Gamma-amino-butyric acid derivatives as GABA B receptor ligands

• US 8,344,028 B2
• Filed: 04/16/2010
• Issued: 01/01/2013
• Est. Priority Date: 04/17/2009
• Status: Expired due to Fees

• Current Assignee: XenoPort, Inc. (Arbor Pharmaceuticals LLC)
• Original Assignee: XenoPort, Inc. (Arbor Pharmaceuticals LLC)
• Inventors: Xu, Feng, Gallop, Mark A., Peng, Ge, Phan, Thu, Dilip, Usha, Wustrow, David J.
• Primary Examiner(s): ZAREK, PAUL E
• Application Number:
  US12/762,152
• Publication Number:
  US 20100267676A1
• Time in Patent Office: 991 Days
• Field of Search: 514/568, 514/649, 514/751, 564/374, 570/182
• US Class Current: 514/568
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/14 Antitussive agents
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• 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 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 229/34 the carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 229/38 having amino groups bound to acyclic carbon atoms and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
• CPC Class Codes: C07C 229/42 with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
• CPC Class Codes: C07C 229/58 having the nitrogen atom of at least one of the amino groups further bound to a carbon atom of a six-membered aromatic ring, e.g. N-phenyl-anthranilic acids
• CPC Class Codes: C07C 229/60 with amino and carboxyl groups bound in meta- or para- positions
• CPC Class Codes: C07C 233/81 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07C 237/30 having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 255/58 : containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
• CPC Class Codes: C07C 255/59 : the carbon skeleton being further substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 311/21 : having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 317/48 : the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
• CPC Class Codes: C07D 213/30 : Oxygen atoms
• CPC Class Codes: C07D 213/74 : Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 333/24 : Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 333/70 : attached in position 2
• CPC Class Codes: C07F 9/301 : Acyclic saturated acids which can have further substituents on alkyl
• CPC Class Codes: C07F 9/306 : Arylalkanephosphinic acids, e.g. Ar-(CH2)n-P(=X)(R)(XH), (X = O,S, Se; n>=1)
• CPC Class Codes: C07F 9/58 : Pyridine rings

Abstract

Gamma-amino-butyric acid derivatives that are GABA_B receptor ligands, pharmaceutical compositions comprising such derivatives, and methods of using such derivatives and pharmaceutical compositions thereof for treating diseases are disclosed.

Claims

1. A compound of Formula (I):

2. The compound of claim 1, wherein the compound is of Formula (II):

3. The compound of claim 1, wherein R¹ and R² are independently chosen from halogen.

4. The compound of claim 1, wherein:

R¹ is hydrogen; and

R² is chloro.

5. The compound of claim 1, wherein:

R³ is —

X—

Y; and

R⁴ is hydrogen.

6. The compound of claim 1, wherein:

R³ is hydrogen; and

R⁴ is —

X—

Y.

7. The compound of claim 1, wherein X is C_1-3 heteroalkyldiyl and is chosen from —

NH(CHR⁷)_n—

, —

O(CHR⁷)_n—

, and —

NH—

SO₂—

;

wherein n is chosen from 0, 1, and 2; and

each R⁷ is independently chosen from hydrogen and C_1-4 alkyl.

8. The compound of claim 1, wherein X is chosen from substituted C_1-3 alkyldiyl and substituted C_1-3 heteroalkyldiyl, wherein each of the one or more substituents is independently chosen from —

OH, —

NH₂, C_1-4 alkyl, C_1-4 alkoxy, and ═

O.

9. The compound of claim 1, wherein Y is chosen from substituted C_6-12 aryl and substituted C_5-12 heteroaryl, wherein each of the one or more substituents is independently chosen from halogen, —

OH, —

NH₂, —

NO₂, —

CN, —

COOH, —

CF₃, —

OCF₃, C_1-4 alkyl, substituted C_1-4 alkyl, C_1-4 heteroalkyl, and substituted C_1-4 heteroalkyl.

10. The compound of claim 9, wherein:

each of the one or more substituents of substituted C_1-4 alkyl is chosen from —

OH, ═

O, —

OCH₃, —

SCH₃, —

N(CH₃)₂, and —

OCH₂CH₃; and

substituted C_1-4 heteroalkyl is chosen from —

C(O)NH₂, —

CH₂COOH, —

COOCH₃, —

COOCH₂CH₃, and —

SO₂CH₃.

11. The compound of claim 1, wherein Y is chosen from phenyl, substituted phenyl, C₅ heteroaryl, substituted C₅ heteroaryl, C₆ heteroaryl, and substituted C₆ heteroaryl.

12. The compound of claim 1, wherein Y is chosen from phenyl, substituted phenyl, thienyl, substituted thienyl, furyl, substituted furyl, imidazolyl, substituted imidazolyl, thiazole, substituted thiazole, oxazole, substituted oxazole, thiazolidine, substituted thiazolidine, oxazolidine, substituted oxazolidine, oxadiazole, substituted oxadiazole, thiadiazole, substituted thiadiazole, pyridyl, substituted pyridyl, indazolyl, substituted indazolyl, isoquinolyl, and substituted isoquinolyl.

13. The compound of claim 2, wherein:

R¹ is hydrogen;

R² is chloro;

R³ is hydrogen; and

R⁴ is —

X—

Y wherein;

X is chosen from a covalent bond, C_1-3 alkyldiyl, substituted C_1-13 alkyldiyl, —

NH(CHR⁷)_n—

, —

O(CHR⁷)_n—

, and —

NH—

SO₂—

;

wherein n is chosen from 0, 1, and 2; and

each R⁷ is independently chosen from hydrogen and C_1-4 alkyl; and

Y is chosen from phenyl, substituted phenyl, C₅ heteroaryl, substituted C₅ heteroaryl, C₆ heteroaryl, and substituted C₆ heteroaryl.

14. The compound of claim 13, wherein Y is chosen from phenyl, substituted phenyl, thienyl, substituted thienyl, furyl, substituted furyl, imidazolyl, substituted imidazolyl, thiazole, substituted thiazole, oxazole, substituted oxazole, thiazolidine, substituted thiazolidine, oxazolidine, substituted oxazolidine, oxadiazole, substituted oxadiazole, thiadiazole, substituted thiadiazole, pyridyl, and substituted pyridyl wherein:

each of the one or more substituent groups is independently chosen from halogen, —

OH, —

NH₂, —

NO₂, —

CN, —

COOH, —

CF₃, —

OCF₃, C_1-4 alkyl, substituted C_1-4 alkyl, C_1-4 heteroalkyl, and substituted C_1-4 heteroalkyl.

15. The compound of claim 2, wherein:

R¹ is hydrogen;

R² is chloro;

R³ is —

X—

Y wherein;

X is chosen from a covalent bond, C_1-13 alkyldiyl, substituted C_1-13 alkyldiyl, —

NH(CHR⁷)_n—

, —

O(CHR⁷)_n—

, and —

NH—

SO₂—

;

wherein n is chosen from 0, 1, and 2; and

each R⁷ is independently chosen from hydrogen and C_1-4 alkyl; and

Y is chosen from phenyl, substituted phenyl, C₅ heteroaryl, substituted C₅ heteroaryl, C₆ heteroaryl, and substituted C₆ heteroaryl; and

R⁴ is hydrogen.

16. The compound of claim 15, wherein Y is chosen from phenyl, substituted phenyl, thienyl, substituted thienyl, furyl, substituted furyl, imidazolyl, substituted imidazolyl, thiazole, substituted thiazole, oxazole, substituted oxazole, thiazolidine, substituted thiazolidine, oxazolidine, substituted oxazolidine, oxadiazole, substituted oxadiazole, thiadiazole, substituted thiadiazole, pyridyl, and substituted pyridyl;

wherein;

each of the one or more substituent groups is independently chosen from halogen, —

OH, —

NH₂, —

NO₂, —

CN, —

COOH, —

CF₃, —

OCF₃, C_1-4 alkyl, substituted C_1-4 alkyl, C_1-4 heteroalkyl, and substituted C_1-4 heteroalkyl.

17. The compound of claim 1, wherein the compound is chosen from:

(3R)-4-amino-3-[4-chloro-3-(phenylcarbonylamino)phenyl]butanoic acid;

(3R)-4-amino-3-[2-(3,4-dichlorophenyl)-4-chlorophenyl]butanoic acid;

4-{2-[(1R)-2-amino-1-(carboxymethyl)ethyl]-5-chlorophenyl}benzoic acid;

(3R)-4-amino-3-(4-chloro-2-(3-thienyl)phenyl)butanoic acid;

(3R)-4-amino-3-[4-chloro-2-(4-chlorophenyl)phenyl]butanoic acid;

2-({5-[(1R)-2-amino-1-(carboxymethyl)ethyl]-2-chlorophenyl}amino)benzoic acid;

3-({5-[(1R)-2-amino-1-(carboxymethyl)ethyl]-2-chlorophenyl}amino)benzoic acid;

4-({5-[(1R)-2-amino-1-(carboxymethyl)ethyl]-2-chlorophenyl}amino)benzoic acid;

(3R)-4-amino-3-(4-chloro-2-(3-pyridyl)phenyl)butanoic acid;

(3R)-4-amino-3-(4-chloro-2-phenoxyphenyl)butanoic acid;

(3R)-4-amino-3-{3-[(3,4-dichlorophenyl)amino]-4-chlorophenyl}butanoic acid;

(3R)-4-amino-3-[4-chloro-2-(phenylcarbonyl)phenyl]butanoic acid;

(3R)-4-amino-3-[4-chloro-2-(2-phenylethyl)phenyl]butanoic acid;

(3R)-4-amino-3-[3-({[3-(3,4-dichlorophenoxy)phenyl]methyl}amino)-4-chlorophenyl]butanoic acid;

(3R)-4-amino-3-{4-chloro-3-[(2-pyridylmethyl)amino]phenyl}butanoic acid;

(3R)-4-amino-3-(4-chloro-3-{[(2-fluorophenyl)methyl]amino}phenyl)butanoic acid;

(3R)-4-amino-3-(3-{[(2,4-dichlorophenyl)methyl]amino}-4-chlorophenyl)butanoic acid;

(3R)-4-amino-3-(4-chloro-3-{[(3-phenoxyphenyl)methyl]amino}phenyl)butanoic acid;

4-amino-3-[4-chloro-3-(phenylamino)phenyl]butanoic acid;

(3R)-4-amino-3-{4-chloro-3-[(3-furylmethyl)amino]phenyl}butanoic acid;

(3R)-4-amino-3-{4-chloro-3-[(imidazol-5-ylmethyl)amino]phenyl}butanoic acid;

3-{5-[(1R)-2-amino-1-(carboxymethyl)ethyl]-2-chlorophenyl}benzoic acid;

(3R)-4-amino-3-{4-chloro-3-[3-(ethoxycarbonyl)phenyl]phenyl}butanoic acid;

(3R)-4-amino-3-(4-chloro-3-(3-pyridyl)phenyl)butanoic acid;

(3R)-4-amino-3-[4-chloro-3-(3-cyanophenyl)phenyl]butanoic acid;

(3R)-4-amino-3-{3-[3-(carboxymethyl)phenyl]-4-chlorophenyl}butanoic acid;

(3R)-4-amino-3-[4-chloro-3-(3-hydroxyphenyl)phenyl]butanoic acid;

3-{3-[(1R)-2-amino-1-(carboxymethyl)ethyl]phenyl}benzoic acid;

(3R)-4-amino-3-[4-chloro-3-(3-methoxyphenyl)phenyl]butanoic acid;

(3R)-4-amino-3-(3-benzimidazol-6-yl-4-chlorophenyl)butanoic acid;

(3R)-4-amino-3-[4-chloro-3-(4-cyanophenyl)phenyl]butanoic acid;

(3R)-4-amino-3-[3-(3-carbamoylphenyl)-4-chlorophenyl]butanoic acid;

(3R)-4-amino-3-{4-chloro-3-[3-(hydroxymethyl)phenyl]phenyl}butanoic acid;

3-{5-[(1R)-2-amino-1-(carboxymethyl)ethyl]-2-chlorophenyl}-4-chlorobenzoic acid;

(3R)-4-amino-3-[4-chloro-3-(3-nitrophenyl)phenyl]butanoic acid;

(3R)-4-amino-3-[4-chloro-3-(4-nitrophenyl)phenyl]butanoic acid;

5-{5-[(1R)-2-amino-1-(carboxymethyl)ethyl]-2-chlorophenyl}pyridine-3-carboxylic acid;

3-{5-[(1R)-1-(aminomethyl)-3-hydroxypropyl]-2-chlorophenyl}benzenecarbonitrile;

4-{5-[(1R)-2-amino-1-(carboxymethyl)ethyl]-2-chlorophenyl}thiophene-2-carboxylic acid;

(3R)-4-amino-3-{4-chloro-3-[(4-pyridylmethyl)amino]phenyl}butanoic acid;

(3R)-4-amino-3-[4-chloro-3-(3-methylthiophenyl)phenyl]butanoic acid;

(3R)-4-amino-3-{4-chloro-3-[3-(methylsulfonyl)phenyl]phenyl}butanoic acid;

5-{5-[(1R)-2-amino-1-(carboxymethyl)ethyl]-2-chlorophenyl}thiophene-2-carboxylic acid;

(3R)-4-amino-3-(4-chloro-3-phenylphenyl)butanoic acid;

3-{5-[(1R)-2-amino-1-(carboxymethyl)ethyl]-2-chlorophenyl}-5-nitrobenzoic acid;

(3R)-4-amino-3-[4-chloro-3-(4-chloro-3-cyanophenyl)phenyl]butanoic acid;

(3R)-4-amino-3-{3-[3-(dimethylamino)phenyl]-4-chlorophenyl}butanoic acid;

3-{5-[(1R)-2-amino-1-(carboxymethyl)ethyl]-2-chlorophenyl}-5-fluorobenzoic acid;

4-{5-[(1R)-2-amino-1-(carboxymethyl)ethyl]-2-chlorophenyl}-3-chlorobenzoic acid;

(3R)-4-amino-3-[4-chloro-3-(4-pyridylmethoxy)phenyl]butanoic acid;

(3R)-4-amino-3-{4-chloro-3-[(3-chlorophenyl)carbonylamino]phenyl}butanoic acid;

(3R)-4-amino-3-(2-{[(3,4-dichlorophenyl)sulfonyl]amino}-4-chlorophenyl)butanoic acid;

(3R)-4-amino-3-{2-[(3,4-dichlorophenyl)carbonylamino]-4-chlorophenyl}butanoic acid;

(3R)-4-amino-3-[4-chloro-3-(2-pyridylamino)phenyl]butanoic acid;

(3R)-4-amino-3-{4-chloro-3-[(4-methoxyphenyl)amino]phenyl}butanoic acid;

(3R)-4-amino-3-[4-chloro-3-(4-pyridylamino)phenyl]butanoic acid;

4-{3-[(1R)-2-amino-1-(carboxymethyl)ethyl]-4-chlorophenoxy}benzoic acid;

3-{5-[(1R)-2-amino-1-(carboxymethyl)ethyl]-2-chlorophenoxy}benzoic acid;

(3R)-4-amino-3-(4-chloro-3-phenoxyphenyl)butanoic acid;

(3R)-4-amino-3-(3-{[(3,4-dichlorophenyl)sulfonyl]amino}-4-chlorophenyl)butanoic acid;

4-{5-[(1R)-2-amino-1-(carboxymethyl)ethyl]-2-chlorophenyl}benzoic acid;

3-({2-[(1R)-2-amino-1-(carboxymethyl)ethyl]-4-chlorophenyl}hydroxymethyl)benzoic acid;

4-[({5-[(1R)-2-amino-1-(carboxymethyl)ethyl]-2-chlorophenyl}amino)methyl]benzoic acid;

(3R)-4-amino-3-(4-chloro-3-{[(1-methylimidazol-5-yl)methyl]amino}phenyl) butanoic acid;

(3R)-4-amino-3-[4-chloro-3-(5-cyano(2-thienyl))phenyl]butanoic acid;

(3R)-4-amino-3-[4-chloro-3-(2-methylpyrimidin-5-yl)phenyl]butanoic acid;

5-{5-[(1R)-2-amino-1-(carboxymethyl)ethyl]-2-chlorophenyl}-2-fluorobenzoic acid;

(3R)-4-amino-3-[4-chloro-3-(3-cyano-6-methylphenyl)phenyl]butanoic acid;

(3R)-4-amino-3-[4-chloro-3-(3-cyano-5-fluorophenyl)phenyl]butanoic acid;

(3R)-4-amino-3-[4-chloro-3-(4-methyl(3-pyridyl))phenyl]butanoic acid;

(3R)-4-amino-3-[4-chloro-3-(3-cyano-6-fluorophenyl)phenyl]butanoic acid;

(3R)-4-amino-3-[4-chloro-3-(6-chloro-3-cyanophenyl)phenyl]butanoic acid;

methyl (3R)-4-amino-3-[4-chloro-3-(4-pyridylmethoxy)phenyl]butanoate;

(3R)-4-amino-3-[4-chloro-3-(3-pyridylmethoxy)phenyl]butanoic acid;

5-{5-[(1R)-2-amino-1-(carboxymethyl)ethyl]-2-chlorophenyl}furan-3-carboxylic acid;

(3R)-4-amino-3-[4-chloro-3-(2-(4-pyridyl)ethoxy)phenyl]butanoic acid;

(3R)-4-amino-3-[4-chloro-3-(4-pyridylethoxy)phenyl]butanoic acid;

(3R)-3-[3-((1R)-1-(4-pyridyl)ethoxy)-4-chlorophenyl]-4-aminobutanoic acid;

(3R)-4-amino-3-[4-chloro-3-(5-cyano(3-thienyl))phenyl]butanoic acid;

(3R)-4-amino-3-{4-chloro-3-[(2-methyl(4-pyridyl))methoxy]phenyl}butanoic acid;

(3R)-4-amino-3-{4-chloro-3-[(3-chloro(4-pyridyl))methoxy]phenyl}butanoic acid;

5-{5-[(1R)-2-amino-1-(carboxymethyl)ethyl]-2-chlorophenyl}thiophene-3-carboxylic acid;

(3R)-4-amino-3-[4-chloro-3-(2-(4-pyridyl)ethyl)phenyl]butanoic acid;

(3R)-4-amino-3-[4-chloro-3-(1,3-thiazol-5-ylmethoxy)phenyl]butanoic acid;

(3R)-4-amino-3-{3-[5-(N,N-dimethylcarbamoyl)(2-thienyl)]-4-chlorophenyl}butanoic acid;

2-{4-Chloro-3-(4-pyridylmethoxy)phenyl]-3-(hydrohydroxyphosphoryl)propylamine;

3-{5-[2-amino-1-((hydrohydroxyphosphoryl)methyl)ethyl]-2-chlorophenyl}benzoic acid;

(3R)-4-amino-3-{4-chloro-3-[5-(ethoxycarbonyl)(2-thienyl)]phenyl}butanoic acid; and

a pharmaceutically acceptable salt of any of the foregoing.

18. The compound of claim 1, wherein the compound is chosen from:

3-({5-[(1R)-2-amino-1-(carboxymethyl)ethyl]-2-chlorophenyl}amino)benzoic acid;

3-{5-[(1R)-2-Amino-1-(carboxymethyl)ethyl]-2-chlorophenyl}benzoic acid;

(3R)-4-amino-3-{4-chloro-3-[(imidazol-5-ylmethyl)amino]phenyl}butanoic acid;

(3R)-4-amino-3-(4-chloro-3-(3-pyridyl)phenyl)butanoic acid;

(3R)-4-amino-3-[4-chloro-3-(3-cyanophenyl)phenyl]butanoic acid;

(3R)-4-amino-3-[3-(3-carbamoylphenyl)-4-chlorophenyl]butanoic acid;

3-{5-[(1R)-2-amino-1-(carboxymethyl)ethyl]-2-chlorophenyl}-4-chlorobenzoic acid;

(3R)-4-amino-3-[4-chloro-3-(3-nitrophenyl)phenyl]butanoic acid;

4-{5-[(1R)-2-amino-1-(carboxymethyl)ethyl]-2-chlorophenyl}thiophene-2-carboxylic acid

(3R)-4-amino-3-{4-chloro-3-[(4-pyridylmethyl)amino]phenyl}butanoic acid;

5-{5-[(1R)-2-amino-1-(carboxymethyl)ethyl]-2-chlorophenyl}thiophene-2-carboxylic acid;

3-{5-[(1R)-2-amino-1-(carboxymethyl)ethyl]-2-chlorophenyl}-5-fluorobenzoic acid;

(3R)-4-amino-3-[4-chloro-3-(4-pyridylmethoxy)phenyl]butanoic acid;

(3R)-4-amino-3-[4-chloro-3-(5-cyano(2-thienyl))phenyl]butanoic acid;

5-{5-[(1R)-2-amino-1-(carboxymethyl)ethyl]-2-chlorophenyl}-2-fluorobenzoic acid;

(3R)-4-amino-3-[4-chloro-3-(3-cyano-6-methylphenyl)phenyl]butanoic acid;

(3R)-4-amino-3-[4-chloro-3-(3-cyano-5-fluorophenyl)phenyl]butanoic acid;

(3R)-4-amino-3-[4-chloro-3-(4-methyl(3-pyridyl))phenyl]butanoic acid;

(3R)-4-amino-3-[4-chloro-3-(3-cyano-6-fluorophenyl)phenyl]butanoic acid;

(3R)-4-amino-3-[4-chloro-3-(6-chloro-3-cyanophenyl)phenyl]butanoic acid;

methyl (3R)-4-amino-3-[4-chloro-3-(4-pyridylmethoxy)phenyl]butanoate;

(3R)-4-amino-3-[4-chloro-3-(3-pyridylmethoxy)phenyl]butanoic acid;

5-{5-[(1R)-2-amino-1-(carboxymethyl)ethyl]-2-chlorophenyl}furan-3-carboxylic acid;

(3R)-4-amino-3-[4-chloro-3-(2-(4-pyridyl)ethoxy)phenyl]butanoic acid;

(3R)-4-amino-3-[4-chloro-3-(4-pyridylethoxy)phenyl]butanoic acid;

(3R)-3-[3-((1R)-1-(4-pyridyl)ethoxy)-4-chlorophenyl]-4-aminobutanoic acid;

(3R)-4-amino-3-[4-chloro-3-(5-cyano(3-thienyl))phenyl]butanoic acid;

(3R)-4-amino-3-{4-chloro-3-[(2-methyl(4-pyridyl))methoxy]phenyl}butanoic acid;

(3R)-4-amino-3-{4-chloro-3-[(3-chloro(4-pyridyl))methoxy]phenyl}butanoic acid;

5-{5-[(1R)-2-amino-1-(carboxymethyl)ethyl]-2-chlorophenyl}thiophene-3-carboxylic acid;

(3R)-4-amino-3-[4-chloro-3-(2-(4-pyridyl)ethyl)phenyl]butanoic acid;

(3R)-4-amino-3-[4-chloro-3-(1,3-thiazol-5-ylmethoxy)phenyl]butanoic acid;

(3R)-4-amino-3-{3-[5-(N,N-dimethylcarbamoyl)(2-thienyl)]-4-chlorophenyl}butanoic acid;

2-{chloro-3-(4-pyridylmethoxy)phenyl]-3-(hydrohydroxyphosphoryl)propylamine; and

a pharmaceutically acceptable salt of any of the foregoing.

19. The compound of claim 1, wherein the compound exhibits GABA_B receptor agonist activity.

20. The compound of claim 1, wherein the compound exhibits GABA_B receptor partial agonist activity.

21. The compound of claim 1, wherein the compound exhibits GABA_B receptor antagonist activity.

22. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable vehicle.

23. The pharmaceutical composition of claim 22, wherein the amount is effective for the treatment of a disease chosen from spasticity, gastro-esophageal reflux disease, emesis, cough, overactive bladder, a substance abuse disorder, an attention disorder, an anxiety disorder, a mood disorder, a cognitive disorder, migraine, and pain.

24. A method of treating a disease in a patient comprising administering to a patient in need of such treatment the pharmaceutical composition of claim 22, wherein the disease is chosen from spasticity, gastro-esophageal reflux disease, emesis, cough, overactive bladder, a substance abuse disorder, an attention disorder, an anxiety disorder, a mood disorder, a cognitive disorder, migraine, and pain.

25. A method of modulating GABA_B receptor function in a patient comprising administering to a patient a compound of claim 1.

26. The compound (3R)-4-amino-3-[4-chloro-3-(4-pyridylmethoxy)phenyl]butanoic acid or a pharmaceutically acceptable salt thereof.

27. The compound 4-{5-[(1R)-2-amino-1-(carboxymethyl)ethyl]-2-chlorophenyl}thiophene-2-carboxylic acid or a pharmaceutically acceptable salt thereof.

28. The compound 5-15- R1R)-2-amino-1-(carboxymethyl)ethyl]-2-chlorophenyl}thiophene-3-carboxylic acid or a pharmaceutically acceptable salt thereof.