# US 2019/0169201 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 2019/0169201 A1
- Document ID: US20190169201A1
- Status: Published application
- Kind: A1
- Application number: 16/325,447
- Filed: 2017-08-15
- Published: 2019-06-06
- Earliest claimed: 2016-08-16
- Assignees: BeiGene, Ltd.
- Applicants: BeiGene, Ltd.
- Inventors: Zhiwei Wang; Yunhang Guo; Gongyin Shi
- Web page: https://patentgrep.com/patent/US20190169201A1

## 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-tetr a-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 1

A crystalline form of Compound 1,

### Claim 2 (depends on 1)

The crystalline form of claim 1, wherein the crystalline form is an anhydrate.

### Claim 3 (depends on 1, 2)

The crystalline form of any one of claim 1 or 2, characterized by an X-ray powder diffraction pattern comprising diffraction peaks having 2θ angle values independently selected from: approximately 14.8±0.2°, 16.4±0.2° and 21.4±0.2°.

### Claim 4 (depends on 1, 2)

The crystalline form of any one of claim 1 or 2, characterized by an X-ray powder diffraction pattern comprising diffraction peaks having 2θ angle values independently selected from: approximately 14.8±0.2°, 15.6±0.2°, 16.4±0.2° and 21.4±0.2°.

### Claim 5 (depends on 1, 2)

The crystalline form of any one of claim 1 or 2, characterized by an X-ray powder diffraction pattern comprising diffraction peaks having 2θ angle values independently selected from: approximately 12.2±0.2°, 12.9±0.2°, 14.8±0.2°, 15.6±0.2°, 16.4±0.2° and 21.4±0.2°.

### Claim 6 (depends on 1, 2)

The crystalline form of any one of claim 1 or 2, characterized by an X-ray powder diffraction pattern comprising diffraction peaks having 2θ angle values independently selected from: approximately 12.2±0.2°, 12.9±0.2°, 14.8±0.2°, 15.6±0.2°, 16.4±0.2°, 17.7±0.2°, 18.5±0.2°, 20.7±0.2° and 21.4±0.2°.

### Claim 7 (depends on 1, 2)

The crystalline form of any one of claim 1 or 2, wherein the crystalline form has an X-ray powder diffraction pattern substantially in accordance with FIG. 1.

### Claim 8 (depends on 2, 3, 4, 5, 6, 7)

The crystalline form of any one of claims 2-7, wherein the crystalline form is characterized by a melting point of 139±2° C. (onset temperature).

### Claim 9 (depends on 2, 3, 4, 5, 6, 7)

The crystalline form of any one of claims 2-7, wherein the crystalline form is characterized by having a DSC substantially in accordance with FIG. 2.

### Claim 10 (depends on 2, 3, 4, 5, 6, 7)

The crystalline form of any one of claims 2-7, wherein the crystalline form is characterized by having a TGA substantially in accordance with FIG. 3.

### Claim 11 (depends on 1, 2, 3, 4, 5, 6, 7)

The crystalline form of any one of claims 1-7, wherein the crystalline form is characterized by a purity of >85% or a purity of >95% or a purity of >99%.

### Claim 12

A crystalline form of the compound having the following structure,
wherein the crystalline form has an X-ray powder diffraction pattern substantially in accordance with FIG. 11.

### Claim 13 (depends on 12)

The crystalline form of claim 12, wherein the crystalline form is characterized by having a unit cell dimensions comprising a=16.7939(4)Å, b=7.9871(2)Å, c=23.5438(5)Å, alpha=90.00 deg., beta=108.0460(10)deg., gamma=90.00 deg.

### Claim 14

A method of preparing the compound of Formula Ia, comprising asymmetrically reducing the compound of Formula I in the presence of the catalyst and/or reductant to produce the compound of Formula Ia,
wherein the R1 is hydrogen or an amino protecting group.

### Claim 15 (depends on 14)

The method of claim 14, where in the amino protecting group is selected from acetyl, propionyl, butyryl, phenylacetyl, benzoyl, toluyl, phenoxyacetyl, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, tert-butyloxycarbonyl, 2-iodoethoxycarbonyl, carbobenzoxy, 4-methoxybenzyloxycarbonyl, (Fluoren-9-ylmethoxy)carbonyl, 4-methoxy-2,3,6-trimethylbenzenesulphonyl, benzyl, methyl or 4-methoxybenzyl.

### Claim 16 (depends on 14)

The method of claim 14, wherein the catalyst is a neutral catalyst system, or a cationic catalyst system.

### Claim 17

A method of resolving a compound of Formula IIa to produce the compound of Formula IIb or improving the chiral purity of the compound of Formula IIb, comprising treating the racemic compound of Formula IIa with a chiral acid,
wherein the R1 is hydrogen, methyl, benzyl, 4-methoxybenzyl or the other conventional amino protecting groups.

### Claim 18

A method of resolving a compound of Formula Ic to produce the compound of formula Id or improving the chiral purity of the compound of Formula Id, comprising treating the racemic compound of Formula Ic with a chiral acid,
wherein R1 is hydrogen, methyl, benzyl, 4-methoxybenzyl or the other conventional amino protecting groups.

### Claim 19 (depends on 17, 18)

The method of claim 17 or 18, wherein the chiral acid is selected from L-malic acid, D-malic acid, L-Mandelic acid, D-Mandelic acid, L-camphorsulfonic acid, D-camphorsulfonic acid, L-tartaric acid, D-tartaric acid, L-DBTA, D-DBTA, L-DTTA or D-DTTA.

### Claim 20

A method of preparing Compound 1 and deuterium-labeled Compound 1, comprising the following:

### Claim 21

A compound of Formula Ie or a salt thereof, or Formula If or a salt thereof used to prepare Compound 1,

### Claim 22 (depends on 2, 3, 4, 5, 6, 7)

A method of preparing the crystalline form of any one of claims 2-7, comprising the steps of dissolving Compound 1 in DCM, swapping to solvent EA, recrystallizing from EA/MTBE, to obtain the target crystalline form.

### Claim 23 (depends on 2, 3, 4, 5, 6, 7)

A method of preparing the crystalline form of any one of claims 2-7, comprising the steps of dissolving Compound 1 in EA, adding hexane, to obtain the target crystalline form.

### Claim 24 (depends on 2, 3, 4, 5, 6, 7)

A method of preparing the crystalline from of any one of claims 2-7, comprising the steps of dissolving Compound 1 in an organic solvent, adding H2O, to obtain the target crystalline form, wherein the organic solvent is selected from acetone or DMAc.

### Claim 25 (depends on 1, 2, 3, 4, 5, 6, 7)

A method of preparing the crystalline from of any one of claims 2-7, comprising the steps of dissolving the crystalline of claims 1-7 in an organic solvent, adding H2O, to obtain the target crystalline form, wherein the organic solvent is selected from acetone or DMAc.

### Claim 26 (depends on 2, 3, 4, 5, 6, 7)

A method of preparing the crystalline from of any one of claims 2-7, comprising the steps of dissolving Compound 1 in an organic solvent, adding n-heptane, to obtain the target crystalline form, wherein the organic solvent is selected from EtOAc, DCM, toluene or 2-MeTHF.

### Claim 27 (depends on 1, 2, 3, 4, 5, 6, 7)

A method of preparing the crystalline from of any one of claims 2-7, comprising the steps of dissolving the crystalline of claims 1-7 in an organic solvent, adding n-heptane, to obtain the target crystalline form, wherein the organic solvent is selected from EtOAc, DCM, toluene or 2-MeTHF.

### Claim 28 (depends on 2, 3, 4, 5, 6, 7)

A method of preparing the crystalline from of any one of claims 2-7, comprising the steps of dissolving Compound 1 in acetone or EtOAc to obtain a solution, placing the solution into n-heptane, evaporating at RT, to obtain the target crystalline form.

### Claim 29 (depends on 1, 2, 3, 4, 5, 6, 7)

A method of preparing the crystalline from of any one of claims 2-7, comprising the steps of dissolving the crystalline of claims 1-7 in acetone or EtOAc to obtain a solution, placing the solution into n-heptane, evaporating at RT, to obtain the target crystalline form.

### Claim 30 (depends on 1, 2, 3, 4, 5, 6, 7, 22, 23, 24, 25, 26, 27, 28, 29)

The method of claims 22-29, wherein Compound 1 or the crystalline of claims 1-7 has ee value more than 90%, preferably more than 97%.

### Claim 31 (depends on 1, 2, 3, 4, 5, 6, 7)

A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of any one of claims 1-7, and a pharmaceutically acceptable excipient.

### Claim 32 (depends on 31)

The pharmaceutical composition of claim 31, wherein the pharmaceutical composition is used in an oral administration.

### Claim 33 (depends on 1, 2, 3, 4, 5, 6, 7, 31, 32)

The pharmaceutical composition of any one of claim 31 or 32, wherein the pharmaceutical composition contains 1 wt %-99 wt % of the crystalline form of any one of claims 1-7.

### Claim 34 (depends on 1, 2, 3, 4, 5, 6, 7, 31)

The pharmaceutical composition of claim 31 wherein the composition contains 1 wt %-70 wt % of the crystalline form of any one of claims 1-7.

### Claim 35 (depends on 1, 2, 3, 4, 5, 6, 7, 31)

The pharmaceutical composition of claim 31, wherein the composition contains 10 wt %-30 wt % of the crystalline form of any one of claims 1-7.

### Claim 36 (depends on 1, 2, 3, 4, 5, 6, 7)

A method of treating a disease associated with undesirable Btk activity in a subject by administering to the subject the crystalline form of any one of claims 1-7.

### Claim 37 (depends on 1, 2, 3, 4, 5, 6, 7)

A method of treating a disease selected from an allergic disease, an autoimmune disease, an inflammatory disease, a cancer, or a combination of two or more thereof, in a subject by administering to the subject the crystalline form of any one of claims 1-7.

### Claim 38 (depends on 1, 2, 3, 4, 5, 6, 7)

A method of treating a B-cell proliferative disease, selected from B-cell malignancies, in a subject by administering to the subject the crystalline form of any one of claims 1-7.

### Claim 39 (depends on 38)

The method of claim 38, wherein the B-cell proliferative disease is B-cell malignancies, selected from lymphoma, non-Hodgkin's lymphoma (NHL), diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), waldenstrom macroglobulinemia (WM), marginal zone lymphoma (MZL), Hairy cell leukemia (HCL), Burkitt's-like leukemia (BL), or a combination of two or more thereof

### Claim 40 (depends on 38)

The method of claim 38, wherein the B-cell proliferative disease is relapsed/refractory B-cell malignancies, selected from relapsed/refractory mantle cell lymphoma (R/R MCL), relapsed/refractory chronic lymphocytic leukemia (R/R CLL), relapsed/refractory small lymphocytic lymphoma (R/R SLL), relapsed/refractory Waldenstrom macroglobulinemia (R/R WM), or a combination of two or more thereof.

### Claim 41 (depends on 1, 2, 3, 4, 5, 6, 7, 38)

The method of claim 38, wherein the crystalline form of any one of claims 1-7 was administrated at a dose of 40 mg-320 mg/day.

### Claim 42 (depends on 1, 2, 3, 4, 5, 6, 7, 38)

The method of claim 38, wherein the crystalline form of any one of claims 1-7 was administrated at a dose of 160 mg twice a day (BID) or 320 mg once a day (QD).