PRODRUGS OF GAMMA-HYDROXYBUTYRIC ACID, COMPOSITIONS AND USES THEREOF

1 . A compound of Formula I:

or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof, wherein,

B is

 —(O)R 1 , —R 2 (OCO)R 3 , substituted or unsubstituted C 5-10 aryl, C 1-12 alkyl, C 5-12 aralkyl, C 2-12 alkenyl, C 6-12 aralkenyl, C 2-12 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclic alkyl, or 5-10 membered heterocyclic aryl, wherein the one or more substituents are selected from the group consisting of C 1-12 alkyl, amino, substituted amino, amino protecting group, —R 4 —S—R 5 , halogen, hydroxyl, cyano, mono-, di- or tri-halo-C 1-6 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 alkoxy, C 5-10 aryl, C 5-10 alkylaryl, C 3-8 cycloalkyl, C 1-12 alkylsulfonyl, 3-8 membered heterocyclic alkyl, 3-10 membered heterocyclic aryl, C 5-10 aryloxyl, C 5-10 arylcarbonyl, C 1-6 alkylcarbonyloxyl or C 1-4 alkyloxycarbonyl;

wherein

R 1 and R 3 are independently C 1-12 alkyl, C 2-12 alkenyl, C 5-12 aralkyl, C 6-12 aralkenyl, C 2-12 alkynyl, C 5-10 aryl, C 3-8 cycloalkyl, 3-10 membered heterocyclic alkyl, 5-10 membered heterocyclic aryl, or

 any of which can be optionally mono- or independently multi-substituted by —R 4 —S—R 5 , halogen, hydroxyl, cyano, amino, substituted amino, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 5-10 aryl, C 1-12 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclic alkyl, or 3-10 membered heterocyclic aryl, C 1-4 alkylsulfonyl, C 5-10 aryloxyl, C 5-10 arylcarbonyl, C 1-4 alkyloxycarbonyl, or C 1-12 alkylcarbonylamino;

R 2 is C 1-6 alkylene, or C 1-6 alkyleneoxyl, any of which is optionally further substituted with C 1-6 alkyl;

R 4 is bond, C 1-6 alkylene, C 5-10 arylene, or C 5-12 arylenealkylene, any of which is optionally further substituted with C 1-3 alkyl, and R 5 is hydrogen or C 1-12 alkyl,

R g is hydrogen, C 1-6 alkyl, phenyl, or phenylmethyl any of which is optionally mono- or independently multi-substituted by halogen, hydroxyl, methylthio, C 1-4 alkyl, or C 5-8 aryl; and R h and R f are independently hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxylcarbonyl, C 3-6 cycloalkoxylcarbonyl, or an amino protecting group;

or

R f and R g together with C, O, N or S atom form a 4-8 membered heterocyclic alkyl or

 any of which is optionally mono- or independently multi-substituted by halogen, hydroxyl, C 1-4 alkyl or an amino protecting group, and R h is hydrogen, C 1-6 alkyl or an amino protecting group.

2 . The compound of claim 1 , wherein the compound has the chemical structure shown in Formula (IA):

or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof, wherein,

R g is hydrogen, C 1-6 alkyl, phenyl, or phenylmethyl, any of which is optionally mono- or independently multi-substituted by halogen, hydroxyl, methylthio, C 1-4 alkyl, or C 5-8 aryl; and R h and R f are independently hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxylcarbonyl, C 3-6 cycloalkoxylcarbonyl or an amino protecting group.

3 . The compound of claim 2 , wherein R g is hydrogen or C 1-3 alkyl.

4 . The compound of claim 2 , wherein at least one of R h and R f is hydrogen or C 1-3 alkyl.

5 . The compound of claim 4 , wherein both R h and R f are hydrogen or C 1-3 alkyl.

6 . The compound of claim 2 , wherein R h is hydrogen or C 1-3 alkyl and R f is —COR 5 , and R 5 is C 1-3 alkyl, C 1-3 alkoxyl, or C 5-6 cycloalkyloxyl.

7 . The compound of claim 2 , wherein when R f or R h is an amino protecting group, R g is not isopropyl or benzyl.

8 . The compound of claim 1 , wherein the compound has the chemical structure shown in Formula (IA):

or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof, wherein,

R f and R g together with C, O, or N atom form a 4-6 membered heterocyclic alkyl or

 any of which is optionally mono- or independently multi-substituted by halogen, hydroxyl, C 1-4 alkyl or an amino protecting group;

R h is hydrogen, C 1-3 alkyl or an amino protecting group.

9 . The compound of claim 8 , wherein the compound has the chemical structure shown in Formula (IA-1):

or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof, wherein,

R h is hydrogen, C 1-3 alkyl or an amino protecting group.

10 . The compound of claim 8 , wherein the compound has the chemical structure shown in Formula (IA-2):

or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof, wherein,

R i is hydrogen, C 1-4 alkyl or an amino protecting group.

11 . The compound of claim 1 , wherein the compound has the chemical structure shown in Formula (IB):

or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof, wherein,

R 1 is C 1-8 alkyl, C 5-8 aryl, C 5-12 aralkyl, 3-10 membered heterocyclic alkyl,

 which are each optionally mono- or independently multi-substituted by halogen, cyano, hydroxyl, C 1-12 alkyl or C 1-4 alkoxy.

12 . The compound of claim 11 , wherein R 1 is

and R 1a and R 1b are independently hydrogen, C 1-12 alkyl, C 1-4 alkoxy or halogen.

13 . The compound of claim 11 , wherein R 1 is

and R 1 is hydrogen, C 1-12 alkyl or halogen.

14 . The compound of claim 1 , wherein the compound has the chemical structure shown in Formula (IC):

or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof, wherein,

R a , R b , R c , R d and R e are independently hydrogen, halogen, C 1-12 alkyl, C 1-12 alkoxy, cyano, C 1-12 alkylsulfonyl, C 1-6 alkylcarbonyloxyl, C 1-4 alkyloxycarbonyl, mono-, di- or tri-halo-C 1-6 alkyl, C 5-10 aryloxyl or C 5-10 arylcarbonyl; and

When R a , R b , R c , R d and R e are all hydrogen, at least one of R a , R b , R c , R d and R e is not protium.

15 . The compound of claim 14 , wherein R b , R c , R d are all hydrogen, and R e and R a are independently hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy, cyano, C 1-3 alkylsulfonyl, C 1-3 alkylcarbonyloxyl, C 1-3 alkyloxycarbonyl, or mono-, di- or tri-halo-C 1-3 alkyl.

16 . The compound of claim 14 , wherein one of R e and R a is hydrogen.

17 . The compound of claim 1 , wherein the compound has the chemical structure shown in Formula (ID):

or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof, wherein,

R 2 is —(CR 6 R 7 ) m —, wherein m=1-6 and R 6 and R 7 are independently hydrogen or C 1-3 alkyl;

R 3 is C 1-12 alkyl, C 5-8 aryl, 3-8 membered heterocyclic alkyl, or 5-8 membered heterocyclic aryl, which are each optionally mono- or independently multi-substituted by halogen, substituted or unsubstituted amino, C 1-6 alkyl or C 1-6 alkoxy, wherein said substituted amino can be optionally mono- or independently multi-substituted by C 1-6 alkyl or C 1-6 alkylcarbonyl.

18 . The compound of claim 17 , wherein the compound has the chemical structure shown in Formula (ID-1):

or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof, wherein,

R 3a , R 3b , R 3c , R 3d and R 3e are independently hydrogen, halogen, C 1-6 alkyl, or C 1-6 alkoxy.

19 . The compound of claim 17 , wherein the compound has the chemical structure shown in Formula (ID-2):

or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof, wherein,

R 9 and R 10 are independently hydrogen, C 1-6 alkyl or C 1-6 alkylcarbonyl; and

R 8 is hydrogen or C 1-6 alkyl.

20 . The compound of claim 1 , wherein the compound has the chemical structure shown in Formula (IE):

or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof, wherein,

R 11 is C 1-8 alkyl or C 5-8 aryl, which are each optionally mono- or independently multi-substituted by halogen, hydroxyl, C 1-6 alkyl or C 1-4 alkoxy;

R 12 is hydrogen or C 1-6 alkyl.

21 . The compound of claim 1 , wherein B is:

C 1-8 alkyl substituted with C 2-6 alkyl, aryl or amino group and B is not linear alkyl; or

C 2-6 alkenyl substituted with C 1-6 alkyl, aryl or amino group; or

substituted or unsubstituted C 3-8 cycloalkyl, wherein the substituent is selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl; or

substituted or unsubstituted 3-8 membered heterocyclic alkyl, wherein the substituent is selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl; or

substituted or unsubstituted 5-8 membered heterocyclic aryl, wherein the substituent is selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl.

22 . The compound of claim 21 , wherein B is —CHR 13 R 14 , wherein R 13 and R 14 are independently selected from the group consisting of C 1-6 alkyl, aryl and amino group,

wherein R 13 and R 14 cannot be methyl at the same time,

optionally, R 13 and R 14 can be cyclized to form a C 3-8 cycloalkyl or R 13 and R 14 together with the O, N or S atom form a 3-8 membered heterocyclic alkyl.

23 . The compound of claim 1 , selected from the group consisting of

24 . The compound of any of claims 1 to 22 , wherein the molecular weight of the compound is no more than 450 Da, or 150-450 Da, or 150-300 Da.

25 . The compound of any of claims 1 to 24 , wherein the hydrogen includes its isotopes and the isotopes are protium and deuterium.

26 . The compound of any of claims 1 to 25 , wherein the compound can be converted to gamma-hydroxybutyric acid and enter into human circulatory system through a biological process after oral administration.

27 . A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 25 , and a pharmaceutically acceptable carrier.

28 . The pharmaceutical composition of claim 27 , wherein the pharmaceutical composition is formulated in a sustained released form.

29 . Use of one or more compounds according to any one of claims 1 to 25 in the manufacture of a medicament for treating a disease, wherein the disease is narcolepsy, excessive daytime sleepiness, cataplexy, neurodegenerative disease, sleep disturbance syndrome, fibromyalgia, chronic fatigue, schizophenia, binge eating disorder, Parkinson disease, tardive dyskinesia, or Alzheimer's disease.

30 . A method of treating a disease, comprising administering to a subject an effective amount of one or more compounds according to any one of claims 1 to 25 , wherein the disease is narcolepsy, excessive daytime sleepiness, cataplexy, neurodegenerative disease, sleep disturbance syndrome, fibromyalgia, chronic fatigue, schizophenia, binge eating disorder, Parkinson disease, tardive dyskinesia, or Alzheimer's disease.

31 . The method of claim 30 , wherein the disease is excessive daytime sleepiness or cataplexy associated with narcolepsy.

32 . The method of claim 30 , wherein the administration is conducted no more than two times per day.

33 . The method of claim 30 , wherein the administration is via oral, nasal, intravenous, subcutaneous, sublingual, or intramuscular administration.

34 . The method of claim 30 , wherein the dosage of the compound is within the range of 1-18 g.