HDAC8 inhibitors for treating cancer

• US 10,308,596 B2
• Filed: 02/11/2016
• Issued: 06/04/2019
• Est. Priority Date: 08/20/2013
• Status: Active Grant

• Current Assignee: City of Hope, Academia Sinica (Government of The Republic of China), Taipei Medical University WAN Fan Hospital (Government of The Republic of China)
• Original Assignee: City of Hope, Academia Sinica (Government of The Republic of China), Taipei Medical University WAN Fan Hospital (Government of The Republic of China)
• Inventors: Kuo, Ya-Huei, Huang, Wei-Jan, Chang, Chung-I
• Primary Examiner(s): Padmanabhan, Sreenivasan
• Assistant Examiner(s): Karol, Jody L
• Application Number:
  US15/042,012
• Publication Number:
  US 20160237027A1
• Time in Patent Office: 1,209 Days
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 259/06 having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07D 209/08 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 209/18 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 213/56 Amides
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 215/14 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 217/16 substituted by oxygen atoms
• CPC Class Codes: C07D 217/20 with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
• CPC Class Codes: C07D 307/91 Dibenzofurans; Hydrogenated dibenzofurans
• CPC Class Codes: C07D 317/60 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 333/24 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

Provided herein, inter alia, are compound and methods of treating cancer by inhibiting HDAC8.

Claims

1. A compound having the formula (I):

2. The compound of claim 1, wherein R¹ is substituted or unsubstituted C₁-C₄ alkoxy and R² is a substituted or unsubstituted C₄-C₆ aryl.

3. The compound of claim 2, wherein R¹ is unsubstituted C₁-C₂ alkoxy and R² is unsubstituted C6 aryl.

4. The compound of claim 1, wherein the compound has formula (II):

6. A method of inhibiting HDAC8 mediated deacetylation of p53, the method comprising contacting HDAC8 with the compound of claim 1 in the presence of p53, thereby inhibiting HDAC8 deacetylation of p53.

7. A method of activating p53 in vivo, the method comprising contacting a cell with the compound of claim 1 in the presence of HDAC8;

wherein the cell is an AML cell.

8. The method of claim 7, wherein the AML cell is an AML stem cell.

9. The compound of claim 1, wherein:

R¹ is substituted or unsubstituted 2 to 20 membered heteroalkyl, substituted or unsubstituted C₃-C₇ cycloalkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl, substituted or unsubstituted C₆-C₇ aryl, or substituted or unsubstituted 3 to 7 membered heteroaryl; and

R² is substituted or unsubstituted C₁-C₂₀ alkyl, substituted or unsubstituted 2 to 20 membered heteroalkyl, substituted or unsubstituted C₃-C₇ cycloalkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl, substituted or unsubstituted C₆-C₇ aryl, or substituted or unsubstituted 3 to 7 membered heteroaryl.

5. A compound selected from the group consisting of: