Therapeutic agent for non-motor symptoms associated with Parkinson's disease

1. A method for treating a non-motor symptom associated with Parkinson's disease or preventing a relapse thereof, wherein the non-motor symptom associated with Parkinson's disease is a psychopathic symptom or cognitive dysfunction, the method comprising administering a therapeutically effective amount of a compound of Formula (1),

wherein:

R 1 and R 2 are each independently hydrogen atom, a C 1-6 alkyl group optionally substituted with 1 to 3 deuterium atoms, or a C 3-8 cycloalkyl group,

R 3 and R 4 are each independently hydrogen atom, deuterium atom, or a C 1-6 alkyl group,

R 5 is an optionally-substituted C 4-7 alkyl group or —(CR 8 R 9 ) r -E,

R 6 and R 7 are each independently hydrogen atom, deuterium atom, fluorine atom, or an optionally-substituted C 1-6 alkyl group,

R 8 and R 9 are each independently hydrogen atom, fluorine atom, or an optionally-substituted C 1-6 alkyl group,

A is an optionally-substituted C 6-10 aryl group or an optionally-substituted 5- to 10-membered heteroaryl group,

r is 1, 2, 3, or 4,

E is an optionally-substituted C 3-8 cycloalkyl group, an optionally-substituted C 4-8 cycloalkenyl group, an optionally-substituted 5- to 10-membered saturated heterocyclic group wherein the saturated heterocyclic group comprises 1 to 3 heteroatoms independently selected from the group consisting of oxygen atom and sulfur atom as a constituent atom of the ring, an optionally-substituted C 6-10 aryl group, or an optionally-substituted 5- to 10-membered heteroaryl group,

L is oxygen atom, sulfur atom, or —NR 10 —,

n is 1, 2, or 3,

R 10 is hydrogen atom, a C 1-6 alkyl group, or a C 3-8 cycloalkyl group,

X is hydrogen atom, a C 1-6 alkyl group optionally substituted with fluorine atom, or a halogen atom,

a substituent on the optionally-substituted C 6-10 aryl group and optionally-substituted 5- to 10-membered heteroaryl group is 1 to 2 substituents each independently selected from the group consisting of a halogen atom; a C 1-6 alkyl group optionally substituted with fluorine atom; a C 1-6 alkyloxy group optionally substituted with fluorine atom; hydroxy group; a C 1-6 alkylthio group; a C 6-10 aryloxy group; a C 6-10 arylthio group; cyano group; —CO 2 R 11 ; —SO 2 R 11 ; —NR 10 SO 2 R 11 ; —OSO 2 R 11 ; —COR 12 ; —SO 2 NR 12 R 13 ; —CONR 12 R 13 ; —NR 12 R 13 ; —NR 10 CONR 12 R 13 ; —NR 10 COR 12 ; —CR 12 ═N(OR 11 ); oxime group; a C 3-8 cycloalkyl group; a C 6-10 aryl group; and a 5- to 10-membered heteroaryl group, wherein R 10 is as defined above, R 11 is a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 6-10 aryl group, or a 5- to 10-membered heteroaryl group, R 12 and R 13 are each independently hydrogen atom, a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 6-10 aryl group, or a 5- to 10-membered heteroaryl group, and the C 6-10 aryl group and 5- to 10-membered heteroaryl group in R 11 , R 12 , and R 13 may be optionally further substituted with a halogen atom, a C 1-6 alkyl group, hydroxy group, or a C 1-6 alkyloxy group,

a substituent on the optionally-substituted C 1-6 alkyl group and optionally-substituted C 4-7 alkyl group is 1 to 2 substituents each independently selected from the group consisting of fluorine atom; hydroxy group; and a C 1-6 alkyloxy group optionally substituted with fluorine atom, and

a substituent on the optionally-substituted C 3-8 cycloalkyl group, optionally-substituted C 4-8 cycloalkenyl group, and optionally-substituted 5- to 10-membered saturated heterocyclic group is 1 to 2 substituents each independently selected from the group consisting of fluorine atom; a C 1-6 alkyl group optionally substituted with fluorine atom; hydroxy group; and a C 1-6 alkyloxy group optionally substituted with fluorine atom,

or a pharmaceutically acceptable salt thereof,

to a patient in need thereof.

2. The method according to claim 1 , wherein R 1 and R 2 are each independently hydrogen atom, methyl group, or methyl group substituted with 1 to 3 deuterium atoms, R 3 is hydrogen atom, deuterium atom, or methyl group, and R 4 is hydrogen atom or deuterium atom.

3. The method according to claim 1 , wherein A is an optionally-substituted C 6-10 aryl group.

4. The method according to claim 1 , wherein X is hydrogen atom.

5. The method according to claim 1 , wherein L is oxygen atom.

6. The method according to claim 1 , wherein n is 1.

7. The method according to claim 1 , wherein R 1 , R 3 , and R 4 are hydrogen atom and R 2 is methyl group.

8. The method according to claim 1 , wherein R 6 and R 7 are each independently hydrogen atom or deuterium atom and R 8 and R 9 are hydrogen atom.

9. The method according to claim 1 , wherein E is an optionally-substituted C 3-8 cycloalkyl group, an optionally-substituted 5- to 10-membered saturated heterocyclic group wherein the saturated heterocyclic group comprises 1 to 3 oxygen atoms as a constituent atom of the ring, or an optionally-substituted phenyl group.

10. The method according to claim 1 , wherein E is an optionally-substituted C 3-8 cycloalkyl group.

11. The method according to claim 1 , wherein r is 1 or 2.

12. The method according to claim 1 , wherein R 5 is an optionally-substituted C 4-7 alkyl group.

13. The method according to claim 1 , wherein the compound of Formula (1) is at least one selected from the group consisting of:

1-[5-(benzyloxy)-1-(cyclohexylmethyl)-1H-pyrazol-3-yl]-N-methylmethanamine;

1-{1-(cyclohexylmethyl)-5-[(2-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{5-[(2-chloro-4-fluorobenzyl)oxy]-1-(cyclohexylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{1-(cyclohexylmethyl)-5-[(4-fluoro-2-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{1-(cyclohexylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(cyclohexylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{5-[(2-chloro-5-fluorobenzyl)oxy]-1-(cyclohexylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{1-(cyclohexylmethyl)-5-[(2,5-dichlorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{1-(cyclopentylmethyl)-5-[(4-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{5-[(2-chlorobenzyl)oxy]-1-(cyclopentylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{1-(cyclopentylmethyl)-5-[(2,4-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{1-(cyclopentylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(cyclopentylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{5-[(2,5-difluorobenzyl)oxy]-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{5-[(2,5-difluorobenzyl)oxy]-1-(3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(3-methoxy-3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{1-(cyclopentylmethyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{1-(2-cyclopentylethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylethanamine;

N-methyl-1-{1-(3-methylbutyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}-methylmethanamine;

1-{1-(3,3-dimethylbutyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{1-(4-fluorobenzyl)-5-[(2-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{5-[(2,5-difluorobenzyl)oxy]-1-(4-fluorobenzyl)-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{5-[(2,5-difluorobenzyl)oxy]-1-(4-methylbenzyl)-1H-pyrazol-3-yl}-N-methylmethanamine;

N-methyl-1-{1-(4-methylbenzyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}methanamine;

1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(cyclopropylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(2-methylpropyl)-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{5-[(2,5-difluorobenzyl)oxy]-1-(2,2-dimethylpropyl)-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(2,2-dimethylpropyl)-1H-pyrazol-3-yl}-N-methylmethanamine;

1-[1-benzyl-5-(benzyloxy)-1H-pyrazol-3-yl]-N-methylmethanamine;

1-{5-[(4-fluoro-2-methylbenzyl)oxy]-1-(tetrahydro-2H-pyran-2-ylmethyl)-1H-pyrazolo-3-yl}-N-methylmethanamine;

1-[5-(benzyloxy)-1-(bicyclo[2.2.1]hept-2-ylmethyl)-1H-pyrazol-3-yl]-N-methylmethanamine;

1-{1-(bicyclo[2,2,1]hept-2-ylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{1-(bicyclo[2,2,1]hept-2-ylmethyl)-5-[(5-chloro-2-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{5-[(3-chlorobenzyl)oxy]-1-(2-oxabicyclo[2,2,2]oct-3-ylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{5-[(2,5-difluorobenzyl)oxy]-1-[(4,4-difluorocyclohexyl)methyl]-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{5-[(2,5-difluorobenzyl)oxy]-1-[(1-fluorocyclohexyl)methyl]-1H-pyrazol-3-yl}-N-methylmethanamine;

2-[({1-(cyclopentylmethyl)-3-[(methylamino)methyl]-1H-pyrazol-5-yl}oxy)methyl]benzonitrile;

1-{1-(4-chlorobenzyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(2-ethylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;

1-[5-(benzyloxy)-1-(1-cyclopentylethyl)-1H-pyrazol-3-yl]-N-methylmethanamine;

1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(1-cyclopentylethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;

1-[5-(benzyloxy)-1-(1-cyclohexylethyl)-1H-pyrazol-3-yl]-N-methylmethanamine;

1-{1-(1-cyclohexylethyl)-5-[(2-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{1-(1-cyclohexylethyl)-5-[(4-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{5-[(2-chlorobenzyl)oxy]-1-(1-cyclohexylethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{1-(1-cyclohexylethyl)-5-[(2-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{1-(1-cyclohexylethyl)-5-[(3-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{1-(1-cyclohexylethyl)-5-[(2,4-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{5-[(2-chloro-4-fluorobenzyl)oxy]-1-(1-cyclohexylethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{1-(1-cyclohexylethyl)-5-[(4-fluoro-2-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{1-(1-cyclohexylethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(1-cyclohexylethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{1-(1-cyclohexylethyl)-5-[(2-fluoro-5-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;

1-[5-(benzyloxy)-1-(1-cyclohexyl-2-fluoroethyl)-1H-pyrazol-3-yl]-N-methylmethanamine;

1-{5-(benzyloxy)-1-[(1-methylcyclohexyl)methyl]-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{5-[(3-chlorobenzyl)oxy]-1-(3,4-dihydro-2H-chromen-2-ylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;

N-({1-(cyclohexylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}methyl)cyclopropanamine;

N-({1-(cyclohexylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}methyl)ethanamine;

1-{1-(cyclohexylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}methanamine;

1-{1-(cyclohexylmethyl)-5-[difluoro(phenyl)methoxy]-1H-pyrazol-3-yl}-N-methylmethanamine;

1-[5-(benzyloxy)-1-(cyclohexylmethyl)-1H-pyrazol-3-yl]-N-methyl( 2 H 2 )methanamine;

1-[5-(benzyloxy)-1-(cyclohexylmethyl)-1H-pyrazol-3-yl]-N-( 2 H 3 )methyl( 2 H 2 )methanamine;

1-[5-(benzyloxy)-1-(cyclohexylmethyl)-1H-pyrazol-3-yl]-N-( 2 H 3 )methylmethanamine;

1-[1-(cyclopentylmethyl)-5-{[(2,5-difluorophenyl)( 2 H 2 )methyl]oxy}-1H-pyrazol-3-yl]-N-methylmethanamine;

1-[5-{[(5-chloro-2-fluorophenyl)( 2 H 2 )methyl]oxy}-1-(cyclopentylmethyl)-1H-pyrazol-3-yl]-N-methylmethanamine;

1-[1-(cyclohexylmethyl)-5-{[(2,5-difluorophenyl)( 2 H 2 )methyl]oxy}-1H-pyrazol-3-yl]-N-methylmethanamine;

1-[5-{[(5-chloro-2-fluorophenyl)( 2 H 2 )methyl]oxy}-1-(cyclohexylmethyl)-1H-pyrazol-3-yl]-N-methylmethanamine; and

1-[5-{[(2,5-difluorophenyl)( 2 H 2 )methyl]oxy}-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl]-N-methyl( 2 H 2 )methanamine,

or a pharmaceutically acceptable salt thereof.

14. The method according to claim 1 , wherein the non-motor symptom associated with Parkinson's disease is cognitive dysfunction.

15. The method according to claim 1 , wherein the non-motor symptom associated with Parkinson's disease is a psychopathic symptom.

16. A method for antagonizing a serotonin 5-HT 2A receptor, inhibiting a serotonin transporter, and antagonizing a serotonin 5-HT 2C receptor, comprising administering a therapeutically effective amount of a compound of Formula (1)

wherein:

R 1 and R 2 are each independently hydrogen atom, a C 1-6 alkyl group optionally substituted with 1 to 3 deuterium atoms, or a C 3-8 cycloalkyl group,

R 3 and R 4 are each independently hydrogen atom, deuterium atom, or a C 1-6 alkyl group,

R 5 is an optionally-substituted C 4-7 alkyl group or —(CR 8 R 9 ) r -E,

R 6 and R 7 are each independently hydrogen atom, deuterium atom, fluorine atom, or an optionally-substituted C 1-6 alkyl group,

R 8 and R 9 are each independently hydrogen atom, fluorine atom, or an optionally-substituted C 1-6 alkyl group,

A is an optionally-substituted C 6-10 aryl group or an optionally-substituted 5- to 10-membered heteroaryl group,

r is 1, 2, 3, or 4,

E is an optionally-substituted C 3-8 cycloalkyl group, an optionally-substituted C 4-8 cycloalkenyl group, an optionally-substituted 5- to 10-membered saturated heterocyclic group wherein the saturated heterocyclic group comprises 1 to 3 heteroatoms independently selected from the group consisting of oxygen atom and sulfur atom as a constituent atom of the ring, an optionally-substituted C 6-10 aryl group, or an optionally-substituted 5- to 10-membered heteroaryl group,

L is oxygen atom, sulfur atom, or —NR 10 —,

n is 1, 2, or 3,

R 10 is hydrogen atom, a C 1-6 alkyl group, or a C 3-8 cycloalkyl group,

X is hydrogen atom, a C 1-6 alkyl group optionally substituted with fluorine atom, or a halogen atom,

a substituent on the optionally-substituted C 6-10 aryl group and optionally-substituted 5- to 10-membered heteroaryl group is 1 to 2 substituents each independently selected from the group consisting of a halogen atom; a C 1-6 alkyl group optionally substituted with fluorine atom; a C 1-6 alkyloxy group optionally substituted with fluorine atom; hydroxy group; a C 1-6 alkylthio group; a C 6-10 aryloxy group; a C 6-10 arylthio group; cyano group; —CO 2 R 11 ; —SO 2 R 11 ; —NR 10 SO 2 R 11 ; —OSO 2 R 11 ; —COR 12 ; —SO 2 NR 12 R 12 ; —CONR 12 R 13 ; —NR 12 R 13 ; —NR 10 CONR 12 R 13 ; —NR 10 COR 12 ; —CR 12 ═N(OR 11 ); oxime group; a C 3-8 cycloalkyl group; a C 6-10 aryl group; and a 5- to 10-membered heteroaryl group, wherein R 10 is as defined above, R 11 is a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 6-10 aryl group, or a 5- to 10-membered heteroaryl group, R 12 and R 13 are each independently hydrogen atom, a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 6-10 aryl group, or a 5- to 10-membered heteroaryl group, and the C 6-10 aryl group and 5- to 10-membered heteroaryl group in R 11 , R 12 , and R 13 may be optionally further substituted with a halogen atom, a C 1-6 alkyl group, hydroxy group, or a C 1-6 alkyloxy group,

a substituent on the optionally-substituted C 1-6 alkyl group and optionally-substituted C 4-7 alkyl group is 1 to 2 substituents each independently selected from the group consisting of fluorine atom; hydroxy group; and a C 1-6 alkyloxy group optionally substituted with fluorine atom, and

a substituent on the optionally-substituted C 3-8 cycloalkyl group, optionally-substituted C 4-8 cycloalkenyl group, and optionally-substituted 5- to 10-membered saturated heterocyclic group is 1 to 2 substituents each independently selected from the group consisting of fluorine atom; a C 1-6 alkyl group optionally substituted with fluorine atom; hydroxy group; and a C 1-6 alkyloxy group optionally substituted with fluorine atom,

or a pharmaceutically acceptable salt thereof,

to a patient in need thereof.

17. The method according to claim 1 , wherein the compound has the action of antagonizing a serotonin 5-HT 2A receptor, inhibiting a serotonin transporter, and antagonizing a serotonin 5-HT 2C receptor.

18. The method according to claim 1 , wherein the compound is administered in combination with at least one medicament selected from the group consisting of an antidepressant, an anxiolytic drug, an antipsychotic agent, a dopamine replacement drug, a dopamine receptor agonist, an antiparkinsonian drug, an anti-epilepsy drug, an analgesic drug, a hormone preparation, an antimigraine drug, an adrenaline β receptor antagonist, an antidementia drug, a therapeutic drug for a mood disorder, an antiemetic drug, and a sleep-inducing drug, to the patient in need thereof.

19. The method according to claim 1 , wherein the compound of Formula (1) is at least one selected from the group consisting of:

1-{1-(cyclopentylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;

1-{5-[(2,5-difluorobenzyl)oxy]-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;

N-methyl-1-{1-(3-methylbutyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}methanamine;

1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(cyclopropylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine; and

1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(2-methylpropyl)-1H-pyrazol-3-yl}-N-methylmethanamine,

or a pharmaceutically acceptable salt thereof.

20. The method according to claim 1 , wherein the compound of Formula (1) is 1-{1-(cyclopentylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine, or a pharmaceutically acceptable salt thereof.

21. The method according to claim 1 , wherein the compound of Formula (1) is 1-{5-[(2,5-difluorobenzyl)oxy]-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine, or a pharmaceutically acceptable salt thereof.

22. The method according to claim 1 , wherein the compound of Formula (1) is N-methyl-1-{1-(3-methylbutyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}methanamine, or a pharmaceutically acceptable salt thereof.

23. The method according to claim 1 , wherein the compound of Formula (1) is 1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(cyclopropylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine, or a pharmaceutically acceptable salt thereof.

24. The method according to claim 1 , wherein the compound of Formula (1) is 1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(2-methylpropyl)-1H-pyrazol-3-yl}-N-methylmethanamine, or a pharmaceutically acceptable salt thereof.