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

The invention relates to a medicinal salt, a crystal form and a preparation method of a TLR7 / 8 agonist compound shown as a formula I, a medicinal composition containing the medicinal salt and medical application of the medicinal salt, and the medicinal salt can be used for preparing medicines for preventing or treating Toll-like receptor 7 / 8 (TLR7 / 8) related diseases. The present invention relates to novel therapeutic agents for human immunodeficiency virus (HIV) infection, hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection and cancer. # imgabs0 #

Description

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, a crystalline composition comprising the crystal forms, a pharmaceutical composition comprising the crystal forms or the crystalline composition and their medical use. Background Art

[0002] Toll-like receptors (TLRs) are a class of structurally conserved proteins that form the first barrier in the innate immune response. By recognizing various conserved pathogen-associated molecular patterns (PAMPs), TLRs can recognize 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 development of many diseases, such as type I diabetes, sepsis, cancer, viral infectious diseases, etc. Therefore, the strategy of manipulating the inflammatory response through small molecule TLRs modulators to treat related diseases is promising.

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

[0004] Both TLR7 and TLR8 can recognize RNA molecules (ssRNA) from single-stranded RNA viruses. TLR7 is mainly expressed in plasmacytoid dendritic cells and B cells. TLR8 is mainly distributed in mDC, macrophages and monocytes, and is also expressed in T cells. TLR7 stimulation mainly 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 mainly distributed in mDC, macrophages and monocytes, and is also expressed in T cells. TLR8 activation mainly produces a pro-inflammatory response, stimulating immune cells to secrete pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α) and IL-6. There is overlap in the distribution and downstream signaling pathways of TLR7 / 8, so there are functional similarities. After TLR7 / 8 is activated, it can exert direct antiviral activity through type I interferon response, and can also regulate innate immunity through pro-inflammatory response to promote the activation of NK and NKT cells, as well as induce adaptive immunity, improve antigen presentation and activate dendritic cells, thereby enhancing T cell response and promoting the differentiation of antibody-producing B cells. The development of TLR7 / 8 agonists has great clinical value in both antiviral and anti-tumor therapy, 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 highly therapeutically effective TLR7 / 8 agonists. Summary of the invention

[0006] In the first aspect of the present invention, there is provided a compound as shown in Formula I or a pharmaceutically acceptable salt, solvent compound, co-crystal or a combination thereof in a solid form, characterized in that the solid form is an amorphous form, different crystal forms of a free state, a pharmaceutically acceptable salt thereof, different crystal forms of a co-crystal, or a combination thereof:

[0007]

[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, hydrochloride, fumarate, oxalate, malate, and succinate are used.

[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 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.

[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 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;

[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 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;

[0020] 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;

[0021] 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;

[0022] 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;

[0023] 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;

[0024] 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;

[0025] The oxalate form B of the compound of formula I 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 the X-ray powder diffraction peak spectrum;

[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 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;

[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 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;

[0028] 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;

[0029] 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.

[0030] 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.

[0031] 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.

[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, 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 in the X-ray powder diffraction peak spectrum: 3.05, 5.93, 20.71, 21.12, 21.89.

[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, 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 in the X-ray powder diffraction peak spectrum: 5.42, 6.03, 6.62, 10.13, 11.56.

[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, 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, 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, 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 in the X-ray powder diffraction peak spectrum: 5.19, 5.57, 8.78, 15.75, 17.85.

[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 in the X-ray powder diffraction peak spectrum: 5.35, 7.65, 9.28, 17.12, 24.52.

[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 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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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, and 18.28.

[0056] 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.

[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, 18.03 in the X-ray powder diffraction peak spectrum.

[0058] 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.

[0059] 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, 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 in the X-ray powder diffraction peak spectrum: 5.19, 5.57, 8.99, 17.78, 20.54.

[0061] 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, 24.27.

[0062] 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.

[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 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.

[0065] 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.

[0066] In some embodiments, 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:

[0067]

[0068] 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 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, 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.

[0069] 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.

[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, 16.045, 22.257, 22.545, 22.733, 25.873.

[0071] 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.

[0072] In some embodiments, the crystal structure of the hydrochloride salt form A belongs to the monoclinic system, P21 (No. 4) space group.

[0073] 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

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] In the 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.

[0079] In a fifth aspect of the present invention, there is provided a method for preparing the hydrochloride crystal 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:

[0080] Dissolve the compound represented by formula I in a crystallization solvent, heat to dissolve, and then dropwise add concentrated hydrochloric acid;

[0081] Adding crystallization agent dropwise;

[0082] stirring to crystallize; and / or cooling to crystallize to obtain the crystals.

[0083] 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.

[0084] 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.

[0085] 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.

[0086] 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

[0087] Figure 1 XRPD diagram of free form A

[0088] Figure 2 DSC and TGA diagrams of free form A

[0089] Figure 3 For free crystal form A 1 HNMR images

[0090] Figure 4 XRPD diagram of free form B

[0091] Figure 5 XRPD diagram of free crystal form C

[0092] Figure 6 DSC and TGA diagrams of free crystal form C

[0093] Figure 7 NMR diagram of free crystal form C

[0094] Figure 8 XRPD diagram of free crystal form D

[0095] Fig. 9 DSC and TGA diagrams of free crystal form D

[0096] Fig.10 NMR diagram of free crystal form D

[0097] Fig.11 XRPD diagram of succinate salt form A

[0098] Fig.12 DSC and TGA diagrams of succinate form A

[0099] Fig.13 Succinate Form A 1 HNMR images

[0100] Fig.14 XRPD diagram of succinate form B

[0101] Fig.15 DSC and TGA diagrams of succinate form B

[0102] Fig.16 Succinate Form B 1 HNMR images

[0103] Fig.17 XRPD diagram of succinate form C

[0104] Fig.18 DSC and TGA diagrams of succinate crystal form C

[0105] Fig.19 Succinate Form C 1 HNMR images

[0106] Fig. 20 XRPD diagram of fumarate salt form A

[0107] Fig.21 DSC and TGA diagrams of fumarate salt form A

[0108] Fig. 22 Fumarate Form A 1 HNMR images

[0109] Fig.23 XRPD diagram of fumarate form B

[0110] Fig.24 DSC and TGA diagrams of fumarate crystal form B

[0111] Fig.25 Fumarate Form B 1 HNMR images

[0112] Fig.26 XRPD pattern of oxalate form A

[0113] Fig. 27 DSC and TGA diagrams of oxalate crystal form A

[0114] Fig.28 Oxalate Form A 1 HNMR images

[0115] Fig.29 XRPD pattern of oxalate form B

[0116] Fig.30 DSC and TGA diagrams of oxalate crystal form B

[0117] Fig.31 Oxalate Form B 1 HNMR images

[0118] Fig.32 XRPD diagram of malate crystal form A

[0119] Fig.33 DSC and TGA diagrams of malate crystal form A

[0120] Fig.34 For malate crystal form A 1 HNMR images

[0121] Fig.35 XRPD diagram of hydrochloride form A (Formula Ia)

[0122] Fig.36 This is the MicroED diffraction single crystal structure diagram of Compound (I) hydrochloride form A. DETAILED DESCRIPTION

[0123] 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.

[0124]

[0125] Crystal form of compound of formula I and preparation method thereof

[0126] The crystal structure of the active pharmaceutical ingredient often affects the chemical stability of the drug. Different crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, and sometimes it may be accompanied by the production of other forms of crystals. Generally speaking, amorphous drug products do not have regular crystal structures and often have other defects, such as poor product stability, fine crystallization, difficult filtration, easy agglomeration, poor fluidity, etc. The polymorphic form of the drug has different requirements for product storage, production and amplification. Therefore, it is very necessary to further study 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).

[0127] The present invention generally relates to different solid forms, different salt forms, different crystalline forms of different salt forms and methods for preparing the same of Compound (I).

[0128] The preparation methods of different crystalline forms of the compound of formula (I) of the present invention are as follows:

[0129] Method for preparing co-crystallization of compound of formula (I):

[0130] (i) combining a solution of a co-crystal former with a solution of a compound of formula I to obtain a co-crystal mixture;

[0131] 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;

[0132] and (iii) supersaturating the co-crystallization mixture to initiate co-crystal formation.

[0133] Preparation method of crystalline form A of the compound represented by formula Ia:

[0134] Dissolve the compound represented by formula I in a crystallization solvent, heat to dissolve, and then dropwise add concentrated hydrochloric acid;

[0135] Adding crystallization agent dropwise;

[0136] stirring to crystallize; and / or cooling to crystallize to obtain the crystals.

[0137] Before the stirring crystallization step, the following steps may be included: adding activated carbon crystals for stirring and decolorization, and then filtering and washing.

[0138] The crystallization solvent in step 1) 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.

[0139] 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.

[0140] abbreviation

[0141] CmaxThe highest concentration measured

[0142] FaSSIF fasting simulated intestinal fluid

[0143] FeSSIF fed simulated intestinal fluid

[0144] DSC Differential Scanning Calorimetry

[0145] Pos.

[0146] Rel.Int.Relative Strength

[0147] TGA Thermogravimetric Analysis

[0148] Tmax is the time at which the maximum concentration (Cmax) is observed

[0149] XRPD X-ray powder diffraction

[0150] NMR analysis ( 1 H NMR)

[0151] Dissolve several milligrams of solid sample in dimethyl sulfoxide-d 6 NMR analysis was performed on a Bruker AVANCE NEO 400 (Bruker, GER) in solvent.

[0152] X-ray powder diffraction (XRPD)

[0153] The solid samples obtained in the experiment were analyzed by X-ray powder diffractometer Panalytical EMPYREAN (PANalytical, UK). The 2θ scanning angle was from 3° to 45°, the scanning step was 0.013°, and the total test time was 5.08 min. The test method was Cu target Kα1 radiation, voltage and 45 kV, current 40 mA, and the sample pan was a zero background sample pan.

[0154] Thermogravimetric analysis (TGA)

[0155] The model of the thermogravimetric analyzer is TA Discovery 550 (TA, US). 2-5 mg of sample was placed in a balanced open aluminum sample pan and automatically weighed in the TGA heating furnace. The sample was heated to the final temperature at a rate of 10 ° C / min, and the nitrogen purge rate at the sample was 60 mL / min, and the nitrogen purge rate at the balance was 40 mL / min.

[0156] Differential Scanning Calorimetry (DSC)

[0157] The model of the differential scanning calorimeter was TA Discovery 250 (TA, US). 1-2 mg of sample was accurately weighed and placed in a DSC Tzero sample pan with holes, and heated to the final temperature at a rate of 10°C / min, with a nitrogen purge rate of 50 mL / min in the furnace.

[0158] Example 1 Free Form A

[0159] Weigh 24.8 mg of the raw material compound of formula I, add 1.0 mL of methyl tert-butyl ether solvent and suspend at room temperature for two days. After centrifugation, the solid is vacuum dried at room temperature for 1 day. Collect the solid for XRPD analysis. XRPD of the solid Figure 1 The same as in Table 1, and confirmed to be the free form A of compound (I). Depending on the solvation state, the free form A may be a solvate, hydrate, anhydrate or polymorph of compound (I).

[0160] exist Figure 2 In the DSC and TGA diagrams of free form A, the TGA results show that the sample loses 2.2% of its weight when heated to 100°C, and decomposition may occur after 300°C; the DSC results show that form A has an endothermic signal peak at 101°C.

[0161] Table 1 X-ray powder diffraction peaks of free form A of compound (I)

[0162]

[0163]

[0164] Example 2 Free Form B

[0165] Weigh 20.0 mg of the raw material compound of formula I, add 0.05 mL of isopropanol to dissolve, slowly add n-heptane to 1.0 mL, stir at room temperature for 1 day to obtain a suspension, centrifuge to obtain a solid, and use the solid wet sample for XRPD analysis. XRPD of the solid Figure 4The results are the same as those in Table 2 and confirmed to be the free-state crystalline form B of compound (I). Since the crystalline form B was converted into the crystalline form C after vacuum drying at room temperature, no characterization by TGA, DSC, NMR, etc. was performed.

[0166] Table 2 X-ray powder diffraction peaks of free crystalline form B_wet of compound (I)

[0167]

[0168]

[0169] Example 3 Free Form C

[0170] The free crystal form C can be obtained by vacuum drying the free crystal form B at room temperature or by gas phase diffusion in isopropanol / n-heptane. The relevant characterization data are as follows: Figures 15 to 17 As shown. XRPD of solid Figure 5 The same as in Table 3, and confirmed to be the free form C of compound (I). Depending on the solvation state, the free form C may be a solvate, hydrate, anhydrate or polymorph of compound (I).

[0171] exist Figure 6 In the DSC and TGA diagrams of free crystalline form C, the TGA results show that crystalline form C has a 1.5% weight loss during heating to 100°C, and may decompose above 300°C; the DSC results show that crystalline form C has an endothermic signal peak at around 114°C.

[0172] Table 3 X-ray powder diffraction peaks of free crystalline form C_dry of compound (I)

[0173]

[0174]

[0175] Example 4 Free Crystal Form D

[0176] Weigh 99.8 mg of the raw material compound of formula I, add 2.5 mL of isopropanol / n-heptane (v / v, 1 / 20), suspend and stir at 50°C for 2 days, centrifuge the suspension, and vacuum dry the solid at 40°C for 17 hours. Collect the solid for XRPD analysis. XRPD of the solid Figure 8 The same as in Table 4, and confirmed to be the free form D of compound (I). Form D is an anhydrous form with good crystallinity. Depending on the solvation state, the free form D may be a solvate, hydrate, anhydrous form or polymorph of compound (I).

[0177] exist Fig. 9In the DSC and TGA diagrams of the free form D, the TGA results show that the form D has a 1.1% weight loss during heating to 100°C, and decomposition may occur above 300°C; the DSC results show that the form D has a broad endothermic signal peak at 50-100°C and an endothermic signal peak at around 134°C.

[0178] Table 4 X-ray powder diffraction peaks of free form D of compound (I)

[0179]

[0180]

[0181] Example 5 Succinate Crystal Form A

[0182] Weigh 49.6 mg of the raw material compound of formula I and 13.0 mg of succinic acid, add 3.0 mL of THF / n-heptane (v / v, 1 / 1), stir at room temperature for 4 days, centrifuge the suspension, and vacuum dry the solid part at 40°C for 19 hours. Collect the solid for XRPD analysis. XRPD of the solid Fig.11 The same as in Table 5, and confirmed to be the succinate crystal form A of compound (I). Depending on the solvation state, the succinate crystal form A of compound (I) may be a solvate, a hydrate, an anhydrate or a polymorph.

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

[0184] exist Fig.12 In the DSC and TGA diagrams of succinate form A, the TGA results show that the sample has a 6.8% weight loss 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.

[0185] Table 5 X-ray powder diffraction peaks of compound (I) succinate salt form A

[0186]

[0187]

[0188]

[0189] Example 6 Succinate Crystal Form B

[0190] Weigh 49.6 mg of the raw material compound of formula I and 13.0 mg of succinic acid, add 3.0 mL of THF / n-heptane (v / v, 1 / 1), stir at room temperature for 3 days, centrifuge the suspension, and vacuum dry the solid part at 40°C for 18 hours. Collect the solid for XRPD analysis. XRPD of the solid Fig.14 The same as in Table 6, and confirmed to be the succinate crystal form B of compound (I). Depending on the solvation state, the succinate crystal form B of compound (I) may be a solvate, a hydrate, an anhydrate or a polymorph.

[0191] XRPD results showed that the succinate salt Form B was a generally crystalline solid.

[0192] exist Fig.15 In the DSC and TGA diagrams of succinate form B, the TGA results show that the sample has a 7.0% weight loss during heating to 100°C, and decomposition may occur after 200°C; the DSC results show a broad endothermic signal peak at 40-100°C.

[0193] Table 6 X-ray powder diffraction peaks of compound (I) succinate crystal form B

[0194]

[0195]

[0196]

[0197] Example 7 Succinate Crystal Form C

[0198] Weigh 500.1 mg of the raw material compound of formula I and 130.1 mg of succinic acid, add 10.0 mL of THF / n-heptane (v / v, 1 / 1), stir at room temperature for 5 days, and form a colloid. Suspend it at 50°C for 3 hours and then suspend it at room temperature for 3 days. Centrifuge the precipitated solid, and dry the solid part at 40°C in vacuum for 18 hours. Collect the solid for XRPD analysis. XRPD of the solid Fig.17 The same as in Table 7, and confirmed to be the succinate crystal form C of compound (I). Depending on the solvation state, the succinate crystal form C of compound (I) may be a solvate, a hydrate, an anhydrate or a polymorph.

[0199] XRPD results showed that the succinate salt Form C was a solid with average crystalline properties.

[0200] exist Fig.18 In the DSC and TGA diagrams of succinate form C, the TGA results show that the sample has a 4.1% weight loss 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.

[0201] Table 7 X-ray powder diffraction peaks of compound (I) succinate salt form C

[0202]

[0203]

[0204] Example 8 Fumarate Crystal Form A

[0205] Weigh 24.9 mg of the raw material compound of formula I 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. XRPD of the solid Fig. 20 The same as in Table 8, and 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, a hydrate, an anhydrate or a polymorph. The XRPD results show that the fumarate crystalline form A is a solid with general crystallinity.

[0206] exist Fig.21 In the DSC and TGA diagrams of fumarate salt form A, 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.

[0207] Table 8 X-ray powder diffraction peaks of compound (I) fumarate crystal form A

[0208]

[0209]

[0210] Example 9 Fumarate Crystal Form B

[0211] Weigh 24.9 mg of the raw material compound of formula I and 6.3 mg of fumaric acid, add 1.0 mL of ethyl acetate, stir at room temperature for 3 days, centrifuge the suspension, and vacuum dry the solid at room temperature. Collect the solid for XRPD analysis. XRPD of the solid Fig.23 The results are the same as those in Table 9 and confirmed to be the fumarate crystalline form B of compound (I). Depending on the solvation state, the fumarate crystalline form B of compound (I) may be a solvate, a hydrate, an anhydrate or a polymorph.

[0212] XRPD results showed that the fumarate salt Form B was a poorly crystalline solid.

[0213] exist Fig.24In the DSC and TGA diagrams of fumarate salt form B, 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.

[0214] Table 9 X-ray powder diffraction peaks of compound (I) fumarate salt form B

[0215]

[0216]

[0217] Example 10 Oxalate Form A

[0218] Weigh 24.8 mg of the raw material compound of formula I 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. XRPD of the solid Fig.26 The results are the same as those in Table 10 and confirmed to be the oxalate crystal form A of compound (I). Depending on the solvation state, the oxalate crystal form A of compound (I) may be a solvate, a hydrate, an anhydrate or a polymorph.

[0219] XRPD results showed that oxalate Form A was a solid with average crystalline properties.

[0220] exist Fig. 27 In the DSC and TGA diagrams of oxalate form A, the TGA results show that the sample has a 9.7% weight loss during heating to 110°C, a 2.0% weight loss during heating from 110°C to 150°C, and may decompose after 210°C; the DSC results show that there is a broad endothermic signal corresponding to the TGA weight loss at 50-100°C, and an endothermic signal peak at 129°C.

[0221] Table 10 X-ray powder diffraction peaks of compound (I) oxalate crystal form A

[0222]

[0223]

[0224] Example 11 Oxalate Form B

[0225] Weigh 39.7 mg of the raw material compound of formula I 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 vacuum dry the solid at room temperature. Collect the solid for XRPD analysis. XRPD of the solid Fig.29The results are the same as those in Table 11 and confirmed to be the oxalate crystal form B of compound (I). Depending on the solvation state, the oxalate crystal form B of compound (I) may be a solvate, a hydrate, an anhydrate or a polymorph.

[0226] XRPD results showed that oxalate Form B was a solid with average crystalline properties.

[0227] exist Fig.30 In the DSC and TGA diagrams of oxalate crystal form B, the TGA results show that the sample has a 9.3% weight loss 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.

[0228] Table 11 X-ray powder diffraction peaks of compound (I) oxalate crystal form B

[0229]

[0230]

[0231] Example 12 Malate Crystal Form A

[0232] Weigh 24.8 mg of the raw material compound of formula I and 7.4 mg 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 resulting jelly, stir at room temperature for 3 days, centrifuge the solid, and dry the solid under vacuum at room temperature. Collect the solid for XRPD analysis. XRPD of the solid Fig.32 The results are the same as those in Table 12 and confirmed to be malate crystal form A of compound (I). Malic acid crystal form A of compound (I) may be a solvate, a hydrate, an anhydrate or a polymorph depending on the solvation state.

[0233] XRPD results showed that malate Form A was a poorly crystalline solid.

[0234] exist Fig.33 In the DSC and TGA diagrams of malate crystal form A, 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.

[0235] Table 12 X-ray powder diffraction peaks of compound (I) malate crystal form A

[0236]

[0237]

[0238] Example 13 (Formula Ia) Hydrochloride Form A

[0239] 1) Add 12 g of the raw material 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; add concentrated hydrochloric acid dropwise;

[0240] 2) After the solution is dissolved, add activated carbon and stir to decolorize for 15 minutes;

[0241] 3) Filtration: first filter once with filter paper, then filter once with a 0.22-0.45um organic filter membrane, and use 6 ml of ethanol for washing during the filtration process;

[0242] 4) After filtration, the filtrate was transferred to a 250 ml reaction bottle and 108 ml of acetone was added dropwise at 40-50°C;

[0243] 5) After the addition is complete, stir and crystallize at room temperature for 15-20 hours;

[0244] 6) After stirring, slowly cool the ice water to 2-8°C and stir for 1h;

[0245] 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 crystal form A.

[0246] The solid was collected for XRPD analysis. XRPD of the solid Fig.35 The same as in Table 13, and confirmed to be the hydrochloride salt form A (Formula Ia) of Compound (I).

[0247] Compound (I) hydrochloride crystal form A has the following Fig.36 The MicroED diffraction crystal structure shown in .

[0248] Table 13 X-ray powder diffraction peaks of Compound (I) hydrochloride salt form A

[0249]

[0250]

[0251]

[0252] MicroED single crystal diffraction: (a) After placing the sample in a transmission electron microscope (TEM), search for the target particle in the imaging mode; (b) In the diffraction mode of the TEM, rotate the target particle at a certain speed and collect a series of diffraction photos at the same time; (c) After having enough diffraction data, the electron density map within the unit cell can be solved; (d) Determine the atomic coordinates within the unit cell through the electron density peak, and thus solve the final structure. The crystallographic data and refinement parameters are shown in Table 14.

[0253] Table 14 MicroED single crystal structure data of compound (I) hydrochloride salt form A

[0254]

[0255]

[0256] 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 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 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 the X-ray powder diffraction peak spectrum; 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 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. 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, and 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 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. 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, 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, 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, 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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