ULK1 inhibitors and methods using same
In certain aspects, the invention provides a method for treating a disease or condition in a subject, the method comprising co-administering to a subject in need thereof a therapeutically effective amount of at least one ULK1-inhibiting pyrimidine, and a therapeutically effective amount of an mTOR inhibitor.
1. A compound, or pharmaceutically acceptable salt thereof, having a structure of Formula A:
wherein in Formula A:
R 10 is selected from the group consisting of: halogen; OR 11 wherein R 11 is H, optionally substituted aryl, or optionally substituted heteroaryl; and NR 1 R 2 wherein R 1 is H or alkyl and R 2 is selected from the group consisting of H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted alkyl, wherein the aryl or heteroaryl of R 2 is optionally substituted with one or more substituent, wherein each substituent of the aryl or heteroaryl of R 2 is selected from the group consisting of alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxy, carboxylic acid, and alkoxy;
R 4 is optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted alkoxy, N-heterocyclic, optionally substituted thiol, optionally substituted alkyl, or hydroxyl;
R 5 is selected from the group consisting of hydroxyl, substituted alkyl, chloro, bromo, substituted alkoxy, optionally substituted aryl, optionally substituted carboxyl, cyano, and nitro, or R 5 and R 6 together form a cyclic structure;
wherein each substituent of the substituted alkyl of R 5 is selected from the group consisting of halogen, cycloalkyl, alkoxy, amino, hydroxyl, and carboxyl; and
R 6 is H or haloalkyl.
2. The compound of claim 1 , wherein
R 10 is NR 1 R 2 ;
R 1 is H;
R 2 is selected from the group consisting of
and
R 6 is H.
3. The compound of claim 1 , wherein
R 10 is NR 1 R 2 ;
R 1 is H;
R 2 is selected from the group consisting of
and
R 6 is H.
4. The compound of claim 1 , wherein
R 10 is NR 1 R 2 ;
R 2 is an alkoxy-substituted phenyl.
5. The compound of claim 4 , wherein R 2 is
6. The compound of claim 1 , wherein R 5 is selected from the group consisting of haloalkyl, chloro, and bromo.
7. The compound of claim 6 , wherein R 5 is CF 3 .
8. The compound of claim 1 , wherein R 4 is optionally substituted aryloxy.
9. The compound of claim 1 , wherein R 4 is optionally substituted heteroaryloxy.
10. The compound of claim 1 , wherein R 6 is H.
11. A compound, or pharmaceutically acceptable salt thereof, having a structure of:
wherein:
R 1 is H or alkyl;
R 2 is
R 4 is optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted alkoxy, or NR 7 R 8 , wherein R 7 is H or alkyl and R 8 is optionally substituted aryl, cyclopropyl, or N-alkylbenzamide, wherein the aryloxy or heteroaryloxy of R 4 is optionally substituted with one or more substituent, wherein each substituent of the aryloxy or heteroaryloxy of R 4 is selected from the group consisting of alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxy, carboxylic acid, and alkoxy;
R 5 is H, hydroxyl, optionally substituted alkyl, halo, optionally substituted alkoxy, and optionally substituted aryl;
wherein each substituent of the substituted alkyl of R 5 is selected from the group consisting of halogen, cycloalkyl, alkoxy, amino, hydroxyl, and carboxyl; and
R 6 is H or haloalkyl.
12. The compound of claim 11 , wherein R 4 is optionally substituted aryloxy or optionally substituted heteroaryloxy.
13. The compound of claim 11 , wherein R 4 is NR 7 R 8 , wherein R 7 is H and R 8 is N-alkylbenzamide.
14. The compound of claim 11 , wherein R 5 is haloalkyl, chloro, or bromo.
15. The compound of claim 11 , wherein R 6 is H.
16. A compound, or pharmaceutically acceptable salt thereof, having a structure of:
wherein:
R 1 is H or alkyl;
R 2 is
R 4 is optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted alkoxy, or NR 7 R 8 , wherein R 7 is H or alkyl and R 8 is optionally substituted aryl, optionally substituted heteroaryl, cycloalkyl, N-alkylbenzamide, or alkyl optionally substituted one or more substituent, wherein each substituent of the alkyl of R 8 is selected from the group consisting of halogen, cycloalkyl, alkoxy, amino, hydroxyl, aryl, alkenyl, or carboxyl;
wherein the aryloxy or heteroaryloxy of R 4 is optionally substituted with one or more substituent, wherein each substituent of the aryl, heteroaryl, aryloxy or heteroaryloxy of R 4 is selected from the group consisting of alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxy, carboxylic acid, and alkoxy;
R 5 is haloalkyl; and
R 6 is H or haloalkyl.
17. The compound of claim 16 , wherein R 4 is NR 7 R 8 , wherein R 7 is H and R 8 is optionally substituted aryl, optionally substituted heteroaryl, cycloalkyl, N-alkylbenzamide, or alkyl optionally substituted one or more substituent, wherein each substituent of the alkyl of R 8 is selected from the group consisting of halogen, cycloalkyl, alkoxy, amino, hydroxyl, aryl, alkenyl, or carboxyl.
18. The compound of claim 17 , wherein R 8 is alkyl optionally substituted with halogen.
19. The compound of claim 17 , wherein R 8 is cycloalkyl.
20. The compound of claim 16 , wherein R 4 is optionally substituted aryloxy or optionally substituted heteroaryloxy.