1-oxyalkyl-2-carboxyl-7-nonsubstituted indole derivatives
View Patent ↗Compounds of Formula I wherein A 1 , B 1 , C 1 , D 1 , E 1 , F 1 and L 1 are as defined herein, which inhibit the activity of anti-apoptotic Mcl-1 protein, compositions containing the compounds, and methods of treating diseases involving overexpressed or unregulated Mcl-1 protein, such as leukemia and lymphoma, are disclosed.
1. A compound of Formula I,
or a therapeutically acceptable salt thereof, wherein
L 1 is a bond;
A 1 is C(O)OH;
B 1 is R 4 ;
C 1 is R 2 or R 3 ;
each of D 1 , E 1 and F 1 is H;
R 2 is heteroaryl which is unfused or fused with benzene, heteroarene or R 2A ; R 2A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 3 is heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R 3A ; R 3A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 4 is alkyl, alkenyl or alkynyl, each of which is substituted with OR 5 ;
R 5 is R 6 , R 7 , R 8 or R 9 ,
R 6 is phenyl which is unfused or fused with benzene, heteroarene or R 6A ; R 6A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 7 is heteroaryl which is unfused or fused with benzene, heteroarene or R 7A ; R 7A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 8 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R 8A ; R 8A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 9 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one, two, three, four or five of independently selected R 9A , OR 9A , SR 9A , S(O)R 9A , SO 2 R 9A , NH 2 , NHR 9A , N(R 9A ) 2 , C(O)R 9A , C(O)NH 2 , C(O)NHR 9A , C(O)N(R 9A ) 2 , NHC(O)R 9A , NR 9A C(O)R 9A , NHSO 2 R 9A , NR 9A SO 2 R 9A , NHC(O)OR 9A , NR 9A C(O)OR 9A , SO 2 NH 2 , SO 2 NHR 9A , SO 2 N(R 9A ) 2 , NHC(O)NH 2 , NHC(O)R 9A NHC(O)N(R 9A ) 2 , NR 9A C(O)N(R 9A ) 2 , OH, (O), C(O)OH, CN, CF 3 , OCF 3 , CF 2 CF 3 , F, Cl, Br or I;
R 9A is R 9B , R 9C or R 9D ;
R 9B is phenyl which is unfused or fused with benzene, heteroarene or R 9B2 ; R 9B2 is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 9C is heteroaryl which is unfused or fused with benzene, heteroarene or R 9C2 ; R 9C2 is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 9D is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R 9D2 ; R 9D2 is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
wherein each foregoing cyclic moiety is independently unsubstituted or substituted with one or two or three independently selected R 10 , OR 10 , C(O)R 10 , NO 2 , N(R 10 ) 2 , C(O)NHR 10 , SO 2 N(R 10 ) 2 , C(O)OH, OH, (O), CF 3 , OCF 3 , F, Cl, Br or I;
R 10 is R 11 , R 12 , R 13 or R 14 ;
R 11 is phenyl which is unfused or fused with benzene, heteroarene or R 11A ; R 11A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 12 is heteroaryl which is unfused or fused with benzene, heteroarene or R 12A ; R 12A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 13 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R 13A ; R 13A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 14 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one, two, three, four or five of independently selected R 15 , OR 15 , SR 15 , S(O)R 15 , SO 2 R 15 , NH 2 , NHR 15 , N(R 15 ) 2 , C(O)R 15 , C(O)NH 2 , C(O)NHR 15 , C(O)N(R 15 ) 2 , NHC(O)R 15 , NR 15 C(O)R 15 , NHSO 2 R 15 , NR 15 SO 2 R 15 , NHC(O)OR 15 , NR 15 C(O)OR 15 , SO 2 NH 2 , SO 2 NHR 15 , SO 2 N(R 15 ) 2 , NHC(O)NH 2 , NHC(O)R 15 NHC(O)N(R 15 ) 2 , NR 15 C(O)N(R 15 ) 2 , OH, (O), C(O)OH, CN, CF 3 , OCF 3 , CF 2 CF 3 , F, Cl, Br or I;
R 15 is R 16 , R 17 , R 18 or R 19 ;
R 16 is phenyl which is unfused or fused with benzene, heteroarene or R 15A ; R 15A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 17 is heteroaryl which is unfused or fused with benzene, heteroarene or R 16A ; R 16A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 18 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R 18A ; R 18A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 19 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with R 20 ;
R 20 is phenyl, heteroaryl, cycloalkyl, cycloalkenyl or heterocycloalkyl;
wherein R 11 , R 12 , R 13 , R 16 , R 17 , and R 18 are independently unsubstituted or substituted with one or two or three or four or five of independently OR 21 , NO 2 , CF 3 , F, Cl, Br or I; and
R 21 is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl or heterocycloalkyl.
2. The compound of claim 1 , wherein
R 2 is heteroaryl;
R 3 is heterocycloalkyl;
R 4 is alkyl substituted with OR 5 ;
R 5 is R 6 , R 7 , R 8 or R 9 ,
R 6 is phenyl which is unfused or fused with benzene, heteroarene or R 6A ; R 6A is cycloalkane;
R 7 is heteroaryl;
R 8 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;
R 9 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one, two, three, four or five of independently selected R 9A , OR 9A , SR 9A , S(O)R 9A , SO 2 R 9A , NH 2 , NHR 9A , N(R 9A ) 2 , C(O)R 9A , C(O)NH 2 , C(O)NHR 9A , C(O)N(R 9A ) 2 , NHC(O)R 9A , NR 9A C(O)R 9A , NHSO 2 R 9A , NR 9A SO 2 R 9A , NHC(O)OR 9A , NR 9A C(O)OR 9A , SO 2 NH 2 , SO 2 NHR 9A , SO 2 N(R 9A ) 2 , NHC(O)NH 2 , NHC(O)R 9A NHC(O)N(R 9A ) 2 , NR 9A C(O)N(R 9A ) 2 , OH, (O), C(O)OH, CN, CF 3 , OCF 3 , CF 2 CF 3 , F, Cl, Br or I;
R 9A is R 9B , R 9C or R 9D ;
R 9B is phenyl;
R 9C is heteroaryl;
R 9D is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;
wherein each foregoing cyclic moiety is independently unsubstituted or substituted with one or two or three independently selected R 10 , OR 10 , C(O)R 10 , NO 2 ,)N(R 10 ) 2 , C(O)NHR 10 , SO 2 N(R 10 ) 2 , C(O)OH, OH, (O), CF 3 , OCF 3 , F, Cl, Br or I;
R 10 is R 11 , R 12 , R 13 or R 14 ;
R 11 is phenyl which is unfused or fused with benzene;
R 12 is heteroaryl;
R 13 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;
R 14 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one, two, three, four or five of independently selected R 15 , OR 15 , SR 15 , S(O)R 15 , SO 2 R 15 , NH 2 , NHR 15 , N(R 15 ) 2 , C(O)R 15 , C(O)NH 2 , C(O)NHR 15 , C(O)N(R 15 ) 2 , NHC(O)R 15 , NR 15 C(O)R 15 , NHSO 2 R 15 , NR 15 SO 2 R 15 , NHC(O)OR 15 , NR 15 C(O)OR 15 , SO 2 NH 2 , SO 2 NHR 15 , SO 2 N(R 15 ) 2 , NHC(O)NH 2 , NHC(O)R 15 NHC(O)N(R 15 ) 2 , NR 15 C(O)N(R 15 ) 2 , OH, (O), C(O)OH, CN, CF 3 , OCF 3 , CF 2 CF 3 , F, Cl, Br or I;
R 15 is R 16 , R 17 , R 18 or R 19 ;
R 16 is phenyl;
R 17 is heteroaryl;
R 18 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;
R 19 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with R 20 ;
R 20 is phenyl, heteroaryl, cycloalkyl, cycloalkenyl or heterocycloalkyl;
wherein R 11 , R 12 , R 13 , R 16 , R 17 , and R 18 are independently unsubstituted or substituted with one or two or three or four or five of independently OR 21 , NO 2 , CF 3 , F, Cl, Br or I; and
R 21 is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl or heterocycloalkyl.
3. The compound of claim 2 wherein
R 5 is R 6 , R 7 , or R 8 ;
R 6 is phenyl which is unfused or fused with benzene, heteroarene or R 6A ; R 6A is cycloalkane;
R 7 is heteroaryl;
R 8 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;
wherein each foregoing cyclic moiety is independently unsubstituted or substituted with one or two or three independently selected R 10 , OR 10 , C(O)R 10 , NO 2 , N(R 10 ) 2 , C(O)NHR 10 , SO 2 N(R 10 ) 2 , C(O)OH, OH, (O), CF 3 , OCF 3 , F, Cl, Br or I;
R 10 is R 11 , R 13 or R 14 ;
R 11 is phenyl which is unfused or fused with benzene;
R 13 is heterocycloalkyl;
R 14 is alkyl or alkenyl, each of which is unsubstituted or substituted with one, two, three, four or five of independently selected R 15 , OR 15 , SO 2 R 15 , N(R 15 ) 2 , F, Cl, Br or I;
R 15 is R 16 , R 18 or R 19 ;
R 16 is phenyl;
R 18 is heterocycloalkyl;
R 19 is alkyl;
wherein R 11 and R 16 are independently unsubstituted or substituted with one or two or three or four or five of independently OR 21 , NO 2 , CF 3 , F, Cl, Br or I; and
R 21 is alkyl.
4. A composition comprising an excipient and a therapeutically effective amount of a compound of claim 1 .
5. A compound selected from the group consisting of
1-(3-(1-naphthyloxy)propyl)-3-piperidin-1-yl-1H-indole-2-carboxylic acid;
3-morpholin-4-yl-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid;
3-(4-carboxypiperidin-1-yl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid; and
1-(3-(1-naphthyloxy)propyl)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid;
or a therapeutically acceptable salt thereof.
6. The compound of claim 1 , where B 1 is 3-(1-naphthyloxy)propyl.
7. 1-(3-(1-Naphthyloxy)propyl)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylic acid or a therapeutically acceptable salt thereof.