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

Patent metadata

Field	Value
Publication number	US-9670211-B2
Application number	US-201615094642-A
Country	US
Kind code	B2
Filing date	Apr 8, 2016
Priority date	Aug 12, 2013
Publication date	Jun 6, 2017
Grant date	Jun 6, 2017

Abstract

The invention provides novel compounds having the general formula:

wherein R 1 , R 2 , R 3 , R 4 , W and X are as described herein, compositions including the compounds and methods of using the compounds.

First claim

The invention claimed is:

1. Compounds of formula (I)

wherein
R 1 is halogen;
R 2 is azetidinyl, which is unsubstituted or substituted by C 1-6 alkylsulfonyl; C 1-6 alkoxycarbonylpyrrolidinyl; C 1-6 alkylcarbonylpyrrolidinyl; cycloalkyl, which is unsubstituted or substituted by C 1-6 alkyl, C 1-6 alkylsulfonyl, carboxy, halogen or hydroxy; dioxo-tetrahydrothiophenyl, which is unsubstituted or substituted by C 1-6 alkyl; dioxo-tetrahydrothiopyranyl; dioxo-thietanyl; oxo-thietanyl; oxo-pyrrolidinyl, which is unsubstituted or substituted by C 1-6 alkyl; oxetanyl; oxopiperidinyl; piperidinyl; tetrahydrofuranyl; tetrahydropyranyl;

 wherein x is 1-6;
R 3 is C 1-6 alkyl;
R 4 is C 1-6 alkyl;
or R 3 and R 4 , with the carbon atom to which they are attached, form cycloalkyl;
W is nitrogen or —CR 5 , wherein R 5 is hydrogen or halogen;
X is —CH or nitrogen;

or pharmaceutically acceptable salts thereof.

2. A compound according to claim 1 , wherein
R 1 is chloro;
R 2 is azetidin-3-yl, methylsulfonylazetidin-3-yl, tert-butoxycarbonylpyrrolidinyl, isopropylcarbonylpyrrolidinyl, cyclopentyl, difluorocyclobutyl, difluorocyclopentyl, carboxycyclohexyl, hydroxycyclobutyl, hydroxycyclohexyl, hydroxycyclopentyl, methylsulfonylcyclobutyl, oxetan-3-yl, piperidin-4-yl, tetrahydrofuranyl, tetrahydropyranyl,

R 3 is methyl or ethyl;
R 4 is methyl or ethyl;
or R 3 and R 4 , with the carbon atom to which they are attached, form cyclopropyl;
W is nitrogen, —CH or —CF;
X is —CH or nitrogen;

or pharmaceutically acceptable salts thereof.

3. A compound according to claim 1 or a pharmaceutically acceptable salt thereof,
wherein
R 1 is halogen;
R 2 is azetidinyl, which is unsubstituted or substituted by C 1-6 alkylsulfonyl; C 1-6 alkoxycarbonylpyrrolidinyl; C 1-6 alkylcarbonylpyrrolidinyl; cycloalkyl, which is unsubstituted or substituted by C 1-6 alkyl, C 1-6 alkylsulfonyl, carboxy, halogen or hydroxy; dioxo-tetrahydrothiophenyl, which is unsubstituted or substituted by C 1-6 alkyl; dioxo-tetrahydrothiopyranyl; dioxo-thietanyl; oxo-thietanyl; oxo-pyrrolidinyl, which is unsubstituted or substituted by C 1-6 alkyl; oxetanyl; oxopiperidinyl; piperidinyl; tetrahydrofuranyl; tetrahydropyranyl;

 wherein x is 1-6;
R 3 is C 1-6 alkyl;
R 4 is C 1-6 alkyl;
or R 3 and R 4 , with the carbon atom to which they are attached, form cycloalkyl;
W is —CR 5 , wherein R 5 is hydrogen or halogen;
X is nitrogen.

4. A compound according to claim 1 or a pharmaceutically acceptable salt thereof,
wherein
R 1 is chloro;
R 2 is azetidin-3-yl, methylsulfonylazetidin-3-yl, tert-butoxycarbonylpyrrolidinyl, isopropylcarbonylpyrrolidinyl, cyclopentyl, difluorocyclobutyl, difluorocyclopentyl, carboxycyclohexyl, hydroxycyclobutyl, hydroxycyclohexyl, hydroxycyclopentyl, methylsulfonylcyclobutyl, oxetan-3-yl, piperidin-4-yl, tetrahydrofuranyl, tetrahydropyranyl,

R 3 is methyl or ethyl;
R 4 is methyl or ethyl;
or R 3 and R 4 , with the carbon atom to which they are attached, form cyclopropyl;
W is —CH or —CF;
X is nitrogen.

5. A compound according to claim 1 or a pharmaceutically acceptable salt thereof,
wherein
R 1 is halogen;
R 2 is dioxo-tetrahydrothiophenyl;
R 3 and R 4 , with the carbon atom to which they are attached, form cycloalkyl;
W is nitrogen;
X is nitrogen.

6. A compound according to claim 1 or a pharmaceutically acceptable salt thereof,
wherein
R 1 is halogen;
R 2 is dioxo-tetrahydrothiophenyl;
R 3 and R 4 , with the carbon atom to which they are attached, form cycloalkyl;
W is nitrogen or —CR 5 , wherein R 5 is hydrogen or halogen;
X is —CH.

7. A compound according to claim 1 , selected from
1′-({5-Chloro-1-[cis-3-(methylsulfonyl)cyclobutyl]-1H-benzimidazol-2-yl}methyl)spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1′-({5-Chloro-1-[trans-3-(methylsulfonyl)cyclobutyl]-1H-benzimidazol-2-yl}methyl)spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1′-{[5-Chloro-1-(2,2-dioxido-2-thiaspiro[3.3]hept-6-yl)-1H-benzimidazol-2-yl]methyl}spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1′-{[5-Chloro-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzimidazol-2-yl]methyl}spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1′-[(5-Chloro-1-cyclopentyl-1H-benzimidazol-2-yl)methyl]spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1′-{[5-Chloro-1-(oxetan-3-yl)-1H-benzimidazol-2-yl]methyl}spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1′-{[5-Chloro-1-(3,3-difluorocyclobutyl)-1H-benzimidazol-2-yl]methyl}spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1′-{[5-Chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-benzimidazol-2-yl]methyl}spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1′-{[5-Chloro-1-(4-hydroxycyclohexyl)-1H-benzimidazol-2-yl]methyl}spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1′-{[5-Chloro-1-(3-hydroxycyclopentyl)-1H-benzimidazol-2-yl]methyl}spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1′-{[5-Chloro-1-(2-oxopyrrolidin-3-yl)-1H-benzimidazol-2-yl]methyl}spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1′-{[5-Chloro-1-(2-oxopiperidin-4-yl)-1H-benzimidazol-2-yl]methyl}spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1′-{[5-Chloro-1-(3 3-difluorocyclopentyl)-1H-benzimidazol-2-yl]methyl}spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
cis-4-{5-Chloro-2-[(2′-oxospiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-1′(2′H)-yl)methyl]-1H-benzimidazol-1-yl}cyclohexanecarboxylic acid;
1′-{[6-Chloro-3-(1,1-dioxidotetrahydrothiophen-3-yl)-3H-imidazo[4,5-b ]pyridin-2-yl]methyl}spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1′-{[5-Chloro-1-(tetrahydrofuran-3-yl)-1H-benzimidazol-2-yl]methyl}spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
tert-Butyl 3-{5-chloro-2-[(2′-oxospiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-1′(2′H)-yl)methyl]-1H-benzimidazol-1-yl}pyrrolidine-1-carboxylate;
1′-{[5-Chloro-1-(1,3-dihydroxypropan-2-yl)-1H-benzimidazol-2-yl]methyl}spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1′-{[5-Chloro-1-(trans-3-hydroxy-3-methylcyclobutyl)-1H-benzimidazol-2-yl]methyl}spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1′-{[5-Chloro-1-(1,1-dioxidotetrahydrothiophen-3-yl)-1H-benzimidazol-2-yl]methyl}spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1′-({5-Chloro-1-[(3S)-1,1-dioxidotetrahydrothiophen-3-yl]-1H-benzimidazol-2-yl}methyl)spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1′-({5-Chloro-1-[(3R)-1,1-dioxidotetrahydrothiophen-3-yl]-1H-benzimidazol-2-yl}methyl)spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1′-{[5-Chloro-1-(1,1-dioxidothietan-3-yl)-1H-benzimidazol-2-yl]methyl}spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1-{[5-Chloro-1-(1,1-dioxidothietan-3-yl)-1H-benzimidazol-2-yl]methyl}-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[2,3-c]pyridin-2-one;
1-{[5-Chloro-1-(1,1-dioxidothietan-3-yl)-1H-benzimidazol-2-yl]methyl}-3,3-diethyl-1,3-dihydro-2H-pyrrolo[2,3-c]pyridin-2-one;
1′-{[5-

Assignees

• Hoffmann La Roche

Inventors

• Gao Lu
• Guo Lei
• Liang Chungen
• Wang Baoxia
• Wang Lisha
• Yun Hongying
• Zhang Weixing
• Zheng Xiufang

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D471/10 Primary

  Spiro-condensed systems · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P31/14

  for RNA viruses · CPC title