Pyridopyrimidinones and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10280165-B2
Application number	US-201715783373-A
Country	US
Kind code	B2
Filing date	Oct 13, 2017
Priority date	Apr 15, 2015
Publication date	May 7, 2019
Grant date	May 7, 2019

Abstract

The invention relates to pyridopyrimidinone compounds of formula I

or pharmaceutically acceptable salts thereof, wherein X, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined herein, as well as pharmaceutical compositions comprising such compounds, and methods of treatment using such compounds.

First claim

The invention claimed is:

1. A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:
X is: —O—Ar; —NR a —Ar; or —Ar;
R 1 is: hydrogen; C 1-6 alkyl; halo; C 1-6 alkoxy; cyano; heteroaryl selected from furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl and pyrimidinyl, each of which may be unsubstituted or substituted once or twice with R b ; —C(O)—NHR c ; —C(O)—R c ; or cyclopropyl which may be unsubstituted or substituted once or twice with R d ;
R 2 is: hydrogen; C 1-6 alkyl; C 1-6 alkoxy; halo; or halo-C 1-6 alkyl;
R 3 is: hydrogen; C 1-6 alkyl; C 1-6 alkoxy; halo; or halo-C 1-6 alkyl;
R 4 is: hydrogen; or C 1-6 alkyl;
R 5 is: hydrogen; or C 1-6 alkyl;
R 6 is: hydrogen; or C 1-6 alkyl;
Ar is: phenyl or pyrazolyl, each of which may be unsubstituted or substituted one or two times with R e ;
R a is: hydrogen; or C 1-6 alkyl;
each R b is independently: C 1-6 alkyl; halo; halo-C 1-6 alkyl; or cyclopropyl;
R c is: C 1-6 alkyl; or halo-C 1-6 alkyl;
R d is: C 1-6 alkyl; halo; halo-C 1-6 alkyl; hydroxy-C 1-6 alkyl; C 1-6 alkoxy-C 1-6 alkyl; or cyano;
each R e is independently: C 1-6 alkyl; halo; halo-C 1-6 alkyl; —NH—C(O)—R f ; cyano; or cyclopropyl; and
R f is furanyl, thienyl, pyrrolyl, pyrazolyl or imidazolyl;
provided that 2-Benzyl-6-methyl-pyrido[1,2-a]pyrimidin-4-one; and 2-Benzyl-pyrido[1,2-a]pyrimidin-4-one; are excluded.

2. The compound of claim 1 , wherein X is Ar, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein R 1 is: C 1-6 alkyl; halo; C 1-6 alkoxy; cyano; or cyclopropyl which may be unsubstituted or substituted once or twice with R d , or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein R 1 is cyclopropyl which may be unsubstituted or substituted once or twice with R d , or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein R 2 is hydrogen, halo or C 1-6 alkyl, or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein R 3 is hydrogen, C 1-6 alkyl or halo-C 1-6 alkyl, or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , wherein R 4 is hydrogen, or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , wherein R 5 is hydrogen, or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 , wherein R 6 is hydrogen, or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , wherein Ar is pyrazolyl substituted one or two times with R e , or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 , wherein Ar is 3-chloro-5-(trifluoromethyl)pyrazol-1-yl, or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 , wherein each R d is independently cyano, C 1-6 alkyl or hydroxy-C 1-6 alkyl, or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 , wherein R d is cyano, or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 , wherein each R e is independently halo or halo-C 1-6 alkyl, or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 , wherein said compound is of formula III

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1 , wherein said compound is of formula IV

or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1 , wherein said compound is of formula V

or a pharmaceutically acceptable salt thereof.

18. The compound of claim 17 , wherein R d is cyano, C 1-6 alkyl or hydroxy-C 1-6 alkyl, or a pharmaceutically acceptable salt thereof.

19. The compound of claim 17 , wherein each R e is independently halo or halo-C 1-6 alkyl, or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1 selected from
(1R,2R)-2-[7-chloro-2-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidin-6-yl]cyclopropanecarbonitrile;
7-methyl-2-[(N-methylanilino)methyl]pyrido[1,2-a]pyrimidin-4-one;
2-[(N-ethylanilino)methyl]-7-methyl-pyrido[1,2-a]pyrimidin-4-one;
2-[(N-ethyl-4-fluoro-anilino)methyl]-7-methyl-pyrido[1,2-a]pyrimidin-4-one;
6-ethyl-2-[(N-ethyl-4-fluoro-anilino)methyl]pyrido[1,2-a]pyrimidin-4-one;
6-ethyl-2-[(N-ethylanilino)methyl]pyrido[1,2-a]pyrimidin-4-one;
2-[(N-ethyl-4-fluoro-anilino)methyl]-6-methyl-pyrido[1,2-a]pyrimidin-4-one;
2-[(N-ethyl-4-fluoro-anilino)methyl]-6-methoxy-pyrido[1,2-a]pyrimidin-4-one;
6-ethoxy-2-[(N-ethyl-4-fluoro-anilino)methyl]pyrido[1,2-a]pyrimidin-4-one;
2-[(N-ethyl-4-fluoro-anilino)methyl]-6-methoxy-7-methyl-pyrido[1,2-a]pyrimidin-4-one;
6-ethoxy-2-[(N-ethyl-4-fluoro-anilino)methyl]-7-methyl-pyrido[1,2-a]pyrimidin-4-one;
2-[(N-ethyl-4-fluoro-anilino)methyl]-6-pyrimidin-5-yl-pyrido[1,2-a]pyrimidin-4-one;
2-[(N-ethyl-4-fluoro-anilino)methyl]-6-(2-furyl)pyrido[1,2-a]pyrimidin-4-one;
2-[(N-ethyl-4-fluoro-anilino)methyl]-4-oxo-pyrido[1,2-a]pyrimidine-6-carbonitrile;
6-bromo-2-[(N-ethyl-4-fluoro-anilino)methyl]pyrido[1,2-a]pyrimidin-4-one;
N-ethyl-2-[(4-fluorophenoxy)methyl]-7-methyl-4-oxo-pyrido[1,2-a]pyrimidine-6-carboxamide;
2-[[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-7-methyl-4-oxo-pyrido[1,2-a]pyrimidine-6-carboxamide;
2-[[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-7-methyl-4-oxo-pyrido[1,2-a]pyrimidine-6-carboxamide;
2-[(3-cyano-2-fluoro-phenyl)methyl]-N-ethyl-7-methyl-4-oxo-pyrido[1,2-a]pyrimidine-6-carboxamide;
2-[[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-4-oxo-pyrido[1,2-a]pyrimidine-6-carboxamide;
2-[(3-cyano-2-fluoro-phenyl)methyl]-N-ethyl-4-oxo-pyrido[1,2-a]pyrimidine-6-carboxamide;
2-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-N,7-dimethyl-4-oxo-pyrido[1,2-a]pyrimidine-6-carboxamide;
2-[(3-chloro-2-fluoro-phenyl)methyl]-N,7-dimethyl-4-oxo-pyrido[1,2-a]pyrimidine-6-carboxamide;
2-[(3-cyclopropyl-2-fluoro-phenyl)methyl]-N,7-dimethyl-4-oxo-pyrido[1,2-a]pyrimidine-6-carboxamide;
2-[(3-cyano-2-fluoro-phenyl)methyl]-N,7-dimethyl-4-oxo-pyrido[1,2-a]pyrimidine-6-carboxamide;
2-[(3-cyano-2-fluoro-phenyl)methyl]-3-fluoro-N,7-dimethyl-4-oxo-pyrido[1,2-a]pyrimidine-6-carboxamide;
2-[(N-ethyl-4-fluoro-anilino)methyl]-N,7-dimethyl-4-oxo-pyrido[1,2-a]pyrimidine-6-carboxamide;
N-ethyl-7-methyl-4-oxo-2-[[3-(trifluoromethyl)pyrazol-1-yl]methyl]pyrido[1,2-a]pyrimidine-6-carboxamide;
2-[[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-N,7-dimethyl-4-oxo-pyrido[1,2-a]pyrimidine-6-carboxamide;
2-[[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-N,7-dimethyl-4-oxo-pyrido[1,2-a]pyrimidine-6-carboxamide;
2-[(3-chloro-2-fluoro-phenyl)methyl]-3-fluoro-N,7-dimethyl-4-oxo-pyrido[1,2-a]pyrimidine-6-carboxamide;
2-[[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-8-methyl-4-oxo-pyrido[1,2-a]pyrimidine-6-carboxamide;
2-[[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-7-methyl-4-oxo-N-(2,2,2-trifluoroethyl)pyrido[1,2-a]pyrimidine-6-carboxamide;
(1S,2S)-2-[2-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-7-methyl-4-oxo-pyrido[1,2-a]pyrimidin-6-yl]cyclopropanecarbonitrile;

Assignees

• Genentech Inc

Inventors

• Volgraf Matthew
• Jiang Yu
• Villemure Elisia
• Sellers Benjamin
• Wu Guosheng
• Lu Aijun

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07C271/28

  to a carbon atom of a non-condensed six-membered aromatic ring · CPC title

• A61P25/30

  for treating abuse or dependence · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/24

  Antidepressants · CPC title