Pyridone and aza-pyridone compounds and methods of use
Pyridone and aza-pyridone compounds of Formula I are provided, including stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, useful for inhibiting Btk kinase, and for treating immune disorders such as inflammation mediated by Btk kinase. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, and treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
1. A process of preparing a compound of formula 230a having the structure of
or a pharmaceutical salt or isomer thereof,
comprising reacting 2,6-dibromo-4-fluorobenzylacetate and a compound of formula of 167e having the structure of
to form the compound of formula 189a having the structure of
and reacting 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) with a compound of formula 189a to form the compound of formula 230a.
2. The process of claim 1 , wherein the reaction is carried out in the presence of potassium acetate, [bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with CH 2 Cl 2 (PdCl 2 dppf:CH 2 Cl 2 ), or 1,4-dioxane.
3. The process of claim 1 , wherein the reaction is carried out in the presence of cesium carbonate, 1,4-dioxane, Xantphos, or tris(dibenzylideneacetone)dipalladium.
4. A process of preparing a compound having formula of 167e having the structure of
or a pharmaceutical salt or isomer thereof,
comprising reacting sodium ethoxide with a compound of formula 167d having the structure of
to form the compound of formula 167e.
5. The process of claim 4 , further comprising reacting hydrogen and a compound of formula 167c having the structure of
to form the compound of formula 167d having the structure of
6. The process of claim 5 , further comprising reacting bromoacetonitrile and a compound of formula 167b having the structure of
to form the compound of formula 167c having the structure of
7. The process of claim 6 , further comprising reacting sodium azide and a compound of formula 167a having the structure of
to form the compound of formula 167b having the structure of
8. The process of claim 7 , further comprising reacting 2-chloro-4,4-dimethylcyclopent-1-enecarbaldehyde and ethoxycarbonylmethylene triphenylphosphorane to form the compound of formula 167a having the structure of
9. A compound having the structure of
10. The compound of claim 9 , wherein the compound is
11. The compound of claim 9 , wherein the compound is
12. The compound of claim 9 , wherein the compound is
13. The compound of claim 9 , wherein the compound is
14. A compound obtained by the process of claim 1 .
15. A compound obtained by the process of claim 4 .
16. A compound obtained by the process of claim 7 .