Imidazole derivatives

• US 10,092,546 B2
• Filed: 01/09/2018
• Issued: 10/09/2018
• Est. Priority Date: 07/14/2015
• 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): Desai, Rita J
• Application Number:
  US15/866,444
• Publication Number:
  US 20180125823A1
• Time in Patent Office: 273 Days
• Field of Search: 514341
• CPC Class Codes: A61K 31/4178 not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: C07B 2200/07 Optical isomers
• CPC Class Codes: C07B 43/04 of amino groups
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/14 containing three or more hetero rings

Abstract

The present invention relates to compounds of formula I

wherein

• R^1′ is CH₃;
• R¹ is methyl, ethyl, CF₃, CH₂OH, cyclopropyl or cyano, or
  • R^1′ and R¹ may form together a 1,1-dioxo-tetrahydro-thiophen-3-yl ring;
• R² is hydrogen, methyl, ethyl, isopropyl, tertbutyl, cyclopropyl, hydroxmethyl, or 2-propyl-2-ol;
• R³ is Cl, F, CF₃, methyl, methoxy, isopropyl, cyano or cyclopropyl;
• R⁴ is hydrogen, methyl, F or Cl;
  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.

The compounds of formula I may be used 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. The compound of claim 1 of formula IA,

3. The compound of formula IA according to claim 2, wherein the compounds is selected from the group consisting of:

N-tert-Butyl-2-(4-chlorophenyl)-6-(2-propan-2-yl-imidazol-1-yl)-pyridine-4-carboxamide;

N-tert-Butyl-2-(4-fluorophenyl)-6-(2-propan-2-yl-imidazol-1-yl)-pyridine-4-carboxamide;

N-tert-Butyl-2-(2-propan-2-yl-imidazol-1-yl)-6-[4-(trifluoromethyl)-phenyl]-pyridine-4-carboxamide;

N-tert-Butyl-2-(2-cyclopropyl-imidazol-1-yl)-6-(4-fluorophenyl)-pyridine-4-carboxamide;

N-tert-Butyl-2-(4-chlorophenyl)-6-(2-cyclopropyl-imidazol-1-yl)-pyridine-4-carboxamide;

N-tert-Butyl-2-(4-fluorophenyl)-6-imidazol-1-yl-pyridine-4-carboxamide;

N-tert-Butyl-2-(4-fluorophenyl)-6-(2-methyl-imidazol-1-yl)-pyridine-4-carboxamide;

N-tert-Butyl-2-(2-ethyl-imidazol-1-yl)-6-(4-fluorophenyl)-pyridine-4-carboxamide;

N-tert-Butyl-2-(4-chlorophenyl)-6-imidazol-1-yl-pyridine-4-carboxamide;

N-tert-Butyl-2-(4-chlorophenyl)-6-(2-methyl-imidazol-1-yl)-pyridine-4-carboxamide;

N-tert-Butyl-2-(4-chlorophenyl)-6-(2-ethyl-imidazol-1-yl)-pyridine-4-carboxamide;

N-tert-Butyl-2-(2-tert-butyl-imidazol-1-yl)-6-(4-chlorophenyl)-pyridine-4-carboxamide;

N-tert-Butyl-2-(2-tert-butyl-imidazol-1-yl)-6-(4-fluorophenyl)-pyridine-4-carboxamide;

N-tert-Butyl-2-(4-fluorophenyl)-6-[2-(hydroxymethyl)-imidazol-1-yl]-pyridine-4-carboxamide;

N-tert-Butyl-2-(4-fluorophenyl)-6-[2-(2-hydroxypropan-2-yl)-imidazol-1-yl]-pyridine-4-carboxamide;

N-tert-Butyl-2-(2-tert-butylimidazol-1-yl)-6-[4-(trifluoromethyl)-phenyl]-pyridine-4-carboxamide;

N-tert-Butyl-2-(2-cyclopropyl-imidazol-1-yl)-6-[4-(trifluoromethyl)-phenyl]-pyridine-4-carboxamide;

N-tert-Butyl-2-(2-methyl-imidazol-1-yl)-6-[4-(trifluoromethyl)-phenyl]-pyridine-4-carboxamide;

N-tert-Butyl-2-(4-chlorophenyl)-6-[2-(hydroxymethyl)-imidazol-1-yl]-pyridine-4-carboxamide;

N-tert-Butyl-2-(2-tert-butyl-imidazol-1-yl)-6-(3,4-difluorophenyl)-pyridine-4-carboxamide;

N-tert-Butyl-2-(2-tert-butyl-imidazol-1-yl)-6-(4-methylphenyl)-pyridine-4-carboxamide;

N-tert-Butyl-2-(2-tert-butyl-imidazol-1-yl)-6-(4-cyclopropyl-phenyl)-pyridine-4-carboxamide;

N-tert-Butyl-2-(2-tert-butyl-imidazol-1-yl)-6-(4-fluoro-3-methyl-phenyl)-pyridine-4-carboxamide;

N-tert-Butyl-2-(2-tert-butyl-imidazol-1-yl)-6-(4-methoxy-phenyl)-pyridine-4-carboxamide;

N-tert-Butyl-2-(2-tert-butyl-imidazol-1-yl)-6-(4-cyano-phenyl)-pyridine-4-carboxamide;

N-tert-Butyl-2-(4-chlorophenyl)-6-[2-(2-hydroxypropan-2-yl)-imidazol-1-yl]-pyridine-4-carboxamide; and

;

N-tert-Butyl-2-[2-(2-hydroxypropan-2-yl)-imidazol-1-yl]-6-[4-(trifluoromethyl)-phenyl]-pyridine-4-carboxamide, or,

a pharmaceutically acceptable acid addition salt thereof.

4. The compound according to claim 1 of formula IB,

5. The compound of formula IB according to claim 4, wherein the compound is:

2-(4-Fluorophenyl)-N-(2-methylbutan-2-yl)-6-(2-propan-2-ylimidazol-1-yl)-pyridine-4-carboxamide;

or,

a pharmaceutically acceptable salt or acid addition salt thereof.

6. The compound of formula IC, according to claim 1

7. The compound according to claim 6 of formula IC wherein the compounds are:

2-(4-Chlorophenyl)-6-(2-propan-2-yl-imidazol-1-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-pyridine-4-carboxamide;

2-(4-Chlorophenyl)-6-(2-cyclopropyl-imidazol-1-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-pyridine-4-carboxamide;

2-(2-tert-Butylimidazol-1-yl)-6-(4-chlorophenyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-pyridine-4-carboxamide;

or,

2-(4-Chlorophenyl)-6-[2-(2-hydroxypropan-2-yl)-imidazol-1-yl]-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-pyridine-4-carboxamide;

or a pharmaceutically acceptable salt or acid addition salt thereof.

8. The compound of formula ID according to claim 1

9. The compound according to claim 8 of formula ID wherein the compound is;

;

2-(4-Chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-6-(2-propan-2-yl-imidazol-1-yl)-pyridine-4-carboxamide;

2-(4-Chlorophenyl)-6-(2-cyclopropyl-imidazol-1-yl)-N-(2-cyclopropyl-propan-2-yl)-pyridine-4-carboxamide;

2-(2-tert-Butylimidazol-1-yl)-6-(4-chlorophenyl)-N-(2-cyclopropyl-propan-2-yl)-pyridine-4-carboxamide;

or,

2-(4-Chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-6-[2-(2-hydroxypropan-2-yl)-imidazol-1-yl]-pyridine-4-carboxamide;

or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1 of formula IE

11. The compound according to claim 10 of formula IE wherein the compound is:

(RS)-2-(4-Fluorophenyl)-N-(3-methyl-1,1-dioxothiolan-3-yl)-6-(2-propan-2-ylimidazol-1-yl)-pyridine-4-carboxamide;

or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer, mixture of enantiomers and/or stereoisomer thereof.

12. The compound according to claim 1 of formula IF

13. The compound according to claim 12 of formula IF 2-(4-Chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-6-(2-propan-2-yl-imidazol-1-yl)-pyridine-4-carboxamide;

or,

a pharmaceutically acceptable acid addition salt thereof.

14. The compound according to claim 1 of formula IG

15. The compound according to 14, wherein the compound is:

2-(2-tert-Butylimidazol-1-yl)-6-(4-chlorophenyl)-N-(2-cyanopropan-2-yl)-pyridine-4-carboxamide;

or;

2-(4-Chlorophenyl)-N-(2-cyanopropan-2-yl)-6-(2-propan-2-yl-imidazol-1-yl)-pyridine-4-carboxamide.

16. A process for the manufacture of a compound of formula I according to claim 1, which process comprises the step of reacting a compound of formula II

17. A process for the manufacture of a compound of formula I according to claim 1, which process comprises the step of reacting a compound of formula IV

18. A pharmaceutical composition comprising a compound according to claim 1 and at least one pharmaceutically acceptable carrier, diluent or excipients.