CN109963855A - A kind of crystal form and preparation method of BTK kinase inhibitor - Google Patents
A kind of crystal form and preparation method of BTK kinase inhibitor Download PDFInfo
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- 239000013078 crystal Substances 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 229940125814 BTK kinase inhibitor Drugs 0.000 title abstract description 4
- 238000002425 crystallisation Methods 0.000 claims abstract description 34
- 230000008025 crystallization Effects 0.000 claims abstract description 33
- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 210000003719 b-lymphocyte Anatomy 0.000 claims description 10
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 7
- 229910002483 Cu Ka Inorganic materials 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 4
- 208000023275 Autoimmune disease Diseases 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 239000003814 drug Substances 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- -1 2,6- difluoro phenoxy Chemical group 0.000 abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 5
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 abstract description 5
- 238000001953 recrystallisation Methods 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 3
- 239000002904 solvent Substances 0.000 abstract description 2
- 231100000053 low toxicity Toxicity 0.000 abstract 1
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
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- 108091000080 Phosphotransferase Proteins 0.000 description 4
- 238000002441 X-ray diffraction Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 102000020233 phosphotransferase Human genes 0.000 description 4
- 238000011160 research Methods 0.000 description 4
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- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 2
- 102000004422 Phospholipase C gamma Human genes 0.000 description 2
- 108010056751 Phospholipase C gamma Proteins 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000013557 residual solvent Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 229910017488 Cu K Inorganic materials 0.000 description 1
- 229910017541 Cu-K Inorganic materials 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 102000003945 NF-kappa B Human genes 0.000 description 1
- 108010057466 NF-kappa B Proteins 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 229940100514 Syk tyrosine kinase inhibitor Drugs 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
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- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
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- 235000019441 ethanol Nutrition 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 108010074605 gamma-Globulins Proteins 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 208000019420 lymphoid neoplasm Diseases 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229940127554 medical product Drugs 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
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- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 230000027425 release of sequestered calcium ion into cytosol Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
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- 238000002560 therapeutic procedure Methods 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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Abstract
The present invention relates to the crystal forms and preparation method of a kind of BTK kinase inhibitor.Specifically, the present invention relates to (R) -1- (1- Antiepilepsirin -3- base) -4- amino -3- (4- (2,6- difluoro phenoxy group) phenyl) -1,6- dihydro-7 H-pyrrolo simultaneously [2,3-d] pyridazine -7- ketone (formula (I) compound) II type crystallization and preparation method.The II type crystallization of formula obtained by the present invention (I) compound has good chemical stability and stability of crystal form, and recrystallisation solvent low toxicity and low residue used, can be preferably applied to clinical treatment.
Description
The present invention relates to the crystal forms and preparation method of a kind of BTK kinase inhibitor, more particularly to (R) -1- (1- Antiepilepsirin -3- base) -4- amino -3- (4- (2,6- difluoro phenoxy group) phenyl) -1,6- dihydro-7 H-pyrrolo simultaneously [2,3-d] pyridazine -7- ketone II type crystallization and preparation method.Formula (I) compound prepared according to the method for the present invention can be used for the treatment of B cell malignant tumour and autoimmune disease.
Bruton tyrosine protein kinase (BTK) is a non-recipient cytoplasm tyrosine kinase, belongs to Tec family kinase, and wherein Tec family kinase member further includes Tec, Itk, Txk and Bmx, and most of these kinases are all mainly expressed in hematopoietic cell.BTK develops B cell, and differentiation, mature and signaling is vital.The property the lost mutation of the function of BTK causes the chain gamma-globulin of X to lack mass formed by blood stasis (XLA) in human body, and immune deficiency relevant to X is caused in mouse.XLA patient has normal pre B cell group in their marrow, but these cells can not mature and entrance circulation.Therefore, the B cell that these patients also do not recycle substantially, and antibody cannot be generated.BTK plays critical effect in the B cell proliferation and activation mediated by B-cell receptor (BCR).BCR is activated, BTK translocates to plasma membrane, and plasma membrane is phosphorylated, and subsequent start-up signal event includes activation phospholipase C γ 2 (PLC γ 2), eventually leads to calcium mobilization and is related to the transcriptional control of Nuclear factor kappa B.Because of the indispensable effect in BCR signal path, the kinase activity of BTK is critical for the development and maintenance of various B cell malignant tumours, the hypotype of (crucial non-Hodgkin lymphoma) including chronic lymphocytic leukemia (CLL) and some non-Hodgkin lymphoma, lymphoma mantle cell (MCL) and diffusivity large B cell lymphoid tumor (DLBCL).In addition, B cell is in rheumatoid arthritis, systemic loupus erythematosus, the effect in the pathogenesis of multiple sclerosis and other immunological diseases is confirmed by clinic.Therefore, targeting micromolecular inhibitor BTK is beneficial in the therapeutic process of B cell malignant tumour and autoimmune disease.
WO2016/007185 is related to a kind of formula (I) compound, that is (R) -1- (1- Antiepilepsirin -3- base) -4- amino -3- (4- (2,6- difluoro phenoxy group) phenyl) -1,6- dihydro-7 H-pyrrolo simultaneously [2,3-d] pyridazine -7- ketone, the compound is novel B TK kinase inhibitor, and in Kinase Selectivity, clinical efficacy or indication and safety etc. make moderate progress.But any research is not carried out to the crystal form of the compound in the patent.
CN106939002A discloses the amorphous substance and I crystal of a kind of formula (I) compound, but above-mentioned amorphous substance and I crystal have that stability is bad, therefore, improve each side's surface properties of above-mentioned product be it is necessary, need to find its better crystal form.
Summary of the invention
The present invention provides (R) -1- (1- Antiepilepsirin -3- base) -4- amino -3- (4- (2,6- difluoro phenoxy group) phenyl) -1,6- dihydro-7 H-pyrrolo simultaneously [2,3-d] pyridazine -7- ketone (as shown in formula (I)) II type crystallization and preparation method
The series of crystallization product that compound shown in formula (I) obtains under different crystallization conditions, X- diffraction and DSC detection have been carried out to gained crystallized product, it was found that compound shown in formula (I) is under conventional crystallization condition, a kind of available crystal form having good stability, we are called the crystallization of II type.The DSC map of II type crystallization in the application, which is shown in 165 DEG C, nearby melting endothermic peak, it is radiated using Cu-Ka, obtain the X-ray powder diffraction collection indicated with 2 θ angles and interplanar distance (d value), there is characteristic peak at its 2 angle θ of angle of diffraction at 4.64,5.18,5.62,11.43,12.21 and 20.47, wherein, the error range at each 2 angle θ of characteristic peak is ± 0.2.
Further, the crystallization is radiated using Cu-Ka, obtain the X-ray powder diffraction collection indicated with 2 θ angle of the angle of diffraction, there is characteristic peak at its 2 angle θ of angle of diffraction at 4.64,5.18,5.62,11.13,11.43,12.21,12.87,14.03,19.60,20.47 and 24.16, wherein, the error range at each 2 angle θ of characteristic peak is ± 0.2.
Further, the X-ray powder diffraction collection of the crystallization is as shown in Figure 3, its 2 angle θ of angle of diffraction is in 4.64 (19.04), 5.18 (17.05), 5.62 (15.71), 8.11 (10.89), 8.99 (9.83), 10.34 (8.55), 11.13 (7.94), 11.43 (7.74), 12.21 (7.24), 12.87 (6.87), 14.03 (6.31), 14.47 (6.12), 14.86 (5.96), 15.63 (5.66), 16.07 (5.51), 16.49 (5.37), 17.78 (4.98), 18.40 (4.82), 19.60 (4 .53), 20.47 (4.34), 21.31 (4.17), 24.16 (3.68), 25.13 (3.54), there is characteristic peak at 26.87 (3.32) and 28.50 (3.13), wherein the error range at each 2 angle θ of characteristic peak is ± 0.2.
The present invention also provides preparation (R) -1- (1- Antiepilepsirin -3- base) -4- amino -3- (4- (2,6- difluoro phenoxy group) phenyl) -1,6- dihydro-7 H-pyrrolo simultaneously [2,3-d] pyridazine -7- ketone II type crystallization method.This method comprises the following steps:
(1) compound shown in any crystal form or unformed formula (I) is dissolved in suitable organic solvent, or compound shown in any crystal form or unformed formula (I) is turned brilliant in organic solvent, cooling, crystallization, the organic solvent are acetonitrile.
(2) it filtering for crystallizing and washs, it is dry.
The method of recrystallization is not particularly limited, and can be carried out with common recrystallization operation method.For example, can with compound shown in raw material formula (I) after organic solvent heating for dissolving slowly cooling crystallization, after the completion of crystallization, through filtration drying, required crystallization can be obtained.Specifically, the crystalline solid of institute's leaching usually under reduced pressure, at 30~100 DEG C or so, is preferably dried in vacuo under 40~60 DEG C of heating conditions, can achieve the effect that remove recrystallization solvent.
It is measured by differential scanning calorimeter (DSC), X- diffracting spectrum, crystal form research has been carried out to compound crystalline solid shown in obtained formula (I), while being detected to the dissolvent residual of gained crystallization.
Compound II type crystallization shown in the formula (I) of the method according to the invention preparation does not contain or only containing the residual solvent of lower content, meet the limitation requirement in relation to medical product residual solvent as defined in National Pharmacopeia, thus crystallization of the invention can be used preferably as medicating active ingredients.
Research has shown that, the II type crystallization of compound shown in formula (I) prepared by the present invention has good stability under conditions of illumination, high temperature, high humidity, and grinding, pressure and it is heated etc. under the conditions ofs, stability of crystal form is good, it can satisfy the medicinal requirements of production and transport storage, stable processing technique is repeatable controllable, can adapt in industrialized production.
The X-ray powder diffraction collection of the unformed sample of compound shown in Fig. 1 formula (I).
The DSC map of the unformed sample of compound shown in Fig. 2 formula (I).
The X-ray powder diffraction collection of the crystallization of compound II type shown in Fig. 3 formula (I).
The DSC map of the crystallization of compound II type shown in Fig. 4 formula (I).
The X-ray powder diffraction collection of the crystallization of compound I type shown in Fig. 5 formula (I).
The DSC map of the crystallization of compound I type shown in Fig. 6 formula (I).
The DVS figure of the crystallization of compound I type shown in Fig. 7 formula (I).
The DVS figure of the crystallization of compound II type shown in Fig. 8 formula (I).
The present invention is explained in greater detail below with reference to embodiment, the embodiment of the present invention is only used to illustrate the technical scheme of the present invention, and non-limiting the spirit and scope of the invention.
Experiment test equipment used
1, DSC is composed
Instrument model: 1 STAR of Mettler Toledo DSC
e System
Purge gass: nitrogen
Heating rate: 10.0 DEG C/min
Temperature range: 40-250 DEG C
2, x-ray diffraction pattern
Instrument model: Bruker D8 Focus X-ray powder diffraction instrument
Ray: monochromatic Cu-K alpha ray (λ=1.5406)
Scanning mode: the θ of θ/2, scanning range: 2-40
o
Voltage: 40kV, electric current: 40mA
Embodiment 1
It takes compound shown in 5g formula (I) (preparing by method disclosed in WO2016/007185) in 100ml single port bottle, 50ml acetonitrile is added, be heated to solid and all dissolve, cool down crystallization, is stirred overnight.Next day filters, dry solid 4.03g, yield 80.6%.The X-ray diffraction of the crystallized sample is shown in Fig. 3, wherein about 4.64 (19.04), 5.18 (17.05), 5.62 (15.71), 8.11 (10.89), 8.99 (9.83), 10.34 (8.55), 11.13 (7.94), 11.43 (7.74), 12.21 (7.24), 12.87 (6.87), 14.03 (6.31), 14.47 (6.12), 14.86 (5.96), 15.63 (5.66), 16.07 (5.51), 16.49 (5.37), 17.78 (4.98), 18.40 (4.82), 19.60 (4.53), 20.47 (4.3 4) there is characteristic peak at, 21.31 (4.17), 24.16 (3.68), 25.13 (3.54), 26.87 (3.32) and 28.50 (3.13).DSC spectrogram is shown in Fig. 4, nearby has melting endothermic peak at 165 DEG C, this crystal form is defined as II crystal form.
Embodiment 3
It takes compound shown in 300mg formula (I) (preparing by method disclosed in WO2016/007185) in 25ml single port bottle, 2ml ethyl alcohol is added, dissolves by heating, cool down crystallization, is stirred overnight.Next day filters, dry solid 241mg, yield 80.3%.The X-ray diffraction of the crystallized sample is shown in Fig. 5, wherein about 4.29 (20.56), 6.58 (13.42), 7.58 (11.66), 10.07 (8.78), 10.72 (8.24), 11.68 (7.57), 12.49 (7.08), 13.74 (6.44), there is characteristic peak at 14.12 (6.26), 15.86 (5.58) and 19.98 (4.44).DSC spectrogram is shown in Fig. 6, nearby has melting endothermic peak at 141 DEG C, this crystal form is defined as I crystal.
Embodiment 4
Compound shown in 200mg formula (I) (preparing by embodiment 2) is taken, 2ml acetonitrile is added, is stirred overnight.Next day filters, dry solid 172mg, yield 86.0%.The X-ray diffraction and DSC map of the crystallized sample are compared through research, determine that product is II crystal form.
Embodiment 5
The resulting II type crystallized product sample of embodiment 1 and the resulting I type crystallized product sample opening of embodiment 3 are divided into placement, it investigates at illumination (4500Lux), heats (40 DEG C, 60 DEG C), the stability of sample under the conditions of high humidity (RH75%, RH90%).Investigating sample time is 5 days and 10 days, and HPLC detection purity is shown in Table 1.
The stability of compound I crystal shown in table 1, formula (I) and II crystal form samples compares
Study on the stability is the result shows that the crystallization of compound I type shown in formula (I) and II type crystallized sample are placed under conditions of opening respectively, and under illumination, hot conditions, the stability of II type crystallization is better than I type crystallized sample, both under super-humid conditions quite.
Embodiment 6
It will be crystallized by compound II type shown in formula (I) made from 1 method of embodiment and be ground, be heated and compressing tablet process, result of study show stable crystal form, detailed experimental data is referring to the following table 2.
The special stability study of compound II crystal form shown in table 2, formula (I)
Embodiment 7
By the resulting II type crystallized product sample of embodiment 1 and the resulting I type crystallized product sample of embodiment 2 at 25 DEG C, DVS test is carried out under different humidity, result of study shows, I crystal is drawn moist larger, when RH is 0%~80%, weight gain 4.18%, (i.e. 25 DEG C under normal storage conditions, RH60% about 3.26%, the II crystal form that absorbs water under) have draw it is moist, RH be 0%~80% when, weight gain 1.18%, absorb water about 0.93% under (i.e. 25 DEG C, RH60%) under normal storage conditions, detailed experimental data is referring to Fig. 7,8.
Claims (6)
- The II type of compound shown in formula (I) crystallizes, it is characterized by: being radiated using Cu-Ka, obtain the X-ray powder diffraction collection indicated with 2 θ angle of the angle of diffraction, there is characteristic peak at its 2 angle θ of angle of diffraction at 4.64,5.18,5.62,11.43,12.21 and 20.47, wherein, the error range at each 2 angle θ of characteristic peak is ± 0.2
- The II type of compound shown in formula (I) according to claim 1 crystallizes, it is characterized by: being radiated using Cu-Ka, obtain the X-ray powder diffraction collection indicated with 2 θ angle of the angle of diffraction, there is characteristic peak at its 2 angle θ of angle of diffraction at 4.64,5.18,5.62,11.13,11.43,12.21,12.87,14.03,19.60,20.47 and 24.16, wherein, the error range at each 2 angle θ of characteristic peak is ± 0.2.
- The II type of compound shown in formula (I) according to claim 1 crystallizes, it is characterised in that has X-ray powder diffraction collection as shown in Figure 3,2 angle θ of the angle of diffraction is 4.64,5.18,5.62,8.11,8.99,10.34,11.13,11.43,12.21,12.87,14.03,14.47,14.86,15.63,16.07,16.49,17.78,18.40,19.60,20.47,21.31,24.16,25.13, there is characteristic peak at 26.87 and 28.50, wherein the error range at each 2 angle θ of characteristic peak is ± 0.2.
- A method of the II type crystallization of compound shown in the formula (I) as described in claims 1 to 3 any one being prepared, the method includes the following steps:1) compound shown in any crystal form or unformed formula (I) is dissolved in suitable organic solvent, cooling, crystallization, or compound shown in any crystal form or unformed formula (I) is turned brilliant in organic solvent, the organic solvent is acetonitrile；2) it filtering for crystallizing and washs, it is dry.
- A kind of pharmaceutical composition, the crystallization of II type and pharmaceutically acceptable carrier containing compound shown in formula described in claims 1 to 3 any one (I).
- Purposes of the pharmaceutical composition described in the crystallization of II type described in claims 1 to 3 any one or claim 5 in the drug of preparation treatment B cell malignant tumour and autoimmune disease.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2017105738241 | 2017-07-14 | ||
| CN201710573824 | 2017-07-14 | ||
| PCT/CN2018/095573 WO2019011316A1 (en) | 2017-07-14 | 2018-07-13 | Crystalline form of btk kinase inhibitor and preparation method therefor |
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| CN109963855A true CN109963855A (en) | 2019-07-02 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106573001A (en) * | 2014-07-07 | 2017-04-19 | 永恒生物科技公司 | Aminopyridazinone compounds as protein kinase inhibitors |
| CN106939002A (en) * | 2016-01-05 | 2017-07-11 | 江苏恒瑞医药股份有限公司 | A kind of crystal form of BTK kinase inhibitors and preparation method thereof |
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- 2018-07-13 WO PCT/CN2018/095573 patent/WO2019011316A1/en active Application Filing
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106573001A (en) * | 2014-07-07 | 2017-04-19 | 永恒生物科技公司 | Aminopyridazinone compounds as protein kinase inhibitors |
| CN106939002A (en) * | 2016-01-05 | 2017-07-11 | 江苏恒瑞医药股份有限公司 | A kind of crystal form of BTK kinase inhibitors and preparation method thereof |
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| WO2019011316A1 (en) | 2019-01-17 |
| CN109963855B (en) | 2021-09-03 |
| TW201908320A (en) | 2019-03-01 |
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