CN108863986B - Difluoromethyl-substituted phenylpiperazine derivatives and uses thereof - Google Patents

Abstract

The invention discloses difluoromethyl substituted phenylpiperazine derivatives, uses thereof, and pharmaceutical compositions comprising the compounds, which can be used for inhibiting 5-hydroxytryptamine reuptake. The invention also relates to processes for the preparation of such compounds and pharmaceutical compositions, and their use in the treatment of central nervous system disorders, in particular affective disorders.

Description

Difluoromethyl-substituted phenylpiperazine derivatives and uses thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a compound and a pharmaceutical composition for treating central nervous system dysfunction, particularly affective disorder, and a using method and application thereof. In particular, described herein are difluoromethyl-substituted phenylpiperazine derivatives that can be used as 5-hydroxytryptamine reuptake inhibitors.

Background

5-hydroxytryptamine (5-HT), a neurotransmitter that transmits signals in the brain and nervous system, plays an important role in Central Nervous System (CNS) dysfunction, especially anxiety, depression, aggression and impulsive mood. The serotonin transporter (5-HT transporter,5-HTT/serotonin transporter, SERT) is a transmembrane transporter with high affinity for 5-HT, which reuptakes serotonin from the synaptic cleft into presynaptic neurons, directly affecting the concentration of serotonin in the synaptic cleft.

Historically, the medical treatment of affective disorders began in the 50's of the 20 th century and included tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) which were mainly effective by blocking the neurotransmitters dopamine, norepinephrine and 5-hydroxytryptamine. However, non-selective and undesirable side effects on targets limit their use. By the 80's of the 20 th century, the appearance of selective 5-hydroxytryptamine reuptake inhibitors (SSRIs) changed this situation. Such drugs are of comparable efficacy to TCAs, but have fewer side effects and less toxicity even when taken in excess (Sarko J. Anddidepressant, old and new. A review of the same additive effects and toxicity in excess. Embedded Med. Clin North Am, 2000; 18(4): 637-54). The selective 5-hydroxytryptamine reuptake inhibitor mainly has an inhibitory effect on 5-HT transporters, can effectively inhibit the presynaptic membrane of the central nervous system from absorbing 5-HT from synaptic clefts by combining with the 5-HT transporters, and increases the 5-HT which can be practically utilized in the gaps, thereby achieving the purpose of treatment.

Of all indications associated with 5-hydroxytryptamine dysfunction, depression is of prime importance, as it has been reported by the world health organization as the fourth most burdensome disease in humans. It is expected that disability from depression will jump to the second place in all diseases by the year 2020. (Bromet E, Andlade LH, Hwang I, et al, Cross-national epidemiology of DSM-IV major depression epsilon. BMC Med.2011,9: 90).

However, clinical studies on depression have shown that the lack of response to known SSRIs is prominent, and another factor that is often overlooked in antidepressant therapy is that the therapeutic effects of SSRIs are often delayed and sometimes the symptoms worsen within the first few weeks of treatment. Furthermore, sexual dysfunction is a common side effect for SSRIs. Therefore, there is a need to develop compounds that can improve the treatment of depression and other 5-hydroxytryptamine related disorders.

The invention provides a new compound with 5-hydroxytryptamine reuptake inhibition activity, and the new compound has good clinical application prospect. Compared with the existing similar compounds, the compound of the invention has better drug effect, pharmacological property and/or toxicological property.

Disclosure of Invention

The following is a summary of some aspects of the invention only and is not intended to be limiting. These aspects and others are described more fully below. All references in this specification are incorporated herein by reference in their entirety. When the disclosure of the present specification differs from the cited documents, the disclosure of the present specification controls.

The present invention relates to a novel class of difluoromethyl-substituted phenylpiperazine derivatives having strong binding affinity to the 5-HT transporter (SERT) and inhibiting 5-HT reuptake, and thus useful for the preparation of a medicament for the treatment of Central Nervous System (CNS) dysfunction, in particular for the treatment of affective disorders including, but not limited to, depression, anxiety, social phobia, obsessive compulsive disorders, panic attacks, specific phobias, agoraphobia, mania, panic disorders and post-traumatic stress disorder.

The compound has stable property and good safety, and has the advantages of pharmacodynamics and pharmacokinetics, such as good brain/plasma ratio (brain plasma ratio), good bioavailability or good metabolic stability and the like, so the compound has good clinical application prospect.

The invention also provides processes for the preparation of such compounds and pharmaceutical compositions containing them.

In one aspect, the invention relates to a compound that is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt of a compound of formula (I) or a prodrug thereof,

wherein R is¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸X and m have the meanings given in the description of the invention.

In some embodiments, X is S or O.

In some embodiments, R¹、R²、R³、R⁴And R⁵Each independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-SH、-COOH、-CONH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂、-C(＝O)-(C₁-C₆Alkyl), -C (═ O) - (C)₁-C₆Alkoxy group), C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy, C₁-C₆Alkylthio radical, C₁-C₆Alkylamino or hydroxy substituted C₁-C₆An alkyl group.

In some embodiments, R¹、R²、R³、R⁴And R⁵Each independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-SH、-COOH、-CONH₂、-C(＝O)-(C₁-C₄Alkyl), -C (═ O) - (C)₁-C₄Alkoxy group), C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy, C₁-C₄Alkylthio radical, C₁-C₄Alkylamino or hydroxy substituted C₁-C₄An alkyl group.

In some embodiments, R¹、R²、R³、R⁴And R⁵Independently of one another H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-SH、-COOH、-CONH₂、-C(＝O)CH₃、-C(＝O)OCH₃Methyl, ethyl, n-propyl, isopropyl, -CF₃、-CH₂CF₃Methoxy, ethoxy, n-propyloxy or isopropyloxy.

In some embodiments, each R is⁸Independently H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂、-C(＝O)-(C₁-C₆Alkyl), -C (═ O) - (C)₁-C₆Alkoxy group), C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxy or C₁-C₆A haloalkoxy group.

In some embodiments, each R is⁸Independently H,D、F、Cl、Br、I、-CN、-NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂、C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl or C₁-C₄A haloalkyl group.

In some embodiments, each R is⁸Independently H, D, -COOH, -C (═ O) NH₂Methyl, ethyl, n-propyl, isopropyl, -CF₃or-CH₂CF₃。

In some embodiments, R⁶And R⁷One of them is-CHF₂The other is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-SH、-COOH、-CONH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂、-C(＝O)-(C₁-C₆Alkyl), -C (═ O) - (C)₁-C₆Alkoxy group), C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy, C₁-C₆Alkylthio radical, C₁-C₆Alkylamino or hydroxy substituted C₁-C₆An alkyl group.

In some embodiments, R⁶And R⁷One of them is-CHF₂The other is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-SH、-COOH、-CONH₂、-C(＝O)-(C₁-C₄Alkyl), -C (═ O) - (C)₁-C₄Alkoxy group), C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy, C₁-C₄Alkylthio radical, C₁-C₄Alkylamino or hydroxy substituted C₁-C₄An alkyl group.

In some embodiments, R⁶And R⁷One of them is-CHF₂The other is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-SH、-COOH、-CONH₂、-C(＝O)CH₃、-C(＝O)OCH₃Methyl, ethyl, n-propyl, isopropyl, -CHF₂、-CF₃、-CH₂CF₃Methoxy, ethoxy, n-propyloxy or isopropyloxy.

In some embodiments, m is 0, 1, 2,3, 4, 5, or 6.

In other embodiments, the compound of the present invention is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt of the compound having one of the following structures or a prodrug thereof:

in another aspect, the present invention relates to a pharmaceutical composition comprising a compound disclosed herein.

In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.

In other embodiments, the pharmaceutical composition of the present invention further comprises a drug for treating central nervous system dysfunction, wherein the drug for treating central nervous system dysfunction is an antidepressant, an anxiolytic, a lithium salt drug as an affective stabilizer, an atypical antipsychotic, an antiepileptic, an anti-parkinson drug, a drug as a selective 5-hydroxytryptamine reuptake inhibitor, a central nervous stimulant, a nicotine antagonist, or any combination thereof.

In still other embodiments, the agents of the present invention for treating central nervous system dysfunction are amitriptyline (amitriptyline), desipramine (desipramine), mirtazapine (mirtazapine), bupropion (bupropion), reboxetine (reboxetine), fluoxetine (fluoxetine), trazodone (trazodone), sertraline (sertraline), duloxetine (duloxetine), fluvoxamine (fluvoxamine), milnacipran (milnacipran), levomilnacipran (leminamide), desvenlafaxine (desvenlafaxine), vilazodone (vilazodone), venlafaxine (venlafaxine), dapoxetine (dapoxetine), nefazodone (nefazodone), femoxetine (femoxetine), chlorpropazine (chlorpromazine), ziprasidone (sulipramine (sulipratropium), ziprasidone (sulbactam), clopram, Piperacillin (peroospirone), clozapine (clozapine), modafinil (modafinil), mecamylamine (mecamylamine), cabergoline (cabergoline), adamantane (amantane), imipramine (imipramine), pramipexole (pramipexole), thyroxine (thyroxine), dextromethorphan (dextromethorphan), quinidine (quinidine), naltrexone (naltrexone), samindorfanin, buprenorphine (buprenorphine), melatonin (melatonin), alprazolam (alprazolam), pipamperone (pipamerone), vetepitant (vestipitant), chlordiazepoxide (chlorpropoxide), perphenazine (perphenazine), or any combination thereof.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition disclosed herein for the manufacture of a medicament for the prevention, treatment or alleviation of central nervous system dysfunction. In some embodiments, the medicament is for preventing, treating, or ameliorating central nervous system dysfunction in a mammal. In other embodiments, the medicament is for preventing, treating, or ameliorating central nervous system dysfunction in a human.

In some embodiments, the central nervous system disorder is depression, anxiety, social phobia, obsessive compulsive disorder, panic attacks, specific phobias, agoraphobia, mania, panic disorder, post-traumatic stress disorder, schizophrenia, sleep disorders, bipolar disorders, obsessive-compulsive disorders, movement disorders, sexual dysfunction, musculoskeletal pain disorders, cognitive disorders, memory disorders, parkinson's disease, huntington's disease, phobias, substance abuse or addiction, withdrawal symptoms from drug addiction, and premenstrual tension syndrome.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition disclosed herein for the preparation of a medicament for the prevention, treatment or alleviation of affective disorders.

In some embodiments, the affective disorder includes, but is not limited to, depression, anxiety, social phobia, obsessive compulsive disorder, panic attacks, specific phobias, agoraphobia, mania, panic disorder, and post-traumatic stress disorder.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition disclosed herein for the manufacture of a medicament for inhibiting 5-hydroxytryptamine reuptake.

In another aspect, the invention relates to methods for the preparation, isolation and purification of compounds of formula (I).

Biological test results show that the compound has strong affinity to human 5-HT transporters (SERT), so that the compound provided by the invention can be used as a better selective 5-hydroxytryptamine reuptake inhibitor.

In addition, some of the compounds of the present invention have a combination of 5-hydroxytryptamine reuptake inhibition and norepinephrine reuptake inhibition, others of the compounds of the present invention have a combination of 5-hydroxytryptamine reuptake inhibition and dopamine reuptake inhibition, and still other compounds of the present invention have triple reuptake inhibition of 5-hydroxytryptamine, norepinephrine and dopamine.

Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict.

The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below.

Detailed description of the invention

Definitions and general terms

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.

It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

The following definitions, as used herein, should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be found in the descriptions of "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and JerryMarch, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.

The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to one or to more than one (i.e., to at least one) of the objects. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.

The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

The term "stereoisomers" refers to compounds having the same chemical structure, but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric (cis/trans) isomers, atropisomers, and the like.

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (lowenergy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization.

"pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.

The term "optionally substituted with … …", is used interchangeably with the term "unsubstituted or substituted with ….," i.e., the structure is unsubstituted or substituted with one or more substituents described herein, including but not limited to D, F, Cl, Br, I, N₃，-CN，-NO₂，-NH₂，-OH，-SH，-COOH，-CONH₂，-C(＝O)NHCH₃，-C(＝O)N(CH₃)₂-C (═ O) -alkyl, -C (═ O) -alkoxy, alkyl, alkoxy, alkylthio, alkylamino, alkenyl, alkynyl, haloalkyl, haloAlkoxy, hydroxy-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like.

In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C₁-C₆Alkyl "means in particular independently disclosed methyl, ethyl, C₃Alkyl radical, C₄Alkyl radical, C₅Alkyl and C₆An alkyl group.

In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.

The terms "halogen" and "halo" are used interchangeably herein to refer to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

The term "alkyl" or "alkyl group" as used herein, denotes a saturated, straight or branched chain, monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. In some embodiments, the alkyl group contains 1 to 6 carbon atoms; in other embodiments, the alkyl group contains 1 to 4 carbon atoms; in still other embodiments, the alkyl group contains 1 to 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)₃) Ethyl group (Et, -CH)₂CH₃) N-propyl (n-Pr, -CH)₂CH₂CH₃) Isopropyl group (i-Pr, -CH (CH)₃)₂) N-butyl (n-Bu, -CH)₂CH₂CH₂CH₃) Isobutyl (i-Bu, -CH)₂CH(CH₃)₂) Sec-butyl (s-Bu, -CH (CH)₃)CH₂CH₃) Tert-butyl (t-Bu, -C (CH)₃)₃) And so on.

The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp²A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z".

The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. a carbon-carbon sp triple bond, wherein said alkynyl radical may optionally be substituted with one or more substituents as described herein.

The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In some embodiments, alkoxy groups contain 1 to 6 carbon atoms; in other embodiments, the alkoxy group contains 1 to 4 carbon atoms; in still other embodiments, alkoxy groups contain 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)₃) Ethoxy (EtO, -OCH)₂CH₃) 1-propoxy (n-PrO, n-propoxy, -OCH)₂CH₂CH₃) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)₃)₂) 1-butoxy (n-BuO, n-butoxy, -OCH)₂CH₂CH₂CH₃) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)₂CH(CH₃)₂) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)₃)CH₂CH₃) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)₃)₃) And so on.

The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" wherein the amino groups are each independently substituted with one or two alkyl groups, wherein the alkyl groups have the meaning as described herein. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, and the like. The alkylamino group is optionally substituted with one or more substituents described herein.

The term "hydroxy-substituted alkyl" denotes an alkyl group substituted with one or more hydroxy groups, wherein the alkyl group has the meaning as described herein; examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-1-propyl, 3-hydroxy-1-propyl, 2, 3-dihydroxypropyl, and the like.

The term "haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group substituted with one or more halogen atoms, wherein the alkyl and alkoxy groups have the meaning as described herein, examples of which include, but are not limited to, trifluoromethyl, trifluoromethoxy, and the like. In some embodiments, C₁-C₆The haloalkyl group containing a fluorine-substituted C₁-C₆An alkyl group; in other embodiments, C₁-C₄The haloalkyl group containing a fluorine-substituted C₁-C₄An alkyl group; in still other embodiments, C₁-C₂The haloalkyl group containing a fluorine-substituted C₁-C₂An alkyl group.

As described herein, the ring system formed by the ring wherein the substituent R is attached to the center by a bond (as shown in the following figures) represents that the substituent R may be substituted at any substitutable or any reasonable position on the ring. For example, formula a represents the position of the substituent R on the piperazine ring at any possible substitution, e.g. formula a¹-a³Shown in the figure:

the term "prodrug", as used herein, denotes a compound which is converted in vivo to a compound of formula (I)The compounds shown are shown. Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)_1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent.

"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, descriptive acceptable salts in detail in J. pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or water-solubleThe bulk product may be obtained by quaternization. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C₁-C₈Sulfonates and aromatic sulfonates.

"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term "hydrate" refers to an association of solvent molecules that is water.

The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.

The term "therapeutically effective amount" means an amount of a compound that, when administered to a subject to treat a disease, is sufficient to effect treatment of the disease. The "therapeutically effective amount" may vary with the compound, the disease and the severity, as well as the condition, age, weight, sex, etc., of the subject to be treated.

The compounds, pharmaceutically acceptable salts thereof, pharmaceutical formulations and compositions thereof, to which the present invention relates, may be useful as selective 5-hydroxytryptamine reuptake inhibitors, with potential use in the treatment of disorders of the central nervous system, particularly affective disorders including, but not limited to, depression, anxiety, social phobia, obsessive compulsive disorder, panic attacks, specific phobias, agoraphobia, mania, panic disorders and post-traumatic stress disorders in humans.

Unless otherwise indicated, all suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are encompassed within the scope of the present invention.

In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated as within this invention and are included as disclosed compounds in this invention. When stereochemistry is indicated by a solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of the structure are so well-defined and defined.

The compounds of formula (I) may be present in the form of salts. In some embodiments, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith. In other embodiments, the salts need not be pharmaceutically acceptable salts and may be intermediates useful in the preparation and/or purification of compounds of formula (I) and/or in the isolation of enantiomers of compounds of formula (I).

Any formulae given herein are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as²H、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、¹⁸F、³¹P、³²P、³⁵S、³⁶Cl and¹²⁵I。

in another aspect, the invention relates to intermediates for the preparation of compounds of formula (I).

Pharmaceutical compositions, formulations and administration of the compounds of the invention

The invention provides a pharmaceutical composition, which comprises a compound shown as a formula (I) or an individual stereoisomer, a racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of the invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, adjuvant or vehicle, and optionally, other therapeutic and/or prophylactic ingredients.

Suitable carriers, adjuvants and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel h.c.et al, Ansel's Pharmaceutical Dosage Forms and Drug delivery systems (2004) Lippincott, Williams & Wilkins, philidelphia; gennaro a.r.et al, Remington: the Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe R.C., Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.

It will also be appreciated that certain compounds of the invention may be present in free form or, if appropriate, in the form of a pharmaceutically acceptable derivative thereof, when used in therapy. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any additional adduct or derivative that upon administration to a patient in need thereof provides, directly or indirectly, a compound of the present invention or a metabolite or residue thereof.

Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, pharmaceutically acceptable excipients may be selected for their specific function in the composition. Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function, and provide alternative functions, depending on how many such excipients are present in the formulation and which other excipients are present in the formulation.

The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. Some commonly used methods in the art are described in Remington's Pharmaceutical Sciences (Mack publishing company).

Thus, in another aspect, the invention relates to a process for preparing a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof, which process comprises admixing the ingredients. Pharmaceutical compositions comprising the disclosed compounds may be prepared by mixing, for example, at ambient temperature and atmospheric pressure.

The compounds disclosed herein are generally formulated in a dosage form suitable for administration to a patient by a desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, e.g., suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.

In some embodiments, the compounds disclosed herein can be formulated in oral dosage forms. In other embodiments, the compounds disclosed herein may be formulated in an inhalation dosage form. In other embodiments, the compounds disclosed herein can be formulated for nasal administration. In still other embodiments, the compounds disclosed herein can be formulated for transdermal administration. In still other embodiments, the compounds disclosed herein may be formulated for topical administration.

The pharmaceutical compositions provided by the present invention may be provided as compressed tablets, milled tablets, chewable lozenges, fast-dissolving tablets, double-compressed tablets, or enteric-coated, sugar-coated or film-coated tablets.

The pharmaceutical composition provided by the present invention may be provided in soft or hard capsules, which may be prepared from gelatin, methylcellulose, starch or calcium alginate.

The pharmaceutical compositions provided by the present invention may be administered parenterally by injection, infusion or implantation for local or systemic administration. Parenteral administration as used herein includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.

The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and solid forms suitable for solution or suspension in a liquid prior to injection. Such dosage forms may be prepared according to conventional methods known to those skilled in The art of pharmaceutical Science (see Remington: The Science and Practice of Pharmacy, supra).

In another aspect, the disclosed pharmaceutical compositions may be formulated in any dosage form suitable for administration to a patient by inhalation, such as a dry powder, aerosol, suspension, or solution composition.

Pharmaceutical compositions suitable for transdermal administration may be prepared as discrete patches intended to remain in intimate contact with the epidermis of the patient for an extended period of time. For example, the active ingredient may be delivered from a patch agent by iontophoresis, as generally described in Pharmaceutical Research,3(6),318 (1986).

Pharmaceutical compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

Use of the Compounds and pharmaceutical compositions of the invention

The compounds and pharmaceutical compositions provided by the present invention can be used for preparing medicines for preventing, treating or relieving central nervous system dysfunction of mammals including human beings, and can also be used for preparing medicines for inhibiting reuptake of 5-hydroxytryptamine.

In particular, the amount of the compound in the pharmaceutical composition of the invention is effective to detectably and selectively inhibit 5-hydroxytryptamine reuptake, and the compounds of the invention are useful as medicaments for the treatment of Central Nervous System (CNS) disorders, particularly affective disorders including, but not limited to, depression, anxiety, social phobia, obsessive compulsive disorders, panic attacks, specific phobias, agoraphobia, mania, panic disorders, and post-traumatic stress disorders in humans.

The compounds of the present invention may be used in, but are in no way limited to, the prevention, treatment, or alleviation of central nervous system dysfunctional disorders by administering to a patient an effective amount of a compound or a pharmaceutical composition of the present invention. The central nervous system dysfunction responsive to 5-hydroxytryptamine regulation further includes, but is not limited to, depression, anxiety, social phobia, obsessive compulsive disorder, panic attacks, specific phobias, agoraphobia, mania, panic disorder, post-traumatic stress disorder, schizophrenia, sleep disorders, bipolar disorders, obsessive-compulsive disorders, movement disorders, sexual dysfunction, musculoskeletal pain disorders, cognitive disorders, memory disorders, parkinson's disease, huntington's disease, phobias, substance abuse or addiction, withdrawal symptoms of drug addiction, premenstrual tension syndrome, and the like.

In addition to being beneficial for human therapy, the compounds and pharmaceutical compositions of the present invention may also find application in veterinary therapy for pets, animals of the introduced species and mammals in farm animals. Examples of other animals include horses, dogs, and cats. Herein, the compound of the present invention includes pharmaceutically acceptable derivatives thereof.

In some embodiments, a disclosed compound or a pharmaceutical composition comprising a disclosed compound may be administered once or several times at different time intervals over a specified period of time according to a dosing regimen. The compounds disclosed herein may be administered simultaneously, or before or after, one or more other therapeutic agents. The compounds of the invention may be administered separately from the other therapeutic agents, by the same or different routes of administration, or in the same pharmaceutical composition.

General synthetic procedure

To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.

In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.

The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin Haojian Yunyu chemical Co., Ltd, Tianjin Shucheng chemical reagent factory, Wuhan Xin Huayuan scientific and technological development Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaolingyi factory.

The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were used as they were previously dried over anhydrous sodium sulfate.

The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.

The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants.

¹H NMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer.¹H NMR Spectrum in CDC1₃、DMSO-d₆、CD₃OD or acetone-d₆TMS (0 ppm) or chloroform (7.26 ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (singlets), d (doublets), t (triplets), m (multiplets), br (broadcasters, broad singlet), dd (doublets), dt (doublets of triplets). Coupling constant J, expressed in Hertz (Hz).

The conditions for determining low resolution Mass Spectrometry (MS) data were: agilent 6120 four-stage rod HPLC-M (column model: Zorbax SB-C18,2.1X 30 mm,3.5 micron, 6 min, flow rate 0.6 mL/min. mobile phase: 5% -95% (CH with 0.1% formic acid)₃CN) in (H containing 0.1% formic acid)₂O) by electrospray ionization (ESI) at 210 nm/254nm, with UV detection.

Pure compounds were detected by UV at 210 nm/254nm using Agilent 1260 pre-HPLC or Calesep pump 250 pre-HPLC (column model: NOVASEP 50/80mm DAC).

The following acronyms are used throughout the invention:

BOC, Boc tert-butoxycarbonyl for h

CDC1₃Deuterated chloroform mmol, mM millimole

nM nanomolar DMSO dimethyl sulfoxide

DMSO-d₆Deuterated dimethyl sulfoxide mg

Saline g

Kg of BSA bovine serum albumin

min mL, mL

The following synthetic schemes describe the steps for preparing the compounds disclosed herein, wherein each R is, unless otherwise indicated¹、R²、R³、R⁴And R⁵Having the definitions set out in the present invention.

Synthesis scheme 1

Compound (A) to (B)8) Can be prepared by synthesis method 1: compound (A) to (B)1) Nucleophilic substitution reaction with piperazine to obtain compound (A)2) Compound (A) to (B)2) Is protected with trifluoroacetyl group to give a compound (b)3) Compound (A) to (B)3) Fluorination to give the compound (A)4) Compound (A) to (B)4) Removing the trifluoroacetyl group to obtain a compound (5) Compound (A) to (B)5) Protection of the secondary amine Boc gives the compound (6) Compound (A) to (B)6) Carrying out coupling reaction with substituted thiophenol compound to obtain compound (A)7) Compound (A) to (B)7) Removing Boc protecting group to obtain compound (A)8)。

Synthesis scheme 2

Compound (A) to (B)12) Can be prepared by a synthesis method 2: compound (A) to (B)1) Coupling with substituted thiophenol compound to obtain compound (A)9) Compound (A) to (B)9) By fluorination to give compounds (A)10) Compound (A) to (B)10) Coupling with N-Boc-piperazine to give compound (b)11) Compound (A) to (B)11) Removing Boc protecting group to obtain compound (A)12)。

The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further illustrated below in connection with the examples.

Examples

Example Synthesis of 4- (difluoromethyl-2- ((2, 4-dimethylphenyl) thio) phenyl) piperazine

Step 1) Synthesis of 3-bromo-4-piperazine-1-benzaldehyde

3-bromo-4-fluorobenzaldehyde (3.0g,14.78mmol), piperazine (5.092g,59.11mmol) and dimethyl sulfoxide (20mL) are sequentially added into a 100mL double-neck bottle, and the temperature is gradually increased to 130 ℃ for reaction under the protection of nitrogen. After 20 hours the reaction was stopped and cooled. The reaction mixture was slowly poured into 100mL of tap water, extracted with dichloromethane (60mL × 3), the organic layers were combined, washed with tap water (50mL × 3) and saturated brine (50mL) in this order, the solvent was directly distilled off under reduced pressure from the organic layer, and the residue was dissolved in dichloromethane and then subjected to silica gel column chromatography to purify the residue (dichloromethane/methanol (v/v) ═ 15/1) directly to obtain the title compound as an off-white solid (1.24g, 31%).

MS(ESI,pos.ion)m/z:269.20[M+H]⁺.

Step 2) Synthesis of 3-bromo-4- (4- (2,2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde

3-bromo-4-piperazine-1-benzaldehyde (1.220g,4.533mmol), dry dichloromethane (40mL), and triethylamine (1.3mL,9.3mmol) were sequentially added to a 100mL single-neck flask, and trifluoroacetic anhydride (0.83mL,5.9mmol) was slowly added thereto at-5 ℃ for 40 minutes, and then the mixture was allowed to react at room temperature. After 5 hours, the reaction was stopped, the solvent was evaporated under reduced pressure, and the residue was dissolved in dichloromethane and then subjected to direct silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 8/1) to give the title compound as a pale yellow solid (0.885g, 54%).

MS(ESI,pos.ion)m/z:365.10[M+H]⁺；

¹H NMR(CDCl₃,400MHz)δ(ppm):9.88(s,1H),8.10(d,J＝1.8Hz,1H),7.81(dd,J＝8.2,1.8Hz,1H),7.10(d,J＝8.2Hz,1H),3.91(t,J＝4.9Hz,2H),3.83(t,J＝4.6Hz,2H),3.22(t,J＝4.8Hz,4H).

Step 3) synthesis of 1- (4- (2-bromo-4-difluoromethyl phenyl) piperazine-1-yl) -2,2, 2-trifluoroacetone

3-bromo-4- (4- (2,2, 2-trifluoroacetyl) piperazin-1-yl) benzaldehyde (0.883g,2.42mmol) was charged into a 50mL one-neck flask, and after complete dissolution with dichloromethane (15mL), diethylaminosulfur trifluoride (1mL,7.4mmol) was slowly added, and the reaction was carried out at room temperature. After 12 hours, TLC showed that the starting material spot had substantially disappeared and the reaction was stopped, dichloromethane (10mL) was added to the reaction solution and a saturated aqueous solution of sodium bicarbonate was slowly added to make it weakly basic, the aqueous layer (20mL × 3) was extracted with dichloromethane, the organic layers were combined, and the solvent was evaporated under reduced pressure and then directly subjected to silica gel column chromatography for purification (petroleum ether/ethyl acetate (v/v) ═ 12/1) to obtain the title compound as a pale yellow oil (0.84g, 90%).

MS(ESI,pos.ion)m/z:387.10[M+H]⁺；

¹H NMR(CDCl₃,400MHz)δ(ppm):7.75(s,1H),7.44(d,J＝8.2Hz,1H),7.07(d,J＝8.3Hz,1H),6.58(t,J＝56.3Hz,1H),3.89(t,J＝4.5Hz,2H),3.81(t,J＝4.4Hz,2H),3.22(t,J＝4.9Hz,4H).

Step 4) Synthesis of 1- (2-bromo-4- (difluoromethyl) phenyl) piperazine

1- (4- (2-bromo-4-difluoromethylphenyl) piperazin-1-yl) -2,2, 2-trifluoroacetone (0.840g,2.17mmol) was charged into a 100mL single-neck flask, and after complete dissolution with tetrahydrofuran (10mL), ethanol (10mL), and tap water (10mL), potassium carbonate (1.200g,8.682mmol) was added and the reaction was carried out at room temperature. The reaction was stopped after 12 hours, TLC showed the starting material was completely reacted, the solvent was distilled off under reduced pressure, and the residue was dissolved in dichloromethane and a small amount of methanol and directly subjected to silica gel column chromatography (dichloromethane/methanol (v/v) ═ 12/1) to give the title compound as a pale yellow oil (0.63g, 99%).

MS(ESI,pos.ion)m/z:291.10[M+H]⁺；

¹H NMR(CDCl₃,400MHz)δ(ppm):7.71(s,1H),7.41(d,J＝8.3Hz,1H),7.08(d,J＝8.3Hz,1H),6.57(t,J＝56.4Hz,1H),3.09(s,8H).

Step 5) Synthesis of 4- (2-bromo-4- (difluoromethyl) phenyl) piperazine-1-carboxylic acid tert-butyl ester

1- (2-bromo-4- (difluoromethyl) phenyl) piperazine (0.625g,2.15mmol) was charged into a 100mL one-neck flask, and after complete dissolution with dichloromethane (25mL), triethylamine (0.6mL,4.3mmol) and tert-butyl dicarbonate (0.60mL,2.61mmol) were added and the reaction was carried out at room temperature. TLC showed the disappearance of the starting point after 5 hours, the reaction was stopped, the solvent was evaporated under reduced pressure, and the residue was dissolved in dichloromethane and directly purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 15/1) to give the title compound as a colorless oil (0.83g, 99%).

MS(ESI,pos.ion)m/z:335.10[M+H-56]⁺；

¹H NMR(CDCl₃,400MHz)δ(ppm):7.71(s,1H),7.40(d,J＝8.2Hz,1H),7.05(d,J＝8.2Hz,1H),6.56(t,J＝56.4Hz,1H),3.61(t,J＝5.0Hz,4H),3.01(t,J＝4.8Hz,4H),1.48(s,9H).

Step 6) tert-butyl 4- (4- (difluoromethyl) -2- ((2, 4-dimethylphenyl) thio) phenyl) piperazine-1-carboxylate Synthesis of (2)

Tert-butyl 4- (2-bromo-4- (difluoromethyl) phenyl) piperazine-1-carboxylate (0.830g,2.12mmol), potassium tert-butoxide (0.596g,5.31mmol), tris (dibenzylideneacetone) dipalladium (0.292g,0.319mmol), bis (2-diphenylphosphinophenyl) ether (0.286g,0.531mmol), 2, 4-dimethylthiophenol (0.352g,2.55mmol), and anhydrous dimethyl sulfoxide (15mL) were sequentially added to a 50mL single-neck flask, and the temperature was gradually raised to 140 ℃ under nitrogen protection for reaction. After 52 hours, TLC showed very little starting material remaining, the reaction was stopped and cooled. The reaction mixture was poured into tap water (100mL), extracted with dichloromethane (100mL × 2), and the dichloromethane layers were combined, washed with tap water (100mL × 4), washed with saturated brine (100mL), and directly subjected to silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 20/1) to give the title compound as a pale orange red solid (0.59g, 62%).

MS(ESI,pos.ion)m/z:449.40[M+H]⁺；

¹H NMR(CDCl₃,600MHz)δ(ppm):7.36(d,J＝7.8Hz,1H),7.22(d,J＝8.1Hz,1H),7.17(s,1H),7.07(d,J＝8.2Hz,1H),7.05(d,J＝7.9Hz,1H),6.63(s,1H),6.39(t,J＝56.5Hz,1H),3.64～3.61(m,4H),3.04(s,4H),2.37(s,3H),2.30(s,3H),1.49(s,9H).

Step 7) Synthesis of 1- (4-difluoromethyl-2- ((2, 4-dimethylphenyl) thio) phenyl) piperazine

Tert-butyl 4- (4- (difluoromethyl) -2- ((2, 4-dimethylphenyl) thio) phenyl) piperazine-1-carboxylate (0.55g,1.2mmol) and methylene chloride (10mL) were sequentially added to a 50mL one-neck flask, and an ethyl hydrogen chloride solution (6mL,4M) was slowly added thereto and reacted at room temperature. After 1 hour, TLC showed the disappearance of the starting material spot in the reaction solution. To the reaction solution was slowly added saturated aqueous sodium bicarbonate solution to pH 8, the layers were separated, the aqueous layer was extracted with dichloromethane (50mL × 3), the dichloromethane layers were combined, concentrated, and the residue was directly subjected to silica gel column chromatography (dichloromethane/methanol (v/v) ═ 25/1) to give the title compound as a pale yellow oil (0.295g, 69%).

MS(ESI,pos.ion)m/z:349.30[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.37(d,J＝7.8Hz,1H),7.22(d,J＝8.0Hz,1H),7.16(s,1H),7.09(d,J＝8.1Hz,1H),7.04(d,J＝7.7Hz,1H),6.62(s,1H),6.38(t,J＝56.5Hz,1H),3.07(s,8H),2.37(s,3H),2.30(s,3H).

¹³C NMR(150MHz,CDCl₃)δ(ppm):151.7(s),142.5(s),139.8(s),136.3(s),135.5(s),132.0(s),130.1(t,J＝22.5Hz),128.1(s),127.1(s),123.6(t,J＝6.3Hz),122.8(t,J＝5.8Hz),119.9(s),114.7(t,J＝238.2Hz),52.9(s),46.4(s),21.3(s),20.7(s).

HPLC:97.96％.

Example Synthesis of 21- (5-difluoromethyl-2- ((2, 4-dimethylphenyl) thio) phenyl) piperazine

Step 1) Synthesis of 3-bromo-4- ((2, 4-dimethylphenyl) thio) benzaldehyde

3-bromo-4-fluorobenzaldehyde (1.0g,4.926mmol), potassium carbonate (1.362g,9.855mmol), 2, 4-dimethylthiophenol (0.817g,5.91mmol) and anhydrous N, N-dimethylformamide (15mL) were sequentially added to a 100mL single-neck flask, and the temperature was gradually raised to 120 ℃ for reaction under nitrogen protection. After 6 hours TLC showed the reaction was complete, the reaction was stopped and cooled. To the reaction mixture was slowly added a saturated aqueous ammonium chloride solution (30mL), tap water (200mL), and ethyl acetate extraction (60mL × 3), and the organic layer was washed with tap water (200mL × 4) and saturated brine (100mL) in this order, and the solvent was directly evaporated under reduced pressure to separate and purify the organic layer by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 200/1) to obtain the title compound as a pale yellow solid (1.33g, 84%).

MS(ESI,pos.ion)m/z:321.20[M+H]⁺；

¹H NMR(CDCl₃,600MHz)δ(ppm):9.82(s,1H),7.99(d,J＝1.5Hz,1H),7.52(dd,J＝8.2,1.6Hz,1H),7.45(d,J＝7.8Hz,1H),7.22(s,1H),7.11(d,J＝7.6Hz,1H),6.56(d,J＝8.2Hz,1H),2.39(s,3H),2.32(s,3H).

Step 2) (2-bromo-4- (difluoromethyl) phenyl) (2, 4-dimethylphenyl) sulfide synthesis

3-bromo-4- ((2, 4-dimethylphenyl) thio) benzaldehyde (0.500g,1.56mmol) was charged into a 50mL one-necked flask, and after complete dissolution with dichloromethane (15mL), diethylaminosulfur trifluoride (0.63mL,4.7mmol) was slowly added, and the reaction was carried out at room temperature. TLC showed that the starting material spot had substantially disappeared after 15 hours, the reaction was stopped, dichloromethane (10mL) was added to the reaction solution, and a saturated aqueous sodium bicarbonate solution was slowly added to make it weakly basic, extracted with dichloromethane (20mL × 3), the organic layers were combined, and the solvent was evaporated under reduced pressure and then directly subjected to silica gel column chromatography for purification (petroleum ether/ethyl acetate (v/v) ═ 200/1) to give the title compound as a pale yellow solid (0.47g, 88%).

¹H NMR(CDCl₃,600MHz)δ(ppm):7.66(s,1H),7.43(d,J＝7.8Hz,1H),7.20(s,1H),7.18(d,J＝8.2Hz,1H),7.09(d,J＝7.7Hz,1H),6.54(t,J＝56.3Hz,1H),6.53(d,J＝7.8Hz,1H),2.39(s,3H),2.33(s,3H).

Step 3)4- (5-difluoromethyl-2- ((2, 4-dimethylphenyl) thio) phenyl) Process for preparation of piperazine-1-carboxylic acid tert-butyl ester Synthesis of

(2-bromo-4- (difluoromethyl) phenyl) (2, 4-dimethylphenyl) sulfide (0.440g,1.28mmol), N-Boc-piperazine (0.360g,1.93mmol), sodium tert-butoxide (0.185g,1.93mmol), (. + -.) -2,2 '-bis- (diphenylphosphino) -1, 1' -binaphthyl (0.06g,0.096mmol), tris (dibenzylideneacetone) dipalladium (0.030g,0.033mmol), and toluene (10mL) were added in sequence to a 50mL single-neck flask, and the reaction was gradually warmed to 110 ℃ under nitrogen. The reaction was stopped after 22 hours and TLC showed a small amount of starting material remaining. The solvent was distilled off under reduced pressure, and the residue was dissolved in methylene chloride and then directly subjected to separation and purification by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 35/1) to give the title compound as a yellow oil (0.47g, 81%).

MS(ESI,pos.ion)m/z:449.40[M+H]⁺；

¹H NMR(CDCl₃,400MHz)δ(ppm):7.40(d,J＝7.8Hz,1H),7.18(s,1H),7.15(s,1H),7.06(d,J＝7.7Hz,1H),6.97(d,J＝8.1Hz,1H),6.54(t,J＝56.6Hz,1H),6.52(d,J＝8.2Hz,1H),3.64(t,J＝4.5Hz,4H),3.03(t,J＝4.7Hz,4H),2.38(s,3H),2.31(s,3H),1.50(s,9H).

Step 4) Synthesis of 1- (5-difluoromethyl-2- ((2, 4-dimethylphenyl) thio) phenyl) piperazine

Tert-butyl 4- (5-difluoromethyl-2- ((2, 4-dimethylphenyl) thio) phenyl) piperazine-1-carboxylate (0.440g,0.981mmol) was charged into a 50mL single-neck flask, and was allowed to completely dissolve in dichloromethane (5mL), an ethyl hydrogen chloride acetate solution (6mL,4M) was slowly added, the reaction was allowed to complete after 1 hour at room temperature, the reaction was stopped, a saturated aqueous sodium bicarbonate solution was slowly added dropwise to the reaction mixture until the pH became 8, dichloromethane was extracted (20mL × 3), the dichloromethane layer was washed with a saturated saline solution (10mL), the organic layer was collected, the solvent was directly evaporated under reduced pressure, the residue was dissolved in dichloromethane and a small amount of methanol, and then stirred with silica gel directly and subjected to silica gel column chromatography (dichloromethane/methanol (v/v) ═ 25/1) to give the title compound as a pale yellow oil (0.33g, 95%).

MS(ESI,pos.ion)m/z:349.40[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.40(d,J＝7.8Hz,1H),7.17(s,2H),7.05(d,J＝7.6Hz,1H),6.95(d,J＝8.1Hz,1H),6.54(t,J＝56.7Hz,1H),6.50(d,J＝8.2Hz,1H),3.10～3.07(m,8H),2.37(s,3H),2.30(s,3H).

¹³C NMR(150MHz,CDCl₃)δ(ppm):149.4(s),142.8(s),139.9(s),138.6(s),136.7(s),131.9(s),130.1(t,J＝22.3Hz),128.0(s),126.9(s),125.6(s),121.4(t,J＝6.3Hz),116.8(t,J＝5.7Hz),114.7(t,J＝238.5Hz),52.8(s),46.3(s),21.2(s),20.6(s).

HPLC:97.91％.

Example Synthesis of 31- (5- (difluoromethyl) -2- ((4-methoxyphenyl) thio) phenyl) piperazine

Step 1) Synthesis of 3-bromo-4- ((4-methoxyphenyl) thio) benzaldehyde

3-bromo-4-fluorobenzaldehyde (1.0g,4.926mmol), potassium carbonate (1.362g,9.855mmol), p-methoxyphenylphenol (0.827g,5.91mmol) and anhydrous N, N-dimethylformamide (15mL) were sequentially added to a 100mL single-neck flask, and the mixture was gradually heated to 120 ℃ under nitrogen protection to react. After 6 hours TLC showed the reaction was complete, the reaction was stopped and cooled. To the reaction mixture was slowly added a saturated aqueous ammonium chloride solution (30mL), tap water (200mL), and ethyl acetate extraction (60mL × 3), and the organic layer was washed with tap water (200mL × 4) and saturated brine (100mL) in this order, and the solvent was directly evaporated under reduced pressure to separate and purify the organic layer by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 200/1) to obtain the title compound as a pale yellow solid (1.1g, 70%).

MS(ESI,pos.ion)m/z:324.10[M+H]⁺；

¹H NMR(CDCl₃,600MHz)δ(ppm):9.83(s,1H),7.98(d,J＝1.5Hz,1H),7.50(dd,J＝8.2,1.6Hz,1H),7.43(d,J＝7.8Hz,1H),7.21(s,1H),7.10(d,J＝7.6Hz,1H),6.55(d,J＝8.2Hz,1H),3.85(s,3H).

Step 2) Synthesis of (2-bromo-4- (difluoromethyl) phenyl) (4-methoxyphenyl) sulfide

3-bromo-4- ((4-methoxyphenyl) thio) benzaldehyde (0.500g,1.547mmol) was charged in a 50mL one-necked flask, and after complete dissolution with dichloromethane (15mL), diethylaminosulfur trifluoride (0.60mL,4.5mmol) was slowly added and the reaction was carried out at room temperature. TLC showed that the starting material spot had substantially disappeared after 15 hours, the reaction was stopped, dichloromethane (10mL) was added to the reaction solution, and a saturated aqueous sodium bicarbonate solution was slowly added to make it weakly basic, extracted with dichloromethane (20mL × 3), the organic layers were combined, and the solvent was evaporated under reduced pressure and then directly subjected to silica gel column chromatography for purification (petroleum ether/ethyl acetate (v/v) ═ 200/1) to give the title compound as a pale yellow solid (0.45g, 85%).

¹H NMR(CDCl₃,600MHz)δ(ppm):7.65(s,1H),7.42(d,J＝7.8Hz,1H),7.19(s,1H),7.17(d,J＝8.2Hz,1H),7.08(d,J＝7.7Hz,1H),6.53(t,J＝56.3Hz,1H),6.52(d,J＝7.8Hz,1H),3.84(s,3H).

Step 3) preparation of tert-butyl 4- (5- (difluoromethyl) -2- ((4-methoxyphenyl) thio) phenyl) piperazine-1-carboxylate Synthesis of

(2-bromo-4- (difluoromethyl) phenyl) (4-methoxyphenyl) sulfide (0.400g,1.16mmol), N-Boc-piperazine (0.360g,1.93mmol), sodium tert-butoxide (0.185g,1.93mmol), (. + -.) -2,2 '-bis- (diphenylphosphino) -1, 1' -binaphthyl (0.06g,0.096mmol), tris (dibenzylideneacetone) dipalladium (0.030g,0.033mmol), and toluene (10mL) were sequentially added to a 50mL single-neck flask, and the temperature was gradually raised to 110 ℃ under nitrogen protection for reaction. The reaction was stopped after 22 hours and TLC showed a small amount of starting material remaining. The solvent was distilled off under reduced pressure, and the residue was dissolved in dichloromethane and then directly subjected to separation and purification by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 35/1) to give the title compound as a yellow oil (0.45g, 86%).

MS(ESI,pos.ion)m/z:451.20[M+H]⁺；

¹H NMR(CDCl₃,400MHz)δ(ppm):7.41(d,J＝7.8Hz,1H),7.19(s,1H),7.16(s,1H),7.07(d,J＝7.7Hz,1H),6.98(d,J＝8.1Hz,1H),6.56(t,J＝56.6Hz,1H),6.53(d,J＝8.2Hz,1H),3.65(t,J＝4.5Hz,4H),3.05(t,J＝4.7Hz,4H),3.85(s,3H),1.51(s,9H).

Step 4) Synthesis of 1- (5- (difluoromethyl) -2- ((4-methoxyphenyl) thio) phenyl) piperazine

Tert-butyl 4- (5-difluoromethyl-2- ((2, 4-dimethylphenyl) thio) phenyl) piperazine-1-carboxylate (0.450g,1.00mmol) was charged into a 50mL one-necked flask, and was allowed to completely dissolve in dichloromethane (5mL), an ethyl hydrogen chloride acetate solution (6mL,4M) was slowly added, the reaction was allowed to complete at room temperature for 1 hour, the reaction was stopped, a saturated aqueous sodium bicarbonate solution was slowly added dropwise to the reaction mixture until the pH became 8, dichloromethane was extracted (20mL × 3), the dichloromethane layer was washed with a saturated saline solution (10mL), the organic layer was collected, the solvent was directly evaporated under reduced pressure, the residue was dissolved in dichloromethane and a small amount of methanol, and then stirred with silica gel directly and subjected to silica gel column chromatography purification (dichloromethane/methanol (v/v) ═ 25/1) to give the title compound as a pale yellow oil (0.34g, 97%).

MS(ESI,pos.ion)m/z:351.10[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.41(d,J＝7.8Hz,1H),7.18(s,2H),7.06(d,J＝7.6Hz,1H),6.96(d,J＝8.1Hz,1H),6.55(t,J＝56.7Hz,1H),6.51(d,J＝8.2Hz,1H),3.11～3.08(m,8H),3.85(s,3H).

¹³C NMR(150MHz,CDCl₃)δ(ppm):149.3(s),142.9(s),139.8(s),138.8(s),136.8(s),131.6(s),130.2(t,J＝22.3Hz),128.1(s),126.8(s),125.7(s),121.5(t,J＝6.3Hz),116.9(t,J＝5.7Hz),114.8(t,J＝238.5Hz),52.9(s),46.5(s),21.3(s),20.7(s).

HPLC:99.66％.

Example Synthesis of 41- (5- (difluoromethyl) -2- ((3, 5-dimethylphenyl) thio) phenyl) piperazine

Step 1) Synthesis of 3-bromo-4- ((3, 5-dimethylphenyl) thio) benzaldehyde

3-bromo-4-fluorobenzaldehyde (1.0g,4.926mmol), potassium carbonate (1.362g,9.855mmol), 3, 5-dimethylthiophenol (0.817g,5.91mmol) and anhydrous N, N-dimethylformamide (15mL) were sequentially added to a 100mL single-neck flask, and the temperature was gradually raised to 120 ℃ for reaction under nitrogen protection. After 6 hours TLC showed the reaction was complete, the reaction was stopped and cooled. To the reaction mixture was slowly added a saturated aqueous ammonium chloride solution (30mL), tap water (200mL), and ethyl acetate extraction (60mL × 3), and the organic layer was washed with tap water (200mL × 4) and saturated brine (100mL) in this order, and the solvent was directly evaporated under reduced pressure to separate and purify the organic layer by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 200/1) to obtain the title compound as a pale yellow solid (1.25g, 82%).

MS(ESI,pos.ion)m/z:321.10[M+H]⁺；

¹H NMR(CDCl₃,600MHz)δ(ppm):9.81(s,1H),7.98(d,J＝1.5Hz,1H),7.50(dd,J＝8.2,1.6Hz,1H),7.43(d,J＝7.8Hz,1H),7.20(s,1H),7.10(d,J＝7.6Hz,1H),6.55(d,J＝8.2Hz,1H),2.38(s,3H),2.30(s,3H).

Step 2) (Synthesis of 2-bromo-4- (difluoromethyl) phenyl) (3, 5-dimethylphenyl) sulfide

3-bromo-4- ((3, 5-dimethylphenyl) thio) benzaldehyde (0.500g,1.56mmol) was charged into a 50mL one-necked flask, and after complete dissolution with dichloromethane (15mL), diethylaminosulfur trifluoride (0.63mL,4.7mmol) was slowly added, and the reaction was carried out at room temperature. TLC showed that the starting material spot had substantially disappeared after 15 hours, the reaction was stopped, dichloromethane (10mL) was added to the reaction solution, and a saturated aqueous sodium bicarbonate solution was slowly added to make it weakly basic, extracted with dichloromethane (20mL × 3), the organic layers were combined, and the solvent was evaporated under reduced pressure and then directly subjected to silica gel column chromatography for purification (petroleum ether/ethyl acetate (v/v) ═ 200/1) to give the title compound as a pale yellow solid (0.45g, 85%).

¹H NMR(CDCl₃,600MHz)δ(ppm):7.63(s,1H),7.40(d,J＝7.8Hz,1H),7.18(s,1H),7.15(d,J＝8.2Hz,1H),7.05(d,J＝7.7Hz,1H),6.50(t,J＝56.3Hz,1H),6.51(d,J＝7.8Hz,1H),2.37(s,3H),2.31(s,3H).

Step 3) preparation of tert-butyl 4- (5-difluoromethyl-2- ((3, 5-dimethylphenyl) thio) phenyl) piperazine-1-carboxylate Synthesis of

(2-bromo-4- (difluoromethyl) phenyl) (3, 5-dimethylphenyl) sulfide (0.400g,1.17mmol), N-Boc-piperazine (0.360g,1.93mmol), sodium tert-butoxide (0.185g,1.93mmol), (. + -.) -2,2 '-bis- (diphenylphosphino) -1, 1' -binaphthyl (0.06g,0.096mmol), tris (dibenzylideneacetone) dipalladium (0.030g,0.033mmol), and toluene (10mL) were added in sequence to a 50mL single-neck flask, and the reaction was gradually warmed to 110 ℃ under nitrogen. The reaction was stopped after 22 hours and cooled to room temperature. The solvent was distilled off under reduced pressure, and the residue was dissolved in methylene chloride and then directly subjected to silica gel column chromatography for purification (petroleum ether/ethyl acetate (v/v) ═ 35/1) to give the title compound as a yellow oil (0.43g, 82%).

MS(ESI,pos.ion)m/z:449.30[M+H]⁺；

¹H NMR(CDCl₃,400MHz)δ(ppm):7.42(d,J＝7.8Hz,1H),7.15(s,1H),7.16(s,1H),7.05(d,J＝7.7Hz,1H),6.95(d,J＝8.1Hz,1H),6.52(t,J＝56.6Hz,1H),6.50(d,J＝8.2Hz,1H),3.63(t,J＝4.5Hz,4H),3.01(t,J＝4.7Hz,4H),2.35(s,3H),2.30(s,3H),1.51(s,9H).

Step 4) Synthesis of 1- (5-difluoromethyl-2- ((3, 5-dimethylphenyl) thio) phenyl) piperazine

Tert-butyl 4- (5-difluoromethyl-2- ((3, 5-dimethylphenyl) thio) phenyl) piperazine-1-carboxylate (0.430g,0.96mmol) was charged into a 50mL one-necked flask, and after complete dissolution with dichloromethane (5mL), ethyl hydrogen chloride acetate solution (6mL,4M) was slowly added, reaction was completed at room temperature for 1 hour, the reaction was stopped, a saturated aqueous sodium bicarbonate solution was slowly added dropwise to the reaction mixture until the pH became 8, dichloromethane was extracted (20mL × 3), the dichloromethane layer was washed with saturated brine (10mL), the organic layer was collected, the solvent was directly evaporated under reduced pressure, the residue was dissolved with dichloromethane and a small amount of methanol, and then stirred with silica gel directly and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 25/1) to give the title compound as a pale yellow oil (0.32g, 96%).

MS(ESI,pos.ion)m/z:349.30[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.43(d,J＝7.8Hz,1H),7.18(s,2H),7.03(d,J＝7.6Hz,1H),6.97(d,J＝8.1Hz,1H),6.52(t,J＝56.7Hz,1H),6.51(d,J＝8.2Hz,1H),3.12～3.09(m,8H),2.39(s,3H),2.32(s,3H).

¹³C NMR(150MHz,CDCl₃)δ(ppm):149.7(s),142.5(s),139.6(s),138.5(s),136.8(s),131.7(s),130.3(t,J＝22.3Hz),128.3(s),126.8(s),125.7(s),121.2(t,J＝6.3Hz),116.7(t,J＝5.7Hz),114.9(t,J＝238.5Hz),52.6(s),46.1(s),21.5(s),20.3(s).

HPLC:98.60％.

Biological assay

Example A: evaluation of the affinity of Compounds for humanized 5-HT transporters expressed in CHO cells

Experimental methods

Homogenizing protein (12. mu.g), 2nM [ mu.g ] to the cell membrane at 22 ℃, [³H]Imipramine and buffer (50mM Tris-HCl (pH 7.4), 120mM NaCl, 5mM KCl and 0.1% BSA) were incubated for 60 minutes with or without test compound.

And in the mixed system of the above conditions, 10 μ M imipramine was added for measuring the non-specific binding value.

The incubated samples were rapidly filtered through a glass fiber filter (GF/B, Packard) pre-soaked with 0.3% PEI under vacuum using a 96-well cell harvester (Unifilter, Packard) and washed several times with ice-cold 50mM Tris-HCl and 150mM NaCl. The filters were dried and the residual radioactivity was counted in scintillation cocktail (Microscint 0, Packard) in a scintillation counter (Topcount, Packard). The results of the experiment are expressed as the percentage inhibition of the specific binding of the radioligand relative to the control.

The standard reference compound is imipramine, and IC is calculated by obtaining competitive curves through experimental tests of series of concentrations₅₀. See Table A for the results of affinity experiments for humanized 5-HT transporters (SERTs) for compounds of the invention.

TABLE A affinity assay for human 5-HT transporters (SERT) for the Compounds of the invention

Example No. 2	IC50(nM)
		Example 1	8
Example 2	10
		Example 3	12
Example 4	6

The experimental result shows that the compound has stronger affinity to human 5-HT transporters (SERT).

Example B pharmacokinetic evaluation of rats following intravenous or intragastric dosing of a Compound of the invention

The present invention evaluates the pharmacokinetic studies of the compounds of the invention in rats and the animal information is detailed in table B.

Table B information sheet of the subject animals of the present invention

Test method

The compounds of the invention were administered to the test animals as 5% DMSO + 5% Kolliphor HS 15+ 2% (2% HCl) + 88% Saline solution or 10% DMSO + 10% Kolliphor HS 15+ 80% physiological Saline solution. For the group administered by intravenous injection, the dose was 1mg/kg or 2mg/kg, followed by intravenous blood (0.3mL) at time points of 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hours after administration and centrifugation at 3,000 or 4,000rpm for 10 minutes, and the plasma solution was collected and stored at-20 ℃ or-70 ℃. For the gavage administration group, the dose was 2.5mg/kg or 5mg/kg, and then blood was taken intravenously (0.3mL) at time points of 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 hours after administration and centrifuged at 3,000 or 4,000rpm for 10 minutes, and the plasma solution was collected and stored at-20 ℃ or-70 ℃.

The plasma solutions collected from the above groups were analyzed by LC/MS/MS. The analysis result shows that the compound of the invention measured by intravenous injection administration and intragastric administration in rat body has better pharmacokinetic properties of large exposure value, low clearance rate, high bioavailability and the like. The compound of the invention has better drugability and better clinical application prospect.

The experimental result shows that the compound has better pharmacokinetic property in the rat body.

In the description herein, references to the description of the term "one embodiment," "an embodiment," "some embodiments," "an example," "a specific example" or "some examples" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment, or example is included in at least one embodiment, or example of the invention. In this specification, a schematic representation of the above terms does not necessarily refer to the same embodiment, implementation, or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments, implementations, or examples. Furthermore, the various examples, embodiments, or examples described in this specification, as well as features of various examples, embodiments, or examples, may be combined and combined by one skilled in the art without contradiction.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims (7)

1. A compound which is a compound represented by formula (I) or a pharmaceutically acceptable salt of the compound represented by formula (I),

wherein:

x is S or O;

R⁶and R⁷One of them is-CHF₂And the other is H or D;

R¹、R²、R³、R⁴and R⁵Each independently is H, D, C₁-C₄Alkyl or C₁-C₄An alkoxy group;

each R⁸Independently is H or D; and

m is 0, 1, 2,3, 4, 5 or 6.

2. The compound of claim 1, wherein R¹、R²、R³、R⁴And R⁵Independently H, D, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propyloxy or isopropyloxy;

each R⁸Independently H or D.

3. The compound of claim 1, which is a compound having one of the following structures or a pharmaceutically acceptable salt of a compound having one of the following structures:

4. a pharmaceutical composition comprising a compound of any one of claims 1-3; and

the pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.

5. Use of a compound according to any one of claims 1 to 3 or a pharmaceutical composition according to claim 4 for the manufacture of a medicament for the prevention, treatment or alleviation of central nervous system dysfunction.

6. Use of a compound according to any one of claims 1 to 3 or a pharmaceutical composition according to claim 4 for the manufacture of a medicament for the prevention, treatment or alleviation of affective disorders.

7. Use according to claim 6, wherein the affective disorder is depression, anxiety, social phobia, obsessive compulsive disorder, panic attacks, specific phobias, agoraphobia, mania, panic disorder or post-traumatic stress disorder.