Flouro-naphthyl derivatives
The present invention relates to compounds of formula wherein R 1 is C 4-6 -cycloalkyl or C 4-6 -heterocycloalkyl, which are optionally substituted by one or two substituents, selected from hydroxy or lower alkyl; A is phenyl, pyridinyl or piperidinyl; R 2 is hydrogen, halogen, lower alkyl, cyano, C 4-6 -cycloalkyl, lower alkoxy, lower alkoxy substituted by halogen, or is a five- or six-membered heteroaryl, optionally substituted by lower alkyl; n is 1 or 2; or to a pharmaceutically acceptable acid addition salt, to a racemic mixture or to its corresponding enantiomer and/or optical isomers thereof. The compounds may be used for the treatment or prophylaxis of Alzheimer's disease, cognitive impairment, schizophrenia, pain or sleep disorders.
1. A compound of formula I
wherein
R 1 is C 4-6 -cycloalkyl or C 4-6 -heterocycloalkyl, which are optionally substituted by one or two substituents, selected from hydroxy or lower alkyl;
A is phenyl, pyridinyl or piperidinyl;
R 2 is hydrogen, halogen, lower alkyl, cyano, C 4-6 -cycloalkyl, lower alkoxy, lower alkoxy substituted by halogen, or is a five- or six-membered heteroaryl, optionally substituted by lower alkyl; n is 1 or 2;
or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof.
2. A compound of formula I according to claim 1 , wherein A is phenyl and the other substituents are as described in claim 1 .
3. A compound of formula I according to claim 2 , which compounds are
1-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-4-(4-methylbenzyl)-2-naphthamide
4-benzyl-1-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-2-naphthamide
4-(4-chlorobenzyl)-1-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-2-naphthamide
4-(4-cyanobenzyl)-1-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-2-naphthamide
1-fluoro-4-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-2-naphthamide
1-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethoxy)benzyl)-2-naphthamide or
1-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-4-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-2-naphthamide.
4. A compound of formula I according to claim 1 , wherein A is pyridinyl and the other substituents are as described in claim 1 .
5. A compound of formula I according to claim 4 , wherein the compounds are
4-((6-chloropyridin-3-yl)methyl)-1-fluoro-N-((1SR,2SR)-2-hydroxycyclohexyl)-2-naphthamide
4-((6-chloropyridin-3-yl)methyl)-1-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-2-naphthamide
4-((6-chloropyridin-3-yl)methyl)-1-fluoro-N-((1S,2S)-2-hydroxycyclohexyl)-2-naphthamide
4-((6-chloropyridin-3-yl)methyl)-1-fluoro-N-((3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl)-2-naphthamide
4-((6-chloropyridin-3-yl)methyl)-1-fluoro-N-((1S,2S)-2-hydroxycyclopentyl)-2-naphthamide
4-((6-chloropyridin-3-yl)methyl)-1-fluoro-N-((1S,2R)-2-hydroxycyclopentyl)-2-naphthamide
4-((6-chloropyridin-3-yl)methyl)-1-fluoro-N-((1SR,2SR)-2-hydroxy-2-methylcyclohexyl)-2-naphthamide
4-((6-chloropyridin-3-yl)methyl)-1-fluoro-N-((1SR,2RS)-2-hydroxy-2-methylcyclohexyl)-2-naphthamide
4-((6-chloropyridin-3-yl)methyl)-1-fluoro-N-((1SR,2RS)-2-hydroxycyclohexyl)-2-naphthamide
1-fluoro-N-((1S,2 S)-2-hydroxycyclhexyl)-4-((6-(1-methyl-1H-pyrazol-4-yl) pyridin-3-yl)methyl)-2-naphthamide
1-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-4-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2-naphthamide
1-fluoro-N-[(3S,4R)-3-hydroxytetrahydropyran-4-yl]-4-[[6-(1-methylpyrazol-4-yl)-3-pyridyl]methyl]naphthalene-2-carboxamide
1-fluoro-N-[(3R,4S)-3-hydroxytetrahydropyran-4-yl]-4-[[6-(1-methylpyrazol-4-yl)-3-pyridyl]methyl]naphthalene-2-carboxamide
1-fluoro-N-((3S,4 S)-4-hydroxytetrahydro-2H-pyran-3-yl)-4-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2-naphthamide
1-fluoro-N-((1SR,2RS)-2-hydroxy-2-methylcyclohexyl)-4-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2-naphthamide
1-fluoro-N-((1SR,2SR)-2-hydroxycyclohexyl)-4-((6-methylpyridin-3-yl)methyl)-2-naphthamide
4-((6-cyclopropylpyridin-3-yl)methyl)-1-fluoro-N-((1S,2S)-2-hydroxycyclohexyl)-2-naphthamide
or 4-[(6-chloropyridin-3-yl)methyl]-1-fluoro-N-[(3S,4R)-3-hydroxyoxan-4-yl]naphthalene-2-carboxamide.
6. A compound of formula I according to claim 1 , wherein A is piperidinyl and the other substituents are as described above.
7. A compound of formula I according to claim 6 , wherein the compound is 4-((4-cyano-4-(pyridin-2-yl)piperidin-1-yl)methyl)-1-fluoro-N-((1S,2 S)-2-hydroxycyclohexyl)-2-naphthamide.
8. A process for the manufacture of a compound of formula I as defined in claim 1 , which process comprises reacting a compound of formula 1:
with a compound of formula 2:
R 1 NH 2 (2)
in the presence of an activating agent, selected from BOP (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate or thionyl chloride, to a compound of formula I:
wherein the substituents are as defined in claim 1 ,
and, if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.
9. A compound manufactured by the process of claim 8 .
10. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutical acceptable carrier and/or adjuvant.
11. Pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutical acceptable carrier and/or adjuvant for use in the treatment of Alzheimer's disease, cognitive impairment, schizophrenia, pain or sleep disorders.
12. A method for the treatment of Alzheimer's disease, cognitive impairment, schizophrenia, pain or sleep disorders, which method comprises administering an effective amount of a compound as defined in claim 1 .