongs life, schizophrenia, the excitement caused by neural system/lax the rhythm obstacle relevant to muscle and other cardiovascular systems obstacle that for example the rhythm of the heart is controlled, with cell proliferation for example vasorelaxation or the vasoconstriction symptom relevant with blood pressure, cancer, irregular pulse, hypertension, congestive heart failure, reproduction/urinary system symptom, sexual function and growing barrier, renal function is abundant, to narcotic responsiveness, emotional handicap, for example depression or oppressive obstacle more specifically, such as, severe type dysthymia disorders and the dysthymic disorder of single episode or recurrent, perhaps two-phase obstacle, two-phase I type obstacle for example, two-phase II type obstacle and cyclothymic temperament obstacle, the emotional handicap caused due to the general symptoms of internal disease, and the emotional handicap that causes of material, anxiety disorder comprises acute stress disorder, agoraphobia, generalized anxiety disorder, obsession, panic attack, paranoid fears, stress disorders after wound, separation anxiety obstacle, social phobia, specific phobia disease, the anxiety that the anxiety disorder that material causes and general medicine symptom produce, acute nerve and mental disorder be heart bypass operation and transplanting for example, apoplexy, and ishemic stroke, cerebral ischemia, trauma of spinal cord, injury of head, term, heartbeat stopped for hypoxgia, the brain function disappearance after hypoglycemic nervosa damage, huntington's chorea, amyotrophic lateral sclerosis, multiple sclerosis, ocular damage, retinopathy, cognitive disorder, idiopathic and drug-induced Parkinson's disease, muscle spasm and trembling with comprising, epilepsy, convulsions waits the relevant obstacle of muscle spasm, cognitive disorder comprises that dementia is (with Alzheimer, local asphyxia, wound, vascular problem or apoplexy, the HIV disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, term, the symptoms of internal disease that other is general or substance abuse were correlated with for hypoxgia), psychiatric disorder, the cognition of lethe obstacle or age-dependent descends, schizophrenia or psychosis comprise that schizophrenia is (paranoid, confusion, tonus or do not divide voltinism), schizophreniform obstacle, schizoaffective disorder, delusional disorder, of short duration mental disorder, total psychotic disease mental disorder, due to the mental disorder of general internal medicine situation generation and the mental disorder that material causes, the obstacle that material is relevant and Addictive Behaviors (comprise the psychiatric disorder that material causes, persistence dementia, persistence lethe obstacle, mental disorder or anxiety disorder, to comprising alcohol, Amphetamine, hemp, cocaine, fantasy, inhalation, nicotine, opioid, the own piperidines of ring benzene, tranquilizer, the material tolerance of soporific or antianxiety agent, rely on or give up), dyskinesia, comprise that the stiff syndrome of can not moving and can not move (comprises Parkinson's disease, drug-induced parkinson's syndrome, postencephalitic parkinsonism, on carrying out property core, benumb, the multisystem atrophy, corticobasal degeneration, the dull-witted complex disease of parkinson's syndrome ALS and basal ganglion calcification), chronic fatigue syndrome, tired, comprise Parkinson fatigue, multiple sclerosis fatigue, the fatigue caused by somnopathy and day-night rhythm obstacle, drug-induced parkinson's syndrome (the parkinson's syndrome that for example tranquilizer causes, the psychosis malin syndrome, the acute dystonia that psychosis causes, acute the cathisophobiaing that tranquilizer causes, the tardive dyskinesia that tranquilizer causes and drug-induced postural tremor), Gilles de la Tourette syndrome, epilepsy and dyskinesia [comprise vibration (for example static vibration, spontaneous vibration, posture vibration and Intentionality vibration), tarantism (Xi Denghamushi (Sydenham) tarantism for example, Huntington's disease, optimum Huntington's chorea, the nervous system type acanthocytosis, symptomatic chorea, drug-induced tarantism and hemiballismus), myoclonus (comprising popularity myoclonus and focal myoclonus), twitch and (comprise single tic, the complicated tic and symptomatic tic), restless leg syndrome and myodystonia (comprise for example idiopathic myodystonia of popularity myodystonia, drug-induced myodystonia, symptomatic myodystonia and paroxysmal myodystonia, with focal myodystonia blepharospasm for example, oral cavity mandibular bone myodystonia, dysphonia spastica, spasmodic torticollis, axial myodystonia, myodystonia writer's cramp and hemiplegia myodystonia), Sheng obstacle (ADHD) is crossed in attention-deficient/activity, conduct disorder, migraine (comprising the migraine headache), the urinary incontinence, material tolerance, material is given up and (is comprised opiate for example, nicotine, tobacco product, alcohol, benzodiazepine

, cocaine, tranquilizer, the material of soporific etc.), psychosis, schizophrenia, anxiety (comprising generalized anxiety disorder, paranoid fears and obsession), emotional handicap (comprise depression, manic, the two-phase obstacle), trigeminal neuralgia, hearing loss, tinnitus, nerve injury comprises ocular damage, retinopathy, the macular degeneration of eyes, vomiting, cerebral edema, pain, comprise acute and chronic pain state, serious pain, intractable pain, inflammatory pain, neuropathic pain, pain after wound, bone and arthralgia (osteoarthritis), recurrent motion pain, dental pain, cancer pain, muscular fascia pain (muscle injury, fibromyalgia), perioperative pain (general surgery, gynaecology's property), chronic pain, neuropathic pain, pain after wound, trigeminal neuralgia, migraine and migraine headache.

Therefore, in specific embodiment, the invention provides following methods is provided in this mammalian subject needed is arranged: improve sleep quality; Increase the sleep maintenance; Increase the REM sleep; Increase the sleep of 2 phases; Reduce the sleep fracture; Cure for insomnia; Improve cognitive; Increasing memory retains; Treatment or obesity controlling; Treatment or control are depressed; The risk for the treatment of, control, improvement or minimizing epilepsy, comprise epilepsy do not occur; Treatment or control pain, comprise neuropathic pain; Treatment or control Parkinson's disease; Treatment or control psychosis; Perhaps treat, control, improve or reduce schizoid risk, described method comprises to the compounds of this invention of patient's drug treatment significant quantity.

Target compound is also for preventing, treat, control, improve or reduce the method for disease described herein, obstacle and symptom risk.In the present composition, the dosage of active ingredient can change, and still, the amount of active ingredient must be the amount that can obtain appropriate dosage forms.Active ingredient can be with dosed administration that optimal drug effect is provided in the patient (animal and human) of this treatment of needs.Selected dosage depends on the result for the treatment of of expectation, depends on route of administration and treatment time length.Dosage will be different with the patient, and this depends on attribute and severity, patient's weight, patient's concrete diet, the medicine simultaneously used and the other factors it will be recognized by those skilled in the art of disease.Usually, with every day 0.0001, to the dosage level between the 10mg/kg body weight to the patient, for example people and the elderly's administration are to obtain the effective antagonistic action of orexin receptor.Dosage range is generally each patient's every day about 0.5mg to 1.0g, can single dose or the form administration of multi-agent.In one embodiment, dosage range is each patient's every day of about 0.5mg to 500mg; Be each patient's every day of about 0.5mg to 200mg in another embodiment; In going back another embodiment, be each patient's every day of about 5mg to 50mg.Pharmaceutical composition of the present invention can solid dosage provide, and described solid dosage comprises for example about 0.5mg to 500mg active ingredient, or comprises about 1mg to 250mg active ingredient.Pharmaceutical composition can solid dosage provide, and described solid dosage comprises about 1mg, 5mg, 10mg, 25mg, 50mg, 100mg, 200mg or 250mg active ingredient.For oral administration, composition can tablet form provide, described tablet contains 1.0 to 1000 milligrams of active ingredients, 1,5,10,15,20,25,50,75,100,150,200,250,300,400,500,600,750,800,900 and 1000 milligram of active ingredient for example, the adjustment of carrying out for the dosage of treated patient being taken according to symptom.This compound can every day 1 to 4 time, preferably the scheme administration of every day 1 time or 2 times.

The compounds of this invention can be combined and be used for the treatment of, prevents with one or more other medicines, controlling, improve or reduce the compounds of this invention or other medicines can be to the risk of the virtuous disease of its tool or symptom, wherein will be medication combined together than any independent medicine safety or effective more.Described other one or more medicines can be by its normally used approach and quantity and the compounds of this invention while or administration successively.When the compounds of this invention and one or more other medicines are used simultaneously, can consider to comprise the pharmaceutical composition of this other medicines and the compounds of this invention in unit dosage.But combination therapy also can comprise that the compounds of this invention and one or more other medicines show the treatment of administration with different overlapping time.When combining with one or more other active ingredients while using, also can consider that the compounds of this invention and other active ingredient dosage when using separately lower than every kind is used.Therefore, pharmaceutical composition of the present invention comprises the pharmaceutical composition that also comprises one or more other active ingredients except containing the compounds of this invention.Above-mentioned drug combination not only comprises the composition of the compounds of this invention and a kind of other active compound, and comprises the composition of itself and two or more active compounds.

Similarly, the compounds of this invention can with for prevention, treatment, control, improve or reduce the compounds of this invention the other medicines of its effective disease or symptom risk are combined to use.Described other medicines can be by its normally used approach and quantity and the compounds of this invention while or administration successively.When the compounds of this invention and one or more other medicines are used simultaneously, can consider also to contain the pharmaceutical composition of this other medicines except the compounds of this invention.Therefore, pharmaceutical composition of the present invention comprises the pharmaceutical composition that also contains one or more other active ingredients except containing the compounds of this invention.

The compound weight ratio of the compounds of this invention and the second active ingredient can change and depend on the effective dose of every kind of component.Usually, use the effective dose of every kind.Therefore, for example, when the compounds of this invention mixes with another kind of medicament, the weight ratio scope of the compounds of this invention and another kind of medicament is generally approximately 1000: 1 to approximately 1: 000, for example approximately arrives approximately 1: 200 at 200: 1.The mixture of the compounds of this invention and other active ingredient usually also in above-mentioned scope, but in each case, all should use the effective dose of every kind of active ingredient.In such mixture, the compounds of this invention and other promoting agent be administration or Combined Preparation respectively.In addition, a kind of administration of composition can be before the administration of other medicament (one or more), during or carry out afterwards.

The compounds of this invention can be used for effectively improving sleep quality prevention and treatment somnopathy and sleep disordered other compound Combined Preparation with well known in the art, described other compound for example comprises, tranquilizer, soporific, anxiolytic, antipsychotic drug, antianxiety agent, antihistaminic agent, benzodiazepine

, barbiturate(s), cyclopyrrole ketone, gaba agonist, the 5HT-2 antagonist comprises 5HT-2A antagonist and 5HT-2A/2C antagonist, histamine antagonist comprises histamine H 3 antagonists, histamine H 3 inverse agonists, imidazopyridine, minor tranquilizer, melatonin agonists and antagonist, fading element can agent, other orexin antagonists, the orexin agonist, prokinetic element (prokineticin) agonist and antagonist, pyrazolopyrimidine, T-shaped calcium-channel antagonists, Triazolopyridine etc., for example: adinazolam, allobarbital, alonimid, alprazolam, amitriptyline, Amobarbital, amoxapine, l-modafinil, APD-125, bentazepam, benzoctamine, brotizolam, Wellbutrin, buspirone, cloth tower veronal, the cloth tower is than appropriate, block not Rayleigh, capuride, carbocloral, somnalclor, Chloral Hydrate, zeisin, chlorimipramine, clonazepam, Domperidone, chlorine nitrogen

, Cloretate, leoponex, clonazepam, cyprazepam, desipramine, dexclamol, stable, Chloralsalicylamide, two valproic acids, benadryl, P-3693A, EMD-281014, Erie look woods, estazolam, Lunesta, ethyl .beta.-chlorovinyl ethynyl carbinol, sibul, fenobam, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, phosphorus is determined amine, Gaboxadol, rigenox, halazepam, hydroxyzine, ibutamoren, imipramine, indene, lithium, L0, lormetazepam, LY-156735, maprotiline, MDL-100907, mecloqualone, melatonin, promind, peaceful, turzolon, methyprylon, midaflur, the Dormicum, modafinil, nefazodone, NGD-2-73, nisobamate, surem, nortriptyline, oxazepan, paraaldehyde, paroxetine, Sodital, perlapine, trilafon, Phenelzine, phenylethyl barbituric acid, verstran

, promethazine, Rapinovet, protriptyline, Selepam, ramelteon, reclazepam, roletamide, secobarbital, Sertraline, suproclone, TAK-375, temazepam, thioridazine, tiagabine, tracazolate, Tranylcypromine, trazodone, triazole benzene phenodiazine, trepipam, trimethoxy ALPHA Tolylic acid amine, trichloroethyl phosphate, trifluoperazine, trimetozine, trimeproprimine, Uldazepam, Venlafaxine, Zaleplone, zolazepam, Zopiclone, pyrazoles is smooth, and salt and composition etc., perhaps the compounds of this invention can be combined the physical method that uses for example phototherapy or electricity irritation in administration.

In another embodiment, target compound can be combined with other compound known in the art, respectively administration or in same administered in pharmaceutical compositions, include but not limited to: insulin sensitizer comprises for example lattice row ketone (Ciglitazone for example of (i) PPAR γ antagonist; Darglitazone; Englitazone; Yi Shalie ketone (MMC-555); Pioglitazone; Rosiglitazone; Troglitazone; Tularik; BRL49653; CLX-0921; 5-BTZD), GW-0207, LG-100641, and LY-300512, etc.); (iii) biguanides, for example melbine and phenformin; (b) insulin or insulin analog, biota for example, LP-100, novarapid, insulin detemir, insulin lispro, sweet capital insulin, lente insulin (long-acting and super long effective); Lys-Pro insulin, GLP-1 (73-7) is (insulintropin); And GLP-1 (7-36)-NH ₂); (c) sulfonylurea, for example own urea of acetophenone sulphonyl; Chlorpropamide; Chlorpropamide; Glibenclamide; Glipizide; Glibenclamide; Glimepiride; Gliclazide; Glipentide; Gliquidone; Glisolamide; Tolazamide and orinase; (d) Alpha-glucosidase inhibitor, acarbose for example, adiposine, cargutocin; Emiglitate; Miglitol; Voigelibo; Paldimycin-Q; Salbostatin; CKD-711; MDL-25,637 and MOR 14 etc.; (e) cholesterol reducing agent, for example (i) HMG-CoA reductase inhibitor (Atorvastatin, itavastatin, Fluvastatin, Lovastatin, Pravastatin, rivastatin, relax and cut down his spit of fland, Simvastatin and other statins), (ii) cholic acid absorbent/chelating agent, for example cholestyramine, Colestipol, the dialkylaminoalkyl derivative of crosslinked dextran;

Etc., (ii) nicotinic alcohol, nicotinic acid or its salt, (iii) paraphyte activated receptor alpha agonists, for example Fenofibric Acid derivative (CI-719, clofibrate, fenofibrate and Bezafibrate), (iv) cholesterol absorption inhibitor, for example stanol ester, cupreol, steroline is Tiqueside for example; And azetidinone, ZETIA etc. for example, (acyl-CoA: cholesterol acyltransferase (ACAT)) inhibitor, for example avasimibe and AC-233, (v) antioxidant, two sulfo-propane for example, (vi) vitamin E, and (vii) thyromimetics; (f) PPAR alfa agonists, Beclobrate for example, Bezafibrate, ciprofibrate, Clofibrate, Etofibrate, fenofibrate and CI-719; And other fiber acid derivative, for example

With

Etc., and as the PPAR alfa agonists described in the WO 97/36579 of Glaxo; (g) PPAR delta agonists; (h) PPAR α/delta agonists; For example muraglitazar, and US 6,414, the compound disclosed in 002; (i) antiobesity agent, (1) growth hormone secretagogues for example, growth hormone secretagogues receptor stimulating agent/antagonist, NN703 for example, Hexarelin, MK-0677, SM-130686, CP-424,391, L-692,429 and L-163,255; (2) Protein-tyrosine-phosphatase-1B (PTP-1B) inhibitor; (3) cannabinoid receptor ligand, for example cannboid CB ₁Receptor antagonist or inverse agonist, Rimonabant (SanofiSynthelabo) for example, AMT-251 and SR-14778 and SR 141716A (SanofiSynthelabo), SLV-319 (Solvay), BAY 65-2520 (Bayer); (4) the fat serotonergic medicament of anti-month bar, fenfluramine for example, Dexfenfluramine, phentermine and sibutramine; (5) β 3-adrenoceptor agonists, AD9677/TAK677 (Dainippon/Takeda) for example, CL-316,243, SB 418790, BRL-37344, L-796568, BMS-196085, BRL-35135A, CGP 12177A, BTA-243, Tracazolate, Zeneca D7114, SR59119A; (6) pancreatic lipase inhibitor, for example orlistat (

), TritonWR ¹³39, RHC80267, Lipstatin, Orlistat, Tea Saponin, diethyl umbelliferone phosphate; (7) neuropeptide Y 1 antagonist, BIBP3226 for example, J-115814, BfflO 3304, LY-357897, CP-671906, GI-264879A; (8) neuropeptide Y 5 antagonist, GW-569180A for example, GW-594884A, GW-587081X, GW-548118X, FR ²26928, FR 240662, FR ²52384,1229U91, GI-264879A, CGP71683A, LY-377897, PD-160170, SR-120562A, SR-120819A and JCF-104; (9) melanin concentration hormone (MCH) receptor antagonist; (10) melanin concentration hormone 1 acceptor (MCH1R) antagonist, for example T-226296 (Takeda); (11) melanin concentration hormone 2 acceptor (MCH ₂R) agonist/antagonist; (12) orexin receptor antagonists, SB-334867-A for example, and those disclosed in patent publications herein; (13) serotonin reuptake inhibitors fluoxetine for example, Paxil and Sertraline; (14) Melanocortins activator, for example Melanotan II; (15) other Mc4r (Melanocortin 4 receptor) activator, CHIR86036 (Chiron) for example, ME-10142 and ME-10145 (Melacure), CHIR86036 (Chiron); PT-141 and PT-14 (Palatin); (16) 5HT-2 activator; (17) 5HT2C (serotonin receptor 2C) activator, BVT933 for example, DPCA37215, WAY161503, R-1065; (18) galanin antagonist; (19) CCK antagonist; (20) CCK-A (cholecystokinin-A) activator, for example AR-R 15849, and GI 181771, JMV-180, A-71378, A-71623 and SR ¹⁴613; (22) corticoliberim activator; (23) histamine receptor-3 (H3) conditioning agent; (24) histamine receptor-3 (H3) antagonists/inverse agonists, hioperamide for example, 3-(1H-imidazol-4 yl) propyl group N-(4-pentenyl) carbamate, clobenpropit, iodophenpropit, imoproxifan, GT2394 (Gliatech) and O-[3-(1H-imidazol-4 yl) propyl alcohol]-carbamate; (25) beta-hydroxysteroid dehydrogenase-1 inhibitor (β-HSD-1); (26) PDE (phosphodiesterase) inhibitor, theophylline for example, PTX, zaprinast, silaenafil, amrinone, milrinone, cilostamide, rolipram and cilomilast; (27) phosphodiesterase-3B (PDE3B) inhibitor; (28) NE (norepinephrine) transport inhibitors, for example GW 320659, despiramine, talsupram and Nomifensine; (29) ghrelin receptor antagonist; (30) leptin, comprise recombinant human leptin (PEG-OB, Hoffman La Roche) and restructuring methionyl human leptin (Amgen); (31) leptin derivative; (32) for example [D-Phe6, beta-Alal l, Phel3, Nlel4] Bn (6-14) and [D-Phe6, Phel3] Bn (6-13) propionamide and Pept.Sci.2002Aug of BRS3 (bell toad element receptor subtype 3) activator; 8 (8): those compounds disclosed in 461-75; (33) CNTF (CNTF), GI-181771 (Glaxo-SmithKline) for example, SR146131 (Sanofi Synthelabo), butabindide, PD170,292 and PD 149164 (Pfizer); (34) CNTF derivative, for example Axokine (Regeneron); (35) monoamine reuptaking inhibitor, for example western cloth song name; (36) UCP-I (protein that is not coupled-1), 2, or 3 activators, phytanic acid for example, 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2)-1-acrylic] benzoic acid (TTNPB), retinoic acid; (37) thyroid hormone beta-agonists, for example KB-2611 (KaroBioBMS); (38) FAS (fatty acid synthetase) inhibitor, for example cerulenin and C75; (39) DGAT1 (diacylglycerol acyltransferase 1) inhibitor; (40) DGAT2 (Diacrylglycerol acyl transferase 2) inhibitor; (41) ACC2 (acetyl-CoA carboxylase-2) inhibitor; (42) glucocorticoid resistance agent; (43) acyl group estrogen, the female sterol of oleoyl for example, it is disclosed in del Mar-Grasa, the people such as M., Obesity Research, in 9:202-9 (2001); (44) DPP IV (DP-IV) inhibitor, isoleucine thiazolidine for example, Val-Pyr, NVP-DPP728, LAF237, MK-431, P93/01, TSL 225, TMC-2A/2B/2C, FE 999011, P9310/K364, and VIP 0177, SDZ 274-444; (46) dicarboxylic ester transporter inhibitors; (47) glucose transporter inhibitor; (48) phosphate transporter inhibitors; (49) melbine (

) and (50) Topiramate (

) and (50) PYY, PYY 3-36, the PYY analog, derivative and fragment be BIM-43073D for example, BIM-43004C (Olitvak, the people such as D.A., Dig.Dis.Sci.44 (3): 643-48 (1999)); (51) neuropeptide Y 2 (NPY2) receptor stimulating agent NPY3-36 for example, N acetyl group [Leu (28,31)] NPY 24-36, TASP-V and ring-(28/32)-Ac-[Lys28-Glu32]-(25-36)-pNPY; (52) neuropeptide tyrosine 4 (NPY4) activator pancreas peptide (PP) and other Y4 activator 1229U91 for example for example; (54) cyclooxygenase-2 inhibitor Etoricoxib for example, Sai-Mi-Xi-Bu, Valdecoxib, SC 69124, Rumi former times cloth, BMS347070, tiracoxib or JTE522, ABT963, CS502 and GW406381 and their pharmaceutically acceptable salts; (55) neuropeptide Y 1 (NPY1) antagonist BIBP3226 for example, J-115814, BIBO 3304, LY-357897, CP-671906, GI-264879A; (56) opioid antagonists for example nalmefene (

), 3-methoxyl group Naltrexone, naloxone, Naltrexone; (57) 11 β HSD-1 (1 type 11-beta hydroxysteroid dehydrogenase) inhibitor is BVT 3498 for example, and BVT 2733; (58) aminorex; (59) amfecloral; (60) amphetamine; (61) benzphetamine; (62) chlorphentermine; (63) amine ester under clobenzorex (64) benzyl chloride; (65) clominorex; (66) clortermine; (67) cyclexedrine; (68) dextro-amphetamine; (69) diphemethoxidine; (70) N-ethyl sympamin; (71) fenbutrazate; (72) fenisorex; (73) Fenproporex; (74) Fludorex; (75) Fluminorex; (76) furfuryl group meth; (77) levamfetamine; (78) levolphacetoperane; (79) mefenorex; (80) metamfepramone; (81) dexoxyn; (82) norpseudoephedrine; (83) pentorex; (84) phenyl diformazan morpholine; (85) phenmetrazine; (86) picilorex; (87) phytopharm 57 and (88) Zonisamide.

In another embodiment, target compound can with antidepressive or antianxiety agent, comprise NRI (comprising tertiary amine three ring and secondary amine tricyclic compoundses), selective serotonin reuptake inhibitor (SSRI), oxidase inhibitor (MAOI), monoamine oxidase reversible inhibitor (RIMA), thrombotonin and NRI (SNRI), corticotropin releasing factor (CRF) antagonist, alpha-2-adrenoceptor antagonists, antagonists of neurokinine-1 receptor, atypical antidepressive, benzene diaza

, 5-HT _1Aagonist or antagonist, especially 5-HT _1Apartial agonist, and corticotropin releasing factor (CRF) antagonist, be combined with.Concrete medicament comprises: amitriptyline, chlorimipramine, P-3693A, imipramine and trimeproprimine, amoxapine, desipramine, maprotiline, nortriptyline and protriptyline; Fluoxetine, fluvoxamine, paroxetine and Sertraline; U-10387, Phenelzine, tranylcypromine and selegiline; Moclobemide; Venlafaxine; Aprepitant; Wellbutrin, lithium, nefazodone, trazodone and viloxazine; Alprazolam, zeisin, clonazepam, dipotassium chlorine nitrogen

, stable, halazepam, lorazepam, oxazepan and verstran ; Buspirone, flesinoxan, gepirone and ipsapirone, and their pharmacy acceptable salts.

In another embodiment second month in a season, target compound can with the sick agent of Kang Aercihaimoshi; Beta-secretase inhibitor; Inhibitors of gamma-secretase; Growth hormone secretagogues; Recombinant human growth hormone; The HMG-CoA reductase inhibitor; NSAED ' s comprises Ibuprofen BP/EP; Vitamin-E; Anti-amyloid antibody; CB-1 receptor antagonist or CB-1 receptor inverse agonists; Microbiotic is doxycycline and Rifampin for example; N-methyl-D-aspartate (NMDA) receptor antagonist, for example Memantine hydrochloride; Anticholinesterase is lycoremine for example, rivastigmine, E2020 and tetrahydroaminoacridine; Growth hormone secretagogues is ibutamoren for example, methylsulfonic acid ibutamoren and Ka Mo Rayleigh; Histamine H 3 antagonists; The AMPA agonist; PDE IV inhibitor; GABAA inverse agonist or nervosa nicotinic agonist, combine use.

In another embodiment second month in a season, target compound can with tranquilizer, soporific, anxiolytic, antipsychotic drug, antianxiety agent, cyclopyrrole ketone, imidazopyridine, pyrazolopyrimidine, minor tranquilizer, melatonin agonists and antagonist, the element energy medicament that fades, benzene phenodiazine , barbiturate(s), 5HT-2 antagonist etc., combine use, for example: adinazolam, allobarbital, alonimid, alprazolam, amitriptyline, Amobarbital, amoxapine, bentazepam, benzoctamine, brotizolam, Wellbutrin, buspirone, cloth tower veronal, the cloth tower is than appropriate, capuride, carbocloral, somnalclor, Chloral Hydrate, zeisin, clomipramine, clonazepam, Domperidone, chlorine nitrogen

, Cloretate, leoponex, cyprazepam, desipramine, dexclamol, stable, Chloralsalicylamide, two valproic acids, benadryl, P-3693A, estazolam, ethchlorvynol, sibul, fenobam, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam, rigenox, halazepam, hydroxyzine, imipramine, lithium, L0, lormetazepam, maprotiline, mecloqualone, melatonin, promind, peaceful, turzolon, midaflur, midazolam, Buddhist nun's method oxazolone, nisobamate, surem, nortriptyline, oxazepan, paraaldehyde, Paro former times spit of fland, Sodital, perlapine, trilafon, Phenelzine, phenylethyl barbituric acid, verstran

, promethazine, Rapinovet, protriptyline, Selepam, reclazepam, rolipram, secobarbital, Sertraline, suproclone, temazepam, thioridazine, tracazolate, Tranylcypromine, trazodone, triazole benzene phenodiazine, trepipam, tricetamide, trichloroethyl phosphate, trifluoperazine, trimetozine, trimeproprimine, Uldazepam, Venlafaxine, Zaleplone, zolazepam, zolpidem and their salt and composition etc., perhaps described target compound can be combined for example actinotherapy or the electricity irritation of use physical method in administration.

In another embodiment, target compound can with levodopa (thering is or not having the outer decarboxylase inhibitor of selective brain for example methyldopa or benserazide), anticholinergic is BIPERIDEN (optionally with its hydrochloride or lactic acid salt) and artane (Trihexyphenidyl) hydrochloride for example, the COMT inhibitor is Entacapone for example, the MOA-B inhibitor, antioxidant, the A2a adenosine receptor antagonists, cholinergic agonist, nmda receptor antagonist, serotonin receptor antagonist and dopamine-receptor stimulant be alentemol for example, bromocriptine, Fenoldopam, methylergol carbamide, Nazagolide, pergolide and pramipexole, the associating use.Be also noted that dopamine agonist can be the form of pharmacologically acceptable salt, alentemol hydrobromate for example, bromocriptine mesylate, fenoldopam mesylate, Nazagolide hydrochloride and LY-127809.Methylergol carbamide and pramipexole are used with the form of non-salt usually.

In another embodiment, target compound can with Sch-6673, alentemol, Trihexyphenidyl, bromocriptine, BIPERIDEN, chlorpromazine, tardan, leoponex, stable, Fenoldopam, fluphenazine, haloperidol, levodopa, levodopa and benserazide, levodopa and methyldopa, methylergol carbamide, loxapine, mesoridazine, morpholine many that (molindolone), Nazagolide, olanzapine, pergolide, trilafon, pimozide, pramipexole, risperidone, dogmatil, tetrabenazine, artane, thioridazine, thiothixene or trifluoperazine, the associating use.

In another embodiment, target compound can with from thiodiphenylamine, thioxanthene, heterocycle dibenzazepine

, butyrophenone, hexichol fourth piperidines and indole ketone tranquilizer compound combine use.The suitable example of thiodiphenylamine comprises chlorpromazine, mesoridazine, thioridazine, Sch-6673, fluphenazine, trilafon and trifluoperazine.The suitable example of thioxanthene comprises tardan and thiothixene.Dibenzazepine example be leoponex.The example of butyrophenone is haloperidol.The example of hexichol fourth piperidines is pimozide.The example of indolone is morpholine many that (molindolone).Other tranquilizer comprises loxapine, dogmatil and risperidone.Be appreciated that tranquilizer with target compound, combine while using can pharmacologically acceptable salt form, chlorpromazine hydrochloride for example, lidanil benzene sulfonate, thioridazine hydrochloride, the Sch-6673 maleate, fluophenazine hydrochloride, fluophenazine enanthate, fluophenazine decanoate, the trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol caprate, oxilapine succinate and quinoline keto hydrochloride not.Trilafon, tardan, leoponex, haloperidol, pimozide and risperidone are used with salt-independent shape usually.

In another embodiment, target compound can with appetite suppressant, aminorex for example, amfecloral, Amphetamine, benzphetamine, chlorphentermine, clobenzorex, Lipociden, MeN-1107, Varanil, dexfenfluramine, dextroamphetamine, diethylpropion, diphemethoxidine, the N-N-ethylamphetamine, fenbutrazate, fenfluramine, fenisorex, Perphoxene, Win 11464, McN 1231, the furfuryl group methyl amphetamine, Levamphetamine, Levophacetoperane, SaH-42548, mefenorex, Mephogarbital, methamphetamine hydrochloride, pseudonorephedrine, phenpentermine, phendimetrazine, Preludin, PHENTERMINE, Phenylpropanolamine, picilorex and sibutramine, selective serotonin reuptake inhibitor (SSRI), halogenation Amphetamine derivative, comprise chlorphentermine, Lipociden, Varanil, dexfenfluramine, fenfluramine, picilorex and sibutramine, and their pharmacologically acceptable salt salt, combine use.

In another embodiment, target compound can with opiate agonist, lipoxygenase inhibitor, 5-LO inhibitor for example, cyclooxygenase inhibitors, cyclooxygenase-2 inhibitor for example, the interleukin inhibitor, interleukin-1 inhibitor for example, nmda antagonist, nitric oxide inhibitor or nitrogen oxide synthetic inhibitor, non-steroidal anti-inflammatory agent, or suppress the cytokine anti-inflammatory agent and combine use, such as, with for example acetaminophen, acetylsalicylic acid, morphine monomethyl ether, fentanyl, Ibuprofen BP/EP, INDOMETHACIN, ketorolac, morphine, Naproxen Base, phenacetin, piroxicam, the steroidal pain killer, sufentanil, Su Lin acid, the compound of tenidap etc., the associating use.Similarly, target compound can with anodyne; Synergistic agent is caffeine for example, H2 antagonist, dimethyl silicone oil, aluminium hydroxide or magnesium hydroxide; The for example phyenlephrinium of agent that decongests, Phenylpropanolamine, pseudoephedrine, oxymetazoline, suprarenin, naphazoline, xylometazoline, propylhexedrine, or SN522; Cough medicine is morphine monomethyl ether for example, hydrocodone, caramiphen, carbetapentane or Dextromethorphane Hbr; Diuretic(s); And quiet type or non-sedating type antihistaminic agent, administration together.

The compounds of this invention can pass through oral cavity, parenteral (for example, muscle, endoperitoneal, intravenous, ICV, intracisternal injection or transfusion, subcutaneous injection, or implant), by suction, spray, nose, vagina, rectum, hypogloeeis or topical approach carry out administration, and can be separately or jointly be mixed with the formulation of suitable unitary dose, and it comprises nontoxic pharmaceutically acceptable carrier, auxiliary agent and the vehicle of routine that is suitable for various route of administration.Except treatment warm-blooded animal mouse for example, rat, horse, ox, sheep, dog, cat, monkey, etc. outside, the compounds of this invention can be effectively for the mankind.

For the pharmaceutical composition that the compounds of this invention is carried out to administration, can be easily with the form of unitary dose, exist, and can be by known any method preparation in the medicament field.All methods all comprise the step that active ingredient is combined with the carrier that forms one or more subordinate compositions.Usually, the preparation method of pharmaceutical composition is, active ingredient and liquid carrier or pulverizing solid carrier or both evenly closely are combined simultaneously, then, if necessary, product formed and makes to the formulation of expectation.In pharmaceutical composition, comprise the active target compound that is enough to the process of disease or symptom are produced the amount of desired effects.As used herein, term " composition " connotation comprises the product of the regulation component that contains specified amount, and any component of the regulation by specified amount is mixed the product directly or indirectly obtained.

Can be according to any method preparation for the manufacture of pharmaceutical composition known in the art for the pharmaceutical composition that orally uses, thereby and such composition can comprise one or more reagent that are selected from sweeting agent, seasonings, tinting material and sanitas pharmaceutically good to eat goods attractive in appearance are provided.Tablet comprises active ingredient and the pharmaceutically acceptable mixture that is suitable for manufacturing the nontoxic vehicle of tablet.These vehicle for example can be, inert diluent, calcium carbonate for example, sodium carbonate, lactose, calcium phosphate and sodium phosphate; Granulation and disintegrating agent, for example, W-Gum or alginic acid; Tackiness agent, starch for example, gelatin or Sudan Gum-arabic, and lubricant, for example Magnesium Stearate, stearic acid or talcum.Tablet can be do not coat or they can be with already known processes, coat thereby the continuous action of longer cycle is provided to postpone disintegration and the absorption in gi tract.The composition orally used also can exist with the form of hard gelatin capsule, wherein active ingredient is and inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin mix, or exist with the form of soft gelatin capsule, and wherein active ingredient is and water or oily medium, peanut oil for example, whiteruss or mixed with olive oil.Aqeous suspension contains active ingredient and is suitable for manufacturing the mixture of the vehicle of aqeous suspension.Oil suspension can be by being suspended in active ingredient in suitable oil and preparing.Can also use oil-water emulsifiers.The dispersible powder and the granule that are suitable for by adding water to prepare aqeous suspension provide active ingredient and dispersion agent or wetting agent, the mixture of suspension agent and one or more sanitass.The pharmaceutical composition of this compound can be the form of sterile water for injection or oil suspension.The compounds of this invention also can be with the form administration of the suppository for rectal administration.Use for part, can use the emulsifiable paste that comprises the compounds of this invention, ointment, gelifying agent, solution or suspension etc.The compounds of this invention can also be prepared for inhalation.The compounds of this invention also can pass through the transdermal patch administration by methods known in the art.

Following scheme and embodiment illustrated prepare the several method of the compounds of this invention.Prepare starting raw material according to methods known in the art or the illustrational method of the application.Use following abbreviation in the application: Me: methyl; Et: ethyl; T-Bu: the tertiary butyl; Ar: aryl; Ph: phenyl; Bn: phenmethyl; Ac: ethanoyl; THF: tetrahydrofuran (THF); DEAD: azoformic acid diethyl fat: DMSO: dimethyl sulfoxide (DMSO); EDC:N-(3-dimethylaminopropyl)-N '-ethyl carbodiimide; HOBT: hydroxybenzotriazole; Boc: tert-butoxycarbonyl; Et3N: triethylamine; DCM: methylene dichloride; DCE: ethylene dichloride; BAS: bovine serum albumin; TFA: trifluoroacetic acid; DMF:N, dinethylformamide; MTBE: methyl tertiary butyl ether; SOCl ₂: thionyl chloride; CDI: carbonyl dimidazoles; Rt: room temperature; HPLC: high performance liquid chromatography.Can prepare in many ways by the compounds of this invention.

Can further modify the finished product in some cases, for example, by processing substituting group.These processing can include but not limited to, reduction known in those skilled in the art, oxidation, alkylation, acidylate and hydrolysis reaction.Thereby can change in some cases the order of carrying out following reaction scheme promotes reaction or avoids unwanted reaction product.The present invention provides following examples so that can be understood more all sidedly.These embodiment are only illustrative and should be considered to limit the invention in any way.

reaction scheme A

2-(2H-1,2.3-triazole-2-yl) phenylformic acid (A-1)

(1.5g, 21.7mmol) 1,2,3-triazoles, 7.08g (21.7mmol) CsCO for solution by 2-iodo-benzoic acid (3.0g, 12.09mmol) in DMF ₃, 114mg (0.60mmol) CuI and the trans-N of 310mg (2.17mmol), N '-dimethyl cyclohexane-1, the 2-diamines is processed.This mixture heats 10 minutes in microwave reactor in 120 ℃.Reaction is cooled to room temperature, with the EtOAc washing, and passes through diatomite filtration.Resistates passes through at SiO ₂(MeOH is at the solution containing in the DCM of 0.1%AcOH) is gradient elution purifying above, obtains required 2-(2H-1,2, the 3-triazole-2-yl) phenylformic acid of very fast wash-out, A-1.The A-1 data: ¹hNMR (500MHz, DMSO-d ₆) δ 13.05 (br s, 1H), 8.12 (s, 2H), 7.81-7.52 (m, 4H) ppm.Next has eluted non-desired 2-(1H-1,2,3-triazole-2-yl) phenylformic acid.

2-(2H-1,2.3-triazole-2-yl) 5-tolyl acid (A-2)

1,2,3-triazoles for solution (2.1g, 30.5mmol), CsCO by the iodo-5-tolyl acid of 2-(4.0g, 15.3mmol) in DMF (10mL) ₃(9.95g, 30.5mmol), CuI (0.145g, 0.76mmol) and trans-N, N '-dimethyl cyclohexane-1,2-diamines (0.43g, 3.05mmol) is processed.This mixture heats 10 minutes in microwave reactor in 120 ℃.Reaction is cooled to room temperature, washes with water, and wash with EtOAc.1N HCl acidifying for water, and extract with EtOAc.Organic phase Na ₂sO ₄drying, filter and concentrate.Resistates passes through at SiO ₂(MeOH is at the solution containing in the DCM of 0.1%AcOH) upper gradient elution purifying, obtain the 2-(2H-1 of very fast wash-out, 2,3-triazole-2-yl)-5-tolyl acid A-2, then eluted non-desired regional isomer, 2-(1H-1,2,3-triazole-2-yl)-5-tolyl acid.The A-2 data: ¹hNMR (500MHz, DMSO-d ₆) d 12.98 (br s, 1H), 8.04 (s, 2H), 7.72-7.45 (m, 3H), 2.41 (s, 3H) ppm.

the bromo-2-of 5-(2H-1,2,3-triazole-2-yl) phenylformic acid (A-3)

(2.11g, 30.6mmol) 1,2,3-triazoles, 14.09g (61.2mmol) K for solution by the bromo-2-iodo-benzoic acid of 5-(10.0g, 30.6mmol) in DMF ₃pO ₄h ₂o and 583mg (3.06mmol) CuI processes.This mixture is at N ₂under under agitation in 60 ℃ the heating 3 hours.Reflection is cooled to room temperature, washes with water, and with 1N HCl acidifying.Mixture distributes three times with EtOAc.Organic layer is merged, use the salt water washing, use MgSO ₄drying, filter and concentrate..Resistates, via column chromatography purifying (mixture of EtOAc in hexane, 1%AcOH buffer reagent), obtains the bromo-2-of required 5-(2H-1,2, the 3-triazole-2-yl) phenylformic acid comparatively fast eluted, A-3.The A-3 data: ¹hNMR (500MHz, DMSO-d ₆) δ 13.4 (br s, 1H), 8.12 (m, 2H), 7.94-7.88 (m, 2H), 7.78-7.73 (m, 1H) ppm.Next elutes the bromo-2-of non-desired 5-(1H-1,2,3-triazole-2-yl) phenylformic acid.

Reaction scheme B

2-(dibutoxy methyl)-fluoro-1-oil of mirbane of 4-(B-1)

By the fluoro-2-nitrobenzaldehyde of 5-(75g, 443mmol), P-TOLUENE SULFO ACID 99's monohydrate (8.4g, 44.3mmol) and propyl carbinol (122mL, 1.33mol) in toluene (630mL) with the Dean and Stark apparatus 15h that refluxes.To react cooling, concentrated and water (1L) and EtOAc (1L) distribution.Organic layer water (1L) and salt solution (1L) washing, use Na ₂sO ₄dry and concentrated.Crude reaction, via column chromatography purifying (mixture of EtOAc in hexane, 1% triethylamine buffer reagent), obtains B-1, is oily matter.The B-1 data: ¹hNMR (500MHz, CDCl ₃) δ 7.92 (dd, J=8.5,4.5Hz, 1H), (7.54 dd, J=9.0,3.0Hz, 1H), (7.15-7.11 m, 1H), 6.05 (s, 1H), 3.67-3.52 (m, 4H), (1.63-1.57 m, 4H), 1.43-1.35 (m, 4H), 0.94-0.91 (m, 6H) ppm; LRMS (M+H) m/z=169.8 measured value; 300.3 theoretical value (finding the acetal loss).

the chloro-6-fluquinconazole of 2-quinoline (B-3)

Add Pd-C (10wt%, 2.3g) in 25 ℃ in solution to B-1 (26.1g, 87mmol) in EtOAc (350mL) under nitrogen atmosphere, and reaction is placed in to (1atm) under nitrogen atmosphere.To react and stir 12 hours, by diatomite filtration concentrated.Resistates is dissolved in THF (350mL), and is cooled to 0 ℃.Drip triethylamine (45.0mL, 323mmol) and the triphosgene (8.6g, 29.1mmol) in THF (60mL) in this solution.Reaction is stirred 10 minutes and is added in the ammonia (46.1mL, 323mmol, 7M solution) in methyl alcohol.To react on 0 ℃ stirs 10 minutes and quickly heats up to room temperature.In room temperature, after 15 minutes, the 4M HCl that reaction is used in dioxane (120mL) is acidified to pH 2.This reacts on stirring at room 1 hour directly concentrated.Toluene and methanol azeotropic for resistates, obtain B-2, is yellow cake piece.B-2 data: LRMS m/z (M+H)=164.9 measured value; 165.1 theoretical value.Yellow cake piece is dissolved in pure oxygen phosphorus chloride (130mL) and refluxes (120 ℃) 1 hour.To reflect coolingly, and remove in a vacuum excessive solvent.The crude reaction thing is dissolved in EtOAc (600mL), and processes in 0 ℃ of slow water (500mL).By EtOAc (2x200mL) aqueous phase extracted, and the organic phase MgSO merged ₄dry and concentrated.Crude reaction, via column chromatography purifying (EtOAc/ methylene dichloride), obtains B-3, is pale solid.The B-3 data: ¹hNMR (500MHz, CDCl ₃) δ 9.29 (s, 1H), 8.04 (dd, J=9.0,5.0Hz, 1H), 7.77-7.72 (m, 1H), 7.59 (dd, J=7.5,2.5Hz, 1H) ppm; LRMS m/z (M+H)=183.2 measured value; 183.0 theoretical value.

Reaction scheme C

the 4-methyl isophthalic acid, 3-benzoxazole-2-mercaptan

By 2-amino-meta-cresol (4.0g, 32.5mmol) and potassium ethyl xanthonate (10.4g, 65.0mmol), the solution in 30mL EtOH refluxes 3 hours.Remove desolventizing by rotary evaporation, resistates is dissolved in about 50mL water, and adds the second acid for adjusting pH to～5.Filter and collect the solid formed, and dry under vacuum, obtain C-1, be white solid.C-data: LC/MS:rt=1.67min; M/z (M+H)=166.0 measured value; 166.0 theoretical value.

the chloro-4-methyl isophthalic acid of 2-, 3-benzoxazole (C-2)

To C-1 (1.6g, 9.7mmol) at POCl ₃add PCl in suspension in (4.5mL, 48.4mmol) ₅(2.2g, 10.6mmol) and about 10mL CH ₂cl ₂.After stirring is spent the night, via rotary evaporation, remove desolventizing, resistates CH ₂cl ₂and 5%Na ₂cO ₃the aqueous solution distributes.Separate each layer, organic layer washes with water, uses Na ₂sO ₄drying, and concentrated.Resistates, via silica gel column chromatography purifying (EtOAc/ hexane), obtains C-2, is white solid.C-2 data: LC/MS:rt=2.28min; M/z (M+H)=168.0 measured value; 168.0 theoretical value.

Reaction scheme D

2,5-bis-is chloro-1,3-benzoxazole (D-1)

To the chloro-2-mercaptobenzoxazole of 5-(5.0g, 26.9mmol) at POCl ₃add PCl in suspension in (12.6mL, 135mmol) ₅(6.2g, 129.6mmol) and about 20mL CH ₂cl ₂.Stir after 5 days, via rotary evaporation, except desolventizing, resistates is at EtOAc and NaHCO ₃between saturated aqueous solution, distribute.Separate each layer, organic layer salt water washing, use Na ₂sO ₄drying, and concentrated.Resistates is dissolved in the CHCl of minimum ₃in, add hexane, and cross a small amount of solid of elimination.Filtrate is concentrated, obtain D-1, be white solid.D-1 data: LC/MS:rt=2.38min; M/z (M+H)=188.0 measured value; 188.0 theoretical value.

Reaction scheme E

methyl ketone (E-1)

Drip 10.2mL (125mmol) methyl vinyl ketone by Boc-quadrol (20.0g, 125mmol) at 250mL Et ₂solution-treated in O, and it is stirred 24 hours.Reaction is cooled to 0 ℃, and adds 22.6mL (162mmol) triethylamine, then add 19.6mL (137mmol) chloroformic acid benzyl ester.Sluggish is heated to room temperature and stirs and spend the night.Reaction is diluted with EtOAc, with 10% aqueous citric acid solution washing, then uses saturated NaHCO ₃washing, then use the salt water washing.Organic phase Na ₂sO ₄drying, filter and concentrate, and obtains E-1, is light yellow oil.E-1 data: LC/MS:rt=2.22min, m/z (M+H)=265.2 measured value; 365.2 theoretical value (finding the loss of Boc group).

the 5-methyl isophthalic acid, 4-Diazesuberane-1-benzyl formate (E-2)

HCl for solution (g) by 39.0g (107mmol) E-1 in 300mL EtOAc is saturated, and the flask capping is also stirred 2 hours.Remove desolventizing by rotary evaporation, resistates is dissolved in 1M HCl, uses Et ₂o washing, with the NaOH alkalization, and with 2: 1 CHCl ₃/ EtOH extraction three times.The organic phase salt water washing merged, concentrated, be dissolved in CH ₂cl ₂in and filter, obtain the 19.2g brown oil.This material dissolves is at 200mL CH ₂cl ₂in, and add wherein 5mL HOAc.After stirring 2h, add 23.1g (109mmol) Na (OAc) ₃bH, and by the gained mixture in stirring at room 48h.Remove some solvents by rotary evaporation, resistates is poured into and is contained saturated NaHCO ₃solution and 2: 1CHCl ₃in the separating funnel of/EtOH.Separate each layer, and with 2: 1CHCl ₃more than/EtOH extracting twice.The salt water washing of minimum for the organic layer merged, concentrated, be dissolved in CH ₂cl ₂in, filter and concentrate, obtain E-2, be brown oil.E-2 data: LC/MS:rt=1.12min; M/z (M+H)=249.1 measured value; 249.2 theoretical value.

the 5-methyl isophthalic acid, 4-Diazesuberane-Isosorbide-5-Nitrae-dioctyl phthalate 1-benzyl ester 4-tert-butyl ester (E-3)

To 23.8g (96mmol) E-2 at 200mL CH ₂cl ₂in solution in add 26.7mL (192mmol) triethylamine and 25.1g (115mmol) tert-Butyl dicarbonate.After stirred overnight at room temperature, reaction CH ₂cl ₂dilution, and pour in separating funnel, saturated NaHCO used ₃solution washing, use Na ₂sO ₄, drying, and concentrated.Resistates, by silica gel column chromatography purifying (EtOAc/ hexane), obtains E-3, is countless oily matter.E-3 data: LC/MS:rt=2.64min; M/z (M+H)=249.2 measured value; 349.4 theoretical value (finding the loss of Boc group).

(5R)-5-methyl isophthalic acid, 4-Diazesuberane-Isosorbide-5-Nitrae-dioctyl phthalate 1-benzyl ester 4-tert-butyl ester (E-4) and

(5S)-5-methyl isophthalic acid, 4-Diazesuberane-Isosorbide-5-Nitrae-dioctyl phthalate 1-benzyl ester 4-tert-butyl ester (E-5)

On 10cm * 50cm Chiralpak AD post, preparation separates the E-3 enantiomorph, uses 60%EtOH and 40% hexane (containing 0.1% diethylamine) to carry out isocratic elution with the flow velocity of 175mL/ minute.Under these conditions, once running can be isolated 6g E-3.Analyzed on 0.46cm * 25cmChrialpak AD post, use 60%EtOH and 40% hexane (containing 0.1% diethylamine) to carry out wash-out with the flow velocity of 1mL/ minute.It is believed that it is that first enantiomorph be eluted (E-4) of (R)-enantiomorph is required enantiomorph, and there is the retention time of 4.12 minutes.It is>the colourless gum of 98%ee.It is believed that it is that second enantiomorph be eluted (E-5) of (S)-enantiomorph is undesirable enantiomorph, and there is the retention time of 4.82 minutes.It is～the colourless gum of 90%ee.

Reaction scheme F

(5R)-5-methyl isophthalic acid, 4-Diazesuberane-1-benzyl formate (F-1)

HCl for solution (g) by 15.0g (43.0mmol) E-4 in 350mL EtOAc is saturated, and the flask capping is also stirred 15 minutes.Solution uses HCl (g) saturated again, and the flask capping is also stirred 30 minutes, then by rotary evaporation, removes volatile matter, obtains the hydrochloride of 13.0g F-1, is colourless gum.F-data: LC/MS:rt=1.10min; M/z (M+H)=249.2 measured value; 249.3 theoretical value.

(5R)-5-methyl-4-[2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-benzyl formate (F-2)

Add 12.2g (63.5mmol) EDC in hydrochloride, 8.8g (46.6mmol) A-1,6.92g (50.8mmol) 1-hydroxyl-7-azepine benzotriazole and the solution of 18.6mL (169mmol) N-methylmorpholine in 200mL DMF of 12.0g (42.3mmol) F-1, and will react on stirred overnight at room temperature.Reaction is at EtOA and 10%KHSO ₄distribute between the aqueous solution, use saturated NaHCO ₃the aqueous solution, water, salt water washing, use MgSO ₄drying, and concentrated via rotary evaporation.Bronsted lowry acids and bases bronsted lowry layer is before extracted with EtOAc again.Organic extract salt water washing, drying, concentrated, and merge with the organic residue obtained previously.Whole organic residue, by silica gel column chromatography purifying (EtOAc/ hexane), are obtained to F-2, are colorless oil.F-2 data: LC/MS:rt=2.25min; M/z (M+H)=420.3 measured value; 420.5 theoretical value.

(7R)-7-methyl isophthalic acid-[2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane (F-3)

To contain the round-bottomed flask decompression vacuum pumping of the solution of 12.2g (29.0mmol) F-2 in 250mL EtOAc, and use N ₂air-blowing is swept three times.Add the Pd (OH) of 20.4g 20% on carbon in flask ₂.By flask decompression vacuum pumping again, and use N ₂air-blowing is swept three times, then uses H ₂purge three times.Reaction is at H ₂stir and spend the night under atmosphere, then filter by Celite pad, with the EtOAc washing, then wash with MeOH.Filtrate is concentrated, obtain F-3, be white solid.F-3 data: LC/MS:rt=0.81& (1.01min finding under these conditions two kinds of conformers); M/z (M+H)=286.2 measured value; 286.3 theoretical value.

the fluoro-2-{ of 6-(5R)-5-methyl-4-[2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl) quinazoline (F-4)

Add 4.40mL (31.5mmol) triethylamine and 1.92g (10.5mmol) B-3 in the solution of 3.0g (10.5mmol) F-3 in 50mL DMF, and mixture is heated to 4h with 75 ℃ in oil bath, to bathe temperature drop and be low to moderate 50 ℃, and will react on this temperature and stir and spend the night.After being cooled to room temperature, EtOAc dilution for reaction, use saturated NaHCO ₃the aqueous solution, water, salt water washing, and use MgSO ₄dry.After concentrated via rotary evaporation, resistates, via flash column chromatography purifying (hexane/EtOAc), obtains F-4, is yellow solid.F-4 data: LC/MS:rt=1.88& (1.95min finding under these conditions two kinds of conformers); M/z (M+H)=432.2 measured value; 432.2 theoretical value; HRMS (APCI) m/z (M+H) 432.1949 measured values; 432.1943 theoretical value.

Reaction scheme G

(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-benzyl formate (G-1)

Add 22.5g (118mmol) EDC in hydrochloride, 15.9g (78mmol) A-2,12.8g (94mmol) 1-hydroxyl-7-azepine benzotriazole and the solution of 43.1mL (392mmol) N-methylmorpholine in 300mL DMF of 22.3g (78mmol) F-1, and will react on stirred overnight at room temperature.Reaction is at EtOAc and saturated NaHCO ₃between the aqueous solution, distribute, water, salt water washing, use MgSO ₄drying, and concentrated via rotary evaporation.Resistates, via silica gel column chromatography purifying (EtOAc/ hexane), obtains G-1, is colourless gum.G-1 data: LC/MS:rt=2.22min; M/z (M+H)=434.2 measured value; 434.2 theoretical value.

(7R)-7-methyl isophthalic acid-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane (' G-2)

To contain the flask decompression vacuum pumping of the solution of 29.6g (68.3mmol) G-1 in 300mL EtOAc and 200ml MeOH, and use N ₂air-blowing is swept three times.Add the Pd (OH) of 2.4g20% on carbon in flask ₂.By flask decompression vacuum pumping again, and use N ₂air-blowing is swept three times, then uses H ₂purge three times.To react at H ₂stir three days under atmosphere, then filter by Celite pad, with the EtOAc washing, then wash with MeOH.Filtrate is concentrated, obtain G-2, be white foam shape thing.G-2 data: LC/MS:rt=0.96& (1.13min finding under these conditions two kinds of conformers); M/z (M+H)=300.0 measured value; 300.2 theoretical value.

the chloro-2-{ of 5-(5R)-5-methyl 4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl }-1, the 3-benzo

azoles (G-3)

Add 29.3mL (210mmol) triethylamine and 13.2g (70.1mmol) D-1 in the solution of 21.0g (70.1mmol) G-2 in 250mL DMF, and mixture is heated to 2h in 75 ℃ in oil bath.After being cooled to room temperature, EtOAc dilution for this reaction, use saturated NaHCO ₃the aqueous solution, water, salt water washing, use MgSO ₄dry.After concentrated via rotary evaporation, resistates, by flash column chromatography purifying (hexane/EtOAc), obtains gum.This gum stirs and spends the night in the mixture of 150ml EtOAc and 300ml hexane.Filtering and obtain G-3, is white solid.G-3 data: LC/MS:rt=2.29min; M/z (M+H)=451.1 measured value; 451.2 theoretical value; HRMS (APCI) m/z (M+H) 451.1631 measured values; 451.1644 theoretical value.

Reaction scheme H

(5R) the bromo-2-of-4-[5-(2H-1,2,3-triazole-2-yl) benzoyl]-the 5-methyl isophthalic acid, 4-Diazesuberane-1-benzyl formate (H-1)

Add 2.52g (13.2mmol) EDC in hydrochloride, 2.35g (8.8mmol) A-3,1.43g (10.5mmol) 1-hydroxyl-7-azepine benzotriazole and the solution of 4.83mL (43.9mmol) N-methylmorpholine in 35mL DMF of 2.5g (8.8mmol) F-1, and will react on stirred overnight at room temperature.Reaction is at EtOAc and saturated NaHCO ₃between distribute, water, salt water washing, use MgSO ₄drying, and concentrated with rotary evaporation.Resistates, via column chromatography purifying (EtOAc/ hexane), obtains H-1, is white solid.H-1 data: LC/MS:rt=2.28& (2.34min finding under these conditions two kinds of conformers); M/z (M+H)=498.1 measured value; 498.1 theoretical value.

(5R)-4-[5-(methoxycarbonyl)-2-(2H-1,2,3-triazole-2-yl) benzoyl]-the 5-methyl isophthalic acid, 4-Diazesuberane-1-benzyl formate (H-2)

In 80 ℃, carbon monoxide is passed into to 2.63g (5.3mmol) H-1,118mg (0.53mmol) acid chloride (II), 218mg (0.53mmol) 1, in 3-bis-(diphenylphosphino)-propane and the solution of 2.21mL (15.8mmol) triethylamine in 20mL methyl alcohol and 10ml of DMSO 10 minutes.Then reflection is placed under the carbon monoxide air bag and in 80 ℃ of stirrings and spends the night.Reaction is at EtOAc and saturated NaHCO ₃between the aqueous solution, distribute, water, salt water washing, use MgSO ₄drying, concentrated with rotary evaporation.Resistates, via silica gel column chromatography purifying (EtOAc/ hexane), obtains H-2, is colourless gum.H-2 data: LC/MS:rt=2.10& (2.16min finding under these conditions two kinds of conformers); M/z (M+H)=478.1 measured value; 478.2 theoretical value.

3-{[(7R)-7-methyl isophthalic acid, 4-Diazesuberane-1-yl] carbonyl }-4-(2H-1,2,3-triazole-2-methyl benzoate (H-3)

To contain the round-bottomed flask decompression vacuum pumping of the solution of 750mg (1.57mmol) H-2 in 100mL EtOAc and 20ml MeOH, and use N ₂purge three times.Add the Pd (OH) of 1.1g 20% on carbon in flask ₂.By flask decompression vacuum pumping again, and use N ₂purge three times, then use H ₂purge three times.Reaction is at H ₂stir 24 hours under gas, then filter by Celite pad, with the EtOAc washing, then wash with MeOH.Filtrate is concentrated, obtain H-3, be colourless gum.H-3 data: LC/MS:rt=1.01& (1.13min finding under these conditions two kinds of conformers); M/z (M+H)=344.1 measured value; 344.2 theoretical value.

3-{[(7R)-4-(5-chloro-1,3-benzoxazole-2-yl)-7-methyl isophthalic acid, 4-Diazesuberane-1-yl] carbonyl }-4-(2H-1,2,3-triazole-2-yl) methyl benzoate (H-4)

Add 0.22mL (1.57mmol) triethylamine and 310mg (1.65mmol) D-1 in the 540mg in 10mL DMF (1.57mmol) H-3, and by mixture in aluminium block in 50 ℃ of heated overnight.After being cooled to room temperature, EtOAc dilution for reaction, use saturated NaHCO ₃, water, salt water washing, and use MgSO ₄dry.Use concentrated by rotary evaporation after, resistates, by flash column chromatography purifying (hexane/EtOAc), obtains H-4, is white solid.H-4 data: LC/MS:rt=2.24min; M/z (M+H)=495.1 measured value; 495.2 theoretical value .HRMS (APCI) m/z (M+H) 495.1561 measured values; 495.1542 theoretical value.

3-{[(7R)-4-(5-chloro-1,3-benzoxazole-2-yl)-7-methyl isophthalic acid, 4-Diazesuberane-1-yl] carbonyl }-4-(2H-1,2,3-triazole-2-yl) phenylformic acid (H-5)

To at MeOH/THF/H ₂add 1.94mL (1.94mmol) 1M aqueous sodium hydroxide solution in 120mg (0.24mmol) H-4 in each 20mL of O, and by mixture in stirred overnight at room temperature.To react concentrated to remove organic solvent, then with the EtOAc dilution, with 1M NaOH washing three times.1M HCl acidifying for water layer, with EtOAc washing three times, merge organic layer water, salt water washing, uses MgSO ₄dry.After concentrated with rotary evaporation, resistates being suspended in the Et2O/ hexane and concentrating, obtaining H-5, is white solid.H-5 data: LC/MS:rt=1.94min; M/z (M+H)=481.1 measured value; 481.1 theoretical value .HRMS (APCI) m/z (M+H) 481.1409 measured values; 481.1386 theoretical value.

Reaction scheme I

[3-{[(7R)-4-(5-chloro-1,3-benzoxazole-2-yl)-7-methyl isophthalic acid, 4-Diazesuberane-1-yl] carbonyl }-4-(2H-1,2,3-triazole-2-yl) phenyl] methyl alcohol (I-1)

Add the solution of 0.70mL (1.62mmol) 2.3M lithium aluminum hydride in THF in the 400mg in 10mL THF (0.81mmol) H-4, and by mixture in stirring at room 30 minutes.To react water and end, then, with the EtOAc dilution, with 1M HCl, water, salt water washing, use MgSO ₄dry.After concentrated with rotary evaporation, resistates is via flash column chromatography purifying (hexane/EtOAc), concentrated, is suspended in Et ₂concentrating in the O/ hexane and again, obtain I-1, is white solid.I-1 data: LC/MS:rt=1.86min; M/z (M+H)=467.1 measured value; 467.2 theoretical value .HRMS (APCI) m/z (M+H) 467.1623 measured values; 467.1593 theoretical value.

Reaction scheme J

2-is chloro-6,7-difluoro quinoxaline (J-1)

4,5-bis-is fluoro-1, and solution for the Glyoxylic acid hydrate (2.34mL, 21.02mmol 50wt% in water) of 2-phenylenediamine (3g, 20.82mmol) in EtOH (100ml) processed, and is heated to reflux 3 hours.This mixture is cooled to room temperature, and solid collected by filtration.This is POCl3 (29.1ml, 312mmol) dilution for material, and refluxes 1 hour.Remove reflux exchanger, in mixture, be blown into nitrogen gas stream, allow it concentrated simultaneously.Resistates dilutes with DCM, is cooled to 0 ℃, and slowly adds 5%Na ₂cO ₃the aqueous solution.Mixture is poured into to separating funnel and separated each layer.Organic phase 5%Na ₂cO ₃washing, use Na ₂sO ₄drying, filter and concentrate.Roughage is dissolved in to CHCl ₃in, by the 12g silica gel treatment and be condensed into fine powder.Being loaded on silica gel by it and, by isocratic elution purifying (mixture of 10%EtOAc in DCM), obtaining J-1, is pale solid.The J-1 data: ¹h NMR (500MHz.CDCl ₃): δ 8.8 (s, 1H), 7.9 (m, 1H), 7.8 (m, 1H) ppm.

the fluoro-2-{ of 6,7-bis-(5R)-5-methyl-4-[2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl } quinoxaline (7-2)

Add 1.04mL (7.5mmol) triethylamine and 500mg (2.5mmol) J-1 in the 711mg in 10mL DMF (2.5mmol) F-3, and mixture is heated 5 hours in 75 ℃ in aluminium block.After being cooled to room temperature, EtOAc dilution for reaction, use saturated NaHCO ₃the aqueous solution, water, salt water washing, and use the MgSO4 drying.After concentrated with rotary evaporation, resistates is via flash column chromatography purifying (hexane/EtOAc), concentrated, is suspended in the Et2O/ hexane and again concentrates, and obtains J-2, is yellow solid.J-2 data: LC/MS:rt=2.20min; M/z (M+H)=450.0 measured value; 450.2 theoretical value .HRMS (APCI) m/z (M+H) 450.1862 measured values; 450.1848 theoretical value.

Reaction scheme K

the chloro-5-thiotolene of 2-is [2,3-d] pyrimidine (K-1) also

Add 2.0mL (16.3mmol) trichloromethylchloroformate in 1.5g (10.9mmol) the 2-amino in acetonitrile (9mL)-4-thiotolene-3-formonitrile HCN, and mixture is heated 15 hours in 100 ℃ in sealed tube.After being cooled to room temperature, reaction being poured into water and distributing between water and EtOAc.Organic phase NH ₄the Cl washing, use MgSO ₄dry and concentrated.Remaining yellow solid is dissolved in ethanol (30mL), and adds 2.4g (36.1mmol) zinc powder and 3.1mL (22.6mmol) ammonium hydroxide in this suspension, and will be reflected in 78 ℃ of heating 1 hour.Reaction mixture, to room temperature, by diatomite filtration, by EtOAc and water dispenser, and extracts mixture with EtOAc (2 * 100mL).Organic phase MgSO ₄dry and concentrated, and by resistates via flash column chromatography purifying (EtOAc/ hexane), obtain K-1, be pale solid.K-1 data: LC/MS:rt=2.03min; M/z (M+H)=185.1 measured value; 185.0 theoretical value.

5-methyl-2-{ (5R)-5-methyl-4-[2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl } thieno-[2.3-d] pyrimidine (K-2)

To the chloro-5-thiotolene of 27mg (0.15mmol) 2-also [2,3-d] add 0.1mL (0.73mmol) triethylamine in pyrimidine and the mixture of 42mg (0.15mmol) F-3 in DMF (1.0mL), and mixture is just liked to heat 15 hours in 90 ℃.After being cooled to room temperature, reaction is poured into water, and distributes between water and EtOAc.The saturated NH of organic phase ₄the Cl washing, use MgSO ₄dry and concentrated.Resistates, via flash column chromatography purifying (EtOAc/ hexane), obtains K-2, is the canescence foam.K-2 data: LC/MS:rt=2.68min; M/z (M+H)=434.1 measured value; 434.2 theoretical value; HRMS m/z (M+H)=434.1769 measured value; 434.1764 theoretical value.

Reaction scheme L

2A-bis-is chloro-5,6,7,8-tetrahydro quinazoline (L-1)

Add 29.4mL (118mmol) sodium methylate and 4.6g (76mmol) urea in 10.0g (58.8mmol) the 2-oxo naphthenic acid ethyl ester in ethanol (200mL), and mixture is heated 15 hours in 80 ℃.After being cooled to room temperature, white solid is filtered, and with cold ether washing several times.Under high vacuum, after drying, white solid is dissolved in pure oxygen phosphorus chloride (77mL), and be heated to 120 ℃ 1 hour.Reaction is cooled to room temperature, and removes excess of oxygen phosphorus chloride by rotary evaporation.Resistates distributes between EtOAc (400mL) water (200mL), and organic phase is used saturated NaHCO successively ₃(200mL) and salt solution (200mL) washing.Organic phase MgSO ₄dry and concentrated.Resistates, via flash column chromatography purifying (EtOAc/ hexane), obtains L-1, is light yellow solid.L-1 data: LC/MS:rt=2.49min; M/z (M+H)=203.1 measured value; 203.0 theoretical value.

2-is chloro-5,6,7,8-tetrahydro quinazoline (L-2)

Adopting the described similar approach of K-1, by 4.7g (23.1mmol) L-1 dechlorination, obtain L-2, is white solid.L-2 data: LC/MS:rt=1.92min; M/z (M+H)=169.2 measured value; 169.1 theoretical value.

2-{ (5R)-5-methyl-4-[2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl }-5,6,7,8-tetrahydro quinazoline (L-3)

Adopting the described similar approach of K-2, by 284mg (1.68mmol) L-2 and 400mg (1.40mmol) F-3 coupling, obtain L-3, is white solid.L-3 data: LC/MS:rt=1.73min; M/z (M+H)=418.1 measured value; 418.2 theoretical value; HRMS m/z (M+H)=418.2348 measured value; 418.2355 theoretical value.

Reaction scheme M

2,4-bis-is chloro-6,7-dihydro-5H-cyclopenta [d] pyrimidine (M-1)

Add the dense HCl of 0.80mL (9.6mmol) and 5.8g (96.0mmol) urea in 10g (64.0mmol) the 2-oxo-cyclopentane ethyl formate in ethanol (130mL), and mixture is heated 4 hours in 80 ℃.After being cooled to room temperature, by solid filtering and with cold ether, wash several times.Under high vacuum after drying, be dissolved in white solid in 1N NaOH (100mL) and be heated to 110 ℃ 1 hour.Reaction is cooled to room temperature, and is acidified to pH 2 with 3N HCl, and solid collected by filtration.By ether washing cold for solid, and under high vacuum dried overnight (by Eur.J.Med.Chem.1980, the method that 75,317-322 improves a little).Under high vacuum after drying, dissolution of solid in pure oxygen phosphorus chloride (55mL), and be heated to 120 ℃ 1 hour.Reaction is cooled to room temperature, and removes excess of oxygen phosphorus chloride via rotary evaporation.EtOAc for resistates (400mL) and water (200mL) distribute, and organic phase is used saturated NaHCO successively ₃(200mL) and salt solution (200mL) washing.Organic phase MgSO ₄dry and concentrated.Resistates, via flash column chromatography purifying (EtOAc/ hexane), obtains M-1, is white solid.M-1 data: LC/MS:rt=2.40min; M/z (M+H)=189.1 measured value; 189.0 theoretical value.

2-is chloro-6,7-dihydro-5H-cyclopenta [d] pyrimidine (M-2)

Adopting the described similar approach of K-1, by 4.2g (22.2mmol) M-1 dechlorination, obtain M-2, is white solid.M-2 data: LC/MS:rt=1.22min; M/z (M+H)=155.1 measured value; 155.0 theoretical value.

2-{ (5R)-5-methyl-4-[2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl }-6,7-dihydro-5H-cyclopenta [d] pyrimidine (M-3)

Adopting the described similar approach of K-2, by 32.5mg (0.21mmol) M-2 and 30mg (0.105mmol) F-3 coupling, obtain M-3, is white solid.The data of M-3: LC/MS:rt=1.88min; M/z (M+H)-404.4 measured value; 404.2 theoretical value; HRMS m/z (M+H)=404.2204 measured value; 404.2199 theoretical value.

Reaction scheme N

2-is chloro-7,8-dihydroquinoline-5 (6H) ketone (N-1)

To the 200mg (1.23mmol) 7 in acetonitrile (6.1mL), add 1.14mL (12.3mmol) Phosphorus Oxychloride in 8-dihydroquinoline-2,5 (1H, 6H)-diketone, and mixture is heated 3 hours in 65 ℃.Reaction is cooled to room temperature, and removes excess of oxygen phosphorus chloride by rotary evaporation.Resistates distributes between EtOAc (400mL) and water (200mL), and organic phase is used saturated NaHCO successively ₃(200mL) and salt solution (200mL) washing.Organic phase MgSO ₄dry and concentrated, obtaining N-1 is the beige solid.N-1 data: LC/MS:rt=1.64min; M/z (M+H)=182.1 measured value; 182.0 theoretical value.

2-{ (5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl }-7,8-dihydroquinoline-5 (6H)-one (N-2)

Adopting the described similar approach of K-2, by 36.4mg (0.21mmol) N-1 and 50mg (0.105mmol) G-2 coupling, obtain N-2, is white solid.N-2 data: LC/MS:rt=1.88min; M/z (M+H)=445.1 measured value; 445.2 theoretical value; HRMS m/z (M+H)=445.2357 measured value; 445.2352 theoretical value.

Reaction scheme O

2-{ (5R)-5-methyl-4-[5-methyl-2-(2H-1,23-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl } pyrido [2.3-d] pyrimidine-7 (8H)-one (O-1)

To at CH ₂cl ₂(17mL) 670mg in (3.47mmol) 2-(methylthio group) pyrido [2,3-J] pyrimidine-7 (8H)-one (uses J.Med.Chem.2000,43, method in 4606-4616 is synthetic) in add 1.55g (6.93mmol) mCPBA, and by mixture in room temperature 1 hour.To reflect directly and concentrate, and be dissolved in again in dioxane (10mL).Add 675mg (2.25mmol) of G-2 and 2.4mL (17.3mmol) triethylamine in this solution.Reaction be heated to 100 ℃ 6 hours.Reaction is cooled to room temperature, uses saturated NH ₄cl ends, and extracts with EtOAc (4x20mL).Organic phase MgSO ₄dry and concentrated.Resistates, via flash column chromatography purifying (EtOAc/ hexane), obtains O-1, is solid.O-1 data: LC/MS:rt=2.01min; M/z (M+H)=445.4 measured value; 445.2 theoretical value.

the chloro-2-{ of 6-(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl } pyrido [2.3-d] pyrimidine-7 (8H)-one (O-2)

Add 347mg (2.60mmol) N-chloro-succinimide (NCS) and 108mg (0.45mmol) benzoyl peroxide in 660mg (1.49mmol) O-1 in DMF (7.4mL), and by mixture in stirring at room 24 hours.EtOAc (75mL) dilution water (4x30mL) washing for reaction.Organic phase MgSO ₄dry and concentrated.Resistates, via flash column chromatography purifying (EtOAc/ hexane), obtains O-2, is white solid.O-2 data: LC/MS:rt=2.19min; M/z (M+H)=479.1 measured value; 479.2 theoretical value; HRMS m/z (M+H)=479.1748 measured value; 479.1710 theoretical value.

Reaction scheme P

the chloro-5-thiotolene of 2-is [2J1 pyrimidine-4-amine (P-1) also

Also in the solution of [2,3] pyrimidines (0.20g, 0.9mmol) in 5mL THF, add ammonium hydroxide (0.57g, 4.5mmol) to the chloro-5-thiotolene of 2,4-bis-, and in stirring at room 2 days.Then EtOAc and water dispenser for this system, use MgSO ₄dry and concentrated, and use normal phase chromatography purifying (0 → 75%EtOAc/ hexane), obtain P-1, be the bone meal.P-1 data: LC/MS:rt=1.48min; M/z (M+H)=200.1 measured value; 200.1 theoretical value.

5-methyl-2-{4-[2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl } thieno-[2,3] pyrimidine-4-amine (P-2)

Add triethylamine (0.25g, 2.5mmol) to P-1 (0.09g, 0.49mmol) and F-3 (0.15g, 0.54mmol) in solution in 2mL DMF, and by this system in 185 ℃ with microwave heating 40 minutes.Then by this system with distributing between EtOAc and water, use MgSO ₄dry and concentrated, and purify (EtOAc/ hexane) with normal phase chromatography, obtain P-2, be white foam shape thing.P-2 data: LC/MS:rt=1.45min; M/z (M+H)=449.1 measured value; 449.1 theoretical value .HRMS m/z (M+H)=449.1869 measured value; 449.1867 theoretical value.

Reaction scheme Q

2-amino-4-methyl-3-furans formonitrile HCN (Q-1)

Add the solution of propane dinitrile (0.9g, 13.5mmol) in TEA (1.36g, 13.5mmol) and 10mL MeOH in solution to pyruvic alcohol (1.0g, 13.5mmol) in 45mL MeOH.After stirred overnight at room temperature, except desolventizing, obtain Q-1 with rotary evaporation, be the brown semisolid.The Q-1 data: ¹h NMR (500MHz, CDCl ₃) δ 2.01 (s, 3H), 4.71 (br s, 2H), 6.57 (s, 1H).

the chloro-5-methyl furan of 2-is [2,3] pyrimidine (O-2) also

Add trichloromethylchloroformate (3.9g, 19.6mmol) in the solution of Q-1 (1.6g, 13.1mmol) in 13mL CAN in sealed tube, and in 95 ℃ of heated overnight.This system cools, to room temperature, and is distributed content between EtOAc/DCM and water, use MgSO ₄dry and concentrated, obtain brown oil.Add zinc powder (2.6g, 39.4mmol), ammonium hydroxide (3.0g, 24.6mmol) in the solution of this brown oil (1.0g, 4.9mmol) in 30mL EtOH, and add hanker 78 ℃ 0.5 hour.Then this system cools and filter by Celite pad.Then filtrate is distributed between EtOAc and water, use MgSO ₄drying, concentrated, and, via normal phase chromatography purifying (EtOAc/ hexane), obtain Q-2, be the yellow crystal solid.Q-2 data: LC/MS:rt=1.65min; M/z (M+H)=169.0 measured value; 169.0 theoretical value.

5-methyl-2-{ (5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl } furo [2,3] pyrimidine (Q-3)

Add triethylamine (0.07g, 0.71mmol) to Q-2 (0.02g, 0.14mmol) and G-2 (0.04g, 0.14mmol) in solution in 2mLDMF, and by this system in 12O ℃ with microwave heating 25 minutes.This reaction mixture being filtered, and, by anti-phase condition purifying (solution of 5% → 95%0.1%TFA aqueous solution: 0.1%TFA in CAN), then use the saturated sodium carbonate alkalization, obtained Q-3, is bone look foam.Q-3 data: LC/MS:rt=2.55min; M/z (M+H)=432.3 measured value; 432.4 theoretical value .HRMS m/z (M+H)=432.2144 measured value; 432.2143 theoretical value.

Reaction scheme R

2-is chloro-5, and the 6-dimethyl furan is [2,3] pyrimidine (R-2) and the chloro-4-oxyethyl group-5 of 2-also, and the 6-dimethyl furan is [2,3] pyrimidine (R-3) also

Amino-4 to the 2-in sealed tube, add trichloromethylchloroformate (3.9g, 19.6mmol) in the 5-dimethyl-solution of 3-furans formonitrile HCN (1.0g, 7.3mmol) in 7mL CAN, and be heated to 95 ℃ and spend the night.This system cools, to room temperature, and is distributed content between EtOAc/DCM and water, use MgSO ₄drying, concentrated, and purify (0->100%EtOAc/ hexane) with normal phase chromatography, obtain R-1, be pink solid.Add zinc powder (0.56g, 8.6mmol), ammonium hydroxide (0.67g, 5.4mmol) in the mixture of this solid (0.23g, 1.0mmol) in 8mL EtOH, and be heated to 78 ℃ and spend the night.Then by this system cools, and by Celite pad, filter.Filtrate is distributed between EtOAc and water, use MgSO ₄dry also filtration, the mixture of acquisition R-2 and R-3, be the brown solid, it directly uses.R-2 data: LC/MS:rt=2.04min; M/z (M+H)=183.0 measured value; 183.0 theoretical value .R-3 data: LC/MS:rt=3.19min; M/z (M+H)=227.1 measured value; 227.0 theoretical value.

Reaction scheme S

5-amino-1,3-dimethyl pyrazole-4-formonitrile HCN (S-1)

Add methyl hydrazine (1.3g, 29.4mmol) in (1-oxyethyl group ethylidene) propane dinitrile (4.0g, 29.4mmol) solution in 75mL MeOH, and this system is stirred to 2h in 65 ℃.Reaction content is poured in the flask that contains 1N HCl.After stirred overnight at room temperature, with rotary evaporation, except desolventizing, obtain the brown semisolid.This material is distributed between EtOAc and water, use MgSO ₄dry and concentrated, obtain S-1, be brown ceramic powder.The S-1 data: ¹h NMR (500MHz, CDCl ₃) δ 2.21 (s, 3H), 3.55 (s, 3H), 4.13 (br s, 2H).

6-is chloro-1,3-dimethyl pyrazole [3,4] pyrimidine (S-2)

Add trichloromethylchloroformate (2.1g, 11.0mmol) in the solution of S-1 (1.0g, 7.3mmol) in 7mL CAN in sealed tube, and be heated to 95 ℃ and spend the night.This system cools, to room temperature, and is distributed content between EtOAc/DCM and water, use MgSO ₄drying, concentrated, and purify (EtOAc/ hexane) with normal phase chromatography, obtain white crystalline powder.To add zinc powder (0.9g, 13.9mmol), ammonium hydroxide (1.1g, 8.7mmol) in the solution of this white crystalline powder (0.37g, 1.7mmol) in 12mL EtOH and be heated to 78 ℃ 0.5 hour.Then by this system cools to and by Celite pad, filter.Filtrate is distributed between EtOAc and water, use MgSO ₄dry and concentrated, obtain S-2, be yellow solid.S-2 data: LC/MS:rt=1.31min; M/z (M+H)=183.1 measured value; 183.0 theoretical value.

Reaction scheme T

5-is bromo-1,3-benzoxazole-2-mercaptan (T-1)

Add potassium ethyl xanthonate (5.1g, 31.9mmol) in solution to 2-amino-4-bromophenol (3.0g, 15.9mmol) in 45mL EtOH, and this system is stirred 3 hours in 80 ℃, be cooled to room temperature and stir and spend the night.Except desolventizing, then be dissolved in water, and use the acetic acid acidifying in vacuum, produce precipitation.Filtering and collect this throw out, obtain T-1, is light yellow white solid.T-1 data: LC/MS:rt=2.17min; M/z (M+H)=230.0 measured value; 230.0 theoretical value.

5-bromo-2 is chloro-1,3-benzoxazole (T-2)

Add Phosphorus Oxychloride (6.0g, 39.1mmol) in solution to T-1 (1.8g, 7.8mmol) in 6mL DCM, then add phosphorus pentachloride (2.4g, 11.7mmol), and by this system in stirred overnight at room temperature.Remove desolventizing in vacuum, and reaction content is distributed between DCM, saturated solution of sodium bicarbonate and water.Organic layer Na ₂sO ₄drying, concentrated, and purify (EtOAc/ hexane) with normal phase chromatography, obtain T-2, be white solid.T-2 data: LC/MS:rt=2.37min; M/z (MS)=232.9 measured value; 232.9 theoretical value.

Reaction scheme U

4-(allyloxy)-2-(methylthio group)-5-vinyl pyrimidine (U-1)

Add 1.12g (19.3mmol) vinyl carbinol and 6.45mL (12.9mmol, 2M is in THF) NaHMDS in the chloro-2-of 3.0g (12.9mmol) 4-(methylthio group) pyrimidine in THF (65mL)-5-ethyl formate.This reacts on stirring at room 2 hours, and ends with salt solution.EtOAc for water (4x20mL) extraction, use MgSO ₄dry and concentrated.In room temperature, crude product mixture is dissolved in THF (50mL) again, and adds 38.7mL (38.7mmol, 1M is in THF) diisobutyl aluminium hydride.To react with saturated sodium-potassium tartrate and end after 45 minutes.EtOAc for water (4x50mL) extraction, use MgSO ₄dry and concentrated.Resistates, via flash column chromatography purifying (EtOAc/ hexane), obtains oily matter.Gained oily matter is dissolved in chloroform (31mL), and adds 4.1g (4.7mmol) MnO in this solution ₂.React on stirring at room 4 hours, by diatomite filtration concentrated, obtain clarification oily matter.Gained oily matter in THF (10mL) is added to 8.3mL (16.7mmol, the solution of 2M in THF) in NaHMDS and the suspension of 6.8g (19.0mmol) Diethylaminoethyl triphenyl phosphonium in THF (40mL), and this reaction is stirred 2 hours.Reaction mixture water (50mL) is ended, and extracts with EtOAc (4 * 50mL).The organic phase MgSO merged ₄dry and concentrated.Resistates, via flash column chromatography purifying (EtOAc/ hexane), obtains oily matter.U-1 data: LC/MS:rt=2.87min; M/z (M+H)=208.9 measured value; 209.1 theoretical value.

(5R)-1-[4-(allyloxy)-5-vinyl pyrimidine-2-yl]-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane (U-2)

To at CH ₂cl ₂(12.0mL) add 1.08g (4.8mmol) mCPBA in the 500mg in (2.40mmol) U-1, and by mixture in stirring at room 1 hour.To react directly concentrated, resistates is dissolved in DMF (10mL).Add 1.67mL (12.0mmol) triethylamine and 1.44g (4.8mmol) G2 in this mixture, and reaction is heated to 100 ℃.After 4 hours, reacting cooling and distributing between EtOAc and water.The organism MgSO merged ₄dry and concentrated.Resistates, via flash column chromatography purifying (EtOAc/ hexane), obtains U-2, is the spumescence solid.U-2 data: LC/MS:rt-2.30min; M/z (M+H)=460.3 measured value; 460.2 theoretical value.

2-{ (5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl }-7H-pyrans [2,3-d] pyrimidine (U-3) also

Degassed 1, add 0.12g (4.8mmol) Zhan 1b catalyzer to 500mg (1.09mmol) U-2 in the mixture in 2-ethylene dichloride (5.4mL), and by mixture in stirring at room 15 hours.Reaction distributes between EtOAc and water, and the organism MgSO merged ₄dry and concentrated.Resistates, via flash column chromatography purifying (EtOAc/ hexane), obtains U-3, is the spumescence solid.U-3 data: LC/MS:rt=1.69min; M/z (M+H)=432.2 measured value; 432.2 theoretical value; HRMS m/z (M+H)=432.2155 measured value; 432.2143 theoretical value.

2-{ (5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl }-6,7-dihydro-5H-pyrans is [2,3-d] pyrimidine (U-4) also

Add the palladium hydroxide of 68mg 20% weight in the mixture of 420mg (0.97mmol) U-3 in degassed ethyl acetate (9.7mL), and reaction mixture is positioned under normal atmosphere hydrogen of room temperature.After 2 hours, reaction is by diatomite filtration concentrated.Resistates, via flash column chromatography purifying (EtOAc/ hexane), obtains U-4, is the spumescence solid.U-4 data: LC/MS:rt=1.63min; M/z (M+H)=434.2 measured value; 434.1 theoretical value; HRMSm/z (M+H)=434.2312 measured value; 434.2299 theoretical value.

Reaction scheme V

the chloro-5-methyl-4-[(1E of 2-)-propyl-1-alkene-1-yl] pyrimidine (V-1)

To the 1.5g (9.2mmol) 2 in DMF (35mL), add 1.5g (10.1mmol) allyl group three potassium fluoborates, 150mg (0.18mmol) PdCl in the chloro-5-methylpyrimidine of 4-bis- ₂(dppf)-DCM and 1.54mL (11mmol) triethylamine.This reacts on 100 ℃ and stirs 15 hours.To reflect the dilution with EtOAc (60mL), water, saturated sodium bicarbonate solution and salt water washing are also concentrated.Resistates, via flash column chromatography purifying (EtOAc/ hexane), obtains oily matter.V-1 data: LC/MS:rt=2.06min; M/z (M+H)=169.1 measured value; 169.6 theoretical value.

the chloro-5-methyl of 2--4-propyl group pyrimidine (V-2)

Add 100mg 10% palladium on carbon in 550mg (3.26mmol) V-1 in ethanol (10mL), and mixture is stirred 15 hours under gasbag pressure hydrogen in room temperature.To react by diatomite filtration concentrated, obtain oily matter.V-2 data: LC/MS:rt=2.04min; M/z (M+H)=171.1 measured value; 171.6 theoretical value.

(5R)-5-methyl isophthalic acid-(' 5-methyl-4-propyl group pyrimidine-2-base)-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane (V-3)

289mg (0.97mmol) G-2,165mg (0.97mmol) V-2 and the mixture of 674uL (4.83mmol) triethylamine in DMF (5mL) are stirred 15 hours in 100 ℃.EtOAc (60mL) dilution for this reaction, water, saturated sodium bicarbonate solution and salt water washing are also concentrated.Resistates, via flash column chromatography purifying (EtOAc/ hexane), obtains foam.V-3 data: LC/MS:rt=2.30min; M/z (M+H)=434.2 measured value; 434.5 theoretical value; HRMSm/z (M+H)=434.2667 measured value; 434.2663 theoretical value.

Reaction scheme W

(5R) the chloro-5-of-1-[4-(trifluoromethyl) pyrimidine-2-base]-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane (W-1)

By 100mg (0.33mmol) G-2,87mg (0.4mmol) 2, the chloro-5-of 4-bis-(trifluoromethyl) pyrimidine and the mixture of 233 μ L (1.67mmol) triethylamines in DMF (2mL) stir 30 minutes in microwave chemosynthesis instrument in 100 ℃.EtOAc (60mL) for reaction, water, saturated sodium bicarbonate solution and salt water washing are also concentrated.Resistates, via purified by flash chromatography (EtOAc/ hexane), obtains the spumescence solid.W-1 data: LC/MS:rt=2.63min; M/z (M+H)=480.1 measured value; 480.9 theoretical value

(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-1-[4-methyl-5-(trifluoromethyl) pyrimidine-2-base]-Isosorbide-5-Nitrae-Diazesuberane (W-2)

By 30mg (0.063mmol) W-1,22mg (0.125mmol) tin tetramethide, 5mg (0.006mmol) PdCl ₂(dppf) and the mixture of 26mg (0.625mmol) LiCl in DMF (1.5mL) in 130 ℃, stir 30 minutes.Add again 22mg (0.125mmol) tin tetramethide, and will react and stir more than 1 hour.To react the dilution with EtOAc (60mL), with saturated sodium bicarbonate solution and salt water washing concentrated.Resistates, via flash column chromatography purifying (EtOAc/ hexane), obtains the spumescence solid.W-2 data: LC/MS:rt=3.48min; M/z (M+H)=460.0 measured value; 460.5 theoretical value; HRMS m/z (M+H)=460.2090 measured value; 460.2067 theoretical value.

(5R)-1-[4-methoxyl group-5-(trifluoromethyl) pyrimidine-2-base]-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane (W-3)

By the mixture in 312mg (0.65mmol) W-1 and 446 μ L (1.95mmol, 4.37N is in methyl alcohol) in stirring at room 30 minutes.To reflect the dilution with EtOAc (60mL), water, saturated sodium bicarbonate and salt water washing are also concentrated.Resistates, via flash column chromatography purifying (EtOAc/ hexane), obtains the spumescence solid.W-3 data: LC/MS:rt=3.27min; M/z (M+H)=476.0 measured value; 476.5 theoretical value; HRMS m/z (M+H)=476.2022 measured value; 476.2017 theoretical value.

Reaction scheme X

2-methyl-6-{ (5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl } cigarette aldehyde (X-I)

By 50mg (0.17mmol) G-2,34mg (0.22mmol) 2,6-dichloropyridine-3-formaldehyde and the mixture of 116 μ L (0.84mmol) triethylamines in DMF (3mL) stir 45 minutes in 100 ℃.EtOAc (60mL) dilution for reaction, water, saturated sodium bicarbonate solution and salt water washing are also concentrated.Resistates, via flash column chromatography purifying (EtOAc/ hexane), obtains the spumescence solid.W-1 data: LC/MS:rt=1.96min; M/z (M+H)=419.1 measured value; 419.5 theoretical value.

2-methyl-6-{ (5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl } pyridin-3-yl) methyl alcohol (X-2)

By 30mg (0.072mmol) X-1 and 2.7mg (0.072mmol) sodium borohydride, the mixture in methyl alcohol (1mL) was in stirring at room 10 minutes.EtOAc (60mL) dilution for reaction, water, saturated sodium bicarbonate solution and salt water washing, by dried over sodium sulfate concentrated, obtain solid.X-2 data: LC/MS:rt=1.25min; M/z (M+H)=421.2 measured value; 421.5 theoretical value; HRMS m/z (M+H)=421.2347 measured value; 421.2347 theoretical value.

table 1

Following compound is used aforesaid method to prepare, but replaces the suitable replacement reagent described in above-mentioned embodiment and embodiment.Required starting raw material be that can buy from the market, described in document or the organic synthesis those skilled in the art not carry out excessive test just easily synthetic.

Following compound is used aforesaid method to prepare, but replaces the suitable replacement reagent described in above-mentioned embodiment and embodiment.Required starting raw material be that can buy from the market, described in document or the organic synthesis those skilled in the art not carry out excessive test just easily synthetic: the fluoro-2-{ of 6-(5S)-5-methyl-4-[2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl } quinazoline; The chloro-2-{ of 5-(5S)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl }-1, the 3-benzoxazole; 3-{[(7S)-4-(5-chloro-1,3-benzoxazole-2-yl)-7-methyl isophthalic acid, 4-Diazesuberane-1-yl] carbonyl }-4-(2H-1,2,3-triazole-2-yl) methyl benzoate; 3-{[(7S)-4-(5-chloro-1,3-benzoxazole-2-yl)-7-methyl isophthalic acid, 4-Diazesuberane-1-yl] carbonyl }-4-(2H-1,2,3-triazole-2-yl) phenylformic acid; [3-{[(7S)-4-(5-chloro-1,3-benzoxazole-2-yl)-7-methyl isophthalic acid, 4-Diazesuberane-1-yl] carbonyl }-4-(2H-1,2,3-triazole-2-yl) phenyl] methyl alcohol; The fluoro-2-{ of 6,7-bis-(5S)-5-methyl-4-[2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl } quinoxaline; 5-methyl-2-{ (5S)-5-methyl-4-[2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl } thieno-[2,3-d] pyrimidine; 2-{ (5S)-5-methyl-4-[2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl }-5,6,7, the 8-tetrahydro quinazoline; 2-{ (5S)-5-methyl-4-[2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl }-6,7-dihydro-5H-cyclopenta [d] pyrimidine; 2-{ (5S)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl }-7,8-dihydroquinoline-5 (6H)-one; The chloro-2-{ of 6-(5S)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl } pyrido [2,3-d] pyrimidine-7 (8H)-one; 5-methyl-2-(4-[2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl } thieno-[2,3] pyrimidine-4-amine; 5-methyl-2-{ (5S)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl } furo [2,3] pyrimidine; 2-{ (5S)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl }-6,7-dihydro-5H-pyrans is [2,3-d] pyrimidine also; (5S)-5-methyl isophthalic acid-(5-methyl-4-propyl group pyrimidine-2-base)-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane; (5S) the chloro-5-of-1-[4-(trifluoromethyl) pyrimidine-2-base]-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane; (5S)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-1-[4-methyl-5-(trifluoromethyl) pyrimidine-2-base]-Isosorbide-5-Nitrae-Diazesuberane; (5S)-1-[4-methoxyl group-5-(trifluoromethyl) pyrimidine-2-base]-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane; 2-methyl-6-{ (5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl } pyridin-3-yl) methyl alcohol; 4-methyl-2-{ (5S) S-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl }-1, the 3-benzoxazole; 5-methyl-2-{ (5S)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl } thieno-[2,3-d] pyrimidine; 2-{ (5S)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl }-5,6,7, the 8-tetrahydro quinazoline; 2-{ (5S)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl }-6,7-dihydro-5H-cyclopenta [d] pyrimidine; 5,6-dimethyl-2-{ (5S)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl } furo [2,3-d] pyrimidine; 4-oxyethyl group-5,6-dimethyl-2-{ (5S)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl } furo [2,3-d] pyrimidine; 1,3-dimethyl-6-{ (5S)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl }-1H-pyrazolo [3,4-d] pyrimidine; The bromo-2-{ of 5-(5S)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl }-1, the 3-benzoxazole; (5S)-5-methyl isophthalic acid-[4-methyl-5-(trifluoromethyl)-pyrimidine-2-base]-4-[2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane; (5S)-1-[4-methoxyl group-5-(trifluoromethyl) pyrimidine-2-base]-5-methyl-4-[2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane.

Although the present invention is described and illustrates according to its some particular, in the situation that do not deviate from the spirit and scope of the present invention, it will be appreciated by those skilled in the art that can the whole bag of tricks and scheme modify, change, improve, replace, delete or add.

Claims

1. be selected from following compound:

The fluoro-2-{ of 6-(5R)-5-methyl-4-[2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl } quinazoline;

The chloro-2-{ of 5-(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl }-1, the 3-benzo

azoles;

(5-is chloro-1, the 3-benzo for 3-{[(7R)-4-

azoles-2-yl)-7-methyl isophthalic acid, 4-Diazesuberane-1-yl] carbonyl }-4-(2H-1,2,3-triazole-2-yl) methyl benzoate;

(5-is chloro-1, the 3-benzo for 3-{[(7R)-4-

azoles-2-yl)-7-methyl isophthalic acid, 4-Diazesuberane-1-yl] carbonyl }-4-(2H-1,2,3-triazole-2-yl) phenylformic acid;

[3-{[(7R)-(5-is chloro-1, the 3-benzo for 4-

azoles-2-yl)-7-methyl isophthalic acid, 4-Diazesuberane-1-yl] carbonyl }-4-(2H-1,2,3-triazole-2-yl) phenyl] methyl alcohol;

The fluoro-2-{ of 6,7-bis-(5R)-5-methyl-4-[2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl } quinoxaline;

5-methyl-2-{ (5R)-5-methyl-4-[2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl } thieno-[2,3-d] pyrimidine;

2-{ (5R)-5-methyl-4-[2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl }-5,6,7, the 8-tetrahydro quinazoline;

2-{ (5R)-5-methyl-4-[2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl }-6,7-dihydro-5H-cyclopenta [d] pyrimidine;

2-{ (5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl }-7,8-dihydroquinoline-5 (6H)-one;

The chloro-2-{ of 6-(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl } pyrido [2,3-d] pyrimidine-7 (8H)-one;

5-methyl-2-{ (5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl } furo [2,3] pyrimidine;

2-{ (5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl }-6,7-dihydro-5H-pyrans is [2,3-d] pyrimidine also;

(5R)-5-methyl isophthalic acid-(5-methyl-4-propyl group pyrimidine-2-base)-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane;

(5R) the chloro-5-of-1-[4-(trifluoromethyl) pyrimidine-2-base]-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane;

(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-1-[4-methyl-5-(trifluoromethyl) pyrimidine-2-base]-Isosorbide-5-Nitrae-Diazesuberane;

(5R)-1-[4-methoxyl group-5-(trifluoromethyl) pyrimidine-2-base]-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane;

2-methyl-6-{ (5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl } pyridin-3-yl) methyl alcohol;

4-methyl-2-{ (5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl }-1, the 3-benzo

azoles;

5-methyl-2-{ (5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl } thieno-[2,3-d] pyrimidine;

2-{ (5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl }-5,6,7, the 8-tetrahydro quinazoline;

2-{ (5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl }-6,7-dihydro-5H-cyclopenta [d] pyrimidine;

5,6-dimethyl-2-{ (5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl } furo [2,3-d] pyrimidine;

4-oxyethyl group-5,6-dimethyl-2-{ (5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl } furo [2,3-d] pyrimidine;

1,3-dimethyl-6-{ (5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl }-1H-pyrazolo [3,4-d] pyrimidine;

The bromo-2-{ of 5-(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl }-1, the 3-benzo

azoles;

(5R)-5-methyl isophthalic acid-[4-methyl-5-(trifluoromethyl)-pyrimidine-2-base]-4-[2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane;

(5R)-1-[4-methoxyl group-5-(trifluoromethyl) pyrimidine-2-base]-5-methyl-4-[2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane;

Perhaps its pharmacologically acceptable salt.

2. the pharmaceutical composition that comprises the compound or pharmaceutically acceptable salt thereof of inert support and claim 1.

3. for the compound or pharmaceutically acceptable salt thereof of the claim 1 of medicine.

4. the application of the compound or pharmaceutically acceptable salt thereof of claim 1 in the medicine for the preparation for the treatment of or prevention somnopathy.

5. the compound of claim 1 or its pharmacologically acceptable salt application in the medicine for the preparation of improving sleep quality.

6. the compound of claim 1 or the application of its pharmacologically acceptable salt in the medicine for the preparation for the treatment of of insomnia patients.

7. the compound of claim 1 or its pharmacologically acceptable salt application in the medicine for the preparation for the treatment of or obesity controlling.

8. compound, described compound is the chloro-2-{ of 5-(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl }-1, the 3-benzo

azoles or its pharmacologically acceptable salt.

9. the compound of claim 8, wherein said compound is the chloro-2-{ of 5-(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl }-1, the 3-benzo

azoles.

10. the compound of claim 8, wherein said compound is the chloro-2-{ of the 5-of pharmaceutical acceptable salt (5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane-1-yl }-1, the 3-benzo

azoles.

11. the pharmaceutical composition of the compound or pharmaceutically acceptable salt thereof that comprises inert support and claim 8.

12. the pharmaceutical composition of the compound that comprises inert support and claim 9.

13. the pharmaceutical composition of the compound of the claim 10 that comprises inert support and pharmaceutical acceptable salt.

14. the application of the compound or pharmaceutically acceptable salt thereof of claim 8 in the medicine for the preparation for the treatment of or prevention somnopathy.

15. the application of the compound or pharmaceutically acceptable salt thereof of claim 8 in the medicine for the preparation of improving sleep quality.

16. the application of the compound or pharmaceutically acceptable salt thereof of claim 8 in the medicine for the preparation for the treatment of of insomnia patients.

17. the application of the compound or pharmaceutically acceptable salt thereof of claim 8 in the medicine for the preparation for the treatment of or obesity controlling.