CN114478586A

CN114478586A - Salt or crystal form of inhibitor containing bicyclic derivatives, and preparation method and application thereof

Info

Publication number: CN114478586A
Application number: CN202111350843.0A
Authority: CN
Inventors: 董华; 呙临松
Original assignee: Jiangsu Hansoh Pharmaceutical Group Co Ltd; Shanghai Hansoh Biomedical Co Ltd
Current assignee: Jiangsu Hansoh Pharmaceutical Group Co Ltd; Shanghai Hansoh Biomedical Co Ltd
Priority date: 2020-11-13
Filing date: 2021-11-15
Publication date: 2022-05-13

Abstract

The invention relates to a salt containing a bicyclic derivative inhibitor, a crystal form thereof, a preparation method and application thereof. In particular to a salt of a compound 6- (((R) -2-hydroxy-2-methylbut-3-alkyne-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-carbonitrile, a crystal form thereof, a preparation method thereof, a pharmaceutical composition containing a therapeutically effective amount of the salt of the compound or the crystal form thereof, and application of the salt as a RET inhibitor in treating cancers, inflammations, chronic liver diseases, diabetes, cardiovascular diseases, AIDS and other related diseases.

Description

Salt or crystal form of inhibitor containing bicyclic derivatives, and preparation method and application thereof

Technical Field

The invention belongs to the field of drug synthesis, and particularly relates to a salt or crystal form of a derivative inhibitor containing a bicyclic ring, and a preparation method and application thereof.

Background

The RET (secreted transforming) protein is encoded by the protooncogene RET located on chromosome 10, is a receptor tyrosine kinase, and consists of an extracellular region, a transmembrane region, and an intracellular kinase region. RET ligands are glial cell-derived neurotrophic factor (GDNF) family ligands (GFLs) such as GDNF, neurturin (NRTN), Artemin (ARTN), persephin (PSPN), and the activation of receptors also needs the combined action of a co-receptor GFR alpha family, GFLs and GFR alpha form a dimer, bind RET and recruit the RET to a membrane area rich in cholesterol, and RET protein is dimerized and autophosphorylated, so that downstream RAS-MAPK, PI3K-AKT, PKC and other signal pathways are activated. RET plays an important role in the development of kidney and enteric nervous system in the process of embryonic development; and is also important for the homeostasis of tissues such as neuroendocrine, hematopoietic and male germ cells.

Dysfunction of RET proteins has led to the development of a variety of diseases. The functional deletion of RET protein during development can cause a series of congenital diseases such as Hirschspung disease (HSCR), congenital renal and urinary tract malformation (CAKUT), etc. The activation mutation of RET protein, including point mutation and fusion of RET protein by chromosomal rearrangement, are also associated with various diseases. RET fusion occurs mainly in 1-2% of patients with non-small cell lung cancer (NSCLC) and 5-10% of thyroid papillary carcinomas, RET mutation occurs mainly in 60% of medullary thyroid carcinomas, and RET protein activating mutation is found in many other tumors such as breast cancer, stomach cancer, intestinal cancer, chronic myelomonocytic leukemia, and the like.

Although there is a great clinical demand, the current treatment aiming at the RET target still has great limitation, different from ALK, EGFR and other targeting drugs which achieve excellent curative effect in clinic, the RET target still has no approved targeting drugs at present. At present, multi-kinase inhibitors (MKI) such as Vandertinib, cabozantinib and the like are mostly selected for clinical medication, and the multi-kinase inhibitors have the defects of high side effect and poor drug effect due to poor selectivity and cannot overcome the problem of drug resistance in the treatment process.

The demand for RET targeting drugs has attracted a large number of domestic and foreign pharmaceutical companies to develop RET specific targeting drugs, of which the more prominent are LOXO-292 by Loxo Oncology, which has entered clinical stage I/II, and BLU-667 by Blueprint, which has also entered clinical stage I. Both of the two targeted drugs show very good curative effect and very good safety in early clinical experiments for patients with RET activating mutation, and simultaneously overcome possible drug resistance mutation in preclinical activity screening, so that more treatment options can be brought to cancers with RET activating mutation in the future.

The RET target does not have a specific targeting drug at present, and has a large clinical demand. The RET inhibitor has higher selectivity, better activity and better safety, can overcome drug-resistant mutation, has the potential of treating various cancers, and has wide market prospect.

Disclosure of Invention

All matters hithertofore set forth in PCT/CN2020/090142 are hereby incorporated by reference.

It is an object of the present invention 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] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile.

In a more preferred embodiment of the invention, the acid in the acid salt is selected from the group consisting of benzenesulfonic acid, hydrochloric acid, p-toluenesulfonic acid, oxalic acid, phosphoric acid, hydrobromic acid; benzenesulfonic acid is preferred.

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 to 3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 0.5, 1,2 or 3.

In a more preferred embodiment of the present invention, the acid salt of the above compound is a hydrate or an anhydrate, and when the acid salt is a hydrate, the number of water is 0.2 to 3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 0.5, 1,2 or 3.

In a more preferred embodiment of the invention, the acid salt of the above 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] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile is in crystalline form, preferably in the form of methanesulfonate, sulfate, hydrobromide, phosphate, benzenesulfonate, oxalate, isethionate, maleate, fumarate, adipate, oxalate, mesylate, acetate, fumarate, mesylate, acetate, or the like, A p-toluenesulfonate crystal form, a citrate crystal form, a malonate crystal form or an L-malate crystal form, more preferably a benzenesulfonate crystal form.

In a more preferred embodiment of the present invention, the acid salt of the above 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] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile, wherein:

an X-ray powder diffraction pattern of the benzenesulfonate salt form I has a characteristic peak at 17.7 + -0.2 degrees in 2 theta, or has a characteristic peak at 8.4 + -0.2 degrees in 2 theta, or has a characteristic peak at 24.8 + -0.2 degrees in 2 theta, or has a characteristic peak at 21.5 + -0.2 degrees in 2 theta, or has a characteristic peak at 17.1 + -0.2 degrees in 2 theta, or has a characteristic peak at 15.2 + -0.2 degrees in 2 theta, or has a characteristic peak at 23.4 + -0.2 degrees in 2 theta, or has a characteristic peak at 19.3 + -0.2 degrees in 2 theta, or has a characteristic peak at 28.2 + -0.2 degrees in 2 theta, or has a characteristic peak at 18.9 + -0.2 degrees in 2 theta, or has a characteristic peak at 11.8 + -0.2 degrees in 2 theta, or has a characteristic peak at 18.6 + -0.2 degrees in 2 theta; preferably, any 2 to 12, or 5 to 8, or 6 to 8, and more preferably any 2,3, 6, 8, 10, or 12 of the diffraction peaks are included.

An X-ray powder diffraction pattern of the benzenesulfonate salt form II has a characteristic peak at 17.7 + -0.2 DEG in 2 theta, or has a characteristic peak at 15.2 + -0.2 DEG in 2 theta, or has a characteristic peak at 21.5 + -0.2 DEG in 2 theta, or has a characteristic peak at 24.8 + -0.2 DEG in 2 theta, or has a characteristic peak at 8.5 + -0.2 DEG in 2 theta, or has a characteristic peak at 19.3 + -0.2 DEG in 2 theta, or has a characteristic peak at 17.1 + -0.2 DEG in 2 theta, or has a characteristic peak at 18.6 + -0.2 DEG in 2 theta, or has a characteristic peak at 23.4 + -0.2 DEG in 2 theta, or has a characteristic peak at 7.7 + -0.2 DEG in 2 theta, or has a characteristic peak at 6.5 + -0.2 DEG in 2 theta, or has a characteristic peak at 13.9 + -0.2 DEG in 2 theta; preferably, any 2 to 12, or 5 to 8, or 6 to 8, and more preferably any 2,3, 6, 8, 10, or 12 of the diffraction peaks are included.

An X-ray powder diffraction pattern of the p-toluenesulfonic acid salt form I has a characteristic peak at 18.4 +/-0.2 degrees of 2 theta, or has a characteristic peak at 15.1 +/-0.2 degrees of 2 theta, or has a characteristic peak at 8.1 +/-0.2 degrees of 2 theta, or has a characteristic peak at 16.9 +/-0.2 degrees of 2 theta, or has a characteristic peak at 7.6 +/-0.2 degrees of 2 theta, or has a characteristic peak at 17.4 +/-0.2 degrees of 2 theta, or has a characteristic peak at 20.9 +/-0.2 degrees of 2 theta, or has a characteristic peak at 17.2 +/-0.2 degrees of 2 theta, or has a characteristic peak at 5.0 +/-0.2 degrees of 2 theta, or has a characteristic peak at 19.0 +/-0.2 degrees of 2 theta, or has a characteristic peak at 22.8 +/-0.2 degrees of 2 theta, or has a characteristic peak at 24.0 +/-0.2 degrees of 2 theta, or has a characteristic peak at 2 degrees of 2 theta, or has a characteristic peak at 13.6 +/-0.2 degrees of 2 theta; preferably, any 2 to 12, or 5 to 8, or 6 to 8, and more preferably any 2,3, 6, 8, 10, or 12 of the diffraction peaks are included.

An X-ray powder diffraction pattern of the hydrochloride form I has a characteristic peak at 10.0 +/-0.2 degrees of 2 theta, or has a characteristic peak at 6.0 +/-0.2 degrees of 2 theta, or has a characteristic peak at 15.6 +/-0.2 degrees of 2 theta, or has a characteristic peak at 16.8 +/-0.2 degrees of 2 theta, or has a characteristic peak at 24.6 +/-0.2 degrees of 2 theta, or has a characteristic peak at 23.0 +/-0.2 degrees of 2 theta, or has a characteristic peak at 20.8 +/-0.2 degrees of 2 theta, or has a characteristic peak at 26.7 +/-0.2 degrees of 2 theta, or has a characteristic peak at 17.5 +/-0.2 degrees of 2 theta, or has a characteristic peak at 21.6 +/-0.2 degrees of 2 theta, or has a characteristic peak at 14.9 +/-0.2 degrees of 2 theta, or has a characteristic peak at 30.7 +/-0.2 degrees of 2 theta; preferably, any 2 to 12, or 5 to 8, or 6 to 8, and more preferably any 2,3, 6, 8, 10, or 12 of the diffraction peaks are included.

An X-ray powder diffraction pattern of the hydrochloride form II has a characteristic peak at 10.0 +/-0.2 degrees of 2 theta, or a characteristic peak at 6.0 +/-0.2 degrees of 2 theta, or a characteristic peak at 6.6 +/-0.2 degrees of 2 theta, or a characteristic peak at 15.6 +/-0.2 degrees of 2 theta, or a characteristic peak at 24.7 +/-0.2 degrees of 2 theta, or a characteristic peak at 23.1 +/-0.2 degrees of 2 theta, or a characteristic peak at 16.8 +/-0.2 degrees of 2 theta, or a characteristic peak at 17.5 +/-0.2 degrees of 2 theta, or a characteristic peak at 20.8 +/-0.2 degrees of 2 theta, or a characteristic peak at 23.9 +/-0.2 degrees of 2 theta, or a characteristic peak at 22.4 +/-0.2 degrees of 2 theta, or a characteristic peak at 26.7 +/-0.2 degrees of 2 theta; preferably, any 2 to 12, or 5 to 8, or 6 to 8, and more preferably any 2,3, 6, 8, 10, or 12 of the diffraction peaks are included.

An X-ray powder diffraction pattern of the hydrobromide crystal form I has a characteristic peak at 9.9 +/-0.2 degrees of 2 theta, or has a characteristic peak at 5.9 +/-0.2 degrees of 2 theta, or has a characteristic peak at 22.8 +/-0.2 degrees of 2 theta, or has a characteristic peak at 20.6 +/-0.2 degrees of 2 theta, or has a characteristic peak at 24.4 +/-0.2 degrees of 2 theta, or has a characteristic peak at 16.7 +/-0.2 degrees of 2 theta, or has a characteristic peak at 21.4 +/-0.2 degrees of 2 theta, or has a characteristic peak at 26.6 +/-0.2 degrees of 2 theta, or has a characteristic peak at 17.4 +/-0.2 degrees of 2 theta, or has a characteristic peak at 24.9 +/-0.2 degrees of 2 theta, or has a characteristic peak at 23.1 +/-0.2 degrees of 2 theta, or has a characteristic peak at 30.6 +/-0.2 degrees of 2 theta; preferably, any 2 to 12, or 5 to 8, or 6 to 8, and more preferably any 2,3, 6, 8, 10, or 12 of the diffraction peaks are included.

An X-ray powder diffraction pattern of oxalate form I has a characteristic peak at 9.5 +/-0.2 degrees of 2 theta, or 19.3 +/-0.2 degrees of 2 theta, or 10.7 +/-0.2 degrees of 2 theta, or 4.7 +/-0.2 degrees of 2 theta, or 6.0 +/-0.2 degrees of 2 theta, or 16.5 +/-0.2 degrees of 2 theta, or 25.0 +/-0.2 degrees of 2 theta, or 27.1 +/-0.2 degrees of 2 theta, or 15.3 +/-0.2 degrees of 2 theta, or 14.5 +/-0.2 degrees of 2 theta, or 18.6 +/-0.2 degrees of 2 theta, or 20.5 +/-0.2 degrees of 2 theta; preferably, any 2 to 12, or 5 to 8, or 6 to 8, and more preferably any 2,3, 6, 8, 10, or 12 of the diffraction peaks are included.

An X-ray powder diffraction pattern of oxalate form II has a characteristic peak at 5.8 +/-0.2 degrees of 2 theta, or a characteristic peak at 4.8 +/-0.2 degrees of 2 theta, or a characteristic peak at 15.7 +/-0.2 degrees of 2 theta, or a characteristic peak at 17.0 +/-0.2 degrees of 2 theta, or a characteristic peak at 9.4 +/-0.2 degrees of 2 theta, or a characteristic peak at 19.2 +/-0.2 degrees of 2 theta, or a characteristic peak at 17.7 +/-0.2 degrees of 2 theta, or a characteristic peak at 16.6 +/-0.2 degrees of 2 theta, or a characteristic peak at 26.1 +/-0.2 degrees of 2 theta, or a characteristic peak at 11.8 +/-0.2 degrees of 2 theta, or a characteristic peak at 18.6 +/-0.2 degrees of 2 theta, or a characteristic peak at 12.5 +/-0.2 degrees of 2 theta; preferably, any 2 to 12, or 5 to 8, or 6 to 8, and more preferably any 2,3, 6, 8, 10, or 12 of the diffraction peaks are included.

An X-ray powder diffraction pattern of oxalate form III has a characteristic peak at 10.4 +/-0.2 degrees of 2 theta, or has a characteristic peak at 5.1 +/-0.2 degrees of 2 theta, or has a characteristic peak at 4.8 +/-0.2 degrees of 2 theta, or has a characteristic peak at 15.8 +/-0.2 degrees of 2 theta, or has a characteristic peak at 14.3 +/-0.2 degrees of 2 theta, or has a characteristic peak at 12.2 +/-0.2 degrees of 2 theta, or has a characteristic peak at 17.8 +/-0.2 degrees of 2 theta, or has a characteristic peak at 5.8 +/-0.2 degrees of 2 theta, or has a characteristic peak at 18.9 +/-0.2 degrees of 2 theta, or has a characteristic peak at 17.0 +/-0.2 degrees of 2 theta, or has a characteristic peak at 23.8 +/-0.2 degrees of 2 theta; preferably, any 2 to 12, or 5 to 8, or 6 to 8, and more preferably any 2,3, 6, 8, 10, or 12 of the diffraction peaks are included.

An X-ray powder diffraction pattern of oxalate form IV has a characteristic peak at 20.5 ± 0.2 ° 2 θ, or a characteristic peak at 18.5 ± 0.2 ° 2 θ, or a characteristic peak at 17.9 ± 0.2 ° 2 θ, or a characteristic peak at 4.8 ± 0.2 ° 2 θ, or a characteristic peak at 16.5 ± 0.2 ° 2 θ, or a characteristic peak at 15.8 ± 0.2 ° 2 θ, or a characteristic peak at 11.5 ± 0.2 ° 2 θ, or a characteristic peak at 12.3 ± 0.2 ° 2 θ, or a characteristic peak at 24.0 ± 0.2 ° 2 θ, or a characteristic peak at 16.2 ± 0.2 ° 2 θ, or a characteristic peak at 23.3 ± 0.2 ° 2 θ, or a characteristic peak at 19.6 ± 0.2 ° 2 θ; preferably, any 2 to 12, or 5 to 8, or 6 to 8, and more preferably any 2,3, 6, 8, 10, or 12 of the diffraction peaks are included.

An X-ray powder diffraction pattern of mesylate crystal form I has a characteristic peak at 10.3 +/-0.2 degrees of 2 theta, or has a characteristic peak at 5.1 +/-0.2 degrees of 2 theta, or has a characteristic peak at 15.6 +/-0.2 degrees of 2 theta, or has a characteristic peak at 25.2 +/-0.2 degrees of 2 theta, or has a characteristic peak at 18.4 +/-0.2 degrees of 2 theta; preferably, any 2 to 12, or 5 to 8, or 6 to 8, and more preferably any 2,3, 6, 8, 10, or 12 of the diffraction peaks are included.

An X-ray powder diffraction pattern of the ethanesulfonate crystal form I has a characteristic peak at 10.2 +/-0.2 degrees of 2 theta, or has a characteristic peak at 5.0 +/-0.2 degrees of 2 theta, or has a characteristic peak at 15.4 +/-0.2 degrees of 2 theta, or has a characteristic peak at 18.9 +/-0.2 degrees of 2 theta, or has a characteristic peak at 24.2 +/-0.2 degrees of 2 theta, or has a characteristic peak at 21.1 +/-0.2 degrees of 2 theta; preferably, any 2 to 12, or 5 to 8, or 6 to 8, and more preferably any 2,3, 6, 8, 10, or 12 of the diffraction peaks are included.

An X-ray powder diffraction pattern of the ethanesulfonate crystal form II has a characteristic peak at 10.2 +/-0.2 degrees of 2 theta, or has a characteristic peak at 5.0 +/-0.2 degrees of 2 theta, or has a characteristic peak at 6.0 +/-0.2 degrees of 2 theta, or has a characteristic peak at 15.4 +/-0.2 degrees of 2 theta, or has a characteristic peak at 5.4 +/-0.2 degrees of 2 theta, or has a characteristic peak at 7.3 +/-0.2 degrees of 2 theta; preferably, any 2 to 12, or 5 to 8, or 6 to 8, and more preferably any 2,3, 6, 8, 10, or 12 of the diffraction peaks are included.

An X-ray powder diffraction pattern of the isethionate salt crystal form I has a characteristic peak at 10.5 +/-0.2 degrees of 2 theta, or has a characteristic peak at 5.2 +/-0.2 degrees of 2 theta, or has a characteristic peak at 18.7 +/-0.2 degrees of 2 theta, or has a characteristic peak at 15.9 +/-0.2 degrees of 2 theta, or has a characteristic peak at 23.0 +/-0.2 degrees of 2 theta; preferably, any 2 to 12, or 5 to 8, or 6 to 8, and more preferably any 2,3, 6, 8, 10, or 12 of the diffraction peaks are included.

An X-ray powder diffraction pattern of the isethionate salt form II has a characteristic peak at 11.9 + -0.2 ° 2 θ, or 18.4 + -0.2 ° 2 θ, or 4.8 + -0.2 ° 2 θ, or 23.4 + -0.2 ° 2 θ, or 16.7 + -0.2 ° 2 θ, or 17.8 + -0.2 ° 2 θ, or 12.8 + -0.2 ° 2 θ, or 23.8 + -0.2 ° 2 θ, or 21.8 + -0.2 ° 2 θ, or 19.0 + -0.2 ° 2 θ, or 25.4 + -0.2 ° 2 θ, or 19.8 + -0.2 ° 2 θ; preferably from 2 to 12, or from 5 to 8, or from 6 to 8, and more preferably from 2,3, 6, 8, 10 or 12 of any of the above diffraction peaks.

An X-ray powder diffraction pattern of the sulfate crystal form I has a characteristic peak at 10.3 +/-0.2 degrees of 2 theta, or has a characteristic peak at 5.1 +/-0.2 degrees of 2 theta, or has a characteristic peak at 15.6 +/-0.2 degrees of 2 theta, or has a characteristic peak at 14.5 +/-0.2 degrees of 2 theta, or has a characteristic peak at 20.2 +/-0.2 degrees of 2 theta, or has a characteristic peak at 19.0 +/-0.2 degrees of 2 theta, or has a characteristic peak at 25.6 +/-0.2 degrees of 2 theta, or has a characteristic peak at 22.1 +/-0.2 degrees of 2 theta, or has a characteristic peak at 23.0 +/-0.2 degrees of 2 theta, or has a characteristic peak at 20.8 +/-0.2 degrees of 2 theta, or has a characteristic peak at 19.2 +/-0.2 degrees of 2 theta, or has a characteristic peak at 24.1 +/-0.2 degrees of 2 theta; preferably, any 2 to 12, or 5 to 8, or 6 to 8, and more preferably any 2,3, 6, 8, 10, or 12 of the diffraction peaks are included.

An X-ray powder diffraction pattern of the sulfate crystal form II has a characteristic peak at 16.1 +/-0.2 degrees of 2 theta, or has a characteristic peak at 5.9 +/-0.2 degrees of 2 theta, or has a characteristic peak at 6.6 +/-0.2 degrees of 2 theta, or has a characteristic peak at 22.0 +/-0.2 degrees of 2 theta, or has a characteristic peak at 21.0 +/-0.2 degrees of 2 theta, or has a characteristic peak at 20.1 +/-0.2 degrees of 2 theta, or has a characteristic peak at 17.0 +/-0.2 degrees of 2 theta, or has a characteristic peak at 25.2 +/-0.2 degrees of 2 theta, or has a characteristic peak at 20.7 +/-0.2 degrees of 2 theta, or has a characteristic peak at 23.1 +/-0.2 degrees of 2 theta; preferably, any 2 to 12, or 5 to 8, or 6 to 8, and more preferably any 2,3, 6, 8, 10, or 12 of the diffraction peaks are included.

An X-ray powder diffraction pattern of the phosphate crystal form I has a characteristic peak at 5.6 +/-0.2 degrees of 2 theta, or 11.5 +/-0.2 degrees of 2 theta, or 20.3 +/-0.2 degrees of 2 theta, or 15.9 +/-0.2 degrees of 2 theta, or 17.2 +/-0.2 degrees of 2 theta, or 16.4 +/-0.2 degrees of 2 theta, or 21.9 +/-0.2 degrees of 2 theta, or 10.2 +/-0.2 degrees of 2 theta; preferably, any 2 to 12, or 5 to 8, or 6 to 8, and more preferably any 2,3, 6, 8, 10, or 12 of the diffraction peaks are included.

An X-ray powder diffraction pattern of the phosphate crystal form II has a characteristic peak at 5.6 +/-0.2 degrees of 2 theta, or 11.4 +/-0.2 degrees of 2 theta, or 15.1 +/-0.2 degrees of 2 theta, or 15.4 +/-0.2 degrees of 2 theta, or 17.2 +/-0.2 degrees of 2 theta, or 20.0 +/-0.2 degrees of 2 theta, or 16.1 +/-0.2 degrees of 2 theta, or 20.3 +/-0.2 degrees of 2 theta, or 21.0 +/-0.2 degrees of 2 theta, or 21.8 +/-0.2 degrees of 2 theta, or 24.7 +/-0.2 degrees of 2 theta; preferably, any 2 to 12, or 5 to 8, or 6 to 8, and more preferably any 2,3, 6, 8, 10, or 12 of the diffraction peaks are included.

In a more preferred embodiment of the invention, the crystalline form I besylate has an X-ray powder diffraction pattern comprising two or three diffraction peaks, 2 Θ, at 17.7 ± 0.2 °, 8.4 ± 0.2 ° and 24.8 ± 0.2 °, optionally further comprising one or more diffraction peaks, 2 Θ, at 21.5 ± 0.2 °, 17.1 ± 0.2 °, 19.3 ± 0.2 °, 15.2 ± 0.2 ° and 23.4 ± 0.2 °; preferably 2,3, 4 or 5 of them.

An X-ray powder diffraction pattern of besylate salt form II comprising two or three diffraction peaks, at 2 Θ, of 17.7 ± 0.2 °, 15.2 ± 0.2 °, and 21.5 ± 0.2 °, optionally further comprising one or more diffraction peaks, at 2 Θ, of 24.8 ± 0.2 °, 8.5 ± 0.2 °, 19.3 ± 0.2 °, 17.1 ± 0.2 °, and 18.6 ± 0.2 °; preferably 2,3, 4 or 5 of them.

An X-ray powder diffraction pattern of crystalline form I of the tosylate salt comprises two or three diffraction peaks, at 2 Θ of 18.4 ± 0.2 °, 15.1 ± 0.2 ° and 8.1 ± 0.2 °, optionally further comprising one or more diffraction peaks, at 2 Θ of 16.9 ± 0.2 °, 7.6 ± 0.2 °, 17.4 ± 0.2 °, 20.9 ± 0.2 ° and 17.2 ± 0.2 °; preferably 2,3, 4 or 5 of them.

An X-ray powder diffraction pattern of hydrochloride form I comprising two or three diffraction peaks, 2 Θ, at 10.0 ± 0.2 °, 6.0 ± 0.2 ° and 15.6 ± 0.2 °, optionally further comprising one or more diffraction peaks, 2 Θ, at 16.8 ± 0.2 °, 24.6 ± 0.2 °, 23.0 ± 0.2 °, 20.8 ± 0.2 ° and 26.7 ± 0.2 °; preferably 2,3, 4 or 5 of them.

An X-ray powder diffraction pattern of hydrochloride form II comprises two or three diffraction peaks at 2 Θ of 10.0 ± 0.2 °, 6.0 ± 0.2 ° and 6.6 ± 0.2 °, optionally further comprising one or more diffraction peaks at 2 Θ of 15.6 ± 0.2 °, 24.7 ± 0.2 °, 23.1 ± 0.2 °, 16.8 ± 0.2 ° and 17.5 ± 0.2 °; preferably 2,3, 4 or 5 of them.

An X-ray powder diffraction pattern of hydrobromide form I comprising two or three diffraction peaks, 2 Θ, at 9.9 ± 0.2 °, 5.9 ± 0.2 ° and 22.8 ± 0.2 °, optionally further comprising one or more diffraction peaks, 2 Θ, at 20.6 ± 0.2 °, 24.4 ± 0.2 °, 16.7 ± 0.2 °, 21.4 ± 0.2 ° and 26.6 ± 0.2 °; preferably 2,3, 4 or 5 of them.

An X-ray powder diffraction pattern of oxalate form I comprising two or three diffraction peaks, in terms of 2 Θ, of 9.5 ± 0.2 °, 19.3 ± 0.2 ° and 10.7 ± 0.2 °, optionally further comprising one or more diffraction peaks, in terms of 2 Θ, of 4.7 ± 0.2 °, 6.0 ± 0.2 °, 16.5 ± 0.2 °, 25.0 ± 0.2 ° and 27.1 ± 0.2 °; preferably 2,3, 4 or 5 of them.

An X-ray powder diffraction pattern of oxalate form II comprising two or three diffraction peaks, in terms of 2 Θ, at 5.8 ± 0.2 °, 4.8 ± 0.2 °, and 15.7 ± 0.2 °, optionally further comprising one or more diffraction peaks, in terms of 2 Θ, at 17.0 ± 0.2 °, 9.4 ± 0.2 °, 19.2 ± 0.2 °, 17.7 ± 0.2 °, and 16.6 ± 0.2 °; preferably 2,3, 4 or 5 of them.

An X-ray powder diffraction pattern of oxalate form III comprising two or three diffraction peaks, in terms of 2 Θ, at 10.4 ± 0.2 °, 5.1 ± 0.2 °, and 4.8 ± 0.2 °, optionally further comprising one or more diffraction peaks, in terms of 2 Θ, at 15.8 ± 0.2 °, 14.3 ± 0.2 °, 12.2 ± 0.2 °, 17.8 ± 0.2 °, and 5.8 ± 0.2 °; preferably 2,3, 4 or 5 of them.

An X-ray powder diffraction pattern of oxalate form IV comprising two or three diffraction peaks, in terms of 2 Θ, at 20.5 ± 0.2 ° 18.5 ± 0.2 ° and 17.9 ± 0.2 °, optionally further comprising one or more diffraction peaks, in terms of 2 Θ, at 4.8 ± 0.2 °, 16.5 ± 0.2 °, 15.8 ± 0.2 °, 11.5 ± 0.2 ° and 12.3 ± 0.2 °; preferably 2,3, 4 or 5 of them.

An X-ray powder diffraction pattern of mesylate form I comprises two or three diffraction peaks, at 2 Θ of 10.3 ± 0.2 °, 5.1 ± 0.2 °, and 15.6 ± 0.2 °, optionally further comprising one or more diffraction peaks, at 2 Θ of 25.2 ± 0.2 °, 18.4 ± 0.2 °; preferably 2,3, 4 or 5 of them.

An X-ray powder diffraction pattern of esylate salt form I comprising two or three diffraction peaks, 2 Θ, at 10.2 ± 0.2 °, 5.0 ± 0.2 °, and 15.4 ± 0.2 °, optionally further comprising one or more diffraction peaks, 2 Θ, at 24.2 ± 0.2 °, 18.9 ± 0.2 °, and 21.1 ± 0.2 °; preferably 2,3, 4 or 5 of them.

An X-ray powder diffraction pattern of esylate salt form II comprising two or three diffraction peaks, in terms of 2 Θ, of 10.2 ± 0.2 °, 5.0 ± 0.2 °, and 6.0 ± 0.2 °, optionally further comprising one or more diffraction peaks, in terms of 2 Θ, of 15.4 ± 0.2 ° and 5.4 ± 0.2 °; preferably 2,3, 4 or 5 of them.

An X-ray powder diffraction pattern of isethionate salt form I comprising two or three diffraction peaks, in terms of 2 Θ, at 10.5 ± 0.2 °, 5.2 ± 0.2 °, and 18.7 ± 0.2 °, optionally further comprising one or more diffraction peaks, in terms of 2 Θ, at 15.9 ± 0.2 ° and 23.0 ± 0.2 °; preferably 2,3, 4 or 5 of them.

An X-ray powder diffraction pattern of isethionate salt form II comprising two or three diffraction peaks, in terms of 2 Θ, at 11.9 ± 0.2 °, 18.4 ± 0.2 °, and 4.8 ± 0.2 °, optionally further comprising one or more diffraction peaks, in terms of 2 Θ, at 23.4 ± 0.2 °, 16.7 ± 0.2 °, 17.8 ± 0.2 °, 12.8 ± 0.2 °, and 23.8 ± 0.2 °; preferably 2,3, 4 or 5 of them.

An X-ray powder diffraction pattern of sulfate form I comprises two or three diffraction peaks, in terms of 2 Θ, of 10.3 ± 0.2 °, 5.1 ± 0.2 °, and 15.6 ± 0.2 °, optionally further comprising one or more diffraction peaks, in terms of 2 Θ, of 14.5 ± 0.2 °, 20.2 ± 0.2 °, 19.0 ± 0.2 °, 25.6 ± 0.2 °, and 22.1 ± 0.2 °; preferably 2,3, 4 or 5 of them.

An X-ray powder diffraction pattern of sulfate form II comprises two or three diffraction peaks, at 2 Θ of 16.1 ± 0.2 °, 5.9 ± 0.2 °, and 6.6 ± 0.2 °, optionally further comprising one or more diffraction peaks, at 2 Θ of 22.0 ± 0.2 °, 21.0 ± 0.2 °, 20.1 ± 0.2 °, 17.0 ± 0.2 °, and 25.2 ± 0.2 °; preferably 2,3, 4 or 5 of them.

An X-ray powder diffraction pattern of phosphate form I comprises two or three diffraction peaks, in terms of 2 Θ, of 5.6 ± 0.2 °, 11.5 ± 0.2 °, and 20.3 ± 0.2 °, optionally further comprising one or more diffraction peaks, in terms of 2 Θ, of 15.9 ± 0.2 °, 17.2 ± 0.2 °, 16.4 ± 0.2 °, and 21.9 ± 0.2 °; preferably 2,3, 4 or 5 of them.

An X-ray powder diffraction pattern of phosphate form II comprises two or three diffraction peaks, in terms of 2 Θ, of 5.6 ± 0.2 °, 11.4 ± 0.2 °, and 15.1 ± 0.2 °, optionally further comprising one or more diffraction peaks, in terms of 2 Θ, of 15.4 ± 0.2 °, 17.2 ± 0.2 °, 20.0 ± 0.2 °, 16.1 ± 0.2 °, and 20.3 ± 0.2 °; preferably 2,3, 4 or 5 of them.

In a more preferred embodiment of the invention, the crystalline form I of the benzenesulfonate salt has an X-ray powder diffraction pattern comprising one or more diffraction peaks, in terms of 2 Θ, 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, the compound contains diffraction peaks at 4, 6, 8 and 10.

The X-ray powder diffraction pattern of the benzene sulfonate crystal form II comprises one or more diffraction peaks with the 2 theta of 17.7 +/-0.2 degrees, 15.2 +/-0.2 degrees, 21.5 +/-0.2 degrees, 24.8 +/-0.2 degrees, 8.5 +/-0.2 degrees, 19.3 +/-0.2 degrees, 17.1 +/-0.2 degrees, 18.6 +/-0.2 degrees, 23.4 +/-0.2 degrees, 7.7 +/-0.2 degrees, 6.5 +/-0.2 degrees and 13.9 +/-0.2 degrees; preferably, the compound contains diffraction peaks at 4, 6, 8 and 10.

An X-ray powder diffraction pattern of the p-toluenesulfonate crystal form I comprises one or more diffraction peaks with 2 theta of 18.4 +/-0.2 degrees, 15.1 +/-0.2 degrees, 8.1 +/-0.2 degrees, 16.9 +/-0.2 degrees, 7.6 +/-0.2 degrees, 17.4 +/-0.2 degrees, 20.9 +/-0.2 degrees, 17.2 +/-0.2 degrees, 5.0 +/-0.2 degrees, 19.0 +/-0.2 degrees, 22.8 +/-0.2 degrees, 24.0 +/-0.2 degrees and 13.6 +/-0.2 degrees; preferably, the compound contains diffraction peaks at 4, 6, 8 and 10.

The X-ray powder diffraction pattern of the hydrochloride crystal form I comprises one or more diffraction peaks with 2 theta of 10.0 +/-0.2 degrees, 6.0 +/-0.2 degrees, 15.6 +/-0.2 degrees, 16.8 +/-0.2 degrees, 24.6 +/-0.2 degrees, 23.0 +/-0.2 degrees, 20.8 +/-0.2 degrees, 26.7 +/-0.2 degrees, 17.5 +/-0.2 degrees, 21.6 +/-0.2 degrees, 14.9 +/-0.2 degrees and 30.7 +/-0.2 degrees; preferably, the compound contains diffraction peaks at 4, 6, 8 and 10.

The X-ray powder diffraction pattern of the hydrochloride crystal form II comprises one or more diffraction peaks with 2 theta of 10.0 +/-0.2 degrees, 6.0 +/-0.2 degrees, 6.6 +/-0.2 degrees, 15.6 +/-0.2 degrees, 24.7 +/-0.2 degrees, 23.1 +/-0.2 degrees, 16.8 +/-0.2 degrees, 17.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 23.9 +/-0.2 degrees, 22.4 +/-0.2 degrees and 26.7 +/-0.2 degrees; preferably, the compound contains diffraction peaks at 4, 6, 8 and 10.

An X-ray powder diffraction pattern of the hydrobromide crystal form I comprises one or more diffraction peaks with 2 theta of 9.9 +/-0.2 degrees, 5.9 +/-0.2 degrees, 22.8 +/-0.2 degrees, 20.6 +/-0.2 degrees, 24.4 +/-0.2 degrees, 16.7 +/-0.2 degrees, 21.4 +/-0.2 degrees, 26.6 +/-0.2 degrees, 17.4 +/-0.2 degrees, 24.9 +/-0.2 degrees, 23.1 +/-0.2 degrees and 30.6 +/-0.2 degrees; preferably, the compound contains diffraction peaks at 4, 6, 8 and 10.

The X-ray powder diffraction pattern of the oxalate crystal form I comprises one or more diffraction peaks with 2 theta of 9.5 +/-0.2 degrees, 19.3 +/-0.2 degrees, 10.7 +/-0.2 degrees, 4.7 +/-0.2 degrees, 6.0 +/-0.2 degrees, 16.5 +/-0.2 degrees, 25.0 +/-0.2 degrees, 27.1 +/-0.2 degrees, 15.3 +/-0.2 degrees, 14.5 +/-0.2 degrees, 18.6 +/-0.2 degrees and 20.5 +/-0.2 degrees; preferably, the compound contains diffraction peaks at 4, 6, 8 and 10.

The X-ray powder diffraction pattern of the oxalate crystal form II comprises one or more diffraction peaks with 2 theta of 5.8 +/-0.2 degrees, 4.8 +/-0.2 degrees, 15.7 +/-0.2 degrees, 17.0 +/-0.2 degrees, 9.4 +/-0.2 degrees, 19.2 +/-0.2 degrees, 17.7 +/-0.2 degrees, 16.6 +/-0.2 degrees, 26.1 +/-0.2 degrees, 11.8 +/-0.2 degrees, 18.6 +/-0.2 degrees and 12.5 +/-0.2 degrees; preferably, the compound contains diffraction peaks at 4, 6, 8 and 10.

The X-ray powder diffraction pattern of oxalate crystal form III comprises one or more diffraction peaks with 2 theta of 10.4 +/-0.2 degrees, 5.1 +/-0.2 degrees, 4.8 +/-0.2 degrees, 15.8 +/-0.2 degrees, 14.3 +/-0.2 degrees, 12.2 +/-0.2 degrees, 17.8 +/-0.2 degrees, 5.8 +/-0.2 degrees, 18.9 +/-0.2 degrees, 17.0 +/-0.2 degrees and 23.8 +/-0.2 degrees; preferably, the compound contains diffraction peaks at 4, 6, 8 and 10.

The X-ray powder diffraction pattern of the oxalate crystal form IV comprises one or more diffraction peaks with the 2 theta of 20.5 +/-0.2 degrees, 18.5 +/-0.2 degrees, 17.9 +/-0.2 degrees, 4.8 +/-0.2 degrees, 16.5 +/-0.2 degrees, 15.8 +/-0.2 degrees, 11.5 +/-0.2 degrees, 12.3 +/-0.2 degrees, 24.0 +/-0.2 degrees, 16.2 +/-0.2 degrees, 23.3 +/-0.2 degrees and 19.6 +/-0.2 degrees; preferably, the compound contains diffraction peaks at 4, 6, 8 and 10.

The X-ray powder diffraction pattern of the mesylate crystal form I comprises one or more diffraction peaks with the 2 theta of 10.3 +/-0.2 degrees, 5.1 +/-0.2 degrees, 15.6 +/-0.2 degrees, 25.2 +/-0.2 degrees and 18.4 +/-0.2 degrees; preferably, the compound contains 4 optional diffraction peaks.

The X-ray powder diffraction pattern of the ethanesulfonate crystal form I comprises one or more diffraction peaks with 2 theta of 10.2 +/-0.2 degrees, 5.0 +/-0.2 degrees, 15.4 +/-0.2 degrees, 18.9 +/-0.2 degrees, 24.2 +/-0.2 degrees and 21.1 +/-0.2 degrees; preferably, the compound contains diffraction peaks at 4 and 6.

The X-ray powder diffraction pattern of the ethanesulfonate crystal form II comprises one or more diffraction peaks with the 2 theta of 10.2 +/-0.2 degrees, 5.0 +/-0.2 degrees, 6.0 +/-0.2 degrees, 15.4 +/-0.2 degrees, 5.4 +/-0.2 degrees and 7.3 +/-0.2 degrees; preferably, the compound contains diffraction peaks at 4 and 6.

The X-ray powder diffraction pattern of the isethionate crystal form I comprises one or more diffraction peaks with 2 theta of 10.5 +/-0.2 degrees, 5.2 +/-0.2 degrees, 18.7 +/-0.2 degrees, 15.9 +/-0.2 degrees and 23.0 +/-0.2 degrees; preferably, the compound contains 4 optional diffraction peaks.

The X-ray powder diffraction pattern of the isethionate crystal form II comprises one or more diffraction peaks with 2 theta of 11.9 +/-0.2 degrees, 18.4 +/-0.2 degrees, 4.8 +/-0.2 degrees, 23.4 +/-0.2 degrees, 16.7 +/-0.2 degrees, 17.8 +/-0.2 degrees, 12.8 +/-0.2 degrees, 23.8 +/-0.2 degrees, 21.8 +/-0.2 degrees, 19.0 +/-0.2 degrees, 25.4 +/-0.2 degrees and 19.8 +/-0.2 degrees; preferably, the compound contains diffraction peaks at 4, 6, 8 and 10.

The X-ray powder diffraction pattern of the sulfate crystal form I comprises one or more diffraction peaks with 2 theta of 10.3 +/-0.2 degrees, 5.1 +/-0.2 degrees, 15.6 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.2 +/-0.2 degrees, 19.0 +/-0.2 degrees, 25.6 +/-0.2 degrees, 22.1 +/-0.2 degrees, 23.0 +/-0.2 degrees, 20.8 +/-0.2 degrees, 19.2 +/-0.2 degrees and 24.1 +/-0.2 degrees; preferably, the compound contains diffraction peaks at 4, 6, 8 and 10.

The X-ray powder diffraction pattern of the sulfate crystal form II comprises one or more diffraction peaks with the 2 theta of 16.1 +/-0.2 degrees, 5.9 +/-0.2 degrees, 6.6 +/-0.2 degrees, 22.0 +/-0.2 degrees, 21.0 +/-0.2 degrees, 20.1 +/-0.2 degrees, 17.0 +/-0.2 degrees, 25.2 +/-0.2 degrees, 20.7 +/-0.2 degrees and 23.1 +/-0.2 degrees; preferably, the compound contains diffraction peaks at 4, 6, 8 and 10.

The X-ray powder diffraction pattern of the phosphate crystal form I comprises one or more diffraction peaks with 2 theta of 5.6 +/-0.2 degrees, 11.5 +/-0.2 degrees, 20.3 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.2 +/-0.2 degrees, 16.4 +/-0.2 degrees, 21.9 +/-0.2 degrees and 10.2 +/-0.2 degrees; preferably, the compound contains diffraction peaks at 4, 6 and 8.

The X-ray powder diffraction pattern of the phosphate crystal form II comprises one or more diffraction peaks with 2 theta of 5.6 +/-0.2 degrees, 11.4 +/-0.2 degrees, 15.1 +/-0.2 degrees, 15.4 +/-0.2 degrees, 17.2 +/-0.2 degrees, 20.0 +/-0.2 degrees, 16.1 +/-0.2 degrees, 20.3 +/-0.2 degrees, 21.0 +/-0.2 degrees, 21.8 +/-0.2 degrees and 24.7 +/-0.2 degrees; preferably, the compound contains diffraction peaks at 4, 6, 8 and 10.

In a more preferred embodiment of the present invention, the crystalline form I besylate has an X-ray powder diffraction pattern as shown in FIG. 1; the X-ray powder diffraction pattern of the benzene sulfonate crystal form II is shown in figure 4; the X-ray powder diffraction pattern of the p-toluenesulfonate crystalline form I is shown in FIG. 7; the X-ray powder diffraction pattern of the hydrochloride form I is shown in figure 10; the X-ray powder diffraction pattern of the hydrochloride crystal form II is shown in figure 13; the X-ray powder diffraction pattern of the hydrobromide crystal form I is shown in figure 15; an X-ray powder diffraction pattern of oxalate form I is shown in figure 18; an X-ray powder diffraction pattern of oxalate form II is shown in figure 21; an X-ray powder diffraction pattern of oxalate form III is shown in figure 22; the X-ray powder diffraction pattern of oxalate form IV is shown in figure 23; the X-ray powder diffraction pattern of the mesylate salt form I is shown in figure 26; the X-ray powder diffraction pattern of the ethanesulfonate crystal form I is shown in figure 29; the X-ray powder diffraction pattern of the ethanesulfonate crystal form II is shown in FIG. 32; the X-ray powder diffraction pattern of the isethionate salt form I is shown in FIG. 35; the X-ray powder diffraction pattern of the isethionate salt crystal form II is shown in FIG. 36; the X-ray powder diffraction pattern of the sulfate crystal form I is shown in figure 39; the X-ray powder diffraction pattern of the sulfate crystal form II is shown in figure 40; the X-ray powder diffraction pattern of the phosphate crystal form I is shown in figure 41; the X-ray powder diffraction pattern of the phosphate crystal form II is shown in figure 42.

In a more preferred embodiment of the present invention, the 2 θ error of diffraction peaks corresponding to the positions of benzenesulfonate crystal form I, benzenesulfonate crystal form II, p-toluenesulfonate crystal form I, hydrochloride crystal form II, hydrobromide crystal form I, oxalate crystal form II, oxalate crystal form III, oxalate crystal form IV, methanesulfonate crystal form I, ethanesulfonate crystal form II, isethionate crystal form I, isethionate crystal form II, sulfate crystal form I, sulfate crystal form II, phosphate crystal form I and phosphate crystal form II in the X-ray powder diffraction patterns of benzenesulfonate crystal form I, p-toluenesulfonate crystal form II, and p-toluenesulfonate crystal form II is ± 0.2 ° ± 0.5 °, preferably + -0.2 deg. + -0.3 deg., most preferably + -0.2 deg..

In a more preferred version of the present invention,

besylate form I has a DSC profile as shown in figure 2; or a TGA profile as shown in figure 3;

besylate form II has a DSC profile as shown in figure 5; or a TGA profile as shown in figure 6;

the p-toluenesulfonate form I has a DSC profile as shown in FIG. 8; or a TGA profile as shown in figure 9;

form I of the hydrochloride salt has a DSC profile as shown in figure 11; or a TGA profile as shown in figure 12;

form II of the hydrochloride salt has a DSC profile as shown in figure 14;

hydrobromide form I has a DSC profile as shown in figure 16; or a TGA profile as shown in figure 17;

oxalate form I has a DSC profile as shown in figure 19; or a TGA profile as shown in figure 20;

form IV of the oxalate salt has a DSC profile as shown in figure 24; or a TGA profile as shown in figure 25;

the mesylate salt form I has a DSC profile as shown in figure 27; or a TGA profile as shown in figure 28;

the ethanesulfonate salt form I has a DSC profile as shown in figure 30; or a TGA profile as shown in figure 31;

the ethanesulfonate salt form II has a DSC profile as shown in figure 33; or a TGA profile as shown in figure 34.

In a more preferred embodiment of the present invention, the preparation method of the acid salt of the above compound and the salt form thereof comprises the following steps:

1) weighing a proper amount of free alkali, and dissolving the free alkali by using a benign solvent;

2) weighing a proper amount of counter ion acid, and dissolving the counter ion acid by using an organic solvent; the amount of the counter-ionic acid is preferably 1.0 to 1.5 equivalents;

3) mixing the two solutions, stirring to separate out or dripping a poor solvent and stirring to separate out;

4) quickly centrifuging or standing and drying to obtain a target product;

wherein:

the benign solvent is selected from one or more of dichloromethane, tetrahydrofuran, 1, 4-dioxane, acetone, methanol, ethanol, 2-methyl-tetrahydrofuran, 2-butanone, N-butanol, isobutanol, N-dimethylformamide, N-dimethylacetamide, N-propanol or tert-butanol;

preferably one or more of tetrahydrofuran, dichloromethane, 1, 4-dioxane, 2-butanone or acetone;

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-methyl-tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1, 4-dioxane, tert-butyl alcohol or N, N-dimethylformamide;

preferably one or more of dichloromethane, tetrahydrofuran or 1, 4-dioxane;

the benign solvent and the organic solution need to be mutually soluble when in use;

the poor 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;

the counter-ionic 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-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxy hydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dibenzoyltartaric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, fumaric acid, and the like, One or more of 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1, 5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, pamoic acid, formic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, or L-malic acid;

preferably one or more of benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, isethionic acid, 1, 5-naphthalenedisulfonic acid, tartaric acid, adipic acid, phosphoric acid, hydrobromic acid, oxalic acid, fumaric acid, formic acid, hippuric acid, lauric acid, stearic acid.

In a more preferred embodiment of the present invention, the method for preparing the acid salt of the compound and the crystal form thereof specifically comprises the following steps:

1) weighing a proper amount of compound salt, and suspending with a poor solvent, wherein the suspension density is preferably 50-200 mg/mL;

2) shaking the obtained suspension for a certain time at a certain temperature, wherein the temperature is preferably 25-50 ℃, and the time is preferably 1-15 days;

3) quickly centrifuging the suspension, removing supernatant, and drying the residual solid in a vacuum drying oven at 50 ℃ to constant weight to obtain a target product;

wherein:

the poor 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-methyl-tetrahydrofuran, isopropanol, n-butanol, isobutanol, n-propanol, methyl tert-butyl ether, n-heptane, tert-butanol, or 2-butanone.

In a more preferred embodiment of the present invention, the acid salt of the above compound is a pharmaceutical composition comprising a therapeutically effective amount of a pharmaceutically acceptable salt of the above compound and one or more pharmaceutically acceptable carriers or excipients.

In a more preferred embodiment of the invention, the use of the acid salt and the crystal form thereof, or the pharmaceutical composition in the preparation of a RET inhibitor medicament is included.

In a more preferred embodiment of the invention, the use of the acid salt and the crystal form thereof, or the pharmaceutical composition for the preparation of a medicament for the treatment and/or prevention of non-small cell lung cancer, fibrosarcoma, pancreatic tumor, medullary thyroid carcinoma, papillary thyroid tumor, soft tissue sarcoma, high solid tumor, breast tumor and colon tumor diseases.

In a further preferred embodiment of the invention, besylate form I, the X-ray powder diffraction pattern has a characteristic peak at 17.7 ± 0.2 ° 2 Θ; preferably, the compound also comprises a characteristic peak at the 2 theta of 8.4 +/-0.2 degrees; more preferably, further comprising characteristic peaks at 24.8 ± 0.2 °, 21.5 ± 0.2 °, 17.1 ± 0.2 ° and 15.2 ± 0.2 ° in 2 θ; further preferably, the compound also comprises characteristic peaks at 23.4 + -0.2 deg., 19.3 + -0.2 deg., 28.2 + -0.2 deg., 18.9 + -0.2 deg., 11.8 + -0.2 deg. and 18.6 + -0.2 deg. of 2 theta.

Characteristic diffraction peaks of X-rays expressed in terms of 2 theta angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 1.

TABLE 1

In a further preferred embodiment of the invention, besylate salt form II, the X-ray powder diffraction pattern has a characteristic peak at 17.7 ± 0.2 ° 2 Θ; preferably, the compound also comprises characteristic peaks at 15.2 +/-0.2 degrees, 21.5 +/-0.2 degrees and 24.8 +/-0.2 degrees of 2 theta; more preferably, the compound also comprises characteristic peaks at 2 theta of 8.5 +/-0.2 degrees, 19.3 +/-0.2 degrees and 17.1 +/-0.2 degrees; further preferably, the composition also comprises characteristic peaks at 18.6 +/-0.2 degrees, 23.4 +/-0.2 degrees, 7.7 +/-0.2 degrees, 6.5 +/-0.2 degrees and 13.9 +/-0.2 degrees of 2 theta.

Characteristic diffraction peaks of X-rays expressed in terms of 2 theta angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 2.

TABLE 2

In a further preferred embodiment of the present invention, crystalline form I, p-toluenesulfonate has a characteristic peak in the X-ray powder diffraction pattern at a2 θ of 18.4 ± 0.2 °; preferably, the compound also comprises characteristic peaks at 15.1 +/-0.2 degrees, 8.1 +/-0.2 degrees and 16.9 +/-0.2 degrees of 2 theta; more preferably, further comprises characteristic peaks at 7.6 ± 0.2 °, 17.4 ± 0.2 ° and 20.9 ± 0.2 ° in 2 θ; further preferably, the composition further comprises characteristic peaks at 17.2 ± 0.2 °, 5.0 ± 0.2 °, 19.0 ± 0.2 °, 22.8 ± 0.2 ° and 24.0 ± 0.2 ° in 2 θ.

Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 3.

TABLE 3

In a further preferred embodiment of the invention, the hydrochloride form I, the X-ray powder diffraction pattern has a characteristic peak at 10.0 ± 0.2 ° 2 Θ; preferably, the compound also comprises characteristic peaks at 2 theta of 6.0 +/-0.2 degrees, 15.6 +/-0.2 degrees and 16.8 +/-0.2 degrees; more preferably, further comprises having characteristic peaks at 24.6 ± 0.2 °, 23.0 ± 0.2 ° and 20.8 ± 0.2 ° in 2 θ; further preferably, the composition also comprises characteristic peaks at 26.7 +/-0.2 degrees, 17.5 +/-0.2 degrees, 21.6 +/-0.2 degrees, 14.9 +/-0.2 degrees and 30.7 +/-0.2 degrees of 2 theta.

Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 4.

TABLE 4

In a further preferred embodiment of the invention, the hydrochloride form II, the X-ray powder diffraction pattern has a characteristic peak at 10.0 ± 0.2 ° 2 Θ; preferably, the compound also comprises characteristic peaks at 2 theta of 6.0 +/-0.2 degrees, 6.6 +/-0.2 degrees and 15.6 +/-0.2 degrees; more preferably, the compound also comprises characteristic peaks at 24.7 +/-0.2 degrees, 23.1 +/-0.2 degrees and 16.8 +/-0.2 degrees of 2 theta; further preferably, the composition also comprises characteristic peaks at 17.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 23.9 +/-0.2 degrees, 22.4 +/-0.2 degrees and 26.7 +/-0.2 degrees of 2 theta.

Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 5.

TABLE 5

In a further preferred embodiment of the present invention, the hydrobromide form I, X-ray powder diffraction pattern has a characteristic peak at 9.9 ± 0.2 ° 2 Θ; preferably, the compound also comprises characteristic peaks at 2 theta of 5.9 +/-0.2 degrees, 22.8 +/-0.2 degrees and 20.6 +/-0.2 degrees; more preferably, further comprises having characteristic peaks at 24.4 ± 0.2 °, 16.7 ± 0.2 ° and 21.4 ± 0.2 ° in 2 θ; further preferably, the composition also comprises characteristic peaks at 26.6 +/-0.2 degrees, 17.4 +/-0.2 degrees, 24.9 +/-0.2 degrees, 23.1 +/-0.2 degrees and 30.6 +/-0.2 degrees of 2 theta.

TABLE 5

In a further preferred embodiment of the invention, the oxalate form I, the X-ray powder diffraction pattern has a characteristic peak at a2 θ of 9.5 ± 0.2 °; preferably, the compound also comprises characteristic peaks at the 2 theta of 19.3 +/-0.2 degrees, 10.7 +/-0.2 degrees and 4.7 +/-0.2 degrees; more preferably, further comprising having characteristic peaks at 6.0 ± 0.2 °, 16.5 ± 0.2 ° and 25.0 ± 0.2 ° in 2 θ; further preferably, the composition also comprises characteristic peaks at 27.1 +/-0.2 degrees, 15.3 +/-0.2 degrees, 14.5 +/-0.2 degrees, 18.6 +/-0.2 degrees and 20.5 +/-0.2 degrees of 2 theta.

Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 6.

TABLE 6

In a further preferred embodiment of the invention, the oxalate salt is in form II, and the X-ray powder diffraction pattern has a characteristic peak at 5.8 ± 0.2 ° 2 Θ; preferably, the compound also comprises characteristic peaks at 4.8 +/-0.2 degrees, 15.7 +/-0.2 degrees and 17.0 +/-0.2 degrees of 2 theta; more preferably, further comprises characteristic peaks at 9.4 ± 0.2 °, 19.2 ± 0.2 ° and 17.7 ± 0.2 ° in 2 θ; further preferably, the composition also comprises characteristic peaks at 16.6 +/-0.2 degrees, 26.1 +/-0.2 degrees, 11.8 +/-0.2 degrees, 18.6 +/-0.2 degrees and 12.5 +/-0.2 degrees of 2 theta.

Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 7.

TABLE 7

In a further preferred embodiment of the invention, the oxalate salt is form III, and the X-ray powder diffraction pattern has a characteristic peak at 10.4 ± 0.2 ° 2 Θ; preferably, the compound also comprises characteristic peaks at 5.1 +/-0.2 degrees, 4.8 +/-0.2 degrees and 15.8 +/-0.2 degrees of 2 theta; more preferably, further comprises characteristic peaks at 14.3 ± 0.2 °, 12.2 ± 0.2 ° and 17.8 ± 0.2 ° in 2 θ; further preferably, the compound also comprises characteristic peaks at 5.8 +/-0.2 degrees, 18.9 +/-0.2 degrees, 17.0 +/-0.2 degrees and 23.8 +/-0.2 degrees of 2 theta.

TABLE 7

In a further preferred embodiment of the invention, the oxalate salt form IV, X-ray powder diffraction pattern has a characteristic peak at 20.5 ± 0.2 ° 2 Θ; preferably, the compound also comprises characteristic peaks at the 2 theta of 18.5 +/-0.2 degrees, 17.9 +/-0.2 degrees and 4.8 +/-0.2 degrees; more preferably, further comprises characteristic peaks at 16.5 ± 0.2 °, 15.8 ± 0.2 ° and 11.5 ± 0.2 ° in 2 θ; further preferably, the composition further comprises characteristic peaks at 12.3 ± 0.2 °, 24.0 ± 0.2 °, 16.2 ± 0.2 °, 23.3 ± 0.2 ° and 19.6 ± 0.2 ° in 2 θ.

Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 8.

TABLE 8

In a further preferred embodiment of the invention, the mesylate salt form I, the X-ray powder diffraction pattern, has a characteristic peak at 10.3 ± 0.2 ° 2 Θ; preferably, the compound also comprises characteristic peaks at 5.1 +/-0.2 degrees, 15.6 +/-0.2 degrees and 25.2 +/-0.2 degrees of 2 theta; more preferably, the composition further comprises a characteristic peak at a2 theta of 18.4 +/-0.2 degrees.

Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 9.

TABLE 1

In a further preferred embodiment of the invention, the ethanesulfonate salt form I, X-ray powder diffraction pattern, has a characteristic peak at 10.2 ± 0.2 ° 2 Θ; preferably, the compound also comprises characteristic peaks at 5.0 +/-0.2 degrees, 15.4 +/-0.2 degrees and 18.9 +/-0.2 degrees of 2 theta; more preferably, the composition further comprises characteristic peaks at 24.2 + -0.2 deg. and 21.1 + -0.2 deg. of 2 theta.

Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 10.

Watch 10

In a further preferred embodiment of the invention, the ethanesulfonate salt of form II, having an X-ray powder diffraction pattern with a characteristic peak at 10.2 ± 0.2 ° 2 Θ; preferably, the compound also comprises characteristic peaks at 5.0 +/-0.2 degrees, 6.0 +/-0.2 degrees and 15.4 +/-0.2 degrees of 2 theta; more preferably, the composition further comprises characteristic peaks at 5.4 + -0.2 DEG and 7.3 + -0.2 DEG in terms of 2 theta.

Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 11.

TABLE 11

In a further preferred embodiment of the invention, the isethionate salt form I, X-ray powder diffraction pattern, has a characteristic peak at 10.5 ± 0.2 ° 2 Θ; preferably, the compound also comprises characteristic peaks at 5.2 +/-0.2 degrees, 18.7 +/-0.2 degrees and 15.9 +/-0.2 degrees of 2 theta; more preferably, the composition further comprises a characteristic peak at 23.0 + -0.2 DEG in terms of 2 theta.

Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 12.

TABLE 12

In a further preferred embodiment of the invention, the isethionate salt form II, X-ray powder diffraction pattern, has a characteristic peak at 11.9 ± 0.2 ° 2 Θ; preferably, the compound also comprises characteristic peaks at the 2 theta of 18.4 +/-0.2 degrees, 4.8 +/-0.2 degrees and 23.4 +/-0.2 degrees; more preferably, the compound also comprises a characteristic peak at the 2 theta of 16.7 +/-0.2 degrees, 17.8 +/-0.2 degrees, 12.8 +/-0.2 degrees, 23.8 +/-0.2 degrees and 21.8 +/-0.2 degrees.

Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 13.

Watch 13

In a further preferred embodiment of the present invention, the sulfate salt form I, X-ray powder diffraction pattern has a characteristic peak at 10.3 ± 0.2 ° 2 Θ; preferably, the compound also comprises characteristic peaks at 2 theta of 5.1 +/-0.2 degrees, 15.6 +/-0.2 degrees and 14.5 +/-0.2 degrees; more preferably, further comprising having characteristic peaks at 20.2 ± 0.2 °, 19.0 ± 0.2 ° and 25.6 ± 0.2 ° in 2 θ; further preferably, the composition also comprises characteristic peaks at 22.1 +/-0.2 degrees, 23.0 +/-0.2 degrees, 20.8 +/-0.2 degrees, 19.2 +/-0.2 degrees and 24.1 +/-0.2 degrees of 2 theta.

Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 14.

TABLE 14

In a further preferred embodiment of the invention, the sulfate salt form II, the X-ray powder diffraction pattern has a characteristic peak at a2 θ of 16.1 ± 0.2 °; preferably, the compound also comprises characteristic peaks at 5.9 +/-0.2 degrees, 6.6 +/-0.2 degrees and 22.0 +/-0.2 degrees of 2 theta; more preferably, further comprises having characteristic peaks at 21.0 ± 0.2 °, 20.1 ± 0.2 ° and 17.0 ± 0.2 ° in 2 θ; further preferably, the composition further comprises characteristic peaks at 25.2 ± 0.2 °, 20.7 ± 0.2 ° and 23.1 ± 0.2 ° of 2 θ.

Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 15.

Watch 15

In a further preferred embodiment of the invention, the phosphate form I, X-ray powder diffraction pattern has a characteristic peak at 5.6 ± 0.2 ° 2 Θ; preferably, the compound also comprises characteristic peaks at the 2 theta of 11.5 +/-0.2 degrees, 20.3 +/-0.2 degrees and 15.9 +/-0.2 degrees; more preferably, the composition further comprises characteristic peaks at 17.2 + -0.2 deg., 16.4 + -0.2 deg., 21.9 + -0.2 deg. and 10.2 + -0.2 deg. in terms of 2 theta.

Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 16.

TABLE 16

In a further preferred embodiment of the present invention, the phosphate form II, X-ray powder diffraction pattern, has a characteristic peak at 24.7 ± 0.2 ° 2 Θ; preferably, the compound also comprises characteristic peaks at 21.8 +/-0.2 degrees, 21.0 +/-0.2 degrees and 20.3 +/-0.2 degrees of 2 theta; more preferably, further comprising characteristic peaks at 16.1 ± 0.2 °, 20.0 ± 0.2 °, 17.2 ± 0.2 ° and 15.4 ± 0.2 ° in 2 θ; more preferably, the compound also comprises characteristic peaks at 15.1 +/-0.2 degrees, 11.4 +/-0.2 degrees and 5.6 +/-0.2 degrees of 2 theta.

Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 17.

TABLE 17

Detailed description of the invention

Unless stated to the contrary, terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and most preferably an alkyl group of 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 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-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 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-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-ethyl, 2-2, 2-2, 2-2, or, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 8 carbon atoms, and most preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.

The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)_m(wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 8 ring atoms; most preferably from 3 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, thietanyl, pyrrolidinyl, pyrrolidinonylImidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl and the like, with oxetanyl, pyrrolidinonyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperazinyl and pyranyl being preferred. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups; wherein the heterocyclic groups of the spiro, fused and bridged rings are optionally linked to other groups by single bonds, or further linked to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms in the ring.

The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.

"haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

"haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

"hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

"alkenyl" refers to alkenyl, also known as alkenylene, wherein the alkenyl may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

"alkynyl" means (CH.ident.C-) wherein the alkynyl may be further substituted with other related groups such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

"hydroxy" refers to an-OH group.

"halogen" means fluorine, chlorine, bromine or iodine.

"amino" means-NH₂。

"cyano" means-CN.

"nitro" means-NO₂。

"carboxy" refers to-C (O) OH.

"THF" refers to tetrahydrofuran.

"EtOAc" refers to ethyl acetate.

"MeOH" refers to methanol.

"DMF" refers to N, N-dimethylformamide.

"DIPEA" refers to diisopropylethylamine.

"TFA" refers to trifluoroacetic acid.

"MeCN" refers to acetonitrile.

"DMA" refers to N, N-dimethylacetamide.

“Et₂O "means diethyl ether.

"DCE" refers to 1,2 dichloroethane.

"DIPEA" refers to N, N-diisopropylethylamine.

"NBS" refers to N-bromosuccinimide.

"NIS" refers to N-iodosuccinimide.

"Cbz-Cl" refers to benzyl chloroformate.

“Pd₂(dba)₃"refers to tris (dibenzylideneacetone) dipalladium.

"Dppf" refers to 1, 1' -bisdiphenylphosphinoferrocene.

"HATU" refers to 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate.

"KHMDS" refers to potassium hexamethyldisilazide.

"LiHMDS" refers to lithium bistrimethylsilyl amide.

"MeLi" refers to methyllithium.

"n-BuLi" refers to n-butyllithium.

“NaBH(OAc)₃"refers to sodium triacetoxyborohydride.

"DMAP" refers to 4-dimethylaminopyridine.

"SEM-Cl" refers to chloromethyl trimethylsilylethyl ether.

"Xantphos" refers to 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene.

"DCM" refers to dichloromethane.

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", "X is A, B and C" and the like all express the same meaning, that is, X can be any one or more of A, B, C.

All hydrogen atoms described in the present invention can be replaced by deuterium, which is an isotope thereof, and any hydrogen atom in the compound of the embodiment related to the present invention can also be replaced by a deuterium atom.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.

"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.

The new crystal form can be identified by powder X-ray diffraction spectrum. However, those skilled in the art will appreciate that the peak intensity and/or peak condition of powder X-ray diffraction may vary depending on experimental conditions, such as different diffraction test conditions and/or preferential orientation. Meanwhile, the measured 2 θ value may have an error of about ± 0.2 and the individual peak may have an error of about ± 0.3 or ± 0.4 due to the different accuracies of different instruments. However, it is known that the relative intensity values of peaks are more dependent on certain properties of the sample being measured than the location of the peaks, such as the size of crystals in the sample, the orientation of crystals, and the purity of the material being analyzed, and thus it is possible to show peak intensity deviations in the range of about ± 20% or more.

Drawings

FIGS. 1-3 are XRPD, DSC, TGA graphic representations 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] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile benzenesulfonate salt form I.

FIGS. 4-6 are XRPD, DSC, TGA graphic representations 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] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile benzenesulfonate salt form II.

FIGS. 7-9 are XRPD, DSC, TGA graphic representations 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] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile p-toluenesulfonate crystalline form I.

FIGS. 10-12 are XRPD, DSC, TGA graphic representations 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] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile hydrochloride form I.

FIGS. 13-14 are XRPD, DSC representations 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] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile hydrochloride form II.

FIGS. 15-17 are XRPD, DSC, TGA graphic representations of crystalline 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] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile hydrobromide.

FIGS. 18-20 are XRPD, DSC, TGA graphic representations 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] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile oxalate form I.

FIG. 21 is a graphical representation of the XRPD 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] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile oxalate form II.

FIG. 22 is a graphical representation of the XRPD 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] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile oxalate form III.

FIGS. 23-25 are XRPD, DSC, TGA graphic representations 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] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile oxalate form IV.

FIGS. 26-28 are XRPD, DSC, TGA graphic representations of crystalline 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] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile methanesulfonate salt.

FIGS. 29-31 are XRPD, DSC, TGA graphic representations of crystalline 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] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile ethanesulfonate.

FIGS. 32-34 are XRPD, DSC, TGA graphic representations 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] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile ethanesulfonate crystalline form II.

FIG. 35 is a graphic representation of the XRPD 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] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile isethionate salt form I.

FIGS. 36-38 are XRPD graphic representations 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] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile isethionate salt form II.

FIG. 39 is a graphical representation of the XRPD 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] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile sulfate form I.

FIG. 40 is a graphical representation of the XRPD 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] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile sulfate crystalline form II.

FIG. 41 is a graphical representation of the XRPD 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] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile phosphate crystalline form I.

FIG. 42 is a graphical representation of an XRPD 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] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile phosphate crystalline form II.

FIG. 43 is a graphical representation of the DVS hygroscopicity profile 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] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile benzenesulfonate crystalline form I.

FIG. 44 is a graphical representation of the DVS hygroscopicity profile 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] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile p-toluenesulfonate.

FIG. 45 is a graphical representation of the DVS hygroscopicity profile 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] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile hydrobromide.

FIG. 46 is a graphical representation of the DVS hygroscopicity profile 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] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile hydrochloride form I.

FIG. 47 is a graphical representation of the DVS hygroscopicity profile 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] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile oxalate form IV.

Detailed Description

The present invention is further described below with reference to examples, which are not intended to limit the scope of the present invention.

Preparation of compounds

Examples

The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated methanol (CD)₃OD) and deuterated chloroform (CDCl)₃) Internal standard is Tetramethylsilane (TMS).

LC-MS was measured using an Agilent 1200Infinity Series Mass spectrometer. HPLC was carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150X 4.6mm column).

The thin layer chromatography silica gel plate adopts a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. The column chromatography generally uses 200-300 mesh Titai Huanghai silica gel as a carrier.

The starting materials in the examples of the present invention are known and commercially available, or can be synthesized according to methods known in the art.

All reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, without specific indication, the solvent is a dry solvent and the reaction temperature is given in degrees celsius.

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-carbonitrile

The first step is as follows: 4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-oxopropoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile

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

MS m/z(ESI):510.1[M+H]⁺.

The second step is that: 6- ((2-hydroxy-2-methylbut-3-yn-1-yl) oxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3,6 diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile

4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-oxopropoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile (160mg, 0.314mmol) was dissolved in anhydrous tetrahydrofuran (15mL) and ethynylmagnesium chloride (6.28mL, 3.14mmol, 0.5M) was slowly added. After the addition was completed, the reaction solution was stirred for one hour. Aqueous ammonium chloride solution was added thereto, the reaction was quenched, and ethyl acetate was added thereto for extraction. The organic phase was dried and then spin dried. 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) -3,6 diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (48mg, yield 28%).

MS m/z(ESI):536.1[M+H]⁺.

The third step: 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] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile

6- ((2-hydroxy-2-methylbut-3-yn-1-yl) oxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3,6 diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (48.2mg, 0.09mmol) by chiral resolution 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] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (16 mg).

Chiral resolution conditions:

watch 18

Instrument for measuring the position of a moving object	CHIRALPAK IBN
		Column shape	5.0cm I.D.×25cm L,10μm
Mobile phase	Hexane/EtOH/DCM＝60/30/10(V/V/V)
		Flow rate of flow	60mL/min
Detection wavelength	UV 254nm
		Column temperature
	35℃

t_R＝9.002min

MS m/z(ESI):536.1[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ8.74(d,J＝2.1Hz,1H),8.60(s,1H),8.42(d,J＝2.5Hz,1H),8.07(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).

Second, compound biological test evaluation

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

First, test the enzymology experiment

Test example 1 measurement of inhibitory Effect of the Compound of the present invention on the Activity of RET wild type and mutant kinase

1. Purpose of the experiment:

the purpose of this test example was to measure the inhibitory ability of compounds on RET wild type and mutant kinase activity.

2.1 Experimental apparatus:

centrifuge (Eppendorf 5810R);

microplate reader (BioTek Synergy H1);

pipettor (Eppendorf & Rainin).

2.2 Experimental reagents:

RET enzyme is available from Carna company under the cat number 08-159;

RET M918T enzyme was purchased from Carna, Inc. under the cat # 08-508;

KIF5B-RET is available from SignalChem under the trade designation R02-19 FG-05;

CCDC6-RET is available from SignalChem under the trade designation R02-19 BG-05;

RET V804M enzyme was purchased from Thermofeisher under the accession number PV 6223;

RET V804L enzyme was purchased from Thermofeisher under the accession number PV 4397;

HTRF KinEASE-TKkit was purchased from Cisbio, having a catalog number of 62TK0 PEC;

ATP was purchased from Thermofeisher, Inc. under the Cat designation PV 3227;

a384 well plate was purchased from Perkinelmer under the trade designation 6007290.

2.3 test compounds:

the compound of the embodiment of the invention is prepared by self.

3. The experimental method comprises the following steps:

the assay used homogeneous time-resolved fluorescence (HTRF) to detect RET kinase activity. The experiment was performed in 384 well plates using assay buffer (25mM HEPES, 10mM MgCl)₂0.01% TritonX-100), adding the compound solution into a 384-well plate, respectively adding diluted RET, RET M918T, CCDC6-RET, KIF5B-RET, RET V804M or RET V804L kinase solution (0.01-2 nM) and TK-substrate biotin (500 nM-1 μ M) and ATP solution with Km (0.19-200 μ M) concentration, wherein the total reaction system is 10 μ L, the mixture is centrifuged at 1000rpm for 1 minute and is uniformly mixed, 10 μ L of the mixture of Sa-XL665 and TK-ab-Cryptate prepared by using a detection solution is added after reacting at room temperature for 45 minutes, the mixture is centrifuged at 1000rpm for 1 minute and is uniformly mixed, a BioTek Synergy H1 instrument is used for reading after reacting at room temperature for 1 hour, and readings at nM and 620nM are recorded.

4. The experimental data processing method comprises the following steps:

IC was obtained by reading with a BioTek Synergy H1 instrument, recording readings at 665nm and 620nm, calculating the ratio (665nm/620nm), calculating the inhibition ratio, fitting the concentration and inhibition ratio to a non-linear regression curve using Graphpad Prism software to obtain IC₅₀The value is obtained.

5. The experimental results are as follows:

the data obtained from the above test methods for testing compounds against various mutant kinases of RET for the specific examples are shown in Table 2-1.

Table 2-1: IC of compound for inhibiting RET multiple mutant kinase activity₅₀Value of

6. And (4) experimental conclusion:

the compound of the embodiment of the invention shows good inhibitory activity to various mutant kinases of RET, and has significant activity in drug-resistant mutations RET M918T, KIF5B-RET and RET V804L.

Test example 2 measurement of KDR kinase Activity inhibition Effect of the Compound of the present invention

1. Purpose of the experiment:

the purpose of this test example was to measure the inhibitory ability of a compound on KDR kinase activity.

2.1 Experimental apparatus:

centrifuge (Eppendorf 5810R);

microplate reader (BioTek Synergy H1);

pipettor (Eppendorf & Rainin).

2.2 Experimental reagents:

KDR kinase is available from Carna under the cat # 08-191;

ATP was purchased from Thermofeisher, Inc. under the Cat designation PV 3227;

the 384 well plates were purchased from Perkinelmer under the designation 6007290.

2.3 test compounds:

the compound of the embodiment of the invention is prepared by self.

3. The experimental method comprises the following steps:

the assay uses homogeneous time-resolved fluorescence (HTRF) to detect KDR kinase activity. The experiment was performed in 384 well plates using assay buffer (25mM HEPES, 10mM MgCl)₂0.01 percent TritonX-100), adding the compound solution into a 384-hole plate, adding a diluted KDR kinase solution (0.05nM), a substrate TK-substrate biotin (500 nM-1 μ M) and a Km concentration (0.19-200 μ M) ATP solution, centrifuging at 1000rpm for 1 minute to mix the mixture uniformly, reacting at room temperature for 45 minutes, adding 10 μ L of Sa-XL665 and TK-ab-Cryptate mixed solution prepared by using a detection solution, centrifuging at 1000rpm for 1 minute to mix uniformly, reacting at room temperature for 1 hour, reading by using a BioTek Synergy H1 microplate reader, and recording readings at 665nM and 620 nM.

4. The experimental data processing method comprises the following steps:

5. The experimental results are as follows:

the test data of the specific examples obtained by the above test method are shown in tables 2-2:

tables 2 to 2: relative IC of compound for RET kinase activity inhibition and KDR kinase activity inhibition₅₀Value of

6. And (4) experimental conclusion:

the above data show that the compounds of the examples shown in the present invention have a strong inhibitory effect on the activity of RET kinase, but have a poor inhibitory effect on the activity of KDR kinase. Comparing two groups of data, the series of compounds of the invention have high selectivity on the inhibitory action of KDR/RET kinase activity.

Second, test cytology experiments

Test example 1 measurement of inhibitory Effect of the Compound of the present invention on TT cell proliferation Activity

1. Purpose of the experiment:

the purpose of this test example was to measure the inhibitory effect of the compounds on the proliferative activity of TT cells.

2.1 Experimental apparatus:

microplate reader (BioTek Synergy H1);

pipettor (Eppendorf & Rainin).

2.2 Experimental reagents:

TT cells were purchased from cell banks of Chinese academy of sciences;

cell Titer-Glo cells were purchased from Promega under the product number G7573.

2.3 test compounds:

the compound of the embodiment of the invention is prepared by self.

3. The experimental method comprises the following steps:

culturing TT cells to appropriate confluency, collecting TT cells, adjusting the cells to appropriate cell concentration using complete medium, spreading the cell suspension in 96-well plate at 90 μ L/well, placing at 37 deg.C and 5% CO₂Incubators attached overnight, with DMSO and incubationsPreparing compound solutions with different concentrations, setting solvent control, adding the compound solution into 96-well plate, placing 10 μ L per well, placing at 37 deg.C and 5% CO₂After the culture in the incubator is continued for 72H, CellTiter-Glo solution is added, after shaking and mixing uniformly, the mixture is incubated for 10 minutes in the dark, and reading is carried out by a BioTek Synergy H1 enzyme-labeling instrument.

4. The experimental data processing method comprises the following steps:

calculating the inhibition rate by using the luminescence signal value, and fitting the concentration and the inhibition rate by using Graphpad Prism software to obtain IC₅₀The value is obtained.

5. The experimental results are as follows:

tables 2 to 3

6. And (4) experimental conclusion:

the above data show that the compounds of the examples of the present invention have good inhibitory effect on the proliferation of TT cells.

Test example 2 assay of inhibitory Effect of the Compound of the present invention on Ba/F3 KIF5B-RET cell proliferation Activity

1. Purpose of the experiment:

the inhibitory effect of the compounds on the proliferative activity of Ba/F3 KIF5B-RET cells was measured.

2. Instruments and reagents:

2.1 Experimental apparatus:

microplate reader (BioTek Synergy H1);

pipettor (Eppendorf & Rainin).

2.2 Experimental reagents:

Ba/F3 KIF5B-RET provided by Beijing Congyuan Bo Biotech, Inc., cell number CVCL _ UE86, available on cell information websitehttps://web.expasy.org/cellosaurus/Inquiring that the stable cell strain does not need to depend on IL-3 for growth;

2.3 test compounds:

the compound of the embodiment of the invention is prepared by self.

3. The experimental method comprises the following steps:

culturing Ba/F3 KIF5B-RET cells to appropriate cell density, collecting cells, adjusting the cells to appropriate cell concentration using complete medium, spreading the cell suspension in 96-well plate at 90. mu.L/well, placing at 37 ℃ and 5% CO₂Adhering the incubator to the wall overnight, preparing compound solutions with different concentrations by using DMSO and a culture medium, setting a solvent control, adding the compound solutions into a 96-well plate, placing 10 mu L of each well, placing at 37 ℃ and 5% CO₂And (3) continuously culturing for 72-144H in the incubator, adding CellTiter-Glo solution, shaking and mixing uniformly, incubating for 10 minutes in a dark place, and reading by using a BioTek Synergy H1 enzyme-labeling instrument.

4. The experimental data processing method comprises the following steps:

5. The experimental results are as follows:

tables 2 to 4:

6. and (4) experimental conclusion:

the data show that the compounds of the embodiment of the invention have good inhibition effect on the proliferation of Ba/F3 KIF5B-RET cells.

Test example 4 inhibition of phosphorylation of signal factor ERK downstream of TT cell by the Compound of the present invention

1. Purpose of the experiment:

and (3) detecting the inhibition effect of the compound on the phosphorylation level of a signal factor ERK downstream of the TT cell.

2. Laboratory instruments and reagents:

2.1 Experimental apparatus:

imager (Biorad ChemiDoc)^TMMP)；

Pipettor (Eppendorf & Rainin).

2.2 Experimental reagents:

the pERK antibody is purchased from Cell Signaling Technology, Inc. under the product number of 4370S;

total ERK antibody was purchased from Cell Signaling Technology, cat 4696S;

internal control GAPDH was purchased from Cell Signaling Technology, Inc. under the designation 5174S;

the fluorescent secondary antibodies were purchased from LI-COR under the accession numbers P/N925-68071 and P/N926-32210.

2.3 test compounds:

the compound of the embodiment of the invention is prepared by self.

3. The experimental method comprises the following steps:

in the experiment, the inhibition effect of the compound on the phosphorylation level of a signal factor ERK downstream of TT cells is measured by a Western Blot method. Culturing TT cells to appropriate confluency, collecting cells, adjusting the cells to appropriate cell concentration with complete medium, spreading the cell suspension in 24-well plate (1 mL/well), placing at 37 deg.C and 5% CO₂Incubators were attached overnight, dilutions of different concentrations (3.7nM, 11.1nM, 33.3nM, 100nM, 300nM) of compounds were added, allowed to act at 37 ℃ for 2 hours, cell supernatants were aspirated, washed once with PBS, proteins were collected with lysates, and Western blot experiments were performed after protein denaturation: protein electrophoresis, electrophoresis under 120V for about 75 minutes, membrane transfer to PVDF membrane by 10V with a semi-dry membrane transfer apparatus for 45 minutes, blocking for 1 hour at room temperature by 5% BSA, cutting PVDF membrane into strips with proper size, respectively incubating overnight at 4 ℃ with prepared antibody diluent, washing membrane for 6 times by TBST, then incubating for 1 hour at room temperature by goat anti-mouse secondary antibody and goat anti-rabbit secondary antibody, washing membrane for 6 times by TBST, and imaging in a Biorad ChemiDocTMMP imaging system.

4. The experimental data processing method comprises the following steps:

the inhibition effect of the compound on the ERK phosphorylation level in TT cells under different concentrations is judged by detecting protein bands.

5. The experimental results are as follows:

the compound of the embodiment can obviously inhibit the phosphorylation level of ERK in TT cells and has a dose-dependent effect. After the compound is incubated with TT cells for 2 hours at 37 ℃, the example compound almost completely inhibits ERK phosphorylation at 300nM, 100nM, 33.3nM and 11.1nM, and inhibits about half of the level of ERK phosphorylation at 3.7 nM. In example 64, 100nM completely inhibits ERK phosphorylation at 300nM, with a reduced degree of inhibition at 33.3nM, half of the level of ERK phosphorylation at 11.1nM and a weaker level at 3.7 nM.

6. And (4) experimental conclusion:

according to the scheme, the compound disclosed by the invention shows a dose-dependent inhibition effect in phosphorylation of a signal factor ERK downstream of TT cells.

Pharmacokinetic determination of Balb/C mice

1. The research aims are as follows:

Balb/C mice were used as test animals to study the pharmacokinetic behavior of the following compounds in the examples given below, administered orally at a dose of 5mg/kg in plasma in mice.

2. Test protocol:

2.1 test drugs:

the embodiment of the invention is self-made.

2.2 test animals:

Balb/C Mouse 6 per example, male, Shanghai Jie Si laboratory animals Ltd, animal production license number (SCXK (Shanghai) 2013) 0006N 0.311620400001794).

2.3 administration:

Balb/C mice, male; p.o. after fasting overnight, the dose was 5mg/kg and the administration volume was 10 mL/kg.

2.4 sample preparation:

0.5% CMC-Na (1% Tween80), sonicated to dissolve, and formulated as a clear solution or homogeneous suspension.

2.5 sample collection:

before and after administration, at 0, 0.5, 1,2, 4, 6, 8 and 24 hours, the mice were bled by orbital bleeding 0.1mL, and placed in EDTA-K₂The plasma was separated by centrifugation at 6000rpm for 6min at 4 ℃ in a test tube and stored at-80 ℃.

2.6 sample treatment:

1) plasma samples 40uL added 160uL acetonitrile precipitation, after mixing 3500 x g centrifugal 5 ~ 20 minutes.

2) Taking 100uL of the treated supernatant solution for LC/MS/MS analysis to analyze the concentration of the compound to be detected.

2.7 liquid phase analysis

Liquid phase conditions: shimadzu LC-20AD pump

Mass Spectrometry conditions AB Sciex API 4000 Mass Spectroscopy

Column chromatography: phenomenex Gemiu 5um C1850 x 4.6mm

The mobile phase: the solution A is 0.1% formic acid water solution, and the solution B is acetonitrile

Flow rate: 0.8mL/min

Elution time: 0-4.0 min, eluent as follows:

tables 2 to 5

3. Test results and analysis

The main pharmacokinetic parameters were calculated using WinNonlin 6.1, and the results of the mouse pharmacokinetic experiments are shown in tables 2-6 below:

TABLE 2-6 mouse pharmacokinetic experiments results

4. And (4) experimental conclusion:

as can be seen from the results of the mouse pharmacokinetic experiments in the table: the compounds of the examples of the invention show good metabolic properties, exposure AUC and maximum blood concentration C_maxAll performed well.

Inhibition experiment of tumor on Ba/F3 KIF5B-RET transplanted tumor model

1. Purpose of the experiment:

the test compounds were evaluated for anti-tumor activity against subcutaneous transplants of Ba/F3 KIF5B-RET cell nude mice.

2. Laboratory instruments and reagents:

2.1 Instrument:

an ultra-clean bench (BSC-1300II A2, Shanghai Bochen industries, Inc.) is provided;

CO₂an incubator (311, Thermo);

centrifuge (Centrifuge 5720R, Eppendorf);

a fully automated cytometer (Countess II, Life);

pipettors (10-20. mu.L, Eppendorf);

microscope (TS100, nikon);

vernier calipers (500- "196", san feng, japan);

cell culture flasks (T25/T75/T225, Corning).

2.2 reagent:

RPMI1640(22400-089，Gibco)；

fetal Bovine Serum (FBS) (10099-141, Gibco);

phosphate Buffered Saline (PBS) (10010-023, Gibco).

2.3 test compounds:

the compound of the embodiment of the invention is prepared by self.

3. And (3) experimental operation:

Ba/F3 KIF5B-RET cells are taken out of the cell bank, added into RPMI1640 culture medium (RPMI1640+ 10% FBS + 1% Glu + 1% P/S) after recovery and placed in CO₂Culturing in incubator (incubator temperature 37 deg.C, CO)₂Concentration of 5%), when the number of cells expanded to the number required for in vivo inoculation, Ba/F3 KIF5B-RET cells were collected. Counting with a full-automatic cell counter, re-suspending the cells with PBS according to the counting result to obtain cell suspension (density 2 × 10)⁷mL), and placing in an ice box for standby.

Female BALB/c nude mice, 6-8 weeks old, were used with body weights of about 18-22 grams. Mice were housed in individual cages of 5 mice per cage in an SPF-class animal house. All cages, bedding and water were sterilized at high temperature before use, and all animals were free to eat and drink. The nude mice were marked with disposable universal ear tags for both small and large mice before the start of the experiment, the skin of the inoculated part was disinfected with 75% medical alcohol before the inoculation, and each mouse was subcutaneously inoculated with 0.1mL (containing 2 x 10) of the right back⁶Individual cells) Ba/F3 KIF5B-RET cells. When the tumor volume reaches 60-200mm³Is initially grouped toThe medicine is prepared from 5 herbs. Each test compound was administered orally 2 times per day for 14 days. Tumor volume was measured 2 times a week, mouse body weight was weighed, and tumor TGI (%) was calculated.

4. Data processing:

tumor volume (mm)³) The calculation formula is as follows: v0.5 x D, wherein D and D are the long and short diameters of the tumor, respectively.

Calculation of TGI (%):

when there was no regression of the tumor, TGI (%) [ (1- (average tumor volume at the end of administration of a certain treatment group-average tumor volume at the start of administration of the treatment group))/(average tumor volume at the end of treatment of the solvent control group-average tumor volume at the start of treatment of the solvent control group) ] × 100%;

when there was regression of the tumor, TGI (%) [1- (average tumor volume at the end of administration of a certain treatment group-average tumor volume at the start of administration of the treatment group)/average tumor volume at the start of administration of the treatment group ] × 100%.

5. The experimental results are as follows:

tables 2-7 pharmacodynamic parameters

Remarking: the data in parentheses indicate the tumor volume at the corresponding time for this example for the Vehicle QD x 3w group (i.e., control group) 6. experimental conclusion:

the data show that the compound of the embodiment of the invention can obviously inhibit the growth of the transplantation tumor of Ba/F3 KIF5B-RET nude mice after oral administration for 14 days.

Salt of compound and crystal form research thereof

1. Compound salt form and crystal form screening thereof

1.1 Compound salt form screening

1.1.1 Experimental purposes:

different counter-ionic acids are selected and by suitable crystallization methods, it is possible to detect which counter-ionic acids can form the compound salt.

1.1.2 Experimental procedures:

1) apparatus and device

Name (R)	Model number	Source
			Analytical balance	XA105	METTLER TOLEDO
Ultrasonic cleaning instrument	SK5200LHC	Shanghai department leads ultrasonic instrument
			Liquid-transfering gun	Eppendorf(50mL,100μL)	Eppendorf

2) Operating procedure

a. Salt form screening by volatilizing dry method

Weighing 160mg of free base, adding 16mL of DCM solvent, heating and stirring at 40 ℃, equally dividing into 16 parts after clearing, respectively adding different counter ion acids, volatilizing overnight at room temperature, measuring DSC if the solid is good after volatilizing, adding 200uL of ethyl acetate for pulping overnight at 50 ℃ if the solid is poor (oily), centrifuging if the solid is good, removing supernatant, further drying the solid in a vacuum drying oven overnight (vacuum drying at 50 ℃) and screening results are shown in the following table 3-1.

TABLE 3-1 salt form screening results of example Compounds

1.2 Compound salt Crystal form screening

1.2.1. Screening of besylate polymorphism by dissolution or suspension salification crystallization of different solvents

15mg of each example compound was weighed, added with 0.4mL of the corresponding solvent, heated to 50 ℃ until all the compounds were not dissolved, added with 1.1 equivalent of 1M benzylbenzenesulfonate solution, kept at a high temperature for a while, cooled to room temperature overnight, observed for precipitation, and if any, rapidly centrifuged, and the supernatant removed, and after the solid was vacuum-dried at 50 ℃ overnight, the XRD of the solid was measured and compared with the initial XRD, and the results are shown in Table 3-2 below.

TABLE 3-2 crystallization experiment results of benzenesulfonate solutions of examples compounds

1.2.2. Screening of p-toluenesulfonate polymorphic forms by dissolution or suspension salifying crystallization of different solvents

10mg of each of the compounds of examples was weighed, added with 0.25mL of the corresponding solvent, and then heated to 50 ℃ until all the compounds were not dissolved, 1.1 equivalents of 1M p-toluenesulfonic acid methanol solution was added, and after a period of high temperature holding, the temperature was lowered to room temperature overnight, and whether or not there was precipitation was observed, and if there was precipitation, the supernatant was removed, and after the solid was vacuum-dried overnight at 50 ℃ and no precipitation was observed, the anti-solvent MtBE was added to the precipitated solid, and XRD of the solid was measured and compared with the initial XRD, and the results are shown in tables 3 to 6 below.

Tables 3 to 6. results of experiments for crystallizing p-toluenesulfonate solution of example Compound

Serial number	Solvent(s)	After addition of acid	P-toluenesulfonate salt
				1	Methanol	Soluble clear	Form I
2	Ethanol	Slight cloudiness	Free base
				3	Acetone (II)	Soluble clear	Form I
4	Acetonitrile	Soluble clear	Form I
				5	Acetic acid isopropyl ester	Stick to the wall	Form I
6	Ethyl acetate	Stick to the wall	Form I
				7	Tetrahydrofuran (THF)	Soluble clear	Form I
8	Dibutanone	Soluble clear	Form I
				9	Methylene dichloride	Soluble clear	Form I

1.2.3. Screening hydrobromide polymorph by dissolution or suspension salifying crystallization of different solvents

Weighing 10mg of free base of the compound of the example, adding 200 μ L of different solvents respectively, heating and stirring at 50 deg.C, adding 1.0M methanol hydrobromide solution, stirring overnight, centrifuging, drying, measuring XRD, DSC and TGA, and characterization results are shown in the following tables 3-8

Tables 3-8 crystallization Experimental results for hydrobromic acid salt solutions of examples

Serial number	Solvent(s)	After addition of acid	Hydrobromide salt
					1	Methylene dichloride	Soluble clear	Form I

1.2.4. Screening hydrochloride polymorphic forms by dissolving out or suspending into salt crystals by different solvents

Weighing 10mg of free base of the compound of the example, adding 200 μ L of different solvents respectively, heating and stirring at 50 deg.C, adding 1.0M hydrochloric acid methanol solution, stirring overnight, centrifuging, drying, measuring XRD, DSC and TGA, and characterization results are shown in the following tables 3-11

TABLE 3-11 screening results for hydrochloride salts of the example compounds

Serial number	Solvent(s)	After addition of acid	Hydrochloride salt
					1	Methanol	Soluble clear	Form I
2	Ethanol	Soluble clear	Form I
				3	Ethyl acetate	Soluble clear	Form I
4	Tetrahydrofuran (THF)	Stick to the wall	Form II
				5	Methylene dichloride	Soluble clear	Form I

1.2.5. Screening oxalate polymorphism by dissolution or suspension salifying crystallization of different solvents

Weighing 12mg of free base of the compound in the example, adding DCM to prepare the concentration of 10mg/ml, 25mg/ml and 50mg/ml respectively, heating and stirring at 40 ℃, adding 1.0M oxalic acid (ethanol solution) with different equivalent ratios, stirring overnight, centrifugally drying, and then measuring XRD, DSC and TGA, wherein the characterization results are shown in the following tables 3-13

TABLE 3-13 screening results for oxalate salts of the example compounds

1.2.6. Screening mesylate polymorphism by different solvent dissolution or suspension salifying crystallization

Weighing 10mg of free alkali of the compound of the example, adding different solvents, heating and stirring at 40 ℃, adding 24uL of 1.0M methanesulfonic acid (methanol solution), stirring overnight, centrifugally drying, measuring XRD and DSC, and representing the results as shown in the following tables 3-15

TABLE 3-15 screening results for the mesylate salt of the example compound

Serial number	Solvent(s)	After addition of acid	Remarks for note	Methanesulfonic acid salt
					1	EA	Stick to the wall	Oil-like	Form I
2	DCM	Soluble clear	Adding an anti-solvent MtBE	Form I
					3	DCM	Soluble clear	Drying, adding EA, and pulping	Form I

1.2.7. Screening of esylate polymorphism by dissolution or suspension salifying crystallization of different solvents

Weighing 10mg of free base of the compound of the example, adding different solvents, heating and stirring at 40 ℃, adding 24uL of 1.0M ethanesulfonic acid (methanol solution), stirring overnight, centrifugally drying, measuring XRD, DSC and TGA, and characterizing the results as shown in the following tables 3-16

TABLE 3-16 screening results for ethanesulfonate, the compound of the examples

Serial number	Solvent(s)	After addition of acid	Remarks for note	Ethanesulfonate salt
						1	EA	Stick to the wall	Better solidification property	Form I
2	DCM	Soluble clear	Drying, adding EA, and pulping	Form I
					3	THF	Soluble clear	MtBE added as an oily solid	Form II

1.2.8. Method for screening isethionate polymorph by dissolution or suspension salifying crystallization of different solvents

Weighing 10mg of free base of the compound of the example, adding different solvents, heating and stirring at 40 ℃, adding 24uL of 1.0M hydroxyethyl sulfonic acid (methanol solution), stirring overnight, centrifugally drying, measuring XRD, DSC and TGA, and characterizing results are shown in the following tables 3-18

TABLE 3-18 screening results for isethionate salts of the example compounds

Serial number	Solvent(s)	After addition of acid	Remarks to note	Isethionic acid salt
					1	EA	Stick to the wall	Good solidifying property	Form I
2	DCM	Soluble clear	Drying, adding EA, and pulping	Form I

1.2.9. Screening sulfate polymorphic forms by dissolving out or suspending into salt crystals with different solvents

Weighing 10mg of free base of the compound of the example, adding different solvents, heating and stirring at 40 ℃, adding 24uL of 1.0M sulfuric acid (methanol solution), stirring overnight, centrifugally drying, measuring XRD, DSC and TGA, and characterizing the results as shown in the following tables 3-19

Tables 3-19 screening results for sulfates of the example compounds

Serial number	Solvent(s)	After addition of acid	Remarks for note	Sulfates of sulfuric acid
					1	EtOH	Soluble clear	Precipitation at room temperature	Form II
2	EA	Stick to the wall	Good solidifying property	Form I
					3	DCM	Soluble clear	Drying, adding EA, and pulping	Form I
4	THF	Soluble clear	Good solidifying property	Form II

1.2.10. Screening phosphate polymorphic forms by dissolution or suspension salifying crystallization of different solvents

Weighing 10mg of free alkali of the compound of the example, adding different solvents, heating and stirring at 40 ℃, adding 24uL of 1.0M phosphoric acid (ethanol solution), stirring overnight, centrifugally drying, measuring XRD and DSC, and representing the results as shown in the following tables 3-21

TABLE 3-21 screening results for phosphates of the example compounds

2. Preparation method of different crystal forms

Preparation of besylate crystal form I

Weighing 50mg of free base, adding 1.4mL of ethanol solvent, heating to 50 ℃, not completely dissolving, adding 1.1 equivalent of 1M benzenesulfonic acid methanol solution, keeping at 50 ℃ for a period of time, observing precipitation, keeping overnight, then cooling to room temperature, rapidly centrifuging, removing supernatant, and vacuum drying the solid at 50 ℃ to obtain the benzenesulfonic acid salt crystal form I which has an XRPD pattern shown in figure 1, a DSC pattern shown in figure 2 and a TGA pattern shown in figure 3 through detection and analysis.

Preparation of besylate Crystal form II

Weighing 15mg of free base, adding 0.4mL of ethanol solvent, heating to 50 ℃, not completely dissolving, adding 1.1 equivalent of 1M benzenesulfonic acid methanol solution, keeping at high temperature for a period of time, cooling to room temperature overnight, observing whether precipitation exists or not, quickly centrifuging if precipitation exists, removing supernatant, and drying the solid in vacuum at 50 ℃ to obtain the benzenesulfonic acid salt crystal form I which has an XRPD pattern shown in figure 4, a DSC pattern shown in figure 5 and a TGA pattern shown in figure 6 through detection and analysis.

Preparation of p-toluenesulfonate Crystal form I

Weighing 10mg of the compound, adding 250uL of methanol solvent, heating to 50 ℃, not completely dissolving, adding 1.1 equivalent of 1M benzenesulfonic acid methanol solution, adding acid, dissolving the solid, adding 1.2ml of methyl tert-butyl ether, separating out a large amount of white solid, filtering, and drying in vacuum to obtain the p-toluenesulfonate crystal form I. By detection analysis, it has an XRPD pattern as shown in figure 7, a DSC pattern as shown in figure 8 and a TGA pattern as shown in figure 9.

Preparation of hydrochloride crystal form I

Weighing 50mg of the compound, adding 1.4mL of ethanol solvent, heating to 50 ℃, adding 1.1 equivalent of 1M hydrochloric acid methanol solution without complete dissolution, adding acid to dissolve the solid, separating out the solid after half an hour, cooling to room temperature, centrifuging, and drying in vacuum to obtain the hydrochloride crystal form I. By detection analysis, the XRPD pattern shown in figure 10, the DSC pattern shown in figure 11 and the TGA pattern shown in figure 12 are shown below.

Preparation of hydrochloride crystal form II

Weighing 10mg of the compound, adding 400uL of tetrahydrofuran solvent, heating to 50 ℃, dissolving, adding 1.1 equivalent of 1M hydrochloric acid methanol solution, adding acid to separate out solid, keeping stirring at high temperature, cooling to room temperature, centrifuging, and drying in vacuum to obtain the hydrochloride crystal form II. It has the following XRPD pattern as shown in FIG. 13 and DSC pattern as shown in FIG. 14 by detection analysis.

Preparation of crystalline form I of hydrobromide

Weighing 15mg of the compound, adding 250uL of dichloromethane solvent, heating to 40 ℃, adding 1.1 equivalent of 1M ethanol hydrobromic acid solution into the mixture without complete dissolution, adding acid into the mixture to dissolve the solid, cooling to room temperature, separating out the solid, centrifuging and drying in vacuum to obtain the hydrobromide crystal form I. By detection analysis, it has the following XRPD pattern as shown in figure 15, DSC pattern as shown in figure 16 and TGA pattern as shown in figure 17.

3. Stability test of Crystal form

3.1 stability test

3.1.1 Experimental methods and results:

firstly, investigating the stability of the benzene sulfonate crystal form I under the conditions of high temperature of 60 ℃, high humidity of 92.5 percent RH and high temperature and high humidity of 50 ℃/75 percent RH, weighing a proper amount of the benzene sulfonate crystal form I, placing for 13 days, and adding a diluent ACN (AcN: H)₂O (1: 1) was prepared as a 0.5mg/mL solution, analyzed by HPLC, and the change of the relevant substance was calculated by the chromatographic peak area normalization method.

Physical and chemical stability results for besylate form I

② investigating the stability of p-toluenesulfonate crystal form I under the conditions of high temperature of 60 ℃, high humidity of 92.5 percent RH, high temperature and high humidity of 50 ℃/75 percent RH, weighing a proper amount of p-toluenesulfonate, placing for 13 days, adding diluent ACN (AcN: H)₂O (1: 1) was prepared as a 0.5mg/mL solution, analyzed by HPLC, and the change of the relevant substance was calculated by the chromatographic peak area normalization method.

Physical and chemical stability results for p-toluenesulfonate

Thirdly, investigating the stability of the crystal form I of the hydrobromide under the conditions of high temperature of 60 ℃, high humidity of 92.5 percent RH, high temperature of 50 ℃/75 percent RH, weighing a proper amount of the crystal form I of the hydrobromide, placing for 14 days, and adding a diluent ACN (AcN: H)₂O (1: 1) was prepared as a 0.5mg/mL solution, analyzed by HPLC, and the change of the relevant substance was calculated by the chromatographic peak area normalization method.

Physical and chemical stability results of hydrobromide crystal form I

Investigating the stability of the hydrochloride crystal form I under the conditions of high temperature of 60 ℃, high humidity of 92.5 percent RH and high temperature and humidity of 50 ℃/75 percent RH, weighing the hydrochloride crystal form I, placing for 10 days, and adding a diluent ACN H₂O (1: 1) was prepared as a 0.5mg/mL solution, analyzed by HPLC, and the change of the relevant substance was calculated by the chromatographic peak area normalization method.

Physical and chemical stability results of hydrochloride form I

Fifthly, investigating the stability of the oxalate crystal form IV under the conditions of high temperature 60 ℃, high humidity 92.5 percent RH, high temperature high humidity 50 ℃/75 percent RH, weighing the oxalate crystal form IV, placing for 14 days, adding a diluent ACN (AcN: H)₂O (1: 1) was prepared as a 0.5mg/mL solution, analyzed by HPLC, and the change of the relevant substance was calculated by the chromatographic peak area normalization method.

Oxalate form IV physicochemical stability results

Fifthly, inspecting the stability of the crystal form I of the ethanesulfonate under the conditions of high temperature of 60 ℃, high humidity of 92.5 percent RH, high temperature of 50 ℃/75 percent RH, weighing the crystal form I of the ethanesulfonate, placing for 13 days, adding a diluent ACN (AcN: H)₂O (1: 1) was prepared as a 0.5mg/mL solution, analyzed by HPLC, and the change of the relevant substance was calculated by the chromatographic peak area normalization method.

Physical and chemical stability results for the esylate form I

Sixthly, investigating the stability of the crystal form I of the sulfate under the conditions of high temperature of 60 ℃, high humidity of 92.5 percent RH and high temperature and humidity of 50 ℃/75 percent RH, weighing the crystal form I of the sulfate, placing for 13 days, and adding a diluent ACN, H₂O (1: 1) was prepared as a 0.5mg/mL solution, analyzed by HPLC, and the change of the relevant substance was calculated by the chromatographic peak area normalization method.

Physicochemical stability results of sulfate form I

4. Crystal form hygroscopicity test

4.1 hygroscopicity test

4.1.1 Experimental purposes:

and inspecting the hygroscopicity of the crystal form of the compound under different relative humidity conditions, and providing a basis for compound storage.

4.1.2 Experimental instruments and parameters:

instrument type	SMS Intrinsic
		Temperature of experiment	25℃
Drying time
		0％RH 120min
Equilibrium dm/dt			0.02%/min (minimum 10min, maximum 180min)
	RH (%) measurement step size	10％
Measuring gradients			0-95-0％
	Number of cycles	2

4.1.3 determination of hygroscopicity:

the hygroscopicity of a drug refers to the property of the drug in its ability or degree to absorb moisture at a certain temperature and humidity. The experiment used a dynamic moisture sorption instrument (DVS) to characterize the ability of a drug to absorb moisture under different humidity conditions.

4.1.4 results of the experiment:

the DVS hygroscopicity profile 43 of besylate salt form i shows that the hygroscopicity is only 0.65% at 80% RH, and besylate salt form i is defined as slightly hygroscopic according to pharmacopoeia specifications.

② DVS hygroscopicity profile 44 of p-toluenesulfonate form I shows that hygroscopicity is 1.21% under 80% RH conditions, according to pharmacopoeia specifications, p-toluenesulfonate is defined as slightly hygroscopic.

③ DVS hygroscopicity profile of the hydrobromide form I as shown in 45, hygroscopicity was 1.1% at 80% RH, according to pharmacopoeia specifications, hydrobromide was defined to be slightly hygroscopic.

The DVS hygroscopicity profile 46 of the hydrochloride form i shows that the hygroscopicity of the hydrochloride form i under the condition of 80% RH is 1.47% respectively, and the hydrochloride form i is defined as slightly hygroscopic according to the pharmacopoeia specifications.

Fifth, DVS hygroscopicity profile 47 of oxalate form IV shows that the hygroscopicity of oxalate form IV is 0.69% under 80% RH, respectively, and oxalate form IV is defined as slightly hygroscopic according to pharmacopoeia regulations.

5. Solubility experiments in different media

5.1 solubility experiments of crystalline forms of the Compound

5.1.1 Experimental purposes:

the solubility of the crystal form of the compound in different organic solvents is compared, so that a basis is provided for evaluation of druggability.

5.1.2 Experimental methods and results:

weighing 2.0mg of benzene sulfonate crystal form I into a 2mL centrifuge tube, then respectively adding 1mL of different pH buffer solutions, artificial simulated gastric fluid (FaSSGF), fasting artificial simulated intestinal fluid (FaSSIF), non-fasting artificial simulated intestinal fluid (FeSSIF) and pure water, placing the mixture on a micro mixing machine for shaking overnight at 37 ℃, filtering a sample solution by using a 0.45 mu m mixed water fiber filter membrane after 24 hours, taking a subsequent filtrate, and testing the content of the subsequent filtrate by using HPLC (high performance liquid chromatography), wherein the solubility of the benzene sulfonate crystal form I in different buffer solution media is shown in the table below, and the results of the solubility results of the benzene sulfonate crystal form I in different pH buffer solutions are shown in the table below

Compound (I)	Besylate 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
		H₂O	0.81

② about 2-3mg of p-toluenesulfonate crystal form I is weighed to be suspended into 1mL of artificial simulated gastric fluid (FaSSGF), fasted artificial simulated intestinal fluid (FaSSIF), non-fasted artificial simulated intestinal fluid (FeSSIF) and pure water for 24 hours, and subsequent filtrate is taken and tested by HPLC, the thermodynamic solubility of the compound at 37 ℃ is tested by external standard method, and simultaneously the corresponding pH value is tested.

Solubility results for p-toluenesulfonate in buffers of different pH

Compound (I)	P-toluenesulfonate salt
		Buffer solution	Solubility (mg/mL)
H₂O	1.08
		FaSSGF	>2.00
FaSSIF	0.03
		FeSSIF	0.76

③ weighing about 2-3mg of hydrochloride crystal form I to suspend in 1mL of artificial simulated gastric fluid (FaSSGF), fasting artificial simulated intestinal fluid (FaSSIF), non-fasting artificial simulated intestinal fluid (FeSSIF) and pure water for 24 hours, taking the subsequent filtrate, detecting by HPLC, determining the thermodynamic solubility of the compound at 37 ℃ by an external standard method, and determining the corresponding pH value at the same time.

Solubility results of hydrochloride salts in different pH buffers

Compound (I)	Hydrochloride salt
		Buffer solution	Solubility (mg/mL)
H₂O	1.52
		FaSSGF	>2.00
FaSSIF	<0.01
		FeSSIF	0.76

。

Claims

1. 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] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile.

2. An acid salt according to claim 1 wherein the acid in the acid salt is selected from the group consisting of benzenesulfonic acid, hydrochloric acid, p-toluenesulfonic acid, oxalic acid, phosphoric acid, hydrobromic acid; benzenesulfonic acid is preferred.

3. The acid salt according to any one of claims 1 to 2, wherein the number of acids is 0.2 to 3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 0.5, 1,2 or 3, and still more preferably 1.

4. An acid salt according to any one of claims 1 to 3, wherein the acid salt is a hydrate or an anhydrate, and when the acid salt is a hydrate, the number of water is 0.2 to 3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 0.5, 1,2 or 3.

5. The acid salt according to any of claims 1 to 4, characterized in that the acid salt 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] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile is in crystalline form, preferably in the form of a mesylate, sulfate, hydrobromide, phosphate, besylate, oxalate, isethionate, maleate, fumarate, adipate, p-toluenesulfonate, citrate crystal form, malonate crystal form or L-malate crystal form, more preferably benzenesulfonate crystal form.

6. The acid salt according to claim 5,

an X-ray powder diffraction pattern of the benzenesulfonate salt form I has a characteristic peak at 17.7 + -0.2 degrees in 2 theta, or has a characteristic peak at 8.4 + -0.2 degrees in 2 theta, or has a characteristic peak at 24.8 + -0.2 degrees in 2 theta, or has a characteristic peak at 21.5 + -0.2 degrees in 2 theta, or has a characteristic peak at 17.1 + -0.2 degrees in 2 theta, or has a characteristic peak at 15.2 + -0.2 degrees in 2 theta, or has a characteristic peak at 23.4 + -0.2 degrees in 2 theta, or has a characteristic peak at 19.3 + -0.2 degrees in 2 theta, or has a characteristic peak at 28.2 + -0.2 degrees in 2 theta, or has a characteristic peak at 18.9 + -0.2 degrees in 2 theta, or has a characteristic peak at 11.8 + -0.2 degrees in 2 theta, or has a characteristic peak at 18.6 + -0.2 degrees in 2 theta; preferably any 2 to 12, or 5 to 8, or 6 to 8, more preferably any 2,3, 6, 8, 10 or 12 of the above diffraction peaks;

an X-ray powder diffraction pattern of the benzenesulfonate salt form II has a characteristic peak at 17.7 + -0.2 DEG in 2 theta, or has a characteristic peak at 15.2 + -0.2 DEG in 2 theta, or has a characteristic peak at 21.5 + -0.2 DEG in 2 theta, or has a characteristic peak at 24.8 + -0.2 DEG in 2 theta, or has a characteristic peak at 8.5 + -0.2 DEG in 2 theta, or has a characteristic peak at 19.3 + -0.2 DEG in 2 theta, or has a characteristic peak at 17.1 + -0.2 DEG in 2 theta, or has a characteristic peak at 18.6 + -0.2 DEG in 2 theta, or has a characteristic peak at 23.4 + -0.2 DEG in 2 theta, or has a characteristic peak at 7.7 + -0.2 DEG in 2 theta, or has a characteristic peak at 6.5 + -0.2 DEG in 2 theta, or has a characteristic peak at 13.9 + -0.2 DEG in 2 theta; preferably any 2 to 12, or 5 to 8, or 6 to 8, more preferably any 2,3, 6, 8, 10 or 12 of the above diffraction peaks;

an X-ray powder diffraction pattern of the p-toluenesulfonic acid salt form I has a characteristic peak at 18.4 +/-0.2 degrees of 2 theta, or has a characteristic peak at 15.1 +/-0.2 degrees of 2 theta, or has a characteristic peak at 8.1 +/-0.2 degrees of 2 theta, or has a characteristic peak at 16.9 +/-0.2 degrees of 2 theta, or has a characteristic peak at 7.6 +/-0.2 degrees of 2 theta, or has a characteristic peak at 17.4 +/-0.2 degrees of 2 theta, or has a characteristic peak at 20.9 +/-0.2 degrees of 2 theta, or has a characteristic peak at 17.2 +/-0.2 degrees of 2 theta, or has a characteristic peak at 5.0 +/-0.2 degrees of 2 theta, or has a characteristic peak at 19.0 +/-0.2 degrees of 2 theta, or has a characteristic peak at 22.8 +/-0.2 degrees of 2 theta, or has a characteristic peak at 24.0 +/-0.2 degrees of 2 theta, or has a characteristic peak at 2 degrees of 2 theta, or has a characteristic peak at 13.6 +/-0.2 degrees of 2 theta; preferably any 2 to 12, or 5 to 8, or 6 to 8, more preferably any 2,3, 6, 8, 10 or 12 of the above diffraction peaks;

an X-ray powder diffraction pattern of the hydrochloride form I has a characteristic peak at 10.0 +/-0.2 degrees of 2 theta, or has a characteristic peak at 6.0 +/-0.2 degrees of 2 theta, or has a characteristic peak at 15.6 +/-0.2 degrees of 2 theta, or has a characteristic peak at 16.8 +/-0.2 degrees of 2 theta, or has a characteristic peak at 24.6 +/-0.2 degrees of 2 theta, or has a characteristic peak at 23.0 +/-0.2 degrees of 2 theta, or has a characteristic peak at 20.8 +/-0.2 degrees of 2 theta, or has a characteristic peak at 26.7 +/-0.2 degrees of 2 theta, or has a characteristic peak at 17.5 +/-0.2 degrees of 2 theta, or has a characteristic peak at 21.6 +/-0.2 degrees of 2 theta, or has a characteristic peak at 14.9 +/-0.2 degrees of 2 theta, or has a characteristic peak at 30.7 +/-0.2 degrees of 2 theta; preferably any 2 to 12, or 5 to 8, or 6 to 8, more preferably any 2,3, 6, 8, 10 or 12 of the above diffraction peaks;

an X-ray powder diffraction pattern of the hydrochloride form II has a characteristic peak at 10.0 +/-0.2 degrees of 2 theta, or a characteristic peak at 6.0 +/-0.2 degrees of 2 theta, or a characteristic peak at 6.6 +/-0.2 degrees of 2 theta, or a characteristic peak at 15.6 +/-0.2 degrees of 2 theta, or a characteristic peak at 24.7 +/-0.2 degrees of 2 theta, or a characteristic peak at 23.1 +/-0.2 degrees of 2 theta, or a characteristic peak at 16.8 +/-0.2 degrees of 2 theta, or a characteristic peak at 17.5 +/-0.2 degrees of 2 theta, or a characteristic peak at 20.8 +/-0.2 degrees of 2 theta, or a characteristic peak at 23.9 +/-0.2 degrees of 2 theta, or a characteristic peak at 22.4 +/-0.2 degrees of 2 theta, or a characteristic peak at 26.7 +/-0.2 degrees of 2 theta; preferably any 2 to 12, or 5 to 8, or 6 to 8, more preferably any 2,3, 6, 8, 10 or 12 of the above diffraction peaks;

an X-ray powder diffraction pattern of the hydrobromide crystal form I has a characteristic peak at 9.9 +/-0.2 degrees of 2 theta, or has a characteristic peak at 5.9 +/-0.2 degrees of 2 theta, or has a characteristic peak at 22.8 +/-0.2 degrees of 2 theta, or has a characteristic peak at 20.6 +/-0.2 degrees of 2 theta, or has a characteristic peak at 24.4 +/-0.2 degrees of 2 theta, or has a characteristic peak at 16.7 +/-0.2 degrees of 2 theta, or has a characteristic peak at 21.4 +/-0.2 degrees of 2 theta, or has a characteristic peak at 26.6 +/-0.2 degrees of 2 theta, or has a characteristic peak at 17.4 +/-0.2 degrees of 2 theta, or has a characteristic peak at 24.9 +/-0.2 degrees of 2 theta, or has a characteristic peak at 23.1 +/-0.2 degrees of 2 theta, or has a characteristic peak at 30.6 +/-0.2 degrees of 2 theta; preferably any 2 to 12, or 5 to 8, or 6 to 8, more preferably any 2,3, 6, 8, 10 or 12 of the above diffraction peaks;

an X-ray powder diffraction pattern of oxalate form I has a characteristic peak at 9.5 +/-0.2 degrees of 2 theta, or 19.3 +/-0.2 degrees of 2 theta, or 10.7 +/-0.2 degrees of 2 theta, or 4.7 +/-0.2 degrees of 2 theta, or 6.0 +/-0.2 degrees of 2 theta, or 16.5 +/-0.2 degrees of 2 theta, or 25.0 +/-0.2 degrees of 2 theta, or 27.1 +/-0.2 degrees of 2 theta, or 15.3 +/-0.2 degrees of 2 theta, or 14.5 +/-0.2 degrees of 2 theta, or 18.6 +/-0.2 degrees of 2 theta, or 20.5 +/-0.2 degrees of 2 theta; preferably any 2 to 12, or 5 to 8, or 6 to 8, more preferably any 2,3, 6, 8, 10 or 12 of the above diffraction peaks;

an X-ray powder diffraction pattern of oxalate form II has a characteristic peak at 5.8 +/-0.2 degrees of 2 theta, or a characteristic peak at 4.8 +/-0.2 degrees of 2 theta, or a characteristic peak at 15.7 +/-0.2 degrees of 2 theta, or a characteristic peak at 17.0 +/-0.2 degrees of 2 theta, or a characteristic peak at 9.4 +/-0.2 degrees of 2 theta, or a characteristic peak at 19.2 +/-0.2 degrees of 2 theta, or a characteristic peak at 17.7 +/-0.2 degrees of 2 theta, or a characteristic peak at 16.6 +/-0.2 degrees of 2 theta, or a characteristic peak at 26.1 +/-0.2 degrees of 2 theta, or a characteristic peak at 11.8 +/-0.2 degrees of 2 theta, or a characteristic peak at 18.6 +/-0.2 degrees of 2 theta, or a characteristic peak at 12.5 +/-0.2 degrees of 2 theta; preferably any 2 to 12, or 5 to 8, or 6 to 8, more preferably any 2,3, 6, 8, 10 or 12 of the above diffraction peaks;

an X-ray powder diffraction pattern of oxalate form III has a characteristic peak at 10.4 +/-0.2 degrees of 2 theta, or has a characteristic peak at 5.1 +/-0.2 degrees of 2 theta, or has a characteristic peak at 4.8 +/-0.2 degrees of 2 theta, or has a characteristic peak at 15.8 +/-0.2 degrees of 2 theta, or has a characteristic peak at 14.3 +/-0.2 degrees of 2 theta, or has a characteristic peak at 12.2 +/-0.2 degrees of 2 theta, or has a characteristic peak at 17.8 +/-0.2 degrees of 2 theta, or has a characteristic peak at 5.8 +/-0.2 degrees of 2 theta, or has a characteristic peak at 18.9 +/-0.2 degrees of 2 theta, or has a characteristic peak at 17.0 +/-0.2 degrees of 2 theta, or has a characteristic peak at 23.8 +/-0.2 degrees of 2 theta; preferably any 2 to 12, or 5 to 8, or 6 to 8, more preferably any 2,3, 6, 8, 10 or 12 of the above diffraction peaks;

an X-ray powder diffraction pattern of oxalate form IV has a characteristic peak at 20.5 ± 0.2 ° 2 θ, or a characteristic peak at 18.5 ± 0.2 ° 2 θ, or a characteristic peak at 17.9 ± 0.2 ° 2 θ, or a characteristic peak at 4.8 ± 0.2 ° 2 θ, or a characteristic peak at 16.5 ± 0.2 ° 2 θ, or a characteristic peak at 15.8 ± 0.2 ° 2 θ, or a characteristic peak at 11.5 ± 0.2 ° 2 θ, or a characteristic peak at 12.3 ± 0.2 ° 2 θ, or a characteristic peak at 24.0 ± 0.2 ° 2 θ, or a characteristic peak at 16.2 ± 0.2 ° 2 θ, or a characteristic peak at 23.3 ± 0.2 ° 2 θ, or a characteristic peak at 19.6 ± 0.2 ° 2 θ; preferably any 2 to 12, or 5 to 8, or 6 to 8, more preferably any 2,3, 6, 8, 10 or 12 of the above diffraction peaks;

an X-ray powder diffraction pattern of mesylate crystal form I has a characteristic peak at 10.3 +/-0.2 degrees of 2 theta, or has a characteristic peak at 5.1 +/-0.2 degrees of 2 theta, or has a characteristic peak at 15.6 +/-0.2 degrees of 2 theta, or has a characteristic peak at 25.2 +/-0.2 degrees of 2 theta, or has a characteristic peak at 18.4 +/-0.2 degrees of 2 theta; preferably any 2 to 12, or 5 to 8, or 6 to 8, more preferably any 2,3, 6, 8, 10 or 12 of the above diffraction peaks;

an X-ray powder diffraction pattern of the ethanesulfonate crystal form I has a characteristic peak at 10.2 +/-0.2 degrees of 2 theta, or has a characteristic peak at 5.0 +/-0.2 degrees of 2 theta, or has a characteristic peak at 15.4 +/-0.2 degrees of 2 theta, or has a characteristic peak at 18.9 +/-0.2 degrees of 2 theta, or has a characteristic peak at 24.2 +/-0.2 degrees of 2 theta, or has a characteristic peak at 21.1 +/-0.2 degrees of 2 theta; preferably from 2 to 12, or from 5 to 8, or from 6 to 8, more preferably from 2,3, 6, 8, 10 or 12 of any of the above diffraction peaks;

an X-ray powder diffraction pattern of the ethanesulfonate crystal form II has a characteristic peak at 10.2 +/-0.2 degrees of 2 theta, or has a characteristic peak at 5.0 +/-0.2 degrees of 2 theta, or has a characteristic peak at 6.0 +/-0.2 degrees of 2 theta, or has a characteristic peak at 15.4 +/-0.2 degrees of 2 theta, or has a characteristic peak at 5.4 +/-0.2 degrees of 2 theta, or has a characteristic peak at 7.3 +/-0.2 degrees of 2 theta; preferably any 2 to 12, or 5 to 8, or 6 to 8, more preferably any 2,3, 6, 8, 10 or 12 of the above diffraction peaks;

an X-ray powder diffraction pattern of the isethionate salt crystal form I has a characteristic peak at 10.5 +/-0.2 degrees of 2 theta, or has a characteristic peak at 5.2 +/-0.2 degrees of 2 theta, or has a characteristic peak at 18.7 +/-0.2 degrees of 2 theta, or has a characteristic peak at 15.9 +/-0.2 degrees of 2 theta, or has a characteristic peak at 23.0 +/-0.2 degrees of 2 theta; preferably any 2 to 12, or 5 to 8, or 6 to 8, more preferably any 2,3, 6, 8, 10 or 12 of the above diffraction peaks;

an X-ray powder diffraction pattern of the isethionate salt form II has a characteristic peak at 11.9 + -0.2 ° 2 θ, or 18.4 + -0.2 ° 2 θ, or 4.8 + -0.2 ° 2 θ, or 23.4 + -0.2 ° 2 θ, or 16.7 + -0.2 ° 2 θ, or 17.8 + -0.2 ° 2 θ, or 12.8 + -0.2 ° 2 θ, or 23.8 + -0.2 ° 2 θ, or 21.8 + -0.2 ° 2 θ, or 19.0 + -0.2 ° 2 θ, or 25.4 + -0.2 ° 2 θ, or 19.8 + -0.2 ° 2 θ; preferably any 2 to 12, or 5 to 8, or 6 to 8, more preferably any 2,3, 6, 8, 10 or 12 of the above diffraction peaks;

an X-ray powder diffraction pattern of the sulfate crystal form I has a characteristic peak at 10.3 +/-0.2 degrees of 2 theta, or has a characteristic peak at 5.1 +/-0.2 degrees of 2 theta, or has a characteristic peak at 15.6 +/-0.2 degrees of 2 theta, or has a characteristic peak at 14.5 +/-0.2 degrees of 2 theta, or has a characteristic peak at 20.2 +/-0.2 degrees of 2 theta, or has a characteristic peak at 19.0 +/-0.2 degrees of 2 theta, or has a characteristic peak at 25.6 +/-0.2 degrees of 2 theta, or has a characteristic peak at 22.1 +/-0.2 degrees of 2 theta, or has a characteristic peak at 23.0 +/-0.2 degrees of 2 theta, or has a characteristic peak at 20.8 +/-0.2 degrees of 2 theta, or has a characteristic peak at 19.2 +/-0.2 degrees of 2 theta, or has a characteristic peak at 24.1 +/-0.2 degrees of 2 theta; preferably any 2 to 12, or 5 to 8, or 6 to 8, more preferably any 2,3, 6, 8, 10 or 12 of the above diffraction peaks;

an X-ray powder diffraction pattern of the sulfate crystal form II has a characteristic peak at 16.1 +/-0.2 degrees of 2 theta, or has a characteristic peak at 5.9 +/-0.2 degrees of 2 theta, or has a characteristic peak at 6.6 +/-0.2 degrees of 2 theta, or has a characteristic peak at 22.0 +/-0.2 degrees of 2 theta, or has a characteristic peak at 21.0 +/-0.2 degrees of 2 theta, or has a characteristic peak at 20.1 +/-0.2 degrees of 2 theta, or has a characteristic peak at 17.0 +/-0.2 degrees of 2 theta, or has a characteristic peak at 25.2 +/-0.2 degrees of 2 theta, or has a characteristic peak at 20.7 +/-0.2 degrees of 2 theta, or has a characteristic peak at 23.1 +/-0.2 degrees of 2 theta; preferably any 2 to 12, or 5 to 8, or 6 to 8, more preferably any 2,3, 6, 8, 10 or 12 of the above diffraction peaks;

an X-ray powder diffraction pattern of the phosphate crystal form I has a characteristic peak at 5.6 +/-0.2 degrees of 2 theta, or 11.5 +/-0.2 degrees of 2 theta, or 20.3 +/-0.2 degrees of 2 theta, or 15.9 +/-0.2 degrees of 2 theta, or 17.2 +/-0.2 degrees of 2 theta, or 16.4 +/-0.2 degrees of 2 theta, or 21.9 +/-0.2 degrees of 2 theta, or 10.2 +/-0.2 degrees of 2 theta; preferably any 2 to 12, or 5 to 8, or 6 to 8, more preferably any 2,3, 6, 8, 10 or 12 of the above diffraction peaks;

7. The acid salt according to claim 5,

an X-ray powder diffraction pattern of besylate form I comprises two or three diffraction peaks, at 2 Θ, of 17.7 ± 0.2 °, 8.4 ± 0.2 °, and 24.8 ± 0.2 °, optionally further comprising one or more diffraction peaks, at 2 Θ, of 21.5 ± 0.2 °, 17.1 ± 0.2 °, 19.3 ± 0.2 °, 15.2 ± 0.2 °, and 23.4 ± 0.2 °; preferably 2,3, 4 or 5 thereof;

an X-ray powder diffraction pattern of besylate salt form II comprising two or three diffraction peaks, at 2 Θ, of 17.7 ± 0.2 °, 15.2 ± 0.2 °, and 21.5 ± 0.2 °, optionally further comprising one or more diffraction peaks, at 2 Θ, of 24.8 ± 0.2 °, 8.5 ± 0.2 °, 19.3 ± 0.2 °, 17.1 ± 0.2 °, and 18.6 ± 0.2 °; preferably 2,3, 4 or 5 thereof;

an X-ray powder diffraction pattern of crystalline form I of the tosylate salt comprises two or three diffraction peaks, at 2 Θ of 18.4 ± 0.2 °, 15.1 ± 0.2 ° and 8.1 ± 0.2 °, optionally further comprising one or more diffraction peaks, at 2 Θ of 16.9 ± 0.2 °, 7.6 ± 0.2 °, 17.4 ± 0.2 °, 20.9 ± 0.2 ° and 17.2 ± 0.2 °; preferably 2,3, 4 or 5 thereof;

an X-ray powder diffraction pattern of hydrochloride form I comprising two or three diffraction peaks, 2 Θ, at 10.0 ± 0.2 °, 6.0 ± 0.2 ° and 15.6 ± 0.2 °, optionally further comprising one or more diffraction peaks, 2 Θ, at 16.8 ± 0.2 °, 24.6 ± 0.2 °, 23.0 ± 0.2 °, 20.8 ± 0.2 ° and 26.7 ± 0.2 °; preferably 2,3, 4 or 5 thereof;

an X-ray powder diffraction pattern of hydrochloride form II comprising two or three diffraction peaks, in terms of 2 Θ, of 10.0 ± 0.2 °, 6.0 ± 0.2 ° and 6.6 ± 0.2 °, optionally further comprising one or more diffraction peaks, in terms of 2 Θ, of 15.6 ± 0.2 °, 24.7 ± 0.2 °, 23.1 ± 0.2 °, 16.8 ± 0.2 ° and 17.5 ± 0.2 °; preferably 2,3, 4 or 5 thereof;

an X-ray powder diffraction pattern of hydrobromide form I comprising two or three diffraction peaks, 2 Θ, at 9.9 ± 0.2 °, 5.9 ± 0.2 ° and 22.8 ± 0.2 °, optionally further comprising one or more diffraction peaks, 2 Θ, at 20.6 ± 0.2 °, 24.4 ± 0.2 °, 16.7 ± 0.2 °, 21.4 ± 0.2 ° and 26.6 ± 0.2 °; preferably 2,3, 4 or 5 thereof;

an X-ray powder diffraction pattern of oxalate form I comprising two or three diffraction peaks, in terms of 2 Θ, of 9.5 ± 0.2 °, 19.3 ± 0.2 ° and 10.7 ± 0.2 °, optionally further comprising one or more diffraction peaks, in terms of 2 Θ, of 4.7 ± 0.2 °, 6.0 ± 0.2 °, 16.5 ± 0.2 °, 25.0 ± 0.2 ° and 27.1 ± 0.2 °; preferably 2,3, 4 or 5 thereof;

an X-ray powder diffraction pattern of oxalate form II comprising two or three diffraction peaks, in terms of 2 Θ, at 5.8 ± 0.2 °, 4.8 ± 0.2 °, and 15.7 ± 0.2 °, optionally further comprising one or more diffraction peaks, in terms of 2 Θ, at 17.0 ± 0.2 °, 9.4 ± 0.2 °, 19.2 ± 0.2 °, 17.7 ± 0.2 °, and 16.6 ± 0.2 °; preferably 2,3, 4 or 5 thereof;

an X-ray powder diffraction pattern of oxalate form III comprising two or three diffraction peaks, in terms of 2 Θ, at 10.4 ± 0.2 °, 5.1 ± 0.2 °, and 4.8 ± 0.2 °, optionally further comprising one or more diffraction peaks, in terms of 2 Θ, at 15.8 ± 0.2 °, 14.3 ± 0.2 °, 12.2 ± 0.2 °, 17.8 ± 0.2 °, and 5.8 ± 0.2 °; preferably 2,3, 4 or 5 thereof;

an X-ray powder diffraction pattern of oxalate form IV comprising two or three diffraction peaks, in terms of 2 Θ, at 20.5 ± 0.2 ° 18.5 ± 0.2 ° and 17.9 ± 0.2 °, optionally further comprising one or more diffraction peaks, in terms of 2 Θ, at 4.8 ± 0.2 °, 16.5 ± 0.2 °, 15.8 ± 0.2 °, 11.5 ± 0.2 ° and 12.3 ± 0.2 °; preferably 2,3, 4 or 5 thereof;

an X-ray powder diffraction pattern of mesylate form I comprises two or three diffraction peaks, at 2 Θ of 10.3 ± 0.2 °, 5.1 ± 0.2 °, and 15.6 ± 0.2 °, optionally further comprising one or more diffraction peaks, at 2 Θ of 25.2 ± 0.2 °, 18.4 ± 0.2 °; preferably 2,3, 4 or 5 thereof;

an X-ray powder diffraction pattern of esylate salt form I comprising two or three diffraction peaks, 2 Θ, at 10.2 ± 0.2 °, 5.0 ± 0.2 °, and 15.4 ± 0.2 °, optionally further comprising one or more diffraction peaks, 2 Θ, at 24.2 ± 0.2 °, 18.9 ± 0.2 °, and 21.1 ± 0.2 °; preferably 2,3, 4 or 5 thereof;

an X-ray powder diffraction pattern of esylate salt form II comprising two or three diffraction peaks, in terms of 2 Θ, of 10.2 ± 0.2 °, 5.0 ± 0.2 °, and 6.0 ± 0.2 °, optionally further comprising one or more diffraction peaks, in terms of 2 Θ, of 15.4 ± 0.2 ° and 5.4 ± 0.2 °; preferably 2,3, 4 or 5 thereof;

an X-ray powder diffraction pattern of isethionate salt form I comprising two or three diffraction peaks, in terms of 2 Θ, at 10.5 ± 0.2 °, 5.2 ± 0.2 °, and 18.7 ± 0.2 °, optionally further comprising one or more diffraction peaks, in terms of 2 Θ, at 15.9 ± 0.2 ° and 23.0 ± 0.2 °; preferably 2,3, 4 or 5 thereof;

an X-ray powder diffraction pattern of isethionate salt form II comprising two or three diffraction peaks, in terms of 2 Θ, at 11.9 ± 0.2 °, 18.4 ± 0.2 °, and 4.8 ± 0.2 °, optionally further comprising one or more diffraction peaks, in terms of 2 Θ, at 23.4 ± 0.2 °, 16.7 ± 0.2 °, 17.8 ± 0.2 °, 12.8 ± 0.2 °, and 23.8 ± 0.2 °; preferably 2,3, 4 or 5 thereof;

an X-ray powder diffraction pattern of sulfate form I comprises two or three diffraction peaks, in terms of 2 Θ, of 10.3 ± 0.2 °, 5.1 ± 0.2 °, and 15.6 ± 0.2 °, optionally further comprising one or more diffraction peaks, in terms of 2 Θ, of 14.5 ± 0.2 °, 20.2 ± 0.2 °, 19.0 ± 0.2 °, 25.6 ± 0.2 °, and 22.1 ± 0.2 °; preferably 2,3, 4 or 5 thereof;

an X-ray powder diffraction pattern of sulfate form II comprises two or three diffraction peaks, at 2 Θ of 16.1 ± 0.2 °, 5.9 ± 0.2 °, and 6.6 ± 0.2 °, optionally further comprising one or more diffraction peaks, at 2 Θ of 22.0 ± 0.2 °, 21.0 ± 0.2 °, 20.1 ± 0.2 °, 17.0 ± 0.2 °, and 25.2 ± 0.2 °; preferably 2,3, 4 or 5 thereof;

an X-ray powder diffraction pattern of phosphate form I comprises two or three diffraction peaks, in terms of 2 Θ, of 5.6 ± 0.2 °, 11.5 ± 0.2 °, and 20.3 ± 0.2 °, optionally further comprising one or more diffraction peaks, in terms of 2 Θ, of 15.9 ± 0.2 °, 17.2 ± 0.2 °, 16.4 ± 0.2 °, and 21.9 ± 0.2 °; preferably 2,3, 4 or 5 thereof;

8. The acid salt according to claim 5,

the X-ray powder diffraction pattern of the benzene sulfonate crystal form I comprises one or more diffraction peaks with the 2 theta of 17.7 +/-0.2 degrees, 8.4 +/-0.2 degrees, 24.8 +/-0.2 degrees, 21.5 +/-0.2 degrees, 17.1 +/-0.2 degrees, 15.2 +/-0.2 degrees, 23.4 +/-0.2 degrees, 19.3 +/-0.2 degrees, 28.2 +/-0.2 degrees, 18.9 +/-0.2 degrees, 11.8 +/-0.2 degrees and 18.6 +/-0.2 degrees; preferably, the compound comprises diffraction peaks at 4, 6, 8 and 10;

the X-ray powder diffraction pattern of the benzene sulfonate crystal form II comprises one or more diffraction peaks with the 2 theta of 17.7 +/-0.2 degrees, 15.2 +/-0.2 degrees, 21.5 +/-0.2 degrees, 24.8 +/-0.2 degrees, 8.5 +/-0.2 degrees, 19.3 +/-0.2 degrees, 17.1 +/-0.2 degrees, 18.6 +/-0.2 degrees, 23.4 +/-0.2 degrees, 7.7 +/-0.2 degrees, 6.5 +/-0.2 degrees and 13.9 +/-0.2 degrees; preferably, the compound comprises diffraction peaks at 4, 6, 8 and 10;

an X-ray powder diffraction pattern of the p-toluenesulfonate crystal form I comprises one or more diffraction peaks with 2 theta of 18.4 +/-0.2 degrees, 15.1 +/-0.2 degrees, 8.1 +/-0.2 degrees, 16.9 +/-0.2 degrees, 7.6 +/-0.2 degrees, 17.4 +/-0.2 degrees, 20.9 +/-0.2 degrees, 17.2 +/-0.2 degrees, 5.0 +/-0.2 degrees, 19.0 +/-0.2 degrees, 22.8 +/-0.2 degrees, 24.0 +/-0.2 degrees and 13.6 +/-0.2 degrees; preferably, the compound comprises diffraction peaks at 4, 6, 8 and 10;

the X-ray powder diffraction pattern of the hydrochloride crystal form I comprises one or more diffraction peaks with 2 theta of 10.0 +/-0.2 degrees, 6.0 +/-0.2 degrees, 15.6 +/-0.2 degrees, 16.8 +/-0.2 degrees, 24.6 +/-0.2 degrees, 23.0 +/-0.2 degrees, 20.8 +/-0.2 degrees, 26.7 +/-0.2 degrees, 17.5 +/-0.2 degrees, 21.6 +/-0.2 degrees, 14.9 +/-0.2 degrees and 30.7 +/-0.2 degrees; preferably, the compound comprises diffraction peaks at 4, 6, 8 and 10;

the X-ray powder diffraction pattern of the hydrochloride crystal form II comprises one or more diffraction peaks with 2 theta of 10.0 +/-0.2 degrees, 6.0 +/-0.2 degrees, 6.6 +/-0.2 degrees, 15.6 +/-0.2 degrees, 24.7 +/-0.2 degrees, 23.1 +/-0.2 degrees, 16.8 +/-0.2 degrees, 17.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 23.9 +/-0.2 degrees, 22.4 +/-0.2 degrees and 26.7 +/-0.2 degrees; preferably, the compound comprises diffraction peaks at 4, 6, 8 and 10;

an X-ray powder diffraction pattern of the hydrobromide crystal form I comprises one or more diffraction peaks with 2 theta of 9.9 +/-0.2 degrees, 5.9 +/-0.2 degrees, 22.8 +/-0.2 degrees, 20.6 +/-0.2 degrees, 24.4 +/-0.2 degrees, 16.7 +/-0.2 degrees, 21.4 +/-0.2 degrees, 26.6 +/-0.2 degrees, 17.4 +/-0.2 degrees, 24.9 +/-0.2 degrees, 23.1 +/-0.2 degrees and 30.6 +/-0.2 degrees; preferably, the compound comprises diffraction peaks at 4, 6, 8 and 10;

the X-ray powder diffraction pattern of the oxalate crystal form I comprises one or more diffraction peaks with 2 theta of 9.5 +/-0.2 degrees, 19.3 +/-0.2 degrees, 10.7 +/-0.2 degrees, 4.7 +/-0.2 degrees, 6.0 +/-0.2 degrees, 16.5 +/-0.2 degrees, 25.0 +/-0.2 degrees, 27.1 +/-0.2 degrees, 15.3 +/-0.2 degrees, 14.5 +/-0.2 degrees, 18.6 +/-0.2 degrees and 20.5 +/-0.2 degrees; preferably, the compound comprises diffraction peaks at 4, 6, 8 and 10;

the X-ray powder diffraction pattern of the oxalate crystal form II comprises one or more diffraction peaks with 2 theta of 5.8 +/-0.2 degrees, 4.8 +/-0.2 degrees, 15.7 +/-0.2 degrees, 17.0 +/-0.2 degrees, 9.4 +/-0.2 degrees, 19.2 +/-0.2 degrees, 17.7 +/-0.2 degrees, 16.6 +/-0.2 degrees, 26.1 +/-0.2 degrees, 11.8 +/-0.2 degrees, 18.6 +/-0.2 degrees and 12.5 +/-0.2 degrees; preferably, the compound comprises diffraction peaks at 4, 6, 8 and 10;

the X-ray powder diffraction pattern of oxalate crystal form III comprises one or more diffraction peaks with 2 theta of 10.4 +/-0.2 degrees, 5.1 +/-0.2 degrees, 4.8 +/-0.2 degrees, 15.8 +/-0.2 degrees, 14.3 +/-0.2 degrees, 12.2 +/-0.2 degrees, 17.8 +/-0.2 degrees, 5.8 +/-0.2 degrees, 18.9 +/-0.2 degrees, 17.0 +/-0.2 degrees and 23.8 +/-0.2 degrees; preferably, the compound comprises diffraction peaks at 4, 6, 8 and 10;

the X-ray powder diffraction pattern of the oxalate crystal form IV comprises one or more diffraction peaks with the 2 theta of 20.5 +/-0.2 degrees, 18.5 +/-0.2 degrees, 17.9 +/-0.2 degrees, 4.8 +/-0.2 degrees, 16.5 +/-0.2 degrees, 15.8 +/-0.2 degrees, 11.5 +/-0.2 degrees, 12.3 +/-0.2 degrees, 24.0 +/-0.2 degrees, 16.2 +/-0.2 degrees, 23.3 +/-0.2 degrees and 19.6 +/-0.2 degrees; preferably, the compound comprises diffraction peaks at 4, 6, 8 and 10;

the X-ray powder diffraction pattern of the mesylate crystal form I comprises one or more diffraction peaks with the 2 theta of 10.3 +/-0.2 degrees, 5.1 +/-0.2 degrees, 15.6 +/-0.2 degrees, 25.2 +/-0.2 degrees and 18.4 +/-0.2 degrees; preferably, the compound contains diffraction peaks at 4 optional positions;

the X-ray powder diffraction pattern of the ethanesulfonate crystal form I comprises one or more diffraction peaks with 2 theta of 10.2 +/-0.2 degrees, 5.0 +/-0.2 degrees, 15.4 +/-0.2 degrees, 18.9 +/-0.2 degrees, 24.2 +/-0.2 degrees and 21.1 +/-0.2 degrees; preferably, the compound contains diffraction peaks at 4 and 6;

the X-ray powder diffraction pattern of the ethanesulfonate crystal form II comprises one or more diffraction peaks with the 2 theta of 10.2 +/-0.2 degrees, 5.0 +/-0.2 degrees, 6.0 +/-0.2 degrees, 15.4 +/-0.2 degrees, 5.4 +/-0.2 degrees and 7.3 +/-0.2 degrees; preferably, the compound contains diffraction peaks at 4 and 6;

the X-ray powder diffraction pattern of the isethionate crystal form I comprises one or more diffraction peaks with 2 theta of 10.5 +/-0.2 degrees, 5.2 +/-0.2 degrees, 18.7 +/-0.2 degrees, 15.9 +/-0.2 degrees and 23.0 +/-0.2 degrees; preferably, the compound contains diffraction peaks at 4 optional positions;

the X-ray powder diffraction pattern of the isethionate crystal form II comprises one or more diffraction peaks with 2 theta of 11.9 +/-0.2 degrees, 18.4 +/-0.2 degrees, 4.8 +/-0.2 degrees, 23.4 +/-0.2 degrees, 16.7 +/-0.2 degrees, 17.8 +/-0.2 degrees, 12.8 +/-0.2 degrees, 23.8 +/-0.2 degrees, 21.8 +/-0.2 degrees, 19.0 +/-0.2 degrees, 25.4 +/-0.2 degrees and 19.8 +/-0.2 degrees; preferably, the compound comprises diffraction peaks at 4, 6, 8 and 10;

the X-ray powder diffraction pattern of the sulfate crystal form I comprises one or more diffraction peaks with 2 theta of 10.3 +/-0.2 degrees, 5.1 +/-0.2 degrees, 15.6 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.2 +/-0.2 degrees, 19.0 +/-0.2 degrees, 25.6 +/-0.2 degrees, 22.1 +/-0.2 degrees, 23.0 +/-0.2 degrees, 20.8 +/-0.2 degrees, 19.2 +/-0.2 degrees and 24.1 +/-0.2 degrees; preferably, the compound comprises diffraction peaks at 4, 6, 8 and 10;

the X-ray powder diffraction pattern of the sulfate crystal form II comprises one or more diffraction peaks with the 2 theta of 16.1 +/-0.2 degrees, 5.9 +/-0.2 degrees, 6.6 +/-0.2 degrees, 22.0 +/-0.2 degrees, 21.0 +/-0.2 degrees, 20.1 +/-0.2 degrees, 17.0 +/-0.2 degrees, 25.2 +/-0.2 degrees, 20.7 +/-0.2 degrees and 23.1 +/-0.2 degrees; preferably, the compound comprises diffraction peaks at 4, 6, 8 and 10;

the X-ray powder diffraction pattern of the phosphate crystal form I comprises one or more diffraction peaks with 2 theta of 5.6 +/-0.2 degrees, 11.5 +/-0.2 degrees, 20.3 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.2 +/-0.2 degrees, 16.4 +/-0.2 degrees, 21.9 +/-0.2 degrees and 10.2 +/-0.2 degrees; preferably, the compound contains diffraction peaks at 4, 6 and 8 optional positions;

9. A crystalline form according to any one of claims 1-8, characterized in that besylate form I has an X-ray powder diffraction pattern as shown in figure 1; the X-ray powder diffraction pattern of the benzene sulfonate crystal form II is shown in figure 4; the X-ray powder diffraction pattern of the p-toluenesulfonate crystalline form I is shown in FIG. 7; the X-ray powder diffraction pattern of the hydrochloride form I is shown in figure 10; the X-ray powder diffraction pattern of the hydrochloride crystal form II is shown in figure 13; the X-ray powder diffraction pattern of the hydrobromide crystal form I is shown in figure 15; an X-ray powder diffraction pattern of oxalate form I is shown in figure 18; an X-ray powder diffraction pattern of oxalate form II is shown in figure 21; an X-ray powder diffraction pattern of oxalate form III is shown in figure 22; an X-ray powder diffraction pattern of oxalate form IV is shown in figure 23; the X-ray powder diffraction pattern of the mesylate salt form I is shown in figure 26; the X-ray powder diffraction pattern of the ethanesulfonate crystal form I is shown in figure 29; the X-ray powder diffraction pattern of the ethanesulfonate crystal form II is shown in FIG. 32; the X-ray powder diffraction pattern of the isethionate salt form I is shown in FIG. 35; the X-ray powder diffraction pattern of the isethionate salt crystal form II is shown in FIG. 36; the X-ray powder diffraction pattern of the sulfate crystal form I is shown in figure 39; the X-ray powder diffraction pattern of the sulfate crystal form II is shown in figure 40; the X-ray powder diffraction pattern of the phosphate crystal form I is shown in figure 41; the X-ray powder diffraction pattern of the phosphate crystal form II is shown in figure 42.

10. The crystalline form according to any one of claims 1 to 8, characterized in that the positions of diffraction peaks having first ten strong relative peak intensities in X-ray powder diffraction patterns of benzenesulfonate form I, benzenesulfonate form II, p-toluenesulfonate form I, hydrochloride form II, hydrobromide form I, oxalate form II, oxalate form III, oxalate form IV, methanesulfonate form I, ethanesulfonate form II, isethionate form I, isethionate form II, sulfate form I, sulfate form II, phosphate form I and phosphate form II are respectively identical to those in FIG. 1, FIG. 4, FIG. 7, FIG. 10, FIG. 13, FIG. 15, FIG. 18, FIG. 21, FIG. 22, FIG. 23, FIG. 26, FIG. 29, FIG. 32, FIG. 35, FIG. 36, FIG. 39, FIG. 40, The 2 θ errors of diffraction peaks at the corresponding positions in FIGS. 41 and 42 are. + -. 0.2 to. + -. 0.5, preferably. + -. 0.2 to. + -. 0.3, and most preferably. + -. 0.2.

11. The crystalline form according to any one of claims 1 to 8, characterized in that,

the hydrochloride form II has a DSC pattern as shown in figure 14;

12. The method for producing an acid salt according to any one of claims 1 to 8, comprising specifically the steps of:

4) quickly centrifuging or standing and drying to obtain a target product;

wherein:

preferably one or more of dichloromethane, tetrahydrofuran or 1, 4-dioxane;

the poor 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;

the counter-ionic acid is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2, 5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxy-hydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, erythorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dibenzoyltartaric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, One or more of glycolic acid, hippuric acid, isethionic 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, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, pamoic acid, formic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, or L-malic acid;

preferably one or more of benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, isethionic acid, 1, 5-naphthalenedisulfonic acid, tartaric acid, adipic acid, phosphoric acid, hydrobromic acid, oxalic acid, fumaric acid, formic acid, hippuric acid, lauric acid, stearic acid;

or, the method comprises the following steps:

2) shaking the obtained suspension, wherein the temperature is preferably 25-50 ℃;

3) quickly centrifuging the suspension, removing supernatant, and drying the residual solid to obtain a target product;

wherein:

13. A pharmaceutical composition comprising a therapeutically effective amount of the acid salt or crystalline form thereof of claims 1-11 and one or more pharmaceutically acceptable carriers or excipients.

14. Use of an acid salt or a crystalline form thereof according to any one of claims 1 to 11, or a pharmaceutical composition according to claim 13, for the manufacture of a RET inhibitor medicament.

15. Use of the acid salt or the crystalline form thereof according to any one of claims 1 to 11, or the pharmaceutical composition according to claim 13, for the preparation of a medicament for the treatment and/or prevention of non-small cell lung cancer, fibrosarcoma, pancreatic tumor, medullary thyroid carcinoma, papillary thyroid tumor, soft tissue sarcoma, highly solid tumor, breast tumor and colon tumor diseases.