WO2022083649A1

WO2022083649A1 - Crystal form of pyridazine derivative

Info

Publication number: WO2022083649A1
Application number: PCT/CN2021/125043
Authority: WO
Inventors: 盛晓红; 盛晓霞
Original assignee: 杭州领业医药科技有限公司
Priority date: 2020-10-20
Filing date: 2021-10-20
Publication date: 2022-04-28
Also published as: CN116615200A

Abstract

Disclosed are a crystal form I of a compound as shown in formula (I) and a crystal form II of a compound as shown in formula (II), wherein the compound as shown in formula (I) and the compound as shown in formula (II) are as described in the present disclosure.

Description

Crystal forms of pyridazine derivatives

Citations to Related Applications

This disclosure claims all rights and interests of the invention patent application with the application number 202011114210.5 and the invention name "Crystal form of Deucravicitinib and its preparation method" submitted to the State Intellectual Property Office of the People's Republic of China on October 20, 2020, and by way of reference It is incorporated in this disclosure in its entirety.

field

The present disclosure generally relates to the field of medicinal chemistry, and more particularly, the present disclosure relates to crystalline forms of pyridazine derivatives.

background

JAK kinase (Janus kinase, JAK) belongs to the intracellular non-receptor tyrosine kinase family, which mediates the signal produced by cytokines and transmits it through the JAK-STAT signaling pathway. Tyrosine kinase 2 (TYK2), a member of the JAK family, plays an important role in mediating the signaling of pro-inflammatory cytokines, including IL-12, IL-23, and type I interferons. Deucravicitinib is a novel, selective TYK2 inhibitor, a class of pyridazine derivatives, currently in clinical studies for the treatment of a broad range of immune-mediated diseases.

Overview

In one aspect, the present disclosure relates to Form I of the compound of formula (I):

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern (XRPD) of the crystal form I expressed at 2θ angle has the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2 ° and 23.2±0.2°.

In another aspect, the present disclosure relates to Form I of the compound of formula (I):

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern represented by the 2θ angle of the crystal form I has the following characteristic peaks: about 8.2°, about 11.3°, about 19.3°, about 20.5° and about 23.2°.

In yet another aspect, the present disclosure relates to Form I of the compound of formula (I):

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form I expressed at 2θ angle has the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2° ±0.2°, and the X-ray powder diffraction pattern of the crystalline form I also has characteristic peaks at at least three of the following 2θ angles: 6.4±0.2°, 10.1±0.2°, 12.6±0.2°, 14.5±0.2°, 16.3±0.2° and 16.4±0.2°.

In yet another aspect, the present disclosure relates to the crystalline form I of the compound represented by formula (I):

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form I in 2θ angle has the following characteristic peaks: about 8.2°, about 11.3°, about 19.3°, about 20.5° and about 23.2°, and all The X-ray powder diffraction pattern of Form I also has characteristic peaks at at least three of the following 2θ angles: about 6.4°, about 10.1°, about 12.6°, about 14.5°, about 16.3°, and about 16.4°.

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form I expressed at 2θ angle has the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2° ±0.2°, and the X-ray powder diffraction pattern of the crystalline form I also has characteristic peaks at the following 2θ angles: 6.4±0.2°, 10.1±0.2°, 12.60±0.2°, 14.5±0.2°, 16.3±0.2° and 16.4±0.2°.

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form I in 2θ angle has the following characteristic peaks: about 8.2°, about 11.3°, about 19.3°, about 20.5° and about 23.2°, and all The X-ray powder diffraction pattern of Form I also has characteristic peaks at the following 2θ angles: about 6.4°, about 10.1°, about 12.6°, about 14.5°, about 16.3° and about 16.4°.

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form I expressed at 2θ angle has the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2° ±0.2°, and the X-ray powder diffraction pattern of the crystalline form I also has characteristic peaks at at least three of the following 2θ angles: 14.8±0.2°, 18.3±0.2°, 18.5±0.2°, 19.9±0.2°, 21.5±0.2°, 24.3±0.2°, 25.0±0.2° and 27.8±0.2°.

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form I in 2θ angle has the following characteristic peaks: about 8.2°, about 11.3°, about 19.3°, about 20.5° and about 23.2°, and all The X-ray powder diffraction pattern of Form I also has characteristic peaks at at least three of the following 2θ angles: about 14.8°, about 18.3°, about 18.5°, about 19.9°, about 21.5°, about 24.3°, about 25.0 ° and about 27.8°.

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form I expressed at 2θ angle has the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2° ±0.2°, and the X-ray powder diffraction pattern of the crystalline form I also has characteristic peaks at the following 2θ angles: 18.3±0.2°, 18.5±0.2°, 19.9±0.2°, 21.5±0.2°, 24.3±0.2° , 25.0±0.2° and 27.8±0.2°.

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form I in 2θ angle has the following characteristic peaks: about 8.2°, about 11.3°, about 19.3°, about 20.5° and about 23.2°, and all The X-ray powder diffraction pattern of Form I also has characteristic peaks at the following 2θ angles: about 18.3°, about 18.5°, about 19.9°, about 21.5°, about 24.3°, about 25.0°, and about 27.8°.

Wherein, using Cu-Kα radiation, the characteristic peaks of the X-ray powder diffraction pattern of the crystal form I represented by the angle of 2θ and its relative intensity are about:

2θ2θ	相对强度％(I)Relative Intensity %(I)
6.4±0.2°6.4±0.2°	13.113.1
8.2±0.2°8.2±0.2°	19.719.7
9.0±0.2°9.0±0.2°	2.32.3
10.1±0.2°10.1±0.2°	14.114.1

11.3±0.2°	57.9
12.6±0.2°	21.7
14.5±0.2°	11.1
16.3±0.2°	16.1
16.4±0.2°	18.0
18.3±0.2°	6.9
18.5±0.2°	10.9
19.3±0.2°	36.9
19.9±0.2°	11.5
20.5±0.2°	33.0
21.1±0.2°	3.9
21.5±0.2°	12.9
22.8±0.2°	8.0
23.2±0.2°	100.0
24.3±0.2°	4.9
25.0±0.2°	8.8
27.1±0.2°	5.0
27.8±0.2°	10.0
32.8±0.2°	2.9

.

Wherein, using Cu-Kα radiation, the crystal form I basically has an X-ray powder diffraction pattern as shown in FIG. 1 .

In yet another aspect, the present disclosure relates to a substantially solvent-free crystalline form I of the compound of formula (I), wherein, using Cu-Kα radiation, the crystalline form I has an X-ray powder diffraction pattern at 2Θ angles Has the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2±0.2°.

In another aspect, the present disclosure relates to a substantially water-free crystalline form I of the compound of formula (I), wherein, using Cu-Kα radiation, the crystalline form I has an X-ray powder diffraction pattern expressed at 2 theta angle having The following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2±0.2°.

In yet another aspect, the present disclosure relates to substantially pure Form I of the compound of formula (I), wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of Form I in 2Θ angles has the following Characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2±0.2°.

In yet another aspect, the present disclosure relates to a solvent-free and water-free crystalline form I of the compound of formula (I), wherein, using Cu-Kα radiation, X-ray powder diffraction of the crystalline form I in 2Θ angles The spectrum has the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2±0.2°.

In another aspect, the present disclosure relates to a method for preparing the crystal form I of the compound represented by formula (I), which comprises dissolving the compound represented by formula (I) in a halohydrin solvent, concentrating to obtain a solid, and dissolving the compound represented by formula (I) in a halogenated alcohol solvent. The solid is dried to obtain the crystal form I, wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form I represented by the 2θ angle has the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3± 0.2°, 20.5±0.2° and 23.2±0.2°.

In yet another aspect, the present disclosure relates to a method for preparing a crystalline form I of a compound of formula (I), comprising in a solution of an acid salt of the compound of formula (I), using a base to free out formula (I) The compound is obtained as a solid, and the solid is isolated, dried, and kept at 120 to 180° C. to obtain the crystal form I, wherein, using Cu-Kα radiation, X-ray powder diffraction of the crystal form I in 2θ angles The spectrum has the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2±0.2°.

In yet another aspect, the present disclosure relates to the crystalline form II of the compound represented by formula (II),

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form II at 2θ angle has the following characteristic peaks: 3.3±0.2°, 5.7±0.2°, 8.6±0.2°, 11.8±0.2°, 14.2 ±0.2° and 18.2±0.2°.

In another aspect, the present disclosure relates to the crystalline form II of the compound represented by formula (II),

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form II at 2θ angle has the following characteristic peaks: about 3.3°, about 5.7°, about 8.6°, about 11.8°, about 14.2° and about 18.2° °.

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form II at 2θ angle has the following characteristic peaks: 3.3±0.2°, 5.7±0.2°, 8.6±0.2°, 11.8±0.2°, 14.2 ±0.2°, 14.9±0.2°, 16.3±0.2°, 17.3±0.2°, 18.2±0.2°, 20.4±0.2°, 21.5±0.2° and 23.6±0.2°.

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form II at 2θ angle has the following characteristic peaks: about 3.3°, about 5.7°, about 8.6°, about 11.8°, about 14.2°, about 14.9°, about 16.3°, about 17.3°, about 18.2°, about 20.4°, about 21.5°, and about 23.6°.

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form II at 2θ angle has the following characteristic peaks: 3.3±0.2°, 5.7±0.2°, 6.5±0.2°, 8.6±0.2°, 11.3 ±0.2°, 11.8±0.2°, 14.2±0.2°, 14.9±0.2°, 16.3±0.2°, 17.3±0.2°, 18.2±0.2°, 19.9±0.2°, 20.4±0.2°, 21.5±0.2°, 23.6 ±0.2°, 24.8±0.2° and 26.0±0.2°.

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form II at 2θ angle has the following characteristic peaks: about 3.3°, about 5.7°, about 6.5°, about 8.6°, about 11.3°, about 11.8°, about 14.2°, about 14.9°, about 16.3°, about 17.3°, about 18.2°, about 19.9°, about 20.4°, about 21.5°, about 23.6°, about 24.8°, and about 26.0°.

Wherein, using Cu-Kα radiation, the characteristic peaks and relative intensities of the X-ray powder diffraction pattern of the crystal form II represented by the angle of 2θ are about:

2θ2θ	相对强度％(I)Relative Intensity %(I)
3.3±0.2°3.3±0.2°	74.174.1
5.7±0.2°5.7±0.2°	66.866.8
6.5±0.2°6.5±0.2°	4.44.4
8.6±0.2°8.6±0.2°	100100

11.3±0.2°	3.4
11.8±0.2°	37.0
14.2±0.2°	37.2
14.9±0.2°	14.4
16.3±0.2°	8.9
17.3±0.2°	12.4
18.2±0.2°	29.5
19.9±0.2°	8.7
20.4±0.2°	4.1
21.5±0.2°	5.5
23.6±0.2°	15.5
24.8±0.2°	6.2
26.0±0.2°	19.0

.

Wherein, using Cu-Kα radiation, the crystal form II basically has an X-ray powder diffraction pattern as shown in FIG. 5 .

In yet another aspect, the present disclosure relates to substantially pure crystalline Form II of the compound of formula (II), wherein, using Cu-Kα radiation, the crystalline Form II has an X-ray powder diffraction pattern at 2 theta having the following Characteristic peaks: 3.3±0.2°, 5.7±0.2°, 8.6±0.2°, 11.8±0.2°, 14.2±0.2° and 18.2±0.2°.

In yet another aspect, the present disclosure relates to a method for preparing the crystal form II of the compound represented by formula (II), which comprises mixing a solution containing the compound represented by formula (I) with an antisolvent to obtain a solid, and separating the solid, Drying to obtain the crystal form II, wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form II at 2θ angle has the following characteristic peaks: 3.3±0.2°, 5.7±0.2°, 8.6± 0.2°, 11.8±0.2°, 14.2±0.2° and 18.2±0.2°.

In another aspect, the present disclosure relates to a method for preparing the crystal form II of the compound represented by the formula (II), which comprises dissolving the compound represented by the formula (I) in a mixed solvent of an organic solvent and water to form a solution, and cooling the compound The solution obtains a solid, and the solid is separated and dried to obtain the crystal form II, wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form II at 2θ angle has the following characteristic peaks: 3.3± 0.2°, 5.7±0.2°, 8.6±0.2°, 11.8±0.2°, 14.2±0.2° and 18.2±0.2°.

In yet another aspect, the present disclosure relates to a method for preparing the crystal form II of the compound represented by formula (II), which comprises stirring an aqueous suspension of the compound represented by formula (I), filtering and drying to obtain the crystal form II, Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form II at 2θ angle has the following characteristic peaks: 3.3±0.2°, 5.7±0.2°, 8.6±0.2°, 11.8±0.2°, 14.2 ±0.2° and 18.2±0.2°.

In yet another aspect, the present disclosure relates to a pharmaceutical composition comprising crystal form I of the compound represented by formula (I) of the present disclosure, crystal form II of the compound represented by formula (II) of the present disclosure, or formula (II) of the present disclosure I) Any mixture of the crystal form I of the compound represented by the formula (II) of the present disclosure and the crystal form II of the compound represented by the formula (II) of the present disclosure, and a pharmaceutically acceptable carrier, diluent or excipient.

In another aspect, the present disclosure relates to a method of treating or preventing a disease or disease state associated with tyrosine kinase 2, comprising administering to an individual in need of the method a therapeutically or prophylactically effective amount of formula (I) of the present disclosure The crystal form I of the compound represented by the formula (II) of the present disclosure or the crystal form I of the compound represented by the formula (I) of the present disclosure and the compound represented by the formula (II) of the present disclosure Any mixture of the crystalline Form II, or a therapeutically effective amount of the pharmaceutical composition of the present disclosure.

Brief Description of Drawings

Fig. 1 shows the X-ray powder diffraction pattern of the crystal form I of the compound represented by formula (I) in an embodiment of the present disclosure;

Fig. 2 shows the differential scanning calorimetry (DSC) curve of the crystal form I of the compound represented by formula (I) in an embodiment of the present disclosure;

Fig. 3 shows the thermogravimetric analysis (TGA) curve of the crystal form I of the compound represented by formula (I) in an embodiment of the present disclosure;

4 shows the dynamic moisture adsorption (DVS) curve of the crystal form I of the compound represented by formula (I) in an embodiment of the present disclosure;

FIG. 5 shows the X-ray powder diffraction pattern of the crystal form II of the compound represented by formula (II) in an embodiment of the present disclosure.

Fig. 6 shows the differential scanning calorimetry (DSC) curve of the crystal form II of the compound represented by formula (II) in an embodiment of the present disclosure;

Fig. 7 shows the thermogravimetric analysis (TGA) curve of the crystal form II of the compound represented by formula (II) in an embodiment of the present disclosure;

FIG. 8 shows a comparison diagram of long-term and accelerated open-placed X-ray powder diffraction patterns of the crystal form I of the compound represented by formula (I) in an embodiment of the present disclosure;

FIG. 9 shows a comparison diagram of the long-term and accelerated open-placed X-ray powder diffraction patterns of the crystal form II of the compound represented by formula (II) in an embodiment of the present disclosure;

Figure 10 shows the results of the competition experiment between the crystal form A obtained in Preparation Example 1 of the present disclosure and the crystal form II of the compound represented by the formula (II) prepared in Example 3;

Figure 11 shows a particle size distribution (PSD) diagram of the crystal form I of the compound represented by formula (I) in an embodiment of the present disclosure; and

FIG. 12 shows a particle size distribution (PSD) graph of the crystal form II of the compound represented by formula (II) in an embodiment of the present disclosure.

detail

In the following description, certain specific details are included to provide a thorough understanding of the various disclosed embodiments. One skilled in the relevant art will recognize, however, that without employing one or more of these specific details, embodiments may be practiced with the use of other methods, components, materials, etc.

Unless otherwise required in this disclosure, throughout this specification and the claims that follow, the words "including" and "comprising" should be construed in an open-ended, inclusive sense, i.e., "including but not limited to".

As used in this disclosure and the appended claims, unless the context clearly dictates otherwise, a singular reference without a quantitative indication includes a plural reference.

Reference throughout this specification to "an embodiment" or "another embodiment" or "an embodiment" or "certain embodiments" is meant to include, in at least one embodiment, those recited in relation to that embodiment. Specific reference to an element, structure or feature. Thus, appearances of the phrases "one embodiment" or "an embodiment" or "another embodiment" in various places throughout the specification are not necessarily all referring to the same embodiment. Furthermore, the particular elements, structures or features may be combined in any suitable manner in one or more embodiments.

It should be understood that the singular form of the article "a" (corresponding to "a", "an" and "the") as used in the specification of the present disclosure and the appended claims includes plural referents unless the context Also clearly stipulated. Thus, for example, reference to a pharmaceutical composition comprising "a pharmaceutically acceptable carrier, diluent or excipient" includes one pharmaceutically acceptable carrier, diluent or excipient, or two or more pharmaceutically acceptable carriers, diluents or excipients carrier, diluent or excipient.

definition

Accordingly, unless stated to the contrary, as used in the specification and appended claims, the following terms have the following meanings:

In the present disclosure, the term "compound of formula (I)" refers to 6-(cyclopropanecarbonylamino)-4-[2-methoxy-3-(1-methyl-1,2,4- Triazol-3-yl)anilino]-N-(trideuteromethyl)pyridazine-3-carboxamide, the chemical generic name is Deucravicitinib, and its structural formula is as follows:

In the present disclosure, the term "compound of formula (II)" refers to 6-(cyclopropanecarbonylamino)-4-[2-methoxy-3-(1-methyl-1,2,4- Triazol-3-yl)anilino]-N-(trideuteromethyl)pyridazine-3-carboxamide dihydrate, namely Deucravicitinib dihydrate, its structural formula is as follows:

In the present disclosure, the term "crystalline form" refers to a compound having a uniquely ordered molecular arrangement or configuration within a crystal lattice as evidenced by X-ray powder diffraction pattern characterization.

In this disclosure, use of the term "about" includes and describes the value or parameter itself. For example, "about x" includes and describes "x" itself. In certain embodiments, the term "about" when used in connection with a measurement or to modify a numerical value, unit, constant or numerical range, refers to a +/- 5% variation.

In this disclosure, the term "substantially as shown in "means not necessarily the same graphs and curves as those depicted in this disclosure, but falls within the limits of experimental error or deviation when considered by one of ordinary skill in the art.

In this disclosure, when referring to X-ray powder diffraction peak positions, the term "substantially the same" as used in this disclosure is meant to take into account typical peak positions and intensity variability. For example, those skilled in the art understand that peak positions (2Θ) can exhibit some variability, typically, as much as 0.1 to 0.2 degrees, depending on the solvent used and the apparatus used to measure the diffraction. Further, those skilled in the art understand that relative peak intensities can reveal inter-instrument variability as well as variability due to crystallinity, preferred orientation, the surface of the sample prepared, and other factors known to those skilled in the art. , and should only be considered qualitative measurements.

In this disclosure, the term "2Θ value" or "2Θ" refers to the peak position in degrees based on an experimental setup of X-ray powder diffraction experiments and is the common abscissa unit for diffraction patterns. The experimental setup requires that if the reflection is diffracted when the incident beam forms an angle θ (θ) with a certain crystal plane, the reflected beam is recorded at an angle 2θ (2θ). It should be understood that the specific 2[Theta] values referred to in this disclosure for a specific crystal form are intended to refer to the 2[Theta] values (in degrees) measured using the X-ray powder diffraction experimental conditions described in this disclosure. For example, as described in this disclosure, using Cu-Kα

as a radiation source.

In this disclosure, for the purposes of "2Θ", the term "about" means ±0.5°.

In this disclosure, the term "substantially pure" refers to both chemical and crystalline purity. In certain embodiments, when "substantially pure" is used to refer to a new crystalline form, it means that the new crystalline form constitutes at least 80% by weight of the compound present, more preferably at least 90% by weight, especially At least 95% by weight, especially at least 99% by weight.

In the present disclosure, the term "substantially free" means containing no more than about 20% by weight. For example, substantially free of solvent means containing no more than about 20% by weight of solvent. Substantially free of water means containing not more than 20% by weight of water.

In this disclosure, the term "mammal" is meant to include animals such as dogs, cats, cows, sheep, horses, humans, and the like. In certain embodiments, mammals include humans.

In this disclosure, the term "patient" refers to animals (eg, humans), companion animals (eg, dogs, cats, or horses), and livestock (eg, cows, pigs, and sheep). In certain embodiments, the patient is a mammal including both males and females. In certain embodiments, the patient is a human.

In the present disclosure, the term "pharmaceutically acceptable" refers to a carrier, vehicle, diluent, excipient and/or salt that must be compatible with the other ingredients of the formulation and not deleterious to its recipient.

In this disclosure, the term "pharmaceutically acceptable carrier, diluent, or excipient" includes, but is not limited to, any adjuvant, carrier, excipient that has been approved by the US Food and Drug Administration for use in humans or animals , glidants, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers Agents, etc., are various forms of carriers that have no adverse effects on the composition of the pharmaceutical composition.

In the present disclosure, the term "carrier" is defined as a compound that facilitates introduction of a crystalline form of the compound into a cell or tissue. Dimethyl sulfoxide (DMSO), for example, is often used as a carrier because it facilitates the introduction of certain organic compounds into cells or tissues of an organism.

In this disclosure, the term "pharmaceutical composition" refers to a formulation of Form I of a compound described in this disclosure with a medium generally accepted in the art for the delivery of biologically active compounds to mammals such as humans. Such media include all pharmaceutically acceptable carriers, diluents or excipients.

In the present disclosure, the term "therapeutically effective amount" refers to a formula (I ) of the compound represented by the crystalline form I (or the crystalline form II of the compound represented by the formula (II) or the crystalline form I of the compound represented by the formula (I) and the crystalline form II of the compound represented by the formula (II) any mixture) or the combination of the crystal form I of the compound represented by the formula (I) (or the combination of the crystal form II of the compound represented by the formula (II) or the crystal form I and the formula (II) of the compound represented by the formula (I) any mixture combination of Form II of the compound shown). According to the crystal form I of the compound represented by the formula (I) (or the crystal form II of the compound represented by the formula (II) or the crystal form I of the compound represented by the formula (I) and the compound represented by the formula (II) Form II), the disease state and its severity, and the age, weight, etc. of the mammal to be treated, constitute a "therapeutically effective amount" of the crystalline form of the compound of formula (I) described in this disclosure The amount of I (or Form II of the compound of Formula (II) or any mixture of Form I of the compound of Formula (I) and Form II of the compound of Formula (II)) will vary However, those skilled in the art can routinely determine the crystal form I of the compound represented by formula (I) (or the crystal form of the compound represented by formula (II) described in the present disclosure according to their own knowledge and the present disclosure. II or any mixture of the crystalline form I of the compound represented by the formula (I) and the crystalline form II of the compound represented by the formula (II).

In the present disclosure, the term "prophylactically effective amount" refers to an amount sufficient to prevent a disease or disease state, or prevent the recurrence thereof. Crystal form I of the compound represented by formula (I) or crystal form II of the compound represented by formula (II) or crystal form I of the compound represented by formula (I) and crystal form of the compound represented by formula (II) A prophylactically effective amount of any mixture of II refers to the amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in preventing a disease or disease state. In the present disclosure, the term "prophylactically effective amount" can include an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

As used in this disclosure, "treating" or "treating" encompasses treating a related disease or disease state in a mammal, such as a human, afflicted with a related disease or disorder, and includes:

(i) inhibit the disease or disease state, i.e. prevent its occurrence; or

(ii) Alleviation of the disease or disease state, even if the disease or disease state resolves or does not progress.

As used in this disclosure, the terms "disease" and "disease state" may be used interchangeably or may be different because a particular disease or disease state may have no known causative agent (and therefore cannot be explained by etiology). ), so it is not recognized as a disease, but as an undesired disease state or disorder in which a clinician has identified a more or less specific set of symptoms.

In this disclosure, the term "physiologically acceptable" refers to a carrier or diluent that does not abrogate the biological activity and properties of the compound.

In the present disclosure, the term "room temperature" refers to 10 to 30°C.

In the present disclosure, the term "concentration" refers to a method of reducing the volume of a solvent by adjusting temperature, air pressure or gas flow, and the like.

Detailed ways

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form I expressed at 2θ angle has the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2° ±0.2°.

2θ2θ	相对强度％(I)Relative Intensity %(I)
6.4±0.2°6.4±0.2°	13.113.1
8.2±0.2°8.2±0.2°	19.719.7
9.0±0.2°9.0±0.2°	2.32.3
10.1±0.2°10.1±0.2°	14.114.1
11.3±0.2°11.3±0.2°	57.957.9
12.6±0.2°12.6±0.2°	21.721.7
14.5±0.2°14.5±0.2°	11.111.1
16.3±0.2°16.3±0.2°	16.116.1
16.4±0.2°16.4±0.2°	18.018.0
18.3±0.2°18.3±0.2°	6.96.9
18.5±0.2°18.5±0.2°	10.910.9
19.3±0.2°19.3±0.2°	36.936.9
19.9±0.2°19.9±0.2°	11.511.5
20.5±0.2°20.5±0.2°	33.033.0
21.1±0.2°21.1±0.2°	3.93.9
21.5±0.2°21.5±0.2°	12.912.9
22.8±0.2°22.8±0.2°	8.08.0
23.2±0.2°23.2±0.2°	100.0100.0

24.3±0.2°	4.9
25.0±0.2°	8.8
27.1±0.2°	5.0
27.8±0.2°	10.0
32.8±0.2°	2.9

.

In certain embodiments, Form I of the compound of formula (I) has an X-ray powder diffraction pattern that exhibits at least one characteristic peak substantially as shown in the X-ray powder diffraction pattern of FIG. 1 .

In certain embodiments, Form I of the compound of formula (I) has an X-ray powder diffraction pattern exhibiting at least two characteristic peaks substantially as shown in the X-ray powder diffraction pattern of FIG. 1 .

In certain embodiments, Form I of the compound of formula (I) has an X-ray powder diffraction pattern exhibiting at least three characteristic peaks substantially as shown in the X-ray powder diffraction pattern of FIG. 1 .

In certain embodiments, Form I of the compound of formula (I) has an X-ray powder diffraction pattern exhibiting at least four characteristic peaks substantially as shown in the X-ray powder diffraction pattern of FIG. 1 .

In certain embodiments, Form I of the compound of Formula (I) has an X-ray powder diffraction pattern exhibiting at least five characteristic peaks substantially as shown in the X-ray powder diffraction pattern of FIG. 1 .

In certain embodiments, Form I of the compound of formula (I) has an X-ray powder diffraction pattern exhibiting at least six characteristic peaks substantially as shown in the X-ray powder diffraction pattern of FIG. 1 .

In certain embodiments, Form I of the compound of Formula (I) has an X-ray powder diffraction pattern exhibiting at least seven characteristic peaks substantially as shown in the X-ray powder diffraction pattern of FIG. 1 .

In certain embodiments, Form I of the compound of Formula (I) has an X-ray powder diffraction pattern exhibiting at least eight characteristic peaks substantially as shown in the X-ray powder diffraction pattern of FIG. 1 .

In certain embodiments, Form I of the compound of Formula (I) has an X-ray powder diffraction pattern exhibiting at least nine characteristic peaks substantially as shown in the X-ray powder diffraction pattern of FIG. 1 .

In certain embodiments, Form I of the compound of Formula (I) has an X-ray powder diffraction pattern exhibiting at least ten characteristic peaks substantially as shown in the X-ray powder diffraction pattern of FIG. 1 .

In certain embodiments, Form I of the compound of formula (I) has an X-ray powder diffraction pattern exhibiting at least eleven characteristic peaks substantially as shown in the X-ray powder diffraction pattern of FIG. 1 .

In certain embodiments, Form I of the compound of formula (I) has an X-ray powder diffraction pattern exhibiting at least twelve characteristic peaks substantially as shown in the X-ray powder diffraction pattern of FIG. 1 .

In certain embodiments, Form I of the compound of formula (I) has an X-ray powder diffraction pattern exhibiting at least thirteen peaks characteristic of the X-ray powder diffraction pattern substantially as shown in FIG. 1 .

In certain embodiments, Form I of the compound of formula (I) has an X-ray powder diffraction pattern exhibiting at least fourteen peaks characteristic of the X-ray powder diffraction pattern substantially as shown in FIG. 1 . .

In certain embodiments, Form I of the compound of formula (I) has an X-ray powder diffraction pattern exhibiting at least fifteen peaks characteristic of the X-ray powder diffraction pattern substantially as shown in FIG. 1 . .

In certain embodiments, Form I of the compound of formula (I) has an X-ray powder diffraction pattern exhibiting at least sixteen peaks characteristic of the X-ray powder diffraction pattern substantially as shown in FIG. 1 .

In certain embodiments, Form I of the compound of formula (I) has an X-ray powder diffraction pattern exhibiting at least seventeen peaks characteristic of the X-ray powder diffraction pattern substantially as shown in FIG. 1 .

In certain embodiments, Form I of the compound of formula (I) has an X-ray powder diffraction pattern exhibiting at least eighteen peaks substantially characteristic of the X-ray powder diffraction pattern as shown in FIG. 1 .

In certain embodiments, Form I of the compound of formula (I) has an X-ray powder diffraction pattern that exhibits at least nineteen peaks characteristic of the X-ray powder diffraction pattern substantially as shown in FIG. 1 . .

In certain embodiments, Form I of the compound of Formula (I) has an X-ray powder diffraction pattern that exhibits at least twenty characteristic peaks substantially as shown in the X-ray powder diffraction pattern of FIG. 1 . .

In certain embodiments, Form I of the compound of formula (I) has an X-ray powder diffraction exhibiting at least twenty one characteristic peaks in the X-ray powder diffraction pattern substantially as shown in FIG. 1 Atlas.

In certain embodiments, Form I of the compound of formula (I) has an X-ray powder diffraction exhibiting at least twenty-two characteristic peaks in the X-ray powder diffraction pattern substantially as shown in FIG. 1 . Atlas.

In certain embodiments, Form I of the compound of formula (I) has an X-ray powder diffraction exhibiting at least twenty three characteristic peaks in the X-ray powder diffraction pattern substantially as shown in FIG. 1 Atlas.

In certain embodiments, Form I of the compound of formula (I) has an endothermic peak at 259±3°C when thermally analyzed using differential scanning calorimetry (DSC).

In certain embodiments, Form I of the compound of formula (I) has an endothermic peak at 259±1°C when thermally analyzed using differential scanning calorimetry (DSC).

In certain embodiments, Form I of the compound of formula (I) has an endothermic peak at about 259°C when thermally analyzed using differential scanning calorimetry (DSC).

In certain embodiments, when thermal analysis is performed using differential scanning calorimetry (DSC), at a heating rate of 10°C/min, the crystalline form I of the compound of formula (I) has at 259±3°C endothermic peak.

In certain embodiments, when thermal analysis is performed using differential scanning calorimetry (DSC), at a heating rate of 10°C/min, the crystalline form I of the compound of formula (I) has at 259±1°C endothermic peak.

In certain embodiments, when thermal analysis is performed using differential scanning calorimetry (DSC), at a heating rate of 10°C/min, the crystalline form I of the compound of formula (I) exhibits adsorption at about 259°C heat peak.

In certain embodiments, the crystalline Form I of the compound of formula (I) has a melting point of 259±3°C.

In certain embodiments, Form I of the compound of formula (I) has substantially the DSC curve shown in FIG. 2 when thermally analyzed using differential scanning calorimetry (DSC).

In certain embodiments, when thermal analysis is performed using differential scanning calorimetry (DSC), at a heating rate of 10° C./min, the crystalline form I of the compound of formula (I) has substantially as shown in FIG. 2 DSC curve shown.

In certain embodiments, Form I of the compound of formula (I) has substantially the TGA curve shown in FIG. 3 when thermally analyzed using thermogravimetric analysis (TGA).

In certain embodiments, when thermal analysis is performed using thermogravimetric analysis (TGA), at a heating rate of 10° C./min, the crystalline form I of the compound of formula (I) has substantially the form shown in FIG. 3 . TGA curve.

In certain embodiments, when thermal analysis is performed using thermogravimetric analysis (TGA), there is less than 0.5% mass loss when heated to 150°C ± 3°C, indicating Form I of the compound of formula (I) For anhydrous.

In certain embodiments, Form I of the compound of formula (I) has substantially the DVS curve shown in FIG. 4 when analyzed using dynamic moisture adsorption (DVS).

In certain embodiments, Form I of the compound of formula (I) exhibits less than 0.03% weight change over the range of 0 to 80% relative humidity when analyzed using Dynamic Moisture Sorption (DVS) and is not hygroscopic .

In certain embodiments, Form I of the compound of formula (I) has substantially very uniform fine particles.

In certain embodiments, the diameter of the crystal form I of the compound represented by formula (I) is generally below 50 μm, which can increase the specific surface area of the drug, improve the dissolution rate, and facilitate the rapid absorption of the drug.

In certain embodiments, the crystal form I of the compound represented by formula (I) of the present disclosure has only a weight change of less than 0.03% in the range of 0-80% relative humidity, is not hygroscopic, and has better stability And workability, more conducive to storage.

In certain embodiments, illustrative examples of halohydrin that can be used in the present disclosure include, but are not limited to, C _1-6 halohydrin.

In certain embodiments, illustrative examples of C _1-6 halohydrins that can be used in the present disclosure include, but are not limited to, C _1-6 chlorohydrins, C _1-6 fluorohydrins, and any mixtures thereof.

In certain embodiments, illustrative examples of C _1-6 fluoroalcohols that can be used in the present disclosure include, but are not limited to, trifluoroethanol.

In certain embodiments, illustrative examples of drying methods that can be used in the present disclosure include, but are not limited to, ambient temperature drying, forced air drying, and reduced pressure drying.

In certain embodiments, the drying apparatus and method are not limited and may be fume hoods, forced air ovens, spray dryers, fluid bed drying and vacuum ovens.

In certain embodiments, drying can be performed under reduced or atmospheric pressure.

In certain embodiments, drying can be performed at a pressure of less than 0.09 MPa.

In certain embodiments, the drying temperature is about 10 to 50°C.

In certain embodiments, the drying temperature is about 40°C.

In certain embodiments, the drying time is about 0.5 to 5 hours.

In certain embodiments, the drying time is about 1 hour.

In certain embodiments, illustrative examples of acid salts of compounds of formula (I) that can be used in the present disclosure include, but are not limited to, hydrochloride, hydrobromide, sulfate, sulfonate, phosphoric acid salt and nitrate.

In certain embodiments, the acid salt of the compound of formula (I) that can be used in the present disclosure is a sulfate salt.

In certain embodiments, illustrative examples of bases that can be used in the present disclosure include, but are not limited to, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, and potassium hydride.

In certain embodiments, the base that can be used in the present disclosure is sodium hydroxide.

In certain embodiments, illustrative examples of solutions of acid salts of compounds of formula (I) that can be used in the present disclosure include, but are not limited to, aqueous solutions.

In certain embodiments, the drying apparatus and method are not limited and can be fume hoods, forced air ovens, spray dryers, fluid bed drying and vacuum ovens.

In certain embodiments, the drying temperature is about 10 to 50°C.

In certain embodiments, the drying temperature is about 40°C.

In certain embodiments, the drying time is about 1 to 24 hours.

In certain embodiments, the drying time is about 16 hours.

In certain embodiments, the temperature maintained is about 140 to 150°C.

In certain embodiments, the temperature maintained is about 150°C;

In certain embodiments, the hold time is about 10 to 30 minutes.

In certain embodiments, the hold time is about 10 minutes.

In certain embodiments, the method for preparing the crystal form I of the compound represented by formula (I) of the present disclosure is simple and has few steps, which is more conducive to improving the efficiency of preparation and controlling parameters.

2θ2θ	相对强度％(I)Relative Intensity %(I)
3.3±0.2°3.3±0.2°	74.174.1
5.7±0.2°5.7±0.2°	66.866.8
6.5±0.2°6.5±0.2°	4.44.4
8.6±0.2°8.6±0.2°	100100
11.3±0.2°11.3±0.2°	3.43.4
11.8±0.2°11.8±0.2°	37.037.0

14.2±0.2°	37.2
14.9±0.2°	14.4
16.3±0.2°	8.9
17.3±0.2°	12.4
18.2±0.2°	29.5
19.9±0.2°	8.7
20.4±0.2°	4.1
21.5±0.2°	5.5
23.6±0.2°	15.5
24.8±0.2°	6.2
26.0±0.2°	19.0

.

In certain embodiments, Form II of the compound of formula (II) has an X-ray powder diffraction pattern that exhibits at least one characteristic peak substantially as shown in the X-ray powder diffraction pattern of FIG. 5 .

In certain embodiments, Form II of the compound of formula (II) has an X-ray powder diffraction pattern exhibiting at least two characteristic peaks substantially as shown in the X-ray powder diffraction pattern of FIG. 5 .

In certain embodiments, Form II of the compound of formula (II) has an X-ray powder diffraction pattern exhibiting at least three characteristic peaks substantially as shown in the X-ray powder diffraction pattern of FIG. 5 .

In certain embodiments, Form II of the compound of formula (II) has an X-ray powder diffraction pattern exhibiting at least four characteristic peaks substantially as shown in the X-ray powder diffraction pattern of FIG. 5 .

In certain embodiments, Form II of the compound of formula (II) has an X-ray powder diffraction pattern exhibiting at least five characteristic peaks substantially as shown in the X-ray powder diffraction pattern of FIG. 5 .

In certain embodiments, Form II of the compound of formula (II) has an X-ray powder diffraction pattern exhibiting at least six characteristic peaks substantially as shown in the X-ray powder diffraction pattern of FIG. 5 .

In certain embodiments, Form II of the compound of formula (II) has an X-ray powder diffraction pattern exhibiting at least seven characteristic peaks substantially as shown in the X-ray powder diffraction pattern of FIG. 5 .

In certain embodiments, Form II of the compound of formula (II) has an X-ray powder diffraction pattern exhibiting at least eight characteristic peaks substantially as shown in the X-ray powder diffraction pattern of FIG. 5 .

In certain embodiments, Form II of the compound of formula (II) has an X-ray powder diffraction pattern exhibiting at least nine characteristic peaks substantially as shown in the X-ray powder diffraction pattern of FIG. 5 .

In certain embodiments, Form II of the compound of formula (II) has an X-ray powder diffraction pattern exhibiting at least ten peaks substantially characteristic of the X-ray powder diffraction pattern as shown in FIG. 5 .

In certain embodiments, Form II of the compound of formula (II) has an X-ray powder diffraction pattern that exhibits at least eleven characteristic peaks substantially as shown in the X-ray powder diffraction pattern of FIG. 5 . .

In certain embodiments, Form II of the compound of formula (II) has an X-ray powder diffraction pattern exhibiting at least twelve characteristic peaks substantially as shown in the X-ray powder diffraction pattern of FIG. 5 .

In certain embodiments, Form II of the compound of formula (II) has an X-ray powder diffraction pattern exhibiting at least thirteen peaks substantially characteristic of the X-ray powder diffraction pattern as shown in FIG. 5 .

In certain embodiments, Form II of the compound of formula (II) has an X-ray powder diffraction pattern exhibiting at least fourteen peaks substantially characteristic of the X-ray powder diffraction pattern as shown in FIG. 5 .

In certain embodiments, Form II of the compound of formula (II) has an X-ray powder diffraction pattern exhibiting at least fifteen peaks characteristic of the X-ray powder diffraction pattern substantially as shown in FIG. 5 . .

In certain embodiments, Form II of the compound of formula (II) has an X-ray powder diffraction pattern exhibiting at least sixteen peaks characteristic of the X-ray powder diffraction pattern substantially as shown in FIG. 5 . .

In certain embodiments, Form II of the compound of formula (II) has an X-ray powder diffraction pattern exhibiting at least seventeen peaks characteristic of the X-ray powder diffraction pattern substantially as shown in FIG. 5 . .

In certain embodiments, Form II of the compound of formula (II) has substantially the DSC curve shown in FIG. 6 when thermally analyzed using differential scanning calorimetry (DSC).

In certain embodiments, when thermal analysis is performed using differential scanning calorimetry (DSC), at a heating rate of 10° C./min, the crystalline form II of the compound represented by formula (II) has substantially as shown in FIG. 6 DSC curve shown.

In certain embodiments, Form II of the compound of formula (II) is between 36°C and 110°C and between 110°C and 132°C when thermally analyzed using differential scanning calorimetry (DSC) There is one desolvation peak, respectively.

In certain embodiments, when thermal analysis is performed using differential scanning calorimetry (DSC), at a heating rate of 10°C/min, the crystalline form II of the compound of formula (II) is between 36°C and 110°C There is a desolvation peak between 110 °C and 132 °C, respectively.

In certain embodiments, Form II of the compound of formula (II) has substantially the TGA curve shown in FIG. 7 when thermally analyzed using thermogravimetric analysis (TGA).

In certain embodiments, when thermal analysis is performed using thermogravimetric analysis (TGA), at a heating rate of 10° C./min, the crystalline form II of the compound represented by formula (II) has substantially as shown in FIG. 7 . TGA curve.

In certain embodiments, when thermal analysis is performed using thermogravimetric analysis (TGA), it is shown that the crystalline form II of the compound represented by formula (II) has a step weight loss, indicating that it is a hydrate.

In certain embodiments, when thermal analysis is performed using thermogravimetric analysis (TGA), it is shown that the crystal form II of the compound represented by formula (II) has a step weight loss, and the step weight loss is about 7.7%, indicating that it is dihydrate.

In certain embodiments, the crystal form II of the compound represented by formula (II) is a block-shaped granular crystal with better morphology and better fluidity, which can reduce the filtration time of the drug substance and the sieving of the preparation. time, which is conducive to accurate metering and improved efficiency in formulation production.

In certain embodiments, the crystalline form II of the compound represented by formula (II) is a block-like granular crystal with better morphology and better formulation processability, which can be used for direct powder compression, avoiding wet The influence of granulation solvent on API is beneficial to control the quality of preparation and improve batch stability.

In certain embodiments, the crystal form II of the compound represented by formula (II) has excellent water stability, is more suitable for wet granulation, has better crystal form stability in water-containing crystallization processes, and has Better storage stability.

In yet another aspect, the present disclosure relates to a method for preparing the crystal form II of the compound represented by formula (II), which comprises mixing a solution of the compound represented by formula (I) with an antisolvent to obtain a solid, and separating and drying the solid , to obtain the crystal form II, wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form II at 2θ angle has the following characteristic peaks: 3.3±0.2°, 5.7±0.2°, 8.6±0.2 °, 11.8±0.2°, 14.2±0.2° and 18.2±0.2°.

In certain embodiments, illustrative examples of solvents that can be used to dissolve the compound represented by formula (I) include, but are not limited to, mixed solvents of organic solvents and water.

In certain embodiments, the volume ratio of organic solvent to water in the solvent in which the compound of formula (I) is dissolved is about 1:0.1 to 0.5.

In certain embodiments, the volume ratio of organic solvent to water in the solvent in which the compound of formula (I) is dissolved is about 1:0.2 to 0.4.

In certain embodiments, illustrative examples of organic solvents that can be used in the present disclosure include, but are not limited to, ketones, cyclic ethers, and mixtures thereof.

In certain embodiments, illustrative examples of organic solvents that can be used in the present disclosure include, but are not limited to, more preferably, acetone, tetrahydrofuran, 1,4-dioxane, and mixtures thereof.

In certain embodiments, illustrative examples of antisolvents that can be used in the present disclosure include, but are not limited to, water.

In certain embodiments, the volume ratio of organic solvent to antisolvent in the solvent in which the compound of formula (I) is dissolved is about 1:1 to 10.

In certain embodiments, the volume ratio of organic solvent to antisolvent in the solvent in which the compound of formula (I) is dissolved is about 1:3 to 5.

In certain embodiments, the mass-to-volume ratio of the compound of formula (I) to the solvent in which it is dissolved is about 10 to 100 mg/mL.

In certain embodiments, the mass-to-volume ratio of the compound of formula (I) to the solvent in which it is dissolved is about 20 to 50 mg/mL.

In certain embodiments, the drying temperature is about 10 to 50°C.

In certain embodiments, the drying temperature is about 40°C.

In certain embodiments, the drying time is about 1 to 24 hours.

In certain embodiments, the drying time is about 16 hours.

In certain embodiments, illustrative examples of organic solvents that can be used in the present disclosure include, but are not limited to, cyclic ethers.

In certain embodiments, illustrative examples of organic solvents that can be used in the present disclosure include, but are not limited to, tetrahydrofuran.

In certain embodiments, the volume ratio of organic solvent to water in the mixed solvent is about 1:0.1 to 0.5.

In certain embodiments, the volume ratio of organic solvent to water in the mixed solvent is about 1:0.2 to 0.4.

In certain embodiments, the mass volume ratio of the compound represented by formula (I) to the mixed solvent is about 10 to 100 mg/mL.

In certain embodiments, the mass volume ratio of the compound represented by formula (I) to the mixed solvent is about 20 to 50 mg/mL.

In certain embodiments, the temperature at which the solution is formed is about 60 to 80°C.

In certain embodiments, the temperature at which the solution is formed is about 65 to 75°C.

In certain embodiments, the cooling temperature is about -5 to 10°C.

In certain embodiments, the temperature of cooling is about 0 to 4°C.

In certain embodiments, the drying temperature is about 10 to 50°C.

In certain embodiments, the drying temperature is about 40°C.

In certain embodiments, the drying time is about 1 to 24 hours.

In certain embodiments, the drying time is about 16 hours.

In certain embodiments, the temperature of agitation is about 10 to 45°C.

In certain embodiments, the stirring temperature is about room temperature.

In certain embodiments, the method for preparing the crystal form II of the compound represented by formula (II) disclosed in the present disclosure is simple, requires small types and amounts of organic solvents, is more conducive to green pharmacy, and has simpler steps.

In certain embodiments, Form I of the compound of formula (I) of the present disclosure has only less than 0.03% weight change in the 0-80% relative humidity range. In certain embodiments, formula (II) The crystal form II of the compound shown is a block-like granular crystal with better morphology and better fluidity, which can reduce the filtration time of the API and the sieving time of the preparation, which is beneficial to the accurate measurement and production of the preparation. Improve efficiency.

pharmaceutical composition

In yet another aspect, the present disclosure relates to a pharmaceutical composition comprising crystal form I of the compound represented by formula (I) of the present disclosure, crystal form II of the compound represented by formula (II) of the present disclosure, or formula of the present disclosure Any mixture of the crystalline form I of the compound represented by (I) and the crystalline form II of the compound represented by the formula (II) of the present disclosure, and a pharmaceutically acceptable carrier, diluent or excipient.

In certain embodiments, the crystalline form I of the compound of formula (I) of the present disclosure is used for the treatment or prevention of tyrosine kinase 2-related diseases or disease states. The routes of administration include, but are not limited to, oral, lingual Subcutaneous, intravenous, intramuscular, nasal, topical and rectal routes of administration.

In certain embodiments, illustrative examples of oral formulations that can be used in the present disclosure include, but are not limited to, tablets, capsules, powders, granules, solutions, and suspensions.

Examples of pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present disclosure include, but are not limited to, any adjuvant, carrier, excipient, adjuvant that has been approved by the U.S. Food and Drug Administration for use in humans or animals. Flow agents, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic pressure agents, solvents or emulsifiers, etc. Various forms of carriers without adverse effects to make up the pharmaceutical composition. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical arts. The pharmaceutical compositions of the present disclosure can be administered by any method that achieves their intended purpose. For example, administration can be by oral, parenteral, topical, enteral, intravenous, intramuscular, inhalation, nasal, intraarticular, intraspinal, transtracheal, ocular, subcutaneous, intraperitoneal, transdermal, or buccal routes. conduct. The route of administration can be parenteral, oral, and intrarectal. The dose administered will depend on the age, health, and weight of the recipient, and, if any, concomitant therapy, the type of concurrent therapy, the frequency of the therapy, and the nature of the desired effect.

Suitable dosage forms include, but are not limited to, capsules, tablets, pellets, dragees, semisolids, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, ointments , gels, tapes, eye drops, solutions, syrups, aerosols, suspensions, emulsions, which can be prepared according to methods known in the art.

Particularly suitable for oral administration are ordinary tablets (plain tablets), sugar-coated tablets, film-coated tablets, pills, capsules, powders, granules, syrups, juices or drops, and those suitable for rectal administration are suppositories, suitable for Parenteral administration is in the form of solutions, also oil-based or aqueous solutions, in addition to suspensions, emulsions or implants, and suitable for topical use as ointments, creams, creams, suppositories or powders. The products of the present disclosure can also be lyophilized and the resulting lyophilisates used, for example, in the preparation of injectables. The products in the present disclosure can also be made into solid dispersions for oral preparations, such as tablets or capsules, and the methods of preparing solid dispersions can adopt conventional methods, such as spray drying/hot melt extrusion/lyophilization, etc., The compounds of the present application can be uniformly dispersed in polymers, including but not limited to celluloses, ? The cellulose can be: hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate and one or more of hydroxyethyl ethyl cellulose acetic acid and combinations thereof, the non-cellulose can be: one or both of polyacrylate, acrylate and methacrylate copolymer the above and combinations thereof. The formulations given may be sterilized and/or contain adjuvants such as wetting agents, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for varying the osmotic pressure, buffer substances, Dyes, flavors and/or numerous additional active ingredients, such as one or more vitamins.

Preservatives, stabilizers, dyes, sweeteners, aromas, flavors, and the like can be provided in the pharmaceutical composition. For example, sodium benzoate, ascorbic acid, and esters of p-hydroxybenzoic acid may be added as preservatives. In addition, antioxidants and suspending agents can be used.

In various embodiments, alcohols, esters, sulfated aliphatic alcohols, etc. can be used as surfactants; sucrose, glucose, lactose, starch, crystalline cellulose, mannitol, light anhydrous silicates, magnesium aluminate , magnesium aluminate methyl silicate, synthetic aluminum silicate, calcium carbonate, calcium bicarbonate, calcium hydrogen phosphate, calcium hydroxymethyl cellulose, etc. can be used as excipients; magnesium stearate, talc, hardened oil, etc. can be used as excipients. Used as a lubricating agent; coconut oil, olive oil, sesame oil, peanut oil, soybean oil can be used as a suspending agent or lubricant; cellulose acetate as a derivative of sugars such as cellulose or sugar, or as a derivative of polyethylene Polymethyl acetate-methacrylate copolymers of phthalates can be used as suspending agents; and plasticizers such as phthalates can be used as suspending agents.

Suitable routes of administration may include, for example, oral (immediate, sustained or controlled release), rectal, transmembrane, parenteral, transdermal, topical or enteral; parenteral External delivery includes intramuscular, subcutaneous, intravenous, intramedullary, and intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injection. The compounds can also be extended at predetermined rates and/or in sustained or controlled release dosage forms including depot injections, osmotic pumps, pills, transdermal (including electromigration) patches, and the like. Timed, pulsed administration.

The pharmaceutical compositions of the present disclosure can be produced by known methods, eg, by conventional mixing, dissolving, granulating, dragee-making, milling, emulsifying, encapsulating, entrapping, or tableting procedures.

Thus, in accordance with the present disclosure, pharmaceutical compositions for use may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into Pharmaceutically acceptable preparations. Appropriate formulations depend on the route of administration chosen. Any of the well known techniques, carriers and excipients may be used as appropriate and understood in the art.

Injectables can be prepared in conventional forms: as solutions or suspensions, solid dosage forms suitable for solution or suspension prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride and the like. In addition, if necessary, the pharmaceutical composition for injection may contain a small amount of non-toxic adjuvants such as wetting agents, pH buffering agents and the like. Physiologically suitable buffers include, but are not limited to, Hank's solution, Ringer's solution, or physiological saline buffer. If desired, absorption enhancing formulations (eg, liposomes) can be used.

For oral administration, the compounds can be readily formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, lozenges, capsules, liquids, gels, syrups, slurries, suspensions, solutions, powders and the like for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral administration can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture and processing the mixture of granules, if necessary after adding suitable auxiliaries, to obtain tablets or Lozenge core. Suitable excipients are especially fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulosic preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl methacrylate cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone (PVP). Disintegrants such as cross-linked polyvinylpyrrolidone, agar or alginic acid or alginates such as sodium alginate can be added if desired. Lozenge cores are suitably coated. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, shellac lacquer solutions and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, shellac solutions, and suitable organic solvent or solvent mixture.

Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin, such as glycerol or sorbitol, and a plasticizer. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active ingredients may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. Additionally, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.

In certain embodiments, the pharmaceutical compositions of the present disclosure may comprise 0.1% to 95% of the crystalline form I of the compound of formula (I) of the present disclosure.

In certain embodiments, the pharmaceutical compositions of the present disclosure may comprise 1% to 70% of the crystalline form I of the compound of formula (I) of the present disclosure.

In any event, the composition or formulation to be administered will contain an amount of Form I of a compound of formula (I) of the present disclosure effective to treat the disease/condition of the subject being treated.

In certain embodiments, the pharmaceutical composition of the present disclosure may comprise 0.1%-95% of the crystalline form II of the compound of formula (II) of the present disclosure.

In certain embodiments, the pharmaceutical compositions of the present disclosure may comprise 1% to 70% of the crystalline form II of the compound of formula (II) of the present disclosure.

In any event, the composition or formulation to be administered will contain an amount of Form II of a compound of formula (II) of the present disclosure effective to treat the disease/condition of the subject being treated.

In certain embodiments, the individual is a mammal.

In certain embodiments, the individual is a human.

In certain embodiments, illustrative examples of diseases or disease states that can be used in the present disclosure include, but are not limited to, diseases or disease states associated with TYK2.

In certain embodiments, illustrative examples of diseases or disease states that can be used in the present disclosure include, but are not limited to, autoimmune and auto-inflammatory related diseases or disease states.

In certain embodiments, illustrative examples of autoimmune and autoinflammatory related diseases or disease states that can be used in the present disclosure include, but are not limited to, psoriasis, plaque psoriasis, psoriatic joints inflammation, lupus, lupus nephritis, Sjogren's syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and ankylosing spondylitis.

In certain embodiments, a method of treating or preventing a disease or disease state associated with tyrosine kinase 2 comprises administering to an individual in need of the method 1 mg-10 g of a compound of formula (I) of the present disclosure Crystal form I, crystal form II of the compound represented by formula (II), or a mixture thereof.

In certain embodiments, a method of treating or preventing a disease or disease state associated with tyrosine kinase 2 comprises administering to an individual in need of the method 10 mg-3000 mg of a compound of formula (I) of the present disclosure Crystal form I, crystal form II of the compound represented by formula (II), or a mixture thereof.

In certain embodiments, a method of treating or preventing a disease or disease state associated with tyrosine kinase 2 comprises administering to an individual in need of the method 1 mg-200 mg of a compound of formula (I) of the present disclosure Crystal form I, crystal form II of the compound represented by formula (II), or a mixture thereof.

In certain embodiments, a method of treating or preventing a disease or disease state associated with tyrosine kinase 2 comprises administering to an individual in need of the method about 1-500 mg, specifically 1 mg, 2 mg, 2.5 mg, 3 mg , 3.5mg, 4mg, 4.5mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 12mg, 15mg, 18mg, 20mg, 24mg, 25mg, 30mg, 35mg, 36mg, 40mg, 45mg, 50mg, 60mg, 70mg, 90mg , 100 mg, 120 mg, 150 mg, or 200 mg of the crystalline form I of the compound represented by formula (I) of the present disclosure, the crystalline form II of the compound represented by formula (II), or a mixture thereof. The number of administrations can be once a day, every other day, twice a day, three times a day, and the like.

In certain embodiments, the method of treating or preventing a tyrosine kinase 2-related disease or condition further comprises simultaneously or sequentially administering at least one disease or condition capable of treating or preventing a tyrosine kinase 2-related disease or condition of other active ingredients.

In certain embodiments, illustrative examples of other active ingredients that can be used in the present disclosure include, but are not limited to, corticosteroids, rolipram, calphostin, cytokine-suppressing anti-inflammatory drugs ( CSAID), interleukin-10, glucocorticoids, salicylates, nitric oxide and other immunosuppressants; nuclear translocation inhibitors such as deoxyspergualin (DSG); Inflammatory drugs (NSAIDs), such as ibuprofen, celecoxib, and rofecoxib; steroids, such as prednisone or dexamethasone; antiviral agents , eg, abacavir; antiproliferative agents, eg, methotrexate, leflunomide, FK506 (tacrolimus); antimalarial agents, eg, hydroxychloroquine; Cytotoxic drugs such as azathiprine and cyclophosphamide; TNF-alpha inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptors and rapamycin (sirolimus) ) or its derivatives.

method of administration

At least one crystalline form I of the compound represented by formula (I), crystalline form II of the compound represented by formula (II), or crystalline form I and formula (II) of the compound represented by formula (I) of the present disclosure can be ) of the compound represented by the crystal form II of the mixture, or comprising at least one of the crystal form I of the compound represented by the formula (I), the crystal form II of the compound represented by the formula (II) or the formula (I) of the present disclosure The pharmaceutical composition of a mixture of Form I of the compound shown and Form II of the compound of Formula (II) is carried out by any suitable method for systemic and/or local delivery of Form I of the compound of the present disclosure. method to administer the drug to the patient. Non-limiting examples of methods of administration include (a) administration by the oral route, including administration in capsules, tablets, granules, sprays, syrups, or other such forms; (b) administration by non- Oral route of administration, such as rectal, vaginal, intraurethral, intraocular, intranasal, or intrathecal, including in aqueous suspensions, oily formulations, etc., or in drops, sprays, suppositories, ointments, ointments, etc. administering; (c) administering via subcutaneous injection, intraperitoneal injection, intravenous injection, intramuscular injection, intradermal injection, intraorbital injection, intracapsular injection, intraspinal injection, intrasternal injection, etc., including infusion pump delivery; (d) local administration such as injection directly in the renal region or cardiac region, for example by depot implantation; and (e) topical administration; as known to those skilled in the art The appropriate mode of administration is considered to be the crystalline form I of the compound represented by formula (I), the crystalline form II of the compound represented by formula (II) or the crystalline form of the compound represented by formula (I) described in this disclosure. A mixture of Form I and Form II of the compound of Formula (II) is contacted with living tissue. For example, transdermal administration includes administration in the form of ointments, creams, gels, aerosols, suspensions, creams, creams or other such forms.

The most appropriate route depends on the nature and severity of the disease state being treated. Those skilled in the art are also familiar with determining methods of administration (oral, intravenous, inhalation, subcutaneous, rectal, etc.), dosage forms, appropriate pharmaceutical excipients, and other matters related to delivery of a crystalline form of a compound to a subject in need thereof.

Pharmaceutical compositions suitable for administration include those in which the active ingredient is contained in an amount effective to achieve its intended effect. The dosage required for a therapeutically effective amount of a pharmaceutical composition described in this disclosure will depend on the route of administration, the type of animal being treated, including humans, and the physical characteristics of the particular animal under consideration. Dosage can be adjusted to achieve the desired effect, but will depend on factors such as body weight, diet, concomitant medication and other factors recognized by those skilled in the medical arts. More specifically, a therapeutically effective amount refers to an amount of a crystalline form of the compound effective to prevent, reduce or ameliorate the symptoms of a disease, or prolong the lifespan of an individual receiving treatment. A therapeutically effective amount is well within the practical ability of those skilled in the art, particularly in light of the detailed disclosure provided in this disclosure.

As will be apparent to those skilled in the art, the dosage for in vivo administration and the particular mode of administration will vary depending on the age, weight and species of mammal being treated, the crystal form of the particular compound used and the specific uses of the crystalline forms of these compounds. Those skilled in the art can use conventional pharmacological methods to determine effective dosage levels, ie, the dosage levels necessary to determine the desired effect. Typically, human clinical use of the product is initiated at lower dose levels, with increasing dose levels until the desired effect is achieved. Alternatively, using established pharmacological methods, acceptable in vitro studies can be used to establish effective doses and routes of administration for the compositions identified by this method.

In non-human animal studies, application of the potential product is initiated at higher dose levels, with dose reductions until the desired effect is no longer achieved or the adverse side effects disappear. Depending on the desired effect and the indication for treatment, the dosage range may be wider. Typically, dosages can range from about 10 μg/kg body weight to 1000 mg/kg body weight, and in certain embodiments from about 100 μg/kg body weight to 300 mg/kg body weight. Alternatively, as understood by those skilled in the art, the dose may be based on and calculated from the patient's body surface area.

The exact formulation, route of administration, and dosage of the pharmaceutical compositions described in this disclosure can be selected by each physician according to the patient's condition. Typically, the dose of the composition administered to a patient may range from about 0.5 mg/kg to 1000 mg/kg of the patient's body weight. The doses may be administered individually or in two or more doses over the course of one or several days, as desired by the patient. Where human doses for a crystalline form of the compound are established for at least some conditions, the present disclosure will use those same doses, or a dose ranging from about 0.1% to 500% of the established human doses, in certain implementations Dosages in the regimen ranged from 25% to 250% of the established human dose. In the absence of established human doses, as is the case with newly discovered pharmaceutical compounds, suitable human doses can be derived from the median effective dose or the median infectious dose, or other suitable values from in vitro or in vivo studies Inferred, as quantified in toxicity studies and efficacy studies in animals.

It should be noted that the attending physician will know how and when to terminate, interrupt or adjust dosing due to toxicity and organ dysfunction. Conversely, if the clinical response is insufficient (excluding toxicity), the attending physician will also know to adjust treatment to higher levels. The size of the dose administered in the treatment of the condition of interest will vary with the severity of the disease state being treated and the route of administration. The severity of the disease state can be assessed, for example, in part by standard prognostic assessment methods. In addition, the dose and possible dose frequency will also vary depending on the age, weight, and response of the individual patient. A protocol comparable to the protocol discussed above can be used in veterinary medicine.

While the exact dosage can be determined on a drug-by-drug basis, in most cases certain generalizations can be made about the agents. The daily dosage regimen for an adult patient is, for example, an oral dose of 0.1 mg to 2000 mg of each active ingredient, in certain embodiments 1 mg to 2000 mg of each active ingredient, eg, 5 mg to 1500 mg of each active ingredient. In other embodiments, the intravenous, subcutaneous or intramuscular dose of each active ingredient used is 0.01 mg to 1000 mg, in certain embodiments 0.1 mg to 1000 mg, such as 1 mg to 800 mg. In the case of administration of a pharmaceutically acceptable salt, the dosage can be calculated as the free base. In certain embodiments, the composition is administered 1 to 4 times daily. Alternatively, the compositions described in the present disclosure may be administered by continuous intravenous infusion, in certain embodiments at doses of up to 2000 mg per day of each active ingredient. As will be appreciated by those of skill in the art, in some instances it may be necessary to administer the compounds described in this disclosure in amounts that exceed or far exceed the above-mentioned dosage ranges in order to effectively and rapidly treat a rapidly progressing disease or infection . In certain embodiments, the compound is administered over a period of continuous treatment, eg, one week or several weeks, or months or years.

Dosage and dosing intervals can be adjusted individually to provide plasma levels of the active moiety sufficient to maintain the adjusted effect or minimum effective concentration (MEC). The MEC is different for each compound, but MEC can be assessed from in vitro data. The dose required to achieve the MEC will depend on individual characteristics and route of administration. However, plasma concentrations can be determined using HPLC (High Performance Liquid Chromatography) assays or bioassays.

Dosing intervals can also be determined using the MEC value. Treatment should be used that maintains plasma levels above the MEC 10-90% of the time, in certain embodiments 30-90% of the time, and in certain embodiments 50-90% of the time The regimen administers the composition.

In the case of topical administration or selective absorption, the effective local concentration of the drug is independent of the plasma concentration.

Of course, the amount of the composition to be administered will depend on the individual being treated, on the weight of the individual, the severity of the distress, the mode of administration, and the judgment of the prescribing physician.

The efficacy and toxicity of the compounds described in this disclosure can be assessed using known methods. For example, the toxicology of a particular compound, or a subset of the compound that shares certain chemical moieties, can be established by assaying the toxicity of a cell line in vitro, such as a mammalian cell line and, in certain embodiments, a human cell line. The results of such studies generally predict toxicity in animals such as mammals, or more specifically, in humans. Alternatively, the toxicity of a particular compound in animal models such as mice, rats, rabbits or monkeys can be determined using known methods. The potency of a particular compound can be determined using several recognized methods, such as in vitro methods, animal models or human clinical trials. Recognized in vitro models exist for nearly every type of disease state, including but not limited to cancer, cardiovascular disease, and various immune dysfunctions. Similarly, acceptable animal models can be used to determine the efficacy of chemotherapeutics for the treatment of these disease states. When selecting a model to measure efficacy, the skilled artisan will be able to select an appropriate model, dosage and route of administration, and treatment regimen under the guidance of the state of the art. Of course, human clinical trials can also be used to determine the efficacy of a compound in humans.

The compositions can, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The package may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may carry instructions for administration. The packaging or dispensing device may also carry a notice associated with the container, the notice being prescribed by a governmental agency regulating the manufacture, use or sale of a drug, the notice reflecting that the drug form has been approved by the agency Approved for human or veterinary administration. Such notices may, for example, be labels approved by the State Food and Drug Administration or the U.S. Food and Drug Administration for prescription drugs, or approved product inserts. Compositions comprising a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof can also be formulated in a suitable container, placed in a compatible pharmaceutical carrier, and labeled for use. treatment for the specified disease state.

Hereinafter, the present disclosure will be explained in detail through the following examples for better understanding of various aspects and advantages of the present application. It should be understood, however, that the following examples are non-limiting and merely illustrative of certain embodiments of the present application.

Example

Testing instruments and methods:

X-ray powder diffraction (XRPD): The instrument is a Bruker D8 Advance diffractometer. Samples were tested at room temperature. The detection conditions are as follows, angle range: 3 to 40° 2θ, step size: 0.02° 2θ, speed: 0.2 sec/step.

Polarized light microscopy (PLM) spectra were obtained from XP-500E polarized light microscope. Take a small amount of powder sample and place it on a glass slide, add a small amount of mineral oil dropwise to disperse the sample, cover it with a cover glass, place it on the stage for observation and take pictures.

Differential Scanning Calorimetry (DSC) data were obtained from TA Instruments Q200 MDSC. The detection method is as follows: take a sample of 1 to 10 mg and place it in a closed small-hole aluminum crucible (where the crystal form I of the compound represented by formula (I) is covered without perforation, and the crystal form of the compound represented by formula (II) is II capping and punching), the sample was raised from room temperature to 300 °C at a heating rate of 10 °C/min under the protection of 50 mL/min of dry N2.

Thermogravimetric analysis (TGA) data were obtained from TA Instruments Q500 TGA. The detection method is as follows: take 5 to 15 mg of the sample and place it in a platinum crucible, adopt the method of segmented high-resolution detection, and raise the sample from room temperature to 40 mL/min under the protection of dry _N2 at a heating rate of 10 °C/min. 300°C.

Dynamic moisture sorption analysis (DVS) data and isothermal sorption analysis data were obtained from TA Instruments Q5000 TGA. The detection method is as follows: take a sample of 1 to 10 mg and place it in a platinum crucible, and detect the weight change during the change of relative humidity from 0% to 80% to 0%.

All reagents used in the examples of the present disclosure are commercially available unless otherwise specified.

Unless otherwise specified, the embodiments of the present disclosure are all operated at room temperature.

Preparation Example 1

According to the preparation method of Example 2 of patent application CN110914260A, the crystal form A of Deucravicitinib (that is, the compound represented by formula (I)) is prepared, and the specific steps are as follows:

A solution was prepared by mixing 2 g of the compound of formula (I) into 143 mL of tetrahydrofuran and 7 mL of water at room temperature (25°C) until the compound of formula (I) was completely dissolved. The solution was polished filter at room temperature and then dried overnight using a Speed vac. The resulting solid was suspended in 12 mL of ethyl acetate at 60°C, and the resulting slurry was aged at 60°C overnight. The slurry was filtered and the wet cake was washed with 5 mL of ethyl acetate. The wet cake was dried in a vacuum oven at a temperature in the range of 50 to 60° C. to obtain 1.4 g of Form A of the compound represented by formula (I).

Example 1

Weigh 100 mg of the compound represented by the formula (I), add 6.5 mL of trifluoroethanol until the solution is clarified, evaporate and concentrate under reduced pressure at 50 ° C until the solvent is dry to obtain a solid, and vacuum dry the solid at 40 ° C for 1 hour to obtain the formula (I). Form I of the compound shown.

The XRPD pattern of the crystal form I of the compound represented by formula (I) is shown in FIG. 1 .

The DSC curve of the crystal form I of the compound represented by formula (I) is shown in FIG. 2 .

The TGA curve of the crystal form I of the compound represented by formula (I) is shown in FIG. 3 .

The DVS curve of the crystal form I of the compound represented by formula (I) is shown in FIG. 4 .

Example 2

Weigh 40 mg of the compound represented by formula (I), add 2 mL of tetrahydrofuran and 0.1 mL of water in turn, ultrasonicate for 10 minutes until the solution is clarified, add 6 _μL of concentrated sulfuric acid (98%), and stir at 4° C. for 40 minutes to precipitate a yellow solid, Centrifugation. The separated yellow solid was dissolved in 2 mL of water by ultrasonic, and sodium hydroxide solution (10 mg of sodium hydroxide was dissolved in 0.5 mL of water) was added dropwise to precipitate a white solid, which was centrifuged. The isolated white solid was vacuum-dried at 40° C. for 16 hours, and then kept at 150° C. for 10 minutes to obtain the crystal form I of the compound represented by formula (I).

The product prepared in Example 2 has the same or similar XRPD spectrum, DSC curve, TGA curve and DVS curve as the product prepared in Example 1, which shows that the product prepared in Example 2 and the product prepared in Example 1 are have the same crystal form.

Example 3

30 mg of the compound represented by formula (I) was weighed, and 1.0 mL of acetone and 0.4 mL of water were sequentially added at room temperature until the solution was dissolved and clarified to obtain a solution. 3.0 mL of water was added to this solution, and a white solid was precipitated. The stirring was continued for 10 minutes, and the solid was separated by centrifugation. The solid was vacuum dried at 40°C for 16 hours to obtain the crystalline form II of the compound represented by formula (II).

The XRPD pattern of the crystal form II of the compound represented by formula (II) is shown in FIG. 5 .

The DSC curve of the crystal form II of the compound represented by formula (II) is shown in FIG. 6 .

The TGA curve of the crystal form II of the compound represented by formula (II) is shown in FIG. 7 .

Example 4

45 mg of the compound represented by formula (I) was weighed, and 1.5 mL of tetrahydrofuran and 0.3 mL of water were sequentially added at room temperature until the solution was dissolved and clarified to obtain a solution. This solution was added to 6.0 mL of water, stirred, and a white solid was precipitated, and the stirring was continued for 10 minutes, and the solid was separated by centrifugation. The solid was vacuum dried at 40°C for 16 hours to obtain the crystalline form II of the compound represented by formula (II).

Example 5

25 mg of the compound represented by formula (I) was weighed, and 1.0 mL of 1,4-dioxane and 0.2 mL of water were sequentially added at room temperature to dissolve and clarify to obtain a solution. 3.0 mL of water was added to this solution, and a white solid was precipitated. The stirring was continued for 10 minutes, and the solid was separated by centrifugation. The solid was vacuum dried at 40°C for 16 hours to obtain the crystalline form II of the compound represented by formula (II).

Example 6

60 mg of the compound represented by formula (I) was weighed, 2.0 mL of tetrahydrofuran and 0.8 mL of water were added in sequence, heated at 70° C. until dissolved and clarified, and then stirred at 4° C. for 16 hours to precipitate a white solid, and the solid was separated by centrifugation. The solid was vacuum dried at 40°C for 16 hours to obtain the crystalline form II of the compound represented by formula (II).

Example 7

Take 30 mg of the crystal form A of the compound represented by formula (I) of Preparation Example 1, add 2 mL of water to form a suspension, stir and crystallize at room temperature for 29 hours, filter, and vacuum dry at room temperature for 8 hours to obtain the compound represented by formula (II) crystal form II.

Example 8

Take 50 mg of the crystal form I of the compound represented by formula (I) prepared according to Example 1, add 3 mL of water to form a suspension, stir and crystallize at room temperature for 26 hours, filter, and vacuum dry at room temperature for 8 hours to obtain the formula (II). Form II of the compound shown.

The products prepared in Examples 4 to 8 have the same or similar XRPD spectra, DSC curves and TGA curves as the products prepared in Example 3, which indicates that the products prepared in Examples 4 to 8 are the same as those prepared in Example 3. have the same crystal form.

Example 9

Crystal stability

Weigh an appropriate amount of the crystal form I prepared in Example 1 and the crystal form II prepared in Example 3, respectively, and place each crystal form sample under long-term and accelerated conditions respectively, and periodically detect XRPD. The experimental results show that the crystal form I and the crystal form II have not been transformed into crystals after long-term exposure and accelerated exposure for 93 days (Fig. 8 and Fig. 9).

Take 10 mg of crystal form A in Preparation Example 1 and 10 mg of crystal form II sample, put them in a 5 mL glass vial, add 2 mL of water, stir for 3 hours, and detect XRPD, all of which are converted to crystal form II (Figure 10).

Example 10

chemical stability

Weigh an appropriate amount of the crystal form I prepared in Example 1 and the crystal form II prepared in Example 3, respectively. 75%RH, open), high temperature (50℃, sealed) and light (4500lux ± 500lux, with UV, sealed) conditions, the purity is checked regularly. The detection methods are shown in Table 1, and the detection results are shown in Table 2.

Table 1. HPLC method for detection of related substances

类目Category	参数 parameter
仪器instrument
Uitimate 3000高效液相色谱仪Uitimate 3000 High Performance Liquid Chromatograph
色谱柱类型Column Type	C18,4.6×150mm,5μmC18, 4.6×150mm, 5μm
紫外波长UV wavelength	UV at 250nmUV at 250nm
流速flow rate	1.0mL/min1.0mL/min

柱温column temperature	35℃35℃
进样量Injection volume	3μL3μL
稀释剂thinner	80％甲醇80% methanol
流动相Amobile phase A	甲醇methanol
流动相Bmobile phase B	水water
流动相比例mobile phase ratio	A:B＝80:20A:B=80:20

Table 2. Chemical stability test results

The results show that both the crystal form I and the crystal form II have considerable chemical stability, and the purity does not drop by more than 0.5% after being placed for 81 days.

Example 11

Particle size distribution

Weigh an appropriate amount of the crystal form I prepared in Example 1 and the crystal form II prepared in Example 3, respectively, and after dispersing with water, set the flow rate to 55%, and use the volume distribution to perform PSD detection.

The experimental results shown in Table 3, Fig. 11 and Fig. 12 show that the samples of crystal form I and crystal form II are unimodal, and the D( _{90 ) of crystal form I is about 50 μm, and the D( 90} ₎ of crystal form II is around 50 μm. 180μm or so.

Table 3. Particle size distribution test results of Form I and Form II

晶型Crystal form	D ₍₁₀₎(μm) D ₍₁₀₎ (μm)	D ₍₅₀₎(μm) D ₍₅₀₎ (μm)	D ₍₉₀₎(μm) D ₍₉₀₎ (μm)
晶型IForm I	23.223.2	37.537.5	46.246.2
晶型IIForm II	59.659.6	97.697.6	176.9176.9

Example 12

Solubility in water

The preparation contains the crystal form I prepared in Example 1, then shake at 25°C ± 2°C, and take samples at 60 min to check the solubility of the sample by HPLC (see Table 1 for the HPLC method).

The experimental results shown in Table 4 show that the solubility of Form I is 17 μg/mL.

Table 4. The water solubility test results of crystal form I

Example 13

tablet dissolution

1) Take the crystal form I prepared in Example 1, mix the crystal form I, anhydrous lactose, microcrystalline cellulose and hydroxypropyl cellulose K4M according to the recipe quantity in Table 5, and screen the mixed combination. The screened mixture is mixed with magnesium stearate, the screened mixture is mixed with magnesium stearate, dry granulated (slug/roller process), and then ground. It is further mixed with magnesium stearate to prepare tablets, each tablet weighing about 300 mg.

Table 5. Form I tablet formulation

原辅料Raw materials	比例(％)Proportion(%)
晶型IForm I	55
羟丙基纤维素K4M Hydroxypropyl Cellulose K4M	2020
无水乳糖anhydrous lactose	3737
微晶纤维素microcrystalline cellulose	3737
硬脂酸镁 Magnesium stearate	11
总计 total	100100

2) Prepare pH 6.8 phosphate buffer.

3) Dissolution method: temperature 37°C, rotation speed 100rpm, medium volume 900mL, slurry method.

4) Sampling and testing at nine time points of 10min, 30min, 1h, 2h, 4h, 6h, 8h, 12h and 24h respectively, the results are shown in Table 6.

Table 6. Dissolution test results of Form I tablets

时间time	晶型I溶出度(％)Form I dissolution (%)
10min10min	3.93.9
30min30min	26.5126.51
60min60min	44.3244.32
120min120min	62.5362.53
240min240min	72.3772.37
6小时6 hours	76.5976.59
8小时8 hours	80.2980.29
12小时12 hours	89.1789.17
24小时24 hours	91.9391.93

According to Table 6, it can be seen that the ordinary tablet directly prepared from crystal form 1 has a good dissolution rate.

In this disclosure, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply that any such relationship exists between these entities or operations. an actual relationship or sequence.

It will be understood from the foregoing that although specific embodiments of the present disclosure have been described for illustrative purposes, various modifications or improvements can be made by those skilled in the art without departing from the spirit and scope of the present disclosure. Such variations or modifications should all fall within the scope of the appended claims of the present disclosure.

Claims

Crystal form I of the compound represented by formula (I):

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form I expressed at 2θ angle has the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2° ±0.2°.
Crystal form I of the compound represented by formula (I):

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern represented by the 2θ angle of the crystal form I has the following characteristic peaks: about 8.2°, about 11.3°, about 19.3°, about 20.5° and about 23.2°.
Crystal form I of the compound represented by formula (I):

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form I expressed at 2θ angle has the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2° ±0.2°, and the X-ray powder diffraction pattern of the crystalline form I also has characteristic peaks at at least three of the following 2θ angles: 6.4±0.2°, 10.1±0.2°, 12.6±0.2°, 14.5±0.2°, 16.3±0.2° and 16.4±0.2°.
Crystal form I of the compound represented by formula (I):

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form I in 2θ angle has the following characteristic peaks: about 8.2°, about 11.3°, about 19.3°, about 20.5° and about 23.2°, and all The X-ray powder diffraction pattern of Form I also has characteristic peaks at at least three of the following 2θ angles: about 6.4°, about 10.1°, about 12.6°, about 14.5°, about 16.3°, and about 16.4°.
Crystal form I of the compound represented by formula (I):

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form I expressed at 2θ angle has the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2° ±0.2°, and the X-ray powder diffraction pattern of the crystalline form I also has characteristic peaks at the following 2θ angles: 6.4±0.2°, 10.1±0.2°, 12.60±0.2°, 14.5±0.2°, 16.3±0.2° and 16.4±0.2°.
Crystal form I of the compound represented by formula (I):

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form I in 2θ angle has the following characteristic peaks: about 8.2°, about 11.3°, about 19.3°, about 20.5° and about 23.2°, and all The X-ray powder diffraction pattern of Form I also has characteristic peaks at the following 2θ angles: about 6.4°, about 10.1°, about 12.6°, about 14.5°, about 16.3° and about 16.4°.
Crystal form I of the compound represented by formula (I):

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form I expressed at 2θ angle has the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2° ±0.2°, and the X-ray powder diffraction pattern of the crystalline form I also has characteristic peaks at at least three of the following 2θ angles: 14.8±0.2°, 18.3±0.2°, 18.5±0.2°, 19.9±0.2°, 21.5±0.2°, 24.3±0.2°, 25.0±0.2° and 27.8±0.2°.
Crystal form I of the compound represented by formula (I):

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form I in 2θ angle has the following characteristic peaks: about 8.2°, about 11.3°, about 19.3°, about 20.5° and about 23.2°, and all The X-ray powder diffraction pattern of Form I also has characteristic peaks at at least three of the following 2θ angles: about 14.8°, about 18.3°, about 18.5°, about 19.9°, about 21.5°, about 24.3°, about 25.0 ° and about 27.8°.
Crystal form I of the compound represented by formula (I):

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form I expressed at 2θ angle has the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2° ±0.2°, and the X-ray powder diffraction pattern of the crystalline form I also has characteristic peaks at the following 2θ angles: 18.3±0.2°, 18.5±0.2°, 19.9±0.2°, 21.5±0.2°, 24.3±0.2° , 25.0±0.2° and 27.8±0.2°.
Crystal form I of the compound represented by formula (I):

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form I in 2θ angle has the following characteristic peaks: about 8.2°, about 11.3°, about 19.3°, about 20.5° and about 23.2°, and all The X-ray powder diffraction pattern of Form I also has characteristic peaks at the following 2θ angles: about 18.3°, about 18.5°, about 19.9°, about 21.5°, about 24.3°, about 25.0°, and about 27.8°.

Crystal form I of the compound represented by formula (I):

2θ Relative Intensity %(I) 6.4±0.2° 13.1 8.2±0.2° 19.7 9.0±0.2° 2.3 10.1±0.2° 14.1 11.3±0.2° 57.9 12.6±0.2° 21.7 14.5±0.2° 11.1 16.3±0.2° 16.1 16.4±0.2° 18.0 18.3±0.2° 6.9 18.5±0.2° 10.9 19.3±0.2° 36.9 19.9±0.2° 11.5 20.5±0.2° 33.0 21.1±0.2° 3.9 21.5±0.2° 12.9 22.8±0.2° 8.0 23.2±0.2° 100.0

.

Crystal form I of the compound represented by formula (I):

Wherein, using Cu-Kα radiation, the crystal form I basically has an X-ray powder diffraction pattern as shown in FIG. 1 .
Form I of the compound of formula (I) according to any one of claims 1 to 12 substantially free of solvent.
Form I of a compound of formula (I) according to any one of claims 1 to 13 that is substantially free of water.
Substantially pure form I of the compound of formula (I) as claimed in any one of claims 1 to 14.
The crystalline form I of the compound represented by formula (I) according to any one of claims 1 to 15 without solvent and without water.
The method for preparing the crystal form I of the compound represented by formula (I) according to any one of claims 1 to 16, comprising dissolving the compound represented by formula (I) in a halohydrin solvent, and concentrating to obtain solid, and the solid was dried to obtain the crystal form I.
The method for preparing the crystal form I of the compound represented by formula (I) according to any one of claims 1 to 16, which comprises in the solution of the acid salt of the compound represented by formula (I), using a base The compound of formula (I) is liberated to obtain a solid, which is isolated, dried, and kept at 120 to 180° C. to obtain the crystalline form I.
Form II of the compound represented by formula (II),

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form II at 2θ angle has the following characteristic peaks: 3.3±0.2°, 5.7±0.2°, 8.6±0.2°, 11.8±0.2°, 14.2 ±0.2° and 18.2±0.2°.
Form II of the compound represented by formula (II),

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form II at 2θ angle has the following characteristic peaks: about 3.3°, about 5.7°, about 8.6°, about 11.8°, about 14.2° and about 18.2° °.
Form II of the compound represented by formula (II),

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form II at 2θ angle has the following characteristic peaks: 3.3±0.2°, 5.7±0.2°, 8.6±0.2°, 11.8±0.2°, 14.2 ±0.2°, 14.9±0.2°, 16.3±0.2°, 17.3±0.2°, 18.2±0.2°, 20.4±0.2°, 21.5±0.2° and 23.6±0.2°.
Form II of the compound represented by formula (II),

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form II at 2θ angle has the following characteristic peaks: about 3.3°, about 5.7°, about 8.6°, about 11.8°, about 14.2°, about 14.9°, about 16.3°, about 17.3°, about 18.2°, about 20.4°, about 21.5°, and about 23.6°.
Form II of the compound represented by formula (II),

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form II at 2θ angle has the following characteristic peaks: 3.3±0.2°, 5.7±0.2°, 6.5±0.2°, 8.6±0.2°, 11.3 ±0.2°, 11.8±0.2°, 14.2±0.2°, 14.9±0.2°, 16.3±0.2°, 17.3±0.2°, 18.2±0.2°, 19.9±0.2°, 20.4±0.2°, 21.5±0.2°, 23.6 ±0.2°, 24.8±0.2° and 26.0±0.2°.
Form II of the compound represented by formula (II),

Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form II at 2θ angle has the following characteristic peaks: about 3.3°, about 5.7°, about 6.5°, about 8.6°, about 11.3°, about 11.8°, about 14.2°, about 14.9°, about 16.3°, about 17.3°, about 18.2°, about 19.9°, about 20.4°, about 21.5°, about 23.6°, about 24.8°, and about 26.0°.
Form II of the compound represented by formula (II),

Wherein, using Cu-Kα radiation, the characteristic peaks and relative intensities of the X-ray powder diffraction pattern of the crystal form II represented by the angle of 2θ are about:

2θ Relative Intensity %(I) 3.3±0.2° 74.1 5.7±0.2° 66.8 6.5±0.2° 4.4 8.6±0.2° 100 11.3±0.2° 3.4 11.8±0.2° 37.0 14.2±0.2° 37.2 14.9±0.2° 14.4 16.3±0.2° 8.9 17.3±0.2° 12.4 18.2±0.2° 29.5 19.9±0.2° 8.7 20.4±0.2° 4.1 21.5±0.2° 5.5 23.6±0.2° 15.5 24.8±0.2° 6.2 26.0±0.2° 19.0

.
Form II of the compound represented by formula (II),

Wherein, using Cu-Kα radiation, the crystal form II basically has an X-ray powder diffraction pattern as shown in FIG. 5 .
Substantially pure form II of the compound of formula (II) as claimed in any one of claims 19 to 26.
A method for preparing the crystal form II of the compound represented by formula (II) according to any one of claims 19 to 27, comprising mixing a solution of the compound represented by formula (I) with an antisolvent to obtain a solid, and The solid is isolated and dried to obtain the crystal form II.
A method for preparing the crystal form II of the compound represented by formula (II) according to any one of claims 19 to 27, comprising dissolving the compound represented by formula (I) in a mixed solvent of an organic solvent and water A solution is formed, the solution is cooled to obtain a solid, and the solid is separated and dried to obtain the crystal form II.
A method for preparing the crystal form II of the compound represented by formula (II) according to any one of claims 19 to 27, comprising stirring an aqueous suspension of the compound represented by formula (I), filtering and drying to obtain The crystal form II.
A pharmaceutical composition comprising the crystalline form I of the compound represented by formula (I) according to any one of claims 1 to 16, the compound represented by formula (II) according to any one of claims 19 to 27 The crystal form II of the compound shown or the crystal form I of the compound represented by the formula (I) described in any one of claims 1 to 16 and the formula (II) described in any one of claims 19 to 27. ) in any mixture of Form II of the compound shown, and a pharmaceutically acceptable carrier, diluent or excipient.
The pharmaceutical composition of claim 31, which is prepared for oral, sublingual, subcutaneous, intravenous, intramuscular, nasal, topical or rectal administration.
The pharmaceutical composition of claim 32, wherein the oral formulation is a tablet, capsule, powder, granule, solution or suspension.
A method of treating or preventing a disease or disease state associated with tyrosine kinase 2, comprising administering to an individual in need of the method a therapeutically or prophylactically effective amount of formula (I) according to any one of claims 1 to 16 ), the crystal form I of the compound represented by the formula (II) described in any one of claims 19 to 27, or the crystal form II of the compound represented by the formula (II) described in any one of claims 19 to 27, or the formula described in any one of claims 1 to 16. Any mixture of the crystal form I of the compound represented by (I) and the crystal form II of the compound represented by the formula (II) described in any one of claims 19 to 27, or a therapeutically effective amount of claims 31 to 27 33. The pharmaceutical composition of any one of claims 33.
The method of claim 34, wherein the individual is a mammal, preferably a human.
The method of claim 34 or 35, wherein the disease or disease state is selected from diseases or disease states associated with TYK2, preferably diseases or disease states associated with autoimmunity and auto-inflammation.
The method of claim 36, wherein the autoimmune and autoinflammatory related disease or condition is selected from the group consisting of psoriasis, plaque psoriasis, psoriatic arthritis, lupus, lupus nephritis, Sjogren's syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and ankylosing spondylitis.
37. The method of any one of claims 34-37, further comprising concurrently or sequentially administering at least one other active ingredient capable of treating or preventing a tyrosine kinase 2-related disease or condition.