Pyrimidine Sulphonamide Derivatives as Chemokine Receptor Modulators

Abstract

A compound of formula (1), or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof and pharmaceutical compositions comprising these, all for use in the treatment of chemokine mediated diseases and disorders.

1 . A compound of formula (1) 
       
         
           
           
               
               
           
         
         wherein R 1  is a group selected from C 3-7 carbocyclyl, C 1-8 alkyl, C 2-6 alkenyl and C 2-6 alkynyl; 
         wherein the group is optionally substituted by 1, 2 or 3 substituents independently selected from fluoro, nitrile, —OR 4 , —NR 5 R 6 , —CONR 5 R 6 , —COOR 7 , —NR 8 COR 9 , —SR 10 , —SO 2 R 10 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 9 , phenyl or heteroaryl; wherein phenyl and heteroaryl are optionally substituted by 1, 2 or 3 substituents independently selected from halo, cyano, nitro, —OR 4 , —NR 5 R 6 , —CONR 5 R 6 , —COOR 7 , —NR 8 COR 9 , —SR 10 , —SO 2 R 10 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 9 , C 1-6 alkyl and trifluoromethyl; 
         X is —CH 2 —, a bond, oxygen, sulphur, sulphoxide, or sulphone; 
         R 2  is C 3-7 carbocyclyl, optionally substituted by 1, 2 or 3 substituents independently selected from: fluoro, —OR 4 , —NR 5 R 6 —CONR 5 R 6 , —COOR 7 , —NR 8 COR 9 , —SR 10 , —SO 2 R 10 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 9 ; 
         or R 2  is a 3-8 membered ring optionally containing 1, 2 or 3 atoms selected from O, S, —NR 8  and whereby the ring is optionally substituted by 1, 2 or 3 substituents independently selected from C 1-3 alkyl, fluoro, —OR 4 , —NR 5 R 6 —CONR 5 R 6 , —COOR 7 , —NR 8 COR 9 , —SR 10 , —SO 2 R 10 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 9 ; 
         or R 2  is phenyl or heteroaryl, each of which is optionally substituted by 1, 2 or 3 substituents independently selected from halo, cyano, nitro, —OR 4 , —NR 5 R 6 , —CONR 5 R 6 , —NR 8 COR 9 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 9 , C 1-6 alkyl and trifluoromethyl; 
         or R 2  is a group selected from C 1-8 alkyl, C 2-6 alkenyl or C 2-6 alkynyl wherein the group is substituted by 1, 2 or 3 substituents independently selected from hydroxy, amino, C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, N—(C 1-6 alkyl)-N-(phenyl)amino, N—C 1-6 alkylcarbamoyl, N,N-di(C 1-6 alkyl)carbamoyl, N—(C 1-6 alkyl)-N-(phenyl)carbamoyl, carboxy, phenoxycarbonyl, —NR 8 COR 9 , —SO 2 R 10 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 9  and —CONR 5 R 6 ; 
         R 3  is trifluoromethyl or a group —NR 5 R 6 , 
         or R 3  is phenyl, napthyl, monocyclic or bicyclic heteroaryl wherein a heteroring may be partially or fully saturated and one or more ring carbon atoms may form a carbonyl group, and wherein each phenyl or heteroaryl group is optionally substituted by 1, 2 or 3 substituents independently selected from halo, cyano, nitro, phenyl, heteroaryl, —OR 4 , —NR 5 R 6 , —CONR 5 R 6 , —COR 7 —, —COR 20 , —COOR 7 , —NR 8 COR 9 , —SR 10 , —SO 2 R 10 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 9 , trifluoromethyl or C 1-6 alkyl [optionally further substituted by 1, 2 or 3 substituents independently selected from halo, cyano, nitro, —OR 20 , —COOR 20 , —COR 20 , —NR 18 R 19 , —CONR 18 R 19 , —NR 18 COR 19 , —SO 2 R 20 , —SO 2 NR 18 R 19 , NR 18 SO 2 R 19 , phenyl or monocyclic or bicyclic heteroaryl, wherein a heteroring may be partially or fully saturated; and wherein each phenyl or heteroaryl group is optionally substituted by 1, 2 or 3 substituents independently selected from halo, cyano, nitro, —OR 20 , —NR 5 R 6 , —CONR 5 R 6 , —COR 7 ′—COOR 7 , —NR 8 COR 9 , —SR 10 , —SO 2 R 10 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 9 , heteroaryl, C 1-6 alkyl (optionally further substituted by 1, 2 or 3 substituents independently selected from halo, cyano, nitro, —OR 20 , —COOR 20 , —COR 20 , —NR 18 R 19 , —CONR 18 R 19 , —NR 18 COR 19 , —SO 2 R 20 , —SO 2 NR 18 R 19 , NR 18 SO 2 R 19 , 
         or R 3  is a group selected from C 3-7 carbocyclyl, C 1-8 alkyl, C 2-6 alkenyl and C 2-6 alkynyl whereby the group is optionally substituted by 1, 2 or 3 substituents independently selected from halo, —OR 4 , —NR 5 R 6 , —CONR 5 R 6 , —COR 7 , —COOR 7 , —NR 8 COR 9 , —SR 10 , —SO 2 R 10 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 9 , phenyl or monocyclic or bicyclic heteroaryl, wherein a heteroring may be partially or fully saturated; and wherein each phenyl or monocyclic or bicyclic heteroaryl group is optionally substituted by 1, 2 or 3 substituents independently selected from halo, cyano, nitro, —OR 4 , —NR 5 R 6 , —CONR 5 R 6 , —COR 7 ′—COOR 7 , —NR 8 COR 9 , —SR 10 , —SO 2 R 10 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 9 , C 1-6 alkyl, or trifluoromethyl; 
         R 4  is hydrogen or a group selected from C 1-6 alkyl and phenyl, wherein the group is optionally substituted by 1 or 2 substituents independently selected from halo, phenyl, —OR 11  and —NR 12 R 13 ; 
         R 5  and R 6  are independently hydrogen or a group selected from C 1-6 alkyl and phenyl and monocyclic or bicyclic heteroaryl, wherein a heteroring may be partially or fully saturated; 
         wherein the group is optionally substituted by 1, 2 or 3 substituents independently selected from halo, phenyl, —OR 14 , —NR 15 R 16 , —COOR 14 , —CONR 15 R 16 , —NR 15 COR 16 , —SO 2 R 10 , —SO 2 NR 15 R 16  and NR 15 SO 2 R 16 ; 
         or 
         R 5  and R 6  together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring system optionally containing a further heteroatom selected from oxygen, —SO (n) — (where n=0, 1 or 2) and nitrogen atoms, in which the ring is optionally substituted by 1, 2 or 3 substituents independently selected from phenyl, heteroaryl, —OR 14 , —COR 20 , —COOR 14 , —NR 15 R 16 , —CONR 15 R 16 , —NR 15 COR 16 , —SO 2 R 10 , —SO 2 NR 15 R 16 , NR 15 SO 2 R 16  or C 1-6 alkyl (optionally further substituted by 1 or 2 or 3 substituents independently selected from halo, —NR 15 R 16  and —OR 17  or cyano, nitro, —OR 20 , —COOR 20 , —COR 20 , —NR 18 R 19 , —CONR 18 R 19 , —NR 18 COR 19 , —SO 2 R 20 , —SO 2 NR 18 R 19 , NR 18 SO 2 R 19  groups); 
         R 10  is hydrogen or a group selected from C 1-6 alkyl or phenyl, wherein the group is optionally substituted by 1, 2 or 3 substituents independently selected from halo, phenyl, —OR 17  and —NR 15 R 16 ; and each of R 7 , R 8 , R 9 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17  is independently hydrogen, C 1-6 alkyl or phenyl. 
         R 18 , R 19 , and R 20  are hydrogen or a group selected from C 1-6 alkyl or heteroaryl (wherein a heteroring may be partially or fully saturated) or phenyl, wherein the group is optionally substituted by 1, 2 or 3 substituents independently selected from halo, nitro, —CN, —OR 4 , —NR 8 R 9 , —CONR 8 R 9 , —COR 7 ′—COOR 7 , —NR 8 COR 9 , —SR 10 , —SO 2 R 10 , —SO 2 NR 8 R 9 , —NR 8 SO 2 R 9 , C 1-6 alkyl or heteroaryl 
         or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof: 
       
     
     
         2 . A compound, pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof according to  claim 1  wherein R 1  is C 1-8 alkyl substituted by phenyl which is optionally substituted by 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, methoxy, methyl and trifluoromethyl. 
     
     
         3 . A compound, pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof according to  claim 1  wherein X is selected from —CH 2 —, a bond, oxygen and sulphur. 
     
     
         4 . A compound, or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof according to  claim 1  wherein R 2  is C 1-8 alkyl optionally substituted by 1, 2 or 3 substituents independently selected from C 1-6 alkoxy, hydroxy and fluoro; or
 R 2  is a 5-6 membered ring optionally containing 1, 2 or 3 heteroatoms selected from O, S, —NR 8  and whereby the ring is optionally substituted by —OR 4 . 
 
     
     
         5 . A compound, pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof according to  claim 1  wherein R 3  is C 3-7 carbocyclyl, C 1-8 alkyl, —NR 5 R 6 , phenyl, monocyclic or bicyclic heteroaryl wherein a heteroring may be partially or fully saturated and one or more ring carbon atoms may form a carbonyl group, and wherein each phenyl or heteroaryl group is optionally substituted by 1, 2 or 3 substituents independently selected from cyano, heteroaryl, —OR 4 , —NR 5 R 6 , —CONR 5 R 6 , —COR 7 —, COR 20 , —NR 8 COR 9 , —SO 2 R 10 , —SO 2 NR 5 R 6 , C 1-6 alkyl [optionally further substituted by 1, 2 or 3 substituents independently selected from —OR 20 , —COR 20 , —NR 18 R 19 , —CONR 18 R 19 , phenyl or monocyclic or bicyclic heteroaryl, wherein a heteroring may be partially or fully saturated; and wherein each phenyl or heteroaryl group is optionally substituted by 1, 2 or 3 substituents independently selected from nitro, —OR 20 , —NR 5 R 6 , —NR 8 COR 9 , heteroaryl, C 1-6 alkyl (optionally further substituted by 1, 2 or 3 substituents independently selected from cyano, —OR 20 . 
     
     
         6 . A compound according to  claim 1  selected from the group consisting of:
 N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[2-hydroxy-1-(hydroxymethyl)ethoxy]-4-pyrimidinyl]-1-azetidinesulfonamide 
 R,S)N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[3,4-dihydroxybutyl]pyrimidin-4-yl]azetidine-1-sulphonamide; and 
 N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[3-hydroxy-2-(hydroxymethyl)propyl]pyrimidin-4-yl]azetidine-1-sulphonamide 
 N-(2-[(2,3-difluorobenzyl)thio]-6-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}pyrimidin-4-yl)azetidine-1-sulfonamide: and 
 N-(2-[(2,3-difluorobenzyl)thio]-6-{[(1S,2S)-2-hydroxy-1-methylpropyl]oxy}pyrimidin-4-yl)azetidine-1-sulfonamide 
 N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[[(2S)-2,3-dihydroxypropyl]oxy]-4-pyrimidinyl]-1-azetidinesulfonamide 
 N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[2-hydroxy-1-(hydroxymethyl)-1-methylethoxy]-4-pyrimidinyl]-1-azetidinesulfonamide 
 N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-2-hydroxy-1-methylethoxy]-4-pyrimidinyl]-2-thiazolesulfonamide 
 N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-2-hydroxy-1-methylethoxy]-4-pyrimidinyl]-4-pyridinesulfonamide 
 N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-2-hydroxy-1-methylethoxy]-4-pyrimidinyl]-1-piperazinesulfonamide N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-2-hydroxy-1-methylethoxy]-4-pyrimidinyl]-1,6-dihydro-1-methyl-6-oxo-3-pyridinesulfonamide 
 N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-2-hydroxy-1-methylethoxy]-4-pyrimidinyl]-1-azetidinesulfonamide N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-2-hydroxy-1-methylethoxy]-4-pyrimidinyl]-methanesulfonamide 
 N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-2-hydroxy-1-methylethoxy]-4-pyrimidinyl]-4-morpholinesulfonamide 
 N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-2-hydroxy-1-methylethoxy]-4-pyrimidinyl]-1-pyrrolidinesulfonamide 
 N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-2-hydroxy-1-methylethoxy]-4-pyrimidinyl]-cyclopropanesulfonamide 
 N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-2-hydroxy-1-methylethoxy]-4-pyrimidinyl]-1-methyl-1H-imidazole-4-sulfonamide 
 N-[2-[[(2,3-Difluorophenyl)methyl]thio]-6-methoxypyrimidin-4-yl]azetidine-1-sulfonamide 
 N-[2-[[(2,3-Difluorophenyl)methyl]thio]-6-methoxypyrimidin-4-yl]piperazine-1-sulfonamide 
 N-[2-[[(2,3-Difluorophenyl)methyl]thio]-6-methoxypyrimidin-4-yl]-1-methyl-1H-imidazole-4-sulfonamide 
 N-[2-[[(2,3-Difluorophenyl)methyl]thio]-6-[(1R,2R)-2,3-dihydroxy-1-methylpropyl]oxy-4-pyrimidinyl]-1-azetidinesulfonamide 
 N-[2-[[(2,3-Difluorophenyl)methyl]thio]-6-[[(1R,2R)-2,3-dihydroxy-1-methylpropyl]oxy]-4-pyrimidinyl]-methanesulfonamide 
 N-[2-[[(2,3-Difluorophenyl)methyl]thio]-6-{[(1R,2S)-2,3-dihydroxy-1-methylpropyl]oxy}-4-pyrimidinyl]-1-azetidinesulfonamide 
 N-[2-[[(2,3-Difluorophenyl)methyl]thio]-6-{[(1R,2S)-2,3-dihydroxy-1-methylpropyl]oxy}-4-pyrimidinyl]-1-piperazinesulfonamide 
 5-(azetidin-1-ylcarbonyl)-N-{2-[(2,3-difluorobenzyl)thio]-6-[(1R)-2-hydroxy-1-methylethoxy]pyrimidin-4-yl}furan-2-sulfonamide 
 or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof. 
 
     
     
         7 . (canceled) 
     
     
         8 . A method for the treatment of asthma, allergic rhinitis, COPD, inflammatory bowel disease, osteoarthritis, osteoporosis, rheumatoid arthritis, or psoriasis, which comprises administering to a patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof according to  claim 1 . 
     
     
         9 . A method for the treatment of cancer, which comprises administering to a patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof according to  claim 1 . 
     
     
         10 . 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 a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof according to  claim 1 . 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof according to  claim 1  and a pharmaceutically-acceptable diluent or carrier. 
     
     
         14 . A process for the preparation of a compound according to  claim 1  or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof, which comprises the steps of:
 (a) treating a compound of formula (2a): 
 
       
         
           
           
               
               
           
         
         
           wherein R 1 , R 2 , R 3  and X are as defined in formula (1) and L is a leaving group with a sulfonamide of formula R 3 SO 2 NH 2  where R 3  is as defined in formula (1); 
         
         and optionally thereafter, one or more of steps (i), (ii), (iii), (iv), or (v) in any order: 
         i) removing any protecting groups; 
         ii) converting the compound of formula (1) into a further compound of formula (1) 
         iii) forming a salt 
         iv) forming a prodrug 
         v) forming an in vivo hydrolysable ester; 
         or 
         (b) treating a compound of formula (2b): 
       
       
         
           
           
               
               
           
         
         wherein R 1  and R 3  are as defined in formula (1), L is a leaving group, PG is a protecting group or hydrogen and where X is oxygen or sulphur, with alcohols HOR 2  or thiols HSR 2  respectively wherein R 2  is as defined in formula (1) in the presence of a suitable base and solvent, and optionally thereafter, one or more of steps (i), (ii), (iii), (iv), or (v) in any order: 
         i) removing any protecting groups; 
         ii) converting the compound of formula (1) into a further compound of formula (1) 
         iii) forming a salt 
         iv) forming a prodrug 
         v) forming an in vivo hydrolysable ester. 
       
     
     
         15 . A compound of the formula (2a) 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and X are as defined in formula (1) and L is a leaving group, provided that when R 1  is benzyl, X is oxygen, R2 is methyl then L is not chlorine or when R 1  is benzyl, X is a bond, R2 is propyl then L is not chlorine. 
     
     
         16 . A combination therapy which comprises administering a compound of  claim 1 , formula (1) or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof, concurrently or sequentially with other therapy and/or another pharmaceutical agent. 
     
     
         17 . A combination therapy as claimed in  claim 16  for the treatment of asthma, allergic rhinitis, COPD, inflammatory bowel disease, irritable bowel syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis, or psoriasis. 
     
     
         18 . A combination therapy as claimed in  claim 16  for the treatment of cancer. 
     
     
         19 . A pharmaceutical composition which comprises a compound of formula (1) or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof as claimed in  claim 1 , in conjunction with another pharmaceutical agent. 
     
     
         20 . (canceled) 
     
     
         21 . (canceled) 
     
     
         22 . A combination therapy which comprises administering a pharmaceutical composition or formulation comprising a compound of formula (1), or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof as claimed in  claim 1 , concurrently or sequentially with other therapy and/or another pharmaceutical agent.