Pyridine and pyrimidine derivatives

• US 10,005,736 B1
• Filed: 02/08/2018
• Issued: 06/26/2018
• Est. Priority Date: 08/12/2015
• 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): VAJDA, KRISTIN ANN
• Application Number:
  US15/891,922
• Publication Number:
  US 20180162824A1
• Time in Patent Office: 138 Days
• Field of Search: 51421207
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: C07D 211/80 having two double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 213/56 Amides
• CPC Class Codes: C07D 239/24 having three or more double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 239/36 as doubly bound oxygen atom or as unsubstituted hydroxy radical
• CPC Class Codes: C07D 333/20 by nitrogen atoms nitro, nitroso radicals C07D333/12
• CPC Class Codes: C07D 403/10 linked by a carbon chain containing aromatic 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, tert-butyl or cyclopropyl;
• R³ is Cl, F, CF₃, cyano, methyl, methoxy or cyclopropyl;
• R⁴ is hydrogen, methyl or F;
• X is N or CH;
• Y is N or CH;
  • with the proviso that X and Y are not simultaneously CH;
    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 formula IA according to claim 1

3. The compound of formula IA according to claim 2, which compound is:

N-tert-Butyl-3-(4-chlorophenyl)-5-(4-methylpyridin-3-yl)-benzamide;

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

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

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

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

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

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

N-tert-Butyl-3-(4-fluorophenyl)-5-(4-methylpyridin-3-yl)-benzamide;

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

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

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

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

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

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

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

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

N-tert-Butyl-3-(4-cyanophenyl)-5-(4-propan-2-ylpyrimidin-5-yl)-benzamide;

N-tert-Butyl-3-(4-methoxyphenyl)-5-(4-propan-2-ylpyrimidin-5-yl)-benzamide;

N-tert-Butyl-3-(4-chlorophenyl)-5-(4-cyclopropyl-pyrimidin-5-yl)-benzamide;

N-tert-Butyl-3-(4-chlorophenyl)-5-(4-ethyl-pyrimidin-5-yl)-benzamide;

N-tert-Butyl-3-(4-chlorophenyl)-5-(4-methyl-pyrimidin-5-yl)-benzamide;

or,

N-tert-Butyl-3-(4-tert-butyl-pyrimidin-5-yl)-5-(4-chlorophenyl)-benzamide.

4. The compound of formula IA according to claim 2, which compound is:

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

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

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

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

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

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

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

or,

N-tert-butyl-3-(4-tert-butylpyridin-3-yl)-5-(4-chlorophenyl)benzamide.

5. The compound of formula IB according to claim 1

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

N-(2-Methylbutan-2-yl)-3-(4-methylphenyl)-5-pyridin-3-ylbenzamide;

N-(2-Methylbutan-2-yl)-3-(4-methylphenyl)-5-pyrimidin-5-ylbenzamide;

N-(2-Methylbutan-2-yl)-3-(4-methylphenyl)-5-(4-propan-2-ylpyrimidin-5-yl)-benzamide;

N-(2-Methylbutan-2-yl)-3-(4-methylphenyl)-5-(4-methylpyridin-3-yl)-benzamide;

N-(2-Methylbutan-2-yl)-3-(4-methylphenyl)-5-(2-methylpyridin-3-yl)-benzamide;

N-(2-Methylbutan-2-yl)-3-(4-methylphenyl)-5-(4-propan-2-ylpyridin-3-yl)-benzamide;

or,

N-(2-Methylbutan-2-yl)-3-(4-methylphenyl)-5-(2-propan-2-ylpyridin-3-yl)-benzamide.

7. The compound of formula IC according to claim 1

8. The compound of formula IC according to claim 6, wherein the compound is:

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

or,

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

9. The compound of formula ID according to claim 1

10. The compound of formula ID according to claim 8, wherein the compound is:

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

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

or,

N-(1-Hydroxy-2-methylpropan-2-yl)-3-(4-propan-2-yl-pyrimidin-5-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide.

11. The compound of formula IE according to claim 1,

12. The compound of formula IE according to claim 10, which compound is:

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

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

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

or,

N-(2-Cyclopropylpropan-2-yl)-3-(4-fluorophenyl)-5-(4-methylpyridin-3-yl)-benzamide.

13. The compound of formula IF according to claim 1,

14. The compound of formula IF according to claim 12, which compound is:

N-(2-Cyanopropan-2-yl)-3-(3-fluoro-4-methylphenyl)-5-(4-propan-2-yl-pyrimidin-5-yl)-benzamide;

N-(2-Cyanopropan-2-yl)-3-(4-fluoro-3-methylphenyl)-5-(4-propan-2-yl-pyrimidin-5-yl)-benzamide;

N-(2-Cyanopropan-2-yl)-3-(4-fluorophenyl)-5-(4-propan-2-yl-pyrimidin-5-yl)-benzamide;

N-(2-Cyanopropan-2-yl)-3-(4-propan-2-yl-pyrimidin-5-yl)-5-[4-(trifluoromethyl)-phenyl]-benzamide;

or,

3-(4-Chlorophenyl)-N-(2-cyanopropan-2-yl)-5-(4-propan-2-yl-pyrimidin-5-yl)-benzamide.

15. The compound of formula IG according to claim 1,

16. The compound of formula IG according to claim 14, which compound is:

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

or,

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

17. A process for the manufacture of a compound of formula I as defined claim 1, which process comprises

a) reacting a compound of formula II

18. A process for the manufacture of a compound of formula I as defined claim 1, which process comprises reacting a compound of formula IV

19. A process for the manufacture of a compound of formula I as defined claim 1, which process comprises reacting a compound of formula XVII

20. A process for the manufacture of a compound of formula I as defined claim 1, which process comprises reacting a compound of formula XVIII

21. A pharmaceutical composition comprising a compound of formula I according to claim 1 and at least one pharmaceutically acceptable excipient, carrier or diluent.

22. A method for the treatment of 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 to a patient in need thereof.