Imidazole derivatives

Patent metadata

Field	Value
Publication number	US-10092546-B2
Application number	US-201815866444-A
Country	US
Kind code	B2
Filing date	Jan 9, 2018
Priority date	Jul 14, 2015
Publication date	Oct 9, 2018
Grant date	Oct 9, 2018

Abstract

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.

First claim

We claim:

1. A compound of formula I

wherein
R 1′ is CH 3 ;
R 1 is methyl, ethyl, CF 3 , CH 2 OH, cyclopropyl or cyano, or
R 1′ and R 1 may form together a 1,1-dioxo-tetrahydro-thiophen-3-yl ring;

R 2 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxmethyl, or
2-propyl-2-ol;

R 3 is Cl, F, CF 3 , methyl, methoxy, isopropyl, cyano or cyclopropyl;
R 4 is hydrogen, methyl, F or Cl;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, a mixture of enantiomers or an enantiomer and/or optical isomer and/or stereoisomer thereof.

2. The compound of claim 1 of formula IA,

wherein
R 2 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxmethyl, or
2-propyl-2-ol;

R 3 is Cl, F, CF 3 , methyl, methoxy, isopropyl, cyano or cyclopropyl;
R 4 is hydrogen, methyl, F or Cl;
or a pharmaceutically acceptable salt or acid addition salt thereof.

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,

wherein
R 2 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxmethyl, or 2-propyl-2-ol;
R 3 is Cl, F, CF 3 , methyl, methoxy, isopropyl, cyano or cyclopropyl;
R 4 is hydrogen, methyl, F or Cl;
or a pharmaceutically acceptable salt or acid addition salt thereof.

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

wherein
R 2 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxmethyl, or 2-propyl-2-ol;
R 3 is Cl, F, CF 3 , methyl, methoxy, isopropyl, cyano or cyclopropyl;
R 4 is hydrogen, methyl, F or Cl;
or a pharmaceutically acceptable salt or acid addition salt thereof.

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

wherein
R 2 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxmethyl, or 2-propyl-2-ol;
R 3 is Cl, F, CF 3 , methyl, methoxy, isopropyl, cyano or cyclopropyl;
R 4 is hydrogen, methyl, F or Cl;
or a pharmaceutically acceptable salt or acid addition salt thereof.

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

wherein
R 2 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxmethyl, or 2-propyl-2-ol;
R 3 is Cl, F, CF 3 , methyl, methoxy, isopropyl, cyano or cyclopropyl;
R 4 is hydrogen, methyl, F or Cl;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, mixture of enantiomers or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

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

Assignees

• Hoffmann La Roche

Inventors

• Hoener Marius
• Wichmann Juergen

Classifications

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• C07B43/04

  of amino groups · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title