A salt or crystal form of a bicyclic derivative inhibitor and its preparation method and application

Abstract

The present application relates to a kind of salt containing di-and cyclic derivative inhibitor, its crystal form and its preparation method and application.Specifically related to the salt of compound 6-(((R)-2-hydroxy-2-methylbut-3-alkyne-1-yl)oxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl)-3,6 diazabicyclo [3.1.1] heptane-3-yl)pyridine-3-yl)pyrazolo [1,5-a] pyridine-3-carbonitrile, its crystal form, its preparation method and pharmaceutical composition containing therapeutically effective amount of the salt of the compound or its crystal form, and as RET inhibitor in the application of treating cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease and AIDS and other related diseases.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to an inhibitor salt or crystal form containing a dicyclic derivative, its preparation method, and its application. Background Technology

[0002] RET (rearranged during transfection) protein, encoded by the proto-oncogene RET located on chromosome 10, is a receptor tyrosine kinase composed of an extracellular domain, a transmembrane domain, and an intracellular kinase domain. RET ligands are glial cell-derived neurotrophic factor (GDNF) family ligands (GFLs), such as GDNF, neurturin (NRTN), artemin (ARTN), and persephin (PSPN). Activation of the receptor also requires the co-receptor GFRα family. GFLs and GFRα form a dimer, binding to RET and recruiting it to a cholesterol-rich membrane region. The RET protein dimers and undergoes autophosphorylation, thereby activating downstream signaling pathways such as RAS-MAPK, PI3K-AKT, and PKC. RET plays a crucial role in the development of the kidneys and enteric nervous system during embryonic development; it is also important for the homeostasis of neuroendocrine, hematopoietic, and male germ cell tissues.

[0003] Disorders of RET protein function lead to a variety of diseases. During development, loss of RET protein function can result in a range of congenital diseases such as Hirschsprung's disease (HSCR) and congenital kidney and urinary tract malformations (CAKUT). Activating mutations in RET protein, including point mutations and RET protein fusions resulting from chromosomal rearrangements, are also associated with various diseases. RET fusions primarily occur in 1–2% of non-small cell lung cancer (NSCLC) patients and 5–10% of papillary thyroid carcinomas, while RET mutations mainly occur in 60% of medullary thyroid carcinomas. Furthermore, activating mutations of RET protein have been found in many other tumors such as breast cancer, gastric cancer, colorectal cancer, and chronic myeloid leukemia.

[0004] Despite significant clinical need, current treatments targeting RET remain extremely limited. Unlike targeted therapies for ALK and EGFR, which have achieved excellent clinical efficacy, there are currently no approved targeted therapies for RET. Current clinical treatments primarily utilize multi-kinase inhibitors (MKIs) such as vandetinib and cabozantinib. However, these MKIs suffer from poor selectivity, high side effects, and poor efficacy, and they also cannot overcome the drug resistance issues that arise during treatment.

[0005] The demand for RET-targeted therapies has attracted numerous domestic and international pharmaceutical companies to conduct research and development of RET-specific targeted drugs. Among the most prominent are Loxo Oncology's LOXO-292, which has entered Phase I / II clinical trials, and Blueprint's BLU-667, which has also entered Phase I clinical trials. Both of these targeted drugs have demonstrated very good efficacy and safety in patients with RET activating mutations in early clinical trials. Furthermore, they have overcome potential drug resistance mutations in preclinical activity screening, and are expected to provide more treatment options for cancers with RET activating mutations in the future.

[0006] Currently, there are no specific targeted drugs for RET, indicating a significant clinical need. RET inhibitors with higher selectivity, better activity, better safety profiles, and the ability to overcome drug resistance mutations have the potential to treat various cancers and possess broad market prospects. Summary of the Invention

[0007] All contents relating to patent PCT / CN2020 / 090142 are incorporated herein by reference.

[0008] The purpose of this invention is to provide an acid salt of the compound 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile.

[0009] In a more preferred embodiment of the present invention, the acid in the acid salt is selected from benzenesulfonic acid, hydrochloric acid, p-toluenesulfonic acid, oxalic acid, phosphoric acid, and hydrobromic acid; benzenesulfonic acid is preferred.

[0010] In a more preferred embodiment of the present invention, the number of acids in the acid salt of the above-mentioned compound 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.

[0011] In a more preferred embodiment of the present invention, the acid salt of the above-mentioned compound is a hydrate or anhydrous form, and when the acid salt is a hydrate, the number of water molecules 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.

[0012] In a more preferred embodiment of the present invention, the acid salt of the above-mentioned compound is characterized in that the acid salt of the compound 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile is a crystal form, preferably a methanesulfonate crystal form, sulfate crystal form, hydrobromide crystal form, phosphate crystal form, benzenesulfonate crystal form, oxalate crystal form, hydroxyethylsulfonate crystal form, maleate crystal form, fumarate crystal form, adipate crystal form, p-methylbenzenesulfonate crystal form, citrate crystal form, malonate crystal form or L-malate crystal form, more preferably a benzenesulfonate crystal form.

[0013] In a more preferred embodiment of the present invention, the acid salt of the above-mentioned compound is characterized in that the compound is 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile, wherein:

[0014] The X-ray powder diffraction pattern of benzenesulfonate crystal form I has a characteristic peak at 2θ of 17.7 ± 0.2°, or at 2θ of 8.4 ± 0.2°, or at 2θ of 24.8 ± 0.2°, or at 2θ of 21.5 ± 0.2°, or at 2θ of 17.1 ± 0.2°, or at 2θ of 15.2 ± 0.2°, or at 2θ of 23.4 ± 0.2°, or The diffraction peaks have the following characteristics: at 2θ = 19.3 ± 0.2°, or at 2θ = 28.2 ± 0.2°, or at 2θ = 18.9 ± 0.2°, or at 2θ = 11.8 ± 0.2°, or at 2θ = 18.6 ± 0.2°; preferably, any 2-12, 5-8, or 6-8 of the above diffraction peaks are included, and more preferably, any 2, 3, 6, 8, 10, or 12 of them are included.

[0015] The X-ray powder diffraction pattern of benzenesulfonate crystal form II has a characteristic peak at 2θ of 17.7 ± 0.2°, or at 2θ of 15.2 ± 0.2°, or at 2θ of 21.5 ± 0.2°, or at 2θ of 24.8 ± 0.2°, or at 2θ of 8.5 ± 0.2°, or at 2θ of 19.3 ± 0.2°, or at 2θ of 17.1 ± 0.2°, or The diffraction peaks have characteristic peaks at 2θ = 18.6 ± 0.2°, or at 2θ = 23.4 ± 0.2°, or at 2θ = 7.7 ± 0.2°, or at 2θ = 6.5 ± 0.2°, or at 2θ = 13.9 ± 0.2°; preferably, any 2-12, 5-8, or 6-8 of the above diffraction peaks are included, more preferably any 2, 3, 6, 8, 10, or 12 of them are included.

[0016] The X-ray powder diffraction pattern of p-toluenesulfonate crystal form I has a characteristic peak at 2θ of 18.4 ± 0.2°, or at 2θ of 15.1 ± 0.2°, or at 2θ of 8.1 ± 0.2°, or at 2θ of 16.9 ± 0.2°, or at 2θ of 7.6 ± 0.2°, or at 2θ of 17.4 ± 0.2°, or at 2θ of 20.9 ± 0.2°, or at 2θ of 17.2 ± 0.2°. The diffraction peak has a characteristic peak at 0.2°, or at 5.0±0.2°, or at 19.0±0.2°, or at 22.8±0.2°, or at 24.0±0.2°, or at 13.6±0.2°; preferably, it includes any 2-12, 5-8, or 6-8 of the above diffraction peaks, more preferably any 2, 3, 6, 8, 10, or 12 of them.

[0017] The X-ray powder diffraction pattern of hydrochloride crystal form I has a characteristic peak at 2θ of 10.0±0.2°, or at 2θ of 6.0±0.2°, or at 2θ of 15.6±0.2°, or at 2θ of 16.8±0.2°, or at 2θ of 24.6±0.2°, or at 2θ of 23.0±0.2°, or at 2θ of 20.8±0.2°, or at... The diffraction peak has a characteristic peak at 2θ = 26.7 ± 0.2°, or at 2θ = 17.5 ± 0.2°, or at 2θ = 21.6 ± 0.2°, or at 2θ = 14.9 ± 0.2°, or at 2θ = 30.7 ± 0.2°; preferably, it includes any 2-12, 5-8, or 6-8 of the above diffraction peaks, more preferably any 2, 3, 6, 8, 10, or 12 of them.

[0018] The X-ray powder diffraction pattern of hydrochloride crystal form II has a characteristic peak at 2θ of 10.0 ± 0.2°, or at 2θ of 6.0 ± 0.2°, or at 2θ of 6.6 ± 0.2°, or at 2θ of 15.6 ± 0.2°, or at 2θ of 24.7 ± 0.2°, or at 2θ of 23.1 ± 0.2°, or at 2θ of 16.8 ± 0.2°, or at... The diffraction peak has a characteristic peak at 2θ = 17.5 ± 0.2°, or at 2θ = 20.8 ± 0.2°, or at 2θ = 23.9 ± 0.2°, or at 2θ = 22.4 ± 0.2°, or at 2θ = 26.7 ± 0.2°; preferably, it includes any 2-12, 5-8, or 6-8 of the above diffraction peaks, more preferably any 2, 3, 6, 8, 10, or 12 of them.

[0019] The X-ray powder diffraction pattern of hydrobromide crystal form I has a characteristic peak at 2θ of 9.9 ± 0.2°, or at 2θ of 5.9 ± 0.2°, or at 2θ of 22.8 ± 0.2°, or at 2θ of 20.6 ± 0.2°, or at 2θ of 24.4 ± 0.2°, or at 2θ of 16.7 ± 0.2°, or at 2θ of 21.4 ± 0.2°, or at... The diffraction peak has a characteristic peak at 2θ = 26.6 ± 0.2°, or at 2θ = 17.4 ± 0.2°, or at 2θ = 24.9 ± 0.2°, or at 2θ = 23.1 ± 0.2°, or at 2θ = 30.6 ± 0.2°; preferably, it includes any 2-12, 5-8, or 6-8 of the above diffraction peaks, more preferably any 2, 3, 6, 8, 10, or 12 of them.

[0020] The X-ray powder diffraction pattern of oxalate crystal form I has a characteristic peak at 2θ of 9.5 ± 0.2°, or at 2θ of 19.3 ± 0.2°, or at 2θ of 10.7 ± 0.2°, or at 2θ of 4.7 ± 0.2°, or at 2θ of 6.0 ± 0.2°, or at 2θ of 16.5 ± 0.2°, or at 2θ of 25.0 ± 0.2°, or at 2 The diffraction peak has a characteristic peak at θ = 27.1 ± 0.2°, or at 2θ = 15.3 ± 0.2°, or at 2θ = 14.5 ± 0.2°, or at 2θ = 18.6 ± 0.2°, or at 2θ = 20.5 ± 0.2°; preferably, it includes any 2-12, 5-8, or 6-8 of the above diffraction peaks, more preferably any 2, 3, 6, 8, 10, or 12 of them.

[0021] The X-ray powder diffraction pattern of oxalate crystal form II has a characteristic peak at 2θ of 5.8 ± 0.2°, or at 2θ of 4.8 ± 0.2°, or at 2θ of 15.7 ± 0.2°, or at 2θ of 17.0 ± 0.2°, or at 2θ of 9.4 ± 0.2°, or at 2θ of 19.2 ± 0.2°, or at 2θ of 17.7 ± 0.2°, or at... The diffraction peak has a characteristic peak at 2θ = 16.6 ± 0.2°, or at 2θ = 26.1 ± 0.2°, or at 2θ = 11.8 ± 0.2°, or at 2θ = 18.6 ± 0.2°, or at 2θ = 12.5 ± 0.2°; preferably, it includes any 2-12, 5-8, or 6-8 of the above diffraction peaks, more preferably any 2, 3, 6, 8, 10, or 12 of them.

[0022] The X-ray powder diffraction pattern of oxalate crystal form III has a characteristic peak at 2θ of 10.4 ± 0.2°, or at 2θ of 5.1 ± 0.2°, or at 2θ of 4.8 ± 0.2°, or at 2θ of 15.8 ± 0.2°, or at 2θ of 14.3 ± 0.2°, or at 2θ of 12.2 ± 0.2°, or at 2θ of 17.8 ± 0.2°. The diffraction peak has a characteristic peak at 0.2°, or at 5.8±0.2°, or at 18.9±0.2°, or at 17.0±0.2°, or at 23.8±0.2°; preferably, it includes any 2-12, 5-8, or 6-8 of the above diffraction peaks, more preferably any 2, 3, 6, 8, 10, or 12 of them.

[0023] The X-ray powder diffraction pattern of oxalate crystal form IV has a characteristic peak at 2θ = 20.5 ± 0.2°, or at 2θ = 18.5 ± 0.2°, or at 2θ = 17.9 ± 0.2°, or at 2θ = 4.8 ± 0.2°, or at 2θ = 16.5 ± 0.2°, or at 2θ = 15.8 ± 0.2°, or at 2θ = 11.5 ± 0.2°, or It has a characteristic peak at 2θ of 12.3±0.2°, or at 2θ of 24.0±0.2°, or at 2θ of 16.2±0.2°, or at 2θ of 23.3±0.2°, or at 2θ of 19.6±0.2°; preferably, it includes any 2-12, 5-8, or 6-8 of the above diffraction peaks, more preferably any 2, 3, 6, 8, 10, or 12 of them.

[0024] The X-ray powder diffraction pattern of methanesulfonate crystal form I has a characteristic peak at 2θ of 10.3±0.2°, or at 2θ of 5.1±0.2°, or at 2θ of 15.6±0.2°, or at 2θ of 25.2±0.2°, or at 2θ of 18.4±0.2°; preferably, it includes any 2-12, 5-8, or 6-8 of the above diffraction peaks, more preferably any 2, 3, 6, 8, 10, or 12 of them.

[0025] The X-ray powder diffraction pattern of ethanesulfonate crystal form I has a characteristic peak at 2θ of 10.2±0.2°, or at 2θ of 5.0±0.2°, or at 2θ of 15.4±0.2°, or at 2θ of 18.9±0.2°, or at 2θ of 24.2±0.2°, or at 2θ of 21.1±0.2°; preferably, it includes any 2-12, 5-8, or 6-8 of the above diffraction peaks, more preferably any 2, 3, 6, 8, 10, or 12 of them.

[0026] The X-ray powder diffraction pattern of ethanesulfonate crystal form II has a characteristic peak at 2θ of 10.2±0.2°, or at 2θ of 5.0±0.2°, or at 2θ of 6.0±0.2°, or at 2θ of 15.4±0.2°, or at 2θ of 5.4±0.2°, or at 2θ of 7.3±0.2°; preferably, it includes any 2-12, 5-8, or 6-8 of the above diffraction peaks, more preferably any 2, 3, 6, 8, 10, or 12 of them.

[0027] The X-ray powder diffraction pattern of hydroxyethyl sulfonate crystal form I has a characteristic peak at 2θ of 10.5±0.2°, or at 2θ of 5.2±0.2°, or at 2θ of 18.7±0.2°, or at 2θ of 15.9±0.2°, or at 2θ of 23.0±0.2°; preferably, it includes any 2-12, 5-8, or 6-8 of the above diffraction peaks, more preferably any 2, 3, 6, 8, 10, or 12 of them.

[0028] The X-ray powder diffraction pattern of hydroxyethyl sulfonate crystal form II has a characteristic peak at 2θ of 11.9 ± 0.2°, or at 2θ of 18.4 ± 0.2°, or at 2θ of 4.8 ± 0.2°, or at 2θ of 23.4 ± 0.2°, or at 2θ of 16.7 ± 0.2°, or at 2θ of 17.8 ± 0.2°, or at 2θ of 12.8 ± 0.2°, or The diffraction peaks have characteristic peaks at 2θ = 23.8 ± 0.2°, or at 2θ = 21.8 ± 0.2°, or at 2θ = 19.0 ± 0.2°, or at 2θ = 25.4 ± 0.2°, or at 2θ = 19.8 ± 0.2°; preferably, any 2-12, 5-8, or 6-8 of the above diffraction peaks are included, more preferably any 2, 3, 6, 8, 10, or 12 of them are included.

[0029] The X-ray powder diffraction pattern of sulfate crystal form I has a characteristic peak at 2θ of 10.3 ± 0.2°, or at 2θ of 5.1 ± 0.2°, or at 2θ of 15.6 ± 0.2°, or at 2θ of 14.5 ± 0.2°, or at 2θ of 20.2 ± 0.2°, or at 2θ of 19.0 ± 0.2°, or at 2θ of 25.6 ± 0.2°, or at... The diffraction peak has a characteristic peak at 22.1±0.2°, or at 23.0±0.2°, or at 20.8±0.2°, or at 29.2±0.2°, or at 24.1±0.2°; preferably, it includes any 2-12, 5-8, or 6-8 of the above diffraction peaks, more preferably any 2, 3, 6, 8, 10, or 12 of them.

[0030] The X-ray powder diffraction pattern of sulfate crystal form II has a characteristic peak at 2θ of 16.1±0.2°, or at 2θ of 5.9±0.2°, or at 2θ of 6.6±0.2°, or at 2θ of 22.0±0.2°, or at 2θ of 21.0±0.2°, or at 2θ of 20.1±0.2°, or at 2θ of 17.0±0.2°, or at 2θ of 25.2±0.2°, or at 2θ of 20.7±0.2°, or at 2θ of 23.1±0.2°; preferably, it includes any 2-12, 5-8, or 6-8 of the above diffraction peaks, more preferably any 2, 3, 6, 8, 10, or 12 of them.

[0031] The X-ray powder diffraction pattern of phosphate crystal form I has a characteristic peak at 2θ of 5.6±0.2°, or at 2θ of 11.5±0.2°, or at 2θ of 20.3±0.2°, or at 2θ of 15.9±0.2°, or at 2θ of 17.2±0.2°, or at 2θ of 16.4±0.2°, or at 2θ of 21.9±0.2°, or at 2θ of 10.2±0.2°; preferably, it includes any 2-12, 5-8, or 6-8 of the above diffraction peaks, more preferably any 2, 3, 6, 8, 10, or 12 of them.

[0032] The X-ray powder diffraction pattern of phosphate crystal form II has a characteristic peak at 2θ of 5.6 ± 0.2°, or at 2θ of 11.4 ± 0.2°, or at 2θ of 15.1 ± 0.2°, or at 2θ of 15.4 ± 0.2°, or at 2θ of 17.2 ± 0.2°, or at 2θ of 20.0 ± 0.2°, or at 2θ of 16.1 ± 0.2°. The diffraction peak has a characteristic peak at 2°, or at 20.3±0.2°, or at 21.0±0.2°, or at 21.8±0.2°, or at 24.7±0.2°; preferably, it includes any 2-12, 5-8, or 6-8 of the above diffraction peaks, more preferably any 2, 3, 6, 8, 10, or 12 of them.

[0033] In a more preferred embodiment of the present invention, the X-ray powder diffraction pattern of benzenesulfonate crystal form I includes two or three diffraction peaks with 2θ values ​​of 17.7±0.2°, 8.4±0.2°, and 24.8±0.2°, and optionally further includes one or more diffraction peaks with 2θ values ​​of 21.5±0.2°, 17.1±0.2°, 19.3±0.2°, 15.2±0.2°, and 23.4±0.2°; preferably including two, three, four, or five of these peaks.

[0034] The X-ray powder diffraction pattern of benzenesulfonate crystal form II includes two or three diffraction peaks with 2θ values ​​of 17.7±0.2°, 15.2±0.2°, and 21.5±0.2°, and optionally further includes one or more diffraction peaks with 2θ values ​​of 24.8±0.2°, 8.5±0.2°, 19.3±0.2°, 17.1±0.2°, and 18.6±0.2°; preferably including two, three, four, or five of these peaks.

[0035] The X-ray powder diffraction pattern of p-toluenesulfonate crystal form I contains two or three diffraction peaks with 2θ values ​​of 18.4±0.2°, 15.1±0.2°, and 8.1±0.2°, and optionally further contains one or more diffraction peaks with 2θ values ​​of 16.9±0.2°, 7.6±0.2°, 17.4±0.2°, 20.9±0.2°, and 17.2±0.2°; preferably, it includes two, three, four, or five of these peaks.

[0036] The X-ray powder diffraction pattern of hydrochloride crystal form I includes two or three diffraction peaks with 2θ values ​​of 10.0±0.2°, 6.0±0.2°, and 15.6±0.2°, and optionally further includes one or more diffraction peaks with 2θ values ​​of 16.8±0.2°, 24.6±0.2°, 23.0±0.2°, 20.8±0.2°, and 26.7±0.2°; preferably including two, three, four, or five of these peaks.

[0037] The X-ray powder diffraction pattern of hydrochloride crystal form II includes two or three diffraction peaks with 2θ values ​​of 10.0±0.2°, 6.0±0.2°, and 6.6±0.2°, and optionally further includes one or more diffraction peaks with 2θ values ​​of 15.6±0.2°, 24.7±0.2°, 23.1±0.2°, 16.8±0.2°, and 17.5±0.2°; preferably including two, three, four, or five of these peaks.

[0038] The X-ray powder diffraction pattern of hydrobromide crystal form I includes two or three diffraction peaks with 2θ values ​​of 9.9±0.2°, 5.9±0.2°, and 22.8±0.2°, and optionally further includes one or more diffraction peaks with 2θ values ​​of 20.6±0.2°, 24.4±0.2°, 16.7±0.2°, 21.4±0.2°, and 26.6±0.2°; preferably including two, three, four, or five of these peaks.

[0039] The X-ray powder diffraction pattern of oxalate crystal form I includes two or three diffraction peaks with 2θ values ​​of 9.5±0.2°, 19.3±0.2°, and 10.7±0.2°, and optionally further includes one or more diffraction peaks with 2θ values ​​of 4.7±0.2°, 6.0±0.2°, 16.5±0.2°, 25.0±0.2°, and 27.1±0.2°; preferably including two, three, four, or five of these peaks.

[0040] The X-ray powder diffraction pattern of oxalate crystal form II includes two or three diffraction peaks with 2θ values ​​of 5.8±0.2°, 4.8±0.2°, and 15.7±0.2°, and optionally further includes one or more diffraction peaks with 2θ values ​​of 17.0±0.2°, 9.4±0.2°, 19.2±0.2°, 17.7±0.2°, and 16.6±0.2°; preferably including two, three, four, or five of these peaks.

[0041] The X-ray powder diffraction pattern of oxalate crystal form III includes two or three diffraction peaks with 2θ values ​​of 10.4±0.2°, 5.1±0.2°, and 4.8±0.2°, and optionally further includes one or more diffraction peaks with 2θ values ​​of 15.8±0.2°, 14.3±0.2°, 12.2±0.2°, 17.8±0.2°, and 5.8±0.2°; preferably including two, three, four, or five of these peaks.

[0042] The X-ray powder diffraction pattern of oxalate crystal form IV contains two or three diffraction peaks at 2θ values ​​of 20.5±0.2°, 18.5±0.2°, and 17.9±0.2°, and optionally further contains one or more diffraction peaks at 2θ values ​​of 4.8±0.2°, 16.5±0.2°, 15.8±0.2°, 11.5±0.2°, and 12.3±0.2°; preferably, it includes two, three, four, or five of these peaks.

[0043] The X-ray powder diffraction pattern of methanesulfonate crystal form I contains two or three diffraction peaks at 2θ values ​​of 10.3±0.2°, 5.1±0.2°, and 15.6±0.2°, and optionally further contains one or more diffraction peaks at 2θ values ​​of 25.2±0.2° and 18.4±0.2°; preferably, it includes two, three, four, or five of these peaks.

[0044] The X-ray powder diffraction pattern of ethanesulfonate crystal form I contains two or three diffraction peaks at 2θ values ​​of 10.2±0.2°, 5.0±0.2°, and 15.4±0.2°, and optionally further contains one or more diffraction peaks at 2θ values ​​of 24.2±0.2°, 18.9±0.2°, and 21.1±0.2°; preferably, it includes two, three, four, or five of these peaks.

[0045] The X-ray powder diffraction pattern of ethanesulfonate crystal form II includes two or three diffraction peaks at 2θ values ​​of 10.2±0.2°, 5.0±0.2°, and 6.0±0.2°, and optionally further includes one or more diffraction peaks at 2θ values ​​of 15.4±0.2° and 5.4±0.2°; preferably including two, three, four, or five of these peaks.

[0046] The X-ray powder diffraction pattern of hydroxyethyl sulfonate crystal form I contains two or three diffraction peaks at 2θ values ​​of 10.5±0.2°, 5.2±0.2°, and 18.7±0.2°, and optionally further contains one or more diffraction peaks at 2θ values ​​of 15.9±0.2° and 23.0±0.2°; preferably, it includes two, three, four, or five of these peaks.

[0047] The X-ray powder diffraction pattern of hydroxyethyl sulfonate crystal form II includes two or three diffraction peaks with 2θ values ​​of 11.9±0.2°, 18.4±0.2°, and 4.8±0.2°, and optionally further includes one or more diffraction peaks with 2θ values ​​of 23.4±0.2°, 16.7±0.2°, 17.8±0.2°, 12.8±0.2°, and 23.8±0.2°; preferably including two, three, four, or five of these peaks.

[0048] The X-ray powder diffraction pattern of sulfate crystal form I includes two or three diffraction peaks with 2θ values ​​of 10.3±0.2°, 5.1±0.2°, and 15.6±0.2°, and optionally further includes one or more diffraction peaks with 2θ values ​​of 14.5±0.2°, 20.2±0.2°, 19.0±0.2°, 25.6±0.2°, and 22.1±0.2°; preferably including two, three, four, or five of these peaks.

[0049] The X-ray powder diffraction pattern of sulfate crystal form II includes two or three diffraction peaks with 2θ values ​​of 16.1±0.2°, 5.9±0.2°, and 6.6±0.2°, and optionally further includes one or more diffraction peaks with 2θ values ​​of 22.0±0.2°, 21.0±0.2°, 20.1±0.2°, 17.0±0.2°, and 25.2±0.2°; preferably including two, three, four, or five of these peaks.

[0050] The X-ray powder diffraction pattern of phosphate crystal form I includes two or three diffraction peaks with 2θ values ​​of 5.6±0.2°, 11.5±0.2°, and 20.3±0.2°, and optionally further includes one or more diffraction peaks with 2θ values ​​of 15.9±0.2°, 17.2±0.2°, 16.4±0.2°, and 21.9±0.2°; preferably including two, three, four, or five of these peaks.

[0051] The X-ray powder diffraction pattern of phosphate crystal form II includes two or three diffraction peaks with 2θ values ​​of 5.6±0.2°, 11.4±0.2°, and 15.1±0.2°, and optionally further includes one or more diffraction peaks with 2θ values ​​of 15.4±0.2°, 17.2±0.2°, 20.0±0.2°, 16.1±0.2°, and 20.3±0.2°; preferably including two, three, four, or five of these peaks.

[0052] In a more preferred embodiment of the present invention, the X-ray powder diffraction pattern of benzenesulfonate crystal form I includes one or more diffraction peaks with 2θ values ​​of 17.7±0.2°, 8.4±0.2°, 24.8±0.2°, 21.5±0.2°, 17.1±0.2°, 15.2±0.2°, 23.4±0.2°, 19.3±0.2°, 28.2±0.2°, 18.9±0.2°, 11.8±0.2°, and 18.6±0.2°; preferably, it includes diffraction peaks at any of 4, 6, 8, and 10 selected locations.

[0053] The X-ray powder diffraction pattern of benzenesulfonate crystal form II includes one or more diffraction peaks with 2θ values ​​of 17.7±0.2°, 15.2±0.2°, 21.5±0.2°, 24.8±0.2°, 8.5±0.2°, 19.3±0.2°, 17.1±0.2°, 18.6±0.2°, 23.4±0.2°, 7.7±0.2°, 6.5±0.2°, and 13.9±0.2°; preferably, it includes diffraction peaks at 4, 6, 8, and 10 selected locations.

[0054] The X-ray powder diffraction pattern of p-toluenesulfonate crystal form I includes one or more diffraction peaks with 2θ values ​​of 18.4±0.2°, 15.1±0.2°, 8.1±0.2°, 16.9±0.2°, 7.6±0.2°, 17.4±0.2°, 20.9±0.2°, 17.2±0.2°, 5.0±0.2°, 19.0±0.2°, 22.8±0.2°, 24.0±0.2°, and 13.6±0.2°; preferably, it includes diffraction peaks at 4, 6, 8, and 10 of these values.

[0055] The X-ray powder diffraction pattern of hydrochloride crystal form I includes one or more diffraction peaks with 2θ values ​​of 10.0±0.2°, 6.0±0.2°, 15.6±0.2°, 16.8±0.2°, 24.6±0.2°, 23.0±0.2°, 20.8±0.2°, 26.7±0.2°, 17.5±0.2°, 21.6±0.2°, 14.9±0.2°, and 30.7±0.2°; preferably, it includes diffraction peaks at 4, 6, 8, and 10 selected locations.

[0056] The X-ray powder diffraction pattern of hydrochloride crystal form II includes one or more diffraction peaks with 2θ values ​​of 10.0±0.2°, 6.0±0.2°, 6.6±0.2°, 15.6±0.2°, 24.7±0.2°, 23.1±0.2°, 16.8±0.2°, 17.5±0.2°, 20.8±0.2°, 23.9±0.2°, 22.4±0.2°, and 26.7±0.2°; preferably, it includes diffraction peaks at 4, 6, 8, and 10 selected locations.

[0057] The X-ray powder diffraction pattern of hydrobromide crystal form I includes one or more diffraction peaks with 2θ values ​​of 9.9±0.2°, 5.9±0.2°, 22.8±0.2°, 20.6±0.2°, 24.4±0.2°, 16.7±0.2°, 21.4±0.2°, 26.6±0.2°, 17.4±0.2°, 24.9±0.2°, 23.1±0.2°, and 30.6±0.2°; preferably, it includes diffraction peaks at 4, 6, 8, and 10 of these values.

[0058] The X-ray powder diffraction pattern of oxalate crystal form I includes one or more diffraction peaks with 2θ values ​​of 9.5±0.2°, 19.3±0.2°, 10.7±0.2°, 4.7±0.2°, 6.0±0.2°, 16.5±0.2°, 25.0±0.2°, 27.1±0.2°, 15.3±0.2°, 14.5±0.2°, 18.6±0.2°, and 20.5±0.2°; preferably, it includes diffraction peaks at 4, 6, 8, and 10 of these values.

[0059] The X-ray powder diffraction pattern of oxalate crystal form II includes one or more diffraction peaks with 2θ values ​​of 5.8±0.2°, 4.8±0.2°, 15.7±0.2°, 17.0±0.2°, 9.4±0.2°, 19.2±0.2°, 17.7±0.2°, 16.6±0.2°, 26.1±0.2°, 11.8±0.2°, 18.6±0.2°, and 12.5±0.2°; preferably, it includes diffraction peaks at 4, 6, 8, and 10 of these values.

[0060] The X-ray powder diffraction pattern of oxalate crystal form III includes one or more diffraction peaks with 2θ values ​​of 10.4±0.2°, 5.1±0.2°, 4.8±0.2°, 15.8±0.2°, 14.3±0.2°, 12.2±0.2°, 17.8±0.2°, 5.8±0.2°, 18.9±0.2°, 17.0±0.2°, and 23.8±0.2°; preferably, it includes diffraction peaks at 4, 6, 8, and 10 of these values.

[0061] The X-ray powder diffraction pattern of oxalate crystal form IV includes one or more diffraction peaks with 2θ values ​​of 20.5±0.2°, 18.5±0.2°, 17.9±0.2°, 4.8±0.2°, 16.5±0.2°, 15.8±0.2°, 11.5±0.2°, 12.3±0.2°, 24.0±0.2°, 16.2±0.2°, 23.3±0.2°, and 19.6±0.2°; preferably, it includes diffraction peaks at 4, 6, 8, and 10 selected locations.

[0062] The X-ray powder diffraction pattern of methanesulfonate crystal form I includes one or more diffraction peaks with 2θ values ​​of 10.3±0.2°, 5.1±0.2°, 15.6±0.2°, 25.2±0.2°, and 18.4±0.2°; preferably, it includes any four of these diffraction peaks.

[0063] The X-ray powder diffraction pattern of ethanesulfonate crystal form I includes one or more diffraction peaks with 2θ values ​​of 10.2±0.2°, 5.0±0.2°, 15.4±0.2°, 18.9±0.2°, 24.2±0.2°, and 21.1±0.2°; preferably, it includes diffraction peaks at 4 and 6 of these values, respectively.

[0064] The X-ray powder diffraction pattern of ethanesulfonate crystal form II includes one or more diffraction peaks with 2θ values ​​of 10.2±0.2°, 5.0±0.2°, 6.0±0.2°, 15.4±0.2°, 5.4±0.2°, and 7.3±0.2°; preferably, it includes diffraction peaks at four and six of these values, respectively.

[0065] The X-ray powder diffraction pattern of hydroxyethyl sulfonate crystal form I contains one or more diffraction peaks with 2θ values ​​of 10.5±0.2°, 5.2±0.2°, 18.7±0.2°, 15.9±0.2°, and 23.0±0.2°; preferably, it contains four diffraction peaks selected from these values.

[0066] The X-ray powder diffraction pattern of hydroxyethyl sulfonate crystal form II includes one or more diffraction peaks with 2θ values ​​of 11.9±0.2°, 18.4±0.2°, 4.8±0.2°, 23.4±0.2°, 16.7±0.2°, 17.8±0.2°, 12.8±0.2°, 23.8±0.2°, 21.8±0.2°, 19.0±0.2°, 25.4±0.2°, and 19.8±0.2°; preferably, it includes diffraction peaks at 4, 6, 8, and 10 selected locations.

[0067] The X-ray powder diffraction pattern of sulfate crystal form I includes one or more diffraction peaks with 2θ values ​​of 10.3±0.2°, 5.1±0.2°, 15.6±0.2°, 14.5±0.2°, 20.2±0.2°, 19.0±0.2°, 25.6±0.2°, 22.1±0.2°, 23.0±0.2°, 20.8±0.2°, 19.2±0.2°, and 24.1±0.2°; preferably, it includes diffraction peaks at 4, 6, 8, and 10 selected locations.

[0068] The X-ray powder diffraction pattern of sulfate crystal form II includes one or more diffraction peaks with 2θ values ​​of 16.1±0.2°, 5.9±0.2°, 6.6±0.2°, 22.0±0.2°, 21.0±0.2°, 20.1±0.2°, 17.0±0.2°, 25.2±0.2°, 20.7±0.2°, and 23.1±0.2°; preferably, it includes diffraction peaks at 4, 6, 8, and 10 selected locations.

[0069] The X-ray powder diffraction pattern of phosphate crystal form I includes one or more diffraction peaks with 2θ values ​​of 5.6±0.2°, 11.5±0.2°, 20.3±0.2°, 15.9±0.2°, 17.2±0.2°, 16.4±0.2°, 21.9±0.2°, and 10.2±0.2°; preferably, it includes diffraction peaks at 4, 6, and 8 selected locations.

[0070] The X-ray powder diffraction pattern of phosphate crystal form II includes one or more diffraction peaks with 2θ values ​​of 5.6±0.2°, 11.4±0.2°, 15.1±0.2°, 15.4±0.2°, 17.2±0.2°, 20.0±0.2°, 16.1±0.2°, 20.3±0.2°, 21.0±0.2°, 21.8±0.2°, and 24.7±0.2°; preferably, it includes diffraction peaks at 4, 6, 8, and 10 selected locations.

[0071] In a more preferred embodiment of the present invention, the X-ray powder diffraction pattern of benzenesulfonate crystal form I is as follows: Figure 1 As shown; the X-ray powder diffraction pattern of benzenesulfonate crystal form II is as follows. Figure 4 As shown; the X-ray powder diffraction pattern of p-toluenesulfonate crystal form I is as follows. Figure 7 As shown; the X-ray powder diffraction pattern of hydrochloride crystal form I is as follows. Figure 10 As shown; the X-ray powder diffraction pattern of hydrochloride crystal form II is as follows. Figure 13 As shown; the X-ray powder diffraction pattern of hydrobromide crystal form I is as follows. Figure 15 As shown; the X-ray powder diffraction pattern of oxalate crystal form I is as follows. Figure 18 As shown; the X-ray powder diffraction pattern of oxalate crystal form II is as follows. Figure 21 As shown; the X-ray powder diffraction pattern of oxalate crystal form III is as follows. Figure 22 As shown; the X-ray powder diffraction pattern of oxalate crystal form IV is as follows. Figure 23 As shown; the X-ray powder diffraction pattern of methanesulfonate crystal form I is as follows. Figure 26 As shown; the X-ray powder diffraction pattern of ethanesulfonate crystal form I is as follows. Figure 29 As shown; the X-ray powder diffraction pattern of ethanesulfonate crystal form II is as follows. Figure 32 As shown; the X-ray powder diffraction pattern of hydroxyethyl sulfonate crystal form I is as follows. Figure 35 As shown; the X-ray powder diffraction pattern of hydroxyethyl sulfonate crystal form II is as follows. Figure 36 As shown; the X-ray powder diffraction pattern of sulfate crystal form I is as follows. Figure 39 As shown; the X-ray powder diffraction pattern of sulfate crystal form II is as follows. Figure 40 As shown; the X-ray powder diffraction pattern of phosphate crystal form I is as follows. Figure 41 As shown; the X-ray powder diffraction pattern of phosphate crystal form II is as follows. Figure 42 As shown.

[0072] In a more preferred embodiment of the present invention, the positions of the top ten diffraction peaks with the highest relative peak intensities in the X-ray powder diffraction patterns of benzenesulfonate crystal form I, benzenesulfonate crystal form II, p-toluenesulfonate crystal form I, hydrochloride crystal form I, hydrochloride crystal form II, hydrobromide crystal form I, oxalate crystal form I, oxalate crystal form II, oxalate crystal form III, oxalate crystal form IV, methanesulfonate crystal form I, ethanesulfonate crystal form I, ethanesulfonate crystal form II, hydroxyethylsulfonate crystal form I, hydroxyethylsulfonate crystal form II, sulfate crystal form I, sulfate crystal form II, phosphate crystal form I, and phosphate crystal form II are respectively... Figure 1 , Figure 4 , Figure 7 , Figure 10 , Figure 13 , Figure 15 , Figure 18 , Figure 21 , Figure 22 , Figure 23 , Figure 26 , Figure 29 , Figure 32 , Figure 35 , Figure 36 , Figure 39 , Figure 40 , Figure 41 and Figure 42 The 2θ error of the diffraction peak at the corresponding position is ±0.2° to ±0.5°, with ±0.2° to ±0.3° being preferred and ±0.2° being the best option.

[0073] In a more preferred embodiment of the present invention,

[0074] Benzenesulfonate crystal form I has the following properties: Figure 2 The DSC spectrum shown; or having the following: Figure 3 The TGA spectrum shown;

[0075] Benzenesulfonate crystal form II has such Figure 5 The DSC spectrum shown; or having the following: Figure 6 The TGA chart shown;

[0076] p-Toluenesulfonate crystal form I has such Figure 8 The DSC spectrum shown; or having the following: Figure 9 The TGA spectrum shown;

[0077] Hydrochloride crystal form I has as Figure 11 The DSC spectrum shown; or having the following: Figure 12 The TGA spectrum shown;

[0078] Hydrochloride crystal form II has such Figure 14 The DSC spectrum shown;

[0079] Hydrobromate crystal form I has the following characteristics: Figure 16 The DSC spectrum shown; or having the following: Figure 17 The TGA spectrum shown;

[0080] Oxalate crystal form I has the following properties: Figure 19 The DSC spectrum shown; or having the following: Figure 20 The TGA spectrum shown;

[0081] Oxalate crystal form IV has the following properties: Figure 24 The DSC spectrum shown; or having the following: Figure 25 The TGA spectrum shown;

[0082] Methanesulfonate crystal form I has such Figure 27 The DSC spectrum shown; or having the following: Figure 28 The TGA spectrum shown;

[0083] Ethyl sulfonate crystal form I has the following properties: Figure 30 The DSC spectrum shown; or having the following: Figure 31 The TGA spectrum shown;

[0084] Ethyl sulfonate crystal form II has the following properties: Figure 33 The DSC spectrum shown; or having the following: Figure 34 The TGA spectrum shown.

[0085] In a more preferred embodiment of the present invention, the method for preparing the acid salt of the above-mentioned compound specifically includes the following steps:

[0086] 1) Weigh out an appropriate amount of free base and dissolve it in a good solvent;

[0087] 2) Weigh an appropriate amount of the counterion acid and dissolve it in an organic solvent; the amount of the counterion acid is preferably 1.0 to 1.5 equivalents.

[0088] 3) Combine the two solutions mentioned above and stir to precipitate, or add a poor solvent and stir to precipitate;

[0089] 4) Quickly centrifuge or allow to stand and dry to obtain the target product;

[0090] in:

[0091] The benign solvent is selected from one or more of dichloromethane, tetrahydrofuran, 1,4-dioxane, acetone, methanol, ethanol, 2-methyltetrahydrofuran, 2-butanone, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol or tert-butanol;

[0092] Preferably, one or more of tetrahydrofuran, dichloromethane, 1,4-dioxane, 2-butanone, or acetone are used;

[0093] The organic solvent is selected from one or more of methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol, or N,N-dimethylformamide;

[0094] Preferably, one or more of dichloromethane, tetrahydrofuran, or 1,4-dioxane are used;

[0095] The above-mentioned benign solvents and organic solutions must be miscible when used;

[0096] The unsuitable solvent is selected from n-heptane, water, methyl tert-butyl ether, n-hexane, cyclohexane, isopropyl ether, and ethyl acetate; preferably one or more of water, methyl tert-butyl ether, or isopropyl ether.

[0097] The aforementioned counterionic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphtholic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxyxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetaminobenzoic acid, 4-aminobenzoic acid, decanoic acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfonic 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 sulfate, and dibenzoyl alcohol. The following are one or more of the following: tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactobionic acid, gentian acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, hydroxyethylsulfonic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, dihydroxynaphthalic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanate, pamoic acid, formic acid, undecanoic acid, trifluoroacetic acid, benzenesulfonic acid, p-methylbenzenesulfonic acid, or L-malic acid;

[0098] Preferred ingredients include one or more of benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydroxyethylsulfonic acid, 1,5-naphthalenedisulfonic acid, tartaric acid, adipic acid, phosphoric acid, hydrobromic acid, oxalic acid, fumaric acid, formic acid, hippuric acid, lauric acid, and stearic acid.

[0099] In a more preferred embodiment of the present invention, the method for preparing the crystal form of the acid salt of the above-mentioned compound specifically includes the following steps:

[0100] 1) Weigh an appropriate amount of the compound salt and suspend it in a poor solvent. The preferred suspension density is 50–200 mg / mL.

[0101] 2) The suspension obtained above is shaken at a certain temperature for a certain period of time, preferably 25-50℃, and preferably 1-15 days.

[0102] 3) Centrifuge the above suspension quickly to remove the supernatant, and dry the remaining solid in a vacuum drying oven at 50°C until constant weight to obtain the target product;

[0103] in:

[0104] The undesirable solvent is selected from one or more of methanol, ethanol, acetonitrile, chlorobenzene, benzene, toluene, acetone, ethyl acetate, water, 88% acetone, isopropyl acetate, 3-pentanone, ethyl formate, 2-methyltetrahydrofuran, isopropanol, n-butanol, isobutanol, n-propanol, methyl tert-butyl ether, n-heptane, tert-butanol, or 2-butanone.

[0105] In a more preferred embodiment of the invention, the acid salt of the above-mentioned compound is a pharmaceutical composition comprising a pharmaceutically acceptable salt of the above-mentioned compound in a therapeutically effective dose, and one or more pharmaceutically acceptable carriers or excipients.

[0106] In a more preferred embodiment of the invention, the use of an acid salt and its crystal form, or a pharmaceutical composition, in the preparation of a RET inhibitor drug is included.

[0107] In a more preferred embodiment of the invention, the use of acid salts and their crystal forms, or pharmaceutical compositions, in the preparation of medicaments for the treatment and / or prevention of non-small cell lung cancer, fibrosarcoma, pancreatic tumors, medullary thyroid carcinoma, papillary thyroid carcinoma, soft tissue sarcoma, high-grade solid tumors, breast tumors, and colon tumors is included.

[0108] In a further preferred embodiment of the present invention, the benzenesulfonate crystal form I has a characteristic peak in its X-ray powder diffraction pattern at 2θ of 17.7 ± 0.2°; preferably, it also has a characteristic peak at 2θ of 8.4 ± 0.2°; more preferably, it also has characteristic peaks at 2θ of 24.8 ± 0.2°, 21.5 ± 0.2°, 17.1 ± 0.2°, and 15.2 ± 0.2°; even more preferably, it also has characteristic peaks at 2θ of 23.4 ± 0.2°, 19.3 ± 0.2°, 28.2 ± 0.2°, 18.9 ± 0.2°, 11.8 ± 0.2°, and 18.6 ± 0.2°.

[0109] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 1.

[0110] Table 1

[0111]

[0112]

[0113] In a further preferred embodiment of the present invention, the benzenesulfonate crystal form II has a characteristic peak in its X-ray powder diffraction pattern at 2θ of 17.7 ± 0.2°; preferably, it also has characteristic peaks at 2θ of 15.2 ± 0.2°, 21.5 ± 0.2°, and 24.8 ± 0.2°; more preferably, it also has characteristic peaks at 2θ of 8.5 ± 0.2°, 19.3 ± 0.2°, and 17.1 ± 0.2°; and even more preferably, it also has characteristic peaks at 2θ of 18.6 ± 0.2°, 23.4 ± 0.2°, 7.7 ± 0.2°, 6.5 ± 0.2°, and 13.9 ± 0.2°.

[0114] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 2.

[0115] Table 2

[0116]

[0117]

[0118] In a further preferred embodiment of the present invention, the X-ray powder diffraction pattern of p-toluenesulfonate crystal form I has a characteristic peak at 2θ of 18.4 ± 0.2°; preferably, it also includes characteristic peaks at 2θ of 15.1 ± 0.2°, 8.1 ± 0.2°, and 16.9 ± 0.2°; more preferably, it also includes characteristic peaks at 2θ of 7.6 ± 0.2°, 17.4 ± 0.2°, and 20.9 ± 0.2°; even more preferably, it also includes characteristic peaks at 2θ of 17.2 ± 0.2°, 5.0 ± 0.2°, 19.0 ± 0.2°, 22.8 ± 0.2°, and 24.0 ± 0.2°.

[0119] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 3.

[0120] Table 3

[0121]

[0122]

[0123] In a further preferred embodiment of the present invention, the hydrochloride crystal form I has a characteristic peak in its X-ray powder diffraction pattern at 2θ of 10.0 ± 0.2°; preferably, it also has characteristic peaks at 2θ of 6.0 ± 0.2°, 15.6 ± 0.2°, and 16.8 ± 0.2°; more preferably, it also has characteristic peaks at 2θ of 24.6 ± 0.2°, 23.0 ± 0.2°, and 20.8 ± 0.2°; and even more preferably, it also has characteristic peaks at 2θ of 26.7 ± 0.2°, 17.5 ± 0.2°, 21.6 ± 0.2°, 14.9 ± 0.2°, and 30.7 ± 0.2°.

[0124] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 4.

[0125] Table 4

[0126]

[0127]

[0128] In a further preferred embodiment of the present invention, the hydrochloride crystal form II has a characteristic peak in its X-ray powder diffraction pattern at 2θ of 10.0 ± 0.2°; preferably, it also has characteristic peaks at 2θ of 6.0 ± 0.2°, 6.6 ± 0.2°, and 15.6 ± 0.2°; more preferably, it also has characteristic peaks at 2θ of 24.7 ± 0.2°, 23.1 ± 0.2°, and 16.8 ± 0.2°; and even more preferably, it also has characteristic peaks at 2θ of 17.5 ± 0.2°, 20.8 ± 0.2°, 23.9 ± 0.2°, 22.4 ± 0.2°, and 26.7 ± 0.2°.

[0129] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 5.

[0130] Table 5

[0131]

[0132]

[0133] In a further preferred embodiment of the present invention, the hydrobromide crystal form I has a characteristic peak in its X-ray powder diffraction pattern at 2θ of 9.9 ± 0.2°; preferably, it also has characteristic peaks at 2θ of 5.9 ± 0.2°, 22.8 ± 0.2°, and 20.6 ± 0.2°; more preferably, it also has characteristic peaks at 2θ of 24.4 ± 0.2°, 16.7 ± 0.2°, and 21.4 ± 0.2°; and even more preferably, it also has characteristic peaks at 2θ of 26.6 ± 0.2°, 17.4 ± 0.2°, 24.9 ± 0.2°, 23.1 ± 0.2°, and 30.6 ± 0.2°.

[0134] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 5.

[0135] Table 5

[0136]

[0137]

[0138] In a further preferred embodiment of the present invention, the oxalate crystal form I has a characteristic peak in its X-ray powder diffraction pattern at 2θ of 9.5 ± 0.2°; preferably, it also has characteristic peaks at 2θ of 19.3 ± 0.2°, 10.7 ± 0.2°, and 4.7 ± 0.2°; more preferably, it also has characteristic peaks at 2θ of 6.0 ± 0.2°, 16.5 ± 0.2°, and 25.0 ± 0.2°; and even more preferably, it also has characteristic peaks at 2θ of 27.1 ± 0.2°, 15.3 ± 0.2°, 14.5 ± 0.2°, 18.6 ± 0.2°, and 20.5 ± 0.2°.

[0139] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 6.

[0140] Table 6

[0141]

[0142]

[0143] In a further preferred embodiment of the present invention, the oxalate crystal form II has a characteristic peak in its X-ray powder diffraction pattern at 2θ of 5.8 ± 0.2°; preferably, it also has characteristic peaks at 2θ of 4.8 ± 0.2°, 15.7 ± 0.2°, and 17.0 ± 0.2°; more preferably, it also has characteristic peaks at 2θ of 9.4 ± 0.2°, 19.2 ± 0.2°, and 17.7 ± 0.2°; and even more preferably, it also has characteristic peaks at 2θ of 16.6 ± 0.2°, 26.1 ± 0.2°, 11.8 ± 0.2°, 18.6 ± 0.2°, and 12.5 ± 0.2°.

[0144] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 7.

[0145] Table 7

[0146]

[0147]

[0148] In a further preferred embodiment of the present invention, the oxalate crystal form III has a characteristic peak in its X-ray powder diffraction pattern at 2θ of 10.4 ± 0.2°; preferably, it also has characteristic peaks at 2θ of 5.1 ± 0.2°, 4.8 ± 0.2°, and 15.8 ± 0.2°; more preferably, it also has characteristic peaks at 2θ of 14.3 ± 0.2°, 12.2 ± 0.2°, and 17.8 ± 0.2°; and even more preferably, it also has characteristic peaks at 2θ of 5.8 ± 0.2°, 18.9 ± 0.2°, 17.0 ± 0.2°, and 23.8 ± 0.2°.

[0149] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 7.

[0150] Table 7

[0151]

[0152]

[0153] In a further preferred embodiment of the present invention, the oxalate crystal form IV has a characteristic peak in its X-ray powder diffraction pattern at 2θ of 20.5 ± 0.2°; preferably, it also has characteristic peaks at 2θ of 18.5 ± 0.2°, 17.9 ± 0.2°, and 4.8 ± 0.2°; more preferably, it also has characteristic peaks at 2θ of 16.5 ± 0.2°, 15.8 ± 0.2°, and 11.5 ± 0.2°; and even more preferably, it also has characteristic peaks at 2θ of 12.3 ± 0.2°, 24.0 ± 0.2°, 16.2 ± 0.2°, 23.3 ± 0.2°, and 19.6 ± 0.2°.

[0154] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 8.

[0155] Table 8

[0156]

[0157]

[0158] In a further preferred embodiment of the present invention, the methanesulfonate crystal form I has a characteristic peak in its X-ray powder diffraction pattern at 2θ of 10.3 ± 0.2°; preferably, it also has characteristic peaks at 2θ of 5.1 ± 0.2°, 15.6 ± 0.2° and 25.2 ± 0.2°; more preferably, it also has a characteristic peak at 2θ of 18.4 ± 0.2°.

[0159] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 9.

[0160] Table 1

[0161]

[0162]

[0163] In a further preferred embodiment of the present invention, the ethanesulfonate crystal form I has a characteristic peak in its X-ray powder diffraction pattern at 2θ of 10.2 ± 0.2°; preferably, it also has characteristic peaks at 2θ of 5.0 ± 0.2°, 15.4 ± 0.2°, and 18.9 ± 0.2°; more preferably, it also has characteristic peaks at 2θ of 24.2 ± 0.2° and 21.1 ± 0.2°.

[0164] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 10.

[0165] Table 10

[0166]

[0167]

[0168] In a further preferred embodiment of the present invention, the ethanesulfonate crystal form II has a characteristic peak in its X-ray powder diffraction pattern at 2θ of 10.2 ± 0.2°; preferably, it also has characteristic peaks at 2θ of 5.0 ± 0.2°, 6.0 ± 0.2°, and 15.4 ± 0.2°; more preferably, it also has characteristic peaks at 2θ of 5.4 ± 0.2° and 7.3 ± 0.2°.

[0169] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 11.

[0170] Table 11

[0171]

[0172] In a further preferred embodiment of the present invention, the hydroxyethyl sulfonate crystal form I has a characteristic peak in its X-ray powder diffraction pattern at 2θ of 10.5 ± 0.2°; preferably, it also has characteristic peaks at 2θ of 5.2 ± 0.2°, 18.7 ± 0.2° and 15.9 ± 0.2°; more preferably, it also has a characteristic peak at 2θ of 23.0 ± 0.2°.

[0173] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 12.

[0174] Table 12

[0175]

[0176] In a further preferred embodiment of the present invention, the hydroxyethyl sulfonate crystal form II has a characteristic peak in its X-ray powder diffraction pattern at 2θ of 11.9 ± 0.2°; preferably, it also has characteristic peaks at 2θ of 18.4 ± 0.2°, 4.8 ± 0.2°, and 23.4 ± 0.2°; more preferably, it also has characteristic peaks at 2θ of 16.7 ± 0.2°, 17.8 ± 0.2°, 12.8 ± 0.2°, 23.8 ± 0.2°, and 21.8 ± 0.2°.

[0177] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 13.

[0178] Table 13

[0179]

[0180]

[0181] In a further preferred embodiment of the present invention, the sulfate crystal form I has a characteristic peak in its X-ray powder diffraction pattern at 2θ of 10.3 ± 0.2°; preferably, it also has characteristic peaks at 2θ of 5.1 ± 0.2°, 15.6 ± 0.2°, and 14.5 ± 0.2°; more preferably, it also has characteristic peaks at 2θ of 20.2 ± 0.2°, 19.0 ± 0.2°, and 25.6 ± 0.2°; and even more preferably, it also has characteristic peaks at 2θ of 22.1 ± 0.2°, 23.0 ± 0.2°, 20.8 ± 0.2°, 19.2 ± 0.2°, and 24.1 ± 0.2°.

[0182] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 14.

[0183] Table 14

[0184]

[0185]

[0186] In a further preferred embodiment of the present invention, the sulfate crystal form II has a characteristic peak in its X-ray powder diffraction pattern at 2θ of 16.1 ± 0.2°; preferably, it also has characteristic peaks at 2θ of 5.9 ± 0.2°, 6.6 ± 0.2°, and 22.0 ± 0.2°; more preferably, it also has characteristic peaks at 2θ of 21.0 ± 0.2°, 20.1 ± 0.2°, and 17.0 ± 0.2°; and even more preferably, it also has characteristic peaks at 2θ of 25.2 ± 0.2°, 20.7 ± 0.2°, and 23.1 ± 0.2°.

[0187] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 15.

[0188] Table 15

[0189]

[0190] In a further preferred embodiment of the present invention, the phosphate crystal form I has a characteristic peak in its X-ray powder diffraction pattern at 2θ of 5.6 ± 0.2°; preferably, it also has characteristic peaks at 2θ of 11.5 ± 0.2°, 20.3 ± 0.2°, and 15.9 ± 0.2°; more preferably, it also has characteristic peaks at 2θ of 17.2 ± 0.2°, 16.4 ± 0.2°, 21.9 ± 0.2°, and 10.2 ± 0.2°.

[0191] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 16.

[0192] Table 16

[0193]

[0194] In a further preferred embodiment of the present invention, the phosphate crystal form II has a characteristic peak in its X-ray powder diffraction pattern at 2θ of 24.7 ± 0.2°; preferably, it also has characteristic peaks at 2θ of 21.8 ± 0.2°, 21.0 ± 0.2°, and 20.3 ± 0.2°; more preferably, it also has characteristic peaks at 2θ of 16.1 ± 0.2°, 20.0 ± 0.2°, 17.2 ± 0.2°, and 15.4 ± 0.2°; even more preferably, it also has characteristic peaks at 2θ of 15.1 ± 0.2°, 11.4 ± 0.2°, and 5.6 ± 0.2°.

[0195] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 17.

[0196] Table 17

[0197]

[0198]

[0199] Detailed description of the invention

[0200] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0201] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester groups. The present invention preferably uses methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuteralkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.

[0202] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and most preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0203] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). m The heteroatom (where m is an integer from 0 to 2) excluding the ring portion of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; most preferably, it contains 3 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include oxobutyl, thiobutyl, pyrrolyl, pyrrolidone, imidazolyl, tetrahydrofuranyl, tetrahydrothiophene, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., with oxobutyl, pyrrolidone, tetrahydrofuranyl, pyrrolidone, morpholinyl, piperazinyl, and pyranyl being preferred. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved may optionally be connected to other groups by single bonds, or may be further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring.

[0204] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0205] "Halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0206] "Haloalkoxy" refers to an alkoxy group that has been substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0207] "Hydroxyalkyl" refers to an alkyl group that has been replaced by a hydroxyl group, where the alkyl group is as defined above.

[0208] "Alkenyl" refers to alkenyl groups, also known as olefin groups. The alkenyl group can be further replaced by other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0209] "Alkyne" refers to (CH≡C-), where the alkynyl group can be further replaced by other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0210] "Hydroxy" refers to the -OH group.

[0211] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0212] "Amino" refers to -NH2.

[0213] “Cyano” refers to -CN.

[0214] "Nitro" refers to -NO2.

[0215] "Carboxyl group" refers to -C(O)OH.

[0216] "THF" refers to tetrahydrofuran.

[0217] “EtOAc” refers to ethyl acetate.

[0218] “MeOH” refers to methanol.

[0219] "DMF" refers to N,N-dimethylformamide.

[0220] "DIPEA" refers to diisopropylethylamine.

[0221] "TFA" refers to trifluoroacetic acid.

[0222] “MeCN” refers to Yi Qing.

[0223] “DMA” stands for N,N-dimethylacetamide.

[0224] “Et2O” refers to diethyl ether.

[0225] “DCE” refers to 1,2-dichloroethane.

[0226] "DIPEA" refers to N,N-diisopropylethylamine.

[0227] “NBS” refers to N-bromosuccinimide.

[0228] “NIS” refers to N-iodosuccinimide.

[0229] “Cbz-Cl” refers to benzyl chloroformate.

[0230] “Pd2(dba)3” refers to tris(dibenzylacetone)dipalladium.

[0231] “Dppf” refers to 1,1'-bis(diphenylphosphine)ferrocene.

[0232] “HATU” refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate.

[0233] "KHMDS" refers to potassium hexamethyldisilamide.

[0234] "LiHMDS" refers to lithium bis(trimethylsilyl)amine.

[0235] “MeLi” refers to methyl lithium.

[0236] “n-BuLi” refers to n-butyllithium.

[0237] "NaBH(OAc)3" refers to sodium triacetoxyborohydride.

[0238] "DMAP" refers to 4-dimethylaminopyridine.

[0239] “SEM-Cl” refers to chloromethyltrimethylsilylethyl ether.

[0240] “Xantphos” refers to 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene.

[0241] "DCM" refers to dichloromethane.

[0242] The different terms such as "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" all express the same meaning, that is, X can be any one or more of A, B, and C.

[0243] All hydrogen atoms described in this invention can be replaced by their isotope deuterium, and any hydrogen atom in the compounds of the embodiments of this invention can also be replaced by a deuterium atom.

[0244] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of the event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0245] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0246] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0247] "Medicinal salts" refer to the salts of the compounds of this invention, which are safe and effective when used in mammals and have the appropriate biological activity.

[0248] New crystal forms can be identified using powder X-ray diffraction (PXRD). However, those skilled in the art know that the peak intensities and / or peak characteristics of PXRD can vary depending on experimental conditions, such as different diffraction test conditions and / or preferred orientations. Furthermore, due to differences in the precision of different instruments, the measured 2θ values ​​may have an error of approximately ±0.2, and individual peaks may have errors of approximately ±0.3 or ±0.4. However, it is known that the relative intensity of a peak depends more on certain properties of the sample being measured than on its position, such as the size of the crystals in the sample, the orientation effect of crystallization, and the purity of the material being analyzed; therefore, peak intensity deviations of approximately ±20% or greater are possible. Attached Figure Description

[0249] Figure 1-3 XRPD, DSC, and TGA illustrations of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile benzenesulfonate crystal form I.

[0250] Figure 4-6 XRPD, DSC, and TGA illustrations of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile benzenesulfonate crystal form II.

[0251] Figure 7-9 XRPD, DSC, and TGA illustrations of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile p-toluenesulfonate crystal form I.

[0252] Figure 10-12 XRPD, DSC, and TGA illustrations of crystal form I of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile hydrochloride.

[0253] Figure 13-14 XRPD and DSC illustrations of crystal form II of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile hydrochloride.

[0254] Figure 15-17 XRPD, DSC, and TGA illustrations of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile hydrobromide crystal form I.

[0255] Figure 18-20 XRPD, DSC, and TGA illustrations of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile oxalate crystal form I.

[0256] Figure 21 XRPD illustration of crystal form II of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile oxalate.

[0257] Figure 22 XRPD illustration of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile oxalate crystal form III.

[0258] Figure 23-25 XRPD, DSC, and TGA illustrations of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile oxalate crystal form IV.

[0259] Figure 26-28 XRPD, DSC, and TGA illustrations of crystal form I of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile methanesulfonate.

[0260] Figures 29-31 XRPD, DSC, and TGA illustrations of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile ethanesulfonate crystal form I.

[0261] Figures 32-34 XRPD, DSC, and TGA illustrations of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile ethanesulfonate crystal form II.

[0262] Figure 35 XRPD illustration of crystal form I of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile hydroxyethyl sulfonate.

[0263] Figures 36-38XRPD illustration of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile hydroxyethyl sulfonate crystal form II.

[0264] Figure 39 XRPD illustration of crystal form I of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile sulfate.

[0265] Figure 40 XRPD illustration of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile sulfate crystal form II.

[0266] Figure 41 XRPD illustration of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile phosphate crystal form I.

[0267] Figure 42 XRPD illustration of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile phosphate crystal form II.

[0268] Figure 43 The DVS hygroscopicity curve of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile benzenesulfonate crystal form I is illustrated.

[0269] Figure 44The DVS hygroscopicity curve of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile for toluenesulfonate is illustrated.

[0270] Figure 45 The DVS hygroscopicity curve of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile hydrobromide is illustrated.

[0271] Figure 46 The DVS hygroscopicity curves of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile hydrochloride crystal form I are illustrated.

[0272] Figure 47 The DVS hygroscopicity curves of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile oxalate crystal form IV are illustrated. Detailed Implementation

[0273] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0274] I. Preparation of Compounds

[0275] Example

[0276] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0277] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C18 150×4.6 mm column).

[0278] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The standard size for TLC is 0.15mm to 0.20mm, while the standard size for TLC separation and purification is 0.4mm to 0.5mm. Column chromatography typically uses 200-300 mesh Yantai Huanghai silica gel as the carrier.

[0279] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using methods known in the art.

[0280] Unless otherwise specified, all reactions in this invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is expressed in degrees Celsius.

[0281] 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]

[0282] (heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile

[0283]

[0284] Step 1: 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-oxopropoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0285]

[0286] 6-Hydroxy-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile (200 mg, 0.441 mmol) was dissolved in DMF (20 mL), and bromoacetone (121 mg, 0.882 mmol), cesium carbonate (431 mg, 1.32 mmol), and sodium iodide (66 mg, 0.441 mmol) were added separately. The reaction was stirred overnight at room temperature. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic phase was dried and then evaporated to dryness. The crude product was purified by column chromatography to give 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-oxopropoxy)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (160 mg, yield: 71%).

[0287] MS m / z (ESI): 510.1 [M+H] + .

[0288] Step 2: 6-((2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0289]

[0290] 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-oxopropoxy)pyrazolo[1,5-a]pyridin-3-carboxynitrile (160 mg, 0.314 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL), and then acetylenyl magnesium chloride (6.28 mL, 3.14 mmol, 0.5 M) was slowly added. After the addition was complete, the reaction mixture was stirred for one hour. An aqueous solution of ammonium chloride was added to quench the reaction, and then ethyl acetate was added for extraction. The organic phase was dried and then evaporated to dryness. The crude product was purified by column chromatography to give 6-((2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxylonitrile (48 mg, yield 28%).

[0291] MS m / z (ESI): 536.1 [M+H] + .

[0292] Step 3: 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

[0293]

[0294] 6-((2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile (48.2 mg, 0.09 mmol) was chirally resolved to give 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile (16 mg).

[0295] Chiral splitting conditions:

[0296] Table 18

[0297] instrument CHIRALPAK IBN Column 5.0cm ID×25cm L, 10μm mobile phase Hexane / EtOH / DCM=60 / 30 / 10(V / V / V) Flow rate 60mL / min Detection wavelength UV 254nm Column temperature 35℃

[0298] t R =9.002min

[0299] MS m / z (ESI): 536.1 [M+H] + .

[0300] 1 H NMR (400MHz, DMSO-d6) δ8.74(d,J=2.1Hz,1H),8.60(s,1H),8.42(d,J=2.5Hz,1H),8.0 7(d,J=2.4Hz,1H),7.85(dd,J=8.8,2.6Hz,1H),7.68(dd,J=8.5,2.4Hz,1H),7.33(d,J =2.1Hz,1H),6.78(m,2H),5.84(s,1H),4.08(s,2H),3.82(s,3H),3.78–3.63(m,4H),3 .61–3.46(m,4H),3.40(s,1H),2.57–2.53(m,1H),1.59(d,J=8.5Hz,1H),1.49(s,3H).

[0301] II. Evaluation of Compound Biological Testing

[0302] The present invention will be further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[0303] I. Enzyme Testing Experiment

[0304] Test Example 1: Determination of the inhibitory effect of the compounds of the present invention on the activity of RET wild-type and mutant kinases.

[0305] 1. Experimental objective:

[0306] The purpose of this test case is to measure the inhibitory effect of the compound on the activity of RET wild-type and mutant kinases.

[0307] 2.1 Experimental Apparatus:

[0308] Centrifuge (Eppendorf 5810R);

[0309] Microplate reader (BioTek Synergy H1);

[0310] Pipettes (Eppendorf & Rainin).

[0311] 2.2 Experimental Reagents:

[0312] RET enzyme was purchased from Carna, catalog number 08-159;

[0313] RET M918T enzyme was purchased from Carna, catalog number 08-508;

[0314] KIF5B-RET was purchased from SignalChem, product number R02-19FG-05;

[0315] CCDC6-RET was purchased from SignalChem, product number R02-19BG-05;

[0316] RET V804M enzyme was purchased from Thermofisher, product number PV6223;

[0317] RET V804L enzyme was purchased from Thermofisher, product number PV4397;

[0318] The HTRF KinEASE-TK kit was purchased from Cisbio, part number 62TK0PEC.

[0319] ATP was purchased from Thermofisher, product number PV3227;

[0320] The 384-well plate was purchased from PerkinElmer, part number 6007290.

[0321] 2.3 Test Compounds:

[0322] The compounds used in this invention embodiment are self-made.

[0323] 3. Experimental methods:

[0324] This experiment used homogeneous time-resolved fluorescence (HTRF) to detect the RET kinase activity of the compound. This experiment was conducted in 384-well plates. Compound solutions of varying concentrations were prepared using experimental buffer (25 mM HEPES, 10 mM MgCl2, 0.01% Triton X-100) and added to the 384-well plates. Then, diluted RET, RET M918T, CCDC6-RET, KIF5B-RET, RET V804M, or RET V804L kinase solutions (0.01–2 nM) and substrate TK-substrate biotin (500 nM–1 μM) and Km (0.19–200 μM) ATP solutions were added, with a total reaction volume of 10 μL. After centrifugation at 1000 rpm for 1 minute to mix thoroughly, and incubation at room temperature for 45 minutes, 10 μL of a mixture of Sa-XL665 and TK-ab-Cryptate prepared using the detection solution was added. After centrifugation at 1000 rpm for 1 minute to mix thoroughly, and incubation at room temperature for 1 hour, the mixture was then processed using BioTek Synergy. The H1 instrument takes readings and records the readings at 665nm and 620nm.

[0325] 4. Experimental data processing methods:

[0326] Readings were taken using a BioTek Synergy H1 instrument at 665 nm and 620 nm, and the ratio (665 nm / 620 nm) was calculated. The inhibition rate was then calculated, and the concentration and inhibition rate were fitted using Graphpad Prism software to obtain the IC50. 50 value.

[0327] 5. Experimental Results:

[0328] The test data obtained by the above test methods for the compounds against various mutant RET kinases in specific embodiments are shown in Table 2-1.

[0329] Table 2-1: IC50 of compounds inhibiting the activity of various mutant RET kinases 50 value

[0330]

[0331] 6. Experimental Conclusion:

[0332] The compounds in the embodiments of the present invention exhibit good inhibitory activity against various mutant RET kinases, and show significant activity against drug-resistant mutant RET M918T, KIF5B-RET and RET V804L.

[0333] Test Example 2: Determination of the inhibitory effect of the compound of the present invention on KDR kinase activity

[0334] 1. Experimental objective:

[0335] The purpose of this test case is to measure the inhibitory effect of the compound on KDR kinase activity.

[0336] 2.1 Experimental Apparatus:

[0337] Centrifuge (Eppendorf 5810R);

[0338] Microplate reader (BioTek Synergy H1);

[0339] Pipettes (Eppendorf & Rainin).

[0340] 2.2 Experimental Reagents:

[0341] KDR kinase was purchased from Carna, catalog number 08-191;

[0342] The HTRF KinEASE-TK kit was purchased from Cisbio, part number 62TK0PEC.

[0343] ATP was purchased from Thermofisher, product number PV3227;

[0344] The 384-well plate was purchased from PerkinElmer, part number 6007290.

[0345] 2.3 Test Compounds:

[0346] The compounds used in this invention embodiment are self-made.

[0347] 3. Experimental methods:

[0348] This experiment used homogeneous time-resolved fluorescence (HTRF) to detect the activity of compounds against KDR kinase. The experiment was conducted in 384-well plates. Compound solutions of different concentrations were prepared using experimental buffer (25 mM HEPES, 10 mM MgCl2, 0.01% Triton X-100) and added to the 384-well plates. Then, diluted KDR kinase solution (0.05 nM), substrate TK-substrate biotin (500 nM–1 μM), and Km concentrations (0.19–200 μM) ATP solutions were added, with a total reaction volume of 10 μL. After centrifugation at 1000 rpm for 1 minute to mix thoroughly, and incubation at room temperature for 45 minutes, 10 μL of a mixture of Sa-XL665 and TK-ab-Cryptate prepared using the detection solution was added. After centrifugation at 1000 rpm for 1 minute to mix thoroughly, and incubation at room temperature for 1 hour, readings were taken using a BioTek Synergy H1 microplate reader, recording readings at 665 nm and 620 nm.

[0349] 4. Experimental data processing methods:

[0350] Readings were taken using a BioTek Synergy H1 instrument at 665 nm and 620 nm, and the ratio (665 nm / 620 nm) was calculated. The inhibition rate was then calculated, and the concentration and inhibition rate were fitted using Graphpad Prism software to obtain the IC50. 50 value.

[0351] 5. Experimental Results:

[0352] The test data for specific embodiments obtained through the above testing methods are shown in Table 2-2:

[0353] Table 2-2: Relative IC50 values ​​of compounds on the inhibition of RET kinase activity and KDR kinase activity 50 value

[0354]

[0355] 6. Experimental Conclusion:

[0356] The above data show that the compounds in the embodiments of this invention have a strong inhibitory effect on RET kinase activity, but a poor inhibitory effect on KDR kinase activity. Comparison of the two sets of data shows that the series of compounds of this invention exhibit high selectivity in inhibiting KDR / RET kinase activity.

[0357] II. Cellular Testing Experiments

[0358] Test Example 1: Determination of the inhibitory effect of the compound of the present invention on the proliferation activity of TT cells.

[0359] 1. Experimental objective:

[0360] The purpose of this test case is to measure the inhibitory effect of the compound on the proliferative activity of TT cells.

[0361] 2.1 Experimental Apparatus:

[0362] Microplate reader (BioTek Synergy H1);

[0363] Pipettes (Eppendorf & Rainin).

[0364] 2.2 Experimental Reagents:

[0365] TT cells were purchased from the Cell Bank of the Chinese Academy of Sciences;

[0366] Cell Titer-Glo cells were purchased from Promega, catalog number G7573.

[0367] 2.3 Test Compounds:

[0368] The compounds used in this invention embodiment are self-made.

[0369] 3. Experimental methods:

[0370] When TT cells reach a suitable confluence, collect the cells and adjust the cell concentration using complete culture medium. Spread the cell suspension into 96-well plates (90 μL per well) and incubate overnight at 37°C with 5% CO2. Prepare compound solutions of different concentrations using DMSO and culture medium, and set up a solvent control. Add 10 μL of the compound solution to each well of the 96-well plate and incubate at 37°C with 5% CO2 for 72 h. Then add CellTiter-Glo solution, shake to mix thoroughly, and incubate in the dark for 10 minutes. Read the values ​​using a BioTek Synergy H1 microplate reader.

[0371] 4. Experimental data processing methods:

[0372] The inhibition rate was calculated using the emission signal value. The concentration and inhibition rate were then fitted with a nonlinear regression curve using Graphpad Prism software to obtain the IC50. 50 value.

[0373] 5. Experimental Results:

[0374] Table 2-3

[0375]

[0376] 6. Experimental Conclusion:

[0377] The above data show that the compound in the embodiments of the present invention has a good inhibitory effect on the proliferation of TT cells.

[0378] Test Example 2: Determination of the inhibitory effect of the compound of the present invention on the proliferation activity of Ba / F3 KIF5B-RET cells.

[0379] 1. Experimental objective:

[0380] The inhibitory effect of the compound on the proliferation activity of Ba / F3 KIF5B-RET cells was measured.

[0381] 2. Instruments and reagents:

[0382] 2.1 Experimental Apparatus:

[0383] Microplate reader (BioTek Synergy H1);

[0384] Pipettes (Eppendorf & Rainin).

[0385] 2.2 Experimental Reagents:

[0386] Ba / F3 KIF5B-RET cells were provided by Beijing Kangyuan Bochuang Biotechnology Co., Ltd., cell number CVCL_UE86, and can be found on cell information websites. https: / / web.expasy.org / cellosaurus / The search revealed that this stable cell line does not require IL-3 for growth;

[0387] Cell Titer-Glo cells were purchased from Promega, catalog number G7573.

[0388] 2.3 Test Compounds:

[0389] The compounds used in this invention embodiment are self-made.

[0390] 3. Experimental methods:

[0391] When Ba / F3 KIF5B-RET cells reached a suitable cell density, the cells were collected and adjusted to a suitable cell concentration using complete culture medium. The cell suspension was then seeded into 96-well plates at 90 μL per well and incubated overnight at 37°C with 5% CO2. Compound solutions of different concentrations were prepared using DMSO and culture medium, with a solvent control included. The compound solutions were added to 96-well plates at 10 μL per well and incubated at 37°C with 5% CO2 for 72-144 hours. CellTiter-Glo solution was then added, and the mixture was shaken to mix thoroughly. The plates were then incubated in the dark for 10 minutes, and the readings were taken using a BioTek Synergy H1 microplate reader.

[0392] 4. Experimental data processing methods:

[0393] The inhibition rate was calculated using the emission signal value. The concentration and inhibition rate were then fitted with a nonlinear regression curve using Graphpad Prism software to obtain the IC50. 50 value.

[0394] 5. Experimental Results:

[0395] Table 2-4:

[0396]

[0397] 6. Experimental Conclusion:

[0398] The above data show that the compound in the embodiments of the present invention has a good inhibitory effect on the proliferation of Ba / F3 KIF5B-RET cells.

[0399] Test Example 4: Inhibitory effect of the compound of the present invention on phosphorylation of ERK, a downstream signaling factor in TT cells.

[0400] 1. Experimental objective:

[0401] The inhibitory effect of the compound on the phosphorylation level of ERK, a downstream signaling factor in TT cells, was investigated.

[0402] 2. Experimental instruments and reagents:

[0403] 2.1 Experimental Apparatus:

[0404] Imaging device (Biorad ChemiDoc) TM MP);

[0405] Pipettes (Eppendorf & Rainin).

[0406] 2.2 Experimental Reagents:

[0407] pERK antibody was purchased from Cell Signaling Technology, catalog number 4370S;

[0408] The total ERK antibody was purchased from Cell Signaling Technology, catalog number 4696S;

[0409] The internal reference GAPDH was purchased from Cell Signaling Technology, part number 5174S;

[0410] The fluorescent secondary antibodies were purchased from LI-COR, catalog numbers P / N 925-68071 and P / N 926-32210.

[0411] 2.3 Test Compounds:

[0412] The compounds used in this invention embodiment are self-made.

[0413] 3. Experimental methods:

[0414] This experiment used Western blotting to measure the inhibitory effect of the compound on the phosphorylation level of ERK, a downstream signaling factor in TT cells. TT cells were cultured to a suitable confluence, and the cells were collected. The cell concentration was adjusted to an appropriate level using complete culture medium. The cell suspension was seeded into 24-well plates (1 mL per well) and incubated overnight at 37°C with 5% CO2. Different concentrations of the compound dilution (3.7 nM, 11.1 nM, 33.3 nM, 100 nM, 300 nM) were added, and the plates were incubated at 37°C for 2 hours. The cell supernatant was aspirated, the cells were washed once with PBS, and the protein was collected using lysis buffer. After protein denaturation, Western blotting was performed. Blot experiment: Protein electrophoresis was performed at 120V for about 75 minutes, followed by transfer to a PVDF membrane at 10V for 45 minutes using a semi-dry transfer apparatus. After blocking with 5% BSA at room temperature for 1 hour, the PVDF membrane was cut into strips of appropriate size and incubated overnight at 4°C with prepared antibody dilution buffer. The membrane was washed 6 times with TBST, and then incubated with goat anti-mouse secondary antibody and goat anti-rabbit secondary antibody at room temperature for 1 hour. The membrane was washed 6 times with TBST and then imaged using the Biorad ChemiDoc™ MP imaging system.

[0415] 4. Experimental data processing methods:

[0416] The inhibitory effect of the compound on ERK phosphorylation levels in TT cells at different concentrations was determined by detecting protein strips.

[0417] 5. Experimental Results:

[0418] The compounds in the examples significantly inhibited ERK phosphorylation in TT cells in a dose-dependent manner. After co-incubation with TT cells at 37°C for 2 hours, the compounds in the examples almost completely inhibited ERK phosphorylation at 300 nM, 100 nM, 33.3 nM, and 11.1 nM, and inhibited about half of the ERK phosphorylation level at 3.7 nM. In contrast, the compounds in Example 64 completely inhibited ERK phosphorylation at 300 nM and 100 nM, with a reduced degree of inhibition at 33.3 nM, inhibiting about half of the ERK phosphorylation level at 11.1 nM, and showing a weaker inhibition at 3.7 nM.

[0419] 6. Experimental Conclusion:

[0420] Based on the above methods, the compound of this invention exhibits a dose-dependent inhibitory effect on the phosphorylation of the downstream signaling factor ERK in TT cells.

[0421] III. Pharmacokinetic Determination in Balb / C Mice

[0422] 1. Research purpose:

[0423] Using Balb / C mice as test animals, the pharmacokinetic behavior of the following compound examples in plasma in mice after oral administration at a dose of 5 mg / kg was studied.

[0424] 2. Test protocol:

[0425] 2.1 Test drug:

[0426] Examples of the present invention, self-made.

[0427] 2.2 Test animals:

[0428] 6 Balb / C Mice per example, male, Shanghai Jiesijie Laboratory Animal Co., Ltd., Animal Production License No. (SCXK(Shanghai)2013 - 0006N0.311620400001794).

[0429] 2.3 Administration:

[0430] Balb / C mice, male; after fasting overnight, administered p.o. respectively, with a dose of 5 mg / kg and a dosing volume of 10 mL / kg.

[0431] 2.4 Sample preparation:

[0432] 0.5% CMC - Na (1% Tween80), dissolved by ultrasound to prepare a clear solution or a homogeneous suspension.

[0433] 2.5 Sample collection:

[0434] Before and after dosing in mice, at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours, 0.1 mL of blood was collected from the orbital cavity, placed in an EDTA - K2 test tube, centrifuged at 6000 rpm for 6 min at 4°C to separate plasma, and stored at - 80°C.

[0435] 2.6 Sample treatment:

[0436] 1) Add 40 uL of plasma sample to 160 uL of acetonitrile for precipitation, mix and centrifuge at 3500×g for 5 - 20 minutes.

[0437] 2) Take 100 uL of the treated supernatant solution for LC / MS / MS analysis of the concentration of the test compound.

[0438] 2.7 Liquid phase analysis

[0439] · Liquid phase conditions: Shimadzu LC - 20AD pump

[0440] Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

[0441] • Column: phenomenex Gemiu 5um C18 50×4.6mm

[0442] • Mobile phase: Solution A is a 0.1% formic acid aqueous solution, and solution B is acetonitrile.

[0443] • Flow rate: 0.8 mL / min

[0444] • Elution time: 0-4.0 minutes, eluent as follows:

[0445] Table 2-5

[0446]

[0447] 3. Experimental Results and Analysis

[0448] The main pharmacokinetic parameters were calculated using WinNonlin 6.1. The results of the mouse pharmacokinetic experiments are shown in Table 2-6 below:

[0449] Table 2-6 Results of Pharmacokinetic Experiments in Mice

[0450]

[0451] 4. Experimental conclusions:

[0452] As can be seen from the results of the mouse pharmacokinetic experiments in the table, the compounds in the embodiments of this invention exhibit good metabolic properties, with low exposure AUC and maximum plasma concentration C. max They all performed well.

[0453] IV. Tumor Inhibition Experiment in Ba / F3 KIF5B-RET Xenograft Model

[0454] 1. Experimental objective:

[0455] To evaluate the antitumor activity of the tested compounds against subcutaneous xenografts of Ba / F3 KIF5B-RET cells in nude mice.

[0456] 2. Experimental instruments and reagents:

[0457] 2.1 Instruments:

[0458] Clean bench (BSC-1300II A2, Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory);

[0459] CO2 incubator (311, Thermo);

[0460] Centrifuge 5720R, Eppendorf;

[0461] Automated cell counter (Countess II, Life);

[0462] Pipettes (10-20 μL, Eppendorf);

[0463] Microscope (TS100, Nikon);

[0464] Vernier calipers (500-196, Mitutoyo, Japan);

[0465] Cell culture flasks (T25 / T75 / T225, Corning).

[0466] 2.2 Reagents:

[0467] RPMI1640 (22400-089, Gibco);

[0468] Fetal bovine serum (FBS) (10099-141, Gibco);

[0469] Phosphate-buffered saline (PBS) (10010-023, Gibco).

[0470] 2.3 Test Compounds:

[0471] The compounds used in this invention embodiment are self-made.

[0472] 3. Experimental Procedure:

[0473] Ba / F3 KIF5B-RET cells were retrieved from the cell bank, revived, and then added to RPMI 1640 medium (RPMI 1640 + 10% FBS + 1% Glu + 1% P / S) and cultured in a CO2 incubator (37℃, CO2 concentration 5%). Once the cell number reached the required level for in vivo seeding, Ba / F3 KIF5B-RET cells were collected. Cells were counted using an automated cell counter, and based on the count results, the cells were resuspended in PBS to prepare a cell suspension (density 2×10⁻⁶). 7 ( / mL), place in an ice box for later use.

[0474] Female BALB / c nude mice, aged 6-8 weeks and weighing approximately 18-22 grams, were used. Mice were housed in an SPF-grade animal facility, five mice per cage. All cages, bedding, and water were sterilized at high temperatures before use. All animals had free access to food and water. Before the experiment, nude mice were tagged with disposable universal ear tags for rats and mice. The injection site was disinfected with 75% medical alcohol before inoculation. Each mouse was subcutaneously inoculated with 0.1 mL (containing 2*10) on the right posterior back. 6(Number of cells) Ba / F3 KIF5B-RET cells. When the tumor volume reaches 60-200 mm. 3 The mice were divided into groups of five for administration. Each test compound was administered orally twice daily for 14 days. Tumor volume and body weight were measured twice weekly, and tumor TGI (%) was calculated.

[0475] 4. Data Processing:

[0476] Tumor volume (mm) 3 The calculation formula is: V = 0.5 * D * d * d, where D and d are the long diameter and short diameter of the tumor, respectively.

[0477] Calculation of TGI (%):

[0478] When the tumor does not regress, TGI(%) = [(1 - (mean tumor volume at the end of treatment - mean tumor volume at the beginning of treatment)) / (mean tumor volume at the end of treatment in the solvent control group - mean tumor volume at the beginning of treatment in the solvent control group)] × 100%;

[0479] When the tumor regresses, TGI(%) = [1 - (mean tumor volume at the end of treatment - mean tumor volume at the start of treatment) / mean tumor volume at the start of treatment] × 100%.

[0480] 5. Experimental Results:

[0481] Table 2-7 Efficacy Parameters

[0482]

[0483] Note: The data in parentheses represent the tumor volume at the corresponding time point in the Vehicle QD x 3w group (i.e., the control group) of this embodiment. 6. Experimental Conclusion:

[0484] The above data show that, after 14 days of continuous oral administration, the compound of the present invention can significantly inhibit the growth of xenografts in Ba / F3KIF5B-RET nude mice.

[0485] III. Study on the salts and crystal forms of compounds

[0486] 1. Screening of compound salt forms and their crystal forms

[0487] 1.1 Screening of compound salt types

[0488] 1.1.1 Experimental Objective:

[0489] By selecting different counterionic acids and using appropriate crystallization methods, we can detect which counterionic acids can form compound salts.

[0490] 1.1.2 Experimental Procedure:

[0491] 1) Instruments and equipment

[0492] name model source Analytical balance XA105 METTLER TOLEDO Ultrasonic cleaner SK5200LHC Shanghai Kedao Ultrasonic Instruments pipette Eppendorf (50 mL, 100 μL) Eppendorf

[0493] 2) Operating Procedures

[0494] a. Salt type screening by evaporation method

[0495] Weigh 160 mg of free base, add 16 mL of DCM solvent, heat and stir at 40 °C, and divide into 16 equal portions after dissolution. Add different counterionic acids to each portion and allow to evaporate overnight at room temperature. If the solidification is good after evaporation, determine the DSC. If the solidification is poor (oily), add 200 μL of ethyl acetate at 50 °C and stir overnight. If the solidification is good, centrifuge, remove the supernatant, and further dry the solid in a vacuum drying oven overnight (50 °C vacuum drying under reduced pressure). The screening results are shown in Table 3-1 below.

[0496] Table 3-1. Salt form screening results of compounds from the examples

[0497]

[0498] 1.2 Screening of compound salt crystal forms

[0499] 1.2.1. Screening of polymorphs of benzenesulfonate by salt crystallization using different solvents (dissolution or suspension).

[0500] Weigh 15 mg of each compound from the examples, add 0.4 mL of the corresponding solvent, and then heat to 50 °C. If the mixture does not dissolve completely, add 1.1 equivalents of 1 M benzenesulfonic acid methanol solution, maintain the high temperature for a period of time, and then cool to room temperature overnight. Observe whether any precipitate forms. If a precipitate forms, centrifuge quickly, remove the supernatant, and dry the solid under vacuum at 50 °C overnight. Measure the XRD of the solid and compare it with the initial XRD. The results are shown in Table 3-2 below.

[0501] Table 3-2. Results of Crystallization Experiments of Compounds in the Examples of Benzenesulfonate Solutions

[0502]

[0503]

[0504] 1.2.2. Screening of p-toluenesulfonate polymorphs by dissolution or suspension in different solvents to form salts and crystallize.

[0505] Weigh 10 mg of each compound from the examples, add 0.25 mL of the corresponding solvent, and then heat to 50 °C. If the mixture does not dissolve completely, add 1.1 equivalents of 1 M p-toluenesulfonic acid methanol solution. After maintaining the high temperature for a period of time, cool to room temperature overnight and observe whether any precipitate forms. If a precipitate forms, centrifuge quickly, remove the supernatant, and vacuum dry the solid at 50 °C overnight. If no solid precipitates, add the antisolvent MtBE until a solid precipitates. Measure the XRD of the solid and compare it with the initial XRD. The results are shown in Tables 3-6 below.

[0506] Table 3-6. Results of crystallization experiments of p-toluenesulfonate compounds in the examples.

[0507] Serial Number solvent Phenomena after adding acid p-Toluenesulfonate 1 methanol Dissolve Form I 2 ethanol Slightly cloudy Free base 3 acetone Dissolve Form I 4 Acetonitrile Dissolve Form I 5 Isopropyl acetate Adhesive wall Form I 6 Ethyl acetate Adhesive wall Form I 7 Tetrahydrofuran Dissolve Form I 8 Dibutyl ketone Dissolve Form I 9 dichloromethane Dissolve Form I

[0508] 1.2.3. Screening of hydrobromide polymorphs by dissolving or suspending in different solvents to form salts and crystallize.

[0509] Weigh 10 mg of the free base of the compound from the examples, add 200 μL of each of the different solvents, heat and stir at 50 °C, add 1.0 M hydrobromic acid methanol solution, stir overnight, centrifuge and dry, and then determine XRD, DSC, and TGA. The characterization results are shown in Tables 3-8 below.

[0510] Table 3-8. Results of the crystallization experiment of the hydrobromide solution of the example compounds

[0511] Serial Number solvent Phenomena after adding acid hydrobromide 1 dichloromethane Dissolve Form I

[0512] 1.2.4. Screening of hydrochloride polymorphs by dissolution or suspension in different solvents to form salt crystals.

[0513] Weigh 10 mg of the free base of the compound from the examples, add 200 μL of each of the different solvents, heat and stir at 50 °C, add 1.0 M hydrochloric acid-methanol solution, stir overnight, centrifuge and dry, and then determine XRD, DSC, and TGA. The characterization results are shown in Table 3-11 below.

[0514] Table 3-11. Screening results of the hydrochloride salts of the examples

[0515] Serial Number solvent Phenomena after adding acid hydrochloride 1 methanol Dissolve Form I 2 ethanol Dissolve Form I 3 Ethyl acetate Dissolve Form I 4 Tetrahydrofuran Adhesive wall Form II 5 dichloromethane Dissolve Form I

[0516] 1.2.5. Screening of oxalate polymorphs by dissolution or suspension in different solvents to form salt crystals.

[0517] Weigh 12 mg of the free base of the compound from the examples, add DCM, and prepare concentrations of 10 mg / ml, 25 mg / ml, and 50 mg / ml respectively. Heat and stir at 40°C, add 1.0 M oxalic acid (ethanol solution) in different equivalence ratios, stir overnight, centrifuge and dry, and then determine XRD, DSC, and TGA. The characterization results are shown in Table 3-13 below.

[0518] Table 3-13. Screening results of oxalate compounds from the examples

[0519]

[0520] 1.2.6. Screening of polymorphs of methanesulfonate by salt crystallization using different solvents (dissolution or suspension).

[0521] Weigh 10 mg of the free base of the compound from the examples, add it to different solvents, heat and stir at 40°C, add 24 μL of 1.0 M methanesulfonic acid (methanol solution), stir overnight, centrifuge and dry, and then determine XRD and DSC. The characterization results are shown in Table 3-15 below.

[0522] Table 3-15. Screening results of methanesulfonates from the examples

[0523] Serial Number solvent Phenomena after adding acid Remark Methanesulfonates 1 EA Adhesive wall oily Form I 2 DCM Dissolve Add antisolvent MtBE Form I 3 DCM Dissolve After drying, add EA and pulp. Form I

[0524] 1.2.7. Screening of ethanesulfonate polymorphs by dissolving or suspending in different solvents to form salts and crystallize.

[0525] Weigh 10 mg of the free base of the compound from the examples, add it to different solvents, heat and stir at 40°C, add 24 μL of 1.0 M ethanesulfonic acid (methanol solution), stir overnight, centrifuge and dry, and then determine XRD, DSC, and TGA. The characterization results are shown in Table 3-16 below.

[0526] Table 3-16. Screening results of the compound ethanesulfonate from the examples

[0527] Serial Number solvent Phenomena after adding acid Remark ethanesulfonate 1 EA Adhesive wall Good solidification properties Form I 2 DCM Dissolve After drying, add EA and pulp. Form I 3 THF Dissolve Add MtBE, oily, solid Form II

[0528] 1.2.8. Screening of hydroxyethyl sulfonate polymorphs by dissolution or suspension in different solvents to form salts and crystallize.

[0529] Weigh 10 mg of the free base of the compound from the examples, add it to different solvents, heat and stir at 40°C, add 24 μL of 1.0 M hydroxyethyl sulfonic acid (methanol solution), stir overnight, centrifuge and dry, and then determine XRD, DSC, and TGA. The characterization results are shown in Table 3-18 below.

[0530] Table 3-18. Screening results of hydroxyethyl sulfonate compounds from the examples

[0531] Serial Number solvent Phenomena after adding acid Remark Hydroxyethyl sulfonate 1 EA Adhesive wall Good solidification properties Form I 2 DCM Dissolve After drying, add EA and pulp. Form I

[0532] 1.2.9. Screening of sulfate polymorphs by salt crystallization through dissolution or suspension in different solvents.

[0533] Weigh 10 mg of the free base of the compound from the examples, add it to different solvents, heat and stir at 40°C, add 24 μL of 1.0 M sulfuric acid (methanol solution), stir overnight, centrifuge and dry, and then determine XRD, DSC, and TGA. The characterization results are shown in Table 3-19 below.

[0534] Table 3-19. Screening results of sulfate compounds from the examples

[0535] Serial Number solvent Phenomena after adding acid Remark sulfates 1 EtOH Dissolve Precipitates at room temperature Form II 2 EA Adhesive wall Good solidification properties Form I 3 DCM Dissolve After drying, add EA and pulp. Form I 4 THF Dissolve Good solidification properties Form II

[0536] 1.2.10. Screening of phosphate polymorphs by salt crystallization through dissolution or suspension in different solvents.

[0537] Weigh 10 mg of the free base of the compound from the examples, add it to different solvents, heat and stir at 40°C, add 24 μL of 1.0 M phosphoric acid (ethanol solution), stir overnight, centrifuge and dry, and then determine XRD and DSC. The characterization results are shown in Table 3-21 below.

[0538] Table 3-21. Screening results of phosphate compounds from the examples

[0539]

[0540]

[0541] 2. Preparation methods for different crystal forms

[0542] ①Preparation of benzenesulfonate crystal form I

[0543] Weigh 50 mg of free base, add 1.4 mL of ethanol solvent, and then heat to 50 °C. If not completely dissolved, add 1.1 equivalents of 1 M benzenesulfonic acid methanol solution. After maintaining the temperature at 50 °C for a period of time, observe the precipitation. Keep in this state overnight, then cool to room temperature, centrifuge rapidly, remove the supernatant, and dry the solid under vacuum at 50 °C to obtain benzenesulfonate crystal form I. Analysis shows that it possesses the following properties: Figure 1 The XRPD diagram shown is as follows: Figure 2 The DSC diagram shown and as follows Figure 3 The TGA diagram shown.

[0544] ②Preparation of benzenesulfonate crystal form II

[0545] Weigh 15 mg of free base, add 0.4 mL of ethanol solvent, and then heat to 50 °C. If not completely dissolved, add 1.1 equivalents of 1 M benzenesulfonic acid methanol solution. Maintain the high temperature for a period of time, then cool to room temperature overnight. Observe whether a precipitate forms. If a precipitate forms, centrifuge quickly, remove the supernatant, and dry the solid under vacuum at 50 °C to obtain benzenesulfonate crystal form I. Analysis shows that it has the following properties: Figure 4 The XRPD diagram shown is as follows: Figure 5 The DSC diagram shown and as follows Figure 6 The TGA diagram shown.

[0546] ③ Preparation of p-toluenesulfonate crystal form I

[0547] 10 mg of the compound was weighed and added to 250 μL of methanol solvent. The mixture was then heated to 50 °C. Since the compound did not completely dissolve, 1.1 equivalents of 1 M benzenesulfonic acid methanol solution were added. After adding acid, the solid dissolved. Then, 1.2 mL of methyl tert-butyl ether was added, precipitating a large amount of white solid. The solid was filtered and dried under vacuum to obtain p-toluenesulfonate crystal form I. Analysis showed that it possessed the following properties: Figure 7 The XRPD diagram shown is as follows: Figure 8 The DSC diagram shown and as follows Figure 9 The TGA diagram shown.

[0548] ④ Preparation of hydrochloride crystal form I

[0549] Weigh 50 mg of the compound and add 1.4 mL of ethanol solvent. Heat to 50 °C; if not completely dissolved, add 1.1 equivalents of 1 M hydrochloric acid methanol solution. The solid dissolves after acid addition, precipitating out after half an hour. Cool to room temperature, centrifuge, and vacuum dry to obtain hydrochloride crystal form I. Analysis reveals the following properties: Figure 10 The XRPD diagram shown is as follows: Figure 11 The DSC diagram shown and as follows Figure 12 The TGA diagram shown.

[0550] ⑤ Preparation of hydrochloride crystal form II

[0551] 10 mg of the compound was weighed and added to 400 μL of tetrahydrofuran solvent. The mixture was then heated to 50 °C to dissolve the compound. 1.1 equivalents of 1 M hydrochloric acid-methanol solution were added, and a solid precipitated after acid addition. The mixture was stirred at high temperature, then cooled to room temperature, centrifuged, and vacuum dried to obtain hydrochloride crystal form II. Analysis revealed the following properties: Figure 13 The XRPD diagram shown and as follows Figure 14 The DSC diagram shown.

[0552] ⑥ Preparation of hydrobromide crystal form I

[0553] Weigh 15 mg of the compound and add 250 μL of dichloromethane solvent. Heat to 40 °C; if not completely dissolved, add 1.1 equivalents of 1 M hydrobromic acid ethanol solution. After adding acid, the solid dissolves. Cool to room temperature, and a solid precipitates. Centrifuge and vacuum dry to obtain hydrobromide crystal form I. Analysis reveals the following properties: Figure 15 The XRPD diagram shown is as follows: Figure 16 The DSC diagram shown and as follows Figure 17 The TGA diagram shown.

[0554] 3. Crystal form stability experiment

[0555] 3.1 Stability Test

[0556] 3.1.1 Experimental methods and results:

[0557] ① The stability of benzenesulfonate crystal form I under high temperature 60℃, high humidity 92.5%RH and high temperature and high humidity 50℃ / 75%RH conditions was investigated. An appropriate amount of benzenesulfonate crystal form I was weighed and placed for 13 days. Then, a diluent ACN:H2O (1:1) was added to prepare a solution with a concentration of 0.5 mg / mL. The solution was analyzed by HPLC, and the changes of related substances were calculated by the chromatographic peak area normalization method.

[0558] Physicochemical stability results of benzenesulfonate crystal form I

[0559]

[0560] ② The stability of p-toluenesulfonate crystal form I was investigated under the conditions of high temperature 60℃, high humidity 92.5%RH and high temperature and high humidity 50℃ / 75%RH. An appropriate amount of p-toluenesulfonate was weighed and placed for 13 days. Then, a diluent ACN:H2O (1:1) was added to prepare a solution with a concentration of 0.5 mg / mL. The solution was analyzed by HPLC, and the changes of related substances were calculated by the chromatographic peak area normalization method.

[0561] Physicochemical stability results of p-toluenesulfonate

[0562]

[0563] ③ The stability of hydrobromide crystal form I under high temperature 60℃, high humidity 92.5%RH and high temperature and high humidity 50℃ / 75%RH conditions was investigated. An appropriate amount of hydrobromide crystal form I was weighed and placed for 14 days. Then, a diluent ACN:H2O (1:1) was added to prepare a solution with a concentration of 0.5 mg / mL. The solution was analyzed by HPLC, and the changes of related substances were calculated by the chromatographic peak area normalization method.

[0564] Physicochemical stability results of hydrobromide crystal form I

[0565]

[0566] ④ The stability of hydrochloride crystal form I under high temperature 60℃, high humidity 92.5%RH and high temperature and high humidity 50℃ / 75%RH conditions was investigated. After weighing hydrochloride crystal form I and storing it for 10 days, a solution with a concentration of 0.5 mg / mL was prepared by adding diluent ACN:H2O (1:1). The solution was analyzed by HPLC, and the changes of related substances were calculated by the chromatographic peak area normalization method.

[0567] Physicochemical stability results of hydrochloride crystal form I

[0568]

[0569] ⑤ The stability of oxalate crystal form IV was investigated under the conditions of high temperature 60℃, high humidity 92.5%RH and high temperature and high humidity 50℃ / 75%RH. After weighing oxalate crystal form IV and storing it for 14 days, a solution with a concentration of 0.5 mg / mL was prepared by adding diluent ACN:H2O (1:1). The solution was analyzed by HPLC, and the changes of related substances were calculated by the chromatographic peak area normalization method.

[0570] Physicochemical stability results of oxalate crystal form IV

[0571]

[0572] ⑤ To investigate the stability of isosulfonate crystal form I under high temperature 60℃, high humidity 92.5%RH and high temperature and high humidity 50℃ / 75%RH conditions, isosulfonate crystal form I was weighed and placed for 13 days, and then diluted with diluent ACN:H2O (1:1) to prepare a solution with a concentration of 0.5 mg / mL. The solution was analyzed by HPLC, and the changes in related substances were calculated by the chromatographic peak area normalization method.

[0573] Physicochemical stability results of ethanesulfonate crystal form I

[0574]

[0575] ⑥ To investigate the stability of sulfate crystal form I under high temperature 60℃, high humidity 92.5%RH and high temperature and high humidity 50℃ / 75%RH conditions, sulfate crystal form I was weighed and placed for 13 days, and then diluted with diluent ACN:H2O (1:1) to prepare a solution with a concentration of 0.5mg / mL. The solution was analyzed by HPLC, and the changes of related substances were calculated by the chromatographic peak area normalization method.

[0576] Physicochemical stability results of sulfate crystal form I

[0577]

[0578]

[0579] 4. Hygroscopicity test of crystal form

[0580] 4.1 Hygroscopicity Test

[0581] 4.1.1 Experimental Objective:

[0582] The hygroscopicity of the compound crystal form under different relative humidity conditions was investigated to provide a basis for compound storage.

[0583] 4.1.2 Experimental instruments and parameters:

[0584] Instrument Model SMS Intrinsic Experimental temperature 25℃ Drying time 0%RH 120min Balance dm / dt 0.02% / min (minimum 10min, maximum 180min) RH (%) measurement step size 10％ Measuring gradient 0-95-0％ Loop count 2

[0585] 4.1.3 Hygroscopicity test:

[0586] Hygroscopicity of a drug refers to its ability or degree to absorb moisture under certain temperature and humidity conditions. The experiment used a dynamic moisture adsorption (DVS) meter to characterize the drug's ability to absorb moisture under different humidity conditions.

[0587] 4.1.4 Experimental Results:

[0588] ① DVS hygroscopicity curve of benzenesulfonate crystal form I Figure 43 As shown, the hygroscopicity is only 0.65% under 80% RH conditions. According to the pharmacopoeia, benzenesulfonate crystal form I is defined as having slight hygroscopicity.

[0589] ② DVS hygroscopicity curve of p-toluenesulfonate crystal form I Figure 44 As shown, the hygroscopicity is 1.21% under 80% RH conditions. According to the pharmacopoeia, p-toluenesulfonate is defined as slightly hygroscopic.

[0590] ③ DVS hygroscopicity curve of hydrobromide crystal form I Figure 45 As shown, the hygroscopicity is 1.1% under 80% RH conditions. According to the pharmacopoeia, hydrobromide is defined as slightly hygroscopic.

[0591] ④ DVS hygroscopicity curve of hydrochloride crystal form I Figure 46 As shown, the hygroscopicity of hydrochloride crystal form I under 80% RH conditions is 1.47%. According to the pharmacopoeia, hydrochloride crystal form I is defined as slightly hygroscopic.

[0592] ⑤ DVS hygroscopicity curve of oxalate crystal form IV Figure 47 As shown, the hygroscopicity of oxalate crystal form IV is 0.69% under 80% RH conditions. According to the pharmacopoeia, oxalate crystal form IV is defined as slightly hygroscopic.

[0593] 5. Solubility experiments in different media

[0594] 5.1 Solubility Experiment of Compound Crystal Forms

[0595] 5.1.1 Experimental Objective:

[0596] Comparing the solubility of compound crystal forms in different organic solvents provides a basis for druggability assessment.

[0597] 5.1.2 Experimental methods and results:

[0598] ① Weigh 2.0 mg of benzenesulfonate crystal form I into a 2 mL centrifuge tube, then add 1 mL of different pH buffer solutions, simulated gastric juice (FaSSGF), fasting simulated intestinal juice (FaSSIF), non-fasting simulated intestinal juice (FeSSIF), and pure water, respectively. Place the tube in a micromixer and shake overnight at 37℃. After 24 hours, filter the sample solution through a 0.45 μm mixed water fiber membrane and collect the filtrate. Analyze the content of benzenesulfonate crystal form I using HPLC. The solubility of benzenesulfonate crystal form I in different buffer solutions is shown in the table below. Results of benzenesulfonate crystal form I solubility in different pH buffer solutions.

[0599] compound Benzenesulfonate crystal form I Buffer solution Solubility (mg / mL) pH 1 >2.00 pH 2 >2.00 pH 3 0.66 pH 4 0.15 pH 5 0.06 pH 6 0.003 FaSSIF 0.007 FaSSGF >2.00 FeSSIF 1.14 <![CDATA[H2O]]> 0.81

[0600] ② Weigh approximately 2-3 mg of p-toluenesulfonate crystal form I and suspend it in 1 mL of artificial simulated gastric juice (FaSSGF), fasting artificial simulated intestinal juice (FaSSIF), non-fasting artificial simulated intestinal juice (FeSSIF), and pure water for 24 hours. Collect the filtrate and detect it by HPLC. Determine the thermodynamic solubility of the compound at 37℃ using the external standard method, and simultaneously determine the corresponding pH value.

[0601] Solubility results of p-toluenesulfonate in different pH buffers

[0602] compound p-Toluenesulfonate Buffer solution Solubility (mg / mL) <![CDATA[H2O]]> 1.08 FaSSGF >2.00 FaSSIF 0.03 FeSSIF 0.76

[0603] ③ Weigh approximately 2-3 mg of hydrochloride crystal form I and suspend it in 1 mL of artificial simulated gastric juice (FaSSGF), fasting artificial simulated intestinal juice (FaSSIF), non-fasting artificial simulated intestinal juice (FeSSIF), and pure water for 24 hours. Collect the filtrate and detect it by HPLC. Determine the thermodynamic solubility of the compound at 37℃ using the external standard method, and simultaneously determine the corresponding pH value.

[0604] Solubility results of hydrochloride in different pH buffers

[0605] compound hydrochloride Buffer solution Solubility (mg / mL) <![CDATA[H2O]]> 1.52 FaSSGF >2.00 FaSSIF <0.01 FeSSIF 0.76 .

Claims

1. An acid salt of a compound 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile, wherein the acid in the acid salt is selected from benzenesulfonic acid, hydrochloric acid, p-toluenesulfonic acid, oxalic acid, phosphoric acid or hydrobromic acid.

2. The acid salt according to claim 1, characterized in that, The number of acids is 0.2-3.

3. The acid salt according to claim 1, characterized in that, The number of acids is 0.2, 0.5, 1, 1.5, 2, 2.5 or 3.

4. The acid salt according to claim 1, characterized in that, The number of acids is 0.5, 1, 2 or 3.

5. The acid salt according to claim 1, characterized in that, The number of acids is 1. 6,6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile, wherein the acid salt is a crystalline form, said crystalline form being selected from: The X-ray powder diffraction pattern of benzenesulfonate crystal form I contains 2 The diffraction peaks are at 17.7±0.2°, 8.4±0.2°, 24.8±0.2°, 21.5±0.2°, 17.1±0.2°, 19.3±0.2°, 15.2±0.2° and 23.4±0.2°. The X-ray powder diffraction pattern of benzenesulfonate crystal form II contains 2 The diffraction peaks are at 17.7±0.2°, 15.2±0.2°, 21.5±0.2°, 24.8±0.2°, 8.5±0.2°, 19.3±0.2°, 17.1±0.2° and 18.6±0.2°. The X-ray powder diffraction pattern of p-toluenesulfonate crystal form I contains 2 The diffraction peaks are at 18.4±0.2°, 15.1±0.2°, 8.1±0.2°, 16.9±0.2°, 7.6±0.2°, 17.4±0.2°, 20.9±0.2° and 17.2±0.2°. The X-ray powder diffraction pattern of hydrochloride crystal form I contains 2 The diffraction peaks are at 10.0±0.2°, 6.0±0.2°, 15.6±0.2°, 16.8±0.2°, 24.6±0.2°, 23.0±0.2°, 20.8±0.2° and 26.7±0.2°. The X-ray powder diffraction pattern of hydrochloride crystal form II contains 2 The diffraction peaks are at 10.0±0.2°, 6.0±0.2°, 6.6±0.2°, 15.6±0.2°, 24.7±0.2°, 23.1±0.2°, 16.8±0.2° and 17.5±0.2°. The X-ray powder diffraction pattern of hydrobromide crystal form I contains 2 The diffraction peaks are at 9.9±0.2°, 5.9±0.2°, 22.8±0.2°, 20.6±0.2°, 24.4±0.2°, 16.7±0.2°, 21.4±0.2° and 26.6±0.2°. The X-ray powder diffraction pattern of oxalate crystal form I contains 2 The diffraction peaks are at 9.5±0.2°, 19.3±0.2°, 10.7±0.2°, 4.7±0.2°, 6.0±0.2°, 16.5±0.2°, 25.0±0.2° and 27.1±0.2°. The X-ray powder diffraction pattern of oxalate crystal form II contains 2 The diffraction peaks are at 5.8±0.2°, 4.8±0.2°, 15.7±0.2°, 17.0±0.2°, 9.4±0.2°, 19.2±0.2°, 17.7±0.2° and 16.6±0.2°. The X-ray powder diffraction pattern of oxalate crystal form III contains 2 The diffraction peaks are at 10.4±0.2°, 5.1±0.2°, 4.8±0.2°, 15.8±0.2°, 14.3±0.2°, 12.2±0.2°, 17.8±0.2° and 5.8±0.2°. The X-ray powder diffraction pattern of oxalate crystal form IV contains 2 The diffraction peaks are at 20.5±0.2°, 18.5±0.2°, 17.9±0.2°, 4.8±0.2°, 16.5±0.2°, 15.8±0.2°, 11.5±0.2° and 12.3±0.2°. The X-ray powder diffraction pattern of methanesulfonate crystal form I contains 2 The diffraction peaks are at 10.3±0.2°, 5.1±0.2°, 15.6±0.2°, 25.2±0.2°, and 18.4±0.2°. The X-ray powder diffraction pattern of ethanesulfonate crystal form I contains 2 The diffraction peaks are at 10.2±0.2°, 5.0±0.2°, 15.4±0.2°, 24.2±0.2°, 18.9±0.2° and 21.1±0.2°. The X-ray powder diffraction pattern of ethanesulfonate crystal form II contains 2 The diffraction peaks are at 10.2±0.2°, 5.0±0.2°, 6.0±0.2°, 15.4±0.2° and 5.4±0.2°. The X-ray powder diffraction pattern of hydroxyethyl sulfonate crystal form I contains 2 The diffraction peaks are at 10.5±0.2°, 5.2±0.2°, 18.7±0.2°, 15.9±0.2° and 23.0±0.2°. The X-ray powder diffraction pattern of hydroxyethyl sulfonate crystal form II contains 2 The diffraction peaks are at 11.9±0.2°, 18.4±0.2°, 4.8±0.2°, 23.4±0.2°, 16.7±0.2°, 17.8±0.2°, 12.8±0.2° and 23.8±0.2°. The X-ray powder diffraction pattern of sulfate crystal form I contains 2 The diffraction peaks are at 10.3±0.2°, 5.1±0.2°, 15.6±0.2°, 14.5±0.2°, 20.2±0.2°, 19.0±0.2°, 25.6±0.2° and 22.1±0.2°. The X-ray powder diffraction pattern of sulfate crystal form II contains 2 The diffraction peaks are at 16.1±0.2°, 5.9±0.2°, 6.6±0.2°, 22.0±0.2°, 21.0±0.2°, 20.1±0.2°, 17.0±0.2° and 25.2±0.2°. The X-ray powder diffraction pattern of phosphate crystal form I contains 2 The diffraction peaks are at 5.6±0.2°, 11.5±0.2°, 20.3±0.2°, 15.9±0.2°, 17.2±0.2°, 16.4±0.2° and 21.9±0.2°. The X-ray powder diffraction pattern of phosphate crystal form II contains 2 The diffraction peaks are at 5.6±0.2°, 11.4±0.2°, 15.1±0.2°, 15.4±0.2°, 17.2±0.2°, 20.0±0.2°, 16.1±0.2° and 20.3±0.2°.

7. The acid salt according to claim 6, characterized in that, The X-ray powder diffraction pattern of benzenesulfonate crystal form I contains 2 The diffraction peaks are at 17.7±0.2°, 8.4±0.2°, 24.8±0.2°, 21.5±0.2°, 17.1±0.2°, 15.2±0.2°, 23.4±0.2°, 19.3±0.2°, 28.2±0.2°, 18.9±0.2°, 11.8±0.2°, and 18.6±0.2°. The X-ray powder diffraction pattern of benzenesulfonate crystal form II contains 2 The diffraction peaks are at 17.7±0.2°, 15.2±0.2°, 21.5±0.2°, 24.8±0.2°, 8.5±0.2°, 19.3±0.2°, 17.1±0.2°, 18.6±0.2°, 23.4±0.2°, 7.7±0.2°, 6.5±0.2° and 13.9±0.2°. The X-ray powder diffraction pattern of p-toluenesulfonate crystal form I contains 2 The diffraction peaks are at 18.4±0.2°, 15.1±0.2°, 8.1±0.2°, 16.9±0.2°, 7.6±0.2°, 17.4±0.2°, 20.9±0.2°, 17.2±0.2°, 5.0±0.2°, 19.0±0.2°, 22.8±0.2°, 24.0±0.2°, and 13.6±0.2°. The X-ray powder diffraction pattern of hydrochloride crystal form I contains 2 The diffraction peaks are at 10.0±0.2°, 6.0±0.2°, 15.6±0.2°, 16.8±0.2°, 24.6±0.2°, 23.0±0.2°, 20.8±0.2°, 26.7±0.2°, 17.5±0.2°, 21.6±0.2°, 14.9±0.2°, and 30.7±0.2°. The X-ray powder diffraction pattern of hydrochloride crystal form II contains 2 The diffraction peaks are at 10.0±0.2°, 6.0±0.2°, 6.6±0.2°, 15.6±0.2°, 24.7±0.2°, 23.1±0.2°, 16.8±0.2°, 17.5±0.2°, 20.8±0.2°, 23.9±0.2°, 22.4±0.2°, and 26.7±0.2°. The X-ray powder diffraction pattern of hydrobromide crystal form I contains 2 The diffraction peaks are at 9.9±0.2°, 5.9±0.2°, 22.8±0.2°, 20.6±0.2°, 24.4±0.2°, 16.7±0.2°, 21.4±0.2°, 26.6±0.2°, 17.4±0.2°, 24.9±0.2°, 23.1±0.2°, and 30.6±0.2°. The X-ray powder diffraction pattern of oxalate crystal form I contains 2 The diffraction peaks are 9.5±0.2°, 19.3±0.2°, 10.7±0.2°, 4.7±0.2°, 6.0±0.2°, 16.5±0.2°, 25.0±0.2°, 27.1±0.2°, 15.3±0.2°, 14.5±0.2°, 18.6±0.2°, and 20.5±0.2°. The X-ray powder diffraction pattern of oxalate crystal form II contains 2 The diffraction peaks are at 5.8±0.2°, 4.8±0.2°, 15.7±0.2°, 17.0±0.2°, 9.4±0.2°, 19.2±0.2°, 17.7±0.2°, 16.6±0.2°, 26.1±0.2°, 11.8±0.2°, 18.6±0.2°, and 12.5±0.2°. The X-ray powder diffraction pattern of oxalate crystal form III contains 2 The diffraction peaks are at 10.4±0.2°, 5.1±0.2°, 4.8±0.2°, 15.8±0.2°, 14.3±0.2°, 12.2±0.2°, 17.8±0.2°, 5.8±0.2°, 18.9±0.2°, 17.0±0.2° and 23.8±0.2°. The X-ray powder diffraction pattern of oxalate crystal form IV contains 2 The diffraction peaks are at 20.5±0.2°, 18.5±0.2°, 17.9±0.2°, 4.8±0.2°, 16.5±0.2°, 15.8±0.2°, 11.5±0.2°, 12.3±0.2°, 24.0±0.2°, 16.2±0.2°, 23.3±0.2° and 19.6±0.2°. The X-ray powder diffraction pattern of ethanesulfonate crystal form II contains 2 The diffraction peaks are at 10.2±0.2°, 5.0±0.2°, 6.0±0.2°, 15.4±0.2°, 5.4±0.2° and 7.3±0.2°. The X-ray powder diffraction pattern of hydroxyethyl sulfonate crystal form II contains 2 The diffraction peaks are at 11.9±0.2°, 18.4±0.2°, 4.8±0.2°, 23.4±0.2°, 16.7±0.2°, 17.8±0.2°, 12.8±0.2°, 23.8±0.2°, 21.8±0.2°, 19.0±0.2°, 25.4±0.2°, and 19.8±0.2°. The X-ray powder diffraction pattern of sulfate crystal form I contains 2 The diffraction peaks are at 10.3±0.2°, 5.1±0.2°, 15.6±0.2°, 14.5±0.2°, 20.2±0.2°, 19.0±0.2°, 25.6±0.2°, 22.1±0.2°, 23.0±0.2°, 20.8±0.2°, 19.2±0.2°, and 24.1±0.2°. The X-ray powder diffraction pattern of sulfate crystal form II contains 2 The diffraction peaks are at 16.1±0.2°, 5.9±0.2°, 6.6±0.2°, 22.0±0.2°, 21.0±0.2°, 20.1±0.2°, 17.0±0.2°, 25.2±0.2°, 20.7±0.2°, and 23.1±0.2°. The X-ray powder diffraction pattern of phosphate crystal form I contains 2 The diffraction peaks are at 5.6±0.2°, 11.5±0.2°, 20.3±0.2°, 15.9±0.2°, 17.2±0.2°, 16.4±0.2°, 21.9±0.2° and 10.2±0.2°. The X-ray powder diffraction pattern of phosphate crystal form II contains 2 The diffraction peaks are at 5.6±0.2°, 11.4±0.2°, 15.1±0.2°, 15.4±0.2°, 17.2±0.2°, 20.0±0.2°, 16.1±0.2°, 20.3±0.2°, 21.0±0.2°, 21.8±0.2°, and 24.7±0.2°.

8. The crystal form according to claim 6, characterized in that, The X-ray powder diffraction (XRD) patterns of benzenesulfonate crystal form I are shown in Figure 1; those of benzenesulfonate crystal form II are shown in Figure 4; those of p-toluenesulfonate crystal form I are shown in Figure 7; those of hydrochloride crystal form I are shown in Figure 10; those of hydrochloride crystal form II are shown in Figure 13; those of hydrobromide crystal form I are shown in Figure 15; those of oxalate crystal form I are shown in Figure 18; those of oxalate crystal form II are shown in Figure 21; those of oxalate crystal form III are shown in Figure 22; and those of oxalate crystal form IV are shown in Figure 4. The X-ray powder diffraction pattern of the following crystal forms is shown in Figure 23; the X-ray powder diffraction pattern of methanesulfonate crystal form I is shown in Figure 26; the X-ray powder diffraction pattern of ethanesulfonate crystal form I is shown in Figure 29; the X-ray powder diffraction pattern of ethanesulfonate crystal form II is shown in Figure 32; the X-ray powder diffraction pattern of hydroxyethylsulfonate crystal form I is shown in Figure 35; the X-ray powder diffraction pattern of hydroxyethylsulfonate crystal form II is shown in Figure 36; the X-ray powder diffraction pattern of sulfate crystal form I is shown in Figure 39; the X-ray powder diffraction pattern of sulfate crystal form II is shown in Figure 40; the X-ray powder diffraction pattern of phosphate crystal form I is shown in Figure 41; and the X-ray powder diffraction pattern of phosphate crystal form II is shown in Figure 42.

9. The crystal form according to claim 6, characterized in that, The 2θ errors of the top ten diffraction peaks with the highest relative intensities in the X-ray powder diffraction patterns of benzenesulfonate crystal form I, benzenesulfonate crystal form II, p-toluenesulfonate crystal form I, hydrochloride crystal form I, hydrochloride crystal form II, hydrobromide crystal form I, oxalate crystal form I, oxalate crystal form II, oxalate crystal form III, oxalate crystal form IV, methanesulfonate crystal form I, ethanesulfonate crystal form I, ethanesulfonate crystal form II, hydroxyethylsulfonate crystal form I, hydroxyethylsulfonate crystal form II, sulfate crystal form I, sulfate crystal form II, phosphate crystal form I, and phosphate crystal form II are ±0.2° compared with the corresponding positions of the diffraction peaks in Figures 1, 4, 7, 10, 13, 15, 18, 21, 22, 23, 26, 29, 32, 35, 36, 39, 40, 41, and 42.

10. The crystal form according to claim 6, characterized in that, Benzenesulfonate crystal form I has the DSC spectrum shown in Figure 2; or the TGA spectrum shown in Figure 3. Benzenesulfonate crystal form II has the DSC spectrum shown in Figure 5; or the TGA spectrum shown in Figure 6. p-Toluenesulfonate crystal form I has the DSC spectrum shown in Figure 8; or the TGA spectrum shown in Figure 9. Hydrochloride crystal form I has the DSC pattern shown in Figure 11; or it has the TGA pattern shown in Figure 12. Hydrochloride crystal form II has the DSC pattern shown in Figure 14; Hydrobromide crystal form I has the DSC spectrum shown in Figure 16; or the TGA spectrum shown in Figure 17. Oxalate crystal form I has the DSC pattern shown in Figure 19; or it has the TGA pattern shown in Figure 20. Oxalate crystal form IV has the DSC pattern shown in Figure 24; or it has the TGA pattern shown in Figure 25. Methanesulfonate crystal form I has the DSC spectrum shown in Figure 27; or the TGA spectrum shown in Figure 28. Ethyl sulfonate crystal form I has the DSC spectrum shown in Figure 30; or has the TGA spectrum shown in Figure 31; Ethyl sulfonate crystal form II has the DSC spectrum shown in Figure 33; or the TGA spectrum shown in Figure 34.

11. The method for preparing the acid salt according to any one of claims 1-5, specifically comprising the following steps: 1) Weigh an appropriate amount of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile free base and dissolve it in a good solvent; 2) Weigh an appropriate amount of the counterion acid and dissolve it in an organic solvent; the amount of the counterion acid is 1.0~1.5 equivalents; 3) Combine the two solutions mentioned above and stir to precipitate, or add a poor solvent and stir to precipitate; 4) Rapid centrifugation or static drying to obtain the target product; in: The benign solvent is selected from one or more of dichloromethane, tetrahydrofuran, 1,4-dioxane, acetone, methanol, ethanol, 2-methyltetrahydrofuran, 2-butanone, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol or tert-butanol; The organic solvent is selected from one or more of methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol, or N,N-dimethylformamide; The above-mentioned benign solvents and organic solutions must be miscible when used; Unsuitable solvents are selected from n-heptane, water, methyl tert-butyl ether, n-hexane, cyclohexane, isopropyl ether, and ethyl acetate; The counterionic acid is selected from the acid salts of benzenesulfonic acid, hydrochloric acid, p-toluenesulfonic acid, oxalic acid, phosphoric acid, or hydrobromic acid; Alternatively, it may include the following steps: 1) Weigh an appropriate amount of the compound salt, suspend it in a poor solvent, and the suspension density is 50~200mg / mL; 2) Shake the obtained suspension at a temperature of 25~50℃; 3) The above suspension is rapidly centrifuged to remove the supernatant, and the remaining solid is dried to obtain the target product; in: The undesirable solvent is selected from one or more of methanol, ethanol, acetonitrile, chlorobenzene, benzene, toluene, acetone, ethyl acetate, water, 88% acetone, isopropyl acetate, 3-pentanone, ethyl formate, 2-methyltetrahydrofuran, isopropanol, n-butanol, isobutanol, n-propanol, methyl tert-butyl ether, n-heptane, tert-butanol, or 2-butanone.

12. The method for preparing the acid salt according to claim 11, specifically comprising the following steps: 1) Weigh an appropriate amount of 6-(((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-(((6-methoxypyridin-3-yl)methyl)-3,6diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile free base and dissolve it in a good solvent; 2) Weigh an appropriate amount of the counterion acid and dissolve it in an organic solvent; the amount of the counterion acid is 1.0~1.5 equivalents; 3) Combine the two solutions mentioned above and stir to precipitate, or add a poor solvent and stir to precipitate; 4) Rapid centrifugation or static drying to obtain the target product; in: The benign solvent is selected from one or more of tetrahydrofuran, dichloromethane, 1,4-dioxane, 2-butanone, or acetone; The organic solvent is selected from one or more of dichloromethane, tetrahydrofuran, or 1,4-dioxane; The above-mentioned benign solvents and organic solutions must be miscible when used; The unsuitable solvent is selected from one or more of water, methyl tert-butyl ether, or isopropyl ether; The counterionic acid is selected from the acid salts of benzenesulfonic acid, hydrochloric acid, p-toluenesulfonic acid, oxalic acid, phosphoric acid, or hydrobromic acid.

13. A pharmaceutical composition comprising a therapeutically effective dose of any one of claims 1 to 10, an acid salt or its crystal form thereof, and one or more pharmaceutically acceptable carriers or excipients.

14. The use of the acid salt or its crystal form according to any one of claims 1 to 10, or the pharmaceutical composition according to claim 13, in the preparation of a RET inhibitor drug.

15. The use of the acid salt or its crystal form according to any one of claims 1 to 10, or the pharmaceutical composition according to claim 13, in the preparation of a medicament for the treatment and / or prevention of non-small cell lung cancer, fibrosarcoma, pancreatic tumors, medullary thyroid carcinoma, papillary thyroid carcinoma, soft tissue sarcoma, high-grade solid tumors, breast tumors, and colon tumors.

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