WO2012089106A1 - Dérivé aromatique d'alcyne au titre d'inhibiteur de protéines kinases et ses applications médicales - Google Patents

Dérivé aromatique d'alcyne au titre d'inhibiteur de protéines kinases et ses applications médicales Download PDF

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WO2012089106A1
WO2012089106A1 PCT/CN2011/084745 CN2011084745W WO2012089106A1 WO 2012089106 A1 WO2012089106 A1 WO 2012089106A1 CN 2011084745 W CN2011084745 W CN 2011084745W WO 2012089106 A1 WO2012089106 A1 WO 2012089106A1
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Prior art keywords
dihydro
indole
ethynyl
mercaptopiperazin
nonanamide
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PCT/CN2011/084745
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English (en)
Chinese (zh)
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孙树萍
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Sun Shuping
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Priority to CN201180068149.8A priority Critical patent/CN103370324B/zh
Publication of WO2012089106A1 publication Critical patent/WO2012089106A1/fr

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/40—Unsubstituted amino or imino radicals
    • 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

Definitions

  • the present invention relates to a class of protein kinase inhibitors, an alkyne derivative, a salt of the compound, and a drug containing the compound or a salt thereof as an active ingredient, which can be used for the treatment of proliferative diseases such as cancer and inflammatory diseases.
  • proliferative diseases such as cancer and inflammatory diseases.
  • diseases associated with Bcr-Abl tyrosine kinase are associated with diseases associated with Bcr-Abl tyrosine kinase.
  • Methionine kinases are generally divided into two major classes of tyrosine kinases and serine/threonine protein kinases.
  • protein kinases tyrosine protein kinases are widely recognized to play a very important role in many cellular functions, particularly in the transmission of cellular signals.
  • Tyrosine protein kinases are divided into two major categories: receptors and non-receptors.
  • Receptor-like tyrosine protein kinases usually consist of extracellular, intercellular, cell membrane and intracellular, non-receptor tyrosine.
  • the acid protein kinase is completely inside the cell.
  • About 20 families of receptor-like tyrosine protein kinases have been discovered, among which the HER subfamily includes EGFR, HER2, HER3, HER4, ligands that bind to receptors of this subfamily, including epidermal growth factor, TGF- ⁇ HB-EGF, etc.
  • another subfamily is a tyrosine protein kinase associated with the insulin receptor, including INS-R, IGF-IR, and IR-R.
  • the PDGF subfamily is composed of PDGFRou PDGFRJ3, CSFIR, C-kit and FLK-II.
  • FLK subfamilies There is also a class of FLK subfamilies, including KDR, FLK-1, FLK-4, and Flt-1. Due to structural and functional similarities, the two subfamilies, PDGF and FLK, are usually grouped together. Non-cellular tyrosine protein kinases also have a variety of subfamilies, such as 'Abl, Src, Frk, Btk, Csk, ZAP-70, and the like. Each subfamily can be further divided into different sub-Asians. For example, Src is one of the largest subfamilies, including Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, and Yrk, which are widely considered to be closely related to tumor formation.
  • Ph 1 chromosome The body, named Ph 1 chromosome, is now called the Ph chromosome. With the advancement of molecular biology, the molecular characteristics of the Ph chromosome and its role in the pathogenesis are becoming clearer.
  • chromosome 9 It is caused by the translocation of chromosomes 9 and 22, and the proto-oncogene c of the long arm end of chromosome 9 (q34) -ABL breaks and merges with the cluster end region (M-BCR gene) of the long arm end (ql l ) of chromosome 22.
  • the c-ABL proto-oncogene is 230 kb in length and normally encodes a 145 kD protein with tyrosine kinase activity, which regulates the expression of growth factor receptors (colony stimulating factor receptor, platelet-derived growth factor, epithelial growth factor).
  • the breakpoint of chromosome 9 usually occurs at the 5/end of the second exon of the c-ABL gene.
  • the second exon and its subsequent sequence translocate to a cluster of unexplained breakpoints (BCR genes) on chromosome 22, spliced into a new fusion gene (Bcr-Abl gene), which translates a Bcr-Abl fuses the protein product P210 (Bcr-Abl protein) with a molecular weight of 210 kD.
  • P210 has abnormal tyrosine kinase activity compared to c-ABL-encoded P145. Studies have confirmed that the pathogenesis of CML is closely related to the Bcr-Abl fusion gene, and its translation product Bcr-Abl protein can promote cell proliferation and inhibit apoptosis.
  • Bcr-Abl protein (P210) provides a binding site for a series of adaptor proteins such as Grb-2, SHC, CRKL, etc., thereby activating RAS (MAPIQ signaling pathway or JAK/STAT signaling pathway, up-regulating nuclear gene c Expression of -myc, bcl-2, c-fos, etc., abnormalities in these signaling pathways cause cancerous cells of the bone marrow precursor cells to undergo abnormal growth, differentiation, and apoptosis.
  • RAS MAPIQ signaling pathway or JAK/STAT signaling pathway
  • JAK/STAT signaling pathway up-regulating nuclear gene c Expression of -myc, bcl-2, c-fos, etc.
  • abnormalities in these signaling pathways cause cancerous cells of the bone marrow precursor cells to undergo abnormal growth, differentiation, and apoptosis.
  • Bcr-Abl fusion gene and its inlay The presence of transcripts is a very important pathogenic factor and a very clear
  • the present invention provides an aralkyne derivative which is a selective tyrosine protein kinase inhibitor whose main function is to exert its anticancer effect by inhibiting tyrosine protein kinase activity.
  • the major tyrosine protein kinases inhibited by such compounds are Abl, P38 ⁇ , PDGF-R, C-Kit and the like. Of course, the possibility of such compounds inhibiting other disease-associated protein kinases is not excluded.
  • a first object of the present invention is to provide a protein kinase inhibitor, an alkyne derivative, and a salt thereof or a solvate thereof.
  • Another object of the present invention is to provide a process for the preparation of the derivative.
  • a third object of the present invention is to provide a pharmaceutical composition containing the derivative.
  • a fourth object of the invention is to provide the use of the derivative.
  • the present invention provides an alkyne derivative having the structure of Formula I, and a configuration isomer thereof, or a pharmaceutically acceptable salt or solvate thereof:
  • Ring A represents a monocyclic or polycyclic aromatic ring or an aromatic heterocyclic ring containing a total of from 1 to 4 heteroatoms selected from 0, N and S, and optionally substituted with from 1 to 3 R 1 groups; a 5 or 6-membered aryl or heterocyclic aryl group, and optionally substituted by 1-3 R 2 groups;
  • n, p, q is 1, 2 or 3;
  • L is selected from - NRCO- or -CONR-;
  • R is selected from hydrogen, dC 5 alkyl group;
  • R 2 is ⁇ base;
  • Y is independently a chemical bond - ⁇ -, - S - or -NR 7 -;
  • R 3 is pendulum 8 R
  • R 4 is selected from hydrogen, halogen, dC 4 alkyl or dC 4 alkoxy;
  • R 5 , R 6 , R 7 are independently selected from H, dC 4 alkyl, dC 4 alkenyl, dC 4 alkynyl, Ci-C 4 cycloalkyl, C r C 6 cycloalkenyl, aryl, heterocyclic Base and heteroaryl;
  • R 8 and R 9 are selected from C r C 5 alkyl groups and may be optionally substituted by R 1Q , and R 8 , R 9 and the atoms to which they are bonded form a 3- to 7-membered ring cycloalkyl group, which is a cycloalkyl group.
  • the fluorene group can be optionally substituted by 1-3-N-, -0-, -S-, NR 1Q ;
  • R 1Q is hydrogen, halogen, cyano, C r6 alkyl, d- 6 hydroxyalkyl, d- 6 haloalkyl, CC 6 cyanoalkyl, or two R 1Q groups together with the atoms to which they are attached A 3-7 membered cycloalkyl or heterocycloalkyl group; preferably, the present invention provides a compound having the structure of formula (II), and a configuration isomer thereof, or a pharmaceutically acceptable salt or solvent compound thereof:
  • Ring C, Ring D is a 5-7 membered aromatic ring or an aromatic heterocyclic ring;
  • R 3 is as described for the structure of formula I.
  • the present invention provides a compound of the following structure, or a pharmaceutically acceptable salt or solvent compound thereof:
  • the present invention provides a compound having the structure of formula (III), and a configuration isomer thereof, or a pharmaceutically acceptable ( ⁇ ) thereof
  • ⁇ ⁇ -ring A is selected from the following five-membered ring or six-membered ring:
  • n 1-2;
  • RR 3 is as described in the structure of formula I;
  • R 11 is hydrogen, dC 6 alkyl or C 3 -C 10 cycloalkyl.
  • the present invention provides a compound of the following structure, or a pharmaceutically acceptable salt or solvent compound thereof:
  • Ring ⁇ , ring D is a 5-7 membered aromatic ring or an aromatic heterocyclic ring
  • R 3 is as described for the structure of formula I.
  • the present invention provides a compound of the following structure, or a pharmaceutically acceptable salt or solvate thereof:
  • R 1U is as described in the structure of formula I;
  • R 12 , R 13 , R 14 , R 15 are hydrogen, d- 6 alkyl or d- 6 hydroxyalkyl;
  • r, t is 1, 2 or 3;
  • R ⁇ m-ring A may also be selected from the following five- or six-membered rings:
  • n 1-2;
  • R 1 is as described in the structure of formula I;
  • R 11 is a dC 6 alkyl group or a C 3 - C 10 cycloalkyl group
  • the present invention provides a compound of the following structure, or a pharmaceutically acceptable salt or solvent compound thereof:
  • the compound of the present invention if it contains a basic group, can form a salt with an acid, and a salt of an aryl acetylene derivative can be produced by a method well known to those skilled in the art.
  • Common acid salts include organic acid salts, or inorganic acid salts, and the like.
  • organic acid salts are citrate, fumarate, oxalate, malate, lactate, sulfonate (eg camphor sulfonate, p-toluene sulfonate, sulfonate) Acid salts, etc.; inorganic acid salts include hydrohalides, sulfates, phosphates, nitrates, and the like.
  • a lower alkyl cross-acid such as sulfonic acid, trifluorosulfonium sulfonic acid, etc.
  • it can form an oxime sulfonate, a trifluorosulfonium sulfonate; and an aryl cross-acid, such as benzoic acid or p-toluene.
  • an aryl cross-acid such as benzoic acid or p-toluene.
  • the like may form a p-benzoate salt, a benzoate; and an organic carboxylic acid, such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid or citric acid, etc.
  • the invention provides a process for the preparation of a compound of formula (I).
  • the compound of formula (I) is synthesized from a compound of formula (VI) and a compound of formula (VII) (shown in Scheme 1):
  • route 3 or route 4 For the compound of formula (VI), it can be synthesized by the following route (route 3 or route 4):
  • the present invention provides a medicament using the aromatic acetylenic derivative of the present invention, a configurational isomer thereof, or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.
  • the above medicament may further comprise one or more pharmaceutically acceptable carriers, including conventional diluents in the pharmaceutical field, excipients, fillers, binders, humectants, disintegrants, absorption promotion.
  • a surfactant, a surfactant, an adsorption carrier, a lubricant, etc., if necessary, a flavoring agent, a sweetener or the like may be added.
  • 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 an aralkyne derivative, a configuration isomer thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a proliferative disease such as cancer and inflammatory diseases such as psoriasis, blood cancer or Solid tumors, especially those associated with Bcr-Abl tyrosine kinases.
  • the inventors of the present invention have experimentally confirmed that the compound of the present invention has particularly excellent anti-value-inhibiting action against K562 or KU812, and can be applied to a drug for treating psoriasis, blood cancer or solid tumor associated with cell proliferation of human or animal cells.
  • step 1 6.7 g of 3-iodo-4-mercaptoaniline hydrochloride was dissolved in dry dichloromethane, and then 9.4 ml of dry triethylamine was added under water bath to prepare a pale yellow solution.
  • the product of step 1 was suspended in dichloromethane, and then slowly added to the above-mentioned reserve liquid under a water bath condition using a constant pressure dropping funnel, and the reaction was stirred at room temperature for 6 hours under a nitrogen atmosphere. After completion of the reaction, the solvent was spin-dried and extracted.
  • Step 3 ( R ) -N-(3-(Imidazo[1,2-b]pyridazin-3-yl)ethynyl) 4-indolylphenyl)-1-(4-decylpiperazine) Synthesis of -2,3-dihydro-1H-indole-5-indoleamide
  • Step 3 (R)-N-(3-((lH-pyrazol[3,4-b]pyridin-5-yl)ethynyl)-4-mercaptophenyl)-l-(4-fluorenyl) Piperazin-1-yl)-2,3-dihydro-1
  • Step 4 (R)-N-(3((2-(Cyclopropylamine)pyrimidin-5-yl)ethynyl)-4-indolylphenyl)-1-(4-indolylpiperazine)- 2,
  • Step 1-C Synthesis of 5-Acetylamino-2,3-indan-1-ol 10 g of the product of the step 1_B was suspended in 100 ml of decyl alcohol, and 3 g of sodium borohydride was added in portions, and the mixture was stirred, and the mixture was stirred at room temperature for 2 hr. After concentration, 8.6 g of the sample compound was obtained.
  • Step I_F Synthesis of 1-(4-mercaptopiperazin-1-yl)-2,3-dihydro-1H-indole-5-amine
  • Example 20 Inhibition of K562 cells by target compound
  • the cell cryotube was taken out from liquid nitrogen, rapidly thawed in a 39 ° C water bath, and transferred to In a 15 ml centrifuge tube, add 10 ml of 10% FBS medium, centrifuge at 100 rpm for 5 min, discard the medium, re-add the medium containing 10% FBS and double antibody, and transfer to a culture flask for culture.
  • the broth containing 2 ⁇ test compound and the positive control imatinib was added to the corresponding well of a 96-well plate, and cultured in a C0 2 cell incubator for 72 hours (the highest concentration of the compound ⁇ , imatinib sulfonate) The highest final concentration ⁇ is 10 gradient concentrations).
  • the 96-well plate was centrifuged, and the medium was removed.
  • 150 ⁇ l per well was added to the ⁇ working solution (0.33 mg/ml XTT; 0.00265 mg/ml PMS), placed in a carbon dioxide incubator for 2 hours, and the microplate oscillator was shaken for 5 min.
  • the absorbance was read at 450 nm.
  • the percent inhibition of a compound is calculated by the following formula:
  • the target compound has a significant inhibitory effect on Bcr-Abl-positive human leukemia cell K562, which is superior to the positive drug imatinib sulfonate.
  • Example 21 Inhibition of target compound on KU812 cells KU812 cells were seeded in RPMI1640 cell culture medium containing 10% fetal bovine serum (100 ku/L supplemented with penicillin and streptomycin), and the culture medium was placed in a cell culture incubator containing 5% CO 2 at 37 ° C. Centrifugation was performed once every 3 days, passage and collection of cells.
  • the logarithmic growth phase cells were prepared into a cell suspension of the desired concentration with RPMI1640 medium containing 10% fetal bovine serum, and added to a 96-well cell culture plate at 3000 cells per well (, ⁇ ), and cultured for 12 hours after each well. Adding different amounts of stock solution, the final concentration of the sample is 10 ( ⁇ g / ml, l ( ⁇ g / ml, ⁇ g / mh 0.1 ( ⁇ g / ml, O.Ol g / ml each concentration has 3 parallel wells.
  • the target compound has a higher inhibitory effect on Bcr-Abl positive human leukemia cell KU812, which is superior to the positive drug STI-571.
  • Example 22 Pharmacokinetic Study of Compounds experimental design
  • Blood collection time 1 day (24 h), number of doses: Single animal overnight fasting: Yes, 2 hours after blood collection allowed to eat. Free drinking water.
  • Body fluid supply After each time point of blood stasis, 0.3 ml of normal saline was administered through the carotid cannula. Blood withdrawal time point (hr) :
  • WO2007075869 The compound disclosed in Example 19 (AP24534) IV has a t 1/2 of 10.2 h; a t 1/2 of po is 1111, and a % is 18.2%. (Journal of Medicinal Chemistry, 2010, Vol. 53, No. 12 4711 ). The compounds of the invention have a high bioavailability.
  • the compound of the present invention has particularly excellent anti-value-inhibiting action against K562 or KU812, and can be applied to a medicament for treating proliferative-related psoriasis, blood cancer or solid tumor of human or animal cells.

Abstract

La présente invention concerne un dérivé d'alcyne aromatique au titre d'inhibiteur de protéines kinases. Le composé est un composé de formule (I) ou l'un de ses sels ou solvates de qualité pharmaceutique, où R1, R2, R3, R4, le cycle A, les cycles B, L, m, n, p ou q sont tels que spécifiquement définis dans la description. De plus, la présente invention concerne également un médicament incluant le composé ou l'un de ses sels au titre de principe actif, ledit médicament pouvant être employé dans le traitement des maladies prolifératives comme le cancer et des maladies inflammatoires, et spécialement des maladies liées à la Bcr-Abl tyrosine kinase.
PCT/CN2011/084745 2010-12-27 2011-12-27 Dérivé aromatique d'alcyne au titre d'inhibiteur de protéines kinases et ses applications médicales WO2012089106A1 (fr)

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CN201180068149.8A CN103370324B (zh) 2010-12-27 2011-12-27 作为蛋白激酶抑制剂的芳炔类衍生物及其医疗用途

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102775411A (zh) * 2012-08-17 2012-11-14 浙江大德药业集团有限公司 作为蛋白激酶抑制剂的芳乙炔基苯甲酰胺类化合物
CN102807558A (zh) * 2012-08-29 2012-12-05 浙江大德药业集团有限公司 作为蛋白激酶抑制剂的含氟二氢化茚酰胺类化合物
WO2014019338A1 (fr) * 2012-07-30 2014-02-06 Astar Biotech Llc Inhibiteurs de protéines kinases
US20140364436A1 (en) * 2012-07-30 2014-12-11 Astar Biotech Llc Protein Kinase Inhibitors
CN104327083A (zh) * 2014-09-12 2015-02-04 辽宁大学 取代二氢茚酰胺类化合物及其药学上可接受的盐及制备方法和应用
JP2015524448A (ja) * 2012-09-17 2015-08-24 南京聖和薬業有限公司Ｎａｎｊｉｎｇ Ｓａｎｈｏｍｅ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ．，Ｌｔｄ． アルキニルへテロ芳香環化合物及びその応用
CN106795152A (zh) * 2014-08-26 2017-05-31 安斯达尔生物技术有限责任公司 蛋白激酶抑制剂
JP2018515550A (ja) * 2015-05-18 2018-06-14 スン プハルマ アドバンセド リサーチ カンパニー リミテド 新規アミドヘテロアリールアロイルヒドラジドエチン
WO2018112136A1 (fr) * 2016-12-15 2018-06-21 Ariad Pharmaceuticals, Inc. Composés d'aminothiazole en tant qu'inhibiteurs de c-kit
CN114340734A (zh) * 2019-06-24 2022-04-12 博善人工智能生物科技有限公司 新化合物和方法
WO2022129914A1 (fr) * 2020-12-16 2022-06-23 Benevolentai Bio Limited Dérivés d'alcyne en tant qu'inhibiteurs de c-abl

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JP2015523402A (ja) * 2012-07-30 2015-08-13 アスター バイオテック リミテッド ライアビリティ カンパニー タンパク質キナーゼ阻害薬
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JP2015524448A (ja) * 2012-09-17 2015-08-24 南京聖和薬業有限公司Ｎａｎｊｉｎｇ Ｓａｎｈｏｍｅ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ．，Ｌｔｄ． アルキニルへテロ芳香環化合物及びその応用
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IL267262A (en) * 2016-12-15 2019-08-29 Ariad Pharma Inc Reliable compounds of azole as c-kit inhibitors
CN110291086A (zh) * 2016-12-15 2019-09-27 阿瑞雅德制药公司 作为c-kit抑制剂的氨基噻唑化合物
US11001580B2 (en) 2016-12-15 2021-05-11 Ariad Pharmaceuticals, Inc. Aminothiazole compounds as c-Kit inhibitors
AU2017376624B2 (en) * 2016-12-15 2021-11-11 Ariad Pharmaceuticals, Inc. Aminothiazole compounds as c-Kit inhibitors
CN110291086B (zh) * 2016-12-15 2023-08-11 阿瑞雅德制药公司 作为c-kit抑制剂的氨基噻唑化合物
US11753404B2 (en) 2016-12-15 2023-09-12 Ariad Pharmaceuticals, Inc. Aminothiazole compounds as c-Kit inhibitors
CN114340734A (zh) * 2019-06-24 2022-04-12 博善人工智能生物科技有限公司 新化合物和方法
WO2022129914A1 (fr) * 2020-12-16 2022-06-23 Benevolentai Bio Limited Dérivés d'alcyne en tant qu'inhibiteurs de c-abl

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