6,7-dihydrobenzo[a]quinolizin-2-one derivatives for the treatment and prophylaxis of hepatitis B virus infection
The invention provides novel compounds having the general formula: wherein R 1 to R 6 , W and X are as described herein and their pharmaceutically acceptable salt, enantiomer or diastereomer thereof, and compositions including the compounds and methods of using the compounds.
1. A compound of formula (I)
wherein
R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, diC 1-6 alkylamino, cyano, N-containing monocyclic heterocycloalkyl and OR 7 , wherein
R 7 is hydrogen; C 1-6 alkyl; or C 1-6 alkyl which is substituted one or more times by fluoro, C 3-7 cycloalkyl, phenyl, hydroxyl, amino, C 1-6 alkoxy, C 1-6 alkylsulfanyl, C 1-6 alkylsulfonyl, diC 1-6 alkylamino, C 1-6 alkoxycarbonylamino, monocyclic heterocycloalkyl, pyrazoyl or imidazolyl;
R 5 is hydrogen or C 1-6 alkyl;
R 6 is hydrogen, C 1-6 alkyl, phenyl-C x H 2x —, C 1-6 alkylcarbonyl, C 1-6 alkylsulfonyl, benzoyl or monocyclic heterocycloalkyl, wherein
x is 1-6;
W is a bond, C y H 2y C(R 8 )(R 9 )C z H 2z or C y H 2y CH(R 8 )CH(R 9 )C z H 2z , wherein
R 8 and R 9 are independently selected from the group consisting of hydrogen, fluoro, hydroxy and C 1-6 alkyl,
y is 0-6;
z is 0-6;
X is a bond; O; S; S(O) 2 ; or NR 10 , wherein R 10 is hydrogen or C 1-6 alkyl;
or R 6 and R 10 , together with the nitrogen to which they are attached, form monocyclic heterocycloalkyl;
with the proviso that when X is a bond, R 6 is not hydrogen, C 1-6 alkyl or phenyl-C x H 2x —;
or a pharmaceutically acceptable salt, enantiomer, or diastereoisomer thereof.
2. The compound according to claim 1 , wherein
R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy, benzyloxy, trifluoromethylmethoxy, methoxyethoxy, methoxypropoxy, ethoxyethoxy, cyclopropylmethoxy, hydroxypropoxy, hydroxydimethylpropoxy, hydoxyhexoxy, (methylpyrrolidinyl)ethoxy, aminohexoxy, dimethylamino-propoxy, (tert-butoxycarb onylamino)hexoxy, methyl sulfanylpropoxy, methyl sulfonylpropoxy, pyrrolidinylpropoxy, (2-oxo-pyrrolidinyl)propoxy, pyrazoylpropoxy, imidazolylpropoxy, morpholinyl-propoxy, dimethylamino, cyano and pyrrolidinyl;
R 5 is hydrogen;
R 6 is hydrogen, methyl, benzyl, acetyl, methylsulfonyl, benzoyl, pyrrolidin-1-yl, 2-oxo-pyrrolidinyl or tetrahydropyranyl;
W is a bond, CH 2 , C(CH 3 ) 2 or C(CH 3 ) 2 CH 2 ;
X is a bond; O; S; S(O) 2 ; or NR 10 , wherein R 10 is hydrogen or methyl;
or R 6 and R 10 , together with the nitrogen to which they are attached, form pyrrolidinyl or 2-oxo-pyrrolidinyl;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
3. The compound according to claim 1 , wherein
R 1 is hydrogen;
R 2 is halogen or C 1-6 alkoxy;
R 3 is cyano, C 1-6 alkyl, pyrrolidinyl or OR 7 , wherein
R 7 is C 1-6 alkyl; or C 1-6 alkyl which is substituted one or more times by fluoro, hydroxy, amino, C 3-7 cycloalkyl, phenyl, C 1-6 alkoxy, C 1-6 alkylsulfanyl, C 1-6 alkylsulfonyl, morpholinyl, 2-oxo-pyrrolidinyl, pyrrolidinyl, diC 1-6 alkylamino, C 1-6 alkoxycarbonylamino, pyrazoyl or C 1-6 alkylpyrrolidinyl;
R 4 is hydrogen;
R 5 is hydrogen;
R 6 is hydrogen, C 1-6 alkyl, phenyl-C x H 2x , C 1-6 alkylcarbonyl, C 1-6 alkylsulfonyl, benzoyl or tetrahydropyranyl, wherein
x is 1-6;
W is a bond, C(R 8 )(R 9 )C z H 2z , wherein
R 8 and R 9 are independently selected from the group consisting of hydrogen and C 1-6 alkyl,
z is 0-6;
X is a bond; O; S; S(O) 2 ; or NR 10 , wherein R 10 is hydrogen or C 1-6 alkyl;
or R 6 and R 10 , together with the nitrogen to which they are attached, form pyrrolidinyl or 2-oxo-pyrrolidinyl;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
4. The compound according to claim 3 , wherein
R 1 is hydrogen;
R 2 is chloro, methoxy or ethoxy;
R 3 is cyano, ethyl, pyrrolidinyl, methoxy, ethoxy, benzyloxy, trifluoromethylmethoxy, methoxyethoxy, methoxypropoxy, ethoxyethoxy, cyclopropylmethoxy, hydroxypropoxy, hydroxy-dimethylpropoxy, hydoxyhexoxy, (methylpyrrolidinyl)ethoxy, aminohexoxy, dimethylaminopropoxy, morpholinylpropoxy, pyrrolidinylpropoxy, (2-oxo-pyrrolidinyl)propoxy, (tert-butoxycarbonylamino)hexoxy, methyl sulfanylpropoxy, methyl sulfonylpropoxy or pyrazoylpropoxy;
R 4 is hydrogen;
R 5 is hydrogen;
R 6 is hydrogen, methyl, benzyl, acetyl, methylsulfonyl, benzoyl or tetrahydropyranyl;
W is a bond, CH 2 , C(CH 3 ) 2 or C(CH 3 ) 2 CH 2 ;
X is a bond; O; S; S(O) 2 ; or NR 10 , wherein R 10 is hydrogen or methyl;
or R 6 and R 10 , together with the nitrogen to which they are attached, form pyrrolidinyl or 2-oxo-pyrrolidinyl;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
5. The compound of formula (IA) according to claim 3 , wherein
R 1 is hydrogen;
R 2 is halogen or C 1-6 alkoxy;
R 3 is cyano, C 1-6 alkyl, pyrrolidinyl or OR 7 , wherein
R 7 is C 1-6 alkyl; or C 1-6 alkyl which is substituted one or more times by fluoro, hydroxy, amino, C 3-7 cycloalkyl, phenyl, C 1-6 alkoxy, C 1-6 alkylsulfanyl, C 1-6 alkylsulfonyl, morpholinyl, 2-oxo-pyrrolidinyl, pyrrolidinyl, diC 1-6 alkylamino, C 1-6 alkoxycarbonylamino, C 1-6 alkylpyrrolidinyl or pyrazoyl;
R 4 is hydrogen;
R 5 is hydrogen;
R 6 is hydrogen, C 1-6 alkyl, phenyl-C x H 2x or C 1-6 alkylcarbonyl, wherein
x is 1-6;
W is C(R 8 )(R 9 )C z H 2z , wherein
R 8 and R 9 are independently selected from the group consisting of hydrogen and C 1-6 alkyl,
z is 0-6;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
6. The compound according to claim 5 , wherein
R 1 is hydrogen;
R 2 is chloro, methoxy or ethoxy;
R 3 is cyano, ethyl, pyrrolidinyl, methoxy, ethoxy, benzyloxy, trifluoromethylmethoxy, methoxypropoxy, ethoxyethoxy, cyclopropylmethoxy, hydroxypropoxy, hydroxydimethylpropoxy, hydoxyhexoxy, (methylpyrrolidinyl)ethoxy, aminohexoxy, dimethylamino-propoxy, morpholinylpropoxy, pyrrolidinylpropoxy, (2-oxo-pyrrolidinyl)propoxy, (tert-butoxycarbonylamino)hexoxy, methyl sulfanylpropoxy, methyl sulfonylpropoxy or pyrazoylpropoxy;
R 4 is hydrogen;
R 5 is hydrogen;
R 6 is hydrogen, methyl, benzyl or acetyl;
W is CH 2 , C(CH 3 ) 2 or C(CH 3 ) 2 CH 2 ;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
7. The compound according to claim 5 , wherein
R 1 is hydrogen;
R 2 is halogen or C 1-6 alkoxy;
R 3 is OR 7 , wherein
R 7 is C 1-6 alkyl; or C 1-6 alkyl which is substituted one or more times by fluoro, hydroxy, amino, C 3-7 cycloalkyl, phenyl, C 1-6 alkoxy, C 1-6 alkylsulfanyl, morpholinyl or C 1-6 alkoxycarbonylamino;
R 4 is hydrogen;
R 5 is hydrogen;
R 6 is hydrogen or C 1-6 alkyl;
W is C(R 8 )(R 9 )C z H 2z , wherein
R 8 and R 9 are independently selected from the group consisting of hydrogen and C 1-6 alkyl,
z is 0-6;
X is O;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
8. The compound according to claim 7 , wherein
R 1 is hydrogen;
R 2 is chloro or methoxy;
R 3 is methoxy, benzyloxy, trifluoromethylmethoxy, methoxypropoxy, ethoxyethoxy, cyclopropylmethoxy, hydroxypropoxy, hydroxydimethylpropoxy, aminohexoxy, morpholinylpropoxy, (tert-butoxycarbonylamino)hexoxy or methyl sulfanylpropoxy;
R 4 is hydrogen;
R 5 is hydrogen;
R 6 is hydrogen or methyl;
W is C(CH 3 ) 2 CH 2 ;
X is O;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
9. The compound according claim 1 , wherein R 2 is halogen or C 1-6 alkoxy, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
10. The compound according claim 9 , wherein R 2 is methoxy or chloro, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
11. The compound according to claim 10 , wherein R 3 is C 1-6 alkoxyC 1-6 alkoxy, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
12. The compound according to claim 11 , wherein R 3 is methoxypropoxy, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
13. The compound according to claim 12 , wherein R 6 is hydrogen or C 1-6 alkyl, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
14. The compound according to claim 13 , wherein R 6 is methyl, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
15. The compound according to claim 14 , wherein W is C(CH 3 ) 2 CH 2 , or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
16. The compound according to claim 1 , selected from the group consisting of
9-Benzyloxy-10-methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
9,10-Dimethoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
10-Methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-2-oxo-9-(2,2,2-trifluoroethoxy)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
10-Methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-9-(3-morpholinopropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
9-(6-Hydroxyhexoxy)-10-methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
9-(3-Hydroxypropoxy)-10-methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
9-(3-Hydroxy-2,2-dimethyl-propoxy)-10-methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
9-(2-Ethoxyethoxy)-10-methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
9-(Cyclopropylmethoxy)-10-methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
10-Methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-9-(3-methylsulfanylpropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
10-Methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-2-oxo-9-(3-pyrrolidin-1-ylpropoxy)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
10-Methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-2-oxo-9-[3-(2-oxopyrrolidin-1-yl)propoxy]-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
9-[3-(Dimethylamino)propoxy]-10-methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
9-[6-(tert-Butoxycarb onylamino)hexoxy]-10-methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carb oxylic acid;
10-Methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-9-(3-methylsulfonylpropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
9-(6-Aminohexoxy)-10-methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
10-Methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-9-[2-(1-methylpyrrolidin-2-yl)ethoxy]-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
10-Methoxy-6-(methoxymethyl)-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
6-(1-Hydroxy-1-methyl-ethyl)-10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
(+)-6-(1-Hydroxy-1-methyl-ethyl)-10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
(−)-6-(1-Hydroxy-1-methyl-ethyl)-10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
6-(2-Benzyloxy-1,1-dimethyl-ethyl)-10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
6-(2-Hydroxy-1,1-dimethyl-ethyl)-10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
(+)-6-(2-Hydroxy-1,1-dimethyl-ethyl)-10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
(−)-6-(2-Hydroxy-1,1-dimethyl-ethyl)-10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
10-Methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
(+)-10-Methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
(−)-10-Methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
10-Chloro-6-(2-methoxy-1,1-dimethyl-ethyl)-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
(+)-10-Chloro-6-(2-methoxy-1,1-dimethyl-ethyl)-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
(−)-10-Chloro-6-(2-methoxy-1,1-dimethyl-ethyl)-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
9,10-Diethoxy-6-(hydroxymethyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
6-(Acetoxymethyl)-9,10-diethoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
10-Methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-2-oxo-9-(3-pyrazol-1-ylpropoxy)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
9-Ethyl-10-methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carb oxylic acid;
10-Methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-2-oxo-9-pyrrolidin-1-yl-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid; and
9-Cyano-10-methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
17. The compound according to claim 1 , selected from the group consisting of
9-Benzyloxy-10-methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
9,10-Dimethoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
10-Methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-2-oxo-9-(2,2,2-trifluoroethoxy)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
10-Methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-9-(3-morpholinopropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
9-(3-Hydroxypropoxy)-10-methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
9-(3-Hydroxy-2,2-dimethyl-propoxy)-10-methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
9-(2-Ethoxyethoxy)-10-methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
9-(Cyclopropylmethoxy)-10-methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
10-Methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-9-(3-methylsulfanylpropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
9-[6-(tert-Butoxycarbonylamino)hexoxy]-10-methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
9-(6-Aminohexoxy)-10-methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
6-(2-Hydroxy-1,1-dimethyl-ethyl)-10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
(+)-6-(2-Hydroxy-1,1-dimethyl-ethyl)-10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
10-Methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
(+)-10-Methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
10-Chloro-6-(2-methoxy-1,1-dimethyl-ethyl)-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid; and
(+)-10-Chloro-6-(2-methoxy-1,1-dimethyl-ethyl)-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
18. The compound according to claim 3 , wherein
R 1 is hydrogen;
R 2 is halogen or C 1-6 alkoxy;
R 3 is C 1-6 alkoxy or C 1-6 alkoxyC 1-6 alkoxy;
R 4 is hydrogen;
R 5 is hydrogen;
R 6 is hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkylsulfonyl, benzoyl or tetrahydropyranyl;
W is a bond, C(R 8 )(R 9 )C z H 2z , wherein
R 8 and R 9 are independently selected from the group consisting of hydrogen and C 1-6 alkyl,
z is 0-6;
X is a bond; S; S(O) 2 ; or NR 10 , wherein R 10 is hydrogen or C 1-6 alkyl;
or R 6 and R 10 , together with the nitrogen to which they are attached, form pyrrolidinyl or 2-oxo-pyrrolidinyl;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
19. The compound according to claim 18 ; wherein
R 1 is hydrogen;
R 2 is chloro or ethoxy;
R 3 is ethoxy, methoxyethoxy or methoxypropoxy;
R 4 is hydrogen;
R 5 is hydrogen;
R 6 is hydrogen, methyl, acetyl, methylsulfonyl, benzoyl or tetrahydropyranyl;
W is a bond or CH 2 ;
X is a bond; S; S(O) 2 ; or R 10 , wherein R 10 is hydrogen or methyl;
or R 6 and R 10 , together with the nitrogen to which they are attached, form pyrrolidinyl or 2-oxo-pyrrolidinyl;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
20. The compound according to claim 1 , selected from the group consisting of
10-Chloro-9-(3-methoxypropoxy)-2-oxo-6-tetrahydropyran-4-yl-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
10-Chloro-9-(2-methoxyethoxy)-6-(methylsulfanylmethyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
10-Chloro-9-(2-methoxyethoxy)-6-(methylsulfonylmethyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
6-(Aminomethyl)-9,10-diethoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
9,10-Diethoxy-6-(methanesulfonamidomethyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
6-(Benzamidomethyl)-9,10-diethoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
9,10-Diethoxy-2-oxo-6-[(2-oxopyrrolidin-1-yl)methyl]-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
6-[[Acetyl(methyl)amino]methyl]-9,10-diethoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
9,10-Diethoxy-2-oxo-6-(pyrrolidin-1-ylmethyl)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid; and
6-[(Dimethylamino)methyl]-9,10-diethoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
21. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, and a therapeutically inert carrier.
22. A compound which is 9-(2-Ethoxyethoxy)-10-methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid or a pharmaceutically acceptable salt thereof.
23. A compound which is 10-Methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid or a pharmaceutically acceptable salt thereof.
24. A compound which is (+)-10-Methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid or a pharmaceutically acceptable salt thereof.
25. A compound which is (−)-10-Methoxy-6-(2-methoxy-1,1-dimethyl-ethyl)-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid or a pharmaceutically acceptable salt thereof.