# US 2023/0057716 A1 · CRYSTALLINE FORM OF (S)-7-(1-ACRYLOYLPIPERIDIN-4-YL)-2-(4-PHENOXYPHENYL)-4,5,6,7-TETRA-HYDROPYRAZOLO[1,5-a]PYRIMIDINE-3-CARBOXAMIDE, PREPARATION, AND USES THEREOF

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- Number: US 2023/0057716 A1
- Document ID: US20230057716A1
- Status: Published application
- Kind: A1
- Application number: 17/901,951
- Filed: 2022-09-02
- Published: 2023-02-23
- Earliest claimed: 2016-08-16
- Assignees: BeiGene Switzerland GmbH
- Applicants: Beigene Switzerland GmbH
- Inventors: Zhiwei WANG; Yunhang GUO; Gongyin SHI
- Web page: https://patentgrep.com/patent/US20230057716A1

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- 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)
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

The present invention relates to a crystalline form of (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide for inhibiting Btk, methods of preparation thereof and pharmaceutical compositions, and use of the crystalline form above in the treatment of a disease, or in the manufacturing of a medicament for the treatment of a disease.

## Claims

### Claim at position 1

-42. (canceled)

### Claim 43

A crystalline form of Compound 1,
made by crystallizing the crystalline form of Compound 1 from an amorphous form of Compound 1.

### Claim 44 (depends on 43)

The crystalline form of claim 43, wherein the amorphous form has an enantiomeric excess value of at least 90%.

### Claim 45 (depends on 44)

The crystalline form of claim 44, wherein the crystalline form has an enantiomeric excess value of at least 45%.

### Claim 46 (depends on 43)

The crystalline form of claim 43, wherein the amorphous form has an enantiomeric excess of at least 97%.

### Claim 47 (depends on 44)

The crystalline form of claim 44, wherein the crystalline form has a purity of at least 99.3%.

### Claim 48 (depends on 44)

The crystalline form of claim 44, wherein the crystalline form has a purity of at least 99.5%.

### Claim 49 (depends on 48)

The crystalline form of claim 48, wherein:
the amorphous form has a mid-point temperature of a glass transition temperature of about 79.7° C.;
the amorphous form has an enantiomeric excess value of at least 97%;
the crystalline form has a melting point onset temperature of 139±2° C.;
the crystalline form does not change its crystal form after being stored at about 80° C. for 2 days;
the crystalline form does not change its crystal form after being stored at about 25° C. under 60% relative humidity for up to 24 months; and
the crystalline form does not change its crystal form after being stored at about 40° C. under 75% relative humidity for up to 6 months.

### Claim 50 (depends on 43)

The crystalline form of claim 43, wherein the amorphous form has a mid-point temperature of a glass transition temperature of about 79.7° C.

### Claim 51 (depends on 43)

The crystalline form of claim 43, wherein the crystalline form has a melting point onset temperature of 139±2° C.

### Claim 52 (depends on 43)

The crystalline form of claim 43, wherein the crystalline form does not change its crystal form after being stored at about 80° C. for 2 days.

### Claim 53 (depends on 43)

The crystalline form of claim 43, wherein the crystalline form does not change its crystal form after being stored at about 25° C. under 60% relative humidity for up to 24 months.

### Claim 54 (depends on 43)

The crystalline form of claim 43, wherein the crystalline form does not change its crystal form after being stored at about 40° C. under 75% relative humidity for up to 6 months.

### Claim 55 (depends on 43)

The crystalline form of claim 43, wherein the crystalline form exhibits an X-ray powder diffraction pattern comprising diffraction peaks having 2θ angle values at 14.8±0.2°, 16.4±0.2° and 21.4±0.2°.

### Claim 56 (depends on 43)

A pharmaceutical composition comprising the crystalline form of claim 43 and a pharmaceutically acceptable excipient.

### Claim 57 (depends on 43)

A composition comprising the crystalline form of claim 43 and an amorphous form of Compound 1.

### Claim 58 (depends on 43)

A method for treating a B-cell proliferative disease in a subject, comprising administering to the subject in need thereof a crystalline form of claim 43,
wherein the B-cell proliferative disease is selected from a group consisting of chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma, Waldenstrom's macroglobulinemia, marginal zone lymphoma, and follicular lymphoma.

### Claim 59 (depends on 58)

The method of claim 58, wherein the crystalline form of Compound 1 is administrated at a dose of 40 mg/day to 320 mg/day.

### Claim 60 (depends on 58)

The method of claim 58, wherein the crystalline form of Compound 1 is administered at a dose of 160 mg twice a day (BID).

### Claim 61 (depends on 58)

The method of claim 58, wherein the crystalline form of Compound 1 is administered at a dose of 320 mg once a day (QD).

### Claim 62 (depends on 58)

The method of claim 58, wherein the crystalline form is an anhydrate.

### Claim 63 (depends on 58)

The method of claim 58, wherein the crystalline form of Compound 1 has an enantiomeric excess value of greater than 97%.

### Claim 64 (depends on 58)

The method of claim 58, wherein the subject has received at least one prior therapy.

### Claim 65 (depends on 58)

The method of claim 58, wherein the B-cell proliferative disease is chronic lymphocytic leukemia or small lymphocytic lymphoma.

### Claim 66 (depends on 58)

The method of claim 58, wherein the B-cell proliferative disease is mantle cell lymphoma.

### Claim 67 (depends on 58)

The method of claim 58, wherein the B-cell proliferative disease is Waldenstrom's macroglobulinemia.

### Claim 68 (depends on 58)

The method of claim 58, wherein the B-cell proliferative disease is marginal zone lymphoma.

### Claim 69 (depends on 58)

The method of claim 58, wherein the B-cell proliferative disease is follicular lymphoma.