# US 11,028,100 B2 · Polymorphs and solid forms of (s)-2-((2-((s)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide, and methods of production

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- Number: US 11,028,100 B2
- Document ID: US11028100B2
- Status: Granted
- Kind: B2
- Application number: 16/875,537
- Filed: 2020-05-15
- Published: 2020-12-24
- Granted: 2021-06-08
- Earliest claimed: 2017-04-28
- Assignees: Genentech, Inc.
- Applicants: Genentech, Inc.
- Inventors: Paroma Chakravarty; Chong Han; Sean M. Kelly; Karthik Nagapudi; Scott Savage
- Web page: https://patentgrep.com/patent/US11028100B2

## CPC

- C07D 498/04: Ortho-condensed systems
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- A61K 9/20: Pills, tablets, {discs, rods (A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095)}
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The present invention relates to crystalline polymorph forms of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide (GDC-0077), having the structure, Formula I: or stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, and processes of preparing the polymorph forms.

## Claims

### Claim 1

A crystalline, anhydrate polymorph of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide having the structure:
said polymorph is designated the Form A polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 5.7, 11.4, 17.2, 19.0, 19.7, and 24.4.

### Claim 2

A crystalline, anhydrate polymorph of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide having the structure:
said polymorph is designated the Form A polymorph characterized by e X-ray powder diffraction pattern substantially as shown in FIG. 4.

### Claim 3

A crystalline, anhydrate polymorph of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide having the structure:
said polymorph is designated the Form A polymorph characterized by the X-ray powder diffraction peaks shown in Table 2, and a differential scanning calorimetry DSC shows a melting endotherm at approximately 212 to 215° C.

### Claim 4

A crystalline, anhydrate polymorph of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide having the structure:
said polymorph is designated the Form A polymorph characterized by the 13C SSNMR (solid-state nuclear magnetic resonance) spectra substantially as shown in FIG. 7A, and the 19F SSNMR (solid-state nuclear magnetic resonance) spectra substantially as shown in FIG. 7B.

### Claim 5 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of the crystalline, anhydrate polymorph of claim 1, and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.

### Claim 6 (depends on 5)

The pharmaceutical composition of claim 5 wherein the therapeutically effective amount is from about 1 to about 100 mg.

### Claim 7 (depends on 5)

The pharmaceutical composition of claim 5 wherein the therapeutically, effective amount is from about 3 to about 15 mg.

### Claim 8 (depends on 5)

The pharmaceutical composition of claim 5 wherein the therapeutically effective amount is about 9 mg.

### Claim 9 (depends on 5)

The pharmaceutical composition of claim 5 wherein the crystalline, anhydrate polymorph is milled.

### Claim 10 (depends on 5)

The pharmaceutical composition of claim 5 in the form of a tablet.

### Claim 11 (depends on 10)

The pharmaceutical composition of claim 10 wherein the therapeutically, effective amount is from about 3 to about 15 mg.

### Claim 12 (depends on 10)

The pharmaceutical composition of claim 10 wherein the therapeutically effective amount is about 9 mg.

### Claim 13 (depends on 2)

A pharmaceutical composition comprising a therapeutically effective amount of the crystalline, anhydrate polymorph of claim 2, and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.

### Claim 14 (depends on 13)

The pharmaceutical composition of claim 13 in the form of a tablet.

### Claim 15 (depends on 14)

The pharmaceutical composition of claim 14 wherein the therapeutically effective amount is from about 3 to about 15 mg.

### Claim 16 (depends on 3)

A pharmaceutical composition comprising a therapeutically effective amount of the crystalline, anhydrate polymorph of claim 3, and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.

### Claim 17 (depends on 16)

The pharmaceutical composition of claim 16 in the form of a tablet.

### Claim 18 (depends on 17)

The pharmaceutical composition of claim 17 wherein the therapeutically effective amount is from about 3 to about 15 mg.

### Claim 19 (depends on 4)

A pharmaceutical composition comprising a therapeutically effective amount of the crystalline, anhydrate polymorph of claim 4, and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.

### Claim 20 (depends on 19)

The pharmaceutical composition of claim 19 in the form of a tablet.

### Claim 21 (depends on 20)

The pharmaceutical composition of claim 20 wherein the therapeutically effective amount is from about 3 to about 15 mg.

### Claim 22

A crystalline, anhydrate polymorph of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide having the structure:
said polymorph is designated the Form D polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 7.5, 8.6, 10.8, 16.8, 19.2, and 20.4.

### Claim 23 (depends on 22)

A pharmaceutical composition comprising a therapeutically effective amount of the crystalline, anhydrate polymorph of claim 22, and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.

### Claim 24

A crystalline, trihydrate polymorph of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide having the structure:
said polymorph is designated the Form B polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 5.4, 10.5, and 25.2.

### Claim 25 (depends on 24)

A pharmaceutical composition comprising a therapeutically effective amount of the crystalline, trihydrate polymorph of claim 24, and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.