3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
The present disclosure relates to inhibitors of zinc-dependent histone deacetylases (HDACs) useful in the treatment of diseases or disorders associated with an HDAC, e.g., HDAC6, having a Formula I: where R, L, X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , and Y 4 are described herein.
1. A compound:
or a pharmaceutically acceptable salt thereof.
2. A composition, comprising a compound:
or a pharmaceutically acceptable salt thereof.
3. The composition of claim 2 , wherein the composition further comprises an ester:
4. The composition of claim 3 , wherein the composition further comprises an amine:
5. The composition of claim 4 , wherein the composition further comprises an aryl halide:
6. The composition of claim 2 , further comprising at least one compound selected from:
7. A process for preparing a compound:
or a pharmaceutically acceptable salt thereof,
comprising a step of treating an ester:
with hydroxylamine and a first base to form the compound:
8. The process of claim 7 , wherein the process further comprises a step of treating an amine:
with an acyl halide in the presence of a second base to form the ester:
9. The process of claim 8 , wherein the process further comprises a step of cyclizing an aryl halide:
in the presence of a catalytic amount of a metal catalyst to form the amine:
10. The process of claim 9 , wherein the process further comprises a step of treating (S)-2-amino-2-phenylethan-1-ol with a benzylic halide:
to form the aryl halide: