NOVEL 2-OXO-6, 7-DIHYDROBENZO[a]QUINOLIZINE-3-CARBOXYLIC ACID DERIVATIVES FOR THE TREATMENT AND PROPHYLAXIS OF HEPATITIS B VIRUS INFECTION

• US 20170342069A1
• Filed: 08/11/2017
• Published: 11/30/2017
• Est. Priority Date: 02/11/2015
• Status: Active Grant

• Current Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Han, Xingchun, Jiang, Min, Yang, Song
• Granted Patent: US 10,093,671 B2
• Time in Patent Office: Days
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The invention provides novel compounds having the general formula:

wherein R¹, R², R³, R⁴, R⁵ and Ar are as described herein, compositions including the compounds and methods of using the compounds.

Claims

1. A compound of formula I

2. A compound according to claim 1, wherein

R¹ is hydrogen;

R² is hydrogen, halogen or C_1-6alkoxy;

R³ is C_1-6alkyl, pyrrolidinyl or OR⁶;

R⁴ is C_1-6alkyl or hydrogen;

R⁵ is hydrogen;

R⁶ is C_1-6alkyl, haloC_1-6alkyl, C_3-7cycloalkylC_1-6alkyl, phenylC_1-6alkyl, hydroxyC_1-6alkyl, C_1-6 alkoxyC_1-6alkyl, carboxyC_1-6alkyl, C_1-6alkylsulfanylC_1-6alkyl, C_1-6alkylsulfonylC_1-6alkyl, cyanoC_1-6alkyl, aminoC_1-6alkyl, C_1-6alkylcarbonylaminoC_1-6alkyl, C_1-6alkylsulfonylaminoC_1-6 alkyl, C_1-6alkoxycarbonylaminoC_1-6alkyl, pyrazolylC_1-6alkyl, triazolylC_1-6alkyl, piperidylC_1-6 alkyl, morpholinylC_1-6alkyl or 2-oxopyrrolidinylC_1-6alkyl;

Ar is phenyl;

phenyl substituted by C_1-6alkyl, C_1-6alkoxy, hydroxy, halogen or phenylC_1-6alkoxy;

thienyl;

thienyl substituted by C_1-6alkyl;

or benzothiophenyl;

or pharmaceutically acceptable salts, or enantiomers thereof.

3. A compound according to claim 1 or 2, or pharmaceutically acceptable salts, or enantiomers thereof, wherein R¹ is hydrogen, R⁴ is hydrogen, R⁵ is hydrogen.

4. A compound according to any one of claims 1 to 3, or pharmaceutically acceptable salts, or enantiomers thereof, wherein R² is C_1-6alkoxy.

5. A compound according to any one of claims 1 to 4, or pharmaceutically acceptable salts, or enantiomers thereof, wherein R² is methoxy.

6. A compound according to any one of claims 1 to 5, or pharmaceutically acceptable salts, or enantiomers thereof, wherein R³ is pyrrolidinyl or OR⁶, wherein R⁶ is C_1-6alkyl, haloC_1-6alkyl, C_3-7 cycloalkylC_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkoxyC_1-6alkyl, carboxyC_1-6alkyl, C_1-6alkylsulfanylC_1-6 alkyl, cyanoC_1-6alkyl, aminoC_1-6alkyl, C_1-6alkylcarbonylaminoC_1-6alkyl, C_1-6alkylsulfonylaminoC_1-6 alkyl or C_1-6alkoxycarbonylaminoC_1-6alkyl.

7. A compound according to any one of claims 1 to 6, or pharmaceutically acceptable salts, or enantiomers thereof, wherein R³ is OR⁶, wherein R⁶ is methyl, isobutyl, trifluoroethyl, cyclopropylmethyl, cyanopropyl, hydroxypropyl, hydroxyhexyl, hydroxydimethylpropyl, methoxypropyl, carboxypropyl, methyl sulfanylpropyl, aminohexyl, methylcarbonylaminohexyl, methyl sulfonylaminohexyl or methoxycarbonylaminohexyl.

8. A compound according to any one of claims 1 to 7, or pharmaceutically acceptable salts, or enantiomers thereof, wherein Ar is phenyl, phenyl substituted by C_1-6alkyl or halogen, thienyl or thienyl substituted by C_1-6alkyl.

9. A compound according to any one of claims 1 to 8, or pharmaceutically acceptable salts, or enantiomers thereof, wherein Ar is phenyl;

phenyl substituted by methyl, fluoro or chloro;

thienyl or thienyl substituted by methyl.

10. A compound according to claim 1 or 2, wherein

R¹ is hydrogen;

R² is C_1-6alkoxy;

R³ is pyrrolidinyl or OR⁶;

R⁴ is hydrogen;

R⁵ is hydrogen;

R⁶ is C_1-6alkyl, haloC_1-6alkyl, C_3-7cycloalkylC_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkoxyC_1-6alkyl or C_1-6alkylsulfanylC_1-6alkyl;

Ar is phenyl substituted by C_1-6alkyl, or thienyl;

or pharmaceutically acceptable salts, or enantiomers thereof.

11. A compound according to claim 1, 2 or 10, wherein

R¹ is hydrogen;

R² is methoxy;

R³ is pyrrolidinyl or OR⁶;

R⁴ is hydrogen;

R⁵ is hydrogen;

R⁶ is isobutyl, trifluoroethyl, cyclopropylmethyl, hydroxydimethylpropyl, methoxypropyl or methyl sulfanylpropyl;

Ar is phenyl substituted by methyl or thienyl;

or pharmaceutically acceptable salts, or enantiomers thereof.

12. A compound according to claim 1, selected from

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

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

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

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

10-Methoxy-6-(4-methoxyphenyl)-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

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

10-Methoxy-9-(3-methoxypropoxy)-6-(4-methyl-2-thienyl)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

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

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

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

9-Methoxy-8-methyl-2-oxo-6-(2-thienyl)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid;

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

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

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

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

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

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

10-Methoxy-2-oxo-9-[3-(1-piperidyl)propoxy]-6-(2-thienyl)-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid formate;

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

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

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

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

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

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

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

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

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

10-Methoxy-9-(3-morpholinopropoxy)-2-oxo-6-(2-thienyl)-6,7-dihydrobenzo[a]quinolizine-3-carboxylate;

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

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

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

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

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

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

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

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

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

or pharmaceutically acceptable salts, or enantiomers thereof.

13. A compound according to claim 1, selected from

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

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

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

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

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

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

10-Methoxy-2-oxo-6-(2-thienyl)-9-(2,2,2-trifluoroethoxy)-6,7-dihydrobenzo[a]quinolizine carboxylic acid;

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

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

or pharmaceutically acceptable salts, or enantiomers thereof.

14. A process for the preparation of a compound according to any one of claims 1 to 13 comprising

(a) hydrolysis of a compound of formula (A)

15. A compound according to any one of claims 1 to 13 for use as therapeutically active substance.

16. A pharmaceutical composition comprising a compound in accordance with any one of claims 1 to 13 and a therapeutically inert carrier.

17. The use of a compound according to any one of claims 1 to 13 for the treatment or prophylaxis of HBV infection.

18. The use of a compound according to any one of claims 1 to 13 for the preparation of a medicament for the treatment or prophylaxis of HBV infection.

19. The use of a compound according to any one of claims 1 to 13 for the inhibition of HBsAg production or secretion, or for the inhibition of HBsAg production or secretion.

20. A compound according to any one of claims 1 to 13 for the treatment or prophylaxis of HBV infection.

21. A compound according to any one of claims 1 to 13, when manufactured according to a process of claim 14.

22. A method for the treatment or prophylaxis of HBV infection, which method comprises administering an effective amount of a compound as defined in any one of claims 1 to 13.

23. The invention as hereinbefore described.