- Tumor-Cell-Specific Targeting of Ibrutinib: Introducing Electrostatic Antibody-Inhibitor Conjugates (AiCs)
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Ibrutinib is an inhibitor of Bruton's tyrosine kinase that has been approved for the treatment of patients with chronic lymphocytic leukemia, mantle cell lymphoma and Waldenstrom's macroglobulinemia and is connected with toxicities. To minimize its toxicities, we linked ibrutinib to a cell-targeted, internalizing antibody. To this end, we synthesized a poly-anionic derivate, ibrutinib-Cy3.5, that retains full functionality. This anionic inhibitor is complexed by our anti-CD20-protamine targeting conjugate and free protamine, and thereby spontaneously assembles into an electrostatically stabilized vesicular nanocarrier. The complexation led to an accumulation of the drug driven by the CD20 antigen internalization to the intended cells and an amplification of its pharmacological effectivity. In vivo, we observed a significant enrichment of the drug in xenograft lymphoma tumors in immune-compromised mice and a significantly better response to lower doses compared to the original drug.
- B?umer, Nicole,B?umer, Sebastian,Becht, Manuel,Berdel, Wolfgang E.,Dersch, Petra,Faust, Andreas,Geyer, Christiane,Greune, Lilo,Lenz, Georg,Margeta, Renato,Rüter, Christian,Schlütermann, Alina,Wittmann, Lisa
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- PROCESSES AND INTERMEDIATES FOR PREPARING A BTK INHIBITOR
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Disclosed is a process for the preparation of certain intermediates, e.g. a process for preparing a compound of formula (I) wherein, R1, R2 and X1 are as defined in the description, and which intermediate and processes are useful in the preparation of a BTK inhibitor, such as ibrutinib.
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- A PROCESS FOR PREPARATION OF 1H-PYRAZOLO[3,4-D] PYRIMIDINE DERIVATIVES
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The present invention relates to an efficient and industrially advantageous process for the preparation of 1H-pyrazolo[3,4-d] pyrimidine derivatives. In particular the present invention provides a process for the preparation of 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4- d]pyrimidine and tert-butyl (R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)piperidine-1-carboxylate. Said compounds are important intermediates in the synthesis of ibrutinib. The method provided for preparing intermediates of ibrutinib has the advantages of a simple operation, high yield and low costs.
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Page/Page column 14-15
(2020/07/05)
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- Preparation method of precursor of ibrutinib
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The invention relates to the pharmaceutical industry, in particular to a preparation method of a drug intermediate, and specifically discloses a preparation method of a precursor of ibrutinib. The preparation method comprises the following steps: (1) reacting a compound (III) with triphenylphosphine and azodicarbonic acid diester to obtain an intermediate (III-B); (2) reacting the intermediate (III-B) with a compound (IV) under the action of a catalyst to obtain an intermediate (V-C); and (3) reacting the intermediate (V-C) under the action of hydrochloric acid to obtain (R)-3-(4-phenoxy phenyl)-1-(piperidine-3-yl)-1H-pyrazolo [3, 4-d] pyrimidine-4-amine (I). The method has the advantages of high yield, high purity, convenience in purification, simplicity and convenience in operation and the like, is suitable for industrial production, and contributes to reducing the cost to a certain extent.
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Paragraph 0037; 0039-0043
(2020/04/22)
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- Method for using zinc chloride to separate and purify ibrutinib intermediate
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The invention discloses a method for using zinc chloride to separate and purify an ibrutinib intermediate, and particularly relates to a separation and purification method of the ibrutinib intermediate (3R)-4-amido-3-(4-phenoxy phenyl)-1-(1-tert-butoxy carbonyl piperidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine. After Mitsunobu reaction for preparing the intermediate is terminated, zinc chloride is added into a mixture, heated and cooled, composition sediment of zinc chloride and triphenylphosphine oxide is removed by filtering, and the intermediate with good purity is obtained. The process omits column chromatography, and is an efficient and low-cost separation and purification method.
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Paragraph 0016-0020
(2019/02/04)
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- The compounds of structure containing conjugated zincon, its pharmaceutical composition and use thereof (by machine translation)
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The present invention relates to compounds having a structure containing conjugated zincon, its pharmaceutical composition and use, and in particular relates to the general formula (I) or a salt thereof to the compound represented by the, pharmaceutical compositions thereof, and its as BTK inhibitors and/or B cell activation inhibitor, for the prevention or treatment B cell activity with abnormal and/or the use of the BTK-related diseases. The compounds of lymphoma, breast cancer, liver cancer, colon cancer, gastric cancer, such as lung cancer and cervical cancer cell has better lethal effect, note has potential for the treatment of cancer and self-immune diseases related to potential. (by machine translation)
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- PROCESS FOR THE SYNTHESIS OF STABLE AMORPHOUS IBRUTINIB
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Disclosed herein is a new route of synthesis and a new stable amorphous form of ibrutinib. Also disclosed are pharmaceutical compositions, oral dosage forms and the use of the amorphous ibrutinib in the treatment of mantle cell lymphoma or chronic lymphocytic leukemia.
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- According to lu tini synthesis method
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The invention discloses a synthesis method of ibrutinib. The method uses Suzuki coupling reaction and Kumada coupling reaction, does not need to separate the intermediate, obtains the intermediate (9) at high yield by a one-pot process, and uses mixed anhydrides instead of acryloyl chloride. The technique utilizes cheap 4-halodianisole as the initial raw material, adopts Suzuki coupling reaction and Kumada coupling reaction, and uses the one-pot process. The whole route is disclosed in the specification. The method can obtain the intermediate (9) (the chemical purity and optical purity are greater than or equal to 99%) at high yield without separating and purifying the intermediate, and avoids microwave, high temperature/high pressure and other specific reaction conditions; and the acrylic acid and mixed anhydrides generated by acyl chloride and sulfonyl chloride are used instead of the acryloyl chloride in the last step to avoid the amidation reaction of the intermediate (10) in multiple sites and reduce the generation of the byproduct, thereby obtaining the high-purity ibrutinib at high yield. The method has the advantages of short process route and lower cost, and is beneficial to the environment and suitable for industrialized scale-up production.
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Paragraph 0055-0057; 0059-0062; 0063-0068
(2017/08/31)
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- PROCESS FOR PREPARING PURE LH-PYRAZOLO[3,4-D] PYRIMIDINE DERIVATIVE
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The present invention relates to an efficient and industrially advantageous process for the preparation of pure lH-pyrazolo[3,4-d] pyrimidine derivative. In particular the present invention provides a process for the preparation of pure 4-amino-3-(4- phenoxyphenyl)-lH-pyrazolo[3,4-d] pyrimidine, a key intermediate of ibrutinib. Particularly, the present invention provides a process for the preparation of 3-amino-4-cyano-5-(4-phenoxy phenyl)pyrazole, wherein none of the intermediates have been isolated, an important precursor for the preparation of 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d] pyrimidine.
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- A METHOD FOR PREPARATION OF IBRUTINIB PRECURSOR
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A method for the preparation of ibrutinib's precursor, 3-(4-phenoxyphenyl)-1-((3R)-piperidin-3-il)-1H-pyrazolof [3,4-d]|pyrimidin-4-amine, involving arylation of N-protected 1-(piperidin-3-yl)pyrazolo[3,4-d]pyrimidin-4-amine in the presence of palladium catalyst, nitrogen-containing ligand, and base, with subsequent removal of the protecting groups by known methods, is reported. (Formula (II))
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Page/Page column 6; 7
(2017/03/28)
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- Preparation method of Bruton's tyrosine kinase inhibitor
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The invention relates to the field of drug synthesis, specifically to a preparation method of a Bruton's tyrosine kinase inhibitor. The new method comprises: carrying out a dark reaction between 4-amino-3-(4-phenoxylphenyl)-1H-pyridino(3,4-d)pyrimidine an
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Paragraph 0044-0046
(2017/08/31)
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- Separation and purification method of ibrutinib intermediate
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The invention discloses a separation and purification method of an ibrutinib intermediate-(3R)-4-amino-3-(4-phenoxyphenyl)-1-(1-tert-butoxycarbonylpiperidine-3-group)-1-1H-pyrazole [3, 4-d] pyrimidine. The separation and purification method includes: after Mitsunobu reaction for preparing the intermediate stops, adding magnesium chloride into a mixture; cooling after back-flowing; filtering to remove compound precipitate of magnesium chloride and triphenyl phosphine oxide to obtain the intermediate high in purity. Column chromatography is omitted in the process, so that the separation and purification method is high in efficiency and low in cost.
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Paragraph 0019
(2017/08/29)
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- PROCESS FOR THE PREPARATION OF 1-[(3R)-3-[4-AMINO-3-(4-PHENOXYPHENVL)-1H- PVRAZOLO[3,4-D]PYRINIIDIN-1-Y1]-1-PIPERIDINVL]-2-PROPEN-1-ONE AND ITS POLYMORPHS THEREOF
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The present invention relates to an improved process for the preparation of 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)- 1 H-pyrazolo[3,4-d]pyrimidin- 1 -yl]- 1 -piperidin yl]-2-propen-1-one compound of formula- 1 and its polymorphs thereof, which is represented by the following structural formula:
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- A PROCESS FOR THE PREPARATION OF IBRUTINIB
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The present invention provides a process for the preparation of ibrutinib of Formula I.
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- BTK inhibitor and uses thereof
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The present invention provides a BTK inhibitor compound (having s structure represented by a formula (I)) and uses of the BTK inhibitor compound in medicines. According to the present invention, the compound and the pharmaceutical composition can be used for treatment of diffuse large B-cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia. The formula (I) is defined in the specification.
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- Pyrazolopyrimidine derivative, preparation method, pharmaceutical composition and application
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The invention discloses a pyrazolopyrimidine derivative, a preparation method, a pharmaceutical composition and application. The invention provides the pyrazolopyrimidine derivative as shown in a formula I and stereoisomer or solvate or pharmaceutically acceptable salts or active metabolite or prodrug thereof. The pyrazolopyrimidine derivative as shown in the formula I has good inhibitory activity on Bruton's tyrosine kinase (Btk) and particularly has good in vitro and in vivo inhibitory activity on growth of tumor cells, and a good marketization prospect is achieved. Please see the formula I in the description.
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- Ibrutinib preparation method, ibrutinib intermediate, and ibrutinib intermediate preparation method
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The present invention provides an ibrutinib preparation method, which comprises that (a) a compound (3) reacts with diethyl sulfate to obtain a compound (4); (b) the compound (4) reacts with a hydrazine dihydrochloride to obtain a compound (5); (c) the compound (5) reacts with formamide to obtain a compound (6); (d) after the compound (6) reacts with (R)-1-Boc-3-hydroxypiperidine, an acid is added to make a compound (7) be subjected to a deprotection reaction to obtain a compound (8); and (e) the compound (8) reacts with acryloyl chloride to obtain a compound (9) ibrutinib. The present invention further provides an ibrutinib intermediate represented by a formula (4) and a preparation method of the intermediate compound (8). According to the present invention, the method has advantages of low cost, good safety and high yield, and is suitable for large-scale production. The reaction route is defined in the specification.
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- Method for synthesizing ibrutinib
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The invention provides a method for synthesizing ibrutinib. The method takes 4,6-dihydroxypyrimidine as an initial raw material, the material is subjected to formylation and chlorination to obtain a compound in a formula 3; the compound in the formula 3 and a compound in a formula 4 are subjected to a reaction to obtain a compound in a formula 5; the compound in the formula 5 is subjected to oxidation to obtain a compound in a formula 6; the compound in the formula 6 is subjected to ammonification to obtain a compound in a formula 7; the compound in the formula 7 and hydrazine hydrate are subjected to a reaction for closing pyrazole ring to obtain a compound in a formula 8; the compound in the formula 8 and a compound in a formula 9 are subjected to an alkylation reaction to obtain a compound in a formula 10; the compound in the formula 10 is subjected to acid deprotection to obtain a compound in a formula 11; and the compound in the formula 11 and acryloyl chloride are subjected to the reaction to obtain ibrutinib. The invention also discloses an ibrutinib intermediate. The raw materials have the advantages of low cost and easy acquisition, no dangerous highly-toxic product, mild reaction condition, no requirement of cryogenic cooling and high temperature, and simple operation, and is suitable for industrial production.
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- Novel inhibitor for FLT3 kinase and application
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The invention provides a novel kinase inhibitor, which includes a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolin, or prodrug thereof. The invention also provides a drug composition including the compound of Formula (I) and application to and method for preventing or treating a cell proliferative disease and/or diseases related to FLT3, particularly in response to diseases of FLT3 kinase (particularly FLT3/ITD mutation type kinase) inhibition.
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Paragraph 0166; 0167; 0170
(2016/10/08)
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- Preparation method of ibrutinib
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The invention relates to the technical field of medicine, in particular to a preparation method of ibrutinib. The preparation method of ibrutinib comprises the following steps that 4-amino-3-(4-phenoxy phenyl)-1H-pyrazol[3,4-d]pyrimidine and S-1-tert-butyloxycarbonyl-3-hydroxyl piperidine are prepared into a compound shown in the formula IV (please see the formula in the description) through a Mitsunobu reaction, and a Boc protecting group of the compound shown in the formula IV is removed to prepare a compound shown in the formula V (please see the formula in the description); the compound shown in the formula V and acrylic ester are prepared into a compound shown in the formula I (please see the formula in the description) in the presence of a catalyst and an activating agent. According to the preparation method, the reaction process is mild in condition, few reaction steps are needed, high temperature and copious cooling are not needed, no high-toxicity reagent is adopted, and the whole synthesizing process is stable and controllable; ibrutinib prepared through the method is high in yield and quality and has the advantages of being good in stability, high in purity, convenient to store and the like.
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Paragraph 0016; 0063; 0064; 0065
(2017/10/20)
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- Direct and two-step bioorthogonal probes for Bruton's tyrosine kinase based on ibrutinib: A comparative study
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Ibrutinib is a covalent and irreversible inhibitor of Bruton's tyrosine kinase (BTK) and has been approved for the treatment of haematological malignancies, such as chronic lymphocytic leukaemia, mantle cell lymphoma and Waldenstr?m's macroglobulinemia. The covalent and irreversible nature of its molecular mode of action allows identification and monitoring of its target in an activity-based protein profiling (ABPP) setting. Fluorescent and biotinylated ibrutinib derivatives have appeared in the literature in recent years to monitor BTK in vitro and in situ. The work described here complements this existing methodology and pertains a comparative study on the efficacy of direct and two-step bioorthogonal ABPP of BTK.
- Liu, Nora,Hoogendoorn, Sascha,Van De Kar, Bas,Kaptein, Allard,Barf, Tjeerd,Driessen, Christoph,Filippov, Dmitri V.,Van Der Marel, Gijsbert A.,Van Der Stelt, Mario,Overkleeft, Herman S.
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p. 5147 - 5157
(2015/05/13)
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- Discovery of (R)-1-(3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone (CHMFL-FLT3-122) as a Potent and Orally Available FLT3 Kinase Inhibitor for FLT3-ITD Positive Acute Myeloid Leukemia
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FLT3-ITD mutant has been observed in about 30% of AML patients and extensively studied as a drug discovery target. On the basis of the structure of PCI-32765 (ibrutinib), a BTK kinase inhibitor that was recently reported to bear FLT3 kinase activity through a structure-guided drug design approach, we have discovered compound 18 (CHMFL-FLT3-122), which displayed an IC50 of 40 nM against FLT3 kinase and achieved selectivity over BTK kinase (over 10-fold). It significantly inhibited the proliferation of FLT3-ITD positive AML cancer cell lines MV4-11 (GI50 = 22 nM), MOLM13/14 (GI50 = 21 nM/42 nM). More importantly, 18 demonstrated 170-fold selectivity between FLT3 kinase and c-KIT kinase (GI50 = 11 nM versus 1900 nM) in the TEL-fusion isogenic BaF3 cells indicating a potential to avoid the FLT3/c-KIT dual inhibition induced myelosuppression toxicity. In the cellular context it strongly affected FLT3-ITD mediated signaling pathways and induced apoptosis by arresting the cell cycle into the G0/G1 phase. In the in vivo studies 18 demonstrated a good bioavailability (30%) and significantly suppressed the tumor growth in MV4-11 cell inoculated xenograft model (50 mg/kg) without exhibiting obvious toxicity. Compound 18 might be a potential drug candidate for FLT3-ITD positive AML.
- Li, Xixiang,Wang, Aoli,Yu, Kailin,Qi, Ziping,Chen, Cheng,Wang, Wenchao,Hu, Chen,Wu, Hong,Wu, Jiaxin,Zhao, Zheng,Liu, Juan,Zou, Fengming,Wang, Li,Wang, Beilei,Wang, Wei,Zhang, Shanchun,Liu, Jing,Liu, Qingsong
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p. 9625 - 9638
(2016/01/12)
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- TREATMENT OF DRY EYE
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The present disclosure provides a method of treating dry eye by inhibition of Bruton's tyrosine kinase (hereinafter "BTK") inhibitors, pharmaceutical formulations comprising the same, and processes for preparing such compounds.
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- Tyrosine kinase inhibitors
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The present disclosure provides compounds such as pyrazolpyrimidine compounds, and pharmaceutically acceptable salts thereof, that are tyrosine kinase inhibitors, in particular BLK, BMX, EGFR, HER2, HER4, ITK, TEC, BTK, and TXK and are therefore useful for the treatment of diseases treatable by inhibition of tyrosine kinases such as cancer and inflammatory diseases such as arthritis, and the like. Also provided are pharmaceutical compositions containing such compounds and pharmaceutically acceptable salts thereof and processes for preparing such compounds and pharmaceutically acceptable salts thereof.
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- PROCESSES AND INTERMEDIATES FOR PREPARING A MEDICAMENT
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Disclosed is a process for the preparation of the following compounds: (I), (II) where R1, R1a and R2a have the definitions in the description, as well as a process to prepare other intermediates that may be useful to synthesise downstream products, especially compounds that are useful as medicaments, for instance Bruton's tyrosine kinase (Btk) inhibitors such as ibrutinib. Also disclosed are other processes, other intermediates and compounds per se.
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Page/Page column 19; 25
(2014/09/29)
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- DEUTERATED IBRUTINIB
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The present invention in one embodiment provides a compound of Formula (I); or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formula (I) are as defined in the specification.
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- REVERSIBLE COVALENT PYRROLO- OR PYRAZOLOPYRIMIDINES USEFUL FOR THE TREATMENT CANCER AND AUTOIMMUNE DISEASES
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Oral pharmaceutical formulations comprising reversible covalent compounds having a Michael acceptor moiety, a process of their production, and use of these formulations for the treatment of diseases treatable by such compounds such as cancer and autoimmune diseases.
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- PYRAZOLOPYRIMIDINE DERIVATIVES AS TYROSINE KINASE INHIBITORS
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The present disclosure provides compounds and pharmaceutically acceptable salts that are tyrosine kinase inhibitors, in particular BLK, BMX, EGFR, HER2, HER4, ITK, Jak3, TEC, Btk, and TXK and are therefore useful for the treatment of diseases treatable by inhibition of tyrosine kinases such as cancer and inflammatory diseases such as arthritis, and the like. Also provided are pharmaceutical compositions containing such compounds and pharmaceutically acceptable salts and processes for preparing such compounds and pharmaceutically acceptable salts.
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- BRUTON'S TYROSINE KINASE ACTIVITY PROBE AND METHOD OF USING
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Described herein are probes for Bruton's tyrosine kinase (Btk). Such probes are used to characterize and develop Btk-selective inhibitors intended for therapeutic use.
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Page/Page column 12
(2008/12/08)
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