CN114478547B

CN114478547B - Solid form bruton's tyrosine kinase inhibitor compounds and uses thereof

Info

Publication number: CN114478547B
Application number: CN202111235132.9A
Authority: CN
Inventors: 曲凡志; 张翱; 丁健; 门利玲; 杨汉煜; 孙静
Original assignee: Shanghai Runshi Pharmaceutical Technology Co ltd; Shanghai Institute of Materia Medica of CAS
Current assignee: Shanghai Runshi Pharmaceutical Technology Co ltd; Shanghai Institute of Materia Medica of CAS
Priority date: 2020-10-23
Filing date: 2021-10-22
Publication date: 2026-01-23
Anticipated expiration: 2041-10-22
Also published as: WO2022083733A1; CN114478547A

Abstract

本发明提供了一种化合物A、其溶剂合物或水合物的固体形式、结晶形式、晶型及制备方法和用途，所得化合物A的结晶形式具有结晶度好、稳定性好，化合物A具有良好的布鲁顿酪氨酸激酶抑制活性、细胞抑制活性、体内抗肿瘤活性、药代性质和代谢稳定性。 This invention provides a compound A, its solvate or hydrate in solid form, crystalline form, crystal form, preparation method, and uses. The crystalline form of the obtained compound A has good crystallinity and stability. Compound A has good Bruton's tyrosine kinase inhibitory activity, cell inhibitory activity, in vivo antitumor activity, pharmacokinetic properties, and metabolic stability.

Description

Solid form bruton's tyrosine kinase inhibitor compounds and uses thereof

Technical Field

The invention relates to a compound shown as a formula (A), a solvate or hydrate solid form, a crystal form, a specific crystal form and a pharmaceutical composition of a small molecular bruton tyrosine kinase inhibitor, and relates to application thereof in preparing medicines for treating bruton tyrosine kinase related diseases.

Background

Bruton's tyrosine kinase, BTK) is a non-receptor tyrosine kinase belonging to the TEC tyrosine kinase family. 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 B Cell Receptor (BCR) signaling pathway, is widely expressed in various types of malignant hematological tumors, and is involved in proliferation, differentiation and apoptosis of B cells. Therefore, BTK has become an important molecular target for the drug treatment of hematological malignancies.

Currently, 4 BTK inhibitors have been marketed in batches, ibrutinib (Ibrutinib, trade name Imbruvica) is the first BTK small molecule inhibitor marketed, which is a first generation of BTK inhibitors approved by the us FDA in 2013 for clinical treatment of mantle cell Lymphoma (MANTLE CELL Lymphoma, MCL) and chronic lymphocytic leukemia (Chronic Lymphocytic Leukemia, CLL), after which ibrutinib continues to expand for an indication, and the currently available indications also include chronic lymphocytic leukemia/small lymphocytic Lymphoma (CLL/Small Lymphocytic Lymphoma, SLL), fahrenheit macroglobulinemia (Waldenstrom Macroglobulinemia, WM), marginal zone Lymphoma (Marginal Zone Lymphoma, MZL), chronic Graft versus Host Disease (chronic Graft-Versus-Host Disease, cGVHD), and the like. Ibrutinib can form covalent bond with cysteine (Cys 481) at position 481 in ATP binding domain of BTK kinase, irreversibly inhibit BTK activation, and block BTK signal path, thereby inhibiting proliferation and survival of B lymphoma cells, and achieving tumor treatment purpose. Ibrutinib has achieved substantial therapeutic effects in clinical treatment. However, as ibrutinib has poor target selectivity, certain toxic and side effects exist clinically. Acartinib (Acalabrutinib, ACP-196, trade name Calquence) was approved in 2017 for the treatment of MCL and CLL, a second generation BTK targeting drug. Relative to ibrutinib, acartinib has higher selectivity to BTK and lower off-target toxicity. In addition, zanubrutinib (zebutinib, BGB-3111) developed by the biological technology limited of baji, was approved by the FDA for use in treated adult MCL patients in 2019, 11 months, and became a chinese native anticancer drug that was first approved by FDA breakthrough therapies. Tirabrutinib (ONO-4059) developed by the japan small field pharmaceutical company, japan medical equipment integrated agency PMDA, 3 months of 2020 was approved for the treatment of recurrent or refractory Primary Central Nervous System Lymphomas (PCNSL) and lymphoplasmacytic lymphomas (LPL). In general, the first generation inhibitors have high BTK inhibition activity but poor target selection and bioavailability, and the second generation inhibitors have good selectivity but lower BTK inhibition rate than the first generation inhibitors. Structurally, the core backbone of the compounds currently on the market or under investigation is predominantly a bicyclic system.

In order to obtain a new generation of BTK inhibitor with high activity of the first generation inhibitor and good selectivity of the second generation inhibitor, a tricyclic compound with a unique structure is disclosed in CN108101905A patent of Shanghai pharmaceutical research of China academy of sciences. Among them, pyrimidoindazine compounds S1 and S10 and pyrimidopyrrole compounds S18, S19 and S20 show higher BTK inhibitory activity, and in further work, S18, S19 and S20S-configuration compounds (i.e., S18S, S19S and S20s)[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.]. but further studies find that these compounds are unstable in the metabolic process of S1, S10, S18S and S19S, the 4-position of the terminal phenyl group is easily oxidized, and the oral bioavailability of compound S20S is not ideal).

Disclosure of Invention

The compound A has excellent BTK inhibition activity, better BTK inhibition selectivity, excellent in-vivo anti-tumor activity, good oral administration performance and good metabolic stability, and has potential of developing into BTK selective inhibitors.

In one aspect, the present invention provides a compound of formula (a), a solvate or hydrate thereof, in solid form.

In another aspect, the present invention provides a compound of formula (a), a solvate or hydrate thereof, in crystalline form.

In some embodiments of the present invention, the crystalline form is a solvent-free and anhydrous crystalline form or a hydrate crystalline form, preferably a solvent-free and anhydrous crystalline form.

In another aspect, the present invention provides crystalline form I of a compound of formula (A), a solvate or hydrate thereof, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2-theta angles of 4.8 + -0.2 DEG, 11.6 + -0.2 DEG, 13.6 + -0.2 deg.

In some aspects of the invention, the crystalline form I has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 theta angles of 4.8 + -0.2 DEG, 11.6 + -0.2 DEG, 13.6 + -0.2 DEG, and 23.4 + -0.2 deg.

In some aspects of the invention, the X-ray powder diffraction pattern of the crystal form I has characteristic diffraction peaks at the following 2 theta angles of 4.8+/-0.2 degrees, 11.6+/-0.2 degrees, 13.6+/-0.2 degrees, 18.7+/-0.2 degrees and 23.4+/-0.2 degrees. .

In some aspects of the invention, the X-ray powder diffraction pattern of the crystal form I has characteristic diffraction peaks at the following 2 theta angles of 4.8+/-0.2 degrees, 11.6+/-0.2 degrees, 13.6+/-0.2 degrees, 16.2+/-0.2 degrees, 18.7+/-0.2 degrees and 23.4+/-0.2 degrees.

In some aspects of the invention, the X-ray powder diffraction pattern of the crystal form I has characteristic diffraction peaks at the following 2 theta angles of 4.8+/-0.2 degrees, 11.6+/-0.2 degrees, 13.6+/-0.2 degrees, 16.2+/-0.2 degrees, 18.7+/-0.2 degrees, 23.4+/-0.2 degrees and 26.1+/-0.2 degrees.

In some aspects of the invention, the X-ray powder diffraction pattern of the crystal form I has characteristic diffraction peaks at the following 2 theta angles of 4.8+/-0.2 degrees, 11.6+/-0.2 degrees, 13.6+/-0.2 degrees, 16.2+/-0.2 degrees, 18.7+/-0.2 degrees, 23.4+/-0.2 degrees, 24.2+/-0.2 degrees, 24.8+/-0.2 degrees and 26.1+/-0.2 degrees.

In some embodiments of the present invention, the above-described form I has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2-theta 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°.

In some embodiments of the present invention, the above-described form I has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2-theta 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°.

In some embodiments of the present invention, the above-described form I has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2-theta 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°.

In some embodiments of the present invention, the above-described form I has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2-theta 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°,22.5±0.2°,23.4±0.2°,24.2±0.2°,24.8±0.2°,26.1±0.2°,27.6±0.2°,30.4±0.2°.

In some aspects of the invention, the above-described crystalline form I has an X-ray powder diffraction pattern with characteristic diffraction peaks (±0.2°):

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

。

peak position (2 theta)	Relative strength%	Peak position (2 theta)	Relative strength%	Peak position (2 theta)	Relative strength%
						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

。

In some aspects of the invention, form I above has an X-ray powder diffraction pattern substantially as shown in figure 3.

In some embodiments of the invention, the above-described crystalline form I has a differential scanning calorimetry trace with an onset of an exothermic peak at 272.89 + -3deg.C.

In some embodiments of the invention, the above-mentioned crystal form I has a differential scanning calorimetry curve with an exothermic peak at 274.74 + -3deg.C.

In some aspects of the invention, form I above has a DSC profile substantially as shown in figure 4.

In another aspect, the present invention provides a crystalline form II of a compound of formula (a), a solvate or hydrate thereof, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Θ angles, 8.5±0.2 °,10.6±0.2 °,15.0±0.2°.

In some aspects of the invention, the X-ray powder diffraction pattern of the crystal form II has characteristic diffraction peaks at the following 2 theta angles of 7.0+/-0.2 degrees, 8.5+/-0.2 degrees, 10.6+/-0.2 degrees, 15.0+/-0.2 degrees and 22.1+/-0.2 degrees.

In some aspects of the invention, the X-ray powder diffraction pattern of the crystal form II has characteristic diffraction peaks at the following 2 theta angles of 7.0+/-0.2 degrees, 7.9+/-0.2 degrees, 8.5+/-0.2 degrees, 10.6+/-0.2 degrees, 15.0+/-0.2 degrees, 22.1+/-0.2 degrees and 25.3+/-0.2 degrees.

In some aspects of the invention, the X-ray powder diffraction pattern of the crystal form II has characteristic diffraction peaks at the following 2 theta angles of 7.0+/-0.2 degrees, 7.9+/-0.2 degrees, 8.5+/-0.2 degrees, 10.6+/-0.2 degrees, 15.0+/-0.2 degrees, 18.0+/-0.2 degrees, 22.1+/-0.2 degrees, 25.3+/-0.2 degrees and 26.3+/-0.2 degrees.

In some embodiments of the present invention, the above-described form II has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2-theta 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°.

In some embodiments of the present invention, the above-described form II has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2-theta 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°.

In some embodiments of the present invention, the above-described form II has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2-theta 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°,26.3±0.2°.

In some embodiments of the present invention, the above-described form II has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2-theta angles ：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°.

In some aspects of the invention, the above-described crystalline form II has an X-ray powder diffraction pattern with characteristic diffraction peaks (±0.2°):

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

。

In some aspects of the invention, form II above has an X-ray powder diffraction pattern substantially as shown in figure 5.

In some embodiments of the present invention, the differential scanning calorimetry curve of form II has three onset points of endothermic peaks at 49.26±3 ℃, 84.59 ±3 ℃ and 168.35 ±3 ℃, respectively.

In some embodiments of the present invention, the aforementioned form II has three endothermic peaks at 69.36 ±3 ℃, 98.45±3 ℃ and 176.96 ±3 ℃ respectively in the differential scanning calorimetric curve.

In some embodiments of the invention, form II above has a DSC profile substantially as shown in figure 6.

In some embodiments of the present invention, the thermogravimetric analysis curve of the crystal form II has a weight loss of 3.417% ± 0.2% at room temperature to 100 ± 3 ℃.

In some embodiments of the invention, form II above has a TGA profile substantially as shown in figure 6.

In another aspect, the present invention provides crystalline form III of a compound of formula (A), a solvate or hydrate thereof, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2-theta angles of 4.3 + -0.2 DEG, 8.6 + -0.2 DEG, 10.6 + -0.2 DEG, 15.1 + -0.2 deg.

In some aspects of the invention, the above-described crystalline form III has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 theta angles of 4.3 + -0.2 DEG, 7.1 + -0.2 DEG, 8.6 + -0.2 DEG, 10.6 + -0.2 DEG, 15.1 + -0.2 DEG, 25.5 + -0.2 deg.

In some aspects of the invention, the X-ray powder diffraction pattern of the crystal form III has characteristic diffraction peaks at the following 2 theta angles of 4.3+/-0.2 degrees, 7.1+/-0.2 degrees, 8.0+/-0.2 degrees, 8.6+/-0.2 degrees, 10.6+/-0.2 degrees, 15.1+/-0.2 degrees, 22.3+/-0.2 degrees and 25.5+/-0.2 degrees.

In another aspect, the present invention provides crystalline form III of a compound of formula (A), a solvate or hydrate thereof, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 theta angles, 4.3 + -0.2 DEG, 8.6 + -0.2 DEG, 10.6 + -0.2 DEG, 15.1 + -0.2 DEG, 16.2 + -0.2 deg.

In some aspects of the invention, the X-ray powder diffraction pattern of the crystal form III has characteristic diffraction peaks at the following 2 theta angles of 4.3+/-0.2 degrees, 7.1+/-0.2 degrees, 8.6+/-0.2 degrees, 10.6+/-0.2 degrees, 15.1+/-0.2 degrees, 16.2+/-0.2 degrees and 25.5+/-0.2 degrees.

In some aspects of the invention, the X-ray powder diffraction pattern of the crystal form III has characteristic diffraction peaks at the following 2 theta angles of 4.3+/-0.2 degrees, 7.1+/-0.2 degrees, 8.0+/-0.2 degrees, 8.6+/-0.2 degrees, 10.6+/-0.2 degrees, 15.1+/-0.2 degrees, 16.2+/-0.2 degrees, 22.3+/-0.2 degrees and 25.5+/-0.2 degrees.

In some aspects of the invention, the X-ray powder diffraction pattern of the crystal form III has characteristic diffraction peaks at the following 2 theta angles of 4.3+/-0.2 degrees, 7.1+/-0.2 degrees, 8.0+/-0.2 degrees, 8.6+/-0.2 degrees, 10.6+/-0.2 degrees, 15.1+/-0.2 degrees, 16.2+/-0.2 degrees, 19.3+/-0.2 degrees, 22.3+/-0.2 degrees and 25.5+/-0.2 degrees.

In some embodiments of the present invention, the above-described form III has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2-theta 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°.

In some embodiments of the present invention, the above-described form III has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2-theta 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°,25.5±0.2°.

In some aspects of the invention, the above-described crystalline form III has an X-ray powder diffraction pattern with characteristic diffraction peaks (±0.2°):

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

。

peak position (2 theta)	Relative strength%	Peak position (2 theta)	Relative strength%	Peak position (2 theta)	Relative strength%
						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

。

In some aspects of the invention, form III above has an X-ray powder diffraction pattern substantially as shown in figure 7.

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

In some embodiments of the present invention, the aforementioned form III has three endothermic peaks at 57.40 ±3 ℃, 96.32 ±3 ℃ and 177.55 ±3 ℃ respectively.

In some embodiments of the invention, form III above has a DSC profile substantially as shown in figure 8.

In some embodiments of the invention, the thermogravimetric analysis of form III above has a weight loss of 3.075% ± 0.2% before 90 ± 3 ℃.

In some embodiments of the invention, form III above has a TGA profile substantially as shown in figure 8.

In another aspect, the present invention provides crystalline form IV of a compound of formula (A), a solvate or hydrate thereof, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 theta angles of 6.3 + -0.2 DEG, 9.7 + -0.2 DEG, 12.8 + -0.2 deg.

In some aspects of the invention, the X-ray powder diffraction pattern of the crystal form IV has characteristic diffraction peaks at the following 2 theta angles of 5.1+/-0.2 degrees, 6.3+/-0.2 degrees, 9.7+/-0.2 degrees, 12.8+/-0.2 degrees and 14.1+/-0.2 degrees.

In some aspects of the invention, the X-ray powder diffraction pattern of form IV has characteristic diffraction peaks at the following 2 theta angles of 5.1+/-0.2 degrees, 6.3+/-0.2 degrees, 9.7+/-0.2 degrees, 12.8+/-0.2 degrees, 14.1+/-0.2 degrees and 19.0+/-0.2 degrees.

In some aspects of the invention, the X-ray powder diffraction pattern of the crystal form IV has characteristic diffraction peaks at the following 2 theta angles of 5.1+/-0.2 degrees, 6.3+/-0.2 degrees, 9.7+/-0.2 degrees, 12.8+/-0.2 degrees, 14.1+/-0.2 degrees, 15.6+/-0.2 degrees, 19.0+/-0.2 degrees and 21.9+/-0.2 degrees.

In some aspects of the invention, the X-ray powder diffraction pattern of form IV has characteristic diffraction peaks at the following 2 theta angles of 5.1+/-0.2 degrees, 6.3+/-0.2 degrees, 9.7+/-0.2 degrees, 12.8+/-0.2 degrees, 14.1+/-0.2 degrees, 19.0+/-0.2 degrees, 20.4+/-0.2 degrees and 23.2+/-0.2 degrees.

In some aspects of the invention, the X-ray powder diffraction pattern of form IV has characteristic diffraction peaks at the following 2 theta angles of 5.1+/-0.2 degrees, 6.3+/-0.2 degrees, 9.7+/-0.2 degrees, 12.8+/-0.2 degrees, 14.1+/-0.2 degrees, 19.0+/-0.2 degrees, 20.4+/-0.2 degrees, 21.9+/-0.2 degrees, 23.2+/-0.2 degrees and 26.3+/-0.2 degrees.

In some embodiments of the present invention, the above-described form IV has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2-theta 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°,26.3±0.2°.

In some aspects of the invention, the above-described form IV has an X-ray powder diffraction pattern with characteristic diffraction peaks (±0.2°):

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

。

peak position (2 theta)	Relative strength%	Peak position (2 theta)	Relative strength%	Peak position (2 theta)	Relative strength%
						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

。

In some aspects of the invention, form IV above has an X-ray powder diffraction pattern substantially as shown in figure 9.

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

In some embodiments of the invention, the differential scanning calorimetry curve of form IV has two endothermic peaks at 70.65±3 ℃ and 166.96±3 ℃, respectively.

In some aspects of the invention, form IV above has a DSC profile substantially as shown in figure 10.

In some embodiments of the invention, the thermogravimetric analysis curve of the crystal form IV has a weight loss of 7.863% ± 0.2% at room temperature of 200 ± 3 ℃.

In some aspects of the invention, form IV above has a TGA profile substantially as shown in figure 10.

In another aspect, the present invention provides crystalline form V of a compound of formula (A), a solvate or hydrate thereof, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2-theta angles of 5.6.+ -. 0.2 °, 7.1.+ -. 0.2 °, 14.3.+ -. 0.2 °.

In some aspects of the invention, the crystalline form V has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 theta angles of 5.6+/-0.2 DEG, 7.1+/-0.2 DEG, 11.5+/-0.2 DEG, 13.8+/-0.2 DEG, and 14.3+/-0.2 deg.

In some aspects of the invention, the crystalline form V has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 theta angles of 5.6+/-0.2 DEG, 7.1+/-0.2 DEG, 11.5+/-0.2 DEG, 13.8+/-0.2 DEG, 14.3+/-0.2 DEG, 17.0+/-0.2 DEG, and 21.9+/-0.2 deg.

In some aspects of the invention, the crystalline form V has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angles of 5.6 + -0.2 DEG, 7.1 + -0.2 DEG, 8.9 + -0.2 DEG, 11.5 + -0.2 DEG, 13.8 + -0.2 DEG, 14.3 + -0.2 DEG, 17.0 + -0.2 DEG, 19.1 + -0.2 DEG, and 21.9 + -0.2 deg.

In some embodiments of the present invention, the crystalline form V has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2-theta 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°.

In some embodiments of the present invention, the crystalline form V has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2-theta 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°,25.2±0.2°.

In some embodiments of the present invention, the crystalline form V has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2-theta 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°,25.2±0.2°,27.2±0.2°.

In some aspects of the invention, the above-described crystalline form V has an X-ray powder diffraction pattern with characteristic diffraction peaks (±0.2°):

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

。

peak position (2 theta)	Relative strength%	Peak position (2 theta)	Relative strength%	Peak position (2 theta)	Relative strength%
						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

。

In some aspects of the invention, form V above has an X-ray powder diffraction pattern substantially as shown in figure 11.

In some embodiments of the invention, the differential scanning calorimetry curve of form V has an endothermic peak at 174.53 ±3 ℃.

In some aspects of the invention, form V above has a DSC profile substantially as shown in figure 15.

In another aspect, the present invention provides crystalline form VI of a compound of formula (A), a solvate or hydrate thereof, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 theta angles, 6.2.+ -. 0.2 °, 9.4.+ -. 0.2 °, 12.5.+ -. 0.2 °.

In some aspects of the invention, the X-ray powder diffraction pattern of form VI has characteristic diffraction peaks at the following 2 theta angles of 6.2 plus or minus 0.2 degrees, 9.4 plus or minus 0.2 degrees, 12.5 plus or minus 0.2 degrees, 15.2 plus or minus 0.2 degrees, and 21.4 plus or minus 0.2 degrees.

In some aspects of the invention, the X-ray powder diffraction pattern of form VI has characteristic diffraction peaks at the following 2 theta angles of 5.0 + -0.2 DEG, 6.2 + -0.2 DEG, 9.4 + -0.2 DEG, 12.5 + -0.2 DEG, 15.2 + -0.2 DEG, 21.4 + -0.2 DEG, 24.7 + -0.2 deg.

In some aspects of the invention, the X-ray powder diffraction pattern of form VI has characteristic diffraction peaks at the following 2 theta angles of 5.0 + -0.2 DEG, 6.2 + -0.2 DEG, 9.4 + -0.2 DEG, 12.5 + -0.2 DEG, 15.2 + -0.2 DEG, 21.4 + -0.2 DEG, 23.5 + -0.2 DEG, 24.7 + -0.2 deg.

In some aspects of the invention, the X-ray powder diffraction pattern of form VI has characteristic diffraction peaks at the following 2 theta angles of 5.0 + -0.2 DEG, 6.2 + -0.2 DEG, 9.4 + -0.2 DEG, 12.5 + -0.2 DEG, 15.2 + -0.2 DEG, 18.8 + -0.2 DEG, 21.4 + -0.2 DEG, 23.5 + -0.2 DEG, 24.7 + -0.2 deg.

In some aspects of the invention, the X-ray powder diffraction pattern of form VI has characteristic diffraction peaks at the following 2 theta angles of 5.0 + -0.2 DEG, 6.2 + -0.2 DEG, 9.4 + -0.2 DEG, 12.5 + -0.2 DEG, 14.0 + -0.2 DEG, 15.2 + -0.2 DEG, 18.8 + -0.2 DEG, 21.4 + -0.2 DEG, 23.5 + -0.2 DEG, 24.7 + -0.2 deg.

In some aspects of the invention, the above-described crystalline form VI has an X-ray powder diffraction pattern with characteristic diffraction peaks (±0.2°):

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

。

peak position (2 theta)	Relative strength%	Peak position (2 theta)	Relative strength%	Peak position (2 theta)	Relative strength%
						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

。

In some aspects of the invention, form VI above has an X-ray powder diffraction pattern substantially as shown in figure 12.

In some embodiments of the present invention, the differential scanning calorimetry curve of form VI has two onset points of endothermic peaks at 45.54 ±3 ℃ and 163.80 ±3 ℃, respectively.

In some embodiments of the invention, the differential scanning calorimetry curve of form VI has two endothermic peaks at 86.78 ±3 ℃ and 165.61 ±3 ℃, respectively.

In some aspects of the invention, form VI above has a DSC profile substantially as shown in figure 13.

In some embodiments of the present invention, the thermogravimetric analysis curve of the crystal form VI has a weight loss of 3.153% ± 0.2% at room temperature to 120±3 ℃ and a weight loss of 1.500% ± 0.2% at 120 to 180 ℃ (±3 ℃).

In some aspects of the invention, form VI above has a TGA profile substantially as shown in figure 13.

In another aspect, the present invention provides crystalline form VII of a compound of formula (A), a solvate or hydrate thereof, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2-theta angles, 5.7.+ -. 0.2 °, 10.8.+ -. 0.2 °, 21.8.+ -. 0.2 °.

In some aspects of the invention, the X-ray powder diffraction pattern of the above-described form VII has characteristic diffraction peaks at the following 2 theta angles of 5.7 + -0.2 DEG, 7.5 + -0.2 DEG, 10.8 + -0.2 DEG, 12.5 + -0.2 DEG, and 21.8 + -0.2 deg.

In some aspects of the invention, the X-ray powder diffraction pattern of form VII has characteristic diffraction peaks at the following 2 theta angles of 5.7 + -0.2 DEG, 7.5 + -0.2 DEG, 10.8 + -0.2 DEG, 12.5 + -0.2 DEG, 17.4 + -0.2 DEG, 21.8 + -0.2 DEG, 25.1 + -0.2 deg.

In some aspects of the invention, the X-ray powder diffraction pattern of form VII has characteristic diffraction peaks at the following 2 theta angles of 5.7+ -0.2 DEG, 7.5+ -0.2 DEG, 10.8+ -0.2 DEG, 11.6+ -0.2 DEG, 12.5+ -0.2 DEG, 17.4+ -0.2 DEG, 18.0+ -0.2 DEG, 21.8+ -0.2 DEG, 25.1+ -0.2 deg.

In some aspects of the invention, the above-described crystalline form VII has an X-ray powder diffraction pattern with characteristic diffraction peaks (±0.2°):

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

。

peak position (2 theta)	Relative strength%	Peak position (2 theta)	Relative strength%	Peak position (2 theta)	Relative strength%
						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

。

In some embodiments of the invention, form VII above has an X-ray powder diffraction pattern substantially as shown in figure 1.

In some embodiments of the present invention, the differential scanning calorimetry curve of form VII has two endothermic peak onset points at 47.52±3 ℃ and 151.56 ±3 ℃, respectively.

In some embodiments of the invention, the differential scanning calorimetry curve of form VII has two endothermic peaks at 74.24±3 ℃ and 156.63 ±3 ℃, respectively.

In some embodiments of the invention, form VII above has a DSC profile substantially as shown in figure 2.

In some embodiments of the present invention, the thermogravimetric analysis curve of the crystal form VII has a weight loss of 8.053% + -0.2% at room temperature to 150+ -3 ℃.

In some embodiments of the invention, form VII above has a TGA profile substantially as shown in figure 2.

In another aspect, the present invention provides a method for preparing a compound of formula (a), a solvate or hydrate thereof, in crystalline form, comprising:

(1) Adding a compound shown in a formula (A) into a solvent to form suspension or solution;

(2) Stirring the suspension or solution, crystallizing, and separating solid;

optionally, a drying step is further included to obtain the compound of formula (A), a solvate or hydrate thereof in crystalline form.

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

In some embodiments of the invention, the above-described method of preparation, wherein the suspension may be prepared by adding a poor solvent to the solution.

In some embodiments of the present invention, the stirring temperature is-20 ℃ to 70 ℃, preferably-10 ℃ to 60 ℃, more preferably 0 ℃ to 50 ℃, still more preferably 15 ℃ to 40 ℃.

In some embodiments of the present invention, the stirring time is 0.1 to 75 hours, preferably 0.5 to 72 hours.

In some embodiments of the present invention, the weight-volume ratio of the compound to the solvent is 1 g:1-90 mL, preferably 1 g:5-50 mL, and more preferably 1 g:10-25 mL.

In some embodiments of the present invention, in the above preparation method, the volume ratio of the two solvents in the mixed solvent is 1:1-100, preferably 1:1-50, more preferably 1:1-20, and even more preferably 1:1-5. The volume ratio of the two solvents was calculated to be 1 for the smaller amount.

In some embodiments of the present invention, the drying time is 0.1 to 75 hours, preferably 1 to 48 hours, more preferably 5 to 24 hours, still more preferably 5 to 12 hours, still more preferably 5 to 10 hours, and the drying is preferably vacuum drying.

In another aspect, the present invention provides a process for preparing crystalline form I of a compound of formula (a), a solvate or hydrate thereof, comprising:

(2) Stirring the suspension or solution, crystallizing, and separating solid to obtain the crystal form I of the compound shown in the formula (A), and the solvate or hydrate thereof.

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

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

In another aspect, the present invention provides a process for preparing crystalline form II of a compound of formula (a), a solvate or hydrate thereof, comprising:

(2) Stirring the suspension or solution, crystallizing, and separating solid to obtain the crystal form II of the compound shown in the formula (A), and the solvate or hydrate thereof.

Or the invention provides a preparation method of the crystal form II of the compound shown in the formula (A), a solvate or a hydrate thereof, which comprises the steps of adding water into the crystal form VII, stirring or beating, crystallizing and separating solids.

In some embodiments of the present invention, the method for preparing the above, wherein the solvent is water.

In some embodiments of the present invention, the above-mentioned preparation method, wherein the stirring or beating temperature is-20 ℃ to 70 ℃, preferably-10 ℃ to 60 ℃, more preferably 0 ℃ to 50 ℃, still more preferably 15 ℃ to 40 ℃, still more preferably room temperature.

In some embodiments of the present invention, the above-mentioned preparation method, wherein the stirring or beating time is 0.1 to 75 hours, preferably 0.5 to 72 hours.

In another aspect, the present invention provides a process for preparing crystalline form III of a compound of formula (a), a solvate or hydrate thereof, comprising:

(1) And (3) placing the crystal form II into a vacuum drying oven for drying to obtain a crystal form III of the compound shown in the formula (A), and a solvate or hydrate of the compound.

In some embodiments of the present invention, the temperature of the vacuum drying is 30 to 70 ℃, preferably 40 to 60 ℃, and more preferably 40 to 50 ℃.

In some embodiments of the present invention, the time of the vacuum drying is 0.1 to 75 hours, preferably 1 to 48 hours, more preferably 5 to 24 hours, still more preferably 5 to 12 hours, and still more preferably 5 to 10 hours.

In another aspect, the present invention provides a process for preparing form IV of a compound of formula (a), a solvate or hydrate thereof, comprising:

(2) Stirring the suspension or solution, crystallizing, and separating solid to obtain the crystal form IV of the compound shown in the formula (A), and the solvate or hydrate thereof.

In some embodiments of the present invention, the above method for preparing, wherein the solvent is methanol.

In some embodiments of the present invention, the stirring temperature is-20 ℃ to 70 ℃, preferably-10 ℃ to 60 ℃, more preferably 0 ℃ to 50 ℃, still more preferably 15 ℃ to 40 ℃, still more preferably room temperature.

In some embodiments of the present invention, the stirring time is 0.1 to 75 hours, preferably 0.5 to 72 hours, more preferably 1 to 48 hours, and even more preferably 2 to 24 hours.

In some embodiments of the present invention, the weight-volume ratio of the compound to the solvent is 1 g:1-90 mL, preferably 1 g:5-50 mL, more preferably 1 g:10-25 mL, and even more preferably 1 g:10-15 mL.

In another aspect, the present invention provides a method for preparing form V of a compound of formula (a), a solvate or hydrate thereof, comprising:

(1) And (3) placing the crystal form IV in a vacuum drying oven for drying to obtain the crystal form V of the compound shown in the formula (A), and a solvate or hydrate of the compound.

In another aspect, the present invention provides a process for preparing crystalline form VI of a compound of formula (a), a solvate or hydrate thereof, comprising:

(2) Stirring the suspension or solution, crystallizing, and separating solid to obtain the crystal form VI of the compound shown in the formula (A), and the solvate or hydrate thereof.

In some embodiments of the present invention, the above method for preparing a polymer comprises a solvent.

In some embodiments of the present invention, the stirring time is 0.1 to 75 hours, preferably 0.5 to 72 hours, and more preferably 1 to 48 hours.

In another aspect, the present invention provides a process for preparing crystalline form VII of a compound of formula (a), a solvate or hydrate thereof, comprising:

(2) Stirring the suspension or solution, crystallizing, and separating solid to obtain crystal form VII of the compound shown in formula (A), solvate or hydrate thereof.

In some embodiments of the present invention, the above method for preparing, wherein the solvent is dichloromethane.

It is another object of the present invention to provide a pharmaceutical composition comprising the aforementioned compound of formula (a) in solid form, a solvate or hydrate thereof, a compound of formula (a) in crystalline form, a solvate or hydrate thereof or a crystalline mixture thereof.

In some embodiments of the present invention, the pharmaceutical composition comprises a compound of formula (a), a solvate or hydrate thereof, and one or more of form I, form II, form III, form IV, form V, and form VI.

In some embodiments of the invention, the pharmaceutical composition comprises a compound of formula (a), a solvate or hydrate thereof, a crystalline form of a compound of formula (a), a solvate or hydrate thereof, or a crystalline mixture thereof, in solid form, as described above, and one or more pharmaceutically acceptable carriers.

In some embodiments of the invention, the pharmaceutical composition comprises a compound of formula (a), a solvate or hydrate thereof, form I, form II, form III, form IV, form V, form VI, or a mixture thereof, and one or more pharmaceutically acceptable carriers.

The invention also provides the application of the compound shown in the formula (A), the solvate or hydrate thereof, the compound shown in the formula (A), the crystal form I, the crystal form II, the crystal form III, the crystal form IV, the crystal form V, the crystal form VI, the crystal form VII or the pharmaceutical composition in preparing medicines for treating BTK related diseases.

In another aspect, the present invention also relates to the use of a compound of formula (a), a solvate or hydrate thereof, a crystalline form I, a crystalline form II, a crystalline form III, a crystalline form IV, a crystalline form V, a crystalline form VI, a crystalline form VII, or a pharmaceutical composition as described above in solid form for the treatment of a BTK related disorder.

In yet another aspect, the present application also provides a compound of formula (a), a solvate or hydrate thereof, a form I, a form II, a form III, a form IV, a form V, a form VI, a form VII, or a pharmaceutical composition thereof in solid form as described above for use in the treatment of a BTK-related disorder.

In some embodiments of the invention, the aforementioned BTK-related disorder involves a deregulation of BTK protein expression, level or activity.

In some embodiments of the invention, the aforementioned BTK-related disorder comprises a neoplastic disease or autoimmune disease, preferably the neoplastic disease is a hematological tumor, more preferably a leukemia or lymphoma, more preferably a B-cell lymphoma, still more preferably a mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, marginal zone lymphoma, follicular lymphoma, fahrenheit macroglobulinemia, or diffuse large B-cell lymphoma.

On the other hand, the application of the compound shown in the formula (A), the solvate or hydrate thereof, the compound shown in the formula (A), the crystal form I, the crystal form II, the crystal form III, the crystal form IV, the crystal form V, the crystal form VI, the crystal form VII or the pharmaceutical composition in preparing medicines for treating tumor diseases or autoimmune diseases is also provided.

In some embodiments of the invention, the neoplastic disease is a hematological tumor, more preferably leukemia or lymphoma, more preferably B-cell lymphoma, still more preferably mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, marginal zone lymphoma, follicular lymphoma, megaloblastic Fahrenheit, or diffuse large B-cell lymphoma.

In some embodiments of the invention, the BTK-related disorder involves a deregulation of BTK protein expression, level or activity.

In another aspect, the invention also relates to a method of treating a condition in a patient, said condition in a patient being a BTK-related condition, by administering to the patient a therapeutically effective amount of a compound of formula (a), a solvate or hydrate thereof, a crystalline form I, a crystalline form II, a crystalline form III, a crystalline form IV, a crystalline form V, a crystalline form VI, a crystalline form VII, or a pharmaceutical composition thereof in solid form as described above.

In some embodiments of the invention, the method of treating a condition in a patient as described above, wherein the BTK-related condition comprises a neoplastic disease or an autoimmune disease, preferably the neoplastic disease is a hematological tumor, more preferably a leukemia or lymphoma, more preferably a B-cell lymphoma, even more preferably mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, marginal zone lymphoma, follicular lymphoma, fahrenheit macroglobulinemia, or diffuse large B-cell lymphoma.

Definition and description

The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular phrase or terminology, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.

The term "solvate" or "solvate" refers to an association of one or more solvent molecules with a compound of formula 2 of the present application, including an association containing both water molecules and one or more other solvent molecules.

The term "hydrate" refers to an association of one or more water molecules with a compound of formula 2 of the present application.

The term "substantially as shown in the figures" 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 the X-ray powder diffraction pattern are shown in the figure thereof, or that the range of error of the starting point or peak temperature of each endothermic or exothermic peak is within + -10 ℃, preferably within 5 ℃, more preferably within 3 ℃, or that the range of error of the starting point or end point of the loss temperature is within + -10 ℃, preferably within 5 ℃, more preferably within 3 ℃, and the percent loss of weight is within + -0.5%, preferably within + -0.3%, within + -0.2%. Further, as the content of a certain crystal form in a product gradually decreases, some diffraction peaks ascribed to the crystal form in the powder X-ray diffraction pattern thereof may be reduced due to factors of the detection sensitivity of the instrument.

The term "characteristic diffraction peak" refers to a diffraction peak useful in representing the crystalline form in an X-ray powder diffraction pattern, which is related to the peak position, peak shape, and relative peak intensity of the diffraction peak, e.g., a small angle peak, sharp peak shape, and a relative peak intensity of at least 2.9% or more, or at least 3% or more, or at least 5% or more, or at least 10% or more, or at least 20% or more, or at least 30% or more, or at least 40% or more, or at least 50% or more, or at least 60% or more, or at least 70% or at least 75% or more.

The term "tumor" encompasses benign tumors, malignant tumors, and borderline tumors, wherein malignant tumors are also collectively referred to as cancers.

The term "treatment" generally refers to obtaining a desired pharmacological and/or physiological effect, including partial or complete stabilization or cure of a disease and/or an effect due to a disease.

As used herein, "treatment" encompasses any treatment of a disease in a patient, including (a) inhibiting the symptoms of the disease, i.e., arresting its development, or (b) alleviating the symptoms of the disease, i.e., causing the disease or symptoms to degenerate. The term "effective amount" or "therapeutically effective amount" means an amount of a compound of the application that (i) treats a particular disease, or (ii) reduces, ameliorates, or eliminates one or more symptoms of a particular disease.

The term "therapeutically effective amount" means an amount of a compound that, when administered to a patient for treating a disease, is sufficient to effect treatment of the disease. The amount of the compound of the present application that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one of ordinary skill in the art based on his own knowledge and disclosure.

The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable adjuvant" refers to those carriers or adjuvants which do not have a significant irritating effect on the organism and which do not impair the biological activity and properties of the active compound.

The "heating temperature", "cooling temperature" or "crystallization temperature" as used herein, unless otherwise specified, may have an error range of + -10, + -5, + -4, + -3, + -2 or + -1 deg.C in degrees Celsius.

Intermediate compounds of the present invention may be prepared by a variety of synthetic methods well 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 alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention.

The chemical reactions of the embodiments of the present invention are accomplished in a suitable solvent that is compatible with the chemical changes of the present invention and the reagents and materials required therefor. In order to obtain the compounds of the present invention, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes on the basis of the embodiments already present.

The present invention will be specifically described by the following examples, which are not meant to limit the present invention in any way.

All solvents used in the present invention are commercially available and can be used without further purification.

In this preparation method and in the present invention, the terms used are as follows:

DCM, dichloromethane, DIAD, diisopropyl azodicarboxylate, DIPEA, diisopropylethylamine, DMF, N, N-dimethylformamide, EA, ethyl acetate, HATU, 2- (7-benzotriazol) -N, N, N ', N ' -tetramethylurea hexafluorophosphate, NBS, N-bromosuccinimide, NIS, N-iodosuccinimide, pd (dppf) Cl ₂, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, pd (PPh ₃)₄, tetrakis (triphenylphosphine) palladium, pdCl ₂, palladium dichloride, pd (OAc) ₂, palladium acetate, pd (PPh ₃)₂Cl₂, bis-triphenylphosphine palladium dichloride, PE, petroleum ether, THF, tetrahydrofuran, DMSO.

Technical effects

The compound (A) has excellent BTK inhibition activity, better BTK inhibition selectivity, excellent in vivo antitumor activity and good oral administration performance, can provide more effective treatment for diseases caused by abnormal expression of BTK, and has better metabolic product types and the occupation ratio under the action of liver microsomes of different species (human liver microsomes, rat liver microsomes and mouse liver microsomes), and basically takes a prototype medicament as a main part (60 min:84% -98%), thereby having better metabolic stability.

1.1X-ray powder diffraction (X-ray powder diffractometer, XRPD)

Instrument model PANALYTICAL EMPYREAN X-ray diffractometer

Test method about 1-2 mg of sample for XRPD detection

The detailed XRPD parameters are as follows:

The X-ray generator is composed of Cu, K alpha,

Light pipe voltage 45kV and light pipe current 40mA

Scanning range is 3-40 degrees (2 theta)

Scanning step length of 0.013 DEG

Scan time 20.4 seconds/step

Light pipe type Empyrean Cu LFF HR (94300337310 x) DK 420877

Rotation time 1s

Sample tray zero background sample tray

Acquisition software HighScore Data Collector

Analysis software Jade 6.

1.2 Differential scanning calorimetric analysis (DIFFERENTIAL SCANNING Calorimeter, DSC)

Instrument model Discovery DSC 250 differential scanning calorimeter

The testing method comprises the steps of taking a sample (1-5 mg) and placing the sample in a DSC sample tray, covering the sample tray, punching holes, and heating the sample to a final temperature at a temperature rising rate of 10 ℃ per minute after the sample is balanced at 25 ℃.

1-5 Mg of sample

Gas flow type nitrogen

Flow rate 50mL/min

Heating initiation temperature 25 DEG C

Termination temperature 300 ℃.

1.3 Thermogravimetric analysis (THERMAL GRAVIMETRIC Analyzer, TGA)

Instrument model Discovery TGA 55 thermogravimetric analyzer

Test method samples were placed in a skinned open aluminum sample pan, and after automatic weighing of the sample mass in a TGA oven, the samples were heated to final temperature at a rate of 10 ℃ per minute.

1-5 Mg of sample

Gas flow type nitrogen

Flow rate of 60mL/min

The heating initial temperature is 25-30 DEG C

Termination temperature 300 ℃.

1.4 Dynamic moisture adsorption and Desorption analysis (DVS)

Vsorp-Enhanced dynamic steam adsorber

Test method a sufficient amount of sample was added to the instrument to simulate dynamic water vapor adsorption and the change in weight at 25 ℃ at different humidity balances was recorded.

The hygroscopicity of the samples was classified according to the weight gain of the samples when 80% rh was reached during adsorption:

(1) Deliquescence by absorbing sufficient water to form a liquid

(2) Has very high hygroscopicity, and the moisture absorption and weight gain are not less than 15 percent

(3) Has hygroscopicity, and weight gain of less than 15% but not less than 2%

(4) Slightly hygroscopic, with a moisture absorption gain of less than 2% but not less than 0.2%

(5) The moisture absorption is not generated, and the moisture absorption weight gain is less than 0.2 percent.

1.4.1 Test parameters for form I:

sample weight 96.821mg

Sample temperature 25 DEG C

Cycle time of 10min

1.4.2 Test parameters for form II:

Sample weight 117.086mg

Sample temperature 25 DEG C

Cycle time of 10min

1.5 High Performance Liquid Chromatography (HPLC)

Instrument model AGILENT HPLC high performance liquid chromatograph 1260

CORTECS C18, 4.6X105 mm,2.7 μm column

Test conditions are that the wavelength is 230nm and the column temperature is 30 DEG C

1.6 Nuclear magnetic resonance Spectrometry (Nuclear Magnetic Resonance Spectroscopy, NMRS)

The model number of the instrument is Bruker AVANCE III HD 300,300/400

Content and test solvent ¹ H-NMR, test solvent DMSO-d6.

Drawings

FIG. 1 is an X-ray powder diffraction pattern of form VII of example 1.

FIG. 2 DSC-TGA spectrum of form VII of example 1.

FIG. 3 is an X-ray powder diffraction pattern of form I of example 2.

FIG. 4 DSC-TGA spectrum of form I of example 2.

FIG. 5 is an X-ray powder diffraction pattern of form II of example 4.

FIG. 6 DSC-TGA spectrum of form II of example 4.

FIG. 7 is an X-ray powder diffraction pattern of form III of example 5.

FIG. 8 DSC-TGA spectrum of form III of example 5.

FIG. 9 is an X-ray powder diffraction pattern of form IV of example 6.

FIG. 10 DSC-TGA spectrum of form IV of example 6.

FIG. 11 is an X-ray powder diffraction pattern of form V of example 7.

FIG. 12 is an X-ray powder diffraction pattern of form VI of example 8.

FIG. 13 DSC-TGA spectrum of form VI of example 8.

FIG. 14 is a DVS plot of form I of example 2.

FIG. 15 DSC-TGA spectrum of form V of example 7.

FIG. 16 is a schematic diagram showing experimental results of REC-1 xenograft tumor model.

FIG. 17 is a schematic diagram of experimental results of TMD8 xenograft tumor model.

FIG. 18 is an XRPD pattern for form I before and after milling.

Detailed Description

For a better understanding of the present invention, reference will now be made to the following examples, which are not intended to limit the scope of the present invention.

Preparation example 1 preparation of the Compound of formula (A)

1. Synthesis of intermediate 3

Into a 250mL round bottom flask was charged 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine (starting material 2,17.28g,1 eq) and anhydrous potassium carbonate (2 eq) and dried in vacuo to remove water. Dried DMF was added as solvent, crushed (S) -methanesulfonic acid 2- ((tert-butoxycarbonyl) amino) -but-3-en-1-yl ester (starting material 1,24.6g,1.5 eq) was replaced with nitrogen. The stirring was heated at 55 ℃ for 12 hours, and the time was prolonged appropriately to ensure the reaction was complete.

After the reaction was completed, water and ethyl acetate were added to extract three times, the ester layers were combined, back-extracted with water once, and washed with saturated brine. And (5) drying the mixture by anhydrous sodium sulfate. Dry column chromatography (eluent: CHCl ₃: meoh=100:1, v/v, same below) afforded product (S) - (1- (4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) but-3-en-2-yl) carbamic acid tert-butyl ester (intermediate 3,19.28 g) in 69.5% yield.

¹H 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％.

2. Synthesis of intermediate 4

To a 350mL pressure-resistant tube was added tert-butyl (S) - (1- (4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) but-3-en-2-yl) carbamate (intermediate 3,9.2 g), 1, 4-dioxane (40 mL) as a solvent, and aqueous ammonia (40 mL). The reaction was sealed at 120 ℃ for 2.5 hours.

After the reaction was completed, the mixture was cooled to room temperature, water and ethyl acetate were added thereto for extraction, and the ester layers were combined and washed with saturated brine. And (5) drying the mixture by anhydrous sodium sulfate. Dry column chromatography (eluent: CHCl ₃: meoh=30:1) afforded product (S) - (tert-butyl 1- (4-amino-5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) but-3-en-2-yl) carbamate (intermediate 4,6.86 g) in 78.0% yield.

¹H NMR(300MHz,CDCl₃)δ8.25(s,1H),7.05(s,1H),5.87-5.74(m,1H),5.72(s,2H),5.34-5.13(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％.

3. Synthesis of intermediate 6

Into a 1L round bottom flask was charged tert-butyl (S) - (1- (4-amino-5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) but-3-en-2-yl) carbamate (intermediate 4,32.9g,1 eq), N- (pyridin-2-yl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (starting material 5,34.8g,1.4 eq) and tetrakis (triphenylphosphine) palladium (17.7 g,0.2 eq). 1, 4-Dioxa-hexacyclic ring (383 mL) was added as solvent and N ₂ was replaced. A2M sodium carbonate solution (76.6 mL) was added with stirring. Stirring was carried out at 90℃under reflux for 5 hours.

Water and ethyl acetate were added for extraction, and the ester layers were combined and washed with saturated brine. And (5) drying the mixture by anhydrous sodium sulfate. The column was run dry, with EA as eluent to remove most of the impurities, and then with CHCl ₃:meoh=30:1 mixture as eluent. The product may contain a small amount of impurities and may be recrystallized from PE to yield a 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.

4. Synthesis of intermediate 7

Into a 1L round bottom flask was added 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 6,32.7g,1 eq) and 600mL DMF was added as solvent. N-bromosuccinimide (12.8 g,1.1 eq) was slowly added with stirring and stirred overnight at room temperature.

After the reaction was completed, water and ethyl acetate were added for extraction, and the ester layers were combined, back-extracted with water once, and saturated brine was washed. And (5) drying the mixture by anhydrous sodium sulfate. The column was run dry, first with a mixture of CHCl ₃: meoh=50:1 as eluent, and then with a mixture of CHCl ₃: meoh=30:1 as eluent. The product (S) - (tert-butyl 1- (4-amino-6-bromo-5- (4- (pyridin-2-ylcarbamoyl) phenyl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) but-3-en-2-yl) carbamate (intermediate 7,25.8 g) was obtained in 68.2% yield.

5. Synthesis of intermediate 8

Into a 250mL round bottom flask were added tert-butyl (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) carbamate (intermediate 7,11.9g,1 eq) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (1.66 g,0.11 eq), 51mL THF was added as solvent and replaced with nitrogen several times to ensure completion. 4M sodium hydroxide solution (8.2 mL) was added with stirring. Reflux stirred at 85 ℃ for 15 hours.

After the reaction was completed, water and ethyl acetate were added to extract, and the ester layers were combined and washed with saturated brine. And (5) drying the mixture by anhydrous sodium sulfate. The product (S) - (4-amino-6-methylene-5- (4- (pyridin-2-ylcarbamoyl) phenyl) -7, 8-dihydro-6H-pyrimido [5,4-b ] pyrazin-7-yl) carbamic acid tert-butyl ester (intermediate 8,8.79 g) was obtained in 85.9% yield by dry column chromatography (eluent: CHCl ₃: meoh=30:1).

6. Synthesis of Compound A

Into a 250mL round bottom flask was added tert-butyl (S) - (4-amino-6-methylene-5- (4- (pyridin-2-ylcarbamoyl) phenyl) -7, 8-dihydro-6H-pyrimido [5,4-b ] pyrazin-7-yl) carbamate (intermediate 8,2.75g,1 eq) and 110mL DCM was added as solvent. Trifluoroacetic acid (10.5 mL) was added dropwise with stirring. Stir at room temperature for 3 hours. After the reaction is finished, the reaction solution is directly spin-dried, the trifluoroacetic acid is carried out by using methanol for several times, and an amino-group-removed Boc protection crude product is obtained after spin-drying and is directly put into the next step.

The product of the previous step was transferred to a 250mL round bottom flask, triethylamine (1 eq) was added, and after stirring for five minutes, 2-butynoic acid (0.511 g,1.1 eq) and 2- (7-oxybenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (2.31 g,1.1 eq) were added, followed by 100mL DCM as solvent. The temperature was reduced to 0℃in an ice-water bath, and triethylamine (1.54 mL+0.77 mL) was added dropwise. Gradually heating to room temperature, and stirring at room temperature for 1.5 hours. The reaction solution was yellowish. Water and DCM were added and the organic phases were combined and washed with saturated brine. Drying over anhydrous sodium sulfate, column chromatography (CHCl ₃: meoh=30:1) gave the final product, compound a (1.88 g), 73.3% yield.

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).

EXAMPLE 1 preparation of crystalline form VII of the Compound of formula (A)

About 20mg of the sample of preparation 1 was weighed at room temperature, put into a glass bottle of a suitable volume, methylene chloride (0.5 mL) was added, and the mixture was sealed with a sealing film, stirred for 3 days, and filtered to obtain a solid. The sample was taken for X-ray powder diffraction and shown as a crystalline solid (form VII), the spectrum is shown in fig. 1, and the XRPD diffraction peak data is shown in table 1. A sample was taken and subjected to 1H-NMR testing, which showed that the sample contained about 10% methylene chloride. The sample is taken for DSC-TGA test, a DSC graph shows that the temperature of the starting point of the endothermic peak is 47.52 ℃ and 151.56 ℃ respectively, the temperature of the peak is 74.24 ℃ and 156.63 ℃ respectively, and the TGA graph shows that the sample has 8.053% weight loss between room temperature and 150 ℃ as shown in figure 2.

Table 1 example 1 XRPD diffraction peak data for form VII

Peak position (2 theta)	Relative strength%	Peak position (2 theta)	Relative strength%	Peak position (2 theta)	Relative strength%
						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

EXAMPLE 2 preparation of Compound of formula (A) form I

At room temperature, 20mg of the sample of preparation 1 was weighed into a glass bottle of an appropriate volume, added to a mixed solvent of n-heptane/toluene (V/v=1/1) of 0.8mL in total, sealed with a sealing film, stirred for 3 days, and filtered to obtain a solid. The sample was taken for X-ray powder diffraction and showed a crystalline solid (form I, anhydrous form) with good crystallinity, the spectrum was shown in figure 3 and the XRPD diffraction peak data was shown in table 2. Samples were taken for DSC-TGA testing, and DSC plots showed a onset of an exothermic peak at 272.89 ℃ at a peak temperature of 274.74 ℃ as shown in FIG. 4.

TABLE 2 XRPD diffraction peak data for example 2 form I

EXAMPLE 3 preparation of Compound of formula (A) form I

At room temperature, 20mg of the sample of preparation 1 was weighed into a glass bottle of an appropriate volume, added to ethyl acetate (0.5 mL), sealed with a sealing film, and stirred for 3 days. Filtering to obtain solid. Samples were taken for X-ray powder diffraction and shown as form I.

EXAMPLE 4 preparation of Compound of formula (A) form II

About 20mg of form VII was weighed into a glass bottle of an appropriate volume, water (0.5 mL) was added, the bottle was sealed with a sealing film, slurried at room temperature for 3 days, and filtered to obtain a solid. The sample was taken for X-ray powder diffraction and showed a crystalline solid (form II) with good crystallinity, the spectrum is shown in figure 5 and the XRPD diffraction peak data is shown in table 3. The sample was taken for DSC-TGA test, the DSC chart showed that the sample had three endothermic peaks, the starting point temperatures of the endothermic peaks were 49.26 ℃, 84.59 ℃ and 168.35 ℃ respectively, the peak temperatures were 69.36 ℃, 98.45 ℃ and 176.96 ℃ respectively, and the TGA chart showed that the sample had a weight loss of 3.417% between room temperature and 100 ℃ as shown in FIG. 6.

TABLE 3 XRPD diffraction peak data for example 4 form II

Peak position (2 theta)	Relative strength%	Peak position (2 theta)	Relative strength%	Peak position (2 theta)	Relative strength%
						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

EXAMPLE 5 preparation of Compound of formula (A) form III

And (5) placing the crystal form II in a 40 ℃ vacuum drying oven for drying for 12 hours to obtain a solid. The sample was taken for X-ray powder diffraction and showed a crystalline solid (form III, anhydrous form) with good crystallinity, the spectrum shown in fig. 7 and the XRPD diffraction peak data shown in table 4. Form III was heated to 160 ℃ and subjected to X-ray powder diffraction with unchanged XRPD pattern. The sample was taken for DSC-TGA test, the DSC chart shows that the sample has three endothermic peaks, the initial point temperatures of the endothermic peaks are 38.13 ℃, 75.07 ℃ and 167.19 ℃, the peak temperatures are 57.40 ℃, 96.32 ℃ and 177.55 ℃, and the TGA chart shows that the temperature of the sample is 3.075% weight loss before 90 ℃, as shown in figure 8.

TABLE 4 XRPD diffraction peak data for example 5 form III

EXAMPLE 6 preparation of Compound form IV of formula (A)

About 20mg of the sample of preparation 1 was weighed into a glass bottle of a suitable volume, methanol (0.3 mL) was added, the bottle was sealed with a sealing film, stirred at room temperature, and filtered after a large amount of solids had been precipitated. The sample was taken for X-ray powder diffraction and showed a crystalline solid (form IV) with good crystallinity, the spectrum is shown in figure 9 and the XRPD diffraction peak data is shown in table 5. The sample is taken for DSC-TGA test, a DSC graph shows that the sample has two endothermic peaks, the initial point temperature of the endothermic peaks is 45.75 ℃ and 159.89 ℃ respectively, the peak temperature is 70.65 ℃ and 166.96 ℃ respectively, and a TGA graph shows that the sample has 7.863% weight loss between room temperature and 200 ℃, and the chart is shown in figure 10.

TABLE 5 XRPD diffraction peak data for example 6 form IV

Peak position (2 theta)	Relative strength%	Peak position (2 theta)	Relative strength%	Peak position (2 theta)	Relative strength%
						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

EXAMPLE 7 preparation of Compound of formula (A) form V

And (5) placing the crystal form IV in a 40 ℃ vacuum drying oven for drying for 12 hours to obtain a solid. Taking a sample for X-ray powder diffraction, showing that the sample is crystalline solid (crystal form V, anhydrous crystal form), the crystallinity is good, the spectrogram is shown in figure 11, the sample is subjected to DSC-TGA test, the DSC chart shows that the sample has two endothermic peaks, the starting point temperature of the endothermic peaks is 36.14 ℃ and 166.61 ℃ respectively, the peak temperature is 65.23 ℃ and 174.53 ℃ respectively, and the TGA chart shows that the sample has 0.874% of weightlessness between room temperature and 280 ℃ and is shown in figure 15. The XRPD diffraction peak data are shown in table 6.

TABLE 6 XRPD diffraction peak data for example 7 form V

Peak position (2 theta)	Relative strength%	Peak position (2 theta)	Relative strength%	Peak position (2 theta)	Relative strength%
						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

EXAMPLE 8 preparation of Compound of formula (A) form VI

About 20mg of the sample of preparation 1 was weighed into a glass bottle of a suitable volume, ethylene glycol (0.5 mL) was added, the bottle was sealed with a sealing film, slurried at room temperature for 3 days, and filtered to obtain a solid. The sample was taken for X-ray powder diffraction and showed a crystalline solid (form VI) with good crystallinity, the spectrum is shown in fig. 12 and the XRPD diffraction peak data is shown in table 7. Taking a sample for DSC-TGA test, wherein a DSC graph shows that the sample has two endothermic peaks, the initial point temperature of the endothermic peaks is 45.54 ℃ and 163.80 ℃ respectively, the peak temperature is 86.78 ℃ and 165.61 ℃ respectively, and a TGA graph shows that the sample has 3.153% of weight loss at room temperature to 120 ℃ and 1.500% of weight loss at 120 to 180 ℃ respectively, as shown in figure 13.

TABLE 7 XRPD diffraction peak data for example 8 form VI

Peak position (2 theta)	Relative strength%	Peak position (2 theta)	Relative strength%	Peak position (2 theta)	Relative strength%
						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

Experimental example 1 solid stability experiments of Compound I and form II of formula (A)

The stability of the compounds of formula (a) form I and form II was investigated upon standing under high humidity (40 ℃ per 75% rh, open) for 7 days.

The compound of formula (A) in form I (5 mg) and form II (5 mg) were weighed separately, placed at the bottom of the sample bottle and spread into a thin layer. Samples were sampled and tested on day 7, and the test results were compared with the initial test results on day 0, as shown in Table 8 below:

TABLE 8 results of solid stability test of Compounds of formula (A) form I and form II

"RH" is relative humidity.

It is concluded that both form I and form II of the compound of formula (A) have good stability.

Experimental example 2 hygroscopicity study of the crystalline form I of the Compound of formula (A)

The compound of formula (a), example 2, form I (about 97 mg) was placed in a DVS sample chamber for testing. Taking a sample after DVS and carrying out X-ray powder diffraction.

Experimental results:

the DVS spectrum of the compound of formula (a) form I is shown in figure 14.

The compound of formula (a) has a hygroscopic weight gain of 0.9% at 25 ℃ and 80% rh, a hygroscopic weight gain of 1.0% at 25 ℃ and 90% rh, and little hygroscopicity, and no conversion of the crystalline form after DVS occurs.

Experimental example 3 grinding test

A sample of form I (example 2, about 10 mg) was taken in an appropriate amount and ground in a mortar for about 5 minutes, and the solid was collected for X-ray powder diffraction. Form I XRPD overlay before and after milling see figure 18.

The conclusion is that the crystal form is unchanged after grinding, which means that the crystal form I can be kept stable in the machining process.

Experimental example 4 evaluation of Bruton kinase (BTK) molecular level enzyme Activity-inhibiting Activity

The enzyme reaction substrate Poly (Glu, tyr) _4:1 was diluted to 20. Mu.g/mL with potassium ion-free PBS (10 mM sodium phosphate buffer, 150mM NaCl,pH 7.2-7.4), reacted at 37℃for 12-16 hours, and after three times with 200. Mu.L/well of T-PBS (PBS containing 0.1% Tween-20), the plate was dried in an oven at 37℃for 1-2 hours. To the above substrate-coated ELISA plate, 49. Mu.L/well (final concentration: 5. Mu.M) of ATP solution diluted with reaction buffer (50mM HEPES pH 7.4,50mM MgCl ₂,0.5mM MnCl₂,0.2mM Na₃VO₄, 1mM DTT) was first added. 1. Mu.L of the compound to be tested (compound well) or DMSO (negative control well) at the corresponding concentration was added to each well, and an enzyme-free control well was used for each experiment. A further 50. Mu.L of BTK tyrosine kinase protein diluted with reaction buffer was added to initiate the reaction.

The reaction system was placed in a 37℃shaker (100 rpm) for 1 hour, then the T-PBS was washed three times, and primary antibody PY 99100. Mu.L/well (Santa Cruz) was added thereto, and the reaction was carried out in a 37℃shaker for 0.5 hour. After washing the plates with T-PBS, 100. Mu.L/well of horseradish peroxidase-labeled goat anti-mouse secondary antibody was added and the mixture was subjected to shaking reaction at 37℃for 0.5 hour. After washing the plate with T-PBS, 100. Mu.L/well of OPD color development solution (2 mg/mL) was added, and the reaction was carried out at 25℃for 1-10 minutes in the absence of light. The reaction was then stopped by adding 2M H ₂SO₄. Mu.L/well and reading with a wavelength-adjustable microplate reader SPECTRA MAX Plus384 at 490nm.

As positive control compounds, compounds S1, S10, ibrutinib, acartinib, S18S, S19S and S20S were used, wherein compounds S1, S10, S18S, S19S and S20S were prepared using methods disclosed in the prior art (e.g. CN 108101905A) or similar methods, ibrutinib and acartinib were purchased from Selleck company.

The inhibition ratio of each compound was determined by the following formula:

The IC ₅₀ value is obtained by adopting a random software of an enzyme label instrument through regression by a four-parameter method. The results are shown in Table 9 below.

TABLE 9 inhibition of BTK by different compounds

Compounds of formula (I)	IC₅₀(nM)
		S1	~1
S10	<10
		Ibrutinib	~1
Acartinib	~10
		S18s	~1
S19s	~1
		S20s	~1
Compound A	0.5

Note that the sample of preparation 1 was used for detection.

The results show that the inhibition activity of the compound A on BTK is superior to that of the previous compounds S1, S10, S18S, S19S and S20S, and is also superior to that of the first-generation BTK inhibitor ibrutinib and the second-generation BTK inhibitor acartinib which are on the market at present.

Experimental example 5in vitro proliferation inhibition Activity detection of Compounds against human B lymphoma cell Ramos (Burkitt lymphoma) and human diffuse large B lymphoma cell TMD8

Cell suspensions (Ramos: 10000 cells/well; TMD8:12000 cells/well) were inoculated into 96-well plates, and after the cell state was stabilized in a37 ℃ incubator for 2 hours, test compounds were added at different concentrations per well (3 multiplex wells were provided per concentration), and a blank control (cell-free well containing only culture solution), a negative control (cell-free well containing only, compound-free well) and a positive compound control were simultaneously set. After 72h of drug addition, 20. Mu.L MTT (5 mg/mL) was added to each well and incubated at 37℃for 4h, 100. Mu.L of triple solution (10% SDS,5% isobutanol, 0.01M HCl) was added and left at 37℃overnight. OD values were determined with an adjustable wavelength microplate reader SPECTRAmax Plus384 at 570 nm.

The inhibition ratio of the compound was determined by the following formula:

the IC ₅₀ value is obtained by adopting a random software of an enzyme label instrument through regression by a four-parameter method. The experiment was independently repeated 3 times, and the results thereof are shown in the following table 10.

The positive control compounds were also identified as compounds S1, S10, ibrutinib, acartinib, S18S, S19S and S20S described above.

TABLE 10 proliferation inhibitory Activity of different Compounds on Ramos cells and TMD8 cells

The above results indicate that at the cellular level, the proliferation inhibition capacity of compound a on B-cell lymphomas is superior to that of the earlier compounds S1, S10, S18S, S19S and S20S, and also superior to that of ibrutinib, a first-generation BTK inhibitor and that of acartinib, a second-generation BTK inhibitor, which have been marketed at present. It is further noted that the compound a of the present invention has a higher proliferation inhibitory activity on Ramos cells and a higher proliferation inhibitory activity on TMD8 cells than other compounds.

Experimental example 6 evaluation of in vivo antitumor Activity

Experimental animals:

TMD8 xenograft tumor model

1) Species mice

2) Line CB-17SCID

3) Week-age and weight of 6-8 weeks, 18-22g

4) Sex of female

5) Supplier Beijing Vitolihua laboratory animal technology Co., ltd

REC-1 xenograft tumor model

1) Species mice

2) Strain BALB/c nude mice

3) Week-age and weight of 6-8 weeks, 17-20g

4) Sex of female

5) Suppliers, shanghai Ling Biotechnology Co., ltd

Cell culture TMD8 cells of human lymphoma were cultured in vitro in suspension under the conditions of RPMI 1640 medium (supplier: gibco; cat# 22400-089; production lot: 4868546) supplemented with 10% fetal bovine serum, 100U/mL penicillin and 100 μg/mL streptomycin, and 37℃5% CO ₂. Conventional treatment passaging was performed twice a week. When the saturation of the cells is 80% -90%, the cells are collected, counted and inoculated.

Human mantle cell lymphoma REC-1 cells were cultured in vitro in suspension under the conditions of RPMI 1640 medium (supplier: gibco; cat# 22400-089; production lot: 1868795) supplemented with 10% fetal bovine serum, 100U/mL penicillin and 100 μg/mL streptomycin, and 37℃5% CO 2. Conventional treatment passaging was performed twice a week. When the saturation of the cells is 80% -90%, the cells are collected, counted and inoculated.

Tumor cell inoculation 0.2ml of 10×10 ⁶ human lymphoma TMD8 cells were inoculated subcutaneously on the right back of each nude mouse (PBS: matrigel=1:1). The administration of the group was started when the average tumor volume reached 104mm ³. Animals were grouped according to tumor volume by an Excel based random grouping software, 6 mice per group.

0.2ML of 5X 10 ⁶ REC-1 cells were inoculated subcutaneously into the right back of each nude mouse (PBS: matrigel=1:1). The administration of the group was started when the average tumor volume reached 100mm ³. Animals were grouped according to tumor volume by an Excel based random grouping software, 6 mice per group.

Preparation of the test substance:

test formulation methods are shown in tables 11 and 12 below:

Table 11 TMD8 xenograft tumor model test object preparation method

Note that ① samples were prepared at the present time, prepared for storage at 4 ℃, and the drug was gently mixed thoroughly prior to administration to the animals by gavage, administration volumes of 10 μl/g, ② were tested using the sample of preparation 1.

Table 12 REC-1 method for preparing test sample of xenograft tumor model

Routine observation of experimental animals the protocol was developed and any modifications passed the evaluation approval of the laboratory animal administration and use committee (IACUC) of the new drug development stock, inc. The use and welfare of experimental animals was performed in compliance with the international committee for laboratory animal assessment and approval (AAALAC) specifications. Daily monitoring of animals for health and mortality, routine examination includes observation of the effects of tumor growth and drug treatment on daily performance of animals such as behavioral activity, intake of water intake (visual inspection only), weight changes (weight measured three times a week), physical signs of appearance or other abnormalities. The number of animal deaths and side effects in the groups were recorded based on the number of animals in each group.

Tumor measurement and experimental indexes, wherein the experimental indexes are used for examining whether tumor growth is inhibited, delayed or cured. Tumor diameters were measured with a vernier caliper three times a week.

The calculation formula of the tumor volume is:

V=0.5a×b²,

a and b represent the major and minor diameters of the tumor, respectively.

The tumor-inhibiting effect of the compound was evaluated by TGI (%) or relative tumor proliferation rate T/C (%). TGI (%) reflects the tumor growth inhibition rate.

Calculation of TGI (%):

TGI (%) = [ 1- (average tumor volume at the end of dosing of a treatment group-average tumor volume at the beginning of dosing of a treatment group)/(average tumor volume at the end of treatment of a solvent control group-average tumor volume at the beginning of treatment of a solvent control group) ] ×100%.

The relative tumor proliferation rate T/C (%) is calculated as follows:

T/C% = T _RTV/C_RTV×100％(T_RTV: treatment group relative tumor volume; C _RTV: negative control group relative tumor volume). The Relative Tumor Volume (RTV) was calculated from the results of the tumor measurements, with the calculation formula rtv=v _t/V₀, where V ₀ is the average tumor volume measured at the time of group administration (i.e. d ₀), V _t is the average tumor volume at the time of a certain measurement, and T _RTV and C _RTV take the same day of data.

Statistical analysis, including mean and Standard Error (SEM) of tumor volumes at each time point for each group. The treatment group showed the best treatment effect on day 15 (REC-1 xenograft tumor model) and day 17 (TMD 8 xenograft tumor model) respectively after dosing, so the difference between groups was evaluated based on this data by statistical analysis. Three or more comparisons were analyzed using one-way ANOVA, and if there was a significant difference in F values, a Games-Howell method was used for testing. All data analysis was performed with SPSS 17.0. p <0.05 was considered a significant difference.

The in vivo efficacy of compound A in human mantle cell lymphoma REC-1 xenograft tumor model is shown in Table 13 and FIG. 16. 15 days after the start of the administration, the tumor volume of the solvent control group tumor-bearing mice reaches 3501mm ³, and the ibrutinib 25mg/kg group has remarkable tumor inhibiting effect (T/C=38%, TGI=64% and p=0.008) compared with the solvent control group, and the tumor volume is 1323mm ³. The tumor volumes of the compound a15mg/kg and 30mg/kg groups were 1034 and 680mm ³, respectively, and had significant tumor inhibition compared to the solvent control group (T/C values of 30% and 19%, TGI values of 73% and 83%, p=0.004 and 0.003, respectively).

Table 13 evaluation of tumor-inhibiting efficacy of compound a on REC-1 xenograft tumor model (calculated based on tumor volume at day 15 post-dose)

Note that a mean ± SEM, b tumor growth inhibition was calculated from T/C and TGI (%) = [1- (T ₁₅-T₀)/(V₁₅-V₀) ]x100; c.p values were calculated from tumor volumes, d. dosing was once daily, e. using the sample of preparation 1.

The in vivo efficacy of compound a in a human lymphoma TMD8 xenograft tumor model is shown in table 14 and figure 17. 17 days after the start of the administration, the tumor volume of the solvent control group tumor-bearing mice reaches 1852mm ³, the ibrutinib 25mg/kg group has remarkable tumor inhibiting effect (T/C= 35.68%, TGI=68.18%, p < 0.001) compared with the solvent control group, and the tumor volume is 661mm ³. The tumor volumes of the 5mg/kg and 10mg/kg groups of compound a were 912 and 553mm ³, respectively, with significant tumor inhibition compared to the solvent control group (T/C values 49.27% and 29.85%, respectively, TGI values 53.78% and 74.35%, respectively, p=0.003 and < 0.001).

Table 14 evaluation of tumor-inhibiting efficacy of compound a on TMD8 xenograft tumor model (calculated based on tumor volume at day 17 post-dose)

Note that a mean ± SEM, b tumor growth inhibition was calculated from T/C and TGI (%) = [1- (T ₁₇-T₀)/(V₁₇-V₀) ]x100; c.p values were calculated from tumor volumes, d. dosing was once daily, e. using the sample of preparation 1.

The results show that in two BTK-sensitive mouse transplantation tumor models, the compound A has obvious tumor growth inhibition activity, and is obviously superior to the first-generation BTK inhibitor ibrutinib which is marketed at present.

In addition, the above experiment in the model of human lymphoma TMD8 xenograft tumor was repeated using compound S18S, and the T/C (%) results are shown in the following table. In the following table, the T/C (%) results for Compound A are also listed as a comparison.

TABLE 15 tumor inhibiting effect of Compounds A and S18 on TMD8 xenograft tumor models

Note that the mode of administration is once daily.

As can be seen from the above data, at lower doses (10 mg/kg), compound A showed better tumor growth inhibition than Compound S18S (15 mg/kg).

Experimental example 7 evaluation of pharmacokinetic properties of rat

SD rats 14, male, weighing 200-220g, were randomly divided into 4 groups of 4/3, and the test compounds were administered by gastric and intravenous administration, respectively, with the specific arrangement shown in Table 16 below

Table 16 methods of administering test compounds

Note that the sample of preparation 1 was used for detection. The drug concentration was 0.3mg/mL in the case of the preparation of 0.5% sodium carboxymethylcellulose (CMC-Na) containing 1% Tween 80, and 0.2mg/mL in the case of the preparation of 5% DMSO/5% Tween 80/90% physiological saline.

Fasted for 12 hours before testing, and drunk freely. Unified feeding is performed 2 hours after administration.

Blood collection time point and sample treatment:

Gastric lavage administration, 0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 hours after administration;

intravenous administration, 5 minutes, 0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 hours after administration;

Venous blood 0.3mL was collected from the retrobulbar venous plexus of the rat at the above set time points, placed in heparinized tubes, centrifuged at 11000rpm for 5 minutes, and plasma was isolated and frozen in a-20 ℃ freezer.

Sample testing and data analysis

The concentration of Compound A in rat plasma was determined by LC/MS/MS method.

Pharmacokinetic parameters were calculated after administration using the non-compartmental model of WinNonlin 5.3 software (Pharsight, USA).

Peak reaching concentration C _max and peak reaching time T _max are measured values;

The area under the drug time curve AUC _0-t value is calculated by adopting a trapezoidal method;

AUC_0-∞＝AUC_0-t+C_t/k_e,

C _t is the blood concentration at the last measurable time point,

K _e is the erasure rate constant;

Elimination half-life t _1/2＝0.693/k_e;

Mean residence time mrt= AUMC/AUC.

Clearance cl=d/AUC _0-∞, steady state volume vss=cl×mrt

Absolute bioavailability f= (AUC _{Stomach lavage}×D_{Vein (V)})/(AUC_{Vein (V)}×D_{Stomach lavage}) x 100%

The test results are shown in Table 17 below:

TABLE 17 pharmacokinetic test results of Compound A and ibrutinib

The results show that the clearance rate of the compound A in rats is obviously lower than that of ibrutinib (20 times), the drug exposure in plasma is also 70 times higher than that of ibrutinib, namely the oral absorption of the compound A is better under the same dosage, and the compound A has better oral bioavailability.

Experimental example 8 evaluation of pharmacokinetic properties of rat

SD rats purchased from Shanghai Sipuler-BiKai laboratory animals Co., ltd, production license number SCXK (Shanghai) 2018-000612, male and female halves, body weight 170-250g, were randomly divided into 2 groups of 6, each of which were respectively given gastric and intravenous administration of test compounds, and the specific arrangement is shown in Table 18 below.

Table 18 methods of administering test compounds

Note that form I samples of example 2 were used for detection. Parenteral administration with 10% aqueous sds: EL, 0.5% MC physiological saline solution=1:2:97 (v: v) was prepared to give a drug concentration of 1.5mg/mL, and N, N-dimethylformamide was prepared as a solution in physiological saline (40:60, v/v) for intravenous administration to give a drug concentration of 3mg/mL.

Fasted for 12 hours before testing, and drunk freely. Unified feeding is performed 4 hours after administration.

Blood collection time point and sample treatment:

gastric lavage administration, 0.25,0.5,1.0,2.0,3.0,5.0,7.0,9.0 and 24 hours after administration;

Intravenous administration, 5 minutes, 0.25,0.5,1.0,2.0,3.0,5.0,7.0 and 24 hours after administration;

Venous blood 0.2mL was collected from the retrobulbar venous plexus of the rat at the above set time point, placed in EDTA-K2-functionalized test tubes, centrifuged at 11000rpm for 5 minutes, separated into plasma for 2 hours, and stored at-70 ℃ for testing.

Sample testing and data analysis

The concentration of Compound A in rat plasma was determined by LC/MS/MS method. The calculation software and parameters are as described in the corresponding parts of experimental example 7. The test results are shown in Table 19 below:

TABLE 19 pharmacokinetic test results of Compound A (form I of example 2)

The above results indicate that compound a (form I of example 2) has low clearance in rats, high drug exposure in plasma, and good oral bioavailability of compound a (form I of example 2).

Therefore, the compound A is an orally taken high-selectivity high-activity BTK inhibitor with novel structure, the in-vitro activity is obviously superior to that of the BTK inhibitor which is marketed abroad at present, the tumor growth inhibition activity is obviously superior to that of a positive control drug ibrutinib at the same dosage, and furthermore, the crystal form of the compound shown in the formula (A) has good crystallinity, and the preferred crystal form has good stability, is easy to prepare medicines and has high bioavailability. The compound A and the specific crystal form thereof are proved to have great development value.

The above embodiments are merely auxiliary illustrations in nature and are not intended to limit the embodiments of the application object or the application or uses of these embodiments. In this document, the term "exemplary" represents "as an example, instance, or illustration. Any one of the exemplary embodiments herein is not necessarily to be construed as preferred or advantageous over other embodiments.

Furthermore, while at least one exemplary embodiment or comparative example has been presented in the foregoing description, it should be appreciated that a vast number of variations exist for the invention. It should also be appreciated that the embodiments described herein are not intended to limit the scope, applicability, or configuration of the claimed subject matter in any way. Rather, the foregoing embodiments will provide a convenient road to those skilled in the art for implementing the described embodiment or embodiments. Furthermore, various changes may be made in the function and arrangement of elements without departing from the scope defined by the claims, which includes known equivalents and all foreseeable equivalents at the time of filing this patent application.

Claims

1. A compound of formula (A) in crystalline form, which is form I, characterized by an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angles of 4.8 + -0.2 DEG, 11.6 + -0.2 DEG, 13.6 + -0.2 DEG, 16.2 + -0.2 DEG, 18.7 + -0.2 DEG, 23.4 + -0.2 DEG,

。

2. The crystalline form of compound of formula (a) according to claim 1, characterized by an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2Θ angles of 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 crystalline form of compound of formula (a) according to claim 1, characterized by an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2Θ angles of 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 °.

4. The crystalline form of compound of formula (a) according to claim 1, form I, characterized by an X-ray powder diffraction pattern having 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 crystalline form of compound of formula (a) according to claim 1, form I, characterized by an X-ray powder diffraction pattern having 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 crystalline form of compound of formula (a) according to claim 1, form I, characterized by an X-ray powder diffraction pattern having 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. A compound of formula (a) in crystalline form according to claim 1, form I, characterized in that it has an X-ray powder diffraction pattern substantially as shown in figure 3.

8. The crystalline form of compound of formula (a) according to any one of claims 1-7, which form I has a differential scanning calorimetry trace with an exotherm peak at 274.74 ±3 ℃.

9. A compound of formula (a) according to any one of claims 1 to 7 in crystalline form I having a DSC profile substantially as shown in figure 4.

10. A compound of formula (A) in crystalline form, which is form II, characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles of 7.0 + -0.2 DEG, 7.9 + -0.2 DEG, 8.5 + -0.2 DEG, 10.6 + -0.2 DEG, 15.0 + -0.2 DEG, 22.1 + -0.2 DEG, 25.3 + -0.2 DEG,

。

11. The crystalline form of compound of formula (a) according to claim 10, characterized by an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2Θ angles of 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 °.

12. The crystalline form of compound of formula (a) according to claim 10, which form II is characterized by an X-ray powder diffraction pattern having 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 crystalline form of compound of formula (a) according to claim 10, which form II is characterized by an X-ray powder diffraction pattern having 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 crystalline form of compound of formula (a) according to claim 10, which form II is characterized by an X-ray powder diffraction pattern having 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°,26.3±0.2°.

15. The crystalline form of the compound of formula (a) according to claim 10, characterized in that it has an X-ray powder diffraction pattern substantially as shown in figure 5.

16. A compound of formula (A) in crystalline form, which is form III, characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles of 4.3 + -0.2 DEG, 7.1 + -0.2 DEG, 8.0 + -0.2 DEG, 8.6 + -0.2 DEG, 10.6 + -0.2 DEG, 15.1 + -0.2 DEG, 16.2 + -0.2 DEG, 22.3 + -0.2 DEG, 25.5 + -0.2 DEG,

。

17. The crystalline form of compound of formula (a) according to claim 16, characterized by an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2Θ angles of 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 crystalline form of compound of formula (a) according to claim 16, which form III is characterized by an X-ray powder diffraction pattern having 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 crystalline form of compound of formula (a) according to claim 16, which form III is characterized by an X-ray powder diffraction pattern having 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°,25.5±0.2°.

20. The crystalline form of the compound of formula (a) according to claim 16, which form III has an X-ray powder diffraction pattern substantially as shown in figure 7.

21. A compound of formula (A) in crystalline form, which is form IV, characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles of 5.1 + -0.2 DEG, 6.3 + -0.2 DEG, 9.7 + -0.2 DEG, 12.8 + -0.2 DEG, 14.1 + -0.2 DEG, 19.0 + -0.2 DEG,

。

22. The crystalline form of compound of formula (a) according to claim 21, characterized by an X-ray powder diffraction pattern having 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 crystalline form of compound of formula (a) according to claim 21, form IV, characterized by an X-ray powder diffraction pattern having 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°,26.3±0.2°.

24. The crystalline form of the compound of formula (a) according to claim 21, characterized in that it has an X-ray powder diffraction pattern substantially as shown in figure 9.

25. A compound of formula (A) in crystalline form, which is form V, characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles of 5.6 + -0.2 DEG, 7.1 + -0.2 DEG, 11.5 + -0.2 DEG, 13.8 + -0.2 DEG, 14.3 + -0.2 DEG, 17.0 + -0.2 DEG, 21.9 + -0.2 DEG,

。

26. The crystalline form of compound of formula (a) according to claim 25, characterized by an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2Θ angles of 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 crystalline form of compound of formula (a) according to claim 25, wherein form V has an X-ray powder diffraction pattern with 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 crystalline form of compound of formula (a) according to claim 25, characterized in that it has an X-ray powder diffraction pattern substantially as shown in figure 11.

29. A compound of formula (A) in crystalline form, which is form VI, characterized by an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angles, 5.0 + -0.2 DEG, 6.2 + -0.2 DEG, 9.4 + -0.2 DEG, 12.5 + -0.2 DEG, 15.2 + -0.2 DEG, 21.4 + -0.2 DEG, 24.7 + -0.2 DEG,

。

30. The compound of formula (a) in crystalline form according to claim 29, wherein the crystalline form VI has an X-ray powder diffraction pattern with 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 °,24.7±0.2 °.

31. The crystalline form of compound of formula (a) according to claim 29, characterized in that it has an X-ray powder diffraction pattern substantially as shown in figure 12.

32. A compound of formula (A) in crystalline form, which is form VII, characterized by an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angles, 5.7 + -0.2 DEG, 7.5 + -0.2 DEG, 10.8 + -0.2 DEG, 12.5 + -0.2 DEG, 17.4 + -0.2 DEG, 21.8 + -0.2 DEG, 25.1 + -0.2 DEG,

。

33. The compound of formula (a) in crystalline form according to claim 32, wherein the crystalline form VII has an X-ray powder diffraction pattern with 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°,25.1±0.2°.

34. The crystalline form of compound of formula (a) according to claim 32, characterized in that it has an X-ray powder diffraction pattern substantially as shown in figure 1.

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

36. The pharmaceutical composition of claim 35, further comprising one or more pharmaceutically acceptable carriers.

37. Use of a compound of formula (a) in crystalline form according to any one of claims 1 to 34, or a pharmaceutical composition according to claim 35 or 36, in the manufacture of a medicament for the treatment of a BTK related disorder.

38. The use of claim 37, wherein the BTK-related disorder involves a deregulation of BTK protein expression, level or activity.

39. The use of claim 37, wherein the BTK-related disorder is selected from a neoplastic disease and an autoimmune disease.

40. The use according to claim 39, wherein the neoplastic disease is a hematological neoplasm.

41. The use according to claim 39, wherein the neoplastic disease is leukemia or lymphoma.

42. The use according to claim 39, wherein the neoplastic disease is a B-cell lymphoma.

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