Novel tricyclic spiroderivatives as modulators of chemokine receptor activity

Abstract

The invention provides compounds of formula (I) wherein m, R 1 , n, R 2 , q, p, X, Y, R 3 , R 4 , t and, R 5 are as defined in the specification, processes for their preparation, pharmaceutical compositions contain them and their use in therapy.

1 - 14 . (canceled) 
   
   
       15 . A method for the treatment of human diseases or conditions in which modulation of chemokine receptor activity is beneficial which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
       wherein 
       m is 0, 1, 2, 3or4; 
       each R 1  independently represents halogen, cyano, hydroxyl, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 6  alkoxy, C 1 -C 6  alkylsulphonyl or sulphonamido (—SO 2 NH 2 ); 
       X represents a bond or —CH 2 — and Y represents a bond or —CH 2 — provided that X and Y do not both simultaneously represent a bond or —CH 2 —; 
       n is 0, 1 or 2; 
       each R 2  independently represents halogen, C 1 -C 6  alkyl or C 1 -C 6  haloalkyl; 
       q is 0 or 1; 
       p is 0 or 2; 
       R 3  represents a group selected from halogen, NR 6 R 7 , carboxyl or C 1 - 6  alkyl wherein said C 1 -C 6  alkyl group is optionally substituted by one or more halogen, amino, hydroxyl, C 1 -C 6 alkoxy, N—( 1 -C 6  alkyl)amino, N,N-di-(C 1 -C 6  alkyl)amino, carboxy or carbamoyl; 
       R4 represents hydrogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl or halogen; 
       t is 0, 1 or 2, provided that p and t are not both 0; 
       R 5  represents a saturated or unsaturated 5- to 10-membered ring system which ring system may comprise at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the ring system being optionally substituted by one or more substituents independently selected from halogen, cyano, oxo, nitro, hydroxyl, carboxyl, —C(O)H, —NR 8 R 9 , —C(O)NR 10 R 11 , 
       —NHC(O)R 12 , —NHSO 2 R 13 , —SO 2 NR 14 R 15 , —NHC(O)NR 16 R 17 , a group selected from C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  alkoxy, C 1 -C 6  alkylthio, C 1 -C 6  alkylsulphonyl, C 1 -C 6  haloalkyl, C 1 -C 6  alkylcarbonyl, phenylcarbonyl, C 3 -C 6  cycloalkyl, phenyl and a saturated or unsaturated 5- to 6-membered heterocyclic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, each group being optionally substituted by one or more substituents independently selected from halogen, cyano, hydroxyl, carboxyl, C 1 - 6  alkyl, C3-C6 cycloalkyl, C 1 -C 6  alkoxy and C 1 -C 6  alkoxycarbonyl; 
       R 6  and R 7  each independently represent hydrogen or a group selected from C 1 -C 6  alkyl and C 1 -C 6  alkylcarbonyl, each of which may be optionally substituted by one or more substituents selected from halogen, amino, hydroxyl, C 1 - 6 alkoxy, N—(C 1 -C 6  alkyl)amino, N,N-di-(C 1 -C 6  alkyl)amino, carboxy, carbamoyl or C 1 -C 6  alkoxycarbonyl, or R6 and R7 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring which may be optionally substituted by one or more substituent selected from halogen, amino, hydroxyl, C 1 - 6 alkoxy, N—(C 1 -C 6  alkyl)amino, N,N-di-(C 1 -C 6  alkyl)amino, carboxy, carbamoyl or C 1 -C 6  alkoxycarbonyl; 
       R 8 , R 9 , R 10 , R 11  each independently represent hydrogen or a group selected from C 1 - 6  alkyl or C 3 - 6  cycloalkyl, each group being optionally substituted by one or more substituents independently selected from halogen, amino, hydroxyl, C 1 -C 6  alkoxy, N—(C 1 -C 6  alkyl)amino, N,N-di-(C 1 -C 6  alkyl)amino, carboxy or carbamoyl; or R 10  and R 11 , together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring which may be optionally substituted with at least one substituent selected from halogen, amino, hydroxyl, C 1 -C 6  alkoxy, N—(C 1 -C 16  alkyl)amino, N,N-di-(C 1 - 6  alkyl)amino, carboxy or carbamoyl; 
       R 12  represents hydrogen or a group selected from C 1 -C 6  alkyl or C 3 - 6  cycloalkyl, each group being optionally substituted by one or more substituents independently selected from halogen, amino, hydroxyl, C 1 -C 6  alkoxy, N—(C 1 -C 6  alkyl)amino, N,N-di-(C 1 -C 6  alkyl)amino, carboxy or carbamoyl; 
       R 13  represents a group selected from C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl, each group being optionally substituted by one or more substituents independently selected from halogen, amino, hydroxyl, C 1 -C 6  alkoxy, N—(C 1 -C 6  alkyl)amino, N,N-di-(C 1 -C 6  alkyl)amino, carboxy or carbamoyl; 
       R 14 , R 15 , R 16  and R 17  each independently represent hydrogen or a from selected from C 1 - 6  alkyl or C 3 -C 6  cycloalkyl, each group being optionally substituted by one or more substituents independently selected from halogen, amino, hydroxyl, C 1 -C 6  alkoxy, N—(C 1 -C 6  alkyl)amino, N,N-di-(C 1 - 6  alkyl)amino, carboxy or carbamoyl; or R 14  and R 15 , or R 16  and R 17 , together with the nitrogen atom to which they are attached each independently form a 4- to 7-membered saturated heterocyclic ring which may be optionally substituted with at least one substituent selected from halogen, amino, hydroxyl, C 1 -C 6  alkoxy, N—(C 1 -C 6  alkyl)amino, N,N-di-(C 1 -C 6  alkyl)amino, carboxy or carbamoyl. 
     
   
   
       16 - 19 . (canceled) 
   
   
       20 . A method of treating an inflammatory disease which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof: 
     
       
         
         
             
             
         
       
       wherein 
       m is 0 1, 2, 3 or 4; 
       each R 1  independently represents halogen, cyano, hydroxyl, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 6  alkoxy, C 1 -C 6  alkylsulphonyl or sulphonamido (—SO 2 NH 2 ); 
       X represents a bond or —CH 2 — and Y represents a bond or —CH 2 —, provided that X and Y do not both simultaneously represent a bond or —CH 2 —; 
       n is 0, 1 or 2; 
       each R 2  independently represents halogen, C 1 -C6 alkyl or C 1 -C 6  haloalkyl; 
       q is 0 or 1; 
       p is 0, 1 or 2; 
       R 3  represents a group selected from halogen, NR 6 R 7 , carboxyl or C 1 - 6  alkyl wherein said C 1 -C 6  alkyl group is optionally substituted by one or more halogen, amino, hydroxyl, C 1 - 6  alkoxy, N—(C 1 -C 6  alkyl)amino, N,N-di-(C 1 -C 6  alkyl)amino, carboxy or carbamoyl; 
       R 4  represents hydrogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl or halogen; 
       t is 0, 1 or 2, provided that p and t are not both 0; 
       R 5  represents a saturated or unsaturated 5- to 10-membered ring system which ring system may comprise at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the ring system being optionally substituted by one or more substituents independently selected from halogen, cyano, oxo, nitro, hydroxyl, carboxyl, —C(O)H, —NR 8 R 9 , —C(O)NR 10 R 11 , —NHC(O)R 12 , —NHSO 2 R 13 , —SO 2 NR 14 R 15 , —NHC(O)NR 16 R 17 , a group selected from C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  alkoxy, C 1 -C 6  alkylthio, 
       C 1 -C 6  alkylsulphonyl, C 1 -C 6  haloalkyl, C 1 -C 6  alkylcarbonyl, phenylcarbonyl, C 3 -C 6  cycloalkyl, phenyl and a saturated or unsaturated 5- to 6-membered heterocyclic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, each group being optionally substituted by one or more substituents independently selected from halogen, cyano, hydroxyl, carboxyl C 1 -C 6  alkyl, C3-C6 cycloalkyl, C 1 -C 6  alkoxy and C 1 -C 6  alkoxycarbonyl; 
       R 6  and R 7 each independently represent hydrogen or a group selected from C 1 -C 6  alkyl and C 1 -C 6  alkylcarbonyl, each of which may be optionally substituted by one or more substituents selected from halogen, amino, hydroxyl, C 1 -C 6 alkoxy, N—(C 1 -C 6  alkyl)amino, N,N-di-(C 1 -C 6  alkyl)amino, carboxy, carbamoyl or  1 -C 6  alkoxycarbonyl, or R6 and R7 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring which may be optionally substituted by one or more substituent selected from halogen, amino, hydroxyl, C 1 - 6  alkoxy, N—(C 1 -C 6  alkyl)amino, N,N-di-(C 1 -C 6  alkyl)amino, carboxy, carbamoyl or C 1 -C 6  alkoxycarbonyl; 
       R 8 , R 9 , R 10 , R 11  each independently represent hydrogen or a group selected from C 1 - 6  alkyl or C 3 - 6  cycloalkyl, each group being optionally substituted by one or more substituents independently selected from halogen, amino, hydroxyl, C 1 -C 6  alkoxy, N—(C 1 -C 6  alkyl)amino, N,N-di-(C 1 -C 6  alkyl)amino, carboxy or carbamoyl; or R 10  and R 11 , together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring which may be optionally substituted with at least one substituent selected from halogen, amino, hydroxyl, C 1 -C 6  alkoxy, N—(C 1 -C 6  alkyl)amino, N,N-di-(C 1 -C 6  alkyl)amino, carboxy or carbamoyl; 
       R 12  represents hydrogen or a group selected from C 1 -C 6  alkyl or C 3 - 6  cycloalkyl, each group being optionally substituted by one or more substituents independently selected from halogen, amino, hydroxyl, C 1 -C 6  alkoxy, N—(C 1 -C 6  alkyl)amino, N,N-di-(C 1 -C 6  alkyl)amino, carboxy or carbamoyl; 
       R 13  represents a group selected from C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl, each group being optionally substituted by one or more substituents independently selected from halogen, amino, hydroxyl, C 1 -C 6  alkoxy, N—(C 1 -C 6  alkyl)amino, N,N-di-(C 1 -C 6  alkyl)amino, carboxy or carbamoyl; 
       R 14 , R 15 , R 16  and R 17  each independently represent hydrogen or a from selected from C 1 - 6  alkyl or C 3 - 6  cycloalkyl, each group being optionally substituted by one or more substituents independently selected from halogen, amino, hydroxyl, C 1 -C 6  alkoxy, N—(C 1 -C 6  alkyl)amino, N,N-di-(C 1 -C 6  alkyl)amino, carboxy or carbamoyl; or R 14  and R 15  , or R 16  and R 17 , together with the nitrogen atom to which they are attached each independently form a 4- to 7-membered saturated heterocyclic ring which may be optionally substituted with at least one substituent selected from halogen, amino, hydroxyl, C 1 -C 6  alkoxy, N—(C 1 -C 6  alkyl)amino, N,N-di-(C 1 -C 6  alkyl)amino, carboxy or carbamoyl. 
     
   
   
       21 . A method of treating an airways disease which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof: 
     
       
         
         
             
             
         
       
       wherein 
       m is 0 1, 2, 3or 4; 
       each R 1  independently represents halogen, cyano, hydroxyl, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 6  alkoxy, C 1 -C 6  alkylsulphonyl or sulphonamido (—SO 2 NH 2 ); 
       X represents a bond or —CH 2 — and Y represents a bond or —CH 2 —, provided that X and Y do not both simultaneously represent a bond or —CH 2 —; 
       n is 0, 1 or 2; 
       each R 2  independently represents halogens C 1 -C 6  alkyl or C 1 -C 6  haloalkyl; 
       q is 0 or 1; 
       p is 0, 1 or 2; 
       R 3  represents a group selected from halogen, NR 6 R 7 , carboxyl or C 1 -C 6  alkyl wherein said C 1 -C 6  alkyl group is optionally substituted by one or more halogen, amino, hydroxyl, C 1 -C 6  alkoxy, N—(C 1 -C 6  alkyl)amino, N,N-di-(C 1 -C 6 alkyl)amino, carboxy or carbamoyl; 
       R4 represents hydrogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl or halogen; 
       t is 0, 1 or 2 provided that p and t are not both 0; 
       R 5  represents a saturated or unsaturated 5- to 10-membered ring system which ring system may comprise at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the ring system being optionally substituted by one or more substituents independently selected from halogen, cyano, oxo, nitro, hydroxyl, carboxyl, —C(O)H, —NR 8 R 9 , —C(O)NR 10 R 11 , —NHC(O)R 12 , —NHSO 2 R 13 , —SO 2 NR 14 R 15 , —NHC(O)NR 16 R 17 , a group selected from C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 C-C 6  alkoxy, C 1 -C 6  alkylthio, C 1 -C 6  alkylsulphonyl, C 1 -C 6  haloalkyl, C 1 -C 6  alkylcarbonyl, phenylcarbonyl, C 3 -C 6  cycloalkyl, phenyl and a saturated or unsaturated 5- to 6-membered heterocyclic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, each group being optionally substituted by one or more substituents independently selected from halogen, cyano, hydroxyl, carboxyl, C 1 -C 6  alkyl, C3-C6 cycloalkyl, C 1 -C 6  alkoxy and C 1 -C 6  alkoxycarbonyl; 
       R 6  and R 7 each independently represent hydrogen or a group selected from C 1 -C 6  alkyl and C 1 -C 6  alkylcarbonyl, each of which may be optionally substituted by one or more substituents selected from halogen, amino, hydroxyl, C 1 -C 6  alkoxy, N—(C 1 -C 6  alkyl)amino, N,N-di-(C 1 -C 6  alkyl)amino, carboxy, carbamoyl or C 1 -C 6  alkoxycarbonyl, or R6 and R7 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring which may be optionally substituted by one or more substituent selected from halogen, amino, hydroxyl, C 1 -C 6  alkoxy, N—(C 1 -C 6  alkyl)amino, N,N-di-(C 1 -C 6  alkyl)amino, carboxy, carbamoyl or C 1 -C 6  alkoxycarbonyl; 
       R 8 , R 9 , R 10 , R 11  each independently represent hydrogen or a group selected from C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl, each group being optionally substituted by one or more substituents independently selected from halogen, amino, hydroxyl, C 1 -C 6  alkoxy, N—(C 1 -C 6  alkyl)amino, N,N-di-(C 1 -C 6 alkyl)amino, carboxy or carbamoyl; or R 10  and R 11 , together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring which may be optionally substituted with at least one substituent selected from halogen, amino, hydroxyl, C 1 -C 6  alkoxy, N—(C 1 -C 6  alkyl)amino, N,N-di-(C 1 -C 6  alkyl)amino, carboxy or carbamoyl; 
       R 12  represents hydrogen or a group selected from C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl, each group being optionally substituted by one or more substituents independently selected from halogen, amino, hydroxyl, C 1 -C 6  alkoxy, N—(C 1 -C 6  alkyl)amino, N,N-di-(C 1 -C 6  alkyl)amino, carboxy or carbamoyl; 
       R 13  represents a group selected from C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl, each group being optionally substituted by one or more substituents independently selected from halogen, amino, hydroxyl, C 1 -C 6  alkoxy, N—(C 1 -C 6  alkyl)amino, N,N-di-(C 1 -C 6  alkyl)amino, carboxy or carbamoyl; 
       R 14 , R 15 , R 16  and R 17  each independently represent hydrogen or a group selected from C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl, each group being optionally substituted by one or more substituents independently selected from halogen, amino, hydroxyl, C 1 -C 6  alkoxy, N—(C 1 -C 6  alkyl)amino, N,N-di-(C 1 -C 6  alkyl)amino, carboxy or carbamoyl; or R 14  and R 15 , or R 16  and R 17 , together with the nitrogen atom to which they are attached each independently form a 4- to 7-membered saturated heterocyclic ring which may be optionally substituted with at least one substituent selected from halogen, amino, hydroxyl, C 1 -C 6 alkoxy, N—(C 1 -C 6  alkyl)amino, N,N-di-(C 1 -C 6  alkyl)amino, carboxy or carbamoyl. 
     
   
   
       22 . The method of  claim 20 , wherein the inflammatory disease is rheumatoid arthritis. 
   
   
       23 . The method of  claim 21 , wherein the airways disease is chronic obstructive pulmonary disease. 
   
   
       24 . The method of  claim 21 , wherein the airways disease is asthma. 
   
   
       25 . The method of  claim 15 , wherein the disease or condition is multiple sclerosis.