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

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-Chloro-1-(1-oxidothietan-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)-7-fluoro-1H-benzimidazol-2-yl]methyl}spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;

1′-{[5-Chloro-1-(6-oxopiperidin-3-yl)-1H-benzimidazol-2-yl]methyl}spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;

1′-{[5-Chloro-1-(5-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-(1-methyl-5-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-(1-ethyl-5-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-[(3S)-1,1-dioxidotetrahydrothiophen-3-yl]-7-fluoro-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]-7-fluoro-1H-benzimidazol-2-yl}methyl)spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;

1′-{[5-Chloro-1-(piperidin-4-yl)-1H-benzimidazol-2-yl]methyl}spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;

1′-{[1-(Azetidin-3-yl)-5-chloro-1H-benzimidazol-2-yl]methyl}spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;

1′-({5-Chloro-1-[(3R)-1-(2-methylpropanoyl)pyrrolidin-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-(methylsulfonyl)azetidin-3-yl]-1H-benzimidazol-2-yl}methyl)spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;

1′-{[5-Chloro-1-(2,2-dimethyl-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-(cis-3-hydroxycyclobutyl)-1H-benzimidazol-2-yl]methyl}spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;

1′-{[5-Chloro-1-(trans-3-hydroxycyclobutyl)-1H-benzimidazol-2-yl]methyl}spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;

1′-{[5-Chloro-1-(1,1-dioxido-1,2-thiazolidin-4-yl)-1H-benzimidazol-2-yl]methyl}spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;

1′-{[5-Chloro-1-(2-oxa-5-azaspiro[3.4]oct-7-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-dioxidotetrahydrothiophen-3-yl)-7-fluoro-1H-indol-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-indol-2-yl]methyl}spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one; and

1′-{[5-Chloro-1-(1,1-dioxidotetrahydrothiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl}spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one.

8. A process for the preparation of a compound of claim 1 , the method comprising:

(a) contacting a compound of formula (A)

with

in the presence of a base;

wherein R 1 to R 4 , W and X are defined as in claim 1 and A is methanesulfonate or chloro, to prepare a compound of claim 1 ;

or

(b) contacting a compound of formula (B)

with Y—R 2 in the presence of a base;

wherein R 1 to R 4 and W are defined as in claim 1 ; and Y is trifluoromethanesulfonate or bromo, to prepare a compound of claim 1 .

9. A pharmaceutical composition comprising a compound in accordance with claim 1 and a therapeutically inert carrier.

10. A method for the treatment or prophylaxis of respiratory syncytial virus infection, which method comprises administering an effective amount of a compound as defined in claim 1 .