Pan-TAM inhibitors and Mer/Axl dual inhibitors

Patent metadata

Field	Value
Publication number	US-10526309-B2
Application number	US-201615765168-A
Country	US
Kind code	B2
Filing date	Sep 30, 2016
Priority date	Oct 2, 2015
Publication date	Jan 7, 2020
Grant date	Jan 7, 2020

Abstract

This invention is in the area of improved therapeutic combinations for and methods of treating selected cancers using selected pyrimidine compounds having pan-TAM or Mer/Axl dual receptor tyrosine kinase inhibitory activity in combination with immune checkpoint inhibitors. In one aspect, an improved treatment for select cancers is disclosed using selected pyrimidine compounds described herein in combination with an immune checkpoint inhibitor, for example, a cytotoxic T-lymphocyte-associated protein 4 (CTLA4) inhibitor, a programmed cell death protein 1 (PD1) inhibitor, or a programmed death-ligand 1 (PDL-1) inhibitor, or combination thereof.

First claim

That which is claimed is:

1. A compound of Formula I or II:

wherein:
X is —OH, —NH 2 , —CH 2 OH or —CH 2 NH 2 ;
R 1 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocycloalkenyl;
R 1a is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted alkylheteroaryl, or substituted or unsubstituted alkylcycloalkyl;
R 2 is

R 3 and R 4 are each independently H, halo, lower alkyl or lower alkoxyl;
and
R 6 is substituted or unsubstituted heteroaryl,

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein X is —OH.

3. The compound of claim 1 , wherein R 1 is:

4. The compound of claim 1 , wherein R 6 is

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

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

7. A compound of Formula I:

wherein:
X is —OH, —NH 2 , —CH 2 OH or —CH 2 NH 2 ,
R 1 is:

R 2 is

 or substituted or unsubstituted heteroaryl,
R 3 and R 4 are each independently H, halo, lower alkyl or lower alkoxyl,
R 5 is H, halo, lower alkyl, lower alkoxyl, CN or SO 2 Me, and
R 6 is substituted or unsubstituted heteroaryl,

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 7 , wherein the compound is selected from the group consisting of:

9. The compound of claim 7 , wherein the compound is:

10. A compound of Formula V, or VII or:

wherein:
X is —OH, —NH 2 , —CH 2 OH or —CH 2 NH 2 ;
R 1 is H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocycloalkenyl;
R 2a and R 3a are each independently H, halo, lower alkyl or lower alkoxyl; and
R 4a is substituted or unsubstituted heteroaryl; or

wherein:
X is —OH, —NH 2 , —CH 2 OH or —CH 2 NH 2 ;
R 1c is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted alkylheteroaryl, or substituted or unsubstituted alkylcycloalkyl;
R 2c and R 3c are each independently —H, halo, lower alkyl or lower alkoxyl; and
R 4c is substituted or unsubstituted heteroaryl;

or a pharmaceutically acceptable salt thereof.

11. A composition comprising the compound of claim 1 , in a pharmaceutically acceptable carrier.

12. A method of treating cancer in a subject in need thereof comprising administering an effective amount of the compound of claim 1 .

13. The method of claim 12 further comprising administering to the subject a therapeutically effective amount of a Toll-like receptor (TLR) agonist.

14. A method of inhibiting an Axl and Mer kinase in a subject in need thereof comprising administering an effective amount of the compound of claim 1 .

15. A method of treating a cancer in a subject comprising administering an effective amount of the compound of claim 1 in a combination or alternation schedule with an immune checkpoint inhibitor.

16. The method of claim 15 , wherein the immune checkpoint inhibitor is a cytotoxic T-lymphocyte-associated protein 4 (CTLA4) inhibitor, a programmed cell death protein 1 (PD1) inhibitor, or a programmed death-ligand 1 (PDL-1) inhibitor.

17. The method of claim 12 , wherein the cancer is colon cancer, prostate cancer, non-small cell lung cancer, breast cancer, or melanoma.

Assignees

• Univ North Carolina Chapel Hill

Inventors

• Wang Xiaodong
• Zhang Dehui
• Kireev Dmitri
• Earp Iii Henry Shelton

Classifications

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• C07D401/12

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

• C07D401/04 Primary

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