Isoxazole hydroxamic acids as histone deacetylase 6 inhibitors
AssigneesThe George Washington University a Congressionally Chartered Not-for-Profit Corporation, The Board of Trustees of the University of Illinois
InventorsAlejandro Villagra, Alan P. Kozikowski, Sida Shen
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Abstract
The present disclosure provides compounds represented by Formula I: and pharmaceutically acceptable salts, solvates, e.g., hydrates, and prodrugs thereof, wherein X and n are as defined as set forth in the specification. The present disclosure also provides compounds of Formula I for use to treat diseases and conditions, e.g., cancer, wherein inhibition of HDAC provides a benefit.
Claims19
A method of increasing efficacy of or reducing side-effects of a cancer treatment in a subject, said method comprising:
- administering a therapeutically effective amount of an HDAC6 inhibitor to a subject in need of a cancer treatment, thereby increasing efficacy of or reducing side-effects of said subject to the cancer treatment,
- wherein the cancer treatment comprises a radiotherapy, a chemotherapy, or a combination thereof, and
- wherein said HDAC6 inhibitor is a compound of the formula:
- or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
- X is selected from the group consisting of:
- R1 is selected from the group consisting of hydrogen and C1-4 alkyl;
- R2 is selected from the group consisting of optionally substituted C6-C14 aryl and aralkyl;
- R3 is selected from the group consisting of optionally substituted C6-C14 aryl, optionally substituted 5- to 14-membered heteroaryl, and —C(═O)NRdRe;
- R4a, R4b, R4e and R4f are independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, —NRaRb, —C(═O)NRaRb, —C(═O)Rc, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, and haloalkoxy;
- R4c and R4d are independently selected from the group consisting of hydrogen and C1-4 alkyl;
- or
- R4c and R4d taken together form a —C(═O)—with the carbon atom to which they are attached;
- R5a, R5b, R5c, and R5d are independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, —NRaRb, —C(═O)NRaRb, —C(═O)Rc, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, and haloalkoxy;
- Z is selected from the group consisting of —O—, —N(R8)—, and —C(═O)—;
- or
- Z is absent;
- R8 is selected from the group consisting of hydrogen, C1-4 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted C6-C14 aryl, aralkyl, optionally substituted 5- to 14-membered heteroaryl, and heteroaralkyl;
- m is 0, 1, or 2;
- n is 1, 2, 3, 4, 5, or 6;
- represents a single or double bond;
- Ra, Rb, Rd, and Re are independently selected from the group consisting of hydrogen, C1-6 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted C6-C14 aryl, optionally substituted 5- to 14-membered heteroaryl;
- or
- Ra and Rb taken together with the nitrogen atom to which they are attached form an optionally substituted 3- to 12-membered heterocyclo;
- or
- Rd and Re taken together with the nitrogen atom to which they are attached form an optionally substituted 3- to 12-membered heterocyclo;
- and
- Rc is C1-4 alkyl,
- with the proviso that when Z is absent, R3 is a bicyclic or tricyclic C10-14 aryl, a bicyclic or tricyclic 9- to 14-membered heteroaryl, or —C(═O)NRdRe.
Dependencies are inferred from the claim text.