Synthesis of small molecule histone deacetylase 6 degraders, compounds formed thereby, and pharmaceutical compositions containing them
Histone deacetylase (“HDAC”)-selective inhibitors covalently bonded to a linker covalently bonded to an E3 ubiquitin ligase ligand, and salts thereof; pharmaceutical compositions containing them; methods of using the composition to inhibit neoplastic cell growth in mammals, including humans.
1. A compound comprising a histone deacetylase 6 (“HDAC6”)-selective inhibitor covalently bonded to a linker, covalently bonded to an E3 ubiquitin ligase ligand:
wherein:
the HDAC6-selective inhibitor is selected from the group consisting of:
wherein each Z is independently selected from —N— or —(CH)—;
the linker is a C 1 -C 12 linear or branched alkylene, alkenylene, or alkynylene, —O—(CH 2 ) m —, or —NH—(CH 2 ) m , wherein “m” is an integer of from 1 to 12; and
the E3 ubiquitin ligase ligand is selected from:
wherein “p” is an integer of from 1 to 12; and
salts thereof.
2. The compound of claim 1 , wherein the linker is C 1 -C 12 linear or branched alkylene, alkenylene, or alkynylene.
3. The compound of claim 2 , wherein each Z is —N—.
4. The compound of claim 2 , wherein each Z is —(CH)—.
5. The compound of claim 1 , wherein the linker is —O—(CH 2 ) m —.
6. The compound of claim 5 , wherein each Z is —N—.
7. The compound of claim 5 , wherein each Z is —(CH)—.
8. The compound of claim 1 , wherein the linker is —NH—(CH 2 ) m .
9. The compound of claim 8 , wherein each Z is —N—.
10. The compound of claim 8 , wherein each Z is —(CH)—.
11. The compound of claim 1 , wherein the HDAC6-selective inhibitor is:
the linker is —O—(CH 2 ) m —; and
the E3 ubiquitin ligase ligand is:
12. The compound of claim 11 , wherein each Z is —N—.
13. The compound of claim 11 , wherein each Z is —(CH)—.
14. The compound of claim 11 , wherein “p” is 3, 4, or 5.