Patent Description:
Fibroblast growth factor (FGF) has been recognized as an important mediator of many physiological processes, such as morphogenesis during development and angiogenesis. The fibroblast growth factor receptor (FGFR) family consists of four members (FGFR1-FGFR4), which are glycoproteins composed of extracellular immunoglobulin (Ig)-like domains, a hydrophobic transmembrane region and a cytoplasmic part containing a tyrosine kinase domain. FGF binding leads to FGFR dimerization, followed by receptor autophosphorylation and activation of downstream signaling pathways. Receptor activation is sufficient for the recovery and activation of specific downstream signaling partners that participate in the regulation of diverse processes such as cell growth, cell metabolism and cell survival. Thus, the FGF/FGFR signaling pathway has pleiotropic effects on many biological processes critical to tumor cell proliferation, migration, invasion, and angiogenesis.

Vinyl indazoles are known in the art for the treatment of cancer. See for example, <CIT> and <CIT>. FGFR inhibitors are also known in the art. See for example, <CIT>, and <CIT> which discloses the compounds of formulae (I) and (II) as discussed below.

Especially, the present invention provides a crystal form G of the compound of formula (II) as defined in claim <NUM>, a preparation method of the crystal form G of the compound of formula (II) as defined in claim <NUM>, a crystal form G of the compound of formula (II) for use in a method of treating tyrosine kinase inhibitor related diseases as defined in claim <NUM>, and a crystal form G of the compound of formula (II) for use in a method of treating a tumor as defined in claim <NUM>.

The present disclosure provides a crystal form A of a compound of formula (I) which is not part of the present invention, wherein the X-ray powder diffraction pattern thereof comprises characteristic diffraction peaks at the following angle 2θ: <NUM>±<NUM>°, <NUM>±<NUM>°, and <NUM>±<NUM>°.

In the present disclosure, the X-ray powder diffraction pattern of the crystal form A may comprise characteristic diffraction peaks at the following angle 2θ: <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, and <NUM>±<NUM>°.

In the present disclosure, the XRPD pattern of the crystal form A may be as shown in <FIG>.

In the present disclosure, the analytical data of the XRPD pattern of the crystal form A may be as shown in Table <NUM>:.

In the present disclosure, the differential scanning calorimetry curve of the crystal form A may have an onset point of an endothermic peak at <NUM> ± <NUM>, <NUM>± <NUM> and <NUM> ± <NUM> respectively, and have an onset point of an exothermic peak at <NUM> ± <NUM>.

In the present disclosure, the DSC pattern of the crystal form A may be as shown in <FIG>.

In the present disclosure, the thermogravimetric analysis curve of the crystal form A may have a weight loss of <NUM>% occurred at <NUM> ± <NUM> and a weight loss of <NUM>% occurred at <NUM>±<NUM>.

In the present disclosure, the TGA pattern of the crystal form A may be as shown in <FIG>.

The present disclosure provides a crystal form B of the compound of formula (I) which is not part of the present invention, wherein the X-ray powder diffraction pattern thereof comprises characteristic diffraction peaks at the following angle 2θ: <NUM>±<NUM>°, <NUM>±<NUM>° and <NUM>±<NUM>°.

In the present disclosure, the X-ray powder diffraction pattern of the crystal form B may comprise characteristic diffraction peaks at the following angle 2θ: <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, and <NUM>±<NUM>°.

In the present disclosure, the XRPD pattern of the crystal form B may be as shown in <FIG>.

In the present disclosure, the analytical data of the XRPD pattern of the crystal form B may be as shown in Table <NUM>:.

The present disclosure provides a crystal form C of the compound of formula (I) which is not part of the present invention, wherein the X-ray powder diffraction pattern thereof comprises characteristic diffraction peaks at the following angle 2θ: <NUM>±<NUM>°, <NUM>±<NUM>°, and <NUM>±<NUM>°.

In the present disclosure, the X-ray powder diffraction pattern of the crystal form C may comprise characteristic diffraction peaks at the following angle 2θ: <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, and <NUM>±<NUM>°.

In the present disclosure, the XRPD pattern of the crystal form C may be as shown in <FIG>.

In the present disclosure, the analytical data of the XRPD pattern of the crystal form C is as shown in Table <NUM>:.

The present disclosure provides a crystal form D of the compound of formula (I) which is not part of the present invention, wherein the X-ray powder diffraction pattern thereof comprises characteristic diffraction peaks at the following angle 2θ: <NUM>±<NUM>°, <NUM>±<NUM>°, and <NUM>±<NUM>°.

In the present disclosure, the X-ray powder diffraction pattern of the crystal form D may comprise characteristic diffraction peaks at the following angle 2θ: <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, and <NUM>±<NUM>°.

In the present disclosure, the XRPD pattern of the crystal form D may be as shown in <FIG>.

In the present disclosure, the analytical data of the XRPD pattern of the crystal form D may be as shown in Table <NUM>:.

The present disclosure provides a crystal form E of the compound of formula (I) which is not part of the present invention, wherein the X-ray powder diffraction pattern thereof comprises characteristic diffraction peaks at the following angle 2θ: <NUM>±<NUM>°, <NUM>±<NUM>°, and <NUM>±<NUM>°.

In the present disclosure, the X-ray powder diffraction pattern of the crystal form E may comprise characteristic diffraction peaks at the following angle 2θ: <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, and <NUM>±<NUM>°.

In the present disclosure, the XRPD pattern of the crystal form E may be as shown in <FIG>.

In the present disclosure, the analytical data of the XRPD pattern of the crystal form E may be as shown in Table <NUM>:.

The present disclosure relates to a compound of formula (II),
<CHM>.

The present disclosure provides a crystal form F of the compound of formula (II) which is not part of the present invention, wherein the X-ray powder diffraction pattern thereof comprises characteristic diffraction peaks at the following angle 2θ: <NUM>±<NUM>°, <NUM>±<NUM>°, and <NUM>±<NUM>°.

In the present disclosure, the X-ray powder diffraction pattern of the crystal form F may comprise characteristic diffraction peaks at the following angle 2θ: <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, and <NUM>±<NUM>°.

In the present disclosure, the XRPD pattern of the crystal form F may be as shown in <FIG>.

In the present disclosure, the analytical data of the XRPD pattern of the crystal form F may be as shown in Table <NUM>:.

In the present disclosure, the differential scanning calorimetry curve of the crystal form F may have an onset point of an endothermic peak at <NUM> ±<NUM> and <NUM> ±<NUM> respectively, and have an onset point of an exothermic peak at <NUM> ±<NUM>.

In the present disclosure, the DSC pattern of the crystal form F may be as shown in <FIG>.

In the present disclosure, the thermogravimetric analysis curve of the crystal form F may have a weight loss of <NUM>% occurred at <NUM> ± <NUM>
In the present disclosure, the TGA pattern of the crystal form F may be as shown in <FIG>.

The present invention provides a crystal form G of the compound of formula (II), wherein the X-ray powder diffraction pattern thereof comprises characteristic diffraction peaks at the following angle 2θ: <NUM>±<NUM>°, <NUM>±<NUM>°, and <NUM>±<NUM>°; wherein said X-ray powder diffraction pattern is obtained using copper K-alpha X-rays at a wavelength of <NUM> Angstroms.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form G comprises characteristic diffraction peaks at the following angle 2θ: <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, and <NUM>±<NUM>°; wherein said X-ray powder diffraction pattern is obtained using copper K-alpha X-rays at a wavelength of <NUM> Angstroms.

In some embodiments of the present invention, the XRPD pattern of the crystal form G is as shown in <FIG>.

In some embodiments of the present invention, the analytical data of the XRPD pattern of the crystal form G is as shown in Table <NUM>:.

In some embodiments of the present invention, the differential scanning calorimetry curve of the crystal form G has an onset point of an endothermic peak at <NUM> ± <NUM>, and has an onset point of an exothermic peak at <NUM> ± <NUM>.

In some embodiments of the present invention, the DSC pattern of the crystal form G is as shown in <FIG>.

In some embodiments of the present invention, the thermogravimetric analysis curve of the crystal form G has a weight loss of <NUM>% occurred at <NUM> ± <NUM> and a weight loss of <NUM>% occurred at <NUM> ± <NUM>.

In some embodiments of the present invention, the TGA pattern of the crystal form G is as shown in <FIG>.

The present disclosure provides a crystal form H of the compound of formula (II) which is not part of the present invention, wherein the X-ray powder diffraction pattern thereof comprises characteristic diffraction peaks at the following angle 2θ: <NUM>±<NUM>°, <NUM>±<NUM>°, and <NUM>±<NUM>°.

In the present disclosure, the X-ray powder diffraction pattern of the crystal form H may comprise characteristic diffraction peaks at the following angle 2θ: <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, and <NUM>±<NUM>°.

In the present disclosure, the XRPD pattern of the crystal form H may be as shown in <FIG>.

In the present disclosure, the analytical data of the XRPD pattern of the crystal form H may be as shown in Table <NUM>:.

In the present disclosure, the differential scanning calorimetry curve of the crystal form H may have an onset point of an endothermic peak at <NUM> ± <NUM> and <NUM> ± <NUM> respectively, and have an onset point of an exothermic peak at <NUM> ± <NUM>.

In the present disclosure, the DSC pattern of the crystal form H may be as shown in <FIG>.

In the present disclosure, the thermogravimetric analysis curve of the crystal form H may have a weight loss of <NUM>% occurred at <NUM> ± <NUM> and a weight loss of <NUM>% occurred at <NUM> ± <NUM>.

In the present disclosure, the TGA pattern of the crystal form H may be as shown in <FIG>.

The present disclosure relates to a compound of formula (III),
<CHM>.

The present disclosure provides s crystal form I of the compound of formula (III) which is not part of the present invention, wherein the X-ray powder diffraction pattern thereof comprises characteristic diffraction peaks at the following angle 2θ: <NUM>±<NUM>°, <NUM>±<NUM>°, and <NUM>±<NUM>°.

In the present disclosure, the X-ray powder diffraction pattern of the crystal form I may comprise characteristic diffraction peaks at the following angle 2θ: <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, and <NUM>±<NUM>°.

In the present disclosure, the XRPD pattern of the crystal form I may be as shown in <FIG>.

In the present disclosure, the analytical data of the XRPD pattern of the crystal form I may be as shown in Table <NUM>:.

In the present disclosure, the differential scanning calorimetry curve of the crystal form I may have an onset point of an endothermic peak at <NUM> ± <NUM> and <NUM> ± <NUM> respectively.

In the present disclosure, the DSC pattern of the crystal form I may be as shown in <FIG>.

In the present disclosure, the thermogravimetric analysis curve of the crystal form I may have a weight loss of <NUM>% occurred at <NUM> ± <NUM> and a weight loss of <NUM>% occurred at <NUM> ± <NUM>.

In the present disclosure, the TGA pattern of the crystal form I may be as shown in <FIG>.

The present disclosure relates to a compound of formula (IV),
<CHM>.

The present disclosure provides a crystal form J of the compound of formula (IV) which is not part of the present invention, wherein the X-ray powder diffraction pattern thereof comprises characteristic diffraction peaks at the following angle 2θ: <NUM>±<NUM>°, <NUM>±<NUM>°, and <NUM>±<NUM>°.

In the present disclosure, the X-ray powder diffraction pattern of the crystal form J may comprise characteristic diffraction peaks at the following angle 2θ: <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, and <NUM>±<NUM>°.

In the present disclosure, the XRPD pattern of the crystal form J may be as shown in <FIG>.

In the present disclosure, the analytical data of the XRPD pattern of the crystal form J may be as shown in Table <NUM>:.

In the present disclosure, the differential scanning calorimetry curve of the crystal form J may have an onset point of an endothermic peak at <NUM> ± <NUM> and <NUM> ± <NUM> respectively.

In the present disclosure, the DSC pattern of the crystal form J may be as shown in <FIG>.

In the present disclosure, the thermogravimetric analysis curve of the crystal form J may have a weight loss of <NUM>% occurred at <NUM> ± <NUM> and a weight loss of <NUM>% occurred at <NUM> ± <NUM>.

In the present disclosure, the TGA pattern of the crystal form J may be as shown in <FIG>.

The present disclosure provides a preparation method of the crystal forms A, B, C, D, E, F, H, I and J of a compound of formula (I), (II), (III) or (IV), which is not part of the present invention, which comprises adding the compound of formula (I), (II), (III) or (IV) to a solvent respectively; and heating and stirring, or recrystallizing.

In the present disclosure, the solvent may be selected from methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, ethyl acetate-ethanol, isopropanol, or ethanol-water.

In the present disclosure, the stirring may be performed at a temperature of <NUM> to <NUM>.

In the present disclosure, the slurrying time may be <NUM> hours to <NUM> hours.

In the present disclosure, the weight ratio of the compound to the solvent may be <NUM>:<NUM> to <NUM>:<NUM>.

The present invention provides a preparation method of the crystal form G of the compound of formula (II), which comprises adding the compound of formula (I) into ethanol, adding hydrochloric acid/ethyl acetate dropwise to the reaction bottle, heating and stirring, cooling to room temperature, and filtering.

In some embodiments of the present disclosure, the heating and stirring of the crystal form G of the compound of formula (II) is performed at a temperature of <NUM> to <NUM>.

In some embodiments of the present invention, the crystal form G of the compound of formula (II) is for use in a method of treating tyrosine kinase inhibitor related diseases.

In some embodiments of the present invention, the crystal form G of the compound of formula (II), for use in a method of treating a tumor.

Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered indefinite or unclear in the absence of a particular definition, but should be understood in the ordinary sense. When a trade name appears herein, it is intended to refer to its corresponding commodity or active ingredient thereof.

The intermediate compounds of the present disclosure can be prepared by various synthetic methods known to those skilled in the art, including the embodiments and reference embodiments described below, the methods formed by combining the embodiments and reference embodiments described below with other chemical synthesis methods, and equivalent alternatives well-known for those skilled in the art.

The chemical reactions of the embodiments and reference embodiments of the present disclosure are carried out in a suitable solvent, and the solvent should be suitable for the chemical change, and the reagents and materials required therefor of the present disclosure. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select the synthetic steps or reaction schemes based on the existing embodiments and reference embodiments.

The present invention will be specifically described below by way of embodiments.

All solvents used in the present disclosure are commercially available and can be directly used without further purification.

The present disclosure employs the following abbreviations: r. stands for room temperature; THF stands for tetrahydrofuran; NMP stands for N-methylpyrrolidone; MeSO<NUM>H stands for methanesulfonic acid; DME stands for dimethoxyethane; DCM stands for dichloromethane; Xphos stands for <NUM>-dicyclohexylphospho-<NUM>',<NUM>',<NUM>'-triisopropylbiphenyl; EtOAc stands for ethyl acetate; MeOH stands for methanol; acetone stands for propanone; <NUM>-Me-THF stands for <NUM>-methyltetrahydrofuran; IPA stands for isopropanol; m-CPBA stands for <NUM>-chloroperoxybenzoic acid; Pd(dppf)Cl<NUM> stands for [<NUM>,<NUM>'-bis(diphenylphosphino)ferrocene]palladium dichloride; DIEA stands for N,N-diisopropylethylamine; DMSO stands for dimethyl sulfoxide; HEPES stands for <NUM>-[<NUM>-(<NUM>-hydroxyethyl)piperazin-<NUM>-yl]ethanesulfonic acid; EGTA stands for ethylene glycol bis(<NUM>-aminoethyl ether) tetraacetic acid; THP stands for tetrahydropyranyl.

Compounds are named manually or by ChemDraw® software, and the commercially available compounds use their vendor directory names.

The detailed XRPD parameters were as follows:.

The detailed DVS parameters are as follows:.

The hygroscopicity was evaluated using the following scales:.

The chromatograph conditions for the analysis method of the compound contents is as shown in Table <NUM>.

The compounds of the present disclosure have excellent in vitro FGFR1 kinase inhibitory activity and SNU-<NUM> cell inhibitory activity, and can be used as a small molecule tyrosine kinase inhibitor; they can inhibit cell proliferation and angiogenesis, have excellent antitumor activity, and have excellent effect in treating various mammals (including humans).

The solubility data of the salts of the present disclosure show that the hydrochloride has the highest solubility in the aqueous phase, and the three salts have similar solubility in simulated intestinal fluid and simulated gastric fluid; and the free base has good solubility in the three biological vehicle, but is extremely difficult to dissolve in water. Crystal forms G, I, and J (crystal forms I and J are not part of the present invention) have excellent thermal stability and stability under accelerated conditions, generate slight impurities under light irradiation conditions, and exhibit good stability under dark condition.

Note: <FIG> and <FIG> are for reference only and not part of the present invention.

In order to better understand the content of the present disclosure, the following embodiments and reference embodiments further illustrate the present disclosure.

Note: Embodiments 1A to <NUM> are for reference only and not part of the present invention
<CHM>.

To a solution of methyl <NUM>-carboxylate-<NUM>-picoline (<NUM>, <NUM> mol) in N,N-dimethylsulfoxide (<NUM>) were added iodine (<NUM>, <NUM> mmol) and trifluoroacetic acid (<NUM>, <NUM> mmol) at <NUM>. The obtained mixture was stirred for <NUM> hour and then heated to <NUM> and stirred for <NUM> hours. After being cooled to <NUM>, the reaction was terminated with saturated sodium thiosulfate solution (<NUM>) and stirred for <NUM> minutes. The aqueous layer was extracted with ethyl acetate (<NUM>×<NUM>) and the organic layers were combined and washed with saturated brine (<NUM>×<NUM>), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by flash silica gel column chromatography to obtain the embodiment 1A. <NUM>H NMR (<NUM>, CHLOROFORM-d) ppm: <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J=<NUM>, <NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM>-<NUM> (s,<NUM>).

To a solution of the embodiment 1A (<NUM>, <NUM> mmol) in trimethyl orthoformate (<NUM>) was slowly added formic acid (<NUM>) dropwise at <NUM>. The obtained mixture were stirred at this temperature for <NUM> minutes, followed by dropwise addition of concentrated sulfuric acid (<NUM>). After the addition, the mixture was heated to <NUM> and stirred for <NUM> minutes, then cooled to <NUM> and stirred for <NUM> hours, cooled to room temperature, and added to water (<NUM>). The aqueous layer was extracted with ethyl acetate (<NUM>×<NUM>). The organic phases were combined, washed with saturated brine (<NUM>×<NUM>), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the embodiment 1B, which was directly used in the next step.

To a solution of the embodiment 1B (<NUM>, <NUM> mmol) in tetrahydrofuran (<NUM>) was added lithium aluminum hydride (<NUM>, <NUM> mmol) in portions at <NUM> under the protection of nitrogen. After the addition, the obtained mixture was stirred for <NUM> hour at this temperature. The reaction was terminated with water (<NUM>) and <NUM>% sodium hydroxide (<NUM>) followed by water (<NUM>), stirred for <NUM> minutes, filtered and concentrated under reduced pressure to obtain the embodiment 1C, which was directly used in the next step.

To a solution of the embodiment 1C (<NUM>, <NUM> mmol) in dichloromethane (<NUM>) was added manganese dioxide (<NUM>, <NUM> mmol), and then the obtained mixture was heated to <NUM> and stirred for <NUM> hours. After being cooled to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography to obtain the embodiment 1D. <NUM>H NMR (<NUM>, CHLOROFORM-d) ppm <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dd, J=<NUM>, <NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

To a solution of the embodiment 1D (<NUM>, <NUM> mmol) in tetrahydrofuran (<NUM>) was added sodium hydride (<NUM>, <NUM>%, <NUM> mmol) in portions at <NUM> under nitrogen atmosphere. After the addition, the mixture was stirred for <NUM> minutes at this temperature, embodiment 1J (<NUM>, <NUM> mmol) was added thereto, and the mixture was heated to <NUM> and stirred for <NUM> hours. After being cooled to room temperature, the mixture was poured into ice water (<NUM>). The aqueous layer was extracted with ethyl acetate (<NUM>×<NUM>). The organic phases were combined, washed with saturated brine (<NUM>×<NUM>), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to obtain embodiment 1E.

This mixture was resolved by chiral HPLC to obtain cis- and trans- isomers, chiral column: Chiralcel OD-<NUM><NUM>×<NUM> I. , <NUM>, mobile phase: ethanol (<NUM>% DEA) -CO<NUM>, from <NUM>% to <NUM>%, Flow rate: <NUM>/min, wavelength: <NUM>.

To a mixed solution of embodiment 1E (<NUM>, <NUM> mmol) in acetone (<NUM>) and water (<NUM>) was addedp-toluenesulfonic acid monohydrate (<NUM>, <NUM> mmol) at room temperature. The reaction solution was heated to <NUM> and stirred for <NUM> hours. After completion of the reaction, water (<NUM>) was added, and dichloromethane (<NUM>×<NUM>) was added for extraction. The organic phases were combined, washed with saturated brine (<NUM>), dried over sodium sulfate, filtered and evaporated to obtain embodiment 1F as yellow solid. LCMS (ESI) m/z: <NUM> [M+<NUM>]+.

To a solution of embodiment 1F (<NUM>, <NUM> mmol) in methanol (<NUM>) was added sodium borohydride (<NUM>, <NUM> mmol) in portions under nitrogen atmosphere at room temperature. The reaction solution was stirred for <NUM> hour. Water (<NUM>) was added to terminate the reaction and ethyl acetate (<NUM>×<NUM>) was added for extraction. The organic phases were combined and washed with saturated brine (<NUM>), dried over sodium sulfate, filtered and evaporated to obtain embodiment <NUM> as a yellow liquid. LCMS (ESI) m/z: <NUM> [M+<NUM>]+.

To a solution of embodiment <NUM> (<NUM>, crude product) in methanol (<NUM>) was added a freshly prepared solution of acetyl chloride (<NUM>) in methanol (<NUM>) at room temperature under nitrogen atmosphere. The reaction solution was stirred at <NUM> for <NUM> hours. The solvent was removed under reduced pressure to obtain the embodiment <NUM> as a yellow solid. LCMS (ESI) m/z: <NUM> [M+<NUM>]+.

To a solution of the embodiment <NUM> (<NUM>, <NUM> mmol) in dichloromethane (<NUM>) were added triethylamine (<NUM>, <NUM> mmol), di-tert-butyl dicarbonate (<NUM>, <NUM> mmol) and DMAP (<NUM>, <NUM> mmol). The obtained reaction solution was stirred at room temperature for <NUM> minutes. After completion of the reaction, the mixture was adjusted to about pH of <NUM> with <NUM> hydrochloric acid, and extracted with dichloromethane (<NUM>×<NUM>). The organic phases were combined, and washed with saturated brine (<NUM>), dried over sodium sulfate, filtered and evaporated, and the residue was purified by flash silica gel column chromatography to obtain embodiment 1I as a yellow solid. LCMS (ESI) m/z: <NUM> [M+<NUM>]+.

To a solution of the embodiment 1I (<NUM>, <NUM> mmol) in dichloromethane (<NUM>) was added Dess-Martin reagent (<NUM>. mg, <NUM> mmol) in portions at room temperature. The reaction solution was stirred at room temperature for <NUM> hours. After completion of the reaction, the reaction solution was cooled in an ice-water bath and white solid was precipitated out. The reaction solution was filtered, and the filtrate was evaporated to dryness to obtain embodiment 1J as a yellow solid. LCMS (ESI) m/z: <NUM> [M+<NUM>]+.

To a solution of embodiment 1J (<NUM>, <NUM>µmol) and tetrahydro-<NUM>-hydropyran-<NUM>-amine (<NUM>, <NUM>µmol) in <NUM>,<NUM>-dichloroethane (<NUM>) was added acetic acid (about <NUM>) at room temperature till the pH value of the solution is about <NUM>. The reaction solution was stirred for <NUM> hours. Sodium cyanoborohydride (<NUM>, <NUM>µmol) was added to the reaction solution at room temperature, and the reaction solution was continued to stir for <NUM> hour. Water (<NUM>) was added to a reaction solution, followed by addition of dichloromethane (<NUM>×<NUM>) for extraction. The organic phases were combined, washed with saturated brine (<NUM>), dried over sodium sulfate, filtered and evaporated, and the residue was purified by flash silica gel column chromatography to obtain embodiment <NUM>. The solid sample was subjected to chiral column resolution to obtain embodiment <NUM>-R configuration (<NUM>) and embodiment <NUM>-S configuration (<NUM>).

Chiral column method: Chiral column, Chiralcel OJ-H <NUM>×<NUM> I. , <NUM>; mobile phase, methanol (<NUM>% DEA (diethylamine))-CO<NUM> from <NUM>% to <NUM>%; flow rate, <NUM>/min; wavelength, <NUM>.

To a solution of embodiment <NUM>-S configuration (<NUM>, <NUM>µmol) (<NUM> product of <NUM>-S configuration was obtained by an amplified reaction of <NUM> scale according to the preparation method of embodiment <NUM>) in methanol (<NUM>) was added a freshly prepared solution of acetyl chloride (<NUM>) in methanol (<NUM>) under nitrogen atmosphere at room temperature. The reaction solution was stirred at <NUM> for <NUM> hours. The solution was removed under vacuum to obtain the embodiment <NUM>. LCMS (ESI) m/z: <NUM> [M+<NUM>]+. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) ppm <NUM> (s, <NUM>), <NUM> (br. , <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (q, J=<NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J=<NUM>, <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (t, J=<NUM>, <NUM>).

As the method described in the embodiment <NUM>, a freshly prepared solution of acetyl chloride (<NUM>) in methanol (<NUM>) was added to a solution of the embodiment <NUM>-R configuration (<NUM>, <NUM>µmol) (<NUM> product of <NUM>-R configuration was obtained by an amplified reaction of <NUM> scale) in methanol (<NUM>) under nitrogen atmosphere at room temperature. The reaction solution was stirred at <NUM> for <NUM> hours. The solution was removed under vacuum to obtain reference embodiment <NUM>. LCMS (ESI) m/z: <NUM>[M+<NUM>]+. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) ppm <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (br. , <NUM>), <NUM> (br. , <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (br. , <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (m, <NUM>).

The reference embodiment <NUM> was dissolved in methanol, dissociated with a saturated aqueous solution of sodium bicarbonate, and extracted with dichloromethane. The organic phase was subjected to rotary evaporation to dryness to obtain a compound of formula (I).

The reference embodiment <NUM> was dissolved in methanol, dissociated with a saturated aqueous solution of sodium bicarbonate, and extracted with dichloromethane. The organic phase was subjected to rotary evaporation to dryness, followed by slurrying with a small amount of methanol for purification, and was filtered to obtain a solid. XRPD was used to detect the state of the crystal form, and the crystal form A of the compound of formula (I) was obtained.

<NUM> of the compound of formula (I) was weighed and added into a glass bottle, followed by addition of <NUM>µL of methanol to obtain a suspension. The suspension sample was placed on a magnetic stirrer (<NUM>) and subjected to a stirring test under darkness. The suspension sample was stirred at <NUM> for <NUM> days and then centrifuged, and then the residual sample was placed in a vacuum oven (<NUM>) and dried overnight. XRPD was used to detect the state of the crystal form, and the crystal form B of the compound of formula (I) was obtained.

<NUM> of the compound of formula (I) was weighed and added into a glass bottle, followed by addition of <NUM>µL of ethyl acetate-ethanol (<NUM>:<NUM>) to obtain a suspension. The suspension sample was placed on a magnetic stirrer (<NUM>) and subjected to a stirring test under darkness. The suspension sample was stirred at <NUM> for <NUM> days and then centrifuged, and then the residual sample was placed in a vacuum oven (<NUM>) and dried overnight. XRPD was used to detect the state of the crystal form, and the crystal form C of the compound of formula (I) was obtained.

<NUM> of the compound of formula (I) was weighed and added into a glass bottle, followed by addition of <NUM>µL of acetone to obtain a suspension. The suspension sample was placed on a magnetic stirrer (<NUM>) and subjected to a stirring test under darkness. The suspension sample was stirred at <NUM> for <NUM> days and then centrifuged, and then the residual sample was placed in a vacuum oven (<NUM>) and dried overnight. XRPD was used to detect the state of the crystal form, and the crystal form D of the compound of formula (I) was obtained.

<NUM> of the compound of formula (I) was weighed and added into a glass bottle, followed by addition of <NUM>µL of isopropanol to obtain a suspension. The suspension sample was placed on a magnetic stirrer (<NUM>) and subjected to a stirring test under darkness. The suspension sample was stirred at <NUM> for <NUM> days and then centrifuged, and then the residual sample was placed in a vacuum oven (<NUM>) and dried overnight. XRPD was used to detect the state of the crystal form, and the crystal form E of the compound of formula (I) was obtained.

<NUM> of the compound of formula (I) was weighed and added into a glass bottle with a magnetic stir bar. The glass bottle was placed on a magnetic stirrer. <NUM> of ethyl acetate was added and the obtained mixture was heated to <NUM> to obtain a clear solution. An appropriate amount of a solution of hydrochloric acid in ethanol (<NUM>) was slowly added (with the molar ratio of the compound of formula (I) to acid of <NUM>:<NUM>), and observed. After the addition of hydrochloric acid, the solution was stirred at <NUM> for <NUM> hours, and stirred at room temperature overnight. Precipitation was formed, and the solution was centrifuged. Then, the residual sample was placed in a vacuum oven (<NUM>) and dried. XRPD was used to detect the state of the crystal form, and the crystal form F of the compound of formula (II) was obtained.

<NUM> of hydrochloride of the compound of formula (I) (Reference embodiment <NUM>) was weighed and placed in a glass bottle, and <NUM>µL of methanol was added. The dissolved sample was quickly centrifuged. The supernatant was placed in a centrifuge tube, and the centrifuge tube was sealed with an aluminum foil poked with pinholes. The centrifuge tube was placed in a fume hood for volatilization. The suspension sample was placed on a magnetic stirrer, stirred (<NUM>) (in dark), and quickly centrifuged after <NUM> days. The supernatant was placed in a fume hood to volatilize to dryness. The residual sample obtained by centrifugation and the solid obtained by volatilization were collected and dried in a vacuum oven at <NUM> overnight. XRPD was used to detect the state of the crystal form, and the crystal form G of the compound of formula (II) was obtained.

Ethanol (<NUM>) was added to the three-necked flask (<NUM>) containing the compound of formula (I) (<NUM>); the reaction solution was heated to <NUM>, and hydrochloric acid/ethyl acetate (<NUM>) was added dropwise to the flask. After stirring at <NUM> for <NUM> hours, the reaction solution was cooled to room temperature and stirred for <NUM> hours; the reaction solution was filtered, and the obtained solid was washed with <NUM> of ethanol; the finally obtained solid was treated by a rotary evaporator (<NUM>, <NUM> hours) to remove a small amount of ethanol contained therein to obtain the crystal form G of the compound of formula (II).

<NUM> of the hydrochloride of the compound of formula (I) (reference embodiment <NUM>) was weighed and placed in a glass bottle, and <NUM>µL of ethanol was added. The dissolved sample was quickly centrifuged, and the supernatant was placed in a centrifuge tube. The centrifuge tube was sealed with an aluminum foil poked with pinholes. The centrifuge tube was placed in a fume hood for volatilization. The suspension sample was placed on a magnetic stirrer, stirred (<NUM>) (in dark), and quickly centrifuged after <NUM> days. The supernatant was placed in a fume hood to volatilize to dryness. The residual sample obtained by centrifugation and the solid obtained by volatilization were collected and dried in a vacuum oven at <NUM> overnight. XRPD was used to detect the state of the crystal form, and the crystal form H of the compound of formula (II) was obtained.

<NUM> of the compound of formula (I) was weighed and added into a glass bottle with a magnetic stir bar. The glass bottle was placed on a magnetic stirrer. <NUM> of ethyl acetate was added and the obtained mixture was heated to <NUM> to obtain a clear solution. An appropriate amount of a solution of citric acid in ethanol (<NUM>) was slowly added (with the molar ratio of the compound of formula (I) to acid of <NUM>:<NUM>), and observed. After the addition of hydrochloric acid, the solution was stirred at <NUM> for <NUM> hours, and stirred at room temperature overnight. Precipitation was formed, and the solution was centrifuged. Then, the residual sample was placed in a vacuum oven (<NUM>) and dried. XRPD was used to detect the state of the crystal form, and the crystal form I of the compound of formula (III) was obtained.

<NUM> of the compound of formula (I) was weighed and added into a glass bottle with a magnetic stir bar. The glass bottle was placed on a magnetic stirrer. <NUM> of ethyl acetate was added and the obtained mixture was heated to <NUM> to obtain a clear solution. An appropriate amount of a solution of L-malic acid in ethanol (<NUM>) was slowly added (with the molar ratio of the compound of formula (I) to acid of <NUM>:<NUM>), and observed. After the addition of hydrochloric acid, the solution was stirred at <NUM> for <NUM> hours, and stirred at room temperature overnight. Precipitation was formed, and the solution was centrifuged. Then, the residual sample was placed in a vacuum oven (<NUM>) and dried. XRPD was used to detect the state of the crystal form, and the crystal form J of the compound of formula (IV) was obtained.

About <NUM> of the compound of formula (I) was weighed accurately, and placed in a sample bottle. <NUM> of acetonitrile was added. The mixture was sonicated for <NUM> minutes, cooled to room temperature, and well mixed. Two control sample solutions were prepared in parallel, and labeled as STD-<NUM> and STD-<NUM>, respectively.

The control sample solution STD-<NUM> was serially diluted <NUM>, <NUM>, <NUM>, <NUM> and <NUM> times and labeled as linear solutions L1, L2, L3, L4 and L5.

The solubility of the compound of formula (I) and its salt in <NUM> vehicles with different pH were tested. About <NUM> of the compounds of formula (I) -(IV) were weighed respectively, then <NUM> of different vehicles (water, SGF, FaSSIF, FeSSIF) were added thereto, respectively, and well mixed to obtain suspensions. Magnetic stir bars were added into the suspensions, and the suspensions were placed on a magnetic stirrer for stirring. After stirring for <NUM> hours, <NUM> hours, and <NUM> hours, the samples were collected and centrifuged. The residual solid samples in the lower layer were detected by XRPD. The concentrations of the samples in the upper layer were determined by HPLC, and the pH value of the samples were also detected. The results of the solubility test are as shown in Table <NUM> and Table <NUM>.

Conclusion: the solubility data of the salts in biological vehicle show that the hydrochloride has the highest solubility in the aqueous phase, and the three salts have similar solubility in simulated intestinal fluid and simulated gastric fluid; and the free base has good solubility in the three biological vehicle, but is extremely difficult to dissolve in water.

About <NUM> of crystal form G, crystal form I, or crystal form J were weighed accurately, and placed on the bottom of a <NUM> glass sample bottle and spread into a thin layer. For an open sample, the bottle mouth thereof was sealed with aluminum foil poked with pinholes to ensure that the sample can fully contact with the ambient air. For a sealed sample, the bottle mouth thereof was sealed with a bottle cap, and wrapped with a sealing film. Two duplicate samples were weighed at each time point of each condition in parallel, and an appropriate amount of sample (not weighed) was taken additionally for XRPD detection. The prepared samples were placed under each condition and were sampled and analyzed when the time point was arrived. On <NUM>th day, <NUM> control samples were weighed in parallel and stored in a refrigerator at -<NUM> until analysis. The samples subjected to light irradiation were prepared by the same method, and placed on the bottom of a <NUM> glass sample bottle. The glass bottle was left open and placed in the upright position in a light irradiation box. In addition, two samples in an appropriate amount were taken as samples in dark, and the glass bottles containing the same were left open, put in the upright position, and wrapped with tin foil, and irradiated with a total luminance of <NUM>×<NUM><NUM> Lux. hr and a near ultraviolet power of <NUM> w. After irradiation, the samples was stored in the refrigerator at -<NUM> for analysis.

The compounds were placed under the following conditions and sampled at different time points to detect the physical properties, and the content and total impurities were analyzed by HPLC. The research conditions and testing items are shown in Table <NUM> to Table <NUM>.

Conclusion: both the influencing factors and accelerated tests show that the crystal form G, I and J have excellent thermal stability and stability under accelerated conditions, generate slight impurities under light irradiation conditions, and exhibit good stability under dark conditions.

<NUM> to <NUM> of the crystal form I of the compound of formula (III) was taken and placed in a DVS sample tray for testing.

The DVS pattern of the crystal form I of the compound of formula (III) is as shown in <FIG>, △W=<NUM>%.

The crystal form I of the compound of formula (III) has a hygroscopic weight gain of <NUM>% at <NUM> ± <NUM> and <NUM> ± <NUM>% RH, which is hygroscopic.

<NUM> to <NUM> of the crystal form J of the compound of formula (IV) was taken and placed in a DVS sample tray for testing.

The DVS pattern of the crystal form J of the compound of formula (IV) is as shown in <FIG>, △W=<NUM>%.

The crystal form J of the compound of formula (IV) has a hygroscopic weight gain of <NUM>% at <NUM> ± <NUM> and <NUM> ± <NUM>% RH, which is hygroscopic.

The enzyme activity was detected by Z'-LYTE™ Detection Kinase Assay, and the IC<NUM> value of the compound was used as an indicator to evaluate the inhibitory effect of the compound against FGFR1.

<NUM> FGFR1, <NUM> Tyr<NUM> peptide and <NUM> ATP in reaction buffer solution (<NUM> Hepes, pH7. <NUM>, <NUM> MgCl<NUM>, <NUM>% BRIJ-<NUM>, <NUM> EGTA, <NUM> MnCl<NUM>, <NUM> DTT).

The experimental results are shown in Table <NUM>:.

Conclusion: The compound of the present disclosure has a significant inhibitory effect against FGFR1.

The evolutionary growth potential of tumors was evaluated by the relationship between tumor volume and time. The long axis (L) and short axis (W) of the subcutaneous tumor were measured twice a week by the caliper and the tumor volume (TV) was calculated by the formula ((L×W<NUM>)/<NUM>). TGI was calculated from the difference between the median tumor volume in the solvent group mice and the median tumor volume in the drug group mice, expressed as a percentage counting for the median tumor volume in the solvent control group, calculated by the following formula: <MAT>.

The original statistical analysis was done by repeating the analysis of variance, followed by post-hoc Scheffe's test method for multiple comparisons, with solvent alone (<NUM>% methylcellulose + <NUM>% Tween in water) as negative control.

Claim 1:
A crystal form G of the compound of formula (II), wherein the X-ray powder diffraction pattern of the crystal form G of the compound of formula (II) comprises characteristic diffraction peaks at the following angle 2θ: <NUM>±<NUM>°, <NUM>±<NUM>°, and <NUM>±<NUM>°; wherein said X-ray powder diffraction pattern is obtained using copper K-alpha X-rays at a wavelength of <NUM> Angstroms
<CHM>