Derivatives of 1-phenyl-2-pyridinyl alkyl alcohols as phosphodiesterase inhibitors

Abstract

The invention relates to inhibitors of the phosphodiesterase 4 (PDE4) enzyme. More particularly, the invention relates to compounds that are derivatives of 1-phenyl-2-pyridinyl alkyl alcohols, methods of preparing such compounds, compositions containing them and therapeutic use thereof.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 2  are different or the same and are each independently:
 (C 1 -C 6 ) alkyl, optionally substituted by (C 3 -C 7 ) cycloalkyl; 
 (C 1 -C 6 ) haloalkyl; or 
 (C 3 -C 7 ) cycloalkyl; 
 
 R 4  is one or more substituents independently selected from the group consisting of H, CN, NO 2 , CF 3  and a halogen atom; 
 Z is a group selected in the list consisting of: 
 [3]-CH 2 —X-[4]; 
 [3]-Y-[4]; 
 [3]-CH 2 CH 2 —K-[4]; 
 [3]-CHR 26 —NR 27 —SO 2 -[4]; 
 [3]-C(CH 3 )(R 5 )—O—(CO)-[4]; 
 [3]-CHR 6 —CH 2 -[4]; 
 [3]-CHR 7 —NH—(CO)-J-[4]; and 
 [3]-C(OH)(OH)-[4]; 
 wherein [3] indicates the point of attachment for group Z with the carboxylic group and [4] indicates the point of attachment for group Z with the phenyl group; 
 R 27  is hydrogen or (C 1 -C 4 ) alkyl; 
 R 26  is: 
 a group —C(CH 3 )(CH 3 )—S—(CO)CH 3 ; 
 a group —CH 2 —CH 2 —CH 2 —O—(CO)CH 3 ; 
 a group (C 1 -C 4 ) alkyl; or 
 a group (C 1 -C 4 ) alkylthio(C 1 -C 4 ) alkyl group; 
 R 5  is hydrogen, (C 1 -C 4 ) alkyl, or a phenyl group; 
 R 6  is hydrogen or a group —NHR 10 ; 
 R 7  is a (C 1 -C 4 ) alkylthio(C 1 -C 4 ) alkyl group; 
 X is: 
 a group [5]-O—(CH2) n -[4]; 
 a group —SO 2 —; 
 a group [5]-O—(CO)—(CH 2 ) n -[4]; 
 a group [5]-(CO)—NH-[4]; 
 a group [5]-(CO)—O—(CH 2 ) n[ 4]; 
 a group [5]—NH—(CO)-[4]; 
 a group [5]-NR 8 —SO 2 —(CH 2 ) n -[4]; 
 a group [5]-O—SO 2 -[4]; 
 a group [5]-SO 2 —NH-[4]; 
 a group [5]—NH—(CO)—(CO)-[4]; 
 a group [5]—NH—(CO)—NH-[4]; 
 a group [5]-S—(CO)-[4]; or 
 a group [5]-NR 9 —(CH 2 ) n -[4]; 
 wherein [5] indicates the point of attachment for group X with the methylene group and [4] indicates the point of attachment for group X with the phenyl group; 
 n is 0 or 1; 
 R 8  is hydrogen, (C 1 -C 4 ) alkyl, or (C 3 -C 8 )heterocycloalkyl(C 1 -C 4 ) alkyl; 
 R 9  is hydrogen, (C 1 -C 4 ) alkyl, or a group —SO2(C 1 -C 4 ) alkyl; 
 Y is: 
 a group [3]-O—(CH2)n-[4]; 
 a group [3]-NR 9 —(CH2)n-[4]; 
 a group [3]-S—(CH2)n-[4]; 
 a group [3]-(CO)—NH-[4]; 
 a group [3]-(CO)—S—[4]; 
 a group [3]-(CO)-[4]; or 
 a group [3]-CH═CH—SO 2 -[4]; 
 K is: 
 a group [6]-SO 2 -[4]; 
 a group [6]—NH—(CO)-[4]; or 
 a group [6]-O—(CO)-[4]; 
 wherein [6] indicates the point of attachment for group K with the ethylene group and [4] indicates the point of attachment for group K with the phenyl group; 
 R 10  is hydrogen or a group —SO 2 — (C 1 -C 4 ) alkyl; 
 J is a bond or a group [7]-CH(NH 2 )-[4]; 
 wherein [7] indicates the point of attachment for group J with the aminocarbonyl group and [4] indicates the point of attachment for group J with the phenyl group; 
 R 3  are one or more optional substituents which may be the same or different, and are independently selected from the group consisting of: 
 (C 1 -C 6 ) alkyl optionally substituted by one or more (C 3 -C 7 )cycloalkyl; 
 (C 1 -C 6 ) haloalkyl; 
 (C 3 -C 7 ) heterocycloalkyl; 
 (C 3 -C 7 ) heterocycloalkyl(C 1 -C 4 ) alkyl; 
 a group —OR 11  wherein R 11  is selected from the group consisting of:
 H: 
 (C 1 -C 6 ) haloalkyl; 
 a group —SO 2 R 12 , wherein R 12  is (C 1 -C 6 ) alkyl; 
 a group —C(O)R 12  wherein R 12  is as above defined; 
 (C 1 -C 10 ) alkyl optionally substituted by one or more (C 3 -C 7 ) cycloalkyl or by a group —NR 13 R 14  as below defined; and 
 (C 3 -C 7 ) cycloalkyl; 
 
 a group —SR 25  wherein R 25  is selected from the group consisting of:
 H: 
 (C 1 -C 6 ) haloalkyl; 
 a group —C(O)R 12 ; 
 (C 1 -C 10 ) alkyl optionally substituted by one or more (C 3 -C 7 ) cycloalkyl or by a group —NR 13 R 14 ; and 
 (C 3 -C 7 ) cycloalkyl; 
 
 halogen atoms; 
 CN; 
 NO 2 ; 
 NR 13 R 14  wherein R 13  and R 14  are different or the same and are independently selected from the group consisting of:
 H; 
 (C 1 -C 4 ) alkyl-NR 15 R 16  wherein R 15  and R 16  are different or the same and are independently selected from the group consisting of: H and (C 1 -C 6 ) alkyl, which is optionally substituted with (C 3 -C 7 ) cycloalkyl or (C 3 -C 7 ) heterocycloalkyl; or they form with the nitrogen atom to which they are linked a (C 3 -C y )heterocycloalkyl which is optionally substituted by (C 1 -C 6 )alkyl; 
 linear or branched (C 1 -C 6 ) alkyl, optionally substituted with (C 3 -C 7 ) cycloalkyl, (C 3 -C 7 ) heterocycloalkyl, a group —OH, (C 1 -C 6 ) alkoxyl or by an aminocarbonyl group; 
 a group —SO 2 R 17 , wherein R 17  is selected in the group consisting of: (C 1 -C 6 ) alkyl optionally substituted by (C 3 -C 7 ) cycloalkyl or (C 3 -C 7 )heterocycloalkyl; (C 3 -C 7 ) heterocycloalkyl; and phenyl optionally substituted by one or more (C 1 -C 6 ) alkyl, halogen or —OH; 
 a group —C(O)R 18 , wherein R 18  is selected in the group consisting of: (C 1 -C 6 ) alkyl optionally substituted by (C 3 -C 7 ) cycloalkyl; (C 1 -C 6 ) alkylcarboxyl; and phenyl optionally substituted by one or more (C 1 -C 6 ) alkyl, halogen or hydroxyl; and a group —NR 2 OR 21 ; wherein R 20  and R 21  are different or the same and are independently selected from the group consisting of: H and (C 1 -C 6 ) alkyl, which is optionally substituted with (C 1 -C 6 )alkoxy; 
 a group —C(O)OR 19 , wherein R 19  is selected in the group consisting of: 
 (C 1 -C 6 ) alkyl optionally substituted by (C 3 -C 7 ) cycloalkyl; and phenyl optionally substituted by one or more (C 1 -C 6 ) alkyl, halogen or —OH; 
 or they form with the nitrogen atom to which they are linked a saturated or partially saturated heterocyclic ring, which is optionally substituted by (C 1 -C 6 ) alkyl; 
 
 (C 1 -C 4 ) alkyl-NR 13 R 14 ; 
 COR 22  wherein R 22  is phenyl, heterocycloalkyl or (C 1 -C 6 ) alkyl; 
 —SO 2 R 23  wherein R 23  is (C 1 -C 4 ) alkyl, —OH or NR 28 R 29  wherein R 28  and R 29  are each independently 14 or (C 1 -C 4 ) alkyl; 
 —COOR 24  wherein R 24  is H or (C 1 -C 4 ) alkyl or (C 1 -C 4 ) alkyl-NR 13 R 14 ; and 
 —CONR 13 R 14  wherein R 13  and R 14  are as defined above; 
 wherein groups R 3 , R 4 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 28  and R 29  may have the same or different meanings at each occurrence, if present in more than one group; 
 or an N-oxide on the pyridine ring, or a pharmaceutically acceptable salts thereof. 
 
     
     
         2 . A compound, N-oxide, or a pharmaceutically acceptable salt according to  claim 1 , which has formula (IC): 
       
         
           
           
               
               
           
         
       
       wherein Z and R 3  are as defined above. 
     
     
         3 . A compound, N-oxide, or a pharmaceutically acceptable salt according to  claim 1 , wherein Z is:
 [3]-CH 2 —X-[4] wherein X is a group [5]—NH—(CO)-[4];   [3]-CH 2 —X-[4], wherein X is a group [5]-O—(CH2)n-[4];   [3]-CH 2 —X-[4], wherein X is a group a group —SO2-;   [3]-C 1-12 —X-[4] wherein X is a group [5]-(CO)—O—(CH2)n[4];   [3]-CH 2 —X-[4] wherein X is a group [5]-(CO)—NH-[4];   [3]-CH 2 —X-[4] wherein X is a group [5]-NR 9 —(CH2)n-[4];   [3]-CH 2 —X-[4] wherein X is a group [5]-SO 2 —NH-[4];   [3]-CH 2 —X-[4] wherein X is a group [5]—NH—(CO)—(CO)-[4];   [3]-CH 2 —X-[4] wherein X is a group [5]-O—(CO)—(CH 2 ) n -[4];   [3]-CH 2 —X-[4] wherein X is a group [5]-S—(CO)-[4];   [3]-CH 2 —X-[4] wherein X is a group [5]-NR 9 —(CH 2 ) n -[4];   [3]-CH 2 —X-[4] wherein X is a group [5]-NR 8 —SO 2 —(CH 2 ) n -[4];   [3]-CH 2 —X-[4], wherein X is a group [5]-O—SO 2 -[4];   [3]-CH 2 —X-[4], wherein X is a group [5]—NH—(CO)—NH-[4];   [3]-CHR 7 —NH—(CO)-J-[4];   [3]-CH 2 CH 2 —K-[4] wherein K is a group [6]—NH—(CO)-[4];   [3]-CH 2 CH 2 —K-[4] wherein K is a group [6]-SO 2 -[4];   [3]-CH 2 CH 2 —K-[4] wherein K is a group a group [6]-O—(CO)-[4];   [3]-Y-[4] wherein Y is a group [3]-(CO)-[4];   [3]-Y-[4], wherein Y is a group [3]-NR 9 —(CH2)n-[4];   [3]-Y-[4], wherein Y is a group [3]-S—(CH2)n-[4];   [3]-Y-[4] wherein Y is a group [3]-(CO)—NH-[4];   [3]-Y-[4] wherein Y is [3]-O—(CH 2 )n-[4];   [3]-Y-[4] wherein Y is [3]-CH═CH—SO 2 -[4];   [3]-CHR 26 —NR 27 —SO 2 -[4];   [3]-CHR 6 —CH 2 -[4];   [3]-C(OH)(OH)-[4]; or   [3]-C(CH 3 )(R 5 )—O—(CO)-[4].   
     
     
         4 . A compound, N-oxide, or a pharmaceutically acceptable salt according to  claim 1 , which is an N-oxide on the pyridine ring. 
     
     
         5 . A compound, N-oxide, or a pharmaceutically acceptable salt according to  claim 1 , which is represented by formula (I)′: 
       
         
           
           
               
               
           
         
       
     
     
         6 . A compound, N-oxide, or a pharmaceutically acceptable salt according to  claim 1 , which is a compound selected from the group consisting of:
 (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3,4-dimethoxyphenoxy)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3,4-dimethoxyphenylsulfonyl)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,4-dimethoxyphenylcarbamoyloxy)ethyl)pyridine 1-oxide;   (S)-4-(2-(benzyloxycarbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-methoxyphenoxy)carbonyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((3,4-dimethoxybenzyloxy)carbonyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-((3,4-dimethoxybenzyl)(methyl)amino)acetoxy)ethyl)pyridine 1-oxide;   3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-2-(3-(cyclopropylmethoxy)-4-(methylsulfonamido)benzoyloxy)-propanoyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3,4-dimethoxybenzylamino)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,4-dimethoxybenzylcarbamoyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-((3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzyloxy)carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3-(cyclopropylmethoxy)-4-(methylsulfonamido)benzoyloxy)acetoxy)-ethyl)pyridine 1-oxide;   4-((S)-2-((R)-2-amino-3-phenylpropanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide;   4-((S)-2-((S)-2-amino-3-(4-(methylsulfonyloxy)phenyl)propanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((3,4-dimethoxyphenylthio)carbonyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-(methylsulfonamido)phenoxy)carbonyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((3,4-dimethoxybenzylthio)carbonyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((3-(cyclopropylmethoxy)-4-(methylsulfonamido)benzyloxy)carbonyloxy)-ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((3,4-dimethoxybenzyl)(methyl)carbamoyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((3,4-dimethoxyphenyl)(methyl)carbamoyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(4-(methylsulfonamido)benzylcarbamoyloxy)ethyl)pyridine 1-oxide;   (S)-4-(2-((4-aminobenzyl)(methyl)carbamoyloxy)-2-(3-(cyclopropyl-methoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(methyl(4-(methylsulfonamido)benzyl)carbamoyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(methyl(4-nitrobenzyl)carbamoyloxy)ethyl)pyridine 1-oxide;   3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-2-(methylsulfonamido)-3-(4-(methylsulfonyloxy)phenyl)propanoyloxy)-ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(3-(cyclopropylmethoxy)-4-(methylsulfonamido)benzyloxy)-3-oxopropanoyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(N-(2-(methoxycarbonyl)phenyl)methylsulfonamido)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3-(cyclopropylmethoxy)-4-(methylsulfonamido)benzamido)acetoxy)-ethyl)pyridine 1-oxide;   3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-2-(3-(cyclopropylmethoxy)-4-(methylsulfonamido)benzamido)-4-(methylthio)butanoyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((3-methoxy-4-(2-morpholinoethoxy)benzyl)(methyl)carbamoyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-methoxy-3-(methylsulfonamido)benzyl)(methyl)carbamoyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-methoxy-3-(N-(2-morpholinoethyl)methylsulfonamido)benzyl)(methyl)-carbamoyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-methoxy-3-(N-(2-morpholinoethyl)methylsulfonamido)phenoxy)carbonyloxy)-ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(methyl(4-(methylsulfonamido)benzyl)amino)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(2-(methoxycarbonyl)phenylsulfonamido)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(2-(methylsulfonyl)benzamido)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-methoxy-3-(N-(2-morpholinoethyl)methylsulfonamido)benzoyloxy)-acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-methoxy-3-(methylsulfonyloxy)benzamido)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-(methylsulfonyloxy)benzamido)acetoxy)ethyl)pyridine 1-oxide;   (S)-4-(2-(2-benzamidoacetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide;   (S)-4-(2-(2-(4-carbamoylbenzamido)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-methoxy-3-(N-(2-morpholinoethyl)methylsulfonamido)benzamido)-acetoxy)ethyl)pyridine 1-oxide;   (S)-4-(2-(2-(3-acetamido-4-methoxyphenylsulfonamido)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3,4-dimethoxybenzoyloxy)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-(N-methylsulfamoyl)benzoyloxy)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(N-(4-(methoxycarbonyl)benzyl)methylsulfonamido)acetoxy)ethyl)pyridine 1-oxide;   (S)-4-(2-(2-(3-(N-(2-amino-2-oxoethyl)methylsulfonamido)-4-methoxy-benzamido)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3,4-dimethoxybenzamido)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(2-methoxy-4-(methylsulfonyloxy)benzoyloxy)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-(methylsulfonamidomethyl)benzoyloxy)acetoxy)ethyl)pyridine 1-oxide;   (S)-4-(2-(2-(3-(N-(2-amino-2-oxoethyl)methylsulfonamido)-4-methoxy-benzoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(N-(3,4-dimethoxyphenyl)sulfamoyl)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-methoxy-3-(methylsulfonyloxy)benzoyloxy)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(N-(3,4-dimethoxyphenyl)sulfamoyl)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-methoxy-3-(methylsulfonyloxy)benzoyloxy)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-methoxy-3-(methylsulfonamido)benzoyloxy)acetoxy)ethyl)pyridine 1-oxide;   (S)-4-(2-(3-(4-acetamidophenyl)propanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(4-(methylsulfonamido)phenyl)propanoyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3,4-dimethoxyphenylsulfonamido)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(3-(cyclopropylmethoxy)-4-(methylsulfonamido)benzamido)propanoyloxy)-ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(2-(4-(cyclopropylmethoxy)-3-(methylsulfonyloxy)-benzoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-(N-(cyclopropylmethyl)methylsulfonamido)-2-hydroxybenzoyl oxy)acetoxy)-ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(2-oxo-2-phenylacetamido)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(N-(3,4-dimethoxybenzyl)methylsulfonamido)acetoxy)ethyl)pyridine 1-oxide;   (S)-4-(2-(2-(benzyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(4-(methylthio)phenylamino)-3-oxopropanoyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(3,4-dimethoxyphenylamino)-3-oxopropanoyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(3,4-dimethoxyphenoxy)-3-oxopropanoyloxy)ethyl)pyridine 1-oxide;   3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((R)-2-(3,4-dimethoxyphenylsulfonamido)-4-(methylthio)butanoyloxy)ethyl)-pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3,4-dimethoxy-N-methylphenylsulfonamido)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(N-(4-(methylthio)phenyl)methylsulfonamido)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(N-(3,4-dimethoxyphenyl)methylsulfonamido)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-(morpholine-4-carbonyl)phenylsulfonamido)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3,4-dimethoxy-N-(2-morpholinoethyl)phenylsulfonamido)acetoxy)ethyl)-pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-methoxyphenylthio)carbonyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((3-methoxyphenylthio)carbonyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((2-methoxyphenylthio)carbonyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(phenylthiocarbonyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((3-(dimethylamino)phenylthio)carbonyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-((2-chlorophenylthio)carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-((4-chlorophenylthio)carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(2-(3-(cyclopropylmethoxy)-4-(N-(2-(4-methylpiperazin-1-yl)ethyl)methylsulfonamido)benzoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((2-fluorophenylthio)carbonyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((3-fluorophenylthio)carbonyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((5-fluoro-2-methoxyphenylthio)carbonyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-(trifluoromethyl)phenylthio)carbonyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((3-(trifluoromethyl)phenylthio)carbonyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((2-(trifluoromethyl)phenylthio)carbonyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-(methylsulfonamido)phenylsulfonamido)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3,4-dimethoxyphenylsulfonyloxy)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2,2-dihydroxy-2-(4-nitrophenyl)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-fluorophenylthio)carbonyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3-(cyclopropylmethoxy)-4-(methylsulfonamido)benzoyloxy)-2-methylpropanoyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((3-(methylsulfonamido)phenylthio)carbonyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-(dimethylamino)phenyl)-2-oxoacetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-(N-methylsulfamoyl)phenylsulfonamido)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(2,5-dimethoxyphenylsulfonamido)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-(methylsulfonyl)phenylsulfonamido)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-(methylthio)phenylamino)-2-oxoacetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((2,5-dimethoxyphenylthio)carbonyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3-(3,4-dimethoxyphenyl)ureido)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-ethoxy-3-(3-(2-methoxyethyl)ureido)phenylsulfonamido)acetoxy)-ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-((4-(methylsulfonamido)phenyl)methylsulfonamido)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(2-methoxy-4-nitrophenylamino)-2-oxoacetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(3-(cyclopropylmethoxy)-4-(methylsulfonamido)benzoyloxy)propanoyloxy)-ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-(methylsulfonamido)phenylthio)carbonyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-((3-chlorophenylthio)carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((3-(cyclopropylmethoxy)-4-(methylsulfonamido)phenylthio)carbonyloxy)-ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-nitrophenylsulfonyl)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(3,5-dimethoxyphenoxy)-3-oxopropanoyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((2,4-dimethoxyphenylthio)carbonyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((3-(N-(2-morpholinoethyl)methylsulfonamido)phenylthio)carbonyloxy)-ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(phenoxycarbonyloxy)ethyl)pyridine 1-oxide;   (S)-4-(2-(2-(benzoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3-(methylsulfonamido)benzoyloxy)acetoxy)ethyl)pyridine 1-oxide;   (S)-4-(2-(2-(benzoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3-(methylsulfonamido)benzoyloxy)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3-(cyclopropylmethoxy)-4-(methylsulfonamido)benzoylthio)acetoxy)ethyl)-pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-methoxy-3-(methylsulfonamido)benzoylthio)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-oxo-3-phenoxypropanoyloxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-(methylsulfonamido)benzoyloxy)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3-(N-methylsulfamoyl)benzoyloxy)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-methoxy-3-(methylsulfonamido)phenylsulfonamido)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(2-(4-methoxy-3-(methylsulfonamido)phenyl)acetoxy)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(2-(2-(4-(cyclopropylmethoxy)-3-(methyl sulfonamido)-phenyl)acetoxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(2-(2-(methylsulfonamido)phenyl)acetoxy)acetoxy)ethyl)pyridine 1-oxide;   4-((S)-2-((R)-5-acetoxy-2-(3,4-dimethoxyphenylsulfonamido)pentanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(2-(methylsulfonamido)benzoyloxy)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(2-(4-(methylsulfonamido)phenyl)acetoxy)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3-methoxy-5-(methylsulfonamido)benzoyloxy)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(2-(3-(methylsulfonamido)phenyl)acetoxy)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-methoxy-3-(methylsulfonyloxy)benzoylthio)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3-(methylsulfonamido)-5-(trifluoromethyl)benzoyloxy)acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-methoxy-3-(N-(2-morpholinoethyl)methylsulfonamido)benzoylthio)-acetoxy)ethyl)pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(2-(4-(cyclopropylmethoxy)-3-(morpholinomethyl)-benzoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3-(dimethylcarbamoyl)phenylsulfonamido)acetoxy)ethyl)pyridine 1-oxide;   3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-2-(3-(dimethylcarbamoyl)phenylsulfonamido)-3-methylbutanoyloxy)ethyl)-pyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3-(dimethylcarbamoyl)-4-methoxyphenylsulfonamido)acetoxy)ethyl)pyridine 1-oxide;   4-((2S)-2-(3-(acetylthio)-3-methyl-2-(phenylsulfonamido)butanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide;   (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(phenylsulfonyl)propanoyloxy)ethyl)pyridine 1-oxide;   3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((R)-2-(N-methylphenylsulfonamido)propanoyloxy)ethyl)pyridine 1-oxide;   (S,Z)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(3-(phenylsulfonyl)acryloyloxy)ethyl)pyridine 1-oxide;   (S,E)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(3-(phenylsulfonyl)acryloyloxy)ethyl)pyridine 1-oxide;   3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-2-(N-methylphenylsulfonamido)propanoyloxy)ethyl)pyridine 1-oxide;   3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((R)-2-(3-(dimethylcarbamoyl)-N-methylphenylsulfonamido)propanoyloxy)ethyl)pyridine 1-oxide;   3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-2-(3-(dimethylcarbamoyl)-N-methylphenylsulfonamido)propanoyloxy)ethyl)pyridine 1-oxide;   3,5-dichloro-4-((R)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-2-(N-methylphenylsulfonamido)propanoyloxy)ethyl)pyridine 1-oxide;   3,5-dichloro-4-((R)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((R)-2-(N-methylphenylsulfonamido)propanoyloxy)ethyl)pyridine 1-oxide;   3,5-dichloro-4-((R)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((R)-2-(3-(dimethylcarbamoyl)-N-methylphenylsulfonamido)propanoyloxy)ethyl)pyridine 1-oxide; and   3,5-dichloro-4-((R)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-2-(3-(dimethylcarbamoyl)-N-methylphenylsulfonamido)propanoyloxy)ethyl)pyridine 1-oxide;   or a pharmaceutically acceptable salt of said compound.   
     
     
         7 . A compound, which is represented by formula (ID): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 2  are different or the same and are each independently:
 (C 1 -C 6 ) alkyl, optionally substituted by (C 3 -C 7 ) cycloalkyl; 
 (C 1 -C 6 ) haloalkyl; or 
 (C 3 -C 7 ) cycloalkyl; 
 
 R 4  is one or more substituents independently selected from the group consisting of H, CN, NO 2 , CF 3  and a halogen atom; 
 Z is a group [3]-CH 2 —X-[4]; wherein [3] indicates the point of attachment for group Z with the carboxylic group and [4] indicates the point of attachment for group Z with the group W; 
 X is a group [5]-O—(CO)—(CH 2 ) n -[4]; wherein [5] indicates the point of attachment for group X with the methylene group and [4] indicates the point of attachment for group X with the W group; 
 n is 0; 
 W is a monocyclic or bicyclic heteroaryl ring; 
 R 3  are one or more optional substituents which may be the same or different, and are each independently: 
 (C 1 -C 6 ) alkyl optionally substituted by one or more (C 3 -C 7 )cycloalkyl; 
 (C 1 -C 6 ) haloalkyl; 
 (C 3 -C 7 ) heterocycloalkyl; 
 (C 3 -C 7 ) heterocycloalkyl(C 1 -C 4 ) alkyl; 
 a group —OR 11  wherein R 11  is:
 H: 
 (C 1 -C 6 ) haloalkyl; 
 a group —SO 2 R 12 , wherein R 12  is (C 1 -C 6 ) alkyl; 
 a group —C(O)R 12  wherein R 12  is as above defined; 
 (C 1 -C 10 ) alkyl optionally substituted by one or more (C 3 -C 7 ) cycloalkyl or by a group —NR 13 R 14  as below defined; or 
 (C 3 -C 7 ) cycloalkyl; 
 
 a group —SR 25  wherein R 25  is:
 H: 
 (C 1 -C 6 ) haloalkyl; 
 a group —C(O)R 12 ; 
 (C 1 -C 10 ) alkyl optionally substituted by one or more (C 3 -C 7 ) cycloalkyl or by a group —NR 13 R 14 ; or 
 (C 3 -C 7 ) cycloalkyl; 
 
 a halogen atom; 
 CN; 
 NO 2 ; 
 NR 13 R 14  wherein R 13  and R 14  are different or the same and are each independently:
 H; 
 (C 1 -C 4 ) alkyl-NR 15 R 16  wherein R 15  and R 16  are different or the same and are independently selected from the group consisting of: H and (C 1 -C 6 ) alkyl, which is optionally substituted with (C 3 -C 7 ) cycloalkyl or (C 3 -C 7 ) heterocycloalkyl; or they form with the nitrogen atom to which they are linked a (C 3 -C y )heterocycloalkyl which is optionally substituted by (C 1 -C 6 )alkyl; 
 linear or branched (C 1 -C 6 ) alkyl, optionally substituted with (C 3 -C 7 ) cycloalkyl, (C 3 -C 7 ) heterocycloalkyl, a group —OH, (C 1 -C 6 ) alkoxyl or by an aminocarbonyl group; 
 a group —SO 2 R 17 , wherein R 17  is selected in the group consisting of: (C 1-6 ) alkyl optionally substituted by (C 3 -C 7 ) cycloalkyl or (C 3 -C 7 ) heterocycloalkyl; 
 (C 3 -C 7 ) heterocycloalkyl; and phenyl optionally substituted by one or more (C 1 -C 6 ) alkyl, halogen or —OH; 
 a group —C(O)R 18 , wherein R 18  is selected in the group consisting of: (C 1 -C 6 ) alkyl optionally substituted by (C 3 -C 7 ) cycloalkyl; (C 1 -C 6 ) alkylcarboxyl; and phenyl optionally substituted by one or more (C 1 -C 6 ) alkyl, halogen or hydroxyl; and a group —NR 2 OR 21 ; wherein R 20  and R 21  are different or the same and are independently selected from the group consisting of: H and (C 1 -C 6 ) alkyl, which is optionally substituted with (C 1 -C 6 )alkoxy; 
 a group —C(O)OR 19 , wherein R 19  is selected in the group consisting of: (C 1 -C 6 ) alkyl optionally substituted by (C 3 -C 7 ) cycloalkyl; and phenyl optionally substituted by one or more (C 1 -C 6 ) alkyl, halogen or —OH; 
 or they form with the nitrogen atom to which they are linked a saturated or partially saturated heterocyclic ring, which is optionally substituted by (C 1 -C 6 ) alkyl; 
 
 (C 1 -C 4 ) alkyl-NR 13 R 14 ; 
 COR 22  wherein R 22  is phenyl, heterocycloalkyl or (C 1 -C 6 ) alkyl; —SO 2 R 23  wherein R 23  is (C 1 -C 4 ) alkyl, —OH or NR 28 R 29  wherein R 28  and R 29  are each independently H or (C 1 -C 4 ) alkyl; 
 —COOR 24  wherein R 24  is H or (C 1 -C 4 ) alkyl or (C 1 -C 4 ) alkyl-NR 13 R 14 ; and 
 —CONR 13 R 14  wherein R 13  and R 14  are as defined above; 
 wherein groups R 3 , R 4 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 28 , R 29  and R 25  may have the same or different meanings at each occurrence, if present in more than one group; 
 or an N-oxide on the pyridine ring, or a pharmaceutically acceptable salt thereof. 
 
     
     
         8 . A combination, comprising a compound, N-oxide on the pyridine ring, or pharmaceutically acceptable salt according to  claim 1  and a second pharmaceutically active component selected from the group consisting of a beta2-agonist, a corticosteroid, and an antimuscarinic agent. 
     
     
         9 . A pharmaceutical composition, comprising a compound, N-oxide on the pyridine ring, or pharmaceutically acceptable salt according to  claim 1  and one or more pharmaceutically acceptable carriers and/or excipients. 
     
     
         10 . A method for the prevention and/or treatment of a disease of a respiratory tract characterized by airway obstruction, such as asthma or COPD, comprising administering to a subject in need thereof a compound, N-oxide on the pyridine ring, or pharmaceutically acceptable salt according to  claim 1 . 
     
     
         11 . A device, comprising a pharmaceutical composition according to  claim 9 . 
     
     
         12 . A kit, comprising a pharmaceutical compositions according to  claim 9  and a device which may be a single- or multi-dose dry powder inhaler, a metered dose inhaler or a soft mist nebulizer.