IP Library › Granted Patent US 9,624,200

Granted Patent B2

US 9,624,200 · App. 14/508,970 · Granted Apr 18, 2017

Therapeutic piperazines

Inventors: Alan P. Kaplan (San Diego, CA); Terence P. Keenan (San Diego, CA); Michael I. Weinhouse (Escondido, CA); Mark E. Wilson (Ramona, CA); Andrew K. Lindstrom (San Diego, CA); William C. Ripka (San Diego, CA); Mi Chen (San Diego, CA)

Assignee: Dart NeuroScience (Cayman) Ltd.

C07D403/06 A61K31/495 A61K31/496 A61K31/5377 A61K31/551 A61K45/06 C07D241/04 C07D243/08 C07D401/04 C07D401/06 C07D401/14 C07D403/04 C07D403/14 C07D409/06 C07D413/06 C07D413/14 C07D417/06 C07D417/14

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Quick Facts

Patent No.: US 9,624,200
App. No.: 14/508,970
Granted: Apr 18, 2017
Kind: B2

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Abstract

The invention includes a compound of formula I: wherein R 1 , Y, A, n, R 4 and Z have any of the values described herein, as well as salts of such compounds, compositions comprising such compounds, and therapeutic methods that comprise the administration of such compounds. The compounds are inhibitors of PDE4 function and are useful for improving cognitive function and/or treating cognitive disorders or impairment, traumatic and/or ischemic injuries of the central and peripheral nervous system and/or psychiatric disorders in animals, especially humans.

Claims (278)

1. A method

of improving cognitive function in an animal comprising administering to the animal an effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is (C 1 -C 6 )alkyl or aryl(C 1 -C 6 )alkyl;

Y is —(C═O);

n is an integer from 0 to 6 inclusive;

A is —(CR c R d )—;

R 4 is aryl or heteroaryl;

Z is a phenyl ring substituted with one or more substituents independently selected from the group consisting of halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkoxy, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxy, piperidinyloxy, piperidinyloxy(C 1 -C 6 )alkyl, and cyano; and

each R c and R d is independently H (hydrogen), OH, NH 2 , or (C 1 -C 6 )alkyl, or optionally R c and R d taken together with the carbon to which they are attached is a 3 to 5 member ring consisting of C (carbon) atoms and optionally one or more O (oxygen) atoms and/or N(X) group, wherein X is absent, H (hydrogen), O (oxygen), OH, (C 1 -C 4 )alkyl, phenyl or benzyl,

wherein any aryl, or heteroaryl of R 1 or R 4 is optionally substituted with one or more substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, hydroxy, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, phenyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, cyano, nitro, halo, (C 1 -C 6 )carboxy, and NR c R d ; and wherein the piperazine core ring of formula (I) is optionally substituted at one or more carbon atoms with one or more substituents independently selected from the group consisting of oxo, halogen, (C 1 -C 6 )alkyl, and (C 1 -C 6 )alkoxy.

2. A method

of promoting neuronal plasticity in an animal comprising administering to the animal an effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is (C 1 -C 6 )alkyl or aryl(C 1 -C 6 )alkyl;

Y is —(C═O);

n is an integer from 0 to 6 inclusive;

A is —(CR c ,R d )—;

R 4 is aryl or heteroaryl;

3. A method

of treating an animal in need of enhancement of memory or cognition comprising administering to the animal an effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is (C 1 -C 6 )alkyl or aryl(C 1 -C 6 )alkyl;

Y is —(C═O);

n is an integer from 0 to 6 inclusive;

A is —(CR c R d )—;

R 4 is aryl or heteroaryl;

4. The method of claim 3 , wherein said animal has a cognitive disorder or impairment.

5. The method of claim 4 , wherein said animal has age-associated memory impairment, delirium, dementia, Alzheimer's disease, Parkinson's disease, Pick's disease, multiple sclerosis, Huntington's disease, mental retardation, Wilson's disease, Creutzfeldt-Jacob disease, neurofibromatosis type I, Wernicke-Korsakoff syndrome, Rubenstein-Taybi Syndrome, autism and/or cerebrovascular disease.

6. The method of claim 3 , wherein said animal has a traumatic and/or ischemic injury.

7. The method of claim 6 , wherein said traumatic and/or ischemic injury comprises subdural hematoma, normal-pressure hydrocephalus, cerebrovascular disease, brain tumor and/or head or brain trauma.

8. The method of claim 3 , wherein said animal has a psychiatric disorder.

9. The method of claim 8 , wherein said psychiatric disorder comprises a neurological disorder, an affective disorder, a psychotic disorder, a neurotic disorder, and/or an attention deficit disorder.

10. The method of claim 3 , wherein said animal has a neurological disorder.

11. The method of claim 3 , wherein said animal has a disorder of the central nervous system.

12. The method of claim 3 , wherein said animal has a disorder of the peripheral nervous system.

13. The method of claim 11 , wherein said disorder of the central nervous system is age-associated memory impairment, mild cognitive impairment, Alzheimer's disease, Parkinson's disease or Pick's Disease.

14. The method of claim 8 , wherein said psychiatric disorder is an attention deficit disorder, a schizophrenic disorder, an affective disorder, or a depressive disorder.

15. The method of claim 1 , wherein said animal is a healthy animal.

16. The method of claim 1 , wherein said animal is an aged animal.

17. The method of claim 1 , wherein

R 1 is (C 2 -C 6 )alkyl, or aryl(C 1 -C 6 )alkyl; and

Z is a phenyl ring substituted with one or more substituents independently selected from the group consisting of halogen, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkoxy and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxy.

18. The method of claim 2 , wherein

R 1 is (C 2 -C 6 )alkyl, or aryl(C 1 -C 6 )alkyl; and

19. The method of claim 3 , wherein

R 1 is (C 2 -C 6 )alkyl, or aryl(C 1 -C 6 )alkyl; and

20. The method of claim 1 , wherein a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(thiophen-2-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(furan-2-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(thiophen-3-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-3-(1H-imidazol-5-yl)propan-1-one;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(1H-imidazol-5-yl)ethanone;

(S)-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)(1H-imidazol-4-yl)methanone;

(S)-1-(4-(3-(cyclopentyloxy)-4-methoxyphenyl)-2-(pyrrolidin-1-ylmethyl)piperazin-1-yl)-2-(5-methyl-1H-1,2,4-triazol-3-yl)ethanone;

(S)-1-(4-(3-(cyclopentyloxy)-4-methoxyphenyl)-2-(morpholinomethyl)piperazin-1-yl)-2-(5-methyl-1H-1,2,4-triazol-3-yl)ethanone;

(R)-1-(2-((1H-pyrazol-1-yl)methyl)-4-(3-(cyclopentyloxy)-4-ethoxyphenyl)piperazin-1-yl)-2-(5-methyl-1H-1,2,4-triazol-3-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(5-methyl-1H-1,2,4-triazol-3-yl)ethanone;

(S)-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)(2,4-dimethylthiazol-5-yl)methanone;

(S)-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)(3,4-dihydroxyphenyl)methanone;

(S)-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)(3-hydroxyphenyl)methanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(2-methyl-1H-imidazol-1-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(1H-imidazol-1-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(thiazol-5-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(2H-tetrazol-5-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(2,4-dimethylthiazol-5-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(furan-2-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(1H-imidazol-2-yl)ethanone;

(S)-1-(2-benzyl-4-(3-cyclobutoxy-4-methoxyphenyl)piperazin-1-yl)-2-(1H-imidazol-4-yl)ethanone;

(S)-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)(1H-pyrazol-3-yl)methanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(5-methyl-1H-pyrazol-3-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(1H-pyrrol-2-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(1H-pyrrol-3-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(4-methylthiazol-2-yl)ethanone;

(S)-1-(2-benzyl-4-(3-cyclobutoxy-4-methoxyphenyl)piperazin-1-yl)-2-(furan-2-yl)ethanone;

(S)-1-(2-benzyl-4-(3-cyclobutoxy-4-methoxyphenyl)piperazin-1-yl)-2-(2,4-dimethylthiazol-5-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(1-methyl-1H-imidazol-4-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(1-methyl-1H-imidazol-5-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(1-methyl-1H-imidazol-2-yl)ethanone;

(S)-1-(2-benzyl-4-(3-cyclobutoxy-4-methoxyphenyl)piperazin-1-yl)-2-(1H-pyrrol-3-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(5-nitro-1H-1,2,4-triazol-3-yl)ethanone;

(S)-1-(2-benzyl-4-(3-isopropoxy-4-methoxyphenyl)piperazin-1-yl)-2-(1H-imidazol-5-yl)ethanone;

(S)-1-(2-benzyl-4-(3-isopropoxy-4-methoxyphenyl)piperazin-1-yl)-2-(1H-pyrrol-3-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(5-methyl-1H-1,2,4-triazol-3-yl)ethanone;

(S)-1-(2-benzyl-4-(3-isopropoxy-4-methoxyphenyl)piperazin-1-yl)-2-(3-methyl-1H-1,2,4-triazol-5-yl)ethanone;

(S)-1-(2-benzyl-4-(3-cyclobutoxy-4-methoxyphenyl)piperazin-1-yl)-2-(3-methyl-1H-1,2,4-triazol-5-yl)ethanone;

(S)-1-(2-benzyl-4-(3,4-bis(difluoromethoxy)phenyl)piperazin-1-yl)-2-(3-methyl-1H-1,2,4-triazol-5-yl)ethanone;

(S)-1-(2-benzyl-4-(3-isopropoxy-4-methoxyphenyl)piperazin-1-yl)-2-(2H-tetrazol-5-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(1H-1,2,3-triazol-1-yl)ethanone;

(S)-1-(2-benzyl-4-(3-cyclobutoxy-4-methoxyphenyl)piperazin-1-yl)-2-(2H-tetrazol-5-yl)ethanone;

(S)-1-(2-benzyl-4-(3-isopropoxy-4-methoxyphenyl)piperazin-1-yl)-2-(5-nitro-1H-1,2,4-triazol-3-yl)ethanone;

(S)-2-(3-amino-1H-1,2,4-triazol-5-yl)-1-(2-benzyl-4-(3-isopropoxy-4-methoxyphenyl)piperazin-1-yl)ethanone;

(S)-1-(2-benzyl-4-(3-cyclobutoxy-4-methoxyphenyl)piperazin-1-yl)-2-(5-nitro-1H-1,2,4-triazol-3-yl)ethanone;

(S)-2-(5-amino-1H-1,2,4-triazol-3-yl)-1-(2-benzyl-4-(3-cyclobutoxy-4-methoxyphenyl)piperazin-1-yl)ethanone;

(S)-1-(2-benzyl-4-(3-cyclobutoxy-4-methoxyphenyl)piperazin-1-yl)-2-(pyrimidin-2-yl)ethanone;

(S)-1-(2-benzyl-4-(3-isopropoxy-4-methoxyphenyl)piperazin-1-yl)-2-(pyridin-2-yl)ethanone;

(S)-1-(2-benzyl-4-(3-cyclobutoxy-4-methoxyphenyl)piperazin-1-yl)-2-(pyridin-2-yl)ethanone;

(S)-1-(2-benzyl-4-(3-isopropoxy-4-methoxyphenyl)piperazin-1-yl)-2-(pyrimidin-2-yl)ethanone;

(S)-1-(2-benzyl-4-(3-cyclobutoxy-4-(difluoromethoxy)phenyl)piperazin-1-yl)-2-(1H-imidazol-4-yl)ethanone;

(S)-1-(2-benzyl-4-(3-cyclobutoxy-4-(difluoromethoxy)phenyl)piperazin-1-yl)-2-(5-methyl-1H-1,2,4-triazol-3-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(difluoromethoxy)-4-methoxyphenyl)piperazin-1-yl)-2-(5-methyl-1H-1,2,4-triazol-3-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(difluoromethoxy)-4-methoxyphenyl)piperazin-1-yl)-2-(1H-imidazol-4-yl)ethanone;

(S)-1-(2-benzyl-4-(3-cyclobutoxy-4-(difluoromethoxy)phenyl)piperazin-1-yl)-2-(pyrimidin-2-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(difluoromethoxy)-4-methoxyphenyl)piperazin-1-yl)-2-(pyrimidin-2-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(difluoromethoxy)-4-methoxyphenyl)piperazin-1-yl)-2-(pyridin-2-yl)ethanone;

(S)-5-((2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)methyl)-2,4-dimethylthiazole;

(S)-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)(4-(hydroxymethyl)phenyl)methanone;

(S)-3-((2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)methyl)phenol;

(S)-4-((2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)methyl)phenol;

(S)-1-(4-(3-(cyclopentyloxy)-4-methoxyphenyl)-2-isobutylpiperazin-1-yl)-2-(1H-imidazol-4-yl)ethanone;

(S)-1-(4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-isobutylpiperazin-1-yl)-2-(1H-imidazol-4-yl)ethanone;

(S)-1-(4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)-2-isobutylpiperazin-1-yl)-2-(1H-imidazol-4-yl)ethanone;

(S)-1-(4-(3-cyclobutoxy-4-methoxyphenyl)-2-isobutylpiperazin-1-yl)-2-(1H-imidazol-4-yl)ethanone;

(S)-1-(4-(3-cyclobutoxy-4-methoxyphenyl)-2-isobutylpiperazin-1-yl)-2-(1-methyl-1H-imidazol-4-yl)ethanone;

(S)-1-(4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-isobutylpiperazin-1-yl)-2-(5-methyl-1H-1,2,4-triazol-3-yl)ethanone;

(S)-1-(4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)-2-isobutylpiperazin-1-yl)-2-(5-methyl-1H-1,2,4-triazol-3-yl)ethanone;

(S)-1-(2-isobutyl-4-(3-isopropoxy-4-methoxyphenyl)piperazin-1-yl)-2-(5-methyl-1H-1,2,4-triazol-3-yl)ethanone;

(S)-2-(1H-imidazol-4-yl)-1-(2-isobutyl-4-(3-isopropoxy-4-methoxyphenyl)piperazin-1-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(pyridin-2-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(pyridin-3-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(pyridin-4-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(pyrazin-2-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(pyrimidin-2-yl)ethanone;

(S)-1-(4-(3-(cyclopentyloxy)-4-methoxyphenyl)-2-isobutylpiperazin-1-yl)-2-(5-methyl-1H-1,2,4-triazol-3-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(pyrimidin-4-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(2-fluorophenyl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(2,6-difluorophenyl)ethanone;

(S)-1-(4-(3-cyclobutoxy-4-methoxyphenyl)-2-isobutylpiperazin-1-yl)-2-(oxazol-5-yl)ethanone;

(S)-1-(4-(3-cyclobutoxy-4-methoxyphenyl)-2-isobutylpiperazin-1-yl)-2-(3-methyl-1,2,4-oxadiazol-5-yl)ethanone;

(S)-1-(4-(3-cyclobutoxy-4-methoxyphenyl)-2-(4-fluorobenzyl)piperazin-1-(1H-pyrazol-4-yl)ethanone;

(S)-1-(4-(3-cyclobutoxy-4-methoxyphenyl)-2-(4-fluorobenzyl)piperazin-1-yl)-2-(5-methyl-1H-1,2,4-triazol-3-yl)ethanone;

(S)-1-(4-(3-cyclobutoxy-4-methoxyphenyl)-2-(4-fluorobenzyl)piperazin-1-yl)-2-(pyrimidin-2-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(4H-1,2,4-triazol-3-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(1H-pyrazol-4-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(oxazol-5-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(3-methyl-1,2,4-oxadiazol-5-yl)ethanone;

(S)-1-(2-benzyl-4-(3-cyclopropoxy-4-methoxyphenyl)piperazin-1-yl)-2-(4H-1,2,4-triazol-3-yl)ethanone;

(S)-1-(2-benzyl-4-(3-cyclobutoxy-4-methoxyphenyl)piperazin-1-yl)-2-(oxazol-5-yl)ethanone;

(S)-1-(2-benzyl-4-(3-cyclobutoxy-4-methoxyphenyl)piperazin-1-yl)-2-(3-methyl-1,2,4-oxadiazol-5-yl)ethanone;

(S)-1-(2-benzyl-4-(3-cyclobutoxy-4-methoxyphenyl)piperazin-1-yl)-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)ethanone;

(S)-1-(2-benzyl-4-(3-cyclobutoxy-4-methoxyphenyl)piperazin-1-yl)-2-(1H-pyrazol-4-yl)ethanone;

(S)-1-(2-benzyl-4-(3-cyclobutoxy-4-methoxyphenyl)piperazin-1-yl)-2-(2-methyloxazol-5-yl)ethanone;

(S)-1-(2-benzyl-4-(3-cyclobutoxy-4-methoxyphenyl)piperazin-1-yl)-2-(3-isopropyl-1H-1,2,4-triazol-5-yl)ethanone;

(S)-1-(2-benzyl-4-(3-cyclobutoxy-4-methoxyphenyl)piperazin-1-yl)-2-(3-ethyl-1H-1,2,4-triazol-5-yl)ethanone;

(S)-1-(2-benzyl-4-(3-cyclobutoxy-4-methoxyphenyl)piperazin-1-yl)-2-(1-methyl-1H-pyrazol-4-yl)ethanone;

(S)-1-(2-benzyl-4-(3-cyclobutoxy-4-methoxyphenyl)piperazin-1-yl)-2-(4H-1,2,4-triazol-3-yl)ethanone;

(S)-1-(2-benzyl-4-(3-isopropoxy-4-methoxyphenyl)piperazin-1-yl)-2-(4H-1,2,4-triazol-3-yl)ethanone;

(S)-1-(2-benzyl-4-(3-cyclobutoxy-4-(difluoromethoxy)phenyl)piperazin-1-yl)-2-(4H-1,2,4-triazol-3-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)piperazin-1-yl)-2-(1H-imidazol-4-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)piperazin-1-yl)-2-(1H-imidazol-5-yl)ethanone;

(S)-1-(2-benzyl-4-(3,4-bis(difluoromethoxy)phenyl)piperazin-1-yl)-2-(1H-imidazol-5-yl)ethanone;

1-((S)-2-benzyl-4-(4-methoxy-3-((S)-1-methylpyrrolidin-3-yloxy)phenyl)piperazin-1-yl)-2-(5-methyl-1H-1,2,4-triazol-3-yl)ethanone;

(S)-2-(5-amino-1H-1,2,4-triazol-3-yl)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)ethanone;

(S)-1-(2-benzyl-4-(4-methoxy-3-(1-methylpiperidin-4-yloxy)phenyl)piperazin-1-yl)-2-(5-methyl-4H-1,2,4-triazol-3-yl)ethanone;

(S)-1-(2-benzyl-4-(3-cyclopropoxy-4-methoxyphenyl)piperazin-1-yl)-2-(3-methyl-1H-1,2,4-triazol-5-yl)ethanone;

(S)-1-(2-benzyl-4-(3-cyclobutoxy-4-methoxyphenyl)piperazin-1-yl)-2-(2-methyl-1H-imidazol-5-yl)ethanone; and

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(1-isopropyl-1H-imidazol-4-yl)ethanone.

21. The method of claim 3 , wherein a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(thiophen-2-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(furan-2-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(thiophen-3-yl)ethanone;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-3-(1H-imidazol-5-yl)propan-1-one;

(S)-1-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-2-(1H-imidazol-5-yl)ethanone;

(S)-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)(1H-imidazol-4-yl)methanone;

(S)-1-(4-(3-(cyclopentyloxy)-4-methoxyphenyl)-2-(pyrrolidinylmethyl)piperazin-1-yl)-2-(5-methyl-1H-1,2,4-triazol-3-yl)ethanone;