Bicyclic compounds and methods of use

Patent metadata

Field	Value
Publication number	US-11236105-B2
Application number	US-202016787551-A
Country	US
Kind code	B2
Filing date	Feb 11, 2020
Priority date	Jun 13, 2017
Publication date	Feb 1, 2022
Grant date	Feb 1, 2022

Abstract

The present invention provides compounds that modulate protein function, specifically phosphodiesterase 4 (PDE4). The invention provides methods of treating, ameliorating, and/or preventing diseases, disorders, and conditions associated with PDE4. Compositions, including in combination with other inflammatory mediators, are also provided.

First claim

What is claimed is:

1. A compound of Formula (II), or a pharmaceutically acceptable salt thereof,

wherein:
Y is H, deuterium, halogen, or an optionally substituted C 1 -C 6 alkyl;
X and X 1 are each independently CH 2 , C═O, SO, SO 2 , or CH 2 CO;
R 1 is H, deuterium, hydroxy, halogen, nitro, cyano, optionally substituted C 1 -C 6 alkoxy, —NH 2 , —NHR 1A , —NR 1A R 1B , —NHC(O)R 1C , —NR 1A C(O)R 1C , —NHSO 2 R 1C , —NR 1A SO 2 R 1C , —N[C(O)R 1A ][C(O)R 1C ], an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C 6 -C 10 aryl, or an optionally substituted 5 to 10 membered heteroaryl;
R 1A , R 1B , and R 1C are independently selected from an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C 6 -C 10 aryl, or an optionally substituted 5 to 10 membered heteroaryl;
R 2 is hydroxy, —NH 2 , —NHR 1A , —NR 1A R 1B , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C 6 -C 10 aryl, or an optionally substituted 5 to 10 membered heteroaryl;
R 3 , R 6 , and R 7 are independently selected from the group consisting of a hydrogen, a deuterium, a halogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 alkoxy, an optionally substituted C 3 -C 6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C 6 -C 10 aryl, and an optionally substituted 5 to 10 membered heteroaryl;
R 4 and R 5 are independently selected from the group consisting of an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C 6 -C 10 aryl, and an optionally substituted 5 to 10 membered heteroaryl; or
R 4 and R 5 , together with the atoms to which they are attached, form an optionally substituted 5 or 6 membered heterocyclyl; and
R 8 is hydrogen or deuterium.

2. The compound of claim 1 ,
wherein:
R 1 is H, deuterium, hydroxy, halogen, cyano, optionally substituted C 1 -C 6 alkoxy, —NHR 1A , —NR 1A R 1B , —NHC(O)R 1C , —NR 1A C(O)R 1C , —NHSO 2 R 1C , —NR 1A SO 2 R 1C , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 6 cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C 6 -C 10 aryl, or an optionally substituted 5 to 10 membered heteroaryl;
when R 2 is an optionally substituted C 1 -C 4 alkyl or NH(C 1 -C 6 alkyl), at least one of R 4 and R 5 is an optionally substituted cyclopropyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C 6 -C 10 aryl, an optionally-substituted 5 to 10 membered heteroaryl, or R 4 and R 5 , together with the atoms to which they are attached, form an optionally substituted 5 or 6 membered heterocyclyl;
wherein, when a C 1 -C 6 alkyl, a C 1 -C 6 alkoxy, a C 3 -C 6 cycloalkyl, a C 6 -C 10 aryl, a 3 to 10 membered heterocyclyl, or a 5 to 10 membered heteroaryl is substituted, the substituted substituents are independently selected from the group consisting of a deuterium, an oxo, a halogen, cyano, a nitro, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 haloalkyl, an optionally substituted C 1 -C 6 alkoxy, an optionally substituted C 3 -C 6 cycloalkyl, an optionally substituted C 6 -C 10 aryl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted 5 to 10 membered heteroaryl, —C(O)R A , —C(O)OR A , —C(O)NR B R C , —OR A , —OC(O)R A , —OC(O)NR B R C , —OS(O)R A , —OS(O) 2 R A , —OS(O)NR B R C , —OS(O) 2 NR B R C , —NR B R C , —NR A C(O)R A , —NR A C(O)OR A , —NR A C(O)NR B R C , —NR A S(O)R A , —NR A S(O) 2 R A , —NR A S(O)NR B R C , —NR A S(O) 2 NR B R C , —SR A , —S(O)R A , —S(O) 2 R A , —S(O)NR B R C , and —S(O) 2 NR B R C ; and
each R A , R B , and R C are independently selected from the group consisting of a hydrogen, a deuterium, an unsubstituted C 1 -C 6 alkyl, an unsubstituted C 2 -C 6 alkenyl, an unsubstituted C 3 -C 6 cycloalkyl, an unsubstituted 3 to 10 membered heterocyclyl, an unsubstituted C 6 -C 10 aryl, and an unsubstituted 5 to 10 membered heteroaryl; or
R B and R C , together with the nitrogen atom to which they are attached, form an optionally substituted 3 to 10 membered heterocyclyl.

3. The compound of claim 1 , wherein one of X and X 1 is CH 2 and the other is C═O.

4. The compound of claim 1 , wherein X is C═O and X 1 is CH 2 .

5. The compound of claim 1 , wherein X and X 1 are each C═O.

6. The compound of claim 1 , wherein R 1 is —NHR 1A , —NR 1A R 1B , —NHC(O)R 1C , —N[C(O)R 1A ][C(O)R 1C ], or —NR 1A C(O)R 1C .

7. The compound of claim 6 , wherein R 1 is —NHC(O)R 1C .

8. The compound of claim 1 , wherein R 1A , R 1B , and R 1C are independently an optionally substituted C 1 -C 6 alkyl or an optionally substituted C 3 -C 6 cycloalkyl.

9. The compound of claim 1 , wherein R 1C is an optionally substituted C 1 -C 6 alkyl.

10. The compound of claim 9 , wherein R 1C is an unsubstituted C 1 -C 6 alkyl.

11. The compound of claim 1 , wherein R 3 , R 6 , and R 7 are independently selected from the group consisting of a hydrogen, a halogen, and an optionally substituted C 1 -C 6 alkyl.

12. The compound of claim 11 , wherein R 3 , R 6 , and R 7 are each hydrogen.

13. The compound of claim 1 , wherein R 2 is an optionally substituted C 1 -C 6 alkyl and one of R 4 and R 5 is an optionally substituted C 1 -C 6 alkyl.

14. The compound of claim 1 , wherein R 2 is an unsubstituted C 1 -C 6 alkyl and each of R 4 and R 5 is an unsubstituted C 1 -C 6 alkyl.

15. The compound of claim 1 , wherein R 4 and R 5 , together with the atoms to which they are attached, form an optionally substituted 5 or 6 membered heterocyclyl.

16. The compound of claim 1 , wherein R 8 is hydrogen.

17. The compound of claim 1 , wherein the compound of Formula (II) is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

18. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

19. A method of treating or ameliorating a disease, disorder, or condition associated with TNF-α, INF-γ, IL-2, IL-17, IL-23, or PDE4 in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of claim 1 , or a pharamaceutically acceptable salt thereof, to the subject,
wherein the disease, disorder, or condition is selected from the group consisting of arthritis, ankylosing spondylitis, osteoarthritis, rheuma

Assignees

• Biotheryx Inc

Inventors

• Sullivan Robert
• Erdman Paul E
• Torres Eduardo
• Fung Leah
• Chan Kyle W H
• Mercurio Frank

Classifications

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C07D495/04 Primary

  Ortho-condensed systems · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title