Heterocyclic compounds as sweetener enhancers

1. A method of enhancing a sweet taste, comprising administering to a subject a sweet tastant and a compound of Formula I:

or a physiologically acceptable salt thereof,

wherein G 1 , G 2 , and G 3 are independently selected from N, S, and C;

R 1 and R 2 are independently absent or selected from the group consisting of C 1-6 alkoxycarbonyl, hydrogen, C 1-6 alkyl, halogen, nitro, optionally substituted C 6-14 aryl, optionally substituted 5-14 membered heteroaryl, Ar-Q, optionally substituted (CH 2 ) n C(═O)—O—R 2a , and optionally substituted (CH 2 ) n C(═O)aryl, or R 1 and R 2 , together with the G 3 and the carbon atom to which R 1 is attached, form a C 6-14 aryl or 5- to 14-membered heterocycle, each of which is optionally substituted with 1-3 substitutents independently selected from the group consisting of amino, hydroxy, nitro, halogen, cyano, thiol, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkenyloxy, optionally substituted C 6-14 aryl; or if the bond to R 1 and/or R 2 is a double bond, then R 1 and R 2 are independently selected from ═NH and ═O;

R 3 is selected from the group consisting of H, C 1-6 haloalkyl, C 1-6 alkyl, oxo, ═NH, optionally substituted C 6-14 aryl, optionally substituted 5-14 membered heterocycle, and L 1 -R 31 ;

R 4 is absent or is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, optionally substituted C 6-14 aryl, and optionally substituted (CH 2 ) n C(═O)aryl, or when the bond to R 4 is a double bond, R 4 is ═O;

R 5 is either absent or is selected from the group consisting of hydrogen, C 1-6 alkyl, and optionally substituted phenyl amide;

R 7 is either absent or selected from the group consisting of H and C 1-6 alkyl;

R 2a is C 1-6 alkyl;

R 31 is H, C 1-6 alkyl, C 1-6 alkenyl, optionally substituted phenyl, amino, C 1-6 alkylamino, or C 1-6 dialkylamino;

L 1 is a linker selected from the group consisting of ==Z 1 -(CH 2 ) n -Z 2 -, -(Het)-C(O)—NH—, ═N—(CH 2 ) n —C(=Z 3 )-Z 4 -, —NH—C(═O)—(CH 2 ) n -

Z 1 is selected from the group consisting of ═N, —NH, O, and S;

Z 2 is absent, O, S, C(═O), C(═S), —C(═O)—O, C(═S)—O, —C(═O)—NH— or —C(═S)—NH;

Z 3 is O or S;

Z 4 is O, S, or NH;

Het is a 5- to 7-membered nitrogen-containing heterocycle;

Q is CH 2 , O, NH, or S;

Ar is optionally substituted aryl or optionally substituted heteroaryl; and

n is 0 to 10.

2. The method according to claim 1 , wherein the compound of Formula I is

or a physiologically acceptable salt thereof,

wherein R 3 is L 1 -R 31 ;

R 4 is absent, H, C 1-6 alkyl, or C 1-6 hydroxyalkyl;

R 5 is absent, H, or C 1-6 alkyl;

R a is H or C 1-6 alkyl; and

G 1 and G 2 are independently C, N, or S.

3. The method according to claim 2 , wherein the compound is

or a physiologically acceptable salt thereof,

wherein R 3 is L 1 -R 31 ;

R 5 is H or C 1-6 alkyl;

G is N or S; and

R a is H or C 1-6 alkyl.

4. The method according to claim 2 , wherein the compound of Formula I is

or a physiologically acceptable salt thereof,

wherein G 1 is S or N;

R 4 is H, C 1-6 alkyl, or C 1-6 hydroxyalkyl;

R 31 is H, C 1-6 alkyl, C 1-6 alkenyl, or optionally substituted phenyl;

R a is H or C 1-6 alkyl;

Z 1 is S or N;

Z 2 is —C(═O)—O, —C(═S)—O—, —O—, —S—, —C(═O)—NH—, or —C(═S)—NH—; and

n is 0 to 4.

5. The method according to claim 4 , wherein the compound of Formula I is

or a physiologically acceptable salt thereof,

wherein R 4 is H, C 1-6 alkyl, or C 1-6 hydroxyalkyl;

R a is H or C 1-6 alkyl;

R 31 is selected from the group consisting of H, C 1-6 alkyl, and C 1-6 alkenyl;

Z 3 is O or S;

Z 4 is O, S, or NH; and

n is 0 to 3.

6. The method according to claim 4 , wherein the compound is

or a physiologically acceptable salt thereof,

wherein R 4 is selected from the group consisting of H, C 1-6 alkyl, and C 1-6 hydroxyalkyl;

R a is H or C 1-6 alkyl;

R b is C 1-6 alkyl, C 1-6 alkyloxy, or hydroxy;

n is 0 to 3; and

p is 0 to 5.

7. The method according to claim 1 , wherein the compound of Formula I is

or a physiologically acceptable salt thereof,

wherein G 1 is N or S;

Q is N or C;

R 3 is H or optionally substituted phenyl;

R 5 is H when G 1 is N, or otherwise is absent;

R 6 is selected from the group consisting of H and C 1-6 alkyl; and

R 7 is selected from the group consisting of H, C 1-6 alkyl, and optionally substituted phenyl, or, when Q is N, R 7 is absent.

8. The method according to claim 7 , wherein the compound is

or a physiologically acceptable salt thereof,

wherein R 3 is H, C 1-6 alkyl, or optionally substituted phenyl; and

R 7 is selected from the group consisting of H, C 1-6 alkyl, and optionally substituted phenyl.

9. The method according to claim 1 , wherein the compound according to Formula I is

or a physiologically acceptable salt thereof,

wherein R 1 and R 2 are independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkoxycarbonyl, and Ar-Q, wherein Q is O, NH, S, or CH 2 , and Ar is an optionally substituted aryl or optionally substituted heteroaryl;

R 3 is H or C 1-6 alkyl;

R 4 is absent, H, or C 1-6 alkyl;

R 5 is absent, H, or C 1-6 alkyl;

G 1 is C or N; and

G 2 is N or S.

10. The method according to claim 9 , wherein the compound is

or a physiologically acceptable salt thereof,

wherein R 3 is H or C 1-6 alkyl;

R 5 is H or C 1-6 alkyl;

Ar is a 5- to 10-membered aryl or heteroaryl group optionally substituted with one or more groups independently selected from the group consisting of NO 2 , halogen, C 1-6 alkyl, and C 1-6 hydroxyalkyl;

Q is O or NH;

R b is H or C 1-6 alkyl; and

n is 0 to 3.

11. The method according to claim 10 , wherein the compound is

or a physiologically acceptable salt thereof,

wherein R 3 is H or C 1-6 alkyl;

each occurrence of R a is independently selected from the group consisting of NO 2 , halogen, C 1-6 alkyl, or C 1-6 hydroxyalkyl;

R b is H or C 1-6 alkyl; and

n is 0 to 3.

12. The method according to claim 9 , wherein the compound is:

or a physiologically acceptable salt thereof,

wherein R 1 is H, C 1-6 alkyl, halogen, or NO 2 ;

R 3 and R 4 are independently H or C 1-6 alkyl;

Q is S, N, or O; and

Ar is a 5- to 6-membered heteroaryl optionally substituted with one or more substituents independently selected from the group consisting of nitro and halogen.

13. The method according to claim 1 , wherein the compound of Formula I is:

or a physiologically acceptable salt thereof,

wherein R 1 and R 3 are independently optionally substituted phenyl;

R 4 is absent or C 1-6 alkyl; and

R 2 and R 7 are independently C 1-6 alkyl.

14. The method according to claim 1 , wherein the compound is:

or a physiologically acceptable salt thereof,

wherein R 1 is H or C 1-6 alkyl;

R 2 is H;

R 3 is C 1-6 alkyl, H, oxo, or ═NH;

R 31 is optionally substituted phenyl; and

n is 0 to 3.

15. The method according to claim 1 , wherein the compound is:

or a physiologically acceptable salt thereof,

wherein R 1 is H or C 1-6 alkyl;

R 2 is H or C 1-6 alkyl;

R 33 is optionally substituted phenyl;

R 34 is H or C 1-6 alkyl; and

m is 1.

16. The method according to claim 1 , wherein the compound is selected from the group consisting of

ethyl 2-(3-methylbenzo[d]thiazol-2(3H)-ylideneamino)acetate;

2-(2-(2-methoxyphenoxy)ethylthio)-1H-benzo[d]imidazole;

methyl 3-(5-nitropyridin-2-yloxy)thiophene-2-carboxylate;

6-(4-chloro-3-nitrophenyl)-3-ethyl-5H-[1,2,4]triazolo[4,3-b][1,2,4]triazole;

6-p-tolylimidazo[2,1-b][1,3,4]thiadiazole;

N-phenyl-4-(3-phenyl-1,2,4-thiadiazol-5-yl)-1,4-diazepane-1-carboxamide;

2(2-(2-(2,6-dimethoxyphenoxy)ethylthio)-1H-benzimidazol-1-yl)ethanol;

1-ethyl-2-methyl-4-nitro-5-(5-chloropyridin-2-ylthio)imidazole;

2,4-diphenyl-5,5-dimethylimidazole-1-oxide;

1-allyl-3-(3-methylbenzo[d]thiazol-2-(3H)-ylidene)thiourea;

2-(2-iminothiazol-3(2H)-yl)-1-(3-nitrophenyl)ethanone;

3-benzyl-1-isopropyl-5-(4-methylthiazol-2-yl)pyrimidine-2,4(1H,3H)-dione;

2-(3-chloro-2-methoxyphenyl)imidazo[1,2-a]pyridine;

N-(4-(4-ethylphenyl)thiazol-2-yl)-3,5-dimethoxybenzamide;

1-phenylthiochromeno[4,3-d]imidazol-4(1H)-one;

N-(4-(4-chlorophenyl)thiazol-2-yl)-2-(dimethylamino)acetamide;

5-chloro-1-methyl-3-(trifluoromethyl)-N-(4-trifluoromethyl)phenyl-1H-pyrazole -4-carboxamide; and

physiologically acceptable salts thereof.

17. The method according to claim 1 , wherein the sweet tastant is selected from the group consisting of sucrose, fructose, and mixtures thereof; and wherein the sweet tastant and the compound of Formula I are administered in a food product.

18. The method according to claim 17 , wherein the food product is a beverage.

19. The method according to claim 18 , wherein the compound according to Formula I and the sweet tastant are in a ratio from about 1:10 6 to about 1:10 3 .

20. The method according to claim 1 , wherein Ar-Q is an optionally substituted 5-14 membered heteroaryloxy or optionally substituted 5-14 membered heteroarylthio.