3,4-disubstituted coumarin and quinolone compounds
View Patent ↗The present invention relates to 3,4-disubstituted coumarin and quinolone derivatives and processes for their preparation. The invention also related to methods for treating infection of Hepatitis C virus by administering a 3,4-disubstituted coumarin or quinolone derivative.
1. A compound having the Formula III:
wherein:
each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R 11 , —N(R 12 )(R 13 ), —N(R 11 )C(O)R 11 , —N(R 11 )SO 2 R 11 , SR 11 ,—C(O)R 11 , —C(O)OR 11 , —C(O)N(R 12 )(R 13 ),—OC(O)R 11 , —OC(O)N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , —SOR 11 , —SO3R 11 , —SO 2 N(R 12)(R 13 ), -alkyl-O—R 11 , cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, and aryl; additionally or alternatively two R 1 substituents on adjacent ring atoms may be combined to form a fused 5 or 6- membered ring, wherein the fused 5 - or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with one or more substituents selected from R 1 ;
each R 11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, and aryl; each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, and aryl; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5 - to 7-membered ring which may optionally contain a further heteroatom,
n is 0 to 4;
R 2 is selected from the group consisting of aralkyl, aryl;
R 3 is selected from the group consisting of aralkyl, aryl, —(CH 2 )aC(O)R 31 , —(CH 2 )aC(O)N(R 32 )(R 33 ), (CH 2 )aC(O)OR 31 , —(CH 2 )aC(O)N(R 32 )(R 33 ), —(CH 2 )aN(R 32 )(R 33 ), —CH═N—R 34 ,
R 31 selected from aralkyl, and aryl;
R 32 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, and aryl;
R 33 is selected from aralkyl, and aryl;
R 34 is selected from aralkyl, and aryl;
a is 0 to 6;
or a pharmaceutically acceptable salt thereof;
with the proviso that R2 is heteroaryl or heteroaralkyl, and/or R 3 , R 31 , R 33 and R 34 are selected from heteroaryl and heteroaralkyl.
2. The compound of claim 1 , having the formula IV:
wherein:
each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R 11 , —N(R 12 )(R 13 ), —N(R 11 )C(O)R 11 , —N(R 11 )SO 2 R 11 , SR 11 , —C(O)R 11 , —C(O)OR 11 , —C(O)N(R 12 )(R 13 ), —OC(O)R 11 , —OC(O)N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , —SOR 11 , —SO3R 11 , —SO 2 N(R 12 )(R 13 ), cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, and aryl; additionally or alternatively two R 1 substituents on adjacent ring atoms may be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with one or more substituents selected from R 1 ;
each R 11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, and aryl; each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, and aryl; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom,
n is 0 to 4;
R 6 is an aryl group;
R 7 is selected from the group consisting of aryl, —C(O)R 31 , —C(O)N(R 32 )(R 33 ), —C(O)OR 31 , —C(O)N(R 32 )(R 33 ), —N(R 32 )(R 33 ),
R 31 selected from aralkyl, and aryl;
R 32 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, and aryl;
R 33 is selected from aralkyl, and aryl;
or a pharmaceutically acceptable salt thereof;
with the proviso that R 6 is heteroaryl or heteroaralkyl, and/or R 7 , R 31 , and R 33 are selected from heteroaryl and heteroaralkyl.
3. The compound of claim 2 , wherein R 7 is an aryl group.
4. The compound of claim 1 , having the formula V:
wherein:
each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R 11 , —N(R 12 )(R 13 ), —N(R 11 )C(O)R 11 , —N(R 11 )SO 2 R 11 , SR 11 , —C(O)R 11 , —C(O)OR 11 , —C(O)N(R 12 )(R 13 ), —OC(O)R 11 , —OC(O)N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , —SOR 11 , —SO3R 11 , —SO 2 N(R 12 )( R 13 ), -alkyl-O—R 11 , cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, and aryl; additionally or alternatively two R 1 substituents on adjacent ring atoms may be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with one or more substituents selected from R 1 ;
each R 11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, and aryl; each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, and aryl; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom,
n is 0 to 4;
R 3 is selected from the group consisting of heteroaralkyl, heteroaryl, —(CH 2 )aC(O)R 31 , —(CH 2 )aC(O)N(R 32 )(R 33 ), (CH 2 )aC(O)OR 31 , —(CH 2 )aC(O)N(R 32 )(R 33 ), —(CH 2 )aN(R 32 )(R 33 ), —CH═N—R 34 ,
R 31 is selected from heteroaralkyl, and heteroaryl;
R 32 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, and aryl;
R 33 is selected from heteroaralkyl, and heteroaryl;
R 34 is selected from heteroaralkyl, and heteroaryl;
a is 0 to 6;
each R 8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R 81 , C(O)R 81 , —O—R 81 , —N(R 82 )(R 83 ), —N(R 81 )C(O)R 81 , —N(R 81 )SO2R 81 , —SR 81 , C(O)N(R 82 )(R 83 ), —OC(O)R 81 , —OC(O)N(R 82 )(R 83 ), SO2,—SOR 81 , —SO3R 81 , —SO2N(R 82 )(R 83 ), cycloalkyl, cycloalkenyl, and aryl each R 81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, and aryl;
each R 82 and R 83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, and; or R 82 and R 83 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom; and
m is 0 to 5;
or a pharmaceutically acceptable salt thereof.
5. A compound having the formula VIIa:
wherein:
each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R 11 , —N(R 12 )(R 13 ), —N(R 11 )C(O)R 11 , —-N(R 11 )SO 2 R 11 ,SR 11 , —C(O)R 11 , —C(O)OR 11 , —C(O)N(R 12 )(R 13 ),—OC(O)R 11 , —OC(O)N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , —SOR 11 , —SO3R 11 , —SO 2 N(R 12 )(R 13 ), cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, and aryl; additionally or alternatively two R 1 substituents on adjacent ring atoms may be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with one or more substituents selected from R 1 ;
each R 11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, and aryl; each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, and aryl; or
R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom,
n is 0 to 4;
R 2 is selected from the group consisting of aralkyl, aryl;
R 4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, —(CH 2 ) b C(O)R 41 , —(CH 2 ) b C(O)N(R 42 )(R 43 ), —(CH 2 ) b C(O)OR 41 , and —(CH2) b C(O )N(R 42 )(R 43 ),
each R 41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, and aryl;
R 42 and R 43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, and aryl;
or R 42 and e 43 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R 34 is selected from aralkyl, and aryl;
or a pharmaceutically acceptable salt thereof;
with the proviso that R 2 is heteroaryl or heteroaralkyl, and/or R 34 is selected from heteroaryl, and heteroaralkyl.
6. The compound of claim 5 , wherein R 2 is an aryl group.
7. The compound of claim 6 , wherein R 4 is H.
8. A compound having the formula VIII:
wherein:
each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R 11 , —N(R 12 )(R 13 ), —N(R 11 )C(O)R 11 , —N(R 11 )SO 2 R 11 , SR 11 , —C(O)R 11 , —C(O)OR 11 , —C(O)N(R 12 )(R 13 ), —OC(O)R 11 , —OC(O)N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , —SOR 11 , —SO3R 11 , —SO 2 N(R 12 )(R 13 ), -alkyl-O—R 11 , cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, and aryl; additionally or alternatively two R 1 substituents on adjacent ring atoms may be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with one or more substituents selected from R 1 ;
each is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, and aryl; each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, and aryl; or
R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5 - to 7-membered ring which may optionally contain a further heteroatom,
n is 0 to 4;
R 4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, —(CH 2 ) b C(O)R 41 , —(CH 2 ) b C(O)N(R 42 )(R 43 ), —(CH 2 ) b C(O)OR 41 , and —(CH2)bC(O)N(R42)(R43),
each R 41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, and aryl;
R 42 and R 43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, and aryl;
or R 42 and e 43 may be taken together with the nitrogen to which they are attached form a 5 - to 7-membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
R 6 is an aryl group;
R 7 is selected from the group consisting of aryl, —C(O)R 31 , —C(O)N(R 32 )(R 33 ), —C(O)OR 31 , —C(O)N(R 32 )(R 33 ), —N(R 32 )(R 33 ),
R 31 selected from aralkyl, and aryl;
R 32 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, and aryl;
R 33 is selected from aralkyl, and aryl;
or a pharmaceutically acceptable salt thereof;
with the proviso that R 6 is heteroaryl or heteroaralkyl, and/or R 7 , R 31 , and R 33 are selected from heteroaryl and heteroaralkyl.
9. The compound of claim 8 , wherein, R 7 is an aryl group.
10. A compound having the formula IX:
wherein:
each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R 11 , —N(R 12 )(R 13 ), —N(R 11 )C(O)R 11 , —N(R 11 )SO 2 R 11 , SR 11 , —C(O)R 11 , —C(O)OR 11 , —C(O)N(R 12 )(R 13 ),—OC(O)R 11 , —OC(O)N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , —SOR 11 , —SO3R 11 , —SO 2 N(R 12 )(R 13 ), -alkyl-O—R 11 , cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, and aryl; additionally or alternatively two R 1 substituents on adjacent ring atoms may be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with one or more substituents selected from R 1 ;
each R 11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, and aryl; each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-aryl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, and aryl; or
R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom,
n is 0 to 4;
R 3 is selected from the group consisting of heteroaralkyl, heteroaryl, —(CH 2 ) a C(O)R 31 , —(CH 2 ) a C(O)N(R 32 )(R 33 ), (CH 2 ) a C(O)OR 31 , —(CH 2 ) a C(O)N(R 32 )(R 33 ), —(CH 2 ) a N(R 32 )(R 33 ), —CH═N—R 34 ,
R 31 selected from heteroaralkyl, and heteroaryl;
R 32 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, and aryl;
R 33 is selected from heteroaralkyl, and heteroaryl;
R 34 is selected from heteroaralkyl, and heteroaryl;
a is 0 to 6;
R 4 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, —(CH 2 ) b C(O)R 41 , —(CH 2 ) b C(O)N(R 42 )(R 43 ), —(CH 2 ) b C(O)OR 41 , and —(CH2) b C(O)N(R42)(R43),
each R 41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, and aryl;
R 42 and R 43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, and aryl;
or R 42 and e 43 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
b is 0 to 6;
each R 8 is independently selected from the group consisting of halo, alkyl, CN, NO2, CO2R 81 , C(O)R 81 , —O—R 81 ,—N(R 82 )(R 83 ), —N(R 81 )C(O)R 81 , —N(R 81 )SO 2 R 81 , —SR 81 , —C(O)N(R 82 )(R 83 ), —OC(O)R 81 , —OC(O)N(R 82 )(R 83 ), SO2, —SOR 81 , —SO3R 81 , —SO 2 N(R 82 )(R 83 ), cycloalkyl, cycloalkenyl, and aryl each R 81 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, and aryl;
each R 82 and R 83 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, and; or R 82 and R 83 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom; and
m is 0 to 5;
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 5 , having the formula
12. The compound of claim 5 , having the formula