Glycine transporter-1 inhibitors

• US 7,538,114 B2
• Filed: 06/26/2007
• Issued: 05/26/2009
• Est. Priority Date: 06/28/2006
• Status: Expired due to Fees

• Current Assignee: Amgen Inc.
• Original Assignee: Amgen Inc.
• Inventors: Harried, Scott S., Xia, Xiaoyang, Hitchcock, Stephen, Qian, Wenyuan, Amegadzie, Albert
• Primary Examiner(s): Wilson; James O
• Assistant Examiner(s): Leeser; Erich A
• Application Number:
  US11/823,027
• Publication Number:
  US 20080004289A1
• Time in Patent Office: 700 Days
• Field of Search: 514/255.04, 514/218, 514/183, 544/396, 544/384, 540/575, 540/470
• US Class Current: 514/255.04
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 33/00 Medicinal preparations containing inorganic active ingredients
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 213/36 : Radicals substituted by singly-bound nitrogen atoms nitro radicals C07D213/26
• CPC Class Codes: C07D 241/04 : having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 241/08 : with oxygen atoms directly attached to ring carbon atoms
• CPC Class Codes: C07D 243/08 : not condensed with other rings
• CPC Class Codes: C07D 295/15 : to an acyclic saturated chain
• CPC Class Codes: C07D 333/20 : by nitrogen atoms nitro, nitroso radicals C07D333/12

Abstract

The present invention provides compounds that are glycine transporter 1 (hereinafter referred to as GlyT-1) inhibitors and are therefore useful for the treatment of diseases treatable by inhibition of GlyT1 such as cognitive disorders associated with Schizophrenia, ADHD (attention deficit hyperactivity disorder), MCI (mild cognitive impairment), and the like. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

Claims

1. A compound of Formula (I):

2. The compound of claim 1 wherein:

n is 1;

R¹ and R² are independently selected from hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, cycloalkyl, or heterocyclyl wherein the aforementioned rings are optionally substituted with R^a, R^b, or R^c independently selected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, monosubstituted amino, or disubstituted amino;

or

R¹ and R², when attached to the same carbon atom, can combine to form cycloalkyl or monocyclic saturated heterocyclyl to give a spiro ring wherein the cycloalkyl or monocyclic saturated heterocyclyl can be optionally substituted with R^d, R^e, or R^f independently selected from alkyl, alkoxy, fluoro, fluoroalkyl, fluoroalkoxy, hydroxy, monosubstituted amino, or disubstituted amino;

or

R¹ and R², when attached to carbon atoms 2 and 5 or 3 and 6 positions of the piperazine ring, can combine to form —

C₁-C₃—

alkylene chain wherein one of the carbon atoms in the alkylene chain is optionally replaced by a —

NR—

, —

O—

, —

S(O)n1- (where R is hydrogen or alkyl and n1 is 0-2) and further wherein one or two hydrogen atoms in the alkylene chain can be optionally substituted with one or two alkyl; and

Ar¹ and Ar² are independently aryl, heteroaryl, cycloalkyl, or heterocyclyl where each of the aforementioned ring is optionally substituted with R^g, R^hor Rⁱ where R^g is alkyl, halo, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, or acylamino and R^h and Rⁱ are independently selected from alkyl, halo, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, acylamino, aryl, heteroaryl, cycloalkyl, or heterocyclyl where the aromatic or alicyclic ring in R^g, R^h and Rⁱ is optionally substituted with R^j, R^k or R^l which are independently selected from alkyl, halo, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, or acylamino.

3. The compound of claim 2 wherein R¹ and R² are independently selected from hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, cycloalkyl, or heterocyclyl wherein the aforementioned rings are optionally substituted with R^a, R^b, or R^c independently selected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, monosubstituted amino, or disubstituted amino.

4. The compound of claim 2 wherein R¹ and R² are hydrogen.

5. The compound of claim 2 wherein R¹ and R² are independently selected from hydrogen, alkyl, haloalkyl, alkoxy, or haloalkoxy provided that at least one of R¹ and R² is other than hydrogen.

6. The compound of claim 2 wherein R¹ is hydrogen and R² alkyl.

7. The compound of claim 2 wherein R¹ and R² are attached to the same carbon atom and are combined to form cycloalkyl optionally substituted with R^d, R^e or R^f independently selected from alkyl, alkoxy, fluoro, fluoroalkyl, fluoroalkoxy, hydroxy, monosubstituted amino, or disubstituted ammo.

8. The compound of claim 2 wherein R¹ and R² are attached to the same carbon atom and are combined to form monocyclic saturated heterocyclyl which are optionally substituted with R^d, R^e or R^f independently selected from alkyl, alkoxy, fluoro, fluoroalkyl, fluoroalkoxy, hydroxy, monosubstituted amino, or disubstituted amino.

9. The compound of claim 2 wherein R¹ and R² are attached to carbon atoms 2 and 5 or 3 and 6 positions of the piperazine ring, and are combined to form —

C₁-C₂—

alkylene chain wherein one or two hydrogen atoms in the alkylene chain can be optionally substituted with one or two alkyl.

10. The compound of claim 2 wherein R¹, R², R³, R⁴ and R⁵ are hydrogen and Arand Ar² are phenyl, each optionally substituted with R^g, R^h or Rⁱ.

11. The compound of claim 2 wherein R³ and R⁵ are hydrogen, R¹, R², and R⁴ are independently hydrogen or alkyl, and Ar¹ and Ar² are phenyl, each optionally substituted with R^g, R^h or Rⁱ provided at least one of R¹, R², and R⁴ is other than hydrogen.

12. The compound of claim 2 wherein R¹, R³, R⁴ and R⁵ are hydrogen, R² is alkyl, and Ar¹ and Ar² are phenyl, each optionally substituted with R^g, R^h or Rⁱ.

13. The compound of claim 2 wherein R¹, R², R³, R⁴ and R⁵ are hydrogen, Ar¹ is phenyl optionally substituted with R^g, R^h or Rⁱ and Ar² is cycloalkyl.

14. The compound of claim 2 wherein R³ and R⁵ are hydrogen, R¹, R², and R⁴ are independently hydrogen or alkyl, Ar¹ is phenyl optionally substituted with R^g, R^h or Rⁱ and Ar² is cycloalkyl provided at least one of R¹, R², and R⁴is other than hydrogen.

15. The compound of claim 2 wherein R¹, R³, R⁴, and R⁵ are hydrogen, R² is alkyl, Ar¹ is phenyl optionally substituted with R^g, R^h or Rⁱ and Ar² is cycloalkyl.

16. The compound of claim 2 wherein R¹, R², R³, R⁴ and R⁵ are hydrogen, Ar¹ is phenyl and Ar² is heteroaryl, each ring optionally substituted with R^g, R^h or Rⁱ.

17. The compound of claim 2 wherein R³ and R⁵ are hydrogen, R¹, R², and R⁴ are independently hydrogen or alkyl, Ar¹ is phenyl and Ar² is heteroaryl, each ring optionally substituted with R^g, R^h or Rⁱ provided at least one of R¹, R², and R⁴ is other than hydrogen.

18. The compound of claim 2 wherein R¹, R³, R⁴ and R⁵ are hydrogen, R² is alkyl, Ar¹ is phenyl and Ar² is heteroaryl, each ring optionally substituted with R^g, R^h or Rⁱ.

19. The compound of claim 2 wherein the compound has the structure:

20. The compound of claim 2 wherein the compound has the structure:

21. The compound of claim 2 wherein the compound has the structure:

22. The compound of claim 2 wherein the compound of Formula (I) has one of the following structures:

26. The compound of claim 2 wherein R⁴ and R⁵ are hydrogen;

R¹ and R² are independently selected from hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, cycloalkyl, or heterocyclyl wherein the aforementioned rings are optionally substituted with R^a, R^b, or R^c independently selected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, monosubstituted amino, or disubstituted amino; and

Ar¹ is aryl, heteroaryl, cycloalkyl, or heterocyclyl and Ar² is heteroaryl, cycloalkyl, or heterocyclyl, where each of the aforementioned ring is optionally substituted with R^g, R^h or Rⁱ where R^g is alkyl, halo, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, or acylamino and R^h and Rⁱ are independently selected from alkyl, halo, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, acylamino, aryl, heteroaryl, cycloalkyl, or heterocyclyl where the aromatic or alicyclic ring in R^g, R^h and Rⁱ is optionally substituted with R^j, R^k or R^l which are independently selected from alkyl, halo, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, or acylamino.

27. The compound of claim 2 wherein R⁴ and R⁵ are hydrogen;

R¹ and R² are independently selected from hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, cycloalkyl, or heterocyclyl wherein the aforementioned rings are optionally substituted with R^a, R^b, or R^c independently selected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, monosubstituted amino, or disubstituted amino; and

Ar¹ and Ar² are aryl, where each of the aforementioned ring is substituted with R^g where R^g is alkyl, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, or acylamino and optionally substituted with R^h or Rⁱ where R^h and Rⁱ are independently selected from alkyl, halo, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, acylamino, aryl, heteroaryl, cycloalkyl, or heterocyclyl where the aromatic or alicyclic ring in R^g, R^h and Rⁱ is optionally substituted with R^j, R^k or R^l which are independently selected from alkyl, halo, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, or acylamino.

28. The compound of claim 2 wherein R⁴ is hydrogen or alkyl and R⁵ are alkyl;

Rand R² are independently selected from hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, cycloalkyl, or heterocyclyl wherein the aforementioned rings are optionally substituted with R^a, R^b, or R^c independently selected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, monosubstituted amino, or disubstituted amino; and

Ar¹ and Ar² are aryl, where each of the aforementioned ring is substituted with R^g where R^g is alkyl, halo, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, or acylamino and optionally substituted with R^h or Rⁱ where R^h and Rⁱ are independently selected from alkyl, halo, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, acylamino, aryl, heteroaryl, cycloalkyl, or heterocyclyl where the aromatic or alicyclic ring in R^g, R^h and Rⁱ is optionally substituted with R^j, R^k or R^l which are independently selected from alkyl, halo, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, or acylamino.

29. The compound of claim 2 wherein R¹, R², R³, R⁴ and R⁵ are hydrogen, Ar¹ is phenyl and Ar² is cycloalkyl, each optionally substituted with R^g, R^h or Rⁱ.

30. The compound of claim 2 wherein R¹, R³, R⁴, and R⁵ are hydrogen, R² is hydrogen or alkyl, Ar¹ is phenyl and Ar² is cyclopentyl or cyclohexyl, each Ar¹ and Ar² optionally substituted with R^g or R^h independently selected from alkyl, halo, haloalkyl, or haloalkoxy.

31. The compound of claim 2 wherein R¹, R², R³, R⁴, and R⁵ are hydrogen, Ar¹ is phenyl and Ar² is heteroaryl, each Ar¹ and Ar² optionally substituted with R^g or R^h independently selected from alkyl, halo, haloalkyl, or haloalkoxy.

32. The compound of claim 2 wherein R¹, R³, R⁴, and R⁵ are hydrogen, R² is alkyl, Ar¹ is phenyl and Ar² is heteroaryl, each Ar¹ and Ar² optionally substituted with R^g or R^h independently selected from alkyl, halo, haloalkyl, or haloalkoxy.

33. The compound of claim 7 where R⁴ and R⁵ are hydrogen.

34. The compound of claim 33 where R³ is hydrogen and Ar¹ and Ar² are phenyl, each optionally substituted with R^g, R^h or Rⁱ.

35. The compound of claim 8 where R⁴ and R⁵ are hydrogen.

36. The compound of claim 35 where R³ is hydrogen and Ar¹ and Ar² are phenyl, each optionally substituted with R^g, R^h or Rⁱ.

37. The compound of claim 9 where R⁴ and R⁵ are hydrogen.

38. The compound of claim 37 where R³ is hydrogen and Ar¹ and Ar² are phenyl, each optionally substituted with R^g, R^h or Rⁱ.

39. The compound of claim 2 wherein R¹, R³, R⁴ and R⁵ are hydrogen, R² is hydrogen or methyl and Ar¹ and Ar² are independently phenyl, each ring optionally substituted with R^g or R^h where R^g and R^h are independently methyl, fluoro, trifluoromethyl, trifluoromethoxy or 2,2,2-trifluoroethoxy.

43. A pharmaceutical composition comprising a compound of any of the claims 1-42 or a mixture a compound of Formula (I) and a pharmaceutically acceptable salt thereof;

and a pharmaceutically acceptable excipient.

23. A compound selected from a group consisting of:

(R)-2-(4-(phenyl(3-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)acetic acid;

2-(4-((3-bromophenyl)(phenyl)methyl)piperazin-1-yl)acetic acid;

2-(4-(phenyl(3-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)acetic acid;

2-(4-((3,5-dichlorophenyl)(phenyl)methyl)piperazin-1-yl)acetic acid;

(S)-2-(4-(phenyl(3-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)acetic acid;

2-(4-((4-bromophenyl)(phenyl)methyl)piperazin-1-yl)acetic acid;

2-(4-(phenyl(4-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)acetic acid;

2-(4-((2-bromophenyl)(phenyl)methyl)piperazin-1-yl)acetic acid;

2-(4-((3-biphenyl)(phenyl)methyl)piperazin-1-yl)acetic acid;

(S)-2-(4-((4-bromophenyl)(phenyl)methyl)piperazin-1-yl)acetic acid;

(R)-2-(4-((4-bromophenyl)(phenyl)methyl)piperazin-1-yl)acetic acid;

(S)-2-(4-((3-bromophenyl)(phenyl)methyl)piperazin-1-yl)acetic acid;

(R)-2-(4-((3-bromophenyl)(phenyl)methyl)piperazin-1-yl)acetic acid;

2-((R)-2-methyl-4-(phenyl(3-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)acetic acid;

2-((R)-4-((3-bromophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

(R)-2-(4-benzhydryl-2-methylpiperazin-1-yl)acetic acid;

2-((R)-4-((R)-(3-iodophenyl)phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-4-((R)-(3-bromophenyl)phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-4-((S-(3-bromophenyl)phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-2-methyl-4-(biphenyl-3-yl-phenyl-methyl)-piperazin-1-yl)-acetic acid;

2-((R)-2-methyl-4-((S)-phenyl(3-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)acetic acid;

2-((R)-2-methyl-4-((R)-phenyl(3-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)acetic acid;

2-((R)-4-((4-chlorophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-2-methyl-4-(biphenyl-4-yl-phenyl-methyl)-piperazin-1-yl)-acetic acid;

2-((R)-4-((4-bromophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-4-((4-cyanophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-4-((3-chlorophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

[(R)-4-((R)-biphenyl-3-yl-phenyl-methyl)-2-methyl-piperazin-1-yl]-acetic acid;

2-((R)-2-methyl-4-((3-(methylthio)phenyl)(phenyl)methyl)piperazin-1-yl)acetic acid;

2-((R)-4-((S)-(2-bromophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-4-((R)-(2-bromophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-2-methyl-4-((R)-phenyl(m-tolyl)methyl)piperazin-1-yl)acetic acid;

2-((R)-4-((R)-(3-isopropylphenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-4-((4-fluorophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-4-((3-fluorophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-2-methyl-4-((R)-phenyl(3-(thiophen-2-yl)phenyl)methyl)piperazin-1-yl)acetic acid;

2-((R)-2-methyl-4-((R)-(3-(methylthio)phenyl)(phenyl)methyl)piperazin-1-yl)acetic acid;

2-((R)-2-methyl-4-((S)-(3-(methylthio)phenyl)(phenyl)methyl)piperazin-1-yl)acetic acid;

2-((R)-2-methyl-4-((R)-(4-(methylthio)phenyl)(phenyl)methyl)piperazin-1-yl)acetic acid;

2-((R)-4-((S)-(2-fluorophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-4-((R)-(2-fluorophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-2-methyl-4-((S)-phenyl(3-(trifluoromethoxy)phenyl)methyl)piperazin-1-yl)acetic acid;

2-((R)-2-methyl-4-((R)-phenyl(3-(trifluoromethoxy)phenyl)methyl)piperazin-1-yl)acetic acid;

[(R)-4-((R)-biphenyl-4-yl-phenyl-methyl)-2-methyl-piperazin-1-yl]-acetic acid;

{(R)-2-methyl-4-[(R)-(2′

-methyl-biphenyl-4-yl)-phenyl-methyl]-piperazin-1-yl]-acetic acid;

{(R)-2-methyl-4-[(R)-(3′

-methyl-biphenyl-4-yl)-phenyl-methyl]-piperazin-1-yl]-acetic acid;

{(R)-2-methyl-4-[(R)-(4′

-methyl-biphenyl-4-yl)-phenyl-methyl]-piperazin-1-yl]-acetic acid;

2-((R)-4-((S)-(2,4-difluorophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-4-((R)-(2,4-difluorophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-4-((S)-(4-fluorophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-4-((R)-(4-fluorophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-4-((S)-(3-fluorophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-4-((R)-(3-fluorophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-2-methyl-4-((R)-phenyl(4-(2-phenylethynyl)phenyl)methyl)piperazin-1-yl)acetic acid;

2-((R)-2-methyl-4-((R)-phenyl(3-(2-pyridin-3-ylethynyl)phenyl)methyl)piperazin-1-yl)acetic acid;

2-((R)-2-methyl-4-((R)-phenyl(3-(2-pyridin-4-ylethynyl)phenyl)methyl)piperazin-1-yl)acetic acid;

(S)-2-(4-benzhydryl-2-methylpiperazin-1-yl)acetic acid;

2-((S)-2-methyl-4- phenyl(3-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)acetic acid;

(S)-2-(4-benzhydryl-3-methylpiperazin-1-yl)acetic acid;

(R)-2-(4-benzhydryl-3-methylpiperazin-1-yl)acetic acid;

2-((2,5-trans)-4-benzhydryl-2,5-dimethylpiperazin-1-yl)acetic acid;

2-((2,5-cis)-4-benzhydryl-2,5-dimethylpiperazin-1-yl)acetic acid;

2-((R)-3-methyl-4-(phenyl(4-diphenyl)methyl)piperazin-1-yl)acetic acid;

(R)-2-(4-(bis(3-chlorophenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

(R)-2-(4-(bis(3-fluorophenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-(4-((3-(trifluoromethyl)phenyl)(4-trifluoromethyl)phenyl)methyl)piperazin-1-yl)acetic acid;

2-(4-((4-fluorophenyl)(3-(diphenyl)methyl))-(R)2methylpiperazin-1-yl)acetic acid

(R)-2-(4-(bis(4-chlorophenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-4-((3-bromophenyl)(4-fluorophenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

(R)-2-(4-(bis(4-fluorophenyl)methyl)-3-methylpiperazin-1-yl)acetic acid;

(R)-2-(4-(bis(4-fluorophenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

(R)-2-(4-(bis(3-(trifluoromethyl)phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-(4-(bis(3-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)acetic acid;

2-((R)-2-methyl-4-(thiophen-2-yl(3-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)acetic acid;

2-((R)-2-methyl-4-((R)-thiophen-2-yl(3(trifluoromethyl)phenyl)methyl)-piperazin-1-yl)acetic acid;

2-((R)-2-methyl-4-((S)-thiophen-2-yl(3-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)acetic acid;

2-((R)-4-(cyclopropyl(3-(trifluoromethyl)phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

(R)-2-(4-(bis(4-chlorophenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

(S)-2-((R)-4-(bis(4-chlorophenyl)methyl)-3-methyl)piperazin-1-yl)propanoic acid;

2-(4-(bis(4-chlorophenyl)methyl)-3-oxopiperazin-1-yl)acetic acid;

(S)-2-((R)-4-(bis(4-chlorophenyl)methyl)-2-methylpiperazin-1-yl)propanoic acid;

(R)-2-((R)-4-(bis(4-chlorophenyl)methyl)-2-methylpiperazin-1-yl)propanoic acid;

2-(4-(bis(4-chlorophenyl)methyl)-2-oxopiperazin-1-yl)acetic acid;

2-((2R,6S)-4-(bis(4-chlorophenyl)methyl)-2,6-dimethylpiperazin-1-yl)acetic acid;

2-(4-(bis(4-chlorophenyl)methyl)-2,2-dimethylpiperazin-1-yl)acetic acid;

2-(4-(bis(4-chlorophenyl)methyl)piperazin-1-yl)propanoic acid;

(R)-2-(4-(bis(4-chlorophenyl)methyl)-2-isopropylpiperazin-1-yl)acetic acid;

2-(4-(bis(4-chlorophenyl)methyl)piperazin-1-yl)acetic acid; and

2-(4-(phenyl(3-(trifluoromethyl)phenyl)methyl)-1,4-diazepan-1-yl)-acetic acid;

or a pharmaceutically acceptable salt thereof.

24. A compound selected from:

(R)-2-(4-(phenyl(3-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)acetic acid;

(R)-2-(4-benzhydryl-2-methylpiperazin-1-yl)acetic acid;

2-((R)-2-methyl-4-((R)-phenyl(m-tolyl)methyl)piperazin-1-yl)acetic acid; and

2-((R)-4-(cyclopropyl(3-(trifluoromethyl)phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

or

a pharmaceutically acceptable salt thereof.

25. A compound selected from:

2-((R)-4-(cyclopropyl(3-(trifluoromethyl)phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid or a pharmaceutically acceptable salt thereof.

40. A compound selected from:

(R)-2-(4-(phenyl(3-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)acetic acid;

or

a pharmaceutically acceptable salt thereof.

41. A compound selected from:

(R)-2-(4-benzhydryl-2-methylpiperazin-1-yl)acetic acid;

or a pharmaceutically acceptable salt thereof.

42. A compound selected from:

2-((R)-2-methyl-4-((R)-phenyl(m-tolyl)methyl)piperazin-1-yl)acetic acid;

or

a pharmaceutically acceptable salt thereof.