Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists

• US 20030055085A1
• Filed: 02/19/2002
• Published: 03/20/2003
• Est. Priority Date: 08/19/1999
• Status: Active Grant

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC), NPS Pharmaceuticals Incorporated (Shire plc)
• Inventors: Slassi, Abdelmalik, Stormann, Thomas M., McLeod, Donald A., Wagenen, Bradford Van, Moe, Scott T., Smith, Daryl L., Sheehan, Susan M., Isaac, Methvin Benjamin
• Granted Patent: US 6,660,753 B2
• Time in Patent Office: Days
• US Class Current: 514/333
• CPC Class Codes: C07D 213/55 Acids; Esters
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 213/78 Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 213/79 Acids; Esters
• 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 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond

Abstract

The present invention provides compounds and pharmaceutical compositions that act as antagonists at metabotropic glutamate receptors, and that are useful for treating neurological diseases and disorders. Methods of preparing the compounds also are disclosed.

Claims

1. A compound of formula 1, or a pharmaceutically acceptable salt thereof:

2. A compound of claim 1 wherein a represents double bond.

3. A compound of claim 2 wherein X is N, Y is N, and Z is O.

4. A compound of claim 3 wherein Ar₁ is optionally substituted pyridyl.

5. A compound of claim 4 wherein Ar₁ is optionally substituted 2-pyridyl.

6. A compound as defined in claim 3 wherein the substituent G is bonded to Ar₂ and not Ar₁.

7. A compound as defined in claim 6 wherein Ar₂ is selected from the group consisting of:

5 member aryl;

6 member aryl;

5-member heteroaryl; and

6 member heteroaryl.

8. A compound of claim 7 wherein Ar₂ is selected from the group consisting of:

6 member aryl and 6 member heteroaryl.

9. A compound of claim 8 wherein Ar₂ is selected from the group consisting of:

pyridyl and phenyl, wherein Ar₂ is further substituted with one or more substituents selected from the group consisting of R₂ and R₄.

10. A compound of claim 9 wherein Ar₂ is phenyl.

11. A compound of claim 9 wherein Ar₂ is pyridyl.

12. A compound as defined in claim 9 wherein G is heteroaryl and wherein G is further substituted with one or more substitutents selected from the group consisting of R₂, R₃, and R₄.

13. A compound as defined in claim 12 wherein G is selected from the group consisting of:

pyridyl;

thiophene;

pyrimidine; and

furan and G is further substituted with one or more substituents selected from the group consisting of R₂ and R₄.

14. A compound as defined in claim 13 wherein G is selected from the group consisting of 2-pyridine, 3-pyridine and 4-pyridine, wherein G is further substituted with one or more substituents selected from the group consisting of R₂ and R₄.

15. A compound as defined in claim 14 wherein G is 3-pyridine.

16. A compound as defined in claim 13 wherein G is 3-thiophene.

17. A compound as defined in claim 13 wherein G is pyrimidine.

18. A compound as defined in claim 13 wherein G is furan.

19. A compound as defined in claim 9 wherein G is substituted aryl, wherein the substituent is R₄.

20. A compound as defined in claim 19 wherein G is substituted phenyl.

21. A compound as defined in claim 20 wherein G is substituted phenyl and R₄ is selected from the group consisting of halo, NR₂R₃, CN, and alkoxy.

22. A compound of claim 9 wherein G is (CH₂)_m—

NR₂R₃ and m is selected from 0 and 1 and R₂ and R₃ may be independently selected from the group consisting of;

H;

alkyl;

haloalkyl;

alkyloxy;

alkylamine;

cycloalkyl;

heterocycloalkyl;

aryl;

heteroaryl;

alkylaryl;

alkylheteroaryl;

haloaryl;

alkyloxyaryl;

alkenylaryl;

alkenyloxyaryl; and

haloheteroaryl.

23. A compound as defined in claim 22 wherein R₂ and R₃ are independently selected from H and C_1-3 alkyl.

24. A compound of claim 9 wherein G is alkenyl.

25. A compound as defined in claim 24 wherein G is selected from the group consisting of:

—

CH₂═

CH₂ and —

CH(CH₃)═

CH₂.

26. A compound as defined in claim 9 wherein G is alkynyl.

27. A compound of claim 9 wherein G is selected from the group consisting of A-alkenyl and A-alkynyl.

28. A compound as defined in claim 27 wherein A is O.

29. A compound as defined in claim 28 wherein G is —

O—

CH2CH═

CH2.

30. A compound as defined in claim 9 wherein G is —

OCH₂CH(Cl)CH₂Cl.

31. A compound as defined in claim 9 wherein G is selected from the group consisting of alkyloxy and A-alkyloxy.

32. A compound as defined in claim 31 wherein G is —

CH₂CH₂OH.

33. A compound as defined in claim 9 wherein G is —

CH₂OC(O)H.

34. A compound as defined in claim 9 wherein G is haloalkyl.

35. A compound as defined in claim 9 wherein G is cycloalkenyl.

36. A compound selected from the group consisting of compounds set forth in Table 2, or a pharmaceutically acceptable salt thereof.

37. A compound as defined in claim 36 wherein the compound is selected from the group consisting of:

3-(5-Methyl-pyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole (B57),

3-(5-Cyano-pyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole (B58),

3-(2-Pyridyl)-5-(5-bromo-2-methoxyphenyl)-1,2,4-oxadiazole (B62),

3-(2-Pyridyl)-5-(5-bromo-2-fluorophenyl)-1,2,4-oxadiazole (B63),

3-(2-Pyridyl)-5-(5-cyano-2-fluorophenyl)-1,2,4-oxadiazole (B64),

3-(2-Pyridyl)-5-(5-bromopyrid-3-yl)-1,2,4-oxadiazole (B65),

3-(2-Pyridyl)-5-(5-chloro-pyrid-3-yl)-1,2,4-oxadiazole (B66),

3-(5-Cyanopyrid-2-yl)-5-(5-bromo-pyrid-3-yl)-1,2,4-oxadiazole (B67),

3-(5-Fluoropyrid-2-yl)-5-(5-bromo-pyrid-3-yl-1,2,4-oxadiazole (B68),

3-(2-Pyridyl)-5-(2-thiomethoxy-pyrid-3-yl)]-1,2,4-oxadiazole (B69),

3-(2-Pyridyl)-5-(5-methylpyrid-3-yl)-1,2,4-oxadiazole (B70),

3-(2-Pyridyl)-5-(5-methoxypyrid-3-yl)-1,2,4-oxadiazole (B72),

3-(2-Pyridyl)-5-(3-cyano-5-methylphenyl)-1,2,4-oxadiazole (B73),

3-(2-Pyridyl)-5-(3-fluoro-5-bromophenyl)-1,2,4-oxadiazole (B74),

3-(2-Pyridyl)-5-(3-iodo-5-bromophenyl)-1,2,4-oxadiazole (B75),

3-(5-Fluoro-2-pyridyl)-5-(3-fluoro-5-bromophenyl)-1,2,4-oxadiazole (B76),

3-(2-Pyridyl)-5-(3-iodo-5-(methylphenylester)-1,2,4-oxadiazole (B78),

3-(2-Pyridyl)-5-(3-methoxy-5-(methoxycarbonyl)phenyl)-1,2,4-oxadiazole (B79),

3-(2-Pyridyl)-5-(3-bromo-5-cyanophenyl)-1,2,4-oxadiazole (B80),

3-(2-Pyridyl)-5-(5-cyano-3-iodophenyl)-1,2,4-oxadiazole (B81),

3-(5-Cyano-2-pyridyl)-5-(3-bromophenyl)-1,2,4-oxadiazole (B59),

3-(5-Cyano-2-pyridyl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole (B60),

3-(5-Cyano-2-pyridyl)-5-(3-bromo-5-fluorophenyl)-1,2,4-oxadiazole (B61),

3-(2-Pyridyl)-5-(5-cyano-2-methoxyphenyl)-1,2,4-oxadiazole (B97),

3-(2-Pyridyl)-5-(2-cyano-5-methoxyphenyl)-1,2,4-oxadiazole (B98),

3-(2-Pyridyl)-5-(5-cyano-pyrid-3-yl)-1,2,4-oxadiazole (B99),

3-(2-Pyridyl)-5-(3-cyano-5-(methoxycarbonyl)phenyl)-1,2,4-oxadiazole (B100),

3-(2-Pyridyl)-5-(5-phenyl-pyrid-3-yl)-1,2,4-oxadiazole (B118),

3-(2-Pyridyl)-5-(3-cyano-5-methoxyphenyl)-1,2,4-oxadiazole (B134),

3-(2-Pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (B137),

3-(2-Pyridyl)-5-(3-cyano-5-propoxyphenyl)-1,2,4-oxadiazole (B141),

2-(3-Cyanophenyl)-4-(pyridin-2-yl)-1,3-thiazole (B146),

2-(3-Bromo-5-iodophenyl)-4-pyridin-2-yl)-1,3-oxazole (B147),

2-(2-Pyridyl)-5-(3-iodophenyl)-1,3,4-oxadiazole (B148),

2-(2-Pyridyl)-5-(3-cyanophenyl)-1,3,4-oxadiazole (B149),

2-(2-Pyridyl)-5-(3-cyanophenyl)-1,3,4-triazole (B150),

3-(5-Chloropyrid-2-yl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole (B83),

3-(5-Chloropyrid-2-yl)-5-(3-cyano-5-chlorophenyl)-1,2,4-oxadiazole (B84),

3-(5-Chloropyrid-2-yl)-5-(3-chloro-5-fluorophenyl)-1,2,4-oxadiazole (B85),

3-(5-Chloropyrid-2-yl)-5-(3-cyano-5-methoxyphenyl)-1,2,4-oxadiazole (B86),

3-(5-Fluoropyrid-2-yl)-5-(3-cyano-5-chlorophenyl)-1,2,4-oxadiazole (B87),

3-(5-Fluoropyrid-2-yl)-5-(3-fluoro-5-chlorophenyl)-1,2,4-oxadiazole (B88),

3-(5-Fluoropyrid-2-yl)-5-(3-cyano-5-methoxyphenyl)-1,2,4-oxadiazole (B89),

3-(5-Cyanopyrid-2-yl)-5-(3-cyano-5-chlorophenyl)-1,2,4-oxadiazole (B90),

3-(5-Cyanopyrid-2-yl)-5-(3-fluoro-5-chlorophenyl)-1,2,4-oxadiazole (B91)

3-(5-Cyanopyrid-2-yl)-5-(3-cyano-5-methoxyphenyl)-1,2,4-oxadiazole (B92),

3-(5-Fluoropyrid-2-yl)-5-(3,5-di-cyanophenyl)-1,2,4-oxadiazole (B93),

3-(3-(4-Dimethylaminobutoxy)-pyrid-2-yl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole (B94),

3-(3-(5-Dimethylaminopentyloxy)-pyrid-2-yl)-5-(3-Cyano-5-fluorophenyl)-1,2,4-oxadiazole (B95), and

[3-(3-(6-Dimethylaminohexyloxy)-pyrid-2-yl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole (B96).

38. A compound as defined in claim 36 wherein the compound is selected from the group consisting of:

3-(2-Pyridyl)-5-(3-allyloxy-5-(methoxycarbonyl)phenyl)-1,2,4-oxadiazole (B77),

3-(2-Pyridyl)-5-(3-N,N-dimethylaminophenyl)-1,2,4-oxadiazole (B82),

3-(2-Pyridyl)-5-(3-cyano-5-(4-pyridyl)phenyl)-1,2,4-oxadiazole (B101),

3-(2-Pyridyl)-5-[2-methoxy-5-(4-pyridyl)phenyl]-1,2,4-oxadiazole (B102),

3-(2-pyridyl)-5-[2-fluoro-5-(4-pyridyl)phenyl]-1,2,4-oxadiazole (B103),

3-(2-Pyridyl)-5-(3-fluoro-5-(4-pyridyl)phenyl)-1,2,4-oxadiazole (B104),

3-(2-Pyridyl)-5-(3-fluoro-5-(3-pyridyl)phenyl)-1,2,4-oxadiazole (B105),

3-(2-Pyridyl)-5-[2-fluoro-5-(3-pyridyl)phenyl]-1,2,4-oxadiazole (B106),

3-(2-Pyridyl)-5-[2-methoxy-5-(3-pyridyl)phenyl]-1,2,4-oxadiazole (B107),

3-(2-Pyridyl)-5-(3-cyano-5-(3-pyridyl)phenyl)-1,2,4-oxadiazole (B108),

3-(5-Fluoro-2-pyridyl)-5-(3-fluoro-5-(3-pyridyl)phenyl)-1,2,4-oxadiazole (B109),

3-(2-Pyridyl)-5-[5-(3-pyridyl-pyrid-3-yl)]-]-1,2,4-oxadiazole (B111),

3-(5-Fluoropyrid-2-yl)]-5-[5-(3-pyridyl-pyrid-3-yl)]-]-1,2,4-oxadiazole (B110),

3-(5-Cyanopyrid-2-yl)-5-(3-(pyrid-3-yl)phenyl)-1,2,4-oxadiazole (B112),

3-(5-Cyanopyrid-2-yl)-5-(3-fluoro-5-(pyrid-3-yl)phenyl)-1,2,4-oxadiazole (B113),

3-(2-Pyridyl)-5-(3-cyano-5-(2-pyridyl)phenyl)-1,2,4-oxadiazole (B124),

3-(2-Pyridyl)-5-[2-methoxy-5-(2-pyridyl)phenyl]-1,2,4-oxadiazole (B125),

3-(2-Pyridyl)-5-[2-fluoro-5-(2-pyridyl)phenyl]-1,2,4-oxadiazole (B126),

3-(2-Pyridyl)-5-[(3-(3-fuorophenyl)-5-fluorophenyl)]-1,2,4-oxadiazole

(B114),

3-(2-Pyridyl)-5-(3-cyano-5-(3-thiophene)phenyl)-1,2,4-oxadiazole (B115),

3-(2-Pyridyl)-5-[5-(3-thienyl)-pyrid-3-yl]-1,2,4-oxadiazole (B116),

3-(2-Pyridyl)-5-[5-(3-furyl)-pyrid-3-yl]-1,2,4-oxadiazole (B117),

3-(2-Pyridyl)-5-[5-(3-methoxyphenyl)-pyrid-3-yl]-1,2,4-oxadiazole (B119),

3-(2-Pyridyl)-5-(3-cyano-5-(5-pyrimidyl)phenyl)-1,2,4-oxadiazole (B120),

3-(2-Pyridyl)-5-(3-cyano-5-(3-aminophenyl)phenyl)-1,2,4-oxadiazole (B121),

3-(2-Pyridyl)-5-(3-cyano-5-(3-fluorophenyl) phenyl)-1,2,4-oxadiazole (B122),

3-(2-Pyridyl)-5-[5-(5-pyrimidyl)-pyrid-3-yl]-1,2,4-oxadiazole (B123),

3-(2-Pyridyl)-5-(3-aminomethyl-5-cyanophenyl)-1,2,4-oxadiazole (B127),

3-(2-Pyridyl)-5-[5[(2-propenyl)-pyrid-3-yl]-1,2,4-oxadiazole (B128),

3-(2-Pyridyl)-5-(3-cyano-5-vinylphenyl)-1,2,4-oxadiazole (B129),

3-(2-Pyridyl)-5-(3-cyano-5-(2-hydroxyethyl)phenyl)-1,2,4-oxadiazole (B130),

3-(2-Pyridyl)-5-(3-cyano-5-(2,3-dichloropropoxy)phenyl)-1,2,4-oxadiazole (B131),

3-(2-Pyridyl)-5-(3-allyloxy-5-carboxyphenyl)-1,2,4-oxadiazole (B135),

3-(2-Pyridyl)-5-(3-allyloxy-5-cyanophenyl)-1,2,4-oxadiazole (B136),

3-(2-Pyridyl)-5-(5-cyano-3-[3-hydroxypropyn-1-yl] phenyl)-1,2,4-oxadiazole (B142),

3-(2-Pyridyl)-5-(2-N-methylaminophenyl)-1,2,4-oxadiazole (B144), and

3-(2-Pyridyl)-5-[5-(3-N-benzyl-1,2,5,6,tetrahydropyridine)-pyrid-3-yl]-1,2,4-oxadiazole (B143).

39. A compound of Formula I, or a pharmaceutically acceptable salt thereof:

40. A compound as defined in claim 39 wherein represents a double bond.

41. The compound of claim 40, wherein X is N, Y is N, and Z is O.

42. The compound of claim 41 wherein Ar₁ is 2-pyridyl and Ar₂ is phenyl.

43. The compound of claim 42, wherein G is selected from the group consisting of —

OCH₃, —

CF₃, —

Cl, —

F, —

Br, —

CH₃, —

NO₂, —

OCF₃, —

SCH₃, and —

CN.

44. The compound of claim 42, wherein Ar₁ is 2-pyridyl and substituted with one or more G, wherein G is selected from the group consisting of —

OCH₃, —

CF₃, —

F, and —

Cl.

45. The compound of claim 41, wherein Ar¹ is 2-pyridyl and Ar² is 1-naphthyl.

46. The compound of claim 39, wherein X is N, Y is C, and Z is O.

47. The compound of claim 46, wherein Ar¹ is 2-pyridyl and is substituted with one or more G selected from the group consisting of —

OCH₃, —

CF₃, —

F, and —

Cl, and wherein Ar² is phenyl and is substituted with one or more G selected from the group consisting of —

OCH₃, —

CF₃, —

Cl, —

F, —

Br, —

CH₃, —

NO₂, —

OCF₃, —

SCH₃, and —

CN.

57. A pharmaceutical composition comprising a therapeutically effective, non-toxic, amount of a compound of claim 39 and a pharmaceutically acceptable carrier.

58. A method for treating a disease associated with Group I mGluR activation comprising the step of administering to a patient in need of such treatment a pharmaceutical composition as defined in claim 57.

59. A method according to claim 58 wherein the disease is a disease associated with mGluR activation.

60. A method according to claim 59 wherein the disease is a neurological disease.

61. A method according to claim 59 wherein the disease is a psychiatric disease.

62. A method according to claim 59 wherein the disease is selected from the group consisting of stroke, head trauma, anoxic injury, ischemic injury, hypoglycemia, epilepsy, pain, migraine headaches, Parkinson'"'"'s disease, senile dementia, Huntington'"'"'s Chorea, anxiety, and Alzheimer'"'"'s disease.

63. A method according to claim 59 wherein the disease is selected from the group consisting of schizophrenia and depression.

48. A compound selected from the group consisting of compounds set forth in Table 1, or a pharmaceutically acceptable salt thereof, where the compound is not compound B4.

49. A compound as defined in claim 48, wherein the compound is selected from the group consisting of:

3-(2-pyridyl)-5-(3-methoxyphenyl)-1,2,4-oxadiazole (B1),

3-(2-pyridyl)-5-(3,5-dichlorophenyl)-1,2,4-oxadiazole (B2),

3-(2-pyridyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole (B3),

3-(2-pyridyl)-5-(2-chlorophenyl)-1,2,4-oxadiazole (B5),

3-(2-pyridyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (B6),

3-(2-pyridyl)-5-(3-methylphenyl)-1,2,4-oxadiazole (B9),

3-(2-pyridyl)-5-(1-naphthyl)-1,2,4-oxadiazole (B10),

3-(2-pyridyl)-5-[3-(trifluoromethoxy)phenyl]-1,2,4-oxadiazole (B11),

3-(2-pyridyl)-5-(2,3-difluorophenyl)-1,2,4-oxadiazole (B16),

3-(2-pyridyl)-5-(2,5-difluorophenyl)-1,2,4-oxadiazole (B17),

3-(2-pyridyl)-5-(3,5-difluorophenyl)-1,2,4-oxadiazole (B18),

3-(2-pyridyl)-5-(3-nitrophenyl)-1,2,4-oxadiazole (B19),

3-(2-pyridyl)-5-(3-cyanophenyl)-1,2,4-oxadiazole (B21),

3-(2-pyridyl)-5-(3-bromophenyl)-1,2,4-oxadiazole (B22),

3-(2-pyridyl)-5-(3,5-dimethoxyphenyl)-1,2,4-oxadiazol (B23),

3-(2-pyridyl)-5-(2,3-dichlorophenyl)-1,2,4-oxadiazole (B25),

3-(2-pyridyl)-5-(3-chloro-5-cyanophenyl)-1,2,4-oxadiazole (B26),

3-(2-pyridyl)-5-(3-fluoro-5-cyanophenyl)-1,2,4-oxadiazole (B27),

3-(2-pyridyl)-5-(3-chloro-5-fluorophenyl)-1,2,4-oxadiazole (B28),

3-(5-chloropyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole (B29)

3-(5-fluoropyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole (B30),

3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole (B31),

3-(3-fluoropyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole (B32),

3-(5-fluoropyrid-2-yl)-5-(3,5-dimethoxyphenyl)-1,2,4-oxadiazole (B33),

3-(5-methoxypyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole (B34),

3-(2-quinolinyl)-5-(3-cyanophenyl)-1,2,4-oxadiazole (B35),

3-(3-chloro-5-trifluoromethylpyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole (B36),

3-(2-pyridyl)-5-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazole (B37),

3-(2-pyridyl)-5-(2-chloro-5-methylthiophenyl)-1,2,4-oxadiazole (B39),

3-(2-pyridyl)-5-(2-bromo-5-methoxyphenyl)-1,2,4-oxadiazole (B42),

3-(2-pyridyl)-5-(2,5,6-trifluorophenyl)-1,2,4-oxadiazole (B45),

2-(3-chlorophenyl)-4-(2-pyridyl)-1,3-oxazole (B50),

2-(3-bromophenyl)-4-(2-pyridyl)-1,3-oxazole (B51), and

2-(3-cyanophenyl)-4-(2-pyridyl)-1,3-oxazole (B52).

50. A compound selected from the group consisting of:

2-(3,5-dichlorophenyl)-4-(2-pyridyl)-1,3-oxazole,

2-(3-methoxyphenyl)-4-(2-pyridyl)-1,3-oxazole,

2-(2-chlorophenyl)-4-(2-pyridyl)-1,3-oxazole,

2-(3-trifluorophenyl)-4-(2-pyridyl)-1,3-oxazole,

2-(3-methylphenyl)-4-(2-pyridyl)-1,3-oxazole,

2-(1-naphthyl)-4-(2-pyridyl)-1,3-oxazole,

2-(3-trifluoromethoxyphenyl)-4-(2-pyridyl)-1,3-oxazole,

2-(2,3-difluorophenyl)-4-(2-pyridyl)-1,3-oxazole,

2-(2,5-difluorophenyl)-4-(2-pyridyl)-1,3-oxazole,

2-(3,5-difluorophenyl)-4-(2-pyridyl)-1,3-oxazole,

2-(3,5-dimethoxyphenyl)-4-(2-pyridyl)-1,3-oxazole,

2-(2,3-dichlorophenyl)-4-(2-pyridyl)-1,3-oxazole,

2-(3-chloro-5-cyanophenyl)-4-(2-pyridyl)-1,3-oxazole,

2-(3-fluoro-5-cyanophenyl)-4-(2-pyridyl)-1,3-oxazole,

2-(3-chloro-5-fluorophenyl)-4-(2-pyridyl)-1,3-oxazole,

2-(3-cyanophenyl)-4-(5-chloropyrid-2-yl)-1,3-oxazole,

2-(3-cyanophenyl)-4-(5-fluoropyrid-2-yl)-1,3-oxazole,

2-(3-cyano-5-fluorophenyl)-4-(5-fluoropyrid-2-yl)-1,3-oxazole,

2-(3-cyanophenyl)-4-(3-fluoropyrid-2-yl)-1,3-oxazole,

2-(3,5-dimethoxyphenyl)-4-(5-floropyrid-2-yl)-1,3-oxazole,

2-(3-cyanophenyl)-4-(5-methoxypyrid-2-yl)-1,3-oxazole,

2-(3-cyanophenyl)-4-(2-quinolinyl)-1,3-oxazole,

2-(3-cyanophenyl)-4-(3-chloro-5-trifluoromethylpyrid-2-yl)-1,3-oxazole,

2-(5-chloro-2-methoxyphenyl)-4-(2-pyridyl)-1,3-oxazole,

2-(2-chloro-5-methylthiophenyl)-4-(2-pyridyl)-1,3-oxazole,

2-(2-bromo-5-methoxyphenyl)-4-(2-pyridyl)-1,3-oxazole,

2-(2,5,6-trifluorophenyl)-4-(2-pyridyl)-1,3-oxazole,

2-[3-chlorophenyl]-4-[pyridin-2-yl]-1,3-oxazole,

2-(2,5,6-trifluorophenyl)-4-(2-pyridyl)-1,3-oxazole,

2-(3-nitrophenyl)-4-(2-pyridyl-1,3-oxazole, and pharmaceutically acceptable salts thereof.

51. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective, non-toxic, amount of a compound of Formula I:

thereof;

wherein

represents a double or single bond;

X, Y, and Z are independently selected from the group consisting of;

N;

O;

S; and

CR₁ and at least one of X, Y, and Z is a heteroatom;

wherein

R₁ is selected from the group consisting of;

H;

alkyl;

—

CF₃;

—

OR₂;

—

—

SR₂;

—

NR₂R₃;

═

O;

═

S;

═

NR₂; and

═

CR₂R₃; and

wherein

R₂ and R₃ may be independently selected from the group consisting of;

H;

alkyl;

haloalkyl;

alkyloxy;

alkylamine;

cycloalkyl;

heterocycloalkyl;

aryl;

heteroaryl;

alkylaryl;

alkylheteroaryl;

haloaryl;

alkyloxyaryl;

alkenylaryl;

alkenyloxyaryl; and

haloheteroaryl; and

Ar₁ and Ar₂ are independently selected from the group consisting of;

aryl and heteroaryl and at least one of Ar₁ and Ar₂ is substituted with at least one substituent G;

wherein

G is selected from the group consisting of;

haloalkyl;

heteroaryl;

cycloalkene;

alkenyl;

alkynyl;

A-alkenyl;

A-alkynyl;

alkyloxy;

A-alkyloxy;

—

R₂OR₃;

—

R₂OC(O)R₃;

(CH₂)_m—

NR₂R₃;

—

OCH₂CH(Cl)CH₂Cl;

and substituted aryl wherein the aryl substituent is R₄, and

wherein

A is a linker selected from the group consisting of;

CH₂;

O;

NH;

S;

SO;

SO_2;

NSO_2;

—

OSO₂; and

—

C(NR₂)NR₃;

m is selected from 0 and 1; and

R₄ is selected from the group consisting of;

halo;

—

OR₂;

—

SR₂;

—

SOR₂;

—

SO₂R₂;

—

SO₂NR₂R₃;

—

R₂OR₃;

—

R₂SR₃;

—

OCOR₂;

—

—

OCONR₂R₃;

—

NR₂COR₃;

—

NR₂CO₂R₃;

—

CN;

—

NO₂;

—

C(NR₂)NR₃;

—

CO₂R₂R₃;

—

CONR₂R₃;

—

C(O)R₂;

—

CH(OR₂)R₃;

—

CH₂(OR₂);

—

A—

(CH₂)_m—

NR₂R₃;

NR₂R₃;

aryl;

aralkyl;

heteroaryl; and

heteroaralkyl; and

Ar₁, Ar₂, and the substituent G are optionally further substituted with one or more substituents selected independently from the group consisting of R₂ and R₄,

with the proviso that when represents a double bond, then either of Ar₁ or Ar₂ is pyridyl and the compound is not;

3-(2-Pyridyl)-5-(2-chlorophenyl)-1,2,4-oxadiazole,

3-(4-Pyridyl)-5-(2-chlorophenyl)-1,2,4-oxadiazole,

3-(4-Pyridyl)-5-(2-chlorophenyl)-1,2,4-oxadiazole,

3-(4-Pyridyl)-5-(4-chlorophenyl)-1,2,4-oxadiazole,

3-(2-chlorophenyl)-5-(4-pyridyl)-1,2,4-oxadiazole,

3-(2-ethoxyphenyl)-5-(3-pyridyl)-1,2,4-oxadiazole,

3-styryl-5-(4-pyridyl)-1,2,4-oxadiazole, 3-(3-Pyridyl)-5-(4-aminophenyl)-1,2,4-oxadiazole,

3-(3-Pyridyl)-5-(4-chlorophenoxymethyl)-1,2,4-oxadiazole,

3-(4-Pyridyl)-5-(4-chlorophenoxymethyl)-1,2,4-oxadiazole,

3-(4-Pyridyl)-5-(3-pyridyl)-1,2,4-oxadiazole,

3-(4-Pyridyl)-5-(4-pyridyl)-1,2,4-oxadiazole,

3-(2-ethyl-4-pyridyl)-5-(2-hydroxyphenyl)-1,2,4-oxadiazole,

3-(2-ethyl-4-pyridyl)-5-(4-pyridyl)-1,2,4-oxadiazole,

3-(2-ethyl-4-pyridyl)-5-(2-ethyl-4-pyridyl)-1,2,4-oxadiazole,

3-(2-ethyl-4-pyridyl)-5-(4-chlorophenylmethyl)-1,2,4-oxadiazole,

3-(2-pyridyl)-5-(4-nitrophenyl)-1,2,4-oxadiazole,

3-(2-pyridyl)-5-(4-aminophenyl)-1,2,4-oxadiazole,

3-(3-pyridyl)-5-(4-nitrophenyl)-1,2,4-oxadiazole,

3-(3-pyridyl)-5-(4-aminophenyl)-1,2,4-oxadiazole,

3-(2-pyridyl)-5-{2-[2-(N,N,dimethylamino)-ethyl]oxyphenyl}-1,2,4-oxadiazole,

3-(4-pyridyl)-5-{2-[2-(N,N,dimethylamino)-ethyl]oxyphenyl}-1,2,4-oxadiazole2-(2-pyridyl)-5-[3-(3-methoxy-4-cyclopentoxy)phenyl]-furan,

2-(3-pyridyl)-5-[3-(3-methoxy-4-cyclopentoxy)phenyl]-furan, or

2-(4-pyridyl)-5-[3-(3-methoxy-4-cyclopentoxyphenyl)]-furan.

52. A method for treating a disease associated with Group I mGluR activation comprising the step of administering to a patient in need of such treatment a pharmaceutical composition as defined in claim 51.

53. A method according to claim 52 wherein the disease is a disease associated with mGluR activation.

54. A method according to claim 53 wherein the disease is a neurological disease.

55. A method according to claim 53 wherein the disease is a psychiatric disease.

56. A method according to claim 53 wherein the disease is selected from the group consisting of stroke, head trauma, anoxic injury, ischemic injury, hypoglycemia, epilepsy, pain, migraine headaches, Parkinson'"'"'s disease, senile dementia, Huntington'"'"'s Chorea, anxiety, and Alzheimer'"'"'s disease.

64. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of compounds as set forth in the following table:

65. A compound of formula II, or a pharmaceutically acceptable salt thereof:

66. A compound as defined in claim 65 wherein represents a double bond.

67. A compound as defined in claim 66 wherein X₂ is N and Y₂ is N.

68. A compound as defined in claim 67 wherein Ar₃ and Ar₄ are independently selected from the group consisting of optionally substituted pyridyl and optionally substituted phenyl wherein Ar₃ and Ar₄ are optionally substituted with a substituent selected from G₂, R₆, and R₈.

69. A compound as defined in claim 68 wherein Ar₃ and Ar₄ are independently selected from the group consisting of 2-pyridyl, and optionally substituted phenyl wherein the substituent is selected from the group consisting of:

aryl;

heteroaryl;

alkyl;

halo, cyano, nitro, hydroxy, and alkoxy.

71. A pharmaceutical composition comprising a therapeutically effective, non-toxic, amount of a compound of claim 65 and a pharmaceutically acceptable carrier.

72. A method for treating a disease associated with Group I mGluR acctivation comprising the step of administering to a patient in need of such treatment a pharmaceutical composition as defined in claim 71.

73. A method according to claim 72 wherein the disease is a disease associated with mGluR activation.

74. A method according to claim 73 wherein the disease is a neurological disease.

75. A method according to claim 73 wherein the disease is a psychiatric disease.

76. A method according to claim 73 wherein the disease is selected from the group consisting of stroke, head trauma, anoxic injury, ischemic injury, hypoglycemia, epilepsy, pain, migraine headaches, Parkinson'"'"'s disease, senile dementia, Huntington'"'"'s Chorea, anxiety, and Alzheimer'"'"'s disease.

70. A compound selected from the group consisting of:

4-(3-Cyanophenyl)-1-(2-pyridyl)-1H-imidazole (B151) and

1-(3-Cyanophenyl)-4-(2-pyridyl)-1H-imidazole (B152).

77. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective, non-toxic, amount of a compound of Formula I:

78. A method for treating a disease associated with Group I mGluR activation comprising the step of administering to a patient in need of such treatment a pharmaceutical composition as defined in claim 77.

79. A method according to claim 78 wherein the disease is a disease associated with mGluR activation.

80. A method according to claim 79 wherein the disease is a neurological disease.

81. A method according to claim 79 wherein the disease is a psychiatric disease.

82. A method according to claim 79 wherein the disease is selected from the group consisting of stroke, head trauma, anoxic injury, ischemic injury, hypoglycemia, epilepsy, pain, migraine headaches, Parkinson'"'"'s disease, senile dementia, Huntington'"'"'s Chorea, anxiety, and Alzheimer'"'"'s disease.