Crystalline forms of heterocyclic shp2 inhibitors

Abstract

The present application belongs to the field of pharmaceutical chemistry, and relates to a crystal form of a heterocyclic SHP2 inhibitor and a preparation method and application thereof, in particular to a crystal form of (R)-6-amino-2-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrimidin-4(3H)-one of formula (I) and a preparation method thereof, and the crystal form can be used for preparing a drug for treating a SHP2-mediated disease.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry, specifically relating to the crystal form of (R)-6-amino-2-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrimidine-4(3H)-one, its preparation method, and its uses. Background Technology

[0002] SHP2 phosphatase is a non-receptor PTP (protein tyrosine phosphatase) encoded by the PTPN11 gene. It comprises two N-terminal SRC (sarcoma gene) homologous domains (SH2), a PTP domain, and a C-terminal tail. X-ray diffraction results indicate that SHP2 interacts with the PTP domain via the N-terminal SH2 domain, blocking ATP entry into the catalytic site; this kinase exists in a self-inhibitory conformation. Some small peptides or proteins that bind to the SH2 domain can activate phosphorylation of this enzyme, promoting cancer development. In cells, SHP2 function is related to downstream receptor tyrosine kinases in the cytoplasm, including RAS-ERK, PI3K-AKT, and JAK-STAT. First, SHP2 binds to RAS and dephosphorylates it, thereby increasing the activity of the effector protein RAF and activating the RAS / ERK / MAPK proliferative signaling pathway. Second, SHP2 participates in the PD-1 / PD-L1 signaling pathway and promotes immune escape. The PD-1 / SHP2 / STAT1 / T-bet signaling axis mediates the immunosuppressive effect of PD-1 on Th1 cells. Therefore, inhibiting PD-1 or SHP2 can restore the immune function of Th1 cells and activate T cells, thereby relieving immunosuppression in the tumor microenvironment.

[0003] SHP2 is associated with the development of a variety of diseases, such as Noonan syndrome, breast cancer, melanoma, gastric cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, anaplastic large cell lymphoma, and glioblastoma.

[0004] Inhibitors targeting the catalytic site of SHP2 generally exhibit poor selectivity and druggability. In recent years, researchers have discovered that inhibiting SHP2 activity through allosteric site modification can improve both activity and selectivity, leading to some progress in drug research. However, the development of superior SHP2 inhibitors remains crucial to obtain drugs with enhanced activity and pharmacokinetic properties for the treatment of SHP2-mediated diseases. Summary of the Invention

[0005] The inventors of this invention have discovered an SHP2 inhibitor, the compound structure of which is shown in Formula (I) below, and its chemical name is (R)-6-amino-2-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrimidin-4(3H)-one (hereinafter referred to as "Compound (I)").

[0006]

[0007] The inventors of this invention have discovered that the compound of formula (I) or its hydrate, solvate or crystals exhibit significant inhibitory activity against SHP2, and are very promising therapeutic agents for SHP2-related diseases.

[0008] Those skilled in the art know that the crystal structure of a pharmaceutically active compound often affects its chemical stability, solubility, and other properties. In the small-scale experiment, the inventors of this invention obtained compound (I) as an oily substance, so further research is needed to find a suitable crystal form for pharmaceutical use.

[0009] The purpose of this invention is to provide a crystalline form of a heterocyclic SHP2 inhibitor with high bioavailability and high stability. Specifically, this invention provides a crystalline form of (R)-6-amino-2-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrimidine-4(3H)-one as shown in formula (I).

[0010]

[0011] The inventors of this invention conducted X-ray powder diffraction, differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA) on the crystal form of the compound of formula (I).

[0012] In some embodiments, the X-ray powder diffraction pattern of crystal form A of compound of formula (I) of the present invention is shown in [reference]. Figure 1 Using Cu-Ka radiation, the X-ray powder diffraction pattern is represented at a 2θ angle, with characteristic peaks at approximately 7.0±0.2, 9.1±0.2, 10.9±0.2, and 17.5±0.2.

[0013] Furthermore, the X-ray powder diffraction pattern of the crystal form A of the compound of formula (I) of the present invention has characteristic peaks at approximately 7.0±0.2, 9.1±0.2, 10.9±0.2, 13.4±0.2, 14.2±0.2, 17.5±0.2, 20.9±0.2, and 22.6±0.2.

[0014] Furthermore, the X-ray powder diffraction pattern of crystal form A of compound (I) of the present invention has characteristic peaks at approximately 7.0±0.2, 9.1±0.2, 10.9±0.2, 13.4±0.2, 13.9±0.2, 14.2±0.2, 15.4±0.2, 17.5±0.2, 18.1±0.2, 20.9±0.2, 21.8±0.2, 22.6±0.2, and 25.6±0.2.

[0015] Furthermore, the X-ray powder diffraction pattern of crystal form A of compound (I) of the present invention has characteristic peaks at approximately 7.0±0.2, 9.1±0.2, 10.9±0.2, 13.4±0.2, 13.9±0.2, 14.2±0.2, 15.4±0.2, 17.5±0.2, 18.1±0.2, 19.7±0.2, 19.9±0.2, 20.9±0.2, 21.8±0.2, 22.6±0.2, 24.7±0.2, 25.6±0.2, 25.9±0.2, 26.9±0.2, 27.4±0.2, 28.7±0.2, 34.2±0.2, and 35.2±0.2.

[0016] Non-limiting, in one specific embodiment, the crystal form A of compound (I) of the present invention has as follows Figure 1 The X-ray powder diffraction pattern shown is shown.

[0017] Non-limiting, in one specific embodiment, the DSC spectrum of crystal form A of compound of formula (I) of the present invention (see [reference]). Figure 2 The results show that the sample has a sharp endothermic peak at 275.9℃.

[0018] Non-limiting, in one specific embodiment, the crystal form A of compound (I) of the present invention has as follows Figure 3 The thermogravimetric analysis (TGA) spectrum shown indicates that it begins to decompose at 285.1℃.

[0019] This invention provides a method for preparing (R)-6-amino-2-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrimidine-4(3H)-one crystal form A as shown in formula (I), comprising preparing (R)-6-amino-2-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl) The process involves placing (R)-6-amino-2-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrimidine-4(3H)-one in an organic solvent and filtering. The form of the raw material (R)-6-amino-2-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrimidine-4(3H)-one is not particularly limited; any crystalline or amorphous form can be used. The organic solvent is methanol, trifluoroethanol, acetone, tetrahydrofuran, dichloromethane, etc.

[0020] In some embodiments, the X-ray powder diffraction pattern of crystal form B of compound of formula (I) of the present invention is shown in [reference]. Figure 4 Using Cu-Ka radiation, the X-ray powder diffraction pattern is represented at a 2θ angle, with characteristic peaks at approximately 12.1 ± 0.2 and 12.9 ± 0.2.

[0021] Furthermore, the X-ray powder diffraction pattern of the crystal form B of the compound of formula (I) of the present invention has characteristic peaks at approximately 12.1±0.2, 12.9±0.2, 14.9±0.2, 17.2±0.2, 17.5±0.2, 20.2±0.2, and 24.3±0.2.

[0022] Furthermore, the X-ray powder diffraction pattern of crystal form B of compound (I) of the present invention has characteristic peaks at approximately 12.1±0.2, 12.9±0.2, 14.9±0.2, 17.2±0.2, 17.5±0.2, 20.2±0.2, 20.7±0.2, 20.9±0.2, 22.1±0.2, 22.6±0.2, 24.3±0.2, 24.7±0.2, and 27.4±0.2.

[0023] Furthermore, the X-ray powder diffraction pattern of crystal form B of compound (I) of the present invention is approximately 7.5±0.2, 9.0±0.2, 10.6±0.2, 10.8±0.2, 12.1±0.2, 12.9±0.2, 13.9±0.2, 14.9±0.2, 16.1±0.2, 17.2±0.2, 17.5±0.2, 18.0±0.2, 19.0±0.2, 19.8±0.2, 20.2±0.2, 20.7±0.2, 20.9±0.2, 21.7±0.2, 22.1±0.2, 22.6±0.2, 23.1±0.2, 23.4±0.2, 24.3±0.2, 24.7± Characteristic peaks are found at 0.2, 24.9±0.2, 25.3±0.2, 25.6±0.2, 25.9±0.2, 26.2±0.2, 26.9±0.2, 27.1±0.2, 27.4±0.2, 27.9±0.2, 28.6±0.2, 29.3±0.2, 29.7±0.2, 30.0±0.2, 30.4±0.2, 31.2±0.2, 32.1±0.2, 33.0±0.2, 33.4±0.2, 34.1±0.2, 34.6±0.2, 35.3±0.2, 35.6±0.2, 36.8±0.2, 37.9±0.2, 38.5±0.2, and 38.9±0.2.

[0024] Non-limiting, in one specific embodiment, the crystal form B of compound (I) of the present invention has the following characteristics: Figure 4 The X-ray powder diffraction pattern shown is shown.

[0025] Non-limiting, in one specific embodiment, the crystal form B of compound (I) of the present invention has the following characteristics: Figure 5 The thermogravimetric analysis (TGA) results show that the sample lost 1.7% of its weight before 50℃, 14.1% of its weight between 50℃ and 120℃, and the decomposition temperature was 239℃.

[0026] The present invention provides a method for preparing (R)-6-amino-2-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrimidin-4(3H)-one crystal form B of formula (I), comprising the steps of placing (R)-6-amino-2-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrimidin-4(3H)-one in an organic solvent and filtering. The form in which the raw material (R)-6-amino-2-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrimidin-4(3H)-one exists is not particularly limited, and any crystalline or amorphous form can be used. The organic solvent is selected from nitromethane and methyl tert-butyl methyl ether.

[0027] The crystal form A and crystal form B prepared according to the method of the present invention contain little or no residual solvent, which meets the limit requirements for residual solvents in pharmaceutical products stipulated in the National Pharmacopoeia and can be used as active pharmaceutical ingredients.

[0028] Another aspect of the present invention provides an amorphous form of compound (I).

[0029] Non-limiting, a typical example of an amorphous compound of formula (I) of the present invention has the following characteristics: Figure 6 The X-ray powder diffraction pattern shown is shown.

[0030] Non-limiting, in one specific embodiment, the DSC spectrum of the amorphous form of the compound of formula (I) of the present invention (see [reference]). Figure 7 The results show that the sample has an exothermic peak for crystallization at 50℃-60℃, an endothermic peak for desolvation at 60℃-90℃, and a melting point of 271℃ after crystallization (accompanied by decomposition).

[0031] Non-limiting, in one specific embodiment, the amorphous form of the compound of formula (I) of the present invention has the following characteristics: Figure 8 The thermogravimetric analysis (TGA) spectrum shown indicates that the sample lost 10.8% of its weight before reaching 100℃, and the decomposition temperature was 278℃.

[0032] The present invention provides a method for preparing the amorphous product of (R)-6-amino-2-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrimidin-4(3H)-one of formula (I), comprising the step of dissolving (R)-6-amino-2-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrimidin-4(3H)-one in an organic solvent; preferably, the organic solvent is selected from a mixture of trifluoroethanol and dichloromethane.

[0033] Another aspect of the present invention provides a crystalline composition wherein (R)-6-amino-2-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrimidin-4(3H)-one crystal form A or B accounts for more than 50% by weight of the crystalline composition, preferably more than 80%, more preferably more than 90%, and most preferably more than 95%.

[0034] Another aspect of the present invention provides a pharmaceutical composition comprising (R)-6-amino-2-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrimidine-4(3H)-one crystal form and a pharmaceutically acceptable carrier, preferably comprising (R)-6-amino-2-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrimidine-4(3H)-one crystal form A or B and a pharmaceutically acceptable carrier.

[0035] Another aspect of the invention provides pharmaceutical compositions in the form of (R)-6-amino-2-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrimidin-4(3H)-one or comprising the above-described compound forms, particularly (R)-6-amino-2-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrimidin-4(3H)-one in crystal form A or B or comprising the above-described compound forms A or B for treating SHP2-mediated diseases, and their use in the preparation of medicaments for treating SHP2-mediated diseases.

[0036] In some preferred embodiments, the present invention provides pharmaceutical compositions of the (R)-6-amino-2-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrimidine-4(3H)-one crystal form or comprising the above-described compound crystal form, particularly (R)-6-amino-2-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrimidine-4(3H)-one crystal form A or B or comprising the above-described compound crystal form A or B for treating SHP2-mediated diseases, and for use in the preparation of medicaments for treating SHP2-mediated diseases, wherein the SHP2-mediated diseases include, but are not limited to, proliferative diseases, metabolic diseases, or hematologic diseases. In some embodiments, the SHP2-mediated disease described in this invention is cancer.

[0037] In some embodiments, the SHP2-mediated diseases described in this invention include, but are not limited to: acoustic neuroma, adenocarcinoma, adrenal carcinoma, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, angiosarcoma), adnexal cancer, benign monoclonal gammopathy, biliary cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., breast adenocarcinoma, papillary breast carcinoma, breast cancer, medullary breast carcinoma, triple-negative breast cancer), brain cancer (e.g., meningioma; glioma, e.g., astrocytoma, oligodendroglioma; medulloblastoma), bronchial cancer, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial cancer, ependymoma, endothelial sarcoma (e.g., Kaposi's sarcoma). Sarcoma, multiple idiopathic hemorrhagic sarcomas, endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma), Ewing sarcoma Cancers including sarcoma, ocular cancer (e.g., intraocular melanoma, retinoblastoma), familial eosinophilia, gallbladder cancer, gastric cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumors (GIST), head and neck cancers (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma (OSCC), pharyngeal cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), hematopoietic system cancers (e.g., leukemia such as acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CML). L-cell and T-cell CLL); lymphomas such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodular marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., "Woldanstrom macroglobulinemia") macroglobulinemia, hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-cell lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-cell lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungiodes, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodular natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); and mixtures of one or more leukemias / lymphomas as described above;And multiple myeloma (MM), heavy chain diseases (e.g., alpha chain disease, gamma chain disease, μ chain disease), angioblastoma, inflammatory myofibroblastoma, immune cell amyloidosis, renal cell carcinoma (e.g., nephroblastoma, also known as Wilms' tumor), hepatocellular carcinoma (e.g., hepatocellular carcinoma (HCC), malignant hepatocellular carcinoma), lung cancer (e.g., bronchial carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma), leiomyosarcoma (LMS), mastocytosis (e.g., generalized mastocytosis), myelodyplastic syndrome (MDS), mesothelioma, myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), idiopathic thrombocythemia (ET), idiopathic extramedullary metaplasia (AMM)). This includes myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), eosinophilic leukocytosis (HES), neuroblastoma, neurofibroma (e.g., type 1 or 2 multiple neurofibroma (NF), Schwannoma), neuroendocrine carcinoma (e.g., gastrointestinal pancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma, ovarian clear cell carcinoma, ovarian serous cystadenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary myxoma (IPMN), islet cell tumor), and penile cancer (e.g., Paget's disease of the penis and scrotum). Diseases including pineal gland tumors, primary neuroectodermal tumors (PNT), prostate cancer (e.g., prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary duct cancer, skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small bowel cancer (e.g., adnexal cancer), soft tissue sarcomas (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland cancer, sweat gland cancer, synovial tumors, testicular cancer (e.g., seminoma, embryonal testicular carcinoma), thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma), urethral cancer, vaginal cancer, and vulvar cancer (e.g., vulvar Paget's disease), medulloblastoma, adenoid cystic carcinoma, melanoma, and glioblastoma.

[0038] In some preferred embodiments, the present invention provides pharmaceutical compositions of (R)-6-amino-2-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrimidine-4(3H)-one crystal form or comprising the above-described compound crystal form, particularly (R)-6-amino-2-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrimidine-4(3H)-one crystal form A or B or pharmaceutical compositions comprising the above-described compound crystal form A or B for the treatment of SHP2-mediated diseases. Methods for treating SHP2-mediated diseases and their use in the preparation of medicaments for treating SHP2-mediated diseases, including but not limited to: non-small cell lung cancer, breast cancer, esophageal cancer, bladder cancer, lung cancer, hematopoietic system cancers, lymphoma, medulloblastoma, medulloblastoma, rectal adenocarcinoma, colon cancer, gastric cancer, pancreatic cancer, liver cancer, adenoid cystic carcinoma, prostate cancer, lung cancer, head and neck squamous cell carcinoma, brain cancer, hepatocellular carcinoma, melanoma, oligodendroglioma, glioblastoma, testicular cancer, ovarian clear cell carcinoma, ovarian serous cystadenocarcinoma, thyroid cancer, multiple myeloma (AML), renal cell carcinoma, mantle cell lymphoma, triple-negative breast cancer, hemoglobinopathies, diabetes, and obesity.

[0039] It is important to note that X-ray powder diffraction patterns are characteristic of specific crystal forms. When determining whether a crystal form is identical to a known crystal form, attention should be paid to the relative positions of the peaks (i.e., 2θ) rather than their relative intensities. This is because the relative intensities of the spectrum (especially at low angles) can vary due to the dominant orientation effect caused by differences in crystal conditions, grain size, or other measurement conditions. The relative intensity of diffraction peaks is not characteristic for determining the crystal form. Furthermore, the 2θ value for the same crystal form may have a slight error, approximately ±0.2°. Therefore, this error should be taken into account when determining each crystal structure. In XRPD patterns, peak positions are usually represented by the 2θ angle or the interplanar spacing d, with a simple conversion relationship: d = λ / 2sinθ, where d represents the interplanar spacing, λ represents the wavelength of the X-rays, and θ is the diffraction angle. It should also be noted that in the identification of mixtures, factors such as decreased content may cause some diffraction lines to be missing. In this case, it is not necessary to rely on all bands observed in a high-purity sample; a single band may be characteristic for a given crystal.

[0040] DSC determines the transition temperature when a crystal absorbs or releases heat due to a change in its crystal structure or melting. For the same crystal form of the same compound, the error in thermal transition temperature and melting point is typically within about 5 °C in consecutive analyses. When we say that a compound has a given DSC peak or melting point, we mean that DSC peak or melting point ±5 °C. It should be noted that for mixtures, the DSC peak or melting point may vary over a wider range. Furthermore, since decomposition occurs during the melting process, the melting temperature is related to the heating rate.

[0041] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0042] In the compounds of this invention, "hydrogen," "carbon," and "oxygen" include all their isotopes. Isotopes should be understood to include those atoms having the same number of atoms but different mass numbers. For example, isotopes of hydrogen include protium, tritium, and deuterium, and isotopes of carbon include... 13 C and 14 C, oxygen isotopes include 16 O and 18 O etc. Attached Figure Description

[0043] Figure 1 The X-ray diffraction pattern of crystal form A of compound (I) is shown.

[0044] Figure 2 The DSC spectrum of crystal form A of compound (I);

[0045] Figure 3 The TGA spectrum of crystal form A of compound (I);

[0046] Figure 4 The X-ray diffraction pattern of crystal form B of compound (I) is shown.

[0047] Figure 5 The TGA spectrum of crystal form B of compound (I);

[0048] Figure 6 The X-ray diffraction pattern of the amorphous form of compound (I);

[0049] Figure 7 The DSC spectrum of the amorphous form of compound (I);

[0050] Figure 8 The TGA spectrum of the amorphous form of compound (I) is shown. Detailed Implementation

[0051] The following representative embodiments are provided to better illustrate the present invention and are not intended to limit the scope of protection of the present invention. Unless otherwise specified, all materials used in the following embodiments are commercially available.

[0052] I. Preparation of Compound (I)

[0053] Example 1: Preparation of (R)-6-amino-2-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrimidin-4(3H)-one

[0054]

[0055] Step 1: Preparation of (R)-N-((R)-1'-(4-amino-5-bromo-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)-2-methylpropane-2-sulfinamide

[0056]

[0057] In a 50L glass reactor, N,N-dimethylformamide (DMF, 9.45 kg) was added and stirred at room temperature. Then, (R)-2-methyl-N-((R)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)propane-2-sulfinamide (1.0 kg, 3.24 mol) and 6-amino-5-bromo-3-methylpyrimidine-2,4(1H,3H)-dione (0.71 kg, 3.23 mol) were added and stirred until homogeneous. 1,8-diazabicycloundec-7-ene (DBU, 2.47 kg, 14.6 mol) was slowly added to the reactor. Benzotriazole-1-tris(trimethylamino)-hexafluorophosphate (BOP reagent, 2.16 kg, 4.89 mol) was divided into four portions, each 0.4–0.6 kg, and added to the reaction solution every 10–15 minutes. After the reaction was complete, ethyl acetate (15.0 kg) was added to a 100 L glass reactor at room temperature, and stirring was started. The reaction solution was then added to the stirred ethyl acetate, followed by purified water (50.0 kg), and stirring was continued for 10 min. The organic phase was separated, concentrated under reduced pressure, and dried to obtain 0.93 kg of the title compound, with a yield of 56.2%.

[0058] Step 2: Preparation of (R)-N-((R)-1'-(4-amino-1-methyl-6-oxo-5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1,6-dihydropyrimidin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)-2-methylpropane-2-sulfinamide

[0059]

[0060] 1,4-Dioxane (19.0 kg) was added to a 50 L glass reactor. Stirring was started, and (R)-N-((R)-1'-(4-amino-5-bromo-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)-2-methylpropane-2-sulfinamide (0.92 kg, 1.8 mol), sodium 2-(trifluoromethyl)piperidin-3-thiolate (0.51 kg, 2.52 mol), and acetic acid (0.11 kg, 1.8 mol) were added. The temperature was raised and maintained at 60–70 °C. The reaction solution was filtered and concentrated under reduced pressure to obtain 1.07 kg of the crude title compound, with a yield of 97.5%.

[0061] Step 3: Preparation of crude (R)-6-amino-2-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrimidin-4(3H)-one

[0062]

[0063] Weigh 30.0 kg of dichloromethane into a 50 L glass reactor, start stirring, and add (R)-N-((R)-1'-(4-amino-1-methyl-6-oxo-5-((2-(trifluoromethyl)pyridin-3-yl)thio)-1,6-dihydropyrimidin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)-2-methylpropane-2-sulfinamide (1.07 kg). Cool down, maintaining the reaction solution temperature at 15–25 °C, and add 2.63 L of hydrogen chloride-dioxane solution dropwise. Stir for 2–3 hours. Centrifuge.

[0064] Then, at 20–30°C, slowly add NaOH aqueous solution (0.3 kg sodium hydroxide, 0.6 kg purified water) to adjust the pH of the system to 8–9, and continue stirring for 2–4 hours. Centrifuge the material, wash with purified water, and transfer the collected free alkali solid to a 50 L glass reactor. Add 3.37 kg of purified water / anhydrous ethanol (20:1) solution and slurry. Centrifuge the material, and wash the solid sequentially with purified water and anhydrous ethanol. Dry to obtain 0.51 kg of crude title compound, yield 57.5%.

[0065] Step 4: Preparation of the refined product (R)-6-amino-2-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrimidin-4(3H)-one

[0066]

[0067] Dimethyl sulfoxide (3.37 kg) was added to a 50 L glass reactor, and stirring was started. Then, the crude product obtained in the above reaction (0.51 kg) was added, and the temperature was raised to 75–85 °C with stirring until dissolved. The mixture was kept at this temperature for 0.5–1.0 hours, and anhydrous ethanol (1.58 kg) was added dropwise to precipitate crystals. The heating was then turned off, and the mixture was allowed to cool naturally to about 60 °C. Anhydrous ethanol (2.04 kg) was then added dropwise, and the reaction temperature was controlled at 40–60 °C. After the addition was complete, the mixture was allowed to cool naturally to room temperature (20–30 °C), and stirring was continued for 1–2 hours to precipitate crystals. The mixture was filtered, and the solid was washed with anhydrous ethanol (0.76 kg) and dried to obtain 0.37 kg of solid, with a yield of 72.5%. 1 H NMR (400MHz, DMSO-d6) δ8.40 (d, J=4.0Hz, 1H), 7.52-7.50 (m, 1H), 7.43 (d, J= 8.5Hz,1H),7.33(d,J=7.5Hz,1H),7.14(t,J=7.5Hz,1H),6.87(t,J=7.5Hz,1 H),6.77(d,J=8.0Hz,1H),4.12(s,1H),3.63-3.53(m,2H),3.31-3.24(m,5H) ,2.09-2.03(m,1H),1.92-1.89(m,2H),1.86-1.82(m,2H),1.77-1.74(m,1H). ESI-MS m / z: 505.2 [M+H] + .

[0068] Example 2: Preparation of crystal form A of compound (I)

[0069] Method 1: Volatile Crystallization Experiment

[0070] 20 mg of compound (I) was weighed and added to 7.0 mL of methanol, 1.0 mL of trifluoroethanol, 9.0 mL of acetone, 4.0 mL of tetrahydrofuran, and 2.3 mL of dichloromethane. After dissolving, the solution was filtered and the filtrate was left exposed to evaporate to dryness at the appropriate temperature. The solid was then subjected to XRPD characterization. The characterization results showed that the crystal form in this experiment was crystal form A.

[0071] Method 2: Crystallization Experiment with Single Solvent Slurry

[0072] 30 mg of compound (I) was weighed and added to each of the following: 2.0 mL isopropanol, 2.0 mL water, 2.0 mL ethyl acetate, 1.5 mL tetrahydrofuran, 1.5 mL chloroform, and 2.0 mL n-heptane. After crystallizing the slurry at room temperature for 3 days, the mixture was centrifuged and vacuum dried overnight at room temperature. The solid was then subjected to XRPD characterization. The characterization results showed that the crystal form in this experiment was crystal form A.

[0073] Method 3: Gas-solid diffusion crystallization experiment

[0074] 2 mg of compound (I) was weighed out and placed in open containers at room temperature in atmospheres of ethanol, water, acetone, diethyl ether, ethyl acetate, tetrahydrofuran, and acetonitrile. After a period of time, the solids were taken for XRPD characterization. The characterization results showed that the crystal form in this experiment was crystal form A.

[0075] X-ray diffraction pattern of crystal form A of compound (I) (see Figure 1 Using Cu-Ka radiation, the X-ray powder diffraction pattern is represented at a 2θ angle, showing characteristic peaks at approximately 7.0, 9.1, 10.9, 13.4, 13.9, 14.2, 15.4, 17.5, 18.1, 19.7, 19.9, 20.9, 21.8, 22.6, 24.7, 25.6, 25.9, 26.9, 27.4, 28.7, 34.2, and 35.2. Figure 1 The 2θ values ​​and the relative intensities of the peaks are listed in Table 1.

[0076] Table 1: XRPD spectra details of crystal form A of compound (I)

[0077]

[0078] The DSC characterization results of crystal form A of compound (I) are shown in Figure 2 In the test, the results showed that the sample had a sharp endothermic peak at 275.9℃;

[0079] The TGA characterization results of crystal form A of compound (I) are shown in Figure 3 The results showed that it began to decompose at 285.1℃.

[0080] The DVS / isothermal adsorption curves of crystal form A show that the weight change is less than 0.2% in the range of 0%RH to 80%RH, indicating that crystal form A is non-hygroscopic.

[0081] Crystal form A was placed in an open, dark place for 10 days under long-term (25℃-60%RH) and accelerated (40℃-75%RH) conditions, and the crystal form remained unchanged, indicating good stability.

[0082] Example 3: Preparation of crystal form B of compound (I)

[0083] Weigh out 50 mg of compound (I), add 6.0 mL of nitromethane, heat to 70 °C to dissolve completely, add 1.2 mL of methyl tert-butyl methyl ether and keep dissolving, filter, place in an ice-salt bath and stir, a solid precipitates, continue stirring for about 15 minutes, centrifuge, and take the solid for characterization. 1 ¹H NMR showed a solvent peak for nitromethane at 4.42 ppm. XRPD characterization results indicated that the crystal form in this experiment was crystal form B. (See [link to relevant documentation]). Figure 4 .

[0084] X-ray powder diffraction pattern of compound (I) crystal form B, expressed at a 2θ angle using Cu-Ka radiation, is shown at approximately 7.5, 9.0, 10.6, 10.8, 12.1, 12.9, 13.9, 14.9, 16.1, 17.2, 17.5, 18.0, 19.0, 19.8, 20.2, 20.7, 20.9, 21.7, 22.1, 22.6, 23.1, 23. Characteristic peaks are found at positions 4, 24.3, 24.7, 24.9, 25.3, 25.6, 25.9, 26.2, 26.9, 27.1, 27.4, 27.9, 28.6, 29.3, 29.7, 30.0, 30.4, 31.2, 32.1, 33.0, 33.4, 34.1, 34.6, 35.3, 35.6, 36.8, 37.9, 38.5, and 38.9. Figure 4 The 2θ values ​​and the relative intensities of the peaks are listed in Table 2.

[0085] Table 2: XRPD spectra details of crystal form B of compound (I)

[0086]

[0087] The TGA characterization results of crystal form B of compound (I) are shown in Figure 5 The test results showed that the sample lost 1.7% of its weight before 50℃, 14.1% of its weight between 50℃ and 120℃, and the decomposition temperature was 239℃.

[0088] Example 4: Preparation of amorphous materials

[0089] Method 1: Weigh 20 mg of compound (I), add 0.4 mL of trifluoroethanol and 2.0 mL of dichloromethane, dissolve, filter, concentrate the filtrate under reduced pressure in a 60 °C water bath, and take the solid for XRPD characterization. The characterization results show that the crystal form in this experiment is amorphous.

[0090] Method 2: Weigh 17 mg of compound (I) and perform DSC detection. The program was to raise the temperature from 25 °C to 280 °C and then lower it back to 25 °C at a rate of 10 °C / min. Take the solid and perform XRPD characterization. The characterization results showed that the crystal form in this experiment was amorphous.

[0091] The X-ray diffraction pattern of the amorphous form of compound (I) is shown below. Figure 6 As shown.

[0092] The DSC characterization results of the amorphous form of compound (I) are shown in Figure 7The test results showed that the sample had an exothermic peak during crystallization at 50℃-60℃, an endothermic peak during solvent removal at 60℃-90℃, and a melting point of 271℃ after crystallization (accompanied by decomposition).

[0093] The TGA characterization results of the amorphous form of compound (I) are shown in Figure 8 The test results showed that the sample lost 10.8% of its weight before reaching 100℃, and the decomposition temperature was 278℃.

[0094] After the amorphous compound of formula (I) was sealed and placed at room temperature for 1 day, samples were taken for XRPD characterization. The results showed that the amorphous compound of formula (I) transformed into crystal form A.

[0095] Comparative Example 1

[0096] The compound represented by the following formula (compound A) was prepared according to the method disclosed in compound 45 of WO2018 / 172984 (PCT / IB2018 / 051973), and identified by proton NMR and mass spectrometry.

[0097]

[0098] Experiment Example 1: Cell Proliferation Inhibition Experiment

[0099] 1. Experimental Materials

[0100] Test compounds: Compounds of formula (I) of the present invention and compounds prepared in comparative examples, each compound was prepared in 20 mM solution using DMSO. The concentrations of the compounds acting on NCI-H358 cells were 100 μM, 25 μM, 6.25 μM, 1.56 μM, 0.391 μM, 0.098 μM, 0.024 μM, 0.006 μM, 0.0015 μM, and 0.00038 μM, respectively.

[0101] Human non-small cell lung cancer cells NCI-H358 were purchased from the American Type Culture Collection (ATCC).

[0102] Reagents: CCK-8 proliferation inhibition assay kit, purchased from Jiangsu Kaiji Biotechnology Co., Ltd., China. Instruments: CKX41 inverted microscope, purchased from Olympus, Japan; multi-functional plate reader, purchased from Molecular Devices, USA; cell incubator, purchased from Thermo Fisher Scientific, USA.

[0103] 2. Experimental Methods

[0104] 2.1 Cell Culture:

[0105] Cell thawing: Remove the NCI-H358 cell cryovials from the liquid nitrogen container and place them in a 37°C water bath. Gently shake to thaw as quickly as possible. After thawing, remove the cryovials, sterilize with alcohol swabs, unscrew the caps, aspirate the cell suspension into centrifuge tubes, add 1 mL of serum-containing complete culture medium, mix well, and centrifuge at 1000 rpm for 5 min. Discard the supernatant, add complete culture medium, and repeatedly pipette until the cells are completely dispersed and resuspended. Seed the cells at an appropriate concentration in culture dishes. Incubate at 37°C in a CO2 incubator with 5% CO2 and 95% humidified air.

[0106] Cell passage: When cells reach approximately 80-90% confluence, discard the original culture medium (1640 medium + 10% FBS + 1% penicillin-streptomycin + 1mM sodium pyruvate). Add 1 mL of PBS to wash away any remaining medium, then discard the PBS. Add 1 mL of trypsin digestion solution and digest for 1-2 min. Under a microscope, observe that the pseudopodia of the cells have retracted and become rounded, but the cells have not yet detached in sheets. At this point, discard the trypsin and terminate the digestion with 1-2 mL of complete culture medium. Gently pipette and collect the cell suspension. Centrifuge at 1000 rpm for 5 min. Remove the supernatant, resuspend the cells in complete culture medium, and seed them into culture dishes at the desired density. Incubate in a CO2 incubator at 37°C, 5% CO2, and 95% humidified air. Change the culture medium or passage the cells every 2-3 days depending on cell growth.

[0107] 2.2 Experimental Procedure:

[0108] After passage, NCI-H358 cells were resuspended in fresh culture medium (1640 medium + 3% FBS + 1% penicillin and streptomycin + 1mM sodium pyruvate). Cell counts were then performed at a concentration of 1.5 x 10⁻⁶ cells / mL. 4 Seeds were generated at a density of 100 μL / mL into 96-well cell culture plates, with 1.5 x 10⁻⁶ cells / mL added to each well. 3 (cells / well). After 24 hours, 100 μL of fresh medium containing different concentrations (2×) of the drug was added to the original medium. The final concentrations of the compound were 100 μM, 25 μM, 6.25 μM, 1.56 μM, 0.391 μM, 0.098 μM, 0.024 μM, 0.006 μM, 0.0015 μM, and 0.00038 μM, with two replicates for each concentration group. After incubation for 168 hours, the medium in the wells was aspirated and dried as much as possible. 100 μL of medium containing CCK-8 was added (CCK-8:medium = 1:10). After incubation for a certain period, the 96-well plate was removed from the incubator and equilibrated at room temperature for 5 minutes. The absorbance (OD value) at 450 nm was measured using a multi-functional plate reader, and the cell proliferation inhibition rate was calculated. The calculation formula is: Inhibition (%) = 100 - (OD) 实验孔- OD空白孔 ) / (OD 溶剂对照孔- OD 空白孔 *100, based on different drug concentrations and their corresponding inhibition rates, IC50 was performed using GraghPad 5.0 software. 50 Curve plotting, data analysis, and final IC calculation. 50 Values. The experimental results are shown in Table 3.

[0109] Table 3

[0110]

[0111] As can be seen from the above experiments, the compound of formula (I) of the present invention exhibits good inhibitory activity against NCI-H358 cells and is very promising as a therapeutic agent for non-small cell lung cancer.

[0112] Experiment Example 2: Pharmacokinetic Experiment

[0113] 1. Experimental Materials

[0114] Compound: The compound of formula (I) of this invention. The drug solvent is Captisol / 50mM sodium acetate, pH 4.6 (10% / 90%, w / v%). Oral administration is prepared as a 0.5 mg / mL clear solution; intravenous administration is prepared as a 0.1 mg / mL clear solution.

[0115] Animals: Male BALB / c mice, SPF grade, purchased from Shanghai Xipu-Bikai Laboratory Animal Co., Ltd.; 18-20g. An acclimatization period of 2-3 days was given before the experiment.

[0116] Instruments: AB (Alberts & Arpels) API 4500 triple quadrupole liquid chromatography-mass spectrometry system, equipped with an electrospray ionization source (ESI), LC-30AD dual pump; SIL-30AC autosampler; CTO-30AC column oven; DGU-20A3R degasser; AnalystQSA01.01 chromatography workstation; Milli-Q ultrapure water system (Millipore Inc.); Qilinbeier Vortex-5 shaker; HITACHI CF16R XII benchtop high-speed refrigerated centrifuge.

[0117] 2. Experimental Methods

[0118] (1) Three mice per group. The compound of formula (I) of the present invention was administered by gavage (IG) at a dose of 10 mg / kg and by intravenous administration (IV) at a dose of 1 mg / kg.

[0119] (2) Blood samples were collected from the orbital venous plexus at 5 min, 15 min, 30 min, 1 h, 2 h, 6 h, 10 h, and 24 h after gavage and intravenous administration into heparinized EP tubes (0.6 mL). After centrifugation at 8000 rpm / min for 5 min, the supernatant plasma was collected and stored at -20℃ for LC-MS / MS analysis. (3) Based on the blood drug concentration data obtained in the above steps, a blood drug concentration-time curve was plotted, and the pharmacokinetic parameters were calculated using WinNonlin software. The experimental results are shown in Table 4.

[0120] Table 4

[0121]

[0122] The pharmacokinetics of compound A in the comparative example were determined using the method described in Experimental Example 2. The results showed that the bioavailability (F) of compound A was 51.2%, which was significantly lower than that of the compound of formula (I) of the present invention.

[0123] Experimental results show that the compound of the present invention has a good half-life T. 1 / 2 It has good area under the curve (AUC) and bioavailability (F), indicating good oral absorption and exposure, making it suitable for drug development.

[0124] Although the present invention has been described in detail above, those skilled in the art will understand that various modifications and changes can be made to the invention without departing from its spirit and scope. The scope of the invention is not limited to the detailed description above, but should be attributed to the claims.

Claims

1. A (R)-6-amino-2-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrimidine-4(3H)-one crystalline form A, characterized in that... X-ray powder diffraction spectra, expressed in 2θ angles, show characteristic peaks at 7.0±0.2, 9.1±0.2, 10.9±0.2, and 17.5±0.

2.

2. The crystal form A according to claim 1, characterized in that... X-ray powder diffraction spectra, expressed in 2θ angles, show characteristic peaks at 7.0±0.2, 9.1±0.2, 10.9±0.2, 13.4±0.2, 14.2±0.2, 17.5±0.2, 20.9±0.2, and 22.6±0.

2.

3. The crystal form A according to claim 2, characterized in that... X-ray powder diffraction spectra, expressed in 2θ angles, show characteristic peaks at 7.0±0.2, 9.1±0.2, 10.9±0.2, 13.4±0.2, 13.9±0.2, 14.2±0.2, 15.4±0.2, 17.5±0.2, 18.1±0.2, 20.9±0.2, 21.8±0.2, 22.6±0.2, and 25.6±0.

2.

4. A (R)-6-amino-2-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrimidine-4(3H)-one crystalline form B, characterized in that... X-ray powder diffraction spectra, expressed in 2θ angles, show characteristic peaks at 12.1±0.2 and 12.9±0.

2.

5. The crystal form B according to claim 4, characterized in that... X-ray powder diffraction spectra, expressed in 2θ angles, show characteristic peaks at 12.1±0.2, 12.9±0.2, 14.9±0.2, 17.2±0.2, 17.5±0.2, 20.2±0.2, and 24.3±0.

2.

6. The crystal form B according to claim 5, characterized in that... X-ray powder diffraction spectra, expressed in 2θ angles, show characteristic peaks at 12.1±0.2, 12.9±0.2, 14.9±0.2, 17.2±0.2, 17.5±0.2, 20.2±0.2, 20.7±0.2, 20.9±0.2, 22.1±0.2, 22.6±0.2, 24.3±0.2, 24.7±0.2, and 27.4±0.

2.

7. An amorphous (R)-6-amino-2-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrimidine-4(3H)-one having the X-ray powder diffraction spectrum shown in Figure 6.

8. A crystal composition comprising crystal form A as described in any one of claims 1-3 or crystal form B as described in any one of claims 4-6, wherein crystal form A or crystal form B accounts for more than 50% by weight of the crystal composition.

9. The crystal composition of claim 8, wherein crystal form A or crystal form B accounts for more than 80% by weight of the crystal composition.

10. The crystal composition of claim 9, wherein crystal form A or crystal form B accounts for more than 90% by weight of the crystal composition.

11. The crystal composition of claim 10, wherein crystal form A or crystal form B accounts for more than 95% by weight of the crystal composition.

12. A pharmaceutical composition comprising crystal form A as described in any one of claims 1-3, crystal form B as described in any one of claims 4-6, or the amorphous form as described in claim 7, and a pharmaceutically acceptable carrier.

13. Use of crystal form A as described in any one of claims 1-3, crystal form B as described in any one of claims 4-6, the amorphous form as described in claim 7, the crystalline composition as described in any one of claims 8-11, or the pharmaceutical composition as described in claim 12 in the preparation of a medicament for treating and / or preventing SHP2-mediated diseases.

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