EA041596B1 - A CRYSTAL FORM OF A COMPOUND THAT SUPPRESSES PROTEIN KINASE ACTIVITY AND ITS APPLICATION - Google Patents

Description

Field of invention

The present invention relates to new crystalline forms of the new compound {5-[(1R)-1(2,6-dichloro-3-fluorophenyl)ethoxy]-6-aminopyridazin-3-yl}-N-{4-[((3S ,5R)-3,5dimethylpiperazinyl)carbonyl]phenyl}carboxamide hydrochloride and its hydrate or solvate. The present invention also relates to a method for preparing this compound, and crystalline forms, and related intermediates, to pharmaceutical compositions containing the described compound, and their use for inhibiting protein kinase (PK) activity. The present invention also relates to a method of using at least one of the compounds described above or one of the crystal forms described above and pharmaceutical compositions for the treatment of a disease, disorder or condition associated with protein kinase modulation.

Prior Art

Protein kinases are enzymes that catalyze the phosphorylation of proteins, in most cases phosphorylation occurs at serine (ser), threonine (thr) and tyrosine (tyr) residues in proteins. Many aspects of cell life (such as growth, differentiation, cell proliferation, cell cycle, and cell survival) depend on the activity of protein kinases. In addition, aberrant protein kinase activity has been associated with many disorders such as cancer and inflammation.

To date, more than 500 types of protein kinases have been discovered. They can be divided into five categories according to the types of amino acid residues of phosphorylated protein substrates: (1) serine/threonine (Ser/Thr) protein kinase: phosphorylates the hydroxyl group of the protein; (2) tyrosine (Tyr) protein kinase: the hydroxyl of the phenolic group of the protein serves as the phosphate receptor; (3) histidine protein kinase: phosphorylates the main group of the histidine, arginine or lysine residue of the protein; (4) tryptophan protein kinase: the phosphate receptor is protein tryptophan residues; (5) aspartyl/glutamyl protein kinase: the acyl group of the protein serves as the phosphate receptor.

Tyrosine protein kinase (PTK) (currently over 100 family members discovered) plays an important role in the regulation of cell differentiation, growth, and activation. PTKs can be divided into two categories, receptor-type and non-receptor-type kinases, according to their structure, the former being known as transmembrane PTKs, the latter known as intracellular PTKs.

The emergence and development of tumors in humans depends on the activation of a number of oncogenes and the inactivation of oncosuppressor genes. In the study of epithelial tumors, the transmembrane protein of receptor tyrosine kinases (RTK) has been found to play a fundamental role in the regulation of cell growth, differentiation, and survival and plays a vital role in the onset and development of tumors.

Among the RTKs, the MET proto-oncogene subfamily contains 2 members, MET and RON (a receptor of Nantes origin).

The C-Met proto-oncogene encodes the Met receptor tyrosine kinase. The Met receptor, a 190 kDa glycosylated dimeric complex, consists of a 50 kDa α-chain that is disulfide-linked to a 145-kDa β-chain. It has been established that the α-chain is extracellular, while the β-chain includes transmembrane and cytoplasmic domains. Met is involved in oncogenesis and metastasis, and Met is altered by the expression of its ligand, hepatocyte growth factor (HGF), causing oncogenesis and metastasis (Jefferson M. et al., Oncogene, 1996, 13, 853-856; Michieli P. et al. ., Oncogene, 1999, 18, 5221-5231). C-Met is overexpressed in a significant number of human cancers and is amplified during the transition from primary tumors to metastases. Numerous studies have shown the association of C-Met and/or HGF/SF expression with the progression of various types of cancer. In addition, overexpression of C-Met or HGF has been shown to correlate with poor prognosis and disease prognosis for a number of major human cancers (including lung cancer, liver cancer, gastric cancer, and breast cancer). C-Met is also directly involved in cancers that do not respond to successful treatment, such as pancreatic cancer, neuroglioma, and hepatocellular carcinoma.

RON homologues include Stk (stem cell tyrosine kinase) (mouse) and Sea (chicken). Its ligand is macrophage-stimulating protein (MSP), which is a serum protein homologous to HGF. The RON gene is located on human chromosome 3p21 and contains 20 exons and 19 introns.

The mature RON protein is a heterodimer composed of α- and β-subunits with a molecular weight of approximately 185 kDa. The RON gene product can be found in various normal human tissues. RON is expressed in human epithelial cells, granulocytes, mononuclear macrophages, megakaryocytes, osteoclasts, cells of the tonsillar germ layer, small intestine, colon, kidney, lung, and bone marrow. In recent years, studies have shown that in many primary human tumors and tumor cell lines, including the digestive system, urinary system, lung, and mammary gland, RON expression is significantly altered.

- 1 041596 etsya in qualitative and quantitative terms. The oncogenic activity of RON correlates with kinase activity, and kinase activity of RON can be significantly activated through mechanisms of overexpression, mutation, and cleavage leading to malignancy, growth, and cell movement. In addition, RON may function alone or in conjunction with other factors to induce tumor invasion and metastasis (International Journal of Pathology and Clinical Medic, 2005, 25(5): 441-443).

CSF1R (colony stimulating factor receptor 1), also known as C-fms (macrophage colony stimulating factor receptor), is a single chain transmembrane receptor tyrosine kinase and is a member of the RTK family that contains immunoglobulin (Ig) motifs. CSF1R is expressed in most cases in cells of monocytic lines, as well as cells of the female reproductive system and placenta. CSF1R has also been found to be expressed in Langerhans cells, a subgroup of smooth muscle cells, B cells, and microglial cells in the skin. The main biological effects of CSF1R signaling are the differentiation, proliferation, migration, and survival of macrophage and osteoclast progenitors in monocytic lines.

Axl belongs to the receptor tyrosine kinase subfamily, which also includes Tyro 3 and Mer. Axl overexpression has been noted in many human cancers and has been associated with infection and metastasis in lung cancer, prostate cancer, breast cancer, gastric cancer, renal cell carcinoma, and glioblastoma. Recent studies have shown that Axl overexpression via a tyrosine kinase switch induces resistance to imatinib in gastrointestinal stromal tumors. Axl expression is induced by chemotherapeutic drugs, and Axl overexpression leads to resistance in acute myeloid leukemias, suggesting that Axl may be involved in the regulation of various aspects of tumorigenesis (Oncogene, 2009, 28:3442).

EphA2 (ephrine receptor A2) belongs to the largest subgroup of ephrine receptor tyrosine kinases (EPH RTKs), and studies have shown that EphA2 is associated with the regulation cascade of pathological conditions, including tumors (Pasquale EB. Eph receptors and ephrins in cancer: bidirectional signaling and beyond. Nat Rev. Cancer, 2010, 10:165-80). Recent studies have shown that by blocking EphA2 in lung cancer, acquired resistance to epidermal growth factor receptor (EGFR) kinase inhibitors can be overcome (Amato et al., Cancer Res., 2016, 76(2): 305-18).

ROS1 is a member of the insulin receptor family. Recently, a rearrangement of ROS1 has been found in a small number of patients with lung cancer, and casolinib, as an inhibitor of ROS1, is very effective in the treatment of such patients (Bergethon et al., J. Clin. Oncol., 2012, 30(8), 863).

In the case of lung cancer, NTRK1 (neurotrophic receptor tyrosine kinase 1) rearrangements leading to oncogenicity and drug susceptibility have also been found (Vaishnavi et al., Nature Medicine, 2013, 19(11), 1469). The NTRK1 gene encodes a protein, the high-affinity nerve growth factor receptor (TRKA (tropomyosin receptor kinase A)).

Anaplastic lymphoma kinase (ALK) belongs to the RTK superfamily. Due to t2 chromosome heterotopy, oncogenic constitutively active ALK fusion proteins are expressed in anaplastic large cell lymphoma (ALCL) and inflammatory myofibroblastic tumor (IMT). Recently, ALK has been considered as a proto-oncogene in a small number of cases of non-small cell lung cancer and neurocytoma (Choi et al., Cancer Res., 2008, 68:(13); Webb et al., Expert Rev. Anticancer Ther., 2009, 9 (3), 331-356).

It has recently been found that 11% of melanoma cases and selected other human cancers, but not normal tissues, express a new ALK isotype (Wiesner et al., Nature, 2015, 526, 453). The new ALK transcript causes alternative transcription initiation (ATI) of the intron in ALK 19 and is known as ALK ^ati .

ALK is also implicated in diseases of the nervous system. ALK has been shown to regulate the functions of the frontal cortex and hippocampus of the adult brain, and ALK has been identified as a new target for psychiatric symptoms (such as schizophrenia, depression, and drug (cocaine) addiction).

Crizotinib has been reported as an effective inhibitor of the HGF family receptor tyrosine kinase (C-Met) and ALK (WO2004076412, WO2006021881, WO2006021886).

Crizotinib

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In the phase I clinical trial of crizotinib, an objective response rate (ORR) of 64% was achieved and disease control was achieved in 90% of cases (J. Clin. Oncology, 2010, 28: 7S, Suppl; abstr. 3). Unfortunately, a strong response to crizotinib is only temporary. Most patients develop resistance and disease progression after 6-18 months of treatment. In particular, a significant proportion of patients have brain metastases that cannot be treated with crizotinib.

Previous patent publications (WO2009/154769A1, WO2012/048259A2, CN103298806B) describe substituted pyridazinecarboxamide compounds as protein kinase inhibitors, most of which effectively inhibit c-Met and ALK with an IC ₅₀ (concentration causing half the maximum inhibition) below 100 nM. Because there are still unmet needs for treatment choices for kinase-mediated diseases, the inventors further screened polymorphic forms of substituted pyridazinecarboxamide compounds to meet the medical needs of patients.

The essence of the invention

The present invention solves the problem of developing {5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]6-aminoniridazin-3-yl}-N-{4-[((3S,5R)- 3,5-dimethylninerazinyl)carbonyl]phenyl}carboxamide hydrochloride formula I f o

Formula I

The invention also relates to a number of relatively pure crystalline forms of the compound of formula I, its hydrates and/or solvates.

In the present invention, crystalline forms of the compound of formula I, hydrates and/or solvates thereof exist in one or more crystalline forms.

First, according to the invention, a crystalline form of the compound of formula I, its hydrates and/or solvates is provided, and the corresponding X-ray powder diffraction pattern has characteristic peaks at 2θ diffraction angles of 4.9±0.2°, 10.0 ±0.2° and 19.3±0.2°. For convenience, this subject matter is referred to as crystalline Form A.

Secondly, the present invention further provides preferred embodiments of the aforementioned crystalline Form A.

Preferably, the X-ray powder diffraction pattern of the above-mentioned crystalline form A has characteristic peaks at 2θ diffraction angles of 4.9±0.2°, 10.0±0.2°, 14.7±0.2°, 16, 9±0.2°, 19.3±0.2° and 20.3±0.2°.

Preferably, the X-ray powder diffraction pattern of crystalline Form A has characteristic peaks at 2θ diffraction angles of 4.9±0.2°, 10.0±0.2°, 14.7±0.2°, 16.9± 0.2°, 19.3±0.2°, 20.3±0.2°, 25.5±0.2° and 30.7±0.2°.

Preferably, the above-mentioned crystalline form A has an X-ray powder diffraction pattern approximately as shown in FIG. 1.

The present invention summarizes the X-ray powder diffraction pattern data for crystalline Form A as shown in Table 1. 1.

Preferably crystalline Form A is >85% pure.

Preferably crystalline Form A is >95% pure.

Preferably, crystalline Form A is >99% pure.

Preferably, crystalline Form A is >99.5% pure.

Preferably crystalline Form A is the dihydrate.

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According to the invention, another crystalline form of the compound of formula I, its hydrates and/or solvates is further provided, and the powder X-ray diffraction pattern corresponding to it has characteristic peaks at 2θ diffraction angles of 10.5±0.2°, 17.4±0 ,2° and

21.1±0.2°. For convenience, this subject matter is referred to as crystalline Form B.

The present invention further provides preferred embodiments of the aforementioned crystalline Form B.

Preferably, the X-ray powder diffraction pattern of the above-mentioned crystalline form B has characteristic peaks at 2θ diffraction angles of 10.5±0.2°, 17.4±0.2°, 19.7±0.2°, 21, 1±0.2°, 23.9±0.2° and 25.5±0.2°.

Preferably, the X-ray powder diffraction pattern of the above-mentioned crystalline form B has characteristic peaks at 2θ diffraction angles of 10.5±0.2°, 17.4±0.2°, 19.7±0.2°, 21, 1±0.2°, 21.5±0.2°, 23.9±0.2°, 25.2±0.2° and 25.5±0.2°.

Preferably, the above-mentioned crystalline form B has an X-ray powder diffraction pattern approximately as shown in FIG. 2.

The present invention summarizes the X-ray powder diffraction pattern data for crystalline form B as shown in Table 1. 2.

table 2

Preferably crystalline Form B is >85% pure.

Preferably, crystalline form B is >95% pure.

Preferably crystalline Form B is >99% pure.

Preferably crystalline Form B is >99.5% pure.

Preferably crystalline Form B is the trihydrate.

According to the invention, another crystalline form of the compound of formula I, its hydrates and/or solvates is additionally provided, and the X-ray powder diffraction pattern corresponding to it has characteristic peaks at 2θ diffraction angles of 10.2±0.2°, 20.6±0 .2° and 21.8±0.2°. For convenience, this subject matter is referred to as crystalline Form C.

Secondly, the present invention further provides preferred embodiments of the aforementioned crystalline Form C.

Preferably, the X-ray powder diffraction pattern of the above crystalline Form C has characteristic peaks at 2θ diffraction angles of 10.210.2°, 14.7±0.2°, 19.4±0.2°, 20.6±0, 2°, 21.8±0.2° and 24.5±0.2°.

Preferably, the X-ray powder diffraction pattern of the above-mentioned crystalline Form C has characteristic peaks at 2θ diffraction angles of 8.7±0.2°, 10.2±0.2°, 14.7±0.2°, 19, 4±0.2°, 20.6±0.2°, 21.8±0.2°, 24.5±0.2° and 25.9±0.2°.

Preferably, the aforementioned crystalline Form C has an X-ray powder diffraction pattern approximately as shown in FIG. 3.

The present invention summarizes the X-ray powder diffraction pattern data for crystalline Form C as shown in Table 1. 3.

Table 3

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Preferably crystalline Form C is >85% pure.

Preferably crystalline Form C is >95% pure.

Preferably, crystalline Form C is >99% pure.

Preferably crystalline Form C is >99.5% pure.

Preferably, crystalline form C is a compound prepared using a methanol solvent.

According to the invention, another crystalline form of the compound of formula I, its hydrates and/or solvates is further provided, and the powder X-ray diffraction pattern corresponding to it has characteristic peaks at 2θ diffraction angles of 9.2±0.2°, 18.0±0 .2° and 18.5±0.2°. For convenience, this subject matter is referred to as crystalline Form D.

Secondly, the present invention further provides preferred embodiments of the aforementioned crystalline Form D.

Preferably, the X-ray powder diffraction pattern of the above crystalline Form D has characteristic peaks at 2θ diffraction angles of 4.5±0.2°, 9.2±0.2°, 18.0±0.2°, 18, 5±0.2°, 19.5±0.2° and 20.1±0.2°.

Preferably, the X-ray powder diffraction pattern of the above crystalline form D has characteristic peaks at 2θ diffraction angles of 4.5±0.2°, 9.2±0.2°, 18.010.2°, 18.5±0, 2°, 19.5±0.2°, 20.1±0.2°, 22.3±0.2° and 23.1±0.2°.

Preferably, the aforementioned crystalline form D has an X-ray powder diffraction pattern approximately as shown in FIG. 4.

The present invention summarizes the X-ray powder diffraction pattern data for crystalline Form D as shown in Table 1. 4.

Preferably crystalline Form D is >85% pure.

Preferably, crystalline Form D is >95% pure.

Preferably, crystalline Form D is >99% pure.

Preferably, crystalline Form D is >99.5% pure.

Preferably, crystalline form D is a compound prepared using a dimethyl sulfoxide solvent.

According to the invention, another crystalline form of the compound of formula I, its hydrates and/or solvates is further provided, and the powder X-ray diffraction pattern corresponding to it has characteristic peaks at 2θ diffraction angles of 4.8±0.2°, 9.6±0 .2° and 25.8±0.2°. For convenience, this subject matter is referred to as crystalline Form E.

Secondly, the present invention further provides preferred embodiments of the aforementioned crystalline form E.

Preferably, the X-ray powder diffraction pattern of the above-mentioned crystalline form E has characteristic peaks at 2θ diffraction angles of 4.8±0.2°, 9.6±0.2°, 16.3±0.2°, 18, 1±0.2°, 20.8±0.2° and 25.8±0.2°.

Preferably, the X-ray powder diffraction pattern of the above crystalline form E has characteristic peaks at 2θ diffraction angles of 4.8±0.2°, 9.6±0.2°, 16.3±0.2°, 18, 1±0.2°, 19.3±0.2°, 20.8±0.2°, 25.8±0.2° and 26.7±0.2°.

Preferably, the above-mentioned crystalline form E has an X-ray powder diffraction pattern approximately as shown in FIG. 5.

The present invention summarizes the X-ray powder diffraction pattern data for crystalline Form E as shown in Table 1. 5.

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Preferably crystalline Form E is >85% pure.

Preferably crystalline Form E is >95% pure.

Preferably, crystalline Form E is >99% pure.

Preferably crystalline Form E is >99.5% pure.

Preferably crystalline Form E is the dihydrate.

The present invention further provides amorphous forms of the compounds of formula I, hydrates and/or solvates thereof, having an x-ray powder diffraction pattern approximately as shown in FIG. 6.

The invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the aforementioned crystalline form A and/or crystalline form B.

The present invention also provides a preferred embodiment of the pharmaceutical compositions mentioned above.

Preferably, the pharmaceutical composition contains a therapeutically effective amount of crystalline Form A or crystalline Form B as provided herein and a pharmaceutically acceptable excipient, adjuvant or carrier.

Preferably, the pharmaceutical composition contains a therapeutically effective amount of crystalline form A and crystalline form B, proposed in this application, and a pharmaceutically acceptable excipient, adjuvant or carrier.

Preferably, the pharmaceutical composition contains a therapeutically effective amount of crystalline form A or crystalline form B according to the invention in combination with at least one other effective ingredient.

Preferably, the pharmaceutical composition contains a therapeutically effective amount of crystalline Form A and crystalline Form B of the invention in combination with at least one other effective ingredient.

Preferably the pharmaceutical composition is in the form of an oral preparation.

Preferably the pharmaceutical composition is in the form of a tablet or capsule.

Preferably, the pharmaceutical composition contains 20 to 150 mg of crystalline form A and/or crystalline form B and is formulated in a total amount of about 50 to 500 mg with at least one excipient, adjuvant and/or carrier.

Preferably, the excipient, adjuvant and/or carrier in the pharmaceutical composition is microcrystalline cellulose, mannitol, crospovidone, croscarmellose sodium, sodium carboxymethyl starch, povidone, hydroxypropyl cellulose and/or stearic acid.

Preferably a Form A pharmaceutical composition or a Form B crystalline form.

Preferably a pharmaceutical composition of form A and crystalline form B.

Preferably a Form A pharmaceutical composition or a Form B crystalline form.

Preferably a pharmaceutical composition of form A and crystalline form B.

contains from 0.01 to 99 wt.% crystalline contains from 0.01 to 99 wt.% crystalline contains from 0.1 to 70 wt.% crystalline contains from 0.1 to 70 wt.% crystalline

Preferably, the pharmaceutical composition contains from 1 to 70% by weight of crystalline form A or crystalline form B.

Preferably, the pharmaceutical composition contains from 1 to 70% by weight of crystalline form A and crystalline form B.

Preferably, the pharmaceutical composition contains from 1 to 50% by weight of crystalline form A or crystalline form B.

Preferably, the pharmaceutical composition contains from 1 to 50% by weight of crystalline form A and crystalline form B.

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Preferably, the pharmaceutical composition contains from 1 to 30% by weight of crystalline form A or crystalline form B.

Preferably, the pharmaceutical composition contains from 1 to 30% by weight of crystalline form A and crystalline form B.

Preferably, the pharmaceutical composition contains 10 to 30% by weight of crystalline form A or crystalline form B.

Preferably, the pharmaceutical composition contains 10 to 30% by weight of crystalline form A and crystalline form B.

The present invention also provides the use of crystalline Form A and/or crystalline Form B in the preparation of a medicament for the treatment of a disease, disorder or condition in a patient, wherein said disease, disorder or condition is mediated by c-Met, RON, Axl, CSF1R, EphA2, ROS1 or ROS1 based fusion protein, TRKA or TRKA based fusion protein, TRKB, TRKC, ALK, ALK ^ati or ALK based fusion protein.

The invention also provides a preferred embodiment of the above-mentioned use of crystalline form A and/or crystalline form B.

Preferably, the ALK-based fusion protein is EML4(echinoderm microtubule-associated protein type 4)-ALK or NPM(nucleophosmin)-ALK kinase.

Preferably the disease, disorder or condition is a cancer and/or a proliferative disorder.

Preferably the disease, disorder or condition is lung cancer, melanoma, colon cancer, breast cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, gastric cancer, skin cancer, bone cancer, glioma, lymphoma , neuroblastoma, hepatocellular carcinoma, papillary renal cell carcinoma and/or squamous cell carcinoma of the head and neck.

Preferably the disease, disorder or condition is non-small cell lung cancer (NSCLC) resistant to crizotinib therapy.

Preferably the disease, disorder or condition is melanoma.

Preferably the disease, disorder or condition is a neurological disease, mental illness, obesity, diabetes, and/or cardiovascular disease.

Preferably the mental illness is schizophrenia, depression and/or substance dependence or abuse.

Preferably, the substance dependence or abuse is cocaine, tobacco or alcohol dependence or abuse.

The present invention also provides a method for treating a disease, disorder or condition by administering crystalline form A and/or crystalline form B as provided herein to a patient.

The present invention further provides preferred embodiments of the method described above for treating a disease, disorder or condition in a patient using crystalline Form A and/or crystalline Form B.

Preferably the disease, disorder or condition is mediated by c-Met, RON, Axl, CSF1R, EphA2, ROS1 or a ROS1 based fusion protein, TRKA or TRKA based fusion protein, TRKB, TRKC, ALK, ALK ^ati or an ALK based fusion protein.

Preferably, the ALK-based fusion protein is EML4-ALK or NPMALK kinase.

Preferably the disease, disorder or condition is a cancer and/or a proliferative disorder.

Preferably the disease, disorder or condition is lung cancer, melanoma, colon cancer, breast cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, gastric cancer, skin cancer, bone cancer, glioma, lymphoma , neuroblastoma, hepatocellular carcinoma, papillary renal cell carcinoma and/or squamous cell carcinoma of the head and neck.

Preferably the disease, disorder or condition is non-small cell lung cancer (NSCLC) resistant to crizotinib therapy.

Preferably the disease, disorder or condition is melanoma.

Preferably the disease, disorder or condition is a neurological disease, mental illness, obesity, diabetes, and/or cardiovascular disease.

Preferably the mental illness is schizophrenia, depression and/or substance dependence or abuse.

Preferably, the substance dependence or abuse is cocaine, tobacco or alcohol dependence or abuse.

The present invention further provides processes for the preparation of a compound of formula I as described below.

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Method 1.

Method 2.

Method 3.

THF/MTBE

1)TFA/DCM

2)IPA, HCI

In / out

Compound of Formula I

2HCI

2HCI )TFA/DCM

2)IPA, HCI

LlOH/HCI ms

The invention further provides intermediates in the preparation of a compound of formula I, as shown below.

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The invention further provides methods for preparing crystalline form A and crystalline form B of compounds of formula I, hydrates and/or solvates thereof, wherein crystalline form A is obtained as follows:

an amorphous sample of the compound of formula I was placed in centrifuge tubes and stored without access to air in ethanol or acetonitrile for 6-10 days at room temperature, obtaining a crystalline form A; or an amorphous sample of the compound of formula I was added to ethanol, stirred at 4-25°C and filtered to obtain crystalline form A; or an amorphous sample of the compound of formula I was added to ethanol at 4-25°C and dissolved to obtain a clear solution, the solution was filtered to obtain a filtrate; then, n-heptane was added to the filtrate with stirring until a large amount of crystals were observed, then filtered to obtain crystal form A; or an amorphous sample of a compound of formula I was added to methyl tert-butyl ether/ethanol or ngeptane/ethanol at 55-70° C. and dissolved to give a clear solution; the solution was filtered to give a filtrate; then, the filtrate was stirred at -20° C. until a solid was observed, and filtered to obtain crystalline Form A; or an amorphous sample of the compound of formula I was added to sec-butyl alcohol and dissolved, obtaining a clear solution, which was filtered, then kept at 35-50°C to evaporate the solvent, obtaining a crystalline form A; or an amorphous sample of the compound of formula I was added to methanol and dissolved to obtain a clear solution, the solution was filtered to obtain a filtrate, then carboxymethyl cellulose was added to the filtrate and kept at room temperature to evaporate the solvent to obtain crystalline form A;

while the method for obtaining crystalline form B is as follows:

crystalline form A was added to methanol, ethanol or water, dissolved to obtain a clear solution, filtered, then kept at room temperature (20°C) to 40°C to evaporate the solvent, obtaining crystalline form B; or crystalline Form A was added to methanol/water, methanol/acetone, methanol/ethyl acetate, methanol/methyl tert-butyl ether, methanol/tetrahydrofuran, methanol/dichloromethane, ethanol/water, ethanol/butanone, ethanol/isopropyl acetate, ethanol/n -heptane, trifluoroethanol/water, trifluoroethanol/ethyl acetate, trifluoroethanol/tetrahydrofuran, water/methanol, water/ethanol, water/trifluoroethanol, water/isopropanol, water/acetone, water/tetrahydrofuran or water/acetonitrile, dissolved to give a clear solution, then the solution was filtered and kept at a temperature in the range from room temperature (20°C) to 40°C to evaporate the solvent, obtaining a crystalline form B; or crystalline form A was added to lower alcohol, water, nitromethane, butanone, ethyl ether, ethyl acetate, tetrahydrofuran, toluene, or n-heptane to form a suspension; then the suspension was stirred for 4-5 days at a temperature from room temperature to 40°C and centrifuged, obtaining a crystalline form B; or crystalline form A was added to a water-saturated ethyl acetate layer, an ethyl acetate-saturated aqueous layer, ethanol/diethyl ether, toluene/acetonitrile, butanone/ethanol, or toluene/isopropyl ether to form a slurry; then the suspension was stirred at 4-40°C for 4-5 days and centrifuged, obtaining a crystalline form B; or crystalline Form A was added to methanol, acetone/water (3:1, v/v) or acetonitrile/water (3:2, v/v) at room temperature and dissolved to give a clear solution; then, hydroxypropyl cellulose, ethyl cellulose, povidone K30, polyallylamine hydrochloride, carboxymethyl cellulose or polyvinyl alcohol was added to this solution, kept at room temperature to evaporate the solvent, obtaining a crystalline form B; or crystalline form A was added to lower alcohol or water at 60-70°C, dissolved to obtain a clear solution, and stirred at 4°C until crystal formation was observed to obtain crystalline form B; or crystalline form A was added to acetone/trifluoroethanol, acetone/water, dioxane/water, acetonitrile/water or methyl tert-butyl ether/n-propanol at 55-70°C, dissolved to give a clear solution; the solution was filtered to give a filtrate, then the filtrate was stirred at -20° C. until crystal formation was observed, then filtered to give crystalline form B; or crystalline form A was added to nitromethane/methanol, acetonitrile/methanol, butanone/ethanol, ethyl acetate/ethanol, 1,4-dioxane/ethanol or tetrahydrofuran/water at 60-70°C and dissolved to obtain a clear solution, filtered and kept at room temperature to evaporate the solvent, obtaining a crystalline form B; or crystalline form A was added to methanol, ethanol, water, trifluoroethanol, n-propanol or dimethyl sulfoxide at room temperature and dissolved to obtain a clear solution; the solution was filtered and acetone, ethyl acetate, methyl tert-butyl ether, isopropyl ether, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, acetonitrile, n-heptane, dichloromethane or

- 9 041596 chloroform until the formation of a large number of crystals was observed, obtaining a crystalline form B; or crystalline Form A was added to methanol or ethanol at room temperature and dissolved to give a clear solution; thereafter, the solution was filtered to obtain a filtrate; then, dichloromethane or tetrahydrofuran was added to the filtrate with stirring, and kept at room temperature to evaporate the solvent, obtaining a crystalline form B; or an amorphous sample of the compound of formula I was placed in centrifuge tubes, and then the centrifuge tubes were placed in an atmosphere of n-butanol, water, nitromethane, ethyl acetate, methyl tert-butyl ether, tetrahydrofuran, methylene chloride, chloroform, or toluene to effect diffusion, obtaining crystalline form B; or an amorphous sample of a compound of formula I was added to n-propanol, water, butanone, ethyl acetate, tetrahydrofuran, dichloromethane, ethanol, isopropanol, n-butanol, acetone, ethyl ether, isopropyl acetate, 1,4-dioxane, acetonitrile, chloroform, sec-butanol , nitromethane or toluene, stirred at 4-40°C for 30 min, then filtered to give crystalline form B; or an amorphous sample of a compound of formula I was added to isopropyl ether/methanol, ethyl acetate/methanol, 1,4-dioxane/methanol, butanone/ethanol, acetonitrile/ethanol, n-heptane/trifluoroethanol, nitromethane/trifluoroethanol, ether/trifluoroethanol, tetrahydrofuran/ trifluoroethanol, acetone/water, tetrahydrofuran/water, acetonitrile/water, methyl tert-butyl ether/isopropanol, isopropyl acetate/n-propanol, methylcyclohexane/n-butanol, acetone/dimethyl sulfoxide, ethyl acetate/dimethyl sulfoxide, acetonitrile/dimethyl sulfoxide, methyl tert-butyl ether/chloroform or toluene/ethyl acetate to form a slurry, stirred at 4-40° C., then filtered to give crystalline form B; or an amorphous sample of the compound of formula I was placed at room temperature in an atmosphere with relative humidity (RH) 85% for 10 days, obtaining a crystalline form B; or crystalline Form A was added to water or methanol and dissolved to give a clear solution; the solution was filtered to give a filtrate; then the filtrate was evaporated on a rotary evaporator to dry at 40-60°C, obtaining a crystalline form B.

The crystalline forms of the present invention are relatively pure.

The term relatively pure as used herein means that at least 85 wt.%, preferably at least 95 wt.%, more preferably at least 99 wt.%, most preferably at least 99.5 wt.% the compound shown by formula I exists in the crystalline form of the present invention. In particular, in crystalline form A and/or crystalline form B.

The above crystalline forms are presented as the sum of the major peaks only. The main peaks are reproducible and are within the measurement error (±0.2).

As used in the present invention, the X-ray powder diffraction pattern shown in FIG. 1 or the X-ray powder diffraction pattern shown in FIG. 2 refers to an X-ray powder diffraction pattern showing the main peaks present in FIG. 1 or 2, where the main peaks denote peaks with a relative intensity of more than 10, preferably more than 30%, of the intensity of the largest peak (with its relative intensity taken as 100%) in FIG. 1 or 2.

The term used in the present invention was added to methanol/acetone, which is used in the description of the method for obtaining crystalline form A or crystalline form B, means that in this method, methanol was first added, and then acetone was added. Similarly, ethanol/water means that ethanol was added first and then water was added; and trifluoroethanol/ethyl acetate means that trifluoroethanol was added first and then ethyl acetate was added. Similarly, for example, solvent 1/solvent 2 means that solvent 1 was added first, and then solvent 2 was added; and solvent 2/solvent 1 means that solvent 2 was added first, and then solvent 1 was added.

The term "therapeutically effective amount" as used herein refers to the amount of a compound that, when administered to a subject for the treatment of a disease or at least one of the clinical symptoms of the disease or disorder, is sufficient to effect such treatment for that disease, disorder or symptom. The therapeutically effective amount may vary depending on the compound, the disease, disorder and/or symptoms of the disease or disorder, the severity of the disease, disorder and/or symptoms of the disease or disorder, the age of the subject being treated and/or the weight of the subject being treated. In any given case, the appropriate amount may be apparent to those skilled in the art, or may be determined through routine experimentation. In the case of combination therapy, the term "therapeutically effective amount" refers to the total number of subjects in combination used to effectively treat the disease, disorder or condition.

All formulations of the pharmaceutical composition of the present invention may be prepared by conventional methods in the pharmaceutical art. For example, the active ingredient can be mixed with one or more excipients, then to prepare the desired composition.

The term pharmaceutically acceptable carriers refers to conventional pharmaceutical carriers suitable for the desired pharmaceutical composition, such as a diluent, an excipient such as water, various organic solvents, etc.; an excipient such as starch, sucrose, etc.; a binder such as cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone (PVP); a moisturizing agent such as glycerin; a disintegrant such as agar, calcium carbonate and sodium bicarbonate; an absorption enhancer such as a quaternary ammonium compound; a surfactant such as hexadecanol; absorbent filler such as kaolin and soap clay; a lubricant such as talc, calcium stearate, magnesium stearate, polyethylene glycol, etc. In addition, the pharmaceutical composition further contains other pharmaceutically acceptable excipients such as a disintegrating agent, stabilizer, thickener, complexing agent, buffering agent, penetration enhancer, polymer, flavors, sweetener, and color. Preferably, the excipient is suitable for the desired composition and mode of administration.

The term disease or disorder or condition refers to any disease, discomfort, disease, symptom or indication.

Description of graphic materials

Fig. 1 is an X-ray powder diffraction pattern for crystalline form A of the compound shown by formula I.

Fig. 2 is an X-ray powder diffraction pattern for crystalline form B of the compound shown by formula I.

Fig. 3 is an X-ray powder diffraction pattern for crystalline form C of the compound shown by formula I.

Fig. 4 is an X-ray powder diffraction pattern for crystalline form D of the compound shown by formula I.

Fig. 5 is an X-ray powder diffraction pattern for crystalline form E of the compound shown by formula I.

Fig. 6 is an X-ray powder diffraction pattern for an amorphous sample of the compound shown by formula I.

Fig. 7 is a dynamic water vapor adsorption pattern for crystalline form A of the compound shown by formula I.

Fig. 8 is a dynamic water vapor adsorption pattern for crystalline form B of the compound shown by formula I.

Fig. 9 is a dynamic water vapor adsorption pattern for an amorphous sample of the compound shown by Formula I.

Fig. 10 shows the results of thermogravimetric analysis for crystalline form A of the compound shown by formula I.

Fig. 11 shows the results of thermogravimetric analysis for crystalline form B of the compound shown by formula I.

Fig. 12 shows the results of thermogravimetric analysis for the crystalline form of an amorphous sample of the compound shown by formula I.

In table. 6 summarizes the equipment and methods for detecting the powder X-ray diffraction patterns shown in FIG. 1-6.

In table. 7 summarizes data regarding equipment and methods for detecting the dynamic water vapor adsorption patterns shown in FIG. 7-9.

In table. 8 summarizes data regarding equipment and methods for detecting the results of thermogravimetric analysis of the scanned patterns shown in FIG. 10-12.

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Table 6

Description of the device X-Ray Powder Diffractometer (XRPD) & Hot stage XRD Equipment Bruker D8 Advance Diffractometer Technical specifications Regulatory wavelength of Κα radiation (40 kV, 40 mA) for copper anode: 1.54 nm, Θ-2Θ goniometer, Mo monochromator, Lynxeye detector Calibration substance A1 ₂ 0z Data acquisition software Diffrac plus XRD Commander Analytical Processing Software MDI Jade 6 Method parameters Description of non-reflective sample plate 24.6mm (diameter) x1.0mm (thickness) Sample plate for high temperature operation with temperature change copper plate Detection angle 3-40°2θ/3-30°2θ (Hot stage XRD) stride length 0.02°20 Speed 0.2 cx step' ¹ Detected sample mass >2 mg

Table 7

Description of the device Dynamic Vapor Sorption (DVS) device Q5000 for TGA (thermogravimetric analysis) from TA Instruments Control software Thermal Advantage Analytical Processing Software Universal Analysis Sample plate Platinum crucible Detected sample mass 1-10 mg Shielding gas Nitrogen Gas flow rate 10 ml/min Detection method Equilibrate at 20°C; humidity 0%; isothermal process for 180 min; termination of the next isothermal process if the change in mass (%) is <0.0100 within 15.00 minutes; step change in humidity: 10% for every 120 minutes until reaching 80.00%; termination of the next isothermal process if the change in mass (%) is <0.0100 within 15.00 minutes; step change in humidity: 10% for every 120 minutes until reaching 0.00% Evaluation standard Non-hygroscopic substance Not more than 0.2%. Medium hygroscopic substance More than 0.2%, but not more than 2.0%.

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hygroscopic substance More than 2%, but not more than 15%. Highly hygroscopic substance More than 15%.

Table 8

Description of the device Scanner for thermogravimetric analysis (Differential Scanning Calorimeter (DSC)) device DSC Q200 from TA Instruments Control software Thermal Advantage Analytical Processing Software Universal Analysis Sample plate Aluminum crucible (sealed and pierceable) Detected sample mass 0.5-5 mg Shielding gas Nitrogen Gas flow rate 40 ml/min Conventional Detection Methods Equilibrate at 20°C; ramping rate (ramp) 10°C/min until 250/300°C is reached.

Examples

The present invention is further illustrated, but not limited, by the following examples, which illustrate the invention. In the examples provided in the present invention, the methods or methods, unless specifically stated otherwise, are conventional methods or methods in the art.

Abbreviations.

Vos: butoxycarbonyl; DCC: dicyclohexylcarbodiimide; DCM: dichloromethane; DIPEA: diisopropylethylamine; DMAP: 4-dimethylaminopyridine; DMF: N,N-dimethylformamide; EDCI 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; HATU: 2-(7-Azabenzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate; BUT WT: 1-hydroxybenzotriazole; IPA: isopropyl alcohol; Meon: methanol; MTBE: methyl tert-butyl ether; NMM: N-methylmorpholine; n.: mol/l; TFA: trifluoroacetate; THF: tetrahydrofuran.

Example 1 Synthesis of compounds of formula I.

Synthesis of compound M1.

8.57 g (0.024 mol; 1.00 eq.) of compound SM1 was dissolved in 85.7 ml of anhydrous methanol and 5% palladium on charcoal (0.86 g) was added under nitrogen atmosphere. The mixture was charged with hydrogen three times and reacted under a hydrogen atmosphere for 3 hours. When the reaction between the starting materials was complete, the filtrate was collected by filtration, then concentrated to a solid and dried under vacuum to give a white solid, which is compound M1, with 100% yield and 97.32% purity.

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LC-MS (liquid chromatography combined with mass spectrometry) [M+H+]: 334.

Synthesis of compound M2.

9.60 g (0.017 mol; 1.00 eq.) of SM2 compound was dissolved in 53 ml of THF, the reaction mixture was cooled to -5 to 5°C. Added dropwise 1 N. an aqueous solution of KOH (1.40 g KOH and 25 ml water), the mixture was incubated at 1-10°C and stirred for 4 h. dilute hydrochloric acid solution to adjust the pH to about 5. The mixture was extracted twice with ethyl acetate (50 ml x 2). The organic layers were combined with saturated aqueous brine, dried over anhydrous sodium sulfate for 1 h, then filtered and concentrated under vacuum to give a viscous oil, 23 ml of dichloromethane was added to dissolve the above viscous oil, and then concentrated under vacuum to again give a thick oil. 69 ml of dichloromethane was added to redissolve this thick oil and concentrated in vacuo to give 9.10 g of intermediate M2 as a yellow solid in 99.7% yield.

LC-MS [M+H+]: 546.

Synthesis of compound M2.

9.60 g (0.017 mol; 1.00 eq.) of SM2 compound was dissolved in 53 ml of THF and the reaction mixture was cooled to 0-10°C. Added dropwise 1 N. aqueous solution of LiOH (1.05 g LiOH + 25 ml water). After adding over 30 minutes, the temperature was gradually raised to room temperature and the reaction mixture was stirred overnight. The reaction was complete and the reaction mixture was concentrated in vacuo. The resulting residue was dissolved in 100 ml of water, 50 ml of methyl tert-butyl ether was added, stirred and the phases were separated. To the aqueous phase was added dropwise 1N. dilute hydrochloric acid solution to adjust the pH to about 5. The mixture was extracted twice with ethyl acetate (50 ml x 2). The organic layers were combined and washed with saturated aqueous brine, dried over anhydrous sodium sulfate for 1 hour. The mixture was filtered and evaporated in vacuo to give 8.58 g of intermediate M2 as a yellow solid. The yield was 94%.

LC-MS [M+H+]: 546.

Synthesis of compound M3.

8.23 g (0.015 mol; 1.15 eq.) of compound M2 was dissolved in 66 ml of dichloromethane and cooled to 1020°C. 4.30 g (0.013 mol; 1.00 eq.) compound M1, 3.00 g (0.022 mol; 1.69 eq.) hydroxybenzotriazole (HOBT), 4.58 g (0.024 mol; 1.85 eq) 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) and 6.90 g (0.068 mol; 5.23 eq) N-methylmorpholine (NMM). The mixture was incubated and stirred at 20–30°C for 16 h; dilute hydrochloric acid solution, stirred for 5 min, after settling, the liquid was separated: the organic layer was washed with 16 ml of 1N. dilute hydrochloric acid solution, 5 ml of 1 N. an aqueous solution of KOH and 30 ml of a saturated aqueous saline solution, respectively, and carried out the separation of the settled liquid. The organic phase was dried using anhydrous sodium sulfate, then filtered and concentrated in vacuo. The resulting residue was washed three times with methyl tert-butyl ether (20 ml + 20 ml + 6 ml) and filtered to collect the solid, the solid was dried to give 7.95 g of compound M3 as a yellowish solid in a yield of 71.6 %.

LC-MS [M+H+]: 861.

Synthesis of compound M3.

7.96 g (0.015 mol; 1.15 eq.) of compound M2 was dissolved in 40 ml of DMF, to which was added 5.23 g (0.014 mol; 1.08 eq.) of HATU, 4.17 g (0.013 mol; 1 00 eq.) of compound M1 and 2.17 ml of diisopropylethylamine. The reaction mixture was stirred overnight at room temperature. 50 ml of a saturated sodium carbonate aqueous solution was added to the reaction system, followed by stirring and filtering. The resulting solid is whipped with 60 ml of water and then filtered. The solid was dissolved in 30 ml dichloromethane, washed twice with water, the organic phase was dried, filtered, concentrated in vacuo and dried to give 10.03 g of compound M3 as a brown solid in 93.2% yield.

LC-MS [M+H+]: 861.

Synthesis of compound M3.

9.77 g (0.018 mol; 1.20 eq.) of compound M2 was dissolved in 75 ml of dichloromethane, to which was added 6.21 g (0.030 mol; 2.00 eq.) of dicyclohexylcarbodiimide, 0.96 g (0.0079 mol ; 0.53 eq.) DMAP and 5.00 g (0.015 mol; 1.00 eq.) compound M1. The reaction mixture was stirred overnight at room temperature. Water (20 ml) was added to the reaction system, the mixture was stirred, and after settling, the liquid was separated: 20 ml of 1 N hydrochloric acid was added to the organic phase. dilute hydrochloric acid solution, stirred for 5 min, after settling, the liquid was separated. The organic layer was washed with 20 ml of dilute hydrochloric acid solution, 6 ml of 1N. aqueous solution of KOH and 35 ml of a saturated aqueous saline solution, respectively, and carried out the separation of the settled

- 14 041596 fluids. The organic phase was dried using anhydrous sodium sulfate, then filtered and concentrated in vacuo. The resulting residue was washed three times by adding methyl tert-butyl ether (25+25+8 ml). Filtration was carried out to collect the solid and the solid was dried to give 10.62 g of compound M3 as a brown solid in 82.3% yield.

LC-MS [M+H+]: 861.

Synthesis of a compound of formula I.

7.95 g (0.092 mol) of compound M3 was dissolved in 30 ml of dichloromethane, the reaction solution was cooled to -5 to +5°C, 15 ml of trifluoroacetate was added dropwise to it with stirring at room temperature over 2 hours. After the mixture was cooled to 10-20° C., 60 ml of a saturated aqueous potassium carbonate solution was slowly added to this reaction mixture, then stirred, and separation was carried out under stationary conditions. The organic layer was washed with saturated aqueous brine and dried over anhydrous sodium sulfate, then filtered and concentrated. The resulting residue was dissolved in 41.2 g of isopropanol, after cooling the mixture to 10-20° C., 5 ml of concentrated hydrochloric acid was added to this reaction mixture with stirring at room temperature. Filtration was carried out to collect the solid and the solid was washed with isopropanol, dried in vacuo to give 5.75 g of the compound of formula I.

LC-MS [M+H+]: 561.

1H-NMR (300 MHz, CDCl3): δ=1.25-1.43 (m, 6H), 1.91 (d, 3H), 3.15-3.48 (m, 4H), 3.66-3.89 (m, 0.5H), 4.55-4.78 (m, 0.5H), 5.49 (s, 2H), 6.26 (q, 1H), 7.10 (t, 1H), 7.33-7.44 (m, 4H), 7.78 (d, 2H), 9.93 (s, 1H) .

Example 2 Process for the Preparation of Crystalline Form A

Method for obtaining 1 crystalline form A.

Approximately 5-10 mg of an amorphous compound of formula I was dissolved in sec-butanol, obtaining a clear solution, after which it was filtered; this solution was kept at 40°C to give crystalline form A.

Method for obtaining 2 crystalline form A.

Approximately 10 mg of an amorphous compound of formula I was dissolved in methanol to give a clear solution and then filtered; 1 mg of carboxymethyl cellulose was added to the solution. The mixture was kept at room temperature to give crystalline Form A.

Methods for obtaining 3 and 4 crystalline form A.

Approximately 10 mg of an amorphous compound of formula I at an appropriate temperature was added to solvent 2, then added to solvent 1 to obtain a clear solution, and further filtered, stirred at -20°C to precipitate a solid. The precipitate was collected by filtration, obtaining the crystalline form A.________________________________________________

No. Temperature (°C) Sample weight (mg) Solvent 1 Solvent 1 (volume, ml) Solvent 2 Solvent 2 (volume, ml) Production method 3 crystalline form A 55 10 ethanol 0.8 Methyl- tert-butyl ether 1.0 Production method 4 crystal form A 70 10 ethanol 0.8 n-heptane 0.8

Method for obtaining 5 crystalline form A.

At room temperature, about 10 mg of an amorphous compound of formula I was dissolved in ethanol to give a clear solution, then filtered. To this solution, n-heptane was added dropwise with stirring until a large amount of solid was observed, filtered, and crystal form A was recovered.

Processes 6 and 7 for crystalline form A.

Approximately 10 mg of an amorphous compound of formula I was placed in a 2.0 ml centrifuge tube and kept at room temperature for 6 days in a closed atmosphere of an appropriate solvent. Received the crystalline form A.

No. Sample weight (mg) Solvent 1 Solvent (volume, ml) Production method 6 of crystal form A 10 ethanol 4.0 Method for obtaining 7 crystalline form A 10 Acetonitrile 4.0

Method for obtaining 8 crystalline form A.

Approximately 15 mg of an amorphous compound of formula I was added to 0.2 ml of ethanol at 4° C., the mixture

- 15 041596 was stirred at the appropriate temperature for 30 minutes and filtered to give crystalline form A.

Example 3 Process for the Preparation of Crystalline Form B

First experimental method.

Approximately 5-10 mg of crystalline form A was dissolved in an appropriate solvent to obtain a clear solution and then filtered. The mixture was kept at the appropriate temperature to evaporate the solvent, obtaining the crystalline form B.___________________

No. Temperature (°C) Mass of crystalline form A (mg) Solvent Solvent (volume, ml) Method for obtaining 1 crystalline form B Room temperature 5 methanol 0.4 Method for obtaining 2 crystalline form B Room temperature 5 ethanol 1.0 Production method 3 crystal form B Room temperature 5 Water 0.1 Production method 4 crystal form B 40 10 ethanol 1.5 Method for obtaining 5 crystalline form B 40 10 Water 0.4

Second experimental method.

Approximately 10 mg of crystalline form A was added to solvent 1, after which it was added to solvent 2 to obtain a clear solution, and filtered, then kept at an appropriate temperature to evaporate the solvents to obtain crystalline form B.

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No. Tempe- temperature (°C) Weight of crystal, form A (mg) Solvent 1 Solvent 1 (volume, ml) Solvent 2 Solvent 2 (volume, ml) Production method 6 of crystal form B Rooms pace. 10 methanol 0.4 Water 0.1 Production method 7 of crystal form B Rooms pace. 10 methanol 0.4 Acetone 0.4 Preparation method 8 of crystal form B Rooms pace. 10 methanol 0.6 ethyl acetate 0.4 Production method 9 of crystal form B Rooms pace. 10 methanol 1.0 Methyl tert-butyl ether 0.4 Production method 10 of crystal form B Rooms pace. 10 methanol 0.6 Tetrahydrofuran 0.6 Preparation method 11 of crystal form B Rooms pace. 10 methanol 0.4 dichloromethane 0.4 Process for obtaining crystal form 12 Rooms pace. 10 ethanol 1.2 Water 0.2 Process for obtaining crystal form 13 Rooms pace. 10 ethanol 1.2 butanone 0.4 Process for obtaining crystal form 14 Rooms pace. 10 ethanol 1.2 Isopropyl acetate 0.4 Process for obtaining crystal form 15 Rooms pace. 10 ethanol 1.2 n-heptane 0.4 Process for obtaining crystal form 16 Rooms pace. 10 Trifluoroethanol 0.2 Water 0.2

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Process for obtaining crystal form 17 Rooms pace. 10 T fluoroethanol 0.2 ethyl acetate 0.2 Process for obtaining crystal form 18 Rooms pace. 10 T fluoroethanol 0.2 Tetrahydrofuran 0.4 Process for obtaining crystal form 19 40 10 Water 0.2 methanol 0.6 Process for obtaining crystal form 20 40 10 Water 0.2 ethanol 0.6 Method for obtaining 21 crystal forms 40 10 Water 0.2 Trifluoroethanol 0.4 Method for obtaining 22 crystal forms 40 10 Water 0.2 Isopropanol 0.4 Process for obtaining crystal form 23 40 10 Water 0.2 Acetone 1.0 Process for obtaining crystal form 24 40 10 Water 0.2 Tetrahydrofuran 0.6 Method for obtaining 25 crystal form 40 10 Water 0.2 Acetonitrile 0.4

Third experimental method.

Approximately 15-30 mg of crystalline form A was added to the appropriate solvent to form a suspension, stirred at room temperature for 5 days, filtered to obtain crystalline form B.

No. Temperature (°C) Mass of crystalline form A (mg) Solvent Solvent (volume, ml) Method for obtaining 26 crystal form B Room temperature 15 ethanol 1.0 Method for obtaining 27 crystal form B Room temperature 15 Isopropanol 2.0 Method for obtaining 28 crystal form B Room temperature 15 Propanol 1.0 Method for obtaining 29 crystal form B Room temperature thirty Water 0.4 Production method 30 of crystal form B Room temperature 15 Nitromethane 2.0 Production method of 31 crystal form B Room temperature 15 butanone 2.0 Production method of 32 crystal form B Room temperature 15 Ether 2.0

Fourth experimental method.

Approximately 15-30 mg of crystalline form A was added to an appropriate solvent to form a suspension, stirred for 5 days at 40°C, filtered to obtain crystalline form B.

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No. Temperature (°C) Mass of crystalline form A (mg) Solvent Solvent (volume, ml) Production method 33 crystalline 40 20 ethanol 1.0 Form B Production Method 34 crystalline 40 15 ethyl acetate 2.0 Form B Method for obtaining 35 crystal form B 40 15 Tetrahydrofuran 2.0 Production Method 36 crystalline 40 15 T oluene 2.0 Form B Production Method 37 crystalline 40 15 n-heptane 2.0 Form B

Fifth experimental method.

Approximately 15-40 mg of crystalline form A was first added to solvent 2, then added to solvent 1 to form a suspension and stirred at the appropriate temperature for 4 days, filtered to obtain crystalline form B. ______________

No. Tempe- temperature (°C) Mass of crystal, form A (mg) Solvent 1 Solvent 1 (volume, ml) Solvent 2 Solvent 2 (volume, ml) Method for obtaining 38 crystal form B Rooms pace. 20 Water-saturated layer of ethyl acetate 2.0 No No Production method of 39 crystal form B Production method Rooms pace. 40 Aqueous layer saturated with ethyl acetate 0.5 No No 40 crystalline 4 15 Ether 1.0 ethanol 1.0 Form B Method for obtaining 41 crystalline 40 15 Acetonitrile 1.0 Toluene 1.0 Form B Method for obtaining 42 crystalline 40 15 ethanol 0.5 butanone 1.5 Form B Method for obtaining 43 crystal form B 40 15 Isopropyl ether 1.0 Toluene 1.0

Sixth experimental method.

Approximately 10 mg of crystalline Form A was added to an appropriate solvent, with acetone:water being 3:1 (v/v), acetonitrile:water being 3:2 (v/v) to give a clear solution upon sonication, which was then filtered and to which 1 mg of polymer was added. The mixture was kept at room temperature to evaporate the solvents to give crystalline Form B.

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No. Tempe- temperature (°C) Weight of crystal, form A (mg) Solvent Solvent (volume, ml) Polymer Method for obtaining 44 crystal form B Rooms pace. 10 methanol 0.5 Hydroxypropylcellulose Method for obtaining 45 crystal form B Rooms pace. 10 methanol 0.5 Ethylcellulose Method for obtaining 46 crystal form B Rooms pace. 10 Acetone water 0.4 Hydroxypropylcellulose Method for obtaining 47 crystal form B Rooms pace. 10 Acetone water 0.4 Ethylcellulose Method for obtaining 48 crystal form B Rooms pace. 10 Acetone water 0.4 Povidone KZO Method for obtaining 49 crystal form B Rooms pace. 10 Acetone water 0.4 polyallylamine hydrochloride Method for obtaining 50 crystal form B Rooms pace. 10 Acetone water 0.4 Carboxymethylcellulose Production method of 51 crystal form B Rooms pace. 10 Acetone water 0.4 Polyvinyl alcohol Method for obtaining 52 crystal form B Rooms pace. 10 Acetonitrile water 0.5 Hydroxypropylcellulose Method for obtaining 53 crystal form B Rooms pace. 10 Acetonitrile water 0.5 Ethylcellulose Method for obtaining 54 crystal form B Rooms pace. 10 Acetonitrile water 0.5 Povidone KZO Method for obtaining 55 crystal form B Rooms pace. 10 Acetonitrile water 0.5 Polyallylamine hydrochloride Method for obtaining 56 crystal form B Rooms pace. 10 Acetonitrile water 0.5 Carboxymethylcellulose Method for obtaining 57 crystal form B Rooms pace. 10 Acetonitrile water 0.5 Polyvinyl alcohol

Seventh experimental method.

Approximately 15-50 mg of crystalline form A was dissolved in an appropriate solvent at an appropriate temperature to obtain a clear solution, then filtered, the filtrate was placed at 4° C. with constant stirring until a solid was observed, and filtered to obtain a crystalline form B. Under conditions where formation of a crystalline form in isopropanol at 4° C. with stirring, then kept at room temperature to evaporate the solvent, obtaining a crystalline form B.

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No. Temperature (°C) Mass of crystalline form A (mg) Solvent Solvent (volume, ml) Method for obtaining 58 crystal form B 60 50 methanol 1.0 Method for obtaining 59 crystal form B 70 15 ethanol 1.2 Method for obtaining 60 crystal form B 70 15 n-Propanol 1.4 Production method of 61 crystal form B 70 10 n-Butanol 2.0 Production method of 62 crystal form B 70 50 Water 0.4 Production method of 63 crystal form B 70 10 Isopropanol 2.0

Eighth experimental method.

Approximately 10-15 mg of crystalline form A was added first to solvent 2, then added to solvent 1, obtaining a clear solution at the appropriate temperature, then filtered, then the filtrate was stirred at -20°C until a solid was observed, recovering the crystalline form B. Under conditions where no formation of a crystalline form is observed upon stirring using methods 69-74 for obtaining crystalline form B, the filtrate was kept at room temperature to evaporate the solvents to obtain crystalline form B.

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No. Tempe- temperature (°C) Weight of crystal, form A (mg) Solvent 1 Solvent 1 (volume, ml) Solvent 2 Solvent 2 (volume, ml) Method for obtaining 64 crystal form B 55 15 Trifluoroethanol 0.1 Acetone 0.3 Method for obtaining 65 crystal form B 55 15 Water 0.2 Acetone 1.0 Method for obtaining 66 crystal form B 70 15 Water 0.3 dioxane 2.0 Method for obtaining 67 crystal form B 70 15 Water 0.3 Acetonitrile 3.0 Method for obtaining 68 crystal form B 55 10 n-Propanol 0.8 Methyl- tert-butyl ether 0.7 Method for obtaining 69 crystal form B 60 15 methanol 0.2 Nitromethane 1.0 Method for producing 70 crystal form B 60 15 methanol 0.3 Acetonitrile 0.5 Production method of 71 crystal form B 70 10 ethanol 1.0 butanone 0.5 Method for obtaining 72 crystal form B 70 10 ethanol 1.6 ethyl acetate 0.5 Method for obtaining 73 crystal form B 70 10 ethanol 1.0 1,4-Dioxane 0.5 Method for obtaining 74 crystal form B 70 15 Water 0.3 Tetrahydrofuran 2.0

Ninth experimental method.

Approximately 10-15 mg of crystalline form A was added to solvent 1, obtaining a clear solution by sonication at room temperature, which was then filtered and added dropwise with stirring to solvent 2 until a large amount of solid was observed, and filtered. , obtaining crystal form B. Under conditions where no solid formation was observed using methods 89 and 90 for crystal form B, the mixture was kept at room temperature to evaporate the solvents, obtaining crystal form B.

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No. Sample weight (mg) Solvent 1 Solvent 1 (volume, ml) Solvent 2 Solvent 2 (volume, ml) Method for obtaining 75 crystal form B 15 methanol 0.4 Acetone 5.0 Method for obtaining 76 crystal form B 15 methanol 0.4 ethyl acetate 3.6 Method for preparing 77 crystal form B 15 methanol 0.4 Methyl tert-butyl ether 1.6 Method for obtaining 78 crystal form B 10 ethanol 0.8 Isopropyl ether 3.0 Method for obtaining 79 crystal form B 10 ethanol 0.8 Isopropyl acetate 5.0 Method for obtaining 80 crystal form B 15 Trifluoroethanol 0.2 Acetone 5.0 Production method of 81 crystal form B 15 Water 0.4 Acetone 13.0 Production method of 82 crystal form B 15 Water 0.4 Tetrahydrofuran 12.0 Method for obtaining 83 crystal form B 15 Water 0.4 1,4-Dioxane 13.0 Method for obtaining 84 crystal form B 15 Water 0.4 Acetonitrile 5.0 Method for obtaining 85 crystal form B 10 n-Propanol 0.8 Isopropyl acetate 5.0 Method for preparing 86 crystal form B 10 n-Propanol 0.8 n-heptane 12.0 Method for preparing 87 crystal form B 15 Dimethyl sulfoxide 0.2 dichloromethane 5.0 Method for preparing 88 crystal form B 15 methanol 0.2 Chloroform 5.0 Method for preparing 89 crystal form B 15 methanol 0.4 dichloromethane 5.0 Method for obtaining 90 crystal form B 10 ethanol 0.8 Tetrahydrofuran 5.0

Tenth experimental method.

Approximately 10 mg of an amorphous sample of a compound of formula I was placed in a 2.0 ml centrifuge tube. The centrifuge tube was then placed in an appropriate solvent atmosphere at room temperature for 6 days to obtain crystalline form B.

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No. Sample weight (mg) Solvent Solvent (volume, ml) Method for obtaining 91 crystal form B 10 n-Butanol 4.0 Method for obtaining 91 crystal form B 10 Water 4.0 Method for obtaining 93 crystal form B 10 Nitromethane 4.0 Method for obtaining 94 crystal form B 10 ethyl acetate 4.0 Method for preparing 95 crystal form B 10 Methyl tert-butyl ether 4.0 Method for preparing 96 crystal form B 10 Tetrahydrofuran 4.0 Method for preparing 97 crystal form B 10 dichloromethane 4.0 Method for preparing 98 crystal form B 10 Chloroform 4.0 Method for preparing 99 crystal form B 10 T oluene 4.0

Eleventh experimental method.

Approximately 15-30 mg of an amorphous sample of a compound of formula I was added to an appropriate solvent at an appropriate temperature and stirred for 30 minutes per day, then filtered to give crystalline form B. _____________________________________

No. Temperature (°C) Sample weight (mg) Solvent Solvent (volume, ml) Method for obtaining 100 crystal form B 4 15 n-Propanol 0.2 Method for obtaining 101 crystal form B 4 thirty Water 0.1 Method for producing 102 crystal form B 4 10 butanone 0.4 Method for obtaining 103 crystal form B 4 10 ethyl acetate 0.4 Method for obtaining 104 crystal form B 4 10 Tetrahydrofuran 0.4 Method for obtaining 105 crystal form B 4 10 dichloromethane 0.4 Method for obtaining 106 crystal form B Room temperature 15 ethanol 0.2 Method for obtaining 107 crystal form B Room temperature 15 Isopropanol 0.2 Method for obtaining 108 crystal form B room temperature 15 n-Butanol 0.2 Method for obtaining 109 crystal form B Room temperature thirty Water 0.1 Method for producing 110 crystal form B room temperature 10 Acetone 0.4 Method for obtaining 111 crystal form B room temperature 10 Ether 0.4 Method for obtaining 112 crystal form B room temperature 10 Isopropyl acetate 0.4

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Method for obtaining 113 crystal form B room temperature 10 1,4-Dioxane 0.4 Method for producing 114 crystal form B Room temperature 10 Acetonitrile 0.4 Method for obtaining 115 crystal form B room temperature 10 Chloroform 0.4 Method for obtaining 116 crystal form B 40 10 secButanol 0.4 Method for obtaining 117 crystalline form B 40 10 Nitromethane 0.4 Method for obtaining 118 crystal form B 40 10 ethyl acetate 0.4 Method for obtaining 119 crystalline Form B 40 10 Tetrahydrofuran 0.4 Method for producing 120 crystal form B 40 10 Acetonitrile 0.4 Method for obtaining 121 crystal form B 40 10 T oluene 0.4

Twelfth experimental method.

Approximately 15-30 mg of an amorphous sample of the compound of formula I was added first to solvent 2, and then added to solvent 1, obtaining a suspension, stirred for 30 minutes at an appropriate temperature, filtered, . obtaining the crystalline form B.____________

No. Tempe- temperature (°C) Sample weight (mg) Solvent 1 Solvent 1 (volume, ml) Solvent 2 Solvent 2 (volume, ml) Method for obtaining 122 crystal form B Rooms pace. 15 methanol 0.2 Isopropyl ether 0.6 Method for obtaining 123 crystal form B 40 15 methanol 0.1 ethyl acetate 0.6

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How to get 124 crystalline 4 15 methanol 0.05 1,4-Dioxane 1.0 Form B How to get 125 crystalline 4 10 ethanol 0.1 butanone 1.0 Form B Method for producing 126 crystal form B Rooms pace. 10 ethanol 0.2 Acetonitrile 3.0 How to obtain 127 crystalline 40 10 ethanol 0.2 n-heptane 0.8 Form B Method for obtaining 128 crystal form B Rooms pace. 15 Trifluoroethanol 0.05 Nitromethane 0.6 Method for obtaining 129 crystalline Form B 4 15 Trifluoroethanol 0.1 Ether 0.8 Method for producing 130 crystal form B 40 15 Trifluoroethanol 0.05 Tetrahydrofuran 0.8 Method for obtaining 131 crystal form B Rooms pace. 15 Water 0.05 Acetone 1.0 Method for obtaining 132 crystal form B 4 15 Water 0.05 Tetrahydrofuran 1.0 Method for obtaining 133 crystal form B Rooms pace. 15 Water 0.05 Acetonitrile 1.0 Method for obtaining 134 crystal form B Rooms pace. 10 Isopropanol 0.2 Methyl- tert-butyl ether 0.6 Method for producing 135 crystal form B 4 10 n-Propanol 0.2 Isopropyl acetate 0.6 Method for obtaining 136 crystal form B 40 10 n-Butanol 0.2 Methylcyclohexane 0.8 Method for obtaining 137 crystalline form B 4 15 Dimethyl sulfoxide 0.1 Acetone 1.6 Method for obtaining 138 crystal form B 40 15 Dimethyl sulfoxide 0.05 ethyl acetate 1.0 Method for obtaining 139 crystal form B Rooms pace. 15 Dimethyl sulfoxide 0.05 Acetonitrile 1.0 Method for producing 140 crystal form B Rooms pace. 10 Chloroform 0.4 Methyl- tert-butyl ether 0.4 Method for obtaining 141 crystal form B Rooms pace. 10 ethyl acetate 0.4 Toluene 0.4

Thirteenth experimental method.

Method for obtaining 142 crystal form B.

Approximately 10 mg of an amorphous sample of the compound of formula I was placed in an atmosphere with relative humidity RH 85% for 10 days at room temperature, obtaining a crystalline form B.

Fourteenth experimental method.

The appropriate amount of sample was added to the appropriate solvent to give

- 26 041596 sonicated a clear solution, which was then filtered, then the filtrate was quickly evaporated on a rotary evaporator at an appropriate water bath temperature, obtaining a crystalline form B.

No. Temperature (°C) Sample weight (mg) Solvent Solvent 1 (volume, ml) Method for obtaining 143 crystal form B 60 15 Water 0.4 Method for obtaining 144 crystal form B 40 1000 methanol 40.0

Example 4 Process for the Preparation of Crystalline Form C

Method for obtaining 1 crystalline form C.

100 mg of crystalline form A of the compound of formula I was added to 2.8 ml of isopropyl ether, then added to 2.8 ml of methanol to form a suspension. The mixture was stirred for 4 days at room temperature and filtered under vacuum, obtaining 73 mg of crystalline Form C.

Method for obtaining 2 crystalline form C.

100 mg of crystalline form A of the compound of formula I was added to 1.0 ml of isopropyl ether, then added to 3.0 ml of methanol to form a suspension. The mixture was stirred at room temperature for 4 days and filtered under vacuum, obtaining 63 mg of crystalline Form C.

Methods for obtaining 3 and 4 crystalline form C.

Approximately 15 mg of crystalline form A of the compound of formula I was dissolved in solvent 2, then dissolved in solvent 1, obtaining a clear solution, which was filtered and stirred at -20°C until a solid was observed, recovering crystalline form C.

No. Tempe- temperature (°C) Sample weight (mg) Solvent 1 Solvent 1 (ml) Solvent 2 Solvent 2 (ml) Obtaining method 3 60 15 methanol 1.1 Isopropyl ether 0.5 Production Method 4 60 15 methanol 0.6 Isopropyl acetate 0.5

Method for obtaining 5 crystalline form C.

Approximately 10 mg of crystalline form A of the compound of formula I was placed in a 2.0 ml centrifuge tube and kept in a closed atmosphere of methanol solvent (4 ml) for 6 days at room temperature, obtaining crystalline form C.

Example 5 Process for the Preparation of Crystal Form D

Method for obtaining 1 crystalline form D.

100 mg of crystalline form A of the compound of formula I was added to 2.0 ml of ethyl acetate, then added to 1.0 ml of dimethyl sulfoxide to form a suspension. The suspension was stirred at room temperature for 1 day to give crystalline Form D.

Method for obtaining 2 crystalline form D.

Approximately 5 mg of crystalline form A of the compound of formula I was dissolved in 0.1 ml of dimethyl sulfoxide, obtaining a clear solution, which was then filtered and kept at 40°C to evaporate the solvent, obtaining crystalline form D.

Method for obtaining 3 crystalline form D.

Approximately 20 mg of crystalline form A of the compound of formula I was added to solvent 2, then added to solvent 1 to form a suspension. The mixture was stirred at the appropriate temperature for 4 days, obtaining a crystalline form D.________________

Temperature (°C) Sample weight (mg) Solvent 1 Solvent 1 (ml) Solvent 2 Solvent 2 (ml) 40 20 ethyl acetate 1.0 Dimethyl sulfoxide 0.5

Processes 4 and 5 for crystalline form D.

Approximately 15 mg of crystalline form A of the compound of formula I was added to solvent 1, obtaining a clear solution by sonication at room temperature, which was then filtered, and then solvent 2 was added dropwise to this solution with stirring until a large formation was observed. amount of solid, extracting the crystalline form D.

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No. Sample weight (mg) Solvent 1 Solvent 1 (ml) Solvent 2 Solvent 2 (ml) Method 4 15 Dimethyl sulfoxide 0.2 Acetone 3.0 Method 5 receipt 15 Dimethyl sulfoxide 0.2 ethyl acetate 5.0

Example 6 Process for the Preparation of Crystalline Form E

Approximately 20 mg of crystalline form A of the compound of formula I was placed in an apparatus with relative humidity RH 85% for 26 days at room temperature, obtaining crystalline form E.

Example 7. Method for obtaining an amorphous form.

Method for obtaining 1 amorphous form.

200 mg of crystalline form A of the compound of formula I was added to 0.6 ml of trifluoroethanol, obtaining a clear solution by sonication, which was then filtered, and the filtrate was quickly evaporated on a rotary evaporator in vacuum at 40°C, obtaining an amorphous form.

Method for obtaining 2 amorphous form.

200 mg of crystalline form A of the compound of formula I was added to 7.0 ml of methanol, obtaining a clear solution by sonication, which was then filtered and quickly evaporated on a rotary evaporator in vacuum at 40°C, obtaining an amorphous form.

Methods for obtaining 3-5 amorphous form.

5-10 mg of crystalline form A of the compound of formula I was dissolved in an appropriate solvent, obtaining a clear solution, which was then filtered and kept at an appropriate temperature to evaporate the solvent, obtaining an amorphous form. _________

No. Temperature (°C) Sample weight (mg) Solvent Solvent (ml) Obtaining method 3 Room temperature 5 Trifluoroethanol 0.4 Production Method 4 40 5 n-Propanol 1.0 Production method 5 40 10 Trifluoroethanol 0.4

Methods for obtaining 6-9 amorphous form.

Approximately 10 mg of crystalline form A of the compound of formula I was dissolved in an appropriate solvent to give a clear solution, which was then filtered and kept at the appropriate temperature to evaporate the solvents to give an amorphous form.

No. Temperature (°C) Sample weight (mg) Solvent 1 Solvent 1 (ml) Solvent 2 Solvent 2 (ml) Production method 6 Rooms pace. 10 Trifluoroethanol 0.2 Acetonitrile 0.2 Production method 7 60 10 n- Propanol 1.0 Toluene 0.4 Production method 8 60 10 secButanol 2.0 1,4-Dioxane 0.4 Production method 9 60 10 n-Butanol 2.0 n-heptane 0.6

Method for obtaining 10 amorphous form.

Approximately 15 mg of crystalline form A of the compound of formula I was added to 2.0 ml of n-heptane, the mixture was stirred at room temperature for 5 days, obtaining an amorphous form.

Methods for obtaining 11 and 12 amorphous form.

Approximately 10-15 mg of crystalline form A of the compound of formula I was dissolved in an appropriate solvent, obtaining a clear solution at the appropriate temperature, which was then filtered and stirred at -20° C. until a solid was observed, recovering the amorphous form.

No. Temperature (°C) Sample weight (mg) Solvent 1 Solvent 1 (ml) Solvent 2 Solvent 2 (ml) Production method 11 70 15 Trifluoroethanol 0.1 Acetonitrile 2.0 Method 12 70 10 secButanol 2.0 n-heptane 0.8

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Method for obtaining 13 amorphous form.

Approximately 15 mg of crystalline form A of the compound of formula I was added to 0.2 ml of trifluoroethanol, obtaining a clear solution by sonication at room temperature, which was then filtered, to which 1.0 ml of isopropyl ether was added dropwise with stirring until did not observe the formation of a large amount of solid, extracting the amorphous form.

Methods for obtaining 14-17 amorphous form.

Approximately 10-15 mg of crystalline form A of the compound of formula I was dissolved in an appropriate solvent to give a clear solution which was then filtered and the filtrate was rapidly evaporated on a rotary evaporator at the appropriate temperature to give an amorphous form.

No. Temperature (°C) Sample weight (mg) Solvent 1 Solvent 1 (ml) Solvent 2 Solvent 2 (ml) Production method 14 40 10 ethanol 1.0 NA NA Production method 15 40 15 methanol 0.4 dichloromethane 0.4 Production method 16 40 10 ethanol 1.5 Chloroform 0.5 Production method 17 40 15 Trifluoroethanol 0.2 Acetonitrile 0.4

NA means no data.

Example 8 Crystal Form Stability

Samples of crystalline form A and B were placed at 80°C for 24 hours, 25°C-RH 60% for 10 days, and 40°C-RH 75% for 10 days, respectively, and no change in crystalline form was observed. .

Crystal Form C was almost completely converted to Crystal Form A under vacuum drying conditions at room temperature overnight.

Most of the crystalline form D, under drying conditions at room temperature or under vacuum drying conditions at room temperature, converted to crystalline form B, which is not stable.

Most of the crystalline form E was converted under the conditions of keeping in a desiccator for 2 days in the crystalline form A, which is an unstable form.

Example 9 Dynamic Vapor Sorption (DVS) Analysis

Crystal form A: the weight change was 2.3% in the range of RH from 0 to 80%. About 1.5% moisture was removed from the hydrate of crystalline form A in the drying step under RH 0% conditions and about 2.3% moisture was absorbed in the RH0%-RH80% range. The desorption step at 30% RH could remove 1.5% moisture and the weight change was less than 2% in the 30-80% RH range.

Crystal form B: the weight change was 2.3% in the range of RH from 0% to 80%. About 4% moisture can be removed from the hydrate of crystalline Form B under RH 10% RH conditions, and about 4% moisture is absorbed under RH 10% RH conditions in the adsorption step, and the weight change is less than 2% in the 10-80% RH range.

Amorphous form: the weight change was about 15.7% in the RH range of 0-80%, which corresponds to a highly hygroscopic substance.

Example 10 Determination of solubility.

The solubility of the crystalline form A of the compound shown by formula I in water is 20-100 mg/ml at room temperature, and the solubility of the amorphous form of the compound shown by formula I used as a free base in water is less than 1 mg/ml.

Example 11 Composition in the form of capsules.

As a specific embodiment of an oral drug, a composition is prepared containing about 20-150 mg of the polymorphs described in Example 1 and/or Example 2 together with finely divided microcrystalline cellulose and/or stearic acid, giving a total amount of about 50 to 500 mg, to be filled into a type 0 capsule.

Example 12 Composition in the form of tablets or capsules.

As a specific embodiment of an oral drug, a composition is prepared containing about 20-150 mg of the polymorphs described in Example 1 and/or Example 2 together with two or more of the following excipients: microcrystalline cellulose, mannitol, crospovidone, croscarmellose sodium, sodium starch glycolate, povidone, hydroxypropyl cellulose and/or stearic acid, distributing the total amount into tablets or capsules containing from about 50 mg to 500 mg.

Example 13 Pharmacokinetic data.

female SD rats (Sprague Dawley) were divided into two groups, three rats in each group. 50 mg/kg of the crystalline form A of the compound of formula I and the amorphous form of the compound of formula I in the form of a free base were administered by intragastric tube in a single dose to each female rat.

- 29 041596 sy SD, respectively; at a specific point in time, blood samples were taken through the jugular vein, plasma was prepared from these samples and stored in a refrigerator at -80°C.

In the above plasma prepared from these samples, protein precipitation was performed using acetonitrile, the supernatant was diluted 3 times with water, then 5 μl of the solution was taken for testing by LC-MS/MS, and the data are shown in Table 1. 9.

Table 9

Compound Ways introductions Dose (mg/kg) Tmax (H) Stax (ng/ml) AUCiast (h*ng/ml) Amorphous form of the compound shown by formula 1 as free base By. 50 4.67 890 8165 Crystal form A of the compound shown by formula 1 By. 50 2.67 1440 11551

By. means oral.

50 mg/kg of the crystalline form A of the compound shown by formula I and the amorphous form of the compound shown by formula I, as a free base, were administered orally to rats, while the Tmax values were 2.67 and 4.67 hours, respectively, the Cmax was 1440 and 890 ng/mL, respectively, and AUC _last (area under the plasma concentration versus time curve from zero to the last time point) were 11551 and 8165 h*ng/mL, respectively.

Based on the above results, it is suggested that the crystalline form A of the compound shown by formula I showed a higher degree of absorption in vivo than the amorphous form of the compound shown by formula I, in the form of a free base.

Example 14 Biochemical kinase activity of a compound of formula I.

The biochemical kinase activity of the compound shown by formula I was tested in Reaction

Biology Corp. located in Malvern, Pennsylvania (Pa.), USA. Testing rules are described by Anastassiadis et al. in Nat. Biotechnol., 2011, 29(11): 1039-45. It was found that the compound

mula I has the potential to inhibit the following kinases. Kinase IC ₅₀ (nM) Kinase IC ₅₀ (nM) ALK 0.16 c-MET 9.59 ALK (C1156Y) 0.28 EPHA1 6.22 ALK (F1174L) 0.16 EPHA2 1.14 ALK (F1174L)-EML4 0.53 EPHB1 8.59 ALK (F1174L)-NPM1 0.47 CSFIR(FMS) 13.44 ALK (F1174S) 0.17 NEK1 6.08 ALK (G1202R) 3.83 ROS/ROS1 1.41 ALK (G1269A) 1.14 ROS1-GOPC 0.98 ALK (G1269S) 1.39 TRKA 8.00 ALK (L1152R) 0.58 TRKA-TFG (TRK-T3) 0.46 ALK (L1196M) 0.32 TRKA-TPM3 0.62 ALK (R1275Q) 1.06 TRKA-TPR 1.22 ALK (S1206R) 0.17 TRKB 3.39 ALK (T1151-L1152insT) 0.26 TRKC 0.46 ALK (T1151M) 0.13 ALK-TFG 0.73 ALK-NPM1 0.68 ALK-TPM3 0.21

While the present invention has been described in its entirety with its preferred embodiments and with reference to the accompanying drawings, it should be noted that various changes and modifications will be apparent to those skilled in the art. It should be understood that such changes and modifications are included within the scope of the present invention.

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Claims (19)

CLAIM 1. Crystal form A of the compound of formula I f o Formula I, wherein the X-ray powder diffraction pattern of crystalline Form A has characteristic peaks at 2θ diffraction angles of 4.9±0.2°, 10.0±0.2°, and 19.3±0.2°, and is crystalline form A is the dihydrate. 2. Crystal form A of the compound of formula I according to claim 1, where the powder x-ray diffraction pattern of the crystalline form A has characteristic peaks at 2θ diffraction angles of 4.9±0.2°, 10.0±0.2°, 14.7 ±0.2°, 16.9±0.2°, 19.3±0.2° and 20.3±0.2°. 3. Crystal form A of the compound of formula I according to claim 1 or 2, where the powder x-ray diffraction pattern of the crystalline form A has characteristic peaks at 2θ diffraction angles of 4.9±0.2°, 10.0±0.2°, 14 .7±0.2°, 16.9±0.2°, 19.3±0.2°, 20.3±0.2°, 25.5±0.2° and 30.7±0, 2°. 4. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form A according to any one of claims 1 to 3 and pharmaceutically acceptable excipients, adjuvants and/or carriers. 5. A pharmaceutical composition containing a therapeutically effective amount of the crystalline form A according to any one of claims 1 to 3 in combination with at least one of the other active ingredients. 6. The pharmaceutical composition according to claim 4 or 5, wherein the pharmaceutical composition is in the form of an oral preparation. 7. Pharmaceutical composition according to any one of claims 4 to 6, wherein the pharmaceutical composition is in the form of a tablet or capsule. 8. Pharmaceutical composition according to any one of claims 4 to 7, containing from 20 to 150 mg of crystalline form A according to any one of claims 1 to 3 with at least one excipient, adjuvant and / or carrier, which in total is about 50 to 500 mg. 9. Pharmaceutical composition according to claim 4, wherein the excipient, adjuvant and/or carrier is microcrystalline cellulose, mannitol, crospovidone, croscarmellose sodium, cellulose, sodium starch glycolate, povidone, hydroxypropyl cellulose and/or stearic acid. 10. The use of a crystalline form A according to any one of claims 1 to 3 or a pharmaceutical composition according to any one of claims 4 to 9 for the manufacture of a medicament for the treatment of a disease, disorder or condition in a patient, where the disease, disorder or condition is mediated by c-Met, RON, Axl, CSF1R, EphA2, ROS1 or ROS1 based fusion protein, TRKA or TRKA based fusion protein, TRKB, TRKC, ALK, ALK ^ati or ALK based fusion protein. 11. Use according to claim 10 wherein the ALK-based fusion protein is an EML4-ALK or NPM-ALK kinase. 12. Use according to claim 10 or 11, wherein the disease, disorder or condition is a cancer and/or a proliferative disorder. 13. Use according to any one of claims 10-12, wherein the disease, disorder or condition is lung cancer, melanoma, colon cancer, breast cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, gastric cancer, skin cancer, bone cancer, glioma, lymphoma, neuroblastoma, hepatocellular carcinoma, papillary renal cell carcinoma and/or head and neck squamous cell carcinoma. 14. Use according to any one of claims 10-13, wherein the disease, disorder or condition is non-small cell lung cancer resistant to crizotinib therapy. 15. Use according to any one of claims 10-13, wherein the disease, disorder or condition is melanoma. 16. A method of treating a disease, disorder, or condition in a patient by administering to the patient a crystalline Form A according to any one of claims 1-3 or a pharmaceutical composition according to any one of claims 4-9. 17. A method of treating a disease, disorder, or condition in a patient according to claim 16, wherein the disease, disorder, or condition is mediated by c-Met, RON, Ax1, CSF1R, EphA2, ROS1, or a ROS1-based fusion protein, TRKA, or a TRKA-based fusion protein , TRKB, TRKC, ALK, ALK ^ati , or an ALK-based fusion protein. 18. A method of treating a disease, disorder, or condition in a patient according to claim 17, wherein the ALK-based fusion protein is EML4-ALK or NPM-ALK kinase. 19. A method of treating a disease, disorder, or condition in a patient according to any one of claims 16-18, wherein -