Allosteric agonists and positive allosteric modulators of Glucagon-like peptide 1 receptor

1 . A compound of formula:

wherein:

each occurrence of R 1 is independently selected optionally substituted C 1 -C 6 alkyl;

R 2 and R 3 are each independently selected from the group consisting of H and optionally substituted C 1 -C 6 alkyl;

R 4 is selected from the group consisting of —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), and optionally substituted C 1 -C 6 alkoxy, or

R 2 is absent and R 3 and R 4 combine with ═C(XR′)—N(R″)—* to form a ring,

wherein the bond marked as * is with the carbonyl group in the compound;

X is selected from the group consisting of O, S, and NR;

R is H;

each occurrence of R′ is independently selected from the group consisting of H, optionally substituted C 1 -C 6 alkyl, (CH 2 ) n C(═O)R 5 , and (CH 2 CH 2 O) n C(═O)R 5 , wherein each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

each occurrence of R 5 is independently selected optionally substituted phenyl;

each occurrence of R″ is independently selected from the group consisting of hydrogen, —NH 2 , —NH(C 1 -C 6 alkyl), and —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl);

wherein each optional substituent is independently selected from the group consisting of fluorine, chlorine, bromine, iodine, —CN, —NH 2 , —OH, —NH(CH 3 ), —N(CH 3 ) 2 , —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CH 2 CF 3 , —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OCF 3 , —OCH 2 CF 3 , —S(═O) 2 —CH 3 , —C(═O)NH 2 , —C(═O)—NHCH 3 , —NHC(═O)NHCH 3 , —C(═O)CH 3 , and —C(═O)OH;

or a salt, solvate, stereoisomer, geometric isomer, or tautomer thereof.

2 . The compound of claim 1 , wherein R′ is

3 . The compound of claim 1 , wherein X is S.

4 . The compound of claim 1 , wherein one, or at least one, occurrence of R 1 is C 1 -C 6 alkyl.

5 . The compound of claim 1 , wherein one, or at least one, occurrence of R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl.

6 . The compound of claim 1 , wherein R 4 is optionally substituted C 1 -C 6 alkoxy.

7 . The compound of claim 1 , wherein R 4 is optionally substituted methoxy, optionally substituted ethoxy, optionally substituted n-propoxy, optionally substituted isopropoxy, optionally substituted n-butoxy, optionally substituted isobutoxy, optionally substituted sec-butoxy, or optionally substituted t-butoxy.

8 . The compound of claim 1 , which is

ethyl 2-amino-7,7-dimethyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate.

9 . A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and an effective amount of at least one compound of claim 1 , or a salt, solvate, stereoisomer, geometric isomer, or tautomer thereof.

10 . The composition of claim 9 , further comprising at least one additional agent useful for treating or ameliorating type II diabetes in a subject, wherein the at least one additional agent is selected from the group consisting of an α-glucosidase inhibitor, a lipase inhibitor, a sulfonyl urea, a meglitinide, a biguanide, a thiazolidinedione, pramlintide, incretin mimetic, DPP-IV inhibitor, and SGLT2 inhibitor.

11 . The composition of claim 10 , wherein at least one of the following applies:

(a) the α-glucosidase inhibitor is selected from the group consisting of acarbose, miglitol, and voglibose;

(b) the lipase inhibitor is orlistat;

(c) the sulfonyl urea is selected from the group consisting of acetohexamide, chlorpropamide, tolbutamide, tolazamide, gliclazide, glyburide or glibenclamide, glipizide, glimepiride, and gliquidone;

(d) the meglitinide is selected from the group consisting of mitiglinide, nateglinide, and repaglinide;

(e) the biguanide is selected from the group consisting of metformin, phenformin, and buformin;

(f) the thiazolidinedione is selected from the group consisting of rosiglitazone, pioglitazone, troglitazone, and tesaglitazar;

(g) the incretin mimetic is selected from the group consisting of exenatide, exedin-4 or AC2993; liraglutide, NN2211, or NNC 90-1170;

(h) the DPP-IV inhibitor is selected from the group consisting of sitagliptin and vildagliptin; and

(i) the SGLT2 inhibitor is selected from the group consisting of dapaglifozin.

12 . A method of treating or ameliorating type II diabetes in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of claim 1 , or a salt, solvate, stereoisomer, geometric isomer, or tautomer thereof.

13 . The method of claim 12 , wherein the compound is administered as a pharmaceutical composition to the subject.

14 . The method of claim 12 , wherein the subject is further administered at least one additional agent useful for treating or ameliorating type II diabetes.

15 . The method of claim 12 , wherein the at least one additional agent is selected from the group consisting of α-glucosidase inhibitor, lipase inhibitor, sulfonyl urea, meglitinide, biguanide, thiazolidinedione, pramlintide, incretin mimetic, DPP-IV inhibitor, and SGLT2 inhibitor.

16 . The method of claim 14 , wherein at least one of the following applies:

(a) administering the compound to the subject allows for administering a lower dose of the at least one additional agent as compared to the dose of the additional agent alone that is required to achieve similar results in treating or ameliorating type II diabetes;

(b) administering the compound to the subject enhances activity, or reduces at least one side effect, of the at least one additional agent;

(c) the compound and the at least one additional agent are co-administered to the subject;

(d) the compound and the at least one additional agent are co-formulated.