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

Patent metadata

Field	Value
Publication number	US-9637485-B2
Application number	US-201514926393-A
Country	US
Kind code	B2
Filing date	Oct 29, 2015
Priority date	Nov 3, 2014
Publication date	May 2, 2017
Grant date	May 2, 2017

Abstract

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.

First claim

The invention claimed is:

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.

Assignees

• Hoffmann La Roche

Inventors

• Han Xingchun
• Jiang Min
• Wang Jianhua
• Zhou Chengang
• Wang Yongguang
• Yang Song

Classifications

• A61P31/20

  for DNA viruses · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title