CN113603685A - Crystal form of Fenebbrutinib compound, preparation method and application thereof - Google Patents
Crystal form of Fenebbrutinib compound, preparation method and application thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention relates to a crystal form of a compound I, a preparation method thereof, a pharmaceutical composition containing the crystal form, and application of the crystal form in preparing a medicine for treating diseases related to Relapsing Multiple Sclerosis (RMS) and primary multiple sclerosis (PPMS). The crystal form of the compound I provided by the invention has important value for the development of the medicine in the future.
Description
Technical Field
The present invention relates to the field of pharmaceutical chemistry. In particular to a crystal form of a Fenebbrutinib compound, a preparation method and application thereof.
Background
The Fenebutriniib is an oral Bruton Tyrosine Kinase (BTK) inhibitor and has potential anti-tumor activity. It inhibits the activity of BTK and inhibits the activation of the b-cell antigen receptor (BCR) signaling pathway after administration. This prevents b-cell activation and BTK-mediated activation of downstream survival pathways, thereby inhibiting the growth of malignant b-cells that overexpress BTK. BTK is a cytoplasmic tyrosine kinase src-associated BTK/Tec family member that is overexpressed in b-cell malignancies; it also plays an important role in the development, activation, signal transduction, proliferation and survival of b lymphocytes.
The chemical name of the fenebuttinib compound is 2- [1, 6-dihydro-3 ' - (hydroxymethyl) -1-methyl-5- [ [5- [ (2S) -2-methyl-4- (3-oxetanyl) -1-piperazinyl ] -2-pyridinyl ] amino ] -6-oxo [3,4' -bipyridine ] -2' -yl ] -3,4,7, 8-tetrahydro-7, 7-dimethyl-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-1 (6H) -one (hereinafter referred to as "compound I"), which has the following structural formula:
the crystal form is a solid form of crystal lattices formed by long-range ordered arrangement of solid molecules of the compound in a microscopic three-dimensional structure. Drug polymorphism refers to the phenomenon of a solid drug molecule in two or more different crystal forms. Because different crystal forms have different physicochemical properties, different crystal forms of solid drug molecules can be dissolved and absorbed in vivo differently, so that the clinical curative effect and safety of the drug are influenced to a certain extent, and especially for insoluble solid drugs, the influence of the crystal forms on the bioavailability is larger. Therefore, the drug crystal form is an important ring in the research and development process of solid drugs and is also an important content of drug quality control.
The inventor of the application unexpectedly discovers that different crystal forms of the compound I provided by the invention have advantages in the aspects of physicochemical properties, preparation processing performance, bioavailability and the like, for example, at least one of the aspects of melting point, solubility, hygroscopicity, purification effect, stability, adhesiveness, compressibility, fluidity, in-vivo and in-vitro dissolution, bioavailability and the like has advantages, provides a better choice for the development of a medicine containing the compound I, and has very important significance.
Disclosure of Invention
The invention mainly aims to provide a novel crystal form of a compound I and a preparation method and application thereof.
According to an object of the present invention, the present invention provides a crystalline form of compound I.
Further, the present invention provides that the crystalline form of compound I may be a crystalline form DCI (hereinafter referred to as crystalline form DCI).
On the one hand, by using Cu-Ka radiation, the X-ray powder diffraction of the crystal form DCI has characteristic peaks at 1,2 or 3 of diffraction angle 2theta values of 3.9 degrees +/-0.2 degrees, 6.7 degrees +/-0.2 degrees and 16.0 degrees +/-0.2 degrees.
Further, by using Cu-Ka radiation, the X-ray powder diffraction of the crystal form DCI has characteristic peaks at 1,2 or 3 of diffraction angle 2theta values of 8.0 degrees +/-0.2 degrees, 14.5 degrees +/-0.2 degrees, 17.1 degrees +/-0.2 degrees; preferably, the X-ray powder diffraction of the crystal form DCI has characteristic peaks at 3 points with diffraction angle 2theta values of 8.0 degrees +/-0.2 degrees, 14.5 degrees +/-0.2 degrees and 17.1 degrees +/-0.2 degrees.
Further, by using Cu-Ka radiation, the X-ray powder diffraction of the crystal form DCI has characteristic peaks at 1,2 or 3 of diffraction angle 2theta values of 10.3 degrees +/-0.2 degrees, 15.2 degrees +/-0.2 degrees, 18.4 degrees +/-0.2 degrees; preferably, the X-ray powder diffraction of the crystal form DCI has characteristic peaks at three points with diffraction angle 2theta values of 10.3 degrees +/-0.2 degrees, 15.2 degrees +/-0.2 degrees and 18.4 degrees +/-0.2 degrees.
Without limitation, the X-ray powder diffraction pattern of the crystalline form DCI is substantially as shown in fig. 1.
Without limitation, heating of the DCI crystal form to 167 ℃, an endothermic peak beginning at about 264 ℃, and an exothermic peak beginning at about 209 ℃, results in a differential scanning calorimetry trace substantially as shown in fig. 2.
According to the purpose of the present invention, the present invention further provides a preparation method of the DCI in the crystal form, wherein the preparation method comprises:
dissolving the solid of the compound I in an ether solvent, then adding an alkane solvent to form a suspension, stirring for a period of time at a certain temperature, separating and drying to obtain the crystal form of the compound I.
Further, the selected ether solvent is preferably 1, 4-dioxane; the alkane solvent is preferably n-heptane; the volume ratio of the alkane solvent to the ether solvent is preferably 1: 1; the temperature is preferably-20 ℃ to 10 ℃, more preferably 5 ℃. The stirring time is preferably 10 to 20 hours, and the drying condition is preferably 20 to 50 ℃.
According to the purpose of the present invention, the present invention also provides a pharmaceutical composition, which comprises an effective therapeutic amount of the DCI in a crystalline form and a pharmaceutically acceptable carrier or adjuvant.
Further, the present invention provides the use of the crystalline form DCI in the manufacture of a medicament for the treatment of Relapsing Multiple Sclerosis (RMS) and primary multiple sclerosis (PPMS).
In the present invention, the "stirring" is performed by a method conventional in the art, such as magnetic stirring or mechanical stirring, wherein the stirring speed is 50-1800 rpm, the magnetic stirring is preferably 300-.
The "separation" is carried out by methods conventional in the art, such as centrifugation or filtration, and the "centrifugation" is carried out by: the sample to be separated is placed in a centrifuge tube and centrifuged at 10000 rpm until the solids are all settled to the bottom of the centrifuge tube.
The "drying" may be carried out at room temperature or higher. The drying temperature is from room temperature to about 50 deg.C, or to 40 deg.C. The drying time can be 2-48 hours or overnight. Drying is carried out in a fume hood, a forced air oven or a vacuum oven.
In the present invention, "crystal" or "polymorph" refers to a solid as confirmed by characterization by X-ray powder diffractogram. It will be understood by those skilled in the art that the physicochemical properties discussed herein can be characterized with experimental error depending on the conditions of the apparatus, the preparation of the sample and the purity of the sample, and in particular, it is well known to those skilled in the art that the X-ray powder diffraction pattern will generally vary with the conditions of the apparatus, and it is specifically noted that the relative intensities of the diffraction peaks in the X-ray powder diffraction pattern may also vary with the experimental conditions, so that the order of the intensities of the diffraction peaks cannot be considered as the sole or determining factor. In fact, the relative intensities of the diffraction peaks in the X-ray powder diffraction pattern are related to the preferred orientation of the crystals, and the intensities of the diffraction peaks shown in the present invention are illustrative and not used for absolute comparison. In addition, experimental errors in diffraction peak positions are typically 5% or less, and these position errors should also be taken into account, typically allowing an error of ± 0.2. In addition, due to the influence of experimental factors such as the thickness of the sample, the overall shift of the diffraction peak angle is caused, and a certain shift is usually allowed. Thus, it will be understood by those skilled in the art that the X-ray powder diffraction patterns of the protected crystalline forms of the present invention need not be identical to the X-ray powder diffraction patterns of the examples referred to herein, and that any crystalline form having an X-ray powder diffraction pattern identical or similar to the characteristic peaks in these patterns is within the scope of the present invention.
One skilled in the art can compare the X-ray powder diffraction pattern listed in the present invention with an X-ray powder diffraction pattern of an unknown crystalline form to confirm whether the two sets of patterns reflect the same or different crystalline forms.
In some embodiments, the crystalline DCI of the present invention is pure, substantially without any other crystalline admixtures. "substantially free" as used herein in reference to a novel form means that the form contains less than 20% by weight of other forms, particularly less than 10% by weight of other forms, more particularly less than 5% by weight of other forms, and even more particularly less than 1% by weight of other forms.
The term "about" when used in reference to a sensible value, such as mass, time, temperature, etc., means that there may be some fluctuation in the range around the specific value, which may be + -10%, + -5%, + -1%, + -0.5% or + -0.1%.
Drawings
FIG. 1 is an XRPD pattern of the crystalline form DCI obtained according to example 1b
Fig. 2 is a DSC diagram of the crystalline form DCI obtained according to example 1 b.
Detailed Description
The invention is illustrated in detail by the following examples describing in detail the methods of making and using the crystalline forms of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
The abbreviations used in the present invention are explained as follows:
XRPD: powder X-ray diffraction
DSC: differential scanning calorimetry
The instrument and method for data acquisition:
the X-ray powder diffractogram according to the invention was collected on a Bruker D2 PHASER X-ray powder diffractometer. The parameters of the X-ray powder diffraction method are as follows:
x-ray Source Cu Ka
Kal (A): 1.54060；Ka2 (A) 1.54439
Ka 2/Ka 1 strength ratio: 0.50
Voltage: 30 kilovolt (kV)
Current: 10 milliampere (mA)
Scanning range: from 3.0 to 40.0 degrees
The Differential Scanning Calorimetry (DSC) chart is collected on a Mettler DSC3, and the method parameters of the Differential Scanning Calorimetry (DSC) are as follows:
scanning rate: 10 ℃/min
Protective gas: nitrogen gas
Unless otherwise specified, the following examples are run at room temperature, where "room temperature" is not a specific temperature value and refers to a temperature range of 10-30 ℃.
According to the present invention, the compound I and/or a salt thereof as a starting material includes, but is not limited to, a solid form (crystalline or amorphous), an oil form, a liquid form and a solution. Preferably, compound I and/or its salt as starting material is in solid form.
The compounds I used in the following examples were prepared by the procedure described in literature.
Example 1: preparation method of crystal form DCI
Example 1 a:
30 mg of the Fenebrunib solid was weighed into a 3mL glass vial, 0.45 mL of 1, 4-dioxane was measured with a pipette, and dissolution was assisted with an ultrasonic cleaner. Under the condition of room temperature, a magnetic stirrer is placed in a glass vial and is integrally placed on the magnetic stirrer, 0.65 mL of n-heptane is slowly dripped into the glass vial by a pipette gun, the solution is turbid, and the glass vial is placed in an environment at 5 ℃ for stirring. And (3) sucking out the solution by using a dropper, adding the solution into a centrifuge tube, placing the centrifuge tube in a 12000 r/min centrifuge for 3 minutes, sucking out the supernatant by using the dropper, collecting solids and testing XRPD (X-ray diffraction pattern), wherein the result shows that the crystal form DCI is shown in the invention.
Example 1 b:
100 mg of the fennebrunib solid was weighed into a 5ml glass vial, 1.1ml of 1, 4-dioxane was measured with a pipette, and dissolution was assisted with an ultrasonic cleaner. At room temperature, a magnetic stirrer was placed in the glass vial and the whole was placed on the magnetic stirrer, and 1ml of n-heptane was slowly dropped into the glass vial by using a pipette gun, and the solution became cloudy. The glass vial was placed in a 5 ℃ environment and stirred. And (3) sucking the solution out by using a dropper, adding the solution into a centrifuge tube, placing the centrifuge tube in a centrifuge for 3 minutes at 12000 r/min, sucking the supernatant by using the dropper, then placing the centrifuge tube in a low-temperature storage room at the temperature of-20 ℃ for 4 days, taking out the centrifuge tube, collecting the solid, and carrying out XRPD test on the solid, wherein the result shows that the crystalline form DCI is shown in the invention. All samples are dried for 1h at 50 ℃, and the solids are collected for XRPD and DSC tests, and the results show that the solid is the crystal form DCI shown in the invention.
The XRPD pattern of the crystalline DCI obtained in example 1b was selected as shown in figure 1, and the XRPD data are shown in table 1.
DSC shows that when heated to 167 ℃, an endothermic peak begins to appear near 264 ℃, and an exothermic peak appears near 209 ℃.
TABLE 1
| Angle of diffraction 2theta | d value | Relative strength |
| 3.87 | 22.84 | 97.8% |
| 6.65 | 13.28 | 100.0% |
| 7.00 | 12.62 | 21.8% |
| 7.97 | 11.09 | 31.9% |
| 10.31 | 8.58 | 30.7% |
| 10.66 | 8.29 | 20.6% |
| 11.49 | 7.70 | 6.9% |
| 12.15 | 7.28 | 13.1% |
| 12.74 | 6.94 | 10.5% |
| 13.41 | 6.60 | 18.2% |
| 13.96 | 6.34 | 18.0% |
| 14.48 | 6.11 | 91.0% |
| 15.20 | 5.82 | 48.9% |
| 16.02 | 5.53 | 95.2% |
| 17.12 | 5.18 | 57.6% |
| 17.85 | 4.97 | 31.3% |
| 18.44 | 4.81 | 43.8% |
| 20.12 | 4.41 | 11.4% |
| 20.53 | 4.32 | 23.2% |
| 25.37 | 3.51 | 28.5% |
| 26.58 | 3.35 | 19.8% |
| 27.28 | 3.27 | 13.9% |
| 28.54 | 3.13 | 11.5% |
| 31.17 | 2.87 | 6.5% |
Example 2: dynamic solubility of crystalline DCI
When performing drug solubility tests to predict in vivo performance of drugs, it is important to simulate in vivo conditions as much as possible, and for oral administration, the use of SGF (simulated gastric fluid), FaSSIF (fasted state simulated intestinal fluid), FeSSIF (fed state simulated intestinal fluid) can simulate in vivo conditions and predict the effect of feeding, and the solubility tested in such media is closer to that in the human environment.
About 20 mg of the crystal form DCI is suspended in 1.5 mL of SGF, 1.5 mL of FeSSIF, 1.5 mL of FaSSIF and 1.5 mL of water respectively to prepare suspension, and the content (mg/mL) of a sample in the solution is tested by high performance liquid chromatography after 1 hour, 4 hours and 24 hours of balance.
Example 3: intrinsic dissolution rate of crystalline DCI
Weighing about 100 mg of the crystal form DCI of the invention, pouring into an inherent dissolution mold, and keeping for 1min under the pressure of 5 kN to prepareThe surface area is 0.5 cm2The die with the sheet is transferred to a dissolution apparatus to test the intrinsic dissolution rate.
Example 4: stability of crystalline DCI
The crystal form DCI prepared by the method is weighed to be about 5mg, and is respectively placed at the temperature of 25 ℃/60% RH, 40 ℃/75% RH, 60 ℃/75% RH and 80 ℃ to determine the purity and the crystal form by HPLC and XRPD.
Example 5: mechanical stability of crystalline DCI
Taking a proper amount of crystal form DCI, selecting a proper tabletting mold, carrying out compression molding without pressure, and carrying out XRPD test before and after tabletting;
or placing the crystal form DCI in a mortar, manually grinding for 5 minutes, and performing XRPD test before and after grinding.
Example 6: wettability of crystalline DCI
Weighing about 10 mg of the crystal form DCI, testing the hygroscopicity of the crystal form DCI by using a dynamic moisture adsorption (DVS) instrument, circulating once under the relative humidity of 0-90-0 percent, and recording the mass change at each temperature.
The description of the hygroscopicity characteristics and the definition of the hygroscopicity increase (Chinese pharmacopoeia 2020 edition general rule 9103 guidance of medicine hygroscopicity experiments, experimental conditions: 25 +/-1 ℃, 80% relative humidity):
deliquescence: absorb sufficient water to form liquid
Has the characteristics of moisture absorption: the moisture-attracting weight gain is not less than 15.0 percent
Moisture absorption: the moisture-attracting weight gain is less than 15.0 percent but not less than 2.0 percent
Slightly hygroscopic: the moisture-drawing weight gain is less than 2.0 percent but not less than 0.2 percent
No or almost no hygroscopicity: the moisture-drawing weight gain is less than 0.2 percent.
Example 7: particle size distribution of crystalline DCI
Taking 10-30 mg of prepared crystal form DCI, then adding about 5mL of isopar G (containing 0.2% of lecithin), fully and uniformly mixing a sample to be tested, adding the sample to be tested into a Hydro MV dispersing device to enable the shading degree to reach a proper pattern, starting an experiment, carrying out a particle size distribution test after 30 seconds of ultrasonic treatment, and measuring the particle size distribution.
Example 8: flowability of crystalline DCI
In the preparation process, the Compressibility index (Compressibility index) or Carr index (Carr index) can be generally adopted to evaluate the flowability of powder or particles, and the determination method comprises the steps of filling a certain amount of crystal form DCI powder particle size into a measuring cylinder and then measuring the volume before tapping; the powder is in the tightest state by tapping method, and the volume after tapping is measured: calculating the bulk density P0 and the tap density Pr: the compressibility factor was calculated according to the formula c = (Pr-P0)/Pr.
The definition standard of the compressibility factor to the powder flowability is referred to USP <1174>, and is detailed in Table 2.
TABLE 2
| Compressibility factor (%) | Fluidity of the resin |
| ≦10 | Is excellent in |
| 11-15 | Good taste |
| 16-20 | In general |
| 21-25 | Can accept |
| 26-31 | Difference (D) |
| 32-37 | Is very poor |
| >38 | Extreme difference |
Example 9: adhesion of crystalline DCI
Adding about 30 mg of crystal form DCI into 8mm circular flat punch, performing tabletting treatment by adopting the pressure of 10kN, keeping for about half a minute after tabletting, weighing the powder amount adsorbed by the punch, and recording the accumulated final adhesion amount of the punch, the highest adhesion amount in the pressing process and the average adhesion amount after continuously pressing twice by adopting the method.
Example 10: preparation of crystalline DCI preparation
And (3) tablet preparation: and (3) taking a proper amount of the crystal form DCI, uniformly mixing the crystal form DCI with auxiliary materials, rolling the mixture to prepare a sheet, crushing the sheet into granules, uniformly mixing the granules with the additional auxiliary materials, and pressing and forming the granules by using a proper mold.
And (3) capsule preparation: taking a proper amount of the crystal form DCI, uniformly mixing the crystal form DCI with auxiliary materials, rolling the mixture to prepare a sheet, crushing the sheet into particles, uniformly mixing the particles with the additional auxiliary materials, and canning the mixture into capsules with proper sizes.
Example 11: stability in crystalline DCI formulations
And packaging the crystal form DCI preparation by using an HDPE bottle, placing the crystal form DCI preparation under the conditions of 25 ℃/60% RH and 40 ℃/75% RH, sampling and detecting crystal forms and impurities, and inspecting the preparation stability of the crystal form DCI.
Example 12: in vitro dissolution of crystalline DCI formulations
The in vitro dissolution condition of the preparation containing the crystal form DCI is tested, and the dissolution is determined according to the determination method of the dissolution and the release of 0931 in the year edition of the Chinese pharmacopoeia 2020.
The above embodiments are merely illustrative of the technical concept and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the content of the present invention and implement the invention, and not to limit the scope of the present invention, and all equivalent changes or modifications made according to the spirit of the present invention should be covered by the scope of the present invention.
Claims (8)
1. Compound I
A crystalline form of (a).
2. The crystalline form of compound I according to claim 1, characterized in that its X-ray powder diffraction pattern has characteristic peaks at 1 or 2 or 3 of values of 3.9 ± 0.2 °, 6.7 ± 0.2 °, 16.0 ± 0.2 ° at 2theta using Cu-Ka radiation.
3. The crystalline form of compound I according to claim 2, characterized in that its X-ray powder diffraction pattern has characteristic peaks at 1 or 2 or 3 of values of 8.0 ± 0.2 °, 14.5 ± 0.2 °, 17.1 ± 0.2 ° at 2theta using Cu-Ka radiation.
4. The crystalline form of compound I according to claim 2, characterized in that its X-ray powder diffraction pattern has characteristic peaks at 3 from 1 or 2 of values of 10.3 ± 0.2 °, 15.2 ± 0.2 °, 18.4 ± 0.2 ° at 2theta using Cu-Ka radiation.
5. A process for preparing a crystalline form of compound I according to claim 2, characterized in that: dissolving the solid of the compound I in an ether solvent, then adding an alkane solvent to form a suspension, stirring for a period of time at a certain temperature, separating and drying to obtain the crystal form of the compound I.
6. The process according to claim 5, wherein the selected ether solvent is preferably 1, 4-dioxane; the alkane solvent is preferably n-heptane; the volume ratio of the alkane to the ether is preferably 1: 1; the temperature is preferably 5 ℃.
7. A pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of compound I according to claim 1 and a pharmaceutically acceptable carrier or adjuvant.
8. Use of a crystalline form of compound I as claimed in claim 1 for the preparation of a medicament for the treatment of Relapsing Multiple Sclerosis (RMS) and primary multiple sclerosis (PPMS) related diseases.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130116235A1 (en) * | 2011-11-03 | 2013-05-09 | Genentech, Inc. | Heteroaryl pyridone and aza-pyridone compounds |
| US20170247381A1 (en) * | 2016-02-29 | 2017-08-31 | Genentech, Inc. | Dosage form compositions comprising an inhibitor of bruton's tyrosine kinase |
| CN110446710A (en) * | 2016-12-15 | 2019-11-12 | 豪夫迈·罗氏有限公司 | The method for preparing BTK inhibitor |
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- 2021-07-23 CN CN202110833711.7A patent/CN113603685A/en not_active Withdrawn
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130116235A1 (en) * | 2011-11-03 | 2013-05-09 | Genentech, Inc. | Heteroaryl pyridone and aza-pyridone compounds |
| CN104125959A (en) * | 2011-11-03 | 2014-10-29 | 霍夫曼-拉罗奇有限公司 | Heteroaryl pyridone and aza-pyridone compounds as inhibitors of BTK activity |
| US20170247381A1 (en) * | 2016-02-29 | 2017-08-31 | Genentech, Inc. | Dosage form compositions comprising an inhibitor of bruton's tyrosine kinase |
| CN110446710A (en) * | 2016-12-15 | 2019-11-12 | 豪夫迈·罗氏有限公司 | The method for preparing BTK inhibitor |
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| 尹文萱等: "有机化学实验", 中国矿业大学出版社, pages: 26 - 28 * |
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