Benzodiazepine derivatives and uses thereof
The present disclosure provides compounds and compositions capable of extending lifespan, and methods of use thereof.
1. A compound having the structure of Formula (I):
or a pharmaceutically acceptable salt thereof,
wherein:
A 1 and A 2 each independently represent a heterocyclic ring, optionally fused to or substituted with one or more aryl or heteroaryl rings;
R 1 and R 2 are each independently an alkyl group;
Z 1 is a linking group selected from y is an integer having a value of 1 to about 10;
Y 2 is N;
R Z2 is (CH 2 ) z R Z2a ;
R Z2a is amino, aryl, or heteroaryl;
z is an integer having a value of 0 to about 10; and
n 1 and n 2 are each independently an integer having a value of 1 to 5.
2. The compound of claim 1 , wherein A 1 is selected from:
wherein:
R A1a is H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R A1b is CHR A1ba ;
R Alba is H, halogen, alkyl, —CO 2 -alkyl, CHO, or CO 2 H;
Ar 1 is aryl or heteroaryl, optionally substituted one or more times with halogen, hydroxyl, cyano, nitro, alkyl, haloalkyl, cycloalkyl, carboxyl, alkoxy, CO 2 H, CO 2 -alkyl, amino, aryl, heteroaryl, or (CH 2 ) p N(R A1ca ) 2 , wherein each R A1ca is independently selected from H or alkyl; and p is an integer having a value from 0 to 5; and
o is an integer having a value of 1 or 2.
3. The compound of claim 1 , wherein
A 2 is
wherein:
R A2a is H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R A2b is CHR A2ba ;
R A2ba is H, halogen, alkyl, —CO 2 -alkyl, CHO, or CO 2 H;
Ar 2 is aryl or heteroaryl, optionally substituted with one or more of R A2c ;
R A2c is halogen, OH, CN, NO 2 , alkyl, alkoxy, CO 2 H, CO 2 -alkyl, or (CH 2 ) r N(R A2ca ) 2 ;
each R A2ca is independently selected from H or alkyl;
q is an integer having a value of 1 or 2; and
r is an integer having a value from 0 to 5.
4. The compound of claim 1 having the structure of Formula (Ia), (Ib), or (Ic):
or a pharmaceutically acceptable salt thereof, wherein:
R A1aa and R A2aa are each independently H, OH, alkyl, alkoxy, alkylamino, or dialkylamino;
R A1b is CHR A1ba ,
R Alba is H, halogen, alkyl, —CO 2 -alkyl, CHO, or CO 2 H;
R A2b is CHR A2ba ,
R A2ba is H, halogen, alkyl, —CO 2 -alkyl, CHO, or CO 2 H;
Ar 1 is aryl or heteroaryl, optionally substituted one or more times with halogen, hydroxyl, cyano, nitro, alkyl, haloalkyl, cycloalkyl, alkoxy, carboxyl, amino, aryl, heteroaryl, CO 2 -alkyl, or (CH 2 ) p N(R Alca ) 2 ;
each R A1ca is independently selected from H or alkyl;
Ar 2 is aryl or heteroaryl, optionally substituted one or more times with halogen, hydroxyl, cyano, nitro, alkyl, haloalkyl, cycloalkyl, alkoxy, carboxyl, amino, aryl, heteroaryl, CO 2 -alkyl, or (CH 2 ) r N(R A2ca ) 2 ;
each R A2ca is independently selected from H or alkyl;
p and r are integers each independently having a value from 0 to 5; and
o and q are integers each independently having a value of 1 or 2.
5. The compound of claim 1 , wherein R 1 and R 2 are methyl.
6. The compound of claim 1 , wherein Z 1 is
wherein:
Y 2 is N;
R Z2 is (CH 2 ) z R Z2a ;
R Z2a is amino, aryl, or heteroaryl; and
z is an integer having a value of 0 to about 10.
7. The compound of claim 6 , where Z 1 is
8. A compound selected from:
or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
10. A method of treating a cancer, comprising administering a therapeutically effective amount of the compound of claim 1 to a subject in need thereof.