# US 9,872,862 B2 · Salt form of a human histone methyltransferase EZH2 inhibitor

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- Number: US 9,872,862 B2
- Document ID: US9872862B2
- Status: Granted
- Kind: B2
- Application number: 15/199,522
- Filed: 2016-06-30
- Published: 2017-05-25
- Granted: 2018-01-23
- Earliest claimed: 2012-04-13
- Assignees: Epizyme, Inc.; Eisai R&D Management Co., Ltd.
- Applicants: Epizyme, Inc.; Eisai R&D Management Co., Ltd.
- Inventors: Kevin Wayne Kuntz; Kuan-Chun Huang; Hyeong Wook Choi; Kristen Sanders; Steven Mathieu; Arani Chanda; Frances Fang
- Web page: https://patentgrep.com/patent/US9872862B2

## CPC

- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61P 35/00: Antineoplastic agents
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Provided herein is N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl (tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxamide hydrobromide. Also provided herein is a particular polymorph form of this compound.

## Claims

### Claim 1

A method of treating a cell proliferative disorder of the lung, comprising administering to a subject in need thereof a therapeutically effective amount of a polymorph of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxamide hydrobromide, wherein the polymorph exhibits an X-ray powder diffraction pattern having one or more characteristic peaks expressed in degrees 2-theta selected from peaks at about 3.9+/−0.3 degrees, about 17.5+/−0.3 degrees, and about 22.0+/−0.3 degrees 2-theta.

### Claim 2 (depends on 1)

The method of claim 1, wherein said polymorph is substantially free of impurities.

### Claim 3 (depends on 1)

The method of claim 1, wherein said polymorph is substantially free of amorphous N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxamide hydrobromide.

### Claim 4 (depends on 1)

The method of claim 1, wherein said polymorph exhibits an X-ray powder diffraction pattern having one or more characteristic peaks expressed in degrees 2-theta selected from peaks at about 3.9+/−0.3 degrees, about 14.3+/−0.3 degrees, about 18.7+/−0.3 degrees, about 23.3+/−0.3 degrees, and about 23.6+/−0.3 degrees 2-theta.

### Claim 5 (depends on 1)

The method of claim 1, wherein said polymorph exhibits an X-ray powder diffraction pattern having at least 5 characteristic peaks expressed in degrees 2-theta at about 3.9+/−0.3 degrees, 10.1+/−0.3 degrees, 14.3+/−0.3 degrees, 17.5+/−0.3 degrees, 18.7+/−0.3 degrees, 20.6+/−0.3 degrees, 20.9+/−0.3 degrees, 21.8+/−0.3 degrees, 22.0+/−0.3 degrees, 23.3+/−0.3 degrees and 23.6+/−0.3 degrees 2-theta.

### Claim 6 (depends on 1)

The method of claim 1, wherein said polymorph exhibits an X-ray powder diffraction pattern having at least 6 characteristic peaks expressed in degrees 2-theta selected from peaks at about 3.9+/−0.3 degrees, 10.1+/−0.3 degrees, 14.3+/−0.3 degrees, 17.5+/−0.3 degrees, 18.7+/−0.3 degrees, 20.6+/−0.3 degrees, 20.9+/−0.3 degrees, 21.8+/−0.3 degrees, 22.0+/−0.3 degrees, 23.3+/−0.3 degrees and 23.6+/−0.3 degrees 2-theta.

### Claim 7 (depends on 1)

The method of claim 1, wherein said polymorph exhibits an X-ray powder diffraction pattern substantially in accordance with FIG. 1.

### Claim 8 (depends on 1)

The method of claim 1, wherein said polymorph exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at 3.9 degrees, 10.1 degrees, 14.3 degrees, 17.5 degrees, 18.7 degrees, 20.6 degrees, 20.9 degrees, 21.8 degrees, 22.0 degrees, 23.3 degrees and 23.6 degrees 2-theta.

### Claim 9 (depends on 1)

The method of claim 1, wherein said polymorph exhibits a differential scanning calorimetry thermogram having a characteristic peak expressed in units of ° C. at a temperature of 255+/−5° C.

### Claim 10 (depends on 1)

The method of claim 1, wherein said polymorph exhibits a differential scanning calorimetry thermogram substantially in accordance with FIG. 3.

### Claim 11 (depends on 1)

The method of claim 1, wherein said cell proliferative disorder of the lung is selected from lung cancer, a precancer or precancerous condition of the lung, benign growths or lesions of the lung, malignant growths or lesions of the lung, hyperplasia of the lung, metaplasia of the lung, and dysplasia of the lung.

### Claim 12 (depends on 11)

The method of claim 11, wherein said lung cancer is selected from malignant lung neoplasms, carcinoma in situ, typical carcinoid tumors, atypical carcinoid tumors, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous cell carcinoma, adenocarcinoma, small cell carcinoma, large cell carcinoma, adenosquamous cell carcinoma, mesothelioma, scar carcinoma, bronchioalveolar carcinoma, giant cell carcinoma, spindle cell carcinoma, large cell neuroendocrine carcinoma, and lung neoplasms having histologic and ultrastructural heterogeneity.

### Claim 13 (depends on 12)

The method of claim 12, wherein said lung cancer is non-small cell lung cancer (NSCLC).

### Claim 14 (depends on 11)

The method of claim 11, wherein said metaplasia of the lung is selected from replacement of columnar epithelium with stratified squamous epithelium, squamous metaplasia, and benign reactive mesothelial metaplasia.

### Claim 15 (depends on 11)

The method of claim 11, wherein said dysplasia of the lung is mucosal dysplasia.

### Claim 16 (depends on 11)

The method of claim 11, wherein said hyperplasia of the lung is asbestos-induced hyperplasia.

### Claim 17 (depends on 1)

The method of claim 1, wherein said subject in need thereof is a subject with a prior lung disease selected from chronic interstitial lung disease, necrotizing pulmonary disease, scleroderma, rheumatoid disease, sarcoidosis, interstitial pneumonitis, tuberculosis, repeated pneumonias, idiopathic pulmonary fibrosis, granulomata, asbestosis, fibrosing alveolitis, and Hodgkin's disease.