Benzimidazole compounds as HDAC6 inhibitors
Inventors
Piscopio, Anthony D. • Zhang, Gan • Hunt, Kevin
Assignees
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Publication Number
US-11339150-B2
Publication Date
2022-05-24
Expiration Date
Abstract
Novel compounds of Formula I are described, where the compounds are selective HDAC6 inhibitors suitable for treatment of diseases associated with HDAC6, where X, Y, Z, A1, A2, Q1 and Q2 are as described.
Core Innovation
The invention relates to benzimidazole-based compounds defined as Formula I or Formula II and includes pharmaceutically acceptable salts. The compounds include a difluoromethyl-1,3,4-oxadiazole linked to a pyrimidin-2-yl unit, with variable substituents at the benzimidazole core and additional allowed substituent classes, together with ring-formation embodiments in which substituents can be taken together with attached atoms to form 5-10-membered heterocycloalkyl or heteroaryl rings.
The compounds are presented as selective HDAC6 inhibitors for treating HDAC6-associated diseases. The description states therapeutic use via administration of Formula I or Formula II compounds, including use in pharmaceutical compositions, to modulate HDAC6 activity and to address diseases linked to HDAC6.
The description includes representative compound series and specific example compounds, together with associated intermediates and analytical characterization including LCMS and 1H NMR. It also reports selectivity, cellular tubulin deacetylation inhibition, and pharmacokinetic evaluation for selected examples.
Claims Coverage
The consolidated claim coverage includes a broad Formula I chemical space defined by multiple substituent variables and optional ring-formation constraints, together with a separate selection of specific substituted benzimidazole derivatives containing a difluoromethyl-1,3,4-oxadiazole-pyrimidinyl motif. The claim set also includes therapeutic and composition claims tied to HDAC6 activity and an anti-cancer agent.
Formula I benzimidazole compound architecture
A compound of Formula I or a pharmaceutically acceptable salt defined by X, Q1, Q2, Y, Z, A1, A2, R1-R7, and linker length parameter n, with specified substituent classes and substitution limits.
Ring-formation constraints
Y with A1, Z with A2, or Z with A1 can be taken together with attached atoms to form 5-10-membered heterocycloalkyl or heteroaryl rings.
Selected difluoromethyl-1,3,4-oxadiazole-pyrimidinyl benzimidazole derivatives
A compound selected from a defined group consisting of substituted benzimidazole derivatives containing a difluoromethyl-1,3,4-oxadiazol-2-yl pyrimidin-2-yl unit, including functional-group variants and pharmaceutically acceptable salts.
HDAC6 activity modulation by administering Formula I compounds
A method for modulating HDAC6 activity in a subject by administering a compound of claim 1 or a pharmaceutically acceptable salt.
Treatment of HDAC6-associated disorders using Formula I compounds
Treating a subject with a disorder or disease associated with HDAC6 by administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt.
Pharmaceutical composition including an anti-cancer agent
A pharmaceutical composition that further includes an anti-cancer agent.
Overall, the claims cover a variable-substituent benzimidazole scaffold under Formula I and a selected group of specific difluoromethyl-1,3,4-oxadiazole-pyrimidinyl benzimidazole compounds, with additional claims directed to HDAC6 modulation, HDAC6-associated disorders, and a pharmaceutical composition including an anti-cancer agent.
Stated Advantages
Compounds are described as selective HDAC6 inhibitors.
More than 90% HDAC6 inhibition at 10 uM is reported for Example 1.
Low inhibition for HDAC1/2/3 is reported alongside HDAC6 selectivity.
Cellular tubulin deacetylation inhibition is reported.
Pharmacokinetic parameters Cmax, AUClast, and T1/2 are reported in male CD1 mice following IV and PO dosing.
Documented Applications
Treating HDAC6-associated diseases by administration of a compound of Formula I or Formula II and related pharmaceutical compositions.
Modulating HDAC6 activity in a subject by administering a compound of claim 1 or a pharmaceutically acceptable salt.
Treating a subject with a disorder or disease associated with HDAC6 by administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt.
Use in diseases linked to HDAC6 including cancers, peripheral neuropathy, chemotherapy-induced peripheral neuropathy, and neurodegenerative diseases.
A pharmaceutical composition that further includes an anti-cancer agent.
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