Triazole derivatives

• US 10,273,217 B2
• Filed: 03/28/2018
• Issued: 04/30/2019
• Est. Priority Date: 10/06/2015
• 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): Stockton, Laura L
• Application Number:
  US15/938,587
• Publication Number:
  US 20180237401A1
• Time in Patent Office: 398 Days
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: C07D 249/02 not condensed with other rings
• CPC Class Codes: C07D 249/08 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links

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, tert-butyl, cyclopropyl, hydroxmethyl, or 2-propyl-2-ol;
• R³ is Cl, F, CF₃, cyano, methyl, methoxy, isopropyl, 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. A compound of formula IA according to claim 1,

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

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

N-tert-Butyl-3-(4-fluorophenyl)-5-(3-methyl-1,2,4-triazol-4-yl)-benzamide;

N-tert-Butyl-3-(4-chlorophenyl)-5-(3-methyl-1,2,4-triazol-4-yl)-benzamide;

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

N-tert-Butyl-3-(3-tert-butyl-1,2,4-triazol-4-yl)-5-(4-fluorophenyl)-benzamide;

N-tert-Butyl-3-(3-tert-butyl-1,2,4-triazol-4-yl)-5-(4-chlorophenyl)-benzamide;

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

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

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

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

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

N-tert-Butyl-3-(4-chlorophenyl)-5-[3-(2-hydroxypropan-2-yl)-1,2,4-triazol-4-yl]-benzamide;

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

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

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

N-tert-Butyl-3-(4-fluoro-3-methyl-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide;

N-tert-Butyl-3-(3-fluoro-4-methyl-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide;

N-tert-Butyl-3-(4-methyl-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide;

N-tert-Butyl-3-(4-cyano-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide; and

N-tert-Butyl-3-(4-cyclopropyl-phenyl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide.

4. A compound of formula IB according to claim 1

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

3-(4-Fluorophenyl)-N-(2-methylbutan-2-yl)-5-(1,2,4-triazol-4-yl)-benzamide;

N-(2-Methylbutan-2-yl)-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5[4-(trifluoromethyl)-phenyl]-benzamide;

3-(4-Fluorophenyl)-N-(2-methylbutan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide; and

3-(4-Chlorophenyl)-N-(2-methylbutan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide.

6. A compound of formula IC according to claim 1

7. A compound of formula IC according to claim 6, wherein the compound is

3-(4-Fluorophenyl)-5-(1,2,4-triazol-4-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide or a pharmaceutically acceptable salt thereof.

8. A compound of formula ID according to claim 1

9. A compound of formula ID according to claim 8, or a pharmaceutically acceptable salt thereof, wherein the compound is

3-(4-Fluorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-(3-propan-2-yl-1,2,4-triazol-4-yl)-benzamide;

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

or

N-(1-hydroxy-2-methylpropan-2-yl)-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5[4-(trifluoromethyl)-phenyl]-benzamide.

10. A compound of formula IE according to claim 1

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

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

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

3-(3-tert-Butyl-1,2,4-triazol-4-yl)-N-(2-cyclopropylpropan-2-yl)-5-(4-fluorophenyl)-benzamide;

3-(3-tert-Butyl-1,2,4-triazol-4-yl)-5-(4-chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-benzamide;

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

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

N-(2-Cyclopropyl-propan-2-yl)-3-(3-propan-2-yl-1,2,4-triazol-4-yl)-5 -[4-(trifluoromethyl)-phenyl]-benzamide; and

3-(4-Chlorophenyl)-N-(2-cyclopropyl-propan-2-yl)-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-benzamide.

12. A compound of formula IF according to claim 1

13. A compound of formula IG according to claim 1

14. A compound of formula IG according to claim 13, wherein the compound is

(RS)-3-(4-Chlorophenyl)-5-[3-(hydroxymethyl)-1,2,4-triazol-4-yl]-N-(3-methyl-1,1-dioxothiolan-3-yl)-benzamide, or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a compound of formula I as claimed in claim 1 and pharmaceutically acceptable excipients.

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

15. A process for the manufacture of a compound of formula I, or a pharmaceutically acceptable salt, as defined in claim l, which process comprises

a) reacting a compound of formula II: