Pyrazolylmethylamine compounds as calcium channel modulators and preparation method thereof

1. A compound selected from the group consisting of pyrazolylmethylamine-piperazine derivatives represented by the following formula 1 and their pharmaceutically acceptable salts thereof,

wherein

Y represents —(CH 2 ) n —C(O)—; or —C(O)—(CH 2 ) n —, wherein n is an integer of 1-4;

R 1 and R 2 , which may be same or different, respectively represent a hydrogen atom; C 1 -C 8 alkyl group; phenyl group; phenyl group substituted with at least one substituent selected from the group consisting of halo, hydroxy, carboxy, carboalkoxy, nitro, cyano, amino, mercapto, thioalkyl, C 1 -C 8 alkyl, C 1 -C 8 cycloalkyl, C 1 -C 8 haloalkyl, C 1 -C 8 alkoxy groups, and C 3 -C 8 heterocycloalkyl group comprising at least one heteroatom selected from O, S, and N; benzyl group; benzyl group substituted with at least one substituent selected from the group consisting of halo, hydroxy, carboxyl, carboalkoxy, nitro, cyano, amino, mercapto, thioalkyl, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 alkoxy groups, and 5-7 membered heterocycloalkyl groups comprising at least one heteroatom selected from O, S and N; phenethyl group; or heteroaryl group comprising at least one heteroatom selected from O, S and N, wherein the heteroaryl group is selected from furyl, pyridyl, pyrimidyl, and piperonyl groups; and

R 3 represents a hydrogen atom; C 1 -C 8 alkyl group; heteroaryl group comprising at least one heteroatom selected from O, S and N, wherein the heteroaryl group is selected from furyl, pyridyl, pyrimidyl, and piperonyl groups; phenyl group; phenyl group substituted with at least one substituent selected from the group consisting of halo, hydroxy, carboxy, carboalkoxy, nitro, cyano, amino, mercapto, thioalkyl, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 cycloalkyl, C 1 -C 8 alkoxy groups, and C 3 -C 8 heterocycloalkyl group comprising at least one heteroatom selected from O, S, and N; benzyl group; benzyl group substituted with at least one substituent selected from the group consisting of halo, hydroxy, carboxy, carboalkoxy, nitro, cyano, amino, mercapto, aryl, haloaryl, thioalkyl, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 haloalkyl, arylcarbonyl, phenyl, and benzyl groups, and 5-7 membered heterocycloalkyl groups comprising at least one heteroatom selected from O, S and N, wherein the aryl can be substituted with at least one substituent selected from the group consisting of halo, alkyl, alkoxy, and phenoxy groups; or R 3 represents a benzoyl group; or furanoyl group.

2. The compound selected from the group consisting of pyrazolylmethylamine-piperazine derivatives and their pharmaceutically acceptable salts thereof according to claim 1 ,

wherein Y represents —(CH 2 ) n —C(O)—; or —C(O)—(CH 2 ) n —, wherein n is an integer of 1-4;

R 1 and R 2 , which may be same or different, respectively represent a hydrogen atom; C 1 -C 8 alkyl; phenyl; benzyl; phenethyl; or heteroaryl groups selected from furyl, pyridyl, pyrimidyl, and piperonyl groups;

R 3 represents phenyl; benzyl; benzhydryl; benzoyl; heteroaryl selected from furyl, pyridyl, pyrimidyl, and piperonyl groups; or furanoyl groups;

wherein the phenyl or benzyl groups in R 1 , R 2 , and R 3 can be respectively substituted with 1-3 substituents selected from the group consisting of halo, hydroxy, nitro, cyano, carboxyl, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 thioalkyl, C 1 -C 8 alkoxy groups, and 5-7 membered heterocycloalkyl groups comprising at least one heteroatom selected from O, S and N;

wherein the heterocycloalkyl groups represent 5-10 membered monocyclic or fused rings comprising at least one heteroatom selected from O, S, and N.

3. A compound selected from the group consisting of pyrazolylmethylamine-piperazine derivatives represented by the following formula 1 and their pharmaceutically acceptable salts thereof,

wherein Y represents —CH 2 —C(O)—; or —C(O)—CH 2 —;

R 1 represents a hydrogen atom, phenyl, carboxylphenyl, C 1 -C 8 alkoxyphenyl, or benzyl groups;

R 2 represents C 1 -C 8 alkyl group; phenyl group; phenyl group substituted with 1-3 substituents selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 thioalkyl, C 1 -C 8 alkoxy, piperidinyl and morpholinyl groups; phenethyl; furyl group; or pyridyl group; and

R 3 represents phenyl; phenyl substituted with 1-3 substituents selected from the group consisting of hydroxy, cyano and C 1 -C 8 alkyl groups; benzyl group; benzyl group substituted with 1-3 substituents selected from the group consisting of phenyl, benzyl, halo, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, and C 1 -C 8 alkoxy groups; heteroaryl group selected from the group consisting of furyl, pyridyl, pyrimidyl, and piperonyl groups; benzhydryl group; benzhydryl group substituted with halogen; or furanoyl group.

4. A compound selected from the group consisting of pyrazolylmethylamine-piperazine derivatives represented by the following formula 1 and their pharmaceutically acceptable salts thereof,

wherein Y represents —CH 2 —C(O)—, or —C(O)—CH 2 —;

R 1 represents a hydrogen atom, phenyl, carboxyphenyl, methoxyphenyl, or benzyl group;

R 2 represents methyl, ethyl, n-propyl, isopropyl, isobutyl, tert-butyl, phenyl, toluoyl, methoxyphenyl, thiomethylphenyl, morpholinophenyl, piperidinophenyl, phenethyl, furyl, or pyridyl group; and

R 3 represents phenyl, hydroxyphenyl, cyanophenyl, dimethylphenyl, benzyl, halobenzyl, dihalobenzyl, methylbenzyl, dimethylbenzyl, trimethylbenzyl, trifluoromethylbenzyl, trimethoxybenzyl, benzhydryl, (halolphenyl)(phenyl)methyl, pyridyl, pyrimidyl, piperonyl, or furanoyl group.

5. A compound selected from the group consisting of pyrazolylmethylamine-piperazine derivatives represented by the following formula 1 and their pharmaceutically acceptable salts thereof,

wherein said compound includes:

3-{[4-(2,3-dimethyl)phenylpiperazin-1-yl]methylcarboxamido}methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 1);

3-[(4-phenylpiperazin-1-yl)methylcarboxamido]methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 2);

3-[(4-benzhydrylpiperazin-1-yl)methylcarboxamido]methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 3);

3-{[4-(2,4-dimethylphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 4);

3-{[4-(3-trifluoromethyl)benzylpiperazin-1-yl]methylcarboxamido}methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 5);

3-{[4-(3,4-dichlorobenzyl)piperazin-1-yl]methylcarboxamido}methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 6);

3-{[4-(4-trifluoromethyl)benzylpiperazin-1-yl]methylcarboxamido}methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 7);

3-{[4-(2,3,4-trimethoxy)benzylpiperazin-1-yl]methylcarboxamido}methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 8);

3-[(4-phenylpiperazin-1-yl)methylcarboxamido]methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 9);

3-{[4-(2,3-dimethylphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 10);

3-[(4-phenylpiperazin-1-yl)methylcarboxamido]methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 11);

3-{[4-(2,3-dimethylphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 12);

3-{[4-(3-trifluoromethylbenzyl)piperazin-1-yl]methylcarboxamido}methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 13);

3-{[4-(4-trifluoromethylbenzyl)piperazin-1-yl]methylcarboxamido}methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 14);

3-{[4-(3-trifluoromethylbenzyl)piperazin-1-yl]methylcarboxamido}methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 15);

3-{[4-(4-trifluoromethylbenzyl)piperazin-1-yl]methylcarboxamido}methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 16);

3-{[4-(2,3,4-trimethoxy)benzylpiperazin-1-yl]methylcarboxamido}methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 17);

3-{[4-(2,3,4-trimethoxy)benzylpiperazin-1-yl]methylcarboxamido}methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 18);

3-[(4-benzhydrylpiperazin-1-yl)methylcarboxamido]methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 19);

3-[(4-benzhydrylpiperazin-1-yl)methylcarboxamido]methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 20);

3-[(4-piperonylpiperazin-1-yl)methylcarboxamido]methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 21);

3-[(4-piperonylpiperazin-1-yl)methylcarboxamido]methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 22);

3-{[4-(3,4-dichloro)benzylpiperazin-1-yl]methylcarboxamido}methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 23);

3-{[4-(3,4-dichloro)benzylpiperazin-1-yl]methylcarboxamido}methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 24);

3-{[4-(4-chlorophenyl)(phenyl)methylpiperazin-1-yl]methylcarboxamido}methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 25);

3-{[4-(4-chlorophenyl)(phenyl)methylpiperazin-1-yl]methylcarboxamido}methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 26);

3-[(4-phenylpiperazin-1-yl)methylcarboxamido]methyl-5-propyl-1-phenyl-1H-pyrazole (Compound No. 27);

3-{[4-(2,3-dimethyl)phenylpiperazin-1-yl]methylcarboxamido}methyl-5-propyl-1-phenyl-1H-pyrazole (Compound No. 28);

3-{[4-(2,4-dimethyl)phenylpiperazin-1-yl]methylcarboxamido}methyl-5-propyl-1-phenyl-1H-pyrazole (Compound No. 29);

3-[(4-benzhydrylpiperazin-1-yl)methylcarboxamido]methyl-5-propyl-1-phenyl-1H-pyrazole (Compound No. 30);

3-{[4-(3-trifluoromethyl)benzylpiperazin-1-yl]methylcarboxamido}methyl-5-propyl-1-phenyl-1H-pyrazole (Compound No. 31);

3-{[4-(4-trifluoromethyl)benzylpiperazin-1-yl]methylcarboxamido}methyl-5-propyl-1-phenyl-1H-pyrazole (Compound No. 32);

3-[(4-piperonylpiperazin-1-yl)methylcarboxamido]methyl-5-propyl-1-phenyl-1H-pyrazole (Compound No. 33);

3-{[4-(2-pyridyl)piperazin-1-yl]methylcarboxamido}methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 34);

3-{[4-(2-pyrimidyl)piperazin-1-yl]methylcarboxamido}methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 35);

3-{[4-(2-pyridyl)piperazin-1-yl]methylcarboxamido}methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 36);

3-{[4-(2-pyrimidyl)piperazin-1-yl]methylcarboxamido}methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 37);

3-{[4-(2-(pyridyl)piperazin-1-yl]methylcarboxamido}methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 38);

3-{[4-(2-pyrimidyl)piperazin-1-yl]methylcarboxamido}methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 39);

3-{[4-(4-t-butyl)benzylpiperazin-1-yl]methylcarboxamido}methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 40);

3-{[4-(2,4,6-trimethyl)benzylpiperazin-1-yl]methylcarboxamido}methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 41);

3-{[4-(4-t-butyl)benzylpiperazin-1-yl]methylcarboxamido}methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 42);

3-{[4-(2,4,6-trimethyl)benzylpiperazin-1-yl]methylcarboxamido}methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 43);

3-{[4-(2,3-dimethylphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-(4-methoxy)phenyl-1-phenyl-1H-pyrazole (Compound No. 44);

3-{[4-(2,4-dimethylphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-(4-methoxy)phenyl-1-phenyl-1H-pyrazole (Compound No. 45);

3-[4-furoylpiperazin-1-yl)methylcarboxamido]methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 46);

3-[(4-furoylpiperazin-1-yl)methylcarboxamido]methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 47);

3-{[4-(2-cyanophenyl)piperazin-1-yl]methylcarboxamido}methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 48);

3-{[4-(2-cyanophenyl)piperazin-1-yl]methylcarboxamido}methyl-5-propyl-1-phenyl-1H-pyrazole (Compound No. 49);

3-{[4-(2,3-dimethylphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-(4-thiomethyl)phenyl-1-phenyl-1H-pyrazole (Compound No. 50);

3-{[4-(2,4-dimethylphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-(4-thiomethyl)phenyl-1-phenyl-1H-pyrazole (Compound No. 51);

3-{[4-(3-hydroxyphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 52);

3-{[4-(3-hydroxyphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 53);

3-[(4-phenylpiperazin-1-yl)methylcarboxamido]methyl-5-(4-thiomethyl)phenyl-1-phenyl-1H-pyrazole (Compound No. 54);

3-{[4-(3-hydroxyphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-(4-thiomethyl)phenyl-1-phenyl-1H-pyrazole (Compound No. 55);

3-{[4-(2,3-dimethylphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-propyl-1-(4-carboxyl)phenyl-1H-pyrazole (Compound No. 56);

3-{[4-(2,3-dimethylphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-isobutyl-1-(4-carboxyl)phenyl-1H-pyrazole (Compound No. 57);

3-{[4-(2,3-dimethylphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-methyl-1-(4-carboxyl)phenyl-1H-pyrazole (Compound No. 58);

3-{[4-(2,3-dimethylphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-(4-morpholino)phenyl-1-phenyl-1H-pyrazole (Compound No. 59);

3-[(4-phenylpiperazin-1-yl)methylcarboxamido]methyl-5-(4-morpholino)phenyl-1-phenyl-1H-pyrazole (Compound No. 60);

3-{[4-(2,4-dimethylphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-(4-morpholino)phenyl-1-phenyl-1H-pyrazole (Compound No. 61);

3-{[4-(3-trifluorobenzyl)piperazin-1-yl]methylcarboxamido}methyl-5-(4-morpholino)phenyl-1-phenyl-1H-pyrazole (Compound No. 62);

3-{[4-(4-trifluorobenzyl)piperazin-1-yl]methylcarboxamido}methyl-5-(4-morpholino)phenyl-1-phenyl-1H-pyrazole (Compound No. 63);

3-{[4-(2,3-dimethylphenyl)piperazin-1-yl]carbonylmethylamino}methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 64);

3-[(4-benzhydrylpiperazin-1-yl)carbonylmethylamino]methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 65);

3-[(4-phenylpiperazin-1-yl)carbonylmethylamino]methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 66);

3-[(4-phenylpiperazin-1-yl)carbonylmethylamino]methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 67);

3-[(4-benzhydrylpiperazin-1-yl)carbonylmethylamino]methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 68);

3-{[4-(2,4-dimethylphenyl)piperazin-1-yl]carbonylmethylamino}methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 69);

3-[(4-phenylpiperazin-1-yl)carbonylmethylamino]methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 70);

3-[(4-benzhydrylpiperazin-1-yl)carbonylmethylamino]methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 71);

3-{[4-(2,4-dimethyl)phenylpiperazin-1-yl]carbonylmethylamino}methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 72);

3-{[4-(2,4-dimethyl)phenylpiperazin-1-yl]carbonylmethylamino}methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 73);

3-{[4-(3,4-dichloro)benzylpiperazin-1-yl]carbonylmethylamino}methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 74);

3-{[4-(3,4-dichlorobenzyl)piperazin-1-yl]carbonylmethylamino}methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 75);

3-{[4-(2,3-dimethylphenyl)piperazin-1-yl]carbonylmethylamino}methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 76);

3-{[4-(2,3-dimethylphenyl)piperazin-1-yl]carbonylmethylamino}methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 77);

3-{[4-(3,4-dichlorobenzyl)piperazin-1-yl]carbonylmethylamino}methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 78);

3-[(4-piperonylpiperazin-1-yl)carbonylmethylamino]methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 79);

3-[(4-piperonylpiperazin-1-yl)carbonylmethylamino]methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 80);

3-{[4-(2,3,4-trimethoxybenzyl)piperazin-1-yl]carbonylmethylamino}methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 81);

3-{[4-(2,3-dimethylphenyl)piperazin-1-yl]carbonylmethylamino}methyl-5-propyl-1-phenyl-1H-pyrazole (Compound No. 82);

3-{[4-(2,4-dimethylphenyl)piperazin-1-yl]carbonylmethylamino}methyl-5-propyl-1-phenyl-1H-pyrazole (Compound No. 83);

3-[(4-phenylpiperazin-1-yl)carbonylmethylamino]methyl-5-propyl-1-phenyl-1H-pyrazole (Compound No. 84);

3-[(4-phenylpiperazin-1-yl)methylcarboxamido]methyl-5-methyl-1-[(4-methoxy)phenyl]-1H-pyrazole (Compound No. 85);

3-[(4-phenylpiperazin-1-yl)methylcarboxamido]methyl-5-[(4-piperidino)phenyl]-1-phenyl-1H-pyrazole (Compound No. 86);

3-[(4-phenylpiperazin-1-yl)methylcarboxamido]methyl-5-isobutyl-1-[(4-methoxy)phenyl]-1H-pyrazole (Compound No. 87);

3-{(4-(2,3-dimethylphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-isobutyl-1-[(4-methoxy)phenyl]-1H-pyrazole (Compound No. 88);

3-[(4-phenylpiperazin-1-yl)methylcarboxamido]methyl-5-(2-pyridyl)-1-phenyl-1H-pyrazole (Compound No. 89);

3-{(4-(2,3-dimethylphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-(2-pyridyl)-1-phenyl-1H-pyrazole (Compound No. 90);

3-[(4-phenylpiperazin-1-yl)methylcarboxamido]methyl-5-[(4-methyl)phenyl]-1-phenyl-1H-pyrazole (Compound No. 91);

3-{(4-(2,3-dimethylphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-[(4-methyl)phenyl]-1-phenyl-1H-pyrazole (Compound No. 92);

3-[(4-phenylpiperazin-1-yl)methylcarboxamido]methyl-5-methyl-1-benzyl-1H-pyrazole (Compound No. 93);

3-{(4-(2,3-dimethylphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-methyl-1-benzyl-1H-pyrazole (Compound No. 94);

3-{[4-(2,3-dimethylphenyl)piperazin-1-yl]carbonylmethylamino}methyl-5-methyl-1H-pyrazole (Compound No. 95);

and their pharmaceutically acceptable salts thereof.

6. A pharmaceutical composition for the prevention and treatment of diseases selected from the group consisting of cerebral disease, cardiac diseases, and pain-related diseases by antagonistic activity of T-type calcium channel comprising a pyrazolylmethylamine-piperazine derivative or its pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient;

wherein the cerebral disease comprises epilepsy, depression, Parkinson's disease, dementia, or sleep disorder;

wherein the cardiac diseases comprise hypertension, cardiac arrhythmia, angina pectoris, myocardial infarction or congestive heart failure; and

wherein the pain-related diseases comprise chronic pains, acute pains, or neuropathic pains.

7. A method for manufacturing pyrazolylmethylamine-piperazine derivatives represented by the formula 1a below by performing a coupling reaction between a haloacetylpiperazine compound represented by the formula 2 below and a pyrazolylmethylamine compound represented by the formula 3 below:

wherein said R 1 , R 2 , and R 3 are the same as defined in claim 1 , and X represents a halogen atom.

8. A method for manufacturing pyrazolylmethylamine-piperazine derivatives represented by the formula 1b below by performing a coupling reaction between a piperazine compound represented by the formula 4 below and a pyrazolylmethylcarbamoylmethyl halide compound represented by the formula 5 below:

wherein said R 1 , R 2 , and R 3 are the same as defined in claim 1 , and X represents a halogen atom.

9. The method for manufacturing pyrazolylmethylamine-piperazine derivatives according to claim 8 , wherein said pyrazolylmethylcarbamoylmethyl halide compound represented by the above formula 5 is manufactured by a process comprising:

(a) converting a pyrazolaldehyde compound represented by the formula 7 below to a pyrazoloxime compound represented by the formula 8 below;

(b) converting said pyrazoloxime compound represented by the formula 8 below to a pyrazolylamine compound represented by the formula 9 below; and

(c) converting said pyrazolylamine compound represented by the formula 9 below to a pyrazolylmethylcarbamoylmethyl halide compound represented by the formula 5 below:

wherein said R 1 and R 2 are the same as defined in claim 1 , and X represents a halogen atom.

10. A compound selected from the group consisting of pyrazolylmethylamine-piperazine derivatives represented by the following formula 1 and their pharmaceutically acceptable salts thereof,

wherein the compound is 3-{[4-(2,3-dimethyl)phenylpiperazin-1-yl]methylcarboxamido}methyl-5-methyl-1-phenyl-1H-pyrazole.