Indole derivatives and methods of using the same
The invention provides indole-4,7-dione derivatives useful for the treatment of diseases in a mammal, pharmaceutical compositions containing the same and methods of using the same in the treatment of cancer and neoplastic diseases including human solid tumors and other mammalian tumors.
1. A compound having the structure:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 2 are independently C 1-6 alkyl optionally substituted with hydroxy, C 1-6 alkyl, C 1-6 alkenyl, C 1-4 alkoxy, OR 7 , NR 7 R 8 , or a combination thereof,
R 3 is H, or C 1-6 alkyl
R 4 is OR 10 wherein R 10 is aryl or heteroaryl optionally substituted with hydroxy, mercapto, amino, carboxylic acid, sulfonic acid, trihalomethyl, C 1-6 alkyl, C 1-6 alkenyl, C 1-4 alkoxy, SR 7 , NR 7 R 8 , CO 2 R 7 , C(═O)R 9 , or any combination thereof;
R 5 is C 1-6 alkyl, C 3-8 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, aryl, heteroaryl, NR 7 R 8 , CO 2 R 7 , OC(═O)R 9 , or
C 1-6 alkyl optionally substituted with hydroxy, mercapto, amino, sulfonic acid, carboxylic acid, halide, C 1-6 alkyl, C 1-6 alkenyl, C 1-4 alkoxy, OR 7 , SR 7 , NR 7 R 8 , CO 2 R 7 , OC(═O)R 9 , heteroaryl, or a combination thereof,
R 6 is H or C 1-6 alkyl, C 3-8 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, aryl, heteroaryl, OR 7 , SR 7 , NR 7 R 8 , CO 2 R 7 , OC(═O)R 9 , or C 1-6 alkyl optionally substituted with hydroxy, mercapto, amino, sulfonic acid, carboxylic acid, halide, C 1-6 alkyl, C 1-6 alkenyl, C 1-4 alkoxy, OR 7 , SR 7 , NR 7 R 8 , CO 2 R 7 , OC(═O)R 9 , heteroaryl, or a combination thereof;
R 7 and R 8 are independently H, C 1-6 alkyl, C 3-8 cycloalkyl, C 2-4 alkenyl, aryl, heteroaryl, or C 1-6 alkyl optionally substituted with hydroxy, mercapto, amino, sulfonic acid, carboxylic acid, halide, C 1-6 alkyl, C 1-6 alkenyl, C 1-4 alkoxy, OR 7 , SR 7 , NR 7 R 8 , CO 2 R 7 , OC(═O)R 9 , heteroaryl, or a combination thereof, or R 7 and R 8 together form a heterocyclic ring optionally substituted with hydroxy, mercapto, halide, C 1-6 alkyl; and
R 9 is H, C 1-6 alkyl, C 3-8 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, heteroaryl, aryl or NR 7 R 8 .
2. The compound of claim 1 , wherein:
R 1 and R 2 are independently C 1-6 alkyl optionally substituted with hydroxy, C 1-6 alkyl, C 1-6 alkenyl, C 1-4 alkoxy, OR 7 , NR 7 R 8 , or a combination thereof;
R 3 is H or C 1-6 alkyl;
R 4 is —OR 10 wherein R 10 is aryl optionally substituted with hydroxy, mercapto, amino, carboxylic acid, C 1-6 alkyl, C 1-6 alkenyl, C 1-4 alkoxy, SR 7 , NR 7 R 8 , CO 2 R 7 , C(═O)R 9 , or a combination thereof;
R 5 is C 1-6 alkyl optionally substituted with hydroxy, amino, sulfonic acid, carboxylic acid, halide, C 1-6 alkyl, C 1-6 alkenyl, C 1-4 alkoxy, NR 7 R 8 , CO 2 R 7 , heteroaryl, or any combination thereof;
R 6 is H, or C 1-6 alkyl optionally substituted with hydroxy, mercapto, amino, sulfonic acid, carboxylic acid, halide, C 1-6 alkyl, C 1-6 alkenyl, C 1-4 alkoxy, OR 7 , SR 7 , NR 7 R 8 , CO 2 R 7 , OC(═O)R 9 , heteroaryl, or any combination thereof; and,
R 7 and R 8 are independently H, C 1-6 alkyl, C 3-8 cycloalkyl, C 2-4 alkenyl, aryl, heteroaryl, or C 1-6 alkyl optionally substituted with hydroxy, amino, carboxylic acid, halide, C 1-6 alkyl, C 1-6 alkenyl, C 1-4 alkoxy, OR 7 , NR 7 R 8 , CO 2 R 7 , OC(═O)R 9 , heteroaryl, or a combination thereof, or R 7 and R 8 together form a heterocyclic ring optionally substituted with hydroxy, mercapto, halide, or C 1-6 alkyl.
3. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically-acceptable carrier.
4. A compound having the structure:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H, or
C 1-6 alkyl optionally substituted with hydroxy, NR 7 R 8 , or a combination thereof,
R 2 is
C 1-6 alkyl substituted with hydroxy,
C 1-4 alkoxy, OR 7 , NR 7 R 8 , or a combination thereof,
R 3 is H, or C 1-6 alkyl,
R 4 is OR 10 wherein R 10 is aryl or heteroaryl optionally substituted with hydroxy, mercapto, amino, nitro, carboxylic acid, sulfonic acid, halide, trihalomethyl, C 1-6 alkyl, C 1-6 alkenyl, C 1-4 alkoxy, OR 7 , SR 7 , NR 7 R 8 , CO 2 R 7 , C(═O)R 9 , or any combination thereof;
R 5 and R 6 are independently H or C 1-4 alkoxy, OR 7 , SR 7 , NR 7 R 8 ,
R 7 and R 8 are independently H, C 3-8 cycloalkyl, C 2-4 alkenyl, aryl, heteroaryl, or C 1-6 alkyl optionally substituted with hydroxy, mercapto, amino, sulfonic acid, carboxylic acid, halide, C 1-6 alkyl, C 1-6 alkenyl, C 1-4 alkoxy, OR 7 , SR 7 , NR 7 R 8 , CO 2 R 7 , OC(═O)R 9 , heteroaryl, or a combination thereof; and,
R 9 is H, C 1-6 alkyl, C 3-8 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, heteroaryl, aryl or NR 7 R 8 .
5. A compound of claim 4 , having the structure:
6. A compound having the structure:
or a pharmaceutically acceptable salt thereof.
7. A compound having the structure:
or a pharmaceutically acceptable salt thereof.