Composition and methods for inhibiting mammalian sterile 20-like kinase 1

Patent metadata

Field	Value
Publication number	US-10774068-B2
Application number	US-201615738986-A
Country	US
Kind code	B2
Filing date	Jun 24, 2016
Priority date	Jun 25, 2015
Publication date	Sep 15, 2020
Grant date	Sep 15, 2020

Abstract

Disclosed herein are compounds, compositions, and methods of their use for the treatment of diabetes.

First claim

What is claimed is:

1. A method of treating diabetes mellitus in a subject comprising administering to the subject a compound of Formula (I) having the structure:

wherein:
is a single bond;
X is —O—;
R 1 and R 2 are each independently C 1-6 alkyl; or R 1 and R 2 together with the nitrogen to which they are attached are combined to form a heterocycloalkyl ring;
R 3 is C 1-6 alkyl;
each R 4 is independently halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, or —CN;
R 5 is aryl or heteroaryl, wherein aryl and heteroaryl are unsubstituted or substituted by one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, —OH, —CH 2 OH, —CN, —CO 2 R 6 , C 3-6 cycloalkyl, and phenyl;
R 6 is H or C 1-6 alkyl;
n is 0, 1, 2, or 3; and
p is 1, 2, or 3;
or a pharmaceutically acceptable salt or solvate thereof.

2. The method of claim 1 , wherein p is 1; n is 1 or 2; and each R 4 is independently halogen or C 1-6 alkyl.

3. The method of claim 2 having the structure of Formula (Ia) or Formula (Ib):

4. The method of claim 3 , wherein R 1 and R 2 are each —CH 3 and R 5 is heteroaryl and wherein heteroaryl is unsubstituted or substituted by one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, —OH, —CH 2 OH, —CN, —CO 2 R 6 , C 3-6 cycloalkyl, and phenyl.

5. The method of claim 4 , wherein R 5 is unsubstituted pyridyl.

6. The method of claim 4 , wherein R 5 is pyridyl substituted by one substituent selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, —OH, —CH 2 OH, —CN, —CO 2 R 6 , C 3-6 cycloalkyl, and phenyl.

7. The method of claim 6 , wherein R 5 is pyridyl substituted by —CH 3 .

8. The method of claim 3 , wherein R 5 is aryl and wherein aryl is unsubstituted or substituted by one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, —OH, —CH 2 OH, —CN, —CO 2 R 6 , C 3-6 cycloalkyl, and phenyl.

9. The method of claim 8 , wherein R 5 is unsubstituted phenyl.

10. The method of claim 8 , wherein R 5 is phenyl and wherein phenyl is substituted by one substituent selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, —OH, —CH 2 OH, —CN, —CO 2 R 6 , C 3-6 cycloalkyl, and phenyl.

11. The method of claim 1 , wherein the compound is selected from:

or a pharmaceutically acceptable salt or solvate thereof.

12. A compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:

13. The compound of claim 12 that is:

or a pharmaceutically acceptable salt or solvate thereof.

14. The compound of claim 12 that is:

or a pharmaceutically acceptable salt or solvate thereof.

15. The compound of claim 12 that is:

or a pharmaceutically acceptable salt or solvate thereof.

16. The compound of claim 12 that is:

or a pharmaceutically acceptable salt or solvate thereof.

Assignees

• Scripps Research Inst
• Univ Bremen

Inventors

• Petrassi Hank Michael James
• Peram Surakattula Murali Mohan Reddy
• Maedler Kathrin
• Ardestani Amin
• Roland Jason T
• Baguley Tyler D
• Tremblay Matthew S
• Shen Weijun
• Schultz Peter G
• Chatterjee Arnab K

Classifications

• C12Y207/11001

  Non-specific serine/threonine protein kinase (2.7.11.1), i.e. casein kinase or checkpoint kinase · CPC title

• A61K31/4709

  Non-condensed quinolines and containing further heterocyclic rings · CPC title

• A61K31/47

  Quinolines; Isoquinolines · CPC title

• A61K31/517

  ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine · CPC title

• C12N9/12

  transferring phosphorus containing groups, e.g. kinases (2.7) · CPC title