Crystalline form of polycyclic carbamoyl pyridone derivative and preparation method and application thereof

Abstract

The present invention provides a crystalline form of an HIV integrase inhibitor molecule. Specifically, the invention provides a free-state crystal form, a basic salt crystal form or an acid salt crystal form of a compound as shown in a formula I. The crystal form provided by the invention can be used for preventing and / or treating related diseases of HIV infection and selectively inhibiting the activity of HIV integrase. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, in particular to a crystalline form of a polycyclic aminoformyl pyridone derivative and a preparation method and application thereof. Background Art

[0002] HIV is still a chronic infection, and the number of HIV-infected people increases year by year. There are no proteins with a similar structure to HIV-1 integrase in the host cell, and inhibiting HIV-1 integrase activity will not affect the normal function of the host cell. Integrase inhibitors block the replication process of HIV by inhibiting the chain transfer reaction, so they are also called integrase chain transfer inhibitors. An observational study in the United States conducted by J Acquir Immune Defic Syndr 2020; 84:396–399 showed that people who used integrase inhibitor-based antiretroviral therapy had a 21% lower risk of serious cardiovascular events compared with alternative drugs. Because of its good antiviral efficacy, high barrier to resistance and safety, it has become the core drug for current antiviral treatment and is recommended as the first choice in the international AIDS treatment guidelines.

[0003] In recent years, with the continuous deepening of research on the structure of integrase and its inhibitors, more and more highly effective and low-toxic integrase inhibitors have emerged. However, resistant strains of integrase inhibitors (Y143C, Q148H and N155H, etc.) have appeared one after another, and the problem of viral resistance has not been solved. It is particularly important to develop highly effective, low-toxic and resistant integrase inhibitors.

[0004] Therefore, it is of great significance to develop an integrase inhibitor that is highly stable and easy to develop into a drug. Summary of the invention

[0005] One object of the present invention is to provide a crystalline form of an HIV integrase inhibitor molecule having the structure of Formula I with high stability.

[0006] In a first aspect of the present invention, there is provided a crystalline form of a compound of formula I,

[0007]

[0008] The crystalline form is selected from the group consisting of:

[0009] Free form A of the compound of formula I;

[0010] Free form B of the compound of formula I;

[0011] Potassium salt of the compound of formula I in crystalline form IA, IB, IC;

[0012] The tert-butylamine salt of the compound of formula I, form II-A;

[0013] The diethylamine salt of the compound of formula I, form III-A;

[0014] Lysine salt of the compound of formula I, crystal form IV-A;

[0015] Sulfate salt of the compound of formula I, crystalline form VA;

[0016] The edisylate salt of the compound of formula I, form VI-A;

[0017] The benzenesulfonate salt of the compound of formula I, crystalline form VII-A;

[0018] p-toluenesulfonate salt of the compound of formula I, Form VIII-A; and

[0019] The hydrobromide salt of the compound of formula I is in form IX-A.

[0020] In another preferred embodiment,

[0021] The crystalline form is the free form A of the compound of formula I, and the free form A of the compound of formula I has the following X-ray powder diffraction characteristic peaks (2θ angle): 25.687°±0.2°, 16.866°±0.2°, 15.019°±0.2°, 24.296°±0.2°, 16.239°±0.2°;

[0022] The crystalline form is the free form B of the compound of formula I, and the free form B of the compound of formula I has the following X-ray powder diffraction characteristic peaks (2θ angle): 15.317°±0.2°, 12.571°±0.2°, 14.255°±0.2°, 20.515°±0.2°, 18.899°±0.2°;

[0023] The crystalline form is the potassium salt crystal form IA of the compound of formula I, and the potassium salt crystal form IA of the compound of formula I has the following X-ray powder diffraction characteristic peaks (2θ angle): 21.976°±0.2°, 7.45°±0.2°, 19.831°±0.2°, 27.93°±0.2°, 23.36°±0.2°;

[0024] The crystalline form is the potassium salt crystal form IB of the compound of formula I, and the potassium salt crystal form IB of the compound of formula I has the following X-ray powder diffraction characteristic peaks (2θ angle): 23.54°±0.2°, 15.611°±0.2°, 5.168°±0.2°, 26.39°±0.2°, 20.874°±0.2°;

[0025] The crystalline form is potassium salt crystal form IC of the compound of formula I, and the potassium salt crystal form IC of the compound of formula I has the following X-ray powder diffraction characteristic peaks (2θ angle): 23.074°±0.2°, 16.44°±0.2°, 5.502°±0.2°, 19.06°±0.2°, 15.278°±0.2°;

[0026] The crystalline form is the tert-butylamine salt crystal form II-A of the compound of formula I, and the tert-butylamine salt crystal form II-A of the compound of formula I has the following X-ray powder diffraction characteristic peaks (2θ angle): 27.19°±0.2°, 18.44°±0.2°, 19.62°±0.2°, 24.346°±0.2°, 19.347°±0.2°;

[0027] The crystalline form is the diethylamine salt crystal form III-A of the compound of formula I, and the diethylamine salt crystal form III-A of the compound of formula I has the following X-ray powder diffraction characteristic peaks (2θ angle): 13.503°±0.2°, 21.353°±0.2°, 15.135°±0.2°, 27.302°±0.2°, 25.513°±0.2°;

[0028] The crystalline form is a lysine salt crystal form IV-A of the compound of formula I, and the lysine salt crystal form IV-A of the compound of formula I has the following X-ray powder diffraction characteristic peaks (2θ angle): 5.503°±0.2°, 17.999°±0.2°, 18.756°±0.2°, 20.28°±0.2°, 19.308°±0.2°;

[0029] The crystalline form is the sulfate crystal form VA of the compound of formula I, and the sulfate crystal form VA of the compound of formula I has the following X-ray powder diffraction characteristic peaks (2θ angle): 5.91°±0.2°, 23.685°±0.2°, 24.017°±0.2°, 22.904°±0.2°, 11.764°±0.2°;

[0030] The crystalline form is the edisylate salt form VI-A of the compound of formula I, and the edisylate salt form VI-A of the compound of formula I has the following X-ray powder diffraction characteristic peaks (2θ angle): 22.599°±0.2°, 23.361°±0.2°, 16.997°±0.2°, 18.562°±0.2°, 20.627°±0.2°;

[0031] The crystalline form is the benzenesulfonate salt form VII-A of the compound of formula I, and the benzenesulfonate salt form VII-A of the compound of formula I has the following X-ray powder diffraction characteristic peaks (2θ angle): 23.346°±0.2°, 20.719°±0.2°, 15.9315°±0.2°, 14.924°±0.2°, 22.8°±0.2°;

[0032] The crystalline form is a p-toluenesulfonate salt of the compound of formula I, form VIII-A, and the p-toluenesulfonate salt of the compound of formula I, form VIII-A, has the following X-ray powder diffraction characteristic peaks (2θ angle): 23.0953°±0.2°, 20.7502°±0.2°, 22.338°±0.2°, 28.076°±0.2°, 10.292°±0.2°; and

[0033] The crystalline form is the hydrobromide salt form IX-A of the compound of formula I, and the hydrobromide salt form IX-A of the compound of formula I has the following X-ray powder diffraction characteristic peaks (2θ angle): 22.922°±0.2°, 20.085°±0.2°, 21.442°±0.2°, 9.61°±0.2°, and 25.306°±0.2°.

[0034] In another preferred embodiment,

[0035] The crystalline form is a free form A of the compound of formula I, and the X-ray powder diffraction pattern of the free form A of the compound of formula I includes 2 or more (3, 4 or 5) X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 16.013°±0.2°, 26.528°±0.2°, 15.347°±0.2°, 23.446°±0.2°, 24.465°±0.2°, 10.976°±0.2°;

[0036] The crystalline form is a free form B of the compound of formula I, and the X-ray powder diffraction pattern of the free form B of the compound of formula I includes 2 or more (3, 4 or 5) X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 20.009°±0.2°, 15.007°±0.2°, 15.96°±0.2°, 28.675°±0.2°, 7.179°±0.2°, 25.661°±0.2°;

[0037] The crystalline form is a potassium salt crystal form IA of the compound of formula I, and the X-ray powder diffraction pattern of the potassium salt crystal form IA of the compound of formula I includes 2 or more (3, 4 or 5) X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 12.56°±0.2°, 31.623°±0.2°, 6.516°±0.2°, 23.066°±0.2°, 24.798°±0.2°, 20.096°±0.2°;

[0038] The crystalline form is a potassium salt crystal form IB of the compound of formula I, and the X-ray powder diffraction pattern of the potassium salt crystal form IB of the compound of formula I includes 2 or more (3, 4 or 5) X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 18.72°±0.2°, 8.464°±0.2°, 21.724°±0.2°, 11.92°±0.2°, 19.52°±0.2°, 9.67°±0.2°;

[0039] The crystalline form is potassium salt crystal form IC of the compound of formula I, and the X-ray powder diffraction pattern of the potassium salt crystal form IC of the compound of formula I includes 2 or more (3, 4 or 5) X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 26.69°±0.2°, 14.04°±0.2°, 23.78°±0.2°, 6.208°±0.2°, 25.023°±0.2°, 29.666°±0.2°;

[0040] The crystalline form is a tert-butylamine salt crystal form II-A of the compound of formula I, and the X-ray powder diffraction pattern of the tert-butylamine salt crystal form II-A of the compound of formula I includes 2 or more (3, 4 or 5) X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 25.77°±0.2°, 8.595°±0.2°, 18.119°±0.2°, 21.808°±0.2°, 26.377°±0.2°, 13.147°±0.2°;

[0041] The crystalline form is the diethylamine salt crystal form III-A of the compound of formula I, and the X-ray powder diffraction pattern of the diethylamine salt crystal form III-A of the compound of formula I includes 2 or more (3, 4 or 5) X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 17.86°±0.2°, 10.9°±0.2°, 23.327°±0.2°, 22.046°±0.2°, 22.937°±0.2°, 24.85°±0.2°;

[0042] The crystalline form is a lysine salt crystal form IV-A of the compound of formula I, and the X-ray powder diffraction pattern of the lysine salt crystal form IV-A of the compound of formula I includes 2 or more (3, 4 or 5) X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 13.667°±0.2°, 22.29°±0.2°, 26.82°±0.2°, 12.651°±0.2°, 7.66°±0.2°, 23.28°±0.2°;

[0043] The crystalline form is the sulfate crystal form VA of the compound of formula I, and the X-ray powder diffraction pattern of the sulfate crystal form VA of the compound of formula I includes 2 or more (3, 4 or 5) X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 27.482°±0.2°, 22.685°±0.2°, 16.304°±0.2°, 14.977°±0.2°, 19.415°±0.2°, 26.241°±0.2°;

[0044] The crystalline form is the edisylate salt form VI-A of the compound of formula I, and the X-ray powder diffraction pattern of the edisylate salt form VI-A of the compound of formula I includes 2 or more (3, 4 or 5) X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 19.782°±0.2°, 29.789°±0.2°, 20.457°±0.2°, 25.778°±0.2°, 22.377°±0.2°, 8.15°±0.2°;

[0045] The crystalline form is a benzenesulfonate salt form VII-A of the compound of formula I, and the X-ray powder diffraction pattern of the benzenesulfonate salt form VII-A of the compound of formula I includes 2 or more (3, 4 or 5) X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 7.89°±0.2°, 10.259°±0.2°, 25.605°±0.2°, 15.634°±0.2°, 28.207°±0.2°, 24.119°±0.2°;

[0046] The crystalline form is a p-toluenesulfonate salt of the compound of formula I, form VIII-A, and the X-ray powder diffraction pattern of the p-toluenesulfonate salt of the compound of formula I, form VIII-A, includes 2 or more (3, 4 or 5) X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 27.206°±0.2°, 15.475°±0.2°, 7.703°±0.2°, 15.711°±0.2°, 28.922°±0.2°, 18.48°±0.2°;

[0047] The crystalline form is the hydrobromide salt form IX-A of the compound of formula I, and the X-ray powder diffraction pattern of the hydrobromide salt form IX-A of the compound of formula I includes 2 or more (3, 4 or 5) X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 28.761°±0.2°, 24.684°±0.2°, 32.311°±0.2°, 26.958°±0.2°, 28.179°±0.2°, 13.346°±0.2°.

[0048] In another preferred embodiment,

[0049] The crystalline form is the free form A of the compound of formula I, and the free form A of the compound of formula I also has one or more X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 22.75°±0.2°, 19.24°±0.2°, 22.453°±0.2°, 20.537°±0.2°, 23.744°±0.2°, 13.397°±0.2° , 28.697°±0.2°, 14.032°±0.2°, 16.4656°±0.2°, 18.004°±0.2°, 27.015°±0.2°, 30.567°±0.2°, 38.445°±0.2°, 28.436°±0.2°, 17.765°±0.2°, 32.87°±0.2°, 23.066°±0.2° .2°、20.754°±0.2°、21.096°±0.2°、5.082°±0.2°、26.235°±0.2°、18.904°±0.2°、37.77°±0.2°、25.082°±0.2°、15.597°±0.2°、11.27°±0.2°、35.2°±0.2°、31.241°±0.2 °, 27.42°±0.2°, 17.404°±0.2°, 33.436°±0.2°, 37.155°±0.2°, 36.367°±0.2°, 33.979°±0.2°, 12.04°±0.2°, 33.658°±0.2°, 28.17°±0.2°, 31.902°±0.2°, 39.26°±0.2°;

[0050] The crystalline form is the free form B of the compound of formula I, and the free form B of the compound of formula I also has one or more X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 24.29°±0.2°, 26.152°±0.2°, 9.73°±0.2°, 25.373°±0.2°, 16.88°±0.2°, 31.054°±0.2°, 38.434°±0.2°, 9.33°±0.2°, 10.921°±0.2°, 30.56°±0.2°, 35.22°±0.2°, 13.38°±0.2°;

[0051] The crystalline form is the potassium salt crystal form IA of the compound of formula I, and the potassium salt crystal form IA of the compound of formula I also has one or more X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 13.281°±0.2°, 33.447°±0.2°, 10.872°±0.2°, 29.749°±0.2°, 26.887°±0.2°, 16.891°±0.2°, 26.006°±0.2°, 19.531°±0.2°, 25.384°±0. 2°, 38.47°±0.2°, 39.211°±0.2°, 18.5°±0.2°, 36.544°±0.2°, 17.324°±0.2°, 35.754°±0.2°, 34.092°±0.2°, 21.088°±0.2°, 37.68°±0.2°, 18.787°±0.2°, 14.115°±0.2°, 36.926°±0.2°, 16.36°±0.2°, 20.412°±0.2°;

[0052] The crystalline form is the potassium salt crystal form IB of the compound of formula I, and the potassium salt crystal form IB of the compound of formula I also has one or more X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 10.33°±0.2°, 17.46°±0.2°, 24.646°±0.2°, 14.3°±0.2°, 12.716°±0.2°, 14.88°±0.2°, 14.07°±0.2°;

[0053] The crystalline form is the potassium salt crystal form IC of the compound of formula I, and the potassium salt crystal form IC of the compound of formula I also has one or more X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 30.766°±0.2°, 18.13°±0.2°, 11.57°±0.2°, 17.518°±0.2°, 28.11°±0.2°, 30.1°±0.2°, 12.74°±0.2°, 20.862°±0.2°, 35.1 °±0.2°, 9.746°±0.2°, 16.019°±0.2°, 25.84°±0.2°, 13.196°±0.2°, 28.86°±0.2°, 10.27°±0.2°, 21.163°±0.2°, 6.853°±0.2°, 8.41°±0.2°, 27.166°±0.2°, 23.977°±0.2°, 11.996°±0.2°, 14.56°±0.2°;

[0054] The crystalline form is the tert-butylamine salt crystal form II-A of the compound of formula I, and the tert-butylamine salt crystal form II-A of the compound of formula I also has one or more X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 17.37°±0.2°, 24.918°±0.2°, 15.458°±0.2°, 21.201°±0.2°, 13.78°±0.2°, 14.876°±0.2° , 29.483°±0.2°, 14.342°±0.2°, 24.031°±0.2°, 22.78°±0.2°, 10.72°±0.2°, 6.025°±0.2°, 28.161°±0.2°, 31.02°±0.2°, 37.86°±0.2°, 38.57°±0.2°, 6.396°±0.2°, 29.06°±0.2°;

[0055] The crystalline form is the diethylamine salt crystal form III-A of the compound of formula I, and the diethylamine salt crystal form III-A of the compound of formula I also has one or more X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 18.483°±0.2°, 27.12°±0.2°, 15.45°±0.2°, 30.68°±0.2°, 16.447°±0.2°, 10.661°±0.2°, 38.568°±0.2°, 12.51°±0.2°, 15.864°±0.2°, 18.129°±0.2°, 26.059°±0.2°, 28.866°±0.2°, 16.701°±0.2°, 26.592°±0.2°, 11 .174°±0.2°、11.571°±0.2°、20.07°±0.2°、7.796°±0.2°、26.38°±0.2°、20.42°±0.2°、17.328°±0.2°、32.4°±0.2°、27.64°±0.2°、22.546°±0.2°、6.415° ±0.2°, 19.35°±0.2°, 18.79°±0.2°, 8.669°±0.2°, 8.83°±0.2°, 31.508°±0.2°, 38.163°±0.2°, 8.134°±0.2°, 34.19°±0.2°, 36.295°±0.2°, 33.06°±0.2°;

[0056] The crystalline form is a lysine salt crystal form IV-A of the compound of formula I, and the lysine salt crystal form IV-A of the compound of formula I also has one or more X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 16.607°±0.2°, 17.618°±0.2°, 14.92°±0.2°, 20.603°±0.2°, 10.12°±0.2°, 24.29°±0.2°, 15.371°±0.2°, 14.039°±0.2°, 28.95°±0.2°, 30.56°±0.2°, 11.35°±0.2°;

[0057] The crystalline form is the sulfate crystal form VA of the compound of formula I, and the sulfate crystal form VA of the compound of formula I also has one or more X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 18.785°±0.2°, 26.55°±0.2°, 34.916°±0.2°, 35.921°±0.2°, 38.403°±0.2°, 20. 624°±0.2°、33.494°±0.2°、25.479°±0.2°、33.048°±0.2°、20.913°±0.2°、22.025°±0.2°、19.507°±0.2°、15.248°±0.2°、17.585°±0.2°、19.891°±0.2°、27.932°± 0.2°、8.01°±0.2°、1.284°±0.2°、27.136°±0.2°、30.61°±0.2°、35.664°±0.2°、31.072°±0.2°、39.569°±0.2°、30.3°±0.2°、32.618°±0.2°、36.535°±0.2°、23.43 4°±0.2°, 17.31°±0.2°, 14.279°±0.2°, 34.056°±0.2°, 24.62°±0.2°, 31.551°±0.2°, 37.22°±0.2°, 28.697°±0.2°, 29.762°±0.2°, 38.846°±0.2°, 21.857°±0.2°;

[0058] The crystalline form is the edisylate salt form VI-A of the compound of formula I, and the edisylate salt form VI-A of the compound of formula I also has one or more X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 24.83°±0.2°, 26.088°±0.2°, 18.143°±0.2°, 26.84°±0.2°, 23.693°±0.2°, 17.953°±0.2°, 25.217°±0.2°, 25.38°±0.2°, 17.533°±0.2°, 28.5°±0.2°, 12.272°±0.2°, 34.74°±0.2°, 35.3°±0.2°, 9.352°±0.2°, 22.888°±0.2°. .2°, 30.378°±0.2°, 38.65°±0.2°, 35.89°±0.2°, 29.105°±0.2°, 33.364°±0.2°, 24.034°±0.2°, 27.079°±0.2°, 15.74°±0.2°, 29.411°±0.2°, 20.986°±0. 2°, 37.81°±0.2°, 32.148°±0.2°, 30.061°±0.2°, 16.43°±0.2°, 22.15°±0.2°, 14.943°±0.2°, 30.883°±0.2°, 36.557°±0.2°, 14.627°±0.2°, 39.23°±0.2°;

[0059] The crystalline form is the benzenesulfonate salt form VII-A of the compound of formula I, and the benzenesulfonate salt form VII-A of the compound of formula I also has one or more X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 29.698°±0.2°, 26.27°±0.2°, 17.603°±0.2°, 20.993°±0.2°, 16.921°±0.2°, 19 .222°±0.2°、27.739°±0.2°、9.846°±0.2°、27.169°±0.2°、18.635°±0.2°、28.997°±0.2°、28.7°±0.2°、10.9°±0.2°、32.333°±0.2°、15.353°±0.2°、5.135°±0.2°、26.46° ±0.2°, 31.357°±0.2°, 24.453°±0.2°, 33.165°±0.2°, 16.21°±0.2°, 4.973°±0.2°, 37.878°±0.2°, 29.218°±0.2°, 36.643°±0.2°, 37.172°±0.2°, 28.502°±0.2°, 35.217° ±0.2°, 14.376°±0.2°, 35.65°±0.2°, 32.855°±0.2°, 38.46°±0.2°, 19.85°±0.2°, 31.95°±0.2°, 36.04°±0.2°, 13.39°±0.2°, 20.16°±0.2°, 14.086°±0.2°, 17.304°±0.2°;

[0060] The crystalline form is the p-toluenesulfonate crystalline form VIII-A of the compound of formula I, and the p-toluenesulfonate crystalline form VIII-A of the compound of formula I also has one or more X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 14.705°±0.2°, 23.818°±0.2°, 31.376°±0.2°, 26.965°±0.2°, 17.653°±0.2°, 24.94°±0.2°, 26.311°±0.2°, 27.837°±0.2°, 28.589°±0.2°, 17.167°±0.2°, 31.826°±0.2°, 36.138°±0.2°, 14.484°±0.2°, 34.414°±0.2°, 25.331°±0.2° .2°、35.824°±0.2°、37.621°±0.2°、20.16°±0.2°、31.159°±0.2°、30.17°±0.2°、35.609°±0.2°、32.966°±0.2°、9.602°±0.2°、14.129°±0.2°、4.844°±0.2°、33.28 4°±0.2°, 16.768°±0.2°, 29.274°±0.2°, 38.261°±0.2°, 38.49°±0.2°, 19.753°±0.2°, 37.885°±0.2°, 35.082°±0.2°, 37.275°±0.2°, 32.477°±0.2°, 32.68°±0.2°;

[0061] The crystalline form is the hydrobromide salt form IX-A of the compound of formula I, and the hydrobromide salt form IX-A of the compound of formula I also has one or more X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 7.987°±0.2°, 6.663°±0.2°, 38.253°±0.2°, 21.803°±0.2°, 13.138°±0.2°, 35.993°±0.2°, 24.118°±0.2°, 32.931°±0.2°, 30.252°±0.2°, 11.395°±0.2°, 20.786°±0.2°, 25.808°±0.2°, 18.306°±0.2°, 16.048° ±0.2°, 33.484°±0.2°, 19.47°±0.2°, 36.993°±0.2°, 17.954°±0.2°, 30.856°±0.2°, 39.22°±0.2°, 16.889°±0.2°, 29.64°±0.2°, 31.647°±0.2°, 14. 81°±0.2°, 10.69°±0.2°, 15.757°±0.2°, 18.694°±0.2°, 22.173°±0.2°, 36.489°±0.2°, 34.129°±0.2°, 30.574°±0.2°, 16.379°±0.2°, 31.48°±0.2°.

[0062] In another preferred embodiment,

[0063] The crystalline form is a free-state crystalline form A of the compound of formula I, and the DSC spectrum of the free-state crystalline form A of the compound of formula I has an endothermic peak at 214-216° C.; and / or

[0064] The crystalline form is the free form B of the compound of formula I, and the DSC spectrum of the free form B of the compound of formula I has an endothermic peak at 208-216°C.

[0065] In another preferred embodiment,

[0066] (A) The crystalline form is the free form A of the compound of formula I, and the free form A of the compound of formula I also has one or more of the following characteristics:

[0067] (1) the free form crystalline form A of the compound of formula I has XRPD data substantially as shown in Table 1; and / or

[0068] (2) The free form of the compound of formula I, Form A, has substantially the following properties: Figure 1 The XRPD spectrum shown;

[0069] (3) The free form of the compound of formula I, Form A, has substantially the following Figure 2 DSC&TGA spectra shown;

[0070] (B) The crystalline form is the free form B of the compound of formula I, and the free form B of the compound of formula I also has one or more of the following characteristics:

[0071] (1) the free form of the compound of formula I, Form B, has XRPD data substantially as shown in Table 2; and / or

[0072] (2) The free form of the compound of formula I, Form B, has substantially the following properties: Figure 3 The XRPD spectrum shown;

[0073] (3) The free form of the compound of formula I, Form B, has substantially the following properties: Figure 4 DSC&TGA spectra shown;

[0074] (IA) The crystalline form is the potassium salt of the compound of formula I, Form IA, and the potassium salt of the compound of formula I, Form IA, also has one or more of the following characteristics:

[0075] (1) the potassium salt of the compound of formula I, Form IA, has XRPD data substantially as shown in Table 3; and / or

[0076] (2) The potassium salt of the compound of formula I, Form IA, has substantially the following Figure 5 The XRPD spectrum shown;

[0077] (IB) The crystalline form is the potassium salt of the compound of formula I, Form IB, and the potassium salt of the compound of formula I, Form IB, also has one or more of the following characteristics:

[0078] (1) the potassium salt of the compound of formula I, Form IB, has XRPD data substantially as shown in Table 4; and / or

[0079] (2) The potassium salt of the compound of formula I, Form IB, has substantially the following Figure 6 The XRPD spectrum shown;

[0080] (IC) The crystalline form is the potassium salt of the compound of formula I, form IC, and the potassium salt of the compound of formula I, form IC, also has one or more of the following characteristics:

[0081] (1) the potassium salt of the compound of formula I, Form IC, has XRPD data substantially as shown in Table 5; and / or

[0082] (2) The potassium salt crystal form IC of the compound of formula I has substantially the following Figure 7 The XRPD spectrum shown;

[0083] The crystalline form (II-A) is the tert-butylamine salt crystalline form II-A of the compound of formula I, and the tert-butylamine salt crystalline form II-A of the compound of formula I also has one or more of the following characteristics:

[0084] (1) the tert-butylamine salt of the compound of formula I, Form II-A, has XRPD data substantially as shown in Table 6; and / or

[0085] (2) The tert-butylamine salt of the compound of formula I, Form II-A, has substantially the following properties: Figure 8 The XRPD spectrum shown;

[0086] The crystalline form (III-A) is the diethylamine salt crystalline form III-A of the compound of formula I, and the diethylamine salt crystalline form III-A of the compound of formula I also has one or more of the following characteristics:

[0087] (1) the diethylamine salt crystalline form III-A of the compound of formula I has XRPD data substantially as shown in Table 7; and / or

[0088] (2) The diethylamine salt of the compound of formula I, Form III-A, has substantially the following properties: Fig. 9 The XRPD spectrum shown;

[0089] (IV-A) The crystalline form is the lysine salt crystal form IV-A of the compound of formula I, and the lysine salt crystal form IV-A of the compound of formula I also has one or more of the following characteristics:

[0090] (1) the lysine salt form IV-A of the compound of formula I has XRPD data substantially as shown in Table 8; and / or

[0091] (2) The lysine salt crystal form IV-A of the compound of formula I has substantially the following Fig.10 The XRPD spectrum shown;

[0092] (VA) The crystalline form is the sulfate salt of the compound of formula I, form VA, and the sulfate salt of the compound of formula I, form VA, also has one or more of the following characteristics:

[0093] (1) the sulfate salt of the compound of formula I, Form VA, has XRPD data substantially as shown in Table 9; and / or

[0094] (2) The sulfate salt of the compound of formula I, crystalline form VA, has substantially the following Fig.11 The XRPD spectrum shown;

[0095] The crystalline form (VI-A) is the edisylate salt of the compound of formula I, crystalline form VI-A, and the edisylate salt of the compound of formula I, crystalline form VI-A, also has one or more of the following characteristics:

[0096] (1) the edisylate salt form VI-A of the compound of formula I has XRPD data substantially as shown in Table 10; and / or

[0097] (2) The ethylenedisulfonate salt form VI-A of the compound of formula I has substantially the following Fig.12 The XRPD pattern shown; and / or

[0098] (3) The ethylenedisulfonate salt form VI-A of the compound of formula I has substantially the following Fig.13 DSC&TGA spectra shown;

[0099] The crystalline form (VII-A) is the benzenesulfonate salt form VII-A of the compound of formula I, and the benzenesulfonate salt form VII-A of the compound of formula I also has one or more of the following characteristics:

[0100] (1) the benzenesulfonate salt form VII-A of the compound of formula I has XRPD data substantially as shown in Table 11; and / or

[0101] (2) The benzenesulfonate salt form VII-A of the compound of formula I has substantially the following Fig.14 The XRPD pattern shown; and / or

[0102] (3) The benzenesulfonate salt form VII-A of the compound of formula I has substantially the following Fig.15 DSC&TGA spectra shown;

[0103] The crystalline form (VIII-A) is the p-toluenesulfonate crystalline form VIII-A of the compound of formula I, and the p-toluenesulfonate crystalline form VIII-A of the compound of formula I also has one or more of the following characteristics:

[0104] (1) the p-toluenesulfonate salt of the compound of Formula I, Form VIII-A, has XRPD data substantially as shown in Table 12; and / or

[0105] (2) The p-toluenesulfonate salt form VIII-A of the compound of formula I has substantially the following Fig.16 The XRPD pattern shown; and / or

[0106] (3) The p-toluenesulfonate salt form VIII-A of the compound of formula I has substantially the following Fig.17 DSC&TGA spectra shown;

[0107] The crystalline form (IX-A) is the hydrobromide salt of the compound of formula I, crystalline form IX-A, and the hydrobromide salt of the compound of formula I, crystalline form IX-A, also has one or more of the following characteristics:

[0108] (1) the hydrobromide salt form IX-A of the compound of formula I has XRPD data substantially as shown in Table 13; and / or

[0109] (2) The hydrobromide salt form IX-A of the compound of formula I has substantially the following Fig.18 The XRPD pattern shown; and / or

[0110] (3) The hydrobromide salt form IX-A of the compound of formula I has substantially the following Fig.19 DSC&TGA spectra shown.

[0111] In a second aspect of the present invention, there is provided a method for preparing the crystalline form according to the first aspect of the present invention, comprising the following steps:

[0112] (a) dissolving the compound of formula I in a first solvent, cooling and crystallizing to obtain a free-state crystalline form;

[0113] (b) dissolving the raw material of the compound of formula I in a first solvent, suspending and stirring at room temperature to crystallize, and (evaporating) to obtain a free state crystalline form;

[0114] (c) dissolving the raw material of the compound of formula I in a first solvent, heating and stirring, cooling to 0° C. for crystallization to obtain a free-state crystalline form;

[0115] (d) dissolving the compound of formula I in a first solvent, adding an anti-solvent, stirring and crystallizing to obtain a free-state crystalline form; or

[0116] (e) dissolving the free crystalline form of the compound of formula I in a second solvent, adding an acid or a base, heating and stirring, and cooling to crystallize to obtain an acid salt crystalline form or a basic salt crystalline form.

[0117] In another preferred embodiment, the first solvent is selected from the following group: C1-C6 alcohol solvents, C1-C6 cyanide solvents, C1-C20 sulfone solvents, C1-C20 amide solvents, C1-C6 halogenated alkane solvents, C1-C6 alkane solvents, C1-C6 ketone solvents, C1-C6 ether solvents, or a combination thereof.

[0118] In another preferred embodiment, the first solvent is selected from the following group: methanol, ethanol, isopropanol, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, dichloromethane, chloroform, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, or a combination thereof; preferably DMSO, methanol, acetonitrile.

[0119] In another preferred embodiment, the anti-solvent is selected from the following group: ethyl acetate, isopropyl acetate, diethyl ether, methyl tert-butyl ether, isopropyl ether, petroleum ether, n-heptane, n-hexane, water, or a combination thereof.

[0120] In another preferred embodiment, the temperature rise is 45-60°C; preferably 50-55°C.

[0121] In another preferred embodiment, the acid or base is added in solid or liquid form.

[0122] In another preferred embodiment, the acid or base is added in the form of a solution thereof.

[0123] In another preferred embodiment, the acid is selected from inorganic acid or organic acid.

[0124] In another preferred embodiment, the inorganic acid is selected from the following group: hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, or a combination thereof; preferably sulfate or hydrobromic acid.

[0125] In another preferred embodiment, the organic acid is selected from the following group: glycerophosphate, L-aspartic acid, maleic acid, L-glutamic acid, pyruvic acid, fumaric acid, citric acid, hippuric acid, succinic acid, L-tartaric acid, L-malic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, ethanedisulfonic acid, acetic acid, hydrobromic acid, lysine, trifluoroacetic acid, or a combination thereof; preferably benzenesulfonic acid, p-toluenesulfonic acid, ethanedisulfonic acid, or a combination thereof.

[0126] In another preferred embodiment, the base is selected from potassium hydroxide, calcium hydroxide, choline, lysine, arginine, tert-butylamine, diethylamine, nicotinamide, N,N-dimethylethanolamine, meglumine; preferably potassium hydroxide, lysine, tert-butylamine, diethylamine or a combination thereof.

[0127] In another preferred embodiment, the second solvent is selected from the following group: water, C1-C6 alcohol solvents, C1-C6 cyanide solvents, C1-C20 sulfone solvents, C1-C20 amide solvents, C1-C6 halogenated alkane solvents, C1-C6 alkane solvents, C6-C10 aromatic solvents, C2-C6 ester solvents, C1-C6 ketone solvents, C1-C6 ether solvents, or a combination thereof.

[0128] In another preferred embodiment, the second solvent is selected from the following group: methanol, ethanol, isopropanol, acetone, tetrahydrofuran, acetonitrile, toluene, 1,4-dioxane, dichloromethane, chloroform, ethyl acetate, isopropyl acetate, 2-methyltetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, methyl tert-butyl ether, n-heptane, or a combination thereof.

[0129] In another preferred embodiment, the step (c) comprises: heating to 45-60°C, maintaining the temperature with stirring, then cooling to room temperature for crystallization, and continuing to maintain the temperature for crystallization.

[0130] In another preferred embodiment, the cooling refers to cooling at a rate of 10-20°C / h.

[0131] In another preferred embodiment, the room temperature refers to 15-30°C.

[0132] In the third aspect of the present invention, a pharmaceutical composition is provided, comprising (a) the crystalline form according to the first aspect of the present invention as an active ingredient; and (b) a pharmaceutically acceptable carrier.

[0133] In another preferred embodiment, the dosage form of the pharmaceutical composition is selected from the following group: powder, capsule, granule, tablet, pill, cream, orodispersible film, suspension or injection.

[0134] In the fourth aspect of the present invention, there is provided the use of the crystalline form described in the first aspect of the present invention or the pharmaceutical composition described in the third aspect of the present invention for preparing a drug or preparation for preventing and / or treating diseases caused by HIV infection.

[0135] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0136] Figure 1 is the X-ray powder diffraction pattern of the free crystalline form A of the compound of formula I;

[0137] Figure 2 The DSC and TGA spectra of the free form A of the compound of formula I;

[0138] Figure 3 The X-ray powder diffraction pattern of the free form B of the compound of formula I is

[0139] Figure 4 The DSC and TGA spectra of the free form B of the compound of formula I;

[0140] Figure 5 is the X-ray powder diffraction pattern of the potassium salt of the compound of formula I, Form IA;

[0141] Figure 6 is the X-ray powder diffraction pattern of the potassium salt of the compound of formula I, Form IB;

[0142] Figure 7 is an X-ray powder diffraction pattern of potassium salt of the compound of formula I, Form IC;

[0143] Figure 8 is an X-ray powder diffraction pattern of the tert-butylamine salt of the compound of formula I, Form II-A;

[0144] Fig. 9is an X-ray powder diffraction pattern of the diethylamine salt of the compound of formula I, Form III-A;

[0145] Fig.10 is an X-ray powder diffraction pattern of lysine salt crystal form IV-A of the compound of formula I;

[0146] Fig.11 It is the X-ray powder diffraction pattern of the sulfate crystal form VA of the compound of formula I.

[0147] Fig.12 is an X-ray powder diffraction pattern of the edisylate salt form VI-A of the compound of formula I;

[0148] Fig.13 The DSC and TGA spectra of the edisylate salt form VI-A of the compound of formula I;

[0149] Fig.14 is an X-ray powder diffraction pattern of benzenesulfonate salt form VII-A of the compound of formula I;

[0150] Fig.15 The DSC and TGA spectra of the benzenesulfonate salt form VII-A of the compound of formula I;

[0151] Fig.16 is an X-ray powder diffraction pattern of the p-toluenesulfonate crystalline form VIII-A of the compound of formula I;

[0152] Fig.17 The DSC and TGA spectra of the p-toluenesulfonate salt of the compound of formula I, Form VIII-A;

[0153] Fig.18 The X-ray powder diffraction pattern of the hydrobromide salt form IX-A of the compound of formula I is shown in FIG.

[0154] Fig.19 The DSC and TGA spectra of the hydrobromide salt form IX-A of the compound of formula I are shown in FIG. DETAILED DESCRIPTION

[0155] After long-term and in-depth research, the inventors have provided a crystalline form of HIV integrase inhibitor molecules. These crystalline forms have advantages in stability, solubility, hygroscopicity, mechanical stability, tableting stability, fluidity, process developability, formulation development and powder processing performance. Based on the above findings, the inventors have completed the present invention.

[0156] the term

[0157] Unless otherwise specified herein, each abbreviation has a common meaning understood by those skilled in the art.

[0158] As used herein, unless otherwise specified, the method of adding a solvent or a solution is to directly pour it or add it at a uniform speed.

[0159] As used herein, when used in reference to a specific recited numerical value, the term "about" means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0160] As used herein, the term "comprising" or "including (comprising)" may be open, semi-closed and closed. In other words, the term also includes "consisting essentially of" or "consisting of".

[0161] As used herein, the term "room temperature" generally refers to 4-30°C, preferably 20±5°C.

[0162] As used herein, the method of "slowly adding" includes, but is not limited to: adding dropwise, adding slowly along the wall of the container, etc.

[0163] Compounds of formula I

[0164] As used herein, the term "compound of formula I" refers to a compound as shown below:

[0165]

[0166] The above compound was first reported in patent CN202111336306 of Jiangsu Aidi Pharmaceutical Co., Ltd. and was prepared by the method in the literature. Herein, unless otherwise specified, the term "raw material of the compound of formula I" refers to the compound of formula I. In the examples, API and the compound of formula I can be used interchangeably.

[0167] Pharmaceutical compositions containing crystalline forms of compounds of formula I and methods of administration

[0168] Since the crystal form of the present invention is a highly stable crystalline form of HIV integrase inhibitor molecule having the structure of the compound of formula I, the crystal form of the present invention and the pharmaceutical composition containing the crystal form of the present invention as the main active ingredient can be used to prevent and / or treat diseases mediated by HIV viral infection.

[0169] The pharmaceutical composition of the present invention comprises a safe and effective amount of the polymorph of the present invention and a pharmaceutically acceptable excipient or carrier.

[0170] Wherein, "safe and effective amount" means: the amount of the compound (or polymorph) is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the polymorph of the present invention per dose, and more preferably, contains 10-200 mg of the polymorph of the present invention per dose. Preferably, the "one dose" is one capsule or tablet.

[0171] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0172] The administration method of the polymorph or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0173] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, microcrystalline cellulose, starches, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, sodium carbonate, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose; (e) solubilizing agents, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0174] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active ingredient in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active ingredient can also be formed into microcapsules with one or more of the above-mentioned excipients.

[0175] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0176] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0177] In addition to the active ingredients, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances.

[0178] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0179] Dosage forms of the polymorphs of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0180] The polymorphs of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0181] When using the pharmaceutical composition, a safe and effective amount of the polymorph of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 10 to 500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0182] The pharmaceutical composition provided by the present invention preferably contains an active ingredient in a weight ratio of 1-99%, and its preferred ratio is that the compound of formula I accounts for 65wt% to 99wt% of the total weight as the active ingredient, and the rest is a pharmaceutically acceptable carrier, diluent or solution or saline solution. The compound and pharmaceutical composition provided by the present invention can be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, etc., and can be present in a suitable solid or liquid carrier or diluent and in a suitable sterilizing apparatus for injection or instillation.

[0183] The various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field. The unit dosage of the preparation formula contains 1 mg-700 mg of the crystalline form or salt crystalline form of the compound of formula I, preferably, the unit dosage of the preparation formula contains 25 mg-300 mg of the compound of formula I.

[0184] The compounds and pharmaceutical compositions of the present invention can be used clinically in mammals, including humans and animals, and can be administered through the oral, nasal, skin, lung or gastrointestinal tract routes. Oral administration is most preferred. The most preferred daily dose is 50-1400 mg / kg body weight, taken at one time, or 25-700 mg / kg body weight taken in divided doses. Regardless of the method of administration, the optimal dose for an individual should be determined based on the specific treatment. Usually, a small dose is started and the dose is gradually increased until the most suitable dose is found.

[0185] In the present invention, unless otherwise specified, the drying method used is a conventional drying method in the art, for example, in the embodiments of the present invention, drying refers to vacuum drying or normal pressure drying in a conventional drying oven. Generally, the drying time is 0.1 to 50 hours or 1 to 30 hours.

[0186] Compared with the prior art, the main advantages of the present invention include:

[0187] (a) The crystal form of the present invention has high stability, low hygroscopicity and high bioavailability, which is beneficial for its drug processing and use in pharmaceutical compositions.

[0188] (b) The crystalline form of the present invention can be used as an active ingredient to prevent and treat diseases caused by AIDS infection.

[0189] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0190] 1. Experimental Materials

[0191] The raw material of the compound of formula I in the example of the present invention is a free solid prepared by referring to Example 1 of Eddie Patent CN202111336306, and other reagents are commercially available industrial grade or analytical grade reagents.

[0192] 2. Test methods

[0193]

[0194] Example 1: Free Form A of Compound of Formula 1

[0195] Method 1: Weigh about 30 mg of raw materials, add about 0.5 mL of DMSO to prepare a clear solution, slowly add poor solvent water to the solution, stir to precipitate a certain amount of solid, and separate the solid to obtain the free form A of the compound of formula I. Its X-ray powder diffraction pattern is as follows Figure 1 , its DSC and TGA spectra are as follows Figure 2 , and its XRPD data are shown in Table 1.

[0196] The results showed that the free crystalline form A had an endothermic peak at 214-216°C, and the TGA graph showed a weight loss of 0.415% at 25-199°C, indicating that the free crystalline form A of the compound of formula 1 has low hygroscopicity.

[0197] Method 2: Weigh about 45 mg of the raw material, add methanol to prepare a clear saturated solution at 50°C, stir for 30 minutes, cool the hot solution to 0°C at a rate of 5°C / h, and after the crystals precipitate, quickly centrifuge or filter at 0°C. The obtained solid is subjected to X-ray powder diffraction to obtain Form A of the compound of Formula I.

[0198] Method 3: Weigh about 30 mg of raw materials, add appropriate amount of acetonitrile to form a suspension state, and stir magnetically at 25℃±0.1℃ for 24 hours. Observe the state of the sample during the experiment to ensure that the suspension state is maintained. If there is any dissolution, add solid. Filter and centrifuge the suspension, and the obtained solid is subjected to X-ray powder diffraction to obtain the free state crystal form A of the compound of formula I.

[0199] Method 4: The filtrate of the solid-liquid suspension equilibrium experiment of Method 3 is slowly evaporated at room temperature, and the solid sample is collected before the sample is completely dried for XRPD and other tests to obtain the free form A of the compound of Formula I.

[0200] Table 1

[0201]

[0202]

[0203] Example 2: Free Form B of Compound I

[0204] About 30 mg of the raw material was weighed, and about 0.5 mL of dichloromethane was added to prepare a clear solution. Methanol was slowly added to the solution, and a certain amount of solid was precipitated by stirring. The solid was separated to obtain the free form B of the compound of formula I. Its X-ray powder diffraction pattern is as follows: Figure 3 Its DSC and TGA spectra are shown in Figure 4 Its XRPD data are shown in Table 2.

[0205] The results showed that the free crystalline form B had an endothermic peak at 208-216°C, and the TGA graph showed a weight loss of 1.445% at 36-199°C.

[0206] Table 2

[0207]

[0208]

[0209] Example 3: Potassium salt of compound of formula I, Form IA

[0210] About 30 mg of the raw material was weighed, and about 1 mL of ethanol was added to each suspension to prepare the suspension. About 0.5 mL of potassium hydroxide ethanol solution (1.1 eq.) was slowly added to the solution. The reaction solution was stirred and heated to 50°C. After being kept and stirred for 2 hours, the temperature was stirred and cooled for crystallization (cooling rate 10°C / h). After the temperature was cooled to 25°C, the temperature was kept and stirred for crystallization for 5 hours. The solid was separated to obtain the potassium salt crystal form IA of the compound of formula I. Its X-ray powder diffraction pattern is as follows: Figure 5 Its XRPD data are shown in Table 3.

[0211] Table 3

[0212]

[0213]

[0214] Example 4: Potassium Salt of Formula I Compound Form IB

[0215] About 30 mg of the raw material was weighed, and about 1 mL of acetone was added to each suspension to prepare the suspension. About 0.5 mL of potassium hydroxide acetone solution (1.1 eq.) was slowly added to the solution. The reaction solution was stirred and heated to 50°C. After being kept and stirred for 2 hours, the temperature was stirred and cooled for crystallization (cooling rate 10°C / h). After the temperature was cooled to 25°C, the temperature was kept and stirred for crystallization for 5 hours. The solid was separated to obtain the potassium salt of the compound of formula I, form IB. Its X-ray powder diffraction pattern is as follows: Figure 6 Its XRPD data are shown in Table 4.

[0216] Table 4

[0217] 2θ Relative Strength 5.168 70.07％ 8.464 33.41％ 9.670 22.16％ 10.330 21.23％ 11.920 31.79％ 12.716 8.93％ 14.070 3.25％ 14.300 14.62％ 14.880 6.73％ 15.611 98.84％ 17.460 20.88％ 18.720 47.22％ 19.520 30.63％ 20.874 60.32％ 21.724 32.71％ 23.540 100.00％ 24.646 18.33％ 26.390 67.87％

[0218] Example 5: Potassium salt of compound of formula I, Form IC

[0219] About 30 mg of the raw material was weighed, and about 1 mL of tetrahydrofuran was added to each suspension to prepare the suspension. About 0.5 mL of a tetrahydrofuran solution of potassium hydroxide (1.1 eq.) was slowly added to the solution. The reaction solution was stirred and heated to 50°C. After being kept and stirred for 2 hours, the temperature was cooled and crystallized (cooling rate 10°C / h). After the temperature was cooled to 25°C, the temperature was kept and stirred for crystallization for 5 hours. The solid was separated to obtain the potassium salt crystal form IC of the compound of formula I. Its X-ray powder diffraction pattern is shown as follows: Figure 7 Its XRPD data are shown in Table 5.

[0220] Table 5

[0221] 2θ Relative Strength 5.502 58.81％ 6.208 41.73％ 6.853 8.64％ 8.410 7.10％ 9.746 16.41％ 10.270 9.51％ 11.570 29.00％ 11.996 4.02％ 12.740 18.89％ 13.196 14.47％ 14.040 52.85％ 14.560 3.22％ 15.278 54.72％ 16.019 16.08％ 16.440 75.22％ 17.518 27.13％ 18.130 33.22％ 19.060 55.19％ 20.862 18.42％ 21.163 9.38％ 23.074 100.00％ 23.780 42.80％ 23.977 5.49％ 25.023 41.53％ 25.840 15.47％ 26.690 54.39％ 27.166 7.10％ 28.110 25.79％ 28.860 10.45％ 29.666 41.46％ 30.100 19.96％ 30.766 35.23％ 35.100 16.54％

[0222] Example 6: Tert-butylamine salt of compound of formula I II-A

[0223] About 30 mg of the raw material was weighed, and about 1 mL of tetrahydrofuran was added to each suspension to prepare the suspension. About 0.5 mL of tetrahydrofuran solution of tert-butylamine (1.1 eq.) was slowly added to the solution. The reaction solution was stirred and heated to 50°C. After being kept and stirred for 2 hours, the temperature was cooled and crystallized (cooling rate 10°C / h). After the temperature was cooled to 25°C, the temperature was kept and stirred for crystallization for 5 hours. The solid was separated to obtain the tert-butylamine salt of the compound of formula I in form II-A. Its X-ray powder diffraction pattern is shown as follows: Figure 8 Its XRPD data are shown in Table 6.

[0224] Table 6

[0225] 2θ Relative Strength 6.025 9.70％ 6.396 5.96％ 8.595 53.92％ 10.720 11.13％ 13.147 40.46％ 13.780 25.22％ 14.342 20.61％ 14.876 23.19％ 15.458 32.30％ 17.370 36.21％ 18.119 53.05％ 18.440 91.84％ 19.347 56.37％ 19.620 59.68％ 21.201 27.76％ 21.808 47.72％ 22.780 11.72％ 24.031 19.29％ 24.346 58.67％ 24.918 34.29％ 25.770 54.87％ 26.377 42.69％ 27.190 100.00％ 28.161 9.28％ 29.060 5.09％ 29.483 22.04％ 31.020 8.37％ 37.860 6.38％ 38.570 6.28％

[0226] Example 7: Diethylamine salt of compound of formula I III-A

[0227] About 30 mg of the raw material was weighed, and about 1 mL of isopropanol was added to each suspension to prepare the suspension. About 0.5 mL of isopropanol solution of diethylamine (1.1 eq.) was slowly added to the solution. The reaction solution was stirred and heated to 50°C. After being kept and stirred for 2 hours, the temperature was stirred and cooled for crystallization (cooling rate 10°C / h). After the temperature was cooled to 25°C, the crystallization was continued by keeping and stirring for 5 hours. The solid was separated to obtain the diethylamine salt of the compound of formula I in form III-A. Its X-ray powder diffraction pattern is shown as follows: Fig. 9 Its XRPD data are shown in Table 7.

[0228] Table 7

[0229]

[0230]

[0231] Example 8: Lysine Salt of Formula I Compound IV-A

[0232] About 30 mg of the raw material was weighed, and about 1 mL of ethanol was added to each suspension to prepare the suspension. About 0.5 mL of lysine ethanol solution (1.1 eq.) was slowly added to the solution. The reaction solution was stirred and heated to 50 ° C. After being kept and stirred for 2 hours, the temperature was stirred and cooled for crystallization (cooling rate 10 ° C / h). After cooling to 25 ° C, the temperature was kept and stirred for crystallization for 5 hours. The solid was separated to obtain the lysine salt form IV-A of the compound of formula I, and its X-ray powder diffraction pattern is shown as follows: Fig.10 Its XRPD data are shown in Table 8.

[0233] Table 8

[0234] 2θ Relative Strength 5.503 100.00％ 7.66 27.96％ 10.12 13.67％ 11.35 4.75％ 12.651 28.26％ 13.667 36.12％ 14.039 10.18％ 14.92 17.62％ 15.371 11.35％ 16.607 23.84％ 17.618 22.96％ 17.999 75.40％ 18.756 68.00％ 19.308 41.42％ 20.28 53.57％ 20.603 14.00％ 22.29 30.78％ 23.28 26.79％ 24.29 12.57％ 26.82 30.07％ 28.95 8.92％ 30.56 7.74％

[0235] Example 9: Sulfate of compound of formula I VA

[0236] About 30 mg of the raw material was weighed, and about 1 mL of tetrahydrofuran was added to each suspension to prepare the suspension. About 0.5 mL of a tetrahydrofuran solution of sulfuric acid (1.1 eq.) was slowly added to the solution. The reaction solution was stirred and heated to 50°C. After being kept and stirred for 2 hours, the temperature was cooled and crystallized (cooling rate 10°C / h). After the temperature was cooled to 25°C, the crystallization was continued by keeping and stirring for 5 hours. The solid was separated to obtain the sulfate salt of the compound of formula I in form VA, and its X-ray powder diffraction pattern was as shown in the figure. Fig.11 Its XRPD data are shown in Table 9.

[0237] About 30 mg of the raw material was weighed and about 1 mL of acetonitrile was added to each suspension. About 0.5 mL of acetonitrile solution of sulfuric acid (1.1 eq.) was slowly added to the solution. The reaction solution was stirred and heated to 50°C. After stirring for 2 hours, the temperature was cooled and crystallized (cooling rate 10°C / h). After cooling to 25°C, the temperature was kept stirred and crystallized for 5 hours. The solid was separated to obtain the sulfate salt of the compound of formula I in form VA.

[0238] Table 9

[0239]

[0240]

[0241] Example 10: Ethylenedisulfonate of Formula I, Form VI-A

[0242] About 30 mg of the raw material was weighed, and about 1 mL of isopropyl acetate (or acetone or acetonitrile, or a combination thereof) was added to prepare a suspension. About 0.5 mL of ethanedisulfonic acid solution (1.1 eq.) was slowly added to the solution. The reaction solution was stirred and heated to 50° C., and stirred for 2 h. The temperature was cooled by stirring. After the temperature dropped to 25° C., the temperature was kept stirred for 5 h for crystallization. The solid was separated to obtain the ethanedisulfonate form VI-A of the compound of formula I, and its X-ray powder diffraction pattern was as shown in FIG. Fig.12 Its DSC and TGA diagrams are shown in Fig.13 Its XRPD data are shown in Table 10.

[0243] The results showed that the edisylate salt form VI-A had an endothermic peak at 177-183°C, and the TGA graph showed a weight loss of 2.17% at 155°C.

[0244] Table 10

[0245]

[0246]

[0247] Example 11: Benzenesulfonate salt of the compound of formula I, Form VII-A

[0248] About 30 mg of the raw material was weighed, and about 1 mL of isopropanol (or any solvent of isopropyl acetate, acetone, tetrahydrofuran or acetonitrile) was added to prepare a suspension. About 0.5 mL of the above solvent in a benzenesulfonic acid solution (1.1 eq.) was slowly added to the solution. The reaction solution was stirred and heated to 50°C. After stirring for 2 hours, the temperature was cooled by stirring. After the temperature dropped to 25°C, the temperature was kept stirring for 5 hours to crystallize. The solid was separated to obtain the benzenesulfonate salt form VII-A of the compound of formula I, and its X-ray powder diffraction pattern was as shown in FIG. Fig.14 Its DSC and TGA diagrams are shown in Figure 15, and its XRPD data are shown in Table 11.

[0249] The results showed that the benzenesulfonate salt form VII-A had an endothermic peak at 178-182°C, and the TGA graph showed a weight loss of 0.85% at 161°C.

[0250] Table 11

[0251]

[0252]

[0253] Example 12: p-Toluenesulfonate of the compound of formula I, Form VIII-A

[0254] About 30 mg of the raw material was weighed, and about 1 mL of isopropanol (or any solvent of isopropyl acetate, acetone, tetrahydrofuran or acetonitrile) was added to prepare a suspension. About 0.5 mL of the above solvent p-toluenesulfonic acid solution (1.1 eq.) was slowly added to the solution. The reaction solution was stirred and heated to 50° C., and stirred for 2 h. Then, the temperature was cooled with stirring. After the temperature dropped to 25° C., the temperature was kept stirred for 5 h for crystallization. The solid was separated to obtain the p-toluenesulfonate salt form VIII-A of the compound of formula I, and its X-ray powder diffraction pattern was as shown in FIG. Fig.16 Its DSC and TGA diagrams are shown in Fig.17 Its XRPD data are shown in Table 12.

[0255] The results showed that the p-toluenesulfonate salt form VIII-A had an endothermic peak at 186-190°C, and the TGA graph showed a weight loss of 0.71% at 170°C.

[0256] Table 12

[0257]

[0258]

[0259] Example 13: Hydrobromide salt of the compound of formula I, Form IX-A

[0260] About 30 mg of the raw material was weighed, and about 1 mL of acetone (or any solvent of tetrahydrofuran or acetonitrile) was added to prepare a suspension. About 0.5 mL of the above solvent hydrobromic acid solution (1.1 eq.) was slowly added to the solution. The reaction solution was stirred and heated to 50°C. After stirring for 2 hours, the temperature was cooled with stirring. After the temperature dropped to 25°C, the temperature was kept stirred for crystallization for 5 hours. The solid was separated to obtain the hydrobromide salt form IX-A of the compound of formula I, and its X-ray powder diffraction pattern was as shown in FIG. Fig.18 Its DSC and TGA diagrams are shown in Fig.19 Its XRPD data are shown in Table 13.

[0261] The results showed that the hydrobromide salt form IX-A had an endothermic peak at 178-190°C, and the TGA graph showed a weight loss of 4.15% at 156°C.

[0262] Table 13

[0263]

[0264]

[0265] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A crystalline form of a compound of formula I, characterized in that The crystalline form is selected from the group consisting of: Free form A of the compound of formula I; Free form B of the compound of formula I; Potassium salt of the compound of formula I in crystalline form IA, IB, IC; The tert-butylamine salt of the compound of formula I, form II-A; The diethylamine salt of the compound of formula I, form III-A; Lysine salt of the compound of formula I, crystal form IV-A; Sulfate salt of the compound of formula I, crystalline form VA; The edisylate salt of the compound of formula I, form VI-A; The benzenesulfonate salt of the compound of formula I, crystalline form VII-A; The p-toluenesulfonate salt of the compound of formula I in form VIII-A; and The hydrobromide salt of the compound of formula I is in form IX-A.

2. The crystalline form of claim 1, wherein The crystalline form is the free form A of the compound of formula I, and the free form A of the compound of formula I has the following X-ray powder diffraction characteristic peaks (2θ angle): 25.687°±0.2°, 16.866°±0.2°, 15.019°±0.2°, 24.296°±0.2°, 16.239°±0.2°; The crystalline form is the free form B of the compound of formula I, and the free form B of the compound of formula I has the following X-ray powder diffraction characteristic peaks (2θ angle): 15.317°±0.2°, 12.571°±0.2°, 14.255°±0.2°, 20.515°±0.2°, 18.899°±0.2°; The crystalline form is the potassium salt crystal form IA of the compound of formula I, and the potassium salt crystal form IA of the compound of formula I has the following X-ray powder diffraction characteristic peaks (2θ angle): 21.976°±0.2°, 7.45°±0.2°, 19.831°±0.2°, 27.93°±0.2°, 23.360°±0.2°; The crystalline form is the potassium salt crystal form IB of the compound of formula I, and the potassium salt crystal form IB of the compound of formula I has the following X-ray powder diffraction characteristic peaks (2θ angle): 23.540°±0.2°, 15.611°±0.2°, 5.168°±0.2°, 26.390°±0.2°, 20.874°±0.2°; The crystalline form is potassium salt crystal form IC of the compound of formula I, and the potassium salt crystal form IC of the compound of formula I has the following X-ray powder diffraction characteristic peaks (2θ angle): 23.074°±0.2°, 16.440°±0.2°, 5.502°±0.2°, 19.060°±0.2°, 15.278°±0.2°; The crystalline form is the tert-butylamine salt crystal form II-A of the compound of formula I, and the tert-butylamine salt crystal form II-A of the compound of formula I has the following X-ray powder diffraction characteristic peaks (2θ angle): 27.190°±0.2°, 18.440°±0.2°, 19.620°±0.2°, 24.346°±0.2°, 19.347°±0.2°; The crystalline form is the diethylamine salt crystal form III-A of the compound of formula I, and the diethylamine salt crystal form III-A of the compound of formula I has the following X-ray powder diffraction characteristic peaks (2θ angle): 13.503°±0.2°, 21.353°±0.2°, 15.135°±0.2°, 27.302°±0.2°, 25.513°±0.2°; The crystalline form is a lysine salt crystal form IV-A of the compound of formula I, and the lysine salt crystal form IV-A of the compound of formula I has the following X-ray powder diffraction characteristic peaks (2θ angle): 5.503°±0.2°, 17.999°±0.2°, 18.756°±0.2°, 20.28°±0.2°, 19.308°±0.2°; The crystalline form is the sulfate crystal form VA of the compound of formula I, and the sulfate crystal form VA of the compound of formula I has the following X-ray powder diffraction characteristic peaks (2θ angle): 5.910°±0.2°, 23.685°±0.2°, 24.017°±0.2°, 22.904°±0.2°, 11.764°±0.2°; The crystalline form is the edisylate salt form VI-A of the compound of formula I, and the edisylate salt form VI-A of the compound of formula I has the following X-ray powder diffraction characteristic peaks (2θ angle): 22.599°±0.2°, 23.361°±0.2°, 16.997°±0.2°, 18.562°±0.2°, 20.627°±0.2°; The crystalline form is the benzenesulfonate salt form VII-A of the compound of formula I, and the benzenesulfonate salt form VII-A of the compound of formula I has the following X-ray powder diffraction characteristic peaks (2θ angle): 23.346°±0.2°, 20.719°±0.2°, 15.9315°±0.2°, 14.924°±0.2°, 22.8°±0.2°; The crystalline form is a p-toluenesulfonate salt of the compound of formula I, form VIII-A, and the p-toluenesulfonate salt of the compound of formula I, form VIII-A, has the following X-ray powder diffraction characteristic peaks (2θ angle): 23.0953°±0.2°, 20.7502°±0.2°, 22.338°±0.2°, 28.076°±0.2°, 10.292°±0.2°; and The crystalline form is the hydrobromide salt form IX-A of the compound of formula I, and the hydrobromide salt form IX-A of the compound of formula I has the following X-ray powder diffraction characteristic peaks (2θ angle): 22.922°±0.2°, 20.085°±0.2°, 21.442°±0.2°, 9.610°±0.2°, and 25.306°±0.2°.

3. The crystalline form of claim 1, wherein The crystalline form is a free form A of the compound of formula I, and the X-ray powder diffraction pattern of the free form A of the compound of formula I includes 2 or more (3, 4 or 5) X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 16.013°±0.2°, 26.528°±0.2°, 15.347°±0.2°, 23.446°±0.2°, 24.465°±0.2°, 10.976°±0.2°; The crystalline form is a free form B of the compound of formula I, and the X-ray powder diffraction pattern of the free form B of the compound of formula I includes 2 or more (3, 4 or 5) X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 20.009°±0.2°, 15.007°±0.2°, 15.96°±0.2°, 28.675°±0.2°, 7.179°±0.2°, 25.661°±0.2°; The crystalline form is a potassium salt crystal form IA of the compound of formula I, and the X-ray powder diffraction pattern of the potassium salt crystal form IA of the compound of formula I includes 2 or more (3, 4 or 5) X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 12.56°±0.2°, 31.623°±0.2°, 6.516°±0.2°, 23.066°±0.2°, 24.798°±0.2°, 20.096°±0.2°; The crystalline form is a potassium salt crystal form IB of the compound of formula I, and the X-ray powder diffraction pattern of the potassium salt crystal form IB of the compound of formula I includes 2 or more (3, 4 or 5) X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 18.72°±0.2°, 8.464°±0.2°, 21.724°±0.2°, 11.92°±0.2°, 19.52°±0.2°, 9.67°±0.2°; The crystalline form is potassium salt crystal form IC of the compound of formula I, and the X-ray powder diffraction pattern of the potassium salt crystal form IC of the compound of formula I includes 2 or more (3, 4 or 5) X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 26.69°±0.2°, 14.04°±0.2°, 23.78°±0.2°, 6.208°±0.2°, 25.023°±0.2°, 29.666°±0.2°; The crystalline form is a tert-butylamine salt crystal form II-A of the compound of formula I, and the X-ray powder diffraction pattern of the tert-butylamine salt crystal form II-A of the compound of formula I includes 2 or more (3, 4 or 5) X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 25.77°±0.2°, 8.595°±0.2°, 18.119°±0.2°, 21.808°±0.2°, 26.377°±0.2°, 13.147°±0.2°; The crystalline form is the diethylamine salt crystal form III-A of the compound of formula I, and the X-ray powder diffraction pattern of the diethylamine salt crystal form III-A of the compound of formula I includes 2 or more (3, 4 or 5) X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 17.86°±0.2°, 10.9°±0.2°, 23.327°±0.2°, 22.046°±0.2°, 22.937°±0.2°, 24.85°±0.2°; The crystalline form is a lysine salt crystal form IV-A of the compound of formula I, and the X-ray powder diffraction pattern of the lysine salt crystal form IV-A of the compound of formula I includes 2 or more (3, 4 or 5) X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 13.667°±0.2°, 22.29°±0.2°, 26.82°±0.2°, 12.651°±0.2°, 7.66°±0.2°, 23.28°±0.2°; The crystalline form is the sulfate crystal form VA of the compound of formula I, and the X-ray powder diffraction pattern of the sulfate crystal form VA of the compound of formula I includes 2 or more (3, 4 or 5) X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 27.482°±0.2°, 22.685°±0.2°, 16.304°±0.2°, 14.977°±0.2°, 19.415°±0.2°, 26.241°±0.2°; The crystalline form is the edisylate salt form VI-A of the compound of formula I, and the X-ray powder diffraction pattern of the edisylate salt form VI-A of the compound of formula I includes 2 or more (3, 4 or 5) X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 19.782°±0.2°, 29.789°±0.2°, 20.457°±0.2°, 25.778°±0.2°, 22.377°±0.2°, 8.15°±0.2°; The crystalline form is a benzenesulfonate salt form VII-A of the compound of formula I, and the X-ray powder diffraction pattern of the benzenesulfonate salt form VII-A of the compound of formula I includes 2 or more (3, 4 or 5) X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 7.89°±0.2°, 10.259°±0.2°, 25.605°±0.2°, 15.634°±0.2°, 28.207°±0.2°, 24.119°±0.2°; The crystalline form is a p-toluenesulfonate salt of the compound of formula I, form VIII-A, and the X-ray powder diffraction pattern of the p-toluenesulfonate salt of the compound of formula I, form VIII-A, includes 2 or more (3, 4 or 5) X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 27.206°±0.2°, 15.475°±0.2°, 7.703°±0.2°, 15.711°±0.2°, 28.922°±0.2°, 18.48°±0.2°; The crystalline form is the hydrobromide salt form IX-A of the compound of formula I, and the X-ray powder diffraction pattern of the hydrobromide salt form IX-A of the compound of formula I includes 2 or more (3, 4 or 5) X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 28.761°±0.2°, 24.684°±0.2°, 32.311°±0.2°, 26.958°±0.2°, 28.179°±0.2°, 13.346°±0.2°.

4. The crystalline form of claim 1, wherein The crystalline form is the free form A of the compound of formula I, and the free form A of the compound of formula I also has one or more X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 22.75°±0.2°, 19.24°±0.2°, 22.453°±0.2°, 20.537°±0.2°, 23.744°±0.2°, 13.397°±0.2° , 28.697°±0.2°, 14.032°±0.2°, 16.4656°±0.2°, 18.004°±0.2°, 27.015°±0.2°, 30.567°±0.2°, 38.445°±0.2°, 28.436°±0.2°, 17.765°±0.2°, 32.87°±0.2°, 23.066°±0.2° .2°、20.754°±0.2°、21.096°±0.2°、5.082°±0.2°、26.235°±0.2°、18.904°±0.2°、37.77°±0.2°、25.082°±0.2°、15.597°±0.2°、11.27°±0.2°、35.2°±0.2°、31.241°±0.2 °, 27.42°±0.2°, 17.404°±0.2°, 33.436°±0.2°, 37.155°±0.2°, 36.367°±0.2°, 33.979°±0.2°, 12.04°±0.2°, 33.658°±0.2°, 28.17°±0.2°, 31.902°±0.2°, 39.26°±0.2°; The crystalline form is the free form B of the compound of formula I, and the free form B of the compound of formula I also has one or more X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 24.29°±0.2°, 26.152°±0.2°, 9.73°±0.2°, 25.373°±0.2°, 16.88°±0.2°, 31.054°±0.2°, 38.434°±0.2°, 9.33°±0.2°, 10.921°±0.2°, 30.56°±0.2°, 35.22°±0.2°, 13.38°±0.2°; The crystalline form is the potassium salt crystal form IA of the compound of formula I, and the potassium salt crystal form IA of the compound of formula I also has one or more X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 13.281°±0.2°, 33.447°±0.2°, 10.872°±0.2°, 29.749°±0.2°, 26.887°±0.2°, 16.891°±0.2°, 26.006°±0.2°, 19.531°±0.2°, 25.384°±0. 2°, 38.47°±0.2°, 39.211°±0.2°, 18.5°±0.2°, 36.544°±0.2°, 17.324°±0.2°, 35.754°±0.2°, 34.092°±0.2°, 21.088°±0.2°, 37.68°±0.2°, 18.787°±0.2°, 14.115°±0.2°, 36.926°±0.2°, 16.36°±0.2°, 20.412°±0.2°; The crystalline form is the potassium salt crystal form IB of the compound of formula I, and the potassium salt crystal form IB of the compound of formula I also has one or more X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 10.33°±0.2°, 17.46°±0.2°, 24.646°±0.2°, 14.3°±0.2°, 12.716°±0.2°, 14.88°±0.2°, 14.07°±0.2°; The crystalline form is the potassium salt crystal form IC of the compound of formula I, and the potassium salt crystal form IC of the compound of formula I also has one or more X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 30.766°±0.2°, 18.13°±0.2°, 11.57°±0.2°, 17.518°±0.2°, 28.11°±0.2°, 30.1°±0.2°, 12.74°±0.2°, 20.862°±0.2°, 35.1 °±0.2°, 9.746°±0.2°, 16.019°±0.2°, 25.84°±0.2°, 13.196°±0.2°, 28.86°±0.2°, 10.27°±0.2°, 21.163°±0.2°, 6.853°±0.2°, 8.41°±0.2°, 27.166°±0.2°, 23.977°±0.2°, 11.996°±0.2°, 14.56°±0.2°; The crystalline form is the tert-butylamine salt crystal form II-A of the compound of formula I, and the tert-butylamine salt crystal form II-A of the compound of formula I also has one or more X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 17.37°±0.2°, 24.918°±0.2°, 15.458°±0.2°, 21.201°±0.2°, 13.78°±0.2°, 14.876°±0.2° , 29.483°±0.2°, 14.342°±0.2°, 24.031°±0.2°, 22.78°±0.2°, 10.72°±0.2°, 6.025°±0.2°, 28.161°±0.2°, 31.02°±0.2°, 37.86°±0.2°, 38.57°±0.2°, 6.396°±0.2°, 29.06°±0.2°; The crystalline form is the diethylamine salt crystal form III-A of the compound of formula I, and the diethylamine salt crystal form III-A of the compound of formula I also has one or more X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 18.483°±0.2°, 27.12°±0.2°, 15.45°±0.2°, 30.68°±0.2°, 16.447°±0.2°, 10.661°±0.2°, 38.568°±0.2°, 12.51°±0.2°, 15.864°±0.2°, 18.129°±0.2°, 26.059°±0.2°, 28.866°±0.2°, 16.701°±0.2°, 26.592°±0.2°, 11 .174°±0.2°、11.571°±0.2°、20.07°±0.2°、7.796°±0.2°、26.38°±0.2°、20.42°±0.2°、17.328°±0.2°、32.4°±0.2°、27.64°±0.2°、22.546°±0.2°、6.415° ±0.2°, 19.35°±0.2°, 18.79°±0.2°, 8.669°±0.2°, 8.83°±0.2°, 31.508°±0.2°, 38.163°±0.2°, 8.134°±0.2°, 34.19°±0.2°, 36.295°±0.2°, 33.06°±0.2°; The crystalline form is a lysine salt crystal form IV-A of the compound of formula I, and the lysine salt crystal form IV-A of the compound of formula I also has one or more X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 16.607°±0.2°, 17.618°±0.2°, 14.92°±0.2°, 20.603°±0.2°, 10.12°±0.2°, 24.29°±0.2°, 15.371°±0.2°, 14.039°±0.2°, 28.95°±0.2°, 30.56°±0.2°, 11.35°±0.2°; The crystalline form is the sulfate crystal form VA of the compound of formula I, and the sulfate crystal form VA of the compound of formula I also has one or more X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 18.785°±0.2°, 26.55°±0.2°, 34.916°±0.2°, 35.921°±0.2°, 38.403°±0.2°, 20. 624°±0.2°、33.494°±0.2°、25.479°±0.2°、33.048°±0.2°、20.913°±0.2°、22.025°±0.2°、19.507°±0.2°、15.248°±0.2°、17.585°±0.2°、19.891°±0.2°、27.932°± 0.2°、8.01°±0.2°、1.284°±0.2°、27.136°±0.2°、30.61°±0.2°、35.664°±0.2°、31.072°±0.2°、39.569°±0.2°、30.3°±0.2°、32.618°±0.2°、36.535°±0.2°、23.43 4°±0.2°, 17.31°±0.2°, 14.279°±0.2°, 34.056°±0.2°, 24.62°±0.2°, 31.551°±0.2°, 37.22°±0.2°, 28.697°±0.2°, 29.762°±0.2°, 38.846°±0.2°, 21.857°±0.2°; The crystalline form is the edisylate salt form VI-A of the compound of formula I, and the edisylate salt form VI-A of the compound of formula I also has one or more X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 24.83°±0.2°, 26.088°±0.2°, 18.143°±0.2°, 26.84°±0.2°, 23.693°±0.2°, 17.953°±0.2°, 25.217°±0.2°, 25.38°±0.2°, 17.533°±0.2°, 28.5°±0.2°, 12.272°±0.2°, 34.74°±0.2°, 35.3°±0.2°, 9.352°±0.2°, 22.888°±0.2°. .2°, 30.378°±0.2°, 38.65°±0.2°, 35.89°±0.2°, 29.105°±0.2°, 33.364°±0.2°, 24.034°±0.2°, 27.079°±0.2°, 15.74°±0.2°, 29.411°±0.2°, 20.986°±0. 2°, 37.81°±0.2°, 32.148°±0.2°, 30.061°±0.2°, 16.43°±0.2°, 22.15°±0.2°, 14.943°±0.2°, 30.883°±0.2°, 36.557°±0.2°, 14.627°±0.2°, 39.23°±0.2°; The crystalline form is the benzenesulfonate salt form VII-A of the compound of formula I, and the benzenesulfonate salt form VII-A of the compound of formula I also has one or more X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 29.698°±0.2°, 26.27°±0.2°, 17.603°±0.2°, 20.993°±0.2°, 16.921°±0.2°, 19 .222°±0.2°、27.739°±0.2°、9.846°±0.2°、27.169°±0.2°、18.635°±0.2°、28.997°±0.2°、28.7°±0.2°、10.9°±0.2°、32.333°±0.2°、15.353°±0.2°、5.135°±0.2°、26.46° ±0.2°, 31.357°±0.2°, 24.453°±0.2°, 33.165°±0.2°, 16.21°±0.2°, 4.973°±0.2°, 37.878°±0.2°, 29.218°±0.2°, 36.643°±0.2°, 37.172°±0.2°, 28.502°±0.2°, 35.217° ±0.2°, 14.376°±0.2°, 35.65°±0.2°, 32.855°±0.2°, 38.46°±0.2°, 19.85°±0.2°, 31.95°±0.2°, 36.04°±0.2°, 13.39°±0.2°, 20.16°±0.2°, 14.086°±0.2°, 17.304°±0.2°; The crystalline form is the p-toluenesulfonate crystalline form VIII-A of the compound of formula I, and the p-toluenesulfonate crystalline form VIII-A of the compound of formula I also has one or more X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 14.705°±0.2°, 23.818°±0.2°, 31.376°±0.2°, 26.965°±0.2°, 17.653°±0.2°, 24.94°±0.2°, 26.311°±0.2°, 27.837°±0.2°, 28.589°±0.2°, 17.167°±0.2°, 31.826°±0.2°, 36.138°±0.2°, 14.484°±0.2°, 34.414°±0.2°, 25.331°±0.2° .2°、35.824°±0.2°、37.621°±0.2°、20.16°±0.2°、31.159°±0.2°、30.17°±0.2°、35.609°±0.2°、32.966°±0.2°、9.602°±0.2°、14.129°±0.2°、4.844°±0.2°、33.28 4°±0.2°, 16.768°±0.2°, 29.274°±0.2°, 38.261°±0.2°, 38.49°±0.2°, 19.753°±0.2°, 37.885°±0.2°, 35.082°±0.2°, 37.275°±0.2°, 32.477°±0.2°, 32.68°±0.2°; The crystalline form is the hydrobromide salt form IX-A of the compound of formula I, and the hydrobromide salt form IX-A of the compound of formula I also has one or more X-ray powder diffraction characteristic peaks (2θ angle) selected from the following group: 7.987°±0.2°, 6.663°±0.2°, 38.253°±0.2°, 21.803°±0.2°, 13.138°±0.2°, 35.993°±0.2°, 24.118°±0.2°, 32.931°±0.2°, 30.252°±0.2°, 11.395°±0.2°, 20.786°±0.2°, 25.808°±0.2°, 18.306°±0.2°, 16.048° ±0.2°, 33.484°±0.2°, 19.47°±0.2°, 36.993°±0.2°, 17.954°±0.2°, 30.856°±0.2°, 39.22°±0.2°, 16.889°±0.2°, 29.64°±0.2°, 31.647°±0.2°, 14. 81°±0.2°, 10.69°±0.2°, 15.757°±0.2°, 18.694°±0.2°, 22.173°±0.2°, 36.489°±0.2°, 34.129°±0.2°, 30.574°±0.2°, 16.379°±0.2°, 31.48°±0.2°.

5. The crystalline form of claim 1, wherein The crystalline form is a free-state crystalline form A of the compound of formula I, and the DSC spectrum of the free-state crystalline form A of the compound of formula I has an endothermic peak at 214-216° C.; and / or The crystalline form is the free form B of the compound of formula I, and the DSC spectrum of the free form B of the compound of formula I has an endothermic peak at 208-216°C.

6. The crystalline form of claim 1, wherein (A) The crystalline form is the free form A of the compound of formula I, and the free form A of the compound of formula I also has one or more of the following characteristics: (1) the free form crystalline form A of the compound of formula I has XRPD data substantially as shown in Table 1; and / or (2) The free form Form A of the compound of Formula I has an XRPD spectrum substantially as shown in FIG1 ; (3) The free form crystalline form A of the compound of formula I has a DSC & TGA spectrum substantially as shown in FIG2 ; (B) The crystalline form is the free form B of the compound of formula I, and the free form B of the compound of formula I also has one or more of the following characteristics: (1) the free form of the compound of formula I, Form B, has XRPD data substantially as shown in Table 2; and / or (2) the free form Form B of the compound of Formula I has an XRPD spectrum substantially as shown in FIG3 ; (3) The free form of the compound of formula I, Form B, has a DSC & TGA spectrum substantially as shown in FIG4 ; (IA) The crystalline form is the potassium salt of the compound of formula I, Form IA, and the potassium salt of the compound of formula I, Form IA, also has one or more of the following characteristics: (1) The potassium salt of the compound of Formula I, Form IA, has XRPD data substantially as shown in Table 3; and / or (2) the potassium salt of the compound of Formula I, Form IA, has an XRPD spectrum substantially as shown in FIG5 ; (IB) The crystalline form is the potassium salt of the compound of formula I, Form IB, and the potassium salt of the compound of formula I, Form IB, also has one or more of the following characteristics: (1) the potassium salt of the compound of formula I, Form IB, has XRPD data substantially as shown in Table 4; and / or (2) the potassium salt of the compound of Formula I, Form IB, has an XRPD spectrum substantially as shown in FIG6 ; (IC) The crystalline form is the potassium salt of the compound of formula I, form IC, and the potassium salt of the compound of formula I, form IC, also has one or more of the following characteristics: (1) the potassium salt of the compound of formula I, Form IC, has XRPD data substantially as shown in Table 5; and / or (2) the potassium salt of the compound of Formula I, Form IC, has an XRPD spectrum substantially as shown in FIG7 ; The crystalline form (II-A) is the tert-butylamine salt crystalline form II-A of the compound of formula I, and the tert-butylamine salt crystalline form II-A of the compound of formula I also has one or more of the following characteristics: (1) the tert-butylamine salt of the compound of formula I, Form II-A, has XRPD data substantially as shown in Table 6; and / or (2) The tert-butylamine salt of the compound of Formula I, Form II-A, has an XRPD spectrum substantially as shown in FIG8 ; The crystalline form (III-A) is the diethylamine salt crystalline form III-A of the compound of formula I, and the diethylamine salt crystalline form III-A of the compound of formula I also has one or more of the following characteristics: (1) the diethylamine salt crystalline form III-A of the compound of formula I has XRPD data substantially as shown in Table 7; and / or (2) the diethylamine salt of the compound of Formula I, Form III-A, has an XRPD spectrum substantially as shown in FIG. 9 ; (IV-A) The crystalline form is the lysine salt crystal form IV-A of the compound of formula I, and the lysine salt crystal form IV-A of the compound of formula I also has one or more of the following characteristics: (1) the lysine salt form IV-A of the compound of formula I has XRPD data substantially as shown in Table 8; and / or (2) the lysine salt of the compound of formula I, Form IV-A, has an XRPD spectrum substantially as shown in FIG10 ; (VA) The crystalline form is the sulfate salt of the compound of formula I, form VA, and the sulfate salt of the compound of formula I, form VA, also has one or more of the following characteristics: (1) the sulfate salt of the compound of formula I, Form VA, has XRPD data substantially as shown in Table 9; and / or (2) the sulfate salt of the compound of Formula I, Form VA, has an XRPD pattern substantially as shown in FIG. 11 ; The crystalline form (VI-A) is the edisylate salt of the compound of formula I, crystalline form VI-A, and the edisylate salt of the compound of formula I, crystalline form VI-A, also has one or more of the following characteristics: (1) the edisylate salt form VI-A of the compound of formula I has XRPD data substantially as shown in Table 10; and / or (2) the edisylate salt of the compound of Formula I, Form VI-A, has an XRPD spectrum substantially as shown in FIG. 12 ; and / or (3) The edisylate salt form VI-A of the compound of formula I has a DSC & TGA spectrum substantially as shown in FIG. 13 ; The crystalline form (VII-A) is the benzenesulfonate salt form VII-A of the compound of formula I, and the benzenesulfonate salt form VII-A of the compound of formula I also has one or more of the following characteristics: (1) the benzenesulfonate salt form VII-A of the compound of formula I has XRPD data substantially as shown in Table 11; and / or (2) the benzenesulfonate salt form VII-A of the compound of formula I has an XRPD spectrum substantially as shown in FIG. 14 ; and / or (3) The benzenesulfonate salt form VII-A of the compound of formula I has a DSC & TGA spectrum substantially as shown in FIG15 ; The crystalline form (VIII-A) is the p-toluenesulfonate crystalline form VIII-A of the compound of formula I, and the p-toluenesulfonate crystalline form VIII-A of the compound of formula I also has one or more of the following characteristics: (1) the p-toluenesulfonate salt form VIII-A of the compound of formula I has XRPD data substantially as shown in Table 12; and / or (2) the p-toluenesulfonate salt of the compound of Formula I, Form VIII-A, has an XRPD spectrum substantially as shown in FIG. 16 ; and / or (3) The p-toluenesulfonate salt form VIII-A of the compound of Formula I has a DSC&TGA spectrum substantially as shown in FIG17 ; The crystalline form (IX-A) is the hydrobromide salt of the compound of formula I, crystalline form IX-A, and the hydrobromide salt of the compound of formula I, crystalline form IX-A, further has one or more of the following characteristics: (1) the hydrobromide salt form IX-A of the compound of formula I has XRPD data substantially as shown in Table 13; and / or (2) the hydrobromide salt form IX-A of the compound of formula I has an XRPD spectrum substantially as shown in FIG. 18 ; and / or (3) The hydrobromide salt form IX-A of the compound of formula I has a DSC&TGA spectrum basically as shown in Figure 19.

7. A method for preparing the crystalline form of claim 1, characterized in that: The steps include: (a) dissolving the compound of formula I in a first solvent, cooling and crystallizing to obtain a free-state crystalline form; (b) dissolving the raw material of the compound of formula I in a first solvent, suspending and stirring at room temperature for crystallization, and (evaporating) obtaining a free-state crystalline form; (c) dissolving the raw material of the compound of formula I in the first solvent, heating and stirring, cooling to 0° C. for crystallization to obtain a free-state crystalline form; (d) dissolving the compound of formula I in a first solvent, adding an anti-solvent, stirring and crystallizing to obtain a free-state crystalline form; or (e) dissolving the free crystalline form of the compound of formula I in a second solvent, adding an acid or a base, heating and stirring, and cooling to crystallize to obtain an acid salt crystalline form or a basic salt crystalline form.

8. A pharmaceutical composition, characterized in that Contains (a) the crystalline form according to claim 1 as an active ingredient; and (b) a pharmaceutically acceptable carrier.

9. The pharmaceutical composition according to claim 8, characterized in that The dosage form of the pharmaceutical composition is selected from the following group: powder, capsule, granule, tablet, pill, cream, orodispersible film, suspension or injection.

10. Use of the crystalline form according to claim 1 or the pharmaceutical composition according to claim 8, characterized in that Used for preparing a medicine or preparation, wherein the medicine or preparation is used for preventing and / or treating diseases caused by HIV infection.

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