Small molecule inhibitors of G protein coupled receptor 6 kinases polypeptides

Patent metadata

Field	Value
Publication number	US-9902739-B2
Application number	US-201515305808-A
Country	US
Kind code	B2
Filing date	Apr 21, 2015
Priority date	Apr 21, 2014
Publication date	Feb 27, 2018
Grant date	Feb 27, 2018

Abstract

This document relates to inhibitors of G protein coupled receptor 6 kinase (GRK6) polypeptides as well as methods and materials for using such inhibitors to treat hematological malignancies, inflammation diseases, and autoimmune disorders.

First claim

What is claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof,
wherein:
X is selected from the group consisting of CH and N;
Z is selected from the group consisting of —C(O)OR 1 and

R 1 is selected from the group consisting of H and (C 1 -C 6 )alkyl;
R 2 is selected from the group consisting of: a substituted (C 1 -C 6 )alkyl, a substituted or unsubstituted (C 2 -C 6 )alkenyl, a substituted or unsubstituted (C 2 -C 6 )alkynyl, (C 1 -C 6 )haloalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl;
R 3 and R 4 are independently selected from the group consisting of: H, halo, a substituted (C 1 -C 6 )alkyl, a substituted or unsubstituted (C 2 -C 6 )alkenyl, a substituted or unsubstituted (C 2 -C 6 )alkynyl, (C 1 -C 6 )haloalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted aralkyl, and a substituted or unsubstituted heteroaralkyl;
or R 2 and R 3 or R 3 and R 4 come together to form a substituted or unsubstituted fused cycloalkyl ring, a substituted or unsubstituted fused heterocycloalkyl ring, a substituted or unsubstituted fused aryl ring, or a substituted or unsubstituted fused heteroaryl ring; and
m is an integer from 1 to 2.

2. The compound of claim 1 , wherein R 2 is a substituted or unsubstituted aryl.

3. The compound of claim 1 , wherein R 2 is a substituted or unsubstituted heteroaryl.

4. The compound of claim 1 , wherein:
R 3 is selected from a group consisting of: a substituted or unsubstituted (C 1 -C 6 )alkynyl, halo, and a substituted or unsubstituted aryl; and
R 4 is H.

5. The compound of claim 1 , wherein:
each of R 1 , R 3 , and R 4 is H; and
R 2 is a substituted or unsubstituted heteroaryl.

6. The compound of claim 5 , wherein R 2 is selected from a group consisting of pyridazinyl, pyridyl, carbazolyl, thiopheneyl, benzothiopheneyl, pyrrolyl, indolyl, quinolinyl, furanyl, and benzofuranyl.

7. The compound of claim 1 , wherein:
each of R 1 and R 4 is H;
R 2 is selected from a group consisting of a substituted or unsubstituted aryl and a substituted or unsubstituted heteroaryl; and
R 3 is selected from a group consisting of halo, a substituted (C 1 -C 6 )alkynyl, and a substituted or unsubstituted aryl.

8. The compound of claim 1 , wherein the compound is selected from a group consisting of:

or a pharmaceutically acceptable salt thereof.

9. A compound of Formula II:

or a pharmaceutically acceptable salt thereof,
wherein:
Z is selected from the group consisting of —C(O)OR 1 and

R 1 is selected from the group consisting of H and (C 1 -C 6 )alkyl;
R 2 is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl; and
m is an integer from 1 to 2.

10. The compound of claim 9 , wherein R 2 is a substituted or unsubstituted furanyl, or a substituted or unsubstituted thiopheneyl.

11. The compound of claim 9 , wherein the compound of Formula IIA is selected from a group consisting of:

or a pharmaceutically acceptable salt thereof.

12. A compound of Formula III:

or a pharmaceutically acceptable salt thereof,
wherein:
X is selected from the group consisting of CH and N;
R 1 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; and
m is an integer from 1 to 2.

13. The compound of claim 12 , wherein R 1 is:

wherein:
each of R 2 and R 3 are independently selected from the group consisting of: H, halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, OR 4 , NO 2 , NR 4 R 5 , CN, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl; and
each of R 4 and R 5 are independently selected from the group consisting of H, (C 1 -C 6 )alkyl, and (C 1 -C 6 )haloalkyl.

14. The compound of claim 12 , wherein R 1 is:

wherein:
R 8 is selected from the group consisting of: H, halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, OR 4b , NO 2 , NR 4b R 5b , CN, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl.

15. The compound of claim 14 , wherein R 8 is:

wherein:
each of R 10 , R 11 , and R 12 are independently selected from a group consisting of: H, halo,
(C 1- C 6 )alkyl, (C 1- C 6 )haloalkyl, CN, NO 2 , OR 13 , NR 14 R 15 , C(O)R 16 , C(O)OR 16 , —NR 17 S(O) 2 R 18 , —S(O) 2 NR 19 R 20 , —NR 17 S(O)R 18 , —S(O) 2 NR 19 R 20 , —S(O)NR 19 R 20 , —NR 21 C(O)R 22 , a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, and a substituted or unsubstituted heterocycloalkyl; or
two of the groups R 10 , R 11 , and R 12 come together to form a substituted or unsubstituted fused cycloalkyl ring, a substituted or unsubstituted fused heterocycloalkyl ring, a substituted or unsubstituted fused aryl ring, or a substituted or unsubstituted fused heteroaryl ring; and
each of R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , and R 22 are independently sele

Assignees

• Mayo Found Medical Education & Res

Inventors

• Stewart Alexander Keith
• Rich Brian
• Sepetov Nikolai
• Greenhouse Robert
• Plekhov Artem
• Yang Wen
• Tong Zhiwei

Classifications

• C07D495/04 Primary

  Ortho-condensed systems · CPC title

• C07D231/18

  One oxygen or sulfur atom · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D403/12

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

• C07D471/06

  Peri-condensed systems · CPC title