Crystal form of biological inhibitor containing acrylketone as well as preparation method and application of crystal form

Abstract

The invention relates to a crystal form containing an acrylketone biological inhibitor and a preparation method and application thereof. In particular, the present invention relates to a crystal form of a compound represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing a therapeutically effective amount of the salt and / or the crystal form, and a use thereof as an inhibitor in the treatment of cancer.

Description

A crystal form containing acrylone biological inhibitor and its preparation method and application

[0001] This application claims priority to Chinese Patent Application No. 2023109411412, filed July 27, 2023. This application incorporates the entirety of the aforementioned Chinese Patent Application. Technical Field

[0002] The present invention belongs to the field of biomedicine, and in particular relates to a crystal form containing acrylone bioinhibitors, a preparation method and an application thereof. Background Art

[0003] FGFR (Fibroblast Growth Factor Receptor) is a tyrosine kinase, comprising four isoforms: FGFR1, FGFR2, FGFR3, and FGFR4. Upon ligand binding, FGFR dimerizes and autophosphorylates, activating downstream signaling pathways including RAS-RAF-MAPK, PI3K-AKT, STAT, and PLCγ. FGFR-mediated signaling plays a crucial role in cell proliferation, migration, differentiation, and survival.

[0004] Overactivation caused by various mutations of FGFR is widely present in many tumors, and inhibition of FGFR is a potential target for the treatment of various cancers. A study published in Clinical Cancer Research in 2015 (Clin Cancer Res; 22(1) January 1, 2016) showed that approximately 7.1% of cancers have FGFR aberrations. FGFR1 amplification aberrations are present in approximately 20% of lung squamous cell carcinomas and approximately 20% of breast cancers. FGFR2 rearrangement aberrations are present in approximately 15% of bile duct carcinomas, FGFR2 point mutations are present in approximately 10% of endometrial cancers, and FGFR2b amplification is present in approximately 10% of gastric cancers. FGFR3 point mutations are present in approximately 20% of metastatic urothelial carcinomas.

[0005] FGFR inhibitors hold great promise as a promising drug in the pharmaceutical industry, potentially becoming a first-line treatment for cholangiocarcinoma and a new option for targeted cancer therapy across a wide range of cancer types. They are also expected to be effective for patients with a variety of FGFR aberrations. However, the current standard treatment for cholangiocarcinoma is chemotherapy, which carries a poor prognosis and lacks a second-line treatment option. The main challenges with FGFR inhibitors include the development of drug resistance in patients approximately seven months after treatment, and the toxicity of drugs targeting the FGFR1 target, which can cause hyperphosphatemia.

[0006] Currently, two pan-FGFR inhibitors are available globally. In April 2019, Johnson & Johnson's Balversa (erdafitinib, JNJ-42756493) was approved for patients with locally metastatic or metastatic bladder cancer harboring FGFR3 or FGFR2 point mutations. In April 2020, Incyte's Pemazyre (pemigatinib, INCB054828) was approved for patients with previously treated advanced cholangiocarcinoma harboring FGFR2 gene fusions or rearrangements.

[0007] Patent PCT / CN2023 / 073557 discloses a series of propylene ketone-containing bioinhibitors. In subsequent research and development, the present inventors conducted a comprehensive study of the crystalline forms of the aforementioned compounds to facilitate product handling, filtration, and drying, and to seek suitable crystals that are easy to store, have long-term product stability, and have high bioavailability.

[0008] Summary of the Invention

[0009] All contents involved in patent PCT / CN2023 / 073557 are added to the present invention by reference.

[0010] The object of the present invention is to provide a crystalline form of a compound represented by general formula (I) or a stereoisomer thereof.

[0011] in:

[0012] R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, aldehyde, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1- 6-deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Alkylcarbonyl, aminocarbonyl, 3-12 membered cycloalkyl-carbonyl, 3-12 membered heterocyclyl-carbonyl, preferably, R1 is selected from deuterium, halogen, amino, hydroxyl, cyano, aldehyde, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Alkylcarbonyl, aminocarbonyl, 3-6 membered cycloalkyl-carbonyl, 3-6 membered heterocyclyl-carbonyl;

[0013] R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl or C 1-6 Alkylamino;

[0014] R3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, C 1-6 Alkylamino or C 3-12 Cycloalkyl;

[0015] R4 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkoxy or C 3-12 Cycloalkyl; preferably selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkoxy or C 3-6 Cycloalkyl;

[0016] R5 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkoxy or C 3-12 Cycloalkyl; preferably selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkoxy or C 3-6 Cycloalkyl;

[0017] R6 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy.

[0018] In certain embodiments of the present invention, the compound is as follows:

[0019] (S)-1-(3-(7-acetyl-4-amino-3-(pyrazolo[1,5-a]pyridin-6-ylideneynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one;

[0020] (S)-1-(3-(4-amino-7-propionyl-3-(pyrazolo[1,5-a]pyridin-6-ylideneynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one;

[0021] (S)-1-(3-(4-amino-7-(cyclopropanecarbonyl)-3-(pyrazolo[1,5-a]pyridin-6-ylideneynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one;

[0022] (S)-1-(3-(7-acetyl-4-amino-3-((3-cyclopropylpyrazolo[1,5-a]pyridin-6-yl)alkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-alkyl)prop-2-en-1-one;

[0023] (S)-1-(3-(7-acetyl-4-amino-3-((2-cyclopropylpyrazolo[1,5-a]pyridin-6-yl)alkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-alkyl)prop-2-en-1-one;

[0024] (S)-1-(3-(4-amino-3-((3-chloropyrazolo[1,5-a]pyridin-6-yl)alkynyl)-7-isobutyl-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-alkyl)prop-2-en-1-one.

[0025] In certain embodiments of the present invention, the crystalline form is a hydrate or an anhydrate; when it is a hydrate, the number of water atoms is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 2.

[0026] In certain embodiments of the present invention, the crystalline form of the compound or its stereoisomer is (S)-1-(3-(7-acetyl-4-amino-3-(pyrazolo[1,5-a]pyridin-6-ylidenealkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one.

[0027] In certain embodiments of the present invention, the crystalline form of (S)-1-(3-(7-acetyl-4-amino-3-(pyrazolo[1,5-a]pyridin-6-ylidenealkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one is Form I;

[0028] The X-ray powder diffraction pattern of Form I has a diffraction peak at 2θ of 9.0±0.2°; or a diffraction peak at 9.6±0.2°; or a diffraction peak at 11.7±0.2°; or a diffraction peak at 13.4±0.2°; or a diffraction peak at 14.9±0.2°; or a diffraction peak at 20.6±0.2°; or a diffraction peak at 21.9±0.2°. ; or has a diffraction peak at 24.2±0.2°; or has a diffraction peak at 24.9±0.2°; or has a diffraction peak at 26.9±0.2°; preferably includes any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9 or 10 thereof;

[0029] Preferably, the X-ray powder diffraction pattern of Form I comprises at least one or more diffraction peaks located at 2θ of 13.4±0.2°, 14.9±0.2°, and 24.9±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 2θ of 9.0±0.2°, 9.6±0.2°, 11.7±0.2°, 21.9±0.2°, and 24.2±0.2°, preferably two, three, four, or five of them;

[0030] More preferably, the X-ray powder diffraction pattern of Form I optionally further comprises one or more diffraction peaks located at 2θ of 12.7±0.2°, 17.6±0.2°, 20.6±0.2°, 24.0±0.2°, and 26.9±0.2°; preferably, at least any 2-3, or 4-5 of them; further preferably, any 2, 3, 4, or 5 of them are included;

[0031] Further preferably, the X-ray powder diffraction pattern of Form I comprises one or more diffraction peaks located at 2θ of 8.2±0.2°, 9.9±0.2°, 13.6±0.2°, 15.5±0.2°, 16.7±0.2°, 18.0±0.2°, 19.3±0.2°, and 19.9±0.2°; preferably, the diffraction peaks are selected from 4, 5, 6, or 8 of them;

[0032] For example, the X-ray powder diffraction pattern of the crystalline form I has diffraction peaks at the following positions at 2θ:

[0033] 14.9±0.2°, 24.9±0.2°;

[0034] 13.4±0.2°, 24.9±0.2°;

[0035] 13.4±0.2°、14.9±0.2°；

[0036] 13.4±0.2°、14.9±0.2°、24.9±0.2°；

[0037] 9.0±0.2°、14.9±0.2°、24.9±0.2°；

[0038] 9.6±0.2°、13.4±0.2°、24.9±0.2°；

[0039] 11.7±0.2°、13.4±0.2°、14.9±0.2°；

[0040] 14.9±0.2°、21.9±0.2°、24.9±0.2°；

[0041] 13.4±0.2°、24.2±0.2°、24.9±0.2°；

[0042] 9.0±0.2°、13.4±0.2°、14.9±0.2°、24.9±0.2°；

[0043] 9.0±0.2°、9.6±0.2°、14.9±0.2°、24.9±0.2°；

[0044] 9.0±0.2°、9.6±0.2°、13.4±0.2°、24.9±0.2°；

[0045] 11.7±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°；

[0046] 11.7±0.2°、14.9±0.2°、21.9±0.2°、24.9±0.2°；

[0047] 9.0±0.2°、13.4±0.2°、21.9±0.2°、24.9±0.2°；

[0048] 9.6±0.2°、13.4±0.2°、14.9±0.2°、24.2±0.2°；

[0049] 9.0±0.2°、9.6±0.2°、11.7±0.2°、14.9±0.2°、24.9±0.2°；

[0050] 9.0±0.2°、11.7±0.2°、13.4±0.2°、21.9±0.2°、24.9±0.2°；

[0051] 9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、24.2±0.2°；

[0052] 11.7±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.9±0.2°；

[0053] 11.7±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°；

[0054] 9.6±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°；

[0055] 9.6±0.2°、11.7±0.2°、14.9±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°；

[0056] 9.6±0.2°、11.7±0.2°、13.4±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°；

[0057] 9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、24.2±0.2°、24.9±0.2°；

[0058] 9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.9±0.2°；

[0059] 9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.2±0.2°；

[0060] 9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°；

[0061] 9.0±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°；

[0062] 9.0±0.2°、9.6±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°；

[0063] 9.0±0.2°、9.6±0.2°、11.7±0.2°、14.9±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°；

[0064] 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°；

[0065] 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、24.2±0.2°、24.9±0.2°；

[0066] 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.9±0.2°；

[0067] 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.2±0.2°；

[0068] 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°；

[0069] 9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°；

[0070] 9.0±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°；

[0071] 9.0±0.2°、9.6±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°；

[0072] 9.0±0.2°、9.6±0.2°、11.7±0.2°、14.9±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°；

[0073] 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°；

[0074] 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°；

[0075] 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.9±0.2°、26.9±0.2°；

[0076] 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.2±0.2°、26.9±0.2°；

[0077] 9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、20.6±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°；

[0078] 9.0±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、20.6±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°；

[0079] 9.0±0.2°、9.6±0.2°、13.4±0.2°、14.9±0.2°、20.6±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°；

[0080] 9.0±0.2°、9.6±0.2°、11.7±0.2°、14.9±0.2°、20.6±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°；

[0081] 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、20.6±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°；

[0082] 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°；

[0083] 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、20.6±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°；

[0084] 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、20.6±0.2°、21.9±0.2°、24.9±0.2°、26.9±0.2°；

[0085] 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、20.6±0.2°、21.9±0.2°、24.2±0.2°、26.9±0.2°；

[0086] 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、20.6±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°；

[0087] 9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、17.6±0.2°、20.6±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°；

[0088] 9.0±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、17.6±0.2°、20.6±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°；

[0089] 9.0±0.2°、9.6±0.2°、13.4±0.2°、14.9±0.2°、17.6±0.2°、20.6±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°；

[0090] 9.0±0.2°、9.6±0.2°、11.7±0.2°、14.9±0.2°、17.6±0.2°、20.6±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°；

[0091] 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、17.6±0.2°、20.6±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°；

[0092] 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、20.6±0.2°、21.9±0.2°、24.2±0.2°、 24.9±0.2°、26.9±0.2°；

[0093] 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、17.6±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°；

[0094] 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、17.6±0.2°、20.6±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°；

[0095] 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、17.6±0.2°、20.6±0.2°、21.9±0.2°、24.9±0.2°、26.9±0.2°；

[0096] 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、17.6±0.2°、20.6±0.2°、21.9±0.2°、24.2±0.2°、26.9±0.2°；

[0097] 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、17.6±0.2°、20.6±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°；

[0098] 9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、17.6±0.2°、20.6±0.2°、21.9±0.2°、24.0±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°；

[0099] 9.0±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、17.6±0.2°、20.6±0.2°、21.9±0.2°、24.0±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°；

[0100] 9.0±0.2°、9.6±0.2°、13.4±0.2°、14.9±0.2°、17.6±0.2°、20.6±0.2°、21.9±0.2°、24.0±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°；

[0101] 9.0±0.2°、9.6±0.2°、11.7±0.2°、14.9±0.2°、17.6±0.2°、20.6±0.2°、21.9±0.2°、24.0±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°；

[0102] 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、17.6±0.2°、20.6±0.2°、21.9±0.2°、24.0±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°；

[0103] 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、20.6±0.2°、21.9±0.2°、24.0±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°；

[0104] 9.0±0.2°, 9.6±0.2°, 11.7±0.2°, 13.4±0.2°, 14.9±0.2°, 17.6±0.2°, 21.9±0.2°, 24.0±0.2°, 24.2±0.2°, 24.9±0.2°, 26.9±0.2°;

[0105] 9.0±0.2°, 9.6±0.2°, 11.7±0.2°, 13.4±0.2°, 14.9±0.2°, 17.6±0.2°, 20.6±0.2°, 24.0±0.2°, 24.2±0.2°, 24.9±0.2°, 26.9±0.2°;

[0106] 9.0±0.2°, 9.6±0.2°, 11.7±0.2°, 13.4±0.2°, 14.9±0.2°, 17.6±0.2°, 20.6±0.2°, 21.9±0.2°, 24.2±0.2°, 24.9±0.2°, 26.9±0.2°;

[0107] 9.0±0.2°, 9.6±0.2°, 11.7±0.2°, 13.4±0.2°, 14.9±0.2°, 17.6±0.2°, 20.6±0.2°, 21.9±0.2°, 24.0±0.2°, 24.9±0.2°, 26.9±0.2°;

[0108] 9.0±0.2°, 9.6±0.2°, 11.7±0.2°, 13.4±0.2°, 14.9±0.2°, 17.6±0.2°, 20.6±0.2°, 21.9±0.2°, 24.0±0.2°, 24.2±0.2°, 26.9±0.2°;

[0109] 9.0±0.2°, 9.6±0.2°, 11.7±0.2°, 13.4±0.2°, 14.9±0.2°, 17.6±0.2°, 20.6±0.2°, 21.9±0.2°, 24.0±0.2°, 24.2±0.2°, 24.9±0.2°.

[0110] In certain embodiments of the present invention, Cu-Kα radiation is used, and the characteristic X-ray diffraction peaks expressed in terms of 2θ angles and interplanar spacing d values ​​are shown in Table 1.

[0111] Table 1

[0112] In certain embodiments of the present invention, the X-ray powder diffraction pattern of Form I is substantially as shown in FIG1 , the DSC pattern is shown in FIG2 , the TGA pattern is shown in FIG3 , and the IR pattern is shown in FIG4 .

[0113] In certain embodiments of the present invention, the crystalline form of (S)-1-(3-(7-acetyl-4-amino-3-(pyrazolo[1,5-a]pyridin-6-ylidenealkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one is Form II;

[0114] The X-ray powder diffraction pattern of Form II has a diffraction peak at 2θ of 5.3±0.2°; or a diffraction peak at 8.3±0.2°; or a diffraction peak at 10.6±0.2°; or a diffraction peak at 14.0±0.2°; or a diffraction peak at 16.0±0.2°; or a diffraction peak at 16.6±0.2°; or a diffraction peak at 19.2±0.2°. ; or has a diffraction peak at 24.7±0.2°; or has a diffraction peak at 26.2±0.2°; or has a diffraction peak at 26.5±0.2°; preferably includes any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9 or 10 thereof;

[0115] Preferably, the X-ray powder diffraction pattern of Form II comprises at least one or more diffraction peaks located at 2θ of 5.3±0.2°, 10.6±0.2°, and 24.7±0.2°, preferably 2 of them, and more preferably 3 of them; optionally, it may further comprise at least one of 2θ of 8.3±0.2°, 16.0±0.2°, 16.6±0.2°, 26.2±0.2°, and 26.5±0.2°, preferably 2, 3, 4, or 5 of them;

[0116] More preferably, the X-ray powder diffraction pattern of Form II optionally further comprises one or more diffraction peaks located at 2θ of 14.0±0.2°, 14.5±0.2°, 19.2±0.2°, 21.6±0.2°, and 25.6±0.2°; preferably, at least any 2-3, or 4-5 of them; further preferably, any 2, 3, 4, or 5 of them are included;

[0117] Further preferably, the X-ray powder diffraction pattern of Form II comprises one or more diffraction peaks located at 2θ of 5.3±0.2°, 8.3±0.2°, 10.6±0.2°, 14.0±0.2°, 16.0±0.2°, 16.6±0.2°, 19.2±0.2°, 24.7±0.2°, 26.2±0.2°, and 26.5±0.2°; preferably, there are diffraction peaks at any of 4, 5, 6, 8 or 10 positions;

[0118] For example, the X-ray powder diffraction pattern of the crystalline form II has diffraction peaks at the following positions at 2θ:

[0119] 5.3±0.2°, 10.6±0.2°;

[0120] 5.3±0.2°, 24.7±0.2°;

[0121] 5.3±0.2°, 10.6±0.2°, 24.7±0.2°;

[0122] 5.3±0.2°, 8.3±0.2°, 10.6±0.2°;

[0123] 5.3±0.2°, 16.0±0.2°, 24.7±0.2°;

[0124] 5.3±0.2°, 10.6±0.2°, 24.7±0.2°, 26.2±0.2°;

[0125] 5.3±0.2°, 10.6±0.2°, 24.7±0.2°, 26.5±0.2°;

[0126] 5.3±0.2°, 10.6±0.2°, 24.7±0.2°, 16.0±0.2°;

[0127] 5.3±0.2°, 8.3±0.2°, 10.6±0.2°, 16.6±0.2°, 24.7±0.2°;

[0128] 5.3±0.2°, 10.6±0.2°, 16.0±0.2°, 21.6±0.2°, 24.7±0.2°;

[0129] 5.3±0.2°, 10.6±0.2°, 14.5±0.2°, 24.7±0.2°, 26.2±0.2°;

[0130] 5.3±0.2°, 8.3±0.2°, 10.6±0.2°, 16.0±0.2°, 24.7±0.2°, 26.2±0.2°;

[0131] 5.3±0.2°, 8.3±0.2°, 10.6±0.2°, 16.0±0.2°, 16.6±0.2°, 26.5±0.2°;

[0132] 5.3±0.2°, 10.6±0.2°, 16.0±0.2°, 24.7±0.2°, 26.2±0.2°, 26.5±0.2°;

[0133] 5.3±0.2°, 8.3±0.2°, 10.6±0.2°, 16.0±0.2°, 16.6±0.2°, 24.7±0.2°, 26.2±0.2°, 26.5±0.2°;

[0134] 5.3±0.2°, 8.3±0.2°, 10.6±0.2°, 14.0±0.2°, 16.0±0.2°, 16.6±0.2°, 25.6±0.2°, 26.5±0.2°;

[0135] 5.3±0.2°, 10.6±0.2°, 14.5±0.2°, 16.0±0.2°, 21.6±0.2°, 24.7±0.2°, 26.2±0.2°, 26.5±0.2°;

[0136] 5.3±0.2°, 8.3±0.2°, 10.6±0.2°, 14.0±0.2°, 16.0±0.2°, 16.6±0.2°, 19.2±0.2°, 24.7±0.2°, 26.2±0.2°, 26.5±0.2°;

[0137] 5.3±0.2°, 8.3±0.2°, 10.6±0.2°, 14.0±0.2°, 16.0±0.2°, 16.6±0.2°, 19.2±0.2°, 21.6±0.2°, 24.7±0.2°, 26.5±0.2°;

[0138] 5.3±0.2°, 8.3±0.2°, 10.6±0.2°, 14.0±0.2°, 14.5±0.2°, 16.0±0.2°, 16.6±0.2°, 24.7±0.2°, 26.2±0.2°, 26.5±0.2°.

[0139] In certain embodiments of the present invention, Cu-Kα radiation is used, and the characteristic X-ray diffraction peaks expressed in terms of 2θ angles and interplanar spacing d values ​​are shown in Table 2.

[0140] Table 2

[0141] In certain embodiments of the present invention, the X-ray powder diffraction pattern of Form II is substantially as shown in FIG5 , the DSC pattern is shown in FIG6 , and the TGA pattern is shown in FIG7 .

[0142] In certain embodiments of the present invention, the crystalline form of (S)-1-(3-(7-acetyl-4-amino-3-(pyrazolo[1,5-a]pyridin-6-ylidenealkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one is Form III;

[0143] The X-ray powder diffraction pattern of Form III has a diffraction peak at 2θ of 5.9±0.2°; or a diffraction peak at 8.7±0.2°; or a diffraction peak at 11.5±0.2°; or a diffraction peak at 11.9±0.2°; or a diffraction peak at 13.4±0.2°; or a diffraction peak at 14.1±0.2°; or a diffraction peak at 14.6±0.2°. Peak; or a diffraction peak at 20.0±0.2°; or a diffraction peak at 24.4±0.2°; or a diffraction peak at 24.9±0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 8-10 of the above diffraction peaks; more preferably comprising any 6, 7, 8, 9 or 10 thereof;

[0144] Preferably, the X-ray powder diffraction pattern of Form III comprises at least one or more diffraction peaks located at 2θ of 5.9±0.2°, 11.5±0.2°, and 11.9±0.2°, preferably 2 of them, and more preferably 3 of them; optionally, it may further comprise at least one of 2θ of 8.7±0.2°, 13.4±0.2°, 14.6±0.2°, 20.0±0.2°, and 24.4±0.2°, preferably 2, 3, 4 or 5 of them;

[0145] More preferably, the X-ray powder diffraction pattern of Form III optionally further comprises one or more diffraction peaks located at 2θ of 8.0±0.2°, 9.7±0.2°, 14.1±0.2°, 24.9±0.2°, and 26.3±0.2°; preferably, at least any 2-3, or 4-5 of them; further preferably, any 2, 3, 4, or 5 of them are included;

[0146] Further preferably, the X-ray powder diffraction pattern of Form III comprises one or more diffraction peaks located at 2θ of 5.9±0.2°, 8.7±0.2°, 11.5±0.2°, 11.9±0.2°, 13.4±0.2°, 14.1±0.2°, 14.6±0.2°, 20.0±0.2°, 24.4±0.2°, and 24.9±0.2°; preferably, there are diffraction peaks at any of 4, 5, 6, 8 or 10 positions;

[0147] For example, the X-ray powder diffraction pattern of the crystalline form III has diffraction peaks at the following positions at 2θ:

[0148] 5.9±0.2°, 11.5±0.2°;

[0149] 5.9±0.2°, 11.9±0.2°;

[0150] 5.9±0.2°, 11.5±0.2°, 11.9±0.2°;

[0151] 5.9±0.2°, 8.7±0.2°, 11.5±0.2°;

[0152] 5.9±0.2°, 8.7±0.2°, 11.9±0.2°;

[0153] 5.9±0.2°, 8.7±0.2°, 11.5±0.2°, 11.9±0.2°;

[0154] 5.9±0.2°, 11.5±0.2°, 11.9±0.2°, 13.4±0.2°;

[0155] 5.9±0.2°, 11.5±0.2°, 11.9±0.2°, 20.0±0.2°;

[0156] 5.9±0.2°, 11.5±0.2°, 11.9±0.2°, 13.4±0.2°, 14.6±0.2°;

[0157] 5.9±0.2°, 8.7±0.2°, 11.5±0.2°, 11.9±0.2°, 20.0±0.2°;

[0158] 5.9±0.2°, 11.5±0.2°, 11.9±0.2°, 20.0±0.2°, 24.4±0.2°;

[0159] 5.9±0.2°, 8.7±0.2°, 11.5±0.2°, 11.9±0.2°, 13.4±0.2°, 14.6±0.2°;

[0160] 5.9±0.2°, 11.5±0.2°, 11.9±0.2°, 14.6±0.2°, 20.0±0.2°, 24.4±0.2°;

[0161] 5.9±0.2°, 8.7±0.2°, 11.5±0.2°, 11.9±0.2°, 14.6±0.2°, 20.0±0.2°;

[0162] 5.9±0.2°, 8.7±0.2°, 11.5±0.2°, 11.9±0.2°, 13.4±0.2°, 14.6±0.2°, 20.0±0.2°, 24.4±0.2°;

[0163] 5.9±0.2°, 11.5±0.2°, 11.9±0.2°, 14.6±0.2°, 20.0±0.2°, 24.4±0.2°, 24.9±0.2°, 26.3±0.2°;

[0164] 5.9±0.2°, 8.0±0.2°, 8.7±0.2°, 11.5±0.2°, 11.9±0.2°, 14.1±0.2°, 14.6±0.2°, 20.0±0.2°;

[0165] 5.9±0.2°, 8.7±0.2°, 11.5±0.2°, 11.9±0.2°, 13.4±0.2°, 14.1±0.2°, 14.6±0.2°, 20.0±0.2°, 24.4±0.2°, 24.9±0.2°;

[0166] 5.9±0.2°, 8.7±0.2°, 11.5±0.2°, 11.9±0.2°, 13.4±0.2°, 14.1±0.2°, 14.6±0.2°, 20.0±0.2°, 24.4±0.2°, 26.3±0.2°;

[0167] 5.9±0.2°, 8.7±0.2°, 9.7±0.2°, 11.5±0.2°, 11.9±0.2°, 13.4±0.2°, 14.1±0.2°, 20.0±0.2°, 24.4±0.2°, 24.9±0.2°.

[0168] In certain embodiments of the present invention, Cu-Kα radiation is used, and the characteristic X-ray diffraction peaks expressed in terms of 2θ angles and interplanar spacing d values ​​are shown in Table 3.

[0169] Table 3

[0170] In certain embodiments of the present invention, the X-ray powder diffraction pattern of Form III is substantially as shown in FIG8 .

[0171] In certain embodiments of the present invention, the crystalline form of (S)-1-(3-(7-acetyl-4-amino-3-(pyrazolo[1,5-a]pyridin-6-ylidenealkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one is Form IV;

[0172] The X-ray powder diffraction pattern of Form IV has a diffraction peak at 2θ of 5.2±0.2°; or a diffraction peak at 7.4±0.2°; or a diffraction peak at 10.5±0.2°; or a diffraction peak at 14.5±0.2°; or a diffraction peak at 14.9±0.2°; or a diffraction peak at 17.9±0.2°; or a diffraction peak at 19.5±0.2°. ; or has a diffraction peak at 24.4±0.2°; or has a diffraction peak at 25.0±0.2°; or has a diffraction peak at 26.2±0.2°; preferably includes any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9 or 10 thereof;

[0173] Preferably, the X-ray powder diffraction pattern of Form IV comprises at least one or more diffraction peaks located at 2θ of 5.2±0.2°, 7.4±0.2°, and 10.5±0.2°, preferably 2 of them, and more preferably 3 of them; optionally, it may further comprise at least one of 2θ of 14.9±0.2°, 19.5±0.2°, 24.4±0.2°, 25.0±0.2°, and 26.2±0.2°, preferably 2, 3, 4, or 5 of them;

[0174] More preferably, the X-ray powder diffraction pattern of Form IV optionally further comprises one or more diffraction peaks located at 2θ of 8.1±0.2°, 14.5±0.2°, and 17.9±0.2°; preferably, at least any 2-3 of them; further preferably, any 2 or 3 of them;

[0175] Further preferably, the X-ray powder diffraction pattern of Form IV comprises one or more diffraction peaks located at 2θ of 5.2±0.2°, 7.4±0.2°, 10.5±0.2°, 14.5±0.2°, 14.9±0.2°, 17.9±0.2°, 19.5±0.2°, 24.4±0.2°, 25.0±0.2°, and 26.2±0.2°; preferably, there are diffraction peaks at any of 4, 5, 6, 8 or 10 positions;

[0176] For example, the X-ray powder diffraction pattern of the crystalline form IV has diffraction peaks at the following positions at 2θ:

[0177] 7.4±0.2°, 10.5±0.2°;

[0178] 5.2±0.2°, 10.5±0.2°;

[0179] 5.2±0.2°, 7.4±0.2°, 10.5±0.2°;

[0180] 5.2±0.2°, 7.4±0.2°, 10.5±0.2°, 14.9±0.2°;

[0181] 5.2±0.2°, 7.4±0.2°, 10.5±0.2°, 24.4±0.2°;

[0182] 5.2±0.2°, 7.4±0.2°, 10.5±0.2°, 26.2±0.2°;

[0183] 5.2±0.2°, 7.4±0.2°, 10.5±0.2°, 14.9±0.2°, 19.5±0.2°;

[0184] 5.2±0.2°, 7.4±0.2°, 10.5±0.2°, 19.5±0.2°, 24.4±0.2°;

[0185] 5.2±0.2°, 7.4±0.2°, 10.5±0.2°, 24.4±0.2°, 26.2±0.2°;

[0186] 5.2±0.2°, 7.4±0.2°, 10.5±0.2°, 14.9±0.2°, 19.5±0.2°, 24.4±0.2°;

[0187] 5.2±0.2°, 7.4±0.2°, 10.5±0.2°, 19.5±0.2°, 24.4±0.2°, 25.0±0.2°;

[0188] 5.2±0.2°, 7.4±0.2°, 10.5±0.2°, 24.4±0.2°, 25.0±0.2°, 26.2±0.2°;

[0189] 5.2±0.2°, 7.4±0.2°, 10.5±0.2°, 14.9±0.2°, 19.5±0.2°, 24.4±0.2°, 25.0±0.2°, 26.2±0.2°;

[0190] 5.2±0.2°, 7.4±0.2°, 8.1±0.2°, 10.5±0.2°, 19.5±0.2°, 24.4±0.2°, 25.0±0.2°, 26.2±0.2°;

[0191] 5.2±0.2°, 7.4±0.2°, 10.5±0.2°, 14.9±0.2°, 17.9±0.2°, 19.5±0.2°, 25.0±0.2°, 26.2±0.2°;

[0192] 5.2±0.2°, 7.4±0.2°, 10.5±0.2°, 14.5±0.2°, 14.9±0.2°, 17.9±0.2°, 19.5±0.2°, 24.4±0.2°, 25.0±0.2°, 26.2±0.2°;

[0193] 5.2±0.2°, 7.4±0.2°, 8.1±0.2°, 10.5±0.2°, 14.9±0.2°, 17.9±0.2°, 19.5±0.2°, 24.4±0.2°, 25.0±0.2°, 26.2±0.2°;

[0194] 5.2±0.2°, 7.4±0.2°, 8.1±0.2°, 10.5±0.2°, 14.5±0.2°, 14.9±0.2°, 19.5±0.2°, 24.4±0.2°, 25.0±0.2°, 26.2±0.2°.

[0195] In certain embodiments of the present invention, Cu-Kα radiation is used, and the characteristic X-ray diffraction peaks expressed in terms of 2θ angles and interplanar spacing d values ​​are shown in Table 4.

[0196] Table 4

[0197] In certain embodiments of the present invention, the X-ray powder diffraction pattern of Form IV is substantially as shown in FIG. 9 .

[0198] In certain embodiments of the present invention, the crystalline form of (S)-1-(3-(7-acetyl-4-amino-3-(pyrazolo[1,5-a]pyridin-6-ylidenealkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one is Form V; the X-ray powder diffraction pattern of Form V has a diffraction peak at 2θ of 7.3±0.2°; or a diffraction peak at 8.1±0.2°; or a diffraction peak at 9.0±0.2°; or a diffraction peak at 9.6±0.2°; or a diffraction peak at 10 .6±0.2° has a diffraction peak; or has a diffraction peak at 11.6±0.2°; or has a diffraction peak at 12.7±0.2°; or has a diffraction peak at 13.4±0.2°; or has a diffraction peak at 14.2±0.2°; or has a diffraction peak at 26.2±0.2°; preferably includes any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9 or 10 thereof;

[0199] Preferably, the X-ray powder diffraction pattern of Form V comprises at least one or more diffraction peaks located at 2θ of 9.0±0.2°, 10.6±0.2°, and 14.2±0.2°, preferably 2 of them, and more preferably 3 of them; optionally, it may further comprise at least one of 2θ of 7.3±0.2°, 8.1±0.2°, 11.6±0.2°, 12.7±0.2°, and 13.4±0.2°, preferably 2, 3, 4, or 5 of them;

[0200] More preferably, the X-ray powder diffraction pattern of Form V optionally further comprises one or more diffraction peaks located at 2θ of 9.6±0.2°, 25.0±0.2°, and 26.2±0.2°; preferably, at least any 2-3 of them; further preferably, any 2 or 3 of them;

[0201] Further preferably, the X-ray powder diffraction pattern of Form V comprises one or more diffraction peaks located at 2θ of 7.3±0.2°, 8.1±0.2°, 9.0±0.2°, 9.6±0.2°, 10.6±0.2°, 11.6±0.2°, 12.7±0.2°, 13.4±0.2°, 14.2±0.2°, and 26.2±0.2°; preferably, the diffraction peaks are selected from 4, 5, 6, 8, or 10 of them;

[0202] For example, the X-ray powder diffraction pattern of the crystalline form V has diffraction peaks at the following positions in 2θ:

[0203] 10.6±0.2°、14.2±0.2°；

[0204] 9.0±0.2°、10.6±0.2°；

[0205] 9.0±0.2°、10.6±0.2°、14.2±0.2°；

[0206] 7.3±0.2°、8.1±0.2°、9.0±0.2°、10.6±0.2°、14.2±0.2°；

[0207] 9.0±0.2°、10.6±0.2°、11.6±0.2°、12.7±0.2°、14.2±0.2°；

[0208] 9.0±0.2°、10.6±0.2°、12.7±0.2°、13.4±0.2°、14.2±0.2°；

[0209] 7.3±0.2°、8.1±0.2°、9.0±0.2°、10.6±0.2°、11.6±0.2°、14.2±0.2°；

[0210] 8.1±0.2°、9.0±0.2°、10.6±0.2°、11.6±0.2°、12.7±0.2°、14.2±0.2°；

[0211] 9.0±0.2°、10.6±0.2°、11.6±0.2°、12.7±0.2°、13.4±0.2°、14.2±0.2°；

[0212] 7.3±0.2°、8.1±0.2°、9.0±0.2°、10.6±0.2°、11.6±0.2°、12.7±0.2°、13.4±0.2°、14.2±0.2°；

[0213] 7.3±0.2°、8.1±0.2°、9.0±0.2°、10.6±0.2°、11.6±0.2°、12.7±0.2°、13.4±0.2°、25.0±0.2°；

[0214] 7.3±0.2°、8.1±0.2°、9.0±0.2°、10.6±0.2°、11.6±0.2°、12.7±0.2°、14.2±0.2°、26.2±0.2°；

[0215] 7.3±0.2°, 8.1±0.2°, 9.0±0.2°, 9.6±0.2°, 10.6±0.2°, 11.6±0.2°, 12.7±0.2°, 13.4±0.2°, 14.2±0.2°, 26.2±0.2°;

[0216] 7.3±0.2°, 8.1±0.2°, 9.0±0.2°, 9.6±0.2°, 10.6±0.2°, 12.7±0.2°, 13.4±0.2°, 14.2±0.2°, 25.0±0.2°, 26.2±0.2°;

[0217] 7.3±0.2°, 8.1±0.2°, 9.0±0.2°, 9.6±0.2°, 10.6±0.2°, 11.6±0.2°, 12.7±0.2°, 14.2±0.2°, 25.0±0.2°, 26.2±0.2°.

[0218] In certain embodiments of the present invention, Cu-Kα radiation is used, and the characteristic X-ray diffraction peaks expressed in terms of 2θ angles and interplanar spacing d values ​​are shown in Table 5.

[0219] Table 5

[0220] In certain embodiments of the present invention, the X-ray powder diffraction pattern of Form V is substantially as shown in FIG10 .

[0221] In certain embodiments of the present invention, the crystalline form of (S)-1-(3-(7-acetyl-4-amino-3-(pyrazolo[1,5-a]pyridin-6-ylidenealkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one is Form VI;

[0222] The X-ray powder diffraction pattern of Form VI has a diffraction peak at 2θ of 7.1±0.2°; or a diffraction peak at 8.5±0.2°; or a diffraction peak at 9.2±0.2°; or a diffraction peak at 9.6±0.2°; or a diffraction peak at 11.6±0.2°; or a diffraction peak at 14.7±0.2°; or a diffraction peak at 15.0±0.2°; or a diffraction peak at 16.7±0.2°; or a diffraction peak at 17.0±0.2°; or a diffraction peak at 17.4±0.2°; or a diffraction peak at 18.5±0.2°; or a diffraction peak at 22. The invention has a diffraction peak at 1±0.2°; or has a diffraction peak at 24.9±0.2°; or has a diffraction peak at 25.3±0.2°; or has a diffraction peak at 26.0±0.2°; or has a diffraction peak at 26.9±0.2°; preferably includes any 2-5 of the above diffraction peaks, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 8-10, or 10-12, or 12-14, or 14-16; more preferably includes any 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 of them.

[0223] In certain embodiments of the present invention, the X-ray powder diffraction pattern of Form VI is substantially as shown in FIG11 , the DSC pattern is shown in FIG12 , and the TGA pattern is shown in FIG13 .

[0224] In certain embodiments of the present invention, the crystalline form of (S)-1-(3-(7-acetyl-4-amino-3-(pyrazolo[1,5-a]pyridin-6-ylidenealkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one is Form VII;

[0225] The X-ray powder diffraction pattern of Form VII has a diffraction peak at 2θ of 7.2±0.2°; or a diffraction peak at 8.6±0.2°; or a diffraction peak at 10.1±0.2°; or a diffraction peak at 10.7±0.2°; or a diffraction peak at 11.7±0.2°; or a diffraction peak at 14.4±0.2°; or a diffraction peak at 14.8±0.2°; or a diffraction peak at 16.7±0. The present invention has a diffraction peak at 2°; or a diffraction peak at 17.5±0.2°; or a diffraction peak at 18.5±0.2°; or a diffraction peak at 25.3±0.2°; preferably includes any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 8-11 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, 10 or 11 of them.

[0226] In certain embodiments of the present invention, the X-ray powder diffraction pattern of Form VII is substantially as shown in FIG14 , the DSC pattern is shown in FIG15 , and the TGA pattern is shown in FIG16 .

[0227] In certain embodiments of the present invention, the crystalline form of (S)-1-(3-(7-acetyl-4-amino-3-(pyrazolo[1,5-a]pyridin-6-ylidenealkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one is Form VIII;

[0228] The X-ray powder diffraction pattern of Form VIII has a diffraction peak at 2θ of 5.3±0.2°; or a diffraction peak at 8.1±0.2°; or a diffraction peak at 8.3±0.2°; or a diffraction peak at 10.6±0.2°; or a diffraction peak at 13.4±0.2°; or a diffraction peak at 14.1±0.2°; or a diffraction peak at 14.8±0.2°; or a diffraction peak at 15.4±0.2°; or a diffraction peak at 16.0 The present invention has a diffraction peak at 19.5±0.2°; or a diffraction peak at 24.5±0.2°; or a diffraction peak at 25.1±0.2°; preferably includes any 2-5 of the above diffraction peaks, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 8-10, or 10-12; more preferably includes any 6, 7, 8, 9, 10, 11 or 12 of them.

[0229] In certain embodiments of the present invention, the X-ray powder diffraction pattern of Form VII is substantially as shown in FIG17 , the DSC pattern is shown in FIG18 , and the TGA pattern is shown in FIG19 .

[0230] In certain embodiments of the present invention, the 2θ errors of the top ten diffraction peak positions with relative peak intensities in the X-ray powder diffraction patterns of the crystalline form I, form II, form III, form IV, form V, form VI, form VII, and form VIII and the diffraction peaks at the corresponding positions in Figures 1, 5, 8, 9, 10, 11, 14, and 17 are ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°.

[0231] The present invention also provides a method for preparing the crystalline form of the above compound or its stereoisomer, which is method one, two or three;

[0232] Method 1: dissolving the compound in a poor solvent, stirring or beating to obtain the corresponding crystal form;

[0233] Method 2: heating the crystal form to obtain the corresponding crystal form;

[0234] Method 3: dissolving the compound or crystal form in a positive solvent, adding an anti-solvent and stirring until a solid precipitates or cooling and crystallizing to obtain the corresponding crystal form;

[0235] The poor solvent is selected from one or more of acetone, ethyl acetate, isopropyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone or 3-pentanone, methyl tert-butyl ether or water; preferably one or more of acetone, acetonitrile or toluene.

[0236] The positive solvent is selected from one or more of dimethyl sulfoxide, acetic acid, methanol, acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone, 3-pentanone or N-methylpyrrolidone;

[0237] The anti-solvent is selected from one or more of alcohol solvents, heptane, cyclohexane, n-hexane, n-pentane, water, ethyl acetate, methyl tert-butyl ether, toluene or isopropyl ether; preferably one or more of methanol, ethyl acetate, water, heptane, methyl tert-butyl ether or isopropyl ether.

[0238] The present invention also provides a method for preparing the crystalline form of the above compound or its stereoisomers.

[0239] The preparation of Form I comprises the following steps: dissolving the compound in solvent A, and beating to obtain the corresponding Form I;

[0240] Alternatively, the preparation of Form I comprises the following steps: mixing the compound with solvent J, and then mixing with solvent K to obtain the corresponding Form I;

[0241] The preparation of Form II comprises the following steps: dissolving the compound in solvent B, and beating to obtain the corresponding Form II;

[0242] Alternatively, the preparation of Form II comprises the following steps: mixing the compound with a solvent L, and then mixing with a solvent M to obtain the corresponding Form II;

[0243] The preparation of Form III comprises the following steps: heating the Form II to obtain the corresponding Form II;

[0244] The preparation of Form IV comprises the following steps: mixing the compound or the crystalline form with solvent C, and then mixing with solvent D to obtain the corresponding Form IV;

[0245] The preparation of Form V comprises the following steps: mixing the compound or the crystal form with solvent E, and then mixing with solvent F to obtain the corresponding Form V;

[0246] The preparation of Form VI comprises the following steps: dissolving the compound in solvent G and stirring to obtain the corresponding Form VI;

[0247] The preparation of Form VII comprises the following steps: heating the Form VI to obtain the corresponding Form VII;

[0248] The preparation of Form VIII comprises the following steps: mixing the compound with solvent H, and then mixing with solvent I to obtain the corresponding Form VIII;

[0249] Wherein, the solvent A is preferably DMSO, ethyl acetate, dichloromethane, isopropyl acetate, methyl tert-butyl ether, MTBE, acetone, tetrahydrofuran, toluene, 2-butanone, 2-methyl-tetrahydrofuran, water or acetonitrile; the solvent B is preferably an alcohol solvent, more preferably methanol, ethanol or isopropanol; the solvent C is preferably a mixed solvent of an alcohol solvent and a halogenated alkane solvent (1:5), more preferably a mixed solution of methanol and dichloromethane (1:5) or a mixed solution of ethanol and dichloromethane (1:5); the solvent D is preferably an ether solvent, more preferably MTBE; the solvent E is preferably an amide solvent, more preferably N-methylpyrrolidone or 1,4-dioxane; the solvent F is preferably an alcohol solvent, preferably isopropanol; the solvent G is preferably an ether solvent, more preferably 1,4-dioxane;

[0250] The heating temperature is preferably 50 to 70°C;

[0251] Solvent H is preferably a mixed solvent of a halogenated alkane solvent and an alcohol solvent (3:1), preferably a mixed solution of dichloromethane and ethanol (3:1); Solvent I is preferably an ether solvent, more preferably MTBE;

[0252] Solvent J is preferably DMSO, acetic acid or DMF, and solvent K is preferably water, acetone, ethyl acetate, acetonitrile, toluene, methyl tert-butyl ether, or n-heptane; solvent J is preferably NMP or 1,4-dioxane, and solvent K is preferably an ether solvent, more preferably methyl tert-butyl ether or isopropyl ether; solvent J is preferably a mixed solvent of an alcohol solvent and a halogenated alkane solvent (1:5), preferably methanol:dichloromethane (1:5) or ethanol:dichloromethane (1:5), and solvent K is preferably n-heptane, isopropyl ether, or n-hexane; solvent L is preferably DMSO, and solvent M is preferably an alcohol solvent, preferably isopropanol, methanol, or ethanol.

[0253] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the above compound or a crystalline form of its stereoisomer, and one or more pharmaceutically acceptable carriers or excipients.

[0254] The present invention also provides the crystalline form of the above-mentioned compound or its stereoisomer, and the use of the above-mentioned pharmaceutical composition in the preparation of drugs for treating and / or preventing FGFR-related diseases, in particular, the use of the above-mentioned pharmaceutical composition in the preparation of drugs for treating and / or preventing FGFR1-4-related diseases.

[0255] The present invention also provides a crystalline form of the above-mentioned compound or a stereoisomer thereof, and use of the above-mentioned pharmaceutical composition in the preparation of a medicament for treating and / or preventing cancer and achondroplasia-related diseases; preferably, the cancer is selected from colorectal cancer, bladder cancer, gastric cancer, thyroid cancer, esophageal cancer, head and neck cancer, brain cancer, glioma, glioblastoma, hepatocellular carcinoma, lung cancer, melanoma, myeloma, pancreatic cancer, renal cell carcinoma, cervical cancer, urothelial carcinoma, prostate cancer, ovarian cancer, breast cancer, leukemia or lymphoma.

[0256] The present invention also provides a method for treating and / or preventing FGFR-related diseases, comprising administering a therapeutically effective amount of the compound described above or a crystalline form of its stereoisomer, or the pharmaceutical composition described above to a subject in need thereof, preferably the FGFR is FGFR1-4.

[0257] The present invention also provides a method for treating and / or preventing cancer and achondroplasia-related diseases, comprising administering a therapeutically effective amount of the compound described above or a crystalline form of its stereoisomer, or the pharmaceutical composition described above, to a subject in need thereof; preferably, the cancer is selected from colorectal cancer, bladder cancer, gastric cancer, thyroid cancer, esophageal cancer, head and neck cancer, brain cancer, glioma, glioblastoma, hepatocellular carcinoma, lung cancer, melanoma, myeloma, pancreatic cancer, renal cell carcinoma, cervical cancer, urothelial carcinoma, prostate cancer, ovarian cancer, breast cancer, leukemia or lymphoma.

[0258] The compound of the present invention adds a non-hydrogen substituent at a specific position of the mother nucleus, which can greatly improve the enzyme activity of FGFR2 V564F and the inhibitory activity of cell resistance mutations, thereby solving the problem that there is no drug to treat V564F resistance with currently available drugs.

[0259] Detailed Description of the Invention

[0260] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 8 carbon atoms, further preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl.

[0261] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0262] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen, C(O) or S(O). m(wherein m is an integer from 0 to 2) heteroatoms, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; most preferably, it contains 3 to 6 ring atoms; further preferably, it contains a 3-8 membered heterocyclic group containing 1-3 nitrogen atoms, optionally substituted with 1-2 oxygen atoms, sulfur atoms, or oxo groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spiroheterocyclic groups, or nitrogen-containing fused heterocyclic groups. Non-limiting examples of monocyclic heterocyclic groups include piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, oxetanyl, or azetidinyl.

[0263] "Aminocarbonyl" refers to NH2-C(O)-.

[0264] "Alkylaminocarbonyl" refers to an aminocarbonyl (NH2-C(O)-) group in which one or both hydrogen atoms are replaced by an alkyl group, wherein alkyl is as defined above.

[0265] "Alkylamino" refers to an amino group in which one or both of the hydrogen atoms are replaced by an alkyl group, wherein the alkyl group is as defined above.

[0266] "Alkylcarbonyl" or "acyl" refers to an (alkyl)-C(O)- group in which alkyl is as previously described.

[0267] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0268] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0269] FIG1 is an XRPD diagram of Form I.

[0270] FIG2 is a DSC diagram of Form I.

[0271] FIG3 is a TGA diagram of Form I.

[0272] FIG4 is an IR diagram of Form I.

[0273] FIG5 is an XRPD diagram of Form II.

[0274] FIG6 is a DSC diagram of Form II.

[0275] FIG7 is a TGA diagram of Form II.

[0276] FIG8 is an XRPD diagram of Form III.

[0277] FIG9 is an XRPD diagram of Form IV.

[0278] FIG10 is an XRPD diagram of Form V.

[0279] FIG11 is an XRPD diagram of Form VI.

[0280] FIG12 is a DSC diagram of Form VI.

[0281] FIG13 is a TGA diagram of Form VI.

[0282] FIG14 is an XRPD diagram of Form VII.

[0283] FIG15 is a DSC diagram of Form VII.

[0284] FIG16 is a TGA diagram of Form VII.

[0285] FIG17 is an XRPD diagram of Form VIII.

[0286] FIG18 is a DSC diagram of Form VIII.

[0287] FIG19 is a TGA chart of Form VIII. DETAILED DESCRIPTION

[0288] The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

[0289] 1. Preparation of Compounds

[0290] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, using deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as the solvents, with tetramethylsilane (TMS) as the internal standard.

[0291] Liquid chromatography-mass spectrometry (LC-MS) was performed on an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed on an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150 × 4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C 18 150×4.6mm chromatographic column).

[0292] Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0293] The starting materials in the examples of the present invention are known and can be purchased commercially, or can be synthesized using or according to methods known in the art.

[0294] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, with dry solvents and reaction temperatures in degrees Celsius.

[0295] Intermediate 1

[0296] Tert-butyl-(S)-3-(4-amino-7-bromo-3-iodo-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate

[0297] Step 1: Preparation of 2-amino-4-chloronicotinaldehyde

[0298] Under nitrogen, tert-butyl 4-chloropyridine-2-carboxylate (30 g, 131.19 mmol) and N,N,N',N'-tetramethylethylenediamine (38.11 g, 327.98 mmol) were dissolved in THF (600 mL). A 2.5 M solution of n-butyllithium in n-hexane (131.19 mL) was added dropwise at -78°C. The mixture was stirred for 2 hours. DMF (28.77 g, 393.57 mmol, 30.47 mL) was then added dropwise, and the reaction was continued for 1 hour. After the reaction was complete, saturated ammonium chloride solution (500 mL) was added to quench the reaction. The reaction solution was extracted with ethyl acetate (250 mL x 3) and washed with saturated sodium chloride solution (250 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. Then, dioxane hydrochloride solution (4.0 M, 50 mL) was added to the concentrated product. After stirring at room temperature for 1 hour, the reaction solution was neutralized with sodium hydroxide solution until alkaline. The reaction solution was extracted with ethyl acetate (250 mL x 3) and washed with saturated sodium chloride aqueous solution (250 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and separated by column chromatography (PE:EA = 1:4) to obtain the title compound (6.16 g, 30%). MS m / z (ESI): 157.1 [M+H] + .

[0299] Step 2: Preparation of 2-amino-5-bromo-4-chloronicotinaldehyde

[0300] Under nitrogen, 2-amino-4-chloronicotinaldehyde (6.16 g, 39.34 mmol) and N-bromosuccinimide (7.70 g, 43.28 mmol) were dissolved in dichloroethane (100 mL), heated to 60°C, and stirred for 2 hours. After the reaction, the reaction mixture was cooled and filtered. The filter cake was washed with dichloroethane (15 mL x 3) and water (15 mL x 3) to obtain the title compound (7.36 g, 80%). MS m / z (ESI): 236.1 [M+H] + .

[0301] Step 3: Preparation of 7-bromo-1H-pyrazolo[4,3-c]pyridin-4-amine

[0302] Under nitrogen, 2-amino-5-bromo-4-chloronicotinaldehyde (7.36 g, 31.26 mmol) and 85% hydrazine hydrate (3.68 g, 62.52 mmol) were dissolved in dimethyl sulfoxide (40 mL) and stirred at 130°C for 4 hours. After the reaction, the reaction solution was extracted with ethyl acetate (150 mL x 3) and washed with saturated sodium chloride solution (150 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to yield the title compound (4.18 g, 63%). MS m / z (ESI): 213.1, 215.1 [M+H] + .

[0303] Step 4: Preparation of 1-(7-bromo-1H-pyrazolo[4,3-c]pyridin-4-yl)pyrrolidine-2,5-dione

[0304] 7-Bromo-1H-pyrazolo[4,3-c]pyridin-4-amine (1.5 g, 7.04 mmol) and succinic anhydride (2.11 g, 21.12 mmol) were mixed at room temperature and gradually heated to 160°C for 30 minutes. After the reaction was complete, the reaction solution was cooled and extracted with ethyl acetate (50 mL x 3) and washed with saturated sodium chloride solution (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (DCM:MeOH = 95:5) to obtain the title compound (1.5 g, 72%). MS m / z (ESI): 295.0 [M+H] + .

[0305] Step 5: Preparation of 1-(7-bromo-3-iodo-1H-pyrazolo[4,3-c]pyridin-4-yl)pyrrolidine-2,5-dione

[0306] Under nitrogen, 1-(7-bromo-1H-pyrazolo[4,3-c]pyridin-4-yl)pyrrolidine-2,5-dione (1.5 g, 5.08 mmol) and N-iodosuccinimide (1.37 g, 6.10 mmol) were dissolved in DMF (20 mL) and stirred at 60°C for 2 hours. After the reaction was complete, the reaction mixture was cooled and filtered. The filtrate was extracted with ethyl acetate (50 mL x 3) and washed with saturated sodium chloride solution (50 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM:MeOH = 95:5) to yield the title compound (1.5 g, 70%). MS m / z (ESI): 421.1 [M+H] + .

[0307] Step 6: Preparation of tert-butyl-(S)-3-(4-amino-7-bromo-3-iodo-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate

[0308] Under nitrogen, 1-(7-bromo-3-iodo-1H-pyrazolo[4,3-c]pyridin-4-yl)pyrrolidine-2,5-dione (1.5 g, 3.56 mmol), tert-butyl-(R)-3-(tosyloxy)pyrrolidine-1-carboxylate (1.46 g, 4.28 mmol), and cesium carbonate (2.32 g, 7.13 mmol) were suspended in DMF (50 mL) and heated to 80°C with stirring overnight. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (50 mL x 3) and washed with saturated sodium chloride (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (PE:EA = 1:1) to yield the title compound (560 mg, 31%). MS m / z (ESI): 508.1 [M+H] + .

[0309] Example 1

[0310] (S)-1-(3-(7-acetyl-4-amino-3-(pyrazolo[1,5-a]pyridin-6-ylidenealkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one

[0311] Step 1: Preparation of 6-((trimethylsilyl)ethynyl)pyrazolo[1,5-a]pyridine

[0312] Under nitrogen, 6-bromopyrazolo[1,5-a]pyridine (2 g, 10.15 mmol), trimethylethynylsilane (1.5 g, 15.23 mmol), Pd(dppf)Cl2 (742 mg, 1.02 mmol), CuI (387 mg, 2.03 mmol), and TEA (2.05 g, 20.3 mmol) were suspended in THF (50 mL) and heated to 60°C with stirring for 2 hours. After the reaction was complete, the reaction mixture was cooled, filtered, extracted with ethyl acetate (50 mL x 3), and washed with saturated sodium chloride solution (50 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (1.89 g, 87%). MS m / z (ESI): 215.1 [M+H] + .

[0313] Step 2: Preparation of 6-ethynylpyrazolo[1,5-a]pyridine

[0314] Under nitrogen, 6-((Trimethylsilyl)ethynyl)pyrazolo[1,5-a]pyridine (1.89 g, 8.82 mmol) and TBAF (3.46 g, 13.23 mmol) were dissolved in tetrahydrofuran (50 mL) and stirred at room temperature for 1 hour. After the reaction, the mixture was extracted with ethyl acetate (50 mL x 3) and washed with saturated sodium chloride solution (50 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (780 mg, 62%). MS m / z (ESI): 143.0 [M+H] + .

[0315] Step 3: Preparation of tert-butyl-(S)-3-(4-amino-7-bromo-3-(pyrazolo[1,5-a]pyridin-6-ylethynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate

[0316] Under nitrogen, tert-butyl-(S)-3-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (500 mg, 0.98 mmol), 6-ethynylpyrazolo[1,5-a]pyridine (168 mg, 1.18 mmol), Pd(dppf)Cl2 (72 mg, 0.01 mmol), CuI (38 mg, 0.02 mmol), and TEA (199 mg, 1.97 mmol) were suspended in DMF (20 mL) and heated to 60°C with stirring for 2 hours. After the reaction was complete, the reaction mixture was cooled, filtered, extracted with ethyl acetate (50 mL x 3), and washed with saturated sodium chloride (50 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (450 mg, 88%). MS m / z(ESI):522.1[M+H] + .

[0317] Step 4: Preparation of tert-butyl-(S)-3-(4-amino-7-(1-butoxyvinyl)-3-(pyrazolo[1,5-a]pyridin-6-ylethynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate

[0318] Under nitrogen protection, tert-butyl-(S)-3-(4-amino-7-bromo-3-(pyrazolo[1,5-a]pyridin-6-ylethynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate (200 mg, 0.38 mmol), 1-(vinyloxy)butane (115 mg, 1.15 mmol), palladium acetate (9 mg, 0.04 mmol), N,N-diisopropylethylamine (148 mg, 1.15 mmol) and bis(2-diphenylphosphinophenyl) ether (41 mg, 0.08 mmol) were suspended in n-butanol (10 mL), heated to 110 ° C and stirred for 2 hours. After the reaction was complete, the reaction mixture was cooled and filtered. The filtrate was extracted with ethyl acetate (30 mL x 3) and washed with saturated sodium chloride solution (20 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (100 mg, 48%). MS m / z (ESI): 542.1 [M+H] + .

[0319] Step 5: Preparation of (S)-1-(3-(7-acetyl-4-amino-3-(pyrazolo[1,5-a]pyridin-6-ylethynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one

[0320] Under nitrogen, tert-butyl-(S)-3-(4-amino-7-(1-butoxyvinyl)-3-(pyrazolo[1,5-a]pyridin-6-ylethynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate (100 mg, 0.18 mmol) was dissolved in a 4M solution of dioxane hydrochloride (10 mL) and stirred at room temperature for 1 hour. The reaction solution was dried, concentrated, and suspended in a mixture of dichloromethane (10 mL) and water (20 mL). A solution of acryloyl chloride (20 mg, 0.22 mmol) in dichloromethane (5 mL) was added dropwise under an ice-water bath and stirred for 10 minutes. After the reaction, the reaction mixture was extracted with dichloromethane (15 mL x 3) and washed with saturated sodium chloride solution (10 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (44 mg, 56%). MS m / z (ESI): 440.2 [M+H] + .

[0321] 1 H NMR (400MHz, DMSO-d6) δ9.33(s,1H),8.58(d,J=2.4Hz,1H),8.14(d,J=2.4Hz,1H ),7.77(d,J=9.2Hz,1H),7.41(d,J=9.2Hz,2H),6.76-6.53(m,2H),6.16(ddd,J=1 6.8,5.2,2.4Hz,1H),6.01-5.85(m,1H),5.69(ddd,J=16.4,10.4,2.4Hz,1H),4.1 2-3.50(m,5H),2.62(s,3H),2.45(q,J=7.6Hz,1H),2.33(dt,J=11.6,6.4Hz,1H).

[0322] Example 2

[0323] (S)-1-(3-(4-amino-7-propionyl-3-(pyrazolo[1,5-a]pyridin-6-ylidenealkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one

[0324] Step 1: Preparation of tert-butyl-(S)-3-(4-amino-3-(pyrazolo[1,5-a]pyridin-6-ylethynyl)-7-vinyl-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate

[0325] Under nitrogen protection, tert-butyl-(S)-3-(4-amino-7-bromo-3-(pyrazolo[1,5-a]pyridin-6-ylethynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate (1.8 g, 3.45 mmol), potassium vinyl fluoroborate (692 mg, 5.17 mmol), Pd(dppf)Cl2 (252 mg, 0.34 mmol) and potassium carbonate (952 mg, 6.89 mmol) were suspended in a mixed solvent of 1,4-dioxane (50 mL) and water (10 mL), heated to 100 ° C and stirred for 16 hours. After the reaction was complete, the reaction mixture was cooled and filtered. The filtrate was extracted with ethyl acetate (30 mL x 3) and washed with saturated sodium chloride solution (20 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (780 mg, 48%). MS m / z (ESI): 470.2 [M+H] + .

[0326] Step 2: Preparation of tert-butyl-(S)-3-(4-amino-7-formyl-3-(pyrazolo[1,5-a]pyridin-6-ylethynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate

[0327] Under nitrogen, tert-butyl-(S)-3-(4-amino-3-(pyrazolo[1,5-a]pyridin-6-ylethynyl)-7-vinyl-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate (373 mg, 0.79 mmol) and potassium osmate (12 mg, 0.04 mmol) were dispersed in a mixture of 1,4-dioxane (50 mL) and water (10 mL). The mixture was stirred at room temperature for 10 minutes, followed by the addition of sodium periodate (849 mg, 3.94 mmol) and continued stirring for 2 hours. After the reaction was complete, the reaction mixture was cooled and filtered. The filtrate was extracted with ethyl acetate (30 mL x 3) and washed with saturated sodium chloride solution (20 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (100 mg, 27%). MS m / z(ESI):472.2[M+H] + .

[0328] Step 3: Preparation of tert-butyl-(3S)-3-(4-amino-7-(1-hydroxypropyl)-3-(pyrazolo[1,5-a]pyridin-6-ylethynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate

[0329] Under nitrogen, tert-butyl-(S)-3-(4-amino-7-formyl-3-(pyrazolo[1,5-a]pyridin-6-ylethynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate (100 mg, 0.21 mmol) and ethylmagnesium bromide (0.2 mL, 0.63 mmol, 3 M in THF) were dissolved in dry tetrahydrofuran (10 mL) and stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was cooled and filtered. The filtrate was extracted with ethyl acetate (30 mL x 3) and washed with saturated sodium chloride solution (20 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (82 mg, 77%). MS m / z (ESI): 502.2 [M+H] + .

[0330] Step 4: Preparation of tert-butyl-(S)-3-(4-amino-7-propionyl-3-(pyrazolo[1,5-a]pyridin-6-ylethynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate

[0331] Under nitrogen, tert-butyl-(3S)-3-(4-amino-7-(1-hydroxypropyl)-3-(pyrazolo[1,5-a]pyridin-6-ylethynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate (82 mg, 0.16 mmol) and Dess-Martin periodinane (104 mg, 0.26 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was cooled and filtered. The filtrate was extracted with dichloromethane (30 mL x 3) and washed with saturated sodium chloride solution (20 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (80 mg, 98%). MS m / z (ESI): 500.2 [M+H] + .

[0332] Step 5: Preparation of (S)-1-(3-(4-amino-7-propionyl-3-(pyrazolo[1,5-a]pyridin-6-ylethynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one

[0333] Under nitrogen, tert-butyl-(S)-3-(4-amino-7-propionyl-3-(pyrazolo[1,5-a]pyridin-6-ylethynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate (80 mg, 0.16 mmol) was dissolved in a 4M solution of dioxane hydrochloride (10 mL) and stirred at room temperature for 1 hour. The reaction solution was dried, concentrated, and suspended in a mixture of dichloromethane (10 mL) and water (20 mL). A solution of acryloyl chloride (17 mg, 0.19 mmol) in dichloromethane (5 mL) was added dropwise under an ice-water bath and stirred for 10 minutes. After the reaction, the reaction mixture was extracted with dichloromethane (15 mL x 3) and washed with saturated sodium chloride solution (10 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (33 mg, 45%). MS m / z (ESI): 454.1 [M+H] + .

[0334] 1 H NMR (400MHz, DMSO-d6) δ9.33(s,1H),8.58(d,J=2.4Hz,1H),8.14(d,J=2.4Hz,1H ),7.77(dd,J=9.2,1.2Hz,1H),7.40(dd,J=9.2,1.2Hz,1H),7.21(s,1H),6.74-6 .51(m,2H),6.16(ddd,J=16.8,4.8,2.4Hz,1H),5.91-5.60(m,2H),4.09-3.55(m ,5H),3.06(q,J=7.2Hz,2H),2.32(dd,J=9.6,5.6Hz,2H),1.14(t,J=7.2Hz,3H).

[0335] Example 3

[0336] The preparation of (S)-1-(3-(4-amino-7-(cyclopropanecarbonyl)-3-(pyrazolo[1,5-a]pyridin-6-ylidenealkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one was carried out according to Example 2. MS m / z (ESI): 466.2 [M+H] + .

[0337] Example 4

[0338] The preparation of (S)-1-(3-(7-acetyl-4-amino-3-((3-cyclopropylpyrazolo[1,5-a]pyridin-6-yl)alkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-alkyl)prop-2-en-1-one was carried out according to Example 1. MS m / z (ESI): 480.2 [M+H] + .

[0339] Example 5

[0340] The preparation of (S)-1-(3-(7-acetyl-4-amino-3-((2-cyclopropylpyrazolo[1,5-a]pyridin-6-yl)alkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-alkyl)prop-2-en-1-one was carried out according to Example 1. MS m / z (ESI): 480.2 [M+H] + .

[0341] Example 6

[0342] The preparation of (S)-1-(3-(4-amino-3-((3-chloropyrazolo[1,5-a]pyridin-6-yl)alkynyl)-7-isobutyl-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-alkyl)prop-2-en-1-one was carried out according to Example 2. MS m / z (ESI): 502.2 [M+H] + .

[0343] 1 H NMR (400MHz, DMSO-d6) δ9.39(s,1H),8.58(d,J=2.8Hz,1H),8.32(s,1H),7.72(d,J=9.2Hz,1H),7.60-7.51(m,1H),6.60(ddd,J=29.6,16.8, 10.4Hz,2H),6.15(dt,J=16.8,2.8Hz,1H),5.69(ddd,J=15.2,9.2,3.6Hz,2H),4.10-3.57(m,6H),2.35-2.23(m,2H),1.17(d,J=6.8Hz,6H).

[0344] Biological test evaluation

[0345] The present invention is further described and explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0346] 1. Enzyme test

[0347] Test Example 1: Determination of the inhibitory effect of the compounds of the present invention on FGFR1-4 and FGFR2 V564F activities

[0348] 1. Experimental purpose: To test the IC of compounds on FGFR1, FGFR2, FGFR3, FGFR4 and FGFR2 V564F at the ATP Km concentration using the TR-FRET method. 50 .

[0349] 2. Experimental instruments and reagents:

[0350] 2.1 Instruments:

[0351] 2.2 Reagents:

[0352] 3. Experimental Methods: The inhibitory activity of compounds against FGFR1, FGFR2, FGFR3, FGFR4, and the FGFR2 V564F kinase domain fragment was determined by TR-FRET (time-resolved fluorescence resonance energy transfer). In all five kinase assays, the highest concentration tested was 1000 nM, and the compounds were diluted three-fold to a total of 11 concentrations (1000 nM to 0.017 nM). A 4× enzyme solution, a serially diluted 4× compound solution, and a 2× ATP / peptide substrate solution were prepared using kinase buffer (50 mM HEPES pH 7.5, 1 mM EGTA, 10 mM MgCl2, 2 mM DTT, 0.01% Tween-20). 2.5 μL of enzyme solution and 2.5 μL of diluted 5× compound solution were added to a 384-well plate, followed by the addition of 5 μL of 2× ATP / Peptide substrate solution. FGFR1, FGFR2, FGFR3, and FGFR2 V564F kinases were reacted at room temperature for 60 minutes, and FGFR4 kinase was reacted at room temperature for 120 minutes. Then, 10 μL of 2× stop and detection mixture prepared with 1× LANCE detection buffer (EDTA concentration of 20 mM and Europium-anti-phosphotyrosine (PT66) concentration of 2 nM) was added to each well. FGFR1, FGFR2, FGFR3, and FGFR4 were reacted at room temperature for 60 minutes, and FGFR2 V564F was reacted at room temperature for 30 minutes. The fluorescence signal value of each well was measured using a microplate reader.

[0353] Enzyme reaction system:

[0354] Enzyme reaction termination and detection mixed solution system:

[0355] 4. Experimental data processing method:

[0356] 1) Inhibition rate (%): The raw data (665 nm / 620 nm reading ratio) were calculated using the following formula to obtain the inhibition rate: Inhibition rate (%) = [(average value of positive control wells – value of sample wells) / (average value of positive control wells – average value of negative control wells)] × 100, where positive control wells are reaction wells without compound or enzyme, and negative control wells are reaction wells without enzyme.

[0357] 2) Curve fitting: Use the log(inhibitor) vs. response--Variable slope (four parameters) function in GraphPad Prism 6 to perform fitting equation analysis on the compound concentration and the corresponding inhibition rate, fit the curve and obtain the compound IC 50 The fitting calculation equation is Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope)).

[0358] 5. Experimental results: IC values ​​of compounds for FGFR1-4 and FGFR2 V564F kinase activity 50 The values ​​are shown in the following table:

[0359] Table 1

[0360] 6. Experimental conclusion: The compounds of the present invention have a good inhibitory effect on the kinase activity of FGFR1-4 and FGFR2 V564F.

[0361] Note: The structures of compound A and compound B are shown below

[0362] 2. Cell Viability Assay

[0363] 1. Experimental purpose: To evaluate the inhibitory effect of the compound on NCI-H716, SNU-16 and BaF3-FGFR2-BICC1 V564F cells through cell proliferation inhibition assay.

[0364] 2. Experimental instruments and reagents:

[0365] 2.1 Instruments:

[0366] 2.2 Reagents:

[0367] 2.3 Cell Source

[0368] 3. Experimental Methods: The inhibitory effects of compounds on NCI-H716, SNU-16, and BaF3 FGFR2-BICC1 V564F cell proliferation were assessed using the CellTiter-Glo assay. The highest concentration tested was 1000 nM, with three-fold dilutions across nine concentrations (1000 nM to 0.15 nM). Cells were plated at appropriate density and compounds were added the following day. After incubation for 72 hours, the cells were assayed using the CellTiter-Glo Luminescence Detection Kit.

[0369] 4. Experimental data processing method:

[0370] 1) Inhibition rate (%): Inhibition rate (%) = [(average value of positive control wells - value of sample wells) / (average value of positive control wells - average value of negative control wells)] × 100, where the positive control wells are reaction wells without compound enzyme, and the negative control wells are reaction wells without enzyme.

[0371] 2) Curve fitting: Use the log(inhibitor) vs. response--Variable slope (four parameters) function in GraphPad Prism 6 to perform fitting equation analysis on the compound concentration and the corresponding inhibition rate, fit the curve and obtain the compound IC 50 The fitting calculation equation is Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)).

[0372] 5. Experimental results:

[0373] Table 2

[0374] 6. Experimental conclusion: The compounds of the present invention have a significant proliferation inhibitory effect on NCI-H716, SNU-16 and BaF3 FGFR2-BICC1 V564F cells.

[0375] 3. Pharmacokinetic Experiments

[0376] 1. Experimental purpose: SD rats were used as test animals to study the pharmacokinetic behavior of the compound of the present invention at a dose of 5 mg / kg orally in rats (plasma).

[0377] 2. Experimental Plan

[0378] 2.1 Test drug: Example of the present invention, homemade.

[0379] 2.2 Experimental animals: 3 male SD rats per group, Shanghai Jiesijie Experimental Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013-0006N0.311620400001794).

[0380] 2.3 Drug preparation: PO, 10% solutol HS15-0.5% CMC-Na, dissolve by ultrasonication, and prepare into a clear solution or homogeneous suspension.

[0381] 2.4 Dosage regimen: 3 male SD rats per group were fasted overnight and administered orally at a dose of 5 mg / kg in a volume of 10 mL / kg.

[0382] 2.5 Sample collection: After oral administration to rats, 0.2 mL of blood was collected from the jugular vein at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours, placed in an EDTA-K2 tube, and centrifuged at 6000 rpm for 6 min at 4°C to separate the plasma, which was then stored at -80°C.

[0383] 2.6 Sample processing:

[0384] 1) Add 100uL of acetonitrile to 20uL of plasma sample for precipitation, mix, and centrifuge at 3500×g for 5-20 minutes.

[0385] 2) The supernatant solution after treatment was subjected to LC / MS / MS analysis to determine the concentration of the test compound. The LC / MS / MS analysis instrument was AB Sciex API 4000Qtrap.

[0386] 2.7 Liquid phase analysis:

[0387] Liquid phase conditions: Shimadzu LC-20AD pump

[0388] ●Chromatographic column: Waters Xbridge C18 5μm, 4.6X 50mm Mobile phase: Liquid A is 0.1% formic acid in water, Liquid B is methanol Flow rate: 1.0mL / min

[0389] Elution time: 0-4.0 minutes, eluent is as follows:

[0390] 2.8 Experimental results and data processing:

[0391] Table 3 Pharmacokinetic parameters

[0392] Experimental conclusion: From the results of the SD rat pharmacokinetic experiment in the table, it can be seen that the example compounds of the present invention exhibit good metabolic properties, with good exposure AUC and maximum blood concentration Cmax.

[0393] 4. In vivo pharmacodynamic study of the compound in a subcutaneous transplanted tumor model of nude mice with the mouse primary B cell line Ba / F3 FGFR2-BICC-V564F

[0394] 1.1 Experimental purpose: To evaluate the in vivo efficacy of the compound in the subcutaneous transplanted tumor model of nude mice bearing the mouse primary B cell line Ba / F3 FGFR2-BICC-V564F.

[0395] 1.2 Experimental instruments and reagents

[0396] 1.2.1 Instruments

[0397] 1. Refrigerator (BCD-268TN, Haier)

[0398] 2. Biological Safety Cabinet (BSC-1300II A2, Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory)

[0399] 3. Clean bench (CJ-2F, Suzhou Fengshi Experimental Animal Equipment Co., Ltd.)

[0400] 4. Electronic pipette assistant (Easypet 3, Eppendorf)

[0401] 5. Constant temperature water bath (HWS-12, Shanghai Yiheng Science) 6. CO2 incubator (Thermo-311, Thermo)

[0402] 7. Centrifuge (Centrifuge 5720R, Eppendorf)

[0403] 8. Automated cell counter (Countess II, Life Technologies)

[0404] 9. Vernier caliper (CD-6" AX, Mitutoyo, Japan) 10. Cell culture flask (T25 / T75 / T225, Corning)

[0405] 11. Electronic balance (CPA2202S, Sartorius)

[0406] 12. Electronic balance (BSA2202S-CW, Sartorius)

[0407] 13. Ultrasonic cleaner (115F0032, Shanghai Kedao) 14. Water purifier (Pacific TII, Thermo)

[0408] 15. Magnetic stirrer (08-2G, Chijiu)

[0409] 1.2.2 Reagents

[0410] 1. RPMI-1640 medium (22400-089, Gibco)

[0411] 2. Fetal bovine serum (FBS) (10099-141C, Gibco)

[0412] 3. Phosphate buffered saline (PBS) (10010-023, Gibco)

[0413] 4. Kolliphor HS15 (42966-1KG, Sigma-Aldrich)

[0414] 5. Sodium carboxymethyl cellulose (30036365, Sinopharm Reagent)

[0415] 1.3 Experimental operation and data processing

[0416] 1.3.1 Animals: BALB / c nude mice, 6-8 weeks old, purchased from the Experimental Animal Management Department of Shanghai Institute of Family Planning Science.

[0417] 1.3.2 Cell culture and cell suspension preparation

[0418] a. Retrieve a strain of Ba / F3 FGFR2-BICC-V564F cells from the cell bank and resuscitate them in RPMI-1640 medium (RPMI-1640 + 10% FBS). Place the resuscitated cells in a cell culture flask (label the flask with the cell type, date, and culturer's name) and culture in a CO2 incubator (37°C, 5% CO2).

[0419] b. Subculture the cells every three days and continue to culture them in a CO2 incubator. Repeat this process until the cell count meets the in vivo efficacy requirement.

[0420] c. Collect cells in the exponential growth phase, count them using an automatic cell counter, and resuspend them in PBS to 3×10 7 cells / mL and placed in an ice box until use.

[0421] 1.3.3 Cell seeding

[0422] a, Nude mice were marked with disposable ear tags for both mice and rats before inoculation.

[0423] b. Mix the cell suspension thoroughly during inoculation, draw out 0.1-1 mL of cell suspension with a 1 mL syringe, remove any bubbles, and place the syringe on an ice pack until ready to use.

[0424] c. Secure the nude mouse with your left hand and disinfect the right side of the nude mouse's back near the right shoulder (inoculation site) with a 75% alcohol cotton ball. Start inoculation 30 seconds later.

[0425] d. The experimental nude mice were inoculated sequentially (0.1 mL of cell suspension per mouse).

[0426] 1.3.4 Tumor measurement, grouping, and drug administration in tumor-bearing mice

[0427] a, Tumors were measured and their sizes were calculated on days 10-14 after inoculation, depending on tumor growth.

[0428] Tumor volume calculation: Tumor volume (mm 3 ) = length (mm) × width (mm) × width (mm) / 2

[0429] b, Tumor-bearing mice were randomly divided into groups according to their weight and tumor size;

[0430] c. According to the grouping results, the test drug was started to be administered (administration method: oral administration; administration volume: 10 mL / kg; administration frequency: once / day; administration cycle: 14 days; solvent: 10% Solutol HS15 / 0.5% CMC-Na).

[0431] d, Tumors were measured and weighed twice a week after the start of the test drug administration.

[0432] e, Animals were euthanized after the experiment.

[0433] f. Data were processed using Excel or other software. Calculation of compound tumor inhibition rate (TGI) (%): If tumors did not regress, TGI (%) = [1 - (average tumor volume at the end of dosing in a given treatment group - average tumor volume at the start of dosing in that treatment group) / (average tumor volume at the end of treatment in the solvent control group - average tumor volume at the start of treatment in the solvent control group)] × 100%. If tumors regressed, TGI (%) = [1 - (average tumor volume at the end of dosing in a given treatment group - average tumor volume at the start of dosing in that treatment group) / average tumor volume at the start of dosing in that treatment group] × 100%.

[0434] 1.4 Experimental conclusion: The compounds of the present invention have excellent tumor inhibition effects and good safety.

[0435] 3. Study on salt forms and their crystal forms

[0436] 1.1 Experimental Instruments

[0437] 1.1.1 Some parameters of physical and chemical testing instruments

[0438] 1.2 Instruments and liquid phase analysis conditions

[0439] 1.2.1 Instruments and Equipment

[0440] 1.2.2 Chromatographic conditions

[0441] Chromatographic column: ZOBAX Bonus RP (4.6*150mm, 3.5μm)

[0442] Flow rate: 1.0 mL / min Column temperature: 35°C

[0443] Detection wavelength: 220 nm Injection volume: 5 μL

[0444] Run time: 15 min Diluent: DMSO

[0445] Mobile phase: A: water (0.05% TFA); B: acetonitrile (0.05% TFA)

[0446] 1. Preparation of different crystal forms of the compound of Example 1

[0447] 1.1 Preparation of Form I

[0448] Method (1): The compound of Example 1 was passed through a column, and then rotary evaporated or freeze-dried to obtain an amorphous solid. 20 mg of the free base amorphous solid was weighed, 100 μL of ethyl acetate (or any one of MTBE, acetone, and acetonitrile) was added, and the mixture was slurried at room temperature for 2 weeks, centrifuged, and vacuum-dried at 40°C to obtain a solid. The obtained solid was detected by XRPD to be Form I, with the XRPD pattern shown in Figure 1, the DSC pattern shown in Figure 2, the TGA pattern shown in Figure 3, and the IR pattern shown in Figure 4.

[0449] Method (2): Weigh 0.5 g of the free base amorphous solid, add 7.5 mL of DMSO, heat to 50°C, cool to room temperature, add 2.5 mL of water, stir at room temperature for 16 hours, filter, and obtain Form I with a yield of 63%.

[0450] Method (3): Weigh 0.1 g of the free base amorphous solid, add 5 mL of DMF, heat to 50°C, cool to room temperature, add 3 mL of water, stir at room temperature for 16 hours, and filter to obtain Form I with a yield of 82%.

[0451] Method (4): Weigh 0.5 g of the free base amorphous solid, add 1.5 mL of acetic acid, heat to 75°C, add 7.5 mL of methanol, cool to room temperature, add 7.5 mL of ethyl acetate, stir at room temperature for 16 hours, filter, and obtain Form I with a yield of 75%.

[0452] Method (5): Weigh 500 mg of the free base amorphous solid, add 20 mL of dioxane, slurry at room temperature for 2 days, filter, and heat the sample at 150°C for 5 minutes to obtain Form I.

[0453] 1.2 Preparation of Form II: Weigh 20 mg of the free base amorphous solid, add 100 μL of methanol (or ethanol or isopropanol), slurry at room temperature for 2 weeks, centrifuge, and vacuum dry at 40°C to obtain a solid. The obtained solid was confirmed to be Form II by XRPD analysis, with the XRPD pattern shown in Figure 5, the DSC pattern shown in Figure 6, and the TGA pattern shown in Figure 7.

[0454] 1.3 Preparation of Form III: Weigh 20 mg of free base Form II solid and heat to 100° C. for 2 h. The resulting solid was confirmed to be Form III by XRPD analysis, which has the XRPD pattern shown in FIG8 .

[0455] 1.4 Preparation of Form IV: Weigh 20 mg of the free base amorphous form (or any crystalline form) and add 0.4 mL of methanol-dichloromethane (1:4) to dissolve the mixture in a 40°C water bath. Filter. Add 2 mL of MTBE under magnetic stirring at room temperature to precipitate a solid. Immediately centrifuge and dry under vacuum at 40°C to obtain a solid. XRPD analysis of the resulting solid indicates Form IV, as shown in Figure 9.

[0456] 1.5 Preparation of Form V: Weigh 20 mg of the free base amorphous form (or any crystalline form), add 0.5 mL of N-methylpyrrolidone, dissolve in a 40°C water bath, and filter. Add 2 mL of isopropanol. After overnight, a solid precipitates. Centrifuge and dry under vacuum at 40°C to obtain a solid. XRPD analysis of the resulting solid indicates Form V, which has the XRPD pattern shown in Figure 10.

[0457] 1.6 Preparation of Form VI: 50 mg of the free base amorphous solid was weighed into a glass vial, and 2 ml of 1,4-dioxane was added. The mixture was stirred at room temperature for 48 hours and filtered to obtain a solid. XRPD analysis of the resulting solid confirmed Form VI, as shown in Figure 11, the DSC pattern in Figure 12, and the TGA pattern in Figure 13.

[0458] 1.7 Preparation of Form VII: Weigh 10 mg of Form VI sample and dry it in a vacuum drying oven at 60°C for 12 h to convert it into Form VII, which has an XRPD pattern as shown in Figure 14, a DSC pattern as shown in Figure 15, and a TGA pattern as shown in Figure 16.

[0459] 1.8 Preparation of Form VIII: Weigh 250 mg of the free base amorphous solid into a round-bottom flask, add 8.75 ml of a mixture of dichloromethane and ethanol (3:1), stir at room temperature until dissolved, slowly add 5 ml of MTBE dropwise, and continue stirring until crystallization occurs. Filter to obtain a solid. XRPD analysis of the resulting solid indicates Form VIII, as shown in Figure 17, the DSC pattern in Figure 18, and the TGA pattern in Figure 19.

[0460] 2. Polymorph screening

[0461] 2.1 Beating method - room temperature: Weigh 10 mg of free base amorphous, add 100 μL of different solvents, and beat at room temperature for 2 weeks as follows:

[0462] 2.2 Polycrystalline Screening - Antisolvent Method: Weigh 20 mg of free base amorphous form, add a good solvent, and sonicate to dissolve. Filter, add antisolvent, and when solid precipitates, immediately centrifuge, dry in a vacuum at 40°C, and characterize. The specific steps are as follows:

[0463] 3. Solid Stability Test

[0464] 3.1 Experimental purpose: To investigate the physicochemical stability of Form I at high temperature (60°C), room temperature (RH = 92.5%), and 50°C (RH = 75%) for 10, 20, and 30 days.

[0465] 3.2 Experimental plan: Approximately 1 mg of Form I was placed in an oven at 60°C, room temperature, high humidity (RH = 92.5%), and 50°C, RH = 75%, for 10, 20, and 30 days. The changes in related substances were calculated using the chromatographic peak area normalization method.

[0466] 3.3 Experimental results: Physicochemical stability of Form I under different conditions:

[0467] Table 4

[0468] From the stability data, it can be seen that Form I is relatively stable under high temperature, high humidity, high temperature and high humidity, and light conditions, with no significant increase in impurities, and can well meet the requirements of later long-term storage and formulation process.

[0469] 4. Hygroscopicity test

[0470] 4.1 Experimental purpose: To investigate the hygroscopicity of compound Form I under different relative humidity conditions.

[0471] 4.2 Experimental Plan: Compound Form I was placed in saturated water vapor at different relative humidity levels to allow the form to reach dynamic equilibrium with the water vapor, and the percentage of weight gain of the form due to moisture absorption after equilibrium was calculated.

[0472] 4.3 Experimental Results: Form I absorbed moisture at 80% relative humidity and gained approximately 1.84% weight, indicating slight hygroscopicity. After two cycles of moisture absorption and desorption at 0-95% relative humidity, the XRPD spectrum of Form I exhibited an additional peak, indicating that no crystal form transformation occurred.

[0473] 5. Study on Crystalline IPK

[0474] 6.1 Experimental Objectives: To study the pharmacokinetic behavior of Form I in rats (plasma) after a single oral administration of different formulations using SD rats as test animals and compare the differences in exposure; to study the pharmacokinetics of Form I after a single intravenous administration and calculate the bioavailability of different formulations after oral administration.

[0475] 6.2 Experimental Plan: Form I was prepared into suspensions using an aqueous solution containing 0.5% HPMC K4M and an aqueous solution containing 1.0% SDS. Both suspensions were administered orally to rats, with three rats per group receiving a 30 mg / kg dose. Form I was then dissolved in a solution containing 5% DMSO, 10% Solutol, and 85% PBS. After membrane filtration, the filtrate was used as an intravenous formulation for animal administration and administered intravenously to rats, with three rats receiving a 2 mg / kg dose.

[0476] 6.3 Experimental Results and Conclusions: The oral bioavailability of the 1.0% SDS aqueous suspension of Form I is higher than 30%, meeting the requirements for drugability.

Claims

1. A crystalline form of a compound represented by general formula (I) or a stereoisomer thereof, in: R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, aldehyde, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1- 6-deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Alkylcarbonyl, aminocarbonyl, 3-12 membered cycloalkyl-carbonyl, 3-12 membered heterocyclyl-carbonyl, preferably, R1 is selected from deuterium, halogen, amino, hydroxyl, cyano, aldehyde, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Alkylcarbonyl, aminocarbonyl, 3-6 membered cycloalkyl-carbonyl, 3-6 membered heterocyclyl-carbonyl; R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl or C 1-6 Alkylamino; R3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, C 1-6 Alkylamino or C 3-12 Cycloalkyl; R4 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkoxy or C 3-12 Cycloalkyl; preferably selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkoxy or C 3-6 Cycloalkyl; R5 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkoxy or C 3-12 Cycloalkyl; preferably selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkoxy or C 3-6 Cycloalkyl; R6 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy.

2. The crystalline form of the compound or its stereoisomer according to claim 1, characterized in that: The compound is shown below: (S)-1-(3-(7-acetyl-4-amino-3-(pyrazolo[1,5-a]pyridin-6-ylideneynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one; (S)-1-(3-(4-amino-7-propionyl-3-(pyrazolo[1,5-a]pyridin-6-ylideneynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one; (S)-1-(3-(4-amino-7-(cyclopropanecarbonyl)-3-(pyrazolo[1,5-a]pyridin-6-ylideneynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one; (S)-1-(3-(7-acetyl-4-amino-3-((3-cyclopropylpyrazolo[1,5-a]pyridin-6-yl)alkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-alkyl)prop-2-en-1-one; (S)-1-(3-(7-acetyl-4-amino-3-((2-cyclopropylpyrazolo[1,5-a]pyridin-6-yl)alkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-alkyl)prop-2-en-1-one; (S)-1-(3-(4-amino-3-((3-chloropyrazolo[1,5-a]pyridin-6-yl)alkynyl)-7-isobutyl-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-alkyl)prop-2-en-1-one.

3. The crystalline form of the compound or its stereoisomer according to claim 1 or 2, characterized in that: The crystal form is a hydrate or anhydrate; when it is a hydrate, the number of water is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 2.

4. The compound according to any one of claims 1 to 3 or the crystalline form of its stereoisomer, characterized in that: It is a crystalline form I of (S)-1-(3-(7-acetyl-4-amino-3-(pyrazolo[1,5-a]pyridin-6-ylidenealkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one; The X-ray powder diffraction spectrum of Form I has a diffraction peak at 2θ of 9.0±0.2°; or a diffraction peak at 9.6±0.2°; or a diffraction peak at 11.7±0.2°; or a diffraction peak at 13.4±0.2°; or a diffraction peak at 14.9±0.2°; or a diffraction peak at 20.6±0.2°; or a diffraction peak at 21.9±0.2° ; or having a diffraction peak at 24.2±0.2°; or having a diffraction peak at 24.9±0.2°; or having a diffraction peak at 26.9±0.2°; preferably including any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 8-10 of the above diffraction peaks; more preferably including any 6, 7, 8, 9 or 10 thereof; Alternatively, it is Form II of (S)-1-(3-(7-acetyl-4-amino-3-(pyrazolo[1,5-a]pyridin-6-ylidenealkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one; The X-ray powder diffraction spectrum of Form II has a diffraction peak at 2θ of 5.3±0.2°; or a diffraction peak at 8.3±0.2°; or a diffraction peak at 10.6±0.2°; or a diffraction peak at 14.0±0.2°; or a diffraction peak at 16.0±0.2°; or a diffraction peak at 16.6±0.2°; or a diffraction peak at 19.2±0.2° ; or having a diffraction peak at 24.7±0.2°; or having a diffraction peak at 26.2±0.2°; or having a diffraction peak at 26.5±0.2°; preferably including any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 8-10 of the above diffraction peaks; more preferably including any 6, 7, 8, 9 or 10 thereof; Alternatively, it is Form III of (S)-1-(3-(7-acetyl-4-amino-3-(pyrazolo[1,5-a]pyridin-6-ylidenealkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one; The X-ray powder diffraction spectrum of Form III has a diffraction peak at 2θ of 5.9±0.2°; or a diffraction peak at 8.7±0.2°; or a diffraction peak at 11.5±0.2°; or a diffraction peak at 11.9±0.2°; or a diffraction peak at 13.4±0.2°; or a diffraction peak at 14.1±0.2°; or a diffraction peak at 14.6±0.2°. Peak; or a diffraction peak at 20.0±0.2°; or a diffraction peak at 24.4±0.2°; or a diffraction peak at 24.9±0.2°; preferably including any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 8-10 of the above diffraction peaks; more preferably including any 6, 7, 8, 9 or 10 thereof; Alternatively, it is Form IV of (S)-1-(3-(7-acetyl-4-amino-3-(pyrazolo[1,5-a]pyridin-6-ylidenealkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one; The X-ray powder diffraction spectrum of Form IV has a diffraction peak at 2θ of 5.2±0.2°; or a diffraction peak at 7.4±0.2°; or a diffraction peak at 10.5±0.2°; or a diffraction peak at 14.5±0.2°; or a diffraction peak at 14.9±0.2°; or a diffraction peak at 17.9±0.2°; or a diffraction peak at 19.5±0.2° ; or having a diffraction peak at 24.4±0.2°; or having a diffraction peak at 25.0±0.2°; or having a diffraction peak at 26.2±0.2°; preferably including any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 8-10 of the above diffraction peaks; more preferably including any 6, 7, 8, 9 or 10 thereof; Alternatively, it is Form V of (S)-1-(3-(7-acetyl-4-amino-3-(pyrazolo[1,5-a]pyridin-6-ylidenealkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one; The X-ray powder diffraction pattern of Form V has a diffraction peak at 2θ of 7.3±0.2°; or a diffraction peak at 8.1±0.2°; or a diffraction peak at 9.0±0.2°; or a diffraction peak at 9.6±0.2°; or a diffraction peak at 10.6±0.2°; or a diffraction peak at 11.6±0.2°; or a diffraction peak at 12.7±0.2°; Or having a diffraction peak at 13.4±0.2°; or having a diffraction peak at 14.2±0.2°; or having a diffraction peak at 26.2±0.2°; preferably including any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 8-10 of the above diffraction peaks; more preferably including any 6, 7, 8, 9 or 10 thereof; Alternatively, it is Form VI of (S)-1-(3-(7-acetyl-4-amino-3-(pyrazolo[1,5-a]pyridin-6-ylidenealkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one; The X-ray powder diffraction spectrum of Form VI has a diffraction peak at 2θ of 7.1±0.2°; or a diffraction peak at 8.5±0.2°; or a diffraction peak at 9.2±0.2°; or a diffraction peak at 9.6±0.2°; or a diffraction peak at 11.6±0.2°; or a diffraction peak at 14.7±0.2°; or a diffraction peak at 15.0±0.2°; or a diffraction peak at 16.7±0.2°; or a diffraction peak at 17.0±0.2°; or a diffraction peak at 17.4±0.2°; or a diffraction peak at 18.5±0.2°; or a diffraction peak at 22. 1±0.2° has a diffraction peak; or has a diffraction peak at 24.9±0.2°; or has a diffraction peak at 25.3±0.2°; or has a diffraction peak at 26.0±0.2°; or has a diffraction peak at 26.9±0.2°; preferably includes any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 8-10, or 10-12, or 12-14, or 14-16 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 thereof; or it is Form VII of (S)-1-(3-(7-acetyl-4-amino-3-(pyrazolo[1,5-a]pyridin-6-ylidenealkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one; The X-ray powder diffraction spectrum of Form VII has a diffraction peak at 2θ of 7.2±0.2°; or a diffraction peak at 8.6±0.2°; or a diffraction peak at 10.1±0.2°; or a diffraction peak at 10.7±0.2°; or a diffraction peak at 11.7±0.2°; or a diffraction peak at 14.4±0.2°; or a diffraction peak at 14.8±0.2°; or a diffraction peak at 16.7±0. 2° has a diffraction peak; or has a diffraction peak at 17.5±0.2°; or has a diffraction peak at 18.5±0.2°; or has a diffraction peak at 25.3±0.2°; preferably includes any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 8-11 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, 10 or 11 thereof; or it is Form VIII of (S)-1-(3-(7-acetyl-4-amino-3-(pyrazolo[1,5-a]pyridin-6-ylidenealkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one; The X-ray powder diffraction spectrum of Form VIII has a diffraction peak at 2θ of 5.3±0.2°; or a diffraction peak at 8.1±0.2°; or a diffraction peak at 8.3±0.2°; or a diffraction peak at 10.6±0.2°; or a diffraction peak at 13.4±0.2°; or a diffraction peak at 14.1±0.2°; or a diffraction peak at 14.8±0.2°; or a diffraction peak at 15.4±0.2°; or a diffraction peak at 16.0 The invention relates to a method for preparing the diffraction peaks of the present invention. The method comprises: first, a diffraction peak at 14.5±0.2°, second, a diffraction peak at 24.5±0.2°, third, a diffraction peak at 25.1±0.2°, fourth, a diffraction peak at 25.1±0.2°, fifth, a diffraction peak at 30.1±0.2°, fifth, a diffraction peak at 19.5±0.2°, fifth, a diffraction peak at 24.5±0.2°, fifth, a diffraction peak at 25.1±0.2°, and fifth, a diffraction peak at 25.1±0.2°. The method comprises: first, a diffraction peak at 14.5±0.2°, third, a diffraction peak at 24.5±0.2°, fourth, a diffraction peak at 25.1±0.2°, fifth, a diffraction peak at 30.1±0.2°, fifth, a diffraction peak at 25.1±0.2°, and fifth, a diffraction peak at 30.1±0.2°. The method comprises: first, a diffraction peak at 14.5±0.2°, third, a diffraction peak at 24.5±0.2°, fourth, a diffraction peak at 25.1±0.2°, fifth, a diffraction peak at 25.1±0.2°, fifth, a diffraction peak at 30 ...

5. The crystalline form of the compound or its stereoisomer according to claim 4, characterized in that: The X-ray powder diffraction pattern of Form I comprises at least one or more diffraction peaks located at 2θ of 13.4±0.2°, 14.9±0.2°, and 24.9±0.2°, preferably 2 of them, and more preferably 3 of them; optionally, it may further comprise at least one of 2θ of 9.0±0.2°, 9.6±0.2°, 11.7±0.2°, 21.9±0.2°, and 24.2±0.2°, preferably 2, 3, 4 or 5 of them; More preferably, the X-ray powder diffraction pattern of Form I optionally further comprises one or more diffraction peaks located at 2θ of 12.7±0.2°, 17.6±0.2°, 20.6±0.2°, 24.0±0.2°, and 26.9±0.2°; preferably, at least any 2-3, or 4-5 of them; further preferably, any 2, 3, 4, or 5 of them are included; Further preferably, the X-ray powder diffraction pattern of Form I comprises one or more diffraction peaks located at 2θ of 8.2±0.2°, 9.9±0.2°, 13.6±0.2°, 15.5±0.2°, 16.7±0.2°, 18.0±0.2°, 19.3±0.2°, and 19.9±0.2°; preferably, it comprises diffraction peaks at 4, 5, 6, or 8 of them; For example, the X-ray powder diffraction pattern of the crystalline form I has diffraction peaks at the following positions at 2θ: 9.0±0.2°、9.6±0.2°、11.7±0.2°、14.9±0.2°、24.9±0.2°； 9.0±0.2°、11.7±0.2°、13.4±0.2°、21.9±0.2°、24.9±0.2°； 9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、24.2±0.2°； 11.7±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.9±0.2°； 11.7±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°； 9.6±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°； 9.6±0.2°、11.7±0.2°、14.9±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°； 9.6±0.2°、11.7±0.2°、13.4±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°； 9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、24.2±0.2°、24.9±0.2°； 9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.9±0.2°； 9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.2±0.2°； 9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°； 9.0±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°； 9.0±0.2°、9.6±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、14.9±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、24.2±0.2°、24.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.2±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°； 9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、14.9±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.2±0.2°、26.9±0.2°； 9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、20.6±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、20.6±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、13.4±0.2°、14.9±0.2°、20.6±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、14.9±0.2°、20.6±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、20.6±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、20.6±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、20.6±0.2°、21.9±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、20.6±0.2°、21.9±0.2°、24.2±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、20.6±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°； 9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、17.6±0.2°、20.6±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、17.6±0.2°、20.6±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、13.4±0.2°、14.9±0.2°、17.6±0.2°、20.6±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、14.9±0.2°、17.6±0.2°、20.6±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、17.6±0.2°、20.6±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、20.6±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、17.6±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、17.6±0.2°、20.6±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、17.6±0.2°、20.6±0.2°、21.9±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、17.6±0.2°、20.6±0.2°、21.9±0.2°、24.2±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、17.6±0.2°、20.6±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°； 9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、17.6±0.2°、20.6±0.2°、21.9±0.2°、24.0±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、17.6±0.2°、20.6±0.2°、21.9±0.2°、24.0±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、13.4±0.2°、14.9±0.2°、17.6±0.2°、20.6±0.2°、21.9±0.2°、24.0±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、14.9±0.2°、17.6±0.2°、20.6±0.2°、21.9±0.2°、24.0±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、17.6±0.2°、20.6±0.2°、21.9±0.2°、24.0±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、20.6±0.2°、21.9±0.2°、24.0±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、17.6±0.2°、21.9±0.2°、24.0±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、17.6±0.2°、20.6±0.2°、24.0±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、17.6±0.2°、20.6±0.2°、21.9±0.2°、24.2±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、17.6±0.2°、20.6±0.2°、21.9±0.2°、24.0±0.2°、24.9±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、17.6±0.2°、20.6±0.2°、21.9±0.2°、24.0±0.2°、24.2±0.2°、26.9±0.2°； 9.0±0.2°、9.6±0.2°、11.7±0.2°、13.4±0.2°、14.9±0.2°、17.6±0.2°、20.6±0.2°、21.9±0.2°、24.0±0.2°、24.2±0.2°、24.9±0.2°； Most preferably, the X-ray powder diffraction pattern of Form I is substantially as shown in FIG1 , the DSC pattern is as shown in FIG2 , the TGA pattern is as shown in FIG3 , and the IR pattern is as shown in FIG4 ; The X-ray powder diffraction pattern of Form II contains at least one or more diffraction peaks located at 2θ of 5.3±0.2°, 10.6±0.2°, and 24.7±0.2°, preferably 2 of them, and more preferably 3 of them; optionally, it may further contain at least one of 2θ of 8.3±0.2°, 16.0±0.2°, 16.6±0.2°, 26.2±0.2°, and 26.5±0.2°, preferably 2, 3, 4 or 5 of them; More preferably, the X-ray powder diffraction pattern of Form II optionally further comprises one or more diffraction peaks located at 2θ of 14.0±0.2°, 14.5±0.2°, 19.2±0.2°, 21.6±0.2°, and 25.6±0.2°; preferably, at least any 2-3, or 4-5 of them; further preferably, any 2, 3, 4, or 5 of them; Further preferably, the X-ray powder diffraction pattern of Form II comprises one or more diffraction peaks located at 2θ of 5.3±0.2°, 8.3±0.2°, 10.6±0.2°, 14.0±0.2°, 16.0±0.2°, 16.6±0.2°, 19.2±0.2°, 24.7±0.2°, 26.2±0.2°, and 26.5±0.2°; preferably, there are diffraction peaks at 4, 5, 6, 8 or 10 selected therefrom; For example, the X-ray powder diffraction pattern of the crystalline form II has diffraction peaks at the following positions at 2θ: 5.3±0.2°、8.3±0.2°、10.6±0.2°、16.6±0.2°、24.7±0.2°； 5.3±0.2°、10.6±0.2°、16.0±0.2°、21.6±0.2°、24.7±0.2°； 5.3±0.2°、10.6±0.2°、14.5±0.2°、24.7±0.2°、26.2±0.2°； 5.3±0.2°、8.3±0.2°、10.6±0.2°、16.0±0.2°、24.7±0.2°、26.2±0.2°； 5.3±0.2°、8.3±0.2°、10.6±0.2°、16.0±0.2°、16.6±0.2°、26.5±0.2°； 5.3±0.2°、10.6±0.2°、16.0±0.2°、24.7±0.2°、26.2±0.2°、26.5±0.2°； 5.3±0.2°、8.3±0.2°、10.6±0.2°、16.0±0.2°、16.6±0.2°、24.7±0.2°、26.2±0.2°、26.5±0.2°； 5.3±0.2°、8.3±0.2°、10.6±0.2°、14.0±0.2°、16.0±0.2°、16.6±0.2°、25.6±0.2°、26.5±0.2°； 5.3±0.2°、10.6±0.2°、14.5±0.2°、16.0±0.2°、21.6±0.2°、24.7±0.2°、26.2±0.2°、26.5±0.2°； 5.3±0.2°、8.3±0.2°、10.6±0.2°、14.0±0.2°、16.0±0.2°、16.6±0.2°、19.2±0.2°、24.7±0.2°、26.2±0.2°、26.5±0.2°； 5.3±0.2°、8.3±0.2°、10.6±0.2°、14.0±0.2°、16.0±0.2°、16.6±0.2°、19.2±0.2°、21.6±0.2°、24.7±0.2°、26.5±0.2°； 5.3±0.2°、8.3±0.2°、10.6±0.2°、14.0±0.2°、14.5±0.2°、16.0±0.2°、16.6±0.2°、24.7±0.2°、26.2±0.2°、26.5±0.2°； Most preferably, the X-ray powder diffraction pattern of Form II is substantially as shown in FIG5 , the DSC pattern is as shown in FIG6 , and the TGA pattern is as shown in FIG7 ; The X-ray powder diffraction pattern of Form III contains at least one or more diffraction peaks located at 2θ of 5.9±0.2°, 11.5±0.2°, and 11.9±0.2°, preferably 2 of them, and more preferably 3 of them; optionally, it may further contain at least one of 2θ of 8.7±0.2°, 13.4±0.2°, 14.6±0.2°, 20.0±0.2°, and 24.4±0.2°, preferably 2, 3, 4 or 5 of them; More preferably, the X-ray powder diffraction pattern of Form III optionally further comprises one or more diffraction peaks located at 2θ of 8.0±0.2°, 9.7±0.2°, 14.1±0.2°, 24.9±0.2°, and 26.3±0.2°; preferably, at least any 2-3, or 4-5 of them; further preferably, any 2, 3, 4, or 5 of them are included; Further preferably, the X-ray powder diffraction pattern of Form III comprises one or more diffraction peaks located at 2θ of 5.9±0.2°, 8.7±0.2°, 11.5±0.2°, 11.9±0.2°, 13.4±0.2°, 14.1±0.2°, 14.6±0.2°, 20.0±0.2°, 24.4±0.2°, and 24.9±0.2°; preferably, there are diffraction peaks at 4, 5, 6, 8 or 10 selected therefrom; For example, the X-ray powder diffraction pattern of the crystalline form III has diffraction peaks at the following positions at 2θ: 5.9±0.2°、11.5±0.2°、11.9±0.2°、13.4±0.2°、14.6±0.2°； 5.9±0.2°、8.7±0.2°、11.5±0.2°、11.9±0.2°、20.0±0.2°； 5.9±0.2°、11.5±0.2°、11.9±0.2°、20.0±0.2°、24.4±0.2°； 5.9±0.2°、8.7±0.2°、11.5±0.2°、11.9±0.2°、13.4±0.2°、14.6±0.2°； 5.9±0.2°、11.5±0.2°、11.9±0.2°、14.6±0.2°、20.0±0.2°、24.4±0.2°； 5.9±0.2°、8.7±0.2°、11.5±0.2°、11.9±0.2°、14.6±0.2°、20.0±0.2°； 5.9±0.2°、8.7±0.2°、11.5±0.2°、11.9±0.2°、13.4±0.2°、14.6±0.2°、20.0±0.2°、24.4±0.2°； 5.9±0.2°、11.5±0.2°、11.9±0.2°、14.6±0.2°、20.0±0.2°、24.4±0.2°、24.9±0.2°、26.3±0.2°； 5.9±0.2°、8.0±0.2°、8.7±0.2°、11.5±0.2°、11.9±0.2°、14.1±0.2°、14.6±0.2°、20.0±0.2°； 5.9±0.2°、8.7±0.2°、11.5±0.2°、11.9±0.2°、13.4±0.2°、14.1±0.2°、14.6±0.2°、20.0±0.2°、24.4±0.2°、24.9±0.2°； 5.9±0.2°、8.7±0.2°、11.5±0.2°、11.9±0.2°、13.4±0.2°、14.1±0.2°、14.6±0.2°、20.0±0.2°、24.4±0.2°、26.3±0.2°； 5.9±0.2°、8.7±0.2°、9.7±0.2°、11.5±0.2°、11.9±0.2°、13.4±0.2°、14.1±0.2°、20.0±0.2°、24.4±0.2°、24.9±0.2°； Most preferably, the X-ray powder diffraction pattern of Form III is substantially as shown in Figure 8; The X-ray powder diffraction pattern of Form IV comprises at least one or more diffraction peaks located at 2θ of 5.2±0.2°, 7.4±0.2°, and 10.5±0.2°, preferably 2 of them, and more preferably 3 of them; optionally, it may further comprise at least one of 2θ of 14.9±0.2°, 19.5±0.2°, 24.4±0.2°, 25.0±0.2°, and 26.2±0.2°, preferably 2, 3, 4 or 5 of them; More preferably, the X-ray powder diffraction pattern of Form IV optionally further comprises one or more diffraction peaks located at 2θ of 8.1±0.2°, 14.5±0.2°, and 17.9±0.2°; preferably, at least any 2-3 of them; further preferably, any 2 or 3 of them; Further preferably, the X-ray powder diffraction pattern of Form IV comprises one or more diffraction peaks located at 2θ of 5.2±0.2°, 7.4±0.2°, 10.5±0.2°, 14.5±0.2°, 14.9±0.2°, 17.9±0.2°, 19.5±0.2°, 24.4±0.2°, 25.0±0.2°, and 26.2±0.2°; preferably, there are diffraction peaks at 4, 5, 6, 8 or 10 of them; For example, the X-ray powder diffraction pattern of the crystalline form IV has diffraction peaks at the following positions at 2θ: 5.2±0.2°、7.4±0.2°、10.5±0.2°、14.9±0.2°、19.5±0.2°； 5.2±0.2°、7.4±0.2°、10.5±0.2°、19.5±0.2°、24.4±0.2°； 5.2±0.2°、7.4±0.2°、10.5±0.2°、24.4±0.2°、26.2±0.2°； 5.2±0.2°、7.4±0.2°、10.5±0.2°、14.9±0.2°、19.5±0.2°、24.4±0.2°； 5.2±0.2°、7.4±0.2°、10.5±0.2°、19.5±0.2°、24.4±0.2°、25.0±0.2°； 5.2±0.2°、7.4±0.2°、10.5±0.2°、24.4±0.2°、25.0±0.2°、26.2±0.2°； 5.2±0.2°、7.4±0.2°、10.5±0.2°、14.9±0.2°、19.5±0.2°、24.4±0.2°、25.0±0.2°、26.2±0.2°； 5.2±0.2°、7.4±0.2°、8.1±0.2°、10.5±0.2°、19.5±0.2°、24.4±0.2°、25.0±0.2°、26.2±0.2°； 5.2±0.2°、7.4±0.2°、10.5±0.2°、14.9±0.2°、17.9±0.2°、19.5±0.2°、25.0±0.2°、26.2±0.2°； 5.2±0.2°、7.4±0.2°、10.5±0.2°、14.5±0.2°、14.9±0.2°、17.9±0.2°、19.5±0.2°、24.4±0.2°、25.0±0.2°、26.2±0.2°； 5.2±0.2°、7.4±0.2°、8.1±0.2°、10.5±0.2°、14.9±0.2°、17.9±0.2°、19.5±0.2°、24.4±0.2°、25.0±0.2°、26.2±0.2°； 5.2±0.2°、7.4±0.2°、8.1±0.2°、10.5±0.2°、14.5±0.2°、14.9±0.2°、19.5±0.2°、24.4±0.2°、25.0±0.2°、26.2±0.2°； Most preferably, the X-ray powder diffraction pattern of Form IV is substantially as shown in Figure 9; The X-ray powder diffraction pattern of Form V comprises at least one or more diffraction peaks located at 2θ of 9.0±0.2°, 10.6±0.2°, and 14.2±0.2°, preferably 2 of them, and more preferably 3 of them; optionally, it may further comprise at least one of 2θ of 7.3±0.2°, 8.1±0.2°, 11.6±0.2°, 12.7±0.2°, and 13.4±0.2°, preferably 2, 3, 4 or 5 of them; More preferably, the X-ray powder diffraction pattern of Form V optionally further comprises one or more diffraction peaks located at 2θ of 9.6±0.2°, 25.0±0.2°, and 26.2±0.2°; preferably comprises at least any 2-3 of them; further preferably, comprises Any 2 or 3 locations; Further preferably, the X-ray powder diffraction pattern of Form V comprises one or more diffraction peaks located at 2θ of 7.3±0.2°, 8.1±0.2°, 9.0±0.2°, 9.6±0.2°, 10.6±0.2°, 11.6±0.2°, 12.7±0.2°, 13.4±0.2°, 14.2±0.2°, and 26.2±0.2°; preferably, there are diffraction peaks at 4, 5, 6, 8 or 10 of them; For example, the X-ray powder diffraction pattern of the crystalline form V has diffraction peaks at the following positions at 2θ: 7.3±0.2°、8.1±0.2°、9.0±0.2°、10.6±0.2°、14.2±0.2°； 9.0±0.2°、10.6±0.2°、11.6±0.2°、12.7±0.2°、14.2±0.2°； 9.0±0.2°、10.6±0.2°、12.7±0.2°、13.4±0.2°、14.2±0.2°； 7.3±0.2°、8.1±0.2°、9.0±0.2°、10.6±0.2°、11.6±0.2°、14.2±0.2°； 8.1±0.2°、9.0±0.2°、10.6±0.2°、11.6±0.2°、12.7±0.2°、14.2±0.2°； 9.0±0.2°、10.6±0.2°、11.6±0.2°、12.7±0.2°、13.4±0.2°、14.2±0.2°； 7.3±0.2°、8.1±0.2°、9.0±0.2°、10.6±0.2°、11.6±0.2°、12.7±0.2°、13.4±0.2°、14.2±0.2°； 7.3±0.2°、8.1±0.2°、9.0±0.2°、10.6±0.2°、11.6±0.2°、12.7±0.2°、13.4±0.2°、25.0±0.2°； 7.3±0.2°、8.1±0.2°、9.0±0.2°、10.6±0.2°、11.6±0.2°、12.7±0.2°、14.2±0.2°、26.2±0.2°； 7.3±0.2°、8.1±0.2°、9.0±0.2°、9.6±0.2°、10.6±0.2°、11.6±0.2°、12.7±0.2°、13.4±0.2°、14.2±0.2°、26.2±0.2°； 7.3±0.2°、8.1±0.2°、9.0±0.2°、9.6±0.2°、10.6±0.2°、12.7±0.2°、13.4±0.2°、14.2±0.2°、25.0±0.2°、26.2±0.2°； 7.3±0.2°、8.1±0.2°、9.0±0.2°、9.6±0.2°、10.6±0.2°、11.6±0.2°、12.7±0.2°、14.2±0.2°、25.0±0.2°、26.2±0.2°； Most preferably, the X-ray powder diffraction pattern of Form V is substantially as shown in Figure 10; The X-ray powder diffraction spectrum of Form VI is substantially as shown in FIG11 , the DSC spectrum is shown in FIG12 , and the TGA spectrum is shown in FIG13 ; The X-ray powder diffraction pattern of Form VII is substantially as shown in FIG14 , the DSC pattern is shown in FIG15 , and the TGA pattern is shown in FIG16 ; The X-ray powder diffraction spectrum of Form VII is substantially as shown in FIG. 17 , the DSC spectrum is as shown in FIG. 18 , and the TGA spectrum is as shown in FIG. 19 .

6. The compound according to any one of claims 1 to 5 or a crystalline form of its stereoisomer, characterized in that: The 2θ errors of the top ten diffraction peak positions with relative peak intensity in the X-ray powder diffraction patterns of Form I, Form II, Form III, Form IV, Form V, Form VI, Form VII and Form VIII of (S)-1-(3-(7-acetyl-4-amino-3-(pyrazolo[1,5-a]pyridin-6-ylidenealkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one and the diffraction peaks at the corresponding positions in Figures 1, 5, 8, 9, 10, 11, 14 and 17, respectively, are ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°.

7. A method for preparing a crystalline form of the compound or its stereoisomer according to any one of claims 3 to 6, characterized in that: It is method one, two or three; Method 1: dissolving the compound in a poor solvent, stirring or beating to obtain the corresponding crystal form; Method 2: heating the crystal form to obtain the corresponding crystal form; Method 3: dissolving the compound or crystal form in a positive solvent, adding an anti-solvent and stirring until a solid precipitates or cooling and crystallizing to obtain the corresponding crystal form; The poor solvent is selected from one or more of acetone, ethyl acetate, isopropyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone or 3-pentanone, methyl tert-butyl ether or water; preferably one or more of acetone, acetonitrile or toluene; The positive solvent is selected from one or more of dimethyl sulfoxide, acetic acid, methanol, acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone, 3-pentanone or N-methylpyrrolidone; The anti-solvent is selected from one or more of alcohol solvents, heptane, cyclohexane, n-hexane, n-pentane, water, ethyl acetate, methyl tert-butyl ether, toluene or isopropyl ether; preferably one or more of methanol, ethyl acetate, water, heptane, methyl tert-butyl ether or isopropyl ether.

8. The preparation method according to claim 7, characterized in that: The preparation of the crystal form I comprises the following steps: dissolving the compound in solvent A, and beating to obtain the corresponding crystal form I; Alternatively, the preparation of Form I comprises the following steps: mixing the compound with solvent J, and then mixing with solvent K to obtain the corresponding Form I; The preparation of the crystal form II comprises the following steps: dissolving the compound in solvent B, and beating to obtain the corresponding crystal form II; Alternatively, the preparation of Form II comprises the following steps: mixing the compound with a solvent L, and then mixing with a solvent M to obtain the corresponding Form II; The preparation of the crystal form III comprises the following steps: heating the crystal form II to obtain the corresponding crystal form II; The preparation of Form IV comprises the following steps: mixing the compound or the form with solvent C, and then mixing with solvent D to obtain the corresponding Form IV; The preparation of Form V comprises the following steps: mixing the compound or the form with solvent E, and then mixing with solvent F to obtain the corresponding Form V; The preparation of Form VI comprises the following steps: dissolving the compound in solvent G and stirring to obtain the corresponding Form VI; The preparation of Form VII comprises the following steps: heating the Form VI to obtain the corresponding Form VII; The preparation of the crystal form VIII comprises the following steps: mixing the compound with a solvent H, and then mixing with a solvent I to obtain the corresponding crystal form VIII; Wherein, the solvent A is preferably DMSO, ethyl acetate, dichloromethane, isopropyl acetate, methyl tert-butyl ether, MTBE, acetone, tetrahydrofuran, toluene, 2-butanone, 2-methyl-tetrahydrofuran, water or acetonitrile; Solvent B is preferably an alcohol solvent, more preferably methanol, ethanol or isopropanol; The solvent C is preferably a mixed solvent of an alcohol solvent and a halogenated alkane solvent (1:5), more preferably a mixed solution of methanol and dichloromethane (1:5) or a mixed solution of ethanol and dichloromethane (1:5); the solvent D is preferably an ether solvent, more preferably MTBE; Solvent E is preferably an amide solvent, more preferably N-methylpyrrolidone or 1,4-dioxane; Solvent F is preferably an alcohol solvent, preferably isopropanol; Solvent G is preferably an ether solvent, more preferably 1,4-dioxane; The heating temperature is preferably 50 to 70°C; The solvent H is preferably a mixed solvent of a halogenated alkane solvent and an alcohol solvent (3:1), preferably a mixed solution of dichloromethane and ethanol (3:1); the solvent I is preferably an ether solvent, more preferably MTBE; The solvent J is preferably DMSO, acetic acid or DMF, the solvent K is preferably one or more of an alcohol solvent, water, acetone, ethyl acetate, acetonitrile, toluene, methyl tert-butyl ether, and n-heptane, and the solvent K is preferably one or more of methanol, ethyl acetate, water, heptane, methyl tert-butyl ether or isopropyl ether; the solvent J is preferably NMP or 1,4-dioxane, the solvent K is preferably an ether solvent, more preferably methyl tert-butyl ether and isopropyl ether; the solvent J is preferably a mixed solvent of an alcohol solvent and a halogenated alkane solvent (1:5), preferably methanol: dichloromethane (1:5) or ethanol: dichloromethane (1:5), and the solvent K is preferably n-heptane, isopropyl ether, and n-hexane; The solvent L is preferably DMSO, and the solvent M is preferably an alcohol solvent, preferably isopropanol, methanol, or ethanol.

9. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 6 or a crystalline form of its stereoisomer, and one or more pharmaceutically acceptable carriers or excipients.

10. Use of the compound according to any one of claims 1 to 6 or the crystalline form of its stereoisomer, or the pharmaceutical composition according to claim 9, in the preparation of drugs for treating and / or preventing FGFR-related diseases, in particular in the preparation of drugs for treating and / or preventing FGFR1-4-related diseases.

11. Use of the compound according to any one of claims 1 to 6 or the crystalline form of its stereoisomer, and the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating and / or preventing cancer and diseases related to achondroplasia; preferably, the cancer is selected from colorectal cancer, bladder cancer, gastric cancer, thyroid cancer, esophageal cancer, head and neck cancer, brain cancer, glioma, glioblastoma, hepatocellular carcinoma, lung cancer, melanoma, myeloma, pancreatic cancer, renal cell carcinoma, cervical cancer, urothelial carcinoma, prostate cancer, ovarian cancer, breast cancer, leukemia or lymphoma.

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