Bruton's tyrosine kinase inhibitor compounds in solid form and uses thereof

Abstract

The application provides a solid form, a crystalline form, a crystal form of compound A, a solvate or a hydrate thereof, a preparation method and application, the obtained crystalline form of compound A has good crystallinity and stability, compound A has good Bruton tyrosine kinase inhibitory activity, cell inhibitory activity, in-vivo anti-tumor activity, pharmacokinetic properties and metabolic stability.

Description

TECHNICAL FIELD

[0001] The present application relates to solid forms, crystalline forms, specific crystal forms of compounds represented by formula (A), solvates or hydrates thereof as small molecule Bruton's tyrosine kinase inhibitors, and pharmaceutical compositions thereof, and the use thereof in the preparation of drugs for treating Bruton's tyrosine kinase related diseases. BACKGROUND

[0002] Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase belonging to the TEC tyrosine kinase family. The TEC family members include Tec, Bmx, BTK, Itk and Txk. BTK is the most widely studied member of the TEC family, is a key regulator in the B cell receptor (BCR) signaling pathway, is widely expressed in various types of malignant hematological tumors, and is involved in the proliferation, differentiation and apoptosis of B cells. Therefore, BTK has become an important molecular target for the treatment of malignant hematological tumors.

[0003] Currently, there are four BTK inhibitors approved for marketing, Ibrutinib (Imbruvica) is the first BTK small molecule inhibitor approved for marketing, which belongs to the first generation of BTK inhibitors, and was approved by the US FDA in 2013 for the clinical treatment of mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) and other diseases. Since then, Ibrutinib has continuously expanded its indications, and currently approved indications also include chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL) with 17p deletion, Waldenstrom macroglobulinemia (WM), marginal zone lymphoma (MZL), and chronic graft-versus-host disease (cGVHD). Ibrutinib can form a covalent bond with the 481st cysteine (Cys481) in the ATP binding domain of BTK, irreversibly inhibit BTK activation, block the BTK signaling pathway, and thus inhibit the proliferation and survival of B lymphoma cells, achieving the purpose of tumor treatment. Ibrutinib has achieved substantial efficacy in clinical treatment. However, due to the poor selectivity of Ibrutinib target, there are certain toxic side effects in clinical treatment. Acalabrutinib (ACP-196, Calquence) was approved for the treatment of MCL and CLL in 2017, and it belongs to the second generation of BTK targeted drugs. Compared with Ibrutinib, Acalabrutinib has higher selectivity for BTK and lower off-target toxicity. In addition, Zanubrutinib (BGB-3111) developed by Bejing Junshi Bio-technology Co., Ltd. was approved by the FDA in November 2019 for the treatment of adult MCL patients, and it became the first Chinese anti-cancer drug approved by the FDA as a breakthrough therapy. Tirabrutinib (ONO-4059) developed by Japan Ono Pharmaceutical Co., Ltd. was approved for marketing by the Japan Pharmaceutical and Medical Device Agency (PMDA) in March 2020, and it is used for the treatment of relapsed or refractory primary central nervous system lymphoma (PCNSL) and lymphoplasmacytic lymphoma (LPL). In general, the first generation of inhibitors has high inhibitory activity on BTK, but poor target selectivity and bioavailability; the second generation of inhibitors has good selectivity, but lower inhibition rate on BTK than the first generation of inhibitors. Structurally, the core skeleton of the currently marketed or under development compounds is mainly a bicyclic system.

[0004] To obtain a new generation of BTK inhibitors that combine the high activity of first-generation inhibitors with the good selectivity of second-generation inhibitors, the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, disclosed a class of structurally unique tricyclic compounds in patent CN108101905A. Among them, pyrimidoindazine compounds S1 and S10 and pyrimidopyrine compounds S18, S19 and S20 showed high BTK inhibitory activity. In further work, compounds with the S configuration of S18, S19 and S20 (i.e. S18s, S19s and S20s) were also synthesized [Yu Xue, et al. Discovery of 4,7-Diamino-5-(4-phenoxyphenyl)-6-methylenepyrimido[5,4-b]pyrrolizines as Novel Bruton's Tyrosine Kinase Inhibitors. J. Med. Chem., 2018, 61, 4608-4627.]. However, further research revealed that compounds S1, S10, S18s, and S19s are unstable during metabolism, and the 4-position of the terminal phenyl group is easily oxidized; while the oral bioavailability of compound S20s is not ideal.

[0005] Summary of the Invention

[0006] Compound A exhibits excellent BTK inhibitory activity, maintains good BTK inhibitory selectivity, possesses excellent in vivo antitumor activity, good oral administration performance, and good metabolic stability, and has the potential to be developed into a selective BTK inhibitor.

[0007]

[0008] On the one hand, the present invention provides compounds of formula (A) in solid form, as well as their solvates or hydrates.

[0009] On the other hand, the present invention provides the compound of formula (A) in crystalline form, its solvate or hydrate.

[0010] In some embodiments of the present invention, the above-mentioned crystalline form is characterized in that the crystalline form is a solvent-free and anhydrous crystalline form or a hydrate crystalline form, preferably a solvent-free and anhydrous crystalline form.

[0011] On the other hand, the present invention provides crystal form I of the compound of formula (A), its solvate or hydrate, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.8±0.2°, 11.6±0.2°, 13.6±0.2°.

[0012] In some embodiments of the present invention, the crystal form I described above has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 4.8±0.2°, 11.6±0.2°, 13.6±0.2°, and 23.4±0.2°.

[0013] In some embodiments of the present invention, the crystal form I described above has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 4.8±0.2°, 11.6±0.2°, 13.6±0.2°, 18.7±0.2°, 23.4±0.2°.

[0014] In some embodiments of the present invention, the crystal form I described above has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 4.8±0.2°, 11.6±0.2°, 13.6±0.2°, 16.2±0.2°, 18.7±0.2°, 23.4±0.2°.

[0015] In some embodiments of the present invention, the crystal form I described above has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 4.8±0.2°, 11.6±0.2°, 13.6±0.2°, 16.2±0.2°, 18.7±0.2°, 23.4±0.2°, 26.1±0.2°.

[0016] In some embodiments of the present invention, the crystal form I described above has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 4.8±0.2°, 11.6±0.2°, 13.6±0.2°, 16.2±0.2°, 18.7±0.2°, 23.4±0.2°, 24.2±0.2°, 24.8±0.2°, 26.1±0.2°.

[0017] In some embodiments of the present invention, the crystal form I described above has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 4.8±0.2°, 11.6±0.2°, 13.6±0.2°, 16.2±0.2°, 18.7±0.2°, 19.4±0.2°, 21.7±0.2°, 23.4±0.2°, 24.2±0.2°, 24.8±0.2°, 26.1±0.2°.

[0018] In some embodiments of the present invention, the crystal form I described above has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 4.8±0.2°, 11.6±0.2°, 13.6±0.2°, 16.2±0.2°, 16.7±0.2°, 18.7±0.2°, 19.4±0.2°, 21.7±0.2°, 23.4±0.2°, 24.2±0.2°, 24.8±0.2°, 26.1±0.2°, 27.6±0.2°.

[0019] In some embodiments of the present invention, the crystal form I described above has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 4.8±0.2°, 11.6±0.2°, 13.6±0.2°, 16.2±0.2°, 16.7±0.2°, 18.7±0.2°, 19.4±0.2°, 20.8±0.2°, 21.7±0.2°, 23.4±0.2°, 24.2±0.2°, 24.8±0.2°, 26.1±0.2°, 27.6±0.2°.

[0020] In some embodiments of the present invention, the crystal form I described above has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 4.8±0.2°, 11.6±0.2°, 13.6±0.2°, 16.2±0.2°, 16.7±0.2°, 18.7±0.2°, 19.4±0.2°, 20.8±0.2°, 21.7±0.2°, 22.5±0.2°, 23.4±0.2°, 24.2±0.2°, 24.8±0.2°, 26.1±0.2°, 27.6±0.2°, and 30.4±0.2°.

[0021] In some embodiments of the present invention, the crystal form I described above has a characteristic diffraction peak (±0.2°) at the following 2θ angle in its X-ray powder diffraction pattern:

[0022] Peak position (2 theta) Peak position (2 theta) Peak position (2 theta) 4.8 19.4 23.7 11.6 20.8 24.2 13.6 21.7 24.8 16.2 22.5 26.1 16.7 22.7 29.2 18.7 23.4 30.4 .

[0023] In some embodiments of the present invention, the crystal form I described above has a characteristic diffraction peak (±0.2°) at the following 2θ angle in its X-ray powder diffraction pattern:

[0024] Peak position (2 theta) Relative intensity % Peak position (2 theta) Relative intensity % Peak position (2 theta) Relative intensity % 4.8 45.9 19.4 10.9 23.7 9.1 11.6 100.0 20.8 9.9 24.2 14.9 13.6 56.0 21.7 11.2 24.8 16.4 16.2 25.9 22.5 9.0 26.1 20.7 16.7 8.6 22.7 8.4 29.2 6.0 18.7 34.1 23.4 60.4 30.4 8.4 .

[0025] In some embodiments of the present invention, the crystal form I described above has substantially the following characteristics: Figure 3 The X-ray powder diffraction pattern shown is shown.

[0026] In some embodiments of the present invention, the differential scanning calorimetry curve of the crystal form I has an exothermic peak starting point at 272.89±3℃.

[0027] In some embodiments of the present invention, the differential scanning calorimetry curve of the crystal form I above has an exothermic peak at 274.74±3℃.

[0028] In some embodiments of the present invention, the crystal form I described above has substantially the following characteristics: Figure 4 The DSC spectrum shown.

[0029] On the other hand, the present invention provides crystal form II of the compound of formula (A), its solvate or hydrate, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 8.5±0.2°, 10.6±0.2°, 15.0±0.2°.

[0030] In some embodiments of the present invention, the crystal form II described above has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 7.0±0.2°, 8.5±0.2°, 10.6±0.2°, 15.0±0.2°, 22.1±0.2°.

[0031] In some embodiments of the present invention, the crystal form II described above has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 7.0±0.2°, 7.9±0.2°, 8.5±0.2°, 10.6±0.2°, 15.0±0.2°, 22.1±0.2°, 25.3±0.2°.

[0032] In some embodiments of the present invention, the crystal form II described above has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 7.0±0.2°, 7.9±0.2°, 8.5±0.2°, 10.6±0.2°, 15.0±0.2°, 18.0±0.2°, 22.1±0.2°, 25.3±0.2°, 26.3±0.2°.

[0033] In some embodiments of the present invention, the crystal form II described above has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 7.0±0.2°, 7.9±0.2°, 8.5±0.2°, 10.6±0.2°, 15.0±0.2°, 17.1±0.2°, 18.0±0.2°, 19.1±0.2°, 22.1±0.2°, 25.3±0.2°, 26.3±0.2°.

[0034] In some embodiments of the present invention, the crystal form II described above has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 4.3±0.2°, 7.0±0.2°, 7.9±0.2°, 8.5±0.2°, 10.6±0.2°, 15.0±0.2°, 17.1±0.2°, 18.0±0.2°, 19.1±0.2°, 22.1±0.2°, 25.3±0.2°, 26.3±0.2°.

[0035] In some embodiments of the present invention, the crystal form II described above has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 4.3±0.2°, 7.0±0.2°, 7.9±0.2°, 8.5±0.2°, 10.6±0.2°, 12.8±0.2°, 15.0±0.2°, 17.1±0.2°, 18.0±0.2°, 19.1±0.2°, 21.3±0.2°, 22.1±0.2°, 25.3±0.2°, and 26.3±0.2°.

[0036] In some embodiments of the present invention, the above-mentioned crystal form II has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 4.3±0.2°, 7.0±0.2°, 7.9±0.2°, 8.5±0.2°, 10.6±0.2°, 11.5±0.2°, 12.8±0.2°, 14.1±0.2°, 15.0±0.2°, 17.1±0.2°, 18.0±0.2°, 19.1±0.2°, 21.3±0.2°, 22.1±0.2°, 25.3±0.2°, 26.3±0.2°.

[0037] In some embodiments of the present invention, the above-mentioned crystal form II has a characteristic diffraction peak (±0.2°) at the following 2θ angle in its X-ray powder diffraction pattern:

[0038] Peak position (2 theta) Peak position (2 theta) Peak position (2 theta) 4.3 14.1 21.3 7.0 15.0 22.1 7.9 17.1 25.1 8.5 18.0 25.3 10.6 18.2 26.3 11.5 19.1 30.7 12.8 .

[0039] In some embodiments of the present invention, the above-mentioned crystal form II has a characteristic diffraction peak (±0.2°) at the following 2θ angle in its X-ray powder diffraction pattern:

[0040]

[0041]

[0042] In some embodiments of the present invention, the above-mentioned crystal form II has substantially the following characteristics: Figure 5 The X-ray powder diffraction pattern shown is shown.

[0043] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned crystal form II has three starting points of endothermic peaks at 49.26±3℃, 84.59±3℃ and 168.35±3℃ respectively.

[0044] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned crystal form II has three endothermic peaks at 69.36±3℃, 98.45±3℃ and 176.96±3℃ respectively.

[0045] In some embodiments of the present invention, the above-mentioned crystal form II has substantially the following characteristics:Figure 6 The DSC spectrum shown.

[0046] In some embodiments of the present invention, the above-mentioned crystal form II has a thermogravimetric analysis curve showing a weight loss of 3.417% ± 0.2% between room temperature and 100 ± 3°C.

[0047] In some embodiments of the present invention, the above-mentioned crystal form II has substantially the following characteristics: Figure 6 The TGA spectrum shown.

[0048] On the other hand, the present invention provides a crystal form III of the compound of formula (A), its solvate or hydrate, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.3±0.2°, 8.6±0.2°, 10.6±0.2°, 15.1±0.2°.

[0049] In some embodiments of the present invention, the crystal form III described above has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 4.3±0.2°, 7.1±0.2°, 8.6±0.2°, 10.6±0.2°, 15.1±0.2°, 25.5±0.2°.

[0050] In some embodiments of the present invention, the crystal form III described above has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 4.3±0.2°, 7.1±0.2°, 8.0±0.2°, 8.6±0.2°, 10.6±0.2°, 15.1±0.2°, 22.3±0.2°, and 25.5±0.2°.

[0051] On the other hand, the present invention provides the crystal form III of the compound of formula (A), its solvate or hydrate, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.3±0.2°, 8.6±0.2°, 10.6±0.2°, 15.1±0.2°, 16.2±0.2°.

[0052] In some embodiments of the present invention, the above-mentioned crystal form III has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 4.3±0.2°, 7.1±0.2°, 8.6±0.2°, 10.6±0.2°, 15.1±0.2°, 16.2±0.2°, 25.5±0.2°.

[0053] In some embodiments of the present invention, the crystal form III described above has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 4.3±0.2°, 7.1±0.2°, 8.0±0.2°, 8.6±0.2°, 10.6±0.2°, 15.1±0.2°, 16.2±0.2°, 22.3±0.2°, and 25.5±0.2°.

[0054] In some embodiments of the present invention, the crystal form III described above has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 4.3±0.2°, 7.1±0.2°, 8.0±0.2°, 8.6±0.2°, 10.6±0.2°, 15.1±0.2°, 16.2±0.2°, 19.3±0.2°, 22.3±0.2°, 25.5±0.2°.

[0055] In some embodiments of the present invention, the above-mentioned crystal form III has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 4.3±0.2°, 7.1±0.2°, 8.0±0.2°, 8.6±0.2°, 10.6±0.2°, 15.1±0.2°, 16.2±0.2°, 17.2±0.2°, 18.1±0.2°, 19.3±0.2°, 22.3±0.2°, and 25.5±0.2°.

[0056] In some embodiments of the present invention, the above-mentioned crystal form III has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 4.3±0.2°, 7.1±0.2°, 8.0±0.2°, 8.6±0.2°, 10.6±0.2°, 15.1±0.2°, 16.2±0.2°, 17.2±0.2°, 18.1±0.2°, 19.3±0.2°, 21.4±0.2°, 22.3±0.2°, 25.5±0.2°.

[0057] In some embodiments of the present invention, the above-mentioned crystal form III has a characteristic diffraction peak (±0.2°) at the following 2θ angle in its X-ray powder diffraction pattern:

[0058] Peak position (2 theta) Peak position (2 theta) Peak position (2 theta) 4.3 11.619.3 7.1 14.621.4 8.0 15.122.3 8.6 16.225.5 9.0 17.226.1 10.4 18.126.5 10.6 18.431.1 .

[0059] In some embodiments of the present invention, the above-mentioned crystal form III has a characteristic diffraction peak (±0.2°) at the following 2θ angle in its X-ray powder diffraction pattern:

[0060] Peak position (2 theta) Relative intensity % Peak position (2 theta) Relative intensity % Peak position (2 theta) Relative intensity % 4.3 68.2 11.6 11.1 19.3 22.1 7.1 45.2 14.6 20.4 21.4 17.9 8.0 47.6 15.1 93.3 22.3 45.6 8.6 72.5 16.2 28 25.5 67.7 9.0 15.0 17.2 22.1 26.1 24.7 10.4 48.7 18.1 24.4 26.5 26.9 10.6 100.0 18.4 20.8 31.1 10.0 .

[0061] In some embodiments of the present invention, the above-mentioned crystal form III has substantially the following characteristics: Figure 7 The X-ray powder diffraction pattern shown is shown.

[0062] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned crystal form III has three starting points of endothermic peaks at 38.13±3℃, 75.07±3℃ and 167.19±3℃ respectively.

[0063] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned crystal form III has three endothermic peaks at 57.40±3℃, 96.32±3℃ and 177.55±3℃ respectively.

[0064] In some embodiments of the present invention, the crystal form III described above has a DSC pattern substantially as shown in Figure 8.

[0065] In some embodiments of the present invention, the above-mentioned crystal form III has a weight loss of 3.075% ± 0.2% before 90 ± 3 °C in its thermogravimetric analysis curve.

[0066] In some embodiments of the present invention, the above-mentioned crystal form III has substantially the following characteristics: Figure 8 The TGA spectrum shown.

[0067] On the other hand, the present invention provides crystal form IV of the compound of formula (A), its solvate or hydrate, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.3±0.2°, 9.7±0.2°, 12.8±0.2°.

[0068] In some embodiments of the present invention, the above-mentioned crystal form IV has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 5.1±0.2°, 6.3±0.2°, 9.7±0.2°, 12.8±0.2°, and 14.1±0.2°.

[0069] In some embodiments of the present invention, the above-mentioned crystal form IV has X-ray powder diffraction patterns with characteristic diffraction peaks at the following 2θ angles: 5.1±0.2°, 6.3±0.2°, 9.7±0.2°, 12.8±0.2°, 14.1±0.2°, and 19.0±0.2°.

[0070] In some embodiments of the present invention, the above-mentioned crystal form IV has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 5.1±0.2°, 6.3±0.2°, 9.7±0.2°, 12.8±0.2°, 14.1±0.2°, 15.6±0.2°, 19.0±0.2°, 21.9±0.2°.

[0071] In some embodiments of the present invention, the above-mentioned crystal form IV has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 5.1±0.2°, 6.3±0.2°, 9.7±0.2°, 12.8±0.2°, 14.1±0.2°, 19.0±0.2°, 20.4±0.2°, 23.2±0.2°.

[0072] In some embodiments of the present invention, the above-mentioned crystal form IV has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 5.1±0.2°, 6.3±0.2°, 9.7±0.2°, 12.8±0.2°, 14.1±0.2°, 19.0±0.2°, 20.4±0.2°, 21.9±0.2°, 23.2±0.2°, 26.3±0.2°.

[0073] In some embodiments of the present invention, the above-mentioned crystal form IV has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 5.1±0.2°, 6.3±0.2°, 9.7±0.2°, 12.8±0.2°, 14.1±0.2°, 15.6±0.2°, 19.0±0.2°, 20.4±0.2°, 21.9±0.2°, 23.2±0.2°, 26.3±0.2°.

[0074] In some embodiments of the present invention, the above-mentioned crystal form IV has a characteristic diffraction peak (±0.2°) at the following 2θ angle in its X-ray powder diffraction pattern:

[0075] Peak position (2 theta) Peak position (2 theta) Peak position (2 theta) 5.1 15.6 23.8 6.3 17.8 24.1 9.7 19.0 25.1 11.6 20.4 25.8 12.8 21.9 26.3 141 232 .

[0076] In some embodiments of the present invention, the above-mentioned crystal form IV has a characteristic diffraction peak (±0.2°) at the following 2θ angle in its X-ray powder diffraction pattern:

[0077] Peak position (2 theta) Relative intensity % Peak position (2 theta) Relative intensity % Peak position (2 theta) Relative intensity % 5.1 14.1 15.6 9.5 23.8 6.9 6.3 44.7 17.8 5.6 24.1 5.1 9.7 52.2 19.0 16.4 25.1 5.6 11.6 4.4 20.4 12.7 25.8 4.5 12.8 100 21.9 9.8 26.3 11.7 14.1 17.5 23.2 15.9 .

[0078] In some embodiments of the present invention, the above-mentioned crystal form IV has substantially the following characteristics: Figure 9 The X-ray powder diffraction pattern shown is shown.

[0079] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned crystal form IV has two starting points of endothermic peaks at 45.75±3℃ and 159.89±3℃, respectively.

[0080] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned crystal form IV has two endothermic peaks at 70.65±3℃ and 166.96±3℃, respectively.

[0081] In some embodiments of the present invention, the above-mentioned crystal form IV has substantially the following characteristics: Figure 10 The DSC spectrum shown.

[0082] In some embodiments of the present invention, the above-mentioned crystal form IV has a thermogravimetric analysis curve showing a weight loss of 7.863% ± 0.2% between room temperature and 200 ± 3°C.

[0083] In some embodiments of the present invention, the above-mentioned crystal form IV has substantially the following characteristics: Figure 10 The TGA spectrum shown.

[0084] On the other hand, the present invention provides crystal form V of the compound of formula (A), its solvate or hydrate, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.6±0.2°, 7.1±0.2°, 14.3±0.2°.

[0085] In some embodiments of the present invention, the crystal form V described above has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 5.6±0.2°, 7.1±0.2°, 11.5±0.2°, 13.8±0.2°, and 14.3±0.2°.

[0086] In some embodiments of the present invention, the crystal form V described above has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 5.6±0.2°, 7.1±0.2°, 11.5±0.2°, 13.8±0.2°, 14.3±0.2°, 17.0±0.2°, 21.9±0.2°.

[0087] In some embodiments of the present invention, the crystal form V described above has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 5.6±0.2°, 7.1±0.2°, 8.9±0.2°, 11.5±0.2°, 13.8±0.2°, 14.3±0.2°, 17.0±0.2°, 19.1±0.2°, 21.9±0.2°.

[0088] In some embodiments of the present invention, the crystal form V described above has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 5.6±0.2°, 7.1±0.2°, 8.9±0.2°, 11.5±0.2°, 13.8±0.2°, 14.3±0.2°, 17.0±0.2°, 18.3±0.2°, 19.1±0.2°, 20.7±0.2°, 21.9±0.2°.

[0089] In some embodiments of the present invention, the crystal form V described above has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 5.6±0.2°, 7.1±0.2°, 8.9±0.2°, 11.5±0.2°, 13.8±0.2°, 14.3±0.2°, 17.0±0.2°, 18.3±0.2°, 19.1±0.2°, 20.7±0.2°, 21.9±0.2°, and 25.2±0.2°.

[0090] In some embodiments of the present invention, the crystal form V described above has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 5.6±0.2°, 7.1±0.2°, 8.9±0.2°, 11.5±0.2°, 13.8±0.2°, 14.3±0.2°, 17.0±0.2°, 18.3±0.2°, 19.1±0.2°, 20.7±0.2°, 21.9±0.2°, 25.2±0.2°, and 27.2±0.2°.

[0091] In some embodiments of the present invention, the crystal form V described above has a characteristic diffraction peak (±0.2°) at the following 2θ angle in its X-ray powder diffraction pattern:

[0092] Peak position (2 theta) Peak position (2 theta) Peak position (2 theta) 4.4 12.7 20.7 5.1 13.4 21.9 5.6 13.8 22.4 7.1 14.3 23.2 8.9 17.0 23.4 9.6 17.9 25.2 11.3 18.3 25.8 11.5 19.1 27.2 .

[0093] In some embodiments of the present invention, the crystal form V described above has a characteristic diffraction peak (±0.2°) at the following 2θ angle in its X-ray powder diffraction pattern:

[0094] Peak position (2 theta) Relative intensity % Peak position (2 theta) Relative intensity % Peak position (2 theta) Relative intensity % 4.4 6.7 12.7 6.7 20.7 11.6 5.1 7.1 13.4 4.1 21.9 19.0 5.6 86.7 13.8 40.6 22.4 6.6 7.1 37.6 14.3 100.0 23.2 5.2 8.9 10.9 17.0 12.6 23.4 8.8 9.6 7.0 17.9 8.3 25.2 8.3 11.3 20.2 18.3 11.8 25.8 5.3 115 369 191 114 272 89 .

[0095] In some embodiments of the present invention, the crystal form V described above has substantially the following characteristics: Figure 11 The X-ray powder diffraction pattern shown is shown.

[0096] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned crystal form V has an endothermic peak at 174.53±3℃.

[0097] In some embodiments of the present invention, the crystal form V described above has substantially the following characteristics: Figure 15 The DSC spectrum shown.

[0098] On the other hand, the present invention provides crystal form VI of the compound of formula (A), its solvate or hydrate, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.2±0.2°, 9.4±0.2°, 12.5±0.2°.

[0099] In some embodiments of the present invention, the crystal form VI described above has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 6.2±0.2°, 9.4±0.2°, 12.5±0.2°, 15.2±0.2°, 21.4±0.2°.

[0100] In some embodiments of the present invention, the above-mentioned crystal form VI has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 5.0±0.2°, 6.2±0.2°, 9.4±0.2°, 12.5±0.2°, 15.2±0.2°, 21.4±0.2°, 24.7±0.2°.

[0101] In some embodiments of the present invention, the crystal form VI described above has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 5.0±0.2°, 6.2±0.2°, 9.4±0.2°, 12.5±0.2°, 15.2±0.2°, 21.4±0.2°, 23.5±0.2°, 24.7±0.2°.

[0102] In some embodiments of the present invention, the above-mentioned crystal form VI has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 5.0±0.2°, 6.2±0.2°, 9.4±0.2°, 12.5±0.2°, 15.2±0.2°, 18.8±0.2°, 21.4±0.2°, 23.5±0.2°, 24.7±0.2°.

[0103] In some embodiments of the present invention, the above-mentioned crystal form VI has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 5.0±0.2°, 6.2±0.2°, 9.4±0.2°, 12.5±0.2°, 14.0±0.2°, 15.2±0.2°, 18.8±0.2°, 21.4±0.2°, 23.5±0.2°, 24.7±0.2°.

[0104] In some embodiments of the present invention, the above-mentioned crystal form VI has a characteristic diffraction peak (±0.2°) at the following 2θ angle in its X-ray powder diffraction pattern:

[0105] Peak position (2 theta) Peak position (2 theta) Peak position (2 theta) 5.0 15.2 23.5 6.2 17.6 24.7 9.4 18.5 25.4 10.1 18.8 26.0 12.5 21.4 30.8 14.0 23.2 .

[0106] In some embodiments of the present invention, the above-mentioned crystal form VI has a characteristic diffraction peak (±0.2°) at the following 2θ angle in its X-ray powder diffraction pattern:

[0107] Peak position (2 theta) Relative intensity % Peak position (2 theta) Relative intensity % Peak position (2 theta) Relative intensity % 5.0 11.5 15.2 22.3 23.5 10.1 6.2 35.8 17.6 2.9 24.7 10 9.4 100 18.5 6.6 25.4 4.1 10.1 3.2 18.8 6.6 26.0 4.8 12.5 65.6 21.4 23.9 30.8 3.2 14.0 5.2 23.2 7.3 .

[0108] In some embodiments of the present invention, the crystal form VI described above has substantially the following characteristics: Figure 12 The X-ray powder diffraction pattern shown is shown.

[0109] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned crystal form VI has two starting points of endothermic peaks at 45.54±3℃ and 163.80±3℃, respectively.

[0110] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned crystal form VI has two endothermic peaks at 86.78±3℃ and 165.61±3℃, respectively.

[0111] In some embodiments of the present invention, the crystal form VI described above has substantially the following characteristics: Figure 13 The DSC spectrum shown.

[0112] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned crystal form VI shows a weight loss of 3.153% ± 0.2% between room temperature and 120 ± 3°C, and a weight loss of 1.500% ± 0.2% between 120 and 180°C (± 3°C).

[0113] In some embodiments of the present invention, the crystal form VI described above has substantially the following characteristics: Figure 13 The TGA spectrum shown.

[0114] On the other hand, the present invention provides a crystal form VII of the compound of formula (A), its solvate or hydrate, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.7±0.2°, 10.8±0.2°, 21.8±0.2°.

[0115] In some embodiments of the present invention, the crystal form VII described above has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 5.7±0.2°, 7.5±0.2°, 10.8±0.2°, 12.5±0.2°, 21.8±0.2°.

[0116] In some embodiments of the present invention, the crystal form VII described above has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 5.7±0.2°, 7.5±0.2°, 10.8±0.2°, 12.5±0.2°, 17.4±0.2°, 21.8±0.2°, and 25.1±0.2°.

[0117] In some embodiments of the present invention, the crystal form VII described above has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 5.7±0.2°, 7.5±0.2°, 10.8±0.2°, 11.6±0.2°, 12.5±0.2°, 17.4±0.2°, 18.0±0.2°, 21.8±0.2°, and 25.1±0.2°.

[0118] In some embodiments of the present invention, the crystal form VII described above has a characteristic diffraction peak (±0.2°) at the following 2θ angle in its X-ray powder diffraction pattern:

[0119] Peak position (2 theta) Peak position (2 theta) Peak position (2 theta) 5.7 14.7 18.7 7.5 15.1 20.0 10.8 16.2 21.8 11.6 17.4 23.3 12.5 18.0 25.1 .

[0120] In some embodiments of the present invention, the crystal form VII described above has a characteristic diffraction peak (±0.2°) at the following 2θ angle in its X-ray powder diffraction pattern:

[0121] Peak position (2 theta) Relative intensity % Peak position (2 theta) Relative intensity % Peak position (2 theta) Relative intensity % 5.7 100.0 14.7 5.4 18.7 3.2 7.5 7.2 15.1 5.4 20.0 3.0 10.8 40.5 16.2 3.0 21.8 11.1 11.6 7.0 17.4 10.1 23.3 4.0 12.5 9.2 18.0 5.9 25.1 5.7 .

[0122] In some embodiments of the present invention, the crystal form VII described above has substantially the following characteristics: Figure 1 The X-ray powder diffraction pattern shown is shown.

[0123] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned crystal form VII has two starting points of endothermic peaks at 47.52±3℃ and 151.56±3℃, respectively.

[0124] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned crystal form VII has two endothermic peaks at 74.24±3℃ and 156.63±3℃, respectively.

[0125] In some embodiments of the present invention, the crystal form VII described above has substantially the following characteristics: Figure 2 The DSC spectrum shown.

[0126] In some embodiments of the present invention, the above-mentioned crystal form VII has a thermogravimetric analysis curve showing a weight loss of 8.053% ± 0.2% between room temperature and 150 ± 3°C.

[0127] In some embodiments of the present invention, the crystal form VII described above has substantially the following characteristics: Figure 2 The TGA spectrum shown.

[0128] On the other hand, the present invention provides a method for preparing the compound of formula (A) in crystalline form, its solvate or hydrate, comprising:

[0129] (1) Add the compound shown in formula (A) to a solvent to make it into a suspension or solution;

[0130] (2) Stir the above suspension or solution to allow crystals to precipitate and separate the solids;

[0131] Optionally, it further includes a drying step to obtain the compound of formula (A) in crystalline form, its solvate or hydrate.

[0132] In some embodiments of the present invention, the preparation method described above, wherein the solvent is selected from a single solvent or a mixture of solvents, preferably, the solvent is selected from one or two of n-heptane, toluene, ethyl acetate, methanol, ethylene glycol or water.

[0133] In some embodiments of the present invention, the above preparation method includes a suspension prepared by adding a poor solvent to a solution.

[0134] In some embodiments of the present invention, the preparation method described above, wherein the stirring temperature is -20°C to 70°C, preferably -10°C to 60°C, more preferably 0°C to 50°C, and even more preferably 15°C to 40°C.

[0135] In some embodiments of the present invention, the preparation method described above includes a stirring time of 0.1 hours to 75 hours, preferably 0.5 hours to 72 hours.

[0136] In some embodiments of the present invention, the above-described preparation method wherein the weight-volume ratio of the compound to the solvent is 1g:1 to 90mL, preferably 1g:5 to 50mL, and more preferably 1g:10 to 25mL.

[0137] In some embodiments of the present invention, in the above-described preparation method, the volume ratio of the two solvents in the mixed solvent is 1:1 to 100, preferably 1:1 to 50, more preferably 1:1 to 20, and even more preferably 1:1 to 5. The volume ratio is calculated by taking the solvent with the smaller amount as 1.

[0138] In some embodiments of the present invention, the above-mentioned preparation method wherein the drying time is 0.1 hours to 75 hours, preferably 1 hour to 48 hours, more preferably 5 hours to 24 hours, more preferably 5 hours to 12 hours, and even more preferably 5 hours to 10 hours; the drying is preferably vacuum drying.

[0139] On the other hand, the present invention provides a method for preparing crystal form I of the compound shown in formula (A), its solvate or hydrate, comprising:

[0140] (1) Add the compound shown in formula (A) to a solvent to make it into a suspension or solution;

[0141] (2) Stir the above suspension or solution to crystallize, separate the solid, and obtain the compound shown in formula (A), its solvate or hydrate crystal form I.

[0142] In some embodiments of the present invention, the preparation method described above, wherein the solvent is selected from a single solvent or a mixture of solvents, preferably, the single solvent may be selected from ethyl acetate, and the mixture of solvents may be selected from toluene and n-heptane.

[0143] In some embodiments of the present invention, the above preparation method includes a suspension prepared by adding a poor solvent to a solution.

[0144] In some embodiments of the present invention, the above-mentioned preparation method includes a stirring temperature of -20°C to 70°C, preferably -10°C to 60°C, more preferably 0°C to 50°C, and even more preferably 15°C to 40°C.

[0145] In some embodiments of the present invention, the preparation method described above includes a stirring time of 0.1 hours to 75 hours, preferably 0.5 hours to 72 hours.

[0146] In some embodiments of the present invention, the above-described preparation method wherein the weight-volume ratio of the compound to the solvent is 1g:1 to 90mL, preferably 1g:5 to 50mL, and more preferably 1g:10 to 25mL.

[0147] In some embodiments of the present invention, in the above-described preparation method, the volume ratio of the two solvents in the mixed solvent is 1:1 to 100, preferably 1:1 to 50, more preferably 1:1 to 20, more preferably 1:1 to 5, and more preferably 1:1.

[0148] On the other hand, the present invention provides a method for preparing crystal form II of the compound shown in formula (A), its solvate or hydrate, comprising:

[0149] (1) Add the compound shown in formula (A) to a solvent to make it into a suspension or solution;

[0150] (2) Stir the above suspension or solution to crystallize, separate the solid, and obtain the crystal form II of the compound shown in formula (A), its solvate or hydrate.

[0151] Alternatively, the present invention provides a method for preparing crystal form II of the compound of formula (A), its solvate or hydrate, comprising: adding water to crystal form VII, stirring or slurrying, crystallizing, and separating the solid.

[0152] In some embodiments of the present invention, the solvent in the above-described preparation method is water.

[0153] In some embodiments of the present invention, the preparation method described above, wherein the stirring or pulping temperature is -20°C to 70°C, preferably -10°C to 60°C, more preferably 0°C to 50°C, even more preferably 15°C to 40°C, and even more preferably room temperature.

[0154] In some embodiments of the present invention, the preparation method described above includes a stirring or pulping time of 0.1 hours to 75 hours, preferably 0.5 hours to 72 hours.

[0155] In some embodiments of the present invention, the above-described preparation method wherein the weight-volume ratio of the compound to the solvent is 1g:1 to 90mL, preferably 1g:5 to 50mL, and more preferably 1g:10 to 25mL.

[0156] On the other hand, the present invention provides a method for preparing crystal form III of the compound shown in formula (A), its solvate or hydrate, comprising:

[0157] (1) The above crystal form II is placed in a vacuum drying oven for drying to obtain the crystal form III of the compound shown in formula (A), its solvate or hydrate.

[0158] In some embodiments of the present invention, the above-mentioned preparation method wherein the vacuum drying temperature is 30-70°C, preferably 40-60°C, and more preferably 40-50°C.

[0159] In some embodiments of the present invention, the above-mentioned preparation method wherein the vacuum drying time is 0.1 hours to 75 hours, preferably 1 hour to 48 hours, more preferably 5 hours to 24 hours, more preferably 5 hours to 12 hours, and even more preferably 5 hours to 10 hours.

[0160] On the other hand, the present invention provides a method for preparing crystal form IV of the compound shown in formula (A), its solvate or hydrate, comprising:

[0161] (1) Add the compound shown in formula (A) to a solvent to make it into a suspension or solution;

[0162] (2) Stir the above suspension or solution to crystallize, separate the solid, and obtain the crystal form IV of the compound shown in formula (A), its solvate or hydrate.

[0163] In some embodiments of the present invention, the solvent in the above-described preparation method is methanol.

[0164] In some embodiments of the present invention, the above-mentioned preparation method includes a stirring temperature of -20°C to 70°C, preferably -10°C to 60°C, more preferably 0°C to 50°C, even more preferably 15°C to 40°C, and even more preferably room temperature.

[0165] In some embodiments of the present invention, the above-mentioned preparation method includes a stirring time of 0.1 hours to 75 hours, preferably 0.5 hours to 72 hours, more preferably 1 hour to 48 hours, and even more preferably 2 hours to 24 hours.

[0166] In some embodiments of the present invention, the above-described preparation method wherein the weight-volume ratio of the compound to the solvent is 1g:1 to 90mL, preferably 1g:5 to 50mL, more preferably 1g:10 to 25mL, and even more preferably 1g:10 to 15mL.

[0167] On the other hand, the present invention provides a method for preparing crystal form V of the compound shown in formula (A), its solvate or hydrate, comprising:

[0168] (1) The above crystal form IV is placed in a vacuum drying oven for drying to obtain the crystal form V of the compound shown in formula (A), its solvate or hydrate.

[0169] In some embodiments of the present invention, the above-mentioned preparation method wherein the vacuum drying temperature is 30-70°C, preferably 40-60°C, and more preferably 40-50°C.

[0170] In some embodiments of the present invention, the above-mentioned preparation method wherein the vacuum drying time is 0.1 hours to 75 hours, preferably 1 hour to 48 hours, more preferably 5 hours to 24 hours, more preferably 5 hours to 12 hours, and even more preferably 5 hours to 10 hours.

[0171] On the other hand, the present invention provides a method for preparing crystal form VI of the compound shown in formula (A), its solvate or hydrate, comprising:

[0172] (1) Add the compound shown in formula (A) to a solvent to make it into a suspension or solution;

[0173] (2) Stir the above suspension or solution to crystallize, separate the solid, and obtain the crystal form VI of the compound shown in formula (A), its solvate or hydrate.

[0174] In some embodiments of the present invention, the solvent in the above-described preparation method is ethylene glycol.

[0175] In some embodiments of the present invention, the above-mentioned preparation method includes a stirring temperature of -20°C to 70°C, preferably -10°C to 60°C, more preferably 0°C to 50°C, even more preferably 15°C to 40°C, and even more preferably room temperature.

[0176] In some embodiments of the present invention, the above-mentioned preparation method includes a stirring time of 0.1 hours to 75 hours, preferably 0.5 hours to 72 hours, and more preferably 1 hour to 48 hours.

[0177] In some embodiments of the present invention, the above-described preparation method wherein the weight-volume ratio of the compound to the solvent is 1g:1 to 90mL, preferably 1g:5 to 50mL, and more preferably 1g:10 to 25mL.

[0178] On the other hand, the present invention provides a method for preparing the crystal form VII of the compound shown in formula (A), its solvate or hydrate, comprising:

[0179] (1) Add the compound shown in formula (A) to a solvent to make it into a suspension or solution;

[0180] (2) Stir the above suspension or solution to crystallize, separate the solid, and obtain the crystal form VII of the compound shown in formula (A), its solvate or hydrate.

[0181] In some embodiments of the present invention, the solvent in the above-described preparation method is dichloromethane.

[0182] In some embodiments of the present invention, the above-mentioned preparation method includes a stirring temperature of -20°C to 70°C, preferably -10°C to 60°C, more preferably 0°C to 50°C, even more preferably 15°C to 40°C, and even more preferably room temperature.

[0183] In some embodiments of the present invention, the above-mentioned preparation method includes a stirring time of 0.1 hours to 75 hours, preferably 0.5 hours to 72 hours, and more preferably 1 hour to 48 hours.

[0184] In some embodiments of the present invention, the above-described preparation method wherein the weight-volume ratio of the compound to the solvent is 1g:1 to 90mL, preferably 1g:5 to 50mL, and more preferably 1g:10 to 25mL.

[0185] Another object of the present invention is to provide a pharmaceutical composition comprising the aforementioned compound of formula (A) in solid form, its solvate or hydrate, its crystalline form, its solvate or hydrate, or a crystalline mixture thereof.

[0186] In some embodiments of the present invention, the above-mentioned pharmaceutical composition comprises one or a mixture of several of the following crystal forms: crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, and crystal form VI of the aforementioned compound of formula (A), its solvate or hydrate.

[0187] In some embodiments of the present invention, the pharmaceutical composition comprises the aforementioned solid form of the compound of formula (A), its solvate or hydrate, its crystalline form, its solvate or hydrate, or a mixture thereof, and contains one or more pharmaceutically acceptable carriers.

[0188] In some embodiments of the present invention, the pharmaceutical composition comprises a compound of formula (A) above, a mixture of one or more of crystal forms I, II, III, IV, V, and VI of its solvate or hydrate, and contains one or more pharmaceutically acceptable carriers.

[0189] The present invention also provides the use of the compound of formula (A) in solid form, its solvate or hydrate, the compound of formula (A) in crystalline form, its solvate or hydrate, the compound of formula (A), its solvate or hydrate, crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, crystal form VI, crystal form VII, or the above pharmaceutical composition in the preparation of a medicament for treating BTK-related diseases.

[0190] On the other hand, the present invention also relates to the use of the compound of formula (A) in solid form, its solvate or hydrate, the compound of formula (A) in crystalline form, its solvate or hydrate, the compound of formula (A), its solvate or hydrate in crystal form, crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, crystal form VI, crystal form VII, or the above-described pharmaceutical composition for the treatment of BTK-related diseases.

[0191] On another aspect, this application also provides the aforementioned solid form of the compound of formula (A), its solvate or hydrate, crystalline form of the compound of formula (A), its solvate or hydrate, crystal form of the compound of formula (A), its solvate or hydrate, crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, crystal form VI, crystal form VII, or the aforementioned pharmaceutical composition for treating BTK-related conditions.

[0192] In some embodiments of the present invention, the aforementioned BTK-related disorders involve dysregulation of BTK protein expression, levels, or activity.

[0193] In some embodiments of the present invention, the aforementioned BTK-related conditions include tumors or autoimmune diseases; preferably, the tumor is a hematologic malignancy; more preferably, leukemia or lymphoma; further preferably, B-cell lymphoma; even more preferably, mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, marginal zone lymphoma, follicular lymphoma, Waldenström macroglobulinemia, or diffuse large B-cell lymphoma.

[0194] On the other hand, the use of the compound of formula (A) in solid form, its solvate or hydrate, the compound of formula (A) in crystalline form, its solvate or hydrate, the compound of formula (A), its solvate or hydrate, crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, crystal form VI, crystal form VII, or the above-described pharmaceutical composition in the preparation of a medicament for treating tumor diseases or autoimmune diseases is also provided.

[0195] In some embodiments of the present invention, the tumor disease is a hematologic malignancy; more preferably, it is leukemia or lymphoma; more preferably, it is B-cell lymphoma; even more preferably, it is mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, marginal zone lymphoma, follicular lymphoma, Waldenström macroglobulinemia, or diffuse large B-cell lymphoma.

[0196] In some embodiments of the present invention, the BTK-related disorders involve dysregulation of BTK protein expression, levels, or activity.

[0197] On the other hand, the present invention also relates to a method of treating a patient’s condition by administering to the patient a therapeutically effective amount of the compound of formula (A) in solid form, its solvate or hydrate, the compound of formula (A) in crystalline form, its solvate or hydrate, the compound of formula (A) in crystal form, its solvate or hydrate, crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, crystal form VI, crystal form VII, or the above-described pharmaceutical composition, wherein the patient’s condition is a BTK-related condition.

[0198] In some embodiments of the present invention, the above-described method for treating a patient's condition includes BTK-related conditions such as tumors or autoimmune diseases; preferably, the tumor is a hematologic malignancy; more preferably, leukemia or lymphoma; more preferably, B-cell lymphoma; and even more preferably, mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, marginal zone lymphoma, follicular lymphoma, Waldenström macroglobulinemia, or diffuse large B-cell lymphoma.

[0199] Definitions and Explanations

[0200] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular phrase or term should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient.

[0201] The term "solvent" or "solvent compound" refers to an association formed by one or more solvent molecules with the compound of Formula 2 of this application, including associations containing both water molecules and one or more other solvent molecules.

[0202] The term "hydrate" refers to an associative compound formed by one or more water molecules and the compound shown in Formula 2 of this application.

[0203] The term "basically as shown" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% of the peaks in an X-ray powder diffraction pattern are displayed in its pattern; or in a DSC pattern, the error range of the onset or peak temperature of each endothermic or exothermic peak is within ±10°C, preferably within 5°C, more preferably within 3°C; or in a TGA pattern, the error range of the onset or end point of the weight loss temperature is within ±10°C, preferably within 5°C, more preferably within 3°C, and the weight loss percentage is within ±0.5%, preferably within ±0.3%, ±0.2%. Furthermore, as the content of a certain crystal form in the product gradually decreases, some diffraction peaks attributable to that crystal form in its powder X-ray diffraction pattern may decrease due to factors related to the instrument's detection sensitivity.

[0204] The term "characteristic diffraction peak" refers to a diffraction peak in an X-ray powder diffraction pattern that can be used to represent the crystal form. It is related to the peak position, peak shape, and relative peak intensity of the diffraction peak. For example, a small-angle peak with a sharp peak shape and a relative peak intensity of at least 2.9%, or at least 3%, or at least 5%, or at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 75%.

[0205] The term "tumor" includes benign tumors, malignant tumors, and borderline tumors, with malignant tumors collectively referred to as cancer.

[0206] The term "treatment" generally refers to achieving the desired pharmacological and / or physiological effects, including partially or completely stabilizing or curing a disease and / or effects resulting from the disease.

[0207] As used herein, “treatment” encompasses any treatment of a patient’s disease, including: (a) suppressing the symptoms of the disease, i.e., preventing its progression; or (b) alleviating the symptoms of the disease, i.e., causing the disease or symptoms to regress. The terms “effective amount” or “therapeutic effective amount” mean (i) the amount of the compound of this application used to treat a particular disease, or (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease.

[0208] The term "therapeutic effective amount" means the amount of a compound that, when administered to a patient for the treatment of a disease, is sufficient to achieve therapeutic effect on that disease. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the present disclosure.

[0209] The terms "pharmaceutical-grade carrier" or "pharmaceuticalally acceptable excipient" refer to carriers or excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound.

[0210] Unless otherwise specified, the "heating temperature", "cooling temperature" or "crystallization temperature" mentioned in this application are in °C or degrees Celsius, and the error range can be ±10, ±5, ±4, ±3, ±2 or ±1 °C.

[0211] The intermediate compounds of the present invention can be prepared by various synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0212] The chemical reactions in the specific embodiments of this invention are carried out in a suitable solvent, which must be suitable for the chemical changes of this invention and the reagents and materials required therefor. To obtain the compounds of this invention, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction flow based on existing embodiments.

[0213] The present invention will be described in detail below through embodiments, which are not intended to limit the present invention in any way.

[0214] All solvents used in this invention are commercially available and can be used without further purification.

[0215] The terminology used in this preparation method and in this invention is as follows:

[0216] DCM: Dichloromethane; DIAD: Diisopropyl azodicarbonate; DIPEA: Diisopropylethylamine; DMF: N,N-Dimethylformamide; EA: Ethyl acetate; HATU: 2-(7-benzotriazole oxide)-N,N,N',N'-Tetramethylurea hexafluorophosphate; NBS: N-bromosuccinimide; NIS: N-iodosuccinimide; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; Pd(PPh3)4: Tetra(triphenylphosphine)palladium; PdCl2: Palladium dichloride; Pd(OAc)2: Palladium acetate; Pd(PPh3)2Cl2: Bistriphenylphosphine palladium dichloride; PE: Petroleum ether; THF: Tetrahydrofuran; DMSO: Dimethyl sulfoxide.

[0217] Technical effect

[0218] The compound represented by formula (A) mentioned in this invention has good crystallinity, and the preferred crystal form has good stability, is easy to drug, and has high bioavailability. Compound (A) of this invention has excellent BTK inhibitory activity and maintains good BTK inhibitory selectivity, has excellent in vivo antitumor activity, and good oral administration performance. It can provide more effective treatment for diseases caused by abnormal BTK expression. Moreover, under the action of different species of liver microsomes (human liver microsomes, rat liver microsomes, and mouse liver microsomes), the types and proportions of metabolites are small, and the main product is basically the original drug (60min: 84%-98%), resulting in better metabolic stability.

[0219] 1.1 X-ray powder diffractometer (XRPD)

[0220] Instrument Model: PANalytical EMPYREAN X-ray Diffractometer

[0221] Test method: Approximately 1–2 mg of sample is used for XRPD detection.

[0222] The detailed XRPD parameters are as follows:

[0223] X-ray generator: Cu, Kα,

[0224] Phototube voltage: 45kV, Phototube current: 40mA

[0225] Scan range: 3°-40° (2θ)

[0226] Scan step size: 0.013°

[0227] Scan time: 20.4 seconds / step

[0228] Fluorescent tube type: Empyrean Cu LFF HR(94300337310x)DK 420877

[0229] Rotation time: 1s

[0230] Sample tray: Zero background sample tray

[0231] Data collection software: HighScore Data Collector

[0232] Analysis software: Jade 6.

[0233] 1.2 Differential Scanning Calorimeter (DSC)

[0234] Instrument Model: Discovery DSC 250 Differential Scanning Calorimeter

[0235] Test method: Take a sample (1-5 mg) and place it in the DSC sample tray. Cover the sample tray and make a hole. After the sample is equilibrated at 25°C, heat it to the final temperature at a heating rate of 10°C / min.

[0236] Sample amount: 1–5 mg

[0237] Type of gas flow: Nitrogen

[0238] Flow rate: 50 mL / min

[0239] Heating start temperature: 25℃

[0240] Termination temperature: 300℃.

[0241] 1.3 Thermogravimetric Analysis (TGA)

[0242] Instrument Model: Discovery TGA 55 Thermogravimetric Analyzer

[0243] Test method: Place the sample in a peeled open aluminum sample tray. After the sample mass is automatically weighed in the TGA heating furnace, heat the sample to the final temperature at a rate of 10℃ / min.

[0244] Sample amount: 1–5 mg

[0245] Type of gas flow: Nitrogen

[0246] Flow rate: 60 mL / min

[0247] Heating start temperature: 25~30℃

[0248] Termination temperature: 300℃.

[0249] 1.4 Dynamic Moisture Adsorption-Desorption Analysis (DVS)

[0250] Instrument Model: Vsorp-Enhanced Dynamic Water Vapor Adsorption Analyzer

[0251] Test method: Add a sufficient amount of sample into the instrument to simulate dynamic water vapor adsorption, and record the weight change at different humidity equilibrations at 25°C.

[0252] Based on the weight gain of the samples when reaching 80% RH during the adsorption process, the hygroscopicity of the samples is classified as follows:

[0253] (1) Deliquescence: It absorbs sufficient water to form a liquid.

[0254] (2) Highly hygroscopic: moisture absorption increases weight by no less than 15%.

[0255] (3) It is hygroscopic: the weight gain due to moisture absorption is less than 15% but not less than 2%.

[0256] (4) Slightly hygroscopic: Moisture absorption weight gain is less than 2% but not less than 0.2%.

[0257] (5) Non-hygroscopic: moisture absorption weight gain is less than 0.2%.

[0258] 1.4.1 Test parameters for crystal form I:

[0259] Sample weight: 96.821 mg

[0260] Sample temperature: 25℃

[0261] Cycle time: 10 min

[0262] 1.4.2 Test parameters for crystal form II:

[0263] Sample weight: 117.086 mg

[0264] Sample temperature: 25℃

[0265] Cycle time: 10 min

[0266] 1.5 High Performance Liquid Chromatography (HPLC)

[0267] Instrument Model: Agilent HPLC 1260 High Performance Liquid Chromatograph

[0268] Chromatographic column: CORTECS C18, 4.6*150mm, 2.7μm

[0269] Test conditions: wavelength 230nm; column temperature 30℃

[0270] 1.6 Nuclear Magnetic Resonance Spectroscopy (NMRS)

[0271] Instrument Model: Bruker AVANCE III HD 300 / 400

[0272] Contents and test solvents: 1 H-NMR, the test solvent was DMSO-d6. Attached Figure Description

[0273] Figure 1 X-ray powder diffraction pattern of crystal form VII in Example 1.

[0274] Figure 2DSC-TGA spectrum of crystal form VII in Example 1.

[0275] Figure 3 X-ray powder diffraction pattern of crystal form I in Example 2.

[0276] Figure 4 DSC-TGA spectrum of crystal form I in Example 2.

[0277] Figure 5 X-ray powder diffraction pattern of crystal form II in Example 4.

[0278] Figure 6 DSC-TGA spectrum of crystal form II in Example 4.

[0279] Figure 7 X-ray powder diffraction pattern of crystal form III in Example 5.

[0280] Figure 8 DSC-TGA spectrum of crystal form III in Example 5.

[0281] Figure 9 X-ray powder diffraction pattern of crystal form IV in Example 6.

[0282] Figure 10 DSC-TGA spectrum of crystal form IV in Example 6.

[0283] Figure 11 X-ray powder diffraction pattern of crystal form V in Example 7.

[0284] Figure 12 X-ray powder diffraction pattern of crystal form VI in Example 8.

[0285] Figure 13 DSC-TGA spectrum of crystal form VI in Example 8.

[0286] Figure 14 DVS diagram of crystal form I in Example 2.

[0287] Figure 15 DSC-TGA spectrum of crystal form V in Example 7.

[0288] Figure 16 : Schematic diagram of experimental results of REC-1 xenograft tumor model.

[0289] Figure 17 Schematic diagram of experimental results of the TMD8 xenograft tumor model.

[0290] Figure 18 XRPD superposition diagrams before and after grinding of crystal form I. Detailed Implementation

[0291] To better understand the content of this invention, further explanation will be provided below with reference to specific embodiments. However, the specific implementation methods are not intended to limit the content of this invention.

[0292] Preparation Example 1: Preparation of Compound (A)

[0293] 1. Synthesis of intermediate 3

[0294]

[0295] In a 250 mL round-bottom flask, add 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (starting material 2, 17.28 g, 1 eq) and anhydrous potassium carbonate (2 eq), and dry under vacuum to remove water. Add dried DMF as a solvent, along with pulverized (S)-methanesulfonic acid 2-((tert-butoxycarbonyl)amino)-but-3-en-1-yl ester (starting material 1, 24.6 g, 1.5 eq), and replace with nitrogen. Heat and stir at 55 °C for 12 hours; the time can be extended appropriately to ensure complete reaction.

[0296] After the reaction was complete, the mixture was extracted three times with water and ethyl acetate. The ester layers were combined, back-extracted once with water, and washed with saturated brine. The solution was dried over anhydrous sodium sulfate. Dry column chromatography (eluent: CHCl3:MeOH = 100:1, v / v) yielded the product (S)-(1-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate (intermediate 3, 19.28 g), with a yield of 69.5%.

[0297] 1 H NMR (300MHz, CDCl3) δ8.60 (s, 1H), 7.39 (s, 1H), 5.82 (ddd, J = 17.1, 10.5, 5.5Hz, 1H), 5.33- 5.14(m,2H),4.80(s,1H),4.63-4.51(m,1H),4.51-4.42(m,1H),4.35(s,1H),1.33(s,9H). ee>99.5%.

[0298] 2. Synthesis of intermediate 4

[0299]

[0300] Add (S)-(1-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)tert-butyl carbamate (intermediate 3,9.2 g) to a 350 mL pressure-resistant tube, add 1,4-dioxane (40 mL) as a solvent, and add ammonia (40 mL). Seal and react at 120 °C for 2.5 hours.

[0301] After the reaction was complete, the mixture was cooled to room temperature, extracted with water and ethyl acetate, and the ester layers were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate. Dry column chromatography (eluent: CHCl3:MeOH = 30:1) yielded the product (S)-(1-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate (intermediate 4, 6.86 g), with a yield of 78.0%.

[0302] 1 H NMR(300MHz, CDCl3)δ8.25(s,1H),7.05(s,1H),5.87-5.74(m,1H),5.72(s,2H),5.34-5.1 3(m,3H),4.56-4.43(m,1H),4.34(dd,J=14.8,4.9Hz,1H),4.30-4.15(m,1H),1.35(s,9H). ee>99.5%.

[0303] 3. Synthesis of intermediate 6

[0304]

[0305] In a 1 L round-bottom flask, add (S)-(1-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate (intermediate 4,32.9 g, 1 eq), N-(pyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzamide (starting material 5,34.8 g, 1.4 eq) and tetra(triphenylphosphine)palladium (17.7 g, 0.2 eq). Add 1,4-dioxane (383 mL) as a solvent and replace N2. Add 2 M sodium carbonate solution (76.6 mL) with stirring. Reflux and stir at 90 °C for 5 hours.

[0306] Extracted with water and ethyl acetate, the ester layers were combined and washed with saturated brine. The product was dried over anhydrous sodium sulfate. Dry column chromatography was performed, first using EA as the eluent to remove most impurities, then using a mixture of CHCl3:MeOH = 30:1 as the eluent. The product may contain small amounts of impurities, which can be precipitated by recrystallization from PE to obtain the pure product. Tert-butyl (S)-(1-(4-amino-5-(4-(pyridin-2-ylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate (intermediate 6, 28.4 g) was obtained in 74.3% yield.

[0307] 4. Synthesis of intermediate 7

[0308]

[0309] In a 1 L round-bottom flask, add (S)-(1-(4-amino-5-(4-(pyridin-2-ylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)tert-butyl carbamate (intermediate 6, 32.7 g, 1 eq) and 600 mL of DMF as solvent. Slowly add N-bromosuccinimide (12.8 g, 1.1 eq) with stirring, and stir overnight at room temperature.

[0310] After the reaction was complete, water and ethyl acetate were added for extraction. The ester layers were combined, back-extracted once with water, and washed with saturated brine. The solution was dried over anhydrous sodium sulfate. Dry column chromatography was performed, first using a mixture of CHCl3:MeOH = 50:1 as the eluent, then changing to a mixture of CHCl3:MeOH = 30:1 as the eluent. The product (S)-(1-(4-amino-6-bromo-5-(4-(pyridin-2-ylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)tert-butyl carbamate (intermediate 7, 25.8 g) was obtained, with a yield of 68.2%.

[0311] 5. Synthesis of intermediate 8

[0312]

[0313] In a 250 mL round-bottom flask, add (S)-(1-(4-amino-6-bromo-5-(4-(pyridin-2-ylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)tert-butyl carbamate (intermediate 7, 11.9 g, 1 eq) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (1.66 g, 0.11 eq). Add 51 mL of THF as solvent and purge with nitrogen gas several times to ensure complete removal. Add 8.2 mL of 4 M sodium hydroxide solution while stirring. Reflux and stir at 85 °C for 15 hours.

[0314] After the reaction was complete, water and ethyl acetate were added for extraction. The combined ester layers were washed with saturated brine. The mixture was dried over anhydrous sodium sulfate. Dry column chromatography (eluent: CHCl3:MeOH = 30:1) yielded the product (S)-(4-amino-6-methylene-5-(4-(pyridin-2-ylcarbamoyl)phenyl)-7,8-dihydro-6H-pyrimidino[5,4-b]pyrrin-7-yl)carbamate tert-butyl ester (intermediate 8, 8.79 g), with a yield of 85.9%.

[0315] 6. Synthesis of Compound A

[0316]

[0317] In a 250 mL round-bottom flask, (S)-(4-amino-6-methylene-5-(4-(pyridin-2-ylcarbamoyl)phenyl)-7,8-dihydro-6H-pyrimido[5,4-b]pyrrin-7-yl)tert-butyl carbamate (intermediate 8, 2.75 g, 1 eq) was added, along with 110 mL of DCM as solvent. Trifluoroacetic acid (10.5 mL) was added dropwise with stirring. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was directly evaporated to dryness, and the trifluoroacetic acid was carried out several times with methanol. After evaporation to dryness, the crude product with de-Boc protection was obtained and directly added to the next step.

[0318] The product from the previous step was transferred to a 250 mL round-bottom flask, and triethylamine (1 eq) was added. After stirring for five minutes, 2-butynedic acid (0.511 g, 1.1 eq) and 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.31 g, 1.1 eq) were added, along with 100 mL of DCM as solvent. The mixture was cooled to 0 °C in an ice-water bath, and triethylamine (1.54 mL + 0.77 mL) was added dropwise. The mixture was gradually heated to room temperature and stirred at room temperature for 1.5 hours. The reaction solution was pale yellow. The mixture was extracted with water and DCM, and the organic phases were combined and washed with saturated brine. The solution was dried over anhydrous sodium sulfate and subjected to column chromatography (CHCl3:MeOH = 30:1) to give the final product, compound A (1.88 g), with a yield of 73.3%.

[0319] 1H NMR(400MHz, CDCl3)δ8.98(s,1H),8.43(dt,J=8.3,1.0Hz,1H),8.34(ddd,J=5.0,1.9,0.9Hz,1H), 8.22(s,1H),8.09-8.03(m,2H),7.81(ddd,J=8.4,7.4,1.9Hz,1H),7.69-7.63(m,2H),7.13(ddd,J= 7.4,4.9,1.0Hz,1H),6.55(d,J=8.2Hz,1H),5.67(m,J=8.1,5.7,2.6Hz,1H),5.56(d,J=2.3Hz,1H) ,5.40(s,2H),5.27(d,J=2.3Hz,1H),4.70(dd,J=11.7,8.1Hz,1H),4.09-3.99(m,1H),1.99(s,3H).

[0320] Example 1: Preparation of crystal form VII of compound (A)

[0321] At room temperature, approximately 20 mg of the sample from Preparation Example 1 was weighed and added to a glass bottle of suitable volume. Dichloromethane (0.5 mL) was added, and the bottle was sealed with a sealing film. The mixture was stirred for 3 days, and the solid was obtained by filtration. X-ray powder diffraction of the sample revealed a crystalline solid (crystal type VII). The spectrum is shown in the attached image. Figure 1 The XRPD diffraction peak data are shown in Table 1. 1H-NMR analysis of the sample revealed approximately 10% dichloromethane. DSC-TGA analysis of the sample showed two endothermic peaks with onset temperatures of 47.52℃ and 151.56℃, and peak temperatures of 74.24℃ and 156.63℃, respectively. The TGA analysis showed an 8.053% weight loss between room temperature and 150℃ (see attached table). Figure 2 .

[0322] Table 1. XRPD diffraction peak data for crystal form VII in Example 1

[0323] Peak position (2 theta) Relative intensity % Peak position (2 theta) Relative intensity % Peak position (2 theta) Relative intensity % 5.705 100 15.146 5.4 21.829 11.1 7.517 7.2 16.247 3.0 22.472 2.2 9.894 2.2 17.417 10.1 23.300 4.0 10.787 40.5 18.033 5.9 25.059 5.7 11.587 7.0 18.729 3.2 26.859 1.9 12.481 9.2 19.674 2.7 29.222 2.0 12.875 2.9 20.037 3.0 29.642 2.6 13.477 1.6 20.463 2.5 30.913 1.0 14.449 2.9 20.905 1.6 14.699 5.4 21.316 2.9

[0324] Example 2: Preparation of crystal form I of compound (A)

[0325] At room temperature, 20 mg of the sample from Preparation Example 1 was weighed and added to a glass bottle of suitable volume. A total volume of 0.8 mL of a heptane / toluene mixed solvent (V / V = 1 / 1) was added, and the bottle was sealed with a sealing film. The mixture was stirred for 3 days, and the solid was obtained by filtration. X-ray powder diffraction of the sample showed it to be a crystalline solid (crystal type I, no crystal type) with good crystallinity. The spectrum is shown in the attached image. Figure 3The XRPD diffraction peak data are shown in Table 2. DSC-TGA testing was performed on the sample. The DSC plot showed an exothermic peak starting at 272.89℃, with a peak temperature of 274.74℃ (see attached figure). Figure 4 .

[0326] Table 2. XRPD diffraction peak data for crystal form I in Example 2.

[0327]

[0328]

[0329] Example 3: Preparation of crystal form I of compound (A)

[0330] At room temperature, 20 mg of the sample from Preparation Example 1 was weighed and added to a glass bottle of suitable volume. Ethyl acetate (0.5 mL) was added, and the bottle was sealed with sealing film and stirred for 3 days. The solid was obtained by filtration. X-ray powder diffraction of the sample showed that it was crystal form I.

[0331] Example 4: Preparation of crystal form II of compound (A)

[0332] Approximately 20 mg of crystal form VII was weighed and added to a glass bottle of suitable volume. Water (0.5 mL) was added, and the bottle was sealed with sealing film. The mixture was then stirred at room temperature for 3 days, and the solid was obtained by filtration. X-ray powder diffraction of the sample showed that it was a crystalline solid (crystal form II) with good crystallinity. The spectrum is shown in the attached image. Figure 5 The XRPD diffraction peak data are shown in Table 3. DSC-TGA tests were performed on the sample. The DSC plot showed three endothermic peaks with onset temperatures of 49.26℃, 84.59℃, and 168.35℃, and peak temperatures of 69.36℃, 98.45℃, and 176.96℃, respectively. The TGA plot showed a 3.417% weight loss between room temperature and 100℃ (see attached figure). Figure 6 .

[0333] Table 3. XRPD diffraction peak data for crystal form II in Example 4.

[0334] Peak position (2 theta) Relative intensity % Peak position (2 theta) Relative intensity % Peak position (2 theta) Relative intensity % 4.260 18.8 18.010 28.3 26.320 33.7 5.201 4.2 18.245 18.2 28.026 6.4 5.201 4.2 19.136 14.3 28.396 2.5 6.965 29.6 20.724 4.4 29.115 4.7 7.858 27.3 20.871 7.7 30.680 11.2 8.514 96.2 21.264 16.1 30.953 5.9 10.589 83.8 22.117 49.3 31.854 3.1 11.508 14.4 23.235 6.7 32.436 2.5 12.847 11.5 23.525 5.1 32.885 2.9 14.133 9.4 23.807 3.8 34.800 2.7 15.041 100.0 25.110 13.9 35.720 4.3 15.843 3.6 25.349 49.7 37.546 3.4 17.101 28 25.833 9.5 39.565 4.2

[0335] Example 5: Preparation of crystal form III of compound (A)

[0336] Crystal form II was dried in a vacuum drying oven at 40℃ for 12 hours to obtain a solid. X-ray powder diffraction of the sample showed it to be a crystalline solid (crystal form III, not crystal form), with good crystallinity. The spectrum is attached. Figure 7The XRPD diffraction peak data are shown in Table 4. Heating crystal form III to 160℃ followed by X-ray powder diffraction did not alter its XRPD spectrum. DSC-TGA analysis of the sample revealed three endothermic peaks with onset temperatures of 38.13℃, 75.07℃, and 167.19℃, and peak temperatures of 57.40℃, 96.32℃, and 177.55℃, respectively. The TGA spectrum showed a 3.075% weight loss before 90℃ (see attached table). Figure 8 .

[0337] Table 4. XRPD diffraction peak data for crystal form III in Example 5.

[0338]

[0339]

[0340] Example 6: Preparation of crystal form IV of compound (A)

[0341] Approximately 20 mg of the sample from Preparation Example 1 was weighed and added to a glass bottle of suitable volume. Methanol (0.3 mL) was added, and the bottle was sealed with a sealing film. The mixture was stirred at room temperature until a large amount of solid precipitated, then filtered. X-ray powder diffraction of the sample revealed it to be a crystalline solid (crystal type IV) with good crystallinity. The spectrum is shown in the attached image. Figure 9 The XRPD diffraction peak data are shown in Table 5. DSC-TGA analysis was performed on the sample. The DSC plot showed two endothermic peaks with onset temperatures of 45.75℃ and 159.89℃, and peak temperatures of 70.65℃ and 166.96℃, respectively. The TGA plot showed a 7.863% weight loss between room temperature and 200℃ (see attached figure). Figure 10 .

[0342] Table 5. XRPD diffraction peak data for crystal form IV in Example 6.

[0343] Peak position (2 theta) Relative intensity % Peak position (2 theta) Relative intensity % Peak position (2 theta) Relative intensity % 5.061 14.1 19.005 16.4 26.319 11.7 6.322 44.7 20.357 12.7 26.742 2.7 9.657 52.2 21.934 9.8 27.473 3.8 11.649 4.4 23.234 15.9 29.263 3.9 12.769 100.0 23.785 6.9 32.439 2.9 14.095 17.5 24.127 5.1 37.220 1.7 15.631 9.5 25.059 5.6 17.797 5.6 25.780 4.5

[0344] Example 7: Preparation of crystal form V of compound (A)

[0345] Crystal form IV was dried in a vacuum drying oven at 40℃ for 12 hours to obtain a solid. X-ray powder diffraction of the sample showed it to be a crystalline solid (crystal form V, no crystal form) with good crystallinity. The spectrum is attached. Figure 11 The sample was subjected to DSC-TGA testing. The DSC plot showed two endothermic peaks, with onset temperatures of 36.14℃ and 166.61℃, and peak temperatures of 65.23℃ and 174.53℃, respectively. The TGA plot showed a weight loss of 0.874% between room temperature and 280℃. (See attached figure) Figure 15The XRPD diffraction peak data are shown in Table 6.

[0346] Table 6. XRPD diffraction peak data for crystal form V in Example 7.

[0347] Peak position (2 theta) Relative intensity % Peak position (2 theta) Relative intensity % Peak position (2 theta) Relative intensity % 4.432 6.7 13.396 4.1 22.406 6.6 5.114 7.1 13.781 40.6 23.232 5.2 5.613 86.7 14.279 100.0 23.431 8.8 6.335 3.0 16.997 12.6 25.191 8.3 7.109 37.6 17.339 2.8 25.833 5.3 8.501 1.7 17.902 8.3 26.581 2.6 8.895 10.9 18.323 11.8 27.172 8.9 9.564 7.0 19.125 11.4 28.104 2.0 10.670 2.9 19.466 2.4 28.459 1.9 11.299 20.2 19.871 1.6 29.335 1.7 11.508 36.9 20.713 11.6 32.343 1.5 12.732 6.7 21.908 19

[0348] Example 8: Preparation of crystal form VI of compound (A)

[0349] Approximately 20 mg of the sample from Preparation Example 1 was weighed and added to a glass bottle of suitable volume. Ethylene glycol (0.5 mL) was added, and the bottle was sealed with sealing film. The mixture was then stirred at room temperature for 3 days, and the solid was obtained by filtration. X-ray powder diffraction of the sample revealed it to be a crystalline solid (crystal type VI) with good crystallinity. The spectrum is shown in the attached image. Figure 12 The XRPD diffraction peak data are shown in Table 7. DSC-TGA tests were performed on the sample. The DSC plot showed two endothermic peaks with onset temperatures of 45.54℃ and 163.80℃, and peak temperatures of 86.78℃ and 165.61℃, respectively. The TGA plot showed a weight loss of 3.153% between room temperature and 120℃, and a weight loss of 1.500% between 120℃ and 180℃. (See attached table). Figure 13 .

[0350] Table 7. XRPD diffraction peak data for crystal form VI in Example 8.

[0351] Peak position (2 theta) Relative intensity % Peak position (2 theta) Relative intensity % Peak position (2 theta) Relative intensity % 4.984 11.5 20.385 2.1 29.560 1.1 6.217 35.8 21.409 23.9 30.849 3.2 9.407 100.0 23.247 7.3 31.882 0.9 10.075 3.2 23.509 10.1 32.377 0.6 11.615 1.2 24.745 10 34.078 0.7 12.547 65.6 25.360 4.1 34.485 1.9 13.766 1.6 25.992 4.8 35.744 0.5 14.041 5.2 26.516 1.0 36.757 1.0 15.212 22.3 27.121 1.1 37.180 1.2 17.601 2.9 27.856 1.7 37.534 1.2 18.547 6.6 28.330 0.7 38.568 0.9 18.796 6.6 28.840 1.3 19.175 0.6 29.288 0.7

[0352] Experimental Example 1: Solid stability test of compound (A) in crystal forms I and II

[0353] The stability of compound (A) crystal form I and crystal form II was investigated after 7 days under high humidity (40°C / 75% RH, open) conditions.

[0354] Weigh out 5 mg each of crystal form I and crystal form II of compound (A) and place them at the bottom of the sample vial, spreading them into a thin layer. Samples were taken for testing on day 7, and the results were compared with the initial test results from day 0. The experimental results are shown in Table 8 below:

[0355] Table 8 shows the solid stability test results for crystal forms I and II of compound (A).

[0356]

[0357] "RH": Relative humidity.

[0358] Conclusion: Both crystal form I and crystal form II of compound (A) have good stability.

[0359] Experimental Example 2: Study on the hygroscopicity of crystal form I of compound (A)

[0360] Approximately 97 mg of crystal form I of compound (A) from Example 2 was placed in the DVS sample chamber for testing. The DVS-treated sample was then subjected to X-ray powder diffraction.

[0361] Experimental results:

[0362] The DVS spectrum of compound (A) crystal form I is shown below. Figure 14 As shown.

[0363] The hygroscopic weight gain of compound I of formula (A) is 0.9% at 25°C and 80% RH and 1.0% at 25°C and 90% RH, indicating slight hygroscopicity. The crystal form did not change after DVS.

[0364] Experiment Example 3: Grinding Test

[0365] A suitable amount of crystal form I (Example 2, approximately 10 mg) was placed in a mortar and ground for about 5 minutes. The solid was then collected for X-ray powder diffraction. See the XRPD superposition images of crystal form I before and after grinding. Figure 18 .

[0366] Conclusion: The crystal form did not change after grinding, indicating that crystal form I can remain stable during machining.

[0367] Experiment Example 4: Evaluation of Bruton's Kinase (BTK) Molecular-Level Enzyme Activity Inhibition

[0368] The enzyme reaction substrate Poly(Glu,Tyr) 4:1 Dilute the substrate in potassium-free PBS (10 mM sodium phosphate buffer, 150 mM NaCl, pH 7.2-7.4) to a concentration of 20 μg / mL and coat the microplate. Incubate at 37°C for 12-16 hours. Wash the plate three times with 200 μL / well of T-PBS (PBS containing 0.1% Tween-20) and dry in a 37°C oven for 1-2 hours. To the microplate coated with the above substrate, first add 49 μL / well of ATP solution diluted with reaction buffer (50 mM HEPES pH 7.4, 50 mM MgCl2, 0.5 mM MnCl2, 0.2 mM Na3VO4, 1 mM DTT) (final concentration 5 μM). Add 1 μL of the test compound (compound well) or DMSO of the appropriate concentration (negative control well) to each well. An enzyme-free control well is required for each experiment. Add 50 μL of BTK tyrosine kinase protein diluted with reaction buffer to initiate the reaction.

[0369] The above reaction system was placed in a shaker (100 rpm) at 37°C for 1 hour, then washed three times with T-PBS. 100 μL of primary antibody PY99 (Santa Cruz) was added to each well, and the plate was incubated at 37°C for 0.5 hours with shaking. After washing with T-PBS, 100 μL of horseradish peroxidase-labeled goat anti-mouse secondary antibody dilution was added to each well, and the plate was incubated at 37°C for 0.5 hours with shaking. After washing with T-PBS, 100 μL of 2 mg / mL OPD chromogenic solution was added to each well, and the plate was incubated at 25°C in the dark for 1-10 minutes. The reaction was then stopped by adding 50 μL of 2 M H2SO4 to each well. The plate was read using a SPECTRA MAX Plus 384 microplate reader at a wavelength of 490 nm.

[0370] Compounds S1, S10, ibrutinib, acalatinib, S18s, S19s, and S20s were used as positive control compounds. Compounds S1, S10, S18s, S19s, and S20s were prepared using methods disclosed in existing technologies (e.g., CN108101905A) or similar methods. Ibrutinib and acalatinib were purchased from Selleck.

[0371] The inhibition rate of each compound was obtained using the following formula:

[0372]

[0373] IC 50 The values ​​were obtained using a four-parameter regression method with the software that came with the microplate reader. The results are listed in Table 9 below.

[0374] Table 9. Inhibitory effects of different compounds on BTK

[0375] Compound IC 50 (nM) S1 ～1 S10 <10 Ibrutinib ～1 Alectinib ～10 S18s ～1 S19s ～1 S20s ～1 Compound A 0.5

[0376] Note: Sample from Preparation Example 1 was used for testing.

[0377] The above results indicate that compound A exhibits superior inhibitory activity against BTK compared to previous compounds S1, S10, S18s, S19s, and S20s, and is also superior to the currently marketed first-generation BTK inhibitor ibrutinib and second-generation BTK inhibitor acalabrutinib.

[0378] Experimental Example 5: Detection of the in vitro proliferation inhibitory activity of the compound against human B-lymphoma cells Ramos (Burkitt lymphoma) and human diffuse large B-lymphoma cells TMD8.

[0379] Cell suspensions (Ramos: 10,000 cells / well; TMD8: 12,000 cells / well) were seeded into 96-well plates and incubated at 37°C for 2 hours until cell stabilization. Different concentrations of the test compound were added to each well (three replicates per concentration). Blank control (wells containing only culture medium, no cells), negative control (wells containing only cells, no compound), and positive compound control were also included. After 72 hours of treatment, 20 μL of MTT (5 mg / mL) was added to each well and incubated at 37°C for 4 hours. Then, 100 μL of triplet solution (10% SDS, 5% isobutanol, 0.01 M HCl) was added, and the plate was incubated overnight at 37°C. OD values ​​were measured at 570 nm using a SPECTRAmax Plus 384 microplate reader.

[0380] The inhibition rate of the compound was obtained using the following formula:

[0381]

[0382] IC 50 The values ​​were obtained using a four-parameter regression method with the software that came with the microplate reader. The experiment was independently repeated three times, and the results are listed in Table 10 below.

[0383] Similarly, the compounds S1, S10, ibrutinib, acalatinib, S18s, S19s, and S20s mentioned above were used as positive control compounds.

[0384] Table 10. Inhibitory activity of different compounds on the proliferation of Ramos cells and TMD8 cells.

[0385]

[0386]

[0387] The above results indicate that, at the cellular level, compound A exhibits superior inhibitory activity against B-cell lymphoma proliferation compared to previous compounds S1, S10, S18s, S19s, and S20s, and also surpasses the currently marketed first-generation BTK inhibitor ibrutinib and second-generation BTK inhibitor acalabrutinib. Furthermore, compared to other compounds, compound A of this invention demonstrates higher inhibitory activity against Ramos cells and even higher inhibitory activity against TMD8 cells.

[0388] Experimental Example 6: Evaluation of in vivo antitumor activity

[0389] Laboratory animals:

[0390] TMD8 xenograft model

[0391] 1) Species: Mouse

[0392] 2) Strain: CB-17SCID

[0393] 3) Age and weight: 6-8 weeks; 18-22g

[0394] 4) Sex: Female

[0395] 5) Supplier: Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0396] REC-1 xenograft tumor model

[0397] 1) Species: Mouse

[0398] 2) Strain: BALB / c nude mice

[0399] 3) Age and weight: 6-8 weeks; 17-20g

[0400] 4) Sex: Female

[0401] 5) Supplier: Shanghai Lingchang Biotechnology Co., Ltd.

[0402] Cell culture: Human lymphoma TMD8 cells were cultured in suspension in vitro under the following conditions: RPMI 1640 medium (supplier: Gibco; catalog number: 22400-089; batch number: 4868546) supplemented with 10% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin, at 37°C with 5% CO2. Routine passages were performed twice a week. When cell saturation reached 80%-90%, cells were harvested, counted, and seeded.

[0403] Human mantle cell lymphoma REC-1 cells were cultured in suspension in vitro under the following conditions: RPMI 1640 medium (supplier: Gibco; catalog number: 22400-089; batch number: 1868795) supplemented with 10% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin, at 37°C with 5% CO2. Routine passages were performed twice a week. When cell saturation reached 80%-90%, cells were harvested, counted, and seeded.

[0404] Tumor cell inoculation: 0.2 mL of 10 × 10⁻⁶ cells was inoculated. 6 Individual TMD8 lymphoma cells were subcutaneously inoculated into the right posterior dorsal region of each nude mouse (PBS:Matrigel = 1:1). The average tumor volume reached 104 mm. 3 The mice were grouped and administered the drug at the designated time. They were randomly assigned to groups of six mice each using an Excel-based randomization software program based on tumor volume.

[0405] Add 0.2 mL of 5×10 6REC-1 cells were subcutaneously inoculated into the right posterior dorsal region of each nude mouse (PBS:Matrigel = 1:1). The average tumor volume reached 100 mm. 3 The mice were grouped and administered the drug at the designated time. They were randomly assigned to groups of six mice each using an Excel-based randomization software program based on tumor volume.

[0406] Preparation of the test substance:

[0407] The preparation methods for the test substances are shown in Tables 11 and 12 below:

[0408] Table 11 Preparation methods of test subjects for TMD8 xenograft tumor models

[0409]

[0410] Note: ① Samples should be prepared and used immediately. After preparation, they should be stored at 4°C. Before administering the drug to animals, the drug should be gently and thoroughly mixed. Administration method: gavage; administration volume: 10 μL / g; ② Samples prepared in Example 1 should be used for testing.

[0411] Table 12 Preparation methods of test substances for REC-1 xenograft tumor model

[0412]

[0413] Note: ① Samples should be prepared and used immediately. After preparation, they should be stored at 4°C. Before administering the drug to animals, the drug should be gently and thoroughly mixed. Administration method: gavage; administration volume: 10 μL / g; ② Samples prepared in Example 1 should be used for testing.

[0414] Routine observation of laboratory animals: The formulation of this experimental protocol and any modifications thereof have been evaluated and approved by the Laboratory Animal Management and Use Committee (IACUC) of WuXi AppTec Co., Ltd. The use and welfare of laboratory animals are conducted in accordance with the regulations of the International Committee for Evaluation and Accreditation of Laboratory Animals (AAALAC). Animal health and mortality are monitored daily. Routine examinations include observing the effects of tumor growth and drug treatment on daily behavior, such as activity levels, food and water intake (visual assessment only), weight changes (measured three times per week), physical appearance, or other abnormalities. The number of deaths and side effects within each group are recorded based on the number of animals in each group.

[0415] Tumor measurement and experimental indicators: Experimental indicators are used to examine whether tumor growth has been inhibited, slowed, or cured. Tumor diameter is measured three times a week using calipers.

[0416] The formula for calculating tumor volume is:

[0417] V = 0.5a × b 2 ,

[0418] a and b represent the long and short diameters of the tumor, respectively.

[0419] The antitumor efficacy of the compounds was evaluated using TGI (%) or relative tumor proliferation rate (T / C) (%). TGI (%) reflects the tumor growth inhibition rate.

[0420] Calculation of TGI (%):

[0421] TGI (%) = [1 - (mean tumor volume at the end of treatment - mean tumor volume at the start of treatment) / (mean tumor volume at the end of treatment in the solvent control group - mean tumor volume at the start of treatment in the solvent control group)] × 100%.

[0422] Relative tumor proliferation rate T / C (%): The calculation formula is as follows:

[0423] T / C% = T RTV / C RTV ×100% (T) RTV : Relative tumor volume in the treatment group; C RTV (Negative control group relative tumor volume). The relative tumor volume (RTV) is calculated based on the tumor measurement results, using the formula RTV = V. t / V0, where V0 is the average tumor volume measured at the time of grouped drug administration (i.e., d0), V t T represents the average tumor volume at a given measurement. RTV With C RTV Take data from the same day.

[0424] Statistical analysis: Statistical analysis included the mean and standard error (SEM) of tumor volume at each time point for each group. The treatment groups showed the best treatment outcomes on day 15 (REC-1 xenograft model) and day 17 (TMD8 xenograft model) after drug administration; therefore, statistical analysis was performed based on this data to assess differences between groups. One-way ANOVA was used for comparisons among three or more groups, and the Games-Howell test was used if a statistically significant difference was found. All data were analyzed using SPSS 17.0. A p-value < 0.05 was considered statistically significant.

[0425] The in vivo efficacy of compound A in a human mantle cell lymphoma REC-1 xenograft model is shown in Table 13. Figure 16 As shown. Fifteen days after the start of drug administration, the tumor volume in the solvent control group of tumor-bearing mice reached 3501 mmHg. 3 Compared with the solvent control group, the ibrutinib 25 mg / kg group showed significant tumor-suppressing activity (T / C = 38%, TGI = 64%, p = 0.008), with a tumor volume of 1323 mmHg. 3The tumor volumes in the 15 mg / kg and 30 mg / kg groups of compound A were 1034 and 680 mm, respectively. 3 Compared with the solvent control group, it showed significant antitumor effects (T / C values ​​were 30% and 19%, TGI values ​​were 73% and 83%, p = 0.004 and 0.003, respectively).

[0426] Table 13 Evaluation of the antitumor efficacy of compound A in the REC-1 xenograft tumor model (based on tumor volume calculated on day 15 after administration).

[0427]

[0428] Note: a. Mean ± SEM; b. Tumor growth inhibition is determined by T / C and TGI (TGI(%) = [1-(T...). 15 -T0) / (V 15 Calculated using [-V0)]×100); cp value calculated based on tumor volume; d. Administration method: once daily; e. Detection using sample from Preparation Example 1.

[0429] The in vivo efficacy of compound A in a human TMD8 xenograft model of lymphoma is shown in Table 14. Figure 17 As shown. Seventeen days after the start of drug administration, the tumor volume in the solvent control group of tumor-bearing mice reached 1852 mmHg. 3 Compared with the solvent control group, the ibrutinib 25 mg / kg group showed a significant tumor-suppressing effect (T / C = 35.68%, TGI = 68.18%, p < 0.001), with a tumor volume of 661 mm. 3 The tumor volumes of compound A at 5 mg / kg and 10 mg / kg were 912 and 553 mm, respectively. 3 Compared with the solvent control group, it showed significant antitumor activity (T / C values ​​were 49.27% ​​and 29.85%, respectively, TGI values ​​were 53.78% and 74.35%, respectively, p = 0.003 and < 0.001).

[0430] Table 14 Evaluation of the antitumor efficacy of compound A in the TMD8 xenograft model (based on tumor volume calculated on day 17 after administration).

[0431]

[0432] Note: a. Mean ± SEM; b. Tumor growth inhibition is determined by T / C and TGI (TGI(%) = [1-(T...). 17 -T0) / (V 17 Calculated using [-V0)]×100); cp value calculated based on tumor volume; d. Administration method: once daily; e. Detection using sample from Preparation Example 1.

[0433] The results showed that in two BTK-sensitive mouse xenograft models, compound A had significant tumor growth inhibitory activity, which was significantly better than ibrutinib, the first-generation BTK inhibitor currently on the market.

[0434] In addition, the above experiments in the human lymphoma TMD8 xenograft model were repeated using compound S18s, and the T / C (%) results are listed in the table below. The T / C (%) results for compound A are also listed in the table below for comparison.

[0435] Table 15. Antitumor effects of compounds A and S18 on the TMD8 xenograft model.

[0436]

[0437] Note: Dosage method: once daily.

[0438] The data above show that at a lower dose (10 mg / kg), compound A exhibits better tumor growth inhibition than compound S18s (15 mg / kg).

[0439] Experimental Example 7: Evaluation of Pharmacokinetic Properties in Rats

[0440] Fourteen male SD rats, weighing 200-220g, were randomly divided into four groups of four (n=3 per group). The test compound was administered via gavage and intravenously, respectively. The specific arrangements are shown in Table 16 below.

[0441] Table 16 Administration methods for test compounds

[0442]

[0443] Note: Samples from Preparation Example 1 were used for testing. For oral administration, a solution containing 1% Tween 80 in 0.5% sodium carboxymethyl cellulose (CMC-Na) was prepared to a drug concentration of 0.3 mg / mL; for intravenous administration, a solution containing 5% DMSO / 5% Tween 80 / 90% physiological saline was prepared to a drug concentration of 0.2 mg / mL.

[0444] Fast for 12 hours before the experiment, but drink water freely. Eat 2 hours after administration of medication.

[0445] Blood collection time and sample processing:

[0446] Gavage administration: 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hours after administration;

[0447] Intravenous administration: 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hours after administration;

[0448] At the above-mentioned time points, 0.3 mL of venous blood was collected from the posterior venous plexus of rats, placed in heparinized test tubes, centrifuged at 11,000 rpm for 5 minutes, and the plasma was separated and frozen at -20°C.

[0449] Sample testing and data analysis

[0450] The concentration of compound A in rat plasma was determined by LC / MS / MS.

[0451] Pharmacokinetic parameters after dosing were calculated using a non-compartmental model with WinNonlin 5.3 software (Pharsight, Inc., USA).

[0452] Peak concentration C max Peak Time T max These are measured values;

[0453] Area under the curve (AUC) during drug administration 0-t Value: Calculated using the trapezoidal rule;

[0454] AUC 0-∞ =AUC 0-t +C t / k e ,

[0455] C t This refers to the blood drug concentration at the last measurable time point.

[0456] k e To eliminate the rate constant;

[0457] Elimination half-life t 1 / 2 =0.693 / k e ;

[0458] Mean residence time MRT = AUMC / AUC.

[0459] Sweep rate CL = D / AUC 0-∞ Steady-state distributed volume Vss = CL × MRT

[0460] Absolute bioavailability F = (AUC) 灌胃 ×D 静脉 ) / (AUC 静脉 ×D 灌胃 )×100%

[0461] The experimental results are shown in Table 17 below:

[0462] Table 17 Pharmacokinetic Results of Compound A and Ibrutinib

[0463]

[0464] The above results indicate that the clearance rate of Compound A in rats is significantly lower than that of ibrutinib (20 times), and the drug exposure in plasma is also 70 times higher than that of ibrutinib. That is, at the same dose, Compound A has better oral absorption and better oral bioavailability.

[0465] Experimental Example 8: Evaluation of Pharmacokinetic Properties in Rats

[0466] SD rats were purchased from Shanghai SIPPR-BK Laboratory Animal Co., Ltd. (production license number: SCXK (Shanghai) 2018-0006). There were 12 rats, with 6 males and 6 females, weighing 170-250 g. They were randomly divided into 2 groups, with 6 rats in each group. The test compound was administered by gavage and intravenous injection respectively. The specific arrangements are shown in Table 18 below.

[0467] Table 18 Administration Methods of the Test Compound

[0468]

[0469] Note: The polymorphic form I sample of Example 2 was used for detection. For gavage administration, it was prepared with 10% SDS aqueous solution: EL: 0.5% MC physiological saline solution = 1:2:97 (v:v:v), and the drug concentration was configured to be 1.5 mg / mL; for intravenous administration, it was prepared into a solution with N,N-dimethylformamide: physiological saline (40:60, v / v), and the administration concentration was configured to be 3 mg / mL.

[0470] The rats were fasted for 12 hours before the experiment and allowed free access to water. They were fed uniformly 4 hours after administration.

[0471] Blood Sampling Time Points and Sample Processing:

[0472] For gavage administration: 0.25, 0.5, 1.0, 2.0, 3.0, 5.0, 7.0, 9.0, and 24 hours after administration;

[0473] For intravenous administration: 5 minutes, 0.25, 0.5, 1.0, 2.0, 3.0, 5.0, 7.0, and 24 hours after administration;

[0474] At the above set time points, 0.2 mL of venous blood was collected from the posterior orbital venous plexus of the rats, placed in an EDTA-K2 anticoagulant tube, centrifuged at 11000 rpm for 5 minutes, the plasma was separated within 2 hours, and stored at -70 °C for further testing.

[0475] Sample Testing and Data Analysis

[0476] The concentration of Compound A in rat plasma was determined by LC / MS / MS method. The calculation software and parameters were the same as those described in the corresponding part of Experimental Example 7. The test results are shown in Table 19 below:

[0477] Table 19 Pharmacokinetic Results of Compound A (Crystal Form I of Example 2)

[0478]

[0479] The above results indicate that compound A (crystal form I of Example 2) has a low clearance rate in rats, a high drug exposure in plasma, and good oral bioavailability.

[0480] Therefore, compound A is a novel, orally administered, highly selective, and highly active BTK inhibitor, exhibiting significantly superior in vitro and in vivo activity compared to currently marketed BTK inhibitors. At the same dosage, its tumor growth inhibitory activity is significantly superior to the positive control drug ibrutinib. Furthermore, the crystal form of the compound represented by formula (A) mentioned in this invention has good crystallinity, and the preferred crystal form possesses good stability, is easy to drug, and has high bioavailability. This demonstrates that compound A and its specific crystal form have significant development value.

[0481] The above embodiments are merely illustrative in nature and are not intended to limit the embodiments of the target application or the application or use of such embodiments. In this document, the term "illustrative" means "as an example, illustration, or description." No illustrative embodiment herein should necessarily be construed as preferred or advantageous over other embodiments.

[0482] Furthermore, although at least one exemplary embodiment or comparative example has been presented in the foregoing embodiments, it should be understood that numerous variations are possible with respect to the invention. It should also be understood that the embodiments described herein are not intended to limit the scope, use, or configuration of the claimed objectives in any way. Rather, the foregoing embodiments will provide a simple guide for those skilled in the art to implement one or more of the described embodiments. Moreover, various changes can be made to the function and arrangement of the elements without departing from the scope defined by the claims, which include known equivalents and all foreseeable equivalents at the time of filing of this patent application.

Claims

1. The compound of formula (A) in crystalline form, having crystal form I, characterized in that, Its X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angles: 4.8±0.2°, 11.6±0.2°, 13.6±0.2°, 16.2±0.2°, 18.7±0.2°, 23.4±0.2°. 。 2. The compound of formula (A) according to claim 1, wherein crystal form I is characterized in that, Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.8±0.2°, 11.6±0.2°, 13.6±0.2°, 16.2±0.2°, 18.7±0.2°, 23.4±0.2°, 26.1±0.2°.

3. The compound of formula (A) according to claim 1, wherein crystal form I is characterized in that, Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.8±0.2°, 11.6±0.2°, 13.6±0.2°, 16.2±0.2°, 18.7±0.2°, 23.4±0.2°, 24.2±0.2°, 24.8±0.2°, and 26.1±0.2°.

4. The compound of formula (A) according to claim 1, wherein crystal form I is characterized in that, Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.8±0.2°, 11.6±0.2°, 13.6±0.2°, 16.2±0.2°, 18.7±0.2°, 19.4±0.2°, 21.7±0.2°, 23.4±0.2°, 24.2±0.2°, 24.8±0.2°, 26.1±0.2°.

5. The compound of formula (A) according to claim 1, wherein crystal form I is characterized in that, Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.8±0.2°, 11.6±0.2°, 13.6±0.2°, 16.2±0.2°, 16.7±0.2°, 18.7±0.2°, 19.4±0.2°, 21.7±0.2°, 23.4±0.2°, 24.2±0.2°, 24.8±0.2°, 26.1±0.2°, 27.6±0.2°.

6. The compound of formula (A) according to claim 1, wherein crystal form I is characterized in that, Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.8±0.2°, 11.6±0.2°, 13.6±0.2°, 16.2±0.2°, 16.7±0.2°, 18.7±0.2°, 19.4±0.2°, 20.8±0.2°, 21.7±0.2°, 23.4±0.2°, 24.2±0.2°, 24.8±0.2°, 26.1±0.2°, 27.6±0.2°.

7. The compound of formula (A) according to claim 1, wherein crystal form I is characterized in that, It has an X-ray powder diffraction pattern that is essentially as shown in Figure 3.

8. The compound of formula (A) in the crystalline form according to any one of claims 1-7, wherein the differential scanning calorimetry curve of crystal form I has an exothermic peak at 274.74±3℃.

9. The compound of formula (A) in crystalline form according to any one of claims 1-7, wherein crystal form I has a DSC spectrum substantially as shown in FIG4.

10. The compound of formula (A) in crystalline form, which is crystal form II, characterized in that, Its X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angles: 7.0±0.2°, 7.9±0.2°, 8.5±0.2°, 10.6±0.2°, 15.0±0.2°, 22.1±0.2°, 25.3±0.2°. 。 11. The compound of formula (A) according to claim 10, wherein crystal form II is characterized in that, Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.0±0.2°, 7.9±0.2°, 8.5±0.2°, 10.6±0.2°, 15.0±0.2°, 18.0±0.2°, 22.1±0.2°, 25.3±0.2°, and 26.3±0.2°.

12. The compound of formula (A) according to claim 10, wherein crystal form II is characterized in that, Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.0±0.2°, 7.9±0.2°, 8.5±0.2°, 10.6±0.2°, 15.0±0.2°, 17.1±0.2°, 18.0±0.2°, 19.1±0.2°, 22.1±0.2°, 25.3±0.2°, 26.3±0.2°.

13. The compound of formula (A) according to claim 10, wherein crystal form II is characterized in that, Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.3±0.2°, 7.0±0.2°, 7.9±0.2°, 8.5±0.2°, 10.6±0.2°, 15.0±0.2°, 17.1±0.2°, 18.0±0.2°, 19.1±0.2°, 22.1±0.2°, 25.3±0.2°, 26.3±0.2°.

14. The compound of formula (A) according to claim 10, wherein crystal form II is characterized in that, Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.3±0.2°, 7.0±0.2°, 7.9±0.2°, 8.5±0.2°, 10.6±0.2°, 12.8±0.2°, 15.0±0.2°, 17.1±0.2°, 18.0±0.2°, 19.1±0.2°, 21.3±0.2°, 22.1±0.2°, 25.3±0.2°, and 26.3±0.2°.

15. The compound of formula (A) according to claim 10, wherein crystal form II is characterized in that, It has an X-ray powder diffraction pattern that is essentially as shown in Figure 5.

16. The compound of formula (A) in crystalline form, which is crystal form III, characterized in that, Its X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angles: 4.3±0.2°, 7.1±0.2°, 8.0±0.2°, 8.6±0.2°, 10.6±0.2°, 15.1±0.2°, 16.2±0.2°, 22.3±0.2°, 25.5±0.2°. 。 17. The compound of formula (A) according to claim 16, wherein crystal form III is characterized in that, Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.3±0.2°, 7.1±0.2°, 8.0±0.2°, 8.6±0.2°, 10.6±0.2°, 15.1±0.2°, 16.2±0.2°, 19.3±0.2°, 22.3±0.2°, 25.5±0.2°.

18. The compound of formula (A) according to claim 16, wherein crystal form III is characterized in that, Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.3±0.2°, 7.1±0.2°, 8.0±0.2°, 8.6±0.2°, 10.6±0.2°, 15.1±0.2°, 16.2±0.2°, 17.2±0.2°, 18.1±0.2°, 19.3±0.2°, 22.3±0.2°, 25.5±0.2°.

19. The compound of formula (A) in its crystalline form according to claim 16, wherein crystal form III is characterized in that, Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.3±0.2°, 7.1±0.2°, 8.0±0.2°, 8.6±0.2°, 10.6±0.2°, 15.1±0.2°, 16.2±0.2°, 17.2±0.2°, 18.1±0.2°, 19.3±0.2°, 21.4±0.2°, 22.3±0.2°, and 25.5±0.2°.

20. The compound of formula (A) according to claim 16, wherein crystal form III is characterized in that, It has an X-ray powder diffraction pattern that is essentially as shown in Figure 7.

21. The compound of formula (A) in crystalline form, which is crystal form IV, characterized in that, Its X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angles: 5.1±0.2°, 6.3±0.2°, 9.7±0.2°, 12.8±0.2°, 14.1±0.2°, and 19.0±0.2°. 。 22. The compound of formula (A) in its crystalline form according to claim 21, wherein crystal form IV is characterized in that, Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.1±0.2°, 6.3±0.2°, 9.7±0.2°, 12.8±0.2°, 14.1±0.2°, 15.6±0.2°, 19.0±0.2°, 21.9±0.2°.

23. The compound of formula (A) according to claim 21, wherein crystal form IV is characterized in that, Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.1±0.2°, 6.3±0.2°, 9.7±0.2°, 12.8±0.2°, 14.1±0.2°, 15.6±0.2°, 19.0±0.2°, 20.4±0.2°, 21.9±0.2°, 23.2±0.2°, and 26.3±0.2°.

24. The compound of formula (A) according to claim 21, wherein crystal form IV is characterized in that, It has an X-ray powder diffraction pattern that is essentially as shown in Figure 9.

25. A compound of formula (A) in crystalline form, having crystal form V, characterized in that, Its X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angles: 5.6±0.2°, 7.1±0.2°, 11.5±0.2°, 13.8±0.2°, 14.3±0.2°, 17.0±0.2°, 21.9±0.2°. 。 26. The compound of formula (A) in its crystalline form according to claim 25, wherein crystal form V is characterized in that, Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.6±0.2°, 7.1±0.2°, 8.9±0.2°, 11.5±0.2°, 13.8±0.2°, 14.3±0.2°, 17.0±0.2°, 19.1±0.2°, 21.9±0.2°.

27. The compound of formula (A) in its crystalline form according to claim 25, wherein crystal form V is characterized in that, Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.6±0.2°, 7.1±0.2°, 8.9±0.2°, 11.5±0.2°, 13.8±0.2°, 14.3±0.2°, 17.0±0.2°, 18.3±0.2°, 19.1±0.2°, 20.7±0.2°, 21.9±0.2°.

28. The compound of formula (A) in its crystalline form according to claim 25, wherein crystal form V is characterized in that, It has an X-ray powder diffraction pattern that is essentially as shown in Figure 11.

29. A compound of formula (A) in crystalline form, having crystal form VI, characterized in that, Its X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angles: 5.0±0.2°, 6.2±0.2°, 9.4±0.2°, 12.5±0.2°, 15.2±0.2°, 21.4±0.2°, 24.7±0.2°. 。 30. The compound of formula (A) according to claim 29, wherein crystal form VI is characterized in that, Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.0±0.2°, 6.2±0.2°, 9.4±0.2°, 12.5±0.2°, 15.2±0.2°, 21.4±0.2°, 23.5±0.2°, and 24.7±0.2°.

31. The compound of formula (A) according to claim 29, wherein crystal form VI is characterized in that, It has an X-ray powder diffraction pattern that is essentially as shown in Figure 12.

32. A compound of formula (A) in crystalline form, having crystal form VII, characterized in that, Its X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angles: 5.7±0.2°, 7.5±0.2°, 10.8±0.2°, 12.5±0.2°, 17.4±0.2°, 21.8±0.2°, 25.1±0.2°. 。 33. The compound of formula (A) according to claim 32, wherein crystal form VII is characterized in that, Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.7±0.2°, 7.5±0.2°, 10.8±0.2°, 11.6±0.2°, 12.5±0.2°, 17.4±0.2°, 18.0±0.2°, 21.8±0.2°, and 25.1±0.2°.

34. The compound of formula (A) according to claim 32, wherein crystal form VII is characterized in that, It has an X-ray powder diffraction pattern that is essentially as shown in Figure 1.

35. A pharmaceutical composition comprising a compound of formula (A) in crystalline form as claimed in any one of claims 1-34.

36. The pharmaceutical composition according to claim 35, characterized in that, The pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.

37. The use of the compound of formula (A) in crystalline form according to any one of claims 1-34, or the pharmaceutical composition according to claim 35 or 36, in the preparation of a medicament for treating BTK-related conditions.

38. The application according to claim 37, wherein the BTK-related condition involves dysregulation of BTK protein expression, level, or activity.

39. The application according to claim 37, wherein the BTK-related conditions are selected from tumor diseases and autoimmune diseases.

40. The application according to claim 39, wherein the tumor disease is a hematologic malignancy.

41. The application according to claim 39, wherein the tumor disease is leukemia or lymphoma.

42. The application according to claim 39, wherein the tumor disease is B-cell lymphoma.

43. The application according to claim 39, wherein the tumor disease is mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, marginal zone lymphoma, follicular lymphoma, Waldenström macroglobulinemia, or diffuse large B-cell lymphoma.

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