# US 10,370,381 B2 · Inhibitors of bruton'S tyrosine kinase

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- Number: US 10,370,381 B2
- Document ID: US10370381B2
- Status: Granted
- Kind: B2
- Application number: 15/903,285
- Filed: 2018-02-23
- Published: 2018-09-06
- Granted: 2019-08-06
- Earliest claimed: 2017-02-24
- Assignees: Gilead Sciences, Inc.
- Applicants: Gilead Sciences, Inc.
- Inventors: Bing Shi
- Web page: https://patentgrep.com/patent/US10370381B2

## CPC

- C07D 487/04: Ortho-condensed systems
- 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 37/00: Drugs for immunological or allergic disorders
- C07D 473/34: attached in position 6, e.g. adenine
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

Provided are forms of 6-amino-9-[(3R)-1-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)-7,9-dihydro-8H-purin-8-one, compositions thereof, methods for their preparation, and methods for their use.

## Claims

### Claim 1

A crystalline hemisulfate, oxalate, hemiedisylate, edisylate, heminapadisylate, fumarate, or succinate of Compound (I):

### Claim 2 (depends on 1)

The Compound (I) hemisulfate of claim 1 characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 6.6, 18.6, and 23.7° 2θ as determined on a diffractometer using Cu-Kα radiation.

### Claim 3 (depends on 2)

The Compound (I) hemisulfate of claim 2, wherein the diffractogram further comprises peaks at 7.1 and 13.7° 2θ±0.2°.

### Claim 4 (depends on 3)

The Compound (I) hemisulfate of claim 3 further characterized by a differential scanning calorimetry curve comprising an endotherm at about 192° C.

### Claim 5 (depends on 1)

The Compound (I) oxalate of claim 1 characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 7.2, 18.2, and 23.3° 2θ as determined on a diffractometer using Cu-Kα radiation.

### Claim 6 (depends on 5)

The Compound (I) oxalate of claim 5, wherein the diffractogram further comprises peaks at 13.8 and 20.2° 2θ±0.2°.

### Claim 7 (depends on 6)

The Compound (I) oxalate of claim 6 further characterized by a differential scanning calorimetry curve comprising an endotherm at about 171° C.

### Claim 8 (depends on 1)

The Compound (I) hemiedisylate of claim 1 characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 5.9, 11.8, and 17.6° 2θ as determined on a diffractometer using Cu-Kα radiation.

### Claim 9 (depends on 8)

The Compound (I) hemiedisylate of claim 8, wherein the diffractogram further comprises peaks at 21.2 and 23.6° 2θ±0.2°.

### Claim 10 (depends on 9)

The Compound (I) hemiedisylate of claim 9 further characterized by a differential scanning calorimetry curve comprising an endotherm at about 165° C.

### Claim 11 (depends on 1)

The Compound (I) edisylate of claim 1 characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 5.7, 16.6, and 24.2° 2θ as determined on a diffractometer using Cu-Kα radiation.

### Claim 12 (depends on 11)

The Compound (I) edisylate of claim 11, wherein the diffractogram further comprises peaks at 11.1 and 22.2° 2θ±0.2°.

### Claim 13 (depends on 12)

The Compound (I) edisylate of claim 12 further characterized by a differential scanning calorimetry curve comprising an endotherm at about 154° C.

### Claim 14 (depends on 1)

The Compound (I) heminapadisylate of claim 1 characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 15.5, 16.5, and 23.8° 2θ as determined on a diffractometer using Cu-Kα radiation.

### Claim 15 (depends on 14)

The Compound (I) heminapadisylate of claim 14, wherein the diffractogram further comprises peaks at 5.6 and 20.3° 2θ±0.2°.

### Claim 16 (depends on 15)

The Compound (I) heminapadisylate of claim 15 further characterized by a differential scanning calorimetry curve comprising an endotherm at about 180° C.

### Claim 17 (depends on 1)

The Compound (I) fumarate of claim 1 characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 13.0, 16.6, and 19.9° 2θ as determined on a diffractometer using Cu-Kα radiation.

### Claim 18 (depends on 17)

The Compound (I) fumarate of claim 17, wherein the diffractogram further comprises peaks at 8.3 and 19.0° 2θ±0.2°.

### Claim 19 (depends on 18)

The Compound (I) fumarate of claim 18 further characterized by a differential scanning calorimetry curve comprising an endotherm at about 158° C.

### Claim 20 (depends on 1)

The Compound (I) succinate of claim 1 characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 13.2, 16.5, and 18.0° 2θ as determined on a diffractometer using Cu-Kα radiation.

### Claim 21 (depends on 20)

The Compound (I) succinate of claim 20, wherein the diffractogram further comprises peaks at 8.2 and 18.6° 2θ±0.2°.

### Claim 22 (depends on 21)

The Compound (I) succinate of claim 21 further characterized by a differential scanning calorimetry curve comprising an endotherm at about 142° C.

### Claim 23 (depends on 1)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and one or more compounds of claim 1.

### Claim 24 (depends on 1)

A kit comprising the compound of claim 1, or a label and/or instructions for use.

### Claim 25

A process for making a crystalline hemisulfate, oxalate, hemiedisylate, edisylate, heminapadisylate, fumarate, or succinate of Compound (I):
wherein the process comprises the steps of:
combining Compound (I) and sulfuric acid, oxalic acid, ethane-1,2-disulfonic acid, naphthalene-1,5-disulfonic acid, fumaric acid or succinic acid in a suitable solvent to obtain a mixture; and
collecting the crystalline hemisulfate, oxalate, hemiedisylate, edisylate, heminapadisylate, fumarate, or succinate of Compound (I).

### Claim 26 (depends on 25)

The process of claim 25, wherein the process comprises the steps of:
i) combining Compound (I) and sulfuric acid in a suitable solvent to obtain a mixture;
ii) heating the mixture obtained in step i) to about 70° C.;
iii) cooling the mixture obtained in step ii) to about 0° C.; and
iv) collecting the solid material obtained in step iii) to obtain the hemisulfate of Compound (I).

### Claim 27 (depends on 25)

The process of claim 25, wherein the process comprises the steps of:
i) dissolving Compound (I) and oxalic acid in a suitable solvent at room temperature to obtain a mixture; and
ii) collecting the solid material obtained in step i) to obtain the oxalate of Compound (I).

### Claim 28 (depends on 25)

The process of claim 25, wherein the process comprises the steps of:
i) combining Compound (I) and ethane-1,2-disulfonic acid dihydrate in a suitable solvent at room temperature to obtain a mixture; and
ii) collecting the solid material obtained in step i) to obtain the hemiedisylate of Compound (I).

### Claim 29 (depends on 25)

The process of claim 25, wherein the process comprises the steps of:
i) combining Compound (I) and ethane-1,2-disulfonic acid dihydrate in a suitable solvent at room temperature to obtain a mixture; and
ii) collecting the solid material obtained in step i) to obtain the edisylate of Compound (I).

### Claim 30 (depends on 25)

The process of claim 25, wherein the process comprises the steps of:
i) combining Compound (I) and naphthalene-1,5-disulfonic acid in a suitable solvent to obtain a mixture;
ii) heating the mixture obtained in step i) to about 50° C.;
iii) cooling the mixture obtained in step ii) to room temperature; and
iv) collecting the solid material obtained in step iii) to obtain the heminapadisylate of Compound (I).

### Claim 31 (depends on 25)

The process of claim 25, wherein the process comprises the steps of:
i) combining Compound (I) and fumaric acid in a suitable solvent;
ii) heating the mixture obtained in step i) to about 50° C.;
iii) cooling the mixture obtained in step ii) to room temperature; and
iv) collecting the solid material obtained in step iii) to obtain the fumarate of Compound (I).

### Claim 32 (depends on 25)

The process of claim 25, wherein the process comprises the steps of:
i) combining Compound (I) and succinic acid in a suitable solvent;
ii) heating the mixture obtained in step i) to about 50° C.;
iii) cooling the mixture obtained in step ii) to room temperature; and
iv) collecting the solid material obtained in step iii) to obtain the succinate of Compound (I).