TW201213305A - Azabicyclo octane derivatives, preparation process and pharmaceutical use thereof - Google Patents

Abstract

The present disclosure relates to azabicyclo octane derivatives, preparation processes and pharmaceutical compositions containing them. Specifically, the present disclosure relates to novel azabicyclo octane derivatives presented by formula (I), the uses for treatment especially for dopamine, norepinephrine and serotonin reuptake inhibitors, in which each substitute group of general formula (I) is as defined in the specification.

Description

201213305 VI. Description of the Invention: [Technical Field of the Invention] A novel azabicyclobutanin-like derivative represented by the general formula (1), a preparation method, and a pharmaceutical composition containing the same, and ',, the therapeutic agent is especially used as a dopamine, norepinephrine transaminant reuptake inhibitor. ', five search color [previous branch surgery] Sudden heart caused by various causes of depression as the main symptom - spoon _ bed symptom group or state, severe cases may appear illusion; = sacred disease = shape, anxiety in some cases The symptoms of exercise agitation are significant. Depression is mainly caused by depression, slow thinking, and decreased will activity. In most cases, there are various physical symptoms. The 6 anti-depressant drugs used in bed are mainly in the following categories: the third generation of classic antidepressants: including monoamine oxidase inhibitors (ΜΑ〇Ι), such as isopropyl hydrazine, acesulfame, etc., and tricyclics. Antidepressants (TCA) such as imipramine, amitriptyline, doxepin, imipramine and maprotiline. Second-generation new antidepressants: these drugs include selective serotonin reuptake inhibitors (SSRIs) 'Fluoxetine' paroxetine, Citalopram, Escitalopram, etc. Selective serotonin and norepinephrine dual reuptake inhibitors (SNRIs) , such as Venlafaxine 'Duloxetine (Duloxetine) and Desvenlafaxine, and penicillin and decalcified kidney receptors (NaSSA), such as rice Mirtazepine and so on. Although 4 95343 201213305 new drugs have developed rapidly, and the current antidepressants are still mainly selective pentosamine (5-HT) reuptake inhibitors, and the most widely used clinical drugs. Tricyclic antidepressants have the longest clinical application time and the most complete pharmacological studies. Although there are many antidepressant drugs currently used in clinical practice, there are almost no ideal drugs with satisfactory therapeutic effects. Generally, the clinical anti-repression effect is about 40% to 5%, and many antidepressants have Or more serious side effects such as sexual dysfunction, weight gain disorder and cardiovascular side effects. In addition, these antidepressant drugs, 疋SSRIS, exert a slower antidepressant effect, usually in 4 to 8 weeks = some serious side effects greatly affect the compound of depression patients Dopamine, norepinephrine and pentasamine reuptake inhibitors, based on serotonin and de-formulation, add polyadenosine to reabsorb the inhibitory function of the inhibitory system. On the basis of its purpose, H Yuan (10) or significantly improve the anti-(four) effect of the new compound, the most important concept of accelerating the time of action to make it more suitable for patients is to introduce it into new drugs. Xiba, such as reuptake inhibitory preparations in the field of antidepressant (4) and the depression drug Nolafensin (5) / have been determined by research. For example, anti-(Bupr〇pion)^;;(^;fenSine)^^^ bed anti-inhibition drug γ,; In Venlafaxine, 曱95343 5 201213305 Both venlafaxine and milnacipran have dual inhibitory effects on norepinephrine reuptake and serotonin reuptake system ( SNRIs), while the recently marketed drug Duloxetine is more active against these two resorption systems. Among these drugs that have dual inhibitory effects on norepinephrine reuptake and serotonin reuptake systems, Venlafaxine and Desvenlafaxine have better antidepressant effects, regardless of their strength. And the time of action is more obvious than other drugs. Clinical studies have shown that dopamine, penta-tryptamine and norepinephrine have varying degrees of functional loss in depression. In the human brain, serotonin is associated with mood, sleep, appetite, sexual function, pain, and learning and memory. 'Norepinephrine is associated with sleep regulation, body dynamics and alertness, and dopamine is associated with recognition, motor function, energy, and Addiction is related. Clinically, dopamine drugs have shown no significant effect in the treatment of depression. For example, the new generation of anti-schizophrenia drug Amisulpride has an ideal therapeutic effect in the clinical treatment of depression' and its It takes more time to work out than SSRIs and SNRIs. Amisulpride is a blocker of dopamine receptors and D3 receptors. Clinically, A misu 1 p H de has a therapeutic effect on depression and its blocking effect on D3 receptors. Thus increasing the release of dopamine 'increased synaptic dopamine concentration is closely related. Other dopamine antipsychotic t-drugs also have different effects on (4). Clinical use of new-generation anti-schizophrenia drugs ("General receptors and Η T 2 inhibitors" in combination with selective pentasamine reuptake inhibitors 6 95343 201213305 Anti-inhibition drugs, such as Symbyax [Olympic Nitrogen (01anzapine) / fluoxetine (Eli Lilly), treatment of bipolar depression showed successful outcomes. This combination of drugs not only increases the efficacy of the drug, but also speeds up the efficacy of the drug. And because of the relatively small dose, the side effects of the drug such as sexual dysfunction, nausea, and vomiting are significantly reduced. The clinically poor green society is fully slated. 'Dopamine plays an important role in depression. Adding dopamine to the drug molecule will be good for the treatment of depression. ..., greatly improved the comprehensive inhibition of SMUBS (Super mixed uptake blockers) on the single knee and the system, can not only ensure the antidepressant effect of selective serotonin resorbent, but also can add norepinephrine and more than 4 effects. The primary goal of combining three monoamine reuptake inhibitions in one compound is to increase the rate of drug treatment for depression.

Death and good deduction of the treatment of multiple symptoms of J depression, while greatly improving the side effects of dopamine, the addition of ingredients in the drug molecule can also improve the disease and dysfunction 'and thus reduce the lack of pleasure associated with depression (Anhe (^ 'The lack of lunar sensation is mainly related to the Limbic system. The system is related to 'enhancing this brain region's dopa neurotransmission, which will enhance the sense of pleasure. At the same time' enhance the dopaminergic neurotransmission in the frontal cortex of the brain. > Patients with memory loss in patients. °, the disease has now disclosed a series of patent applications for dopamine neurotransmitter uptake inhibitors, norepinephrine uptake inhibitors and / or serotonin uptake inhibitors 'such as W02008013856, W02008074716, W02008153937 and W02009141412. 95343 7 201213305 Although a series of dopamine reuptake inhibitors for the treatment of depression have been published, there is still a need to develop new treatments or palliatives that are better able to inhibit dopamine reuptake and can be used for depression or similar diseases. Drugs. After continuous efforts, the design of the present invention has the general formula (I The compound of the structure shown has a large structural difference from the compound specifically disclosed in the prior art, and exhibits excellent effects and effects. [Invention] In order to overcome the deficiencies of the prior art, it is an object of the present invention to provide Azabicyclooctane derivatives of the formula (I), and their tautomers, enantiomers, diastereomers, racemates and pharmaceutically acceptable salts, and metabolites and before metabolism Body or prodrug

(I) where:

Ar is selected from aryl or heteroaryl, wherein the aryl or heteroaryl is further optionally one or more selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, nitro, cyano, haloalkyl, hydroxyalkane. Alkyl, cycloalkyl, heterocyclyl, -OR7,-0-C(0)R7, -C(0)R7, -C(0)0R7, -S(0)0R7, -NR8R9 or -C(0 Substituting a group of NR8R9; R1 and R2 are each independently selected from the group consisting of an argon atom, an alkyl group, an alkenyl group, an alkynyl group, a halogen, a nitro group, a cyano group, a cycloalkyl group, a heterocyclic group, -or7, -oc (o) R7, -c(o)r7, -C(0)0R7, _S(0)0R7, -NR8R9 or -C(0)NR8R9, wherein the alkyl group, 8 95343 201213305 dilute, alkynyl 'cycloalkyl group Or a heterocyclic group may be further selected from one or more selected from the group consisting of an alkyl group, a sulfonyl group, a fluorenyl group, a cyano group, a cycloalkyl group, a heterocyclic group, a (10) 7, -0-C(0)R7, -C ( 0) R7, -C(〇)〇R7, _s(0)〇R7, _nr8r9 or

Substituting a group of -C_R8R9, or R>R2~ forming a double bond, provided that R1 and R2 are not simultaneously a hydrogen atom; X 1^4, 1^5 and 1^ are each independently selected from a hydrogen atom, producing a certain , Heterocyclyl, aryl, heteroaryl, -C(0)R7, fluorene, .LC()), R7 or -C(0)NR8R9, heterocyclic, aryl or heteroaryl If necessary -= one: multiple selected from the group consisting of alkyl, halogen, exact, gas, pro-, hetero-, k-, -0-C(0)R7 "c(9)R7 "c(〇)〇R7, _s - Substituted by a group of NR8R9 or -C(〇)NR8R9; :: from a broad atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, a cycloalkyl group, a heterocyclic group, an aryl group or The heteroaryl group is further substituted by one or more groups selected from the group consisting of a ring-shaped m-record, a dentate, a nitro group, a cyano group, a soil 8 '9 group, a aryl group or a heteroaryl group; Atom, an alkyl group, a dilute group, an alkynyl group, a cycloalkyl group, a yl group, wherein an anthracene group, an alkenyl group, a block group, a group selected from the group consisting of an alkyl group, and a "3 heteroaryl group" are further protected by one or more An aryl or heteroaryl group is substituted for a nitro chaotic group, a ring-based group, a heterocyclic group, and a second:::: phase-connected _-- Form a heterocyclic group, group, a is a prime, a nitro group or more groups selected from burning, the substituted group. A % alkyl, heterocyclic, aryl or heteroaryl 95343 9 201213305 A preferred embodiment of the invention, a compound of the formula (I) and its enantiomers, diastereomers or pharmaceutically acceptable Salt, where: '

Ar is selected from the group consisting of aryl' wherein the aryl group is further substituted with one or more bases selected from alkyl, halogen or -OR7, and R7 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, and a heterocyclic group. An aryl group, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of an alkyl group, a cycloalkyl group, a thiol group or a dentate Or replaced by a regiment. BEST MODE FOR CARRYING OUT THE INVENTION A compound represented by the formula (I), and an enantiomer, a diastereomer thereof or a pharmaceutically acceptable salt thereof, wherein:

Ar is selected from the group consisting of phenyl, wherein the phenyl group is further substituted with one or more groups selected from the group consisting of alkyl, halogen or -OR7; and R7 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, and a heterocyclic ring. a aryl group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is further optionally further selected from one or more selected from the group consisting of an alkyl group, a cycloalkyl group, a thiol group or a dentate group. Replaced by the Yi group. A preferred embodiment of the invention, a compound of the formula (I), and an enantiomer, a diastereomer thereof or a pharmaceutically acceptable salt thereof, wherein: ~ R1 is selected from a hydrogen atom, an alkyl group or a halogen; Selected from a hydrogen atom, an alkyl group, a halogen, -0R7 or -0~C(〇)r7, wherein the alkyl group is optionally substituted by one or more halogens; 'or, R1 and R2 together form a double bond' condition Wherein ri and r2 are hydrogen atoms from time to time; and the aryl or heteroaryl R7 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, 95343 10 201213305, wherein the alkyl group, the cycloalkyl group, the heterocyclic group The aryl or heteroaryl group is further substituted by one or more groups selected from an alkyl group, a cycloalkyl group, a hydroxyl group or a halogen, as needed. A preferred embodiment of the invention is a compound of the formula (I): an enantiomer, a diastereomer thereof or a pharmaceutically acceptable salt thereof, wherein:

Ar is selected from the group consisting of phenyl, wherein the stupid group is further substituted by one or more groups selected from an alkyl group or an iS element; R1 is selected from a hydrogen atom or a halogen; and R2 is selected from a hydrogen atom, an alkyl group, a halogen or -0R7, wherein the alkyl group is optionally substituted by one or more halogens; or, R1 and R2 together form a double bond, provided that R1 and R2 are not simultaneously a deuterium atom; R3, R4, R5 and R6 are each a hydrogen atom; R7 is selected from a hydrogen atom, an alkyl group or a cycloalkyl group, wherein the alkyl group or the cycloalkyl group is further substituted by one or more groups selected from the group consisting of an alkyl group, a cycloalkyl group, a trans group or a halogen, as needed. . A preferred embodiment of the invention is a compound of the formula (I): an enantiomer, a diastereomer thereof or a pharmaceutically acceptable salt thereof, wherein:

Ar is selected from phenyl, wherein the phenyl group is further substituted by one or more groups selected from an alkyl group or a halogen; R1 is selected from a hydrogen atom or a halogen; and R2 is selected from a hydrogen atom, an alkyl group, a halogen or - 0-C(0)R7, wherein the alkyl group is optionally substituted by one or more halogens; or, R1 and R2 together form a double bond, provided that R1 and R2 are different from 95343 to 201213305 as a hydrogen atom; R3, R4 And R 7 and R 6 are each independently a hydrogen atom; and R 7 is selected from an aryl or heteroaryl group, wherein the aryl or heteroaryl group is further further protected by one or more groups selected from an alkyl group, a cycloalkyl group, a hydroxyl group or a halogen. Replaced by the regiment. A preferred embodiment of the invention is a compound of the formula (I), and an enantiomer, a diastereomer thereof or a pharmaceutically acceptable salt thereof, wherein R3, R4, R5 and R6 are each independently selected from 1 atom. The compound of the formula (I) may contain at least 3 asymmetric carbon atoms and may therefore be a mixture of optically pure diastereomers, diastereomeric mixtures, diastereomeric racemates, diastereomeric racemates. The form exists or exists as a meso form compound. The invention includes all of these forms. The mixture of diastereomers, diastereomeric racemates or diastereomeric racemates can be isolated by conventional methods, for example by column chromatography, thin layer chromatography and HPLC. Typical compounds of the present invention include, but are not limited to: Compound No. Compound Structure and Nomenclature OH Η.Ά.Ο N Η 丄 (3af, 5 Friends, 551, 6a None)-3a-phenyl_2,3,4,5 ,6,6a-hexazacycloindole[c] ° than the mouth each -5-alcohol 2, / 0 η_Ά〇Ν Η 12 95343 201213305 (3af,5疋,69^5733)5, 55",63^0 -5-methoxy_3a_phenyl-2,3,4,5, 6, 6a-hexahydro-1 and-cyclopenta[〇]pyrene 3, 〇J η,Ά〇Ν Η (3&amp ;Friend,5)?,6aiS73ai9,55",68^)-5-ethoxy _3a-phenyl-2, 3, 4, 5, 6, 6a-hexahydro-1 and-cyclopenta[〇 > 比比4, 〇/ Η — α (3aA, 5 especially 6aiS73a5·, 55", 6a^〇-3a-(3, 4-diphenyl)-5-methoxy-2, 3, 4 , 5, 6, 6a-hexahydro-1 and -cyclopenta[c] ° ratio σ 5, ΟΗ K Cl (3aA, 5 especially GaiS/SaS, 551, 6a friend)-3a-(3, 4- Dichlorophenyl)-2,3,4,5, 6, 6a-hexa-argon-1 and -cyclopenta[c] 0 are compared to p--5-alcohol 6, OH Η.Ά〇~α Ν Η ( 3aA, 5Left, 551, 6a^〇-3a-(4-Phenylphenyl)-5-carbyl-2, 3, 4,5,6,6a-hexa-1, and -cycloindole[C] π ratio p is 7, OH H"rj"'〇-cl Η Cl (3aA, 551, 6a573a5·, 5 left, 6a friend)-3a-(3,4-dichlorophenyl)-2, 3, 4, 5, 6, 6a-hexahydro-1 and-cyclopenta [c] ° ratio 11 each 5-alcohol 13 95343 201213305 8, 9〆^ -------1 H Cl base)-5-decyloxy-2, 3, 4, 5, 6, 6a - hexahydro-if cyclopenta[c> than blowing 9, oJ - NH (3a^, 5^, 685/38^, 55, 6a^)-3a_(3 phenyl)-5-ethoxy-2 , 3, 4, 5, 6, 6a-hexahydrocyclopenta[c] ° ratio D 10, h"M"0~c, H (3ae,551, 6a573aiS,57?,6a/?)-3a -(3,l^^~~ base)-5-ethoxy-2,3,4,5, 6, 6a-hexahydrocyclopenta[c]e piroxime 11, y or NH (3a/ P, 5 left, 6357335^ 551, 6aA〇~5_(cyclopropylmethoxy)-3a-(3,4-dichlorophenyl)-2, 3, 4, 5, 6, 6a-hexahydro- 1 and -cyclopenta[c] ° ratio σ each 12' Η (3aiS, 551, 6a skin)-6a-(3, 4-dioxaphenyl)-5-methoxy-2, 3, 3a, 4, 5, 6-hexahydro-1 and-cyclopenta[c]pyrrole 14 95343 201213305 13, 〇/ NH (3af,6a«-6a-(3, 4-dichlorophenyl)-5-oxime Base-2,3,3a,4,5,6-hexanitro-1 and -cycloindolo[c]° piroxime 14, ?J α κ (3a5; 55; 6a)?)-6a-(3, 4-dichlorophenyl)-5- Ethoxy 2,3,3a, 4,5,6-hexanitro-1 and -cycloindole [c] ° are each 15 . Αα Η (3a7?, 5 feet 68«-6&-(3, 4-diphenyl)-5-ethoxy-2,3,3a, 4,5,6-hexanitro-1 and - 戍 戍 [c] ° ratio of each of the 16, y 〇Κ α benzoic acid [(SaA, 5 and, 551, 6a left) -3a-(3, 4-dichlorophenyl)-2, 3, 4, 5, 6, 6a-hexahydro-1 and -cyclopenta[(:]11 to 11-5-yl]esters 17' K3 K Cl thiophene-2-decanoic acid [(3a^ 5 especially 6a573a5; 55; 6aA) _3a-(3, 4-diphenyl)-2,3,4,5,6,6a-hexahydro-1 and-cyclopenta[<:]11 to 17-5- Ester 18' FW Cl 15 95343 201213305 (3a especially 551, 5 friends, 6ae)-3a-(3, 4-dichlorophenyl)-5-fluoro-2, 3, 4, 5, 6, 6a- Hexahydro-1 and -cyclopenta[c]n ratio 11 each 19' ΐ C, (3a left, 6a5/3avS, 6a/?)-3a-(3, 4-dichlorophenyl)-5-B Base-2, 3, 4, 5, 6, 6a-hexahydro-1 and -cyclopenta 20' W Cl (3a and 6a^〇-3a-(3, 4-dichlorophenyl)-5 -methylene-1,2,3,4, 6, 6a-hexahydrocyclopenta[C] ]° ratio 21, K Cl (3a·/?,6aA)_3a_(3, 4_dibenzene Base)_5_(2_sayethyl)_2,3,4,5,6,6a_hexanitro-1 and-cyclopenta[^7]11 are 22, K c丨 (3a: 6351/38 ^, 6a_A〇- 3a-(3,4-dichlorophenyl)-5-mercapto-2, 3, 4, 5, 6, 6a-hexahydro-1 and -cyclopenta[c]σ ratio 17 each 23, h„ LJ„,^a_ci N Cl (3a and, GavSTSaiS1, 6ae)-3a-(3,4-dichlorophenyl)_5,5-difluoro_1,2,3,4,6,6a-hexanitroso戍和[c]° ratio 16 95343 201213305 24, F h"合,Ό~*α H ci 一(3a 尤5尤6a573a5; 55; 6a«-3a-(3, 4-dichlorophenyl) -5-fluoro-2, 3, 4, 5, 6, 6a-hexahydro-1 and -cycloindole and each __ 25, M Cl (3a)?, 5 especially 6a573a5; 55; 6a7?)-3a- (3, 4-dichlorophenyl)-5-methyl-2, 3, 4, 5, 6, 6a-hexahydro-1 in cyclopenta _ 26' OH Η"Γ)"'Ό_α Η __ (3ae,5 especially 6a5")-6a_(3,4-dichlorophenyl)-5-carbyl-2,3,3a,4,5,6-hexahydro-1β-cyclopenta[clβ ratio 27, OH H^0~a Ν Η -----一(SaiS1,55",6a^〇-6a_(3,4-diphenyl)-5-radio-2, 3, 3a,4 , 5,6-hexahydro-1β-cyclopenta[c]° piroxime The invention relates to a compound of the formula (i), an enantiomer thereof, a diastereomer thereof or a pharmaceutically acceptable salt thereof, Wherein the compound of formula (I) is added in free or pharmaceutically acceptable acid In the form of, the acid addition salt includes a hydrochloride, a hydrobromide, a methanesulfonate, a sulfate, a phosphate, a fumarate, a maleate, a malate, a citrate, Acetate or trifluoroacetate, fumarate, tartrate or p-toluenesulfonate, preferably trifluoroacetate, fumarate, hydrochloride, p-toluenesulfonate, tartrate, phosphate , maleate and sulfonate. 17 95343 201213305 Typical compounds of the invention include, but are not limited to: Example number compound structure and nomenclature 1 OH η_Ά〇Ά〇η 0 (3aiP, 5 especially 6a573a5; 55; 6ai?)-3a-phenyl_2, 3 , 4,5,6,6a-hexanitro-1 and _cyclopenta[c]e are each 5-aminotrifluoroacetate 2 0〆η, Ά〇H ff"V0H ο (3a)?, 5 especially 6a573a5; 55; 6aA〇-5-methoxy-3a-phenyl-2, 3, 4, 5, 6, 6a-hexahydro-IF cyclopenta[c]pyrrole trifluoroacetate 3 〇J η,,Α"Ό ά〇η 0 (3af, 5 especially 5iS*, 6af)_5_ ethoxy_3a_phenyl-2, 3, 4, 5, 6, 6a-hexahydro-IF cyclopenta[c Pyrrole trifluoroacetate 4 〇 / η — C丨HCI (3ae, 5 feet 6853385, 551, 6a^〇-3a-(3, 4-dichlorophenyl)-5-methoxy-2, 3, 4, 5, 6, 6a-hexahydro-1F cyclopenta[C] ° ratio 17 hydrochloride 5 OH il F Cl FF~〇H 0 18 95343 201213305 (3aA*,5 especially 6a573a5",551, 6a ^)-3a-(3,4-dichlorophenyl)-2,3,4,5,6,6a-hexahydro-IFcyclopenta[c]pyrrole-5-ol trifluoroacetate 6 OH H 'y-》~~Cl H ff"V0H 0 (3ae,5 especially 55",6a^〇-3a-(4-chlorophenyl)-5-radio-2 , 3, 4, 5,6,6a-hexahydro-1 and-cyclopenta[c]pyrrole trifluoroacetate 7 OH H"only HF Cl ff-V0H o (3a^ 551, 6a573ai9, 5 feet 6a^ )-3a-(3,4-diphenyl)-2,3,4,5, 6, 6a-hexahydro-IFcyclopenta[c]pyridinium p--5-alcohol tri-acetate 8 W _c, HCI (3a^, 55*, 5 brother 6a^〇-3a-(3, 4-diphenyl)-5-decyloxy-2, 3, 4, 5, 6, 6a-hexahydrogen -1#·cyclopenta[c] ° ratio p hydrochloride 9 Ν H HCI (3aA*, 5 especially 685738^, 551, 6aA〇-3a-(3, 4-dichlorophenyl)-5- Ethoxy-2,3,4,5, 6, 6a-hexahydro-1^-cyclopenta[c]π ratio 17 hydrochlorides 19 95343 201213305

10 Cl NH HCI (3a friend, 55", 6a573a5", 5 skin, 6aA〇-3a-(3, 4-dichlorophenyl)-5-ethoxy-2, 3, 4, 5, 6, 6a - hexahydro-H cyclopenta[c]pyrrole hydrochloride 11 J α 9 HCI (3a^ 5)?,6a573a5; 55; 6a^?)-5-(cyclopropylmethoxy)-3a-( 3,4-dichlorophenyl)-2,3,4,5, 6, 6a-hexahydro-1 and-cyclopenta[[> pyrryl hydrochloride 12 Η HCI (3a5; 55; 6a friend )-6a-(3,4-diphenyl)-5-methoxy-2,3,3a,4,5,6-hexahydro-IFcyclopenta[c] 0 to p each hydrochloride 〇 / 13 Ν Η HCI (3a7?, 5 brother 6350-63-(3, 4-dichlorophenyl)-5-methoxy-2, 3, 3a, 4, 5, 6-hexahydro-1) 7-cyclopenta[c]pyrrole hydrochloride 14 Ν HCI 20 95343 201213305 (3a5; 55; 6a7?)-6a-(3, 4-diphenyl)-5-ethoxy-2, 3, 3a,4,5,6-hexahydro-1 and -cyclopenta[c] ° ratio p hydrochloride 15 Η HCI (3a^, 5 friends, 69^)-63^-(3, 4_two Gas phenyl)_5_ethoxy-2,3,3a,4,5,6-hexahydro-1Fcyclopenta[c] 0 to p each hydrochloride 16 :>-〇h"H"'0 ~ci K HC, Cl benzoic acid [(3a7?, 5 especially 55*, 6ae) -3a-(3, 4-diphenyl)-2,3,4,5, 6, 6a-hexanitro-1 and-cyclopenta->]pyrrole-5-yl]ester hydrochloride 17 h.,^..,<Qkci N Cl π HCI thiophene-2-decanoic acid [( 3a7?,5 especially 6a573a5; 55; 6a« _3a-(3, 4-diphenyl)-2,3,4,5,6,6a-hexahydro-1 and-cyclopenta[<^] 11 to 17-5-base] vinegar hydrochloride F h„^.„<Q^ci M ci 18 Η Η〇^γΟΗ 0 (38 feet 55<,63573351,5^>,6&^&gt ;)-3&-(3,4-dichlorophenyl)_5_fluoro-2,3,4,5,6,6a-hexachloro-1 and-cyclopenta[c]βpyrrolic acid Salt 21 95343 201213305 h_点..Ό~α Ν Cl 19 Η ηο^Υ〇η 0 (3a^ 6a_/P)-3a_(3,4-dichlorophenyl)-5-ethyl-2, 3, 4, 5, 6, 6a-hexahydro-1 minute-cyclopenta[C]pyrrole fumarate N Cl 20 π Η〇^γΟΗ 0 (3ay?,6a573a5",63 friends))_38_(3,4 -dichlorophenyl)-5-methylene-1,2,3,4,6,6a-hexahydrocyclopenta[C]]π ratio 11 fumarate ϋ ci 21 ΗΟ^γΟΗ 0 ( 3a^,6a^/?))-3a-(3,4-diphenyl)-5-(2-fluoroethyl)-2, 3, 4, 5, 6, 6a-hexahydro-1 and -cyclopenta[c]pyrrole fumarate M ci 22 Η ηο^Υ〇η 0 (33·^,6a^〇)_3a-(3, 4-Dichlorophenyl)-5-methyl_2,3,4,5,6,6a-hexanitro-1·^cyclopenta[C] ° ratio π each fumarate 23 H Cl Η ( Λ^Υ〇η 0 22 95343 201213305 (3a·/?,635733^, 6a^〇)_3a_(3,4-dichlorophenyl)-5,5-diqi-1,2,3, 4,6 ,6a-hexahydrocyclopenta[C]pyrrole fumarate 24 F Η"Η·"0~α K Cl HO and ^0H Ο (3ae,5 friends,6857385·,551,6a and)-3a -(3, 4-diphenyl)-5-follow-2,3,4,5,6,6a-hexanitro-1 and-cycloindolo[C]pyrrole fumarate 25 〇/ Η„ ώ, „^~λ_α W Cl ΗΟ^γΟΗ Ο (3aA*, 5 friends, 6a573aiS, 5iS, 6aA〇_3a_(3,4-dichlorophenyl)-5-decyloxy-2, 3, 4, 5, 6, 6a-hexahydro-1 and-cyclopenta[c]pyrrole fumarate 26 〇/ W Cl HO.XX 0' ο (3a)?,5 especially 6a573a5; 56; 6ai?)-3a -(3,4-dichlorophenyl)-5-decyloxy-2, 3, 4, 5, 6, 6a-hexahydro-lf cyclopenta[c]pyrrole p-toluenesulfonate 27 〇/ H"_C| K Cl h3po4 (3ae, 5 feet 6a573a5",551,6aA〇-3a-(3,4-dichlorophenyl)-5-decyloxy-2, 3, 4, 5, 6, 6a - hexahydro-1 and -cyclopenta[c]11 ratio p per acid salt 23 95343 201213305 / N Cl 28 H HO 入 =^OH (3a^ 5 brother 551, 6aA〇-3a-(3, 4-dichlorophenyl)-5-methoxy-2, 3, 4, 5, 6, 6a - hexahydro-1τ7-cyclopenta[c]pyrrole maleate W Cl 29 0 OH h〇W〇H OH 0 (3a^ 5 feet 55",68^-38-(3,4-dichlorobenzene 5-)-5-methoxy-2,3,4,5, 6, 6a-hexahydro-1 and-cyclopenta[c]pyrrole L-(〇-tartrate N Cl 30 0 OH h〇WH OH 0 (3af,5 especially 6537385",551,6ae)-3a-(3,4-dichlorophenyl)-5-decyloxy-2, 3, 4, 5, 6, 6a-hexahydro-1# · Cyclopenta[c]pyrrole D-(-)-tartrate 〇〆M ci 31 Η °,w〇/S,OH (3ae,5 brother 551, 6ae)-3a-(3,4-dichlorobenzene 5-)-5-methoxy-2, 3, 4, 5, 6, 6a-hexahydro-1F cyclopenta[c]pyrrolesulfonate 24 95343 201213305 32 Η,ώ.,Ο^α Η Cl ΗοΛ^γΟΗ 0 (3a brother 5 especially 6a573aiS, 551, 6a^〇-3a-(3, 4-diphenyl)-5-methyl-2, 3, 4, 5, 6, 6a-hexahydrogen -1 and -cyclopenta[c]吼p each fumarate 33 OH N Η HCI (3a especially 5 brother 6a«-6a-(3, 4-diphenyl)-5-hydroxy-2, 3 , 3a,4,5,6-hexahydro-1 and-cyclopenta[c]indole hydrochloride 34 ?H c, N Η HCI (3aiS, 55&quo t;, 6a left) _6a_(3,4_dichlorophenyl)_5_transyl-2,3,3a, 4,5,6-hexahydro-1 in the ring 戍[¢7]0 to 11 each Hydrochloride OH Ν 35 Η 0 0 ΗΟ^^ΟΗ (3a5; 551, 6af)-6a-(3, 4-dichlorophenyl)-5-hydroxy-2, 3, 3a, 4, 5, 6- Hexahydro-1 and-cyclopenta[c]-port pyrrole maleate 36 OH Ν Η 〇〇Η H〇VSr〇H OH 0 25 95343 201213305 (3a6; 55; 6a^〇-6a-(3, 4-dichlorophenyl)-5-hydroxy-2,3,3a,4,5,6-hexahydro-1 and-cyclopenta[c]»pyrrole L-(-)-tartrate OH 37 Η H2so4 (3a5; 55; 6a^〇-6a-(3, 4-diphenyl)-5-hydroxy-2,3,3a,4,5,6-hexahydro-1 and-cyclopenta[c ]pyrrole sulfate 38 OH N Ho ο (3aiS,55",6aA〇_6a_(3,4-dichlorophenyl)_5_radio-2,3,3a,4,5,6-hexanitro-1 #_环戍和[c]0比罗 fumarate 39 〇/ H〇Cl HO person,Υ〇Η 0 (3a especially 5 especially 6&Λ-3η-(3, 4-dichlorophenyl)- 5-decyloxy-2, 3, 4, 5, 6, 6a-hexahydro-1#-cyclopenta[c] °pyrluminate 40 Η 〇Cl HO human^VH Ο (3a5; 55 ; 6ay?)-3a-(3,4-dichlorophenyl)-5-decyloxy-2, 3, 4, 5, 6, 6a-six -1 - cyclopenta[c] ° pyrol fumarate The present invention relates to the preparation of a compound of the formula (i) of the present invention and 26 95343 201213305 its enantiomer, diastereomer or its pharmaceutically acceptable substance a method of using a salt, the method comprising:

The compound of the formula (IA) is converted into the compound of the formula (I); preferably, the carbonyl group of the compound (IA) can be reduced to a hydroxyl group by a reducing agent such as sodium borohydride, and the hydroxyl group is further converted to -OR7, if necessary. Deprotecting the group PG to obtain a compound of the formula (I); or, the carbonyl group of the compound (IA) can be reduced to a hydroxyl group by a reducing agent such as sodium borohydride, the hydroxyl group is further converted into a dentate, and the protecting group PG is removed. a compound of the formula (I); & or, a compound of the compound (ΙΑ) is further converted to an alkenyl group, an alkyl group, an alkynyl group, a nitro group, a cyano group, a cycloalkyl group, a heterocyclic group, or a fluorenyl group. R7, -C(0)0R7, -S(0)0R7, -NR8R9 or -C(0)NR8R9, deprotecting group pG, to give a compound of formula (I); wherein: PG is a protecting group for N , preferably -c(〇)R7, _c(〇)〇R7 or -c(o)nr8r9;

Ar, R3 to R9 are as defined in the formula (I). Another aspect of the invention relates to a compound of the formula (IA) or a pharmaceutically acceptable salt thereof, 95343 27 201213305 Ο

PG wherein: PG is a protecting group for N' is preferably -C(0)R7, -C(〇)〇R7 or -C(0)NR8R9;

Ar is selected from a aryl or heteroaryl group wherein the aryl or heteroaryl group is further further selected from one or more selected from the group consisting of an alkyl group, a thiol group, a aryl group, a dentate group, a nitro group, a cyano group, and a functional group. , a hydroxyl group, a cycloalkyl group, a heterocyclic group, -0-C(0)R7, _C(0)R, -C(0)〇R7, -S(〇)〇R7, _nr8r9 bite-C( 0) Substituted by a group of NR8R9; R, R, R and R are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, a hetero group, a heteroaryl group, -C(0)R7, -C (〇)〇R7 4_c(〇)NR8R9, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl step is selected from one or more selected from the group consisting of silk, halogen, thio, cyano, and a heterocyclic group, -OR7, "(W, _c(9)r7, _c(8)(10)7, _s(〇)〇R7, -NR8R9 or -c(o)nr8r9 is substituted; R is selected from n atom, silk, ring county, miscellaneous A cyclyl, aryl or heteroalkyl group, a fluorenyl group, a thiol group, a heterocyclic group, an aryl group or a group of one or more selected from the group consisting of an alkyl group, a thiol group, a cycloalkyl group, a heterocyclic group, and a sulfonium group. 4 a group of a murine group, a D9 group or a heteroaryl group; each independently selected from a hydrogen atom, an alkyl group, an alkyl group, a heterocyclic group, a aryl group thereof, a cyano group, a cyclo- or heteroaryl group, wherein the alkyl, alkenyl, 95343 28 201213305 cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally selected from the group consisting of alkyl, hydroxy, halogen, nitro Substituted by a group of a cyano group, a phenyl group or a polyaryl group or a heteroaryl group; a ring, a heterocyclic group, a hetero ring group selected from an alkylaryl group or a heterocyclic group, a hydroxyl group, an aryl group Or a heterocyclic group in which R8 and R9 are substituted with a selected N atom, and the heterocyclic group is further substituted by one or more of four, nitro, cyano, cycloalkyl, heterocyclic, or a group. (d) Difficult (four), - (iv) enantiomers of formula (10), diastereomers or pharmaceutically acceptable salts thereof, straight, broad compounds and selected from hydrogen atoms. /, a preferred embodiment of the invention, a formula (IA) an enantiomer, a diastereomer or a pharmaceutically acceptable salt thereof, wherein:

Ar is selected from the group consisting of aryl, wherein the aryl group is optionally substituted with a group selected from an alkyl group, a halogen or -OR7; and one or more R7 are selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, -, base 'where the county, ring county, heterocyclic group, aryl group or ^ or heteroaryl is further substituted by one or more selected from the group consisting of an alkyl group and a ring. a basic hair- or a pharmaceutically acceptable salt of the formula (IA), wherein: σ is a phenyl group selected from the group consisting of a phenyl group and a pharmaceutically acceptable salt. Wherein the phenyl group is optionally substituted with a group selected from the group consisting of a radical, a money or a -(10); or a fragment or a plurality of R is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, *Alkyl, aryl or heteroaryl wherein the alkyl, cycloalkyl, heterocyclyl, aryl + & aryl or heteroaryl is as desired 95343 29 201213305 further selected from one or more selected from alkyl, Substituted by a cycloalkyl, hydroxy or halogen group. Another aspect of the invention relates to a process for the preparation of a compound of the formula (IA), an enantiomer thereof, a diastereomer or a pharmaceutically acceptable salt thereof, the method comprising:

PG (old) The compound of the formula (IB) is reacted with Ar-Li or Ar-MgBr under the conditions of a catalyst such as cuprous iodide to obtain a compound of the formula (IA); wherein: PG is a protecting group for N , preferably -C(0)R7, -C(0)0R7 or -C(0)NR8R9; R3, R4, R5 and R6 are a hydrogen atom;

Ar, R7 to R9 are as defined in the compounds of formula (I). Another aspect of the invention relates to the use of a compound of the formula (I) according to the invention and its enantiomers, diastereomers or pharmaceutically acceptable salts thereof for the preparation of dopamine, norepinephrine and serotonin reuptake inhibitors . Another aspect of the invention relates to a method of inhibiting reuptake of dopamine, norepinephrine and serotonin comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I) and its enantiomers, diastereomers Or a pharmaceutically acceptable salt thereof. Another aspect of the present invention relates to the compound 30 95343 201213305 represented by the formula (I) of the present invention, and an enantiomer, a diastereomer thereof or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for treating depression or anxiety disorder the use of. Another aspect of the present invention relates to a compound of the formula (I) of the present invention, and an enantiomer, a diastereomer thereof or a pharmaceutically acceptable salt thereof, as a medicament for treating depression or anxiety disorder. Further, another aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention and an enantiomer, diastereomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or agent thereof Shape agent. The use of the pharmaceutical composition for the preparation of dopamine, norepinephrine and serotonin reuptake inhibitors. Use of the pharmaceutical composition for the manufacture of a medicament for the treatment of depression or anxiety disorder. Another aspect of the invention relates to a method of inhibiting dopamine neurotransmitter uptake, norepinephrine uptake and/or serotonin uptake, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I) or A pharmaceutical composition of a pharmaceutically acceptable salt. Another aspect of the invention relates to a pharmaceutical composition comprising a compound of the formula (I) according to the invention, and an enantiomer, diastereomer thereof or a pharmaceutically acceptable salt thereof, for inhibiting dopamine, norepinephrine and serotonin reuptake Drug. The compounds of the present invention and their pharmaceutically acceptable salts can be administered orally, dermally or parenterally (e.g., by injection, inhalation, spray, sublingual, rectal or vaginal). "Injectable administration" includes intravenous injection, joint injection, intramuscular injection, subcutaneous injection, parenteral injection, and infusion. Dermal administration includes topical or cross-administration. Oral administration is carried out according to methods well known to those skilled in the art, and there may be one or more adjuvants such as diluents, 31 95343 201213305 sweeteners, flavoring agents, colorants and preservatives. The amount of the pharmaceutically active compound in each case should be in the range of from 1 to 90% by weight of the total composition, preferably from 0.5 to 5 G by weight, i.e., sufficient to achieve the metering range provided below. If necessary, multiple specified doses can be provided daily. In tablets, the active ingredient is mixed with non-toxic, pharmaceutically acceptable excipients. These excipients include: inert diluents (such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate), granulation or disintegrants (such as corn starch, alginic acid) and binders (such as stearic acid, The stearic acid and talc tablets may be uncoated, and may be coated by a known method to alleviate the decomposition and absorption in the gastrointestinal tract to prolong the efficacy, such as glyceryl stearate or glyceryl distearate. These compounds can also be prepared in a solid, rapid release mode. θ In hard capsules, the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or china clay; in soft capsules, the active ingredient and water or oil The vehicle is mixed with peanut oil, paraffin wax or olive oil. In the aqueous suspension, the active ingredient is mixed with a pharmaceutically acceptable excipient. These excipients are suspending agents (such as hydroxy strontium cellulose sodium, methyl cellulose). , hydroxypropyl-mercapto cellulose, sodium alginate, polyvinylpyrrolidone, gum arabic), dispersing agents or wetting agents [including naturally occurring rouge (such as imprinted fat) or alkyl oxides and fatty acids Condensation (such as polyoxyethylene stearic acid vinegar) or a condensation product of ethyl oxide and long-chain fatty alcohol (such as hepta-hexaethoxyhexadecanol) or ethyl ether and derived from fatty acids and hexitols a partial ester condensate (such as polyethylene sorbitan monooleate)]. The aqueous suspension may also mean one or more preservatives (eg, hydroxybenzoic acid ethyl acetate, propyl paraben) One or more colorants; one or more fragrances 95343 32 201213305 and one or more sweeteners (such as sucrose or saccharin). Dispersible powders or granules suitable for the preparation of aqueous suspensions by means of water, active ingredients Prepared by mixing with a dispersing or wetting agent, a suspending agent and one or more preservatives. Other excipients such as sweeteners, colorants or fragrances may also be added thereto. Including the active ingredient substance of the present invention or a composition thereof The syrup may additionally include a sweetener such as saccharin, sweetener, glycerin or sugar, and a flavoring agent, for example, a sweetener such as a vanilla or orange extract. Further, it may also include a suspending aid or a thickening agent (e.g., Hydroxymethyl fiber Sodium), a humectant (such as a condensation product of a fatty alcohol with ethylene oxide) or a preservative (such as p-hydroxybenzoate). The injection or infusion solution is prepared in a conventional manner, for example, by adding an isotonicity agent, A preservative (such as p-hydroxybenzoate) or a stabilizer (such as an alkali metal salt of ethylenediaminetetraacetic acid), if necessary, an emulsifier and/or a dispersant, and when water is used as a diluent, The organic solvent is used as a dissolving or cosolvent and transferred to an injection vial or vial or vial. Suitable suppositories are, for example, admixed with a carrier for this purpose, such as a neutral or polyethylene glycol or a derivative thereof. Suitable excipients can be, for example, water, in pharmaceutically acceptable organic solvents (such as sarcophagus, for example, petroleum fractions), vegetable derived oils (for example, peanut oil or sesame oil), mono- or polyfunctional alcohols (eg, ethanol). Or glycerol), carriers [such as natural mineral powders (eg, kaolin, clay, talc), synthetic mineral powders (eg, highly dispersible ceria and citrate), sugars (eg, raw sugar, lactose, and grapes) ), emulsifiers (eg, lignin, sulphite waste, sulfhydryl cellulose, starch, and polyvinylpyrrolidone) and lubricants (eg, magnesium stearate, 33 95343 201213305 talc, stearic acid, and lauryl) Sodium sulfate). The preparation may be administered in a usual manner, preferably by oral or dermal route, preferably orally. In the case of oral administration, the tablet may of course include additives (such as sodium citrate, calcium carbonate and dicalcium phosphate) and other additives (such as starch, preferably mash potato starch, gelatin and the like) in addition to the above-mentioned carriers. ). It is also possible to use a lubricant to form tablets such as magnesium fatty acid, sodium lauryl sulfate and talc. In the case of an aqueous suspension, the active substance may be mixed with various flavoring agents or coloring agents in addition to the above-mentioned excipients. For the active substance solution for parenteral use, a suitable liquid carrier material can be used. The intravenous injection dose is from 1 to 1000 mg per hour, preferably from 5 to 500 mg per hour. However, it may be desirable to deviate from the above dosages depending on the weight or method of administration, the individual's response to the drug, the nature of the formulation used, and the time or interval of administration. Therefore, it may be sufficient in some cases to use a minimum dose less than the above specified, but in other cases the specified upper limit must be exceeded. When administered in large doses, it is recommended to divide it into a single dose several times a day. Of course, as is well known to those skilled in the art, the dosage of the drug to be administered depends on a variety of factors including, but not limited to, the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, and the patient's behavior. The dosage of the patient, the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment mode such as the mode of treatment, the daily dose of the compound of formula (I) or pharmaceutically acceptable The type of salt can be verified according to traditional treatment options. 34 95343 201213305 DETAILED DESCRIPTION OF THE INVENTION Unless otherwise stated, the terms used in the specification and claims have the following meanings. "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups of from 1 to 20 carbon atoms. It preferably contains an alkyl group of from 12 to 12 carbon atoms, non-limiting examples include sulfhydryl groups, Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, anthracene, dimercaptopropyl, 1,2-dimercaptopropyl , 2, 2-dimethylpropyl, 丨-ethylpropyl, 2-nonylbutyl, 3-mercaptobutyl, n-hexyl, i-ethyl-2-indodopropyl, M 2_ three Mercaptopropyl, 1,1-didecylbutyl, L 2-dimethylbutyl, 2,2-didecylbutyl, 1,3-didecylbutyl, 2-ethylbutyl , 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimercaptobutyl, n-heptyl, 2-decylhexyl, 3-decylhexyl, 4-anthracene Hexyl, 5-methylhexyl, 2,3-dimercaptopentyl, 2,4-dimercaptopentyl, 2,2-dimethylpentyl, 3,3-didecylpentyl, 2 -ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-didecylhexyl, 2,2-diindole Hexyl group, 3, 3-dimercaptohexyl, 4, 4-dimethyl Hexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ylethylpentyl, n-decyl, 2- Mercapto-2-ethylhexyl, 2-methylethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and Various branched isomers, etc. More preferred are lower alkyl groups containing from i to 6 %i atoms, non-limiting examples including deuterated, ethestyl, isopropyl, n-butyl, isobutyl Base, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimercaptopropyl, 2,2-didecyl 95343 35 201213305 propyl, 1- Ethylpropyl, 2-mercaptobutyl, 3-methylbutyl, n-hexyl, ethyl-2-mercaptopropyl, 1,1,2-trimethylpropyl, monodecylbutyl 1,2-dimercaptobutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-mercaptopentyl, 3-methylpentyl a group, 4-methylindenyl, 2 dimercaptobutyl, etc. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment. Preferably, one or more of the following groups are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, thiol, alkyl, thiol, thiol, thiol, thiol, aryl , cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkyloxy, cycloalkylthio, heterocyclic thio, alkyl, _〇_C(〇 R7, -C(0)R7, -C(0)0R7, -S(0)〇R7, -NR8R9 or -c(〇)NR8R9. Dilute refers to at least two carbon atoms and at least one carbon-carbon An alkyl group as defined above consisting of a double bond. For example, a vinyl group, a propenyl group, a 2-propenyl group, a 1-, 2- or 3-butenyl group or the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, thiol, hydroxy, nitro, decyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, carbonyl, -OR7, -0-C(0)R7, ~c(〇)R7, _c(〇)〇r7, _s(〇)〇r7, -NR8R9 or -C(0)NR8R9 . An alkynyl group having at least two carbon atoms and at least one carbon-carbon triple bond as defined above. For example, ethynyl, propynyl, 2-propynyl, di, 2- or 3-butynyl The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from 36 95343 201213305 self-burning, dilute, block, or pendant , sulfur-based, alkylamino, halogen, =, thiol, nitro, cyano, cyclo, heterocyclic, aryl, heteroaryl, oxy, heterocyclic, thiol, Heteroweithiol, a few groups, HQ__R7, _c(q)r7, _c(9)(10)

-NRY or ,) nr8r9. (10)) 〇R, cycloalkyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic cigarette substituent which includes 3 to 2 carbon atoms, preferably 3 to 1 broken atoms, more preferably The cycloalkyl ring contains 3 to 1 carbon atoms. The monocyclic cycloalkyl group is not a qualitative example comprising a cyclopropyl group, a cycloalkyl group, a cyclofilament, a cyclopentyl group, a 2 hexane, a cyclohexyl group, Cyclohexadienyl, cycloheptyl, cycloheptatrienyl, octyl-based J-ring alkyl groups include spiro rings, fused rings, and ring-and-loop groups. "Spiral ring base" refers to 5 to 20 members. a single polycyclic group sharing a carbon earth atom (called a spiro atom) between the single rings, which may contain one or more double bonds 'but no-rings have a completely common π-electron system. Preferably ^ 6 to 14 members' is more preferably 7 to 7. According to the number of common snail atoms between the ring and the ring, the snail group is divided into a single snail group, a Wei group or a polyspiro group (4) as a single snail group and a (four) ring. More preferably 4 to 4 members, 4 members / 5 members, 4 members / 6 members, 5 members / 5 members or 5 members / 6 members of the single screw jade * base. Sexual instance contains

A fused ring, meaning 5 to 20 members, each ring in the system shares an all-carbon polycyclic group of a pair of carbon atoms adjacent to the other rings in the system, wherein 201213305 one or more rings may contain ~ One or more double bonds have a fully conjugated 7-inch electronic system. It is preferably 6 ' but no one is 7 to 10 members. Depending on the number of constituent rings, it may be from 8 to 14 members, more preferably a polycyclic fused cycloalkyl group, preferably a bicyclic ring or a tricyclic ring, a tricyclic ring, a tetracyclic ring or a 5-membered/6 membered bicyclic alkyl group. The feed ring is preferably 5 members/5 members & ^ 邛 restrictive examples include

It is intended that the two rings share two non-bridged cycloalkyl groups, which means 5 to 2 employees, and the directly connected carbon is good for all carbonous towns, but no one ring is finished. Or preferably 6 to U members, more preferably 7 to 1 (^ er π electronic system. Can be divided into double ring, three ring, four ring ring; ^ number of rings composed of three rings or four rings, more Selected as bis, alkyl, preferably bicyclic, example inclusion, clothing. Bridged cycloalkyl non-limiting

The cycloalkyl ring may be slightly bonded to the parent structure: the ring example includes indane, tetragas, and the ring is a cycloalkyl group, and is not limited to the benzene which is optionally substituted. And scales. The cyclodextrin can be di-, when substituted, the substituent is preferably 95433 38 201213305 is one or more of the following groups 'independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, dentate, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Base, heterocycloalkylthio, carbonyl, -OR7, -〇-C(0)R7, -C(0)R7, _C(0)0R7, -S(0)〇R7, -NR8R9 or -C(〇 ) NR8R9. "Heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent which includes from 3 to 20 ring atoms wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(0)m (wherein m is a hetero atom of integer 〇 to 2), but does not include a ring moiety of -0-0-, -Ο-s- or -SS-, and the remaining ring atoms are carbon. It preferably includes 3 to 12 ring atoms, Wherein 1 to 4 are heteroatoms, more preferably the cycloalkyl ring contains 3 to 10 ring atoms. Non-limiting examples of monocyclic cycloalkyl groups include a transalkyl group, a brittle base, a methyl group, a morphyl group, Thioprine, high thiol, etc. Polycyclic bases include spiro, fused ring and bridge "spiroheterocyclyl, which refers to 5 to 20 members, sharing a single atom between single rings (called a spiro atom) a polycyclic heterocyclic group, wherein one ', or so))» (wherein m is an integer G to an atom selected from nitrogen, oxyribol), and the remaining ring atoms are two = ". Preferably 6 to 14 members, more two single snails ====number of atoms, the spiro group is divided into a base and a double snail i burned 0' more spiro heterocyclic group' is preferably a single spirometry example 1 member or 5-member/6-membered single-spindle base. Non-restricted spiral ring base 95343 39 2 01213305 .ib t

s 0—and

"A fused heterocyclic group is 5 to 20 members, each ring in the system shares a contiguous relationship with other rings in the system - a polycyclic heterocyclic group to an atom, and one or more rings may contain one or more A biguanide, but not a hetero atom with a fully conjugated 7-inch electronic system in which one or more ring atoms are selected from nitrogen, oxygen or S0))P (where P is an integer from 0 to 2), the remainder The ring atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into material, three-ring, four-ring ring, ring-shaped ring wire, and more or less Preferred is a 5-member/5 or 5-member/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused bases include

〇-

N

9

彳口 0 0 “Bridge heterocyclyl” means 5 to! 4 members, a polycyclic heterocyclic group of any two ring-bonded atoms, these may contain one: no / bond, but none - a ring has a completely recorded hetero atom of τ ^ 固 solid, the remaining ring atoms For carbon. Preferably 6 to 7 to 10 members. 7 to 丨. member. According to the number of constituent rings, it can be divided into 95343 40 201213305 p ancient s four clothes or more % bridge Wei Ke, which is more bicyclic, tricyclic or tetracyclic, and is bicyclic or tricyclic. Non-limiting examples of bridged ring alkyl groups include. The heterocyclic ring may be referred to as an aryl, heteroaryl or shoe ring, the "parent linkage" of the -(tetra) ring to a heterocyclic group, non-limiting examples contain:

The isoindolyl group may be optionally substituted or unsubstituted, and when the substituent to be taken is preferably one or more of the following groups, independently selected from the group consisting of a group, an alkynyl group, an alkoxy group, and a sulfur-burning group. , anthranyl, (iv), 'y, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, carbonyl, ?-〇-C(0)R7, _C(0)R7, -C(0)0R7, -s(〇)〇R7, _nr8r9 〇R, -C(0)NR8R9. & "Aryl" means a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring with a ring of adjacent carbon atoms, having a conjugated electron-accumulating enthalpy (ie, having an adjacent barrier) The atomic ring) group is preferably a 6 system such as a stupid group and a naphthyl group. The aryl ring may be fused to a heteroaryl group, a cycloalkyl ring, wherein the diheterocyclic group is bonded to the parent structure or a non-limiting example comprises: 'long aryl ring'

〇

95343 41 201213305

»<x> The aryl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy groups. Sulfur-based, aryl-based, ketone, thiol, thiol, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cyclooxy, heterocycloalkoxy A group, a cycloalkylthio group, a heterocycloalkylthio group, _〇R7, _〇_c(〇)r7, -C(0)R7, -C(0)0R7, -S(8)OR7, ~Nr8r9 or _c_r8r9. "Heteroaryl" refers to an aryl group containing from 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen. Heteroaryl is preferably = to ^ members, more preferably 5 members or 6 members, such as sulfhydryl, 嗟 父 parent: bite base: each base, Ν _ _ base ^ each base, Fuding base, · Qinji, Imidazolyl, tetrazolyl, and the like. The heteroaryl ring ^ ^ μ ^ is fused to an aryl group, a heterocyclic group or a % alkyl group, wherein the ring is bonded to the parent structure, and a non-limiting example comprises: 4 a ring of a heteroaryl group

The substituent is preferably one or more of the following base rings, independently

Ίο Heteroaryl group may be taken as needed (four) or not........ When η is substituted, the vacancy group, the methoxy group, the thiol group, the alkyl group, and the Hyun, women, 95343 42 201213305 -C(0)R7, -C(0)0R7, -S(〇)〇R7,. The hospital is deuterated in an amount of - 〇 _ (alkyl) and - 〇 - (unsubstituted ring-based), wherein the alkyl group is as defined above. Non-limiting examples include methoxy, ethyl, propoxy, butoxy, cyclopropoxy, cyclot0oxy, cyclopentyloxy, cyclohexyloxy and the like. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently independently of the group, the dilute group, the alkynyl group, the alkoxy group, Sulfur-based, alkylamino, dentate, thiol, thiol, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy , cycloalkylthio, heterocyclic thiol, —R7, —oc(o)r7, —c(〇)r7, —C(0)0r7, —s(〇)〇r7, _nr8r9 or —C( 〇) NR8R9. A halogenated group means that the alkyl group is substituted by one or more molecules. The alkyl group is substituted by a group. "Hydroxy" refers to the -OH group. "Halogen" means fluorine, gas, bromine or iodine. "Amine" refers to -nh2. "Cyano" means -CN. Nitro refers to _N〇2. "As needed" or "as needed" means that the event or environment described subsequently may, but need not, occur, including where the event or environment occurs or does not occur. For example, "a heterocyclic group which is optionally substituted by an alkyl group means that an alkyl group may be, but is not necessarily, present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the heterocyclic group is not substituted by an alkyl group. The term 'pharmaceutical composition' means an ageing substance containing one or more of the 95334 43 201213305 compounds or physiologically/pharmaceutically acceptable salts or prodrugs thereof and other chemical components described herein, as well as other grades. For example, physiological/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration of the organism, thereby facilitating the absorption of the sexual component and thereby exerting biological activity. ' / m and R7 to R9 are as defined in the compound of the formula (1). Method for synthesizing the compound of the present invention In order to accomplish the object of the present invention, the present invention adopts the following technical scheme. A method for preparing a compound of the formula (1), the method comprising:

(A) (I) (1) A compound of the formula (10) (using a well-known method "Tetrahedn 2_, 67_74", material (4)) in a pure Heb spot or Ar-MgBr reaction to obtain a compound of the formula (IA); The reaction catalyst is a cuprous salt, preferably cuprous, secret cuprous, more preferably cuprous or gas steel, and the temperature of the i reaction is from 8 to 10 (10). C, preferably a medium; the solvent of the reaction is an organic solvent, preferably a toluene; methyl chloride, benzene or toluene, more preferably diethyl ether or tetrahydro: ethyl, the reaction time is from 1 minute to 72 hours. Preferably, the hour is more preferably from 15 minutes to 12 hours; from 15 minutes to (2) the compound of the formula (ΙΑ) is further converted to the formula 〇). Preferably, the carbonyl group of the compound (ΙΑ) can be reduced. 4 1 such as 嗍 gasification 201213305 纳' reduction to a hydroxyl group, if necessary, further conversion of the hydroxyl group to -OR7, or if necessary, remove the protective group PG to obtain a compound of the formula (I); or 'compound (IA) The carbonyl group may be further reduced to a halogen group by a reducing agent such as sodium borohydride, or the hydroxyl group may be further converted to a halogen, or the protecting group PG ' may be removed as needed to obtain a compound of the formula (I); or the carbonyl group of the compound (IA) may be further Conversion to alkenyl, alkyl, alkynyl, nitro, cyano, cycloalkyl, heterocyclic, -〇_c(〇)R7, _c(〇)R7, a C(0)0R7, ~S( 0) 〇R7, -NR8R9 or -C(0)NR8R9, or if necessary, the protecting group PG is removed to obtain a compound of the formula (丨); : PG is a protecting group for N, preferably -C(0)R7, -CC〇)qr7 or -c(o)nr8r9; R3 'R4, R5 and R6 are a hydrogen atom;

Ar, R1, 尺2, and ^ to R9 are as defined in the general formula (1). [Embodiment] The following examples are combined to further describe the present invention, but this embodiment is not intended to limit the scope of the invention. EXAMPLES The structure of the compounds was determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). The NMR shift (5) is given in units of 1 (T6 (Ppm). The NMR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated monomethyl sulfoxide (DMS0-A), deuterated chloroform (CDCI3). ), deuterated methanol (Cl ^ 〇 D), internal standard is tetradecyl decane (TMS). 3

Determination of MS 甩FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer. 95343 45 201213305

Thermo, model: Finnigan LCQ advantage MAX). The HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4. 6 mm chromatography column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm chromatography column). The specification of the thin layer chromatography tantalum sheet is Yantai Yellow Sea HSGF254 or Qingdao GF254 tannin sheet, and the specification of the thin layer chromatography (TLC) is 0.15mm to 0. 2mm. 4 mm to 0. 5mm 〇 chromatography column generally uses Yantai Huanghai 200 200 to 300 mesh 矽 gel as a carrier. The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc. , Dary Chemicals and other companies. An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L. The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume. The pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus. The hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times. The microwave reaction used a CEM Discover-S Model 908860 microwave reactor. Unless otherwise stated in the examples, the solution means an aqueous solution. There is no particular description in the examples, and the reaction temperature is room temperature. Room temperature is the optimum reaction temperature and is 20. (: to 30. (: 46 95343 201213305 The reaction process in the examples was monitored by thin layer chromatography (TLc). The system used for the development of the reaction was: di-methane and decyl alcohol systems, n-hexane and acetic acid. In the vinegar system, the volume ratio of the solvent is adjusted according to the polarity of the compound. The system of the eluent for the column chromatography of the purified compound and the developer system for the thin layer chromatography include: A: petroleum ether and ethyl acetate system , B: n-hexane and ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and may be adjusted by adding a small amount of an organic or acidic reagent such as triethylamine and acetic acid. Example 1 (3a especially 5尤6a5>/3a5;55; 6a^?)_3a-phenyl-2, 3, 4, 5, 6, 6a-hexahydrocyclopentaI» ratio p--5-ol trifluoroacetic acid|

First step (3af, 68^9)-5-oxo_3a-stupyl-3, 4,6,6a-tetrahydro-1 and _cyclopenta[c]pyrrole-2-furic acid third Ester 〇 ° C, under a nitrogen atmosphere, copper bromide (2.77 g, 20 mmol) was dispersed in 30 mL of ether, slowly added 2M phenyl lithium solution (20 mL, 40 47 95343 201213305 mmol), The reaction was carried out at 0 ° C for 1 hour, and 20 mL of 5-oxo-1,3,6,6a-tetrahydrocyclopenta[c]pyrrole-2-furic acid tert-butyl ester la was added dropwise (using a known method "Tetrahedron" , (2008, 64, 67-74" prepared) (2.23 g, 10 mmol) in diethyl ether, which was reacted at 0 ° C for 3 hours. The reaction solution was poured into a 300 mL saturated gasification solution, and the liquid phase was extracted with an ethyl ether (50 mL×4). The organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by column chromatography using eluent system B to give the title product (3a??, oxo-3a_phenyl_3,4,6,6a-tetrazol-1 and -cyclopenta[c] Pyrrole-2-carboxylic acid tert-butyl ester lb (1.9 g, pale yellow oil), yield: 63. 1 ° / 〇 4 ^ R (400 MHz, CDCl3): 5 7.40 - 7.35 (m, 2H), 7.32-7.25 (m, 3H), 3.93-3.61 (m, 3H), 3.38-3.23 (m, 1H), 3.22-3.07 (m, 1H), 2.84 (d, 1H), 2.69 (d, 1H), 2.69-2.57 (m, 1H), 2.35-2.25 (m, 1H), 1.47 (s, 9H) The second step (3a7?, 5疋6a573a5; 55; 6af)-5-hydroxy-3a-benzene Base-1, 3, 4, 5, 6, 6a-hexahydrocyclopenta[ί:]πΛσ each of the third butyl phthalate will be (3a_/P,6a5")-5_oxo_3a _Phenyl_3,4,6,6a_tetrazine_1 and _cyclopenta[c]D are dissolved in 15 mL of methanol than σ each butyl phthalate lb (300 mg, 1 mmol) Adding sodium hydride (60 mg '1.5 mmol) at -78 °C for 1 hour. Add 2 mL of acetone, liter The reaction mixture was concentrated with EtOAc EtOAc (EtOAc m. , GatS/SaS, 551, 6aA)-5-carbyl-3a-phenyl 48 95343 201213305 -1,3, 4, 5, 6, 6a-hexahydrocyclopenta[c].Bilo-Z-carboxylic acid Third butyl vinegar lc (300 mg, light yellow oil), yield: loo%. The third step (3a>?, 5 especially 6a573a5·, 55; 6a7P)-3a-stupid-2, 3, 4 , 5, 6, 6a-hexahydro-ΙΖί-cyclopentabi-5-ol trifluoroacetate under nitrogen atmosphere, (3a疋5yP, 6avSy3a5^, 55^, 6ay?)-5-hydroxy-3a -Phenyl-1,3,4,5,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester lc (300 mg, 0.99 mmol) dissolved in 15 mL of dichloropurine During the calcination, trifluoroacetic acid (0.2 mL, 2.97 mmol) was added dropwise, and the mixture was reacted for 3 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC to give the title product (3a, 5 pi, g,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, - hexa-li7-cyclopenta->] pyrrol-5-ol trifluoroacetate 1 (200 mg, white solid), yield: 63.7%. MS m/z (ESI): 204.2 [M+l] Ή NMR (400 MHz, CDCh): δ 7.42-7.35 (m, 2H), 7.3^ 7.26 (m, 1H), 7.24-7.20 (m, 2H) , 4.59-4.52 (m, lH) 3.79-3.71 (m, 1H), 3.53-3.43 (m, 2H), 3.42-3.33 (m 1H), 3. 31-3. 23 (m, 1H), 2· 46-2. 37 (m,1H), 2.34—2.24 (in, 2H), 2.07-1.98 (m, 1H) Example 2 (3ai?, 5 brother 6a573a5; 55; 6a«-5-methoxyl_ 3a-phenyl-2,3,4,5,6,6a-hexahydro-1 and-cyclopenta-1>]pyrrole trifluoroacetate 95343 49 201213305

2« 2 First step (3a especially 5 feet 6a573a5; 55; 6aA)-5-decyloxy-3a-phenyl-1,3, 4, 5, 6, 6a-hexahydrocyclopenta[c]pyrrole 2-3 tert-butyl citrate will (3a^?, 5 especially 63573 &5;55; 6af)-5-hydroxy-3a-phenyl-1,3,4,5, 6, 6a-hexahydrocyclo Pentylene [dibutyl butyl phthalate lc (400 mg, 1.32 mmol) was dissolved in 15 mL of tetrahydrofuran, and 60% sodium hydride (64 mg, 2.64 mmol) was added. After reacting for 30 minutes, decyl p-toluenesulfonate (240 / zL, 1.59 mmol) was added dropwise, and the reaction was stirred for 16 hours. A small amount of decyl alcohol was added, and the reaction mixture was concentrated under reduced pressure. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -3a-phenyl-1,3,4,5, 6, 6a-hexahydrocyclopenta[c]pyrrole-2-furic acid tert-butyl ester 2a (260 mg, white oil), yield: 62. 2%. NMR (400 MHz, CDCh): 5 7.37-7.30 (m, 2H), 7.29-7.20 (m, 3H), 3.98-3.91 (m, 1H), 3.82-3.66 (m, 1H) , 50 95343 201213305 3.65-3.55 (m, 1H), 3.30 (s, 3H), 2.89-2.80 (m, 1H), 2.49-2.41 (m, 1H), 2.39-2.20 (m, 3H), 2.14-2.03 (m, 1H), 1.77-1.65 (m, 1H), 1.47 (s, 9H) The second step (3a疋5疋6a573a5; 55; 6a>?)-5-decyloxy-3a-phenyl-2 , 3, 4, 5, 6, 6a-hexahydro-1 and -cyclopentapine»»Bilotrifluoroacetate will (3ai?, 5 brothers 6a5y3a5·, 55; 6aJ?)-5-decyloxy- 3a-phenyl-1,3,4,5, 6, 6a-hexahydrocyclopenta[c]n is more soluble than ruthenium-2-decanoic acid 3B (260 mg, 0.82 mmol) in 15 mL II In the methyl chloride, trifluoroacetic acid (0.3 mL, 4.1 mmol) was added dropwise, and the mixture was reacted for 3 hours. The reaction mixture was concentrated under reduced pressure and purified by HPLC. To the title product (33 brothers 5疋63573&5;55; such as?) -5-decyloxy-3a-phenyl-2, 3, 4, 5, 6, 6a_hexahydro-If cyclopenta[c The ratio of each of the trifluoroacetic acid salts 2 (230 mg 'colorless oil), yield: 82.7% MS m/z (ESI): 218.2 [M+l] !H NMR (400 MHz, CDCh ): 5 7.42-7.36 (m, 2H), 7.32-7.28 (m, 1H), 7.24-7.21 (in, 2H), 4.02-3.98 (m, 1H), 3.68-3.57 (m, 2H), 3.56- 3.49 (m, 1H), 3.45 (s> 3H), 3.40-3.33 (m, 1H), 3.32-3.25 (m, 1H), 2.49-2.41 (m, 1H), 2.33-2.24 (m, 2H), 2. 13-2.05 (m, 1H). Example 3 (3a·/?, 5·/?, 55", 6a_/?)_5_ethoxyphenyl-2, 3, 4, 5, 6, 6a-hexahydro-1 and-cyclopenta [c]° ratio π each trifluoroacetate 95343 51 201213305

First step (3a^?, 5疋6a573a5; 55; 6aA〇-5-ethoxy-3a-phenyl_1,3, 4, 5, 6, 6a-hexahydrocyclopenta[c]n ratio Ρ2_2_decanoic acid tert-butyl ester 4〇人〇1c (3a7?, 5 feet 6a573a5; 55; 6aA〇-5-hydroxy-3a-phenyl-1,3, 4, 5, 6, 6a - Hexahydrocyclopenta[c]n is more soluble in sigma 2-butyrate tert-butyl ester lc (460 mg, 1.52 ramol) in 15 mL of tetrahydrofuran, 60% sodium hydride (73 mg, 3.04 mmol) The reaction was carried out for 30 minutes, and ethyl iodide (150 // L, 1·82 mmol) was added dropwise, and the reaction was carried out for 16 hours. A small amount of methanol was added, and the reaction mixture was concentrated under reduced pressure, and purified by eluent column chromatography using eluent column chromatography. The residue obtained gave the title product (3ai?, 5, 6 aksy 3a5; 5 and 6aA 〇~5-ethoxy-3a-phenyl-1,3,4,5,6,6a-hexahydrocyclopenta[c Pyrrole-2-butyrate tert-butyl ester 3a (251 mg, white oil), yield: 49.9%. NMR (400 MHz, CDCh): δ 7.36-7.30 (m, 2 Η), 7 28 -7.20 (m, 3H), 4.06-3.98 (m, 1H), 3.93-3.76 (m, 1H) 3.75-3.65 (m, 1H), 3.65-3.54 (m, 1H), 3.47-3.40 (m 95343 52 201213305 2H), 2. 88-2. 77 (m, 1H), 2.48-2.31 (m, 2H), 2. 3〇, 2 2〇(m, 1H), 2. 13-2. 03 (m, 1H), 1. 75-1. 65 (m, 1H), 1.47(s 9H), 1. 22-1. 16 (t, 3H) 'Step 2 (3a^ 5·/?, 55", 6a left)_5 - Ethoxy-3a-stupyl-2, 3, 4, 5, 6, 6a-hexahydro- 1 pico-cyclopenta[c]° piroxime triacetate (3a^5 especially 68^57381^, 55*, 6a and) _5_ethoxy-3a_ stupid-1,3, 4, 5, 6, 6a-hexahydrocyclopenta[c]pyrrole-2-carboxylic acid tert-butyl 3a (240 mg, 0.73 mmol) was dissolved in 15 mL of di-methane, and tri-acetic acid (0.3 mL) was added dropwise. , 3.62 mmol), the reaction was carried out for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by HPLC to give the title product (3a, 5, 6a573, s, s, s, s , 3, 4, 5, 6, 6a-hexahydro-1 and -cyclopentazone|>] pirocene trifluoroacetate 3 (215 mg, colorless oil), yield: 85.3%. MS m/z (ESI): 232.2 [M+l] NMR (400 MHz, CDCla): δ 7.42-7.35 (m, 2H), 7. 32-. 7. 27 (m,1H), 7.25 -7.20 (m, 2H), 4.14-4. 09 (m, 1H), 3.71-3.60 (m, 4H), 3.59-3.50 (m, 1H), 3.43-3.36 (m, 1H), 3. 32- 3. 25 (m, 1H), 2.47-2.40 (m, 1H), 2.35-2.23 (m, 2H), 2.10-2.03 (m, 1H), 1.31-1.26 (m, 3H) Example 4 (3a) , 5 friends, 551, 6aA〇-3a-(3, 4-diphenyl)-5-decyloxy-2, 3, 4, 5, 6, 6a-hexahydro-li7-cyclopenta[ c]pyrrole hydrochloride 95343 53 201213305

HCI

First step (3a7?,6a573a5; 6ay?)-3a-(3,4-diphenyl)-5-oxo_3, 4, 6, 6a-tetrahydro-If cyclopenta[c]pyrrole 2- phthalic acid tert-butyl vinegar Disperse copper iodide (660 mg ' 3. 47 mmol) in 16 tetrahydrofuran, and then add 3, 4-dichlorophenyl magnesium bromide (0. 73 g, 6. 9 mmo 1) and 3 · 3 mL of dimethyl chaos (670/zL, 5.22 mmo 1) in tetrahydrofuran solution, reacted at 0 ° C for 30 minutes 'drop 3 · 3 mL 5-oxo -1,3, 6, 6a-tetrahydrocyclopenta[c]pyrrole-2-furic acid tert-butyl ia (5i7 mg, 2.31 mmol) and tridecylchlorodecane (670 /zL, 5.22 mmol) The tetrahydrofuran solution was added dropwise and reacted at 0 ° C for 30 minutes. The reaction was quenched with aq. EtOAc EtOAc (EtOAc) The obtained residue was purified to give the title product (3a, 6 s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, Pentylene [c]pyrrole-2-yl decanoate 4a (350 mg 'yellow liquid), yield: 4 〇 8 〇 / 〇 H NMR (400 MHz, CDCh): β 7. 47 (d, 1Η), 7.41 (d, 1H), 7. 18-7. 15 (dd,1H), 3.89, 3.62 (m, 3H), 3. 39-3.31 (m, 1H), 3.17-3.11 (m , 1H), 2.78-2.62 (m, 3H), 2.36-2.29 54 95343 201213305 (m, 1H), 1.50 (s, 9H) Step 2 (3aiP, 6a573a5; 55; 6a>?)-3a-(3 , 4-diphenyl)5-hydroxy-1,3,4,5,6'6a-hexahydrocyclopenta[c]pyrrole-2-butyric acid tert-butyl ester (3aiP, 6a5/3a5; 6aiP)-3a-(3, 4-dihydrophenyl)+oxo-3,4,6,6a-n^-lH,;^[c]^—2_MtM4a (350 mg '0.95 face 1) dissolved in In 5 mL of methanol, sodium nitrite (37 mg, 0.98 _1) was added in batches (TC reaction 3 〇) Naturally, it is raised to room temperature to react with H. The reaction mixture is concentrated under reduced pressure, and the mixture is added with 2% acetic acid ethyl acetate and 20 mL of water, and the aqueous phase is extracted with acetic acid (9), and the organic phases are combined and dried over anhydrous sulphur. Filtration, column chromatography to purify the obtained residue in eluent system A to give the title product (3a^?, 5^?, Ba^/Sa^, 55, 6a^)-3a-(3, 4~ - - ^ « 'one gas base'-5-ylamino-1'3'4'5,6々-hexahydrocyclopenta[small bilo, 2, formic acid tert-butyl) (351 mg 'colorless oil ), yield: 丨〇〇%. Brilliant R (400 MHz, CDC13): (5 7 4? Μ η 7.13-7.10 (dd, 1H), 4.15(d, 1H) 3 ^ 7'35 (d> 1HX , 61-3.49 (, 2H), , 84_, 78 (,; " ^71 ^ ^ 2H)' 2.13-2.08 (m' 1H), 1 76-1 μ r ' 2.46-2. 38 (Team 9H ) A*70 Cm, 1H), 1.49 (s, third step (3af, 5 especially 6a5y3a5*, 55; 6ai?)-3a-(3 4, _ -l'3,4'5'6'6a- _ — [c], 2a = ) 5:: ^ will (3a especially 5 especially 6a573a6; 55; 6an (3 曰 * 4 - qi phenyl) 95343 55 201213305 -5-hydroxy-1,3, 4, 5 , 6, 6a-hexahydrocyclopenta[c> bic acid-2-carboxylic acid terpene vinegar 4b (351 mg '0. 94 mmol) The solution was dissolved in 5 mL of tetrahydrofuran, and 60% sodium hydride (53. 6 mg, 1.34 mmol) and 0. 20 mL of methyl benzoic acid methyl ester (251 mg ' 1. 34 mmo 1) tetrahydroanthracene solution, reaction for 16 hours. The reaction was quenched by the addition of 10 mL of EtOAc. EtOAc (EtOAc) The obtained residue was purified to give the title product (3a^5, 6a573a5; 55; 6ai?) -3a-(3, 4-diphenyl)-5-methoxy-1,3, 4, 5, 6, 6a-hexahydrocyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 4c (360 mg, colorless oil), yield: 100%. NMR NMR (400 MHz, CDCh): δ 7. 42 (d, 1Η), 7. 35 (d, 1H), 7.13-7.11 (dd, 1H), 3.99-3.93 (m, 1H), 3.92-3.66 ( m, 2H), 3.66-3.53 (m, 1H), 3.53-3. 38 (m, 1H), 3.32 (s 3H), 2.83-2.76 (m, 1H), 2.40-2.32 (m, 2H), 2.17 -2 11 (m, 1H), 1.79-1.71 (m, 1H), 1.49 (s, 9H) The fourth step (3a^ 5 feet 6a5y3a5*, 5^9, 6a^〇-3a-(3, 4- Dichlorophenyl)_5_ oxime-2, 3, 4, 5, 6, 6a-hexahydro-1#~cyclopenta[c]pyrrole trifluoroacetate will (3a foot 5疋6a573a& 5 and 6a «-3a-(3,4-dichlorophenyl)-5-methoxy-1,3,4, 5, 6, 6a-hexahydrocyclopenta[c]°pyr-2-carboxylic acid third Butyl ester 4c (360 mg, 0.99 ramol) was dissolved in 5 mL of dichloromethane, and trifluoroacetic acid (693 yL, 9.3 mmol) was added to react for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by HPLC. , the title product 95343 56 201213305 (3a especially 5 left '6a573a5; 55; 6aiP)-3a-(3, 4-dichlorophenyl)__5_ 曱oxy-2, 3, 4, 5, 6, 6a-six Argon-1 and -cyclopenta[c]nt (rhodium trifluoroacetate (360 mg, pale yellow oil), yield: 96.5%. Step 5 (3a>P, 5 brothers 6a573a5; 55 ; 6a^P)-3a-( 3, 4-diphenyl)_5_methoxy-2,3' 4, 5, 6, 6a-hexanitro-If-cyclopenta[c]pyrrole hydrochloride (3af, 5·/?, 6a573aiS, 551, 6aj^)~3a-(3 4--gasbenzene; ^) -5-decyloxy-2' 3' 4, 5, 6' 6a-hexahydro, 1 in cyclopentapyrrole Acetate 4d (360 mg, 0.9 mmol) was dissolved in 4 Torr of water, and sodium oxyhydroxide was added until the pH of the reaction solution was greater than 7', extracted with dichlorohydrazine (5 〇 mL), and the organic phase was dried with anhydrous sulphuric acid. The filtrate was concentrated under reduced pressure. To the residue was added 5 mL of ethyl acetate vinegar. A solution of 2.6 liters of hydrogenated hydrogen in ethyl acetate was added until the pH of the reaction mixture was less than 2. The reaction mixture was concentrated under vacuum. Dry, add the title product (3ae, 5 skin, 6a573a5", 551, 6a and) ~3a-(3 4--chlorobenzoyl)-5-methoxy-2, 3, 4, 5, 6 2%。 6a-hexahydro-1 in cyclopenta[c]pyrrole hydrochloride 4 (250 mg, light yellow solid), yield: 86.2%. Muscle MS m/z (ESI): 286.1 [M+l] !H NMR (400 MHz, DMSO-i/e): δ 9.74 (s>1H)> 9 2 〇(s 1H), 7.68 (s, 1H), 7.60 (d, 1H), 7.4 〇 (d 1H) 3 83 (s' 1H), 3. 63 (d, 1H), 3·50-3.40 (ιη, 1H), 3 39_3 26 (m 1H ), 3.23 (s, 3H), 3. 19-3. 13 (m, 1H), 3 〇g 2.33 (d, 1H)' 2.28-2.17 (m, 1H), 2.16-2.01 (m, 1H)' 1.80 (d, 1H) 'Example 5 95343 57 201213305 (3a7?, 5 billion 6a573a5; 55; 6a/?)-3a-(3, 4-difluoro^ 2, 3, 4, 5, 6, 6a- Hexahydro-IF cyclopenta[c]pyrrole-5-alcohol three gas B &

Will (3a>?,57?,6a573a5;55; 6a«-3a-(3,4-dichlorophenyl)-5-hydroxy-1,3,4,5,6,6a-hexahydrocyclopenta [c]pyrrole-2-carboxylic acid tert-butyl ester 4b (372 mg, 1 ramol) was dissolved in 5 mL of dichloromethane, and then trifluoroacetic acid (1. 5 mL, 20 mmol) was reacted for 16 hours. The reaction mixture was purified by HPLC to give the title product (3a, 5,5,5,5,3,3,5,3,5,6,6,6,3,3,3,3,4-diphenyl)- 2, 3, 4, 5, 6, 6a- Hexahydro-1 -cyclopentazone |» ratio 1» each _5-alcoholic triacetate 5 (340 mg, pale yellow solid), yield: 88.1% MS m/z (ESI): 272.1 [M+l] *H NMR (400 MHz, dISO-ώ): δ 9.19 (s, 1H), 8.69 (s, 1H), 7. 64-7. 63 (d, 1H), 7. 62-7 60 (d, 1H), 7.38-7.35 (dd, 2H), 4.30-4.20 (m, 1H), 3.79-3.68 (m, 1H), 3.53-3.41 (ra, 1H), 3.35-3.23 (in, 2H), 3.18-3.07 (m, 1H), 2.28-2.14 (m, 2H), 2.05-2.00 (m, 1H), 1.73-1.69 (in, 1H) Example 6 95343 58 201213305 (3a〇?,6a573a5 55; 6aii〇-3a-(4~chlorophenyl)_5_radio-2,3,4,5,6'6a-hexahydro-Ifcyclopenta[c]scale trifluoroacetate OH dish

first step

And 5.1 inL tridecylchlorodecane, -3 Torr. The reaction was carried out for 3 minutes, -" it was reacted for 30 minutes, and 100 mL of 5-oxo-1,3,6,6&_tetrahydrocyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester was added dropwise. La (4·46 g, 20 mmol) in tetrahydrofuran solution 'Add 5 · 1 mL of tridecyl gas decane, add _78 〇 c for 1 hour. Add 20 mL of 1 M hydrochloric acid to quench the reaction, add 5 〇 mL of water, It was extracted with ethyl acetate (70 mL×3). The organic phase was washed with saturated sodium chloride solution (5 mL) and saturated sodium hydrogen carbonate (50 mL). The filtrate was purified by eluent column chromatography using eluent system B to give the title product (3a.sup.6a5*) -3a-(4-chlorophenyl)-5-oxo-3, 4, 6, 6a-tetrahydro-1 and -cyclopenta[c] mouth ratio 59 95343 201213305 ?-carboxylic acid tert-butyl ester 6a (5.9 g, yellow oil), yield: 87.8%. NMR (400 MHz, CDCh): δ 7. 34 (d, 2Η), 7. 24-7. 21 (m, 2H), 3.87-3.61 (m, 3H), 3.36-3.22 (m, 1H), 3.16 -3.06 (m, 1H), 2.77-2.56 (m, 3H), 2.32-2.27 (m, 1H), 1.46 (s, 9H) Step 2 (3a疋5疋6a573a5; 55; 6a«-3a-( 4-chlorophenyl)-5-hydroxy-1,3,4,5, 6, 6a-hexahydrocyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester (3af,6a5〇-3a-( 4-chlorophenyl)-5-oxo-3, 4, 6, 6a-tetrahydro-1 and-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 6a (3. 36 g, 10 mmol Dissolved in 40 mL of methanol, and added sodium borohydride (757 mg, 20 mmol) in portions under ice-cooling for 1 hour. The reaction was quenched by adding 50 mL of hydrazine, and the reaction mixture was concentrated under reduced pressure. The mixture was separated, and the aqueous layer was evaporated (EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjs (4-chlorophenyl)-5-yl-1,3,4,5,6,6a-hexahydrocyclopenta[c]D-pyrrol-2-carboxylic acid tert-butyl ester 6b (3.1 g , white solid), Yield: 91.2%. !H NMR (400 MHz, CDCh): δ 7.30-7.26 (m, 2H), 7.19-7.15 (ηι, 2H), 4.45-4.38 (m, 1H) , 3.87-3.84 (d, 1H), 3.72-3.67 (m, 1H), 3.56-3.53 (d, 1H), 3.49-3.46 (m, 1H), 2.83-2.76 (m, 1H), 2.43-2.36 ( m, 2H), 2.10-2.04 (ra, 1H), 1.76(s, 1H), 1.72-1. 65 (m, 1H), 1.45 (s, 9H) The third step (3a especially 5 Foot 6a573a5; 55; 6af)-3a-(4-chlorophenyl)-5-hydroxy 60 95343 201213305 -2, 3, 4, 5, 6, 6a-hexahydro-1 and-cyclopenta[c]pyrrole -5-alcohol trifluoroacetate will (3aiP, 5 especially 6a573a5; 55; 6a)?)-3a-(4-chlorophenyl)-5-hydroxy-1,3, 4, 5, 6, 6a-six Hydrogencyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 6b (500 mg, 1.48 mmol) was dissolved in 30 mL of methylene chloride, and trifluoroacetic acid (0.57 mL ' 7.4 lysine 1) was added. Reaction for 4 hours. The reaction mixture was concentrated under reduced pressure and purified by HPLC to give the title product (3a, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, , 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 : 238.1 [M+l] *H NMR (400 MHz, CDaOD): δ 7.39-7.33 (m, 4H), 4.42 (s, 1H), 3. 80 (d, 1H), 3. 56-3. (m, 1H), 3.43 (d, 1H), 3. 35 (d, 1H), 3. 28 Cd, 1H), 2. 37~2. 30 (m, 2H), 2 24-2.20 ( m, 1H), 1.91 (d, 1H) Example 7 (3a^551, 6a573av9,5 and (3,4-dichlorophenyl)-2,3,4,5,6,6a-hexahydro- 1 and -cyclopenta[匚]° ratio slightly 5-alcohol trifluoroacetate

QH

0 ^γΟΗ 7b 95343 61 201213305 First step (3ai?,55",6aiS73aiS,5·/?,6ai〇_5-benzoquinoneoxy_3a_(3,4_diphenyl)-1,3 , 4, 5, 6, 6a-hexahydrocyclopenta[c]. Butyl-2-carboxylic acid tert-butyl ester benzoic acid (360 mg, 2.95 mmol) and diethyl azodicarboxylate (514 Mg, 2.95 mmol) was dissolved in 5 mL of diethyl ether, and 5 mL (3aA, 5 brothers 5iS", 6a〇_3a_(3,4-dichlorophenyl)_5_yl-1,3,4,5, 6, 6a-hexahydrocyclopenta[c]pyrrole-2-furic acid tert-butyl ester 4b (1. 0 g, 2. 6 mmol) and triphenyl-filled (774 mg, 2.95 mmol) of diethyl ether The solution was reacted for 16 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified to the titled product (3a^?, 55", 5 especially 6a^)_5_benzoquinone by gel column chromatography. Oxygen_3a_(3,4_diphenyl)-1,3,4,5, 6, 6a-hexahydrocyclopenta[c]α ratio σ each-2-decanoic acid tertidine 7a ( 900 mg, light yellow oil), yield: 70.3%. Second step (3a^ 551,6a573a5",5 no,6a〇-3a_(3,4_二气笨基)_5_经基-1 ,3, 4, 5, 6, 6a-hexahydrocyclopentazone||>]pyrrole-2-a The third butyl ester will be (38 pic, 55', 63173731^, 5^/?, 63_/?) _5_benzoquinone oxy_33_(3,4-dichlorophenyl)-1,3, 4, 5, 6,6a-hexahydrocyclopenta[e]0 pirin-2-butyrate tert-butyl ester 7a (900 mg, 1.89 mmol) was dissolved in 10 mL of sterol and water (V/V = 1 / In the mixed solution of 1), sodium hydroxide was added until the pH of the reaction solution was greater than 7, and the reaction was carried out for 2 hours. The reaction mixture was concentrated under reduced pressure and extracted with dichloromethane (30 mL×3). The filtrate was concentrated under reduced pressure to give the titled product (33.sup.sssssssssssssssssssssssssssssssssssss , 6a-hexahydrocyclopenta[c]e is a ratio of D to butyl tridecanoate 7b (650 mg, light yellow oil), yield: 92. 5%. The third step (3ai? , 5&6a573a& 5 brother 6a〇-3a-(3, 4-dichlorophenyl)-2, 3, 4, 5, 6, 6a-hexahydro-1 and-cyclopenta[匚]°Bilo -5-alcohol trifluoroacetate will be (3a7?, 5 and 68^335; 5疋6ai?)-3a-(3,4-diphenyl)-5-yl-1,3,4,5 , 6, 6a-hexahydrocyclopenta[c]a than σ each-2-carboxylic acid tert-butyl ester 7b (650 mg, 1.75 mmol) dissolved in 10 raL dichloro Burning, London tris acetate (2.6 mL, 35 mmo 1), for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by HPLC to afford title product (3a>?, 55; 6a573a5; 5 especially 6a)-3a-(3, 4-dichlorophenyl)-2, 3, 4, 5, 2%。 6a-hexahydro-1 and -cyclopenta[匚] ° ratio slightly 5-alcohol trifluoroacetate 7 (500 mg, light yellow oil), yield: 74.2%. MS m/z (ESI): 272.1 [M+1] 4 FiMR (400 MHz, DMSO-忒): (5 7. 67 (d, 1H), 7.59 (d, 1H), 7.42-7.40 (dd, 1H) ), 4.30 (m, 1H), 3.48-3.39 (m, 3H), 3. 23-3. 15 (m, 1H), 3. 15-3. 09 (dd, 1H), 2.33-2.29 (dd, 1H), 1.94-1.78 (m, 3H) Example 8 (3a7?, 55; 5 brother 6a^?)-3a-(3,4-diphenyl)-5-decyloxy-2, 3, 4, 5, 6, 6a-hexahydro-1/M裒penta[c]° ratio p hydrochloride

63 95343 201213305

〆

Second step

α First step (3a疋55; 6a573a5; 5 brother 6aT?)-3a-(3, 4-diphenyl)-5-methoxy-1,3, 4, 5, 6, 6a-hexahydrogen Cyclopentazepine]pyrrole-2-carboxylic acid tert-butyl ester (3a brother 5 parent 6a573a5; 5 brother 6aA〇-3a-(3, 4-diphenyl)-5-radio-1,3, 4 , 5, 6, 6a-hexahydrocyclopenta[c]D is dissolved in 10 mL of tetrahydroanthracene at a ratio of p-butyl-3-butyrate tert-butyl ester 7b (700 mg, 1.88 mmol) at 0 Add 60% sodium hydride (150 mg, 3.76 mmol), and mix for several minutes. Add 0.57 mL of p-benzoyl decanoate (700 mg, 3.76 mmol) in tetrahydrofuran and warm to room temperature. After the reaction was carried out for 16 hours, the reaction was quenched with a small amount of water, and then a mixture of 25 mL of ethyl acetate was added, and the organic phase was washed with water (25 mL×2). The resulting residue was purified by eluent column chromatography using eluent column chromatography to afford title product (3a7?, 55; 6a573a5; 5 especially 6ai?)-3a-(3,4-dichlorophenyl)-5-indole Oxy-1,3,4,5,6,6a-hexahydrocyclopenta[c]pyrrole-2-furic acid tert-butyl ester 8a (500 mg, pale yellow oil), yield: 68. 9%. Second (3af, 55; 6a573a5; 5 especially 6aA〇-3a-(3, 4-diphenyl)-5-methoxy-2, 3, 4, 5, 6, 6a-hexahydro-1 pico-ring Ethylene [c] 吼 11 each hydrochloride will (3a;?, 5 parent 6 & 573 & 5 brother 6ai?)-3a-(3, 4-diphenyl)-5-methoxy-1 ,3, 4, 5, 6, 6a-hexahydrocyclopenta[c]° ratio D each-2-carboxylic acid 64 95343 201213305 Tributyl ester 8a (500 mg, 1. 88 mmol) dissolved in 5 mL of acetic acid To the ester, a solution of 2.6 hydrazine hydrogenation in ethyl acetate was added until the reaction solution had a pjj value of less than 2, and the reaction was carried out for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by HPLC to give the title product (3a 551, 6 a ·, 5/?, 6ae)-3a-(3, 4-diphenyl)-5-decyloxy-2, 3, 4, 5, 6, 6a-hexahydro-1/indolyl [ c] 0 to p each hydrochloride 8 (300 mg, pale yellow solid), yield: 71.9%. MS m/z (ESI): 286.1 [M+l] NMR (400 MHz, dUSO-ώ ): δ 9.13 (s, 2H), 7.68 (d, 1H), 7.61 (d, 1H), 7.43-7.40 (dd, 1H), 4.00-3.94 (m, 1H), 3.58-3.31 (m, 3H) , 3.23-3.13 (m, 2H), 3.08 (s, 3H), 2.35-2.30 (m, 1H), 2.13-2.00 (m, 2H), 1.89-1.83 (m, 1H) Example 9 (3a^ 5 And, 6a573ai9, 551, 6ay?)-3a-(3, 4-diphenyl)-5-ethoxy-2,3,4,5, 6, 6a-hexahydro-1 and-cyclopenta[c]°

The first step (3a foot 5 especially 55; 6ay?)-3a-(3, 4-diphenyl)-5-ethoxy 65 95343 201213305 -1,3, 4, 5, 6, 6a-hexahydrogen Cyclopenta[c]α ratio π-bis-nonanoic acid tert-butyl vinegar (3a^,5 especially 6a573a5; 55; 6aiP)-3a-(3, 4-diphenyl)-5-yl group _1, 3,4,5, 6, 6a-hexacycline [c]® piroxicamperic acid tert-butyl ester 4b (300 mg, 0.81 mmol) was dissolved in 3 mL of tetrahydrofuran 0 C was added 60% emulsified sodium (97 mg '2.42 mmol) and bismuth bromide (377 mg, 2.42 mmol), and naturally raised to room temperature for 16 hours. Add 1 liter of water and 10 mL of ethyl acetate, and separate the aqueous phase with ethyl acetate (1 〇 mL). The combined organic phases are dried over anhydrous magnesium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue was purified with EtOAc EtOAc (EtOAc): 3, 4, 5, 6, 6a-hexahydrocyclopenta[c]otb-lo-indolic acid tert-butyl ester 9a (280 mg 'light yellow oil), yield: 86.8%. !H NMR (400 MHz, CDCh): δ 7. 38 (d, 1Η), 7. 32 (d, 1H), 7.09-7.06 (dd, 1H), 4.04-3.96 (m, 1H), 3.88-3.60 (m, 2H), 3.62-3.49 (m, 1H), 3.45-3.40 (m, 3H), 2.79-2.69 (m, 1H), 2.37-2.29 (m, 2H), 2.12-2.07 (m, 1H) , 1.74-1.67 (m, 1H), 1.45 (s, 9H), 1.20-1.16 (t, 3H) The second step (3a7?, 6a573a5; 55; 6ai?)-3a-(3,4-dichlorobenzene -5-ethoxy-2,3,4,5,6,6a-hexahydro-1 and-cyclopenta[c]pyrrole hydrochloride (3a^5 brother 6a573a5; 55; 6ai?) -3a-(3,4-dichlorophenyl)-5-ethoxy-1,3,4,5, 6, 6a-hexahydrocyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 9a (280 mg, 0.7 mmol) was dissolved in 2 mL of ethyl acetate. A solution of 2. 6 hydrazine hydrogenated in ethyl acetate was added until the pH of the reaction mixture was less than 2' 66 95343 201213305. The reaction mixture was concentrated under reduced pressure to give the title product (3a,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, , 6a- hexahydro-1 and -cyclopenta[c]pyrrole hydrochloride 9 (235 mg, white solid), yield: 99.9%. MS m/z (ESI): 300.1 [M+l] <RTI ID=0.0> 7.38 (dd, 1H), 4.13-4.11 (m, 1H), 3.95-3.90 (m, 1H), 3.61 (d, 1H), 3.46-3.40 (m, 3H), 3.30 (s, 1H), 3.08- 3.02 (m, 1H), 2.30-2.20 (m, 2H), 2. 12-2.07 (m, 1H), 1.79-1.73 (m, 1H), 1.13-1.10 (t, 3H) Example 10 (3aiP, 55; 6a573a5; 5 especially 6a«-3a-(3, 4-diphenyl)-5-ethoxy-2, 3, 4, 5, 6, 6a-hexa-1 and-cyclopenta[ c]D bilo hydrochloride

The first step (3a brother 5 especially 6a573a5; 55; 6a«-3a-(3, 4-diphenyl)-5-〇·甲67 95343 201213305 stupid base oxy)-1,3, 4, 5, 6, 6a-hexahydrocyclopenta[c]npirin~2-decanoic acid tert-butyl ester (3a especially 5 especially 6a573a5; 5 and 6a«-3a-(3, 4-dichlorophenyl) -5-transcarbyl-1,3,4,5, 6, 6a-hexahydrocyclopenta[c]0 is dissolved in D-butyl 3-butyrate 4b (500 mg, 1.35 mmol) In 5 mL of the butyl acetonate, p-toluene sulfonium chloride (282 mg, 1.48 mmol) was added dropwise for 16 hours. Hydrochloric acid was added dropwise until the pH of the reaction solution was 2, and 20 mL of water and 20 mL of ethyl acetate were added. The liquid phase was separated with ethyl acetate (20 mL×2), and the organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography with eluent system A. The title product (3a/?,5疋6a573a5·,551,6a〇-3a-(3,4-diphenyl)_5-methylphenylsulfonyloxy)-1,3, 4, 5, 6, 6a-hexahydrocyclopenta[c]. bis- 2 -carboxylic acid tert-butyl ester 10a (420 mg, colorless oil), yield: 4 〇 /. 'H NMR (400 MHz, CDCh): 5 7.82 (d, 2H), 7 44-〇7 38 (m,3H)' 7. 28(s,1H), 7. 05(d,1H), 5. 05-4.97 (m 1H) 3.85-3.67 (m, 2H), 3.65-3.51 (m, 1H) , 3.48-3 37 (m 1H), 2.79 (s, 1H), 2.50 (s, 3H), 2.50-2.19 C ', shell, <3H), 2.00-1.79 (in, 1H), 1.49 (s, 9H) (3a friend, 5iS, 6aiSy3a5*, 5疋6a/i〇-3a-(3, 4-dichlorophenyl)~5 -1,3, 4, 5, 6, 6a-hexahydrocyclopenta [c] 吼 曱 曱 曱 第 = = = = = = = = = = = = = = = = = = = ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~曱Phenyl fluorescein oxy)-l,3, 4, 5, 6, 6a-hexon for stupid, whey pentane 95343 68 201213305 0 than σ each -2-decanoic acid third vinegar 10a (400 mg , 0. 76 mmol) of ethanol solution, reacted at room temperature for 24 hours, and reacted at 50 ° C for 5 hours. 50 mL of water and 50 mL of ethyl acetate were added, the organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated, and the residue obtained was purified by eluent column chromatography to eluant system A to give the title product -3a- (3,4-dichlorophenyl)-5-ethoxy-1,3,4,5, 6, 6a-hexahydrocyclopenta[c]D than tert-butyl phthalate 10b (180 mg, yellow oil), Yield: 50.2 ° / 〇.

Wl'iMRUOOMHz, CDC13): ά 7. 42(s,1H), 7.37(d,1H), 7.15 (d, 1H), 4.14-4.08 (m, 1H), 3.90-3.47 (m, 3H) , 3.46-3.40 (m, 2H), 3.37-3.23 (m, 1H), 2.92-2.83 (m, 1H), 2.38-2.25 (m, 1H), 2. 17-2. 04 (m, 2H), 1.90-1.76 (m, 1H), 1.46 (s, 9H), 1.19-1.15 (t, 3H) The third step (3a brother 55; 6a573a5; 5 especially 6a burning -3a-(3, 4-dichlorophenyl) )-5-ethoxy-2,3,4,5, 6, 6a-hexahydro-1 and-cyclopenta[c]e than clonate hydrochloride (3af, 55; 6a573a5; 5 brother 6a〇 -3a-(3,4-diphenyl)-5-ethoxy-1,3,4,5, 6, 6a-hexahydrocyclopenta[c]pyrrole-2-furic acid tert-butyl ester To a 10b (150 mg, 0. 38 mmol), a solution of 2.6 hr of hydrogen chloride in ethyl acetate was added until the pH of the reaction mixture was 2, and the reaction was carried out for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title product (3ae, 55 ", 6a573a5· , 5 skin, 6a skin)-3a-(3,4-dichlorophenyl)-5-ethoxy-2, 3, 4, 5, 6, 6a-hexahydro-1 and-cyclopenta[c&gt ; pyridine hydrochloride 10 (181 mg, pale yellow solid), yield: 100%. MS / / (ESI): 300.1 [M+l] 69 95343 201213305 !H NMR (400 MHz, DMSO-i/ e): δ 9.47 (s, 2H), 7.68 (d, 1H), 7.59 (d , 1H), 7.42-7.39 (dd, 1H), 4.08-4.03 (m, 1H), 3.52 (d, 1H), 3.30-3.20 (m, 3H), 3.19-3.09 (m, 2H), 2.46 (d , 1H), 2.37-2.32 (m, 1H), 2.07-1.96 (m, 2H), 1.95-1.88 (in, 1H), 0.97 (t, 3H) Example 11 (3ay?, 5 left, eaS/SaS , 55; 6aA〇-5-(cyclopropylhydroxy)-3a-(3,4-diphenyl)-2, 3, 4, 5, 6, 6a-hexahydro-1 and-cyclopenta [c]^^ Each hydrochloride

The first step (3aA, 5 brothers GavSySaS, 551, 6a^〇-5-(cyclopropyl decyloxy)-3a-(3, 4-diphenyl)-1,3, 4, 5, 6, 6a-hexahydrocyclopenta[c]0 is more than tert-butyl phthalate, (3aA\5 especially 6a573a5", 551,6af)-3a-(3,4-dichlorophenyl)-5 -hydroxy-1,3,4,5,6,6a-hexahydrocyclopenta[〇> than butrol-2-carboxylic acid tert-butyl ester 4b (1.8 g, 4.8 mmol) dissolved in 60 mL In tetrahydrofuran, 60% sodium hydride (581 mg, 14.5 mmol), bromomethylcyclopropene (1.41 mL, 14. 5 mmol) and tetrabutyl moth were added at 0 °C. (886 mg '70 95343 201213305 2· 4 mmol) 'The reaction was allowed to rise to room temperature for 19 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The residue was dried over MgSO.sub.sub.sub.subsubsubsubsubsubsubsubsubsubsubsubsubsubsub (cyclopropyl decyloxy)_3a_(3, 4-monopropenyl)-1,3,4,5,6,6a-hexanitrocyclopenta[〇比略_2_曱 acid tert-butyl ester lla (l. 60 g 'yellow oil ), yield: π. 4%. j^JMRMOOMHz, CDC13): <5 7.39(d,1H), 7.33(d,1H), 7. 09 (dd, 1H), 4. 08 -3 . . . (m, 1H), 3. , 1.80 -1.66 (in, 1H), 1.46 (s, 9H), 1.10-0.95 (m, 1H), 0.54 (dt, 2H), 0.19 (q, 2H) The second step (3a brother 5 skins, 6a573a5· , 551, 6a^〇-5-(cyclopropylmethoxy)-3a_(3,4-diphenyl)_2, 3,4, 5, 6, 6a-hexahydro-1 and-cyclopenta [c]e piric acid hydrochloride (3ae, 5 friends, 6a573avS, 55", 6ae)-5-(cyclopropyl decyloxy)-3a-(3, 4-diphenyl)_1,3 , 4, 5, 6, 6a-hexahydrocyclopenta[c]B is added to a solution of 2.6 Μ hydrogenated hydrogenate in a solution of tert-butyl-2-carboxylic acid tert-butyl ester lla (1.5 g, 3.53 mmol). The pH of the solution was 2 and the reaction was carried out for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue obtained was purified by HPLC to give the title product (3a, 5, 6, 5, 5, 5, 5, 5, 5, 6, 5, 5, 5, 6 - 6 -(cyclopropylmethoxy)-3a-(3, 4- Chlorophenyl)-2,3,4,5, 6, 6a-hexahydro-if cyclopenta[c]n-pyryl hydrochloride 11 (1.20 g 'yellow solid) 'yield: 93.8%. MS m /z (ESI): 326.1 [M+l] 71 95343 201213305 *H NMR (400 MHz, CDCh): δ 11.65 (s, 1H), 8 28 (s 1H), 7.44 (d,1H), 7. 31 (s, in), 7. 1〇(d, 1H) 4.20-4.10 (in, 1H), 3.76-3.09 (m, 6H), 2.43 (d, 1H) 2. 23 (in, 2H), 2. 08 (m, 2H), 1·l〇(br, 1H), 〇β5 (d 2H), 0.25 (s, 2H) * Example 12, 13 (3a5", 55^63/0-63-(3 , 4-dichlorophenyl)-5-decyloxy_2, 3 plus & $ hexahydro-1 and-cyclopenta[c]D ratio succinate (33^5^685)-68- (3,4-dichlorophenyl)-5-methoxy-2,3 3a 4 5 hexahydro-1 and-cyclopenta[c]indole.

Will (3a#, 5 and, GaiS/SaiS1, 55", 6a_ff)-3a~(3, 4-diphenyl)-5-nonyloxy-2' 3, 4, 5, 6' 6a-six Hydrogen-if cyclopenta[c]pyrrole hydrochloride 4 (737. 8 mg' 2.29 mmol) was subjected to chiral separation, and the isomer was separated by chiral column using Ηριχ method. Separation conditions: chirality Column Chiralpakl A, mobile phase: decyl alcohol: diethanolamine = 1 〇〇: 〇 1, flow rate: 0.8 ml / min) 'Collect the corresponding components, remove the solvent by rotary evaporation, and dry at room temperature for 4 hours under vacuum to obtain the title Product (3a parent 55I, 6a^_6a_(3,4-dichlorophenyl)-5-methoxy-2,3,3a,4,5,6-hexahydro-ljy-cyclopenta[c]pyrrole Hydrochloride 12 (277.7 mg, white solid, e e. = 97 8 〇 / 〇) and (3ae, 5 Yun 6 & 5 ·)-6 &-(3, 4-diphenyl)-5-oxime Oxy-2,3,3a,4,5,6-hexahydro-If cyclopenta[c]indole hydrochloride 13 (260. 7 95343 72 201213305 mg' white solid, ee. = 98.5%). Example 14, 15 (4) 55; 6ay?), 6a_(3, chlorophenyl) + ethoxy-2, 3, 3a, 4, 5, 6-hexahydro~1 and cyclopenta[c]pyrrole Acid salt (3 from 'slightly 6a_(3, 4, diphenyl) + ethoxy-2, 3 , 3a,4, 5, 6-hexahydro and 'cyclopenta[c]pyrrole hydrochloride

HCI HCI will (3 from 5A>, 6a5y3咕6a«-3a-(3, 4-two gas stupid), two R ethylenediyl 2' 3, 4' 5' 6, one hexahydro-1 and - cyclopentane And [C]pyrrole hydrochloride mg U8 _〇1) was subjected to chiral separation, using Ηρα method, by hand Du; Gui isomer separation (separation conditions: chiral column OnralpaklA, mobile phase: sterol : Diethanolamine = 1 〇〇: 〇. [, flow rate: 〇 8 ml/min) 'Collect the corresponding components, remove the solvent by rotary evaporation, and dry under vacuum for 4 hours to give the title product (3aS, 55; 6a ^-6a_· (3, 4-dihydrophenyl) _5_ethoxy 2, 3, for example, 4, 5, 6-hexahydrocyclopenta[C]pyrrole hydrochloride 14 (286. 2 mg , white solid) and (3a^>, 5疋6a 幻~6a_(3' 4-diphenyl)-5-ethoxy-2, 3, 3a, 4, 5, 6-hexahydro-if Cyclopenta[c]pyrrole hydrochloride 15 (326.9 mg, white solid). Example 16 Benzoic acid [(3a brother 5疋6a573a5; 55; 6aA〇-3a-(3, 4-diphenyl)) 2 , 3, 4, 5, 6, 6a-hexahydro-1 and-cyclopenta[c]pyrrole-5-yl]ester hydrochloride 95343 73 201213305

Ci

16 First step (3af, 5疋6a573a5; 55; 6af)-5-benzoquinoxy-3a-(3, 4-dichlorophenyl)-1,3, 4, 5, 6, 6a-hexahydro Cyclopenta-Butyl-2-decanoic acid tert-butyl ester benzoic acid (244 mg, 2.00 mmol) and (3ay?, 5疋6a573a5; 55; 6a7?)-3a-(3, 4-diphenylphenyl) ) 5-hydroxy-1,3,4,5, 6, 6a-hexahydrocyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 4b (744 mg, 2. 00 mmol) dissolved in 20 mL two To the chloroform, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (460 mg, 2.40 mmol) and 4-diamine. The ratio was 0 (12. 2 mg, 0.20 mmol) and the reaction was carried out for 12 hours. The reaction mixture was concentrated under reduced pressure, and then purified, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -Dichlorophenyl)-1,3,4,5, 6, 6a-hexahydrocyclopenta[c]. Butyl-2-butyric acid tert-butyl ester 16a (530 mg, white solid), yield · · 56.0%. The second step is benzoic acid [(3ay?, 5 feet 6a573a5; 55; 6aA〇-3a-(3, 4-dichlorophenyl)-2, 3, 4, 5, 6, 6a-hexahydro-1 and -cyclopenta[c]pyrrole-5-yl]ester hydrochloride 74 95343 201213305 to (3a; P, 5 especially 6357336: 55; 6a; P)-5-benzoquinoneoxy-3a-(3, 4 -monochlorophenyl)~],3,4,5, 6, 6a-hexahydrocycloindole 〇Jo than p each-2-f acid second butyl S曰16a (500 mg,1· 〇5 mmol) 2. The solution of 2. Μ hydrogen sulfide in ethyl acetate was added until the reaction solution had a pH value of 2, and the reaction was carried out for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title product benzoic acid [(3 &^5^6β573&5,, 55;6&)?) -3a-(3,4-diphenyl)-2, 3, 4, 5, 6, 6a-hexahydro-1 and -cyclopenta[c] each-5-yl ] vinegar hydrochloride 16 (390 mg 'white solid), yield: 9 〇. MS m/z (ESI): 377.7 [M+l] <RTI ID=0.0&0> 7. 60(d, 1H), 7.53 (m, 2H), 7.44-7.41 (dd, 1H), 5.55-5.50 (m, 1H), 3.85-3.74 (m, 3H), 3.47-3.36 (m, 2H ), 2.78-2.70 (m, 1H), 2.61-2.52 (m, 2H), 2.13-2.07 (m, 1H) Example 17 °Cert-2-carboxylic acid [(3a^5 especially SaS/SaiS1,551, 6a)-3a-(3,4-diphenyl)-2, 3, 4, 5, 6, 6a-hexahydro-1 and-cyclopenta[c]pyrrole-5-yl]ester hydrochloride

95343 75 201213305 First step (3a7?,5 especially 6a573a5*,55; 6a7?)-3a-(3,4-dichlorophenyl)-5-(thiophene-2-decyloxy-1,3, 4, 5, 6, 6a-hexahydrocyclopenta[c]pyrrole-2-furic acid tert-butyl ester 2_ 〇 曱 曱 ( (256 mg, 2. 00 mmol) and (3a brother 5 brother 6a573a5 551, 6aA〇-3a-(3,4-dichlorophenyl)-5-hydroxy-1,3,4,5, 6, 6a-hexahydrocyclopenta[c]pyrrole-2-carboxylic acid Butyl ester 4b (744 mg, 2. 00 mmol) was dissolved in 20 mL of methane, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (460 mg) was added. , 2.40 mmol) and 4-diaminoamine 0-precipitate (12. 2 mg, 0.20 mmol), react for 12 hours. Concentrate the reaction solution under reduced pressure, using a gel column chromatography to eluent system A The obtained residue was purified to give the title compound ( </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> </RTI> <RTIgt; , 3, 4, 5, 6, 6a-hexahydrocyclopenta[c]pyrrole-2-furic acid tert-butyl ester 17a (210 mg, white solid), yield: 20.0%. MS m/z (ESI): 384 [M+l-100] The second step is thiophene-2-decanoic acid [(3a especially 5 friends, 551, 6a and)-3a-(3, 4-dichlorophenyl) -2, 3, 4, 5, 6, 6a-hexahydro-1 and -cyclopenta[c]pyrrole-5-yl]ester hydrochloride (3a especially 5疋6a573a5; 55; 6a left)-3a-( 3, 4-dihydrophenyl) -5-(嗟-phen-2-yloxy-1,3, 4, 5, 6, 6a-hexahydrocyclopenta[c]° ratio p -2- Add 2.6 Μ hydrogen peroxide in ethyl acetate to the reaction solution for pH 2 and react for 2 hours. 76 95343 201213305 Concentrate the reaction solution under reduced pressure to obtain the reaction solution of the third hydrazine citrate 17a (190 mg, 0.39 mmol). Title product porphin formic acid ^ [(3aA*, 5 especially 6&amp;ι9/335&quot;, 55&quot;, 6a^〇-3a_(3, 4~ dibenzobenzene 2, 3, 4, 5, 6, 6a-hexanitrogen -1 and -cyclopenta[&lt;^] 〇 洛 __5~义·] t 酉 酉 魄 魄 魄 ( 17 (160 mg, colorless liquid), yield: 97.0%. MS m / z (ESI): 382.0 [M+l] Ή NMR (400 MHz, CDaOD): δ 7.88 (dd, 1H) 7 83 (dd, 1H), 7.68 (d, 1H), 7.59 (d, 1H), 7.43- 7'4〇(d^ 1H), 7.23-7.21 (dd, 1H), 5.54-5.49 (ra, 1H), 3. 83.3 ?5 (m, 3H), 3.46-3.37 (m, 2H), 2.73- 2.66 (m, iH) 2.55-2.53 (m, 2H), 2.11-2.06 (m, 1H) Example 18 (3a)?, 5 and 6a573a5·, 57?, 6a)-3a-(3, 4- Dioxophenyl)-5-fluoro-2, 3, 4, 5, 6, 6a-six Hydrogen-1 ugly-cyclopentamidine]pyrrole fumarate

0

First step (3ay?, 6a573a5; 5 especially 6a7?)-3a-(3,4-dichlorophenyl)-5-fluoro-1,3,4, 5, 6, 6a-hexahydrocyclopenta[ c] 0 to p each _2-carboxylic acid tertidine (3a^P, 5疋6a573a5; 55; 6aA〇-3a-(3,4-diphenyl) 77 95343 201213305 -5-hydroxy- 1,3, 4, 5, 6, 6a-hexahydrocyclopenta[c&gt; is more soluble in 5 mL of dichlorochloride than β-butyl 3-carboxylic acid tert-butyl ester 4b (372 mg ' 1. 〇〇_〇1) In decane, diethylaminosulfur trifluoride (187 mg, 1.1 mmol) was added at -60 ° C for 1 hour at -60 ° C. The reaction solution was concentrated under reduced pressure and chromatographically filtered The residue obtained was purified by eluent system B to give the titled product (3a, 55; 6a573a5, 5, and 6a)-3a-(3, 4-dichlorophenyl)-5-fluoro-1,3 , 4, 5, 6, 6a-hexahydrocyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 18a (280 mg, colorless liquid), yield: 74.8% 沱 NMR (400 MHz , CDC13): δ 7.45-7.42 (m, 2H), 7. 21-7. 18 (dd, 1H), 5. 42-5. 24 (m, 1H), 4. 04-3. 72 (m, 1H), 3.70-3.50 (m, 1H), 3.46 (d, 1H), 3.42-3.31 (in, 1H), 3.07-2.98 (ra, 1H), 2. 52-2. 34 (in, 3H), 2.01-1.81 (m, 1H), 1. 50 (s, 9H) The second step (3aA\ 55&quot;,6a573ai9,5·/?,6a_^)-3a_(3, 4-diphenyl)_5-gas-2, 3, 4, 5, 6, 6a-six Hydrogen-1 and -cyclopenta[c]pyrrole hydrochloride to (3a)P, 55; 6a573a5*, 5疋6ai?)-3a-(3, 4-diphenyl)-5-fluoro-1 , 3, 4, 5, 6, 6a-hexahydrocyclopenta[c]pyrrole-2-furic acid tert-butyl ester 18a (280 mg '0.75 mmol) was added with 2. 6 Μ hydrogen chloride in ethyl acetate The solution was brought to pH 2 of the reaction solution and reacted for 12 hours. Concentration of the reaction mixture under reduced pressure gave the title product (3a br. 56; 6a573a5; 5 especially 6aA〇-3a-(3, 4-dichlorophenyl)-5-fluoro-2, 3, 4, 5, 6, 6a- Hexahydro-1 and -cyclopenta[c] ° ratio 11 hydrochloride 18b (270 mg, colorless liquid), yield: 1 〇〇〇 / 0. NMR (400 MHz, DMSO-c/O: s 6.82 (d, 1H), 6.73 (d, 78 95343 201213305 1H), 6.58-6.55 (dd, 1H), 4.53-4.38 (m, 1H), 2.88 (d, 1H), 2.80-2.75 (m, 1H) ), 2.72-2.63 (m, 2H), 2.58-2.54 (m, 1H), 1.75-1.56 (m, 3H), 1.28-1.11 (m, 1H) The third step (3a foot 55; 6a573a5; 6aA)- 3a-(3,4-dichlorophenyl)-5-fluoro-2,3,4,5,6,6a-hexa-1,-cyclopenta[c]ebiproxilate will 3ae, 55; 6a573a5; 5 no, 6af)-3a-(3, 4-diphenyl)-5-fluoro-2,3,4,5, 6, 6a-hexanitro-1 and ring [^^. Biluohydrochloride 18b (232 mg '0.75 mmol) was dissolved in 5 mL of water and 5 mL of methanol, and sodium hydroxide (60 mg, 1.50 mmol) was added and allowed to react at room temperature for 2 hours. Add 20 mL of water and 20 mL of dioxane, layer. The aqueous layer is extracted with two gas oxime (20 mL×2), and the organic phase is combined with anhydrous sulfuric acid, dried, filtered, and concentrated under reduced pressure. The filtrate was reacted with 3 mL of ethyl acetate and fumaric acid (80.0 mg, y. 75 mmol) for 12 hours. The residue was filtered and dried in vacuo to give title product (3af, 55; 6 &amp;3&amp;5; 5 brother 6ai?)-3a-(3, 4-diphenyl)-5-gas-2, 3, 4, 5' 6,6a-hexahydro-1 and -cycloindole[c ]nit^fumarate 18 (236 rag, white solid), Yield: 81. 1%. MS m/z (ESI): 274.0 [M+l] NMR (400 MHz, DMSO-heart): 5. 7.63 (d, 1H), 7. -3.20 (m, 1H), 3. 17-3 n (m, 1H), 3.03-2. 95 (m, 2H), 2.42-2.21 (m, 3H) 1.96-1.80 (m, 1H) ' 19 95343 79 201213305 (3a/?,6a5/3a5·,6a and)-3a-(3,4-diphenyl)-5-ethyl-2, 3, 4, 5, 6, 6a-hexahydrogen -1 and - cyclopenta-fumarate

First step (3ai?, 6a573a5; 6a and)-3a-(3,4-diphenyl)-5-ethylidene-3,4'6'6a-tetrahydro-cyclopenta[c]pyrrole 2-3 tert-butyl carboxylic acid was added to hexamethyl bisphosphonate green in the broad-ethyl-diphenyl-phosphorus (1.8 g, 4.73 dissolved in ι〇虬四(四)' i site, 4.05 mmol) 78 C reaction time. 5 hours. Add i〇mL (3ae, 6a5〇3a (3'4 a gas base)_5_oxo-3 4,l tetraaza-cyclopenta[c] than 2,butyl carboxylic acid 2, such as (10) 〇呃, 135 _1 ;) The tetrahydrogenated solution was reacted at room temperature for 12 hours. Add this water, separate the liquid, extract the aqueous phase with ethyl acetate, train mT 〇, ,, and take c30mLX3), combine the organic phase, dry magnesium sulfate, R ^ decompression 'Nongji' with % hose column The residue obtained by chromatography was eluted to give the title product (10) ▲ still 仏, (10) -3a-(3,4-diphenyl)_5~ and [small ratio _2-carboxylic acid butyl-butyrene _ 3,4,6,6a-tetraqilu cyclopentane yield H _19_?, pale yellow liquid), 80 95343 201213305 MS m/z (ESI): 282 [M+l-100] second step ( 3a brother 6a^〇-3a-(3,4-dichlorophenyl)-5__ Emei-1,3,4,5, 6, 6a-hexahydrocyclopenta[e]n ratio B, 2~ Tert-butyl formate T (3a especially 6a5/3a5; 6aA〇-3a-(3,4-dichlorophenyl)-5__ethylidene-3, 4, 6, 6a-tetrahydro-1β-ring Pentam[c] 〇比洛~2~• Formic acid Thirteen 酉 19a (264 mg, 0.69 mmol) was dissolved in 10 mL of ethanol, added with platinum dioxide (19 mg, 〇.〇7 mmol), hydrogen The reaction was carried out for 5 hours under an atmosphere. The reaction mixture was filtered to reduce the concentration of the sputum. The obtained residue was purified by the eluent column chromatography to afford the title product (3a _3a-(3, 4-) chlorobenzene -5-ethyl-1,3,4,5,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester I9b (265 mg, yellow oil), yield: 100% MS m/z (ESI): 285.1 [M+l-100] The third step (3a foot 6a5V3a5; 6ai〇-3a-(3, 4-dichlorophenyl)-5-ethyl-2, 3, 4, 5, 6, 6a-hexahydro-10,000-cyclopentadol (3a especially 6a5&gt;3a5; 6a«-3a-(3,4-dichlorophenyl)-5-ethyl- 1,3, 4, 5, 6, 6a-hexahydrocyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 19b (265 mg, 0·69 mmol) was dissolved in 1 mL of dichloromethane and added Trifluoroacetic acid (197 mg ' 1.73 mmol), reaction for 12 hours. The reaction solution was washed with saturated sodium bicarbonate solution (10 mL×2), water (1 〇mL×2), and saturated sodium chloride solution (10 mL×2). The organic phase was separated, dried over anhydrous sulphuric acid, filtered, and concentrated under reduced pressure to give the title product (3a, g, g, s, s, s, s, s, s, s, s, s, s, s, s, s, s, , 3, 4, 5, 6, 6a~·hexahydro-1#-cyclopenta[c]pyrrole 19c (200 mg, yellow liquid), yield: 1%. The fourth step (3a#,6aiSy3ai9, 6a疋)-3a-(3,4-dichlorophenyl)-5-ethyl-2, 3, 4, 5, 6, 6a-hexahydro-1 and ring Pentative [c]D than o-fumarate will be (3a^P, 6a5y3a5; 6aiP)-3a-(3,4-dichlorophenyl)-5-ethyl-2, 3, 4, 5, 6 , 6a-hexahydro-1#-cyclopentazone each 19c (200 mg, 0.69 mmol) was dissolved in 10 mL of ethyl acetate, and fumaric acid (80. 0 mg, 0.69 mraol) was added. hour. The reaction solution was filtered, and the cake was collected and dried in vacuo to give the title product (3ae, GaSy^vS1, 6a-free)-3a-(3, 4-dichlorophenyl)-5-ethyl-2, 3, 4, 5 , 6, 6a-hexahydro-1 and -cyclopenta[c]e than hafumarate 19 (155 mg, white solid), yield: 55.4%. MS m/z (ESI): 284.1 [M+1] &lt;RTI ID=0.0&gt;&gt; s, 2H), 3.57 (d, 1H), 3.30-3. 20 (m, 1H), 3.10-2.93 (m, 310/ 2.30-2.18 (m, 1H), 2.15-2. 05 (m, 1H) , 1.80- 1.61 (m, 2H), 1.33-114 (m, 3H), 0.82 (t, 3H) Example 20 (3a)P, 6ai*?)-3a-(3,4-dichlorophenyl) -5, methylene-1,2,3,4, 6, 6a-hexahydrocyclopenta[c]]11biproxate

95343 82 201213305

First step (3aiP' 6a5y3a5; 6a none) -3a-(3,4-dichlorophenyl)-5-methylene-3, 4, 6, 6a-tetrahydro-1 and -cyclopentapine|&gt ;] pyridin-2-decanoic acid third vinegar bromine-mercapto-triphenyl-Dendrobium (1.11 g, 2.84 mmol) dissolved in 1 〇mL tetrahydrofuran 'Add at -78 ° C Hexamethyl decylaminoamine clock (4.86 mL, 2.43 mmol) was reacted at -78 °C for 30 minutes. Add 5 roL (3a no, 6a5y3a5; 6a^?)-3a-(3, 4-diphenyl)-5-oxo-3, 4, 6, 6a-tetrahydro-1 and _cyclopenta[ c] A solution of dipyridyl-2-carboxylic acid terpene 4a (300 mg, 0.81 mol) in tetrahydrofuran at room temperature for 12 hours. Add 100 mL of saturated ammonium hydride solution, separate the liquid, extract the aqueous phase with ethyl acetate (30 mL×3), combine the organic phase, dry over anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was purified to give the title product (38^6 &51/385;63)?)-3&-(3,4-diphenyl)-5-indolyl-3, 4, 6, 6a-Tetrahydro-1 and -cyclopentabutrol-2-carboxylic acid tert-butyl ester 20a (198 mg 'light yellow liquid), yield: 66.3%. 4 丽R(400 MHz, CDC13): (5 7. 43(d,1H), 7.40(d,1H), 7.15 (dd, 1H), 5.00 (d, 2H), 3.77-3.55 (m, 3H), 3.32-3.25 (m, 1H), 2.92-2.83 (m, 1H), 2.80-2.70 (m&gt; 3H), 2.38 (d, 1H), 1.45 (s, 9H) Step 2 83 95343 201213305 ( 3a^ GaiSVBaiS*, 6a_A〇-3a-(3, 4-diphenyl)_5-indenyl-1,2,3, 4, 6, 6a-hexahydrocyclopentane|» 3ai?,GaS/BaiS1,6a friend)-3a-(3,4-dichlorophenyl)-5-indenyl-3, 4, 6, 6a-tetrahydro-1 and-cyclopenta[c] Pyrrol-2-pyruic acid tert-butyl ester 20a (198 mg, 0.54 mmol) was dissolved in 5 mL of dioxane and added trifluoroacetic acid (153 mg, 1.34 mmol) for 12 hours. The mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate (5 mL?), water (5 mL?)? (3ay?,6a5y3a5;6ai?) -3a-(3,4-dichlorophenyl)-5-methylene-1,2,3,4, 6, 6a-hexahydrocyclopenta[c]pyrrole 20b (150 mg, yellow liquid), yield: 1%. The third step (3ai?, 6a5/3a5; 6a and)-3a-(3, 4- Dioxophenyl)-5-arylene-1,2,3,4,6,6a-hexahydrocyclopenta[c]&lt;* ratio p fumarate will (3a·/?, 6a And -3a_(3,4~dichlorophenyl)_5-methylene-1,2,3,4,6,6a-hexahydrocyclopentapine|&gt;]pyrrole 2〇b (i3〇mg, 48. 48 mmol) dissolved in 10 mL of ethyl acetate 'Add fumaric acid (56. 〇, 〇 48 mmol) 'Reaction for 12 hours. The reaction cake was collected and dried in vacuo to give the title product (3af, Phenylphenyl)-5_arylene-1,2,3,4,6,6a-hexahydrocyclopenta[c]pyrrole fumarate 2〇 (108 mg, white solid), yield: 58. 0%. MS m/z (ESI): 268.0 [M+l]^ NMR (400 MHz, CDCh): δ 7. 65 (d, 13⁄4) 7 59 (d 1H) 7. 38 (dd, 1H) , 6.48 (s, 2H), 4.90 (a, 2H), 3.52-3.45 95343 84 201213305 (dd, 1H), 3.40 (s, 2H), 3.10-2.96 (m, 2H), 2.82 (d, 1H), 2.75-2.55 (m, 2H), 2.34 (d, 1H) Example 21 (3aiP, 6&amp;5·/335·, 6aA〇-3a-(3, 4-diphenyl)-5-(2- Fluoroethyl)-2, 3, 4, 5, 6, 6a-hexahydro-1 and-cyclopenta-fumarate

The first step (3 &amp; friend, 6aW) _3a_(3,4_dichlorophenyl)_5_(2_ethoxy-2-oxo-ethylidene)-3, 4, 6, 6a-tetrahydro-1 And-cyclopenta[c]D to 17-butyl-2-carboxylic acid tert-butyl ester. Sodium hydride (277 mg, 6.91 mmol) was suspended in 30 mL of tetrahydrofuran, and 2-diethoxy group was added. Ethylphosphonium acetate (1.55 g, 6.91 mmol) was reacted for 30 minutes. Add 20 mL (3a疋GaiS/BaiS1,6ae) -3a-(3,4-dichlorophenyl)-5-oxo-3, 4, 6, 6a-tetrahydro-1 and -cyclopenta[c a solution of n-butyl-2-carboxylic acid tert-butyl ester 4a (1. 28 g, 3.45 mmol) in tetrahydro 85 95343 201213305 furan for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue obtained was purified eluting with EtOAc EtOAc EtOAc EtOAc (EtOAc -5-(2-ethoxy-2-oxo-ethylidene)-3, 4, 6, 6a-tetrahydro-1 and -cyclopenta[c]B than pyro-2-pyruic acid Butyl ester 21a (1.05 g, colorless liquid), yield: 69. 0%. !H NMR (400 MHz, CDCh): δ 7.40-7.31 (m, 2 Η), 7.13-7.05 (in, 1H), 5.84-5.52 (m, 1H), 4.18-4.10 (m, 2H), 3. 87-3. 13 (m, 6H), 2.96-2.80 (m, 2H), 2.79-2.48 (m, 1H), 1.46 -1.42 (m, 9H), 1.29-1.25 (m, 4H) The second step (3aiP, 6a5y3a5; 6aA〇-3a-(3, 4-dichlorophenyl)-5-(2-ethoxy-2 -oxo-ethyl)-1,3,4,5, 6, 6a-hexahydrocyclopenta[c]° pyridine-2-carboxylic acid tert-butyl ester (3a especially 6a5y3a5*,6a^〇- 3a-(3,4-dichlorophenyl)-5-(2-ethoxy-2-oxo-ethylidene)-3, 4, 6, 6a-tetrahydro-1 and -cyclopenta-2 -Dibutyl methacrylate 21a (484 mg, 1.10 mmol) was dissolved in 20 mL of ethanol, and platinum dioxide (48 mg, 10%) was added thereto, and the reaction was carried out for 1 hour under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was evaporated. With a rubber hose Chromatography The residue obtained was purified using eluent B to give the title product (3a) P,6a)?)-3a-(3,4-dichlorophenyl)-5-(2-ethoxy-2- Oxo-ethyl)-1,3,4,5,6,6a-hexahydrocyclopentarene|&gt;]pyrrole-2-carboxylic acid tert-butyl ester 21b (387 mg 'colorless oil), yield : 87. 6%. 'H NMR (400 MHz, CDCh): d 7. 38 (d, 1H), 7. 33 (d, 1H), 7.10-7. 08 (dd, 1H), 4.14-4. 09 (m, 2H), 3.76-3.23 (m, 86 95343 201213305 5H), 2. 85-2. 74 (m, 1H), 2.49-2.37 (m, 3H), 2.35-2.22 (m, 2H), 1.73-1.65 (m, 1H), 1.46 (s, 9H), 1.39-1.22 (m, 3H) Brother three steps (3a^ eaS/SaiS1,6a^〇-3a-(3, 4-dichlorophenyl) -5_(2-ethyl)-1,3,4,5,6,6a-hexahydrocyclopentane &amp;[c]npyr-2-carboxylic acid tert-butyl ester (3a)?,6a5/ 3a5; 6a^?)-3a-(3,4-diphenyl)-5-(2-ethoxy-2-oxo-ethyl)-1,3, 4, 5, 6, 6a- Hexahydrocyclopentazone I bromide-2-carboxylic acid tert-butyl ester 21b (350 mg, 0.80 mmol) was dissolved in 10 mL of tetrahydrofuran, and lithium tetrahydrogenate (60 mg, 1.60 mmol) was added for 2 hours. . After adding 50 mL of water and 50 mL of ethyl acetate, the mixture was separated and the aqueous phase was extracted with ethyl acetate (50 mL×4), and the organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and washed with silica gel column chromatography. The resulting residue was purified by Detachment B to give the title product (3 &amp;&lt;&quot;&&&&&&&&&&&&&&&&&&&&&&&&&&& -1,3,4,5, 6, 6a-hexahydrocyclopenta[c]pyrrole-2-furic acid tert-butyl ester 21c (270 mg, colorless liquid), yield: 84.3%. !H NMR (400 MHz, CDCla): δ 7.38-7.36 (d, 1Η), 7.32-7.31 (d, 1H), 7.09-7.06 (dd, 1H), 3.75-3.57 (ra, 4H), 3.51 (s , 1H), 3.33-3.24 (m, 1H), 3.83-3.75 (m, 1H), 2.31-2.07 (m, 3H), 1.71-1.62 (m, 3H), 1.48-1.44 (m, 9H), 1.35 -1.21 (m, 2H) The fourth step (3aj?, 635/385; 6aA〇-3a-(3,4-dichlorophenyl)-5-(2-difluoroethyl 87 95343 201213305)-1, 3, 4, 5, 6, 6a-hexahydrocyclopentanyl-2-phthalic acid tributyl hydrazine (3ai&lt;?,6a7?)-3a-(3,4-diphenyl)-5- (2-hydroxyethyl)-1,3,4,5,6,68-hexahydrocyclopenta[[], 1 each 2-carboxylic acid tert-butyl ester 21c (270 mg, 0·68 mmol) Dissolved in 5 mL of dichlorohydrazine in '60-degrees (: adding diethylaminosulfur trifluoride (12611^, 0.74111111〇1), -60° (: 1 hour reaction. Concentrate the reaction solution under reduced pressure, use The residue obtained by purifying the column chromatography with eluent system B gave the title product (3ae, GaiS/BaiS, 6a^〇_3a_(3,4-disuccinyl)-5-(2-diqi B) -1, 3, 4, 5, 6, 6a-hexahydrocyclopenta[c]pyrrole-2-furic acid tert-butyl ester 21d (100 mg, colorless liquid), yield: 36.9%. ]H NMR (400 M Hz, CDCh): δ 7. 37 (d, 1Η), 7. 32 (d, 1H), 7.09-7.06 (dd, 1H), 4.39-4.36 (t, 1H), 4.51-4.39 (t, 1H) , 3.78-3.39 (m, 4H), 3.74-3.22 (m, 1H), 2.83-2.74 (m, 1H), 2.32-2.19 (m, 2H), 1.86-1.64 (in, 3H), 1.46 (s, 9H), 1.37-1.28 (m, 1H) The fifth step (3a especially 6a5/3a5; 6aA〇-3a-(3,4-dichlorophenyl)-5-(2-difluoroethyl)-2, 3, 4, 5, 6, 6a-hexahydro-1 and -cyclopenta[c]n ratios (3a brother GaS/BaS, 6aA〇-3a-(3, 4-diphenyl)) 5-(2-difluoroethyl)-1,3,4,5, 6, 6a-hexahydrocyclopenta[c]° 嘻-2-carboxylic acid tert-butyl ester 21d (145 mg, 0.36 Methyl) was dissolved in 5 mL of dichloromethane, and trifluoroacetic acid (822 mg, 7.2 mmol) was added for 2 hours. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate (10 mL), EtOAc (EtOAc) (EtOAc) The title product was obtained (3a-foot-3a-(3,4-diphenyl)-5-(2-difluoroethyl)-2, 3, 4, 5, 6, 6a-hexahydro-1#-cyclic Pentacene [c]pyrrole 21e (lll mg 'colorless liquid), yield: 100%. Step 6 (3ae, eaS/SaS, 6aA〇-3a-(3, 4-diphenyl)-5-( 2-fluoroethyl)-2,3,4,5, 6, 6a-hexahydro-1 and-cyclopenta-rhofuranoate (33^,635|/3&amp;51,6&amp;^&gt ;)-33_(3,4_二气笨基)-5-(2-difluoroethyl)-2, 3, 4, 5, 6, 6a-hexahydro-1 and -cyclopentazone]β Biloxi 21e (108 mg, 0.36 mmol) was dissolved in 3 mL of ethyl acetate, and fumaric acid (40.0 mg '0.36 mmol) was added and reacted for 12 hours. The reaction mixture was filtered, and the mixture was filtered, dried and dried in vacuo. , the title product is obtained ((3a especially 6a5/3a5; 6a and)-3a-(3,4-dichlorophenyl)-5-(2-fluoroethyl)-2, 3, 4, 5, 6, 6a - hexahydro-1 and -cyclopenta[c]D ratio p fumarate 21 (108 mg, white solid) Yield: 72.0% MS m/z (ESI): 302.0 [M+l] *H NMR (400 MHz, DMSO-i/O: δ 7.61-7.55 (m, 2H), 7.39-7.32 (m , 1H), 6.48 (s, 2H), 4.35 (t, 1H), 4.47 (t, 1H), 3.51-3.49 (m, 1H), 3.18-3.13 (m, 1H), 2. 99-2. 88 (m, 3H), 2. 34-2. 23 (m, 1H), 2. 18-2. 08 (m, 1H), 1.88-1.79 (in, 1H), 1.74-1.60 (m, 3H), 1.21-1.14 (m, 1H) Example 22 (3a^ GaiS/BaS1,6af)-3a-(3, 4-dioxaphenyl)-5__methyl-2, 3, 4, 5, 6, 6a- Hexahydro-1 and-cyclopenta[&lt;^]°biprofenate 95343 89 201213305

Ci

(3a7?, eaS/BaS, 6ai?)-3a-(3,4-diphenyl)_5-methyl-1,3,4,5, 6, 6a-hexahydrocyclopenta[c]* »Compared to p each 2-carboxylic acid tert-butyl vinegar (3aiP, 6a5y3a5; 6a«-3a-(3, 4-diphenyl)-5-methylene_3, 4,6, 6a-tetrazo _1 and - cyclopenta[c]° piroxicam-2 - formic acid tertidine 20a (300 mg, 0.8 mmol) was dissolved in 15 mL of ethanol and added to the surface of the dioxide (30 rag, 10%) The reaction was carried out for 2 hours under a hydrazine atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography with eluent system B to give the title product (3a 6a5/3a5; 6aiP)-3a-(3 ,4-dichlorophenyl)-5-methyl-1,3,4,5, 6, 6a-hexahydrocyclopenta[c]pyrrole-2-ytidine butyl ester 22a (150 mg, Colorless oil), Yield: 5 〇. NMR NMR (400 MHz, CDCh): δ 7.43-7.35 (m, 2 Η), 16-7. 10 (m, 1 Η), 3.90-3.44 (m, 4H ), 2.82-2.70 (m, 2H), 2.28-2. 12 (m, 2H), 1.76-1. 58 (m, 2H), l.1 (M. 〇 6 (m, 3H) ' 95343 90 201213305 (3a_/P, 6a5!/3ak9, 6a none)-3a_(3,4-dichlorophenyl)-5-methyl_2, 3, 4, 5, 6, 6a-hexahydro-1 And -cyclopenta[c]*» ratio Slightly fumaric acid to (3ai?,6a5&gt;3a5; 6a magic-3a-(3,4-dichlorophenyl)_5_methyl_1, 3, 4, 5, 6,6a-hexazacyclopenta [c] 0 piroxicam-2 - decanoic acid tributyl ketone 22a (150 mg '0.40 mmol) was added 1.5 Μ of hydrogenated hydrogen acetate in ethyl acetate to the reaction solution at pH 2 for 12 hours. The reaction solution was concentrated under reduced pressure, and 5 mL of water and 5 mL of decyl alcohol were added, and sodium hydroxide (60 mg, 1.50 mmol) was added and reacted for 2 hours. 20 mL of water and 20 mL of dichloromethane were added, and the solution was separated. The mixture was extracted with two gas chambers (20 mL×2). The organic phase was combined, dried over anhydrous magnesium sulfate, and dried under reduced pressure. Methyl) 'Reaction 12 hr. Filtration' was collected and filtered in vacuo to give title product (3 &amp; Base-2, 3, 4, 5, 6, 6a-hexahydro-1 and cyclopenta[c]pyrrole fumarate 22 (73 mg, white solid), yield: 37. 〇%. !H NMR (400 MHz, DMSO-^): ^ 7.59-7.55 (m, 2H), 7.37-7.33 (m, 1H), 6.48 (s, 2H), 3.53-3.41 (m, 2H), 3.00-2.83 (m, 3H), 2.24-2.16 (m, 1H), 2.08-1.95 (m, 1H), 1.89-1.76 (m, 1H), 1.59-1.53 (in, 1H), 1.16-1.08 (m, 1H) , 0.98-0.94 (m, 3H) Example 23 (3a7?, GaS/SaS, 6a«-3a~(3,4-dichlorophenyl)-5, 5_difluoro-1,2, 3, 4 , 6, 6a-hexacyclopenta[c]pyrrole fumarate 95343 201213305

First step (3a brother 6a5^a5; 6a^?)-3a-(3,4-dichlorophenyl)-5,5-difluoro-3,4,6,6a-tetrahydro-1 and ring Pentylene [c]pyrrole-2-carboxylic acid tert-butyl ester (3a^ GaiS'/SaiS', 6a^〇_3a_(3, 4-diphenyl)_5_oxo-3, 4, 6, 6a-tetrahydro-1 and -cyclopenta[c]pyrrole-2-furic acid tert-butyl ester 4a (730 mg, 2. 00 mmol) was dissolved in 10 mL of dioxane, and added to the ice bath. Aminosulfur trifluoride (0. 94 mL, 2.50 mmol) was reacted for 18 hours at room temperature. The reaction mixture was concentrated under reduced pressure. (3a·/?,GaiS'/SaiS,6a^〇_3a_(3,4_diphenyl)-5,5_digas-3, 4, 6, 6a-tetrahydro-1 and -cyclopentyl And [c]pyrrole-2-carboxylic acid tert-butyl ester 23a (200 mg, pale yellow liquid), yield: 26.0%.

GaiS/BavS1,6a_/??_3a-(3,4-dichlorophenyl-5,5-dioxa-1,2,3,4, 6, 6a-hexahydrocyclopenta[c〇n ratio σ Each will (3ay?, BaiS/SaiS&quot;, 68^/?)_38_(3,4_dichlorophenyl)_5,5_two 92 95343 201213305 Fluorine-3, 4, 6, 6a-tetrahydro-If ring Pentylene [c]pyrrole-2-carboxylic acid tert-butyl ester 23a (160 mg, 0.45 mmol) was dissolved in 5 mL of dichloropyrene, and triacetic acid (822 mg '7.2 mmol) was added. The reaction solution was washed with a saturated aqueous solution of sodium hydrogencarbonate (10 mL×2), water (5 mL×2), and a saturated sodium carbonate solution (5 mL×2), and the organic phase was combined, dried over anhydrous magnesium sulfate and filtered. The title product -3,3-(dichlorophenyl-5,5-difluoro-1,2,3,4,6,6a-hexahydrocyclopenta[c]pyrrole 23b (80 mg, colorless) was obtained Liquid), yield: 67. 0〇/〇 third step (3a^?, 685/385, 6aA)-3a-(3,4-dichlorophenyl)-5, 5-difluoro-1,2 , 3, 4, 6, 6a-hexahydrocyclopenta[c]° 嘻 fumarate will (3a especially 68^-38-(3, 4-diphenylphenyl 5, 5-di--1) , 2, 3, 4, 6, 6a-hexahydrocyclopenta[c]pyrrole 23b (74 mg, 0.25 mmol) dissolved in 3 mL of ethyl acetate The fumaric acid (29. 〇mg, 〇. 25 mmol) was added and the reaction was carried out for 12 hours. The reaction mixture was filtered, and the filter cake was collected, dried in vacuo, and the title product (68^19/38^, 68··??) _3a~(3,4-Dichlorophenylene)-5,5-fluorois, 2,3,4,6,6a-hexacycline [c]° than slightly fumarate 23 (68 Mg, white solid), Yield: 67. 0%. NMR (400 MHz, DMS0-A): 5 7. 64 (d,1H),7 59 (d UO, 7.40-7.37 (dd,1H),6 · 56 (s, 2H), 3.34-3.30 (d, 1H), 3.23-3.17 (m, 1H), 3. 11 - 3. 01 (m, ih) 2 96-2 83 (m, 2H), 2 63-2. 53 (m, 2H), 2. 19-1. 95 (m 2H) Example 24 (3a^, 5^, Qd.S/3Q, S, 5^, 68^)-3^ -(3,4-dichlorobenzene) gas 95343 93 201213305 -2, 3, 4, 5, 6, 6a-hexahydro-1 million-cyclopenta[&lt;:]° ratio η each fumarate

First step (3a brother 5疋6a5y3aiS,55; 6aA〇-3a-(3,4-dichlorophenyl)_5-fluoro_1, 3, 4, 5, 6, 6a-hexahydrocyclopenta[c ]Pylobutyric acid tert-butyl ester will (3a/?,56&quot;,GaiS/SakS&quot;,5·/?,6aA)-3a_(3,4-diphenyl)-5-hydroxy- 1,3, 4, 5, 6, 6a-hexahydrocyclopentazone»»Butyl-2-butyrate tert-butyl ester 7b (260 mg '0. 80 mmol) was dissolved in 5 mL of dioxane, Diethylaminosulfur trifluoride (0.46 mL, 1.22 mmol) was added to an ice-water bath, and the mixture was reacted at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography with eluent system B. Title product /3a5·,551,6ae)-3a-(3,4-diphenyl)-5-fluoro-1,3,4,5, 6, 6a-hexahydrocyclopenta[c]pyrrole- 2-% butyl citrate 24a (250 mg, pale yellow liquid), yield: 96.0%. NMR NMR (400 MHz, CDCh): d 7. 43 (d, 1H), 7. 36 (d, 1H), 7. 12-7. 10 (dd, 1H), 5.41-5. 19 (m, 1H ), 3.98-3.76 (m, 2H), 3.74-3.60 (m, 1H), 3.59-3.45 (m, 1H), 2.96-2.85 (m, 1H), 2.56-2.29 (m, 3H), 2.16-1.98 (in, 1H) 94 95343 201213305 Step 2 (3ai?, 5 and, 6a573a5; 55; 6af)-3a-(3, 4-diphenyl)-5-fluoro~2, 3, 4, 5, 6, 6a-hexahydro-1 and -cyclopenta[c]n ratio α will be (3a especially 5 brother 6a573a5; 55; 6a and)-3a-(3, 4-diphenyl)-5-fluoro 1,3, 4, 5, 6, 6a-hexahydrocyclopenta[(^.) is soluble in 5 mL of dichlorinated than each of the 13-butyric acid tributyl sulfonium 24a (25 〇 mg, 〇. 67 mmol) In a hospital, di-acetic acid (822 mg, 7.2 mmol) was added and reacted for 2 hours. The reaction was washed with saturated sodium bicarbonate solution (10 mL×2), water (5 mL×2), and saturated sodium carbonate solution (5 mL×2). , liquid separation, combined organic phase, dry over anhydrous magnesium sulfate 'over; consider, concentrated sputum under reduced pressure to give the title product (3a ^? ' 5 feet 6a573a5; 55; 6a left) -3a- (3, 4- two gas Phenyl)-5-fluoro-2,3'4,5,6,6a-hexahydro-1 and-cyclopenta[c]pyrrole 24b (125. 6 mg, colorless liquid), Rate: 68. 6% Third step (3ai?, 5疋6a573a5; 55; 6ai?)-3a-(3, 4-diphenyl)-5-fluoro_2' 3, 4, 5, 6, 6a-hexahydro-1 and-cyclopenta[c]pyrrole fumarate (3a疋5 especially 6a573a5; 55; 6a7?)-3a-(3,4-dichlorophenyl)-5-fluoro- 2, 3, 4, 5, 6, 6a-hexahydro-1 and -cyclopenta[c]pyrrole 24b (125. 6 mg'0·46 mmol) were dissolved in 3 mL of ethyl acetate and fumaric acid was added. (53. 〇mg '0.46 mmol), reaction for 12 hours. The reaction mixture was filtered, and the filter cake was collected and dried in vacuo to give the title product (3ay?, 5y?, 6a573a5; 55; 6ay?)-3a-(3, 4- Dioxophenyl)-5-fluoro-2,3,4,5,6,6a-hexahydrocyclopenta[c] ton of fumaric acid 24 (50 mg, white solid), yield: 30.0%. !H NMR (400 MHz, DUSO-de): δ 7.65 (d, 1Η), 7.59 (d, 95 95343 201213305 1H), 7.39-7.36 (dd, 1H), 6.52 (s, 2H), 5. 32- 5. 12 (m, 1H), 3. 48-3. 38 (m, 2H), 3. 32-3. 24 (m, 1H), 3.07-2.96 (m, 2H), 2.42-2.12 (m, 3H), 1.97-1.87 (in, 1H) Example 25 (3aiP, 5 especially 685/335; 56; 6aW-3a-(3,4-dichlorophenyl)-5-decyloxy-2, 3, 4, 5, 6, 6a-hexahydro-1 furnace · cyclopentaphthyl fumarate

First step (3a^5 especially 6a573a5; 55; 6af)-3a-(3, 4-diphenyl)-5-decyloxy-2, 3, 4, 5, 6, 6a-hexahydro-1F Cyclopenta[c]° 〇(3aA,5疋6a573a5·,551,6aA〇-3a-(3,4-dichlorophenyl)-5-methoxy-1,3, 4, 5 , 6, 6a-hexahydrocyclopenta[c]D is slightly dissolved in 20 mL of di-methane and slightly triacetate (3. 87 mL). , 92 mmol), react for 5 hours. Concentrate the reaction solution under reduced pressure' Add 20 mL of a mixed solution of water and sterol (y/V = 1/i), add sodium hydroxide until the pH of the reaction solution is greater than 7, and react for 2 hours. The reaction mixture was decompressed under reduced pressure, and 1 mL of a two-gas methane and 1 mL of water were added, and the liquid phase was separated. 96 95343 201213305 was extracted with methylene chloride (100 mL×2), and the organic phase was combined with anhydrous magnesium sulfate. Dry, filter, and concentrate the filtrate under reduced pressure to give the title product (3a and 5, GavS/SaS, 551, 6a)-3a-(3, 4-dichlorophenyl)-5-methoxy-2,3 , 4, 5, 6, 6a-hexahydro-1 and -cyclopenta[c]e ratio 25a (l. 29 g, yellow liquid), yield: 98. 0%. MS m/z (ESI) : 286.1 [Μ] The second step (3a skin, 5 feet GaiSV^aS 551,6aA)-3a-(3,4-dichlorophenyl)-5-decyloxy-2, 3, 4, 5, 6, 6a-hexahydro-1ZM裒penta[c]e The acid salt will be (3af, 5 friends, 6a5y3a5·, 551, 6a free)-3a-(3, 4-diphenyl)-5-methoxy-2, 3, 4, 5, 6, 6a- Hexahydro-1 and-cyclopenta[c]pyrrole 25a (1. 291 g, 4. 51 mmol) was dissolved in 10 mL of ethyl acetate and fumaric acid (523 mg '4·51 mmol) was added. Hour. The reaction mixture was passed through and the filter cake was collected and dried in vacuo to give the title product (38 pi, 5 疋GaiS/SaiS1,551,6aA〇-3a-(3, 4-dichlorophenyl)-5 -Methoxy-2,3,4,5,6,6a-hexahydro-1 pi-cyclopenta[c]nitn each fumarate 25 (1. 69 g, white solid), yield: 93 5% MS m/z (ESI): 286.0 [Μ] !Η NMR (400 MHz, CDCh): δ 7. 63 (d, 1H), 7. 59 (d, 1H) 7.37 (dd, 1H) , 6.47 (s, 2H), 3.82-3.77 (m, 1H), 3·5〇 (d, 1H), 3.70 (dd, 1H), 3.23 (s' 3H), 3.I8 (d, 1H), 3. 10-3. 06 (m, 1H), 3. 02-2. 96 (m, 1H) 5 2 27-2 20 (m 2H), 2.12 (dd, 1H), 1.73-1.69 (m, ih Example 26 95343 97 201213305 (3a brother 5疋5 and 6aA〇-3a-(3, 4- Dichlorophenyl)-5-decyloxy-2,3,4,5, 6, 6a-hexahydro-1 and-cyclopenta[〇]pyridol

Will (3a especially 5疋6a573a5; 55; 6a) P)-3a-(3, 4-diphenyl)-5-nonyloxy-2, 3, 4, 5, 6, 6a-hexahydro-1 And - cyclopentazone 25a (3. 66 g, 12.8 mmol) was dissolved in 40 mL of ethyl acetate. Toluene acid (2.43 g, 12.8 mmol) was added and reacted for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title product (3a /?, 5, 6a573a5*, 55; 6a--3a-(3, 4-diphenyl)-5-decyloxy-2, 3, 4, 5 , 6, 6a-hexahydro-1 and -cyclopenta[c]n than p-toluenesulfonate 26 (6. 10 g, yellow solid), yield: 100%. MS m/z (ESI) : 286.1 [Μ] *Η NMR (400 MHz, CDCh): (5 8. 99 (s, 1H), 8. 44 (s, 1H), 7.66 (d, 1H), 7.61 (d, 1H), 7.49 -7.47 (m, 2H), 7.39 (dd, 1H), 7. 13-7. 10 (m, 2H), 3.88-3.84 (m, 1H), 3.69-3.64 (m, 1H), 3.52-3.46 ( m, 1H), 3.38-3.32 (m, 1H), 3.25(s, 3H), 3.24-3.18 (m, 1H), 3.16-3.09 (m, ih), 2. 36-2. 32 (m, 1H ), 2.29 (s, 3H), 2. 28-2. 20 (m, ih), 2.07-2.02 (m, 1H), 1.86-1.80 (m, 1H) 98 95343 201213305 Example 27 (3a&gt;?, 5 brother 6a573a5; 55; 6ay?)-3a-(3, 4-dichlorophenyl)-5-decyloxy-2, 3, 4, 5, 6, 6a-hexahydro-1#·cyclopenta [c]n ratio p

H3po4 Η_·

Will (3a especially 5 especially 6a573a5; 551,6a7P)-3a-(3, 4-diphenyl)-5-nonyloxy-2, 3, 4, 5, 6, 6a-hexahydro-1 and Cyclopenta[c]pyrrole-pestrin 26 (5.1 g, 10.7 mmol) dissolved in 100 mL of a mixture of decyl alcohol and water (V/V=l/1), added with hydr Sodium (856 mg, 21.4 mmol) was reacted for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAc EtOAc (EtOAc) 50 mL of hexane and acid (1. 05 g, 10.7 mmol) were added and reacted for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title product (3a??, 5? 6a573a5; 55; 6a)?)-3a-(3,4-dichlorophenyl)-5-decyloxy-2, 3, 4, 5, 6, 6a-hexahydro-1 and -cyclopenta[c]n ratio p each of the acid salt 27 (4.11 g, pale yellow oil), yield: 100.0%. Example 28 (3a)?, 5 especially 6a573a5; 55; 6av?)-3a-(3,4-dichlorophenyl)-5-decyloxy 99 95343 201213305 -2, 3, 4, 5, 6, 6a-hexahydro-1 and-cyclopenta[chb-maleate

Will (3a/?, 5 friend, 551, 6a and)-3a-(3, 4-dichlorophenyl)-5-nonyloxy-2, 3, 4, 5, 6, 6a-hexahydro-1 #·Cyclopenta[&lt;:&gt;Compound 25a (317 mg, 1.11 mmo 1) was dissolved in 5 mL of ethyl acetate, and maleic acid (64 mg, 0.55 _〇1) was added. 2 hours. The reaction solution was concentrated under reduced pressure to give the title product (3a,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, , 6, 6a-hexa-argon-1 and -cyclopenta[匸&gt; bromo maleate 28 (381 mg, white solid), yield: 100. 0%. Example 29 (3a7?, 5疋6357335·,55; 6af)-3a-(3,4-dichlorophenyl)-5-decyloxy-2, 3, 4, 5, 6, 6a-hexahydro-1 and-cyclopenta[c Pyrrole L-(+)-tartrate

100 95343 201213305

OH Ο 25a 29 will (3af, 5 brother 6a573a5; 55; 6a7?)-3a-(3, 4-dichlorophenyl)-5-nonyloxy-2, 3, 4, 5, 6, 6a-six Argon-1 and -cyclopenta[c]α ratio σ each 25a (302 mg ' 1. 06 mmol) was dissolved in 10 mL of a mixed solution of ethyl acetate and decyl alcohol (V/V=l/1), added L-(+)-tartaric acid (79 mg, 0.53 mmo 1), reacted for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title product (3a??, 5? 6a573a5; 55; 6aA〇-3a-(3, 4-diphenyl)-5-methoxy-2, 3, 4, 5, 6, 6a-hexahydro-1 and -cyclopenta[c]n ratio 17 L-(〇-tartrate 29 (383 mg, white solid), yield: 100. 0%. Example 30 (3a&gt; P, 5 especially 6a573a5; 55; 6a^P)-3a-(3, 4-diphenyl)-5-methoxy-2, 3, 4, 5, 6, 6a-hexahydro-1 and Cyclopenta[c]11 to π each D-(-)-tartrate

ΟΗ Ο 25a 30 will (3af, 5 especially 6a573a5; 55; 6ay?)-3a_(3, 4-diphenyl) 101 95343 201213305 -5-methoxy-2, 3, 4, 5, 6, 6a -hexahydro-1)7-cyclopenta[c]pyrrole 25a (338 mg, 1.18 mmol) was dissolved in 1 mL of a mixed solution of ethyl acetate and methanol (V/V = 1/1). D-(_)-tartaric acid (89 mg, 0.559 mmol) was added and the mixture was reacted for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (3a, 5,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, , 6, 6a-hexahydro-1 and cyclopenta[c]pyrrole D-(-)-tartrate 30 (426 mg, white solid), yield: 100.0%. Example 31 (3ae, 5 and 6a573a5*, 55; 6a/?)-3a-(3,4-dichlorophenyl)-5-decyloxy-2, 3, 4, 5, 6, 6a- Hexahydro-1 and _cyclopenta[c]e

Will (3aA*, 5 feet 6a573a5·, 551, 6aA〇-3a-(3, 4-dichlorophenyl) methoxy-2, 3, 4, 5, 6, 6a-hexahydro-1 million-ring Pentacin [c] 0 is a solution of 25a (259 mg, 〇·91 mmol) in 10 mL of ethyl acetate, and then added with m-acid (86 mg '0. 91 mmol) for 2 hours. Liquid, the title product was obtained (3ai&lt;?, 5 brother 6a573a5; 55; 6aA〇-3a-(3, 4-diphenyl)-5-methoxy-2, 3, 4, 5, 6, 6a- Hexahydro-1 and-cyclopenta[c]pyridyl 102 95343 201213305 Sulfonate 31 (348 mg, pale yellow oil), yield: 100. 0 / /. Example 32 (3a 疋 57 ?,55; 6a7?)-3a-(3,4-dichlorophenyl)-5-mercapto-2, 3, 4, 5, 6, 6a-hexahydro-1 and-cyclopenta[匚] ° ratio of 17 fumarate

The first step (3a especially 55; 6a573a5; 5 feet 6a7?)-3a-(3,4-dichlorophenylsulfonylphenyl phenyloxy)-1, 3, 4, 5, 6, 6a-hexahydrogen Cyclopenta[c]4bp each of the tert-butyl 2-carboxylic acid will be (3a7?, 55; 6a573a5; 5 brother 6ai〇-3a-(3, 4-dichlorophenyl)-5-hydroxy-1,3 , 4, 5, 6, 6a-hexahydrocyclopenta[c]° ratio σ each -2-decanoic acid tert-butyl ester 7b (3.4 g, 9.13 mmol) dissolved in 32 mL 〇bite Add p-benzoquinone chloride (1. 91 g, 10.04 mmol) for 16 hours. Add 1 Μ hydrochloric acid to adjust the pH to 4 or less, add 120 mL of water and 100 mL of ethyl acetate, and separate. The aqueous phase was extracted with EtOAc (EtOAc (EtOAc)EtOAc. ·/?,551,6ai573akS&quot;,5j/?,6aA〇_3a_(3,4_Dichlorophenyl曱103 95343 201213305 phenylsulfonyloxy)-1,3, 4, 5, 6, 6a- Hexahydrocyclopentazone|»Bisole-2-carboxylic acid tert-butyl ester 32a (3.0 g, white oil), yield: 62. 5%. The second step (3a especially 5 feet 6a573a5; 55; 6ay?)-3 A-(3,4-diphenyl)-5-mercapto-1,3,4,5, 6, 6a-hexahydrocyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester Cuprous (2. 67 g, 14 mmol) was dissolved in 20 mL of tetrahydrofuran, cooled to -8 ° C, and 17.5 mL of 1. 6 decyl lithium in diethyl ether solution was added dropwise, -8 ° C After 2 hours of reaction, 10 mL (3a7?, 55; 6a573a5; 5 especially 6Ar) -3&amp;-(3,4-diphenyl)-5-(/?-indole phenyloxy)_ 1,3, 4, 5, 6, 6a-hexafluorocyclopenta[c]pyrrole-2-furic acid tert-butyl ester 32a (1. 05 g, 2 mmol) in tetrahydrofuran solution, reaction 16 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The residue obtained is purified by eluent column chromatography using eluent column chromatography to afford the title product (3a) P, 5, 6a573a5; 55; 6a) P)-3a-(3, 4-dichlorophenyl)- 5-Methyl-1,3,4,5,6,6a-hexahydrocyclopenta[c]pyrrole-2-furic acid tert-butyl ester 32b (480 mg, colorless oil), yield: 64 . 8%. !H NMR (400 MHz, CDCh): δ 7. 38 (d, 1Η), 7. 32 (d, 1H), 7.08 (dd, 1H), 3.71-3.31 (m, 6H), 2.78-2.75 (m , 1H), 2.23-2.12 (m, 3H), 1.45 (s, 9H), 1.06 (d, 3H) The third step (3ai?, 5 feet 6a573a5; 55; 6ay?)-3a-(3,4- Dioxophenyl)-5-mercapto-2,3,4,5, 6, 6a-hexahydro-1 and-cyclopenta[£:]° ratios each mouth 104 95343 201213305 Will (3a especially 5疋6a573a6 56; 6a&gt;P)-3a-(3,4-dichlorophenyl)-5-methyl-1,3,4,5, 6, 6a-hexahydrocyclopenta[c]0bi- 2-butylic acid tert-butyl ester 32b (480 mg, 1.30 _〇1) was dissolved in 5 mL of dichloromethane, and 1. 9 mL of trifluoroacetic acid was added thereto, and the mixture was reacted for 2 hours, and the reaction mixture was concentrated under reduced pressure. To the residue was added 12 mL of a mixed solution of decyl alcohol and water (V/V = 1/1), and 1.04 g of sodium hydroxide was added thereto for 5 hours. The reaction mixture was concentrated with EtOAcjjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH (3, 4-diphenyl)-5-mercapto-2,3,4,5, 6, 6a-hexahydro-1^cyclopenta[c]pyrrole 32c (376 mg, yellow oil) , Yield: 1%. MS m/z (ESI): 270.1 [Μ] Step 4 (3a foot 5疋6a573a5; 55; 6a^〇-3a-(3, 4-diphenyl)-5-mercapto-2, 3, 4, 5, 6, 6a-hexahydro-1#_cyclopenta-fumarate (3a and 5疋6aiS73a5·,551,6a^〇-3a-(3, 4-diphenyl) -5-Methyl-2,3,4,5, 6, 6a-hexahydro-1 and -cyclopenta[c]«Bilo 32c (376 mg' 1. 39 mmol) dissolved in 5 mL of ethyl acetate Adding fumaric acid (161. 5 mg, 1.39 mmol), and reacting for 16 hours. The reaction mixture was filtered, and the filter cake was washed with 1 mL of ethyl acetate. The filter cake was collected and dried in vacuo to give the title product (3a , 5 friends, 6a573a5·, 55*, 6a friends) -3a_(3, 4-two gas base) one 5-inch base-2, 3, 4, 5, 6, 6a-hexahydro-1 skin-ring Pheno[c]pyrrole fumarate 32 (408 mg, white solid), yield: 70.0%. MS m/z (ESI): 270.1 [Μ] Η NMR (400 MHz, DMSO-^) : 5 7.62 (d, 1H), 7.58 (d, 105 95343 201213305 1H), 7.36 (dd, 1H), 6.47 (s, 2H), 3.56 (d, 1H), 3.23 (dd, 1H), 3.04 (dd , 1H), 3.06-2.93 (m, 2H), 2.24-2.17 (m, 1H), 2.05 (dd, 1H), 1.88-1.80 (in, 1H), 1.66-1.59 (in, 1H), 1.21-1.13 (m, 1H), 0.95 (d, 3H) Example 33, 34 (3a·/?, 6aiS)_6a_(3,4_diphenyl)-5_transyl 2,3,3a, 4,5,6-hexahydro-1 and- Cyclopenta[c] ° piric acid hydrochloride (3a5*, 55&quot;, 6a^〇-6a-(3,4-dichlorophenyl)-5-carbyl-2,3,3a,4,5 ,6-hexahydro-1 /indolyl[c] ° ratio σ each hydrochloride

Will (3a especially 5 especially 6a573a5; 55; 6aA〇-3a-(3, 4-diphenyl)-5-yl-based-1,3,4,5,6,6a-hexahydrocyclopenta[c The n is chiralized by p-butyl phthalic acid tert-butyl ester 4b (33.23 g, 89.3 mmol), and the isomers are separated by chiral column using HPLC method (separation conditions) : chiral column Chiralpak ADH, mobile phase: carbon dioxide: decyl alcohol = 85:15, flow rate: 2.0 ml/min), the corresponding components were collected, the solvent was removed by rotary evaporation, and dried under vacuum at room temperature for 24 hours to obtain 3aA,5 especially 6a5〇-6a-(3,4-dichlorophenyl)-5-hydroxy_1,3,3a,4,5,6-hexahydrocyclopenta[c]pyrrole-2-carboxylic acid Tributyl vinegar 33a (16. 15 g, white solid) and (3&amp;51,551, 6aA〇-6a-(3,4-dichlorophenyl)-5-pyridyl-1,3,3a,4, 5,6-Hexazacycloindolo[c]n than tert-but-2-decanoate tert-butyl ester 34a (16.37 g, white solid). (3ai?,5疋6a«-6a-(3, 4- Dichlorophenyl)-5-hydroxy-1,3,3a,4,5,6-106 95343 201213305 Hexahydrocyclopenta[C]pyrrole-2-carboxylic acid tert-butyl ester 33a (16. 15 g, 43.4 Ment) and (3a5; 55; 6a7?)-6a-(3, 4-diphenyl)-5-hydroxy-1,3, 3a,4,5,6-hexahydrocyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 34a (16.37 g, 44.0 mmol) dissolved in 160 mL of 1 hydrazine hydrogenated acetic acid 'Reaction for 16 hours in vinegar solution. Part of the reaction solution was concentrated under reduced pressure, filtered, and the filter cake was collected and dried under vacuum to give the title product (3a brother 5 brother 6α5·)-6β-(3, 4-diphenyl)-5- Hydroxy 2,3,3a,4,5,6-hexahydro-1 and-cyclopenta[c]pyrrole hydrochloride 33 (13. 40 g 'white solid' e·e· = 99. 0%) And (3a5; 55; 6a7?)-6a-(3,4-dichlorophenyl)-5-hydroxy-2,3,3a,4,5,6-hexahydro-1 and-cyclopenta[c ]«* π each hydrochloride 34 (13 58 g, white solid, ee = 99.9%). Example 35 (3a5·, 551, 6a friend)-6a-(3, 4-diphenyl)- 5-perylene-2,3,3a,4,5,6-hexahydro-1 pico-cyclopenta[c]° ratio σ each maleate

(3a5; 55; 6a and) -6a-(3,4-diphenyl)-5-hydroxy _2,3 such as 4 5 6 hexahydro-1 and -cyclopenta[C]D ratio slightly 95343 107 201213305 will be (3a5; 55; 6af)-6a-(3, 4-dichlorophenyl)-5-hydroxy-2,3,3a, 4, 5,6~6 gas_1 and _cycloindole[( ^]*»Bilo hydrochloride 34 (800 mg ' 2. 15 mmol) was dissolved in 8 mL of a mixed solvent of methanol and water (V/V = l/1), and sodium hydroxide (172 mg, 4. 29 mmol), react at 80 ° C for 3 hours. Add 20 mL of dioxane and 20 mL of water, separate the liquid, extract the aqueous phase with a gas-fired product (20 mL×3), combine the organic phases, dry with anhydrous sulfuric acid, filter, The filtrate was concentrated under reduced pressure to give the title product (3a5; 55; 6aA?-6a-(3,4-dichlorophenyl)-5-hydroxydi 2,3,3a,4,5,6-hexahydro-1^ Cyclopenta[c&gt; bromo 35a (632 mg, pale yellow solid), yield: 89.6%. 'H NMR (400 MHz, DMSO-^): (5 7.53 (d, 1H), 7.47 (d, 1H) ), 7.26 (dd, 1H), 4.66 (s, 2H), 3.97-3.92 (m, 1H), 3. 18(d, 1H), 2.89 (dd, 1H), 2.78 (d, 1H), 2.72- 2.68 (m, 1H), 2.63 (d, 1H), 2. 20-2. 13 (m, 1H), 2. 04 (dd, 1H), 1.94-1.89 (in, 1H), 1.51-1.46 (m , 1H) The second step (3a5 ·, 551, 6ai〇-6a-(3, 4-dichlorophenyl)-5-carbyl-2, 3, 3a, 4, 5, Θα gas-1 and - cyclopenta[c]11 ratio Maleate will be (3aS, 551, 6a friend)-6a-(3, 4-diphenyl)-5-carbyl-2, 3, 3a, 4, 5, 6-hexahydro-1 and Cyclopenta[c]pyrrole 35a (100 mg, 0.37 mmol) was dissolved in 2 mL of ethyl acetate. Add maleic acid (42 mg '0.37 mmol) for 16 hours. Filter the reaction solution and collect the filter. The cake was vacuum dried to give the title product (3a &amp; 5 and 6ae)_6a_(3,4-diphenyl)-5-hydroxydi 2,3,3a,4,5,6-hexahydro-1 pico-ring Penta[c]pyrrole maleate 35 (130 mg, white solid) 'yield · 91.55%. 108 95343 201213305 4 NMR (400 MHz, DMSO-忒): (5 7.64 (d, 1H), 7. 62 (d, 1H), 7.37 (dd, 1H), 6.02 (m, 2H), 4.27-4.23 ( m, 1H), 3.74 (d, 1H), 3.48 (dd, 1H), 3.28 (d, 2H), 3.16-3.10 (ra, 1H), 2.27-2. 18 (m, 2H), 2.03 (dd, 1H), 1.75-1.68 (m, 1H) Example 36 (3a5·, 551, 6a and)-6a-(3,4-dichlorophenyl)-5-pyridyl-2, 3, 3a, 4, 5,6-hexahydro-1 and -cyclopenta[c]° ratio p each L-(-)-tartrate

(3a5; 551,6a«-6a-(3,4-dichlorophenyl)-5-hydroxy-2, 3, 3a, 4, 5, 6-hexahydro-1 and -cyclopenta] Ha 35a (100 mg, 0. 37 mmol) was dissolved in 2 mL of ethyl acetate, and then L-(-)-tartaric acid (55 mg, 0. 37 mmol) was added and reacted for 16 hours. The reaction mixture was filtered, and the filter cake was collected. Drying to give the title product (3a5; 551, 6a^?)-6a-(3,4-dichlorophenyl)-5-carbyl 2,3,3a, 4,5,6-hexanitro-1 and _ Cyclopenta[c]B piroxime L-(_)_tartrate 36 (106 mg, white solid), Yield: 67. 9%. !H NMR (400 MHz, dWSO-ώ): δ 7.62 ( d, 1H), 7.60 (d, 1H), 7.36 (dd, 1H), 4.24-4.20 (m, 1H), 4.01-3.97 (ra, 109 95343 201213305 2H), 3· 70 (d, 1H), 3.44 (dd,1H),3 24 (d 2H) 3. 11_3. 05 (m, 1H), 2. 25~2. 14 (m, 2H) 2 04 (dd 1H) 1.74-1.66 (in, 1H) ' Example 37 (3^5, 5ι9, 6a^)~6a_(3,4-one mouse base)~·5~ warp group 2 3 3a 4 5 hexahydro-1 and-cyclopenta sulfate

(3a5; 55; 6a〇-6a-(3,4-dichlorophenyl)-5-carbyl-2,3,3a,4,5,6-hexahydro-1 and -cyclopenta[c ]D 嘻35a (100 mg, 〇. 37 mmol) was dissolved in 2 mL of ethyl acetate, concentrated sulfuric acid (36 mg, 〇. 37 mmol) was added and reacted for 16 hours. The reaction mixture was filtered, and the filter cake was collected and dried in vacuo. , the title product was obtained (3a5; 55; 6a«-6a-(3, 4-diphenyl)-5-hydroxydi 2, 3, 3a, 4, 5, 6-hexahydro-1F cyclopentapine|&gt ;]pyrrole sulfate 37 (116 mg, white solid), yield: 85.3%. WNMRMOOMHz, DMSO-忒): (5 7.64-7.60 (m, 2H), 7.37 (dd, 1H), 4.28-4.22 (m, 1H), 3.73 (d, 1H), 3.47 (dd, 1H), 3.30-3.25 (m, 2H), 3.16-3.08 (m, 1H), 2.26-2.14 (m, 2H), 2.03 (dd , 1H), 1.76-1.68 (m, 1H) Example 38 110 95343 201213305 (3a5; 55; 6a) P)-6a-(3, 4-diphenyl)-5-hydroxy-2, 3, 3a ,4, 5, Θ α Hydrogen-1 and -cyclopenta[c]βbiproxate

Will (3a5&quot;,55&quot;,6a_A〇-6a_(3,4-dichlorophenyl)_5-carbyl-2,3,3a,4,5,6-hexahydro-1 and-cyclopenta[c [D] ρ 35a (100 mg, 0.37 mmol) was dissolved in 2 mL of ethyl acetate, and fumaric acid (42 mg, 0. 37 mmol) was added to react for 16 hours. The reaction mixture was filtered and the cake was collected. Drying in vacuo gave the title product (3a5; 55; 6af)-6a-(3,4-dichlorophenyl)-5-hydroxy-2,3,3a,4,5,6-hexahydro-1 and ring戊[c]pyrrole fumarate 38 (130 mg 'white solid), yield: 91. 5%. NMR (400 MHz, DMSO-purine): 5 7. 59-7.57 (m, 2H), 7.34 (dd, 1H), 6.47 (s, 2H), 4.17-4.10 (m, 1H), 3.54 (d, 1H), 3.29 (dd, 1H), 3.12-3.06 (m, 2H), 3.01-2.93 ( m, 1H), 2. 24-2. 17 (m, 1H), 2.14-1.99 (m, 2H), 1.67-1.60 (m, 1H) Example 39 (3af, 5疋6a«-3a-(3 , 4-dichlorophenyl)-5-decyloxy-2, 3, 4, 5, 6, 6a-hexahydro-1 pico-cyclopenta[c]0 than decanoylate 111 95343 201213305

25a 39a 39b 39 Will (3a&gt;?,5 especially 6537335,55; 6af)-3a-(3,4-dichlorophenyl)-5-nonyloxy-2, 3, 4, 5, 6, 6a -Hexahydro-1 and -cyclopentayl 25a (33. 7 g, 117.7 mmol) were subjected to chiral separation, and the isomers were separated by chiral column using HPLC method. Separation conditions: hand Column CHIRALPAK 0Z, mobile phase: carbon dioxide: isopropanol: diethanolamine = 65:35: 0.1, flow rate: 2. 0 ml / min), collect the corresponding components, remove the solvent by rotary evaporation, and in the chamber Drying under vacuum for 4 hours gives (3a5; 55; 6a)?)-3a-(3,4-dichlorophenyl)-5-foxy-2,3,4,5,6,6a-hexahydro -1 and -cyclopenta[c]D, bilo 39a (14. 28 g, 49. 9 mmol) and (3ay?, 5 especially 6a«-3a-(3, 4-dichlorophenyl)-5-曱oxy-2, 3, 4, 5, 6, 6a-hexahydro-1 and -cyclopenta[c]n ratio 17 each 39b (15. 06 g, 52.6 mmol). (3a*/ P,57P, 6a5〇-3a_(3,4-dichlorophenyl)-5_methoxy-2,3,4,5,6,6&amp;-hexahydro-1 and-cyclopenta-4]pyrrole 391 (15.06舀, 52.6 mmol) was dissolved in 150 mL of ethyl acetate, and fumaric acid (6.11 g, 52.6 mmol) was added for 16 hours. The liquid was collected and dried in vacuo to give the title product (3a7?,5^6850-38-(3, 4-diphenyl)-5-decyloxy-2, 3, 4, 5, 6, 6a - hexahydro-1 and -cyclopenta[匸&gt; blister-rich 112 95343 201213305 methic acid 39 (1. 0 g, white solid), yield: 80. 3%. 4 NMR (400 MHz, DMSO- A): 5 11.63 (s, 3H), 7. 65 (d, 1H), 7.59 (d, 1H), 7.38 (dd, 1H), 6.53 (s, 2H), 3.85- 3.80 (in, 1H), 3.61 (d, 1H), 3.47 (dd, 1H), 3.32 (d, 1H), 3.23 (s, 3H), 3. 16 (dd, 1H), 3.10-3.03 (m, 1H), 2.31-2.20 ( m, 2H), 2.09 (dd, 1H), 1.81-1.75 (m, 1H) Example 40 (3a5; 55; 6a^?)-3a-(3,4-dichlorophenyl)-5-anthracene Base-2, 3, 4, 5, 6, 6a-hexahydro-IF cyclopenta[c&gt;pyrrolidate

(3a5; 55; 6a«-3a-(3, 4-diphenyl)-5-methoxy~2, 3, 4, 5, 6, 6a-hexahydro-1 and -cyclopenta[ 〇]°Biha 39a (14. 28 g, 49. 9 mmol) was dissolved in 150 mL of ethyl acetate, and fumaric acid (5. 79 g '49. 9 mmol) was added for 16 hours. The reaction mixture was filtered. The filter cake was collected and dried in vacuo to give the title product (2,3,3,4,5,6,6,6,6,6,5,6,6a-hexahydro-1 pi-cyclopenta[c]pyrrole fumaric acid Salt 40 (1. 1 g, white solid), yield: 85·2〇/〇. H FiMR (400 MHz, DMS0-c/6): ίο·?* (s, 3H), 7.65 (d 113 95343 201213305 1H), 7.59 (d, 1H), 7.38 (dd, 1H), 6.48 (s , 2,,,,,,,,,,,,, 3.01 (m, 1H), 2.29-2.20 (m, 2H), 2.11 (dd, 1H), 1.79-1.73 (m, 1H) Test Example: Biological Evaluation Example 1 Effect of Compounds on Forced Swimming in Mice Test Animals: Adult ICR male mice, purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd., weighing 20 to 24 g, 8 per cage, 12/12 hour light/dark cycle adjustment, temperature 23±1 °C constant temperature, humidity 50 ° 60 ° / 〇, free to eat into the water. After the animals are purchased from the experimental animal center, the experiment can be started after 3 to 7 days of adaptive feeding. Sample preparation: Animals were randomly divided into a negative control group and a test drug treatment group according to a chaotic number table. The treatment drug was prepared in 1% DMSO physiological saline before the experiment, and it was formulated into a good suspension, and the negative control group was used. 1% DMSO saline (10 mL/kg) was administered. Test procedure: The mice were transferred to the laboratory and allowed to stand for one hour to adapt to the environment. After 60 minutes of administration (intraperitoneal injection or oral administration), the mice were placed in a beaker having a height of about 18 cm and an inner diameter of 14 cm, and the temperature was 24 to 25 ° C and the water depth was 15 cm. The mice were allowed to swim for 4 minutes in the last 4 minutes after the mice were forced to swim for a period of 4 minutes. The forced swimming time of the test group was compared with the negative control group to determine the anti-suppression effect of the drug. Strength and characteristics. The minimum effective dose of the test compound for injection of the present invention is shown in Table 1 of 114 95343 201213305: Table 1 Example number Minimum dose (mg/kg) 4 0.5 (intraperitoneal injection) 5. 0 (oral) 5 2.0 (peritoneal cavity) Injection) 2. 0 (oral) 8 1.0 (intraperitoneal injection) 9 5.0 (intraperitoneal injection) 10 1.0 (intraperitoneal injection) 12 2.0 (oral) 16 0.5 (intraperitoneal injection) 18 5. 0 (oral) 22 0. 5 (abdominal cavity) Injection) 33 5 (oral) 34 1.0 (intraperitoneal injection) Conclusion: The compounds of the present invention have a significant inhibitory effect on the immobility time of swimming in mice. Example 2 Tail Suspension test (TST) Test animals: Adult ICR male mice, purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd., weighing 20 to 24 g, 8 animals/cage, 12/ 12-hour light/dark cycle adjustment, temperature 23±1°C constant temperature, humidity 50 to 60%, free access to water. After the animals are purchased from the experimental animal center, the experiment can be started after 3 to 7 days of adaptive feeding. Sample preparation: Animals were randomly divided into negative control group and test drug treatment group according to the chaotic digital table. The therapeutic drug was prepared in 1% DMS0 physiological saline before the experiment, and it was formulated into a good suspension, negative control group. Administration 115 95343 201213305 1% MS0 physiological saline (〗 〇 mL / kg). Test Procedure · Transfer the mice to the laboratory and allow them to adjust to the environment. After 6 minutes of administration (intraperitoneal injection or oral administration), the fixed tail end 20 is closed. 'The mouse (4) is placed on the universal soundproof box (4) barb of Shanghai Jiliang Animal Behavior Analysis System, 6 minutes, mining _ tail Analyze software 3.0 analyzes the immobile time for the next 4 minutes in 6 minutes. The suspension time of the test drug group was compared with the negative control group to determine the antidepressant effect, strength and characteristics of the drug. The minimum effective dose of mice injected with the test compound of the present invention is shown in Table 2: Table 2 Example No. Minimum dose 3 5.0 (abdominal injection ' 4 5. 0 (abdominal injection 5. ' 5. 0 (oral Τ &quot; 5 5. 0 (abdominal injection ^ 2. 0 (π月~~~~ 8 5.0 (abdominal cavity 9 5.0 (abdominal injection! 12 5. 0 (mouth month ^~~' 13 5. 0 (oral Τ _ 15 5.0 (π^) 16 5. 0 (intraperitoneal injection) 18 5. 0 (intraperitoneal injection) 20 5. 0 (abdominal cavity; - 22 5. 0 (abdominal cavity conclusion: the compound of the present invention has significant time on the immobile tail suspension time) Inhibition. 95343 116 201213305 Example 3 oxime (da), norepinephrine (να) and pentasamine (5_ht) in vitro resorption test Take young male rats, purchased from Shanghai Xipuer-Beikai experimental animal limited Company, animal production license number: SCXK (Shanghai) 2008-0016, weight 150 to 250 grams. The rats were quickly decapitated and the brain was removed. The cell culture dish was placed on crushed ice and the rat brain was placed. On the cell culture dish, the brain area (frontal cortex, striatum hippocampus) was quickly separated and placed into a 10 volume frozen T The tissue of the ris solution was homogenized. The Tris solution was pre-saturated with 〇2:C〇2 95:5.

Tris Buffer (triterpene hydroxydecyl decane buffer) consisting of: sucrose 〇. 32 Μ 'glucose 1 mM mM, Tris-HCl 10 mM, pH 7.4. Cut the brain tissue into small pieces with small scissors and pour off the supernatant. Fresh Tris buffer was added to the test tube, and the brain tissue was lightly broken by a manual tissue homogenizer to prepare a brain tissue homogenate. The brain tissue homogenate was centrifuged on a centrifuge, 1000 X g, 10 min, 4 °c. The supernatant is aspirated and the residue in the tube is discarded to remove nerve nuclei and other debris. The supernatant was again centrifuged at 20' 000 X g for 20 minutes at 4 ° C to obtain preliminary synaptic bodies. The obtained synaptosome-centrifuged precipitate was reconstituted into a uniform homogenate with a modified Krebs solution. The tissue homogenate was placed in a small test tube (three copies of the same sample), each tube was approximately 9 〇 to 15 〇 "g protein, and different concentrations of the experimental drug were added to the tissue homogenate. The blank group was added to the same volume. Configure the solvent for the drug and incubate for 1 minute at 371. After 10 minutes of incubation, add 5〇nM of the same position 117 95343 201213305 labeled neurotransmitter: [3H]DA (56·8) Ci mmol-1), [3Η]5-ΗΤ(27·7 Ci mmol-丨)' and [3H]NA(14.1 Ci mmol-1) (the above neurotransmitters were purchased from China Isotope Corporation). Continue At the temperature of 37 ° C for 15 minutes, the synaptosomes were ingested by isotopically labeled neurotransmitters. After incubation for 5 minutes, they were filtered by a glass fiber screening program to block their uptake and filtration. The film was previously immersed in a 0.1% polyethyleneimine solution for 1 hour in GF/C. The film was rinsed three times with 0.9% NaCl, and the cut filter paper was placed in a scintillation bottle and added. 500 //L scintillation fluid (Soluene-350), and placed overnight, liquid flash count. , subtract the blank count, and perform the mapping analysis with the drug concentration. Only the data with linear relationship above 0.99 can be used. IC5〇 is calculated from the curve. The composition of the modified Krebs solution is as follows: NaCl 140, KC1 5 mM, KH2PO41· 2 mM, NaHCCb 25 mM, MgS〇41. 2 mM, CaCl21.4 mM' Glucose 10 mM, Ascorbic acid 1. 1 mM, ethylenediaminetetraacetic acid Sodium (Disodium EDTA) 0. 13 mM, Pargyline 0. 1 mM, pH 7. 40 0 The compound of the present invention is applied to dopamine (DA), norepinephrine (NA) and serotonin (5-HT). The pICso values for reuptake inhibition in rat synaptosomes are shown in Table 3: 118 95343 201213305

Example Number SERT (5-HT Spinner)

NET (ΝΑ transporter)

DAT

Conclusion: The reabsorption of poly(p-) and penta-tryptamine (5-ΗΤ) by the compounds of the present invention has triple norepinephrine plus dopamine (DA) resorption inhibition, and at the same time The safe range of pICso does not exceed 6.5, preventing the stimulant-like effect caused by the inhibition of the action of the amine (DA). And reinforced Doba Example 4 Mouse Marble Landing Test Test animals: Adult ICR male mice, purchased from Shanghai Xipuer Yibun Experimental Animal Co., Ltd. Sample preparation: Animals were randomly divided into a negative control group and a test drug treatment group according to a chaotic number table. The treatment drug was prepared in 1% DMS 〇 physiological saline before the experiment, and it was formulated into a good suspension. Negative control The group was given 1% MS0 physiological saline (10 mL/kg). Test procedure: The mice were placed in a transparent plastic box (35 cm x l9 cm x 17.5 cm) containing 5 cm of wood chips. After the mice were given different doses of the test compound by gavage, they were placed in the observation box for 20 minutes, and then taken out and placed in the 119 95343 201213305 cage. Place 20 transparent glass marbles (lcm diameter) in the observation box. After the placement is completed, put the mice back into the observation box 30 minutes after the mice are administered. It is necessary to place the same box with the first time and start measuring 30. Minutes were recorded for the mice to bury the bomb within 30 minutes. The standard for marble burial: more than 2/3 of the marble itself is covered and buried. The results of the experiment: The compound of Example 33 and the compound of Example 34 were all effective in inhibiting the bomb burial behavior of the mouse, and the effects of the two compounds were all in a dose-effect relationship, wherein the minimum effective dose of the compound of Example 33 was 2.0. The minimum effective dose of the compound of Example 34 at mg/kg was 1.0 mg/kg. [Simple description of the diagram] None [Key component symbol description] None 120 95343

Claims (1)

201213305 VII. Patent application scope: I. Compounds represented by formula (1) and their enantiomers, (tetra) or pharmaceutically acceptable salts: Wherein: Ar is selected from aryl or heteroaryl, wherein the aryl or heteroaryl is further selected from one or more selected from the group consisting of alkyl, alkenyl, alkynyl, halonitro, cyano, haloalkyl, Hydroxyalkyl, cycloalkyl, heterocyclic, _R7 Substituting a group of 'NR8R9 or -C(0)NR8R9; R1 and R2 are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a halogen, a nitro group, a cyano group, a cycloalkyl group, a heterocyclic group, a R7, _〇_C ((^R7, -C(0)R7, -C(0)〇R7, -S(0)0R7, -NR8R9 or -C(0)NR8R9, wherein the alkyl group, The base group, the fast group, the cycloalkyl group or the heterocyclic group are further selected from one or more selected from the group consisting of alkyl, ii, nitro, cyano, cycloalkyl, heterocyclic, -ORR,-0-C. (0) R7, -C(0)R7, -C(0)0R7, -S(0)0R7, -nr8r9 or -c(o)nr8r9 are substituted, or r1 and R2 form a double a bond, provided that R1 and R2 are not simultaneously a hydrogen atom; R3, R4, R5 and R6 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -C(0) R7, -C(〇)〇R7 or -C(0)NR8R9, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or hetero 1 95343 201213305 aryl group is further selected from one or more selected from the group consisting of a group of a radical, a tetracyclyl group, a cyano group, a cycloalkyl group, a heterocyclic group, 7, 〇 〇 cc, RR'~C, a di-C_R7, -S_mv(10) nr8r9: R is selected from a nitrogen atom, a 6-group, Cyclic base a heterocyclic group, an aryl group: a heteroaryl group, wherein a city group, a group, a heterocyclic group, an aryl group or a heteroaryl group is further selected from one or more selected from the group consisting of an alkyl group, a thiol group, and a aryl group. , the chaotic group, the cyclofilament, the heterocyclic group, the aryl group or the aryl group R and R9 are each independently selected from the group consisting of a gas group, a heterocyclic group, an aryl group or a heteroalkynyl alkynyl group, a thiol group and a heterocyclic group. a group, a aryl group, a dilute group, one or more selected from the group consisting of an alkyl group and a hydroxy group, if necessary, a step-by-step group: r, a group-form cyano group, a thiol group, which 1 Atom-forming a heterocyclic group, a thiol group, a sulfonyl group, a heterocyclic group, an aryl group 2, a group selected from an alkane or a heteroaryl group. For example, the enantiomers, diastereomers J = compounds represented by formula (1) and salts for cola and cola thereof, wherein: Substituted by a group of - or -GR7; and an aryl group of two, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heterocyclic group, wherein the m, the m needs further further by a ::, _ yl, aryl Substituted by a group of a aryl or heteroaryl opsin. , a secret group, a thiol group or a tooth 95343 2 201213305 3. The compound of the formula (I) and its enantiomer, diastereomer or pharmaceutically acceptable salt thereof, as described in claim 2, Wherein: Ar is selected from the group consisting of phenyl, wherein the phenyl group is further substituted by one or more groups selected from the group consisting of alkyl, halogen or -OR7; and R7 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, and a heterocyclic group. a cycloalkyl, aryl or heteroaryl group, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of alkyl, cycloalkyl, hydroxy or halogen. Replaced by the group. 4. A compound of the formula (I), an enantiomer, a diastereomer thereof or a pharmaceutically acceptable salt thereof, according to claim 1, wherein: R is selected from a hydrogen atom, an alkyl group or Halogen; R is selected from the group consisting of a hydrogen atom, an alkyl group, a halogen, an ORR or an 〇_c(〇)r7, wherein the alkyl group is optionally substituted by one or more dentates; or, R1 and R2 together form a double a bond, provided that R2 is not a hydrogen atom at the same time; and R7 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, and the aromatic group The base or heteroaryl group is further substituted with one or more groups selected from an alkyl group, a cycloalkyl group, a hydroxyl group or a halogen, as needed. 5. A compound of the formula (1), an enantiomer, a diastereomer thereof or a pharmaceutically acceptable salt thereof, according to the scope of the invention, wherein: Ar is selected from the group consisting of phenyl, wherein the benzene The base view needs to be further substituted by one or more groups selected from the group consisting of: a halogen atom or a tooth; 95343 3 201213305 R2 is selected from a hydrogen atom, an alkyl group, a halogen or -OR7, Wherein the alkyl group is optionally substituted by one or more halogens; or 'R1 and R2' form a double bond, provided that R1 and R2 are not simultaneously a hydrogen atom; R3, R4, R5 and R6 are each a hydrogen atom; R7 is selected from a hydrogen atom, an alkyl group or a cycloalkyl group, wherein the alkyl group or the cycloalkyl group is further substituted with one or more groups selected from an alkyl group, a cycloalkyl group, a hydroxyl group or a halogen, as needed. 6. The compound of the formula (I), and the enantiomer, diastereomer or pharmaceutically acceptable salt thereof, according to claim 1, wherein: Ar is selected from the group consisting of phenyl, wherein the benzene The base is required to be further substituted by one or more groups selected from the group consisting of an alkyl group or a hydroxyl group; R1 is selected from a hydrogen atom or a hydroxyl; R2 is selected from a hydrogen atom, an alkyl group, a halogen or -〇_c(〇)R7 Wherein the alkyl group is optionally substituted by one or more halogens; or, R1 and R2 together form a double bond, provided that R2 is not simultaneously a hydrogen atom; R3, R4, R5 and R6 are each a hydrogen atom; From the aryl or heteroaryl group, the aryl or heteroaryl group is optionally substituted with one or more groups selected from the group consisting of a group, a group, and a group. The compound of the formula (1) and the enantiomer, diastereomer or pharmaceutically acceptable salt thereof, wherein R3, R4, R5 and R6 are as defined in any one of claims 1 to 4; Each is a hydrogen atom. The compound of the formula (I), and the enantiomer, diastereomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, wherein The compounds are: (3a^5 and ,6857385, 551,6a friend)-3a-phenyl-2, 3, 4, 5, 6, 6a-hexahydro-1 and -cyclopenta[c]n ratio p -5-alcohol; (3ai?, 5 especially 6a573a5; 55; 6a^P)-5-methoxy-3a-phenyl-2, 3, 4, 5, 6, 6a-hexa-1 and ring戊[c]° ratio p; (3a疋5 especially 6a573a6; 55; 6a-5-ethoxy-3a-phenyl-2, 3, 4, 5, 6, 6a-hexahydro-1 and -cyclopenta[c]° ratio; (3af,5 left, 6aLS73a5·,551,6a and)-3a-(3,4-diphenyl)-5-decyloxy-2, 3, 4 , 5, 6, 6a-hexahydro-1 and -cyclopenta[匸&gt;ratio;(3&friend, 5 friends, 685733$ 551, 6ae)-3a-(3, 4-dichlorophenyl) -2,3,4,5,6,6a-hexahydro-1 and -cyclopenta[c]n ratio σ-5-ol; (3a7?,5 especially 6a573a5; 55; 6aiP)-3a-( 4-chlorophenyl)-5-hydroxy-2,3,4,5,6,6a-hexahydro-1 and-cyclopenta[c]nbi; (3a, 551, 6a573aiS, 5 and, 6a^〇-3a-(3,4-dichlorophenyl)_2,3,4,5,6,6a_hexanitro- 1 and -cycloindole [c*]n ratio 17 _5_Sf·; (3ae, 551, 5 no, 6ai〇-3a-(3, 4-diphenyl)-5-decyloxy-2, 3, 4, 5, 6, 6a-hexahydro-1 and -cyclopentadol; (3a7?, 5 brothers 6a5y3a5·, 551, 6a and)-3a-(3, 4-dichlorophenyl)- 5-ethoxy-2,3,4,5, 6, 6a-hexahydro-1 and-cyclopentapyrrole; 5 95343 201213305 (3a friend, 551, 5 skin, 6a left)-3a-(3 , 4-dichlorophenyl)-5-ethoxy-2, 3, 4, 5, 6, 6a-hexahydro-1 pico-cyclopenta[c]pyrene; (3a7?,5-foot 6a573a5 55; 6a^〇-5-(cyclopropyldecyloxy)_3a_(3,4-disorderylphenyl)_2,3,4,5,6,6a-hexanitro-1 and-cyclopentyl ; (3a«S*,55&quot;,6a/?)-6a-(3,4-diphenyl)-5-decyloxy-2, 3, 3a, 4, 5, 6-hexahydro-li7 -cyclopentazone&gt;]pyrrole;(3a&gt;?,5 especially 6350-63-(3,4-diphenyl)-5-methoxy-2, 3, 3a, 4, 5,6- Hexahydro-1#-cyclopenta[c]pyrrole; (3a5; 55; 6a7?)-6a-(3, 4-diphenyl)-5-ethoxy-2, 3, 3a, 4, 5,6-hexahydro-1 and-cyclopenta[c]pyrrole; (3a^ 5: 6a5&quot;)-6a-(3, 4-diphenyl)-5-ethoxy-2, 3, 3a,4, 5, 6-hexahydro-1 and -cyclopenta And [c]pyrrole; benzoic acid [(38 friends, 5疋6857385, 551, 6aA〇-3a-(3, 4-dichlorophenyl)-2, 3, 4, 5, 6, 6a-hexahydro- 1 and -cyclopenta[c]pyrrole-5-yl] ester; °cerebrene_2_decanoic acid [(3a·/?,5 especially 6a5!/3ai9,5iS&quot;,6aA〇-Sa-CS, 4 -dichlorophenyl)_2, 3, 4, 5, 6, 6a_ hexahydro-1 and -cyclopenta[c]0 pyrol-5-yl] ester; (3a^?, 55; 6a573a5; 5 brother 6ay?)-3a-(3,4-diphenyl)-5-fluoro-2, 3, 4, 5, 6, 6a-hexahydro-1 and -cyclopenta[c&gt;bilo; (3a #,6a5/3a5; 6ai?)_3a-(3,4-diphenyl)-5-ethyl-2, 3, 4, 5, 6, 6a-hexahydro-1 and-cyclopenta[c Pyrrole; 6 95343 201213305 (3a no, BaS/BaS, 6aA〇-3a-(3, 4-dichlorophenyl)_5-indenyl-1,2, 3, 4, 6, 6a--hexahydrogen Cyclopenta[c]pyrrole; (3aA, GakSyBaiS1, 6aA〇~3a-(3,4-dichlorophenyl)-5-(2-fluoroethyl)-2, 3, 4, 5, 6, 6a-hexahydro-1 and-cyclopenta-&gt;]pyrrole;(3a&gt;?, 6aiP)-3a-(3,4-diphenyl)-5-mercapto-2, 3, 4, 5 , 6, 6a-hexahydro-1 pico-cyclopenta[c]pyrrol; (3aiP, 6a5y3a5; 6aie)-3a-(3, 4-diphenyl)-5, 5-difluoro-1, 2, 3, 4, 6, 6a-hexahydrocyclopentane And [c]pyrrole; (3af, 57?, 6&amp;673&"55; 6a^)-3a-(3,4-dichlorophenyl)-5-fluoro-2, 3, 4, 5, 6, 6a-hexahydro-1 and-cyclopenta[c]pyrrole; (3a7?, 5/?, GaiS/SakS1, 55&quot;, 6a^〇-3a-(3, 4-diphenyl)-5- Methyl-2, 3, 4, 5, 6, 6a-hexahydro-1 and -cyclopenta[c] 0 pir; (3a especially 5疋6a5〇-6a-(3, 4-diphenyl) -5-hydroxy 2, 3, 3a, 4, 5,6-hexahydro-1 and -cyclopenta[c] „Bilo; or (3a5; 55; 6a^?)-6a-(3, 4 - Diphenyl) _5_hydroxy 2, 3, 3a, 4, 5, 6-hexahydro-1 and -cyclopenta[c]n pir. 9. The compound of the formula (1), and the enantiomer, diastereomer or pharmaceutically acceptable salt thereof, according to any one of the items of the above-mentioned item, wherein the compound of the formula (1) is in a free state or can be administered In the form of an acid addition salt, the acid addition salt includes hydrochloride, hydrogen desert acid salt, methylation salt, sulfate, phosphate, fumarate, maleate, malate, : citrate, acetate, trifluoroacetate, fumarate, tartrate or p-toluenesulfonate. The compound of the formula (I) 95343 7 201213305, and the enantiomer, diastereomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, wherein The compound is: (3aA, 5 pic, 551, 6ae)-3a-phenyl-2, 3, 4, 5, 6, 6a-hexahydro-1#-cyclopenta[c]c than p-5- Alcohol trifluoroacetate; (3a) P, 5 especially 55; 6a^-5-decyloxy-3a-phenyl-2, 3, 4, 5, 6, 6a-hexahydro-1 and -cyclopenta [(:] 吼 三氟 trifluoroacetate; (3a7?, 5疋6a573a5; 55; 6a^)-5-ethoxy-3a-phenyl-2, 3, 4, 5, 6, 6a-hexahydro -1 and -cyclopenta[c]π ratio p trifluoroacetate; (3a^ 5疋6a573ai9, 551, 6a)?)-3a-(3,4-dichlorophenyl)-5-methoxy Base-2,3,4,5,6,6a-hexahydro-1 and-cyclopenta[匸]〇 are the corresponding hydrochlorides; (3aW, 5 friends, 685733^, 55&quot;, 6a^〇_ 3a-(3,4-diphenyl)-2,3,4,5,6,6a-hexahydro-1 and-cyclopenta[c]D than indole-5-ol trifluoroacetate; (3a /?,5疋6a573a5; 55; 6aA〇-3a-(4-chlorophenyl)-5-hydroxy-2,3,4,5,6,6a-hexahydro-1 and-cyclopenta[c] nitB each trifluoroacetate; (3a^ 551, 6a573a5· 5 friends, 6aA)-3a-(3, 4-diphenyl)-2, 3, 4, 5, 6, 6a-hexahydro-li7-cyclopentazone|&gt;&gt;bibromo-5-ol Trifluoroacetate; (3a^551, 5 friend, 6aA)-3a-(3,4-diphenyl)-5-methoxy-2, 3, 4, 5, 6, 6a-hexahydro- 1 and _cyclopenta[〇> 比 盐 hydrochloride; 8 95343 201213305 (3a7?, 5 left, 685733) 5, 55*, 6a and) _3a_(3,4_dichlorophenyl)-5- Ethoxy-2,3,4,5,6,6a-hexahydro-1 and-cyclopentamidine hydrochloride; (3aA*,551, 6a573a5·,5 left,6a friend)-3a-( 3, 4-dichlorophenyl)-5-ethoxy-2,3,4,5, 6, 6a-hexafluoro-IF cyclopenta[匚> 比 盐 hydrochloride; (3ae, 5 feet 551,6a friend)-5-(cyclopropylmethoxy)-3a-(3,4-dichlorophenyl)-2, 3, 4, 5, 6, 6a-hexahydro-1F cyclopenta[ c]° ratio 11 hydrochloride; (3a5; 55; 6aii〇-6a-(3,4-dichlorophenyl)-5-decyloxy-2, 3, 3a, 4, 5, 6-six Hydrogen-1 and -cyclopenta[c]pyrrole hydrochloride; (3a brother 5 brother 6a«-6a-(3, 4-dichlorophenyl)-5-methoxy-2, 3, 3a, 4 , 5,6-hexahydro-1 and-cyclopenta[c]n pyrryl hydrochloride; (3a5; 55; 6af)-6a-(3,4-dichlorophenyl)-5-ethoxy -2, 3, 3a, 4, 5 , 6-hexahydro-1 and -cyclopenta[c]D ratio p hydrochloride; (3a&gt;?, 5-foot 6&5·)-68-(3,4-dichlorophenyl)-5 -ethoxy-2,3,3a,4,5,6-hexahydro-1 and-cyclopenta[c]pyrrole hydrochloride; [(3a^?,5 especially 55; 6aA〇-3a-( 3, 4-dichlorophenyl)-2,3,4,5, 6, 6a-hexahydro-1 and-cyclopenta[c]n ratio p--5-yl]benzoate hydrochloride ; [(3af, 5 especially 6a573a5; 55; 6aA〇-3a-(3, 4-dichlorophenyl)-2, 3, 4, 5, 6, 6a-hexahydro-1#-cyclopenta[o ]σΛρ基基]0 phenophene-2-carboxylate hydrochloride; (3a friend, 551,6857385, 5 friend, 6aA〇-3a-(3,4-dichlorobenzene 9 95343 201213305 base)-5- Gas-2, 3, 4, 5, 6, 6a-hexahydro-1 and -cycloindolo-fumarate; (3ae, 6a5y3akS, 6a^〇_3a_(3, 4-dichlorophenyl)- 5-ethyl-2, 3, 4, 5, 6, 6a-hexahydro-1#-cyclopenta[^:]°biprofenate; (3ae, BaiS/BaiS, 6aA〇-3a- (3,4-dichlorophenyl)-5-methylene-1,2,3,4, 6, 6a-hexahydrocyclopenta[c]° than slightly fumarate; (3a: BaiS/ SaiS,6af)-3a-(3,4-diphenyl)-5-(2-fluoroethyl)-2, 3, 4, 5, 6, 6a-hexahydro-1 and-cyclopentapine | &gt;]° 嘻 fumarate ; (3ae,GaS/BatS1,6a^〇-3a-(3,4-dichlorophenyl)-5-mercapto-2, 3, 4, 5, 6, 6a-hexahydro-1 and -cyclopentyl And |»Bilofumarate; (3a^?,6a5y3ak9, 6ae)-3a-(3,4-diphenyl)-5, 5-difluoro-1,2, 3, 4, 6, 6a-hexahydrocyclopenta[c]e than lofumarate; (3a skin, 5 brother 6a573a5*, 5iS, 6aA〇-3a-(3, 4-diphenyl)-5-fluoro-2 , 3, 4, 5, 6, 6a-hexahydro-1 and -cyclopenta[c]π than slightly fumarate; (3af,5 no, 6a573a5·,551,6a friend)-3a-(3 , 4-dichlorophenyl)-5-methoxy-2,3, 4, 5, 6, 6a-hexahydro-1 and-cyclopenta-pyrrolidine; (3a foot 5 brother 6a5/ 3a5·, 55*, 6ae)-3a-(3,4-dichlorophenyl)-5-methoxy-2, 3, 4, 5, 6, 6a-hexahydro-1/indolyl [ c] 0 σ each pair of tosylate; (3a, 5疋6857385^ 551, 6af)-3a-(3, 4-diphenyl)-5-decyloxy-2, 3, 4, 5, 6, 6a-hexahydro-1 and -cyclopenta[〇]〇 ratio 17 each 10 95343 201213305 phosphate; (3a&gt;P, 5 especially 6a573a5; 55; 6a)?)-3a-(3, 4 -dichlorophenyl)-5-decyloxy-2,3,4,5, 6, 6a-hexahydro-1 and-cyclopenta-pyrrolidine; (3aA, 5 and, 68^ 57335^ 55V 6a_^〇-3a-(3,4_Dichlorophenyl)-5-methoxy-2, 3, 4, 5, 6, 6a-hexahydro-1 and-cyclopentapyrrole L -( + )-tartrate; (3a especially 5 no, 6a573a5&quot;, 551, 6ae) *~3a_(3, 4-dichlorophenyl)-5-methoxy-2, 3, 4, 5, 6 , 6a-hexahydro-IF cyclopenta[c]pyrrole D-(_)-tartrate; (3ai?,5 especially 6a573a5; 55; 6ay?)-3a-(3,4-dichlorophenyl)- 5-methoxy-2,3,4,5,6,6a-hexahydro-1 and-cyclopenta[c]° than slightly methanesulfonate; (3aie, 560 million 6a573a5·, 55; 6af) -3a-(3,4-diphenyl)-5-mercapto-2,3,4,5, 6, 6a-hexahydro-1 and-cyclopenta[c]n than slightly fumarate ; (3a#, 5疋,685^-68-(3, 4-diphenyl)-5-yl-yl-2,3,3a,4,5,6-hexahydro-1 and _cyclopenta [c]° ratio hydrochloric acid; (3a5; 55; 6a7?)-6a-(3,4-dichlorophenyl)-5-hydroxy-2, 3, 3a, 4, 5, 6-hexahydro -1/Γ-cyclopenta[&lt;:&gt; piric acid hydrochloride; (3aiS, 551, 6ae)-6a-(3,4-dichlorophenyl)-5-pyridyl-2, 3, 3a, 4, 5, 6-hexahydro-1ΖΓ-cyclopenta[c]4bn each maleate; (3a5&quot;,55&quot;,6a friend)-6a-(3,4-dichlorophenyl)- 5-base-2, 3, 3a, 4, 5,6-hexahydro-1 and-cyclopenta[dD ratio L-(-)-tartar 11 95343 201213305 acid salt; (3a5; 55; 6a7?)-6a-(3, 4-dibenzene 5-)-5-hydroxy-2,3,3a,4,5,6-hexahydro-1ZM pentyl sulphate; (3a5; 55; 6ai?)-6a-(3, 4-diphenyl) )-5-hydroxy-2,3,3a, 4,5,6-hexahydro-1 and-cyclopenta[c]pyrrole fumarate; (3a7?,5 especially 6a5〇-3a-(3, 4-dichlorophenyl)-5-methoxy-2,3,4,5,6,6a-hexahydro-1 and-cyclopenta[c]pyrrole fumarate; or (3a5; 55; 6af)-3a-(3,4-dichlorophenyl)-5-decyloxy-2, 3, 4, 5, 6, 6a-hexahydro-1 and-cyclopenta[c]pyrrole fumaric acid salt. A process for the preparation of a compound of the formula (I), an enantiomer, a diastereomer thereof or a pharmaceutically acceptable salt thereof, according to the first aspect of the patent application, which comprises: The compound of the formula (IA) is converted into a compound of the formula (I); or, after the carbonyl group of the compound of the formula (IA) can be reduced to a hydroxyl group, the hydroxyl group is further converted into a halogen, and the protecting group PG is removed to obtain a compound of the formula (I). Or, the carbonyl group of the compound of the formula (IA) is further converted into an alkenyl group, an alkyl group, an alkynyl group, a nitro group, a cyano group, a cycloalkyl group, a heterocyclic group, -0-C(0)R7, -C(0 R7, _C(0)0R7, -S(0)0R7, -NR8R9 or -C(0)NR8R9, deprotecting PG to give a compound of the formula (I); 12 95343 201213305 wherein: PG is N protection And Ar, R3 to R9 are as defined in the first item of the patent application. 12. The method according to claim 11, wherein the carbonyl group of the compound of the formula (IA) can be reduced to a hydroxyl group, and if necessary, the hydroxyl group is further converted to -OR7, and the protecting group PG is removed to obtain the formula (I). Compound. 13. The method of claim 11, wherein PG is C(0)R7, -C(0)0R7 or -C(0)NR8R9. A compound of the formula (A), an enantiomer thereof, a diastereomer or a pharmaceutically acceptable salt thereof: PG (ΙΑ) wherein: PG is a protecting group of hydrazine; and Ar is selected from aryl or hetero An aryl group, wherein the aryl or heteroaryl group is further further selected from one or more selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, nitro, cyano, haloalkyl, hydroxyalkyl, cycloalkyl, hetero Substituted by a group of a cyclic group, -ORR, -0-C(0)R7, -C(0)R7, -C(0)0R7, -S(0)0R7, -NR8R9 or -C(0)NR8R9 ; R 3 , R 4 , R 5 and R 6 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -C(0)R7, -C(0)0R7 or -C ( 0) NR8R9 wherein the alkyl, cycloalkyl, heterocyclyl, aryl or hetero 13 95343 201213305 aryl group is further optionally further selected from one or more selected from the group consisting of alkyl, halogen, nitro, cyano, cycloalkyl Substituted by a heterocyclic group, _〇_c(〇)r7, -C(0)0R7, -S(0)0R7, -NRY or a gas (0)NRV group; R7 is selected from a ruthenium atom, a silk , cyclohexyl, heterocyclic, aryl or heteroaryl, wherein fluorenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is required - Steps are selected from one or more selected from the group consisting of phenanthrenyl, ruthenium, (tetra) cyano, fluorenyl, heterocyclic, aryl arylalkenyl === yldiyl or heteroaryl, _;: diyl: The base group needs to be a step-by-step, heterocyclic group: an aryl group or a heteroaryl group, the gas group 'ring slope or 'R and R9 are connected to the N atom: medium = ring group as needed Substituted by a group such as a halogen group, a halogen group, a thiol group, and a thiol group. 'Double earth, heterocyclic group, aryl or heteroaryl 15 · as claimed in claim 14 and its enantiomers, diastereomers;; compound represented by formula (IA) 16. The enantiomers and diastereomers of the compound r5m represented by the formula (IA) are each a salt of a hydrogen atom, wherein 〜, Π. as claimed in the scope of the oxime, and its enantiomers, non-dialogous formula (10) The compound of the compound shown in (10), or a pharmaceutically acceptable salt thereof, wherein: 95343 201213305 Ar is selected from the group consisting of an aryl group, wherein the aryl group is further optionally one or more selected from the group consisting of alkyl, halogen or _01^7. Substituted by a group; and R7 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, and an aryloxa group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group A dream is required to be replaced by one or more groups selected from the group consisting of a burnt group, a ring-based base, a light base or a functional element. 1S. A compound of the formula (IA), and an enantiomer, diastereomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 14, wherein: Ar is selected from the group consisting of phenyl, wherein the benzene The base is required to be further substituted by one or a group selected from the group consisting of a halogen group, a halogen or -OR7; and R7 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein The alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further substituted with one or more groups selected from alkyl, cycloalkyl, hydroxy or halogen, as desired. 19. A method of preparing a compound of the formula (IA), an enantiomer, a diastereomer thereof or a pharmaceutically acceptable salt thereof, according to claim 14 of the patent application, the method comprising: ϊο (IB) The compound of the formula (IB) is reacted with Ar-Li or Ar-MgBr to obtain a compound of the formula (IA): wherein: 15 95343 201213305 PG is a protecting group for N; &quot;, as a hydrogen atom; 2 as by AmR9 The definition is as described in item 1 of the patent scope. 2. The method of claim 19, wherein % is -C(〇)R7, -C(〇)〇R7 or c(〇)nr8r9. 21. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 1G, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable Carrier or excipient. 22. The use of a compound of the formula (I) as defined in any one of claims 1 to 10, and an enantiomer, diastereomer thereof or a pharmaceutically acceptable salt thereof, for use in Dopamine, norepinephrine and pentosamine reuptake inhibitors were prepared. 23. Use of a pharmaceutical composition as described in claim 21 for the preparation of dopamine, norepinephrine and a penta-inhibitor. Dan 24. A use of a compound of the formula (I) as defined in any one of claims 1 to 10, and an enantiomer, a diastereomer thereof or a pharmaceutically acceptable salt thereof It is used in the preparation of therapeutic agents for the treatment of depression or anxiety disorders. 25·-Application of the pharmaceutical composition of Article 21 of the scope of application for the treatment of depression or anxiety disorders 16 95343 201213305 IV. Designated representative map: (1) The representative representative of the case is: The figure (). (There is no picture in this case) (2) A brief description of the symbol of the representative figure··(None) 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 3 95343