# US 9,434,686 B2 · Deacetylase inhibitors and uses thereof

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- Number: US 9,434,686 B2
- Document ID: US9434686B2
- Status: Granted
- Kind: B2
- Application number: 13/861,519
- Filed: 2013-04-12
- Published: 2013-12-12
- Granted: 2016-09-06
- Earliest claimed: 2008-07-23
- Assignees: President and Fellows of Harvard College; Dana-Farber Cancer Institute, Inc.
- Applicants: President and Fellows of Harvard College; Dana-Farber Cancer Institute, Inc.
- Inventors: Weiping Tang; James E. Bradner; Stuart L. Schreiber
- Web page: https://patentgrep.com/patent/US9434686B2

## CPC

- C07C 259/06: having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
- A61P 17/00: Drugs for dermatological disorders
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 251/86: having doubly-bound carbon atoms of hydrazone groups bound to carbon atoms of six-membered aromatic rings
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides novel compounds of formula (I) and pharmaceutical compositions thereof. The inventive compounds are useful as deacetylase inhibitors (e.g., histone deacetylase inhibitors) and may be useful in the treatment of proliferative diseases such as cancer. In particular, the inventive compounds are HDAC6 inhibitors. The invention also provide synthetic methods for preparing the inventive compounds.

## Claims

### Claim 1

A method of treating a histone deacetylase-associated cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I):
or a pharmaceutically acceptable form thereof;
wherein:
n is an integer between 1 and 10, inclusive;
m is an integer between 0 and 5, inclusive;
k is an integer between 0 and 5, inclusive;
p is an integer between 0 and 5, inclusive;
R2 is an optionally substituted acyl moiety;
R3 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —ORC; —C(═O)RC; —CO2RC; —CN; —SCN; —SRC; —SORC; —SO2RC; —NO2; —N(RC)2; —NHC(═O)RC; or —C(RC)3; wherein each occurrence of RC is independently hydrogen; a protecting group; an aliphatic moiety; a heteroaliphatic moiety; an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino; alkylamino; dialkylamino; heteroaryloxy; or a heteroarylthio moiety;
R4 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —ORD; —C(═O)RD; —CO2RD; —CN; —SCN; —SRD; —SORD; —SO2RD; —NO2; —N(RD)2; —NHC(═O)RD; or —C(RD)3; wherein each occurrence of RD is independently hydrogen; a protecting group; an aliphatic moiety; a heteroaliphatic moiety; an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino; alkylamino; dialkylamino; heteroaryloxy; or a heteroarylthio moiety;
R5 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —ORE; —C(═O)RE; —CO2RE; —CN; —SCN; —SRE; —SORE; —SO2RE; —NO2; —N(RE)2; —NHC(═O)RE; or —C(RE)3; wherein each occurrence of RE is independently hydrogen; a protecting group; an aliphatic moiety; a heteroaliphatic moiety; an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino; alkylamino; dialkylamino; heteroaryloxy; or a heteroarylthio moiety; and
wherein the histone deacetylase-associated cancer is selected from the group consisting of leukemia, multiple myeloma, lymphoma, and skin cancer.

### Claim 2 (depends on 1)

The method of claim 1, wherein n is 4 to 7, inclusive.

### Claim 3 (depends on 2)

The method of claim 2, wherein n is 6.

### Claim 4 (depends on 1)

The method of claim 1, wherein m is 0, 1, or 2.

### Claim 5 (depends on 1)

The method of claim 1, wherein p is 0, 1, or 2.

### Claim 6 (depends on 1)

The method of claim 1, wherein k is 0, 1, or 2.

### Claim 7 (depends on 1)

The method of claim 1, wherein R2 is —C(═O)RB, wherein RB is —OR′ or —N(R″)2, wherein R′ is hydrogen or an optionally substituted alkyl moiety, and R″ is hydrogen, —OH, an optionally substituted aryl moiety, or an optionally substituted heteroaryl moiety.

### Claim 8 (depends on 7)

The method of claim 7, wherein R2 is —CO2H.

### Claim 9 (depends on 7)

The method of claim 7, wherein RB is —OR′; and R′ is an optionally substituted alkyl moiety.

### Claim 10 (depends on 7)

The method of claim 7, wherein RB is —NHR″, and R″ is —OH, an optionally substituted aryl moiety, or an optionally substituted heteroaryl moiety.

### Claim 11 (depends on 10)

The method of claim 10, wherein R″ is —OH.

### Claim 12 (depends on 10)

The method of claim 10, wherein R″ is an optionally substituted aryl moiety.

### Claim 13 (depends on 12)

The method of claim 12, wherein the aryl moiety is of the structure:

### Claim 14 (depends on 1)

The method of claim 1, wherein the compound is selected from the group consisting of:
and pharmaceutically acceptable forms thereof,
wherein n is 4, 5, 6, or 7.

### Claim 15 (depends on 1)

The method of claim 1, wherein the compound is:
or a pharmaceutically acceptable form thereof.

### Claim 16 (depends on 1)

The method according to claim 1, wherein the subject is a mammal.

### Claim 17 (depends on 16)

The method according to claim 16, wherein the subject is human.

### Claim 18 (depends on 1)

The method according to claim 1, wherein the cancer is skin cancer.

### Claim 19 (depends on 1)

The method according to claim 1, wherein the step of administering comprises administering the compound orally or intravenously.

### Claim 20 (depends on 1)

The method according to claim 1, wherein the cancer is leukemia.

### Claim 21 (depends on 1)

The method according to claim 1, wherein the cancer is multiple myeloma.

### Claim 22 (depends on 18)

The method according to claim 18, wherein the skin cancer is malignant melanoma.

### Claim 23 (depends on 1)

The method according to claim 1, wherein the cancer is lymphoma.

### Claim 24 (depends on 23)

The method according to claim 23, wherein the lymphoma is cutaneous T-cell lymphoma.