Pyrazol compounds as EAAT3 inhibitors

• US 10,457,644 B2
• Filed: 11/19/2018
• Issued: 10/29/2019
• Est. Priority Date: 05/27/2016
• Status: Active Grant

• Current Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Hoener, Marius, Wichmann, Juergen
• Primary Examiner(s): Saeed, Kamal A
• Application Number:
  US16/195,441
• Publication Number:
  US 20190119218A1
• Time in Patent Office: 344 Days
• Field of Search: None
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Abstract

The invention provides novel compounds having the general formula (I)

wherein R¹, R^1′, R², R³, R⁴ are as defined herein, compositions including the compounds and methods of using the compounds.

Claims

1. A compound of formula (I):

2. A compound according to claim 1, wherein R¹ is methyl.

3. A compound according to claim 1, wherein R² is selected from the group consisting of

i) methyl,

ii) ethyl,

iii) isopropyl,

iv) tert-butyl,

v) cyclopropyl, and

vi) cyclopropylmethyl.

4. A compound according to claim 1, wherein R³ is selected from the group consisting of

i) hydrogen,

ii) chloro,

iii) fluoro,

iv) methyl

v) isopropyl,

vi) methoxy,

vii) cyano,

viii) cyclopropyl, and

ix) trifluoromethyl.

5. A compound according to claim 1, wherein R³ is selected from the group consisting of

i) chloro,

ii) fluoro,

iii) cyano, and

iv) trifluoromethyl.

6. A compound according to claim 1, wherein R⁴ is H.

7. A compound according to claim 1, wherein

R^1′

and R¹ are both methyl;

R² is selected from the group consisting of

i) methyl,

ii) ethyl,

iii) isopropyl,

iv) tert-butyl,

v) cyclopropyl, and

vi) cyclopropylmethyl;

R³ is selected from the group consisting of

i) hydrogen,

ii) chloro,

iii) fluoro,

iv) methyl

v) isopropyl,

vi) methoxy,

vii) cyano, and

viii) cyclopropyl

R⁴ is selected from the group consisting of

i) hydrogen,

ii) chloro,

iii) fluoro, and

iv) methyl;

or pharmaceutically acceptable salts.

8. A compound according to claim 1, selected from

N-tert-butyl-3-(4-chlorophenyl)-5-(2-methylpyrazol-3-yl)benzamide;

N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-fluorophenyl)benzamide;

N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-[4-(trifluoromethyl)phenyl]benzamide;

N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-chlorophenyl)benzamide;

N-tert-butyl-3-(4-chlorophenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;

N-tert-butyl-3-(4-fluorophenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;

N-tert-butyl-3-(2-propan-2-ylpyrazol-3-yl)-5-[4-(trifluoromethyl)phenyl]benzamide;

N-tert-butyl-3-(3,4-difluorophenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;

N-tert-butyl-3-(4-methylphenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;

N-tert-butyl-3-(4-propan-2-ylphenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;

N-tert-butyl-3-(4-methoxyphenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;

N-tert-butyl-3-(3-chloro-4-fluorophenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;

N-tert-butyl-3-phenyl-5-(2-propan-2-ylpyrazol-3-yl)benzamide;

N-tert-butyl-3-(4-cyclopropylphenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;

N-tert-butyl-3-(4-fluoro-3-methylphenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;

N-tert-butyl-3-(4-chloro-3-fluorophenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;

N-tert-butyl-3-(4-cyanophenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;

3-(2-tert-butylpyrazol-3-yl)-5-(4-chlorophenyl)-N-(2-methylbutan-2-yl)benzamide;

3-(4-chlorophenyl)-N-(2-methylbutan-2-yl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;

N-tert-butyl-3-(3-fluoro-4-methylphenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;

3-(4-chlorophenyl)-N-(2-cyanopropan-2-yl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;

3-(2-tert-butylpyrazol-3-yl)-5-(4-chlorophenyl)-N-(2-cyanopropan-2-yl)benzamide;

N-tert-butyl-3-(2-cyclopropylpyrazol-3-yl)-5-(4-fluorophenyl)benzamide;

N-tert-butyl-3-(4-chlorophenyl)-5-(2-ethylpyrazol-3-yl)benzamide;

N-tert-butyl-3-(4-chlorophenyl)-5-[2-(cyclopropylmethyl)pyrazol-3-yl]benzamide;

3-(4-chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;

N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-fluoro-3-methylphenyl)benzamide;

N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-phenylbenzamide;

N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(3-fluoro-4-methylphenyl)benzamide;

N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-methylphenyl)benzamide;

N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-methoxyphenyl)benzamide;

N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(3-chloro-4-fluorophenyl)benzamide;

N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-chloro-3-fluorophenyl)benzamide;

N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-propan-2-ylphenyl)benzamide;

3-(2-tert-butylpyrazol-3-yl)-5-(4-chlorophenyl)-N-(2-cyclopropylpropan-2-yl)benzamide;

N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(3,4-difluorophenyl)benzamide;

N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-cyclopropylphenyl)benzamide;

N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-cyanophenyl)benzamide;

3-(4-chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;

3-(4-chlorophenyl)-5-(2-propan-2-ylpyrazol-3-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)benzamide;

3-(2-tert-butylpyrazol-3-yl)-5-(4-chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)benzamide;

3-(2-tert-butylpyrazol-3-yl)-5-(4-chlorophenyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)benzamide;

N-tert-butyl-3-(2-cyclopropylpyrazol-3-yl)-5-[4-(trifluoromethyl)phenyl]benzamide;

N-tert-butyl-3-[2-(cyclopropylmethyl)pyrazol-3-yl]-5-[4-(trifluoromethyl)phenyl]benzamide;

N-tert-butyl-3-(4-chlorophenyl)-5-(2-cyclopropylpyrazol-3-yl)benzamide;

N-tert-butyl-3-[2-(cyclopropylmethyl)pyrazol-3-yl]-5-(4-fluorophenyl)benzamide;

N-tert-butyl-3-(2-ethylpyrazol-3-yl)-5-(4-fluorophenyl)benzamide;

N-tert-butyl-3-(2-ethylpyrazol-3-yl)-5-[4-(trifluoromethyl)phenyl]benzamide;

and/or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 1, selected from

N-tert-butyl-3-(4-chlorophenyl)-5-(2-methylpyrazol-3-yl)benzamide;

N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-fluorophenyl)benzamide;

N-tert-butyl-3-(4-chlorophenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;

N-tert-butyl-3-(4-fluorophenyl)-5-(2-propan-2-ylpyrazol-3-yl)benzamide;

N-tert-butyl-3-(2-propan-2-ylpyrazol-3-yl)-5-[4-(trifluoromethyl)phenyl]benzamide;

N-tert-butyl-3-(2-cyclopropylpyrazol-3-yl)-5-(4-fluorophenyl)benzamide;

N-tert-butyl-3-(4-chlorophenyl)-5-(2-ethylpyrazol-3-yl)benzamide;

N-tert-butyl-3-(4-chlorophenyl)-5-[2-(cyclopropylmethyl)pyrazol-3-yl]benzamide;

N-tert-butyl-3-(2-tert-butylpyrazol-3-yl)-5-(4-cyanophenyl)benzamide;

N-tert-butyl-3-(4-chlorophenyl)-5-(2-cyclopropylpyrazol-3-yl)benzamide;

N-tert-butyl-3-(2-ethylpyrazol-3-yl)-5-(4-fluorophenyl)benzamide;

or a pharmaceutically acceptable salt thereof.

10. A process to prepare a compound according to claim 1 comprising

a) the reaction of a compound of formula (II) in the presence of a compound of formula (III), wherein R¹, R^1′

, R², R³ and R⁴ are as defined in any one of claims 1 to 9;

11. A pharmaceutical composition comprising a compound according to claim 1 and a therapeutically inert carrier.

12. A method for the treatment of ocular conditions, which method comprises administering an effective amount of a compound according to claim 1.

13. A compound manufactured according to a process of claim 10.