CRYSTALLINE COMPOUND OR ITS BASIC SALT, METHOD OF ITS PRODUCTION AND ITS APPLICATION

Abstract

The present invention relates to a crystalline compound or a basic salt thereof, a preparation method therefor, and a use thereof. The compound is a PD-1 / PD-L1 inhibitor having a compound structure as represented by the following formula (I). The crystalline compound has moderate hygroscopicity, improved solubility, good crystallinity, and stable physicochemical properties, and the basic salt of the crystalline compound has good crystallinity, good solubility, and stable physicochemical properties, meets industrial production requirements, and satisfies the need for the development of clinical pharmaceutical formulations. The crystalline compound or the basic salt thereof in the present invention can be widely applied to the preparation of drugs for treating PD-1 / PD-L1 signaling pathway-mediated tumors, immune-related diseases and disorders, contagious diseases, infectious diseases, or metabolic diseases.

Description

A crystalline compound or its basic salt and its preparation method and application Technical Field

[0001] The present invention belongs to the field of drug development, and specifically relates to a crystalline PD-1 / PD-L1 inhibitor compound or basic salt, and a preparation method and application thereof. Background Art

[0002] The immune system plays a crucial role in controlling and eliminating diseases such as cancer. However, tumor cells often develop strategies to evade or suppress immune surveillance to promote their malignant growth. One important mechanism is to alter the expression of co-stimulatory and co-inhibitory immune checkpoint molecules on immune cells. Blocking the signaling pathways of immune checkpoint molecules, such as PD-1, has proven to be a very promising and effective therapeutic approach. Programmed cell death molecule 1 (PD-1), also known as CD279, is a receptor molecule expressed on the surface of activated T cells, natural killer T cells, B cells, and macrophages. Its structure consists of an extracellular domain resembling the variable region of an immunoglobulin, a transmembrane region, and an intracellular domain. The intracellular domain contains two phosphorylation sites located within the immunoreceptor tyrosine kinase-based inhibitory domain and the immunoreceptor tyrosine kinase-based switch domain, suggesting that PD-1 can negatively regulate T cell receptor-mediated signaling pathways.

[0003] PD-1 has two ligands, PD-L1 and PD-L2, which differ in their expression profiles. PD-L1 protein is upregulated in macrophages and dendritic cells following treatment with lipopolysaccharide (LPS) and granulocyte-macrophage colony-stimulating factor (GM-CSF), and is also upregulated in T and B cells following stimulation via the T cell receptor and B cell receptor signaling pathways. It is also highly expressed in nearly all tumor cells and is upregulated following interferon (IFN)gamma stimulation. Indeed, tumor PD-L1 expression is thought to be prognostic in a variety of tumor types. PD-L2 expression, in contrast, is more concentrated, primarily on dendritic cells.

[0004] When PD-1-expressing T cells come into contact with cells expressing its ligand, functional activities responsive to antigen stimulation, such as cell proliferation, cytokine release, and cytolytic activity, are inhibited. Therefore, the interaction between PD-1 and its ligand functions as an intrinsic negative feedback mechanism, preventing T cell overactivation during infection, immune tolerance, or tumor development, thereby reducing autoimmune disease and promoting autoimmune tolerance. Chronic antigenic stimulation, such as that seen in tumors or chronic infections, causes T cells to express high levels of PD-1 and become inactive and ineffective in responding to these long-term antigens—a phenomenon known as T cell exhaustion. B cells also experience the inhibitory effects of PD-1 and its ligand, leading to corresponding functional exhaustion.

[0005] Several preclinical animal studies have shown that PD-1 and its ligands can negatively regulate immune responses. PD-1-deficient mice develop lupus erythematosus-like acute proliferative glomerulonephritis and dilated cardiomyopathy. Blocking the PD-1 / PD-L1 interaction with antibodies targeting PD-L1 has been shown to restore and enhance T cell activation in multiple systems. Monoclonal antibodies targeting PD-L1 have also shown benefits for patients with advanced cancer. Preclinical animal tumor models have also shown that blocking the PD-1 / PD-L1 signaling pathway with monoclonal antibodies can enhance immune responses and result in responses against a range of histologically distinct tumors. Using a model of chronic LCMV infection, the PD-1 / PD-L1 interaction has been found to inhibit virus-specific CD8 T cell activation, expansion, and acquisition of effector cell function. In addition to enhancing immune responses to chronic antigens, blocking the PD-1 / PD-L1 pathway has also been shown to enhance responses to vaccines, including therapeutic vaccines in the setting of chronic infection.

[0006] These results indicate that small molecule inhibitors targeting the PD-1 / PD-L1 interaction can be an effective therapeutic approach to block the PD-1 / PD-L1-mediated inhibitory signaling pathway to enhance or restore T cell function, and will have a good therapeutic effect in the immunotherapy of various cancers and other immune-related diseases.

[0007] Shanghai Abbisko Therapeutics Co., Ltd. has discovered a small molecule compound with PD-1 / PD-L1 inhibitory effects through long-term research (WO2019149183A1, international publication date: August 8, 2019). Representative compounds are as follows:

[0008] The Chinese name is: (2S,2'S)-1,1'-((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(azaalkanediyl))bis(oxo))bis(4-cyclopropylpyridine-6,3-diyl))bis(methylene))bis(piperidine-2-carboxylic acid) (compound of formula (I)). This compound has a strong inhibitory effect on the protein interaction of PD-1 / PD-L1, and this inhibitory effect can enhance or restore T cell activation at the cellular level, which can meet the current domestic and international needs for targeted treatment of tumors, immune-related diseases and disorders, infectious diseases, infectious diseases or metabolic diseases.

[0009] During later pharmaceutical research, it was discovered that the compound of formula (I) reported in WO2019149183A1 is a lyophilized amorphous trifluoroacetate compound with poor solid-state properties, high moisture absorption, poor solubility, and unsuitable for clinical formulation development. Therefore, to meet the needs of clinical research and marketed pharmaceutical formulations, it is urgent to develop an aggregated form suitable for drug development to overcome the shortcomings of the existing technology.

[0010] Summary of the Invention

[0011] To address the problems of the prior art, the inventors conducted in-depth research on the different aggregation forms of the compound of formula (I). After extensive salt and crystal form screening experiments, they developed several crystalline free-state compounds or their basic salts. The crystalline free-state compounds significantly improved the physicochemical properties of the compound of formula (I), such as hygroscopicity, solubility, and physicochemical stability. The basic salts of the crystalline compounds significantly improved the physicochemical properties, such as solubility and physicochemical stability. The crystalline free-state compounds or their basic salts have improved bioavailability, meet industrial production requirements, and can meet the needs of clinical drug formulation development. The crystalline compounds or their basic salts have very important clinical application value and are expected to accelerate the development of a new generation of PD-1 / PD-L1 small molecule inhibitors.

[0012] The first aspect of the present invention provides a crystalline form of a basic salt of a compound of formula (I):

[0013] Wherein, the basic salt is selected from lithium salt, sodium salt, potassium salt, magnesium salt, calcium salt or ammonium salt.

[0014] As a preferred embodiment, the basic salt of the crystalline compound of formula (I) is a sodium salt.

[0015] As a further preferred embodiment, the molar ratio of the free compound of formula (I) to sodium atoms per molecule of the crystalline sodium salt of the compound of formula (I) is 1:1 or 1:2. A molar ratio of 1:1 is referred to as a monosodium salt, and a molar ratio of 1:2 is referred to as a disodium salt.

[0016] As a further preferred embodiment, the molar ratio of the free compound of formula (I) to sodium atoms in each molecule of the crystalline sodium salt of the compound of formula (I) is 1:2.

[0017] As a preferred embodiment, the crystalline sodium salt of the compound of formula (I) is an anhydrate or a hydrate.

[0018] As a further preferred embodiment, the molar ratio of the free compound of formula (I) to water molecules per molecule of the crystalline sodium salt hydrate of the compound of formula (I) is 1.0:(0.1-10.0). Among them, a molar ratio of 1.0:0.5 is called a hemihydrate, a molar ratio of 1.0:1.0 is called a monohydrate, a molar ratio of 1.0:2.0 is called a dihydrate, and so on are called trihydrate, tetrahydrate, pentahydrate, etc.

[0019] As a further preferred embodiment, the molar ratio of the free compound of formula (I) to water molecules per molecule of the crystalline sodium salt hydrate of the compound of formula (I) is 1.0: (1.0-5.0).

[0020] As a further preferred embodiment, the molar ratio of the free compound of formula (I) to water molecules per molecule of the crystalline sodium salt hydrate of the compound of formula (I) is 1.0:4.0 or 1.0:2.0.

[0021] As a further preferred embodiment, the crystalline form of the basic salt of the compound of formula (I) is the disodium salt hydrate form A, and its X-ray powder diffraction pattern (XRPD) includes five or more peaks at diffraction angles (2θ) of 8.60±0.2°, 9.97±0.2°, 12.92±0.2°, 15.03±0.2°, 17.62±0.2°, 17.93±0.2°, 20.04±0.2°, 22.07±0.2°, 23.18±0.2°, 23.60±0.2° and 27.06±0.2°.

[0022] As the most preferred embodiment, the disodium salt hydrate crystalline form A has an X-ray powder diffraction pattern (XRPD) comprising a peak (±0.2°) substantially identical to the diffraction angle (2θ) shown in FIG1 , and its X-ray powder diffraction data are shown in Table 1:

[0023] Table 1

[0024] This crystalline form is designated as disodium salt hydrate Form A.

[0025] As the most preferred embodiment, the basic salt of the compound of formula (I) is a disodium salt hydrate crystal form A, and the unit cell of the disodium salt hydrate crystal form A is a monoclinic system, and the unit cell parameters are α=90°,β=94.8(2)°,γ=90°,the unit cell volume V is The Z' is 0.5, and the asymmetric unit consists of 0.5 API anions, 1 sodium ion, and 2 water molecules. Its single crystal unit cell structure is shown in Figure 7.

[0026] As the most preferred embodiment, the basic salt of the compound of formula (I) is a disodium salt hydrate crystal form A, and its DSC / TGA spectrum is substantially as shown in FIG8 .

[0027] As a further preferred embodiment, the crystalline form of the basic salt of the compound of formula (I) is the disodium salt anhydrate form B, and its X-ray powder diffraction pattern (XRPD) includes five or more peaks at diffraction angles (2θ) of 6.60±0.2°, 7.46±0.2°, 12.43±0.2°, 13.32±0.2°, 13.63±0.2°, 15.54±0.2°, 17.32±0.2°, 18.68±0.2° and 21.73±0.2°.

[0028] As the most preferred embodiment, the disodium salt anhydrate crystalline form B has an X-ray powder diffraction pattern (XRPD) comprising a peak (±0.2°) substantially identical to the diffraction angle (2θ) shown in FIG2 , and its X-ray powder diffraction data are shown in Table 2:

[0029] Table 2

[0030] This crystalline form is designated as disodium salt anhydrate form B and has a melting point of 316.4°C.

[0031] As the most preferred embodiment, the basic salt of the compound of formula (I) is the disodium salt anhydrate form B, and its DSC / TGA spectrum is substantially as shown in FIG9 .

[0032] The second aspect of the present invention provides a method for preparing the basic salt of the aforementioned crystalline form of the compound of formula (I), comprising the following steps:

[0033] 1) dissolving or dispersing the free form compound of formula (I) in water or a suitable organic solvent, and adding an alkaline solution to the above system; alternatively, adding the free form compound of formula (I) to the alkaline solution;

[0034] 2) collecting the solid product precipitated during the above-mentioned salt-forming reaction, or obtaining a crystalline product by creating a supersaturation in the salt-forming system;

[0035] The basic salt is selected from lithium salt, sodium salt, potassium salt, magnesium salt, calcium salt or ammonium salt.

[0036] As a preferred solution, the alkaline solution is selected from an aqueous solution or an organic solvent solution of lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide or ammonia.

[0037] As a preferred solution, the method for creating supersaturation in the salt-forming system in step 2) of the preparation method includes one or more of the following: adding seed crystals, volatilizing the solvent, adding an anti-solvent, or cooling.

[0038] As a preferred embodiment, the organic solvent in the salt formation process of step 1) of the preparation method is selected from alcohols, chloroalkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, benzenes, amides or sulfoxides, or mixtures thereof, or aqueous solutions thereof.

[0039] As a further preferred embodiment, the organic solvent in the salt formation process of step 1) of the preparation method is selected from methanol, ethanol, n-propanol, isopropanol, dichloromethane, heptane, acetonitrile, acetone, methyl ethyl ketone, toluene, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether or 2-methoxyethyl ether, or a mixture thereof, or an aqueous solution thereof.

[0040] The third aspect of the present invention provides a method for preparing the aforementioned crystalline form of the basic salt of the compound of formula (I), comprising the following steps: converting one crystalline form of the basic salt of the compound of formula (I) into another crystalline form of the salt by a crystalline form conversion method, the crystalline form conversion method including: heating or crystal conversion by suspension in a solvent.

[0041] As a preferred embodiment, the solvent is selected from methanol, ethanol, n-propanol, isopropanol, dichloromethane, heptane, acetonitrile, acetone, methyl ethyl ketone, toluene, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether or 2-methoxyethyl ether, or a mixture thereof, or an aqueous solution thereof.

[0042] The fourth aspect of the present invention provides a crystalline free-state compound of formula (I):

[0043] As a preferred embodiment, the crystalline free-state compound of formula (I) is Form C, Form D, Form E or Form F.

[0044] As a further preferred embodiment, the crystalline form of the compound of formula (I) is a free crystalline form C, and its X-ray powder diffraction pattern (XRPD) includes five or more peaks at diffraction angles (2θ) of 7.80±0.2°, 11.97±0.2°, 12.42±0.2°, 15.98±0.2°, 17.37±0.2°, 18.82±0.2°, 22.47±0.2°, 23.30±0.2°, 25.01±0.2° and 25.63±0.2°.

[0045] As a further preferred embodiment, the free crystalline Form C has an X-ray powder diffraction pattern (XRPD) comprising a peak (±0.2°) substantially identical to the diffraction angle (2θ) shown in FIG3 , and its X-ray powder diffraction data are shown in Table 3:

[0046] Table 3

[0047] This crystalline form is designated as free form C and has a melting point of 169.5°C.

[0048] As the most preferred embodiment, the crystalline form of the compound of formula (I) is the free form C, and its DSC / TGA spectrum is basically as shown in FIG10 .

[0049] As a further preferred embodiment, the crystalline form of the compound of formula (I) is the free form D, and its X-ray powder diffraction pattern (XRPD) includes five or more peaks at diffraction angles (2θ) of 7.97±0.2°, 11.82±0.2°, 12.18±0.2°, 14.87±0.2°, 16.13±0.2°, 17.18±0.2°, 19.21±0.2°, 20.72±0.2° and 25.28±0.2°.

[0050] As a further preferred embodiment, the free crystalline form D has an X-ray powder diffraction pattern (XRPD) comprising a peak (±0.2°) substantially identical to the diffraction angle (2θ) shown in FIG4 , and its X-ray powder diffraction data are shown in Table 4:

[0051] Table 4

[0052] This crystalline form is designated as free-state crystalline form D and has a melting point of 239.9°C.

[0053] As the most preferred embodiment, the crystalline form of the compound of formula (I) is the free form D, and its DSC / TGA spectrum is basically as shown in FIG11 .

[0054] As a further preferred embodiment, the crystalline form of the compound of formula (I) is the free crystalline form E, and its X-ray powder diffraction pattern (XRPD) includes five or more peaks at diffraction angles (2θ) of 8.16±0.2°, 12.05±0.2°, 12.83±0.2°, 15.19±0.2°, 16.18±0.2°, 16.59±0.2°, 17.62±0.2°, 18.41±0.2°, 22.90±0.2° and 25.65±0.2°.

[0055] As a further preferred embodiment, the free crystalline form E has an X-ray powder diffraction pattern (XRPD) comprising a peak (±0.2°) substantially identical to the diffraction angle (2θ) shown in FIG5 , and its X-ray powder diffraction data are shown in Table 5:

[0056] Table 5

[0057] This crystalline form is designated as free form E and has a melting point of 226°C.

[0058] As the most preferred embodiment, the crystalline form of the compound of formula (I) is the free form E, and its DSC spectrum is basically as shown in FIG12 .

[0059] As a further preferred embodiment, the crystalline form of the compound of formula (I) is the free form F, and its X-ray powder diffraction pattern (XRPD) includes five or more peaks at diffraction angles (2θ) of 6.92±0.2°, 9.10±0.2°, 12.42±0.2°, 13.46±0.2°, 14.38±0.2°, 15.84±0.2°, 19.04±0.2°, 22.00±0.2° and 26.23±0.2°.

[0060] As a further preferred embodiment, the free crystalline form F has an X-ray powder diffraction pattern (XRPD) comprising a peak (±0.2°) substantially identical to the diffraction angle (2θ) shown in FIG6 , and its X-ray powder diffraction data are shown in Table 6:

[0061] Table 6

[0062] This crystalline form is designated as free-state Form F and has a melting point of 221°C.

[0063] As the most preferred embodiment, the crystalline form of the compound of formula (I) is the free form F, and its DSC / TGA spectrum is basically as shown in FIG13 .

[0064] In a fifth aspect, the present invention provides an application of the aforementioned crystalline free-form compound of formula (I), wherein the crystalline free-form compound of formula (I) is used as a raw material to prepare any of the aforementioned crystalline basic salts of the compound of formula (I).

[0065] The sixth aspect of the present invention provides a pharmaceutical composition comprising a clinically effective amount of the aforementioned crystalline basic salt of the compound of formula (I), or the crystalline free form of the compound of formula (I), and a pharmaceutically acceptable carrier.

[0066] As a preferred embodiment, the clinically effective amount means that the pharmaceutical composition contains 0.01-99.0% W / W of the crystalline basic salt or free form of the compound of formula (I) relative to the total content of the pharmaceutical composition.

[0067] In a seventh aspect, the present invention provides a basic salt of the aforementioned crystalline compound of formula (I), or a free crystalline compound of formula (I) for use in the preparation of a drug for treating tumors, immune-related diseases and disorders, infectious diseases, infectious diseases or metabolic diseases mediated by the PD-1 / PD-L1 signaling pathway; preferably, the tumor is cancer.

[0068] As a preferred embodiment, the infectious disease is selected from bacterial infectious diseases, viral infectious diseases or fungal infectious diseases.

[0069] As a preferred embodiment, the tumor is selected from lymphoma, sarcoma, melanoma, glioblastoma, synovioma, meningioma, biliary tract tumor, neural tumor, seminoma, Wilms tumor, hepatocellular papilloma, papilloma, leiomyoma, rhabdomyomas, hemangiomas, lymphangiomas, osteomas, lipomas, fibromas, central nervous system tumors, spinal axon tumors, brain stem gliomas, multiple myeloma, ovarian tumors, myelodysplastic syndrome or mesothelioma, anal cancer, testicular cancer, urethral cancer, penile cancer, bladder cancer, ureter cancer, uterine cancer, ovarian cancer, fallopian tube cancer, cervical cancer, vaginal cancer, vulvar cancer, Merkel cell carcinoma, embryonal carcinoma, chronic or acute leukemia, bronchial cancer, esophageal cancer, nasopharyngeal cancer, hepatocellular carcinoma, basal cell carcinoma, lung cancer, adenocarcinoma, papillary carcinoma, rectal cancer, colon cancer, stomach cancer, head and neck cancer, bone cancer, skin cancer, small intestine cancer, cancer of the endocrine system, renal pelvis cancer, epidermoid carcinoma, transitional cell carcinoma, or choriocarcinoma;

[0070] The immune-related diseases and disorders are selected from rheumatoid arthritis, renal failure, lupus erythematosus, asthma, psoriasis, ulcerative colitis, pancreatitis, allergies, fibrosis, anemia, fibromyalgia, Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, Crohn's disease, ulcerative colitis, allergic contact dermatitis and eczema, systemic sclerosis and multiple sclerosis;

[0071] The infectious disease or contagious disease is selected from sepsis, liver infection, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus, papillomavirus or influenza;

[0072] The metabolic disease is selected from diabetes, diabetic ketoacidosis, hyperglycemic hyperosmolar syndrome, hypoglycemia, gout, malnutrition, vitamin A deficiency, scurvy, vitamin D deficiency or osteoporosis.

[0073] As a preferred embodiment, the lymphoma is selected from lymphocytic lymphoma, primary central nervous system lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma, follicular center lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma or primary mediastinal large B-cell lymphoma;

[0074] The sarcoma is selected from Kaposi's sarcoma, fibrosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, leiomyosarcoma, rhabdomyosarcoma, soft tissue sarcoma, angiosarcoma or lymphangiosarcoma;

[0075] The chronic or acute leukemia is selected from acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia or chronic lymphocytic leukemia.

[0076] As a preferred embodiment, the tumor is selected from small cell lung cancer, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, chondroma, colorectal cancer, gastrointestinal cancer, endometrial cancer, head and neck squamous cell carcinoma, abdominal wall cancer, renal cell carcinoma, or prostate cancer that has recurred or become resistant to existing drugs.

[0077] As a preferred embodiment, the tumor is selected from thymic tumor, pleomorphic adenoma, renal tubular adenoma, cystadenoma, pituitary adenoma, prostate cancer, thyroid cancer, parathyroid cancer, adrenal cancer, breast cancer, cystadenocarcinoma or pancreatic cancer.

[0078] In an eighth aspect, the present invention provides a basic salt of the aforementioned crystalline form of the compound of formula (I), or the aforementioned crystalline free form of the compound of formula (I), which is used as a drug for treating tumors, immune-related diseases and disorders, infectious diseases, infectious diseases or metabolic diseases mediated by the PD-1 / PD-L1 signaling pathway.

[0079] The present invention also provides a method for treating tumors, immune-related diseases and disorders, infectious diseases, infectious diseases or metabolic diseases mediated by the PD-1 / PD-L1 signaling pathway, comprising administering the aforementioned crystalline basic salt of the compound of formula (I) or the aforementioned crystalline free form of the compound of formula (I) to a patient in need. BRIEF DESCRIPTION OF THE DRAWINGS

[0080] Figure 1 shows the X-ray powder diffraction pattern of the disodium salt hydrate of the compound of formula (I) of the present invention, Form A. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0081] Figure 2 shows the X-ray powder diffraction pattern of the disodium salt anhydrate form B of the compound of formula (I) of the present invention. The abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0082] Figure 3 shows the X-ray powder diffraction pattern of the free form of the compound of formula (I) of the present invention, crystalline form C. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0083] Figure 4 shows the X-ray powder diffraction pattern of the free form of the compound of formula (I) of the present invention, crystalline form D. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0084] Figure 5 shows the X-ray powder diffraction pattern of the free form of the compound of formula (I) of the present invention, crystalline form E. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0085] Figure 6 shows the X-ray powder diffraction pattern of the free form of the compound of formula (I) of the present invention, Form F. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0086] FIG7 shows the single crystal unit cell structure of the disodium salt hydrate form A of the compound of formula (I) of the present invention.

[0087] Figure 8 shows the DSC / TGA graph of the disodium salt hydrate of the compound of formula (I) of the present invention, Form A. The abscissa represents temperature (°C), the left ordinate represents heat flow (w / g), and the right ordinate represents weight (%).

[0088] Figure 9 shows the DSC / TGA graph of the disodium salt anhydrate form B of the compound of formula (I) of the present invention. The abscissa represents temperature (°C), the left ordinate represents heat flow (w / g), and the right ordinate represents weight (%).

[0089] Figure 10 shows the DSC / TGA graph of the free form of the compound of formula (I) of the present invention, Form C. The abscissa represents temperature (°C), the left ordinate represents weight (%), and the right ordinate represents heat flow (w / g).

[0090] Figure 11 shows the DSC / TGA graph of the free form of the compound of formula (I) of the present invention, Form D. The abscissa represents temperature (°C), the left ordinate represents heat flow (w / g), and the right ordinate represents weight (%).

[0091] Figure 12 shows the DSC graph of the free form of the compound of formula (I) of the present invention, crystalline form E. The abscissa represents temperature (°C), and the ordinate represents heat flow (w / g).

[0092] Figure 13 shows the DSC / TGA graph of the free form of the compound of formula (I) of the present invention, Form F. The abscissa represents temperature (°C), the left ordinate represents heat flow (w / g), and the right ordinate represents weight (%).

[0093] Figure 14 shows a DVS diagram of the free form of the compound of formula (I) of the present invention, crystalline form C. The abscissa represents relative humidity (%), and the ordinate represents weight change (%).

[0094] Figure 15 shows a DVS diagram of the free form of the compound of formula (I) of the present invention, crystalline form D. The abscissa represents relative humidity (%), and the ordinate represents weight change (%).

[0095] Figure 16 shows a DVS diagram of the free form of the compound of formula (I) of the present invention, Form F. The abscissa represents relative humidity (%), and the ordinate represents weight change (%).

[0096] Figure 17 shows a DVS diagram of the disodium salt hydrate of the compound of formula (I) of the present invention, Form A. The abscissa represents relative humidity (%), and the ordinate represents weight change (%).

[0097] Figure 18 shows the X-ray powder diffraction pattern of the amorphous potassium salt of the compound of formula (I) of the present invention. The abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0098] Figure 19 shows the X-ray powder diffraction pattern of the amorphous arginine salt of the compound of formula (I) of the present invention. The abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity. DETAILED DESCRIPTION

[0099] The inventors of the present invention have conducted in-depth research on the different aggregation forms of the compound of formula (I) and provided a crystalline PD-1 / PD-L1 inhibitor free form or its basic salt. The crystalline free form compound greatly improves the physicochemical properties of the compound of formula (I), such as hygroscopicity, solubility, and physicochemical stability. The basic salt of the crystalline compound greatly improves the physicochemical properties, such as solubility and physicochemical stability. This allows the crystalline free form compound of formula (I) or its basic salt form to meet the development needs of clinical pharmaceutical preparations and has very important clinical application value. It can be widely used in the preparation of drugs for treating tumors, immune-related diseases and disorders, infectious diseases, infectious diseases, or metabolic diseases, especially for treating ovarian cancer, pancreatic cancer, prostate cancer, breast cancer, cervical cancer, glioblastoma, multiple myeloma, metabolic diseases, neurodegenerative diseases, metastasis of primary tumor sites, or bone metastasis. It is expected to accelerate the development of a new generation of PD-1 / PD-L1 inhibitor drugs. On this basis, the present invention was completed.

[0100] DETAILED DESCRIPTION: Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

[0101] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0102] The compound of formula (I) has a variety of isolated free forms or basic salts that exhibit polymorphism or single crystal phenomena. For example, each of the sodium salts exhibits polymorphism. These "polymorphs" differ in their X-ray powder diffraction patterns, physicochemical and pharmacokinetic properties, and thermodynamic stability.

[0103] As used herein, "salt" refers to a compound prepared by reacting an organic acid or base drug with a pharmaceutically acceptable inorganic or organic acid or base.

[0104] Methods and Materials

[0105] The diffraction data of the free form of the compound of formula (I) or its basic salt were collected using a Bruker D8 ADVANCE (Bruker, Germany) X-ray powder diffractometer at room temperature, with an X-ray source of Cu Kα ( Light tube voltage and current: 40kV, 40mA). When preparing the sample, place an appropriate amount of sample on the zero background sample pan and gently press the surface flat. The sample was scanned from 3° to 40° (2θ), with a step size of 0.02° (2θ) and a scanning time of 0.02s per step. The diffraction pattern was analyzed using DIFFRAC.EVA (V4.3.1). The measurement differences associated with this type of X-ray powder diffraction analysis results are caused by a variety of factors including the following: (a) errors in sample preparation (such as sample height), (b) instrument errors, (c) calibration differences, (d) operator errors (including those that occur when determining peak positions), and (e) the properties of the substance (such as preferred orientation errors). Calibration errors and sample height errors often result in displacement of all peaks in the same direction. Generally speaking, this calibration factor will make the measured peak position consistent with the expected peak position and can be within the range of ±0.2° of the expected 2θ value. The angle 2θ values ​​(°) and intensity values ​​(as % of the highest peak) of each polymorph obtained in the examples of the present invention are listed in Tables 1 to 6.

[0106] The experimental method for characterizing the crystalline form of the free form of the compound of formula (I) or its basic salt using differential scanning calorimetry (DSC) is to take a small amount of the crystalline form sample and place it in an aluminum pan that is compatible with the instrument and can be pressed with a lid. After loading the sample, the aluminum pan is pressed with a lid, and then the pan is inserted into the instrument for detection. The instrument model used for all differential scanning calorimetry in this patent is a TA Discovery DSC25, and the scanning parameters are set to use a nitrogen atmosphere and a heating rate of 10°C / min.

[0107] The experimental method for characterizing the crystalline form of the free form of the compound of formula (I) or its basic salt by thermogravimetric analysis (TGA) is to take a small amount of the crystalline form sample, place it in an aluminum pan provided with the instrument, load the sample, and then insert it into the instrument for detection. The instrument model used for all thermogravimetric analysis methods in this patent is a TA Discovery TGA550, and the scanning parameters are set to use a nitrogen atmosphere and a heating rate of 10°C / min.

[0108] The experimental method for characterizing the free form of the compound of formula (I) or its basic salt using the dynamic moisture sorption method (DVS) is to take a small amount of the crystalline sample, place it in a precision sample tray that is matched with the instrument, and after loading the sample, send it to the instrument for detection. The instrument model used for the dynamic moisture sorption method in this patent is DVS Intrinsic plus. The experimental parameters are set to use nitrogen as the carrier gas, the constant temperature is set to 25°C, the mass percentage change rate per unit time (dm / dt) = 0.002% / min as the judgment standard for reaching equilibrium, and the program humidity change cycle is set to 50-95-0-95-50% RH. In the range of 0-90% RH, the RH change is 10% as a step, and in the range of 90% RH-95% RH, the RH change is 5% as a step.

[0109] The stability and solubility of the free form of the crystalline compound of formula (I) or its basic salt were determined by HPLC. The specific test method is shown in the following table.

[0110] The reagents in the embodiments of the present invention are known and commercially available, or can be synthesized by methods known in the art. The raw materials used in the experiments are prepared according to patent WO2019149183A1, or optionally subjected to conventional treatment in the art to obtain a free state.

[0111] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, with dry solvents and temperatures expressed in degrees Celsius (°C).

[0112] Unless otherwise specified, the various crystal forms referred to in the present invention may be an anhydrous crystal form or a crystal-containing crystal form. If it is a crystal-containing crystal form, preferably each crystal contains 1, 2, 3, 4 or 5 molecules of crystalline water, and more preferably each crystal contains 2 or 4 molecules of crystalline water.

[0113] The present invention is further described in detail and completely below through the accompanying drawings and specific examples, which are only used to illustrate specific embodiments of the present invention and should not be interpreted as limiting the scope of the present invention in any way.

[0114] Preparation of specific embodiments

[0115] Example 1 Preparation of Disodium Salt Hydrate Form A

[0116] Approximately 10 mg of the free compound of formula (I) was dissolved in 0.5 mL of ethanol / water (volume ratio: 10:1). An ethanol / water solution containing 2 equivalents of sodium hydroxide was added, and the mixture was stirred at room temperature for 3 days. The mixture was filtered, and the filter cake was oven-dried at 50°C. Disodium salt hydrate Form A is a highly crystalline solid with a solid-solid transition peak at 237.3°C.

[0117] After detection and analysis, it has an XRPD pattern as shown in FIG1 and a DSC / TGA pattern as shown in FIG8 .

[0118] Example 2 Preparation of Disodium Salt Anhydrate Form B

[0119] About 10 mg of the disodium salt hydrate Form A of the compound of formula (I) was heated to 245° C. to obtain the disodium salt anhydrate Form B, which had a melting point of 316.4° C. The disodium salt anhydrate Form B was a highly crystalline solid.

[0120] After detection and analysis, it has an XRPD pattern as shown in FIG2 and a DSC / TGA pattern as shown in FIG9 .

[0121] Example 3 Preparation of Free Form C

[0122] Approximately 25 mg of the free form of the compound of formula (I) was added to 200 μL of ethyl acetate and suspended at 45°C for 7 days. The solid sample was then isolated by centrifugation and dried overnight in vacuo at 40°C. The free form Form C was a highly crystalline solid with a melting peak at 169.5°C.

[0123] After detection and analysis, it has an XRPD pattern as shown in FIG3 and a DSC / TGA pattern as shown in FIG10 .

[0124] Example 4 Preparation of Free Form D

[0125] About 10 mg of the free form compound of formula (I) was added to 200 μL of ethyl acetate and suspended at 45° C. for 7 days, filtered, and the filter cake was oven-dried at 50° C. The free form D was a medium-crystalline solid with a melting peak at 239.9° C. as shown by DSC.

[0126] After detection and analysis, it has the XRPD pattern shown in FIG4 , and the DSC and TGA patterns shown in FIG11 .

[0127] Example 5 Preparation of Free Form E

[0128] 5 mg of the free form C of the compound of formula (I) was heated to 166°C to obtain a solid sample of the free form E. The free form E is a solid with moderate crystallinity and a melting peak at 224.7°C.

[0129] After detection and analysis, it has an XRPD pattern as shown in FIG5 and a DSC pattern as shown in FIG12.

[0130] Example 6 Preparation of Free Form F

[0131] 5 mg of the free form compound of formula (I) was added to 200 μL of methanol and suspended at 50° C. for 7 days. The solid sample was then isolated by centrifugation and dried overnight in vacuo at 40° C. The free form F was a solid with medium crystallinity and a melting peak at 221.1° C.

[0132] After detection and analysis, it has an XRPD pattern as shown in FIG6 , and a DSC and TGA pattern as shown in FIG13 .

[0133] Example 7 Preparation of amorphous potassium salt

[0134] About 10 mg of the free compound of formula (I) was dissolved in 0.5 mL of trifluoroethanol, and a trifluoroethanol solution containing 2 equivalents of potassium hydroxide was added. The mixture was stirred at room temperature for 3 days, filtered, and the filter cake was dried in an oven at 50°C.

[0135] After detection and analysis, it has an XRPD pattern as shown in Figure 18. The potassium salt is obtained as an amorphous solid.

[0136] Example 8 Preparation of amorphous arginine salt

[0137] About 10 mg of the free compound of formula (I) was dissolved in 0.5 mL of trifluoroethanol, and a trifluoroethanol solution containing 2 equivalents of arginine was added. The mixture was stirred at room temperature for 3 days, filtered, and the filter cake was dried in an oven at 50°C.

[0138] After detection and analysis, it has an XRPD pattern as shown in Figure 19. The arginine salt was obtained as an amorphous solid.

[0139] Example 9: Single Crystal Structure Analysis of Disodium Salt Hydrate Form A

[0140] 1. Experimental equipment

[0141] Transmission electron microscope: Thermo Scientific Glacios

[0142] Detector: Thermo Scientific Ceta-D

[0143] Sample holder: Autoloader

[0144] 2. Experimental conditions

[0145] Voltage: 200kV

[0146] Temperature: 83K

[0147] Vacuum value: 10 -7 Pa high vacuum

[0148] 3. Application software

[0149] Data collection: Thermo Scientific EPU-D

[0150] Data processing: XDS, SHELXT, SHELXL

[0151] 4. Sample preparation

[0152] A small amount of powder sample was transferred directly onto a TEM grid, and excess powder was blown off with a rubber bulb. The grid was then rapidly frozen in liquid ethane using a Thermo Scientific Vitrobot cryo-EM sample preparation system, transferred to liquid nitrogen for storage, and then examined under an electron microscope.

[0153] 5. Image Collection

[0154] A number of particles of appropriate size and with clear diffraction signals were selected, and a series of diffraction data generated by particle rotation were automatically collected using EPU-D software.

[0155] 6. Data processing

[0156] The diffraction images are indexed and intensity integrated to obtain the unit cell parameters and HKL files, and multiple sets of data are fused to solve the crystal structure.

[0157] 7. Analysis results

[0158] 19 sets of diffraction patterns were collected from 26 different particles of the sodium salt of the compound of formula (I). They were indexed and integrated using XDS, and the unit cell constants were obtained as follows: α=90°,β=94.8(2)°,γ=90°,unit cell volume

[0159] 8. Structure determination

[0160] The nine best-quality data sets were combined using XSCALE, resulting in a total of 16,135 diffraction points, 2,821 of which were independent. The above data successfully determined the crystal structure of Form A of the disodium salt hydrate, which is monoclinic, with space group C2 (No. 5) and a molecular weight of 450.48 g·mol. -1 , Z' is 0.5, and the asymmetric unit consists of 0.5 API anions, 1 sodium ion, and 2 water molecules. The single crystal unit cell structure is shown in Figure 7. Crystallographic data and refinement parameters are shown in the table below.

[0161] Example 10 Solubility Determination

[0162] Weigh the desired amount of compound into a glass vial and add the desired amount of vehicle. Add a stir bar to the vial and stir at room temperature for 24 hours. Observe the appearance of the sample after 24 hours. Filter the appropriate amount of sample through a 0.45 μm PVDF filter membrane and collect the filtrate. Test the pH of the filtrate and dilute the sample with MeOH. Inject the diluted sample into an HPLC column to determine the concentration.

[0163] The preparation process of pH buffer is shown in the following table:

[0164] The preparation process of biological medium is shown in the following table:

[0165] The experimental results are shown below:

[0166] Equilibrium solubility data of free crystal forms C, D, and F

[0167] As can be seen from the above data, compared with other test conditions, the free crystalline form C has improved solubility in a pH 1.2 buffer system. Compared with the free crystalline form C, the solubility values ​​of the free crystalline form D and the free crystalline form F in various test conditions, such as pH 1.2-6.8 buffer system, water and simulated biological media (FaSSGF, FaSSIF and FeSSIF) are all increased by at least 10 times, showing significantly improved solubility. Even more surprisingly, compared with the free crystalline form C, the solubility value of the free crystalline form F in the simulated biological medium (FaSSIF) is increased by nearly 100 times, and the solubility value in the simulated biological medium (FeSSIF) is increased by hundreds of times.

[0168] Solubility data of disodium salt hydrate form A and disodium salt anhydrate form B

[0169] The above data demonstrate that the sodium salt of the crystalline form of the compound of formula (I) exhibits significantly improved solubility, with solubility at least several dozen times higher than that of the free form of the compound of formula (I), Form C. In particular, the disodium salt anhydrate, Form B, exhibits excellent solubility in various buffer solutions and biological media.

[0170] Example 11 Stability determination

[0171] Take appropriate amount of samples and put them into small bottles, place them at 50℃, 80℃, 50℃&75%RH (Open) for 7 days to evaluate thermal stability. Take appropriate amount of samples and put them into transparent small bottles, amber small bottles, and aluminum foil transparent small bottles, place them in a light box for 10 days to obtain 1.2×10 6 Lux·hr and comprehensive near-UV energy photostability evaluation of not less than 200W·hr / m2. The experimental results are shown below.

[0172] Stability data of free form C

[0173] Stability data of free form D

[0174] Stability data of free form F

[0175] Stability data of disodium salt hydrate form A

[0176] Stability data of disodium salt anhydrate form B

[0177] From the above results, we can see that

[0178] 1) Under conditions of 50°C, 50°C / 75% RH (open), 80°C for 7 days and light stress for 10 days, 1.2×10 6 Lux·hr and a comprehensive near-ultraviolet energy of not less than 200W·hr, the free crystalline forms C, D and F all have extremely high physicochemical stability.

[0179] 2) Disodium salt hydrate Form A exhibited good chemical stability under all stability testing conditions, with no significant impurity growth, but exhibited polymorphic transformation under high temperature and light exposure. Disodium salt anhydrate Form B exhibited good physical stability under all stability testing conditions, with no observed polymorphic transformation, but was sensitive to light. Therefore, the development of disodium salt polymorphs requires careful attention to storage conditions, avoiding high temperatures and light exposure.

[0180] Example 12 Hygroscopic behavior test

[0181] The present invention uses the dynamic moisture adsorption method to measure the moisture absorption weight gain of various crystal forms at various relative humidities (moisture absorption weight gain / weight before moisture absorption*100%) to evaluate the hygroscopicity of different crystalline compounds. The results are shown in Figures 14-17 and the following table:

[0182] Note: “ / ” means “not detected”

[0183] From the above data, it can be seen that the free crystalline forms C, D and F all have moderate hygroscopicity and show no change in crystalline form after DVS testing.

[0184] The disodium salt hydrate form A and the amorphous potassium salt have comparable hygroscopicity, with a weight increase of more than 10% at 80% RH, and showed no change in form after DVS testing.

[0185] Based on the above experimental results, it can be seen that the free-state crystalline Form C has high crystallinity, is amenable to scalable preparation, has moderate hygroscopicity, and exhibits extremely high physicochemical stability under all stability test conditions. However, the free-state crystalline Form C only has improved solubility in a pH 1.2 buffer system.

[0186] The free-state Form D has moderate crystallinity, is amenable to scalable preparation, exhibits moderate hygroscopicity, and exhibits extremely high physicochemical stability under various stability testing conditions. Furthermore, the free-state Form D exhibits significantly improved solubility under various pH conditions.

[0187] The free crystalline form E has medium crystallinity and is currently not easy to scale up for preparation.

[0188] The free-state Form F has moderate crystallinity, is amenable to scalable preparation, exhibits moderate hygroscopicity, and exhibits extremely high physicochemical stability under various stability testing conditions. Furthermore, the free-state Form F exhibits significantly improved solubility under various pH conditions.

[0189] Through salt screening of a large number of basic salts, only the sodium salt was obtained as a crystalline salt form, specifically the disodium salt hydrate Form A and the anhydrate Form B. The sodium salt can be prepared in highly crystalline salt forms, allowing for scalable production. Furthermore, under different pH conditions and in a variety of biological media, the various sodium salt forms exhibit significantly higher solubility than the free Form C.

[0190] Specifically, Form A of the disodium salt hydrate exhibits high physicochemical stability under various conditions, including 50°C, 50°C / 75% RH, or brown light. It exhibits high chemical stability under high temperature and light, but undergoes crystal transformation. Further development of formulations or storage and transportation require careful attention to avoid light and maintain an ambient temperature that is not too high.

[0191] The disodium salt anhydrate form B has high physical and chemical stability under various conditions such as 50°C, 50°C / 75% RH or brown light; it has high physical stability under high temperature and high humidity conditions, but is sensitive to light. Further development of formulations or storage and transportation require attention to avoid light.

[0192] All documents mentioned herein are incorporated herein by reference, just as if each document were individually incorporated by reference. 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 present invention.

Claims

1. A crystalline basic salt of a compound of formula (I): , wherein the base salt is selected from the group consisting of lithium salt, sodium salt, potassium salt, magnesium salt, calcium salt and ammonium salt.

2. A crystalline base salt of a compound of formula (I) according to claim 1, wherein the crystalline base salt of a compound of formula (I) is a sodium salt; and each molecule of the crystalline sodium salt of a compound of formula (I) comprises a compound of formula (I) in free form and a sodium atom in a molar ratio of 1:1 or 1:

2.

3. A crystalline basic salt of a compound of formula (I) according to claim 2, wherein each molecule of the crystalline sodium salt of a compound of formula (I) comprises a compound of formula (I) in free form and a sodium atom in a molar ratio of 1:

2.

4. A crystalline base salt of a compound of formula (I) according to claim 2, wherein the crystalline sodium salt of the compound of formula (I) is an anhydrous salt or a hydrate; preferably, each molecule of the hydrate of the crystalline sodium salt of the compound of formula (I) comprises the compound of formula (I) in free form and a water molecule in a molar ratio of 1.0:(0.1-10.0); more preferably, each molecule of the hydrate of the crystalline sodium salt of the compound of formula (I) comprises the compound of formula (I) in free form and a water molecule in a molar ratio of 1.0:(1.0-5.0); most preferably, each molecule of the hydrate of the crystalline sodium salt of the compound of formula (I) comprises the compound of formula (I) in free form and a molecule of water in a molar ratio of 1.0:4.0 or 1.0:2.

0.

5. A crystalline basic salt of a compound of formula (I) according to claim 4, wherein the crystalline basic salt of a compound of formula (I) is crystalline form A of the hydrate of the disodium salt, in the X-ray powder diffraction pattern of which five or more peaks are present at diffraction angles (2θ) of 8.60±0.2°, 9.97±0.2°, 12.92±0.2°, 15.03±0.2°, 17.62±0.2°, 17.93±0.2°, 20.04±0.2°, 22.07±0.2°, 23.18±0.2°, 23.60±0.2° and 27.06±0.2°; preferably, the X-ray powder diffraction (XRPD) pattern of the crystalline form A of the disodium salt hydrate exhibits peaks that are substantially identical to the peaks at the diffraction angles (2θ) shown in Fig.

1.

6. A crystalline basic salt of a compound of formula (I) according to claim 5, characterized in that the unit cell of crystalline form A of the disodium salt hydrate belongs to the monoclinic crystal system and has the following unit cell parameters: a=20.00(5) Å, b=5.798(16) Å, c=20.44(11) Å, α=90°, β=94.8(2)°, γ=90°; the unit cell has a volume V of 2362(15) Å3 and belongs to space group C2 (No. 5).

7. A crystalline base salt of a compound of formula (I) according to claim 4, wherein the crystalline base salt of a compound of formula (I) is crystalline form B of the anhydrous disodium salt, in the X-ray powder diffraction pattern of which five or more peaks are present at diffraction angles (2θ) of 6.60±0.2°, 7.46±0.2°, 12.43±0.2°, 13.32±0.2°, 13.63±0.2°, 15.54±0.2°, 17.32±0.2°, 18.68±0.2° and 21.73±0.2°; preferably, the X-ray powder diffraction (XRPD) pattern of the crystalline form B of the anhydrous disodium salt exhibits peaks substantially identical to the peaks at the diffraction angles (2θ) shown in Fig.

2.

8. A method for producing a crystalline basic salt of a compound of formula (I) according to any one of claims 1 to 7, comprising the following steps: 1) dissolving or dispersing a compound of formula (I) in free form in water or a suitable organic solvent and adding an alkaline solution to the above system to undergo a salt formation reaction; or adding a compound of formula (I) in free form to an alkaline solution to undergo a salt formation reaction; 2) collecting the solid product precipitated during the above salt formation reaction, or creating a certain degree of supersaturation in the salt formation system to obtain a crystalline basic salt of the compound of formula (I); wherein the basic salt is selected from the group consisting of a lithium salt, a sodium salt, a potassium salt, a magnesium salt, a calcium salt and an ammonium salt; the alkaline solution is selected from the group consisting of solutions of lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide and ammonia in water or in an organic solvent.

9. The method of production according to claim 8, wherein the methods for creating a degree of supersaturation in the salt formation system in step 2) include one or more of the following steps: adding a seed crystal, evaporating the solvent, adding an antisolvent, and cooling.

10. The method of production according to claim 8, wherein the organic solvent is selected from the group consisting of alcohols, chloroalkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, benzenes, amides and sulfoxides, as well as mixtures and aqueous solutions thereof; Preferably, the organic solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, dichloromethane, heptane, acetonitrile, acetone, methyl ethyl ketone, toluene, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether and 2-methoxyethyl ether, as well as mixtures and aqueous solutions thereof.

11. A method for producing a crystalline base salt of a compound of formula (I) according to any one of claims 1 to 7, comprising the following step: converting one crystalline form of a base salt of a compound of formula (I) into another crystalline form of this salt using a method of transforming a crystalline form, wherein the method of transforming a crystalline form comprises heating or transforming a crystalline form suspended in a solvent selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, dichloromethane, heptane, acetonitrile, acetone, methyl ethyl ketone, toluene, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether and 2-methoxyethyl ether, as well as mixtures and aqueous solutions thereof.

12. A crystalline form of the compound of formula (I) in free form:- ; preferably, the crystalline form of the compound of formula (I) in free form is crystalline form C, crystalline form D, crystalline form E or crystalline form F.

13. A free crystalline form of the compound of formula (I) according to claim 12, wherein the free crystalline form of the compound of formula (I) is a crystalline form C, in the X-ray powder diffraction pattern of which five or more peaks are present at diffraction angles (2θ) of 7.80±0.2°, 11.97±0.2°, 12.42±0.2°, 15.98±0.2°, 17.37±0.2°, 18.82±0.2°, 22.47±0.2°, 23.30±0.2°, 25.01±0.2° and 25.63±0.2°; preferably, the X-ray powder diffraction (XPD) pattern of crystalline form C exhibits peaks that are substantially identical to the peaks at the diffraction angles (2θ) shown in Fig.

3.

14. A free crystalline form of the compound of formula (I) according to claim 12, wherein the free crystalline form of the compound of formula (I) is crystalline form D, in which the X-ray powder diffraction pattern (XRPD) exhibits five or more peaks at diffraction angles (2θ) of 7.97±0.2°, 11.82±0.2°, 12.18±0.2°, 14.87±0.2°, 16.13±0.2°, 17.18±0.2°, 19.21±0.2°, 20.72±0.2° and 25.28±0.2°; preferably, the X-ray powder diffraction (XPD) pattern of crystalline form D exhibits peaks that are substantially identical to the peaks at the diffraction angles (2θ) shown in Fig.

4.

15. A free crystalline form of the compound of formula (I) according to claim 12, wherein the free crystalline form of the compound of formula (I) is crystalline form E, in the X-ray powder diffraction pattern of which five or more peaks are present at diffraction angles (2θ) of 8.16±0.2°, 12.05±0.2°, 12.83±0.2°, 15.19±0.2°, 16.18±0.2°, 16.59±0.2°, 17.62±0.2°, 18.41±0.2°, 22.90±0.2° and 25.65±0.2°; preferably, the X-ray powder diffraction (XPD) pattern of crystalline form E exhibits peaks substantially identical to the peaks at the diffraction angles (2θ) shown in Fig.

5.

16. A free crystalline form of the compound of formula (I) according to claim 12, wherein the free crystalline form of the compound of formula (I) is a crystalline form F, in the X-ray powder diffraction pattern of which five or more peaks are present at diffraction angles (2θ) of 6.92±0.2°, 9.10±0.2°, 12.42±0.2°, 13.46±0.2°, 14.38±0.2°, 15.84±0.2°, 19.04±0.2°, 22.00±0.2° and 26.23±0.2°; preferably, the X-ray powder diffraction (XPD) pattern of crystalline form F exhibits peaks substantially identical to the peaks at the diffraction angles (2θ) shown in Fig.

6.

17. The use of a crystalline form of a compound of formula (I) in free form according to any one of claims 12 to 16, wherein the crystalline form of a compound of formula (I) in free form is used as a starting material for the preparation of a crystalline base salt of a compound of formula (I) according to any one of claims 1 to 7.

18. A pharmaceutical composition comprising a clinically effective amount of a crystalline base salt of a compound of formula (I) according to any one of claims 1 to 7 or a crystalline form of a compound of formula (I) in free form according to any one of claims 12 to 16 and a pharmaceutically acceptable carrier; preferably, the pharmaceutical composition contains 0.01-99.0 wt.% of the crystalline base salt of the compound of formula (I) or the crystalline form of the compound of formula (I) in free form from the total content of the pharmaceutical composition.

19. The use of a crystalline base salt of a compound of formula (I) according to any one of claims 1 to 7 or a crystalline form of a compound of formula (I) in free form according to any one of claims 12 to 16 for the preparation of a medicament for the treatment of a tumor mediated by the PD-1 / PD-L1 signaling pathway, an immune disease and disorder, a contagious disease, an infectious disease or a metabolic disease; Preferably, the tumor is a malignant neoplasm.

20. The use according to claim 19, wherein the infectious disease is a bacterial infectious disease, a viral infectious disease or a fungal infectious disease.

21. The use according to claim 19, wherein the tumor is a lymphoma, sarcoma, melanoma, glioblastoma, synovioma, meningioma, biliary tract tumor, neuroma, seminoma, nephroblastoma, hepatocellular papilloma, papilloma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, lipoma, fibroma, central nervous system tumor, spinal tumor, brainstem glioma, multiple myeloma, ovarian tumor, myelodysplastic syndrome or mesothelioma, anal cancer, testicular cancer, urethral cancer, penile cancer, bladder cancer, ureteral cancer, uterine cancer, ovarian cancer, fallopian tube cancer, cervical cancer, vaginal cancer, vulvar cancer, Merkel cell carcinoma, embryonal carcinoma, chronic or acute leukemia, bronchial carcinoma, esophageal cancer, nasopharyngeal carcinoma, hepatocellular carcinoma, basal cell carcinoma, lung cancer, adenocarcinoma, papillary carcinoma, rectal cancer, colon cancer, gastric cancer, head and neck cancer, bone cancer,skin cancer, small bowel cancer, endocrine cancer, renal pelvis carcinoma, epidermoid carcinoma, transitional cell carcinoma, or choriocarcinoma; The immune disease and disorder is rheumatoid arthritis, renal failure, lupus erythematosus, asthma, psoriasis, ulcerative colitis, pancreatitis, allergy, fibrosis, anemia, fibromyalgia, Alzheimer's disease, congestive heart failure, stroke, aortic valve stenosis, atherosclerosis, osteoporosis, Parkinson's disease, Crohn's disease, ulcerative colitis, allergic contact dermatitis and eczema, systemic sclerosis or multiple sclerosis; the contagious disease or infectious disease is sepsis, liver infection, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus, human papilloma virus, or influenza; and Metabolic disease is diabetes mellitus, diabetic ketoacidosis, hyperglycemic hyperosmolar syndrome, hypoglycemia, gout, malnutrition, vitamin A deficiency, scurvy, vitamin D deficiency, or osteoporosis.

22. The use according to claim 21, wherein the lymphoma is a lymphocytic lymphoma, a primary central nervous system lymphoma, a T-cell lymphoma, a diffuse large B-cell lymphoma, a follicular center cell lymphoma, a Hodgkin's lymphoma, a non-Hodgkin's lymphoma, or a primary mediastinal large B-cell lymphoma; the sarcoma is Kaposi's sarcoma, fibrosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, leiomyosarcoma, rhabdomyosarcoma, soft tissue sarcoma, angiosarcoma, or lymphangiosarcoma; and Chronic or acute leukemia is acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic granulocytic leukemia, or chronic lymphoblastic leukemia.

23. The use according to claim 19, wherein the tumor is small cell lung cancer, squamous cell non-small cell lung cancer, non-squamous cell non-small cell lung cancer, chondroma, colorectal cancer, gastric and intestinal cancer, endometrial cancer, squamous cell carcinoma of the head and neck, carcinoma of the abdominal wall, renal cell carcinoma, or recurrent or existing drug-resistant prostate cancer.

24. The use according to claim 19, wherein the tumor is a tumor of the thymus gland, pleomorphic adenoma, renal tubular adenoma, cystadenoma, pituitary adenoma, prostate cancer, thyroid cancer, parathyroid cancer, adrenal cancer, breast cancer, cystadenocarcinoma, or pancreatic cancer.

25. A crystalline base salt of a compound of formula (I) according to any one of claims 1 to 7 or a crystalline form of a compound of formula (I) in free form according to any one of claims 12 to 16 for use as a medicament for the treatment of a tumor mediated by the PD-1 / PD-L1 signaling pathway, an immune disease and disorder, a contagious disease, an infectious disease or a metabolic disease.