ULK1 inhibitors and methods using same

Patent metadata

Field	Value
Publication number	US-10689397-B2
Application number	US-201916269468-A
Country	US
Kind code	B2
Filing date	Feb 6, 2019
Priority date	Aug 25, 2014
Publication date	Jun 23, 2020
Grant date	Jun 23, 2020

Abstract

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.

First claim

What is claimed is:

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.

Assignees

• Salk Inst For Biological Studi
• Sanford Burnham Prebys Medical Discovery Inst
• Univ Yale

Inventors

• Shaw Reuben J
• Egan Daniel F
• Cosford Nicholas
• Turk Benjamin
• Vamos Mitchell
• Panickar Dhanya Raveendra
• Chun Matthew
• Sheffler Douglas

Classifications

• C07D239/557

  with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid · CPC title

• C07K7/08

  having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68) · CPC title

• C07D417/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title