CN101155792A

CN101155792A - Amidopropoxyphenyl orexin receptor antagonists

Info

Publication number: CN101155792A
Application number: CNA200680011562XA
Authority: CN
Inventors: P·J·科尔曼; J·施赖尔
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 2005-04-12
Filing date: 2006-04-10
Publication date: 2008-04-02

Abstract

The present invention is directed to amidopropoxyphenyl 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

Amidopropoxyphenyl orexin receptor antagonists

Background of invention

Orexin (inferior colliculus secretin) comprises two kinds of neuropeptides that produce in hypothalamus: orexin A (OX-A) (a kind of 33 amino acid whose peptide) and orexin B (OX-B) (a kind of 28 amino acid whose peptide) (people such as Sakurai T, 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 T, Cell, 1998,92,573-585).Orexin is also regulated the state of sleep and insomnia, and this may open new treatment approach people such as (, Cell, 1999,98,437451) Chemelli R.M for narcolepsy or insomniac.Two kinds of orexin acceptors are cloned and are characterized in Mammals.They belong to the g protein coupled receptor superfamily (people such as Sakurai T, Cell, 1998,92,573-585): orexin-1 acceptor (OX or OX1R) is to OX-A optionally and orexin-2 acceptor (OX or OX2R) can be in conjunction with OX-A and OX-B.Suppose that the physiological action that has orexin to participate in is considered to by expressing simultaneously as OX 1 acceptor of two hypotypes of orexin acceptor and OX 2 acceptors one of them or two.The orexin acceptor be in mammal brain, find and its in the pathology relevant, have multiple connotation with general orexin systematic function obstacle.

The orexin acceptor be in mammal brain, find and its to have multiple connotation in pathology for example depressed; Anxiety; Habituation; Obsession; The emotionality neurosis; Depressive neurosis; Anxiety neurosis; Dysthymia; 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 (Huntington ' s disease) and Tourette syndrome (Tourette syndrome) for example; Eating disorder is apocleisis for example, Bulimia nerovsa, emaciation and obesity; Cardiovascular disorder; Diabetes; Appetite/sense of taste disorder; Vomit, tell, feel sick; Asthma; Cancer; Parkinson's disease; Cushing (Cushing) syndrome/disease; Basophilic adenoma; Prolactinoma; Hyperprolactinemia; Pituitary body knurl/adenoma; Hypothalamic disorder; Inflammatory bowel; Motility disturbances of the stomach; Stomach ulcer; Adiposogenital dystrophy (Froehlich ' s syndrome); The suprarenal gland disease of pituitary gland; The pituitary body disease; The suprarenal gland subpituitarism; The suprarenal gland hyperpituitarism; The hypothalamic hypoadenia; Kalman (Kallman) syndrome (anosmia, hyposmia); Functional or psychological amenorrhoea; Subpituitarism; The hypothalamus thyroprivia; Hypothalamus-suprarenal gland dysfunction; The special property sent out hyperprolactinemia; The hypothalamus obstacle of growth hormone deficiency; The special property sent out growth deficiency; Nanism; Gigantosoma; Acromegaly; Biology and day-night rhythm disorder; With disease neurological disorder for example, sleep disordered relevant of neuropathic pain with the restless legs syndromes; The heart and lung disease, acute and congestive heart failure; Hypopiesia; Hypertension; Urinary retention; Osteoporosis; Stenocardia; Myocardial infarction; Ischemia or congested apoplexy; Subarachnoid hemorrhage; Ulcer; Transformation reactions; Benign prostatauxe; Chronic renal failure; Ephrosis; The sugar dosis tolerata is grand low; Migraine; Hyperpathia; Pain; That improve or exaggerate for example hyperpathia of pain sensitivity; Cusalgia and pain are quick; Severe pain; Burn pain; Atypical face ache; Neuropathic pain; Backache; Plyability zone pain syndromes I and II; Arthritis pain; Sport injury pain; The pain relevant with infection is HIV for example, pain after the chemotherapy; Pain after the apoplexy; Postoperative pain; Neurodynia; Vomiting is felt sick, and tells; The symptom relevant with 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; Hypnolepsy; Insomnia; Parasomnia; Trouble with jet lag; And the nerve degeneration kind obstacle comprises that the disease on the nosonomy for example suppresses the compound disease of releasing-dementia-Parkinson's disease-myatrophy; Grey ball-pons-black substance is degenerated; Epilepsy; Epilepsy obstacle and other and the bad relevant disease of general orexin systematic function.

Some orexin acceptor is picked up anti-agent and is disclosed in PCT patent publications WO 99/09024, WO99/58533, and WO 00/47576, WO 00/47577, and WO 00/47580, and WO 01/68609, WO 01/85693, WO 01/96302, and WO 2002/044172, and WO 2002/051232, WO 2002/051838, WO2002/089800, WO 2002/090355, and WO 2003/002559, WO 2003/002561, WO2003/032991, WO 2003/037847, and WO 2003/041711, WO 03/051368, WO 2003/051872, and WO 2003/051873, and WO 2004/004733, WO 2004/033418, WO 2004/083218, and WO2004/085403 is among the WO 2005/060959.

The invention summary

The present invention relates to amino propoxy-phenyl compound, it is the orexin receptor antagonist, is used for the treatment of or prevents the caused nervosa of orexin acceptor and spirituality obstacle and disease.The invention still further relates to the pharmaceutical composition and these compounds and the purposes of composition in prevention or caused this class disease of treatment orexin acceptor that contain these compounds.

Detailed Description Of The Invention

The present invention relates to formula I compound:

Wherein:

A is selected from phenyl, naphthyl and heteroaryl;

R ^1a, R ^1bAnd R ^1cIf can not exist when the valency of A does not allow such replacement, and the group that independently is selected from comprises:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4)-(C=O) _m-O _n-C _1-6Alkyl, wherein m is 0 or 1, n be 0 or 1 (if wherein m be 0 or n be 0, a singly-bound then appears) and wherein alkyl be unsubstituted or with 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 with one or more R of being selected from ¹³Substituting group replace,

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

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

(8)-(C=O) _m-O _n-heterocyclic radical, wherein heterocyclic radical is unsubstituted or with one or more R of being selected from ¹³Substituting group replace,

(9)-(C=O) _m-NR ¹⁰R ¹¹, R wherein ¹⁰And R ¹¹The group that independently is selected from comprises:

(a) hydrogen,

(b) C _1-6Alkyl, it is unsubstituted or uses R ¹³Replace,

(c) C _3-6Thiazolinyl, it is unsubstituted or uses R ¹³Replace,

(d) cycloalkyl, it is unsubstituted or uses R ¹³Replace,

(e) phenyl, it is unsubstituted or uses R ¹³That replace and

(f) heterocyclic radical, it is unsubstituted or uses R ¹³Replace,

(10)-S(O) ₂-NR ¹⁰R ¹¹，

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

(12)-CO ₂H，

(13)-CN and

(14)-NO ₂；

R ²The group that is selected from comprises:

(1) hydrogen,

(2) C _1-6Alkyl, it is unsubstituted or with one or more R of being selected from ¹³Substituting group replace,

(3)-C _3-6Cycloalkyl, it is unsubstituted or with one or more R of being selected from ¹³Substituting group replace,

(4)-and phenyl, it is unsubstituted or with one or more R of being selected from ¹³Substituting group replace and

(5)-and heteroaryl, it is unsubstituted or with one or more R of being selected from ¹³Substituting group replace;

R ³And R ⁴The group that independently is selected from comprises:

(1) hydrogen,

(5)-and heteroaryl, it is unsubstituted or with one or more R of being selected from ¹³Substituting group replace,

Perhaps R ³And R ⁴Form C with the carbon that links to each other with them _3-6Cycloalkyl ring, it is unsubstituted or uses R ¹³Replace;

R ⁵And R ⁶The group that independently is selected from comprises:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4)-O _n-C _1-6Alkyl, wherein alkyl is unsubstituted or with one or more R of being selected from ¹³Substituting group replace,

(5)-O _n-C _3-6Alkyl, wherein cycloalkyl is unsubstituted or with one or more R of being selected from ¹³Substituting group replace,

(6)-and phenyl, it is unsubstituted or with one or more R of being selected from ¹³Substituting group replace,

(7)-and heterocyclic radical, it is unsubstituted or with one or more R of being selected from ¹³Substituting group replace,

(8)-CN，

Perhaps R ⁵And R ⁶Form C with the carbon that links to each other with them _3-6Cycloalkyl ring, it is unsubstituted or uses R ¹³Replace;

R ^7a, R ^7bAnd R ^7cThe group that independently is selected from comprises:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4)-(C=O) _m-O _n-C _1-6Alkyl, wherein alkyl is unsubstituted or with one or more R of being selected from ¹³Substituting group replace,

(6)-(C=O) _m-C _2-4Thiazolinyl, wherein thiazolinyl is unsubstituted or with one or more R of being selected from ¹³Substituting 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 and

(14)-NO ₂；

R ¹³The group that is selected from comprises:

(1) halogen,

(2) hydroxyl,

(3)-(C=O) _m-O _n-C _1-6Alkyl, wherein alkyl is unsubstituted or with one or more R of being 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 with one or more R of being selected from ¹⁴Substituting group replace,

(6)-(C=O) _m-C _2-4Thiazolinyl, wherein thiazolinyl is unsubstituted or with 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 with one or more R of being selected from ¹⁴Substituting group generation,

(8)-(C=O) _m-O _n-heterocyclic radical, wherein heterocyclic radical is unsubstituted or with 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 and

(14)-NO ₂；

R ¹⁴The group that is selected from comprises:

(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) heterocyclic radical,

(10)-CO ₂H and

(11)-CN；

And pharmacy acceptable salt.

As an embodiment of The compounds of this invention,, wherein:

A is selected from phenyl and heteroaryl;

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4) C _1-6Alkyl, it is unsubstituted or uses halogen, hydroxyl, phenyl or-O-C _1-6Alkyl replaces,

(5)-O-C _1-6Alkyl, it is unsubstituted or uses halogen, hydroxyl, phenyl or-O-C _1-6Alkyl replaces,

(6) C _3-6Cycloalkyl, it is unsubstituted or uses halogen, hydroxyl or phenyl replace,

(7) C _2-4Thiazolinyl, it is unsubstituted or uses C _3-6Cycloalkyl or phenyl replace,

(8) phenyl or naphthyl, it is unsubstituted or uses halogen, hydroxyl, C _1-6Alkyl ,-O-C _1-6Alkyl ,-SH ,-S-C _1-6Alkyl ,-NO ₂,-CO ₂H ,-CN or-NR ¹⁰R ¹¹Replace,

(9)-and the O-phenyl, it is unsubstituted or uses halogen, hydroxyl, C _1-6Alkyl ,-O-C _1-6Alkyl ,-SH ,-S-C _1-6Alkyl ,-NO ₂,-CO ₂H ,-CN or-NR ¹⁰R ¹¹Replace,

(10) heterocyclic radical, it is unsubstituted or uses halogen, hydroxyl, C _1-6Alkyl ,-O-C _1-6Alkyl ,-SH ,-S-C _1-6Alkyl ,-NO ₂,-CO ₂H ,-CN or-NR ¹⁰R ¹¹Replace,

(11)-NR ¹⁰R ¹¹, R wherein ¹⁰And R ¹¹The group that independently is selected from comprises hydrogen and C _1-6Alkyl,

(12)-S(O) ₂-NR ¹⁰R ¹¹，

(13)-S (O) _q-R ¹², wherein q is 0,1 or 2 and R wherein ¹²Be C _1-6Alkyl, C _3-6Cycloalkyl or phenyl, it is unsubstituted or uses halogen, hydroxyl, phenyl or-O-C _1-6Alkyl replaces,

(14)-CO ₂H，

(15)-CO ₂-R ¹²，

(16)-CN and

(17)-NO ₂；

R ²The group that is selected from comprises:

(1) hydrogen,

(2) C _1-6Alkyl, it is unsubstituted or uses halogen, C _3-6Cycloalkyl or phenyl replace,

(3)-C _3-6Cycloalkyl, it is unsubstituted or uses halogen, C _1-6That alkyl or phenyl replaces and

(4) phenyl, it is unsubstituted or uses halogen, hydroxyl, C _1-6Alkyl ,-O-C _1-6Alkyl or-NO ₂Replace;

R ³And R ⁴The group that independently is selected from comprises:

(1) hydrogen,

(2) C _1-6Alkyl, it is unsubstituted or uses halogen, C _3-6That cycloalkyl or phenyl replace and

(3) C _3-6Cycloalkyl, it is unsubstituted or uses halogen, C _3-6Cycloalkyl or phenyl replace, perhaps R ³And R ⁴Form C with the carbon that links to each other with them _3-6Cycloalkyl ring;

R ⁵And R ⁶The group that independently is selected from comprises:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4) C _1-6Alkyl, it is unsubstituted or uses halogen, hydroxyl, phenyl or-O-C _1-6Alkyl replaces;

(5)-O-C _1-6Alkyl, it is unsubstituted or uses halogen, hydroxyl or phenyl replace,

(7)-and phenyl, it is unsubstituted or uses halogen, hydroxyl, C _1-6Alkyl ,-O-C _1-6Alkyl or-NO ₂Replace,

Perhaps R ⁵And R ⁶Form C with the carbon that links to each other with them _3-6Cycloalkyl ring, it is unsubstituted or replaces with halogen, hydroxyl or phenyl;

R ^7a, R ^7bAnd R ^7cThe group that independently is selected from comprises:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(7) phenyl or naphthyl, it is unsubstituted or uses halogen, hydroxyl, C _1-6Alkyl ,-O-C _1-6Alkyl or-NO ₂Replace,

(8) heterocyclic radical, it is unsubstituted or uses halogen, hydroxyl, C _1-6Alkyl or-O-C _1-6Alkyl replaces,

(9)-S(O) ₂-NR ¹⁰R ¹¹，

(10)-S (O) _q-R ¹²And

(11)-CN；

And pharmacy acceptable salt.

One embodiment of the invention comprise formula Ib compound:

R wherein ^1a, R ², R ³, R ⁴, R ⁵, R ⁶, R ^7a, R ^7bAnd R ^7cAs defined in this Application; Or its pharmacy acceptable salt or its independent enantiomorph or non-corresponding isomer.

One embodiment of the invention comprise formula Ic compound:

R wherein ^1a, R ², R ³, R ⁴, R ⁵And R ⁶As defined in this Application; Or its pharmacy acceptable salt or its independent enantiomorph or non-corresponding isomer.

One embodiment of the invention comprise formula Id compound:

R wherein ^1aAnd R ²As defined in this Application; Or its pharmacy acceptable salt.

One embodiment of the invention comprise formula Ie compound:

R wherein ², R ³, R ⁴, R ⁵, R ⁶, R ^7a, R ^7bAnd R ^7cAs defined in this Application; Or its pharmacy acceptable salt or its independent enantiomorph or non-corresponding isomer.

One embodiment of the invention comprise formula If compound:

R wherein ², R ³, R ⁴, R ⁵And R ⁶As defined in this Application; Or its pharmacy acceptable salt or its independent enantiomorph or non-corresponding isomer.

One embodiment of the invention comprise formula Ig compound:

R wherein ²As defined in this Application; Or its pharmacy acceptable salt.

An embodiment of The compounds of this invention, wherein the group that is selected from of A comprises:

(1) phenyl,

(2)  azoles base,

(3) different  azoles base,

(4) thiazolyl,

(5) thiadiazolyl group,

(6) pyrazolyl and

(7) pyridyl.

In this embodiment, the present invention includes the compound that A is a phenyl.Still in this embodiment, the present invention includes the compound that A is a thiazolyl.

Embodiment, wherein a R as The compounds of this invention ^1a, R ^1bAnd R ^1cThe group that independently is selected from comprises:

(1) hydrogen,

(2) halogen,

(3) C _1-6Alkyl, it is unsubstituted or uses halogen, hydroxyl, phenyl or-O-C _1-6Alkyl replaces,

(4) C _2-4Thiazolinyl, it is unsubstituted or uses C _3-6Cycloalkyl or phenyl replace,

(5) phenyl, it is unsubstituted or uses halogen, hydroxyl, C _1-6Alkyl ,-O-C _1-6Alkyl ,-SH ,-S-C _1-6Alkyl ,-NO ₂,-CO ₂H or-CN replaces,

(6)-and the O-phenyl, it is unsubstituted or uses halogen, hydroxyl, C _1-6Alkyl ,-O-C _1-6Alkyl ,-SH ,-S-C _1-6Alkyl ,-NO ₂,-CO ₂H or-CN replaces,

(7)-NR ¹⁰R ¹¹, R wherein ¹⁰And R ¹¹The group that independently is selected from comprises hydrogen and C _1-6Alkyl,

(8) tetrazyl,

(9) thienyl,

(10) triazolyl,

(11) benzothienyl,

(12) pyrazolyl,

(13) imidazolyl,

(14)-NO ₂And

(15)-CN。

In this embodiment, compound of the present invention, wherein R ^1cBe hydrogen or do not exist, and R ^1aAnd R ^1bThe group that is selected from comprises:

(1) halogen,

(5) C _2-4Thiazolinyl, it is unsubstituted or uses C _3-6Cycloalkyl or phenyl replace,

(2) phenyl, it is unsubstituted or uses halogen, hydroxyl, C _1-6Alkyl ,-O-C _1-6Alkyl ,-SH ,-S-C _1-6Alkyl ,-NO ₂,-CO ₂H or-CN replaces,

(3)-and the O-phenyl, it is unsubstituted or uses halogen, hydroxyl, C _1-6Alkyl ,-O-C _1-6Alkyl ,-SH ,-S-C _1-6Alkyl ,-NO ₂,-CO ₂H or-CN replaces,

(6)-NR ¹⁰R ¹¹, R wherein ¹⁰And R ¹¹The group that independently is selected from comprises hydrogen and C _1-6Alkyl,

(7) tetrazyl,

(8) thienyl,

(9) triazolyl,

(10) benzothienyl,

(11) pyrazolyl,

(12) imidazolyl,

(13)-NO ₂And

(14)-CN。

In this embodiment, A is a phenyl in the compound that the present invention includes, R ^1bBe hydrogen, R ^1cBe hydrogen and R ^1aThe group that independently is selected from comprises:

(1) halogen,

(2) phenyl or naphthyl, it is unsubstituted or uses halogen, hydroxyl, C _1-6Alkyl ,-O-C _1-6Alkyl or-NO ₂Replace,

(3)-and the O-phenyl, it is unsubstituted or uses halogen, hydroxyl, C _1-6Alkyl or-O-C _1-6Alkyl replaces,

(4) C _1-6Alkyl, it is unsubstituted or uses halogen, hydroxyl or phenyl replace,

(7) tetrazyl,

(8) thienyl,

(9) triazolyl,

(10) benzothienyl,

(11) pyrazolyl,

(12) imidazolyl,

(13)-NO ₂And

(14)-CN。

In this embodiment, A is a phenyl in the compound that the present invention includes, R ^1bBe hydrogen, R ^1cBe hydrogen and R ^1aIt is phenyl.

One embodiment of the invention comprise that A is a thiazolyl, R ^1aBe C _1-6Alkyl, R ^1bBe phenyl and R ^1cNon-existent compound.

As the embodiment of The compounds of this invention,, R wherein ²The group that is selected from comprises:

(1) hydrogen,

(2)CH ₃，

(3)CH ₂CH ₃，

(4)CH ₂CH ₂F，

(5) CH ₂-phenyl,

(6) CH ₂-cyclopropyl,

(7) CH ₂-cyclobutyl,

(8) cyclopropyl,

(9) cyclobutyl and

(10)CH ₂CH ₂CH ₃。

In this embodiment, the present invention includes following compound, wherein R ²Be CH ₃, CH ₂CH ₃, cyclopropyl or cyclobutyl.

One embodiment of the invention comprise following compound, wherein R ³Be hydrogen and R ⁴Be hydrogen.One embodiment of the invention comprise following compound, wherein R ³Be cyclopropyl and R ⁴Be hydrogen.

One embodiment of the invention comprise following compound, wherein R ⁵Be hydrogen and R ⁶Be hydrogen.One embodiment of the invention comprise following compound, wherein R ⁵And R ⁶Form cyclopropyl or cyclobutyl ring with the carbon that links to each other with them.

One embodiment of the invention comprise following compound, wherein R ^7a, R ^7bAnd R ^7cThe group that independently is selected from comprises:

(1) hydrogen,

(2) fluorine,

(3) chlorine and

(4) bromine.

In this embodiment, the present invention includes following compound, wherein R ^7aBe fluorine, R ^7bBe hydrogen and R ^7cBe hydrogen.

The specific embodiments of The compounds of this invention comprises target compound or its pharmacy acceptable salt that is selected from the embodiment of the present application.

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 the 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 comprised these compounds.Formula I represents not have the structure of the classes of compounds of preferred steric configuration.

As known in the art, separately synthetic of these non-corresponding isomer or their chromatographic separation can realize through suitably improving by the disclosed method of the application.Their absolute steric configuration can pass through the crystalline product that produced or if desired, determines with the derive x-ray crystalline diffraction of the crystallization of intermediate that forms of the reagent that comprises known absolute configuration asymmetric center.

If desired, 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 racemic mixture and the enantiomorphous pure compound with compound is coupled to form the mixture of diastereomer, then separates independent diastereomer by for example standard method such as fractional crystallization or chromatography.Coupling reaction often is to use the acid of enantiomer-pure or alkali to form salt.The chirality residue that adds by removing, the diastereomer derivative can be transformed into pure enantiomorph then.The racemic mixture of compound also can directly separate by the chromatographic process of using chiral stationary phase, and this 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 or halogen that the application is used comprise fluorine, chlorine, bromine and iodine.Similarly, C _1-6, as C _1-6In the alkyl, be defined as having 1,2,3,4, the straight or branched group of 5 or 6 carbon, C thus _1-8Alkyl specifically comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, amyl group and hexyl.The group that is defined as replacing independently with substituting group can be replaced independently by a plurality of such substituting groups.The employed term of the application " heterocycle " comprises unsaturated and saturated heterocycle fragment, and wherein unsaturated heterocycle fragment (i.e. " heteroaryl ") comprises benzimidazolyl-, benzoglyoxaline ketone group; benzofuryl, benzo furazan base, benzopyrazoles base; the benzotriazole base, benzothienyl, benzoxazol base; carbazyl, carbolinyl, cinnolines base; furyl, imidazolyl, indolinyl; indyl, indenes piperazine base, indazolyl; isobenzofuran-base, pseudoindoyl, isoquinolyl; isothiazolyl, different  azoles base, naphthopyridine base; the  di azoly,  azoles base,  azoles quinoline; different  azoles quinoline, oxetanyl, pyrazinyl; pyrazolyl, pyridazinyl, pyridopyridine base; pyridazinyl, pyridyl, pyrimidyl; pyrryl, quinazolyl, quinolyl; quinoxalinyl, tetrazyl, tetrazolium pyridyl; thiadiazolyl group, thiazolyl, thienyl; triazolyl and N-oxygen compound thereof, and wherein saturated heterocycle fragment comprises azetidinyl, 1; 4-dioxane base, six hydrogen azepine  bases, piperazinyl; piperidyl, pyridin-2-ones base, pyrrolidyl; morpholinyl; tetrahydrofuran base, thiomorpholine base and tetrahydro-thienyl, and N-oxide compound.

Term " pharmacy acceptable salt " is meant that described alkali or acid comprise inorganic or organic alkali and inorganic or organic acid by the pharmaceutically acceptable nontoxic alkali or the salt of acid preparation.The salt that is derived from mineral alkali comprises aluminium, ammonium, and calcium, copper, iron, ferrous, lithium, magnesium, manganic salt, bivalent manganese, potassium, sodium, zinc or the like.Particularly preferably be ammonium, calcium, magnesium, potassium and sodium salt.The salt of solid form can exist to surpass a kind of crystalline structure, can also be the form of hydrate.The salt that is derived from pharmaceutically acceptable organic nontoxic alkali comprises the primary, and 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, NN '-dibenzyl-ethylenediamin, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, 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 or the like.

When compound of the present invention was alkalescence, salt can comprise inorganic and organic acid by pharmaceutically acceptable non-toxic acid preparation.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, glutinous acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succsinic acid, sulfuric acid, tartrate, tosic acid or the like.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, mean when mentioning the compound of formula I also to comprise pharmacy acceptable salt.

Explain the present invention with embodiment and the disclosed compound of the application.Particular compound among the present invention comprises compound and its pharmacy acceptable salt and the independent diastereomer thereof that is selected from the disclosed compound of following examples.

Target compound can be used for the method for antagonism patient's orexin receptor active, and described patient for example needs the Mammals of inhibition like this, and described method comprises that this compound with significant quantity carries out administration.The present invention relates to the disclosed compound of the application and pick up the purposes of anti-agent as the orexin receptor active.Except primate, especially beyond the people, various other Mammalss also can be treated according to method of the present invention.

The invention further relates to preparation and be used for method at the medicine of humans and animals antagonism orexin receptor active or the treatment described obstacle of the application and disease, it comprises compound of the present invention and pharmaceutically carrier or mixing diluents.

Zhi Liao object Mammals normally is preferred human in the method, sex.Term " treatment significant quantity " meaning is the amount of the target compound tissue that will cause researcher, animal doctor, doctor or other clinician and attempt to obtain, system, animal or human's biology or a medicinal response.Will be appreciated that those skilled in the art by the The compounds of this invention treatment of using significant quantity suffer from present the patient of this obstacle or prophylactically the treatment patient that suffers from this obstacle can exert an influence to nervosa and spirituality obstacle.Use as the application, term " treatment " is meant that all can slow down, interrupt, are detained, control or stop the method for described nervosa of the application and the development of spirituality obstacle, but the symptom of not necessarily representing all obstacles all disappears, it also comprises the prophylactic treatment to described symptom, especially in the patient who suffers from such disease or obstacle easily.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.

Term " composition " as used in this application, connotation comprises the product of the appointment composition that comprises specified amount, and the appointment composition of specified amount mixes institute's any product of generation directly or indirectly.The connotation of this term relevant with 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 decompose, perhaps any product that directly or indirectly produces by the reaction of the other types of one or more compositions or interaction by one or more compositions.Therefore, pharmaceutical composition of the present invention comprises by compound of the present invention is mixed any composition for preparing with pharmaceutically acceptable carrier.Term " pharmaceutically acceptable " meaning is that carrier, thinner or excipient must be compatible with other composition in the formulation and be harmless to its recipient.

The compounds of this invention can determine easily by means commonly known in the art that as the effectiveness of orexin acceptor OX1R and/or OX2R antagonist do not test and do not need to carry out over-drastic, 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.In order to measure intracellular calcium, Chinese hamster ovary (CHO) cell of expressing rat orexin-1 acceptor or people's orexin-2 acceptor is cultivated in the improved DMEM of Iscove, and described DMEM contains 2mML-glutamine, 0.5g/ml G418, xanthoglobulin-thymidine supplement of 1%, 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-Dickinson black 384 hole clear bottom sterile plate that scribble poly--D-Methionin 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 ₂Following hatching is spent the night.Ala as agonist ^6,12People orexin-A is prepared to the 1mM stock solution that contains 1% bovine serum albumin (BSA), and (HBSS that comprises 20mM HEPES, 0.1%BSA and 2.5mM probenecid pH7.4) is diluted to the ultimate density of employed 70pM in the test with the test damping fluid.Test compounds is prepared into the 10mM stock solution with DMSO, dilutes in the 384-orifice plate then, 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 60 μ l contain the test damping fluid of 1 μ M Fluo-4AM ester, 0.02%pluronic acid and 1%BSA, hatch then 60min (37 ℃, 5%CO ₂).Sucking-off is loaded with the solution of dyestuff then, and tests the damping fluid washed cell 3 times with 100 μ l.The identical damping fluid of 30 μ l is stayed in each hole.In fluorescence imaging plate reader (FLIPR, Molecular Devices), in plate, add test compounds with the volume of 25 μ l, hatched 5 minutes, add 25 μ l agonists at last.With the fluorescence in each hole of interval measurement of 1 second 5 minutes, with the height of each fluorescence peak and the 70pM Ala that replaces antagonist with damping fluid ^6,12The height of the fluorescence peak that orexin-A causes compares.Determine the IC50 value (suppressing the needed compound concentrations of 50% exciting response) of every kind of antagonist.Can measure the inherent orexin receptor antagonist activity of the compound that can be used among the present invention by these tests.

Especially, the compound of following examples has the antagonism rat and increases the activity that the appetite Qin-1 acceptor and/or people increase the appetite Qin-2 acceptor in above-mentioned test, have the IC50 less than about 50 μ M usually.Preferred compound has the activity of antagonism rat orexin-1 acceptor and/or people's orexin-2 acceptor among the present invention in above-mentioned test, and IC50 is less than about 100nM.Such result is used as the embodiment that increases the appetite Qin-1 acceptor and/or increase the compound intrinsic activity of the appetite Qin-2 receptor antagonist.

It is relevant with the various biological function that the orexin acceptor has been considered to.This points out these acceptors may play a role in the various diseases process of people or other species.Compound of the present invention has treatment, prevents, improves, controls and reduces the various nervosas relevant with the orexin acceptor and the effectiveness 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 that increase is attempted to sleep divided by object by object the length of one's sleep; Improve the sleep beginning; 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 the time that wakes after sleep begins at first; 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 or lasting of slow wave (i.e. 3 or 4 phases) sleep cycle; 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 of treatment or minimizing transition; Increase is to the satisfaction of sleep intensity; Increasing sleep keeps; The special aypnia of sending out; Sleeping problems; Insomnia, hypersomnia, the special property sent out hypersomnia, reproducibility hypersomnia, the inherent hypersomnia, narcolepsy, disruptive sleep, sleep apnea, awakening, nocturnal myoclonus, REM interruptions of sleep, the jet flight trouble with 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; Alzheimers sunset syndromes; The symptom relevant with day-night rhythm and with moving through the time zone obstacle of the mind ﹠ body relevant with the shift work time, the symptom that medicine produced that causes the REM sleep to reduce as side effect; Fibromyalgia; Show as expendable sleep and myalgia or the syndromes of the sleep apnea relevant between sleep period with dyspnoea; The symptom that descends and to be produced by sleep quality; The disturbance of food intake relevant and relevant therewith complication with excessive food intake, the mandatory disturbance of food intake, fat (owing 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, blood fat matter is too much, uterine endometrium, breast, prostate gland and colorectal carcinoma.Osteoarthritis, obstructive sleep apnea, chololithiasis, cholelithiasis, heart trouble, the irregular and irregular pulse of heart rhythm, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, apoplexy, polycystic ovary disease, craniopharyngioma, Prader-Willi syndromes, hypophysis syndromes, the main body that GH-lacks, general stature is short and small, sexual function retardation syndromes, and other pathology symptom, it shows as the metabolic activity of reduction or the rest energy expenditure of the total no lipid amount per-cent of conduct reduces, for example, children acute lymphocytoblast leukemia, metabolic syndrome, have another name called the X syndromes, the insulin resistant syndromes, reproductive hormone is unusual, property and regenerative function obstacle, the reproductive performance that for example weakens, infertile, hypogonadism among the male sex and the hirsutism among the women, the fetus defective fat relevant with mother, the gastrointestinal peristalsis obstacle, for example fat relevant stomach oesophagus adverse current, dyspnoea, for example fat hypoventilation syndromes (Pickwickian syndromes), expiratory dyspnea, cardiovascular disorder, inflammation, for example system inflammation of vascular structure, arteriosclerosis, hypercholesterolemia, hyperuricemia, pain in the back, cholecystopathy, gout, kidney, the anesthetic risks of increase, reduce the risk of fat secondary consequence, for example reduce the risk of left ventricular hypertrophy; Unusual indefinite active disease or obstacle take place in the brain, comprise depression, migraine, neuropathic pain, Parkinson's disease, psychosis and schizophrenia, and disease or obstacle with unusual combining movement are particularly by ganglion cerebral; The cognitive function of strengthening; Strengthen memory; Increasing memory keeps; Increase immune response; Increase immunologic function; Hectic fever; Night sweat; Prolongs life; Schizophrenia; The excitement that is caused by neural system/lax rhythm is the obstacle relevant with muscle and other cardiovascular systems obstacle of rhythm of the heart control for example; 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 depressed or oppressive more specifically obstacle, such as, the severe type dysthymia disorders and the dysthymic disorder of the ictal or recurrent of single, perhaps two-phase obstacle, two-phase I type obstacle for example, two-phase II type obstacle and cyclothymic temperament obstacle, because the emotional handicap that emotional handicap that the general symptoms of internal disease cause and material cause; Anxiety disorder comprises acute stress disorder, agoraphobia, generalized anxiety disorder, obsession, panic attack, paranoid fears, stress disorders after the wound, separation anxiety obstacle, social phobia, specific phobia disease, the anxiety that 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, oxygen supply in term deficiency, heartbeat stops, the brain function disappearance after the hypoglycemic nervosa damage; Huntington's chorea; Amyotrophic lateral sclerosis; Multiple sclerosis; Ocular damage, retinopathy; Cognitive disorder; Special property sent out and drug-induced Parkinson's disease; Muscle spasm and tremble epilepsy, the obstacle that muscle spasms such as convulsions are relevant with comprising; Cognitive disorder comprises dementia (with Alzheimer, local asphyxia, wound, vascular problem or apoplexy, HIV disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, oxygen supply in term deficiency, the symptoms of internal disease that other is general or substance abuse are correlated with); Psychiatric disorder, lethe obstacle or the cognition relevant with the age descend; 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 is because the mental disorder that mental disorder that general internal medicine situation produces and material cause; Obstacle and Addictive Behaviors that material is relevant (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, dependence or withdrawal); Dyskinesia, comprise that the stiff syndromes of can not moving and can not move (comprises Parkinson's disease, drug-induced parkinsonism, parkinsonism after the encephalitis, benumb on the carrying out property nuclear, the multisystem atrophy, corticobasal degeneration, dull-witted complex disease of parkinsonism ALS and basal ganglion calcification), chronic fatigue syndrome, tired, comprise Parkinson fatigue, multiple sclerosis fatigue, the fatigue that causes by somnopathy and day-night rhythm obstacle, drug-induced parkinsonism (the parkinsonism that causes of tranquilizer for example, the pernicious syndromes of psychosis, the acute dystonia that psychosis causes, acute the cathisophobiaing that tranquilizer causes, tardive dyskinesia that tranquilizer causes and drug-induced postural tremor), Gilles de la Tourette syndromes, epilepsy and dyskinesia [comprise vibration (for example static vibration, spontaneous vibration, posture vibration and purpose 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 legs syndromes and myodystonia (comprise for example special property the sent out myodystonia of popularity myodystonia, drug-induced myodystonia, symptomatic myodystonia and paroxysmal myodystonia and focal myodystonia be 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; (comprising opiate for example, nicotine, tobacco product, alcohol, benzodiazepine, cocaine, tranquilizer, the material of soporific etc.) given up in material tolerance, material; 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 comprises acute and the chronic pain state, serious pain, intractable pain, inflammatory pain, neuropathic pain, pain after the wound, bone and arthralgia (osteoarthritis), recurrent motion pain, tooth pain, cancer pain, muscular fascia pain (muscle injury, fibromyalgia), peri-operation period pain (general surgery, gynaecology's property), chronic pain, neuropathic pain, pain after the wound, trigeminal neuralgia, migraine and migraine headache.

Therefore, as the preferred embodiments of the invention, provide methods of treatment: improve sleep quality to the mammalian subject that following needs are arranged; 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 keeps; Treatment or controlling obesity; Treatment or control are depressed; The risk of treatment, control, improvement or minimizing epilepsy comprises epilepsy does not take place; Treatment or pain management comprise neuropathic pain; Treatment or control Parkinson's disease; Treatment or control psychosis; Perhaps treat, control, improve or reduce schizoid risk, described method comprises that the The compounds of this invention with the treatment significant quantity carries out administration to the patient.

Target compound can be further used for preventing, treat, control, improving or reduce the method for the described disease of the application, obstacle and symptom risk.The dosage of activeconstituents can change in the composition of the present invention, and still, the amount of activeconstituents must be the amount that can obtain appropriate dosage forms.Activeconstituents can be to provide dosed administration that optimal drug renders a service in the patient (animal and human) of this treatment of needs.Selected dosage depends on the desired therapeutic effect, 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 that uses simultaneously and the other factors that 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 acceptor.Dosage range is generally each patient's every day about 0.5mg to 1.0g, and it can be with the form administration of single agent or multi-agent.Preferably, this dosage range be each patient's every day about 0.5mg to 500mg; More preferably each patient's every day, about 0.5mg was to 200mg; Even more preferably each patient's every day about 5mg to 50mg.Pharmaceutical composition of the present invention can provide with the form of solid dosage formulation, and it comprises about 0.5mg to the 500mg activeconstituents, more preferably comprises about 1mg to the 250mg activeconstituents.Pharmaceutical composition is preferably comprising about 1mg, 5mg, and 10mg, 25mg, 50mg, 100mg, the form of the solid dosage formulation of 200mg or 250mg activeconstituents provides.For oral administration, composition preferably offers the patient of needs treatment with the tablet form that comprises 1.0 to 1000 milligrams of activeconstituentss, particularly comprise 1,5,10,15,20,25,50,75,100,150,200,250,300,400,500,600,750,800,900 and 1000 milligrams activeconstituents is used for the adjustment of carrying out according to the dosage that symptom is taken the patient who is treated.This compound can be with every day 1 to 4 time, preferred once a day or twice instructions of taking administration.

Compound of the present invention can combine with one or more other medicines and be used for the treatment of, prevents, control, improve or reduce compound of the present invention or other medicines can have the disease of effectiveness or the risk of symptom to it, wherein medicine is combined than any independent medicine safety or effectively more.Like this, other one or more medicines can be by its normally used approach and quantity and compound of the present invention while or order administration.When compound of the present invention and one or more other medicines use simultaneously, preferably in unit dosage, comprise the pharmaceutical composition of this other medicines and The compounds of this invention.But combination therapy can comprise that also compound of the present invention and one or more other medicines show the treatment of administration with different overlapping time.Should expect that also when being used in combination with one or more other activeconstituentss, compound of the present invention and other activeconstituents can use to be lower than every kind of dosage when using separately.Therefore, pharmaceutical composition of the present invention comprises the pharmaceutical composition that also comprises one or more other activeconstituentss except that containing compound of the present invention.Above-mentioned drug combination not only comprises the composition of compound of the present invention and a kind of other active compound, and comprises the composition of itself and two or more active compounds.

Similarly, compound of the present invention can be used in combination the other medicines of its effective disease or symptom risk with being used to prevent, treat, control, improve or reducing The compounds of this invention.Such other medicines can pass through its normally used approach and quantity and compound of the present invention administration simultaneously or sequentially.When compound of the present invention and one or more other medicines use simultaneously, preferably except that compound of the present invention, also contain the pharmaceutical composition of this its 1 its medicine.Therefore, pharmaceutical composition of the present invention comprises the pharmaceutical composition that also contains one or more other activeconstituentss except that containing compound of the present invention.

The compound weight ratio of the compound of the present invention and second activeconstituents can change and depend on the effective dose of every kind of composition.Usually, use every kind effective dose.Therefore, for example, when compound of the present invention mixed with another kind of medicament, the weight ratio scope of compound of the present invention and another kind of medicament was normally from about 1000: 1 to about 1: 1000, preferred about 200: 1 to about 1: 200.The mixture of compound of the present invention and other activeconstituents usually also in above-mentioned scope, but in each case, all should use the effective dose of every kind of activeconstituents.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 before the administration of other medicament (one or more), during or carry out afterwards.

Compound of the present invention can be used for improving effectively sleep quality and prevention and treat somnopathy and other sleep disordered compound Combined Preparation with well known in the art, and described other compound for example comprises tranquilizer, soporific, anxiolytic, antipsychotic drug, antianxiety agent, antihistaminic agent, benzodiazepine, barbiturate(s), cyclopyrrole ketone, gaba agonist, 5HT-2 antagonist comprise 5HT-2A antagonist and 5HT-2A/2C antagonist, and histamine antagonist comprises histamine H 3 antagonists, histamine H 3 inverse agonists, imidazopyridine, minor tranquilizer, melatonin agonists and antagonist, fade plain can agent, other orexin antagonist, orexin agonist, plain (prokineticin) agonist of short motion and antagonist, pyrazolopyrimidine, T type calcium channel is picked up anti-agent, Triazolopyridine or the like, for example: adinazolam, allobarbital, alonimid, alprazolam, amitriptyline, Amobarbital, amoxapine, l-modafinil, APD-125, bentazepam, benzoctamine, brotizolam, Wellbutrin, buspirone, cloth tower veronal, cloth tower block not Rayleigh than appropriate, 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 decided 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 oxazepans, 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 benzene Ammoniom-Acetate, trichloroethyl phosphate, trifluoperazine, trimetozine, trimeproprimine, Uldazepam, Venlafaxine, Zaleplone, zolazepam, Zopiclone, pyrazoles is smooth, and salt and composition or the like, and compound perhaps of the present invention can be united the physical method that uses for example phototherapy or electricity irritation in administration.

In another embodiment, target compound can with antidepressive or antianxiety agent, comprise NRI (comprising tertiary amine three ring and secondary amine tricyclic compoundses), choosing falling property serotonin reuptake inhibitors (SSRIs), oxidase inhibitor (MAOIs), monoamine oxidase reversible inhibitor (RIMAs), thrombotonin and NRI (SNRIs), 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 are used in combination.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 oxazepans and prazepam; 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; The tethelin succagoga; 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, tartrate rivastigmine, E2020 and tetrahydroaminoacridine; The tethelin succagoga is ibutamoren for example, methylsulfonic acid ibutamoren and Ka Mo Rayleigh; Histamine H 3 antagonists; The AMPA agonist; The PDEIV inhibitor; GABAA inverse agonist or nervosa nicotinic agonist are used in combination.

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, plain energy medicament fades, benzene phenodiazine , barbiturate(s), 5HT-2 antagonist or the like, be used in combination, 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, chloroethyl amylene alkynes is enjoyed, sibul, fenobam, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam, rigenox, halazepam, hydroxyzine, imipramine, lithium, L0, lormetazepam, maprotiline, mecloqualone, melatonin, promind, peacefulness, turzolon, midaflur, midazolam, Buddhist nun's method oxazolone, nisobamate, surem, nortriptyline oxazepans, 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 or the like, perhaps described target compound can be united for example actinotherapy or the electricity irritation of use physical method in administration.

In another embodiment, target compound can with levodopa (having or not having the outer decarboxylase inhibitor of selective brain for example methyldopa or benserazide), anticholinergic is for example pacified gram convulsion (randomly with its hydrochloride or lactic acid salt) and artane (Trihexyphenidyl) hydrochloride, the COMT inhibitor is Entacapone for example, the MOA-B inhibitor, antioxidant, 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 are used in combination.Can predict the form that dopamine agonist can be a pharmacy acceptable salt, alentemol hydrobromate for example, bromocriptine mesylate, fenoldopam mesylate, Nazagolide hydrochloride and LY-127809.Methylergol carbamide and pramipexole use with the form of non-salt usually.

In another embodiment, target compound can with Sch-6673, alentemol, Trihexyphenidyl, bromocriptine, peace gram convulsion, 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 are used in combination.

In another embodiment, target compound can be used in combination with the compound from thiodiphenylamine, thioxanthene, heterocycle dibenzo azepine , butyrophenone, hexichol fourth piperidines and indole ketone tranquilizer.The thiodiphenylamine suitable examples comprises chlorpromazine, mesoridazine, thioridazine, Sch-6673, fluphenazine, trilafon and trifluoperazine.The thioxanthene suitable examples comprises tardan and thiothixene.The example of dibenzo azepine  is a leoponex.The example of butyrophenone is a haloperidol.The example of hexichol fourth piperidines is a pimozide.The example of indolone is morpholine many that (molindolone).Other tranquilizer comprises loxapine, dogmatil and risperidone.Tranquilizer can be predicted and when being used in combination, the form of pharmacy acceptable salt can be with target compound, 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 use with salt-independent shape usually.

In another embodiment, target compound can with appetite suppressant, for example aminorex, 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, 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 comprises chlorphentermine, Lipociden, Varanil, dexfenfluramine, fenfluramine, picilorex and sibutramine; And their pharmacy acceptable salts, be used in combination.

In another embodiment, target compound can with opium agonist, lipoxygenase inhibitor, 5-lipoxygenase inhibitor for example, cyclooxygenase inhibitors, for example cyclooxygenase-2 inhibitor, the interleukin inhibitor, Bai Jieqin-1 inhibitor for example, nmda antagonist, nitric oxide inhibitor or nitrogen oxide synthetic inhibitor, non-steroidal anti-inflammatory agent, or inhibition cytokine anti-inflammatory agent is used in combination, 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 or the like is used in combination.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, perhaps left-handed desoxyephedrine; 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.

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

Be used for that compound of the present invention is carried out the pharmaceutical composition of administration and can be easily exist with the form of unitary dose, and can be by known any method preparation in the medicament field.All methods all comprise the step that activeconstituents is combined with the carrier of forming one or more subordinate compositions.Usually, the preparation of drug combination method is, activeconstituents and liquid carrier or pulverizing solid carrier or both are evenly closely combined simultaneously, then, if desired, product formed and makes the formulation of expectation.In pharmaceutical composition, thereby comprise process or the symptom generation desired effects of the active target compound of sufficient amount to disease.Use as the application, term " composition " connotation comprises the product of the appointment composition that contains specified amount, and any product that is directly or indirectly obtained by the appointment composition mixing of specified amount.

The pharmaceutical composition that is used to orally use can be according to any method preparation that is used to make pharmaceutical composition known in the art, thereby and such composition can comprise one or more reagent that are selected from sweeting agent, seasonings, tinting material and sanitas good to eat goods pharmaceutically attractive in appearance are provided.Tablet comprises activeconstituents and the pharmaceutically acceptable mixture that is suitable for making the nontoxic vehicle of tablet.These vehicle for example can be, inert diluent, lime carbonate for example, yellow soda ash, 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.Thereby tablet can be do not coat or they can be to provide the continuous action of longer cycle to postpone disintegration and the absorption in gi tract with what already known processes coated.The composition that orally uses also can exist with the form of hard gelatin capsule, wherein activeconstituents is and inert solid diluent, for example, lime carbonate, calcium phosphate or kaolin blended, perhaps the form with soft gelatin capsule exists, and wherein activeconstituents is and water or oily medium, peanut oil for example, whiteruss or mixed with olive oil.Aqeous suspension contains activeconstituents and is suitable for making the mixture of the vehicle of aqeous suspension.Oil suspension can be prepared by activeconstituents is suspended in the suitable oil.Can also use oil-water emulsifiers.Be suitable for providing activeconstituents and dispersion agent or wetting agent, the mixture of suspension agent and one or more sanitass by adding dispersible powder and the granule that entry prepares aqeous suspension.The pharmaceutical composition of this compound can be the form of sterile water for injection or oil suspension.Compound of the present invention also can be with the form administration of the suppository that is used for rectal administration.Use for the part, can use the emulsifiable paste that comprises The compounds of this invention, ointment, gelifying agent, solution or suspension or the like.Compound of the present invention can also be prepared and be used for inhalation.Compound of the present invention also can be by methods known in the art by the transdermal patch administration.

Following scheme and embodiment illustrated the preparation The compounds of this invention several method.Prepare starting raw material according to methods known in the art or the illustrational method of the application.Use following abbreviation among 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.Compound of the present invention can be produced in many ways.

The finished product can be modified further in some cases, for example, and by handling 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 the order of carrying out following reaction scheme in some cases promotes reaction or avoids unwanted reaction product.The present invention provides following examples so that can be understood more all sidedly.These embodiment only are illustrative and should be considered to limit the invention in any way.

Option A

2-[3-(4-fluorobenzene hydrogen) propyl group]-1H-isoindole-1,3 (2H)-diketone (A-2)

With carbinol A-1(2.00g, methylene dichloride 9.76mmol) (100mL) solution with the 4-fluorophenol (1.09g, 9.76mmol), triphenylphosphine (2.55g, 9.76mmol) and diethyl azodiformate (1.69g 9.76mmol) handles.After at room temperature stirring 24 hours, the concentration response thing also passes through flash chromatography (SiO ₂, the 30%EtOAc/ hexane) thus purifying provides aryl ethers A-2 A-2Data: ¹HNMR (500MHz, CDCl ₃) δ 7.85-7.80 (m, 2H), 7.74-7.68 (m, 2H), 6.95-6.90 (m, 2H), 6.75-6.80 (m, 2H), 4.03-3.96 (m, 2H), 3.93-3.88 (m, 2H), 2.23-2.18 (m, 2H) ppm.

3-(4-fluorobenzene oxygen) third-1-amine (A-3)

With phthalic imidine A-2(1.86g, EtOH 6.22mmol) (50mL) solution with water is closed hydrazine, and (0.748mL 12.44mmol) handles also reflux 2hr.Form thick throw out.Reactant dilutes with MTBE and filters.Concentrated filtrate but be not further purified. A-3Data: LRMSm/z (M+H) 170.1, observed value, 170.1, theoretical value.

N-[3-(4-fluorobenzene oxygen) propyl group]-2-methyl-5-phenyl-1,3-thiazoles-4-methane amide (A-4)

With amine A-3(0.200g, 1.18mmol), 2-methyl-4-phenyl-thiazolyl 3-carboxylic acid (0.259g, 1.18mmol), EDC (0.338g, 1.71mmol), (0.238g, 1.77mmol), DMF (5mL) solution of triethylamine (0.6mL) heats 10min down at 150 ℃ to HOBT in microwave reactor.Be cooled to after the rt, with EtOAc with solution dilution, water, saturated NH ₄The Cl aqueous solution and salt water washing.Organic solution MgSO ₄Drying is filtered and is concentrated.Residuum flash chromatography (SiO ₂The 50%EtOAc/ hexane) thus purifying obtains waxy solid A-4 A-4Data: LRMSm/z (M+H) 370.9, observed value, 371.1, theoretical value.

N-[3-(4-fluorobenzene) propyl group]-N, 2-dimethyl-5-phenyl-1,3-thiazoles-4-methane amide (A-5)

With acid amides A-4(0.09g, DMF 0.242mmol) (2mL) solution sodium hydride (oil dispersion of 14mg60%; 0.363mmol) and methyl iodide (0.052g, 0.363mmol) processing.Stir after the 24h the saturated NH of reaction ₄The cancellation of the Cl aqueous solution with the EtOAc dilution and with salt water washing organic solution, is passed through MgSO ₄Drying is filtered and is concentrated.Residuum flash chromatography (SiO ₂The 50%EtOAc/ hexane) thus purifying obtains water white oil A-5 A-5Data: HRMS m/z (M+H) 385.1345, observed value, 385.1381, theoretical value.

Table A

Following compound uses method for preparing, but replace suitable to the replacement reagent described in the above-mentioned embodiment, for example organometallic compound or amine.Required starting raw material be purchased described in obtainable, the document or the organic synthesis those skilled in the art do not carry out just synthetic easily of over-drastic test.

Option b

N-[3 (4-fluorobenzene oxygen) propyl group]-2-phenyl-iodide methane amide (B-1)

With amine A-3(5.0g, DMF 29.55mmol) (300mL) solution with the 2-iodobenzoic acid (8.06g, 32.51mmol), EDC (8.49g, 44.33mmol), HOBT (5.99g, 44.33mmol) and triethylamine (12.36mL) under rt, stir 12h and handle.Mixture dilutes and water with EtOAc, saturated NH ₄The Cl aqueous solution and salt water washing.Organic solution is passed through MgSO ₄Drying is filtered and is concentrated.Residuum flash chromatography (SiO ₂0 to 50%EtOAc/ hexane) thus purifying obtains oily B-1 B-1Data: LRMSm/z (M+H) 400.0, observed value, 400.0, theoretical value.

N-ethyl-N-[3-(4-fluorobenzene oxygen) propyl group]-2-phenyl-iodide methane amide (B-2)

With amine B-1(8.53g, DMF 21.3mmol) (200mL) solution sodium hydride (oil dispersion of 769mg60%; 32.0mmol) and iodic ether (4.99g 32.0mmol) handles.After stirring 24h, the saturated NH of reaction ₄The quencher of the Cl aqueous solution, with the EtOAc dilution, MgSO is passed through in organic solution salt water washing ₄Drying is filtered and is concentrated.Residuum flash chromatography (SiO ₂0 to 50%EtOAc/ hexane) thus purifying obtains colorless oil B-2 B-2Data: HRMSm/z (M+H) 428.0484, observed value, 428.0518, theoretical value.

N-ethyl-N-[3-(4-fluorobenzene oxygen) propyl group]-4 '-methoxyl group-1,1 ' xenyl-2-methane amide (B-3)

With amine B-2(0.05g, THF 0.117mmol) (2.0mL) solution 4-anisole ylboronic acid, Pd (dppf) ₂(0.009g 0.012mmol) handles with the CsCO3 aqueous solution of 0.5mL 1M.Be reflected at and be heated to 160 ℃ of lasting 10min in the microwave, cool off and dilute with EtOAc.The saturated NH of organic solution ₄The Cl solution washing passes through MgSO ₄Drying is filtered and is concentrated.Residuum flash chromatography (SiO ₂0 to 50%EtOAc/ hexane) thus purifying obtains colorless oil B-3 B-3Data: HRMSm/z (M+H) 408.1940, observed value, 408.1970, theoretical value.

Table B

Scheme C

1-cyclopropyl-3-(4-fluorobenzene oxygen) propyl carbamic acid (±)-tert-butyl ester (C-2)

With amine C-1(1.0g, DMF 8.68mmol) (50mL) solution with the BOC-acid anhydride (2.08g, 9.55mmol) and Et ₃(3.03mL 21.70mmol) handles N.Stir after the 12h, reactant is with the DCM dilution and use saturated NaHCO ₃The aqueous solution and salt water washing.Organic solution is passed through MgSO ₄Drying obtains 1.8g oily residuum thereby filter and concentrate.The solution of this residuum (1.8g, 8.37mmol) with the 4-fluorophenol (0.989g, 8.82mmol), Ph ₃P (2.32g, 8.82mmol) and DEAD (1.54g 8.82mol) handles.Stir after the 1h, reactant is concentrated, and with flash chromatography (SiO ₂The 10%EtOAc/ hexane) thus purifying obtains oily C-2 C-2Data: LRMSm/z (M+H) 310.2, observed value, 310.2, theoretical value.

(±)-1-cyclopropyl-3-(4-fluorobenzene oxygen) third-1-amine (C-3)

Will C-2(2.16g, THF 6.98mmol) (25mL) solution is handled under 0 ℃ with HCl (in the 5mL4M dioxane).Solution is heated to rt and stirs 12h, and is warmed to rt, with the argon degassing, and concentrates.Residuum is water-soluble, with EtOAc washing, the saturated NaHCO of water ₃The aqueous solution is handled.Extract this aqueous solution and pass through MgSO with EtOAc ₄Dry organic solution obtains orange oily thereby filter and concentrate C-3 ¹HNMR(500MHz，CDCl ₃)δ6.99-6.93(m，2H)，6.85-6.79(m，2H)，4.12-4.05(m，2H)，2.29-2.22(m，IH)，2.07-1.79(m，2H)，0.81-0.75(m，IH)，0.72-0.49(m，2H)，0.22-0.18(m，2H)ppm。

(±)-N-[1-cyclopropyl-3-(the stupid oxygen of 4-fluorine) propyl group]-N-ethyl-1,1 '-xenyl-2-methane amide (C-4)

With amine C-3(0.16g, DMF 0.765mmol) (3mL) solution, the 2-Phenylbenzoic acid (0.152g, 0.765mmol), EDC (0.220g, 1.15mmol), HOBT (0.155g, 1.15mmol) and Et ₃N (0.320mL) heats 10min down at 150 ℃ in microwave reactor.Be cooled to after the rt, mixture is distributed in water and ethyl acetate, use the salt water washing, drying is filtered and is concentrated.Residuum with flash chromatography (60min in from 100% hexane to the 20%EtOAc/ hexane) thus purifying provides 0.160g acid amides product.With this product (0.05g, DMF 0.128mmol) (1mL) solution with sodium hydride (3mg, 0.128mmol) and iodic ether (0.04g 0.257mmol) handles.Behind the 2h, reaction mixture dilutes with EtOAc, the aqueous citric acid solution with 10%, saturated NaHCO ₃The aqueous solution and salt water washing.Solution passes through MgSO ₄Dry filter also concentrates.Residuum flash chromatography (SiO ₂From 100% hexane to the 20%EtOAc/ hexane) thereby purifying provides white solid C-4 C-4Data: HRMSm/z (M+H) 418.2176, observed value, 418.2177, theoretical value.

Table C

Scheme D

N-{[1-(methylol) cyclopropyl] methyl } 2-methyl-5-phenyl-1,3-thiazoles-4-methane amide (D-2)

With amido alcohol D-1(0.072g, DMF 0.709mmol) (5mL)/Et ₃N (0.6mL) solution with 2-methyl-4-phenyl-thiazolyl-3-carboxylic acid (0.155g, 0.709mmol), EDC (0.203g, 1.06mmol) and HOBT (0.143g 1.06mmol) handles.Mixture heats 10min down at 150 ℃ in microwave reactor.Be cooled to after the rt, mixture is distributed in water and ethyl acetate, use the salt water washing, drying is filtered and is concentrated.Residuum flash chromatography (SiO ₂100%EtOAc) thereby purifying provides acid amides D-2 D-2Data: ¹HNMR (500MHz, CDCl ₃) δ 7.88-7.73 (m, IH), 7.60-7.52 (m, 2H), 7.42-7.33 (m, 3H), 3.39-3.35 (m, 4H), 2.71 (s, 3H), 0.52-0.48 (m, 4H) ppm.

N-(1-[(4-fluorobenzene oxygen) and methyl] cyclopropyl } methyl)-2-methyl-5-phenyl-1,3-thiazoles-4-methane amide (D-3)

With carbinol D-2(0.137g, methylene dichloride 0.453mmol) (5mL) solution with the 4-fluorophenol (0.051g, 0.453mmol), triphenylphosphine (0.119g, 0.453mmol) and diisopropyl azodiformate (0.090g 0.453mmol) handles.Under rt, stir after the 72hr, reactant is concentrated and with flash chromatography (SiO ₂The 35%EtOAc/ hexane) thus purifying provides aromatic oxide D-3 D-3Data: ¹HNMR (500MHz, CDCl ₃) δ 8.19-8.16 (m, IH), 7.59-7.52 (m, 2H), 7.40-7.35 (m, 3H), 6.99-6.88 (m, 4H), 5.05-4.95 (m, 2H), 3.49-3.45 (m, 2H), 2.73 (s, 3H), 0.75-0.61 (m, 4H) ppm.

N-(1-[(4-fluorobenzene oxygen) and methyl] cyclopropyl } methyl)-N, 2-dimethyl-5-phenyl-1,3-thiazoles-4-methane amide (D-4)

With acid amides D-3(0.04g, DMF 0.101mmol) (1mL) solution with sodium hydride (60% oil dispersion of 6mg, 0.15mmol) and methyl iodide (10 μ g 0.150mmol) handle.Stir after the 1h, mixture is distributed in water and ethyl acetate, use the salt water washing, drying is filtered and is concentrated.Residuum flash chromatography (SiO ₂The 50%EtOAc/ hexane) thus purifying provides oily D-4 D-4Data: HRMSm/z (M+H) 411.1545, observed value, 411.1537, theoretical value.

Table D

Scheme E

N-(tertbutyloxycarbonyl)-N-cyclobutyl-β-Beta Alanine ethyl ester E-2

(3.55g, (5.0g 49.9mmol) handles EtOH/THF 49.9mmol) (75mL/75mL) solution, and reactant stirs 12h under rt with ethyl propenoate with cyclobutyl amine.With mixture with triethylamine (10.1g, 99.8mmol) and BOC ₂(11.99g 54.9mmol) handles O, stirs 18h and concentrated.Residuum chromatography (SiO ₂0 to 20% EtOAc in the hexane) thus purifying provides E -2 E-2Data: ¹HNMR (500MHz, CDCl ₃) δ 4.15 (m, 2H), 3.51 (m, 2H), 2.55 (m, 2H), 2.09 (m, 4H), 1.62 (m, 3H), 1.43 (s, 9H), 1.25 (t, 3H) ppm.

Cyclobutyl (3-hydroxypropyl) t-butyl carbamate E-3

With ester E-2(12.57g, THF 46.3mmol) (400mL) solution LAH (Et of 34.7mL 4M ₂O solution) under 0 ℃, handle.Stir after the 30min reaction water (5.27mL), 15%NaOH (5.27mL) and water (15.8mL) quencher carefully.Add solid sodium sulfate and mixture is stirred 2h.Mixture is by diatomite filtration and use the THF washing leaching cake.Concentrated filtrate obtains E-3 E-3Data: ¹HNMR (500MHz, CDCl ₃) δ 4.16 (m, IH), 3.58 (m, 2H), 3.40 (m, 2H), 2.11 (m, 4H), 1.64 (m, 5H), 1.44 (s, 9H) ppm.

Cyclobutyl [3-(4-fluorobenzene oxygen) propyl group] t-butyl carbamate E-4

With carbinol E-3(5.0g, DCM 21.8mmol) (200mL) solution with the 4-fluorophenol (2.44g, 112mmol) and the triphenylphosphine of resin-bonded (10.29g 39.2mmol) handles.(5.29g, 26.2mmol), reactant stirs 12h under rt to add diisopropyl azodiformate in this mixture.Residuum chromatography (SiO ₂0 to 20% EtOAc in the hexane) thus purifying provides E-4 E-4Data: LRMSm/z (M-BOC+H) 224.1, observed value, 224.1, theoretical value.

N-[3-(4-fluorobenzene oxygen) propyl group] cyclobutyl ammonium chloride E-5

With carbamate E-4(4.4g, EtOAc 13.6mmol) (130mL) solution is handled saturated up to solution with HCl (g).Stir after the 1.5h, mixture is concentrated the HCl salt white solid that produces E-5.LRMSm/z (M+H) 224.1, observed value, 224.1, theoretical value.

N-cyclobutyl-N-[3-(4-fluorobenzene oxygen) propyl group]-1,1 '-xenyl-2-methane amide E-6

With the salt acid amide E-5(0.07g, DMF 0.269mmol) (2.5mL) solution with the 2-biphenyl carboxylic acids (0.053g, 0.269mmol), EDC-HCl (0.077g, 0.40mmol), HOBT (0.055g, 0.404mmol) and triethylamine (0.109g 1.08mmol) handles.Stir under rt after the 48h, reaction solution is with the EtOAc dilution and use saturated NaHCO ₃Solution washing.Organic phase is passed through Na ₂SO ₄Carry out drying, filter and concentrate.Gained material chromatogram (SiO ₂0 to 20% EtOAc in the hexane) impure thereby purifying provides E-6This material further by reverse phase gradient wash-out (have in the water of 0.1%THF 5 to 95% MeCN) thus carrying out purifying provides pure component.These components are mixed, neutralization, with the EtOAc extraction, and by saturated Na ₂SO ₄The aqueous solution carries out drying.Concentrate organic solution to produce E-6HRMSm/z (M+H) 404.2039, observed value, 404.2021, theoretical value.

N-cyclobutyl-N-[3-(4-fluorobenzene oxygen) propyl group]-2-phenyl-iodide methane amide E-7

Compound E-7Be by with synthetic E-6The time described similar program preparation.Substitute 2-biphenyl phenylformic acid with the 2-iodobenzoic acid. E-7Data: LRMSm/z (M+H) 453.91, observed value, 454.30, theoretical value.

Table E

Following compound uses the method preparation among the such scheme E, uses cyclopropylamine in step 1, and replace suitable to the replacement reagent described in the above-mentioned embodiment, for example organometallic compound or amine.Required starting raw material be purchased described in obtainable, the document or the organic synthesis those skilled in the art do not carry out just synthetic easily of over-drastic test.

Scheme F

N-cyclobutyl-N-[3-(4-fluorobenzene oxygen) propyl group]-2-(1H-imidazoles-1-yl) benzamide F-1

With iodide E-7(0.048g, and DMF 0.106mmol) (0.5mL) solution imidazoles (0.07g, 0.106mmol), CsCO ₃(0.069g, 0.212mmol) with anti--N, N '-diformazan hexanaphthene-1, (0.003g 0.021mmol) handles the 2-diamines.Mixture heats 12h down at 120 ℃, is cooled to rt, with EtOAc dilution and water and salt water washing.Organic phase is passed through Na ₂SO ₄Carry out drying, filter and concentrate.Residuum with reverse phase gradient wash-out (contain in the water of 0.1%TFA 5 to 95% MeCN) thus carrying out purifying provides pure component.These components are mixed, neutralization, with the EtOAc extraction, and by saturated Na ₂SO ₄The aqueous solution carries out drying.Concentrate organic solution to produce F-1 F-1Data: HRMS m/z (M+H) 394.191, observed value, 394.1926, theoretical value.

Table F

Scheme G

N-cyclobutyl-N-[3-(4-fluorobenzene oxygen) propyl group]-2-(1-methyl isophthalic acid H-pyrazoles-4-yl) benzamide G-1

With iodide E-7(0.071g, THF 0.157mmol) (2mL) solution with the pyrazoles boric acid ester (0.033g, 0.157mmol), 1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (II) (0.011g, 0.016mmol) and CsCO ₃(0.03g 0.157mmol) handles.Reaction mixture heats 10min at the sealed tube of putting into microwave reactor down at 160 ℃.The cooling reactant also dilutes with EtOAc.The saturated NH of organic solution ₄The Cl solution washing passes through Na ₂S _O4 dryings are filtered and are concentrated.Residuum with reverse phase gradient wash-out (have in the water of 0.1%THF 5 to 95% MeCN) thus carrying out purifying provides pure component.These components are mixed, neutralization, with the EtOAc extraction, and by saturated Na ₂SO ₄The aqueous solution carries out drying.Concentrate organic solution to produce G-1 G-1Data: HRMS m/z (M+H) 408.2089, observed value, 408.2082, theoretical value.

Table G

Following compound uses method for preparing, but replace suitable to the replacement reagent described in the above-mentioned embodiment, for example organometallic compound or amine.That required starting raw material foot is purchased is obtainable, described in the document or the organic synthesis those skilled in the art do not carry out two over-drastic and test easy synthetic.

Though the present invention is described and illustrates with reference to its some particular, those skilled in the art will envision that various modifications, variation, improvement to method and scheme, replace, delete or add, can under the situation of not leaving the spirit and scope of the present invention, make.

Claims

1. formula I compound:

Wherein:

A is selected from phenyl, naphthyl and heteroaryl;

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(a) hydrogen,

(b) C _1-6Alkyl, it is unsubstituted or uses R ¹³Replace,

(c) C _3-6Thiazolinyl, it is unsubstituted or uses R ¹³Replace,

(d) cycloalkyl, it is unsubstituted or uses R ¹³Replace,

(e) phenyl, it is unsubstituted or uses R ¹³That replace and

(f) heterocyclic radical, it is unsubstituted or uses R ¹³Replace,

(10)-S(O) ₂-NR ¹⁰R ¹¹，

(12)-CO ₂H，

(13)-CN and

(14)-NO ₂；

R ²The group that is selected from comprises:

(1) hydrogen,

R ³And R ⁴The group that independently is selected from comprises:

(1) hydrogen,

R ⁵And R ⁶The group that independently is selected from comprises:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(5)-O _n-C _3-6Cycloalkyl, wherein cycloalkyl is unsubstituted or with one or more R of being selected from ¹³Substituting group replace,

(8)-CN，

R ^7a, R ^7bAnd R ^7cThe group that independently is selected from comprises:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(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 and

(14)-NO ₂；

R ¹³The group that is selected from comprises:

(1) halogen,

(2) hydroxyl,

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

(7)-(C=O) _m-O _n-phenyl or-(C=O) _m-O _n-naphthyl, wherein phenyl or naphthyl is unsubstituted or with 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 and

(14)-NO ₂；

R ¹⁴The group that is selected from comprises:

(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) heterocyclic radical,

(10)-CO ₂H and

(11)-CN；

And pharmacy acceptable salt.

2. compound as claimed in claim 1, wherein:

A is selected from phenyl and heteroaryl;

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(12)-S(O) ₂-NR ¹⁰R ¹¹，

(14)-CO ₂H，

(15)-CO ₂-R ¹²，

(16)-CN and

(17)-NO ₂；

R ²The group that is selected from comprises:

(1) hydrogen,

R ³And R ⁴The group that independently is selected from comprises:

(1) hydrogen,

(3) C _3-6Cycloalkyl, it is unsubstituted or uses halogen, C _3-6Cycloalkyl or phenyl replace,

Perhaps R ³And R ⁴Form C with the carbon that links to each other with them _3-6Cycloalkyl ring;

R ⁵And R ⁶The group that independently is selected from comprises:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

R ^7a, R ^7bAnd R ^7cThe group that independently is selected from comprises:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(9)-S(O) ₂-NR ¹⁰R ¹¹，

(10)-S (O) _q-R ¹²And

(11)-CN；

And pharmacy acceptable salt.

3. compound as claimed in claim 1, wherein the group that is selected from of A comprises:

(1) phenyl,

(2)  azoles base,

(3) different  azoles base,

(4) thiazolyl,

(5) thiadiazolyl group,

(6) pyrazolyl and

(7) pyridyl.

4. as compound as described in the claim 3, its chemical formula is formula Ib:

Or its pharmacy acceptable salt or its independent enantiomorph or diastereomer.

5. as compound as described in the claim 4, its chemical formula is formula Ic:

6. compound as claimed in claim 3, wherein A is a thiazolyl.

7. compound as claimed in claim 6, its chemical formula are formula Ie:

8. compound as claimed in claim 7, its chemical formula are formula If:

9. compound as claimed in claim 8, its chemical formula are formula Ig:

Or its pharmacy acceptable salt.

10. compound as claimed in claim 1, wherein R ^1bBe hydrogen, R ^1cBe hydrogen and R ^1aThe group that independently is selected from comprises:

(1) hydrogen,

(2) halogen,

(7)-NR ¹⁰R ¹¹, R wherein ¹⁰And R ¹¹Independently be selected from hydrogen and C _1-6Alkyl,

(8) tetrazyl,

(9) thienyl,

(10) triazolyl,

(11) benzothienyl,

(12) pyrazolyl,

(13) imidazolyl,

(14)-NO ₂And

(15)-CN。

11. compound as claimed in claim 10, wherein A is a phenyl, R ^1bBe hydrogen, R ^1cBe hydrogen and R ^1aIt is phenyl.

12. compound as claimed in claim 1, wherein A is a thiazolyl, R ^1aBe C _1-6Alkyl, R ^1bBe phenyl, R ^1cDo not exist.

13. compound as claimed in claim 1, wherein R ²The group that is selected from comprises:

(1) hydrogen,

(2)CH ₃，

(3)CH ₂CH ₃，

(4)CH ₂CH ₂F，

(5) CH ₂-phenyl,

(6) CH ₂-cyclopropyl,

(7) CH ₂-cyclobutyl,

(8) cyclopropyl,

(9) cyclobutyl and

(10)CH ₂CH ₂CH ₃。

14. compound as claimed in claim 13, wherein R ²Be CH ₃, CH ₂CH ₃, cyclopropyl or cyclobutyl.

15. compound as claimed in claim 1, wherein R ³Be hydrogen and R ⁴Be hydrogen.

16. compound as claimed in claim 1, wherein R ³Be cyclopropyl and R ⁴Be hydrogen.

17. compound as claimed in claim 1, wherein R ⁵Be hydrogen and R ⁶Be hydrogen.

18. compound as claimed in claim 1, wherein R ⁵And R ⁶Form cyclopropyl or cyclobutyl ring with the carbon that links to each other with them.

19. compound as claimed in claim 1, wherein R ^7a, R ^7bAnd R ^7cThe group that independently is selected from comprises:

(1) hydrogen,

(2) fluorine,

(3) chlorine and

(4) bromine.

20. compound as claimed in claim 1, wherein R ^7aBe fluorine, R ^7bBe hydrogen and R ^7cBe hydrogen.

21. be selected from following compound:

N-[3-(4-fluorobenzene oxygen) propyl group]-2-methyl-5-phenyl-1,3-thiazoles-4-methane amide;

N-[3-(4-fluorobenzene oxygen) propyl group]-N, 2-dimethyl-5-phenyl-1,3-thiazoles-4-methane amide;

N-ethyl-N-[3-(4-fluorobenzene oxygen) propyl group]-2-methyl-5-phenyl-1,3-thiazoles-4-methane amide;

N-(cyclobutylmethyl)-N-[3-(4-fluorobenzene oxygen) propyl group]-2-methyl-5-phenyl-1,3-thiazoles-4-methane amide;

N-(cyclopropyl methyl)-N-[3-(4-fluorobenzene oxygen) propyl group]-2-methyl-5-phenyl-1,3-thiazoles-4-methane amide;

N-phenmethyl-N-[3-(4-fluorobenzene oxygen) propyl group]-2-methyl-5-phenyl-1,3-thiazoles-4-methane amide;

N-[3-(4-fluorobenzene oxygen) propyl group]-the N-methyl isophthalic acid, 1 '-xenyl-2-methane amide;

N-(2-fluoro ethyl)-N-[3-(4-fluorobenzene oxygen) propyl group]-2-methyl-5-phenyl-1,3-thiazoles-4-methane amide;

N-[3-(4-fluorobenzene oxygen) propyl group]-2-methyl-5-phenyl-N propyl group-1,3-thiazoles-4-methane amide;

N-ethyl-N-[3-(4-fluorobenzene oxygen) propyl group]-1,1 '-xenyl-2-methane amide;

N-(cyclopropyl methyl)-N-[3-(4-fluorobenzene oxygen) propyl group]-1,1 '-xenyl-2-methane amide;

N-ethyl-N-[3-(4-fluorobenzene oxygen) propyl group]-2-(1H-pyrroles-1-yl)-benzamide;

N-ethyl-N-[3-(4-fluorobenzene oxygen) propyl group]-2-(1H-pyrazol-1-yl)-benzamide;

N-ethyl-N-[3-(4-fluorobenzene oxygen) propyl group]-5-phenyl-1,3- azoles-4-methane amide;

N-ethyl-N-[3-(4-fluorobenzene oxygen) propyl group]-2-(1H-tetrazolium-1-yl)-benzamide;

N-ethyl-N-[3-(4-fluorobenzene oxygen) propyl group]-4-phenyl-1,2,3-thiadiazoles-5-methane amide;

3-(2-chloro-phenyl-)-N-ethyl-N-[3-(4-fluorobenzene oxygen) propyl group]-the different  azoles of 5-methyl-4-methane amide;

2-(dimethylamino)-N-ethyl-N-[3-(4-fluorobenzene oxygen) propyl group] benzamide;

N-ethyl-2-fluorine N-[3-(4-fluorobenzene oxygen) propyl group] benzamide;

2-chloro-N-ethyl-N-[3-(4-fluorobenzene oxygen) propyl group] benzamide;

2-bromo-N-ethyl-N-[3 (4-fluorobenzene oxygen) propyl group] benzamide;

N-ethyl-N-[3-(fluorobenzene oxygen) propyl group]-the 2-phenoxy benzamide;

3-chloro-N-ethyl-N-[3-(4-fluorobenzene oxygen) propyl group] benzamide;

4-chloro-N-ethyl-N-[3-(4-fluorobenzene oxygen) propyl group] benzamide;

N-ethyl-N-[3-(4-fluorobenzene oxygen) propyl group]-4 '-methoxyl group-1,1 ' xenyl-2-methane amide;

N-ethyl-N-[3-(4-fluorobenzene oxygen) propyl group]-4 '-nitro-1,1 '-xenyl-2-methane amide;

N-ethyl-N-[3-(4-fluorobenzene oxygen) propyl group]-3 '-methyl isophthalic acid, 1 '-xenyl-2-methane amide;

N-ethyl-N-[3-(4-fluorobenzene oxygen) propyl group]-2-thiene-3-yl-benzamide;

4 '-cyano group-N-ethyl-N-[3-(4-fluorobenzene oxygen) propyl group]-1,1 '-xenyl-2-methane amide;

2-[(E)-2-cyclohexyl vinyl]-N-ethyl-N-[3-(4-fluorobenzene oxygen) propyl group] benzoyl;

N-ethyl-N-[3-(4-fluorobenzene oxygen) propyl group]-2-(2-naphthyl) benzamide;

2-(1-thionaphthene-3-yl)-N-ethyl-N-[3-(4-fluorobenzene oxygen) propyl group] benzamide;

(±)-N-[1-cyclopropyl-3-(4-fluorobenzene oxygen) propyl group]-N-ethyl-1,1 '-xenyl-2-methane amide;

(±)-N-[1-cyclopropyl-3-(4-fluorobenzene oxygen) propyl group]-N, 2-dimethyl-5-phenyl-1,3-thiazoles-4-methane amide;

(±)-N-[1-cyclopropyl-3 (4-fluorobenzene oxygen) propyl group]-N-ethyl-2-methyl-5-phenyl-1,3-thiazoles-4-methane amide;

(±)-N-[1-cyclopropyl-3-(4-fluorobenzene oxygen) propyl group]-the N-methyl isophthalic acid, 1 '-xenyl-2-methane amide;

N-{1-[(4-fluorobenzene oxygen) methyl] cyclopropyl } methyl)-N, 2-dimethyl-5-phenyl-1,3-thiazoles-4-methane amide;

N-ethyl-N-(1-[(4-fluorobenzene oxygen) and methyl] cyclopropyl } methyl)-2-methyl-5-phenyl-1,3-thiazoles-4-methane amide;

N-(cyclopropyl methyl)-N-(1-(4-fluorobenzene oxygen) methyl] and cyclopropyl } methyl)-2-methyl-5-phenyl-1,3-thiazoles-4-methane amide;

N-(1-(4-fluorobenzene oxygen) methyl] and cyclobutyl } methyl)-N, 2-dimethyl-5-phenyl-1,3-thiazoles-4-methane amide;

N-cyclobutyl-N-[3-(4-fluorobenzene oxygen) propyl group]-1,1 '-xenyl-2-methane amide;

N-cyclobutyl-N-[3-(4-fluorobenzene oxygen) propyl group]-2-iodobenzene methane amide;

N-cyclobutyl-N-[3-(4-fluorobenzene oxygen) propyl group]-2-methyl 5-phenyl-1,3-thiazoles-4-methane amide;

N-cyclobutyl-N-[3-(4-fluorobenzene oxygen) propyl group]-2-(trifluoromethoxy) benzamide;

N-cyclobutyl-N-[3-(4-fluorobenzene oxygen) propyl group]-2-(1H-pyrroles-1-yl) benzamide;

N-cyclobutyl-N-[3-(4-fluorobenzene oxygen) propyl group]-2-(1H-pyrazol-1-yl) benzamide;

N-cyclobutyl-N-[3-(4-fluorobenzene oxygen) propyl group]-4 '-methoxyl group-1,1 '-xenyl-2-methane amide;

N-cyclobutyl-2-(dimethylamino)-N-[3-(4-fluorobenzene oxygen) propyl group] benzamide;

N-cyclobutyl-N-[3-(4-fluorobenzene oxygen) propyl group]-1-methyl-4-phenyl-1H-pyrazole-3-formamide;

N-cyclobutyl-3 '-fluoro-N-[3-(4-fluorobenzene oxygen) propyl group]-1,1 '-xenyl-2-methane amide;

N-cyclobutyl-N-[3-(4-fluorobenzene oxygen) propyl group]-2-methyl-5-phenyl-2H-1,2,3-triazole-4-methane amide;

N-cyclopropyl-N-[3-(4-fluorobenzene oxygen) propyl group]-2-methyl-5-phenyl-1,3-thiazoles-4-methane amide;

N-cyclopropyl-N-[3-(4-fluorobenzene oxygen) propyl group]-1,1 '-xenyl-2-methane amide;

N-cyclopropyl-N-[3-(4-fluorobenzene oxygen) propyl group]-2-(trifluoromethoxy) benzamide;

N-cyclopropyl-N-[3-(4-fluorobenzene oxygen) propyl group]-2-(1H-pyrroles-1-yl) benzamide;

N-cyclopropyl-N-[3-(4-fluorobenzene oxygen) propyl group]-2-(1H-pyrazol-1-yl) benzamide;

N-cyclopropyl-N-[3-(4-fluorobenzene oxygen) propyl group]-4 '-methoxyl group-1,1 '-xenyl-2-methane amide;

N-cyclopropyl-2-(dimethylamino)-N-[3-(4-fluorobenzene oxygen) propyl group] benzamide;

N-cyclopropyl-N-[3-(4-fluorobenzene oxygen) propyl group]-1-methyl-4-phenyl-1H-pyrazole-3-formamide;

N-cyclopropyl-3 '-fluoro-N-[3-(4-fluorobenzene oxygen) propyl group]-1,1 '-xenyl-2-methane amide;

N-cyclopropyl-N-[3-(4-fluorobenzene oxygen) propyl group]-2-methyl-5-phenyl-2H-1,2,3-triazole-4-methane amide;

N-cyclobutyl-N-[3-(4-fluorobenzene oxygen) propyl group]-2-(1H-imidazoles-1-yl) benzamide;

N-cyclobutyl-N-[3-(4-fluorobenzene oxygen) propyl group]-5-methyl-2-(1H-pyrazol-1-yl) benzamide;

N-cyclobutyl-N-[3-(4-fluorobenzene oxygen) propyl group]-2-(2H-1,2,3-triazole-2-yl) benzamide;

N-cyclobutyl-N-[3-(4-fluorobenzene oxygen) propyl group]-2-(4H-1,2,4-triazole-4-yl) benzamide;

N-cyclobutyl-N-[3-(4-fluorobenzene oxygen) propyl group]-5-methyl-2-(2H-1,2,3-triazole-2-yl) benzamide;

N-cyclobutyl-N-[3-(4-fluoro-3-toluene oxygen) propyl group]-5-methyl-2-(2H-1,2,3-triazole-2-yl) benzamide;

N-cyclobutyl-N-[3-(4-fluoro-3-toluene oxygen) propyl group]-2-(2H-1,2,3-triazole-2-yl) benzamide;

N-cyclobutyl-N-[3-(4-fluorobenzene oxygen) propyl group]-2-(1-methyl isophthalic acid H-pyrazoles-4-yl) benzamide;

N-cyclobutyl-N-[3-(4-fluorobenzene oxygen) propyl group]-2-(1H-pyrazoles-4-yl) benzamide;

N-cyclobutyl-N-[3-(4-fluoro-3-toluene oxygen) propyl group]-2-(1H-pyrazoles-4-yl) benzamide;

N-cyclobutyl-N-[3-(4-fluoro-3-toluene oxygen) propyl group]-5-methyl-2-(1H-pyrazoles-4-yl) benzamide;

N-cyclobutyl-N-[3-(4-fluorobenzene oxygen) propyl group]-2-methyl-5-(1H-pyrazoles-4-yl)-1,3-thiazoles-4-methane amide;

N-cyclobutyl-N-[3-(4-fluorobenzene oxygen) propyl group]-2-methyl-5-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1,3-thiazoles-4-methane amide;

N-cyclobutyl-N-[3-(4-fluorobenzene oxygen) propyl group]-2-methyl-5-pyridin-3-yl-1,3-thiazoles-4-methane amide;

N-cyclobutyl-N-[3-(4-fluorobenzene oxygen) propyl group]-2-methyl-5-pyridin-4-yl-1,3-thiazoles-4-methane amide;

N-cyclobutyl-N-[3-(4-fluorine 3-toluene oxygen) propyl group]-2-methyl-5-(1H-pyrazoles-4-yl)-1,3-thiazoles-4-methane amide;

N-cyclobutyl-N-[3-(4-fluorine 3-toluene oxygen) propyl group]-2-methyl-5-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1,3-thiazoles-4-methane amide;

Or its pharmacy acceptable salt.

22. a pharmaceutical composition, it contains inert support and compound as claimed in claim 1 or its pharmacy acceptable salt.

23. a method that improves the mammalian subject sleep quality, it comprises compound as claimed in claim 1 or its pharmacy acceptable salt that gives the patient treatment significant quantity.

24. a method that increases mammalian subject REM sleep, it comprises compound as claimed in claim 1 or its pharmacy acceptable salt that gives the patient treatment significant quantity.

25. a method that increases the sleep of 2 phases of mammalian subject, it comprises compound as claimed in claim 1 or its pharmacy acceptable salt that gives the patient treatment significant quantity.

26. a method that reduces the fracture of mammalian subject sleep pattern, it comprises compound as claimed in claim 1 or its pharmacy acceptable salt that gives the patient treatment significant quantity.

27. a method for the treatment of the mammalian subject insomnia, it comprises compound as claimed in claim 1 or its pharmacy acceptable salt that gives the patient treatment significant quantity.

28. the method for the treatment of or controlling the mammalian subject obesity, it comprises compound as claimed in claim 1 or its pharmacy acceptable salt that gives the patient treatment significant quantity.