Bicyclic organic compounds suitable for the treatment of inflammatory or allergic conditions

Abstract

A compound of formula (I): in free or salt form, wherein R 1 , R 3 , Q a , Q b and Q are as defined herein, for the treatment of a disease mediated by the S1P2 or S1P3 receptor, such as inflammatory or obstructive airways disease.

1 - 11 . (canceled) 
     
     
         12 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       in free or salt form, wherein
 Q is selected from CH 2 , C(O), and C(S); 
 Q a  is CH 
 Q b  is N; 
 
       
         
           
           
               
               
           
         
       
       is selected from C 6 -C 15 -aromatic carbocyclic group, C 5 -C 15 -carbocyclic group, and a 4- to 15-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur;
 R 1  is selected from C 1 -C 8 -alkyl optionally substituted by —OH, halogen, CN, O—C 1 -C 8 -alkyl, NR 1c R 1d , carboxy-C 1 -C 8 -alkyl, and COOH, —C(R 1a R 1b ) m C(O)CR 1c R 1d R 1e , —C(R 1a R 1b ) m C(O)NR 1c R 1d , —C(R 1a R 1b ) t NR 1c R 1d , C(R 1a R 1b ) m CR 1c R 1d R 1e , C(R 1a R 1b ) m SO 2 R 1f , C(R 1a R 1b ) m SOR 1g , and C(R 1a R 1b ) m SR 1h ; 
 R 1f , R 1g  and R 1h  are independently selected from C 1 -C 8 -alkyl, C 1 -C 8 -hydroxyalkyl, C 1 -C 8 -alkylamino(C 1 -C 8 -alkyl), di(C 1 -C 8 -alkyl)amino(C 1 -C 8 -alkyl), C 1 -C 8 -cyanoalkyl, C 6 -C 15 -aromatic carbocyclic group, a C 3 -C 15 -carbocyclic group, C 1 -C 8 -haloalkyl and a 4- to 10-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur; 
 each R 1a  and R 1b  are independently selected from H, —OH, and C 1 -C 8 -alkyl optionally substituted by —OH and halogen; 
 R 1c  and R 1d  are H; 
 C 6 -C 15 -aromatic carbocyclic group, C 7 -C 15 -aralkyl, C 3 -C 15 -carbocyclic group, a 4- to 15-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur; 
 C 1 -C 8 -alkoxy optionally substituted by OH, —CN, halogen, NR 4 R 5 , a C 6 -C 15 -aromatic carbocyclic group, C 3 -C 15 -carbocyclic group and a 4- to 15-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur; 
 C 2 -C 8 -alkenyl optionally substituted by —OH, —CN, halogen, NR 4 R 5 , a C 6 -C 15 -aromatic carbocyclic group, C 3 -C 15 -carbocyclic group and a 4- to 15-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur; 
 C 2 -C 8 -alkynyl optionally substituted by —OH, —CN, halogen, NR 4 R 5 , a C 6 -C 15 -aromatic carbocyclic group, C 3 -C 15 -carbocyclic group and a 4- to 15-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur; and 
 C 1 -C 8 -alkyl optionally substituted by —OH, —CN, halogen, NR 4 R 5 , C 1 -C 8 -alkoxycarbonyl, COOH, a C 6 -C 15 -aromatic carbocyclic group, C 3 -C 15 -carbocyclic group and a 4- to 15-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur; 
 R 1e  is selected from H and C 1 -C 8 -alkyl; 
 R 3  is selected from C 6 -C 15 -aromatic carbocyclic group optionally substituted by —C(R 3a R 3b ) n C(O)NR 3c R 3d  or —C(R 3a R 3b ) n C(O)OH, a C 7 -C 15 -aralkyl, C 1 -C 8 -alkyl substituted by a C 3 -C 15 -carbocyclic group, a C 3 -C 15 -carbocyclic group, a 4- to 15-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur, C 1 -C 8 -alkylaminocarbonyl, di(C 1 -C 8 -alkyl)aminocarbonyl, C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl)amino, —C(R 3a R 3b ) n C(O)NR 3c R 3d  and —C(R 3a R 3b ) n C(O)OH; 
 R 3a  and R 3b  are independently selected from H, —OH, and C 1 -C 8 -alkyl optionally substituted by —OH and halogen; 
 R 3c  and R 3d  are H, 
 C 6 -C 15  aromatic carbocyclic group, C 3 -C 15 -carbocyclic group, or R 3c  and R 3d , together with the N that they are attached, form a 4- to 15-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur, a 4- to 15-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur, 
 C 1 -C 8 -alkoxy optionally substituted by a C 6 -C 15 -aromatic carbocyclic group, C 3 -C 15 -carbocyclic group and a 4- to 15-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur, a C 1 -C 8 -alkoxycarbonyl optionally substituted by a C 6 -C 15 -aromatic carbocyclic group, C 3 -C 15 -carbocyclic group and a 4- to 15-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur; and 
 C 1 -C 8 -alkyl optionally substituted by —OH, —CN, halogen, NR 4 R 5 , a C 6 -C 15 -aromatic carbocyclic group, C 3 -C 15 -carbocyclic group and a 4- to 15-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur; 
 R 4  and R 5  are independently selected from H and C 1 -C 8 -alkyl; 
 m and n are independently selected from an integer of 0, 1, 2 and 3; and 
 t is integer selected from 1, 2 and 3; 
 
       wherein said C 6 -C 15 -aromatic carbocyclic group, C 7 -C 15 -aralkyl, C 3 -C 15 -carbocyclic group and 4- to 15-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur, unless otherwise stated, are each optionally substituted by C 7 -C 15 -aralkyl, C 1 -C 8 -alkyl CN, C 1 -C 8 -alkylsulfonyl, C 1 -C 8 -haloalkylsulfonyl, halogen, C 1 -C 8 -alkoxy, OH, C 1 -C 8 -alkylcarbonyl, —C(O)—C 6 -C 15 -aromatic carbocyclic group, —C(O)—C 3 -C 15 -carbocyclic group, —C(O)-4- to 15-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur, C 1 -C 8 -cyanoalkyl, C 1 -C 8 -cyanoalkoxy, C 1 -C 8 -haloalkyl, C 1 -C 8 -haloalkoxy, C 1 -C 8 -alkylaminocarbonyl, di(C 1 -C 8 -alkyl)aminocarbonyl, C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl)amino, COOH, C 1 -C 8 -alkoxycarbonyl, 4- to 15-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur optionally substituted by C 7 -C 15 -arakyl, C 1 -C 8 -alkyl, CN, C 1 -C 8 -alkylsulfonyl, C 1 -C 8 -haloalkylsulfonyl, halogen, C 1 -C 8 -alkoxy, OH, C 1 -C 8 -alkylcarbonyl, C 1 -C 8 -Cyanoalkyl, C 1 -C 8 -Cyanoalkoxy, C 1 -C 8 -haloalkyl, C 1 -C 8 -haloalkoxy, C 1 -C 8 -alkylaminocarbonyl, di(C 1 -C 8 -alkyl)aminocarbonyl, C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl)amino COOH, or C 1 -C 8 -alkoxycarbony, a C 6 -C 15 -aromatic carbocyclic group optionally substituted by C 7 -C 15 -arakyl, C 1 -C 8 -alkyl, CN, halogen, C 1 -C 8 -alkoxy, OH, C 1 -C 8 -alkylcarbonyl, C 1 -C 8 -Alkylaminocarbonyl, di(C 1 -C 8 -alkyl)aminocarbonyl, C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl)amino, COOH, CF 3 , or C 1 -C 8 -alkoxycarbonyl or a C 3 -C 15 -carbocyclic group optionally substituted by C 7 -C 15 -arakyl, C 1 -C 8 -alkyl, CN, halogen, C 1 -C 8 -alkoxy, OH, C 1 -C 8 -alkylcarbonyl, C 1 -C 8 -Alkylaminocarbonyl, di(C 1 -C 8 -alkyl)aminocarbonyl, C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl)amino, COOH, CF 3 , or C 1 -C 8 -alkoxycarbony. 
     
     
         13 . The compound of  claim 12 , wherein:
 Q is selected from CH 2  and C(O);   
       
         
           
           
               
               
           
         
       
       is selected from C 6 -C 15 -aromatic carbocyclic group, a C 5 -C 15 -carbocyclic group, and a 4- to 15-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur;
 R 1  is —C(R 1a R 1b ) m C(O)NR 1c R 1d , —C(R 1a R 1b ) m C(O)CR 1c R 1d R 1e , —C(R 1a R 1b ) t NR 1c R 1d , C(R 1a R 1b ) m CR 1c R 1d R 1e , C(R 1a R 1b ) m SO 2 R 1f ; 
 R 1a  and R 1b  are independently selected from H, —OH, and C 1 -C 8 -alkyl optionally substituted by —OH and halogen; 
 R 1c  is H; 
 C 6 -C 15 -aromatic carbocyclic group, C 7 -C 15 -aralkyl, C 3 -C 15 -carbocyclic group, a 4- to 15-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur; 
 C 1 -C 8 -alkoxy optionally substituted by OH, —CN, halogen, NR 4 R 5 , a C 6 -C 15 -aromatic carbocyclic group, C 3 -C 15 -carbocyclic group and a 4- to 15-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur; 
 C 2 -C 8 -alkenyl optionally substituted by —OH, —CN, halogen, NR 4 R 5 , a C 6 -C 15 -aromatic carbocyclic group, C 3 -C 15 -carbocyclic group and a 4- to 15-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur; 
 C 2 -C 8 -alkynyl optionally substituted by —OH, —CN, halogen, NR 4 R 5 , a C 6 -C 15 -aromatic carbocyclic group, C 3 -C 15 -carbocyclic group and a 4- to 15-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur; and 
 C 1 -C 8 -alkyl optionally substituted by —OH, —CN, halogen, NR 4 R 5 , C 1 -C 8 -alkoxycarbonyl, COOH, a C 6 -C 15 -aromatic carbocyclic group, C 3 -C 15 -carbocyclic group and a 4- to 15-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur; 
 R 1d  and R 1e  are H; 
 R 1f  is C 6 -C 15 -aromatic carbocyclic group, a C 3 -C 15 -carbocyclic group, C 1 -C 8 -haloalkyl and a 4- to 10-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur; 
 R 3  is selected from C 6 -C 15 -aromatic carbocyclic group, C 3 -C 15 -carbocyclic group, alkylamino carbonyl, —C(R 3a R 3b )C(O)NR 3c R 3d  and —C(R 3a R 3b ) n C(O)OH; 
 R 3a  and R 3b  are independently selected from H, —OH, and C 1 -C 8 -alkyl optionally substituted by —OH, halogen; 
 R 3c  and R 3d  are H; 
 C 6 -C 15 -aromatic carbocyclic group, C 3 -C 15 -carbocyclic group; 
 a 4- to 15-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur, and 
 C 1 -C 8 -alkyl optionally substituted by —OH, —CN, halogen, NR 4 R 5 , a C 6 -C 15 -aromatic carbocyclic group, C 3 -C 15 -carbocyclic group and a 4- to 15-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur; 
 m and n are independently selected from an integer of 0, 1 and 2; and 
 t is an integer selected from 1 and 2; 
 
       wherein said C 6 -C 15 -aromatic carbocyclic group, C 7 -C 15 -aralkyl, C 3 -C 15 -carbocyclic group and 4- to 15-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur, unless otherwise stated, are each optionally substituted by C 7 -C 15 -arakyl, C 1 -C 8 -alkyl CN, C 1 -C 8 -alkylsulfonyl, C 1 -C 8 -haloalkylsulfonyl, halogen, C 1 -C 8 -alkoxy, OH, C 1 -C 8 -alkylcarbonyl, —C(O)—C 6 -C 15 -aromatic carbocyclic group, —C(O)—C 3 -C 15 -carbocyclic group, —C(O)-4- to 15-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur, C 1 -C 8 -cyanoalkyl, C 1 -C 8 -cyanoalkoxy, C 1 -C 8 -haloalkyl, C 1 -C 8 -haloalkoxy, C 1 -C 8 -alkylaminocarbonyl, di(C 1 -C 8 -alkyl)aminocarbonyl, C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl)amino, COOH, C 1 -C 8 -alkoxycarbonyl, 4- to 15-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur optionally substituted by C 7 -C 15 -arakyl, C 1 -C 8 -alkyl, CN, C 1 -C 8 -alkylsulfonyl, C 1 -C 8 -haloalkylsulfonyl, halogen, C 1 -C 8 -alkoxy, OH, C 1 -C 8 -alkylcarbonyl, C 1 -C 8 -Cyanoalkyl, C 1 -C 8 -Cyanoalkoxy, C 1 -C 8 -haloalkyl, C 1 -C 8 -haloalkoxy, C 1 -C 8 -alkylaminocarbonyl, di(C 1 -C 8 -alkyl)aminocarbonyl, C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl)amino COOH, or C 1 -C 8 -alkoxycarbony, a C 6 -C 15 -aromatic carbocyclic group optionally substituted by C 7 -C 15 -arakyl, C 1 -C 8 -alkyl, CN, halogen, C 1 -C 8 -alkoxy, OH, C 1 -C 8 -alkylcarbonyl, C 1 -C 8 -alkylaminocarbonyl, di(C 1 -C 8 -alkyl)aminocarbonyl, C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl)amino, COOH, CF 3 , or C 1 -C 8 -alkoxycarbonyl or a C 3 -C 15 -carbocyclic group optionally substituted by C 7 -C 15 -arakyl, C 1 -C 8 -alkyl, CN, halogen, C 1 -C 8 -alkoxy, OH, C 1 -C 8 -alkylcarbonyl, C 1 -C 8 -alkylaminocarbonyl, di(C 1 -C 8 -alkyl)aminocarbonyl, C 1 -C 8 -alkylamino, di(C 1 -C 5 -alkyl)amino, COOH, CF 3 , or C 1 -C 8 -alkoxycarbonyl. 
     
     
         14 . The compound of  claim 12 , wherein Q is C(O). 
     
     
         15 . The compound of  claim 12 , wherein 
       
         
           
           
               
               
           
         
       
       is phenyl. 
     
     
         16 . A pharmaceutical composition comprising a compound of  claim 12  and at least one pharmaceutically acceptable diluent or carrier. 
     
     
         17 . A method of treatment for an inflammatory or allergic condition, comprising administering to a subject in need thereof a compound of  claim 12  in free or salt form. 
     
     
         18 . The method of  claim 17 , wherein the condition is an inflammatory or obstructive airway disease. 
     
     
         19 . A process for the preparation of a compound of Formula (I) according to  claim 12 , which comprises the steps of:
 (i) reacting a compound of formula (II):   
       
         
           
           
               
               
           
         
       
       wherein 
       
         
           
           
               
               
           
         
       
       R 3 , Q b  is N and Q are as defined in  claim 12 , with a compound of formula (III):
   X—R′  (III)
 
 
       wherein X is a leaving group and R′ is selected from C 1 -C 8 -alkyl or C 1 -C 8 -alkoxycarbonyl to provide a compound of formula (IV): 
       
         
           
           
               
               
           
         
         wherein when R′ is C 1 -C 8 -alkoxycarbonyl, the alkoxycarbonyl is hydrolysed to the respective acid and the resultant compound is reacted with an amine to generate the amide derivative, and 
         (iii) removing any protecting groups and recovering the resultant compound of formula (I), in free or salt form.