1-oxyalkyl-2-carboxy-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 Mdl-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 3-(1-naphthyloxy)propyl;
C 1 is R 1 ;
D 1 , E 1 and F 1 are each H;
R 1 is phenyl which is unfused or fused with benzene;
wherein R 1 is unsubstituted or substituted with one or two or three or four or five substituents independently selected from the group consisting of R 10 , OR 10 , OCH 2 R 10 , SR 10 , S(O)R 10 , SO 2 R 10 , C(O)R 10 , CO(O)R 10 , OC(O)R 10 , OC(O)OR 10 , NO 2 , NH 2 , NHR 10 , N(R 10 ) 2 , CH 2 R 10 , C(O)NH 2 , C(O)NHR 10 , C(O)N(R 10 ) 2 , NHC(O)R 10 , NR 10 C(O)R 10 , C(O)NHOH, C(O)NHOR 10 , C(O)NHSO 2 R 10 , C(O)NR 10 SO 2 R 10 , SO 2 NH 2 , SO 2 NHR 10 , SO 2 N(R 10 ) 2 , CF 3 , CF 2 CF 3 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 10 , C(N)N(R 10 ) 2 , ═NO-(alkylene)-C(O)CF 3 , CNOH, CNOCH 3 , OH, (O), N 3 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br and 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 12A 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 substituents independently selected from the group consisting of 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 and 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 substituents independently selected from the group consisting of R 21 , OR 21 , OCH 2 R 21 , SR 21 , S(O)R 21 , SO 2 R 21 , C(O)R 21 , CO(O)R 21 , OC(O)R 21 , OC(O)OR 21 , NO 2 , NH 2 , NHR 21 , N(R 21 ) 2 , CH 2 R 21 , C(O)NH 2 , C(O)NHR 21 , C(O)N(R 21 ) 2 , NHC(O)R 21 , NR 21 C(O)R 21 , C(O)NHOH, C(O)NHOR 21 , C(O)NHSO 2 R 21 , C(O)NR 21 SO 2 R 21 , (alkylene)-C(O)CF 3 , CNOH, CNOCH 3 , OH, (O), N 3 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br and I; and
R 21 is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl or heterocycloalkyl.
2. The compound of claim 1 , or a therapeutically acceptable salt thereof, wherein
R 1 is unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of 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 and 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 substituents independently selected from the group consisting of R 15 , OR 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 and 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 81A ; 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 substituents independently selected from the group consisting of OR 21 , NO 2 , CF 3 , F, Cl, Br and I; and
R 21 is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl or heterocycloalkyl.
3. The compound of claim 2 , or a therapeutically acceptable salt thereof, wherein
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 substituents independently selected from the group consisting of 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 and 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 substituents independently selected from the group consisting of OR 21 , NO 2 , CF 3 , F, Cl, Br and I; and
R 21 is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl or heterocycloalkyl.
4. The compound of claim 3 , or a therapeutically acceptable salt thereof, wherein
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 substituents independently selected from the group consisting of R 15 , OR 15 , SO 2 R 15 , N(R 15 ) 2 , F, Cl, Br and 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 substituents independently selected from the group consisting of OR 21 , NO 2 , CF 3 , F, Cl, Br and I; and
R 21 is alkyl.
5. The compound of claim 1 , or therapeutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
3-(2-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid;
3-(1-naphthyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid;
3-(3-(((3-(dimethylamino)propyl)amino)carbonyl)phenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid;
3-(1,1′-biphenyl-2-yl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid;
3-(2-methylphenyl)-1-(3-(2-naphthyloxy)propyl)-1H-indole-2-carboxylic acid;
3-(3-methylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid;
3-(3-chlorophenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid;
1-(3-(1-naphthyloxy)propyl)-3-phenyl-1H-indole-2-carboxylic acid;
1-(3-(1-naphthyloxy)propyl)-3-(2-(trifluoromethyl)phenyl)-1H-indole-2-carboxylic acid;
1-(3-(1-naphthyloxy)propyl)-3-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxylic acid;
1-(3-(1-naphthyloxy)propyl)-3-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxylic acid;
1-(3-(1-naphthyloxy)propyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxylic acid;
3-(2,3-dimethylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid;
3-(2,5-dimethylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid;
3-(3,4-dimethylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid;
3-(3,5-dimethylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid;
3-(2,5-dimethoxyphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid;
3-(3,4-dimethoxyphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid;
1-(3-(1-naphthyloxy)propyl)-3-(3-(piperidin-1-ylcarbonyl)phenyl)-1H-indole-2-carboxylic acid;
3-(4-fluoro-3-(morpholin-4-ylcarbonyl)phenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid;
3-(3-(((2-methoxyethyl)amino carbonyl)phenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid;
3-(3-((dimethylamino)sulfonyl)phenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid;
3-(3-(morpholin-4-ylmethyl)phenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid; carboxylic acid;
3-(2-isopropylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid;
and 3-(2,6-dimethylphenyl)-1-(3-(1-naphthyloxy)propyl)-1H-indole-2-carboxylic acid.
6. A composition comprising an excipient and the compound or therapeutically acceptable salt of claim 1 .
7. A composition comprising an excipient and the compound or therapeutically acceptable salt of claim 2 .
8. A composition comprising an excipient and the compound or therapeutically acceptable salt of claim 3 .
9. A composition comprising an excipient and the compound or therapeutically acceptable salt of claim 4 .
10. A composition comprising an excipient and the compound or therapeutically acceptable salt of claim 5 .
11. 1-[3-(1-Naphthyloxy)propyl]-3-[4-(trifluoromethoxy)phenyl]-1H-indole-2-carboxylic acid or a therapeutically acceptable salt thereof.
12. A composition comprising an excipient and 1-[3-(1-naphthyloxy)propyl]-3-[4-(trifluoromethoxy)phenyl]-1H-indole-2carboxylic acid or a therapeutically acceptable salt thereof.