Novel substituted indolo 4,3 fg quinolines useful for treating migraine

Abstract

Provided herein are novel ergoline derivatives and pharmaceutical compositions thereof. In other embodiments, provided herein are methods of treatment, prevention, or amelioration of a variety of medical disorders such as, for example, migraine using the compounds and compositions disclosed herein. In still other embodiments, provided herein are methods of agonizing receptors such as, for example, the 5-HT 1D and or 5-HT 1B receptor using the compounds and compositions disclosed herein. In still other embodiments, provided herein are methods of antagonizing or inhibiting activity at receptors such as, for example, the 5-HT 2B receptor using the compounds and compositions disclosed herein. In still other embodiments, provided herein are methods of regulating serotonin transport using the compounds and compositions disclosed herein.

What is claimed is: 
     
         1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts, hydrates or solvates thereof wherein: 
         R 1  is (C 1 -C 4 ) alkyl or (C 1 -C 4 ) perfluoroalkyl; 
         R 2  is alkyl, substituted alkyl, acyl, substituted acyl, halo, heteroalkyl, substituted heteroalkyl, —NO 2 , —N 3 , —OH, —S(O) k R 100 , —OR 101 , —NR 102 R 103 , —CONR 104 R 105 , —CO 2 R 106  or —OC(O)R 107 ; 
         R 3  and R 4  are independently hydrogen, deuterium, fluoro, hydroxy or methoxy; 
         R 5  is hydrogen, (C 1 -C 3 ) alkyl, substituted (C 1 -C 4 ) alkyl or (C 1 -C 3 ) perfluoroalkyl; 
         R 6  is 
       
       
         
           
           
               
               
           
         
         R 7  is isopropyl, sec-butyl, isobutyl, or t-butyl; 
         R 8  is hydrogen, (C 1 -C 4 ) alkyl substituted (C 1 -C 4 ) alkyl, benzyl or substituted benzyl; 
         R 9  is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, (C 2 -C 4 ) alkenyl or (C 2 -C 4 ) alkynyl; 
         R 10  is hydrogen, OH, ═O, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) substituted alkyl, —CO 2 R 108  or —CONR 109 R 110 , 
         R 11  is hydrogen, OH, ═O, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) substituted alkyl, —CO 2 R 111  or —CONR 112 R 113 , 
         R 12  is hydrogen, OH, ═O, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) substituted alkyl, —CO 2 R 114  or —CONR 115 R 116 ; 
         R 13  is hydrogen or halogen; 
         R 101 , R 102 , R 103 , R 104 , R 105 , R 106 , R 107 , R 108 , R 109 , R 110 , R 111 , R 112 , R 113 , R 114 , R 115  and R 116  are independently hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; and 
         k is 0, 1 or 2; 
         n is 0, 1, 2 or 3; 
         wherein substituted with reference to a saturated carbon atom is limited to —R a , halo, —O − , ═O, —OR b , —SR b , —S − , ═S, —NR c R c , ═NR b , ═N—OR b , trihalomethyl, —CF 3 , —CN, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O) 2 R b , —S(O) 2 NR b , —S(O) 2 O − , —S(O) 2 OR b , —OS(O) 2 R b , —OS(O) 2 O − , —OS(O) 2 OR b , —P(O)(O − ) 2 , —P(O)(OR b )(O − ), —P(O)(OR b )(OR b ), —C(O)R b , —C(S)R b , —C(NR b )R b , —C(O)O − , —C(O)OR b , —C(S)OR b , —C(O)NR c R c , —C(NR b )NR c R c , —OC(O)R b , —OC(S)R b , —OC(O)O − , —OC(O)OR b , —OC(S)OR b , —NR b C(O)R b , —NR b C(S)R b , —NR b C(O)O − , —NR b C(O)OR b , —NR b C(S)OR b , —NR b C(O)NR c R c , —NR b C(NR b )R b  and —NR b C(NR b )NR c R c , where R a  is selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; each R b  is independently hydrogen or R a ; and each R c  is independently R b  or alternatively, the two R c s are taken together with the nitrogen atom to which they are bonded form a 4-, 5-, 6- or 7-membered cycloheteroalkyl which may optionally include from 1 to 4 of the same or different additional heteroatoms selected from the group consisting of O, N and S; and substituted with reference to an unsaturated carbon atom or an nitrogen atom in a heteroalkyl group is limited to —R a , halo, —O − , —OR b , —SR b , —S − , —NR c R c , trihalomethyl, —CF 3 , —CN, —OCN, —SCN, —NO, —NO 2 , —N 3 , —S(O) 2 R b , —S(O) 2 O − , —S(O) 2 OR b , —OS(O) 2 R b , —OS(O) 2 O − , —OS(O) 2 OR b , —P(O)(O − ) 2 , —P(O)(OR b )(O − ), —P(O)(OR b )(OR b ), —C(O)R b , —C(S)R b , —C(NR b )R b , —C(O)O − , —C(O)OR b , —C(S)OR b , —C(O)NR c R c , —C(NR b )NR c R c , —OC(O)R b , —OC(S)R b , —OC(O)O − , —OC(O)OR b , —OC(S)OR b , —NR b C(O)R b , —NR b C(S)R b , —NR b C(O)O − , —NR b C(O)OR b , —NR b C(S)OR b , —NR b C(O)NR c R c , —NR b C(NR b )R b  and —NR b C(NR b )NR c R c  where R a , R b  and R c  are as defined above; 
         provided that when R 1  and R 5  are methyl, R 2 , R 3 , R 4 , R 10 , R 11 , R 12  and R 13  are hydrogen and R 6  is 
       
       
         
           
           
               
               
           
         
          that: 
         R 7  is not isopropyl, R 8  is not hydrogen and R 9  is not n-propyl; 
         R 7  is not isopropyl, R 8  is not hydrogen and R 9  is not isobutyl; 
         R 7  is not isopropyl, R 8  is not hydrogen and R 9  is not isopropyl; 
         provided that when R 1  and R 5  are methyl, R 3  is —OCH 3 , R 2 , R 4 , R 10 , R 11 , R 12  and R 13  are hydrogen and R 6  is 
       
       
         
           
           
               
               
           
         
          that: 
         R 7  is not isopropyl, R 8  is not hydrogen and R 9  is not isopropyl; 
         provided that when R 1  and R 5  are methyl, R 2 , R 3 , R 4 , R 10 , R 11  and R 12  are hydrogen, R 13  is bromine and R 6  is 
       
       
         
           
           
               
               
           
         
          that: 
         R 7  is not isopropyl, R 8  is not hydrogen and R 9  is not isopropyl; 
         R 7  is not isopropyl, R 8  is not hydrogen and R 9  is not isobutyl; 
         provided that when R 1  is n-propyl, R 5  is methyl, R 2 , R 3 , R 4 , R 10 , R 11  and R 12  are hydrogen, R 13  is bromine and R 6  is 
       
       
         
           
           
               
               
           
         
          that: 
         R 7  is not isopropyl, R 8  is not hydrogen and R 9  is not isopropyl; 
         provided that when R 2 , R 3 , R 4 , R 10 , R 11 , R 12  and R 13  are hydrogen and R 6  is 
       
       
         
           
           
               
               
           
         
          that: 
         R 1  is not allyl; 
         provided that when R 1  is ethyl, R 5  is methyl, R 2 , R 3 , R 4 , R 10 , R 11 , R 12  and R 13  are hydrogen and R 6  is 
       
       
         
           
           
               
               
           
         
          that: 
         R 7  is not isopropyl, R 8  is not hydrogen and R 9  is not isopropyl; 
         provided that when R 1  is n-propyl, R 5  is methyl, R 2 , R 3 , R 4 , R 10 , R 11 , R 12  and R 13  is hydrogen and R 6  is 
       
       
         
           
           
               
               
           
         
          that: 
         R 7  is not isopropyl, R 8  is not hydrogen and R 9  is not isopropyl; 
         provided that when R 1  is CH 2 OCOCH 3 , R 5  is methyl, R 2 , R 3 , R 4 , R 10 , R 11 , R 12  and R 13  are hydrogen and R 6  is 
       
       
         
           
           
               
               
           
         
          that: 
         R 7  is not isopropyl, R 8  is not hydrogen and R 9  is not isobutyl; 
         R 7  is not isopropyl, R 8  is not hydrogen and R 9  is not isopropyl; 
         provided that when R 1  is CH 2 OH, R 5  is methyl, R 2 , R 3 , R 4 , R 10 , R 11 , R 12  and R 13  are hydrogen and R 6  is 
       
       
         
           
           
               
               
           
         
          that: 
         R 7  is not isopropyl, R 8  is not hydrogen and R 9  is not isobutyl; 
         R 7  is not isopropyl, R 8  is not hydrogen and R 9  is not isopropyl; 
         provided that when R 1  and R 5  are methyl and R 2 , R 3  and R 4  are hydrogen that: 
         R 6  is not 
       
       
         
           
           
               
               
           
         
         provided that when R 1  and R 5  are methyl and R 2 , R 3  and R 4  are hydrogen that: 
         R 6  is not 
       
       
         
           
           
               
               
           
         
          provided that when R 1  and R 5  are methyl and R 2 , R 3  and R 4  are hydrogen that: R 6  is not 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The compound of  claim 1 , wherein R 6  is 
       
         
           
           
               
               
           
         
       
       R 7  is isopropyl, R 8  is hydrogen or methyl, R 9  is n-propyl, isopropyl or isobutyl and R 10 , R 11  and R 12  are hydrogen. 
     
     
         3 . The compound of  claim 1 , wherein R 1  is (C 1 -C 4 ) alkyl or (C 1 -C 4 ) perfluoroalkyl and R 6  is 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein R 1  is —CH 3 , —C 2 H 5 , —C 3 H 7 , i-C 3 H 7 , —CF 3 , —C 2 F 5 , —C 3 F 7  or i-C 3 F 7  and R 6  is 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1 , wherein R 1  is —CH 3 , —C 2 H 5 , —C 3 H 7 , i-C 3 H 7 , —CF 3 , —C 2 F 5 , —C 3 F 7  or i-C 3 F 7 , R 2  is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) substituted alkyl, (C 1 -C 4 ) acyl, (C 1 -C 4 ) substituted acyl, halo, —NO 2 , —OR 101 , —NR 102 R 103 , —CONR 104 R 105 , —CO 2 R 106  or —OC(O)R 107 , n is 0 or 1, R 3  and R 4  are independently hydrogen or deuterium, R 5  is —CH 3 , —C 2 H 5 , —C 3 H 7 , —CF 3 , C 2 F 5  or —C 3 F 7 , R 6  is 
       
         
           
           
               
               
           
         
       
       R 10 , R 11  and R 12  are independently hydrogen, OH or (C 1 -C 4 ) alkyl; and R 13  is hydrogen or bromine. 
     
     
         6 . The compound of  claim 1 , wherein R 1  is —CH 3 , —C 2 H 5 , -nC 3 H 7 , —CF 3 , C 2 F 5  or -nC 3 F 7 , R 2  is (C 1 -C 2 ) alkyl, (C 1 -C 2 ) substituted alkyl, halo, —NO 2 , —OR 101 , —NR 102 R 103 , —CONR 104 R 105 , —CO 2 R 106  or —OC(O)R 107 , n is 0, R 3  and R 4  are independently hydrogen or deuterium, R 5  is —CH 3  or —CF 3 , R 6  is 
       
         
           
           
               
               
           
         
       
       R 7  is isopropyl, R 8  is hydrogen or methyl, R 9  is n-propyl, isopropyl or isobutyl, R 10 , R 11  and R 12  are hydrogen; and R 13  is hydrogen. 
     
     
         7 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable vehicle.