Small molecule modulators of pantothenate kinases

Patent metadata

Field	Value
Publication number	US-10899734-B2
Application number	US-201716307473-A
Country	US
Kind code	B2
Filing date	Jun 23, 2017
Priority date	Jun 23, 2016
Publication date	Jan 26, 2021
Grant date	Jan 26, 2021

Abstract

The present disclosure relates to chemical compounds that modulate pantothenate kinase (PanK) activity for the treatment of metabolic disorders (such as diabetes mellitus type II), neurologic disorders (such as pantothenate kinase-associated neurodegeneration), pharmaceutical compositions containing such compounds, and their use in treatment. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

First claim

What is claimed is:

1. A compound having a structure represented by a formula:

wherein A is CH 2 ;
wherein Q 1 is CH; and wherein R 2 is selected from —SCH 3 , C1-C8 acyclic alkyl, C2-C8 acyclic alkenyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxyhaloalkyl, cyclopropyl, cyclobutyl, and oxetane, wherein the cyclopropyl, cyclobutyl, and oxetane are optionally substituted with 1, 2, or 3 groups independently selected from —OH, C1-C4 alkyl, and C1-C4 alkoxy; or
wherein Q 1 is N; and R 2 is selected from halogen, —SCH 3 , C1-C8 acyclic alkyl, C2-C8 acyclic alkenyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxyhaloalkyl, cyclopropyl, cyclobutyl, and oxetane, wherein the cyclopropyl, cyclobutyl, and oxetane are optionally substituted with 1, 2, or 3 groups independently selected from —OH, C1-C4 alkyl, and C1-C4 alkoxy;
wherein Q 2 is a structure selected from:

wherein each of R 3a and R 3b is independently selected from hydrogen, halogen, —OH, C1-C4 alkoxy, and C1-C4 alkyl; and
wherein R 4 is halogen or CN,
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein Q 1 is CH and R 2 is selected from C1-C8 acyclic alkyl, C2-C8 acyclic alkenyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, and cyclopropyl; or wherein Q 1 is N and R 2 is selected from halogen, C1-C8 acyclic alkyl, C2-C8 acyclic alkenyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, and cyclopropyl; and wherein Q 2 is a structure selected from:

3. The compound of claim 1 , wherein Q 2 is a structure selected from:

4. The compound of claim 1 , wherein Q 2 is a structure selected from:

5. The compound of claim 1 , wherein the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

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

8. The compound of claim 1 , wherein the compound is:

9. A method of treating a disorder associated with pantothenate kinase activity in a subject, the method comprising administering to the subject an effective amount of at least one compound having a structure represented by a formula:

or a pharmaceutically acceptable salt thereof,
wherein A is CH 2 ;
wherein Q 1 is CH; and wherein R 2 is selected from —SCH 3 , C1-C8 acyclic alkyl, C2-C8 acyclic alkenyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxyhaloalkyl, cyclopropyl, cyclobutyl, and oxetane, wherein the cyclopropyl, cyclobutyl, and oxetane are optionally substituted with 1, 2, or 3 groups independently selected from —OH, C1-C4 alkyl, and C1-C4 alkoxy; or
wherein Q 1 is N; and R 2 is selected from halogen, —SCH 3 , C1-C8 acyclic alkyl, C2-C8 acyclic alkenyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxyhaloalkyl, cyclopropyl, cyclobutyl, and oxetane, wherein the cyclopropyl, cyclobutyl, and oxetane are optionally substituted with 1, 2, or 3 groups independently selected from —OH, C1-C4 alkyl, and C1-C4 alkoxy;
wherein Q 2 is a structure selected from:

wherein each of R 3a and R 3b is independently selected from hydrogen, halogen, —OH, C1-C4 alkoxy, and C1-C4 alkyl;
wherein R 4 is halogen or CN; and
wherein the disorder is hyperglycemia, neurodegeneration, or diabetes, wherein hyperglycemia is caused by misregulated and/or elevated coenzyme A; and neurodegeneration is caused by a deficiency of pantothenate kinase or coenzyme A.

10. The method of claim 9 , wherein the neurodegeneration is pantothenate kinase-associated neurodegeneration (PKAN).

11. The compound of claim 1 , wherein Q 1 is CH.

12. The compound of claim 1 , wherein R 2 is cyclopropyl.

13. The compound of claim 1 , wherein each of R 3a and R 3b is hydrogen.

14. The compound of claim 1 , wherein Q 2 is a structure:

15. The compound of claim 1 , wherein the compound is:

16. The method of claim 9 , wherein the compound is:

Assignees

• St Jude Childrens Res Hospital
• St Jude Childrens Res Hospital Inc

Inventors

• Sharma Lalit Kumar
• Lee Richard E
• Rock Charles O
• Jackowski Suzanne
• Yun Mi Kyung
• Subramanian Chitra
• Liu Jiuyu

Classifications

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D403/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D401/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/501

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title