EP2 Agonists

Abstract

The invention provides EP2 agonists, methods for their preparation, pharmaceutical compositions containing these compounds, and methods of using these compounds and compositions for lowering intraocular pressure and thereby treating glaucoma.

1 . A compound selected from the group comprising: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     pharmaceutically acceptable salt or solvate thereof, 
     wherein:
 R 1  is (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, (CR 2 R 3 ) b —X—(C 3 -C 12 )alkyl, (CR 2 R 3 ) b —X-cyclo(C 3 -C 12 )alkyl, (CR 2 , R 3 ) b —X-cyclo(C 2 -C 12 )alkenyl, (CR 2 R 3 ) b —X—(C 6 -C 12 )aryl or (CR 2 R 3 ) b —X-(3-10)membered heterocyclyl, with the proviso that R 1  is not tert-butyl, and wherein R 1  is optionally substituted with 1 to 3 R 5  groups; 
 X is a bond, O, —S— or —NR 4 ; 
 R 2 , R 3  and R 4  are each independently H or (C 1 -C 6 )alkyl; 
 each R 5  is independently —CN, —OH, —F, —Cl, —Br, —I, —NO 2 , —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —N 3 , (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(C═O)R 6 , —(C═O)OR 6 , —O(C═O)R 7 , —O(C═O)NR 7 , —NR 8 (C═O)R 9 , —(C═O)NR 8 R 9 , 
 
     —NR 8 R 9 , —NR 8 OR 9 , —S(O) j NR 8 R 9 , —S(O) j (C 1 -C 6 )alkyl, —OS(O) j R 9 , —NR 8 S(O) j R 9 , —(CR 10 R 11 ) k (C 6 -C 12  aryl), —(CR 10 R 11 ) k (3-10)membered heterocyclyl, —(CR 10 R 11 ) k (C═O)—(CR 10 R 11 ) q (C 6 -C 12 )aryl, —(CR 10 R 11 ) k (C═O)(CR 10 R 11 ) q (3-10)-membered heterocyclyl, 
     —(CR 10 R 11 ) k O(CR 10 R 11 ) q (C 6 -C 12 )aryl, —(CR 10 R 11 ) k O(CR 10 R 11 ) q (3-10)membered heterocyclyl, —(CR 10 R 11 ) k S(O) j (CR 10 R 11 ) q (C 6 -C 12 )aryl or —(CR 10 R 11 ) k S(O) j (CR 10 R 11 ) q (3-10) membered heterocyclyl;
 any (C 1 -C 6 )alkyl, (C 6 -C 12 )aryl and (3-10)membered heterocyclyl of the foregoing R 5  groups are each optionally independently substituted with 1 to 3 substituents, each independently selected from —CN, —F, —Cl, —Br, —I, —NO 2 , —CF 3 , 
 
     —CHF 2 , —CH 2 F, —OCF 3 , —N 3 , —OR 12 , —(C═O)R 12 , —(C═O)OR 13 , —O(C═O)R 13 , —NR 13 (C═O)R 14 , —(C═O)NR 15 R 16 , —NR 17 R 18 , —NR 14 OR 15 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(CR 16 R 17 ) u (C 6 -C 12 )aryl and —(CR 16 R 17 ) u (3-10)membered heterocyclyl;
 R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17  and R 18  are each independently H, (C 1 -C 6 )alkyl, —(C═O)N(C 1 -C 6 )alkyl, —(CR 19 R 20 ) v (C 6 -C 12 )aryl or —(CR 19 R 20 ) v (3-10)membered heterocyclyl; 
 any (C 1 -C 6 )alkyl, (C 6 -C 12 )aryl and (3-10)membered heterocyclyl of the foregoing R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17  and R 18  groups are each optionally independently substituted with 1 to 3 substituents, each independently selected from —CN, —OH, —F, —Cl, —Br, —I, —NO 2 , —NR 21 R 22 , —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , 
 
     (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl and (C 1 -C 6 )alkoxy;
 R 19 , R 20 , R 21  and R 22  are each independently H or (C 1 -C 6 )alkyl; 
 any 1 or 2 carbon atoms of the (3-10)membered heterocyclyl of each of the R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17  and R 18  groups are optionally substituted with oxo (═O); 
 and wherein any of the above-mentioned substituents comprising a —CH 3  (methyl), —CH 2  (methylene) or —CH (methine) group which is not attached to an —F, 
 
     —Cl, —Br, —I, —SO or —SO 2  group or to a N, O or S atom, are optionally independently substituted with —OH, —F, —Cl, —Br, —I, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, —NH 2 , —NH(C 1 -C 6 )alkyl or —N((C 1 -C 6 )alkyl) 2 ;
 j is 0, 1 or 2; and 
 b, k, q, u and v are each independently 0, 1, 2, 3, 4, 5 or 6. 
 
   
   
       2 . The compound of  claim 1 , wherein R 1  is (C 1 -C 12 )alkyl. 
   
   
       3 . The compound of  claim 1 , wherein R 1  is (C 1 -C 6 )alkyl. 
   
   
       4 . The compound of  claim 1 , wherein R 1  is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH(CH 3 )CH 2 CH 3  or —CH 2 CH(CH 3 )CH 3 . 
   
   
       5 . The compound of  claim 1 , wherein R 1  is —CH 2 CH 2 OCH 3 , —CH 2 CH 2 OCH 2 CH 2 OCH 3 , —CH(CH 3 )CH 2 OH or —CH(CH 3 )CH 2 OCH 3 . 
   
   
       6 . The compound of  claim 1 , wherein R 1  is —CH(CH 3 ) 2 . 
   
   
       7 - 18 . (canceled)