Non-peptide antagonists of GLP-1 receptor and methods of use

• US 6,469,021 B1
• Filed: 10/26/2001
• Issued: 10/22/2002
• Est. Priority Date: 12/10/1998
• Status: Expired due to Fees

• Current Assignee: Agouron Pharmaceuticals Incorporated (Pfizer Inc.)
• Original Assignee: Agouron Pharmaceuticals Incorporated (Pfizer Inc.)
• Inventors: Ling, Anthony L., Johnson, Michael David, Gregor, Vlad Edward, Rajapakse, Ranjan Jagath, Chou, Tso-sheng, Bychowski, Richard A., Hong, Yufeng, Kiel, Dan, Gonzalez, Javier, Teng, Min, Truesdale, Larry Kenneth, Kuki, Atsuo, Dhanoa, Daljit S.
• Primary Examiner(s): AULAKH, CHARANJIT
• Application Number:
  US09/831,572
• Time in Patent Office: 361 Days
• Field of Search: 514/292, 514/287, 514/253, 514/232.8, 514/248, 546/85, 546/87, 546/64, 544/126, 544/233, 544/361
• US Class Current: 514/292
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/48 of the pancreatic hormones
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 249/08 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 471/14 Ortho-condensed systems
• CPC Class Codes: C07D 491/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/14 Ortho-condensed systems

Abstract

Non-peptide compounds that act as antagonists of the intestinal hormone glucagons-like peptide 1 (GLP-1) have a 9H-b-carboline central motif. The compounds exhibit advantageous physical, chemical and biological properties and inhibit GLP-1 peptide binding to the GLP-1 receptor and/or prevent activation of the receptor by bound GLP-1. The invention further relates to a method of inhibiting the binding of GLP-1 to the GLP-1 receptor and a method of inhibiting the activation of the GLP-1 receptor. Intermediate compounds useful for making non-peptide GLP-1 receptor antagonists are also described.

Claims

1. A compound of formula:

wherein;

R¹ is a phenyl or pyridyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, nitro, trifluoromethyl, cyano, C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₁-C₆ alkoxy groups;

R² is;

 

where R′

is;

hydrogen;

a hydroxy group;

—

OR⁵, where R⁵ is a C₁-C₆ alkyl or C₂-C₆ alkenyl group optionally substituted with a hydroxy group or an amino, C₁-C₆ alkoxy, cycloalkyl, thioether, heterocycloalkyl, aryl, or heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of alkyl, hydroxyalkyl, carboxyl, C₁-C₆ alkoxycarbonyl, oxygen, halogen, and trifluoromethyl groups;

or —

NR⁶R⁷, where R⁶ and R⁷ are each independently hydrogen or a C₁-C₆ alkyl, C₂-C₆ alkenyl, amino, or imino group optionally substituted with a hydroxy group, a C₁-C₆ alkoxy group, or an amino, thioether, heterocycloalkyl, aryl, or heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of oxygen, halogen, trifluoromethyl, and carboxyl groups, or where —

NR⁶R⁷ forms a 5- or 6-membered heterocyclic ring optionally containing, in addition to the nitrogen heteroatom, a heteroatom selected from the group consisting of O, N, and S;

—

(CH₂)_n—

O—

R″

, where n is 1 or 2, and R″

is hydrogen, a C₅-C₇heteroaryl group, or

 

where R⁸ is hydrogen, a C₁-C₆ alkyl group, a C₃-C₆ cycloalkyl group, or a 5- or 6-membered heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of halogens, methyl, and trifluoromethyl;

—

(CH₂)_p—

N(R″

)(R′

″

), where p is 1 or 2, R″

is as defined above, and R′

″

is hydrogen or an alkyl or alkoxy group optionally substituted with a C₃-C₆ cycloalkyl group optionally substituted with cyano;

—

CH=N—

R″

″

, where R″

″

is hydrogen, a hydroxy group, or —

OR⁹, where R⁹ is an alkyl, cycloalkyl, aryl, or heteroaryl group;

or

a 5- or 6-membered heterocyclic ring containing one to three heteroatoms independently selected from the group consisting of O, N, and S, the ring being optionally substituted with one or two substituents independently selected from the group consisting of methyl, methoxymethyl, oxygen, and C₁-C₆ alkoxy groups;

R³ is hydrogen or a C₁-C₆ alkyl, C₂-C₆ alkenyl, or (C₁-C₃ alkoxy)C₁-C₃ alkyl group;

or R² and R³ together with the atoms to which they are bound form a 5- or 6-membered ring containing one or two heteroatoms selected from the group consisting of O, N, and S, the ring being optionally substituted with oxygen, hydroxyl, or a C₁-C₆ alkyl group optionally substituted with a 5- or 6-membered heterocycloalkyl containing one or two heteroatoms independently selected from the group consisting of O, N, and S; and

R⁴ is hydrogen or an amino, halogen, hydroxyl, nitro, trifluoromethyl, cyano, C₁-C₆ alkyl, or C₂-C₆ alkenyl group;

where when R¹ is an unsubstituted phenyl, R² is

 

R³ is H, and R⁴ is H, R⁵ is not an ethyl group;

pharmaceutically acceptable salt or pharmaceutically acceptable solvate of said compound.

2. A compound, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate according to claim 1, wherein:

R¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, nitro, trifluoromethyl, and cyano groups;

R² is

 

where R′

is as defined above and wherein a hydrogen-bond acceptor substituent is positioned 3-5 Å

from the carbonyl group; and

R³ is hydrogen or methoxymethyl.

3. A compound, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate according to claim1, wherein R¹ is 2,5-dichlorophenyl or 3,5-dinitrophenyl.

4. A compound, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate according to claim 1, wherein R² and R³ together with the atoms to which they are bound form a 5- or 6-membered ring that is a lactone or lactam.

5. A compound, pharmaceutically acceptable salt or pharmaceutically acceptable solvate according to claim 1, wherein R² is selected from the group consisting of:

6. A compound pharmaceutically acceptable salt, or pharmaceutically acceptable solvate according to claim 1, wherein R² and R³ and the atoms to which they are bound together form a 5- to 6-membered ring selected from the group consisting of:

7. A compound, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate according to claim 1, wherein the compound is of the formula:

where R⁵ is as defined above.

8. A compound, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate according to claim 1, wherein the compound is selected from the group consisting of:

9. A pharmaceutical composition comprising an effective amount of a compound, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate according to claim 1, and a pharmaceutically acceptable carrier.

10. A method for regulating the secretion of insulin in mammals comprising administering to a mammal an effective amount of a compound of formula:

wherein;

R¹ is a phenyl or pyridyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, nitro, trifluoromethyl, cyano, C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₁-C₆ alkoxy groups;

R² is;

 

where R′

is;

hydrogen;

a hydroxy group;

—

OR⁵, where R⁵ is a C₁-C₆ alkyl or C₂-C₆ alkenyl group optionally substituted with a hydroxy group or an amino, C₁-C₆ alkoxy, cycloalkyl, thioether, heterocycloalkyl, aryl, or heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of alkyl, hydroxyalkyl, carboxyl, C₁-C₆ alkoxycarbonyl, oxygen, halogen, and trifluoromethyl groups;

or —

NR⁶R⁷, where R⁶ and R⁷ are each independently hydrogen or a C₁-C₆ alkyl, C₂-C₆ alkenyl, amino, or imino group optionally substituted with a hydroxy group, a C₁-C₆ alkoxy group, or an amino, thioether, heterocycloalkyl, aryl, or heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of oxygen, halogen, trifluoromethyl, and carboxyl groups, or where —

NR⁶R⁷ forms a 5- or 6-membered heterocyclic ring optionally containing, in addition to the nitrogen heteroatom, a heteroatom selected from the group consisting of O, N, and S;

—

(CH₂)_n—

O—

R″

, where n is 1 or 2, and R″

is hydrogen, a C₅-C₇heteroaryl group, or

 

where R⁸ is hydrogen, a C₁-C₆ alkyl group, a C₃-C₆ cycloalkyl group, or a 5- or 6-membered heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of halogens, methyl, and trifluoromethyl;

—

(CH₂)_p—

N(R″

)(R′

″

), where p is 1 or 2, R″

is as defined above, and R′

″

is hydrogen or an alkyl or alkoxy group optionally substituted with a C₃-C₆ cycloalkyl group optionally substituted with cyano;

—

CH═

N—

R″

″

, where R″

″

is hydrogen, a hydroxy group, or —

OR⁹, where R⁹ is an alkyl, cycloalkyl, aryl, or heteroaryl group;

or

a 5- or 6-membered heterocyclic ring containing one to three heteroatoms independently selected from the group consisting of O, N, and S, the ring being optionally substituted with one or two substituents independently selected from the group consisting of methyl, methoxymethyl, oxygen, and C₁-C₆ alkoxy groups;

R³ is hydrogen or a C₁-C₆ alkyl, C₂-C₆ alkenyl, or (C₁-C₃ alkoxy)C₁-C₃ alkyl group;

or R² and R³ together with the atoms to which they are bound form a 5- or 6-membered ring containing one or two heteroatoms selected from the group consisting of O, N, and S, the ring being optionally substituted with oxygen, hydroxyl, or a C₁-C₆ alkyl group optionally substituted with a 5- or 6-membered heterocycloalkyl containing one or two heteroatoms independently selected from the group consisting of O, N, and S; and

R⁴ is hydrogen or an amino, halogen, hydroxyl, nitro, trifluoromethyl, cyano, C₁-C₆ alkyl, or C₂-C₆ alkenyl group;

pharmaceutically acceptable salt, or pharmaceutically acceptable solvate of said compound.

11. A method for inhibiting GLP-1 activity comprising administering to a patient an effective amount of a compound of formula:

wherein;

R¹ is a phenyl or pyridyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, nitro, trifluoromethyl, cyano, C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₁-C₆ alkoxy groups;

R² is;

 

where R′

is;

hydrogen;

a hydroxy group;

—

OR⁵, where R⁵ is a C₁-C₆ alkyl or C₂-C₆ alkenyl group optionally substituted with a hydroxy group or an amino, C₁-C₆ alkoxy, cycloalkyl, thioether, heterocycloalkyl, aryl, or heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of alkyl, hydroxyalkyl, carboxyl, C₁-C₆ alkoxycarbonyl, oxygen, halogen, and trifluoromethyl groups;

or -NR⁶R⁷, where R⁶ and R⁷ are each independently hydrogen or a C₁-C₆ alkyl, C₂-C₆ alkenyl, amino, or imino group optionally substituted with a hydroxy group, a C₁-C₆ alkoxy group, or an amino, thioether, heterocycloalkyl, aryl, or heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of oxygen, halogen, trifluoromethyl, and carboxyl groups, or where —

NR⁶R⁷ forms a 5- or 6-membered heterocyclic ring optionally containing, in addition to the nitrogen heteroatom, a heteroatom selected from the group consisting of O, N, and S;

—

(CH₂)—

O—

R″

, where n is 1 or 2, and R″

is hydrogen, a C₅-C₇heteroaryl group, or

 

where R⁸ is hydrogen, a C₁-C₆ alkyl group, a C₃-C₆ cycloalkyl group, or a 5- or 6-membered heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of halogens, methyl, and trifluoromethyl;

—

(CH₂)_p—

N(R″

)(R′

″

), where p is 1 or 2, R″

is as defined above, and R′

″

is hydrogen or an alkyl or alkoxy group optionally substituted with a C₃-C₆ cycloalkyl group optionally substituted with cyano;

—

CH═

N—

R″

″

, where R″

″

is hydrogen, a hydroxy group, or —

OR⁹, where R⁹ is an alkyl, cycloalkyl, aryl, or heteroaryl group;

or

a 5- or 6-membered heterocyclic ring containing one to three heteroatoms independently selected from the group consisting of O, N, and S, the ring being optionally substituted with one or two substituents independently selected from the group consisting of methyl, methoxymethyl, oxygen, and C₁-C₆ alkoxy groups;

R³ is hydrogen or a C₁-C₆ alkyl, C₂-C₆ alkenyl, or (C₁-C₃ alkoxy)C₁-C₃ alkyl group;

or R² and R³ together with the atoms to which they are bound form a 5- or 6-membered ring containing one or two heteroatoms selected from the group consisting of O, N, and S, the ring being optionally substituted with oxygen, hydroxyl, or a C₁-C₆ alkyl group optionally substituted with a 5- or 6-membered heterocycloalkyl containing one or two heteroatoms independently selected from the group consisting of O, N, and S; and

R⁴ is hydrogen or an amino, halogen, hydroxyl, nitro, trifluoromethyl, cyano, C₁-C₆ alkyl, or C₂-C₆ alkenyl group;

pharmaceutically acceptable salt or pharmaceutically acceptable solvate of said compound.

12. A method of inhibiting the binding of GLP-1 to the GLP-1 receptor comprising administering to a patient an effective amount of a compound of formula:

wherein;

R¹ is a phenyl or pyridyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, nitro, trifluoromethyl, cyano, C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₁-C₆ alkoxy groups;

R² is;

 

where R′

is;

hydrogen;

a hydroxy group;

—

OR⁵, where R⁵ is a C₁-C₆ alkyl or C₂-C₆ alkenyl group optionally substituted with a hydroxy group or an amino, C₁-C₆ alkoxy, cycloalkyl, thioether, heterocycloalkyl, aryl, or heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of alkyl, hydroxyalkyl, carboxyl, C₁-C₆ alkoxycarbonyl, oxygen, halogen, and trifluoromethyl groups;

or —

NR⁶R⁷, where R⁶ and R⁷ are each independently hydrogen or a C₁-C₆ alkyl, C₂-C₆ alkenyl, amino, or imino group optionally substituted with a hydroxy group, a C₁-C₆ alkoxy group, or an amino, thioether, heterocycloalkyl, aryl, or heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of oxygen, halogen, trifluoromethyl, and carboxyl groups, or where —

NR⁶R⁷ forms a 5- or 6-membered heterocyclic ring optionally containing, in addition to the nitrogen heteroatom, a heteroatom selected from the group consisting of O, N, and S;

—

(CH₂)_n—

O—

R″

, where n is 1 or 2, and R″

is hydrogen, a C₅-C₇heteroaryl group, or

 

where R₈ is hydrogen, a C₁-C₆ alkyl group, a C₃-C₆ cycloalkyl group, or a 5- or 6-membered heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of halogens, methyl, and trifluoromethyl;

—

(CH₂)_p—

N(R″

)(R′

″

), where p is 1 or 2, R″

is as defined above and R′

″

is hydrogen or an alkyl or alkoxy group optionally substituted with a C₃-C₆ cycloalkyl group optionally substituted with cyano;

—

CH═

N—

R″

″

, where R″

″

is hydrogen, a hydroxy group, or —

OR⁹, where R⁹ is an alkyl, cycloalkyl, aryl, or heteroaryl group;

or

a 5- or 6-membered heterocyclic ring containing one to three heteroatoms independently selected from the group consisting of O, N, and S, the ring being optionally substituted with one or two substituents independently selected from the group consisting of methyl, methoxymethyl, oxygen, and C₁-C₆ alkoxy groups;

R³ is hydrogen or a C₁-C₆ alkyl, C₂-C₆ alkenyl, or (C₃-C₃ alkoxy)C_1-C3 alkyl group;

or R² and R³ together with the atoms to which they are bound form a 5- or 6-membered ring containing one or two heteroatoms selected from the group consisting of O, N, and S, the ring being optionally substituted with oxygen, hydroxyl, or a C₁-C₆ alkyl group optionally substituted with a 5- or 6-membered heterocycloalkyl containing one or two heteroatoms independently selected from the group consisting of O, N, and S; and

R⁴ is hydrogen or an amino, halogen, hydroxyl, nitro, trifluoromethyl, cyano, C₁-C₆ alkyl, or C₂-C₆ alkenyl group;

pharmaceutically acceptable salt, or pharmaceutically acceptable solvate or active metabolite of said compound.

13. A method of inhibiting activation of the GLP-1 receptor comprising administering to a patient an effective amount of a compound of formula:

wherein;

R¹ is a phenyl or pyridyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, nitro, trifluoromethyl, cyano, C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₁-C₆ alkoxy groups;

R² is;

 

where R′

is;

hydrogen;

a hydroxy group;

—

OR⁵, where R⁵ is a C₁-C₆ alkyl or C₂-C₆ alkenyl group optionally substituted with a hydroxy group or an amino, C₁-C₆ alkoxy, cycloalkyl, thioether, heterocycloalkyl, aryl, or heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of alkyl, hydroxyalkyl, carboxyl, C₁-C₆ alkoxycarbonyl, oxygen, halogen, and trifluoromethyl groups;

or —

NR⁶R⁷, where R⁶ and R⁷ are each independently hydrogen or a C₁-C₆ alkyl, C₂-C₆ alkenyl, amino, or imino group optionally substituted with a hydroxy group, a C₁-C₆ alkoxy group, or an amino, thioether, heterocycloalkyl, aryl, or heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of oxygen, halogen, trifluoromethyl, and carboxyl groups, or where —

NR⁶R⁷ forms a 5- or 6-membered heterocyclic ring optionally containing, in addition to the nitrogen heteroatom, a heteroatom selected from the group consisting of O, N, and S;

—

(CH₂)_n—

O—

R″

, where n is 1 or 2, and R″

is hydrogen, a C₅-C₇heteroaryl group, or

 

or where R⁸ is hydrogen, a C₁-C₆ alkyl group, a C₃-C₆ cycloalkyl group, or a 5- or 6-membered heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of halogens, methyl, and trifluoromethyl;

—

(CH₂)_p—

N(R″

)(R′

″

), where p is 1 or 2, R″

is as defined above, and R′

″

is hydrogen or an alkyl or alkoxy group optionally substituted with a C₃-C₆ cycloalkyl group optionally substituted with cyano;

—

CH═

N—

R″

″

, where R″

″

is hydrogen, a hydroxy group, or —

OR⁹, where R⁹ is an alkyl, cycloalkyl, aryl, or heteroaryl group;

or

a 5- or 6-membered heterocyclic ring containing one to three heteroatoms independently selected from the group consisting of O, N, and S, the ring being optionally substituted with one or two substituents independently selected from the group consisting of methyl, methoxymethyl, oxygen, and C₁-C₆ alkoxy groups;

R³ is hydrogen or a C₁-C₆ alkyl, C₂-C₆ alkenyl, or (C₁-C₃ alkoxy)C₁-C₃ alkyl group;

or R² and R³ together with the atoms to which they are bound form a 5- or 6-membered ring containing one or two heteroatoms selected from the group consisting of O, N, and S, the ring being optionally substituted with oxygen, hydroxyl, or a C₁-C₆ alkyl group optionally substituted with a 5- or 6-membered heterocycloalkyl containing one or two heteroatoms independently selected from the group consisting of O, N, and S; and

R⁴ is hydrogen or an amino, halogen, hydroxyl, nitro, trifluoromethyl, cyano, C₁-C₆ alkyl, or C₂-C₆ alkenyl group;

pharmaceutically acceptable salt, or pharmaceutically acceptable solvate of said compound.

14. A method for regulating the secretion of insulin in mammals comprising administering to a mammal an effective amount of a compound of formula:

wherein;

R¹ is a phenyl or pyridyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, nitro, trifluoromethyl, cyano, C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₁-C₆ alkoxy groups;

R² is;

 

where R′

is;

hydrogen;

a hydroxy group;

—

OR⁵, where R⁵ is a C₁-C₆ alkyl or C₂-C₆ alkenyl group optionally substituted with a hydroxy group or an amino, C₁-C₆ alkoxy, cycloalkyl, thioether, heterocycloalkyl, aryl, or heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of alkyl, hydroxyalkyl, carboxyl, C₁-C₆ alkoxycarbonyl, oxygen, halogen, and trifluoromethyl groups;

or —

NR⁶R⁷, where R⁶ and R⁷ are each independently hydrogen or a C₁-C₆ alkyl, C₂-C₆ alkenyl, amino, or imino group optionally substituted with a hydroxy group, a C₁-C₆ alkoxy group, or an amino, thioether, heterocycloalkyl, aryl, or heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of oxygen, halogen, trifluoromethyl, and carboxyl groups, or where —

NR⁶R⁷ forms a 5- or 6-membered heterocyclic ring optionally containing, in addition to the nitrogen heteroatom, a heteroatom selected from the group consisting of O, N, and S;

—

(CH₂)_n—

O—

R″

, where n is 1 or 2, and R″

is hydrogen, a C₅-C₇heteroaryl group, or

 

where R⁸ is hydrogen, a C₁-C₆ alkyl group, a C₃-C₆ cycloalkyl group, or a 5- or 6-membered heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of halogens, methyl, and trifluoromethyl;

—

(CH₂)_p—

N(R″

)(R′

″

), where p is 1 or 2, R′

is as defined above, and R′

″

is hydrogen or an alkyl or alkoxy group optionally substituted with a C₃-C₆ cycloalkyl group optionally substituted with cyano;

—

CH═

N—

R″

″

, where R″

″

is hydrogen, a hydroxy group, or —

OR⁹, where R⁹ is an alkyl, cycloalkyl, aryl, or heteroaryl group;

or

a 5- or 6-membered heterocyclic ring containing one to three heteroatoms independently selected from the group consisting of O, N, and S, the ring being optionally substituted with one or two substituents independently selected from the group consisting of methyl, methoxymethyl, oxygen, and C₁-C₆ alkoxy groups;

R³ is hydrogen or a C₁-C₆ alkyl, C₂-C₆ alkenyl, or (C₁-C₃ alkoxy)C₁-C₃ alkyl group;

or R² and R³ together with the atoms to which they are bound form a 5- or 6-membered ring containing one or two heteroatoms selected from the group consisting of O, N, and S, the ring being optionally substituted with oxygen, hydroxyl, or a C₁-C₆ alkyl group optionally substituted with a 5- or 6-membered heterocycloalkyl containing one or two heteroatoms independently selected from the group consisting of O, N, and S; and

R⁴ is hydrogen or an amino, halogen, hydroxyl, nitro, trifluoromethyl, cyano, C₁-C₆ alkyl, or C₂-C₆ alkenyl group;

pharmaceutically acceptable salt, or pharmaceutically acceptable solvate of said compound.

15. A compound of formula:

wherein;

R¹ is a phenyl or pyridyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, nitro, trifluoromethyl, cyano, C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₁-C₆ alkoxy groups;

R² is;

 

where R′

is;

hydrogen;

a hydroxy group;

—

OR⁵, where R⁵ is a C₁-C₆ alkyl or C₂-C₆ alkenyl group optionally substituted with a hydroxy group or an amino, C₁-C₆ alkoxy, cycloalkyl, thioether, heterocycloalkyl, aryl, or heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of alkyl, hydroxyalkyl, carboxyl, C₁-C₆ alkoxycarbonyl, oxygen, halogen, and trifluoromethyl groups;

or —

NR⁶R⁷, where R⁶ and R⁷ are each independently hydrogen or a C₁-C₆ alkyl, C₂-C₆ alkenyl, amino, or imino group optionally substituted with a hydroxy group, a C₁-C₆ alkoxy group, or an amino, thioether, heterocycloalkyl, aryl, or heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of oxygen, halogen, trifluoromethyl, and carboxyl groups, or where —

NR⁶R⁷ forms a 5- or 6-membered heterocyclic ring optionally containing, in addition to the nitrogen heteroatom, a heteroatom selected from the group consisting of O, N, and S;

—

(CH₂)_n—

O—

R″

, where n is 1 or 2, and R″

is hydrogen, a C₅-C₇heteroaryl group, or

 

where R⁸ is hydrogen, a C₁-C₆ alkyl group, a C₃-C₆ cycloalkyl group, or a 5- or 6-membered heteroaryl group optionally substituted with one or more substituents independently selected from the group consisting of halogens, methyl, and trifluoromethyl;

(CH₂)_p—

N(R″

)(R′

″

), where p is 1 or 2, R″

is as defined above, and R′

″

is hydrogen or an alkyl or alkoxy group optionally substituted with a C₃-C₆ cycloalkyl group optionally substituted with cyano;

—

CH═

N—

R″

″

, where R″

″

is hydrogen, a hydroxy group, or —

OR⁹, where R⁹ is an alkyl, cycloalkyl, aryl, or heteroaryl group;

or

a 5- or 6-membered heterocyclic ring containing one to three heteroatoms independently selected from the group consisting of O, N, and S, the ring being optionally substituted with one or two substituents independently selected from the group consisting of methyl, methoxymethyl, oxygen, and C₁-C₆ alkoxy groups;

R³ is hydrogen or a C₁-C₆ alkyl, C₂-C₆ alkenyl, or (C₁-C₃ alkoxy)C₁-C₃ alkyl group;

or R² and R³ together with the atoms to which they are bound form a 5- or 6-membered ring containing one or two heteroatoms selected from the group consisting of O, N, and S, the ring being optionally substituted with oxygen, hydroxyl, or a C₁-C₆ alkyl group optionally substituted with a 5- or 6-membered heterocycloalkyl containing one or two heteroatoms independently selected from the group consisting of O, N, and S; and

R⁴ is hydrogen or an amino, halogen, hydroxyl, nitro, trifluoromethyl, cyano, C₁-C₆ alkyl, or C₂-C₆ alkenyl group;

pharmaceutically acceptable salt, or pharmaceutically acceptable solvate of said compound;

wherein said compound, pharmaceutically acceptable salt or pharmaceutically acceptable solvate is a GLP-1 receptor antagonist having an IC₅₀ binding affinity of less than 1 μ

M.

16. A pharmaceutical composition comprising an effective amount of a GLP-1 receptor antagonist according to claim 15 and a pharmaceutically acceptable carrier.

17. A method of inhibiting activation of the GLP-1 receptor comprising administering to a patient an effective amount of a GLP-1 receptor antagonist according to claim 15.

18. A compound selected from the group consisting of: