WO2017174023A1 - Composé biphényle servant comme inhibiteur de l'ezh2 - Google Patents

Composé biphényle servant comme inhibiteur de l'ezh2 Download PDF

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WO2017174023A1
WO2017174023A1 PCT/CN2017/079700 CN2017079700W WO2017174023A1 WO 2017174023 A1 WO2017174023 A1 WO 2017174023A1 CN 2017079700 W CN2017079700 W CN 2017079700W WO 2017174023 A1 WO2017174023 A1 WO 2017174023A1
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group
alkyl
pharmaceutically acceptable
acceptable salt
acid
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PCT/CN2017/079700
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English (en)
Chinese (zh)
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吴颢
韦昌青
廖勇刚
姬国靖
赵新涛
胡国平
黎健
陈曙辉
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南京明德新药研发股份有限公司
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • 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
    • C07D405/12—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

Definitions

  • the present invention relates to a novel class of compounds as EZH2 inhibitors, in particular to compounds of formula (III) or pharmaceutically acceptable salts thereof.
  • DNA and histone packaging form chromatin.
  • chromatin Approximately 150 base pairs of DNA are entangled in two rounds of histone octamers (two of histones 2A, 2B, 3 and 4) to form the basic unit of chromatin, the nucleosome.
  • Changes in the ordered structure of chromatin can cause changes in the transcription of related genes. This process is highly controlled because the depth of change in gene expression patterns affects basal cellular processes such as differentiation, proliferation, and apoptosis.
  • histones most notably its N-terminal tail mediates the control of changes in chromatin structure (and thus transcription).
  • modifications are often referred to as epigenetic modifications because they can cause heritable changes in gene expression without affecting the sequence of the DNA itself.
  • Covalent modifications eg, methylation, acetylation, phosphorylation, and ubiquitination
  • amino acid side chains are enzymatically mediated.
  • HMT histone methyltransferase
  • composition of the complexes isolated by the different groups is slightly different, it generally includes EED, EZH2, SUZ12 and RbAp48 or their Drosophila homologs.
  • EED EED
  • EZH2 SUZ12
  • RbAp48 Drosophila homologs
  • only the reconstituted complex including EED, EZH2, and SUZ12 retained histone methyltransferase activity against the 27th lysine of histone H3.
  • EZH2 (enhancer of zeste homolog 2; human EZH2 gene: Cardoso et al, European J of Human Genetics, Vol. 8, 174-180, 2000) is a catalytic structure of polycomb inhibiting complex 2 (PRC2), its function is through the pair of groups Protein H3 lysine 27 is trimethylated (H3K27me3) to silence target gene function.
  • PRC2 polycomb inhibiting complex 2
  • Histone H3 is one of the five major histone proteins involved in chromatin of eukaryotic cells. Histone H3 has a major globular domain and a long N-terminal tail, and histones are involved in the structure of nucleosomes, like pearls on necklaces. Histones are highly modified after translation and histone H3 is the most extensive modification of five histones. Histone H3 is an important protein in the emerging field of epigenetics, and its sequence variation and multiple modification states are thought to play a role in dynamic and long-term regulation of genes.
  • epigenetic enzyme activity leads to cancer-associated cell proliferation uncontrolled and other cancer-related phenotypes, such as enhanced cell migration and invasion.
  • epigenetic enzymes in many other human diseases, including metabolic diseases (such as diabetes), inflammatory diseases (such as Crohn's disease), and neurodegenerative diseases ( For example, Alzheimer's disease) and cardiovascular disease. Therefore, the selective regulation of the abnormal effects of epigenetic enzymes has broad prospects for the treatment of a range of diseases.
  • EZH2 inhibitors have a therapeutic effect on cancer, and patents that have been filed by PCT are PCT/US2011/035336, PTC/US2011/035340, PCT/US2011/035344 and U.S. Patent No. 8,410,088. It is an ideal tumor recognition feature or subgroup (eg genotype).
  • R 31 is selected from H, halogen, CN, OH, amino, or selected from, optionally substituted by 1, 2 or 3 R: 5- to 6-membered aryl, 5- to 12-membered heteroaryl, C 1-6 alkane a group, a C 1-6 heteroalkyl group, a C 3-9 cycloalkyl group, and a 3-9 membered heterocycloalkyl group;
  • R is selected from H, OH, CN, NH 2 , COOH, halogen, or selected from, optionally substituted by 1, 2 or 3 R's: 5- to 6-membered aryl, 5- to 12-membered heteroaryl, C 1 a -6 alkyl group, a C 1-6 heteroalkyl group, a C 3-9 cycloalkyl group, and a 3-9 membered heterocycloalkyl group;
  • R' is selected from the group consisting of F, Cl, Br, I, OH, CN, NH 2 , COOH, Me, Et, CH 2 F, CHF 2 , CF 3 , NH(CH 3 ), N(CH 3 ) 2 ;
  • the number of heteroatoms or heteroatoms is independently selected from 1, 2 or 3.
  • the above R is selected from the group consisting of H, OH, CN, NH 2 , COOH, halogen, or selected from the group consisting of 1, 2 or 3 R's substituted: 5-6 aryl, 5 ⁇ 6-membered heteroaryl, C 1-3 alkyl, C 1-3 alkyl-NH-, N,N-di(C 1-3 alkyl)amino, C 1-3 alkyl-O-, C 1 -3 alkyl-S-, C 3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl.
  • the above R is selected from the group consisting of H, OH, CN, NH 2 , COOH, halogen, or selected from the group consisting of 1, 2 or 3 R' substitutions: Me, Et, isopropyl, ring Propyl, NH(CH 3 ), N(CH 3 ) 2 , Phenyl, pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolidinyl, piperidine Pyridyl, morpholinyl, piperazinyl, azetidinyl.
  • the above R is selected from the group consisting of: H, OH, CN, NH 2 , COOH, F, Cl, Br, I, Me, Et, CH 2 F, CHF 2 , CF 3 , NH(CH 3 ) , N(CH 3 ) 2 , Cyclopropyl,
  • R 31 is selected from the group consisting of H, F, Cl, Br, I, CN, OH, amino, or selected from the group consisting of 1, 2 or 3 R: 5- to 6-membered aryl , 5-6-membered heteroaryl, C 1-3 alkyl, C 1-3 alkyl-NH-, N,N-di(C 1-3 alkyl)amino, C 1-3 alkyl-O- C 1-3 alkyl-S-, C 3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl.
  • the above R 31 is selected from the group consisting of H, F, Cl, Br, I, CN, OH, amino, or selected from the group consisting of 1, 2 or 3 R: Me, Et, Isopropyl Base, NH(CH 3 ), N(CH 3 ) 2 , Phenyl, pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolidinyl, piperidine Pyridyl, morpholinyl, piperazinyl, azetidinyl, cyclopropyl.
  • R 31 is selected from the group consisting of H, F, Cl, Br, I, CN, OH, amino, or selected from the group consisting of 1, 2 or 3 R: Me, Et, Isopropyl Base, NH(CH 3 ), N(CH 3 ) 2 ,
  • R 31 is selected from the group consisting of H, F, Cl, Br, I, CN, OH, amino, Me, Et, isopropyl, NH(CH 3 ),
  • the above compounds, pharmaceutically acceptable salts thereof, and tautomers thereof are selected from the group consisting of:
  • R 31 and D 3 are as defined above.
  • the above R is selected from the group consisting of H, OH, CN, NH 2 , COOH, halogen, or selected from the group consisting of 1, 2 or 3 R's substituted: 5-6 aryl, 5 ⁇ 6-membered heteroaryl, C 1-3 alkyl, C 1-3 alkyl-NH-, N,N-di(C 1-3 alkyl)amino, C 1-3 alkyl-O-, C 1 -3 alkyl-S-, C 3-6 cycloalkyl and 3 to 6 membered heterocycloalkyl, the other variables are as defined above.
  • the above R is selected from the group consisting of H, OH, CN, NH 2 , COOH, halogen, or selected from the group consisting of 1, 2 or 3 R' substitutions: Me, Et, isopropyl, ring Propyl, NH(CH 3 ), N(CH 3 ) 2 , Phenyl, pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolidinyl, piperidine Pyridyl, morpholinyl, piperazinyl, azetidinyl, other variables are as defined above.
  • the above R is selected from the group consisting of: H, OH, CN, NH 2 , COOH, F, Cl, Br, I, Me, Et, CH 2 F, CHF 2 , CF 3 , NH(CH 3 ) , N(CH 3 ) 2 , Cyclopropyl, Other variables are as defined above.
  • the above R 31 is selected from the group consisting of H, F, Cl, Br, I, CN, OH, amino, or selected from the group consisting of 1, 2 or 3 R: 5- to 6-membered aryl , 5-6-membered heteroaryl, C 1-3 alkyl, C 1-3 alkyl-NH-, N,N-di(C 1-3 alkyl)amino, C 1-3 alkyl-O- C 1-3 alkyl-S-, C 3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl, and other variables are as defined above.
  • the above R 31 is selected from the group consisting of H, F, Cl, Br, I, CN, OH, amino, or selected from the group consisting of 1, 2 or 3 R: Me, Et, Isopropyl Base, NH(CH 3 ), N(CH 3 ) 2 , Phenyl, pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolidinyl, piperidine Pyridyl, morpholinyl, piperazinyl, azetidinyl, cyclopropyl, other variables are as defined above.
  • R 31 is selected from the group consisting of H, F, Cl, Br, I, CN, OH, amino, or selected from the group consisting of 1, 2 or 3 R: Me, Et, Isopropyl Base, NH(CH 3 ), N(CH 3 ) 2 , Other variables are as defined above.
  • R 31 is selected from the group consisting of: H, F, Cl, Br, I, CN, OH, amino, Me, Et, isopropyl, NH(CH 3 ), N(CH 3 ) 2 , Other variables are as defined above.
  • the compounds of the invention are selected from:
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • Another object of the present invention is to provide the use of the above compound or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition for the preparation of a medicament for treating various conditions associated with EZH2 receptor.
  • C 1-12 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 ;
  • C 3-12 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 .
  • C 1-12 alkyl or heteroalkyl, C 3-12 cyclo or heterocycloalkyl, C 1-12 alkyl or heteroalkyl substituted by C 3-12 cycloalkyl or heterocycloalkyl includes, but is not limited to:
  • pharmaceutically acceptable as used herein is intended to mean that those compounds, materials, compositions and/or dosage forms are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues. Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
  • the parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.
  • a "pharmaceutically acceptable salt” is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phen
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the compounds provided herein also exist in the form of prodrugs.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art.
  • the diastereomers are resolved and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on vectors, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are hereby incorporated by reference.
  • excipient generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable.
  • it means that two hydrogen atoms are substituted.
  • Ketone substitution does not occur on the aryl group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted at most by two R, And each case has an independent option for R.
  • substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • substituent When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in AX, the structure is actually A. When a bond of a substituent can be cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring. When the recited substituents do not indicate which atom is attached to a compound included in the chemical structural formula including but not specifically mentioned, such a substituent may be bonded through any atomic phase thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, a structural unit It is indicated that it can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • halo or halogen
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
  • haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • Alkoxy represents the above alkyl group having a specified number of carbon atoms attached through an oxygen bridge.
  • the C 1-6 alkoxy group includes a C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
  • Cycloalkyl includes saturated cyclic groups such as cyclopropyl, cyclobutyl or cyclopentyl.
  • the 3-7 cycloalkyl group includes C 3 , C 4 , C 5 , C 6 and C 7 cycloalkyl groups.
  • Alkenyl includes hydrocarbon chains in a straight or branched configuration wherein one or more carbon-carbon double bonds, such as vinyl and propylene groups, are present at any stable site on the chain.
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring” means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
  • 5- to 7-membered ring includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • heterocycle or “heterocyclyl” means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • the nitrogen atom may be substituted or unsubstituted (ie N or NR, where R is H or this article has Other substituents that have been defined).
  • the heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites.
  • the nitrogen atom in the heterocycle is optionally quaternized.
  • a preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one.
  • aromatic heterocyclic group or "heteroaryl” as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • bridged rings are also included in the definition of heterocycles.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
  • heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl,
  • hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, phenyl, etc.) by itself or as part of another substituent means straight-chain, branched or cyclic
  • the hydrocarbon radical or a combination thereof may be fully saturated, mono- or polyunsaturated, may be monosubstituted, disubstituted or polysubstituted, and may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (methine), may include a divalent or polyvalent radical having the specified number of carbon atoms (e.g., C 1 -C 10 represents 1 to 10 carbons).
  • Hydrocarbyl includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members.
  • An aromatic hydrocarbon group such as benzene, naphthalene or the like.
  • hydrocarbyl means a straight or branched chain radical or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl).
  • a homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl.
  • the unsaturated alkyl group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). ), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and Structure.
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom.
  • heteroalkyl by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the heteroatom or heteroatom group can be located at any internal position of the heterohydrocarbyl group (including where the hydrocarbyl group is attached to the rest of the molecule).
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • alkoxy alkylamino and “alkylthio” (or thioalkoxy) are customary expressions and refer to those alkane which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Base group alkoxy
  • cycloalkyl refers to any heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized “hydrocarbyl group” or “heterohydrocarbyl group”, respectively.
  • a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule.
  • cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted, disubstituted or polysubstituted, may be monovalent, divalent or polyvalent, it may be monocyclic or Polycyclic (such as 1 to 3 rings; at least one of which is aromatic), which are fused together or covalently linked.
  • heteroaryl refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • aryl or heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyridyl Azyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxan Azyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, 5-
  • aryl groups when used in conjunction with other terms (e.g., aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen.
  • alkyl groups substituted by an atom such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
  • leaving group refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction).
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, toluene An acid ester, a p-bromobenzenesulfonate, a p-toluenesulfonate or the like; an acyloxy group such as an acetoxy group, a trifluoroacetoxy group or the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and t-butyl groups
  • acyl groups such as alkanoyl groups (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the solvent used in the present invention is commercially available.
  • the present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyl
  • Step 1 The compound bromomethyl(triphenyl)phosphorate (21.24 g, 59.46 mmol) was added to THF (100.00 mL). NaH (60%, 1.30 g, 54.05 mmol) was added at 0 ° C and stirred for 30 min. Then p-bromobenzaldehyde 1-1 (10.00 g, 54.05 mmol) was added and stirring was continued at 0 °C for 12 hours. After the reaction mixture was concentrated, EtOAc (EtOAc EtOAc (EtOAc) MS ESI calculated C 8 H 7 Br[M+H] + 183, found 183.
  • Step 2 Compound 1-2 (100.00 mg, 546.30 umol), methyl 3-[ethyl(tetrahydropyran-4-yl)amino]-2-methyl-5-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (146.89 mg, 364.20 umol), Cs 2 CO 3 (355.99 mg, 1.09 mmol) and Pd (dppf) Cl 2 (26.65 mg, 36.42 umol) was added to a mixed solvent of THF (10.00 mL) / H2O (2.00 mL), and the mixture was stirred at 80 ° C for 12 hours under nitrogen atmosphere.
  • Step 3 Compound 1-3 (110.00 mg, 289.86 umol) was added to a mixed solvent of H 2 O (5.00 mL) / MeOH (5.00 mL) / THF (5.00 mL), and OsO 4 (14.74 mg, 57.97 umol) and NMO (67.91 mg, 579.72 umol) were stirred at room temperature for 12 hours. The reaction mixture was concentrated, and the residue was purified mjjjjjj MS ESI calcd for C 24 H 31 NO5 [M + H] + 414, found 414.
  • Step 4 Compound 1-4 (100.00 mg, 241.83 umol) was added to a mixed solvent of EtOH (10.00 mL) / H 2 O (3.00 mL), then NaOH (29.02 mg, 725.50 umol) was added, the reaction was Stir at 60 ° C for 12 hours. After completion of the reaction, the reaction mixture was adjusted to pH 6-7 with EtOAc (2M), and filtered to afford compound 1-5 (60.00 mg, crude) as a brown oil. MS ESI calcd for C 23 H 29 NO 5 [M + H] + 400, found 400.
  • Step 5 Compound 1-5 (50.00 mg, 125.16 umol) was added to DMSO (3.00 mL), then HOBt (25.37 mg, 187.74 umol), EDCI (35.99 mg, 187.74 umol) and Et 3 N (38.00 mg) were added. , 375.49 umol), stirred at room temperature for 2 hours, then compound 1-6 was added, and stirred at 50 ° C for 22 hours. The mixture was poured into water, filtered, and the filter cake was washed with water to obtain a target compound 1 which was purified.
  • Step 1 Compound 2-1 (400.00 mg, 1.05 mmol) was added to DCM (15.00 mL). The mixture was then added saturated NaHCO 3 (40mL) solution, and extracted with DCM (50mL * 3), NaHSO 3 (2M, 70mL) aqueous solution, and purified by silica gel column to give compound 2-2 (200mg, yield 48%) as a yellow Oily liquid. MS ESI calcd for C 24 H 29 NO4 [M + H] + 396, found 396.
  • Step 2 Compound 2-2 (150.00 mg, 379.28 umol) was added to EtOH (15.00 mL), then EtOAc (66. After the completion of the reaction, the reaction mixture was concentrated to give a purified crystals of 2-3 (100 mg, yield 54%) as a colorless oil. MS ESI calculated for C 28 H 38 N2O5 [M+H] + 483, found 483.
  • Step 3 Compound 2-3 (100.00 mg, 207.21 umol) was added to a mixed solvent of dioxane (10.00 mL) / water (2.00 mL), and NaOH (24.87 mg, 621.63 umol) was added. Stir at 60 ° C for 12 hours. After completion of the reaction, the reaction mixture was adjusted to pH 6-7 with EtOAc (2M). MS ESI calcd for C 27 H 36 N 2 O 5 [M+H] + 469, found 469.
  • Step 4 Compound 2-4 (60.00 mg, 128.04 umol) was added to DMF (3.00 mL), then TBTU (82.22 mg, 256.08 umol), DIEA (33.10 mg, 256.08 umol) and 3-(aminomethyl) 4,6-Dimethyl-1H-pyridin-2-one (38.97 mg, 256.08 umol), stirred at room temperature for 12 hours.
  • the title compound 2 (20.00 mg, yield 25%) was obtained by preparative chromatography.
  • Step 2 To a mixture of compound 3-2 (11.00 g, 47.61 mmol) and compound 3-3 (11.01 g, 119.03 mmol, 11.01 ml), anhydrous AlCl 3 (19.05 g, 142.83 mmol, 7.81 ml) was added. The suspension was stirred at 80 ° C for 7 hours, extracted with water and dichloromethane at 0 ° C, dried over saturated brine and anhydrous sodium sulfate and evaporated.
  • Step 3 To a mixture of compound 3-4 (2.00 g, 6.97 mmol) and compound 3-5 (2.32 g, 7.67 mmol) in dioxane (15 ml) / water (3 ml) was added K 2 CO 3 ( 1.93 g, 13.9 mmol) and Pd(dppf)Cl 2 (509.71 mg, 697.00 ⁇ mol). The mixture was stirred at 105 ° C for 0.5 hour under a nitrogen atmosphere. The mixture was filtered through celite, and the filtrate was diluted with water and evaporated. The residue was purified by silica gel eluting eluting elute MS ESI calcd for C 22 H 25 NO 5 [M + H] + 384, found 384.
  • Step 4 Et added to DCM (20ml) Compound 3-6 (1.6g, 3.97mmol) was 3 N (1.77g, 17.54mmol, 2.43ml ), and the mixture was cooled to 0 °C slowly added dropwise compound 3-7 (2.12 g, 7.51 mmol, 1.24 ml). The suspension was stirred at 0 °C for 2 hours. It was diluted with water and extracted with dichloromethane. The residue was purified by silica gel chromatography eluting elut elut elut elut elut MS ESI calcd for C 23 H 24 F 3 NO 7 S [M + H] + 516, found 516.
  • Step 5 Compound 3-8 (2.20g, 4.27mmol) and Compound 3-9 (510.93mg, 8.54mmol) in tetrahydrofuran (20ml) was added K 3 PO 4 (1.81g Under nitrogen, 8.54 mmol And Pd(dppf)Cl 2 (312.27 mg, 427.00 ⁇ mol). Stir at 66 ° C for 4 hours under nitrogen. The mixture was filtered through celite, and the filtrate was evaporated and evaporated. The residue was purified by silica gel column chromatography toield MS ESI calcd for C 23 H 24 NO 7 [M + H] + 382, found 382.
  • Step 7 Thionyl chloride (46.54 mg, 391.16 ⁇ mol, 28.38 ⁇ L) was slowly added dropwise to a solution of compound 3-11 (75.00 ml, 195.58 ⁇ mol) in DCM (5.00 ml). The suspension was stirred at 20 ° C for 12 hours. Diluted with water and extracted with methylene chloride. EtOAc (EtOAc m. MS ESI calcd for C 23 H 28 ClNO 3 [M + H] + 402, found 402.
  • Step 8 A solution of compound 3-12 (70.00 mg, 174.16 ⁇ mol) in MeCN (5.00 ml) was added to compound 3-13 (22.76 mg, 261.24 ⁇ mol, 22.99 ⁇ l), and the mixture was stirred at 20 ° C for 2 hours. Then K 2 CO 3 (48.14 mg, 348.32 ⁇ mol) was added, and the mixture was further stirred at 90 ° C for 2 hours. It was diluted with water and extracted with dichloromethane. The residue was purified by silica gel chromatography eluting elut372 MS ESI calcd for C 28 H 37 NO 4 [M + H] + 452, found 452.
  • Step 9 To a solution of compound 3-14 (20.00 mg, 44.19 ⁇ mol) in MeOH/THF/H 2 O (1.00 mL, 1.00 mL, 0.5 mL) NaOH (4.42 mg, 110.48 ⁇ mol), the suspension at 80 ° C After stirring for 1 hour, the organic phase was concentrated to dryness crystals crystals crystals crystals crystals crystalsssssssssssssssssssssssssssssss MS ESI calcd for C 26 H 34 N 2 O 4 [M + H] + 439, found 439.
  • Step 10 To a solution of compound 3-15 (20.00 mg, 45.60 ⁇ mol) and compound 3-16 (10.41 mg, 68.40 ⁇ mol) in DMF (5 ml), DIEA (17.68 mg, 136.80 ⁇ mol, 23.89 ⁇ L) and TBTU (21.96) Mg, 68.40 ⁇ mol). The mixture was stirred at 25 ° C for 12 hours, and the crude product was purified by preparative HPLC to afford title compound 3 (15 mg, yield 56.82%).
  • EZH2 reaction buffer 50 mM Tris-HCl (pH 8.0), 0.01% Brij35, 1 mM EDTA, 1 mM DTT, 1 mM PMSF, 1% DMSO
  • HMTs reaction buffer 50 mM Tris-HCl (pH 8.5), 5 mM MgCl2, 50 mM NaCl, 0.01% Brij35, 1 mM DTT, 1% DMSO
  • DNMT1 reaction buffer 50 mM Tris-HCl (pH 7.5), 5 mM EDTA, 0.01% Brij35, 5 mM DTT, 0.1 mM PMSF, 5% glycerol, 1% DMSO
  • DNMTs Reaction Buffer 50 mM Tris-HCl (pH 7.5), 50 mM NaCl, 5 mM EDTA, 5 mM DTT, 0.1 mM PMSF, 5% glycerol, 1% DMSO
  • Methyl donor S-adenosine-1-[methyl-3H]methionine (SAM)
  • Substrate 5M histone, or nucleosome of 0.05 mg/mL HeLa cells or core histone from chicken, S-adenosyl-L-[methyl-3H-]methionine: 1 uM

Abstract

L'invention concerne un nouveau type de composés servant comme inhibiteur de l'EZH2; plus particulièrement, l'invention concerne un composé tel que représenté par la formule (III) et un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2017/079700 2016-04-08 2017-04-07 Composé biphényle servant comme inhibiteur de l'ezh2 WO2017174023A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10266542B2 (en) 2017-03-15 2019-04-23 Mirati Therapeutics, Inc. EZH2 inhibitors
US11091495B2 (en) 2018-01-31 2021-08-17 Mirati Therapeutics, Inc. Substituted imidazo[1,2-c]pyrimidines as PRC2 inhibitors
CN115551842A (zh) * 2020-06-08 2022-12-30 南京明德新药研发有限公司 联苯类化合物

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WO2012142504A1 (fr) * 2011-04-13 2012-10-18 Epizyme, Inc. Composés de benzène substitués par aryle ou hétéroaryle
WO2017011590A1 (fr) * 2015-07-13 2017-01-19 Arvinas, Inc. Modulateurs de protéolyse à base d'alanine et procédés d'utilisation associés
WO2017011371A1 (fr) * 2015-07-10 2017-01-19 Arvinas, Inc Modulateurs de protéolyse à base de mdm2 et méthodes d'utilisation associées

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WO2012142504A1 (fr) * 2011-04-13 2012-10-18 Epizyme, Inc. Composés de benzène substitués par aryle ou hétéroaryle
WO2017011371A1 (fr) * 2015-07-10 2017-01-19 Arvinas, Inc Modulateurs de protéolyse à base de mdm2 et méthodes d'utilisation associées
WO2017011590A1 (fr) * 2015-07-13 2017-01-19 Arvinas, Inc. Modulateurs de protéolyse à base d'alanine et procédés d'utilisation associés

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10266542B2 (en) 2017-03-15 2019-04-23 Mirati Therapeutics, Inc. EZH2 inhibitors
US11091495B2 (en) 2018-01-31 2021-08-17 Mirati Therapeutics, Inc. Substituted imidazo[1,2-c]pyrimidines as PRC2 inhibitors
US11220509B2 (en) 2018-01-31 2022-01-11 Mirati Therapeutics, Inc. Substituted imidazo[1,2-c]pyrimidines as PRC2 inhibitors
US11485738B2 (en) 2018-01-31 2022-11-01 Mirati Therapeutics, Inc. Substituted imidazo[1,2-c]pyrimidines as PRC2 inhibitors
CN115551842A (zh) * 2020-06-08 2022-12-30 南京明德新药研发有限公司 联苯类化合物
CN115551842B (zh) * 2020-06-08 2024-04-23 南京明德新药研发有限公司 联苯类化合物

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