Substituted 1,3-thiazoles as synthetic intermediates for preparation of Raf kinase inhibitors
View Patent ↗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.
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.