Imidazoquinolines with Immuno-Modulating Properties

Abstract

The present invention provides compounds of formula (I) wherein R a , R 1 , R 2 , R 3 , X 1 , Y 1 , Z 1 , A, n and m are as defined in the specification, and pharmaceutically acceptable salts thereof, as well as processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

1 .- 17 . (canceled) 
     
     
         18 . A method of treating, or reducing the risk of, a disease or condition in which modulation of TLR7 activity is beneficial which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  represents a straight chain C 1 -C 6  alkyl, optionally substituted by one or more substituents independently selected from halogen, cyano, hydroxyl and C 1 -C 3  alkoxy; 
 Z 1  represents a C 2 -C 6  alkylene group; 
 X 1  represents NR 5  or >N—COR 5 ; 
 Y 1  represents C 1 -C 6  alkylene; 
 each R 2  is independently selected from halogen, cyano, hydroxy, thiol, C 1 -C 3  alkyl, C 1 -C 3  hydroxyalkyl, C 1 -C 3  haloalkyl, C 1 -C 3  alkoxy, C 1 -C 3  haloalkoxy, C 1-3 alkylthio, C 1-3 alkylsulfonyl and C 1-3 alkylsulfinyl; 
 R 3  represents C 1-6 alkyl optionally substituted by C 1-6 alkoxy; 
 each R a  is independently selected from halogen, cyano, hydroxy, thiol, C 1 -C 3  alkyl, C 1 -C 3  hydroxyalkyl, C 1 -C 3  haloalkyl, C 1 -C 3  alkoxy, C 1 -C 3  haloalkoxy, C 1-3 alkylthio, C 1-3 alkylsulfonyl and C 1-3 alkylsulfinyl; 
 R 5  represents hydrogen, a 3- to 8-membered saturated heterocyclic ring comprising a ring group O, S(O) p  or NR 10 , a C 1 -C 6  alkyl group or C 3 -C 6  cycloalkyl group, the latter two groups being optionally substituted by one or more substituents independently selected from NR 7 R 8  or R 9 , 
 or R 5  is a C 1 -C 6  alkylene which may be linked to a carbon atom within a C 2 -C 6 alkylene group Z 1  so as to form a saturated 4-7 membered nitrogen containing ring; 
 R 7  and R 8  each independently represent hydrogen, a 3- to 8-membered saturated heterocyclic ring comprising a ring group O, S(O) p  or NR 10a , C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl, the latter two groups being optionally substituted by one or more groups independently selected from halogen, cyano, S(O) q R 11 , OR 12 , CO 2 R 12 , OC(O)R 12 , SO 2 NR 12 R 13 , CONR 12 R 13 , NR 12 R 13 , NR 12 SO 2 R 14 , NR 12 COR 13 , or a 3- to 8-membered saturated heterocyclic ring comprising a ring group O, S(O) p  or NR 10b , 
 or R 7  and R 8  together with the nitrogen atom to which they are attached form a 3- to 8-membered saturated heterocyclic ring comprising a ring nitrogen atom and optionally one or more further heteroatoms independently selected from nitrogen, oxygen, sulphur and sulphonyl, the heterocyclic ring being optionally substituted by one or more substituents independently selected from halogen, cyano, S(O) q R 15 , OR 15 , CO 2 R 15 , COR 15 , OC(O)R 15 , SO 2 NR 15 R 16 , CONR 15 R 16 , NR 15 R 16 , NR 15 SO 2 R 17 , NR 15 COR 16 , NR 15 CO 2 R 16 , heteroaryl, C 1 -C 6  haloalkyl, C 3 -C 8  cycloalkyl and C 1 -C 6  alkyl, the latter two groups being optionally substituted by one or more groups independently selected from cyano, S(O) q R 18 , OR 18 , CO 2 R 18 , SO 2 NR 18 R 19 , CONR 18 R 19  or NR 18 R 19 ; 
 R 9  represents halogen, cyano, CO 2 R 20 , S(O) q R 20 , OR 20 , SO 2 NR 20 R 22 , CONR 20 R 22 , NR 20 SO 2 R 21 , NR 20 CO 2 R 21 , NR 20 COR 22  or a 3- to 8-membered saturated heterocyclic ring comprising a ring group NR 10c ; 
 R 10 , R 10a , R 10b  and R 10c  independently represent hydrogen, CO 2 R 23 , S(O) q R 23 , COR 24 , or a C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl or C 3 -C 8  cycloalkyl group, each of which may be optionally substituted by one or more substituents independently selected from halogen, cyano, OR 25  or NR 25 R 26 ; 
 R 11 , R 12 , R 13 , R 15 , R 16 , R 18 , R 19 , R 20 , R 22 , R 24 , R 25  and R 26  each independently represent hydrogen, C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl; 
 R 14 , R 17 , R 21  and R 23  each independently represent C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl; 
 m, n, p and q each independently represent an integer 0, 1 or 2; and 
 A represents a monocyclic or bicyclic C 6 -C 10  aryl; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         19 . The method of  claim 18  wherein the disease or condition is selected from the group consisting of allergic diseases, viral diseases, asthma, COPD, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, cancer, hepatitis B, hepatitis C, HIV, HPV, bacterial infections and dermatosis. 
     
     
         20 . The method of  claim 19  wherein the disease or condition is asthma. 
     
     
         21 . The method of  claim 19  wherein the disease or condition is COPD. 
     
     
         22 . The method of  claim 19  wherein the disease or condition is allergic rhinitis.