CN101541754A

CN101541754A - Azabicyclic compounds as inhibitors of monoamines reuptake

Info

Publication number: CN101541754A
Application number: CNA2007800419418A
Authority: CN
Inventors: 芭芭拉·伯塔尼; 罗马诺·迪法比奥; 法布里齐奥·米凯利; 乔瓦纳·特德斯科; 西尔维娅·特雷尼
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 2006-09-11
Filing date: 2007-09-07
Publication date: 2009-09-23
Also published as: GB0617863D0; ZA200901322B

Abstract

The present invention relates to novel compounds of formula (I)', pharmaceutically acceptable salts, prodrugs or solvates thereof: wherein R1 is hydrogen or C1-4alkyl; R2 is a group A, K or W wherein A is (II) K is an a or ss naphthyl group, optionally substituted by 1 or 2 groups R18, each of them being the same or different; and W is (III) and wherein G is a 5,6-membered monocyclic heteroaryl, or a 8- to 11-membered heteroaryl bicyclic group; such G may be substituted by (R15)p, which can be the same or different; p is an integer from 0 to 5; R3 is selected in the group consisting of: hydrogen, fluorine, and C1-4alkyl; or corresponds to a group X or X1; R4 is selected in the group consisting of: hydrogen, fluorine, and C1-4alkyl; or corresponds to a group X or X1; R5 is hydrogen or C1-4alkyl; R7 is hydrogen or C1-4alkyl; or is a group X, X1, X2 or X3; wherein X is (IV) X1 is (V) X2 is (VI) and X3 is (VII) R6 is hydrogen or C1-4alkyl; or is a group X or X1; R9 is C1-4alkyl; R10 is selected from a group consisting of: hydrogen, halogen, hydroxy, cyano, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy, C1-4alkanoyl and SF5; or corresponds to a group R8; R8 is a 5-6 membered heterocycle group, which may be substituted by one or two substituents selected from a group consisting of: halogen, cyano, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy and C1-4alkanoyl; R11 is selected from a group consisting of: hydrogen, halogen, hydroxy, cyano, C1-4alkyl, haloC1-4alkyl, C1-4aIkoxy, haloC1-4alkoxy, C1-4alkanoyl and SF5; or corresponds to a group R8; R12 is selected from a group consisting of: hydrogen, halogen, hydroxy, cyano, C1-4alkyl, haloC1-4alkyl, C1-4aIkoxy, haloC1-4alkoxy, C1-4alkanoyl and SF5; or corresponds to a group R8; R13 is selected from a group consisting of: hydrogen, halogen, hydroxy, cyano, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy, C1-4alkanoyl and SF5; or corresponds to a group R8.

Description

Azabicyclic compounds as inhibitors of monoamines reuptake

The present invention relates to intermediate used among new compound, their preparation method, these methods, contain their pharmaceutical composition and they are as serotonin (5-HT), Dopamine HCL (DA) and the purposes of norepinephrine (NE) reuptake inhibitor in treatment.

Cerebral tissue is made of the neuronal cell that can transmit information by specific cellularstructure (being called as cynapse) each other.Handshaking between the neurone in the cynapse takes place by the neurochemical courier who is called neurotransmitter, all acts on particular target protein molecule (being called as acceptor) in postsynaptic and presynaptic.Monoamine is represented the little neurotransmitter molecule of a class, and it has the common chemical feature and comprises serotonin (5-HT), Dopamine HCL (DA) and norepinephrine (NE).

The monoamine neurotransmitter is released to the synaptic cleft between the neurone, and with the acceptor interaction that is present on the target cell membrane.The conversion of neurochemistry signal mainly removes the neurotransmitter molecule by other protein molecules (for the SERT of 5-HT, for the DAT of DA with for the NET of NE) that are called as monoamine transporter and takes place.Translocator can move in the presynaptic ending in conjunction with the neurotransmitter molecule and with it, and this cell mechanism is called as reuptake.Suppress the increase that the reuptake process can cause monoamine on the cynapse level from pharmacology, the result causes the enhancing of the physiologically active of neurotransmitter.

Serotonin in the brain can neurotransmission (serotonergic neurotransmission) be subjected to the mediation of a big receptoroid of the ionic channel of the part gate that contains the acceptor of G albumen coupling and comprise 14 kinds of hypotypes, and relates to different physiological roles.

Have in SERT that the compound of rejection is predicted to be possessed Mammals, comprise the ability of the multiple disease that the philtrum treatment is relevant with this neural system, described disease is eating disorder, severe depression and mood disorder, obsessive compulsive disorder, panic disorder, alcoholism, pain, lethe and anxiety disorder for example.These diseases comprise the disease relevant with dysthymia disorders, as pseudodementia or Ganser's syndrome, migraine, Bulimia nerovsa, obesity, syndrome or late luteal phase syndrome before the menstruation, tobacco abuse, panic disorder, posttraumatic syndrome, the loss of memory, senile dementia (dementia of ageing), acquired immune deficiency syndrome (AIDS), the dull-witted compound disease (dementia complex) of AIDS, old memory dysfunction (memory dysfunction in ageing), social phobia, attention deficit-hyperkinetic syndrome (attention deficit hyperactivity disorder), chronic tired syndrome, premature ejaculation, it is difficult to erect, anorexia nervosa, somnopathy (disorders of sleep), autism, mutism or trichotillomania.

Severe depression is the illness of a kind of emotion aspect, or the illness of mood, it is characterized by the multiple symptom that comprises following mood: degree of depth sadness, useless (worthlessness), desperate and all enjoyment are all lost interest (anhedonia), expect repeatedly death, mental retardation (mental slowing), energy expenditure (loss of energy), often with anxiety and relevant can not the making a decision of excitement.These symptoms are persistence, and may change in alleviation with seriously.

The physiopathology of only knowing severe depression is the multiplefactor symptom, and because this point, and it has involved a plurality of neurotransmitter system.Yet, believe that usually this illness originates from the reduction of the cynapse concentration of monoamine neurotransmitter (mainly being NE and 5-HT) in critical brain zone (critical brain areas), this has caused " the monoamine theory " of dysthymia disorders.

Before many series clinical and clinical evidence show that the neurotransmission that strengthens the serotonin mediation can treat severe depression effectively, selectivity serotonin reuptake inhibitor (SSRIs) has been mainly used in the treatment of dysthymia disorders in 20 years in fact in the past.Fluoxetine as the SSRI of first introducing, is the prototype of this group.Other members comprise paroxetine, Sertraline, fluvoxamine, citalopram.

Yet, do not know clearly also these reagent are what how to do in order to alleviate depression disease.As the thymoleptic of other kinds, although the quick blocking-up of serotonin reuptake had the hysteresis in several weeks before the mood castering action begins.The adaptive change of supposing supervention can betide cynapse place of serotonin energy after the long term administration of SSRIs, the release of neurotransmitter is regulated and increased to the decrement of promptly regulating autoreceptor release.The delay that the stimulant effect begins is considered to use at present the major defect of SSRIs.In addition, although SSRIs has good tolerability usually, 5-HT has caused receptor subtype such as 5-HT in the concentration rising of maincenter cynapse and peripheral synapse _2CAnd 5-HT ₃Stimulation, and be accompanied by the side effect of stomach and intestine and property, wherein said 5-HT _2CAnd 5-HT ₃Participate in producing exciting and uneasy.

The success of SSRIs has remotivated the research and development interest of selective norepinephrine reuptake inhibitor (SNRIs) as possible thymoleptic.A large amount of such compounds have been synthesized, as nisoxetine, maprotiline, tomoxetine and Reboxetine.In addition, chemical compound lot comprises former tricyclic antidepressants (tricyclic) thymoleptic, has blended NET and SERT restraining effect, as imipramine and amitriptyline (SERT usefulness (potency)＞NET) and Desipramine, nortriptyline and protriptyline (NET usefulness＞SERT) wherein.

The control of the pharmacology of DAT has the ability of rising DA concentration in the mesolimbic system in principle, thereby has reversed the anhedonia of one of cardinal symptom as major depression.DAT suppresses composition, with the blocking-up of SERT and NET, also can have the ability of improving power and attention-deficient and the cognitive impairment of enhancing seen in patients with depression.Another aspect, the carefully blocking-up of control DAT is to avoid potential strengthening effect and abuse liability.Yet, on pharmacology, have the inhibiting compound of DAT, as right Methylphenidylacetate (Dexmethylphenidate), Methylphenidylacetate (Methylphenidate) and Wellbutrin (Bupropion), by the marketization of success.

Clinical study shows that the patient to the SSRIs Low Response benefits from the combined treatment with the medicine that strengthens dopaminergic cooperation the (tone).The result, having strong SERT suppresses activity and suppresses the method for substitution that active compound can so become present combined treatment in conjunction with the well balanced NET blocking-up and the DAT of appropriateness, be used for the treatment of unresponsive patient, higher efficient and treatment handiness and the quicker antidepressant effect that begins is provided.

Because their useful DAT inhibition, think that The compounds of this invention can be used for treating parkinson's syndrome, dysthymia disorders, obesity, narcolepsy, drug addiction or drug abuse, comprise cocaine abuse, attention deficit move obstacle, Ji Ledelatulei syndrome (Gilles de la Tourettes disease) and senile dementia more.The dopamine reuptake inhibitor has strengthened the release of ethanoyl choline indirectly by dopamine neuron; therefore and also can be used for treating lethe, for example alzheimer's disease, presenile dementia, old memory dysfunction and the lethe in the chronic tired syndrome.Think that norepinephrine reuptake inhibitor can be used for improving attention, alertness, awakening, vigilance and is used for the treatment of dysthymia disorders.

An object of the present invention is to provide new pharmaceutical composition, it is included as the compound of serotonin (5-HT), Dopamine HCL (DA) and norepinephrine (NE) reuptake inhibitor.

In addition, the purpose of this invention is to provide new compound, it is serotonin (5-HT), Dopamine HCL (DA) and norepinephrine (NE) reuptake inhibitor.

In first aspect, the invention provides pharmaceutical composition, it comprises formula (A) compound or pharmaceutically acceptable salt thereof, solvate or prodrug and pharmaceutically acceptable carrier,

Wherein

R ₁Be hydrogen or C _1-4Alkyl;

R ₂Be group A, K or W

Wherein

A is

K is α or β naphthyl, and it is optional by 1 or 2 radicals R ₁₈Replace each R ₁₈Can be identical or different;

With

W is

With, wherein

G is 5,6-unit's bicyclic heteroaryl or 8-to 11-unit heteroaryl bicyclic groups; This G can be by (R ₁₅) _pReplace R ₁₅Can be identical or different;

P is the integer of 0-5;

R ₃Be selected from: hydrogen, fluorine and C _1-4Alkyl; Or be equivalent to radicals X or X ₁

R ₄Be selected from: hydrogen, fluorine and C _1-4Alkyl; Or be equivalent to radicals X or X ₁

R ₅Be hydrogen or C _1-4Alkyl;

R ₇Be hydrogen or C _1-4Alkyl; Or be radicals X, X ₁, X ₂Or X ₃

Wherein

X is

X ₁For

X ₂For

With

X ₃For

R ₆Be hydrogen or C _1-4Alkyl; Or be radicals X or X ₁

R ₉Be C _1-4Alkyl;

R ₁₀Be selected from: hydrogen, halogen, hydroxyl, cyano group, C _1-4Alkyl, halo C _1-4Alkyl, C _1-4Alkoxyl group, halo C _1-4Alkoxyl group, C _1-4Alkyloyl and SF ₅Or be equivalent to radicals R ₈

R ₈Be 5-6 unit heterocyclic radical, it can be selected from by one or two, and following substituting group is optional to be replaced: halogen, cyano group, C _1-4Alkyl, halo C _1-4Alkyl, C _1-4Alkoxyl group and C _1-4Alkyloyl;

R ₁₁Be selected from: hydrogen, halogen, hydroxyl, cyano group, C _1-4Alkyl, halo C _1-4Alkyl, C _1-4Alkoxyl group, halo C _1-4Alkoxyl group, C _1-4Alkyloyl and SF ₅Or be equivalent to radicals R ₈

R ₁₂Be selected from: hydrogen, halogen, hydroxyl, cyano group, C _1-4Alkyl, halo C _1-4Alkyl, C _1-4Alkoxyl group, halo C _1-4Alkoxyl group, C _1-4Alkyloyl and SF ₅Or be equivalent to radicals R ₈

R ₁₃Be selected from: hydrogen, halogen, hydroxyl, cyano group, C _1-4Alkyl, halo C _1-4Alkyl, C _1-4Alkoxyl group, halo C _1-4Alkoxyl group, C _1-4Alkyloyl and SF ₅Or be equivalent to radicals R ₈

R ₁₄Be selected from: hydrogen, halogen, hydroxyl, cyano group, C _1-4Alkyl, halo C _1-4Alkyl, C _1-4Alkoxyl group, halo C _1-4Alkoxyl group, C _1-4Alkyloyl and SF ₅Or be equivalent to radicals R ₈

R ₁₅Be selected from: halogen, hydroxyl, cyano group, C _1-4Alkyl, halo C _1-4Alkyl, C _1-4Alkoxyl group, halo C _1-4Alkoxyl group, C _1-4Alkyloyl and SF ₅Or be equivalent to radicals R ₈

R ₁₆Be hydrogen, C _1-4Alkyl, C ₃- ₆Cycloalkyl or C ₃- ₆Cycloalkyl C _1-3Alkyl;

R ₁₇Be hydrogen or C _1-4Alkyl;

R ₁₈Be selected from: halogen, cyano group, C _1-4Alkyl;

R ₁₉Be halo C _1-2Alkyl;

N is 1 or 2.

Compound 6-as follows (4-fluorophenyl)-3-azabicyclo [4.1.0] heptane has been disclosed among the number of patent application WO2004072025 (" Preparation of N-arylheterocycles as melaninconcentrating hormone (MCH) antagonists "), and wherein this compound is as the intermediate of synthetic final compound.In this patent application, do not point out the therepic use of this compound.

It is " A Novel and Selective Monoamine Oxidase B substrate " Rimoldi that compound 3-methyl as follows-6-phenyl-3-azabicyclo [4.1.0] heptane has been disclosed in exercise question, J. wait the people, Bioorganic and Medicinal Chemistry (2005), 13 (20), in the publication of 5808-5813.Yet, do not point out the therepic use of this compound.

On the other hand, the invention provides the treatment Mammals and comprise the people, particularly treat described compound to the illness of the reuptake inhibition active reaction of serotonin (5-HT), Dopamine HCL (DA) and norepinephrine (NE) or the method for disease, described method comprises formula as defined above (A) compound or pharmaceutically acceptable salt thereof, solvate or the prodrug of effective dosage.

In one embodiment, the invention provides treatment and wherein suppress the method that serotonin (5-HT), Dopamine HCL (DA) and norepinephrine (NE) are useful illnesss, described method comprises formula as defined above (A) compound or pharmaceutically acceptable salt thereof, solvate or the prodrug to the Mammals that these needs are arranged (for example people) effective dosage.

On the other hand, the invention provides formula (A) compound or pharmaceutically acceptable salt thereof, solvate or prodrug as defined above, it is used for the treatment of.

In one embodiment, the invention provides formula (A) compound or pharmaceutically acceptable salt thereof, solvate or prodrug as defined above, it is used for the treatment of and suppresses serotonin (5-HT), Dopamine HCL (DA) and norepinephrine (NE) in the Mammals is useful illness.

On the other hand, the invention provides formula (A) compound or pharmaceutically acceptable salt thereof, solvate or prodrug as defined above and be used for the treatment of purposes in the medicine that reuptake to serotonin (5-HT), Dopamine HCL (DA) and norepinephrine (NE) suppresses the illness of active reaction or disease in preparation.

In one embodiment, the invention provides formula (A) compound or pharmaceutically acceptable salt thereof, solvate or prodrug as defined above and be used for the treatment of the purposes that suppresses in the Mammals in the medicine that serotonin (5-HT), Dopamine HCL (DA) and norepinephrine (NE) are useful illnesss in preparation.

On the one hand, the invention provides formula (I) compound or pharmaceutically acceptable salt thereof, solvate or prodrug:

Wherein

R ₁Be hydrogen or C _1-4Alkyl;

R ₂Be group A, K or W;

Wherein

A is

With

W is

With, wherein

P is the integer of 0-5;

R ₅Be hydrogen or C _1-4Alkyl;

R ₇Be hydrogen or C _1-4Alkyl; Or be radicals X, X ₁, X ₂Or X ₃

Wherein

X is

X ₁For

X ₂For

With

X ₃For

R ₆Be hydrogen or C _1-4Alkyl; Or be radicals X or X ₁

R ₉Be C _1-4Alkyl;

R ₁₇Be hydrogen or C _1-4Alkyl;

R ₁₈Be selected from: halogen, cyano group, C _1-4Alkyl;

R ₁₉Be halo C _1-2Alkyl;

N is 1 or 2;

Condition is:

If R ₂Be A, R ₃, R ₄, R ₅, R ₆, R ₇, R ₁₀, R ₁₁, R ₁₃, R ₁₄Be hydrogen, and R ₁₂Be fluorine, then R ₁Be C _1-4Alkyl;

If R ₂Be A, R ₃, R ₄, R ₅, R ₆, R ₇, R ₁₀, R ₁₁, R ₁₃, R ₁₄Be hydrogen, and R ₁Be methyl, then R ₁₂Be halogen, hydroxyl, cyano group, C _1-4Alkyl, halo C _1-4Alkyl, C _1-4Alkoxyl group, halo C _1-4Alkoxyl group, C _1-4Alkyloyl and SF ₅Or be equivalent to radicals R ₈

On the other hand, the invention provides formula (IF) compound or pharmaceutically acceptable salt thereof, solvate or prodrug:

Wherein

R ₁Be hydrogen or C _1-4Alkyl;

R ₂Be group A or W;

Wherein

A is

With

W is

And wherein

P is the integer of 0-5;

R ₅Be hydrogen or C _1-4Alkyl;

R ₆Be hydrogen or C _1-4Alkyl; Or be radicals X or X ₁

Wherein

X is

X ₁For

X ₂For

With

X ₃For

And wherein

R ₇Be hydrogen or C _1-4Alkyl; Or be radicals X, X ₁, X ₂Or X ₃

R ₈Be 5-6 unit heterocyclic radical, it can be selected from following substituting group by one or two and replace: halogen, cyano group, C _1-4Alkyl, halo C _1-4Alkyl, C _1-4Alkoxyl group and C _1-4Alkyloyl;

R ₉Be C _1-4Alkyl;

N is 1 or 2;

Condition is:

If R ₁₁Or R ₁₃One of be not hydrogen, R then ₁₀, R ₁₂Or R ₁₄In at least one be not hydrogen;

If R ₂Be A, R ₃, R ₄, R ₅, R ₆, R ₇, R ₁₀, R ₁₁, R ₁₃, R ₁₄Be hydrogen, and R ₁₂Be fluorine, then R ₁Be not hydrogen;

If R ₂Be A, R ₃, R ₄, R ₅, R ₆, R ₇, R ₁₀, R ₁₁, R ₁₃, R ₁₄Be hydrogen, and R ₁Be methyl, then R ₁₂Be not hydrogen.

On the other hand, the invention provides formula (IG) compound or pharmaceutically acceptable salt thereof, solvate or prodrug:

Wherein

R ₁Be hydrogen or C _1-4Alkyl;

R ₂For

P is the integer of 0-5;

R ₅Be hydrogen or C _1-4Alkyl;

R ₆Be hydrogen or C _1-4Alkyl; Or be radicals X or X ₁

Wherein

X is

X ₁For

X ₂For

With

X ₃For

And wherein

R ₇Be hydrogen or C _1-4Alkyl; Or be radicals X, X ₁, X ₂Or X ₃

R ₉Be C _1-4Alkyl;

R ₁₀Be selected from: halogen, hydroxyl, cyano group, C _1-4Alkyl, halo C _1-4Alkyl, C _1-4Alkoxyl group, halo C _1-4Alkoxyl group, C _1-4Alkyloyl and SF ₅Or be equivalent to radicals R ₈

R ₁₁Be hydrogen, C _1-4Alkyl, C ₃- ₆Cycloalkyl or C ₃- ₆Cycloalkyl C _1-3Alkyl;

N is 1 or 2.

Owing to have the condensed cyclopropane ring, think that formula (I) compound has the substituting group (R that links to each other with bicyclic system that " cis " arranges ₂And R ₇Group all is positioned at the identical faces of this bicyclic system).

Should be appreciated that formula (I) compound has at least two three-dimensional centers, i.e. 1 and 6 in the 3-of molecule azabicyclo [4.1.0] heptane part.Therefore can there be two kinds of steric isomers in this compound, and they are enantiomer for the three-dimensional center in the cyclopropane ring.Should be appreciated that also the level of biological activity of the molecule of common most of biologic activity may be different between each steric isomer of specifying molecule.This means that scope of the present invention comprises all one steric isomers (diastereomer and enantiomer) and its all mixture, include but not limited to racemic mixture, it demonstrates the suitable biologic activity for method as herein described.

In one embodiment of the invention, provide the formula (I) that is equivalent to formula (I) compound ' compound or pharmaceutically acceptable salt thereof, solvate or prodrug, it has " cis " arranges, and two key tables significant by black matrix and cyclopropyl part adjacency show:

Wherein, R ₁, R ₂, R ₃, R ₄, R ₅, R ₆, R ₇, R ₁₇As above-mentioned definition for formula (I) compound.

From now on any part in the literary composition, ' (apostrophe (prime)) is used for expression and has radicals R symbol ₂And R ₇Key have the compound that " cis " arranges, wherein radicals R ₂And R ₇Significant two key tables of black matrix by adjacency cyclopropyl part show.

In one embodiment of the invention, in abutting connection with having radicals R ₂And R ₇Significant two key tables of black matrix of cyclopropyl part show the mixture (including but not limited to racemic mixture) of those cis-isomerides.

At formula (I) ' in the compound, have at least two three-dimensional centers, as follows they be positioned at the cyclopropane part; According to shown in following scheme, by optical resolution, can obtain having the formula (I) of single absolute configuration 1 and 6 three-dimensional center to the mixture that contains two kinds of steric isomers (they are the enantiomer with respect to the three-dimensional center at 1 and 6 place) ' steric isomer of compound:

Can use the Cahn-Ingold-Prelog nomenclature to determine in the absolute configuration at 1 and 6 three-dimensional center according to the priority ranking of group.

In another embodiment of the present invention, provide the formula (I) of the three-dimensional chemical isomer that is equivalent to formula (I) compound " compound or pharmaceutically acceptable salt thereof, solvate or prodrug, it has the radicals R of having ₂And R ₇" cis " of key arranged, and has single but unknown configuration 1 and 6 three-dimensional center:

R wherein ₁, R ₂, R ₃, R ₄, R ₅, R ₆, R ₇, R ₁₇Define as following formula (I) compound.

In the context of the present invention, at formula (I) " in the compound for having radicals R ₂And R ₇The representation as implied above in abutting connection with two keys of cyclopropyl part represent cis-stereoisomer, its three-dimensional center at 1 and 6 has single but unknown absolute configuration.

In the context of the invention, expection formula (I) " three-dimensional chemical isomer be rich in a kind of configuration at 1 and 6 center.In one embodiment, this isomer equals 90%e.e (enantiomeric excess) at least.In another embodiment, described isomer equals 95%e.e at least.In another embodiment, described isomer equals 99%e.e at least.

From now on any part in the literary composition, " (two apostrophes (double prime)) is used for expression in abutting connection with having radicals R to symbol ₂And R ₇Two keys of cyclopropyl part have the three-dimensional chemical isomer of the The compounds of this invention that " cis " arrange, and with formula as implied above (I) " representation of compound represents that those steric isomers have single but unknown absolute configuration 1 and 6 three-dimensional center

The absolute configuration of the optically active isomer of some compounds of the present invention uses initial VCD (vibration circular dichroism) to determine.

Chiral molecules has vibration circular dichroism (VCD).The vibration circular dichroism (VCD) be meant chiral molecules in the vibrational excitation process with the left side and the existing different interactions of the right circular polarization ir radiation.

The VCD spectrum of chiral molecules depends on its three-dimensional structure.The most important thing is that the VCD spectrum of chiral molecules is the sensitivity function of its absolute configuration, for flexible molecule, is the sensitivity function of its conformation.Therefore in general, VCD can determine the structure of chiral molecules.VCD spectrum is measured in the seventies in 19th century the earliest.Afterwards, the VCD instrument was obtaining developing rapidly aspect spectral range and the sensitivity.At present, the VCD spectrum of liquid and solution can use dispersiveness and Fourier transform (FT) VCD instrument at main infrared substantially (IR) spectral range (v 〉=650cm ^-1) the interior measurement, and at acceptable resolving power (1-5cm ^-1) aspect has highly sensitive.Recently, can obtain commercial FT VCD instrument, this has greatly promoted VCD spectrographic accessibility (accessibility).

At present, VCD is used for determining that as a kind of reliable method the absolute configuration of chiral molecules has obtained approval widely (referring to people such as for example Shah RD, Curr Opin Drug Disc Dev 2001; 4:764-774; People such as Freedman TB, Helv Chim Acta 2002; 85:1160-1165; People .Chirality 2002 such as DyatkinAB; 14:215-219; Solladie '-Cavallo A, people such as Balaz M, Tetrahedron Assym 2001; 12:2605-2611; People .Circular dichroism such as Nafie LA, principles and applications, the 2nd edition. New York: John Wiley﹠amp; Sons; 2000. 97-131 page or leaf; People .:Yan B such as Nafie LA, Gremlish H-U, editor .Infrared and Ramanspectroscopy of biological materials. New York: Marcel Dekker; 2001. 15-54 page or leaf; People such as Polavarapu PL, J Anal Chem 2000; 366:727-734; People such as Stephens PJ, Chirality 2000; 12:172-179; Solladie '-people such as Cavallo A, Eur J Org Chem 2002:1788-1796).

This method need contrast viewed IR and VCD spectrum with the spectrum that calculates at particular configuration, thereby obtains the information of absolute configuration and comformation in solution aspect simultaneously.

The experimental spectrum of the chiral molecules that given its absolute configuration and/or conformation are unknown and to be measured, then general method is as follows:

1) all possible structure is defined; 2) predict the spectrum of these structures; Then 3) will predict that spectrum and experimental spectrum contrast.Correct structure will obtain and test the spectrum that is consistent; And incorrect structure will obtain and test the spectrum that does not conform to.

VCD spectrum is always measured simultaneously with vibrating the absorption spectrum (" infrared (IR) spectrum ") that do not polarize, and these two vibrational spectrums can provide together than independent VCD spectrum more information.In addition, simultaneously do not polarize absorption spectrum and VCD spectrum of vibration is carried out automatic prediction.

For said determination, the VCD and the IR spectrum that do not polarize adopt Gauss's 98 software packages to calculate.

In one embodiment of the invention, provide to be equivalent to formula (I) ' formula (IA) compound or pharmaceutically acceptable salt thereof, solvate or the prodrug of the three-dimensional chemical isomer of compound, its three-dimensional center at 1 and 6 has configuration as shown below:

In the context of the invention, the three-dimensional chemical isomer of expection formula (IA) is rich in a kind of configuration at 1 and 6 three-dimensional center.In one embodiment, this isomer equals 90%e.e (enantiomeric excess) at least.In another embodiment, described isomer equals 95%e.e at least.In another embodiment, described isomer equals 99%e.e at least.

From now on any part herein, the suffix in the bracket " A " are used to be illustrated in the three-dimensional chemical isomer that 1 and 6 three-dimensional center has the The compounds of this invention of the configuration as shown in following formula (IA) compound.

In another embodiment of the present invention, provide to be equivalent to formula (I) ' formula (IB) compound or pharmaceutically acceptable salt thereof, solvate or the prodrug of the three-dimensional chemical isomer of compound, its three-dimensional center at 1 and 6 has configuration as shown below:

In the context of the invention, the three-dimensional chemical isomer of expection formula (IB) is rich in a kind of configuration at 1 and 6 center.In one embodiment, this isomer equals 90%e.e (enantiomeric excess) at least.In another embodiment, described isomer equals 95%e.e at least.In another embodiment, described isomer equals 99%e.e at least.

From now on any part herein, the suffix in the bracket " B " are used to be illustrated in the three-dimensional chemical isomer that 1 and 6 three-dimensional center has the The compounds of this invention of the configuration as shown in following formula (IB) compound.

Term " C _1-4Alkyl " be meant all isomeric form of the alkyl with 1-4 carbon atom, for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl and the tertiary butyl.

Term ' C used herein ₃-C ₆Cycloalkyl ' be meant the non-fragrant monocyclic hydrocarbon ring of 3-6 carbon atom, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; And undersaturated cycloalkyl comprises cyclopentenyl and cyclohexenyl etc.

Term ' C used herein ₃- ₆Cycloalkyl C _1-3Alkyl ' be meant the alkyl that contains 1-3 carbon atom, one of them hydrogen atom quilt is C as defined above ₃-C ₆Cycloalkyl replaces, for example the methyl cyclopropyl.

Term " C _1-4Alkoxyl group " be meant the straight or branched alkoxyl group (or " alkyl oxy ") with 1-4 carbon atom, for example methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert.-butoxy.

Term ' C used herein _1-4Alkyloyl ' can be the alkyloyl of straight or branched, for example ethanoyl, ethyl carbonyl, n-propyl carbonyl, sec.-propyl carbonyl, normal-butyl carbonyl or tertiary butyl carbonyl etc.

Term used herein ' halo C _1-4Alkyl ' be meant alkyl with one or more carbon atoms, and wherein at least one hydrogen atom is replaced by halogen (preferred fluorine), for example trifluoromethyl etc.

Term used herein ' halo C _1-4Alkoxyl group ' can be the C of the above-mentioned definition that replaced by at least one halogen _1-4Alkoxyl group is as OCH ₂CF ₃, OCHF ₂Or OCF ₃

Term used herein ' halo C _1-2Alkyl ' can be the C of the above-mentioned definition that replaced by at least one halogen (preferred fluorine) _1-2Alkyl, as-CH ₂CF ₃,-CHF ₂Or-CF ₃

Term " SF ₅" be meant Pentafluorosulfanyl.

Term " halogen " and abbreviation " halogen " thereof are meant fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).When before term " halogen " is used in another group, using, represent that this group is replaced by one or more halogen atom.

Term used herein ' 5,6-unit bicyclic heteroaryl ' be meant 5 or 6 yuan and have at least one heteroatoms (being selected from nitrogen, oxygen and sulphur) and contain the fragrant monocyclic heterocycles of at least 1 carbon atom.

Exemplary 5,6-unit bicyclic heteroaryl includes, but is not limited to: furyl, thienyl, pyrryl, pyridyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, triazolyl and tetrazyl.

Term used herein ' 8 to 11-unit bicyclic heteroaryls ' be meant 8-11 unit and have at least one heteroatoms (being selected from nitrogen, oxygen and sulphur) and contain the fragrant bicyclic heterocycle of at least 1 carbon atom.

8 to 11 yuan of exemplary bicyclic heteroaryls include, but is not limited to: benzofuryl, benzothienyl, indyl, pseudoindoyl, azaindolyl, quinolyl, isoquinolyl, benzoxazolyl, benzimidazolyl-, benzothiazolyl, quinazolyl and phthalazinyl.

Term 5-6 unit heterocycle is meant and contains 1-4 heteroatoms that is independently selected from nitrogen, oxygen and sulphur, and wherein nitrogen and sulfur heteroatom can be randomly oxidized, and nitrogen heteroatom can be randomly by quaternised, saturated, undersaturated or fragrant 5-6 unit monocyclic heterocycles.Heterocycle comprises heteroaryl as defined above.This heterocycle can link to each other by any heteroatoms or carbon atom.Therefore, this term includes, but is not limited to morpholinyl, pyridyl, pyrazinyl, pyrazolyl, thiazolyl, triazolyl, imidazolyl, oxadiazole Ji, oxazolyl, isoxazolyl, pyrrolidone-base (pyrrolidinonyl), pyrrolidyl, piperidyl, glycolylurea base (hydantoinyl), Valerolactim base, Oxyranyle, oxetanyl, tetrahydrofuran base, THP trtrahydropyranyl, tetrahydro pyridyl, tetrahydro-pyrimidine base, tetrahydro-thienyl, tetrahydro thiapyran base etc.

Any can link to each other with the rest part of molecule on any suitable position in these groups.

In one embodiment, R ₁Be hydrogen or C _1-4Alkyl (for example methyl).In another embodiment, R ₁Be hydrogen.

In one embodiment, R ₂Be group A or K.In another embodiment, R ₂Be group A.In another embodiment, R ₂Be group K.

In one embodiment, group K is the β naphthyl.

In one embodiment, R ₃Be hydrogen or radicals X.In another embodiment, R ₃Be hydrogen.In another embodiment, R ₃Be radicals X.

In one embodiment, R ₄Be hydrogen.

In one embodiment, R ₅Be hydrogen.

In one embodiment, R ₆Be hydrogen.

In one embodiment, R ₇Be hydrogen or radicals X, X ₁Or X ₂In another embodiment, R ₇Be hydrogen.In another embodiment, R ₇Be radicals X, X ₁Or X ₂

In one embodiment, R ₇Be radicals X.

In one embodiment, R ₇Be radicals X ₁

In one embodiment, R ₇Be radicals X ₂

In one embodiment, n is 1 or 2.In another embodiment, n is 1.

In one embodiment, R ₁₆Be hydrogen, C _1-4Alkyl, C ₃- ₆Cycloalkyl or C ₃- ₆Cycloalkyl C _1-3Alkyl.In another embodiment, R ₁₆Be hydrogen or C _1-4Alkyl.In another embodiment, R ₁₆Be hydrogen.In another embodiment, R ₁₆Be C _1-4Alkyl (for example methyl or ethyl).

In one embodiment, R ₁₇Be hydrogen or C _1-4Alkyl.In another embodiment, R ₁₇Be hydrogen.In another embodiment, R ₁₇Be C _1-4Alkyl (for example methyl).

In one embodiment, R ₁₈Be halogen.In another embodiment, R ₁₈Be chlorine.

In one embodiment, R ₁₀Be hydrogen.

In one embodiment, R ₁₄Be hydrogen.

In one embodiment, R ₁₀Be hydrogen.

In one embodiment, R ₁₁Be hydrogen, halogen, halo C _1-4Alkyl, halo C _1-4Alkoxyl group.In another embodiment, R ₁₁Be hydrogen, halogen (for example chlorine) or halo C _1-4Alkyl (for example trifluoromethyl).In another embodiment, R ₁₁Be halogen (for example chlorine) or halo C _1-4Alkyl (for example trifluoromethyl).In another embodiment, R ₁₁Be chlorine.

In one embodiment, R ₁₂Be halogen, halo C _1-4Alkyl, halo C _1-4Alkoxyl group.In another embodiment, R ₁₂Be halogen (for example chlorine or fluorine), halo C _1-4Alkyl (for example trifluoromethyl) or halo C _1-4Alkoxyl group (for example trifluoromethoxy).In another embodiment, R ₁₂Be chlorine.

In one embodiment, R ₁₃Be hydrogen, halogen, halo C _1-4Alkyl, halo C _1-4Alkoxyl group.In another embodiment, R ₁₃Be hydrogen.

In one embodiment, formula (IC) compound or pharmaceutically acceptable salt thereof, solvate or prodrug, wherein R are provided ₁, R ₂, R ₇And R ₁₇Suc as formula defining in (I) compound.

In formula (IC), in one embodiment, R ₁Be hydrogen or C _1-4Alkyl (for example methyl), R ₂Be group A or K, R ₇Be hydrogen or radicals X, X ₁Or X ₂And R ₁₇Be hydrogen or C _1-4Alkyl.

In formula (IC), in another embodiment, R ₁Be hydrogen, R ₂Be group A or K, R ₇Be hydrogen or radicals X, X ₁Or X ₂And R ₁₇Be hydrogen.

In one embodiment, formula (ID) compound or pharmaceutically acceptable salt thereof, solvate or prodrug, wherein R are provided ₇Be radicals X and R ₂, R ₁₆With n suc as formula defining in (I) compound:

In formula (ID), in one embodiment, R ₂Be group A.

In formula (ID), in another embodiment, R ₂Be group A, R ₁₆Be hydrogen, C _1-4Alkyl, C ₃- ₆Cycloalkyl or C ₃- ₆Cycloalkyl C _1-3Alkyl, R ₁₀Be hydrogen, R ₁₄Be hydrogen, R ₁₁Be hydrogen, halogen, halo C _1-4Alkyl or halo C _1-4Alkoxyl group, R ₁₂Be halogen, halo C _1-4Alkyl or halo C _1-4Alkoxyl group, R ₁₃Be hydrogen, halogen, halo C _1-4Alkyl or halo C _1-4Alkoxyl group and n are 1.

In formula (ID), in one embodiment, R ₂Be group K.

In formula (ID), in another embodiment, R ₂Be group K, it is unsubstituted β-naphthalene nucleus, R ₁₆Be hydrogen, C _1-4Alkyl, C ₃- ₆Cycloalkyl or C ₃- ₆Cycloalkyl C _1-3Alkyl and n are 1.

In one embodiment, formula (IE) compound or pharmaceutically acceptable salt thereof, solvate or prodrug, wherein R are provided ₁, R ₂, R ₃And R ₁₇Suc as formula defining in (I) compound:

In formula (IE), in one embodiment, R ₁Be hydrogen, R ₂Be group A or K, R ₃Be radicals X or X ₁And R ₁₇Be hydrogen or C _1-4Alkyl.

In formula (IE), in another embodiment, R ₁Be hydrogen, R ₂Be group A, R ₃Be radicals X, R ₁₇Be hydrogen, R ₁₆Be hydrogen, C _1-4Alkyl, C ₃- ₆Cycloalkyl or C ₃- ₆Cycloalkyl C _1-3Alkyl, R ₁₀Be hydrogen, R ₁₄Be hydrogen, R ₁₁Be hydrogen, halogen, halo C _1-4Alkyl or halo C _1-4Alkoxyl group, R ₁₂Be halogen, halo C _1-4Alkyl or halo C _1-4Alkoxyl group, R ₁₃Be hydrogen, halogen, halo C _1-4Alkyl or halo C _1-4Alkoxyl group and n are 1.

In one embodiment, provide as defined above formula (IC), (ID) and (IE) compound, its three-dimensional center at 1 and 6 has single but unknown configuration.Those compounds are called (IC) ", (ID) " and (IE) ".

In another embodiment, provide as defined above formula (IC), (ID) and (IE) compound, its three-dimensional center at 1 and 6 has the configuration shown in following formula (IA) compound.Those compounds are called (ICA), (IDA) and (IEA).

In another embodiment, provide as defined above formula (IC), (ID) and (IE) compound, its three-dimensional center at 1 and 6 has the configuration shown in following formula (IB) compound.Those compounds are called (ICB), (IDB) and (IEB).

In the context of the present invention, all aspects and the embodiment that is used for description formula (I) compound also all is applied to formula (A) compound.

For example, for comprising that in the present invention formula (A) compound, its pharmacologically acceptable salt, solvate and prodrug also provides those corresponding embodiments that are used for description formula (I) compound [be formula (A) ', (A) ", (AA), (AB), (AC), (AD), (AE) compound etc.].

Some group/substituting groups that comprise among the present invention can exist with isomer.Present invention resides in all the such isomer in its scope, comprise racemic modification, enantiomer, tautomer and composition thereof.

Be used for preparing their formula (I) compound or some group of intermediate and can have one or more tautomeric forms.The present invention comprises all these tautomeric forms in its scope, comprise mixture.

Term used herein " salt " is meant any salt, quaternary ammonium salt and the inner salt that forms by the The compounds of this invention of inorganic or organic acid or alkali preparation, and also comprises pharmacologically acceptable salt.Pharmacologically acceptable salt especially is fit to drug use, has better water-solubility because they are compared with parent compound.These salt must have acceptable negatively charged ion of physiology or positively charged ion clearly.

The salt of formula (I) compound can prepare by ordinary method, and comprises within the scope of the invention.

Compounds more of the present invention can with one or how normal acid or alkali form acid or base addition salt.Present invention resides in all possible stoichiometry and non-stoichiometric forms in its scope.

Pharmacologically acceptable salt also can use ordinary method other salt by formula (I) compound, comprises the pharmacologically acceptable salt preparation of other formula (I) compound.

The pharmacologically acceptable salt that is fit to of The compounds of this invention comprises the acid salt that forms with mineral acid, described mineral acid example hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid; With the salt that forms with organic acid, described organic acid such as tartrate, acetate, trifluoroacetic acid, citric acid, oxysuccinic acid, lactic acid, fumaric acid, phenylformic acid, naphthoic acid, formic acid, propionic acid, hydroxyethanoic acid, gluconic acid, toxilic acid, succsinic acid, camphorsulfonic acid (camphor sulfuric acid), 2-isethionic acid (isothionic acid), glactaric acid, gentisinic acid, Yi Yansuan, saccharic acid (saccharic acid), glucuronic acid, furancarboxylic acid (furoic acid), L-glutamic acid, xitix, anthranilic acid, Whitfield's ointment, toluylic acid, amygdalic acid, pamoic acid (pouncing on acid), methylsulfonic acid, ethyl sulfonic acid, pantothenic acid, stearic acid,-sulfinic acid (sulfinilic acid), Lalgine, galacturonic acid and aryl sulfonic acid, for example Phenylsulfonic acid and tosic acid; Base addition salt with basic metal and alkaline-earth metal and organic bases formation, described organic bases such as N, N-dibenzyl-ethylenediamin, chloroprocaine, choline, diethanolamine, quadrol, meglumin (meglumaine) (N-methyl glucoside amine), Methionin and PROCAINE HCL, PHARMA GRADE; Salt with inside formation.Have non-pharmaceutically useful negatively charged ion or cationic salt within the scope of the invention, it and/or uses in non-treatment as the useful as intermediates of preparation pharmacologically acceptable salt, for example, and external environment.

The technician of organic chemistry filed will understand many organic compound can form complex compound with solvent, and wherein they react or they are from wherein precipitating or crystallizing out.These complex compounds are called " solvate ".For example, the complex compound with water formation is called " hydrate ".The solvate of The compounds of this invention is in scope of the present invention.The solvent that formula (I) compound can be fit to by crystallization or evaporation obtains the corresponding solvent thing to be easy to separate with solvent molecule bonded mode.

And prodrug is also in scope of the present invention.Term used herein " prodrug " is meant the compound that transforms in vivo, and for example by hydrolysis in blood, this compound is converted into it and has pharmaceutically-active activity form.Pharmaceutically useful prodrug is described in T.Higuchi and V.Stella, the Prodrugs as Novel Delivery Systems of A.C.S.Symposium Series, Vol.14, Edward B.Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association andPergamon Press, 1987, and D.Fleisher, S.Ramon and H.Barbra " Improved oraldrug delivery:solubility limitations overcome by the use of prodrugs ", AdvancedDrug Delivery Reviews (1996) 19 (2) 115-130.

Prodrug prepares by according to certain mode functional group being modified usually, and this mode makes that above-mentioned modification is cleaved, thereby obtains parent compound through conventional processing or internal metabolism.Prodrug for example comprises the The compounds of this invention that wherein hydroxyl, amine or sulfydryl combine with group arbitrarily, and after being applied to the patient, their cracking form hydroxyl, amine or sulfydryl.Therefore, the example of exemplary prodrug includes, but is not limited to acetic ester (salt), manthanoate (salt) and benzoic ether (salt) derivative of alcohol, sulfydryl and the amine functional group of structure (I) compound.And, (COOH) in the situation, can use ester, for example methyl esters, ethyl ester etc. at carboxylic acid.Described ester can itself be activated and/or in the intravital internal milieu of people hydrolyzable.Hydrolyzable ester group is included in the human body and decomposes and the group of release parent acid or its salt rapidly in the suitable pharmaceutically useful body.

Hereinafter, formula (I) compound of definition and their pharmacologically acceptable salt, solvate and prodrug (the midbody compound in chemical process) are called " compound of the present invention " aspect the present invention is any.

And the The compounds of this invention of some crystallized forms can exist by polymorphic, and it is also included among the present invention.

It will be appreciated by those skilled in the art that in the preparation of compound of the present invention, may need and/or wish that the one or more sensitive groups of protection in the molecule are to prevent undesirable side reaction.The protecting group of using for the present invention that is fit to is well known to a person skilled in the art, and can use in a usual manner.Referring to, for example, " Protective groups in organic synthesis ", T.W.Greene and P.G.M.Wuts (JohnWiley﹠amp; Sons 1991) or " Protecting Groups ", P.J.Kocienski (Georg Thieme Verlag1994).The example of the amine protecting group that is fit to (for example comprises acyl group class protecting group; formyl radical, trifluoroacetyl group, ethanoyl); aromatic amino ester formate (urethane) class protecting group (for example; benzyloxycarbonyl (Cbz) and the Cbz that replaces); the aliphatic carbamate protecting group (for example; 9-fluorenyl methoxy carbonyl (Fmoc), tert-butoxycarbonyl (Boc), isopropoxy carbonyl, cyclohexyloxy carbonyl) and the protecting group (for example, benzyl, trityl, chloro trityl) of alkyls.The example of the oxygen protecting group that is fit to can comprise, alkyl silyl for example is as trimethyl silyl or t-butyldimethylsilyl; Alkyl ether is as the THP trtrahydropyranyl or the tertiary butyl; Or the ester class, as acetic ester.

The present invention also comprises isotope-labeled compound, it is identical with the compound with following described in the formula (I), is substituted but wherein one or more atoms have atomic mass or the total mass number atom different with common atomic mass that exists of nature or total mass number.Can be incorporated into the isotropic substance that isotopic example in compound of the present invention and its pharmacologically acceptable salt comprises hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, iodine and chlorine, for example ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I and ¹²⁵I.

Contain other the isotopic The compounds of this invention of above-mentioned isotropic substance and/or other atom and non-pharmacologically acceptable salt within the scope of the invention.The isotope-labeled compound of the present invention (for example mix radio isotope as ³H, ¹⁴The compound of C), can be used for the experiment of medicine and/or substrate tissue distribution.Tritium is for promptly ³H and carbon-14 are promptly ¹⁴The C isotropic substance is because convenient preparation and detection are particularly preferred. ¹¹C and ¹⁸The F isotropic substance is particularly useful for PET (positron emission transaxial tomography), and ¹²⁵The I isotropic substance is particularly useful for SPECT (single photon emission computerized tomography), and they all are used for the brain imaging.And, use heavier isotropic substance (as deuterium, promptly ²H) replace the treatment advantage that can provide certain because they have better metabolic stability, the dosage demand of transformation period or reduction in the body of Zeng Jiaing for example, and therefore in some environment heavier isotropic substance may be preferred.Isotope-labeled compound of the present invention and Qi Fei pharmacologically acceptable salt can be prepared by disclosed method among following proposal and/or the embodiment usually, by with making things convenient for the isotope-labeled reagent of available to replace nonisotopically labelled reagent.

In one embodiment, The compounds of this invention is selected from following compounds:

(1S, 6R/1R, 6S)-and 6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane;

(1S, 6R/1R, 6S)-6-(3, the 4-dichlorophenyl)-and 3-azabicyclo [4.1.0] heptan-1-yl] methyl alcohol;

(1R, 6S/1S, 6R)-6-(3, the 4-dichlorophenyl)-3-azabicyclo [4.1.0] heptane;

And pharmacologically acceptable salt, solvate or prodrug.

In another embodiment, The compounds of this invention is selected from following compounds:

(1R, 6S/1S, 6R)-6-phenyl-3-azabicyclo [4.1.0] heptane;

(1R, 6S)-6-phenyl-3-azabicyclo [4.1.0] heptane;

(1S, 6R)-6-phenyl-3-azabicyclo [4.1.0] heptane;

(1R, 6S/1S, 6R)-6-[4-(trifluoromethyl) phenyl]-3-azabicyclo [4.1.0] heptane;

(1R, 6S/1S, 6R)-6-[3-(trifluoromethyl) phenyl]-3-azabicyclo [4.1.0] heptane;

(1S, 6R)-6-(3, the 4-dichlorophenyl)-3-(1-methylethyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane;

And pharmacologically acceptable salt, solvate or prodrug.

(1S, 6R)-6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane;

(1R, 6S)-6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane;

[(1S, 6R/1R, 6S)-6-(3, the 4-dichlorophenyl)-and 3-azabicyclo [4.1.0] heptan-1-yl] methyl alcohol;

[(1S, 6R or 1R, 6S)-6-(3, the 4-dichlorophenyl)-and 3-azabicyclo [4.1.0] heptan-1-yl] methyl alcohol;

[(1R, 6S or 1S, 6R)-6-(3, the 4-dichlorophenyl)-and 3-azabicyclo [4.1.0] heptan-1-yl] methyl alcohol;

(1R, 6S/1S, 6R)-6-(3, the 4-dichlorophenyl)-3-azabicyclo [4.1.0] heptane;

(1R, 6S)-6-(3, the 4-dichlorophenyl)-3-azabicyclo [4.1.0] heptane;

(1S, 6R)-6-(3, the 4-dichlorophenyl)-3-azabicyclo [4.1.0] heptane;

(1S, 4R, 6R/1R, 4S, 6S)-6-(3, the 4-dichlorophenyl)-4-methyl isophthalic acid-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane;

(1S, 6R)-6-(3, the 4-dichlorophenyl)-3-methyl isophthalic acid-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane;

(1R, 6S/1S, 6R)-6-[4-chloro-3-(trifluoromethyl) phenyl]-the 1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane;

(1R, 6S/1S, 6R)-and 6-(4-chloro-phenyl-)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane;

(1R, 6S/1S, 6R)-and 6-(3, the 4-dichlorophenyl)-1-[(oxyethyl group) methyl]-3-azabicyclo [4.1.0] heptane;

(1R, 6S or 1S, 6R)-and 6-(3, the 4-dichlorophenyl)-1-[(oxyethyl group) methyl]-3-azabicyclo [4.1.0] heptane;

(1S, 6R or 1R, 6S)-and 6-(3, the 4-dichlorophenyl)-1-[(oxyethyl group) methyl]-3-azabicyclo [4.1.0] heptane;

(1S, 6R/1R, 6S)-and the 1-[(methoxyl group) methyl]-the 6-{4-[(trifluoromethyl) the oxygen base] phenyl }-3-azabicyclo [4.1.0] heptane;

(1S, 6R/1R, 6S)-6-[3-chloro-4-(trifluoromethyl) phenyl]-the 1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane;

(1R, 6S/1S, 6R)-and the 1-[(methoxyl group) methyl]-6-(2-naphthyl)-3-azabicyclo [4.1.0] heptane;

(1R, 6S or 1S, 6R)-and the 1-[(methoxyl group) methyl]-6-(2-naphthyl)-3-azabicyclo [4.1.0] heptane;

(1S, 6R or 1R, 6S)-and the 1-[(methoxyl group) methyl]-6-(2-naphthyl)-3-azabicyclo [4.1.0] heptane;

(1S, 6R/1R, 6S)-and 6-(3-chloro-4-fluorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane;

(1R, 6S/1S, 6R)-and 6-(3, the 4-dichlorophenyl)-1-{[(2,2, the 2-trifluoroethyl) the oxygen base] methyl }-3-azabicyclo [4.1.0] heptane;

(1S, 6R, 7R/1R, 6S, 7S)-and 6-(3, the 4-dichlorophenyl)-7-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane;

And pharmacologically acceptable salt, solvate or prodrug.

(1R, 6S or 1S, 6R)-6-[4-chloro-3-(trifluoromethyl) phenyl]-the 1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane;

(1S, 6R or 1R, 6S)-6-[4-chloro-3-(trifluoromethyl) phenyl]-the 1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane;

(1S, 6R or 1R, 6S)-6-[3-chloro-4-(trifluoromethyl) phenyl]-the 1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane;

(1R, 6S or 1S, 6R)-6-[3-chloro-4-(trifluoromethyl) phenyl]-the 1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane;

And pharmacologically acceptable salt, solvate or prodrug.

In another embodiment, The compounds of this invention is (1S, 6R)-6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane or its pharmacologically acceptable salt.

In another embodiment, The compounds of this invention be (1S, 6R or 1R, 6S)-the 1-[(methoxyl group) methyl]-6-(2-naphthyl)-3-azabicyclo [4.1.0] heptane or its pharmacologically acceptable salt.

In another embodiment, The compounds of this invention is:

(1S, 6R)-6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane hydrochloride;

(1S, 6R)-6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane (2R, 3R)-2,3 dihydroxybutanedioic acid salt (L-tartrate);

(1S, 6R)-6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane succinate (monosuccinic acid salt);

(1S, 6R)-6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane phosphoric acid salt;

Or its solvate.

The present invention also provides and has prepared the method for formula (I) compound or its salt as defined above.

The compounds of this invention can prepare according to several different methods.Reaction scheme below and hereinafter, unless otherwise indicated, R ₁To R ₁₉, A, K, W, G, p, X, X ₁, X ₂, X ₃With n suc as formula defining in (I) compound.

In specification sheets full text, general formula is by expressions such as Roman number (I), (II), (III), (IV).The minor of these general formulas is defined as (Ia), (Ib), (Ic) etc... (IVa), (IVb), (IVc) etc.

The compounds of this invention can be according to following synthetic schemes preparation.

Synthetic schemes

Formula (Ib) compound, i.e. R wherein ₁=C _1-4Alkyl, R ₇=radicals X (wherein n=1 and R ₁₆=C _1-4Alkyl or C _1-3Alkyl C _3-6Cycloalkyl) formula (I) compound can basis Scheme 1, obtain according to the alkylation of standard: by R wherein ₁=H and R ₁₆=C _1-4Alkyl or C _1-3Alkyl C _3-6The formula of cycloalkyl (Ia) compound begins, and for example uses RY alkylating reagent (R=C _1-4Alkyl, Y=halogen), as CH ₃I, trialkylamine such as TEA in DCM, carry out under the temperature between 0 ℃ and the room temperature.

Perhaps, formula (Ib) compound can use suitable aldehyde RCHO (R=C _1-3Alkyl), reductive agent such as NaCNBH ₃, in non-proton or protonic solvent (as toluene, THF or MeOH), 80 ℃ to the temperature between the room temperature, obtain by reduction amination.

Scheme 1

Formula (Ia) compound, i.e. R wherein ₇Formula (I) compound of=radicals X (wherein n=1) can basis Scheme 2, be suitable N-protected base by Pg wherein, formula (II) compound that typically is Boc or benzyl begins, and the deprotection base by the N-Pg group obtains.

For example, remove, can use the DCM solution of TFA, under the temperature between 0 ℃ and the room temperature, carry out for Boc.

For example, remove, can use H for the N-benzyl ₂With Pd/C or carbonochloridic acid α-chloro-ethyl ester, under refluxing, in DCE, and then in MeOH.

Scheme 2

Formula (IIb) compound, i.e. R wherein ₁₆=C _1-4Alkyl or C _1-3Alkyl C ₃- ₆Cycloalkyl and wherein Pg be suitable N-protected base, formula (II) compound that typically is Boc or benzyl can basis Scheme 3, obtain according to the alkylation of standard: by R wherein ₁₆The formula of=H (IIa) compound begins, and for example uses R ₁₆Y alkylating reagent (R ₁₆=C _1-4Alkyl or C _1-3Alkyl C _3-6Cycloalkyl, Y=halogen), as CH ₃I in the presence of highly basic such as NaH, in aprotic solvent such as DMF, carries out under the temperature between 0 ℃ and the room temperature.

Scheme 3

Formula (IIa ₁) the i.e. R wherein of compound ₃=R ₄The formula of=H (IIa) compound can be suitable N-protected base by Pg wherein, and formula (III) compound that typically is Boc or benzyl begins, according to Scheme 4, (use ZnEt by the Simmons-Smith Cyclopropanation process of standard ₂, CH ₂I ₂DCM solution) obtain.

Scheme 4

Formula (Ic) compound i.e. R wherein ₁=R ₃=R ₄=R ₁₆The formula of=H (I) compound can be suitable N-protected base by Pg wherein, and formula (III) compound that typically is Boc begins, according to Scheme 5, (use ZnEt by the Simmons-Smith Cyclopropanation process ₂, CH ₂I ₂DCM solution) obtain, this method is by adding amine as 2, two (1, the 1-the dimethyl ethyl)-4-picolines of 6-improve.

Scheme 5

Formula (IIa ₁) the i.e. R wherein of compound ₃=R ₄=H and wherein Pg be suitable N-protected base, formula (IIa) compound that typically is Boc can be begun by formula (Ic) compound, according to Scheme 6, according to the method for standard, for example use Boc acid anhydrides and TEA in DCM, obtain to the temperature between the room temperature at 0 ℃.

Scheme 6

Formula (IIa ₂) compound, i.e. R wherein ₃=R ₄The formula of=F (IIa) compound can be begun by formula (III) compound, according to Scheme 7, use dibromodifluoromethane, according to Journal of Fluorine Chemistry (2003), 119 (1), the method described in the 75-80 obtains.

Scheme 7

Formula (IIa ₃) compound, i.e. R wherein ₃=R ₄=CH ₃Formula (IIa) compound can begin by formula (III) compound, according to Scheme 8, according to being similar to Synlett (2002), (1), the method described in the 176-178 promptly uses 2, and the improved Simmons-Smith Cyclopropanation process of 2-diiodo propane obtains.

Scheme 8

Formula (III) compound can be suitable N-protected base by Pg wherein, and formula (IV) compound that typically is Boc begins, according to Scheme 9, use appropriate reductant, for example LiAlH ₄, in aprotic solvent such as ether or THF, in-40 to-10 ℃ temperature range, obtain.

Scheme 9

Formula (IV) compound can be begun by the formula V compound, according to Scheme 10,, use suitable aryl boric acid or boric acid ester, Pd (PPh according to the Suzuky coupling method of standard ₃) ₄With alkali such as Na ₂CO ₃, in the mixture of solvent such as toluene, second alcohol and water, obtain down at 80 ℃.

Scheme 10

Wherein-and to represent the formula V compound of trifluoromethanesulfonic acid base can be suitable N-protected base by Pg wherein to OTf, formula (VI) compound that typically is Boc begins, according to Scheme 11, by with alkali (for example sodium hydride) reaction, and then with trifluoromethanesulfonic acid reagent (triflating agent) N-phenyl trifluoromethanesulfonate Toluidrin for example, in aprotic solvent (as DMF), react to the temperature between the room temperature and obtain at 0 ℃.

Scheme 11

R wherein ₅=R ₆=H and Pg are that suitable protecting group such as the formula of Boc (VIa) compound can bases Scheme 12, by the commercially available wherein R that gets ₅=R ₆The formula of=H (VII) compound and Boc acid anhydrides and TEA in DCM, react to the temperature between the room temperature and obtain at 0 ℃.

Scheme 12

R wherein ₅=R ₆=CH ₃And Pg is that formula (VIb) compound of suitable protecting group can basis Scheme 13, by according to being similar to J.Org.Chem., the method acidylate described in 1995.60,5825 is R wherein ₅=R ₆=CH ₃And Pg is that the compound (VIII) of suitable protecting group obtains.

Scheme 13

R wherein ₆=R ₅=CH ₃And Pg is that suitable protecting group such as the formula of Boc (VIII) compound can be by R wherein ₆=R ₅=CH ₃Compound (IX) beginning, according to Scheme 14, prepare according to the method described in the WO2002085886.

Scheme 14

Formula (Id) compound, i.e. R wherein ₁=C _1-4The formula of alkyl (I) compound can be begun by formula (Ie) compound, according to Scheme 15, use the method acquisition that is similar to described in the such scheme 1.

Scheme 15

Formula (Ie ₁) compound, i.e. R wherein ₆=R ₅=H or CH ₃And R ₃=R ₄=CH ₃Formula (I) compound can basis Scheme 16, begin by formula (X) compound, according to being similar to Synlett (2002), (1), and the method described in the 176-178 promptly uses 2, and the improved Simmons-Smith Cyclopropanation process of 2-diiodo propane carries out conventional N-Pg deprotection base subsequently and obtains.

Scheme 16

R wherein ₆=R ₅=H or-CH ₃And R ₃=R ₄Formula (the Ie of=F ₂) compound can begin by formula (X) compound, according to Scheme 17, use dibromodifluoromethane, according to Journal of Fluorine Chemistry (2003), 119 (1), the method described in the 75-80 is carried out conventional N-Boc deprotection base subsequently and is obtained.

Scheme 17

Formula (Ie ₃) compound, i.e. R wherein ₆=R ₅=H or-CH ₃And R ₃=R ₄The formula of=H (I) compound can be begun by formula (X) compound, according to Scheme 18,, carry out conventional N-Pg deprotection base subsequently and obtain by the Simmons-Smith Cyclopropanation process of standard.

Scheme 18

Formula (Ie ₄) compound, i.e. R wherein ₆=R ₅=H or-CH ₃And R ₁₆=H, C _1-4Alkyl or C _1-3Alkyl C ₃- ₆The formula of cycloalkyl (I) compound can be by R wherein ₆=R ₅=H or-CH ₃And R ₁₆=H, C _1-4Alkyl or C _1-3Alkyl C ₃- ₆Cycloalkyl and Pg are that formula (XI) compound of suitable protecting group begins, according to Scheme 19, carry out conventional N-Pg deprotection base subsequently and obtain.

Scheme 19

Formula (XIa) compound, i.e. R wherein ₁₆=C _1-4Alkyl or C _1-3Alkyl C ₃- ₆The formula of cycloalkyl (XI) compound can be begun by following defined formula (XIb) compound, according to Scheme 20,, for example use R by the alkylation of standard ₁₆Y alkylating reagent (R ₁₆=C _1-4Alkyl, Y=halogen), as CH ₃I in the presence of highly basic such as NaH, in aprotic solvent such as DMF, reacts to the temperature between the room temperature and obtains at 0 ℃.

Scheme 20

Formula (XIb) compound, i.e. R wherein ₁₆The formula of=H (XI) compound can basis Scheme 21, according to being similar to Synlett (2002), (1), the method described in the 176-178 obtains: by R wherein ₆=R ₅=H or CH ₃And Pg is that formula (XII) compound of suitable protecting group begins,, use ethyl diazoacetate and acetic acid rhodium, in aprotic solvent (as DCE, DCM or MeCN), under the temperature between the room temperature to 80 ℃, react, use appropriate reductant such as LiAlH subsequently ₄Or BH ₃THF carries out the ester reduction under the temperature between-20 ℃ to 70 ℃.

Scheme 21

R wherein ₆=R ₅=H or CH ₃And Pg is that formula (XII) compound of suitable protecting group can be begun by formula (XIII) compound, according to Scheme 22,, use suitable aryl boric acid or ester to obtain according to above-mentioned Suzuky coupling method.

Scheme 22

R wherein ₆=R ₅=H or CH ₃, it is that formula (XIII) compound of suitable protecting group can be by R wherein that-OTf represents trifluoromethanesulfonic acid base (triflate) and Pg ₆=R ₅=H or CH ₃And Pg is that formula (VIII) compound of suitable protecting group begins, according to Scheme 23, by with alkali (as sodium hydride) reaction, then with trifluoromethanesulfonic acid reagent such as N-phenyl trifluoromethanesulfonate Toluidrin, in aprotic solvent (as DMF), 0 ℃ of reaction and obtaining to the temperature between the room temperature.

Scheme 23

Formula (If) compound, i.e. R wherein ₁=C _1-4Alkyl or C _1-3Alkyl C ₃- ₆Cycloalkyl, R ₅=H, R ₆=radicals X (n=1 wherein, R ₁₆=C _1-4Alkyl) and R ₇The formula of=H (I) compound can be by formula (Ig) compound, i.e. R wherein ₁=H, R ₅=H, R ₆=radicals X (n=1 wherein, R ₁₆=C _1-4Alkyl or C _1-3Alkyl C ₃- ₆Cycloalkyl) and R ₇The formula of=H (I) compound begins, according to Scheme 24,, for example use R by the alkylation of standard ₁Y alkylating reagent (R ₁=C _1-4Alkyl, the Y=halogen), as CH ₃I, trialkylamine such as TEA are in DCM, 0 ℃ of reaction and obtaining to the temperature between the room temperature.

Perhaps, formula (If) compound can use suitable aldehyde RCHO (R=C _1-3Alkyl), reductive agent such as NaCNBH ₃, in non-proton or protonic solvent such as toluene, THF or MeOH, at 80 ℃ of reduction aminations and obtaining to the temperature between the room temperature.

Scheme 24

R wherein ₁₆=C _1-4Alkyl or C _1-3Alkyl C _3-6The formula of cycloalkyl (Ig) compound can be begun by formula (XV) compound, according to Scheme 25, obtain by the N-Pg deprotection based method of routine.

Scheme 25

R wherein ₃=R ₄=H, F or-CH ₃, R ₁₆=C _1-4Alkyl or C _1-3Alkyl C ₃- ₆The formula of cycloalkyl (XV) compound can basis Scheme 26, by R wherein ₁₆=C _1-4Alkyl or C _1-3Alkyl C ₃- ₆The formula of cycloalkyl (XVI) compound begins, and obtains by the method described in scheme 5,6 and 7 respectively.

Scheme 26

R wherein ₁₆=C _1-4Alkyl or C _1-3Alkyl C ₃- ₆The formula of cycloalkyl (XVI) compound can basis Scheme 27, begin by formula (XVII) compound, by using suitable alkylating reagent (as MeI), in the presence of highly basic (as NaH), in aprotic solvent such as THF or DMF, carry out alkylation to the temperature between the room temperature and obtain at 0 ℃.

Scheme 27

Wherein Pg is suitable protecting group as-CH ₂The formula of-Ph (XVII) compound can pass through European J.of Org.Chemistry, and (15), the Prins reaction described in 3336,2004 obtains.

Formula (Ih) compound, i.e. R wherein ₆=R ₆=R ₅=R ₄=R ₃=R ₁The formula of=H (I) compound can according to Scheme 28Shown in, obtain by corresponding regional isomerism chromatography separation by formula (XVIII).

Scheme 28

Formula (Ih) compound, i.e. R wherein ₆=R ₅=R ₄=R ₃=R ₁The formula of=H (I) compound and formula (XVIII) compound can bases Scheme 29, be formula (XIX) and (XXX) compound and for example borine reduce and obtain by in THF, under reflux temperature, making precursor respectively.

Scheme 29

Formula (XIX) and (XXX) compound can begin by formula (XXXI) compound, according to Scheme 30, reset by Beckmann, for example use toluene sulfonyl chloride, in acetone, by room temperature reaction and obtaining to the temperature that refluxes.

Scheme 30

Formula (XXXI) compound can be begun by formula (XXXII) compound, according to Scheme 31, for example use the oxyamine monohydrate, in ethanol, at room temperature react and obtain.

Scheme 31

Formula (XXXII) compound can be begun by formula (XXXIII) compound, according to Scheme 32, according to J.Am.Chem.Soc.2004, described in 126,8654, by can be SiMe with M wherein ₂After the allyl deriv of Cl or MgBr (XXXIV) reaction, make suitable propargyl aldehyde reset and obtain.

Scheme 32

Formula (XXXIII) compound can basis Scheme 33, prepare by for example using Dess-Martin oxygenant (Dess-Martin periodinane) oxidation at room temperature in DCM by suitable alcohol (XXXV).

Scheme 33

Formula (XXXV) compound can be according to being similar to JOC, and 2005,70, method described in 4043 and basis Scheme 34By propargyl alcohol and suitable iodo aromatic hydrocarbons (XXXVI) preparation.

Scheme 34

Formula (IIa ₁) compound, i.e. R wherein ₃=R ₄=H, Pg are that formula (IIa) compound of suitable N-protected base (typically being Boc) can basis Scheme 35,, obtain by in THF, under reflux temperature, using borane reduction by beginning as formula (XXXVII) compound of giving a definition.

Scheme 35

R wherein ₃=R ₄=R ₅=R ₆The formula of=H (XXXVII) compound can basis Scheme 36, by R wherein ₃=R ₄=R ₅=R ₆The compound of=H (XXXVIII) beginning, by in DMF, 0 ℃ to the temperature range of room temperature, used the sodium hydride reduction 1-3 hour and obtain.

Scheme 36

R wherein ₃=R ₄=R ₅=R ₆The formula of=H (XXXVIII) compound can be by R wherein ₂Be aryl or heteroaryl, R ₃=R ₄=R ₅=R ₆The compound of=H (XXXIX) beginning, according to Scheme 37, by in DCM, 0 ℃ to the temperature between the room temperature with methylsulfonyl chloride and TEA reaction and obtain.

Scheme 37

R wherein ₃=R ₄=R ₅=R ₆The formula of=H (XXXIX) compound can be by R wherein ₃=R ₄=R ₅=R ₆=H and Pg are silyl protecting group (as: 1, the 1-dimethyl ethyl) diphenylmethyl silane) compound (XL) beginning, according to Scheme 38, for example remove reaction by the Pg that uses TBAF in THF, to carry out standard, in solvent such as THF and methanol mixture, at room temperature obtain subsequently with ammonium hydroxide reaction several hours.

Scheme 38

R wherein ₃=R ₄=R ₅=R ₆=H and Pg are silyl protecting group (as: 1, the 1-dimethyl ethyl) diphenylmethyl silane) formula (XL) compound can basis Scheme 39By making compound (XLI) and diazomalonic acid ester (diazomalonate) (according to Synthetic Comunication, 1987,17, method described in the 1709-1716 prepares) and rhodium acetate (II), under 100 ℃, react and obtain according to the method described in the WO/2005/058884 that is similar to.

Scheme 39

Wherein Pg is silyl protecting group (as: 1, a 1-dimethyl ethyl) diphenylmethyl silane) formula (XLI) compound can be by compound (XLII) beginning as defined above of Pg wherein, according to Scheme 40, by using suitable aryl or heteroaryl boric acid or boric acid ester, Pd (PPh ₃) ₄And alkali is (as Na ₂CO ₃), in the mixture of solvent (as toluene, second alcohol and water), under 80 ℃, carry out the Suzuky coupling method and obtain.

Scheme 40

When Pg corresponding to such scheme 39 and 40 in during defined implication, (1, the 1-dimethyl ethyl) diphenylmethyl silane can basis for the corresponding compounds of formula (XLII) [(3-bromo-3-butene-1-yl) oxygen base] Scheme 41, the corresponding compounds 3-bromo-3-butene-1-alcohol by making formula (XLIII) and chloro (1, the 1-dimethyl ethyl) diphenylmethyl silane and imidazoles, in DCM, prepared in reaction at room temperature.

Scheme 41

Perhaps, formula (Im) compound, i.e. R wherein ₁, R ₃, R ₄, R ₅, R ₆Be hydrogen and R ₇For formula as defined above (I) compound of radicals X (wherein n=1) can basis Scheme 42, be the N-protected base by Pg wherein, typically be formula (XLIV) compound of Boc, obtain by N-Pg group deprotection base.For example, when Pg is Boc, use the DCM solution of TFA, to the temperature range of room temperature, carry out at 0 ℃.

Scheme 42

Formula (XLIV) compound can basis as defined above Scheme 43, by R wherein ₁₆The formula of=H (XLV) compound begins, and according to the alkylation of standard, for example uses R ₁₆Y alkylating reagent such as MeI, in the presence of highly basic such as NaH, in aprotic solvent such as DMF or THF, at 0 ℃ to the temperature range internal reaction of room temperature and obtain.

Scheme 43

Formula (XLV) compound can be by R wherein as defined above _jBe formula (XLVI) compound of alkyl, according to Scheme 44,, under refluxing, use BH by mainly being among the THF at aprotic solvent ₃Or LiAlH ₄While reducing amide and ester group, and use the Pg group typically to be Boc subsequently, for example under alkaline condition, at room temperature obtain by using the Boc acid anhydrides to carry out the protection of " original position " nitrogen.

Scheme 44

Formula (XLVI) compound can basis Scheme 45, by R wherein _jAs defined above and L be formula (XLVII) compound of suitable leavings group, by using NH ₃MeOH solution, depress adding, in hydrogenation apparatus (for example Parr) to leavings group (L) for example the methylsulfonic acid base carry out nucleophilic displacement, subsequently under identical condition, by being that acid amides obtains with the intermediate amine intramolecular cyclization.

Scheme 45

Formula (XLVII) compound can basis as defined above Scheme 46, by formula (XLVIII) compound as defined above of L wherein, by using diazo dimethyl malonate and rhodium catalyst, for example Rh ₂(OAc) ₂, in chlorinated solvent such as chlorinated benzene or DCE, carry out the Cyclopropanated of carbene catalyzed (mediated) in the temperature range between 40 ℃ to 80 ℃ and obtain.If use asymmetric rhodium catalyst, this reaction can be the stereospecificity reaction.

Scheme 46

Formula (XLVIII) compound can basis as defined above Scheme 47, by formula (XLIX) compound, for example use methylsulfonyl chloride or toluene sulfonyl chloride to obtain leavings group such as methylsulfonic acid base or toluenesulphonic acids base by suitable oxygen is functionalized, in DCM, under alkaline condition, reaction under 0 ℃ or room temperature and obtaining.

Scheme 47

Formula (XLIX) compound can basis Scheme 48,,, use suitable boric acid, Pd (PPh according to the Suzuky coupling method of standard by formula (L) compound ₃) ₄With alkali such as Na ₂CO ₃, in the mixture of solvent such as toluene, second alcohol and water, 80 ℃ of reactions and obtaining down.

Scheme 48

Perhaps, formula (Im) compound, i.e. R wherein ₁, R ₃, R ₄, R ₅, R ₆Be hydrogen and R ₇For formula as defined above (I) compound of radicals X (wherein n=1) can basis Scheme 49, by radicals R wherein ₂And R ₁₆Suc as formula defined formula (LXIV) compound in (I),, and carry out two keys simultaneously and reduce and obtain by the deprotection of tert-butoxycarbonyl protecting group.For example, reaction conditions can be included in and at room temperature use trifluoroacetic acid and triethyl-silicane to handle in the toluene.Can use other reductive agent, for example sodium triacetoxy borohydride or sodium borohydride.Also can use other solvent, for example methylene dichloride, phenylfluoroform or chlorinated benzene.

Scheme 49

Formula (LXIV) compound can be by radicals R wherein as defined above ₂Suc as formula defined formula (LI) compound in (I), according to Scheme 50, by using alkylating reagent R ₁₆Y[wherein Y is leavings group, halogen or group-OSO ₂R (R=aryl or alkyl)] make hydroxy alkylated and obtain.For example, reaction conditions can comprise and use potassium hydroxide at room temperature to handle formula (LI) compound in DMSO, and addition R subsequently ₁₆Y.Can use other alkali, for example sodium hydroxide, potassium tert.-butoxide, cesium hydroxide or lithium hydroxide.Also can use other solvent, for example methylene dichloride or tetrahydrofuran (THF).

Scheme 50

Formula (LI) compound can be by radicals R wherein as defined above ₂And X ₂Suc as formula defined formula (LII) compound in (I), according to Scheme 51, pass through radicals X ₂In ester moiety reduction and obtain.For example, reaction conditions can be included among the THF, at room temperature uses lithium borohydride and EtOH to handle.Can use other reductive agents, for example lithium aluminium hydride, sodium borohydride or diisobutyl aluminium hydride.

Scheme 51

Formula (LII) compound can be by radicals R wherein as defined above ₂And X ₂Suc as formula defined formula (LIII) compound in (I), according to Scheme 52, by in the presence of suitable alkylating reagent, obtaining with suitable alkali reaction.For example, reaction conditions can be included in the N-Methyl pyrrolidone, under low temperature (for example-20 to+10 ℃), uses trimethyl carbinol lithium and CH ₂ICl handles.Can use other alkylating reagent, for example CH ₂I ₂Can use other solvent, for example DMF or THF.Can use other alkali, for example LDA or NaH.

Scheme 52

Formula (LIII) compound can be by radicals X wherein as defined above ₂Suc as formula defined formula (LIV) compound in (I), according to Scheme 53, by with R wherein ₂Suc as formula defined suitable boric acid R in (I) compound ₂B (OH) ₂Carry out linked reaction and obtain.For example, reaction conditions can be included in Pd (OAc) ₂, PPh ₃Exist down with diisopropyl ethyl amine toluene and water, in the temperature range of room temperature to 80 ℃, use R as defined above ₂B (OH) ₂Handle.Can use other catalyzer, for example Pd (PPh ₃) ₄, PdCl ₂(dppf).

Scheme 53

Formula (LIV) compound can be by radicals X wherein as defined above ₂Suc as formula defined formula (LV) compound in (I), according to Scheme 54Obtain by forming the trifluoromethanesulfonic acid derivative.For example, reaction conditions can be included in diisopropyl ethyl amine and exist down, and in toluene, uses trifluoromethanesulfanhydride anhydride to handle at 0 ℃ to the temperature range of room temperature.

Scheme 54

Formula (In) compound, i.e. R wherein ₁, R ₅, R ₆, R ₃, R ₄Be hydrogen and R ₇Be radicals X, wherein n is that 1 formula (I) compound can basis Scheme 55,, begin preparation by formula (LXII) compound by following method.

Scheme 55

The example of reaction conditions: a=EtOH, 8 hours, room temperature; B=BOC ₂O; K ₂CO ₃, continue 48 hours to room temperature by 0 ℃; C=EtONa, toluene, by 0 ℃ to room temperature, spend the night; D=1) NaH and 1,1,1-three fluoro-N-phenyl-N-[(trifluoromethyls) alkylsulfonyl] Toluidrin, DMF, 1 hour; 2) toluene/EtOH; R ₂B (OH) ₂, K ₂CO ₃, Pd (Ph ₃P) ₄, 80 ℃, 1 hour; E=LiAlH ₄, THF by-20 ℃ to room temperature, 2 hours; F=Et ₂Zn, CH ₂I ₂DCM, room temperature is spent the night; G=NaH, R ₁₆I, DMF, by 0 ℃ to room temperature.

Formula (Io) compound, i.e. R wherein ₁, R ₅, R ₆, R ₃, R ₄Be hydrogen and R ₁For formula (I) compound of alkyl can basis Scheme 56, begin by formula (XXX) compound, by following method preparation.

Scheme 56

The example of reaction conditions: a=R ₁Y, NaH, DMF; B=R ₁₇MgBr, THF, NaCNBH ₃

When needing formula (I) ' when the given enantiomer of compound or its salt or diastereomer, it can for example obtain by the mixture that uses ordinary method to split corresponding enantiomer or diastereomer.

Therefore, for example, the specific enantiomer of this compound or diastereomer can be by the mixtures of corresponding enantiomer or diastereomer, use chiral chromatography for example chirality HPLC obtains (for method the separating referring to for example E2a and E3a of reference, E5a and E6a separate, E9a and E10a separate, and E19a and E20a separate, and E26a and E27a separate).

Perhaps, the specific enantiomer of this compound or diastereomer can use the chirality crystallization method to obtain (for method the separating referring to for example E34 and E35 of reference) as using the chiral acid precipitator method by the mixture of corresponding enantiomer or diastereomer.

In addition, the specific enantiomer of The compounds of this invention or diastereomer can use described any general method synthetic herein by the intermediate of suitable optically-active.

Perhaps, the intermediate that the specific enantiomer of The compounds of this invention or diastereomer can be rich in by suitable stereochemistry uses described any general method and method for splitting by described method and any above-mentioned routine to combine to synthesize herein and obtains.

The intermediate that the intermediate of optically-active or stereochemistry are rich in can obtain by following method: use conventional method to split (for the method for reference referring to for example P60) in the mixture of corresponding enantiomer or diastereomer or by carrying out stereoselectivity reaction (for the method for reference referring to for example P67) or by different method for splitting is combined.

And the specific enantiomer of this compound or diastereomer can obtain by above-mentioned ordinary method is combined.

The compounds of this invention can be used for treating illness or the disease that the monoamine neurotransmitter reuptake of compound is suppressed active reaction.This activity of The compounds of this invention can make them be used for the treatment of the relevant obstacle of Parkinson (family name) syndrome, dysthymia disorders, eating disorder, somnopathy, material, attention deficit how moving obstacle, anxiety disorder, cognitive impairment, sexual dysfunction, mandatory nerve (OC) pedigree obstacle (obsessivecompulsive spectrum disorders), Ji Ledelatulei syndrome and senile dementia, and the illness of the active sensitivity of other monoamine neurotransmitter reuptake to compound-inhibitions.

In the context of the invention, be used to describe the term of indication described herein according to Diagnostic andStatistical Manual of Mental Disorders, the 4th edition, publish (DSM-IV) and/or International Classification of Diseases by American PsychiatricAssociation, the tenth edition (ICD-10) classifies.The various diseases hypotype of being mentioned herein may be interpreted as a part of the present invention.Below numeral in the bracket of cited disease back be meant sorting code number in DSM-IV.

Term " dysthymia disorders " comprising:

Dysthymia disorders and mood disorder comprise major depressive episode, manic episode, mixed type outbreak (MixedEpisode) and hypomania; The depressibility obstacle comprises the depressibility obstacle (311) of serious depressibility obstacle, dysthymic disorder (300.4), NOS; Other mood disorder comprises because the mood disorder (293.83) that the general medicine situation causes, it comprises the hypotype that has depressed feature, has main depressed sample outbreak (Major Depressive-like Episode), has manic feature and have composite character), the mood disorder (296.90) of mood disorder that material causes (comprise and have depressed feature, have manic feature and have the hypotype of composite character) and NOS;

Bipolar disorder comprises the bipolar disorder (296.80) of I type bipolar disorder, II type bipolar disorder (with the major depressive episode of sending out again of hypomania) (296.89), circulation emotionality (spirit) obstacle (301.13) and NOS;

Term " anxiety disorder " comprising:

Anxiety disorder comprises panic attack; Panic disorder comprises panic disorder (300.01) with agoraphobia and the panic disorder (300.21) with agoraphobia; Agoraphobia; The agoraphobia (300.22) that does not have the panic disorder history, specific phobia (300.29, be called simple phobia in the past) comprise animal-type, the physical environment type, blood-injection-damage type (Blood-Injection-Injury Type), the hypotype of situation type (Situational Type) and other type), (social anxiety disorder of social phobia, 300.23), obsessive compulsive disorder (300.3), posttraumatic stress disorder (309.81), acute stress disorder (308.3), generalized-anxiety disorder (300.02), because the anxiety disorder (293.84) that the general medicine situation causes, the anxiety disorder that material causes, separation anxiety disorder (309.21) has the adjustment disorder (309.24) of anxiety disorder and the anxiety disorder (300.00) of NOS;

Term " obstacle that material is relevant " comprising:

The relevant obstacle (Substance-related disorders) of material comprises that psychoactive substance use disorders (Substance Use Disorders) is as substance depilatory, material addiction (Substance Craving) and substance abuse; The persistence perceptual disturbance (flashback) that obstacle that material causes such as material poisoning, material de-addiction (Substance Withdrawal), delirium that material causes, persistence dementia that material causes, persistence amnestic disorder that material causes, mental disorder that material causes, mood disorder that material causes, anxiety disorder that material causes, sexual dysfunction that material causes, somnopathy that material causes and halluoinogen cause; Obstacle that alcohol is relevant such as alcohol dependence (303.90), alcohol abuse (305.00), alcoholism (303.00), abstinence from alcohol (Alcohol Withdrawal) (291.81), alcoholic delirium, alcohol withdrawal delirium, the persistence dementia that alcohol causes (Alcohol Induced Persisting Dementia), the persistence amnestic disorder that alcohol causes, psychotic disorders due to the alcohol, the mood disorder that alcohol causes, the anxiety disorder that alcohol causes, the sexual dysfunction that alcohol causes, the illness (291.9) that the somnopathy that alcohol causes and the alcohol of NOS are relevant; Obstacle that Amphetamine (or amphetamine-type material) is relevant such as Amphetamine (Amphetamine) rely on (304.40), amphetamine abuse (305.70), amphetamine intoxication (292.89), amphetamine withdrawal (292.0), amphetamine intoxication delirium, the mental disorder that Amphetamine causes, the mood disorder that Amphetamine causes, the anxiety disorder that Amphetamine causes, the sexual dysfunction that Amphetamine causes, the obstacle (292.9) that the somnopathy that Amphetamine causes and the Amphetamine of NOS are relevant; The obstacle (292.9) that the caffeine of the anxiety disorder that obstacle that caffeine is relevant such as caffeinism (305.90), caffeine cause, the somnopathy that caffeine causes and NOS is relevant; The obstacle that hemp is relevant such as cannabis rely on (304.30), cannabis abuse (305.20), cannabism (292.89), cannabis intoxication delirium, mental disorder that hemp causes, anxiety disorder that hemp causes and the relevant obstacle (292.9) of hemp of NOS; The obstacle that Cocaine is relevant such as Cocaine rely on (304.20), cocaine abuse (305.60), cocaine poisoning (292.89), cocaine withdrawal (292.0), cocaine intoxication delirium, mental disorder that Cocaine causes, mood disorder that Cocaine causes, anxiety disorder that Cocaine causes, sexual dysfunction that Cocaine causes, somnopathy that Cocaine causes and the relevant obstacle (292.9) of Cocaine of NOS; The mental disorder that persistence perceptual disturbance (flashback) (292.89), hallucinogen intoxication delirium, the halluoinogen that obstacle that halluoinogen is relevant such as hallucinogen dependence (304.50), hallucinogen abuse (305.30), hallucinogen intoxication (292.89), halluoinogen cause causes, the mood disorder that halluoinogen causes, anxiety disorder that halluoinogen causes and the relevant obstacle (292.9) of halluoinogen of NOS; Obstacle that inhalation is relevant such as inhalant dependence (304.60), inhalant abuse (305.90), inhalant intoxication (292.89), inhalant intoxication delirium, persistence dementia that inhalation causes, mental disorder that inhalation causes, mood disorder that inhalation causes, anxiety disorder that inhalation causes and the relevant obstacle (292.9) of inhalation of NOS; The relevant obstacle (292.9) of Nicotine of obstacle that Nicotine is relevant such as nicotine dependence (305.1), nicotine withdrawal (Nicotine Withdrawal) (292.0) and NOS; Obstacle that opioid (Opioid) is relevant such as opioid dependence (Opioid Dependence) (304.00), opioid abuse (Opioid Abuse) (305.50), opium poisping (Opioid Intoxication) (292.89), opioid withdrawal (Opioid Withdrawal) (292.0), opioid intoxication delirium, the mental disorder that opium causes, the mood disorder that opium causes, the sexual dysfunction that opium causes, the obstacle (292.9) relevant of somnopathy that opium causes and NOS with opium; Obstacle that phencyclidine (or Phencyclidines material) is relevant such as phencyclidine dependence (304.60), phencyclidine abuse (305.90), phencyclidine intoxication (292.89), phencyclidine intoxication delirium, mental disorder that phencyclidine causes, mood disorder that phencyclidine causes, anxiety disorder that phencyclidine causes and the relevant obstacle (292.9) of phencyclidine of NOS; Tranquilizer-, soporific-or anxiolytic-relevant obstacle such as tranquilizer, soporific or anxiolytic rely on (304.10), tranquilizer, soporific or anxiolytic abuse (305.40), tranquilizer, soporific or anxiolytic intoxication (292.89), tranquilizer, soporific or anxiolytic de-addiction (292.0), tranquilizer, soporific or anxiolytic intoxication delirium, tranquilizer, soporific or anxiolytic de-addiction delirium (Withdrawal Delirium), tranquilizer-, soporific-or anxiolytic-persistence dementia, tranquilizer-, soporific-or anxiolytic-persistence amnestic disorder, tranquilizer-, soporific-or the mental disorder that causes of anxiolytic, tranquilizer-, soporific-or the mood disorder that causes of anxiolytic, tranquilizer-, soporific-or the anxiety disorder that causes of anxiolytic, tranquilizer-, soporific-or the sexual dysfunction that causes of anxiolytic, tranquilizer-, soporific-or the tranquilizer of the somnopathy that causes of anxiolytic and NOS-, soporific-or anxiolytic-relevant obstacle (292.9); The relevant obstacle (Polysubstance-Related Disorder) of many materials is as many substance depilatories (304.80); With other (or unknown) relevant obstacle such as anabolic steroid, nitrate inhalation (Nitrate Inhalants) and Nitrous Oxide of material;

Term " somnopathy " comprising:

Somnopathy, it comprise primary somnopathy such as dyssomnias such as primary insomnia (307.42), primary hypersomnia (307.44), narcolepsy (347), with the somnopathy (307.47) of breathing relevant somnopathy (780.59), circadian rhythm sleep disorder (307.45) and NOS; The parasomnia (307.47) of primary somnopathy such as parasomnias such as nightmare disorder (307.47), night terror (307.46), somnambulism (307.46) and NOS; The somnopathy that relates to other mental disorder is as insomnia (307.42) that relates to other mental disorder and the hypersomnia (307.44) that relates to other mental disorder; Because the somnopathy that the general medicine situation causes; With the somnopathy that material causes, comprise the hypotype of insomnia type, hypersomnia type, parasomnia type and mixed type;

Term " eating disorder " comprising:

Eating disorder as anorexia nervosa (307.1), comprises abstain from meat, wine, etc type and eating without restraint/the purgation type of following hypotype; Bulimia nervosa (307.51) comprises following hypotype purgation type and non-purgation type; Obesity; Force eating disorder; Disease of eating too much at one meal; With unspecified eating disorder (307.50):

Term " attention deficit/hyperkinetic syndrome " comprising:

Attention deficit/hyperkinetic syndrome comprises attention deficit/hyperkinetic syndrome mating type (HyperactivityDisorder Combined Type) (314.01), attention deficit/hyperkinetic syndrome is main does not note type (Hyperactivity Disorder Predominantly Inattentive Type) (314.00), the hypotype of the attention deficit/hyperkinetic syndrome (314.9) of attention deficit/hyperkinetic syndrome sexuality is crossed driving by force (Hyperactivity Disorder Hyperactive-ImpulseType) (314.01) and NOS; Supermotility sexual dysfunction (Hyperkinetic Disorder); Disruptive behaviour obstacle (Disruptive Behaviour Disorders) is outbreak type (321.81), adolescency outbreak type (312.82) and do not indicate outbreak type (312.89), the hypotype of the disruptive behaviour obstacle of oppositional defiant disorder (Oppositional Defiant Disorder) (313.81) and NOS Childhood of comprising as conduct disorder; And tic disorder such as tourette (family name) mental disorder (307.23);

Term " cognitive impairment " comprising:

Cognitive impairment is included in for example cognitive impairment in the Alzheimer's of other disease such as schizophrenia, bipolar disorder, dysthymia disorders, other psychiatric disorders and the psychotic symptoms relevant with cognitive impairment;

Term " sexual dysfunction " comprising:

Sexual dysfunction, it comprises dysaphrodisia such as hypothyroid dysaphrodisia (302.71) and sexual aversion disorder (302.79); Sexual arousal dysfunction such as female sexual arousal disorder (302.72) and male erectile disorder (302.72); Orgasm disorder (orgasmic disorders) is as female orgasmic disorder (302.73), male orgasmic disorder (302.74) and premature ejaculation (302.75); Sexual pain disorder such as dyspareunia (302.76) and vulvismus (306.51); The sexual dysfunction of NOS (302.70); The parasexuality (302.9) of sexual perversion such as exhibitionism (302.4), fetishism (302.81), frotteurism (302.89), PEDoPhIlIa (302.2), masochism (302.83), sexual sadism (302.84), eonism (302.3), Voyeurism (302.82) and NOS; Gender identity disorder such as children's gender identity disorder (302.6) and teenager or adult's gender identity disorder (302.85); And the sexual dysfunction (302.9) of NOS;

Term " mandatory nerve (OC) pedigree obstacle (obsessive compulsive spectrumdisorders) " comprising:

Mandatory nerve (OC) pedigree obstacle comprises obsessive compulsive disorder (300.3), body shape obstacle comprises body deformability mental disorder (300.7) and hyperchondroplasia disease (hyperchondriasis) (300.7), bulimia nervosa (307.51), anorexia nervosa (307.1), the eating disorder (307.50) of classifying in other place is not as eating without restraint, the impulse control disorder in other local classification (does not comprise intermittent explosive obstacle (intermitted explosive disorder) (312.34), compulsive buying or shopping, repeatability oneself's injury (repetitive self-mutilation), onychophagy, spirituality scratch (psychogenic excoriation), kleptomania (312.32), pathological gambling (312.31), epilation (sending out) addiction (312.39) and Internet are habit-forming), sex perversion (302.70) and non-parasexuality habituation (nonparaphilic sexual addictions), Sydeham ' s tarantism, torticollis, autism (299.0), mandatory storing disease (compulsive hoarding) and dyskinesia comprise tourette (family name) syndrome (307.23).

All multi-form and hypotypes of disease described in the literary composition are considered to a part of the present invention.

In one embodiment, The compounds of this invention can be used as anodyne.For example they can be used for treating chronic inflammatory pain (for example, following the pain of rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, urarthritis and juvenile arthritis); Musculoskeletal pain; Low back pain and cervicodynia; Sprain and strain; Neuropathic pain; Sympathetic nerve maintenance pain (sympathetically maintained pain); Myositis; Follow the pain of cancer and fibromyalgia; Follow migrainous pain; Follow the pain of influenza or other virus infection such as common cold; Rheumatic fever; Accompaniment functions bowel disturbance such as non-ucler dyspepsia, the pain of non-cardiac chest pain and irritable bowel syndrome; Follow the pain of myocardial ischemia; Post-operative pain; Headache; Toothache; And dysmenorrhoea.

The compounds of this invention can be used for treating neuropathic pain.Neuropathic pain syndrome can take place subsequently at neuronal damage, even and after original damage has been cured, sustainable several months of this pain or several years.Neuronal damage can occur in the specific region of peripheral nerve, dorsal root, spinal cord or brain.Neuropathic pain syndrome is usually according to causing their disease or incident to classify.Neuropathic pain syndrome comprises: diabetic neuropathy; Sciatica; The low back pain of nonspecific property; The multiple sclerosis pain; Fibromyalgia; The neuropathy that HIV-is relevant; Postherpetic neuralgia; Trigeminal neuralgia; And the pain that causes by health wound, amputation, cancer, toxin or chronic inflammatory illness.These diseases are difficult to treat very much, although more known medicines have limited effectiveness, fully pain management is almost can not realize.The symptom of neuropathic pain is visibly different, and it often is described to spontaneous shooting and lancinating pain, or persistent burning pain.In addition, follow the pain of normal non-pain perception in addition, as the pain perception behind " numb " (paresthesia and insensitive), touch-sensitive increase (oxypathy), the non-noxious stimulation (dynamically, static, thermal anomaly pain), destructive stimulus susceptibility is increased (hot, cold, mechanical hyperalgesia), removes and stimulate the pain sensation (hyperpathia) that the back continues or selectivity to feel the lacking or lack of conduction path (hypalgia).

The compounds of this invention also can be used for the improvement of inflammatory diseases, for example treats tetter (for example, tan severely, burn, eczema, dermatitis, psoriasis); The acute injury of illness in eye such as glaucoma, the retinitis, retinopathy, uveitis and ocular tissue (as conjunctivitis); Tuberculosis (for example, asthma, bronchitis, pulmonary emphysema, allergic rhinitis, respiratory distress syndrome, pigeon-fanciers' disease (pigeon fancier ' s disease), farmer lung, chronic obstructive pulmonary disease (COPD); Gastrointestinal tract disease (for example, aphthous ulcer, Crohn's disease, spy (different anti-) answering property gastritis, varialoforme gastritis, ulcerative colitis, coeliac disease, Crohn disease, irritable bowel syndrome, inflammatory bowel, gastroesophageal reflux disease); Have other illness of inflammation component such as migraine, multiple sclerosis, myocardial ischemia.

In one embodiment, The compounds of this invention can be used for treating dysthymia disorders and anxiety disorder.

In another embodiment, The compounds of this invention can be used for treating dysthymia disorders.

" treatment " comprises prevention, and wherein this is suitable for relevant illness.

On the other hand, the invention provides the treatment Mammals and comprise the people, the monoamine neurotransmitter reuptake of particularly treating compound suppresses the illness of active reaction or the method for disease, and described method comprises the The compounds of this invention of effective dosage.

In one embodiment, the invention provides treatment and wherein suppress the method that serotonin (5-HT), Dopamine HCL (DA) and norepinephrine (NE) are useful illnesss, described method comprises the The compounds of this invention to the Mammals that these needs are arranged (for example people) effective dosage.

In another embodiment, the invention provides treatment and wherein suppress the method that serotonin (5-HT), Dopamine HCL (DA) and norepinephrine (NE) are useful illnesss, described method comprises the (1S to the Mammals that these needs are arranged (for example people) effective dosage, 6R)-and 6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane or its pharmacologically acceptable salt.

In another embodiment, the invention provides the method for treatment dysthymia disorders, described method comprises the (1S to the Mammals that these needs are arranged (for example people) effective dosage, 6R)-and 6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane or its pharmacologically acceptable salt.

In another embodiment, the invention provides treatment and wherein suppress the method that serotonin (5-HT), Dopamine HCL (DA) and norepinephrine (NE) are useful illnesss, described method comprises the (1S to the Mammals that these needs are arranged (for example people) effective dosage, 6R or 1R, 6S)-the 1-[(methoxyl group) methyl]-6-(2-naphthyl)-3-azabicyclo [4.1.0] heptane or its pharmacologically acceptable salt.

On the other hand, the invention provides the The compounds of this invention that is used for the treatment of.

In another embodiment, the invention provides to be used for the treatment of and suppress the compound that serotonin (5-HT), Dopamine HCL (DA) and norepinephrine (NE) are useful illnesss in the Mammals.

On the one hand, the invention provides The compounds of this invention and be used for the treatment of purposes in the medicine of the illness that the monoamine neurotransmitter reuptake suppressed active reaction or disease in preparation.

In one embodiment, the invention provides The compounds of this invention and be used for the treatment of the purposes that suppresses in the Mammals in the medicine that serotonin (5-HT), Dopamine HCL (DA) and norepinephrine (NE) are useful illnesss in preparation.

In another embodiment, the invention provides (1S, 6R)-and 6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane or its pharmacologically acceptable salt be used for the treatment of the purposes that suppresses in the Mammals in the medicine that serotonin (5-HT), Dopamine HCL (DA) and norepinephrine (NE) they are useful illnesss in preparation.

In another embodiment, the invention provides (1S, 6R or 1R, 6S)-the 1-[(methoxyl group) methyl]-6-(2-naphthyl)-3-azabicyclo [4.1.0] heptane or its pharmacologically acceptable salt be used for the treatment of the purposes that suppresses in the Mammals in the medicine that serotonin (5-HT), Dopamine HCL (DA) and norepinephrine (NE) they are useful illnesss in preparation.

The compounds of this invention also can use with combination with other therapeutic agents.Therefore, on the other hand, the invention provides the combination (combination) that comprises The compounds of this invention and other therapeutical agent.

Compound of the present invention can use with following drug regimen, to treat or prevention of psychotic disorders: i) antipsychotic drug; The medicine that ii) is used for the outer side effect of pyramidal tract, anticholinergic (for example Benzatropine, biperiden, procyclidine and Trihexyphenidyl) for example, antihistaminic (for example diphenhydramine) and dopaminergic (for example amantadine); Iii) thymoleptic; Iv) antianxiety agent; V) cognition enhancer anticholinesterase (for example tacrine, E2020, profit are cut down this bright and lycoremine) for example.

Compound of the present invention can be used in combination with thymoleptic, with treatment or prevention dysthymia disorders and affective disorder.

Compound of the present invention can use with following drug regimen, to treat or prevention two-phase disease: i) mood stabilizer; Ii) antipsychotic drug; Iii) thymoleptic.

Compound of the present invention can use with following drug regimen, to treat or prevention of anxiety disease: i) antianxiety agent; Ii) thymoleptic.

Compound of the present invention can use with following drug regimen, to improve nicotine withdrawal and to reduce nicotine cravings: i) nicotine replacement therapy, for example sublingual formulation of Nicotine beta-cyclodextrin and Nicotine patch; Ii) Bupropion (bupropion).

Compound of the present invention can use with following drug regimen, gives up and reduces alcohol addiction to improve alcohol: i) nmda receptor antagonist, for example acamprosate; Ii) GABA receptor stimulant, for example uncle's ammonia ester (tetrabamate); Iii) opiate receptor antagonist, for example TREXUPONT.

Compound of the present invention can use with following drug regimen, gives up and reduces paregorism to improve opium: i) opium μ receptor stimulant/opium kappa receptor antagonist, for example buprenorphine; Ii) opiate receptor antagonist, for example TREXUPONT; Iii) vasodilative antihypertensive drug, for example lofexidine.

Compound of the present invention can use with following drug regimen, to treat or the prevention somnopathy: i) benzodiazepine

Class, for example temazepam, lormetazepam, estazolam and triazolam; Ii) non--benzodiazepine

Class soporific, for example zolpidem, Zopiclone, Zaleplone and indene (indiplon); Iii) barbiturates, for example somnifen, neo-barb, Sodital, secobarbital and phenylethyl barbituric acid; Iv) thymoleptic; V) other calmness-soporifics, for example Chloral Hydrate and Wy-1485.

Compound of the present invention can use with following drug regimen, to treat apositia: i) appetite stimulator, for example Cyproheptadine; Ii) thymoleptic; Iii) antipsychotic drug; Iv) zinc; V) premenstruum medicine, for example Vitamin B6 and Progesterone.

Compound of the present invention can use with following drug regimen, to treat or the prevention Bulimia nerovsa: i) thymoleptic; Ii) opiate receptor antagonist; Iii) antiemetic ondansetron for example; Iv) testosterone receptor antagonist, for example flutamide; V) mood stabilizer; Vi) zinc; Vii) premenstruum medicine.

Compound of the present invention can use with following drug regimen, to treat or the prevention autism: i) antipsychotic drug; Ii) thymoleptic; Iii) antianxiety agent; Iv) stimulant, for example Methylphenidylacetate, amphetamine preparation and pemoline.

Compound of the present invention can use with following drug regimen, with treatment or prevention ADHD:i) stimulant, for example Methylphenidylacetate, amphetamine preparation and pemoline; Ii) non--stimulant, for example norepinephrine reuptake inhibitor (for example Tomoxetine hydrochloride), α 2 adrenoceptor agonists (for example clonidine), thymoleptic, modafinil and anticholinesterase (for example lycoremine and E2020).

Compound of the present invention can use with following drug regimen, to treat personality disorder: i) antipsychotic drug; Ii) thymoleptic; Iii) mood stabilizer; Iv) antianxiety agent.

Compound of the present invention can use with following drug regimen, to treat or the prevention male sexual disorder: i) Phosphodiesterase V inhibitors, for example Vardenafil and Virga; Ii) dopamine agonist/Dopamine HCL transport inhibitors, for example Apomorphine and Bupropion (buproprion); Iii) alpha adrenergic receptor antagonist, for example phentolamine; Iv) prostaglandin agonists, for example Prostaglandin E1; V) testosterone agonist, for example testosterone; Vi) serotonin transport inhibitors, for example serotonin reuptake inhibitor; V) noradrenaline transporter inhibitor, for example Reboxetine and vii) 5-HT1A agonist, for example Flibaserin.

Compound of the present invention can with the same preparation of specific treatment male sexual disorder and estrogen agonist for example estradiol be used in combination, with treatment or prevention Female sexual dysfunction.

Antipsychotic drug comprises typical antipsychotic drug (for example chlorpromazine, thioridazine, mesoridazine, Fluphenazine, trilafon, prochlorperazine, trifluoperazine, thiothixene (thiothixine), haloperidol, molindone and loxapine); And atypical antipsychotic agents (for example leoponex, olanzapine, risperidone, Quetiapine, Aripiprazole (aripirazole), Ziprasidone and amisulpride).

Thymoleptic comprise serotonin reuptake inhibitor (for example citalopram, escitalopram, fluoxetine, paroxetine and Sertraline); Dual serotonin/norepinephrine reuptake inhibitor (for example Venlafaxine, duloxetine and Midalcipran); Norepinephrine reuptake inhibitor (for example Reboxetine); Tricyclic antidepressant (for example amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline and Trimipramine); Oxidase inhibitor (for example Isocarboxazid, moclobemide, Phenelzine and Tranylcypromine); And other drug (for example Bupropion, mianserin, mirtazapine, nefazodone and trazodone).

Mood-stabilizing drug comprises valproic acid lithium, Sodium Valproate/valproic acid/Sodium hydrogen divalproate, Carbamzepine, lamotrigine, gabapentin, topiramate and tiagabine.

Antianxiety agent comprises benzodiazepine

Class, for example alprazolam and lorazepam.

For the application in the medicine, usually with the form administration of compound of the present invention with the standard drug composition.Therefore on the other hand, the invention provides pharmaceutical composition, it comprises The compounds of this invention and (being on the physiology) acceptable carrier pharmaceutically.Described pharmaceutical composition can be used for treating any one disease described in the literary composition.

In one embodiment, provide pharmaceutical composition, it comprises (1S, 6R)-6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane or its pharmacologically acceptable salt and pharmaceutically acceptable carrier.

The compounds of this invention can be according to any ordinary method administration, for example by in oral, parenteral (for example intravenously), oral cavity, hypogloeeis, the nose, rectum or the mode administration that is fit to through skin and this pharmaceutical composition.

Effective The compounds of this invention, when oral administration, it can be formulated as liquid or solid, for example syrup, suspensoid or emulsion, tablet, capsule and lozenge.

Liquid preparation generally includes described compound or suspension or the solution of salt in suitable liquid vehicle, and described liquid vehicle is aqueous solvent for example, as water, ethanol or glycerine, or non-aqueous solvent, as polyoxyethylene glycol or oil.Described preparation also can comprise suspending agent, sanitas, seasonings or tinting material.

The composition of tablet form can use the conventional pharmaceutical carrier that the is fit to preparation of using of any preparation solid preparation.The example of these carriers comprises Magnesium Stearate, starch, lactose, sucrose and Mierocrystalline cellulose.

The composition of capsule form can use conventional encapsulated method preparation.The piller that for example contains activeconstituents can use the standard vector preparation, in the hard gelatin capsule of packing into then; Perhaps, can use any suitable pharmaceutical carrier to prepare dispersion liquid or suspension, described pharmaceutical carrier for example contains glue, Mierocrystalline cellulose, silicate or oil, and in the soft gelatin capsule of then dispersion liquid or suspension being packed into.

Typical parenteral composition is included in the described compound in sterile aqueous carrier or the acceptable oil of parenteral (for example polyoxyethylene glycol, polyvinylpyrrolidone, Yelkin TTS, peanut oil or sesame oil) or the solution or the suspension of salt.Perhaps, can be with described solution freeze-drying, then before administration with suitable solvent reconstruct (reconstituted).

The composition of nose administration can be mixed with aerosol, drops, gelifying agent and pulvis routinely.Aerosol generally comprises solution or the thin suspension of active substance in pharmaceutically useful water-based or non-aqueous solvent, and described aerosol is present in the sealed vessel with list or multiple doses sterile form usually, reinjects with atomiser-type appts when it can or use for the form of cartridge case.Perhaps, described sealed vessel can be the unit partitioning device, and the aerosol dispenser of single dose nasal inhaler or assembling dosage valve for example makes that the content in the container just is drained after the primary treatment.When formulation comprises aerosol dispenser, it will comprise propelling agent, and it can be pressurized gas, as air or the organic propelling agent such as the fluorochlorohydrocarbon of compression.Aerosol dosage forms can also be taked the form of pump-atomizer.

The composition that is fit to oral cavity or sublingual administration comprises tablet, lozenge and pastille, and wherein activeconstituents is with carrier (for example sugar and gum arabic, tragakanta or gelatin and glycerine) preparation.

The composition of rectal administration is the form that contains the suppository of conventional suppository bases (for example cocoa ester) routinely.

The composition that is fit to percutaneous dosing comprises ointment, gel and paster.

In one embodiment, composition is a unit dosage, as tablet, capsule or ampoule.

Calculate each dose unit of oral administration for example comprises 0.5 to the 250mg The compounds of this invention of (and comprise for example 0.05 to 25mg for administered parenterally) with free alkali.

Calculate with free alkali, pharmaceutically useful The compounds of this invention usually with for example oral dosage be 1mg to 500mg, as 1mg to 400mg, as 10-250mg or intravenously, subcutaneous or intramuscular dosage be 0.1mg to 100mg, as 0.1mg to 50mg, as the per daily dose scheme administration (adult patients) of 1-25mg formula (I) compound or its salt, described compound is used every day 1-2 time for example every day 1-4 time.In one embodiment, The compounds of this invention administration once a day.

This compound is fit to continue to use during one section successive treatment, for example continues 1 week or longer time.

For oral administration, typical dosage can be every day 1 to 200mg, for example every day 60-200mg.

When The compounds of this invention or its pharmaceutically acceptable derivates and second active therapeutic agent were used in combination with opposing same disease state, the dosage the when dosage of every kind of compound can be with this compound of independent use was different.Those skilled in the art can know appropriate dosage easily.Be understandable that being used for can be along with sanatory character and patient's age and situation in the amount of the required The compounds of this invention of treatment and change, and finally considers decision carefully by attending doctor or animal doctor.

Combination refers to for using the said medicine preparation that can exist easily with the form of pharmaceutical preparation, so pharmaceutical preparation comprises combination and pharmaceutically acceptable carrier or vehicle as defined above, and this is also included within another aspect of the present invention.The single component of this type of combination can be by approach order or administration simultaneously in the pharmaceutical preparation that separates or make up of any routine.

The invention still further relates to and be adapted at treating the new test kit (kit-of-parts) that uses in the illness as defined above, second formulation that it comprises first formulation that contains The compounds of this invention and contains other therapeutical agent, their are simultaneously, separately or the order administration.

When being the order administration, all at first administrations of the The compounds of this invention or second therapeutical agent.When being administration simultaneously, this combination can be in identical or different administered in pharmaceutical compositions.

When in identical preparation, making up, be understandable that these two kinds of compounds must be stable, and each other and and other component of preparation between be compatible.When separately preparing, they can be with the preparation of any routine, easily in this area the known mode of this compounds is provided.

Biological test

Cytobiology

A) generation of the stable LLCPK clone of expression hSERT, hNET and hDAT

The stable clone of expressing human serotonin transporter (hSERT) can produce by uriniferous tubules (LLC-PK1 or the LLCPK) cell that the hSERT transfection lewis lung carcinoma pig among the mammalian expression vector pCDNA3.1Hygro (+) is cloned in use.

The stable clone of expressing human norepinephrine transporter (hNET) can produce by the hNET transfection LLCPK cell that use is cloned among the mammalian expression vector pRC/CMV.

The stable clone of expressing human dopamine transporter (hDAT) can produce by the hDAT transfection LLCPK cell that use is cloned among the mammalian expression vector pDESTCDNA3.1.

An example of the reference method of use hDAT, hSERT and hNET transfection LLCPK cell can be at H.Gu, and S.C.Wall and G.Rudnick finds among J.Biol.Chem. (1994) 269:7124-7130.

Each clone is cultivated in Dulbecco improvement Iger (family name) substratum (DMEM) that contains 10% foetal calf serum (FBS) additional with the Geneticin (geneticin) of 400 μ g/ml Totomycin (hSERT) or 500 μ g/ml (hNET) or 1000 μ g/ml (hDAT) independently.Cell remained under 37 ℃ contain 5%CO in the air ₂Wet environment in.

B) be used for expressing the generation of the BacMam virus of mammalian cell hSERT, hNET and hDAT

Being used for SPA-is by using the BacMam virus to each independent people SERT, NET and the generation of DAT translocator to infect the generation of HEK-293F cell in conjunction with the film of measuring.HSERT and hDAT are cloned in the pFBMRfA carrier, and hNET is cloned in the pFASTBacMam1 carrier.The generation of BacMam virus and purposes are described in people such as Condreay JP, Proc.Natl.Acad.Sci.USA, 1999,96:127-132and Hassan NJ et al, Protein Expression and Purification, 47 (2): 591-598, in 2006.

Avidity to human transport protein SERT, NET and DAT

The compounds of this invention can be determined by one of following test to people's serotonin transporter (SERT), people's norepinephrine transporter (NET) with to the avidity of people's dopamine transporter (DAT).Described avidity is usually by the IC that obtains in the competitive assay ₅₀(displace in the translocator 50% the required compound concentration of radiolabeled part) calculates, with " the K that is calculated by following equation _i" value representation:

K_{i} = \frac{{IC}_{50}}{1 + L / K_{D}}

Wherein L=radioligand, and K _D=radioligand is to the avidity (Cheng and Prusoff, Biochem.Pharmacol.22:3099,1973) of translocator.In the context of the present invention, pKi value (antilogarithm that is equivalent to Ki) is used to substitute the Ki use; Estimate pKi result and only be accurate to about 0.3-0.5.

A) filtration on the film of hSERT, hNET and the formation of hDAT LLCPK clone is in conjunction with test

Membrane prepare

HSERT-LLCPK or hDAT-LLCPK or hNET-LLCPK clone are used for the membrane prepare of radioligand-binding assay.Each clone is cultivated in Dulbecco improvement Iger (family name) substratum (DMEM) that contains 10% foetal calf serum (FBS) additional with the Geneticin (geneticin) of 400 μ g/ml Totomycin (hSERT) or 500 μ g/ml (hNET) or 1000 μ g/ml (hDAT) independently.When cell reaches 70-80% and converges, remove substratum, and with cell with phosphate buffered saline (PBS) results that contain 5mM EDTA.Cell suspending liquid was descended centrifugal 5 minutes at 4 ℃ under 900g.The precipitation that generates is suspended in the test damping fluid of 30-50 volume once more, and (50mM Tris pH 7.7 contains 120mM NaCl, 5mM KCl, 10 μ M Pargylines and 0.1% xitix) in, and use glass-teflon Potter homogenizer homogenize, and under 48000g, descended centrifugal 20 minutes at 4 ℃.The film precipitation that generates is suspended in the test damping fluid of equal volume once more, under 37 ℃, hatched 20 minutes, and centrifugal under 48000g according to the front.Regulate the final protein concentration of each goods, obtain hSERT-LLCPK, hDAT-LLCPK and the hNET-LLCPK of about 480 μ g albumen/ml, it is determined by the Bio-Rad protein determination kit.With film with the aliquot of 1ml when-80 ℃ storage is up to needs down.

Scheme is measured in filtration for hSERT, hNET and hDAT

Monoamine transporter filters in conjunction with the general document of measuring and can be: Michael J.Owens, et al, Neurotrasmitter receptor and transporter binding profile of antidepressants andtheir metabolites, JPET, 283:1305-1322,1997; Per Allard, Jan O.Marcusson, Svate B.Ross, [3H] WIN-35,428binding in the human brain, Brain Res., 706:347-350,1996.

The compounds of this invention in conjunction with the avidity of the reuptake position of SERT can use on the hSERT-LLCPK cytolemma, carry out [ ³H] citalopram filters in conjunction with measuring and estimates.In detail, deep hole 96 orifice plates (1ml, NUNC, cod.260252) in, in the cumulative volume of 400 μ l, each concentration is at war with in duplicate in conjunction with measuring.(solution of 100X in pure DMSO, scope is from 10 with 4 μ l test compounds ^-6To 10 ^-127 point curves of M, final concentration) or DMSO (being used for determining total combination) or final concentration be that the DMSO solution of the fluoxetine of 10 μ M (is used for determining non-specific binding, NSB) joins in the hole; Subsequently, with final concentration be 0.25nM 200 μ l[N-methyl- ³H] citalopram (Amersham Biosciences, 80Ci/mmol) the solution of test in the damping fluid join institute porose in, and in the test damping fluid, start this reaction at last with the film (protein concentrations in about 2.5 μ g/ holes) that dilutes at 1: 80 by adding 200 μ l/ holes.Should react and at room temperature carry out 2 hours, and stop by using Perkin-Elmer FilterMat-196 harvesting device, in 0.5% polymine (PEI), filtering fast in the GF/B Unifilter 96-filter plate (Perkin-Elmer) of preliminary wetting then.With the filter plate ice-cold 0.9%NaCl solution washing in 1ml/ hole 3 times.With this plate in baking oven 50 ℃ dry 60 minutes down, then opaque bottom strip of paper used for sealing is placed this plate below, and the Microscint 20 (Perkin-Elmer) of 50 μ l joined in each hole.Plate is sealed with TopSeal, and use the radioactive intensity 4 minutes of TopCount liquid scintillation counter (Packard-Perkin-Elmer) counting sample, and per minute record count (CPM).

Can in 96 well format, and in the final test volume of 400 μ l, carry out basically according to previous described method in conjunction with measuring for the competition of hNET for hSERT, except use hNET-LLCPK cytolemma (1: 40 dilution, i.e. albumen/hole of 4.8 μ g) and [ ³H] nisoxetine as radioligand (the 1.5nM[N-methyl- ³H] nisoxetine, Amersham Biosciences, 84Ci/mmol).10 μ M Desipramines are used for NSB.

Competition for hDAT can be basically according to previous described method for hSERT and hNET in conjunction with measuring, in 96 well format, and in the final test volume of 400 μ l, carry out, except use hDAT-LLCPK cytolemma (1: 20, i.e. albumen/hole of 9.6 μ g) and [ ³H] WIN-35,428 as radioligand (the 10nM[N-methyl- ³H] WIN-35,428, Perkin Elmer, 85.6Ci/mmol).In addition, 10 μ M GBR-12909 are used for NSB, and the incubation time of association reaction is at room temperature 1 hour.

B) for people DAT, NET and SERT bonded scintillation proximity assay (SPA)

Use hSERT/hDAT/hNET BacMam virus that the HEK-293F cell is transduceed

With HEK-293F suspension cell line (Invitrogen) according to routine in shaking bottle suspension culture, in 293Freestyle Expression substratum (Invitrogen) growth.Under the MOI of 100 virions/cell (infection multiplicity), use suitable translocator BacMam to transduce culture, and at 37 ℃, 5%CO ₂Air in cultivated 48 hours, in the vibration insulation can of humidity, under 90rpm, vibrate.By at 1000g, gathered in the crops culture down in centrifugal 10 minutes for 4 ℃ then, and with cell precipitation when storing until needs down for-80 ℃.

The preparation of BacMam hSERT/hDAT/hNET-HEL293F cytolemma

The cell precipitation of transduction is used damping fluid-A (50mM HEPES, 1mM EDTA, the 1mM leupeptin, the 25ug/mL bacitracin, 1mM phenyl methanesulfonamide acyl fluorides, PMSF, 2 μ M Pepstatin As, pH7.7) suspending once more is the 10x volume, and uses 2x15 pulse per second (PPS) (bursts) to carry out homogenize in glass waying blenden (Waring blender).Then with this homogenate under 500g centrifugal 20 minutes.Subsequently, collect supernatant liquor, and 13, under the 000g centrifugal 30 minutes.To precipitate then that to use damping fluid-B (50mM TRISpH 7.4,130mM NaCl) to suspend once more be the former precipitation volume of 4x, and force its pin, obtain the suspension of homogeneous by 0.8mm.With the aliquots containig of film when storing up to needs down for-80 ℃.Test quantitative protein concentration by Bradford.

For the SPA-of hSERT, hNET and hDAT in conjunction with testing program

The compounds of this invention also can be by the SPA technology of utilization on the BacMam-of aforementioned preparation recombinant chou people SERT, NET and DAT film to the avidity of hSERT, hNET or hDAT, use [ ³H] citalopram, [ ³H] nisoxetine or [ ³H] WIN-35,428 combination tests are estimated.For the SPA technology (GE Healthcare Amersham), has only the translocator in conjunction with radioactivity can cause that pearl excites, therefore do not need separation and combination/unconjugated radioligand.

For the hSERT test design in conjunction with SPA be based on the Trilux beta counter (Wallac, Perkin-Elmer).Briefly, the test compounds in pure DMSO (or 1 μ M fluoxetine is as positive control) of 0.5 μ L is joined in the 50 μ L SPA mixtures, contain in this mixture at test damping fluid (20mM HEPES, 145mM NaCl, 5mM KCl, pH 7.3) in 2mg/mL SPA pearl (Amersham RPNQ0001), 4 μ g/mL hSERT Bacmam films, 0.01%pluronic F-127,2.5nM[ ³H] citalopram.At room temperature hatched at least 2 hours.Stable counting, and counting was three days.

Perhaps, by using Viewlux beta counter (Wallac, Perkin-Elmer), utilize imaging PS-WGA pearl (Amersham RPNQ0260) in the final test volume of 30 μ L, in 384-well plate format (Greiner 781075), carry out hDAT, hNET and hSERT SPA-in conjunction with test.In brief, for hDAT or hNET or hSERT in conjunction with SPA, join the hole by using Hummingbird (Genomic Solutions) test compounds in pure DMSO and 0% and 100% of 0.3 μ L effectively to be contrasted (DMSO is used for total combination and 10 or 1 μ M indatraline as positive control), the SPA mixture that adds 30 μ L subsequently, this mixture contains at test damping fluid (20mM HEPES, 145mM NaCl, 5mM KCl, pH 7.3-7.4) 1mg/mL SPA pearl (hSERT) or 2mg/ml SPA pearl (hDAT and hNET) in, the hDAT of 40 μ g/ml or 20 μ g/ml or 6 μ g/ml or hNET or hSERT BacMam film, 0.02%pluronic F-127,10nM[ ³H] WIN-35,428 or 10nM[ ³H] nisoxetine or 3nM[ ³H] citalopram.At room temperature hatched at least 2 hours, and preferably spent the night in the dark.By using 600s 6x frame and method (binning) and 613nm emission filter (emission filter) to utilize Viewlux instrument record bonded radioactivity.

Compound is to the avidity scope of human transport protein SERT, NET and DAT

For each of these three kinds of translocator SERT, NET and DAT, formula (I) ' compound demonstrates the pKi greater than 4.5 usually.In one embodiment, for these three kinds of translocators each, formula (I) compound demonstrates the pKi greater than 5.5 usually.In another embodiment, for each of this three kinds of translocators, formula (I) ' compound demonstrates the pKi greater than 6.5 usually.In another embodiment, for each of this three kinds of translocators, formula (I) ' compound demonstrates the pKi greater than 7.5 usually.

In one embodiment, the invention provides have the formula (I) of hSERT pKi between 7 and 8.5 ' compound.In another embodiment, the invention provides have the formula (I) of hSERT pKi between 8.5 and 10 ' compound.

In one embodiment, the invention provides and have formula (I) compound of hDAT pKi between 6.5 and 7.5.In another embodiment, the invention provides have the formula (I) of hDAT pKi between 7.5 and 8.5 ' compound.

In one embodiment, the invention provides have the formula (I) of hNET pKi between 6.5 and 7.5 ' compound.In another embodiment, the invention provides have the formula (I) of hNET pKi between 7.5 and 8.5 ' compound.

In one embodiment, the invention provides have hSERT pKi between 8.5 and 10, the formula (I) of hDAT pKi between 7.5 and 8.5 ' compound.

In one embodiment, the invention provides and have hSERT pKi between 9 and 10, hNET pKi between 8.0 and 8.5, the formula (I) of hDAT pKi between 7.5 and 8.0 ' compound.

Embodiment

The present invention further explains by following non-limiting examples.

In the step below, after each starting material, the preparation example of reference or the numbering of embodiment are generally provided.This provides only for helping the general chemistry worker.Starting material is not necessarily from the preparing the batch of reference.

Wherein with reference to using " similarly " or " similar " step, understandable as one skilled in the art, this type of step can comprise less variation, as temperature of reaction, and agent/solvent amount, reaction times, treatment condition or chromatography purification condition.

Compound uses ACD/Name PRO 6.02 chemical name softwares (Advanced ChemistryDevelopment Inc., Toronto, Ontario, M5H2L3, Canada) name.

All temperature refer to ℃.

Proton resonance (NMR) wave spectrum usually on the Varian instrument 300,400 or 500MHz, or on the Bruker instrument 300 and 400MHz under record.Use the residual solvent line to report with the chemical shift of ppm (δ) as unit as interior mark.Splitting the branch mode is appointed as: s, and unimodal; D, bimodal; T, triplet; Q, quartet; M, multiplet; B, broad peak.In 25-90 ℃ temperature range, record NMR wave spectrum.When detecting, provide the maximum chemical shift of content more than a conformer.

Mass spectrum (MS) carries out on 4II three quadrupole mass spectrometers (Micromass UK) or Agilent MSD1100 mass spectrograph usually, operate with ES (+) and ES (-) ionization mode, or on Agilent LC/MSD1100 mass spectrograph, unite HPLC instrument Agilent 1100Series with ES (+) and ES (-) ionization mode and analyze.In mass spectrum, only reported peak in the molion bunch.

When record HPLC walk-up retention time, this analysis is on HPLC Agilent 1100Series instrument, uses following method to carry out: post: Luna C18100A 50x2mm, 3 microns; Moving phase: (MeCN+0.05%TFA)/(H2O+0.05%TFA), gradient: in 8 minutes 0/100 to 95/5; Flow velocity: 1ml/min.

Fast silica gel chromatogram method (by Merck AG Darmstadt, Germany provides) or carry out on the silica gel of 230-400 sieve mesh by Varian Mega Be-Si prepacked column or by pre-filling Biotage silicagel column.

In many preparations, use manual flash chromatography (Flash+) of Biotage or automatic flash chromatography (Horizon or SP1) system purifying.These all instruments carry out with the Biotage silica column.

X-ray powder diffraction (XRPD): should be appreciated that spectrum and diffraction data will change a little according to various factors such as temperature, concentration and employed instrument.Those skilled in the art will recognize that the XRPD peak position is subjected to the influence of height of specimen difference.Therefore, cited peak position can be subjected to such variation in the literary composition.Those skilled in the art it is also recognized that the relative intensity at peak can change owing to preferred directive action.

Dsc (DSC): should be realized that the endotherm(ic)peak of Ce Lianging is relevant with several factors herein, it comprises the purity of instrument, heating rate, calibration standard, humidity and the use sample of use.The fusing point of reporting in the experiment is to assess on the basis of the beginning of the endotherm(ic)peak that writes down during the dsc analysis.

Use following abbreviation herein: the TBAF=tetrabutylammonium fluoride, DCE=ethylene dichloride, Tlc refer to the thin-layer chromatography on silica plate, drying refers to solution through anhydrous sodium sulfate drying, r.t. (RT) refers to room temperature, Rt=retention time, DMSO=methyl-sulphoxide; The DCM=methylene dichloride; DMF=N, N '-dimethyl formamide; MeOH=methyl alcohol; TEA or Et ₃The N=triethylamine; The THF=tetrahydrofuran (THF); EA, AcOEt or EtOAc=ethyl acetate; The cy=hexanaphthene; EtOH=ethanol; ZnEt ₂=zinc ethyl; The MTBE=methyl tertiary butyl ether; The TFA=trifluoroacetic acid; Et ₂The O=ether; The IPA=Virahol; DMPU=1,3-dimethyl-3,4,5,6-tetrahydrochysene-2 (1H)-pyrimidone (pyrimidinone); SPE post=solid-phase extraction column; SCX post=strong cat ion exchange column; MCX: mixed type cationic exchange coloum; NH post: the silica column that secondary amine is functionalized.

Preparation example 1:1-(1, the 1-dimethyl ethyl) 3-methyl 4-hydroxyl-5,6-dihydro-1,3 (2H)-pyridine dicarboxylate (P1)

Under 0 ℃ and under nitrogen atmosphere,, drip TEA (43mL) in the 4-oxo-solution of 3-piperidine carboxylic acid methyl ester hydrochloride (14.94g) in exsiccant DCM (250mL) under stirring with 5 minutes.Mixture was stirred 5 minutes down at 0 ℃, make it reach room temperature then, at room temperature under nitrogen atmosphere, stir then with two (1, the 1-dimethyl ethyl) esters (18.6g) of a collection of adding coke acid, and with solution and spend the night.With saturated NH ₄The Cl aqueous solution (350ml) is poured in this solution, and mixture is transferred in the separating funnel.Reaction flask is washed with DCM (100ml), and this volume washing lotion is poured in the separating funnel.Separate each phase, and water is washed with DCM (3x70mL).With the organic phase that merges through anhydrous Na ₂SO ₄Drying, removal of solvent under reduced pressure by flash chromatography (using 1: 3 wash-out of ethyl acetate/hexanaphthene) purifying, obtains title compound (19.8g) with crude product.

NMR( ¹H，CDCl ₃)：δ11.95-12.02(m，1H)4.07(br.s.，2H)3.77-3.82(m，3H)3.58(t，2H)2.34-2.43(m，2H)1.46-1.50(m，9H)

Preparation example 2:1-(1, the 1-dimethyl ethyl) 3-methyl 4-{[(trifluoromethyl) alkylsulfonyl] the oxygen base }-5,6-dihydro-1,3 (2H)-pyridine dicarboxylate (P2)

Method A: under 0 ℃ and under nitrogen atmosphere, 1-(1 under stirring, the 1-dimethyl ethyl) 3-methyl 4-oxo-1,3-piperidines dicarboxylic ester (500mg, P1) add NaH in the solution in exsiccant DMF (5mL) (60% in mineral oil, 117mg), and reaction mixture was stirred 10 minutes down at 0 ℃ in batches, drip (0.847g) solution in exsiccant DMF (2mL) of N-phenyl-two (fluoroform sulfimide (methanesulfonimide)) then, and continue to stir 0.5 hour.With saturated NH ₄Cl (30mL) and ether (30mL) are poured in the reaction mixture, separate each phase, and water is washed with ether (3x15mL).With the organic phase that merges through anhydrous Na ₂SO ₄Drying, and removal of solvent under reduced pressure obtain the thick title compound of 1.5g.

Method B: under 0 ℃ and under nitrogen atmosphere, 1-(1 under stirring, the 1-dimethyl ethyl) 3-methyl 4-oxo-1,3-piperidines dicarboxylic ester (500mg, P1) add NaH in the solution in exsiccant THF (12mL) (60% in mineral oil, 156mg) in batches, and reaction mixture stirred 30 minutes in 0 ℃, then (1.028g), and continue at 0 ℃ of stirring 1 hour with a collection of adding N-phenyl-two (fluoroform sulphonamide), and in stirred overnight at room temperature.10g ice is poured in the stirred mixture, and reduction vaporization THF at room temperature.Resistates is dissolved in the ethyl acetate (30mL), and with mixture Na ₂CO ₃The aqueous solution (10%, 3x20mL) wash, with organic layer through anhydrous Na ₂SO ₄Drying, and removal of solvent under reduced pressure obtain the thick title compound of 1.7g.

Merge the crude product that derives from method A and B, and, obtain the title compound of 1.340g by flash chromatography (using 1: 9 wash-out of ethyl acetate/hexanaphthene) purifying.

NMR( ¹H，CDCl ₃)：δ4.29(br.s.，2H)3.82-3.87(m，3H)3.64(t，2H)2.50-2.57(m，2H)1.46-1.52(m，9H)。MS(m/z)：390[MH]+，412[MNa]+.

Preparation example 3:1-(1, the 1-dimethyl ethyl) 3-methyl 4-(3, the 4-dichlorophenyl)-5,6-dihydro-1,3 (2H)-pyridine dicarboxylate (P3)

Under nitrogen atmosphere, to 1-(1, the 1-dimethyl ethyl) 3-methyl 4-{[(trifluoromethyl) alkylsulfonyl] the oxygen base }-5,6-dihydro-1,3 (2H)-pyridine dicarboxylate (200mg, P2), 3,4-dichlorophenyl boric acid (108mg) and Pd (PPh ₃) ₄Add toluene (2.5mL), ethanol (2mL) and Na in the mixture (21mg) successively ₂CO ₃(the 2M aqueous solution, 2mL).Mixture was stirred 1 hour down at 80 ℃, make reaction mixture reach room temperature then.With saturated NH ₄The Cl aqueous solution (15mL) is poured in this solution, and mixture is transferred in the separating funnel.With mixture with ethyl acetate (3x20mL) extraction, with the organic phase that merges through anhydrous Na ₂SO ₄Drying, and evaporate this solvent, obtain crude product, it by flash chromatography (using 1: 3 wash-out of ethyl acetate/hexanaphthene) purifying, is obtained title compound (198mg).

NMR( ¹H，CDCl ₃)：δ7.42(d，1H)7.25(d，1H)6.98(dd，1H)4.26(br.s.，2H)3.61(t，2H)3.55-3.58(m，3H)2.47(br.s.，2H)1.50-1.54(m，9H)

Preparation example 4:4-(3, the 4-dichlorophenyl)-5-(hydroxymethyl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid 1,1-dimethyl ethyl ester (P4)

At N ₂Under the atmosphere, under-20 ℃, with the 1-(1 of 1 minute time under stirring, the 1-dimethyl ethyl) 3-methyl 4-(3, the 4-dichlorophenyl)-5,6-dihydro-1, (538mg P3) drips LiAlH in the solution in exsiccant ether (10mL) to 3 (2H)-pyridine dicarboxylates ₄(diethyl ether solution of 1M, 1mL).Reaction mixture was stirred 15 minutes down at-20 °, then with saturated NH ₄The Cl aqueous solution (50mL) and ether (50mL) are poured in this solution, and with mixture vigorous stirring 20 minutes at room temperature.Separate each phase, and water is extracted with ether (3x20mL).With the organic phase that merges through anhydrous Na ₂SO ₄Drying, and removal of solvent under reduced pressure obtain crude product, and it by flash chromatography (using 1: 3 wash-out of ethyl acetate/hexanaphthene) purifying, is obtained title compound (474mg).

NMR( ¹H，DMSO-d6)：δ7.62(d，1H)7.56(d，1H)7.26(dd，1H)4.90(t，1H)4.02(br.s.，2H)3.79(d，2H)3.49(t，2H)2.35(br.s.，2H)1.42-1.46(m，9H)

Preparation example 5:(1S, 6R/1R, 6S)-and 6-(3, the 4-dichlorophenyl)-1-(hydroxymethyl)-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1-dimethyl ethyl ester (P5)

Method A:

Under argon atmospher, under 0 ℃, the CH under stirring ₂I ₂(13.39g) drip ZnEt in the solution in exsiccant DCM (83mL) ₂(hexane solution of 1M 25mL), stirs mixture 20 minutes down at 0 ℃, and then in-20 ℃ of coolings down.At this moment, drip 4-(3, the 4-dichlorophenyl)-5-(hydroxymethyl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid 1,1-dimethyl ethyl ester (734mg, P4) solution in exsiccant DCM (3.5mL), reaction mixture restir 30 minutes stirred 40 minutes down and at room temperature stirs and spend the night at 0 ℃ then.With saturated NH ₄The Cl aqueous solution (100mL) is poured in the reaction flask, and with mixture vigorous stirring 10 minutes, separates each phase, and this organic layer of reduction vaporization.Resistates is dissolved with ether (50mL), and this volume washing lotion is joined previous NH ₄In the Cl solution: this total mixture is poured in the separating funnel.With organic phase with saturated NH ₄Cl (3x20mL), use HCl (5%) (20mL) to handle then,, and carry out two different processing organic phase and tart aqueous phase separation.

The evaporation organic phase obtains crude product (280mg), and it by flash chromatography (using 1: 3 wash-out of ethyl acetate/hexanaphthene) purifying, is obtained still impure title compound (70mg).

Water is washed with ether (50mL), and is alkalized consumingly with the NaOH of 2N, then with basic solution with ether (3x50mL) extraction, with the organic phase that merges through anhydrous Na ₂SO ₄Drying, and removal of solvent under reduced pressure obtain crude product (210mg), its contain promising main component [(1S, 6R/1R, 6S)-6-(3, the 4-dichlorophenyl)-3-azabicyclo [4.1.0] heptan-1-yl] methyl alcohol)].

MS(m/z)：272[MH] ⁺.

Under argon atmospher, this crude product of part (159mg) is dissolved among the exsiccant DCM (5mL), and at room temperature stirs, at room temperature add two (1, the 1-dimethyl ethyl) esters (156mg) of coke acid, and the mixture stirring is spent the night.Solvent evaporated under reduced pressure, and with resistates ether (15mL) dissolving.With this solution with saturated NH ₄Cl (15mL) washes, with water with ether (3x10mL) extraction, with the organic phase that merges through anhydrous Na ₂SO ₄Drying, and removal of solvent under reduced pressure obtains crude product, the title compound merging that it is impure with the 70mg that had before obtained.This material is passed through flash chromatography (using 1: 2 to 1: 1 wash-out of ether/normal hexane) purifying once more, obtain still impure title compound, it is for containing 4-(3, the 4-dichlorophenyl)-5-(hydroxymethyl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid 1, the mixture (170mg) of 1-dimethyl ethyl ester.

MS(m/z)：372[MH] ⁺.

Method B: at room temperature, with coke acid two (1, the 1-dimethyl ethyl) ester (838mg) joins [(1S, 6R/1R, 6S)-6-(3, the 4-dichlorophenyl)-3-azabicyclo [4.1.0] heptan-1-yl] methyl alcohol (840mg, E4, according to E4, the impure compound that method described in the method A obtains) in the solution in exsiccant DCM (25mL), and mixture stirred spend the night.With mixture in 40 ℃ the heating 2 hours, and then at room temperature the cooling.With saturated NH ₄Cl (50mL) and DCM (20mL) join in the reaction mixture, stir after 10 minutes, separate each phase.Organic phase is evaporated, and resistates is dissolved in the ether (50mL).With organic phase with saturated NH ₄Cl (3x30mL) washing, and through anhydrous Na ₂SO ₄Drying, and removal of solvent under reduced pressure.The thick oily matter (920mg) that obtains is passed through flash chromatography (using 1: 3 wash-out of ethyl acetate/hexanaphthene) purifying, obtain impure title compound, it is for containing 4-(3, the 4-dichlorophenyl)-5-(hydroxymethyl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid 1,1-dimethyl ethyl ester (260mg) and impure (1R, 6S)-6-(3, the 4-dichlorophenyl)-1-[({[(1, the 1-dimethyl ethyl) oxygen base] carbonyl } the oxygen base) methyl]-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1, the mixture of 1-dimethyl ethyl ester (185mg) [MS (m/z): 472[MH] ⁺].

Under argon gas, will (1R, 6S)-6-(3, the 4-dichlorophenyl)-1-[({[(1, the 1-dimethyl ethyl) oxygen base] carbonyl } the oxygen base) methyl]-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1-dimethyl ethyl ester is dissolved among the MeOH (7mL), and the solution that stirs is cooled off down at 0 °.(0.5M 3mL), and stirs mixture 20 minutes down at 0 ℃, stirs 30 minutes down at 50 ℃, and stirs 1,5 hour down at 70 ℃ to drip NaOH.Reduction vaporization MeOH dilutes aqueous resistates water (20mL), and extracts with ether (3x20mL).With the organic phase that merges through anhydrous Na ₂SO ₄Drying, and removal of solvent under reduced pressure obtain the still impure title compound of another batch, and it is for containing 4-(3, the 4-dichlorophenyl)-5-(hydroxymethyl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid 1, the mixture (130mg) of 1-dimethyl ethyl ester.

MS(m/z)：372[MH] ⁺.

Method C: under 0 ℃ and under nitrogen atmosphere, (P16 drips BH in THF 0.19g) (3mL) solution to 6-(3, the 4-dichlorophenyl)-2-oxo-3-azabicyclo [4.1.0] heptane-1-carboxylate methyl ester under stirring ₃(1M/THF 2.38mL), makes reaction mixture reach room temperature to the THF complex compound then, and stirs 4 hours under refluxing.Reaction mixture is cooled to 0 ℃, and with the 20%HCl aqueous solution with pH regulator to 2-3, remove ice bath then, and mixture at room temperature stirred 15 minutes.Add DCM, and with the 2N NaOH aqueous solution with pH regulator to 8-9.With organic phase salt water washing, and through Na ₂SO ₄Drying, and solvent evaporated under reduced pressure.Crude product is dissolved among the DCM, adds Boc ₂O (0.136g), and reaction mixture stirred under room temperature 1 hour.With this reaction mixture extracted with diethyl ether, with organic phase with saturated NaHCO ₃The aqueous solution, salt water washing are through Na ₂SO ₄Drying, and removal of solvent under reduced pressure obtain the thick title compound of 0.195g of colorless oil, it need be further purified promptly use.

Preparation example 6:(1S, 6R/1R, 6S)-and 6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1-dimethyl ethyl ester (P6)

Under argon gas, under 0 ℃, (1S, 6R/1R under stirring, 6S)-6-(3, the 4-dichlorophenyl)-and 1-(hydroxymethyl)-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1-dimethyl ethyl ester (110mg, P5, according to P5, the impure compound that method described in the method A obtains) (60% in mineral oil, 11.7mg), and continues to stir 30 minutes with a collection of adding NaH in the solution in exsiccant THF (2mL).Subsequently, drip CH ₃I (18.2 μ L), and make reaction mixture reach room temperature, and stirred 1.5 hours, add the NaH (5.3mg) and the CH of amount in addition then ₃I (8.3 μ L).Reaction mixture was at room temperature stirred 2 hours, be cooled to 0 ℃ then, add saturated NH ₄The Cl aqueous solution (15mL) and ether (20mL), and with mixture vigorous stirring 10 minutes at room temperature.Separate each phase, and water is extracted with ether (3x10mL).The organic phase that merges is washed with salt solution (3x20mL), through anhydrous Na ₂SO ₄Dry, evaporating solvent obtains crude product (106mg), it is passed through flash chromatography (using 40: 60 wash-outs of ether/normal hexane) purifying, obtain still impure title compound, it is for containing 4-(3, the 4-dichlorophenyl)-and the 5-[(methoxyl group) methyl]-3,6-dihydro-1 (2H)-pyridine carboxylic acid 1, the mixture (80mg) of 1-dimethyl ethyl ester.

MS(m/z)：386[MH] ⁺

Preparation example 7:3-(3, the 4-dichlorophenyl)-2-propine-1-alcohol (P7)

Method A: according to being similar to JOC 2005,70, the method described in the 4043-4053, by 3,4-two chloroiodobenzones (4g carries out twice preparation) beginning, preparation title compound (2.94g).

Method B: with 3,4-two chloroiodobenzones (300mg), propargyl alcohol (128 μ L), CuI (10mg), K ₂CO ₃(302mg), Pd (PPh ₃) ₄(12mg) mixture in DMF (2mL) shone 20 minutes in 100 ℃ with microwave.Add saturated NH then ₄The Cl aqueous solution adds DCM subsequently.After separating two-phase, the dry and vacuum-evaporation with organic layer.Crude product by flash chromatography (using cyclohexane/ethyl acetate 7/3 wash-out) purifying, is obtained title compound (40mg).

NMR( ¹H，CDCl ₃)：δ7.58(s，1H)，7.41(d，1H)，7.27(d，1H)，4.52(d，2H)，1.75(t，1H)

Preparation example 8:3-(3, the 4-dichlorophenyl)-2-propynal (P8)

In 3-(3, the 4-the dichlorophenyl)-solution of 2-propine-1-alcohol (2.980g, P7 derive from method A described in the P7 and B) in exsiccant DCM (74mL), add Dess-Martin oxygenant (Dess-Martinperiodinane) (9.43g).Mixture at room temperature stirred spend the night.Then with NaS ₂O ₃(19g) with saturated NaHCO ₃Solution joins in the mixture, and it was at room temperature stirred 1 hour.Separate organic phase then, and wash with salt.Dry and concentrating under reduced pressure obtains thick title product (2.9g) with organic layer, it need be further purified promptly use.

NMR( ¹H，CDCl ₃)：δ9.48(s，1H)，7.73(s，1H)，7.55(d，1H)，7.42(m，1H)。

Preparation example 9:(1S, 5S/1R, 5R)-1-(3, the 4-dichlorophenyl) two ring [3.1.0] oneself-3-ketone (P9)

According to being similar to J.Am.Chem.Soc.2004, the method described in 126,8654, (2.9g, P8) preparation obtain the title compound of 880mg output, are orange foam-like material by 3-(3, the 4-dichlorophenyl)-2-propynal.

NMR( ¹H，CDCl ₃)：δ7.45(d，1H)，7.28(s，1H)，7.11(d，1H)，2.89(m，2H)，2.70(d，1H)，2.42(d，1H)，2.05(m，1H)，1.38(m，1H)，0.72(m，1H)。

Preparation example 10:(1S, 5S/1R, 5R)-1-(3, the 4-dichlorophenyl) two ring [3.1.0] oneself-3-ketoxime (P10)

At room temperature, in water (7mL) solution of oxyamine monohydrate (1.26g) and sodium acetate (2.3g), add (1S, 5S/1R, 5R)-1-(3, the 4-dichlorophenyl) two rings [3.1.0] oneself-3-ketone (0.860g, ethanol P9) (18ml) solution, and reaction mixture stirred spend the night.After ethanol is removed in decompression, the aqueous solution is extracted with DCM.Dry and concentrating under reduced pressure obtains title compound (870mg) with organic phase.

NMR( ¹H，CDCl ₃)：δ7.40(d，1H)，7.26(m，1H)，7.05(m，1H)，3.33-2.60(m，4H)，1.89(m，1H)，1.15(m，1H)，0.68(m，1H)。MS(m/z)：256[MH]+.

Preparation example 11:(1R, 6R/1S, 6S)-1-(3, the 4-dichlorophenyl)-3-azabicyclo [4.1.0] heptan-4-ketone and (1R, 6S/1S, 6R)-6-(3, the 4-dichlorophenyl)-3-azabicyclo [4.1.0] heptan-4-ketone (P11)

To (1S, 5S/1R, 5R)-1-(3, the 4-dichlorophenyl) two ring [3.1.0] oneself-the 3-ketoxime (0.870g, add in acetone P10) (29ml) solution yellow soda ash (aqueous solution of 5%w/w, 25ml).The acetone soln that under vigorous stirring, adds Tosyl chloride (969mg) then, and mixture at room temperature stirred 30 minutes.With reaction mixture reflux 4 hours, and at room temperature spend the night.After acetone is removed in decompression, resistates is dissolved in saturated NaHCO ₃In the solution, and it is extracted with DCM.Dry and the concentrating under reduced pressure with organic phase.Crude product by flash chromatography (DCM/MeOH is by 98/2 to 95/5) purifying, is obtained the mixture of the title compound of 640mg.

MS(m/z)：256[MH]+.

The oxygen base of preparation example 12:[(3-bromo-3-butene-1-yl)] (1, the 1-dimethyl ethyl) diphenylmethyl silane (P12)

According to being similar to the method described in the WO2005058884, by 3-bromo-3-butene-1-alcohol (4g), chloro (1, the 1-dimethyl ethyl) diphenylmethyl silane (8.27ml), imidazoles (2.34g) and N, N-dimethyl-4-pyridine amine (0.025g) beginning, the title compound of the colorless oil of preparation 8.7g output.

Preparation example 13:{[3-(3, the 4-dichlorophenyl)-3-butene-1-yl] the oxygen base } (1, the 1-dimethyl ethyl) diphenylmethyl silane (P13)

Will [(3-bromo-3-butene-1-yl) oxygen base] (1, the 1-dimethyl ethyl) diphenylmethyl silane (P12,3.50g) and (3, the 4-dichlorophenyl) boric acid (2.06g) is dissolved in the toluene (45mL), with the solution degasification of stirring, add four (triphenylphosphines) then and close palladium (0) (0.363g) and ethanol (33mL), and with mixture degasification once more.The Na that adds 2N ₂CO ₃The aqueous solution (24mL), and with mixture heating up to 80 ℃, and under nitrogen atmosphere, under this temperature, stirred 3 hours.After being cooled to room temperature, with the reaction mixture extracted with diethyl ether, organic phase is washed with salt, through Na ₂SO ₄Drying, and removal of solvent under reduced pressure.Crude product by flash chromatography (using cy/EA by 100/0 to 95/5 wash-out) purifying, is obtained the title compound (2.65g) of colorless oil.

NMR( ¹H，CDCl ₃)：δ7.55-7.69(m，4H)，7.40-7.47(m，3H)，7.34-7.40(m，4H)，7.32(d，1H)，7.11(dd，1H)，5.25(dd，2H)，3.75(t，2H)，2.28-3.12(m，2H)，0.62-1.26(m，9H)。

Preparation example 14:2-(3, the 4-dichlorophenyl)-2-(2-{[(1,1-dimethyl ethyl) (phenylbenzene) silylation] the oxygen base } ethyl)-1,1-cyclopropane dicarboxylic acid dimethyl esters (P14)

With { [3-(3, the 4-dichlorophenyl)-and 3-butene-1-yl] the oxygen base } (1, the 1-dimethyl ethyl) diphenylmethyl silane (P13,2.25g), diazomalonic acid dimethyl ester (1.2g) is (according to being similar to Synthetic Communications, 17 (4), 1709-16, method described in 1987 preparation) and rhodium acetate (II) dipolymer (0.060g) admixed together, and heated 40 minutes down at 100 ℃.After the cooling, resistates is handled with DCM, and mixture is filtered.With filtrate evaporated under reduced pressure, and with crude product by flash chromatography (Cy/EA is by 1/0 to 95/5) purifying, obtain the title compound (2.38g) of colorless oil.

NMR( ¹H，CDCl ₃)：δ7.51-7.61(m，4H)，7.25-7.47(m，8H)，7.05(dd，1H)3.83(s，3H)，3.45(s，3H)，3.30-3.62(m，2H)，2.00-2.29(m，2H)，1.83(d，1H)，1.57(s，1H)，0.94-1.13(m，9H)。

Preparation example 15:1-(aminocarboxyl)-2-(3, the 4-dichlorophenyl)-2-(2-hydroxyethyl) methyl cyclopropanecarboxylate (P15)

Under 0 ℃, with tetrabutyl ammonium fluoride (TBAF) (5.6mL, 1.1M/TFH) be added drop-wise to the 2-(3 under stirring, the 4-dichlorophenyl)-2-(2-{[(1, the 1-dimethyl ethyl) (phenylbenzene) silylation] the oxygen base } ethyl)-1, (P14 is in THF 2.38g) (27mL) solution for 1-cyclopropane dicarboxylic acid dimethyl ester.After 4 hours, remove ice bath, and reaction mixture was at room temperature stirred 3 hours.Removal of solvent under reduced pressure with ether and water treatment, is washed with organic phase resistates, through Na with salt ₂SO ₄Dry also vacuum evaporating solvent obtains thick lactone intermediate (2.08g).This product is dissolved in the mixture of THF (15mL) and methyl alcohol (10mL), at room temperature drips NH ₄The OH aqueous solution (28%, 16mL), and with reaction mixture stirring 4 hours.With the mixture concentrating under reduced pressure, resistates with DCM and water dissolution, is washed organic phase, through Na with salt ₂SO ₄Dry also vacuum evaporating solvent.Crude product by FC (using DCM/ methyl alcohol by 1/0 to 9/1 wash-out) purifying, is obtained the title compound (0.89g) of white foam shape.

NMR( ¹H，CDCl ₃)：δ8.14(br.s.，1H)，7.60(dd，1H)，7.41-7.50(m，2H)，5.79(br.s.，1H)，3.47-3.59(m，2H)，3.13-3.15(m，3H)，2.29-2.33(m，1H)，2.23-2.26(m，1H)，2.04-2.22(m，2H)。

Preparation example 16:(1S, 6R/1R, 6S)-6-(3, the 4-dichlorophenyl)-2-oxo-3-azabicyclo [4.1.0] heptane-1-carboxylate methyl ester (P16)

Under 0 ℃, (P15 adds triethylamine (0.25mL) in DCM 0.46g) (6mL) solution to 1-(aminocarboxyl)-2-(3, the 4-dichlorophenyl)-2-(2-hydroxyethyl) methyl cyclopropanecarboxylate under stirring, and adds methylsulfonyl chloride (0.16mL) subsequently.Remove ice bath, and reaction mixture was at room temperature stirred 3 hours.With mixture with other DCM extraction, with organic phase with saturated NH ₄Cl, salt washing are through Na ₂SO ₄Drying, and solvent evaporated under reduced pressure obtain the intermediate methanesulfonates of the white foam shape of 0.54g.At room temperature, add NaI (0.22g) in stirring the solution of this product in DMF (6mL) down, add NaH subsequently (60% in oil, 63mg), and with reaction mixture stirring 0.5 hour in batches.With reaction mixture ether and NH ₄The Cl solution extraction, organic phase water, salt washing are through Na ₂SO ₄Dry also vacuum evaporating solvent.Crude product by FC (using cy/EA by 9/1 to 1/9 wash-out) purifying, is obtained title product (0.19g).

NMR( ¹H，CDCl ₃)：δ7.45(d，1H)7.39(d，1H)7.19(dd，1H)5.79(br.s.，1H)3.52(s，3H)3.29-3.38(m，1H)3.20-3.28(m，1H)2.37(td，1H)2.29(d，1H)2.12-2.17(m，1H)1.97(d，1H)。MS(m/z)：314[MH] ⁺.

Preparation example 18:3-{[3-(oxyethyl group)-3-oxopropyl] amino } ethyl butyrate (P18)

At room temperature, with EtOH (20mL) solution stirring of 3-aminobutyric acid ethyl ester (4.2g) and 2-ethyl propenoate (3.83mL) 8 hours.Solvent evaporated under reduced pressure, and with the chromatography purification of resistates by on the NH post, use and carry out wash-out by the gradient of 100% hexanaphthene to 90% ethyl acetate/hexanaphthene.Separate the title compound that obtains colorless oil, 3.9g (MS (m/z): 232[MH] ⁺.

Preparation example 19:3-{{[(1, the 1-dimethyl ethyl) the oxygen base] carbonyl } [3-(oxyethyl group)-3-oxopropyl] amino } ethyl butyrate (P19)

To contain 3-{[3-(oxyethyl group)-3-oxopropyl] amino } (P18,3.5g), 1, the mixture of 4-diox (8.1mL), water (16.2mL) and 5% solution of potassium carbonate (8.4mL) uses the ice bath cooling to ethyl butyrate.Under agitation, add Di-tert butyl pyrocarbonate (3.51mL) lentamente.Stirred 15 minutes, and at room temperature continue then to stir 3 hours.Mixture was placed room temperature following 48 hours.Behind the concentrating under reduced pressure, resistates is extracted with ether (2x200mL).Mutually at first with 1N HCl washing, water (20mL) washs then, and final drying with ether.Evaporating solvent obtains thick material (4.6g), then it need be further purified promptly to use.

NMR( ¹H，CDCl ₃)：δ4.08-4.20(m，4H)，3.64-3.72(m，1H)，3.32-3.53(m，2H)，2.39-2.74(m，4H)，1.43-1.52(m，9H)，1.19-1.33(m，9H)

Preparation example 20:1-(1, the 1-dimethyl ethyl) 3-ethyl 4-hydroxyl-6-methyl-5,6-dihydro-1,3 (2H)-pyridine dicarboxylate and 1-(1, the 1-dimethyl ethyl) 3-ethyl 4-hydroxy-2-methyl-5,6-dihydro-1,3 (2H)-pyridine dicarboxylate (P20)

With 3-{{[(1, the 1-dimethyl ethyl) oxygen base] carbonyl } [3-(oxyethyl group)-3-oxopropyl] amino } ethyl butyrate (P19,2,5g) be dissolved in the toluene (15mL), and under 0 ℃, join in the alcohol sodium solution, this alcohol sodium solution be by will be dispersed in the mineral oil 60% sodium hydride (0.453g) slowly and join in batches in toluene (5mL) solution of ethanol (0.7mL) and form.This mixture at room temperature stirred spend the night.Solvent evaporated under reduced pressure then, and resistates is dissolved in the ethyl acetate (20mL), dry and vacuum concentration washed with 1N HCl (20mL).By the purified by flash chromatography on silica gel, use the gradient of 5-50% ethyl acetate/hexanaphthene to carry out wash-out, obtain the title compound (0.7g) of faint yellow oily, it is the mixture of regional isomer.

MS(m/z)：230[M-56] ⁺，186[MH-100] ⁺.

Preparation example 21:1-(1, the 1-dimethyl ethyl) 3-ethyl 4-(3, the 4-dichlorophenyl)-6-methyl-5,6-dihydro-1,3 (2H)-pyridine dicarboxylate and 1-(1, the 1-dimethyl ethyl) 3-ethyl 4-(3, the 4-dichlorophenyl)-and 2-methyl-5,6-dihydro-1,3 (2H)-pyridine dicarboxylate (P21)

Under 0 ℃, under nitrogen atmosphere, regional isomer 1-(1, the 1-dimethyl ethyl) 3-ethyl 6-methyl-4-oxo-1 under stirring, 3-piperidines dicarboxylic ester and 1-(1, the 1-dimethyl ethyl) 3-ethyl 4-(3, the 4-dichlorophenyl)-and 2-methyl-5,6-dihydro-1,3 (2H)-pyridine dicarboxylate (P20,0.7g) the solution of mixture in exsiccant DMF (6mL) in add 60% sodium hydride (0.118g) be dispersed in the mineral oil in batches, and reaction mixture was stirred 10 minutes down at 0 ℃.Drip 1,1 then, 1-three fluoro-N-phenyl-N-[(trifluoromethyls) alkylsulfonyl] solution of Toluidrin (0.88g) in exsiccant DMF (1mL), and continue to stir 1 hour.With saturated NH ₄Cl (10mL) and ether (30mL) are poured in the reaction mixture.Separate organic phase, dry and vacuum concentration.Then with resistates by the chromatography purification on the silica gel, use 5-50% ethyl acetate/hexanaphthene gradient to carry out wash-out.

With isolating material (MS (m/z): 440[M+Na] ⁺, 362[MH-56] ⁺) (0.65g) be dissolved in the mixture of toluene (15mL) and ethanol (11mL); The sodium carbonate solution (4.7mL) that adds (3, the 4-dichlorophenyl) boric acid (0.357g) and 2.0M, and with suspension nitrogen gas stream degasification several minutes.Add Pd (Ph then ₃P) ₄(0.045g), and with reaction mixture heated 1 hour in 80 ℃.Then it is cooled to room temperature, solvent evaporated under reduced pressure, and resistates distributed between ethyl acetate (50mL) and water (50mL).Organic layer is washed with salt solution (20mL), dry and concentrated.By the chromatography purification on the silica gel, use 5-25% Yi Suanyizhi hexanaphthene gradient to carry out wash-out, obtain title compound, it is the mixture of regional isomer, is faint yellow oily thing (0.45g).

MS(m/z)：437[M+Na] ⁺.

Preparation example 22:4-(3, the 4-dichlorophenyl)-5-(hydroxymethyl)-2-methyl-3,6-dihydro-1 (2H)-pyridine carboxylic acid 1,1-dimethyl ethyl ester (P22)

With regional isomer 1-(1, the 1-dimethyl ethyl) 3-ethyl 4-(3, the 4-dichlorophenyl)-and 6-methyl-5,6-dihydro-1,3 (2H)-pyridine dicarboxylate and 1-(1, the 1-dimethyl ethyl) 3-ethyl 4-(3, the 4-dichlorophenyl)-and 2-methyl-5,6-dihydro-1,3 (2H)-pyridine dicarboxylate (P21,0.45g) mixture be dissolved in the toluene (15mL), and be cooled to-20 ℃.Under-20 ℃, drip the THF solution (0.869mL) of 1.0M lithium aluminum hydride, and mixture was stirred 2 hours under this temperature.To react then with saturated NH ₄Cl solution (10mL) stops, and dilutes with ethyl acetate (20mL); Separate organic layer, water (20mL) is washed, dry and vacuum concentration.By the chromatography purification on the silica gel, use 100% hexanaphthene-50% cyclohexane/ethyl acetate gradient to carry out wash-out, obtain the title compound of the colorless oil of 240mg.The structure of main regional isomer is tested by nOe NMR and is confirmed.

NMR( ¹H，CDCl ₃)：δ7.42(d，1H)，7.28(d，1H)，7.03(dd，1H)，4.52-4.63(m，1H)，4.44-4.45(m，1H)，3.97-4.09(m，2H)，3.69-3.79(m，1H)，2.69-2.81(m，1H)，2.00-2.08(m，1H)，1.47-1.54(m，9H)，1.38-1.43(m，1H)，1.19(d，3H)。

Preparation example 23:({3-[4-chloro-3-(trifluoromethyl) phenyl]-3-butene-1-yl } the oxygen base) (1, the 1-dimethyl ethyl) diphenylmethyl silane (P23)

(P12,1.0g) beginning according to the method that is similar in the aforesaid preparation example 13, obtains title compound (1.85g) by [(3-bromo-3-butene-1-yl) oxygen base] (1, the 1-dimethyl ethyl) diphenylmethyl silane.

NMR( ¹H，CDCl ₃)：δ7.17-7.22(m，1H)，7.08-7.15(m，4H)，6.83-6.98(m，7H)，6.77-6.80(m，1H)，4.87-4.91(m，1H)，4.69-4.74(m，1H)，3.22-3.30(m，2H)，2.22-2.29(m，2H)，0.50-0.56(m，9H)。

Preparation example 24:2-[4-chloro-3-(trifluoromethyl) phenyl]-2-(2-{[(1,1-dimethyl ethyl) (phenylbenzene) silylation] the oxygen base } ethyl)-1,1-cyclopropane dicarboxylic acid dimethyl ester (P24)

By (3-[4-chloro-3-(trifluoromethyl) phenyl]-3-butene-1-yl } the oxygen base) (1, the 1-dimethyl ethyl) diphenylmethyl silane (P23,1.85g) beginning, according to the method that is similar in the aforesaid preparation example 14, obtain the title compound (1.92g) of colorless oil.

NMR( ¹H，CDCl ₃)：δ7.50-7.62(m，5H)，7.29-7.46(m，8H)，3.82-3.85(m，3H)，3.50-3.59(m，1H)，3.36-3.44(m，4H)，2.17-2.26(m，2H)，1.85-1.89(m，1H)，1.59-1.72(m，1H)，1.01-1.08(m，9H)

Preparation example 25:1-(aminocarboxyl)-2-[4-chloro-3-(trifluoromethyl) phenyl]-2-(2-hydroxyethyl) methyl cyclopropanecarboxylate (P25)

According to the method that is similar in the aforesaid preparation example 15, make 2-[4-chloro-3-(trifluoromethyl) phenyl]-2-(2-{[(1, the 1-dimethyl ethyl) (phenylbenzene) silylation] the oxygen base } ethyl)-1,1-cyclopropane dicarboxylic acid dimethyl ester (P24,1.92g) react in the THF of 20mL with the THF solution (4.7mL) of 1.1M TBAF, and use 28% NH then ₄OH (14mL) handles this thick intermediate in THF (10mL)/MeOH (7mL) mixture, after the crystallization of DCM/5% hexane, obtain the title compound (0.64g) of white solid.

NMR( ¹H，CDCl ₃)：δ8.18(br.s.，1H)，7.59-7.61(m，1H)，7.46-7.48(m，1H)，7.44-7.46(m，1H)，5.79(br.s.，1H)，3.48-3.58(m，2H)，3.14-3.15(m，3H)，2.30-2.33(m，1H)，2.23-2.26(m，1H)，2.05-2.22(m，2H)

Preparation example 26:(1R, 6S/1S, 6R)-6-[4-chloro-3-(trifluoromethyl) phenyl]-2-oxo-3-azabicyclo [4.1.0] heptane-1-carboxylate methyl ester (P26)

According to being similar to aforesaid preparation example 16, the method for method A makes 1-(aminocarboxyl)-2-[4-chloro-3-(trifluoromethyl) phenyl]-2-(2-hydroxyethyl) methyl cyclopropanecarboxylate (P25,0.64g) and Et ₃N (0.37mL) and trifluoromethanesulfchloride chloride (0.19mL) are reacted in DCM (10mL), and handle this intermediate with 60% sodium hydride (84mg) that is dispersed in the mineral oil in DMF (5mL) then, obtain title compound (0.35g).

NMR( ¹H，CDCl ₃)：δ7.64-7.73(m，1H)，7.45-7.48(m，2H)，6.83(br.s.，1H)，3.47-3.50(m，3H)，3.32-3.41(m，1H)，3.19-3.28(m，1H)，2.26-2.42(m，2H)，2.11-2.19(m，1H)，2.00-2.04(m，1H)。

Preparation example 27:(1R, 6S/1S, 6R)-6-[4-chloro-3-(trifluoromethyl) phenyl]-1-(hydroxymethyl)-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1-dimethyl ethyl ester (P27)

Under 0 ℃ and under nitrogen atmosphere, under stirring (1R, 6S/1S, 6R)-6-[4-chloro-3-(trifluoromethyl) phenyl]-(P26 drips BH in THF 0.35g) (8mL) solution to 2-oxo-3-azabicyclo [4.1.0] heptane-1-carboxylate methyl ester ₃(1M/THF 4.03mL), makes reaction mixture reach room temperature to the THF complex compound then, and stirs 4 hours under refluxing.Reaction mixture is cooled to 0 ℃, and regulates pH to 2-3, remove ice bath then, and mixture was at room temperature stirred 15 minutes with the 20%HCl aqueous solution.Add DCM, and make pH reach 8-9 with 2N NaOH.Separate organic phase, through Na ₂SO ₄Drying, and solvent evaporated under reduced pressure.Under 0 ℃, thus obtained crude product (310mg) is handled in DCM (10mL) with Di-tert butyl pyrocarbonate (220mg), and stirred under these conditions 1 hour.Add NH then ₄Cl separates organic phase, and uses NaHCO ₃, salt washing, dry and reduction vaporization obtains crude product.It by purified by flash chromatography, is used 1: 9 to 1: 1 wash-out of AcOEt/Cy, obtain title compound (300mg).

MS(m/z)：406[MH] ⁺，350[MH-56] ⁺.

Preparation example 28:1-(1, the 1-dimethyl ethyl) 3-methyl 4-oxo-1,3-piperidines dicarboxylic ester (P28)

In methylene dichloride (250mL) suspension of ice-cooled 4-oxo-3-piperidine carboxylic acid methyl ester hydrochloride (15.01g), add two (1, the 1-dimethyl ethyl) esters (17.76g) of coke acid, drip triethylamine (27mL) then.Make the mixture of generation reach room temperature, and stirred 4 hours.With saturated NH ₄C1 pours in the reaction mixture, and separates each phase, with organic layer through Na ₂SO ₄Drying is filtered and reduction vaporization.Diethyl ether is joined in the resistates, and filter through Celite filler (celite pad).Removal of solvent under reduced pressure obtains title compound (16.96g).

MS(m/z)：258[MH] ⁺，202[MH-56] ⁺.

Preparation example 29:1-(1, the 1-dimethyl ethyl) 3-methyl 4-(4-chloro-phenyl-)-5,6-dihydro-1,3 (2H)-pyridine dicarboxylate (P29)

To ice-cooled 1-(1, the 1-dimethyl ethyl) 3-methyl 4-oxo-1,3-piperidines dicarboxylic ester (P28, N 8.5g), be added in 60% sodium hydride (1.46g) in the mineral oil in dinethylformamide (85mL) solution, and the mixture that generates was stirred 10 minutes down at 0 ℃.In this mixture, add 1,1,1-three fluoro-N-phenyl-N-[(trifluoromethyls) alkylsulfonyl] N of Toluidrin (12.39g), dinethylformamide (62mL) solution, and make the mixture of generation reach room temperature, and stirred 1 hour.Add diethyl ether and saturated NH ₄Cl.Water layer is washed with diethyl ether, and then the organic layer of collecting is washed with water.With organic phase through Na ₂SO ₄Drying is filtered and reduction vaporization.Crude product is passed through flash chromatography (using cyclohexane/ethyl acetate by 1/0 to 9/1 wash-out) purifying; obtain 1-(1; the 1-dimethyl ethyl) alkylsulfonyl 3-methyl 4-{[(trifluoromethyl)] the oxygen base }-5,6-dihydro-1,3 (2H)-pyridine dicarboxylate (7.73g).In toluene (41mL) solution of this compound (3g) and (4-chloro-phenyl-) boric acid (1.38g), add Pd (PPh ₃) ₄Ethanol (0.32g) (30mL) solution adds Na subsequently ₂CO ₃(2M, 22.5mL), and with the mixture that generates in 80 ℃ of heating 2 hours.Make reaction mixture reach room temperature, add diethyl ether then, and separate each phase.With organic layer through Na ₂SO ₄Drying is filtered and reduction vaporization.The crude product that generates is passed through flash chromatography (using cyclohexane/ethyl acetate by 1/0 to 8/2 wash-out) purifying, obtain title compound (2.35g).

MS(m/z)：352[MH] ⁺，296[MH-56] ⁺.

Preparation example 30:4-(4-chloro-phenyl-)-5-(hydroxymethyl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid 1,1-dimethyl ethyl ester (P30)

Under-20 ℃, 1-(1, the 1-dimethyl ethyl) the 3-methyl 4-(4-chloro-phenyl-)-5 under stirring, (P29 drips 1MLiAlH in diethyl ether 1.85g) (37.04mL) solution to 6-dihydro-1,3 (2H)-pyridine dicarboxylate ₄Diethyl ether solution (3.68mL), and the mixture that generates stirred 20 minutes down at-20 ℃.The aqueous solution (4.44mL), diethyl ether and the water that add 2%HCl, and separate organic phase, through Na ₂SO ₄Drying is filtered and reduction vaporization, obtains title compound (1.487g).

NMR( ¹H，CDCl ₃)：δppm?7.33(d，2H)7.12(d，2H)4.13(s，2H)4.03(s，2H)3.61(t，2H)2.40(s，2H)1.46-1.52(m，9H)

Preparation example 31:(1R, 6S/1S, 6R)-and 6-(4-chloro-phenyl-)-1-(hydroxymethyl)-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1-dimethyl ethyl ester (P31).

(hexane solution of 1M adds methylene iodide (3.88mL) in anhydrous methylene chloride 24.07mL) (19.6mL) suspension, and the mixture that generates was stirred 15 minutes to ice-cooled zinc ethyl.In the refrigerative mixture, add 4-(4-chloro-phenyl-)-5-(hydroxymethyl)-3 rapidly, 6-dihydro-1 (2H)-pyridine carboxylic acid 1,1-dimethyl ethyl ester (P30,1.04g) anhydrous methylene chloride (11.3mL) solution, make it reach room temperature, and add 2 then, 6-two (1, the 1-dimethyl ethyl)-4-picoline (9.88g), and then mixture was stirred 2 hours.(1M 30mL), and stirred 30 minutes to add the HCl aqueous solution.Separate organic phase, and, use 3M NaOH alkalization to be pH～12 mutually acidity, and extract with diethyl ether then with the HCl extraction.Separate organic layer, through Na ₂SO ₄Drying is filtered and reduction vaporization.The crude product that generates (is used methylene chloride/ammoniacal liquor by flash chromatography, 90/7.5/2.5 purifying wash-out), obtain [6-(4-chloro-phenyl-)-3-azabicyclo [4.1.0] heptan-1-yl] methyl alcohol and [4-(4-chloro-phenyl-)-1,2,5,6-tetrahydrochysene-3-pyridyl] methanol mixture (190mg), its (188mg) is dissolved in the anhydrous methylene chloride (8mL).In this solution, add two (1, the 1-dimethyl ethyl) esters (181.15mg) of coke acid, and the mixture that generates was stirred 2 hours.Drip triethylamine (0.055mL) then, and mixture was stirred 2 hours.Add methylene dichloride (5mL) and saturated NH ₄Cl (10mL), and with mixture vigorous stirring 10 minutes.Separate organic layer, through Na ₂SO ₄Drying is filtered and reduction vaporization, obtains still impure title compound, and it contains 4-(4-chloro-phenyl-)-5-(hydroxymethyl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid 1,1-dimethyl ethyl ester (270mg).

MS(m/z)：338[MH] ⁺，282[MH-56] ⁺；324[MH] ⁺，270[MH-56] ⁺.

Preparation example 32:(1R, 6S/1S, 6R)-and 6-(4-chloro-phenyl-)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1-dimethyl ethyl ester (P32)

With impure (1R, 6S/1S, 6R)-6-(4-chloro-phenyl-)-1-(hydroxymethyl)-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1-dimethyl ethyl ester (P31,270mg) and NaH (60% in mineral oil, 28.8mg) use the nitrogen gas stream degasification, add N, dinethylformamide (7.5mL) down at 0 ℃ then.Make the mixture of generation reach room temperature, and stirred 30 minutes.Drip methyl iodide (0.099mL), and stirred 2 hours.Under 0 ℃, carry out other three reinforced NaH (60% in mineral oil, difference 9.6mg, 9.6mg and 19.2mg) and methyl iodide (difference 0.049mL, 0.049ml and 0.074mL), and whole mixtures were stirred 18 hours., after the period ethyl acetate, water and ice are poured in this mixture at this section, and separated each phase.Organic layer is washed with salt, through Na ₂SO ₄Dry also reduction vaporization obtains impure title compound, and it contains 4-(4-chloro-phenyl-)-5-[(methoxyl group) methyl]-3,6-dihydro-1 (2H)-pyridine carboxylic acid 1,1-dimethyl ethyl ester (280mg).

MS(m/z)：352[MH] ⁺，296[MH-56] ⁺；338[MH] ⁺.

Preparation example 33:1-(1, the 1-dimethyl ethyl) 3-methyl 4-{4-[(trifluoromethyl) oxygen base] phenyl }-5,6-dihydro-1,3 (2H)-pyridine dicarboxylate (P33)

Under nitrogen atmosphere, to 1-(1, the 1-dimethyl ethyl) 3-methyl 4-{[(trifluoromethyl) alkylsulfonyl] the oxygen base }-5,6-dihydro-1,3 (2H)-pyridine dicarboxylate (2.5g, P2), the 4-[(trifluoromethyl) and the oxygen base] phenyl } boric acid (1.52g) and Pd (PPh ₃) ₄Add toluene (34mL), ethanol (25mL) and Na in the mixture (265mg) successively ₂CO ₃(2M,, 19mL).Mixture was stirred 2 hours down at 80 ℃, make reaction mixture reach room temperature then.With water Et ₂O extracts (2 times), with the organic phase that merges through anhydrous Na ₂SO ₄Drying, and evaporating solvent obtains crude product, and it by flash chromatography (using ethyl acetate/hexanaphthene by 1: 9 to 3: 7 wash-out) purifying, is obtained title compound (2.5g).

NMR( ¹H，CDCl ₃)：δppm?7.10-7.27(m，4H)4.13-4.35(m，2H)3.57-3.68(m，2H)3.53(s，3H)2.30-2.58(m，2H)1.53(s，9H)；MS(m/z)：402[MH] ⁺.

Preparation example 34:5-(hydroxymethyl)-4-{4-[(trifluoromethyl) oxygen base] phenyl }-3,6-dihydro-1 (2H)-pyridine carboxylic acid 1,1-dimethyl ethyl ester (P34)

At N ₂Under the atmosphere, under-20 ℃, 1-(1, the 1-dimethyl ethyl) the 3-methyl 4-{4-[(trifluoromethyl under stirring) the oxygen base] phenyl }-5, (P33 2g) drips LiAlH in the solution in exsiccant ether (40mL) to 6-dihydro-1,3 (2H)-pyridine dicarboxylate ₄(diethyl ether solution of 1M, 3.6mL).Reaction mixture was stirred 20 minutes down at-20 °, then with saturated NH ₄Cl and ether are poured in this solution, and with mixture vigorous stirring 30 minutes at room temperature.Separate two-phase, and with the water layer extracted with diethyl ether.With the organic phase that merges through anhydrous Na ₂SO ₄Drying, and removal of solvent under reduced pressure obtain title compound (1.69g).

NMR( ¹H，CDCl ₃)：δppm?7.12-7.26(m，4H)4.15(s，2H)3.95-4.09(m，2H)3.63(t，2H)2.31-2.52(m，2H)1.53(s，9H)；MS(m/z)：374[MH] ⁺.

Preparation example 35:(1S, 6R/1R, 6S)-and the 6-{4-[(trifluoromethyl) the oxygen base] phenyl }-3-azabicyclo [4.1.0] heptan-1-yl) methyl alcohol (P35)

At N ₂Under the atmosphere, under 0 ℃, the CH under stirring ₂I ₂(36g) with 2, drip ZnEt in the two solution of (1, the 1-dimethyl ethyl)-4-picoline (28g) in exsiccant DCM (150mL) of 6- ₂(hexane solution of 1M, 68mL); Mixture was stirred 30 minutes down at 0 ℃, and be cooled to-20 ℃ then.Dropwise 5-(hydroxymethyl)-4-{4-[(trifluoromethyl) oxygen base] phenyl }-3,6-dihydro-1 (2H)-pyridine carboxylic acid 1,1-dimethyl ethyl ester (P34,1.69g) solution in exsiccant DCM (50mL), and reaction mixture stirred 30 minutes down at-20 ℃, at room temperature stir then and spend the night.1M HCl is joined in the reaction flask, and with mixture vigorous stirring 30 minutes; Separate two-phase, and water layer is alkalized with 3N NaOH.With basic solution extracted with diethyl ether (2 times).With the organic layer vacuum concentration that merges, and with the resistates ether dissolution.With this solution with saturated NH ₄The Cl aqueous solution is washed, and water is alkalized with 3N NaOH.With this basic solution extracted with diethyl ether (2 times).With the organic layer that merges through anhydrous Na ₂SO ₄Drying, and removal of solvent under reduced pressure obtain title compound (170mg).

NMR( ¹H，CDCl ₃)：δppm?7.36(d，2H)7.16(d，2H)3.39(d，1H)3.05-3.29(m，3H)2.64-2.86(m，2H)1.85-2.07(m，2H)1.05-1.13(m，1H)0.96-1.05(m，1H)；MS(m/z)：288[MH] ⁺.

Preparation example 36:(1S, 6R/1R, 6S)-and 1-(hydroxymethyl)-6-{4-[(trifluoromethyl) the oxygen base] phenyl }-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1-dimethyl ethyl ester (P36)

At N ₂Under the atmosphere, under 0 ℃, (1S under stirring, 6R/1R, 6S)-and the 6-{4-[(trifluoromethyl) the oxygen base] phenyl }-3-azabicyclo [4.1.0] heptan-1-yl) methyl alcohol (170mg) (P35) adds Di-tert butyl pyrocarbonate (129mg) in the solution in exsiccant DCM (6mL), and reaction mixture stirred 15 minutes down at 0 ℃.With saturated NH ₄The Cl aqueous solution and DCM join in this solution, and separate organic phase then, dry and removal of solvent under reduced pressure.Crude product by flash chromatography (using cyclohexane/ethyl acetate by 8: 2 to 7: 3 wash-outs) purifying, is obtained title compound (173mg).

NMR( ¹H，CDCl ₃)：δppm?7.35(d，2H)7.17(d，2H)3.73-3.90(m，2H)3.09-3.51(m，4H)2.06-2.20(m，1H)1.89-2.06(m，1H)1.51(s，9H)1.03-1.10(m，1H)0.93-1.02(m，1H)。

Preparation example 37:3-methyl 1-(phenyl methyl) 4-oxo-1,3-piperidines dicarboxylic ester (P37)

At N ₂Under the atmosphere, at room temperature, add TEA (9mL) in the 4-oxo-solution of 3-piperidine carboxylic acid ester (5g) in exsiccant DCM (50ml) under stirring, then under 0 ℃, add chloroformic acid benzyl ester (4.2mL) lentamente, and continue to stir 30 minute down, and at room temperature stirred 1 hour at 0 ℃.Under 0 ℃, mixture is stopped with 2N HCl.Water is extracted (2 times) with DCM, and the organic layer that merges is washed with the saturated NaCl aqueous solution, dry and vacuum concentration obtains title compound (7.5g).

NMR( ¹H，CDCl ₃)：δppm?12.00(s，1H)7.31-7.50(m，5H)5.19(s，2H)4.16(s，2H)3.80(s，3H)3.67(t，2H)2.42(s，2H)

Preparation example 38:3-methyl 1-(phenyl methyl) 4-{[(trifluoromethyl) alkylsulfonyl] the oxygen base }-1,3-piperidines dicarboxylic ester (P38)

At N ₂Under the atmosphere, under 0 ℃, 3-methyl 1-(phenyl methyl) the 4-oxo-1 under stirring, 3-piperidines dicarboxylic ester (7.5g) (P37) is added in 60%NaH (1.13g) in the mineral oil in the solution in exsiccant DMF (80m1).After stirring 10 minutes under 0 ℃, add 1,1,1-three fluoro-N-phenyl-N-[(trifluoromethyls) alkylsulfonyl] Toluidrin (9.64g), and with mixture stirring 1 hour.Then with mixture with saturated NH ₄The Cl aqueous solution stops, and this is used Et mutually ₂O extracts (2 times).The organic layer that merges is washed with the saturated NaCl aqueous solution, and dry and vacuum concentration obtains title compound (10g).

NMR( ¹H，CDCl ₃)：δppm?7.34-7.46(m，5H)5.19(s，2H)4.38(s，2H)3.85(s，3H)3.72(t，J＝5.31Hz，2H)2.55(s，2H)；MS(m/z)：424[MH] ⁺

Preparation example 39:3-methyl 1-(phenyl methyl) 4-[3-chloro-4-(trifluoromethyl) phenyl]-5,6-dihydro-1,3 (2H)-pyridine dicarboxylate (P39)

At N ₂Under the atmosphere; under 0 ℃; 3-methyl 1-(phenyl methyl) 4-{[(trifluoromethyl under stirring) alkylsulfonyl] the oxygen base }-1,3-piperidines dicarboxylic ester (3g) (P38) with in [3-chloro-4-(trifluoromethyl) phenyl] boric acid (1.826g) solution in exsiccant toluene (37mL) adds the Pd (PPh that is dissolved among the anhydrous EtOH (26ml) ₃) ₄(292mg), add 2M Na subsequently ₂CO ₃(21mL).Reaction mixture was heated 2 hours in 80 ℃.Then with Et ₂O joins in this solution, and separates organic phase.With water layer Et ₂O extracts, and the organic phase that merges is washed with the saturated NaCl aqueous solution, dry and vacuum concentration.Crude product by flash chromatography (using cyclohexane/ethyl acetate by 9: 1 to 8: 2 wash-outs) purifying, is obtained title compound (3.03g).

NMR( ¹H，CDCl ₃)：δppm?7.43-7.52(m，2H)7.31-7.43(m，5H)7.24(d，1H)5.21(s，2H)4.21-4.44(m，2H)3.64-3.77(m，2H)3.55(s，3H)2.51(s，2H)；MS(m/z)：454[MH]+

Preparation example 40:4-[3-chloro-4-(trifluoromethyl) phenyl]-5-(hydroxymethyl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid phenyl methyl ester (P40)

At N ₂Under the atmosphere, under-20 ℃, 3-methyl 1-(phenyl methyl) 4-[3-chloro-4-(trifluoromethyl) phenyl under stirring]-5, (P39 3.03g) drips LiAlH in the solution in exsiccant ether (60mL) to 6-dihydro-1,3 (2H)-pyridine dicarboxylate ₄(diethyl ether solution of 1M, 6.25mL).Reaction mixture was stirred 20 minutes down at-20 °, then with saturated NH ₄The Cl aqueous solution and ether join in the reaction mixture.Separate two-phase, and with the water layer extracted with diethyl ether.The organic phase that merges is washed with salt, through anhydrous Na ₂SO ₄Drying, removal of solvent under reduced pressure obtains crude product then, and it by flash chromatography (using cyclohexane/ethyl acetate by 9: 1 to 7: 3 wash-outs) purifying, is obtained title compound (700mg).

NMR( ¹H，CDCl ₃)：δppm?7.30-7.56(m，8H)5.21(s，2H)4.25(s，2H)3.94-4.08(m，2H)3.72(t，2H)2.44(s，2H)；MS(m/z)：426[MH] ⁺

Preparation example 41:(1S, 6R/1R, 6S)-6-[3-chloro-4-(trifluoromethyl) phenyl]-1-(hydroxymethyl)-3-azabicyclo [4.1.0] heptane-3-carboxylic acid phenyl methyl ester (P41)

At N ₂Under the atmosphere, under 0 ℃, the CH under stirring ₂I ₂(13.25g) add 1M ZnEt in the solution in exsiccant DCM ₂Hexane solution (24mL), after 30 minutes, reaction mixture is cooled to-20 ℃.Add 4-[3-chloro-4-(trifluoromethyl) phenyl]-5-(hydroxymethyl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid phenyl methyl ester (700mg) is the solution in exsiccant DCM (total amount of DCM is 60ml) (P40); Under-20 ℃, stir solution and mix 30 minutes, and at room temperature stir and spend the night.Use 0.1M HCl to stop reaction mixture, and stirred 30 minutes.Separate organic layer, wash, dry and vacuum concentration with the saturated NaCl aqueous solution.Crude product is passed through flash chromatography (using cyclohexane/ethyl acetate by 9: 1 to 7: 3 wash-outs) purifying, obtain the impure title compound of 430mg, it is for containing 4-[3-chloro-4-(trifluoromethyl) phenyl]-5-(hydroxymethyl)-3, the mixture of 6-dihydro-1 (2H)-pyridine carboxylic acid phenyl methyl ester (analyzing the ratio that obtains=2: 1) by NMR.

MS(m/z)：440[MH] ⁺，426[MH] ⁺

Preparation example 42:3-methyl 1-(phenyl methyl) 4-(2-naphthyl)-5,6-dihydro-1,3 (2H)-pyridine dicarboxylate (P42)

According to being similar to the method described in the aforesaid preparation example 33, by 3-methyl 1-(phenyl methyl) 4-{[(trifluoromethyl) alkylsulfonyl] the oxygen base }-1, (3g, P38) beginning prepares the title compound that output is 2.28g to 3-piperidines dicarboxylic ester.

NMR( ¹H，CDCl ₃)：δppm?7.08-7.90(m，12H)5.23(s，2H)4.28-4.48(m，2H)3.64-3.84(m，2H)3.49(s，3H)2.53-2.72(bs，2H)

Preparation example 43:5-(hydroxymethyl)-4-(2-naphthyl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid phenyl methyl ester (P43)

According to being similar to the method described in the aforesaid preparation example 34, by 3-methyl 1-(phenyl methyl) 4-(2-naphthyl)-5, (2.28g, P42) beginning prepares the title compound that output is 1.275g to 6-dihydro-1,3 (2H)-pyridine dicarboxylate.

NMR( ¹H，CDCl ₃)：δppm?7.21-7.91(m，12H)5.23(s，2H)4.20-4.37(m，2H)4.00-4.18(m，2H)3.64-3.83(m，2H)2.43-2.63(m，2H)

Preparation example 44:(1S, 6R/1R, 6S)-and the 1-[(methoxyl group) methyl]-6-(2-naphthyl)-3-azabicyclo [4.1.0] heptane-3-carboxylic acid benzyl esters (P44)

Step a)

According to being similar to the method described in the aforesaid preparation example 41, by 5-(hydroxymethyl)-4-(2-naphthyl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid phenyl methyl ester (1.275g) (P43) begins, prepare a collection of impure (1R, 6S)-1-(hydroxymethyl)-6-(2-naphthyl)-3-azabicyclo [4.1.0] heptane-3-carboxylic acid phenyl methyl ester (850mg).

Step b)

According to being similar to E14, the method described in the steps A, by (1R, 6S)-1-(hydroxymethyl)-6-(2-naphthyl)-3-azabicyclo [4.1.0] heptane-3-carboxylic acid phenyl methyl ester (850mg) beginning, prepare the title compound that output is 600mg.

NMR( ¹H，CDCl ₃)：δppm?7.04-7.90(m，12H)5.20(t，2H)4.01(m，1H)3.78-3.92(d，1H)3.44-3.56(m，2H)3.16-3.24(m，1H)3.10(s，3H)2.98-3.03(m，1H)2.16-2.30(m，1H)1.95-2.12(m，1H)1.16-1.25(m，1H)1.01-1.12(m，1H)；MS(m/z)：402[MH] ⁺

Preparation example 45:{[3-(3-chloro-4-fluorophenyl)-3-butene-1-yl] the oxygen base } (1, the 1-dimethyl ethyl) diphenylmethyl silane (P45)

According to being similar to the method described in the aforesaid preparation example 13, (3.890g, P12) beginning prepares the title compound that output is 3.624g to (1, the 1-dimethyl ethyl) diphenylmethyl silane by [(3-bromo-3-butene-1-yl) oxygen base].

NMR( ¹H，CDCl ₃)：δppm?7.00-7.65(m，13H)5.29(m，1H)5.11(m，1H)3.74(t，2H)2.70(t，2H)1.02(s，9H)

Preparation example 46:2-(3-chloro-4-fluorophenyl)-2-(2-{[(1,1-dimethyl ethyl) (phenylbenzene) silylation] the oxygen base } ethyl)-1,1-cyclopropane dicarboxylic acid dimethyl esters (P46)

According to being similar to the method described in the preparation example 14, by { [3-(3-chloro-4-fluorophenyl)-3-butene-1-yl] oxygen base } (1, the 1-dimethyl ethyl) diphenylmethyl silane (P45,3.624g) and by diazenyl dimethyl malonate (1.98g) beginning, prepare the title compound that output is 2.61g.

NMR( ¹H，CDCl ₃)：δppm?7.25-7.62(m，11H)7.04-7.11(m，1H)6.99(t，1H)3.82(s，3H)3.49-3.59(m，1H)3.33-3.46(m，4H)2.10-2.26(m，2H)1.76-1.87(m，1H)1.59-1.66(m，1H)0.99-1.10(m，9H)；MS(m/z)：569[MH] ⁺

Preparation example 47:1-(aminocarboxyl)-2-(3-chloro-4-fluorophenyl)-2-(2-hydroxyethyl) methyl cyclopropanecarboxylate (P47)

According to being similar to the method described in the aforesaid preparation example 15, by 2-(3-chloro-4-fluorophenyl)-2-(2-{[(1, the 1-dimethyl ethyl) (phenylbenzene) silylation] the oxygen base } ethyl)-1,1-cyclopropane dicarboxylic acid dimethyl ester (2.61g, P46) beginning prepares the title compound that output is 1.05g.

NMR( ¹H，CDCl ₃)：δppm?8.19(s，1H)7.34(d，1H)7.14-7.22(m，1H)7.10(t，1H)5.76(s，1H)3.42-3.66(m，2H)3.06-3.26(m，3H)1.89-2.35(m，4H)；MS(m/z)：316[MH] ⁺

Preparation example 48:(1S, 6R/1R, 6S)-6-(3-chloro-4-fluorophenyl)-2-oxo-3-azabicyclo [4.1.0] heptane-1-carboxylate methyl ester (48)

According to being similar to the method described in the preparation example 16, (1.05g, P47) beginning prepares the title compound that output is 360mg by 1-(aminocarboxyl)-2-(3-chloro-4-fluorophenyl)-2-(2-hydroxyethyl) methyl cyclopropanecarboxylate.

NMR( ¹H，CDCl ₃)：δppm?7.42(dd，1H)7.21-7.27(m，1H)7.10(t，1H)5.83(s，1H)3.53(s，3H)2.85-3.42(m，2H)2.33-2.48(m，1H)2.24-2.32(m，1H)2.09-2.22(m，1H)1.99(d，1H)；MS(m/z)：298[MH] ⁺

Preparation example 49:(1S, 6R/1R, 6S)-and 6-(3-chloro-4-fluorophenyl)-1-(hydroxymethyl)-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1-dimethyl ethyl ester (P49)

According to being similar to the method described in the preparation example 5 (method C), by (1S, 6R/1R, 6S)-6-(3-chloro-4-fluorophenyl)-2-oxo-3-azabicyclo [4.1.0] heptane-1-carboxylate methyl ester (360mg, P48) beginning prepares the title compound that output is 184mg.

NMR( ¹H，CDCl ₃)：δppm?7.37(dd，1H)7.16-7.24(m，1H)7.09(t，1H)3.72-3.89(m，2H)3.26-3.46(m，3H)3.11-3.26(m，1H)1.90-2.16(m，2H)1.51(s，9H)1.01(dd，2H)

Preparation example 50:(1S, 6R/1R, 6S)-and 6-(3-chloro-4-fluorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1-dimethyl ethyl ester (P50)

According to being similar to embodiment 14, method described in the steps A, by (1S, 6R/1R, 6S)-6-(3-chloro-4-fluorophenyl)-1-(hydroxymethyl)-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1, (184mg, P49) beginning prepares the title compound that output is 164mg to 1-dimethyl ethyl ester.

NMR( ¹H，CDCl ₃)：δppm?7.38(d，1H)7.14-7.23(m，1H)7.07(t，1H)3.86(s，1H)3.70(d，1H)3.27-3.42(m，2H)3.15(s，3H)3.00-3.11(m，1H)2.86(d，1H)1.92-2.13(m，2H)1.44-1.54(m，9H)0.90-1.03(m，2H)

Preparation example 51:(1R, 6S/1S, 6R)-and 6-(3, the 4-dichlorophenyl)-1-[(oxyethyl group) methyl]-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1-dimethyl ethyl ester (P51)

Under nitrogen atmosphere, (1S under stirring, 6R/1R, 6S)-6-(3, the 4-dichlorophenyl)-1-(hydroxymethyl)-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1-dimethyl ethyl ester (P5, (60% in mineral oil 0.1g) to add sodium hydride in the solution in exsiccant DMF (2mL), 13mg), and continue to stir 5 minutes.At this section after the period, add iodoethane (28 μ L), and reaction mixture at room temperature stirred spend the night.Add the sodium hydride (3mg) and the iodoethane (28 μ L) of amount in addition, and with mixture restir 4 hours.Add saturated NaHCO ₃The aqueous solution, and mixture extracted with DCM.With the organic phase vacuum concentration, and with crude product by flash chromatography (use cy/EA by 1/0 to 8/2 wash-out) purifying, obtain title compound (79mg).

NMR( ¹H，MeOH-d ₄)：δ7.48(s，1H)7.35(d，1H)7.15(d，1H)3.7-3.4(m，2H)3.3(m，3H)3.15(m，2H)2.85(d，1H)2.0(m，2H)1.5(s，9H)1.1(t，3H)0.95(m，2H)；

MS(m/z)：422[M+Na] ⁺

Preparation example 52:4-{[(trifluoromethyl) alkylsulfonyl] the oxygen base }-3,6-dihydro-1 (2H)-pyridine carboxylic acid 1,1-dimethyl ethyl ester (P52)

-78 ℃ down and under nitrogen atmosphere, in stirring the solution of diisopropylamine (0.77ml) in exsiccant THF (12mL) down, add butyllithium (hexane solution of 2.5M, 2.2ml), and with reaction mixture-78 ℃ of stirrings 15 minutes down.Add DMPU (1.8ml) and 4-oxo-1-piperidine carboxylic acid 1, THF (5ml) solution of 1-dimethyl ethyl ester (1g), and with reaction mixture-78 ℃ of stirrings 2 hours down.Add N-phenyl-two (fluoroform sulphonamide) THF (6ml) solution (1.97g) then, and continue down to stir 9 hours, and at room temperature stirred 16 hours at 0 ℃.Removal of solvent under reduced pressure, and with crude product by flash chromatography (use ethyl acetate/hexanaphthene 2: 8 wash-outs) purifying, obtain the title compound of 1.375g.

NMR( ¹H，CDCl ₃)：δ5.79(br.s.，2H)4.07(m，2H)3.65(m，，2H)2.47(m，2H)1.50(s，9H)。

Preparation example 53:4-(3, the 4-dichlorophenyl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid 1,1-dimethyl ethyl ester (P53)

Under nitrogen atmosphere, to the 4-{[(trifluoromethyl) alkylsulfonyl] the oxygen base }-3,6-dihydro-1 (2H)-pyridine carboxylic acid 1,1-dimethyl ethyl ester (P52,500mg), 3,4-dichlorophenyl boric acid (330mg) and Pd (PPh ₃) ₄Add toluene (6.5mL), ethanol (5mL) and Na in the mixture (50mg) successively ₂CO ₃(2M,, 5mL).Mixture was stirred 2 hours down at 80 ℃, make reaction mixture reach room temperature then.With saturated NH ₄Cl (30mL) is poured in this solution, and mixture is transferred in the separating funnel.With mixture with ethyl acetate (3x40mL) extraction, with the organic phase that merges through anhydrous Na ₂SO ₄Drying, and evaporating solvent obtains crude product, and it by flash chromatography (using 1: 9 wash-out of ethyl acetate/hexanaphthene) purifying, is obtained title compound (400mg).

MS(m/z)：328[MH] ⁺

Preparation example 54:3-(1, the 1-dimethyl ethyl) 7-ethyl (1S, 6R/1R, 6S)-6-(3, the 4-dichlorophenyl)-and 3-azabicyclo [4.1.0] heptane-3,7-dicarboxylic ester and 4-(3, the 4-dichlorophenyl)-6-[2-(oxyethyl group)-2-oxoethyl]-3,6-dihydro-1 (2H)-pyridine carboxylic acid 1,1-dimethyl ethyl ester (P54)

To 4-(3, the 4-dichlorophenyl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid 1, (P53 adds acetic acid rhodium dimer (110mg) to 1-dimethyl ethyl ester in DCE 825mg) (10ml) solution.Mixture is heated down at 40 ℃, and the maintenance internal temperature is under 50 ℃ in adition process, adds DCE (2.5ml) solution of ethyl diazoacetate (0.31ml) in 4 hours with syringe pump.Removal of solvent under reduced pressure, and with crude product by flash chromatography (use ethyl acetate/hexanaphthene 2: 8 wash-outs) purifying, obtain the mixture of the title compound of 170mg.

MS(m/z)：414[MH] ⁺

Preparation example 55:(1S, 6R/1R, 6S)-6-(3, the 4-dichlorophenyl)-7-(hydroxymethyl)-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1-dimethyl ethyl ester and 4-(3, the 4-dichlorophenyl)-and 6-(2-hydroxyethyl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid 1,1-dimethyl ethyl ester (P55)

At N ₂Under the atmosphere, under-20 ℃, under stirring (1, the 1-dimethyl ethyl) 7-ethyl (1S, 6R/1R, 6S)-6-(3, the 4-dichlorophenyl)-3-azabicyclo [4.1.0] heptane-3,7-dicarboxylic ester and 4-(3, the 4-dichlorophenyl)-and 6-[2-(oxyethyl group)-2-oxoethyl]-3,6-dihydro-1 (2H)-pyridine carboxylic acid 1,1-dimethyl ethyl ester (P54, obtain according to the method that is similar to aforesaid P54, drip LiAlH in the solution in dry toluene 38mg) (1mL) ₄(diethyl ether solution of 1M, 0.37mL).Reaction mixture was stirred 1 hour down at-20 ℃, add saturated NH then ₄Cl, and with the product ethyl acetate extraction.Separate each phase, with organic phase through Na ₂SO ₄Drying, and removal of solvent under reduced pressure obtain the mixture (30mg) into the title compound of crude product.

MS(m/z)：372[MH] ⁺

Preparation example 56:(1S, 6R/1R, 6S)-6-(3, the 4-dichlorophenyl)-and the 7-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1-dimethyl ethyl ester and 4-(3, the 4-dichlorophenyl)-and 6-[2-(methoxyl group) ethyl]-3,6-dihydro-1 (2H)-pyridine carboxylic acid 1,1-dimethyl ethyl ester (P56)

Under nitrogen atmosphere, under 0 ℃, (the 1S under stirring, 6R/1R, 6S)-and 6-(3, the 4-dichlorophenyl)-7-(hydroxymethyl)-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1-dimethyl ethyl ester and 4-(3, the 4-dichlorophenyl)-6-(2-hydroxyethyl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid 1, and 1-dimethyl ethyl ester (P55, (60% in mineral oil 30mg) to add NaH in the solution in exsiccant DMF (1mL), 5mg), and with mixture stirred 30 minutes down at 0 ℃.Add methyl iodide (10 μ L), and make this reaction mixture reach room temperature, and stirred 2 hours.Add cold water, and with the product ethyl acetate extraction.Organic phase is washed with salt, through Na ₂SO ₄Drying, and solvent evaporated under reduced pressure obtain the mixture (35mg) into the title compound of crude product.

MS(m/z)：386[MH] ⁺

Preparation example 57:3-(1, the 1-dimethyl ethyl) 1-ethyl (1S, 6R/1R, 6S)-6-(3, the 4-dichlorophenyl)-and 3-azabicyclo [4.1.0] heptan-4-alkene-1,3-dicarboxylic ester (P57)

Step a)

In 50-L chuck laboratory reaction device, pack into trimethyl carbinol lithium (1.85Kg, 23.1mol, 3eq) and 1-Methyl-2-Pyrrolidone (19.1Kg).Mixture was stirred～30 minutes, and the solution that generates is loaded in the pressurized vessel to using later on.

By 0.45 μ m Meissner ^TMPipeline internal filter (in-line filter) 1-(1 that in clean, 50-L chuck laboratory reaction device, packs into, the 1-dimethyl ethyl) 3-ethyl 4-(3, the 4-dichlorophenyl)-5,6-dihydro-1, the toluene solution of 3 (2H)-pyridine dicarboxylates (, containing the P72 that theoretical amount is 3.09Kg) according to being similar to the method preparation described in the P72.Pipeline and filter are washed with a spot of toluene.By underpressure distillation with toluene by removing fully in the reaction mixture.Add 1-Methyl-2-Pyrrolidone (16.0Kg), and the solution that generates is cooled to 20 ℃, because time limitation keeps spending the night.(4.15Kg 3.05eq) is loaded in the reactor, and the slurry that generates is cooled to-4 ℃ with the chloro methyl iodide.With 28 minutes time, add the 1-Methyl-2-Pyrrolidone solution (16.9Kg, the alkali of～2.4eq) of the trimethyl carbinol lithium of a previous preparation, and the solution that generates is warmed to 19 ℃, and stirred 80 minutes.(0.69Kg 1.5eq), uses～10 minutes time slowly to add entry (8.5Kg) subsequently to add acetate simultaneously.Mixture was stirred～5 minutes, and add entry (13.1Kg) with 18 minutes time.The slurry that generates is cooled to 11 ℃ and kept 100 minutes.Pass through solid collected by filtration.Water (3.9Kg) and methyl alcohol (9.21Kg) are encased in the reactor cleaning this solid, and the methanol aqueous solution that obtains is used to wash this product piece.The yellow solid that generates is dried to constant weight in 55 ℃ of vacuum drying ovens, obtains the 2.57Kg productive rate and be 81% title compound.

NMR( ¹H，CDCl ₃)：δ7.32(2H，m)，7.08(1H，m)，6.62(1H，br?m)，5.13(1H，br?m)，4.24(1H，br?m)，3.76(3H，br?m)，2.29(1H，m)，1.56(1H，m)，1.49(9H，s)，0.91(3H，br?m)

Step B) (recrystallization)

In 50-L chuck laboratory reaction device, pack into (±)-3-(1, the 1-dimethyl ethyl) 1-ethyl (1S, 6R)-6-(3, the 4-dichlorophenyl)-3-azabicyclo [4.1.0] heptan-4-alkene-1,3-dicarboxylic ester (P57,4.40Kg, 11.0moles, 1eq) and heptane (15.1Kg, 22.1L, 5vol).The slurry that generates is heated to about 80 ℃, and is filtered in the clean 50-L chuck laboratory reaction device.With filter and pipeline with heptane (3.0Kg, 4.4L, 1vol) washing, and washings and filtrate combined.Solution is heated to 80 ℃, and is cooled to 22 ℃ with time of 107 minutes then.Do not form crystallization, so take out sub-fraction.In this part, spontaneously form crystal, and it has been back in the reactor, caused rapid crystallization.Slurry is heated back 80 ℃, and be cooled to 22 ℃ with 105 minutes.In process of cooling, at 52 ℃ with the small portion sucking-off.Scraping is equipped with the bottle wall of this part with the beginning crystallization, when its temperature reaches 47 ℃, slurry and the bulk solution (bulk solution) that generates is merged.By solid collected by filtration, (3.0Kg, 4.4L 1vol) wash, and this washings is used to wash this filter cake with heptane with this reactor.In 50-60 ℃ vacuum drying oven with solid drying to constant weight, obtain 2.954Kg, productive rate is 67% title compound, it is a pale solid.

NMR( ¹H，CDCl ₃)：δ7.35(2H，m)，7.27(CDCl ₃)，7.11(1H，m)，6.65(1H，br?m)，5.16(1H，br?m)，4.27(1H，br?m)，3.79(3H，br?m)，2.32(1H，m)，1.59(1H，m)，1.52(9H，s)，0.94(3H，br?m)

Preparation example 58:(1S, 6R/1R, 6S)-6-(3, the 4-dichlorophenyl)-1-(hydroxymethyl)-and 3-azabicyclo [4.1.0] heptan-4-alkene-3-carboxylic acid 1,1-dimethyl ethyl ester (P58)

With 3-(1, the 1-dimethyl ethyl) 1-ethyl (1S, 6R/1R, 6S)-6-(3, the 4-dichlorophenyl)-3-azabicyclo [4.1.0] heptan-4-alkene-1, the 3-dicarboxylic ester (P57,39.97g, 0.9694mol, 1eq) be dissolved in THF (80mL, 2vol) in.Add 2M LiBH ₄THF solution (120mL, 0.242mol 2.5eq), and cool off the solution that generates with room-temperature water bath.With times of 65 minutes add ethanol (28.5mL, 0.485mol, 5eq).This reaction mixture was stirred 40 minutes, and the adding heptane (200mL, 5vol).With～10 minutes time, (10mL, 550mole 5.7eq), and stirred the slurry that generates 15-20 minute to add entry.(200mL 5vol), stirs mixture 15 minutes, and sedimentation is two-layer, and separates to add more water.(200mL 5vol) washes, and passes through Whatman trade mark #2 filter paper filtering then, and vacuum concentration with the organic layer water.With the oily matter that generates dry in 60 ℃ of vacuum drying ovens～72 hours, obtain 29.48g, productive rate is 82% title compound, it is a vitreous solid.

NMR( ¹H，CDCl ₃)： 7.38(2H，br?m)，7.15(1H，br?m)，6.60(1H，br?m)，5.12(1H，br?m)，4.24(1H，br?m)，3.38(2H，br?m)，3.29(1H，br?m)，1.51(10H，brm)，1.30(1H?br?m)。

Preparation example 59:(1S, 6R/1R, 6S)-and 6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptan-4-alkene-3-carboxylic acid 1,1-dimethyl ethyl ester (P59)

Will (1S, 6R/1R, 6S)-6-(3, the 4-dichlorophenyl)-1-(hydroxymethyl)-and 3-azabicyclo [4.1.0] heptan-4-alkene-3-carboxylic acid 1, (P58,28.4g 76.7mmol) are dissolved among the DMSO (225mL) 1-dimethyl ethyl ester.(powder, 17.2g 0.3mol) handle, and stirred 15 minutes with potassium hydroxide with solution then.(9.5ml 0.15mol), and at room temperature stirred this reaction mixture 90 minutes to drip methyl iodide with times of 15 minutes.Then its water (115ml) and MTBE (250ml) are stopped, and stirred 1 hour.Separate each phase then, and upper strata (organic) phase water (115ml) is washed, and vacuum concentration, buttery title compound (32g weight of crude product) obtained.

NMR( ¹H，CDCl ₃)：δ7.40(1H，d，J＝4Hz)，7.37(1H，d，J＝8Hz)，7.15(1H，dd，J＝8，4Hz)，6.55(1H，br?m)，5.08(1H，br?m)，4.19(1H，br?m)，3.27(1H，br?m)，3.10(3H，br?s)，3.04(1H，br?m)，2.96(1H，br?m)，1.49(9H，br?s)，1.42(1H，d，J＝4Hz)，1.28(1H，br?m)。

MS(m/z)：328[M-t-Bu+2H]+

Preparation example 60:(1S, 6R)-6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptan-4-alkene-3-carboxylic acid 1,1-dimethyl ethyl ester (P60)

With (1S, 6R/1R, 6S)-6-(3, the 4-dichlorophenyl)-and the 1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptan-4-alkene-3-carboxylic acid 1,1-dimethyl ethyl ester (P59,36 grams 9.4mmol) are dissolved among the 370mL (n-heptane solution of 5%IPA), and two enantiomers are separated by chirality HPLC.

Rt=5.7 minute [used post: ChiralpakAD in this processing, 20um, 20x250mm, (envrionment temperature) processing parameter: flow velocity: 15mL/min; Detect: 225﹠amp; 280nm; Charging: 100mg/mL]

Behind the evaporating solvent, separate obtaining buttery product (16.2g, optical purity, 99.2%).

Preparation example 61:3-(3, the 4-dichlorophenyl)-3-butene-1-alcohol (P61)

Under argon atmospher, in the round-bottomed flask of mechanical stirrer was housed, with 3, (128g, 672mmol) (78g 517mmol) was dissolved in toluene (1230ml) and the ethanol (492mL) 4-dichlorophenyl boric acid with 3-bromo-3-butene-1-alcohol.In this solution, add four (triphenylphosphines) close palladium (0) (29.8g, 25.8mmol), add subsequently the 2M aqueous sodium carbonate (517ml, 1033mmol).The mixture that generates is heated under 75 ℃ internal temperature.After 30 minutes, form dense thick precipitation.After 1 hour, add entry (50ml) solid is dissolved once more, reaction mixture becomes little yellow oyster white.After 3 hours, this reaction mixture is carried out aftertreatment.

Flask is cooled to room temperature (form precipitation), and with mixture with saturated NaHCO ₃The aqueous solution (468mL), water (468mL) and AcOEt (468mL) handle.Solid dissolving when adding entry; Separating each strips with AcOEt (2x936mL) mutually and with water.Dry organic phase (the Na that merges ₂SO ₄), vacuum concentration obtains crude product (200g), is the dense thick oily matter of black.By flash chromatography on silica gel method purifying, use hexanaphthene/AcOEt this oily matter by 8/2 to 7/3 wash-out.Evaporating solvent obtains dark dense thick buttery title compound (73g).

NMR( ¹H，CDCl ₃)：δppm?7.51(d，1H)，7.41(d，1H)，7.26(dd，1H)，5.34-5.53(m，1H)，5.02-5.29(m，1H)，3.60-3.95(m，2H)，2.57-2.94(m，2H)，1.50(t，1H)

Preparation example 62: methylsulfonic acid 3-(3, the 4-dichlorophenyl)-3-butene-1-Ji ester (P62)

In round-bottomed flask, (P61,73g 336mmol) are dissolved among the DCM (900ml), obtain xanchromatic solution with 3-(3, the 4-dichlorophenyl)-3-butene-1-alcohol.Then use ice bath keep internal temperature be lower than+5 ℃ under, add triethylamine (69.9ml, 504mmol).

Then use ice bath keep internal temperature be lower than+5 ℃ under, in 30 minutes, drip methylsulfonyl chloride (36.7ml, 471mmol).Under agitation make mixture reach room temperature.After 3 hours, use ice bath keep internal temperature be lower than+10 ℃ under, come termination reaction mixture (suspension) by the saturated aqueous ammonium chloride solution of careful adding (400ml).When adding end, the pH of water is near 1.Separates two.Water layer is stripped with DCM (3x300mL).The organic layer water (2x200mL) that merges is washed dry (Na ₂SO ₄), and evaporation, obtain crude product (101g), it is passed through (1000g) purifying of silica filler (pad), use hexanaphthene/EtOAc by 9/1 to 1/1 wash-out, obtain the title compound (90.8g) of deep yellow oily.

NMR( ¹H，CDCl ₃)：δppm?7.49(d，1H)，7.44(d，1H)，7.24(dd，1H)，5.46(d，1H)，5.25(d，1H)，4.32(t，2H)，2.98(s，3H)，2.93(t，2H)

HPLC (walk-up): Rt=5.37 minute

Preparation example 63:2-(3, the 4-dichlorophenyl)-2-{2-[(methylsulfonyl) oxygen base] ethyl }-1,1-cyclopropane dicarboxylic acid dimethyl esters (P63)

In round-bottomed flask, (P62,90.8g 308mmol) are dissolved in the chlorinated benzene (200ml), obtain green solution with methylsulfonic acid 3-(3, the 4-dichlorophenyl)-3-butene-1-Ji ester.

Adding acetic acid rhodium dimer (6.80g, 15.38mmol).This suspension is warmed to+65 ℃ internal temperature, and dropping is dissolved in the diazomalonic acid dimethyl ester (78g in the chlorinated benzene (150ml), 492mmol, for preparation method's document referring to Synthetic Communication 1987,17 (14), 1709-1713) (during 2.5 hours) keep internal temperature to be lower than 65-67 ℃ simultaneously.When adding end, mixture is cooled to room temperature.It is diluted with DCM (300ml), and filter with separating catalyst through the Celite filler.

Solution for vacuum is evaporated to 1/3 volume, by silica filler (silica gel 1.3Kg) purifying, uses cyclohexane/ethyl acetate crude product (277g), obtain title compound (128.25g) by 7/3 to 1/1 wash-out.

NMR( ¹H，CDCl ₃)：δppm?7.41(d，1H)，7.39(d，1H)，7.15(dd，1H)，4.08-4.22(m，1H)，3.94-4.06(m，1H)，3.85(s，3H)，3.48(s，3H)，2.95(s，3H)，2.42(dt，1H)，2.21(d，1H)，1.89-2.03(m，1H)，1.82(d，1H)

HPLC (walk-up): Rt=5.15 minute

Preparation example 64:(1S, 6R/1R, 6S)-6-(3, the 4-dichlorophenyl)-2-oxo-3-azabicyclo [4.1.0] heptane-1-carboxylate methyl ester (P64)

In 5L Parr reactor, with 2-(3, the 4-dichlorophenyl)-2-{2-[(methylsulfonyl) the oxygen base] ethyl }-1, (P63,158g 372mmol) are dissolved in the methanol solution (3000ml) of 2M ammonia 1-cyclopropane dicarboxylic acid dimethyl ester, obtain xanchromatic solution.

Solution is warmed to+75 ℃, and under this temperature, the mixture stirring that generates is spent the night (internal pressure=2atm).After 24 hours, this reaction is finished.

With solution concentration, obtain resistates, with its with another batch 2-(3, the 4-dichlorophenyl)-2-{2-[(methylsulfonyl) the oxygen base] ethyl-1, the similar resistates for preparing (89.3g) that 1-cyclopropane dicarboxylic acid ester carries out mixes.Evaporating solvent obtains thick oily matter (280g).In this oily matter, add the AcOEt (5L) and the 1M HCl aqueous solution (2.5L), and in the 10L reactor with mixture vigorous stirring 30 minutes.

The suspension that obtains diluting (organic phase, water and solid mixture).

Filter this solid, wash with ethyl acetate, and dry, obtain first title compound (54.9g).

Separate organic layer and water layer.Then organic phase is washed dry (Na with the 1M HCl aqueous solution (2L) ₂SO ₄) and be concentrated into 1/10 volume.Be settled out solid.With its filtration, (150ml) washes with ether, and vacuum-drying, obtains second batch title compound (34.4g).

With filtering mother liquor vacuum concentration, obtain brown oil.This resistates is ground with ether (1x50mL).Filter the solid that generates, wash and drying, obtain the 3rd batch title compound (7.27g), be linen solid with cold ether.

The concentrated mother liquor part, and, use the AcOEt wash-out at the enterprising circumstances in which people get things ready for a trip spectrometry of Biotage 75M (silica gel) purifying, obtain solid, it is ground with ether (35ml), obtain the 4th batch title compound (6.2g).

Obtain the product that total amount is 102.7g thus.

NMR( ¹H，CDCl ₃)：δppm?7.47(d，1H)，7.41(d，1H)，7.20(dd，1H)，5.73(br.s.，1H)，3.54(s，3H)，3.07-3.41(m，2H)，2.32-2.45(m，1H)，2.28(d，1H)，2.17(d，1H)，1.93(d，1H)

Preparation example 65:(1S, 6R/1R, 6S)-and 6-(3, the 4-dichlorophenyl)-1-(hydroxymethyl)-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1-dimethyl ethyl ester (P65)

Step a)

In round-bottomed flask, will (1S, 6R/1R, 6S)-(P64,90g 286mmol) are dissolved among the THF (1450ml) 6-(3, the 4-dichlorophenyl)-2-oxo-3-azabicyclo [4.1.0] heptane-1-carboxylate methyl ester, obtain grey suspension.Keep internal temperature be lower than+5 ℃ under, drip 1M borine tetrahydrofuran complex (1633ml, 1633mmol).The mixture that generates was refluxed 7 hours at leisure.Mixture is cooled to+3 ℃, and stops by the careful methyl alcohol (200ml) that adds; Then keep internal temperature be lower than+6 ℃ under, add the 6M HCl aqueous solution (450ml).Mixture was at room temperature stirred 5 hours.The acidic solution vacuum concentration to remove THF, is added entry (900ml) then.The pH of final solution is near 1.This solution is washed with ether (2x200mL).The aqueous solution is alkalized up to pH 8-9 by add salt of wormwood in batches, add THF (1200ml) then, and in next step, directly use the mixture that generates.

Step b)

In round-bottomed flask filling derive from step a) mixture (about 2700ml, pH=8-9).At room temperature add Di-tert butyl pyrocarbonate (80ml 343mmol), and stirs mixture and spends the night in batches.Separate organic layer and water layer.With water layer with ethyl acetate strip (3x600mL).Dry organic layer (the Na that merges ₂SO ₄) and concentrate, obtain thick oily matter (165g), it through silica filler (silica gel 1500g) purifying, is used cyclohexane/ethyl acetate 8/2 wash-out, obtain title compound (110g), be the spumescence colorless oil.

NMR( ¹H，CDCl ₃)：δppm?7.39-7.42(m，1H)，7.37(d，1H)，7.17(d，1H)，3.73-3.90(m，2H)，2.99-3.49(m，4H)，1.91-2.13(m，2H)，1.48(s，9H)，0.92-1.07(m，2H)。

HPLC (walk-up): Rt=6.12 minute

Preparation example 66:(1S, 6R/1R, 6S)-and 6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1-dimethyl ethyl ester (P66)

In the 1L round-bottomed flask, with (1S, 6R/1R, 6S)-and 6-(3, the 4-dichlorophenyl)-1-(hydroxymethyl)-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1-dimethyl ethyl ester (P65,47.56g, 128mmol) be dissolved among the THF (800ml), obtain colourless solution.Keeping internal temperature under 0 ℃, and the adding sodium hydride (10.22g, 256mmol).After 30 minutes, under identical temperature, drip MeI (15.98ml, 256mmol).The mixture that generates at room temperature stirred spend the night.

Keep internal temperature be lower than+15 ℃ under, with mixture by dripping saturated NaHCO ₃The aqueous solution (500ml) stops.Filter the suspension that generates, in solid water-soluble (200ml).Separate two-phase, and water is extracted with ethyl acetate (3x200ml).Merge organic layer, dry (Na ₂SO ₄), evaporation obtains thick material (54g), by the silica gel chromatography purifying, uses cyclohexane/ethyl acetate by 95/5 to 75/25 wash-out it, obtains the title compound (42.33g) of colorless oil.

NMR( ¹H，CDCl ₃)：δppm?7.40-7.43(m，1H)，7.36(d，1H)，7.16(d，1H)，3.85(d，1H)，3.67(d，1H)，3.26-3.40(m，2H)，3.14(s，3H)，2.97-3.10(m，1H)，2.81-2.91(m，1H)，1.90-2.07(m，2H)，1.49(s，9H)，0.91-1.02(m，2H)

HPLC (walk-up): Rt=7.15 minute

Preparation example 67:(2S)-2-(3; the 4-dichlorophenyl)-and the 2-{2-[(methylsulfonyl) the oxygen base] ethyl }-1; 1-cyclopropane dicarboxylic acid dimethyl esters and (2R)-2-(3, the 4-dichlorophenyl)-2-{2-[(methylsulfonyl) oxygen base] ethyl }-1,1-cyclopropane dicarboxylic acid dimethyl esters (P67)

Under 25 ℃, with methylsulfonic acid 3-(3, the 4-dichlorophenyl)-3-butene-1-Ji ester (2.0g, 6.78mmol) and Rh ₂[(S)-4-Cl-nttl] ₄(0.105g 0.066mmol) is dissolved in the chlorinated benzene (10ml) (according to Helv.Chem.Act., vol.88 (2005), the p.216 Preparation of catalysts described in the and ss.).In 2 hours, drip diazomalonic acid dimethyl ester (1.7g, chlorinated benzene 10.75mmol) (10ml) solution.

The evaporation chlorinated benzene, and with resistates through silicon-dioxide (230-400 sieve mesh) chromatography purification, use hexanaphthene/AcOEt 8/2,7/3 wash-out, obtain title compound (2.65g).

Chirality HPLC (post: Chiralpak AD-H (25x0.46cm); Moving phase: normal hexane/ethanol 70/30%v/v; Flow velocity: 1.0ml/min; DAD:210-340: enantiomer 1 (Rt=9.6 minute)/enantiomer 2 (Rt=11.7 minute)=60/40 area %

Preparation example 68:(1S, 6R/1R, 6S)-and 6-(3, the 4-dichlorophenyl)-1-(hydroxymethyl)-4-methyl-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1-dimethyl ethyl ester (P68)

With 4-(3, the 4-dichlorophenyl)-5-(hydroxymethyl)-2-methyl-3,6-dihydro-1 (2H)-pyridine carboxylic acid 1, (P22, two batches of preparing according to the method described in the aforementioned P22 that is similar to 260mg) are dissolved among the DCM (5mL) 1-dimethyl ethyl ester.Under-20 ℃, it is joined by the hexane solution (4.19mL) with the 1.0M zinc ethyl join in the suspension that obtains in DCM (10mL) solution of methylene iodide (0.676mL).Suspension at room temperature stirred spend the night.Then with the reaction mixture saturated NH of 20mL ₄Cl solution stops, and two-phase was stirred 30 minutes.Organic layer is washed with salt solution (20mL), dry and concentrated.By the chromatography purification on the silica gel, use 5-40% ethyl acetate/hexanaphthene gradient elution, obtain the colorless oil of 75mg.

NMR( ¹H，CDCl ₃)：δ7.40-7.42(m，1H)，7.38(d，1H)，7.17(dd，1H)，3.39-3.48(m，2H)，3.20-3.27(m，1H)，2.44(m，1H)，2.06-2.16(m，1H)，1.81-1.91(m，1H)，1.61-1.69(m，1H)，1.47-1.50(s，9H)，1.24-1.28(d，3H)，0.84-0.94(m，2H)。

Preparation example 69:(1R, 6S/1S, 6R)-and 6-(3, the 4-dichlorophenyl)-1-{[(methylsulfonyl) the oxygen base] methyl }-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1-dimethyl ethyl ester (P69)

Will (1R, 6S/1S, 6R)-6-(3, the 4-dichlorophenyl)-1-(hydroxymethyl)-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1-dimethyl ethyl ester (P5,132mg) and triethylamine (74 μ L) be dissolved among the DCM (5mL).At room temperature add methylsulfonyl chloride (38 μ L).After stirring is spent the night, add DCM and saturated NH ₄The Cl aqueous solution.The evaporation organic solvent obtains title compound (140mg).

NMR( ¹H，CDCl ₃)：δ7.4(m，2H)7.1(d，1H)3.9(d，2H)3.75(m，1H)3.7(s，2H)3.4(m，2H)2.9(m，3H)1.7(m，1H)1.5(s，9H)1.1-1.2(dd，2H)；MS(m/z)：450[MH]+

Preparation example 70:1-(1, the 1-dimethyl ethyl) 3-ethyl 4-oxo-1,3-piperidines dicarboxylic ester (P70)

At room temperature, (AlfaAesar) (12.7, (7.25kg AlfaAesar), and stirs suspension 15 minutes then kg) to add triethylamine in the suspension at heptane for 5kg, 24.08moles to 3-Eufin-4-piperidone hydrochloride.Then at room temperature, (1.2eq. AlfaAesar) joined in the n-heptane solution of reactant (4.1Kg) for 6.3kg, 28.89moles with Di-tert butyl pyrocarbonate with 20 minutes times.This reaction mixture was at room temperature stirred about 40 minutes.At room temperature join water (25L) in this reaction mixture then and stirred 15 minutes.Separate each layer then, and remove water layer.Then organic layer is washed with 1N HCl (25L) and water (22L).Then the organic layer that generates being 20 ℃ at jacket temperature descends by vacuum distilling simmer down to oily matter.In case simmer down to oily matter joins ethanol (13.7kg)/water (17.5kg) in this reaction mixture then, and is warmed to 50 ℃.In case temperature of reaction settles out, then this reaction mixture is cooled to-10 ℃ with 0.25 ℃/minute speed.This reaction mixture is kept more than 6 hours under-10 ℃.Filter the solid that generates then, and use filtrate to wash this reactor, and washing leaching cake.Taking out N then ₂Under the perfect vacuum under at room temperature dry solid that should reclaim.Separate the title compound (productive rate 97%) that obtains 6354 grams.

NMR( ¹H，DMSO-d6)：δppm?1.13-1.30(m，3H)1.40(s，9H)2.32(t，J＝5.98Hz，2H)3.48(t，J＝5.98Hz，2H)3.95(s，2H)4.21(q，J＝7.08Hz，2H)

Preparation example 71:1-(1, the 1-dimethyl ethyl) 3-ethyl 4-{[(trifluoromethyl) alkylsulfonyl] the oxygen base }-5,6-dihydro-1,3 (2H)-pyridine dicarboxylate (P71)

With 1-(1, the 1-dimethyl ethyl) 3-ethyl 4-oxo-1, (P70,380.48g 1.40moles) are dissolved in the toluene (2.97Kg) 3-piperidines dicarboxylic ester.Solution stirring also was cooled to-7 ℃, and uses N then in 10 minutes then, and (271.56g 2.10mol) handles the N-diisopropyl ethyl amine, keeps being reflected at simultaneously being lower than under-7 ℃.After reaction mixture stirred about 10 minutes, (436.29g 1.55mol), kept temperature to be lower than 5 ℃ simultaneously to add trifluoromethanesulfanhydride anhydride.Reaction mixture was stirred 31 minutes down at 1 ℃.

HPLC:Rt=2.69 minute (at Agilent Zorbax SB C 18 (50x3.0mm, 1.8um) on carry out HPLC instrument Agilent 1100Series and analyze, moving phase: water: acetonitrile: TFA (0.05%), at 2.5 minutes inside gradients by 0-95%, keep 0.2 minute, and then balance; T=60 ℃; Flow velocity=1.5mL/ minute)

Preparation example 72:1-(1, the 1-dimethyl ethyl) 3-ethyl 4-(3, the 4-dichlorophenyl)-5,6-dihydro-1,3 (2H)-pyridine dicarboxylate (P72)

With 1-(1, the 1-dimethyl ethyl) 3-ethyl 4-{[(trifluoromethyl) alkylsulfonyl] the oxygen base }-5, the toluene solution of 6-dihydro-1,3 (2H)-pyridine dicarboxylate (deriving from the preparation method described in the P71) is cooled to approximately-5 ℃.Add N then, the N-diisopropyl ethyl amine (288.10g, 2.23mol), water (376.20g), triphenylphosphine (27.52g, 0.105mol) and acid chloride (II) tripolymer (7.88g, 0.0117mol).Reaction mixture is warmed to 21 ℃, and stirred 1 hour.Adding 3,4-dichlorophenyl boric acid (268.80g, 1.41mol) after, reaction mixture is heated to 70 ℃, and stirs 48 minutes (temperature temporarily reaches 87.4 ℃ under heating).This reaction mixture is cooled to-6.4 ℃, and (1N 3286g), keeps temperature of reaction to be lower than 5 ℃ simultaneously to add sodium hydroxide subsequently.Then, reaction mixture is warmed to 20 ℃, and stirred 1 hour.Separate each layer, and with carbon

(gac) (57.57g) joins in this organic phase.After 2 hours, reaction mixture is filtered by Celite 545.At this moment, remove any remaining water layer, and reaction mixture is cooled to 21 ℃.Then, (aqueous solution of 20%w/w 4330g), keeps temperature of reaction to be lower than 28 ℃ simultaneously to add sodium bisulfite.Reaction mixture was stirred 17 hours 30 minutes, carry out layer subsequently and separate.(3792g) washes with the organic layer water.After carrying out other layer separation, the organic layer that will contain title compound is used for next stage.

HPLC:Rt=2.94 minute (at Agilent Zorbax SB C 18 (50x3.0mm, 1.8um) on carry out HPLC instrument Agilent 1100Series and analyze, moving phase: water: acetonitrile: TFA (0.05%), at 2.5 minutes inside gradients by 0 to 95%, keep 0.2 minute, and then balance; T=60 ℃; Flow velocity=1.5mL/ minute)

Embodiment 1:(1S, 6R/1R, 6S)-and 6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo-[4.1.0] heptane hydrochloride (E1)

Steps A

Under argon atmospher, under 0 ℃, (the 1S under stirring, 6R/1R, 6S)-6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1, (80mg P6) drips CF in the solution in exsiccant DCM (5mL) to 1-dimethyl ethyl ester ₃The solution of COOH (1.5mL) in exsiccant DCM (5mL), and mixture stirred 1.5 hours down at 0 ℃.Solvent evaporated under reduced pressure keeps resistates 2 hours under vacuum, and then by preparation property HPLC purifying, obtains trifluoroacetate (40mg) [the system MDAP FractionLynx-Mass Directed Autopurification System of title compound ^TM(the automatic purification system of mass spectrometric detection); Target product: m/z 286[M+H]+(post: Luna C18,250x21mm, 10mm; Moving phase: A:H ₂O+0.1%TFA; B:CH ₃CN+0.1%TFA; Gradient: in 30 minutes by 20% (B) to 35% (B) ,-＞100% (B) in 3 minutes down continues 2 minutes at 100% (B) then; Flow velocity 17ml/min; UV wavelength region 210-350nm; Mass range 100-900amu (ES+); Ionization ES+)]

Step B

Under argon gas, under 0 ℃, the dropping NaOH aqueous solution in stirring the solution of this material (18mg) in exsiccant ether (10mL) down (1M, 10mL), and at room temperature with mixture vigorous stirring 10 minutes.Separate each phase, and with water with ether (2x10mL) extraction, with the organic phase that merges through anhydrous Na ₂SO ₄Drying, and removal of solvent under reduced pressure obtains the free alkali (13mg) of title compound.Under argon gas, under 0 ℃, drip HCl (diethyl ether solution of 1M, 100 μ L) in the solution of this compound (13mg) in exsiccant ether (1.5mL) under stirring, mixture was stirred 10 minutes and at room temperature stirred 30 minutes down at 0 ℃.Remove by decant and to desolvate, and with throw out under high vacuum dry 30 minutes, and and then dry two hours, obtain the title compound (15mg) of white solid.

NMR( ¹H，DMSO-d6)：δ8.71(br.s.，2H)7.73(d，1H)7.59(d，1H)7.41(dd，1H)3.45(d，1H)3.09-3.16(m，2H)3.04(s，3H)2.92(d，1H)2.73-2.82(m，1H)2.66(d，1H)2.01-2.17(m，2H)1.22-1.29(m，2H)；MS(m/z)：286[MH]+

Embodiment 2a and 3a:(1S, 6R)-6-(3, the 4-dichlorophenyl)-the 1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane (E2a) and ((1R, 6S)-6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane (E3a)

With 18mg (1S, 6R/1R, 6S)-6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-free alkali of 3-azabicyclo-[4.1.0] heptane hydrochloride (E1) carries out half preparation HPLC (chiral column Chiralpak AS-H, 250x 21mm, elutriant A: normal hexane; B: Virahol+0.1% Isopropylamine, the gradient 5%B of degree of grade, flow velocity 14ml/min detects UV at the 230nm place.Operational analysis HPLC uses chiral column Chiralpak AS-H, 250x 4.6mm, elutriant A: normal hexane; B: Virahol+0.1% Isopropylamine, the gradient 5%B of degree of grade, flow velocity 1ml/min detects the retention time that the UV acquisition provides at the 210-340nm place), obtain:

Embodiment 2a (enantiomer 1, Rt.=7.99 minute) and embodiment 3a (enantiomer 2, Rt.=14.92 minute).

Determining of the absolute configuration of 2a and 3a:

E2a and the E3a of another batch are applied to initial VCD (vibration circular dichroism) analysis to determine the absolute configuration of these optically active isomers.

Embodiment 2a (enantiomer 1) is equivalent to (1S, 6R)-6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane

NMR( ¹H，CDCl ₃)δppm?7.43(d，1H)，7.36(d，1H)，7.18(d，1H)，3.31(d，1H)，3.12-3.15(m，3H)，3.08(d，1H)，2.95(d，1H)，2.83(d，1H)，2.73-2.80(m，1H)，2.63-2.70(m，1H)，1.91-2.00(m，1H)，1.79-1.87(m，1H)，0.99-1.04(m，2H)

Embodiment 3a (enantiomer 2) is equivalent to (1R, 6S)-6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane

NMR( ¹H，CDCl ₃)δppm?7.43(d，1H)，7.35(d，1H)，7.17(dd，1H)，3.31(d，1H)，3.13(s，3H)，3.08(d，1H)，2.95(d，1H)，2.83(d，1H)，2.72-2.80(m，1H)，2.62-2.70(m，1H)，1.89-2.00(m，1H)，1.77-1.87(m，1H)，0.94-1.07(m，2H)

Embodiment 2a:(1S, 6R)-6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane (E2a)

Method B:

Will (1S, 6R/1R, 6S)-and 6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptan-4-alkene-3-carboxylic acid 1, (P60,10 grams 25.8mmol) are dissolved in the toluene (100mL) 1-dimethyl ethyl ester.(31.1mmol 1.2eq), uses trifluoroacetic acid (20 grams, 13.46mL, 181.2mmol, 7eq) processing subsequently for 3.6 grams, 4.96mL with triethyl-silicane with this solution.This reaction mixture was at room temperature stirred 48 hours, use 1N sodium hydroxide (100mL) to stop then, and stirred 10 minutes.The pH of mixture is approximately 13.Separate each phase, and use 1N sodium hydroxide (100mL) and water (10mL) to wash mutually toluene, vacuum concentration obtains buttery product (8.5 gram) then.

NMR( ¹H，CDCl ₃)：δppm?0.98-1.04(m，2H)1.75-1.87(m，2H)1.89-1.99(m，1H)2.59-2.70(m，1H)2.71-2.80(m，1H)2.82(d，J＝9.80Hz，1H)2.94(d，J＝9.89Hz，1H)3.07(d，J＝12.91Hz，1H)3.12(d，J＝1.01Hz，3H)3.31(d，J＝12.82Hz，1H)7.11-7.21(m，1H)7.35(dd，J＝8.29，0.96Hz，1H)7.43(d，J＝2.11Hz，1H)

Method C:

Will (2R, 3R)-2, two [(phenylcarbonyl group) oxygen base] Succinic Acid of 3--(1S, 6R)-and 6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane (1: 1) (E34,37.8g, 58.7mmol) dilute with DCM (500ml), and use 10%w/w K ₂CO ₃The aqueous solution (500ml) is handled.Separate each phase, and water layer is stripped with DCM (1x400mL).With the organic phase drying (Na that collects ₂SO ₄) and evaporation, obtain title compound (17.4g).

NMR( ¹H，CDCl ₃)：

ppm?7.45(s，1H)，7.36(d，1H)，7.19(d，1H)，3.32(d，1H)，3.14(s，3H)，3.09(d，1H)，2.96(d，1H)，2.84(d，1H)，2.73-2.81(m，1H)，2.64-2.71(m，1H)，1.92-2.00(m，1H)，1.79-1.88(m，1H)，0.97-1.07(m，2H)。

Chirality HPLC:(post: AS-H (25x0.46cm); Elutriant: normal hexane/(2-propyl alcohol+0.1% Isopropylamine) 95/5v/v; Flow velocity: 1ml/min; DAD:210-340nm; CD:230nm; Enantiomer 1 (Rt=7.828 minute)/enantiomer 2 (Rt=14,430 minutes)==the 98.88/1.12 area

Another batch E2a is carried out rotational analysis; Use Rudolph Research AnalyticalAUTOPOL V polarimeter, locate to measure specific rotation at 589nm (sodium ' D ' line).Test conditions: test pool: 0.5dm (50mm) homothermic trace test pond remains under 25 ℃; Solvent: CCl ₄Concentration: 38mg/450 μ l=8.4gm/1200ml.Observed specific rotation: α=-0.23 °; Specific rotation [α] _D=-5.47.

Embodiment 2b:(1S, 6R)-6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane hydrochloride (E2b)

Method A:

To (1S, 6R)-6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-add the 1 normal HCl (Et of 1M in DCM (0.2ml) solution of 3-azabicyclo [4.1.0] heptane (E2a, by above-mentioned chirality partly prepare the amount that HPLC obtains) ₂O solution), vacuum evaporating solvent, and with thus obtained material Et ₂O grinds, and obtains the title compound of 5mg, and it is the slight hygroscopic solid of white.

Method B:

Will (1S, 6R)-6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-(E2a, 4.6g 16.07mmol) are dissolved in Et to 3-azabicyclo [4.1.0] heptane ₂Among the O (60ml), and solution is cooled to 0 ℃ (ice bath).Under 0 ℃, under agitation drip 1M hydrochloric acid diethyl ether solution (17.68ml, 1.1eq.).Form the suspension of white, and mixture was stirred 2 hours down at 25 ℃.Filter this solid, (46ml) washes with ether, and 40 ℃ of following vacuum-dryings 12 hours, obtains the title compound (5.0g) of white solid.Productive rate 96%.

NMR( ¹H，DMSO-d6，600MHz)：δ(ppm)：9.05(bs，2H)，7.77(d，1H)，7.59(d，1H)，7.45(dd，1H)，3.46(d，1H)，3.14(m，1H)，3.13(d，1H)，3.06(s，3H)，2.99(d，1H)，2.79(m，1H)，2.63(d，1H)，2.17(m，1H)，2.07(m，1H)，1.30(d，1H)，1.27(d，1H)

Embodiment 3b:(1R, 6S)-6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane hydrochloride (E3b)

To ((1R, 6S)-6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-add the 1 normal HCl (Et of 1M in DCM (0.2ml) solution of 3-azabicyclo [4.1.0] heptane (E3a, by above-mentioned chirality partly prepare the amount that HPLC obtains) ₂O solution), vacuum evaporating solvent, and with thus obtained material Et ₂O grinds, and obtains the title compound of 5mg, and it is the slight hygroscopic solid of white.

Embodiment 4:[(1S, 6R/1R, 6S)-6-(3, the 4-dichlorophenyl)-and 3-azabicyclo [4.1.0] heptan-1-yl] methyl alcohol (E4)

Method A:

Under argon atmospher, with 2, two (1, the 1-the dimethyl ethyl)-4-picolines (35.836g) of 6-join CH ₂I ₂(46.9g) in the solution in exsiccant DCM (260mL), then under 0 ℃, with 5 minutes times dropping ZnEt ₂(hexane solution of 1M, 87.5mL).After stirring 30 minutes under 0 ℃, reaction mixture is cooled off down at-20 ℃, drip 4-(3, the 4-dichlorophenyl)-5-(hydroxymethyl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid 1,1-dimethyl ethyl ester (2g, P4) solution in exsiccant DCM (20mL), and with reaction mixture-20 ℃ of following restir 30 minutes, and at room temperature stir then and spend the night.(1M 300mL), and with reaction mixture vigorous stirring 20 minutes, separates each phase, and uses 3M NaOH that water layer is alkalized to be pH=12 to add the HCl aqueous solution.

The aqueous solution with ether (3x150mL) extraction, is evaporated organic phase, and resistates is used saturated NH ₄Cl (100mL) and ether (100mL) are handled, and with mixture vigorous stirring 10 minutes, separate each phase then.Water is washed with ether (3x50mL), used 3M NaOH alkalization to be pH=12 then, and extract with ether (3x150ml).

With the organic phase that merges through anhydrous Na ₂SO ₄Drying, and removal of solvent under reduced pressure obtain the impure material of 840mg.

MS(m/z)：272[MH] ⁺.

Method B:

Under 0 ℃ and under nitrogen atmosphere, (P16 drips BH in THF 0.5g) (2.5mL) solution to 6-(3, the 4-dichlorophenyl)-2-oxo-3-azabicyclo [4.1.0] heptane-1-carboxylate methyl ester under stirring ₃(1M/THF 12.8mL), makes reaction mixture reach room temperature and stirred 5 hours under refluxing the THF complex compound then.Et with the 1.0M HCl of the MeOH of 1mL and 5mL ₂O solution joins in the reaction mixture, and solution was at room temperature stirred 2 hours.With the mixture concentrating under reduced pressure, and crude product is passed through FC (use DCM/ methyl alcohol/28%NH ₄The OH aqueous solution 9/1/0.1 wash-out) purifying obtains the title compound of 82mg, is yellow oil.

Method C:

With (1S, 6R/1R, 6S)-6-(3, the 4-dichlorophenyl)-and 1-(hydroxymethyl)-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1-dimethyl ethyl ester (P5,50mg, according to P5, the impure compound that method described in the method A obtains) by preparation property HPLC (post: Luna C18,250x21mm, 10mm; Moving phase: A:H ₂O+0.1%TFA; B:CH ₃CN+0.1%TFA; Gradient: in 30 minutes by 15% (B) to 35% (B) ,-＞100% (B) in 3 minutes down continues 2 minutes at 100% (B) then; Flow velocity: 17ml/min; The UV wavelength region: 210-350nm) purifying obtains its trifluoroacetate (23mg).Under argon gas, under 0 ℃, drip NaOH (1M in the solution of this product (23mg) in exsiccant ether (10mL) under stirring, 10mL), and with mixture vigorous stirring 10 minutes at room temperature, separate each phase then, and with water with ether (2x10mL) extraction.With the organic phase that merges through anhydrous Na ₂SO ₄Drying, and removal of solvent under reduced pressure obtain the free alkali (16mg) of title compound.

Embodiment 5a and 6a:[(1S, 6R or 1R, 6S)-6-(3, the 4-dichlorophenyl)-3-azabicyclo [4.1.0] heptan-1-yl] methyl alcohol (E5a) and [(1R, 6S or 1S, 6R)-6-(3, the 4-dichlorophenyl)-3-azabicyclo [4.1.0] heptan-1-yl] methyl alcohol (E6a)

Will [(1S, 6R/1R, 6S)-6-(3, the 4-dichlorophenyl)-and 3-azabicyclo [4.1.0] heptan-1-yl] (E4 82mg) carries out half preparation HPLC (chiral column Chiralpak AD-H, 25x4.6cm, elutriant A: normal hexane to methyl alcohol; B: Virahol+0.1% Isopropylamine 70/30v/v, flow velocity 0.8ml/min. detects UV at the 230nm place), obtain:

[(1S, 6R or 1R, 6S)-and 6-(3, the 4-dichlorophenyl)-3-azabicyclo [4.1.0] heptan-1-yl] methyl alcohol (E5a, enantiomer 1, Rt.=6.263 minute) and [(1R, 6S or 1S, 6R)-6-(3, the 4-dichlorophenyl)-3-azabicyclo [4.1.0] heptan-1-yl] methyl alcohol (E6a, enantiomer 2, Rt.=15.699 minute).

Embodiment 5b:[(1S, 6R or 1R, 6S)-6-(3, the 4-dichlorophenyl)-and 3-azabicyclo [4.1.0] heptan-1-yl] methylate hydrochlorate (E5b)

To [(1S, 6R or 1R, 6S)-6-(3, the 4-dichlorophenyl)-and 3-azabicyclo [4.1.0] heptan-1-yl] add the 1 normal HCl (Et of 1M in the DCM solution of methyl alcohol (E5a, the amount that obtains by above-mentioned preparation example) ₂O solution), vacuum evaporating solvent, and with thus obtained material Et ₂O grinds, and obtains the corresponding hydrochloride of 30mg, and it is the slight hygroscopic solid of white.

Embodiment 6b:[(1R, 6S or 1S, 6R)-6-(3, the 4-dichlorophenyl)-and 3-azabicyclo [4.1.0] heptan-1-yl] methyl alcohol (E6b)

To [(1R, 6S or 1S, 6R)-6-(3, the 4-dichlorophenyl)-and 3-azabicyclo [4.1.0] heptan-1-yl] add the 1 normal HCl (Et of 1M in the DCM solution of methyl alcohol (E6a, the amount that obtains by above-mentioned preparation example) ₂O solution), vacuum evaporating solvent, and with thus obtained material Et ₂O grinds, and obtains the corresponding hydrochloride of 30mg, and it is the slight hygroscopic solid of white.

NMR( ¹H，DMSO-d6)：d?ppm?8.78(d，2H)7.76(d，1H)7.58(dd，1H)7.37-7.46(m，1H)4.75(t，1H)3.49-3.60(m，1H)3.06-3.23(m，2H)2.95-3.05(m，1H)2.72-2.88(m，2H)1.99-2.21(m，2H)1.15-1.26(m，2H)

Embodiment 7:(1S, 6R/1R, 6S)-6-(3, the 4-dichlorophenyl)-and 3-azabicyclo [4.1.0] heptan-1-yl] methylate hydrochlorate (E7)

Under argon gas, under 0 ℃, [(1S under stirring, 6R/1R, 6S)-6-(3, the 4-dichlorophenyl)-3-azabicyclo [4.1.0] heptan-1-yl] methyl alcohol (E4,16mg) drip the HCl (diethyl ether solution of 1M in the solution in exsiccant ether (1.5mL), 0.12ml), mixture was stirred 10 minutes down at 0 ℃, and at room temperature stirred 30 minutes.Remove by decant and to desolvate, and, obtain the title compound (18mg) of white solid throw out under high vacuum dry 30 minutes.

NMR( ¹H，DMSO-d6)：δ8.66(b?r.s.，2H)7.73(d，1H)7.57(d，1H)7.40(dd，1H)4.75(t，1H)3.52(d，1H)3.06-3.18(m，2H)2.93-3.03(m，1H)2.70-2.83(m，2H)1.99-2.17(m，2H)1.15-1.24(m，2H)；MS(m/z)：272[MH] ⁺

Embodiment 8:(1R, 6S/1S, 6R)-6-(3, the 4-dichlorophenyl)-3-azabicyclo [4.1.0] heptane (E8)

At N ₂Down, to (1R, 6R/1S, 6S)-1-(3, the 4-dichlorophenyl)-3-azabicyclo [4.1.0] heptan-4-ketone and (1R, 6S/1S, 6R)-6-(3, the 4-dichlorophenyl)-3-azabicyclo [4.1.0] heptan-4-ketone (640mg, P11) add in the solution in exsiccant tetrahydrofuran (THF) (16ml) borine THF (the THF solution of 1M, 7.53ml), and with mixture reflux 3 hours, and at room temperature spending the night, and reflux 2 hours then.Mixture is cooled to 0 ℃ then, and adds methyl alcohol (8mL) carefully, (the 1M/ ether, 25mL) gas is emitted in monitoring simultaneously, and solution is at room temperature stirred spend the night to add hydrochloric acid subsequently.Then the solvent vacuum is removed, and salt of wormwood (10% solution) is joined in the resistates.With the water layer dichloromethane extraction, then organic phase is washed dry and concentrating under reduced pressure with saturated NaCl solution.Title compound is separated by nh 2 column (aminic cartridge) (using cyclohexane/ethyl acetate by 9/1 to 7/3 wash-out), obtain the title compound of 150mg output.

NMR( ¹H，CDCl ₃)：δ7.37(m，2H)，7.15(d，1H)，3.35(m，1H)，3.12(d，1H)，2.78(m，2H)，2.05(m，2H)，1.35(m，1H)，1.04(m，1H)，0.94(m，1H)；MS(m/z)：242[MH] ⁺.

Embodiment 9a and 10a:(1R, 6S)-6-(3, the 4-dichlorophenyl)-3-azabicyclo [4.1.0] heptane (E9a) and (1S, 6R)-6-(3, the 4-dichlorophenyl)-3-azabicyclo [4.1.0] heptane (E10a)

Will (1R, 6S/1S, 6R)-(E8 150mg) carries out half preparation HPLC (chiral column Chiralpak AD-H, 25x 4.6cm, elutriant A: normal hexane to 6-(3, the 4-dichlorophenyl)-3-azabicyclo [4.1.0] heptane; B: Virahol+0.1% Isopropylamine 99/1v/v, flow velocity 1ml/min. detects UV at the 230nm place), obtain:

Embodiment 9a (E9a, enantiomer 1, Rt.=15.22 minute) and embodiment 10a (E10a, enantiomer 2, Rt.=15.33 minute).

Determining of the absolute configuration of 9a and 10a:

New a collection of E9a (7mg) and E10a (9mg) (are prepared according to the method that is similar to following 9B and 10B, and handle corresponding hydrochloride with NaOH then, and obtain free alkali) carry out initial VCD (vibration circular dichroism) and contrast the absolute configuration that VCD analyzes to determine these optically active isomers.

Embodiment 9a (enantiomer 1) be equivalent to (1R, 6S)-6-(3, the 4-dichlorophenyl)-3-azabicyclo [4.1.0] heptane

NMR( ¹H，CDCl ₃)：δppm?7.32-7.37(m，2H)，7.10(dd，1H)，3.34(dd，1H)，3.07(d，1H)，2.51-2.79(m，2H)，1.97-2.08(m，1H)，1.85-1.97(m，1H)，1.21-1.36(m，1H)，0.92-1.01(m，1H)，0.81-0.91(m，1H)

Embodiment 10a (enantiomer 2) be equivalent to (1S, 6R)-6-(3, the 4-dichlorophenyl)-3-azabicyclo [4.1.0] heptane:

Embodiment 9b:(1R, 6S)-6-(3, the 4-dichlorophenyl)-3-azabicyclo [4.1.0] heptane hydrochloride (E9b)

To (1R, 6S)-(E9a adds the 1 normal HCl (Et of 1M to 6-(3, the 4-dichlorophenyl)-3-azabicyclo [4.1.0] heptane in DCM solution 40mg) ₂O solution), vacuum evaporating solvent, and with thus obtained material Et ₂O grinds, and obtains the title compound of 45mg, and it is the slight hygroscopic solid of white.

NMR( ¹H，MeOH-d ₄)：δppm?7.52(d，1H)7.45(d，1H)7.28(dd，1.52Hz，1H)3.46-3.65(m，7.07Hz，1H)3.10(d，1H)2.88-3.04(m，1H)2.49-2.82(m，1H)1.97-2.28(m，2H)1.37-1.56(m，1H)1.07-1.19(m，1H)0.92-1.06(m，1H)

Embodiment 10b:(1S, 6R)-6-(3, the 4-dichlorophenyl)-3-azabicyclo [4.1.0] heptane hydrochloride (E10b)

To (1S, 6R)-(E10a adds the 1 normal HCl (Et of 1M to 6-(3, the 4-dichlorophenyl)-3-azabicyclo [4.1.0] heptane in DCM solution 40mg) ₂O solution), vacuum evaporating solvent, and with thus obtained material Et ₂O grinds, and obtains the title compound of 45mg, and it is the slight hygroscopic solid of white.

Embodiment 11:(1S, 4R, 6R/1R, 4S, 6S)-6-(3, the 4-dichlorophenyl)-4-methyl isophthalic acid-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane (E11)

Will (1S, 6R/1R, 6S)-and 6-(3, the 4-dichlorophenyl)-1-(hydroxymethyl)-4-methyl-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1, (P68 70mg) is dissolved among the DMF (30mL) 1-dimethyl ethyl ester, and is cooled to 0 ℃; Add 60% sodium hydride (10.9mg) that is dispersed in the mineral oil then in batches.Mixture was stirred 30 minutes down at 0 ℃, and add methyl iodide (0.017mL) then.Mixture slowly is warmed to room temperature, and stirred 1.5 hours.60% sodium hydride and the 0.017mL methyl iodide in the mineral oil of being dispersed in that adds other 7.2mg, and with mixture restir 1 hour.Then with reaction mixture with saturated NH ₄Cl solution (30mL) stops, and adds Et ₂O (30mL).With water Et ₂O (3X 30mL) washes, and merges organic phase, through Na ₂SO ₄Dry and concentrated.By the chromatography purification on the silica gel, use 10%-30% ethyl acetate/hexanaphthene gradient to carry out wash-out, obtain compound (50mg), it is dissolved among the DCM (1.2mL), be cooled to 0 ℃, and react with trifluoroacetic acid (0.22mL).Mixture is warmed to room temperature lentamente, and under this temperature, stirred 2 hours.This volatile matter of vaporising under vacuum, and with resistates by the SCX column purification, at first use MeOH, and use 2.0M NH then ₃The MeOH eluant solution.HPLC is further purified by preparation property, obtains the title compound of 20mg.

XBridge?PREP?C18，100x19mm，5μm

Moving phase: A:H ₂O+0.1%TFA; B:CH ₃CN

Gradient: 20 (B) continue 1 minute, and by 20% to 35% (B), by 35% to 100% (B), 100% (B) continues 1.5 minutes in 0.5 minute in 12 minutes

Flow velocity: 17mL/min

NMR( ¹H，CDCl ₃)：δ7.46(d，1H)，7.33(d，1H)，7.20(dd，1H)，3.54(d，1H)，3.06-3.17(m，3H)，2.89-3.01(m，2H)，2.72(d，1H)，2.27-2.53(m，1H)，1.91-2.07(m，1H)，1.27-1.46(m，1H)，1.04(d，3H)，0.87-0.98(m，2H)。MS(m/z)：300[M+H] ⁺.

Embodiment 12:(1S, 6R)-6-(3, the 4-dichlorophenyl)-3-methyl isophthalic acid-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane (E12)

Will (1S, 6R)-6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-(E2a 25mg) is dissolved in the methyl alcohol (1mL) 3-azabicyclo [4.1.0] heptane; Add acetate (0.015mL), add the aqueous solution (0.06mL) of sodium triacetoxy borohydride (27.8mg) and 37% formaldehyde subsequently.Reaction mixture at room temperature stirred spend the night.Evaporate this volatile matter then, and with resistates at DCM (20mL) and saturated NaHCO ₃Distribute between the aqueous solution (20mL), dry and concentrated.By chromatography (NH post) purifying, use 0-100% ethyl acetate-hexanaphthene gradient to carry out wash-out, obtain title compound (16mg).

NMR( ¹H，CDCl ₃)：δ7.44(d，1H)，7.35(d，1H)，7.18(dd，1H)，3.15(s，3H)，2.90(dd，2H)，2.78(d，1H)，2.70(d，1H)，2.23-2.30(m，5H)，1.96-2.13(m，2H)，1.05(d，1H)，1.01(d，1H)；MS(m/z)：300[M+H] ⁺.

Embodiment 13:(1S, 6R)-6-(3, the 4-dichlorophenyl)-3-methyl isophthalic acid-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane hydrochloride (E13)

Will (1S, 6R)-(E12 16mg) handles with the diethyl ether solution (0.064mL) of 1.0M hydrochloric acid 6-(3, the 4-dichlorophenyl)-3-methyl isophthalic acid-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane.Add the 0.5mL ether, and form colorless solid.Remove organic phase behind this solid of decant.Because it is 5: 1 the colorless solid (16mg) of isomer mixture that the protonation on the nitrogen-atoms obtains.

NMR ( ¹H, DMSO-d6): δ .10.49 (br.s., 1H), 7.84 (d, 1H), 7.57-7.65 (m, 1H), 7.51-7.55 (m, 1H), 3.68-3.66 (m, 1H), and 3.22-3.35 (m, 1H), 3.00-3.17 (m, 5H), 2.76-2.93 (m, 2H), 2.68-2.75 (m, 3H), 2.29-2.43 (m, 1H), 2.10-2.21 (m, 1H), 1.32 (d, 1H), 1.27 (d, 1H) (peaks that relate to main type); MS (m/z): 300[MH] ⁺.

Embodiment 14:(1R, 6S/1S, 6R)-6-[4-chloro-3-(trifluoromethyl) phenyl]-the 1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane (E14)

Steps A

Will (1R, 6S/1S, 6R)-6-[4-chloro-3-(trifluoromethyl) phenyl]-1-(hydroxymethyl)-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1, (P27 0.3g) is dissolved among the DMF (5mL) 1-dimethyl ethyl ester, and is cooled to 0 ℃; Be added in the 60%NaH (39mg) in the mineral oil, and reaction mixture was stirred 30 minutes down at 0 ℃.Add methyl iodide (92 μ l) then, and mixture is warmed to room temperature lentamente.Add NaH (20mg) and MeI (50 μ l) twice in addition, and mixture was stirred 1.5 hours altogether.Then under 0 ℃ with reaction mixture with saturated NH ₄Cl solution (5mL) stops, and dilutes with ether (20mL); Separate organic phase, (20mL) washes with salt solution, dry and vacuum concentration.Then with crude mixture by the chromatography purification on the silica gel, use 10-50% ethyl acetate/hexanaphthene gradient to carry out wash-out, obtain (the 1R of colorless oil, 6S)-6-[4-chloro-3-(trifluoromethyl) phenyl]-the 1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1-dimethyl ethyl ester (107mg).

MS(m/z)：420[MH] ⁺，363[M-56] ⁺.

Step B

Will from steps A (1R, 6S)-6-[4-chloro-3-(trifluoromethyl) phenyl]-the 1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1-dimethyl ethyl ester is dissolved among the DCM (4mL), and TFA (0.2mL) is joined in this solution.Reaction mixture is at room temperature stirred 1 hour, and vacuum-evaporation volatile matter then.Resistates is dissolved among the DCM (10mL), with saturated NaHCO ₃Solution (10mL), salt solution (10mL) are washed, dry and vacuum concentration.With resistates purifying on the SCX post at first, use MeOH to use 2.0N NH subsequently earlier ₃The MeOH eluant solution, and then by the chromatography purification on the silica gel, use 3%MeOH/DCM to 8%MeOH/DCM+2%2.0N NH ₃The MeOH solution gradient carry out wash-out, obtain the title compound of 55mg.

NMR( ¹H，CDCl ₃)：δ7.72(d，1H)，7.48-7.53(m，1H)，7.42-7.46(m，1H)，3.42(d，1H)，3.08-3.14(m，4H)，3.04(d，1H)，2.81-2.90(m，1H)，2.66-2.76(m，2H)，1.97-2.06(m，1H)，1.85-1.93(m，2H)，1.11(d，1H)，1.04(d，1H)；)；MS(m/z)：320[MH] ⁺.

Embodiment 15:(1R, 6S/1S, 6R)-6-[4-chloro-3-(trifluoromethyl) phenyl]-the 1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane hydrochloride (E15)

To (1R, 6S/1S, 6R)-6-[4-chloro-3-(trifluoromethyl) phenyl]-the 1-[(methoxyl group) methyl]-(E14 adds the 1 normal HCl (Et of 1M to 3-azabicyclo [4.1.0] heptane in DCM solution 55mg) ₂O solution), vacuum evaporating solvent, and with thus obtained material Et ₂O grinds, and obtains the title compound of 61mg, is white solid.

NMR( ¹H，DMSO-d6)：δ8.48-8.86(m，2H)，7.95(s，1H)，7.63-7.77(m，2H)，3.51(d，1H)，3.13-3.22(m，2H)，3.03(s，3H)，2.73-2.88(m，2H)，2.72-2.88(m，2H)，2.05-2.16(m，1H)，1.26-1.36(m，2H))；MS(m/z)：320[MH] ⁺.

Embodiment 16:(1R, 6S/1S, 6R)-and 6-(4-chloro-phenyl-)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane (E16).

Under nitrogen atmosphere, to ice-cooled (1R, 6S/1S/6R)-and 6-(4-chloro-phenyl-)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1-dimethyl ethyl ester (P32, use is similar to the impure compound of the method acquisition of aforesaid P32, drips trifluoroacetic acid (1mL) in methylene dichloride 280mg) (5mL) solution.Make reaction mixture reach room temperature, and stirred then 1 hour.Solvent evaporated under reduced pressure.Thick material is passed through SCX (5g) column purification, being prepared property HPLC (post: LunaAXIA C18,100x 21mm, 5um then; Moving phase: A:H2O+0.1%TFA; B:CH ₃CN; Gradient: 15% (B) → 35% (B) (curve 7 in 15 minutes ^*), 35% (B) → 100% (B) in 2 minutes, 100% (B) continues 0.1 minute; Flow velocity 17ml/min; UV scope: 210-350nm; Mass range: 100-900amu (ES+); Ionization: ES+).The compound that obtains is passed through the SCX post, obtain title compound (70mg).

NMR( ¹H，CDCl ₃)：δppm?7.25(s，4H)3.30(d，1H)3.08-3.14(m，4H)2.85-2.91(m，2H)2.63-2.80(m，2H)1.81-1.99(m，2H)0.99-1.05(m，2H)。

Embodiment 17:(1R, 6S/1S, 6R)-and 6-(4-chloro-phenyl-)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane hydrochloride (E17)

To (1R, 6S/1S, 6R)-and 6-(4-chloro-phenyl-)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane (E16, the anhydrous diethyl ether solution (0.278mL) of adding 1.0M HCl in anhydrous methylene chloride 70mg) (2mL) solution.Solvent evaporated under reduced pressure is also ground the solid that generates with anhydrous diethyl ether, obtain title compound (76mg).

NMR( ¹H，DMSO-d ₆)：δppm?8.33-9.07(m，2H)7.44(d，2H)7.38(d，2H)3.47(d，1H)3.15(d，1H)3.07-3.19(m，1H)3.00-3.07(m，3H)2.94(d，1H)2.74-2.84(m，1H)2.58(d，1H)2.09-2.23(m，1H)1.96-2.09(m，1H)1.27(d，1H)1.21(d，1H)

Embodiment 18:(1R, 6S/1S, 6R)-and 6-(3, the 4-dichlorophenyl)-1-[(oxyethyl group) methyl]-3-azabicyclo [4.1.0] heptane hydrochloride (E18)

Steps A

Under nitrogen atmosphere, (1R under stirring, 6S/1S, 6R)-6-(3, the 4-dichlorophenyl)-and the 1-[(oxyethyl group) methyl]-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1, (P51 78mg) adds trifluoroacetic acid (1.5mL) in the solution in exsiccant DCM (5mL) to 1-dimethyl ethyl ester, and continues to stir 2 hours.After this, add toluene, and evaporating solvent obtains crude product, it is dissolved among the DCM, the dense NaHCO of organic phase ₃The aqueous solution is washed, the evaporation organic solvent.Crude product at first (is used DCM/ (methyl alcohol+1%2N NH by flash chromatography ₃MeOH solution) by 0 to 20% wash-out) purifying, and then by the LC-MS purifying, obtain 27mg (1R, 6S/1S, 6R)-6-(3, the 4-dichlorophenyl)-1-[(oxyethyl group) methyl]-3-azabicyclo [4.1.0] heptane, be the free alkali of title compound.

Step B

This compound of 10mg is dissolved among the DCM (1ml), and adds the Et of 1 normal 1N HCl ₂O solution.Solvent removed in vacuo obtains title compound (12mg).

NMR( ¹H，MeOH-d ₄)：δ7.58(d，1H)7.38(d，1H)7.25(dd，1H)3.64(d，1H)3.15(m，5H)2.79(m，1H)2.57(d，1H)2.11(m，2H)1.19(d，1H)1.12(d，1H)0.98(t，3H)；

MS(m/z)：300[MH]+

Embodiment 19a and 20a:(1R, 6S or 1S, 6R)-6-(3, the 4-dichlorophenyl)-and the 1-[(oxyethyl group) methyl]-3-azabicyclo [4.1.0] heptane (E19a) and (1S, 6R or 1R, 6S)-6-(3, the 4-dichlorophenyl)-1-[(oxyethyl group) methyl]-3-azabicyclo [4.1.0] heptane (E20a)

Will (1R, 6S/1S, 6R)-6-(3, the 4-dichlorophenyl)-and the 1-[(oxyethyl group) methyl]-3-azabicyclo [4.1.0] heptane hydrochloride (E18,28mg) carry out half preparation SFC, obtain isolating enantiomer, by using chiral column ChiralpakAD-H (25x4.6cm), elutriant: 2-propyl alcohol+0.1% Isopropylamine 13%, T35 ℃, P 100bar, flow velocity 2.0mL/min, detect DAD 210-340nm, CD 225nm.Obtain:

Embodiment 19a (enantiomer 1, Rt.=14.36 minute, 11mg, colorless oil, MS (m/z): 300[MH]+) and embodiment 20a (enantiomer 2, Rt.=15.70 minute, 7mg, colorless oil, MS (m/z): 300[MH]+).

Embodiment 19b:(1R, 6S or 1S, 6R)-and 6-(3, the 4-dichlorophenyl)-1-[(oxyethyl group) methyl]-3-azabicyclo [4.1.0] heptane hydrochloride (E19b)

To (1R, 6S or 1S, 6R)-and 6-(3, the 4-dichlorophenyl)-1[(oxyethyl group) methyl]-(E19a adds the 1 normal HCl (Et of 1M to 3-azabicyclo [4.1.0] heptane in DCM 11mg) (0.2ml) solution ₂O solution), vacuum evaporating solvent, and with thus obtained material Et ₂O grinds, and obtains the title compound of 8.9mg, and it is the slight hygroscopic solid of white.

MS(m/z)：300[MH] ⁺

Embodiment 20b:(1S, 6R or 1R, 6S)-and 6-(3, the 4-dichlorophenyl)-1-[(oxyethyl group) methyl]-3-azabicyclo [4.1.0] heptane hydrochloride (E20b)

To (1S, 6R or 1R, 6S)-and 6-(3, the 4-dichlorophenyl)-1-[(oxyethyl group) methyl]-(E20a adds the 1 normal HCl (Et of 1M to 3-azabicyclo [4.1.0] heptane in DCM 7mg) (0.2ml) solution ₂O solution), vacuum evaporating solvent, and with thus obtained material Et ₂O grinds, and obtains the title compound of 5.8mg, and it is the slight hygroscopic solid of white.

NMR( ¹H，MeOH-d ₄)：δ7.70(d，1H)7.49(d，1H)7.36(dd，1H)3.75(d，1H)3.37(m，1H)3.26(m，3H)3.15(m，1H)2.89(m，1H)2.69(d，1H)2.23(q，2H)1.29(d，1H)1.23(d，1H)1.13(t，3H)；MS(m/z)：300[MH] ⁺

Embodiment 21:(1S, 6R/1R, 6S)-and the 1-[(methoxyl group) methyl]-the 6-{4-[(trifluoromethyl) the oxygen base] phenyl }-3-azabicyclo [4.1.0] heptane (E21)

At N ₂Under the atmosphere, under 0 ℃, (1S under stirring, 6R/1R, 6S)-and 1-(hydroxymethyl)-6-{4-[(trifluoromethyl) the oxygen base] phenyl }-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1, and 1-dimethyl ethyl ester (P36, (60% in mineral oil 173mg) to add NaH in the solution in exsiccant THF (3mL), 24mg), and continue to stir 30 minutes.Drip CH ₃I (52 μ L), and this reaction mixture is warmed to room temperature lentamente, and stirred 3 hours.Add saturated NH ₄The Cl aqueous solution, and then with the mixture vacuum concentration.With water extracted with diethyl ether (2 times), and then the organic layer that merges is washed with the saturated NaCl aqueous solution, through anhydrous Na ₂SO ₄Drying, and evaporation obtains thick product.Crude product is dissolved among the exsiccant DCM (4mL), and at N ₂Add TFA (3.5mL) down at 0 ℃ under the atmosphere.This reaction mixture is warmed to room temperature lentamente, and stirred 1 hour.With the mixture vacuum concentration, and with resistates by the SCX column purification.Thus obtained thick material by the HPLC chromatography purification, is obtained title compound (35mg).

LC condition: post Luna AXIA C18,100x21mm, 5 μ m

Mobile phase A: H ₂O+0.1%TFA; B:CH ₃CN

Gradient: in 18 minutes by 20% (B) to 35% (B), in 7 minutes by 35% (B) to 80% (B), in 1 minute by 75% (B) to 100% (B), 100% (B) continues 3 minutes.

Flow velocity 17ml/min

UV scope: 210-350nm

Mass range: 100-900amu (ES+)

Ionization: ES+

R _t=3.37 minutes

MS(m/z)：302[M+H] ⁺

Embodiment 22:(1S, 6R/1R, 6S)-and the 1-[(methoxyl group) methyl]-the 6-{4-[(trifluoromethyl) the oxygen base] phenyl }-3-azabicyclo [4.1.0] heptane hydrochloride (E22)

Under stirring (1S, 6R/1R, 6S)-the 1-[(methoxyl group) methyl]-the 6-{4-[(trifluoromethyl) the oxygen base] phenyl-3-azabicyclo [4.1.0] heptane (E21,35mg) drip in the solution in the exsiccant ether HCl (diethyl ether solution of 1M, 0.12ml).Remove by decant and to desolvate, and will precipitate vacuum-drying, obtain the title compound (30mg) of white solid.

NMR( ¹H，MeOH-d ₄)：δppm?7.52(d，2H)7.24(d，2H)3.72(d，1H)3.27(d，1H)3.25-3.21(m，1H)3.16-3.12(m，3H)3.07(d，1H)2.97-2.84(m，1H)2.74(d，1H)2.32-2.12(m，2H)1.31(d，1H)1.22(d，1H)

Embodiment 23:(1S, 6R/1R, 6S)-6-[3-chloro-4-(trifluoromethyl) phenyl]-the 1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane (E23)

Steps A

At N ₂Under the atmosphere, under 0 ℃, (1S under stirring, 6R/1R, 6S)-6-[3-chloro-4-(trifluoromethyl) phenyl]-1-(hydroxymethyl)-3-azabicyclo [4.1.0] heptane-3-carboxylic acid phenyl methyl ester (430mg) (P41, impure compound by above-mentioned preparation example acquisition) (60% in mineral oil, 59mg), and continues to stir 30 minutes to add NaH in the solution in exsiccant THF (6mL).Drip CH ₃I (113 μ L), and make this reaction mixture reach room temperature, and stir and spend the night.Add saturated NH ₄The Cl aqueous solution, and then with the mixture vacuum concentration.With water extracted with diethyl ether (2 times), and then the organic layer that merges is washed with the saturated NaCl aqueous solution, through anhydrous Na ₂SO ₄Drying, and evaporation obtains thick product.Crude product is passed through flash chromatography (using cyclohexane/ethyl acetate by 9: 1 to 8: 2 wash-outs) purifying, obtain 300mg impure (1R, 6S)-6-[3-chloro-4-(trifluoromethyl) phenyl]-the 1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane-3-carboxylic acid phenyl methyl ester.

Step B

Thus obtained impure product is dissolved in exsiccant 1, in the 4-diox (6mL), and in this solution, adds 6N HCl (1mL).With reaction mixture refluxed 4 hours, and then other 6N HCl (2mL) is joined in this solution.It is at room temperature stirred spend the night, and refluxed then 5 hours.Should react with the 3N NaOH aqueous solution (pH=12) termination, and use Et ₂O extracts (3 times).The organic layer that merges is washed dry and vacuum concentration with the saturated NaCl aqueous solution.Resistates is passed through the SCX column purification.Thus obtained thick material by the HPLC chromatography purification, is obtained the free alkali (20mg) of title compound.

LC chromatography condition: post: Gemini C18AXIA, 50x21mm, 5 μ m

Mobile phase A: NH ₄HCO ₃The 10mM aqueous solution, pH=10; B:CH3CN

Gradient: in 1 minute by 30% (B) to 35% (B), in 7 minutes by 35% (B) to 75% (B), in 1 minute by 75% (B) to 100% (B), 100% (B) continues 1 minute.

Flow velocity 17ml/min

UV scope: 210-350nm

Mass range: 100-900amu (ES+)

Ionization: ES+

R _t=3.38 minutes

MS(m/z)：320[M+H]+

Embodiment 24:(1S, 6R/1R, 6S)-6-[3-chloro-4-(trifluoromethyl) phenyl]-the 1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane hydrochloride (E24)

Under stirring (1S, 6R/1R, 6S)-6-[3-chloro-4-(trifluoromethyl) phenyl]-the 1-[(methoxyl group) methyl]-(E23 20mg) drips HCl (diethyl ether solution of 1M) to 3-azabicyclo [4.1.0] heptane in the solution in the exsiccant ether.Remove by decant and to desolvate, and dry under vacuum should precipitation, obtain the title compound (21mg) of white solid.

NMR (free alkali, ¹H, CDCl ₃): δ ppm 7.71 (s, 1H) 7.46 (dd, 2H) 3.40 (d, 1H) 3.12 (s, 3H) 2.99-3.10 (m, 2H) 2.76-2.91 (m, 1H) 2.65-2.76 (m, 2H) 1.91-2.07 (m, 2H) 1.79-1.91 (m, 1H) 1.10 (d, 1H) 1.02 (d, 1H); MS (m/z): 320[MH] ⁺

Embodiment 25:(1R, 6S/1S, 6R)-and the 1-[(methoxyl group) methyl]-6-(2-naphthyl)-3-azabicyclo [4.1.0] heptane (E25)

Will (1R, 6S/1S, 6R)-and the 1-[(methoxyl group) methyl]-(P44 600mg) is dissolved in 1 to 6-(2-naphthyl)-3-azabicyclo [4.1.0] heptane-3-carboxylic acid phenyl methyl ester, in the 4-diox (7mL), and adds the 6.0N HCl aqueous solution (7mL).With reaction mixture refluxed 4 hours, and then in 85 ℃ of heating 18 hours.After being cooled to room temperature, water is washed with ether (30mL), alkalized, and extract with DCM (3X50mL) with 3.0M NaOH.Merge organism, through Na ₂SO ₄Dry and concentrated.Crude product mixture by the chromatography purification on the silica gel, is at first used 5%MeOH/DCM, and use 5%MeOH/DCM+2%2.0M NH then ₃The MeOH eluant solution.Obtain the title compound (145mg) of colorless oil.

NMR( ¹H，CDCl ₃)：δ7.77-7.86(m，3H)，7.72-7.76(m，1H)，7.42-7.52(m，3H)，3.37(d，1H)，3.18(d，1H)，3.10(s，3H)，3.02(d，1H)，2.80-2.89(m，2H)，2.70-2.79(m，1H)，1.96-2.08(m，2H)，1.25(d，1H)，1.11(d，1H)；)；MS(m/z)：268[MH] ⁺.

Embodiment 26a and 27a:(1R, 6S or 1S, 6R)-the 1-[(methoxyl group) methyl]-6-(2-naphthyl)-3-azabicyclo [4.1.0] heptane (E26a) and (1S, 6R or 1R, 6S)-the 1-[(methoxyl group) methyl]-6-(2-naphthyl)-3-azabicyclo [4.1.0] heptane (E27a)

Will (1R, 6S/1S, 6R)-and the 1-[(methoxyl group) methyl]-(E25 140mg) carries out half preparation HPLC to 6-(2-naphthyl)-3-azabicyclo [4.1.0] heptane, uses chiral column Chiralcel OJ, 25x4.6cm, elutriant A: normal hexane; B: ethanol 0.1% Isopropylamine 85/15, flow velocity 0.9mL/min detects UV at the 228nm place, obtains:

Embodiment 26a (enantiomer 1, Rt.=5.77 minute, 52mg, colorless oil) and embodiment 27a (enantiomer 2, Rt.=7.40 minute, 40mg, colorless oil).

Embodiment 28:(1R, 6S/1S, 6R)-and the 1-[(methoxyl group) methyl]-6-(2-naphthyl)-3-azabicyclo [4.1.0] heptane hydrochloride (E28)

To (1R, 6S/1S, 6R)-and the 1-[(methoxyl group) methyl]-(E25 adds the 1 normal HCl (Et of 1M to 6-(2-naphthyl)-3-azabicyclo [4.1.0] heptane in DCM solution 5mg) ₂O solution), vacuum evaporating solvent, and with thus obtained material Et ₂O grinds, and obtains the corresponding hydrochloride of 5mg white solid.

MS(m/z)：268[MH] ⁺.

Embodiment 26b:(1R, 6S or 1S, 6R)-and the 1-[(methoxyl group) methyl]-6-(2-naphthyl)-3-azabicyclo [4.1.0] heptane hydrochloride (E26b)

To (1R, 6S or 1S, 6R)-and the 1-[(methoxyl group) methyl]-(E26a adds the 1 normal HCl (Et of 1M to 6-(2-naphthyl)-3-azabicyclo [4.1.0] heptane in DCM solution 52mg) ₂O solution), vacuum evaporating solvent, and with thus obtained material Et ₂O grinds, and obtains the title compound of the white solid of 53mg.

NMR( ¹H，CDCl ₃)：δ7.24-7.32(m，4H)，7.09-7.14(m，1H)，6.90-6.98(m，2H)，3.32(d，1H)，2.76-2.88(m，2H)，2.60-2.65(m，1H)，2.54-2.58(m，3H)，2.40-2.49(m，1H)，2.24-2.29(m，1H)，1.99-2.10(m，1H)，1.76-1.84(m，1H)，0.92-0.95(m，1H)，0.80-0.84(m，1H)；MS(m/z)：268[MH] ⁺.

Embodiment 27b:(1S, 6R or 1R, 6S)-and the 1-[(methoxyl group) methyl]-6-(2-naphthyl)-3-azabicyclo [4.1.0] heptane hydrochloride (E27b)

To (1S, 6R or 1R, 6S)-and the 1-[(methoxyl group) methyl]-(E27a adds the 1 normal HCl (Et of 1M to 6-(2-naphthyl)-3-azabicyclo [4.1.0] heptane in DCM solution 40mg) ₂O solution), vacuum evaporating solvent, and with thus obtained material Et ₂O grinds, and obtains the title compound of the white solid of 40mg.

NMR( ¹H，DMSO-d6)：δ.7.83-7.90(m，3H)，7.80-7.83(m，1H)，7.60(dd，1H)，7.44-7.52(m，2H)，3.20-3.40(m，1H)，3.13(d，1H)，2.93-3.05(m，5H)，2.74-2.83(m，1H)，2.63(d，1H)，1.99-2.17(m，2H)，1.25-1.32(m，2H))；MS(m/z)：268[MH] ⁺.

Embodiment 29:(1S, 6R/1R, 6S)-and 6-(3-chloro-4-fluorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane hydrochloride (E29)

According to being similar to the method described in the embodiment 18, by (1S, 6R/1R, 6S)-and 6-(3-chloro-4-fluorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1, (164mg P50) begins 1-dimethyl ethyl ester, prepares the title compound of 115mg output.

NMR( ¹H，DMSO-d ₆)：δppm?8.28(s，1H)7.66(d，1H)7.25-7.47(m，2H)3.41(d，1H)3.01-3.14(m，5H)2.92(d，1H)2.75(d，1H)2.68(d，1H)1.98-2.10(m，2H)1.17-1.26(m，2H)；MS(m/z)：270[MH] ⁺

Embodiment 30:(1R, 6S/1S, 6R)-and 6-(3, the 4-dichlorophenyl)-1-{[(2,2, the 2-trifluoroethyl) the oxygen base] methyl }-3-azabicyclo [4.1.0] heptane (E30)

Step a)

Under stirring 2; 2; (60% in mineral oil to add sodium hydride in DMF (1mL) solution of 2-TFE (12 μ l); 5.7mg), after 10 minutes, add (1R; 6S/1S; 6R)-and 6-(3, the 4-dichlorophenyl)-1-{[(methylsulfonyl) the oxygen base] methyl }-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1-dimethyl ethyl ester (P69, DMF 60mg) (2mL) solution.After 4 hours, add other 2,2, DMF (1mL) solution of 2-TFE (12 μ L), and (60% in mineral oil, 5.7mg) to add sodium hydride.After 2 days, add other 2,2, DMF (1mL) solution and the sodium hydride (5.7mg) of 2-TFE (12 μ L), and with this reaction mixture in 60 ℃ of heating 5 hours.Add DCM and saturated NaHCO ₃Solution, and removal of solvent under reduced pressure obtain (1R, 6S/1S, 6R)-6-(3, the 4-dichlorophenyl)-1-{[(2,2,2-trifluoroethyl) oxygen base of crude product] methyl }-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1-dimethyl ethyl ester (6mg).

Step b)

With crude product (1R, 6S/1S, 6R)-6-(3, the 4-dichlorophenyl)-1-{[(2,2, the 2-trifluoroethyl) the oxygen base] methyl }-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1-dimethyl ethyl ester (6mg, E30, step a) is dissolved among the exsiccant DCM (1mL), and adds TFA (0.5mL).Reaction mixture was stirred 2 hours, and evaporating solvent obtains thick material then, and it is dissolved among the DCM again.With organic phase with saturated NaHCO ₃Solution is washed, and is dry and concentrated.Crude product (is used DCM/ methyl alcohol/NH by flash chromatography ₃/ MeOH2N 49/1/1 wash-out) purifying obtains title compound (3.9mg).

NMR( ¹H，CDCl ₃)：δ7.5(s，1H)7.45(d，1H)7.35(m，1H)，3.9(d，2H)3.7(d，1H)3.6(m，2H)3.25(d，1H)3.15(m，2H)2.3(m，1H)2.2(m，1H)1.25(m，2H)。

Embodiment 31:(1S, 6R, 7R/1R, 6S, 7S)-and 6-(3, the 4-dichlorophenyl)-7-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane (E31)

(1S under stirring, 6R/1R, 6S)-6-(3, the 4-dichlorophenyl)-and the 7-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1-dimethyl ethyl ester and 4-(3, the 4-dichlorophenyl)-6-[2-(methoxyl group) ethyl]-3,6-dihydro-1 (2H)-pyridine carboxylic acid 1, (P56 35mg) adds trifluoroacetic acid (0.75ml) in the solution in exsiccant DCM (4mL) to 1-dimethyl ethyl ester.Mixture was at room temperature stirred 2 hours, removal of solvent under reduced pressure then, and crude product (used DCM: MeOH: NH by flash chromatography ₃Water=95: 5: 0.5 wash-outs) purifying obtains the mixture that 10mg contains title compound.MS(m/z)：286[MH] ⁺

With (1S, 6R, 7R/1R, 6S, 7S)-6-(3, the 4-dichlorophenyl)-7-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane (3.5mg) purifying, and with 4-(3, the 4-dichlorophenyl)-and 6-[2-(methoxyl group) ethyl]-1,2,3, the 6-tetrahydropyridine separates, by partly preparing HPLC, use chiral column Chiralpak AS-H, elutriant A: normal hexane; B: ethanol, the gradient 30%B of degree of grade, flow velocity 0.8ml/min detects UV at the 225nm place.

NMR( ¹H，CDCl ₃)：δ7.37(d，1H)7.33(d，1H)7.13(dd，1H)4.01(dd，1H)3.78(dd，1H)3.44(s，3H)3.28-3.36(m，1H)3.12-3.23(m，1H)2.79-2.89(m，1H)2.52-2.65(m，1H)1.96-2.12(m，1H)1.80-1.96(m，1H)1.28-1.47(m，2H)；MS(m/z)：286[MH]+

Embodiment 32:(1S, 6R/1R, 6S)-and 6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane (E32)

Method A:

According to the method that is similar among the method B for preparing above-claimed cpd E2a, by (1S, 6R/1R, 6S)-6-(3, the 4-dichlorophenyl)-and the 1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptan-4-alkene-3-carboxylic acid 1,1-dimethyl ethyl ester (P59) beginning can obtain title compound.

Method B:

In round-bottomed flask, with (1S, 6R/1R, 6S)-and 6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane-3-carboxylic acid 1,1-dimethyl ethyl ester (P66,42.33g, 110mmol) be dissolved among the DCM (450ml), obtain colourless solution.Use ice bath with keep internal temperature be lower than+5 ℃ drip down trifluoroacetic acid (103ml, 1343mmol).After adding is finished, remove ice bath, and mixture was at room temperature stirred 2 hours.

Use ice bath with keep internal temperature be lower than+10 ℃ under, this reaction is stopped by the saturated wet chemical (250ml) of dropping.Then mixture is made water (200ml) and DCM (200ml) dilution.Separate two-phase.Water is extracted with ethyl acetate (2x150ml), and with organic phase (milky white solution) vacuum-evaporation, and use ethyl acetate (400ml) dissolving.

The organic phase that merges is washed dry (Na with salt solution (300ml) ₂SO ₄) and vacuum-evaporation, obtain xanchromatic oily matter (34g).It is dissolved in the ether (600ml), and washes with 1M wet chemical (3x200ml).With organic phase drying (Na ₂SO ₄) and vacuum-evaporation, obtain the title compound (28.9g) of colorless oil.

NMR( ¹H，CDCl ₃)：δppm?7.45(s，1H)，7.36(d，1H)，7.19(d，1H)，3.32(d，1H)，3.14(s，3H)，3.09(d，1H)，2.96(d，1H)，2.84(d，1H)，2.73-2.81(m，1H)，2.64-2.71(m，1H)，1.92-2.00(m，1H)，1.79-1.88(m，1H)，0.97-1.07(m，2H)。

HPLC (walk-up): Rt=3.97 minute

Embodiment 33:(1S, 6R)-6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane (2R, 3R)-2,3 dihydroxybutanedioic acid salt (L-tartrate) is (E33)

Method a)

The method of the steps A by being similar to embodiment 38, the step that dispenses azeotropic drying prepares the material of 3.7 grams, it is dissolved in Virahol (60ml, 16.7vols) in, and in this solution, add L-tartrate [(2R, 3R)-(+)-tartrate] (2.7 grams, 18.1mmol, 1.4eq), and solution is heated to 80 ℃ then.Then in case to this temperature, add entry (12ml, 3.2vols), and with solution stirring 10 minutes.Then the solution that generates is cooled to 0 ℃ with 0.2 ℃/min speed, and kept 7 hours down at 0 ℃ then.(10ml 2.7vol) washes twice then with the slurries filtration that generates, and with Virahol.Then the solid that obtains was descended dry 5 hours at 50 ℃ under high vacuum, obtain the title compound (3.7 grams, 8.5mmol, the rate of recovery 65%) of pale solid.

NMR( ¹H，DMSO-d6)：δppm?1.22(s，2H)，2.03(t，J＝5.26Hz，2H)，2.67-2.79(m，2H)，2.83-2.90(m，1H)，3.04(s，4H)，3.11(d，J＝13.19Hz，1H)，3.43(d，J＝13.55Hz，1H)，3.85(s，2H)，7.33-7.39(m，1H)，7.56-7.60(m，1H)，7.68(d，J＝2.01Hz，1H)。

MS(m/z)：286[MH]+

Method b)

Under agitation, to 300.1mg (1S, 6R)-6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-add 0.5mL Virahol (IPA) in the L-tartrate of 3-azabicyclo [4.1.0] heptane (E2a) and 157.3mg.Add other 0.5mL Virahol, and the solution that uses the air gun heating to generate.Remove heating, and add other 2.5mL IPA, obtain slurry thus,, make it have flowability (obtaining the volume of total solvent volume) for the 4.5mL IPA of adding to the IPA that wherein adds other 1mL.The slurry that generates is carried out temperature cycle＞24 hour between 0 and 40 ℃.Then with sample filtering, and with the solid that obtains 70 ℃ of following vacuum-dryings 24 hours.

The diffractogram of 1 type of title compound E33 [using method b) generate batch of material] as shown in Figure 3.

The XRPD peak * of 1 type of the title compound of embodiment 33 (have 5% or bigger relative intensity) is shown in the following table 3 and (has write down XRPD angle and d-spacing):

Table 3

[X-ray powder diffraction (XRPD) analysis is carried out on PANalytical X ' Pert Pro powder diffractometer (model PW3040/60, sequence number DY2599), uses X ' Celerator detector.Testing conditions: radiation: Cu K _α, producer voltage: 40kV, producer electric current: 40mA, start angle: 2.0 ° of 2 θ, termination point: 45.0 ° of 2 θ, step-length: 0.017 ° of 2 θ, per time in step: 32.3024 seconds.Sample uses no background (front fill) technology to be prepared]

The beginning of fusing point/decomposition [E33,1 type, using method b) preparation batch of material]: 198 ℃ of (TA instrument Q1000 sequence number Q1000-0577.In having (crimped) aluminium dish that plays fold of pin hole lid with 10 ℃ of min ^-1Heated sample).

The DSC thermogram of 1 type of embodiment 33 title compounds [using method b) preparation batch of material] is shown among Fig. 4.

Method c)

The tartaric methanol solution of adding L-in the material of the 500mg that the steps A according to embodiment 38 in being dissolved in methyl alcohol (5mL) prepares (1.21mL, 1mmol/mL).It was stirred 15 minutes, and form white precipitate.It is collected by vacuum filtration, and wash, obtain the title compound of 246mg with methyl alcohol (2mL).

NMR ( ¹H, DMSO-d6): δ ppm 1.24 (s, 2H) 1.99-2.14 (m, 2H) 2.47-2.53 (m, 1H) 2.67 (d, J=9.99Hz, 1H) 2.72-2.83 (m, 1H) 2.92 (d, J=9.99Hz, 1H) 3.05 (s, 3H) 3.12 (d, J=13.20Hz, 1H) 3.47 (d, J=13.38Hz, 1H) 3.92 (s, 2H) 7.39 (dd, J=8.34,2.10Hz, 1H) 7.59 (d, J=8.29Hz, 1H) 7.70 (1H) diffractogram of 1 type of title compound E33 as shown in Figure 5 for d, J=2.05Hz.

The XRPD peak * of 1 type of title compound E33 [using method c) preparation batch of material] is as follows Table 4Shown in (having write down XRPD angle and d-spacing):

Table 4

* value shown here is rounded to 1 decimal place.This diffractogram of displacement (displacement) that depends on sample can be offset to a little higher than or be lower than 2 θ values.

[X-ray powder diffraction (XRPD) is analyzed having on the PANalytical X ' Pert-Pro MPD of Johansson Ka1 monochromator and is carried out, and uses X ' Celerator detector.Testing conditions is as follows: radiation: Cu (Ka1), 1.540598 dusts (unicolor); Detector: X ' Celerator; Voltage: 45kV; Electric current: 40mA; Start angle: 2.0 ° of 2 θ; Termination point: 50.0 ° of 2 θ; Step-length: 0.02 °; Time/step: 40.0 seconds; Sweep velocity: 0.05 °/second; Incident beam: the divergent slit of 2 ° of fixed anti-scatter slits and program controlled; Diffracted beam: the anti-scatter slit of 0.02 radian (rad) soller slit and program controlled; Do not have in the background sampling receptacle at silicon and to prepare sample)].

In one embodiment, determined the unique and distinctive peak * of 1 type of title compound E33, and be shown in down Table 5In (having write down XRPD angle and d spacing):

Table 5

The beginning of fusing point/decomposition [E33,1 type, using method c) preparation batch of material]: 191.17 ℃ of (TA instrument model Q1000DSC; Dish: the aluminium dish of sealing; Purgative gas: N ₂, 50mL/min; Temperature range: 30-300 ℃, 15 ℃/minute).

The DSC thermogram of 1 type of title compound E33 [using method c) preparation batch of material] is shown among Fig. 6.

Decompose 1 type of title compound E33 fusion back, so the integration at the peak of different samples can produce different slightly initial, peak maximums (Peak Max) and enthalpy.

Embodiment 34 and 35:(2R, 3R)-2, two [(phenylcarbonyl group) oxygen base] Succinic Acid-(1S of 3-, 6R)-6-(3, the 4-dichlorophenyl)-the 1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane (E34) and (2S, 3S)-2, two [(phenylcarbonyl group) oxygen base] Succinic Acid-(1R of 3-, 6S)-and 6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane (E35)

Step a)

In 1 hour; to (1S; 6R/1R; 6S)-6-(3; the 4-dichlorophenyl)-and the 1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane (E32; 61.5g, drip in acetone 215mmol) (300ml) solution dibenzoyl-L-tartrate be dissolved in the acetone (622ml) (115g, 322mmol).Be settled out solid, and mixture was at room temperature stirred 2 hours.Filter this solid, (2x100ml) washes with acetone, and vacuum-drying, obtains compd E 34 (35.8g).

Chirality HPLC (post: AS-H (25x0.46cm), 5 microns; Elutriant: normal hexane/(2-propyl alcohol+0.1 Isopropylamine) 95/5v/v; Flow velocity: 1ml/min; Wavelength: 225nm; Retention time refers to the salt analysis): enantiomer 1 (Rt=12.14 minute)/enantiomer 2 (Rt=17.29 minute)=86/13 area %

With the mother liquor vacuum concentration, and resistates is suspended among the DCM (700ml).It is washed with saturated wet chemical/water 1: 1 (700ml).Water is stripped with DCM (2x500ml).With the organic phase drying (Na that collects ₂SO ₄), evaporation obtains resistates 6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane (45g).

Chirality HPLC:(post: AS-H (25x0.46cm), 5 microns; Elutriant: normal hexane/(2-propyl alcohol+0.1 Isopropylamine) 95/5v/v; Flow velocity: 1ml/min; Wavelength: 225nm; Retention time refers to free alkali): enantiomer 1/ enantiomer 2=34/62 area %

Step b)

In 45 minutes; 6-(3 to the remnants that derive from step a) that are dissolved in acetone (220m1); the 4-dichlorophenyl)-the 1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane (45g, drip in 157mmol) dibenzoyl-D-tartrate be dissolved in acetone (450ml) (85g, 236mmol).Be settled out solid, and the mixture that generates was at room temperature stirred 2 hours.Filter this solid, (2x100ml) washes with acetone, and vacuum-drying, obtains compd E 35 (43.8g).

Chirality HPLC: enantiomer 1/ enantiomer 2=7.5/90.9 area %

With the mother liquor vacuum concentration, and resistates is suspended among the DCM (700ml).

It is washed with saturated wet chemical/water 1: 1 (700ml).Water is stripped with DCM (2x500ml).With the organic phase drying (Na that collects ₂SO ₄), evaporation obtains remaining 6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane (25.6g).

Chirality HPLC: enantiomer 1/ enantiomer 2=54/35 area %

Step c)

In 1 hour; 6-(3 to the remnants that derive from step b) that are dissolved in acetone (125ml); the 4-dichlorophenyl)-and the 1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane (25.6g; drip 89mmol) dibenzoyl-L-tartrate be dissolved in acetone (250ml) (48.1g, 134mmol).Be settled out solid, and the mixture that generates was at room temperature stirred 2 hours.Filter this solid, (2x100ml) washes with acetone, and vacuum-drying, obtains compd E 34 (15g).

Chirality HPLC: enantiomer 1/ enantiomer 2=92.5/5.5 area %

With the mother liquor vacuum concentration, and resistates is suspended among the DCM (350ml).It is washed with saturated wet chemical/water 1: 1 (350ml).Water is stripped with DCM (2x300ml).With the organic phase drying (Na that collects ₂SO ₄), evaporation obtains remaining 6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane (18g).

Chirality HPLC: enantiomer 1/ enantiomer 2=37.7/49.7 area %

Step d)

In 45 minutes; 6-(3 to the remnants that derive from step c) that are dissolved in acetone (90ml); the 4-dichlorophenyl)-and the 1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane (18g; 62.89mmol) in drip the dibenzoyl-D-tartrate be dissolved in acetone (180ml) (33.8g, 94.33mmol).Be settled out solid, and the mixture that generates was at room temperature stirred 2 hours.Filter this solid, (2x80ml) washes with acetone, and vacuum-drying, obtains compd E 35 (11g).

Chirality HPLC: enantiomer 1/ enantiomer 2=14.5/84.5 area %

With the mother liquor vacuum concentration, and resistates is suspended among the DCM (500m1).

It is washed with saturated wet chemical/water 1: 1 (500ml).Water is stripped with DCM (2x300ml).With the organic phase drying (Na that collects ₂SO ₄), evaporation obtains remaining 6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane (12.6g).

Chirality HPLC: enantiomer 1/ enantiomer 2=49.2/31.2 area %

Step e)

In 1 hour; the 6-(3 of the remnants that derive from step d) in being dissolved in acetone (65ml); the 4-dichlorophenyl)-and the 1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane (12.6g; drip 44mmol) dibenzoyl-L-tartrate be dissolved in acetone (125ml) (23.66g, 66mmol).Be settled out solid, and the mixture that generates was at room temperature stirred 2 hours.Filter this solid, (2x100ml) washes with acetone, and vacuum-drying, obtains compd E 34 (3.1g).Productive rate 10.57%.

Chirality HPLC: enantiomer 1/ enantiomer 2=94.1/5.0 area %

Step f)

To derive from step a) (35.8g, 55.54mmol), step c) (15g, 23.27mmol), (2R of step e) (3.1g 4.8mmol), 3R)-2, two [(phenylcarbonyl group) oxygen base] Succinic Acid of 3--(1S, 6R)-6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-material (3.1g of 3-azabicyclo [4.1.0] heptane (E34) and another batch same quality, 4.8mmol) be suspended in the acetone (570ml), and be heated to backflow 30 minutes gradually.Mixture was at room temperature stirred 2 hours.Filter this solid, obtain the white solid of 47.25g.With this solid suspension in acetone (470ml), and reflux 30 minutes.This mixture was at room temperature stirred 2 hours.Filter this solid, obtain the white solid of 41.80g.With this solid suspension in acetone (420ml), and reflux 30 minutes.Mixture was at room temperature stirred 2 hours, filter this solid, obtain pure compd E 34 (38g), be white solid.

NMR( ¹H，MeOH-d ₄)：δppm?8.14(d，4H)，7.57-7.67(m，3H)，7.41-7.54(m，5H)，7.29-7.38(m，1H)，5.93(s，2H)，3.61-3.76(m，1H)，3.16-3.29(m，2H)，3.13(s，3H)，2.98-3.07(m，1H)，2.79-2.92(m，1H)，2.66-2.78(m，1H)，2.08-2.29(m，2H)，1.12-1.31(m，2H)

Chirality HPLC: enantiomer 1/ enantiomer 2=99/1 area %

Embodiment 36:(1S, 6R)-6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane succinate (monosuccinic acid salt) is (E36)

Under agitation, to 300.7mg (1S, 6R)-6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-add the Virahol (IPA) of 0.5mL in the succsinic acid of 3-azabicyclo [4.1.0] heptane (E2a) and 123.4mg.Add other 0.5mL Virahol, and use the air gun heating to help dissolving.Add other Virahol 2x0.5mL, 1mL, 0.5mL and 1mL are to obtain mobile slurry (obtaining total solvent volume is the IPA that 4.5mL adds).The slurry that generates was carried out temperature cycle three days between 0 to 40 ℃.Then with sample filtering, and with the solid title compound that obtains 70 ℃ of following vacuum-dryings 24 hours.

NMR ( ¹H, DMSO-d6): 7.67 (d, 1H), 7.59 (d, 1H), 7.36 (dd, 1H), 3.40 (d, 1H), 3.09 (d, 1H), 3.05 (s, 3H), 3.01 (m, 1H), 2.87 (d, 1H), 2.77-2.70 (m, 2H), 2.34 (s, 4H), 2.01 (m, 2H), 1.21 (m, 2H) [batch of material that use is similar to above-mentioned method acquisition carries out the NMR analysis]

Embodiment 37:(1S, 6R)-6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane phosphoric acid salt (monophosphate) is (E37)

Use 301.5mg (1S, 6R)-6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane (E2a, oily matter) and 0.2mL 5%w/w isopropanol water solution (the IPA aqueous solution) preparation solution.Under agitation, the phosphoric acid (aqueous solution of 5M) that in this solution, adds 209.6 microlitres.The solvent that adds other 0.1mL stirs simultaneously and obtains slurry.Adding 0.3mL also adds the solvent of 0.1mL then, obtains mobile slurry (total amount of the IPA aqueous solution of adding is 0.7mL).The slurry that generates was carried out temperature cycle 24 hours between 0 to 40 ℃.Filter this sample then, and with the solid title compound that obtains 70 ℃ of following vacuum-dryings 24 hours.

The analytical data of the following E37 that writes down is to use another batch compound to obtain.

NMR( ¹H，DMSO-d6)：7.63(d，1H)，7.56(d，1H)，7.36(dd，1H)，7.27(d，1H)，3.03(s，3H)，3.01(d，1H)，2.90(d，1H)，2.85(m，1H)，2.69(d，1H)，2.64(m，1H)，1.95(m，2H)，1.17(m，2H)

The diffractogram of 1 type of title compound E37 as shown in Figure 7.

The XRPD peak * of 1 type of the title compound of embodiment 37 (have 5% or bigger relative intensity) is shown in the following table 6 and (has write down XRPD angle and d spacing):

The DSC thermogram of 1 type of title compound E37 is shown among Fig. 8.

The beginning (E37,1 type) of fusion: 199 ℃ of (TA instrument Q1000 sequence number Q1000-0577.In having the aluminium dish that plays fold of pin hole lid with 10 ℃ of min ^-1Heated sample).

Decompose 1 type of title compound E37 fusion back, so the integration at the peak of different samples can produce different slightly initial, peak maximums and enthalpy.

Embodiment 38:(1S, 6R)-6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane trifluoroacetate (ion: counter ion are than uncertain) is (E38)

Steps A:

Will (1S, 6R)-6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptan-4-alkene-3-carboxylic acid 1, (P60 11g) is dissolved in the toluene (110mL) 1-dimethyl ethyl ester.(5.46ml, 34.17mmol), (14.81ml 199.3mmol) handles to use trifluoroacetic acid subsequently with triethyl-silicane with solution.This reaction mixture was at room temperature stirred 24 hours, stop with sodium hydroxide then, and stirred 10 minutes.The pH of mixture is approximately 13.Separate each phase, and, obtain buttery product intermediate, further come dry it by carrying out three azeotropic with toluene phase vacuum concentration.

Step B, method A:

The 3g material for preparing in the steps A is dissolved in the ethyl acetate, and adds heptane, become muddiness up to solution.Solution is heated until dissolving, and make its cooling then.Observe the formation crystallization.Filter this solid then, and reclaim the title compound that obtains 1g.

Step B, method B:

The 6g material for preparing in the steps A is dissolved in the 12mL ethyl acetate.(60mL) joins in this solution with heptane, and then two-phase mixture is heated to～70 ℃, obtain a single phase soln.In this solution, add other part heptane (60mL), and solution is heated to backflow (90 ℃).Under agitation solution is cooled to 67 ℃ then, under this temperature, uses according to step B, the title crystal that obtains before the method described in the method A is carried out seeding (seeded).Then solution is cooled to ambient temperature overnight.

The precipitation that will generate is filtered by vacuum filtration then, and washes with heptane (5mL).Obtain title compound (1.5g), it is crystalline solid (yield 25%)

NMR( ¹H，CDCl ₃)：δppm?1.23(dd，2H)2.16-2.25(m，1H)2.31-2.43(m，1H)2.84(d，J＝9.99Hz，1H)2.92-2.97(m，1H)3.15(s，3H)3.18-3.28(m，2H)3.76(d，J＝13.20Hz，1H)7.34-7.39(m，1H)7.40-7.43(m，1H)7.51(d，J＝1.96Hz，1H)9.65(s，1H)

The diffractogram of 1 type of title compound E38 is shown among Fig. 1.

The peak * of 1 type of the title compound of embodiment 38 is shown in down Table 1In (having write down XRPD angle and d spacing):

Table 1

* value shown here is rounded to 1 decimal place.Depend on the displacement of sample, this diffractogram can be offset to a little higher than or be lower than 2 θ values.

[X-ray powder diffraction (XRPD) is analyzed having on the PANalytical X ' Pert-Pro MPD of Johansson Ka1 monochromator and is carried out, and uses X ' Celerator detector.Testing conditions is as follows: radiation: Cu (Ka1), 1.540598 dusts (unicolor); Detector: X ' Celerator; Voltage: 45kV; Electric current: 40mA; Start angle: 2.0 ° of 2 θ; Termination point: 50.0 ° of 2 θ; Step-length: 0.02 °; Time/step: 40.0 seconds; Sweep velocity: 0.05 °/second; Incident beam: the divergent slit of 2 ° of fixed anti-scatter slits and program controlled; Diffracted beam: the anti-scatter slit of 0.02 radian soller slit and program controlled; Do not have in the background sampling receptacle at silicon and to prepare sample)].

In one embodiment, determined the unique and distinctive peak * of 1 type of the title compound of embodiment 38, and be shown in down Table 2In (having write down XRPD angle and d spacing):

Table 2

The beginning (E38,1 type) of fusion: 123.91 ℃ of (TA instrument model Q1000DSC; Dish: the aluminium dish of sealing; Purgative gas: N ₂, 50mL/min; Temperature range: 30-300 ℃, 15 ℃/minute).

The DSC thermogram of title compound 1 type of embodiment 38 is shown among Fig. 2.

Be to be understood that all combinations that the present invention includes concrete kind mentioned above.

Comprise that the application of specification sheets and claims can be used as the basis for priority of any subsequent application.Claims of described subsequent application can relate to any feature or the combination of features of describing among the present invention.They can be product, composition, method or purposes claim form, and can comprise following claims as an example, and are not limited only to this.

Claims

1. pharmaceutical composition, it comprises formula (A) ' compound or pharmaceutically acceptable salt thereof, solvate or prodrug and pharmaceutically acceptable carrier,

Wherein

R ₁Be hydrogen or C _1-4Alkyl;

R ₂Be group A, K or W;

Wherein

A is

With

W is

With, wherein

G is 5-or 6-unit's bicyclic heteroaryl or 8-to 11-unit heteroaryl bicyclic groups; This G can be by (R ₁₅) _pReplace R ₁₅Can be identical or different;

P is the integer of 0-5;

R ₅Be hydrogen or C _1-4Alkyl;

R ₇Be hydrogen or C _1-4Alkyl; Or be radicals X, X ₁, X ₂Or X ₃

Wherein

X is

X ₁For

X ₂For

With

X ₃For

R ₆Be hydrogen or C _1-4Alkyl; Or be radicals X or X ₁

R ₉Be C _1-4Alkyl;

R ₁₆Be hydrogen, C _1-4Alkyl, C _3-6Cycloalkyl or C _3-6Cycloalkyl C _1-3Alkyl;

R ₁₇Be hydrogen or C _1-4Alkyl;

R ₁₈Be selected from: halogen, cyano group, C _1-4Alkyl;

R ₁₉Be halo C _1-2Alkyl;

N is 1 or 2.

2. formula (I) ' compound or pharmaceutically acceptable salt thereof, solvate or prodrug,

Wherein

R ₁Be hydrogen or C _1-4Alkyl;

R ₂Be group A, K or W;

Wherein

A is

With

W is

With, wherein

P is the integer of 0-5;

R ₅Be hydrogen or C _1-4Alkyl;

R ₇Be hydrogen or C _1-4Alkyl; Or be radicals X, X ₁, X ₂Or X ₃

Wherein

X is

X ₁For

X ₂For

With

X ₃For

R ₆Be hydrogen or C _1-4Alkyl; Or be radicals X or X ₁

R ₉Be C _1-4Alkyl;

R ₁₇Be hydrogen or C _1-4Alkyl;

R ₁₈Be selected from: halogen, cyano group, C _1-4Alkyl;

R ₁₉Be halo C _1-2Alkyl;

N is 1 or 2;

Condition is:

3. according to the compound of claim 2, or its pharmacologically acceptable salt, solvate or prodrug, described compound is formula (IC) compound,

R wherein ₁, R ₂, R ₇And R ₁₇Suc as formula (I) ' in the compound define.

4. according to the compound of claim 2 or 3, or its pharmacologically acceptable salt, solvate or prodrug, described compound is formula (ID) compound,

R wherein ₂, R ₁₆With n suc as formula (I) ' in the compound define.

5. according to formula (ID) compound of claim 4, wherein n is 1.

6. according to the formula (I) of claim 2 " compound or pharmaceutically acceptable salt thereof, solvate or prodrug, the three-dimensional chemical isomer of described compound for having single absolute configuration 1 and 6 three-dimensional center,

R wherein ₁, R ₂, R ₃, R ₄, R ₅, R ₆, R ₇, R ₁₇As following formula (I) ' compound defines.

7. according to each formula (I) among the claim 2-6 ' compound, and pharmacologically acceptable salt, solvate or prodrug, described compound is selected from:

(1R, 6S/1S, 6R)-6-(3, the 4-dichlorophenyl)-3-azabicyclo [4.1.0] heptane;

(1R, 6S)-6-(3, the 4-dichlorophenyl)-3-azabicyclo [4.1.0] heptane;

(1S, 6R)-6-(3, the 4-dichlorophenyl)-3-azabicyclo [4.1.0] heptane;

(1R, 4S, 6S/1S, 4R, 6R)-6-(3, the 4-dichlorophenyl)-4-methyl isophthalic acid-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane;

(1S, 6R, 7R/1R, 6S, 7S)-and 6-(3, the 4-dichlorophenyl)-7-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane.

8. according to each formula (I) among the claim 2-7 ' compound, and pharmacologically acceptable salt, solvate or prodrug, described compound is selected from:

(1S, 6R)-6-(3, the 4-dichlorophenyl)-1-[(methoxyl group) methyl]-3-azabicyclo [4.1.0] heptane.

9. treatment wherein suppresses the method that serotonin (5-HT), Dopamine HCL (DA) and norepinephrine (NE) are useful illnesss, and described method comprises in the claim 2-8 of the Mammals that these needs are arranged (for example people) effective dosage each compound.

10. method according to claim 9, wherein the illness that will treat is a dysthymia disorders.

11. be used for the treatment of the purposes that suppresses in the Mammals in the medicine that serotonin (5-HT), Dopamine HCL (DA) and norepinephrine (NE) are useful illnesss in preparation according to each described compound among the claim 2-8.

12. purposes according to claim 11, wherein said illness is a dysthymia disorders.

13. according to each described compound among the claim 2-8, it is used for the treatment of.

14. according to each described compound among the claim 2-8, it is used for the treatment of and suppresses serotonin (5-HT), Dopamine HCL (DA) and norepinephrine (NE) in the Mammals is useful illness.

15. according to each described compound among the claim 2-8, it is used for the treatment of dysthymia disorders.

16. treatment wherein suppresses the method that serotonin (5-HT), Dopamine HCL (DA) and norepinephrine (NE) are useful illnesss, described method comprises formula (A) compound or pharmaceutically acceptable salt thereof, solvate or the prodrug to the claim 1 of the Mammals that these needs are arranged (for example people) effective dosage.

17. method according to claim 16, wherein the illness that will treat is a dysthymia disorders.

18. formula according to claim 1 (A) compound or pharmaceutically acceptable salt thereof, solvate or prodrug are used for the treatment of the purposes that suppresses in the Mammals in the medicine that serotonin (5-HT), Dopamine HCL (DA) and norepinephrine (NE) are useful illnesss in preparation.

19. purposes according to claim 18, wherein said illness is a dysthymia disorders.

20. formula according to claim 1 (A) compound or pharmaceutically acceptable salt thereof, solvate or prodrug, it is used for the treatment of and suppresses serotonin (5-HT), Dopamine HCL (DA) and norepinephrine (NE) in the Mammals is useful illness.

21. formula according to claim 1 (A) compound or pharmaceutically acceptable salt thereof, solvate or prodrug, it is used for the treatment of dysthymia disorders.

22. pharmaceutical composition, it comprises each described compound or pharmaceutically acceptable salt thereof, solvate or prodrug and pharmaceutically acceptable carrier among the claim 2-8.