WO2019107922A1 - Arylpyrazolylpiperazine or arylpyrazolyldiazepane derivative acting as 5-ht7 receptor regulator and pharmaceutical composition comprising same for treatment or prevention of central nervous system disorder - Google Patents

Abstract

The present invention relates to an arylpyrazolylpiperazine or arylpyrazolyldiazepane derivative represented by Structural Formula 1 and a pharmaceutically acceptable salt thereof. An arylpyrazolylpiperazine or arylpyrazolyldiazepane derivative and a pharmaceutically acceptable salt thereof according to the present invention exhibit excellent affinity for serotonin 5-HT₇ receptor and can exert a therapeutic effect on a central nervous system disorder.

Description

Derivatives of arylpyrazolylpiperazine or arylpyrazolyldiazepane acting as modulators of 5-HT7 receptors and pharmaceutical compositions for the treatment or prevention of central nervous system diseases comprising the same

The present invention relates to derivatives of arylpyrazolylpiperazine or arylpyrazolyldiazepine acting as modulators of the 5-HT7 receptor and pharmaceutical compositions for treating or preventing central nervous system diseases.

Serotonin, a neurotransmitter, acts on 14 different serotonin receptors distributed in various organs, resulting in various physiological phenomena. Each receptor triggers a variety of physiological responses through its interaction with serotonin. The 5-HT ₇ receptors are the most recently discovered serotonin subtype receptors, particularly the hypothalamus, the thalamus, the hippocampus, and the cortex. The 5-HT ₇ receptors are involved in body temperature regulation, vital rhythm, learning and memory, sleep, It is known to have such an important function. It is also known to be involved in diseases such as depression, migraine and anxiety, and neurological diseases such as inflammatory pain and neuropathic pain.

Although a lot of efforts to develop, such as 5-HT ₇ receptor antagonists or agonists of the currently selected 5-HT ₇ receptor antagonists are known to be not much. Antagonists having sulfonamide as a basic skeleton have been reported, such as WO 1997-29097, WO 2003-048118, WO 1997-48648, WO 1997-48681, WO 1997-49695, and WO 1999-24022, WO 2000-00472, Materials acting on the 5-HT ₇ receptor as isoquinoline derivatives have been reported.

However, despite these studies, it has been shown that 5-HT ₇ receptors, which have an excellent and excellent pharmacokinetic profile for 5-HT ₇ receptors, and which are effective for controlling temperature, biorhythm, sleep, There is still a need for finding modulators.

An object of the present invention are 5-HT ₇ sleep by acting on receptors, depression, migraine, anxiety, and inflammatory pain, pain-related nerve disease, and body temperature, such as neuropathic pain, the pharmaceutical to a living body rhythm, smooth muscle related diseases, including central nervous system diseases Derivatives of arylpyrazolylpiperazine or arylpyrazolyldiazepane and pharmaceutically acceptable salts thereof.

It is another object of the present invention to provide derivatives of aryl pyrazolylpiperazine or aryl pyrazolyl diazepane which are excellent in efficacy against central nervous system diseases as described above and a method for preparing pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a pharmaceutical composition comprising the above arylpyrazolylpiperazine or arylpyrazolyldiazepine derivative having excellent efficacy against central nervous system diseases and a pharmaceutically acceptable salt thereof as an active ingredient I have to.

According to one aspect of the present invention,

A derivative of the aryl pyrazolyl piperazine or aryl pyrazolyl diazepane represented by the following structural formula 1 and a pharmaceutically acceptable salt thereof are provided.

[Structural formula 1]

In formula 1,

n is 1 or 2,

R represents a hydrogen atom, a halogen group, a cyano group, an amino group, a nitro group, a hydroxyl group, a carboxyl group, a substituted or unsubstituted C1 to C30 alkyl group, a substituted or unsubstituted C3 to C30 cycloalkyl group, To C30 heterocycloalkyl groups, substituted or unsubstituted C6 to C30 aryl groups, substituted or unsubstituted C1 to C30 heteroaryl groups, substituted or unsubstituted C1 to C30 alkoxy groups, substituted or unsubstituted C3 to C30 cycloalkoxy A substituted or unsubstituted C1 to C30 heterocycloalkoxy group, a substituted or unsubstituted C6 to C30 aryloxy group, or a substituted or unsubstituted C1 to C30 heteroaryloxy group.

Preferably, R may be a hydrogen atom, a halogen group, a cyano group, a substituted or unsubstituted C1 to C30 alkyl group, or a substituted or unsubstituted C1 to C30 alkoxy group.

More preferably, R may be a hydrogen atom, a halogen group, a cyano group, a C1 to C4 alkyl group, or a C1 to C4 alkoxy group.

The compound represented by the structural formula 1 is any one selected from the following compounds 1 to 23.

According to another aspect of the present invention,

(1) A compound represented by the following structural formula 2 tert - butoxy-bis (dimethylamino) methane (tert-Butoxy bis (dimethylamino) methane), and after the reaction, by reacting with hydrazine (hydrazine) and sequentially Boc (tert -butyloxycarbonyl) -protected intermediate of formula < RTI ID = 0.0 > 1 < / RTI > And

(2) Boc-deprotection of a compound represented by the following structural formula 1 to prepare a derivative of the arylpyrazolylpiperazine or arylpyrazolyldiazepane represented by the structural formula 1, There is provided a process for preparing a derivative of a zolylpiperazine or an arylpyrazolyldiazepane and a pharmaceutically acceptable salt thereof.

[Structural formula 2]

In formula 2,

n is 1 or 2,

R represents a hydrogen atom, a halogen group, a cyano group, an amino group, a nitro group, a hydroxyl group, a carboxyl group, a substituted or unsubstituted C1 to C30 alkyl group, a substituted or unsubstituted C3 to C30 cycloalkyl group, To C30 heterocycloalkyl groups, substituted or unsubstituted C6 to C30 aryl groups, substituted or unsubstituted C1 to C30 heteroaryl groups, substituted or unsubstituted C1 to C30 alkoxy groups, substituted or unsubstituted C3 to C30 cycloalkoxy A substituted or unsubstituted C1 to C30 heterocycloalkoxy group, a substituted or unsubstituted C6 to C30 aryloxy group, or a substituted or unsubstituted C1 to C30 heteroaryloxy group.

[Structural formula 1 ']

In structural formula 1 '

n is 1 or 2,

R represents a hydrogen atom, a halogen group, a cyano group, an amino group, a nitro group, a hydroxyl group, a carboxyl group, a substituted or unsubstituted C1 to C30 alkyl group, a substituted or unsubstituted C3 to C30 cycloalkyl group, To C30 heterocycloalkyl groups, substituted or unsubstituted C6 to C30 aryl groups, substituted or unsubstituted C1 to C30 heteroaryl groups, substituted or unsubstituted C1 to C30 alkoxy groups, substituted or unsubstituted C3 to C30 cycloalkoxy A substituted or unsubstituted C1 to C30 heterocycloalkoxy group, a substituted or unsubstituted C6 to C30 aryloxy group, or a substituted or unsubstituted C1 to C30 heteroaryloxy group.

Preferably, the compound represented by the formula 2 can be prepared by reacting a compound represented by the following formula 3 with N-Boc-piperazine or N-Boc-diazepane.

[Structural Formula 3]

In Structure 3,

R represents a hydrogen atom, a halogen group, a cyano group, an amino group, a nitro group, a hydroxyl group, a carboxyl group, a substituted or unsubstituted C1 to C30 alkyl group, a substituted or unsubstituted C3 to C30 cycloalkyl group, To C30 heterocycloalkyl groups, substituted or unsubstituted C6 to C30 aryl groups, substituted or unsubstituted C1 to C30 heteroaryl groups, substituted or unsubstituted C1 to C30 alkoxy groups, substituted or unsubstituted C3 to C30 cycloalkoxy A substituted or unsubstituted C1 to C30 heterocycloalkoxy group, a substituted or unsubstituted C6 to C30 aryloxy group, or a substituted or unsubstituted C1 to C30 heteroaryloxy group.

Preferably, the Boc-deprotection reaction can be carried out using any one solution selected from hydrochloric acid, trifluoroacetic acid, and trimethylsalyl triflate (TMSOTf).

According to another aspect of the present invention,

There is provided a pharmaceutical composition for the treatment or prevention of central nervous system diseases, which comprises the above-mentioned derivatives of arylpyrazolylpiperazine or arylpyrazolyldiazepine and a pharmaceutically acceptable salt thereof as an active ingredient.

The central nervous system disorders may be selected from sleep disorders, depression, migraine, anxiety, autism, inflammatory pain, neuropathic pain, thermoregulatory disorders, biorhythm disorders and smooth muscle related diseases.

The derivative of the arylpyrazolylpiperazine or arylpyrazolyldiazepane and the pharmaceutically acceptable salt thereof may act as a modulator of the 5-HT ₇ receptor.

The derivatives of the aryl pyrazolyl piperazine or aryl pyrazolyl diazepane of the present invention and pharmaceutically acceptable salts thereof exhibit excellent binding affinity to 5-HT ₇ serotonin receptors and are useful for the treatment of sleep, depression, migraine, anxiety, autism, And inflammatory pain, pain-related neurological diseases such as neuropathic pain, and treatment and prevention of body temperature control, biorhythm, and smooth muscle-related diseases.

FIG. 1 shows the results of measurement of c-AMP activity against the 5-HT7 serotonin receptor according to Experimental Example 2. FIG.

FIG. 2 shows the results of beta-arrestin activity measurement for the 5-HT7 serotonin receptor according to Experimental Example 3. FIG.

The invention is capable of various modifications and may have various embodiments, and particular embodiments are exemplified and will be described in detail in the detailed description. It is to be understood, however, that the invention is not to be limited to the specific embodiments, but includes all modifications, equivalents, and alternatives falling within the spirit and scope of the invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, the present invention will be described in detail with reference to the accompanying drawings.

The term "substituted" as used herein means that at least one hydrogen atom is replaced by a substituent selected from the group consisting of deuterium, C1 to C30 alkyl groups, C3 to C30 cycloalkyl groups, C2 to C30 heterocycloalkyl groups, C1 to C30 halogenated alkyl groups, C6 to C30 aryl groups, C1 to C30 heteroaryl groups, A C1 to C30 alkoxy group, a C3 to C30 cycloalkoxy group, a C1 to C30 heterocycloalkoxy group, a C2 to C30 alkenyl group, a C2 to C30 alkynyl group, a C6 to C30 aryloxy group, a C1 to C30 heteroaryloxy group, (-OSiH ₃ ), -OSiR ¹ H ₂ (wherein R ¹ is a C1 to C30 alkyl group or a C6 to C30 aryl group), -OSiR ¹ R ² H (R ¹ and R ² are each independently a C1 to C30 alkyl group or a C6 to C30 aryl ^{group), -OSiR 1 R 2 R 3} , (R 1, R 2, and R ³ are each independently a C1 to C30 alkyl or C6 to C30 aryl group), C1 to C30 acyl group, C2 to C30 acyl An oxy group, a C2 to C30 heteroaryloxy group, a C1 to C30 sulfonyl group, a C1 to C30 alkylthiol group, C3 to C30 cycloalkyl, a thiol group, C1 to C30 heterocycloalkyl thiol group, C6 to C30 aryl thiol groups, C1 to C30 heteroaryl, thiol, C1 to C30 phosphoric acid amide group, a silyl group _{^{(SiR 1 R 2 R 3)}} ( R ^1, R ^2, and R ³ are each independently a hydrogen atom, C1 to C30 alkyl or C6 to C30 aryl group), an amine group (-NRR ') (here, R and R' are each independently a hydrogen atom , A C1 to C30 alkyl group, and a C6 to C30 aryl group), a carboxyl group, a halogen group, a cyano group, a nitro group, an azo group, and a hydroxy group .

Further, two adjacent substituents among the substituents may be fused to form a saturated or unsaturated ring.

The carbon number range of the alkyl group or aryl group in the above "substituted or unsubstituted C1 to C30 alkyl group" or "substituted or unsubstituted C6 to C30 aryl group" Quot; means the total number of carbon atoms constituting the alkyl moiety or the aryl moiety when it is considered to be " substituted ". For example, a phenyl group substituted with a butyl group at the para position means an aryl group having 6 carbon atoms substituted with a butyl group having 4 carbon atoms.

As used herein, unless otherwise defined, it is meant that one functional group contains 1 to 4 heteroatoms selected from the group consisting of N, O, S, and P, and the remainder is carbon.

As used herein, "hydrogen" means monohydrogen, double hydrogen, or tritium, unless otherwise defined.

As used herein, unless otherwise defined, the term "alkyl group" means an aliphatic hydrocarbon group.

The alkyl group may be a "saturated alkyl group" which does not contain any double or triple bonds.

The alkyl group may be an "unsaturated alkyl group" comprising at least one double bond or triple bond.

The alkyl group, whether saturated or unsaturated, can be in a pulverized, linear or cyclic form.

The alkyl group may be a C1 to C30 alkyl group. More specifically, a C1 to C20 alkyl group, a C1 to C10 alkyl group, or a C1 to C6 alkyl group.

For example, the C1 to C4 alkyl groups may have 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain may be optionally substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, Indicating that they are selected from the group.

Specific examples of the alkyl group include a methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, t-butyl group, pentyl group, hexyl group, ethenyl group, Butyl group, cyclopentyl group, cyclohexyl group, and the like.

An "amine group" includes an amino group, an arylamine group, an alkylamine group, an arylalkylamine group, or an alkylarylamine group, and may be represented by -NRR ', wherein R and R' , A C1 to C30 alkyl group, and a C6 to C30 aryl group.

"Cycloalkyl group" includes monocyclic or fused-ring polycyclic (i. E., Rings that divide adjacent pairs of carbon atoms) functional groups.

"Heterocycloalkyl group" means that the cycloalkyl group contains 1 to 4 hetero atoms selected from the group consisting of N, O, S and P in the cycloalkyl group, and the remainder is carbon. When the heterocycloalkyl group is a fused ring, at least one ring of the fused rings may contain from 1 to 4 heteroatoms.

"An aromatic group" means a functional group in which all elements of a functional group in the form of a ring have a p-orbital, and these p-orbital forms a conjugation. Specific examples thereof include an aryl group and a heteroaryl group.

An "aryl group" includes a monocyclic or fused ring polycyclic (i. E., A ring that divides adjacent pairs of carbon atoms) functional groups.

"Heteroaryl group" means that the aryl group contains 1 to 4 hetero atoms selected from the group consisting of N, O, S and P, and the remainder is carbon. When the heteroaryl group is a fused ring, at least one ring of the fused rings may contain from 1 to 4 heteroatoms.

In the aryl group and the heteroaryl group, the number of atoms in the ring is the sum of carbon number and non-carbon atom number.

When used in combination, such as "alkylaryl" or "arylalkyl group ", the terms alkyl and aryl of each of the above have the meanings and contents indicated above.

The term "arylalkyl group " means an aryl substituted alkyl radical, such as benzyl, and is included in the alkyl group.

The term "alkylaryl group " means an alkyl substituted aryl radical and is included in the aryl group.

Hereinafter, the derivatives of the arylpyrazolylpiperazine or arylpyrazolyldiazepane of the present invention and the pharmaceutically acceptable salts thereof will be described. The derivatives of arylpyrazolylpiperazine or arylpyrazolyldiazepane of the present invention can be represented by the following structural formula (1).

[Structural formula 1]

In formula 1,

n is 1 or 2,

R represents a hydrogen atom, a halogen group, a cyano group, an amino group, a nitro group, a hydroxyl group, a carboxyl group, a substituted or unsubstituted C1 to C30 alkyl group, a substituted or unsubstituted C3 to C30 cycloalkyl group, To C30 heterocycloalkyl groups, substituted or unsubstituted C6 to C30 aryl groups, substituted or unsubstituted C1 to C30 heteroaryl groups, substituted or unsubstituted C1 to C30 alkoxy groups, substituted or unsubstituted C3 to C30 cycloalkoxy A substituted or unsubstituted C1 to C30 heterocycloalkoxy group, a substituted or unsubstituted C6 to C30 aryloxy group, or a substituted or unsubstituted C1 to C30 heteroaryloxy group.

Preferably, R may be a hydrogen atom, a halogen group, a cyano group, a substituted or unsubstituted C1 to C30 alkyl group, or a substituted or unsubstituted C1 to C30 alkoxy group.

More preferably, R may be a hydrogen atom, a halogen group, a cyano group, a C1 to C4 alkyl group, or a C1 to C4 alkoxy group.

Examples of the substituted or unsubstituted C2 to C30 heteroaryl group include a substituted or unsubstituted pyridinyl group, a substituted or unsubstituted pyrimidinyl group, a substituted or unsubstituted thiazinyl group, a substituted or unsubstituted thiophenyl group , A substituted or unsubstituted pyrrolyl group, a substituted or unsubstituted benzothiophenyl group, a substituted or unsubstituted indolyl group, a substituted or unsubstituted imidazo [1,2-a] pyridinyl group, a substituted or unsubstituted A substituted or unsubstituted indazolyl group, a substituted or unsubstituted phenothiazinyl group, a substituted or unsubstituted phenazinyl group, a substituted or unsubstituted carbazolyl group, a substituted or unsubstituted dibenzoyl group, Substituted or unsubstituted imidazolyl groups, substituted or unsubstituted thiazolyl groups, substituted or unsubstituted tetrazolyl groups, substituted or unsubstituted oxadiazolyl groups, substituted or unsubstituted oxatriazolyl groups, However, A substituted or unsubstituted thiazolyl group, a substituted or unsubstituted benzothiazolyl group, a substituted or unsubstituted pyrazinyl group, a substituted or unsubstituted pyridazinyl group, a substituted or unsubstituted furyl group, a substituted or unsubstituted thiazolyl group, A substituted or unsubstituted quinoxalinyl group, a substituted or unsubstituted quinolinyl group, a substituted or unsubstituted quinolinyl group, a substituted or unsubstituted quinoxalinyl group, a substituted or unsubstituted phthalazinyl group, a substituted or unsubstituted naphthyridinyl group, Or a substituted or unsubstituted phenanthrolinyl group, preferably a substituted or unsubstituted pyridinyl group, a substituted or unsubstituted pyrimidinyl group, a substituted or unsubstituted aryidinyl group, a substituted or unsubstituted pyrazolinyl group, A substituted or unsubstituted thiazolyl group, a substituted or unsubstituted thiophenyl group, a substituted or unsubstituted pyrrolyl group, a substituted or unsubstituted benzothiophenyl group, a substituted or unsubstituted indolyl group, A substituted or unsubstituted benzothiazolyl group, a substituted or unsubstituted phenothiazyl group, a substituted or unsubstituted phenazinyl group, a substituted or unsubstituted benzothiazolyl group, , A substituted or unsubstituted carbazolyl group, or a substituted or unsubstituted dibenzothiophenyl group.

The compound represented by the structural formula 1 may be any one selected from the following compounds 1 to 23.

Compound 1: 1- (3-Phenyl-1H-pyrazol-4-yl) piperazine

Compound 2: 1- (3- (2-Fluorophenyl) -1H-pyrazol-4-yl) piperazine

Compound 3: 1- (3- (3-Fluorophenyl) -1H-pyrazol-4-yl) piperazine

Compound 4: 1- (3- (4-Fluorophenyl) -1H-pyrazol-4-yl) piperazine

Compound 5: 1- (3- (2-Chlorophenyl) -lH-pyrazol-4-yl) piperazine

Compound 6: 1- (3- (3-Chlorophenyl) -lH-pyrazol-4-yl) piperazine

Compound 7: 1- (3- (4-Chlorophenyl) -1H-pyrazol-4-yl) piperazine

Compound 8: 1- (3- (2-Methoxyphenyl) -lH-pyrazol-4-yl) piperazine

Compound 9: 1- (3- (3-Methoxyphenyl) -lH-pyrazol-4-yl) piperazine

Compound 10: 1- (3- (4-Methoxyphenyl) -lH-pyrazol-4-yl) piperazine

Compound 11: 1- (3- (4-Bromophenyl) -lH-pyrazol-4-yl) piperazine

Compound 12: 1- (3- (p-Tolyl) -1H-pyrazol-4-yl) piperazine

Compound 13: 1- (3- (4-Cyanophenyl) -lH-pyrazol-4-yl) piperazine

Compound 14: 1- (3- (2-Methoxyphenyl) -lH-pyrazol-4-yl) -1,4-

Compound 15: 1- (3- (3-Methoxyphenyl) -lH-pyrazol-4-yl) -1,4-

Compound 16: 1- (3- (4-Methoxyphenyl) -lH-pyrazol-4-yl) -1,4-

Compound 17: 1- (3- (3-Fluorophenyl) -1H-pyrazol-4-yl) -1,4-

Compound 18: 1- (3- (4-Fluorophenyl) -1H-pyrazol-4-yl) -1,4-

Compound 19: 1- (3- (3-Chlorophenyl) -1H-pyrazol-4-yl) -1,4-

Compound 20: 1- (3- (4-Chlorophenyl) -1H-pyrazol-4-yl) -1,4-

Compound 21: 1- (3- (3-Methylphenyl) -1H-pyrazol-4-yl) -1,4-

Compound 22: 1- (3- (4-Methylphenyl) -1H-pyrazol-4-yl) -1,4-

Compound 23: 1- (3-Phenyl-1 H-pyrazol-4-yl) -1,4-

Hereinafter, the method for producing the aryl pyrazolyl piperazine or aryl pyrazolyl diazepane derivative of the present invention and a pharmaceutically acceptable salt thereof will be described.

First, a compound represented by the following structural formula 2 is prepared by reacting a compound represented by the following structural formula 3 with N-Boc-piperazine or N-Boc-diazepane.

[Structural Formula 3]

In Structure 3,

R represents a hydrogen atom, a halogen group, a cyano group, an amino group, a nitro group, a hydroxyl group, a carboxyl group, a substituted or unsubstituted C1 to C30 alkyl group, a substituted or unsubstituted C3 to C30 cycloalkyl group, To C30 heterocycloalkyl groups, substituted or unsubstituted C6 to C30 aryl groups, substituted or unsubstituted C1 to C30 heteroaryl groups, substituted or unsubstituted C1 to C30 alkoxy groups, substituted or unsubstituted C3 to C30 cycloalkoxy A substituted or unsubstituted C1 to C30 heterocycloalkoxy group, a substituted or unsubstituted C6 to C30 aryloxy group, or a substituted or unsubstituted C1 to C30 heteroaryloxy group.

[Structural formula 2]

In formula 2,

n is 1 or 2,

R represents a hydrogen atom, a halogen group, a cyano group, an amino group, a nitro group, a hydroxyl group, a carboxyl group, a substituted or unsubstituted C1 to C30 alkyl group, a substituted or unsubstituted C3 to C30 cycloalkyl group, To C30 heterocycloalkyl groups, substituted or unsubstituted C6 to C30 aryl groups, substituted or unsubstituted C1 to C30 heteroaryl groups, substituted or unsubstituted C1 to C30 alkoxy groups, substituted or unsubstituted C3 to C30 cycloalkoxy A substituted or unsubstituted C1 to C30 heterocycloalkoxy group, a substituted or unsubstituted C6 to C30 aryloxy group, or a substituted or unsubstituted C1 to C30 heteroaryloxy group.

Next, the compound represented by the formula 2 is reacted with tert -butoxy bis (dimethylamino) methane, and then sequentially reacted with hydrazine to obtain Boc ( tert -butyloxycarbonyl) -protected intermediate represented by the following structural formula 1 '.

[Structural formula 1 ']

In structural formula 1 '

n is 1 or 2,

R represents a hydrogen atom, a halogen group, a cyano group, an amino group, a nitro group, a hydroxyl group, a carboxyl group, a substituted or unsubstituted C1 to C30 alkyl group, a substituted or unsubstituted C3 to C30 cycloalkyl group, To C30 heterocycloalkyl groups, substituted or unsubstituted C6 to C30 aryl groups, substituted or unsubstituted C1 to C30 heteroaryl groups, substituted or unsubstituted C1 to C30 alkoxy groups, substituted or unsubstituted C3 to C30 cycloalkoxy A substituted or unsubstituted C1 to C30 heterocycloalkoxy group, a substituted or unsubstituted C6 to C30 aryloxy group, or a substituted or unsubstituted C1 to C30 heteroaryloxy group.

Finally, the intermediate represented by the structural formula 1 'is obtained by removing the Boc ( tert- butyloxycarbonyl) group by a Boc-deprotection reaction and reacting the aryl pyrazolyl piperazine or aryl pyrazolyl diazepane of the present invention represented by the formula 1 Can be prepared.

The Boc-deprotection reaction can be carried out by using 1N hydrochloric acid dissolved in diethyl ether, ethanol, water or the like, or by using trifluoroacetic acid or trimethylsalyl triflate (TMSOTf) dissolved in an organic solvent such as dichloromethane .

Hereinafter, the pharmaceutical composition for treating or preventing central nervous system diseases of the present invention will be described.

The pharmaceutical composition for the treatment or prevention of central nervous system diseases of the present invention is characterized by containing the above-mentioned aryl pyrazolyl piperazine or aryl pyrazolyl diazepane derivatives and pharmaceutically acceptable salts thereof as an active ingredient.

Examples of the central nervous system diseases include sleep disorders, depression, migraine, anxiety, autism, inflammatory pain, neuropathic pain, thermoregulatory disorder, biorhythmia, and smooth muscle-related diseases, And diseases related to the central nervous system can all be applied.

The derivatives of arylpyrazolylpiperazine or arylpyrazolyldiazepane and pharmaceutically acceptable salts thereof are characterized by acting as modulators of the 5-HT ₇ receptor.

The pharmaceutical composition of the present invention can be formulated into pharmaceutical preparations by incorporating a carrier, adjuvant or diluent together with the aryl pyrazolyl piperazine / diazepane derivative compound represented by the structural formula 1 or a pharmaceutically acceptable salt thereof, May be prepared in a form suitable for parenteral administration. For oral administration, the preparation may be in the form of tablets, capsules, solutions, syrups, suspensions and the like. For parenteral administration, the preparation may be in the form of injections for intraperitoneal, subcutaneous, muscular and transdermal administration.

The pharmaceutical composition of the present invention is a modulator acting on a 5-HT ₇ serotonin receptor, and the effective dose per day is 0.01 to 1000 mg / day on an adult basis. The administration dose varies depending on the age, body weight, sex, The condition and the degree of the disease. Depending on the judgment of the doctor or the pharmacist, it may be administered once or several times a day at a predetermined time interval.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail with reference to preferred embodiments for better understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited thereto.

[Example: preparation of compound]

Example 1.1: tert-Butyl 4- (2-oxo-2-phenylethyl) piperazine-1-carboxylate

To the reaction vessel was added tert-butylpiperazine-1-carboxylate (200 mg, 1.07 mmol), dissolved in dichloromethane (MC, 3 mL), K ₂ CO ₃ (444 mg, 3.21 mmol) After stirring for 30 minutes, 2-bromo-1-phenylethane-1-one (213 mg, 1.07 mmol) was added and the mixture was stirred at 0 ° C for 10 minutes and then at room temperature for 18 hours. After completion of the reaction, distilled water was added, and the organic layer was extracted with MC, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (Hex: EA = 3: 1) and concentrated under reduced pressure to give the desired compound (261 mg, 0.860 mmol, 80% yield).

^{1 H NMR (400 MHz, CDCl} 3) δ 8.10-7.94 (m, 2H), 7.60-7.53 (m, 2H), 7.48-7.41 (m, 2H), 3.83 (s, 2H) 3.50 (t, J = 5.0 Hz, 4H), 2.56 (t, J = 4.9 Hz, 4H), 1.46 (s, 9H)

Example 1.2: tert-Butyl 4- (3-phenyl-1H-pyrazol-4-yl) piperazine-

A reaction vessel tert- butyl 4- (2-oxo-2-phenylethyl) piperazine-l-carboxylate (242 mg, 0.800 mmol) was dissolved in THF after the bredereck's reagent (tert - butoxy-bis (dimethylamino) Methane, 0.070 mL, 0.360 mmol), which was stirred for 18 hours at 55 ° C. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain an intermediate? -Dimethylamino-?,? - unsaturated ketone. The following reaction was carried out without further purification.

The hydrazine hydrate (0.040 mL, 1.12 mmol) was added to the reaction vessel, which was then dissolved in EtOH (5 mL), and the mixture was stirred at 80 ° C. for 5 hours Was heated to reflux. After completion of the reaction, ethyl ether was added thereto, and the resulting precipitate was filtered and concentrated under reduced pressure to obtain 78.8 mg (0.240 mmol, 63% yield) of the desired compound.

^{1 H NMR (400 MHz, CDCl} 3) δ 7.93 (d, J = 7.4 Hz, 2H), 7.39-7.22 (m, 4H), 3.51 (s, 4H), 2.71 (s, 4H), 1.46 (s, 9H)

Example 2.1: Compound 1 (1- (3-phenyl-1H-pyrazol-4-yl) piperazine)

1-carboxylate (760 mg, 2.31 mmol) was dissolved in EtOH followed by the addition of a 4.0 M HCl dioxane solution (17 mL, ) And the mixture was stirred at room temperature for 2 hours. After completion of the reaction, MC was added thereto, and the resulting precipitate was filtered under reduced pressure to obtain a solid compound, which was then dried under reduced pressure to obtain 402 mg (1.76 mmol, 76% yield) of the final compound.

^{1 H NMR (400 MHz, MeOD} ) δ 7.91 (d, J = 7.2 Hz, 2H), 7.43 (s, 1H), 7.40-7.33 (m, 2H), 7.30-7.23 (m, 1H), 2.92-2.84 (m, 4 H), 2.81 - 2.72 (m, 4 H)

Example 2.2: Compound 2 (1- (3- (2-fluorophenyl) -1H-pyrazol-4-yl)

(53.0 mg, 0.150 mmol) obtained in accordance with the synthesis method of Example 1.1 and 1.2, tert -butyl 4- (3- (2- fluorophenyl) -1H-pyrazol- A final compound (26 mg, 0.100 mmol, 73% yield) was obtained by the synthetic method of Example 2.1 using 4.0 M HCl dioxane solution (0.39 mL).

¹ H NMR (400 MHz, MeOD) [delta] 7.83-7.72 (m, IH), 7.63 (s, IH), 7.51-7.42 (m, IH), 7.35-7.21 4H), 3.14-3.06 (m, 4H)

Example 2.3: Compound 3 (1- (3- (3-fluorophenyl) -1H-pyrazol-4-yl)

Pyrazol-4-yl) piperazine-1-carboxylate (564 mg, 1.63 mmol) obtained in the same manner as in Example 1.1 and 1.2, 4.0 M HCl A 319 mg (1.29 mmol, 79% yield) of the final compound was obtained by the synthetic procedure of Example 2.1, using dioxane solution (3.1 mL).

^{1 H NMR (400 MHz, MeOD} ) δ 8.24 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.74-7.68 (m, 1H), 7.65-7.57 (m, 1H), 7.29 (td , J = 8.5, 2.2 Hz, 1H), 3.42-3.35 (m, 4H), 3.23-3.15 (m, 4H)

Example 2.4: Compound 4 (1- (3- (4-fluorophenyl) -1H-pyrazol-4-yl)

(200 mg, 0.580 mmol) obtained in accordance with the synthesis method of Example 1.1 and 1.2, tert -butyl 4- (3- (4-fluorophenyl) -1H-pyrazol- 4.0 M HCl A solution of 51 mg (0.210 mmol, 36% yield) of the final compound was obtained by the synthetic method of Example 2.1 using dioxane solution (2.0 mL).

^{1 H NMR (400 MHz, MeOD} ) δ 8.28 (s, 1H), 8.03-7.96 (m, 2H), 7.39-7.30 (m, 2H), 3.43-3.36 (m, 4H), 3.22-3.15 (m, 4H)

Example 2.5: Compound 5 (1- (3- (2-chlorophenyl) -1H-pyrazol-4-yl) piperazine) Synthesis

(200 mg, 0.550 mmol) obtained in the same manner as in Example 1.1 and 1.2, tert -butyl 4- (3- (2-chlorophenyl) -1H-pyrazol- M HCl A solution of 269 mg (0.230 mmol, 42% yield) of the final compound was obtained by the synthetic procedure of Example 2.1 using dioxane solution (1.5 mL).

^{1 H NMR (400 MHz, MeOD} ) δ 8.35 (s, 1H), 7.75-7.66 (m, 2H), 7.62 (t, J = 7.5 Hz, 1H), 7.56 (t, J = 7.0 Hz, 1H), 3.27 (br s, 4H), 3.20 (brs, 4H)

Example 2.6: Compound 6 (1- (3- (3-chlorophenyl) -1H-pyrazol-4-yl) piperazine) Synthesis

1-carboxylate (300 mg, 0.830 mmol) obtained in the same manner as in Example 1.1 and 1.2, tert -butyl 4- (3- (3-chlorophenyl) M HCl A solution of 243 mg (0.920 mmol, 100% yield) of the final compound was obtained by the synthetic method of Example 2.1 using dioxane solution (2.2 mL).

^{1 H NMR (400 MHz, MeOD} ) δ 8.28 (s, 1H), 7.96 (t, J = 3.1 Hz, 1H), 7.91 (dt, J = 7.3, 1.5 Hz, 1H), 7.62-7.53 (m, 2H ), 3.41-3.34 (m, 4H), 3.23-3.16 (m, 4H)

Example 2.7: Compound 7 (1- (3- (4-chlorophenyl) -1H-pyrazol-4-yl) piperazine) Synthesis

1-carboxylate (150 mg, 0.410 mmol) obtained in the same manner as in Example 1.1 and 1.2, tert -butyl 4- (3- (4-chlorophenyl) M HCl A solution of 83 mg (0.310 mmol, 76% yield) of the final compound was obtained by the method of Example 2.1 using dioxane solution (1.6 mL).

^{1 H NMR (400 MHz, MeOD} ) δ 7.95-7.89 (m, 2H), 7.48 (s, 1H), 7.41-7.35 (m, 2H), 2.95-2.88 (m, 4H), 2.82-2.75 (m, 4H)

Example 2.8: Compound 8 (1- (3- (2-methoxyphenyl) -1H-pyrazol-4-yl) piperazine) Synthesis

Pyrazol-4-yl) piperazine-1-carboxylate (200 mg, 0.560 mmol) obtained in the same manner as in Example 1.1 and 1.2, 4.0 M HCl A solution of 168 mg (0.650 mmol, 100% yield) of the final compound was obtained by the synthetic method of Example 2.1 using dioxane solution (1.5 mL).

^{1 H NMR (400 MHz, MeOD} ) δ 8.36 (s, 1H), 8.00 (d, J = 6.9 Hz, 1H), 7.57 (t, J = 7.4 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1H), 7.19 (t, J = 13.7 Hz, 1H), 3.96 (s, 3H), 3.36 (brs, 4H), 3.23 (brs, 4H)

Example 2.9: Compound 9 (1- (3- (3-methoxyphenyl) -1H-pyrazol-4-yl) piperazine) Synthesis

Pyrazol-4-yl) piperazine-1-carboxylate (885 mg, 2.47 mmol) obtained in the same manner as in Example 1.1 and 1.2, 4.0 M HCl A solution of 274 mg (0.930 mmol, 38% yield) of the final compound was obtained by the synthetic procedure of Example 2.1, using dioxane solution (4.0 mL).

^{1 H NMR (400 MHz, MeOD} ) δ 8.26 (s, 1H), 7.54-7.44 (m, 3H), 7.15-7.08 (m, 1H), 3.88 (s, 3H), 3.40-3.34 (m, 4H) , 3.24-3.17 (m, 4H)

Example 2.10: Compound 10 (1- (3- (4-methoxyphenyl) -lH-pyrazol-4-yl) piperazine) Synthesis

Pyrazol-4-yl) piperazine-1-carboxylate (358 mg, 0.900 mmol) obtained in the same manner as in Example 1.1 and 1.2, 4.0 M HCl A 239 mg (0.810 mmol, 90% yield) of the final compound was obtained by the synthetic method of Example 2.1 using dioxane solution (3.0 mL).

^{1 H NMR (400 MHz, MeOD} ) δ 8.22 (s, 1H), 7.82-7.77 (m, 2H), 7.08-7.02 (m, 2H), 3.78 (s, 3H), 3.33-3.27 (m, 4H) , 3.12-3.08 (m, 4H)

Example 2.11: Compound 11 (1- (3- (4-bromophenyl) -1H-pyrazol-4-yl) piperazine) Synthesis

1-carboxylate (147 mg, 0.360 mmol) obtained in the same manner as in the synthesis of Example 1.1 and 1.2 was dissolved in tetrahydrofuran After dissolving in EtOH, 98 mg (0.280 mmol, 78% yield) of the final compound was obtained by the synthetic method of Example 2.1 using 4.0 M HCl in dioxane solution (1.1 mL).

^{1 H NMR (400 MHz, MeOD} ) δ 7.90-7.85 (m, 2H), 7.61-7.56 (m, 2H), 3.77 (s, 2H), 3.48 (t, J = 5.0 Hz, 4H), 2.53 (t , J = 4.8 Hz, 4H), 1.46 (s, 9H)

Example 2.12: Compound 12 (1- (3- (p-tolyl) -1H-pyrazol-4-yl) piperazine) Synthesis

(132 mg, 0.380 mmol) obtained in the same manner as in Example 1.1 and 1.2, tert -butyl 4- (3- (p-tolyl) -1H-pyrazol-4-yl) piperazine- HCl A solution of the final compound (69 mg, 0.250 mmol, 64% yield) was obtained by the method of Example 2.1 using dioxane solution (0.70 mL).

^{* 1 H NMR (400 MHz,} MeOD) δ 8.34 (s, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 7.9Hz, 2H), 3.44-3.36 (m, 4H) , 3.25-3.17 (m, 4H), 2.42 (s, 3H)

Example 2.13: Compound 13 (1- (3- (4-cyanophenyl) -1H-pyrazol-4-yl) piperazine)

Yl) piperazine-1-carboxylate (300 mg, 0.85 mmol) obtained in the same manner as in Example 1.1 and 1.2 was dissolved in tetrahydrofuran After dissolving in EtOH, the final compound (180 mg, 0.62 mmol, 73% yield) was obtained by the method of Example 2.1 using 4.0 M HCl in dioxane solution (2.0 mL).

^{1 H NMR (400 MHz, MeOD} ) δ 9.45 (s, 2H), 8.17 (d, J = 8.4 Hz, 2H), 7.89 (d, J = 8.8 Hz, 2H), 7.76 (s, 1H), 3.22 ( s, 4H), 2.99-2.97 (m, 4H)

Example 3.1: tert-Butyl 4- (3- (2-methoxyphenyl) -lH-pyrazol-4-yl) -1, 4-diazepane-

(600 mg, 3.00 mmol) was dissolved in dichloromethane (MC, 4 mL), K ₂ CO ₃ (1,244 mg, 9.00 mmol) was added to the reaction vessel, and tert -butyl 1,4-diazepane- Bromo-1- (2-methoxyphenyl) ethan-1-one (687 mg, 3.00 mmol) was added thereto. The mixture was stirred at 0 ° C for 30 minutes, Lt; / RTI > After completion of the reaction, distilled water was added thereto, and the organic layer was extracted with MC, dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The following reaction was carried out without further purification. To a solution of tert-butyl 4- (2- (2-methoxyphenyl) -2-oxoethyl) -1,4-diazepane-1-carboxylate (1,135 mg, 3.25 mmol) After dissolving, bredereck's reagent ( tert -butoxybis (dimethylamino) methane, 395 mg, 2.27 mmol) was added, and the mixture was stirred at 55 ° C for 20 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain an intermediate? -Dimethylamino-?,? - unsaturated ketone. The following reaction was carried out without further purification.

The obtained β-dimethylamino-,? - unsaturated ketone (1,386 mg, 3.43 mmol) was dissolved in EtOH (10 mL) and hydrazine hydrate (363 mg, 11.32 mmol) Lt; / RTI > for one hour. The concentrate was purified by column chromatography (Hex: EA = 1: 1) and concentrated under reduced pressure to obtain the desired compound (390 mg, 1.05 mmol, 35% yield).

^{1 H NMR (400 MHz, CDCl} 3) δ 8.39 (d, J = 7.6 Hz, 1H), 7.46 (s, 1H), 7.31-7.26 (m, 2H), 7.07-7.03 (m, 1H), 3.94 ( (s, 3H), 3.59-3.51 (m, 4H), 3.11-3.06 (m, 4H), 1.92-1.88

Example 4.1: Compound 14 (1- (3- (2-methoxyphenyl) -1H-pyrazol-4-yl) -1,4-

The reaction vessel was charged with tert -butyl 4- (3- (2-methoxyphenyl) -lH-pyrazol-4-yl) -1,4-diazepane- 1-carboxylate (390 mg, 1.05 mmol) After dissolving in EtOH, 4.0 M HCl in dioxane solution (4.3 mL) was added, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was filtered under reduced pressure and purified by column chromatography (CHCl ₃ : MeOH: NH ₄ OH: H ₂ O = 80: 20: 1: 1) and concentrated under reduced pressure. The compound thus purified was reacted with 1.1 equivalents of 1 M HCl ether. The reaction mixture was concentrated under reduced pressure, and the resulting solid compound was dried to obtain 200 mg (0.65 mmol, 62% yield) of the final compound.

^{1 H NMR (400 MHz, DMSO} ): δ 9.29 (s, 2H), 7.71 (s, 1H), 7.52 (d, J = 7.4, 1H), 7.44 (t, J = 7.6, 1H), 7.14 (d , J = 8.4, 1H), 7.06 (t, J = 7.4, 1H), 3.79 (s, 3H), 3.31 (s, 2H), 3.16-3.08 (m, 6H), 1.95 (s, 2H)

Example 4.2: Compound 15 (1- (3- (3-methoxyphenyl) -lH-pyrazol-4-yl) -1,4-

Diazepane-1-carboxylate (365 mg, 0.25 mmol) obtained in the same manner as in Example 3.1, except that tert- butyl 4- (3- (3- methoxyphenyl) 0.97 mmol) and 4.0 M HCl in dioxane (4.0 mL), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was filtered under reduced pressure and purified by column chromatography (CHCl ₃ : MeOH: NH ₄ OH: H ₂ O = 80: 20: 1: 1) and concentrated under reduced pressure. The compound thus purified was reacted with 1.1 equivalents of 1 M HCl ether. The reaction mixture was concentrated under reduced pressure to obtain the final compound (160 mg, 0.52 mmol, 53% yield).

^{1 H NMR (400 MHz, DMSO} ): δ 9.32 (s, 2H), 7.67 (s, 1H), 7.50 (d, J = 7.6, 1H), 7.44 (s, 1H), 7.36 (t, J = 8.0 J = 5.4, 2H), 2.00 (t, J = 5.2, 2H), 3.80 (s, 3H), 3.23-3.21 (m, 6H)

Example 4.3: Compound 16 (1- (3- (4-methoxyphenyl) -lH-pyrazol-4-yl) -1,4-

Diazepane-1-carboxylate (102 mg, 0.34 mmol) obtained in the same manner as in Example 3.1, except that tert -butyl 4- (3- (4-methoxyphenyl) 0.27 mmol) and 4.0 M HCl in dioxane (1.1 mL), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was filtered under reduced pressure and purified by column chromatography (CHCl ₃ : MeOH: NH ₄ OH: H ₂ O = 80: 20: 1: 1) and concentrated under reduced pressure. The compound thus purified was reacted with 1.1 equivalents of 1 M HCl ether. The reaction mixture was concentrated under reduced pressure and the resulting solid compound was dried to obtain 48 mg (0.15 mmol, 57% yield) of the final compound.

^{1 H NMR (400 MHz, DMSO} ): δ 9.29 (s, 2H), 7.84 (d, J = 8.8, 2H), 7.69 (s, 1H), 7.03 (d, J = 8.8, 2H), 3.80 (s , 3H), 3.24-3.20 (m, 6H), 3.07 (t, J = 5.6, 2H), 2.00 (t, J = 5.2, 2H)

Example 4.4: Compound 17 (1- (3- (3-Fluorophenyl) -1H-pyrazol-4-yl) -1,4-

(357 mg, 0.15 mmol) obtained in the same manner as in Example 3.1, except that tert-butyl 4- (3- (3-fluorophenyl) 0.99 mmol) and 4.0 M HCl dioxane solution (3.9 mL), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was filtered under reduced pressure and purified by column chromatography (CHCl ₃ : MeOH: NH ₄ OH: H ₂ O = 80: 20: 1: 1) and concentrated under reduced pressure. The compound thus purified was reacted with 1.1 equivalents of 1 M HCl ether. The reaction mixture was concentrated under reduced pressure and the resulting solid compound was dried to obtain 176 mg (0.59 mmol, 60% yield) of the final compound.

^{1 H NMR (400 MHz, DMSO} ): δ 9.27 (s, 2H), 7.79 (d, J = 8.0, 1H), 7.68-7.67 (m, 2H), 7.49-7.44 (m, 1H), 7.13-3.11 J = 5.6, 2H), 2.00 (t, J = 5.2, 2H)

Example 4.5: Compound 18 (1- (3- (4-Fluorophenyl) -1H-pyrazol-4-yl) -1,4-

Diazepane-1-carboxylate (320 mg, 0.25 mmol) obtained in the same manner as in Example 3.1, except that tert- butyl 4- (3- (4- fluorophenyl) 0.88 mmol) and 4.0 M HCl in dioxane (3.5 mL), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was filtered under reduced pressure and purified by column chromatography (CHCl ₃ : MeOH: NH ₄ OH: H ₂ O = 80: 20: 1: 1) and concentrated under reduced pressure. The compound thus purified was reacted with 1.1 equivalents of 1 M HCl / ether. The reaction mixture was concentrated under reduced pressure to obtain the final compound (110 mg, 0.37 mmol, 42% yield).

^{1 H NMR (400 MHz, DMSO} ): δ 9.37 (s, 2H), 7.97-7.93 (m, 2H), 7.70 (s, 1H), 7.28 (t, J = 8.8, 2H), 3.21 (s, 6H ), 3.04 (t, J = 5.4, 2H), 1.8 (s, 2H)

Example 4.6: Compound 19 (1- (3- (3-chlorophenyl) -1H-pyrazol-4-yl) -1,4-

Diazepane-1-carboxylate (178 mg, 0.47 mmol) obtained in the same manner as in Example 3.1, except that tert-butyl 4- (3- mmol) and 4.0 M HCl in dioxane (2.0 mL), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was filtered under reduced pressure and purified by column chromatography (CHCl ₃ : MeOH: NH ₄ OH: H ₂ O = 80: 20: 1: 1) and concentrated under reduced pressure. The compound thus purified was reacted with 1.1 equivalents of 1 M HCl ether. The reaction mixture was concentrated under reduced pressure, and the resulting solid compound was dried to obtain 102 mg (0.32 mmol, 68% yield) of the final compound.

^{1 H NMR (400 MHz, DMSO} ): δ 9.35 (s, 2H), 7.92-7.90 (m, 2H), 7.69 (s, 1H), 7.48 (t, J = 8.0, 1H), 7.37-7.35 (m J = 5.6, 2H), 2.01 (t, J = 5.6, 2H)

Example 4.7: Compound 20 (1- (3- (4-chlorophenyl) -1H-pyrazol-4-yl) -1,4-

Diazepane-1-carboxylate (82 mg, 0.21 < RTI ID = 0.0 > mmol) and 4.0 M HCl in dioxane (1.0 mL), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was filtered under reduced pressure and purified by column chromatography (CHCl ₃ : MeOH: NH ₄ OH: H ₂ O = 80: 20: 1: 1) and concentrated under reduced pressure. The compound thus purified was reacted by adding 1.1 equivalents of 1 M HCl ether, followed by concentration under reduced pressure to obtain a solid compound, which was dried to obtain 46 mg (0.15 mmol, 71% yield) of the final compound.

^{1 H NMR (400 MHz, DMSO} ): δ 9.46 (s, 2H), 7.96 (d, J = 8.4, 2H), 7.71 (s, 1H), 7.49 (d, J = 8.4, 2H), 3.23 (s , 6H), 3.05 (t, J = 5.2, 2H), 2.00 (s, 2H)

Example 4.8: Synthesis of compound 21 (1- (3- (3-methylphenyl) -1H-pyrazol-4-yl) -1,4-

Diazepane-1-carboxylate (184 mg, 0.51 mmol) obtained in the same manner as in Example 3.1, except that tert-butyl 4- (3- ) And 4.0 M HCl in dioxane (2.0 mL), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was filtered under reduced pressure and purified by column chromatography (CHCl ₃ : MeOH: NH ₄ OH: H ₂ O = 80: 20: 1: 1) and concentrated under reduced pressure. The compound thus purified was reacted with 1.1 equivalents of 1 M HCl ether. The reaction mixture was concentrated under reduced pressure to obtain the final compound (122 mg, 0.42 mmol, 82% yield).

^{1 H NMR (400 MHz, DMSO} ): δ 9.32 (s, 2H), 7.69-7.67 (m, 3H), 7.33 (t, J = 7.6, 1H), 7.15-7.13 (d, J = 7.2, 1H) , 3.23-3.19 (m, 6H), 3.06 (t, J = 5.6, 2H), 2.35 (s, 3H), 2.00 (t, J = 5.2, 2H)

Example 4.9: Synthesis of compound 22 (1- (3- (4-methylphenyl) -1H-pyrazol-4-yl) -1,4-

Diazepane-1-carboxylate (205 mg, 0.57 mmol) obtained in the same manner as in Example 3.1, except that tert-butyl 4- (3- ) And 4.0 M HCl in dioxane (2.2 mL), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was filtered under reduced pressure and purified by column chromatography (CHCl ₃ : MeOH: NH ₄ OH: H ₂ O = 80: 20: 1: 1) and concentrated under reduced pressure. The compound thus purified was reacted by adding 1.1 equivalents of 1 M HCl ether, followed by concentration under reduced pressure to obtain a solid compound, which was dried to obtain 130 mg (0.44 mmol, 77% yield) of the final compound.

^{1 H NMR (400 MHz, DMSO} ): δ 9.32 (s, 2H), 7.79 (d, J = 8.0, 2H), 7.68 (s, 1H), 7.26 (d, J = 8.0, 2H), 3.23-3.20 (m, 6H), 3.07 ( t, J = 5.6, 2H), 2.34 (s, 3H), 2.00 (t, J = 5.2, 2H)

Example 4.10: Compound 23 (1- (3-phenyl-1H-pyrazol-4-yl) -1,4-diazepane) Synthesis

(381 mg, 1.11 mmol) obtained in the same manner as in Example 3.1, tert-butyl 4- (3-phenyl-1H-pyrazol-4-yl) HCl in dioxane (4.0 mL), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was filtered under reduced pressure and purified by column chromatography (CHCl ₃ : MeOH: NH ₄ OH: H ₂ O = 80: 20: 1: 1) and concentrated under reduced pressure. The compound thus purified was reacted with 1.1 equivalents of 1 M HCl ether. The reaction mixture was concentrated under reduced pressure to obtain the final compound (238 mg, 0.85 mmol, 77% yield).

J = 7.6, 2H), 7.33 (t, J = 7.6, 2H), 7.90 (s, 1H), 3.22 (m, 6 H) 3.06 (m, 2 H), 2.01 (m,

[Example: compound preparation]

The formulations were prepared in various forms using aryl pyrazolyl piperazine or aryl pyrazolyl diazepane derivatives prepared by the above examples.

Example 5: Direct pressurized purification

After 5.0 mg of the active ingredient was sieved, 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate were mixed and pressurized to make tablets.

Example 6: Wet-type purification

After 5.0 mg of the active ingredient was sieved, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of Polysorbate 80 was dissolved in pure water, and an appropriate amount of this solution was added, followed by atomization. After drying, the granules were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressurized to make tablets.

Example 7: Powder and Capsule

After 5.0 mg of the active ingredient was sieved, the mixture was mixed with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone and 0.2 mg of magnesium stearate. 5 gelatin capsules.

Example 8: Injection

Injections were prepared by containing 100 mg as an active ingredient, 180 mg of mannitol, 26 mg of Na ₂ HPO _{4 12} H ₂ O and 2974 mg of distilled water.

[Experimental Example]

Experimental Example 1: Measurement of binding affinity for 5-HT7 serotonin receptor

Human recombinant 5-HT ₇ receptor expressed in CHO cells was used as a receptor. To the container was added 50 mM Tris-HCl buffer (pH 7.4) containing 1 nM of [ ³ H] LSD, 15 μg / well of 5-HT ₇ receptor membrane, various concentrations of test drug, 10 mM MgCl ₂ and 0.1 mM EDTA Was added to make a final reaction volume of 0.25 ml, which was then incubated at 25 ° C for 90 minutes. After incubation, the reaction was terminated by rapid filtration through a Whatman GF / C glass fiber filter previously dipped in 0.3% polyethyleneimine using a Brandel harvester and washed with cold 50 mM Tris-HCl buffer. The filter was covered with Meltelex, sealed in a sample bag, dried in an oven and counted with a MicroBeta, Wallac. Nonspecific binding was measured in the presence of 0.5 μM Mianserin. The K _i value of the test drug was calculated by nonlinear regression method (GraphPad Prism Program, San Diego, USA) for the isotherm obtained by repeatedly testing the drug in 10-11 steps twice in two test tubes.

The% inhibition and binding affinity ( K _i ) of 5-HT ₇ serotonin receptor at 10 μM concentration of the novel compounds according to the examples of the present invention are shown in Table 1 below.

Experimental compound	% inhibition (10 [mu] M)	K i (nM)
Compound 1	96	78
Compound 2	95.6	81
Compound 3	99	47
Compound 4	96.5	73
Compound 5	96.1	64
Compound 6	98.2	19
Compound 7	99.8	23
Compound 8	88.3	347
Compound 9	89.2	226
Compound 10	96.6	49
Compound 11	98.7	18
Compound 12	98.6	27

Experimental Example 2: Measurement of c-AMP activity on 5-HT7 serotonin receptor

Approximately 20,000 HEK293T cells co-trasfected with 5HT7a and GloSensor-22F plasmids were inserted into clear-bottomed cell-culture plates (384 wells) and cultured in a thermostat (37 ° C) for 6 hours. Subsequently, the culture medium was removed, and 20 μl of D-luciferin stock (200 μg / μl) diluted to 160: 1 was added to 20 mM HEPES and 1 × HBSS (in 3 ^rd H ₂ O) Respectively. 30 nM, 100 nM, 300 nM, 1 μM, 10 nM, 10 nM, 10 nM, 1 nM, 3 nM, 3 μM, 10 μM, and 30 μM, and the luminescence was measured 15 minutes later. The results are shown in Table 2 and FIG. 1 below, and SB-269970 was used as a control group.

Experimental compound	cAMP_ antagonism
	pIC 50 (± SEM)	IC 50 (nM)	Inhibition (%)
Compound 5	5.08 ± 0.064	8,380	101.7
Compound 6	5.29 ± 0.077	5,087	80.8
Compound 7	5.34 ± 0.096	4,576	74.7
SB-269970	9.03 + 0.044	0.9	100.9

According to this, Compound 5, Compound 6 and Compound 7 appeared to antagonize the G-protein signaling system at the 5-HT7 receptor.

Experimental Example 3: Measurement of beta-alignin activity on 5-HT7 serotonin receptor

HTLA cells transfected with 5HT7a_Tango plasmids in clear-bottomed cell-culture plates (384 wells) were added at about 10,000 to 20,000 per well and cultured in a constant temperature (37 ° C) for 6 hours. Thereafter, the culture medium was removed, and the culture medium was removed and cultured in a new culture medium at a concentration of 3 pM, 10 pM, 30 pM, 100 pM, 300 pM, 1 nM, 3 nM, 10 nM, 30 nM, 100 nM, 300 nM, The compounds prepared at M M, 10, M, 30 MM were treated and cultured in a constant temperature (37 캜) for 22 hours. After 22 hours, the culture medium was removed and 20 μl of Bright-Glo Luciferase stock diluted 20: 1 in 20 mM HEPES, 1 × HBSS (in 3 ^rd H ₂ O) Respectively. The results are shown in Table 3 and FIG. 2 below.

Experimental compound	β-arrestin_ hyperactivity
	pEC 50 (± SEM)	EC 50 (nM)	Emax (%)
Compound 5	6.40 + - 0.12	397	34.2
Compound 6	6.93 + 0.081	118	44.9
Compound 7	6.93 + - 0.056	118	55.4
5-HT	7.32 + 0.063	48	99.7

According to this, Compound 5, Compound 6 and Compound 7 showed an antagonistic action in the beta-allestin signal system, and Emax value was found to be a partial agonist because it was between 34% and 55%.

Experimental Example 4: Measurement of sleep efficacy in an in vivo animal model

The animals used for the in-vivo experiments were mice (C57BL / 6), male (8-10weeks). Electroencephalography (EEG) and electromyography (EMG) are used for sleep analysis, ie, EEG signals and muscle electrical signals. To measure the EEG, an epidural electrode was inserted into the skull of a rat, a wire electrode was inserted into the rat's trapezius to measure EMG, and the signal was transmitted to Neuro Nexus's SMARTBOX through a connector manufactured by itself. Was converted into digital data and stored in a computer. The stored signal is created and analyzed directly by a program called MATLAB, and the analysis method is as follows. First, the state of awake of the mouse is distinguished by the magnitude of the signal measured in the EMG (muscle signal). The EEG signal is used to distinguish between REM sleep and NREM sleep in the water. If the REM sleep and theta range (5.1 ~ 10Hz) dominate if the delta range (0.3 ~ 5Hz) do. Finally, the delta range and theta range are classified as quite wakefulness when they are similar in composition but not in sleep. Through the above process, we obtain information such as duration and latency for each state when we obtain the sleep state according to the whole time. This process was carried out one day before the introduction of the derivative, the day after the introduction of the derivative, and the comparison shows how the derivative actually affected sleep.

Experimental results showed that the EEG / EMG signal measured that the substance of this patent regulates the REM sleep and non-RME sleep at the sleep stage.

The derivatives of the aryl pyrazolyl piperazine or aryl pyrazolyl diazepane of the present invention and pharmaceutically acceptable salts thereof exhibit excellent binding affinity to 5-HT ₇ serotonin receptors and are useful for the treatment of sleep, depression, migraine, anxiety, autism, And inflammatory pain, pain-related neurological diseases such as neuropathic pain, and treatment and prevention of body temperature control, biorhythm, and smooth muscle-related diseases.

Claims (9)

1. A derivative of an arylpyrazolylpiperazine or an arylpyrazolyldiazepane represented by the following structural formula 1 and a pharmaceutically acceptable salt thereof:

   [Structural formula 1]

   

   In formula 1,

   n is 1 or 2,

   R represents a hydrogen atom, a halogen group, a cyano group, an amino group, a nitro group, a hydroxyl group, a carboxyl group, a substituted or unsubstituted C1 to C30 alkyl group, a substituted or unsubstituted C3 to C30 cycloalkyl group, To C30 heterocycloalkyl groups, substituted or unsubstituted C6 to C30 aryl groups, substituted or unsubstituted C1 to C30 heteroaryl groups, substituted or unsubstituted C1 to C30 alkoxy groups, substituted or unsubstituted C3 to C30 cycloalkoxy A substituted or unsubstituted C1 to C30 heterocycloalkoxy group, a substituted or unsubstituted C6 to C30 aryloxy group, or a substituted or unsubstituted C1 to C30 heteroaryloxy group.
2. The method according to claim 1,

   And R is a hydrogen atom, a halogen group, a cyano group, a substituted or unsubstituted C1 to C30 alkyl group, or a substituted or unsubstituted C1 to C30 alkoxy group, and the aryl pyrazolyl piperazine or aryl pyrazolyl di Derivatives and pharmaceutically acceptable salts thereof.
3. 3. The method of claim 2,

   And R is a hydrogen atom, a halogen group, a cyano group, a C1 to C4 alkyl group, or a C1 to C4 alkoxy group, and a pharmaceutically acceptable salt thereof.
4. The method according to claim 1,

   A compound represented by the structural formula (1), wherein the derivative is any one selected from the following compounds 1 to 23, and a pharmaceutically acceptable salt thereof.

   

   

   

   

   

   
5. (1) Compounds and tert represented by the formula 2-butoxy-bis (dimethylamino) methane (tert-Butoxy bis (dimethylamino) methane), and after the reaction, by reacting with hydrazine (hydrazine) and sequentially Boc (tert -butyloxycarbonyl) -protected intermediate of formula < RTI ID = 0.0 > 1 < / RTI > And

   (2) Boc-deprotection of a compound represented by the following structural formula 1 to prepare a derivative of the arylpyrazolylpiperazine or arylpyrazolyldiazepane represented by the structural formula 1, A process for the preparation of a derivative of a zolylpiperazine or arylpyrazolyldiazepane and a pharmaceutically acceptable salt thereof.

   [Structural formula 2]

   

   In formula 2,

   n is 1 or 2,

   R represents a hydrogen atom, a halogen group, a cyano group, an amino group, a nitro group, a hydroxyl group, a carboxyl group, a substituted or unsubstituted C1 to C30 alkyl group, a substituted or unsubstituted C3 to C30 cycloalkyl group, To C30 heterocycloalkyl groups, substituted or unsubstituted C6 to C30 aryl groups, substituted or unsubstituted C1 to C30 heteroaryl groups, substituted or unsubstituted C1 to C30 alkoxy groups, substituted or unsubstituted C3 to C30 cycloalkoxy A substituted or unsubstituted C1 to C30 heterocycloalkoxy group, a substituted or unsubstituted C6 to C30 aryloxy group, or a substituted or unsubstituted C1 to C30 heteroaryloxy group.

   [Structural formula 1 ']

   

   In structural formula 1 '

   n is 1 or 2,

   R represents a hydrogen atom, a halogen group, a cyano group, an amino group, a nitro group, a hydroxyl group, a carboxyl group, a substituted or unsubstituted C1 to C30 alkyl group, a substituted or unsubstituted C3 to C30 cycloalkyl group, To C30 heterocycloalkyl groups, substituted or unsubstituted C6 to C30 aryl groups, substituted or unsubstituted C1 to C30 heteroaryl groups, substituted or unsubstituted C1 to C30 alkoxy groups, substituted or unsubstituted C3 to C30 cycloalkoxy A substituted or unsubstituted C1 to C30 heterocycloalkoxy group, a substituted or unsubstituted C6 to C30 aryloxy group, or a substituted or unsubstituted C1 to C30 heteroaryloxy group.
6. 6. The method of claim 5,

   Wherein the compound represented by the structural formula 2 is prepared by reacting a compound represented by the following structural formula 3 with N-Boc-piperazine or N-Boc-diazepane, wherein the aryl pyrazolylpiperazine or aryl pyrazolyldiazide Lt; RTI ID = 0.0 > pharmaceutically < / RTI > acceptable salt thereof.

   [Structural Formula 3]

   

   In Structure 3,

   R represents a hydrogen atom, a halogen group, a cyano group, an amino group, a nitro group, a hydroxyl group, a carboxyl group, a substituted or unsubstituted C1 to C30 alkyl group, a substituted or unsubstituted C3 to C30 cycloalkyl group, To C30 heterocycloalkyl groups, substituted or unsubstituted C6 to C30 aryl groups, substituted or unsubstituted C1 to C30 heteroaryl groups, substituted or unsubstituted C1 to C30 alkoxy groups, substituted or unsubstituted C3 to C30 cycloalkoxy A substituted or unsubstituted C1 to C30 heterocycloalkoxy group, a substituted or unsubstituted C6 to C30 aryloxy group, or a substituted or unsubstituted C1 to C30 heteroaryloxy group.
7. 6. The method of claim 5,

   Wherein the Boc-deprotection reaction is carried out using any one of a solution selected from hydrochloric acid, trifluoroacetic acid, and trimethylsalyl triflate (TMSOTf), wherein the aryl pyrazolyl piperazine or the derivative of aryl pyrazolyl diazepane And pharmaceutically acceptable salts thereof.
8. A pharmaceutical composition for the treatment or prevention of central nervous system diseases, which comprises an aryl pyrazolyl piperazine or an aryl pyrazolyl diazepane derivative of any one of claims 1 to 4 and a pharmaceutically acceptable salt thereof as an active ingredient.
9. 9. The method of claim 8,

   Wherein the central nervous system disease is any one selected from the group consisting of sleep disorders, depression, migraine, anxiety, autism, inflammatory pain, neuropathic pain, thermoregulatory disorders, biorhythm disorders and smooth muscle related diseases A pharmaceutical composition.

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