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

Abstract

The invention provides novel compounds having the general formula: wherein R 1 , R 2 , R 3 , R 4 , R 5 , W and X are as described herein, compositions including the compounds and methods of using the compounds.

1 .- 14 . (canceled) 
     
     
         15 . A method for the treatment of respiratory syncytial virus infection, the method comprising administering an effective amount of a compound having formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 W is nitrogen or —CR 9 , wherein R 9  is halogen; 
 X is nitrogen or —CR 10 , provided that 
 when X is —CR 10 , R 1  is hydrogen, R 2  is halogen, R 3  is hydrogen, wherein R 10  is C 1-6 alkylsulfonylphenyl; 
 when X is nitrogen, R 1  is halogen, R 2  is hydrogen, R 3  is 
 
       
         
           
           
               
               
           
         
         R 4  and R 5 , with the carbon atom to which they are attached, form cycloalkyl; 
         R 6  is hydrogen or C 1-6 alkyl; 
         R 7  is hydrogen, aminocarbonyl, C 1-6 alkoxycarbonyl-C y H 2y —, C 1-6 alkylcarbonyl, C 1-6 alkylsulfonyl, carboxy or cyano, wherein y is 0-6; 
         R 8  is C 1-6 alkylsulfonyl, C 1-6 alkoxy, cyano or hydroxy; 
         or pharmaceutically acceptable salts thereof. 
       
     
     
         16 . (canceled) 
     
     
         17 . The method of  claim 15 , wherein
 W is nitrogen or —CF;   X is nitrogen or —CR 10 , provided that   when X is —CR 10 , R 1  is hydrogen, R 2  is chloro, R 3  is hydrogen, wherein R 10  is methylsulfonylphenyl;   when X is nitrogen, R 1  is chloro, R 2  is hydrogen, R 3  is   
       
         
           
           
               
               
           
         
         R 4  and R 5 , with the carbon atom to which they are attached, form cyclopropyl; 
         R 6  is hydrogen or methyl; 
         R 7  is hydrogen, aminocarbonyl, ethoxycarbonyl, methoxycarbonyl, ethoxycarbonylmethyl, methylcarbonyl, methyl sulfonyl, carboxy or cyano; 
         R 8  is methoxy, methylsulfonyl, ethylsulfonyl, cyano or hydroxy; 
         or pharmaceutically acceptable salts thereof. 
       
     
     
         18 . The method of  claim 15 , wherein:
 R 1  is halogen;   R 2  is hydrogen;   R 3  is   
       
         
           
           
               
               
           
         
         R 4  and R 5 , with the carbon atom to which they are attached, form cycloalkyl; 
         R 6  is hydrogen or C 1-6 alkyl; 
         R 7  is hydrogen, aminocarbonyl, C 1-6 alkoxycarbonyl-C y H 2y —, C 1-6 alkylcarbonyl, C 1-6 alkylsulfonyl, carboxy or cyano, wherein y is 0-6; 
         R 8  is C 1-6 alkylsulfonyl, C 1-6 alkoxy, cyano or hydroxy; 
         W is nitrogen; 
         X is nitrogen. 
       
     
     
         19 . The method of  claim 15 , wherein:
 R 1  is chloro;   R 2  is hydrogen;   R 3  is   
       
         
           
           
               
               
           
         
         R 4  and R 5 , with the carbon atom to which they are attached, form cyclopropyl; 
         R 6  is hydrogen or methyl; 
         R 7  is hydrogen, aminocarbonyl, ethoxycarbonyl, methoxycarbonyl, ethoxycarbonylmethyl, methylcarbonyl, methyl sulfonyl, carboxy or cyano; 
         R 8  is methoxy, methylsulfonyl, ethyl sulfonyl, cyano or hydroxy; 
         W is nitrogen; 
         X is nitrogen. 
       
     
     
         20 . The method of  claim 15 , wherein:
 R 1  is hydrogen;   R 2  is halogen;   R 3  is hydrogen;   R 4  and R 5 , with the carbon atom to which they are attached, form cycloalkyl;   W is nitrogen;   X is —CR 10 , wherein R 10  is C 1-6 alkylsulfonylphenyl.   
     
     
         21 . The method of  claim 15 , wherein:
 R 1  is halogen;   R 2  is hydrogen;   R 3  is carboxyphenyl;   R 4  and R 5 , with the carbon atom to which they are attached, form cycloalkyl;   W is —CR 9 , wherein R 9  is halogen;   X is nitrogen.   
     
     
         22 . The method of  claim 15 , wherein the compound is selected from the group consisting of:
 5-{5-Chloro-2-[(2′-oxospiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-1′(2′H)-yl)methyl]-1H-benzimidazol-1-yl}pyridine-2-carbonitrile;   1′-({5-Chloro-1-[2-(methylsulfonyl)pyridin-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-(ethyl sulfonyl)pyridin-2-yl]-1H-benzimidazol-2-yl}methyl)spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;   Ethyl (4-{5-chloro-2-[(2′-oxospiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-1′(2′H)-yl)methyl]-1H-benzimidazol-1-yl}phenyl)acetate;   1′-[(5-Chloro-1-phenyl-1H-benzimidazol-2-yl)methyl]spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;   Ethyl 4-{5-chloro-2-[(2′-oxospiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-1′(2′H)-yl)methyl]-1H-benzimidazol-1-yl}benzoate;   1′-({5-Chloro-1-[6-(methylsulfonyl)pyridin-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-(methylsulfonyl)phenyl]-1H-benzimidazol-2-yl}methyl)spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;   1′-({5-chloro-1-[4-(methylsulfonyl)phenyl]-1H-benzimidazol-2-yl}methyl)spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;   Methyl 3-{5-chloro-2-[(2′-oxospiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-1′(2′H)-yl)methyl]-1H-benzimidazol-1-yl}benzoate;   3-{5-Chloro-2-[(2′-oxospiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-1′(2′H)-yl)methyl]-1H-benzimidazol-1-yl }benzonitrile;   1′-{[1-(3-Acetylphenyl)-5-chloro-1H-benzimidazol-2-yl]methyl}spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;   1′-{[5-Chloro-1-(6-methoxypyridin-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-(methylsulfonyl)pyridin-3-yl]-1H-benzimidazol-2-yl}methyl)spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;   1′-({5-Chloro-1-[6-(methylsulfonyl)pyridin-2-yl]-1H-benzimidazol-2-yl}methyl)spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;   1′-({5-Chloro-1-[3-methyl-5-(methylsulfonyl)phenyl]-1H-benzimidazol-2-yl}methyl)spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;   4-{5-Chloro-2-[(2′-oxospiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-1′(2′H)-yl)methyl]-1H-benzimidazol-1-yl}benzoic acid;   3-{5-Chloro-2-[(2′-oxospiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-1′(2′H)-yl)methyl]-1H-benzimidazol-1-yl}benzoic acid;   4-{5-Chloro-2-[(6′-fluoro-2′-oxospiro[cyclopropane-1,3′-indol]-1′(2′H)-yl)methyl]-1H-benzimidazol-1-yl}benzoic acid;   4-{5-Chloro-2-[(6′-fluoro-2′-oxospiro[cyclopropane-1,3′-indol]-1′(2′H)-yl)methyl]-1H-benzimidazol-1-yl}benzoic acid;   1′-{[5-Chloro-1-(6-hydroxypyridin-3-yl)-1H-benzimidazol-2-yl]methyl}spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;   1′-({6-Chloro-3-[4-(methyl sulfonyl)phenyl]-1H-indol-2-yl}methyl)spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one; and   1′-({6-Chloro-3-[3-(methylsulfonyl)phenyl]-1H-indol-2-yl}methyl)spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one,   or a pharmaceutically acceptable salt thereof.   
     
     
         23 . The method of  claim 15 , wherein the compound is formulated as a pharmaceutical composition comprising a compound and at least one therapeutically inert carrier.