CN101163482A

CN101163482A - N-alkyl-azacycloalkyl nmda/nr2b antagonists

Info

Publication number: CN101163482A
Application number: CNA2006800127260A
Authority: CN
Inventors: M·E·莱顿; K·J·罗齐纳克; M·J·凯利三世; P·E·桑德森
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 2005-04-19
Filing date: 2006-04-14
Publication date: 2008-04-16
Also published as: WO2006113471A2; CA2603876A1; EP1874318A2; AU2006236625A1; WO2006113471A3; JP2008536927A

Abstract

Compounds represented by Formula (I): and/or pharmaceutically acceptable salts, individual enantiomers and stereoisomers thereof, are effective as NMDA/NR2B antagonists useful for treating conditions such as pain, Parkinson's disease, Alzheimer's disease, epilepsy, depression, anxiety, ischemic brain injury including stroke.

Description

N-alkyl-azacycloalkyl nmda/NR2B antagonist

Invention field

The present invention relates to N-alkyl-azacycloalkyl chemical compound.Particularly, the present invention relates to N-alkyl-azacycloalkyl chemical compound as the NMDA/NR2B antagonist that can be used for treating neurological's patient's condition such as pain, parkinson, Alzheimer, epilepsy, depression, anxiety, the ischemic brain injury that comprises apoplexy and other patient's condition.

Background of invention

Ion such as glutamate play crucial effect in relating to chronic pain and the neurovirulent process relevant with pain, it mainly works by N-methyl-D-aspartate (" NMDA ") receptor.Therefore, by using ion channel antagonist, particularly nmda antagonist that this effect is suppressed to help parkinson and treatment of pain and control.

Nmda receptor is the assorted poly-assembly of multiple subunit, cloned wherein two main subunit families of called after NR1 and NR2.Be not limited to theory, it has been generally acknowledged that multiple functional nmda receptor is just by expressing the glycine and the NR1 of glutamate recognition site and being combined to form of NR2 subunit respectively in the mammalian central nervous system (" CNS ").NR2 subunit family is divided into four independent subunit types again: NR2A, NR2B, NR2C and NR2D.T.Ishii waits the people, J.Biol.Chem., 268: 2836-2843 (1993) and D.J.Laurie etc., Mol.Brain Res., 51: 23-32 (1997) has described the multiple combination that obtains and how to have produced physiology and pharmacological characteristics such as ion channel gate characteristic, magnesium sensitivity, pharmacological characteristics and the different multiple nmda receptor of anatomy distribution.

For example, though find that in brain NR1 is arranged, the distribution of NR2 subunit is different.Especially, think that the distribution form of NR2B reduces the probability of side effect when treating parkinson or pain.Therefore, expectation provides the novel nmda antagonist of targeting in the NR2B receptor.

Summary of the invention

The present invention relates to the chemical compound represented by formula I:

(wherein W, X, A, B, R ¹, R ², R ³And R ⁴As described herein) or its officinal salt.The present invention further provides use The compounds of this invention and compositions and treated and prevent neurological's patient's condition, comprised pain, parkinson, Alzheimer, epilepsy, depression, anxiety, comprise the ischemic brain injury of apoplexy and the method for other patient's condition.

Detailed Description Of The Invention

The compounds of this invention is represented by formula I:

And officinal salt, one enantiomer and stereoisomer, wherein:

W is aryl or heteroaryl, and described aryl or heteroaryl are optional to be independently selected from following substituent group replacement by 1-5: halogen, C _3-6Cycloalkyl, cyano group, C _1-4Alkoxyl and C _1-6Alkyl, wherein said alkoxyl is optional to be replaced by one or more halogens, and described alkyl is optional is selected from following substituent group and replaces by one or more: hydrogen, halogen and hydroxyl;

X does not exist or is selected from C _1-4Alkoxyl and C _1-3Alkyl, optional by one or more be selected from hydrogen, halogen, hydroxyl, (=O) and the substituent group of cyano group replace;

A is a key or C _1-3Alkyl optional be selected from following substituent group and replace by one or more: hydrogen, halogen, hydroxyl and C _1-3Alkyl, wherein said alkyl is optional by one or more halogen, hydroxyl, C of being selected from _1-4The substituent group of alkoxyl and cyano group replaces;

B is C ₁Alkyl optional be selected from following substituent group and replace by one or more: hydrogen, halogen, hydroxyl and C _1-3Alkyl, wherein said alkyl is optional to be selected from following substituent group and to replace by one or more: halogen, hydroxyl, C _1-4Alkoxyl and cyano group form a ring that comprises A and B simultaneously, and wherein each carbon atom among the A and each carbon atom among the B can be chosen wantonly and participate in the described ring of bridge joint;

R ¹And R ²Respectively be independently selected from hydrogen and C _1-3Alkyl; And

R ³And R ⁴Respectively be independently selected from: hydrogen, hydroxyl, cyano group and C _1-3Alkyl, wherein said alkyl is optional to be selected from following substituent group and to replace by one or more: halogen, hydroxyl, C _1-4Alkoxyl and cyano group,

R wherein ³And R ⁴Connected ring is chosen the cycloalkyl that participates in forming bridge joint wantonly together.

One embodiment of the invention provide the chemical compound shown in the chemical formula (I), and/or its officinal salt, one enantiomer and stereoisomer, wherein:

W is an aryl, chooses wantonly by 1-5 and is independently selected from following substituent group replacement: halogen, C _3-6Cycloalkyl, C _1-4Alkoxyl and C _1-6Alkyl, wherein said alkyl is optional to be selected from following substituent group and to replace by one or more: hydrogen, halogen and hydroxyl;

X is selected from C _1-4Alkoxyl and C _1-3Alkyl optional be selected from following substituent group and replace by one or more: hydrogen, halogen, hydroxyl and (=O);

R ¹And R ²Respectively be independently selected from hydrogen and C _1-3Alkyl;

R ³And R ⁴Each is hydrogen independently;

A is a key or C _1-3Alkyl optional be selected from following substituent group and replace by one or more: hydrogen and halogen; And

B is C ₁Alkyl optional be selected from following substituent group and replace by one or more: hydrogen and halogen, form the ring that comprises A and B simultaneously, and wherein each carbon atom among the A and the carbon atom among the B can be chosen wantonly and participate in the described ring of bridge joint.

Another embodiment of the present invention comprises the chemical compound that Ia represents:

And/or its officinal salt, one enantiomer and stereoisomer, wherein:

X is C _1-3Alkyl optional be selected from following substituent group and replace by one or more: hydrogen, halogen, hydroxyl and (=O);

A is a key or C _1-3Alkyl optional be selected from following substituent group and replace by one or more: hydrogen and halogen.

Another embodiment of the present invention comprises the chemical compound that formula Ib represents:

And/or its officinal salt, one enantiomer and stereoisomer, wherein:

X is C _1-3Alkyl optional be selected from following substituent group and replace by one or more: hydrogen, halogen, hydroxyl and (=O); And

B is C ₁Alkyl optional be selected from following substituent group and replace by one or more: hydrogen and halogen.

Another embodiment of the present invention comprises the chemical compound that Ic represents:

And/or its officinal salt, one enantiomer and stereoisomer, wherein:

W is an aryl, chooses wantonly by 1-5 and is independently selected from following substituent group replacement: halogen, C _3-6Cycloalkyl, C _1-4Alkoxyl and C _1-6Alkyl, wherein said alkyl is optional to be selected from following substituent group and to replace by one or more: hydrogen, halogen and hydroxyl; And

X is C _1-3Alkyl optional be selected from following substituent group and replace by one or more: hydrogen, halogen, hydroxyl and (=O).

Another embodiment of the present invention comprises the chemical compound that Id represents:

And/or its officinal salt, one enantiomer and stereoisomer, wherein:

X is C _1-3Alkyl optional be selected from following substituent group and replace by one or more: hydrogen and halogen;

While R ³And R ⁴Coupled ring can participate in forming the cycloalkyl of bridge joint together.

Another embodiment of the present invention comprises the chemical compound that formula Ie represents:

And/or its officinal salt, one enantiomer and stereoisomer, wherein:

B is C ₁Alkyl optional be selected from following substituent group and replace by one or more: hydrogen and halogen, form the ring that comprises A and B simultaneously, and wherein each carbon atom can be chosen wantonly and participate in the described ring of bridge joint among each carbon atom among the A and the B.

As used in this article, " alkyl " and the group that contains prefix " alkane (alk) ", for example alkane, alkanoyl, thiazolinyl and alkynyl, the carbochain of expression straight or branched or its combination.The example of suitable alkyl comprise methyl, ethyl, propyl group, isopropyl, butyl, the second month in a season-and tert-butyl, amyl group, hexyl and heptyl.Therefore, C _1-6Alkyl is defined as the group that has 1,2,3,4,5 or 6 carbon in straight or branched is arranged, such C _1-6Alkyl comprises methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, amyl group and hexyl.Similarly, C _1-4Alkyl is defined as the group that has 1,2,3 or 4 carbon in straight or branched is arranged, such C _1-4Alkyl specifically comprises methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group and the tert-butyl group.Similarly, as C ₀In the alkyl, when alkyl is end group, C ₀Be hydrogen atom, and when alkyl is bridged group, C ₀It is direct key." thiazolinyl ", " alkynyl " and similar term comprise the carbochain that contains at least one unsaturated C-C key.

As used in this article, term " alkoxyl " separately or in combination, comprises alkyl ether groups, term ' alkyl ' as hereinbefore defined wherein, and ' ether ' two alkyl of expression and an oxygen atom between the two.The example of suitable alkoxyl comprises methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, methoxyl group methane (also being expressed as ' dimethyl ether ') and Ethyl Methyl Ether (also being expressed as ' ethyl-methyl ether ').

As used in this article, term " cycloalkyl " expression does not contain heteroatomic carbocyclic ring, and comprise single-, two-and the carbocyclic ring of three ring fillings, and fused rings system.This fused rings system comprises that a partially or completely undersaturated ring such as phenyl ring are to form fused rings system such as benzo-fused carbocyclic ring.Cycloalkyl comprises the loop systems of condensed loop systems of this class such as spiro-condensed.The example of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, decahydronaphthalene, amantadine, indanyl, indenyl, fluorenyl and 1,2,3,4-naphthane.

As used in this article, " aryl " is illustrated in each ring and is at most 7 yuan any stable monocycle or bicyclo-carbocyclic ring, and wherein at least one ring is an aromatic ring.The example of such aryl comprises phenyl, naphthyl and tolyl.

As used in this article, " cycloalkyl of bridge joint " represents two or more cycloalkyl, Heterocyclylalkyl or its combination that connects by adjacent or non-adjacent atom.The example of the cycloalkyl of this bridge joint comprise 8-azabicyclo [3.2.1] oct-3-yl and 3-azabicyclo [3.1.0] oneself-the 6-base.

Except as otherwise noted, stable 5-～7-unit the monocycle of term as used herein " heteroaryl " expression-or stable 9-～fused bicyclic heterocycle system of 10-unit, it comprises aromatic ring, its any ring can be saturated, piperidyl for example, fractional saturation or undersaturated, pyridine radicals for example, and form by carbon atom and 1～4 hetero atom that is selected from N, O and S, wherein nitrogen and sulfur heteroatom can be chosen wantonly oxidized, and nitrogen heteroatom can be chosen wantonly by quaternized, comprises the condensed any bicyclic groups of wherein any heterocycle defined above and phenyl ring.Heterocycle can connect on any hetero atom that produces rock-steady structure or carbon atom.The example of such heteroaryl includes but not limited to pyridine, pyrimidine, piperazine, thiophene,  azoles, thiazole, triazole, thiadiazoles,  diazole, pyrroles, 1,2,4- diazole, 1,34- diazole, 1,2,4-thiadiazoles, 1,3,4-thiadiazoles and 1,2, the 4-triazole.

Except as otherwise noted, term " assorted (hetero) " comprises one or more O, S or N atom.For example, Heterocyclylalkyl and heteroaryl are included in and contain the ring system that one or more O, S or N atom comprise the mixture of these atoms in the ring.Hetero atom substituted ring carbon atom.Therefore, for example, heterocycle C ₅Alkyl is to contain 4～do not have five of carbon atom-unit's ring.The example of Heterocyclylalkyl comprises the fixed base of a word used for translation, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, tetrahydrofuran base, imidazolinyl, pyrrolidin-2-one, piperidines-2-ketone and thio-morpholinyl.

In the described in the whole text structure of the application, the hydrogen atom on the unsubstituted nitrogen-atoms may be significantly be expressed out or for implicit.

Identical agreement also is applicable to all other general structure and the individual structure of expression.Certainly, nitrogen-atoms also can be replaced by dehydrogenation outer atom and/or part, and is described as other place among the application.

As understood by a person skilled in the art, term halo used herein or halogen comprise chloro, fluoro, bromo and iodo.

Term " the optional replacement " comprise replacement with unsubstituted.Therefore, for example optional aryl that replaces can be represented pentafluorophenyl group or phenyl ring.Further, the optional multiple partial that replaces, for example alkaryl is represented alkyl and aryl is optional is substituted.If optional being substituted is only arranged in the multiple partial, then will represent especially as " alkaryl, aryl is optional to be replaced by halogen or hydroxyl ".

Described herein chemical compound can comprise one or more asymmetric centers, therefore may produce diastereomer and optical isomer.The present invention includes all these possible diastereomers with and racemic mixture, the enantiomer after their the pure basically fractionation, all possible geometric isomer and officinal salt thereof.Formula I (comprising formula Ia, Ib, Ic, Id and Ie) is expressed as does not have definite spatial chemistry on some position.The present invention includes all stereoisomers and the officinal salt thereof of formula I.In addition, the mixture and the isolating specific stereoisomer that also comprise stereoisomer.In the synthetic method process that is used for preparing this chemical compound, or in using racemization well known by persons skilled in the art or epimereation process, the product of this method can be the mixture of stereoisomer.

As known in the art can be by methodology disclosed herein suitably being improved independently synthetic and its chromatographic isolation that realizes these diastereomers.If desired, can carry out x-ray crystal diffraction method and determine its absolute stereo chemistry by carry out deutero-crystallized product or crystallization of intermediate with the reagent that comprises asymmetric center with known absolute configuration.

If expectation can separate the racemic mixture of chemical compound to tell one enantiomer.Separation can be undertaken by method well known in the art, the chemical compound that is coupled to enantiomer-pure as the racemic mixture with chemical compound to be to form the mixture of diastereomer, separates one diastereomer by standard method such as fractional crystallization or chromatography subsequently.Coupling reaction is generally the acid or the alkali that use enantiomer-pure and forms salt.Can non-mapping derivant be converted into pure enantiomer by the chirality residue cracking that will add then.Can also use chiral stationary phase directly by the racemic mixture of chromatography separating compound, it is a method well known in the art.

Perhaps, can use the reagent of optically pure starting material or configuration known by the synthetic any enantiomer that obtains chemical compound of stereo selectivity by method well known in the art.

As used in this article, the salt that is equipped with from pharmaceutically useful avirulence alkali or processed with acid of " officinal salt " expression.When chemical compound of the present invention when being tart, its corresponding salt can prepare easily from pharmaceutically acceptable avirulence alkali, comprises inorganic base and organic base.The salt that is obtained by this inorganic base comprises the salt of aluminum, ammonium, calcium, copper (ic and ous), ferrum, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc etc.The salt that is obtained by pharmaceutically acceptable avirulence organic base comprises primary, the amine of the second month in a season and tertiary ammonium salt and cyclammonium salt and replacement such as natural generation and salt synthetic replacement amine.Can comprise ion exchange resin from salifiable other the pharmaceutically acceptable organic avirulence alkali of its shape, for example arginine, betanin, caffeine, choline, N, N '-Dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dianol, ethanolamine, aminophylline, N-ethylmorpholine, N-ethylpiperidine, glucamine, glycosamine, histidine, hydrabamine, 2-aminopropane., lysine, cardiografin, morpholine, piperazine, piperidines, polyamines resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropyl amine (TPA) and tromethane.

When chemical compound of the present invention was alkalescence, its corresponding salt can prepare easily from pharmaceutically acceptable avirulence acid, comprises mineral acid and organic acid.This class acid comprises, for example acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethyl sulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethylsulfonic acid., lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, glactaric acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulphuric acid, tartaric acid, p-methyl benzenesulfonic acid etc.The example of officinal salt includes, but not limited to the inorganic acid salt or the acylate of alkaline residue such as amine; The alkali salt of acidic residues such as carboxylic acid or organic salt or the like.Officinal salt comprises nontoxic salt or the quaternary ammonium salt of parent compound from the routine of nontoxic mineral acid or organic acid formation.For example, the nontoxic salt of this routine comprises those salt derived from mineral acid example hydrochloric acid, hydrobromic acid, sulphuric acid, sulfamic acid, phosphoric acid, nitric acid etc.; Salt from preparations such as organic acid such as acetic acid, propanoic acid, succinic acid, glycolic, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-anilinesulfonic acid., 2-acetoxy-benzoic acid, fumaric acid, p-methyl benzenesulfonic acid, methanesulfonic acid, ethionic acid, oxalic acid, ethylenehydrinsulfonic acids.

Zhi Liao experimenter or patient are the mammal of wherein expecting antagonism NMDA/NR2B receptor active in the method for the invention, as the mankind, and sex.Experimenter who treats in the method for the present invention or patient also can be animals, as dog, cat, horse, pig or cattle.Term " treatment effective dose " is meant tissue, system, animal or human's biology or the amount of the motif compound that medical science is replied determined by research worker, veterinary, practitioner or other clinician.As used in this article, term " treatment " is meant treatment and stops or prophylactically treat the described patient's condition, the particularly patient's condition in the patient who easily suffers from this disease or disease.

Term used herein " compositions " is meant the product that comprises the special component that contains specified quantitative, and the spawn that directly or indirectly obtains from the combination of the concrete composition of specified quantitative.This term that relates to pharmaceutical composition comprises the product that contains active component and constitute the inert composition of carrier, and from combination, complexation or the set of any two or more described compositions, or from the disassociation of one or more described compositions, or from the reaction of other type of one or more described compositions or the spawn that interacts and directly or indirectly obtain.Therefore, pharmaceutical composition of the present invention comprise by with chemical compound of the present invention and pharmaceutically suitable carrier mixed any compositions." pharmaceutically acceptable " is meant must have the compatibility with other composition of preparation and not to the deleterious carrier of its receiver, diluent or excipient.

Term " giving of chemical compound " and/or " giving chemical compound " are construed as expression provides chemical compound of the present invention or The compounds of this invention to the individuality of needs treatment prodrug.

Pharmaceutical composition of the present invention comprises formula I chemical compound (and/or its officinal salt), pharmaceutically suitable carrier and optional other therapeutic component or the auxiliary agent as active component.Compositions of the present invention comprises the compositions that is suitable for oral, rectum, part and non-intestinal (comprising subcutaneous, intramuscular and intravenous) administration, though optimal approach depends on specific main body, gives the character and the order of severity of the patient's condition of active component for it in any given situation.Pharmaceutical composition can exist with unit dosage form easily, and can be by known any method preparation in the pharmaceutics field.

The present invention relates to the method that is used at the medicine of humans and animals antagonism NMDA/NR2B receptor active of producing in addition, and it comprises chemical compound of the present invention and pharmaceutical carriers or diluent combination.

In practice, can formula I compound or pharmaceutically acceptable salt thereof of the present invention be combined as mixture closely as active component and pharmaceutical carriers according to the pharmacy compounding technique of routine.Carrier can be depending on the dosage form that expectation is used for administration such as oral administration or non-intestinal (comprising intravenous) administration and takes various ways.Therefore, pharmaceutical composition of the present invention can be used as and is suitable for oral discontinuous unit existence, as capsule, cachet or the tablet of each self-contained scheduled volume active component.In addition, compositions can be used as powder, granule, solution, the suspension in aqueous liquid, non-aqueous liquid, emulsion oil-in-water or the existence of water-in-oil type liquid emulsion.Except above-mentioned common dosage form, formula I chemical compound and/or its officinal salt also can be by sustained release device and/or delivery apparatus administrations.Can prepare compositions by any method of pharmaceutics.Usually, this method comprises and makes active component and constitute the carrier-bound step that one or more must composition.Usually, by equably and closely active component and liquid-carrier or pulverizing solid carrier or both being mixed with compositions.Can easily product be configured as required outward appearance then.

Therefore, pharmaceutical composition of the present invention can comprise pharmaceutically suitable carrier and formula I chemical compound or officinal salt.Formula 1 compound or pharmaceutically acceptable salt thereof and one or more other therapeutical active compound combinations can also be included in the pharmaceutical composition.

The pharmaceutical carriers of using can be for example solid, liquid or gas.The example of solid carrier comprises lactose, Gypsum Fibrosum powder, sucrose, Talcum, gelatin, agar, pectin, arabic gum, magnesium stearate and stearic acid.The example of liquid-carrier is syrup, Oleum Arachidis hypogaeae semen, olive oil and water.The example of carrier gas comprises carbon dioxide and nitrogen.

When preparation is used for the compositions of peroral dosage form, can use any pharmaceutical media easily.For example, can make water, glycol, oils, alcohol, flavoring agent, antiseptic, coloring agent etc. form oral liquid such as suspension, elixir and solution; Can use carrier such as starch, sugar, microcrystalline Cellulose, diluent, granulating agent, lubricant, binding agent, disintegrating agent etc. to form oral solid formulation, as powder, capsule and tablet.Because administration easily, tablet and capsule are preferred peroral dosage form, thereby use the solid pharmaceutical carriers.Optional, can carry out coating to tablet by the moisture or non-water technology of standard.

The tablet that can comprise the present composition by compression or molded and shaped preparation, optional one or more auxiliary elements or the auxiliary agent of using.Can be by in the machine that is fit to, compressing, optionally prepare compressed tablet with binding agent, lubricant, inert diluent, surfactant or the free-flowing form of dispersant such as the active component of powder or particle form.The mixture of powder compound that can be by using the inert liquid diluent moistening in the machine that is fit to is molded and shaped to prepare molded tablet.Preferred every active component that comprises about 0.5mg～about 5g, preferably each cachet or capsule comprise the active component of about 0.5mg～about 5g.

Pharmaceutical composition of the present invention comprises formula I chemical compound (perhaps its officinal salt), the pharmaceutically suitable carrier as active component and chooses any one kind of them or multiple other therapeutic agent or auxiliary agent.Compositions of the present invention comprises the compositions that is suitable for oral, rectum, part and non-intestinal (comprising subcutaneous, intramuscular and intravenous) administration, though optimal route of administration depends on specific main body, gives the character and the order of severity of the patient's condition of active component to it in any given situation.Pharmaceutical composition can exist with unit dosage form easily, and can be by known any method preparation in the pharmaceutics field.

Can be solution or the suspension of reactive compound in water with the preparation of pharmaceutical compositions of the present invention that is suitable for parenterai administration.Can comprise suitable surfactant, for example hydroxypropyl cellulose.Can also in glycerol, liquid macrogol and the mixture in oils thereof, prepare dispersion.In addition, can comprise that antiseptic is to prevent disadvantageous growth of microorganism.

The pharmaceutical composition of the present invention that is suitable for injecting application comprises aseptic aqueous solution or dispersion.In addition, said composition can be and is used for preparing this aseptic injection solution or the sterilized powder form of dispersion temporarily.In all situations, final injectable dosage formulations must be aseptic, and must be effectively for ease of the fluid of injection.Pharmaceutical composition must be stable under production and condition of storage; Therefore, preferably it is saved as the pollution of avoiding microorganism such as antibacterial and fungus.Carrier can be solvent or disperse medium, and it comprises for example water, ethanol, polyhydric alcohol (as glycerol, propylene glycol and liquid macrogol), vegetable oil and suitable mixture thereof.

Pharmaceutical composition of the present invention can be the dosage form that is fit to topical application, for example, and aerosol, cream, ointment, washing liquid, pulvis subtilis etc.In addition, compositions can be the dosage form that is applicable in the transdermal device.Can use formula I compound or pharmaceutically acceptable salt thereof of the present invention to prepare these preparations by conventional processing method.For example, the preparation of cream or the ointment cream or the ointment that have required denseness with generation by compound with water wetted material and water and about 5 weight %～about 10 weight %.

Pharmaceutical composition of the present invention can be wherein, and carrier is the dosage form of solid suitable rectally.Preferred mixture forms the suppository of dosage unit.The carrier that is fit to comprises cocoa butter and other material that is generally used in this area.Can by at first compositions is mixed with remollescent or melting carrier, cooling and molding and form suppository easily in mould subsequently.

Except above-mentioned carrier components, above-mentioned pharmaceutical formulations can suitably comprise the carrier components that one or more are other, as diluent, buffer, flavoring agent, binding agent, surfactant, thickening agent, lubricant, antiseptic (comprising antioxidant) etc.In addition, can comprise other auxiliary agent so that preparation and intended recipient's blood is isoosmotic.Can with the preparation of compositions that comprises the described chemical compound of formula I and/or its officinal salt powder or liquid concentrate form also.

Can be by the application of methodology explanation The compounds of this invention as known in the art as NMDA/NR2B receptor active antagonist.Bonded inhibition of following mensuration and nmda receptor and calcium pass through the effusive functional antagonism of NMDA path:

Based on the functional trial of cell to measure the IC of NR2B antagonist ₅₀

Pass through the receptor-mediated Ca of NR1a/NR2B by following calcium current component analysis process evaluation ²⁺Flow into the ability that the selected compounds of measuring suppresses the NR1a/NR2B nmda receptor:

On the 96-orifice plate, every hole is 3 * 10 with L (tk-) the cell bed board of NR1a/NR2B receptor transfection ⁴Individual cell was also grown one to two day in conventional growth medium (having Sodium Pyruvate, 4500mg glucose, pen/strep, glutamine, the Dulbeccos MEM of 10%FCS and 0.5mg/mL Geneticin).Induced the NR1a/NR2B-in these cells to express in 16-24 hour by in the presence of 500 μ M ketamines, adding the 4-20nM dexamethasone.The solution of preparation NR2B antagonist also continuously with the DMSO dilution, obtains 10 kinds of solution that concentration differs 3 times in DMSO.By being gone into to test buffer, 250 times of dilutions of described DMSO solution (do not contain Mg ²⁺Hanks balanced salt solution (HBSS) (Gibco#14175-079), contain 20mM HEPES, 2mM CaCl ₂, 0.1%BSA and 250 μ M probenecid (Sigma#P-8761)) in preparation 96 hole medicine plates.After inducing, with cell test buffer washed twice (Labsystem cell washer, dilute 3 times, obtain 100 μ L) and loaded one hour with 4 μ M calcium fluorescence indicator fluo-3AM (molecular probe #P-1241) in the test buffer that comprises Pluronic F-127 (molecular probe #P-3000) and 10 μ M ketamines at 37 ℃.Then cell is washed eight times with the test buffer, in each hole, leave 100 μ L buffer.In FLIPR (Fluorometric Imaging Plate Reader, Molecular Devices), use 488nm excitation wavelength and 530nm emission wavelength to measure fluorescence intensity immediately.After opening entry fluorescence intensity five seconds, agonist solution (glutamate, Glu/the glycine of 40 μ M that adds 50 μ L, ultimate density is 10 μ M), after one minute, when fluorescence signal is stablized, add the NR2B antagonist of 50 μ L and from the contrast solution of medicine plate and write down fluorescence intensity again 30 minutes.By being fitted among the following equation #1, terminal point fluorescent value nonlinear least squareization measures IC ₅₀Value.

Equation #1:

Wherein, Ymin is the average terminal point fluorescence that comprises in the control wells of 1 μ M AMD-2, and Ymax is the average terminal point fluorescence in the hole that comprises 0.1%DMSO in the test buffer.

Measure K ₁The combination test of NR2B antagonist

At room temperature comprising in 96 hole microtitration plates in the 20mM Hepes buffer (pH7.4) of 150mM NaCl and carrying out radioligand in conjunction with test, final test volume is 1.0mL.The solution of preparation NR2B antagonist and become series ground with the DMSO dilution in DMSO obtains 10 parts of solution that concentration separately differs 3 times 20 μ L.Use AMD-1 (ultimate densities of 10 μ M) to estimate non-specific binding (NSB) and also measure total combination (TB) by adding DMSO (2% ultimate density).To microtitration plate add the AMD-2 (ultimate density of 1nM) of film expression NR1a/NR2B receptor (ultimate density of 40pM) and tritiate in porose.After at room temperature cultivating 3 hours, (PEI 0.05 (pre-preg among polyaziridine (poiyethyieninine) the Sigma P-3143) filters and washs 10 times with the cold 20mM Hepes buffer that is 1mL at every turn by Packard GF/B filter with sample.After with the filter plate vacuum drying, add the Packard Microscint-20 of 40 μ L and in Packard TopCount, measure bonded radioactivity.By binding radioactivity (CPM combination) nonlinear least squareization is fitted to following equation #2 and measures apparent dissociation constant (K ₁), the maximum percent (%I that suppresses _Max), the minimum percent (%I that suppresses _Min) and slope (nH).

Equation #2:

Wherein, K _DBe the radioligand measured by the hot saturation experiments apparent dissociation constant to receptor, SB be the specificity binding radioactivity from the difference mensuration of TB and NSB control wells.

Can realize synthesizing of AMD-1 and AMD-2 according to following reaction scheme:

The precursor E that can synthesize the AMD-1 that is used for the synthesizing radioactive labelling according to following method:

Reaction 1

According to the method for reaction 1, at room temperature with the methanol solution of hydrogen chloride bubbling by cinnamonitrile A.Decompression is removed volatile matter and the residue that obtains is ground and filters with ether, obtains intermediate imidoether B.At ambient temperature imidoether B is dissolved in the methanol, uses amine D (available from Acros Chemicals) to handle at ambient temperature and under argon, stir.Decompression is removed volatile matter and residue is ground with preparation HPLC purification or with ether, obtains amidine E.

Synthesize tritiate AMD-2 according to following method:

Reaction 2

Following method according to explanation in the reaction 2 prepares tritiate AMD-2: (2mg 0.008mmol) is dissolved in dimethyl formamide (0.6mL) and the potassium carbonate (1.2mg) 1 hour with precursor E.At room temperature add the tritiate iodomethane (50mCi, 0.0006mmol is in 1mL toluene, available from American Radiolabeled Chemicals) of high specific acitivity, and stirred 2 hours.Using Whatman PTFE 0.45 μ m not have the syringe defecator reactant mixture filters to remove any insoluble substance potassium carbonate, with dehydrated alcohol (2mL, available from Pharmco) washing, and at room temperature use rotary evaporator that the filtrate that merges is concentrated into drying; So also removed any unreacted tritiate iodomethane.Residue passes through the HPLC chromatography at Phenomenx Luna C8 semi-preparative column (Luna 5micro C8 (2), 250 * 10.0mm) go up purification, use the gradient system of 20/80 the acetonitrile/water that contains 0.1% trifluoroacetic acid～contain 100% acetonitrile of 0.1% trifluoroacetic acid to carry out eluting in 20 minutes.The total activity of product is 8mCi.(Waters Sep-Pak  PLUS C18 post, available from Waters Corporation, Milford Massachusetts) goes up also water eluting, is further purified with the dehydrated alcohol eluting subsequently by being adsorbed on post.Before submission is used for final analysis, product is diluted with dehydrated alcohol (10mL).

Can be according to people such as C.F.Claiborne (Bioorganic﹠amp; Med.Chem.Letters 13, and the described conventional method of 697-700 (2003) synthesizes AMD-1.

Be prepared as follows unlabelled AMD-2:

Reaction 3

According to reaction 3, at room temperature with the methanol solution of hydrogen chloride bubbling by cinnamonitrile A.Decompression is removed volatile matter and the residue that obtains is ground and filters with ether, obtains intermediate imidoether B.At ambient temperature imidoether B is dissolved in the methanol, handles with amine F at ambient temperature and under argon, stir.Decompression is removed volatile matter and residue is ground with preparation HPLC purification or with ether, obtains amidine G.

The compounds of this invention is at functional trial with in conjunction with the IC that shows respectively in testing less than 50 μ M ₅₀And K ₁Value.At functional trial with in, respectively less than the IC of 5 μ M in conjunction with test ₅₀And K ₁Value is favourable.At functional trial and in conjunction with test respectively less than the IC of 1 μ M ₅₀And K ₁Value is more favourable.At functional trial and in conjunction with test respectively less than the IC of 0.1 μ M ₅₀And K ₁Value is more favourable.

The compounds of this invention is a NMDA NR2B receptor antagonist body, thereby can be used for treating, prevent, control, improve or alleviate risk by receptor-mediated disease of NR2B and disease.This disease and disease include but not limited to that neuropathic pain is (as postherpetic neuralgia, nerve injury, " pain (dynias) " is as vulvodynia, phantom pain, the root avulsion, the diabetic neuropathy of pain, the compressibility mononeuropathy, ischemia neuropathy, the traumatic mononeuropathy of pain or the polyneuropathy of pain), central pain syndrome (may be caused by almost any focus of neural any level) and postoperative pain syndrome are (as postmastectomy syndrome, the syndrome of thoracotomy postoperative, stump pain)), bone and arthralgia (osteoarthritis, rheumatoid arthritis, ankylosing spondylitis), repetitious kinesalgia, carpal tunnel syndrome, toothache, cancer pain, muscular fasciae pain (muscle injury, fibromyalgia), intra-operative pain be (general surgery, gynecological), chronic pain, the inflammatory pain in dysmenorrhea and the pain relevant with angor and multiple source is (as osteoarthritis, rheumatoid arthritis, rheumatism, tenosynovitis and gout), headache, migraine and cluster headache, depressed, anxiety, schizophrenia, apoplexy, traumatic brain injury, Alzheimer, cerebral ischemia, spinal cord injury, cerebrovascular, Meniere, dizzy, amyotrophic lateral sclerosis, the Heng Shi chorea, sensorineural hearing loss, tinnitus, degeneration of macula, glaucoma, by epilepsy or neurological's damage of poisoning or causing by the glucose and/or the oxygen damage of brain by neurotoxin, by looking the vision loss that the road neurodegeneration causes, restless legs syndrome, multiple system atrophy, the non-vascular headache, constitutional hyperpathia, Secondary cases hyperpathia, the constitutional allodynia, Secondary cases allodynia or other pain that causes by the maincenter sensitization.

Formula I chemical compound can be used for the treatment or the prevention dyskinesia, as parkinson, the dyskinesia (comprising the side effect that the normal dose levodopa occurs together), tardive dyskinesia, drug-induced parkinson, parkinson after the encephalitis (family name) syndrome, progressive supranuclear plasy, multiple system atrophy, corticobasal degeneration, parkinson-ALS chronic brain syndrome, the ganglion basal calcification, motion can not, motion can not-stiff syndrome, bradykinesia, dystonia, the parkinson disease that Drug therapy is brought out, coprolalia syndrome, the Huntingon disease, tremble, chorea, myoclonus, tic disorders and dystonia.

As used herein, term " movement disorder " comprise motion can not with motion can not-parkinson disease that stiff syndrome, the dyskinesia and Drug therapy are brought out (acutely cathisophobiaing of bringing out of acute dystonia, the psychosis that parkinson's syndrome, neuroleptic malignant syndrome, the psychosis that brings out as psychosis brings out, tardive dyskinesia that psychosis brings out and Drug therapy bring out position tremble).The example of " motion can not-stiff syndrome " comprises parkinson, drug-induced parkinson, postencephalitic parkinsonism, progressive supranuclear plasy, multiple system atrophy, corticobasal degeneration, parkinson-ALS chronic brain syndrome and ganglion basal calcification.The example of " dyskinesia " comprises trembling and (comprises rest tremor, postural tremor and intentional tremor), chorea is (as Sydenham's chorea, the Heng Yandunshi chorea, optimum Huntington's chorea, Neuroacanthocytosis, symptomatic chorea, drug-induced chorea and Hemiballism), myoclonus (comprising general myoclonus and focal myoclonus), twitch and (comprise the simplicity tic, complexity is twitched and symptomatic tic) and dystonia (comprise general dystonia such as spy's property sent out dystonia, drug-induced dystonia, symptomatic dystonia and ictal dystonia, and focal dystonia such as blepharospasm, mouth lower jaw flesh obstacle, dysphonia spastica, spasmodic torticollis, the axle dystonia, dystonia writers spasm and hemiplegia dystonia).

In addition, formula I chemical compound can be used for therapeutant abuse property disease, comprises the tolerance and/or the dependency of the opium of pain being treated by reducing, and/or by treating for example withdrawal syndrome of ethanol, opioid, heroin and ***e.As used herein, term " drug dependence disease " comprises that drug dependence or abuse are with or without physical dependence.With the material of these disease associations be: ethanol, amphetamine (or class amphetamine material), caffeine, Fructus Cannabis, ***e, hallucinogen, inhalant, Fructus Cannabis, nicotine, opioid, phencyclidine (or class phencyclidine chemical compound), sedative hypnotic or benzodiazepines and other (or unknown) material, and the combination of above-mentioned all substances.

Especially, term " substance abuse disease " comprises that drug withdrawal disease such as ethanol withdrawal are with or without perceptual disturbance; Alcohol withdrawal delirium; Amphetamine withdrawal; Cocaine withdrawal; The nicotine withdrawal; Opioid withdrawal; Tranquilizer, hypnotic or antianxiety drug withdrawal are with or without perceptual disturbance; Tranquilizer, hypnotic or antianxiety drug withdrawal delirium; And because the withdrawal syndrome of other material.The standard that should be appreciated that the nicotine withdrawal treatment comprises the treatment of the symptom relevant with smoking cessation.

Other " substance abuse disease " is included in the anxiety disorder outbreak that has material to bring out during the withdrawal; The affective disorder outbreak that has material to bring out during the withdrawal; With the sleep disorder outbreak that has material to bring out during the withdrawal.

Especially, formula I chemical compound is used to help to stop the consumption of Nicotiana tabacum L., and is used for the treatment of nicotine dependence and nicotine withdrawal.Formula I chemical compound produces the addiction of ring wholly or in part to smoking in nicotine consumer such as smoker.Further, withdrawal symptom weakens, and follows usually and abandon acquired body weight that Nicotiana tabacum L. consumes and reduce or do not exist.For smoking cessation, formula I chemical compound can with nicotinic agonist or nicotine partial agonist or oxidase inhibitor (MAOI) or help to abandon Nicotiana tabacum L. consume in the effective another kind of active component of proof unite use, for example, antidepressant such as BUP, doxepin, ornortriptyline; Perhaps antianxiety drug such as buspirone or clonidine.

The compounds of this invention also can be used for treating or prevent by HIV inductive with treat inductive neuropathy, chronic pelvic pain, neuroma pain, plyability regional pain syndrome, chronic arthritis pain and relevant neuralgia by HIV, treatment or prevent chronic back pain, and be used for the treatment of or prevent by traumatic nerve injury, nerve compression or sunken centre, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, cancer and chemotherapy pain that cause or associated.

Should be appreciated that chemical compound of the present invention can prevent effective dosage level to carry out administration, preventing the above-mentioned patient's condition, and prevention is by receptor-mediated other patient's condition of NMDA NR2B.

Can with formula I chemical compound be used for the treatment of/prevent/suppress or alleviate the disease of formula I compounds for treating or the other medicines use in conjunction of the patient's condition.These other medicine can by used for this purpose usually approach and amount, with formula I chemical compound simultaneously or administration continuously.When formula I chemical compound and one or more other medicines use simultaneously, preferably except formula I chemical compound, also comprise the pharmaceutical composition of these other medicines.Therefore, pharmaceutical composition of the present invention comprises those pharmaceutical compositions that also comprise one or more other active component except that formula I chemical compound.Can with formula I chemical compound associating, include but not limited to individually or at the example of other active component of identical administered in pharmaceutical compositions: (1) NSAID (non-steroidal anti-inflammatory drug); (2) cox 2 inhibitor; (3) bradykinin b 1 receptor antagonist; (4) sodium channel blockers and antagonist; (5) nitric oxide synthase (NOS) inhibitor; (6) glycine site antagonist; (7) potassium channel openers (opener); (8) AMPA/ kainate (kainate) receptor antagonist body; (9) calcium-channel antagonists; (10) GABA-A receptor modulators (as the GABA-A receptor stimulating agent); (11) matrix metalloproteinase (MMP) inhibitor; (12) thrombolytic agent; (13) opioid such as morphine; (14) neutrophil cell inhibitive factor (NIF); (15) levodopa; (16) carbidopa; (17) levodopa/carbidopa; (18) dopamine agonist such as bromocriptine, pergolide, pramipexole, ropinirole; (19) anticholinergic; (20) amantadine; (21) carbidopa; (22) catechol O-transmethylase (" COMT ") inhibitor such as An Takapeng and tolcapone; (23) monoamine oxidase-B (" MAO-B ") inhibitor; (24) opiate (opiate) agonist or antagonist; (25) 5HT receptor stimulating agent or antagonist; (26) nmda receptor agonist or antagonist; (27) NK1 antagonist; (28) selective serotonin reuptake inhibitor (" SSRI ") and/or selective serotonin and NRI (" SSNRI "); (29) tricyclics; (30) norepinephrine regulator; (31) lithium; (32) valproate; (33) neurontin (gabapentin); (34) lyrica; (35) antiplatelet drug; (36) VR1 antagonist; (37) COX-3 inhibitor; (38) antioxidant; (39) metal-chelator; (40) CGRP antagonist, and (41) memantine.

Comprise levodopa (being with or without the outer decarboxylase inhibitor of selective brain such as carbidopa or Benserazide) with the suitable antiparkinsonism medicine of deramcicline combination, Anticholinergics such as biperiden (optional) and benzhexol (benzhexol) hydrochlorate and dopamine agonist such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide and pramipexole with its hydrochlorate or lactate form.Should be appreciated that dopamine agonist can be a pharmaceutical acceptable salt, for example Alentemol Hydrobromide, bromocriptine methanesulfonate, Fenoldopam Mesylate, naxagolide hydrochloride and pergolide mesylate.Lisuride and pramipexole use with salt-independent shape usually.

Deramciclane or its officinal salt, can be selected from the combination of following chemical compound and give: acephenazine, alentemol, benzhexol, bromocriptine, biperiden, haloperidol, chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine, haloperidol, levodopa, levodopa and Benserazide, levodopa and carbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, risperidone, sulpiride; tetrabenazine; benzhexol; thioridazine; tiotixene and trifluoperazine.

The phenothiazine, thioxanthene, heterocycle Dibenzazepine, butyrophenone, diphenylbutylpiperidine and the indolone that comprise nerous sedative with suitable nerous sedative or its officinal salt of deramcicline combination.The example of suitable phenothiazines comprises chlorpromazine, mesoridazine, thioridazine, acephenazine, fluphenazine, perphenazine and trifluoperazine.The example of suitable thioxanthene class comprises chlorprothixene and tiotixene.The example of Dibenzazepine is a clozapine.The example of butyrophenone is a haloperidol.The example of diphenylbutylpiperidine is a pimozide.The example of indolone is molindolone.Other neuroleptics comprises loxapine, sulpiride and risperidone.Should be appreciated that when uniting use with deramcicline, neuroleptics can be a pharmaceutical acceptable salt, for example chlorpromazine hydrochloride, mesoridazine besilate, Thioridazine Hydrochloride, Acetophenazine Dimaleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazin decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, Halopericol Decanoate, loxapine succinate and Molindone Hydrochloride.Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide and risperidone use with salt-independent shape usually.

Can adopt the cream, ointment, gel, solution or the suspension that comprise The compounds of this invention to be used for topical application.Mouthwass and gargarism are also included within the topical application scope that is used for purpose of the present invention.

The preparation that is designed for human oral can comprise and the suitable and convenient blended about 0.5mg of the carrier～about 5g activating agent measured that accounts for total composition about 5～about 95% easily.Unit dosage form comprises the active component of about 1mg～about 1000mg usually.

Can be by the The compounds of this invention treatment or the described herein patient's condition of prevention of the about 0.01mg of per kilogram of body weight administration every day～about 140mg.

Yet, should be appreciated that, can be depending on multiple factor for the given dose of any particular patient.These factors comprise patient's age, body weight, general health state, sex and diet.Other factors comprises the type and the order of severity of the specified disease of administration time and route of administration, discharge rate, drug regimen and treatment.For example, can treat inflammatory pain effectively by the The compounds of this invention of the about 0.01mg～75mg of per kilogram of body weight administration every day, perhaps alternatively every day every the about 0.5mg of patient's administration～about 3.5g.Can treat neuropathic pain effectively by the The compounds of this invention of the about 0.01mg of per kilogram of body weight administration every day～about 125mg, or alternatively every day every the about 0.5mg of patient's administration～about 5.5g.

Unless otherwise indicated, the abbreviation of using in this article is as follows:

The TEA triethylamine

The NaOAc sodium acetate

The DMF dimethyl formamide

The DIPEA diisopropylethylamine

The EtOAc ethyl acetate

The TFA trifluoroacetic acid

The TFAA trifluoroacetic anhydride

The THF oxolane

The DMAP 4-dimethylaminopyridine

The RT room temperature

H hour

Min minute

The DCM dichloromethane

The MeCN acetonitrile

Selectfluor 1-(chloromethyl)-4-fluoro-1,4-diazo bicyclic [2.2.2] octane two or four

Borofluoride

MeOH methanol

EtOH ethanol

IPA 2-propanol

N-BuOH 1-butanols

EDC 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride

HOBt 1-hydroxyl-benzotriazole

NMP N-N-methyl-2-2-pyrrolidone N-

DAST (lignocaine) sulfur trifluoride

Can use the starting material, reagent and the conventional synthetic method that obtain easily easily to prepare The compounds of this invention according to following reaction scheme and specific embodiment or its modification.In these reactions, also might use this known but do not have the more detailed modification of mentioning as those skilled in the art.Can be by those skilled in the art by easily understand and understand the conventional method of the claimed chemical compound of preparation the present invention with reference to following reaction scheme.

The preparation of formula I chemical compound can be undertaken by the structure as intermediate II.

Shown in reaction scheme 1, the synthetic of formula I chemical compound finished via intermediate II.Usually, under the standard alkylation conditions with intermediate II with 4-chloro-1H-pyrazolo [3,4-d] pyrimidine 1 alkylation (R.K.Robins, J.Amer.Chem.Soc.78,784-790 (1956)), described condition is for example hot alcoholic solvent, comprises isopropyl alcohol or 1-butanols, at alkali, comprise that sodium carbonate or diisopropylethylamine exist down.Intermediate II can also be used the derivant alkylation of the due care of chemical compound 1.Suitable protecting group comprises for example N-THP trtrahydropyranyl of (alkoxymethyl)-2 radical derivative, shown in chemical compound 2 and isomer 3 thereof.In alkylated reaction, use 2 and 3 to generate intermediate III and IV respectively.Such suitable protecting group be easy to by with Bronsted acid for example salt acid treatment intermediate III or IV remove, and form formula I chemical compound.

Scheme 1

Describe some in the scheme 2 and contained the synthetic of alkoxyl-heterocyclic chemical compound.In a first step, under alkali condition, the amine 4 usefulness halogenide 5 of due care are handled the heterocycle 6 that obtains alkanisation.Under standard conditions such as acid hydrolysis, remove the nitrogen-protecting group group in 6, and, intermediate 7 is converted into final compound by the reaction sequence described in the scheme 1.In addition, under reducing condition (example is as shown in Example 12), the amino-heterocycle alkanisation that will suit to protect with epoxide (example is as shown in Example 6), aldehydes or ketones; Amino-heterocycle alkanisation of perhaps using alpha-brominated ketone (example as shown in Example 14) to suit to protect.Under each these situation, use standard chemical process, comprise and remove nitrogen-protecting group group and pass through the reaction sequence described in the scheme 1 that intermediate can be further processed and be final chemical compound.

Scheme 2

The synthetic of some chemical compounds that contain aryl-two fluoro-ethyl described in the scheme 3.In a first step, in the presence of purple bronze, with 2-bromo-2,2-difluoroacetic acid 8 arylations obtain ester 10 with 4-chloroiodobenzone 9.The another kind of ester 10 is synthetic to be included in Lewis acid as the aluminum chloride existence down, uses acid chloride such as ethyl oxalyl chloride with the aromatic ring acidylate, uses reagent such as DAST with the ketone ester halogenation subsequently.Under alkali condition, ester 10 hydrolysis are obtained acid 11.Carboxylic acid 11 is converted into acid chloride 12, and its amine 13 that is used for the suitable protection of acidylate under standard conditions obtains amide 14.Under standard conditions such as acid hydrolysis, amide 14 deprotections are obtained amine 15.Standard conditions obtain intermediate 16 as handling down with monoborane complex or LAH with amine 15 reduction.By the reaction sequence described in the scheme 1 intermediate 16 is converted into final compound.

Method 3

The synthetic of some chemical compounds that contain the fluorine piperidines described in the scheme 4.In a first step, under alkali condition, ketone 17 is converted into silicon enol-ether 18 by handling with silicyl triflate.With electrophilic fluorine source such as Selectfluor  (available from Air Products and Chemicals, Inc., Allentown Pa.) handles 18 and obtains alpha-fluoro ketone 19.Reduction 19 obtains alcohol 20 under standard conditions.Alcohol 20 can be converted into activity leaving group such as mesylate 21 and triazo-compound reaction and obtain triazo-compound 22.Remove blocking group and obtain amine 23 under standard conditions, it can obtain amide 25 with acid chloride 24 couplings under standard conditions.Amide 25 reduces under standard conditions and obtains intermediate 26.By the reaction sequence described in the scheme 1 intermediate 26 is converted into final compound.

Scheme 4

Some contain azabicyclo [3.1.0] oneself-the 6-based compound synthetic can from the diamidogen of suitable protection as outer-3-azabicyclo [3.1.0] oneself-acquisition of 6-aminocarbamic acid tertiary butyl ester; the latter can be by the reaction sequence described in the scheme 1 and 3 according to literature method (Norris, T., Braish; T.F.; Butters, M., DeVries; K.M.; Hawkins, J.M., Massett; S.S.; Rose, P.R., Santafianos; D.; Sklavounos, C.J.Chem.Soc., Perkin Trans.1 (2000) 1615-1622) preparation.

The synthetic of some chemical compounds that contain octahydro ring penta [c] pyrroles-4-base described in the scheme 5.In a first step, under acid condition, amine 27 and ketenes 28 reactions obtain ketone 29.Ketone 29 is reduced under standard conditions and obtains alcohol 30.After adjusting blocking group under the standard conditions, alcohol 31 can be converted into leaving group such as mesylate 32.Replace mesylate with triazo-compound and obtain 33, and obtain amine 34 at deprotection under standard conditions such as acid hydrolysis.Amine 34 obtains amine 35 with 24 couplings under standard conditions.Reduction amine 35 obtains intermediate 36.By the reaction sequence described in the scheme 1 intermediate 36 is converted into final compound.

Scheme 5

The synthetic of some chemical compounds that contain azabicyclo [3.2.1] oct-3-yl described in the scheme 6.In a first step, the reaction of ketone 37 and oxammonium hydrochloride. obtains imines 38.Bridge 39 in imines 38 is reduced under standard conditions and obtains.The outer amine relevant with 39 (by embodiment 45 explanations) obtains by the sodium metal that reducing condition is changed in alcoholic solvent such as propanol.Primary amine with bridge 39 in the group sealing of suitable protection obtains 40, under suitable condition such as acid hydrolysis the secondary amine deprotection is obtained amine 41.Amine 41 obtains amine 43 with 42 couplings under standard conditions.Amine 43 deprotection under standard conditions obtains amine 44, and amine 44 reduction are obtained intermediate 45.By the reaction sequence described in the scheme 1 intermediate 45 is converted into final compound.

Scheme 6

In some cases, end-product further can be modified, for example be modified by handling substituent group.These processing include but not limited to the common known reduction of those skilled in the art, oxidation, alkylation, acidylate, halo and hydrolysis.

In some cases, can change the order of carrying out described reaction scheme to promote reaction or to avoid unwanted product.Provide the following example to make the present invention to be understood more fully.These embodiment only illustrate, and not should be understood to limit by any way the present invention.

Embodiment 1

N-{1-[2-(benzyloxy) ethyl] pyrrolidine-3-yl }-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Steps A: 1-[2-(benzyloxy) ethyl] pyrrolidine-3-yl } t-butyl carbamate

With [(2-bromine oxethyl) methyl] benzene (1.7g, 0.81mmol) under room temperature, add pyrrolidine-3-aminocarbamic acid tert-butyl ester (1.5g, 0.81mmol) and TEA (2.3mL is 1.6mmol) in the solution in dichloromethane (100mL).After 1 hour, add 1M NaOH (500mL), and use the dichloromethane extraction water layer.With the organic facies that merges through dried over sodium sulfate, filtration and concentrate.Obtain title compound (1.4g) through silica gel chromatography (1% isopropyl alcohol/dichloromethane → 30% isopropyl alcohol/dichloromethane) purification.MS：321(M+H ⁺)。

Step B:1-[2-(benzyloxy) ethyl] pyrrolidine-3-amine

To 1-[2-(benzyloxy) ethyl] and pyrrolidine-3-yl } (1.2g, 3.9mmol) the middle trifluoroacetic acid (10mL) that adds stirs the solution that obtains t-butyl carbamate under room temperature.After 60 minutes, reactant mixture is concentrated the trifluoroacetate (1.2g) that obtains title compound.MS：221(M+H ⁺)。

Step C:N-{1-[2-(benzyloxy) ethyl] pyrrolidine-3-yl }-1H-pyrazolo [3,4-d] pyrimidine-4-amine

To 1-[2-(benzyloxy) ethyl] pyrrolidine-3-amine (0.10g, 0.35mmol) add in the solution in isopropyl alcohol (5mL) DIPEA (2mL) and 4-chloro-1-(tetrahydrochysene-pyrans-2-yl)-1H-pyrazolo [3,4-d] pyrimidine (0.82g, 0.35mmol).After it is cooled to room temperature and concentrates, then with solution in 85 ℃ of heating 4 hours.The residue that obtains is dissolved in the methanol (3mL), and handles with the saturated solution of HCl in ethyl acetate (10mL).After 1 hour, mixture is concentrated, and the residue that obtains is handled with saturated sodium bicarbonate, and use ethyl acetate extraction.With the organic layer that merges through dried over sodium sulfate, filter and be concentrated into drying.Obtain title compound (0.78g), white solid through silica gel chromatography (2% isopropyl alcohol/dichloromethane → 30% isopropyl alcohol/dichloromethane) purification.MS：339(M+H ⁺)； ¹H?NMR(400MHz，DMSO-d ₆)：δ13.48(s，1H)，11.08-10.75(m，2H)，8.78(s，1H)，8.25(s，2H)，7.32(s，5H)，4.78(s，1H)，4.48(s，1H)，3.98(s，1H)，3.78-3.22(m，4H)，2.48(s，2H)，2.09-1.94(m，2H)，1.81(m，1H)。

The following example 2-5 uses and the above preparation of similar methods described in the embodiment 1.

Embodiment 2

N-{1-[2-(2-benzene ethyoxyl) ethyl] pyrrolidine-3-yl }-1H-pyrazolo [3,4-d] pyrimidine-4-amine

MS：353(M+H ⁺)； ¹H?NMR(400MHz，DMSO-d ₆)：δ10.78(s，1H)，8.58(s，1H)，7.38-7.15(m，5H)，4.86(s，1H)，4.00(m，1H)，3.90(m，1H)，3.78-3.15(m，10H)，2.38-2.10(m，2H).

Embodiment 3

N-{1-[2-(benzyloxy) ethyl] piperidines-3-yl }-1H-pyrazolo [3,4-d] pyrimidine-4-amine

MS：353(M+H ⁺)； ¹H?NMR(400MHz，CD ₃OD)：δ8.45(s，2H)，7.38-7.20(m，7H)，4.65(s，1H)，4.50-4.40(m，3H)，3.80-3.25(m，5H)，3.00-2.80(m，2H)，2.15-1.25(m，4H).

Embodiment 4

N-{1-[2-(benzyloxy) ethyl] piperidin-4-yl }-1H-pyrazolo [3,4-d] pyrimidine-4-amine

MS：353(M+H ⁺)； ¹H?NMR(400MHz，DMSO-d ₆)：δ10.78(s，1H)，8.52(s，2H)，7.40-7.22(m，5H)，4.85(s，1H)，4.08(m，1H)，3.85(m，1H)，3.78-3.20(m，10H)，2.40-2.08(m，2H).

Embodiment 5

N-[1-(2-benzene oxygen ethyl) piperidin-4-yl]-1H-pyrazolo [3,4-d] pyrimidine-4-amine

MS：339(M+H ⁺)； ¹H?NMR(400MHz，DMSO-d ₆)：δ10.78(s，1H)，8.60(s，1H)，7.38-7.15(m，5H)，4.85(s，1H)，3.95(m，1H)，3.90(m，1H)，3.80-3.22(m，10H)，2.40-2.15(m，2H).

Embodiment 6

1-phenyl-3-[3-(1H-pyrazolo [3,4-d] pyrimidine-4-base is amino) pyrrolidine-1-yl] propan-2-ol

Steps A: [1-(2-hydroxyl-3-phenyl propyl) pyrrolidine-3-yl] t-butyl carbamate:

To pyrrolidine-3-aminocarbamic acid tert-butyl ester (3.1g, 16mmol) add in the solution in ethanol (100mL) 2-benzyl rings oxidative ethane (2.2g, 16mmol), and with the reactant mixture that obtains in 100 ℃ of heating.After 1 hour, concentrated reaction mixture obtains title compound (2.5g).MS：321(M+H ⁺)。

Step B:1-(3-amino-pyrrolidine-1-yl)-3-phenyl propan-2-ol

(1.5g adds trifluoroacetic acid (0.75mL) in 4.7mmol), and the solution that obtains is stirred under room temperature to [1-(2-hydroxyl-3-phenyl propyl) pyrrolidine-3-yl] t-butyl carbamate.After 30 minutes, reactant mixture is concentrated the trifluoroacetate (1.3g) that obtains title compound.MS：221(M+H ⁺)。

Step C:1-phenyl-3-[3-(1H-pyrazolo [3,4-d] pyrimidine-4-base is amino) pyrrolidine-1-yl] propan-2-ol

To 1-(3-amino-pyrrolidine-1-yl)-3-phenyl propan-2-ol (0.22g, 0.77mmol) add DIPEA (0.5mL) and 4-chloro-1-(tetrahydrochysene-pyrans-2-yl)-1H-pyrazolo [3 in the solution in 1-butanols (0.5mL), 4-d] pyrimidine (0.18g, 0.77mmol), and with gained solution under microwave radiation in 150 ℃ the heating 10 minutes.With mixture cooling and concentrated.The residue of gained is dissolved in the methanol (3mL), and handles with the saturated solution (10mL) of HCl in ethyl acetate.After 1 hour,, and handle residue, use ethyl acetate extraction with saturated sodium bicarbonate with solution concentration.The organic layer that merges through dried over sodium sulfate, filter and be concentrated into drying.Obtain title compound (0.12g), white solid through silica gel chromatography (1% isopropyl alcohol/dichloromethane → 30% isopropyl alcohol/dichloromethane) purification.HRMS (M+H ⁺): value of calculation=339.1928, measured value=339.1918.

Embodiment 7

N-[1-(2,2-two fluoro-3-phenyl propyl) pyrrolidine-3-yl]-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Steps A: [1-(2-oxygen-3-phenyl propiono) pyrrolidine-3-yl] t-butyl carbamate

Under the room temperature, (4.4g 23mmol) adds 2-oxygen-3-phenylpropionic acid (3.8g in the solution in dichloromethane (50mL) to pyrrolidine-3-aminocarbamic acid tert-butyl ester, 23mmol), HOBT (3.2g, 23mmol), DIPEA (3.0g, 23mmol) and EDC (4.5g, 23mmol).After 1 hour, add saturated sodium bicarbonate, use the ethyl acetate extraction water layer.The organic facies that merges is through dried over sodium sulfate, filtration and concentrated.Obtain title compound (2.5g) through silica gel chromatography (2% isopropyl alcohol/dichloromethane → 30% isopropyl alcohol/dichloromethane) purification.MS：333(MH+H ⁺)。

Step B:[1-(2,2-two fluoro-3-phenyl propionos) pyrrolidine-3-yl] t-butyl carbamate

(2.5g, (2.4g 15mmol), and is heated to 50 ℃ with the solution of gained 7.5mmol) to add DAST in the solution in dichloromethane (50mL) to [1-(2-oxygen-3-phenyl propiono) pyrrolidine-3-yl] t-butyl carbamate.After 5 hours, reactant mixture is cooled to room temperature, inclines, use ethyl acetate extraction in ice.The organic facies that merges obtains title compound (2.2g) through dried over sodium sulfate, filtration and concentrated.MS：335(M+H ⁺)。

Step C:1-(2,2-two fluoro-3-phenyl propyl) pyrrolidine-3-amine

(2.2g adds trifluoroacetic acid (15mL) in 6.4mmol), and the solution that obtains is stirred under room temperature to [1-(2,2-two fluoro-3-phenyl propionos) pyrrolidine-3-yl] t-butyl carbamate.After 60 minutes, reactant mixture is concentrated into drying.The residue that obtains is used in THF, and (39mL, the 1M monoborane in 39mmol) is handled, and is heated to 80 ℃ and kept 1 hour.Reactant mixture is cooled to room temperature,, and is heated to 80 ℃ with 6N HCl (25mL) quencher.After 1 hour, reactant mixture is cooled to room temperature, alkalizes to pH＞8, and use chloroform extraction with NaOH.The organic facies that merges obtains title compound (1.7g) through dried over sodium sulfate, filtration and concentrated.MS：241(M+H ⁺)。

Step D:N-[1-(2,2-two fluoro-3-phenyl propyl) pyrrolidine-3-yl]-1H-pyrazolo [3,4-d] pyrimidine-4-amine

To 1-(2,2-two fluoro-3-phenyl propyl) pyrrolidine-3-amine (0.070g, 0.29mmol) add DIPEA (0.5mL) and 4-chloro-1-(tetrahydrochysene-pyrans-2-yl)-1H-pyrazolo [3 in the solution in 1-butanols (0.5mL), 4-d] pyrimidine (0.070g, 0.29mmol), and with gained solution under microwave radiation in 150 ℃ the heating 10 minutes.Cooling and concentrated gained mixture.The residue that obtains is dissolved in the methanol (3mL), and handles with the saturated solution of HCl in ethyl acetate (10mL).After 1 hour, concentrated solution, the residue that obtains is handled with saturated sodium bicarbonate, and uses ethyl acetate extraction.The organic facies that merges through dried over sodium sulfate, filter and be concentrated into drying.Obtain title compound (0.50g), white solid through silica gel chromatography (2% isopropyl alcohol/dichloromethane → 30% isopropyl alcohol/dichloromethane) purification.HRMS (MH+H ⁺): value of calculation=359.1751, measured value=359.1804; ¹H NMR (400MHz, CD ₃OD): δ 8.30 (s, 1H), 8.10 (s, 1H), 7.30-7.20 (m, 5H), 4.75 (m, 1H), 3.28-3.20 (m, 5H), 3.08-2.90 (m, 2H), 2.80-2.62 (m, 4H), 2.40 (m, 1H), 1.90 (m, 1H).

Embodiment 8

N-[1-(2,2-two fluoro-3-phenyl propyl) piperidin-4-yl]-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Steps A: 1-(2-oxygen-3-phenyl propiono) piperidin-4-yl] t-butyl carbamate

Under the room temperature, (0.53g, (0.33mL is 3.9mmol) with a DMF 3.2mmol) to add oxalyl chloride in the solution in dichloromethane (3.0mL) to 2-oxygen-3-phenylpropionic acid.Add after 1 hour DIPEA (2.5mL, 14mmol), add subsequently the piperidin-4-yl t-butyl carbamate (0.71g, 3.6mmol).After 14 hours, reactant mixture is poured in the 1M citric acid, and uses ethyl acetate extraction.The organic layer that merges through dried over sodium sulfate, filtration and concentrated, obtains title compound (0.95g) with saturated sodium bicarbonate, water, salt water washing.MS：291(M-55)。

Step B:[1-(2,2-two fluoro-3-phenyl propionos) piperidin-4-yl] t-butyl carbamate

Under the room temperature, to [1-(2-oxygen-3-phenyl propiono) piperidin-4-yl] t-butyl carbamate (0.95g, 2.7mmol) add in the solution in DCE (10mL) DAST (0.68mL, 5.5mmol).Reactant mixture is heated to 60 ℃.After 14 hours, reactant mixture is cooled to room temperature, inclines, and use ethyl acetate extraction in frozen water.The organic layer that merges, filters and concentrates through dried over sodium sulfate with 1M citric acid, 1M NaOH, salt water washing, obtains title compound (0.94g), brown solid.MS：369(M+H ⁺)。

Step C:1-(2,2-two fluoro-3-phenyl propionos) piperidines-4-amine

Under the room temperature, (0.94g 2.6mmol) adds the saturated solution of HCl in ethyl acetate (5.0mL) in the solution in dichloromethane (10mL) to [1-(2,2-two fluoro-3-phenyl propionos) piperidin-4-yl] t-butyl carbamate.After 2 hours, concentrated reaction mixture.The residue that obtains is dissolved in the acetonitrile/water (1: 1), be loaded into Mega BE-SCX ion exchange resin (available from Varian Inc., Walnut Creek, CA) in, with acetonitrile flushing, with 10% ammonia spirit eluting in ethanol and concentrated.The grease that obtains is dissolved in dichloromethane and the methanol, handles with the saturated solution of HCl in ethyl acetate, obtains the hydrochlorate (0.10g) of title compound.MS：269(MH+H ⁺)。

Step D:1-(2,2-two fluoro-3-phenyl propyl) piperidines-4-amine

At 0 ℃ under nitrogen, to 1-(2,2-two fluoro-3-phenyl propionos) piperidines-4-amine (0.10g; 0.30mmol) be added in THF (3.6mL in the solution in THF (1mL); 3.6mmol) in the 1M monoborane, and reactant mixture is warmed to room temperature, be heated to 70 ℃ then.After 2 hours, reactant mixture is cooled to room temperature,, is heated to 70 ℃ with 6N HCl (10mL) quencher.After 1 hour, reactant mixture is alkalized to pH＞8, and use ethyl acetate extraction with 5M NaOH.The organic facies water and the salt water washing that merge through dried over sodium sulfate, are filtered and are concentrated.The crude product product that obtains is dissolved in dichloromethane and the methanol, handles with the saturated solution of HCl in ethyl acetate, and concentrates, and obtains the hydrochlorate (0.10g) of title compound.MS：255(M+H ⁺)。

Step e: N-[1-(2,2-two fluoro-3-phenyl propyl) piperidin-4-yl]-1H-pyrazolo [3,4-d] pyrimidine-4-amine

To 1-(2,2-two fluoro-3-phenyl propyl) piperidines-4-amine (0.10g, 0.31mmol) add DIPEA (2.5mL) and 4-chloro-1-(tetrahydrochysene-pyrans-2-yl)-1H-pyrazolo [3 in the solution in 1-butanols (2.5mL), 4-d] pyrimidine (0.78g, 0.33mmol), and the solution that obtains is heated to 90 ℃ kept 4 hours.Reactant mixture is cooled to room temperature and concentrated.The residue that obtains is dissolved in dichloromethane and the methanol, handles 2 hours with the saturated solution of HCl in ethyl acetate (5.0mL) under the room temperature.Reactant mixture 1M NaOH quencher, and use ethyl acetate extraction.The organic facies salt water washing that merges through dried over sodium sulfate, is filtered and is concentrated.Through reverse-phase chromatography (5% acetonitrile/0.1% trifluoroacetic acid/water → 95% acetonitrile/0.1% trifluoroacetic acid/water, XTerra  MSC8 post, available from WatersCorporation, Milford, Massachusetts) purification obtains product, it is dissolved in dichloromethane and the methanol, handle with the saturated solution of HCl in ethyl acetate, obtain the hydrochlorate (0.54g) of title compound, white solid.HRMS (M+H ⁺): value of calculation=373.1947, measured value=373.1964; ¹HNMR (400MHz, CD ₃OD): δ 8.60-8.52 (s, 2H), 7.41-7.31 (m, 5H), 4.69-4.51 (s, 1H), 3.86-3.68 (m, 4H), 3.46-3.33 (m, 4H), 2.41-2.31 (m, 2H), 2.19-2.03 (m, 2H).

Embodiment 9

N-[1-(2-phenethyl) piperidin-4-yl]-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Title compound use with embodiment 1 above in the similar methods preparation of report.HRMS (M+H ⁺): value of calculation=323.1373, measured value=323.1999; ¹H NMR (500MHz, CD ₃OD): δ 8.68-5.85 (m, 2H), 7.40-7.25 (m, 5H), 4.75-4.65 (m, 1H), 3.86-3.79 (m, 2H), 3.44-3.38 (m, 1H), 3.17-3.10 (m, 2H), 2.47-2.39 (m, 2H), 2.18-2.07 (m, 2H).

Embodiment 10

N-[1-(3-phenyl propyl) piperidin-4-yl]-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Title compound use with embodiment 1 above in the similar methods preparation of report.HRMS (M+H ⁺): value of calculation=337.2135, measured value=337.2164; ¹H NMR (500MHz, CD ₃OD): δ 8.23-8.19 (s, 1H), 8.15-8.11 (s, 1H), 7.29-7.23 (m, 2H), and 7.23-7.18 (m, 2H), 7.18-7.13 (m, 1H), 4.19-4.09 (m, 1H), 3.06-2.98 (m, 2H), 2.68-2.61 (m, 2H), 2.47-2.39 (m, 2H), 2.24-2.13 (m, 2H), 2.10-2.01 (m, 2H), 1.91-1.82 (m, 2H), 1.75-1.64 (m, 2H).

Embodiment 11

N-[(1S, 3R)-3-(3-phenyl-1,2,4- diazole-5-yl) cyclopenta]-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Steps A: 1-[2-(4-tolyl) ethyl] piperidin-4-yl } t-butyl carbamate

Under nitrogen atmosphere, to piperidin-4-yl t-butyl carbamate (0.40g, 2.0mmol) add 2-(4-tolyl) ethanol (0.27g in the solution in toluene (1.0mL), 2.0mmol), potassium carbonate (0.014g, 0.10mmol) and dichloro (pentamethyl cyclopentadienyl group) iridium (III) dimer (0.040g, 0.050mmol), and reactant mixture is heated to 110 ℃.After 17 hours, reactant mixture is filtered, use ethyl acetate rinse, and concentrate.Obtain title compound (0.25g), white solid through silica gel chromatography (the different propane/dichloromethane of 1% isopropyl alcohol/dichloromethane → 40%) purification.HRMS (M+H ⁺): value of calculation=319.2380, measured value=319.2373.

Step B:N-[(1S, 3R)-3-(3-phenyl-1,2,4- diazole-5-yl) cyclopenta]-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Title compound use with embodiment 8 above in the similar methods preparation of step C and E report.HRMS (M+H ⁺): value of calculation=337.2135, measured value=337.2145; ¹H NMR (400MHz, CD ₃OD): δ 8.22 (s, 1H), 8.13 (s, 1H), 7.10 (s, 4H), 4.17 (s, 1H), 3.13-3.10 (m, 2H), 2.82-2.78 (m, 2H), 2.65-2.61 (m, 2H), 2.29 (s, 1H), 2.11-2.08 (m, 2H), 1.77-1.72 (m, 2H).

Embodiment 12

N-{1-[1-methyl-2-(4-tolyl) ethyl] piperidin-4-yl }-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Steps A: 1-[1-methyl-2-(4-tolyl) ethyl] piperidin-4-yl } t-butyl carbamate

In room temperature under nitrogen, to the piperidin-4-yl t-butyl carbamate (0.85g, 4.2mmol) and 1-(4-tolyl) acetone (0.55mL, add in clean mixture 3.5mmol) isopropyl titanate (2.1mL, 7.1mmol).After 20 hours, add sodium cyanoborohydride (0.44g, 7.1mmol) solution in EtOH (10mL) under the room temperature.After 16 hours, by adding 1M NaOH with the slow quencher of reactant mixture, the precipitation that obtains is filtered through celite, and uses ethyl acetate rinse.Filtrate water, salt water washing through dried over sodium sulfate, are filtered and are concentrated.Through silica gel chromatography (1% isopropyl alcohol/dichloromethane → 20% isopropyl alcohol/dichloromethane) purification, obtain title compound (0.86g), yellow oil.HRMS (M+H ⁺): value of calculation=333.2537, measured value=333.2527.

Step B:N-{1-[1-methyl-2-(4-tolyl) ethyl] piperidin-4-yl }-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Title compound use with embodiment 8 above in the similar methods preparation of step C and E report.HRMS (M+H ⁺): value of calculation=351.2292, measured value=351.2291; ¹H NMR (500MHZ, CD ₃OD): δ 8.71-8.65 (s, 1H), 8.63-8.56 (s, 1H), 7.24-7.11 (m, 4H), 4.78-4.65 (m, 1H), 3.82-3.52 (m, 3H), 3.48-3.36 (m, 2H), 3.36-3.33 (m, 1H), 2.80-2.69 (m, 1H), 2.49-2.36 (s, 2H), 2.35-2.29 (s, 3H), 2.29-2.16 (m2H), and 1.33-1.21 (m, 3H).

Embodiment 13

N-(1-benzyl piepridine-4-yl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Title compound use with embodiment 1 above in the similar methods preparation of report.HRMS (M+H ⁺): value of calculation=309.1822, measured value=309.1839; ¹H NMR (500MHz, CD ₃OD): δ 8.24-8.18 (s, 1H), 8.16-8.09 (s, 1H), 7.39-7.31 (m, 4H), 7.31-7.25 (m, 1H), and 4.19-4.08 (m, 1H), 3.60-3.55 (s, 2H), 3.02-2.94 (m, 2H), 2.28-2.17 (m, 2H), 2.08-2.00 (m, 2H), 1.76-1.65 (m, 2H).

Embodiment 14

1-phenyl-2-[4-(1H-pyrazolo [3,4-d] pyrimidine-4-base is amino) piperidines-1-yl] ethanol

Steps A: [1-(2-oxygen-2-phenethyl) piperidin-4-yl] t-butyl carbamate

To 2-bromo-1-phenyl ethyl ketone (0.63g, 3.2mmol) and piperidin-4-yl t-butyl carbamate (0.68g, 3.4mmol) (0.57mL 3.5mmol), ℃ keeps the mixture heated to 130 that obtains 10 minutes under the microwave radiation to add DIPEA in the solution in THF (5mL).Reactant mixture is inclined in 1M NaOH, use ethyl acetate extraction.The organic facies salt water washing that merges through dried over sodium sulfate, is filtered and is concentrated.Through silica gel chromatography (50% ethyl acetate/hexane → 100% ethyl acetate/hexane) purification, obtain title compound (0.79g), yellow solid.HRMS (M+H ⁺): value of calculation=319.2016, measured value=319.2022.

Step B:2-(4-amino piperidine-1-yl)-1-phenyl ethyl ketone

According to step C method of reporting among the embodiment mentioned above 8, title compound prepares from [1-(2-oxygen-2-phenethyl) piperidin-4-yl] t-butyl carbamate.MS：219(M+H ⁺)。

Step C:2-(4-amino piperidine-1-yl)-1-phenylethanol

Under the room temperature, to 2-(4-amino piperidine-1-yl)-1-phenyl ethyl ketone (0.35g, 1.1mmol) add in the solution in MeOH (3mL) Sodium Borohydride (0.13g, 3.3mmol).After 1 hour, reactant mixture is by dropwise adding entry (3mL) quencher.Reactant mixture is inclined in 1M NaOH, and use ethyl acetate extraction.The organic facies salt water washing that merges through dried over sodium sulfate, is filtered and is concentrated, and obtains title compound (0.34g), white solid.HRMS (M+H ⁺): value of calculation=221.1649, measured value=221.1657.

Step D:1-phenyl-2-[4-(1H-pyrazolo [3,4-d] pyrimidine-4-base is amino) piperidines-1-yl] ethanol

Title compound use with embodiment 1 above in the similar methods preparation of step C report.HRMS (M+H ⁺): value of calculation=339.1928, measured value=339.1935; ¹H NMR (400MHz, CD ₃OD): δ 8.68-8.63 (m, 1H), 8.63-8.55 (m, 1H), 7.53-7.45 (m, 2H), 7.45-7.30 (m, 3H), 5.22-5.12 (m, 1H), 4.76-4.61 (m, 1H), 4.02-3.91 (m, 1H), 3.89-3.79 (m, 1H), 3.76-3.45 (m, 1H), 2.52-2.28 (m, 2H), and 2.28-2.04 (m, 2H).

Embodiment 15

1-phenyl-2-[4-(1H-pyrazolo [3,4-d] pyrimidine-4-base is amino) piperidines-1-yl] ethyl ketone

According to step C method of reporting among the embodiment 1 above, title compound is from 2-(4-amino piperidine-1-yl)-1-phenyl ethyl ketone (embodiment 14, step B) preparation.HRMS (M+H ⁺): value of calculation=337.1772, measured value=337.1778; ¹H NMR (500MHZ, CD ₃OD): δ 8.25 (s, 1H), 8.17 (s, 1H), 8.06-8.00 (m, 2H), 7.65-7.59 (m, 1H), 7.54-7.47 (m, 2H), 4.24-4.14 (m, 1H), 4.02 (s, 2H), 3.16-3.07 (m, 2H), 2.44-2.34 (m, 2H), 2.11-2.03 (m, 2H), and 1.86-1.75 (m, 2H).

Embodiment 16

(1R)-and 1-(2-fluorophenyl)-2-[4-(1H-pyrazolo [3,4-d] pyrimidine-4-base is amino) piperidines-1-yl] ethanol

According to method of reporting among the embodiment mentioned above 6, title compound prepares from (2R)-2-fluorophenyl oxirane.MS?357(M+H ⁺)。

Embodiment 17

N-[1-(2-fluoro-2-phenethyl) piperidin-4-yl]-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Steps A: fluorine (phenyl) methyl acetate

In the time of 0 ℃ under the nitrogen, to hydroxyl (phenyl) methyl acetate (2.0g, 12mmol) add in the solution in dichloromethane (25mL) DAST (2.5mL, 20mmol).Reactant mixture is warmed to room temperature.After 1 hour, reactant mixture is inclined in frozen water, and use ethyl acetate extraction.The organic facies salt water washing that merges through dried over sodium sulfate, is filtered and is concentrated, and obtains title compound (2.0g), yellow oil.MS：337(2M+H ⁺)。

Step B: fluorine (phenyl) acetic acid

In the time of 0 ℃, (2.0g, (2.0g 36mmol), is warmed to room temperature with reactant mixture 12.0mmol) to add the KOH mineral sheet in the solution in methanol (20mL) and water (5mL) to fluorine (phenyl) methyl acetate.After 3 hours, reactant mixture is cooled to 0 ℃, is acidified to pH＜3 with 6N HCl, and uses ethyl acetate extraction.The organic facies salt water washing that merges through dried over sodium sulfate, is filtered and is concentrated, and obtains title compound (1.8g), brown solid.

Step C:N-[1-(2-fluoro-2-phenethyl) piperidin-4-yl]-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Title compound use with embodiment 8 above in the similar methods preparation of steps A, C, D and E report.HRMS (M+H ⁺): value of calculation=341.1885, measured value=341.1888; ¹H NMR (400MHz, CD ₃OD): δ 8.70-8.65 (s, 1H), 8.64-8.59 (s, 1H), 7.55-7.43 (m, 5H), 6.25-6.18 (m, 0.5H), 6.13-6.06 (m, 0.5H), 4.79-4.64 (m, 1H), 4.03-3.95 (m, 1H), 3.95-3.70 (m, 2H), 3.69-3.47 (m, 1H), 3.47-3.33 (m, 2H), 2.52-2.32 (m, 2H), 2.30-2.10 (m, 2H).

Embodiment 18

N-[1-(2,2-two fluoro-2-phenethyls) piperidin-4-yl]-1H-pyrazolo [3,4-d] pyrimidine-4-amine

According to steps A, C, D and E method of reporting among the embodiment 8 above, title compound is from difluoro (phenyl) acetic acid (Hagele, G., Haas, A.J.of Fluorine Chemistry (1996) 76,15-19) preparation.HRMS (M+H ⁺): value of calculation=359.1791, measured value=359.1797; ¹H NMR (400MHz, CD ₃OD): δ 8.82-8.72 (s, 1H), 8.64-8.58 (s, 1H), 7.70-7.63 (m, 2H), 7.63-7.53 (m, 3H), and 4.78-4.64 (m, 1H), 4.24-4.08 (m, 2H), 4.01-3.87 (m, 2H), 3.63-3.47 (m, 2H), 2.49-2.37 (m, 2H), 2.35-2.20 (m, 2H).

Embodiment 19

N-{1-[2-(4-chlorphenyl)-2,2-two fluoro ethyls] piperidin-4-yl }-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Steps A: (4-chlorphenyl) (difluoro) acetic acid

To 1-chloro-4-iodobenzene (5.9g, 25mmol) add in the solution in DMSO (100mL) bromine (difluoro) ethyl acetate (5.0g, 25mmol) and copper powder (3.1g, 49mmol), and with the mixture of gained in 80 ℃ of heating.After 20 hours, reactant mixture is inclined in dipotassium hydrogen phosphate, and Trihydride (56g, 250mmol) in the solution in water (500mL), companion's vigorous stirring.Suspension is filtered, and the solid that obtains washes with ether.Filtrate is added in the saline, with ether extraction (2x).The organic facies salt water washing that merges through dried over sodium sulfate, is filtered and is concentrated.The grease that obtains is dissolved in the methanol (100mL), and handles with 50%KOH aqueous solution (250mL) under room temperature.After 2 hours, reactant mixture is concentrated, be dissolved in CHCl ₃In, and extract with 1M HCl.Water layer alkalizes with NaOH.And use CHCl ₃Extraction.The organic facies that merges is filtered and is concentrated through dried over sodium sulfate, obtains title compound (3.5g), waxy solid.

Step B:{1-[(4-chlorphenyl) (difluoro) acetyl group] piperidin-4-yl } t-butyl carbamate

Title compound use with embodiment 8 above in the similar methods preparation of steps A report.MS：389(M+H ⁺)。

Step C:1-[2-(4-chlorphenyl)-2,2-two fluoro ethyls] piperidines-4-amine

To the 1-[(4-chlorphenyl) and (difluoro) acetyl group] piperidin-4-yl } (solution that obtains stirs under room temperature the tert-butyl ester for 0.42g, 1.1mmol) the middle trifluoroacetic acid (5mL) that adds.After 60 minutes, concentrated reaction mixture is handled and is concentrated with the saturated solution of HCl in ethyl acetate.In the residue that obtains, add THF (1mL) under the nitrogen and (6.6mL, 6.6mmol) the 1 M monoborane in is heated to 70 ℃ with reactant mixture at THF.After 2 hours, reactant mixture is cooled to room temperature,, and is heated to 70 ℃ with 6NHCl (20mL) quencher.After 1 hour, reactant mixture is alkalized to pH＞8, and use ethyl acetate extraction with 5M NaOH.The organic facies water and the salt water washing that merge through dried over sodium sulfate, are filtered and are concentrated, and obtain title compound (0.25g).MS：275(M+H ⁺)。

Step D:N-{1-[2-(4-chlorphenyl)-2,2-two fluoro ethyls] piperidin-4-yl }-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Title compound use with embodiment 8 above in the similar methods preparation of step e report.HRMS (M+H ⁺): value of calculation=393.1401, measured value=393.1421; ¹H NMR (400MHz, CD ₃OD): δ 8.20 (s, 1H), 8.10 (s, 1H), 7.58-7.42 (m, 4H), 4.10 (m, 1H), 3.10-2.95 (m, 2H), 2.86 (m, 2H), 2.48 (m, 2H), 1.85 (m, 2H), 1.58 (m, 2H).

Embodiment 20

N-{1-[2,2-two fluoro-2-(4-tolyl) ethyl] piperidin-4-yl }-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Title compound uses and the above similar methods preparation of embodiment 19 reports.HRMS (M+H ⁺): value of calculation=373.1947, measured value=373.1961; ¹H NMR (500MHz, CD ₃OD): δ 8.75-8.63 (s, 1H), 8.63-8.57 (s, 1H), 7.56-7.48 (m, 2H), 7.41-7.34 (m, 2H), and 4.76-4.62 (m, 1H), 4.17-4.01 (m, 2H), 3.99-3.83 (m, 2H), 3.59-3.41 (m, 2H), 2.47-2.36 (m, 5H), 2.31-2.13 (m, 2H).

Embodiment 21

N-{1-[2,2-two fluoro-2-(4-fluorophenyl) ethyl] piperidin-4-yl }-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Use with embodiment 19 above in the similar methods of step B, C and D report, title compound from difluoro (4-fluorophenyl) acetic acid (Hagele, G., Haas, A.J.of FluorineChemistry (1996) 76,15-19) preparation.HRMS (M+H ⁺): value of calculation=377.1696, measured value=377.1690; ¹H NMR (400MHz, CD ₃OD): δ 8.68-8.57 (m, 2H), 7.74-7.66 (m, 2H), 7.36-7.29 (m, 2H), 4.73-4.62 (m, 1H), 4.17-4.03 (m, 2H), 3.95-3.82 (m, 2H), 3.54-3.41 (m, 2H), 2.47-2.37 (m, 2H), 2.26-2.12 (m, 2H).

Embodiment 22

N-{1-[2,2-two fluoro-2-(2-fluorophenyl) ethyl] piperidin-4-yl }-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Title compound use with embodiment 19 above in the similar methods preparation of report.HRMS (M+H ⁺): value of calculation=377.1696, measured value=377.1677; ¹H NMR (400MHz, CD ₃OD): δ 8.71-8.63 (s, 1H), 8.63-8.57 (s, 1H), 7.73-7.61 (m, 2H), 7.44-7.30 (m, 2H), and 4.75-4.63 (m, 1H), 4.24-4.09 (m, 2H), 3.96-3.82 (m, 2H), 3.59-3.43 (m, 2H), 2.46-2.36 (m, 2H), 2.27-2.13 (m, 2H).

Embodiment 23

N-{1-[2-(2, the 6-difluorophenyl)-2,2-two fluoro ethyls] piperidin-4-yl }-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Steps A: 1,3-two fluoro-2-iodobenzenes

To 2-bromo-1,3-two fluorobenzene (5.7g, 30mmol) 1, add in the solution in the 4-two  alkane Hydro-Giene (Water Science). (0.28g, 1.5mmol), sodium iodide (8.9g, 59mmol) and N, N '-dimethyl ethane-1, the 2-diamidogen (0.32mL, 3.0mmol), and under nitrogen atmosphere with reactant mixture in 110 ℃ of heating.After 48 hours, reactant mixture inclines in the aqueous solution (20mL is in 200mL water) of ammonium hydroxide, uses ethyl acetate extraction.The organic facies salt water washing that merges through dried over sodium sulfate, is filtered and is concentrated, and obtains title compound (5.1g).

Step B:N-{1-[2-(2, the 6-difluorophenyl)-2,2-two fluoro ethyls] piperidin-4-yl }-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Title compound is according to method of reporting preparation among the embodiment 19 mentioned above.HRMS (M+H ⁺): value of calculation=395.1602, measured value=395.1598; ¹H NMR (400MHz, CD ₃OD): δ 8.65-8.61 (s, 1H), 8.61-8.58 (s, 1H), 7.71-7.62 (m, 1H), 7.23-7.15 (m, 2H), and 4.70-4.59 (m, 1H), 4.23-4.06 (m, 2H), 3.88-3.76 (m, 2H), 3.50-3.38 (m, 2H), 2.43-2.34 (m, 2H), 2.21-2.07 (m, 2H).

Embodiment 24

N-(1-{2,2-two fluoro-2-[4-(trifluoromethyl) phenyl] ethyl } piperidin-4-yl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Title compound use with embodiment 19 above in the similar methods preparation of report.HRMS (M+H ⁺): value of calculation=427.1664, measured value=427.1645; ¹H NMR (400MHz, CD ₃OD): δ 8.73-8.65 (s, 1H), 8.64-8.57 (s, 1H), 7.94-7.84 (m, 4H), 4.76-4.63 (m, 1H), 4.22-4.08 (m, 2H), 3.96-3.84 (m, 2H), 3.56-3.43 (m, 2H), 2.47-2.37 (m, 2H), 2.29-2.15 (m, 2H).

Embodiment 25

N-{1-[2-(4-bromophenyl)-2,2-two fluoro ethyls] piperidin-4-yl }-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Steps A: difluoro (4-bromophenyl) acetic acid

Under the room temperature nitrogen atmosphere, to aluminum chloride (2.2g, 16mmol) and chlorine (oxygen) ethyl acetate (1.9mL, add in suspension 16mmol) dropwise bromobenzene (1.5mL, 14mmol).After 24 hours, dropwise add frozen water solution and saturated sodium bicarbonate solution.The water layer ethyl acetate extraction, the salt water washing of the organic facies of merging through dried over sodium sulfate, is filtered and is concentrated.Through silica gel chromatography (1% ethyl acetate/hexane → 10% ethyl acetate/hexane) purification, obtain keto ester (1.4g), yellow oil.Under the room temperature, to the grease that obtains (1.4g, 5.6mmol) add in the solution in DCE (15mL) DAST (2.1mL, 17mmol).Reactant mixture is heated to 60 ℃.After 14 hours, reactant mixture is cooled to room temperature, inclines, and use ethyl acetate extraction in frozen water.The organic layer salt water washing that merges through dried over sodium sulfate, is filtered and the concentrated difluoro ester, grease of obtaining.The grease that obtains is dissolved in methanol: water (100mL: 20mL), be cooled to 0 ℃, and (1.0g 17mmol), stirs simultaneously to add the KOH sheet.After 2 hours, the reactant mixture washed with dichloromethane.Then, the water layer of merging alkalizes to pH＞8 with 5M NaOH, and uses ethyl acetate extraction.The organic facies salt water washing that merges through dried over sodium sulfate, is filtered and is concentrated, and obtains title compound (14g), waxy solid.

Step B:N-{1-[2-(4-bromophenyl)-2,2-two fluoro ethyls] piperidin-4-yl }-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Use with embodiment 19 above in the similar methods of step B, C and D report, title compound prepares from difluoro (4-bromophenyl) acetic acid.HRMS (M+H ⁺): value of calculation=437.0876, measured value=437.0846; ¹H NMR (500MHz, CD ₃OD): δ 8.72-8.66 (s, 1H), 8.63-8.60 (s, 1H), 7.79-7.74 (m, 2H), 7.61-7.56 (m, 2H), and 4.75-4.65 (m, 1H), 4.17-4.07 (m, 2H), 3.95-3.87 (m, 2H), 3.55-3.43 (m, 2H), 2.47-2.38 (m, 2H), 2.28-2.16 (m, 2H).

Embodiment 26

N-{1-[2-(4-cyclopropyl phenyl)-2,2-two fluoro ethyls] piperidin-4-yl }-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Title compound use with embodiment 25 above in the similar methods preparation of report.HRMS (M+H ⁺): value of calculation=399.2104, measured value=399.2110; ¹H NMR (500MHz, CD ₃OD): δ 8.70-8.64 (s, 1H), 8.64-8.58 (s, 1H), 7.54-7.48 (m, 2H), and 7.29-7.23 (m, 2H), 4.76-4.63 (m, 1H), 4.14-4.01 (m, 2H), 3.97-3.85 (m, 2H), 3.56-3.41 (m, 2H), 2.47-2.37 (m, 2H), 2.27-2.14 (m, 2H), 2.04-1.96 (m, 1H), 1.09-1.03 (m, 2H), 0.79-0.73 (m, 2H).

Embodiment 27

N-{1-[2,2-two fluoro-2-(4-methoxyphenyl) ethyl] piperidin-4-yl }-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Title compound use with embodiment 25 above in the similar methods preparation of report.HRMS (M+H ⁺): value of calculation=389.1896, measured value=389.1905; ¹H NMR (500MHz, CD ₃OD): δ 8.22-8.18 (s, 1H), 8.14-8.07 (s, 1H), 7.49-7.44 (m, 2H), 7.01-6.96 (m, 2H), 4.13-4.02 (m, 1H), 3.85-3.82 (s, 3H), 3.06-2.98 (m, 2H), 2.94-2.88 (m, 2H), 2.49-2.40 (m, 2H), 1.98-1.90 (m, 2H), and 1.68-1.57 (m, 2H).

Embodiment 28

N-[(3R, 4R)-3-fluoro-1-(2-phenethyl) piperidin-4-yl]-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Steps A: the 4-{[tert-butyl group (dimethyl) silicyl] oxygen }-3,6-dihydropyridine-1 (2H)-carboxylic acid benzene methyl

Under the room temperature, to 4-Oxypertine-1-carboxylic acid benzene methyl (170g, 750mmol) add in the solution in DMF (400mL) DIPEA (195mL) and (dimethyl) silicyl trifluoromethanesulfonic acid tert-butyl ester (220g, 840mmol).After 5 hours, reactant mixture inclines in saline, and uses ethyl acetate extraction.The organic facies that merges is filtered and is concentrated through dried over sodium sulfate, obtains title compound (240g).MS：348(M+H ⁺)。

Step B:3-fluoro-4-Oxypertine-1-carboxylic acid benzene methyl

Under the room temperature, to the 4-{ tert-butyl group (dimethyl) silicyl] oxygen }-3,6-dihydropyridine-1 (2H)-carboxylic acid benzene methyl (240g, 700mmol) add 1-(chloromethyl)-4-fluoro-1 in the solution in DMF (1.0L), 4-diazo bicyclic [2.2.2] octane two tetrafluoroborates (310g, 880mmol).After 2 hours, reactant mixture is inclined in saline, and use ethyl acetate extraction.The organic facies that merges is filtered and is concentrated through dried over sodium sulfate, obtains title compound (251g).MS：252(M+H ⁺)。

Step C: cis and trans-3-fluoro-4-hydroxy piperidine-1-carboxylic acid benzene methyl

In the time of 0 ℃, to 3-fluoro-4-Oxypertine-1-carboxylic acid benzene methyl (24g, 97mmol) in the solution in methanol (250mL) with fraction add Sodium Borohydride (5.5g, 150mmol), to prevent the warm speed that surpasses room temperature of reactant mixture.After 4 hours, concentrated reaction mixture.The residue that obtains is dissolved in the ethyl acetate, uses the salt water washing, through dried over sodium sulfate, filters and be concentrated into drying.Through silica gel chromatography (10% ethyl acetate/hexane → 60% ethyl acetate/hexane) purification, obtain two kinds of title compounds:

Cis-3-fluoro-4-hydroxy piperidine-1-carboxylic acid benzene methyl: 18g; Colorless oil; MS:254 (M+H ⁺); ¹H MMR (400MHz, CDCl ₃): δ 7.40-7.32 (m, 5H), 5.20 (s, 2H), 4.72-4.52 (m, 1H), 4.15-3.25 (m, 6H), 2.17 (s, 1H), 1.88-1.67 (m, 2H);

Trans-3-fluoro-4-hydroxy piperidine-1-carboxylic acid benzene methyl: 4.5g; Colorless oil; MS:254 (M+H ⁺); ¹H NMR (400MHz, CDCl ₃): δ 7.40-7.32 (m, 5H), 5.18 (s, 2H), 4.40-3.80 (m, 4H), 3.25-3.05 (m, 2H), 2.30 (s, 1H), 2.00 (s, and 1H) 1.58 (s, 1H).

Step D: cis-3-fluoro-4-[(mesyl) oxygen] piperidines-1-carboxylic acid benzene methyl

In the time of-10 ℃, to cis-3-fluoro-4-hydroxy piperidine-1-carboxylic acid benzene methyl (24g, 97mmol) add in the solution in dichloromethane (150mL) DIPEA (28mL, 190mmol) and mesyl chloride (9.0g, 79mmol), and with reactant mixture slowly be warmed to room temperature.After 3 hours, reactant mixture inclines in saline, uses dichloromethane extraction, through dried over sodium sulfate, filters and concentrates, and obtains title compound (31g), grease.MS：332(M+H ⁺)。

Step e: trans-the 4-azido-3-fluorine piperidines-1-carboxylic acid benzene methyl

To cis-3-fluoro-4-[(mesyl) oxygen] (10g, (9.8g 150mmol), and is heated to 80 ℃ with reactant mixture to piperidines-1-carboxylic acid benzene methyl 30mmol) to add Hydrazoic acid,sodium salt in the solution in DMF (25mL).After 48 hours, reactant mixture is inclined in saline, use ethyl acetate extraction,, filter and concentrate through dried over sodium sulfate.Through silica gel chromatography (0% isopropyl alcohol/dichloromethane → 10%IPA/ dichloromethane) purification, obtain title compound (6.6g), grease.MS：279(M+H ⁺)。

Step F: trans-the 4-azido-3-fluorine piperidines

To trans-4-azido-3-fluorine piperidines-1-carboxylic acid benzene methyl (15g, 54mmol) add in the solution in TFA (5mL) thioanisole (13g, 110mmol), and with solution in 70 ℃ the heating 1 hour.Cooling mixture also concentrates.The residue that obtains is dissolved in the ethyl acetate (60mL), handles and concentrate with the saturated solution of HCl in ethyl acetate (50mL) under the room temperature.From ethyl acetate and hexane recrystallization, obtain title compound (6.5g), white solid.MS：145(M+H ⁺)。

Step G: trans-the 4-azido-3-fluoro-1-(phenylacetyl group) piperidines

Under the room temperature, to trans-4-azido-3-fluorine piperidines (1.2g, 8.7mmol) add in the solution in dichloromethane (25mL) DIPEA (3.8mL, 26mmol) and phenyllacetyl chloride (1.3g, 8.7mmol).After 1 hour, reactant mixture is inclined in saturated sodium bicarbonate, and use chloroform extraction.The organic facies that merges obtains title compound (1.7g) through dried over sodium sulfate, filtration and concentrated.MS：263(M+H ⁺)。

Step H: trans-3-fluoro-1-(2-phenethyl) piperidines-4-amine

Under nitrogen, (1.7g 6.5mmol) is added in THF (79mL, 1M monoborane 79mmol), and reactant mixture is heated to 80 ℃ in the solution in THF (20mL) to trans-4-azido-3-fluoro-1-(phenylacetyl group) piperidines in room temperature.After 1 hour, reactant mixture is cooled to room temperature,, and is heated to 80 ℃ with 6N HCl (50mL) quencher.After 1 hour, reactant mixture is alkalized to pH＞8, and use chloroform extraction with 5M NaOH.The organic facies that merges is filtered and is concentrated through dried over sodium sulfate, obtains title compound (1.0g).MS：223(M+H ⁺)。

Step I:N-[is trans-3-fluoro-1-(2-phenethyl) piperidin-4-yl]-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Title compound use with embodiment 1 above in the similar methods preparation of step C report.HRMS (M+H ⁺): value of calculation=341.1878, measured value=341.1885; ¹H NMR (400MHz, CD ₃OD): δ 8.30 (s, 1H), 8.15 (s, 1H), 7.38-7.18 (m, 5H), 4.70-4.40 (m, 2H), 3.40 (m, 1H), 3.00 (m, 1H), 2.85-2.58 (m, 4H), 2.30 (m, 2H), 2.25 (m, 1H), 1.60 (m, 1H).

Embodiment 29

N-[cis-3-fluoro-1-(2-phenethyl) piperidin-4-yl]-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Steps A: cis-4-azido-3-fluorine piperidines

Use with embodiment 28 above in the similar methods of step D, E and F report, title compound is from trans-3-fluoro-4-hydroxy piperidine-1-carboxylic acid benzene methyl (embodiment 28, step C) preparation.MS：145(M+H ⁺)。

Step B:N-[cis-3-fluoro-1-(2-phenethyl) piperidin-4-yl]-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Title compound use with embodiment 28 above in the similar methods preparation of step G, H and I report.HRMS (M+H ⁺): value of calculation=341.1876, measured value=341.1885; ¹HNMR (400MHz, CD ₃OD) 8.30-8.20 (m, 2H), 7.32-7.18 (m, 5H), 5.00-4.80 (m, 1H), 4.50-4.40 (m, 1H), 3.40 (m, 1H), 3.10 (m, 1H), 2.85-2.60 (m, 4H), 2.50-2.10 (m, 3H), 1.90 (m, 1H).

Embodiment 30

N-{ is trans-3-fluoro-1-[2-(4-tolyl) ethyl] and piperidin-4-yl }-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Title compound use with embodiment 28 above in the similar methods preparation of step G, H and I report.HRMS (M+H ⁺): value of calculation=355.4317, measured value=355.4216; ¹HNMR (400MHz, CD ₃OD) 8.65 (s, 2H), 7.30-7.18 (m, 4H), 4.58-4.20 (m, 2H), 4.15-3.85 (m, 1H), 3.80-3.35 (m, 7H), 3.15 (m, 2H), 2.38 (s, 3H).

Embodiment 31

N-{ cis-3-fluoro-1-[2-(4-tolyl) ethyl] piperidin-4-yl }-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Title compound use with embodiment 29 above in the similar methods preparation of report.HRMS (M+H ⁺): value of calculation=355.4317, measured value=355.4128; ¹H NMR (400MHz, CD ₃OD) 8.62 (s, 2H), 7.28-7.20 (m, 4H), 5.38-4.80 (m, 1H), 4.20-3.83 (m, 1H), 3.85-3.42 (m, 7H), 3.25 (m, 2H), 2.35 (s, 3H).

Embodiment 32

N-[is trans-3-fluoro-1-(2-fluoro-2-phenethyl) piperidin-4-yl]-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Steps A: 2-[is trans-4-azido-3-fluorine piperidines-1-yl]-the 1-phenylethanol

Title compound use with embodiment 6 above in the similar methods preparation of steps A report.MS：265(M+H ⁺)。

Step B: trans-the 4-azido-3-fluoro-1-(2-fluoro-2-phenethyl) piperidines

Title compound use with embodiment 17 above in the similar methods preparation of steps A report.MS：267(M+H ⁺)。

Step C: trans-3-fluoro-1-(2-fluoro-2-phenethyl) piperidines-4-amine

Title compound use with embodiment 28 above in the similar methods preparation of step H report.MS：241(M+H ⁺)。

Step D:N-[is trans-3-fluoro-1-(2-fluoro-2-phenethyl) piperidin-4-yl]-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Title compound use with embodiment 1 above in the similar methods preparation of step C report.HRMS (M+H ⁺): value of calculation=359.1780, measured value=359.1791; ¹H NMR (400MHZ, CD ₃OD): δ 8.25-8.15 (m, 2H), 7.40-7.35 (m, 5H), 5.80-5.60 (m, 1H), 4.80-4.35 (m, 2H), 3.45 (m, 1H), 3.10-2.95 (m, 2H), 2.85-2.70 (m, 1H), 2.40 (m, 2H), 2.18 (m, 1H), 1.70 (m, 1H).

Embodiment 33

N-[anti-form-1-(2,2-two fluoro-2-phenethyls)-3-fluorine piperidin-4-yl]-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Steps A: trans-the 4-azido-1-[difluoro (phenyl) acetyl group]-3-fluorine piperidines

Under the room temperature, to difluoro (phenyl) acetic acid (Hagele, G., Haas, A.J.of FluorineChemistry (1996) 76,15-19) (1.7g, 10.4mmol) add oxalyl chloride in the solution in dichloromethane (25mL) (5.2mL, 2M in dichloromethane, 10.4mmol) and a DMF.After 1 hour, under the room temperature, (1.5g is 10mmol) and in the solution of resin-DIPEA (40mmol eq) in dichloromethane (50mL) reactant mixture to be added trans-4-azido-3-fluorine piperidines.After 2 hours, reactant mixture is filtered and concentrates, obtain title compound (2.5g), solid.MS：299(M+H ⁺)。

Step B:N-[(3R, 4R)-1-(2,2-two fluoro-2-phenethyls)-3-fluorine piperidin-4-yl]-1H-pyrazolo [3,4-d] pyrimidine-4-amine

According to the similar methods of step H among the embodiment 28 above and I report, title compound is from trans-4-azido-1-[difluoro (phenyl) acetyl group]-preparation of 3-fluorine piperidines.HRMS (M+H ⁺): value of calculation=377.1676, measured value=377.1696; ¹H NMR (400MHz, CD ₃OD): δ 8.20 (s, 1H), 8.10 (s, 1H), 7.55-7.45 (m, 5H), 4.51-4.31 (m, 2H), 3.17-3.10 (m, 3H), 2.80 (m, 2H), 2.52 (m, 2H), 2.00 (m, 1H), 1.51 (m, 1H).

Embodiment 34

N-[cis-1-(2,2-two fluoro-2-phenethyls)-3-fluorine piperidin-4-yl]-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Use with embodiment 33 above in the similar methods of report, title compound is from cis-4-azido-3-fluorine piperidines (embodiment 29, steps A) preparation.HRMS (M+H ⁺): value of calculation=377.1676, measured value=377.1696; ¹H NMR (400MHz, CD ₃OD): δ 8.22 (m, 2H), 7.56 (m, 2H), 7.44 (m, 3H), 4.84-4.70 (m, 1H), 4.39-4.33 (m, 1H), 3.31-3.12 (m, 3H), 2.87-2.57 (m, 3H), 2.07 (m, 1H), 1.70 (m, 1H).

Embodiment 35

N-{ anti-form-1-[2,2-two fluoro-2-(4-tolyl) ethyl]-3-fluorine piperidin-4-yl }-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Title compound use with embodiment 33 above in the similar methods preparation of report.HRMS (M+H ⁺): value of calculation=391.1853, measured value=391.1811; ¹H NMR (400MHz, CD ₃OD): δ 8.22 (s, 1H), 8.12 (s, 1H), 7.55-7.22 (m, 4H), 4.58-4.30 (m, 2H), 3.30-3.12 (m, 3H), 2.78 (m, 1H), 2.52 (m, 2H), 2.42 (s, 3H), 1.98 (m, 1H), 1.62 (m, 1H).

Embodiment 36

N-(anti-form-1-and 2,2-two fluoro-2-[4-(trifluoromethyl) phenyl] ethyl }-3-fluorine piperidin-4-yl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Title compound use with embodiment 33 above in the similar methods preparation of report.HRMS (M+H ⁺): value of calculation=445.1570, measured value=445.1567; ¹H NMR (400MHz, CD ₃OD): δ 8.31-8.22 (m, 2H), 7.81-7.62 (m, 4H), 4.42-4.20 (m, 1H), 3.21 (m, 2H), 2.89-2.62 (m, 4H), 2.04 (m, 2H), 1.73 (m, 1H).

Embodiment 37

N-(cis-1-{2,2-two fluoro-2-[4-(trifluoromethyl) phenyl] ethyl }-3-fluorine piperidin-4-yl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Title compound use with embodiment 34 above in the similar methods preparation of report.HRMS (M+H ⁺): value of calculation=445.1570, measured value=445.1539; ¹H NMR (400MHz, CD ₃OD): δ 8.70 (s, 1H), 8.62 (s, 1H), 7.82 (m, 4H), 5.1 8-5.12 (m, 1H), 3.88-3.78 (m, 4H), 3.52-3.19 (m, 2H), 2.42 (m, 2H), 2.08 (m, 1H).

Embodiment 38

N-[1-(2,2-two fluoro-2-phenethyls) azacyclo-heptan-4-yl]-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Steps A: 1-[difluoro (phenyl) acetyl group] azacyclo-heptan-4-ketone

Title compound use with embodiment 19 above in the similar methods preparation of step B report.MS：268(M+H ⁺)。

Step B:N-[1-(2,2-two fluoro-2-phenethyls) azacyclo-heptan-4-yl]-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Title compound use with embodiment 28 above in the similar methods preparation of step C, D, E, H and I report.HRMS (M+H ⁺): value of calculation=373.1947, measured value=373.1955; ¹H NMR (400MHz, CD ₃OD): δ 8.67 (s, 1H), 8.57 (s, 1H), 7.66-7.55 (m, 5H), 4.72 (m, 1H), 4.19-4.10 (m, 2H), 3.89-3.65 (m, 4H), 2.42-2.34 (m, 3H), 2.21-2.08 (m, 1H), 1.98-1.90 (m, 1H).Through chirality HPLC (15% isopropanol/hexane/0.1%DEA → 20% isopropanol/hexane/0.1%DEA; Chiralpak AD, available from ChiralTechnologies, Inc., Exton, Pa) purification, obtain the optical voidness product, it is with anhydrous hydrochloric acid solution-treated in ethyl acetate and concentrate, and obtains the hydrochlorate of title compound: (R or S)-N-[1-(2,2-two fluoro-2-phenethyls) azacyclo-heptan-4-yl]-1H-pyrazolo [3,4-d] pyrimidine-4-amine: peak 1, HRMS (M+H ¹): value of calculation=373.1947, measured value=373.1953; (S or R)-N-{1-[2,2-two fluoro-2-(4-tolyl) ethyl] azacyclo-heptan-4-yl }-1H-pyrazolo [3,4-d] pyrimidine-4-amine: peak 2, HRMS (M+H ⁺): value of calculation=373.1947, measured value=373.1958.

Embodiment 39

N-[1-(2,2-two fluoro-2-(4-tolyl) ethyl) azacyclo-heptan-4-yl]-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Title compound use with embodiment 38 above in the similar methods preparation of report.Through chirality HPLC (Chiralcel OJ, the purification of 60% isopropanol/hexane/0.1%DEA) obtains the enantiomer of title compound: (R or S)-N-{1-[2,2-two fluoro-2-(4-tolyl) ethyl] azacyclo-heptan-4-yl }-1H-pyrazolo [3,4-d] pyrimidine-4-amine: peak 1, HRMS (M+H ⁺): value of calculation=387.2104, measured value=387.2075; ¹H NMR (400MHz, CD ₃OD): δ 8.22 (s, 1H), 8.10 (s, 1H), 7.43 (d, J=6.4Hz, 2H), 7.27 (d, J=6.4Hz, 2H), 4.38 (m, 1H), 3.20 (t, J=11.4Hz, 2H), 2.88-2.77 (m, 4H), 2.38 (s, 3H), 1.99-1.96 (m, 1H), 1.80-1.71 (m, 3H), 1.64-1.62 (m, 1H); (S or R)-N-{1-[2,2-two fluoro-2-(4-tolyl) ethyl] azacyclo-heptan-4-yl }-1H-pyrazolo [3,4-d] pyrimidine-4-amine: peak 2, HRMS (M+H ⁺): value of calculation=387.2104, measured value=387.2104; ¹H NMR (400MHz, CD ₃OD): δ 8.22 (s, 1H), 8.10 (s, 1H), 7.43 (d, J=6.4Hz, 2H), 7.27 (d, J=6.4Hz, 2H), 4.38 (m, 1H), 3.20 (t, J=11.4Hz, 2H), 2.88-2.77 (m, 4H), 2.38 (s, 3H), 1.99-1.96 (m, 1H), 1.80-1.71 (m, 3H), 1.64-1.62 (m, 1H).

Embodiment 40

N-{ is outer-3-[2,2-two fluoro-2-(4-tolyl) ethyl]-3-azabicyclo [3.1.0] oneself-the 6-yl-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Use with embodiment 19 above in the similar methods of report, title compound from outer-3-azabicyclo [3.1.0] oneself-(method by document prepares the 6-aminocarbamic acid tert-butyl ester: Norris, T., Braish, T.F., Butters, M., DeVries, K.M., Hawkins, J.M., Massett, S.S., Rose, P.R., Santafianos, D., Sklavounos, C.J.Chem.Soc., Perkin Trans.1 (2000) 1615-1622) preparation.HRMS (M+H ⁺): value of calculation=371.1791, measured value=371.1801; ¹H NMR (400MHz, CD ₃OD): δ 8.62-8.57 (s, 1H), 8.54-8.49 (s, 1H), 7.51-7.44 (m, 2H), 7.39-7.32 (m, 2H), 4.16-3.80 (m, 3H), 3.63-3.56 (m, 1H), 2.51-2.42 (m, 2H), 2.42-2.36 (s, 3H).

Embodiment 41

Raceme-N-[(3aS ^*, 4R ^*, 6aR ^*)-2-(2-phenethyl) octahydro ring penta [c] pyrroles-4-yl]-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Steps A: raceme-2-benzyl six hydrogen ring penta [c] pyrroles-4 (1H)-ketone

Under the room temperature, to N-benzyl-1-methoxyl group-N-[(trimethyl silyl) methyl] hexamethylenetetramine (and 11g, 46mmol) and ring penta-2-alkene-1-ketone (3.8g, 46mmol) add in the solution in dichloromethane (50mL) TFA (12mL, 68mmol).After 1 hour, reactant mixture is inclined in 1 MNaOH (500mL), and use ethyl acetate extraction.Drying is filtered and be concentrated into to the organic facies that merges through dried over sodium sulfate.The residue that obtains is dissolved in the ethyl acetate, handles with the saturated solution of HCl in ethyl acetate, and concentrate, obtain the HCl salt (11g) of title compound, solid.MS：216(M+H ⁺)。

Step B: raceme-(3aS ^*, 4S ^*, 6aR ^*)-2-benzyl octahydro ring penta [c] pyrroles-4-alcohol

In the time of-78 ℃, to raceme-(10g 46mmol) adds L-Selectride (8.8g in the solution in THF (50mL) to 2-benzyl octahydro ring penta [c] pyrroles-4 (1H)-ketone, 46mmol, available from Sigma-Aldrich, Inc., St.Louis Mo), and slowly is warmed to room temperature with reactant mixture.After 2 hours, reactant mixture is inclined in 1M NaOH (500mL), and use ethyl acetate extraction.The organic facies that merges is filtered and is concentrated through dried over sodium sulfate.Through silica gel chromatography (0%IPA/ dichloromethane → 10% isopropyl alcohol/dichloromethane) purification, obtain title compound (5.0g).MS：218(M+H ⁺)。

Step C: raceme-tert-butyl group (3aS ^*, 4S ^*, 6aR ^*)-4-hydroxyl six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acids

To raceme-(3aS ^*, 4S ^*, 6aR ^*)-2-benzyl octahydro ring penta [c] pyrroles-4-alcohol (1.4g, 6.2mmol) adding heavy carbonic di tert butyl carbonate (1.5g in the solution of ethanol (100mL), 7.0mmol) and palladium carbon, 20wt%Pd (dry basis), wet (available from Sigma-Aldrich, Inc., St.Louis, Mo.), and in room temperature reactant mixture is placed under the 50psi hydrogen.After 20 hours, reactant mixture is filtered and concentrates, obtain title compound (0.85g).MS：228(M+H ⁺)。

Step D: raceme-(3aS ^*, 4R ^*, 6aR ^*)-4-azido six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acid tert-butyl esters

Title compound use with embodiment 28 above in the similar methods preparation of step D and E report.MS：253(M+H ⁺)。

Step e: raceme-N-[(3aS, 4R, 6aR)-2-(2-phenethyl) octahydro ring penta [c] pyrroles-4-yl]-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Title compound use with embodiment 28 above in the similar methods preparation of step G, H and I report.HRMS (M+H ⁺): value of calculation=349.2135, measured value=349.2146; ¹HNMR (400MHz, CD ₃OD): δ 8.32 (s, 1H), 8.20 (s, 1H), 7.35-7.15 (m, 5H), 4.38 (s, 1H), 2.89-2.60 (m, 10H), 2.38 (s, 1H), 2.20-2.08 (m, 2H), 1.70 (m, 1H), 1.50 (m, 1H).

Embodiment 42

Raceme-N-[(3aS ^*, 4R ^*, 6aR ^*)-2-(2,2-two fluoro-2-phenethyls) octahydro ring penta [c] pyrroles-4-yl]-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Use with embodiment 33 above in the similar methods of report, title compound is from raceme-(3aS ^*, 4R ^*, 6aR ^*)-4-azido octahydro ring penta [c] pyrroles (seeing embodiment 41, step D) preparation.HRMS (M+H ¹): value of calculation=385.1947, measured value=385.1923; ¹HNMR. (400MHz, CD ₃OD): δ 8.28 (s, 1H), 8.15 (s, 1H), 7.60 (s, 2H), 7.38 (m, 3H), 4.32 (s, 1H), 3.10 (m, 2H), 2.80-2.42 (m, 6H), 2.00 (m, 2H), 1.52 (m, 1H), 1.40 (m, 1H).

Embodiment 43

Raceme-N-{ (3aS ^*, 4R ^*, 6aR ^*)-2-[2,2-two fluoro-2-(4-tolyl) ethyl] octahydro ring penta [c] pyrroles-4-yl }-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Use with embodiment 33 above in the similar methods of report, title compound is from raceme-(3aS ^*, 4R ^*, 6aR ^*)-4-azido octahydro ring penta [c] pyrroles (seeing embodiment 41, step e) preparation.HRMS (M+H ⁺): value of calculation=399.2104, measured value=399.2095; ¹HNMR (400MHz, CD ₃OD): δ 8.82 (s, 1H), 8.60 (s, 1H), 7.58-7.40 (m, 4H), 4.70 (s, 1H), 4.28-4.10 (m, 4H), 3.29-3.08 (m, 3H), 2.50-2.30 (m, 4H), 2.28-2.00 (m, 2H), 1.80 (m, 1H).

Embodiment 44

In-N-[8-(2,2-two fluoro-2-phenethyls)-8-azabicyclo [3.2.1] oct-3-yl]-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Steps A: 3-(oximido)-8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

Under the room temperature, to 3-oxygen-8-azabicyclo [3.2.1] octane-8-carboxylic acid difluoro tert-butyl ester (3.0g, 13mmol) add in the solution in methanol (35mL) oxammonium hydrochloride. (4.6g, 61mmol) and sodium acetate (11g, 133mmol).72 hours, mixture is inclined in water, and extract with ether.The organic facies salt water washing that merges through dried over sodium sulfate, is filtered and is concentrated, and obtains title compound (3.1g), white solid.MS：241(M+H ⁺)。

Step B: interior-3-amino-8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

Following method is according to by Suzuki, M., and Ohuchi, Y., Asanuma, H., Kaneko, T., Yokomori, S., Ito, C., Isobe, Y., Muramatsu, M.Chem.Pharm.Bull. (2001) 49 (1), 29-39 institute reported method.To 3-(oximido)-8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (2.0g, 8.3mmol) add platinum dioxide (0.10g) in the solution in acetic acid (25mL), and solution is exposed in the Parr hydrogenation apparatus in the 50psi hydrogen (available from Parr InstrumentCompany, Moline, Ill.).After 17 hours, mixture is filtered and concentrates.Residue inclines in 5M NaOH, and uses dichloromethane extraction.The organic facies salt water washing that merges through dried over sodium sulfate, is filtered and is concentrated, and obtains title compound (2.0g), grease.MS：227(M+H ⁺)。

Step C: interior-the 3-{[(benzyloxy) carbonyl] amino }-8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

Under the room temperature, outwards-3-amino-8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (2.0g, 8.7mmol) add in the solution in dichloromethane (18mL) DIPEA (3.0mL, 17mmol) and benzyl chloroformate (1.1mL, 13mmol).After 2 hours, reactant mixture is diluted with ethyl acetate, water, 1M citric acid, water, 1M NaOH, salt water washing through dried over sodium sulfate, are filtered and are concentrated, and obtain title compound (3.3g).MS：361(M+H ⁺)。

Step D: interior-8-azabicyclo [3.2.1] oct-3-yl carbamic acid benzene methyl

Title compound use with embodiment 1 above in the similar methods preparation of step B report.MS：261(M+H ⁺)。

Step e: interior-8-[difluoro (phenyl) acetyl group]-8-azabicyclo [3.2.1] oct-3-yl } the carbamic acid benzene methyl

Title compound use with embodiment 19 above in the similar methods preparation of step B report.MS：415(M+H ⁺)。

Step F: interior-N-[8-(2,2-two fluoro-2-phenethyls)-8-azabicyclo [3.2.1] oct-3-yl]-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Title compound use with embodiment 28 above in the similar methods preparation of step F, H and I report.HKMS (M+Ff): value of calculation=385.1947, measured value=385.1933; ¹HNMR (400MHz, CD ₃OD): δ 8.88 (s, 1H), 8.66 (s, 1H), 7.69-7.67 (m, 2H), 7.61-7.57 (m, 3H), 4.60 (m, 1H), 4.31 (br s, 2H), 4.00 (m, 2H), 2.75 (m, 2H), 2.59-2.45 (m, 6H).

Embodiment 45

Outward-N-[8-(2,2-two fluoro-2-phenethyls)-8-azabicyclo [3.2.1] oct-3-yl]-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Steps A: outer-3-amino-8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

In room temperature under nitrogen atmosphere, to 3-(oximido)-8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (1.0g, 4.2mmol; Embodiment 44, steps A) (1.0g 42mmol), went through 10 minutes to add sodium metal with fraction in the solution in the 1-propanol (15mL is through 4  molecular sieve dryings).With reactant mixture reflux 4.5 hours, with being cooled to room temperature.The quencher of reactant mixture water is also used dichloromethane extraction.The organic facies that merges extracts with 2M HCl, and with the potassium hydroxide solid water layer that merges is alkalized, and uses dichloromethane extraction.The organic facies that merges is filtered and is concentrated through dried over sodium sulfate, obtains title compound (0.36g), colorless oil.MS：227(M+H ⁺)。

Step B: outer-N-[8-(2,2-two fluoro-2-phenethyls)-8-azabicyclo [3.2.1] oct-3-yl-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Title compound use with embodiment 44 above in the similar methods preparation of step C, D, E and F report.HRMS (M+H ⁺): value of calculation=385.1947, measured value=385.1960; ¹H NMR (400MHz, CD ₃OD): δ 8.18 (s, 1H), 8.07 (s, 1H), 7.57-7.55 (m, 2H), 7.45-7.43 (m, 3H), 4.49-4.48 (m, 1H), 3.14 (br s, 2H), 3.06 (t, J=13.6Hz, 2H), and 1.95-1.93 (m, 2H), 1.80-1.76 (m, 4H), 1.70-1.64 (m, 2H).

Embodiment 46

N-(1-{2-[4-(difluoromethyl) phenyl]-2,2-two fluoro ethyls } piperidin-4-yl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Title compound use with embodiment 19 above in the similar methods preparation of report.HRMS (M+H ⁺): value of calculation=409.1759, measured value=4019.1725; ¹H NMR (500MHz, CD ₃OD): δ 8.74-8.65 (s, 1H), 8.65-8.58 (s, 1H), 7.83-7.73 (m, 4H), 7.01-6.75 (m, 1H), and 4.77-4.64 (m, 1H), 4.22-4.07 (m, 2H), 3.98-3.87 (m, 2H), 3.58-3.44 (m, 2H), 2.48-2.37 (m, 2H), 2.29-2.15 (m, 2H).

Embodiment 47

N-{1-[2-(4-ethylphenyl)-2,2-two fluoro ethyls] piperidin-4-yl }-1H-pyrazolo [3,4-d] pyrimidine-4-amine

To N-{1-[2-(4-bromophenyl)-2,2-two fluoro ethyls] piperidin-4-yl }-1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazolo [3,4-d] (embodiment 46 for pyrimidine-4-amine, 0.21g, 0.39mmol) add in the solution in dry toluene (1.5mL) ethyl-boron dihydroxide (0.04g, 0.59mmol), anhydrous phosphoric acid potassium; Trivalent (0.25g, 1.18mmol), connection (diphenyl methylene acetone) palladium (Pd (dba) ₂) (0.01g, 0.02mmol) with 1,2,3,4,5-pentapheneyl-1 '-(di-t-butyl phosphino-) ferrocene (Q-phos) (0.028g, 0.04mmol).Gained solution heated 48 hours in hot oil bath in 120 ℃, stirred simultaneously.With the mixture cooling, be dissolved in the ethyl acetate (30mL), use 1M NaOH, water is used the salt water washing at last then.Drying is filtered and be concentrated into to the organic facies that merges through dried over sodium sulfate.The residue that obtains is dissolved in the methanol (2.5mL), through reverse-phase chromatography (5% acetonitrile/0.1% trifluoroacetic acid/water → 95% acetonitrile/0.1% trifluoroacetic acid/water, XTerra  MSC8 post is available from WatersCorporation, Milford, Massachusetts).With the partial concentration of needs, the residue that obtains is dissolved in the methanol (3mL), and at room temperature uses the saturated solution of HCl in ethyl acetate (10mL) to handle.After 1 hour, solid is separated out from solution, then it is filtered, and obtains the hydrochlorate (0.014g) of title compound, yellow solid.HRMS (MH-H ⁺): value of calculation=387.2104, measured value=387.2055; ¹H NMR (500MHz, CD ₃OD): δ 8.64-8.54 (m, 2H), 7.57-7.51 (m, 2H), 7.43-7.38 (m, 2H), 4.72-4.60 (m, 1H), 4.14-3.98 (m, 2H), 3.96-3.82 (m, 2H), 3.54-3.39 (m, 2H), 2.77-2.69 (m, 2H), 2.46-2.36 (m, 2H), 2.26-2.12 (m, 2H), and 1.30-1.22 (m, 3H).

Embodiment 48

N-((3S, 4S)-1-{2-[4-(difluoromethyl) phenyl]-2,2-two fluoro ethyls }-3-fluorine piperidin-4-yl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Title compound use with embodiment 33 above in the similar methods preparation of report.MS(M+H ⁺)＝426.2； ¹H?NMR(500MHz，CD ₃OD)：δ8.77(s，1H)，8.62(s，1H)，7.74(q，J＝8.3Hz，4H)，6.86(t，J＝55.9Hz，1H)，3.86(m，3H)，3.59(br?s，1H)，3.22(br?s，2H)，2.40(br?s，1H)，2.03(s，1H)。

Embodiment 49

N-((3S, 4S)-3-fluoro-1-{2-[4-(trifluoromethyl) phenyl] ethyl } piperidin-4-yl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Title compound use with embodiment 33 above in the similar methods preparation of report.MS(M+H ⁺)409.2； ¹H?NMR(500MHz，CD ₃OD)：δ8.72(s，1H)，8.66(s，1H)，7.68(d，J＝8.1Hz，2H)，7.56(d，J＝7.8Hz，2H)，5.25(m，1H)，5.05(s，1H)，4.11(s，1H)，3.97(s，1H)，3.56(s，2H)，3.39(s，1H)，2.54(s，1H)，2.38-2.18(m，1H)，2.04(s，1H)。

Embodiment 50

N-(1-{2,2-two fluoro-2-[4-(trifluoromethyl) phenyl] ethyl } azacyclo-heptan-4-yl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine

Title compound use with embodiment 38 above in the similar methods preparation of report.Through chirality HPLC (20% isopropyl alcohol/80% hexane/0.1%DEA, Chiralpak AD, available from ChiralTechnologies, Inc., Exton, Pa) purification obtains the enantiomer of title compound: (R or S)-N-(1-{2,2-two fluoro-2-[4-(trifluoromethyl) phenyl] ethyl } azacyclo-heptan-4-yl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine: peak 1, HRMS (M+H ⁺): value of calculation=441.1821, measured value=441.1782; ¹H NMR (400MHz, CD ₃OD): δ 8.21 (s, 1H), 8.09 (s, 1H), 7.78 (s, 4H), 4.33 (m, 1H), 3.27 (m, 2H), 2.85-2.76 (m, 4H), 1.97-1.94 (m, 2H), 1.72-1.59 (m, 4H); (S or R)-N-(1-{2,2-two fluoro-2-[4-(trifluoromethyl) phenyl] ethyl } azacyclo-heptan-4-yl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine: peak 2, HRMS (M+H ⁺): value of calculation=441.1821, measured value=441.1821; ¹H NMR (400MHz, CD ₃OD): δ 8.21 (s, 1H), 8.09 (s, 1H), 7.78 (s, 4H), 4.33 (m, 1H), 3.27 (m, 2H), 2.85-2.76 (m, 4H), 1.97-1.94 (m, 2H), 1.72-1.59 (m, 4H).

Claims

1. the chemical compound of formula (I) and/or its officinal salt, one enantiomer and stereoisomer:

Wherein:

W is aryl or heteroaryl, and wherein said aryl or heteroaryl are optional to be independently selected from following substituent group replacement by 1-5: halogen, C _3-6Cycloalkyl, cyano group, C _1-4Alkoxyl and C _1-6Alkyl, wherein said alkoxyl is optional to be replaced by one or more halogens, and described alkyl is optional is selected from following substituent group and replaces by one or more: hydrogen, halogen and hydroxyl;

And, R ³And R ⁴Connected ring is chosen the cycloalkyl that participates in forming bridge joint wantonly together.

2. the chemical compound of claim 1 and/or its single enantiomer, diastereomer or officinal salt, wherein:

R ³And R ⁴Each is hydrogen independently;

3. chemical compound and/or its single enantiomer, diastereomer or the officinal salt of formula (Ia) expression:

Wherein:

4. chemical compound and/or its single enantiomer, diastereomer or the officinal salt of formula (Ib) expression:

Wherein:

5. chemical compound and/or its single enantiomer, diastereomer or the officinal salt of formula (Ic) expression:

Wherein:

6. chemical compound and/or its single enantiomer, diastereomer or the officinal salt of formula (Id) expression:

Wherein:

While R ³And R ⁴Coupled ring can be chosen the cycloalkyl that participates in forming bridge joint wantonly together.

7. chemical compound and/or its single enantiomer, diastereomer or the officinal salt of formula (Ie) expression:

Wherein:

8. chemical compound is selected from:

And/or its single enantiomer, diastereomer or officinal salt.

9. pharmaceutical composition comprises the chemical compound of the claim 1 of inert carrier and treatment effective dose.

10. the pharmaceutical composition of claim 9 further comprises another kind of therapeutic agent, is selected from: (i) NSAID (non-steroidal anti-inflammatory drug); (ii) cox 2 inhibitor; (iii) bradykinin b 1 receptor antagonist; (iv) sodium channel blockers and antagonist; (v) nitric oxide synthase (NOS) inhibitor; (vi) glycine site antagonist; (vii) potassium channel openers (opener); (viii) AMPA/ kainate (kainate) receptor antagonist body; (ix) calcium-channel antagonists; (x) GABA-A receptor modulators (as the GABA-A receptor stimulating agent); (xi) matrix metalloproteinase (MMP) inhibitor; (xii) thrombolytic agent; (xiii) opioid such as morphine; (xiv) neutrophil cell inhibitive factor (NIF); (xv) levodopa; (xvi) carbidopa; (xvii) levodopa/carbidopa; (xviii) dopamine agonist such as bromocriptine, pergolide, pramipexole, ropinirole; (xix) anticholinergic; (xx) amantadine; (xxi) carbidopa; (xxii) catechol O-transmethylase (" COMT ") inhibitor such as An Takapeng and tolcapone; (xxiii) monoamine oxidase-B (" MAO-B ") inhibitor; (xiv) opiate (opiate) agonist or antagonist; (xv) 5HT receptor stimulating agent or antagonist; (xvi) nmda receptor agonist or antagonist; (xvii) NK1 antagonist; (xviii) selective serotonin reuptake inhibitor (" SSRI ") and/or selective serotonin and NRI (" SSNRI "); (xxix) tricyclics; (xxx) norepinephrine regulator; (xxxi) lithium; (xxxii) valproate; And (xxxiii) neurontin (gabapentin).

11. the pharmaceutical composition of claim 9 is used for the treatment of pain, parkinson, Alzheimer, epilepsy, depression, anxiety and comprises the ischemic brain injury of apoplexy.

12. the pharmaceutical composition of claim 9 is used for the treatment of parkinson.

13. treatment or prevention need the patient of this treatment or prevention pain, parkinson, Alzheimer, epilepsy, depression, anxiety, comprise the method for the ischemic brain injury of apoplexy, comprise the compound or pharmaceutically acceptable salt thereof that gives described patient treatment effective dose or prevention effective dose according to claim 1.

14. treatment or prevention need the patient's of this treatment or prevention chronic, internal organs, inflammatory and the syndromic method of neuropathic pain, comprise the compound or pharmaceutically acceptable salt thereof according to claim 1 that gives described patient treatment effective dose or prevention effective dose.

15. a patient who treats or prevent in this treatment of needs or prevention the method by traumatic nerve injury, nerve compression or sunken centre, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, cancer and chemotherapy pain that cause or associated comprises the compound or pharmaceutically acceptable salt thereof according to claim 1 that gives described patient treatment effective dose or prevention effective dose.

16. a method for the treatment of or preventing the patient's who needs this treatment or prevention chronic back pain comprises the compound or pharmaceutically acceptable salt thereof according to claim 1 that gives described patient treatment effective dose or prevention effective dose.

17. a method for the treatment of or preventing the patient's who needs this treatment or prevention phantom limb pain comprises the compound or pharmaceutically acceptable salt thereof according to claim 1 that gives described patient treatment effective dose or prevention effective dose.

18. treatment or prevention need patient's the HIV of this treatment or prevention inductive with treat inductive neuropathy, chronic pelvic pain, neuroma pain, plyability regional pain syndrome, chronic arthritis pain and relevant neuralgic method by HIV, comprise the compound or pharmaceutically acceptable salt thereof that gives described patient treatment effective dose or prevention effective dose according to claim 1.

19. treat or prevent the patient's who needs this treatment or prevention the epilepsy and the method for local and general tonic seizures for one kind, comprise the compound or pharmaceutically acceptable salt thereof that gives described patient treatment effective dose or prevention effective dose according to claim 1.