Chemical modulators of immune checkpoints and therapeutic use

Patent metadata

Field	Value
Publication number	US-2017190675-A1
Application number	US-201615395464-A
Country	US
Kind code	A1
Filing date	Dec 30, 2016
Priority date	Dec 30, 2015
Publication date	Jul 6, 2017
Grant date	—

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

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,
one of R 1a , R 1b , R 1c , R 1d and R 1e is OR 4 or NR 8 —SO 2 —R 9 , and the remaining are independently selected from 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 ; or R 1b and R 1c , R 1c and R 1d , or R 1d and R 1e together form a ring;
A is heteroaryl;
D is hydrogen, halogen, nitro, alkyl, cyano, haloalkyl, aryl or heteroaryl, with 0-5 substituents independently selected from 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 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, and —C(O)—O-alkoxyalkyl-C(O)—NH-alkyl, and —C(O)-heterocycle;
R 5 , R 6 and R 7 are each independently selected from hydrogen, alkyl, —C(O)-alkyl, —C(O)-alkoxyalkyl, alkenyl, alkynyl, and heteroalkyl;
R 8 is selected from hydrogen and alkyl; and
R 9 is selected from hydrogen, alkyl, aryl, heteroaryl, arylalkyl, heterocycle, and heteroarylalkyl.

2 . The method of claim 1 , wherein
A is a 5 or 6 membered heteroaryl.

3 . (canceled)

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

5 . The method of claim 1 , wherein
A is a bicyclic heteroaryl; and D is hydrogen, halogen, nitro, alkyl, cyano, haloalkyl.

6 . The method of claim 1 , wherein
R 1a is OR 4 ; R 1b , R 1c and R 1e are hydrogen; and R 1d is hydrogen or halogen.

7 . 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.

8 - 18 . (canceled)

19 . The method of claim 1 , wherein the cancer is selected from the group consisting of melanoma, lymphoma, pancreatic cancer, multiple myeloma, prostate cancer, renal cell carcinoma, bladder cancer and non-small cell lung cancer, esophageal, gastric, colon, liver, ovarian, breast, or a combination thereof.

20 . 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), or a pharmaceutically acceptable salt thereof,

wherein,
one of R 1a , R 1b , R 1c , R 1d and R 1e is OR 4 or NR 8 —SO 2 —R 9 , and the remaining are independently selected from 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 ; or R 1b and R 1c , R 1c and R 1d , or R 1d and R 1e together ring;
A is heteroaryl;
D is hydrogen, halogen, nitro, alkyl, cyano, haloalkyl, aryl or heteroaryl, with 0-5 substituents independently selected from 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 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, and —C(O)—O-alkoxyalkyl-C(O)—NH-alkyl, and —C(O)-heterocycle;
R 5 , R 6 and R 7 are each independently selected from hydrogen, alkyl, —C(O)-alkyl, —C(O)-alkoxyalkyl, alkenyl, alkynyl, and heteroalkyl;
R 8 is selected from hydrogen and alkyl; and
R 9 is selected from hydrogen, alkyl, aryl, heteroaryl, arylalkyl, heterocycle, and heteroarylalkyl.

21 . The method of claim 20 , wherein
A is a 5 or 6 membered heteroaryl.

22 . (canceled)

23 . The method of claim 20 , wherein
D is a 6 membered aryl.

24 . The method of claim 20 , wherein
A is a bicyclic heteroaryl; and D is hydrogen, halogen, nitro, alkyl, cyano, haloalkyl.

25 . The method of claim 20 , wherein
R 1a is OR 4 ; R 1b , R 1c and R 1e are hydrogen; and R 1d is hydrogen or halogen.

26 . The method of claim 20 , 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.

27 - 37 . (canceled)

38 . The method of claim 20 , 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 cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), or a combination thereof.

39 . The method of claim 20 , wherein the downregulating an immune checkpoint results in activating the immune system.

40 . 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.

41 . A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and an effective amount of a compound of claim 40 .

42 . 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.

43 . The method of claim 20 , further comprising administering at least one of cisplatin, oxaliplatin, a kinase inhibitor, pembrolizumab, ipilimumab, trastuzumab, cetuximab, panitumumab, lambrolizumab and nivolumab.

Assignees

• Univ Duke

Inventors

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

Classifications

• C07D249/08 Primary

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

• A61K31/166

  having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol · CPC title

• A61K31/351

  not condensed with another ring · CPC title

• A61K31/4196

  1,2,4-Triazoles · CPC title

• A61K45/06

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