METHODS OF TREATING FRAGILE X SYNDROME, DOWN'S SYNDROME, AUTISM AND RELATED DISORDERS

1 . A method of treating a subject having at least one condition selected from fragile X syndrome, fragile X-associated tremor/ataxia syndrome, Down's syndrome and autism, comprising administering to the subject a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is selected from acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl;

R 2 and R 3 are independently selected from hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl or optionally, R 2 and R 3 together with the carbon atom to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;

R 4 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; and

R 5 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl.

2 . The method of claim 1 , wherein the compound is a compound of Formula

or a pharmaceutically acceptable salt thereof.

3 . A method of claim 1 , wherein the compound is a compound of Formula

or a pharmaceutically acceptable salt thereof.

4 . The method of claim 1 , wherein R 5 is selected from phenyl, 4-chlorophenyl, 4-fluorophenyl, 2-chlorophenyl, thien-2-yl, 5-chlorothien-2-yl, 5-bromothien-2-yl, 5-methylthien-2-yl and 2-imidazolyl.

5 . The method of claim 1 , wherein R 1 is selected from C 1-6 alkyl, substituted C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, substituted phenyl, C 7-9 phenylalkyl and pyridyl.

6 . The method of claim 1 , wherein R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, cyclohexyl or 3-pyridyl.

7 . The method of claim 1 , wherein R 2 and R 3 are independently selected from hydrogen, C 1-4 alkyl, substituted C 1-4 alkyl, C 1-4 alkoxycarbonyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxycarbonyl, phenyl, substituted phenyl, C 7-9 phenylalkyl and pyridyl.

8 . The method of claim 1 , wherein R 2 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl, 2-pyridyl, 3-pyridyl or 4-pyridyl and R 3 is hydrogen.

9 . The method of claim 1 , wherein R 2 is hydrogen, methyl, n-propyl or isopropyl and R 3 is hydrogen.

10 . The method of claim 1 , wherein R 4 is selected from hydrogen, C 1-6 alkyl, substituted C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, substituted phenyl, C 7-9 phenylalkyl and substituted C 7-9 phenylalkyl.

11 . The method of claim 1 , wherein R 4 is hydrogen.

12 . The method of claim 1 , wherein R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, cyclohexyl or 3-pyridyl, R 2 is hydrogen, methyl, n-propyl or isopropyl, R 3 is hydrogen and R 4 is hydrogen.

13 . The method of claim 1 , wherein the compound of Formula (I) is selected from:

4-{[(1S)-Isobutanoyloxyethoxy]carbonylamino}-(3R)-phenyl-butano ic acid;

4-{[(1R)-Isobutanoyloxyethoxy]carbonylamino}-(3R)-phenyl-butanoic acid;

4-{[(1S)-Isobutanoyloxyisobutoxy]carbonylamino}-(3R)-phenyl-butanoic acid;

4-{[(1R)-Isobutanoyloxyisobutoxy]carbonylamino}-(3R)-phenyl-butanoic acid;

and a pharmaceutically acceptable salt of any of the foregoing.

14 . The method of claim 2 , wherein the compound of Formula (II) is selected from:

4-{[(1S)-Isobutanoyloxyethoxy]carbonylamino}-(3R)-(4-chlorophenyl)-butanoic acid;

4-{[(1R)-Isobutanoyloxyethoxy]carbonylamino}-(3R)-(4-chlorophenyl)-butanoic acid;

4-{[(1S)-Isobutanoyloxyisobutoxy]carbonylamino}-(3R)-(4-chlorophenyl)-butanoic acid;

4-{[(1R)-Isobutanoyloxyisobutoxy]carbonylamino}-(3R)-(4-chlorophenyl)-butanoic acid; and

a pharmaceutically acceptable salt of any of the foregoing.

15 . The method of claim 3 , wherein the compound of Formula (III) is selected from:

4-{[(1S)-Isobutanoyloxyethoxy]carbonylamino}-(3R)-(4-fluorophenyl)-butanoic acid;

4-{[(1R)-Isobutanoyloxyethoxy]carbonylamino}-(3R)-(4-fluorophenyl)-butanoic acid;

4-{[(1S)-Isobutanoyloxyisobutoxy]carbonylamino}-(3R)-(4-fluorophenyl)-butanoic acid;

4-{[(1R)-Isobutanoyloxyisobutoxy]carbonylamino}-(3R)-(4-fluorophenyl)-butanoic acid; and

a pharmaceutically acceptable salt of any of the foregoing.

16 . The method of claim 1 , wherein the subject has fragile X syndrome.

17 . The method of claim 1 , wherein the subject has fragile X-associated tremor/ataxia syndrome.

18 . The method of claim 1 , wherein the subject has Down's syndrome.

19 . The method of claim 1 , wherein the subject has autism.

20 . The method of claim 1 , comprising administering to the subject at least one member selected from an mGluR antagonist, acamprosate, an acamprosate prodrug, an antipsychotic agent, a muscarinic receptor antagonist, a stimulant, a nicotinic receptor agonist, an endocannabinoid receptor antagonist, an AMPA agonist, an antidepressant, an α2-adrenergic agonist, and an anticonvulsant.

21 . The method of claim 1 , wherein the compound is administered to the subject with a pharmaceutically acceptable vehicle.

22 . The method of claim 1 , wherein the compound is administered orally to the subject.

23 . The method of claim 1 , wherein the compound is administered to the subject in an oral sustained release dosage form.