IP Library › Granted Patent US 9,458,153

Granted Patent B2

US 9,458,153 · App. 14/610,454 · Granted Oct 4, 2016

Dihydroquinolizinones for the treatment and prophylaxis of hepatitis B virus infection

Inventors: Xingchun Han (Shanghai, CN); Hassan Javanbakht (Basel, CH); Min Jiang (Shanghai, CN); Chungen Liang (Shanghai, CN); Jianping Wang (Shanghai, CN); Yongguang Wang (Shanghai, CN); Zhanguo Wang (Shanghai, CN); Robert James Weikert (Basel, CH); Song Yang (Shanghai, CN); Chengang Zhou (Shanghai, CN)

Assignee: Hoffmann-La Roche INC.

C07D455/06 C07D471/04

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Quick Facts

Patent No.: US 9,458,153
App. No.: 14/610,454
Granted: Oct 4, 2016
Kind: B2

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Abstract

The invention provides novel compounds having the general formula: wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as described herein, compositions including the compounds and methods of using the compounds.

Claims (375)

1. A compound of formula IA,

wherein

R 1 is hydrogen, halogen or C 1-6 alkoxy;

R 2 is hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, hydroxy or phenyl-C x H 2x —O—;

R 4 is hydrogen or halogen;

R 5 is hydrogen or C 1-6 alkyl;

R 6 is hydrogen; C 1-6 alkyl, which is unsubstituted or once, twice or three times substituted by fluoro; C 3-7 cycloalkyl; C 1-6 alkylC 3-7 cycloalkyl; or phenyl-C x H 2x —;

R 7 is hydrogen; C 1-6 alkyl, which is unsubstituted or substituted with one to three substituents independently selected from fluoro, hydroxy and ethenyl; C 1-6 alkoxyC 1-6 alkyl; C 1-6 alkoxyC 1-6 alkoxyC 1-6 alkyl; aminoC 1-8 alkyl; C 1-6 alkylcarbonylaminoC 1-8 alkyl; C 1-6 alkylsulfonylaminoC 1-8 alkyl; C 1-6 alkylsulfanylC 1-6 alkyl; C 1-6 alkylsulfonylC 1-6 alkyl; cyanoC 1-6 alkyl; C 3-7 cycloalkylC 1-6 alkyl; cyanoC 3-7 cycloalkylC 1-6 alkyl; phenylC 1-6 alkyl; pyrrolidinylcarbonylC 1-6 alkyl; C 2-6 alkynyl; hydroxyC 1-6 alkylC 2-6 alkynyl; aminoC 1-6 alkoxyC 1-6 alkyl; C 1-6 alkylaminoC 1-6 alkoxyC 1-6 alkyl; carboxyC 1-6 alkyl; C 1-6 alkoxycarbonylaminoC 1-8 alkyl; heteroarylC 1-6 alkyl, wherein heteroaryl is N-containing monocyclic heteroaryl; or heterocycloalkylC 1-6 alkyl, wherein heterocycloalkyl is monocyclic heterocycloalkyl;

x is 1-6;

or pharmaceutically acceptable salts, or enantiomers thereof.

2. A compound according to claim 1 , wherein

R 1 is hydrogen, fluoro, chloro or methoxy;

R 2 is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy, propoxy, cyclopropyl, hydroxy or phenylmethyl-O—;

R 4 is hydrogen or chloro;

R 5 is hydrogen or methyl;

R 6 is hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, trifluoromethylmethyl, cyclopropyl, cyclobutyl, methylcyclopropyl or phenylmethyl;

R 7 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, difluoromethylmethyl, difluoromethylethyl, trifluoromethylmethyl, ethyldifluoromethyl, vinyldifluoromethyl, propargyl, hydroxymethylpropargyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxyethyl, methoxyethyl-O-ethyl, aminoethyl, aminopentyl, aminohexyl, aminooctyl, tert-butoxycarbonylaminopentyl, tert-butoxycarbonylaminohexyl, tert-butoxycarbonylaminooctyl, methylcarbonylaminoethyl, methylcarbonylaminopentyl, methylsulfonylaminoethyl, methylsulfonylaminopentyl, methylsulfonylethyl, methylsulfonylpropyl, methylsulfanylpropyl, cyanopropyl, cyanocyclopropylmethyl, cyclopropylmethyl, cyclohexylethyl, hydroxyethyl, hydroxypropyl, hydroxy-dimethylpropyl, hydroxy-difluoropropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, aminoethyl-O-propyl, ethylamino-ethyl-O-propyl-, imidazolylethyl, pyrazolylpropyl, triazolylpropyl, morpholinylethyl, morpholinylpropyl, (2-oxo-pyrrolidinyl)ethyl, (2-oxo-pyrrolidinyl)propyl, phenylmethyl, phenylethyl, pyrrolidinylethyl, pyrrolidinylpropyl, pyrrolidinylcarbonylmethyl, tetrahydropyranylmethyl or carboxypropyl;

or pharmaceutically acceptable salts, or enantiomers thereof.

3. A compound according to claim 1 , wherein

R 1 is hydrogen or halogen;

R 2 is C 1-6 alkyl, halogen or C 3-7 cycloalkyl;

R 4 is hydrogen;

R 5 is hydrogen or C 1-6 alkyl;

R 6 is C 1-6 alkyl or C 1-6 alkylC 3-7 cycloalkyl;

R 7 is C 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl; or phenylC 1-6 alkyl;

or pharmaceutically acceptable salts, or enantiomers thereof.

4. A compound according to claim 1 , wherein

R 1 is hydrogen, fluoro or chloro;

R 2 is methyl, ethyl, fluoro, chloro or cyclopropyl;

R 4 is hydrogen;

R 5 is hydrogen or methyl;

R 6 is methyl, ethyl, isopropyl, isobutyl, tert-butyl or methylcyclopropyl;

R 7 is methyl, ethyl, methoxyethyl, methoxypropyl or phenylmethyl;

or pharmaceutically acceptable salts, or enantiomers thereof.

5. A compound according to claim 1 , wherein

R 1 is hydrogen;

R 2 is C 1-6 alkoxy;

R 4 is hydrogen or halogen;

R 5 is hydrogen or C 1-6 alkyl;

R 6 is hydrogen; C 1-6 alkyl, which is unsubstituted or once, twice or three times substituted by fluoro; C 3-7 cycloalkyl; C 1-6 alkylC 3-7 cycloalkyl; or phenyl-C x H 2x —;

R 7 is hydrogen; C 1-6 alkyl, which is unsubstituted or substituted with one to three substituents independently selected from fluoro, hydroxy and C 2-6 alkenyl; C 1-6 alkoxyC 1-6 alkyl; C 1-6 alkoxyC 1-6 alkoxyC 1-6 alkyl; aminoC 1-8 alkyl; C 1-6 alkylcarbonylaminoC 1-8 alkyl; C 1-6 alkylsulfonylaminoC 1-8 alkyl; C 1-6 alkylsulfanylC 1-6 alkyl; C 1-6 alkylsulfonylC 1-6 alkyl; cyanoC 1-6 alkyl; cyanoC 3-7 cycloalkylC 1-6 alkyl; C 3-7 cycloalkylC 1-6 alkyl; phenylC 1-6 alkyl; pyrrolidinylcarbonylC 1-6 alkyl; C 2-6 alkynyl; hydroxyC 1-6 alkylC 2-6 alkynyl; aminoC 1-6 alkoxyC 1-6 alkyl; C 1-6 alkylaminoC 1-6 alkoxyC 1-6 alkyl; carboxyC 1-6 alkyl; C 1-6 alkoxycarbonylaminoC 1-8 alkyl; imidazolylC 1-6 alkyl; pyrazolylC 1-6 alkyl; triazolylC 1-6 alkyl; morpholinylC 1-6 alkyl; (2-oxo-pyrrolidinyl)C 1-6 alkyl; pyrrolidinylC 1-6 alkyl; or tetrahydropyranylC 1-6 alkyl;

x is 1-6;

or pharmaceutically acceptable salts, or enantiomers thereof.

6. A compound according to claim 1 , wherein

R 1 is hydrogen;

R 2 is methoxy, ethoxy or propoxy;

R 4 is hydrogen or chloro;

R 5 is hydrogen or methyl;

R 6 is hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, trifluoromethylmethyl, cyclopropyl, cyclobutyl, methylcyclopropyl or phenylmethyl;

or pharmaceutically acceptable salts, or enantiomers thereof.

7. A compound according to claim 1 , wherein

R 1 is hydrogen or halogen;

R 2 is halogen, C 1-6 alkyl, C 1-6 alkoxy or C 3-7 cycloalkyl;

R 4 is hydrogen;

R 5 is hydrogen or C 1-6 alkyl;

R 6 is C 1-6 alkyl, which is unsubstituted or once, twice or three times substituted by fluoro; C 3-7 cycloalkyl or C 1-6 alkylC 3-7 cycloalkyl;

R 7 is C 1-6 alkyl, which is unsubstituted or substituted with one to three substituents independently selected from fluoro and hydroxy; C 1-6 alkoxyC 1-6 alkyl; aminoC 1-8 alkyl; C 1-6 alkylcarbonylaminoC 1-8 alkyl; C 1-6 alkylsulfonylaminoC 1-8 alkyl; C 1-6 alkylsulfanylC 1-6 alkyl; C 1-6 alkylsulfonylC 1-6 alkyl; C 3-7 cycloalkylC 1-6 alkyl; phenylC 1-6 alkyl; C 1-6 alkylaminoC 1-6 alkoxyC 1-6 alkyl; C 1-6 alkoxycarbonylaminoC 1-8 alkyl; morpholinylC 1-6 alkyl or tetrahydropyranylC 1-6 alkyl;

or pharmaceutically acceptable salts, or enantiomers thereof.

8. A compound according to claim 1 , wherein

R 1 is hydrogen, fluoro, or chloro;

R 2 is fluoro, chloro, methyl, ethyl, methoxy, ethoxy or cyclopropyl;

R 4 is hydrogen;

R 5 is hydrogen or methyl;

R 6 is methyl, ethyl, isopropyl, isobutyl, tert-butyl, trifluoromethylmethyl, cyclobutyl or methylcyclopropyl;

R 7 is methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl, difluoromethylmethyl, difluoroethylmethyl, difluoromethylethyl, trifluoromethylmethyl, ethyl difluoromethyl, methoxyethyl, methoxypropyl, ethoxyethyl, aminohexyl, aminooctyl, tert-butoxycarbonylaminopentyl, tert-butoxycarbonylaminooctyl, methylcarbonylaminopentyl, methylsulfonylaminopentyl, methylsulfonylpropyl, methylsulfanylpropyl, hydroxypropyl, hydroxy-dimethylpropyl, hydroxy-difluoropropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, ethyl amino-ethyl-O-propyl-, morpholinylethyl, morpholinylpropyl, phenylmethyl or tetrahydropyranylmethyl;

or pharmaceutically acceptable salts, or enantiomers thereof.

9. A compound according to claim 1 , or pharmaceutically acceptable salts, or enantiomers thereof, wherein R 7 is methoxyethyl, methoxypropyl, hydroxydimethylpropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, aminobutyl, aminopentyl or aminohexyl.

10. A compound according to claim 1 , selected from

9-Benzyloxy-10-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

9-Hydroxy-10-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

9,11-Dimethoxy-6-methyl-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

9-Ethoxy-10-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

9,10-Diethoxy-6-ethyl-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-9,10-Diethoxy-6-ethyl-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-9,10-Diethoxy-6-ethyl-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

9-Benzyloxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-9-Benzyloxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-9-Benzyloxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-6-Ethyl-10-methoxy-2-oxo-9-(2,2,2-trifluoroethoxy)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-6-Ethyl-10-methoxy-2-oxo-9-(2,2,2-trifluoroethoxy)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-Ethyl-9isopropoxy-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-Ethyl-10-methoxy-2-oxo-9-(2-phenylethoxy)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

9-Butoxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

9-(2-Cyclohexylethoxy)-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-Ethyl-10-methoxy-2-oxo-9-prop-2-ynoxy-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-Ethyl-10-methoxy-2-oxo-9-(2-oxo-2-pyrrolidin-1-yl-ethoxy)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-Ethyl-10-methoxy-9-[2-(2-methoxyethoxy)ethoxy]-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-Ethyl-10-methoxy-9-(2-morpholinoethoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-Ethyl-9-(2-hydroxyethoxy)-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-Ethyl-9-(3-hydroxy-2,2-dimethyl-propoxy)-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-6-Ethyl-9-(3-hydroxy-2,2-dimethyl-propoxy)-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-6-Ethyl-9-(3-hydroxy-2,2-dimethyl-propoxy)-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-Ethyl-9-(3-hydroxypropoxy)-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-Ethyl-9-(2-imidazol-1-ylethoxy)-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-Ethyl-10-methoxy-9-(2-methoxyethoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-6-Ethyl-10-methoxy-9-(2-methoxyethoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-6-Ethyl-10-methoxy-9-(2-methoxyethoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

9-(Cyclopropylmethoxy)-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-9-(Cyclopropylmethoxy)-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-9-(Cyclopropylmethoxy)-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-Ethyl-9-isobutoxy-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-6-Ethyl-9-isobutoxy-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-6-Ethyl-9-isobutoxy-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

9-Ethoxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-9-Ethoxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-9-Ethoxy-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-Ethyl-10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-6-Ethyl-10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-6-Ethyl-10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

9-(2-Ethoxyethoxy)-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-9-(2-Ethoxyethoxy)-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-9-(2-Ethoxyethoxy)-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

9-(2,2-Difluoroethoxy)-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-9-(2,2-Difluoroethoxy)-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-9-(2,2-Difluoroethoxy)-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-Ethyl-10-methoxy-2-oxo-9-(tetrahydropyran-4-ylmethoxy)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-6-Ethyl-10-methoxy-2-oxo-9-(tetrahydropyran-4-ylmethoxy)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-6-Ethyl-10-methoxy-2-oxo-9-(tetrahydropyran-4-ylmethoxy)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-Ethyl-10-methoxy-2-oxo-9-(2-pyrrolidin-1-ylethoxy)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

9-(3-Cyanopropoxy)-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-Ethyl-10-methoxy-9-(2-methylsulfonylethoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-Ethyl-10-methoxy-2-oxo-9-[2-(2-oxopyrrolidin-1-yl)ethoxy]-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-6-Ethyl-10-methoxy-2-oxo-9-[2-(2-oxopyrrolidin-1-yl)ethoxy]-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-Ethyl-9-[2-(methanesulfonamido)ethoxy]-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

9-[(1-Cyanocyclopropyl)methoxy]-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

9-(2-Acetamidoethoxy)-6-ethyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

10-Chloro-9-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

9,10-Dimethoxy-6-methyl-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-9,10-Dimethoxy-6-methyl-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-9,10-Dimethoxy-6-methyl-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

9,10-Dimethoxy-7-methyl-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-Ethyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(6R)-(+)-6-Ethyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(6S)-(−)-6-Ethyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

9-Methoxy-6,10-dimethyl-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

9,10-Diethoxy-6-methyl-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

9-Ethoxy-6-methyl-10-hydroxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

9,10-Diethoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

2-Oxo-9,10-dipropoxy-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-Ethyl-10-methoxy-2-oxo-9-propoxy-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-6-Ethyl-10-methoxy-2-oxo-9-propoxyl-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-6-Ethyl-10-methoxy-2-oxo-9-propoxyl-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

8-Chloro-9-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

8-Chloro-9,10-dimethoxy-6-methyl-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

10-Benzyloxy-9-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

10-Ethoxy-9-methoxy-6-methyl-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

9-Methoxy-6-methyl-2-oxo-10-propoxy-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6,10-Diethyl-9-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

10-Cyclopropyl-6-ethyl-9-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-10-Cyclopropyl-6-ethyl-9-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-10-Cyclopropyl-6-ethyl-9-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

9,10-Dimethoxy-2-oxo-6-propyl-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-Cyclopropyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-Isopropyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-6-Isopropyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-6-Isopropyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-Isobutyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-6-Isobutyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-6-Isobutyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

10-Chloro-6-isobutyl-9-(2-methoxyethoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-10-Chloro-6-isobutyl-9-(2-methoxyethoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-10-Chloro-6-isobutyl-9-(2-methoxyethoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

10-Chloro-6-isopropyl-9-(2-methoxyethoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-10-Chloro-6-isopropyl-9-(2-methoxyethoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-10-Chloro-6-isopropyl-9-(2-methoxyethoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

10-Fluoro-6-isopropyl-9-(2-methoxyethoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

11-Chloro-6-isopropyl-9-(2-methoxyethoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

9,10-Dimethoxy-2-oxo-6-(trifluoromethyl)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

9-Benzyloxy-6-ethyl-10-methyl-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-9-Benzyloxy-6-ethyl-10-methyl-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-9-Benzyloxy-6-ethyl-10-methyl-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-10-Chloro-9-ethoxy-6-ethyl-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-10-Chloro-9-ethoxy-6-ethyl-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

10-Chloro-6-isopropyl-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-10-Chloro-6-isopropyl-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-10-Chloro-6-isopropyl-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

10-Methoxy-6-isopropyl-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-10-Methoxy-6-isopropyl-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-10-Methoxy-6-isopropyl-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-Isopropyl-10-methoxy-2-oxo-9-(2,2,2-trifluoroethoxy)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-6-Isopropyl-10-methoxy-2-oxo-9-(2,2,2-trifluoroethoxy)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-6-Isopropyl-10-methoxy-2-oxo-9-(2,2,2-trifluoroethoxy)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-6-Isopropyl-10-methoxy-9-(2-methoxyethoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-6-Isopropyl-10-methoxy-9-(2-methoxyethoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-tert-Butyl-10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-6-tert-Butyl-10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-6-tert-Butyl-10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

10-Methoxy-9-(2-methoxyethoxy)-6-(1-methylcyclopropyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-10-Methoxy-9-(2-methoxyethoxy)-6-(1-methylcyclopropyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-10-Methoxy-9-(2-methoxyethoxy)-6-(1-methylcyclopropyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

11-Chloro-10-fluoro-6-isopropyl-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-11-Chloro-10-fluoro-6-isopropyl-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-11-Chloro-10-fluoro-6-isopropyl-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

10-Fluoro-6-isopropyl-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-tert-Butyl-9-(2,2-difluoro-3-hydroxy-propoxy)-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-9-(2,2-Difluoroethoxy)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-9-(2,2-Difluoroethoxy)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

9-(3-Hydroxy-2,2-dimethyl-propoxy)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-9-(3-Hydroxy-2,2-dimethyl-propoxy)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-9-(3-Hydroxy-2,2-dimethyl-propoxy)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

9-(3-Hydroxypropoxy)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-Isopropyl-10-methoxy-9-(4-methoxybutoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-tert-Butyl-9-(3-hydroxy-2,2-dimethyl-propoxy)-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-6-tert-Butyl-9-(3-hydroxy-2,2-dimethyl-propoxy)-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-6-tert-Butyl-9-(3-hydroxy-2,2-dimethyl-propoxy)-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-tert-Butyl-9-(5-hydroxypentoxy)-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-6-tert-Butyl-9-(5-hydroxypentoxy)-10-methoxy-2-oxo-6, 7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-6-tert-Butyl-9-(5-hydroxypentoxy)-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-tert-Butyl-9-(6-hydroxyhexoxy)-10-methoxy-2-oxo-6 7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-6-tert-Butyl-9-(6-hydroxyhexoxy)-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-6-tert-Butyl-9-(6-hydroxyhexoxy)-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-tert-Butyl-9-(4-hydroxybutoxy)-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-tert-Butyl-9-(4-hydroxybut-2-ynoxy)-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

9-(6-Aminohexoxy)-6-tert-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

9-[6-(tert-Butoxycarbonylamino)hexoxy]-6-tert-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-9-[6-(tert-Butoxycarbonylamino)hexoxy]-6-tert-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-9-[6-(tert-Butoxycarbonylamino)hexoxy]-6-tert-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-9-(6-Aminohexoxy)-6-tert-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid hydrochloride;

(−)-9-(6-Aminohexoxy)-6-tert-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid hydrochloride;

9-(8-Aminooctoxy)-6-tert-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

9-[8-(tert-Butoxycarbonylamino)octoxy]-6-tert-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-9-[8-(tert-Butoxycarbonylamino)octoxy]-6-tert-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-9-[8-(tert-Butoxycarbonylamino)octoxy]-6-tert-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-9-(8-Aminooctoxy)-6-tert-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid hydrochloride;

(−)-9-(8-Aminooctoxy)-6-tert-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid hydrochloride;

9-[5-(tert-Butoxycarbonylamino)pentoxy]-6-tert-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-9-(5-Aminopentoxy)-6-tert-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid hydrochloride;

(−)-9-(5-Aminopentoxy)-6-tert-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid hydrochloride;

9-(5-Acetamidopentoxy)-6-tert-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-tert-Butyl-9-[5-(methanesulfonamido)pentoxy]-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

9-(2-Aminoethoxy)-6-tert-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

9-[3-(2-Aminoethoxy)propoxy]-6-tert-butyl-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-tert-Butyl-9-[3-[2-(ethylamino)ethoxy]propoxy]-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-tert-Butyl-9-(3,3-difluoropropoxy)-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-tert-Butyl-9-(1,1-difluoropropoxy)-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-tert-Butyl-9-(1,1-difluoroallyloxy)-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-tert-Butyl-10-methoxy-9-(3-methylsulfanylpropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-6-tert-Butyl-10-methoxy-9-(3-methylsulfanylpropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-6-tert-Butyl-10-methoxy-9-(3-methylsulfanylpropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-tert-Butyl-10-methoxy-9-(3-methylsulfonylpropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-6-tert-Butyl-10-methoxy-9-(3-methylsulfonylpropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-6-tert-Butyl-10-methoxy-9-(3-methylsulfonylpropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-tert-Butyl-10-methoxy-9-(2-morpholinoethoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid hydrochloride;

(+)-6-tert-Butyl-10-methoxy-9-(2-morpholinoethoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-6-tert-Butyl-10-methoxy-9-(2-morpholinoethoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-tert-Butyl-10-methoxy-9-(3-morpholinopropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid hydrochloride;

(+)-6-tert-Butyl-10-methoxy-9-(3-morpholinopropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-6-tert-Butyl-10-methoxy-9-(3-morpholinopropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-tert-Butyl-10-methoxy-2-oxo-9-[3-(2-oxopyrrolidin-1-yl)propoxy]-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-tert-Butyl-10-methoxy-2-oxo-9-(3-pyrrolidin-1-ylpropoxy)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-Cyclobutyl-10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

9,10-Dimethoxy-2-oxo-6-(2,2,2-trifluoroethyl)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

10-Methoxy-9-(3-methoxypropoxy)-2-oxo-6-(2,2,2-trifluoroethyl)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-10-Methoxy-9-(3-methoxypropoxy)-2-oxo-6-(2,2,2-trifluoroethyl)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-10-Methoxy-9-(3-methoxypropoxy)-2-oxo-6-(2,2,2-trifluoroethyl)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-tert-Butyl-10-chloro-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-6-tert-Butyl-10-chloro-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-6-tert-Butyl-10-chloro-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

10-Chloro-9-(3-methoxypropoxy)-6-(1-methylcyclopropyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-10-Chloro-9-(3-methoxypropoxy)-6-(1-methylcyclopropyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-10-Chloro-9-(3-methoxypropoxy)-6-(1-methylcyclopropyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

10-Methoxy-9-(3-methoxypropoxy)-6-(1-methylcyclopropyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-10-Methoxy-9-(3-methoxypropoxy)-6-(1-methylcyclopropyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-10-Methoxy-9-(3-methoxypropoxy)-6-(1-methylcyclopropyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-Benzyl-9,10-dimethoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

10-Chloro-6-ethyl-9-(2-methoxyethoxy)-7-methyl-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(6R*,7S*)-10-Chloro-6-ethyl-9-(2-methoxyethoxy)-7-methyl-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(6R*,7R*)-10-Chloro-6-ethyl-9-(2-methoxyethoxy)-7-methyl-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

10,11-Difluoro-6-isopropyl-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(+)-10,11-Difluoro-6-isopropyl-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

(−)-10,11-Difluoro-6-isopropyl-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-tert-Butyl-10-methoxy-2-oxo-9-(3-pyrazol-1-ylpropoxy)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

6-tert-Butyl-10-methoxy-2-oxo-9-[3-(1,2,4-triazol-1-yl)propoxy]-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid; and

6-tert-Butyl-9-(3-carboxypropoxy)-10-methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

or pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

11. A compound according to claim 1 , selected from