WO2008113255A1 - Dérivés de benzamide avec activité antiproliférative, leurs préparations pharmaceutiques - Google Patents

Dérivés de benzamide avec activité antiproliférative, leurs préparations pharmaceutiques Download PDF

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WO2008113255A1
WO2008113255A1 PCT/CN2008/000500 CN2008000500W WO2008113255A1 WO 2008113255 A1 WO2008113255 A1 WO 2008113255A1 CN 2008000500 W CN2008000500 W CN 2008000500W WO 2008113255 A1 WO2008113255 A1 WO 2008113255A1
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compound
group
formula
alkoxy
compound according
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PCT/CN2008/000500
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English (en)
Chinese (zh)
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Shuxin Li
Yongxue Liu
Yanjin Zhao
Chunguang Han
Xianzhao Kuang
Linyi Huang
Wensong Xiao
Xiaomei Sun
Xiaodong Deng
Yang Xue
Qingquan Ye
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The Institute Of Radiation Medicine, Academy Of Military Medical Sciences, Pla
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Priority to CN2008800159294A priority Critical patent/CN101730703B/zh
Publication of WO2008113255A1 publication Critical patent/WO2008113255A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
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    • 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
    • C07D239/38—One sulfur atom
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    • 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
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    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C07D239/96—Two oxygen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having 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
    • C07D241/20—Nitrogen atoms
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
    • C07D317/66—Nitrogen atoms not forming part of a nitro radical
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • MS-275 is the first histone deacetylase inhibitor that has been shown to have oral anticancer activity in animals.
  • MS-275 is undergoing clinical studies of leukemia and solid tumors in the United States.
  • some new compounds with better performance have yet to be developed in order to obtain HDAC inhibitors with high anticancer activity, small side effects and more stability.
  • Another object of the present invention is to provide a process for the preparation of the above compound or a pharmaceutically acceptable acid salt thereof.
  • R 2 is hydrogen or C r C 4 alkyl
  • L is S or NH
  • E is N or C-A
  • Gi is -S-C3 ⁇ 4- or -SC(CH 3 )(H)-;
  • J is selected from the following groups:
  • X 2 is selected from fluorine or dC 4 alkoxy
  • Preferred compounds of formula (I) of the invention have the structure of formula (IG):
  • X 2 is selected from fluorine or C, -C 4 alkoxy
  • R4 is hydrogen or C r C 6 alkyl.
  • Hetl is an aryl or heteroaryl group which may be optionally substituted, each group may be arbitrarily combined with one or more aryl or heterocyclic groups, or with one or more saturated or partially unsaturated cycloalkyl or hetero Ring, each ring can be arbitrarily substituted;
  • the present invention also provides a process for the preparation of the benzamide derivatives of the present invention.
  • the solvent used in the above preparation method may be selected from various options such as chloroform, dichlorodecane, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, xylene, toluene, dimethyl sulfoxide. , triethylamine, and other organic solvents; the reaction temperature is -30 - +80 ° C; if necessary, a base such as sodium hydroxide, triethylamine, pyridine, etc. may be added, such as hydrochloric acid, acetic acid, trifluoroacetic acid and the like.
  • Step 3 Synthesis of N-(2-amino-5-fluorophenyl)-3-(4-((4-decyloxyphenylamino)methyl)phenyl acrylamide (Compound 39).
  • 1.44g of N,N-carbonyldiimidazole was dissolved in 10ml of anhydrous tetrahydrofuran, reacted at 45 ° C for 1.5h, cooled, and set aside.
  • 1.33g of 4-fluoro-1, 2-Phenylenediamine is dissolved in anhydrous tetrahydrofuran, l.Olg trifluoroacetic acid is added dropwise, and the reaction mixture is added dropwise.
  • the product has a melting point of m.p. 219.5-221 °C;
  • the melting point of the product is m.p. 165-167 ° C;
  • the product has a melting point of m.p. 212-215 ° C;

Abstract

L'invention concerne de nouveaux dérivés de benzamide de formule I. Les définitions des substituants Het, G1, G2, G3, Y, X1, X2, X3 et X4 sont données dans la description. L'invention concerne également des procédés de préparation de ces composés, des compositions pharmaceutiques contenant ces composés et l'utilisation de ces composés en tant que principes actifs dans des médicaments pour le traitement de maladies associées avec la prolifération, par exemple la leucémie et les tumeurs solides.
PCT/CN2008/000500 2007-03-16 2008-03-14 Dérivés de benzamide avec activité antiproliférative, leurs préparations pharmaceutiques WO2008113255A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN2008800159294A CN101730703B (zh) 2007-03-16 2008-03-14 具有抗增殖活性的苯甲酰胺类衍生物及其药用制剂

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN200710086587.2 2007-03-16
CN200710086587 2007-03-16
CN200710143940 2007-08-15
CN200710143940.6 2007-08-15

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WO2008113255A1 true WO2008113255A1 (fr) 2008-09-25

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Cited By (22)

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WO2010064737A1 (fr) * 2009-02-16 2010-06-10 Nishio Tetsuya Composé hétérocyclique et son utilisation
WO2012149528A1 (fr) * 2011-04-29 2012-11-01 Exelixis, Inc. Inhibiteurs de la forme inductible de la 6-phosphofructose-2-kinase
CN102775356A (zh) * 2011-05-13 2012-11-14 江苏恒谊药业有限公司 4-氨基喹唑啉衍生物及其应用
WO2013004332A1 (fr) * 2011-07-07 2013-01-10 Merck Patent Gmbh Azahétérocycles substitués pour le traitement du cancer
US8759535B2 (en) 2010-02-18 2014-06-24 High Point Pharmaceuticals, Llc Substituted fused imidazole derivatives, pharmaceutical compositions, and methods of use thereof
WO2015006875A1 (fr) * 2013-07-18 2015-01-22 Methylgene Inc. Procédé de préparation de pyrimidines substituées
US8957066B2 (en) 2011-02-28 2015-02-17 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
JP2015528812A (ja) * 2012-07-27 2015-10-01 ザ ブロード インスティテュート, インコーポレーテッドThe Broad Institute, Inc. ヒストンデアセチラーゼの阻害剤
US9265734B2 (en) 2008-09-03 2016-02-23 Biomarin Pharmaceutical Inc. Compositions including 6-aminohexanoic acid derivatives as HDAC inhibitors
US9499496B2 (en) 2012-06-05 2016-11-22 University Of Kansas Inhibitors of respiratory syncytial virus
US9540395B2 (en) 2011-02-28 2017-01-10 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US9840491B2 (en) 2015-02-05 2017-12-12 Forma Therapeutics, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US9902728B2 (en) 2014-12-30 2018-02-27 Forma Therapeutics, Inc. Pyrrolo and pyrazolopyrimidines as ubiquitin-specific protease 7 inhibitors
US9932351B2 (en) 2015-02-05 2018-04-03 Forma Therapeutics, Inc. Thienopyrimidinones as ubiquitin-specific protease 7 inhibitors
US9938300B2 (en) 2015-02-05 2018-04-10 Forma Therapeutics, Inc. Isothiazolopyrimidinones, pyrazolopyrimidinones, and pyrrolopyrimidinones as ubiquitin-specific protease 7 inhibitors
US10000495B2 (en) 2014-12-30 2018-06-19 Forma Therapeutics, Inc. Pyrrolotriazinones and imidazotriazinones as ubiquitin-specific protease 7 inhibitors
US10029988B2 (en) 2013-03-15 2018-07-24 Biomarin Pharmaceutical Inc. HDAC inhibitors
US10059723B2 (en) 2011-02-28 2018-08-28 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US10172840B2 (en) 2014-12-01 2019-01-08 Vtv Therapeutics Llc Bach1 inhibitors in combination with Nrf2 activators and pharmaceutical compositions thereof
US10662199B2 (en) 2011-04-28 2020-05-26 The Broad Institute, Inc. Inhibitors of histone deacetylase
US10793538B2 (en) 2012-12-20 2020-10-06 The Broad Institute, Inc. Cycloalkenyl hydroxamic acid derivatives and their use as histone deacetylase inhibitors
EP4100109A4 (fr) * 2020-02-06 2024-03-27 Childrens Hospital Med Ct Composés, compositions, méthodes pour le traitement de maladies et de lésions nerveuses et procédés pour la préparation de composés

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