# US 11,298,354 B2 · Methods of use and pharmaceutical combinations of HDAC inhibitors with BET inhibitors

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- Number: US 11,298,354 B2
- Document ID: US11298354B2
- Status: Granted
- Kind: B2
- Application number: 16/305,567
- Filed: 2017-06-09
- Published: 2020-10-15
- Granted: 2022-04-12
- Earliest claimed: 2016-06-09
- Assignees: Dana-Farber Cancer Institute, Inc.; Acetylon Pharmaceuticals, Inc.
- Applicants: Dana-Farber Cancer Institute, Inc.; Acetylon Pharmaceuticals, Inc.
- Inventors: Kwok-kin Wong; Yan Liu; Dennis O. Adeegbe; Steven Norman Quayle
- Web page: https://patentgrep.com/patent/US11298354B2

## CPC

- A61K 31/505: Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- 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 31/551: having two nitrogen atoms, e.g. dilazep
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The disclosure relates to pharmaceutical combinations comprising an HDAC6 selective inhibitor and a BET inhibitor for the treatment of cancer in a subject in need thereof. Also provided herein are methods for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of an HDAC6 selective inhibitor and a BET inhibitor.

## Claims

### Claim 1

A method for treating lung cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a histone deacetylase 6 (HDAC6) selective inhibitor and a therapeutically effective amount of a bromodomain and extraterminal (BET) inhibitor, wherein the HDAC6 selective inhibitor is a compound of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein,
ring B is aryl or heteroaryl;
R1 is an aryl or heteroaryl, each of which may be optionally substituted by OH, halo, or C1-6-alkyl; and
R is H or C1-6-alkyl.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 1)

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

### Claim 4 (depends on 1)

The method of claim 1, wherein the BET inhibitor is selected from the group consisting of;
N-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamide (ABBV-075),
((S)-7,8-dimethoxy-N,4-dimethyl-1-(4-(4-methylpiperazin-1-yl)phenyl)-4,5-dihydro-3H-benzo[d][1,2]diazepine-3-carboxamide) (BAY1238097),
3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-α,α-dimethyl-5-[(S)-phenyl(tetrahydro-2H-pyran-4-yl)methyl]-5H-pyrido[3,2-b]indole-7-methanol (BMS986158),
N-[6-(3-methanesulfonamido-4-methylphenyl)-3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]carbamate (bromosporine),
2-[2-(3-chloro-4-methoxyphenyl)ethyl]-5-(dimethyl-1,2-oxazol-4-yl)-1-[(2S)-2-(morpholin-4-yl)propyl]-1H-1,3-benzodiazole (CBP30),
(6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetamide (CPI-203),
2-[(4S)-6-(4-chlorophenyl)-1-methyl-4H-[1,2]oxazolo[5,4-d][2]benzazepin-4-yl]acetamide (CPI-0610),
[(2S)-5-(cyclobutyloxy)-3,4-dihydro-2-methyl-6-[1-(4-piperidinyl)-1H-pyrazol-4-yl]-1(2H)-quinolinyl]cyclopropylmethanone (FT-1101),
7-(3,5-dimethyl-1,2-oxazol-4-yl)-8-methoxy-1-[(1R)-1-pyridin-2-ylethyl]-3H-imidazo[4,5-c]quinolin-2-one (GSK2820151),
7,3,5-dimethyl-4-isoxazolyl-1,3-dihydro-8-methoxy-1-[1R-1-(2-pyridinyl)ethyl]-2H-imidazo[4,5-c]quinolin-2-one (I-BET151),
4-[(2S,4R)-1-acetyl-4-[(4-chlorophenyl)amino]-1,2,3,4-tetrahydro-2-methyl-6-quinolinyl]-benzoic acid (I-BET726),
(S)-2-(6-(4-chlorophenyl)-8-methoxy-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (I-BET-762),
(S)-6-(3,5-dimethylisoxazol-4-yl)-3-(pyridin-2-yl)-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-2(1H)-one (INCB054329),
8-(6,7-dihydro-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-2,2,4-trimethyl-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one (INCB057643),
3-(4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpholinoethyl)-1H-benzo[d]imidazol-2-yl)ethyl)phenoxy)-N,N-dimethylpropan-1-amine (ISOX DUAL),
(6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetic acid, 1,1-dimethylethyl ester (JQ1),
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002),
8-phenyl-2-(1-piperazinyl)-4H-1-benzopyran-4-one, dihydrochloride (LY303511),
(E)-4-[2-(2-amino-4-hydroxy-5-methylphenyl)diazenyl]-N-2-pyridinylbenzenesulfonamide (MS436),
4-(4-chlorophenyl)-N-(4-hydroxyphenyl)-2,3,9-trimethyl-, (6S)-6H-Thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetamide (MK8628),
4-bromo-N-(2,3-dihydro-6-methoxy-1,3-dimethyl-2-oxo-1H-benzimidazol-5-yl)-2-methyl-benzenesulfonamide (OF-1),
3-(3,5-dimethyl-4-isoxazolyl)-5-hydroxy-α-phenylbenzenemethanol (OXF BD 02),
2-methoxy-N-(3-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-6-yl)benzenesulfonamide (PFI-1),
(2E)-1-(2-hydroxyphenyl)-3-[(1R,4R)-5-(2-pyridinyl)-2,5-diazabicyclo[2,2,1]hept-2-yl]-2-propen-1-one (PFI-3),
2-methoxy-N-(3-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-6-yl)benzenesulfonamide (PF-6405761),
2-[4-(2-hydroxyethoxy)-3,5-dimethylphenyl]-5,7-dimethoxy-4(3H)-quinazolinone (RVX-208),
(S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide (TEN-010), and
4-acetyl-N-[5-[(diethylamino)sulfonyl]-2-hydroxyphenyl]-3-ethyl-5-methyl-1H-pyrrole-2-carboxamide (XD 14),
or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 4)

The method of claim 4, wherein the BET inhibitor is JQ1:
or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

The method of claim 1, wherein the HDAC6 selective inhibitor or the BET inhibitor are administered at a sub-therapeutic dose.

### Claim 7 (depends on 1)

The method of claim 1, wherein the HDAC6 selective inhibitor induces apoptosis of cancer cells.

### Claim 8 (depends on 1)

The method of claim 1, wherein the lung cancer is non-small cell lung cancer, small cell lung cancer, or lung carcinoid tumor.

### Claim 9 (depends on 1)

The method of claim 1, wherein the HDAC6 selective inhibitor and the BET inhibitor are together formulated as a single formulation or the HDAC6 selective inhibitor and the BET inhibitor are each formulated as separate formulations.

### Claim 10 (depends on 1)

The method of claim 1, wherein the HDAC6 selective inhibitor and the BET inhibitor are administered at substantially the same time or the HDAC6 selective inhibitor and the BET inhibitor are administered at different times.

### Claim 11 (depends on 1)

The method of claim 1, wherein the cancer is resistant or refractory cancer.