Aza-oxo-indoles for the treatment and prophylaxis of respiratory syncytial virus infection

Patent metadata

Field	Value
Publication number	US-10189838-B2
Application number	US-201514942725-A
Country	US
Kind code	B2
Filing date	Nov 16, 2015
Priority date	May 14, 2013
Publication date	Jan 29, 2019
Grant date	Jan 29, 2019

Abstract

The invention provides novel compounds having the general formula:

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , W 1 , W 2 , W 3 , A and X are as described herein, compositions including the compounds and methods of using the compounds for the treatment and prophylaxis of respiratory syncytial virus infection.

First claim

The invention claimed is:

1. Compounds of formula (I)

wherein
A is phenyl or pyridinyl, which is unsubstituted or substituted by C 1-6 alkyl, C 1-6 alkoxy, halogen, trifluoromethyl or cyano;
X is nitrogen, —CH or —CR 7 ; provided that
when X is —CR 7 , R 1 is hydrogen, wherein R 7 is C 1-6 alkylsulfonyl-C y H 2y —;
when X is nitrogen or —CH, R 1 is C 1-6 alkylsulfonylphenyl-C y H 2y —, thietan-3-yl-C y H 2y —, dioxothietan-3-yl-C y H 2y —, oxetan-3-yl-C y H 2y —, aminooxetan-3-yl-C x H 2x —, C 1-6 alkylsufinyl-C y H 2y —,

 or R 1 is —C y H 2y —SO 2 R 8 , wherein R 8 is C 1-6 alkyl, cycloalkyl, C 1-6 alkylcarbonylamino, C 1-6 alkylamino, diC 1-6 alkylamino, amino, morpholinyl, pyrrolidinyl, piperazinyl,

 or R 1 is —C y H 2y —COR 9 , wherein R 9 is cycloalkylsulfonylamino, cycloalkylsulfonylamino(C 1-6 alkyl) or C 1-6 alkylsulfonylamino(C 1-6 alkyl); or R 1 is —C x H 2x —NR 10 R 11 , wherein R 10 and R 11 , together with the nitrogen atom, to which they are attached, form

R 2 and R 3 are hydrogen or deuterium simultaneously;
R 4 and R 5 , with the carbon atom to which they are attached, form cyclopropyl;
R 6 is hydrogen or halogen;
W 1 is nitrogen or —CR 12 , wherein R 12 is hydrogen or halogen;
W 2 is —CH or nitrogen;
W 3 is —CH or nitrogen; provided that at most one of W 1 , W 2 and W 3 is nitrogen;
x is 2-6;
y is 1-6;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , wherein
A is phenyl, which is unsubstituted or once or twice substituted by C 1-6 alkyl, C 1-6 alkoxy, halogen, trifluoromethyl or cyano; or pyridinyl, which is unsubstituted or once substituted by C 1-6 alkyl or halogen or pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 , wherein
A is phenyl, which is unsubstituted or once or twice substituted by methyl, ethyl, fluoro, chloro, bromo, methoxy, trifluoromethyl or cyano; or pyridinyl, which is unsubstituted or once substituted by methyl or chloro;
X is nitrogen, —CH or —CR 7 ; provided that
when X is —CR 7 , R 1 is hydrogen, wherein R 7 is ethylsulfonylethyl, methylsulfonylethyl or methylsulfonylpropyl;
when X is nitrogen or —CH, R 1 is aminosulfonylpropyl, cyclopropylsulfonylaminocarbonylethyl, cyclopropylsulfonylamino(methyl)carbonylethyl, cyclopropylsulfonylethyl, cyclopropylsulfonylpropyl, dimethylaminosulfonylethyl, dimethylaminosulfonylpropyl, ethylsulfonylethyl, ethylsulfonylpropyl, methylaminosulfonylpropyl, methylsulfinylpropyl, methylsulfonylamino(methyl)carbonylethyl, methylsulfonylaminoethyl, methylsulfonylaminopropyl, methylsulfonylbutyl, methylsulfonylethyl, methylsulfonylphenylmethyl , 4-(methylsulfonyl)piperazin-1-ylethyl, methylsulfonylpropyl, piperazin-1-ylsulfonylpropyl, thietan-3-ylethyl,

R 2 and R 3 are hydrogen or deuterium simultaneously;
R 6 is hydrogen, fluoro, chloro or bromo;
W 1 is nitrogen, —CH or —CF;
W 2 is —CH or nitrogen;
W 3 is —CH or nitrogen; provided that at most one of W 1 , W 2 and W 3 is nitrogen;

or pharmaceutically acceptable salt thereof.

4. A compound according to claim 2 , wherein
R 6 is hydrogen;
W 1 is —CH;
W 2 is nitrogen; and
W 3 is —CH.

5. A compound according to claim 3 , wherein
R 6 is hydrogen;
W 1 is —CH;
W 2 is nitrogen; and
W 3 is —CH.

6. A compound according to claim 2 , wherein
A is phenyl or pyridinyl, which is once substituted by halogen;
X is nitrogen, —CH or —CR 7 ; provided that
when X is —CR 7 , R 1 is hydrogen, wherein R 7 is C 1-6 alkylsulfonyl-C y H 2y —;
when X is nitrogen or —CH, R 1 is C 1-6 alkylsulfonyl-C y H 2y —;
R 2 is hydrogen;
R 3 is hydrogen;
R 6 is hydrogen or halogen;
W 1 is nitrogen or —CR 12 , wherein R 12 is hydrogen or halogen;
W 2 is —CH;
W 3 is —CH or nitrogen; provided that W 1 and W 3 are not nitrogen simultaneously;
x is 2-6;
y is 1-6.

7. A compound according to claim 2 , wherein
A is

X is nitrogen, —CH or —CR 7 ; provided that
when X is —CR 7 , R 1 is hydrogen, wherein R 7 is ethylsulfonylethyl;
when X is nitrogen or —CH, R 1 is ethylsulfonylethyl, methylsulfonylethyl, or methylsulfonylpropyl;
R 2 is hydrogen;
R 3 is hydrogen;
R 6 is hydrogen, fluoro, chloro or bromo;
W 1 is nitrogen, —CH or —CF;
W 2 is —CH;
W 3 is —CH or nitrogen;
provided that W 1 and W 3 are not nitrogen simultaneously.

8. A compound having formula:
1′-({1-[2-(Methylsulfonyl)ethyl]-1H-indol-2-yl}methyl)spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1 ′-({5-Methoxy-1-[2-(methylsulfonyl)ethyl]-1H-indol-2-yl}methyl)spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1-[2-(Methylsulfonyl)ethyl]-2-[(2′-oxospiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-1′(2′H)-yl)methyl]-1H-indole-5-carbonitrile;
1′-({5-Fluoro-1-[2(methylsulfonyl)ethyl]-1H-indol-2-yl}methyl)spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1′-({5-Bromo-1-[2-(methylsulfonyl)ethyl]-1H-indol-2-yl}methyl)spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1′-({4-Chloro-1-[2-(methylsulfonyl)ethyl]-1H-indol-2-yl}methyl)spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1′-({7-Chloro-1-[2-(methylsulfonyl)ethyl]-1H-indol-2-yl}methyl)spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1′-({5-Ethyl-1-[2-(methylsulfonyl)ethyl]-1H-indol-2-yl}methyl)spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′′(1′H)-one;
1′({5,7-Difluoro-1-[2-(methylsulfonyl)ethyl]-1H-indol-2-yl}methyl)spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1′-({1-[2-(Methylsulfonyl)ethyl]-5-(trifluoromethyl)-1H-indol-2-yl}methyl)spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1′-({5,6-Difluoro-1-[2-(methylsulfonyl)ethyl]-1H-indol-2-yl}methyl)spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1′-({5-Chloro-7-fluoro-1-[2-(methylsulfonyl)ethyl]-1H-indol-2-yl}methyl)spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1′-({5-Methyl-1-[2-(methylsulfonyl)ethyl]-1H-indol-2-yl}methyl)spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1′-({1-[2-(Methylsulfonyl)ethyl]-1H-pyrrolo[3,2-c]pyridin-2-yl}methyl)spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1′-({5-Chloro-1-[2-(ethylsulfonyl)ethyl]-1H-indol-2-yl}methyl)spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1′-({5-Chloro-1-[2-(ethylsulfonyl)ethyl]-1H-pyrrolo[2,3-b]pyridin-2-yl}methyl)spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1′-({5-Chloro-1-[2-(ethylsulfonyl)ethyl]-1H-indol-2-yl}methyl)spiro[cyclopropane-1,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one;
1′-({5-Chloro-1-[2-(methylsulfonyl)ethyl]-1H-indol-2-yl}methyl)spiro[cyclopropane-1,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one;
1′-({5-Chloro-1-[2-(methylsulfonyl)ethyl]-1H-pyrrolo[2,3-b]pyridin-2-yl}methyl)spir

Assignees

• Hoffmann La Roche
• Hoffmann La Roche

Inventors

• Wang Lisha
• Gao Lu
• Huang Mengwei
• Guo Lei
• Liang Chungen
• Zhu Wei
• Feng Song
• Zheng Xiufang
• Zhang Weixing
• Wu Guolong
• Wang Baoxia
• Yun Hongying

Classifications

• A61P31/16

  for influenza or rhinoviruses · CPC title

• A61P31/12

  Antivirals · CPC title

• C07D471/10 Primary

  Spiro-condensed systems · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title