Substituted 1,3-thiazoles as synthetic intermediates for preparation of Raf kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9556177-B2
Application number	US-201414444007-A
Country	US
Kind code	B2
Filing date	Jul 28, 2014
Priority date	Jun 29, 2007
Publication date	Jan 31, 2017
Grant date	Jan 31, 2017

Abstract

The present disclosure provides compounds having Formula II-vi-a:

wherein Cy 1 , Cy 2 , and A − are defined as set forth in the specification. These compounds are synthetic intermediates used to prepare inhibitors of Raf protein kinase.

First claim

We claim:

1. A compound of formula II-vi-a:

wherein:
A − is a chiral anion of a chiral acid selected from the group consisting of camphorsulfonic acid (−), tartaric acid (+), malic acid (−), N-acetyl-L-leucine (−), ditoluoyl-L-tartaric acid (−), deoxycholic acid (+), quinic acid (−), camphoric acid (+), tert-butoxycarbonyl-alanine (−), tartaric acid (−), ditoluoyl-D-tartaric acid (+), camphorsulfonic acid (+), dibenzoyl-D-tartaric acid (+), L-citramalic (+), 5-acetyl mandelic acid (+), tert-butoxycarbonyl-isoleucine (+), (S)-mandelic acid, and (R)-mandelic acid;
Cy 1 is

and
Cy 2 is an unsubstituted or substituted 5-10 membered saturated, partially unsaturated, or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms, independently selected from the group consisting of nitrogen, oxygen, and sulfur, wherein the substituents are selected from the group consisting of Cl, F, CF 3 and C 1-4 alkyl.

2. The compound of claim 1 , wherein the chiral acid is (S)-mandelic acid or (R)-mandelic acid mandelic acid.

3. The compound of claim 2 , wherein the chiral acid is (S)-mandelic acid.

4. The compound of claim 1 , wherein the chiral acid is ditoluoyl-D-tartaric acid (+).

5. The compound of claim 1 , wherein the chiral acid is ditoluoyl-L-tartaric acid (−).

6. The compound of claim 1 , wherein Cy 2 is an unsubstituted or substituted 6 membered aromatic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, wherein the substituents are selected from the group consisting of Cl, F, CF 3 , and C 1-4 alkyl.

7. The compound of claim 1 , wherein Cy 2 is an unsubstituted or substituted pyridinyl, wherein the substituents are selected from the group consisting of Cl, F, CF 3 , and C 1-4 alkyl.

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

9. The compound of claim 3 , wherein the compound is

10. A compound of formula II-vi-b:

wherein:
A − is a chiral anion of a chiral acid selected from the group consisting of camphorsulfonic acid (−), tartaric acid (+), malic acid (−), N-acetyl-L-leucine (−), ditoluoyl-L-tartaric acid (−), deoxycholic acid (+), quinic acid (−), camphoric acid (+), tert-butoxycarbonyl-alanine (−), tartaric acid (−), ditoluoyl-D-tartaric acid (+), camphorsulfonic acid (+), dibenzoyl-D-tartaric acid (+), L-citramalic (+), 5-acetyl mandelic acid (+); and tert-butoxycarbonyl-isoleucine (+), (S)-mandelic acid, and (R)-mandelic acid;
Cy 1 is

and
Cy 2 is an unsubstituted or substituted 5-10 membered saturated, partially unsaturated, or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms, independently selected from the group consisting of nitrogen, oxygen, and sulfur, wherein the substituents are selected from the group consisting of Cl, F, CF 3 and C 1-4 alkyl.

11. The compound of claim 10 , wherein the chiral acid is (S)-mandelic acid or (R)-mandelic acid mandelic acid.

12. The compound of claim 11 , wherein the chiral acid is (S)-mandelic acid.

13. The compound of claim 10 , wherein the chiral acid is ditoluoyl-D-tartaric acid (+).

14. The compound of claim 10 , wherein the chiral acid is ditoluoyl-L-tartaric acid (−).

15. The compound of claim 10 , wherein the compound is:

16. The compound of claim 12 , wherein the compound is

17. A compound of formula II-iv:

wherein
Cy 1 is

and
Cy 2 is an unsubstituted or substituted 5-10 membered saturated, partially unsaturated, or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms, independently selected from the group consisting of nitrogen, oxygen, and sulfur, wherein the substituents are selected from the group consisting of Cl, F, CF 3 and C 1-4 alkyl.

18. The compound of claim 17 , wherein Cy 2 is an unsubstituted or substituted 6 membered aromatic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, wherein the substituents are selected from the group consisting of Cl, F, CF 3 , and C 1-4 alkyl.

Assignees

• Millennium Pharm Inc
• Sunesis Pharmaceuticals Inc

Inventors

• Chen Weirong
• Lane Benjamin
• Peng Hairuo

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title