Pharmaceutical salt of TLR7 / 8 agonist, crystal form, preparation method of pharmaceutical salt, pharmaceutical composition and application of pharmaceutical salt and crystal form of TLR7 / 8 agonist

Abstract

Provided are a pharmaceutically acceptable salt, a crystal form and a preparation method of a TLR7 / 8 agonist compound of formula I, a pharmaceutical composition containing the pharmaceutically acceptable salt, and a medical use of the pharmaceutically acceptable salt, which can be used for preparing drugs for preventing or treating Toll-like receptor 7 / 8 (TLR7 / 8) related diseases, such as a new therapeutic agent for human immunodeficiency virus (HIV) infection, hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection and cancer.

Description

A pharmaceutically acceptable salt, crystal form, preparation method, pharmaceutical composition and use of a TLR7 / 8 agonist Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry. Specifically, the present invention relates to a pharmaceutically acceptable salt of a TLR7 / 8 agonist, a crystal form and a preparation method thereof, a pharmaceutical composition comprising the pharmaceutically acceptable salt, and the medical use of the pharmaceutically acceptable salt. The present invention also relates to different crystal forms of different salts, their preparation methods, crystalline compositions comprising the crystal forms, pharmaceutical compositions comprising the crystal forms or crystalline compositions, and their medical uses. Background Art

[0002] Toll-like receptors (TLRs) are a class of structurally conserved proteins that form the first line of defense in the innate immune response. By recognizing various conserved pathogen-associated molecular patterns (PAMPs), TLRs can identify invasive microorganisms and endogenous molecules released after tissue damage or non-physiological cell death, and activate signaling cascades, leading to the production of pro-inflammatory cytokines. The inflammatory process is crucial to the occurrence and progression of many diseases, such as type 1 diabetes, sepsis, cancer, and viral infections. Therefore, the strategy of manipulating the inflammatory response through small molecule TLRs modulators to treat related diseases is very promising.

[0003] The human TLRs family has 10 known members, which are type I transmembrane proteins characterized by a leucine-rich extracellular domain and a cytoplasmic tail containing the conserved Toll / interleukin (IL)-1 receptor (TIR) ​​domain. In this family, TLR3, TLR7, TLR8, and TLR9 are localized in the endosomal compartment.

[0004] Both TLR7 and TLR8 recognize RNA molecules (ssRNA) from single-stranded RNA viruses. TLR7 is primarily expressed in plasmacytoid dendritic cells and B cells. TLR8 is primarily distributed in mDCs, macrophages, and monocytes, and is also expressed in T cells. TLR7 stimulation primarily induces the production of type I interferons, including interferon-α (IFN-α), and causes the transcription of interferon-stimulated genes (ISGs). Interferon-α is one of the main drugs for the treatment of chronic hepatitis B or C. TLR8 is primarily distributed in mDCs, macrophages, and monocytes, and is also expressed in T cells. TLR8 activation primarily produces a pro-inflammatory response, stimulating immune cells to secrete pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α) and IL-6. The distribution and downstream signaling pathways of TLR7 / 8 overlap, and therefore they share functional similarities. Upon activation, TLR7 / 8 can exert direct antiviral activity through the type I interferon response. It can also regulate innate immunity through pro-inflammatory responses, promoting the activation of NK and NKT cells. It can also induce adaptive immunity, improve antigen presentation, and activate dendritic cells, thereby enhancing T cell responses and promoting the differentiation of antibody-producing B cells. The development of TLR7 / 8 agonists has significant clinical value in both antiviral and anti-tumor therapies, and can also be used in antibody-drug conjugates and vaccine adjuvants.

[0005] There are currently several related TLR7 / 8 agonist patent applications, but there is still a need to continue to develop highly active, safer and therapeutically effective TLR7 / 8 agonists.

[0006] Summary of the Invention

[0007] In a first aspect, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, solvate, cocrystal, or combination thereof in a solid form, characterized in that the solid form is an amorphous form, different crystalline forms of the free state, a pharmaceutically acceptable salt thereof, different crystalline forms of the cocrystal, or a combination thereof:

[0008] In some embodiments, the solid form is selected from the group consisting of inorganic acid salts such as hydrochloric acid, phosphate, and sulfate; or organic acid salts such as acetate, methanesulfonate, L-tartrate, lactate, p-toluenesulfonate, fumarate, oxalate, malate, benzoate, citrate, D-tartrate, succinate, pamoate, and xinafoate. Preferably, the solid form is hydrochloric acid, fumarate, oxalate, malate, and succinate.

[0009] In some embodiments, the solid form is selected from the group consisting of:

[0010] The hydrochloride salt of the compound of formula I;

[0011] a fumarate salt of a compound of formula I;

[0012] an oxalate salt of a compound of formula I;

[0013] a malate salt of a compound of formula I; or

[0014] A succinate salt of the compound of formula I.

[0015] In some embodiments, in the solid form, in the inorganic acid salt or organic acid salt of the compound of formula I, the compound of formula I and the inorganic acid or organic acid are present in the co-crystal in a ratio of 1-3:3-1; preferably, the ratio of the compound of formula I to the inorganic acid or organic acid is 1:1, 1:2, 1:3, 3:1 or 2:1; more preferably, the ratio of the compound of formula I to the inorganic acid or organic acid is 1:1 or 1:2.

[0016] In some embodiments, the solid form is selected from the following group: amorphous form, free form A of the compound of formula I, free form B of the compound of formula I, free form C of the compound of formula I, free form D of the compound of formula I, fumarate form A of the compound of formula I, fumarate form B of the compound of formula I, oxalate form A of the compound of formula I, oxalate form B of the compound of formula I, malate form A of the compound of formula I, succinate form A of the compound of formula I, succinate form B of the compound of formula I, succinate form C of the compound of formula I, hydrochloride form A of the compound of formula I.

[0017] In some embodiments, the solid form is selected from the group consisting of:

[0018] The free form A of the compound of formula I has one or more 2θ diffraction peaks selected from the group consisting of: 3.39, 6.16, 6.68, 8.39, 9.40, 10.06, 10.44, 10.65, 10.98, 11.34, 11.55, 12.42, 13.27, 14.08, 14.56, 14.9 8, 15.61, 16.04, 16.45, 17.08, 17.59, 18.29, 18.70, 19.24, 19.43, 19.98, 20.21, 20.68, 21.40, 22.06, 22.53, 23.31, 23.92, 24.40, 24.78, 25.60, 27.13 and 28.06;

[0019] The free form B of the compound of formula I has one or more 2θ diffraction peaks selected from the following group in the X-ray powder diffraction peak pattern: 3.05, 5.35, 5.93, 8.88, 10.55, 10.96, 11.31, 11.72, 12.07, 12.78, 13.94, 14.76, 15.13, 15.85, 16.52, 17. 34, 18.38, 18.85, 19.12, 19.29, 19.66, 19.99, 20.71, 21.12, 21.89, 22.55, 23.39, 24.73, 25.28, 25.86, 26.40, 26.88, 27.47, 27.91, 31.73, 32.25, 33.02 and 33.44;

[0020] The free form C of the compound of formula I has one or more 2θ diffraction peaks selected from the following group in the X-ray powder diffraction peak pattern: 5.42, 6.03, 6.62, 9.21, 10.13, 11.56, 12.39, 13.37, 13.96, 14.53, 15.45, 15.97, 16.39, 17.05, 18.61, 18.86, 19.27, 20.65, 21.24, 21.63, 22.37, 23.02, 24.44, 25.37, 26.58, 29.01 and 31.62;

[0021] The free form D of the compound of formula I has one or more 2θ diffraction peaks selected from the following group in the X-ray powder diffraction peak pattern: 5.39, 5.84, 7.46, 10.89, 11.74, 13.25, 15.11, 15.89, 16.39, 16.59, 17.22, 18.77, 19.16, 19.52, 20.42, 21.03, 21.74, 22.64, 23.23, 24.40, 25.01, 26.45, 26.94, 28.11, 28.58, 30.51, 33.71 and 37.15;

[0022] The fumarate crystalline form A of the compound of formula I, which has one or more 2θ diffraction peaks selected from the following group in the X-ray powder diffraction peak pattern: 5.19, 5.57, 8.78, 11.90, 12.83, 15.13, 15.75, 16.20, 17.36, 17.85, 18.39, 18.72, 20.36, 20.87, 21.83, 22.59, 23.40, 24.21, 25.85, 26.23, 26.60, 27.40, 28.51, 28.95, 29.60 and 30.30;

[0023] The fumarate crystalline form B of the compound of formula I, which has one or more 2θ diffraction peaks selected from the following group in the X-ray powder diffraction peak pattern: 5.35, 7.65, 9.28, 10.10, 10.83, 14.32, 15.79, 17.12, 19.10, 20.46, 21.83, 22.49, 23.47, 24.52 and 27.55;

[0024] The oxalate salt form A of the compound of formula I, which has one or more 2θ diffraction peaks selected from the following group in the X-ray powder diffraction peak pattern: 6.28, 6.98, 7.40, 9.49, 10.37, 11.47, 11.92, 12.65, 14.04, 14.90, 15.51, 15.95, 17.57, 18.02, 18.31, 18.85, 19.15, 19.49, 20.67, 21.15, 21.78, 22.62, 22.87, 23.19, 24.23, 24.57, 25.31, 25.86, 26.49, 27.24, 28.14 and 28.74;

[0025] The oxalate salt form B of the compound of formula I, which has one or more 2θ diffraction peaks selected from the group consisting of: 6.55, 7.39, 9.24, 10.16, 11.65, 12.39, 13.70, 14.63, 17.31, 17.59, 18.64, 19.35, 19.78, 20.42, 20.96, 21.78, 23.31, 23.94, 25.16, 26.15, 27.34, and 29.25 in an X-ray powder diffraction peak pattern;

[0026] The malate crystalline form A of the compound of formula I, which has one or more 2θ diffraction peaks selected from the following group in the X-ray powder diffraction peak pattern: 5.21, 5.61, 8.78, 9.03, 11.86, 12.68, 15.21, 15.63, 16.01, 17.10, 17.64, 17.90, 18.03, 18.28, 18.60, 19.81, 20.21, 23.33, 23.71, 24.02, 24.42, 25.62, 27.36, 27.91 and 28.38;

[0027] The succinate salt form A of the compound of formula I has one or more 2θ diffraction peaks selected from the following group in the X-ray powder diffraction peak pattern: 5.21, 5.70, 8.98, 9.24, 9.97, 10.48, 12.83, 14.38, 15.41, 15.91, 16.19, 16.45, 16.83, 17.55, 18. 03, 18.64, 18.88, 20.04, 20.63, 21.07, 21.80, 22.19, 23.06, 23.58, 24.12, 24.34, 24.66, 25.28, 25.89, 26.48, 27.67, 28.26, 28.66, 29.16, 30.32 and 31.71;

[0028] The succinate salt form B of the compound of formula I, which has one or more 2θ diffraction peaks selected from the following group in the X-ray powder diffraction peak pattern: 4.80, 5.19, 5.57, 8.99, 9.51, 12.40, 12.90, 13.35, 13.94, 14.92, 15.59, 16.55, 16.98, 17.78, 18.27, 18.68, 19.50, 21.16, 20.54, 21.09, 21.84, 22.35, 23.98, 24.27, 25.75, 26.08, 26.67, 27.05, 27.44, 28.14, 28.68, 29.58, 30.07, 30.97 and 31.40;

[0029] The succinate salt form C of the compound of formula I has one or more 2θ diffraction peaks selected from the following group in the X-ray powder diffraction peak pattern: 6.41, 6.95, 7.54, 10.52, 10.68, 11.25, 11.69, 12.38, 13.01, 13.94, 14.29, 15.26, 15.53, 16.29, 17.14, 17.61, 18.03, 18.32, 19.08, 19.50, 20.50, 21.55, 21.78, 22.17, 22.60, 23.06, 24.03, 24.64, 25.19, 25.62, 26.84, 27.32, 27.88 and 28.18.

[0030] In another preferred embodiment, the free crystalline form A of the compound of formula I has at least a 2θ diffraction peak selected from the following group: 3.39, 6.16, 6.68, 10.06, and 12.42 in the X-ray powder diffraction peak spectrum.

[0031] In another preferred embodiment, the free crystalline form A of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 3.39, 6.16, 6.68, 10.06, 12.42, 18.7, 20.68, and 21.4.

[0032] In another preferred embodiment, the free form A of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 3.39, 6.16, 6.68, 10.06, 10.44, 12.42, 18.29, 18.7, 20.68, and 21.4.

[0033] In another preferred embodiment, the free form B of the compound of formula I has at least a 2θ diffraction peak selected from the following group: 3.05, 5.93, 20.71, 21.12, and 21.89 in the X-ray powder diffraction peak spectrum.

[0034] In another preferred embodiment, the free form B of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 3.05, 5.35, 5.93, 12.78, 18.38, 20.71, 21.12, and 21.89.

[0035] In another preferred embodiment, the free form B of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 3.05, 5.35, 5.93, 12.78, 18.38, 18.85, 19.66, 20.71, 21.12, and 21.89.

[0036] In another preferred embodiment, the free form C of the compound of formula I has at least a 2θ diffraction peak selected from the following group: 5.42, 6.03, 6.62, 10.13, and 11.56 in the X-ray powder diffraction peak spectrum.

[0037] In another preferred embodiment, the free form C of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 5.42, 6.03, 6.62, 9.21, 10.13, 11.56, 12.39, 17.05.

[0038] In another preferred embodiment, the free form C of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 5.42, 6.03, 6.62, 9.21, 10.13, 11.56, 12.39, 17.05, 20.65, and 21.24.

[0039] In another preferred embodiment, the free form D of the compound of formula I has at least a 2θ diffraction peak selected from the following group: 5.39, 5.84, 11.74, 13.25, and 17.22 in the X-ray powder diffraction peak spectrum.

[0040] In another preferred embodiment, the free form D of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 5.39, 5.84, 10.89, 11.74, 13.25, 15.11, 17.22, and 19.16.

[0041] In another preferred embodiment, the free form D of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 5.39, 5.84, 10.89, 11.74, 13.25, 15.11, 15.89, 17.22, 19.16, and 22.64.

[0042] In another preferred embodiment, the fumarate salt form A of the compound of formula I has at least a 2θ diffraction peak selected from the following group: 5.19, 5.57, 8.78, 15.75, and 17.85 in the X-ray powder diffraction peak spectrum.

[0043] In another preferred embodiment, the fumarate salt form A of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 5.19, 5.57, 8.78, 15.75, 17.36, 17.85, 20.36, and 24.21.

[0044] In another preferred embodiment, the fumarate salt form A of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 5.19, 5.57, 8.78, 15.75, 16.2, 17.36, 17.85, 20.36, 23.4, and 24.21.

[0045] In another preferred embodiment, the fumarate salt form B of the compound of formula I has at least a 2θ diffraction peak selected from the following group: 5.35, 7.65, 9.28, 17.12, and 24.52 in the X-ray powder diffraction peak spectrum.

[0046] In another preferred embodiment, the fumarate salt form B of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 5.35, 7.65, 9.28, 10.1, 10.83, 17.12, 23.47, 24.52.

[0047] In another preferred embodiment, the fumarate salt form B of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 5.35, 7.65, 9.28, 10.1, 10.83, 17.12, 19.1, 21.83, 23.47, and 24.52.

[0048] In another preferred embodiment, the oxalate salt form A of the compound of formula I has at least a 2θ diffraction peak selected from the following group: 6.98, 7.4, 9.49, 18.02, and 19.49 in the X-ray powder diffraction peak spectrum.

[0049] In another preferred embodiment, the oxalate salt form A of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 6.98, 7.4, 9.49, 18.02, 18.31, 19.15, 19.49, 22.62.

[0050] In another preferred example, the oxalate salt form A of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 6.98, 7.4, 9.49, 18.02, 18.31, 19.15, 19.49, 22.62, 22.87, and 23.19.

[0051] In another preferred embodiment, the oxalate salt form B of the compound of formula I has at least a 2θ diffraction peak selected from the following group: 6.55, 7.39, 9.24, 13.7, and 17.31 in the X-ray powder diffraction peak spectrum.

[0052] In another preferred embodiment, the oxalate salt form B of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 6.55, 7.39, 9.24, 12.39, 13.7, 17.31, 17.59, 20.96.

[0053] In another preferred example, the oxalate salt form B of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 6.55, 7.39, 9.24, 12.39, 13.7, 17.31, 17.59, 18.64, 20.96, and 21.78.

[0054] In another preferred embodiment, the malate salt form A of the compound of formula I has at least a 2θ diffraction peak selected from the following group: 5.61, 8.78, 17.64, 17.9, and 18.03 in the X-ray powder diffraction peak spectrum.

[0055] In another preferred example, the malate salt form A of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 5.21, 5.61, 8.78, 17.1, 17.64, 17.9, 18.03, and 18.28.

[0056] In another preferred example, the malate salt form A of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 5.21, 5.61, 8.78, 15.63, 17.1, 17.64, 17.9, 18.03, 18.28, and 20.21.

[0057] In another preferred embodiment, the succinate salt form A of the compound of formula I has at least a 2θ diffraction peak selected from the following group: 5.21, 5.7, 8.98, 17.55, and 18.03 in the X-ray powder diffraction peak spectrum.

[0058] In another preferred example, the succinate salt form A of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 5.21, 5.7, 8.98, 9.24, 16.19, 17.55, 18.03, and 20.63.

[0059] In another preferred example, the succinate salt form A of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 5.21, 5.7, 8.98, 9.24, 15.91, 16.19, 16.45, 17.55, 18.03, and 20.63.

[0060] In another preferred embodiment, the succinate salt form B of the compound of formula I has at least a 2θ diffraction peak selected from the following group: 5.19, 5.57, 8.99, 17.78, and 20.54 in the X-ray powder diffraction peak spectrum.

[0061] In another preferred example, the succinate salt form B of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 5.19, 5.57, 8.99, 15.59, 17.78, 20.54, 23.98, and 24.27.

[0062] In another preferred example, the succinate salt form B of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 5.19, 5.57, 8.99, 15.59, 16.55, 17.78, 20.54, 23.04, 23.98, and 24.27.

[0063] In another preferred embodiment, the succinate salt form C of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 6.41, 7.54, 11.25, 11.69, 13.94.

[0064] In another preferred example, the succinate salt form C of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 6.41, 6.95, 7.54, 11.25, 11.69, 13.94, 18.03, and 24.03.

[0065] In another preferred example, the succinate salt form C of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 6.41, 6.95, 7.54, 10.52, 11.25, 11.69, 13.94, 18.03, 21.55, and 24.03.

[0066] In some embodiments, the solid form is a hydrochloride salt form A of the compound of formula I, wherein the hydrochloride salt is represented by formula Ia:

[0067] In some embodiments, the hydrochloride crystalline form A has one or more 2θ diffraction peaks selected from the following group in the X-ray powder diffraction peak pattern: 5.664, 6.037, 6.218, 6.729, 8.070, 9.454, 9.735, 10.99, 10.254, 10.743, 11.11, 11.29, 11.632, 11.981, 12.188, 12.524, 12.895, 13.478, 13.933, 14.773, 15.006 、15.643、16.045、16.741、17.175、17.507、18.020、18.32、19.409、19.626、20.402、20.726、21.19、21.508、22.257、22.545、22.733、23.304、23.929、24.664、25.341、25.873、26.33、26.651、27.163、27.634、27.908、28.549、 29.536, 30.027, 30.744, 31.33, 32.63, 33.024, 33.376, 33.683, 35.904, 36.508, 37.578, 38.437 and 39.365.

[0068] In another preferred embodiment, the hydrochloride salt form A has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 11.11, 12.188, 16.045, 22.257, 22.545.

[0069] In another preferred embodiment, the hydrochloride salt form A has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 10.099, 11.11, 12.188, 16.045, 22.257, 22.545, 22.733, 25.873.

[0070] In another preferred embodiment, the hydrochloride salt form A has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 10.099, 11.11, 12.188, 15.643, 16.045, 22.257, 22.545, 22.733, 25.341, and 25.873.

[0071] In some embodiments, the crystal structure of the hydrochloride salt form A belongs to the monoclinic system, P21 (No. 4) space group.

[0072] In some embodiments, the hydrochloride salt form A has the following unit cell parameters: α=90°,β=116.1(2)°,γ=90°,unit cell volume

[0073] In another preferred embodiment, Z' of the hydrochloride crystal form A is 1, and the asymmetric unit of the crystal consists of 1 cation of the compound of formula I, 2 Cl - It consists of an anion and 1 H2O molecule.

[0074] In a second aspect of the present invention, a pharmaceutical composition is provided, comprising the solid form as described in the first aspect of the present invention, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, solvent, or a combination thereof.

[0075] In the third aspect of the present invention, there is provided a use of the solid form as described in the first aspect of the present invention, or the pharmaceutical composition as described in the second aspect of the present invention in the preparation of a medicament for treating or preventing tumors or infections caused by viruses.

[0076] In another preferred embodiment, the virus is selected from the group consisting of HBV, HCV, HIV, influenza virus, or a combination thereof; and / or the tumor is preferably lung cancer, pancreatic cancer, kidney cancer, head and neck cancer, breast cancer, lymphoma, skin cancer, urothelial carcinoma, gastric cancer, hepatocellular carcinoma and colorectal cancer.

[0077] In a fourth aspect of the present invention, a method for preparing co-crystals of a compound of formula (I) is provided, comprising: (i) combining a solution of a co-crystal former with a solution of a compound of formula I to obtain a co-crystal mixture; or (ii) combining a suspension of a co-crystal former with a suspension of a compound of formula I to obtain a co-crystal mixture; and (iii) supersaturating the co-crystal mixture to induce co-crystal formation.

[0078] In a fifth aspect of the present invention, there is provided a method for preparing the hydrochloride crystalline form A of the compound represented by formula Ia according to the first aspect of the present invention, characterized in that the method comprises the following steps:

[0079] Dissolve the compound represented by formula I in a crystallization solvent, heat to dissolve, and then add concentrated hydrochloric acid dropwise;

[0080] Add crystallization agent dropwise;

[0081] stirring to crystallize; and / or cooling to crystallize to obtain the crystals.

[0082] In another preferred embodiment, before the stirring crystallization step, the process further includes: adding activated carbon crystals for stirring and decolorization, and then filtering and washing.

[0083] In some embodiments, in step 1), the crystallization solvent is selected from: water, methanol, ethanol, 4-methyl-2-pentanone, cyclohexane, n-heptane, propanol, isopropanol, n-butanol, isobutanol, tert-butyl acetate, hexane, toluene, acetone, acetonitrile, dioxane, THF, ethyl acetate, methyl tert-butyl ether, ethylene glycol methyl ether, dimethyl sulfoxide, dichloromethane, N,N-dimethylformamide, or a combination thereof.

[0084] In some embodiments, the crystallization solvent is selected from: methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, acetone, ethyl acetate, water or a mixed solvent thereof; preferably ethanol, acetone, and water.

[0085] 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 described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0086] Figure 1 is the XRPD pattern of free form A

[0087] Figure 2 is the DSC and TGA diagram of free form A

[0088] Figure 3 shows the free form A 1 HNMR spectra

[0089] Figure 4 is the XRPD pattern of free form B

[0090] Figure 5 is the XRPD pattern of free form C

[0091] Figure 6 shows the DSC and TGA diagrams of free form C

[0092] Figure 7 is the NMR spectrum of free form C

[0093] Figure 8 is the XRPD pattern of free form D

[0094] Figure 9 shows the DSC and TGA diagrams of free form D

[0095] Figure 10 is the NMR spectrum of free form D

[0096] Figure 11 is the XRPD pattern of succinate salt form A

[0097] Figure 12 is the DSC and TGA diagram of succinate salt form A

[0098] Figure 13 is a succinate crystal form A 1 HNMR spectra

[0099] Figure 14 is an XRPD pattern of succinate salt Form B

[0100] Figure 15 is the DSC and TGA diagram of succinate salt form B

[0101] Figure 16 is a diagram of the succinate salt form B. 1 HNMR spectra

[0102] Figure 17 is an XRPD pattern of succinate salt form C

[0103] Figure 18 is the DSC and TGA diagram of succinate salt form C

[0104] Figure 19 is a diagram of the succinate salt form C. 1 HNMR spectra

[0105] Figure 20 is the XRPD pattern of fumarate salt form A

[0106] Figure 21 is the DSC and TGA diagram of fumarate salt form A

[0107] Figure 22 is a diagram of the fumarate crystal form A 1 HNMR spectra

[0108] Figure 23 is the XRPD pattern of fumarate salt form B

[0109] Figure 24 is the DSC and TGA diagram of fumarate salt form B

[0110] Figure 25 is a diagram of the fumarate crystal form B 1 HNMR spectra

[0111] Figure 26 is the XRPD pattern of oxalate crystal form A

[0112] Figure 27 is the DSC and TGA diagram of oxalate crystal form A

[0113] Figure 28 is the oxalate crystal form A 1 HNMR spectra

[0114] Figure 29 is an XRPD pattern of oxalate crystal form B

[0115] Figure 30 is the DSC and TGA diagram of oxalate crystal form B

[0116] Figure 31 is the oxalate crystal form B 1 HNMR spectra

[0117] Figure 32 is the XRPD pattern of malate crystal form A

[0118] Figure 33 is the DSC and TGA diagram of malate crystal form A

[0119] Figure 34 is a diagram of malate crystal form A 1 HNMR spectra

[0120] Figure 35 is an XRPD pattern of hydrochloride salt form A (Formula Ia)

[0121] Figure 36 is a MicroED diffraction single crystal structure diagram of Compound (I) hydrochloride Form A. DETAILED DESCRIPTION

[0122] WO 2023 / 104165 provides a TLR7 / 8 agonist, the structure of which is shown in Formula I, and discloses compounds of Formula I and methods for synthesizing the same, etc., which are incorporated herein by reference in their entirety.

[0123] Crystal form of compound of formula I and preparation method thereof

[0124] The crystal structure of a pharmaceutically active ingredient often affects the chemical stability of the drug. Differences in crystallization and storage conditions may lead to changes in the crystal structure of the compound, sometimes accompanied by the production of other morphological forms. Generally speaking, amorphous pharmaceutical products do not have a regular crystal structure and often have other defects, such as poor product stability, fine crystallization, difficulty in filtration, easy agglomeration, poor fluidity, etc. The polymorphic form of a drug has different requirements for product storage, production, and scale-up. Therefore, it is very necessary to conduct in-depth research on the crystal form of the compound of formula (I) and related preparation methods to improve the various properties of the compound shown in formula (I).

[0125] This document generally relates to different solid forms, different salt forms, different crystalline forms of different salt forms of Compound (I) and methods of preparing the same.

[0126] The preparation methods of different crystalline forms of the compound of formula (I) of the present invention are as follows:

[0127] Method for preparing co-crystallization of compound of formula (I):

[0128] (i) combining a solution of a co-crystal former with a solution of a compound of formula I to obtain a co-crystal mixture;

[0129] or (ii) combining a suspension of the co-crystal former with a suspension of the compound of Formula I to obtain a co-crystal mixture;

[0130] and (iii) supersaturating the co-crystallization mixture to initiate co-crystal formation.

[0131] Preparation method of crystalline form A of the compound represented by formula Ia:

[0132] Dissolve the compound represented by formula I in a crystallization solvent, heat to dissolve, and then add concentrated hydrochloric acid dropwise;

[0133] Add crystallization agent dropwise;

[0134] stirring to crystallize; and / or cooling to crystallize to obtain the crystals.

[0135] Before the stirring crystallization step, the following steps may be included: adding activated carbon crystals for stirring and decolorization, and then filtering and washing.

[0136] The crystallization solvent in step 1) is selected from the group consisting of water, methanol, ethanol, 4-methyl-2-pentanone, cyclohexane, n-heptane, propanol, isopropanol, n-butanol, isobutanol, tert-butyl acetate, hexane, toluene, acetone, acetonitrile, dioxane, THF, ethyl acetate, methyl tert-butyl ether, ethylene glycol methyl ether, dimethyl sulfoxide, dichloromethane, N,N-dimethylformamide, or a combination thereof.

[0137] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0138] abbreviation

[0139] Cmax Maximum concentration measured

[0140] FaSSIF fasting simulated intestinal fluid

[0141] FeSSIF fed simulated intestinal fluid

[0142] DSC Differential Scanning Calorimetry

[0143] Pos. Position

[0144] Rel.Int.Relative Strength

[0145] TGA Thermogravimetric Analysis

[0146] Tmax The time of maximum observed concentration (Cmax)

[0147] XRPD X-ray powder diffraction

[0148] NMR analysis ( 1 H NMR)

[0149] Dissolve several milligrams of solid sample in dimethyl sulfoxide-d 6 NMR analysis was performed on a Bruker AVANCE NEO 400 (Bruker, Germany).

[0150] X-ray powder diffraction (XRPD)

[0151] The solid sample was analyzed using an X-ray powder diffractometer (PANalytical EMPYREAN, UK). The 2θ scan angle ranged from 3° to 45°, with a scan step size of 0.013°, and the total measurement time was 5.08 min. The measurement was performed using a Cu target, Kα1 radiation, a voltage of 45 kV, a current of 40 mA, and a zero-background sample pan.

[0152] Thermogravimetric analysis (TGA)

[0153] The thermogravimetric analyzer (TA Discovery 550, US) was used. A 2-5 mg sample was placed in a equilibrated open aluminum sample pan and automatically weighed in the TGA furnace. The sample was heated to the final temperature at a rate of 10°C / min. A nitrogen purge rate of 60 mL / min was maintained at the sample and 40 mL / min at the balance.

[0154] Differential Scanning Calorimetry (DSC)

[0155] The differential scanning calorimeter was a TA Discovery 250 (TA, US). 1-2 mg of sample was accurately weighed and placed in a perforated DSC Tzero sample pan. The sample was heated to the final temperature at a rate of 10°C / min, with nitrogen purge rate of 50 mL / min.

[0156] Example 1 Free Form A

[0157] 24.8 mg of the raw material compound of Formula I was weighed, 1.0 mL of methyl tert-butyl ether solvent was added, and the mixture was suspended at room temperature for two days. After centrifugation, the solid was vacuum-dried at room temperature for one day. The solid was collected for XRPD analysis. The XRPD Figure 1 of the solid was the same as that in Table 1 and was confirmed to be the free-state crystalline Form A of Compound (I). Depending on the solvation state, the free-state crystalline Form A may be a solvate, hydrate, anhydrate, or polymorph of Compound (I).

[0158] In the DSC and TGA diagrams of the free form A in Figure 2, the TGA results show that the sample loses 2.2% of its weight when heated to 100°C and may decompose after 300°C; the DSC results show that form A has an endothermic signal peak at 101°C.

[0159] Table 1 X-ray powder diffraction peaks of free form A of compound (I)

[0160] Example 2 Free Form B

[0161] 20.0 mg of the raw material compound of Formula I was weighed, 0.05 mL of isopropanol was added to dissolve the clear solution, and n-heptane was slowly added dropwise to 1.0 mL. The mixture was stirred at room temperature for 1 day to obtain a suspension, which was centrifuged to obtain a solid. The wet solid sample was analyzed by XRPD. The XRPD pattern of the solid, Figure 4, is identical to that in Table 2 and confirmed to be the free-state crystalline Form B of Compound (I). Since Form B converted to Form C after vacuum drying at room temperature, TGA, DSC, and NMR characterization were not performed.

[0162] Table 2 X-ray powder diffraction peaks of free form B_wet of compound (I)

[0163] Example 3 Free Form C

[0164] Free Form C can be obtained by vacuum drying from free Form B at room temperature or by vapor diffusion in isopropanol / n-heptane. The relevant characterization data are shown in Figures 15 to 17. The XRPD pattern of the solid, Figure 5, is the same as that in Table 3 and is confirmed to be free Form C of Compound (I). Depending on the solvation state, free Form C may be a solvate, hydrate, anhydrate, or polymorph of Compound (I).

[0165] In the DSC and TGA diagrams of the free form C in Figure 6, the TGA results show that form C loses 1.5% of its weight when heated to 100°C and may decompose above 300°C; the DSC results show that form C has an endothermic signal peak at around 114°C.

[0166] Table 3 X-ray powder diffraction peaks of free crystalline form C_dry of compound (I)

[0167] Example 4 Free Form D

[0168] 99.8 mg of the raw material compound of Formula I was weighed, 2.5 mL of isopropanol / n-heptane (v / v, 1 / 20) was added, and the mixture was suspended and stirred at 50°C for 2 days. After centrifugation of the suspension, the solid was vacuum dried at 40°C for 17 hours. The solid was collected for XRPD analysis. The XRPD pattern of the solid, Figure 8, is identical to that in Table 4 and is confirmed to be the free-state Form D of Compound (I). Form D is a well-crystalline anhydrate. Depending on the solvation state, the free-state Form D may be a solvate, hydrate, anhydrate, or polymorph of Compound (I).

[0169] In the DSC and TGA diagrams of the free form D in Figure 9, the TGA results show that form D loses 1.1% of its weight when heated to 100°C, and decomposition may occur above 300°C; the DSC results show that form D has a broad endothermic signal peak at 50-100°C and an endothermic signal peak at around 134°C.

[0170] Table 4 X-ray powder diffraction peaks of free form D of compound (I)

[0171] Example 5 Succinate Crystal Form A

[0172] 49.6 mg of the starting compound of Formula I and 13.0 mg of succinic acid were weighed, 3.0 mL of THF / n-heptane (v / v, 1 / 1) were added, and the mixture was stirred at room temperature for 4 days. The suspension was centrifuged, and the solid portion was dried under vacuum at 40°C for 19 hours. The solid was collected for XRPD analysis. The XRPD Figure 11 of the solid was the same as that in Table 5, confirming that it was Form A of the succinate salt of Compound (I). Depending on the solvation state, Form A of the succinate salt of Compound (I) may be a solvate, hydrate, anhydrate, or polymorph.

[0173] XRPD results showed that the succinate salt Form A was a generally crystalline solid.

[0174] In the DSC and TGA diagrams of succinate salt form A in Figure 12, the TGA results show that the sample loses 6.8% of its weight during heating to 100°C, and decomposition may occur after 210°C; the DSC results show a broad endothermic signal at 50-70°C and an endothermic signal peak at around 86°C.

[0175] Table 5 X-ray powder diffraction peaks of Compound (I) succinate salt Form A

[0176] Example 6 Succinate Crystal Form B

[0177] 49.6 mg of the starting compound of Formula I and 13.0 mg of succinic acid were weighed, 3.0 mL of THF / n-heptane (v / v, 1 / 1) was added, and the mixture was stirred at room temperature for 3 days. The suspension was centrifuged, and the solid portion was dried under vacuum at 40°C for 18 hours. The solid was collected for XRPD analysis. The XRPD pattern of the solid, Figure 14, is identical to that in Table 6 and is confirmed to be Form B succinate salt of Compound (I). Depending on the solvation state, Form B succinate salt of Compound (I) may be a solvate, hydrate, anhydrate, or polymorph.

[0178] XRPD results showed that the succinate salt Form B was a generally crystalline solid.

[0179] In the DSC and TGA diagrams of succinate salt form B in Figure 15, the TGA results show that the sample loses 7.0% of its weight during heating to 100°C and may decompose after 200°C; the DSC results show a broad endothermic signal peak at 40-100°C.

[0180] Table 6 X-ray powder diffraction peaks of Compound (I) succinate salt Form B

[0181] Example 7 Succinate Form C

[0182] 500.1 mg of the raw material compound of Formula I and 130.1 mg of succinic acid were weighed, and 10.0 mL of THF / n-heptane (v / v, 1 / 1) was added. The mixture was stirred at room temperature for 5 days, resulting in a colloid. The colloid was suspended at 50°C for 3 hours and then suspended again at room temperature for 3 days. The precipitated solid was centrifuged and the solid portion was dried under vacuum at 40°C for 18 hours. The solid was collected for XRPD analysis. The XRPD Figure 17 of the solid was identical to that in Table 7 and confirmed to be Form C of the succinate salt of Compound (I). Depending on the solvation state, Form C of the succinate salt of Compound (I) may be a solvate, hydrate, anhydrate, or polymorph.

[0183] XRPD results showed that the succinate salt Form C was a generally crystalline solid.

[0184] In the DSC and TGA diagrams of succinate salt form C in Figure 18, the TGA results show that the sample loses 4.1% of its weight during heating to 120°C, and decomposition may occur after 210°C; the DSC results show a broad endothermic signal at 30-80°C, and an endothermic signal peak at around 104°C.

[0185] Table 7 X-ray powder diffraction peaks of Compound (I) succinate salt Form C

[0186] Example 8 Fumarate Crystal Form A

[0187] Weigh 24.9 mg of the raw material formula I compound and 6.3 mg of fumaric acid, add 1.0 mL of THF / n-heptane (v / v, 1 / 1), stir at room temperature for 3 days, centrifuge the suspension, and vacuum dry the solid at room temperature. Collect the solid for XRPD analysis. The XRPD Figure 20 of the solid is the same as that in Table 8 and is confirmed to be the fumarate crystalline form A of compound (I). Depending on the solvation state, the fumarate crystalline form A of compound (I) can be a solvate, hydrate, anhydrous or polymorphic form. The XRPD result shows that the fumarate crystalline form A is a solid with general crystallinity.

[0188] In the DSC and TGA diagrams of fumarate salt form A in Figure 21, the TGA results show that the sample loses 12.8% of its weight when heated to 150°C, and decomposition may occur after 230°C; the DSC results show that there is a broad endothermic signal corresponding to the TGA weight loss at 50-100°C.

[0189] Table 8 X-ray powder diffraction peaks of compound (I) fumarate salt form A

[0190] Example 9 Fumarate Crystal Form B

[0191] Take 24.9mg raw material formula I compound and 6.3 milligrams of fumaric acid, add 1.0mL ethyl acetate, stirring at room temperature 3 days, by suspension centrifugation, solid room temperature vacuum drying.Collect solid and be used for XRPD analysis.The XRPD Figure 23 of solid is identical with the one in table 9, and is confirmed as the fumarate crystalline form B of compound (I).Different according to solvation state, the fumarate crystalline form B of compound (I) can be solvate, hydrate, anhydrous or polymorph.

[0192] XRPD results showed that the fumarate salt Form B was a poorly crystalline solid.

[0193] In the DSC and TGA diagrams of fumarate salt form B in Figure 24, the TGA results show that the sample loses 4.6% of its weight during heating to 100°C, and decomposition may occur after 230°C; the DSC results show that there is a broad endothermic signal corresponding to the TGA weight loss at 50-100°C, and there are endothermic signal peaks at around 116°C and 191°C.

[0194] Table 9 X-ray powder diffraction peaks of compound (I) fumarate salt form B

[0195] Example 10 Oxalate Form A

[0196] Weigh 24.8 mg of the raw material formula I compound and 5 mg of oxalic acid, add 1.0 mL of THF / n-heptane (v / v, 1 / 1), stir at room temperature for 3 days, centrifuge the suspension, and vacuum dry the solid at room temperature. Collect the solid for XRPD analysis. The XRPD Figure 26 of the solid is the same as that in Table 10 and is confirmed to be the oxalate crystal form A of compound (I). Depending on the solvation state, the oxalate crystal form A of compound (I) can be a solvate, hydrate, anhydrous or polymorphic form.

[0197] XRPD results showed that the oxalate salt form A was a solid with average crystalline properties.

[0198] In the DSC and TGA diagrams of oxalate form A in Figure 27, the TGA results show that the sample has a 9.7% weight loss during heating to 110°C and a 2.0% weight loss during heating from 110°C to 150°C, and decomposition may occur after 210°C; the DSC results show a broad endothermic signal corresponding to the TGA weight loss at 50-100°C, and an endothermic signal peak at 129°C.

[0199] Table 10 X-ray powder diffraction peaks of Compound (I) oxalate salt form A

[0200] Example 11 Oxalate Form B

[0201] Weigh 39.7 mg of raw material formula I compound and 7.9 mg of oxalic acid, add 1.0 mL of ethyl acetate, stir at room temperature for 3 days, centrifuge the suspension, and dry in vacuum at room temperature. Collect solid for XRPD analysis. XRPD Figure 29 of the solid is identical with that in Table 11, and is confirmed to be the oxalate crystal form B of compound (I). Depending on the solvation state, the oxalate crystal form B of compound (I) can be a solvate, hydrate, anhydrous or polymorph.

[0202] XRPD results showed that the oxalate salt form B was a solid with average crystalline properties.

[0203] In the DSC and TGA diagrams of oxalate crystal form B in Figure 30, the TGA results show that the sample loses 9.3% of its weight during heating to 150°C, and decomposition may occur after 210°C; the DSC results show a broad endothermic signal peak at 50-100°C and an endothermic signal peak at around 148°C.

[0204] Table 11 X-ray powder diffraction peaks of Compound (I) oxalate crystal form B

[0205] Example 12 Malate Form A

[0206] Weigh 24.8 mg of raw material formula I compound and 7.4 milligrams of L-malic acid, add 1.0 mL of methyl tert-butyl ether, stir at room temperature for 3 days, add 1.0 mL of ethyl acetate to the jelly obtained, stir at room temperature for 3 days, centrifuge the solid, and dry in vacuum at room temperature. Collect the solid for XRPD analysis. The XRPD Figure 32 of the solid is the same as that in Table 12, and is confirmed to be the malate crystalline form A of compound (I). Depending on the solvation state, the malic acid crystalline form A of compound (I) can be a solvate, hydrate, anhydrous or polymorphic form.

[0207] XRPD results showed that malate Form A was a poorly crystalline solid.

[0208] In the DSC and TGA diagrams of malate crystal form A in Figure 33, the TGA results show that the sample loses 9.3% of its weight during heating to 150°C, and decomposition may occur after 220°C; the DSC results show that there is a broad endothermic signal corresponding to the TGA weight loss at 50-100°C, and there are endothermic signal peaks at 107°C and 217°C.

[0209] Table 12 X-ray powder diffraction peaks of Compound (I) malate crystal form A

[0210] Example 13 (Formula Ia) Hydrochloride Form A

[0211] 1) Add 12 g of the compound of formula I, 30 ml of ethanol, and 1.2 ml of purified water to a 100 ml three-necked flask at room temperature, stir, and heat to 45-50°C to dissolve; then add concentrated hydrochloric acid dropwise;

[0212] 2) After the solution is clear, add activated carbon and stir to decolorize for 15 minutes;

[0213] 3) Filter, first filter once with filter paper, then filter once with a 0.22-0.45 μm organic filter membrane, and wash with 6 ml of ethanol during the filtration process;

[0214] 4) After filtration, transfer the filtrate to a 250 ml reaction flask and add 108 ml of acetone dropwise at 40-50°C;

[0215] 5) After the addition is complete, stir at room temperature for 15-20 hours to crystallize;

[0216] 6) After stirring, slowly cool the ice water to 2-8°C and stir for 1 hour;

[0217] 7) Filter, wash the filter cake with acetone, and dry the filter cake at 40-45° C. to obtain a white solid (Formula Ia) hydrochloride salt Form A.

[0218] The solid was collected for XRPD analysis. The XRPD pattern 35 of the solid was identical to that in Table 13 and was confirmed to be the hydrochloride salt Form A of Compound (I) (Formula Ia).

[0219] Compound (I) hydrochloride Form A has a MicroED diffraction crystal structure as shown in FIG36 .

[0220] Table 13 X-ray powder diffraction peaks of Compound (I) hydrochloride form A

[0221] MicroED single crystal diffraction: (a) After placing the sample in a transmission electron microscope (TEM), search for the target particle in imaging mode. (b) In the TEM's diffraction mode, rotate the target particle at a constant speed while collecting a series of diffraction images. (c) Once sufficient diffraction data is obtained, the electron density map within the unit cell can be solved. (d) The atomic coordinates within the unit cell are determined from the electron density peaks, leading to the final structure. See Table 14 for crystallographic data and refinement parameters.

[0222] Table 14 MicroED single crystal structure data of Compound (I) hydrochloride form A

[0223] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound as shown in formula I or a pharmaceutically acceptable salt, solvate, cocrystal or combined solid form thereof, characterized in that: The solid form is an amorphous form, different crystal forms of the free state, a pharmaceutically acceptable salt thereof, different crystal forms of the co-crystal, or a combination thereof:

2. The solid form according to claim 1, characterized in that The solid form is selected from the following groups: inorganic acid salts such as hydrochloric acid, phosphate, sulfate; or organic acid salts such as acetate, methanesulfonate, L-tartrate, lactate, p-toluenesulfonate, fumarate, oxalate, malate, benzoate, citrate, D-tartrate, succinate, pamoate, xinafoate. Preferably, hydrochloride, fumarate, oxalate, malate, succinate.

3. The solid form of claim 1, wherein The solid form is selected from the group consisting of: The hydrochloride salt of the compound of formula I; A fumarate salt of a compound of formula I; An oxalate salt of a compound of formula I; A malate salt of a compound of formula I; or A succinate salt of the compound of formula I.

4. The solid form of claim 1, wherein In the solid form, in the inorganic acid salt or organic acid salt of the compound of formula I, the compound of formula I and the inorganic acid or organic acid are present in the co-crystal in a ratio of 1-3:3-1; preferably, the ratio of the compound of formula I to the inorganic acid or organic acid is 1:1, 1:2, 1:3, 3:1 or 2:1; more preferably, the ratio of the compound of formula I to the inorganic acid or organic acid is 1:1 or 1:

2.

5. The solid form of claim 1, wherein The solid form is selected from the following group: amorphous form, free crystalline form A of the compound of formula I, free crystalline form B of the compound of formula I, free crystalline form C of the compound of formula I, free crystalline form D of the compound of formula I, fumarate crystalline form A of the compound of formula I, fumarate crystalline form B of the compound of formula I, oxalate crystalline form A of the compound of formula I, oxalate crystalline form B of the compound of formula I, malate crystalline form A of the compound of formula I, succinate crystalline form A of the compound of formula I, succinate crystalline form B of the compound of formula I, succinate crystalline form C of the compound of formula I, and hydrochloride crystalline form A of the compound of formula I.

6. The solid form of claim 1, wherein the solid form is selected from the group consisting of: The free form A of the compound of formula I has one or more 2θ diffraction peaks selected from the following group in the X-ray powder diffraction peak spectrum: 3.39, 6.16, 6.68, 8.39, 9.40, 10.06, 10.44, 10.65, 10.98, 11.34, 11.55, 12.42, 13.27, 14.08, 14.56, 14.9 8, 15.61, 16.04, 16.45, 17.08, 17.59, 18.29, 18.70, 19.24, 19.43, 19.98, 20.21, 20.68, 21.40, 22.06, 22.53, 23.31, 23.92, 24.40, 24.78, 25.60, 27.13 and 28.06; The free form B of the compound of formula I has one or more 2θ diffraction peaks selected from the following group in the X-ray powder diffraction peak spectrum: 3.05, 5.35, 5.93, 8.88, 10.55, 10.96, 11.31, 11.72, 12.07, 12.78, 13.94, 14.76, 15.13, 15.85, 16.52, 17. 34, 18.38, 18.85, 19.12, 19.29, 19.66, 19.99, 20.71, 21.12, 21.89, 22.55, 23.39, 24.73, 25.28, 25.86, 26.40, 26.88, 27.47, 27.91, 31.73, 32.25, 33.02 and 33.44; The free form C of the compound of formula I has one or more 2θ diffraction peaks selected from the group consisting of 5.42, 6.03, 6.62, 9.21, 10.13, 11.56, 12.39, 13.37, 13.96, 14.53, 15.45, 15.97, 16.39, 17.05, 18.61, 18.86, 19.27, 20.65, 21.24, 21.63, 22.37, 23.02, 24.44, 25.37, 26.58, 29.01 and 31.62 in the X-ray powder diffraction peak spectrum; The free form D of the compound of formula I has one or more 2θ diffraction peaks selected from the group consisting of 5.39, 5.84, 7.46, 10.89, 11.74, 13.25, 15.11, 15.89, 16.39, 16.59, 17.22, 18.77, 19.16, 19.52, 20.42, 21.03, 21.74, 22.64, 23.23, 24.40, 25.01, 26.45, 26.94, 28.11, 28.58, 30.51, 33.71 and 37.15 in the X-ray powder diffraction peak spectrum; The fumarate crystalline form A of the compound of formula I has one or more 2θ diffraction peaks selected from the group consisting of 5.19, 5.57, 8.78, 11.90, 12.83, 15.13, 15.75, 16.20, 17.36, 17.85, 18.39, 18.72, 20.36, 20.87, 21.83, 22.59, 23.40, 24.21, 25.85, 26.23, 26.60, 27.40, 28.51, 28.95, 29.60 and 30.30 in the X-ray powder diffraction peak spectrum; The fumarate crystalline form B of the compound of formula I has one or more 2θ diffraction peaks selected from the group consisting of 5.35, 7.65, 9.28, 10.10, 10.83, 14.32, 15.79, 17.12, 19.10, 20.46, 21.83, 22.49, 23.47, 24.52 and 27.55 in the X-ray powder diffraction peak spectrum; The oxalate crystalline form A of the compound of formula I has one or more 2θ diffraction peaks selected from the group consisting of 6.28, 6.98, 7.40, 9.49, 10.37, 11.47, 11.92, 12.65, 14.04, 14.90, 15.51, 15.95, 17.57, 18.02, 18.31, 18.85, 19.15, 19.49, 20.67, 21.15, 21.78, 22.62, 22.87, 23.19, 24.23, 24.57, 25.31, 25.86, 26.49, 27.24, 28.14 and 28.74 in the X-ray powder diffraction peak spectrum; The oxalate form B of the compound of formula I has one or more 2θ diffraction peaks selected from the following group in the X-ray powder diffraction peak spectrum: 6.55, 7.39, 9.24, 10.16, 11.65, 12.39, 13.70, 14.63, 17.31, 17.59, 18.64, 19.35, 19.78, 20.42, 20.96, 21.78, 23.31, 23.94, 25.16, 26.15, 27.34 and 29.25; The malate crystalline form A of the compound of formula I, which has one or more 2θ diffraction peaks selected from the following group in the X-ray powder diffraction peak spectrum: 5.21, 5.61, 8.78, 9.03, 11.86, 12.68, 15.21, 15.63, 16.01, 17.10, 17.64, 17.90, 18.03, 18.28, 18.60, 19.81, 20.21, 23.33, 23.71, 24.02, 24.42, 25.62, 27.36, 27.91 and 28.38; The succinate salt form A of the compound of formula I has one or more 2θ diffraction peaks selected from the following group in the X-ray powder diffraction peak spectrum: 5.21, 5.70, 8.98, 9.24, 9.97, 10.48, 12.83, 14.38, 15.41, 15.91, 16.19, 16.45, 16.83, 17.55, 18. 03, 18.64, 18.88, 20.04, 20.63, 21.07, 21.80, 22.19, 23.06, 23.58, 24.12, 24.34, 24.66, 25.28, 25.89, 26.48, 27.67, 28.26, 28.66, 29.16, 30.32 and 31.71; The succinate crystalline form B of the compound of formula I, which has one or more 2θ diffraction peaks selected from the following group in the X-ray powder diffraction peak spectrum: 4.80, 5.19, 5.57, 8.99, 9.51, 12.40, 12.90, 13.35, 13.94, 14.92, 15.59, 16.55, 16.98, 17.78, 18.27, 18.68, 19.50, 21.16, 20.54, 21.09, 21.84, 22.35, 23.98, 24.27, 25.75, 26.08, 26.67, 27.05, 27.44, 28.14, 28.68, 29.58, 30.07, 30.97 and 31.40; The succinate crystalline form C of the compound of formula I has one or more 2θ diffraction peaks selected from the following group in the X-ray powder diffraction peak spectrum: 6.41, 6.95, 7.54, 10.52, 10.68, 11.25, 11.69, 12.38, 13.01, 13.94, 14.29, 15.26, 15.53, 16.29, 17.14, 17.61, 18.03, 18.32, 19.08, 19.50, 20.50, 21.55, 21.78, 22.17, 22.60, 23.06, 24.03, 24.64, 25.19, 25.62, 26.84, 27.32, 27.88 and 28.

18. In another preferred embodiment, the free form A of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 3.39, 6.16, 6.68, 10.06, 12.

42. In another preferred embodiment, the free form A of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 3.39, 6.16, 6.68, 10.06, 12.42, 18.7, 20.68, 21.

4. In another preferred embodiment, the free form A of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 3.39, 6.16, 6.68, 10.06, 10.44, 12.42, 18.29, 18.7, 20.68, 21.

4. In another preferred embodiment, the free form B of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 3.05, 5.93, 20.71, 21.12, 21.

89. In another preferred embodiment, the free form B of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 3.05, 5.35, 5.93, 12.78, 18.38, 20.71, 21.12, 21.

89. In another preferred embodiment, the free form B of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 3.05, 5.35, 5.93, 12.78, 18.38, 18.85, 19.66, 20.71, 21.12, and 21.

89. In another preferred embodiment, the free form C of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 5.42, 6.03, 6.62, 10.13, 11.

56. In another preferred embodiment, the free form C of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 5.42, 6.03, 6.62, 9.21, 10.13, 11.56, 12.39, 17.

05. In another preferred embodiment, the free form C of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 5.42, 6.03, 6.62, 9.21, 10.13, 11.56, 12.39, 17.05, 20.65, 21.

24. In another preferred embodiment, the free form D of the compound of formula I has at least a 2θ diffraction peak selected from the following group: 5.39, 5.84, 11.74, 13.25, 17.22 in the X-ray powder diffraction peak spectrum. In another preferred embodiment, the free form D of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 5.39, 5.84, 10.89, 11.74, 13.25, 15.11, 17.22, and 19.

16. In another preferred embodiment, the free form D of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 5.39, 5.84, 10.89, 11.74, 13.25, 15.11, 15.89, 17.22, 19.16, 22.

64. In another preferred embodiment, the fumarate salt form A of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 5.19, 5.57, 8.78, 15.75, 17.

85. In another preferred embodiment, the fumarate salt form A of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 5.19, 5.57, 8.78, 15.75, 17.36, 17.85, 20.36, and 24.

21. In another preferred embodiment, the fumarate salt form A of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 5.19, 5.57, 8.78, 15.75, 16.2, 17.36, 17.85, 20.36, 23.4, and 24.

21. In another preferred embodiment, the fumarate salt form B of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 5.35, 7.65, 9.28, 17.12, 24.

52. In another preferred embodiment, the fumarate salt form B of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 5.35, 7.65, 9.28, 10.1, 10.83, 17.12, 23.47, 24.

52. In another preferred embodiment, the fumarate form B of the compound of formula I is The diffraction peak spectrum has at least a 2θ diffraction peak selected from the following group: 5.35, 7.65, 9.28, 10.1, 10.83, 17.12, 19.1, 21.83, 23.47, and 24.

52. In another preferred embodiment, the oxalate form A of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 6.98, 7.4, 9.49, 18.02, 19.

49. In another preferred embodiment, the oxalate form A of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 6.98, 7.4, 9.49, 18.02, 18.31, 19.15, 19.49, 22.

62. In another preferred embodiment, the oxalate form A of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 6.98, 7.4, 9.49, 18.02, 18.31, 19.15, 19.49, 22.62, 22.87, 23.

19. In another preferred embodiment, the oxalate crystal form B of the compound of formula I has at least a 2θ diffraction peak selected from the following group: 6.55, 7.39, 9.24, 13.7, 17.31 in the X-ray powder diffraction peak spectrum. In another preferred embodiment, the oxalate crystal form B of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 6.55, 7.39, 9.24, 12.39, 13.7, 17.31, 17.59, 20.

96. In another preferred embodiment, the oxalate form B of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 6.55, 7.39, 9.24, 12.39, 13.7, 17.31, 17.59, 18.64, 20.96, 21.

78. In another preferred embodiment, the malate crystalline form A of the compound of formula I has at least a 2θ diffraction peak selected from the following group: 5.61, 8.78, 17.64, 17.9, 18.03 in the X-ray powder diffraction peak spectrum. In another preferred embodiment, the malate salt form A of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 5.21, 5.61, 8.78, 17.1, 17.64, 17.9, 18.03, 18.

28. In another preferred embodiment, the malate salt form A of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 5.21, 5.61, 8.78, 15.63, 17.1, 17.64, 17.9, 18.03, 18.28, and 20.

21. In another preferred embodiment, the succinate salt form A of the compound of formula I has at least a 2θ diffraction peak selected from the following group: 5.21, 5.7, 8.98, 17.55, 18.03 in the X-ray powder diffraction peak spectrum. In another preferred embodiment, the succinate salt form A of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 5.21, 5.7, 8.98, 9.24, 16.19, 17.55, 18.03, 20.

63. In another preferred embodiment, the succinate salt form A of the compound of formula I is The diffraction peak spectrum has at least a 2θ diffraction peak selected from the following group: 5.21, 5.7, 8.98, 9.24, 15.91, 16.19, 16.45, 17.55, 18.03, and 20.

63. In another preferred embodiment, the succinate salt form B of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 5.19, 5.57, 8.99, 17.78, 20.

54. In another preferred embodiment, the succinate salt form B of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 5.19, 5.57, 8.99, 15.59, 17.78, 20.54, 23.98, and 24.

27. In another preferred embodiment, the succinate salt form B of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 5.19, 5.57, 8.99, 15.59, 16.55, 17.78, 20.54, 23.04, 23.98, and 24.

27. In another preferred embodiment, the succinate salt form C of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 6.41, 7.54, 11.25, 11.69, 13.

94. In another preferred embodiment, the succinate salt form C of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 6.41, 6.95, 7.54, 11.25, 11.69, 13.94, 18.03, 24.

03. In another preferred embodiment, the succinate salt form C of the compound of formula I has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 6.41, 6.95, 7.54, 10.52, 11.25, 11.69, 13.94, 18.03, 21.55, and 24.

03.

7. The solid form of claim 1, wherein The solid form is a hydrochloride salt form A of the compound of formula I, wherein the hydrochloride salt is as shown in formula Ia:

8. The solid form of claim 7, wherein The hydrochloride crystal form A has one or more 2θ diffraction peaks selected from the following group in the X-ray powder diffraction peak spectrum: 5.664, 6.037, 6.218, 6.729, 8.070, 9.454, 9.735, 10.99, 10.254, 10.743, 11.11, 11.29, 11.632, 11.981, 12.188, 1 2.524, 12.895, 13.478, 13.933, 14.773, 15.006, 15.643, 16.045, 16.741, 17.175, 17.507, 18.020, 18.32, 19.409, 19.626, 20.402, 20.726, 21.19, 21.508, 22.257, 33.024, 33.376, 33.683, 35.904, 36.508, 37.578, 38.437 and 39.

365. In another preferred embodiment, the hydrochloride crystal form A has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 11.11, 12.188, 16.045, 22.257, 22.

545. In another preferred embodiment, the hydrochloride salt form A has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 10.099, 11.11, 12.188, 16.045, 22.257, 22.545, 22.733, 25.

873. In another preferred embodiment, the hydrochloride salt form A has at least a 2θ diffraction peak selected from the following group in the X-ray powder diffraction peak spectrum: 10.099, 11.11, 12.188, 15.643, 16.045, 22.257, 22.545, 22.733, 25.341, and 25.

873.

9. The solid form of claim 7, wherein The crystal structure of the hydrochloride salt form A belongs to the monoclinic system, P21 (No.4) space group.

10. The solid form of claim 7, wherein The hydrochloride crystal form A has the following unit cell parameters: α=90°,β=116.1(2)°,γ=90°,unit cell volume In another preferred embodiment, Z' of the hydrochloride crystal form A is 1, and the asymmetric unit of the crystal consists of 1 cation of the compound of formula I, 2 Cl - Anions and 1 H2O molecule.

11. A pharmaceutical composition comprising the solid form of any one of claims 1-10, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, solvent, or a combination thereof.

12. Use of the solid form according to any one of claims 1 to 10, or the pharmaceutical composition according to claim 11, in the preparation of a medicament for treating or preventing a tumor or an infection caused by a virus. In another preferred embodiment, the virus is selected from the following group: HBV, HCV, HIV, influenza virus, or a combination thereof; and / or the tumor is preferably lung cancer, pancreatic cancer, kidney cancer, head and neck cancer, breast cancer, lymphoma, skin cancer, urothelial carcinoma, gastric cancer, hepatocellular carcinoma and colorectal cancer.

13. A method for preparing co-crystals of a compound of formula (I), comprising: (i) combining a solution of a co-crystal former with a solution of a compound of formula I to obtain a co-crystal mixture; or (ii) combining a suspension of the co-crystal former with a suspension of the compound of formula I to obtain a co-crystal mixture; and (iii) supersaturating the co-crystal mixture to initiate co-crystal formation.

14. A method for preparing the crystalline form A of the compound of formula Ia according to any one of claims 7 to 10, characterized in that: The method comprises the following steps: Dissolve the compound represented by formula I in a crystallization solvent, heat to dissolve, and then dropwise add concentrated hydrochloric acid; Adding crystallization agent dropwise; stirring to crystallize; and / or cooling to crystallize to obtain the crystals. In another preferred embodiment, before the stirring crystallization step, the process further includes: adding activated carbon crystals for stirring and decolorization, and then filtering and washing.

15. The preparation method according to claim 14, characterized in that: In step 1), the crystallization solvent is selected from: water, methanol, ethanol, 4-methyl-2-pentanone, cyclohexane, n-heptane, propanol, isopropanol, n-butanol, isobutanol, tert-butyl acetate, hexane, toluene, acetone, acetonitrile, dioxane, THF, ethyl acetate, methyl tert-butyl ether, ethylene glycol methyl ether, dimethyl sulfoxide, dichloromethane, N,N-dimethylformamide, or a combination thereof.

16. The method of claim 15, wherein the crystallization solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, acetone, ethyl acetate, water or a mixed solvent thereof; preferably ethanol, acetone and water.

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