Aryl dihydro-2H benzo[b][1,4]oxazine sulfonamide and related compounds for use as agonists of RORγ and the treatment of disease

Patent metadata

Field	Value
Publication number	US-11059796-B2
Application number	US-202016812538-A
Country	US
Kind code	B2
Filing date	Mar 9, 2020
Priority date	Jun 11, 2015
Publication date	Jul 13, 2021
Grant date	Jul 13, 2021

Abstract

The invention provides aryl dihydro-2H-benzo[b][1,4]oxazine sulfonamide and related compounds, pharmaceutical compositions, methods of promoting RORγ activity, methods of increasing the amount of IL-17 in a subject, and methods of treating cancer and other medical disorders using such compounds.

First claim

What is claimed is:

1. A compound represented by Formula I-B:

or a pharmaceutically acceptable salt thereof; wherein:
X is phenyl substituted by 1, 2, or 3 substituents independently selected from the group consisting of chloro, fluoro, C 1-2 fluoroalkyl, C 1-2 alkoxy, and C 1-2 fluoroalkoxy;
R 2A is —(C 1-6 alkylene)—CO 2 H or —(C 1-6 alkylene)—N(R 4 )C(O)R 7 ;
R 3 represents independently for each occurrence C 1-2 fluoroalkyl, chloro, fluoro, cyclopropyl, C 1-3 alkyl, C 1-2 alkoxy, or C 1-2 fluoroalkoxy;
R 4 is hydrogen or C 1-6 alkyl;
R 7 is C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 hydroxyhaloalkyl, C 3-6 cycloalkyl, or C 3-6 hydroxycycloalkyl; and
n is 1.

2. The compound of claim 1 , wherein X is phenyl substituted by 1, 2, or 3 substituents independently selected from the group consisting of chloro, fluoro, C 1-2 fluoroalkyl, C 1-2 alkoxy, and C 1-2 fluoroalkoxy, where at least 1 substituent is located at a meta-position on the phenyl group.

3. The compound of claim 1 , wherein R 2A is —(CH 2 ) 2 —CO 2 H or —CH 2 C(CH 3 ) 2 —CO 2 H.

4. The compound of claim 1 , wherein R 3 is —CF3, which is attached at a meta-position on the phenyl group.

5. The compound of claim 2 , wherein R 2A is —(CH 2 ) 2 —CO 2 H or —CH 2 C(CH 3 ) 2 —CO 2 H.

6. The compound of claim 2 , wherein R 3 is —CF 3 , which is attached at a meta-position on the phenyl group.

7. The compound of claim 3 , wherein R 3 is —CF 3 , which is attached at a meta-position on the phenyl group.

8. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

9. A pharmaceutical composition comprising a compound of claim 2 and a pharmaceutically acceptable carrier.

10. A pharmaceutical composition comprising a compound of claim 3 and a pharmaceutically acceptable carrier.

11. A pharmaceutical composition comprising a compound of claim 4 and a pharmaceutically acceptable carrier.

12. A pharmaceutical composition comprising a compound of claim 5 and a pharmaceutically acceptable carrier.

13. A pharmaceutical composition comprising a compound of claim 6 and a pharmaceutically acceptable carrier.

14. A pharmaceutical composition comprising a compound of claim 7 and a pharmaceutically acceptable carrier.

15. A method of treating a disorder selected from the group consisting of cancer, bacterial infection, fungal infection, and immune deficiency disorder, comprising administering a therapeutically effective amount of a compound of claim 1 to a subject in need thereof to ameliorate a symptom of the disorder.

16. The method of claim 15 , wherein the disorder is cancer.

17. The method of claim 15 , wherein the disorder is colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, lung cancer, leukemia, bladder cancer, stomach cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, thyroid cancer, kidney cancer, uterus cancer, esophagus cancer, liver cancer, an acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, or retinoblastoma.

18. A method of increasing the amount of IL-17 in a subject, comprising administering to a subject an effective amount of a compound of claim 1 to increase the amount of IL-17 in the subject.

19. The method of claim 17 , wherein the subject is a human.

20. A method of promoting the activity of RORγ, comprising exposing a RORγ to an effective amount of a compound of claim 1 to promote the activity of said RORγ.

Assignees

• Univ Michigan Regents

Inventors

• Aicher Thomas Daniel
• Taylor Clarke B
• Vanhuis Chad A

Classifications

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D417/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• A61P31/10

  Antimycotics · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title