Novel 6,7-dihydrobenzo[a]quinolizin-2-one derivatives for the treatment and prophylaxis of hepatitis B virus infection

• US 20160122344A1
• Filed: 10/29/2015
• Published: 05/05/2016
• Est. Priority Date: 11/03/2014
• 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, Wang, Jianhua, Zhou, Chengang, Wang, Yongguang, Yang, Song
• Granted Patent: US 9,637,485 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• 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 to R⁶, 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.

Claims

1. A compound of formula (I)

2. A compound according to claim 1, wherein

R¹, R², R³ and R⁴ are independently selected from hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy, benzyloxy, trifluoromethylmethoxy, methoxyethoxy, methoxypropoxy, ethoxyethoxy, cyclopropylmethoxy, hydroxypropoxy, hydroxydimethylpropoxy, hydoxyhexoxy, (methylpyrrolidinyl)ethoxy, aminohexoxy, dimethylamino-propoxy, (tert-butoxycarbonylamino)hexoxy, methylsulfanylpropoxy, methylsulfonylpropoxy, pyrrolidinylpropoxy, (2-oxo-pyrrolidinyl)propoxy, pyrazoylpropoxy, imidazolylpropoxy, morpholinyl-propoxy, dimethylamino, cyano or pyrrolidinyl;

R⁵ is hydrogen;

R⁶ is hydrogen, methyl, benzyl, acetyl, methylsulfonyl, benzoyl, pyrrolidin-1-yl, 2-oxo-pyrrolidinyl or tetrahydropyranyl;

W is a bond, CH₂, C(CH₃)₂ or C(CH₃)₂CH₂;

X is a bond;

O;

S;

S(O)₂;

or NR¹⁰, wherein R¹⁰ is hydrogen, methyl;

or R⁶ and R¹⁰, together with the nitrogen to which they are attached, form pyrrolidinyl or 2-oxo-pyrrolidinyl;

or pharmaceutically acceptable salts, enantiomers or diastereomers thereof.

3. A compound according to claim 1, wherein

R¹ is hydrogen;

R² is halogen or C_1-6alkoxy;

R³ is cyano, C_1-6alkyl, pyrrolidinyl or OR⁷, wherein

R⁷ is C_1-6alkyl;

or C_1-6alkyl which is substituted once or more times by fluoro, hydroxy, amino, C_3-7cycloalkyl, phenyl, C_1-6alkoxy, C_1-6alkylsulfanyl, C_1-6alkylsulfonyl, morpholinyl, 2-oxo-pyrrolidinyl, pyrrolidinyl, diC_1-6alkylamino, C_1-6alkoxycarbonylamino, pyrazoyl or C_1-6alkylpyrrolidinyl;

R⁴ is hydrogen;

R⁵ is hydrogen;

R⁶ is hydrogen, C_1-6alkyl, phenyl-C_xH₂, C_1-6alkylcarbonyl, C_1-6alkylsulfonyl, benzoyl or tetrahydropyranyl, wherein

x is 1-6;

W is a bond, C(R⁸)(R⁹)C_zH_2z, wherein

R⁸ and R⁹ are independently selected from hydrogen and C_1-6alkyl,

z is 0-6;

X is a bond;

O;

S;

S(O)₂;

or NR¹⁰, wherein R¹⁰ is hydrogen, C_1-6alkyl;

or R⁶ and R¹⁰, together with the nitrogen to which they are attached, form pyrrolidinyl or 2-oxo-pyrrolidinyl;

or pharmaceutically acceptable salts, enantiomers or diastereomers thereof.

4. A compound according to claim 3, wherein

R¹ is hydrogen;

R² is chloro, methoxy or ethoxy;

R³ 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, methylsulfanylpropoxy, methylsulfonylpropoxy or pyrazoylpropoxy;

R⁴ is hydrogen;

R⁵ is hydrogen;

R⁶ is hydrogen, methyl, benzyl, acetyl, methylsulfonyl, benzoyl or tetrahydropyranyl;

W is a bond, CH₂, C(CH₃)₂ or C(CH₃)₂CH₂;

X is a bond;

O;

S;

S(O)₂;

or NR¹⁰, wherein R¹⁰ is hydrogen, methyl;

or R⁶ and R¹⁰, together with the nitrogen to which they are attached, form pyrrolidinyl or 2-oxo-pyrrolidinyl;

or pharmaceutically acceptable salts, enantiomers or diastereomers thereof.

5. A compound of formula (IA) according to claim 3, wherein

6. A compound according to claim 1, wherein

R¹ is hydrogen;

R² is chloro, methoxy or ethoxy;

R³ 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, methylsulfanylpropoxy, methylsulfonylpropoxy or pyrazoylpropoxy;

R⁴ is hydrogen;

R⁵ is hydrogen;

R⁶ is hydrogen, methyl, benzyl or acetyl;

W is CH₂, C(CH₃)₂ or C(CH₃)₂CH₂;

or pharmaceutically acceptable salts, enantiomers or diastereomers thereof.

7. A compound according to claim 5, wherein

R¹ is hydrogen;

R² is halogen or C_1-6alkoxy;

R³ is OR⁷, wherein

R⁷ is C_1-6alkyl;

or C_1-6alkyl which is substituted once or more times by fluoro, hydroxy, amino, C_3-7cycloalkyl, phenyl, C_1-6alkoxy, C_1-6alkylsulfanyl, morpholinyl or C_1-6alkoxycarbonylamino;

R⁴ is hydrogen;

R⁵ is hydrogen;

R⁶ is hydrogen or C_1-6alkyl;

W is C(R⁸)(R⁹)C_zH_2z, wherein

R⁸ and R⁹ are independently selected from hydrogen and C_1-6alkyl,

z is 0-6;

X is O;

or pharmaceutically acceptable salts, enantiomers or diastereomers thereof.

8. A compound according to claim 7, wherein

R¹ is hydrogen;

R² is chloro or methoxy;

R³ is methoxy, benzyloxy, trifluoromethylmethoxy, methoxypropoxy, ethoxyethoxy, cyclopropylmethoxy, hydroxypropoxy, hydroxydimethylpropoxy, aminohexoxy, morpholinylpropoxy, (tert-butoxycarbonylamino)hexoxy or methylsulfanylpropoxy;

R⁴ is hydrogen;

R⁵ is hydrogen;

R⁶ is hydrogen or methyl;

W is C(CH₃)₂CH₂;

X is O;

or pharmaceutically acceptable salts, enantiomers or diastereomers thereof.

9. A compound according claim 1, wherein R² is halogen or C_1-6alkoxy.

10. A compound according claim 9, wherein R² is methoxy or chloro.

11. A compound according to claim 10, wherein R³ is C_1-6alkoxyC_1-6alkoxy.

12. A compound according to claim 11, wherein R³ is methoxypropoxy.

13. A compound according to claim 12, wherein R⁶ is hydrogen or C_1-6alkyl.

14. A compound according to claim 13, wherein R⁶ is methyl.

15. A compound according to claim 14, wherein W is C(CH₃)₂CH₂.

16. A compound according to claim 1, selected from

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-Butoxycarbonylamino)hexoxy]-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-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-carboxylic acid;

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

or,

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

or pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

17. A compound according to claim 1, selected from

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;

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

or,

or pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

18. A compound according to claim 3, wherein

R¹ is hydrogen;

R² is halogen or C_1-6alkoxy;

R³ is C_1-6alkoxy or C_1-6alkoxyC_1-6alkoxy;

R⁴ is hydrogen;

R⁵ is hydrogen;

R⁶ is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, C_1-6alkylsulfonyl, benzoyl or tetrahydropyranyl;

W is a bond, C(R⁸)(R⁹)C_zH_2z, wherein

R⁸ and R⁹ are independently selected from hydrogen and C_1-6alkyl,

z is 0-6;

X is a bond;

S;

S(O)₂;

or NR¹⁰, wherein R¹⁰ is hydrogen, C_1-6alkyl;

or R⁶ and R¹⁰, together with the nitrogen to which they are attached, form pyrrolidinyl or 2-oxo-pyrrolidinyl;

or pharmaceutically acceptable salts, enantiomers or diastereomers thereof.

19. A compound according to claim 18;

wherein

R¹ is hydrogen;

R² is chloro or ethoxy;

R³ is ethoxy, methoxyethoxy or methoxypropoxy;

R⁴ is hydrogen;

R⁵ is hydrogen;

R⁶ is hydrogen, methyl, acetyl, methylsulfonyl, benzoyl or tetrahydropyranyl;

W is a bond or CH₂;

X is a bond;

S;

S(O)₂;

or NR¹⁰, wherein R¹⁰ is hydrogen, methyl;

or R⁶ and R¹⁰, together with the nitrogen to which they are attached, form pyrrolidinyl or 2-oxo-pyrrolidinyl;

or pharmaceutically acceptable salts, enantiomers or diastereomers thereof.

20. A compound according to claim 1, selected from

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;

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

or pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

21. A process for the preparation of a compound of formula (I) according to claim 1 comprising one of the following steps:

(a) hydrolyzation of a compound of formula (A)

22. A compound or pharmaceutically acceptable salts, enantiomers or diastereomers according to claim 1 for use as therapeutically active substance.

23. A pharmaceutical composition comprising a compound according to claim 1 and a therapeutically inert carrier.

24. The use of a compound or pharmaceutically acceptable salts, enantiomers or diastereomers according to claim 1 for the treatment of an HBV infection.

26. The use of a compound or pharmaceutically acceptable salts, enantiomers or diastereomers according to claim 1 for the inhibition of HBsAg production or secretion.

29. A method for the treatment of an HBV infection, which method comprises administering a therapeutically effective amount of a compound or pharmaceutically acceptable salts, enantiomers or diastereomers as defined in claim 1.

25. (canceled)

27. (canceled)

28. (canceled)

30. (canceled)