CN1976935A

CN1976935A - Pyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]-pyrimidine adenosine A2a receptor antagonists

Info

Publication number: CN1976935A
Application number: CN 200580019904
Authority: CN
Inventors: B·R·奈斯达特; 郝劲松; 刘洪�; C·D·鲍伊尔; S·契卡拉曼尼尔; U·G·夏; A·史丹佛; J·M·哈里斯
Original assignee: Schering Corp
Current assignee: Merck Sharp and Dohme LLC
Priority date: 2004-04-21
Filing date: 2005-04-19
Publication date: 2007-06-06
Also published as: ZA200608778B

Abstract

Compounds having the structural formula I or a pharmaceutically acceptable salt thereof, wherein R is optionally substituted phenyl, furanyl, thienyl, pyridyl, pyridyl N-oxide, oxazolyl or pyrrolyl, or cycloalkenyl R<1>, R<2>, R<3>, R<4> and R<5> are H, alkyl or alkoxyalkyl; and Z is optionally substituted aryl or heteroaryl are disclosed. Also disclosed is the use of compounds of formula I in the treatment of central nervous system diseases, in particular Parkinson's disease, alone or in combination with other agents for treating Parkinson's disease, and pharmaceutical compositions comprising them.

Description

Pyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]-pyrimidine adenosine A 2AReceptor antagonist

Background technology

The pyrazolo that the present invention relates to replace-[4,3-e]-1,2,4-triazolo [1,5-c]-pyrimidine adenosine A _2aReceptor antagonist, described compound be in central nervous system disease, the particularly application in the Parkinson's disease treatment, and the medicinal compositions that contains described compound.

Known adenosine is a kind of interior originality conditioning agent with different physiological roles.On the cardiovascular systems level, adenosine is a kind of powerful vasodilator and a kind of heart depressor (depressor).On central nervous system, adenosine can cause calmness, anxiety and antiepileptic action.On respiratory system, can cause bronchoconstriction.On the kidney level, it brings into play biphasic effect, causes vasoconstriction and make vasorelaxation when lower concentration when high dosage.Adenosine is playing the steatolysis inhibitor and the effect of antithrombotics on thrombocyte on the adipocyte.

The effect of adenosine is by regulating with the interaction of the specific receptors of different films, and these acceptors belong to the receptor family with the G albumen coupling.Biochemistry and pharmaceutical research add molecular biological progress, have identified at least four kinds of Adenosine Receptors hypotype: A ₁, A _2a, A _2bAnd A ₃A ₁And A ₃For high-affinity, can suppress the activity of adenylate cyclase, and A _2aAnd A _2bFor low affinity, can promote the activity of same enzyme.Can be used as A ₁, A _2a, A _2bAnd A ₃The neplanocin of the antagonist of acceptor is also differentiated.

A _2aThe selective antagonist of acceptor has the meaning on the pharmacology because of side effect is less.In central nervous system, A _2aAntagonist has the antidepressant characteristic and stimulates cognitive function.In addition, data shows the A that high density is arranged in the brain basal nuclei _2aAcceptor, known its control to motion has importance.Therefore, A _2aAntagonist can improve because neurodegenerative disorders, for example sport injury that caused of Parkinson's disease, senile dementia, Alzheimer's disease and psychosis.

Found that some xanthine-related compounds are A ₁The selective antagonist of acceptor, and found that xanthine and non--Xanthine compounds have high A _2aAffinity and to A _2aAnd A ₁Has selectivity in various degree.Triazolo-pyrimidine adenosine A _2aReceptor antagonist for example before had been disclosed among WO 95/01356, US 5,565,460, WO 97/05138, WO 98/52568, WO01/92264 and the WO 03/032996.

Adenosine A is disclosed in the PCT/US03/40456 that submitted on December 17th, 2003 _2aReceptor antagonist can be applicable to the periodically treatment or the prevention of main drive disease (PLMS) in extrapyramidal syndrome, myodystonia, restless legs syndrome (RLS) or the sleep, also discloses the treatment that it can be used for scatterbrained hyperactivity disease (ADHD) in WO 02/055083.

Summary of the invention

The present invention relates to have compound in structural formula I

Or its pharmacy acceptable salt, wherein

R is R ⁶-phenyl, R ⁶-furyl, R ⁶-thienyl, R ⁶-pyridyl, R ⁶-pyridyl oxynitride, R ⁶- azoles base, R ⁶-pyrryl or cycloalkenyl group;

R ¹, R ², R ³, R ⁴And R ⁵Independently be selected from H, alkyl and alkoxyalkyl;

R ⁶Be 1 to 3 independently be selected from following substituting group: H, alkyl ,-CF ₃, halogen ,-NO ₂,-CN ,-NR ⁷R ⁸, alkoxyl group, alkylthio, alkyl sulfinyl and alkane alkylsulfonyl;

R ⁷Be H or alkyl;

R ⁸Be H, alkyl, alkyl C (O)-or alkyl-SO ₂-;

Z is R ⁹, R ¹⁰-aryl or R ⁹, R ¹⁰-heteroaryl;

R ⁹For thiazolinyl, hydroxyalkyl, alkoxyalkyl, alkoxyl group-alkoxyl group-alkyl-, (two-alkoxyl group)-alkyl, (hydroxyl)-alkoxyalkyl, R ¹⁵-cycloalkyl, R ¹⁵-cycloalkylalkyl, cycloalkyl-oxygen base, cycloalkyl-O-alkoxyl group, cyano group alkyl ,-C (O) R ¹³,-N (R ¹¹) (R ¹²), N (R ¹¹) (R ¹²)-alkyl-,-C (O) N (R ¹³) (R ¹⁶) ,-alkylidene group-C (O)-N (R ¹¹) ₂,-C (O)-(R ¹⁵-Heterocyclylalkyl), R ¹⁵-Heterocyclylalkyl-alkyl, R ¹⁵-Heterocyclylalkyl-alkoxyl group, R ¹⁹-heteroaryl, CF ₃-alkylidene group-O-alkyl, CF ₃-hydroxyalkyl, (CF ₃) (hydroxyl) alkoxyl group, cyano group-alkoxyl group ,-alkylidene group-C (O)-O-alkyl ,-SO ₂-N (alkyl) ₂, (cycloalkyl) hydroxyalkyl, (hydroxyalkyl) alkoxyl group, (dihydroxyl) alkyl, (dihydroxyl) alkoxyl group or-C (=NOR ¹⁷)-CF ₃

R ¹⁰Be 1 to 3 and independently be selected from following substituting group: hydrogen, alkyl, thiazolinyl, hydroxyl, alkoxyl group, hydroxyalkyl, hydroxyl-alkoxyl group, alkoxyalkyl, alkoxyl group alkoxyl group, alkoxyl group-alkoxyl group-alkyl-, (two-alkoxyl group)-alkyl, (hydroxyl)-alkoxyalkyl, R ¹⁵-cycloalkyl, R ¹⁵-cycloalkylalkyl, cycloalkyl-oxygen base, cycloalkyl-O-alkoxyl group, alkyl-SO ₂-, alkyl-SO-, halogeno-group ,-CN, cyano group alkyl ,-CHF ₂,-CF ₃,-OCHF ₂,-OCF ₃,-C (O) R ¹³,-O-alkylidene group-C (O) OR ¹³,-C (O) O-alkyl ,-N (R ¹¹) (R ¹²), N (R ¹¹) (R ¹²)-alkyl, N (R ¹¹) (R ¹²)-alkoxyl group ,-C (O) N (R ¹³) (R ¹⁶), R ¹⁹-heteroaryl, R ¹⁵-Heterocyclylalkyl, R ¹⁵-Heterocyclylalkyl-alkyl, R ¹⁵-Heterocyclylalkyl-alkoxyl group, R ¹⁵-Heterocyclylalkyl-oxygen base, CF ₃-alkylidene group-O-alkyl, CF ₃-hydroxyalkyl, (CF ₃) (hydroxyl) alkoxyl group, cyano group-alkoxyl group ,-alkylidene group-C (O)-O-alkyl ,-SO ₂-N (alkyl) ₂, (cycloalkyl) hydroxyalkyl, (hydroxyalkyl) alkoxyl group, (dihydroxyl) alkyl, (dihydroxyl) alkoxyl group ,-C (=NOR ¹⁷)-alkyl and-C (=NOR ¹⁷)-CF ₃

Or the R on adjacent carboatomic ring atom ⁹Group and R ¹⁰Group forms-O-(CH jointly ₂) ₂-O-,-CH ₂-O-(CH ₂) ₂-O-,-O-(CH ₂) ₂-,-(CH ₂) ₃-O-,-O-(CH ₂) ₃-O-,-(CH ₂) ₃-or-CH ₂-CH=CH-is wherein by R ⁹And R ¹⁰Substituting group and the formed ring of its ring carbon atom that is linked to each other are by R ¹⁶Replace;

Or the R on adjacent carboatomic ring atom ⁹Group and R ¹⁰Group forms-N (R jointly ¹¹)-C (O)-O-,-N (R ¹¹)-C (O)-S-or-N (R ¹²)-(CH ₂) ₂-;

Or the R on adjacent carboatomic ring atom ⁹Group and R ¹⁰Group forms-(CH jointly ₂) ₂CH (OR ¹⁸)-,-CH ₂CH (OR ¹⁸) CH ₂-,-(CH ₂) ₃CH (OR ¹⁸)-,-(CH ₂) ₂CH (OR ¹⁸) CH ₂-,-(CH ₂) ₂C (O)-,-CH ₂C (O) CH ₂-,-(CH ₂) ₃C (O)-,-(CH ₂) ₂C (O) CH ₂-,-O (CH ₂) ₂CH (OR ¹⁸)-or-OCH ₂CH (OR ¹⁸) CH ₂-, wherein should be by R ⁹And R ¹⁰The formed ring of the ring carbon atom that substituting group is connected with them is chosen wantonly on carbon atom and is replaced by hydroxyalkyl or alkoxyalkyl;

Each R ¹¹Independently be selected from H and alkyl;

Each R ¹²Independently be selected from: H, alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl ,-C (O)-alkyl ,-C (O) O-alkyl, (alkoxyl group) hydroxyalkyl, alkoxyalkyl-C (O)-,-SO ₂Alkyl ,-alkylidene group-C (O) alkyl and-alkylidene group-C (O) O-alkyl;

R ¹³For H, alkyl or-CF ₃

R ¹⁵Be 1 to 3 independently be selected from following substituting group: H, alkyl ,-OH, alkoxyl group, alkoxyalkyl and hydroxyalkyl; Or two R ¹⁵Substituting group, the carbon that the two is connected with them form jointly-C (=O)-group;

R ¹⁶Be H, alkyl, alkoxyalkyl, OH or hydroxyalkyl;

R ¹⁷Be H or alkyl;

R ¹⁸Be H or alkyl; And

R ¹⁹Be 1 or 2 independently be selected from following substituting group: H, alkyl, hydroxyalkyl, alkoxyalkyl ,-C (O) N (R ¹¹) (R ¹²) and-N (R ¹¹) ₂

Another aspect of the invention is a kind of medicinal compositions, it is included in the formula I compound of at least a treatment significant quantity in the pharmaceutically acceptable carrier.

Of the present invention is a kind of treatment central nervous system disease more on the other hand, for example dysthymia disorders, cognitive illnesses and neurodegenerative disorders, for example Parkinson's disease, senile dementia or psychosis, and the method for apoplexy, it comprises the compound that needs at least a formula I of the Mammals of such treatment.

It is diseases related to the present invention also relates to attention, the treatment of for example absent minded disorders (ADD) and absent minded Attention Deficit Hyperactivity Disorder (ADHD).The present invention also relates to the treatment or the prevention of extrapyramidal symptom (for example myodystony, sit quietly difficulty, false Parkinson's disease and tardive dyskinesia), the treatment of primary (spontaneity) myodystony, with the patient who shows myodystony because of usefulness tricyclic antidepressants, lithium or anti-coagulant treatment, or the treatment or the prevention of the patient's of use Cocaine myodystony, it comprises the compound that needs at least a formula I of the Mammals of such treatment.The invention further relates to the abnormal motion obstacle, for example periodically treatment of main drive disease (PLMS) in restless legs syndrome (RLS) or the sleep, it comprises the compound that at least a formula I of the patient of these needs is arranged.

Particularly, the present invention describes the parkinsonian method of treatment, and it comprises the compound that needs at least a formula I of the Mammals of such treatment.

Of the present invention more on the one hand for a kind of unite the compound that uses at least a formula I can be with one or more in order to treat the parkinsonian method of parkinsonian pharmacological agent, described medicine has for example inhibitor (MAO-B), the DOPA decarboxylase inhibitor (DCI) of Dopamine HCL, dopaminergic agonist, monoamine oxidase B, or catechol-O-methyltransferase (COMT) inhibitor.Also claimed a kind of medicinal compositions, it is included in that the compound of at least a formula I in the pharmaceutically acceptable carrier and one or more are known can be in order to treat parkinsonian medicine.

The present invention also comprises the method for a kind of RLS of treatment or PLMS, it comprises that compound that at least a formula I of the patient of these needs is arranged and another can be in order to the combinations of the medicine of treatment RLS or PLMS, and described medicine has for example levodopa/carbidopa, levodopa/benserazide (benserazide), dopamine agonist, benzodiazepine, OPIOIDS material (opioid), anticonvulsive agent or iron.

Detailed Description Of The Invention

Preferred formula I compound for those wherein R be R ⁶-phenyl, R ⁶-furyl, R ⁶-thienyl, R ⁶-pyridyl or R ⁶- azoles base, more preferably R ⁶-furyl or R ⁶-pyridyl.R ⁶Be preferably H, halogen or alkyl, particularly H, F or methyl.

R ¹, R ², R ³, R ⁴And R ⁵Respectively be preferably H.

The preferred definition of Z is R ⁹, R ¹⁰-aryl, more preferably R ⁹, R ¹⁰-phenyl.When Z is R ⁹, R ¹⁰During-phenyl, R then ⁹Be preferably hydroxyalkyl, alkoxyalkyl, (hydroxyl)-alkoxyalkyl, (hydroxyalkyl) alkoxyl group, R ¹⁵-cycloalkyl, cyano group alkyl, R ¹⁹-heteroaryl or (cycloalkyl) hydroxyalkyl, and R ¹⁰Be preferably 1 or 2 independently be selected from following substituting group: H, halogeno-group ,-C (O) R ¹³, alkoxyl group, hydroxyalkyl, hydroxy alkoxy base, alkoxyl group alkoxyl group, alkoxyalkyl and cyano group alkyl.More preferably, R ⁹For hydroxyalkyl (for example hydroxyethyl), (hydroxyalkyl) alkoxyl group (for example-CH (OCH ₃) (CH ₂OH)), R ¹⁵-cycloalkyl, cyano group alkyl (for example cyanogen methyl), R ¹⁹-heteroaryl or (cycloalkyl)-hydroxyalkyl, and R ¹⁰Be preferably 1 or 2 substituting group that independently is selected from H, halogeno-group and alkoxyl group.Particularly preferred compound is for wherein there being a R ¹⁰Substituting group, particularly this R wherein ¹⁰Substituting group is a fluoro, more especially o-fluoric compound.Work as R ⁹Be R ¹⁵During-cycloalkyl, then this cycloalkyl is preferably cyclopropyl and R ¹⁵(for example be preferably OH ).Work as R ⁹Be R ¹⁹-heteroaryl, then this heteroaryl is preferably  azoles base or  di azoly and R ¹⁹Be preferably alkyl, hydroxyalkyl or alkoxyalkyl, for example methyl ,-C (CH ₃) ₂OH or methoxyl methyl.

When Z is R ⁹, R ¹⁰During-heteroaryl, then this heteroaryl moieties is preferably pyridyl.R ⁹Be preferably hydroxyalkyl, alkoxyalkyl, (hydroxyl)-alkoxyalkyl, (hydroxyalkyl) alkoxyl group or cyano group alkyl, and R ¹⁰Be preferably 1 or 2 substituting group that independently is selected from H, halogeno-group and alkyl.

An embodiment preferred is a kind of formula I compound, and wherein R is R ⁶-furyl or R ⁶-pyridyl; R ², R ³, R ⁴And R ⁵Respectively be H; And Z is R ⁹, R ¹⁰-phenyl, wherein R ⁹Be hydroxyalkyl, cyano group alkyl, (hydroxyalkyl) alkoxyl group, R ¹⁵-cycloalkyl, R ¹⁹-heteroaryl or (cycloalkyl) hydroxyalkyl, and R ¹⁰Be the o-fluoro.

In above-mentioned definition, " R ⁹, R ¹⁰-aryl " and " R ⁹, R ¹⁰-heteroaryl " refer to all have a R ⁹With a R ¹⁰Substituent aryl and heteroaryl groups.

The term as used herein alkyl comprises the straight or branched fat hydrocarbon chain of 1 to 6 carbon atom, for example methyl, ethyl, sec.-propyl and the tertiary butyl.

" aryl " represented aromatic monocyclic or encircled ring system more, and it comprises 6 to about 14 carbon atoms, is preferably 6 to about 10 carbon atoms.The limiting examples of suitable aromatic yl group comprises phenyl and naphthyl.

Heteroaryl refers to monocycle, dicyclo or the benzo-fused assorted aromatic group of 5 to 10 atoms, and it contains 2 to 9 carbon atoms and 1 to 4 heteroatoms that independently is selected from N, O and S, and prerequisite is that described ring does not contain adjacent oxygen and/or sulphur atom.In the N-oxide compound of ring nitrogen is also included within.The bicyclic heteroaryl examples of groups is: pyridyl,  azoles base, different  azoles base,  di azoly, furyl, pyrryl, thienyl, imidazolyl, pyrazolyl, tetrazyl, thiazolyl, isothiazolyl, thiadiazolyl group, pyrazinyl, pyrimidyl, pyridazinyl and triazolyl.The bicyclic heteroaryl examples of groups is: naphthyridine (naphthyridyl) (for example 1,5 or 1,7), imidazopyridyl, Pyridopyrimidine base and 7-azaindolyl.The example of benzo-fused heteroaryl groups is: indyl, quinolyl, isoquinolyl, 2 base, benzothienyl (that is: thianaphthenyl (thianaphthenyl)), benzimidazolyl-, benzofuryl, benzoxazol base, benzisoxa  azoles base, benzothiazolyl and benzo furazan base.All positional isomerss include interior, for example 2-pyridyl, 3-pyridyl and 4-pyridyl.Term-(R ⁹, R ¹⁰)-, R ¹¹And R ¹⁹The heteroaryl that replaces-refer to wherein can have substituting group as defined above by substituted ring carbon atom by such group.When heteroaryl groups is a benzo-fused ring, then substituting group can be connected on phenyl ring position and hetero-aromatic ring position one or both of, and this heteroaryl groups can be connected in the rest part of molecule by phenyl ring position or hetero-aromatic ring position.

Heterocyclylalkyl is represented 4 to 7 atoms, is preferably the saturated rings of 5 or 6 annular atomses, and wherein 1 or 2 ring members is selected from O, S and NR ¹³, and all the other atoms are carbon.There is no adjacent oxygen and/or sulphur atom in the ring.The limiting examples of heterocycloalkyl ring is: piperidyl, pyrrolidyl, piperazinyl, morpholinyl, parathiazan base, thiazolidyl, 1,3-dioxolanyl, 1,4-dioxane base,  azoles base, tetrahydrofuran base, tetrahydro-thienyl and tetrahydro thiapyran base.

" hydroxyalkyl " expression HO-alkyl-group, alkyl group wherein defines as described above.The limiting examples of suitable hydroxyalkyl group comprises: methylol and 2-hydroxyethyl.

" alkoxyl group " expression alkyl-O-group, alkyl group wherein defines as described above.The limiting examples of suitable alkoxy base comprises: methoxyl group, oxyethyl group, positive propoxy, different positive propoxy and n-butoxy.It is tied in parent molecule by ether-oxygen bond.

" alkylthio " expression alkyl-S-group, alkyl group wherein defines as described above.The limiting examples of suitable alkylthio group comprises: methylthio group, ethylmercapto group and iprotiazem base.It is binding on parent molecule by sulphur.

" cycloalkyl " expression comprises the 3 non-aromatic monocyclic systems to about 6 carbon atoms.The limiting examples of suitable monocyclic cycloalkyl comprises: cyclopropyl, cyclopentyl and cyclohexyl, therefore, " cycloalkyloxy group " representative ring alkyl-O-group.

" cycloalkenyl group " refers to comprise about 3 to about 10 carbon atoms, is preferably about 5 non-aromatics list or multi-loop systems to about 10 carbon atoms, and it contains a carbon-to-carbon double bond at least.Preferred cyclenes basic ring contains about 5 to about 7 annular atomses.The limiting examples of suitable monocycle cycloalkenyl group comprises: cyclopentenyl, cyclohexenyl, cycloheptenyl etc.The limiting examples of suitable many rings cycloalkenyl group is norbornene (norbornylenyl).

Halogeno-group is fluoro, chloro, bromo or iodo.

Term " (two-alkoxyl group)-alkyl " refers to by the alkyl chain of two alkoxy bases replacements.Similarly, " (hydroxyl)-alkoxyalkyl " refers to by the alkyl chain of oh group and alkoxy base replacement; (CF ₃) (hydroxyl) alkoxyl group refers to CF ₃The alkoxy base that group and hydroxyl replace; (cycloalkyl) hydroxyalkyl refers to the hydroxyalkyl group that replaced by group of naphthene base; (dihydroxyl) alkyl refers to by the alkyl chain of two oh groups replacements; And (dihydroxyl) alkoxyl group refers to by the alkoxy base of two oh groups replacements.Substituent in each at these, alkyl chain can be ramose.

Adjacent R ⁹And R ¹⁰The example of the circular part that phenyl that group is coupled or the carbon on the heteroaryl ring form is:

Term " optional replacement " refers to replace by specific group is optional on available position.

About the part in the compound (for example substituting group, group or ring) quantity, unless otherwise defined, otherwise phrase " one or more " and " at least one " refer to that such part can be many as chemically allowing, and the maximum number of this type of part really location survey surely fully in those skilled in the art's ken.

Term as used herein " composition " is intended to comprise the product of the specific composition that comprises specified quantitative, and the direct or indirect product that produces of combination of any specific composition by this specified quantitative.

Introduce the line in this ring system, for example

Represent this line (key) may be connected on any commutable ring carbon atom.

As known in the art, from specific atoms draw but end points not the key of display part represent a methyl group to be connected in this atom by this key, except as otherwise noted.For example

Expression

Should notice that also any carbon or the heteroatoms that does not satisfy chemical valence in literal, schema, embodiment, structural formula and any form herein suppose that all it has the hydrogen atom that can satisfy chemical valence.

The prodrug of The compounds of this invention and solvate also plan to be included in this paper.Term as used herein " prodrug " refers to the compound for prodrug, after it gives the patient, can experience chemical conversion and production I compound or its salt and/or solvate by metabolism or chemical process.Discussion to prodrug can be referring to T.Higuchi and V.Stella, Pro-drugsas NovelDelivery Systems (1987) Volume 14, A.C.S.Symposium Series and Bioreversible Carriersin Drug Design, (1987) Edward B.Roche edits, American Pharmaceutical Association and Pergamon Press, this two all be attached to herein by reference.

The physical property of " solvate " expression compound of the present invention and one or more solvent molecule is associated.This physical property association relates to ion or covalency bond in various degree, comprising: hydrogen bond.In some instances, solvate can be separated, for example when one or more solvent molecule is attached in the lattice of crystalline solid." solvate " comprise solution-phase and inseparable solvate the two.The limiting examples of suitable solvate comprises: ethylate, methylate etc." hydrate " is H for solvent molecule wherein ₂The solvate of O.

The polymorphic of salt, solvate and the prodrug of formula I compound and formula I compound is included among the present invention.

" significant quantity " or " treatment significant quantity " is intended to describe can be effectively as adenosine A _2aReceptor antagonist also thereby produces the The compounds of this invention of required curative effect or the amount of composition in suitable patient's body.

" patient " comprise the human and animal the two.

The salt of formula I compound formation also within the scope of the invention.Should understand and also comprise when mentioning formula I compound herein and mention its salt, unless otherwise.Term as used herein " salt " refers to and inorganic and/or formed acid-salt of organic acid and and the inorganic and/or formed basic salt of organic bases.In addition,, for example, but be not limited to pyridine or imidazoles, contain acidic moiety again, for example, but be not limited to carboxylic acid, then may form zwitter-ion (" inner salt ") and also plan to be included within the term as used herein " salt " when formula I compound had both contained basic moiety.The salt of preferably pharmaceutically acceptable (that is: can accept on nontoxic, the physiology) is though other salt also can use.The salt of formula I compound can be by for example making formula I compound and a certain amount of (for example equivalent) acid or alkali reaction in medium (for example salt can in sedimentary medium wherein or at aqueous medium), freeze-drying subsequently forms.

The exemplary acids additive salt comprises: acetate, adipate, alginate, ascorbate salt, aspartate, benzoate, benzene sulfonate, hydrosulfate, borate, butyrates, Citrate trianion, camphorate, camsilate, cyclopentane propionate, digluconate, dodecyl sulfate, esilate, fumarate, glucose enanthate (glucoheptanoates), glycerophosphate, Hemisulphate, enanthate, hexanoate, hydrochloride, hydrobromate, hydriodate, the 2-isethionate, lactic acid salt, malate, mesylate, the 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pectinic acid salt (pectinate), persulphate, 3-phenylpropionic acid salt, phosphoric acid salt, picrate, Pivalate, propionic salt, salicylate, succinate, vitriol, sulfonate (for example those that address herein), tartrate, thiocyanate-, tosylate (being also referred to as tosilate), undecylate etc.In addition, the known acid that is considered to usually be applicable to from basic medicinally compound generation pharmacologically acceptable salt.

Exemplary alkaline salt comprises: ammonium salt, an alkali metal salt, for example sodium, lithium and sylvite, alkaline earth salt, for example calcium and magnesium salts, the salt that is become with organic bases (for example organic amine), for example dibenzylethylenediamine dipenicillin G (benzathines), dicyclohexyl amine, Hai Baming (hydrabamines) (with N, two (dehydrogenation-abietyl amine) quadrols of N-form), N-methyl D-grape amine, N-methyl D-grape acid amides, TERTIARY BUTYL AMINE and and amino acid, for example salt that generates such as arginine, Methionin.The alkalescence nitrogen-containing group can be quaternized with following reagent: for example elementary alkyl halide (for example muriate of methyl, ethyl, propyl group and butyl, bromide and iodide), sulfuric acid dialkyl (for example dimethyl, diethyl, dibutyl and diamyl sulfuric ester), long-chain halogenide (for example muriate, bromide and the iodide of decyl, lauryl, nutmeg base and stearyl), aralkyl halide (for example benzyl and styroyl bromination thing) and other.

All these type of hydrochlorates and alkali salt expection all are pharmacy acceptable salts within the scope of the present invention, and for purpose of the present invention, all hydrochlorates and alkali salt all are regarded as being equal to the free form of its corresponding compound.

Formula I compound, and salt, solvate and prodrug can be its tautomeric form (for example being acid amides or imido ether).All these type of tautomeric forms all are considered as a part of the present invention in herein.

The present invention sends out compound all steric isomers (for example geometrical isomer, optical isomer etc.) of (comprising salt, solvate and the prodrug of described compound and the salt and the solvate of prodrug), those compounds that may exist owing to the asymmetric carbon on each substituting group for example, comprise: enantiomeric form (itself even can exist when no asymmetric carbon), rotational isomeric form, atropisomer (atropisomer) and diastereomer form are included in the scope of the present invention.Each steric isomer of The compounds of this invention may, for example essentially no other isomer, or can for example be racemic modification or with all other or other mix through the steric isomer of selection.Chiral centre of the present invention can be S or R configuration, defines as IUPAC 1974 Recommendations.The use of term " salt ", " solvate ", " prodrug " etc. can be equal to enantiomorph, steric isomer, rotational isomer, tautomer, racemic modification or the prodrug of The compounds of this invention.

Formula I compound can be by known method, from starting raw material preparation known in the art or by the methods known in the art preparation; Referring to for example WO 95/01356, J.Med.Chem., 39 (1996) 1164-1171 and WO 01/92264

Compound of the present invention can prepare by several methods.The non-limiting example of proper method is illustrated in the schema 1.

Schema 1

Aldehyde 2 is produced 3 with hydrazine reaction, be preferable under the room temperature, in DMF, react.3 and alkylating agent, for example the reaction of bromide 4 can produce muriate 5.This type of transforms under room temperature,, for example carries out among the DMF at solvent for example in the presence of the NaH at alkali.5 and 6 (the protection forms of hydrazine) reaction produces 7.This reaction is preferable under 80-100 ℃ the temperature of rising to be carried out in DMF.Blocking group Q is preferably tertbutyloxycarbonyl (Boc).By making compound 7 change into 9 with piperazine 8 reactions.This reaction is preferable over temperature and rises under 80-100 ℃ under DMF and catalyzer KI exist and carry out.Blocking group Q in 9 is Boc, then handles and generation hydrazine 10 with the HCl/ dioxane.With carboxylic acid (for example use this acid and carbodiimide, or use premixed acid anhydride, for example itself and isopropyl chlorocarbonate) with 10 acidylates.Hydrazides 11 is cyclized into I.This cyclization can be under 120 ℃, and with N, two (trimethyl silyl) ethanamides of O-carry out, and maybe can use other known cyclization method.

In some cases, initial R group can contain the protectiveness group, for example trimethyl silyl (protection acetylene) or tertiary butyl dimethyl silica-based (protection alcohol).This protectiveness group can be removed after transforming accepted way of doing sth I compound by the method for knowing.

Another approach is illustrated in the schema 2.

Schema 2

As making compound 7 deprotections for 9, and as for 10 with 12 acidylates.As for 11 with hydrazides 13 cyclisation.Make 14 aminations and produce I, this process is preferably carried out in DMF and in the presence of the KI under 100-160 ℃ temperature.Also can heat under the temperature by 190-210 ℃ of microwave exposure generation in the container of sealing.

Other method is illustrated in the schema 3.

Schema 3

Will be with 8 by hydroxyalkyl pyrazoles 15 aminations of method preparation well known in the art.This amination reaction relates to reagent, and for example methylsulfonyl chloride or thionyl chloride and alkali (being typically amine) activate alcohol.Make activatory alcohol and 8 reactions, produce piperazine 16.In acid for example in the presence of the methylsulfonic acid, make 16 to obtain 17 with the alkyl orthoformate reaction.With 17 with hydrazides 18 at solvent for example in the methyl-phenoxide, in for example heating in the presence of the isopropylformic acid of acid, obtain three and encircle 19.With aqueous acid, be typically spirit of salt processing 19 and obtain amine 20.Preferably for example 4-dimethylaminopyridine and solvent obtain I with cyanogen bromide cyclisation 20 for example in the presence of the acetonitrile solution at catalyzer.

Other method is shown in the schema 4:

Schema 4

Under 100-160 ℃ temperature, 21 aminations are produced I, described amination is preferably carried out in DMF and in the presence of KI.Also can heat under the temperature by 190-210 ℃ of the generation of microwave exposure in sealed vessel.

In above-mentioned flow process, a kind of I compound can be by the method for knowing, for example with NaBH ₄Ketone is reduced into alcohol, changes into different formula I compounds.

Other can be illustrated in order to the route of synthesis for preparing this type of material among the WO 01/92264, and it is equal to US 09/865071, and publication number 2002/0099061 is attached to herein by reference.

Abbreviation as used in this specification is as follows: Me (methyl); Bu (butyl); Et (ethyl); Ac (ethanoyl); Boc (tert-butoxycarbonyl); DMF (dimethyl formamide); THF (tetrahydrofuran (THF)); DIPEA (diisopropylethylamine); RT (room temperature); BSA (N, two (the trimethyl silyl)-ethanamides of O-); BINAP (2,2 '-two (diphenylphosphino)-1,1 '-dinaphthalene); PLC (preparation property chromatography); TFA (trifluoroacetic acid); HOBt (hydroxybenzotriazole); DAST (three fluoridize diethylamino sulphur); EDCI (1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride); Ms (mesylate); TBAF (tetrabutylammonium); And TBS (t-butyldimethylsilyl).

Preparation 1

Step 1: stir POCl ₃(84ml, 0.9mol) and be cooled to 5-10 ℃, dropwise add simultaneously DMF (17.8ml, 0.23mol).Mixture heating up is added 2-amino-4 to room temperature (RT) and gradation, and 6-dihydroxy-pyrimidine VI (14g, 0.11mol).Heated 5 hours down in 100 ℃.Under vacuum, remove excessive POCl ₃, residue is poured in the frozen water, and is stirred and spend the night.Go out the material of drying by solid collected by filtration and by recrystallize in filtered ethyl acetate (EtOAc) solution, obtain aldehyde VII, 230 ° of fusing points (dec).Mass spectrum: M+=192.PMR(DMSO)：δ8.6(δ，2H)；δ10.1(s，1H)。

Step 2: under room temperature, (0.38g, 2mmol) (0.31g is 2.5mmol) in containing N, N-diisopropylethylamine (0.44ml, CH 2.5mmol) with 2-furans hydrazides with the product of step 1 ₃Mixture among the CN (50ml) stirs and spends the night.Remove the solvent of reaction mixture, and residue is distributed between EtOAc and water.With MgSO ₄Dry organic layer is removed solvent, and is made residue from CH ₃Recrystallize among the CN obtains required compound VIII.Mass spectrum: MH+=282.

Step 3: (75mg 1.5mmol) adds to product (0.14g, hot CH 0.5mmol) of step 2 with hydrazine hydrate ₃In the CN solution.Refluxed 1 hour.Be cooled to room temperature, collect yellow product IX.Mass spectrum: MH+=260.

Step 4: under 120 ℃, (5.4g, product 0.021mol) be in hexamethyl-two silicon amine disilazine (100ml) and N, heated overnight in the mixture of two (trimethyl silyl) ethanamides (35ml) of O-with step 3.In vacuum, remove volatile matter and make residue pulp in hot water, obtain solid sediment.Make its recrystallize from 80% acetic acid aqueous solution, obtain title compound.Fusing point＞300 ℃.Mass spectrum: MH+=242.

Preparation 2

With preparation 1 product (6.0g, 25mmol), the xylene monosulfonic acid glycol ester (11.1g, 30mmol), and NaH (60% in oil, 1.19g, 30mmol) mixing in dry DMF (30ml) in.In N ₂Under stirred 24 hours and filtered, obtain being lacteous solid title compound (PMR is in DMSO: δ 4.47+4.51 triplet, 8.03s).By the filtrate chromatography is separated remaining material.

Preparation 3

Step 1: to the 2-amino-4 that is dissolved in DMF (100ml), 6-dichloro pyrimidine-5-carboxylic aldehyde (25.0g, add in 130mmol) DIPEA (28.4ml, 163mmol), add then hydrazine hydrate (6.32ml, 130mmol).After initial heat release, stirred 24 hours and in vacuum, be concentrated into～50g.Add water (50ml), filter, wash with water and drying, obtain being the monochloride of brown solid.

Step 2: to the product of the step 1 that is dissolved in DMF (150ml) (15.0g, be added in 88mmol) 60%NaH in the mineral oil (4.25g, 106mmol).Slowly add 1-bromo-2-monochloroethane (22.1ml, 265mmol).Under room temperature, stirred 2 hours, concentrate and on silica gel chromatography, obtain being the dichloride of pale solid.

Step 3: with the product of step 2 (12.2g, 52.5mmol) and carbazic acid tertiary butyl ester (8.33g, 63mmol) mixing among DMF (70ml).In 80 ℃ of down heating 24 hours, make it cooling, concentrate and on silica gel chromatography, solid title carbazates obtains being white in color.

Preparation 4

Step 1: (5.0g 15mmol) is dissolved in 1: 1 CH will to prepare 3 product ₃OH-CH ₂Cl ₂(80ml).Add 4.0M HCl/ dioxane (20ml, 80mmol) and placed 18 hours.With NH ₃The aqueous solution alkalizes to pH 11, concentrates, and water (50ml) is handled, and filtration washes with water, and dry, obtains being the hydrazine of yellow solid.

Step 2: with the product of step 2 (0.30g, 1.32mmol), 5-methyl furan-2-carboxylic acid (0.20g, 1.6mmol), EDCI (0.30g, 1.6mmol), HOBtH ₂O (0.21g, 1.6mmol) and N-methylmorpholine (0.17g 1.6mmol) mixes in DMF (6ml).Stirred 1.5 hours, and concentrated and, obtain being the hydrazides of yellow oily through the PLC purifying.

Step 3: (0.68g 2.0mmol) mixes with BSA (6ml) with the product of step 3.Heated 24 hours and make it cooling down in 120 ℃.Concentrate and with CH ₃OH handles residue.Through the PLC purifying, the solid title compound obtains being white in color.

In a similar fashion, use suitable carboxylic acid, obtain preparing 4-2 to 4-20:

Preparation 5

With 4-bromobenzyl alcohol (2.00g, 10.7mmol), piperazine (5.52g, 64mmol), NaO-tBu (1.44g, 15.0mmol), ±-BINAP (0.40g, 0.64mmol) and Pd ₂(dba) ₃(0.12g 0.21mmol) mixes in toluene (15ml).Heated 18 hours down in 100 ℃, in nitrogen, stir.Make it to cool off and extract with 2N HCl.Alkalize to pH=14 and with CH with the NaOH aqueous solution ₂Cl ₂Extraction.Through MgSO ₄Drying, concentrate and on silica gel chromatography, obtain being the piperazine of yellow solid.

In a similar fashion, obtain preparing 5-2,5-3,5-4 and 5-5.For preparation 5-6, use Cs ₂CO ₃Replace NaO-tBu and dioxane as solvent.For preparation 5-7, use chloropyridine and Cs ₂CO ₃Replace NaO-tBu and DMSO as solvent.From bromo-pyridine and the K that is dissolved in DMSO ₂CO ₃In obtain preparing 5-8.As preparation 5, producing preparation 5-9, a kind of light green solid, and preparation 5-10, a kind of yellow oil.

Preparation 6

Make 2-methoxy ethyl-(4-bromophenyl methyl) ether (making) and piperazine reaction according to preparation 5 in DMF by 4-bromo benzyl bromo and 2-methyl cellosolve and sodium hydride are reacted.Crude product obtains being the title piperazine of yellow oily through silica gel column chromatography.

Produce preparation 6-2 in a similar fashion.

Preparation 7

Step 1: to the 4-that is dissolved in toluene (20ml) (4-cyano-phenyl) piperazine-1-carboxylic acid tert-butyl ester (2.30g, 8.0mmol, reaction by aryl-piperazine and Boc-acid anhydride makes) in add DIBAH (diisobutyl aluminium hydride) (1.0M in toluene, 12.8ml, 12.8mmol).Heated 1.5 hours down in 50 ℃, make it cooling, add MeOH (10ml) and water (10ml).Filter and concentrate.Make residue through silica gel column chromatography, obtain being the Boc-piperazine of yellow solid.

Step 2: to being dissolved in CH ₂Cl ₂The product of step 1 (5ml) (0.50g, 1.7mmol) the middle TFA (5.0ml) that adds.Stirred 0.75 hour and concentrated, the tfa salt of the preparation 7 of the oil that obtains taking on a red color.

Preparation 8

To the 1-that is dissolved in EtOH (15ml) (4-acetylphenyl) piperazine (1.00g, 4.9mmol) the middle NaBH that adds ₄(0.93g, 25mmol).Reflux 4 hours makes it cooling, and adds 0.5N NaOH (20ml).With CH ₂Cl ₂Extraction is through MgSO ₄Drying concentrate, and through silica gel column chromatography, solid title alcohol obtains being white in color.

Preparation 9

Step 1: to being dissolved in CH ₂Cl ₂Preparation 7 (10ml), the product of step 1 (0.43g, add in 1.5mmol) the 1-methylpiperazine (0.81ml, 7.4mmol) and HOAc (0.5ml).Add NaCNBH ₃(0.46g 7.4mmol) and in 40 ℃ heated 3 hours down.Make it cooling, and add 0.5N NaOH (20ml).With CH ₂Cl ₂Extraction is through MgSO ₄Drying concentrate, and through silica gel column chromatography, solid amine obtains being white in color.

Step 2: according to preparation 7, step 2 is with the product deprotection of step 1.Handle this tfa salt and with CH with 1.0N NaOH ₂Cl ₂Extraction.Through MgSO ₄Drying also concentrates, and obtains being the title piperazine of yellow oily.

Preparation 10

(0.26g, (4M is in dioxane, and 5.0ml 20mmol), adds entry (0.04ml) again to add HCl in 1.3mmol) to the product of the preparation 5-10 that is dissolved in TFA (5ml).Stirred 2 hours down in 50 ℃, add entry (5ml), stirred 1 hour and concentrated.With methyl alcohol system NH ₃The alkalization and through the PLC purifying, obtain being the title piperazine of yellow solid.

Preparation 11

Step 1: to the 4-bromaniline that is dissolved in ether (15ml) (4.30g, 25mmol) the middle Et that adds ₃N (2.70g, 27mmol).With the ice bath refrigerative dropwise add simultaneously the chloroformic acid 2-chloroethene ester that is dissolved in ether (10ml) (3.82g, 27mmol).Stirred 0.5 hour and filtered.Use 1N HCl, use salt water washing ether again.Dry (MgSO ₄) and concentrate, obtain a solid.In hexane, heat, make it cooling and collect this to be lacteous solid carbamate.

Step 2: with the product of step 1 (4.19g, 15mmol) add KOH (1.19g, 85%, 18mmol), in the solution of EtOH (28ml) and water (12ml), in ice bath, cool off.Replace with water-bath, stirred 1.5 hours, concentrate, and dilute with water (10ml).Filter, obtain being lacteous solid title compound.

Step 3: the product of step 2 is changed into title aryl-piperazine, a kind of yellow solid according to preparation 5 step.

Preparation 12

Step 1: with 3,4-difluoro-benzoic acid ethyl ester (2.00g, 10.7mmol), piperazine-1-carboxylic acid tert-butyl ester (2.20g, 11.8mmol) and K ₂CO ₃(1.80g 13.1mmol) mixes in DMF (10ml).Heated 7 hours and make it cooling down in 100 ℃.Concentrate and, obtain being the aryl-piperazine of yellow oily through silica gel column chromatography.

Step 2: (3.1g, solution 8.8mmol) are cooled to 0 ℃ will to be dissolved in the product of the step 1 of THF (20ml).Dropwise add LiAlH ₄(1.0M in THF, 5.3ml, 5.3mmol).Stirred 2 hours down in 0 ℃.Add frozen water and citric acid (3.0g).With extracted with diethyl ether, drying (MgSO ₄) and concentrate, obtain being the alcohol of yellow oily.

Step 3: under 0 ℃, (1.47g 4.8mmol) is dissolved in CH to the product of step 2 ₂Cl ₂Add Et in the solution (20ml) ₃N (0.80ml, 5.7mmol), add then MsCl (0.65g, 5.7mmol).Stirred 2 hours down in 0 ℃, under room temperature, stirred 1 hour again.Concentrate, obtain thick methanesulfonates.

Step 4: all thick methanesulfonates that derive from step 2 are dissolved in MeOH (20ml).Adding NaOMe (0.77g, 14.2mmol).Heated 1.5 hours down in 60 ℃, make it cooling, and dilute with water (30ml).Use extracted with diethyl ether, dry (MgSO ₄) and concentrate, obtain being the methyl ether of yellow oily.

Step 5: (1.00g 3.1mmol) is dissolved in CH with the product of step 4 ₂Cl ₂(4ml), be cooled to 0 ℃, and slowly add TFA (20ml).Stirred 2.5 hours down in 0 ℃, concentrate, and in CH ₂Cl ₂And distribute between the 1N NaOH.Dry (MgSO ₄) and concentrate, obtain being the title compound of yellow oily.

Preparation 13

With 3, the 4-difluoro acetophenone (2.00g, 12.8mmol), piperazine (5.52g, 64mmol) and K ₂CO ₃(2.12g 15.4mmol) is mixed in the toluene (20ml).Heated 20 hours and make it cooling down in 110 ℃.Alkalize to pH 13 with NaOH.With CH ₂Cl ₂Extraction washes with water, dry (MgSO ₄) and concentrate, obtain being the title compound of yellow solid.

In a similar fashion, from 2 ', 4 '-difluoro acetophenone production prepares 13-2, a kind of yellow oil; Prepare 13-3, a kind of yellow solid from the production of 5-fluoro-1-indone; And from 2 '-methoxyl group-4 '-fluoro acetophenone production prepares 13-4, a kind of yellow solid.From 2-chlorine benzoxazol be dissolved in CH ₂Cl ₂Et ₃N produces preparation 13-5, a kind of white solid.From 2 ', 4 '-difluorobenzaldehyde production prepares 13-6.

Preparation 14

Step 1: with 5-bromo-2-hydroxy-benzyl alcohol (3.00g, 14.8mmol) and TsOHH ₂O is mixed in the ethylene glycol (15ml).Heated 3 hours down in 80 ℃, make it cooling, and between water and EtOAc, distribute.Wash with water, use the salt water washing again, dry (MgSO ₄) and concentrate, obtain being the benzylic ether of yellow oily.

Step 2: (3.52g 14.3mmol) is dissolved in CH with the product of step 1 ₂Cl ₂Solution (25ml) is cooled to 0 ℃.(1.73ml 21mmol), adds SOCl again to add pyridine ₂(1.14ml, 15.7mmol).Make it be warming up to room temperature, stirred 3 hours, add pyridine (1.73ml) and SOCl ₂(1.14ml), and stirred 20 hours.Wash dry (MgSO with water ₄) and concentrate.Chromatography on silica gel obtains being the muriate of yellow oily.

Step 3: with the product of step 2 (2.64g, 9.9mmol), K ₂CO ₃(1.65g, 11.9mmol) and KI (0.83g 5.0mmol) is mixed among the DMF (25ml).Stirred 120 hours and concentrated.In CH ₂Cl ₂And distribute between the water, water is also used the salt water washing again, and dry (MgSO ₄).Concentrate, obtain being the benzo two oxa-English in heptan (benzodioxepine) of yellow oily.

Step 4:, the product of step 3 is changed into aryl-piperazine, a kind of brownish oil according to preparation 5 method.

For preparation 14-2, according to the step 2 and 3 of preparation 48, with 4-fluorosalicylic acid ethyl ester bromination and reduction.Be similar to preparation 14 again, obtain being the aryl-piperazine of yellow solid.

For preparation 14-3,,, and continue to obtain being the aryl-piperazine of yellow oily in the class mode with the reduction of 4-bromo ortho-oxybenzoic acid according to the step 3 of preparation 48.

Preparation 15

Step 1: to being dissolved in 1, the 2-allyl group of 2-ethylene dichloride (250ml)-4-bromine phenol (3.13g, between adding in 14.6mmol)-the chlorine peroxybenzoic acid (70%, 3.59g, 14.5mmol).Be heated to 70 ℃, stirred 4 hours and add more peracid (2.50g).Reheat 2 hours makes it cooling, concentrates, and distributes between ether and 1N NaOH.Dry (MgSO ₄) and concentrate, obtain being the alcohol of yellow oily.

Step 2: to the product of the step 1 that is dissolved in DMF (20ml) (2.40g, add in 10.5mmol) NaH (60% in oil, 0.59g, 14.8mmol).Stirred 15 minutes, and be cooled to 0 ℃, and add CH ₃I (1.78g, 12.5mmol).Stirred 2 hours, and made it warm, and between ether and 0.5N NaOH, distribute.Dry (MgSO ₄) and concentrate, obtain containing the methyl ether that is yellow oily of small amount of mineral oil.

Step 3: the product of step 2 is changed into title compound, a kind of yellow oil according to preparation 5 method.

Similarly, according to preparation 34, step 1 changes into TBS ether with the product of step 1, and reacts according to the method and the piperazine of preparation 5, obtains being the preparation 15-2 of yellow oily.

Preparation 16

Step 1: with 3, the 4-difluoro benzoyl chloride (1.01g, 5.7mmol) and Et ₃(0.57g 5.6mmol) is mixed among the EtOAc (10ml) and is cooled to 0 ℃ N.(0.62g 7.2mmol), stirred 0.5 hour, made it warm, and used 1N HCl, used 1N NaHCO more dropwise to add N-(2-methoxy ethyl)-methylamine ₃Washing.Dry (MgSO ₄) and concentrate, obtain being the acid amides of yellow oily.

Step 2: with the product of step 1 (1.20g, 5.2mmol), piperazine (2.24g, 26mmol) and K ₂CO ₃Be mixed in the dry DMF (10ml).In nitrogen, 120 ℃ the heating 20 hours and make it the cooling.With the EtOAc dilution, filter, and concentrate.Between EtOAc and 1N HCl, distribute.With water layer with Na ₂CO ₃Alkalization adds NaCl (5g), and extracts with EtOAc/EtOH (9: 1).Dry (MgSO ₄) and concentrate, obtain being the title compound of dense thick yellow oil.

In a similar fashion, prepare 16-2 to 16-5 from suitable amine production.

Preparation 17

Step 1: with 3, the 4-difluoro nitrobenzene (4.00g, 25mmol), piperazine (10.8g, 125mmol) and K ₂CO ₃(4.17g 30mmol) is mixed in the toluene (30ml).Reflux 24 hours makes it cooling, and extracts with 1N HCl.Alkalize to pH 13 and with CH with the NaOH aqueous solution ₂Cl ₂Extraction.Use the salt water washing, dry (MgSO ₄) and concentrate, obtain being the aryl-piperazine of yellow solid.

Step 2: to being dissolved in CH ₂Cl ₂The product of step 1 (20ml) (1.51g, 6.7mmol) the middle Et that adds ₃(1.12ml 8.1mmol), adds Boc to N again ₂O (1.47g, 6.7mmol).Stirred 1 hour and with the full NaHCO that closes ₃, use the salt water washing again.Dry (MgSO ₄) and concentrate, obtain being the carbamate of yellow solid.

Step 3: (2.18g 6.7mmol) is dissolved in 1: 1 CH with the product of step 2 ₃Among the OH/EtOAc (40ml) and add 5%Pd/C (0.50g).Hydrogenation is 1.5 hours under 55psi, through diatomite filtration and concentrated, obtains being the arylamines of brown oil.

Step 4: to being dissolved in CH ₂Cl ₂The product of step 3 (15ml) (1.00g, 3.3mmol) and DIPEA (0.88ml, add in 5.1mmol) trifluoroacetic anhydride (0.57ml, 4.1mmol).Stirred 2 hours and add second part DIPEA and acid anhydride.Stirred 1 hour and with saturated NaHCO ₃, wash with water again.Dry (MgSO ₄) and concentrate, obtain being the acid amides of yellow solid.

Step 5: with the product of step 4 (0.70g, 1.8mmol) and K ₂CO ₃(0.37g 1.27mmol) is mixed in the dry DMF (8ml).Add CH ₃(0.12ml 2.0mmol), stirred 18 hours I, heated 2 hours down in 60 ℃ again.Concentrate and between ether and water, distribute.Use the salt water washing, dry (MgSO ₄) and concentrate, obtain being the methyl nitrosourea of yellow oily.

Step 6: (1.01g 2.5mmol) is dissolved in CH with the product of step 5 ₃OH (5ml).The K that adds water-soluble (3.5ml) ₂CO ₃(0.34g, 2.5mmol).Stirred 1 hour, and concentrated, and in CH ₂Cl ₂And distribute between the water.Use the salt water washing, dry (MgSO ₄) and concentrate, obtain being the amine of yellow solid.

Step 7: to being dissolved in CH ₂Cl ₂The product of step 6 (10ml) (0.77g, 2.5mmol) and DIPEA (0.65ml, add in 3.7mmol) AcCl (0.22ml, 3.0mmol).Stirred 1 hour, and concentrated, and in CH ₂Cl ₂And distribute between the water.Use the salt water washing, dry (MgSO ₄) and concentrate, obtain being the acid amides of yellow oily.

Step 8: (0.90g 2.5mmol) is dissolved in CH with the product of step 7 ₂Cl ₂(10ml).Add TFA (6.0ml).Stirred 1 hour, and concentrated, and in CH ₂Cl ₂And distribute between 1N NaOH.Use the salt water washing, dry (MgSO ₄) and concentrate, obtain being the title compound of yellow oily.

In a similar fashion, but use Vinyl chloroformate in step 7, preparation is the preparation 17-2 of yellow oily:

Preparation 18

Step 1: with 1-(4-cyano group-2-fluorophenyl) piperazine (1.57g, 7.6mmol) and Et ₃(1.28ml 9.2mmol) is mixed in CH to N ₂Cl ₂(10ml) and add Boc ₂O (1.67g, 7.6mmol).Stirred 1 hour and with saturated NaHCO ₃Washing.Dry (MgSO ₄) and concentrate, obtain being the thick carbamate of yellow solid.

Step 2: (2.73g 8.9mmol) is dissolved in CH with the product of step 1 ₃OH (30ml).Add HOAc (2.6ml), add PtO then ₂(0.60g).Hydrogenation is 18 hours under 60psi.Through diatomite filtration and add 1N NaOH (6ml).Concentrate and in CH ₂Cl ₂And distribute between the water.Use the salt water washing, dry (MgSO ₄) and concentrate, obtain being the amine of water white oil.

Step 3: with the product of step 2 (1.25g, 4.0mmol) and DIPEA (1.06ml 6.1mmol) is mixed in CH ₂Cl ₂(5ml).Adding AcCl (0.35ml, 4.8mmol).Stirred 1 hour, and concentrated, and in CH ₂Cl ₂And distribute between the water.Use the salt water washing, dry (MgSO ₄) and concentrate, obtain being the acid amides of yellow oily.

Step 4: (1.38g 3.9mmol) is dissolved in CH with the product of step 3 ₂Cl ₂(1ml).Add TFA (8.0ml).Stirred 0.5 hour, and concentrated, and in CH ₂Cl ₂And distribute between the 1N NaOH, saturated with NaCl.Dry (MgSO ₄) and concentrate.Through the PLC purifying, obtain being the piperazine of yellow oily.

In a similar fashion, in step 3, use Vinyl chloroformate to be the preparation 18-2 of yellow oily with production:

Preparation 19

Step 1: with 5-bromine indoline (3.56g, 18mmol) and Et ₃(1.92g is 19mmol) at CH for N ₂Cl ₂Mix (40ml).Cooling and adding Boc in ice bath ₂O (4.14g, 19mmol).Make it warm, stirred 2 hours and the more Boc of adding ₂O (0.50g).Stirred 2 hours and with 1N HCl, again with 1N NaHCO ₃Washing.Dry (MgSO ₄) and concentrate.This solid is heated with hexane, make it cooling, and filter, obtain being canescence crystalline carbamate, fusing point 124-6 ℃.

Step 2:, the product of step 1 is changed into title compound, a kind of yellow oil according to preparation 5 method.

Preparation 20

Step 1: to being dissolved in CH ₃The preparation 12 of OH, add in the solution of the product of step 3 (deriving from 1.40g, the initial alcohol of 45mmol) KCN (1.03g, 15.8mmol).Heated 1 hour down in 60 ℃, make it cooling, and between ether and 0.5N NaOH, distribute.Dry (MgSO ₄), concentrate and on silica gel chromatography, obtain being the nitrile of yellow oily.

Step 2: (0.63g 2.0mmol) is dissolved in CH with the product of step 1 ₂Cl ₂(2ml) and be cooled to 0 ℃.Add TFA (10ml).Stirred 2 hours, and concentrated, and with 7N methyl alcohol system NH ₃Alkalization.Concentrate and, obtain being the title compound of yellow solid through the PLC purifying.

Preparation 21

According to preparation 9, the step of step 2 is from preparing 12, and the product of step 2 removes the Boc group, obtains being the title compound of yellow oily.

Preparation 22

Step 1: (1.20g 5.9mmol) adds NaBH in the solution to the 3-bromo-4-fluorobenzaldehyde that is dissolved in EtOH (20ml) ₄(0.103g, 2.7mmol).Stirred 2 hours, and concentrated, add NH ₄Cl (0.6g) also distributes between ether and water.Dry (MgSO ₄) and concentrate, obtain being the alcohol of water white oil.

Step 2: make product (1.20g, the 5.9mmol) solution that is dissolved in THF (50ml) cooling and add NaH (60% in oil, and 0.33g 8.2mmol), adds CH again in ice of step 1 ₃I (1.00ml, 7.1mmol).Stirred 3 hours and between ether and water, distribute.Dry (MgSO ₄) and concentrate, obtain being the thick methyl ether of yellow oily.

Step 3:, obtain being the aryl-piperazine of yellow oily according to the product of preparation 5 usefulness piperazine treatment steps 2.

Preparation 23

Step 1: will be dissolved in the preparation 17 of THF (40ml), (1.50g, solution 5.1mmol) is cooling in ice for the product of step 3.Add DIPEA (1.08ml, 6.2mmol), add again chloroformic acid 2-chloroethene ester (0.76g, 5.3mmol).Stirred 3 hours and in ether and saturated NaHCO ₃Between distribute.Dry (MgSO ₄) and concentrate, obtain being the carbamate of brown solid.

Step 2: (2.05g 5.1mmol) is dissolved in THF (150ml) with the product of step 1.Adding NaH (60% in oil, 0.25g, 6.1mmol).Heated 18 hours down in 60 ℃, make it cooling, and between ether and water, distribute.Dry (MgSO ₄) and concentrate, obtain being the thick  azoles quinoline ketone (oxazolinone) of yellow solid.

Step 3: according to preparation 9, the method for step 2 removes the Boc gene from the product of step 2, obtains being the thick title compound of yellow solid.

Use and step 1 and 3 similar modes, prepare 23-2 and 23-3 with Acetyl Chloride 98Min. and methylsulfonyl chloride production.

Preparation 24

Step 1: will prepare 17, the product of step 3 (1.53g, 5.2mmol) and DIPEA (1.10ml, the 6.2mmol) solution that is dissolved in THF (40ml) cooling in ice.Dropwise add the 4-bromobutanoylchloride (1.01g, 5.4mmol).Stirred 2 hours and in ether and saturated NaHCO ₃Between distribute.Dry (MgSO ₄) and concentrate, obtain being the carbamate of yellow solid.

Step 2: (2.30g 5.2mmol) is dissolved in DMF (100ml) with the product of step 1.Adding NaH (60% in oil, 0.25g, 6.1mmol).Heated 18 hours down in 90 ℃, make it cooling, concentrate, and between ether and water, distribute.Dry (MgSO ₄) and concentrate, obtain being the rough lactan of yellow solid.

Step 3: according to preparation 9 step 2, remove the Boc group, obtain being the thick title compound of yellow solid from the product of step 2.

Preparation 25

Step 1: according to preparation 17, the method for step 2 changes into the Boc-derivative, a kind of yellow solid with the product for preparing 13.

Step 2: to product (0.77g, 2.4mmol) the middle NaBH that adds of the step 1 that is dissolved in EtOH (15ml) ₄(0.046g, 1.2mmol).Stirred 2 hours, and added NaBH ₄(0.023g 0.6mmol), stirred 1 hour and added together and measure.Stirred 1 hour, and concentrated, and in CH ₂Cl ₂And distribute between the water.Use the salt water washing, dry (MgSO ₄) and concentrate, obtain being the alcohol of light yellow solid.

Step 3: to the product of the step 2 that is dissolved in THF (10ml) (0.61g, add in 1.9mmol) NaH (60% in oil, 0.12g, 3.0mmol).Stirred 10 minutes and add CH ₃I (0.32g, 2.3mmol).Stirred 72 hours and add CH ₃I (0.16g, 1.2mmol).Stirred 24 hours and add NaH (60% in oil, 0.062g, 1.5mmol) and CH ₃I (0.16g, 1.2mmol).Stirred 24 hours and add NaH (60% in oil, 0.034g, 0.8mmol).Stirred 24 hours, on ice and use extracted with diethyl ether.Use the salt water washing, dry (MgSO ₄) and concentrate, obtain being the thick methyl ether of yellow solid.

Step 4: according to the method for preparation 9 step 2, the product of step 3 is transformed, behind the PLC purifying, obtain being the title compound of yellow oily.

Preparation 26

Step 1: to the 5-bromo-2-hydroxy-benzyl alcohol that is dissolved in DMF (10ml) (1.97g, add in 9.7mmol) NaH (60% in oil, 0.81g, 20.4mmol).Stirred 10 minutes, and added CH ₃(1.39ml 22.3mmol), and stirred 1 hour I.Concentrate and between EtOAc and 5% citric acid, distribute.With 1N NaOH, use the salt water washing again.Dry (MgSO ₄) and concentrate, obtain being the thick two-ether of yellow oily.

Step 2: the product of step 1 is changed into aryl-piperazine, a kind of brown solid according to preparation 5 method.

Preparation 27

Step 1: with dense H ₂SO ₄(0.10ml) be added in refrigerative CH in the ice ₃In the OH (10ml).Dropwise add and be dissolved in CH ₃(4-bromophenyl) oxyethane of OH (5ml) (3.14g, 15.8mmol).Heated 18 hours down in 65 ℃, add 4N HCl/ dioxane (5ml) and also make it cooling.Between ether and water, distribute dry (MgSO ₄) and concentrate, obtain containing the crude product that is yellow oily that isomerization benzylalcohol is less important composition.

Step 2: the product of step 1 is changed into aryl-piperazine, a kind of yellow oil according to preparation 5 method.

Preparation 28

Step 1: will be dissolved in the preparation 27 of THF (20ml), (1.70g, the solution of product 8.0mmol) is cooling in ice for step 1.Adding NaH (60% in oil, 0.38g, 9.6mmol).Stirred 10 minutes, and added CH ₃(1.36g 9.6mmol), and stirred 2 hours I.Between ether and salt solution, distribute dry (MgSO ₄) and concentrate, obtain containing the crude product that be yellow oily of benzylalcohol as less important composition.

Step 2: the product of step 1 is changed into aryl-piperazine according to preparation 5 method.Be the title compound and the by product-benzylalcohol monoether of yellow oily, 28A, a kind of yellow solid by chromatographic separation.

Preparation 29

Step 1: (3.0g, 1mmol) solution that is dissolved in THF (20ml) is cooled to 0 ℃ and dropwise add and be dissolved in THF (13.2ml, 1.0M LiAlH 13.2mmol) with diester ₄Heated 2 hours down in 60 ℃, make it cooling, and add entry (0.50ml), add 15%NaOH (0.50ml) again, add again (0.50ml).Filter and concentrate, the solid glycol obtains being white in color.

Step 2: be similar to preparation 26, step 1 changes into diether with this glycol, a kind of water white oil.

Step 3:,, obtain being the aryl-piperazine of brown oil with the product of piperazine treatment step 2 according to the method for preparation 5.

In a similar fashion, obtain preparing 29-2 from 4-phthalate bromine acid anhydride.

Preparation 29-2

Preparation 30

Step 1: with dense H ₂SO ₄(0.08ml) add to refrigerative ethylene glycol in ice (1.40g, 22.6mmol) in.Adding (4-bromophenyl) oxyethane (3.00g, 15.1mmol).Heated 2.5 hours and make it cooling down in 135 ℃.Between ether and water, distribute, use the salt water washing, dry (MgSO ₄) and concentrate.Chromatography on silica gel obtains being the dioxane of yellow solid.

Step 2:, the product of step 1 is changed into aryl-piperazine, a kind of yellow solid according to preparation 5 method.

Preparation 31

Step 1: under 0 ℃, to the preparation 22 that is dissolved in DMF (20ml), the product of step 1 (1.50g, add in 7.3mmol) NaH (60% in oil, 0.35g, 0.21g NaH, 8.8mmol).Stirred 10 minutes.And adding 2-bromo-ethyl-methyl ether (1.22g, 8.8mmol).Heated 18 hours down in 60 ℃, add K ₂CO ₃(1.40g), KI (1.21g) and other bromo-ether (1.22g).Heated 18 hours down in 100 ℃, make it cooling, and between ether and water, distribute.Dry (MgSO ₄) and concentrate, obtain being the crude product of yellow oily.

Step 2:,, obtain being the aryl-piperazine of yellow oily with the product of piperazine treatment step 1 according to the method for preparation 5.

Preparation 32

Step 1:, add Bu among product of step 2 (0.31g) and the ADDP (0.51g) to the preparation 12 that is dissolved in benzene (40ml) ₃P (0.5ml).Stir and also dropwise added CF in 10 minutes ₃CH ₂OH (0.72ml).After 1 hour, wash dry (K with water ₂CO ₃), concentrate and on silica gel chromatography, obtain this ether.

Step 2: according to preparation 9, step 2 obtains being the aryl-piperazine of yellow oily with the product deprotection of step 1.

Preparation 33

Step 1: to being dissolved in 2M methyl alcohol system CH ₃NH ₂Preparation 18 (50ml), the product of step 1 (3.0g, add in 9.8mmol) Raney nickel (～0.5g).Hydrogenation is 18 hours under 60psi, by diatomite filtration, and concentrates.In CH ₂Cl ₂And distribute between the water.Dry (MgSO ₄) and concentrate, obtain being the crude product of water white oil.

Step 2 and 3: the step 3 and 4 according to preparation 18 is carried out, and obtains being the amine of water white oil.

In the mode of similar preparation 18-2, the product of step 1 is changed into preparation 33-2.

Preparation 33-2

Preparation 34

Step 1: under 0 ℃, to the preparation 22 that is dissolved in DMF (20ml), the product of step 1 (5.4g, add in 26mmol) tert-butyldimethylsilyl chloride (4.17g, 28mmol) and imidazoles (2.69g, 40mmol).Stirred 2 hours and between 1: 1 ether-hexane and water, distribute.Use the salt water washing, dry (MgSO ₄) and concentrate, obtain being the product of water white oil.

Step 2:, obtain being the aryl-piperazine of yellow solid according to the product of preparation 5 method with piperazine treatment step 1.

Preparation 35

Step 1: to being dissolved in CH ₂Cl ₂Preparation 17 (15ml), the product of step 6 (0.85g, 2.7mmol) and DIPEA (0.72ml adds CH in 4.1mmol) ₃SO ₂Cl (0.26ml, 3.3mmol).Stirred 1 hour and concentrated, in CH ₂Cl ₂And distribute between the water, use the salt water washing, dry (MgSO ₄) and concentrate, obtain being the product of light yellow solid.

Step 2: as preparation 9, step 2 is the product of treatment step 1 like that, obtains being the product of yellow oily.

In a similar fashion, use methoxyl group ethanoyl muriate replaced C H but in step 1 ₃SO ₂Cl obtains preparing 35-2.

Preparation 35-2

Preparation 36

Step 1: according to preparation 18, step 1 will prepare the solution that 34 product changes into the Boc-derivative.

Step 2: be similar to preparation 35, step 1 changes into the product of step 1 solution of thick methanesulfonates.

Step 3: with the 3 normal products that are dissolved in the KCN treatment step 3 of 5: 1 EtOH-water.Refluxed 18 hours, and concentrated, and between ether and water, distribute.Use the salt water washing, dry (MgSO ₄) concentrate, and on silica gel chromatography, obtain being the product of yellow oily.

Step 4: according to preparation 9, step 2 with the product deprotection of step 4, obtains being the aryl-piperazine of yellow oily.

Preparation 37

Step 1: according to preparation 22, step 2 changes into methyl ether with alcohol (method according to Synthesis 1997,23 obtains).

Preparation 38

Step 1: with 4-bromo-3-fluoroaniline (2.76g, the 14.5mmol) solution that is dissolved in THF (30ml) cooling in ice.Add DIPEA (3.1ml, 17.4mmol), add then allyl chlorocarbonate (1.67ml, 15.2mmol).Stirred 2 hours and in ether and saturated NaHCO ₃The middle distribution.Dry (MgSO ₄) and concentrate, obtain being the carbamate of yellow oily.

Step 2: with-the chlorine peroxybenzoic acid (～70%, 5.38g ,～20mmol) handle and to be dissolved in CH ₂Cl ₂The product of step 1 (40ml) (4.00g, 14.6mmol).Stirred 18 hours and with saturated NaHCO ₃(+2g Na ₂S ₂O ₃) washing.Dry (MgSO ₄), and concentrate, obtain a yellow solid.With 2: 1 hexane-CH ₂Cl ₂Wash, obtain being the epoxide of yellow solid.

Step 3: with the product (3.52g) of step 2 reflux 10 minutes in pyridine (30ml).Concentrate and in CH ₂Cl ₂And distribute between the 1N HCl.With 1N NaHCO ₃Washing, dry (MgSO ₄), concentrate and on silica gel chromatography, obtain being the alcohol of yellow solid.

Step 4: according to preparation 22, step 2 is used CH ₃The product of I treatment step 3 obtains being the ether of yellow solid.

Step 5: the product of using piperazine treatment step 4 according to the method for preparation 5.By the chromatographic separation product, obtain being the alcohol of yellow solid.

Preparation 39

Step 1: according to preparation 18, the product that step 1 will prepare 13-6 changes into the Boc-derivative.

Step 2: under 0 ℃, in the product (1.5g) of step 1 is dissolved in the solution of THF (50ml), add trifluoromethyl trimethyl silane (1.1mL), add TBAF (0.4mL) again.After 1 hour, with 0.5N HCl (10ml) quencher.Stirred 15 minutes, and added EtOAc, use saturated NaHCO ₃Washing, dry (K ₂CO ₃), and concentrate, obtain being the alcohol of yellow solid.

Step 3: according to preparation 9, step 2 with the product deprotection of step 2, obtains being the aryl-piperazine of yellow oily.

Similarly, from the 4-fluorobenzaldehyde, by the processing of N-Cbz-piperazine, preparation is the preparation 39-2 of yellow oily as ketone preparation 47.

Preparation 40

Step 1 and 2: according to preparation 22, step 1 and 2 method are reduced this ketone and alkylide.

Step 3:,, obtain being the aryl-piperazine of yellow oily with the product of piperazine treatment step 2 according to the method for preparation 5.

Preparation 41

Step 1: be dissolved in to 60%NaH (0.24g) and add diethoxy phosphoryl-acetate ethyl ester (1.2ml) in the suspension of THF (20ml).0.5 after hour, be cooled to 0 ℃ and also add the preparation 39 that is dissolved in THF (5ml), the product of step 1 (0.93g).Make it warm, stirred 2 hours and with saturated NH ₄The Cl quencher.With the EtOAc extraction, dry (K ₂CO ₃), concentrate, and on silica gel chromatography, obtain ester.

Step 2: in the product (1.3g) of the step 1 that is dissolved in EtOAc (60ml), add 10%Pd-C (0.15g).Hydrogenation is 1 hour under 1 normal atmosphere, by diatomite filtration, and concentrates, and obtains being buttery reductive ester.

Preparation 42

Step 1: will prepare 17, (2.2g, 6.7mmol) (0.64ml 7.4mmol) is mixed among the DMF (30ml) product of step 3 with isocyanic acid 2-chloro-ethyl ester.In 60 ℃ of down heating 18 hours, make it cooling and in CH ₂Cl ₂And distribute between the water.Dry (MgSO ₄) and concentrate, obtain being the thick urea of yellow solid.

Step 2: in the crude product of the above-mentioned steps 1 that is dissolved in DMF (100ml), add NaH (60% in oil, 0.38g, 0.23g NaH, 9.5mmol).Heated 72 hours down in 60 ℃, make it cooling, concentrate, and wash with water, obtain being the ring-type urea of yellow solid.

Step 3: according to preparation 9, step 2 obtains being the aryl-piperazine of yellow solid with the product deprotection of step 2.

Preparation 43

To be dissolved in CH ₂Cl ₂Dess-Martin periodinane oxidation preparation 39, the product of step 1 and according to preparation 9, step 2 obtains being the aryl-piperazine of yellow oily with the ketone deprotection of gained.

Preparation 44

Step 1: with Racemic glycidol (0.63g, the 8.5mmol) solution that is dissolved in ether (30ml) cooling in ice.Add DIPEA (1.6ml, 8.5mmol) photoreactive gas (1.85M in toluene, 5.8ml, 10.8mmol).Stirred 2 hours, and filtered, and concentrate.Be dissolved in the ether (50ml) and add preparation 17, the product of step 3 (2.50g, 7.7mmol) and DIPEA (1.6ml, 8.5mmol).Stirred 2 hours, with saturated NaHCO ₃Washing, dry (MgSO ₄), and concentrate, obtain being the carbamate of yellow solid.

Step 2: as preparation 38, the such product of treatment step 1 in the step 3, and on silica gel chromatography, obtain being the alcohol of yellow solid.

Step 3: as preparation 38, the such product of treatment step 2 in step 4 step, obtain being yellow oily ether.

Step 4: according to preparation 9, step 2 with the product deprotection of step 3, obtains being the aryl-piperazine of yellow solid.

Preparation 45

According to preparation 9, step 2 will prepare 44, and the product deprotection of step 2 obtains being the aryl-piperazine of yellow solid.

Preparation 46

Step 1: with 2 ', 4 ', 5 '-trifluoroacetophenone (2.50g, 14.4mmol), the N-Boc-piperazine (2.87g, 145.4mmol) and K ₂CO ₃(2.37g 17.2mmol) is mixed among the DMF (20ml).Heated 4 hours down in 40 ℃, make it cooling, and stirred 64 hours.Between ether and water, distribute dry (MgSO ₄) and concentrate, obtain being the aryl-piperazine of yellow solid.

Step 2: according to preparation 9, step 2 with the product deprotection of step 1, obtains being the aryl-piperazine of yellow solid.

Produce similarly for water white oil preparation 46-2.

Preparation 47

Step 1: with 3 ', 4 '-difluoro acetophenone (0.25g), piperazine-1-benzyl carboxylate (1.84ml) and K ₂CO ₃(1.32g) mixture that is dissolved in toluene (4ml) heated 0.5 hour down in 150 ℃ with microwave.Make it to cool off and between EtOAc and water, distribute.Dry (K ₂CO ₃), concentrate and on silica gel chromatography, obtain aryl-piperazine.

Step 2: to being dissolved in CH ₂Cl ₂Add tetramethyleneimine (0.37g) in the product of step 1 (10ml) (0.35g), add sodium triacetoxy borohydride (1.1g) again.Stirred 48 hours, and used saturated NaHCO ₃Quencher and with CH ₂Cl ₂Extraction.Dry (K ₂CO ₃), concentrate, and, obtain amine through the PLC purifying.

Step 3: according to embodiment 41, step 2, the product hydrogenation (16 hours) with step 2 obtains being the buttery piperazine.

In step 1, by 2,4,5-trifluoro-benzene formonitrile HCN is initial and use DMF as solvent, produces N-Cbz aryl-piperazine and according to step 3 deprotection, obtains preparing 47-2.

Preparation 48

Step 1: with NaH (60% in oil, 0.46g, 0.28g NaH, 12mmol) and CH ₃I (0.62ml, 10mmol) handle the 4-fluorosalicylic acid methyl esters be dissolved in DMF (20ml) (1.42g, 7.7mmol).Stirred 18 hours and between EtOAc and 5% citric acid, distribute.Use 1N NaOH, use the salt water washing again, dry (MgSO ₄) and concentrate, obtain being yellow oily ether.

Step 2: with the product of step 1 (1.43g, 7.2mmol) and iron powder (0.018g) be mixed in CH ₂Cl ₂(15ml).Dropwise add and be dissolved in CH ₂Cl ₂Br (5ml) ₂(0.44ml, 8.7mmol).Stirred 18 hours and, washed with 1N NaOH again with water.Dry (MgSO ₄) and concentrate, obtain being the bromide of yellow solid.

Step 3: (1.15g 4.1mmol) is dissolved in solution cooling in ice of THF (15ml) with the product of step 2.Dropwise add BH ₃Me ₂S (2.0M in THF, 4.2ml, 8.4mmol).In 60 ℃ of down heating 18 hours, make it cooling, with the methyl alcohol quencher, concentrate and in EtOAc and saturated NaHCO ₃Between distribute.Water and salt solution elder generation after scouring, dry (MgSO ₄) and concentrate, obtain being the alcohol of yellow oily.

Step 4: according to preparation 34, step 1 changes into TBS ether with the product of step 3, obtains a water white oil.

Step 5:,, obtain being the aryl-piperazine of yellow solid with the product of piperazine treatment step 4 according to the method for preparation 5.

For preparation 48-2, with ethyl 5 bromosalicylic acid methylation of ester and with BH ₃Me ₂The S reduction.According to the alcohol of above-mentioned steps 4 and 5 processing gained, obtain being the aryl-piperazine of brown oil.

Preparation 49

As preparation 22, reduce preparation 46 product in the step 1 like that, obtain being the aryl-piperazine of yellow solid.

Preparation 50

Step 1: according to the preparation 22, the method for step 2 methylates 2-bromo-5-fluorine phenol, obtain into water white oil ether.

Step 2: with the product of step 1 (5.36g, 26.1mmol) in ether (100ml), be cooled to-40 ℃ and dropwise add n-BuLi (2.5M in hexane, 14.6ml, 37mmol).Stirred 1 hour, add CuI (2.48g, 13.1mmol) and stir more than 2 hours.The adding allyl bromide 98 (3.80g, 31mmol).Make it warm, stirred 18 hours and pass through diatomite filtration.With saturated NH ₄Cl uses the salt water washing again, dry (MgSO ₄) and concentrate, obtain being the allylic cpd of yellow oily.

Step 3: will be dissolved in CH ₂Cl ₂(4.17g 25.1mmol) is cooled to ℃ the product of step 2 (40ml).Add BBr ₃(5.02g, 20mmol).Make its warm and reflux 18 hours., separate organic layer, dry (MgSO on ice ₄), concentrate and on silica gel chromatography, obtain being the phenol of yellow oily.

Step 4-5: according to preparation 15, step 1 and 2 method are carried out, and obtain the ether into water white oil behind silica gel column chromatography.

Step 6: according to preparation 48, the method for step 2 with the product bromination of step 5, obtains being the bromide of yellow oily.

Step 7:,, obtain being the aryl-piperazine of yellow oily with the product of piperazine treatment step 6 according to the method for preparation 5.

Preparation 51

According to preparation 34, alcohol (by the method preparation of Synthesis 1997,23) is transformed, obtain being the aryl-piperazine of yellow oily.

Preparation 52

According to preparation 34,, obtain being the aryl-piperazine of yellow solid with alcohol (by the method preparation of Bioorg.Med.Chem.Letters 2001,2783).

For preparation 52-2, according to preparation 18, step 1, with this substance B oc-protection and according to preparation 22, step 2 methylates.According to preparation 9, step 2 obtains being the preparation 55-2 of yellow solid with the material deprotection of gained.

Preparation 53

Step 1: will prepare 25, the product of step 1 (2.95g, 9.2mmol) and Et ₃(1.53ml 11.0mmol) is mixed in CH to N ₂Cl ₂(15ml).Be cooled to 0 ℃ and add the t-butyldimethylsilyl triflate (2.21ml, 9.6mmol).Stirred 2 hours, and concentrated and between ether and water, distribute.With saturated NaHCO ₃Washing, dry (MgSO ₄), and concentrate, obtain being the enol-ether of yellow oil.

Step 2: (4.00g 9.2mmol) is dissolved in CH with the product of step 1 ₂Cl ₂(25ml).Be cooled to 0 ℃ and add between-the chlorine peroxybenzoic acid (70-75%, 2.00g ,～9mmol).Stir 4 hours with saturated NaHCO ₃Washing, dry (MgSO ₄), concentrate, and on silica gel chromatography, solid ketone obtains being white in color.

Step 3: to product (1.07g, 2.4mmol) the middle NaBH that adds of the step 2 that is dissolved in THF (15ml) ₄(0.090g, 2.4mmol).Stirred 3 hours and between ether and water, distribute, dry (MgSO ₄), and concentrate, obtain being yellow oily thick alcohol.

Step 4: the crude product of above-mentioned steps 3 is dissolved in DMF (5ml).Add NaH (60% in oil, 0.133g, 0.080g NaH, 3.3mmol), stirred 10 minutes, and add CH ₃I (0.16ml, 2.5mmol).Stirred 1 hour and between ether and water, distribute.Dry (MgSO ₄) and concentrate, obtain being the thick ether of yellow oily.

Step 5: under 0 ℃, the crude product of this above-mentioned steps 4 is dissolved in TFA (15ml).Stirred 0.5 hour and concentrated.With the ammonia soln alkalization and with CH ₂Cl ₂Extraction.Dry (MgSO ₄), and concentrate, obtain being the aryl-piperazine of yellow oily.

Preparation 54

Step 1: with 3 '-bromo-4 '-fluoro acetophenone (2.60g, 12.0mmol), ethylene glycol (3.3ml, 59mmol) and TsOHH ₂(0.23g 1.2mmol) is mixed in the toluene (60ml) O.Water proof (waterseparation) backflow (Dean-Stark) 4 hours makes it cooling, and in hexane and 1N NaHCO ₃Between distribute.With water, use the salt water washing again, dry (MgSO ₄), and concentrate, obtain ketal as water white oil.

Step 2: the product according to the piperazine treatment step 1 of preparation 5 method obtains roseate aryl-piperazine, mp 53-6 ℃.

In a similar fashion, with 3 '-bromoacetophenone changes into preparation 54-2.

Preparation 55

Handle 1-(3-bromophenyl) ethanol according to preparation 34, obtain being the aryl-piperazine of pale solid.

Preparation 56

Step 1: (1.0M in toluene, 7.1ml adds BH in 7.1mmol) to the assorted  azoles alkane (oxazaborolidine) of (R)-2-methyl-CBS-boron ₃Me ₂S (2.0M in THF, 3.0ml, 6.0mmol).Stirred 0.5 hour and be cooled to-78 ℃.Adding 3 '-bromo-4 '-fluoro acetophenone (1.50g, 6.9mmol).Make it be warmed to-20 ℃ and stirred 5 hours down, slowly add MeOH (20ml) in-20 ℃.Concentrate and on silica gel chromatography, obtain alcohol into water white oil.

Step 2 and 3: according to preparation 34, the product of step 1 is changed into aryl-piperazine, carry out the piperazine post-reaction treatment by concentrating, in CH ₂Cl ₂And distribute dry (MgSO between the water ₄), and concentrate, obtain being the TBS-ether products of yellow oily.

With the assorted Hu azoles alkane of (S)-2-methyl-CBS-boron, produce its enantiomorph body in a similar fashion, be the preparation 56-2 of yellow oily.

By 3 '-bromoacetophenone begins, and it is right that preparation is the enantiomorph of yellow oily in a similar fashion: preparation 56-3 and 56-4.

Preparation 56-3 Preparation 56-4

Preparation 57

Handle 3-bromo-4-fluorobenzaldehyde according to preparation 39 with the trifluoromethyl trimethyl silane, but, obtain trimethyl silyl ether without the HCl aftertreatment.Make this ether and piperazine reaction according to preparation 5, obtain title aryl-piperazine.

Preparation 58

According to preparation 22, step 1 is with NaBH ₄The product of Processing of Preparation 13-3 obtains being the title aryl-piperazine of yellow solid.

Preparation 59

Step 1: according to preparation 36, step 2 becomes methanesulfonates, a kind of light orange oil with 1-(3-bromophenyl) ethanol conversion.

Step 2: with the product of step 1 (3.33g, 11.9mmol) and morpholine (3.31g 38mmol) is mixed in the acetonitrile (10ml).Heated 4 hours down in 80 ℃, make it cooling, concentrate, and between ether and water, distribute.With 1N HCl extraction, with Na ₂CO ₃Aqueous solution alkalization, and with CH ₂Cl ₂Extraction.Dry (MgSO ₄), and concentrate, obtain greenish orange look oily product.

Preparation 60

Step 1: under 0 ℃, to the methyl 3-bromo-4-fluorobenzoic acid ester that is dissolved in ether (30ml) (3.02g, dropwise add in 13.0mmol) MeMgBr (3.0M is dissolved in ether, 11ml, 33mmol).Stir 1 hour also on ice.With 1N HCl acidifying, separate this ether, use 1NNaHCO ₃Washing, dry (MgSO ₄), and concentrate, obtain product into water white oil.

Step 2: according to the method for preparation 5, the product with piperazine treatment step 1 obtains being canescence crystalline title aryl-piperazine, fusing point 171-4 ℃.

In a similar fashion, from 3 '-bromoacetophenone production prepares 60-2, a kind of yellow solid.

Preparation 61

According to preparation 34 Processing of Preparation 50, the product of step 4 obtains being the title aryl-piperazine of yellow oily.

Preparation 62

According to preparation 22, step 1 reduction 4-bromo-1-indone (according to Synth.Comm.1994,2277 preparations).Change into TBS ether and react according to preparation 34 with piperazine.According to embodiment 2, step 2 will obtain the alcohol as brown oil through the aryl-piperazine deprotection of TBS protection.

Preparation 63

According to preparation 22, step 1 reduction 1-(3-bromophenyl)-2-acetone, according to preparation 34 change into TBS ether and with the piperazine reaction, obtain being the aryl-piperazine of yellow oily.

Similarly, 1-(4-bromophenyl)-2-acetone conversion is become preparation 63-2, a yellow solid.Similarly, 3-bromo-5-acetylpyridine is changed into preparation 63-3, a kind of yellow oil.

Preparation 64

Step 1: under-78 ℃, to the Diisopropylamine that is dissolved in THF (80ml) (6.26ml, add in 45mmol) n-BuLi (2.5M is dissolved in hexane, 15.1ml, 30.2mmol).Stirred 0.5 hour and dropwise add the 2-bromine fluoro-benzene be dissolved among the THF (5ml) (6.00g, 34.3mmol).Stirred 2 hours and add trimethylsilyl chloride (4.92ml, 37.7mmol).Stirred 2 hours, and made it warm, and stirred 18 hours.Concentrate, between hexane and water, distribute, use the salt water washing, dry (MgSO ₄), and concentrate, obtain being the silane of yellow oily.

Step 2: with AlCl ₃(4.57g 34.3mmol) is dissolved in CH ₂Cl ₂Suspension (30ml) be cooled to 0 ℃ and add Acetyl Chloride 98Min. (2.44ml, 34.3mmol).Stirred 10 minutes and added and be dissolved in CH ₂Cl ₂The product of step 1 (10ml) (7.70g, 31.1mmol).Stirred 5 hours and add 1NHCl.With CH ₂Cl ₂Dry (MgSO ₄), and concentrate, obtain the ketone of yellow oily.

Step 3 and 4: according to preparation 53, step 1 changes into the silyl enol-ether with the product of step 2, again according to preparation 5 and piperazine reaction, obtains being the title aryl-piperazine of yellow solid.

In a similar fashion, with 2, the 6-difluoro bromobenzene begins preparation preparation 64-2, a yellow solid.

Preparation 65

Step 1-4: according to preparation 53, step 1-4 processing 3 '-bromo-4 '-fluoro acetophenone, obtain bromide.

Step 5: according to preparation 5 product of step 4 and piperazine are reacted, obtain being the title aryl-piperazine of yellow oily.

Preparation 66

Step 1: mix 2,4-two bromofluoro benzenes (6.00g, 31mmol) and AlCl ₃(10.4g, 34.3mmol) and be heated to 60 ℃.Dropwise add Acetyl Chloride 98Min. (3.66g, 47mmol).Heated 1.5 hours down in 95 ℃, be cooled to 0 ℃, and add frozen water, add dense HCl (15ml) then.Use extracted with diethyl ether, dry (MgSO ₄), concentrate and on silica gel chromatography, obtain being brown buttery ketone.

Step 2 and 3: according to preparation 64, the product of step 3 and 4 treatment steps 1 obtains being the title aryl-piperazine of yellow oily.

Preparation 67

According to preparation 22, the method for step 1 is used NaBH ₄The product of Processing of Preparation 66 obtains being the title aryl-piperazine of yellow oily.

Preparation 68

Step 1: will be dissolved in ether (20ml) 3-bromo-4-fluorobenzaldehyde (2.00g, 9.9mmol) be cooled to 0 ℃ and dropwise add EtMgBr (3.0M is dissolved in ether, 4.9ml, 14.8mmol).Stirred 1 hour and add 1N HCl.With this ether of salt water washing, dry (MgSO ₄) and concentrate, obtain being the alcohol of water white oil.

Step 2 and 3: this alcohol is changed into TBS ether and according to preparation 34 and piperazine reaction, obtains being the aryl-piperazine of yellow oily.

In a similar fashion, make 3-bromo-6-fluorobenzaldehyde and MeMgBr the reaction and with the alcohol that is produced change into the preparation 68-2, a kind of viscous solid.

Preparation 69

In preparation 68, under the condition of step 1, make 3-bromo-4-fluorobenzaldehyde and cyclopropyl bromination reactive magnesium, and according to preparation 56, step 2 and 3 is handled this alcohol, obtains being black buttery title aryl-piperazine.

In a similar fashion, obtain being the preparation 69-2 of yellow oily.

Preparation 70

According to preparation 68, step 1 with MeMgBr Processing of Preparation 65, the product of step 2, then in preparation 56, is handled with piperazine under the condition of step 3, obtains being the title aryl-piperazine of yellow oily.

Preparation 71

Step 1: under 10 ℃, to being dissolved in CH ₂Cl ₂(15ml) and acetate (0.5ml) 3 '-bromo-4 '-(3.00g dropwise adds in 13.8mmol) and is dissolved in CH fluoro acetophenone ₂Cl ₂Bromine (20ml) (2.43g, 15.2mmol).Stirred 15 minutes and concentrated, obtain being the thick bromide of yellow oily.

Step 2: (6.24g, 41.5mmol) suspension in THF (40ml) is cooled to 0 ℃ with the samarium powder.Product and CH with above-mentioned steps 1 ₂I ₂(11.1g 41.5mmol) is mixed among the THF (60ml) and dropwise adds in this suspension.Stir and also slowly added 1N HCl (200ml) in 0.5 hour.Use extracted with diethyl ether, dry (MgSO ₄), concentrate, and on silica gel chromatography, obtain being the ring propyl alcohol of yellow oily.

Step 3: the product that makes step 2 according to preparation 5 react with piperazine and on silica gel chromatography, obtain being the title Propiophenone of yellow oily.

Preparation 72

Step 1: will be dissolved in 1: 1 Sharpless oxidation mixture AD-mix-β (15.3g) in t-BuOH (100ml) aqueous solution and be cooled to 0 ℃.Between adding-and bromstyrol (2.00g, 10.9mmol).Descended stirring 8 hours and made its warm 18 hours in 0 ℃.Add Na ₂SO ₃(16.0g) and EtOAc (100ml).Stirred 0.5 hour, and separated organic layer, dry (MgSO ₄), concentrate and on silica gel chromatography, obtain being the glycol of yellow oily.

Step 2: according to preparation 34, step 1 with the product of 1.0 normal TBS-Cl treatment steps 1, obtains being the TBS ether of yellow oily.

Step 3: according to preparation 22, step 2 methylates the product of step 2, obtains being the methyl ether of yellow oily.

Step 4: the product that makes step 3 according to preparation 5 and piperazine reaction and on silica gel chromatography, obtain being dark-coloured oily title aryl-piperazine.

Similarly, use AD-mix-α, obtain enantiomorph, be the preparation 72-2 of dark-coloured oil.

In a similar fashion, prepare 72-3 and 72-4 from the production of 4-bromstyrol.

In preparation 56, under the condition of step 3,, obtain being the preparation 72-5 of yellow oily with the product of piperazine processing above-mentioned steps 3.

Preparation 73

According to preparation 34, step 1 transforms preparation 71, and the product of step 2 obtains TBS ether, again in preparation 56, handles with piperazine under the condition of step 3, obtains being the title aryl-piperazine of yellow solid.

Preparation 74

Step 1: according to preparation 17, step 2 changes into the Boc-derivative with the product for preparing 5-5.

Step 2: according to preparation 48, step 3 is used BH ₃Me ₂The product of S reduction step 1, and on silica gel chromatography, obtain being the amine of yellow oily.

Step 3: will be dissolved in the step 2 of THF (15ml) product (2.00g, 6.9mmol) and Et ₃(1.15ml 8.3mmol) is cooled to 0 ℃ to N.The adding methyl-chloroformate (0.53ml, 6.9mmol).Stirred 2 hours down at 0 ℃, in EtOAc and saturated NaHCO ₃Between distribute dry (MgSO ₄), and concentrate, obtain being the carbamate of yellow oily.

Step 4: according to preparation 17, step 8 obtains being the title aryl-piperazine of yellow oily with the product deprotection of step 3.

For preparation 74-2, earlier 3-bromo-4-fluorobenzonitrile is changed into 1-(3-cyano group-6-fluorophenyl) piperazine according to preparation 5.According to above-mentioned steps this material is transformed, obtain preparing 74-2, a kind of yellow oil.

Preparation 75

Step 1: will prepare 69 cyclopropyl-carbinol intermediate (4.90g, 20mmol) with vinyl acetate (9.26ml, 100mmol) and Amano lipolytic enzyme C-II (2.50g) be mixed in the isopropyl ether (200ml).Stirred 18 hours down in 27 ℃.Filter, concentrate, and on silica gel chromatography, obtain (R)-acetic ester (on Chiralcel OD, analyzing) through HPLC as water white oil.

Step 2: according to preparation 5, the acetic ester of piperazine and step 1 is reacted and on silica gel chromatography, obtain being the title aryl-piperazine of yellow oily.

Preparation 76

According to preparation 56, step 2 and 3 method are handled in preparation 75, and (the S)-alcohol that obtains by chromatography in the step 1 obtains being the title aryl-piperazine of yellow oily.

Preparation 77

Step 1 and 2: according to Synth.Comm.2003,1611 method, with 3 '-bromo-4 '-fluoro acetophenone changes into 2-(2,4-dinitrobenzene-sulfonyloxy) derivative, and with ethanamide in CH ₃The reaction that (refluxed 18 hours) among the CN, solid  azoles obtains being white in color behind silica gel column chromatography.

Step 3: according to preparation 5, make the product and the piperazine reaction of step 2, obtain being the title aryl-piperazine of yellow oily.

In a similar fashion, from 3 '-bromo-4 '-fluorobenzene acetone, produce preparation 77-2.

In a similar fashion, prepare 64 certainly, the ketone of step 2 is produced preparation 77-3.

Preparation 78

Step 1: with 2,3 '-two bromo-4 '-fluoro acetophenone (3.4g, 11.5mmol) and thioacetamide (1.00,13.2mmol) be mixed in the dioxane and in 80 ℃ of heating 2 hours down.Make it cooling, concentrate and in ether and saturated NaHCO ₃Between distribute dry (MgSO ₄), concentrate, and on silica gel chromatography, obtain being the thiazole of yellow solid.

Step 2: according to preparation 5, make the product and the piperazine reaction of step 1, obtain being the aryl-piperazine of yellow oily.

Preparation 79

Step 1: to the 3-bromo-4-fluorobenzoic acid that is dissolved in THF (100ml) (5.00g, add in 22.8mmol) isopropyl chlorocarbonate (1.0M is dissolved in toluene, 22.8ml, 22.8mmol), add again N-methylmorpholine (2.76ml, 25.1mmol).Stirred 1 hour and add aminoacetaldehyde dimethyl acetal (dimethyl acetal) (2.49ml, 22.8mmol).Stirred 0.75 hour and in ether and saturated NaHCO ₃Between distribute.Dry (MgSO ₄), and concentrate, obtain being the acid amides of yellow oily.

Step 2: (3.75g is 12.3mmol) with Eaton ' s reagent (10%P with the product of step 1 ₂O ₅In CH ₃SO ₃Among the H, 30ml) mix.Heated 18 hours down in 110 ℃, make it cooling,, and stirred 0.5 hour on ice.Collect this solid, obtain the  azoles of gray powder.

Step 3: according to preparation 5, make the product and the piperazine reaction of step 2, obtain being the aryl-piperazine of yellow oily.

Preparation 80

Step 1: to the iodobenzene diethyl ester that is dissolved in acetonitrile (140ml) (5.34g, add in 16.6mmol) trifluoromethanesulfonic acid (5.5ml, 62mmol).Stirred 30 minutes and add 3 '-bromo-4 '-fluoro acetophenone (3.00g, 13.8mmol).Reflux 2 hours makes it cooling, concentrates, and in EtOAc and saturated NaHCO ₃Between distribute.Dry (MgSO ₄), concentrate, and on silica gel chromatography, obtain being the  azoles of yellow oily.

Step 2: according to preparation 5, make the product and the piperazine reaction of step 1, obtain being the aryl-piperazine of yellow solid.

Preparation 81

Step 1: to be dissolved in 3 of methane amide (10ml) '-bromo-4 '-fluoro acetophenone (3.50g, add in 16.1mmol) bromine (0.83ml, 16.1mmol).Heated 2 hours down in 75 ℃, heated 5 hours down in 135 ℃ again.Make it the cooling and in EtOAc and saturated NaHCO ₃Between distribute.Dry (MgSO ₄), concentrate, and on silica gel chromatography, obtain being the  azoles of yellow oily.

Step 2: according to preparation 5, make the product and the piperazine reaction of step 1, obtain being the title compound of yellow oily.

Preparation 82

Step 1 and 2: use preparation 77, step 1 and 2 method, with 3 '-fluoro-4 '-the methoxy methyl phenyl ketone changes into aryl-thiazole  azoles.

Step 3: according to preparation 50, the method for step 3 is used BBr ₃With the product demethylation of step 2, obtain being the phenol of yellow solid.

Step 4: with the product of step 3 (1.73g, 9.0mmol) and Et ₃(2.5ml 7.9mmol) is dissolved in CH to N ₂Cl ₂Solution (50ml) is cooled to-78 ℃.Dropwise add trifluoromethanesulfanhydride anhydride (1.82ml, 10.7mmol).Stirred 2 hours, and made it be warmed to 0 ℃, with 1N NaOH (20ml) washing.Dry (MgSO ₄) and concentrate, obtain being the triflate of yellow solid.

Step 5: with the product of step 4 (1.70g, 5.2mmol), piperazine (2.7g, 31.3mmol), Cs ₂CO ₃(2.55g, 7.9mmol), (±)-BINAP (0.20g, 0.3mmol) and Pd (OAc) ₂(0.047g 0.21mmol) is mixed among the DMF (20ml).Heated 18 hours down in 90 ℃, make it cooling, filter, and between EtOAc and 1N HCl, distribute.This aqueous solution is alkalized to pH13, use CH ₂Cl ₂Extraction, dry (MgSO ₄), and concentrate, obtain being the title compound of yellow solid.

Preparation 83

Step 1: according to preparation 17, step 2 will prepare 54 product and change into the Boc-derivative.

Step 2: will be dissolved in THF (40ml) KO-tBu (1.00g, 8.9mmol) be heated to 50 ℃ and dropwise add step 1 product (2.00g, 6.2mmol) and ethyl formate (1.5ml 19mmol) is dissolved in the mixture of THF (20ml).After 2 hours, make it to cool off and between EtOAc and water, distribute.With 1N NaOH washing organic layer.With the water layer mixing and with NH ₄Cl is acidified to pH 7-8.With the EtOAc extraction, dry (MgSO ₄), and concentrate, obtain being the thick formylation compound of yellow solid.

Step 3: with the crude product of step 2 (2.10g, 6.0mmol), hydrazine (0.28ml, 9.0mmol) and AcOH (0.69ml 12mmol) is mixed among the EtOH (30ml).Reflux 2 hours also concentrates.Between EtOAc and 1N NaOH, distribute.Dry (MgSO ₄), concentrate, and on silica gel chromatography, obtain being the pyrazoles of yellow solid.

Step 4: according to preparation 53, step 5 deprotection, and on silica gel chromatography, obtain being the piperazine of yellow oily.

In a similar fashion, the product (heating 4 hours) with EtOAc treatment step 1 also continues to obtain being the preparation 83-2 of yellow solid as in step 3 and 4.

Preparation 84

Step 1: will prepare 83-2 the diketone intermediate (1.50g, 4.7mmol) and hydroxylamine hydrochloride (0.66g 10.9mmol) is mixed among the EtOH (50ml).Reflux 5 hours makes it cooling, concentrates, and is concentrated with the ammonia treatment of 7N methyl alcohol system, and on silica gel chromatography, obtain being the different  azoles of yellow oily.

Step 2: according to preparation 53, step 5 deprotection, and on silica gel chromatography, obtain being the title compound of yellow oily.

Preparation 85

Step 1: to the 3-bromo-4-fluorobenzonitrile that is dissolved in ethanol (125ml) (10g, 50mmol) the middle Et that adds ₃N (16.1ml, 115mmol), add then hydroxylamine hydrochloride (7.64g, 110mmol).Be heated to 75 ℃ and stirred 24 hours.Make it cooling, concentrate and between EtOAc and water, distribute.Dry (MgSO ₄) and concentrate, the solid amidoxime obtains being white in color.

Step 2: in the product of step 1, add diacetyl oxide (20ml).Reflux 2 hours.With the water dilution, with dense NH ₄OH transfers to 8 with pH.In Et ₂Distribute between O and the water.Dry (MgSO ₄) and concentrate the solid 1,2 that obtains being white in color, 4- diazole.

Step 3: according to preparation 5 product of step 2 and piperazine are reacted, obtain being the title compound of yellow oily.

Similarly, the 3-bromobenzylcyanide is changed into preparation 85-2.

Preparation 86

Step 1: to the 3-bromo-4-fluorobenzoic acid that is dissolved in DMSO (35ml) (2.50g, add in 110mmol) acetic acid hydrazides (1.02g, 13.7mmol) and EDCI (2.63g 13.7mmol), adds HOBtH again ₂O (1.85g, 13.7mmol).Stirred 24 hours.Between EtOAc and water, distribute.Dry (MgSO ₄) and concentrate, obtain being the hydrazides of yellow oily.

Step 2: in the product of step 1, add Phosphorus Oxychloride (30ml).Reflux 17 hours makes it cooling, concentrates, and distributes between EtOAc and water.Dry (MgSO ₄), concentrate, and with CH ₂Cl ₂/ hexane recrystallize obtains being brown solid 1,3,4- diazole.

Step 3: according to preparation 5, make the product and the piperazine reaction of step 2, obtain being the title compound of yellow solid.

Preparation 87

Step 1: under 0 ℃, to being dissolved in CH ₂Cl ₂3-bromo-benzoyl chloride (75ml) (5.0g, add in 23mmol) pyridine (3.7ml, 46mmol) and acetic acid hydrazides (2.2g, 30mmol).Stirred 1 hour, in CH ₂Cl ₂With saturated NaHCO ₃Between distribute.Dry (MgSO ₄), concentrating, the solid hydrazides obtains being white in color.

Step 2: according to preparation 86, step 2 makes the product and the Phosphorus Oxychloride reaction of step 1, the solid 1,3 that obtains being white in color, 4- diazole.

Step 3: according to preparation 5, make the product and the piperazine reaction of step 3, obtain being the title compound of yellow solid.

Preparation 88

Step 1: to being dissolved in 3 of DMSO (25ml), the 4-difluorobenzonitrile (1.5g, add in 11mmol) piperazine-1 carboxylic acid tert-butyl ester (2.4g, 13mmol) and K ₂CO ₃(2.2g, 16mmol).Be heated to 110 ℃ and stirred 24 hours.Make it cooling and add entry (300ml).Filter, wash with water, and dry under vacuum, and solid aryl-piperazine obtains being white in color.

Step 2: to product (1.0g, 3.3mmol) the middle Et that adds of the step 1 in ethanol (12ml) ₃N (1.0ml, 7.5mmol), add then hydroxylamine hydrochloride (0.50g, 7.2mmol).Be heated to 75 ℃ and stirred 24 hours. make it cooling, concentrate and between EtOAc and water, distribute.Dry (MgSO ₄) and concentrate, obtain acid amides, white solid.

Step 3: in the product of step 2, add diacetyl oxide (12ml).Reflux 2 hours.With the water dilution, with NH ₄OH transfers to 8 with pH.In Et ₂Distribute between O and the water.Dry (MgSO ₄) and concentrate, obtain being 1,2 of yellow solid, 4- diazole.

Step 4: to being dissolved in CH ₂Cl ₂The product of step 3 (15ml) (0.64g, add in 1.8mmol) TFA (1.4ml, 17mmol).Stirred 4 hours, with NH ₄OH transfers to 11 and in CH with pH ₂Cl ₂And distribute between the water.Dry (MgSO ₄) and concentrate, the solid title compound obtains being white in color.

In a similar fashion, replace diacetyl oxide, produce preparation 88-2, a kind of brown solid with propionic anhydride.

Preparation 89

Step 1: with 3-bromo-4-fluorobenzonitrile (10.0g, 50mmol) and CH ₃(4.8g 150mmol) is mixed in the ether (10ml) OH.Adding 1M is dissolved in the HCl of ether (110ml 110mmol) and in 5 ℃ kept 12 days.Filter, obtain imido acid (imidate) hydrochloride of white solid.

Step 2: (1.85g 6.9mmol) is dissolved in 7M NH with the product of step 1 ₄OH/CH ₃OH (20ml, 140mmol) in.Kept under 5 ℃ 4 days and concentrated, solid amidine hydrochloride obtains being white in color.

Step 3: (1.00g, 3.9mmol) (0.48g 4.7mmol) is mixed in CH with 4-methoxyl group-3-butene-2-ketone with the product of step 2 ₃Among the OH (10ml).Be heated to 50 ℃ and add and to be dissolved in CH ₃The NaOMe of OH (5ml) (0.43g, 7.9mmol).Heated 24 hours, and made it cooling, and concentrate.Soluble in water, transfer to pH 7 and with CH with AcOH ₂Cl ₂Extraction.Use the salt water washing, dry (MgSO ₄), concentrate, and on silica gel chromatography, the solid pyrimidine obtains being white in color.

Step 4: according to preparation 5, make the product and the piperazine reaction of step 3, obtain being the title compound of brown oil.

Preparation 90

(4.19ml, 34.9mmol) solution that is dissolved in THF (100ml) is cooled to-78 ℃ with Diisopropylamine.Slowly add butyllithium (2.5M is dissolved in hexane, 12.9ml, 32mmol).Stirred 40 minutes, (4.9ml 27mmol), and stirred 1 hour under-78 ℃ dropwise to add 2-furans formonitrile HCN (furonitrile).Adding dry ice also stirred 1 hour, placed 30 minutes down in-78 ℃.Make it be warming up to room temperature and add entry (150ml).Use extracted with diethyl ether, and be acidified to pH=2 with dense HCl again.Use extracted with diethyl ether, dry (MgSO ₄), and concentrate, obtain being the title acid of yellow solid.

Preparation 91

Step 1: (4.90g 24mmol) adds K in the solution to the 3-bromo-4-fluorobenzaldehyde that is dissolved in MeOH (60ml) ₂CO ₃(6.66g, 48mmol) and the tosyl group methyl isocyanate (5.42g, 28mmol).Reflux 3 hours makes it cooling, concentrate, and on silica gel chromatography, obtain being the  azoles of yellow solid.

Step 2: according to preparation 5, make the product and the piperazine reaction of step 1, obtain being the title aryl-piperazine of yellow oily.

Preparation 92

Step 1: to (±) that be dissolved in THF (80ml)-methyl lactate (8.0g, add in 77mmol) TBS-Cl (11.6g, 77mmol) and imidazoles (6.3g, 92mmol).Stir and also heated 0.5 hour down in 50 ℃ again in 4 hours.Make it cooling, add water and use extracted with diethyl ether.Dry (MgSO ₄) and concentrate, obtain being the crude product of colorless oil.

Step 2: the product and the 7N NH that make 2 steps 2 ₃Heating was 18 hours under/MeOH (40ml) mixed and is incorporated in 50 ℃.It is left standstill also concentrated in 3 days, obtain being the crude amide of yellow oily.

Step 3: (14.7g, 72mmol) with preparation 77, the solution of the product of step 1 (from the 6.0g methyl phenyl ketone) mixes with the product of step 2.Reflux 40 hours makes it cooling, and adds 7NNH ₃/ MeOH (20ml).Concentrate and on silica gel chromatography, obtain being the  azoles of yellow solid.

Step 4: (1.8g, 6.3mmol) (6.8g 31mmol) is mixed in CH with pyridinium chlorochromate  with the product of step 3 ₂Cl ₂(50ml).Stirred 18 hours and add ether (100ml).By diatomite filtration, concentrate, and on silica gel chromatography, obtain being the ketone of yellow solid.

Step 5: with the product of step 4 (1.13g, ether 4.0mmol) (25ml) solution be cooled to 0 ℃ and dropwise add MeMgBr (3.0M in ether, 2.0ml, 6.0mmol).Stirred 1 hour and add 100ml 8%NH ₄Cl.With extracted with diethyl ether and use NaHCO ₃, use the salt water washing again.Dry (MgSO ₄) and concentrate, the solid product obtains being white in color.

Step 6: according to preparation 5, make the product and the piperazine reaction of step 5, obtain being the title aryl-piperazine of dark-coloured oil.

Preparation 93

Step 1: according to preparation 92, step 1 will prepare 92, and the product of step 3 changes into TBS ether.

Step 2: according to preparation 5, make the product and the piperazine reaction of step 1, obtain being the title aryl-piperazine of yellow solid.

Preparation 94

Step 1: to being cooled to 0 ℃ of dense NH ₄Dropwise add among the OH (40ml) methoxyacetyl chloride (10.0g, 92mmol).Stirred 1 hour, and concentrated, handle with 9: 1 ether/MeOH, filter, and concentrate, the solid acid amides obtains being white in color.

Step 2: as prepare 92, described in the step 3, with the product of alkylsulfonyl oxygen base-ketone treatment step 1.Concentrate and on silica gel chromatography, obtain being the  azoles of yellow oily.

Preparation 95

Step 1: to being dissolved in CH ₃The 3-bromo-4-fluorobenzoic acid of CN (120ml) (5.0g, add in 22.8mmol) EDCI (5.25g, 27.4mmol) and HOBtH ₂O (3.70g, 27.4mmol).Stirred 2 hours and under 0 ℃, (1.43ml 45.7mmol) is dissolved in CH during 15 minutes this solution slowly to be added hydrazine ₃In the solution of CN (20ml).Make it warm and stirred 1 hour.Between EtOAc and water, distribute.Dry (MgSO ₄) and concentrate, the solid hydrazides obtains being white in color.

Step 2: to being dissolved in CH ₂Cl ₂The product of step 1 (40ml) (1.00g, add in 4.29mmol) pyridine (0.52ml, 6.44mmol).Be cooled to 0 ℃ and add dimethylcarbamyl chloride (0.44ml 4.72mmol), adds THF (20ml) again.Stirred 4 hours, and made it warm, and stirred 12 hours.In CH ₂Cl ₂And distribute between the water.Dry (MgSO ₄) and concentrate, obtain being the hydrazides of solid state.

Step 3: in the product of step 2, add Phosphorus Oxychloride (15ml).Reflux 5 hours makes it cooling, concentrates, and distributes between EtOAc and water.Dry (MgSO ₄) and concentrate, obtain into 1,3 of orange solids, 4- diazole.

Step 4: according to preparation 5, make the product and the piperazine reaction of step 3, obtain being the title aryl-piperazine of yellow oily.

Preparation 96

Step 1: according to preparation 5,3-bromo-4-fluorobenzonitrile and piperazine are reacted, obtain being the piperazine of the replacement of brown oil.

Step 2: to being dissolved in CH ₂Cl ₂The product of step 1 (175ml) (7.1g, 35mmol) the middle Et that adds ₃N (9.7ml, 69mmol) and dimethyl aminopyridine (1.1g, 8.7mmol), add again two carbonic acid, two-tertiary butyl ester (9.8g, 45mmol).Stirred 24 hours and in CH ₂Cl ₂And distribute between the water.Dry (MgSO ₄) and concentrate, obtain being the piperazine of the protection of brown oil.

Step 3: to product (10.0g, 33mmol) the middle Et that adds of the step 2 that is dissolved in ethanol (150ml) ₃N (12ml, 85mmol) and hydroxylamine hydrochloride (5.7g, 82mmol).Heated 20 hours and make it cooling down in 75 ℃.Add 1N HCl pH is transferred to 6, concentrate, and between EtOAc and water, distribute.Dry (MgSO ₄) and concentrate, obtain being the amidoxime of yellow solid.

Step 4: to the product of the step 3 that is dissolved in pyridine (10ml) (0.79g, add in 2.3mmol) methoxyacetyl chloride (0.320ml, 3.5mmol).Heated 4 hours and make it cooling down in 110 ℃.In CH ₂Cl ₂And distribute between the water.Dry (MgSO ₄) and concentrate, obtain being 1,2 of brown oil, 4- diazole.

Step 5: according to preparation 88, step 4 deprotection, and on silica gel chromatography, obtain being the title compound of yellow oily.

Preparation 97

Step 1: to the preparation 96 that is dissolved in pyridine (20ml), the product of step 3 (2.0g, add in 5.9mmol) acetate 1-chloroformyl-1-methylethyl ester (1.1ml, 7.7mmol).Heated 18 hours and make it cooling down in 110 ℃.In CH ₂Cl ₂And distribute between the water.Dry (MgSO ₄) and concentrate, obtain being 1,2 of yellow oily, 4- diazole.

Step 2: according to preparation 88, step 4 is removed the Boc group, and on silica gel chromatography, obtain into the buttery piperazine.

Step 3: to the product of the step 2 that is dissolved in MeOH (6ml) (0.40g, add in 1.2mmol) 1N NaOH (5.5ml, 5.5mmol) and stirred 0.5 hour.Concentrate, between EtOAc and water, distribute, dry (MgSO ₄), and concentrate, the solid title compound obtains being white in color.

Preparation 98

Step 1: to being dissolved in CH ₂Cl ₂Preparation 96 (15ml), the product of step 3 (1.0g, add in 3.0mmol) pyridine (0.96ml, 12mmol), add then the ethyl oxalyl chloride (0.43ml, 3.8mmol).Stirred 18 hours and in CH ₂Cl ₂And distribute between the water.Dry (MgSO ₄) and concentrate, obtain being 1,2 of yellow oily, 4- diazole.

Step 2: to the product of the step 1 that is dissolved in EtOH (12ml) (1.0g, add in 2.4mmol) cyclopropylamine (0.50ml, 7.2mmol).Heated 3 hours down in 80 ℃, make it cooling, and concentrate, obtain being the acid amides of yellow oily.

Step 3: according to preparation 88, step 4 deprotection, and on silica gel chromatography, obtain being the title piperazine of yellow solid.

Embodiment 1

With preparation 2 product (0.150g, 0.34mmol), the product of preparation 8 (0.15g, 0.77mmol) and DIPEA (0.071ml 0.41ml) is mixed among the DMF (6ml).Heated 18 hours and make it cooling down in 80 ℃.Concentrate and grind three times with MeOH.Filter, obtain being the title compound of yellow solid, MS m/e 474 (M+1).

In a similar fashion, use preparation 2 with suitable piperazine and where necessary by PLC purifying crude product, the production following compounds:

Embodiment 2

Step 1: will prepare 4 product (0.173g, 0.54mmol), the product of preparation 56 (0.367g, 1.09mmol) and KI (0.090g 0.55mmol) is mixed among the DMF (6ml).In 120 ℃ of heating 24 hours and concentrated down.Through the PLC purifying, obtain being the piperazine product of yellow solid.

Step 2: to the product of the step 1 that is dissolved in THF (5ml) (0.149g, add in 0.24mmol) TBAF (1.0M in THF, 0.29ml, 0.29mmol).Stirred 18 hours and concentrated.Add MeOH (5ml), stir, filter, and wash this solid with MeOH.Drying obtains being the title compound of pale solid, MS:m/e 506 (M+1).

In a similar fashion, use suitable muriate together to prepare following compounds with preparation 56 from preparation 4:

Embodiment 3

According to embodiment 2, step 1 and 2 with the product of the product Processing of Preparation 4-5 for preparing 72-5, obtains being the title compound of pale solid, MS:m/e 539 (M+1).

Embodiment 4

(0.181g 0.37mmol) is dissolved in THF (30ml) with the product of embodiment 1-18.Add NaBH ₄(0.070g, 1.8mmol).Under room temperature, stirred 3 hours, stirred 2 hours down in 60 ℃ again.Concentrate and adding CH ₃OH (10ml).Filter, obtain being the title compound of yellow solid, MS:m/e 492 (M+1).

Embodiment 5

(0.35g 0.62mmol) is dissolved among the TFA (8ml), cools off in ice bath with the product of embodiment 1-25.Stirred 1 hour, and concentrated, and with 7N methyl alcohol system NH ₃Handle residue.Concentrate and, obtain being the title compound of yellow solid, MS:m/e 471 (M+1) through the PLC purifying.

Embodiment 6

To the product of the embodiment 5 that is dissolved in DMF (5ml) (0.090g, add in 0.19mmol) DIPEA (0.041ml, 0.23mmol) and diacetyl oxide (0.022ml, 0.23mmol).Stirred 2 hours, and concentrated, handle and filtration the solid title compound that obtains being white in color, MS:m/e 513 (M+1) with MeOH

Embodiment 7

According to preparation 68,, obtain embodiment 7, a kind of yellow solid, MS:m/e 534 (M+1) with methyl-magnesium-bromide (THF solvent) Processing Example 1-51 and through the PLC purifying.

Similarly, with methyl-magnesium-bromide Processing Example 1-53 and through the PLC purifying, obtain embodiment 7-2, a kind of yellow solid, MS:m/e 506 (M+1).

Embodiment 7-2

Similarly, with the 2-fluorine analogue of cyclopropyl bromination magnesium Processing Example 1-2 (making) and through the PLC purifying, obtain embodiment 7-3, a kind of yellow solid, MS:m/e 518 (M+1) through similar method.

Embodiment 7-3

In a similar fashion, prepare embodiment 7-4, a kind of yellow solid, MS:m/e 520 (M+1) with sec.-propyl bromination magnesium.

Embodiment 7-4

Embodiment 8

Step 1: according to the method for embodiment 1, use the product of the product Processing of Preparation 2 of preparation 56, obtain being the silyl ether of yellow solid.

Step 2: according to embodiment 2, step 2 is with the product deprotection of step 1 and through the PLC purifying, the solid title compound that obtains being white in color, MS:m/e 492 (M+1).

Prepare the enantiomorph body from preparing 56-2 in a similar fashion, embodiment 8-2 also is a white solid, MS:m/e 492 (M+1).

Embodiment 8-2

From preparing 69 preparation embodiment 8-3, a kind of yellow solid, MS:m/e 518 (M+1).

Embodiment 8-3

From preparing 70 preparation embodiment 8-4, a kind of white solid, MS:m/e 522 (M+1).

Embodiment 8-4

Prepare embodiment 8-5, a kind of yellow solid, MS:m/e 500 (M+1) from the product of preparation 69-2.

Embodiment 8-5

56-3 prepares embodiment 8-6, a kind of yellow solid, MS:m/e 474 (M+1) from preparation.

Embodiment 8-6

Similarly, 56-4 prepares enantiomorph body embodiment 8-7 from preparation, also is a kind of yellow solid, MS:m/e 474 (M+1).

Embodiment 8-7

From preparing 75 product (no TBS protection) preparation embodiment 8-8, a kind of yellow solid, MS:m/e 518 (M+1).

Embodiment 8-8

Prepare embodiment 8-9, a kind of yellow solid, MS:m/e 518 (M+1) from preparing 76 product.

Embodiment 8-9

From preparation 4-6 and preparation 69 preparation embodiment 8-10, a kind of yellow solid, MS:m/e 529 (M+1).

Embodiment 8-10

Embodiment 9

To be dissolved in CH ₂Cl ₂Dess-Martin periodinane with the product oxidation of embodiment 1-78.By the ketone purifying of PLC, obtain being the title compound of yellow solid, MS:m/e544 (M+1) with gained.

Embodiment 10

Ketone (60 ℃, 16 hours) with the hydroxylamine hydrochloride Processing Example 9 that is dissolved in pyridine.Through the PLC purifying, obtain being the title compound of yellow solid, MS:m/e 559 (M+1).

Embodiment 11

According to embodiment 4 reduction embodiment 1-89.Through the PLC purifying, the solid title compound obtains being white in color.MS：m/e?492(M+1)。

Similarly, obtain being the embodiment 11-2 of yellow solid, MS:m/e 510 (M+1) from the product of embodiment 1-97.

Embodiment 11-2

Similarly, from the product of the embodiment 1-107 solid embodiment 11-3 that obtains being white in color, MS:m/e 475 (M+1).

Embodiment 11-3

Embodiment 12

With similar embodiment 2, the mode of step 1, use the suitable muriate that derives from preparation 4 to prepare following compounds with preparation 80:

The suitable muriate that use derives from preparation 4 prepares following compounds with preparation 81:

Similarly, 77-2 prepares the embodiment 12-17 that is yellow solid, MS:m/e=554 (M+1) from preparation.

77-3 prepares the embodiment 12-18 that is yellow solid, MS:m/e=540 (M+1) from preparation.

From preparing the embodiment 12-19 that 80 preparations are yellow solid, MS:m/e=554 (M+1).

The suitable muriate that use derives from preparation 4 prepares following compounds with preparation 80:

From preparing the embodiment 12-23 that 91 preparations are yellow solid, MS:m/e=526 (M+1) From preparing the embodiment 12-24 that 82 preparations are yellow solid, MS:m/e=554 (M+1).

From preparing the embodiment 12-25 that 82 preparations are yellow solid, MS:m/e=540 (M+1)

From preparing the embodiment 12-26 that 83 preparations are yellow solid, MS:m/e=525 (M+1).

83-2 prepares the embodiment 12-27 that is yellow solid, MS:m/e=553 (M+1) from preparation.

From preparing the embodiment 12-28 that 84 preparations are yellow solid, MS:m/e=540 (M+1).

From preparing the embodiment 12-29 that 84 preparations are yellow solid, MS:m/e=554 (M+1)

From preparing the embodiment 12-30 that 78 preparations are yellow solid, MS:m/e=556 (M+1)

From preparing the embodiment 12-31 that 79 preparations are yellow solid, MS:m/e=526 (M+1)

Embodiment 13

In the mode of similar embodiment 12, use the suitable muriate that derives from preparation 4 to prepare following compounds with preparation 85:

In a similar fashion, use the suitable muriate that derives from preparation 4 to prepare following compounds with preparation 86:

From preparing 87, preparation is the embodiment 13-10 of yellow solid, MS:m/e=523 (M+1).

From preparation 85-2, preparation is the embodiment 13-11 of brown solid, MS:m/e=537 (M+1).

From preparing the embodiment 13-12 that 88 preparations are brown solid, MS:m/e=555 (M+1).

Embodiment 14

In the mode of similar embodiment 12, use preparation 4-6 to prepare the title compound that is yellow solid, MS:m/e=533 (M+1) with preparation 65.

Embodiment 15

In the mode of similar embodiment 12,4-8 prepares title compound, a kind of brown solid, MS:m/e=565 (M+1) with preparation 89 in conjunction with preparation.

Embodiment 16

Be similar to embodiment 12, in conjunction with preparing 4-6 and preparing 92 with preparation title compound, a kind of yellow solid, MS:m/e=584 (M+1).

Similarly, prepare embodiment 16-2, a kind of yellow solid, MS:m/e=598 (M+1) from preparation 4-8.

Similarly, in conjunction with preparing 4-6 and preparing 93 with preparation embodiment 16-3, a kind of yellow solid, MS:m/e=570 (M+1).

Similarly, prepare embodiment 16-4, a kind of yellow solid, MS:m/e=584 (M+1) from preparation 4-8.

Similarly, in conjunction with preparing 4-6 and preparing 94 with preparation embodiment 16-5, a kind of yellow solid, MS:m/e=570 (M+1).

Similarly, prepare embodiment 16-6, a kind of yellow solid, MS:m/e=584 (M+1) from preparation 4-8.

Similarly, prepare embodiment 16-7, a kind of yellow solid, MS:m/e=588 (M+1) from preparation 4-20.

Embodiment 17

In the mode of similar embodiment 12, in conjunction with preparing 4-6 and preparing 97 with preparation title compound, a kind of brown solid, MS:m/e=585 (M+1).

Use derives from the suitable muriate of preparation 4 and prepares 97 to prepare following compounds:

Similarly, in conjunction with preparing 4-6 and preparing 96 with preparation embodiment 17-6, a kind of white solid, MS:m/e=571 (M+1).

Use derives from the suitable muriate of preparation 4 and prepares 96 to prepare following compounds:

Similarly, in conjunction with preparing 4-8 and preparing 88-2 with preparation embodiment 17-11, a kind of white solid, MS:m/e=557 (M+1).

Similarly, in conjunction with preparing 4-8 and preparing 98 with preparation embodiment 17-12, a kind of brown solid, MS:m/e=624 (M+1).

Embodiment 18

In the mode of similar embodiment 12, in conjunction with preparing 4-8 and preparing 95 with preparation title compound, a kind of brown solid, MS:m/e=584 (M+1).

Embodiment 19

In the mode of similar embodiment 12, in conjunction with preparing 4-8 and preparing 36 with preparation title compound, a kind of yellow solid, MS:m/e=512 (M+1).

Because the adenosine A of The compounds of this invention _2aReceptor antagonist activity, it can be in order to treatment dysthymia disorders, cognitive function disease and neurodegenerative disorders, for example Parkinson's disease, senile dementia, Alzheimer for example, psychosis, attention deficit syndrome, EPS, myodystonia, RLS and PLMS.Particularly, compound of the present invention can improve because for example sport injury that causes of Parkinson's disease of neurodegenerative disorders.

Knownly can be used for treating Parkinson's disease and can unite the other medicines that give with formula I compound and comprise:

L-DOPA, dopaminergic agonist, for example quinpirole, Ropinirole, pramipexole, pergolide and bromocriptine (bromocriptine); MAO-B inhibitor, for example deprenyl (deprenyl) and selegiline (selegiline); DOPA decarboxylase inhibitor, for example carbidopa and benserazide (benserazide); With the COMT inhibitor, for example tolcapone and Entacapone.

In the application's book, one to three kind of different I compound of term " at least a formula I compound " expression can be used in a kind of medicinal compositions or the methods of treatment.Be preferably and use a kind of formula I compound.Similarly, one to three kind of different medicine of " one or more can be used for the medicine of Parkinson's disease treatment " expression is preferably a kind of medicine, can be used in a kind of medicinal compositions or the methods of treatment.Preferably unite and use a kind of medicine and a kind of formula I compound.

The pharmaceutical active of compound of the present invention can pass through following mensuration A _2aExternal and the body inner analysis of receptor active is determined.

Human adenosine A _2aAnd A ₁Receptor competition binding analysis scheme

Membrane derived:

A _2a: human A _2aThe Adenosine Receptors film, MD, Beltsville, Receptor Biology company, catalogue #RB-HA2a.In film dilution buffer liquid, be diluted to 17 μ g/100 μ l (referring to following).

Analysis buffer:

Film dilution buffer liquid: Dulbecco ' s phosphate buffered saline (PBS) (Gibco/BRL)+10mMMgCl ₂

Diluted chemical compound damping fluid: salt solution (the Gibco/BRL)+10mM MgCl of Dulbecco ' s phosphate buffered ₂(being supplemented with 1.6mg/ml methylcellulose gum and 16%DMSO).Fresh preparation every day.

Part:

A _2a: [3H]-SCH 58261, customization (custom) is synthetic, Amersham PharmaciaBiotech, Piscataway, NJ.The storing solution of preparation 1nM in film dilution buffer liquid.Final analysis concentration is 0.5nM.

A ₁：[3H]-DPCPX，Amersham?Pharmacia?Biotech、Piscataway，NJ。The storing solution of preparation 2nM in film dilution buffer liquid.Final analysis concentration is 1nM.

Non-specific binding:

A _2a: when measuring non-specific binding, and adding 100nM CGS 15923 (RBI, Natick, MA).The operation storing solution of preparation 400nM in the diluted chemical compound damping fluid.

A ₁: when measuring non-specific binding, add 100 μ M NECA (RBI, Natick, MA).The operation storing solution of preparation 400 μ M in the diluted chemical compound damping fluid.

Diluted chemical compound:

Preparation 1mM compound is dissolved in the storing solution of 100%DMSO.In the diluted chemical compound damping fluid, dilute.In the scope of 3 μ M to 30pM, measure 10 concentration.The operation storing solution of preparation 4X final concentration in the diluted chemical compound damping fluid.

Analytical procedure:

On 96 porose discs of deep hole, analyze.The bulk analysis volume is 200 μ l.Add 50 μ l diluted chemical compound damping fluids (all part combinations) or 50 μ l CGS, 15923 working solution (A _2aNon-specific binding) or 50 μ l NECA working solution (A ₁Non-specific binding) or the medicine working solution of 50 μ l.([3H]-SCH 58261 is used for A to add 50 μ l part storing solutions _2a, [3H]-DPCPX is used for A ₁).The diluted film that contains suitable acceptor that adds 100 μ l.Mix.Under room temperature, cultivated 90 minutes.Use the Brandel cell harvestor to be collected on the Packard GF/B filtering table.Add 45 μ l Microscint 20 (Packard), and use Packard Top Count trace scintillometer counting.Measure IC by the match of using repeatedly curve fitting procedure mensuration (Excel) to carry out displacement curve ₅₀Value.Use the Cheng-Prusoff equation to measure the Ki value.

Haloperidol-inductive catalepsy in the rat

Use body weight as the male Sprague-Dawley rat of 175-200g (Charles River, Calco, Italy).This animal was being tested preceding 90 minutes through vertical trellis, given dopamine-receptor antagonist-haloperidol (1mg/kg sc) brings out the catalepsy state by subcutaneous.For this test, rat placed on the wire screen of one 25 * 43 resin glass cage, this cage places on the table face with about 70 degree angles.Equal abduction of the four limbs of rat and elongation are placed (" frog posture ") on these lattice.Using this type of non-natural posture is necessary for the specificity of catalepsy test.Apart from (decline l latent period), measure 120 seconds at most when the mensuration sole is localized when the first time, a pawl was mobile fully.

In scoring preceding 1 and 4 hour the time, with the A to be assessed of selection _2AAdenosine antagonist gives animal with 0.03 to 3mg/kg dosage range per os.

In the experiment that separates, measure reference compound, L-DOPA (25,50 and 100mg/kg, catalepsy effect ip).

The 6-OHDA damage of rat median forebrain bundle

All the experiment in all use body weight 275-300g bull Sprague-Dawley rat (Charles River, Calco, Como, Italy).Rat is divided into four one group in every cage, freely takes food and water, place the light/dark circulation of temperature control and 12 hours.The day before yesterday that undergos surgery, make the rat fasting overnight, but can arbitrarily drink water.

According to people such as Ungerstedt (Brain ResearcH, 24 (1970), p.485-493, European Journalof Pharmacology, 5 (1968), p.107-110) illustrated method changes a little, carries out one-sided 6-hydroxydopamine (6-OHDA) infringement of median forebrain bundle.In brief, (400mg/kg, ip) (10mpk ip) handles, so that the suction of the terminal contratoxin of blocking-up norepinephrine energy with Desipramine (desipramine) with this Animal Anesthesia and in injection preceding 30 minutes of 6-OHDA with Chloral Hydrate.Then, this animal is placed on the three-dimensional positioning framework.Three-dimensional elements of a fix place (anterior fontanelle back-2.2 (AP) is raised and taken off to skin on the skull, anterior fontanelle side+1.5 (ML), endocranium front side 7.8 (DV), collection of illustrative plates (Pellegrino L.J. according to people such as Pellegrino, Pellegrino A.S. and Cushman A.J., AStereotaxic Atlas of the Rat Brain, 1979, New York:Plenum Press).Again in skull, the top boring of infringement position and the syringe needle that will be connected in a Hamilton injection tube are put into left MFB.Then 8 μ g 6-OHDA-HCl are dissolved in the 4 μ l salt solution (containing 0.05% xitix as antioxidant), and the use infusion pump was with 1 μ l/1 minute constant flow rate infusion.After 5 minutes syringe needle being extracted and this wound sewed up makes this animal repair for 2 weeks.

After damaging for two weeks, (50mg/kg, (25mg/kg ip) and by automatization tropometer measuring device selects (starting characteristics test) to counting based on all the offside upset number of times in 2 hours duration of test ip) to add Bian silk hydrazine to give L-DOPA to rat.Anyly show that the rat of at least 200 complete upset/2 hour all is not included in the research.

Make rat 3 days (Dopamine Receptors supersensitivity reaches the highest) reception test medicines after starting characteristics test through selecting.With new A _2AReceptor antagonist is with between 0.1 to 3mg/kg dosage range, and (4mpk ip) adds Bian silk hydrazine (4mpk, ip) different time points (that is: 1,6, the 12 hour) oral administration before the injection and assess its upset behavior in the L-DOPA of subthreshold dosage.

Use above-mentioned testing sequence, obtain following result from preferred and/or representative compounds of the present invention.

Binding analysis result for The compounds of this invention shows its A _2aThe Ki value is 0.4 to 10nM, and wherein the Ki value of preferred compound is between 0.3 to 5.0nM.For example the Ki of the compound of embodiment 12-31 is 0.3nM.

Selectivity is determined divided by the Ki to the A2a acceptor by using the Ki to the A1 acceptor.The selectivity scope of preferred compound of the present invention is about 100 to about 2000.

In the catalepsy activity test to rat, the decline that shows the preferred compound of oral 1mg/kg has the reduction of 40-75% latent period.

In 6-OHDA infringement test, the rat of preferred compound that per os gives 1mg/kg has 170-440 time upset in during 2 hours analyze.

In haloperidol-inductive catalepsy test, the combination of the formula I compound of subthreshold amount and the L-DOPA of subthreshold amount demonstrates and can significantly suppress catalepsy, and its expression has synergy.In 6-OHDA infringement test, the experimental animal of the combination of the formula I compound that is given and the L-DOPA of subthreshold amount confirms that significantly more offside upset is arranged.

For from compound medicinal compositions of the present invention, can use the pharmaceutically acceptable carrier of solid-state or liquid inertia.The preparation of solid-state form comprises powder, tablet, dispersible granules, capsule, cachet and suppository.Powder and tablet can comprise about 5 to about 70% active ingredient.Suitable solid-state carrier is known in the art, for example magnesiumcarbonate, Magnesium Stearate, talcum powder, sucrose, lactose.Tablet, powder, cachet and capsule can be as being suitable for the solid dosage that per os gives.

During preparation suppository, earlier with low melt wax, for example the mixture of glycerin fatty acid ester or theobroma oil melt, and by stirring active ingredient are dispersed in wherein.The homogeneous mixture that will melt is poured in the mold of suitable size again, makes it cooling and thereby curing.

The preparation of liquid form comprises solution, suspension and emulsion.For example, it can be non-water or the water-propylene glycol solution of using through enteral administration.

The preparation of liquid form also can comprise the solution that gives in the intranasal.

The aerosol preparations that is suitable for sucking comprises the solid of solution and powdered form, its can with pharmaceutically acceptable carrier, the combination of for example a kind of inertia pressurized gas.

The preparation that also comprises solid-state form, it can change into the preparation of per os or the non-liquid form that gives through intestines in the short period of time before using.This type of liquid form comprises solution, suspension and emulsion.

Compound of the present invention also can transmit through skin.The form of transdermal composition can be breast frost, lotion, aerosol and/or emulsion, and can be contained in the matrix of the field routine use that is used for this order ground or reservoir type in the skin patch.

Preferred described series of compounds per os gives.

Preferred described medicinal preparations thing is a unit dosage form.In such form, said preparation can be divided into again and contain an amount of active ingredient, for example reaches the unitary dose of the significant quantity of required purpose.

The amount of the active formula I compound in the unitary dose of preparation can more preferably change or adjustment in about 1mg to 300mg scope according to specific purposes from about 0.1mg to 1000mg.

The visual patient's of actual dose who uses needs change with the sanatory severity of institute.For the decision of the suitable dosage of particular case in newpapers and periodicals industry technical scope.Usually, treatment is the smaller dose from the dose,optimum that is lower than compound.After this, slightly increase dosage again till the best effect that reaches under this situation.For convenience's sake, every day total dose can optionally separate and Yu Yitian in divide and to give for several times.

The dosage of compound of the present invention and pharmacy acceptable salt thereof and frequency can be adjusted according to the judgement of clinicist after the factors such as severity of considering for example patient's age, disease and body weight and institute's desire treatment symptom.The dosage of the formula I compound that the typical case recommends is from 10mg to 2000mg/ sky, be preferably 10 to 1000mg/ days, give with two to four divided dose per os, to relax central nervous system disease, for example Parkinson's disease or other listed hereinbefore disease or illness.

The dosage of dopaminergic medicine and dosage can consider that the severity of patient's age, sex and situation and disease decides by the clinicist according to recommended doses and the dosage regimen inserted in the packing.When the combination of giving construction I compound and dopaminergic medicine, expect dosage when the effective dose of these compositions should be lower than each composition and gives with monotherapy.

Though the present invention is illustrated in conjunction with aforesaid particular, they are many to substitute, modify and change will be conspicuous to those skilled in the art.All these substitute, modify and change all within the spirit and scope of the present invention.

Claims

1. compound with following structural

Or its pharmacy acceptable salt, wherein

R ⁷Be H or alkyl;

R ⁸Be H, alkyl, alkyl C (O)-or alkyl-SO ₂-;

Z is R ⁹, R ¹⁰-aryl or R ⁹, R ¹⁰-heteroaryl;

Or the R on adjacent carboatomic ring atom ⁹Group and R ¹⁰Group forms-O-(CH jointly ₂) ₂-O-,-CH ₂-O-(CH ₂) ₂-O-,-O-(CH ₂) ₂-,-(CH ₂) ₃-O-,-O-(CH ₂) ₃-O-,-(CH ₂) ₃-or-CH ₂-CH=CH-wherein passes through R ⁹And R ¹⁰The formed ring of the ring carbon atom that substituting group is connected with them is by R ¹⁶Replace;

Or the R on adjacent carboatomic ring atom ⁹Group and R ¹⁰Group forms-(CH jointly ₂) ₂CH (OR ¹⁸)-,-CH ₂CH (OR ¹⁸) CH ₂-,-(CH ₂) ₃CH (OR ¹⁸)-,-(CH ₂) ₂CH (OR ¹⁸) CH ₂-,-(CH ₂) ₂C (O)-,-CH ₂C (O) CH ₂-,-(CH ₂) ₃C (O)-,-(CH ₂) ₂C (O) CH ₂-,-O (CH ₂) ₂CH (OR ¹⁸)-or-OCH ₂CH (OR ¹⁸) CH ₂-, wherein pass through R ⁹And R ¹⁰The formed ring of the ring carbon atom that substituting group is connected with them is chosen replacement wantonly by hydroxyalkyl or alkoxyalkyl on carbon atom;

Each R ¹¹Independently be selected from H and alkyl;

R ¹³For H, alkyl or-CF ₃

R ¹⁵Be 1 to 3 independently be selected from following substituting group: H, alkyl ,-OH, alkoxyl group, alkoxyalkyl and hydroxyalkyl; Or two R ¹⁵Both carbon of being connected of substituting group and they form jointly-C (=O)-group;

R ¹⁶Be H, alkyl, alkoxyalkyl, OH or hydroxyalkyl;

R ¹⁷Be H or alkyl;

R ¹⁸Be H or alkyl; And

2. the compound of claim 1, wherein R is R ⁶-phenyl, R ⁶-furyl, R ⁶-thienyl, R ⁶-pyridyl or R ⁶- azoles base.

3. the compound of claim 2, wherein R ⁶Be H, halogen or alkyl.

4. the compound of claim 1, wherein R ², R ³, R ⁴And R ⁵Be H.

5. the compound of claim 1, wherein Z is R ⁹, R ¹⁰-phenyl.

6. the compound of claim 5, wherein R ⁹Be hydroxyalkyl, alkoxyalkyl, (hydroxyl)-alkoxyalkyl, (hydroxyalkyl) alkoxyl group, R ¹⁵-cycloalkyl, cyano group alkyl, R ¹⁹-heteroaryl or (cycloalkyl) hydroxyalkyl and R ¹⁰Be 1 or 2 independently be selected from following substituting group: H, halogeno-group ,-C (O) R ¹³, alkoxyl group, hydroxyalkyl, hydroxy alkoxy base, alkoxyl group alkoxyl group, alkoxyalkyl and cyano group alkyl.

7. the compound of claim 1, wherein R is R ⁶-furyl or R ⁶-pyridyl; R ², R ³, R ⁴And R ⁵Respectively be H; And Z is R ⁹, R ¹⁰-phenyl; R ⁹Be hydroxyalkyl, (hydroxyalkyl) alkoxyl group, R ¹⁵-cycloalkyl, cyano group alkyl, R ¹⁹-heteroaryl or (cycloalkyl) hydroxyalkyl; And R ¹⁰Be the o-fluoro.

8. the compound of claim 1, described compound is selected from:

9. medicinal compositions, it is included in the compound of the claim 1 of the treatment significant quantity in the pharmaceutically acceptable carrier.

10. the compound of claim 1 is used for the treatment of in dysthymia disorders, Parkinson's disease, senile dementia, organic psychosis, attention deficit syndrome, extrapyramidal symptom, myodystony, restless legs syndrome or the sleep purposes in the medicine of main drive disease periodically in preparation.

11. a medicinal compositions, it is included in the compound of claim 1 of the treatment significant quantity in the pharmaceutically acceptable carrier and 1 to 3 kind, and other can be in order to treat the combination of parkinsonian medicine.

Unite and be used for the treatment of parkinsonian purposes 12. the compound of claim 1 and 1 to 3 kind are selected from the other medicines of L-DOPA, dopaminergic agonist, MAO-B inhibitor, DOPA decarboxylase inhibitor and COMT inhibitor.