Imidazole derivatives

• US 10,029,989 B2
• Filed: 12/04/2017
• Issued: 07/24/2018
• Est. Priority Date: 06/04/2015
• 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): Kifle, Bruck
• Application Number:
  US15/830,399
• Publication Number:
  US 20180118692A1
• Time in Patent Office: 232 Days
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/16 the ring being unsaturated
• CPC Class Codes: C07D 233/60 with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
• CPC Class Codes: C07D 233/61 with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
• CPC Class Codes: C07D 233/64 with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine

Abstract

The present invention relates to compounds of formula I

wherein

• R^1′ is CH₃;
• R¹ is methyl, ethyl, CF₃, cyclopropyl, CH₂OH or
  • R^1′ and R¹ may form together with the carbon atom to which they are attached a 1,1-dioxo-thiolan-3-yl ring;
• R² is hydrogen, methyl, ethyl, isopropyl, tertbutyl, cyclopropyl, CH₂OH or C(CH₃)₂OH;
• R³ is Cl, F, CF₃, cyano, methyl or cyclopropyl;
• R⁴ is hydrogen, methyl or F;
  or to a pharmaceutically acceptable salt or acid addition salt, to a racemic mixture, or to its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof for use in the treatment of psychiatric disorders such as schizophrenia, bipolar disorder, obsessive-compulsive disorder or autism spectrum disorder.

Claims

1. A compound of formula (I):

2. A compound of claim 1 of formula IA:

3. A compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

N-tert-Butyl-3-(4-chlorophenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide;

N-tert-Butyl-3-(4-chlorophenyl)-5-imidazol-1-ylbenzamide;

N-tert-Butyl-3-(4-chlorophenyl)-5-(2-methylimidazol-1-yl)-benzamide;

N-tert-Butyl-3-(4-chlorophenyl)-5-(2-ethylimidazol-1-yl)-benzamide;

N-tert-Butyl-3-(4-chlorophenyl)-5-(2-cyclopropylimidazol-1-yl)-benzamide;

N-tert-Butyl-3-(4-fluorophenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide;

N-tert-Butyl-3-(2-ethylimidazol-1-yl)-5-(4-fluorophenyl)-benzamide;

N-tert-Butyl-3-(4-fluorophenyl)-5-(2-methylimidazol-1-yl)-benzamide;

N-tert-Butyl-3-(2-cyclopropylimidazol-1-yl)-5-(4-fluorophenyl)-benzamide;

N-tert-Butyl-3-(2-propan-2-ylimidazol-1-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide;

N-tert-Butyl-3-(3-fluoro-4-methylphenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide;

N-tert-Butyl-3-(3,4-difluorophenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide;

N-tert-Butyl-3-(4-chloro-3-fluorophenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide;

N-tert-Butyl-3-(4-cyclopropylphenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide;

N-tert-Butyl-3-(4-methylphenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide;

N-tert-Butyl-3-(4-fluoro-3-methylphenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide;

N-tert-Butyl-3-(2-tert-butylimidazol-1l-yl)-5-(4-chlorophenyl)-benzamide;

N-tert-Butyl-3-(4-chlorophenyl)-5-[2-(hydroxymethyl)-imidazol-1-yl]-benzamide;

N-tert-Butyl-3-(2-tert-butylimidazol-1-yl)-5-(4-fluorophenyl)-benzamide;

N-tert-Butyl-3-(2-tert-butylimidazol-1-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide;

N-tert-Butyl-3-(4-fluorophenyl)-5-[2-(2-hydroxypropan-2-yl)-imidazol-1-yl]-benzamide;

N-tert-Butyl-3-[2-(2-hydroxypropan-2-yl)-imidazol-1-yl]-5-[4-(trifluoromethyl)-phenyl]-benzamide; and

N-tert-Butyl-3-(4-chlorophenyl)-5-[2-(2-hydroxypropan-2-yl)-imidazol-1-yl]-benzamide.

4. A compound of claim 1 of formula IB:

5. A compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

3-(4-Chlorophenyl)-5-[2-(hydroxymethyl)-imidazol-1-yl]-N-(2-methylbutan-2-yl)-benzamide;

3-(2-tert-Butylimidazol-1-yl)-5-(4-chlorophenyl)-N-(2-methylbutan-2-yl)-benzamide;

3-(4-Chlorophenyl)-N-(2-methylbutan-2-yl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide or

3-(4-Chlorophenyl)-5-(2-cyclopropylimidazol-1-yl)-N-(2-methylbutan-2-yl)-benzamide.

6. A compound of claim 1 of formula IC:

7. A compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

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

3-(4-Chlorophenyl)-5-(2-methylimidazol-1-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide; and

3-(4-Chlorophenyl)-5-(2-cyclopropylimidazol-1-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide.

8. A compound of claim 1 of formula ID:

9. A compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

3-(4-Chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide;

3-(4-Chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-5-(2-ethylimidazol-1-yl)-benzamide;

3-(4-Chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-5-(2-methylimidazol-1-yl)-benzamide;

3-(4-Chlorophenyl)-5-(2-cyclopropylimidazol-1-yl)-N-(2-cyclopropyl-propan-2-yl)-benzamide;

N-(2-Cyclopropylpropan-2-yl)-3-(4-fluorophenyl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide;

N-(2-Cyclopropylpropan-2-yl)-3-(2-ethylimidazol-1-yl)-5-(4-fluorophenyl)-benzamide;

N-(2-Cyclopropylpropan-2-yl)-3-(4-fluorophenyl)-5-(2-methylimidazol-1-yl)-benzamide; and

3-(2-Cyclopropylimidazol-1-yl)-N-(2-cyclopropylpropan-2-yl)-5-(4-fluorophenyl)-benzamide.

10. A compound of claim 1 of formula IE:

11. A compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

(RS)-3-(4-Chlorophenyl)-N-(3-methyl-1,1-dioxothiolan-3-yl)-5-(2-propan-2-ylimidazol-1-yl)-benzamide; and

(RS)-3-(4-chlorophenyl)-5-(2-cyclopropylimidazol-1-yl)-N-(3-methyl-1,1-dioxothiolan-3-yl)-benzamide.

12. A compound of claim 1 of formula IF:

13. A compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

3-(4-Chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-(2-propan-2-yl-imidazol-1-yl)-benzamide;

3-(4-Chlorophenyl)-5-(2-cyclopropylimidazol-1-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-benzamide; and

3-(2-tert-Butylimidazol-1-yl)-5-(4-chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-benzamide.

14. A process for the manufacture of a compound of claim 1 of formula I wherein the process comprises the steps:

a) reacting a compound of formula;

15. A pharmaceutical composition comprising a compound of claim 1 and one or more pharmaceutically acceptable excipients.

16. A method for the treatment schizophrenia, bipolar disorder, obsessive-compulsive disorder or autism spectrum disorder, which method comprises administering a therapeutically effective amount of a compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, to a human in need of such treatment.