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WO2019134539A1 - Composé de dihydropyrazolone et de pyrimidine, son procédé de préparation et son utilisation - Google Patents

Composé de dihydropyrazolone et de pyrimidine, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2019134539A1
WO2019134539A1 PCT/CN2018/122768 CN2018122768W WO2019134539A1 WO 2019134539 A1 WO2019134539 A1 WO 2019134539A1 CN 2018122768 W CN2018122768 W CN 2018122768W WO 2019134539 A1 WO2019134539 A1 WO 2019134539A1
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Prior art keywords
compound
group
alkyl
pharmaceutically acceptable
polymorph
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English (en)
Chinese (zh)
Inventor
刘金明
何婷
蔡家强
王利春
王晶翼
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Priority to CN201880072261.0A priority Critical patent/CN111315747B/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present application relates to a dihydropyrazolone pyrimidine compound, a process for its preparation and its use.
  • the cell cycle is a highly regulated and controlled process that is tightly regulated by a complex network of proteins, metabolism, and microenvironment interactions, designed to allow cells to proliferate only to specific stimuli and appropriate conditions (S. Diaz-Moralli , M. Tarrado-Castellarnau, A. Miranda, M. Cascante, Pharmacology & Therapeutics, 2013, 138: 255-271).
  • the standard cell cycle in turn undergoes G1 phase, S phase (DNA synthesis phase), G2 phase, and M phase (cell division phase).
  • G1 phase S phase
  • G2 phase DNA synthesis phase
  • M phase cell division phase
  • cell cycle checkpoints can be activated during G1/S phase, S phase, and G2/M phase, and induce cell cycle arrest until repair is completed; if repair is unsuccessful, cell senescence or cells will be driven Apoptosis (R. Visconti, MRDella, D. Grieco, Journal of Experimental & Clinical Cancer Research, 2016, 35: 153).
  • Wee1 protein kinase is a member of the serine/threonine protein kinase family and is a key component of the G2/M checkpoint of the cell cycle, playing a key role in cell division (CJMatheson, DSBackos, P. Reigan, Trends in Pharmacological Sciences, 2016, 37: 872). Entry into the mitosis from the G2/M checkpoint depends on the phosphorylation state of CDK1 (also known as CDC2) and the binding state of cyclin B.
  • CDK1 also known as CDC2
  • Wee1 Before mitosis, Wee1 phosphorylates the Tyr15 site of CDK1, and then the myelin transcription factor (MYT1) phosphorylates the Thr14 site of CDK1, maintains the inactive state of CDK1, and inhibits cells from entering M phase. Therefore, Wee1 is a negative regulator of cells from the G2 phase to the M phase.
  • MYT1 myelin transcription factor
  • the present application will provide a novel structure of Wee1 protein kinase inhibitor, and found that compounds of such structure exhibit excellent Wee1 protein inhibition and drugs. Duration of effectiveness.
  • An aspect of the present application provides a dihydropyrazolone pyrimidine compound having a Wee1 protein kinase inhibitory activity, or a pharmaceutically acceptable salt thereof, a stereoisomer, a tautomer, a polymorph, a solvent a substance, metabolite or prodrug having the structure of formula I below:
  • X is selected from CH and N;
  • R 1 is selected from the group consisting of hydroxy-C 1-6 alkyl-, C 1-6 alkoxy-C 1-6 alkyl- and cyano-C 3-6 cycloalkyl-;
  • R 2 is selected from a 7-10 membered fused heterocyclic group, and the 7-10 membered fused heterocyclic group is optionally substituted by one or more C 1-6 alkyl groups, and each C 1-6 alkyl group may be the same or different;
  • R 2 is selected from piperidinyl, the piperidinyl is optionally substituted by one or more -NR 5 R 6 ;
  • R 5 , R 6 are each independently selected from C 1-6 alkyl;
  • R 3 is selected from the group consisting of C 1-6 alkyl and C 2-6 alkenyl
  • R 4 is selected from the group consisting of hydrogen and halogen.
  • the compound has the structure of formula I-1 below:
  • the compound has the structure of formula I-2 below:
  • R 1 and R 2 are as defined in formula I.
  • Another aspect of the present application provides a method of preparing a compound of formula (I):
  • Hal 1 is halogen (for example F, Cl or Br);
  • Hal 2 is halogen (for example Cl, Br or I), a boronic acid group or a boronic acid ester group;
  • R 1 , R 2 , R 3 , R 4 The meaning of X and X is the same as that of the above formula I.
  • the present application also provides a method of preparing a compound of Formula 1-2:
  • Hal 1 is halogen (for example F, Cl or Br);
  • Hal 2 is halogen (for example Cl, Br or I), a boronic acid group or a boronic acid ester group;
  • PG is a protecting group, which may be selected from a benzyl group, P-methoxybenzyl, tert-butoxycarbonyl, benzyloxycarbonyl, preferably tert-butoxycarbonyl;
  • R 1 and R 2 are as defined above for the general formula I-2.
  • compositions comprising the compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite thereof or Prodrug, and one or more pharmaceutically acceptable carriers.
  • Another aspect of the present application provides a method of preparing the pharmaceutical composition, which comprises the compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph thereof
  • the solvate, metabolite or prodrug is combined with one or more pharmaceutically acceptable carriers.
  • Another aspect of the present application provides a pharmaceutical formulation comprising the compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or A drug, or the pharmaceutical composition.
  • Another aspect of the application provides the compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, the pharmaceutical composition or
  • the pharmaceutical preparation is used for the preparation of a disease for preventing or treating Wee1 protein kinase, and preferably the disease is cancer.
  • Another aspect of the application provides the compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, or the pharmaceutical composition, It is used for the treatment of Wee1 protein kinase-related diseases, preferably the disease is cancer.
  • Another aspect of the present application provides a method of preventing or treating a Wee1 protein kinase-associated disease, the method comprising administering to an individual in need thereof an effective amount of the compound or a pharmaceutically acceptable salt thereof, a stereoisomer, and a mutual An isomer, polymorph, solvate, metabolite or prodrug, or the pharmaceutical composition; preferably, the disease is cancer.
  • alkyl is defined as a straight or branched saturated aliphatic hydrocarbon group. In some embodiments, an alkyl group has from 1 to 12, such as from 1 to 6 carbon atoms.
  • C1-6 alkyl refers to a straight or branched chain group having from 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl), which is optionally substituted by one or more (such as 1 to 3) suitable substituents such as halogen (at this time)
  • haloalkyl such as CF 3 , C 2 F 5 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 Cl or -CH 2 CH 2 CF 3 , and the like
  • cycloalkyl refers to a saturated or partially unsaturated, non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg, a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl).
  • the group has 3 to 15, for example 3 to 6 carbon atoms.
  • C 3-6 cycloalkyl refers to a saturated or partially unsaturated non-aromatic monocyclic ring having 3 to 6 ring-forming carbon atoms or a polycyclic (such as bicyclic) hydrocarbon ring (eg, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), which is optionally substituted with one or more (such as 1 to 3) suitable substituents, such as A substituted cyclopropyl group.
  • a polycyclic hydrocarbon ring eg, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl
  • suitable substituents such as A substituted cyclopropyl group.
  • halo or halogen group, as used herein, is defined to include fluoro, chloro, bromo or iodo.
  • alkoxy refers to an alkyl group, as defined above, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of C1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, and the like. .
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic group, for example having 2, 3, 4, 5, 6, 7, 8 or 9 carbons in the ring.
  • it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group.
  • substituted means that one or more (eg, 1, 2, 3 or 4) hydrogens on the designated atom are replaced by the selection of the indicated group, provided that the specified atom is not exceeded.
  • the normal valence of the current case and the substitution form a stable compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
  • substituent may be unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together independently The optional substituents selected are substituted. If the nitrogen of the substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected. Substitute substitution.
  • each substituent is selected independently of the other.
  • each substituent may be the same or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10 under reasonable conditions.
  • a point of attachment of a substituent may come from any suitable position of the substituent.
  • the invention also includes all pharmaceutically acceptable isotopically-labeled compounds which are identical to the compounds of the invention, except that one or more atoms are of the same atomic number but the atomic mass or mass number differs from the atomic mass prevailing in nature. Or atomic substitution of mass.
  • isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., 2 H, 3 H); isotopes of carbon (e.g., 11 C, 13 C, and 14 C); isotopes of chlorine (e.g.
  • isotope of fluorine eg 18 F
  • isotopes of iodine eg 123 I and 125 I
  • isotopes of nitrogen eg 13 N and 15 N
  • isotopes of oxygen eg 15 O, 17 O and 18 O
  • isotope of phosphorus eg, 32 P
  • isotope of sulfur eg, 35 S.
  • Certain isotopically-labeled compounds of the invention e.g., those incorporating radioisotopes
  • are useful in drug and/or substrate tissue distribution studies e.g., assays).
  • the radioisotope ruthenium (i.e., 3 H) and carbon-14 (i.e., 14 C) are particularly useful for this purpose because of their ease of incorporation and ease of detection.
  • Substitution with positron emitting isotopes eg, 11 C, 18 F, 15 O, and 13 N
  • PET positron emission tomography
  • Isotopically labeled compounds of the invention can be prepared by replacing the previously employed non-labeled reagents with suitable isotopically labeled reagents by methods analogous to those described in the accompanying routes and/or examples and preparations.
  • the pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be substituted with an isotope, for example, D 2 O, acetone-d 6 or DMSO-d 6 .
  • stereoisomer denotes an isomer formed by at least one asymmetric center.
  • asymmetric center which can produce a racemic mixture, a single enantiomer, a mixture of diastereomers, and Separate diastereomers.
  • Specific individual molecules can also exist as geometric isomers (cis/trans).
  • the compounds of the invention may exist as mixtures (often referred to as tautomers) of two or more different forms in a rapidly balanced structure.
  • tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait.
  • the dihydropyrimidinyl group may exist in equilibrium in the following tautomeric forms in solution. It is to be understood that the scope of the present application covers all such ratios in any ratio (eg, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99). %) isomer or a mixture thereof.
  • Solid lines can be used in this article Solid wedge Virtual wedge
  • the carbon-carbon bond of the compound is depicted.
  • the use of solid lines to delineate linkages bonded to an asymmetric carbon atom is intended to include all possible stereoisomers at the carbon atom (eg, specific enantiomers, racemic mixtures, etc.).
  • the use of a solid or virtual wedge to characterize a bond to an asymmetric carbon atom is intended to indicate the presence of the stereoisomers shown. When present in a racemic mixture, solid and virtual wedges are used to define relative stereochemistry rather than absolute stereochemistry.
  • the compounds are intended to be stereoisomers (including cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, geometry Forms of isomers, rotamers, conformers, atropisomers, and mixtures thereof exist.
  • the compounds may exhibit more than one type of isomerism and consist of a mixture thereof (e.g., a racemic mixture and a diastereomeric pair).
  • the present application encompasses all possible crystalline forms or polymorphs of the compounds, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • compositions of the present application may exist in free form for treatment or, where appropriate, in the form of their pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, solvates, metabolites or prodrugs which, after administration to a patient in need thereof, can be directly or indirectly A compound of the invention or a metabolite or residue thereof is provided.
  • the pharmaceutically acceptable salts of the compounds of the present application include the acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, bicarbonate/carbonate, hydrogen sulfate/sulfate, fumarate, glucoheptonate, gluconate , glucuronate, hexafluorophosphate, hydrobromide/bromide, hydroiodide/iodide, maleate, malonate, methyl sulfate, naphthoate ( Naphthylate), nicotinate, nitrate, orotate, oxalate, palmitate and other similar salts.
  • Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, choline salts, diethylamine salts, lysine salts, magnesium salts, meglumine salts, potassium salts, sodium salts, tromethamine salts, and other similar salts.
  • the compounds of the present application may exist in the form of a solvate, preferably a hydrate, wherein the compound of the present application contains a polar solvent as a structural element of the crystal lattice of the compound, especially such as water, methanol or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, especially such as water, methanol or ethanol.
  • the amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric ratios.
  • the application also includes metabolites of the compounds, ie, substances formed in vivo upon administration of the compounds. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic hydrolysis, and the like of the administered compound. Accordingly, the application includes metabolites of the compounds, including compounds made by contacting the compound with a mammal for a time sufficient to produce its metabolites.
  • the present application further encompasses prodrugs of the compounds which are certain derivatives of the compounds which may themselves have less or no pharmacological activity, may be cleavable by, for example, hydrolytic hydrolysis when administered to or in the body. Conversion to the compound with the desired activity. Typically such prodrugs will be functional group derivatives of the compounds which are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 ( Edited by EBRoche, American Pharmaceutical Association).
  • the prodrug can be replaced, for example, by using certain parts known to those skilled in the art as "pro-moiety” (for example as described in “Design of Prodrugs", H. Bundgaard (Elsevier, 1985)" Prepared by the appropriate functional groups present in the compounds of the present application.
  • the present application also encompasses such compounds containing a protecting group.
  • a protecting group In any process in which the compound is prepared, it may be necessary and/or desirable to protect sensitive groups or reactive groups on any of the molecules of interest, thereby forming a chemically protected form of the compound. This can be achieved by conventional protecting groups such as those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P. GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. Protecting groups, which are incorporated herein by reference. The protecting group can be removed at a suitable subsequent stage using methods known in the art.
  • X is selected from CH and N;
  • R 1 is selected from the group consisting of hydroxy-C 1-6 alkyl-, C 1-6 alkoxy-C 1-6 alkyl- and cyano-C 3-6 cycloalkyl-;
  • R 2 is selected from a 7-10 membered fused heterocyclic group, and the 7-10 membered fused heterocyclic group is optionally substituted by one or more C 1-6 alkyl groups, and each C 1-6 alkyl group may be the same or different;
  • R 2 is selected from piperidinyl, the piperidinyl is optionally substituted by one or more -NR 5 R 6 ;
  • R 5 , R 6 are each independently selected from C 1-6 alkyl;
  • R 3 is selected from the group consisting of C 1-6 alkyl and C 2-6 alkenyl
  • R 4 is selected from the group consisting of hydrogen and halogen.
  • the compound has the structure shown in Formula I-1.
  • X in Formula I or Formula I-1 is CH.
  • X in Formula I or Formula I-1 is N.
  • portions, of Formula I or Formula I-1 wherein R 1 is selected from hydroxy -C 1-4 alkyl -, C 1-3 alkoxy -C 1-4 alkyl - cyano and -C 3- 6 cycloalkyl-.
  • R 1 is selected from the group consisting of 2-hydroxypropan-2-yl, 2-methoxypropan-2-yl, and 1-cyanocycloprop-1-yl.
  • R 2 in Formula I or Formula I-1 is selected from a 7-10 membered bicyclic fused heterocyclyl optionally substituted by one or more C 1-6 An alkyl group (e.g., C 1-4 alkyl, C 1-2 alkyl) is substituted. In some embodiments, R 2 is selected from an 8-membered fused heterocyclyl, which is substituted with a C 1-6 alkyl (eg, C 1-4 alkyl, C 1-2 alkyl) .
  • R 2 is selected from the group consisting of an 8-membered bicyclic fused heterocyclyl group, which is a C 1-6 alkyl group (eg, C 1-4 alkyl, C 1-2 Alkyl) substitution. In some preferred embodiments, R 2 is selected from In some preferred embodiments, R 2 is 5-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl.
  • R 2 in Formula I or Formula I-1 is piperidinyl, the piperidinyl is substituted by one or more —NR 5 R 6 , and R 5 and R 6 are each independently selected from C 1 -4 alkyl.
  • R 2 is piperidinyl, the piperidinyl is substituted by one or more -NR 5 R 6 , and R 5 and R 6 are each independently selected from C 1-2 alkyl.
  • R 2 is R 5 and R 6 are each independently selected from a C 1-6 alkyl group (e.g., a C 1-4 alkyl group, a C 1-2 alkyl group).
  • R 2 is 4-dimethylaminopiperidin-1-yl.
  • R 3 of Formula I or Formula I-1 is selected from the group consisting of C 1-4 alkyl and C 2-4 alkenyl. In some preferred embodiments, R 3 is selected from the group consisting of allyl and isopropyl.
  • R 4 of Formula I or Formula I-1 is selected from the group consisting of hydrogen, fluorine, chlorine, and bromine. In some embodiments, R 4 is selected from the group consisting of hydrogen and fluorine. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is fluoro.
  • the compound has the structure of Formula I-2,
  • R 1 and R 2 are as defined in formula I.
  • R 1 is selected from the group consisting of hydroxy-C 1-6 alkyl-, C 1-6 alkoxy-C 1-6 alkyl-, and cyano-C 3-6 cycloalkyl-.
  • R 2 is selected from 7-10 membered fused heterocyclyl, and the 7-10 membered fused heterocyclyl is optionally substituted by one or more C 1-6 alkyl, each C 1-6 alkane
  • the groups may be the same or different; or R 2 is selected from the group consisting of piperidinyl, which is substituted by one or more -NR 5 R 6 , and R 5 and R 6 are each independently selected from C 1-6 alkyl.
  • R 1 is selected from the group consisting of hydroxy-C 1-4 alkyl-, C 1-3 alkoxy-C 1-4 alkyl-, and cyano-C 3-6 cycloalkyl-; preferably R 1 is selected from the group consisting of 2-hydroxyprop-2-yl, 2-methoxyprop-2-yl and 1-cyanocycloprop-1-yl.
  • R 2 is selected from an 8-membered fused heterocyclyl, and the 8-membered fused heterocyclyl is substituted with a C 1-6 alkyl;
  • R 2 is selected from an 8-membered bicyclic fused heterocyclic group substituted by a C 1-6 alkyl group (eg, C 1-4 alkyl, C 1-2 alkyl);
  • R 2 is selected from
  • R 2 is 5-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl.
  • R 2 is selected from R 5 and R 6 are each independently selected from C 1-6 alkyl (e.g., C 1-4 alkyl, C 1-2 alkyl); preferably, R 2 is 4-dimethylaminopiperidin-1-yl .
  • the compound has the structure of Formula I-2 above,
  • R 1 is selected from the group consisting of hydroxy-C 1-6 alkyl-, C 1-6 alkoxy-C 1-6 alkyl- and cyano-C 3-6 cycloalkyl-;
  • R 2 is selected from a 7-10 membered fused heterocyclic group, and the 7-10 membered fused heterocyclic group is optionally substituted by one or more C 1-6 alkyl groups, and each C 1-6 alkyl group may be the same or different; Or R 2 is selected from the group consisting of piperidinyl, which is substituted by one or more -NR 5 R 6 , and R 5 and R 6 are each independently selected from C 1-6 alkyl.
  • the compound has the structure of Formula I-2 above,
  • R 1 is selected from the group consisting of hydroxy-C 1-4 alkyl-, C 1-3 alkoxy-C 1-4 alkyl- and cyano-C 3-6 cycloalkyl-; preferably, R 1 is selected From 2-hydroxypropan-2-yl, 2-methoxypropan-2-yl and 1-cyanocycloprop-1-yl;
  • R 2 is selected from an 8-membered fused heterocyclic group substituted by a C 1-6 alkyl group; preferably, R 2 is selected from Preferably, R 2 is 5-methylhexahydropyrrole [3,4-c]pyrrole-2(1H)-yl;
  • R 2 is selected from R 5 and R 6 are each independently selected from C 1-6 alkyl; preferably, R 2 is 4-dimethylaminopiperidin-1-yl.
  • the compound has the structure:
  • Another object of the present application is to provide a process for the preparation of a compound of formula (I):
  • Hal 1 is halogen (for example F, Cl or Br);
  • Hal 2 is halogen (for example Cl, Br or I), a boronic acid group or a boronic acid ester group;
  • R 1 , R 2 , R 3 , R 4 The meaning of X and X is the same as that of the above formula I.
  • Compound IN-1 can be reacted with an alkyl hydrazine compound to provide compound IN-2, preferably carried out in a suitable organic solvent.
  • the organic solvent may be selected from the group consisting of tetrahydrofuran, dichloromethane, chloroform, dimethylformamide, dimethylacetamide, dioxane, and any combination thereof, preferably tetrahydrofuran.
  • the reaction is preferably carried out in the presence of a suitable organic base.
  • the organic base may be selected from the group consisting of triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, preferably diisopropylethylamine.
  • the reaction is preferably carried out at a suitable temperature, preferably 50-70 °C.
  • the reaction is preferably carried out for a suitable period of time, for example 6-16 hours.
  • the compound IN-1 may also be first reacted with hydrazine hydrate, and then reacted with an aldehyde compound to obtain the compound IN-2.
  • the reaction with hydrazine hydrate is preferably carried out in a suitable organic solvent.
  • the organic solvent may be selected from the group consisting of ethanol, methanol, tetrahydrofuran, dichloromethane, chloroform, dimethylformamide, dimethylacetamide, dioxane, and any combination thereof, preferably ethanol.
  • the reaction is preferably carried out at a suitable temperature, preferably from 0 to 25 °C.
  • the reaction is preferably carried out for a suitable period of time, for example 1-6 hours.
  • the reduction reaction with the aldehyde compound is preferably carried out in a suitable organic solvent and in the presence of a reducing agent.
  • the solvent may be selected from the group consisting of methanol, ethanol, dichloromethane, chloroform, acetonitrile, preferably methanol.
  • the reducing agent may be selected from sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, etc., preferably sodium cyanoborohydride.
  • the reaction temperature is usually preferably from 0 to 25 ° C, and the reaction time is usually preferably from 1 to 3 hours.
  • the cyclization reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent may be selected from the group consisting of methanol, ethanol, tetrahydrofuran, dioxane, and any combination thereof, preferably ethanol.
  • the base used for the cyclization may be selected from inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, etc., preferably sodium hydroxide.
  • the cyclization reaction temperature is usually preferably room temperature (20 to 30 ° C), and the cyclization reaction time is usually preferably from 0.5 to 2 hours.
  • the coupling reaction is preferably carried out in the presence of a metal catalyst and a base.
  • the metal catalyst is a copper salt catalyst, preferably cuprous iodide, copper acetate or the like.
  • the base is an inorganic base such as potassium carbonate, cesium carbonate, sodium carbonate, 2,2-bipyridine or potassium phosphate, preferably potassium carbonate.
  • the ligand for the coupling reaction is selected from the group consisting of trans-N,N'-dimethyl-1,2-cyclohexanediamine, N,N'-dimethylethylenediamine, preferably trans-N,N '-Dimethyl-1,2-cyclohexanediamine.
  • the solvent for the coupling reaction is selected from the group consisting of benzene, toluene, dioxane, dimethylformamide, ethylene glycol dimethyl ether, and the like, or a mixed solvent thereof, preferably dioxane and dimethylformamide.
  • the coupling reaction temperature is usually preferably from 80 to 110 °C.
  • the reaction time is usually preferably from 4 to 6 hours.
  • the oxidation reaction can be preferably carried out in a suitable organic solvent and in the presence of an oxidizing agent.
  • the solvent may be selected from the group consisting of benzene, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide and the like, preferably acetonitrile.
  • the oxidizing agent may be selected from the group consisting of m-chloroperoxybenzoic acid, potassium peroxymonosulfate complex salt, and the like, preferably a potassium peroxymonosulfate complex salt.
  • the reaction temperature is usually preferably room temperature (20 to 30 ° C), and the reaction time is usually preferably from 0.5 to 3 hours.
  • the reaction is preferably carried out in an inert solvent including toluene, benzene, chloroform, dioxane, dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide or the like or a mixed solvent thereof, preferably toluene.
  • the reaction is preferably carried out in the presence of a suitable organic base which may be selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine and the like, preferably diisopropylethylamine.
  • the reaction temperature is usually preferably from 60 to 120 ° C, and the reaction time is usually preferably from 4 to 12 hours.
  • a further object of the present application is to provide a process for the preparation of a compound of formula 1-2:
  • Hal 1 is halogen (for example F, Cl or Br);
  • Hal 2 is halogen (for example Cl, Br or I), a boronic acid group or a boronic acid ester group;
  • PG is a protecting group, which may be selected from a benzyl group, P-methoxybenzyl, tert-butoxycarbonyl, benzyloxycarbonyl, preferably tert-butoxycarbonyl;
  • R 1 and R 2 are as defined above for the general formula I-2.
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent may be selected from the group consisting of tetrahydrofuran, dichloromethane, chloroform, dimethylformamide, dimethylacetamide, dioxane, and any combination thereof, preferably tetrahydrofuran.
  • the reaction is preferably carried out in the presence of a suitable organic base.
  • the organic base may be selected from the group consisting of triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, preferably diisopropylethylamine.
  • the reaction is preferably carried out at a suitable temperature, preferably from 50 to 70 °C.
  • the reaction is preferably carried out for a suitable period of time, for example 6-16 hours.
  • the reaction for removing the protecting group PG can be applied to a hydrolysis reaction method of a carboxylic acid ester well known in the field of organic chemistry, in which the protecting group PG is a tert-butoxycarbonyl group, the reaction preferably passes through an ester in the presence of an acid.
  • the acid hydrolysis reaction proceeds.
  • the acid may be a mineral acid or a suitable organic acid including, but not limited to, hydrochloric acid, sulfuric acid, formic acid, trifluoroacetic acid;
  • the reaction solvent may be selected from dioxane, dichloromethane, ethyl acetate or a mixed solvent thereof.
  • the acid can also be used as a reaction solvent, preferably trifluoroacetic acid.
  • the reaction temperature is usually preferably from 40 to 70 °C.
  • the reaction time is usually preferably from 1 to 3 hours.
  • the cyclization reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent may be selected from the group consisting of methanol, ethanol, tetrahydrofuran, dioxane, and any combination thereof, preferably ethanol.
  • the base used in the cyclization reaction may be selected from inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, etc., preferably sodium hydroxide.
  • the cyclization reaction temperature is usually preferably room temperature (20 to 30 ° C), and the cyclization reaction time is usually preferably from 0.5 to 2 hours.
  • the coupling reaction is preferably carried out in the presence of a metal catalyst and a base.
  • the metal catalyst is a copper salt catalyst, preferably cuprous iodide, copper acetate or the like.
  • the base is an inorganic base such as potassium carbonate, cesium carbonate, sodium carbonate, 2,2-bipyridine or potassium phosphate, preferably potassium carbonate.
  • the ligand for the coupling reaction is selected from the group consisting of trans-N,N'-dimethyl-1,2-cyclohexanediamine, N,N'-dimethylethylenediamine, preferably trans-N,N '-Dimethyl-1,2-cyclohexanediamine.
  • the solvent for the coupling reaction is selected from the group consisting of benzene, toluene, dioxane, dimethylformamide, ethylene glycol dimethyl ether, and the like, or a mixed solvent thereof, preferably dioxane and dimethylformamide.
  • the coupling reaction temperature is preferably from 80 to 110 °C.
  • the reaction time is preferably 4 to 6 hours.
  • the oxidation reaction can be preferably carried out in a suitable organic solvent and in the presence of an oxidizing agent.
  • the solvent may be selected from the group consisting of benzene, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide and the like, preferably acetonitrile.
  • the oxidizing agent may be selected from the group consisting of m-chloroperoxybenzoic acid, potassium peroxymonosulfate complex salt, and the like, preferably a potassium peroxymonosulfate complex salt.
  • the reaction temperature is usually preferably room temperature (20 to 30 ° C), and the reaction time is usually preferably from 0.5 to 3 hours.
  • the reaction is preferably carried out in an inert solvent selected from the group consisting of toluene, benzene, chloroform, dioxane, dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like, or a mixed solvent thereof, preferably Toluene.
  • the reaction is preferably carried out in the presence of a suitable organic base which may be selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine and the like, preferably diisopropylethylamine.
  • the reaction temperature is preferably from 60 to 120 ° C, and the reaction time is usually preferably from 4 to 12 hours.
  • Another object of the present application is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, a stereoisomer, a tautomer, a polymorph, a solvent a compound, metabolite or prodrug, and one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carrier herein is meant a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting humans and/or others within the scope of sound medical judgment. Animal tissue without excessive toxicity, irritation, allergic reactions or other problems or complications corresponding to a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable carriers for use in the pharmaceutical compositions include, but are not limited to, sterile liquids such as water and oils, including those oils of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, Sesame oil and so on. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. It is also possible to use physiological saline and an aqueous solution of glucose and glycerin as a liquid carrier, particularly for injection.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, Ethanol and the like.
  • the composition may also contain minor amounts of wetting agents, emulsifying agents or pH buffering agents as needed.
  • Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are as described in Remington's Pharmaceutical Sciences (1990).
  • the pharmaceutical composition can act systemically and/or locally.
  • they may be administered in a suitable route, for example by injection (for example intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, including instillation) or transdermal administration; or by oral, buccal, or oral administration.
  • injection for example intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, including instillation
  • transdermal administration for example intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, including instillation
  • oral, buccal, or oral administration for example by injection (for example intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, including instillation) or transdermal administration; or by oral, buccal, or oral administration.
  • the pharmaceutical compositions can be administered in a suitable dosage form.
  • the dosage forms include, but are not limited to, tablets, capsules, troches, hard candy, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions. Injectable solutions, elixirs, syrups, and the like.
  • the amount or amount of the compound in the pharmaceutical composition may be from about 0.01 mg to about 1000 mg, suitably from 0.1 to 500 mg, preferably from 0.5 to 300 mg, more preferably from 1 to 150 mg.
  • Another object of the present application is to provide a method of preparing the pharmaceutical composition, which comprises the compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph thereof
  • the solvate, metabolite or prodrug is combined with one or more pharmaceutically acceptable carriers.
  • Another object of the present application is to provide a pharmaceutical preparation comprising the compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite thereof or Prodrug, or a mixture thereof, or the pharmaceutical composition.
  • Another object of the present application is to provide a compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, or a combination thereof Use of the medicament for the preparation of a medicament for preventing or treating a Wee1 protein kinase-related disease.
  • the Wee1 protein kinase associated disease is cancer.
  • Another object of the present application is to provide a compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, or a combination thereof
  • a compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, or a combination thereof For use in the prevention or treatment of Wee1 protein kinase-associated diseases.
  • the Wee1 protein kinase associated disease is cancer.
  • Another object of the present application is to provide a method for preventing or treating a Wee1 protein kinase-related disease, which comprises administering an effective amount of the compound or a pharmaceutically acceptable salt thereof, a stereoisomer, and each other to an individual in need thereof
  • the Wee1 protein associated disease is cancer.
  • the cancer includes, but is not limited to, head and neck cancer, ovarian cancer, colorectal cancer, bladder cancer, breast cancer, non-small cell lung cancer, and endometrial cancer.
  • an effective amount refers to an amount of a compound that, to a certain extent, relieves one or more symptoms of the condition being treated after administration.
  • the dosing regimen can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the urgent need for treatment. It is noted that the dose value can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering the composition or the composition of the supervised composition.
  • an effective dose will be from about 0.0001 to about 50 mg per kg body weight per day, for example from about 0.01 to about 10 mg/kg/day (single or divided doses). For a 70 kg person, this would add up to about 0.007 mg/day to about 3500 mg/day, such as from about 0.7 mg/day to about 700 mg/day.
  • a dose level that is not higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose may still be employed without causing any harmful side effects, provided that the larger The dose is divided into several smaller doses to be administered throughout the day.
  • treating means reversing, alleviating, inhibiting the progression of a condition or condition to which such a term applies or the progression of one or more symptoms of such a condition or condition, or preventing such A condition or condition or one or more symptoms of such condition or condition.
  • “Individual” as used herein includes human or non-human animals.
  • Exemplary human individuals include a human individual (referred to as a patient) or a normal individual having a disease, such as the disease described herein.
  • non-human animal includes all vertebrates, such as non-mammals (eg, birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals, and/or domesticated animals (eg, sheep, dogs, Cats, cows, pigs, etc.).
  • the structure of the compound described in the following examples was confirmed by 1 H-NMR or MS.
  • the 1 H-NMR measuring instrument was measured using a Bruker 400 MHz nuclear magnetic resonance apparatus, and the solvent was CD 3 OD, CDCl 3 or DMSO-d 6 , and the internal standard substance was TMS. The total ⁇ value was expressed by ppm.
  • the mass spectrometer (MS) assay instrument used an Agilent (ESI) mass spectrometer, model Agilent 6120B.
  • Thin layer chromatography silica gel plates were prepared using an aluminum plate (20 x 20 cm) manufactured by Merck, and separated by thin layer chromatography using GF 254 (0.4 to 0.5 mm).
  • the reaction was monitored by thin layer chromatography (TLC) or LC-MS.
  • the developing solvent system used was: dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system, solvent volume ratio. The adjustment is carried out depending on the polarity of the compound or by adding triethylamine or the like.
  • Microwave reaction Initiator + 400 W, RT ⁇ 300 ° C microwave reactor.
  • Column chromatography generally uses 200 to 300 mesh silica gel as a carrier.
  • the system of the eluent includes: a dichloromethane and methanol system, a petroleum ether and an ethyl acetate system, and the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may also be adjusted by adding a small amount of triethylamine.
  • the reaction temperature of the examples is room temperature (20 ° C to 30 ° C) unless otherwise specified.
  • the reagents used in the present application were purchased from Acros Organics, Aldrich Chemical Company, Shanghai Tebo Chemical Technology Co., Ltd., and the like.
  • Second step Preparation of ethyl 4-(2-allylmethyl)-2-(methylthio)pyrimidine-5-carboxylate
  • Methyl 6-bromopyridine-2-carboxylate (5 g, 23.1 mmol) was dissolved in diethyl ether (100 mL). Methyl magnesium iodide (17 mL, 50.8 mmol) was added under nitrogen, and stirred at room temperature for 0.5 hr. The organic layer was combined and washed with a saturated aqueous solution of sodium hydrogen carbonate and brine and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave the title compound (5 g, yield: 100%).
  • the third step preparation of 2-methyl-5-(4-nitrophenyl)hexahydropyrrole [3,4-c]pyrrole
  • Second step Preparation of ethyl 2-(methylthio)-4-(2-(propan-2-ylidene)indenyl)pyrimidine-5-carboxylate
  • the third step 2-allyl-1-(6-(1-cyanocycloprop-1-yl)pyridin-2-yl)-6-((4-(4-dimethylaminopiperidine-1) Of phenyl)amino)amino)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one
  • the third step 2-allyl-1-(6-(2-methoxypropan-2-yl)pyridin-2-yl)-6-((4-(5-methylhexahydropyrrole[3] Of 4-(4-c]pyrrole-2(1H)-yl)-phenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one
  • Example 7 6-((4-(4-(Dimethylamino)piperidin-1-yl)phenyl)amino)-1-(6-(2-hydroxypropan-2-yl)pyridine-2- Preparation of 2-acetyl-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one (Compound 7)
  • Second step 6-((4-(4-(Dimethylamino)piperidin-1-yl)phenyl)amino)-1-(6-(2-hydroxypropan-2-yl)pyridine-2- Of 2-acetyl-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one
  • Example 8 2-allyl-6-((4-(4-(dimethylamino)piperidin-1-yl)-3-fluorophenyl)amino)-1-(6-(2-hydroxyl) Propane-2-yl)pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one (Compound 8)
  • Methyl 3-bromobenzoate (1 g, 4.65 mmol) was added to diethyl ether (20 mL) under EtOAc. EtOAc (EtOAc m. After that, it was naturally raised to room temperature for 12 hours. The reaction mixture was poured into a saturated aqueous solution of EtOAc. EtOAc.
  • the third step 2-allyl-1-(3-(2-hydroxypropan-2-yl)phenyl)-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine- Preparation of 3(2H)-one
  • Step 5 2-allyl-6-((4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)-1-(3-(2-hydroxypropane-2-) Of phenyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one
  • the compound has a significant inhibitory effect on Wee1 kinase.
  • the Wee1 inhibitor AZD1775 and the test compound were administered to the male SD rats at the clinical trial stage by intravenous (IV) and gavage (PO), respectively, and the pharmacokinetic characteristics of the test compounds were examined.
  • the doses of IV and PO were 1 mg/kg and 5 mg/kg, respectively, and the medium of IV was 5% DMSO: 5% Solutol: 90% physiological saline, and the solvent of PO was 0.5% MC.
  • Blood was collected at different time points after IV and PO administration. The blood was anticoagulated with EDTA-K 2 and centrifuged to obtain a plasma sample. Plasma samples were processed by precipitation protein and analyzed by LC-MS/MS.
  • T 1/2 of Compound 1 and Compound 2 of the present application administered by a dose of 5 mg/kg T 1/2 was 4.37 hours and 3.79 hours, respectively, indicating that the half-life of the compound of the present application is higher than that of the compound AZD1775. More than 1 time, the effect of the drug is longer, and has a significant advantage.
  • the compound of the present application can be administered once a day, which can reduce the number of administrations and improve patient compliance.
  • the Wee1 inhibitor AZD1775 and the test compound were administered to female Balb/c mice at the clinical trial stage by intravenous (IV) and intragastric (PO), respectively, and the pharmacokinetic characteristics of the test compounds were examined.
  • IV and PO were 1 mg/kg and 10 mg/kg, respectively, and the medium of IV was 5% DMSO: 5% Solutol: 90% physiological saline, and the solvent of PO was 0.5% MC.
  • Blood was collected at different time points after IV and PO administration. The blood was anticoagulated with EDTA-K 2 and centrifuged to obtain a plasma sample. Plasma samples were processed by precipitation protein and analyzed by LC-MS/MS.
  • mice have good drug exposure and are suitable for oral administration.
  • the data in Table 5 shows that the compound 1 of the present application has a T 1/2 of 1.15 hours and 2.90 hours in the intravenous and intragastric administration modes, respectively, indicating that the half-life of the compound of the present application is more than doubled than that of the compound AZD1775. Longer duration and significant advantages. Moreover, the compound of the present application can be administered once a day, which can reduce the number of administrations and improve patient compliance.

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Abstract

L'invention concerne un composé de dihydropyrazolone et de pyrimidine, un procédé de préparation associé et une utilisation correspondante. Plus particulièrement, la présente invention concerne un composé de formule I, une composition pharmaceutique et une formulation pharmaceutique comprenant ledit composé, un procédé de préparation dudit composé, et une utilisation dudit composé dans la préparation de médicaments pour la prévention ou le traitement de maladies liées à la protéine Wee1.
PCT/CN2018/122768 2018-01-05 2018-12-21 Composé de dihydropyrazolone et de pyrimidine, son procédé de préparation et son utilisation Ceased WO2019134539A1 (fr)

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US10807994B2 (en) 2017-10-09 2020-10-20 Nuvation Bio Inc. Heterocyclic compounds and uses thereof
US11028058B2 (en) 2017-07-18 2021-06-08 Nuvation Bio Inc. Heterocyclic compounds as adenosine antagonists
US11254670B2 (en) 2019-01-18 2022-02-22 Nuvation Bio Inc. 1,8-naphthyridinone compounds and uses thereof
US11261192B2 (en) 2018-03-09 2022-03-01 Recurium Ip Holdings, Llc Substituted 1,2-dihydro-3H-pyrazolo[3,4-D]pyrimidin-3-ones
US11299493B2 (en) 2017-10-09 2022-04-12 Nuvation Bio Inc. Heterocyclic compounds and uses thereof
US11306071B2 (en) 2019-01-18 2022-04-19 Nuvation Bio Inc. Heterocyclic compounds as adenosine antagonists
US11332473B2 (en) 2019-04-09 2022-05-17 Nuvation Bio Inc. Substituted pyrazolo[3,4-d]pyrimidines as Wee1 inhibitors
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CN115197221A (zh) * 2021-04-02 2022-10-18 轩竹生物科技股份有限公司 二氢吡唑并嘧啶酮类大环衍生物及其用途
WO2023041066A1 (fr) * 2021-09-18 2023-03-23 优领医药科技(香港)有限公司 Dérivé de dihydropyrazolone contenant de la pyrimidine, sel pharmaceutiquement acceptable de celui-ci, son procédé de préparation et son application
WO2024012549A1 (fr) * 2022-07-15 2024-01-18 映恩生物制药（苏州）有限公司 Composé hétérocyclique à cinq chaînons pyrimido, son procédé de préparation et son utilisation

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CN114591334B (zh) * 2020-12-04 2023-10-20 山东轩竹医药科技有限公司 二氢吡唑并嘧啶酮衍生物
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US11028058B2 (en) 2017-07-18 2021-06-08 Nuvation Bio Inc. Heterocyclic compounds as adenosine antagonists
US10793561B2 (en) 2017-07-18 2020-10-06 Nuvation Bio Inc. 1,8-naphthyridinone compounds and uses thereof
US11299493B2 (en) 2017-10-09 2022-04-12 Nuvation Bio Inc. Heterocyclic compounds and uses thereof
US10807994B2 (en) 2017-10-09 2020-10-20 Nuvation Bio Inc. Heterocyclic compounds and uses thereof
US11261192B2 (en) 2018-03-09 2022-03-01 Recurium Ip Holdings, Llc Substituted 1,2-dihydro-3H-pyrazolo[3,4-D]pyrimidin-3-ones
US11306071B2 (en) 2019-01-18 2022-04-19 Nuvation Bio Inc. Heterocyclic compounds as adenosine antagonists
US11254670B2 (en) 2019-01-18 2022-02-22 Nuvation Bio Inc. 1,8-naphthyridinone compounds and uses thereof
US11332473B2 (en) 2019-04-09 2022-05-17 Nuvation Bio Inc. Substituted pyrazolo[3,4-d]pyrimidines as Wee1 inhibitors
JP2022539460A (ja) * 2019-06-28 2022-09-09 シャンハイ ファーマシューティカルズ ホールディング カンパニー，リミティド ピラゾロン縮合ピリミジン化合物、その製造方法及び使用
CN115197221A (zh) * 2021-04-02 2022-10-18 轩竹生物科技股份有限公司 二氢吡唑并嘧啶酮类大环衍生物及其用途
CN115197221B (zh) * 2021-04-02 2024-05-24 轩竹(北京)医药科技有限公司 二氢吡唑并嘧啶酮类大环衍生物及其用途
WO2023041066A1 (fr) * 2021-09-18 2023-03-23 优领医药科技(香港)有限公司 Dérivé de dihydropyrazolone contenant de la pyrimidine, sel pharmaceutiquement acceptable de celui-ci, son procédé de préparation et son application
CN115838375A (zh) * 2021-09-18 2023-03-24 优领医药科技(香港)有限公司 含嘧啶并二氢吡唑啉酮类衍生物、其药学上可接受的盐及其制备方法和应用
WO2024012549A1 (fr) * 2022-07-15 2024-01-18 映恩生物制药（苏州）有限公司 Composé hétérocyclique à cinq chaînons pyrimido, son procédé de préparation et son utilisation

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