Pyridazinone compounds and methods for the treatment of cystic fibrosis

Abstract

The invention relates to a compound of having the following formulae and methods of treating cystic fibrosis:

1 . A compound of Formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, ester or prodrug thereof; 
         Wherein   represents a single or double bond; 
         m is 0, 1, 2, 3 or 4; 
         d is 0, 1 or 2; 
         X 10  is CH, CH 2 , N, S or O; 
         Cy 1  is absent, an aryl, substituted aryl, carbocycle, substituted carbocycle, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl group having one, two or three rings; 
         Cy 2  is an aryl, substituted aryl, carbocycle, substituted carbocycle, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl group having one, two or three rings; Preferably, Cy 2  is a C 5 -C 7  aryl or heteroaryl; Preferably Cy 2  is substituted with —OR 200 , —SR 200 , —C(O)R 200 , —C(O)N(R 200 ) 2 , —NC(O)R 200 , —S(O) 2 R 200  wherein R 200  is hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl; 
         A 1  is absent, —[C(R 100 )(R 101 )]n-, —C(O)—, —C(S)—, —S(O)—, —C(O)N(R 100 )—, —S(O) 2 N(R 100 )—, —S(O) 2 —, —[C(R 25 )(R 26 )]n-, —[C(R 25 )(R 26 )]n-C═C—[C(R 27 )(R 28 )]p, or —[C(R 25 )(R 26 )]n-C≡C—[C(R 27 )(R 28 )]p, carbocycle, substituted carbocycle, heterocycle, substituted heterocycle, aromatic, substituted aromatic, heteroaromatic or substituted heteroaromatic; wherein n is 0, 1, 2, 3, 4, 5, 6 or 7; 
         wherein each R 100  and R 101  is hydrogen, deuterium, halogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl and substituted aryl, —OR 200 , —SR 200 , —C(O)R 200 , —C(O)N(R 200 ) 2 , —NC(O)R 200 , —S(O) 2 R 200  wherein R 200  is hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl; alternatively two of R 100  and R 101  groups together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring; Preferably each R 100  and R 101  is independently selected from C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl and C 3 -C 8  cycloalkyl; 
         A 2  is absent or —[C(R 100 )(R 101 )]n-, —C(O)—, —C(S)—, —S(O)—, —C(O)N(R 100 )—, —C(O)N(R 100 )(R 101 ), N(R 100 )(R 101 ), —S(O) 2 —, —S(O) 2 R 100 , —S(O)R 100 , —S(O) 2 N(R 100 )R 101 ), —[C(R 25 )(R 26 )]n-, —[C(R 25 )(R 26 )]n-C═C—[C(R 27 )(R 28 )]p, or —[C(R 25 )(R 26 )]n-C≡C—[C(R 27 )(R 28 )]p; 
         A 3  is absent or —[C(R 100 )(R 101 )]n-, —C(O)—, —C(S)—, —S(O)—, —C(O)N(R 100 )—, —C(O)N(R 100 )(R 101 ), N(R 100 )(R 101 ), —S(O) 2 —, S(O) 2 R 100 , S(O)R 100 , S(O) 2 N(R 100 )(R 101 ), —[C(R 25 )(R 26 )]n-, —[C(R 25 )(R 26 )]n-C═C—[C(R 27 )(R 28 )]p, or —[C(R 25 )(R 26 )]n-C≡C—[C(R 27 )(R 28 )]p; 
         A 4  is absent or —[C(R 25 )(R 26 )]n-, —[C(R 25 )(R 26 )]n-C═C—[C(R 27 )(R 28 )]p, or —[C(R 25 )(R 26 )]n-C≡C—[C(R 27 )(R 28 )]p; 
         wherein each R 25 , R 26 , R 27  and R 28  is independently selected hydrogen, deuterium, halogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, —OR 100 , —SR 100 , —NR 100 R 101 , —C(O)R 100 , —C(O)OR 100 , —C(O)NR 100 R 101 , —N(R 100 )C(O)R 101 , —S(O) 2 R 100 , —S(O)R 100 , —SR 100 , —S(O) 2 N(R 100 )R 101 , —CF 3 , —CN, —NO 2 , and —N 3 ; alternatively two of R 25 , R 26 , R 27  and R 28  groups together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring; preferably a cyclopropyl group; 
         p is 0, 1, 2, 3, 4, 5, 6, or 7; 
         R 2  is independently selected from hydrogen, deuterium, halogen, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl —OR 100 , —SR 100 , —NR 100 R 101 , —C(O)R 100 , —C(O)OR 100 , —C(O)NR 100 R 101 , —N(R 100 )C(O)R 101 , —S(O) 2 R 100 , —S(O)R 100 , —SR 100 , —S(O) 2 N(R 100 )R 101 , —CF 3 , —CN, —NO 2 , —N 3 ; 
         alternatively two R 2  together with the atoms to which they are attached may form an optionally substituted 3, 4, 5, 6 or 7 membered ring, preferably a cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, aryl, substituted aryl, heteroaryl or substituted heteroaryl group; and, 
         each R 3  and R 4  is independently selected from hydrogen, deuterium, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, or —OR 100 , —SR 100 , —NR 100 R 101 , —C(O)R 100 , —C(O)OR 100 , —C(O)NR 100 R 101 , —N(R 100 )C(O)R 101 , —S(O) 2 R 100 , —S(O)R 100 , —SR 100 , —S(O) 2 N(R 100 )R 101 , —CF 3 , —CN, —NO 2 , —N 3 . 
       
     
     
         2 - 51 . (canceled)