WO2016180334A1 - Inhibiteur irréversible de tyrosine kinase de bruton à double site, composition et application associées - Google Patents

Inhibiteur irréversible de tyrosine kinase de bruton à double site, composition et application associées Download PDF

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Publication number
WO2016180334A1
WO2016180334A1 PCT/CN2016/081669 CN2016081669W WO2016180334A1 WO 2016180334 A1 WO2016180334 A1 WO 2016180334A1 CN 2016081669 W CN2016081669 W CN 2016081669W WO 2016180334 A1 WO2016180334 A1 WO 2016180334A1
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WO
WIPO (PCT)
Prior art keywords
piperididine
compound
arh
pharmaceutically acceptable
tyrosine kinase
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PCT/CN2016/081669
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English (en)
Chinese (zh)
Inventor
周星露
刘兴国
戈震
Original Assignee
杭州和正医药有限公司
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Priority claimed from CN201510242552.8A external-priority patent/CN104844609B/zh
Priority claimed from CN201610286399.3A external-priority patent/CN105777759B/zh
Application filed by 杭州和正医药有限公司 filed Critical 杭州和正医药有限公司
Publication of WO2016180334A1 publication Critical patent/WO2016180334A1/fr

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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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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

Definitions

  • the invention belongs to the field of medicine, in particular to a two-site irreversible Bruton tyrosine kinase inhibitor, a composition and application thereof.
  • Covalent inhibitors also known as irreversible inhibitors, are a class of inhibitors that exert their biological functions by irreversible binding of covalent bonds to target protein residues.
  • Covalent inhibitor drugs have made important contributions to human health over the past few decades. Covalent inhibitors enhance affinity to the target by covalent bonding to the target protein relative to the non-covalent inhibitor, which is the underlying cause of the high bioactivity of the covalent inhibitor.
  • due to the non-covalent targeting of anti-tumor drugs, especially the production of a large number of tini-resistant drugs against kinases people have paid more attention to covalent inhibitor drugs.
  • many large pharmaceutical companies have developed covalent inhibitors for specific enzyme targets.
  • afatinib was officially approved by the US FDA on July 12, 2013 for the treatment of metastatic non-small cell lung cancer with epidermal growth factor receptor (EGFR) gene mutation, becoming the first FDA-approved treatment of lung cancer.
  • EGFR epidermal growth factor receptor
  • New drug for irreversible inhibitors has also been a research hotspot in recent years, and great progress has been made.
  • the FDA approved two anti-hepatitis C virus covalent inhibitor drugs, namely, telaprevir. (Telaprevir) and Boceprevir (Boceprevir).
  • Btk Bruton's tyrosine kinase
  • BCR cell surface B-cell receptor
  • Btk is a key regulator of B cell development, activation, signaling, and survival.
  • Bkt plays a role in numerous other hematopoietic signaling pathways, such as Toll like receptor (TLR) and cytokine receptor-mediated TNF- ⁇ production in macrophages, in mast cells.
  • TLR Toll like receptor
  • TNF- ⁇ cytokine receptor-mediated TNF- ⁇ production in macrophages, in mast cells.
  • Immunoglobulin E receptor (Fc ⁇ R1) signaling signaling that inhibits apoptosis of Fas/APO-1 cells in B-lineage lymphoid cells, and collagen-stimulated platelet aggregation.
  • Fc ⁇ R1 Immunoglobulin E receptor
  • Btk inhibitors inhibit Btk autophosphorylation by binding to Btk by acting on the BCR signaling pathway, preventing Btk activation, thereby blocking cell conduction and inducing apoptosis.
  • Btk inhibitors have strong selectivity and low toxic and side effects, especially the listing of ibufenib, which has been designated as a “breakthrough” new drug by the FDA, and its research and development prospects are broad.
  • Ibbutinib reacts with the sulfhydryl group of the Btk enzyme cysteine (Cys481) residue and forms a covalent bond, which inactivates the Btk enzyme and exerts its therapeutic effect.
  • ibbutinibinib is easily metabolized during metabolism (digested by metabolic enzymes to be dihydroxylated or inactivated by other thiol-containing enzymes, cysteine, glutathione, etc.) And affecting the efficacy (see the following formula), its clinical dose reached 560mg / day, and the burden on patients is increased, so there is still a need to develop a more efficient BTK inhibitor for the treatment of related diseases.
  • the new molecule has a double reaction site, and after being in vivo (or intracellularly) by other thiol-containing enzymes, cysteine, glutathione, etc., it still has A site which reacts with a thiol group of a Btk enzyme cysteine (Cys481) residue, an alpha halogenated amide group (see the following formula), thereby exerts an activity enhancing effect.
  • the Bruton tyrosine kinase inhibitor provided by the present invention has the structure of Formula I:
  • the BTK inhibitor provided by the present invention has the following structure:
  • Rd 1, Rd 2, Rd 3, Rd 4, Rd 5 is independently H, halo, -CF 3, -CN, - NO 2 , -OH, C 1 -C 3 alkoxy group, or -NH 2
  • X is selected from fluorine, chlorine or bromine.
  • optical isomer thereof or a pharmaceutically acceptable salt or solvate thereof, wherein: X is selected from the group consisting of fluorine, chlorine or bromine.
  • the BTK inhibitor provided by the present invention has the structure of the general formula (IV):
  • Rd 1, Rd 2, Rd 3, Rd 4, Rd 5 is independently H, halo, -CF 3, -CN, - NO 2 , -OH, C 1 -C 3 alkoxy group, or -NH 2
  • X is selected from fluorine, chlorine or bromine
  • Y 1 , Y 2 are independently selected from C, N
  • Y 1 , Y 2 have at least One is selected from N.
  • optical isomer thereof or a pharmaceutically acceptable salt or solvate thereof, wherein: X is selected from fluorine, chlorine or bromine, Y 1 , Y 2 are independently selected from C, N, and Y 1 , Y 2 are at least One is selected from N.
  • aryl refers to an all-carbon monocyclic or fused polycyclic group of 5 to 12 carbon atoms having a fully conjugated pi-electron system.
  • aromatic rings are: benzene rings, naphthalene rings, and anthracene rings. The aromatic ring may be unsubstituted or substituted.
  • the substituent of the aromatic ring is selected from the group consisting of halogen, nitro, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkoxy a C 3 -C 6 cycloalkyl group, a halogenated C 3 -C 6 cycloalkyl group;
  • heteroaryl refers to an unsaturated ring group of 5 to 12 ring atoms having a fully conjugated pi-electron system corresponding to one or more carbons of the above "aryl” being heteroatoms such as oxygen. Replacement with nitrogen, sulfur, etc.
  • the heteroaryl ring may be a single ring or a double ring, that is, fused by two rings.
  • Specific heterocyclic aryl (heteroaryl) groups may be: pyridyl, pyrimidinyl, pyrazinyl, isoxazolyl, isothiazolyl, pyrazolyl, thiazolyl, oxazolyl and imidazolyl, and the like.
  • the heterocyclic aryl group can be unsubstituted or substituted.
  • the substituent of the heterocyclic aryl group is selected from the group consisting of halogen, nitro, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 Alkoxy, C 3 -C 6 cycloalkyl, halogenated C 3 -C 6 cycloalkyl;
  • alkoxy refers to an -O-alkyl group, wherein alkyl is as defined above.
  • alkoxy as used herein include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.
  • Alkoxy also includes substituted alkoxy groups. The alkoxy group can be optionally substituted one or more times with a halogen.
  • the alkenyl moiety can be branched, straight or cyclic (in this case, it will also be referred to as "cycloalkenyl").
  • the alkenyl group may be a monovalent group or a divalent group (i.e., an alkenylene group).
  • the alkenyl group can be optionally substituted.
  • the alkenyl group may have 2 to 10 carbon atoms.
  • the alkenyl group can also be said to have a "lower alkenyl group" having 2 to 6 carbon atoms.
  • pharmaceutically acceptable derivative refers to a salt or solvate of a selected compound.
  • solvate refers to a variable stoichiometric complex formed from a solute (eg, a compound of the formula (I) to formula (V) of the present invention) and a solvent.
  • a solute eg, a compound of the formula (I) to formula (V) of the present invention
  • a solvent for the purposes of the present invention, the solvent does not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to, water, methanol, ethanol, and acetic acid.
  • the solvent preferably used is a pharmaceutically acceptable solvent.
  • Suitable pharmaceutically acceptable solvents include, but are not limited to, water, ethanol, and acetic acid. More preferably, the solvent used is water.
  • Salts of the compounds of the invention can be prepared by the present invention using methods well known to those skilled in the art.
  • the salt may be an organic acid salt, a mineral acid salt or the like, and the organic acid salt includes a decanoate, a fumarate, an oxalate, a malate, a lactate, a camphor sulfonate, and a pair.
  • Tosylate, mesylate, etc.; the inorganic acid salt includes a hydrohalide, a sulfate, a phosphate, a nitrate, and the like.
  • a lower alkylsulfonic acid such as methanesulfonic acid, trifluoromethanesulfonic acid or the like may form a mesylate salt, a triflate salt; and an arylsulfonic acid such as benzenesulfonic acid or p-toluenesulfonic acid.
  • p-toluenesulfonate besylate; forming an appropriate salt with an organic carboxylic acid such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid or citric acid;
  • glutamic acid or aspartic acid can form glutamate or aspartate.
  • Corresponding salts may also be formed with inorganic acids such as hydrohalic acids (e.g., hydrofluoric acid, hydrobromic acid, hydroiodic acid, hydrochloric acid), nitric acid, carbonic acid, sulfuric acid or phosphoric acid.
  • hydrohalic acids e.g., hydrofluoric acid, hydrobromic acid, hydroiodic acid, hydrochloric acid
  • nitric acid e.g., carbonic acid, sulfuric acid or phosphoric acid.
  • a second object of the present invention is to provide a pharmaceutical composition comprising at least one active ingredient together with one or more pharmaceutically acceptable carriers or excipients, said active ingredient It may be a BTK inhibitor compound of the present invention, an optical isomer of the compound, the compound or an optical isomer thereof in a pharmaceutically acceptable salt, a solvate of the compound or an optical isomer thereof Any one or any of a variety.
  • the carrier includes conventional diluents, excipients, fillers, binders, wetting agents, disintegrating agents, absorption enhancers, surfactants, adsorption carriers, lubricants, etc. in the pharmaceutical field, and may also be added if necessary. Agent, sweetener, etc.
  • the medicament of the present invention can be prepared into various forms such as tablets, powders, granules, capsules, oral liquids and injectable preparations, and the medicaments of the above respective dosage forms can be prepared according to a conventional method in the pharmaceutical field.
  • the present invention provides the use of a compound of the formula (I) to formula (V) as disclosed herein, and an optical isomer thereof, or a pharmaceutically acceptable salt or solvate thereof thereof, to inhibit Bruce A tyrosine kinase (Btk) activity or a disease, disorder or condition that benefits from inhibition of Bruton's tyrosine kinase (Btk) activity.
  • composition comprising a therapeutically effective amount of at least one compound administered to a subject in need thereof, thereby inhibiting Bruton's tyrosine kinase activity of said subject.
  • a method wherein the compound has a structural formula of the formula (I) to the formula (V).
  • a subject in need thereof is suffering from an autoimmune disease, such as inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease (Still's disease), juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves'disease, rheumatoid arthritis Syndrome Syndrome), multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, visual ocular palsy-myoclonus syndrome, coercion Spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, Scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayas
  • a subject in need thereof has cancer.
  • the cancer is a B cell proliferative disorder, such as diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell pro-lymphocytic leukemia, Lymphocyte plasma lymphoma/Waldenstrom macroglobulinemia Macroglobulinemia), spleen marginal lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, lymph node marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinum (thymus) large B-cell lymph Tumor, intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma/leukemia or lymphomatoid granulomatosis.
  • B cell proliferative disorder such as diffuse large B-cell lymphoma, follicular lymphom
  • the invention also provides the use of a compound of the invention or a pharmaceutically acceptable salt thereof for the preparation of a BTK inhibitor, in particular for the preparation of a medicament for the treatment of a cell proliferative disorder.
  • the cell proliferative diseases include cancer.
  • the present invention also provides a compound of the formula (I) to the formula (V), and an optical isomer thereof, or a pharmaceutically acceptable salt or solvate thereof, alone or in combination with other drugs for treating hyperplasia Applications in diseases such as cancer.
  • Antineoplastic agents which can be used in combination with a compound provided by the present invention or a pharmaceutically acceptable salt thereof include, but are not limited to, at least one of the following classes: mitotic inhibitors (e.g., vinblastine, vindesine, and vinorelbine); tubulin Decomposition inhibitors (such as Taxol); alkylating agents (such as cisplatin, carboplatin and cyclophosphamide); antimetabolites (such as 5-fluorouracil, tegafur, methotrexate, cytarabine and hydroxyl Urea); insertable antibiotics (such as arrhenone, mitomycin and bleomycin); enzymes (such as aspartate); topoisomerase inhibitors (such as etoricin and camptothecin); biological response regulation Agent (such as interferon).
  • mitotic inhibitors e.g., vinblastine, vindesine, and vinorelbine
  • tubulin Decomposition inhibitors such as Taxol
  • the present invention also provides a process for the preparation of the general formula (I') and a pharmaceutically acceptable derivative thereof, which is synthesized by the synthetic route shown in the following scheme:
  • Compound 1 (prepared by the method of WO2012158795) is refluxed with R 1 B(OH) 2 in the presence of potassium phosphate, a palladium catalyst and a suitable solvent or a mixed solvent such as dioxane/water.
  • the obtained compound 2 is reacted with Boc-protected 3-hydroxypiperidine in the presence of triphenylphosphine, DIAD and a suitable solvent such as THF to give compound 3, followed by hydrolysis under acidic conditions to give key intermediate 4.
  • the key intermediate DCC and a suitable solvent such as DCM are condensed with a substituted acrylic acid moiety to give a compound of the formula (I').
  • R 1 corresponds to the compound of the above formula (I) to formula (V), and an appropriate substituted boronic acid can be selected according to actual needs.
  • substituted boronic acids include, but are not limited to, 4-phenoxybenzeneboronic acid, 4-(4-methoxyphenoxy)benzeneboronic acid, 4-(3-methoxyphenoxy)benzeneboronic acid, 4-( 3,4-Dimethoxyphenoxy)benzeneboronic acid, 4-(4-fluorophenoxy)benzeneboronic acid, 4-(4-chlorophenoxy)benzeneboronic acid, 6-phenoxypyridine-3- Boric acid, 6-(2-fluorophenoxy)pyridin-3-ylboronic acid, 6-(4-fluorophenoxy)pyridin-3-ylboronic acid and the like.
  • the present inventors have confirmed by experiments that the compound of the present invention has an anti-proliferative inhibitory effect on tumor cell lines such as A549, SGC7901, MCF-7, PC-9, HL-60, and the like, and can be applied to the treatment of human or animal cell proliferation-related entities.
  • tumor cell lines such as A549, SGC7901, MCF-7, PC-9, HL-60, and the like.
  • the inventors of the present invention have confirmed by experiments that the compound of the present invention has good pharmacokinetic properties and can be applied to orally treating solid tumors or blood cancers associated with cell proliferation of human or animal cells or suffering from autoimmune diseases.
  • the inventors of the present invention confirmed by experiments that the compound of the present invention has a two-site reaction property.
  • Example 41 In vitro Btk kinase inhibitory activity and in vitro antitumor activity assay
  • the drug was dissolved in DMSO to make a 10 mM stock solution, and diluted to a 50x test concentration.
  • the test concentration was diluted by 3 to 25nM, 8.33nM, 2.78nM, 0.93nM, 0.31nM, 0.10nM. .
  • 10 ⁇ L of 50x drug stock solution was added to a 96-well plate, and 90 ⁇ L of 1x kinase buffer was added and shaken on the shaker for 10 minutes. Transfer 5 ⁇ L from each well of a 96-well plate to a 384-well plate, and set 2 duplicate wells in a 384-well plate.
  • Kinase Reaction Prepare 2.5x Kinase Buffer: Add the enzyme to the 1x Kinase Buffer.
  • the antitumor activity of the synthesized compounds was determined by using different solid tumors and leukemia cell lines:
  • Cell lines human lung cancer cells (A549, PC9), human breast cancer cells (MCF7), human gastric cancer cells (SGC7901), acute promyelocytic leukemia cells (HL60), human lung cancer cells gefitinib-resistant cells (PC9) -IR).
  • MCF7 DMEM + fetal bovine serum
  • HL60 RPMI 1640+ fetal calf serum
  • PC9 DMEM + fetal bovine serum
  • PC9-IR DMEM + fetal bovine serum
  • Drug preparation method The drug was dissolved in DMSO to make a 10 mM stock solution, and diluted to a certain ratio to obtain 5 different concentrations (test concentration 100x).
  • the selected six tumor cells A549, MCF7, SGC7901, HL60, PC9, PC9-IR were incubated in a 37 ° C, 5% CO 2 cell incubator, and were passaged when the cell density was 70-90%. Cells were passaged with Duck's EDTA and passaged for later experiments.
  • Tumor cells A549, MCF7, SGC7901, HL60, PC9, PC9-IR were seeded in a 96-well plate at 4000 cells/200 ⁇ L/well and incubated overnight at 37 ° C in a 5% CO 2 cell incubator.
  • 2 ⁇ L of compound was added to each well to a final concentration of 50 ⁇ M, 10 ⁇ M, 2 ⁇ M, 0.4 ⁇ M, and 0.08 ⁇ M for 72 hours at 37 ° C in a 5% CO 2 cell incubator with DMSO (2%) as a control.
  • 20 ⁇ L of CCK-8 solution was added and placed in a 37 ° C, 5% CO 2 cell incubator for 4 hours.
  • cell inhibition rate % [(control group OD value - blank group OD value) - (medical group OD value - blank group OD value)] / (control cell OD value - blank group OD value) ⁇ 100%, the half-inhibitory concentration (IC 50 ) was calculated by CalcuSyn software.
  • the pharmacokinetic properties of compounds 5-2, 5-3 and 5-19 in rats were investigated.
  • the specific methods were as follows: SD rats were used as experimental animals, and given by gavage The drug was administered at a dose of 20 mg/kg, and 5 mg/kg was administered intravenously to the tail vein.
  • the time of blood collection from the tail vein of the intragastric administration was 0.17, 0.33, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 hours; the time of blood collection by intravenous administration was 0.05, 0.1, 0.17, 0.5. 1,2,4,6,8,12,24 hours.
  • 0.3 ml of whole blood was taken, and 0.1 ml of plasma was taken after centrifugation and analyzed by LC-MS.
  • Example 45 Treatment of differential arthritis with compounds 5-2 and 5-19

Abstract

La présente invention concerne un inhibiteur irréversible de tyrosine kinase de Bruton à double site, une composition et une application associées. La composition de la présente invention présente un effet anti-prolifération sur des souches de cellules tumorales telles que A549, SGC7901, MCF-7, HL-60 et PC9-IR, et peut être appliquée à un médicament destiné au traitement de tumeurs solides ou d'un cancer du sang associés à une prolifération de cellules humaines ou animales ; la composition de la présente invention a une meilleure propriété pharmacocinétique, et peut être appliquée à une administration par voie orale pour traiter les tumeurs solides, le cancer du sang ou des maladies auto-immunes liés à la prolifération de cellules humaines ou animales ; et la composition de la présente invention présente la caractéristique d'une réaction à double site.
PCT/CN2016/081669 2015-05-12 2016-05-11 Inhibiteur irréversible de tyrosine kinase de bruton à double site, composition et application associées WO2016180334A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201510242552.8A CN104844609B (zh) 2015-05-12 2015-05-12 双位点不可逆布鲁顿酪氨酸激酶抑制剂
CN201510242552.8 2015-05-12
CN201610286399.3A CN105777759B (zh) 2016-04-29 2016-04-29 一种布鲁顿酪氨酸激酶抑制剂
CN201610286399.3 2016-04-29

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WO2016180334A1 true WO2016180334A1 (fr) 2016-11-17

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109369654A (zh) * 2018-11-20 2019-02-22 山东大学 1，3-二取代-4-氨基吡唑并嘧啶类化合物及其制备方法和应用
CN110483520A (zh) * 2018-05-14 2019-11-22 杭州和正医药有限公司 布鲁顿酪氨酸激酶抑制剂的晶型、制备方法及其应用
WO2020117135A1 (fr) * 2018-12-04 2020-06-11 Deva Holding Anonim Sirketi Procédé de préparation de dérivés de 1h-pyrazolo[3,4-d]pyrimidine

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CN102159214A (zh) * 2008-07-16 2011-08-17 药品循环公司 用于实体肿瘤的治疗的布鲁顿酪氨酸激酶的抑制剂
WO2014187319A1 (fr) * 2013-05-21 2014-11-27 Jiangsu Medolution Ltd Pyrazolopyrimidines substituées utiles comme inhibiteurs de kinases
CN104211703A (zh) * 2013-05-30 2014-12-17 江苏先声药物研究有限公司 一类作为布鲁顿激酶抑制剂的稠杂环化合物
CN104844609A (zh) * 2015-05-12 2015-08-19 杭州和正医药有限公司 双位点不可逆布鲁顿酪氨酸激酶抑制剂

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102159214A (zh) * 2008-07-16 2011-08-17 药品循环公司 用于实体肿瘤的治疗的布鲁顿酪氨酸激酶的抑制剂
WO2014187319A1 (fr) * 2013-05-21 2014-11-27 Jiangsu Medolution Ltd Pyrazolopyrimidines substituées utiles comme inhibiteurs de kinases
CN104211703A (zh) * 2013-05-30 2014-12-17 江苏先声药物研究有限公司 一类作为布鲁顿激酶抑制剂的稠杂环化合物
CN104844609A (zh) * 2015-05-12 2015-08-19 杭州和正医药有限公司 双位点不可逆布鲁顿酪氨酸激酶抑制剂

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110483520A (zh) * 2018-05-14 2019-11-22 杭州和正医药有限公司 布鲁顿酪氨酸激酶抑制剂的晶型、制备方法及其应用
CN110483520B (zh) * 2018-05-14 2021-04-16 杭州和正医药有限公司 布鲁顿酪氨酸激酶抑制剂的晶型、制备方法及其应用
CN109369654A (zh) * 2018-11-20 2019-02-22 山东大学 1，3-二取代-4-氨基吡唑并嘧啶类化合物及其制备方法和应用
WO2020117135A1 (fr) * 2018-12-04 2020-06-11 Deva Holding Anonim Sirketi Procédé de préparation de dérivés de 1h-pyrazolo[3,4-d]pyrimidine

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