SUBSTITUTED PYRAZOLO [1,5-a] PYRIMIDINES AS METABOTROPIC GLUTAMATE ANTAGONISTS

• US 20090143580A1
• Filed: 01/06/2009
• Published: 06/04/2009
• Est. Priority Date: 09/27/2005
• Status: Active Grant

• Current Assignee: Erwin Goetschi, Juergen Wichmann, Silvia Gatti Mcarthur, Thomas Johannes Woltering
• Original Assignee: Erwin Goetschi, Juergen Wichmann, Silvia Gatti Mcarthur, Thomas Johannes Woltering
• Inventors: Wichmann, Juergen, Goetschi, Erwin, Woltering, Thomas Johannes, McArthur, Silvia Gatti
• Granted Patent: US 8,093,263 B2
• Time in Patent Office: Days
• US Class Current: 544/281
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

The present invention relates to compounds of formula (I)

wherein A, E G, J, L, M, R¹, R², and R³ are as defined in the specification and claims. The invention also relates to pharmaceutical compositions containing such compounds and methods for preparing the compounds and compositions. The compounds are metabotropic glutamate receptor antagonists and are useful for the treatment of a variety of CNS disorders.

Claims

1. A compound of formula (I):

wherein

either E, J, and M are N, G is C, and L is CH;

or L and G are N, E is C, and J and M are CH;

R¹ and R² are each independently H, halogen, C_1-6-alkyl optionally substituted by one or more F or C_1-6-alkoxy, or C_1-6-alkoxy optionally substituted by one or more F;

R³ is H, —

C(CH₃)₂OH, or linear C_1-4-alkyl or C_3-4-cycloalkyl each of which is optionally substituted by one or more substituent(s) selected from the group consisting of 1 to 6 F and 1 to 2 OH;

A is selected from the group consisting of aryl and 5 or 6-membered heteroaryl each of which is optionally substituted by one to four R^a;

R^a is F, OH, amino, C_1-6-alkyl optionally substituted by OH, C_1-6-alkoxy, C_3-4-cycloalkyl, —

CO—

R^b, SO₂—

R^c or SO₂—

NR^dR^e;

R^b is amino;

R^c is OH or C_1-6-alkyl;

R^d and R^e can be the same or different and are selected from the group consisting of;

H;

straight or branched C_1-6-alkyl optionally substituted by one or more substituent(s) selected from the group consisting of F, cyano, OH, di(C_1-6-alkyl)amino, C_3-6-cycloalkyl, 5 or 6-membered heterocycloalkyl, aryl and 5 or 6-membered heteroaryl;

C_3-6-cycloalkyl;

aryl; and

5 or 6-membered heteroaryl;

or R^d and R^e together with the nitrogen atom to which they are attached, form a heterocyclic ring of 4 to 6 ring members which is optionally substituted by OH or C_1-6-alkyl;

or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 having formula (I-b):

3. The compound of claim 2, wherein:

R¹ is halo or CF₃;

R² is H, halo, or C_1-6-alkyl or C_1-6-alkoxy each of which is optionally substituted by one or more F;

R³ is H, linear C_1-4-alkyl, or C_3-4-cycloalkyl each of which is optionally substituted by 1 to 6 F;

A is selected from the group consisting of aryl and 5 or 6-membered heteroaryl each of which is optionally substituted by one to four R^a;

R^a is amino or SO₂—

NR^dR^e;

wherein R^d and R^e are each H;

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 3, wherein:

R¹ is Cl, F or CF₃;

R² is H, F, methyl, OEt, CHF₂, CF₃, OCF₃ or OCH₂CF₃;

R³ is H, methyl or cyclopropyl, each of which is optionally substituted by 2 or 3 F;

A is selected from the group consisting of phenyl, thiophenyl, pyridinyl, pyrimidinyl and pyrazolyl, each of which is optionally substituted by one R^a;

R^a is amino or SO₂—

NR^dR^e;

wherein R^d and R^e are each H;

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4, selected from the group consisting of:

3-{5-[8-Trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-[1,2,4]oxadiazol-3-yl}-benzenesulfonamide;

4-{5-[8-Trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-[1,2,4]oxadiazol-3-yl}-benzenesulfonamide;

4-{5-[6-(4-Chloro-phenyl)-8-methyl-imidazo[1,2-a]pyridin-3-yl]-[1,2,4]oxadiazol-3-yl}-benzenesulfonamide;

3-{5-[6-(4-Chloro-phenyl)-8-methyl-imidazo[1,2-a]pyridin-3-yl]-[1,2,4]oxadiazol-3-yl}-benzenesulfonamide;

5-{5-[6-(4-Chloro-phenyl)-8-methyl-imidazo[1,2-a]pyridin-3-yl]-[1,2,4]oxadiazol-3-yl}-thiophene-2-sulfonic acid amide;

4-{5-[8-Methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-[1,2,4]oxadiazol-3-yl}-benzenesulfonamide;

3-{5-[8-Methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-[1,2,4]oxadiazol-3-yl}-benzenesulfonamide;

5-{5-[8-Methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-[1,2,4]oxadiazol-3-yl}-thiophene-2-sulfonic acid amide; and

5-{5-[8-Methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyridin-2-ylamine.

6. The compound of claim 4, selected from the group consisting of:

5-{5-[8-Methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyrimidin-2-ylamine;

4-{5-[6-(4-Trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-[1,2,4]oxadiazol-3-yl}-benzenesulfonamide;

3-{5-[6-(4-Trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-[1,2,4]oxadiazol-3-yl}-benzenesulfonamide;

5-{5-[6-(4-Trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-[1,2,4]oxadiazol-3-yl}-thiophene-2-sulfonic acid amide;

5-{5-[6-(4-Chloro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-[1,2,4]oxadiazol-3-yl}-thiophene-2-sulfonic acid amide;

5-{5-[6-(4-Trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyridin-2-ylamine;

5-{5-[6-(4-Chloro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyridin-2-ylamine;

4-{5-[8-Methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyridin-2-ylamine; and

4-{5-[6-(4-Trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyridin-2-ylamine.

7. A compound of claim 1 having formula (I-c):

8. The compound of claim 7, wherein:

R¹ is halo or CF₃;

R² is H, halo, or C_1-6-alkyl or C_1-6-alkoxy each of which is optionally substituted by one or more F;

R³ is H, linear C_1-4-alkyl, or C_3-4-cycloalkyl each of which is optionally substituted by 1 to 6 F;

A is selected from the group consisting of aryl and 5 or 6-membered heteroaryl each of which is optionally substituted by one to four R^a;

R^a is amino or SO₂—

NR^dR^e;

wherein R^d and R^e are each H;

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8, wherein:

R¹ is Cl, F or CF₃;

R² is H, F, methyl, OEt, CHF₂, CF₃, OCF₃ or OCH₂CF₃;

R³ is H, methyl or cyclopropyl, each of which is optionally substituted by 2 or 3 F;

A is selected from the group consisting of phenyl, thiophenyl, pyridinyl, pyrimidinyl and pyrazolyl, each of which is optionally substituted by one R^a;

R^a is amino or SO₂—

NR^dR^e;

wherein R^d and R^e are each H;

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 9, selected from the group consisting of:

4-{3-[4-Trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidin-8-yl]-[1,2,4]oxadiazol-5-yl}-benzenesulfonamide; and

5-{5-[4-Trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidin-8-yl]-[1,2,4]oxadiazol-3-yl}-thiophene-2-sulfonic acid amide.

11. The compound of claim 1, wherein L and G are N, E is C, and J and M are CH.

12. The compound of claim 1, wherein A is aryl optionally substituted by one to four R^a.

13. The compound of claim 1, wherein A is a 5 or 6-membered heteroaryl optionally substituted by one to four R^a.

14. The compound of claim 1, wherein R^d and R^e are each independently H;

straight or branched C_1-6-alkyl optionally substituted by one or more substituent(s) selected from the group consisting of F, cyano, OH, di(C_1-6-alkyl)amino, and C_3-6-cycloalkyl;

or

C_3-6-cycloalkyl.

15. The compound of claim 1, wherein one of R^d and R^e is straight or branched C_1-6-alkyl optionally substituted by one or more substituent(s) selected from the group consisting of 5 or 6-membered heterocycloalkyl, aryl and 5 or 6-membered heteroaryl.

16. The compound of claim 1, wherein one of R^d and R^e is aryl.

17. The compound of claim 1, wherein one of R^d and R^e is a 5 or 6-membered heteroaryl.

18. The compound of claim 1, wherein R^d and R^e, together with the nitrogen atom to which they are attached, form a heterocyclic ring of 4 to 6 ring members which is optionally substituted by OH or C_1-6-alkyl;