Salt containing acrylketone biological inhibitor, salt crystal form, and preparation method and application thereof

Abstract

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

Description

[0001] This application claims the priority of Chinese patent application No. 202310937311X filed on July 27, 2023. This application cites the entire text of the above Chinese patent application. Technical Field

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

[0003] FGFR (Fibroblast Growth Factor Receptor) is a tyrosine kinase, including four subtypes: FGFR1, FGFR2, FGFR3, and FGFR4. When FGFR binds to the ligand, FGFR dimerizes and autophosphorylates, thereby activating downstream signaling pathways: RAS-RAF-MAPK, PI3K-AKT, STAT, and PLCγ. FGFR-mediated signal transduction plays an important 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 many cancers. In a study published in Clinical Cancer Research (Clin Cancer Res; 22(1) January 1, 2016) in 2015, sequencing of 4853 solid tumors of various types showed that FGFR aberrations were present in approximately 7.1% of cancers. 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 cholangiocarcinomas, FGFR2 point mutations are present in approximately 10% of endometrial carcinomas, and FGFR2b amplifications are present in approximately 10% of gastric cancers. FGFR3 point mutations are present in approximately 20% of metastatic urothelial carcinomas.

[0005] As a drug, FGFR inhibitors have good application prospects in the pharmaceutical industry. They are expected to become the first-line treatment for cholangiocarcinoma and a new choice for targeted cancer therapy regardless of cancer type. They are expected to be used for cancer patients with various FGFR aberrations. However, the current standard treatment for cholangiocarcinoma is chemotherapy, which has a poor prognosis and no second-line treatment. The main problems with FGFR inhibitors are that patients develop drug resistance about 7 months after taking the drug, and drugs related to the FGFR1 target have hyperphosphatemia toxicity.

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

[0007] Patent PCT / CN2023 / 073557 discloses a series of biological inhibitors containing propylene ketones. In subsequent research and development, in order to facilitate the handling, filtration and drying of the products, suitable crystals that are easy to store, have long-term stability and high bioavailability are sought. The present invention has conducted a comprehensive study on the salts of the above-mentioned compounds and their crystal forms. Summary of the invention

[0008] All contents involved in patent PCT / CN2023 / 073557 are added to the present invention by reference.

[0009] The object of the present invention is to provide a compound represented by general formula (I) or an acid salt of its stereoisomer, and a crystalline form of the salt thereof.

[0010]

[0011] in:

[0012] R 1 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 Haloalkoxy, C 1-6 Alkylcarbonyl, aminocarbonyl, 3-12 membered cycloalkyl-carbonyl, 3-12 membered heterocyclyl-carbonyl, preferably, R 1 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 Haloalkoxy, C1-3 Alkylcarbonyl, aminocarbonyl, 3-6 membered cycloalkyl-carbonyl, 3-6 membered heterocyclyl-carbonyl;

[0013] R 2 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, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl or C 1-6 Alkylamino;

[0014] R 3 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, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, C 1-6 Alkylamino or C 3-12 Cycloalkyl;

[0015] R 4 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, C1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkoxy or C 3-6 Cycloalkyl;

[0016] R 5 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;

[0017] R 6 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;

[0018] The acid in the acid salt is an inorganic acid or an organic acid; preferably, the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid; the organic acid is selected from 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, ethanesulfonic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dimethicone, 1,2-dimethoxy- ... Benzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, p-toluenesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid or L-malic acid; preferably hydrochloric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid or benzenesulfonic acid.

[0019] In certain embodiments of the present invention, the compound is as follows:

[0020] (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;

[0021] (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;

[0022] (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;

[0023] (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;

[0024] (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;

[0025] (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.

[0026] In certain embodiments of the present invention, the number of acids in the acid salt is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 0.5, 1, 2 or 3, and further preferably 1.

[0027] In certain embodiments of the present invention, the acid salt is a hydrate or an anhydrate; when the acid salt 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;

[0028] The crystal form is a hydrate crystal form or anhydrous crystal form; when the crystal form is a hydrate, the number of water is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3.

[0029] In certain embodiments of the present invention, the acid salt of the compound or its stereoisomer is (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 hydrochloride, hydrobromide, methanesulfonate, p-toluenesulfonate or benzenesulfonate.

[0030] The present invention also provides a hydrochloride salt form, a hydrobromide salt form, a methanesulfonate salt form, a p-toluenesulfonate salt form or a benzenesulfonate salt 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)pyrrolidine-1-methyl)prop-2-en-1-one.

[0031] In certain embodiments of the present invention, the hydrochloride salt 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 hydrochloride salt form A;

[0032] The X-ray powder diffraction spectrum of Form A has a diffraction peak at 2θ of 8.0±0.2°; or a diffraction peak at 11.3±0.2°; or a diffraction peak at 11.8±0.2°; or a diffraction peak at 14.3±0.2°; or a diffraction peak at 14.6±0.2°; or a diffraction peak at 17.5±0.2°; or a diffraction peak at 19.1±0.2° ; or having a diffraction peak at 21.2±0.2°; or having a diffraction peak at 22.7±0.2°; or having a diffraction peak at 26.1±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;

[0033] Preferably, the X-ray powder diffraction pattern of Form A contains at least one or more diffraction peaks located at 2θ of 8.0±0.2°, 11.8±0.2°, and 14.3±0.2°, preferably 2 of them, and more preferably 3 of them; optionally, it may further contain at least one of 2θ of 11.3±0.2°, 14.6±0.2°, 17.5±0.2°, 21.2±0.2°, and 22.7±0.2°, preferably 2, 3, 4 or 5 of them;

[0034] More preferably, the X-ray powder diffraction pattern of Form A optionally further comprises one or more diffraction peaks located at 2θ of 15.9±0.2°, 19.1±0.2°, 24.0±0.2°, 26.1±0.2°, 27.4±0.2°, 28.7±0.2°, 30.0±0.2°; preferably at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, or 7 thereof;

[0035] Further preferably, the X-ray powder diffraction pattern of Form A comprises one or more diffraction peaks located at 2θ of 8.0±0.2°, 11.3±0.2°, 11.8±0.2°, 14.3±0.2°, 14.6±0.2°, 17.5±0.2°, 19.1±0.2°, 21.2±0.2°, 22.7±0.2°, and 26.1±0.2°; preferably, there are diffraction peaks at 4, 5, 6, 8, or 10 of them;

[0036] For example, the X-ray powder diffraction pattern of the crystalline form A has diffraction peaks at the following positions at 2θ:

[0037] 8.0±0.2°, 11.8±0.2°;

[0038] 8.0±0.2°、14.3±0.2°；

[0039] 8.0±0.2°、11.8±0.2°、14.3±0.2°；

[0040] 8.0±0.2°、11.8±0.2°、11.3±0.2°；

[0041] 8.0±0.2°、14.3±0.2°、14.6±0.2°；

[0042] 8.0±0.2°、11.8±0.2°、17.5±0.2°；

[0043] 8.0±0.2°、14.3±0.2°、21.2±0.2°；

[0044] 8.0±0.2°、11.8±0.2°、14.3±0.2°、11.3±0.2°；

[0045] 8.0±0.2°、11.8±0.2°、14.3±0.2°、14.6±0.2°；

[0046] 8.0±0.2°、11.8±0.2°、14.3±0.2°、11.3±0.2°、14.6±0.2°；

[0047] 8.0±0.2°、11.8±0.2°、14.3±0.2°、17.5±0.2°、21.2±0.2°；

[0048] 8.0±0.2°、11.8±0.2°、14.3±0.2°、11.3±0.2°、15.9±0.2°；

[0049] 8.0±0.2°、11.8±0.2°、14.3±0.2°、14.6±0.2°、19.1±0.2°、24.0±0.2°；

[0050] 8.0±0.2°、11.8±0.2°、14.3±0.2°、11.3±0.2°、14.6±0.2°、26.1±0.2°；

[0051] 8.0±0.2°、11.8±0.2°、14.3±0.2°、17.5±0.2°、21.2±0.2°、27.4±0.2°；

[0052] 8.0±0.2°, 11.3±0.2°, 11.8±0.2°, 14.3±0.2°, 14.6±0.2°, 17.5±0.2°, 21.2±0.2°, 22.7±0.2°;

[0053] 8.0±0.2°, 11.8±0.2°, 14.3±0.2°, 15.9±0.2°, 17.5±0.2°, 21.2±0.2°, 24.0±0.2°, 26.1±0.2°;

[0054] 8.0±0.2°, 11.8±0.2°, 14.3±0.2°, 11.3±0.2°, 15.9±0.2°, 19.1±0.2°, 28.7±0.2°, 30.0±0.2°;

[0055] 8.0±0.2°, 11.3±0.2°, 11.8±0.2°, 14.3±0.2°, 14.6±0.2°, 17.5±0.2°, 19.1±0.2°, 21.2±0.2°, 22.7±0.2°, 26.1±0.2°;

[0056] 8.0±0.2°, 11.3±0.2°, 11.8±0.2°, 14.3±0.2°, 14.6±0.2°, 15.9±0.2°, 17.5±0.2°, 19.1±0.2°, 21.2±0.2°, 22.7±0.2°;

[0057] 8.0±0.2°, 11.3±0.2°, 11.8±0.2°, 14.3±0.2°, 14.6±0.2°, 17.5±0.2°, 21.2±0.2°, 22.7±0.2°, 24.0±0.2°, 26.1±0.2°.

[0058] In certain embodiments of the present invention, Cu-Kα radiation is used, and the characteristic X-ray diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are shown in Table 1.

[0059] Table 1

[0060]

[0061]

[0062] In certain embodiments of the present invention, the hydrochloride crystal form A has an X-ray powder diffraction pattern substantially as follows Figure 1 Its DSC spectrum is shown as Figure 2 shown.

[0063] In certain embodiments of the present invention, the hydrochloride salt 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 hydrochloride salt form B;

[0064] The X-ray powder diffraction spectrum of Form B has a diffraction peak at 2θ of 4.4±0.2°; or a diffraction peak at 8.8±0.2°; or a diffraction peak at 10.5±0.2°; or a diffraction peak at 11.4±0.2°; or a diffraction peak at 13.2±0.2°; or a diffraction peak at 14.2±0.2°; or a diffraction peak at 20.1±0.2° ; or having a diffraction peak at 23.1±0.2°; or having a diffraction peak at 26.5±0.2°; or having a diffraction peak at 27.5±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;

[0065] Preferably, the X-ray powder diffraction pattern of Form B contains at least one or more diffraction peaks located at 2θ of 4.4±0.2°, 10.5±0.2°, and 13.2±0.2°, preferably 2 of them, and more preferably 3 of them; optionally, it may further contain at least one of 2θ of 8.8±0.2°, 11.4±0.2°, 20.1±0.2°, 23.1±0.2°, and 26.5±0.2°, preferably 2, 3, 4 or 5 of them;

[0066] More preferably, the X-ray powder diffraction pattern of Form B optionally further comprises one or more diffraction peaks located at 2θ of 14.2±0.2°, 15.0±0.2°, 17.7±0.2°, 21.1±0.2°, and 27.5±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;

[0067] Further preferably, the X-ray powder diffraction pattern of Form B comprises one or more diffraction peaks located at 2θ of 4.4±0.2°, 8.8±0.2°, 10.5±0.2°, 11.4±0.2°, 13.2±0.2°, 14.2±0.2°, 20.1±0.2°, 23.1±0.2°, 26.5±0.2°, 27.5±0.2; preferably, there are diffraction peaks at 4, 5, 6, 8 or 10 selected from them;

[0068] For example, the X-ray powder diffraction pattern of the crystalline form B has diffraction peaks at the following positions at 2θ:

[0069] 4.4±0.2°, 10.5±0.2°;

[0070] 4.4±0.2°, 13.2±0.2°;

[0071] 4.4±0.2°, 10.5±0.2°, 13.2±0.2°;

[0072] 4.4±0.2°, 10.5±0.2°, 8.8±0.2°;

[0073] 4.4±0.2°, 13.2±0.2°, 20.1±0.2°;

[0074] 4.4±0.2°, 10.5±0.2°, 13.2±0.2°;

[0075] 4.4±0.2°, 10.5±0.2°, 13.2±0.2°, 8.8±0.2°;

[0076] 4.4±0.2°, 10.5±0.2°, 13.2±0.2°, 20.1±0.2°;

[0077] 4.4±0.2°, 10.5±0.2°, 13.2±0.2°, 26.5±0.2°;

[0078] 4.4±0.2°, 10.5±0.2°, 13.2±0.2°, 8.8±0.2°, 15.0±0.2°;

[0079] 4.4±0.2°, 10.5±0.2°, 13.2±0.2°, 20.1±0.2°, 17.7±0.2°;

[0080] 4.4±0.2°, 10.5±0.2°, 13.2±0.2°, 26.5±0.2°, 21.1±0.2°;

[0081] 4.4±0.2°, 10.5±0.2°, 13.2±0.2°, 8.8±0.2°, 14.2±0.2°, 15.0±0.2°;

[0082] 4.4±0.2°, 10.5±0.2°, 13.2±0.2°, 20.1±0.2°, 15.0±0.2°, 17.7±0.2°;

[0083] 4.4±0.2°, 10.5±0.2°, 13.2±0.2°, 26.5±0.2°, 21.1±0.2°, 27.5±0.2°;

[0084] 4.4±0.2°, 10.5±0.2°, 13.2±0.2°, 8.8±0.2°, 11.4±0.2°, 20.1±0.2°, 23.1±0.2°, 26.5±0.2°;

[0085] 4.4±0.2°, 10.5±0.2°, 11.4±0.2°, 13.2±0.2°, 14.2±0.2°, 20.1±0.2°, 15.0±0.2°, 17.7±0.2°;

[0086] 4.4±0.2°, 8.8±0.2°, 10.5±0.2°, 13.2±0.2°, 15.0±0.2°, 26.5±0.2°, 21.1±0.2°, 27.5±0.2°;

[0087] 4.4±0.2°, 8.8±0.2°, 10.5±0.2°, 11.4±0.2°, 13.2±0.2°, 14.2±0.2°, 20.1±0.2°, 15.0±0.2°, 17.7±0.2°, 27.5±0.2;

[0088] 4.4±0.2°, 8.8±0.2°, 10.5±0.2°, 13.2±0.2°, 15.0±0.2°, 17.7±0.2°, 26.5±0.2°, 21.1±0.2°, 26.5±0.2°, 27.5±0.2°;

[0089] 4.4±0.2°, 8.8±0.2°, 10.5±0.2°, 11.4±0.2°, 13.2±0.2°, 14.2±0.2°, 20.1±0.2°, 23.1±0.2°, 26.5±0.2°, 27.5±0.2.

[0090] In certain embodiments of the present invention, Cu-Kα radiation is used, and the X-ray characteristic diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are shown in Table 2.

[0091] Table 2

[0092]

[0093]

[0094] In certain embodiments of the present invention, the hydrochloride crystal form B has an X-ray powder diffraction pattern substantially as follows Figure 3Its DSC-TGA spectrum is shown in Figure 4 shown.

[0095] In certain embodiments of the present invention, the hydrobromide salt 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 hydrobromide salt form A;

[0096] The X-ray powder diffraction spectrum of Form A has a diffraction peak at 2θ of 4.6±0.2°; or a diffraction peak at 10.1±0.2°; or a diffraction peak at 13.6±0.2°; or a diffraction peak at 14.1±0.2°; or a diffraction peak at 18.1±0.2°; or a diffraction peak at 22.7±0.2°; or a diffraction peak at 27.0±0.2° ; or having a diffraction peak at 27.3±0.2°; or having a diffraction peak at 31.3±0.2°; or having a diffraction peak at 32.0±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;

[0097] Preferably, the X-ray powder diffraction pattern of Form A contains at least one or more diffraction peaks located at 2θ of 4.6±0.2°, 13.6±0.2°, and 22.7±0.2°, preferably 2 of them, and more preferably 3 of them; optionally, it may further contain at least one of 2θ of 10.1±0.2°, 14.1±0.2°, 27.0±0.2°, 27.3±0.2°, and 31.3±0.2°, preferably 2, 3, 4 or 5 of them;

[0098] More preferably, the X-ray powder diffraction pattern of Form A optionally further comprises one or more diffraction peaks located at 2θ of 18.1±0.2°, 18.7±0.2°, 26.4±0.2°, 32.0±0.2°, 35.8±0.2°, 36.7±0.2°; preferably at least any 2-3, or 4-5, or 5-6 thereof; further preferably, any 2, 3, 4, 5, or 6 thereof;

[0099] Further preferably, the X-ray powder diffraction pattern of Form A comprises one or more diffraction peaks located at 2θ of 4.6±0.2°, 10.1±0.2°, 13.6±0.2°, 14.1±0.2°, 18.1±0.2°, 22.7±0.2°, 27.0±0.2°, 27.3±0.2°, 31.3±0.2°, and 32.0±0.2°; preferably, there are diffraction peaks at 4, 5, 6, 8 or 10 of them;

[0100] For example, the X-ray powder diffraction pattern of the crystalline form A has diffraction peaks at the following positions at 2θ:

[0101] 4.6±0.2°, 22.7±0.2°;

[0102] 4.6±0.2°, 13.6±0.2°;

[0103] 4.6±0.2°, 13.6±0.2°, 22.7±0.2°;

[0104] 4.6±0.2°, 10.1±0.2°, 22.7±0.2°;

[0105] 4.6±0.2°, 13.6±0.2°, 27.0±0.2°;

[0106] 4.6±0.2°, 13.6±0.2°, 22.7±0.2°, 27.3±0.2°;

[0107] 4.6±0.2°, 13.6±0.2°, 22.7±0.2°, 27.0±0.2°;

[0108] 4.6±0.2°, 10.1±0.2°, 14.1±0.2°, 22.7±0.2°;

[0109] 4.6±0.2°, 13.6±0.2°, 22.7±0.2°, 18.7±0.2°;

[0110] 4.6±0.2°, 10.1±0.2°, 18.1±0.2°, 22.7±0.2°, 26.4±0.2°;

[0111] 4.6±0.2°, 13.6±0.2°, 22.7±0.2°, 27.0±0.2°, 35.8±0.2°;

[0112] 4.6±0.2°, 13.6±0.2°, 22.7±0.2°, 27.3±0.2°, 36.7±0.2°;

[0113] 4.6±0.2°, 13.6±0.2°, 22.7±0.2°, 18.1±0.2°, 18.7±0.2°, 26.4±0.2°;

[0114] 4.6±0.2°, 10.1±0.2°, 14.1±0.2°, 22.7±0.2°, 27.3±0.2°, 31.3±0.2°;

[0115] 4.6±0.2°, 13.6±0.2°, 14.1±0.2°, 18.1±0.2°, 18.7±0.2°, 27.0±0.2°;

[0116] 4.6±0.2°, 10.1±0.2°, 13.6±0.2°, 14.1±0.2°, 18.1±0.2°, 22.7±0.2°, 27.0±0.2°, 27.3±0.2°;

[0117] 4.6±0.2°, 10.1±0.2°, 18.1±0.2°, 22.7±0.2°, 27.0±0.2°, 27.3±0.2°, 31.3±0.2°, 32.0±0.2°;

[0118] 4.6±0.2°, 10.1±0.2°, 13.6±0.2°, 14.1±0.2°, 27.0±0.2°, 27.3±0.2°, 31.3±0.2°, 32.0±0.2°;

[0119] 4.6±0.2°, 10.1±0.2°, 13.6±0.2°, 14.1±0.2°, 18.1±0.2°, 22.7±0.2°, 27.0±0.2°, 27.3±0.2°, 31.3±0.2°, 32.0±0.2°;

[0120] 4.6±0.2°, 13.6±0.2°, 14.1±0.2°, 18.1±0.2°, 22.7±0.2°, 27.0±0.2°, 27.3±0.2°, 31.3±0.2°, 32.0±0.2°, 35.8±0.2°;

[0121] 4.6±0.2°, 10.1±0.2°, 13.6±0.2°, 18.1±0.2°, 18.7±0.2°, 22.7±0.2°, 27.0±0.2°, 27.3±0.2°, 31.3±0.2°, 32.0±0.2°.

[0122] In certain embodiments of the present invention, Cu-Kα radiation is used, and the characteristic X-ray diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are shown in Table 3.

[0123] Table 3

[0124]

[0125] In certain embodiments of the present invention, the hydrobromide salt form A has an X-ray powder diffraction pattern substantially as follows: Figure 5 Its DSC-TGA spectrum is shown in Figure 6 shown.

[0126] In certain embodiments of the present invention, the mesylate salt 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 mesylate salt form A;

[0127] The X-ray powder diffraction spectrum of Form A has a diffraction peak at 2θ of 5.4±0.2°; or a diffraction peak at 8.7±0.2°; or a diffraction peak at 10.8±0.2°; or a diffraction peak at 16.8±0.2°; or a diffraction peak at 17.4±0.2°; or a diffraction peak at 21.6±0.2°; or a diffraction peak at 23.3±0.2° ; or having a diffraction peak at 23.9±0.2°; or having a diffraction peak at 25.6±0.2°; or having a diffraction peak at 26.7±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;

[0128] Preferably, the X-ray powder diffraction pattern of Form A contains at least one or more diffraction peaks located at 2θ of 8.7±0.2°, 10.8±0.2°, and 17.4±0.2°, preferably 2 of them, and more preferably 3 of them; optionally, it may further contain at least one of 2θ of 5.4±0.2°, 16.8±0.2°, 21.6±0.2°, 25.6±0.2°, and 26.7±0.2°, preferably 2, 3, 4 or 5 of them;

[0129] More preferably, the X-ray powder diffraction pattern of Form A optionally further comprises one or more diffraction peaks located at 2θ of 9.0±0.2°, 15.5±0.2°, 17.9±0.2°, 18.3±0.2°, 19.5±0.2°, 22.8±0.2°, 23.3±0.2°, 23.9±0.2°; preferably at least any 2-3, or 4-5, or 6-7, or 8-9 thereof; further preferably, any 2, 3, 4, 5, 6, 7, 8, or 9 thereof;

[0130] Further preferably, the X-ray powder diffraction pattern of Form A comprises one or more diffraction peaks located at 2θ of 5.4±0.2°, 8.7±0.2°, 10.8±0.2°, 16.8±0.2°, 17.4±0.2°, 21.6±0.2°, 23.3±0.2°, 23.9±0.2°, 25.6±0.2°, and 26.7±0.2°; preferably, there are diffraction peaks at 4, 5, 6, 8 or 10 selected from them;

[0131] For example, the X-ray powder diffraction pattern of the crystalline form A has diffraction peaks at the following positions at 2θ:

[0132] 8.7±0.2°, 17.4±0.2°;

[0133] 10.8±0.2°, 17.4±0.2°;

[0134] 8.7±0.2°, 10.8±0.2°, 17.4±0.2°

[0135] 5.4±0.2°, 8.7±0.2°, 17.4±0.2°;

[0136] 10.8±0.2°, 17.4±0.2°, 21.6±0.2°;

[0137] 5.4±0.2°, 16.8±0.2°, 8.7±0.2°, 17.4±0.2°;

[0138] 10.8±0.2°, 17.4±0.2°, 21.6±0.2°, 25.6±0.2°;

[0139] 8.7±0.2°, 10.8±0.2°, 17.4±0.2°, 26.7±0.2°;

[0140] 10.8±0.2°, 17.4±0.2°, 21.6±0.2°, 9.0±0.2°, 15.5±0.2°;

[0141] 5.4±0.2°、16.8±0.2°、8.7±0.2°、17.4±0.2°、17.9±0.2°；

[0142] 10.8±0.2°、17.4±0.2°、19.5±0.2°、21.6±0.2°、25.6±0.2°；

[0143] 8.7±0.2°、10.8±0.2°、17.4±0.2°、26.7±0.2°、23.9±0.2°；

[0144] 8.7±0.2°、10.8±0.2°、17.4±0.2°、21.6±0.2°、25.6±0.2°、26.7±0.2°；

[0145] 8.7±0.2°、17.4±0.2°、5.4±0.2°、16.8±0.2°、21.6±0.2°、25.6±0.2°；

[0146] 10.8±0.2°、17.4±0.2°、16.8±0.2°、21.6±0.2°、25.6±0.2°、26.7±0.2°；

[0147] 8.7±0.2°、10.8±0.2°、17.4±0.2°、16.8±0.2°、21.6±0.2°、25.6±0.2°；

[0148] 5.4±0.2°、8.7±0.2°、10.8±0.2°、16.8±0.2°、17.4±0.2°、16.8±0.2°、21.6±0.2°、25.6±0.2°；

[0149] 10.8±0.2°、16.8±0.2°、17.4±0.2°、21.6±0.2°、23.3±0.2°、23.9±0.2°、25.6±0.2°、26.7±0.2°；

[0150] 5.4±0.2°、8.7±0.2°、10.8±0.2°、16.8±0.2°、17.4±0.2°、17.9±0.2°、21.6±0.2°、23.3±0.2°、23.9±0.2°、25.6±0.2°；

[0151] 5.4±0.2°、8.7±0.2°、10.8±0.2°、16.8±0.2°、17.4±0.2°、21.6±0.2°、23.3±0.2°、23.9±0.2°、25.6±0.2°、26.7±0.2°；

[0152] 5.4±0.2°, 8.7±0.2°, 9.0±0.2°, 10.8±0.2°, 16.8±0.2°, 17.4±0.2°, 16.8±0.2°, 21.6±0.2°, 23.9±0.2°, 25.6±0.2°;

[0153] 10.8±0.2°, 15.5±0.2°, 16.8±0.2°, 17.4±0.2°, 18.3±0.2°, 21.6±0.2°, 23.3±0.2°, 23.9±0.2°, 25.6±0.2°, 26.7±0.2°.

[0154] In certain embodiments of the present invention, Cu-Kα radiation is used, and the X-ray characteristic diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are shown in Table 4.

[0155] Table 4

[0156]

[0157]

[0158] In certain embodiments of the present invention, the mesylate salt form A has an X-ray powder diffraction pattern substantially as follows: Figure 7 Its DSC-TGA spectrum is shown in Figure 8 shown.

[0159] In certain embodiments of the present invention, the p-toluenesulfonate 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 p-toluenesulfonate crystalline form A;

[0160] The X-ray powder diffraction spectrum of Form A has a diffraction peak at 2θ of 4.7±0.2°; or a diffraction peak at 5.7±0.2°; or a diffraction peak at 6.6±0.2°; or a diffraction peak at 11.4±0.2°; or a diffraction peak at 13.2±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 17.0±0.2 ° has a diffraction peak; or has a diffraction peak at 18.2±0.2°; or has a diffraction peak at 19.6±0.2°; or has a diffraction peak at 21.0±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;

[0161] Preferably, the X-ray powder diffraction pattern of Form A contains at least one or more diffraction peaks located at 2θ of 4.7±0.2°, 5.7±0.2°, and 6.6±0.2°, preferably 2 of them, and more preferably 3 of them; optionally, it may further contain at least one of 2θ of 11.4±0.2°, 16.0±0.2°, 17.0±0.2°, 18.2±0.2°, and 19.6±0.2°, preferably 2, 3, 4 or 5 of them;

[0162] More preferably, the X-ray powder diffraction pattern of Form A optionally further comprises one or more diffraction peaks located at 2θ of 13.2±0.2°, 14.0±0.2°, and 21.0±0.2°; preferably, at least any 2-3 of them; further preferably, any 2 or 3 of them;

[0163] Further preferably, the X-ray powder diffraction pattern of Form A comprises one or more diffraction peaks located at 2θ of 4.7±0.2°, 5.7±0.2°, 6.6±0.2°, 11.4±0.2°, 13.2±0.2°, 16.0±0.2°, 17.0±0.2°, 18.2±0.2°, 19.6±0.2°, and 21.0±0.2°; preferably, there are diffraction peaks at 4, 5, 6, 8, or 10 of them;

[0164] For example, the X-ray powder diffraction pattern of the crystalline form A has diffraction peaks at the following positions at 2θ:

[0165] 4.7±0.2°, 5.7±0.2°;

[0166] 4.7±0.2°, 6.6±0.2°;

[0167] 4.7±0.2°、5.7±0.2°、6.6±0.2°；

[0168] 4.7±0.2°、5.7±0.2°、16.0±0.2°；

[0169] 4.7±0.2°、6.6±0.2°、18.2±0.2°；

[0170] 4.7±0.2°、5.7±0.2°、6.6±0.2°、11.4±0.2°；

[0171] 4.7±0.2°、5.7±0.2°、16.0±0.2°、18.2±0.2°；

[0172] 4.7±0.2°、5.7±0.2°、6.6±0.2°、14.0±0.2°；

[0173] 4.7±0.2°、5.7±0.2°、6.6±0.2°、11.4±0.2°、16.0±0.2°；

[0174] 4.7±0.2°、5.7±0.2°、16.0±0.2°、17.0±0.2°、18.2±0.2°；

[0175] 4.7±0.2°、6.6±0.2°、14.0±0.2°、18.2±0.2°、19.6±0.2°；

[0176] 4.7±0.2°、5.7±0.2°、6.6±0.2°、11.4±0.2°、16.0±0.2°、17.0±0.2°；

[0177] 4.7±0.2°、5.7±0.2°、6.6±0.2°、17.0±0.2°、18.2±0.2°、19.6±0.2°；

[0178] 4.7±0.2°、5.7±0.2°、6.6±0.2°、11.4±0.2°、16.0±0.2°、21.0±0.2°；

[0179] 4.7±0.2°、5.7±0.2°、6.6±0.2°、11.4±0.2°、16.0±0.2°、17.0±0.2°、18.2±0.2°、19.6±0.2°；

[0180] 4.7±0.2°、5.7±0.2°、6.6±0.2°、11.4±0.2°、13.2±0.2°、16.0±0.2°、17.0±0.2°、21.0±0.2°；

[0181] 4.7±0.2°, 5.7±0.2°, 6.6±0.2°, 11.4±0.2°, 17.0±0.2°, 18.2±0.2°, 19.6±0.2°, 21.0±0.2°;

[0182] 4.7±0.2°, 5.7±0.2°, 6.6±0.2°, 11.4±0.2°, 13.2±0.2°, 16.0±0.2°, 17.0±0.2°, 18.2±0.2°, 19.6±0.2°, 21.0±0.2°;

[0183] 4.7±0.2°, 5.7±0.2°, 6.6±0.2°, 11.4±0.2°, 13.2±0.2°, 14.0±0.2°, 16.0±0.2°, 17.0±0.2°, 18.2±0.2°, 19.6±0.2°;

[0184] 4.7±0.2°, 5.7±0.2°, 6.6±0.2°, 11.4±0.2°, 14.0±0.2°, 16.0±0.2°, 17.0±0.2°, 18.2±0.2°, 19.6±0.2°, 21.0±0.2°.

[0185] In certain embodiments of the present invention, Cu-Kα radiation is used, and the X-ray characteristic diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are shown in Table 5.

[0186] Table 5

[0187]

[0188] In certain embodiments of the present invention, the p-toluenesulfonate crystalline form A has an X-ray powder diffraction pattern substantially as follows: Fig. 9 shown.

[0189] In certain embodiments of the present invention, the p-toluenesulfonate 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 p-toluenesulfonate crystalline form B;

[0190] The X-ray powder diffraction pattern of Form B has a diffraction peak at 2θ of 5.7±0.2°; or a diffraction peak at 7.2±0.2°; or a diffraction peak at 8.5±0.2°; or a diffraction peak at 13.1±0.2°; or a diffraction peak at 16.4±0.2°; or a diffraction peak at 17.0±0.2°; or a diffraction peak at 18.2±0.2°; Or having a diffraction peak at 18.7±0.2°; or having a diffraction peak at 21.5±0.2°; or having a diffraction peak at 21.8±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;

[0191] Preferably, the X-ray powder diffraction pattern of Form B contains at least one or more diffraction peaks located at 2θ of 5.7±0.2°, 16.4±0.2°, and 17.0±0.2°, preferably 2 of them, and more preferably 3 of them; optionally, it may further contain at least one of 2θ of 7.2±0.2°, 8.5±0.2°, 13.1±0.2°, 18.2±0.2°, and 21.5±0.2°, preferably 2, 3, 4 or 5 of them;

[0192] More preferably, the X-ray powder diffraction pattern of Form B optionally further comprises one or more diffraction peaks located at 2θ of 18.7±0.2°, 21.8±0.2°, 22.5±0.2°, 22.7±0.2°, and 26.0±0.2°; preferably, at least any 2-3, or 4-5 of them; further preferably, any 2, 3, 4, or 5 of them;

[0193] Further preferably, the X-ray powder diffraction pattern of Form B comprises one or more diffraction peaks located at 2θ of 5.7±0.2°, 7.2±0.2°, 8.5±0.2°, 13.1±0.2°, 16.4±0.2°, 17.0±0.2°, 18.2±0.2°, 18.7±0.2°, 21.5±0.2°, and 21.8±0.2°; preferably, there are diffraction peaks at 4, 5, 6, 8 or 10 of them;

[0194] For example, the X-ray powder diffraction pattern of the crystalline form B has diffraction peaks at the following positions at 2θ:

[0195] 5.7±0.2°, 16.4±0.2°;

[0196] 5.7±0.2°, 17.0±0.2°;

[0197] 5.7±0.2°、16.4±0.2°、17.0±0.2°；

[0198] 5.7±0.2°、7.2±0.2°、16.4±0.2°；

[0199] 5.7±0.2°、8.5±0.2°、17.0±0.2°；

[0200] 5.7±0.2°、13.1±0.2°、16.4±0.2°、17.0±0.2°；

[0201] 5.7±0.2°、7.2±0.2°、16.4±0.2°、18.2±0.2°；

[0202] 5.7±0.2°、8.5±0.2°、17.0±0.2°、21.5±0.2°；

[0203] 5.7±0.2°、7.2±0.2°、8.5±0.2°、16.4±0.2°、17.0±0.2°；

[0204] 5.7±0.2°、13.1±0.2°、16.4±0.2°、17.0±0.2°、18.2±0.2°；

[0205] 5.7±0.2°、8.5±0.2°、16.4±0.2°、17.0±0.2°、21.5±0.2°；

[0206] 5.7±0.2°、7.2±0.2°、16.4±0.2°、17.0±0.2°、18.2±0.2°、21.5±0.2°；

[0207] 5.7±0.2°、7.2±0.2°、8.5±0.2°、13.1±0.2°、17.0±0.2°、21.5±0.2°；

[0208] 5.7±0.2°、7.2±0.2°、8.5±0.2°、13.1±0.2°、16.4±0.2°、18.2±0.2°；

[0209] 5.7±0.2°、16.4±0.2°、17.0±0.2°、7.2±0.2°、8.5±0.2°、13.1±0.2°、18.2±0.2°、21.5±0.2°；

[0210] 5.7±0.2°, 7.2±0.2°, 8.5±0.2°, 17.0±0.2°, 18.2±0.2°, 18.7±0.2°, 21.5±0.2°, 21.8±0.2°;

[0211] 5.7±0.2°, 7.2±0.2°, 8.5±0.2°, 13.1±0.2°, 16.4±0.2°, 18.7±0.2°, 21.5±0.2°, 21.8±0.2°;

[0212] 5.7±0.2°, 7.2±0.2°, 8.5±0.2°, 13.1±0.2°, 16.4±0.2°, 17.0±0.2°, 18.2±0.2°, 18.7±0.2°, 21.5±0.2°, 21.8±0.2°;

[0213] 5.7±0.2°, 7.2±0.2°, 8.5±0.2°, 13.1±0.2°, 16.4±0.2°, 17.0±0.2°, 18.2±0.2°, 18.7±0.2°, 21.8±0.2°, 22.7±0.2°;

[0214] 5.7±0.2°, 7.2±0.2°, 8.5±0.2°, 13.1±0.2°, 16.4±0.2°, 17.0±0.2°, 18.2±0.2°, 18.7±0.2°, 21.5±0.2°, 21.8±0.2°.

[0215] In certain embodiments of the present invention, Cu-Kα radiation is used, and the X-ray characteristic diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are shown in Table 6.

[0216] Table 6

[0217]

[0218] In certain embodiments of the present invention, the p-toluenesulfonate crystalline form B has an X-ray powder diffraction pattern substantially as follows: Fig.10 Its DSC-TGA spectrum is shown in Fig.11 shown.

[0219] In certain embodiments of the present invention, the benzenesulfonate 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 benzenesulfonate crystalline form A;

[0220] The X-ray powder diffraction spectrum of Form A has a diffraction peak at 2θ of 5.2±0.2°; or a diffraction peak at 6.9±0.2°; or a diffraction peak at 11.4±0.2°; or a diffraction peak at 16.9±0.2°; or a diffraction peak at 17.7±0.2°; or a diffraction peak at 18.0±0.2°; or a diffraction peak at 21.0±0.2° ; or having a diffraction peak at 22.8±0.2°; or having a diffraction peak at 24.1±0.2°; or having a diffraction peak at 25.9±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;

[0221] Preferably, the X-ray powder diffraction pattern of Form A contains at least one or more diffraction peaks located at 2θ of 5.2±0.2°, 11.4±0.2°, and 21.0±0.2°, preferably 2 of them, and more preferably 3 of them; optionally, it may further contain at least one of 2θ of 6.9±0.2°, 16.9±0.2°, 17.7±0.2°, 22.8±0.2°, and 24.1±0.2°, preferably 2, 3, 4 or 5 of them;

[0222] More preferably, the X-ray powder diffraction pattern of Form A optionally further comprises one or more diffraction peaks located at 2θ of 13.8±0.2°, 16.3±0.2°, 18.0±0.2°, 18.7±0.2°, 20.5±0.2°, 25.9±0.2°, 27.2±0.2°; preferably at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, or 7 thereof;

[0223] Further preferably, the X-ray powder diffraction pattern of Form A comprises one or more diffraction peaks located at 2θ of 5.2±0.2°, 6.9±0.2°, 11.4±0.2°, 16.9±0.2°, 17.7±0.2°, 18.0±0.2°, 21.0±0.2°, 22.8±0.2°, 24.1±0.2°, and 25.9±0.2°; preferably, there are diffraction peaks at 4, 5, 6, 8, or 10 of them;

[0224] For example, the X-ray powder diffraction pattern of the crystalline form A has diffraction peaks at the following positions at 2θ:

[0225] 11.4±0.2°, 21.0±0.2°;

[0226] 5.2±0.2°、11.4±0.2°；

[0227] 5.2±0.2°、11.4±0.2°、21.0±0.2°；

[0228] 11.4±0.2°、6.9±0.2°、21.0±0.2°；

[0229] 5.2±0.2°、11.4±0.2°、16.9±0.2°；

[0230] 11.4±0.2°、17.7±0.2°、22.8±0.2°、21.0±0.2°；

[0231] 5.2±0.2°、6.9±0.2°、11.4±0.2°、16.9±0.2°；

[0232] 5.2±0.2°、11.4±0.2°、21.0±0.2°、22.8±0.2°；

[0233] 5.2±0.2°、6.9±0.2°、11.4±0.2°、16.9±0.2°、21.0±0.2°；

[0234] 5.2±0.2°、11.4±0.2°、21.0±0.2°、22.8±0.2°、24.1±0.2°；

[0235] 5.2±0.2°、11.4±0.2°、16.9±0.2°、17.7±0.2°、24.1±0.2°；

[0236] 5.2±0.2°、11.4±0.2°、21.0±0.2°、6.9±0.2°、16.9±0.2°、17.7±0.2°；

[0237] 5.2±0.2°、11.4±0.2°、21.0±0.2°、17.7±0.2°、22.8±0.2°、24.1±0.2°；

[0238] 11.4±0.2°、21.0±0.2°、6.9±0.2°、17.7±0.2°、22.8±0.2°、24.1±0.2°；

[0239] 5.2±0.2°、6.9±0.2°、11.4±0.2°、16.9±0.2°、17.7±0.2°、18.0±0.2°、24.1±0.2°、25.9±0.2°；

[0240] 5.2±0.2°, 6.9±0.2°, 11.4±0.2°, 16.9±0.2°, 21.0±0.2°, 22.8±0.2°, 24.1±0.2°, 25.9±0.2°;

[0241] 5.2±0.2°, 6.9±0.2°, 11.4±0.2°, 17.7±0.2°, 18.0±0.2°, 21.0±0.2°, 22.8±0.2°, 24.1±0.2°;

[0242] 5.2±0.2°, 6.9±0.2°, 11.4±0.2°, 16.9±0.2°, 17.7±0.2°, 18.0±0.2°, 21.0±0.2°, 22.8±0.2°, 24.1±0.2°, 25.9±0.2°;

[0243] 5.2±0.2°, 6.9±0.2°, 11.4±0.2°, 13.8±0.2°, 17.7±0.2°, 18.0±0.2°, 21.0±0.2°, 22.8±0.2°, 24.1±0.2°, 25.9±0.2°;

[0244] 5.2±0.2°, 6.9±0.2°, 11.4±0.2°, 16.9±0.2°, 17.7±0.2°, 18.0±0.2°, 21.0±0.2°, 22.8±0.2°, 24.1±0.2°, 27.2±0.2°.

[0245] In certain embodiments of the present invention, Cu-Kα radiation is used, and the X-ray characteristic diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are shown in Table 7.

[0246] Table 7

[0247]

[0248]

[0249] In certain embodiments of the present invention, the benzenesulfonate crystalline form A has an X-ray powder diffraction pattern substantially as follows: Fig.12 Its DSC-TGA spectrum is shown in Fig.13 shown.

[0250] In certain embodiments of the present invention, the positions of the top ten diffraction peaks with the highest relative peak intensity in the X-ray powder diffraction patterns of the hydrochloride form A, the hydrochloride form B, the hydrobromide form A, the methanesulfonate form A, the p-toluenesulfonate form A, the p-toluenesulfonate form B, and the benzenesulfonate form A are respectively Figure 1 , Figure 3 , Figure 5 , Figure 7 , Fig. 9 , Fig.10 and Fig.12 The 2θ error of the diffraction peak at the corresponding position is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°.

[0251] The present invention also provides a method for preparing the above compound or the acid salt of its stereoisomer, characterized in that it is method one or method two;

[0252] Method 1 includes the following steps:

[0253] 1) dissolving the compound in an organic solvent;

[0254] 2) adding a counter ion acid; the amount of the counter ion acid is preferably 1.2 equivalents; the counter ion acid can be dissolved in an organic solvent;

[0255] 3) stirring and mixing to evaporate the solvent;

[0256] 4) separating and obtaining the acid salt;

[0257] Method 2 includes the following steps:

[0258] 1) suspending the compound in an organic solvent;

[0259] 2) adding a counter ion acid; the amount of the counter ion acid is preferably 1.2 equivalents; the counter ion acid can be dissolved in an organic solvent;

[0260] 3) Stir to dissolve, and continue stirring to precipitate;

[0261] 4) separating and obtaining the acid salt;

[0262] Wherein: the organic solvent is selected from methanol, ethanol, isopropanol, ethyl acetate, dichloromethane, acetone, toluene, chloroform, acetonitrile, carbon tetrachloride, ethylene dichloride, tetrahydrofuran, 2-butanone, 3-pentanone, isopropyl ether, 1,4-dioxane, tert-butanol, N,N-dimethylformamide, n-butanol, isobutanol, N,N-dimethylacetamide, n-propanol; preferably tetrahydrofuran, acetone or acetonitrile;

[0263] The counter ion acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, ethanesulfonic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulfuric acid, dibenzoyltartaric acid, ethane-1 , 2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactosonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, p-toluenesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid or L-malic acid; preferably hydrochloric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid or benzenesulfonic acid.

[0264] The present invention also provides a method for preparing a crystalline form of the acid salt of the above compound or its stereoisomer, characterized in that it comprises the following steps:

[0265] 1) The compound is suspended with a poor solvent;

[0266] 2) Weigh an appropriate amount of counter ion acid and dissolve it in an organic solvent; the amount of the counter ion acid is preferably 1.2 equivalents;

[0267] 3) Combine the above two solutions and stir to dissolve, continue stirring to precipitate or add a poor solvent dropwise and stir to precipitate;

[0268] 4) rapidly centrifuging or standing to dry to obtain the crystal form;

[0269] Wherein: 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;

[0270] The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol or N,N-dimethylformamide; preferably methanol, ethanol or acetonitrile; the above benign solvent and organic solution need to be miscible when used;

[0271] The counter ion acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, ethanesulfonic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulfuric acid, dibenzoyltartaric acid, ethane-1 , 2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactosonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, p-toluenesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid or L-malic acid; preferably hydrochloric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid or benzenesulfonic acid.

[0272] The present invention also provides a method for preparing a crystal form of the acid salt of the above compound or its stereoisomer, which comprises the following steps: dissolving the compound in a solvent, and then mixing with the acid solution to obtain a corresponding crystal form;

[0273] Wherein, the solvent is preferably methanol, ethanol, isopropanol, ethyl acetate, dichloromethane, acetone, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butanone, 3-pentanone, isopropyl ether, 1,4-dioxane, tert-butanol, N,N-dimethylformamide, n-butanol, isobutanol, N,N-dimethylacetamide, n-propanol; more preferably tetrahydrofuran, acetone or acetonitrile;

[0274] The solvent in the acid solution is preferably an alcohol solvent, more preferably methanol, ethanol or isopropanol.

[0275] The present invention also provides a pharmaceutical composition, which contains a therapeutically effective amount of the above-mentioned compound or an acid salt of its stereoisomer, a crystalline form of the acid salt of the above-mentioned compound or its stereoisomer, and one or more pharmaceutically acceptable carriers or excipients.

[0276] The present invention also provides an acid salt of the above-mentioned compound or its stereoisomer, a crystalline form of the acid salt of the above-mentioned compound or its stereoisomer, and use of the above-mentioned pharmaceutical composition in the preparation of drugs for treating and / or preventing FGFR-related diseases, in particular, use in the preparation of drugs for treating and / or preventing FGFR1-4-related diseases.

[0277] The present invention also provides an acid salt of the above-mentioned compound or its stereoisomer, a crystal form of the acid salt of the above-mentioned compound or its stereoisomer, and a 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.

[0278] The compounds of the present invention add non-hydrogen substituents at specific positions of the mother nucleus, which can greatly improve the enzyme activity of FGFR2V564F and the inhibitory activity of cell resistance mutations, thereby solving the problem that there is no drug to treat V564F resistance in currently marketed drugs.

[0279] Detailed description of the invention

[0280] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and 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, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0281] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0282] Figure 1 This is an XRPD diagram of hydrochloride form A.

[0283] Figure 2 This is a DSC diagram of hydrochloride form A.

[0284] Figure 3 This is an XRPD diagram of hydrochloride form B.

[0285] Figure 4 This is a DSC-TGA diagram of hydrochloride form B.

[0286] Figure 5 This is an XRPD diagram of hydrobromide salt form A.

[0287] Figure 6 This is a DSC-TGA diagram of hydrobromide form A.

[0288] Figure 7 This is an XRPD diagram of mesylate Form A.

[0289] Figure 8 This is a DSC-TGA diagram of mesylate form A.

[0290] Fig. 9 This is an XRPD diagram of p-toluenesulfonate Form A.

[0291] Fig.10 This is an XRPD diagram of p-toluenesulfonate Form B.

[0292] Fig.11 This is a DSC-TGA diagram of p-toluenesulfonate Form B.

[0293] Fig.12 This is an XRPD diagram of benzenesulfonate salt form A.

[0294] Fig.13 This is a DSC-TGA diagram of benzenesulfonate form A. DETAILED DESCRIPTION

[0295] The present invention is further described below with reference to examples, but these examples are not intended to limit the scope of the present invention.

[0296] 1. Preparation of Compounds

[0297] Example

[0298] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in parts per million (ppm). The NMR measurement is performed using a Bruker AVANCE-400 nuclear magnetic spectrometer, and the measurement solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), and the internal standard was tetramethylsilane (TMS).

[0299] Liquid chromatography-mass spectrometry (LC-M) was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed using 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).

[0300] 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.

[0301] The starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized by or according to methods known in the art.

[0302] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature is in degrees Celsius.

[0303] Intermediate 1

[0304] Tert-butyl-(S)-3-(4-amino-7-bromo-3-iodo-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate

[0305]

[0306] Step 1: Preparation of 2-amino-4-chloronicotinaldehyde

[0307]

[0308] Under nitrogen protection, tert-butyl 4-chloropyridine-2-carboxylate (30g, 131.19mmol) and N,N,N',N'-tetramethylethylenediamine (38.11g, 327.98mmol) were dissolved in THF (600mL), and n-butyl lithium n-hexane solution (2.5M, 131.19mL) was added dropwise at -78°C. After the addition was completed, the reaction was stirred for 2 hours. Then DMF (28.77g, 393.57mmol, 30.47mL) was added dropwise, and the reaction was continued for 1 hour. After the reaction was completed, saturated ammonium chloride solution (500mL) was added to quench the reaction, and the reaction solution was extracted with ethyl acetate (250mLx3), washed with saturated sodium chloride aqueous solution (250mLx3), and the organic phase was collected and dried over anhydrous sodium sulfate. After filtering, the organic solvent was concentrated under reduced pressure. Then, dioxane hydrochloride solution (4.0M, 50mL) was added to the concentrated product, and after stirring at room temperature for 1 hour, the reaction solution was neutralized with sodium hydroxide solution to make it alkaline, and the reaction solution was extracted with ethyl acetate (250mLx3), washed with saturated sodium chloride aqueous solution (250mLx3), and the organic phase was collected and dried over anhydrous sodium sulfate, filtered, and separated by column chromatography (PE:EA=1:4) to obtain the title compound (6.16g, 30%). MS m / z(ESI):157.1[M+H] + .

[0309] Step 2: Preparation of 2-amino-5-bromo-4-chloronicotinaldehyde

[0310]

[0311] Under nitrogen protection, 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 was completed, the reaction solution was cooled and filtered, and 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] + .

[0312] Step 3: Preparation of 7-bromo-1H-pyrazolo[4,3-c]pyridin-4-amine

[0313]

[0314] Under nitrogen protection, 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 was completed, the reaction solution was extracted with ethyl acetate (150 mL x 3), washed with saturated sodium chloride aqueous solution (150 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound (4.18 g, 63%). MS m / z (ESI): 213.1, 215.1 [M + H] + .

[0315] Step 4: Preparation of 1-(7-bromo-1H-pyrazolo[4,3-c]pyridin-4-yl)pyrrolidine-2,5-dione

[0316]

[0317] At room temperature, 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, and the temperature was gradually raised to 160°C and reacted for 30 minutes. After the reaction was completed, the reaction solution was cooled, extracted with ethyl acetate (50 mL x 3), washed with saturated sodium chloride aqueous solution (50 mL x 3), and 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%). MSm / z (ESI): 295.0 [M+H] + .

[0318] Step 5: Preparation of 1-(7-bromo-3-iodo-1H-pyrazolo[4,3-c]pyridin-4-yl)pyrrolidine-2,5-dione

[0319]

[0320] Under nitrogen protection, 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 completed, the reaction solution was filtered after cooling, and the filtrate was extracted with ethyl acetate (50 mL x 3), washed with saturated sodium chloride aqueous solution (50 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and column chromatography (DCM: MeOH = 95: 5) was performed to obtain the title compound (1.5 g, 70%). MS m / z (ESI): 421.1 [M+H] + .

[0321] 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

[0322]

[0323] Under nitrogen protection, 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), heated to 80 ° C and stirred overnight. After the reaction was completed, the reaction solution was extracted with ethyl acetate (50 mL x 3), washed with saturated sodium chloride aqueous solution (50 mL x 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (PE:EA=1:1) to obtain the title compound (560 mg, 31%). MS m / z(ESI):508.1[M+H] + .

[0324] Example 1

[0325] (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

[0326]

[0327] Step 1: Preparation of 6-((trimethylsilyl)ethynyl)pyrazolo[1,5-a]pyridine

[0328]

[0329] Under nitrogen protection, 6-bromopyrazolo[1,5-a]pyridine (2 g, 10.15 mmol), trimethylethynylsilane (1.5 g, 15.23 mmol), Pd(dppf)Cl 2(742mg, 1.02mmol), CuI (387mg, 2.03mmol) and TEA (2.05g, 20.3mmol) were suspended in THF (50mL), heated to 60°C and stirred for 2 hours. After the reaction was completed, the reaction solution was filtered after cooling, extracted with ethyl acetate (50mL x 3), washed with saturated sodium chloride aqueous solution (50mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography to obtain the title compound (1.89g, 87%). MS m / z (ESI): 215.1 [M+H] + .

[0330] Step 2: Preparation of 6-ethynylpyrazolo[1,5-a]pyridine

[0331]

[0332] Under nitrogen protection, 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 was completed, ethyl acetate (50 mL x 3) was used for extraction, and saturated sodium chloride aqueous solution was used for washing (50 mL x 3). The organic phase was collected and dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography to obtain the title compound (780 mg, 62%). MSm / z(ESI):143.0[M+H] + .

[0333] 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

[0334]

[0335] Under nitrogen protection, 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)Cl 2(72mg, 0.01mmol), CuI (38mg, 0.02mmol) and TEA (199mg, 1.97mmol) were suspended in DMF (20mL), heated to 60°C and stirred for 2 hours. After the reaction was completed, the reaction solution was filtered after cooling, extracted with ethyl acetate (50mL x 3), washed with saturated sodium chloride aqueous solution (50mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography to obtain the title compound (450mg, 88%). MS m / z (ESI): 522.1 [M+H] + .

[0336] 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

[0337]

[0338] 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-diphenylphosphophenyl) 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 completed, the reaction solution was filtered after cooling, and the filtrate was extracted with ethyl acetate (30 mL x 3) and washed with saturated sodium chloride aqueous solution (20 mL x 3). The organic phase was collected and dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography to obtain the title compound (100 mg, 48%). MS m / z (ESI): 542.1 [M+H] + .

[0339] 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

[0340]

[0341] Under nitrogen protection, 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 hydrochloric acid dioxane solution (4M, 10 mL) and stirred at room temperature for 1 hour. After drying and concentrating the reaction solution, it was suspended in a mixed solution of dichloromethane (10 mL) and water (20 mL) with sodium bicarbonate (76 mg, 0.9 mmol), and a dichloromethane (5 mL) solution of acryloyl chloride (20 mg, 0.22 mmol) was added dropwise under an ice-water bath, and stirred for 10 minutes. After the reaction was completed, the reaction solution was extracted with dichloromethane (15 mL x 3), washed with saturated sodium chloride aqueous solution (10 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography to obtain the title compound (44 mg, 56%). MS m / z (ESI): 440.2 [M+H] + .

[0342] 1 H NMR (400 MHz, DMSO-d 6 )δ9.33(s,1H),8.58(d,J=2.4Hz,1H),8.14(d,J=2.4Hz,1H),7.77(d,J=9.2 Hz,1H),7.41(d,J=9.2Hz,2H),6.76-6.53(m,2H),6.16(ddd,J=16.8,5.2,2 .4Hz,1H),6.01-5.85(m,1H),5.69(ddd,J=16.4,10.4,2.4Hz,1H),4.12-3. 50(m,5H),2.62(s,3H),2.45(q,J=7.6Hz,1H),2.33(dt,J=11.6,6.4Hz,1H).

[0343] Example 2

[0344] (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

[0345]

[0346] 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

[0347]

[0348] 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)Cl 2 (252mg, 0.34mmol) and potassium carbonate (952mg, 6.89mmol) were suspended in a mixed solvent of 1,4-dioxane (50mL) and water (10mL), heated to 100℃ and stirred for 16 hours. After the reaction was completed, the reaction solution was filtered after cooling, and the filtrate was extracted with ethyl acetate (30mL x 3) and washed with saturated sodium chloride aqueous solution (20mL x 3). The organic phase was collected and dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography to obtain the title compound (780mg, 48%). MS m / z(ESI):470.2[M+H] + .

[0349] 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

[0350]

[0351] Under nitrogen protection, 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 mixed solvent of 1,4-dioxane (50 mL) and water (10 mL). After stirring at room temperature for 10 minutes, sodium periodate (849 mg, 3.94 mmol) was added and the stirring reaction was continued for 2 hours. After the reaction was completed, the reaction solution was filtered after cooling, and the filtrate was extracted with ethyl acetate (30 mL x 3) and washed with saturated sodium chloride aqueous solution (20 mL x 3). The organic phase was collected and dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography to obtain the title compound (100 mg, 27%). MSm / z(ESI):472.2[M+H] + .

[0352] 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

[0353]

[0354] Under nitrogen protection, 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, 3M in THF) were dissolved in dry tetrahydrofuran (10 mL) and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered after cooling, and the filtrate was extracted with ethyl acetate (30 mL x 3) and washed with saturated sodium chloride aqueous solution (20 mL x 3). The organic phase was collected and dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography to obtain the title compound (82 mg, 77%). MS m / z (ESI): 502.2 [M+H] + .

[0355] 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

[0356]

[0357] Under nitrogen protection, 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 completed, the reaction solution was filtered after cooling, and the filtrate was extracted with dichloromethane (30 mL x 3) and washed with saturated sodium chloride aqueous solution (20 mL x 3). The organic phase was collected and dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography to obtain the title compound (80 mg, 98%). MS m / z (ESI): 500.2 [M+H] + .

[0358] 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

[0359]

[0360] Under nitrogen protection, 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 hydrochloric acid dioxane solution (4M, 10 mL) and stirred at room temperature for 1 hour. After drying and concentrating the reaction solution, it was suspended in a mixed solution of dichloromethane (10 mL) and water (20 mL) with sodium bicarbonate (76 mg, 0.9 mmol), and a dichloromethane (5 mL) solution of acryloyl chloride (17 mg, 0.19 mmol) was added dropwise under an ice-water bath, and stirred for 10 minutes. After the reaction was completed, the reaction solution was extracted with dichloromethane (15 mL x 3), washed with saturated sodium chloride aqueous solution (10 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography to obtain the title compound (33 mg, 45%). MS m / z (ESI): 454.1 [M+H] + .

[0361] 1 H NMR (400 MHz, DMSO-d 6 )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).

[0362] Example 3

[0363]

[0364] Refer to Example 2 for 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.

[0365] MS m / z(ESI):466.2[M+H] + .

[0366] Example 4

[0367]

[0368] 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 with reference to Example 1.

[0369] MS m / z(ESI):480.2[M+H] + .

[0370] Example 5

[0371]

[0372] 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 with reference to Example 1.

[0373] MS m / z(ESI):480.2[M+H] + .

[0374] Example 6

[0375]

[0376] Refer to Example 2 for 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.

[0377] MS m / z(ESI):502.2[M+H] + .

[0378] 1 H NMR (400 MHz, DMSO-d 6)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).

[0379] Biological test evaluation

[0380] The present invention is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present invention.

[0381] 1. Enzyme test

[0382] Test Example 1. Determination of the inhibitory effect of the compounds of the present invention on FGFR1-4 and FGFR2V564F activities 1. Experimental purpose:

[0383] The IC values ​​of the compounds on FGFR1, FGFR2, FGFR3, FGFR4 and FGFR2V564F were tested at the ATP Km concentration using the TR-FRET method. 50 .

[0384] 2. Experimental instruments and reagents:

[0385] 2.1 Instruments:

[0386] Instrument Name factory Specifications Centrifuge Eppendorf 5810R Micro centrifuge Dalong Xingchuang Experimental Instrument Co., Ltd. D1008 ELISA reader Bio Tek H1MFD

[0387] 2.2 Reagents:

[0388] Reagents and Materials factory Part Number FGFR1 Carna 08-133 FGFR2 Carna 08-134 FGFR3 Carna 08-135 FGFR4 Carna 08-136 FGFR2V564F SignalChem F05-12FG-05 <![CDATA[ULight TM -JAK-1(Tyr1023)Peptide]]> Perkinelmer TRF0121-D Europium-anti-phosphotyrosine(PT66) PerkinElmer AD0068

[0389] 3. Experimental methods:

[0390] The inhibitory activity of the compound on FGFR1, FGFR2, FGFR3, FGFR4 and FGFR2V564F kinase domain fragments was detected by TR-FRET (time-resolved fluorescence resonance energy transfer). The highest concentration of the compound detected in the 5 kinase assays was 1000 nM, 3-fold dilution, a total of 11 concentrations (1000 nM-0.017 nM). A 4× enzyme solution, a gradient dilution of a 4× compound solution, and a 2× ATP / Peptide substrate solution were prepared using a 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, and then 5 μL of 2× ATP / Peptide substrate solution was added. FGFR1, FGFR2, FGFR3 and FGFR2V564F 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× termination and detection mixture prepared with 1×LANCE detection buffer with an EDTA concentration of 20 mM and a Europium-anti-phosphotyrosine (PT66) concentration of 2 nM was added. FGFR1, FGFR2, FGFR3 and FGFR4 were reacted at room temperature for 60 minutes, and FGFR2V564F was reacted at room temperature for 30 minutes. The fluorescence signal value of each plate well was determined using an enzyme reader.

[0391] Enzyme reaction system:

[0392]

[0393]

[0394] Enzyme reaction termination and detection mixed solution system:

[0395]

[0396] 4. Experimental data processing method:

[0397] 1) Inhibition rate (%): The original data (665nm / 620nm reading ratio) was calculated according to the following formula to obtain the inhibition rate.

[0398] Inhibition rate % = [(average value of positive control wells - 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.

[0399] 2) Curve fitting: Use log(inhibitor) vs.response--Variable slope(four parameters) in GraphPad Prism 6 to fit the compound concentration and the corresponding inhibition rate, fit the curve and obtain the compound IC 50 value.

[0400] The fitting calculation equation is Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope)).

[0401] 5. Experimental results:

[0402] IC of compounds against FGFR1-4 and FGFR2V564F kinase activity 50 The values ​​are shown in the following table:

[0403] Table 1

[0404]

[0405]

[0406] 6. Experimental conclusion:

[0407] The compounds of the present invention have good inhibitory effects on the activity of FGFR1-4 and FGFR2 V564F kinases. Note: The structures of compound A and compound B are shown below

[0408]

[0409] 2. Cell Viability Experiment

[0410] 1. Experimental purpose:

[0411] The cell proliferation inhibition experiment was used to evaluate the inhibitory effect of the compounds on the proliferation of NCI-H716, SNU-16 and BaF3-FGFR2-BICC1V564F cells.

[0412] 2. Experimental instruments and reagents:

[0413] 2.1 Instruments:

[0414] Instrument Name factory Specifications Full-function microplate reader Bio Tek H1MFD Centrifuge eppendorf 5702R Cell Counter Life Countess II <![CDATA[CO 2 Incubator]]> Thermo 311 Biological Safety Cabinets Shanghai Boxun Industry BSC-1300IIA2

[0415] 2.2 Reagents:

[0416]

[0417]

[0418] 2.3 Cell sources

[0419]

[0420] 3. Experimental methods:

[0421] The CellTiter-Glo method was used to detect the inhibitory effect of the compounds on the proliferation of NCI-H716, SNU-16 and BaF3FGFR2-BICC1V564F cells. The highest concentration of the compound tested was 1000nM, 3-fold dilution, a total of 9 concentrations (1000nM-0.15nM). After the cells were plated at an appropriate density, the compounds were added on the second day, and the cells were incubated for 72 hours before detection using the CellTiter-Glo Luminescebt detection kit.

[0422] 4. Experimental data processing method:

[0423] 1) Inhibition rate (%):

[0424] Inhibition rate % = [(average value of positive control wells - 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.

[0425] 2) Curve fitting: Use log(inhibitor) vs.response--Variable slope(four parameters) in GraphPad Prism 6 to fit the compound concentration and the corresponding inhibition rate, fit the curve and obtain the compound IC 50 value.

[0426] The fitting calculation equation is Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope)).

[0427] 5. Experimental results:

[0428] Table 2

[0429]

[0430] 6. Experimental conclusion:

[0431] The compounds of the examples of the present invention have significant proliferation inhibitory effects on NCI-H716, SNU-16 and BaF3FGFR2-BICC1V564F cells.

[0432] 3. Pharmacokinetic Experiments

[0433] 1. Experimental purpose:

[0434] SD rats were used as test animals to study the pharmacokinetic behavior of the compounds of the present invention in rats (plasma) at a dose of 5 mg / kg orally.

[0435] 2. Experimental Plan

[0436] 2.1 Test drug: Example of the present invention, homemade.

[0437] 2.2 Experimental animals: 3 SD rats per group, male, Shanghai Jiesijie Experimental Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013-0006N0.311620400001794).

[0438] 2.3 Drug preparation: PO, 10% solutol HS15-0.5% CMC-Na, dissolve by ultrasonication, and prepare into a clear solution or homogeneous suspension.

[0439] 2.4 Dosage regimen: 3 male SD rats per group; after fasting overnight, the dose was 5 mg / kg, and the administration volume was 10 mL / kg;

[0440] 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 and placed in EDTA-K 2 The plasma was separated by centrifugation at 6000 rpm for 6 min at 4°C in the test tube and stored at -80°C.

[0441] 2.6 Sample processing:

[0442] 1) Add 100uL acetonitrile to 20uL of plasma sample for precipitation, mix and centrifuge at 3500×g for 5 to 20 minutes.

[0443] 2) The supernatant solution after treatment is taken for LC / MS / MS analysis of the concentration of the test compound, and the LC / MS / MS analysis instrument is: ABSciex API 4000Qtrap.

[0444] 2.7 Liquid phase analysis:

[0445] Liquid phase conditions: Shimadzu LC-20AD pump

[0446] ·Chromatographic column: Waters Xbridge C18 5μm, 4.6X 50mm Mobile phase: Liquid A is 0.1% formic acid in water, Liquid B is methanol

[0447] Flow rate: 1.0mL / min

[0448] Elution time: 0-4.0 minutes, eluent is as follows:

[0449] Time / minute Liquid A Liquid B 0.2 90％ 10％ 1.2 2％ 98％ 3.0 2％ 98％ 3.1 90％ 10％ 4.0 Stop

[0450] 2.8 Experimental results and data processing:

[0451] Table 3 Pharmacokinetic parameters

[0452]

[0453] Experimental conclusion:

[0454] From the results of the SD rat pharmacokinetic experiment in the table, it can be seen that the compounds of the present invention show good metabolic properties, exposure AUC and maximum blood drug concentration C max All performed well.

[0455] 4. In vivo pharmacodynamic study of the compound in the subcutaneous transplanted tumor model of nude mice with the mouse original B cell line Ba / F3FGFR2-BICC-V564F

[0456] 1.1 Experimental Purpose

[0457] Evaluation of compounds in the mouse primary B cell line Ba / F 3 In vivo efficacy in the FGFR2-BICC-V564F nude mouse subcutaneous transplant tumor model.

[0458] 1.2 Experimental instruments and reagents

[0459] 1.2.1 Instruments

[0460] 1. Refrigerator (BCD-268TN, Haier)

[0461] 2. Biological safety cabinet (BSC-1300II A2, Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory)

[0462] 3. Clean bench (CJ-2F, Suzhou Fengshi Experimental Animal Equipment Co., Ltd.)

[0463] 4. Electronic pipette assistant (Easypet 3, Eppendorf)

[0464] 5. Constant temperature water bath (HWS-12, Shanghai Yiheng Science)

[0465] 6. CO 2 Incubator (Thermo-311, Thermo)

[0466] 7. Centrifuge (Centrifuge 5720R, Eppendorf)

[0467] 8. Fully automated cell counter (Countess II, Life Technologies)

[0468] 9. Vernier caliper (CD-6" AX, Mitutoyo, Japan)

[0469] 10. Cell culture flask (T25 / T75 / T225, Corning)

[0470] 11. Electronic balance (CPA2202S, Sartorius)

[0471] 12. Electronic balance (BSA2202S-CW, Sartorius)

[0472] 13. Ultrasonic cleaner (115F0032, Shanghai Kedao)

[0473] 14. Water Purifier (Pacific TII, Thermo)

[0474] 15. Magnetic stirrer (08-2G, Chijiu)

[0475] 1.2.2 Reagents

[0476] 1. RPMI-1640 medium (22400-089, Gibco)

[0477] 2. Fetal bovine serum (FBS) (10099-141C, Gibco)

[0478] 3. Phosphate buffered saline (PBS) (10010-023, Gibco)

[0479] 4. Kolliphor HS15 (42966-1KG, Sigma-Aldrich)

[0480] 5. Sodium carboxymethyl cellulose (30036365, Sinopharm Reagent)

[0481] 1.3 Experimental operation and data processing

[0482] 1.3.1 Animals

[0483] BALB / c nude mice, 6-8 weeks old, ♀, purchased from the Experimental Animal Management Department of Shanghai Institute of Family Planning Science 1.3.2 Cell culture and cell suspension preparation

[0484] a, take out a Ba / F strain from the cell bank 3FGFR2-BICC-V564F cells were revived with RPMI-1640 medium (RPMI-1640 + 10% FBS), and the revived cells were placed in a cell culture flask (labeled with cell type, date, culturer's name, etc. on the flask wall) and placed in a CO 2 Culture in an incubator (incubator temperature 37°C, CO 2 The concentration is 5%).

[0485] b, The cells were subcultured every three days and kept in CO 2 Repeat this process until the cell number meets the in vivo drug efficacy requirements.

[0486] 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.

[0487] 1.3.3 Cell seeding

[0488] a, Nude mice were marked with disposable universal ear tags for mice and rats before inoculation;

[0489] b. Mix the cell suspension during inoculation, draw 0.1-1 mL of cell suspension with a 1 mL syringe, remove bubbles, and then place the syringe on an ice pack for later use;

[0490] 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 after 30 seconds.

[0491] d. The experimental nude mice were inoculated sequentially (0.1 mL of cell suspension was inoculated per mouse).

[0492] 1.3.4 Tumor measurement, grouping, and drug administration in tumor-bearing mice

[0493] a, Based on tumor growth, tumors were measured and their size was calculated on days 10-14 after inoculation;

[0494] Tumor volume calculation: Tumor volume (mm 3 ) = length (mm) × width (mm) × width (mm) / 2

[0495] b, Tumor-bearing mice were randomly divided into groups according to their weight and tumor size;

[0496] 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).

[0497] d, Tumors were measured and weighed twice a week after the start of the test drug administration.

[0498] e, Animals were euthanized after the experiment.

[0499] f. Process the data using software such as Excel. Calculation of compound tumor inhibition rate TGI (%): When the tumor does not regress, TGI (%) = [1-(average tumor volume at the end of a treatment group administration - average tumor volume at the beginning of administration of the treatment group) / (average tumor volume at the end of treatment of the solvent control group - average tumor volume at the beginning of treatment of the solvent control group)] × 100%. When the tumor regresses, TGI (%) = [1-(average tumor volume at the end of administration of a treatment group - average tumor volume at the beginning of administration of the treatment group) / average tumor volume at the beginning of administration of the treatment group] × 100%.

[0500] 1.4 Experimental conclusion:

[0501] The compound of the present invention has excellent tumor inhibition effect and good safety.

[0502] 3. Study on salt form and its crystal form

[0503] 1.1 Experimental Instruments

[0504] 1.1.1 Some parameters of physical and chemical testing instruments

[0505]

[0506] 1.2 Instruments and liquid phase analysis conditions

[0507] 1.2.1 Instruments and equipment

[0508] Instrument Name model Analytical Balance Sartorius BSA224S-CW Water Purifier Milli-Q Plus, Millipore High performance liquid chromatography Agilent1260 Pump Agilent G1311B Injector G1329B Column oven G1316A Detector G1315D

[0509] 1.2.2 Chromatographic conditions

[0510] Chromatographic column: ZOBAX Bonus RP (4.6*150mm, 3.5μm); Flow rate: 1.0mL / min Column temperature: 35℃ Detection wavelength: 220nm Injection volume: 5μL Run time: 15min Diluent: DMSO Mobile phase: A: Water (0.05% TFA); B: Acetonitrile (0.05% TFA)

[0511] T(min) A(％) B(％) 0.00 95.0 5.0 8.00 20.0 80.0 12.00 10.0 90.0 12.01 95.0 5.0 15.00 95.0 5.0

[0512] 1. Preparation of different salt forms of the compound of Example 1

[0513] 1.1 Preparation of Hydrochloride Form A

[0514] Weigh 10 mg of free base solid, add 1 mL of tetrahydrofuran, dissolve by ultrasonication at room temperature, and filter. Add 27 μL of hydrochloric acid methanol solution at a molar ratio of 1:1.2, and evaporate to dryness at room temperature. The obtained solid is detected as hydrochloride crystal form A, with the following characteristics: Figure 1 The XRPD pattern shown in Figure 2 DSC graph shown.

[0515] 1.2 Preparation of Hydrochloride Form B

[0516] Weigh 10 mg of the free base solid, add 200 μL of acetonitrile, add 27 μL of hydrochloric acid methanol solution at a molar ratio of 1:1.2, stir at room temperature for 2 hours, centrifuge, and vacuum dry at 40°C to obtain a solid. The obtained solid was detected to be hydrochloride crystal form B, with the following characteristics: Figure 3 The XRPD pattern shown in Figure 4 DSC-TGA graph shown.

[0517] 1.3 Preparation of Hydrobromide Form A

[0518] Weigh 10 mg of the free base solid, add 200 μL of acetone, add 27 μL of hydrobromic acid methanol solution at a molar ratio of 1:1.2, stir at room temperature for 2 h, centrifuge, and vacuum dry at 40°C to obtain a solid. The obtained solid was detected to be hydrobromide salt form A, with the following characteristics: Figure 5 The XRPD pattern shown in Figure 6 DSC-TGA graph shown.

[0519] 1.4 Preparation of Methanesulfonate Form A

[0520] Weigh 10 mg of the free base solid, add 200 μL of acetone, add 27 μL of methanesulfonic acid methanol solution at a molar ratio of 1:1.2, stir at room temperature for 2 h, centrifuge, and vacuum dry at 40°C to obtain a solid. The obtained solid was detected to be mesylate crystal form A, with the following characteristics: Figure 7 The XRPD pattern shown in Figure 8 DSC-TGA graph shown.

[0521] 1.5 Preparation of p-toluenesulfonate Form A

[0522] Weigh 10 mg of the free base solid, add 200 μL of acetone, add 27 μL of p-toluenesulfonic acid methanol solution at a molar ratio of 1:1.2, stir at room temperature for 2 h, centrifuge, and vacuum dry at 40°C to obtain a solid. The obtained solid was detected to be p-toluenesulfonate salt form A, with the following characteristics: Fig. 9 XRPD pattern shown.

[0523] 1.6 Preparation of p-toluenesulfonate Form B

[0524] Weigh 10 mg of the free base solid, add 200 μL of acetonitrile, add 27 μL of p-toluenesulfonic acid methanol solution at a molar ratio of 1:1.2, stir at room temperature for 2 h, centrifuge, and vacuum dry at 40°C to obtain a solid. The obtained solid was detected to be p-toluenesulfonate crystal form B, with the following characteristics: Fig.10 The XRPD pattern shown in Fig.11 DSC-TGA graph shown.

[0525] 1.7 Preparation of benzenesulfonate salt form A

[0526] Weigh 10 mg of the free base solid, add 200 μL of acetone, add 27 μL of benzenesulfonic acid methanol solution at a molar ratio of 1:1.2, stir at room temperature for 2 h, centrifuge, and vacuum dry at 40°C to obtain a solid. The obtained solid was detected to be benzenesulfonate salt form A, with the following characteristics: Fig.12 The XRPD pattern shown in Fig.13 DSC-TGA graph shown.

[0527] 2. Solid stability test

[0528] 2.1 Experimental Purpose:

[0529] The physicochemical stabilities of hydrobromide salt form A, benzenesulfonate salt form A and methanesulfonate salt form A were investigated at high temperature of 60°C, room temperature and high humidity of RH=92.5% and 50°C RH=75% for 7 days and 14 days.

[0530] 2.2 Experimental plan:

[0531] About 1 mg of hydrobromide salt form A, benzenesulfonate salt form A and methanesulfonate salt form A were taken respectively and placed in an oven at 60°C, room temperature with high humidity RH=92.5% and 50°C with RH=75%, and observed for 7 days and 14 days. The changes of related substances were calculated by the chromatographic peak area normalization method.

[0532] 2.3 Experimental results:

[0533] The physicochemical stability results of hydrobromide salt form A, benzenesulfonate salt form A and methanesulfonate salt form A under different conditions:

[0534] Table 4

[0535]

[0536] From the stability data, it can be seen that the benzenesulfonate salt form A is relatively stable under high temperature, high humidity, and high temperature and high humidity conditions, and no significant increase in impurities is observed, which can well meet the requirements of later long-term storage and formulation process.

[0537] 3. Comparative PK study of benzenesulfonate form A and free base in rats

[0538] 4.1 Experimental Purpose

[0539] SD rats were used as test animals to study the pharmacokinetic behavior of benzenesulfonate crystalline form A and free base in rats (plasma) after a single oral administration, and to compare the differences in exposure.

[0540] 4.2 Experimental plan:

[0541] The benzenesulfonate crystal form A was prepared into a suspension with medium chain triglyceride, and the free base was prepared into a suspension with an aqueous solution containing 0.5% HPMC. The suspensions were all gavaged and administered to rats, with three rats in each group in parallel, and the dosage was 30 mg / kg.

[0542] 4.3 Experimental results and conclusions:

[0543] The AUC and bioavailability of benzenesulfonate salt form A are higher than those of the free base, which has unexpected technical effects.

Claims

1. A compound represented by general formula (I) or an acid salt of its stereoisomer, and a crystal form of the salt 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 Haloalkoxy; The acid in the acid salt is an inorganic acid or an organic acid; preferably, the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid; the organic acid is selected from 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, ethanesulfonic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dimethicone, 1,2-dimethoxy- ... Benzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, p-toluenesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid or L-malic acid; preferably hydrochloric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid or benzenesulfonic acid.

2. The compound according to claim 1 or the acid salt of its stereoisomer, and the crystal form of its salt, 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 compound according to claim 1 or 2 or the acid salt of its stereoisomer, and the crystal form of its salt, characterized in that: The number of acids in the acid salt is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 0.5, 1, 2 or 3, further preferably 1.

4. The compound according to any one of claims 1 to 3 or the acid salt of its stereoisomer, and the crystal form of its salt, characterized in that: The acid salt is a hydrate or an anhydrate; when the acid salt is a hydrate, the number of water is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3; The crystal form is a hydrate crystal form or anhydrous crystal form; when the crystal form is a hydrate, the number of water is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3.

5. The compound according to any one of claims 1 to 4 or the acid salt of its stereoisomer and the crystal form of its salt, characterized in that: It is the hydrochloride salt form A 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 the hydrochloride salt form A has a diffraction peak at 2θ of 8.0±0.2°; or a diffraction peak at 11.3±0.2°; or a diffraction peak at 11.8±0.2°; or a diffraction peak at 14.3±0.2°; or a diffraction peak at 14.6±0.2°; or a diffraction peak at 17.5±0.2°; or a diffraction peak at 19.1±0.2°. or having a diffraction peak at 21.2±0.2°; or having a diffraction peak at 22.7±0.2°; or having a diffraction peak at 26.1±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 the hydrochloride salt form B 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 the hydrochloride crystal form B has a diffraction peak at 2θ of 4.4±0.2°; or a diffraction peak at 8.8±0.2°; or a diffraction peak at 10.5±0.2°; or a diffraction peak at 11.4±0.2°; or a diffraction peak at 13.2±0.2°; or a diffraction peak at 14.2±0.2°; or a diffraction peak at 20.1±0.2°. Peak; or a diffraction peak at 23.1±0.2°; or a diffraction peak at 26.5±0.2°; or a diffraction peak at 27.5±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 the hydrobromide salt form A 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 the hydrobromide salt form A has a diffraction peak at 2θ of 4.6±0.2°; or a diffraction peak at 10.1±0.2°; or a diffraction peak at 13.6±0.2°; or a diffraction peak at 14.1±0.2°; or a diffraction peak at 18.1±0.2°; or a diffraction peak at 22.7±0.2°; or a diffraction peak at 27.0±0.2°. or having a diffraction peak at 27.3±0.2°; or having a diffraction peak at 31.3±0.2°; or having a diffraction peak at 32.0±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 a mesylate salt form A 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 the mesylate salt form A has a diffraction peak at 2θ of 5.4±0.2°; or a diffraction peak at 8.7±0.2°; or a diffraction peak at 10.8±0.2°; or a diffraction peak at 16.8±0.2°; or a diffraction peak at 17.4±0.2°; or a diffraction peak at 21.6±0.2°; or a diffraction peak at 23.3±0.2°. or having a diffraction peak at 23.9±0.2°; or having a diffraction peak at 25.6±0.2°; or having a diffraction peak at 26.7±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 a p-toluenesulfonate salt form A 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 the p-toluenesulfonate crystalline form A has a diffraction peak at 2θ of 4.7±0.2°; or a diffraction peak at 5.7±0.2°; or a diffraction peak at 6.6±0.2°; or a diffraction peak at 11.4±0.2°; or a diffraction peak at 13.2±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 17.0±0.2°. 0.2° has a diffraction peak; or has a diffraction peak at 18.2±0.2°; or has a diffraction peak at 19.6±0.2°; or has a diffraction peak at 21.0±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; Alternatively, it is a p-toluenesulfonate salt form B 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 the p-toluenesulfonate salt form B has a diffraction peak at 2θ of 5.7±0.2°; or a diffraction peak at 7.2±0.2°; or a diffraction peak at 8.5±0.2°; or a diffraction peak at 13.1±0.2°; or a diffraction peak at 16.4±0.2°; or a diffraction peak at 17.0±0.2°; or a diffraction peak at 18.2±0.2°. or having a diffraction peak at 18.7±0.2°; or having a diffraction peak at 21.5±0.2°; or having a diffraction peak at 21.8±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 a benzenesulfonate salt form A 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 benzenesulfonate salt form A has a diffraction peak at 2θ of 5.2±0.2°; or a diffraction peak at 6.9±0.2°; or a diffraction peak at 11.4±0.2°; or a diffraction peak at 16.9±0.2°; or a diffraction peak at 17.7±0.2°; or a diffraction peak at 18.0±0.2°; or a diffraction peak at 21.0±0.2°. or has a diffraction peak at 22.8±0.2°; or has a diffraction peak at 24.1±0.2°; or has a diffraction peak at 25.9±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 of them.

6. The compound according to claim 5 or the acid salt of its stereoisomer, and the crystal form of its salt, characterized in that: The X-ray powder diffraction pattern of the hydrochloride salt form A comprises at least one or more diffraction peaks located at 2θ of 8.0±0.2°, 11.8±0.2°, and 14.3±0.2°, preferably 2 of them, and more preferably 3 of them; optionally, it may further comprise at least one of 2θ of 11.3±0.2°, 14.6±0.2°, 17.5±0.2°, 21.2±0.2°, and 22.7±0.2°, preferably 2, 3, 4 or 5 of them; More preferably, the X-ray powder diffraction pattern of the hydrochloride salt form A optionally further comprises one or more diffraction peaks located at 2θ of 15.9±0.2°, 19.1±0.2°, 24.0±0.2°, 26.1±0.2°, 27.4±0.2°, 28.7±0.2°, 30.0±0.2°; preferably at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, or 7 thereof; Further preferably, the X-ray powder diffraction pattern of the hydrochloride salt form A comprises one or more diffraction peaks located at 2θ of 8.0±0.2°, 11.3±0.2°, 11.8±0.2°, 14.3±0.2°, 14.6±0.2°, 17.5±0.2°, 19.1±0.2°, 21.2±0.2°, 22.7±0.2°, and 26.1±0.2°; preferably, there are diffraction peaks at 4, 5, 6, 8 or 10 selected therefrom; For example, the X-ray powder diffraction spectrum of the hydrochloride salt form A has diffraction peaks at the following positions at 2θ: 8.0±0.2°、11.8±0.2°、14.3±0.2°、11.3±0.2°、14.6±0.2°； 8.0±0.2°、11.8±0.2°、14.3±0.2°、17.5±0.2°、21.2±0.2°； 8.0±0.2°、11.8±0.2°、14.3±0.2°、11.3±0.2°、15.9±0.2°； 8.0±0.2°、11.8±0.2°、14.3±0.2°、14.6±0.2°、19.1±0.2°、24.0±0.2°； 8.0±0.2°、11.8±0.2°、14.3±0.2°、11.3±0.2°、14.6±0.2°、26.1±0.2°； 8.0±0.2°、11.8±0.2°、14.3±0.2°、17.5±0.2°、21.2±0.2°、27.4±0.2°； 8.0±0.2°、11.3±0.2°、11.8±0.2°、14.3±0.2°、14.6±0.2°、17.5±0.2°、21.2±0.2°、22.7±0.2°； 8.0±0.2°、11.8±0.2°、14.3±0.2°、15.9±0.2°、17.5±0.2°、21.2±0.2°、24.0±0.2°、26.1±0.2°； 8.0±0.2°、11.8±0.2°、14.3±0.2°、11.3±0.2°、15.9±0.2°、19.1±0.2°、28.7±0.2°、30.0±0.2°； 8.0±0.2°、11.3±0.2°、11.8±0.2°、14.3±0.2°、14.6±0.2°、17.5±0.2°、19.1±0.2°、21.2±0.2°、22.7±0.2°、26.1±0.2°； 8.0±0.2°、11.3±0.2°、11.8±0.2°、14.3±0.2°、14.6±0.2°、15.9±0.2°、17.5±0.2°、19.1±0.2°、21.2±0.2°、22.7±0.2°； 8.0±0.2°、11.3±0.2°、11.8±0.2°、14.3±0.2°、14.6±0.2°、17.5±0.2°、21.2±0.2°、22.7±0.2°、24.0±0.2°、26.1±0.2°； The X-ray powder diffraction pattern of the most preferred hydrochloride salt form A is substantially as shown in FIG1 ; the DSC pattern is as shown in FIG2 ; The X-ray powder diffraction pattern of the hydrochloride salt form B comprises at least one or more diffraction peaks located at 2θ of 4.4±0.2°, 10.5±0.2°, and 13.2±0.2°, preferably 2 of them, and more preferably 3 of them; optionally, it may further comprise at least one of 2θ of 8.8±0.2°, 11.4±0.2°, 20.1±0.2°, 23.1±0.2°, and 26.5±0.2°, preferably 2, 3, 4 or 5 of them; More preferably, the X-ray powder diffraction pattern of the hydrochloride salt form B optionally further comprises one or more diffraction peaks located at 2θ of 14.2±0.2°, 15.0±0.2°, 17.7±0.2°, 21.1±0.2°, and 27.5±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 the hydrochloride salt form B comprises one or more diffraction peaks located at 2θ of 4.4±0.2°, 8.8±0.2°, 10.5±0.2°, 11.4±0.2°, 13.2±0.2°, 14.2±0.2°, 20.1±0.2°, 23.1±0.2°, 26.5±0.2°, 27.5±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 hydrochloride salt form B has diffraction peaks at the following positions at 2θ: 4.4±0.2°、10.5±0.2°、13.2±0.2°、8.8±0.2°、15.0±0.2°； 4.4±0.2°、10.5±0.2°、13.2±0.2°、20.1±0.2°、17.7±0.2°； 4.4±0.2°、10.5±0.2°、13.2±0.2°、26.5±0.2°、21.1±0.2°； 4.4±0.2°、10.5±0.2°、13.2±0.2°、8.8±0.2°、14.2±0.2°、15.0±0.2°； 4.4±0.2°、10.5±0.2°、13.2±0.2°、20.1±0.2°、15.0±0.2°、17.7±0.2°； 4.4±0.2°、10.5±0.2°、13.2±0.2°、26.5±0.2°、21.1±0.2°、27.5±0.2°； 4.4±0.2°、10.5±0.2°、13.2±0.2°、8.8±0.2°、11.4±0.2°、20.1±0.2°、23.1±0.2°、26.5±0.2°； 4.4±0.2°、10.5±0.2°、11.4±0.2°、13.2±0.2°、14.2±0.2°、20.1±0.2°、15.0±0.2°、17.7±0.2°； 4.4±0.2°、8.8±0.2°、10.5±0.2°、13.2±0.2°、15.0±0.2°、26.5±0.2°、21.1±0.2°、27.5±0.2°； 4.4±0.2°、8.8±0.2°、10.5±0.2°、11.4±0.2°、13.2±0.2°、14.2±0.2°、20.1±0.2°、15.0±0.2°、17.7±0.2°、27.5±0.2； 4.4±0.2°、8.8±0.2°、10.5±0.2°、13.2±0.2°、15.0±0.2°、17.7±0.2°、26.5±0.2°、21.1±0.2°、26.5±0.2°、27.5±0.2°； 4.4±0.2°、8.8±0.2°、10.5±0.2°、11.4±0.2°、13.2±0.2°、14.2±0.2°、20.1±0.2°、23.1±0.2°、26.5±0.2°、27.5±0.2； The X-ray powder diffraction pattern of the most preferred hydrochloride salt form B is substantially as shown in FIG3 ; the DSC-TGA pattern is shown in FIG4 ; The X-ray powder diffraction pattern of the hydrobromide salt form A comprises at least one or more diffraction peaks located at 2θ of 4.6±0.2°, 13.6±0.2°, and 22.7±0.2°, preferably 2 of them, and more preferably 3 of them; optionally, it may further comprise at least one of 2θ of 10.1±0.2°, 14.1±0.2°, 27.0±0.2°, 27.3±0.2°, and 31.3±0.2°, preferably 2, 3, 4 or 5 of them; More preferably, the X-ray powder diffraction pattern of the hydrobromide salt form A optionally further comprises one or more diffraction peaks located at 2θ of 18.1±0.2°, 18.7±0.2°, 26.4±0.2°, 32.0±0.2°, 35.8±0.2°, 36.7±0.2°; preferably at least any 2-3, or 4-5, or 5-6 thereof; further preferably, any 2, 3, 4, 5, or 6 thereof; Further preferably, the X-ray powder diffraction pattern of the hydrobromide salt form A comprises one or more diffraction peaks located at 2θ of 4.6±0.2°, 10.1±0.2°, 13.6±0.2°, 14.1±0.2°, 18.1±0.2°, 22.7±0.2°, 27.0±0.2°, 27.3±0.2°, 31.3±0.2°, and 32.0±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 hydrobromide salt form A has diffraction peaks at the following positions at 2θ: 4.6±0.2°、10.1±0.2°、18.1±0.2°、22.7±0.2°、26.4±0.2°； 4.6±0.2°、13.6±0.2°、22.7±0.2°、27.0±0.2°、35.8±0.2°； 4.6±0.2°、13.6±0.2°、22.7±0.2°、27.3±0.2°、36.7±0.2°； 4.6±0.2°、13.6±0.2°、22.7±0.2°、18.1±0.2°、18.7±0.2°、26.4±0.2°； 4.6±0.2°、10.1±0.2°、14.1±0.2°、22.7±0.2°、27.3±0.2°、31.3±0.2°； 4.6±0.2°、13.6±0.2°、14.1±0.2°、18.1±0.2°、18.7±0.2°、27.0±0.2°； 4.6±0.2°、10.1±0.2°、13.6±0.2°、14.1±0.2°、18.1±0.2°、22.7±0.2°、27.0±0.2°、27.3±0.2°； 4.6±0.2°、10.1±0.2°、18.1±0.2°、22.7±0.2°、27.0±0.2°、27.3±0.2°、31.3±0.2°、32.0±0.2°； 4.6±0.2°、10.1±0.2°、13.6±0.2°、14.1±0.2°、27.0±0.2°、27.3±0.2°、31.3±0.2°、32.0±0.2°； 4.6±0.2°、10.1±0.2°、13.6±0.2°、14.1±0.2°、18.1±0.2°、22.7±0.2°、27.0±0.2°、27.3±0.2°、31.3±0.2°、32.0±0.2°； 4.6±0.2°、13.6±0.2°、14.1±0.2°、18.1±0.2°、22.7±0.2°、27.0±0.2°、27.3±0.2°、31.3±0.2°、32.0±0.2°、35.8±0.2°； 4.6±0.2°、10.1±0.2°、13.6±0.2°、18.1±0.2°、18.7±0.2°、22.7±0.2°、27.0±0.2°、27.3±0.2°、31.3±0.2°、32.0±0.2°； The X-ray powder diffraction pattern of the most preferred hydrobromide salt form A is substantially as shown in FIG5 ; the DSC-TGA pattern is shown in FIG6 ; The X-ray powder diffraction pattern of the mesylate salt form A comprises at least one or more diffraction peaks located at 2θ of 8.7±0.2°, 10.8±0.2°, and 17.4±0.2°, preferably 2 of them, and more preferably 3 of them; optionally, it may further comprise at least one of 2θ of 5.4±0.2°, 16.8±0.2°, 21.6±0.2°, 25.6±0.2°, and 26.7±0.2°, preferably 2, 3, 4 or 5 of them; More preferably, the X-ray powder diffraction pattern of the mesylate salt form A optionally further comprises one or more diffraction peaks located at 2θ of 9.0±0.2°, 15.5±0.2°, 17.9±0.2°, 18.3±0.2°, 19.5±0.2°, 22.8±0.2°, 23.3±0.2°, 23.9±0.2°; preferably at least any 2-3 of them, or 4-5, or 6-7, or 8-9; further preferably, any 2, 3, 4, 5, 6, 7, 8, 9 thereof; Further preferably, the X-ray powder diffraction pattern of the mesylate salt form A comprises one or more diffraction peaks located at 2θ of 5.4±0.2°, 8.7±0.2°, 10.8±0.2°, 16.8±0.2°, 17.4±0.2°, 21.6±0.2°, 23.3±0.2°, 23.9±0.2°, 25.6±0.2°, and 26.7±0.2°; preferably, there are diffraction peaks at 4, 5, 6, 8 or 10 selected from them; For example, the X-ray powder diffraction spectrum of the mesylate salt form A has diffraction peaks at the following positions at 2θ: 10.8±0.2°、17.4±0.2°、21.6±0.2°、9.0±0.2°、15.5±0.2°； 5.4±0.2°、16.8±0.2°、8.7±0.2°、17.4±0.2°、17.9±0.2°； 10.8±0.2°、17.4±0.2°、19.5±0.2°、21.6±0.2°、25.6±0.2°； 8.7±0.2°、10.8±0.2°、17.4±0.2°、26.7±0.2°、23.9±0.2°； 8.7±0.2°、10.8±0.2°、17.4±0.2°、21.6±0.2°、25.6±0.2°、26.7±0.2°； 8.7±0.2°、17.4±0.2°、5.4±0.2°、16.8±0.2°、21.6±0.2°、25.6±0.2°； 10.8±0.2°、17.4±0.2°、16.8±0.2°、21.6±0.2°、25.6±0.2°、26.7±0.2°； 8.7±0.2°、10.8±0.2°、17.4±0.2°、16.8±0.2°、21.6±0.2°、25.6±0.2°； 5.4±0.2°、8.7±0.2°、10.8±0.2°、16.8±0.2°、17.4±0.2°、16.8±0.2°、21.6±0.2°、25.6±0.2°； 10.8±0.2°、16.8±0.2°、17.4±0.2°、21.6±0.2°、23.3±0.2°、23.9±0.2°、25.6±0.2°、26.7±0.2°； 5.4±0.2°、8.7±0.2°、10.8±0.2°、16.8±0.2°、17.4±0.2°、17.9±0.2°、21.6±0.2°、23.3±0.2°、23.9±0.2°、25.6±0.2°； 5.4±0.2°、8.7±0.2°、10.8±0.2°、16.8±0.2°、17.4±0.2°、21.6±0.2°、23.3±0.2°、23.9±0.2°、25.6±0.2°、26.7±0.2°； 5.4±0.2°、8.7±0.2°、9.0±0.2°、10.8±0.2°、16.8±0.2°、17.4±0.2°、16.8±0.2°、21.6±0.2°、23.9±0.2°、25.6±0.2°； 10.8±0.2°、15.5±0.2°、16.8±0.2°、17.4±0.2°、18.3±0.2°、21.6±0.2°、23.3±0.2°、23.9±0.2°、25.6±0.2°、26.7±0.2°； The X-ray powder diffraction pattern of the most preferred mesylate salt form A is substantially as shown in FIG7 ; the DSC-TGA pattern is shown in FIG8 ; The X-ray powder diffraction pattern of the p-toluenesulfonate salt form A comprises at least one or more diffraction peaks located at 2θ of 4.7±0.2°, 5.7±0.2°, and 6.6±0.2°, preferably 2 of them, and more preferably 3 of them; optionally, it may further comprise at least one of 2θ of 11.4±0.2°, 16.0±0.2°, 17.0±0.2°, 18.2±0.2°, and 19.6±0.2°, preferably 2, 3, 4 or 5 of them; More preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form A optionally further comprises one or more diffraction peaks located at 2θ of 13.2±0.2°, 14.0±0.2°, and 21.0±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 the p-toluenesulfonate salt form A comprises one or more diffraction peaks located at 2θ of 4.7±0.2°, 5.7±0.2°, 6.6±0.2°, 11.4±0.2°, 13.2±0.2°, 16.0±0.2°, 17.0±0.2°, 18.2±0.2°, 19.6±0.2°, and 21.0±0.2°; preferably, there are diffraction peaks at 4, 5, 6, 8 or 10 of them; For example, the X-ray powder diffraction spectrum of the p-toluenesulfonate crystalline form A has diffraction peaks at the following positions at 2θ: 4.7±0.2°、5.7±0.2°； 4.7±0.2°、5.7±0.2°、6.6±0.2°、11.4±0.2°、16.0±0.2°； 4.7±0.2°、5.7±0.2°、16.0±0.2°、17.0±0.2°、18.2±0.2°； 4.7±0.2°、6.6±0.2°、14.0±0.2°、18.2±0.2°、19.6±0.2°； 4.7±0.2°、5.7±0.2°、6.6±0.2°、11.4±0.2°、16.0±0.2°、17.0±0.2°； 4.7±0.2°、5.7±0.2°、6.6±0.2°、17.0±0.2°、18.2±0.2°、19.6±0.2°； 4.7±0.2°、5.7±0.2°、6.6±0.2°、11.4±0.2°、16.0±0.2°、21.0±0.2°； 4.7±0.2°、5.7±0.2°、6.6±0.2°、11.4±0.2°、16.0±0.2°、17.0±0.2°、18.2±0.2°、19.6±0.2°； 4.7±0.2°、5.7±0.2°、6.6±0.2°、11.4±0.2°、13.2±0.2°、16.0±0.2°、17.0±0.2°、21.0±0.2°； 4.7±0.2°、5.7±0.2°、6.6±0.2°、11.4±0.2°、17.0±0.2°、18.2±0.2°、19.6±0.2°、21.0±0.2°； 4.7±0.2°、5.7±0.2°、6.6±0.2°、11.4±0.2°、13.2±0.2°、16.0±0.2°、17.0±0.2°、18.2±0.2°、19.6±0.2°、21.0±0.2°； 4.7±0.2°、5.7±0.2°、6.6±0.2°、11.4±0.2°、13.2±0.2°、14.0±0.2°、16.0±0.2°、17.0±0.2°、18.2±0.2°、19.6±0.2°； 4.7±0.2°、5.7±0.2°、6.6±0.2°、11.4±0.2°、14.0±0.2°、16.0±0.2°、17.0±0.2°、18.2±0.2°、19.6±0.2°、21.0±0.2°； The most preferred X-ray powder diffraction pattern of p-toluenesulfonate salt Form A is substantially as shown in FIG9 ; The X-ray powder diffraction pattern of the p-toluenesulfonate salt form B comprises at least one or more diffraction peaks located at 2θ of 5.7±0.2°, 16.4±0.2°, and 17.0±0.2°, preferably 2 of them, and more preferably 3 of them; optionally, it may further comprise at least one of 2θ of 7.2±0.2°, 8.5±0.2°, 13.1±0.2°, 18.2±0.2°, and 21.5±0.2°, preferably 2, 3, 4 or 5 of them; More preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form B optionally further comprises one or more diffraction peaks located at 2θ of 18.7±0.2°, 21.8±0.2°, 22.5±0.2°, 22.7±0.2°, and 26.0±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 the p-toluenesulfonate salt form B comprises one or more diffraction peaks located at 2θ of 5.7±0.2°, 7.2±0.2°, 8.5±0.2°, 13.1±0.2°, 16.4±0.2°, 17.0±0.2°, 18.2±0.2°, 18.7±0.2°, 21.5±0.2°, and 21.8±0.2°; preferably, there are diffraction peaks at 4, 5, 6, 8 or 10 of them; For example, the X-ray powder diffraction spectrum of the p-toluenesulfonate salt form B has diffraction peaks at the following positions at 2θ: 5.7±0.2°、7.2±0.2°、8.5±0.2°、16.4±0.2°、17.0±0.2°； 5.7±0.2°、13.1±0.2°、16.4±0.2°、17.0±0.2°、18.2±0.2°； 5.7±0.2°、8.5±0.2°、16.4±0.2°、17.0±0.2°、21.5±0.2°； 5.7±0.2°、7.2±0.2°、16.4±0.2°、17.0±0.2°、18.2±0.2°、21.5±0.2°； 5.7±0.2°、7.2±0.2°、8.5±0.2°、13.1±0.2°、17.0±0.2°、21.5±0.2°； 5.7±0.2°、7.2±0.2°、8.5±0.2°、13.1±0.2°、16.4±0.2°、18.2±0.2°； 5.7±0.2°、16.4±0.2°、17.0±0.2°、7.2±0.2°、8.5±0.2°、13.1±0.2°、18.2±0.2°、21.5±0.2°； 5.7±0.2°、7.2±0.2°、8.5±0.2°、17.0±0.2°、18.2±0.2°、18.7±0.2°、21.5±0.2°、21.8±0.2°； 5.7±0.2°、7.2±0.2°、8.5±0.2°、13.1±0.2°、16.4±0.2°、18.7±0.2°、21.5±0.2°、21.8±0.2°； 5.7±0.2°、7.2±0.2°、8.5±0.2°、13.1±0.2°、16.4±0.2°、17.0±0.2°、18.2±0.2°、18.7±0.2°、21.5±0.2°、21.8±0.2°； 5.7±0.2°、7.2±0.2°、8.5±0.2°、13.1±0.2°、16.4±0.2°、17.0±0.2°、18.2±0.2°、18.7±0.2°、21.8±0.2°、22.7±0.2°； 5.7±0.2°、7.2±0.2°、8.5±0.2°、13.1±0.2°、16.4±0.2°、17.0±0.2°、18.2±0.2°、18.7±0.2°、21.5±0.2°、21.8±0.2°； The most preferred p-toluenesulfonate salt form B has an X-ray powder diffraction pattern substantially as shown in FIG10 ; a DSC-TGA pattern as shown in FIG11 ; The X-ray powder diffraction pattern of the benzenesulfonate salt form A comprises at least one or more diffraction peaks located at 2θ of 5.2±0.2°, 11.4±0.2°, and 21.0±0.2°, preferably 2 of them, and more preferably 3 of them; optionally, it may further comprise at least one of 2θ of 6.9±0.2°, 16.9±0.2°, 17.7±0.2°, 22.8±0.2°, and 24.1±0.2°, preferably 2, 3, 4 or 5 of them; More preferably, the X-ray powder diffraction pattern of the benzenesulfonate salt form A optionally further comprises one or more diffraction peaks located at 2θ of 13.8±0.2°, 16.3±0.2°, 18.0±0.2°, 18.7±0.2°, 20.5±0.2°, 25.9±0.2°, 27.2±0.2°; preferably at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, or 7 thereof; Further preferably, the X-ray powder diffraction pattern of the benzenesulfonate salt form A comprises one or more diffraction peaks located at 2θ of 5.2±0.2°, 6.9±0.2°, 11.4±0.2°, 16.9±0.2°, 17.7±0.2°, 18.0±0.2°, 21.0±0.2°, 22.8±0.2°, 24.1±0.2°, and 25.9±0.2°; preferably, there are diffraction peaks at 4, 5, 6, 8 or 10 selected therefrom; For example, the X-ray powder diffraction spectrum of the benzenesulfonate salt form A has diffraction peaks at the following positions at 2θ: 5.2±0.2°、6.9±0.2°、11.4±0.2°、16.9±0.2°、21.0±0.2°； 5.2±0.2°、11.4±0.2°、21.0±0.2°、22.8±0.2°、24.1±0.2°； 5.2±0.2°、11.4±0.2°、16.9±0.2°、17.7±0.2°、24.1±0.2°； 5.2±0.2°、11.4±0.2°、21.0±0.2°、6.9±0.2°、16.9±0.2°、17.7±0.2°； 5.2±0.2°、11.4±0.2°、21.0±0.2°、17.7±0.2°、22.8±0.2°、24.1±0.2°； 11.4±0.2°、21.0±0.2°、6.9±0.2°、17.7±0.2°、22.8±0.2°、24.1±0.2°； 5.2±0.2°、6.9±0.2°、11.4±0.2°、16.9±0.2°、17.7±0.2°、18.0±0.2°、24.1±0.2°、25.9±0.2°； 5.2±0.2°、6.9±0.2°、11.4±0.2°、16.9±0.2°、21.0±0.2°、22.8±0.2°、24.1±0.2°、25.9±0.2°； 5.2±0.2°、6.9±0.2°、11.4±0.2°、17.7±0.2°、18.0±0.2°、21.0±0.2°、22.8±0.2°、24.1±0.2°； 5.2±0.2°、6.9±0.2°、11.4±0.2°、16.9±0.2°、17.7±0.2°、18.0±0.2°、21.0±0.2°、22.8±0.2°、24.1±0.2°、25.9±0.2°； 5.2±0.2°、6.9±0.2°、11.4±0.2°、13.8±0.2°、17.7±0.2°、18.0±0.2°、21.0±0.2°、22.8±0.2°、24.1±0.2°、25.9±0.2°； 5.2±0.2°、6.9±0.2°、11.4±0.2°、16.9±0.2°、17.7±0.2°、18.0±0.2°、21.0±0.2°、22.8±0.2°、24.1±0.2°、27.2±0.2°； The X-ray powder diffraction pattern of the most preferred benzenesulfonate salt form A is substantially as shown in FIG. 12 ; the DSC-TGA pattern is shown in FIG. 13 .

7. The compound according to any one of claims 5 to 6 or the acid salt of its stereoisomer, and the crystal form of its salt, characterized in that: The 2θ errors of the top ten diffraction peak positions with relative peak intensities in the X-ray powder diffraction patterns of hydrochloride form A, hydrochloride form B, hydrobromide form A, methanesulfonate form A, p-toluenesulfonate form A, p-toluenesulfonate form B and benzenesulfonate form A 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, 3, 5, 7, 9, 10 and 12 are respectively ±0.2° to ±0.5°; preferably ±0.2° to ±0.3°, and most preferably ±0.2°.

8. A method for preparing a crystalline form of an acid salt of a compound or a stereoisomer thereof according to any one of claims 1 to 7, characterized in that: It includes the following steps: 1) suspending the compound with a poor solvent; 2) Weigh an appropriate amount of counter ion acid and dissolve it in an organic solvent; the amount of the counter ion acid is preferably 1.2 equivalents; 3) Combine the above two solutions and stir to dissolve, continue stirring to precipitate or add a poor solvent dropwise and stir to precipitate; 4) rapidly centrifuging or standing to dry to obtain the crystal form; in: 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 organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol or N,N-dimethylformamide; preferably methanol, ethanol or acetonitrile; the above benign solvent and organic solution need to be miscible when used; The counter ion acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, ethanesulfonic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulfuric acid, dibenzoyltartaric acid, ethane-1 , 2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactosonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, p-toluenesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid or L-malic acid; preferably hydrochloric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid or benzenesulfonic acid.

9. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 7 or an acid salt of its stereoisomer and a crystalline form of its salt, and one or more pharmaceutically acceptable carriers or excipients.

10. Use of the compound according to any one of claims 1 to 7 or the acid salt of its stereoisomer and the crystalline form of its salt, and the pharmaceutical composition according to claim 9 in the preparation of drugs for treating and / or preventing FGFR-related diseases, especially 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 7 or the acid salt of its stereoisomer and the crystal form of its salt, and the pharmaceutical composition according to claim 9 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.

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