KR101389374B1 - 5-(Substituted alkylaminomethyl)isoxazole derivatives as T-type calcium channel antagonists - Google Patents

Abstract

The present invention relates to a 5- (substituted alkylaminomethyl) isoxazole-based compound exhibiting pharmacological activity against T-type calcium channels, a pharmaceutically acceptable salt thereof, a process for producing these compounds, ≪ / RTI >

Description

5- (substituted alkylaminomethyl) isoxazole-based compounds as T-type calcium channel antagonists {5- (Substituted alkylaminomethyl) isoxazole derivatives as T-type calcium channel antagonists}

The present invention relates to a 5- (substituted alkylaminomethyl) isoxazole-based compound exhibiting pharmacological activity against T-type calcium channels, a pharmaceutically acceptable salt thereof, a process for producing these compounds, ≪ / RTI >

The calcium channel plays an important role in various signal transduction in cells by increasing the concentration of calcium by stimulation of neurons. These calcium channels are divided into a high-voltage activated calcium channel and a low-voltage activated calcium channel, and 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.

There have been many efforts to develop antagonists of T-type calcium channel so far, but selective T-type calcium channel antagonists are extremely rare. As a substance acting on the T-type calcium channel, Korean Patent Registration Nos. 784,195, 754,325 and 749743 disclose compounds having quinazoline as a basic skeleton structure, and Korean Patent No. 743,255 discloses a compound having 1,3 - dioxoisoindole as a basic skeleton structure.

However, it is still selective for T-type calcium channels and has good pharmacokinetic profiles, good epilepsy with good ADME (absorption, distribution, metabolism, and release); cancer; Heart disease such as hypertensive, deep arrhythmia, angina pectoris, myocardial infarction, congestive heart failure; There is a need for antagonists of T-type calcium channels that are effective in the treatment of pain disorders such as neuropathic pain, chronic and acute pain.

Korean Patent Registration No. 616,099 discloses a piperazinyl alkyl isoxazole compound in which an aromatic group such as phenyl or naphthalene is substituted at the 3-position of the isoxazole ring. However, the compound of the present invention relates to a novel compound in which an aliphatic alkyl group is substituted at the 3-position of the isoxazole ring, and it is an object of the present invention to provide a novel compound in which an aliphatic alkyl group is substituted at the 3- Has been improved.

The present invention provides a novel 5- (substituted alkylaminomethyl) isoxazole-based compound wherein an aliphatic alkyl group is substituted at the 3-position of a pentagonal ring of isoxazole, or a pharmaceutically acceptable salt thereof, .

The present invention also provides a pharmaceutical composition having a T-type calcium channel antagonistic action, wherein the 5- (substituted alkylaminomethyl) isoxazole-based compound or a pharmaceutically acceptable salt thereof is contained as an active ingredient There is another purpose.

The present invention also relates to a pharmaceutical composition for treating epilepsy, depression, Parkinson ' s disease, and the like, wherein the 5- (substituted alkylaminomethyl) isoxazole compound and a pharmaceutically acceptable salt thereof are contained as active ingredients, For the treatment and prevention of brain diseases selected from dementia and sleep disorder; For cancer treatment and prophylaxis; For the treatment and prevention of heart diseases selected from hypertensive, heart arrhythmia, angina pectoris, myocardial infarction, congestive heart failure; Or pain relievers selected from neuropathic pain, chronic and acute pain. ≪ Desc / Clms Page number 2 >

In order to achieve the above object, the present invention provides a 5- (substituted alkylaminomethyl) isoxazole-based compound represented by the following formula (1) exhibiting excellent pharmacological activity as a T-type calcium channel antagonist and as a pain relief agent, And salts thereof as possible.

In Formula 1,

에서

가 단일결합일 때 X는 N 또는 CH를 나타내고,

가 이중결합일 때 X는 C를 나타내고,

in

Is a single bond, X represents N or CH,

Is a double bond, X represents C,

Y represents N or CH,

R ¹ is a C ₁ -C ₆ alkyl group substituted or unsubstituted with 1 to 2 substituents selected from phenyl and halophenyl; Or a phenyl group substituted or unsubstituted with 1 to 4 substituents selected from halo, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, and C ₁ -C ₆ haloalkoxy Lt; / RTI >

R ² and R ³ are the same or different from each other, and represent a hydrogen atom; Or a C ₁ -C ₆ alkyl group,

를 나타내고, R ⁴ is a hydrogen atom; or

Lt; / RTI >

R ⁵ is a C ₁ -C ₆ alkyl group; ^{-C (O) NR 6 R 7} ; -C (O) OR < ⁸ >

R ⁶ and R ⁷ , which are the same or different from each other, are a hydrogen atom; Or a C ₁ -C ₆ alkyl group,

R ⁸ is a hydrogen atom; An alkali metal atom; Or a C ₁ -C ₆ alkyl group,

n represents an integer of 0 to 5;

FIG. 1 is a graph showing the 50% withdrawal threshold as a result of comparing the therapeutic effect of the compound of the present invention with the compound of the present invention, gabapentin and KST005468, respectively, in mechanical allodynia treatment.
FIG. 2 is a graph showing withdrawal latency (sec) as a result of comparing the effect of cold allodynia treatment with Compound No. 6 of the present invention and gabapentin and KST005468, respectively.
FIG. 3 is a graph showing withdrawal latency (sec) as a result of comparing the compound of the present invention with the compound of the present invention, gabapentin and KST005468, respectively, for the treatment of heat hyperalgesia.

The 5- (substituted alkylaminomethyl) isoxazole-based compound represented by Formula 1 according to the present invention may form a pharmaceutically acceptable salt by a conventional method in the art. For example, a non-toxic inorganic acid such as hydrochloric acid, hydrobromic acid, sulfonic acid, amidosulfuric acid, phosphoric acid, or nitric acid, or an acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, tartaric acid, citric acid, para toluenesulfonic acid, Together with non-toxic organic acids such as acids, to form salts with pharmaceutically acceptable acids.

The substituent used to define the 5- (substituted alkylaminomethyl) isoxazole-based compound represented by Formula 1 according to the present invention will be described in more detail as follows.

The term "alkyl group" includes both straight, branched and cyclic carbon chains having 1 to 6 carbon atoms, and preferred alkyl groups include methyl, ethyl, a tert -butyl group, a cyclopentyl group, and a cyclohexyl group. The term "haloalkyl group" includes straight chain, branched and cyclic carbon chains having 1 to 6 carbon atoms, including 1 to 13 halogen atoms such as fluoro, chloro, bromo and iodo, The alkyl group includes fluoromethyl, trifluoromethyl, 1,2-dichloroethyl, 1,1-dichloroethyl and pentafluoroethyl groups. "Alkoxy group" means an alkyl group of carbon linked to an oxygen, wherein alkyl is as defined above. "Haloalkoxy group" means an alkoxy group containing from 1 to 13 halogen atoms, such as fluoro, chloro, bromo, and iodo, wherein alkoxy is as defined above and the preferred haloalkoxy group is fluoromethoxy group , A trifluoromethoxy group, a 1,2-dichloroethoxy group, a 1,1-dichloroethoxy group, and a pentafluoroethoxy group.

In the 5- (substituted alkylaminomethyl) isoxazole-based compound represented by Formula 1, R ¹ is preferably a diphenylmethyl group, a di ( p -chlorophenyl) methyl group, a di ( p- a methyl group, a phenyl group, m - cyanophenyl group, m - group fluoro, p - fluorophenyl group, m - chloro phenyl, p - chlorophenyl group, a 3,4-dichlorophenyl group, 3,5-dichlorophenyl group, m - methylphenyl , p - methylphenyl, 3,4-dimethylphenyl group, 2,4-dimethylphenyl group, m - methoxyphenyl, p - methoxyphenyl, 3,4-dimethoxy-phenyl, m - trifluoromethyl-phenyl group, a p - Trifluoromethylphenyl group or a p -trifluoromethoxyphenyl group, R ² represents a hydrogen atom, R ³ represents a hydrogen atom, R ⁴ represents a hydrogen atom, isoxazol-5-ylmethyl group , 3-methylisoxazol-5-ylmethyl group, or 3-isopropylisoxazol-5-ylmethyl group, R ⁵ is methyl, ethyl, n-propyl, isopropyl, n-butyl group, isobutyl group, tert - in the case of a compound represents a butyl group, an amide group, a methyl carboxylate group, or sodium carboxylate.

Particularly preferred 5- (substituted alkylaminomethyl) isoxazole compounds represented by the above formula (1) are as follows.

Compound 1: [2- [4- (3-Chlorophenyl) -piperazin- 1-yl] -ethyl] - (3- methylisoxazol-

Compound 2: [2- [4- (3-Chlorophenyl) -piperazin-1-yl] -ethyl] - (3- ethylisoxazol-

Compound 3: [2- [4- (3-Chlorophenyl) -piperazin-l-yl] -ethyl] - (3- isopropylisoxazol-

Compound 4: [2- [4- (4-Chlorophenyl) -piperazin-l-yl] -ethyl] - (3-methylisoxazol-

Compound 5: [2- [4- (4-Chlorophenyl) -piperazin-1-yl] -ethyl] - (3- ethylisoxazol-

Compound 6: [2- [4- (4-Chlorophenyl) -piperazin- 1-yl] -ethyl] - (3- isopropylisoxazol-

Compound 7: [2- (4-Benzhydryl-piperazin-1-yl) ethyl] - (3- methylisoxazol-

Compound 8: [2- (4-Benzhydryl-piperazin-1-yl) ethyl] - (3- ethylisoxazol-

Compound 9: [2- (4-Benzhydryl-piperazin- 1-yl) ethyl] - (3- isopropylisoxazol-5-ylmethyl) amine

Compound 10: (3-Methylisoxazol-5-ylmethyl) - [2- (4-phenylpiperazin-1-yl) ethyl] amine

Compound 11: (3- ethylisoxazol-5-ylmethyl) - [2- (4-phenylpiperazin-1-yl) ethyl] amine

Compound 12: (3-Isopropylisoxazol-5-ylmethyl) - [2- (4-phenylpiperazin-1-yl) ethyl] amine

Compound 13: N - ((3-isopropylisoxazol-5-yl) methyl) -N -methyl-2- (4- (3- (trifluoromethyl) phenyl) piperazin- Amine

Compound 14: 2- (4- (2,4-dimethylphenyl) piperazin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) ethanamine

Compound 15: 2- (4- (2,4-dimethylphenyl) piperazin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) - N - methyl ethanamine

Compound 16: 2- (4- (4-chlorophenyl) piperazin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) - N - methyl ethanamine

Compound 17: N - ((3- tert -Butylisoxazol -5-yl) methyl) -2- (4- (4- chlorophenyl) piperazin-

Compound 18: N - ((3- tert - butyl-isoxazol-5-yl) methyl) -2- (4- (4-chlorophenyl) piperazin-1-yl) - N - methyl ethanamine

Compound 19: N - ((3- tert -Butylisoxazol -5-yl) methyl) -2- (4- (3- (trifluoromethyl) phenyl) piperazin-

Compound 20: N - ((3- tert -Butylisoxazol -5-yl) methyl) -N -methyl-2- (4- (3- (trifluoromethyl) phenyl) piperazin- Ethanamine

Compound 21: N - ((3- tert - Butylisoxazol -5-yl) methyl) -2- (4- (2,4-dimethylphenyl) piperazin-

Compound 22: 2- (4- (4-chlorophenyl) piperazin-1-yl) - N - ((3- isobutyl-isoxazol-5-yl) methyl) ethanamine

Compound 23: 2- (4- (4-chlorophenyl) piperazin-1-yl) - N - ((3- isobutyl-isoxazol-5-yl) methyl) - N - methyl ethanamine

Compound 24: N - ((3-isobutylisoxazol-5-yl) methyl) -2- (4- (3- (trifluoromethyl) phenyl) piperazin-

Compound 25: N - ((3-isobutylisoxazol-5-yl) methyl) -N -methyl-2- (4- (3- (trifluoromethyl) phenyl) piperazin- Amine

Compound 26: N - (2- (4- (4- chlorophenyl) piperazin-1-yl) ethyl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) propan-2-amine

Compound 27: N - (2- (4- (2,4- dimethylphenyl) piperazin-1-yl) ethyl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) propan -2 - amine

Compound 28: 2- (4- (3,4-dimethylphenyl) piperazin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) ethanamine

Compound 29: 2- (4- (3,4-dimethylphenyl) piperazin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) - N - methyl ethanamine

Compound 30: N - (2- (4- (3,4- dimethylphenyl) piperazin-1-yl) ethyl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) propan -2 - amine

Compound 31: N - ((3-isopropyl-isoxazol-5-yl) methyl) - N - (ethyl-2- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl)) Propane-2-amine

Compound 32: N - ((3- tert -Butylisoxazol -5-yl) methyl) -2- (4- (3,4-dimethylphenyl) piperazin-

Compound 33: N - ((3- tert - butyl-isoxazol-5-yl) methyl) -2- (4- (3,4-dimethylphenyl) piperazin-1-yl) - N - methyl ethanamine

Compound 34: N - ((3- tert - butyl-isoxazol-5-yl) methyl) -2- (4- (2,4-dimethylphenyl) piperazin-1-yl) - N - methyl ethanamine

Compound 35: N - ((3-tert - butyl-isoxazol-5-yl) methyl) - N - (2- (methyl) phenyl-4- (3- (trifluoromethyl) piperazin-1-yl) ethyl ) Propan-2-amine

Compound 36: 2- (4- (2,4-dimethylphenyl) piperazin-1-yl) - N - ((3- isobutyl-isoxazol-5-yl) methyl) ethanamine

Compound 37: 2- (4- (3,4-dimethylphenyl) piperazin-1-yl) - N - ((3- isobutyl-isoxazol-5-yl) methyl) ethanamine

Compound 38: N - ((3-isopropylisoxazol-5-yl) methyl) -2- (4- (3-trifluoromethylphenyl) piperazin-

Compound 39: N - ((3-isopropylisoxazol-5-yl) methyl) -2- (4- (4- methoxyphenyl) piperazin-

Compound 40: N - ((3- isopropyl-isoxazol-5-yl) methyl) -2- (4- (4-methoxyphenyl) piperazin-1-yl) - N - methyl ethanamine

Compound 41: N - ((3-isopropylisoxazol-5-yl) methyl) -2- (4-p-tolylpiperazin-

A-methyl-2- (4- (2,4-dimethylphenyl) piperazin-1-yl) - N - ((3- isobutyl-isoxazol-5-yl) methyl) - N: Compound 42

Compound 43: 2- (4- (3,4-dimethylphenyl) piperazin-1-yl) - N - ((3- isobutyl-isoxazol-5-yl) methyl) - N - methyl ethanamine

Compound 44: 2- (4- (3-chlorophenyl) piperazin-1-yl) - N - ((3-isopropyl-isoxazol-5-yl) methyl) - N - methyl ethanamine

Compound 45: N - ((3-isopropylisoxazol-5-yl) methyl) -2- (4- (4- (trifluoromethyl) phenyl) piperazin-

Compound 46: N - ((3-isopropylisoxazol-5-yl) methyl) -N -methyl-2- (4- (4- (trifluoromethyl) phenyl) piperazin- Amine

Compound 47: N - ((3-isopropylisoxazol-5-yl) methyl) -2- (4- (3- methoxyphenyl) piperazin-

Compound 48: N - ((3-Isopropylisoxazol-5-yl) methyl) -2- (4- m -tolylpiperazin-

Compound 49: N - ((3- isopropyl-isoxazol-5-yl) methyl) - N - methyl -2- (4-p- tolyl-l-yl) ethanamine

Compound 50: 2- (4- (4-fluorophenyl) piperazin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) ethanamine

Compound 51: 2- (4- (4-fluorophenyl) piperazin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) - N - methyl ethanamine

Compound 52: 2- (4- (3,4-dichlorophenyl) piperazin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) ethanamine

Compound 53: 2- (4- (3,4-dichlorophenyl) piperazin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) - N - methyl ethanamine

Compound 54: N - ((3-isopropyl-isoxazol-5-yl) methyl) -2- (4- (3-methoxyphenyl) piperazin-1-yl) - N - methyl ethanamine

Compound 55: N - ((3- isopropyl-isoxazol-5-yl) methyl) - N - methyl -2- (4- m - tolyl-l-yl) ethanamine

Compound 56: 3- (4- (3-chlorophenyl) piperazin-1-yl) - N - ((3-isopropyl-isoxazol-5-yl) methyl) propan-1-amine

Compound 57: 3- (4- (3-chlorophenyl) piperazin-1-yl) - N - ((3-isopropyl-isoxazol-5-yl) methyl) - N - methyl-1-amine

Compound 58: 3- (4- (3,4-dimethylphenyl) piperazin-1-yl) - N - ((3-isopropyl-isoxazol-5-yl) methyl) propan-1-amine

Compound 59: 3- (4- (3,4-dimethylphenyl) piperazin-1-yl) - N - ((3-isopropyl-isoxazol-5-yl) methyl) - N - methyl-1- Amine

Compound 60: N - ((3-isopropylisoxazol-5-yl) methyl) -3- (4-

Compound 61: N - ((3-isopropylisoxazol-5-yl) methyl) -N -methyl-3- (4-p-tolylpiperazin-1-yl) propan-

3- (4- (4-phenyl), fluoro-piperazin-1-yl) - N - ((3-isopropyl-isoxazol-5-yl) methyl) propan-1-amine

Compound 63: 3- (4- (4-phenyl), fluoro-piperazin-1-yl) - N - ((3-isopropyl-isoxazol-5-yl) methyl) - N - methyl-1-amine

Compound 64: N - ((3-isopropylisoxazol-5-yl) methyl) -3- (4- (4- methoxyphenyl) piperazin- 1 -yl) propan-

Compound 65: N - ((3- isopropyl-isoxazol-5-yl) methyl) -3- (4- (4-methoxyphenyl) piperazin-1-yl) - N - methyl-1-amine

Compound 66: 2- (4- (3,4-dimethoxyphenyl) piperazin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) ethanamine

Compound 67: 3- (4- (4-Chlorophenyl) piperazin-1-yl) - N - ((3-isopropylisoxazol-5- yl) methyl) propan-

Compound 68: 3- (4- (4-chlorophenyl) piperazin-1-yl) - N - ((3-isopropyl-isoxazol-5-yl) methyl) - N - methyl-1-amine

Compound 69: N - ((3-isopropylisoxazol-5-yl) methyl) -3- (4- (3-methoxyphenyl) piperazin- 1 -yl) propan-

Compound 70: N - ((3-isopropyl-isoxazol-5-yl) methyl) -3- (4- (3-methoxyphenyl) piperazin-1-yl) - N - methyl-1-amine

Compound 71: N - ((3- isopropyl-isoxazol-5-yl) methyl) -3- (4- m - tolyl-piperazin-1-yl) propan-1-amine

Compound 72: N - ((3- isopropyl-isoxazol-5-yl) methyl) - N - methyl -3- (4- m - tolyl-piperazin-1-yl) propan-1-amine

Compound 73: 3- (4- (3,4-dichlorophenyl) piperazin-1-yl) - N - ((3-isopropyl-isoxazol-5-yl) methyl) propan-1-amine

Compound 74: 3- (4- (3,4-dichlorophenyl) piperazin-1-yl) - N - ((3-isopropyl-isoxazol-5-yl) methyl) - N - methyl-1- Amine

Compound 75: 3- (4- (3,4-dimethoxyphenyl) piperazin-1-yl) - N - ((3-isopropyl-isoxazol-5-yl) methyl) propan-1-amine

Compound 76: 2- (4- (4-chlorophenyl) -2-methylpiperazin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) ethanamine

Compound 77: 2- (4- (3,4-dichlorophenyl) -2-methylpiperazin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) ethanamine

Compound 78: N - ((3-isopropylisoxazol-5-yl) methyl) -2- (4- (4- (trifluoromethoxy) phenyl) piperazin-

Compound 79: 2- (4- (3,5-dichlorophenyl) piperazin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) ethanamine

Compound 80: 2- (1- (4-fluorophenyl) piperidin-4-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) ethanamine

Compound 81: 2- (l- (4-Chlorophenyl) piperidin-4-yl) - N - ((3- isopropyl isoxazol-

Compound 82: N - ((3- tert -Butylisoxazol -5-yl) methyl) -2- (1- (4- chlorophenyl) piperidin-

Compound 83: N - ((3- tert - Butylisoxazol -5-yl) methyl) -2- (1- (4- fluorophenyl) piperidin-

Compound 84: N - ((3-isopropylisoxazol-5-yl) methyl) -2- (1- (4- (trifluoromethyl) phenyl) piperidin-

Compound 85: N - ((3-isopropylisoxazol-5-yl) methyl) -2- (1-p-tolylpiperidin-

Compound 86: 2- (1- (3,4-dichlorophenyl) piperidin-4-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) ethanamine

Compound 87: N - ((3-isopropylisoxazol-5-yl) methyl) -2- (1- (4- methoxyphenyl) piperidin-

Compound 88: 2- (l- (3-Chlorophenyl) piperidin-4-yl) - N - ((3-isopropylisoxazol-

Compound 89: 2- (1- (3-fluorophenyl) piperidin-4-yl) - N - ((3-isopropyl-isoxazol-5-yl) methyl) ethanamine

Compound 90: N - ((3- isopropyl-isoxazol-5-yl) methyl) -2- (1- m - tolyl rilpi-4-yl) ethanamine

Compound 91: N - ((3-isopropylisoxazol-5-yl) methyl) -2- (1- (3- (trifluoromethyl) phenyl) piperidin-

Compound 92: 2- (1- (2- ((3-isopropylisoxazol-5-yl) methylamino) ethyl) -1,2,3,6-tetrahydropyridin-4-yl) benzonitrile

Compound 93: N - ((3-isopropylisoxazol-5-yl) methyl) -2- (4-phenyl-1,2,3,6-tetrahydropyridin-

Compound 94: 2- (4- (4-chlorophenyl) -1,2,3,6-tetrahydro-pyridin-4-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) Ethanamine

Compound 95: 3- (1- (2- ((3-isopropylisoxazol-5-yl) methylamino) ethyl) -1,2,3,6-tetrahydropyridin-4-yl) benzonitrile

Compound 96: N - ((3-isopropylisoxazol-5-yl) methyl) -2- (4- (4-methoxyphenyl) -1,2,3,6-tetrahydropyridin- ) Ethanamine

Compound 97: N , N -bis ((3-isopropylisoxazol-5-yl) methyl) -2- (4- o- tolyl- 1,2,3,6-tetrahydropyridin- Ethanamine

Compound 98: 2- (4- (3,4-dichlorophenyl) -1,2,3,6-tetrahydro-pyridin-4-yl) - N - ((3- isopropyl-isoxazol-5-yl ) Methyl) ethanamine

Compound 99: 2- (4- (3,4-Dichlorophenyl) -1,2,3,6-tetrahydropyridin-4-yl) - N , N- 5-yl) methyl) ethanamine

Compound 100: 2- (4- (3,4-dichlorophenyl) piperidin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) ethanamine

Compound 101: N - ((3-isopropylisoxazol-5-yl) methyl) -2- (4- phenylpiperidin- 1 -yl)

Compound 102: methyl 5 - ((2- (4-phenylpiperazin-1-yl) ethylamino) methyl) isoxazole-

Compound 103: Ethyl 5 - ((2- (4-phenylpiperazin-1-yl) ethylamino) methyl) isoxazole-

Compound 104: Ethyl 5 - ((2- (4-phenylpiperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate hydrochloride

Compound 105: Sodium 5 - ((2- (4-phenylpiperazin-1-yl) ethylamino) methyl) isoxazole-

Compound 106 Ethyl 5 - ((2- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) ethylamino) methyl) isoxazole-

Compound 107: A mixture of sodium 5 - ((2- (4- (bis (4-fluorophenyl) methyl) piperazin- 1 -yl) ethylamino) methyl) isoxazole-

Compound 108: ethyl 5 - ((2- (4-benzhydrylpiperazin-1-yl) ethylamino) methyl) isoxazole-

Compound 109: Sodium 5 - ((2- (4-benzhydrylpiperazin-1-yl) ethylamino) methyl) isoxazole-

Compound 110: 2- (4-benzhydryl-piperazin-1-yl) - N - ((3- methyl-isoxazol-5-yl) methyl) ethanamine

Compound 111: 2- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) - N - ((3- methyl-isoxazol-5-yl) methyl) ethanamine

Compound 112: 2- (4- (bis (4-chlorophenyl) methyl) piperazin-1-yl) - N - ((3- methyl-isoxazol-5-yl) methyl) ethanamine

Compound 113: ethyl 5 - ((2- (4- (bis (4-chlorophenyl) methyl) piperazin-1-yl) ethylamino) methyl) isoxazole-

Compound 114: 5 - ((2- (4- (Bis (4-fluorophenyl) methyl) piperazin-1-yl) ethylamino) methyl) isoxazole-

Compound 115: 5 - ((2- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) ethylamino) methyl) - N-methyl-isoxazole-3-carboxamide

Compound 116: 5 - ((2- (4- (Bis (4-fluorophenyl) methyl) piperazin-1-yl) ethylamino) methyl) -N, N -dimethylisoxazole-

Meanwhile, the present invention includes a process for producing a 5- (substituted alkylaminomethyl) isoxazole-based compound represented by the above formula (1), and the process according to the present invention can be represented by the following reaction formula (1).

[Reaction Scheme 1]

In the above Reaction Scheme 1, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , n, X, and Y are as defined in Formula 1, respectively.

인 상기 화학식 1로 표시되는 화합물을 제조할 수 있다. 또한 R⁴=수소인 상기 화학식 1로 표시되는 화합물을 알킬화 반응시켜 R⁴=

인 상기 화학식 1로 표시되는 화합물을 제조할 수 있다.According in the scheme 1, by reductive amination reaction of the amine compound with an aldehyde compound represented by Formula 3 or Formula 4, represented by Formula 2 or Formula 5, R ⁴ = hydrogen or

The compound represented by the above formula (1) can be prepared. In addition, R ⁴ = by alkylation of a compound of the formula (1) is hydrogen R ⁴ =

The compound represented by the above formula (1) can be prepared.

The reductive amination reaction to be carried out in the reaction scheme 1 may be carried out using a molecular sieve (4 Å, 4 to 8 mesh). When the reactivity of the starting material is low, gaseous acids 1 to 3 Equivalent may be added. In addition, a reducing agent may be used to reduce the imine formed by the condensation reaction between an amine and an aldehyde. NaBH (OAc) ₃ , NaBH ₃ CN, NaBH ₄ and the like can be used as the reducing agent. The amount of the reducing agent used varies depending on the reactivity, and is about 2 to 10 equivalents, preferably about 2 to 3 equivalents do. As the reaction solvent which can be used in the reductive amination reaction of the present invention, a conventional organic solvent may be used, and specifically, tetrahydrofuran, 1,2-dichloroethane, acetonitrile, methylene chloride, In the examples, methanol was mainly used. The reaction temperature can be smoothly maintained even at a temperature around the room temperature. Specifically, the reaction temperature is maintained in the temperature range of 10 to 40 占 폚, preferably 20 to 30 占 폚. The reaction time is about 3 to 24 hours, preferably 6 to 12 hours. The progress of the reaction is tracked using thin layer chromatography (TLC). After the reaction is completed, saturated NaHCO ₃ aqueous solution is added and the reaction product is extracted with an appropriate organic solvent. As the extraction solvent, ether, methylene chloride, and ethyl acetate can be used, and the most suitable extraction solvent is methylene chloride.

인 상기 화학식 1로 표시되는 화합물은, R⁴=H인 상기 화학식 1로 표시되는 화합물을 적절한 알데하이드 화합물 또는 케톤 화합물과 알킬화 반응시켜 제조할 수 있다. 상기 알킬화 반응은 환원화 알킬반응을 통해 이루어진다. 이때 환원제로는 NaBH(OAc)₃, NaBH₃CN, NaBH₄ 등을 사용할 수 있으며, 환원제의 사용량은 반응성에 따라 다소 차이가 있는데 2 내지 10 당량 정도이며, 바람직하기로는 2 내지 3 당량 범위로 사용한다. 본 발명의 환원성 아민화 반응에서 사용 가능한 반응용매로는 통상의 유기용매를 사용할 수 있으며, 구체적으로는 테트라하이드로퓨란, 1,2-디클로로에탄, 아세토니트릴, 메틸렌클로라이드, 메탄올 등이며, 본 발명의 실시예에서는 메탄올을 주로 사용하였다. 반응온도는 실온 주변의 온도를 유지하더라도 원활하게 진행될 수 있으며, 구체적으로는 10 내지 40℃ 온도범위, 바람직하기로는 20 내지 30℃ 온도범위를 유지하는 것이다. 반응 시간은 3 내지 24 시간 정도이며, 바람직하게 6 내지 12 시간이 적당하다. 반응의 진행정도는 박층 크로마토그래피(TLC)를 사용하여 추적한다. 반응이 완결된 후, 포화 NaHCO₃ 수용액을 가하고 적당한 유기용매로 반응물을 추출하며, 추출용매로는 에테르, 메틸렌클로라이드, 에틸 아세테이트를 사용할 수 있으며, 가장 적합한 추출용매는 메틸렌클로라이드이다. And R ⁴ =

The compound represented by Formula 1 may be prepared by alkylating a compound represented by Formula 1, wherein R ⁴ = H, with a suitable aldehyde compound or a ketone compound. The alkylation reaction is accomplished through a reductive alkylation reaction. NaBH (OAc) ₃ , NaBH ₃ CN, NaBH ₄ and the like can be used as the reducing agent. The amount of the reducing agent used varies depending on the reactivity, and it is about 2 to 10 equivalents, preferably about 2 to 3 equivalents do. As the reaction solvent which can be used in the reductive amination reaction of the present invention, a conventional organic solvent may be used, and specifically, tetrahydrofuran, 1,2-dichloroethane, acetonitrile, methylene chloride, In the examples, methanol was mainly used. The reaction temperature can be smoothly maintained even at a temperature around the room temperature. Specifically, the reaction temperature is maintained in the temperature range of 10 to 40 占 폚, preferably 20 to 30 占 폚. The reaction time is about 3 to 24 hours, preferably 6 to 12 hours. The progress of the reaction is tracked using thin layer chromatography (TLC). After the reaction is completed, saturated NaHCO ₃ aqueous solution is added and the reaction product is extracted with an appropriate organic solvent. As the extraction solvent, ether, methylene chloride, and ethyl acetate can be used, and the most suitable extraction solvent is methylene chloride.

In addition, the method of preparing a pharmaceutically acceptable salt of the compound represented by the formula (1) can be easily prepared by a conventional synthetic method according to known literature, and can be purified without purification. Hereinafter, a method for preparing a pharmaceutically acceptable salt of the compound represented by the formula (1) will be described, focusing on the production process of the hydrochloride. That is, the above-mentioned extraction solvent is dried and evaporated, the residue is dissolved in a small amount of ether, and about 1 to about 10 equivalents of an ether solution of hydrogen chloride is added thereto, whereby a desired hydrochloride of the target compound is produced in a solid form. The organic solvent which can be used for preparing the hydrogen chloride solution may be chloroform, methylene chloride, ether, methanol, ethyl acetate or a mixed solvent thereof. Preferably, ether is useful. At this time, the product obtained in a solid form can be separated by using a centrifugal separator or a solvent removing device using a simple cotton. The solid is rinsed with diethyl ether two to three times and dried well to obtain hydrochloride of high purity.

Meanwhile, the aldehyde compound represented by Formula 3 and the amine compound represented by Formula 5, which are used as raw materials in the production method according to Reaction Scheme 1, can be synthesized by the production method shown in the following Reaction Scheme 2.

[Reaction Scheme 2]

In the above Reaction Scheme 2, R < ⁵ >

The preparation method of the following Reaction Scheme 2 will be described in more detail as follows.

First, the oxime compound represented by Formula 7 is prepared using the alkylaldehyde represented by Formula 6 and hydroxylamine. That is, the reaction is carried out by adding hydroxylamine hydrochloride and a base such as Na ₂ CO ₃ to a solution of the alkylaldehyde represented by Formula 6 dissolved in a solvent mixed with ethanol and water, and heating the reaction mixture at 50 to 100 ° C. When the reaction is completed, water is added to the reaction mixture to dilute the reaction mixture, and the mixture is extracted with an organic solvent such as ethyl acetate to obtain the oxime compound represented by the formula (7).

Then, the oxime compound represented by the formula (7) is reacted with the propargyl alcohol to prepare an isoxazole alcohol represented by the formula (8). That is, the oxime compound represented by the formula (7) is dissolved in an organic solvent such as tetrahydrofuran, the temperature is lowered to about -10 ° C to 0 ° C, N -chlorosuccinimide is slowly added, and the mixture is reacted with stirring for about 1 hour. Then, an organic base such as propyl alcohol and triethylamine is added to the reaction mixture, followed by stirring at room temperature for about 12 hours. When the reaction is completed, the reaction solution is diluted with water and a saturated aqueous solution of NaHCO ₃ , extracted with an organic solvent such as methylene chloride, and purified by silica gel column chromatography to obtain isosazole of formula (8).

Then, an aldehyde compound represented by Formula 3 is prepared by an oxidation reaction of the isoxazole alcohol represented by Formula 8 below. The oxidation reaction can be carried out by an oxidation reaction using PCC or a Sowan oxidation reaction. The PCC oxidation reaction is carried out in a temperature range of 0 ° C to 50 ° C.

In addition, an isocyanate alcohol represented by the above formula (8) is converted into an azide and then reduced to produce an amine compound represented by the above formula (5). That is, the isocyanate alcohol represented by the above formula (8) is substituted with chloride by using thionyl chloride and reacted with an azide inorganic substance such as NaN ₃ to prepare an azide compound represented by the above formula (9). The azide compound represented by the formula (9) is reduced with triphenylphosphine (Ph ₃ P) and water to obtain an amine compound represented by the formula (5). The reduction reaction is carried out in a temperature range of room temperature to 90 占 폚.

The amine compound represented by Formula 2 and the aldehyde compound represented by Formula 4, which are used as raw materials in the production method according to Reaction Scheme 1, can be synthesized by the production method shown in the following Reaction Scheme 3.

[Reaction Scheme 3]

R ¹ , R ² , R ³ , n, and X are as defined in Formula 1, respectively.

가 N- 임)을 생성하고, 하이드라진 등과 같은 탈프탈라지논 반응을 통해 상기 화학식 2로 표시되는 화합물을 얻을 수 있다. 또한 상기 화학식 14로 표시되는 피페라지닐에탄올을 이용하여 트리부틸실릴기(TBS) 등과 같은 실릴보호기를 도입하여 상기 화학식 15로 표시되는 화합물을 얻고, 아릴 보로닉 산을 이용하여 축합반응을 통해 상기 화학식 16으로 표시되는 화합물을 생성하고, 탈보호기 반응을 통해 상기 화학식 17로 표시되는 화합물을 얻은 후, 프탈이미드와 미쯔노부 반응을 통해 상기 화학식 13으로 표시되는 화합물 (

가 N- 임)을 얻은 후, 하이드라진 등과 같은 탈프탈라지논 반응을 통해 상기 화학식 2로 표시되는 화합물을 얻을 수 있다. 또한 상기 화학식 18로 표시되는 화합물을 아릴할라이드와 n-부틸리튬으로 형성된 아릴리튬을 이용하여 상기 화학식 19로 표시되는 화합물을 형성하고, 메실클로라이드와 유기염기를 이용하여 이중결합을 도입하여 상기 화학식 20으로 표시되는 화합물을 얻을 수 있다. 또한 상기 화학식 18로 표시되는 화합물을 트리부틸틴을 이용하여 상기 화학식 22로 표시되는 화합물을 얻고, 스틸리 축합반응을 통해 상기 화학식 20으로 표시되는 화합물을 얻을 수 있다. 또한 상기 화학식 18로 표시되는 화합물과 LDA, 1,1,1-트리플루오르-N-페틸-N-(트리플루오르메틸설포닐)메탄설폰아마이드를 이용하여 상기 화학식 23으로 표시되는 트리플레이트를 얻고, 상기 화학식 23으로 표시되는 화합물과 비스(피나콜라토)디보론, 팔라듐 촉매를 이용해서 상기 화학식 24로 표시되는 화합물을 형성한 후, 스즈끼 축합반응을 이용해서 상기 화학식 20으로 표시되는 화합물을 얻을 수 있다. 상기 화학식 20으로 표시되는 화합물은 수소화 반응을 통해 이중결합을 단일 결합으로 만들어서 상기 화합물 21로 표시되는 화합물을 얻을 수 있다. 상기 화학식 20 또는 21로 표시되는 화합물은 산 조건 하에서 탈보호 반응을 하여 상기 화학식 25로 표시되는 화합물을 얻고, 2-브로모에틸 또는 3-브로모프로필프탈이미드를 이용해서 상기 화학식 13으로 표시되는 화합물을 얻은 후, 하이드라진 등과 같은 탈프탈라지논 반응을 통해 상기 화학식 2로 표시되는 화합물을 얻을 수 있다.According to Scheme 3, arylpiperazine represented by Formula 12 was synthesized by condensing an aryl compound represented by Formula 10 and piperazine represented by Formula 11, and bromoethyl or bromopropylphthalazine The compound represented by the above formula (13) (

Is N-), and the compound represented by the above formula (2) can be obtained through a reaction of a thalidazinone such as hydrazine. Further, a silyl protecting group such as a tributylsilyl group (TBS) is introduced by using piperazinylethanol represented by the above formula (14) to obtain a compound represented by the above formula (15), and a condensation reaction is carried out using an arylboronic acid The compound represented by the formula (16) is produced, and the compound represented by the formula (17) is obtained through a deprotection reaction. Then, a compound represented by the formula (13) is obtained through phthalimide and mitsunobu reaction

Is N-), and then a compound represented by the above formula (2) can be obtained through a reaction of a hydthalazine such as hydrazine. Also, a compound represented by Formula 19 is formed using an aryl halide formed of an aryl halide and n-butyllithium, and a double bond is introduced using mesyl chloride and an organic base to form a compound represented by Formula 20 Can be obtained. Further, the compound represented by Formula 18 is obtained by using tributyltin as the compound of Formula 18, and the compound represented by Formula 20 is obtained through the condensation reaction of Stille. The triflate represented by Formula 23 was obtained by using the compound represented by Formula 18 and LDA and 1,1,1-trifluoro- N -phenethyl- N- (trifluoromethylsulfonyl) methanesulfonamide, The compound represented by Formula 24 is formed by using the compound represented by Formula 23 and bis (pinacolato) diboron or palladium catalyst, and then Suzuki condensation reaction is performed to obtain the compound represented by Formula 20 have. The compound represented by Formula 20 may be converted into a single bond by hydrogenation to obtain a compound represented by Formula 21. The compound represented by Chemical Formula 20 or 21 is deprotected under acid conditions to obtain the compound represented by Chemical Formula 25, and then 2-bromoethyl or 3-bromopropylphthalimide is used to produce the compound represented by Chemical Formula 13 , And then the compound represented by the formula (2) can be obtained through a reaction of a hydthalazine such as hydrazine.

The intermediate compound or the target compound prepared through the above-described preparation method can be purified by carrying out a conventional purification method.

Meanwhile, the present invention includes a pharmaceutical composition comprising the 5- (substituted alkylaminomethyl) isoxazole compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient for the purpose of prevention and treatment of diseases .

The pharmaceutical composition of the present invention can be prepared by incorporating 5- (substituted alkylaminomethyl) isoxazole-based compound represented by the above formula (1) or its pharmaceutically acceptable salt with other conventional carrier, adjuvant or diluent, And may be formulated into a form suitable for oral administration or parenteral administration. In the case of oral administration, it can be prepared in the form of tablets, capsules, solutions, syrups, suspensions, etc. In the case of parenteral administration, it can be prepared in the form of injections for peritoneal, subcutaneous, muscular and transdermal administration.

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 relates to a 5- (substituted alkylaminomethyl) isoxazole-based compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, for the purpose of prevention and treatment of diseases Medicinal uses.

That is, since the present invention has activity against T-type calcium channel, it includes medicinal use for the purpose of prevention and treatment of brain diseases, cancer, heart diseases, or for pain relief.

The present invention will be described in more detail with reference to the following examples and experimental examples. However, the present invention is not limited to these examples and experimental examples.

[Example]

Example 1. (3-isopropyl isoxazol-5-yl) methanol

Of ethanol and water 1: iso in a solvent 60 mL mixture of 1-butane al (5.0 g, 22 mmol), hydroxylamine hydrochloride (6.3 g, 90.1 mmol) and _{Na 2 CO 3 (9.5 g,} 90.1 mmol) was placed the And the mixture was stirred. The reaction mixture was refluxed at 90 < 0 > C for 24 hours. The temperature of the reaction mixture was lowered to room temperature, diluted with 30 mL of water, extracted with ethyl acetate, and the organic solution was dried over MgSO ₄ , filtered and concentrated under reduced pressure to obtain an oxime compound.

The resulting oxime compound was dissolved in 40 mL of THF, the temperature was lowered to 0 ° C, N -chlorosuccinimide (10.1 g, 76 mmol) was slowly added thereto, and the mixture was stirred for 1 hour. Propyl alcohol (5.6 mL, 94.7 mmol) and triethylamine (10.6 g, 75.8 mmol) were added, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, 15 mL of water and a saturated aqueous solution of NaHCO ₃ were added to the reaction solution and extracted with methylene chloride. The organic solution was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain the title compound (4.0 g, 28.3 mmol, 50%).

^{1 H NMR (300 MHz, CDCl} 3) δ 6.11 (s, 1H), 4.68 (s, 2H), 3.90 (s, 1H), 3.05-2.95 (m, 1H), 1.24 (d, J = 7.0 Hz, 6H)

Example 2. 3-Isopropylisoxazole-5-carbaldehyde

PCC (7.91 g, 36.7 mmol) and silica gel (7.91 g) were added to methylene chloride (180 mL), and then (3-isopropylisoxazol-5-yl) methanol (2.59 g, 18.4 mmol) was added at room temperature. The reaction solution was stirred for 5 hours at room temperature, filtered through silica gel, and the obtained organic solution was concentrated under reduced pressure to give the title compound (2.25 g, 16.2 mmol, 99%).

^{1 H NMR (300 MHz, CDCl} 3) δ 9.95 (s, 1H), 6.88 (s, 1H), 3.21-3.12 (m, 1H), 1.34 (d, J = 7.0 Hz, 6H)

(3-methyl-isoxazol-5-ylmethyl) amine (Compound No. 1)

3-Methylisoxazole-5-carbaldehyde (300 mg, 2.7 mmol), 3-chlorophenylpiperazinylethylamine (777 mg, 3.24 mmol) and 4A molecular sieve were mixed with 20 mL of methylene chloride, After stirring, NaBH (OAc) ₃ (1.72 g, 8.10 mmol) was added, and the mixture was stirred at room temperature for 5 hours. Saturated NaHCO ₃ aqueous solution was added and the mixture was extracted with methylene chloride. The organic solution was dried over MgSO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (300 mg, 0.90 mmol, 33%).

(Compound No. 3) [0157] [166] [166] Example 4. [166] 2- [4- (3-chlorophenyl) -piperazin-

3-isopropylisoxazole-5-carbaldehyde (1.6 g, 11.5 mmol) was dissolved in methanol (40 mL), and then 3-chlorophenylpiperazinylethylamine (3.2 g, 12.7 mmol) (0.5 mL) was added and stirred for 2 hours. To the reaction mixture was added NaBH (OAc) ₃ (7.3 g, 34.5 mmol) and stirred for 8 hours, then the solvent was concentrated under reduced pressure. The concentrate was diluted with water and saturated aqueous NaHCO ₃ solution (10 mL each) and extracted with methylene chloride. The organic solution was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MC: MeOH = 10: 1) to obtain the title compound (3.2 g, 8.5 mmol, 74%).

Example 5. Preparation of 4- (2- ( tert -butyldimethylsilyloxy) ethyl) piperidine

Butyldimethylsilyl chloride - 2- (piperidin-4-yl) ethanol (2.3 g, 17.8 mmol) of tert was dissolved in methylene chloride (TBSCl; 3.2 g, 21.3 mmol ) and imidazole (2.4 g, 35.6 mmol) And the reaction was allowed to proceed at room temperature for 2 hours. After completion of the reaction was confirmed by TLC, NH ₄ Cl was added to terminate the reaction. After extraction with methylene chloride, the residue was purified by silica gel column chromatography (MC: MeOH: TEA = 85: 10: 5). The purified compound was treated with aqueous 0.5 N NaOH solution and extracted with a solvent (MC: MeOH = 10: 1) to obtain the compound (4.2 g, 12.4 mmol, 98%).

_{^{1 H NMR (CDCl 3, 300}} MHz) δ 0.03 (s, 6H), 0.87 (s, 9H), 1.07-1.12 (q, J = 4.97 Hz, 2H), 1.43-1.47 (t, J = 6.33 Hz, J = 13.28, 2.42 Hz, 2H), 3.01 (m, 2H), 1.47-1.62 (m, 1H), 1.62-1.66 (bd, J = (D, J = 9.25 Hz, 2H), 3.61-3.65 (t, J = 6.43 Hz, 2H)

Example 6. Preparation of 4- (2- ( tert -butyldimethylsilyloxy) ethyl) -1- (4-fluorophenyl) piperidine

4A molecular sieves, 4-fluorophenylboronic acid (0.49 g, 3.53 mmol) and Cu (OAc) ₂ (0.03 g, 0.17 mmol) were dissolved in methylene chloride in the order of 0 Lt; 0 > C for 5 minutes. A solution of 4- (2- ( tert -butyldimethylsilyloxy) ethyl) piperidine (0.43 g, 1.76 mmol) in methylene chloride was added dropwise to the reaction mixture, and the reaction was carried out for 24 to 36 hours . The reaction progress was confirmed by TLC. When the reaction was completed, 4A molecular sieve and Cu (OAc) ₂ were removed by filtration under reduced pressure. The filtrate was evaporated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (0.34 g, 1.02 mmol, 58%).

_{^{1 H NMR (CDCl 3, 300}} MHz) δ 0.07 (s, 6H), 0.92 (s, 9H), 1.41-1.42 (m, 2H), 1.52-1.55 (m, 3H), 1.81 (bd, J = 6.48 (T, J = 7.18,2.48 Hz, 2H), 3.54 (d, J = 12.25 Hz, 2H), 3.70 (t, J = 3.20 Hz, 2H), 6.87-6.98 , 4H)

Example 7. 2- (1- (4-fluorophenyl) piperidin-4-yl) ethanol

To the solution was added 4- (2- ( tert -butyldimethylsilyloxy) ethyl) -1- (4-fluorophenyl) piperidine (1.1 g, 3.26 mmol) in THF and cooled to 0 ° C. TBAF (2.83 mL, 9.77 mmol) was added to the reaction mixture, and the mixture was reacted for 20 minutes. After the reaction was continued for 3 hours, NHCl ₃ was added to the reaction mixture to terminate the reaction. H ₂ O and methylene chloride. The organic solution was dried over MgSO ₄ , filtered under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give the title compound (0.7 g, 3.45 mmol , 99%).

¹ H NMR (CDCl ₃ , 300 MHz)? 1.27-1.29 (m, 1H), 1.40-1.48 (m, 2H), 1.50-1.60 (m, 4H), 1.82 (bd, J = 12.50 Hz, 2H) 2.65 (td, J = 11.98 Hz , J = 2.19 Hz, 2H), 3.54 (bd, J = 12.25 Hz, 2H), 3.76 (bs, 2H), 6.87-6.99 (m, 4H)

Example 8. 2- (2- (1- (4-Fluorophenyl) piperidin-4-yl) ethyl) isoindoline-

Phthalamide (0.12 g, 0.85 mmol) and triphenylphosphine (0.22 g, 0.85 mmol) were dissolved in THF in a round bottom flask and then 2- (1- (4-fluorophenyl) piperidin- ) Ethanol (0.12 g, 0.57 mmol) in THF was added dropwise at room temperature. Diisopropyl azodicarboxylate (DIAD; 0.17 mL, 0.85 mmol) was slowly added dropwise and reacted for 4 hours, and the completion of the reaction was confirmed by TLC. The reaction mixture was extracted with methylene chloride, dried over MgSO ₄ and filtered under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to obtain the title compound (0.17 g, 0.49 mmol, 78%).

_{^{1 H NMR (CDCl 3, 300}} MHz) δ 1.43-1.47 (m, 4H), 1.68 (bt, J = 6.23 Hz, 2H), 1.92 (bd, J = 9.07 Hz, 2H), 2.64 (bt, J = 10.62 Hz, 2H), 3.55 ( bd, J = 12.04 Hz, 2H), 3.77 (t, J = 7.18 Hz, 2H), 6.88-6.98 (m, 4H), 7.72-7.75 (m, 4H), 7.85 ( m, 2H)

Example 9. Synthesis of 2- (1- (4-fluorophenyl) piperidin-4-yl) ethanamine

Isoindole-1,3-dione (0.17 g, 0.49 mmol) was added to ethanol and the temperature was raised to 80 ° C. After dissolving, monohydrazine (0.07 mL, 1.47 mmol) was added and reacted for 8 hours. The resulting solid was filtered off under reduced pressure and the filtrate was purified by silica gel column chromatography (EA: MeOH: ammonia water = 10: 1: 0.1) to give the title compound (0.09 g, 0.43 mmol, 89%).

_{^{1 H NMR (CDCl 3, 300}} MHz) δ 1.37-1.49 (m, 7H), 1.81 (bd, J = 10.56 Hz, 2H), 2.65 (t, J = 11.62 Hz, 2H), 2.78 (t, J = 6.99 Hz, 2H), 3.54 (bd, J = 12.39 Hz, 2H), 6.87-6.98 (m, 4H)

Example 10 2- (1- (4-fluorophenyl) piperidin-4-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) ethanamine

Ethylamine (50 mg, 0.22 mmol) and aldehyde (34 mg, 0.24 mmol) were dissolved in methylene chloride and reacted for 3 hours. NaBH (OAc) ₃ (143 mg, 0.67 mmol) was added thereto and reacted for 3 hours. After completion of the reaction by TLC, the reaction mixture was poured into water using methylene chloride. The organic solution was dried over MgSO ₄ , filtered under reduced pressure, and then purified by silica gel column chromatography to obtain the title compound (38 mg, 0.11 mmol, 49% .

_{^{1 H NMR (CDCl 3, 300}} MHz) δ 1.29 (d, J = 6.95 Hz, 6H), 1.38-1.53 (m, 7H), 1.79 (bd, J = 11.28 Hz, 2H), 2.64 (t, J = 2H), 2.72 (t, J = 7.23 Hz, 2H), 3.04-3.08 (m, 1H), 3.53 (bd, J = 12.33 Hz, 2H) 1H), 6.86-6.98 (m, 4H)

Example 11. Preparation of 2- (1- (3-chlorophenyl) piperidin-4-yl) acetaldehyde

(48 mg, 0.17 mmol) obtained in the same manner as in Example 7 and methyl 2- (1- (3-chlorophenyl) piperidin-4-yl) ethanol were dissolved in methylene chloride. PCC (95 mg, 0.44 mmol) were added. SO ₂ also added the same amount as PCC. The reaction mixture was reacted at room temperature for 4 to 8 hours and then filtered through celite. The filtrate was washed with saturated aqueous NaHCO ₃ solution and the aqueous solution was extracted again with methylene chloride (10 mL × 3 times). The organic solution was combined, dried over MgSO ₄ , filtered under reduced pressure, and then purified by silica gel column chromatography to obtain the title compound (19 mg, 0.07 mmol, 40%).

Example 12. Preparation of 5- (chloromethyl) -3-isopropylisoxazole

To the solution of (3-isopropylisoxazol-5-yl) methanol (0.84 g, 5.95 mmol) in methylene chloride was added triethylamine (2.48 mL, 17.85 mmol). A solution of thionyl chloride (1.29 mL, 17.85 mmol) in methylene chloride was slowly added dropwise to the reaction solution while stirring the reaction solution at room temperature. After the reaction was completed, a 1M aqueous NaHCO ₃ solution (20 mL) was slowly added dropwise to the reaction solution and layered to obtain an organic solution layer. The aqueous layer was extracted with methylene chloride (15 mL x 3) to give an organic solution layer. The obtained organic solution layers were combined, dried over MgSO ₄ , filtered under reduced pressure, and then purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to obtain the title compound (0.73 g, 4.6 mmol, 77%).

_{^{1 H NMR (CDCl 3, 400}} MHz) δ 6.19 (s, 1H), 4.58 (s, 2H), 3.11-3.00 (m, 1H, J = 6.96 Hz), 1.33 (d, 6H, J = 16.06 Hz)

Example 13. 5- (Azimethyl) -3-isopropylisoxazole

NaI (0.34 g, 2.3 mmol) and NaN ₃ (1.49 g, 4.6 mmol) were added to a solution of 5- (chloromethyl) -3-isopropylisoxazole (0.73 g, 4.6 mmol) in N, N- 23.02 mmol). The reaction solution was heated to 60 캜 with stirring and reacted for 12 hours. After the reaction was completed, 10 mL of distilled water was added to the reaction vessel and extracted with ethyl acetate (20 mL × 5). The organic layer was combined, dried over MgSO ₄ , filtered under reduced pressure, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 8) to give the title compound (0.24 g, 1.43 mmol, 31%).

_{^{1 H NMR (CDCl 3, 400}} MHz) δ 6.15 (s, 1H), 4.41 (s, 2H), 3.12-3.03 (m, 1H, J = 6.95 Hz), 1.34 (d, 6H, J = 15.66 Hz)

Example 14. (3-Isopropylisoxazol-5-yl) methanamine

5- (Azimethyl) -3-isopropylisoxazole (0.24 g, 1.43 mmol) was dissolved in a mixed solution of THF and H ₂ O (THF: H ₂ O = 10: 1) and triphenylphosphine Ph ₃ P; 0.37 g, 1.43 mmol), and the mixture was reacted at 70 ° C for 4 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, distilled water was added to the reaction vessel, and the reaction mixture was extracted with ethyl acetate (20 mL × 3). The organic layer was combined, dried over MgSO ₄ , filtered under reduced pressure, and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (0.14 g, 0.97 mmol, 68%).

_{^{1 H NMR (CDCl 3, 300}} MHz) δ 6.00 (s, 1H), 3.93 (s, 2H), 3.09-3.00 (m, 1H, J = 6.95 Hz), 1.49 (b, 2H), 1.29 (d, 6H, J = 6.95 Hz)

Example 15 2- (1- (3-Chlorophenyl) piperidin-4-yl) - N - ((3- isopropyl isoxazol-

To a solution of 2- (1- (3-chlorophenyl) piperidin-4-yl) acetaldehyde (22 mg, 0.09 mmol) in methylene chloride was added (3-isopropylisoxazol- Methanamine (19 mg, 0.1 mmol) was added dropwise and stirred for 30 minutes under a stream of nitrogen. NaBH (OAc) ₃ (59 mg, 0.28 mmol) was added to the reaction solution, followed by stirring at room temperature for 3 hours. When the reaction was completed, water was added to terminate the reaction, 10 mL of a saturated aqueous solution of NaHCO ₃ was added, and organic material was extracted with methylene chloride. The organic layer was combined, dried over MgSO ₄ , filtered under reduced pressure, and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (15 mg, 0.04 mmol, 45%).

_{^{1 H NMR (CDCl 3, 400}} MHz) δ 7.15-6.75 (m, 4H), 6.10 (s, 1H), 4.05 (s, 2H), 3.89 (m, 2H), 3.07-3.03 (m, 1H), 2H), 1.51-1.29 (m, 6H), 1.27 (d, 6H, J = 3.00 Hz), 2.73-2.67 (m, 4H)

Example 16. Synthesis of tert -butyl 4- (2-cyanophenyl) -5,6-dihydropyridin-1 (2 H ) -carboxylate

2-Bromobenzonitrile (914 mg, 5.02 mmol) was dissolved in anhydrous tetrahydrofuran (46 mL) under an argon atmosphere, cooled to -78 ° C and a solution of normal butyl lithium dissolved in hexane (2.0 mL, 2.5 M) was slowly added dropwise and reacted for 30 minutes. Tert -Butoxycarbonyl-4-piperidone (1.0 g, 5.02 mmol) dissolved in tetrahydrofuran (4.3 mL) was slowly added dropwise at -78 ° C and reacted for 1 hour. Methanol sulfonyl chloride (1.6 mL, 20.08 mmol) and triethylamine (5.6 mL, 40.15 mmol) were added dropwise at -78 ° C, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction was confirmed by TLC, the reaction mixture was extracted with ethyl acetate, and the organic solution layer was washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and distilled under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 20: 1) to give the title compound (658 mg, 45%).

^{1 H NMR (300 MHz, CDCl} 3) δ 7.51 (d, J = 7.8 Hz, 1H), 7.43 (dt, J = 10.6 Hz, 3.9 Hz, 1H), 7.22 (t, J = 7.8 Hz, 2H), 5.83 (bs, 1H), 3.96 (d, J = 2.9 Hz, 2H), 3.52 (t, J = 5.6 Hz, 2H), 2.39 (bs, 2H), 1.37 (s, 9H)

Example 17. Synthesis of tert -butyl 4- (tributylstannyl) -5,6-dihydropyridin-1 (2 H ) -carboxylate

Diisopropylamine (4.2 mL, 30.11 mmol) was dissolved in anhydrous tetrahydrofuran (90 mL) under an argon atmosphere, cooled to 0 ° C and a butyllithium solution (15.1 mL, 2.5 M) dissolved in hexane was slowly added dropwise . After 30 minutes, tributyltin hydride (7.5 mL, 25.09 mmol) was slowly added dropwise at 0 ° C, and after 30 minutes, 1- tert -butoxycarbonyl-4-piperidone dissolved in tetrahydrofuran (10 mL) (5.0 g, 25.09 mmol) was slowly added dropwise at -78 < 0 > C. After 2 hours, methanesulfonyl chloride (7.8 mL, 100.38 mmol) and triethylamine (28.0 mL, 200.75 mmol) were added dropwise at -78 째 C, and the mixture was stirred at room temperature for 15 hours. The reaction was terminated by TLC followed by extraction with hexane and acetonitrile. The organic layer was combined, dried over MgSO ₄ , filtered under reduced pressure, and concentrated. The residue was purified by silica gel column chromatography [hexane / ethyl acetate = 50: 1] to obtain the title compound (5.4 g, 45%).

^{1 H NMR (300 MHz, CDCl} 3) δ 5.73 (bs, 1H), 3.90 (d, J = 2.6 Hz, 2H), 3.45 (t, J = 5.5 Hz, 2H), 2.26 (bs, 2H), 1.51 -1.43 (m, 6H), 1.46 (s, 9H), 1.36-1.27 (m, 6H), 0.89 (t, J = 7.2 Hz, 15H)

Example 18. Synthesis of tert -butyl 4- (4-chlorophenyl) -5,6-dihydropyridin-1 (2 H ) -carboxylate

(2 H ) -carboxylate (5.4 g, 11.36 mmol), 1-bromo-4-chlorobenzene (prepared from tert -butyl 4- 2.6 g, 13.64 mmol) and Pd (PPh ₃ ) ₄ (1.3 g, 1.14 mmol) were dissolved in 81 mL of anhydrous toluene, and the mixture was refluxed overnight at 120 ° C. After distillation under reduced pressure, the obtained mixture was purified by silica gel column chromatography (hexane / ethyl acetate = 15: 1) to obtain the title compound (3.5 g, 100%).

^{1 H NMR (400 MHz, CDCl} 3) δ 7.34-7.27 (m, 4H), 6.01 (bs, 1H), 4.06 (bs, 2H), 3.63 (bs, 2H), 2.47 (bs, 2H), 1.48 ( s, 9H)

Example 19. Synthesis of tert -butyl 4- (trifluoromethylsulfonyloxy) -5,6-dihydropyridin-1 (2 H ) -carboxylate

Diisopropylamine (1.7 mL, 12.05 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL) under an argon atmosphere, cooled to -78 ° C and a butyllithium solution (4.8 mL, 2.5 M) dissolved in hexane was slowly added dropwise Respectively. After 15 minutes, 1- tert -butoxycarbonyl-4-piperidone (2.0 g, 10.04 mmol) dissolved in tetrahydrofuran (25 mL) was slowly added dropwise at -78 째 C, and after 20 minutes, tetrahydrofuran N -pentyl- N - (trifluoromethylsulfonyl) methanesulfonamide (3.9 g, 11.04 mmol) dissolved in tetrahydrofuran (12 mL) was slowly added dropwise and stirred at 0 ° C for 3 hours . After completion of the reaction was confirmed by TLC, the mixture was distilled under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 20: 1) to give the title compound (3.9 g, 100%).

^{1 H NMR (300 MHz, CDCl} 3) δ 5.77 (bs, 1H), 4.05 (d, J = 2.9 Hz, 2H), 3.64 (t, J = 5.7 Hz, 2H), 2.47-2.44 (m, 2H) , 1.48 (s, 9H)

Example 20. tert - butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxa-view it is 2-yl) -5,6-dihydropyridin--1 (2 H ) -Carboxylate < / RTI >

Under an argon atmosphere tert - butyl 4- (trifluoromethyl sulfonyloxy) -5,6-dihydropyridin--1 (2 H) - carboxylate (3.9 g, 11.74 mmol), bis (pinacolato) diboron (3.3 g, 13.03 mmol), potassium acetate (3.5 g, 35.5 mmol), dppf (325 mg, 0.59 mmol), PdCl 2 (dppf) 2 (479 mg, 0.59 mmol) in anhydrous 1,4-dioxane (59 mL ) And stirred overnight at 80 ° C. The reaction was terminated by TLC and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and then distilled under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9: 1) to give the title compound (2.7 g, 74%).

^{1 H NMR (300 MHz, CDCl} 3) δ 6.37 (bs, 1H), 3.86 (bs, 2H), 3.34 (t, J = 5.2 Hz), 2.13 (bs, 2H), 1.37 (s, 9H), 1.17 (s, 10H)

Example 21. Synthesis of tert -butyl 4- (3,4-dichlorophenyl) -5,6-dihydropyridin-1 (2 H ) -carboxylate

Under an argon atmosphere tert - butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxa-view it is 2-yl) -5,6-dihydropyridin--1 (2 H) -carboxylate (2.7 g, 8.67 mmol), 4- bromo-1,2-dichlorobenzene (2.2 g, 9.53 mmol), tribasic potassium (2.8 g, 13.00 mmol) and Pd (PPh _{3) 4} ( 361 mg, 0.31 mmol) was dissolved in anhydrous 1,4-dioxane (7 mL), water (1.8 mL) was added, and the mixture was stirred overnight at 85 ° C. The reaction was terminated by TLC and distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6: 1) to give the title compound (2.1 g, 72%).

^{1 H NMR (300 MHz, CDCl} 3) δ 7.45 (d, J = 1.9 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.49 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 6.06 (bs, 1H), 4.08 (d, J = 2.4 Hz, 1H), 3.64 (t, J = 5.6 Hz, 2H), 2.48 (bs, 2H), 1.50 (s, 9H)

Example 22. Synthesis of tert -butyl 4- (3,4-dichlorophenyl) piperidine-1-carboxylate

tert - Butyl 4- (3,4-dichloro-phenyl) -5,6-dihydropyridin--1 (2 H) - carboxylate (2.3 g, 6.91 mmol) was dissolved in anhydrous methanol (58 mL), Pd / C (147 mg, 1.38 mmol) was added thereto, followed by stirring at room temperature under a hydrogen atmosphere overnight. After filtration with Celite and decompression, the reaction was confirmed by NMR. The silica gel mixture was filtered and purified by silica gel to obtain the title compound (2.03 g, 89%).

^{1 H NMR (300 MHz, CDCl} 3) δ 7.23 (d, J = 8.3 Hz, 1H), 7.17 (d, J = 1.8 Hz, 3H), 6.92 (dd, J = 8.3 Hz, 1.8 Hz, 1H), 4.15 (d, J = 11.0 Hz , 2H), 2.71 (t, J = 12.4 Hz, 2H), 2.54 (d, J = 12.1 Hz, 1H), 1.65 (d, J = 12.3 Hz, 2H), 1.54- 1.44 (m, 2 H), 1.39 (s, 9 H)

Example 23. Synthesis of 4- (3,4-dichlorophenyl) piperidine

(2.03 g, 6.15 mmol) was dissolved in anhydrous dichloromethane (31 mL) and then cooled to 0 < 0 > C under an argon atmosphere. Tert -Butyl 4- (3,4- dichlorophenyl) piperidine- And trifluoroacetic acid (16.0 mL, 209.0 mmol) was added dropwise thereto, followed by stirring at room temperature for 5 hours. After the reaction was completed by TLC, the reaction mixture was washed with 1 N aqueous sodium hydroxide solution and then extracted with dichloromethane. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and distilled under reduced pressure to give the title compound (1.3 g, 91%).

^{1 H NMR (300 MHz, CDCl} 3) δ 7.23 (d, J = 8.3 Hz, 1H), 7.17 (d, J = 1.8 Hz, 1H), 6.92 (dd, J = 8.3 Hz, 1.8 Hz, 1H), 3.03 (d, J = 13.8 Hz , 2H), 2.60 (t, J = 12.1 Hz, 2H), 2.48 (t, J = 13.8 1H), 1.63 (d, J = 12.7 1H), 1.51-1.43 (m, 2H + 1H)

Example 24. Synthesis of 2- (2- (4- (3,4-dichlorophenyl) piperidin-1-yl) ethyl) isoindoline-1,3-dione

Under an argon atmosphere 4- (3,4-dichlorophenyl) piperidine (1.3 g, 5.65 mmol) in anhydrous N, N - was dissolved in dimethylformamide (17 mL), N - (2- bromoethyl ) Phthalimide (1.4 g, 5.65 mmol), sodium carbonate (599 mg, 5.65 mmol) and sodium iodide (169 mg, 1.13 mmol) were added dropwise and the mixture was stirred at 90 ° C overnight. The reaction was terminated by TLC, washed with saturated aqueous NaHCO ₃ solution and then extracted with a mixture of hexane and ethyl acetate (hexane: ethyl acetate = 2: 1). The organic solution layer was washed again with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and distilled under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5: 1) to give the title compound (1.0 g, 45%) as a white solid.

^{1 H NMR (300 MHz, CDCl} 3) δ 7.87-7.81 (m, 2H), 7.73-7.68 (m, 2H), 7.43 (d, J = 2.1 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.19 (dd, J = 8.4 Hz, 2.1 Hz, 1H), 6.07 (bs, 1H), 3.75 (t, J = 8.6 Hz, 2H), 3.00 (d, J = 13.1 Hz, 2H), 2.56 J = 8.6 Hz, 2H), 2.41-2.30 (m, 1H), 2.03 (dt, J = 14.3 Hz, 5.6 Hz,

Example 25. Synthesis of 2- (4- (3,4-dichlorophenyl) piperidin-l-yl) ethanamine

(1.0 g, 2.48 mmol) was dissolved in anhydrous ethanol (10 ml) under an argon atmosphere, and then a solution of 2- (4- (3,4- dichlorophenyl) piperidin- 1 -yl) ethyl) isoindoline- (9 mL), hydrazine hydrate solution (0.47 mL, 7.44 mmol) was added dropwise, and the mixture was stirred at 70 째 C for 2 hours. The reaction solution was extracted with dichloromethane. The organic layer was washed again with water and a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and distilled under reduced pressure to obtain the title compound (542 mg, 80%).

^{1 H NMR (300 MHz, CDCl} 3) δ 7.38 (d, J = 1.5 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.14 (dd, J = 8.4 Ha, 1.5 Hz, 1H), 2.83 (d, J = 13.1 Hz , 2H), 2.49 (t, J = 7.7 Hz, 2H), 2.23-2.2.00 (m, 1H + 2H), 1.99 (dt, J = 17.5 Hz, 7.3 Hz, 2H ), 1.76 - 1.54 (m, 2H + 2H), 1.33 (bs, 2H)

Example 26. Synthesis of 2- (4- (3,4-dichlorophenyl) piperidin-l-yl) ethanamine

(1.0 g, 2.48 mmol) was dissolved in anhydrous ethanol (10 ml) under an argon atmosphere, and then a solution of 2- (4- (3,4- dichlorophenyl) piperidin- 1 -yl) ethyl) isoindoline- (9 mL), hydrazine hydrate solution (0.47 mL, 7.44 mmol) was added dropwise, and the mixture was stirred at 70 째 C for 2 hours. The reaction solution was extracted with dichloromethane. The organic layer was washed again with water and a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and distilled under reduced pressure to obtain the title compound (542 mg, 80%).

^{1 H NMR (300 MHz, CDCl} 3) δ 7.38 (d, J = 1.5 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.14 (dd, J = 8.4 Ha, 1.5 Hz, 1H), 2.83 (d, J = 13.1 Hz , 2H), 2.49 (t, J = 7.7 Hz, 2H), 2.23-2.2.00 (m, 1H + 2H), 1.99 (dt, J = 17.5 Hz, 7.3 Hz, 2H ), 1.76 - 1.54 (m, 2H + 2H), 1.33 (bs, 2H)

Example 27. Preparation of 2- (4- (3,4-dichlorophenyl) piperidin-l-yl) - N - ((3- isopropylisoxazol- (4- (3,4-dichlorophenyl) -5,6-dihydropyridin--1 (2 H) - yl) - N, N - bis ((3-isopropyl-isoxazol-5-yl) methyl ) Ethaneamine Synthesis

Under an argon atmosphere 2- (4- (3,4-dichlorophenyl) -5,6-dihydropyridin--1 (2 H) - yl) ethanamine (549 mg, 2.02 mmol) in anhydrous dichloromethane (41 was added dropwise 3-isopropylisoxazole-5-carbaldehyde (281 mg, 2.02 mmol) dissolved in dichloromethane (8 mL) and then 4 Å molecular sieve powder (1.29 g ). After 2 hours, sodium triacetoxyborohydride (643 mg, 3.03 mmol) was added dropwise and the mixture was stirred at room temperature for 2 hours. The reaction was terminated by TLC, washed with 1 N aqueous sodium hydroxide solution and then extracted with dichloromethane. The organic solution layer was washed again with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and distilled under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ / MeOH = 50: 1) to obtain the title compound, respectively.

2- (4- (3,4-dichlorophenyl) piperidin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) ethanamine: yield 72%, ¹ H _{NMR (300 MHz, CDCl 3)} δ 7.31 (d, J = 1.6 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.07 (dd, J = 8.5 Hz, 1.6 Hz, 1H), 5.94 ( bs, 1H), 3.78 (s , 2H), 3.02 (bs, 2H), 2.96-2.87 (m, 1H), 2.68 (t, J = 5.7 Hz, 2H), 2.57-2.48 (m, 4H), 2.35 (bs, 2H), 2.26 (bs, IH), 1.15 (d, J = 6.9 Hz, 6H)

2- (4- (3,4-dichlorophenyl) -5,6-dihydropyridin--1 (2 H) - yl) - N, N - bis ((3-isopropyl-isoxazol-5-yl ) methyl) ethanamine: yield ^{3%, 1 H NMR (300} MHz, CDCl 3) δ 7.44 (d, J = 2.1 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.20 (dd, J = 8.4 Hz, 2.1 Hz, 1H ), 6.09 (s, 2H), 6.08 (bs, 1H), 3.87 (s, 4H), 3.18 (q, J = 3.0 Hz, 2H), 3.10-3.01 (m, 2H ), 2.81-2.65 (m, 7H), 2.50 (bs, 2H), 1.29 (d, J = 6.9 Hz,

Example 28. N, N - bis ((3-isopropyl-isoxazol-5-yl) methyl) -2- (4- o - tolyl-5,6-dihydropyridine -1 (2 H) - one ) Ethaneamine Synthesis

(-Tolyl-5,6-dihydropyridine -1 (2 H) - 4- o yl) 2 under an argon atmosphere for ethanamine (23 mg, 0.11 mmol) was dissolved in anhydrous dichloromethane (3 mL) 3-isopropylisoxazole-5-carbaldehyde (0.02 mg, 0.11 mmol) dissolved in dichloromethane (2 mL) was added dropwise, followed by addition of 4 분 molecular sieve powder (54 mg). After 2 hours, sodium triacetoxyborohydride (0.03 g, 0.16 mmol) was added dropwise and the mixture was stirred at room temperature for 2 hours. The reaction was terminated by TLC, washed with 1 N aqueous sodium hydroxide solution and then extracted with dichloromethane. The organic solution layer was washed again with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and distilled under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ / MeOH = 50: 1) to give the title compound (4.5 mg, 9%).

^{1 H NMR (300 MHz, CDCl} 3) δ 7.18-7.10 (m, 4H), 6.11 (s, 2H), 5.53 (bs, 1H), 3.89 (s, 4H), 3.16 (d, J = 2.9 Hz, 2H), 3.11-3.00 (m, 2H), 2.82 (t, J = 6.6 Hz, 2H), 2.74-2.67 (m, 4H), 2.39 , ≪ / RTI > J = 7.0 Hz, 12H)

Based on the method illustrated in the above examples, the compound represented by Formula 1 was synthesized. Spectroscopic data of the compound represented by the formula (1) thus prepared are shown below.

Compound 1: [2- [4- (3-Chlorophenyl) -piperazin- 1-yl] -ethyl] - (3- methylisoxazol-

33% ^{yield: 1 H NMR (400 MHz,} CDCl 3) δ ppm 2.24 (s, 3H) 2.45-2.56 (m, 6H) 2.71 (t, J = 5.81 Hz, 2H) 3.14 (br t, J = 5.05 Hz , 5H) 3.86 (s, 2H ) 5.96 (s, 1H) 6.74 (t, J = 6.69 Hz, 2H) 6.82 (t, J = 2.15 Hz, 1H) 7.11 (t, J = 8.08 Hz, 2H)

Compound 2: [2- [4- (3-Chlorophenyl) -piperazin-1-yl] -ethyl] - (3- ethylisoxazol-

33% ^{yield: 1 H NMR (400 MHz,} CDCl 3) δ ppm 1.25 (t, J = 7.58 Hz, 3H) 2.05 (br s, 1H) 2.49-2.59 (m, 6H) 2.67 (q, J = 7.75 Hz , 2H) 2.75 (t, J = 5.94 Hz, 2H) 3.17 (br t, J = 5.31 Hz, 4H) 3.90 (s, 2H) 6.01 (s, 1H) 6.77 (td, J = 8.27, 2.15 Hz, 2H ), 6.85 (t, J = 2.15 Hz, 1 H), 7.14 (t, J = 8.21 Hz,

Compound 3: [2- [4- (3-Chlorophenyl) -piperazin-l-yl] -ethyl] - (3- isopropylisoxazol-

74% ^{yield: 1 H NMR (400 MHz,} CDCl 3) δ ppm 1.15 (d, J = 7.07 Hz, 6H) 2.41 (br d, J = 5.81 Hz, 6H) 2.63 (t, J = 5.81 Hz, 2H) J = 5.05 Hz, 4H) 3.77 (s, 2H) 5.92 (s, 1H) 6.64 (t, J = 7.83 Hz, 2H) 6.73 (d, J = 1.77 Hz, 1 H) 7.01 (t, J = 8.08 Hz, 1 H)

Compound 4: [2- [4- (4-Chlorophenyl) -piperazin-l-yl] -ethyl] - (3-methylisoxazol-

44% ^{yield: 1 H NMR (400 MHz,} CDCl 3) δ ppm 2.28 (s, 3H), 2.59-2.67 (m, 6H), 2.79 (t, J = 5.94 Hz, 2H), 3.17 (br t, J 2H), 7.20 (d, J = 9.09 Hz, 2H), 6.83 (d, J =

Compound 5: [2- [4- (4-Chlorophenyl) -piperazin-1-yl] -ethyl] - (3- ethylisoxazol-

29% ^{yield: 1 H NMR (400 MHz,} CDCl 3) δ ppm 1.25 (t, J = 7.71 Hz, 3H), 2.28 (s, 1H), 2.56 (br t, J = 6.32 Hz, 4H), 2.50- 2H), 2.67 (q, J = 7.75 Hz, 2H), 2.75 (t, J = 5.94 Hz, 2H), 3.14 (br t, J = 5.05 Hz, 4H), 3.90 , 6.02 (s, IH), 6.77 - 6.85 (m, 2H), 7.14 - 7.21 (m, 2H)

Compound 6: [2- [4- (4-Chlorophenyl) -piperazin- 1-yl] -ethyl] - (3- isopropylisoxazol-

27% ^{yield: 1 H NMR (400 MHz,} CDCl 3) δ ppm 1.22 (d, J = 7.07 Hz, 6H), 2.00 (br s, 1H), 2.44-2.58 (m, 6H), 2.71 (t, J = 5.94 Hz, 2H), 2.95-3.02 (m, 1H), 3.08 (br t, J = 5.05 Hz, 4H), 3.85 (s, 2H), 5.99 (s, 1H), 6.77 (d, J = 9.09 Hz, 2H), 7.13 (d, J = 9.09 Hz, 6H)

Compound 7: [2- (4-Benzhydryl-piperazin-1-yl) ethyl] - (3- methylisoxazol-

36% ^{yield: 1 H NMR (400 MHz,} CDCl 3) δ ppm 2.22 (s, 3H), 2.43-2.48 (m, 10H), 2.67 (t, J = 5.94 Hz, 2H), 3.83 (s, 2H) J = 7.58 Hz, 2H), 7.24 (t, J = 7.58 Hz, 4H), 7.40 (d, J = 7.58 Hz, 4H)

Compound 8: [2- (4-Benzhydryl-piperazin-1-yl) ethyl] - (3- ethylisoxazol-

39% ^{yield: 1 H NMR (400 MHz,} CDCl 3) δ ppm 1.25 (q, J = 7.41 Hz, 3H), 2.47 (br s, 6H), 2.51 (t, J = 6.06 Hz, 4H), 2.65 ( 1H, J = 7.58 Hz, 2H), 2.71 (t, J = 6.06 Hz, 2H), 3.08 (br s, , 7.15 (t, J = 6.1 Hz, 2H), 7.26 (t, J = 7.45 Hz, 4H), 7.40 (d, J = 7.07 Hz, 4H)

Compound 9: [2- (4-Benzhydryl-piperazin- 1-yl) ethyl] - (3- isopropylisoxazol-5-ylmethyl) amine

52% ^{yield: 1 H NMR (400 MHz,} CDCl 3) δ ppm 1.22 (d, J = 6.82 Hz, 6H), 2.03 (br s, 1H), 2.42 (br s, 6H), 2.46 (t, J = 6.06 Hz, 4H), 2.67 ( t, J = 5.81 Hz, 2H), 2.95-3.02 (m, 1H), 3.81 (s, 2H), 4.20 (s, 1H), 5.98 (s, 1H), 7.08- J = 8.08 Hz, 4H), 7.17 (m, 2H), 7.23 (t, J = 7.58 Hz,

Compound 10: (3-Methylisoxazol-5-ylmethyl) - [2- (4-phenylpiperazin-1-yl) ethyl] amine

59% ^{yield: 1 H NMR (400 MHz,} CDCl 3) δ ppm 2.21 (s, 3H), 2.43-2.57 (m, 7H), 2.69 (t, J = 5.94 Hz, 2H), 2.91 (s, 1H) , 3.12 (t, J = 5.05 Hz, 4H), 3.83 (s, 2H), 5.93 (s, 1H), 6.78 (t, J = 7.20 Hz, 1H), 6.85 (d, J = 7.83 Hz, 2H) , 7.19 (t, J = 7.33 Hz, 2 H)

Compound 11: (3- ethylisoxazol-5-ylmethyl) - [2- (4-phenylpiperazin-1-yl) ethyl] amine

25% ^{yield: 1 H NMR (400 MHz,} CDCl 3) δ ppm 1.26 (t, J = 7.58 Hz, 3H), 2.11 (br s, 1H), 2.51-2.61 (m, 6H), 2.67 (q, J 2H), 2.76 (t, J = 5.94 Hz, 2H), 3.18 (br t, J = 5.31 Hz, 4H), 3.91 (s, 2H), 6.02 J = 7.20 Hz, 1H), 6.92 (d, J = 7.83 Hz, 2H), 7.20-7.30

Compound 12: (3-Isopropylisoxazol-5-ylmethyl) - [2- (4-phenylpiperazin-1-yl) ethyl] amine

41% ^{yield: 1 H NMR (400 MHz,} CDCl 3) δ ppm 1.28 (d, J = 6.82 Hz, 6H), 2.0 (br s, 1H), 2.56-2.66 (m, 6H), 2.79 (t, J = 5.94 Hz, 2H), 3.01-3.08 (m, 1H), 3.21 (br t, J = 5.05 Hz, 4H), 3.92 (s, 2H), 6.04 (s, 1H), 6.86 (t, J = 7.27 1H), 6.93 (d, J = 7.83 Hz, 2H), 7.22-7.31 (m, 2H)

Compound 13: N - ((3-isopropylisoxazol-5-yl) methyl) -N -methyl-2- (4- (3- (trifluoromethyl) phenyl) piperazin- Amine

67% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.32-7.38 (m, 1H), 7.04-7.11 (m, 3H), 6.06 (s, 1H), 3.75 (s, 2H), 3.24-3.27 (m, 4H), 3.02-3.11 ( m, 1H), 2.56-2.66 (m, 8H), 2.37 (s, 3H), 1.29 (d, J = 6.9 Hz, 6H)

Compound 14: 2- (4- (2,4-dimethylphenyl) piperazin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) ethanamine

50% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.01-6.92 (m, 3H), 6.06 (s, 1H), 3.93 (s, 2H), 3.08-3.01 (m, 1H), 2.61-2.55 (m, 8H), 2.28 ( d, J = 3.3 Hz, 6H), 2.06 (s, 1H), 1.31 (d, J = 21.8 Hz, 6H)

Compound 15: 2- (4- (2,4-dimethylphenyl) piperazin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) - N - methyl ethanamine

93% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 6.92-7.01 (m, 3H), 6.06 (s, 1H), 3.75 (s, 2H), 3.02-3.09 (m, 1H), 2.91-2.94 (m, 4H), 2.57-2.66 ( m, 8H), 2.36 (s, 3H), 2.28 (s, 6H), 1.29 (d, J = 7.0 Hz, 6H)

Compound 16: 2- (4- (4-chlorophenyl) piperazin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) - N - methyl ethanamine

67% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.19-7.23 (m, 2H), 6.82-6.86 (m, 2H), 6.05 (s, 1H), 3.74 (s, 2H), 3.15-3.19 (m, 4H), 3.01-3.08 ( m, 1H), 2.56-2.64 (m, 8), 2.36 (s, 3H), 1.29 (d, J = 6.9 Hz, 6H)

Compound 17: N - ((3- tert -Butylisoxazol -5-yl) methyl) -2- (4- (4- chlorophenyl) piperazin-

33% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.20 (dd, J = 5.0, 2.1 Hz, 2H), 6.84 (dd, J = 5.1, 2.0 Hz, 2H), 6.07 (s, 1H), 2H), 3.91 (s, 2H), 3.14-3.18 (m, 4H), 2.77-2.81 (m, 2H), 2.55-2.60

Compound 18: N - ((3- tert - butyl-isoxazol-5-yl) methyl) -2- (4- (4-chlorophenyl) piperazin-1-yl) - N - methyl ethanamine

97% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.21 (d, J = 6.8 Hz, 2H), 6.84 (d, J = 6.9 Hz, 2H), 6.08 (s, 1H), 3.74 (s, 2H), 3.15-3.19 (m, 4H), 2.56-2.64 (m, 8H)

Compound 19: N - ((3- tert -Butylisoxazol -5-yl) methyl) -2- (4- (3- (trifluoromethyl) phenyl) piperazin-

37% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.33-7.38 (m, 1H), 7.05-7.12 (m, 3H), 6.08 (s, 1H), 3.93 (s, 2H), 3.23-3.27 (m, 4H), 2.78-2.82 (m, 2H), 2.57-2.63 (m, 6H), 1.34

Compound 20: N - ((3- tert -Butylisoxazol -5-yl) methyl) -N -methyl-2- (4- (3- (trifluoromethyl) phenyl) piperazin- Ethanamine

97% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.28-7.35 (m, 1H), 7.05-7.11 (m, 3H), 6.09 (s, 1H), 3.75 (s, 2H), 3.24-3.27 (m, 4H), 2.59-2.66 (m, 8H), 2.37 (s, 3H), 1.34

Compound 21: N - ((3- tert - Butylisoxazol -5-yl) methyl) -2- (4- (2,4-dimethylphenyl) piperazin-

35% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 6.92-7.00 (m, 3H), 6.10 (s, 1H), 3.93 (s, 2H), 2.90-2.93 (m, 4H), 2.80-2.84 (m, 2H), 2.60-2.63 (m, 6H), 2.28 (d, J = 3.5 Hz, 6H)

Compound 22: 2- (4- (4-chlorophenyl) piperazin-1-yl) - N - ((3- isobutyl-isoxazol-5-yl) methyl) ethanamine

33% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.19 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.9 Hz, 2H), 6.01 (s, 1H), 3.92 (s, 2H), 3.13-3.17 (m, 4H ), 2.76-2.79 (m, 2H), 2.51-2.60 (m, 8H), 1.94-2.04 (m, 1H), 0.96 (d, J = 6.6 Hz, 6H)

Compound 23: 2- (4- (4-chlorophenyl) piperazin-1-yl) - N - ((3- isobutyl-isoxazol-5-yl) methyl) - N - methyl ethanamine

99% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.17-7.21 (m, 2H), 6.80-6.86 (m, 2H), 6.01 (s, 1H), 3.75 (s, 2H), 3.15-3.18 (m, 4H), 2.58-2.64 ( m, 8H), 2.53-2.55 (d, J = 8.9 Hz, 2H), 2.35 (s, 3H), 1.92-2.01 (m, 1H), 0.96 (d, J = 6.7 Hz, 6H)

Compound 24: N - ((3-isobutylisoxazol-5-yl) methyl) -2- (4- (3- (trifluoromethyl) phenyl) piperazin-

54% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.35 (t, J = 7.9 Hz, 1H), 7.04-7.11 (m, 3H), 6.01 (s, 1H), 3.93 (s, 2H), 1H), 0.97 (d, J = 6.7 Hz, 6H), 2.32-2.61 (m,

Compound 25: N - ((3-isobutylisoxazol-5-yl) methyl) -N -methyl-2- (4- (3- (trifluoromethyl) phenyl) piperazin- Amine

91% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.37-7.32 (m, 1H) 7.10-7.04 (. M 3H) 6.02 (s, 1H) 3.76 (s, 2H) 3.27-3.23 (m, 4H ) 2.66-2.60 (m, 8H) 2.54 (d, J = 7.1 Hz, 2H) 2.36 (s, 3H) 1.85 (s, 1H) 0.97 (d, J = 6.6 Hz, 6H)

Compound 26: N - (2- (4- (4- chlorophenyl) piperazin-1-yl) ethyl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) propan-2-amine

78% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.20 (d, J = 6.9 Hz, 2H), 6.83 (d, J = 6.9 Hz, 2H), 6.04 (s, 1H), 3.74 (s, 2H), 3.13-3.17 (m, 4H), 2.98-3.05 (m, 2H), 2.67-2.72 (m, 2H), 2.59-2.63 d, J = 7.0 Hz, 6H), 1.05 (d, J = 6.6 Hz, 6H)

Compound 27: N - (2- (4- (2,4- dimethylphenyl) piperazin-1-yl) ethyl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) propan -2 - amine

86% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 6.92-7.01 (m, 3H), 6.06 (s, 1H), 3.75 (s, 2H), 2.99-3.06 (m, 2H), 2.89-2.92 (s, 3H), 2.27 (s, 3H), 1.29 (m, 2H), 2.48-2.73 (m, 2H), 2.55-2.65 , J = 6.9 Hz, 6H), 1.06 (d, J = 6.6 Hz, 6H)

Compound 28: 2- (4- (3,4-dimethylphenyl) piperazin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) ethanamine

34% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.03 (d, J = 7.9 Hz, 1H), 6.75 (s, 1H), 6.69 (dd, J = 8.1, 2.2 Hz, 1H), 6.05 ( (m, 2H), 3.92 (s, 2H), 3.13-3.16 (m, 4H), 3.04-3.11 s, 3H), 2.19 (s, 3H), 1.29 (d, J = 7.0 Hz,

Compound 29: 2- (4- (3,4-dimethylphenyl) piperazin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) - N - methyl ethanamine

88% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.03 (d, J = 8.2 Hz, 1H), 6.75 (s, 1H), 6.69 (dd, J = 8.2, 2.5 Hz, 1H), 6.06 ( 3H), 2.24 (s, 1H), 3.74 (s, 2H), 3.14-3.18 (m, 4H), 3.04-3.11 3H), 2.19 (s, 3H), 1.29 (d, J = 7.0 Hz, 6H)

Compound 30: N - (2- (4- (3,4- dimethylphenyl) piperazin-1-yl) ethyl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) propan -2 - amine

97% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.03 (d, J = 8.2 Hz, 1H), 6.75 (s, 1H), 6.68 (dd, J = 8.2, 2.5 Hz, 1H), 6.05 ( 2H), 2.74 (s, 3H), 2.74 (m, 2H) 2H), 2.24 (s, 3H), 2.19 (s, 3H), 1.05 (d, J = 6.6 Hz, 6H)

Compound 31: N - ((3-isopropyl-isoxazol-5-yl) methyl) - N - (ethyl-2- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl)) Propane-2-amine

81% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.32-7.37 (m, 1H), 7.04-7.10 (m, 3H), 6.05 (s, 1H), 3.75 (s, 2H), 3.21-3.25 (m, 4H), 2.99-3.05 ( m, 2H), 2.70-2.73 (m, 2H), 2.61-2.68 (m, 4H), 2.49-2.51 (m, 2H), 1.29 (d, J = 7.0 Hz , 6H), 1.05 (d, J = 6.6 Hz, 6H)

Compound 32: N - ((3- tert -Butylisoxazol -5-yl) methyl) -2- (4- (3,4-dimethylphenyl) piperazin-

30% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.03 (d, J = 8.2 Hz, 1H), 6.75 (s, 1H), 6.69 (dd, J = 8.2, 2.5 Hz, 1H), 6.08 ( 2H), 2.24 (s, 3H), 2.19 (s, 2H), 3.92 (s, 2H), 3.13-3.16 (m, 4H), 2.77-2.81 3H)

Compound 33: N - ((3- tert - butyl-isoxazol-5-yl) methyl) -2- (4- (3,4-dimethylphenyl) piperazin-1-yl) - N - methyl ethanamine

81% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.03 (d, J = 8.2 Hz, 1H), 6.76 (d, J = 2.3 Hz, 1H), 6.69 (dd, J = 8.2, 2.6 Hz, 3H), 2.24 (s, 3H), 2.19 (s, 3H) (s, 3 H), 1.34 (s, 9 H)

Compound 34: N - ((3- tert - butyl-isoxazol-5-yl) methyl) -2- (4- (2,4-dimethylphenyl) piperazin-1-yl) - N - methyl ethanamine

84% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 6.92-7.01 (m, 3H), 6.09 (s, 1H), 3.75 (s, 2H), 2.92 (t, J = 4.7 Hz, 4H), 3H), 2.28 (s, 6H), 1.34 (s, 9H)

Compound 35: N - ((3-tert - butyl-isoxazol-5-yl) methyl) - N - (2- (methyl) phenyl-4- (3- (trifluoromethyl) piperazin-1-yl) ethyl ) Propan-2-amine

76% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.32-7.37 (m, 1H), 7.04-7.10 (m, 3H), 6.07 (s, 1H), 3.75 (s, 2H), 3.21-3.25 2H), 1.33 (s, 9H), 1.06 (m, 2H) (d, J = 6.6 Hz, 6 H)

Compound 36: 2- (4- (2,4-dimethylphenyl) piperazin-1-yl) - N - ((3- isobutyl-isoxazol-5-yl) methyl) ethanamine

20% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 6.92-7.01 (m, 3H), 6.02 (s, 1H), 3.94 (s, 2H), 2.89-2.92 (m, 4H), 2.76-2.80 (m, 2H), 2.52-2.60 ( m, 8H), 2.28 (s, 3H), 2.27 (s, 3H), 0.97 (d, J = 6.6 Hz, 6H)

Compound 37: 2- (4- (3,4-dimethylphenyl) piperazin-1-yl) - N - ((3- isobutyl-isoxazol-5-yl) methyl) ethanamine

37% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.03 (d, J = 8.2 Hz, 1H), 6.75 (s, 1H), 6.69 (dd, J = 8.2, 2.5 Hz, 1H), 3.93 ( (s, 3H), 2.19 (s, 3H), 1.92-1.97 (m, 2H) m, 1 H), 0.97 (d, J = 6.7 Hz, 6 H)

Compound 38: N - ((3-isopropylisoxazol-5-yl) methyl) -2- (4- (3-trifluoromethylphenyl) piperazin-

48% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.35 (t, J = 7.9 Hz, 1H), 7.11-7.05 (m, 3H), 6.04 (s, 1H), 3.93 (s, 2H), 3.24 (t, J = 4.9 Hz , 4H), 3.11-3.02 (m, 1H), 2.79 (t, J = 5.8 Hz, 2H), 2.62-2.56 (m, 6H), 1.85 (s, 1H), 1.27 (d, J = 9.9 Hz, 6H)

Compound 39: N - ((3-isopropylisoxazol-5-yl) methyl) -2- (4- (4- methoxyphenyl) piperazin-

49% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 6.82-6.92 (m, 4H), 6.04 (s, 1H), 3.91 (s, 2H), 3.77 (s, 3H), 3.03-3.11 (m , 5H), 2.79 (t, J = 5.8 Hz, 2H), 2.55-2.62 (m, 6H), 1.28 (d, J = 6.9 Hz, 6H)

Compound 40: N - ((3- isopropyl-isoxazol-5-yl) methyl) -2- (4- (4-methoxyphenyl) piperazin-1-yl) - N - methyl ethanamine

86% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 6.83-6.92 (m, 4H), 6.05 (s, 1H), 3.77 (s, 3H), 3.74 (s, 2H), 3.04-3.12 (m , 5H), 2.55-2.66 (m, 8H), 2.36 (s, 3H), 1.30 (d, J = 7.0 Hz, 6H)

Compound 41: N - ((3-isopropylisoxazol-5-yl) methyl) -2- (4-p-tolylpiperazin-

26% yield; ¹ H _{NMR (400 MHz, CDCl 3)} δ 7.07 (d, J = 8.2 Hz, 2H), 6.84 (d, J = 13.9 Hz, 2H), 6.04 (s, 1H), 3.91 (s, 2H), 3.14 (t , J = 4.9 Hz, 4H) , 3.05 (septet, J = 6.9 Hz, 1H), 2.78 (t, J = 5.8 Hz, 2H), 2.60-2.27 (m, 6H), 2.55 (s, 3H), 1.95 (s, 1 H), 1.28 (d, J = 6.9 Hz, 6 H)

Compound 42: 2- (4- (2,4-dimethylphenyl) piperazin-1-yl) - N - ((3- isobutyl-isoxazol-5-yl) methyl) - N - methyl ethanamine

83% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 6.92-7.01 (m, 3H), 6.03 (s, 1H), 3.76 (s, 2H), 2.90-2.93 (m, 4H), 2.58-2.63 (m, 7H), 2.55 ( d, J = 7.2 Hz, 2H), 2.36 (s, 3H), 2.28 (s, 6H), 1.93-2.02 (m, 1H), 0.97 (d, J = 6.6 Hz, 6H)

Compound 43: 2- (4- (3,4-dimethylphenyl) piperazin-1-yl) - N - ((3- isobutyl-isoxazol-5-yl) methyl) - N - methyl ethanamine

87% ^{yield: 1 H NMR (400 MHz,} CDCl 3) δ 7.02 (d, J = 8.2 Hz, 1H), 6.75 (s, 1H), 6.68 (dd, J = 8.2, 2.5 Hz, 1H), 6.02 ( 3H), 2.23 (s, 3H), 2.18 (s, 3H), 2.50 (s, , 1.93-198 (m, 1 H), 0.96 (d, J = 6.6 Hz, 6 H)

Compound 44: 2- (4- (3-chlorophenyl) piperazin-1-yl) - N - ((3-isopropyl-isoxazol-5-yl) methyl) - N - methyl ethanamine

94% yield; ¹ H _{NMR (400 MHz, CDCl 3)} δ 7.15 (t, J = 8.0 Hz, 1H), 6.86 (s, 1H), 6.78 (t, J = 10.8 Hz, 2H), 6.04 (s, 1H), 3.73 (s , 2H), 3.19 (t, J = 5.1 Hz, 4H), 3.05 (septet, J = 6.9 Hz, 1H), 2.04-2.63 (m, 6H), 2.34 (s, 3H), 1.27 (t, J = 7.0 Hz, 6H)

Compound 45: N - ((3-isopropylisoxazol-5-yl) methyl) -2- (4- (4- (trifluoromethyl) phenyl) piperazin-

38% ^{yield: 1 H NMR (400 MHz,} CDCl 3) δ 7.47 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 6.04 (s, 1H), 3.92 (s, 2H), 3.27-3.29 (m, 4H ), 3.02-3.09 (m, 1H), 2.76-2.79 (m, 2H), 2.25-2.60 (m, 6H), 1.28 (d, J = 7.0 Hz, 6H)

Compound 46: N - ((3-isopropylisoxazol-5-yl) methyl) -N -methyl-2- (4- (4- (trifluoromethyl) phenyl) piperazin- Amine

91% ^{yield: 1 H NMR (400 MHz,} CDCl 3) δ 7.47 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 6.05 (s, 1H), 3.74 (s, 2H), 3.28-3.31 (m, 4H ), 3.02-3.09 (m, 1H), 2.55-2.65 (m, 8H), 2.36 (s, 3H), 1.29 (d, J = 7.0 Hz, 6H)

Compound 47: N - ((3-isopropylisoxazol-5-yl) methyl) -2- (4- (3- methoxyphenyl) piperazin-

26% yield; ¹ H _{NMR (400 MHz, CDCl 3)} δ 7.17 (t, J = 8.2 Hz, 1H), 6.53 (d, J = 8.2 Hz, 1H), 6.46 (s, 1H), 6.42 (d, J = 6.2 Hz, 1H ), 6.04 (s, 1H) , 3.92 (s, 2H), 3.79 (s, 3H), 3.19 (t, J = 5.1 Hz, 4H), 3.05 (septet, J = 6.9Hz, 1H), 2.79 (t , J = 6.1 Hz, 2H) , 2.56-2.61 (m, 6H), 1.27 (d, J = 7.0 Hz, 6H)

Compound 48: N - ((3-Isopropylisoxazol-5-yl) methyl) -2- (4- m -tolylpiperazin-

67% yield; ¹ H _{NMR (400 MHz, CDCl 3)} δ 7.15 (t, J = 7.9 Hz, 1H), 6.75 (s, 1H), 6.74 (d, J = 8.1 Hz, 1H), 6.7 (d, J = 7.6 Hz, 1H ), 6.04 (s, 1H) , 3.91 (s, 2H), 3.18 (t, J = 4.9 Hz, 4H), 3.06 (septet, J = 7.0 Hz, 1H), 2.78 (t, J = 6.2 Hz, 2H ), 2.32-2.60 (m, 6H) , 2.32 (s, 3H), 1.81 (s, 1H), 1.28 (d, J = 7.0 Hz, 6H)

Compound 49: N - ((3- isopropyl-isoxazol-5-yl) methyl) - N - methyl -2- (4-p- tolyl-l-yl) ethanamine

97% yield; ¹ H _{NMR (300 MHz, CDCl 3)} δ 7.08 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 6.05 (s, 1H), 3.74 (s, 1H), 3.16 (t , J = 4.6 Hz, 4H) , 3.06 (septet, J = 6.9 Hz, 1H), 2.56-2.66 (m, 6H), 2.36 (s, 3H), 2.28 (s, 3H), 1.29 (d, J = 7.0 Hz, 6H)

Compound 50: 2- (4- (4-fluorophenyl) piperazin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) ethanamine

53% ^{yield: 1 H NMR (400 MHz,} CDCl 3) δ 6.93-6.97 (m, 2H), 6.85-6.88 (m, 2H), 6.03 (s, 1H), 3.91 (s, 2H), 3.01-3.91 (m, 5H), 2.76-2.79 (m, 2H), 2.55-2.60 (m, 6H), 1.27 (d, J = 6.9 Hz,

Compound 51: 2- (4- (4-fluorophenyl) piperazin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) - N - methyl ethanamine

82% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 6.94-6.99 (m, 2H), 6.85-6.90 (m, 2H), 6.05 (s, 1H), 3.75 (s, 2H), 3.01-3.15 (m, 5H), 2.57-2.67 (m, 8H), 2.36 (s, 3H), 1.29 (d, J = 6.9 Hz,

Compound 52: 2- (4- (3,4-dichlorophenyl) piperazin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) ethanamine

58% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.26 (d, J = 8.8 Hz, 1H), 6.94 (d, J = 2.8 Hz, 1H), 6.73 (dd, J = 8.9, 2.9 Hz, 1H), 6.04 (s, 1H), 3.91 (s, 2H), 3.14-3.18 (m, 4H), 3.02-3.07 6H), 1.28 (d, J = 7.0 Hz, 6 H)

Compound 53: 2- (4- (3,4-dichlorophenyl) piperazin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) - N - methyl ethanamine

89% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.26 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 2.8 Hz, 1H), 6.73 (dd, J = 8.9, 2.8 Hz, 2H), 2.35 (s, 3H), 3.06-3.19 (m, 4H) , 1.29 (d, J = 6.9 Hz, 6 H)

Compound 54: N - ((3-isopropyl-isoxazol-5-yl) methyl) -2- (4- (3-methoxyphenyl) piperazin-1-yl) - N - methyl ethanamine

47% yield; ¹ H _{NMR (300 MHz, CDCl 3)} δ 7.18 (t, J = 8.2 Hz, 1H), 6.55 (d, J = 6.0 Hz, 1H), 6.47 (s, 1H), 6.42 (d, J = 6.3 Hz, 1H ), 6.05 (s, 1H) , 3.80 (s, 3H), 3.74 (s, 2H), 3.21 (t, J = 5.1 Hz, 4H), 3.06 (septet, J = 6.9 Hz, 1H), 2.56-2.65 (m, 8H), 2.36 (s, 3H), 1.29 (d, J = 7.0 Hz, 6H)

Compound 55: N - ((3- isopropyl-isoxazol-5-yl) methyl) - N - methyl -2- (4- m - tolyl-l-yl) ethanamine

82% yield; ¹ H _{NMR (400 MHz, CDCl 3)} δ 7.15 (t, J = 7.7 Hz, 1H) 6.75 (s, 1H) 6.73 (d, J = 7.9 Hz, 1H) 6.68 (d, J = 7.3 Hz, 1H) 6.05 ( s, 1H) 3.74 (s, 2H) 3.20 (t, J = 4.9 Hz, 4H) 3.05 (septet, J = 6.9 Hz, 1H) 2.63 (t, J = 5.5 Hz, 6H) 2.57 (t, J = 9.8 (D, J = 6.9 Hz, 6H), 2.32 (s, 3H)

Compound 56: 3- (4- (3-chlorophenyl) piperazin-1-yl) - N - ((3-isopropyl-isoxazol-5-yl) methyl) propan-1-amine

74% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.15 (t, J = 8.1 Hz, 1H), 6.86-6.87 (m, 1H), 6.76-6.81 (m, 2H), 6.02 (s, 1H ), 3.88 (s, 2H), 3.17-3.21 (m, 4H), 3.02-3.06 (m, 1H), 2.74 (t, J = 6.8 Hz, 2H), 2.57-2.60 t, J = 7.1 Hz, 2H ), 1.72-1.76 (m, 2H), 1.27 (d, J = 7.0 Hz, 6H)

Compound 57: 3- (4- (3-chlorophenyl) piperazin-1-yl) - N - ((3-isopropyl-isoxazol-5-yl) methyl) - N - methyl-1-amine

99% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.16 (t, J = 8.1 Hz, 1H), 6.88 (s, 1H), 6.78-6.82 (m, 2H), 6.03 (s, 1H), 2H), 3.10-3.22 (m, 4H), 3.01-3.08 (m, 1H), 2.58-2.61 (m, 4H), 2.31 1.29 (d, J = 6.9 Hz, 6 H)

Compound 58: 3- (4- (3,4-dimethylphenyl) piperazin-1-yl) - N - ((3-isopropyl-isoxazol-5-yl) methyl) propan-1-amine

68% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.02 (d, J = 8.2 Hz, 1H), 6.76 (d, J = 2.3 Hz, 1H), 6.69 (dd, J = 8.2, 2.4 Hz, 1H), 6.03 (s, 1H ), 3.88 (s, 2H), 3.13-3.17 (m, 4H), 3.02-3.07 (m, 1H), 2.74 (t, J = 6.8 Hz, 2H), 2.60-2.63 (m, 4H), 2.48 ( t, J = 7.1 Hz, 2H), 2.24 (s, 3H), 2.19 (s, 3H), 1.73-1.78 (m, 2H), 1.28 (d, J = 7.0 Hz, 6H)

Compound 59: 3- (4- (3,4-dimethylphenyl) piperazin-1-yl) - N - ((3-isopropyl-isoxazol-5-yl) methyl) - N - methyl-1- Amine

73% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.03 (d, J = 8.2 Hz, 1H), 6.76 (s, 1H), 6.70 (dd, J = 8.1, 2.4 Hz, 1H), 6.04 ( (m, 4H), 2.42-2.50 (m, 4H), 2.31 (m, 2H) (m, 2H), 1.29 (d, J = 6.9 Hz, 6H), 2.24 (s, 3H)

Compound 60: N - ((3-isopropylisoxazol-5-yl) methyl) -3- (4-

49% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.07 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 6.03 (s, 1H), 3.88 (s, 2H), 3.13-3.17 (m, 4H ), 3.02-3.07 (m, 1H), 2.74 (t, J = 6.7 Hz, 2H), 2.59-2.63 (m, 4H), 2.48 (t, J = 7.1 Hz , 2H), 2.27 (s, 3H), 1.72-1.77 (m, 2H), 1.27 (d, J = 6.9 Hz,

Compound 61: N - ((3-isopropylisoxazol-5-yl) methyl) -N -methyl-3- (4-p-tolylpiperazin-1-yl) propan-

60% ^{yield: 1 H NMR (400 MHz,} CDCl 3) δ 7.08 (d, J = 9.3 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 6.03 (s, 1H), 3.68 (s, 2H), 3.14-3.18 (m, 4H), 3.03-3.10 (m, 1H), 2.60-2.63 (m, 4H), 2.30 2H), 1.29 (d, J = 7.0 Hz, 6H)

Compound 62: 3- (4- (4-phenyl), fluoro-piperazin-1-yl) - N - ((3-isopropyl-isoxazol-5-yl) methyl) propan-1-amine

70% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 6.92-6.98 (m, 2H), 6.84-6.88 (m, 2H), 6.02 (s, 1H), 3.87 (s, 2H), 3.01-3.12 (m, 5H), 2.73 (t, J = 6.7 Hz, 2H), 2.58-2.61 (4H), 2.47 (t, J = 7.1 Hz, 2H), 1.71-1.78 J = 7.0 Hz, 6H)

Compound 63: 3- (4- (4-phenyl), fluoro-piperazin-1-yl) - N - ((3-isopropyl-isoxazol-5-yl) methyl) - N - methyl-1-amine

82% ^{yield: 1 H NMR (400 MHz,} CDCl 3) δ 6.85-6.99 (m, 4H), 6.03 (s, 1H), 3.67 (s, 2H), 3.00-3.15 (m, 5H), 2.60-2.63 (m, 4H), 2.42-2.49 ( m, 4H), 2.30 (s, 3H), 1.72-1.80 (m, 2H), 1.28 (d, J = 7.0 Hz, 6H)

Compound 64: N - ((3-isopropylisoxazol-5-yl) methyl) -3- (4- (4- methoxyphenyl) piperazin- 1 -yl) propan-

31% yield; ¹ H _{NMR (400 MHz, CDCl 3)} δ 6.90 (d, J = 5.2 Hz, 2H), 6.83 (d, J = 5.7 Hz, 2H), 6.02 (s, 1H), 3.88 (s, 2H), 3.77 (s , 3H), 3.09 (t, J = 4.7 Hz, 4H), 3.04 (septet, J = 6.9 Hz, 1H), 2.73 (t, J = 6.8 Hz, 2H), 2.61 (t, J = 4.9 Hz, 4H ), 2.48 (t, J = 7.2 Hz, 2H), 1.74 (t, J = 7.0 Hz, 2H), 1.27 (d, J = 7.0 Hz, 6H)

Compound 65: N - ((3- isopropyl-isoxazol-5-yl) methyl) -3- (4- (4-methoxyphenyl) piperazin-1-yl) - N - methyl-1-amine

49% yield; ¹ H _{NMR (400 MHz, CDCl 3)} δ 6.90 (d, J = 6.9 Hz, 2H), 6.84 (d, J = 6.7 Hz, 2H), 6.03 (s, 1H), 3.77 (s, 3H), 3.68 (s 2H), 3.10 (t, J = 5.1 Hz, 4H), 3.05 (septet, J = 6.9 Hz, 1H), 2.62 (t, J = 4.8 Hz, 4H), 2.42-2.48 (s, 3H), 1.75 ( quintet, J = 7.7 Hz, 2H), 1.29 (d, J = 5.2 Hz, 6H)

Compound 66: 2- (4- (3,4-dimethoxyphenyl) piperazin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) ethanamine

70% ^{yield: 1 H NMR (400 MHz,} CDCl 3) δ 6.78 (d, J = 8.7 Hz, 1H), 6.57 (s, 1H), 6.44 (dd, J = 8.6, 2.5 Hz, 1H), 6.03 ( 2H), 3.86 (s, 3H), 3.83 (s, 3H), 3.01-3.11 (m, 5H), 2.76-2.79 (m, 2H), 2.55-2.61 6H), 1.27 (d, J = 7.0 Hz, 6 H)

Compound 67: 3- (4- (4-Chlorophenyl) piperazin-1-yl) - N - ((3-isopropylisoxazol-5- yl) methyl) propan-

62% ^{yield: 1 H NMR (400 MHz,} CDCl 3) δ 7.16-7.20 (m, 2H), 6.80-6.83 (m, 2H), 6.01 (s, 1H), 3.86 (s, 2H), 3.12-3.15 (m, 4H), 2.99-3.04 ( m, 1H), 2.72 (t, J = 6.8 Hz, 2H), 2.56-2.59 (m, 4H), 2.45 (t, J = 7.1 Hz, 2H), 1.70- 1.76 (m, 2H), 1.25 (d, J = 7.0 Hz, 6H)

Compound 68: 3- (4- (4-chlorophenyl) piperazin-1-yl) - N - ((3-isopropyl-isoxazol-5-yl) methyl) - N - methyl-1-amine

68% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.17-7.21 (m, 2H), 6.82-6.86 (m, 2H), 6.03 (s, 1H), 3.67 (s, 2H), 3.15-3.18 (m, 4H), 2.30 (s, 3H), 1.72-1.79 (m, 2H), 1.28 (d, J = 7.0 Hz, 6 H)

Compound 69: N - ((3-isopropylisoxazol-5-yl) methyl) -3- (4- (3-methoxyphenyl) piperazin- 1 -yl) propan-

36% yield; ¹ H _{NMR (400 MHz, CDCl 3)} δ 7.17 (t, J = 8.2 Hz, 1H), 6.54 (d, J = 6.1 Hz, 1H), 6.46 (s, 1H), 6.41 (d, J = 6.2 Hz, 1H 2H), 3.87 (s, 3H), 3.19 (t, J = 5.1 Hz, 4H), 3.04 (septet, J = 7.0 Hz, 1H), 2.73 , J = 6.8 Hz, 2H) , 2.59 (t, J = 5.0 Hz, 4H), 2.47 (t, J = 7.3 Hz, 2H), 1.74 (d, J = 7.0 Hz, 2H), 1.27 (d, J = 7.0 Hz, 6H)

Compound 70: N - ((3-isopropyl-isoxazol-5-yl) methyl) -3- (4- (3-methoxyphenyl) piperazin-1-yl) - N - methyl-1-amine

77% yield; ¹ H _{NMR (400 MHz, CDCl 3)} δ 7.17 (t, J = 8.2 Hz, 1H), 6.55 (d, J = 6.0 Hz, 1H), 6.47 (s, 1H), 6.42 (d, J = 5.8 Hz, 1H ), 6.03 (s, 1H) , 3.79 (s, 3H), 3.68 (s, 2H), 3.20 (t, J = 5.1 Hz, 4H), 3.04 (septet, J = 6.9 Hz, 1H), 2.60 (t , J = 4.9 Hz, 4H) , 2.41-2.48 (m, 4H), 2.30 (s, 3H), 1.74 (quintet, J = 7.6 Hz, 2H), 1.28 (d, J = 7.0 Hz, 6H)

Compound 71: N - ((3- isopropyl-isoxazol-5-yl) methyl) -3- (4- m - tolyl-piperazin-1-yl) propan-1-amine

69% ^{yield: 1 H NMR (400 MHz,} CDCl 3) δ 7.14 (t, J = 7.7 Hz, 1H), 6.72-6.74 (m, 2H), 6.68 (d, J = 7.3 Hz, 1H), 6.02 ( (m, 4H), 2.73 (t, J = 6.7 Hz, 2H), 2.58-2.61 (m, 4H) , 2.47 (t, J = 7.1 Hz, 2H), 1.72-1.76 (m, 2H), 1.27 (d, J = 6.9 Hz, 6H)

Compound 72: N - ((3- isopropyl-isoxazol-5-yl) methyl) - N - methyl -3- (4- m - tolyl-piperazin-1-yl) propan-1-amine

53% ^{yield: 1 H NMR (400 MHz,} CDCl 3) δ 7.15 (t, J = 7.7 Hz, 1H), 6.73-6.75 (m, 2H), 6.68 (d, J = 7.3 Hz, 1H), 6.03 ( 2H), 3.18-3.21 (m, 4H), 3.03-3.07 (m, 1H), 2.59-2.62 (m, 4H), 2.41-2.48 , 3H), 2.30 (s, 3H), 1.73-1.77 (m, 2H), 1.28 (d, J = 7.0 Hz, 6H)

Compound 73: 3- (4- (3,4-dichlorophenyl) piperazin-1-yl) - N - ((3-isopropyl-isoxazol-5-yl) methyl) propan-1-amine

18% yield; ¹ H _{NMR (400 MHz, CDCl 3)} δ 7.27 (d, J = 8.9 Hz, 1H), 6.95 (s, 1H), 6.74 (d, J = 6.0 Hz, 1H), 6.10 (s, 1H), 3.93 (s , 2H), 3.18 (t, J = 5.1 Hz, 4H), 3.04 (septet, J = 6.9 Hz, 1H), 2.80 (t, J = 6.5 Hz, 2H), 2.64 (t, J = 5.0 Hz, 4H ), 2.53 (t, J = 6.9 Hz, 2H), 2.18 (s, 2H), 2.05 (s, 3H), 1.78 (quintet, J = 6.7 Hz, 2H), 1.27 (d, J = 4.4 Hz, 6H )

Compound 74: 3- (4- (3,4-dichlorophenyl) piperazin-1-yl) - N - ((3-isopropyl-isoxazol-5-yl) methyl) - N - methyl-1- Amine

63% yield; ¹ H _{NMR (400 MHz, CDCl 3)} δ 7.26 (d, J = 9.6 Hz, 1H), 6.95 (s, 1H), 6.74 (d, J = 6.1 Hz, 1H), 6.02 (s, 1H), 3.67 (s 2H), 3.17 (t, J = 5.1 Hz, 4H), 3.05 (septet, J = 7.0 Hz, 1H), 2.58 (t, J = 4.9 Hz, 4H), 2.40-2.48 (s, 3H), 1.75 ( quintet, J = 7.2 Hz, 2H), 1.28 (d, J = 7.0 Hz, 6H)

Compound 75: 3- (4- (3,4-dimethoxyphenyl) piperazin-1-yl) - N - ((3-isopropyl-isoxazol-5-yl) methyl) propan-1-amine

51% ^{yield: 1 H NMR (400 MHz,} CDCl 3) δ 6.79 (d, J = 8.7 Hz, 1H), 658 (d, J = 2.6 Hz, 1H), 6.46 (dd, J = 8.7, 2.7 Hz, 1H), 6.03 (s, 1H ), 3.88 (s, 2H), 3.87 (s, 3H), 3.84 (s, 3H), 3.03-3.12 (m, 5H), 2.74 (t, J = 6.8 Hz, 2H J = 7.0 Hz, 2H), 1.72-1.78 (m, 2H), 1.27 (d, J = 7.0 Hz, 6H)

Compound 76: 2- (4- (4-chlorophenyl) -2-methylpiperazin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) ethanamine

49% ^{yield: 1 H NMR (400 MHz,} CDCl 3) δ 7.19 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 6.03 (s, 1H), 3.90 (s, 2H), 3.30-3.35 (m, 2H), 2.90-3.06 (m, 4H), 2.71-2.72 (m, 2H), 2.61-2.64 (s, 1H), 1.28 (d, J = 7.0 Hz, 6H), 1.12 (d, J = 5.9 Hz,

Compound 77: 2- (4- (3,4-dichlorophenyl) -2-methylpiperazin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) ethanamine

29% ^{yield: 1 H NMR (400 MHz,} CDCl 3) δ 7.23-7.25 (m, 1H), 6.90 (s, 1H), 6.70 (dd, J = 8.9, 2.9 Hz, 1H), 6.02 (s, 1H ), 3.89 (d, J = 3.5 Hz, 2H), 3.28-3.32 (m, 2H), 2.88-3.05 (m, 4H), 2.47-2.82 (m, 4H), 2.29-2.34 (m, 2H), (D, J = 7.0 Hz, 6H), 1.10 (d, J = 6.2 Hz, 3H)

Compound 78: N - ((3-isopropylisoxazol-5-yl) methyl) -2- (4- (4- (trifluoromethoxy) phenyl) piperazin-

50% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.13-7.16 (m, 2H), 6.88-6.93 (m, 2H), 6.07 (s, 1H), 3.94 (s, 2H), 3.05-3.23 (m, 5H), 2.78-2.83 (m, 2H), 2.58-2.64 (m, 6H), 1.32 (d, J = 6.9 Hz,

Compound 79: 2- (4- (3,5-dichlorophenyl) piperazin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) ethanamine

30% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 6.80 (s, 1H), 6.74 (s, 2H), 6.05 (s, 1H), 3.93 (s, 3H), 3.19-3.22 (m, 4H 2H), 2.55-2.58 (m, 6H), 1.82 (s, IH), 1.29 (d, J = 7.0 Hz, 6H)

Compound 80: 2- (1- (4-fluorophenyl) piperidin-4-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) ethanamine

49% _{^{yield: 1 H NMR (CDCl 3,}} 300 MHz) δ 1.29 (d, J = 6.95 Hz, 6H), 1.38-1.53 (m, 7H), 1.79 (bd, J = 11.28 Hz, 2H), 2.64 ( (t, J = 12.07 Hz, 2H), 2.72 (t, J = 7.23 Hz, 2H), 3.04-3.08 (m, 1H), 3.53 (bd, J = 12.33 Hz, 2H) 6.03 (s, 1 H), 6.86 - 6.98 (m, 4 H)

Compound 81: 2- (l- (4-Chlorophenyl) piperidin-4-yl) - N - ((3- isopropyl isoxazol-

67% _{^{yield: 1 H NMR (CDCl 3,}} 300 MHz) δ 0.97 (d, J = 6.60 Hz, 6H), 1.51 (m, 8H), 1.78 (bd, J = 11.57 Hz, 2H), 2.64-2.74 ( m, 4H), 3.06 (m , 1H), 3.61 (d, J = 12.62 Hz, 2H), 3.89 (s, 2H), 6.03 (s, 1H), 6.85 (dd, J = 4.71 Hz, J = 2.16 Hz, 2H), 7.19 (dd, J = 4.73 Hz, J = 2.13 Hz, 2H)

Compound 82: N - ((3- tert -Butylisoxazol -5-yl) methyl) -2- (1- (4- chlorophenyl) piperidin-

54% Yield: ¹ H NMR (CDCl ₃ , 300 MHz)? 0.96 (d, J = 4.98 Hz, 9H), 1.23-1.40 (m, 3H), 1.49 (t, J = 3.24 Hz, bd, J = 9.24 Hz, 2H ), 1.92-1.97 (m, 3H), 2.53 (q, J = 2.85 Hz, 3H), 2.65-2.72 (m, 4H), 3.59 (bd, J = 9.24 Hz, 2H ), 3.90 (s, 2H) , 5.99 (s, 1H), 6.84 (dt, J = 6.75 Hz, J = 2.49 Hz, 2H), 7.18 (dt, J = 6.75 Hz, J = 2.46 Hz, 2H)

Compound 83: N - ((3- tert - Butylisoxazol -5-yl) methyl) -2- (1- (4- fluorophenyl) piperidin-

45% _{^{yield: 1 H NMR (CDCl 3,}} 300 MHz) δ 1.33 (s, 9H), 1.36-1.53 (m, 7H), 1.79 (bd, J = 11.62 Hz, 2H), 2.64 (t, J = 11.72 2H), 2.72 (t, J = 7.01 Hz, 2H), 3.53 (bd, J = 12.44 Hz, 2H), 3.89 (s, 2H), 6.06 )

Compound 84: N - ((3-isopropylisoxazol-5-yl) methyl) -2- (1- (4- (trifluoromethyl) phenyl) piperidin-

27% Yield: ¹ H NMR (CDCl ₃ , 300 MHz)? 1.28 (d, J = 6.95 Hz, 6H), 1.46-1.53 (m, 3H), 1.78 (bd, J = 12.56 Hz, 2H) bs, 2H), 2.69-2.82 (m , 4H), 3.03-3.08 (m, 1H), 3.78 (bd, J = 12.62 Hz, 2H), 3.89 (s, 2H), 6.04 (s, 1H), 6.91 (d, J = 8.69 Hz, 2H), 7.45 (d, J = 8.72 Hz, 2H)

Compound 85: N - ((3-isopropylisoxazol-5-yl) methyl) -2- (1- p -tolylpiperidin-

47% _{^{yield: 1 H NMR (CDCl 3,}} 300 MHz) δ 1.28 (d, J = 5.21 Hz, 6H), 1.34-1.46 (m, 3H), 1.51 (s, 4H), 1.77 (bd, J = 8.68 2H), 2.26 (s, 3H), 2.63 (td, J = 8.85 Hz, J = 1.65 Hz, 2H), 2.71 (t, J = 5.16 Hz, 2H) 3.59 (bd, J = 9.29 Hz , 2H), 3.89 (s, 2H), 6.03 (s, 1H), 6.86 (d, J = 6.41 Hz, 2H), 7.06 (d, J = 6.26 Hz, 2H)

Compound 86: 2- (1- (3,4-dichlorophenyl) piperidin-4-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) ethanamine

94% _{^{yield: 1 H NMR (CDCl 3,}} 300 MHz) δ 1.27 (d, J = 6.95 Hz, 6H), 1.32-1.36 (m, 2H), 1.46-1.52 (m, 3H), 1.76 (bd, J = 12.33 Hz, 2H), 2.68 (td, J = 12.00 Hz, J = 2.58 Hz, 4H), 3.02-3.06 (m, 1H), 3.59 (bd, J = 12.48 Hz, 2H), 3.88 (s, 2H ), 6.02 (s, 1H) , 6.72 (dd, J = 8.95 Hz, J = 2.87 Hz, 1H), 6.94 (d, J = 2.86 Hz, 2H), 7.23 (d, J = 8.93 Hz, 2H)

Compound 87: N - ((3-isopropylisoxazol-5-yl) methyl) -2- (1- (4- methoxyphenyl) piperidin-

22% _{^{yield: 1 H NMR (CDCl 3,}} 300 MHz) δ 1.29 (d, J = 6.94 Hz, 6H), 1.43-1.54 (m, 3H), 1.78 (bd, J = 9.58 Hz, 2H), 2.62 ( bt, J = 11.14 Hz, 2H ), 2.74 (t, J = 7.06 Hz, 2H), 2.88 (bs, 4H), 3.01-3.11 (m, 1H), 3.49 (bd, J = 11.78 Hz, 2H), 2H), 6.93 (d, J = 9.08 Hz, 2H), 6.83 (d, J =

Compound 88: 2- (l- (3-Chlorophenyl) piperidin-4-yl) - N - ((3-isopropylisoxazol-

45% _{^{yield: 1 H NMR (CDCl 3,}} 400 MHz) δ 7.15-6.75 (m, 4H), 6.10 (s, 1H), 4.05 (s, 2H), 3.89 (m, 2H), 3.07-3.03 (m 2H), 1.51-1.29 (m, 6H), 1.27 (d, 6H, J = 3.00 Hz), 2.73-2.67 (m, 4H)

Compound 89: 2- (1- (3-fluorophenyl) piperidin-4-yl) - N - ((3-isopropyl-isoxazol-5-yl) methyl) ethanamine

23% _{^{yield: 1 H NMR (CDCl 3,}} 400 MHz) δ 7.17-6.48 (m, 4H), 6.02 (s, 1H), 3.89 (s, 2H), 3.67 (m, 2H), 3.07-3.03 (m 2H), 1.51-1.33 (m, 6H), 1.28 (d, 6H, J = 3.89 Hz), 2.74-2.69 (m, 4H)

Compound 90: N - ((3- isopropyl-isoxazol-5-yl) methyl) -2- (1- m - tolyl rilpi-4-yl) ethanamine

11% _{^{yield: 1 H NMR (CDCl 3,}} 400 MHz) δ 7.15 (t, 1H, J = 7.82 Hz), 6.76 (m, 2H), 6.66 (dd, 1H, J = 7.89 Hz), 6.03 (s, 3H), 1.78 (m, 2H), 1.51 (m, 5H), 3.73 (m, 2H) ), 1.28 (d, 6H, J = 2.86 Hz)

Compound 91: N - ((3-isopropylisoxazol-5-yl) methyl) -2- (1- (3- (trifluoromethyl) phenyl) piperidin-

37% _{^{yield: 1 H NMR (CDCl 3,}} 400 MHz) δ 7.34-7.02 (m, 4H), 6.02 (s, 1H), 3.89 (s, 2H), 3.71 (m, 2H), 3.07 (m, 1H ), 2.77-2.70 (m, 4H), 1.81 (m, 2H), 1.52-1.32 (m, 6H), 1.28 (d, 6H, J =

Compound 92: 2- (1- (2- ((3-isopropylisoxazol-5-yl) methylamino) ethyl) -1,2,3,6-tetrahydropyridin-4-yl) benzonitrile

57% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.64 (td, J = 4.1 Hz, 2.5 Hz, 1H), 7.53 (dt, J = 10.5 Hz, 3.9 Hz, 1H), 7.35-7.27 (m 2H), 6.06 (s, IH), 5.99 (bs, IH), 3.92 (s, 2H), 3.19 (q, J = 2.7 Hz, 2H), 3.09-3.0 J = 5.9 Hz, 2H), 2.73 (t, J = 5.5 Hz, 2H), 2.65 (t, J = 5.9 Hz, 2H), 2.55 (bs, 2H), 1.27 (d, J = 7.0 Hz, 6H)

Compound 93: N - ((3-isopropylisoxazol-5-yl) methyl) -2- (4-phenyl-1,2,3,6-tetrahydropyridin-

39% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.24 (d, J = 6.9 Hz, 2H), 7.15 (t, J = 7.2 Hz, 2H), 7.07 (t, J = 6.7 Hz, 1H) , 5.90 (bs, 2H), 3.73 (s, 2H), 2.99 (bs, 2H), 2.93-2.84 (m, 1H), 2.64 (t, J = 5.4 Hz, 2H), 2.60 (bs, 1H), 2.53 (t, J = 5.2 Hz , 2H), 2.46 (t, J = 5.6 Hz, 2H), 2.40 (bs, 2H), 1.13 (d, J = 6.9 Hz, 6H)

Compound 94: 2- (4- (4-chlorophenyl) -1,2,3,6-tetrahydro-pyridin-4-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) Ethanamine

25% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.32-7.25 (m, 4H), 6.04 (bs, 2H), 3.91 (s, 2H), 3.14 (d, J = 3.1 Hz, 2H), 3.09-3.00 (m, 1H), 2.81 (t, J = 6.0 Hz, 2H), 2.69 (t, J = 5.6 Hz, 2H), 2.63 (t, J = 6.0 Hz, 2H), 2.52 (bs, 2H ), 2.04 (bs, 1H), 1.27 (d, J = 7.0 Hz, 6H)

Compound 95: 3- (1- (2- ((3-isopropylisoxazol-5-yl) methylamino) ethyl) -1,2,3,6-tetrahydropyridin-4-yl) benzonitrile

53% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.63 (s, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 6.12 (bs, 1H), 6.03 (s, 1H), 3.90 (s, 2H), 3.16 (q, J = 2.8 Hz, 2H), 3.08-2.99 2.81 (t, J = 5.9 Hz , 2H), 2.70 (t, J = 5.6 Hz, 2H), 2.63 (t, J = 5.9 Hz, 2H), 2.52 (bs, 2H), 1.97 (bs, 1H)

Compound 96: N - ((3-isopropylisoxazol-5-yl) methyl) -2- (4- (4-methoxyphenyl) -1,2,3,6-tetrahydropyridin- ) Ethanamine

35% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.31 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.9 Hz, 2H), 6.03 (s, 1H), 5.95 (bs, 1H), 3.90 (s, 2H ), 3.78 (s, 3H), 3.12 (d, J = 3.1 Hz, 2H), 3.08-2.99 (m, 1H), 2.80 (t, J = 6.0 Hz, 2H), 2.68 (t, J = 5.6 Hz , 2H), 2.61 (t, J = 6.0 Hz, 2H), 2.52 (bs, 2H), 2.00 (bs, 1H), 1.26 (d, J = 7.0 Hz, 6H)

Compound 97: N, N -bis ((3-isopropylisoxazol-5-yl) methyl) -2- (4- o- tolyl- 1,2,3,6-tetrahydropyridin- Ethanamine

9% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.18-7.10 (m, 4H), 6.11 (s, 2H), 5.53 (bs, 1H), 3.89 (s, 4H), 3.16 (d, J = 2.9 Hz, 2H), 3.11-3.00 (m, 2H), 2.82 (t, J = 6.6 Hz, 2H), 2.74-2.67 (m, 4H), 2.39 (bs, 2H), 2.30 (s, 3H) , 1.30 (d, J = 7.0 Hz, 12 H)

Compound 98: 2- (4- (3,4-dichlorophenyl) -1,2,3,6-tetrahydro-pyridin-4-yl) - N - ((3- isopropyl-isoxazol-5-yl ) Methyl) ethanamine

72% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.31 (d, J = 1.6 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.07 (dd, J = 8.5 Hz, 1.6 Hz 2H), 2.96-2.87 (m, 1H), 2.68 (t, J = 5.7 Hz, 2H), 2.57-2.48 2H), 2.26 (bs, IH), 1.15 (d, J = 6.9 Hz, 6H)

Compound 99: 2- (4- (3,4-Dichlorophenyl) -1,2,3,6-tetrahydropyridin-4-yl) - N, N- 5-yl) methyl) ethanamine

3% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.44 (d, J = 2.1 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.20 (dd, J = 8.4 Hz, 2.1 Hz , 1H), 6.09 (s, 2H), 6.08 (bs, 1H), 3.87 (s, 4H), 3.18 (q, J = 3.0 Hz, 2H), 3.10-3.01 (m, 2H), 2.81-2.65 ( m, 7H), 2.50 (bs, 2H), 1.29 (d, J = 6.9 Hz, 12H)

Compound 100: Synthesis of 2- (4- (3,4-dichlorophenyl) piperidin- 1 -yl) - N - ((3-isopropylisoxazol-5- yl) methyl) ethanamine

77% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.31 (d, J = 1.6 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.07 (dd, J = 8.5 Hz, 1.6 Hz 2H), 2.46-2.35 (m, 2H +), 2.68 (t, J = 1H), 1.97 (dt, J = 17.6 Hz, 7.3 Hz, 2H + 1H), 1.77-1.71 (m, 4H), 1.15 (d, J = 5.8 Hz, 6H)

Compound 101: N - ((3-isopropylisoxazol-5-yl) methyl) -2- (4- phenylpiperidin- 1 -yl)

37% ^{yield: 1 H NMR (300 MHz,} CDCl 3) δ 7.29-7.24 (m, 2H), 7.21-7.13 (m, 3H), 6.02 (s, 1H), 3.87 (s, 2H), 3.06-2.94 (m, 2H + 1H), 2.74 (t, J = 5.8 Hz, 2H), 2.52-2.41 (m, 2H + 1H), 2.03 (dt, J = 15.8 Hz, 5.5 Hz, 2H + 1H), 1.78- 1.72 (m, 4H), 1.25 (d, J = 7.0 Hz, 6H)

Compound 102: methyl 5 - ((2- (4-phenylpiperazin-1-yl) ethylamino) methyl) isoxazole-

53.5% _{^{yield: 1 H NMR (CDCl 3,}} 400 MHz) δ 7.29 (t, 2H), 6.95 (d, 2H, J = 1.20 Hz), 6.89 (t, 1H), 6.62 (s, 1H), 4.03 ( s, 2H), 3.98 (s, 3H), 3.21 (m, 4H), 2.78 (t, 2H), 2.63-2.57 (m, 6H), 2.00 (bs, 1H).

Compound 103: Ethyl 5 - ((2- (4-phenylpiperazin-1-yl) ethylamino) methyl) isoxazole-

53.5% _{^{yield: 1 H NMR (CDCl 3,}} 400 MHz) δ 7.27 (t, 2H), 6.92 (d, 2H, J = 10.66 Hz), 6.84 (t, 1H), 6.61 (s, 1H), 4.46 ( (m, 4H), 2.45 (m, 2H), 4.02 (s, 2H), 3.21 (m, 4H), 2.75 (t, 2H), 2.61-2.55 (m, 6H), 1.90 (bs,

Compound 104: Ethyl 5 - ((2- (4-phenylpiperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate hydrochloride

Ethyl 5 - ((2- (4-piperazin-1-yl) ethylamino) methyl) oxazol-3-carboxylate (Compound 103) (40 mg 10 mmol) , 1M-HCl Et 2 O solution, 10 mL To obtain 42 mg (95%) of the desired compound by crystallization.

95% Yield: ¹ H NMR (CDCl ₃ , 400 MHz)? 7.26 (t, 2H), 6.90 (d, 2H, J = 10.24 Hz), 6.84 q, 2H), 4.03 (s, 2H), 3.23 (m, 4H), 2.75 (t, 2H), 2.61-2.55 (m, 6H), 1.42 (t,

Compound 105: Sodium 5 - ((2- (4-phenylpiperazin-1-yl) ethylamino) methyl) isoxazole-

Ethyl) amino) methyl) isoxazole-3-carboxylate (Compound 103) (40 mg, 10 mmol) was reacted with Na Salt compound 35 mg (90%) of the desired compound was obtained.

90% _{^{yield: 1 H NMR (CDCl 3,}} 400 MHz) δ 7.27 (t, 2H), 6.92 (d, 2H, J = 10.66 Hz), 6.84 (t, 1H), 6.61 (s, 1H), 4.03 ( 2H), 3.21 (m, 4H), 2.75 (t, 2H), 2.61-2.55

Compound 106 Ethyl 5 - ((2- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) ethylamino) methyl) isoxazole-

56.0% _{^{yield: 1 H NMR (CDCl 3,}} 400 MHz) δ 7.37 (t, 4H), 7.00 (t, 4H), 6.59 (s, 1H), 4.43 (q, 2H), 4.21 (s, 1H), 3.96 (s, 2H), 2.70 (t, 2H), 2.52-2.31 (m, 10H), 1.42 (t, 3H).

Compound 107: A mixture of sodium 5 - ((2- (4- (bis (4-fluorophenyl) methyl) piperazin- 1 -yl) ethylamino) methyl) isoxazole-

90% _{^{yield: 1 H NMR (CDCl 3,}} 400 MHz) δ 7.35 (t, 4H), 6.97 (t, 4H), 6.57 (s, 1H), 4.21 (s, 1H), 3.96 (s, 2H), 2.70 (t, 2H), 2.52 - 2.31 (m, 10H).

Compound 108: ethyl 5 - ((2- (4-benzhydrylpiperazin-1-yl) ethylamino) methyl) isoxazole-

55.8% _{^{yield: 1 H NMR (CDCl 3,}} 400 MHz) δ 7.42 (t, 4H), 7.29 (t, 4H), 7.17 (t, 2H), 6.57 (s, 1H), 4.46 (q, 2H), 2H), 2.73 (t, 2H), 2.53-2.46 (m, 10H), 1.40 (t, 3H).

Compound 109: Sodium 5 - ((2- (4-benzhydrylpiperazin-1-yl) ethylamino) methyl) isoxazole-

90% _{^{yield: 1 H NMR (CDCl 3,}} 400 MHz) δ 7.44 (t, 4H), 7.26 (t, 4H), 7.16 (t, 2H), 6.57 (s, 1H), 4.22 (s, 1H), 3.96 (s, 2H), 2.73 (t, 2H), 2.53 - 2.46 (m, 10H).

Compound 110: 2- (4-benzhydryl-piperazin-1-yl) - N - ((3- methyl-isoxazol-5-yl) methyl) ethanamine

52.1% _{^{yield: 1 H NMR (CDCl 3,}} 400 MHz) δ 7.42 (t, 4H), 7.29 (t, 4H), 7.20 (t, 2H), 5.97 (s, 1H), 4.23 (s, 1H), 2.70 (t, 2H), 2.53-2.46 (m, 10H), 2.27 (s, 3H).

Compound 111: 2- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) - N - ((3- methyl-isoxazol-5-yl) methyl) ethanamine

56.1% _{^{yield: 1 H NMR (CDCl 3,}} 400 MHz) δ 7.35 (t, 4H), 6.98 (t, 4H), 5.96 (s, 1H), 4.20 (s, 1H), 3.86 (s, 2H), 2.69 (t, 2H), 2.51 - 2.43 (m, 10H), 2.26 (s, 3H).

Compound 112: 2- (4- (bis (4-chlorophenyl) methyl) piperazin-1-yl) - N - ((3- methyl-isoxazol-5-yl) methyl) ethanamine

55.6% _{^{yield: 1 H NMR (CDCl 3,}} 400 MHz) δ 7.32-7.22 (q, 8H), 5.97 (s, 1H), 4.18 (s, 1H), 3.87 (s, 2H), 2.71 (t, 2H ), 2.53-2.39 (m, 10H), 2.26 (s, 3H).

Compound 113: ethyl 5 - ((2- (4- (bis (4-chlorophenyl) methyl) piperazin-1-yl) ethylamino) methyl) isoxazole-

57.8% _{^{yield: 1 H NMR (CDCl 3,}} 400 MHz) δ 7.31-7.25 (q, 8H), 5.96 (s, 1H), 4.34 (q, 2H), 4.18 (s, 1H), 3.97 (s, 2H ), 2.69 (t, 2H), 2.50-2.43 (m, 10H), 1.40 (t, 3H).

Compound 114: 5 - ((2- (4- (Bis (4-fluorophenyl) methyl) piperazin-1-yl) ethylamino) methyl) isoxazole-

Ethyl) amino) methyl) isoxazole-3-carboxylate (Compound 106) (50 mg, 1.03 < RTI ID = 0.0 & mmol), NH ₄ OH (0.2 mL), and methanol (1.1 mL) were stirred at room temperature for 2 hours, and then the solvent was removed and purified by column chromatography to obtain 42.8 mg (85%) of the target compound.

85% _{^{yield: 1 H NMR (CDCl 3,}} 400 MHz) δ 7.36 (t, 4H), 6.97 (t, 4H), 6.70 (bs, 1H), 6.61 (s, 1H), 5.61 (bs, 1H), 4.21 (s, 1H), 3.97 (s, 2H), 2.70 (t, 2H), 2.52-2.33 (m, 10H).

Compound 115: 5 - ((2- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) ethylamino) methyl) - N-methyl-isoxazole-3-carboxamide

Ethyl) amino) methyl) isoxazole-3-carboxylate (Compound 106) (50 mg, 1.03 < RTI ID = 0.0 & mmol), methanol (5 mL) and 2M-methylamine (1.5 mL), and the mixture was stirred at room temperature for 3 hours. After removing the solvent, 46.5 mg (95%) of Compound 64 was obtained from the column chromatography.

95% _{^{yield: 1 H NMR (CDCl 3,}} 400 MHz) δ 7.36 (t, 4H), 6.97 (t, 4H), 6.78 (bs, 1H), 6.59 (s, 1H), 4.21 (s, 1H), 3.96 (s, 2H), 3.00 (d, 3H, J = 6.67 Hz), 2.70 (t, 2H), 2.52-2.31 (m, 10H).

Compound 116: 5 - ((2- (4- (Bis (4-fluorophenyl) methyl) piperazin-1-yl) ethylamino) methyl) -N, N -dimethylisoxazole-

Ethyl) amino) methyl) isoxazole-3-carboxylate (Compound 106) (50 mg, 1.03 < RTI ID = 0.0 & mmol), methanol (5 mL) and 2M-dimethylamine (1.5 mL), and the mixture was stirred at room temperature for 3 hours. After removal of the solvent, 49.0 mg (95%) of Compound 65 was obtained from the column chromatography.

95% _{^{yield: 1 H NMR (CDCl 3,}} 400 MHz) δ 7.36 (t, 4H), 6.97 (t, 4H), 6.49 (s, 1H), 4.21 (s, 1H), 3.96 (s, 2H), 3.25 (s, 3H), 3.12 (s, 3H), 2.72 (t, 2H), 2.52-2.44 (m, 10H).

[Formulation Example]

Meanwhile, the novel compounds represented by Formula 1 according to the present invention can be formulated into 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: Tablets (direct pressurization)

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 assembly)

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.

Formulation 3: Powder and Capsule

5.0 mg of the active ingredient was sieved and mixed with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone and 0.2 mg of magnesium stearate. The mixture was filtered through a hard No. 5 gelatin capsules.

Formulation 4: Injection

100 mg as an active ingredient, 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ .12H ₂ O and 2974 mg of distilled water were added to prepare an injection.

[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. Then 10 minutes before the FDSS6000 instrument was washed once with HEPES buffer containing 10 mM CaCl ₂ , and the final volume was adjusted to 81 μL. Two 96-well drug plates containing KCl (final concentration 75 mM) and a blocking agent to activate the T-type calcium channel separately from the cell-prepared 96-well plate were prepared. 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.

Detailed calcium imaging techniques were used to selectively expose excitation wavelengths (340 nm and 380 nm) to a cell by means of a computer-controlled filter wheel illuminating four light sources of a xenon lamp mounted on a 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 transfer to the T-type calcium channel of the novel compounds according to the invention is shown in Table 1 below.

Experimental compound FDSS
% Inhibition rate, (10 [mu] M) Experimental compound FDSS
% Inhibition rate, (10 [mu] M) Compound 1 23.98 Compound 41 35.70 Compound 2 32.45 Compound 42 63.65 Compound 3 34.87 Compound 43 62.60 Compound 4 22.03 Compound 44 63.24 Compound 5 26.84 Compound 45 65.87 Compound 6 40.52 Compound 46 73.87 Compound 7 31.62 Compound 47 30.52 Compound 8 46.57 Compound 48 38.62 Compound 9 60.66 Compound 49 45.93 Compound 10 14.68 Compound 50 43.94 Compound 11 12.72 Compound 51 47.47 Compound 12 21.95 Compound 52 68.36 Compound 13 8.07 Compound 53 68.56 Compound 14 10.35 Compound 54 35.10 Compound 15 3.42 Compound 55 45.32 Compound 16 19.15 Compound 56 43.68 Compound 17 16.67 Compound 57 54.44 Compound 18 13.98 Compound 58 41.09 Compound 19 51.72 Compound 59 49.10 Compound 20 69.72 Compound 60 37.20 Compound 21 51.86 Compound 61 39.21 Compound 22 54.90 Compound 62 34.87 Compound 23 60.02 Compound 63 56.17 Compound 24 60.72 Compound 64 22.59 Compound 25 86.99 Compound 65 25.84 Compound 26 51.31 Compound 66 9.13 Compound 27 50.79 Compound 67 25.91 Compound 28 35.29 Compound 68 32.58 Compound 29 35.50 Compound 69 18.57 Compound 30 59.99 Compound 70 34.44 Compound 31 69.98 Compound 71 25.76 Compound 32 51.14 Compound 72 43.82 Compound 33 57.47 Compound 73 47.22 Compound 34 46.64 Compound 74 69.88 Compound 35 66.27 Compound 75 20.17 Compound 36 66.33 Compound 76 48.50 Compound 37 57.40 Compound 77 48.85 Compound 38 52.40 Compound 78 50.38 Compound 39 11.22 Compound 79 53.92 Compound 40 12.64 Mibefradil 79.29

Experimental Example 2: Measurement of ion current inhibition for T-type calcium channel using automatic patch clamp

1. Cell culture and preparation

HEK293 cell line (α1G cell line: KCTC 10519BP), in which α1G T-type calcium channel and Kir2.1 were stably expressed, was supplied from Gene Bank of Korea Research Institute of Bioscience and Biotechnology. T-type calcium channel-expressing cells were cultured in DMEM medium (Dulbecco's modified Eagle's medium) containing 10% fetal bovine serum (FBS) at 37 ° C. in which 95% oxygen and 5% Were cultured in MEM medium containing 10% FBS. Twenty hours prior to use to express the hERG channel, 1 μg / mL doxycycline was applied to the media to activate the Tet-expression system. The cells used for the experiment were passed once every 3 days and were used when the cells were filled with 50% to 80% of the culture dish. Before the experiment, trypsin-EDTA (0.25 ×) was used to separate the cells from the dish. The cells were then made into a single cell using a pipette, and trypsin was removed using a centrifuge (1100 rpm, 3 minutes) And then automatically floated with a patch liner at room temperature.

2. Experimental solution

For the measurement of the activity of T-type calcium channel, 140 mM NaCl, 2 mM CaCl ₂ , 4 mM KCl, 1 mM MgCl ₂ , 5 mM D-glucose and 10 mM HEPES (pH 7.4) And 50 mM KCl, 10 mM NaCl, 60 mM KF, 2 mM MgCl ₂ , 10 mM HEPES, and 20 mM EGTA (pH 7.2) were used as the intracellular solutions. In order to keep the whole cell state well, a seal enrichment solution was added, and in the case of T-type calcium channel expressing cells, an extracellular solution containing 10 mM Ba ²⁺ was added and then recorded. Each test compound is 100% dimethyl sulfoxide (DMSO) as a 100 mM stock solution dissolved in make, to the T- type calcium channel activity measurement and diluted in 10 nM to 100 μM in the extracellular solution is added Ba ²⁺ IC ₅₀ Were measured. The results are shown in Table 2 below.

Experimental compound a1G IC ₅₀ ([mu] M) Compound 6 0.88 KST005468 1.43 Mibefradil 1.43

According to the results shown in the above Table 2, the compound having an aromatic group (KST005468) substituted at the 3-position of mibefradil and isoxazole ring known as T-type calcium channel blockers has an α1G IC ₅₀ value of 1.43 μM, The compound of the present invention can be confirmed to have an improved? 1G IC ₅₀ value of 0.88.

Experimental Example 3: Experimental animal model of neuropathic pain (Na Model)

1. Preparation of experimental animals

Anesthesia was induced with a mixed gas of 4% enflurane and 95% oxygen in male rat SD (Rat Sprague Dawley) weighing 150-200 g. Anesthesia was maintained with 2 ~ 3% enflurane and 95% oxygen mixture gas throughout the procedure. The nerve plexus model (Na model) was created by cutting 1 ~ 2 mm between the first and second trunk nerves of the superior inferior caudal trunk distributed in the tail of the rats to induce neuropathic pain.

2. Drug experiment

All behavioral tests were performed by a blind study by a researcher who did not know whether the drug was administered.

(A) Mechanical allodynia

Rats were placed in round acrylic vials (5.5 × 15, 6.5 × 18 cm, depending on body size), pulled out of the tail only, and placed on the plate. Measurement of mechanical allodynia was performed using an up-down method (Chaplan et al, 1994) using various von-Frey hair (0.4, 0.6, 1.0, 2.0, 4.0, 6.0, 8.0, (G) of von-Frey hair with a 50% avoidance response to stimulation of the tail with the tail. The reduction in the avoidance response threshold was statistically significant compared with that before the nerve injury, Was determined to have occurred.

(B) cold allodynia

Rats were placed in a round acrylic vial and taken out of the tail only, draped, and placed in 4 ° C water to measure the time until the tail showed evasive response. Experimental results were obtained by the mean of five measurements at intervals of 5 minutes. When not escaping by 15 seconds, the tail was removed from the water to prevent sensitization of the tail, resulting in 15 seconds. In cases of significant early avoidance than before surgery, it was estimated to be the result of cold allodynia.

(C) warm allodynia

Experiments were carried out in the same manner as cold aliquots, except that the water temperature was 40 ° C. It was estimated that the case of avoiding significantly earlier than before the operation was the result of allodynia.

The results of the above-mentioned behavior test showed that when the significant avoidance reaction was observed after the nerve injury compared to before the nerve injury, the pain was induced.

The experimental results of the neuropathic pain animal model according to Experimental Example 3 are shown in Figs. 1, 2 and 3, respectively. According to the experimental results shown in the drawings, the compounds according to the present invention exhibit equivalent or superior activities as those of gabapentin drugs which are commercially available as pain relieving agents. In addition, the compound of the present invention exhibits excellent pain relieving effect as compared with the compound (KST005468) in which the aromatic group is substituted at the 3-position of the isoxazole ring as a known compound. Especially, the treatment of 1 hour after the administration of the drug The effect was very good.

As described above, the 5- (substituted alkylaminomethyl) isoxazole compound represented by Formula 1 or the pharmaceutically acceptable salt thereof according to the present invention has excellent activity as an antagonist of T-type calcium ion channel .

Thus, the compounds of the present invention are effective as antagonists of the T-type calcium ion channel and thus are useful for the treatment of brain diseases selected from epilepsy, depression, Parkinson ' s disease, dementia, sleep disorder, Prophylactic; For cancer treatment and prophylaxis; For the treatment and prevention of heart diseases selected from hypertensive, heart arrhythmia, angina pectoris, myocardial infarction, congestive heart failure; Or pain relievers selected from neuropathic pain, chronic and acute pain; ≪ / RTI >

Claims (7)

A compound represented by the formula (1): wherein R is selected from the group consisting of a 5- (substituted alkylaminomethyl) isoxazole-based compound represented by the following formula 1 and a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

In Formula 1,

in

Is a single bond, X represents N or CH,

Is a double bond, X represents C,
Y represents N or CH,
R ¹ is a C ₁ -C ₆ alkyl group substituted or unsubstituted with 1 to 2 substituents selected from phenyl and halophenyl; Or a phenyl group substituted or unsubstituted with 1 to 4 substituents selected from halo, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, and C ₁ -C ₆ haloalkoxy Lt; / RTI >
R ² and R ³ are the same or different from each other, and represent a hydrogen atom; Or a C ₁ -C ₆ alkyl group,
R ⁴ is a hydrogen atom; or

Lt; / RTI >
R ⁵ is a C ₁ -C ₆ alkyl group; ^{-C (O) NR 6 R 7} ; -C (O) OR < ⁸ >
R ⁶ and R ⁷ , which are the same or different from each other, are a hydrogen atom; Or a C ₁ -C ₆ alkyl group,
R ⁸ is a hydrogen atom; An alkali metal atom; Or a C ₁ -C ₆ alkyl group,
n represents an integer of 0 to 5; .
The method according to claim 1,
Wherein R ¹ is diphenylmethyl group, di (p - chlorophenyl) methyl, di (p - fluorophenyl) methyl group, a phenyl group, m - cyanophenyl group, m - group fluoro, p - group fluorophenyl, m - chloro phenyl, p - chlorophenyl group, a 3,4-dichlorophenyl group, 3,5-dichlorophenyl group, m - methylphenyl group, p - methylphenyl, 3,4-dimethylphenyl group, 2,4-dimethylphenyl group, m - methoxyphenyl , a p -methoxyphenyl group, a 3,4-dimethoxyphenyl group, an m -trifluoromethylphenyl group, a p -trifluoromethylphenyl group or a p -trifluoromethoxyphenyl group,
R ² represents a hydrogen atom,
R ³ represents a hydrogen atom,
R ⁴ represents a hydrogen atom, isoxazol-5-ylmethyl group, 3-methylisoxazol-5-ylmethyl group or 3-isopropylisoxazol-5-ylmethyl group,
Wherein R ⁵ represents a methyl group, an ethyl group, a normal propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert -butyl group, an amide group, a methyl carboxylate group or a sodium carboxylate group.
[2- [4- (3-Chlorophenyl) -piperazin-1-yl] -ethyl] - (3-methylisoxazol-5-ylmethyl) amine;
[2- [4- (3-Chlorophenyl) -piperazin-1-yl] -ethyl] - (3-ethylisoxazol-5-ylmethyl) amine;
[2- [4- (3-Chlorophenyl) -piperazin-1-yl] -ethyl] - (3-isopropylisoxazol-5-ylmethyl) amine;
[2- [4- (4-Chlorophenyl) -piperazin-1-yl] -ethyl] - (3-methylisoxazol-5-ylmethyl) amine;
[2- [4- (4-Chlorophenyl) -piperazin-1-yl] -ethyl] - (3-ethylisoxazol-5-ylmethyl) amine;
[2- [4- (4-Chlorophenyl) -piperazin-1-yl] -ethyl] - (3-isopropylisoxazol-5-ylmethyl) amine;
[2- (4-Benzhydryl-piperazin-1-yl) ethyl] - (3-methylisoxazol-5-ylmethyl) amine;
[2- (4-Benzhydryl-piperazin-1-yl) ethyl] - (3-ethylisoxazol-5-ylmethyl) amine;
[2- (4-Benzhydryl-piperazin-1-yl) ethyl] - (3-isopropylisoxazol-5-ylmethyl) amine;
(3-methylisoxazol-5-ylmethyl) - [2- (4-phenylpiperazin-1-yl) ethyl] amine;
(3-ethylisoxazol-5-ylmethyl) - [2- (4-phenylpiperazin-1-yl) ethyl] amine;
(3-isopropylisoxazol-5-ylmethyl) - [2- (4-phenylpiperazin-1-yl) ethyl] amine;
N - ((3-isopropylisoxazol-5-yl) methyl) -N -methyl-2- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) ethanamine;
2- (4- (2,4-Dimethylphenyl) piperazin-1-yl) - N - ((3-isopropylisoxazol-5-yl) methyl) ethanamine;
2- (4- (2,4-Dimethylphenyl) piperazin-1-yl) - N - ((3-isopropylisoxazol-5-yl) methyl) -N -methylethanamine;
2- (4- (4-Chlorophenyl) piperazin-1-yl) - N - ((3-isopropylisoxazol-5-yl) methyl) -N -methylethanamine;
N - ((3- tert -butyl isoxazol-5-yl) methyl) -2- (4- (4-chlorophenyl) piperazin-1-yl) ethanamine;
N - ((3- tert -butylisoxazol -5-yl) methyl) -2- (4- (4-chlorophenyl) piperazin-1-yl) - N -methylethanamine;
N - ((3- tert -butylisoxazol -5-yl) methyl) -2- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) ethanamine;
N - ((3- tert -butylisoxazol -5-yl) methyl) -N -methyl-2- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) ethanamine;
N - ((3- tert - butylisoxazol -5-yl) methyl) -2- (4- (2,4-dimethylphenyl) piperazin-1-yl) ethanamine;
2- (4- (4-Chlorophenyl) piperazin-1-yl) - N - ((3-isobutylisoxazol-5-yl) methyl) ethanamine;
2- (4- (4-chlorophenyl) piperazin-1-yl) - N - (3-isobutylisoxazol-5-yl) methyl) - N -methylethanamine;
N - ((3-isobutylisoxazol-5-yl) methyl) -2- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) ethanamine;
N - ((3-isobutylisoxazol-5-yl) methyl) -N -methyl-2- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) ethanamine;
N - (2- (4- (4- chlorophenyl) piperazin-1-yl) ethyl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) propan-2-amine;
N - (2- (4- (2,4- dimethylphenyl) piperazin-1-yl) ethyl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) propan-2-amine;
2- (4- (3,4-Dimethylphenyl) piperazin-1-yl) - N - ((3-isopropylisoxazol-5-yl) methyl) ethanamine;
2- (4- (3,4-Dimethylphenyl) piperazin-1-yl) - N - (3-isopropylisoxazol-5-yl) methyl) -N -methylethanamine;
N - (2- (4- (3,4- dimethylphenyl) piperazin-1-yl) ethyl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) propan-2-amine;
N - ((3- isopropyl-isoxazol-5-yl) methyl) - N - (2- (4- (3- ( trifluoromethyl) phenyl) piperazin-1-yl) ethyl) propane -2 - amine;
N - ((3- tert -butyl-isoxazol-5-yl) methyl) -2- (4- (3,4-dimethylphenyl) piperazin-1-yl) ethanamine;
N - ((3- tert - butylisoxazol -5-yl) methyl) -2- (4- (3,4-dimethylphenyl) piperazin-1-yl) -N -methylethanamine;
N - ((3- tert -butyl-isoxazol-5-yl) methyl) -2- (4- (2,4-dimethylphenyl) piperazin-1-yl) -N -methylethanamine;
N - ((3-tert-butyl-isoxazol-5-yl) methyl) - N - (ethyl-2- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl)) propane- 2-amine;
2- (4- (2,4-dimethylphenyl) piperazin-1-yl) - N - ((3- isobutyl-isoxazol-5-yl) methyl) ethanamine;
2- (4- (3,4-dimethylphenyl) piperazin-1-yl) - N - ((3- isobutyl-isoxazol-5-yl) methyl) ethanamine;
N - ((3-isopropylisoxazol-5-yl) methyl) -2- (4- (3-trifluoromethylphenyl) piperazin-1-yl) ethanamine;
N - ((3-isopropylisoxazol-5-yl) methyl) -2- (4- (4-methoxyphenyl) piperazin-1-yl) ethanamine;
N - ((3-isopropylisoxazol-5-yl) methyl) -2- (4- (4-methoxyphenyl) piperazin-1-yl) - N -methylethanamine;
N - ((3-isopropylisoxazol-5-yl) methyl) -2- (4- p -tolylpiperazin-1-yl) ethanamine;
2- (4- (2,4-dimethylphenyl) piperazin-1-yl) - N - ((3- isobutyl-isoxazol-5-yl) methyl) - N - methyl ethanamine;
2- (4- (3,4-Dimethylphenyl) piperazin-1-yl) - N - ((3-isobutylisoxazol-5-yl) methyl) -N -methylethanamine;
2- (4- (3-Chlorophenyl) piperazin-1-yl) - N - (3-isopropylisoxazol-5-yl) methyl) -N -methylethanamine;
N - ((3-isopropylisoxazol-5-yl) methyl) -2- (4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) ethanamine;
N - ((3-isopropylisoxazol-5-yl) methyl) -N -methyl-2- (4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) ethanamine;
N - ((3-isopropylisoxazol-5-yl) methyl) -2- (4- (3-methoxyphenyl) piperazin-1-yl) ethanamine;
N - ((3-isopropylisoxazol-5-yl) methyl) -2- (4- m -tolylpiperazin-1-yl) ethanamine;
N - ((3-isopropylisoxazol-5-yl) methyl) -N -methyl-2- (4- p -tolylpiperazin-1-yl) ethanamine;
2- (4- (4-Fluorophenyl) piperazin-1-yl) - N - ((3-isopropylisoxazol-5-yl) methyl) ethanamine;
2- (4- (4-fluorophenyl) piperazin-1-yl) - N - ((3-isopropylisoxazol-5-yl) methyl) -N -methylethanamine;
2- (4- (3,4-Dichlorophenyl) piperazin-1-yl) - N - ((3-isopropylisoxazol-5-yl) methyl) ethanamine;
2- (4- (3,4-Dichlorophenyl) piperazin-1-yl) - N - ((3-isopropylisoxazol-5-yl) methyl) -N -methylethanamine;
N - ((3-isopropylisoxazol-5-yl) methyl) -2- (4- (3-methoxyphenyl) piperazin-1-yl) - N -methylethanamine;
N - ((3-isopropylisoxazol-5-yl) methyl) -N -methyl-2- (4- m -tolylpiperazin-1-yl) ethanamine;
3- (4- (3-chlorophenyl) piperazin-1-yl) - N - ((3-isopropyl-isoxazol-5-yl) methyl) propan-1-amine;
3- (4- (3-Chlorophenyl) piperazin-1-yl) - N - ((3-isopropylisoxazol-5-yl) methyl) -N -methylpropan-1- amine;
3- (4- (3,4-dimethylphenyl) piperazin-1-yl) - N - ((3-isopropyl-isoxazol-5-yl) methyl) propan-1-amine;
3- (4- (3,4-Dimethylphenyl) piperazin-1-yl) - N - (3-isopropylisoxazol-5-yl) methyl) -N -methylpropan-1- amine;
N - ((3-isopropylisoxazol-5-yl) methyl) -3- (4- p -tolylpiperazin-1-yl) propan-1-amine;
N - ((3-isopropylisoxazol-5-yl) methyl) -N -methyl-3- (4- p -tolylpiperazin-1-yl) propan-1-amine;
3- (4- (4-phenyl) piperazin-1-yl-fluorophenyl) - N - ((3-isopropyl-isoxazol-5-yl) methyl) propan-1-amine;
3- (4- (4-fluorophenyl) piperazin-1-yl) - N - ((3-isopropylisoxazol-5-yl) methyl) -N -methylpropan-1- amine;
N - ((3-isopropylisoxazol-5-yl) methyl) -3- (4- (4-methoxyphenyl) piperazin-1-yl) propan-1 -amine;
N - ((3-isopropylisoxazol-5-yl) methyl) -3- (4- (4-methoxyphenyl) piperazin-1-yl) -N -methylpropan-1-amine;
2- (4- (3,4-Dimethoxyphenyl) piperazin-1-yl) - N - ((3-isopropylisoxazol-5-yl) methyl) ethanamine;
3- (4- (4-chlorophenyl) piperazin-1-yl) - N - ((3-isopropylisoxazol-5-yl) methyl) propan-1-amine;
3- (4- (4-chlorophenyl) piperazin-1-yl) - N - ((3-isopropylisoxazol-5-yl) methyl) -N -methylpropan-1- amine;
N - ((3-isopropylisoxazol-5-yl) methyl) -3- (4- (3-methoxyphenyl) piperazin-1-yl) propan-1 -amine;
N - ((3-isopropylisoxazol-5-yl) methyl) -3- (4- (3-methoxyphenyl) piperazin-1-yl) -N -methylpropan-1-amine;
N - ((3-isopropylisoxazol-5-yl) methyl) -3- (4- m -tolylpiperazin-1-yl) propan-1-amine;
N - ((3-isopropylisoxazol-5-yl) methyl) -N -methyl-3- (4- m -tolylpiperazin-1-yl) propan-1-amine;
3- (4- (3,4-Dichlorophenyl) piperazin-1-yl) - N - ((3-isopropylisoxazol-5-yl) methyl) propan-l-amine;
3- (4- (3,4-dichlorophenyl) piperazin-1-yl) - N - ((3-isopropyl-isoxazol-5-yl) methyl) - N - methyl-1-amine;
3- (4- (3,4-dimethoxyphenyl) piperazin-1-yl) - N - ((3-isopropyl-isoxazol-5-yl) methyl) propan-1-amine;
2- (4- (4-chlorophenyl) -2-methylpiperazin-1-yl) - N - ((3-isopropylisoxazol-5-yl) methyl) ethanamine;
2- (4- (3,4-Dichlorophenyl) -2-methylpiperazin-1-yl) - N - ((3-isopropylisoxazol-5-yl) methyl) ethanamine;
N - ((3-isopropylisoxazol-5-yl) methyl) -2- (4- (4- (trifluoromethoxy) phenyl) piperazin-1-yl) ethanamine;
2- (4- (3,5-dichlorophenyl) piperazin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) ethanamine;
2- (1- (4-fluorophenyl) piperidin-4-yl) - N - ((3-isopropylisoxazol-5-yl) methyl) ethanamine;
2- (1- (4-chlorophenyl) piperidin-4-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) ethanamine;
N - ((3- tert - butylisoxazol -5-yl) methyl) -2- (1- (4-chlorophenyl) piperidin-4-yl) ethanamine;
N - ((3- tert -butyl-isoxazol-5-yl) methyl) -2- (1- (4-fluorophenyl) piperidin-4-yl) ethanamine;
N - ((3-isopropylisoxazol-5-yl) methyl) -2- (1- (4- (trifluoromethyl) phenyl) piperidin-4-yl) ethanamine;
N - ((3-isopropylisoxazol-5-yl) methyl) -2- (1- p -tolylpiperidin-4-yl) ethanamine;
2- (1- (3,4-dichlorophenyl) piperidin-4-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) ethanamine;
N - ((3-isopropylisoxazol-5-yl) methyl) -2- (1- (4-methoxyphenyl) piperidin-4-yl) ethanamine;
2- (1- (3-chlorophenyl) piperidin-4-yl) - N - ((3-isopropyl-isoxazol-5-yl) methyl) ethanamine;
2- (1- (3-fluorophenyl) piperidin-4-yl) - N - ((3-isopropyl-isoxazol-5-yl) methyl) ethanamine;
N - ((3-isopropylisoxazol-5-yl) methyl) -2- (1- m -tolylpiperidin-4-yl) ethanamine;
N - ((3-isopropylisoxazol-5-yl) methyl) -2- (1- (3- (trifluoromethyl) phenyl) piperidin-4-yl) ethanamine;
2- (1- (2- ((3-isopropylisoxazol-5-yl) methylamino) ethyl) -1,2,3,6-tetrahydropyridin-4-yl) benzonitrile;
N - ((3-isopropylisoxazol-5-yl) methyl) -2- (4-phenyl-1,2,3,6-tetrahydropyridin-4-yl) ethanamine;
2- (4- (4-chlorophenyl) -1,2,3,6-tetrahydropyridin-4-yl) - N - ((3-isopropylisoxazol-5-yl) methyl) ethanamine;
3- (1- (2 - ((3-isopropylisoxazol-5-yl) methylamino) ethyl) -1,2,3,6-tetrahydropyridin-4-yl) benzonitrile;
N - ((3- isopropyl-isoxazol-5-yl) methyl) -2- (4- (4-methoxyphenyl) -1,2,3,6-tetrahydro-pyridin-4-yl) ethanamine ;
N, N -bis ((3-isopropylisoxazol-5-yl) methyl) -2- (4- o -tolyl-1,2,3,6-tetrahydropyridin-4-yl) ethanamine;
Yl) - N - ((3-isopropylisoxazol-5-yl) methyl) piperidine- Ethanamine;
N, N -bis ((3-isopropyl-isoxazol-5-yl) ) Methyl) ethanamine;
2- (4- (3,4-dichlorophenyl) piperidin-1-yl) - N - ((3- isopropyl-isoxazol-5-yl) methyl) ethanamine;
N - ((3-isopropylisoxazol-5-yl) methyl) -2- (4-phenylpiperidin-1-yl) ethanamine;
Methyl 5 - ((2- (4-phenylpiperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate;
Ethyl 5 - ((2- (4-phenylpiperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate;
Ethyl 5 - ((2- (4-phenylpiperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate hydrochloride;
Sodium 5 - ((2- (4-phenylpiperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate;
Ethyl 5 - ((2- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate;
Sodium 5 - ((2- (4- (Bis (4-fluorophenyl) methyl) piperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate;
Ethyl 5 - ((2- (4-benzhydrylpiperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate;
Sodium 5 - ((2- (4-benzhydrylpiperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate;
2- (4-benzhydrylpiperazin-1-yl) - N - ((3-methylisoxazol-5-yl) methyl) ethanamine;
2- (4- (Bis (4-fluorophenyl) methyl) piperazin-1-yl) - N - ((3-methylisoxazol-5-yl) methyl) ethanamine;
2- (4- (bis (4-chlorophenyl) methyl) piperazin-1-yl) - N - ((3- methyl-isoxazol-5-yl) methyl) ethanamine;
Ethyl 5 - ((2- (4- (bis (4-chlorophenyl) methyl) piperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxylate;
5 - ((2- (4- (Bis (4-fluorophenyl) methyl) piperazin-1-yl) ethylamino) methyl) isoxazole-3-carboxamide;
5 - ((2- (4- (Bis (4-fluorophenyl) methyl) piperazin-1-yl) ethylamino) methyl) -N -methylisoxazole-3-carboxamide;
5 - ((2- (4- (Bis (4-fluorophenyl) methyl) piperazin-1-yl) ethylamino) methyl) -N, N -dimethylisoxazole-3-carboxamide; And
Lt; RTI ID = 0.0 > pharmaceutically < / RTI > acceptable salts thereof.
A brain disease selected from the group consisting of epilepsy, depression, Parkinson's disease, dementia, and sleep disorder, characterized in that the compound of any one of claims 1 to 3 is used as an active ingredient. And prophylactic agents; For cancer treatment and prophylaxis; For the treatment and prevention of heart diseases selected from hypertensive, heart arrhythmia, angina pectoris, myocardial infarction, congestive heart failure; Or pain relievers selected from neuropathic pain, chronic and acute pain; ≪ / RTI > delete delete delete

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