KR101247690B1 - 1,4-Diazepane pyrazole derivatives as T-type calcium channel antagonists - Google Patents

Abstract

The present invention relates to a 1,4-diazepane pyrazole compound and a pharmaceutically acceptable salt thereof, a method for preparing these compounds, and a pharmaceutical composition containing these compounds as an active ingredient. It is about.

Description

 {1,4-Diazepane pyrazole derivatives as T-type calcium channel antagonists} having activity on Τ-type calcium channels

The present invention relates to a 1,4-diazepane pyrazole compound and a pharmaceutically acceptable salt thereof, a method for preparing these compounds, and a pharmaceutical composition containing these compounds as an active ingredient. It is about.

The calcium channel plays an important role in various signal transduction in cells by increasing the concentration of calcium by stimulation of neurons. The calcium channel is divided into a high-voltage activated calcium channel and a low-voltage activated calcium channel. A typical low-voltage activated calcium channel is a T-type calcium channel.

It is well known that T-type calcium channels are present in the central muscle, the endocrine glands of the adrenal gland, the oriental nodule, the heart, and antagonists of T-type calcium channels are effective in treating brain diseases and heart diseases such as epilepsy, hypertension and angina . [1] Hosravani, Houman et al., "Effects of Cav3.2 channel mutations linked to idiopathic generalized epilepsy", Annals of Neurology , 2005 , 57 (5) , 745-749; 2) Vitko, Iuliia et al., "Functional characterization and neuronal modeling of the effects of epilepsy variants of CACNA1H, a T-type calcium channel ", Journal of Neuroscience , 2005 , 25 (19) , 4844-4855; . 3) Clozel, Cardiovas Drugs Ther , 1990, 4, 731-736; 4) Hefti, Arzneimittelforschung , 1990 , 40 , 417-421; 5) Moosmang, Sven et al., &Quot; Antihypertensive Effects of the Putative T-Type Calcium Channel Antagonist Mibefradil Is Mediated by the L-Type Calcium Channel Cav. 1.2 ", Circulation Research , 2006 , 98 (1)

In addition, recently, T-type calcium channel antagonists have been reported to be effective in the treatment of chronic pain. [Flatters, Sarah JL, "T -type calcium channels: A potential target for the treatment of chronic pain", Drugs of the Future, 2005, 40, 573-580] α1G knockout spinal nerve ligation in (knock-out) mice (spinal nerve ligation) to cause neuropathic pain, T-type calcium channel antagonist has been reported to reduce neuropathic pain. [Molecules & Cells, 2008, 25 , 242-246]. In addition, Mibefradil and Ethosuximide as T-type calcium channel antagonists reported that the degree of inhibition of the mechanical thermal induction reaction in the spinal nerve ligation animal model was dependent on the dose of the drug , Suggesting that T-type calcium channel antagonists are effective in the treatment of neuropathic pain. Dogrul, Ahmet et al., "Reversal of experimental neuropathic pain by T-type calcium channel blockers", Pain , 2003 , 105 , 159-168]

In addition, calcium plays an important role as an intracellular signaling substance and regulates various cellular actions. Calcium is known to be involved in cell growth during cell action, so it can be predicted that an antagonist of T-type calcium channel will have anticancer effect Do. [ Nat. Rev. Mol. Cell Biol. 2003 , 4 , 517-529]

 Mibefradil (Ro 40-5967, WO 98/49149), which was marketed as an antagonist of T-type calcium channel, was used as a therapeutic agent for hypertension and angina pectoris. Mibefradil was used for cytochrome P-450 3A4 and 2D6 The drug has been metabolized and metabolized by other drugs, resulting in several adverse effects resulting in inadequate use as a drug. Thus, the urgent development of an antagonist of T-type calcium channel is required.

Although many efforts have been made to develop an antagonist of T-type calcium channel, there are not many antagonists of selective T-type calcium channel.

Selective T-type calcium channel, good pharmacokinetic profile, good ADME (absorption, distribution, metabolism, excretion), but selective T-type calcium channel, good pharmacokinetic profile, ADME (absorption, distribution, metabolism, excretion) Treatment of brain diseases such as epilepsy, depression, Parkinson's disease, dementia, sleep disorders; Cancer treatment; Treatment of heart diseases such as hypertensive, deep vein, angina pectoris, myocardial infarction, congestive heart failure; Pain relief, such as neuropathic pain, chronic and acute pain; There is a need for an antagonist of a T-type calcium channel effective for the treatment.

It is an object of the present invention to provide a 1,4-diazepan pyrazole compound or a pharmaceutically acceptable salt thereof.

It is another object of the present invention to provide a pharmaceutical composition having a T-type calcium channel antagonism in which the 1,4-diazepane pyrazole compound or a pharmaceutically acceptable salt thereof is included as an active ingredient. .

In addition, the present invention is epilepsy, depression, Parkinson's disease (dementia) that contains the above-mentioned 1,4-diazepane pyrazole compound or a pharmaceutically acceptable salt thereof as an active ingredient. Treatment of brain diseases such as sleep disorders; Cancer treatment; Treatment of heart diseases such as hypertensive, deep vein, angina pectoris, myocardial infarction, congestive heart failure; Another object is to provide a pharmaceutical composition for pain relief such as neuropathic pain, chronic and acute pain.

In order to realize the above object, the present invention is characterized by a 1,4-diazepane pyrazole compound represented by the following formula (1) and a pharmaceutically acceptable salt thereof effective as a T-type calcium channel antagonist.

In Formula 1,

(이때 m은 치환기 개수로 0, 1, 2, 또는 3의 정수이다)를 나타내고, R ¹ is a C ₁ -C ₆ alkyl group, a C ₅ -C ₁₆ cycloalkyl group, R ^3- (CH ₂ ) _n -where n is an integer of 0, 1, 2, or 3, or

(Where m is an integer of 0, 1, 2, or 3 in the number of substituents),

R ² represents a C ₁ -C ₆ alkyl group,

R ³ is selected from a C ₁ -C ₆ alkyl group, a 5-10 membered heterocycloalkyl group containing 1 to 2 oxygen atoms (O), or an oxygen atom (O), a sulfur atom (S), and a nitrogen atom (N) A heteroaromatic ring group of 5 to 15 membered monocyclic or fused ring form containing 1 to 4 selected heteroatoms, wherein the heterocycloalkyl or heteroaromatic ring is halo, C ₁ -C ₈ may be substituted or unsubstituted with 1 to 3 substituents selected from alkyl and phenyl,

R ⁴ represents a halogen atom, a C ₁ -C ₈ alkyl group, a C ₁ -C ₈ haloalkyl group, or a C ₁ -C ₈ alkoxy group,

X represents a single bond, -C (O)-, or -SO _2- .

Since the compound of the present invention shows antagonistic activity on T-type calcium channel, it can be usefully used as a prophylactic or therapeutic agent for diseases related to brain disease, heart disease, cancer, epilepsy, pain and the like.

The 1,4-diazepane pyrazole compound represented by Chemical Formula 1 according to the present invention may form a pharmaceutically acceptable salt by a conventional method in the art. Non-toxic inorganic acids such as hydrochloric acid, bromic acid, sulfonic acid, amido sulfuric acid, phosphoric acid, nitric acid, or acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, tartaric acid, citric acid, paratoluenesulfonic acid, methanesulfone In addition to nontoxic organic acids such as acids, pharmaceutically acceptable salts of these acids may be added.

The substituents used to define the 1,4-diazepane pyrazole compound represented by Chemical Formula 1 according to the present invention will be described in more detail as follows.

An "alkyl group" is a linear or branched chain carbon chain on the milled with from 1 to 6 carbon atoms group in the present invention, specifically, methyl group, ethyl group, normal propyl group, an isopropyl group, a n-butyl group, isobutyl group, tert - Butyl group and the like. The "cycloalkyl group" in the present invention is a carbon chain group in the form of a monocyclic, polycyclic or conjugated ring having 5 to 16 carbon atoms, specifically, a cyclopentyl group, a cyclohexyl group, an adamantyl group and the like. "Haloalkyl group" in the present invention is a linear, pulverized and cyclic carbon chain group containing 1 to 13 halogen atoms, such as fluoro, chloro, bromo, iodo, having 1 to 6 carbon atoms, Examples thereof include a fluoromethyl group, trifluoromethyl group, 1,2-dichloroethyl group, 1,1-dichloroethyl group, pentafluoroethyl group and the like. "Alkoxy group" in the present invention is an alkyl group of carbon linked to oxygen, wherein alkyl is as defined above. The "heterocycloalkyl group" in the present invention is a cycloalkyl group composed of 5 to 10 elements including 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur, and in some cases, halo, C ₁ -C ₆ alkyl, and the like. It may be substituted with a substituent, and specifically, it is a pyrrolidyl group, a piperidyl group, a piperazinyl group, a morpholinyl group, a tetrahydropyranyl group, a dihydropyranyl group, etc. In the present invention, the "heteroaromatic ring group" is an aromatic heterohydrocarbon group having 5 to 15 carbon atoms consisting of a monocyclic ring or a conjugated ring containing 1 to 4 heteroatoms selected from N, O, and S. Specifically, a pyrrolyl group, Aryl group, thiophenyl group, pyrazolyl group, imidazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, triazolyl group, oxadiazolyl group, thiadiazolyl group, tetrazolyl group , Pyridinyl group, pyrazinyl group, triazinyl group, pyridazinyl group, pyrimidinyl group, indolyl group, indolinyl group, isoindoleyl group, benzofuryl group, benzofurazanyl group, dibenzofuryl group, iso Benzopuryl group, indazolyl group, benzoimidazolyl group, imidazopyridinyl group, benzooxazolyl group, benzoisoxazolyl group, benzothiazolyl group, dibenzothiophenyl group, naphthyridyl group, benzoisothiazolyl group , Quinol Group, such as an iso-quinolinyl group, a quinoxalinyl group, a phthalazinyl possess group, a quinolinyl group, a quinazolinyl group, a carbazolyl group, possess phenacyl group, a phenoxy thiazinyl group, a piperidinyl group, or an arc.

In the 1,4-diazepane pyrazole compound represented by Formula 1, preferably, R ¹ is a methyl group, an ethyl group, n -propyl group, isopropyl group, isobutyl group, tert -butyl group, 3,3 -Dimethylbutyl group, cyclohexyl group, adamantyl group, tetrahydropyranyl group, tetrahydropyranylmethyl group, 2,2-dimethyl-tetrahydropyranylmethyl group, phenyl group, 2-methylphenyl group, 3- Methylphenyl group, 4-methylphenyl group, 2,6-dimethylphenyl group, phenylsulfonyl group, 2-chlorophenylsulfonyl group, 3-chlorophenylsulfonyl group, 4-chlorophenylsulfonyl group, 2,4,5-trichlorophenyl Sulfonyl group, 2-fluorophenylsulfonyl group, 3-fluorophenylsulfonyl group, 4-fluorophenylsulfonyl group, 2,4-difluorophenylsulfonyl group, 2- (trifluoromethyl) phenylsulfonyl group, 3- (trifluoromethyl) phenylsulfonyl group, 4- (trifluoromethyl) phenylsulfonyl group, 2-methoxyphenylsulfonyl group, 3-meth Cyphenylsulfonyl group, 4-methoxyphenylsulfonyl group, 3,4-dimethoxyphenylsulfonyl group, benzoyl group, 2-chlorobenzoyl group, 3-chlorobenzoyl group, 4-chlorobenzoyl group, 3,4-di Chlorobenzoyl group, 3,5-dichlorobenzoyl group, 2-fluorobenzoyl group, 3-fluorobenzoyl group, 4-fluorobenzoyl group, 2-bromobenzoyl group, 3-bromobenzoyl group, 4- Bromobenzoyl group, 2- (trifluoromethyl) benzoyl group, 3- (trifluoromethyl) benzoyl, 4- (trifluoromethyl) benzoyl group, oxazol-2-yl group, (oxazole-2- (Methyl), (4-phenyl-5-propyloxazol-2-yl) methyl group, benzoxazol-2-yl group, (benzoxazol-2-yl) methyl group, (6-fluorobenzoxazole-2 -Yl) methyl group, (6-methylbenzooxazol-2-yl) methyl group, thiazol-2-yl group, thiazol-2-ylmethyl group, benzo [ d ] thiazol-2-yl group, benzo [ d ] thia Zol-2-ylmethyl group, imidazol-5-yl group, (imidazol-5-yl) methyl group, (2-phenyl-1 H -imidazol-5-yl) methyl group, benzoimidazol-5- Diary, ( 1H -benzoimidazol-5-yl) methyl group, or (2-phenyl- 1H -benzoimidazol-5-yl) methyl group, wherein R ² is a methyl group, an ethyl group, n -propyl group, iso propyl group, an isobutyl group, or tert - butyl group in the case of compound.

Specific examples of the 1,4-diazepan pyrazole compound represented by Chemical Formula 1 are as follows:

2- (4-(( 1H -Benzo [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acetamide (Compound No. 1),

N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) -2- (4-((2-phenyl-1 H -imidazol-5-yl) methyl)- 1,4-diazepan-1-yl) acetamide (Compound No. 2),

2- (4- (3,3-dimethylbutyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) Methyl) acetamide (Compound No. 3),

2- (4- (benzo [ d ] thiazol-2-yl) methyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazole -3-yl) methyl) acetamide (Compound No. 4),

2- (4- (2-chlorobenzoyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acet Amide (compound number 5),

N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) -2- (4- (3- (trifluoromethyl) benzoyl) -1,4-diazepan- 1-yl) acetamide (Compound No. 6),

2- (4- (4-fluorobenzoyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) Acetamide (Compound No. 7),

N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) -2- (4- (phenylsulfonyl) -1,4-diazepan-1-yl) acetamide (Compound number 8),

N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) -2- (4- (2- (trifluoromethyl) phenylsulfonyl) -1,4-diaza Jepan-1-yl) acetamide (Compound No. 9),

2- (4- (4-fluorophenylsulfonyl) -diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acetamide (Compound number 10),

N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) -2- (4-((6-methylbenzooxazol-2-yl) methyl) -1,4 -Diazepan-1-yl) acetamide (Compound No. 11),

N - tert -butyl-2- (4- (2-((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methylamino) -2-oxoethyl) -1,4-dia Jepan-1-yl) acetamide (Compound No. 12),

N- (2,6-dimethylphenyl) -2- (4- (2-((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methylamino) -2-oxoethyl)- 1,4-diazepan-1-yl) acetamide (Compound No. 13),

2- (4-((6-fluorobenzooxazol-2-yl) methyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H- Pyrazol-3-yl) methyl) acetamide (Compound No. 14),

2- (4- (3-fluorobenzoyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) Acetamide (Compound No. 15),

2- (4- (3-chlorobenzoyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acet Amide (compound number 16),

2- (4- (3-bromobenzoyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) Acetamide (Compound No. 17),

N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) -2- (4- (4- (trifluoromethyl) benzoyl) -1,4-diazepan- 1-yl) acetamide (Compound No. 18),

2- (4- (3,4-Dichlorobenzoyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) Methyl) acetamide (Compound No. 19),

2- (4- (3,5-Dichlorobenzoyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) Methyl) acetamide (Compound No. 20),

2- (4- (3-fluorophenylsulfonyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) Methyl) acetamide (Compound No. 21),

2- (4- (3-chlorophenylsulfonyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl Acetamide (Compound No. 22),

N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) -2- (4- (3- (trifluoromethyl) phenylsulfonyl) -1,4-diaza Jepan-1-yl) acetamide (Compound No. 23),

2- (4- (2,4-Difluorophenylsulfonyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazole-3 -Yl) methyl) acetamide (Compound No. 24),

2- (4- (3,4-dimethoxyphenylsulfonyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazole-3 -Yl) methyl) acetamide (Compound No. 25),

N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) -2- (4- (2,4,5-trichlorophenylsulfonyl) -1,4-diaza Jepan-1-yl) acetamide (Compound No. 26),

2- (4 - ((2,2-dimethyl-tetrahydro -2 H - Failan 4-yl) methyl) -1,4-dia plate making 1-yl) - N - ((5- isobutyl -1 -Phenyl-1 H -pyrazol-3-yl) methyl) acetamide (Compound No. 27),

N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) -2- (4-((4-methyl-5-propyloxazol-2-yl) methyl)- 1,4-diazepan-1-yl) acetamide (Compound No. 28),

N- (tricyclo [3.3.1.1 (3,7)] decane) -2- (4- (2-((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methylamino) -2-oxoethyl) -1,4-diazepan-1-yl) acetamide (Compound No. 29).

On the other hand, the present invention includes a method for preparing the 1,4-diazepane pyrazole compound represented by the formula (1), the production method according to the present invention can be represented by the following reaction schemes 1, 2, 3.

[Reaction Scheme 1]

In Reaction Scheme 1, R ¹ and R ² are each as defined in Chemical Formula 1, and Y represents a halogen atom or an aldehyde group.

According to the preparation method according to Scheme 1, 2-chloro- N -pyrazoyl methyl acetamide represented by Chemical Formula 3 is prepared by treating chloroacetyl chloride with pyrazolemethylamine represented by Chemical Formula 2. Thereafter, 2-chloro- N -pyrazoyl methyl acetamide represented by Formula 3 is treated with 1,4-diazepane to prepare 1,4-diazepan pyrazole, which is the main intermediate represented by Formula 4. . In addition, the 1,4-diaza represented by Chemical Formula ^{1 may} be subjected to a reduction-aminoation reaction or an alkylation reaction of the 1,4-diazepan pyrazole represented by Chemical Formula 4 with the compound represented by R ¹ -Y. Engraving pyrazole compound is prepared.

On the other hand, the present invention includes a pharmaceutical composition comprising the 1,4-diazepane pyrazole compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient for the purpose of preventing and treating diseases.

The pharmaceutical composition of the present invention may be formulated by a conventional formulation method, including other conventional carriers, adjuvants or diluents, together with the 1,4-diazepane pyrazole compound represented by Formula 1 or a pharmaceutically acceptable salt thereof. It may be prepared in a form suitable for oral or parenteral administration. In the case of oral administration, it may be prepared in the form of tablets, capsules, solutions, syrups, suspensions, etc., and in the case of parenteral administration, it may be prepared in the form of injections for intraperitoneal, subcutaneous, muscle, and transdermal.

The effective dose per day as a T-type calcium channel antagonist of the pharmaceutical composition of the present invention is 0.01 to 1000 mg / day on an adult basis. The administration dose varies depending on the age, body weight, sex, dosage form, And may be administered once or several times a day at a predetermined time interval according to the judgment of a doctor or a pharmacist.

Accordingly, the present invention provides a pharmaceutical use of the 1,4-diazepane pyrazole compound represented by Formula 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same for the purpose of preventing and treating a disease. To provide.

That is, the present invention has activity against T-type calcium channels, and therefore, can treat brain diseases such as epilepsy, depression, Parkinson's disease, dementia, and sleep disorders; Cancer treatment; Treatment of heart diseases such as hypertensive, deep vein, angina pectoris, myocardial infarction, congestive heart failure; Pain relief, such as neuropathic pain, chronic and acute pain; Includes medicinal uses for the purpose.

The present invention as described above will be described in more detail through the following Examples and Experimental Examples, but the present invention is not limited to these Examples and Experimental Examples.

[Example]

Preparation Example 1 Preparation of 2-Chloro- N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acetamide

Pyrazolmethylamine (3.0 g, 13.1 mmol) was added to 130 mL of a purified dichloromethane solvent, and chloroacetyl chloride (1.15 mL, 14.3 mmol) was slowly added thereto while stirring at 0 ° C., followed by stirring at room temperature to obtain 90% yield.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.52-7.40 (m, 5H), 6.25 (s, 1H), 4.59 (d, 2H, J = 5.60 Hz), 4.11 (s, 2H), 2.51 (d, 2H, J = 7.19 Hz), 1.89-1.80 (m, 1H), 0.88 (d, 6H, J = 6.62 Hz).

Preparation Example 2 Preparation of 2- (1,4-diazepane-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acetamide

To 50 mL of purified dichloromethane solvent, 2-chloro- N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acetamide (1.25 g, 4.09 mmol) and N, Homopiperazine (1.23 g, 12.0 mmol) was slowly added with stirring N -diisopropylethylamine (EDIPA; 1.42 mL, 8.18 mmol) and stirred at room temperature for 12 hours to obtain 72% yield.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.85 (bs, 1H), 7.46-7.33 (m, 5H), 6.11 (s, 1H), 4.49 (d, 2H, J = 5.66 Hz), 3.40 (s, 2H), 3.19 (s, 2H), 2.89-2.68 (m, 8H), 2.47 (d, 2H, J = 7.18 Hz), 2.24 (s, 1H), 1.82-1.68 (m, 3H), 0.82 (d , 6H, J = 6.62 Hz).

Example 1. 2- (4-(( 1H -Benzo [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1 -Phenyl-1 H -pyrazol-3-yl) methyl) acetamide

2- (chloromethyl) -1 H -benzoimidazole (48 mg, 0.29 mmol), EDIPA (150 μL, 0.87 mmol), 2- (1,4) in 5 mL of N, N -dimethylformamide (DMF) Add -diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acetamide (140 mg, 0.38 mmol) at 70 ° C. for 8 hours. Stirred at reflux. After completion of the reaction, the mixture was cooled to room temperature, washed with H ₂ O, and extracted with dichloromethane. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure to give 82 mg (57%) of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz) δ 8.07 (t, 6H, J = 3.72 Hz). 7.46 (bs, 2H), 7.40-7.27 (m, 5H), 7.20-7.16 (m, 2H), 6.14 (s, 1H), 4.53 (d, 2H, J = 4.03 Hz), 3.74 (s, 2H) , 3.19 (s, 2H), 2.76-2.71 (m, 8H), 2.45 (d, 2H, J = 5.39 Hz), 1.83-1.73 (m, 3H), 0.82 (d, 6H, J = 4.96 Hz).

¹³ C NMR (CDCl ₃ , 75 MHz) δ 171.0, 152.6, 149.3, 144.7, 139.6, 129.1, 128.2, 125.7, 122.2, 104.6, 62.5, 56.7, 55.8, 55.3, 55.0, 37.1, 35.1, 29.0, 28.4, 22.4 .

Example 2. N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) -2- (4-((2-phenyl-1 H -imidazol-5-yl ) Methyl) -1,4-diazepan-1-yl) acetamide

In the same manner as in Example 1, 5- (chloromethyl) -2-phenyl-1 H -imidazole hydrochloride (62 mg, 0.27 mmol), EDIPA (140 μL, 0.81 mmol), 2- (1,4- 97 mg (68%) using diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acetamide (130 mg, 0.35 mmol) ) The target compound was obtained.

¹ H NMR (CDCl ₃ , 300 MHz) δ 8.18 (bs, 1H), 7.83 (d, 6H, J = 6.89 Hz). 7.34-7.28 (m, 8H), 6.87 (s, 1H), 6.13 (s, 1H), 4.52 (d, 2H, J = 5.40 Hz), 3.45 (s, 1H), 3.37 (bs, 1H), 3.17 (s, 2H), 2.73-2.61 (m, 8H), 2.46 (d, 2H, J = 7.17 Hz), 1.83-1.74 (m, 1H), 1.68 (bs, 2H). 0.83 (d, 6H, J = 6.60 Hz).

¹³ C NMR (CDCl ₃ , 75 MHz) δ 171.3, 149.5, 144.6, 139.6, 130.5, 128.7, 125.7, 125.1, 104.7, 62.4, 55.5, 53.8, 52.6, 50.2, 37.0, 35.1, 28.9, 28.4, 22.4.

Example 3. 2- (4- (3,3-dimethylbutyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazole- 3-yl) methyl) acetamide

3.3-dimethylbutanal (50 μL, 0.17 mmol), 2- (1,4-diazane-1-yl) -N -((5-isobutyl-1-phenyl-1 H in 3 mL of dichloromethane Pyrazol-3-yl) methyl) acetamide (81 mg, 0.22 mmol), NaBH (OAc) ₃ (106 mg, 0.50 mmol) and molecular sieves were added and stirred for 20 minutes. After completion of the reaction, the mixture was washed with H ₂ O and extracted with dichloromethane. The organic layer was dried over anhydrous MgSO ₄ , filtered, concentrated under reduced pressure and purified to give 60 mg (79%) of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.79 (bs, 1H), 7.46-7.35 (m, 5H), 6.12 (s, 1H), 4.50 (d, 2H, J = 5.69 Hz), 3.16 (s, 2H), 2.75-2.62 (m, 8H), 2.48 (d, 2H, J = 7.18 Hz), 2.44-2.40 (m, 2H), 1.82-1.73 (m, 3H), 1.35-1.31 (m, 2H) 0.87-0.77 (m, 15 H).

¹³ C NMR (CDCl ₃ , 100 MHz) δ 171.0, 149.6, 144.3, 139.9, 129.1, 127.9, 125.7, 104.7, 62.3, 55.8, 55.2, 54.2, 40.5, 37.0, 35.2, 29.7, 29.5, 28.4, 27.6, 22.4 .

Example 4. 2- (4- (benzo [ d ] thiazol-2-yl) methyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acetamide

In the same manner as in Example 3, benzothiazol-2-carbaaldehyde (25 μL, 0.15 mmol), 2- (1,4-diazepan-1-yl) -N -((5-isobutyl-1 57 mg (71%) of the title compound were obtained using -phenyl-1 H -pyrazol-3-yl) methyl) acetamide (74 mg, 0.20 mmol).

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.93 (d, 2H, J = 7.90 Hz), 7.86-7.78 (m, 2H), 7.46-7.31 (m, 7H), 6.12 (s, 1H), 4.52 ( d, 2H, J = 5.62 Hz), 3.22 (s, 2H), 2.86-2.77 (m, 8H), 2.47 (d, 2H, J = 7.18 Hz), 1.86-1.74 (m, 3H), 0.82 (d , 6H, J = 6.62 Hz).

¹³ C NMR (CDCl ₃ , 75 MHz) δ 173.9, 170.9, 153.4, 149.5, 144.3, 139.9, 135.3, 129.1, 127.9, 125.8, 124.8, 122.7, 121.7, 104.6, 61.9, 60.6, 56.7, 56.3, 55.0, 37.1 , 35.2, 28.4, 22.4.

Example 5. 2- (4- (2-chlorobenzoyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl Methyl) acetamide

2- (1,4-diazepane-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acetamide in 3 mL of tetrahydrofuran (44 mg, 0.12 mmol) in triethylamine (TEA; 50 μL, 0.36 mmol) was added thereto, followed by stirring. 2-chlorobenzoyl chloride (20 μL, 0.15 mmol) was added thereto, followed by stirring for 2 hours. After completion of the reaction, the mixture was washed with H ₂ O and extracted with dichloromethane. The organic layer was dried over anhydrous MgSO ₄ , filtered, concentrated under reduced pressure and purified to give 52 mg (86%) of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.70-7.62 (m, 1H), 7.47-7.24 (m, 9H), 6.12 (d, 1H, J = 12.65 Hz), 4.51 (q, 2H, J = 5.63 Hz), 3.83-7.78 (m, 2H), 3.33-3.25 (m, 2H), 3.23 (s, 1H), 3.18 (s, 1H), 2.91-2.47 (m, 6H), 2.00-1.74 (m, 3H), 0.85 (q, 6H, J = 3.53 Hz).

¹³ C NMR (CDCl ₃ , 75 MHz) δ 170.2, 168.2, 149.3, 144.4, 139.8, 136.4, 130.1, 129.7, 129.1, 128.0, 127.5, 127.1, 125.6, 106.4, 61.8, 57.3, 56.3, 56.0, 54.9, 49.3 , 47.8, 45.3, 44.4, 37.1, 35.2, 28.3, 27.0, 22.4.

Example 6. N - ((5- isobutyl-1-phenyl -1 H - pyrazol-3-yl) methyl) -2- (4- (3- (triple) benzoyl) -1,4 -Diazepan-1-yl) acetamide

In the same manner as in Example 3, 2- (1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acet Amide (50 mg, 0.12 mmol), TEA (56 μL, 0.41 mmol), 3- (trifluoromethyl) benzoyl chloride (27 μL, 0.18 mmol) was used to give 53 mg (73%) of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.70-7.35 (m, 9H), 6.11 (d, 1H, J = 9.79 Hz), 4.50 (q, 2H, J = 5.55 Hz), 4.10 (d, 2H, J = 5.63 Hz), 3.47-3.36 (m, 2H), 3.20 (d, 2H, J = 15.58 Hz), 2.90-2.68 (m, 4H), 2.48 (d, 2H, J = 7.08 Hz), 1.98- 1.76 (m, 3 H), 0.82 (q, 6 H, J = 3.35 Hz).

¹³ C NMR (CDCl ₃ , 75 MHz) δ 170.1, 170.0, 149.3, 144.4, 139.8, 137.3, 130.0, 129.1, 128.1, 126.2, 125.6, 123.7, 104.5, 61.7, 57.7, 56.3, 55.7, 55.0, 50.0, 4837 , 46.3, 45.4, 37.0, 35.1, 28.7, 28.4, 26.7, 22.4.

Example 7. 2- (4- (4-fluorobenzoyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazole-3- (1) methyl) acetamide

In the same manner as in Example 3, 2- (1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acet Amide (66 mg, 0.18 mmol), TEA (74 μL, 0.54 mmol), 4-fluorobenzoyl chloride (27 μL, 0.23 mmol) gave 54 mg (69%) of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.71-7.65 (m, 1H), 7.47-7.29 (m, 7H), 7.06-7.00 (m, 2H), 6.10 (d, 1H, J = 9.11 Hz), 4.50 (q, 2H, J = 5.58 Hz), 3.72 (bs, 2H), 3.40 (t, 2H, J = 6.20 Hz), 3.18 (d, 2H, J = 15.86 Hz), 2.86-2.67 (m, 4H ), 2.47 (d, 2H, J = 9.52 Hz), 1.94-1.75 (m, 3H), 0.83 (d, 6H, J = 6.46 Hz).

¹³ C NMR (CDCl ₃ , 75 MHz) δ 170.7, 170.3, 149.4, 144.4, 139.8, 132.6, 128.9, 128.0, 125.7, 115.7, 104.8, 61.6, 57.6, 56.3, 55.7, 54.9, 50.0, 48.8, 46.2, 45.4 , 37.0, 35.1, 28.8, 28.3, 26.8, 22.4.

Example 8. N - ((5- isobutyl-1-phenyl -1 H - pyrazol-3-yl) methyl) -2- (4- (phenylsulfonyl ponnil) -1,4-diamine-1-printing plate Acetamide

In the same manner as in Example 3, 2- (1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acet Amide (59 mg, 0.16 mmol), TEA (66 μL, 0.47 mmol) and benzenesulfonyl chloride (26 μL, 0.21 mmol) were used to give 69 mg (86%) of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.73-7.31 (m, 11H), 6.09 (s, 1H), 4.47 (d, 2H, J = 5.63 Hz), 3.34-3.28 (m, 4H), 3.15 ( s, 2H), 2.76-2.69 (m, 4H), 2.46 (d, 2H, J = 7.18 Hz), 1.83-1.73 (m, 3H), 0.82 (d, 6H, J = 6.61 Hz).

¹³ C NMR (CDCl ₃ , 75 MHz) δ 170.2, 149.3, 144.4, 139.8, 139.1, 132.5, 129.1, 128.0, 126.9, 125.6, 104.6, 61.4, 57.2, 55.0, 48.4, 47.1, 37.0, 35.1, 28.3, 22.4 .

Example 9. N - ((5- isobutyl-1-phenyl -1 H - pyrazol-3-yl) methyl) -2- (4- (2- (triple) ponnil phenylsulfonyl) -1 , 4-diazepan-1-yl) acetamide

In the same manner as in Example 3, 2- (1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acet Amide (57 mg, 0.15 mmol), TEA (64 μL, 0.46 mmol), 2- (trifluoromethyl) benzene-1-sulfonyl chloride (49 mg, 0.20 mmol) was used to give 73 mg (82%) of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.99-7.32 (m, 10H), 6.12 (s, 1H), 4.50 (d, 2H, J = 5.60 Hz), 3.44-3.38 (m, 4H), 3.22 ( s, 2H), 2.81 (t, 2H, J = 5.37 Hz), 2.47 (d, 2H, J = 7.18 Hz), 1.95-1.74 (m, 3H), 0.83 (d, 6H, J = 6.62 Hz).

¹³ C NMR (CDCl ₃ , 75 MHz) δ 170.3, 149.4, 144.4, 139.7, 138.9, 132.4, 131.1, 129.0, 128.5, 128.0, 127.6, 125.7, 104.6, 61.8, 57.7, 55.4, 49.0, 47.3, 37.1, 35.1 , 28.7, 28.3, 22.3.

Example 10. 2- (4- (4-fluorophenylsulfonyl) -diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) Methyl) acetamide

In the same manner as in Example 3, 2- (1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acet Amide (55 mg, 0.15 mmol), TEA (62 μL, 0.44 mmol), 4-fluorobenzene-1-sulfonyl chloride (38 mg, 0.19 mmol) was used to give 66 mg (85%) of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.75-7.12 (m, 10H), 6.10 (s, 1H), 4.48 (d, 2H, J = 5.62 Hz), 3.34-3.28 (m, 4H), 3.16 ( s, 2H), 2.77-2.71 (m, 4H), 2.47 (d, 2H, J = 7.18 Hz), 1.84-1.74 (m, 3H), 0.83 (d, 6H, J = 6.62 Hz).

¹³ C NMR (CDCl ₃ , 75 MHz) δ 170.2, 166.6, 163.3, 149.3, 144.4, 139.9, 135.3, 129.6, 129.1, 128.0, 125.6, 116.5, 104.661.5, 57.2, 55.1, 48.5, 47.1, 37.0, 35.2 , 28.4, 22.4.

Example 11. N - ((5- isobutyl-1-phenyl -1 H-pyrazol-3-yl) methyl) -2- (4 - ((6-Methyl-2-yl) methyl) -1,4-diazepan-1-yl) acetamide

In the same manner as in Example 1, 2- (chloromethyl) -6-methylbenzooxazole (25 mg, 0.14 mmol), EDIPA (65 μL, 0.37 mmol), 2- (1,4-diazepane-1 66 mg (93%) of the target compound were obtained using -yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acetamide (60 mg, 0.16 mmol). Got it.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.75 (bs, 1H), 7.56 (d, 1H, J = 8.09 Hz), 7.47-7.31 (m, 6H), 7.13 (d, 1H, J = 8.09 Hz) , 6.12 (s, 1H), 4.51 (d, 2H, J = 5.57 Hz), 3.91 (s, 2H), 3.19 (s, 2H), 2.95-2.76 (m, 8H), 2.50-2.48 (m, 5H ), 1.83-1.75 (m, 3H), 0.84 (d, 6H, J = 6.59 Hz).

¹³ C NMR (CDCl ₃ , 75 MHz) δ 170.9, 163.3, 151.2, 149.5, 144.3, 139.9, 138.7, 135.4, 129.1, 127.9, 125.7, 119.3, 110.8, 104.6, 62.0, 56.1, 55.2, 54.1, 37.0, 35.2 , 28.3, 27.7, 22.4, 21.7.

Example 12. N-tert-butyl-2- (4- (2 - ((5-isobutyl-1-phenyl -1 H-pyrazol-3-yl) methyl) -2-oxoethyl) -1 , 4-diazepan-1-yl) acetamide

In the same manner as in Example 1, 2-bromo- N - tert -butylacetamide (49 mg, 0.25 mmol), EDIPA (131 μL, 0.75 mmol), 2- (1,4-diazepane-1- 83) (69%) of the title compound was obtained using yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acetamide (120 mg, 0.32 mmol). .

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.72 (bs, 1H), 7.47-7.33 (m, 5H), 7.03 (bs, 1H), 6.09 (s, 1H), 4.49 (d, 2H, J = 5.51 Hz), 3.16 (s, 2H), 2.90 (s, 2H), 2.76-2.64 (m, 8H), 2.47 (d, 1H, J = 7.17 Hz), 1.84-1.71 (m, 3H), 1.31 (s , 9H), 0.82 (d, 6H, J = 6.62 Hz).

¹³ C NMR (CDCl ₃ , 75 MHz) δ 170.6, 169.8, 149.3, 144.3, 139.8, 129.0, 128.0, 125.6, 104.5, 62.8, 62.2, 56.8, 55.1, 54.7, 50.4, 37.1, 35.1, 28.8, 28.3, 28.1 , 22.3.

Example 13. N- (2,6-dimethylphenyl) -2- (4- (2-((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methylamino) -2- Oxoethyl) -1,4-diazepan-1-yl) acetamide

In the same manner as in Example 1, 2-bromo- N- (2,6-dimethylphenyl) acetamide (30 mg, 0.12 mmol), EDIPA (67 μL, 0.37 mmol), 2- (1,4- 56 mg (84%) using diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acetamide (60 mg, 0.16 mmol) ) The target compound was obtained.

¹ H NMR (CDCl ₃ , 300 MHz) δ 8.61 (bs, 1H), 7.76 (bs, 1H), 7.48-7.35 (m, 5H), 7.08 (s, 3H), 6.12 (s, 1H), 4.52 ( d, 2H, J = 5.45 Hz), 3.21 (d, 2H, J = 8.07 Hz), 2.94-2.78 (m, 8H), 2.49 (d, 1H, J = 7.17 Hz), 2.20 (s, 6H), 1.87-1.73 (m, 3 H), 0.85 (d, 6 H, J = 6.61 Hz).

¹³ C NMR (CDCl ₃ , 75 MHz) δ 170.5, 170.0, 149.3, 144.4, 139.9, 135.0, 133.7, 129.1, 128.3, 127.2, 125.7, 104.5, 62.4, 62.1, 57.4, 56.6, 55.2, 37.1, 35.2, 28.4 , 27.9, 22.4, 18.6.

Example 14 2- (4-((6-fluorobenzooxazol-2-yl) methyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl -1 H -pyrazol-3-yl) methyl) acetamide

In the same manner as in Example 1, 2- (chloromethyl) -6-fluorobenzoxazole (40 mg, 0.22 mmol), EDIPA (113 μL, 0.65 mmol), 2- (1,4-diazepane- 106 mg (94%) target compound using 1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acetamide (104 mg, 0.28 mmol) Got.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.74 (bs, 1H), 7.59 (q, 1H, J = 4.88 Hz), 7.44-7.31 (m, 5H), 7.20 (dd, 1H, J = 7.96, 2.39 Hz), 7.08-7.01 (m, 1H), 6.10 (s, 1H), 4.49 (d, 2H, J = 5.62 Hz), 3.89 (s, 2H), 3.17 (s, 2H), 2.86-2.73 (m , 8H), 2.46 (d, 2H, J = 7.19 Hz), 1.83-1.72 (m, 3H), 0.81 (d, 6H, J = 6.62 Hz).

¹³ C NMR (CDCl ₃ , 75 MHz) δ 170.8. 164.5, 162.2, 158.9, 150.8, 149.5, 144.3, 139.8, 137.2, 129.1, 127.9, 125.7, 120.3, 112.5, 104.7, 98.9, 62.0, 56.0, 55.2, 55.0, 54.0, 37.0, 35.1, 28.3, 27.7, 23.4.

Example 15. 2- (4- (3-fluorobenzoyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazole-3- (1) methyl) acetamide

In the same manner as in Example 5, 2- (1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acet TEA in Amide (59 mg, 0.16 mmol) (67 μL, 0.48 mmol) was added thereto, followed by stirring to obtain 72 mg (91%) of the title compound using 3-fluorobenzoyl chloride (25 μL, 0.21 mmol).

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.73-7.68 (m, 1H), 7.48-7.31 (m, 6H), 7.14-7.02 (m, 3H), 6.12 (d, 1H, J = 9.90 Hz), 4.51 (q, 2H, J = 5.59 Hz), 3.76-3.38 (m, 4H), 3.20 (d, 2H, J = 15.73 Hz), 2.89-2.65 (m, 4H), 2.48 (dd, 2H, J = 7.12, 2.14 Hz), 1.97-1.73 (m, 3H), 0.83 (q, 6H, J = 2.97 Hz).

¹³ C NMR (CDCl ₃ , 75 MHz) δ 170.3, 164.1, 160.8, 149.3, 144.4, 139.8, 138.5, 130.4, 129.1, 128.0, 125.6, 122.3, 116.6, 114.1, 104.6, 61.6, 57.8, 56.3, 55.7, 54.9 , 49.9, 48.6, 46.2, 45.3, 37.1, 35.1 28.7, 28.4, 26.7, 22.4.

Example 16. 2- (4- (3-Chlorobenzoyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl Methyl) acetamide

In the same manner as in Example 5, 2- (1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acet Amide (59 mg, 0.16 mmol), TEA (66 μL, 0.47 mmol), 3-chlorobenzoyl chloride (26 μL, 0.20 mmol) gave 58 mg (73%) of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.73-7.67 (m, 1H), 7.50-7.19 (m, 9H), 6.12 (d, 1H, J = 14.63 Hz), 4.51 (q, 2H, J = 5.63 Hz), 3.76-3.38 (m, 4H), 3.20 (d, 2H, J = 14.63 Hz), 2.90-2.68 (m, 4H), 2.50 (dd, 2H, J = 7.17, 2.21 Hz), 1.98-1.76 (m, 3H), 0.85 (q, 6H, J = 3.17 Hz).

¹³ C NMR (CDCl ₃ , 75 MHz) δ 182.7, 170.0, 144.4, 138.3, 134.6, 129.9, 129.1, 128.0, 126.8, 125.6, 124.7, 104.6, 61.6, 57.8, 56.3, 55.8, 55.0, 50.0, 48.6, 46.2 , 45.3, 37.1, 35.1, 28.7, 26.7, 22.4, 21.1.

Example 17. 2- (4- (3-Bromobenzoyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazole-3- (1) methyl) acetamide

In the same manner as in Example 5, 2- (1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acet Amide (75 mg, 0.20 mmol), TEA (85 μL, 0.61 mmol), 3-bromobenzoyl chloride (35 μL, 0.26 mmol) was used to give 87 mg (77%) of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.71-7.66 (m, 1H), 7.53-7.22 (m, 9H), 6.10 (d, 1H, J = 9.28 Hz), 4.51 (q, 2H, J = 5.62 Hz), 3.74-3.37 (m, 4H), 3.19 (d, 2H, J = 14.07 Hz), 2.87-2.65 (m, 4H), 2.50 (d, 2H, J = 7.11 Hz), 1.96-1.71 (m , 3H), 0.83 (dd, 6H, J = 6.52, 2.61 Hz).

¹³ C NMR (CDCl ₃ , 75 MHz) δ 170.2, 169.8, 149.3, 144.4, 139.8, 138.5, 132.5, 130.1, 129.7, 129.1, 128.0, 125.6, 125.2, 122.6, 104.6, 61.6, 57.7, 56.2, 22.7, 54.9 , 50.0, 48.6, 46.2, 45.3, 37.1, 35.1, 28.7, 28.3, 26.7, 22.4.

Example 18. N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) -2- (4- (4- (trifluoromethyl) benzoyl) -1,4 -Diazepan-1-yl) acetamide

In the same manner as in Example 5, 2- (1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acet Amide (67 mg, 0.18 mmol), TEA (75 μL, 0.54 mmol), 4- (trifluoromethyl) benzoyl chloride (35 μL, 0.23 mmol) was used to give 75 mg (77%) of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.71-7.33 (m, 10H), 6.12 (d, 1H, J = 10.06 Hz), 4.51 (q, 2H, J = 5.60 Hz), 3.78-3.35 (m, 4H), 3.20 (d, 2H, J = 17.87 Hz), 2.91-2.66 (m, 4H), 2.48 (dd, 2H, J = 7.13, 2.59 Hz), 2.01-1.74 (m, 3H), 0.83 (d , 6H, J = 4.07 Hz).

¹³ C NMR (CDCl ₃ , 75 MHz) δ 170.2, 170.1, 149.3, 144.4, 140.1, 129.1, 128.0, 127.0, 125.7, 104.6, 61.7, 57.6, 56.3, 55.6, 54.9, 49.8, 48.6, 46.2, 45.3, 37.0 , 35.1, 28.8, 28.3, 26.8, 22.4.

Example 19. 2- (4- (3,4-Dichlorobenzoyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazole- 3-yl) methyl) acetamide

In the same manner as in Example 5, 2- (1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acet Amide (83 mg, 0.22 mmol), TEA (100 μL, 0.67 mmol), 3,4-dichlorobenzoyl chloride (61 mg, 0.29 mmol) was used to give 97 mg (80%) of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.70-7.64 (m, 1H), 7.47-7.11 (m, 8H), 6.10 (d, 1H, J = 8.93 Hz), 4.49 (q, 2H, J = 5.63 Hz), 3.72-3.36 (m, 4H), 3.18 (d, 2H, J = 15.50 Hz), 2.86-2.67 (m, 4H), 2.46 (d, 2H, J = 7.11 Hz), 1.94-1.74 (m , 3H), 0.82 (dd, 6H, J = 6.56, 2.55 Hz).

¹³ C NMR (CDCl ₃ , 75 MHz) δ 170.0, 169.1, 149.3, 144.4, 139.8, 136.3, 133.8, 132.9, 130.6, 129.1, 128.0, 126.0, 125.6, 104.6, 61.6, 57.6, 56.3, 55.6, 54.9, 49.9 , 4837, 46.1, 45.4, 37.1, 35.1, 28.7, 28.3, 26.7, 22.4.

Example 20. 2- (4- (3,5-Dichlorobenzoyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazole- 3-yl) methyl) acetamide

In the same manner as in Example 5, 2- (1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acet Amide (70 mg, 0.19 mmol), TEA (79 μL, 0.57 mmol) and 3,5-dichlorobenzoyl chloride (33 μL, 0.25 mmol) gave 60 mg (59%) of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.73-7.67 (m, 1H), 7.48-7.34 (m, 6H), 7.21 (dd, 1H, J = 12.06, 1.67 Hz), 6.11 (d, 1H, J = 8.43 Hz), 4.51 (t, 2H, J = 5.82 Hz), 3.73-3.37 (m, 4H), 3.21 (d, 2H, J = 11.96 Hz), 2.88-2.68 (m, 4H), 2.49 (d , 2H, J = 7.08 Hz), 1.96-1.77 (m, 3H), 0.84 (dd, 6H, J = 6.55, 2.20 Hz).

¹³ C NMR (CDCl ₃ , 75 MHz) δ 170.1, 168.5, 149.1, 144.4, 139.8, 139.2, 135.4, 129.5, 129.1, 128.0, 125.6, 125.1, 104.5, 61.6, 57.7, 56.2, 55.7, 55.0, 50.0, 48.6 , 46.2, 45.3, 37.1, 28.6, 28.4, 26.6, 22.4.

Example 21. 2- (4- (3-fluorophenylsulfonyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazole- 3-yl) methyl) acetamide

In the same manner as in Example 5, 2- (1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acet Amide (71 mg, 0.19 mmol), TEA (80 μL, 0.58 mmol), 3-fluorobenzene-1-sulfonyl chloride (33 μL, 0.25 mmol) was used to give 87 mg (86%) of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.52-7.51 (m, 1H), 7.48-7.27 (m, 9H), 6.12 (s, 1H), 4.49 (d, 2H, J = 5.60 Hz), 3.36- 3.31 (m, 4H), 3.19 (s, 2H), 2.80-2.74 (m, 4H), 2.48 (d, 2H, J = 7.16 Hz), 1.87-1.75 (m, 3H), 0.84 (d, 6H, J = 6.61 Hz).

¹³ C NMR (CDCl ₃ , 75 MHz) δ 170.0, 164.1, 149.3, 144.4, 139.8, 130.9, 129.1, 128.0, 125.6, 122.6, 119.8, 114.4, 104.5, 61.5, 57.3, 55.0, 48.5, 47.2, 37.0, 35.1 , 28.3, 28.1, 22.4.

Example 22. 2- (4- (3-Chlorophenylsulfonyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazole-3 -Yl) methyl) acetamide

In the same manner as in Example 5, 2- (1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acet Amide (78 mg, 0.21 mmol), TEA (88 μL, 0.63 mmol), 3-chlorobenzene-1-sulfonyl chloride (38 μL, 0.27 mmol) was used to give 94 mg (82%) of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.73-7.72 (m, 1H), 7.62-7.33 (m, 9H), 6.11 (s, 1H), 4.49 (d, 2H, J = 5.60 Hz), 3.36- 3.30 (m, 4H), 3.19 (s, 2H), 2.80-2.74 (m, 4H), 2.48 (d, 2H, J = 7.17 Hz), 1.87-1.75 (m, 3H), 0.84 (d, 6H, J = 6.62 Hz).

¹³ C NMR (CDCl ₃ , 75 MHz) δ 170.1, 149.3, 144.4, 139.8, 135.3, 132.6, 130.5, 129.1, 128.0, 126.9, 125.6, 125.0, 104.5, 61.4, 57.3, 55.0, 48.5, 47.2, 37.0, 35.1 , 28.3, 28.1, 22.4.

Example 23. N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) -2- (4- (3- (trifluoromethyl) phenylsulfonyl) -1 , 4-diazepan-1-yl) acetamide

In the same manner as in Example 5, 2- (1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acet Amide (49 mg, 0.13 mmol), TEA (55 μL, 0.40 mmol), 3- (trifluoromethyl) benzene-1-sulfonyl chloride (28 μL, 0.17 mmol) was used to give 61 mg (79%) of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz) δ 8.00 (s, 1H), 7.91 (d, 1H, J = 7.85 Hz), 7.82 (d, 1H, J = 7.79 Hz), 7.66-7.32 (m, 7H) , 6.10 (s, 1H), 4.48 (d, 2H, J = 5.60 Hz), 3.37-3.31 (m, 4H), 3.18 (s, 2H), 2.81-2.74 (m, 4H), 2.47 (d, 2H , J = 7.18 Hz), 1.87-1.74 (m, 3H), 0.83 (d, 6H, J = 6.61 Hz).

¹³ C NMR (CDCl ₃ , 75 MHz) δ 170.0, 149.3, 144.4, 140.6, 139.8, 132.0, 131.6, 130.0, 129.1, 128.0, 125.6, 125.0, 123.9, 104.6, 61.4, 57.3, 55.0, 48.5, 47.2, 37.0 , 35.1, 28.3, 28.1, 22.4.

Example 24. 2- (4- (2,4-Difluorophenylsulfonyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H- Pyrazol-3-yl) methyl) acetamide

In the same manner as in Example 5, 2- (1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acet Amide (51 mg, 0.14 mmol), TEA (58 μL, 0.41 mmol), 2,4-difluorobenzene-1-sulfonyl chloride (24 μL, 0.18 mmol) was used to give 60 mg (79%) of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.86-7.64 (m, 2H), 7.45-7.32 (m, 5H), 6.97-6.87 (m, 2H), 6.11 (s, 1H), 4.48 (d, 2H , J = 5.60 Hz), 3.42-3.34 (m, 4H), 3.19 (s, 2H), 2.79-2.75 (m, 4H), 2.47 (d, 2H, J = 7.17 Hz), 1.87-1.74 (m, 3H), 0.82 (d, 6H, J = 6.62 Hz).

¹³ C NMR (CDCl ₃ , 75 MHz) δ 170.2, 149.3, 144.4, 139.8, 132.7, 129.1, 128.0, 125.6, 111.9, 111.6, 106.0, 105.7, 105.4, 104.6, 61.5, 57.5, 55.2, 48.4, 46.9, 37.0 , 35.1, 28.3, 22.4.

Example 25. 2- (4- (3,4-Dimethoxyphenylsulfonyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H- Pyrazol-3-yl) methyl) acetamide

In the same manner as in Example 5, 2- (1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acet Amide (50 mg, 0.14 mmol), TEA (57 μL, 0.41 mmol), 3,4-dimethoxybenzene-1-sulfonyl chloride (42 mg, 0.18 mmol) was used to give 58 mg (75%) of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.62-7.60 (m, 1H), 7.45-7.30 (m, 6H), 7.19 (d, 1H, J = 1.09 Hz), 6.88 (d, 1H, J = 8.47 Hz), 6.10 (s, 1H), 4.47 (d, 2H, J = 5.59 Hz), 3.89 (d, 6H, J = 9.72 Hz), 3.34-3.28 (m, 4H), 3.15 (s, 2H), 2.76-2.70 (m, 4H), 2.46 (d, 2H, J = 7.18 Hz), 1.84-1.73 (m, 3H), 0.81 (dd, 6H, J = 6.61, 0.61 Hz).

¹³ C NMR (CDCl ₃ , 75 MHz) δ 170.2, 152.4, 149.4, 144.4, 139.8, 130.9, 129.1, 128.0, 125.6, 120.7, 110.6, 109.6, 104.6, 61.3, 57.2, 56.2, 55.0, 48.3, 47.1, 37.0 , 35.1, 28.3, 28.0, 22.4.

Example 26. N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) -2- (4- (2,4,5-trichlorophenylsulfonyl) -1 , 4-diazepan-1-yl) acetamide

In the same manner as in Example 5, 2- (1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acet Amide (50 mg, 0.14 mmol), TEA (57 μL, 0.41 mmol), 2,4,5-trichlorobenzene-1-sulfonyl chloride (50 mg, 0.18 mmol) was used to give 76 mg (92%) of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz) δ 8.11 (s, 1H), 7.69-7.72 (m, 1H), 7.58 (s, 1H), 7.46-7.32 (m, 5H), 6.11 (s, 1H), 4.50 (d, 2H, J = 5.56 Hz), 3.46-3.35 (m, 4H), 3.21 (s, 2H), 2.82-2.78 (m, 4H), 2.47 (d, 2H, J = 7.16 Hz), 1.94 -1.74 (m, 3H), 0.83 (d, 6H, J = 6.61 Hz).

¹³ C NMR (CDCl ₃ , 75 MHz) δ 170.2, 149.3, 144.4, 139.8, 137.6, 137.1, 133.2, 131.7, 130.5, 129.0, 128.0, 125.6, 104.6, 61.8, 57.6, 55.4, 49.0, 47.2, 37.1, 35.2 , 28.6, 22.4.

Example 27 2- (4 - ((2,2-dimethyl-tetrahydro -2 H - Failan 4-yl) methyl) -1,4-dia plate making 1-yl) - N - ((5- Isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acetamide

As in Example 3 in the same manner using 2,2-dimethyl-tetrahydro -2 H-carbazol-4-Failan aldehyde (16 mg, 0.11 mmol), 2- (1,4- diamond plate making 1-yl) - N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acetamide (54 mg, 0.15 mmol), NaBH (OAc) ₃ (72 mg, 0.34 mmol) 33 mg (60%) of the title compound were obtained.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.80-7.77 (m, 1H), 7.48-7.36 (m, 5H), 6.12 (s, 1H), 4.50 (d, 2H, J = 4.19 Hz), 3.74- 3.57 (m, 2H), 3.18 (s, 2H), 2.76-2.55 (m, 7H), 2.48 (d, 2H, J = 5.39 Hz), 2.23 (bs, 2H), 1.85-1.75 (m, 4H) , 1.59 (t, 2H, J = 11.67 Hz), 0.19 (d, 6H, J = 6.89 Hz). 1.10-0.94 (m, 2H), 0.84 (d, 6H, J = 4.96 Hz).

¹³ C NMR (CDCl ₃ , 75 MHz) δ 170.1, 149.5, 144.3, 139.9, 129.1, 128.0, 125.7, 104.7, 71.6, 65.0, 61.9, 61.4, 56.1, 55.0, 54.4, 42.0, 37.1, 35.2, 31.7, 31.4 , 29.7, 28.4, 22.4, 21.9.

Example 28. N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) -2- (4-((4-methyl-5-propyloxazol-2-yl ) Methyl) -1,4-diazepan-1-yl) acetamide

In the same manner as in Example 1, 2- (chloromethyl) -4-phenyl-5-propyloxazole (27 mg, 0.11 mmol), EDIPA (59 μL, 0.34 mmol), 2- (1,4-diaza 56 mg (98%) using jepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acetamide (54 mg, 0.15 mmol) The desired compound was obtained.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.79-7.75 (m, 1H), 7.63-7.28 (m, 10H), 6.12 (s, 1H), 4.50 (d, 2H, J = 5.68 Hz), 3.77 ( s, 2H), 3.19 (s, 2H), 2.85-3.75 (m, 10H), 2.47 (d, 2H, J = 7.17 Hz), 1.83-1.69 (m, 5H), 0.97 (t, 3H, J = 7.35 Hz), 0.83 (d, 6H, J = 6.61 Hz).

¹³ C NMR (CDCl ₃ , 75 MHz) δ 170.8, 159.5, 149.6, 148.3, 144.3, 139.9, 134.4, 132.3, 129.1, 128.5, 1279, 127.3, 126.8, 125.7, 104.7, 62.0, 56.1, 55.1, 54.9, 54.6 , 53.9, 37.0, 35.2, 28.3, 27.8, 22.4, 21.6, 13.8.

Example 29. N- (tricyclo [3.3.1.1 (3,7)] decane) -2- (4- (2-((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl ) Methylamino) -2-oxoethyl) -1,4-diazepan-1-yl) acetamide

In the same manner as in Example 1, 2-bromo- N- (tricyclo [3.3.1.1 (3,7)] decane) acetamide (31 mg, 0.11 mmol), EDIPA (60 μL, 0.34 mmol) , 2- (1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acetamide (55 mg, 0.15 mmol) To obtain 56 mg (88%) of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.76-7.73 (m, 1H), 7.48-7.34 (m, 5H), 6.94 (bs, 1H), 6.10 (s, 1H), 4.49 (d, 2H, J = 5.51 Hz), 3.18 (s, 2H), 2.90 (s, 2H), 2.77-2.65 (m, 8H), 2.48 (d, 2H, J = 7.18 Hz), 2.05 (bs, 3H), 1.95 (d , 6H, J = 2.62 Hz), 1.83-1.72 (m, 3H), 1.66 (s, 6H), 0.83 (d, 6H, J = 6.61 Hz).

¹³ C NMR (CDCl ₃ , 75 MHz) δ 170.6, 169.4, 149.3 144.3, 139.8, 129.1, 128.0, 125.6, 104.5, 62.9, 62.2, 56.9, 55.1, 51.1, 41.7, 37.1, 36.3. 35.1, 29.4, 28.4, 28.1, 22.4.

[Example]

On the other hand, the novel compound represented by Formula 1 according to the present invention can be formulated in various forms according to the purpose. The following is a description of some formulations containing the compound of Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

Formulation 1: tablet (direct pressure)

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.

Formulation 2: Tablet (Wet Granulation)

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 pressed into tablets.

Formulation 3: Powders and Capsules

5.0 mg of the active ingredient was sieved, followed by mixing with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. The mixture was filtered through a hard No. Filled in 5 gelatin capsules.

Formulation 4: Injection

Injectables were prepared by containing 100 mg as the active ingredient, followed by the addition of 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ .12H ₂ O and 2974 mg of distilled water.

[Experimental Example]

Meanwhile, the novel compounds represented by Formula 1 according to the present invention were tested for their antagonistic action on T-type calcium channels as shown in the following Experimental Examples. As a result of the experiment,% inhibition of T-type calcium channel was determined using FDSS6000, and IC ₅₀ was calculated using an automatic patch clamp mainly on some compounds showing excellent activity.

Experimental Example 1: Detection of T-type calcium channel activity using FDSS6000

The α1G T-type calcium channel and Kir2.1 were cultured in a 96-well plate (Titertek product) in a 96-well plate treated with poly-L-lysine (0.05 mg / Cells of HEK293 cell line (α1G cell line: KCTC 10519BP, Korea Research Institute of Bioscience and Biotechnology) were stably distributed at a density of 4 × 10 ⁴ cells / well. Cells attached to the 96-well plate on the day of the experiment were washed with HEPES buffer (150 mM NaCl, 5 KCl, 1 MgCl ₂ , 2 CaCl ₂ , 10 HEPES, 10 mM) using a 96-well plate automatic washing machine Glucose, pH 7.4), and then reacted in a HEPES buffer solution containing 5 μM fluoro-3 / AM and 0.001% Pluronic F-127 at room temperature for 1 hour to be labeled with a fluorescent dye And washed twice again with HEPES buffer solution. It was then washed once with HEPES buffer containing 10 mM CaCl ₂ and adjusted to a final volume of 81 μL 10 minutes before measuring the FDSS6000 instrument. Apart from the 96-well plates in which the cells were prepared, two 96-well drug plates were prepared to contain KCl (final concentration 75 mM) and blocker drug to activate T-type calcium channels. Most cell-based HTS devices have a liquid application system for drug injection, but since there is no liquid suction system, 27 μL of the blocking agent and KCl to be searched in 5 mM CaCl ₂ HEPES buffer Lt; RTI ID = 0.0 > 135 < / RTI > Specific FDSS6000 measurement conditions were a change in intracellular calcium concentration, which was changed by KCl administration after drug pretreatment for 75 seconds after recording the reference value of 20 seconds. The area of the 340/380 ratio value in the control group not treated with the test substance Was 100%, and the inhibitory effect of the test substance on the percentage (%) was obtained. Mibefradil of 10 μM was always used as the reference drug.

As a detailed calcium imaging technique, the excitation wavelengths (340 nm and 380 nm) were selectively exposed to cells by a computer-controlled filter wheel in view of four light sources of xenon lamps mounted on the FDSS6000. Data were collected every 1.23 seconds and the emitter fluorescence light passing through a 515 nm long-pass filter passed through a cooled CCD camera embedded in the instrument and passed through a 96-well Lt; RTI ID = 0.0 > 340/380 < / RTI > All image data and analysis were performed using a program dedicated to FDSS6000 provided by Hamamatsu Photonics.

The% inhibition rate of calcium migration of T-type calcium channels of the novel compounds according to the present invention is shown in Table 1 below.

Test Example 2: hERG potassium ion channel inhibitory effect test

HEK-hERG cell lines stably expressing hERG (IonGate Biosciences, Frankfurt, Germany) were subjected to 10% fetal bovine serum (FBS) in DMEM (Dulbecco's Modified Eagle's Medium, Sigma, St. Louis, MO, USA). , Cambrex, Walkersville, MD, USA) and 0.5 mg / mL zeocin (zeocin, Invitrogen, Carlsbad, Calif., USA) were added and cultured. All cell lines used were subcultured after covering the culture flask for about 80% after 5 days of culture.

The composition of the solution in the electrode used for the measurement of potassium ion current was 115 mM K-aspartate, 20 mM KCl, 10 mM EGTA, 10 mM HEPES, 2.5 mM tris-phosphocreatine. , 0.1 mM Na ₂ GTP and 5 mM MgCl ₂ (pH 7.2, 290 mOsm / Kg H ₂ O), and the composition of the extracellular perfusate was 135 mM NaCl, 5 mM KCl, 1 mM MgCl ₂ , 2 mM CaCl ₂ , 10 mM glucose, and 10 mM HEPES (pH 7.2, 300 mOsm / Kg H ₂ O).

Test compounds were used diluted to the desired concentration with extracellular perfusate. The drug was applied by gravity by placing the capillary tip for gas chromatography connected with a 7-array polyethylene tube within 100 μm of the HEK-hERG cell line.

The potassium ion current was measured using a typical whole-cell patch clamp method using an EPC10 (Instrutech Co., NY, USA) patch clamp amplifier. In addition, as an electrode, borosilicate glass capillary (outer diameter: 1.65 mm, inner diameter: 1.2 mm, Corning 7052, Garner Glass Co., Claremont, CA, USA) was used as a P-97 flaming-brown micropipette puller (P -97 Flaming-Brown micropipette puller, manufactured by Sutter Instrument Co.) was used. The electrode was coated with Sealgard 184 (Sylgard 184, Dow Corning, Midland, MI, USA), trimmed with micropurge (microforge, Narishige, Tokyo, Japan), and the resistance was 2 to 2 when the solution was filled in the electrode. 3 kPa was used. A culture dish containing cells was placed on an inverted microscope (Nikon Corporation), and the extracellular perfusate containing the test compound was perfused at a rate of 1-2 mL / min. The membrane capacitance and series resistance were corrected for more than 80%. The sampling rate was 2 kHz, and the low pass filter was 2 kHz (-3 dB; 8). Potassium ion current was measured using a -pole Bassel filter. All experiments were conducted at room temperature (21-24 ° C).

Experimental results were analyzed using Pulse / Pulsefit (v9.0, HEKA Elcktronik, Lambrecht, Germany) and Igor macros. All results are expressed as mean ㅁ standard error. The concentration response curve was calculated by the Hill formula [Block = (1 + IC ₅₀ / [drug] ⁿ ) ^-1 ] to calculate the concentration (IC ₅₀ ) that suppresses the ion current by 50%. The results are shown in Table 1 below.

Experimental compound FDSS a _1G FDSS a _1H hERG IC ₅₀ (μM) 10 μM 1 [mu] M 10 μM 1 [mu] M Compound number 1 78.23 10.88 79.42 11.08 3.53 ± 1.13 Compound number 2 68.43 2.94 71.38 29.71 1.31 ± 0.45 Compound number 3 55.78 18.44 50.41 9.27 Compound number 4 69.38 9.55 64.48 6.1 1.00 ± 0.15 Compound number 5 68.99 11.74 61.08 3.59 12.25 ± 0.86 Compound number 6 76.57 7.19 73.54 4.05 4.43 ± 0.94 Compound No. 7 71.19 11.26 65.44 6.3 3.63 ± 1.44 Compound number 8 84.04 12.57 74.39 12.35 7.24 ± 1.56 Compound number 9 52.51 11.22 48.08 9.73 Compound number 10 74.20 24.35 77.21 21.13 3.80 ± 1.45 Compound number 11 77.97 18.05 71.15 14.01 0.97 ± 0.25 Compound number 12 49.58 21.11 60.93 18.1 3.00 ± 0.59 Compound number 13 69.02 15.01 67.12 20.87 3.48 ± 1.11 Compound number 14 79.76 16.8 79.17 16.24 0.78 ± 0.14 Compound number 15 76.13 17.2 69.79 10.06 3.47 ± 0.87 Compound number 16 83.03 19.47 70.1 15.67 2.33 ± 0.26 Compound number 17 77.11 12.27 71.01 8.5 2.27 ± 0.34 Compound no.18 86.70 12.68 73.89 4.94 1.37 ± 0.09 Compound number 19 87.74 23.35 79.27 23.34 2.82 ± 0.25 Compound number 20 82.13 24.32 77.56 18.16 2.33 ± 0.21 Compound number 21 81.60 28.79 76.28 20.36 2.71 ± 0.21 Compound number 22 62.14 16.56 56.2 17.74 Compound number 23 54.13 15.03 47.62 21.12 Compound number 24 75.43 11.43 69.82 20.53 4.60 ± 0.61 Compound number 25 68.88 16.32 73.36 16.61 5.87 ± 1.25 Compound number 26 16.71 2.98 16.57 17.89 Compound number 27 32.23 7.08 36.94 19.84 Compound number 28 77.94 14.05 69.45 19.57 0.23 ± 0.02 Compound number 29 82.53 24.47 80.95 23.28 1.40 ± 0.25 mibefradil 81.00 - 76.00 - 1.40 ± 0.29

Claims (5)

A compound characterized in that it is selected from 1,4-diazepan pyrazole compound represented by the following formula (1) and a pharmaceutically acceptable salt thereof:
[Formula 1]

In Chemical Formula 1,
R ¹ is a C ₁ -C ₆ alkyl group, a C ₅ -C ₁₆ cycloalkyl group, R ^3- (CH ₂ ) _n -where n is an integer of 0, 1, 2, or 3, or

(Where m is an integer of 0, 1, 2, or 3 in the number of substituents),
R ² represents a C ₁ -C ₆ alkyl group,
R ³ is selected from a C ₁ -C ₆ alkyl group, a 5-10 membered heterocycloalkyl group containing 1 to 2 oxygen atoms (O), or an oxygen atom (O), a sulfur atom (S), and a nitrogen atom (N) A heteroaromatic ring group of 5 to 15 membered monocyclic or fused ring form containing 1 to 4 selected heteroatoms, wherein the heterocycloalkyl or heteroaromatic ring is halo, C ₁ -C ₈ may be substituted or unsubstituted with 1 to 3 substituents selected from alkyl and phenyl,
R ⁴ represents a halogen atom, a C ₁ -C ₈ alkyl group, a C ₁ -C ₈ haloalkyl group, or a C ₁ -C ₈ alkoxy group,
X represents a single bond, -C (O)-, or -SO _2- .
The method of claim 1,
R ¹ is a methyl group, ethyl group, n -propyl group, isopropyl group, isobutyl group, tert -butyl group, 3,3-dimethylbutyl group, cyclohexyl group, adamantyl group, tetrahydropyranyl group, tetra Hydropyranylmethyl group, 2,2-dimethyl-tetrahydropyranylmethyl group, phenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2,6-dimethylphenyl group, phenylsulfonyl group, 2 -Chlorophenylsulfonyl group, 3-chlorophenylsulfonyl group, 4-chlorophenylsulfonyl group, 2,4,5-trichlorophenylsulfonyl group, 2-fluorophenylsulfonyl group, 3-fluorophenylsulfonyl group, 4- Fluorophenylsulfonyl group, 2,4-difluorophenylsulfonyl group, 2- (trifluoromethyl) phenylsulfonyl group, 3- (trifluoromethyl) phenylsulfonyl group, 4- (trifluoromethyl) phenyl Sulfonyl group, 2-methoxyphenylsulfonyl group, 3-methoxyphenylsulfonyl group, 4-methoxyphenylsulfonyl group, 3,4-dimethoxyphenylsulfonyl group, benzoyl group, 2- Chlorobenzoyl group, 3-chlorobenzoyl group, 4-chlorobenzoyl group, 3,4-dichlorobenzoyl group, 3,5-dichlorobenzoyl group, 2-fluorobenzoyl group, 3-fluorobenzoyl group, 4- Florobenzoyl group, 2-bromobenzoyl group, 3-bromobenzoyl group, 4-bromobenzoyl group, 2- (trifluoromethyl) benzoyl group, 3- (trifluoromethyl) benzoyl, 4- ( Trifluoromethyl) benzoyl group, oxazol-2-yl group, (oxazol-2-yl) methyl group, (4-phenyl-5-propyloxazol-2-yl) methyl group, benzoxazol-2-yl group, (Benzoxazol-2-yl) methyl group, (6-fluorobenzooxazol-2-yl) methyl group, (6-methylbenzooxazol-2-yl) methyl group, thiazol-2-yl group, thiazole- 2-ylmethyl group, benzo [ d ] thiazol-2-yl group, benzo [ d ] thiazol-2-ylmethyl group, imidazol-5-yl group, (imidazol-5-yl) methyl group, (2-phenyl- 1H -imidazol-5-yl) methyl group, benzoimidazol-5-yl group, ( 1H -benzoimidazol-5-yl) methyl group, or (2-phenyl- 1H -benzoimidazol-5-yl Methyl groups ,
Wherein R ² is methyl, ethyl, n - propyl group, an isopropyl group, an isobutyl group, or tert - butyl group to the compound according to claim.
The method of claim 1,
2- (4-(( 1H -Benzo [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acetamide,
N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) -2- (4-((2-phenyl-1 H -imidazol-5-yl) methyl)- 1,4-diazepan-1-yl) acetamide,
2- (4- (3,3-dimethylbutyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) Methyl) acetamide,
2- (4- (benzo [ d ] thiazol-2-yl) methyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazole -3-yl) methyl) acetamide,
2- (4- (2-chlorobenzoyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acet Amide,
N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) -2- (4- (3- (trifluoromethyl) benzoyl) -1,4-diazepan- 1-day) acetamide,
2- (4- (4-fluorobenzoyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) Acetamide,
N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) -2- (4- (phenylsulfonyl) -1,4-diazepan-1-yl) acetamide ,
N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) -2- (4- (2- (trifluoromethyl) phenylsulfonyl) -1,4-diaza Engraving-1--1-) acetamide,
2- (4- (4-fluorophenylsulfonyl) -diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acetamide ,
N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) -2- (4-((6-methylbenzooxazol-2-yl) methyl) -1,4 -Diazepan-1-yl) acetamide,
N - tert -butyl-2- (4- (2-((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methylamino) -2-oxoethyl) -1,4-dia Engraving-1--1-) acetamide,
N- (2,6-dimethylphenyl) -2- (4- (2-((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methylamino) -2-oxoethyl)- 1,4-diazepan-1-yl) acetamide,
2- (4-((6-fluorobenzooxazol-2-yl) methyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H- Pyrazol-3-yl) methyl) acetamide,
2- (4- (3-fluorobenzoyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) Acetamide,
2- (4- (3-chlorobenzoyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) acet Amide,
2- (4- (3-bromobenzoyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) Acetamide,
N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) -2- (4- (4- (trifluoromethyl) benzoyl) -1,4-diazepan- 1-day) acetamide,
2- (4- (3,4-Dichlorobenzoyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) Methyl) acetamide,
2- (4- (3,5-Dichlorobenzoyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) Methyl) acetamide,
2- (4- (3-fluorophenylsulfonyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) Methyl) acetamide,
2- (4- (3-chlorophenylsulfonyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl Acetamide,
N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) -2- (4- (3- (trifluoromethyl) phenylsulfonyl) -1,4-diaza Engraving-1--1-) acetamide,
2- (4- (2,4-Difluorophenylsulfonyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazole-3 -Yl) methyl) acetamide,
2- (4- (3,4-dimethoxyphenylsulfonyl) -1,4-diazepan-1-yl) -N -((5-isobutyl-1-phenyl-1 H -pyrazole-3 -Yl) methyl) acetamide,
N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) -2- (4- (2,4,5-trichlorophenylsulfonyl) -1,4-diaza Engraving-1--1-) acetamide,
2- (4 - ((2,2-dimethyl-tetrahydro -2 H - Failan 4-yl) methyl) -1,4-dia plate making 1-yl) - N - ((5- isobutyl -1 -Phenyl-1 H -pyrazol-3-yl) methyl) acetamide,
N -((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methyl) -2- (4-((4-methyl-5-propyloxazol-2-yl) methyl)- 1,4-diazepan-1-yl) acetamide,
N- (tricyclo [3.3.1.1 (3,7)] decane) -2- (4- (2-((5-isobutyl-1-phenyl-1 H -pyrazol-3-yl) methylamino) -2-oxoethyl) -1,4-diazepan-1-yl) acetamide, and
A compound selected from the group consisting of pharmaceutically acceptable salts thereof.
Treatment of brain diseases selected from epilepsy, depression, Parkinson's disease, dementia, sleep disorders comprising the compound of any one of claims 1 to 3, and For prevention; Cancer treatment; For the treatment and prevention of heart diseases selected from hypertensive, heart arrhythmia, angina pectoris, myocardial infarction, congestive heart failure; Or a pharmaceutical composition useful for pain relief agents selected from neuropathic pain, chronic and acute pain.
Reacting pyrazolemethylamine represented by Formula 2 with chloroacetyl chloride to prepare 2-chloro- N -pyrazoyl methyl acetamide represented by Formula 3;

(Wherein R ² is as defined in claim 1 above)
Reacting 2-chloro- N -pyrazoyl methyl acetamide represented by Chemical Formula 3 with 1,4-diazephan to prepare 1,4-diazepan pyrazole represented by Chemical Formula 4; And

(Wherein R ² is as defined in claim 1 above)
Preparing a 1,4-diazepane pyrazole compound represented by the following Chemical Formula 1 by reacting 1,4-diazepane pyrazole represented by the following Chemical Formula 4 with a compound represented by R ¹ -Y;

(In the above reaction scheme, R ¹ and R ² are each as defined in claim 1, and Y represents a halogen atom or an aldehyde group.)
Method for producing a 1,4-diazepan pyrazole compound comprising a.