Quinolone M1 receptor positive allosteric modulators
View Patent ↗The present invention is directed to quinolone compounds of general formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimer's disease, pain or sleep disorders, and to novel M1 receptor positive allosteric modulator compounds of formulae (II) to (VIII). The invention is also directed to pharmaceutical compositions comprising the compounds, and to the use of the compounds and compositions in the treatment of diseases in which the M1 receptor is involved.
1. A compound of formula (II):
and pharmaceutically acceptable salts thereof, wherein
R 2 and R 5 are each halogen;
R 9 , R 10 , R 11 , R 12 and R 13 are independently selected from the group consisting of
(1) hydrogen,
(2) halogen,
(3) cyano,
(4) —R 6 ,
(5) —O—R 6 ,
(6) —S(O) n —R 7 , and
(7) —OH,
wherein R 6 and R 7 are selected from the group consisting of
(a) —C 1-6 alkyl, and
(b) —(CH 2 ) m -aryl,
wherein said R 6 and R 7 alkyl or aryl moiety is optionally substituted with one or more aryl;
R 8 is selected from the group consisting of
(1) hydrogen,
(2) —C 1-6 alkyl, and
(3) —CH 2 -aryl,
wherein said R 8 alkyl or aryl moiety is optionally substituted with one or more
(a) halogen,
(b) cyano, and
(c) —O—C 1-6 alkyl, wherein said alkyl is optionally substituted with one or more halo;
m is 1, 2 or 3; and
n is 0, 1 or 2.
2. A compound of claim 1 , wherein R 9 , R 10 , R 11 , R 12 and R 13 are independently selected from the group consisting of
(1) hydrogen,
(2) halogen,
(3) —O—C 1-6 alkyl,
(4) —C 1-6 alkyl,
(5) hydroxyl, and
(6) cyano,
wherein the R 9 to R 13 alkyl moiety is optionally substituted with one or more halogen.
3. A compound of claim 1 , wherein R 8 is hydrogen.
4. A compound of claim 3 , wherein R 2 and R 5 are independently selected from chloro and fluoro.
5. A compound of claim 1 , wherein R 2 and R 5 are both fluoro.
6. A compound of claim 5 , wherein one or more of R 9 , R 10 , R 11 , R 12 and R 13 is halogen.
7. A compound of claim 6 , wherein two or more of R 9 , R 10 , R 11 , R 12 and R 13 is halogen.
8. A compound of claim 7 , wherein R 9 and R 13 are halogen.
9. A compound of claim 8 , wherein R 10 , R 11 and R 12 are hydrogen.
10. A compound of claim 1 , which is selected from the group consisting of
1-(4-(trifluoromethyl)benzyl)-5,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
5,8-difluoro-1-(3-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
5,8-difluoro-4-oxo-1-[2-(trifluoromethyl)benzyl]-1,4-dihydroquinoline-3-carboxylic acid;
1-(2,6-difluorobenzyl)-5,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
5,8-difluoro-4-oxo-1-[3-(trifluoromethyl)benzyl]-1,4-dihydroquinoline-3-carboxylic acid;
5,8-difluoro-4-oxo-1-[4-(trifluoromethyl)benzyl]-1,4-dihydroquinoline-3-carboxylic acid;
5,8-difluoro-4-oxo-1-[4-(trifluoromethoxy)benzyl]-1,4-dihydroquinoline-3-carboxylic acid;
1-(3,4-difluorobenzyl)-5,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
1-(2-cyanobenzyl)-5,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
1-(4-bromo-2-fluorobenzyl)-5,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
5,8-difluoro-4-oxo-1-(pyridin-3-ylmethyl)-1,4-dihydroquinoline-3-carboxylic acid;
1-(3,5-difluorobenzyl)-5,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
5,8-difluoro-4-oxo-1-[3-(trifluoromethoxy)benzyl]-1,4-dihydroquinoline-3-carboxylic acid;
1-[2-chloro-5-(trifluoromethyl)benzyl]-5,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
5,8-difluoro-1-[2-fluoro-5-(trifluoromethyl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
1-[4-chloro-3-(trifluoromethyl)benzyl]-5,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
5,8-difluoro-1-(4-fluorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
5,8-difluoro-1-(3-fluoro-4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
1-[4-(difluoromethoxy)benzyl]-5,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
1-benzyl-5,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
and pharmaceutically acceptable salts thereof.
11. A compound of claim 10 , which is selected from the group consisting of
1-(4-(trifluoromethyl)benzyl)-5,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
5,8-difluoro-1-(3-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
5,8-difluoro-4-oxo-1-[2-(trifluoromethyl)benzyl]-1,4-dihydroquinoline-3-carboxylic acid;
1-(2,6-difluorobenzyl)-5,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
5,8-difluoro-4-oxo-1-[3-(trifluoromethyl)benzyl]-1,4-dihydroquinoline-3-carboxylic acid;
5,8-difluoro-4-oxo-1-[4-(trifluoromethyl)benzyl]-1,4-dihydroquinoline-3-carboxylic acid;
and pharmaceutically acceptable salts thereof.
12. A compound of claim 10 in salt form, wherein the salt is selected from the group consisting of a lithium salt, ammonium salt, sodium salt, calcium salt and potassium salt.
13. A pharmaceutical composition comprising a compound of claim 11 and a pharmaceutically acceptable carrier.