Composition comprising PDE4 inhibitor, formulation, preparation method therefor, and use thereof

Abstract

Provided are a composition comprising a PDE4 inhibitor and a formulation, a preparation method therefor, and use thereof for treating and / or preventing respiratory diseases or related diseases thereof.

Description

Compositions, formulations, preparation methods and uses containing PDE4 inhibitors

[0001] Cross-references to related applications

[0002] This application claims priority and benefits from the following patent applications, the disclosure of which is incorporated herein by reference in its entirety:

[0003] Chinese Patent Application No. 202510061034.X, filed with the China National Intellectual Property Administration on January 14, 2025;

[0004] Chinese Patent Application No. 202510315713.5, filed with the China National Intellectual Property Administration on March 17, 2025;

[0005] Chinese Patent Application No. 202511141256.9, filed with the China National Intellectual Property Administration on August 14, 2025; and

[0006] Chinese Patent Application No. 202512041755.7 was filed with the China National Intellectual Property Administration on December 30, 2025. Technical Field

[0007] This disclosure relates to compositions, formulations, and uses thereof comprising PDE4 inhibitors. This disclosure also relates to solid forms of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2(1H)-one (hereinafter referred to as "Compound A") and / or its tautomers, methods for preparing said solid forms, and pharmaceutical compositions comprising said solid forms. This disclosure further relates to the use of said compositions and formulations for the treatment and / or prevention of respiratory diseases or related diseases, particularly for the treatment and / or prevention of lung diseases or related diseases. Background Technology

[0008] The phosphodiesterase (PDE) family comprises 11 enzyme families (PDE1-PDE11), among which PDE4 is a subtype of the phosphodiesterase family with unique cAMP activity. The downstream signaling pathways of PDE4-cAMP mainly include cAMP-dependent protein kinase (PKA) and cAMP-activated exchanger protein (EPAC). PDE4 inhibitors can reduce cAMP degradation, thereby enhancing the activity of antifibrotic mediators (PGE2, prostaglandins, and adenosine). These mediators signal through G protein-coupled receptors, thus exerting antifibrotic effects. PGE2 exhibits various antifibrotic effects, including inhibiting fibroblast activation, enhancing fibroblast susceptibility to apoptosis, and maintaining the integrity of alveolar epithelial cells. PGE2 can stimulate cAMP in lung fibroblasts through prostaglandin 2 receptors, disrupting calcium signaling and inducing antifibrotic activity. PGE2 and treprostacyclin can also inhibit TGF-β-induced myofibroblast differentiation and promote the reversion of differentiated myofibroblasts into fibroblasts. The secretion of pro-inflammatory and anti-inflammatory cytokines in these downstream cascade reactions inhibits superoxide production. Therefore, inhibiting PDE4 has become a novel strategy in the treatment of respiratory diseases or related conditions.

[0009] For compounds that are poorly soluble in water, possible formulations include, for example, powder inhalers, inhalation solutions, and inhalation suspensions. When developing inhalation solutions, for instance, organic reagents such as ethanol must be added as solvents, which can lead to significant respiratory irritation with prolonged inhalation. Therefore, for poorly soluble compounds, inhalation suspensions and powder inhalers are preferred formulations. Powder inhalers generally require an inspiratory flow rate greater than 30 L / min and demand a high degree of hand-mouth coordination from the patient.

[0010] Therefore, this disclosure aims to develop an inhalation suspension for poorly water-soluble compounds in PDE4 inhibitors, which is suitable for children and adult patients with an inspiratory flow rate of less than 30 L / min. Furthermore, the nebulized inhalation of the suspension requires less hand-mouth coordination, is easy to administer to patients, and has good patient compliance.

[0011] Invention Overview

[0012] In one aspect, this disclosure provides compound A (4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one), which undergoes tautomerism at certain temperatures. This disclosure relates to compound A and / or its tautomers in solid form:

[0013] Compound A and its tautomers

[0014] In one aspect, this disclosure provides a crystalline form of compound A (4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one) (and / or its tautomers) selected from crystal form I and crystal form II as defined in this application.

[0015] In one aspect, this application provides compositions comprising PDE4 inhibitors, formulations thereof, and uses thereof for treating lung diseases. Specifically, this application provides compositions comprising a compound of formula (I) or a tautomer thereof, a solvate, an anhydrous form, a pharmaceutically acceptable salt, or a crystalline form, and a surfactant, wherein the compound of formula (I) is:

[0016] Each group is as defined in the specification.

[0017] In one aspect, this application provides a composition comprising compound A (4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one) or its tautomer, solvate, anhydrous form, pharmaceutically acceptable salt or crystalline form, and a surfactant:

[0018] In one aspect, this application provides compositions comprising anhydrous crystalline form I or crystalline form II of compound A (and / or its tautomers) as defined in this application:

[0019] In one embodiment, this application provides a composition comprising an anhydrous form I or II of a compound A (and / or its tautomers) as defined in this application and a surfactant.

[0020] In one aspect, this application provides a method for preparing a composition, wherein a compound of formula (I) or its tautomer, solvate, anhydrous form, pharmaceutically acceptable salt or crystalline form is mixed with a surfactant, preferably, crystal form I or crystal form II is mixed with the surfactant.

[0021] In one aspect, this application provides for the use of the compositions of this application in the preparation of a medicament for treating and / or preventing respiratory diseases or related diseases. Attached Figure Description

[0022] Figure 1 shows the X-ray powder diffraction pattern of crystal form I of the anhydrous compound A.

[0023] Figure 2 shows the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) spectra of crystal form I of the anhydrous compound A.

[0024] Figure 3 is a scanning electron microscope image of crystal form I of the anhydrous compound A.

[0025] Figure 4 shows the X-ray powder diffraction pattern of crystal form II of the anhydrous compound A.

[0026] Figure 5 shows the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) spectra of crystal form II of the anhydrous compound A.

[0027] Figure 6 is a scanning electron microscope image of crystal form II of the anhydrous compound A.

[0028] Figure 7 shows a comparison of the XRPD spectra of crystal form I of the anhydrous compound A before and after the room temperature stability experiment.

[0029] Figure 8 shows a comparison of the XRPD spectra of the anhydrate crystal form I of compound A in the water activity experiment.

[0030] Figure 9 shows a comparison of the high-performance liquid chromatography (HPLC) spectra of the anhydrous compound A in crystal form I before and after the solid stability experiment.

[0031] Figure 10 shows a comparison of the high-performance liquid chromatography (HPLC) spectra of the anhydrous form II of compound A before and after the solid stability experiment.

[0032] Figure 11 shows a comparison of the X-ray powder diffraction patterns of crystal form I and crystal form II of the anhydrous compound A before and after the solid stability experiment.

[0033] Figure 12 shows a comparison of the X-ray powder diffraction patterns of crystal form I of the anhydrous compound A before and after the high humidity stability experiment.

[0034] Figure 13 shows a comparison of the X-ray powder diffraction patterns of crystal form I of the anhydrous compound A before and after the physical grinding experiment.

[0035] Figure 14 shows scanning electron microscope images of crystal form I of the anhydrous compound A before and after the physical grinding experiment.

[0036] Figure 15 shows the XRPD spectra of samples obtained by competitive pulping of crystal form I and crystal form II of the anhydrous compound A.

[0037] Figure 16 shows the XRPD spectra of the samples obtained by competitive pulping of crystal form I and crystal form II of the anhydrous compound A at 50℃.

[0038] Figure 17 shows the XRPD spectra of the samples obtained by competitive pulping of crystal form I and crystal form II of the anhydrous compound A at room temperature.

[0039] Figure 18 shows the XRPD spectra of samples obtained by competitive pulping of crystal form I and crystal form II of compound A anhydrous hydrate at 30-40℃.

[0040] Figure 19 shows a scanning electron microscope image of the micronized sample of the anhydrous compound A in crystal form I.

[0041] Figure 20 shows a scanning electron microscope image of the crystal form II micronized sample of the anhydrous compound A.

[0042] Figure 21 is a scanning electron microscope image of a suspension prepared from a micronized sample of anhydrous compound A in crystal form I after being left at room temperature for 15 days.

[0043] Figure 22 is a scanning electron microscope image of a suspension prepared from a micronized sample of anhydrous compound A in crystal form II after being left at room temperature for 15 days.

[0044] Figure 23 shows the X-ray powder diffraction pattern of compound A obtained by medium-pressure column chromatography.

[0045] Figure 24 shows the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) spectra of compound A obtained by medium-pressure column chromatography.

[0046] Figure 25 is an electron microscope image of prescription 1.

[0047] Figure 26 is an electron microscope image of prescription 2.

[0048] Figure 27 is an electron microscope image of prescription 3.

[0049] Figure 28 shows the X-ray powder diffraction patterns of the suspension prepared from the micronized sample of anhydrous compound A (crystal form I) before and after storage at 30°C for 180 days.

[0050] Figure 29 shows the X-ray powder diffraction patterns of the suspension prepared from the crystal form II micronized sample of the anhydrous compound A before and after storage at 30°C for 180 days.

[0051] Invention Details

[0052] definition

[0053] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better interpret this disclosure.

[0054] The terms “including,” “comprising,” “having,” “containing,” or “involving,” as used herein, and their other variations thereof, are inclusive or open-ended and do not exclude other unlisted elements or method steps.

[0055] As used herein, the term “about” means that a person skilled in the art would consider the value to be within an acceptable standard error, such as ±0.05, ±0.1, ±0.2, ±0.3, ±1, ±2, or ±3.

[0056] As used in this disclosure, the term "solid form" includes all solid forms of compound A or any of its hydrates, such as crystalline or amorphous forms.

[0057] As used herein, the term "amorphous" refers to any solid material that is not ordered in three dimensions. In some cases, amorphous solids can be characterized by known techniques, including XRPD crystallography, solid-state nuclear magnetic resonance (ssNMR) spectroscopy, DSC, or some combination of these techniques. As illustrated below, amorphous solids produce diffuse X-ray powder diffraction patterns (XRPD patterns), which typically include one or two broad peaks (i.e., peaks with a basis width of about 5°2θ or greater).

[0058] As used in this article, the terms “crystal form,” “crystal type,” or “crystal” refer to any solid material exhibiting a three-dimensional arrangement, which, in contrast to amorphous solid materials, produces characteristic XRPD spectra with clearly defined peaks.

[0059] As used in this article, the term "X-ray powder diffraction pattern (XRPD pattern)" refers to an experimentally observed diffraction pattern or parameters derived from it. XRPD patterns are typically characterized by peak position (x-axis) and / or peak intensity (y-axis).

[0060] As used herein, the term "2θ" refers to the peak position in degrees, based on an experimental setup for X-ray diffraction experiments, and is typically the horizontal axis unit in a diffraction pattern. If the reflection is diffracted when the incident beam forms an angle θ with a lattice plane, the experimental setup requires recording the reflected beam at a 2θ angle. It should be understood that specific 2θ values ​​for particular crystal forms mentioned herein are intended to represent 2θ values ​​(in degrees) measured using the X-ray diffraction experimental conditions described herein. For example, as described herein, using Cu-Kα (Kα1) 1.540598 and Kα2 1.544426) as a radiation source.

[0061] As used in this article, "I%" represents the percentage of peak intensity.

[0062] As used herein, the term "differential scanning calorimetry (DSC) spectrum" refers to a curve recorded by a differential scanning calorimeter. Unless otherwise stated, the temperature mentioned when describing characteristic peaks in a DSC spectrum refers to the peak's onset temperature.

[0063] As used in this article, the term "thermogravimetric analysis (TGA) curve" refers to the curve recorded by a thermogravimetric analyzer.

[0064] As used herein, the term "substantially identical" for X-ray diffraction peak positions means taking into account representative peak position and intensity variations. For example, those skilled in the art will understand that peak positions (2θ) will show some variation, typically up to ±0.1, ±0.2, or ±0.3 degrees, and the instrument used to measure diffraction will also show some variation. Additionally, those skilled in the art will understand that relative peak intensities will show variations between instruments as well as variations due to degree of crystallinity, preferred orientation, the prepared sample surface, and other factors known to those skilled in the art. Similarly, as used herein, "substantially identical" for DSC spectra is also intended to cover variations known to those skilled in the art related to these analytical techniques. For example, for well-defined peaks, there will typically be variations of up to ±0.3 °C in differential scanning calorimetry, and even greater variations (e.g., up to ±1 °C) for broad peaks.

[0065] The liquid NMR spectra in this application are preferably acquired on a Bruker 400M NMR spectrometer, with DMSO-d6 as the solvent unless otherwise specified.

[0066] The polarization microscopy data in this application are preferably acquired using a Polarizing Microscope ECLIPSE LV100POL (Nikon, JPN).

[0067] The numerical ranges used in this document (such as “1-10”, “1-6”, “2-10”, “2-6”, “3-10”, “5-10”, “3-6”) cover any number of the numerical ranges (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10).

[0068] The prepared salt or its crystalline form can be recovered by methods including decantation, centrifugation, evaporation, gravity filtration, vacuum filtration, or any other technique for solid recovery under pressure or depressurization. The recovered solids can optionally be dried. "Drying" in this disclosure refers to being carried out under reduced pressure (preferably vacuum) until the content of residual solvent is reduced to the limits given in the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH"). The residual solvent content depends on the type of solvent but does not exceed about 5000 ppm, or preferably about 4000 ppm, or more preferably about 3000 ppm. The drying can be carried out in a disc dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, rotary flash dryer, rapid dryer, etc. The drying can be carried out at temperatures below about 100°C, below about 80°C, below about 60°C, below about 50°C, below about 30°C, or any other suitable temperature, under atmospheric pressure or reduced pressure (preferably vacuum), for any desired time (e.g., about 1, 2, 3, 5, 10, 15, 20, 24 hours or overnight) to achieve the desired results, provided that the quality of the salt does not deteriorate. The drying can be carried out any desired number of times until the desired product quality is achieved. The dried product may optionally undergo a pulverizing operation to produce a desired particle size. Grinding or micronization can be performed before or after drying. Techniques that can be used to reduce particle size include, but are not limited to, ball milling, roller milling, hammer milling, and jet milling.

[0069] As used herein, the term "anhydrous hydrate" preferably refers to a crystalline form in which no water molecules are present as structural elements.

[0070] A "good solvent" is a solvent that has a high solubility for the solute.

[0071] "Antisolvent" refers to a solvent that is miscible with the solvent in a given solution system, but slightly soluble, sparingly soluble, very slightly soluble, or almost insoluble or insoluble in the solute.

[0072] "Alkanes having 5-10 carbon atoms" refers to straight-chain or branched saturated hydrocarbon groups having 5 to 10 carbon atoms. Preferably, the alkane is an alkane containing 5-8 carbon atoms. Preferably, the alkane is selected from n-pentane, n-hexane, n-heptane, and n-octane.

[0073] "Alkenes with 5 to 10 carbon atoms" refers to straight-chain or branched hydrocarbon groups with 5 to 10 carbon atoms and at least one carbon-carbon double bond.

[0074] "Alkynes with 5 to 10 carbon atoms" refers to straight-chain or branched hydrocarbon groups having 5 to 10 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds.

[0075] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0076] Therefore, "haloalkanes having 5-10 carbon atoms" refers to the aforementioned "alkane having 5-10 carbon atoms" which is substituted with one or more halogen groups. "Aromatics having 6-10 carbon atoms" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 shared π electrons arranged in a ring) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 "Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl).

[0077] "Ethers having 2-10 carbon atoms" refers to chain or cyclic compounds of the formula RO-R' having 2-10 carbon atoms, where R and R' each represent C. 1-6 Alkyl and C 1-6 One or more (e.g., 1, 2, 3, or 4) carbon atoms in the alkyl group are optionally replaced by oxygen atoms, or R and R' together with the attached oxygen atoms form a 3-8 membered cyclic ether, which optionally contains 1-2 oxygen atoms. In one embodiment, the ether is an ether having 3-10 carbon atoms. In one embodiment, the ether is a 3-6 membered cyclic ether containing 1-2 oxygen atoms, preferably selected from tetrahydrofuran, 2-methyltetrahydrofuran, and dioxane. In one embodiment, the ether is a chain ether containing 1-2 oxygen atoms and having 2-6 carbon atoms, preferably diethyl ether, propyl ether, butyl ether, diisopropyl ether, and methyl tert-butyl ether, more preferably diethyl ether, diisopropyl ether, and methyl tert-butyl ether.

[0078] "Ketones with 3-10 carbon atoms" refers to chain or cyclic compounds of the formula RC(=O)-R' with 3-10 carbon atoms, where R and R' each represent C. 1-6 Alkyl and C 1-6One or more (e.g., 1, 2, 3, or 4) carbon atoms in the alkyl group are optionally replaced by oxygen atoms, or R and R' together with the attached carbon atoms form a 3-8 membered cyclic ketone. In one embodiment, the ketone is a 3-6 carbon chain hydrocarbon ketone selected from acetone, butanone, pentanone, and hexanone, preferably selected from acetone and butanone.

[0079] "Esters with 4-10 carbon atoms" refers to esters with the formula RC(=O)O-R', where R and R' each represent C. 1-6 alkyl.

[0080] "Alcohols having 3-8 carbon atoms" refers to those with the formula R-OH, where R represents C. 1-6 alkyl.

[0081] “C 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms.

[0082] “C 1-4 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 4 carbon atoms, including methyl, ethyl, n-propyl, 2-propyl-n-butyl, 2-butyl, 3-methyl-2-propyl, 1,1-dimethylethyl, etc.

[0083] “C 1-4 "Halogenated alkyl" refers to a C-aryl group that has been replaced by 1-3 halogen atoms. 1-4 Alkyl groups, including fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, fluoroethyl, trifluoroethyl, etc.

[0084] "Heterocycle" refers to a 3-7 member saturated or partially unsaturated cyclic group containing 1-3 nitrogen, oxygen and sulfur atoms. Preferably, the heterocycle is a 5-6 member saturated or partially unsaturated heterocycle, which optionally contains 1-2 additional heteroatoms selected from nitrogen, oxygen and sulfur in addition to the nitrogen atom shown.

[0085] "FPF" stands for fine particle fraction, which is one of the main indicators of the atomization characteristics of inhaled suspensions and represents the proportion of particles that can be deposited in the lungs.

[0086] “MMAD” stands for mass median aero-dynamic diameter, which is one of the main indicators of the atomization characteristics of inhaled suspensions.

[0087] "Radiation-induced lung injury" generally refers to damage to lung tissue caused by ionizing radiation (such as radiotherapy). Radiation therapy used for thoracic tumors can lead to radiation-induced lung injury. These radiation therapies include external beam radiation therapy, internal beam radiation therapy, radionuclide therapy, total body irradiation, intraoperative radiation therapy, and 4D radiation therapy. More specifically, they include three-dimensional conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), image-guided radiotherapy (IGRT), stereotactic body radiotherapy (SBRT), proton therapy, and brachytherapy.

[0088] Radiation-induced pneumonia is an early manifestation of radiation-induced lung injury. It differs from common inflammatory lung diseases. More specifically, common inflammatory lung diseases, such as pneumonia, have different causes than radiation-induced pneumonia. Pneumonia is an infection of the lungs caused by bacteria, viruses, or other microorganisms, primarily affecting the alveoli. Bacterial and viral pneumonias are the most common. Clinically, it has a shorter onset time, with symptoms mainly including cough and high fever. Treatment primarily involves symptomatic relief and antibiotics to combat the bacterial or viral infection, and it usually resolves spontaneously once the underlying cause is removed. In contrast, radiation-induced lung injury continues to progress.

[0089] Radiation-induced pulmonary fibrosis (IPF) is a late-stage manifestation of radiation-induced lung injury. It is a type of pulmonary fibrosis with a relatively clear etiology, distinct from idiopathic pulmonary fibrosis (IPF). IPF is a chronic, progressive, fibrotic interstitial lung disease of unknown cause, with typical symptoms including progressive dyspnea and dry cough, ultimately leading to death from respiratory failure. IPF is a disease primarily characterized by extracellular fibrosis deposition, with a long and insidious onset; in most cases, lung function is already severely impaired at diagnosis. In contrast, patients with early-stage radiation-induced lung injury typically exhibit clinical symptoms, and early anti-inflammatory drug intervention usually prevents progression to pulmonary fibrosis.

[0090] The compositions or formulations disclosed herein can be conveniently delivered in spray form from a pressurized package or aerosolizer using suitable propellants such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases.

[0091] D used in this disclosure 90 It is defined as the diameter, where 90% of the particles in the swarm are below these values.

[0092] The terms “application,” “giving,” or “administering” mean the introduction of a therapeutic agent or a composition containing a therapeutic agent into a host body using any of a variety of methods and delivery systems known to those skilled in the art. The terms “application,” “giving,” or “administering” are used interchangeably herein.

[0093] The term "treatment" generally refers to achieving the desired pharmacological and / or physiological effect. This effect can be therapeutic, depending on whether it partially or completely stabilizes or cures the disease and / or causes side effects due to the disease.

[0094] The term "treatment" means administering the composition or preparation described in this application to improve or eliminate a disease or one or more symptoms related to said disease, and includes:

[0095] (i) Suppress the disease or disease state, that is, curb its development;

[0096] (ii) Relieve the disease or disease state, even if the disease or disease state subsides.

[0097] The term “prevention” means administering the composition or formulation described in this application to prevent a disease or one or more symptoms associated with said disease, and includes: preventing the occurrence of a disease or disease state in a mammal, particularly when such mammals are susceptible to the disease state but have not yet been diagnosed with it. The terms “effective amount” or “therapeutic effective amount” mean the amount of the disclosed composition used to (i) treat or prevent a particular disease, condition, or disorder, (ii) alleviate, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the disclosed composition constituting a “therapeutic effective amount” varies depending on the compounds in the composition, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the content of this disclosure.

[0098] The terms “subject,” “patient,” or “subject” are used interchangeably herein and refer to an animal, preferably a mammal, preferably a primate, which has become the subject of treatment, observation, or experimentation, including human and non-human primates (such as apes, monkeys, orangutans, and chimpanzees, such as cynomolgus monkeys, spider monkeys, and macaques, such as rhesus monkeys), with humans being the most preferred. In some embodiments, the subject has experienced and / or exhibited at least one symptom of a disease or condition to be treated and / or prevented.

[0099] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0100] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present disclosure that falls within the definition of "pharmaceutically acceptable".

[0101] The term “optional” or “optionally” means that the event or situation described below may or may not occur, including both the occurrence and non-occurrence of the event or situation.

[0102] Crystal forms and their preparation methods

[0103] In one embodiment, this disclosure provides crystal form I of an anhydrous compound A (and / or its tautomers):

[0104] The XRPD pattern of crystal form I includes characteristic peaks at diffraction angles (2θ) of approximately 12.6±0.3, 20.3±0.3, 20.9±0.3, 22.0±0.3, and 23.1±0.3°.

[0105] In some embodiments, the XRPD spectrum of crystal form I includes characteristic peaks at approximately 4.0±0.3, 12.6±0.3, 20.3±0.3, 20.9±0.3, 22.0±0.3, 22.5±0.3, 23.1±0.3, 24.1±0.3, 25.2±0.3 and 26.2±0.3 2θ (°).

[0106] In some embodiments, the XRPD spectrum of crystal form I includes characteristic peaks at approximately 4.0±0.3, 8.4±0.3, 11.3±0.3, 12.6±0.3, 15.3±0.3, 16.9±0.3, 20.3±0.3, 20.9±0.3, 22.0±0.3, 22.5±0.3, 23.1±0.3, 24.1±0.3, 25.2±0.3, 26.2±0.3, and 26.7±0.3 2θ (°).

[0107] In some embodiments, the XRPD spectrum of crystal form I includes peaks at approximately the following 2θ (°) positions: 4.0±0.3, 8.4±0.3, 11.3±0.3, 11.9±0.3, 12.6±0.3, 14.0±0.3, 15.3±0.3, 16.9±0.3, 18.3±0.3, 18.9±0.3, 19.9±0.3, 20.3±0.3, 20.9±0.3, 21.2±0.3. 22.0±0.3, 22.5±0.3, 23.1±0.3, 24.1±0.3, 24.7±0.3, 25.2±0.3, 25.8±0.3, 26.2±0.3, 26.7±0.3, 27.9±0.3, 29.1±0.3, 29.5±0.3, 29.8±0.3, 30.4±0.3, 31.3±0.3, 31.6±0.3, 38.2±0.3 and 40.3±0.3.

[0108] In the most preferred embodiment, the XRPD pattern of crystal form I includes peaks at the following diffraction angles (2θ):

[0109] In a more preferred embodiment, the XRPD pattern of crystal form I includes peaks at substantially the same diffraction angle (2θ) as shown in Figure 1. In the most preferred embodiment, crystal form I has a substantially identical XRPD pattern to that shown in Figure 1.

[0110] In a more preferred embodiment, the differential scanning calorimetry (DSC) spectrum of crystal form I includes large endothermic peaks at approximately 96±3℃ and 129±3℃, and preferably smaller endothermic peaks at 113±3℃, 118±3℃ and 124±3℃, with multiple thermal events present in the DSC.

[0111] In a more preferred embodiment, in thermogravimetric analysis (TGA), the crystal form I shows no significant weight loss before being heated to its melting point.

[0112] In a more preferred embodiment, the DSC-TGA spectrum of crystal form I includes essentially the same characteristic peaks as shown in Figure 2. In the most preferred embodiment, crystal form I has essentially the same DSC-TGA spectrum as shown in Figure 2. The DSC-TGA spectrum of crystal form I indicates that crystal form I is amorphous and that the compound exhibits complex transmorphic behavior under heating conditions. Furthermore, 1H NMR analysis was performed on crystal form I at both room temperature and 50°C. The chemical shifts in the 1H NMR spectrum of this sample differed at high temperature and room temperature, possibly due to tautomerism; indicating that the compound may possess tautomeric polymorphs.

[0113] In a more preferred embodiment, the scanning electron microscope image of crystal form I is substantially the same as that shown in Figure 3.

[0114] In some embodiments, this disclosure provides a method for preparing crystal form I, which includes the following steps:

[0115] 1) Add 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers) to a good solvent to obtain a solution;

[0116] 2) Add the antisolvent to the solution obtained in step 1), and obtain the crystal form under stirring.

[0117] More specifically, this disclosure provides a method for preparing crystal form I, which includes the following steps:

[0118] 1) Add compound A (4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one) (and / or its tautomers) to a good solvent, stir to dissolve compound A to obtain a solution, and optionally filter it to obtain a filtrate;

[0119] 2) Add the antisolvent to the solution or filtrate obtained in step 1), collect the precipitated solid by filtration, and optionally dry it to obtain crystal form I.

[0120] In some embodiments, this disclosure provides a method for preparing crystal form I, comprising the steps of: adding 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomer) to an antisolvent to obtain a suspension, and stirring to obtain crystal form I.

[0121] In some embodiments, this disclosure provides a method for preparing crystal form I, comprising dissolving compound A (and / or its tautomers) in a good solvent (which may be carried out at room temperature or under heating conditions (e.g., to 30-70°C, preferably 50°C)) to form a solution (the mixture may be filtered to obtain a solution if necessary). An antisolvent is then added to the solution, and a solid is precipitated under stirring (the addition of the antisolvent and stirring may be carried out at room temperature or under cooling conditions (e.g., to 0-10°C, preferably 5°C)), which is then filtered to obtain crystals.

[0122] In some embodiments, the good solvent is an ether having 3-10 carbon atoms, preferably a cyclic ether, such as furans (including tetrahydrofurans) and dioxanes, preferably tetrahydrofuran, 2-methyltetrahydrofuran or dioxane. Alternatively, the good solvent is a simple ketone having 3-10 carbon atoms, preferably an acyclic ketone, such as acetone or butanone; the antisolvent is a hydrocarbon having 5-10 carbon atoms (including alkanes having 5-10 carbon atoms, haloalkanes having 5-10 carbon atoms, alkenes having 5-10 carbon atoms, alkynes having 5-10 carbon atoms, and aromatics, specifically including but not limited to n-hexane, n-heptane, and toluene), an ether having 2-6 carbon atoms (preferably a chain ether, such as diethyl ether, diisopropyl ether, or methyl tert-butyl ether), an ester having 4-10 carbon atoms (preferably ethyl acetate or isopropyl acetate), an alcohol having 3-8 carbon atoms (preferably isopropanol), and water. Preferably, the antisolvent is a chain ether containing 1-2 oxygen atoms and having 2-6 carbon atoms. More preferably, the antisolvent is an alkane containing 5-8 carbon atoms, preferably n-heptane.

[0123] In some embodiments, in the method for preparing crystal form I, the weight-volume ratio (g / mL) of compound A (and / or its tautomers) to a good solvent is about 1:(1-50), preferably about 1:(5-30), more preferably 1:10 or 1:30; more preferably 1:(5-10); and preferably 1:5, 1:6, 1:7, 1:8 or 1:9.

[0124] In some embodiments, in the method for preparing crystal form I, the volume ratio of the good solvent to the anti-solvent is about 1:1 to 1:10, preferably 1:3.

[0125] On the other hand, this disclosure provides crystal form II of the anhydrous hydrate of compound A (and / or its tautomers):

[0126] The XRPD spectrum of crystal form II includes characteristic peaks at approximately 12.5±0.3, 17.3±0.3, 20.6±0.3, and 23.2±0.3 2θ (°).

[0127] In some embodiments, the XRPD spectrum of crystal form II includes characteristic peaks at approximately 4.1±0.3, 8.3±0.3, 12.5±0.3, 17.3±0.3, 20.6±0.3, 21.0±0.3, 23.2±0.3, 23.5±0.3 and 26.5±0.3 2θ (°).

[0128] In some embodiments, the XRPD spectrum of crystal form II includes characteristic peaks at approximately 4.1±0.3, 8.3±0.3, 10.9±0.3, 12.5±0.3, 17.3±0.3, 19.0±0.3, 19.5±0.3, 20.6±0.3, 21.0±0.3, 23.2±0.3, 23.5±0.3, and 26.5±0.3 2θ (°).

[0129] In some embodiments, the XRPD spectrum of crystal form II includes peaks at approximately the following 2θ (°) positions: 4.1±0.3, 8.3±0.3, 10.9±0.3, 11.5±0.3, 12.0±0.3, 12.5±0.3, 13.4±0.3, 16.1±0.3, 16.7±0.3, 17.3±0.3, 19.0±0.3, 19.5 ±0.3, 20.6±0.3, 21.0±0.3, 21.3±0.3, 21.5±0.3, 22.1±0.3, 23.2±0.3, 23.5±0.3, 24.4±0.3, 24.6±0.3, 25.4±0.3, 25.7±0.3, 26.5±0.3, 27.7±0.3, 28.2±0.3 and 29.7±0.3.

[0130] In the most preferred embodiment, the XRPD pattern of crystal form II includes peaks at the following diffraction angles (2θ):

[0131] In a more preferred embodiment, the XRPD pattern of crystal form II includes a peak at a diffraction angle (2θ) that is substantially the same as that shown in Figure 4. In the most preferred embodiment, crystal form II has an XRPD pattern that is substantially the same as that shown in Figure 4.

[0132] In a more preferred embodiment, the differential scanning calorimetry (DSC) spectrum of crystal form II includes endothermic peaks at approximately 108±3 °C and 128±3 °C, and an exothermic peak at approximately 270±3 °C. In a more preferred embodiment, in thermogravimetric analysis (TGA), crystal form II shows no significant weight loss before being heated to its melting point.

[0133] In a more preferred embodiment, the DSC-TGA spectrum of crystal form II includes substantially the same characteristic peaks as shown in Figure 5. In the most preferred embodiment, crystal form II has a DSC-TGA spectrum substantially the same as shown in Figure 5.

[0134] In a more preferred embodiment, the scanning electron microscope image of crystal form II is substantially the same as that shown in Figure 6.

[0135] In some embodiments, this disclosure provides a method for preparing crystal form II, comprising the following steps:

[0136] Under heating conditions, 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers) or crystal form I is suspended in a solvent system to obtain crystal form II.

[0137] In some embodiments, this disclosure provides a method for preparing crystal form II, comprising the following steps:

[0138] 1) Add 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers) or crystal form I to a good solvent to obtain a solution;

[0139] 2) Add the antisolvent to the solution obtained in step 1), and stir at room temperature or under heating conditions to obtain the crystal form II.

[0140] More specifically, in some embodiments, a solvent system is used to convert the anhydrous crystalline form I of compound A (and / or its tautomers) into crystalline form II under heating conditions (e.g., heating to 30-70°C, preferably 50°C), crystalline form I is suspended in an antisolvent system (e.g., 1-5 days, such as 3 days), and the crystals are obtained by filtration.

[0141] In some embodiments, the solvent system is a two-solvent system consisting of a good solvent and an anti-solvent system.

[0142] The solvent system is a mixture of a good solvent and an anti-solvent system.

[0143] The good solvent is an ether having 3-10 carbon atoms, preferably a cyclic ether, such as furans (including tetrahydrofurans) and dioxanes, preferably tetrahydrofuran, 2-methyltetrahydrofuran or dioxane, or a simple ketone having 3-10 carbon atoms, preferably a non-cyclic ketone, such as acetone or butanone. The antisolvent is a hydrocarbon having 5-10 carbon atoms (including alkanes having 5-10 carbon atoms, haloalkanes having 5-10 carbon atoms, alkenes having 5-10 carbon atoms, alkynes having 5-10 carbon atoms, and aromatics having 6-10 carbon atoms, specifically including but not limited to n-hexane, n-heptane, and toluene), an ether having 2-6 carbon atoms (preferably a chain ether, such as diethyl ether, diisopropyl ether, or methyl tert-butyl ether), an ester having 4-10 carbon atoms (preferably ethyl acetate or isopropyl acetate), an alcohol having 3-8 carbon atoms (preferably isopropanol), and water. Preferably, the antisolvent is a chain ether containing 1-2 oxygen atoms and having 2-6 carbon atoms. More preferably, the antisolvent is an alkane containing 5-8 carbon atoms, preferably n-heptane.

[0144] In some embodiments, in the preparation method of crystal form II, the weight-volume ratio (g / mL) of compound A (and / or its tautomers) to a good solvent is about 1:(1-50), preferably about 1:(5-30), more preferably 1:10 or 1:30; more preferably 1:(5-10); and preferably 1:5, 1:6, 1:7, 1:8 or 1:9.

[0145] In some embodiments, in the method for preparing crystal form II, the volume ratio of the good solvent to the anti-solvent is about 1:1 to 1:10.

[0146] Specifically, this disclosure relates to the following aspects:

[0147] In one embodiment, this disclosure relates to the crystalline form of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers).

[0148] In a more specific embodiment, this disclosure provides crystal form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers), which includes peaks at approximately 12.6 ± 0.3, 20.3 ± 0.3, 20.9 ± 0.3, 22.0 ± 0.3, and 23.1 ± 0.3 2θ (°) in an X-ray powder diffraction (XRPD) pattern obtained using Cu Kα radiation.

[0149] In a more specific embodiment, this disclosure provides crystal form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers), wherein the XRPD spectrum further includes peaks at about 4.0±0.3, 22.5±0.3, 24.1±0.3, 25.2±0.3 and 26.2±0.32θ (°).

[0150] In a more specific embodiment, this disclosure provides crystal form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers), wherein the XRPD spectrum further includes peaks at about 8.4±0.3, 11.3±0.3, 15.3±0.3, 16.9±0.3 and 26.7±0.32θ (°).

[0151] In a more specific embodiment, this disclosure provides crystal form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers), wherein the XRPD spectrum includes peaks at approximately the following 2θ (°) positions: 4.0±0.3, 8.4±0.3, 11.3±0.3, 11.9±0.3, 12.6±0.3, 14.0±0.3, 15.3±0.3, 16.9±0.3, 18.3±0.3, 18.9±0.3, 19.9±0. 0.3, 20.3±0.3, 20.9±0.3, 21.2±0.3, 22.0±0.3, 22.5±0.3, 23.1±0.3, 24.1±0.3, 24.7±0.3, 25.2±0.3, 25.8±0.3, 26.2±0.3, 26.7±0.3, 27.9±0.3, 29.1±0.3, 29.5±0.3, 29.8±0.3, 30.4±0.3, 31.3±0.3, 31.6±0.3, 38.2±0.3 and 40.3±0.3.

[0152] In a more specific embodiment, this disclosure provides crystal form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers), wherein the XRPD spectrum includes peaks at approximately the following positions:

[0153] In a more specific embodiment, this disclosure provides crystal form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers) having substantially the same XRPD pattern as shown in FIG1.

[0154] In a more specific embodiment, this disclosure provides crystal form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers) which includes endothermic peaks at 96±3 °C and 129±3 °C in differential scanning calorimetry (DSC) spectra.

[0155] In a more specific embodiment, this disclosure provides crystal form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers) having a thermogravimetric analysis (TGA) spectrum showing that the crystal form does not exhibit significant weight loss before being heated to its melting point.

[0156] In a more specific embodiment, this disclosure provides crystal form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers) having substantially the same DSC-TGA pattern as shown in FIG2.

[0157] In one embodiment, this disclosure provides a method for preparing crystal form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers), comprising:

[0158] Method 1: Includes the following steps:

[0159] 1) A solution was obtained by adding 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers) to a good solvent; and

[0160] 2) Add the antisolvent to the solution obtained in step 1), and obtain the crystal form under stirring; or

[0161] Method 2: Includes the following steps:

[0162] 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers) were added to an antisolvent to obtain a suspension, which was then stirred to obtain the crystal form.

[0163] In a more specific implementation, step 1) of method one or method two is carried out at room temperature or under heating conditions, wherein the heating is to 30-70°C, preferably to 50°C.

[0164] In a more specific implementation, the stirring in step 2) of method one is carried out at room temperature or under cooling conditions, wherein the cooling is to 0-10°C, preferably to 5°C.

[0165] In a more specific embodiment, this disclosure provides a method for preparing crystal form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers), wherein the good solvent is selected from ether solvents having 3-10 carbon atoms and ketone solvents having 3-10 carbon atoms.

[0166] In a more specific embodiment, this disclosure provides a method for preparing crystal form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers), wherein the ether solvent is a 3-6 membered cyclic ether containing 1-2 oxygen atoms, preferably selected from tetrahydrofuran, 2-methyltetrahydrofuran, and dioxane; wherein the ketone solvent is a 3-6 carbon chain ketone, preferably selected from acetone and butanone.

[0167] In a more specific embodiment, this disclosure provides a method for preparing crystal form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers), wherein the antisolvents in methods one and two are each an alkane having 5-10 carbon atoms, a haloalkane having 5-10 carbon atoms, an olefin having 5-10 carbon atoms, an alkyne having 5-10 carbon atoms, an aromatic hydrocarbon having 6-10 carbon atoms, an ether having 2-6 carbon atoms, an ester having 4-10 carbon atoms, an alcohol having 3-8 carbon atoms, and water; preferably, each of the antisolvents is an alkane containing 5-8 carbon atoms.

[0168] In a more specific embodiment, this disclosure provides a method for preparing crystal form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers), wherein the antisolvent is selected from n-hexane, n-heptane, ethyl acetate, isopropanol, toluene, diethyl ether, diisopropyl ether, methyl tert-butyl ether, and water.

[0169] In a more specific embodiment, this disclosure provides a method for preparing crystal form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers), wherein the weight-volume ratio (g / mL) of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers) to a good solvent is about 1:(1-50), preferably 1:(5-30), more preferably 1:10 or 1:30; more preferably 1:(5-10); and preferably 1:5, 1:6, 1:7, 1:8 or 1:9.

[0170] In a more specific embodiment, this disclosure provides a method for preparing crystal form I of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers), wherein the volume ratio of the good solvent to the antisolvent is about 1:1 to 1:10, preferably 1:3.

[0171] In one embodiment, this disclosure provides crystal form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers) which includes peaks at approximately 12.5 ± 0.3, 17.3 ± 0.3, 20.6 ± 0.3, and 23.2 ± 0.3 2θ (°) in X-ray powder diffraction (XRPD) spectra obtained using Cu Kα radiation.

[0172] In a more specific embodiment, this disclosure provides crystal form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers), wherein the XRPD spectrum further includes peaks at about 4.1±0.3, 8.3±0.3, 21.0±0.3, 23.5±0.3 and 26.5±0.32θ (°).

[0173] In a more specific embodiment, this disclosure provides crystal form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers), the XRPD spectrum of which further includes peaks at about 10.9 ± 0.3, 19.0 ± 0.3 and 19.5 ± 0.3 2θ (°).

[0174] In a more specific embodiment, this disclosure provides crystal form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers), wherein the XRPD spectrum includes peaks at approximately the following 2θ (°) positions: 4.1±0.3, 8.3±0.3, 10.9±0.3, 11.5±0.3, 12.0±0.3, 12.5±0.3, 13.4±0.3, 16.1±0.3, 1 6.7±0.3, 17.3±0.3, 19.0±0.3, 19.5±0.3, 20.6±0.3, 21.0±0.3, 21.3±0.3, 21.5±0.3, 22.1±0.3, 23.2±0.3, 23.5±0.3, 24.4±0.3, 24.6±0.3, 25.4±0.3, 25.7±0.3, 26.5±0.3, 27.7±0.3, 28.2±0.3 and 29.7±0.3.

[0175] In a more specific embodiment, this disclosure provides crystal form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers), wherein the XRPD spectrum includes peaks at approximately the following positions:

[0176] In a more specific embodiment, this disclosure provides crystal form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers) having substantially the same XRPD pattern as shown in FIG4.

[0177] In a more specific embodiment, this disclosure provides crystal form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers), which includes endothermic peaks at about 108±3 °C and 128±3 °C and an exothermic peak at about 270±3 °C in a differential scanning calorimeter (DSC) spectrum.

[0178] In a more specific embodiment, this disclosure provides crystal form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers) having a thermogravimetric analysis (TGA) spectrum showing that the crystal form does not exhibit significant weight loss before being heated to its melting point.

[0179] In a more specific embodiment, this disclosure provides crystal form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers) having substantially the same DSC-TGA pattern as shown in FIG5.

[0180] In one embodiment, this disclosure provides a method for preparing crystal form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers), comprising:

[0181] Method I: It includes the following steps:

[0182] Suspending 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers) or crystal form I in a solvent system at room temperature or under heating conditions yields crystal form II; or

[0183] Method II, which includes the following steps:

[0184] 1) Add 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers) or crystal form I to a good solvent to obtain a solution;

[0185] 2) Add the antisolvent to the solution obtained in step 1), and stir at room temperature or under heating conditions to obtain the crystal form II.

[0186] In a more specific embodiment, this disclosure provides a method for preparing crystal form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers), wherein the heating in step 2) of method I or method II is heating to 30-70°C, preferably 50°C.

[0187] In a more specific embodiment, this disclosure provides a method for preparing crystal form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers), wherein the solvent system is a two-solvent system consisting of a good solvent and an antisolvent system.

[0188] In a more specific embodiment, this disclosure provides a method for preparing crystal form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers), wherein the good solvent is selected from ether solvents having 3-10 carbon atoms and ketone solvents having 3-10 carbon atoms.

[0189] In a more specific embodiment, this disclosure provides a method for preparing crystal form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers), wherein the ether solvent is a 3-6 membered cyclic ether containing 1-2 oxygen atoms, preferably selected from tetrahydrofuran, 2-methyltetrahydrofuran, and dioxane; wherein the ketone solvent is a 3-6 carbon chain ketone, preferably selected from acetone and butanone.

[0190] In a more specific embodiment, this disclosure provides a method for preparing crystal form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers), wherein the antisolvent is an alkane having 5-10 carbon atoms, a haloalkane having 5-10 carbon atoms, an olefin having 5-10 carbon atoms, an alkyne having 5-10 carbon atoms, an aromatic hydrocarbon having 6-10 carbon atoms, an ether having 2-6 carbon atoms, an ester having 4-10 carbon atoms, an alcohol having 3-8 carbon atoms, and water; preferably, the antisolvent is an alkane containing 5-8 carbon atoms.

[0191] In a more specific embodiment, this disclosure provides a method for preparing crystal form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers), wherein the antisolvent is selected from n-hexane, n-heptane, ethyl acetate, isopropanol, toluene, diethyl ether, diisopropyl ether, methyl tert-butyl ether, and water.

[0192] In a more specific embodiment, this disclosure provides a method for preparing crystal form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers), wherein the weight-volume ratio (g / mL) of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers) to a good solvent is about 1:(1-50), preferably about 1:(5-30), more preferably 1:10 or 1:30; more preferably 1:(5-10); and preferably 1:5, 1:6, 1:7, 1:8 or 1:9.

[0193] In a more specific embodiment, this disclosure provides a method for preparing crystal form II of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (and / or its tautomers), wherein the volume ratio of the good solvent to the antisolvent is about 1:1 to 1:10.

[0194] In one embodiment, this disclosure provides a composition comprising crystal form I and / or crystal form II and a pharmaceutically acceptable carrier or excipient.

[0195] In one embodiment, this disclosure provides the use of crystal form I or crystal form II, or a composition comprising therethe, in the preparation of a medicament for the prevention and / or treatment of phosphodiesterase-related diseases. In a more specific embodiment, the phosphodiesterase-related diseases are chronic obstructive pulmonary disease (COPD) and / or asthma.

[0196] In one embodiment, this disclosure relates to a composition comprising a compound of formula (I) or a tautomer thereof, a solvate, an anhydrous form, a pharmaceutically acceptable salt or crystalline form, and a surfactant, wherein the compound of formula (I) is:

[0197] in:

[0198] Ring A is a 5-6 member saturated or partially unsaturated heterocycle, which, in addition to the nitrogen atom shown, optionally contains 1-2 additional heteroatoms selected from nitrogen, oxygen and sulfur;

[0199] R1 is selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and -OR;

[0200] R2 is selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and -OR;

[0201] Each R is independently selected from hydrogen and C. 1-4 alkyl;

[0202] n is 1, 2, or 3.

[0203] In a more specific embodiment, the composition disclosed herein further comprises disodium ethylenediaminetetraacetate (also known as disodium edetate). In a further embodiment, the concentration of the disodium ethylenediaminetetraacetate in the composition of the invention is 0.005 to 2% by weight; preferably 0.01 to 1%; preferably 0.01%.

[0204] In a more specific embodiment, the composition disclosed herein further comprises sodium chloride. In a further embodiment, the concentration of sodium chloride in the composition of the invention is 0.01 to 2% by weight, preferably 0.1 to 1%; preferably 0.5 to 1%; preferably 0.9%.

[0205] In a more specific embodiment, the compositions of this disclosure optionally include a pH adjuster. The pH adjuster is selected from one or more of sodium citrate (also known as sodium citrate), citric acid, hydrochloric acid, sodium hydroxide, phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, and sodium bicarbonate.

[0206] In a more specific embodiment, the pH value of the composition disclosed herein is 3.5 to 8.5; preferably 4.0 to 7.8; preferably 3.5-7.8; preferably 6.4-7.8; preferably 3.5-7.0; and more preferably 6.4-7.0.

[0207] In a more specific embodiment, in the compositions of the present invention, the concentration, by weight, of the compound of formula (I) or its tautomers, solvates, anhydrous forms, pharmaceutically acceptable salts, or crystalline forms in the composition is 0.01 to 2%; preferably 0.02 to 2%; preferably 0.02 to 1%; preferably 0.02 to 0.5%; preferably 0.02 to 0.1%; preferably 0.02%, 0.025%, 0.05%, 0.075%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, or 0.5%.

[0208] In a more specific embodiment, in the composition of the present invention, the surfactant concentration, by weight, is 0.01 to 2%; preferably, the concentration is 0.02 to 2%; preferably, the concentration is 0.02 to 1%; preferably, the concentration is 0.02 to 0.5%; preferably, the concentration is 0.02 to 0.1%; preferably, the concentrations are 0.02%, 0.025%, 0.04%, 0.06%, 0.1%, 0.2%, 0.5%, 0.58%, 1%, or 2%; and preferably, the concentrations are 0.02%, 0.025%, 0.04%, 0.1%, or 0.5%.

[0209] In a more specific embodiment, in the composition of this disclosure, the mass ratio of the compound of formula (I) to the surfactant is 1:3 to 3:1; preferably 1:3 to 1:1; preferably 1:2 to 1:1; preferably 1:1.5 to 1:1; for example, 1:3, 1:2, 1:1.9, 1:1.8, 1:1.7, 1:1.6, 1:1.5, 1:1.4, 1:1.3, 1:1.2, 1:1.1 or 1:1.

[0210] In a more specific embodiment, in the composition disclosed herein, the mass ratio of the compound of formula (I) to the surfactant is 3:1 to 1:3, preferably 2.5:1 to 1:1, and more preferably selected from 1:1, 1.25:1, 1.5:1, 1.75:1, 2.0:1 and 2.5:1.

[0211] In a more specific embodiment, in the composition disclosed herein, the mass ratio of the compound of formula (I) to the surfactant is from 3:1 to 1.25:1, preferably from 2.5:1 to 1.25:1, and more preferably selected from 1.25:1, 1.5:1, 1.75:1, 2.0:1 and 2.5:1.

[0212] In a more specific embodiment, in the compositions disclosed herein, the compound of formula (I) is selected from the group consisting of compounds, or their tautomers, solvates, anhydrous forms, pharmaceutically acceptable salts, or crystalline forms:

[0213] Preferably, the compound of formula (I) is a compound of the following formula or its tautomer, or its solvate, anhydrous form, pharmaceutically acceptable salt, or crystalline form:

[0214] In a more specific embodiment, in the compositions disclosed herein, the surfactant is selected from nonionic surfactants, anionic surfactants, cationic surfactants, and amphoteric surfactants, or combinations thereof.

[0215] In a more specific embodiment, in the compositions disclosed herein, the surfactant is selected from one or more of polyethylene glycol, Span, poloxamer, polysorbate, sodium oleate, sodium lauryl sulfate, hexadecyltrimethylammonium bromide, and lecithin; preferably, the surfactant is selected from one or more of polyethylene glycol, Span, poloxamer, and polysorbate.

[0216] In a more specific embodiment, in the compositions disclosed herein, said composition is in suspension form.

[0217] In a more specific embodiment, the composition is in the form of a suspension in which the particle size of the compound of formula (I) or its tautomers, solvates, anhydrous forms, pharmaceutically acceptable salts or crystals is less than 3 μm, preferably 1-2 μm.

[0218] In a more specific embodiment, in the compositions disclosed herein, said composition is formulated for inhalation administration.

[0219] In more specific embodiments, in the compositions disclosed herein, said compositions are formulated for administration in the form of a spray, including metered-dose sprays and non-metered-dose sprays. Optionally, the MMAD is 1-10 μm, preferably 1-6 μm, and more preferably 1-5 μm.

[0220] In a more specific embodiment, the composition disclosed herein is in the form of an aqueous suspension.

[0221] In a more specific embodiment, the composition of this disclosure is in the form of an aqueous suspension, wherein the concentration of the compound of formula (I) in the aqueous suspension is from 0.2 mg / mL to 5 mg / mL, preferably from 0.25 mg / mL to 2 mg / mL, and more preferably from 0.25 mg / mL to 1 mg / mL. Further, the concentration of the compound of formula (I) in the aqueous suspension is selected from 0.2 mg / mL, 0.25 mg / mL, 0.3 mg / mL, 0.35 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, and 5 mg / mL, preferably from 0.25 mg / mL, 1 mg / mL, 2 mg / mL, and 3 mg / mL.

[0222] In a more specific embodiment, the composition of this disclosure is in the form of an aqueous suspension, wherein the aqueous suspension is in unit dose form. Further, each unit dose is 1 to 8 mL of the aqueous suspension, preferably 2 to 8 mL. Further, each unit dose is selected from the following volumes of the aqueous suspension: 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, and 8 mL, preferably 2 mL.

[0223] In one embodiment, this disclosure relates to a spray comprising a composition as defined herein and a pharmaceutically acceptable carrier.

[0224] In one embodiment, this disclosure relates to a suspension comprising, by weight, 0.02% to 2% of a compound of the following formula or its tautomer or crystalline form, 0.02% to 1.4% of polysorbate, 0.01% to 1% of disodium EDTA, 0.5% to 1% of sodium chloride, and 0.01% to 0.1% of sodium citrate, optionally 0.03% to 0.1% of Span, and optionally 0.15% to 0.5% of poloxamer.

[0225] In one embodiment, this disclosure relates to a suspension comprising, by weight, 0.02% of a compound of the following formula or its tautomer or crystalline form, 0.02% of polysorbate (preferably polysorbate 80), 0.01% of disodium ethylenediaminetetraacetate, 0.9% of sodium chloride, and 0.02% or 0.05% of sodium citrate.

[0226] In one embodiment, this disclosure relates to a suspension comprising, by weight, 0.1% of a compound of the following formula or its tautomer or crystalline form, 0.05% of polysorbate (preferably polysorbate 80), 0.01% of disodium EDTA, 0.9% of sodium chloride, and 0.05% of sodium citrate; or

[0227] By weight, it comprises 1% of a compound of the following formula or its tautomer or crystalline form, 0.7% polysorbate, 0.01% disodium EDTA, 0.9% sodium chloride, 0.05% sodium citrate, 0.06% Span 85 and 0.3% poloxamer 407; or

[0228] By weight, it comprises 2% of the following compound or its tautomer or crystalline form, 1.4% polysorbate, 0.01% disodium EDTA, 0.9% sodium chloride, 0.05% sodium citrate, 0.1% Span 85 and 0.5% poloxamer 407.

[0229] In one embodiment, this disclosure provides a composition, by weight, comprising 0.1% of a compound of the following formula or its tautomer or crystalline form, 0.04% of polysorbate, 0.01% of disodium ethylenediaminetetraacetate, 0.9% of sodium chloride, and 0.05% of sodium citrate; or

[0230] By weight, it comprises 0.025% of the following compound or its tautomer or crystalline form, 0.02% of polysorbate, 0.01% of disodium ethylenediaminetetraacetate, 0.9% of sodium chloride and 0.05% of sodium citrate:

[0231] Furthermore, the composition is an aqueous suspension in unit dose form, wherein each unit dose is 1 to 8 mL of the aqueous suspension, preferably 1-5 mL, for example 1 mL, 2 mL, 3 mL, 4 mL or 5 mL, more preferably 1-2 mL, and most preferably 2 mL.

[0232] In the above embodiments, the compound contained in the composition is 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2-(1H)-one or its tautomer in crystalline form; preferably, the crystalline form is crystal form I or crystal form II; preferably, the crystalline form is crystal form I.

[0233] In some embodiments, this disclosure provides compositions comprising, in crystalline form, a compound of the formula 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2-(1H)-one or a tautomer thereof:

[0234] In a more specific embodiment, this disclosure provides a composition comprising the above-described crystalline form, wherein the crystalline form is crystal type I, and its X-ray powder diffraction (XRPD) spectrum obtained using Cu Kα radiation includes peaks at approximately 12.6 ± 0.3, 20.3 ± 0.3, 20.9 ± 0.3, 22.0 ± 0.3, and 23.1 ± 0.3 2θ (°). In a more specific embodiment, the XRPD spectrum of the crystalline form further includes peaks at approximately 4.0 ± 0.3, 22.5 ± 0.3, 24.1 ± 0.3, 25.2 ± 0.3, and 26.2 ± 0.3 2θ (°). In a more specific embodiment, the XRPD spectrum of the crystalline form further includes peaks at approximately 8.4 ± 0.3, 11.3 ± 0.3, 15.3 ± 0.3, 16.9 ± 0.3, and 26.7 ± 0.3 2θ (°).

[0235] In a more specific embodiment, this disclosure provides a composition comprising the above-described crystalline form, wherein the XRPD spectrum of the crystalline form includes peaks at approximately the following 2θ (°) positions: 4.0±0.3, 8.4±0.3, 11.3±0.3, 11.9±0.3, 12.6±0.3, 14.0±0.3, 15.3±0.3, 16.9±0.3, 18.3±0.3, 18.9±0.3, 19.9±0.3, 20.3±0.3, 20.9± 0.3, 21.2±0.3, 22.0±0.3, 22.5±0.3, 23.1±0.3, 24.1±0.3, 24.7±0.3, 25.2±0.3, 25.8±0.3, 26.2±0.3, 26.7±0.3, 27.9±0.3, 29.1±0.3, 29.5±0.3, 29.8±0.3, 30.4±0.3, 31.3±0.3, 31.6±0.3, 38.2±0.3 and 40.3±0.3.

[0236] In a more specific embodiment, this disclosure provides a composition comprising the above-described crystalline form, wherein the XRPD spectrum of the crystalline form includes peaks at approximately the following positions:

[0237] In a more specific embodiment, this disclosure provides a composition comprising the crystal form described above, wherein the crystal form has substantially the same XRPD pattern as shown in FIG1.

[0238] In a more specific embodiment, the crystalline form includes endothermic peaks at 96±3℃ and 129±3℃ in the differential scanning calorimetry (DSC) spectrum. In a more specific embodiment, the crystalline form has a thermogravimetric analysis (TGA) spectrum showing no significant weight loss before heating to the melting point. In a more specific embodiment, the crystalline form has a DSC-TGA spectrum substantially the same as that shown in Figure 2.

[0239] In a more specific embodiment, this disclosure provides a composition comprising a crystalline form, wherein the crystalline form is crystal type II, and its X-ray powder diffraction (XRPD) spectrum obtained using Cu Kα radiation includes peaks at approximately 12.5 ± 0.3, 17.3 ± 0.3, 20.6 ± 0.3, and 23.2 ± 0.3 2θ (°). In a more specific embodiment, the XRPD spectrum of the crystalline form further includes peaks at approximately 4.1 ± 0.3, 8.3 ± 0.3, 21.0 ± 0.3, 23.5 ± 0.3, and 26.5 ± 0.3 2θ (°). In a more specific embodiment, the XRPD spectrum of the crystalline form further includes peaks at approximately 10.9 ± 0.3, 19.0 ± 0.3, and 19.5 ± 0.3 2θ (°).

[0240] In a more specific embodiment, this disclosure provides a composition comprising a crystalline form, wherein the XRPD spectrum of the crystalline form includes peaks at approximately the following 2θ (°) positions: 4.1±0.3, 8.3±0.3, 10.9±0.3, 11.5±0.3, 12.0±0.3, 12.5±0.3, 13.4±0.3, 16.1±0.3, 16.7±0.3, 17.3±0.3, 1 9.0±0.3, 19.5±0.3, 20.6±0.3, 21.0±0.3, 21.3±0.3, 21.5±0.3, 22.1±0.3, 23.2±0.3, 23.5±0.3, 24.4±0.3, 24.6±0.3, 25.4±0.3, 25.7±0.3, 26.5±0.3, 27.7±0.3, 28.2±0.3 and 29.7±0.3.

[0241] In a more specific embodiment, this disclosure provides a composition comprising a crystalline form, wherein the XRPD spectrum of the crystalline form includes peaks at approximately the following positions:

[0242] In a more specific embodiment, this disclosure provides compositions comprising a crystalline form having substantially the same XRPD pattern as shown in FIG4.

[0243] In a more specific embodiment, this disclosure provides a composition comprising a crystalline form, wherein the crystalline form includes endothermic peaks at approximately 108 ± 3 °C and 128 ± 3 °C and an exothermic peak at approximately 270 ± 3 °C in a differential scanning calorimetry (DSC) spectrum. In a more specific embodiment, the crystalline form has a thermogravimetric analysis (TGA) spectrum showing that the crystalline form does not exhibit significant weight loss upon heating to its melting point. In a more specific embodiment, this disclosure provides a composition comprising a crystalline form having a DSC-TGA spectrum substantially identical to that shown in Figure 5.

[0244] In a more specific embodiment, this disclosure provides a composition comprising the crystalline form thereof, which further comprises a surfactant.

[0245] In a more specific embodiment, this disclosure provides a composition comprising the crystalline form thereof, which further comprises disodium ethylenediaminetetraacetate.

[0246] In a more specific embodiment, this disclosure provides a composition comprising the crystalline form thereof, which further comprises sodium chloride.

[0247] In a more specific embodiment, this disclosure provides a composition comprising the crystalline form thereof, which includes a pH adjuster. Further, wherein the pH adjuster is selected from one or more of sodium citrate, citric acid, hydrochloric acid, sodium hydroxide, phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, and sodium bicarbonate.

[0248] In a more specific embodiment, this disclosure provides a composition comprising the crystalline form thereof, wherein the pH of the composition is 3.5 to 8.5; preferably 4.0 to 7.8; preferably 6.4 to 7.8; preferably 3.5 to 7.0; preferably 6.4 to 7.0.

[0249] In a more specific embodiment, this disclosure provides a composition comprising the crystalline form, wherein the concentration of the crystalline form in the composition, by weight, is 0.01 to 2%; preferably 0.02 to 2%; preferably 0.02 to 1%; preferably 0.02 to 0.5%; preferably 0.02 to 0.1%; preferably 0.02%, 0.025%, 0.04%, 0.06%, 0.1%, 0.2%, 0.5%, 0.58%, 1% or 2%; preferably 0.02%, 0.025%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4% or 0.5%.

[0250] In a more specific embodiment, this disclosure provides a composition comprising the crystalline form thereof, wherein the surfactant concentration is 0.01 to 2% by weight; preferably, 0.02 to 2%; preferably, 0.02 to 1%; preferably 0.02 to 0.5%; preferably 0.02 to 0.1%; and preferably 0.02%, 0.025%, 0.04%, 0.1%, or 0.5%.

[0251] In a more specific embodiment, this disclosure provides a composition comprising the crystalline form, wherein the mass ratio of the crystalline form to the surfactant is 1:3 to 1:1; preferably 1:2 to 1:1; preferably 1:1.5 to 1:1.

[0252] In a more specific embodiment, this disclosure provides a composition comprising the crystalline form, wherein the mass ratio of the crystalline form to the surfactant is 3:1 to 1:3, preferably 2.5:1 to 1:1, and more preferably selected from 1:1, 1.25:1, 1.5:1, 1.75:1, 2.0:1, and 2.5:1.

[0253] In a more specific embodiment, this disclosure provides compositions comprising the crystalline form thereof, wherein the surfactant is selected from nonionic surfactants, anionic surfactants, cationic surfactants, and amphoteric surfactants, or combinations thereof.

[0254] In a more specific embodiment, this disclosure provides a composition comprising the crystalline form thereof, wherein the surfactant is selected from one or more of polyethylene glycol, Span, poloxamer, polysorbate, sodium oleate, sodium lauryl sulfate, hexadecyltrimethylammonium bromide, and lecithin; preferably, the surfactant is selected from one or more of polyethylene glycol, Span, poloxamer, and polysorbate.

[0255] In a more specific embodiment, this disclosure provides a composition comprising the crystalline form, which is in the form of an aqueous suspension. Further, in the aqueous suspension, the concentration of the crystalline form is from 0.2 mg / mL to 5 mg / mL. Further, in the aqueous suspension, the concentration of the crystalline form is selected from 0.2 mg / mL, 0.25 mg / mL, 0.3 mg / mL, 0.35 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, and 5 mg / mL, preferably selected from 0.25 mg / mL, 1 mg / mL, 2 mg / mL, and 3 mg / mL. Further, the aqueous suspension is in unit dose form. Further, each unit dose is 1 to 8 mL of the aqueous suspension, preferably 2 to 8 mL. Furthermore, each unit dose is selected from the following volumes of the aqueous suspension: 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL and 8 mL, preferably 2 mL.

[0256] In some embodiments, this disclosure provides a spray comprising the composition described herein and a pharmaceutically acceptable carrier.

[0257] In one embodiment, this disclosure relates to a method for preparing a composition comprising a compound of formula (I) or a tautomer thereof, a solvate, an anhydrous form, a pharmaceutically acceptable salt or crystalline form, and a surfactant, the method comprising:

[0258] Step (a): Add the compound of formula (I) or its tautomer, solvate, anhydrous form, pharmaceutically acceptable salt or crystalline form to the surfactant solution to form a suspension;

[0259] Among them, compound (I) is:

[0260] in:

[0261] Ring A is a 5-6 member saturated or partially unsaturated heterocycle, which, in addition to the nitrogen atom shown, optionally contains 1-2 additional heteroatoms selected from nitrogen, oxygen and sulfur;

[0262] R1 is selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and -OR;

[0263] R2 is selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and -OR;

[0264] Each R is independently selected from hydrogen and C. 1-4 alkyl;

[0265] n is 1, 2, or 3;

[0266] Preferably, the compound of formula (I) is selected from the following compounds, or their tautomers, solvates, anhydrous forms, pharmaceutically acceptable salts, or crystalline forms:

[0267] Preferably, the compound of formula (I) is a compound of the following formula or its tautomer, or its solvate, anhydrous form, pharmaceutically acceptable salt, or crystalline form:

[0268] Preferably, the compound of formula (I) is in the crystalline form of anhydrous precipitates of the following formula or their tautomers:

[0269] Preferably, the crystal form is crystal form I or crystal form II.

[0270] In a more specific embodiment, in the method described above in this disclosure, the method includes the following steps prior to step (a):

[0271] Step (a-2): Micronize the compound of formula (I) or its tautomers, solvates, anhydrous compounds, pharmaceutically acceptable salts or crystalline forms to obtain particles with a D90 of 5 to 20 μm.

[0272] In a more specific embodiment, the method described above in this disclosure includes, prior to step (a-2):

[0273] Step (a-1): Prepare an aqueous solution of the surfactant by adding the surfactant, optionally disodium ethylenediaminetetraacetate and optionally sodium chloride to water to form an aqueous solution, and optionally adding a pH adjuster to adjust the pH of the solution to 3.5 to 8.5.

[0274] In a more specific embodiment, in the method described above in this disclosure, the step (a) is followed by:

[0275] Step (b): Homogenize the suspension obtained in step (a) under high pressure until the average particle size is less than 3 μm, preferably 1-2 μm.

[0276] In a more specific embodiment, in the above-described method of this disclosure, the surfactant is selected from nonionic surfactants, anionic surfactants, cationic surfactants, and amphoteric surfactants, or combinations thereof; preferably, the surfactant is selected from one or more of polyethylene glycol, Span, poloxamer, polysorbate, sodium oleate, sodium lauryl sulfate, hexadecyltrimethylammonium bromide, and lecithin; preferably, the surfactant is selected from one or more of polyethylene glycol, Span, poloxamer, and polysorbate.

[0277] In a more specific embodiment, in the method described above in this disclosure, the pH adjuster is selected from one or more of sodium citrate, citric acid, hydrochloric acid, sodium hydroxide, phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, and sodium bicarbonate.

[0278] In one embodiment, this disclosure relates to the use of the compositions of this disclosure in the preparation of a medicament for treating and / or preventing respiratory diseases or related diseases.

[0279] In one embodiment, this disclosure relates to compositions of this disclosure for the treatment and / or prevention of respiratory diseases or related diseases.

[0280] In one embodiment, this disclosure relates to a method of treating a respiratory disease or a related disease, comprising administering a therapeutically effective amount of the composition of this disclosure to a subject.

[0281] In one embodiment, this disclosure relates to the use of the compositions of this disclosure in the treatment and / or prevention of respiratory diseases or related diseases.

[0282] In a more specific embodiment, in the use or treatment of the preparation of the medicament disclosed herein, said medicament or composition of the present disclosure is administered in an amount equivalent to about 0.025 mg / day to about 1000 mg / day of the compound of formula (I), preferably about 0.1 mg / day to about 200 mg / day.

[0283] In a more specific embodiment, in the use or treatment of the preparation of the medicament disclosed herein, said medicament or the composition of the present disclosure is administered in an amount equivalent to about 0.025 mg / day, 0.05 mg / day, 0.1 mg / day, about 0.5 mg / day, 1 mg / day, about 5 mg / day, about 10 mg / day, about 20 mg / day, about 30 mg / day, about 40 mg / day, about 50 mg / day, about 100 mg / day and about 200 mg / day of the compound of formula (I).

[0284] In a more specific embodiment, in the use or treatment of the medicament prepared in this disclosure, the daily dose of said medicament or the composition of this disclosure is for administration once or in two, three, four, five, six, seven, eight, nine or ten times, for example in two, three or four times.

[0285] In a more specific embodiment, in the use or treatment of the medicament prepared in this disclosure, said medicament or the composition of this disclosure is used for administration by inhalation.

[0286] In a more specific embodiment, in the use or treatment of the medicament prepared in this disclosure, said medicament or composition of this disclosure is a spray dosage form.

[0287] In a more specific embodiment, in the use or treatment of the prepared medicine of this disclosure, the respiratory disease is a lung disease, bronchiectasis, or asthma, and the lung disease is preferably lung injury, lung inflammation, pulmonary fibrosis, or chronic obstructive pulmonary disease.

[0288] In a more specific embodiment, in the use or treatment of the prepared medicine of this disclosure, the lung injury is radiation-induced lung injury; preferably, the radiation-induced lung injury is selected from radiation-induced pneumonia and radiation-induced pulmonary fibrosis.

[0289] In a more specific embodiment, in the use or treatment of the prepared medicine of this disclosure, the chronic obstructive pulmonary disease is selected from chronic bronchitis-type chronic obstructive pulmonary disease, emphysema-type chronic obstructive pulmonary disease, and mixed chronic obstructive pulmonary disease.

[0290] In a more specific embodiment, in the use or treatment of the prepared medicine of this disclosure, the chronic obstructive pulmonary disease includes stable chronic obstructive pulmonary disease and acute exacerbation chronic obstructive pulmonary disease.

[0291] In a more specific embodiment, in the use or treatment of the prepared medicament of this disclosure, said medicament also includes a pharmaceutical instruction leaflet indicating its use in combination with an additional therapeutic agent.

[0292] In a more specific embodiment, in the use or treatment of the prepared medicine of this disclosure, said additional therapeutic agent is selected from bronchodilators, inhaled corticosteroids, theophylline drugs, mucolytics, cardiovascular drugs and osteoporosis prevention drugs.

[0293] In a more specific embodiment, in the use or treatment of the prepared medicine of this disclosure, said additional therapeutic agent is selected from short-acting and long-acting β2 agonists, short-acting and long-acting anticholinergic drugs, antibacterial agents, antiviral agents, antifungal agents, antitumor agents, antihistamines, proteins, enzymes, hormones, nonsteroidal anti-inflammatory substances, cytokines, steroids and insulin. Beneficial effects

[0294] This disclosure provides at least one of the following beneficial technical effects:

[0295] The crystalline form of compound A (and / or its tautomers) disclosed herein has excellent efficacy in the prevention and / or treatment of phosphodiesterase-related diseases.

[0296] The crystalline form of compound A (and / or its tautomers) disclosed herein possesses excellent physical properties (including solubility, dissolution rate, light resistance, low hygroscopicity, high temperature resistance, high humidity resistance, and / or flowability).

[0297] The crystalline form of compound A (and / or its tautomers) of this disclosure has superior properties in terms of bioavailability, physical and / or chemical stability, grinding stability and / or ease of preparation.

[0298] The crystalline form of compound A (and / or its tautomers) disclosed herein has good powder properties, making it more suitable and convenient for mass production and for formulation.

[0299] The crystalline form of compound A (and / or its tautomers) disclosed herein can reduce irritation, improve absorption, address metabolic rate issues, significantly reduce toxicity caused by drug accumulation, improve safety, and / or effectively ensure the quality and efficacy of pharmaceutical products.

[0300] The crystalline form of compound A (and / or its tautomers) disclosed herein exhibits good storage stability.

[0301] The compositions disclosed herein exhibit good physical and / or chemical stability. The compositions disclosed herein exhibit even better physical and / or chemical stability when used in small sample quantities.

[0302] The compositions disclosed herein exhibit good storage stability.

[0303] The compositions disclosed herein have low toxicity and high safety.

[0304] The compositions disclosed herein enable highly efficient nebulized inhalation.

[0305] The compositions disclosed herein have excellent effects in the prevention and / or treatment of respiratory diseases or related diseases.

[0306] The compositions disclosed herein have good bioavailability, can significantly reduce the toxicity caused by drug accumulation, improve safety, and / or improve the quality and efficacy of the formulation. Example

[0307] The following representative embodiments are intended to help illustrate this disclosure and are not intended to limit the scope of this disclosure, nor should they be construed as limiting the scope of this disclosure.

[0308] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0309] The detection instruments and conditions used in the following examples are as follows:

[0310] (1) X-ray powder diffraction (XRPD)

[0311] Instrument model: Bruker D8 advance, equipped with LynxEye detector

[0312] Test conditions: The anode target material is copper, the optical tube is set to (40KV 40mA), the 2θ scanning angle of the sample is from 3° to 40°, and the scanning step is 0.02°.

[0313] (2) Differential Scanning Calorimetry (DSC)

[0314] Instrument Model: TA Discovery DSC 250 (TA Instruments, US)

[0315] Test conditions: heating rate of 10℃ / min, dry nitrogen gas was used as the purging gas.

[0316] (3) Thermogravimetric analysis (TGA)

[0317] Instrument model: Discovery TGA 55 (TA Instruments, US)

[0318] Test conditions: Automatic weighing inside the heating furnace, heating rate of 10℃ / min, and dry nitrogen gas used as purging gas.

[0319] (4) Polarizing microscopy analysis (PLM)

[0320] Instrument Model: Polarizing Microscope ECLIPSE LV100POL (Nikon, JPN)

[0321] Abbreviations: THF: Tetrahydrofuran; DABCO: 1,4-diazabicyclo[2.2.2]octane; Pd2(dba)3: Tris(dibenzylacetone)dipalladium(0); HP(t-Bu)3BF4: Tri-tert-butylphosphine tetrafluoroborate; Pd / C: Palladium / Carbon

[0322] Example 1: Preparation of 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridine-2(1H)-one (compound A)

[0323] first step:

[0324] Methyltriphenylphosphine iodide (33.4 g, 64 mmol), potassium tert-butoxide (9.3 g, 64 mmol), and anhydrous THF (100 mL) were added sequentially to a three-necked flask and reacted at room temperature for 1 hour under an argon atmosphere. A-1 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzaldehyde (7.7 g, 32 mmol) was dissolved in anhydrous THF (20 mL) and slowly added dropwise to the reaction mixture through a constant-pressure dropping funnel. After the addition was complete, the reaction was continued for 3 hours. Most of the THF was evaporated by vacuum concentration, and the reaction mixture was quenched with saturated ammonium chloride solution (30 mL). The mixture was extracted three times with ethyl acetate (3 × 50 mL), and the organic phases were combined. The organic phase was washed once with saturated sodium chloride aqueous solution, separated, and dried over anhydrous sodium sulfate. The mixture was then separated by medium-pressure column chromatography and concentrated to give a colorless, transparent oil A-2 in 92% yield.

[0325] 1 H NMR (400MHz, CDCl3) δ7.11(d,J=8.2Hz,1H),6.99(d,J=2.0Hz,1H),6.96(dd,J=8.2,2.0Hz,1H),6.65(dd,J=17.6,12.2Hz,1H),6.62(t,J=76.0Hz ,1H),5.68(dd,J=17.5,0.8Hz,1H),5.25(dd,J=10.8,0.8Hz,1H),3.89(d ,J=6.9Hz,2H),1.34-1.26(m,1H),0.68-0.63(m,2H),0.38-0.34(m,2H).

[0326] Step Two:

[0327] A-2 (1.1 g, 4.56 mmol), 1-benzyl-4-bromopyridin-2(1H)-one (1.2 g, 4.56 mmol), Pd2(dba)3 (42 mg, 0.0456 mmol), HP(t-Bu)3BF4 (53 mg, 0.1824 mmol), and DABCO (1.53 g, 13.68 mmol) were added sequentially to a sealed tube. Anhydrous dioxane (15 mL) was added, the mixture was purged with argon, and the stopper was tightened. The reaction mixture was stirred at 100 °C for 36 hours. After the reaction solution cooled to room temperature, the reaction was quenched with saturated sodium bicarbonate aqueous solution (10 mL). The mixture was extracted three times with ethyl acetate (3 × 20 mL). The organic phases were then combined, washed twice with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The mixture was separated by medium-pressure column chromatography to give a white solid A-3 in 52.4% yield.

[0328] 1 H NMR (400MHz, CDCl3) δ7.36-7.26(m,5H),7.21(d,J=7.1Hz,1H),7.13(d,J=8.0Hz,1H),7.08-6.98(m,3H),6.8 3-6.31(m,4H),5.12(s,2H),3.91(d,J=6.9Hz,2H),1.32-1.27(m,1H),0.68-0.63(m,2H),0.38-0.34(m,2H).

[0329] Step 3:

[0330] A-3 (70 mg, 0.17 mmol) was dissolved in methanol (20 mL), and Pd / C (20 mg) was added. The mixture was stirred at 90 °C for 5 hours under a hydrogen atmosphere. Palladium on carbon was removed by diatomaceous earth filtration. The diatomaceous earth layer was washed with ethyl acetate (3 × 10 mL), and the organic phases were combined. A white solid of 47 mg was separated by medium-pressure column chromatography, which was identified as compound A, with a yield of 83.8%. Its XRPD spectrum is shown in Figure 23, and its DSC and TGA spectra are shown in Figure 24.

[0331] 1H NMR (400MHz, MeOD) δ7.33 (d, J=6.6Hz, 1H), 7.01 (d, J=8.1Hz, 1H), 6.88 (d, J= 4.4Hz,1H),6.76(d,J=8.1Hz,1H),6.70-6.47(m,1H),6.32(d,J=6.8Hz,1H),6 .29(s,1H),3.86(dd,J=6.8,1.6Hz,2H),2.90(t,J=7.6Hz,2H),2.81(t,J=7.4 Hz,2H),1.25(m,1H),0.66-0.56(m,2H),0.35(d,J=5.0Hz,2H).MS(ESI):m / zC 18 H 20 Calculated value of F2NO3 (M+H) + 336.13, Measured value (M+H) + 336.14.

[0332] Example 2: Preparation of Crystal Form I of Anhydrous Compound A (Method 1)

[0333] Compound A (3.18 g) was added to acetone (22.3 mL) and stirred at room temperature until completely dissolved. The resulting solution was filtered and the filtrate was collected. Heptane (66.8 mL) was slowly added dropwise to the filtrate, and the mixture was stirred overnight at room temperature, resulting in the precipitation of a solid. The suspension was filtered and dried under vacuum at 40 °C to obtain the crystal form. X-ray powder diffraction (XRPD) pattern is shown in Figure 1; DSC and TGA analyses are shown in Figure 2; and the crystal morphology is observed under a scanning electron microscope as shown in Figure 3.

[0334] Thermogravimetric analysis (TGA) showed that the crystal form sample did not lose significant weight before being heated to its melting point, indicating that the crystal form does not contain water of crystallization.

[0335] Example 3: Preparation of Crystal Form I of Anhydrous Compound A (Method 2)

[0336] Compound A (200 mg) was added to ethyl acetate (4 mL), and the resulting suspension was stirred overnight at room temperature. The suspension was filtered and dried under vacuum at 40 °C to obtain the crystal form. X-ray powder diffraction analysis showed that its XRPD pattern was the same as that in Figure 1.

[0337] Example 4: Preparation of Crystal Form I of Anhydrous Compound A (Method 3)

[0338] Compound A (200 mg) was added to isopropanol (6 mL), and the resulting suspension was stirred overnight at room temperature. The suspension was filtered and dried under vacuum at 40 °C to obtain the crystalline form. X-ray powder diffraction analysis showed that its XRPD pattern was the same as that in Figure 1.

[0339] Example 5: Preparation of Crystal Form I of Anhydrous Compound A (Method 4)

[0340] Compound A (200 mg) was added to methyl tert-butyl ether (6 mL), and the resulting suspension was stirred overnight at room temperature. The suspension was filtered and dried under vacuum at 40 °C to obtain the crystalline form. X-ray powder diffraction analysis showed that its XRPD pattern was the same as that in Figure 1.

[0341] Example 6: Preparation of Crystal Form I of Anhydrous Compound A (Method 5)

[0342] Compound A (200 mg) was added to n-heptane (6 mL), and the resulting suspension was stirred overnight at 50 °C. The suspension was filtered and dried under vacuum at 40 °C to obtain the crystalline form. X-ray powder diffraction analysis showed that its XRPD pattern was the same as that in Figure 1.

[0343] Example 7: Preparation of Crystal Form I of Anhydrous Compound A (Method Six)

[0344] Compound A (200 mg) was added to THF (1.6 mL) and stirred at room temperature until completely dissolved. 4 mL of water was slowly added dropwise to the filtrate, and the mixture was stirred overnight at room temperature. A solid precipitated, and the suspension was filtered and dried under vacuum at 40 °C to obtain the crystalline form. The XRPD pattern was obtained by X-ray powder diffraction, as shown in Figure 1.

[0345] Example 8: Preparation of crystal form II of the anhydrous compound A (Method 1)

[0346] Compound A (30.0 g) was added to acetone (210 mL) and stirred at 50 °C until completely dissolved. The resulting solution was filtered and the filtrate was collected. Heptane (630 mL) was slowly added dropwise to the filtrate. After the addition was complete, the mixture was kept at 50 °C for 4 hours and stirred overnight at room temperature. A solid precipitated, and the suspension was filtered and dried under vacuum at 40 °C to obtain the crystalline form. X-ray powder diffraction (XRPD) pattern is shown in Figure 4; DSC and TGA analyses are shown in Figure 5; and the crystal morphology is shown in Figure 6 under a scanning electron microscope. Thermogravimetric analysis (TGA) showed no significant weight loss before heating to the melting point, indicating that the crystalline form does not contain water of crystallization.

[0347] Example 9: Preparation of crystal form II of the anhydrous compound A (Method 2)

[0348] 15.0 g of crystal form I of compound A was added to a mixed solvent of acetone (105 mL) and n-heptane (315 mL), stirred at 50 °C for 4 hours, and then stirred overnight at room temperature. A solid precipitated, the suspension was filtered, and the crystal form was obtained after vacuum drying at 40 °C. The XRPD pattern of the crystal form was obtained by X-ray powder diffraction, as shown in Figure 4.

[0349] Example 10: Preparation of Crystal Form II of Compound A Anhydrous Compound (Method 3)

[0350] Compound A (200 mg) was added to water (6 mL), and the suspension was stirred overnight at room temperature. The suspension was filtered, and the crystal form was obtained after vacuum drying at 40 °C. The XRPD pattern of the crystal was obtained by X-ray powder diffraction, as shown in Figure 4.

[0351] Example 11: Preparation of Crystal Form II of Compound A Anhydrous Compound (Method 4)

[0352] Compound A (200 mg) was added to methyl tert-butyl ether (6 mL), and the suspension was stirred overnight at 50 °C. The suspension was filtered and dried under vacuum at 40 °C to obtain the crystal form. The XRPD pattern of the crystal was obtained by X-ray powder diffraction, as shown in Figure 4.

[0353] Example 12: Preparation of Crystal Form II of Anhydrous Compound A (Method 5)

[0354] Compound A (200 mg) was added to n-heptane (6 mL), and the suspension was stirred overnight at 70 °C. The suspension was filtered, and the crystal form was obtained after vacuum drying at 40 °C. The XRPD pattern of the crystal was obtained by X-ray powder diffraction, as shown in Figure 4.

[0355] Example 13: Preparation of Crystal Form II of Anhydrous Compound A (Method Six)

[0356] Compound A (200 mg) was added to acetone (4 mL) and stirred at room temperature until completely dissolved. Water (5.6 mL) was slowly added dropwise to the filtrate, and the mixture was stirred overnight at room temperature. A solid precipitated, and the suspension was filtered and dried under vacuum at 40 °C to obtain the crystalline form. The XRPD pattern of the crystalline form was obtained by X-ray powder diffraction, as shown in Figure 4.

[0357] Experimental Example

[0358] Experiment Example 1: Room Temperature Stability Experiment

[0359] Crystal form I prepared in Example 2 and crystal form II prepared in Example 8 were placed in pharmaceutical low-density polyethylene bags, sealed, and left at room temperature for 180 days. XRPD was then measured using a Bruker D8 advance X-ray powder diffractometer. The results showed that the crystal forms of both crystal form I and II remained unchanged after 180 days, indicating good stability. A comparison of the X-ray powder diffraction patterns of crystal form I before and after 180 days at room temperature is shown in Figure 7.

[0360] Experiment Example 2: Water Activity Experiment

[0361] Water activity experiments were conducted on crystal form I prepared in Example 2. At room temperature, crystal form I was added to acetone with different proportions of water to prepare suspensions. After 3 days, the remaining solids were determined by XRPD using a Bruker D8 advance X-ray powder diffractometer. The results are shown in Figure 8. Crystal form I remained stable in acetone / water (1 / 1, aw = 0.89), and no hydrate crystal form was found.

[0362] Experiment Example 3: Solid Stability Experiment

[0363] The solid stability of crystal form I prepared in Example 2 and crystal form II prepared in Example 8 was evaluated over 7 days under conditions of 60℃ and 40℃ / 75% RH. Partial solid samples were dissolved and subjected to HPLC purity analysis (see Figures 9 and 10), and the remaining solid was analyzed by XRPD using a Bruker D8 Advance X-ray powder diffractometer to determine its crystal form (see Figure 11). No significant degradation or crystal form transformation was observed during the test, indicating that crystal forms I and II are physically and chemically stable under the test conditions.

[0364] Experiment Example 4: High Humidity Stability Experiment

[0365] The crystal form I prepared in Example 2 was placed in an open container for 7 days under 92.5% RH / 25℃ conditions to investigate its stability. The XRPD pattern was measured using a Bruker D8advance X-ray powder diffractometer (see Figure 12). The results showed that the crystal form of the sample of crystal form I did not change within 7 days under 92.5% RH / 25℃, and its stability was excellent.

[0366] Experiment Example 5: Physical Grinding Stability Experiment

[0367] After physical grinding of crystal form I obtained in Example 2 for 2 minutes, the XRPD pattern was determined using a Bruker D8 advance X-ray powder diffractometer (see Figure 13). The results showed that the crystal form of crystal form I remained unchanged, exhibiting excellent stability. Scanning electron microscope images before and after grinding are shown in Figure 14.

[0368] Experiment Example 6: Crystal Transformation Experiment

[0369] The crystal transformation experiments of crystal form I prepared in Example 2 and crystal form II prepared in Example 8 were conducted by competitive slurry mixing in different solvents. Equal amounts of the different crystal forms were added to a saturated solution of the compound, and the resulting suspensions were stirred at room temperature or 50°C. The resulting solids were then subjected to XRPD analysis using a Bruker D8 Advance X-ray powder diffractometer. Detailed results are shown in Table 1 and Figures 15, 16, 17, and 18. All mixtures transformed into crystal form I at room temperature to 35°C and into crystal form II at 40 to 50°C. Therefore, crystal form I and crystal form II are interconvertible in the solvent system; crystal form I is stable at room temperature to 35°C, while crystal form II is stable at ≥40°C.

[0370] Table 1

[0371] Experiment Example 7: Stability Experiment

[0372] 15 mg of disodium ethylenediaminetetraacetate and 75 mg of sodium citrate were placed in a measuring cup, and 150 mL of water was added and stirred to dissolve them to prepare a blank solution. The crystal form I prepared in Example 2 or the crystal form II prepared in Example 8 were micronized to D90 ≤ 10 μm. Their scanning electron microscope images are shown in Figure 19 and Figure 20, respectively. 1.0 g of the micronized crystal form I or crystal form II sample was taken, 1.6 g of Tween 80 was added, and then the above blank solution was added. The mixture was homogenized under high pressure at 850 bar for 6 min to obtain a suspension of the crystal form I or crystal form II sample. After the suspensions of crystal form I or crystal form II samples were placed at room temperature for 15 days, a portion of the suspension was filtered and washed. The filter cake was then spread on a glass slide, dried, and observed under a scanning electron microscope. The particle size of crystal form I samples in the suspension remained essentially unchanged compared to the initial size, while the particle size of crystal form II samples in the suspension significantly increased and aggregated compared to the initial size. This indicates that crystal form I samples are more stable than crystal form II samples in the suspension. The scanning electron microscope images of their suspensions after 15 days at room temperature are shown in Figures 21 and 22, respectively. After the suspensions of crystal form I and crystal form II samples were stored at 30°C for 180 days, X-ray powder diffraction patterns (Figures 28 and 29) showed that the crystal forms of crystal form I and crystal form II remained unchanged in the suspension, and no crystal transformation occurred.

[0373] The crystalline form disclosed herein exhibits good stability, and its color and properties remain unchanged after prolonged storage at room temperature (e.g., 180 days). Furthermore, the crystalline form of this disclosure also exhibits good stability under high temperature or high humidity conditions; for example, when crystal form I is stored at high temperature (e.g., 60°C) for 30 days, its crystal form remains unchanged.

[0374] In addition, the crystalline form disclosed herein has good fluidity, is easy to pulverize, and facilitates the preparation of pharmaceutical compositions.

[0375] Example 8: Rat Pharmacokinetic Study

[0376] The suspensions prepared using crystal form I and crystal form II in Example 7 were used to conduct pharmacokinetic studies in rats.

[0377] 1. Animal husbandry and management

[0378] 1) Animals

[0379] 2) Rearing environment

[0380] 3) Environment

[0381] Rats were allowed to acclimatize to the above environment for at least two days prior to drug administration.

[0382] 4) Random grouping

[0383] Assess the health status of the animals. Select healthy animals and randomly group them before administration.

[0384] 5) Clinical observation

[0385] Clinical observation will be conducted within 2 hours after administration, and after sampling at each time point.

[0386] 2. Animal research design

[0387] 1) Experimental Design Note: M: Male; R: Rats

[0388] 2) Dosage

[0389] The drug was administered via nebulization according to the experimental design dosage described above.

[0390] 3) Sample collection

[0391] 0.25 mL of blood was collected from the ophthalmic venous plexus of SD rats. The blood was then placed in a clean test tube containing EDTA-K2 (4%) and centrifuged at 2000 g for 10 minutes at 4 °C. The resulting plasma was transferred to another clean test tube and stored at -20 °C until analysis.

[0392] 3. Research Results

[0393] 3.1 Clinical observation

[0394] All animals showed normal behavior compared to before intratracheal nebulization administration.

[0395] 3.2 Data Analysis and Processing

[0396] Chromatograms were integrated using Analysis 1.6.2 software. A weighted (1 / x²) method was employed. The concentration of compound A was calculated using the formula y = ax + b, where y is the ratio of the compound peak area to the internal standard peak area.

[0397] Each run includes a standard curve used to calculate the concentrations of quality control samples and unknown samples.

[0398] Pharmacokinetic parameters were fitted using Winnonlin 6.3 software.

[0399] 3.2.2 Pharmacokinetic parameters

[0400] The pharmacokinetic parameters of compound A after intratracheal administration of crystal form I or II to rats are shown in Tables 2 and 3. It can be seen that the suspensions prepared from crystal forms I and II of compound A have essentially the same pK, suggesting that crystal forms I and II are bioequivalent.

[0401] Table 2. Pharmacokinetic parameters of compound A after intratracheal administration of crystal form I in rats (1 mg / rat, N = 3)

[0402] Table 3. Pharmacokinetic parameters of compound A after intratracheal administration of crystal form II in rats (1 mg / rat, N = 3)

[0403] Moreover, the method for preparing the crystalline form disclosed herein is simple, easy to implement, and operates under mild reaction conditions. Furthermore, it does not require multiple purification steps, is safe and environmentally friendly, and is beneficial for the industrial production of the crystalline form.

[0404] Experiment Example 9: Preparation of Suspensions with Different Formulations

[0405] General preparation scheme

[0406] The suspension is prepared by a process including the following steps:

[0407] (1) Weigh out the prescribed amount of surfactant, disodium ethylenediaminetetraacetate and sodium chloride, add water for injection and stir to dissolve, then add pH adjuster to adjust the pH of the solution to obtain an excipient aqueous solution;

[0408] (2) Add the micronized crystal form I of compound A to the aqueous solution of excipients, stir and suspend until uniform, to form a coarse suspension;

[0409] (3) Homogenize the crude suspension under high pressure to obtain the final suspension;

[0410] (4) The final suspension is filled and packaged to obtain the final product.

[0411] The above experiments were conducted using different surfactants and optional pH adjusters, with the following formulations.

[0412] Table 4

[0413] Formulas 9 and 10 were further developed, and the dosages corresponding to Formulas 1-8 and Formulas 9-10 are shown in the table below:

[0414] The pH of the blank excipient solution and the high-pressure homogenization conditions are shown below:

[0415] Table 5

[0416] To further analyze drug stability, suspensions of formulations 1 through 10 were placed in a 40°C oven for 30 days. Afterward, their content, related substances, and redispersibility were analyzed. The results are as follows:

[0417] Table 6

[0418] The results from formulations 1 through 8 show that the suspensions exhibit good chemical stability under different pH and drug concentration conditions. After being stored at 40°C for one month, the content and related substances did not change significantly. However, formulation 3, due to its surfactant concentration being lower than the drug concentration, suffers from poor physical stability. The particles, after settling, cannot be redispersed uniformly, preventing the agglomerated particles from being atomized and leading to product non-compliance. In contrast, the other seven formulations all had surfactant concentrations at or above the drug concentration, and the suspensions were able to redisperse uniformly.

[0419] Furthermore, studies on formulations 9 and 10 revealed that reducing the surfactant concentration to below the drug concentration also resulted in good sample stability. Moreover, the sample volume (or unit dose) also had a certain impact on the stability of the suspension. Specifically, although the surfactant concentration in formulation 9 was further reduced compared to formulation 3, its smaller volume and thinner sedimentation layer allowed for uniform dispersion after shaking, exhibiting better stability than the other seven formulations.

[0420] Therefore, it is evident that due to the low surfactant-to-drug concentration ratio in Formulation 3, coupled with a thick sedimentation layer, severe particle agglomeration occurred, making it difficult to redisperse uniformly after shaking. Although Formulation 9 has a further reduced surfactant concentration compared to Formulation 3, its smaller volume (e.g., 1-3 mL, preferably 1-2 mL) and thinner sedimentation layer allow for uniform dispersion after shaking, demonstrating better stability compared to the other eight formulations.

[0421] Experimental Example 10: Particle Morphology Characterization

[0422] To analyze the morphology of suspensions with different particle sizes, small amounts of suspensions from formulations 1, 3, and 5 were dropped onto a filter membrane, filtered, and washed. The drug particles were then adhered to a glass slide, sputtered with gold, and observed under a scanning electron microscope. The results, shown in Figures 25, 26, and 27, indicate that when the particle size was large, most of the suspension particles were plate-like. As the average particle size decreased, the proportion of spherical particles increased. These results suggest that during high-pressure homogenization, plate-like particles were broken down into spherical particles, and the average particle size decreased with increasing homogenization pressure.

[0423] Example 11 Characterization of suspension atomization characteristics

[0424] The main indicators of the atomization characteristics of inhaled suspensions are the fine particle fraction (FPF) and the mass median aero-dynamic diameter (MMAD). MMAD reflects the overall particle size level. The size of the atomized particles determines the deposition location. Generally, particles of 1–5 μm can be deposited in the lower respiratory tract and lungs, particles of 5–10 μm can be deposited in the upper respiratory tract, particles larger than 10 μm cannot be deposited in the lungs, and particles smaller than 1 μm are exhaled. More specifically, particles of 1–3 μm can be deposited in the lower lung tissues such as small bronchi and alveoli, while particles of 3–5 μm can only be deposited in the upper lung tissues such as large trachea and bronchi. FPF represents the proportion of particles that can be deposited in the lungs.

[0425] A new generation of drug delivery nebulizer (NGI) was used for the determination, with a flow rate of 15 L / min and a variation range of ±5%. The device was placed in a cooling device at 5°C for 90 min before operation. Different formulation suspensions were taken, shaken well, and 2 mL was accurately pipetted into a PARI BOY compressed air nebulizer for nebulization. After nebulization, the nebulizer cup and mouthpiece were cleaned with 50% ethanol, and the cleaning solution was collected in a 50 mL volumetric flask. The adapter, artificial throat, and each collection plate of the NGI instrument were cleaned with 50% ethanol, and the cleaning solution was collected in a 25 mL volumetric flask. The drug concentration in each washing solution was then analyzed by HPLC. The HPLC results were imported into the CITDA data analysis system to calculate the values ​​of different indicators.

[0426] The specific results are as follows:

[0427] Table 7

[0428] The results show that at low drug concentrations (≤0.2%), the MMAD decreases and the FPF increases as the average particle size of the suspension decreases. At high drug concentrations (≥0.5%), although the average particle size of the suspension remains consistent, the increased number of drug particles in the droplets leads to a larger MMAD and a smaller FPF. In summary, reducing the average particle size or concentration of the suspension to achieve an MMAD less than 5 μm facilitates more efficient nebulized inhalation.

[0429] Experimental Example 12: Rat Pharmacokinetic Test

[0430] 11.1 Experimental Objective: To investigate the pharmacokinetic characteristics of the drug administered by single and multiple inhalations to Sprague-Dawley (SD) rats, to evaluate the macro-steady-state status in the animals after multiple administrations, and to preliminarily assess its bioavailability by comparing it with the intravenous administration group.

[0431] 11.2 Sample Preparation: Suspensions of formulations 7 and 8 were selected for nebulized inhalation. A 0.4 mg / mL injection solution was also prepared: 0.01 g of compound A (crystal form I) was weighed, 1.25 mL of dimethyl sulfoxide was added, and the solution was stirred to dissolve. Then, 2.5 mL of [the solution was added]. Add HS15, stir until well mixed, and finally add an appropriate amount of water for injection to a final volume of 25 mL. Mix thoroughly and filter using a 0.2 μm nylon membrane to obtain the final product.

[0432] 11.3 Aerosol generation conditions: The suspension needs to be continuously stirred for 10 min before administration. Use one exposure chamber of the inhalation exposure system, use 3 PARI nebulizer cups, generate the test solution in single chamber mode, set the aerosol generation flow rate to 22 L / min, the suction flow rate to 20 L / min, the initial liquid addition volume to 4 mL, and the replenishment rate to 0.5 mL / min.

[0433] 11.4 Protocol Design: A total of 24 SD rats, half male and half female, were used and divided into 4 groups of 6 rats each. Group 3 received the drug once daily for 7 consecutive days, while the other groups received a single dose. The grouping and dosage are shown in Table 8 below:

[0434] Table 8 Note: The low-dose group used Formula 7 suspension, while the medium-dose and high-dose groups used Formula 8 suspension.

[0435] 11.5 Administration

[0436] Administration routes: Group 1: intravenous injection; Groups 2-4: inhalation administration

[0437] Dosage volume: Group 1: 2.5 mL / kg

[0438] Dosing frequency: Groups 1, 2 and 4 were given a single dose, while Group 3 was given a dose for 7 consecutive days, with each dose administered at an interval of 24±8 hours.

[0439] Administration method: For the first group of animals, the required concentration of the test sample was accurately drawn using a suitable disposable sterile syringe and intravenous infusion needle, and administered via tail vein injection within 30 seconds.

[0440] Groups 2-4 animals:

[0441] Low-dose group: Continuous inhalation of the test sample aerosol at a concentration of 10 mg / mL for 10 minutes;

[0442] Medium-dose group: Continuous inhalation of the test sample aerosol at a concentration of 20 mg / mL for 15 minutes;

[0443] High-dose group: Continuous inhalation of the test sample aerosol at a concentration of 20 mg / mL for 50 minutes.

[0444] 11.6 Calculation of actual delivered dose:

[0445] The formula for calculating the actual delivered dose is:

[0446] Dose(mg / kg)=RMV×Concentration×Duration / BW / 1000,

[0447] Animal minute ventilation (RMV) is calculated using the following formula:

[0448] RMV(L / min)=0.608×BW(kg)0.852,

[0449] In the formula, BW represents the animal's body weight in kg; Concentration represents the measured average aerosol concentration of the test sample in μg / L; and Duration represents the duration of drug administration in min. After drug administration, the average aerosol concentration is calculated based on all measured analytical concentrations, and the actual delivered dose is then calculated.

[0450] Results: After intravenous injection of the drug at a dose of 1 mg / kg into SD rats, the mean terminal elimination half-life of the drug in plasma was 0.61 h, and the steady-state apparent volume of distribution (Vss) was 0.73 mL / kg. The apparent volume of distribution (Vz) was less than the total body fluid volume of the rats, indicating that the drug was mainly distributed in the blood. The main pharmacokinetic parameters after intravenous administration are shown in Table 9.

[0451] Table 9

[0452] After SD rats were administered the suspension by inhalation at doses of 0.834 mg / kg, 2.521 mg / kg, and 11.064 mg / kg, respectively, the plasma systemic drug exposure levels (C) were as follows: max and AUC last The pharmacokinetic parameters increase with increasing dose. The main pharmacokinetic parameters after inhalation administration are shown in Table 10.

[0453] Table 10: Major pharmacokinetic parameters in animal plasma after inhalation administration Note: F% represents absolute bioavailability.

[0454] Conclusion: AUC of inhalation administration vs. intravenous administration last In comparison, the absolute bioavailability (F%) of the drug in male SD rats was 33.83%, 20.84%, and 2.11%, respectively, while the absolute bioavailability (F%) in female SD rats was 32.27%, 50.06%, and 1.41%, respectively. After continuous inhalation administration of 2.251 mg / kg to SD rats for 7 days, no significant accumulation was observed, and the pharmacokinetic characteristics after 7 days were essentially consistent with those after a single dose.

[0455] After single inhalation administration of the suspension to SD rats at doses of 0.834 mg / kg, 2.251 mg / kg, and 11.064 mg / kg, and intravenous injection of 1 mg / kg, there was no significant sex difference in exposure levels between male and female rats. Systemic exposure levels of compound A in plasma (C...) max and AUC last The exposure increases with increasing dose, but the percentage increase in exposure is less than the percentage increase in dose (except for female animals in the dose range of 0.834–2.251 mg / kg). In the dose range of 0.834 mg / kg to 11.064 mg / kg, it exhibits nonlinear pharmacokinetic characteristics.

[0456] In addition to those described herein, various modifications to this disclosure will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. All references cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) are incorporated herein by reference in their entirety.

Claims

A composition comprising a compound of Formula (I) or a tautomer, solvate, anhydrate, pharmaceutically acceptable salt, or crystalline form thereof and a surfactant, wherein, Compounds of formula (I) are: wherein: Ring A is a 5-6 membered saturated or partially unsaturated heterocycle, which optionally contains, in addition to the indicated nitrogen atom, 1-2 additional heteroatoms selected from nitrogen, oxygen and sulfur; R1is selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl and -OR; R2is selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl and -OR; each R is independently selected from hydrogen and C 1-4 alkyl; n is 1, 2 or 3. The composition of claim 1, further comprising disodium edetate. The composition of claim 1 or 2, further comprising sodium chloride. The composition of any one of claims 1-3, comprising a pH adjusting agent. The composition of claim 4, the pH adjusting agent is selected from one or more of sodium citrate, citric acid, hydrochloric acid, sodium hydroxide, phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium bicarbonate. The composition of any one of claims 1-5, wherein the pH of the composition is from 3.5 to 8.5; preferably from 4.0 to 7.8; preferably from 6.4 to 7.

8. The composition of any one of claims 1-6, wherein the concentration of the compound of formula (I) or a tautomer, solvate, anhydrate, pharmaceutically acceptable salt or crystalline form thereof in the composition is from 0.01 to 2% by weight; preferably from 0.02 to 2%; preferably from 0.02 to 1%; preferably from 0.02 to 0.5%; preferably from 0.02 to 0.1%; preferably 0.02%, 0.025%, 0.05%, 0.075%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4% or 0.5%. The composition of any one of claims 1-7, wherein the concentration of the surfactant is from 0.01 to 2% by weight; preferably the concentration is from 0.02 to 2%; preferably the concentration is from 0.02 to 1%; preferably from 0.02 to 0. 5%; preferably from 0.02 to 0.1%; preferably 0.02 %, 0.025%, 0.04%, 0.06%, 0.1%, 0.2%, 0.5%, 0.58%, 1% or 2%; preferably 0.02%, 0.025%, 0.04%, 0.1% or 0.5%. The composition of any one of claims 1-8, wherein the mass ratio of the compound of formula (I) to the surfactant is from 1:3 to 1:1; preferably from 1:2 to 1:1; preferably from 1:1.5 to 1:

1. The composition of any one of claims 1-8, wherein the mass ratio of the compound formula (I) to the surfactant is from 3:1 to 1:3, preferably from 2.5:1 to 1:1, preferably selected from 1:1, 1.25:1, 1.5:1, 1.75:1, 2.0:1 and 2.5:

1. The composition of any one of claims 1-10, wherein the compound of Formula (I) is selected from the following compounds, or a tautomer, solvate, anhydrate, pharmaceutically acceptable salt, or crystalline form thereof: Preferably, the compound of formula (I) is a compound of the following formula or a tautomer thereof, or a solvate, anhydrate, pharmaceutically acceptable salt or crystalline form thereof: The composition of any one of claims 1-11, wherein the surfactant is selected from a non-ionic surfactant, an anionic surfactant, a cationic surfactant and an amphoteric surfactant, or a combination thereof. The composition of any one of claims 1-12, wherein the surfactant is selected from one or more of polyethylene glycol, a Span, a poloxamer, a polysorbate, sodium oleate, sodium lauryl sulfate, cetyltrimethylammonium bromide and lecithin; preferably the surfactant is selected from one or more of polyethylene glycol, a Span, poloxamer and a polysorbate. The composition of any one of claims 1-13, wherein the composition is in the form of a suspension; optionally, in the suspension, the particle size of the compound of formula (I) or a tautomer, solvate, anhydrate, pharmaceutically acceptable salt, or crystalline form thereof is less than 3 μm, preferably 1-2 μm. The composition of any one of claims 1-14, wherein the composition is formulated for inhalation administration. The composition of any one of claims 1-15, wherein the composition is formulated for administration in the form of a nebulizer, including metered dose and non-metered dose nebulizers; optionally, the MMAD is 1-10 μm, preferably 1.0-6 μm, preferably 1-5 μm. The composition of any one of claims 1-16, in the form of an aqueous suspension. The composition of claim 17, wherein the concentration of the compound of formula (I) in the aqueous suspension is 0.2 mg / mL to 5 mg / mL, preferably 0.25 mg / mL to 2 mg / mL, further preferably 0.25 mg / mL to 1 mg / mL. The composition of claim 18, wherein the concentration of the compound of formula (I) in the aqueous suspension is selected from the group consisting of 0.2 mg / mL, 0.25 mg / mL, 0.3 mg / mL, 0.35 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, and 5 mg / mL, preferably from the group consisting of 0.25 mg / mL, 1 mg / mL, 2 mg / mL, and 3 mg / mL. The composition of any one of claims 17-19, wherein the aqueous suspension is in unit dose form. The composition of claim 20, wherein each unit dose is 1 to 8 mL of the aqueous suspension, preferably 2 to 8 mL. The composition of claim 20, wherein each unit dose is the aqueous suspension in a volume selected from the group consisting of 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, and 8 mL, preferably 2 mL. The composition of claim 1 comprising, by weight, 0.02% to 2% of a compound of the following formula or a tautomer thereof or a crystalline form thereof, 0.02% to 1.4% of a polysorbate, 0.01% to 1% of disodium edetate, 0.5% to 1% of sodium chloride, and 0.01% to 0.1% of sodium citrate, optionally 0.03% to 0.1% of a Span, and optionally 0.15% to 0.5% of a poloxamer: The composition of claim 1 comprising, by weight, 0.02% of the compound of the following formula or a tautomer thereof or a crystalline form thereof, 0.02% of polysorbate, 0.01% of disodium edetate, 0.9% of sodium chloride, and 0.02% or 0.05% of sodium citrate: The composition of claim 1, comprising 0.1% of the compound of formula (I) or a tautomer or a crystalline form thereof, 0.05% of polysorbate, 0.01% of disodium edetate, 0.9% of sodium chloride, and 0.05% of sodium citrate, by weight; or The composition of claim 1, comprising 1% of the compound of formula (I) or a tautomer or a crystalline thereof, 0.7% of polysorbate, 0.01% of disodium edetate, 1.9% of sodium chloride, 0.05% of sodium citrate, 0.06% of Span 85, and 0.3% of poloxamer 407, by weight; or comprising 2% by weight of a compound of the following formula or a tautomer thereof or a crystalline form thereof, 1.4% of polysorbate, 0.01% of disodium edetate, 0.9% of sodium chloride, 0.05% of sodium citrate, 0.1% of Span 85 and 0.5% of poloxamer 407: The composition of claim 1, comprising 0.1% of the compound of formula (1) or a tautomer or a crystalline form thereof, 0.04% of polysorbate, 0.01% of disodium edetate, 2.9% of sodium chloride, and 0.05% of sodium citrate, by weigh; or comprising 0.025% by weight of a compound of the following formula or a tautomer thereof or a crystalline form thereof, 0.02% of polysorbate, 0.01% of disodium edetate, 0.9% of sodium chloride, and 0.05% of sodium citrate: The composition of claim 26, which is an aqueous suspension in unit dosage form, wherein each unit dosage is from 1 to 8 mL of the aqueous suspension, preferably 1-5 mL, further preferably 1-2 mL, preferably 2 mL. A composition comprising a crystalline form of the compound 4-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenethyl]pyridin-2-(1H)-one or a tautomer thereof: The composition of claim 28, wherein the crystalline form comprises peaks at about 12.6 ± 0.3, 20.3 ± 0.3, 20.9 ± 0.3, 22.0 ± 0.3, and 23.1 ± 0.3 2Q (°) in an X-ray powder diffraction (XRPD) pattern obtained using Cu Ka radiation. The composition of claim 29, wherein the XRPD pattern of the crystalline form further comprises peaks at about 4.0 ± 0.3, 22.5 ± 0.3, 24.1 ± 0.3, 25.2 ± 0.3, and 26.2 ± 0.3 2Q (°). The composition of claim 29 or 30, wherein the XRPD pattern of the crystalline form further comprises peaks at about 8.4 ± 0.3, 11.3 ± 0.3, 15.3 ± 0.3, 16.9 ± 0.3, and 26.7 ± 0.3 2Q (°). The composition of claim 29, wherein the XRPD pattern of the crystalline form comprises peaks at about the following 2Q (°) positions: 4.0 ± 0.3, 8.4 ± 0.3, 11.3 ± 0.3, The composition of claim 29, wherein the XRPD pattern of the crystalline form comprises peaks at about: The composition of claim 29, wherein the crystalline form has an XRPD pattern substantially the same as shown in Figure 1. The composition of any one of claims 29-34, wherein the crystalline form comprises endothermic peaks at 96 ± 3 °C and 129 ± 3 °C in a differential scanning calorimetry (DSC) pattern. The composition of any one of claims 29-35, wherein the crystalline form has a thermogravimetric analysis (TGA) pattern showing no significant weight loss of the crystalline form prior to heating to the melting point. The composition of any one of claims 29-36, wherein the crystalline form has a DSC-TGA pattern substantially the same as shown in Figure 2. The composition of claim 28, wherein the crystalline form comprises peaks at about 12.5 ± 0.3, 17.3 ± 0.3, 20.6 ± 0.3, and 23.2 ± 0.3 2Θ (°) in an X-ray powder diffraction (XRPD) pattern obtained using Cu Ka radiation. The composition of claim 38, wherein the XRPD pattern of the crystalline form further comprises peaks at about 4.1 ± 0.3, 8.3 ± 0.3, 21.0 ± 0.3, 23.5 ± 0.3, and 26.5 ± 0.3 2Θ (°). The composition of claim 38 or 39, wherein the XRPD pattern of the crystalline form further comprises peaks at about 10.9 ± 0.3, 19.0 ± 0.3, and 19.5 ± 0.3 2Θ (°). The composition of claim 38, wherein the XRPD pattern of the crystalline form comprises peaks at about the following 2Θ (°) positions: 4.1 ± 0.3, 8.3 ± 0.3, 10.9 ± 0.3, 11.5 ± 0.3, 12.0 ± 0.3, 12.5 ± 0.3, 13.4 ± 0.3, 16.1 ± 0.3, 16.7 ± 0.3, 17.3 ± 0.3, 19.0 ± 0.3, 19.5 ± 0.3, 20.6 ± 0.3, 21.0 ± 0.3, 21.3 ± 0.3, 21.5 ± 0.3, 22.1 ± 0.3, 23.2 ± 0.3, 23.5 ± 0.3, 24.4 ± 0.3, 24.6 ± 0.3, 25.4 ± 0.3, 25.7 ± 0.3, 26.5 ± 0.3, 27.7 ± 0.3, 28.2 ± 0.3, and 29.7 ± 0.

3. The composition of claim 38, wherein the XRPD pattern of the crystalline form comprises peaks at about: The composition of claim 38, wherein the crystalline form has an XRPD pattern substantially the same as shown in FIG.

4. The composition of any one of claims 38-43, wherein the crystalline form comprises endothermic peaks at about 108 ± 3 °C and 128 ± 3 °C and an exothermic peak at about 270 ± 3 °C in a differential scanning calorimetry (DSC) pattern. The composition of any one of claims 38-44, wherein the crystalline form has a thermogravimetric analysis (TGA) pattern showing no significant weight loss of the crystalline form prior to heating to the melting point. The composition of any one of claims 38-45, wherein the crystalline form has a DSC-TGA pattern substantially the same as shown in FIG.

5. The composition of any one of claims 28-46, further comprising a surfactant. The composition of any one of claims 28-47, further comprising disodium edetate. The composition of any one of claims 28-48, further comprising sodium chloride. The composition of any one of claims 28-49, comprising a pH adjusting agent. The composition of claim 50, the pH adjusting agent is selected from one or more of sodium citrate, citric acid, hydrochloric acid, sodium hydroxide, phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium bicarbonate. The composition of claim 50, the pH adjusting agent is selected from one or more of the group consisting of sodium citrate, citric acid, hydrochloric acid, sodium hydroxide, phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium bicarbonate. The composition of any one of claims 28-51, wherein the pH of the composition is from 3.5 to 8.5; preferably from 4.0 to 7.8; preferably from 6.4 to 7.

8. The composition of any one of claims 28-52, wherein the concentration of the crystalline form in the composition is from 0.01 to 2% by weight; preferably from 0.02 to 2%; preferably from 0.02 to 1%; preferably from 0.02 to 0.5%; preferably from 0.02 to 0.1%; preferably 0.02%, 0.025%, 0.05%, 0.075%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, or 0.5%. The composition of any one of claims 28-53, wherein the concentration of the surfactant is from 0.01 to 2% by weight; preferably the concentration is from 0.02 to 2%; preferably the concentration is from 0.02 to 1%; preferably from 0.02 to 0. 5%; preferably 0.02%, 0.025%, 0.04%, 0.06%, 0.1%, 0.2%, 0.5%, 0.58%, 1%, or 2%; preferably from 0.02 to 0.1%; preferably 0.02%,0.025%, 0.04%, 0.1%, or 0.5%. The composition of any one of claims 28-54, wherein the mass ratio of the crystalline form to surfactant is from 1:3 to 1:1; preferably from 1:2 to 1:1; preferably from 1:1.5 to 1:

1. The composition of any one of claims 28-55, wherein the mass ratio of the crystalline form to surfactant is from 3:1 to 1:3, preferably from 2.5:1 to 1:1, preferably selected from the group consisting of 1:1, 1.25:1, 1.5:1, 1.75:1, 2.0:1, and 2.5:

1. The composition of any one of claims 28-56, wherein the surfactant is selected from the group consisting of non-ionic surfactants, anionic surfactants, cationic surfactants, and amphoteric surfactants, or a combination thereof. The composition of any one of claims 28-57, wherein the surfactant is selected from one or more of polyethylene glycol, a Span, a poloxamer, a polysorbate, sodium oleate, sodium dodecyl sulfate, cetyltrimethylammonium bromide, and lecithin; preferably the surfactant is selected from one or more of polyethylene glycol, a Span, poloxamer, and polysorbate. The composition of any one of claims 28-58, in the form of an aqueous suspension; optionally, in the suspension, the particle size of the compound of Formula (I) or a tautomer, solvate, anhydrate, pharmaceutically acceptable salt, or crystalline form thereof is less than 3 pm, preferably from 1-2 pm. The composition of claim 59, wherein in the aqueous suspension, the concentration of the crystalline form is from 0.2 mg / mL to 5 mg / mL, preferably from 0.25 mg / mL to 2 mg / mL, further preferably from 0.25 mg / mL to 1 mg / mL. The composition of claim 60, wherein the concentration of the crystalline form in the aqueous suspension is selected from the group consisting of 0.2 mg / mL, 0.25 mg / mL, 0.3 mg / mL, 0.35 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL and 5 mg / mL, preferably selected from the group consisting of 0.25 mg / mL, 1 mg / mL, 2 mg / mL and 3 mg / mL. The composition of any one of claims 59-61, wherein the aqueous suspension is in unit dosage form. The composition of claim 62, wherein each unit dosage is 1 to 8 mL of the aqueous suspension, preferably 2 to 8 mL. The composition of claim 63, wherein each unit dosage is the aqueous suspension in a volume selected from the group consisting of 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL and 8 mL, preferably 1-5 mL, further preferably 1-2 mL, preferably 2 mL. A spray comprising the composition of any one of claims 1-64 and a pharmaceutically acceptable carrier; optionally, a metered dose spray and a non-metered dose spray; optionally, an MMAD of 1-10 μm, preferably 1.0-6 μm, preferably 1-5 μm. A method of preparing a composition comprising a compound of formula (I) or a tautomer, solvate, anhydrate, pharmaceutically acceptable salt or crystalline form thereof and a surfactant, the method comprising: Step (a): adding a compound of formula (I) or a tautomer, solvate, anhydrate, pharmaceutically acceptable salt or crystalline form thereof to a solution of a surfactant to form a suspension; wherein the compound of formula (I) is: wherein: Ring A is a 5-6 membered saturated or partially unsaturated heterocyclic ring optionally containing, in addition to the indicated nitrogen atom, 1-2 additional heteroatoms selected from nitrogen, oxygen and sulfur; R1is selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl and -OR; R2is selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl and -OR; each R is independently selected from hydrogen and C 1-4 alkyl; n is 1, 2 or 3; Preferably, wherein the compound of Formula (I) is selected from the following compounds, or a tautomer, solvate, anhydrate, pharmaceutically acceptable salt, or crystalline form thereof: Preferably, the compound of formula (I) is a compound of the following formula or a tautomer thereof, or a solvate, anhydrate, pharmaceutically acceptable salt or crystalline form thereof: Preferably, the compound of formula (I) is a crystalline form of the compound of formula (I) or a tautomer thereof: Preferably, the crystalline form is Form I or Form II. The method of claim 66, wherein prior to step (a) comprises: Step (a-2): micronizing the compound of formula (I) or a tautomer, solvate, anhydrate, pharmaceutically acceptable salt or crystalline form thereof to obtain particles having a D90 of 5 to 20 μm. The method of claim 66 or 67, wherein prior to step (a-2) comprises: Step (a-1): preparing a solution of the surfactant in water, comprising adding the surfactant, optionally disodium ethylenediaminetetraacetate, and optionally sodium chloride to water to form a solution in water, and optionally adding a pH adjusting agent to adjust the pH of the solution to 3.5 to 8.

5. The method of any one of claims 66 to 68, wherein after step (a) comprises: Step (b): high pressure homogenizing the suspension obtained in step (a) to an average particle size of less than 3 μm, preferably 1-2 μm. The method of any one of claims 66-69, wherein the surfactant is selected from the group consisting of non-ionic surfactants, anionic surfactants, cationic surfactants, and amphoteric surfactants, or a combination thereof; preferably, wherein the surfactant is selected from one or more of polyethylene glycol, a Span, a Pluronic, a polysorbate, sodium oleate, sodium dodecyl sulfate, cetyltrimethylammonium bromide, and lecithin; preferably, the surfactant is selected from one or more of polyethylene glycol, a Span, Pluronic, and a polysorbate. The method of claim 68, wherein the pH adjusting agent is selected from one or more of sodium citrate, citric acid, hydrochloric acid, sodium hydroxide, phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium bicarbonate. Use of a composition according to any one of claims 1-64 for the manufacture of a medicament for the treatment and / or prevention of a respiratory disease or a disease related thereto. The use of claim 72, wherein the medicament is administered in an amount equivalent to about 0.025 mg / day to about 1000 mg / day of the compound of formula (I), preferably about 0.1 mg / day to about 200 mg / day. The use of claim 72, wherein the medicament is administered in an amount equivalent to the compound of formula (I) about 0.025 mg / day, 0.05 mg / day, 0.1 mg / day, about 0.5 mg / day, 1 mg / day, about 5 mg / day, about 10 mg / day, about 20 mg / day, about 30 mg / day, about 40 mg / day, about 50 mg / day, about 100 mg / day, and about 200 mg / day. The use of any one of claims 72-74, wherein the daily dose of the medicament is for administration in one dose or in two, three or four doses. The use of any one of claims 72-75, wherein the medicament is for administration by inhalation. The use of any one of claims 72-76, wherein the medicament is in the form of a spray. The use of any one of claims 72-77, wherein the respiratory disease is a pulmonary disease, bronchiectasis, or asthma, preferably the pulmonary disease is lung injury, lung inflammation, lung fibrosis, or chronic obstructive pulmonary disease. The use of claim 78, wherein the lung injury is radiation-induced lung injury; preferably, the radiation-induced lung injury is selected from the group consisting of radiation pneumonitis and radiation-induced pulmonary fibrosis. The use of claim 78, wherein the chronic obstructive pulmonary disease is selected from the group consisting of chronic bronchitis type chronic obstructive pulmonary disease, emphysema type chronic obstructive pulmonary disease, and mixed type chronic obstructive pulmonary disease. The use of claim 78, wherein the chronic obstructive pulmonary disease comprises stable chronic obstructive pulmonary disease and acute exacerbation chronic obstructive pulmonary disease. The use of any one of claims 72-81, wherein the medicament further comprises a package insert indicating the use in conjunction with an additional therapeutic agent. The use of claim 82, wherein the additional therapeutic agent is selected from the group consisting of bronchodilators, inhaled glucocorticoids, theophylline drugs, mucolytic agents, cardiovascular system drugs, and osteoporosis prophylactic drugs. The use of claim 82, wherein the additional therapeutic agent is selected from the group consisting of short- and long-acting beta2 agonists, short- and long-acting anticholinergic agents, antibacterial agents, antiviral agents, antifungal agents, antineoplastic agents, antihistamines, proteins, enzymes, hormones, non-steroidal anti-inflammatory substances, cytokines, steroids, and insulin.

Images