Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists

• US 6,660,753 B2
• Filed: 02/19/2002
• Issued: 12/09/2003
• Est. Priority Date: 08/19/1999
• Status: Expired due to Fees

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: NPS Pharmaceuticals Incorporated (Shire plc)
• Inventors: Van Wagenen, Bradford, McLeod, Donald A., Smith, Daryl L., Sheehan, Susan M., Slassi, Abdelmalik, Stormann, Thomas M., Moe, Scott T., Isaac, Methvin Benjamin
• Primary Examiner(s): NORTHINGTON DAVIS, ZINNA
• Application Number:
  US10/076,618
• Publication Number:
  US 20030055085A1
• Time in Patent Office: 658 Days
• Field of Search: 546/269.1, 514/340
• US Class Current: 514/340
• 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 I, or a pharmaceutically acceptable salt thereof:

wherein

---- represents a double or single bond;

X and Y are N;

Z is O;

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

optionally substituted phenyl and optionally substituted 2-pyridyl wherein at least one of Ar₁ and Ar₂ is phenyl and at least one of Ar₁ and Ar₂ is 2-pyridyl 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;

pyridyl;

thiophene;

pyrimidine;

furan;

cycloalkene;

alkenyl;

alkynyl;

A-alkenyl;

A-alkynyl;

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;

SO₂;

NSO₂;

—

OSO₂; and

—

C(NR₂)NR₃;

m is selected from 0 and 1;

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

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-(4-aminophenyl)-1,2,4-oxadiazole,

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

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

3-(2-pyridyl)-5-phenyl-1,2,4-oxadiazole.

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

3. A compound of claim 1 wherein Ar₁ is optionally substituted 2-pyridyl.

4. A compound as defined in claim 2 wherein the substituent G is bonded to Ar₂ and not Ar₁.

5. A compound of claim 4 wherein Ar₂ is further substituted with one or more substituents selected from the group consisting of R₂ and R₄.

6. A compound of claim 5 wherein Ar₂ is phenyl.

7. A compound of claim 5 wherein Ar₂ is 2-pyridyl.

8. A compound as defined in claim 5 wherein G is selected from the group consisting of:

pyridyl;

thiophene;

pyrimidine; and

furan, and wherein G is further substituted with one or more substituents selected from the group consisting of R₂, R₃, and R₄.

9. A compound as defined in claim 8 wherein G is selected from the group consisting of 2-pyridine, 3-pyridine and 4-pyridine.

10. A compound as defined in claim 9 wherein G is 3-pyridine.

11. A compound as defined in claim 8 wherein G is 3-thiophene.

12. A compound as defined in claim 8 wherein G is pyrimidine.

13. A compound as defined in claim 8 wherein G is furan.

14. A compound as defined in claim 8 wherein G is substituted aryl, wherein the substituent is R₄.

15. A compound as defined in claim 14 wherein G is substituted phenyl.

16. A compound as defined in claim 15 wherein G is substituted phenyl and R₄ is selected from the group consisting of halo, NR₂R₃, and CN.

17. A compound of claim 5 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.

18. A compound as defined in claim 17 wherein R₂ and R₃ are independently selected from H and C_1-3 alkyl.

19. A compound of claim 5 wherein G is alkenyl.

20. A compound as defined in claim 19 wherein G is selected from the group consisting of:

—

CH₂═

CH₂ and —

CH(CH₃)═

CH₂.

21. A compound as defined in claim 5 wherein G is alkynyl.

22. A compound of claim 5 wherein G is selected from the group consisting of A-alkenyl and A-alkynyl.

23. A compound as defined in claim 22 wherein A is O.

24. A compound as defined in claim 23 wherein G is —

O—

CH₂CH═

CH₂.

25. A compound as defined in claim 5 wherein G is —

OCH₂CH(Cl)CH₂Cl.

26. A compound as defined in claim 5 wherein G is selected from the group consisting of alkyloxy and A-alkyloxy.

27. A compound as defined in claim 5 wherein G is —

CH₂CH₂OH.

28. A compound as defined in claim 5 wherein G is —

CH₂OC(O)H.

29. A compound as defined in claim 5 wherein G is haloalkyl.

30. A compound as defined in claim 5 wherein G is cycloalkenyl.

31. A compound 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-(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-(3-cyano-5-(methoxycarbonyl)phenyl)-1,2,4-oxadiazole (B100),

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

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

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).

32. A compound selected from the group consisting of:

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

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

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

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), and

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

     144).

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

wherein

X and Y are N;

Z is O;

Ar¹ and Ar² are independently selected from the group consisting of optionally substituted phenyl and optionally substituted 2-pyridyl wherein at least one of Ar₁ and Ar₂ is phenyl and at least one of Ar₁ and Ar₂ is 2-pyridyl,

wherein

at least one of Ar¹ and Ar² is substituted with at least one substituents G,

wherein

 

G is selected from the group consisting of —

F, —

Cl, —

Br, —

I, —

SR₁, —

SOR, —

SO₂R₁, —

SO₂NR₁R₂, —

OCOR₁, —

OCONR₁R₂, —

NR₁COR₂, —

NR₁CO₂R₂, —

CN, —

NO₂, —

CO₂R₁, —

CONR₁R₂, —

C(O)R₁, —

CH(OR₁)R₂, —

CH₂(OR₁), —

R₁, and —

A—

(CH₂)_n—

NR₁R₂,

wherein

 

R₁ and R₂ are independently selected from the group consisting of —

H, —

CF₃, —

C₁-C₁₀ alkyl, -cycloalkyl, -alkyl-aryl, -alkyl-heteroaryl, -heterocycloalkyl, -aryl and where R₁ and R₂ may combine to form a ring, and A is defined as CH₂, O, NH, S, SO, or SO₂ and n is 1,2,3, or 4,

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-nitrophenyl)-1,2,4-oxadiazole,

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

3-(2-pyridyl)-5-phenyl-1,2,4-oxadiazole.

34. A compound as defined in claim 33 wherein ---- represents a double bond.

35. The compound of claim 33 wherein Ar¹ is 2-pyridyl and Ar² is phenyl.

36. The compound of claim 35, wherein G is selected from the group consisting of —

CF₃, —

Cl, —

F, —

Br, —

CH₃, —

NO₂, —

OCF₃, —

SCH₃, and —

CN.

37. The compound of claim 35, wherein Ar₁ is 2-pyridyl and substituted with one or more G, wherein G is selected from the group consisting of —

CF₃, —

F, and —

Cl.

45. A pharmaceutical composition comprising a therapeutically effective, non-toxic, amount of a compound of claim 33 and a pharmaceutically acceptable carrier.

46. 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 45.

47. A method according to claim 46 wherein the disease is a disease associated with mGluR activation.

48. A method according to claim 47 wherein the disease is a neurological disease.

49. A method according to claim 47 wherein the disease is a psychiatric disease.

50. A method according to claim 47 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.

51. A method according to claim 47 wherein the disease is selected from the group consisting of schizophrenia and depression.

38. A compound 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-(3-methylphenyl)-1,2,4-oxadiazole (B9),

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-(2pyridyl)-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), and

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

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

wherein

---- represents a double or single bond;

X and Y are N;

Z is O;

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

optionally substituted phenyl and optionally substituted 2-pyridyl wherein at least one of Ar₁ and Ar₂ is phenyl and at least one of Ar₁ and Ar₂ is 2-pyridyl 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;

pyridyl;

thiophene;

pyrimidine;

furan;

cycloalkene;

alkenyl;

alkynyl;

A-alkenyl;

A-alkynyl;

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;

SO₂;

NSO₂;

—

OSO₂; and

—

C(NR₂)NR₃;

m is selected from 0 and 1;

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

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-(4-aminophenyl)-1,2,4-oxadiazole,

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

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

3-(2-pyridyl)-5-phenyl-1,2,4-oxadiazole, and

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

40. 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 39.

41. A method according to claim 40 wherein the disease is a disease associated with mGluR activation.

42. A method according to claim 41 wherein the disease is a neurological disease.

43. A method according to claim 41 wherein the disease is a psychiatric disease.

44. A method according to claim 41 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.

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

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

wherein

X and Y are N;

Z is O;

Ar¹ and Ar² are independently selected from the group consisting of optionally substituted phenyl and optionally substituted 2-pyridyl wherein at least one of Ar₁ and Ar₂ is phenyl and at least one of Ar₁ and Ar2 is 2-pyridyl,

wherein

Ar¹ and Ar² are optionally substituted with one or more substituents G,

wherein

 

G is selected from the group consisting of —

F, —

Cl, —

Br, —

I, —

SR₁, —

SOR, —

SO₂R₁, —

SO₂NR₁R₂, —

OCOR₁, —

OCONR₁R₂, —

NR₁CO₂R₂, —

NR₁CO₂R₂, —

CN, —

NO₂, —

CO₂R₁, —

CONR₁R₂, —

C(O)R₁, —

CH(OR₁)R₂, —

CH₂(OR₁), —

R₁, and —

A—

(CH₂)_n—

NR₁R₂,

wherein

 

R₁ and R₂ are independently selected from the group consisting of —

H, —

CF₃, —

C_1-C10 alkyl, -cycloalkyl, -alkyl-aryl, -alkyl-heteroaryl, -heterocycloalkyl, -aryl and where R₁ and R₂ may combine to form a ring, and A is defined as CH₂, O, NH, S, SO, or SO₂ and n is 1, 2, 3, or 4,

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

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

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

3-(2-pyridyl)-5-phenyl-1,2,4-oxadiazole.

54. 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 53.

55. A method according to claim 54 wherein the disease is a disease associated with mGluR activation.

56. A method according to claim 55 wherein the disease is a neurological disease.

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

58. A method according to claim 55 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.