# US 12,595,246 B2 · Crystalline and amorphous forms of N-(5-((4-ethylpiperazin-1-yl)methyl)pyridine-2-yl)-5-fluoro-4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-amine and its salts, and preparation methods and therapeutic uses thereof

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- Number: US 12,595,246 B2
- Document ID: US12595246B2
- Status: Granted
- Kind: B2
- Application number: 17/440,398
- Filed: 2020-03-20
- Published: 2022-05-26
- Granted: 2026-04-07
- Earliest claimed: 2019-03-20
- Assignees: Beta Pharma, Inc.
- Applicants: Beta Pharma, Inc.
- Inventors: Michael Nicholas Greco; Michael John Costanzo; Jirong Peng; Don Zhang
- Web page: https://patentgrep.com/patent/US12595246B2

## CPC

- C07D 401/14: containing three or more hetero rings
- A61P 35/00: Antineoplastic agents
- 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

Crystalline and amorphous forms of N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl-5-fluoro-4-(3-iso-propyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-amine (Compound 1) and various salts thereof, preparation methods of these crystalline and amorphous forms, pharmaceutical compositions containing these crystalline or amorphous forms, and use of these crystalline and amorphous forms, or pharmaceutical compositions thereof, for treatment of diseases or disorders associated with cyclin-dependent kinase (CDK), especially CDK4 and CDK6, activities, such as various cancers, are disclosed.

## Claims

### Claim 1

A crystalline form of the compound of Formula 1, or a pharmaceutical acceptably salt thereof:
wherein the crystalline form is designated as a Form A, a Form B, a Form C, or a Form D;
wherein the Form A is characterized by an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at diffraction angles 2θ of approximately 5.9°, 11.9°, and 25.6°;
wherein the Form B is characterized by an X-ray powder diffraction pattern comprising any three (3) of characteristic any three (3) of peaks at diffraction angles 2° of approximately 4.7°, 11.2°, 14.1°, 15.3° and 21.2°;
wherein the Form C is characterized by an X-ray powder diffraction pattern comprising characteristic peaks at diffraction angles 2θ of approximately 6.4°, 12.8° and 20.7°; and
wherein the Form D, is characterized by an X-ray powder diffraction pattern comprising any three (3) of characteristic peaks at diffraction angles 2θ of approximately 4.8°, 8.3°, 10.5°, 11.5°, and 14.0°.

### Claim 2 (depends on 1)

The crystalline form of claim 1, wherein the Form A is further characterized by any of the follow: (a) the XRPD pattern comprises any three (3) of characteristic peaks at diffraction angles 2θ of approximately 5.6°, 5.9°, 11.9°, 16.5°, 25.6° and 26.2°; (b) the XRPD pattern comprises any three (3) of characteristic peaks, expressed in terms of the interplanar distance, at 15.7A, 14.9A, 7.5A, 5.4A, 3.5A and 3.4A; (c) a differential scanning calorimetry (DSC) profile comprising characteristic peaks at 100.3° C., 124.3° C. and 166.3° C., with a melting point having an onset temperature of approximately 162.3° C.; (d) an X-ray powder diffraction pattern as shown in FIG. 2A; and/or (e) a DSC profile as shown in FIG. 3.

### Claim 3 (depends on 1)

The crystalline form of claim 1, wherein the crystalline Form B is further characterized by any of the following: (a) the X-ray powder diffraction pattern comprising any three (3) of characteristic peaks, expressed in terms of the interplanar distance, at 18.7A, 7.9A, 6.3A, 5.8A and 4.2A; (b) a DSC profile comprising characteristic peaks at 61.5° C., 118.8° C. and 166.8° C., with a melting point having an onset temperature of approximately 165.4° C.; (c) an X-ray powder diffraction pattern as shown in FIG. 4; and/or (d) a DSC profile as shown in FIG. 6.

### Claim 4 (depends on 1)

The crystalline form of claim 1, wherein the crystalline Form C is further characterized by any of the following: (a) the X-ray powder diffraction pattern comprising any three (3) of characteristic peaks at diffraction angles 2θ of approximately 5.7°, 6.4°, 9.2°, 12.8°, 15.7° and 20.7°; (b) the X-ray powder diffraction pattern comprising any three (3) of characteristic peaks, expressed in terms of the interplanar distance, at 15.5A, 13.8A, 9.6A, 6.9A, 5.6A and 4.3A; (c) a DSC profile comprising a characteristic peak at 162.8° C., with a melting point having an onset temperature of approximately 160.9° C.; (d) an X-ray powder diffraction pattern as shown in FIG. 4; and/or (e) a DSC profile as shown in FIG. 7.

### Claim 5 (depends on 1)

The crystalline form of claim 1, wherein the crystalline Form D is further characterized by any of the following: (a) the X-ray powder diffraction pattern comprising any three (3) of characteristic peaks at diffraction angles 2θ of approximately 18.2°, 20.0°, 23.5°, and 28.5°; (b) a DSC profile comprising characteristic peaks at 55.9° C., 118.8° C. and 168.4° C.; (c) an X-ray powder diffraction pattern as shown in FIG. 10; and/or (d) a DSC profile as shown in FIG. 8.

### Claim 6

An acid addition salt of N-(5- ((4-Ethylpiperazin-yl) methyl)pyridin-2-yl-5-fluoro-4-(3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-amine in crystalline form, wherein the acid is hydrochloric acid (HCl), wherein the compound N-(5- ((4-ethylpiperazin-yl)methyl)pyridin-2-yl-5-fluoro-4-(3-isopropyl-2-methyl-2H-indazol-5- yl)pyrimidin-2-amine and hydrochloride (HCl) in about 1:1 molar ratio, in a crystalline form (Form A) characterized by an X-ray powder diffraction pattern comprising characteristic peaks at any three (3) of diffraction angles 2θ of approximately 4.7°, 9.2°, 11.2°, 19.5° and 28.3°.

### Claim 7 (depends on 6)

The acid addition salt of claim 6, in a crystalline form (Form A) characterized by any of the following: (a) an X-ray powder diffraction pattern as shown in FIG. 18; (b) a DSC profile comprising characteristic peaks at 44.8° C. and 277.9° C., with a melting point having an onset temperature of approximately 275.4° C.; and/or (c) a TGA profile as shown in FIG. 16.