# US 9,751,832 B2 · Selective histone deactylase 6 inhibitors

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- Number: US 9,751,832 B2
- Document ID: US9751832B2
- Status: Granted
- Kind: B2
- Application number: 14/907,321
- Filed: 2014-07-30
- Published: 2016-06-30
- Granted: 2017-09-05
- Earliest claimed: 2013-07-30
- Assignees: H. Lee Moffitt Cancer Center and Research Institute, Inc.; The Board of Trustees of the University of Illinois
- Applicants: H. Lee Moffitt Cancer Center and Research Institute, Inc.; Board of Trustees of the University of Illinois
- Inventors: Eduardo M. Sotomayor; Joel A. Bergman; Alan P. Kozikowski; Alejandro V. Villagra; Karrune V. Woan
- Web page: https://patentgrep.com/patent/US9751832B2

## CPC

- C07C 275/34: having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- A61K 31/17: having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine (isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64)
- A61K 31/185: Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids (hydroxamic acids A61K31/16; peroxy acids A61K31/327)
- A61K 31/4045: Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
- A61K 31/416: condensed with carbocyclic ring systems, e.g. indazole
- A61K 31/42: Oxazoles
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/505: Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07C 275/28: having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C 275/40: being further substituted by nitrogen atoms not being part of nitro or nitroso groups
- C07D 209/14: Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D 213/75: Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
- C07D 231/56: Benzopyrazoles; Hydrogenated benzopyrazoles
- C07D 233/26: Radicals substituted by carbon atoms having three bonds to hetero atoms
- C07D 233/74: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
- C07D 233/78: Radicals substituted by oxygen atoms
- C07D 239/42: One nitrogen atom (nitro radicals C07D239/30)
- C07D 261/14: Nitrogen atoms
- C07D 295/13: to an acyclic saturated chain
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Disclosed are selective histone deactylase inhibitors (HDACi) that having Formula I. Specifically, the disclosed subject matter relates to compounds having activity as selective HDAC6 inhibitors, methods of making and using the compounds, and compositions comprising the compounds. In still further aspects, the disclosed subject matter relates to methods for treating oncological disorders in a patient. Methods of making and using these inhibitors for the treatment of cancer, in particular melanoma are also disclosed.

## Claims

### Claim 1

A compound having Formula I:
wherein
A is aryl, heteroaryl, or C1-C8 alkyl, any of which is optionally substituted with one or more groups chosen from acetyl, C1-C5 alkyl, amino, —NR6R7, —C(O)NR6R7, C1-C4 alkoxy, C1-C4 alkylhydroxy, C5-C6 cycloalkyl, C5-C6 heterocycloalkyl, aryl, heteroaryl, halo, hydroxy, thiol, cyano, or nitro; and
R1 is hydrogen and R2 is C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkynyl, C1-C8 haloalkyl, C5-C6 cycloalkyl, C5-C6 heterocycloalkyl, C1-C3 alkylaryl, aryl, C1-C3 alkylheteroaryl, or heteroaryl, any of which is optionally substituted with acetyl, C1-C5 alkyl, amino, —NR6R7, —C(O)NR6R7, C1-C4 alkoxy, C1-C4 alkylhydroxy, C5-C6 cycloalkyl, C5-C6 heterocycloalkyl, aryl, heteroaryl, carbonyl, halo, hydroxy, thiol, cyano, or nitro; and
R6 and R7 are independently H, C1-C4 alkyl, or are joined such that together they form an alkylene bridge comprising 4 or 5 atoms so that a 5 or 6-membered ring is formed with the nitrogen;
or a pharmaceutically acceptable salt or hydrate thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein A is phenyl, pyridyl, oxazolidyl, pyrimidyl, pyrimidinyl, or 1H-indazolyl, optionally substituted with C1-C5 alkyl, amino, alkoxy, alkylhydroxy, halo, hydroxy, or thiol.

### Claim 3 (depends on 1)

The compound of claim 1, wherein A is pyrimidinyl or 1H-indazolyl substituted with C1-C5 alkyl, C1-C4 alkoxyl, or halo.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R2 is C1-C8 alkyl, C5-C6 cycloalkyl, C5-C6 heterocycloalkyl, aryl, or heteroaryl, any of which is optionally substituted with C1-C5 alkyl, amino, —NR6R7, C1-C4 alkoxy, C1-C4 alkylhydroxy, carbonyl, hydroxy, thiol, or cyano.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R2 is C1-C5 alkyl, or C1-C5 alkyl substituted with a methoxy, amino, —NR6R7, alkylhydroxy, carbonyl, hydroxy, cyano.

### Claim 6 (depends on 1)

The compound of claim 1, wherein R2 is C1-C4 alkyl.

### Claim 7 (depends on 1)

The compound of claim 1, wherein the compound is chosen from: