Chemical modulators of immune checkpoints and therapeutic use

Patent metadata

Field	Value
Publication number	US-10189797-B2
Application number	US-201615395464-A
Country	US
Kind code	B2
Filing date	Dec 30, 2016
Priority date	Dec 30, 2015
Publication date	Jan 29, 2019
Grant date	Jan 29, 2019

Abstract

Compounds and pharmaceutical compositions that down-regulate immune checkpoints such as PD-1, PD-L1 and CTLA-4 are provided. Also provided are methods of treating a disease by down-regulating immune checkpoints such as PD-1, PD-L1 and CTLA-4. The methods are useful for treating cancer and viral infection in a subject.

First claim

What is claimed is:

1. A method of treating cancer in a subject in need thereof, the method comprising
administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof,

wherein,
R 1a is OR 4 or NR 8 —SO 2 —R 9 ;
R 1b , R 1c and R 1e are hydrogen;
R 1d is halogen;
A is heteroaryl selected from the group consisting of benzoimidazolyl, 1,2,4-triazolyl, indolyl, pyridinyl, pyrimidinyl, thiazolyl, and quinolinyl;
D is hydrogen, halogen, nitro, alkyl, cyano, haloalkyl, aryl or heteroaryl, selected from the group consisting of benzoimidazolyl, 1,2,4-triazolyl, indolyl, pyridinyl, pyrimidinyl, and quinolinyl with 0-5 substituents independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, cyano, haloalkyl, alkoxyalkyl, heteroalkyl, alkenyl, alkynyl, heterocycle, carboxyl, heterocyclealkyl, OR 4 , SR 5 , NR 6 R 7 , and NR 8 —SO 2 —R 9 ;
R 4 is selected from the group consisting of hydrogen, —C(O)-alkyl, —C(O)-alkenyl, —C(O)-alkoxyalkyl, —C(O)-heteroalkyl, —C(O)-heteroaryl, —C(O)—O-heteroalkyl, —C(O)—O-heteroaryl, —C(O)—O-alkyl, —C(O)—O-alkenyl, —C(O)—O-alkoxyalkyl, —C(O)—NH-alkyl, and —C(O)-heterocycle;
R 5 , R 6 and R 7 are each independently selected from the group consisting of hydrogen, alkyl, —C(O)-alkyl, —C(O)-alkoxyalkyl, alkenyl, alkynyl, and heteroalkyl;
R 8 is selected from the group consisting of hydrogen and alkyl; and
R 9 is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, arylalkyl, heterocycle, and heteroarylalkyl; and

wherein the cancer is breast cancer.

2. The method of claim 1 , wherein
D is a 6 membered aryl.

3. The method of claim 1 , wherein
D is hydrogen, halogen, nitro, alkyl, cyano, or haloalkyl.

4. The method of claim 1 , wherein
R 1a is OR 4 .

5. The method of claim 1 , wherein the compound of formula (I) is selected from the group consisting of:
4-chloro-2-(5-nitro-1H-benzo[d]imidazol-2-yl)phenol;
4-fluoro-2-(5-nitro-1H-benzo[d]imidazol-2-yl)phenol; and
4-chloro-2-(5-(4-nitrophenyl)-4H-1,2,4-triazol-3-yl)phenol, or a pharmaceutically acceptable salt thereof.

6. A method of downregulating an immune checkpoint in a subject in need thereof, the method comprising
administering to the subject an effective amount of a compound of formula (I) pharmaceutically acceptable salt thereof,

Wherein,
R 1a is OR 4 or NR 8 —SO 2 —R 9 ;
R 1b , R 1c and R 1e are hydrogen;
R 1d is halogen;
A is heteroaryl selected from the group consisting of benzoimidazolyl, 1,2,4-triazolyl, indolyl, pyridinyl, pyrimidinyl, thiazolyl, and quinolinyl;
D is hydrogen, halogen, nitro, alkyl, cyano, haloalkyl, aryl or heteroaryl, with 0-5 substituents independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, cyano, haloalkyl, alkoxyalkyl, heteroalkyl, alkenyl, alkynyl, heterocycle, carboxyl, heterocyclealkyl, OR 4 , SR 5 , NR 6 R 7 , and NR 8 —SO 2 —R 9 ;
R 4 is selected from the group consisting of hydrogen, —C(O)-alkyl, —C(O)-alkenyl, —C(O)-alkoxyalkyl, —C(O)-heteroalky, —C(O)-heteroaryl, —C(O)—O-heteroalkyl, —C(O)—O-heteroaryl, —C(O)—O-alkyl, —C(O)—O-alkenyl, C(O)—O-alkoxyalkyl, —C(O)—NH-alkyl and —C(O)-heterocycle;
R 5 , R 6 and R 7 are each in selected from the group consisting of hydrogen, alkyl, —C(O)-alkyl, —C(O)-alkoxyalkyl, alkenyl, alkynyl, and heteroalkyl;
R 8 is selected from the group consisting of hydrogen and alkyl; and
R 9 is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, arylalkyl, heterocycle, and heteroarylalkyl; and

wherein the immune checkpoint is selected from the group consisting of programmed cell death protein 1 (PD-1), programmed death-ligand 1(PD-L1) and cytoxic T-lymphocyte-associated protein 4(CTLA-4), or a combination thereof.

7. The method of claim 6 , wherein
D is a 6 membered aryl.

8. The method of claim 6 , wherein
D is hydrogen, halogen, nitro, alkyl, cyano, or haloalkyl.

9. The method of claim 6 , wherein
R 1a is OR 4 .

10. The method of claim 6 , wherein the compound of formula (I) is selected from the group consisting of:
4-chloro-2-(5-nitro-1H-benzo[d]imidazol-2-yl)phenol;
4-fluoro-2-(5-nitro-1H-benzo[d]imidazol-2-yl)phenol; and
4-chloro-2-(5-(4-nitrophenyl)-4H-1,2,4-triazol-3-yl)phenol;
or a pharmaceutically acceptable salt thereof.

11. The method of claim 6 , wherein the downregulating an immune checkpoint results in activating the immune system.

12. A compound selected from the group consisting of:
4-fluoro-2-(5-nitro-1H-benzo[d]imidazol-2-yl)phenol;
4-chloro-2-(5-nitro-1H-benzo[d]imidazol-2-yl)phenol; and
4-chloro-2-(5-(4-nitrophenyl)-4H-1,2,4-triazol-3-yl)phenol.

13. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and an effective amount of a compound of claim 12 .

14. The method of claim 1 , further comprising administering at least one of cisplatin, oxaliplatin, a kinase inhibitor, pembrolizumab, ipilimumab, trastuzumab, cetuximab, panitumumab, lambrolizumab and nivolumab.

15. The method of claim 6 , further comprising administering at least one of cisplatin, oxaliplatin, a kinase inhibitor, pembrolizumab, ipilimumab, trastuzumab, cetuximab, panitumumab, lambrolizumab and nivolumab.

16. The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

17. The method of claim 16 , wherein R 1a is OR 4 .

18. The method of claim 16 , wherein D is hydrogen, halogen, nitro, alkyl, cyano, or haloalkyl.

19. The method of claim 17 , wherein R 4 is hydrogen and D is nitro.

Assignees

• Univ Duke

Inventors

• Chen Wei
• Lyerly Herbert Kim
• Ren xiu-rong
• Wang Jiangbo
• Guo Hongtao
• Hobeika Amy
• Mook Robert A

Classifications

• A61K31/137

  Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone} · CPC title

• A61K31/343

  condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone · CPC title

• A61K39/3955

  against proteinaceous materials, e.g. enzymes, hormones, lymphokines · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D249/08 Primary

  1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles · CPC title