# US 10,308,653 B2 · Diazepane derivatives and uses thereof

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- Number: US 10,308,653 B2
- Document ID: US10308653B2
- Status: Granted
- Kind: B2
- Application number: 15/426,708
- Filed: 2017-02-07
- Published: 2017-05-25
- Granted: 2019-06-04
- Earliest claimed: 2014-08-08
- Assignees: Dana-Farber Cancer Institute, Inc.
- Applicants: Dana-Farber Cancer Institute, Inc.
- Inventors: James E. Bradner; Dennis Buckley
- Web page: https://patentgrep.com/patent/US10308653B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/16: Central respiratory analeptics
- A61P 15/16: Masculine contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 31/16: for influenza or rhinoviruses
- A61P 31/18: for HIV
- A61P 31/20: for DNA viruses
- A61P 31/22: for herpes viruses
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 39/02: Antidotes
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present disclosure provides compounds of Formula (I), and pharmaceutically compositions thereof. Compounds of Formula (I) have been found to bind bromodomains and/or bromodomain-containing proteins (e.g., bromo and extra terminal (BET) proteins). Also provided are methods, uses, and kits of the compounds and pharmaceutical compositions for inhibiting the activity (e.g., increased activity) of bromodomains and/or bromodomain-containing proteins and for treating and/or preventing in a subject diseases associated with bromodomains or bromodomain-containing proteins (e.g., proliferative diseases, cardiovascular diseases, viral infections, fibrotic diseases, neurological diseases, metabolic diseases, endocrine diseases, and radiation poisoning). The compounds, pharmaceutical compositions, and kits are also useful for male contraception.

## Claims

### Claim 1

A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
RA is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
RB is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
or RA and RB are joined to form a substituted or unsubstituted, carbocyclic ring, or a substituted or unsubstituted, heterocyclic ring;
RC is hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group;
each instance of RD is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —ORa, —N(Ra)2, —SRa, —CN, —SCN, —C(═NRa)Ra, —C(═NRa)ORa, —C(═NRa)N(Ra)2, —C(═O)Ra, —C(═O)ORa, —C(═O)N(Ra)2, —NO2, —NRaC(═O)Ra, —NRaC(═O)ORa, —NRaC(═O)N(Ra)2, —OC(═O)Ra, —OC(═O)ORa, or —OC(═O)N(Ra)2;
each instance of Ra is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two Ra groups are joined to form a substituted or unsubstituted, heterocyclic ring, or a substituted or unsubstituted, heteroaryl ring;
m is 0, 1, 2, 3, or 4;
X is —O—, —S—, —N(RX1)—, or —C(RX2)2—, wherein RX1 is hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group, and wherein each instance of RX2 is independently hydrogen, halogen, or substituted or unsubstituted C1-6 alkyl;
RE is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —ORa, —N(Ra)2, —SRa, —CN, —SCN, —C(═NRa)Ra, —C(═NRa)ORa, —C(═NRa)N(Ra)2, —C(═O)Ra, —C(═O)ORa, —C(═O)N(Ra)2, —NO2, —NRaC(═O)Ra, —NRaC(═O)ORa, —NRaC(═O)N(Ra)2, —OC(═O)Ra, —OC(═O)ORa, or —OC(═O)N(Ra)2;
RF is hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group;
RG is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted phenyl, or a nitrogen protecting group;
each instance of RH is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —ORa, —N(Ra)2, —SRa, —CN, —SCN, —C(═NRa)Ra, —C(═NRa)ORa, —C(═NRa)N(Ra)2, —C(═O)Ra, —C(═O)ORa, —C(═O)N(Ra)2, —NO2, —NRaC(═O)Ra, —NRaC(═O)ORa, —NRaC(═O)N(Ra)2, —OC(═O)Ra, —OC(═O)ORa, or —OC(═O)N(Ra)2; and
n is 0, 1, 2, 3, or 4.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 1)

The compound of claim 1, wherein RA is hydrogen.

### Claim 4 (depends on 1)

The compound of claim 1, wherein RA is substituted or unsubstituted acyl.

### Claim 5 (depends on 1)

The compound of claim 1, wherein RA is substituted or unsubstituted carbocyclyl or heterocyclyl.

### Claim 6 (depends on 1)

The compound of claim 1, wherein RA is substituted or unsubstituted aryl or heteroaryl.

### Claim 7 (depends on 1)

The compound of claim 1, wherein RA is selected from the group consisting of:

### Claim 8 (depends on 1)

The compound of claim 1, wherein RB is substituted or unsubstituted carbocyclyl or heterocyclyl.

### Claim 9 (depends on 1)

The compound of claim 1, wherein RB is substituted or unsubstituted aryl or heteroaryl.

### Claim 10 (depends on 1)

The compound of claim 1, wherein RB is a moiety selected from the group consisting of:

### Claim 11 (depends on 1)

The compound of claim 1, wherein RA and RB are joined to form a substituted or unsubstituted, carbocyclic or heterocyclic ring.

### Claim 12 (depends on 1)

The compound of claim 1, wherein RA and RB are joined to form a moiety selected from the group consisting of:

### Claim 13 (depends on 1)

The compound of claim 1, wherein X is —O— or —S—.

### Claim 14 (depends on 1)

The compound of claim 1, wherein RF is substituted or unsubstituted, C1-6 alkyl.

### Claim 15 (depends on 1)

The compound of claim 1, wherein RG is substituted or unsubstituted, C1-6 alkyl.

### Claim 16 (depends on 1)

The compound of claim 1, wherein the compound is of formula:
and RA is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 1)

The compound of claim 1, wherein the compound is of formula:
and RA is selected from the group consisting of:
and RB is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 1)

The compound of claim 1, wherein the compound is formula:
and RA and RB are joined to form a moiety selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 1)

The compound of claim 1, wherein RA is a moiety selected from the group consisting of:

### Claim 20 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

### Claim 21 (depends on 1)

A method of treating a disease associated with a bromodomain-containing protein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 22 (depends on 1)

A method of treating a disease associated with a bromodomain in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 23 (depends on 1)

A method of treating a disease associated with aberrant activity of a bromodomain-containing protein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 24 (depends on 1)

A method for male contraception, the method comprising administering to a male subject in need thereof an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.