WO2022171088A1 - Pyrazolo[3,4-d]pyrimidin-3-one derivative - Google Patents

Pyrazolo[3,4-d]pyrimidin-3-one derivative Download PDF

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Publication number
WO2022171088A1
WO2022171088A1 PCT/CN2022/075545 CN2022075545W WO2022171088A1 WO 2022171088 A1 WO2022171088 A1 WO 2022171088A1 CN 2022075545 W CN2022075545 W CN 2022075545W WO 2022171088 A1 WO2022171088 A1 WO 2022171088A1
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Prior art keywords
alkyl
substituted
cycloalkyl
alkoxy
compound
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PCT/CN2022/075545
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French (fr)
Chinese (zh)
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谢雨礼
樊后兴
钱立晖
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微境生物医药科技(上海)有限公司
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Priority to CN202280014278.7A priority Critical patent/CN116867787A/en
Publication of WO2022171088A1 publication Critical patent/WO2022171088A1/en

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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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medicinal chemistry, and more particularly, relates to a compound with Wee-1 kinase inhibitory effect, a preparation method thereof, and the use of the compound in the preparation of antitumor drugs.
  • Wee-1 protein kinase is an important negative regulator of cell cycle checkpoints.
  • Cell cycle checkpoints include the G1 phase checkpoint for the transition from G1 (cell quiescence) to S phase (DNA synthesis phase), the G2 phase checkpoint for the transition from G2 (preparation for cell division) to M (cell division), and the M Spindle checkpoint for the transition from metaphase (mid-phase) to anaphase (anaphase).
  • Wee-1 protein kinase plays an important role in the G2 phase checkpoint.
  • the entry of cells into M phase depends on the kinase activity of CDK1.
  • Wee-1 inhibits the activity of CDK1 by phosphorylating Tyr 15 of CDK1 protein, preventing cells from entering M phase (cell division phase).
  • Polo kinase kinase phosphorylates Wee-1, activates the degradation of Wee-1 protein, and promotes cell entry into M phase.
  • Wee-1 kinase activity determines the activity of the G2 checkpoint, which in turn regulates the transition of cells from G2 to M phase.
  • Cell cycle checkpoints are mainly activated after DNA damage and play an important role in DNA repair in cells. Normal activation of cell cycle checkpoints arrests the cell cycle and promotes DNA repair. Inhibit the function of checkpoints, DNA damage cannot be repaired, and cells undergo apoptosis. Compared with normal cells, various tumor cells mainly rely on the activation of the G2 checkpoint to repair DNA damage and avoid apoptosis due to the impaired function of p53, an important protein of the G1 phase checkpoint. Therefore, inhibiting the G2 phase checkpoint can selectively kill tumor cells.
  • Wee-1 kinase determines the repair or death of tumor cells after DNA damage, and inhibition of Wee-1 activity can promote unrepaired tumor cells after DNA damage to enter M period, induce apoptosis.
  • Wee-1 is also involved in DNA synthesis, DNA homology repair, post-translational modification of chromosomal histones and other functions closely related to tumorigenesis and development.
  • Wee-1 expression is greatly elevated in a large number of tumors including liver, breast, cervical, melanoma and lung cancer.
  • the high expression of Wee-1 is positively correlated with tumor development and poor prognosis, suggesting that Wee-1 kinase may be involved in tumor occurrence and development.
  • Studies in in vitro cell models and in vivo animal models have shown that inhibiting Wee-1 activity while inducing DNA damage can significantly inhibit the growth of various tumors.
  • AstraZeneca's Wee-1 inhibitor AZD1775 (MK-1775, Adavosertib) has entered the phase 2 clinical research stage, and more than 30 clinical trials are under development.
  • Patents related to AZD1775 include US20070254892, WO2007126122, EP2213673, WO2008133866, WO2011034743 and the like.
  • Abbott and Abbvie have also conducted research on Wee-1 inhibitors, and related patents mainly include US2012220572, WO2013126656, WO2013012681, WO2013059485, WO2013013031 and so on.
  • the present invention provides a compound represented by the general formula (1), an optical isomer or a pharmaceutically acceptable salt thereof:
  • n 0 or 1
  • n 0 or 1
  • v 1, 2 or 3;
  • X 1 and X 2 are independently CH, N, CF, CCl or CMe;
  • W is N or CH
  • R 1 is C1-C6 alkyl, halogen substituted C1-C3 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted C1-C6 alkyl, C3-C5 alkenyl or C3-C5 alkynyl;
  • R 2a and R 2b are independently H or C1-C3 alkyl, or R 2a and R 2b together with the C atom to which they are attached form a C3-C6 cycloalkyl;
  • R 3a and R 3b are independently H or C1-C3 alkyl, or R 3a and R 3b together with the C atom to which they are attached form a C3-C6 cycloalkyl;
  • R 4 is halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, N(C1-C6 alkyl) 2 , NH(C1-C6 alkyl), C1-C6 alkylthio, C2-C6 alkene base, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl, heteroaryl or (4-12 membered) heterocycloalkyl, the C1-C6 alkyl, C1-C6 alkoxy, C1- C6 alkylthio, C3-C6 cycloalkyl, aryl, heteroaryl and (4-12 membered) heterocycloalkyl can be optionally substituted with 1-3 of the following groups: H, halogen, OH, CN , C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen substituted C1-C3 alkyl, CN substituted
  • R 5 and R 6 are independently C1-C3 alkyl, deuterated C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl, or R 5 and R 6 together with which they are attached The atoms form (3-10 membered) heterocycloalkyl;
  • each R is independently H, halogen, CN, C1 - C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen-substituted C1-C6 alkyl, or halogen-substituted C1-C6 alkoxy;
  • R 8 is H, C1-C6 alkyl, C3-C6 cycloalkyl, deuterated C1-C6 alkyl, halogen substituted C1-C6 alkyl, CN substituted C1-C6 alkyl, OH substituted C1-C6 alkyl, C1-C3 alkoxy substituted C1-C6 alkyl, C3-C6 cycloalkyl substituted C1-C6 alkyl or (4-7 membered) heterocycloalkyl.
  • R 4 is halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, N(C1-C6 alkyl) 2 , NH(C1-C6 alkyl), C1-C6 alkylthio, C2-C6 Alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl, heteroaryl or (4-12 membered) heterocycloalkyl, the C1-C6 alkyl, C1-C6 alkoxy, C1 -C6 alkylthio, C3-C6 cycloalkyl, aryl, heteroaryl and (4-12 member) heterocycloalkyl can be optionally substituted by 1-3 of the following groups: H, halogen, OH, CN, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, hal
  • v 1, 2 or 3;
  • W is N or CH
  • R 1 is C1-C6 alkyl, halogen substituted C1-C3 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted C1-C6 alkyl, C3-C5 alkenyl or C3-C5 alkynyl;
  • R 2a and R 2b are independently H or C1-C3 alkyl, or the C atoms to which R 2a and R 2b are connected together form a C3-C6 cycloalkyl;
  • R 4 is halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, N(C1-C6 alkyl) 2 , NH(C1-C6 alkyl), C1-C6 alkylthio, C2-C6 alkene base, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl, heteroaryl or (4-12 membered) heterocycloalkyl, the C1-C6 alkyl, C1-C6 alkoxy, C1- C6 alkylthio, C3-C6 cycloalkyl, aryl, heteroaryl and (4-12 membered) heterocycloalkyl can be optionally substituted with 1-3 of the following groups: H, halogen, OH, CN , C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen substituted C1-C3 alkyl, CN substituted
  • R 5 and R 6 are independently C1-C3 alkyl, deuterated C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C3-C6 cycloalkyl, or R 5 and R 6 together with which they are attached The atoms form (3-10 membered) heterocycloalkyl;
  • R 7 is H, halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen-substituted C1-C6 alkyl or halogen-substituted C1-C6 alkoxy;
  • R 8 is H, C1-C6 alkyl, C3-C6 cycloalkyl, deuterated C1-C6 alkyl, halogen substituted C1-C6 alkyl, CN substituted C1-C6 alkyl, OH substituted C1-C6 alkyl, C1-C3 alkoxy substituted C1-C6 alkyl, C3-C6 cycloalkyl substituted C1-C6 alkyl or (4-7 membered) heterocycloalkyl.
  • R 1 is Me, Et, R 1 is preferably R 1 is more preferably
  • R 4 is Me, Et, CF 3 , CHF 2 , F, Cl, Br, I, CN, OMe, OEt, CN, SMe, SEt, OCF 3 , NMe 2 , NHMe, R 4 is preferably Me, Et, CF 3 , F, Cl, CN, OMe, OEt, SMe, OCF 3 , NMe 2 , R 4 is more preferably Me, Et, OMe, OEt, R 4 is more preferably Me, Et, OMe, OEt,
  • R 8 is H, Me, Et, CD 3 , R 8 is preferably H, Me, Et, CD 3 , More preferably R 8 is H, Me, Et or CD 3 ; more preferably R 8 is Me.
  • the compound of general formula (1) has one of the following structures:
  • Another object of the present invention is to provide a pharmaceutical composition, which contains a pharmaceutically acceptable carrier, diluent and/or excipient, and the compound of the general formula (1) or general formula (1A) of the present invention, its An optical isomer or a pharmaceutically acceptable salt thereof is used as an active ingredient.
  • Another object of the present invention provides the compound represented by the general formula (1), or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate or the above-mentioned pharmaceutical composition of the present invention Use in the preparation of medicines for treating, regulating or preventing diseases related to Wee-1.
  • Another object of the present invention also provides a method for treating, regulating or preventing Wee-1-mediated diseases, comprising administering to a subject a therapeutically effective amount of the compound represented by the general formula (1) of the present invention, or Its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates or the above-mentioned pharmaceutical compositions.
  • the compounds of general formula (1) described above can be synthesized using standard synthetic techniques or well-known techniques combined with methods incorporated herein.
  • the solvents, temperatures and other reaction conditions mentioned herein may vary.
  • Starting materials for the synthesis of compounds can be obtained synthetically or from commercial sources.
  • the compounds described herein and other related compounds with various substituents can be synthesized using well known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., Vols.
  • the compounds described herein are according to methods well known in the art.
  • the conditions of the method such as reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction and the like are not limited to the following explanations.
  • the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily carried out by those skilled in the art to which the present invention belongs.
  • the present invention also provides a method for preparing the compound represented by the general formula (1), wherein the compound of the general formula (1) can be prepared by the following method A:
  • Method A includes the following steps: firstly, compound A1 and A2 are subjected to coupling reaction to form compound A3, compound A3 is subjected to oxidation reaction to obtain compound A4, and compound A4 and compound B6 are further reacted to form target compound A5.
  • “Pharmaceutically acceptable” as used herein refers to a substance, such as a carrier or diluent, that does not abolish the biological activity or properties of the compound and is relatively non-toxic, ie, administered to a subject, does not cause undesired biological effects or Interacts in a detrimental manner with any of the components it contains.
  • pharmaceutically acceptable salt refers to a compound in which it exists in a form that does not cause significant irritation to the administered organism and that does not abrogate the biological activity and properties of the compound.
  • pharmaceutically acceptable salts are obtained by reacting a compound of general formula (1) with an acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, phosphoric acid and other inorganic acids, formic acid, acetic acid, etc.
  • propionic acid oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and other organic acids and acidic amino acids such as aspartic acid and glutamic acid.
  • references to pharmaceutically acceptable salts include solvent addition forms or crystalline forms, especially solvates or polymorphs.
  • Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol.
  • Solvates of compounds of general formula (1) are conveniently prepared or formed according to the methods described herein.
  • the hydrate of the compound of general formula (1) is conveniently prepared by recrystallization from a mixed solvent of water/organic solvent.
  • the organic solvent used includes, but is not limited to, tetrahydrofuran, acetone, ethanol or methanol.
  • the compounds mentioned herein can exist in unsolvated as well as solvated forms. In sum, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • compounds of general formula (1) are prepared in various forms including, but not limited to, amorphous, comminuted and nano-particle size forms.
  • the compound of the general formula (1) includes a crystalline form and can also be a polymorph.
  • Polymorphs include different lattice arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction spectra, infrared spectra, melting points, density, hardness, crystal form, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to dominate.
  • compounds of general formula (1) may exist in chiral centers and/or axial chirality and are thus available as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomeric compounds Enantiomeric forms, and cis-trans isomers occur.
  • Each chiral center or axial chirality will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds, are included within the scope of the present invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C).
  • a deuterated compound can be formed by replacing a hydrogen atom with deuterium, and the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. It has the advantages of stability, enhanced efficacy, and prolonged half-life of drugs in vivo. All alterations in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • alkyl refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 6 carbon atoms. Preference is given to lower alkyl groups containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl. As used herein, “alkyl” includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens.
  • Preferred alkyl groups are selected from CH3 , CH3CH2 , CF3 , CHF2 , CF3CH2 , CF3 ( CH3 ) CH , iPr , nPr , iBu , nBu or tBu .
  • alkylene refers to a divalent alkyl group as defined above.
  • alkylene groups include, but are not limited to, methylene and ethylene.
  • alkenyl refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, including straight or branched chain groups of 1 to 14 carbon atoms. Preference is given to lower alkenyl groups containing 1 to 4 carbon atoms, such as vinyl, 1-propenyl, 1-butenyl or 2-methpropenyl.
  • alkynyl refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight and branched chain groups of 1 to 14 carbon atoms. Lower alkynyl groups containing 1 to 4 carbon atoms, such as ethynyl, 1-propynyl or 1-butynyl, are preferred.
  • cycloalkyl refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic), and if the carbocyclic ring contains at least one double bond, a partially unsaturated cycloalkyl group may be referred to as a "cycloalkyl” alkenyl", or if the carbocycle contains at least one triple bond, a partially unsaturated cycloalkyl group may be referred to as a "cycloalkynyl”.
  • Cycloalkyl groups may include monocyclic or polycyclic (eg, having 2, 3 or 4 fused rings) groups and spiro rings. In some embodiments, the cycloalkyl group is monocyclic.
  • the cycloalkyl group is monocyclic or bicyclic.
  • the ring-forming carbon atoms of a cycloalkyl group can optionally be oxidized to form oxo or thiol groups.
  • Cycloalkyl also includes cycloalkylene.
  • the cycloalkyl group contains 0, 1 or 2 double bonds.
  • cycloalkyl groups contain 1 or 2 double bonds (partially unsaturated cycloalkyl groups).
  • cycloalkyl groups can be fused to aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups.
  • cycloalkyl groups can be fused to aryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused to aryl and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl and cycloalkyl groups.
  • cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl , norpinyl, norcarbenyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexane and the like.
  • alkoxy refers to an alkyl group bonded to the remainder of the molecule through an ether oxygen atom.
  • Representative alkoxy groups are alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.
  • alkoxy includes unsubstituted and substituted alkoxy, especially alkoxy substituted with one or more halogens.
  • Preferred alkoxy groups are selected from OCH3 , OCF3, CHF2O , CF3CH2O , i - PrO, n- PrO , i- BuO, n- BuO or t- BuO.
  • aryl refers to a hydrocarbon aromatic group that is monocyclic or polycyclic, eg, a monocyclic aryl ring fused with one or more carbocyclic aromatic groups.
  • aryl groups include, but are not limited to, phenyl, naphthyl, and phenanthryl.
  • aryloxy refers to an aryl group bonded to the remainder of the molecule through an ether oxygen atom.
  • aryloxy groups include, but are not limited to, phenoxy and naphthoxy.
  • arylene refers to a divalent aryl group as defined above.
  • arylene groups include, but are not limited to, phenylene, naphthylene, and phenanthrene.
  • heteroaryl refers to an aromatic group containing one or more heteroatoms (O, S, or N), which is monocyclic or polycyclic.
  • a monocyclic heteroaryl ring is fused with one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups.
  • heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, furyl, thienyl, Isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzene pyridyl, pyrrolopyrimidinyl, 1H-pyrro[3,2-b]pyridyl, 1H-pyrro[2,3-c]pyridyl, 1H-pyrro[3,2-c]pyridyl, 1H- Pyrro[2,3-b]pyridyl,
  • heterocycloalkyl refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, having at least one independently selected from boron, phosphorus , nitrogen, sulfur, oxygen and phosphorus heteroatom ring members.
  • a partially unsaturated heterocycloalkyl group may be referred to as a "heterocycloalkenyl” if the heterocycloalkyl group contains at least one double bond, or a partially unsaturated heterocycloalkyl group if the heterocycloalkyl group contains at least one triple bond May be referred to as "heterocycloalkynyl".
  • Heterocycloalkyl groups may include monocyclic, bicyclic, spirocyclic, or polycyclic (eg, having two fused or bridged rings) ring systems.
  • a heterocycloalkyl group is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen.
  • the ring-forming carbon atoms and heteroatoms of heterocycloalkyl groups can be optionally oxidized to form oxo or sulfide groups or other oxidized bonds (eg C(O), S(O), C(S) or S(O) 2, N-oxide, etc.), or the nitrogen atom can be quaternized.
  • a heterocycloalkyl group can be attached via a ring carbon atom or a ring heteroatom.
  • the heterocycloalkyl group contains 0 to 3 double bonds.
  • the heterocycloalkyl group contains 0 to 2 double bonds.
  • moieties having one or more aromatic rings fused to (ie, sharing a bond with) the heterocycloalkyl ring such as piperidine, morpholine, azacyclotriene or Benzo derivatives of thienyl and the like.
  • a heterocycloalkyl group containing a fused aromatic ring can be attached via any ring-forming atom, including a ring-forming atom of a fused aromatic ring.
  • heterocycloalkyl include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa -9-Azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrole Alkyl, quininyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, scopolamine, 4,5,6,7-tetrahydrothiazolo[5,4 -c]pyri
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • halo or halogen-substituted appearing before a group name indicates that the group is partially or fully halogenated, that is, substituted with F, Cl, Br or I in any combination, preferably replaced by F or Cl.
  • Substituent "-O-CH 2 -O-" means that two oxygen atoms in the substituent are connected to two adjacent carbon atoms of heterocycloalkyl, aryl or heteroaryl, such as:
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a single bond.
  • membered ring includes any cyclic structure.
  • membered is meant to denote the number of backbone atoms that make up the ring.
  • cyclohexyl, pyridyl, pyranyl, and thienyl are six-membered rings
  • cyclopentyl, pyrrolyl, furyl, and thienyl are five-membered rings.
  • fragment refers to a specific portion or functional group of a molecule.
  • a chemical moiety is generally considered to be a chemical entity contained in or attached to a molecule.
  • acceptable refers to a formulation component or active ingredient that does not have undue deleterious effects on the health of the general target of treatment.
  • treatment include alleviating, inhibiting or ameliorating the symptoms or conditions of a disease; inhibiting the development of complications; ameliorating or preventing the underlying metabolic syndrome; inhibiting the development of a disease or symptom, such as controlling the development of a disease or condition; alleviating a disease or symptom; reducing a disease or symptom; alleviating complications caused by a disease or symptom, or preventing or treating symptoms caused by a disease or symptom.
  • a compound or pharmaceutical composition when administered, results in amelioration, especially improvement in severity, delay in onset, slow progression, or reduction in duration of a disease, symptom or condition. Whether fixed or temporary, continuous or intermittent, the conditions attributable to or associated with the administration.
  • Active ingredient refers to the compound represented by the general formula (1), and the pharmaceutically acceptable inorganic or organic salts of the compound of the general formula (1).
  • the compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality) and are thus available as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomeric compounds in the form of enantiomers.
  • the number of asymmetric centers that can exist depends on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds, are included within the scope of the present invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • composition a compound capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.
  • administering refers to the direct administration of the compound or composition, or the administration of a prodrug, derivative, or analog of the active compound Wait.
  • the present invention provides a method for treating diseases using the compound or pharmaceutical composition of general formula (1) or general formula (1A) of the present invention, and the compound or pharmaceutical composition of general formula (1) or general formula (1A) can generally be used to inhibit Wee- 1 kinase and thus can be used to treat one or more conditions associated with Wee-1 kinase activity. Accordingly, in certain embodiments, the present invention provides a method for treating a Wee-1 kinase mediated disorder comprising administering to a patient in need thereof a compound of the present invention, or a pharmaceutically acceptable composition thereof A step of.
  • methods for cancer treatment comprising administering to an individual in need thereof an effective amount of any of the foregoing pharmaceutical compositions comprising a compound of general structural formula (1) or general formula (1A).
  • the cancer is mediated by Wee-1.
  • the cancer includes, but is not limited to, hematological malignancies (leukemia, lymphoma, myeloma including multiple myeloma, myelodysplastic syndrome and myelodysplastic syndrome) and solid tumors (cancer such as prostate, breast , lung, colon, pancreas, kidney, ovary and soft tissue cancer and osteosarcoma, and stromal tumor) and so on.
  • the compounds of the present invention and their pharmaceutically acceptable salts can be prepared into various formulations, which contain the compounds of the present invention or their pharmaceutically acceptable salts and pharmacologically acceptable excipients or carriers within a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the safe and effective amount of the compound is determined according to the age, disease condition, course of treatment and other specific conditions of the object to be treated.
  • “Pharmaceutically acceptable excipient or carrier” means: one or more compatible solid or liquid filler or gelling substances, which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity .
  • “Compatibility” as used herein means that the components of the composition can be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • pharmacologically acceptable excipients or carrier moieties are cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate
  • the compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylform
  • compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is
  • the administration dose is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
  • the melting point was measured with X-4 melting point apparatus, and the thermometer was not calibrated; 1 H-NMR was recorded with a Varian Mercury 400 nuclear magnetic resonance apparatus, and the chemical shift was expressed in ⁇ (ppm); the silica gel used for separation was 200-300 if not specified The proportions of the eluents are all volume ratios.
  • CDCl 3 represents deuterated chloroform
  • Cs 2 CO 3 represents cesium carbonate
  • CuI represents cuprous iodide
  • DCM represents dichloromethane
  • DIPEA represents diisopropylethylamine
  • dioxane represents 1 ,4-dioxane
  • EA for ethyl acetate
  • EtOH for ethanol
  • h for hour
  • K 2 CO 3 potassium carbonate
  • LC-MS for liquid phase-mass spectrometry
  • m-CPBA for m-chloroperoxybenzoic acid
  • mL stands for milliliter
  • MeOH stands for methanol
  • min stands for minutes
  • MS stands for mass spectrometry
  • NaBH(OAc) 3 stands for sodium triacetoxyborohydride
  • NIS stands for N-chlorosuccinimide
  • NMR stands for nuclear magnetic resonance
  • Pd(dppf)Cl 2 stands for [1,1'-bis(dipheny
  • intermediates A3-2 to A3-23 can be obtained.
  • intermediates B6-1, B6-3, B6-4 and B6-17 Using different starting materials, similar to the synthesis of intermediates B6-1, B6-3, B6-4 and B6-17, intermediates B6-2, B6-5 to B6-16 and B6-18 to 6-79 can be obtained.
  • A3-1 (500 mg, 1.28 mmol) was dissolved in DCM (20 mL), m-CPBA (310 mg, 1.8 mmol) was added, and the reaction was carried out at room temperature for 1 h. LC-MS monitoring showed that the reaction was completed, the system was washed with a saturated solution of sodium bicarbonate, the organic phase was dried, spin-dried, and directly to the next step, ESI-MS m/z: 405.5 [M+H] + .
  • A3-1 (500 mg, 1.28 mmol) was dissolved in DCM (20 mL), m-CPBA (310 mg, 1.8 mmol) was added, and the reaction was carried out at room temperature for 1 h. LC-MS monitoring showed that the reaction was completed, the system was washed with a saturated solution of sodium bicarbonate, the organic phase was dried, spin-dried, and directly to the next step, ESI-MS m/z: 405.5 [M+H] + .
  • A3-1 (500 mg, 1.28 mmol) was dissolved in DCM (20 mL), m-CPBA (310 mg, 1.8 mmol) was added, and the reaction was carried out at room temperature for 1 h. LC-MS monitoring showed that the reaction was completed, the system was washed with a saturated solution of sodium bicarbonate, the organic phase was dried, spin-dried, and directly to the next step, ESI-MS m/z: 405.5 [M+H] + .
  • A3-1 (500 mg, 1.28 mmol) was dissolved in DCM (20 mL), m-CPBA (310 mg, 1.8 mmol) was added, and the reaction was carried out at room temperature for 1 h. LC-MS monitoring showed that the reaction was completed, the system was washed with a saturated solution of sodium bicarbonate, the organic phase was dried, spin-dried, and directly to the next step, ESI-MS m/z: 405.5 [M+H] + .
  • serially diluted compounds and enzymes were mixed, incubated at room temperature (25° C.) for 15 minutes, centrifuged at 1000 rpm for 1 minute to mix, and 5 ⁇ L of substrate was added to initiate the reaction. After 60 minutes of reaction at room temperature, 5 ⁇ L of ADP-GLO reagent was added, mixed by centrifugation at 1000 rpm for 1 minute, and incubated at room temperature for 60 minutes, and then 10 ⁇ L of kinase detection reagent was added to incubate for 60 minutes to detect chemiluminescence. Compared with the DMSO group, the percentage of compound inhibited enzyme activity was calculated, and then the IC 50 was calculated.
  • R 4 is an alkyl group, an alkoxy group or a heterocycloalkyl group, etc.
  • the compound All have strong inhibitory activity against Wee-1 kinase, such as compound 1 and compound 32, the activity is about 3 times higher than that of the control drug MK-1775.
  • Example 118 In vitro antiproliferative activity of compounds on MIA PaCa-2 cells
  • 3000/well MIA PaCa-2 cells were plated in a 384-well plate, and after overnight adherence, DMSO or compounds with a maximum concentration of 5 ⁇ M, 1:5 serial dilution were added. Cell survival was assessed by measuring intracellular ATP content 72 hours after dosing. The percent inhibition of cell survival by the compounds compared to the DMSO group was calculated and IC50 values were calculated and the results are shown in Table 5 below.
  • Example 119 In vitro antiproliferative activity of compound combined with gemcitabine (Gemcitabine, GMC) on MIA PaCa-2 cells
  • the compounds of the present invention have strong anti-proliferative activity on MIA PaCa-2 cells.
  • the activity of compound 32 is more than 10 times higher than that of the control drug MK-1775.
  • the compounds of the present invention have stronger combined activity with GMC, for example, the IC 50 of compound 11 is less than 1 nM.
  • the compound of the present invention has strong combined activity with GMC, which indicates that it may have better effect in clinical combination with chemotherapeutic drugs.

Abstract

Disclosed in the present invention is a pyrazolo[3,4-d]pyrimidin-3-one derivative. Specifically, the present invention relates to a compound as represented by general formula (1) and a preparation method therefor, and a use of the compound of general formula (1) and of isomers, crystal forms, pharmaceutically acceptable salt, hydrate, or solvate thereof as a Wee-1 inhibitor in preparation of antitumor drugs.

Description

吡唑并[3,4-d]嘧啶-3-酮衍生物Pyrazolo[3,4-d]pyrimidin-3-one derivatives
本申请要求申请日为2021年2月9日的中国申请CN202110182325.6的优先权。本申请引用上述中国申请的全文。This application claims the priority of Chinese application CN202110182325.6 with a filing date of February 9, 2021. This application cites the full text of the above Chinese application.
技术领域technical field
本发明属涉及药物化学领域，更具体而言，涉及具有Wee-1激酶抑制作用的化合物、及其制备方法和该类化合物在抗肿瘤药物制备中的用途。The invention belongs to the field of medicinal chemistry, and more particularly, relates to a compound with Wee-1 kinase inhibitory effect, a preparation method thereof, and the use of the compound in the preparation of antitumor drugs.
背景技术Background technique
Wee-1蛋白激酶是细胞周期检查点中重要的负调控蛋白。细胞周期检查点包括G1(细胞静息期)到S期(DNA合成期)转变的G1期检查点，G2(细胞***准备期)到M(细胞***期)期转变的G2期检查点以及M期metaphase(细胞***期中期)到anaphase(细胞***期后期)转变的纺锤体检查点。Wee-1蛋白激酶在G2期检查点中发挥了重要的作用。细胞进入M期依赖于CDK1激酶活性，Wee-1通过磷酸化CDK1蛋白的Tyr 15，抑制CDK1的活性，阻止细胞进入M期(细胞***期)。而Polo kinase激酶磷酸化Wee-1，激活Wee-1蛋白的降解，促进细胞进入M期。由此可见，Wee-1激酶活性决定了G2检查点的活性，进而调节细胞G2到M期的转变。Wee-1 protein kinase is an important negative regulator of cell cycle checkpoints. Cell cycle checkpoints include the G1 phase checkpoint for the transition from G1 (cell quiescence) to S phase (DNA synthesis phase), the G2 phase checkpoint for the transition from G2 (preparation for cell division) to M (cell division), and the M Spindle checkpoint for the transition from metaphase (mid-phase) to anaphase (anaphase). Wee-1 protein kinase plays an important role in the G2 phase checkpoint. The entry of cells into M phase depends on the kinase activity of CDK1. Wee-1 inhibits the activity of CDK1 by phosphorylating Tyr 15 of CDK1 protein, preventing cells from entering M phase (cell division phase). Polo kinase kinase phosphorylates Wee-1, activates the degradation of Wee-1 protein, and promotes cell entry into M phase. Thus, Wee-1 kinase activity determines the activity of the G2 checkpoint, which in turn regulates the transition of cells from G2 to M phase.
细胞周期检查点主要在DNA损伤后激活，对细胞中DNA的修复发挥了重要作用。细胞周期检查点的正常激活阻滞细胞周期促进DNA修复。抑制检查点的功能，DNA损伤无法修复，细胞发生凋亡。与正常细胞相比，多种肿瘤细胞由于G1期检查点重要蛋白p53蛋白的功能受损，主要依赖于G2期检查点的激活修复DNA损伤，规避凋亡。因此，抑制G2期检查点，可以选择性的杀伤肿瘤细胞。而Wee-1激酶活性在G2期检查点中的重要作用，提示Wee-1激酶决定了DNA损伤后肿瘤细胞的修复或死亡，抑制Wee-1活性可以促进DNA损伤后未修复的肿瘤细胞进入M期，诱发凋亡。Cell cycle checkpoints are mainly activated after DNA damage and play an important role in DNA repair in cells. Normal activation of cell cycle checkpoints arrests the cell cycle and promotes DNA repair. Inhibit the function of checkpoints, DNA damage cannot be repaired, and cells undergo apoptosis. Compared with normal cells, various tumor cells mainly rely on the activation of the G2 checkpoint to repair DNA damage and avoid apoptosis due to the impaired function of p53, an important protein of the G1 phase checkpoint. Therefore, inhibiting the G2 phase checkpoint can selectively kill tumor cells. The important role of Wee-1 kinase activity in the G2 phase checkpoint suggests that Wee-1 kinase determines the repair or death of tumor cells after DNA damage, and inhibition of Wee-1 activity can promote unrepaired tumor cells after DNA damage to enter M period, induce apoptosis.
研究表明，除了在G2检查点中的作用以外，Wee-1还参与了DNA合成，DNA同源修复，染色体组蛋白翻译后修饰等与肿瘤发生和发展密切相关的功能。在大量包括肝癌，乳腺癌，***，黑色素瘤和肺癌等肿瘤中，Wee-1表达大大升高。而Wee-1的高表达与肿瘤的发展和预后较差成正相关，提示Wee-1激酶可能参与了肿瘤的发生和发展。体外细胞模型和体内动物模型的研究表明在诱发DNA损伤的同时抑制Wee-1活性能够显著抑制多种肿瘤的生长。Studies have shown that, in addition to its role in the G2 checkpoint, Wee-1 is also involved in DNA synthesis, DNA homology repair, post-translational modification of chromosomal histones and other functions closely related to tumorigenesis and development. Wee-1 expression is greatly elevated in a large number of tumors including liver, breast, cervical, melanoma and lung cancer. The high expression of Wee-1 is positively correlated with tumor development and poor prognosis, suggesting that Wee-1 kinase may be involved in tumor occurrence and development. Studies in in vitro cell models and in vivo animal models have shown that inhibiting Wee-1 activity while inducing DNA damage can significantly inhibit the growth of various tumors.
因此，开发特异性的高活性Wee-1激酶的小分子抑制剂对于肿瘤治疗，尤其是靶向诸如P53缺失的G1检查点受损的肿瘤具有重要的临床价值。Therefore, the development of specific and highly active small-molecule inhibitors of Wee-1 kinase has important clinical value for tumor therapy, especially targeting tumors with impaired G1 checkpoint such as P53 deletion.
目前，AstraZeneca的Wee-1抑制剂AZD1775(MK-1775,Adavosertib)已进入临床2期研究阶段，有超过30项临床试验正在开发。与AZD1775相关的专利有US20070254892、WO2007126122、EP2213673、WO2008133866、WO2011034743等。Abbott和Abbvie对Wee-1抑制剂也展开过研究，相关专利主要有US2012220572、WO2013126656、WO2013012681、WO2013059485、WO2013013031等。Almac公司关于Wee-1抑制剂的专利包括WO2014167347、WO2015019037、WO2015092431、WO2018011570、WO2018062932、WO2019138227等。Girafpharma公司的Wee-1专利包括WO2019074979和WO2019074981。Zeno公司关于Wee-1研究的专利包括WO2018028008和WO2019173082。At present, AstraZeneca's Wee-1 inhibitor AZD1775 (MK-1775, Adavosertib) has entered the phase 2 clinical research stage, and more than 30 clinical trials are under development. Patents related to AZD1775 include US20070254892, WO2007126122, EP2213673, WO2008133866, WO2011034743 and the like. Abbott and Abbvie have also conducted research on Wee-1 inhibitors, and related patents mainly include US2012220572, WO2013126656, WO2013012681, WO2013059485, WO2013013031 and so on. Almac's patents on Wee-1 inhibitors include WO2014167347, WO2015019037, WO2015092431, WO2018011570, WO2018062932, WO2019138227 and the like. Girafpharma's Wee-1 patents include WO2019074979 and WO2019074981. Zeno's patents on Wee-1 research include WO2018028008 and WO2019173082.
研究中的Wee-1抑制剂仍然存在一些问题，单药的治疗效果较差，而和其它化疗药物联用的细胞活性也不够强，因此临床上联用效果也不够理想。靶向治疗到后期通常会产生耐药性，化疗成为晚期肿瘤治疗的常用手段，单用化疗药物治疗往往产生较大的副作用，病人耐受性差，因此发明和化疗药物具有很好联用效果的Wee-1抑制剂具有非常重要的意义。There are still some problems with the Wee-1 inhibitor under study. The therapeutic effect of the single drug is poor, and the cell activity of the combination with other chemotherapeutic drugs is not strong enough, so the clinical effect of the combination is not ideal. Targeted therapy usually produces drug resistance in the later stage. Chemotherapy has become a common method for advanced tumor treatment. Chemotherapy alone often produces large side effects and patient tolerance is poor. Therefore, the invention has a good combined effect with chemotherapy drugs. Wee-1 inhibitors are very important.
发明内容SUMMARY OF THE INVENTION
本发明提供了一种通式(1)所示的化合物、其光学异构体或其药学上可接受的盐：The present invention provides a compound represented by the general formula (1), an optical isomer or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022075545-appb-000001
Figure PCTCN2022075545-appb-000001
通式(1)中：In general formula (1):
m为0或1；m is 0 or 1;
n为0或1；n is 0 or 1;
v为1、2或3；v is 1, 2 or 3;
X 1和X 2独立为CH、N、CF、CCl或CMe； X 1 and X 2 are independently CH, N, CF, CCl or CMe;
W为N或CH；W is N or CH;
R 1为C1-C6烷基、卤素取代C1-C3烷基、C3-C6环烷基、C3-C6环烷基取代C1-C6 烷基、C3-C5烯基或C3-C5炔基； R 1 is C1-C6 alkyl, halogen substituted C1-C3 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted C1-C6 alkyl, C3-C5 alkenyl or C3-C5 alkynyl;
R 2a和R 2b独立为H或C1-C3烷基，或R 2a和R 2b连同其所连接的C原子形成C3-C6环烷基； R 2a and R 2b are independently H or C1-C3 alkyl, or R 2a and R 2b together with the C atom to which they are attached form a C3-C6 cycloalkyl;
R 3a和R 3b独立为H或C1-C3烷基，或R 3a和R 3b连同其所连接的C原子形成C3-C6环烷基； R 3a and R 3b are independently H or C1-C3 alkyl, or R 3a and R 3b together with the C atom to which they are attached form a C3-C6 cycloalkyl;
R 4为卤素、CN、C1-C6烷基、C1-C6烷氧基、N(C1-C6烷基) 2、NH(C1-C6烷基)、C1-C6烷硫基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、芳基、杂芳基或(4-12元)杂环烷基，所述C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基、C3-C6环烷基、芳基、杂芳基和(4-12元)杂环烷基可任选被1-3个下列基团所取代：H、卤素、OH、CN、C1-C3烷基、C3-C6环烷基、C1-C3烷氧基、卤素取代C1-C3烷基、CN取代C1-C3烷基、C3-C6环烷基取代C1-C3烷基、C1-C3烷氧基取代C1-C3烷基、卤素取代C1-C3烷氧基或(4-7元)杂环烷基； R 4 is halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, N(C1-C6 alkyl) 2 , NH(C1-C6 alkyl), C1-C6 alkylthio, C2-C6 alkene base, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl, heteroaryl or (4-12 membered) heterocycloalkyl, the C1-C6 alkyl, C1-C6 alkoxy, C1- C6 alkylthio, C3-C6 cycloalkyl, aryl, heteroaryl and (4-12 membered) heterocycloalkyl can be optionally substituted with 1-3 of the following groups: H, halogen, OH, CN , C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen substituted C1-C3 alkyl, CN substituted C1-C3 alkyl, C3-C6 cycloalkyl substituted C1-C3 alkyl, C1-C3 alkoxy substituted C1-C3 alkyl, halogen substituted C1-C3 alkoxy or (4-7 membered) heterocycloalkyl;
R 5和R 6独立为C1-C3烷基、氘代C1-C3烷基、C2-C6烯基、C2-C6炔基或C3-C6环烷基，或者R 5和R 6连同其所连接的原子形成(3-10元)杂环烷基； R 5 and R 6 are independently C1-C3 alkyl, deuterated C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl, or R 5 and R 6 together with which they are attached The atoms form (3-10 membered) heterocycloalkyl;
每个R 7独立为H、卤素、CN、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、卤素取代C1-C6烷基或卤素取代C1-C6烷氧基； each R is independently H, halogen, CN, C1 - C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen-substituted C1-C6 alkyl, or halogen-substituted C1-C6 alkoxy;
R 8为H、C1-C6烷基、C3-C6环烷基、氘代C1-C6烷基、卤素取代C1-C6烷基、CN取代C1-C6烷基、OH取代C1-C6烷基、C1-C3烷氧基取代C1-C6烷基、C3-C6环烷基取代C1-C6烷基或(4-7元)杂环烷基。 R 8 is H, C1-C6 alkyl, C3-C6 cycloalkyl, deuterated C1-C6 alkyl, halogen substituted C1-C6 alkyl, CN substituted C1-C6 alkyl, OH substituted C1-C6 alkyl, C1-C3 alkoxy substituted C1-C6 alkyl, C3-C6 cycloalkyl substituted C1-C6 alkyl or (4-7 membered) heterocycloalkyl.
本发明的一些方案中，其中所述通式(1)中，
Figure PCTCN2022075545-appb-000002
为
Figure PCTCN2022075545-appb-000003
Figure PCTCN2022075545-appb-000004
Figure PCTCN2022075545-appb-000005
Figure PCTCN2022075545-appb-000006
其中R 4为卤素、CN、C1-C6烷基、C1-C6烷氧基、N(C1-C6烷基) 2、NH(C1-C6烷基)、C1-C6烷硫基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、芳基、杂芳基或(4-12元)杂环烷基，所述C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基、C3-C6环烷基、芳基、杂芳基和(4-12元)杂环烷基可任选被1-3个下列基团所取代：H、卤素、OH、CN、C1-C3烷基、C3-C6环烷基、C1-C3烷氧基、卤素取代C1-C3烷基、CN取代C1-C3烷基、C3-C6环烷基取代C1-C3烷基、C1-C3烷氧基取代C1-C3烷基、卤素取代C1-C3烷氧基、NR 10R 11或(4-7元)杂环烷基；R 8为H、C1-C6烷基、C3-C6环烷基、氘代C1-C6烷基、卤素取代C1-C6烷基、CN取代C1-C6烷基、OH取代C1-C6烷基、C1-C3烷氧基取代C1-C6烷基、C3-C6环烷基取代C1-C6烷基或(4-7元)杂环烷基。 In some aspects of the present invention, wherein in the general formula (1),
Figure PCTCN2022075545-appb-000002
for
Figure PCTCN2022075545-appb-000003
Figure PCTCN2022075545-appb-000004
Figure PCTCN2022075545-appb-000005
Figure PCTCN2022075545-appb-000006
wherein R 4 is halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, N(C1-C6 alkyl) 2 , NH(C1-C6 alkyl), C1-C6 alkylthio, C2-C6 Alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl, heteroaryl or (4-12 membered) heterocycloalkyl, the C1-C6 alkyl, C1-C6 alkoxy, C1 -C6 alkylthio, C3-C6 cycloalkyl, aryl, heteroaryl and (4-12 member) heterocycloalkyl can be optionally substituted by 1-3 of the following groups: H, halogen, OH, CN, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen substituted C1-C3 alkyl, CN substituted C1-C3 alkyl, C3-C6 cycloalkyl substituted C1-C3 alkyl , C1-C3 alkoxy substituted C1-C3 alkyl, halogen substituted C1-C3 alkoxy, NR 10 R 11 or (4-7 membered) heterocycloalkyl; R 8 is H, C1-C6 alkyl, C3-C6 cycloalkyl, deuterated C1-C6 alkyl, halogen substituted C1-C6 alkyl, CN substituted C1-C6 alkyl, OH substituted C1-C6 alkyl, C1-C3 alkoxy substituted C1-C6 alkyl group, C3-C6 cycloalkyl substituted C1-C6 alkyl or (4-7 membered) heterocycloalkyl.
本发明的一些方案中，其中所述通式(1)具有通式(1A)的结构：In some aspects of the present invention, wherein the general formula (1) has the structure of the general formula (1A):
Figure PCTCN2022075545-appb-000007
Figure PCTCN2022075545-appb-000007
通式(1A)中:In general formula (1A):
v为1、2或3；v is 1, 2 or 3;
W为N或CH；W is N or CH;
R 1为C1-C6烷基、卤素取代C1-C3烷基、C3-C6环烷基、C3-C6环烷基取代C1-C6烷基、C3-C5烯基或C3-C5炔基； R 1 is C1-C6 alkyl, halogen substituted C1-C3 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted C1-C6 alkyl, C3-C5 alkenyl or C3-C5 alkynyl;
R 2a和R 2b独立为H或C1-C3烷基，或R 2a和R 2b共所连的C原子形成C3-C6环烷基； R 2a and R 2b are independently H or C1-C3 alkyl, or the C atoms to which R 2a and R 2b are connected together form a C3-C6 cycloalkyl;
R 4为卤素、CN、C1-C6烷基、C1-C6烷氧基、N(C1-C6烷基) 2、NH(C1-C6烷基)、C1-C6烷硫基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、芳基、杂芳基或(4-12元)杂环烷基，所述C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基、C3-C6环烷基、芳基、杂芳基和 (4-12元)杂环烷基可任选被1-3个下列基团所取代：H、卤素、OH、CN、C1-C3烷基、C3-C6环烷基、C1-C3烷氧基、卤素取代C1-C3烷基、CN取代C1-C3烷基、C3-C6环烷基取代C1-C3烷基、C1-C3烷氧基取代C1-C3烷基、卤素取代C1-C3烷氧基或(4-7元)杂环烷基； R 4 is halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, N(C1-C6 alkyl) 2 , NH(C1-C6 alkyl), C1-C6 alkylthio, C2-C6 alkene base, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl, heteroaryl or (4-12 membered) heterocycloalkyl, the C1-C6 alkyl, C1-C6 alkoxy, C1- C6 alkylthio, C3-C6 cycloalkyl, aryl, heteroaryl and (4-12 membered) heterocycloalkyl can be optionally substituted with 1-3 of the following groups: H, halogen, OH, CN , C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen substituted C1-C3 alkyl, CN substituted C1-C3 alkyl, C3-C6 cycloalkyl substituted C1-C3 alkyl, C1-C3 alkoxy substituted C1-C3 alkyl, halogen substituted C1-C3 alkoxy or (4-7 membered) heterocycloalkyl;
R 5和R 6独立为C1-C3烷基、氘代C1-C3烷基、C2-C6烯基、C2-C6炔基和C3-C6环烷基，或者R 5和R 6连同其所连接的原子形成(3-10元)杂环烷基； R 5 and R 6 are independently C1-C3 alkyl, deuterated C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C3-C6 cycloalkyl, or R 5 and R 6 together with which they are attached The atoms form (3-10 membered) heterocycloalkyl;
R 7为H、卤素、CN、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、卤素取代C1-C6烷基或卤素取代C1-C6烷氧基； R 7 is H, halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen-substituted C1-C6 alkyl or halogen-substituted C1-C6 alkoxy;
R 8为H、C1-C6烷基、C3-C6环烷基、氘代C1-C6烷基、卤素取代C1-C6烷基、CN取代C1-C6烷基、OH取代C1-C6烷基、C1-C3烷氧基取代C1-C6烷基、C3-C6环烷基取代C1-C6烷基或(4-7元)杂环烷基。 R 8 is H, C1-C6 alkyl, C3-C6 cycloalkyl, deuterated C1-C6 alkyl, halogen substituted C1-C6 alkyl, CN substituted C1-C6 alkyl, OH substituted C1-C6 alkyl, C1-C3 alkoxy substituted C1-C6 alkyl, C3-C6 cycloalkyl substituted C1-C6 alkyl or (4-7 membered) heterocycloalkyl.
本发明的一些方案中，其中所述通式(1)和通式(1A)中，R 1为Me、Et、
Figure PCTCN2022075545-appb-000008
Figure PCTCN2022075545-appb-000009
Figure PCTCN2022075545-appb-000010
R 1优选为
Figure PCTCN2022075545-appb-000011
R 1更优选为
Figure PCTCN2022075545-appb-000012
In some solutions of the present invention, in the general formula (1) and general formula (1A), R 1 is Me, Et,
Figure PCTCN2022075545-appb-000008
Figure PCTCN2022075545-appb-000009
Figure PCTCN2022075545-appb-000010
R 1 is preferably
Figure PCTCN2022075545-appb-000011
R 1 is more preferably
Figure PCTCN2022075545-appb-000012
本发明的一些方案中，其中所述通式(1)和通式(1A)中，
Figure PCTCN2022075545-appb-000013
为
Figure PCTCN2022075545-appb-000014
Figure PCTCN2022075545-appb-000015
Figure PCTCN2022075545-appb-000016
优选为
Figure PCTCN2022075545-appb-000017
Figure PCTCN2022075545-appb-000018
Figure PCTCN2022075545-appb-000019
更优选为
Figure PCTCN2022075545-appb-000020
Figure PCTCN2022075545-appb-000021
Figure PCTCN2022075545-appb-000022
更优选为
Figure PCTCN2022075545-appb-000023
Figure PCTCN2022075545-appb-000024
更优选为
Figure PCTCN2022075545-appb-000025
In some aspects of the present invention, wherein in the general formula (1) and general formula (1A),
Figure PCTCN2022075545-appb-000013
for
Figure PCTCN2022075545-appb-000014
Figure PCTCN2022075545-appb-000015
Figure PCTCN2022075545-appb-000016
preferably
Figure PCTCN2022075545-appb-000017
Figure PCTCN2022075545-appb-000018
Figure PCTCN2022075545-appb-000019
more preferably
Figure PCTCN2022075545-appb-000020
Figure PCTCN2022075545-appb-000021
Figure PCTCN2022075545-appb-000022
more preferably
Figure PCTCN2022075545-appb-000023
Figure PCTCN2022075545-appb-000024
more preferably
Figure PCTCN2022075545-appb-000025
本发明的一些方案中，其中所述通式(1)和通式(1A)中，R 4为Me、Et、CF 3、CHF 2、F、Cl、Br、I、CN、OMe、OEt、CN、SMe、SEt、OCF 3、NMe 2、NHMe、
Figure PCTCN2022075545-appb-000026
Figure PCTCN2022075545-appb-000027
Figure PCTCN2022075545-appb-000028
Figure PCTCN2022075545-appb-000029
R 4优选为Me、Et、CF 3、F、Cl、CN、OMe、OEt、SMe、OCF 3、NMe 2、
Figure PCTCN2022075545-appb-000030
Figure PCTCN2022075545-appb-000031
Figure PCTCN2022075545-appb-000032
R 4更优选为Me、Et、OMe、OEt、
Figure PCTCN2022075545-appb-000033
Figure PCTCN2022075545-appb-000034
R 4更优选为Me、Et、OMe、OEt、
Figure PCTCN2022075545-appb-000035
Figure PCTCN2022075545-appb-000036
In some solutions of the present invention, in the general formula (1) and general formula (1A), R 4 is Me, Et, CF 3 , CHF 2 , F, Cl, Br, I, CN, OMe, OEt, CN, SMe, SEt, OCF 3 , NMe 2 , NHMe,
Figure PCTCN2022075545-appb-000026
Figure PCTCN2022075545-appb-000027
Figure PCTCN2022075545-appb-000028
Figure PCTCN2022075545-appb-000029
R 4 is preferably Me, Et, CF 3 , F, Cl, CN, OMe, OEt, SMe, OCF 3 , NMe 2 ,
Figure PCTCN2022075545-appb-000030
Figure PCTCN2022075545-appb-000031
Figure PCTCN2022075545-appb-000032
R 4 is more preferably Me, Et, OMe, OEt,
Figure PCTCN2022075545-appb-000033
Figure PCTCN2022075545-appb-000034
R 4 is more preferably Me, Et, OMe, OEt,
Figure PCTCN2022075545-appb-000035
Figure PCTCN2022075545-appb-000036
本发明的一些方案中，其中所述通式(1)和通式(1A)中，R 8为H、Me、Et、CD 3、
Figure PCTCN2022075545-appb-000037
Figure PCTCN2022075545-appb-000038
Figure PCTCN2022075545-appb-000039
R 8优选为H、Me、Et、CD 3、
Figure PCTCN2022075545-appb-000040
Figure PCTCN2022075545-appb-000041
R 8更优选为H、Me、Et或CD 3；R 8更优选为Me。 In some solutions of the present invention, in the general formula (1) and general formula (1A), R 8 is H, Me, Et, CD 3 ,
Figure PCTCN2022075545-appb-000037
Figure PCTCN2022075545-appb-000038
Figure PCTCN2022075545-appb-000039
R 8 is preferably H, Me, Et, CD 3 ,
Figure PCTCN2022075545-appb-000040
Figure PCTCN2022075545-appb-000041
More preferably R 8 is H, Me, Et or CD 3 ; more preferably R 8 is Me.
在本发明的另一具体实施例中，通式(1)化合物具有以下结构之一：In another specific embodiment of the present invention, the compound of general formula (1) has one of the following structures:
Figure PCTCN2022075545-appb-000042
Figure PCTCN2022075545-appb-000042
Figure PCTCN2022075545-appb-000043
Figure PCTCN2022075545-appb-000043
Figure PCTCN2022075545-appb-000044
Figure PCTCN2022075545-appb-000044
Figure PCTCN2022075545-appb-000045
Figure PCTCN2022075545-appb-000045
Figure PCTCN2022075545-appb-000046
Figure PCTCN2022075545-appb-000046
Figure PCTCN2022075545-appb-000047
Figure PCTCN2022075545-appb-000047
本发明的另一个目的是提供了一种药物组合物，其含有药学上可接受的载体、稀释剂和/或赋形剂，以及本发明通式(1)或通式(1A)化合物、其光学异构体或其药学上可接受的盐作为活性成分。Another object of the present invention is to provide a pharmaceutical composition, which contains a pharmaceutically acceptable carrier, diluent and/or excipient, and the compound of the general formula (1) or general formula (1A) of the present invention, its An optical isomer or a pharmaceutically acceptable salt thereof is used as an active ingredient.
本发明的再一个目的提供了本发明的通式(1)所示的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或上述药物组合物用于制备治疗、调节或预防与Wee-1相关疾病的药物中的应用。Another object of the present invention provides the compound represented by the general formula (1), or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate or the above-mentioned pharmaceutical composition of the present invention Use in the preparation of medicines for treating, regulating or preventing diseases related to Wee-1.
本发明的再一个目的还提供治疗、调节或预防与Wee-1介导的相关疾病的方法，包括对受试者给与治疗有效量的本发明的通式(1)所示的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或上述药物组合物。Another object of the present invention also provides a method for treating, regulating or preventing Wee-1-mediated diseases, comprising administering to a subject a therapeutically effective amount of the compound represented by the general formula (1) of the present invention, or Its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates or the above-mentioned pharmaceutical compositions.
本发明人通过充分的研究发现，结构如通式(1)所示化合物，R 4为烷基、环烷基或杂环烷基时，化合物均具有很强的Wee-1抑制活性，以及和化疗药物吉西他滨(Gemcitabine,GMC)的联合给药活性，上述结果表明，本发明化合物在临床上和化疗药物联用可能具有更好的效果。 Through sufficient research, the inventors have found that when the structure of the compound represented by the general formula (1), when R 4 is an alkyl group, a cycloalkyl group or a heterocycloalkyl group, the compound has a strong Wee-1 inhibitory activity, and The combined administration activity of the chemotherapeutic drug gemcitabine (GMC), the above results show that the compound of the present invention may have better effects in clinical combination with chemotherapeutic drugs.
应理解，本发明的前述一般性描述和以下详细描述都是示例性和说明性的，旨在提供对所要求保护的本发明的进一步说明。It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.
化合物的合成compound synthesis
下面具体地描述本发明通式(1)化合物的制备方法，但这些具体方法不对本发明构成任何限制。The preparation method of the compound of the general formula (1) of the present invention is specifically described below, but these specific methods do not constitute any limitation to the present invention.
以上说明的通式(1)化合物可使用标准的合成技术或公知的技术与文中结合的方法来合成。此外，在此提到的溶剂，温度和其他反应条件可以改变。用于化合物的合成的起始物料可以由合成或从商业来源上获得。本文所述的化合物和其他具有不同取代基的有关化合物可使用公知的技术和原料来合成，包括发现于March，ADVANCED ORGANIC CHEMISTRY 4 th Ed.，(Wiley 1992)；Carey和Sundberg，ADVANCED ORGANIC CHEMISTRY 4 th Ed.，Vols.A和B(Plenum 2000，2001)，Green和Wuts，PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd Ed.，(Wiley 1999)中的方法。化合物制备的一般方法可通过使用适当的试剂和在此提供的分子式中引入不同基团的条件来改变。 The compounds of general formula (1) described above can be synthesized using standard synthetic techniques or well-known techniques combined with methods incorporated herein. In addition, the solvents, temperatures and other reaction conditions mentioned herein may vary. Starting materials for the synthesis of compounds can be obtained synthetically or from commercial sources. The compounds described herein and other related compounds with various substituents can be synthesized using well known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., Vols. A and B (Plenum 2000, 2001), Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3rd Ed., (Wiley 1999). The general methods of compound preparation can be varied by the use of appropriate reagents and conditions for the introduction of various groups into the formulae provided herein.
一方面，本文所述的化合物根据工艺中公知的方法。然而方法的条件，例如反应物、溶剂、碱、所用化合物的量、反应温度、反应所需时间等不限于下面的解释。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易的进行。一方面，本发明还提供了一种所述的通式(1)所示化合物的制备方法，其中通式(1)化合物可采用下列方法A制备：In one aspect, the compounds described herein are according to methods well known in the art. However, the conditions of the method such as reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction and the like are not limited to the following explanations. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily carried out by those skilled in the art to which the present invention belongs. On the one hand, the present invention also provides a method for preparing the compound represented by the general formula (1), wherein the compound of the general formula (1) can be prepared by the following method A:
方法A包含下列步骤：首先化合物A1和A2进行偶联反应生成化合物A3，化合物A3进行氧化反应得到化合物A4，化合物A4和化合物B6进一步反应生成目标化合物A5。Method A includes the following steps: firstly, compound A1 and A2 are subjected to coupling reaction to form compound A3, compound A3 is subjected to oxidation reaction to obtain compound A4, and compound A4 and compound B6 are further reacted to form target compound A5.
Figure PCTCN2022075545-appb-000048
Figure PCTCN2022075545-appb-000048
上述反应方程式中，W、X 1、X 2、R 1、R 2a、R 2b、R 3a、R 3b、R 4、R 5、R 6、R 7、R 8、m、n和v的定义如前所述，Z为Br、I或-B(OH) 2，E为
Figure PCTCN2022075545-appb-000049
In the above reaction equation, the definitions of W, X 1 , X 2 , R 1 , R 2a , R 2b , R 3a , R 3b , R 4 , R 5 , R 6 , R 7 , R 8 , m, n and v As before, Z is Br, I or -B(OH) 2 and E is
Figure PCTCN2022075545-appb-000049
化合物的进一步形式further forms of compounds
“药学上可接受”这里指一种物质，如载体或稀释液，不会使化合物的生物活性或性质 消失，且相对无毒，如，给予个体某物质，不会引起不想要的生物影响或以有害的方式与任何其含有的组分相互作用。"Pharmaceutically acceptable" as used herein refers to a substance, such as a carrier or diluent, that does not abolish the biological activity or properties of the compound and is relatively non-toxic, ie, administered to a subject, does not cause undesired biological effects or Interacts in a detrimental manner with any of the components it contains.
术语“药学上可接受的盐”指一种化合物的存在形式，该形式不会引起对给药有机体的重要的刺激，且不会使化合物的生物活性和性质消失。在某些具体方面，药学上可接受的盐是通过通式(1)化合物与酸反应获得，如盐酸、氢溴酸、氢氟酸、硫酸、磷酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、三氟乙酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯磺酸、对甲苯磺酸等有机酸以及天冬氨酸、谷氨酸等酸性氨基酸。The term "pharmaceutically acceptable salt" refers to a compound in which it exists in a form that does not cause significant irritation to the administered organism and that does not abrogate the biological activity and properties of the compound. In certain specific aspects, pharmaceutically acceptable salts are obtained by reacting a compound of general formula (1) with an acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, phosphoric acid and other inorganic acids, formic acid, acetic acid, etc. , propionic acid, oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and other organic acids and acidic amino acids such as aspartic acid and glutamic acid.
应理解药学上可接受的盐的参考包括溶剂添加形式或结晶形式，尤其是溶剂化物或多晶型。溶剂化物含有化学计量或非化学计量的溶剂，且是在与药学上可接受溶剂如水，乙醇等，结晶化过程中选择性形成的。当溶剂是水时形成水合物，或当溶剂是乙醇时形成醇化物。通式(1)化合物的溶剂化物按照本文所述的方法，很方便的制得或形成。举例说明，通式(1)化合物的水合物从水/有机溶剂的混合溶剂中重结晶而方便的制得，使用的有机溶剂包括但不限于，四氢呋喃、丙酮、乙醇或甲醇。此外，在此提到的化合物能够以非溶剂化和溶剂化形式存在。总之，对于在此提供的化合物和方法为目的，溶剂化形式被认为相当于非溶剂化形式。It should be understood that references to pharmaceutically acceptable salts include solvent addition forms or crystalline forms, especially solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol. Solvates of compounds of general formula (1) are conveniently prepared or formed according to the methods described herein. For example, the hydrate of the compound of general formula (1) is conveniently prepared by recrystallization from a mixed solvent of water/organic solvent. The organic solvent used includes, but is not limited to, tetrahydrofuran, acetone, ethanol or methanol. Furthermore, the compounds mentioned herein can exist in unsolvated as well as solvated forms. In sum, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
在其他具体实施例中，通式(1)化合物被制备成不同的形式，包括但不限于，无定形，粉碎形和毫微-粒度形式。此外，通式(1)化合物包括结晶型，也可以作为多晶型。多晶型包括化合物的相同元素组成的不同晶格排列。多晶型通常有不同的X-射线衍射光谱、红外光谱、熔点、密度、硬度、晶型、光和电的性质、稳定性和溶解性。不同的因素如重结晶溶剂，结晶速率和贮存温度可能引起单一晶型为主导。In other specific embodiments, compounds of general formula (1) are prepared in various forms including, but not limited to, amorphous, comminuted and nano-particle size forms. In addition, the compound of the general formula (1) includes a crystalline form and can also be a polymorph. Polymorphs include different lattice arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction spectra, infrared spectra, melting points, density, hardness, crystal form, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to dominate.
在另一个方面，通式(1)化合物可能存在手性中心和/或轴手性，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式、和顺反异构体的形式出现。每个手性中心或轴手性将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。In another aspect, compounds of general formula (1) may exist in chiral centers and/or axial chirality and are thus available as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomeric compounds Enantiomeric forms, and cis-trans isomers occur. Each chiral center or axial chirality will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds, are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds.
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)、碘-125( 125I)和C-14( 14C)。又例如，可用重氢取代氢原子形成氘代化合物，氘与碳构成的键比普通氢和碳构成的键更坚固，相比于未氘代药物，通常氘代药物具有降低毒副作用、增加药物稳定性、增强疗效、延长药物体内半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射 性与否，都包含在本发明的范围之内。 The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C). For another example, a deuterated compound can be formed by replacing a hydrogen atom with deuterium, and the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. It has the advantages of stability, enhanced efficacy, and prolonged half-life of drugs in vivo. All alterations in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
术语the term
如果无另外说明，用于本发明申请，包括说明书和权利要求书中的术语，定义如下。必须注意，在说明书和所附的权利要求书中，如果文中无另外清楚指示，单数形式“一个”包括复数意义。如果无另外说明，使用质谱、核磁、HPLC、蛋白化学、生物化学、重组DNA技术和药理的常规方法。在本申请中，如果无另外说明，使用“或”或“和”指“和/或”。Unless otherwise stated, terms used in the present application, including the specification and claims, are defined as follows. It must be noted that, in the specification and the appended claims, the singular form "a" includes the plural unless the context clearly dictates otherwise. Conventional methods of mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology were used unless otherwise stated. In this application, the use of "or" or "and" means "and/or" unless stated otherwise.
除非另有规定，“烷基”指饱和的脂肪烃基团，包括1至6个碳原子的直链和支链基团。优选含有1至4个碳原子的低级烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基。如本文所用，“烷基”包括未取代和取代的烷基，尤其是被一个或多个卤素所取代的烷基。优选的烷基选自CH 3、CH 3CH 2、CF 3、CHF 2、CF 3CH 2、CF 3(CH 3)CH、 iPr、 nPr、 iBu、 nBu或 tBu。 Unless otherwise specified, "alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 6 carbon atoms. Preference is given to lower alkyl groups containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl. As used herein, "alkyl" includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens. Preferred alkyl groups are selected from CH3 , CH3CH2 , CF3 , CHF2 , CF3CH2 , CF3 ( CH3 ) CH , iPr , nPr , iBu , nBu or tBu .
除非另有规定，“亚烷基”指二价的如上所定义的烷基。亚烷基基的例子包括但不限于，亚甲基和亚乙基。Unless otherwise specified, "alkylene" refers to a divalent alkyl group as defined above. Examples of alkylene groups include, but are not limited to, methylene and ethylene.
除非另有规定，“烯基”指含有碳-碳双键的不饱和脂肪烃基团，包括1至14个碳原子的直链或支链基团。优选含有1至4个碳原子的低级烯基，例如乙烯基、1-丙烯基、1-丁烯基或2-甲基丙烯基。Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, including straight or branched chain groups of 1 to 14 carbon atoms. Preference is given to lower alkenyl groups containing 1 to 4 carbon atoms, such as vinyl, 1-propenyl, 1-butenyl or 2-methpropenyl.
除非另有规定，“炔基”指含有碳-碳叁键的不饱和脂肪烃基团，包括1至14个碳原子的直链和支链基团。优选含有1至4个碳原子的低级炔基，例如乙炔基、1-丙炔基或1-丁炔基。Unless otherwise specified, "alkynyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight and branched chain groups of 1 to 14 carbon atoms. Lower alkynyl groups containing 1 to 4 carbon atoms, such as ethynyl, 1-propynyl or 1-butynyl, are preferred.
除非另有规定，“环烷基”是指非芳香族烃环***(单环、双环或多环)，如果碳环含有至少一个双键，那么部分不饱和环烷基可被称为“环烯基”，或如果碳环含有至少一个三键，那么部分不饱和环烷基可被称为“环炔基”。环烷基可以包括单环或多环(例如具有2、3或4个稠合环)基团和螺环。在一些实施方案中，环烷基为单环的。在一些实施方案中，环烷基为单环的或双环的。环烷基的成环碳原子可以任选地被氧化以形成氧代或硫离子基。环烷基还包括亚环烷基。在一些实施方案中，环烷基含有0、1或2个双键。在一些实施方案中，环烷基含有1或2个双键(部分不饱和环烷基)。在一些实施方案中，环烷基可以与芳基、杂芳基、环烷基和杂环烷基稠合。在一些实施方案中，环烷基可以与芳基、环烷基和杂环烷基稠合。在一些实施方案中，环烷基可以与芳基和杂环烷基稠合。一些实施方案中，环烷基可以与芳基和环烷基稠合。环烷基的实例包括环丙基、环丁基、环戊基、环己基、环庚基、环戊烯基、环己烯基、环已二烯基、环庚三烯基、降莰基、降蒎 基、降蒈基、双环[1.1.1]戊烷基、双环[2.1.1]己烷基等等。Unless otherwise specified, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic), and if the carbocyclic ring contains at least one double bond, a partially unsaturated cycloalkyl group may be referred to as a "cycloalkyl" alkenyl", or if the carbocycle contains at least one triple bond, a partially unsaturated cycloalkyl group may be referred to as a "cycloalkynyl". Cycloalkyl groups may include monocyclic or polycyclic (eg, having 2, 3 or 4 fused rings) groups and spiro rings. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. The ring-forming carbon atoms of a cycloalkyl group can optionally be oxidized to form oxo or thiol groups. Cycloalkyl also includes cycloalkylene. In some embodiments, the cycloalkyl group contains 0, 1 or 2 double bonds. In some embodiments, cycloalkyl groups contain 1 or 2 double bonds (partially unsaturated cycloalkyl groups). In some embodiments, cycloalkyl groups can be fused to aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused to aryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused to aryl and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl and cycloalkyl groups. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl , norpinyl, norcarbenyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexane and the like.
除非另有规定，“烷氧基”指通过醚氧原子键合到分子其余部分的烷基。代表性的烷氧基为具有1-6个碳原子的烷氧基，如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基和叔丁氧基。如本文所用，“烷氧基”包括未取代和取代的烷氧基，尤其是被一个或多个卤素所取代的烷氧基。优选的烷氧基选自OCH 3、OCF 3、CHF 2O、CF 3CH 2O、 i-PrO、 n-PrO、 i-BuO、 n-BuO或 t-BuO。 Unless otherwise specified, "alkoxy" refers to an alkyl group bonded to the remainder of the molecule through an ether oxygen atom. Representative alkoxy groups are alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy, especially alkoxy substituted with one or more halogens. Preferred alkoxy groups are selected from OCH3 , OCF3, CHF2O , CF3CH2O , i - PrO, n- PrO , i- BuO, n- BuO or t- BuO.
除非另有规定，“芳基”指碳氢芳香基团，芳基是单环或多环的，例如单环芳基环与一个或多个碳环芳香基团稠和。芳基的例子包括但不限于，苯基、萘基和菲基。Unless otherwise specified, "aryl" refers to a hydrocarbon aromatic group that is monocyclic or polycyclic, eg, a monocyclic aryl ring fused with one or more carbocyclic aromatic groups. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and phenanthryl.
除非另有规定，“芳氧基”指通过醚氧原子键合到分子其余部分的芳基。芳氧基的例子包括但不限于苯氧基和萘氧基。Unless otherwise specified, "aryloxy" refers to an aryl group bonded to the remainder of the molecule through an ether oxygen atom. Examples of aryloxy groups include, but are not limited to, phenoxy and naphthoxy.
除非另有规定，“亚芳基”指二价的如上所定义的芳基。亚芳基的例子包括但不限于，亚苯基、亚萘基和亚菲基。Unless otherwise specified, "arylene" refers to a divalent aryl group as defined above. Examples of arylene groups include, but are not limited to, phenylene, naphthylene, and phenanthrene.
除非另有规定，“杂芳基”指含有一个或多个杂原子(O、S或N)的芳香基团，杂芳基是单环或多环的。例如单环杂芳基环与一个或多个碳环芳香基团或其它单环杂环烷基基团稠和。杂芳基的例子包括但不限于，吡啶基、哒嗪基、咪唑基、嘧啶基、吡唑基、***基、吡嗪基、喹啉基、异喹啉基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、吲哚基、苯并咪唑基、苯并呋喃基、苯并噻唑基、苯并噻吩基、苯并噁唑基、苯并吡啶基、吡咯并嘧啶基、1H-吡咯[3,2-b]吡啶基、1H-吡咯[2,3-c]吡啶基、1H-吡咯[3,2-c]吡啶基、1H-吡咯[2,3-b]吡啶基、
Figure PCTCN2022075545-appb-000050
Unless otherwise specified, "heteroaryl" refers to an aromatic group containing one or more heteroatoms (O, S, or N), which is monocyclic or polycyclic. For example, a monocyclic heteroaryl ring is fused with one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, furyl, thienyl, Isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzene pyridyl, pyrrolopyrimidinyl, 1H-pyrro[3,2-b]pyridyl, 1H-pyrro[2,3-c]pyridyl, 1H-pyrro[3,2-c]pyridyl, 1H- Pyrro[2,3-b]pyridyl,
Figure PCTCN2022075545-appb-000050
除非另有规定，“杂环烷基”指非芳香族环或环***，其可以任选地含有一个或多个亚烯基作为环结构的一部分，其具有至少一个独立地选自硼、磷、氮、硫、氧和磷的杂原子环成员。如果杂环烷基含有至少一个双键，那么部分不饱和杂环烷基可被称为“杂环烯基”，或如果杂环烷基含有至少一个三键，那么部分不饱和杂环烷基可被称为“杂环炔基”。杂环烷基可以包括单环、双环、螺环或多环(例如具有两个稠合或桥接环)环***。在一些实施例中，杂环烷基为具有1、2或3个独立地选自氮、硫和氧的杂原子的单环基团。杂环烷基的成环碳原子和杂原子可以任选地氧化以形成氧代或硫离子基或其他氧化键(例如C(O)、S(O)、C(S)或S(O)2、N-氧化物等)，或氮原子可以季铵化。杂环烷基可以经由成环碳原子或成环杂原子而连接。在一些实施例中，杂环烷基含有0至3个双键。在一些实施例中，杂环烷基含有0至2个双键。杂环烷基的定义中还包括具有一个或多个与杂环烷基环稠合(即，与其共用键)的芳香族环的部分，例如哌啶、吗啉、氮杂环庚三烯或噻吩 基等的苯并衍生物。含有稠合芳香族环的杂环烷基可以经由任何成环原子，包括稠合芳香族环的成环原子而连接。杂环烷基的实例包括但不限于氮杂环丁基、氮杂环庚基、二氢苯并呋喃基、二氢呋喃基、二氢吡喃基、N-吗啉基、3-氧杂-9-氮杂螺[5.5]十一烷基、1-氧杂-8-氮杂螺[4.5]癸烷基、哌啶基、哌嗪基、氧代哌嗪基、吡喃基、吡咯烷基、奎宁基、四氢呋喃基、四氢吡喃基、1,2,3,4-四氢喹啉基、莨菪烷基、4,5,6,7-四氢噻唑并[5,4-c]吡啶基、4,5,6,7-四氢-1H-咪唑并[4,5-c]吡啶、N-甲基哌啶基、四氢咪唑基、吡唑烷基、丁内酰胺基、戊内酰胺基、咪唑啉酮基、乙内酰脲基、二氧戊环基、邻苯二甲酰亚胺基、嘧啶-2,4(1H,3H)-二酮基、1,4-二氧六环基、吗啉基、硫代吗啉基、硫代吗啉-S-氧化物基、硫代吗啉-S,S-氧化物基、哌嗪基、吡喃基、吡啶酮基、3-吡咯啉基、噻喃基、吡喃酮基、四氢噻吩基、2-氮杂螺[3.3]庚烷基、吲哚啉基、
Figure PCTCN2022075545-appb-000051
Figure PCTCN2022075545-appb-000052
Unless otherwise specified, "heterocycloalkyl" refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, having at least one independently selected from boron, phosphorus , nitrogen, sulfur, oxygen and phosphorus heteroatom ring members. A partially unsaturated heterocycloalkyl group may be referred to as a "heterocycloalkenyl" if the heterocycloalkyl group contains at least one double bond, or a partially unsaturated heterocycloalkyl group if the heterocycloalkyl group contains at least one triple bond May be referred to as "heterocycloalkynyl". Heterocycloalkyl groups may include monocyclic, bicyclic, spirocyclic, or polycyclic (eg, having two fused or bridged rings) ring systems. In some embodiments, a heterocycloalkyl group is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The ring-forming carbon atoms and heteroatoms of heterocycloalkyl groups can be optionally oxidized to form oxo or sulfide groups or other oxidized bonds (eg C(O), S(O), C(S) or S(O) 2, N-oxide, etc.), or the nitrogen atom can be quaternized. A heterocycloalkyl group can be attached via a ring carbon atom or a ring heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties having one or more aromatic rings fused to (ie, sharing a bond with) the heterocycloalkyl ring, such as piperidine, morpholine, azacyclotriene or Benzo derivatives of thienyl and the like. A heterocycloalkyl group containing a fused aromatic ring can be attached via any ring-forming atom, including a ring-forming atom of a fused aromatic ring. Examples of heterocycloalkyl include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa -9-Azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrole Alkyl, quininyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, scopolamine, 4,5,6,7-tetrahydrothiazolo[5,4 -c]pyridyl, 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidine, butyrolactone Amido, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, pyrimidine-2,4(1H,3H)-dione, 1 ,4-dioxane, morpholinyl, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazinyl, pyranyl , pyridone, 3-pyrroline, thiopyranyl, pyranone, tetrahydrothienyl, 2-azaspiro[3.3]heptyl, indolinyl,
Figure PCTCN2022075545-appb-000051
Figure PCTCN2022075545-appb-000052
除非另有规定，“卤素”(或卤代基)是指氟、氯、溴或碘。在基团名前面出现的术语“卤代”(或“卤素取代”)表示该基团是部分或全部卤代，也就是说，以任意组合的方式被F，Cl，Br或I取代，优选被F或Cl取代。Unless otherwise specified, "halogen" (or halo) refers to fluorine, chlorine, bromine or iodine. The term "halo" (or "halogen-substituted") appearing before a group name indicates that the group is partially or fully halogenated, that is, substituted with F, Cl, Br or I in any combination, preferably replaced by F or Cl.
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。"Optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
取代基“-O-CH 2-O-”指该取代基中二个氧原子和杂环烷基、芳基或杂芳基二个相邻的碳原子连接，比如：
Figure PCTCN2022075545-appb-000053
Substituent "-O-CH 2 -O-" means that two oxygen atoms in the substituent are connected to two adjacent carbon atoms of heterocycloalkyl, aryl or heteroaryl, such as:
Figure PCTCN2022075545-appb-000053
当一个连接基团的数量为0时，比如-(CH 2) 0-，表示该连接基团为单键。 When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a single bond.
当其中一个变量选自化学键时，表示其连接的两个基团直接相连，比如X-L-Y中L代表化学键时表示该结构实际上是X-Y。When one of the variables is selected from a chemical bond, it means that the two groups it connects are directly connected. For example, when L in X-L-Y represents a chemical bond, it means that the structure is actually X-Y.
术语“元环”包括任何环状结构。术语“元”意为表示构成环的骨架原子的数量。例如，环己基、吡啶基、吡喃基、噻喃基是六元环，环戊基、吡咯基、呋喃基和噻吩基是五元环。The term "membered ring" includes any cyclic structure. The term "membered" is meant to denote the number of backbone atoms that make up the ring. For example, cyclohexyl, pyridyl, pyranyl, and thienyl are six-membered rings, and cyclopentyl, pyrrolyl, furyl, and thienyl are five-membered rings.
术语“片断”指分子的具体部分或官能团。化学片断通常被认为是包含在或附在分子中的化学实体。The term "fragment" refers to a specific portion or functional group of a molecule. A chemical moiety is generally considered to be a chemical entity contained in or attached to a molecule.
除非另有说明，用楔形实线键
Figure PCTCN2022075545-appb-000054
和楔形虚线键
Figure PCTCN2022075545-appb-000055
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022075545-appb-000056
和直形虚线键
Figure PCTCN2022075545-appb-000057
表示立体中心的相对构型，用波浪线
Figure PCTCN2022075545-appb-000058
表示楔形 实线键
Figure PCTCN2022075545-appb-000059
或楔形虚线键
Figure PCTCN2022075545-appb-000060
或用波浪线
Figure PCTCN2022075545-appb-000061
表示直形实线键
Figure PCTCN2022075545-appb-000062
或直形虚线键
Figure PCTCN2022075545-appb-000063
Use solid wedge keys unless otherwise specified
Figure PCTCN2022075545-appb-000054
and wedge-dotted keys
Figure PCTCN2022075545-appb-000055
Indicate the absolute configuration of a stereocenter, using a straight solid key
Figure PCTCN2022075545-appb-000056
and straight dashed keys
Figure PCTCN2022075545-appb-000057
Indicate the relative configuration of the stereocenter, with a wavy line
Figure PCTCN2022075545-appb-000058
Represents a solid wedge key
Figure PCTCN2022075545-appb-000059
or wedge-dotted key
Figure PCTCN2022075545-appb-000060
or with wavy lines
Figure PCTCN2022075545-appb-000061
Represents a straight solid key
Figure PCTCN2022075545-appb-000062
or straight dashed key
Figure PCTCN2022075545-appb-000063
除非另有说明，用
Figure PCTCN2022075545-appb-000064
表示单键或双键。 Unless otherwise specified, use
Figure PCTCN2022075545-appb-000064
Indicates a single or double bond.
特定药学及医学术语Certain Pharmacy and Medical Terms
术语“可接受的”，如本文所用，指一个处方组分或活性成分对一般治疗目标的健康没有过分的有害影响。The term "acceptable", as used herein, refers to a formulation component or active ingredient that does not have undue deleterious effects on the health of the general target of treatment.
术语“治疗”、“治疗过程”或“疗法”如本文所用，包括缓和、抑制或改善疾病的症状或状况；抑制并发症的产生；改善或预防潜在代谢综合症；抑制疾病或症状的产生，如控制疾病或情况的发展；减轻疾病或症状；使疾病或症状减退；减轻由疾病或症状引起的并发症，或预防或治疗由疾病或症状引起的征兆。如本文所用，某一化合物或药物组合物，给药后，可以使某一疾病、症状或情况得到改善，尤指其严重度得到改善，延迟发病，减缓病情进展，或减少病情持续时间。无论固定给药或临时给药、持续给药或间歇给药，可以归因于或与给药有关的情况。The terms "treatment", "course of treatment" or "therapy" as used herein include alleviating, inhibiting or ameliorating the symptoms or conditions of a disease; inhibiting the development of complications; ameliorating or preventing the underlying metabolic syndrome; inhibiting the development of a disease or symptom, such as controlling the development of a disease or condition; alleviating a disease or symptom; reducing a disease or symptom; alleviating complications caused by a disease or symptom, or preventing or treating symptoms caused by a disease or symptom. As used herein, a compound or pharmaceutical composition, when administered, results in amelioration, especially improvement in severity, delay in onset, slow progression, or reduction in duration of a disease, symptom or condition. Whether fixed or temporary, continuous or intermittent, the conditions attributable to or associated with the administration.
“活性成分”指通式(1)所示化合物，以及通式(1)化合物的药学上可接受的无机或有机盐。本发明的化合物可以含有一个或多个不对称中心(手性中心或轴手性)，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式出现。可以存在的不对称中心，取决于分子上各种取代基的性质。每个这种不对称中心将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。"Active ingredient" refers to the compound represented by the general formula (1), and the pharmaceutically acceptable inorganic or organic salts of the compound of the general formula (1). The compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality) and are thus available as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomeric compounds in the form of enantiomers. The number of asymmetric centers that can exist depends on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds, are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds.
“化合物(compound)”、“组合物(composition)”、“药剂(agent)”或“医药品(medicine or medicament)”等词在此可交替使用，且都是指当施用于个体(人类或动物)时，能够透过局部和/或全身性作用而诱发所亟求的药学和/或生理反应的一种化合物或组合物。The terms "compound," "composition," "agent," or "medicine or medicament" are used interchangeably herein, and all refer to when administered to an individual (human or animal), a compound or composition capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.
“施用(administered、administering或、administration)”一词在此是指直接施用所述的化合物或组合物，或施用活性化合物的前驱药(prodrug)、衍生物(derivative)、或类似物(analog)等。The term "administered, administering or, administration" as used herein refers to the direct administration of the compound or composition, or the administration of a prodrug, derivative, or analog of the active compound Wait.
虽然用以界定本发明较广范围的数值范围与参数皆是约略的数值，此处已尽可能精确地呈现具体实施例中的相关数值。然而，任何数值本质上不可避免地含有因个别测试方法所致的标准偏差。在此处，“约”通常是指实际数值在一特定数值或范围的正负10％、5％、1％或0.5％之内。或者是，“约”一词代表实际数值落在平均值的可接受标准误差之内，视本领域技术人员的考虑而定。除了实验例之外，或除非另有明确的说明，当可理解此处所用的所有范围、数量、数值与百分比(例如用以描述材料用量、时间长短、温度、 操作条件、数量比例及其它相似者)均经过“约”的修饰。因此，除非另有相反的说明，本说明书与附随权利要求书所揭示的数值参数皆为约略的数值，且可视需求而更动。至少应将这些数值参数理解为所指出的有效位数与采用一般进位法所得到的数值。Notwithstanding that the numerical ranges and parameters setting forth the broader scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains the standard deviation resulting from individual testing methods. As used herein, "about" generally means within plus or minus 10%, 5%, 1%, or 0.5% of the actual value of a particular value or range. Alternatively, the word "about" means that the actual value lies within an acceptable standard error of the mean, as considered by those skilled in the art. Except for the experimental examples, or unless expressly stated otherwise, all ranges, amounts, numerical values and percentages used herein (eg, to describe material amounts, time periods, temperatures, operating conditions, quantitative ratios and the like) are to be understood. ) are modified by "about". Accordingly, unless stated to the contrary, the numerical parameters disclosed in this specification and the appended claims are approximations that can be modified as required. At a minimum, these numerical parameters should be construed to mean the number of significant digits indicated and the numerical values obtained using ordinary rounding.
除非本说明书另有定义，此处所用的科学与技术词汇的含义与本领域技术人员所理解的惯用的意义相同。此外，在不和上下文冲突的情形下，本说明书所用的单数名词涵盖该名词的复数型；而所用的复数名词时亦涵盖该名词的单数型。Unless otherwise defined in this specification, scientific and technical terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, unless contradicting the context, the singular noun used in this specification covers the plural form of the noun; and the plural noun used also covers the singular form of the noun.
治疗用途therapeutic use
本发明提供了使用本发明通式(1)或通式(1A)化合物或药物组合物治疗疾病的方法，通式(1)或通式(1A)化合物或药物组合物通常可用于抑制Wee-1激酶，因此可用于治疗与Wee-1激酶活性相关的一种或多种病症。因此，在某些实施方式中，本发明提供了用于治疗Wee-1激酶介导的病症的方法，所述方法包括向有需要的患者施用本发明化合物、或其药学上可接受的组合物的步骤。The present invention provides a method for treating diseases using the compound or pharmaceutical composition of general formula (1) or general formula (1A) of the present invention, and the compound or pharmaceutical composition of general formula (1) or general formula (1A) can generally be used to inhibit Wee- 1 kinase and thus can be used to treat one or more conditions associated with Wee-1 kinase activity. Accordingly, in certain embodiments, the present invention provides a method for treating a Wee-1 kinase mediated disorder comprising administering to a patient in need thereof a compound of the present invention, or a pharmaceutically acceptable composition thereof A step of.
在一些实施例中，提供了用于癌症治疗的方法，该方法包括给予有需要的个体有效量的任何前述的包括结构通式(1)或通式(1A)化合物的药物组合物。在一些实施例中，癌症由Wee-1介导。在其它实施例中，该癌症包括但不限于血液恶性肿瘤(白血病、淋巴瘤、骨髓瘤包括多发性骨髓瘤、骨髓异常增生综合症和骨髓增生姓综合症)和实体瘤(癌例如***、乳腺、肺、结肠、胰腺、肾、卵巢以及软组织癌和骨肉瘤，以及间质瘤)等。In some embodiments, methods for cancer treatment are provided, the methods comprising administering to an individual in need thereof an effective amount of any of the foregoing pharmaceutical compositions comprising a compound of general structural formula (1) or general formula (1A). In some embodiments, the cancer is mediated by Wee-1. In other embodiments, the cancer includes, but is not limited to, hematological malignancies (leukemia, lymphoma, myeloma including multiple myeloma, myelodysplastic syndrome and myelodysplastic syndrome) and solid tumors (cancer such as prostate, breast , lung, colon, pancreas, kidney, ovary and soft tissue cancer and osteosarcoma, and stromal tumor) and so on.
给药途径Route of administration
本发明的化合物及其药学上可接受的盐可制成各种制剂，其中包含安全、有效量范围内的本发明化合物或其药学上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全、有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。化合物的安全、有效量根据治疗对象的年龄、病情、疗程等具体情况来确定。The compounds of the present invention and their pharmaceutically acceptable salts can be prepared into various formulations, which contain the compounds of the present invention or their pharmaceutically acceptable salts and pharmacologically acceptable excipients or carriers within a safe and effective amount. . The "safe and effective amount" refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound is determined according to the age, disease condition, course of treatment and other specific conditions of the object to be treated.
“药学上可以接受的赋形剂或载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能与本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药理上可以接受的赋形剂或载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure PCTCN2022075545-appb-000065
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗 氧化剂、防腐剂、无热原水等。 "Pharmaceutically acceptable excipient or carrier" means: one or more compatible solid or liquid filler or gelling substances, which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity . "Compatibility" as used herein means that the components of the composition can be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Examples of pharmacologically acceptable excipients or carrier moieties are cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants ( Such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as
Figure PCTCN2022075545-appb-000065
), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
施用本发明化合物时，可以口服、直肠、肠胃外(静脉内、肌肉内或皮下)、局部给药。The compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium fatty acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。Besides these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds. When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is The administration dose is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。The above features mentioned in the present invention or the features mentioned in the embodiments can be combined arbitrarily. All the features disclosed in this specification can be used in combination with any composition, and each feature disclosed in the specification can be replaced by any alternative features that serve the same, equivalent or similar purpose. Therefore, unless otherwise stated, the disclosed features are only general examples of equivalent or similar features.
具体实施方式Detailed ways
在下面的说明中将会详细阐述上述化合物、方法、药物组合物的各个具体方面、特性和优势，使本发明的内容变得十分明了。在此应理解，下述的详细说明及实例描述了具体的实施例，仅用于参考。在阅读了本发明的说明内容后，本领域的技术人员可对本发明作各种改动或修改，这些等价形势同样落于本申请所限定的范围。In the following description, various specific aspects, properties and advantages of the above-described compounds, methods, and pharmaceutical compositions will be set forth in detail so that the content of the present invention will become apparent. It should be understood herein that the following detailed description and examples describe specific embodiments and are provided for reference only. After reading the description of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent situations also fall within the scope defined by the present application.
所有实施例中，熔点用X-4熔点仪测定，温度计未校正； 1H-NMR用Varian Mercury 400核磁共振仪记录，化学位移以δ(ppm)表示；分离用硅胶未说明均为200-300目，洗脱液的配比均为体积比。 In all examples, the melting point was measured with X-4 melting point apparatus, and the thermometer was not calibrated; 1 H-NMR was recorded with a Varian Mercury 400 nuclear magnetic resonance apparatus, and the chemical shift was expressed in δ (ppm); the silica gel used for separation was 200-300 if not specified The proportions of the eluents are all volume ratios.
本发明采用下述缩略词：CDCl 3代表氘代氯仿；Cs 2CO 3代表碳酸铯；CuI代表碘化亚铜；DCM代表二氯甲烷；DIPEA代表二异丙基乙基胺；dioxane代表1,4-二氧六环；EA代表乙酸乙酯；EtOH代表乙醇；h代表小时；K 2CO 3代表碳酸钾；LC-MS代表液相-质谱；m-CPBA代表间氯过氧苯甲酸；mL代表毫升；MeOH代表甲醇；min代表分钟；MS代表质谱；NaBH(OAc) 3代表三乙酰氧基硼氢化钠；NIS代表N-氯代琥珀酰亚胺；NMR代表核磁共振；℃代表摄氏度；Pd(dppf)Cl 2代表[1,1'-双(二苯基膦基)二茂铁]二氯化钯；PE代表石油醚；r.t.代表室温；TEA代表三乙胺；TFA代表三氟乙酸；THF代表四氢呋喃。 The following abbreviations are used in the present invention: CDCl 3 represents deuterated chloroform; Cs 2 CO 3 represents cesium carbonate; CuI represents cuprous iodide; DCM represents dichloromethane; DIPEA represents diisopropylethylamine; dioxane represents 1 ,4-dioxane; EA for ethyl acetate; EtOH for ethanol; h for hour; K 2 CO 3 for potassium carbonate; LC-MS for liquid phase-mass spectrometry; m-CPBA for m-chloroperoxybenzoic acid; mL stands for milliliter; MeOH stands for methanol; min stands for minutes; MS stands for mass spectrometry; NaBH(OAc) 3 stands for sodium triacetoxyborohydride; NIS stands for N-chlorosuccinimide; NMR stands for nuclear magnetic resonance; Pd(dppf)Cl 2 stands for [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; PE stands for petroleum ether; rt stands for room temperature; TEA stands for triethylamine; TFA stands for trifluoroacetic acid ; THF stands for tetrahydrofuran.
制备例1 2-烯丙基-1-(6-((二甲基(氧代)-λ 6-亚磺酰亚胺)氨基)吡啶-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑[3,4-d]嘧啶-3-酮(中间体A3-1)的制备 Preparation Example 1 2-allyl-1-(6-((dimethyl(oxo)-λ 6 -sulfimide)amino)pyridin-2-yl)-6-(methylthio)- Preparation of 1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (Intermediate A3-1)
Figure PCTCN2022075545-appb-000066
Figure PCTCN2022075545-appb-000066
步骤1：化合物A0-1的合成Step 1: Synthesis of Compound A0-1
将4-氯-2-(甲硫基)嘧啶-5-甲酸乙酯(13.5g,58.06mmol)，1-烯丙基肼-1-羧酸叔丁酯(10g,58.06mmol)，DIPEA(18.72g,145.16mmol)溶于THF(300mL)中，升温回流反应过夜，LC-MS监测，反应完毕，反应液浓缩，残留物用EA(200mL)溶解，有机相用水洗(150mL)，饱和食盐水洗(100mL)，干燥，浓缩，得到黄色油状物A0-1(21g,收率98％)，ESI-MS m/z:369.1[M+H] +。 4-Chloro-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester (13.5 g, 58.06 mmol), 1-allylhydrazine-1-carboxylate tert-butyl ester (10 g, 58.06 mmol), DIPEA ( 18.72g, 145.16mmol) was dissolved in THF (300mL), the temperature was raised and refluxed overnight, monitored by LC-MS, the reaction was completed, the reaction solution was concentrated, the residue was dissolved in EA (200mL), the organic phase was washed with water (150mL), saturated common salt Washed with water (100 mL), dried and concentrated to give A0-1 (21 g, yield 98%) as a yellow oil, ESI-MS m/z: 369.1 [M+H] + .
步骤2：化合物A1-1的合成Step 2: Synthesis of Compound A1-1
将A0-1(21g,57mmol)溶于DCM(70mL)中，加入TFA(70mL)，室温反应过夜，LC-MS监测，反应完毕。直接浓缩，残留物用EtOH(120mL)溶解，冰浴下滴加氢氧化钠水溶液(6M,66mL)，滴加完毕，室温搅拌反应1h，LC-MS监测，反应完毕，反应液直接浓缩，残留物经柱层析(DCM/MeOH＝100/1to 10.1)得到黄色固体A1-1(10g，收率79％),ESI-MS m/z:223.1[M+H] +。 A0-1 (21 g, 57 mmol) was dissolved in DCM (70 mL), TFA (70 mL) was added, and the reaction was performed at room temperature overnight. The reaction was completed by LC-MS monitoring. Concentrated directly, the residue was dissolved in EtOH (120 mL), and aqueous sodium hydroxide solution (6M, 66 mL) was added dropwise under an ice bath, the dropwise addition was completed, the reaction was stirred at room temperature for 1 h, monitored by LC-MS, the reaction was completed, the reaction solution was directly concentrated, and the residue The material was subjected to column chromatography (DCM/MeOH=100/1 to 10.1) to obtain A1-1 (10 g, yield 79%) as a yellow solid, ESI-MS m/z: 223.1 [M+H] + .
步骤3：化合物A3-1的合成Step 3: Synthesis of Compound A3-1
将A2-1(2.5g,10mmol)，A1-1(2.22g,10mmol)，CuI(1.9g,10mmol)，K 2CO 3(2.07g,15mmol)，N,N’-二甲基乙二胺(970mg,11mmol)溶于dioxane(100mL)中，氩气保护，升温80℃反应过夜，LC-MS监测，反应完毕，过滤，滤液浓缩，残留物经柱层析(DCM/MeOH＝100/1～20/1)得到浅黄色固体A3-1(1.95g，收率50％)，ESI-MS m/z:391.1[M+H] +。 A2-1 (2.5 g, 10 mmol), A1-1 (2.22 g, 10 mmol), CuI (1.9 g, 10 mmol), K 2 CO 3 (2.07 g, 15 mmol), N,N'-dimethylethanedi Amine (970 mg, 11 mmol) was dissolved in dioxane (100 mL), under argon protection, heated at 80 °C and reacted overnight, monitored by LC-MS, the reaction was completed, filtered, the filtrate was concentrated, and the residue was subjected to column chromatography (DCM/MeOH=100/ 1～20/1) to obtain light yellow solid A3-1 (1.95 g, yield 50%), ESI-MS m/z: 391.1 [M+H] + .
采用不同的原料，类似中间体A3-1的合成，可以得到中间体A3-2至A3-23。Using different starting materials, similar to the synthesis of intermediate A3-1, intermediates A3-2 to A3-23 can be obtained.
表1.中间体A3-2至A3-23的结构式Table 1. Structural formulas of intermediates A3-2 to A3-23
Figure PCTCN2022075545-appb-000067
Figure PCTCN2022075545-appb-000067
Figure PCTCN2022075545-appb-000068
Figure PCTCN2022075545-appb-000068
Figure PCTCN2022075545-appb-000069
Figure PCTCN2022075545-appb-000069
制备例2 2,5-二甲基-1,2,3,4-四氢异喹啉-7-胺(中间体B6-1)的制备Preparation Example 2 Preparation of 2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-amine (Intermediate B6-1)
Figure PCTCN2022075545-appb-000070
Figure PCTCN2022075545-appb-000070
步骤1：化合物B1-1的合成Step 1: Synthesis of Compound B1-1
将7-硝基-1,2,3,4-四氢异喹啉(10.0g,46.10mmol,HCl)溶于TFA(50.0mL)中，氩气保护，冰浴至0℃，加入NIS(15.7g,69.88mmol)，室温反应过夜，反应液呈黑色。LC-MS监测，反应完毕，反应液倒入冰水中，用NaOH调PH＝8-9，析出固体，过滤，固体即产物，干燥，得到黑色固体B1-1(14g,直接用于下一步反应)，ESI-MS m/z:305.0[M+H] +。 7-Nitro-1,2,3,4-tetrahydroisoquinoline (10.0 g, 46.10 mmol, HCl) was dissolved in TFA (50.0 mL), under argon protection, ice-bathed to 0 °C, NIS ( 15.7 g, 69.88 mmol), reacted at room temperature overnight, and the reaction solution was black. LC-MS monitoring, the reaction was completed, the reaction solution was poured into ice water, adjusted to PH=8-9 with NaOH, a solid was precipitated, filtered, the solid was the product, and dried to obtain a black solid B1-1 (14 g, directly used in the next step of the reaction) ), ESI-MS m/z: 305.0 [M+H] + .
步骤2：化合物B2-1的合成Step 2: Synthesis of Compound B2-1
将B1-1(14.0g,46.0mmol)和(Boc) 2O(25.1g,115mmol,26.4mL)溶于DCM(200mL)中，加入TEA(14.0g,138mmol,19.2mL)，室温反应过夜。LC-MS监测，反应完全。反应液中加水(100mL)，摇匀，分液，水相用DCM(150mL*3)萃取。合并有机相，干燥，过滤，浓缩，残留物经硅胶柱层析(PE/EA＝100/1to 10/1)，得到白色固体B2-1(10.0g，收率53.7％),ESI-MS m/z:405.0[M+H] +。 B1-1 (14.0 g, 46.0 mmol) and (Boc) 2 O (25.1 g, 115 mmol, 26.4 mL) were dissolved in DCM (200 mL), TEA (14.0 g, 138 mmol, 19.2 mL) was added, and the reaction was carried out at room temperature overnight. LC-MS monitoring showed that the reaction was complete. Water (100 mL) was added to the reaction solution, shaken, and separated, and the aqueous phase was extracted with DCM (150 mL*3). The organic phases were combined, dried, filtered, concentrated, and the residue was subjected to silica gel column chromatography (PE/EA=100/1 to 10/1) to obtain a white solid B2-1 (10.0 g, yield 53.7%), ESI-MS m /z:405.0[M+H] + .
步骤3：化合物B3-1的合成Step 3: Synthesis of Compound B3-1
将B2-1(6.00g,14.8mmol)、甲基硼酸(8.90g,148.4mmol)、Pd(dppf)Cl 2.CH 2Cl 2(1.2g,1.5mmol)和Cs 2CO 3(2M水溶液,14.8mL)溶于dioxane(100mL)中，氩气保护下，升温至100℃反应5h。LC-MS监测，反应完毕。向反应液中加入水(100mL)，EA(100mL*3)萃取。合并有机相，干燥，过滤，浓缩，残留物经硅胶柱层析(PE/EA＝100/1to 10/1)，得到白色固体B3-1(2.5g，收率57.6％)，ESI-MS m/z:293.1[M+H] +。 B2-1 (6.00 g, 14.8 mmol), methylboronic acid (8.90 g, 148.4 mmol), Pd(dppf)Cl 2 . CH 2 Cl 2 (1.2 g, 1.5 mmol) and Cs 2 CO 3 (2M aqueous solution, 14.8 mL) was dissolved in dioxane (100 mL), and under the protection of argon, the temperature was raised to 100 °C for reaction for 5 h. LC-MS monitoring, the reaction was completed. Water (100 mL) was added to the reaction solution, and EA (100 mL*3) was extracted. The organic phases were combined, dried, filtered, concentrated, and the residue was subjected to silica gel column chromatography (PE/EA=100/1 to 10/1) to obtain a white solid B3-1 (2.5 g, yield 57.6%), ESI-MS m /z:293.1[M+H] + .
步骤4：化合物B4-1的合成Step 4: Synthesis of Compound B4-1
将B3-1(485mg,2mmol)溶于EA(50mL)中，加入HCl/dioxane(4M,10mL)，室温反应1.5h。LC-MS监测，反应完毕。直接浓缩，用于下一步反应，ESI-MS m/z:193.1[M+H] +。 B3-1 (485 mg, 2 mmol) was dissolved in EA (50 mL), HCl/dioxane (4 M, 10 mL) was added, and the reaction was carried out at room temperature for 1.5 h. LC-MS monitoring, the reaction was completed. Concentrated directly for the next reaction, ESI-MS m/z: 193.1 [M+H] + .
步骤5：化合物B5-1的合成Step 5: Synthesis of Compound B5-1
将上步所得B4-1(理论量，2mmol)溶于DCM和MeOH混合液(DCM/MeOH＝10/1,50mL)中，甲醛水溶液(0.5mL)，TEA(607mg，6mmol)，氩气保护，冰浴，搅拌30分钟，加入三乙酰氧基硼氢化钠(848mg,4mmol)，室温反应过夜。LC-MS监测，反应完毕。反应液用碳酸氢钠水溶液洗，干燥，浓缩，残留物经硅胶柱层析(DCM/MeOH＝100/1to20/1)，得到浅黄色固体B5-1(300mg，收率72.7％)，ESI-MS m/z:207.1[M+H] +。 The B4-1 obtained in the previous step (theoretical amount, 2 mmol) was dissolved in a mixture of DCM and MeOH (DCM/MeOH=10/1, 50 mL), aqueous formaldehyde solution (0.5 mL), TEA (607 mg, 6 mmol), argon protection , ice bath, stirred for 30 minutes, added sodium triacetoxyborohydride (848 mg, 4 mmol), and reacted at room temperature overnight. LC-MS monitoring, the reaction was completed. The reaction solution was washed with aqueous sodium bicarbonate solution, dried, concentrated, and the residue was subjected to silica gel column chromatography (DCM/MeOH=100/1 to 20/1) to obtain light yellow solid B5-1 (300 mg, yield 72.7%), ESI- MS m/z: 207.1 [M+H] + .
步骤6：化合物B6-1的合成Step 6: Synthesis of Compound B6-1
将B5-1(300mg,1.45mmol)溶于甲醇(50mL)中，加入Pd/C，通入氢气，室温反应过夜。LC-MS监测，反应结束。过滤，浓缩，得到棕色固体B6-1(230mg，收率90％)，ESI-MS m/z:177.2[M+H] +。 B5-1 (300 mg, 1.45 mmol) was dissolved in methanol (50 mL), Pd/C was added, hydrogen gas was passed through, and the reaction was carried out at room temperature overnight. LC-MS monitoring, the reaction was complete. Filtration and concentration gave brown solid B6-1 (230 mg, 90% yield), ESI-MS m/z: 177.2 [M+H] + .
制备例3 5-异丙基-2-甲基-1,2,3,4-四氢异喹啉-7-胺(中间体B6-3)的制备Preparation Example 3 Preparation of 5-isopropyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine (Intermediate B6-3)
Figure PCTCN2022075545-appb-000071
Figure PCTCN2022075545-appb-000071
步骤1：化合物B1-3的合成Step 1: Synthesis of Compound B1-3
将7-硝基-1,2,3,4-四氢异喹啉(10.0g,46.10mmol,HCl)溶于TFA(50.0mL)中，氩气保护，冰浴至0℃，加入NIS(15.7g,69.88mmol)，室温反应过夜，反应液呈黑色。LC-MS监测，反应完毕，反应液倒入冰水中，用NaOH调PH＝8-9，析出固体，过滤，固体即产物，干燥，得到黑色固体B1-3(14g,直接用于下一步反应)，ESI-MS m/z:305.0[M+H] +。 7-Nitro-1,2,3,4-tetrahydroisoquinoline (10.0 g, 46.10 mmol, HCl) was dissolved in TFA (50.0 mL), under argon protection, ice-bathed to 0 °C, NIS ( 15.7 g, 69.88 mmol), reacted at room temperature overnight, and the reaction solution was black. LC-MS monitoring, the reaction was completed, the reaction solution was poured into ice water, adjusted to PH=8-9 with NaOH, a solid was precipitated, filtered, the solid was the product, and dried to obtain a black solid B1-3 (14 g, directly used in the next step of the reaction) ), ESI-MS m/z: 305.0 [M+H] + .
步骤2：化合物B2-3的合成Step 2: Synthesis of Compound B2-3
将B1-3(14.0g,46.0mmol)和(Boc) 2O(25.1g,115mmol,26.4mL)溶于DCM(200mL)中，加入TEA(14.0g,138mmol,19.2mL)，室温反应过夜。LC-MS监测，反应完全。反应液中加水(100mL)，摇匀，分液，水相用DCM(150mL*3)萃取。合并有机相，干燥，过滤，浓缩，残留物经硅胶柱层析(PE/EA＝100/1to 10/1)，得到白色固体B2-3(10.0g，收率53.7％),ESI-MS m/z:405.0[M+H] +。 B1-3 (14.0 g, 46.0 mmol) and (Boc) 2 O (25.1 g, 115 mmol, 26.4 mL) were dissolved in DCM (200 mL), TEA (14.0 g, 138 mmol, 19.2 mL) was added, and the reaction was carried out at room temperature overnight. LC-MS monitoring showed that the reaction was complete. Water (100 mL) was added to the reaction solution, shaken, and separated, and the aqueous phase was extracted with DCM (150 mL*3). The organic phases were combined, dried, filtered, concentrated, and the residue was subjected to silica gel column chromatography (PE/EA=100/1 to 10/1) to obtain a white solid B2-3 (10.0 g, yield 53.7%), ESI-MS m /z:405.0[M+H] + .
步骤3：化合物B3-3的合成Step 3: Synthesis of Compound B3-3
将B2-3(6.00g,14.8mmol)、丙基-1-烯-2-硼酸(12.7g,148.4mmol)、Pd(dppf)Cl 2.CH 2Cl 2(1.2g,1.5mmol)和Cs 2CO 3(2M水溶液,14.8mL)溶于dioxane(100mL)中，氩气保护下，升温至100℃反应5h。LC-MS监测，反应完毕。向反应液中加入水(100mL)，EA(100mL*3)萃取。合并有机相，干燥，过滤，浓缩，残留物经硅胶柱层析(PE/EA＝100/1to10/1)，得到白色固体B3-3(3.1g，收率65.9％)，ESI-MS m/z:319.2[M+H] +。 Combine B2-3 (6.00 g, 14.8 mmol), propyl-1-ene-2-boronic acid (12.7 g, 148.4 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2 (1.2 g, 1.5 mmol) and Cs 2 CO 3 (2M aqueous solution, 14.8 mL) was dissolved in dioxane (100 mL), and the temperature was raised to 100° C. for 5 h under argon protection. LC-MS monitoring, the reaction was completed. Water (100 mL) was added to the reaction solution, and EA (100 mL*3) was extracted. The organic phases were combined, dried, filtered, concentrated, and the residue was subjected to silica gel column chromatography (PE/EA=100/1to10/1) to obtain a white solid B3-3 (3.1 g, yield 65.9%), ESI-MS m/ z: 319.2[M+H] + .
步骤4：化合物B4-3的合成Step 4: Synthesis of Compound B4-3
将B3-3(637mg,2mmol)溶于EA(50mL)中，加入HCl/dioxane(4M,10mL)，室温反应1.5h。LC-MS监测，反应完毕。直接浓缩，用于下一步反应，ESI-MS m/z:219.1[M+H] +。 B3-3 (637 mg, 2 mmol) was dissolved in EA (50 mL), HCl/dioxane (4 M, 10 mL) was added, and the reaction was carried out at room temperature for 1.5 h. LC-MS monitoring, the reaction was completed. Concentrated directly for the next reaction, ESI-MS m/z: 219.1 [M+H] + .
步骤5：化合物B5-3的合成Step 5: Synthesis of Compound B5-3
将上步所得B4-3(理论量，2mmol)溶于DCM和MeOH混合液(DCM/MeOH＝10/1,50mL)中，甲醛水溶液(0.5mL)，TEA(607mg，6mmol)，氩气保护，冰浴，搅拌30分钟，加入三乙酰氧基硼氢化钠(848mg,4mmol)，室温反应过夜。LC-MS监测，反应完毕。反应液用碳酸氢钠水溶液洗，干燥，浓缩，残留物经硅胶柱层析(DCM/MeOH＝100/1to20/1)，得到浅黄色固体B5-3(295mg，收率63.5％)，ESI-MS m/z:233.1[M+H] +。 The B4-3 obtained in the previous step (theoretical amount, 2 mmol) was dissolved in a mixture of DCM and MeOH (DCM/MeOH=10/1, 50 mL), aqueous formaldehyde solution (0.5 mL), TEA (607 mg, 6 mmol), argon protection , ice bath, stirred for 30 minutes, added sodium triacetoxyborohydride (848 mg, 4 mmol), and reacted at room temperature overnight. LC-MS monitoring, the reaction was completed. The reaction solution was washed with aqueous sodium bicarbonate solution, dried, concentrated, and the residue was subjected to silica gel column chromatography (DCM/MeOH=100/1 to 20/1) to obtain light yellow solid B5-3 (295 mg, yield 63.5%), ESI- MS m/z: 233.1 [M+H] + .
步骤6：化合物B6-3的合成Step 6: Synthesis of Compound B6-3
将B5-3(300mg,1.3mmol)溶于甲醇(50mL)中，加入Pd/C，通入氢气，室温反应过夜。LC-MS监测，反应结束。过滤，浓缩，得到棕色固体B6-3(230mg，收率86.7％)，ESI-MS m/z:205.2[M+H] +。 B5-3 (300 mg, 1.3 mmol) was dissolved in methanol (50 mL), Pd/C was added, hydrogen gas was passed through, and the reaction was carried out at room temperature overnight. LC-MS monitoring, the reaction was complete. Filtration and concentration gave brown solid B6-3 (230 mg, 86.7% yield), ESI-MS m/z: 205.2 [M+H] + .
制备例4 5-环丙基-2-甲基-1,2,3,4-四氢异喹啉-7-胺(中间体B6-4)的制备Preparation Example 4 Preparation of 5-cyclopropyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine (Intermediate B6-4)
Figure PCTCN2022075545-appb-000072
Figure PCTCN2022075545-appb-000072
步骤1：化合物B1-4的合成Step 1: Synthesis of Compound B1-4
将7-硝基-1,2,3,4-四氢异喹啉(10.0g,46.10mmol,HCl)溶于TFA(50.0mL)中，氩气保护，冰浴至0℃，加入NIS(15.7g,69.88mmol)，室温反应过夜，反应液呈黑色。LC-MS监测，反应完毕，反应液倒入冰水中，用NaOH调PH＝8-9，析出固体，过滤，固体即产物，干燥，得到黑色固体B1-4(14g,直接用于下一步反应)，ESI-MS m/z:305.0[M+H] +。 7-Nitro-1,2,3,4-tetrahydroisoquinoline (10.0 g, 46.10 mmol, HCl) was dissolved in TFA (50.0 mL), under argon protection, ice-bathed to 0 °C, NIS ( 15.7 g, 69.88 mmol), reacted at room temperature overnight, and the reaction solution was black. LC-MS monitoring, the reaction was completed, the reaction solution was poured into ice water, adjusted to PH=8-9 with NaOH, a solid was precipitated, filtered, the solid was the product, and dried to obtain a black solid B1-4 (14 g, directly used in the next step of the reaction) ), ESI-MS m/z: 305.0 [M+H] + .
步骤2：化合物B2-4的合成Step 2: Synthesis of Compound B2-4
将B1-1(14.0g,46.0mmol)和(Boc) 2O(25.1g,115mmol,26.4mL)溶于DCM(200mL)中，加入TEA(14.0g,138mmol,19.2mL)，室温反应过夜。LC-MS监测，反应完全。 反应液中加水(100mL)，摇匀，分液，水相用DCM(150mL*3)萃取。合并有机相，干燥，过滤，浓缩，残留物经硅胶柱层析(PE/EA＝100/1to 10/1)，得到白色固体B2-4(10.0g，收率53.7％),ESI-MS m/z:405.0[M+H] +。 B1-1 (14.0 g, 46.0 mmol) and (Boc) 2 O (25.1 g, 115 mmol, 26.4 mL) were dissolved in DCM (200 mL), TEA (14.0 g, 138 mmol, 19.2 mL) was added, and the reaction was carried out at room temperature overnight. LC-MS monitoring showed that the reaction was complete. Water (100 mL) was added to the reaction solution, shaken, and separated, and the aqueous phase was extracted with DCM (150 mL*3). The organic phases were combined, dried, filtered, concentrated, and the residue was subjected to silica gel column chromatography (PE/EA=100/1 to 10/1) to obtain a white solid B2-4 (10.0 g, yield 53.7%), ESI-MS m /z:405.0[M+H] + .
步骤3：化合物B3-4的合成Step 3: Synthesis of Compound B3-4
将B2-4(3.00g,7.42mmol)，环丙基硼酸(3.19g,37.1mmol)，碳酸铯(4.84g,14.8mmol)和Pd(dppf)Cl2.CH2Cl2(606mg,742umol)溶解在1,4-二氧六环(40ml)和水(4ml)中，氩气保护下，加热到100℃搅拌反应5小时。LC-MS监测显示反应结束。将反应液旋干，粗产物经过柱层析制备纯化(SiO2,EtOAc/PE＝0/1-1/9)得白色固体(1.4g，收率：59.3％)。 1H NMR(400MHz,DMSO-d6)δ7.95(d,J＝2.0Hz,1H),7.62(d,J＝2.3Hz,1H),4.62(br s,2H),3.63(br t,J＝5.9Hz,2H),2.98(t,J＝5.9Hz,2H),2.04-1.94(m,1H),1.47-1.35(m,9H),1.05-0.93(m,2H),0.74-0.62(m,2H) B2-4 (3.00g, 7.42mmol), cyclopropylboronic acid (3.19g, 37.1mmol), cesium carbonate (4.84g, 14.8mmol) and Pd(dppf)Cl2.CH2Cl2 (606mg, 742umol) were dissolved in 1, 4-dioxane (40ml) and water (4ml) were heated to 100°C and stirred for 5 hours under argon protection. LC-MS monitoring showed that the reaction was complete. The reaction solution was spun dry, and the crude product was purified by column chromatography (SiO2, EtOAc/PE=0/1-1/9) to obtain a white solid (1.4 g, yield: 59.3%). 1 H NMR(400MHz,DMSO-d6)δ7.95(d,J=2.0Hz,1H),7.62(d,J=2.3Hz,1H),4.62(br s,2H),3.63(br t,J =5.9Hz,2H),2.98(t,J=5.9Hz,2H),2.04-1.94(m,1H),1.47-1.35(m,9H),1.05-0.93(m,2H),0.74-0.62( m, 2H)
步骤4：化合物B4-4的合成Step 4: Synthesis of Compound B4-4
将B3-4(637mg,2mmol)溶于EA(50mL)中，加入HCl/dioxane(4M,10mL)，室温反应1.5h。LC-MS监测，反应完毕。直接浓缩，用于下一步反应，ESI-MS m/z:219.1[M+H] +。 B3-4 (637 mg, 2 mmol) was dissolved in EA (50 mL), HCl/dioxane (4 M, 10 mL) was added, and the reaction was carried out at room temperature for 1.5 h. LC-MS monitoring, the reaction was completed. Concentrated directly for the next reaction, ESI-MS m/z: 219.1 [M+H] + .
步骤5：化合物B5-4的合成Step 5: Synthesis of Compound B5-4
将上步所得B4-4(理论量，2mmol)溶于DCM和MeOH混合液(DCM/MeOH＝10/1,50mL)中，甲醛水溶液(0.5mL)，TEA(607mg，6mmol)，氩气保护，冰浴，搅拌30分钟，加入三乙酰氧基硼氢化钠(848mg,4mmol)，室温反应过夜。LC-MS监测，反应完毕。反应液用碳酸氢钠水溶液洗，干燥，浓缩，残留物经硅胶柱层析(DCM/MeOH＝100/1to20/1)，得到浅黄色固体B5-4(285mg，收率61.4％)，ESI-MS m/z:233.1[M+H] +。 The B4-4 obtained in the previous step (theoretical amount, 2 mmol) was dissolved in a mixture of DCM and MeOH (DCM/MeOH=10/1, 50 mL), aqueous formaldehyde solution (0.5 mL), TEA (607 mg, 6 mmol), argon protection , ice bath, stirred for 30 minutes, added sodium triacetoxyborohydride (848 mg, 4 mmol), and reacted at room temperature overnight. LC-MS monitoring, the reaction was completed. The reaction solution was washed with aqueous sodium bicarbonate solution, dried, concentrated, and the residue was subjected to silica gel column chromatography (DCM/MeOH=100/1 to 20/1) to obtain light yellow solid B5-4 (285 mg, yield 61.4%), ESI- MS m/z: 233.1 [M+H] + .
步骤6：化合物B6-4的合成Step 6: Synthesis of Compound B6-4
将B5-4(465mg,2mmol)溶于甲醇(50mL)中，加入Pd/C，通入氢气，室温反应过夜。LC-MS监测，反应结束。过滤，浓缩，得到棕色固体B6-4(390mg，收率96.5％)，ESI-MS m/z:203.2[M+H] +。 B5-4 (465 mg, 2 mmol) was dissolved in methanol (50 mL), Pd/C was added, hydrogen gas was passed through, and the reaction was carried out at room temperature overnight. LC-MS monitoring, the reaction was complete. Filtration and concentration gave brown solid B6-4 (390 mg, 96.5% yield), ESI-MS m/z: 203.2 [M+H] + .
制备例5 5-甲氧基-2-甲基-1,2,3,4-四氢异喹啉-7-胺(中间体B6-17)的制备Preparation Example 5 Preparation of 5-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine (Intermediate B6-17)
Figure PCTCN2022075545-appb-000073
Figure PCTCN2022075545-appb-000073
步骤1：化合物B1-17的合成Step 1: Synthesis of Compound B1-17
将7-硝基-1,2,3,4-四氢异喹啉(10.0g,46.10mmol,HCl)溶于TFA(50.0mL)中，氩气保护，冰浴至0℃，加入NIS(15.7g,69.88mmol)，室温反应过夜，反应液呈黑色。LC-MS监测，反应完毕，反应液倒入冰水中，用NaOH调PH＝8-9，析出固体，过滤，固体即产物，干燥，得到黑色固体B1-17(14g,直接用于下一步反应)，ESI-MS m/z:305.0[M+H] +。 7-Nitro-1,2,3,4-tetrahydroisoquinoline (10.0 g, 46.10 mmol, HCl) was dissolved in TFA (50.0 mL), under argon protection, ice-bathed to 0 °C, NIS ( 15.7 g, 69.88 mmol), reacted at room temperature overnight, and the reaction solution was black. LC-MS monitoring, the reaction was completed, the reaction solution was poured into ice water, adjusted to PH=8-9 with NaOH, a solid was precipitated, filtered, the solid was the product, and dried to obtain a black solid B1-17 (14 g, directly used in the next step of the reaction) ), ESI-MS m/z: 305.0 [M+H] + .
步骤2：化合物B2-17的合成Step 2: Synthesis of Compound B2-17
将B1-1(14.0g,46.0mmol)和(Boc) 2O(25.1g,115mmol,26.4mL)溶于DCM(200mL)中，加入TEA(14.0g,138mmol,19.2mL)，室温反应过夜。LC-MS监测，反应完全。反应液中加水(100mL)，摇匀，分液，水相用DCM(150mL*3)萃取。合并有机相，干燥，过滤，浓缩，残留物经硅胶柱层析(PE/EA＝100/1 to 10/1)，得到白色固体B2-17(10.0g，收率53.7％),ESI-MS m/z:405.0[M+H] +。 B1-1 (14.0 g, 46.0 mmol) and (Boc) 2 O (25.1 g, 115 mmol, 26.4 mL) were dissolved in DCM (200 mL), TEA (14.0 g, 138 mmol, 19.2 mL) was added, and the reaction was carried out at room temperature overnight. LC-MS monitoring showed that the reaction was complete. Water (100 mL) was added to the reaction solution, shaken, and separated, and the aqueous phase was extracted with DCM (150 mL*3). The organic phases were combined, dried, filtered, concentrated, and the residue was subjected to silica gel column chromatography (PE/EA=100/1 to 10/1) to obtain a white solid B2-17 (10.0 g, yield 53.7%), ESI-MS m/z: 405.0[M+H] + .
步骤3：化合物B3-17的合成Step 3: Synthesis of Compound B3-17
将B2-17(500mg,1.24mmol)，甲醇(39.6mg,1.24mmol)，CuI(236mg,1.24mmol)，Cs2CO3(806mg,2.47mmol)和(1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine(175.96mg,1.24mmol)溶解在甲醇(8ml)中，氮气保护下，微波加热到110℃搅拌反应1小时。LC-MS监测显示反应结束。将反应液旋干，粗产物经过柱层析制备纯化(SiO2,EtOAc/PE＝1/10)得白色固体(420mg，收率：27.5％)。 1H NMR(400MHz,Chloroform-d)δ7.67(s,1H),7.55(d,J＝1.9Hz,1H),4.64(s,2H),3.94(s,3H),3.68(t,J＝5.9Hz,2H),2.82(br t,J＝5.8Hz,2H),1.51(s,9H) B2-17 (500mg, 1.24mmol), methanol (39.6mg, 1.24mmol), CuI (236mg, 1.24mmol), Cs2CO3 (806mg, 2.47mmol) and (1R,2R)-N1,N2-dimethylcyclohexane-1, 2-diamine (175.96 mg, 1.24 mmol) was dissolved in methanol (8 ml), under nitrogen protection, heated to 110 °C by microwave and stirred for 1 hour. LC-MS monitoring showed that the reaction was complete. The reaction solution was spun dry, and the crude product was purified by column chromatography (SiO2, EtOAc/PE=1/10) to obtain a white solid (420 mg, yield: 27.5%). 1 H NMR(400MHz, Chloroform-d)δ7.67(s,1H),7.55(d,J=1.9Hz,1H),4.64(s,2H),3.94(s,3H),3.68(t,J ＝5.9Hz, 2H), 2.82(br t, J＝5.8Hz, 2H), 1.51(s, 9H)
步骤4：化合物B4-17的合成Step 4: Synthesis of Compound B4-17
将B3-17(617mg,2mmol)溶于EA(50mL)中，加入HCl/dioxane(4M,10mL)，室温反应1.5h。LC-MS监测，反应完毕。直接浓缩，用于下一步反应，ESI-MS m/z:209.1[M+H] +。 B3-17 (617 mg, 2 mmol) was dissolved in EA (50 mL), HCl/dioxane (4 M, 10 mL) was added, and the reaction was carried out at room temperature for 1.5 h. LC-MS monitoring, the reaction was completed. Concentrated directly for the next reaction, ESI-MS m/z: 209.1 [M+H] + .
步骤5：化合物B5-17的合成Step 5: Synthesis of Compound B5-17
将上步所得B4-17(理论量，2mmol)溶于DCM和MeOH混合液(DCM/MeOH＝10/1,50mL)中，甲醛水溶液(0.5mL)，TEA(607mg，6mmol)，氩气保护，冰浴，搅拌30分钟，加入三乙酰氧基硼氢化钠(848mg,4mmol)，室温反应过夜。LC-MS监测，反应完毕。反应液用碳酸氢钠水溶液洗，干燥，浓缩，残留物经硅胶柱层析(DCM/MeOH＝100/1to20/1)，得到浅黄色固体B5-17(300mg，收率67.5％)，ESI-MS m/z:223.1[M+H] +。 The B4-17 (theoretical amount, 2 mmol) obtained in the previous step was dissolved in a mixture of DCM and MeOH (DCM/MeOH=10/1, 50 mL), aqueous formaldehyde solution (0.5 mL), TEA (607 mg, 6 mmol), argon protection , ice bath, stirred for 30 minutes, added sodium triacetoxyborohydride (848 mg, 4 mmol), and reacted at room temperature overnight. LC-MS monitoring, the reaction was completed. The reaction solution was washed with aqueous sodium bicarbonate solution, dried, concentrated, and the residue was subjected to silica gel column chromatography (DCM/MeOH=100/1 to 20/1) to obtain light yellow solid B5-17 (300 mg, yield 67.5%), ESI- MS m/z: 223.1 [M+H] + .
步骤6：化合物B6-17的合成Step 6: Synthesis of Compound B6-17
将B5-17(450mg,2mmol)溶于甲醇(50mL)中，加入Pd/C，通入氢气，室温反应过夜。LC-MS监测，反应结束。过滤，浓缩，得到棕色固体B6-17(370mg，收率95.1％)，ESI-MS m/z:193.1[M+H] +。 B5-17 (450 mg, 2 mmol) was dissolved in methanol (50 mL), Pd/C was added, hydrogen was passed through, and the reaction was carried out at room temperature overnight. LC-MS monitoring, the reaction was complete. Filtration and concentration gave B6-17 as a brown solid (370 mg, 95.1% yield), ESI-MS m/z: 193.1 [M+H] + .
采用不同的原料，类似中间体B6-1、B6-3、B6-4以及B6-17的合成，可以得到中间体B6-2、B6-5至B6-16以及B6-18至6-79。Using different starting materials, similar to the synthesis of intermediates B6-1, B6-3, B6-4 and B6-17, intermediates B6-2, B6-5 to B6-16 and B6-18 to 6-79 can be obtained.
表2.中间体B6-2至B6-79的结构式Table 2. Structural formulas of intermediates B6-2 to B6-79
Figure PCTCN2022075545-appb-000074
Figure PCTCN2022075545-appb-000074
Figure PCTCN2022075545-appb-000075
Figure PCTCN2022075545-appb-000075
Figure PCTCN2022075545-appb-000076
Figure PCTCN2022075545-appb-000076
Figure PCTCN2022075545-appb-000077
Figure PCTCN2022075545-appb-000077
Figure PCTCN2022075545-appb-000078
Figure PCTCN2022075545-appb-000078
实施例1 2-烯丙基-1-(6-((二甲基(氧代)-λ 6-亚磺酰亚胺)氨基)吡啶-2-基)-6-((2,5-二甲基-1,2,3,4-四氢喹唑啉-7-基)氨基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(化合物1)的合成 Example 1 2-allyl-1-(6-((dimethyl(oxo)-λ 6 -sulfinylimide)amino)pyridin-2-yl)-6-((2,5- Dimethyl-1,2,3,4-tetrahydroquinazolin-7-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one ( Synthesis of compound 1)
Figure PCTCN2022075545-appb-000079
Figure PCTCN2022075545-appb-000079
将A3-1(500mg,1.28mmol)溶于DCM(20mL)中，加入m-CPBA(310mg，1.8mmol)，室温反应1h。LC-MS监测，反应完毕，体系碳酸氢钠饱和溶液洗，有机相干燥，旋干，直接下一步，ESI-MS m/z:405.5[M+H] +。 A3-1 (500 mg, 1.28 mmol) was dissolved in DCM (20 mL), m-CPBA (310 mg, 1.8 mmol) was added, and the reaction was carried out at room temperature for 1 h. LC-MS monitoring showed that the reaction was completed, the system was washed with a saturated solution of sodium bicarbonate, the organic phase was dried, spin-dried, and directly to the next step, ESI-MS m/z: 405.5 [M+H] + .
将上步所得中间体溶于DMF(10mL)中，加入B6-1(226mg,1.28mmol)，TFA(146mg,1.28mmol)，氩气保护，80℃反应10h。LC-MS监测，反应完毕。加入DCM(50mL)稀释，水(20mL*2)洗，有机相干燥，旋干，残留物经硅胶柱层析(DCM/MeOH＝100/1to10/1)，得到浅黄色固体化合物1(300mg,产率45％)。The intermediate obtained in the previous step was dissolved in DMF (10 mL), B6-1 (226 mg, 1.28 mmol), TFA (146 mg, 1.28 mmol) were added, and the reaction was carried out at 80° C. for 10 h under argon protection. LC-MS monitoring, the reaction was completed. DCM (50 mL) was added to dilute, washed with water (20 mL*2), the organic phase was dried, spin-dried, and the residue was subjected to silica gel column chromatography (DCM/MeOH=100/1 to 10/1) to obtain compound 1 (300 mg, yield 45%).
1H NMR(400MHz,CDCl 3)δ:8.80(s,1H),7.65(t,J＝8.0Hz,1H),7.47-7.32(m,2H),7.22(s,1H),6.66(d,J＝7.9Hz,1H),5.63(dd,J＝13.9,7.3Hz,1H),4.97(dd,J＝13.5,9.4Hz,2H),4.89(d,J＝6.3Hz,2H),3.54(s,2H),3.31(s,6H),2.72(s,4H),2.45(s,3H),2.20(s,3H),ESI-MS m/z:517.6[M+H] +。 1 H NMR (400 MHz, CDCl 3 ) δ: 8.80 (s, 1H), 7.65 (t, J=8.0 Hz, 1H), 7.47-7.32 (m, 2H), 7.22 (s, 1H), 6.66 (d, J＝7.9Hz, 1H), 5.63(dd, J＝13.9, 7.3Hz, 1H), 4.97(dd, J＝13.5, 9.4Hz, 2H), 4.89(d, J＝6.3Hz, 2H), 3.54( s, 2H), 3.31(s, 6H), 2.72(s, 4H), 2.45(s, 3H), 2.20(s, 3H), ESI-MS m/z: 517.6 [M+H] + .
实施例2 2-烯丙基-1-(6-((二甲基(氧代)-λ 6-亚磺酰亚胺)氨基)吡啶-2-基)-6-((5-异丙基-2-甲基-1,2,3,4-四氢喹唑啉-7-基)氨基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(化合物33)的合成 Example 2 2-allyl-1-(6-((dimethyl(oxo)-λ 6 -sulfinylimide)amino)pyridin-2-yl)-6-((5-isopropyl yl-2-methyl-1,2,3,4-tetrahydroquinazolin-7-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3 -Synthesis of ketone (compound 33)
Figure PCTCN2022075545-appb-000080
Figure PCTCN2022075545-appb-000080
将A3-1(500mg,1.28mmol)溶于DCM(20mL)中，加入m-CPBA(310mg，1.8mmol)，室温反应1h。LC-MS监测，反应完毕，体系碳酸氢钠饱和溶液洗，有机相干燥，旋干，直接下一步，ESI-MS m/z:405.5[M+H] +。 A3-1 (500 mg, 1.28 mmol) was dissolved in DCM (20 mL), m-CPBA (310 mg, 1.8 mmol) was added, and the reaction was carried out at room temperature for 1 h. LC-MS monitoring showed that the reaction was completed, the system was washed with a saturated solution of sodium bicarbonate, the organic phase was dried, spin-dried, and directly to the next step, ESI-MS m/z: 405.5 [M+H] + .
将上步所得中间体溶于DMF(10mL)中，加入B6-3(261mg,1.28mmol)，TFA(146mg,1.28mmol)，氩气保护，80℃反应10h。LC-MS监测，反应完毕。加入DCM(50mL)稀释，水(20mL*2)洗，有机相干燥，旋干，残留物经硅胶柱层析(DCM/MeOH＝100/1to 10/1)，得到浅黄色固体化合物33(293mg,产率42％)。The intermediate obtained in the previous step was dissolved in DMF (10 mL), B6-3 (261 mg, 1.28 mmol), TFA (146 mg, 1.28 mmol) were added, and the reaction was carried out at 80° C. for 10 h under argon protection. LC-MS monitoring, the reaction was completed. DCM (50 mL) was added to dilute, washed with water (20 mL*2), the organic phase was dried, spin-dried, and the residue was subjected to silica gel column chromatography (DCM/MeOH=100/1 to 10/1) to obtain compound 33 (293 mg) as a pale yellow solid , the yield is 42%).
1H NMR(400MHz,CDCl 3)δ8.82(s,1H),8.36(s,1H),7.70(t,J＝7.9Hz,2H),7.46(s,1H),7.30(d,J＝7.8Hz,1H),7.17(d,J＝2.2Hz,1H),6.70(d,J＝8.0Hz,1H),5.65(d,J＝6.5Hz,1H),5.01(d,J＝11.3Hz,2H),4.88(d,J＝6.3Hz,2H),3.91(s,2H),3.33(s,6H),3.11-3.04(m,3H),2.99(d,J＝6.0Hz,2H),2.67(s,3H),1.21(s,3H),1.19(s,3H),ESI-MS m/z:547.3[M+H] +。 1 H NMR (400MHz, CDCl 3 ) δ 8.82(s, 1H), 8.36(s, 1H), 7.70(t, J=7.9Hz, 2H), 7.46(s, 1H), 7.30(d, J= 7.8Hz, 1H), 7.17 (d, J=2.2Hz, 1H), 6.70 (d, J=8.0Hz, 1H), 5.65 (d, J=6.5Hz, 1H), 5.01 (d, J=11.3Hz) ,2H),4.88(d,J＝6.3Hz,2H),3.91(s,2H),3.33(s,6H),3.11-3.04(m,3H),2.99(d,J＝6.0Hz,2H) , 2.67(s,3H), 1.21(s,3H), 1.19(s,3H), ESI-MS m/z: 547.3[M+H] + .
实施例3 2-烯丙基-1-(6-((二甲基(氧代)-λ 6-亚磺酰亚胺)氨基)吡啶-2-基)-6-((5-环丙基-2-甲基-1,2,3,4-四氢喹唑啉-7-基)氨基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(化合物34)的合成 Example 3 2-allyl-1-(6-((dimethyl(oxo)-λ 6 -sulfinylimide)amino)pyridin-2-yl)-6-((5-cyclopropane yl-2-methyl-1,2,3,4-tetrahydroquinazolin-7-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3 -Synthesis of ketone (compound 34)
Figure PCTCN2022075545-appb-000081
Figure PCTCN2022075545-appb-000081
将A3-1(500mg,1.28mmol)溶于DCM(20mL)中，加入m-CPBA(310mg，1.8mmol)，室温反应1h。LC-MS监测，反应完毕，体系碳酸氢钠饱和溶液洗，有机相干燥，旋干，直接下一步，ESI-MS m/z:405.5[M+H] +。 A3-1 (500 mg, 1.28 mmol) was dissolved in DCM (20 mL), m-CPBA (310 mg, 1.8 mmol) was added, and the reaction was carried out at room temperature for 1 h. LC-MS monitoring showed that the reaction was completed, the system was washed with a saturated solution of sodium bicarbonate, the organic phase was dried, spin-dried, and directly to the next step, ESI-MS m/z: 405.5 [M+H] + .
将上步所得中间体溶于DMF(10mL)中，加入B6-4(258mg,1.28mmol)，TFA(146mg,1.28mmol)，氩气保护，80℃反应10h。LC-MS监测，反应完毕。加入DCM(50mL)稀释，水(20mL*2)洗，有机相干燥，旋干，残留物经硅胶柱层析(DCM/MeOH＝100/1to10/1)，得到浅黄色固体化合物34(320mg,产率46％)。The intermediate obtained in the previous step was dissolved in DMF (10 mL), B6-4 (258 mg, 1.28 mmol), TFA (146 mg, 1.28 mmol) were added, and the reaction was carried out at 80° C. for 10 h under argon protection. LC-MS monitoring, the reaction was completed. DCM (50 mL) was added to dilute, washed with water (20 mL*2), the organic phase was dried, spin-dried, and the residue was subjected to silica gel column chromatography (DCM/MeOH=100/1 to 10/1) to obtain compound 34 as a pale yellow solid (320 mg, yield 46%).
1H NMR(400MHz,CDCl 3)δ8.81(s,1H),7.67(t,J＝7.9Hz,1H),7.51(s,1H),7.35-7.29(m,2H),6.95(d,J＝2.3Hz,1H),6.68(d,J＝8.0Hz,1H),5.65(ddt,J＝16.6,10.1,6.3Hz,1H),5.03-4.94(m,2H),4.89(d,J＝6.3Hz,2H),3.58(s,2H),3.32(s,6H),2.98(t,J＝6.1Hz,2H),2.77(t,J＝6.1Hz,2H),2.49(s,3H),1.36-1.17(m,1H),0.93-0.85(m,2H),0.61-0.52(m,2H),ESI-MS m/z:545.2[M+H] +。 1 H NMR (400MHz, CDCl 3 ) δ 8.81(s, 1H), 7.67(t, J=7.9Hz, 1H), 7.51(s, 1H), 7.35-7.29(m, 2H), 6.95(d, J=2.3Hz,1H),6.68(d,J=8.0Hz,1H),5.65(ddt,J=16.6,10.1,6.3Hz,1H),5.03-4.94(m,2H),4.89(d,J ＝6.3Hz, 2H), 3.58(s, 2H), 3.32(s, 6H), 2.98(t, J＝6.1Hz, 2H), 2.77(t, J＝6.1Hz, 2H), 2.49(s, 3H ), 1.36-1.17 (m, 1H), 0.93-0.85 (m, 2H), 0.61-0.52 (m, 2H), ESI-MS m/z: 545.2 [M+H] + .
实施例4 2-烯丙基-1-(6-((二甲基(氧代)-λ 6-亚磺酰亚胺)氨基)吡啶-2-基)-6-((5-甲氧基-2-甲基-1,2,3,4-四氢喹唑啉-7-基)氨基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(化合物47)的合成 Example 4 2-allyl-1-(6-((dimethyl(oxo)-λ 6 -sulfinylimide)amino)pyridin-2-yl)-6-((5-methoxy yl-2-methyl-1,2,3,4-tetrahydroquinazolin-7-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3 -Synthesis of ketone (compound 47)
Figure PCTCN2022075545-appb-000082
Figure PCTCN2022075545-appb-000082
将A3-1(500mg,1.28mmol)溶于DCM(20mL)中，加入m-CPBA(310mg，1.8mmol)，室温反应1h。LC-MS监测，反应完毕，体系碳酸氢钠饱和溶液洗，有机相干燥，旋干，直接下一步，ESI-MS m/z:405.5[M+H] +。 A3-1 (500 mg, 1.28 mmol) was dissolved in DCM (20 mL), m-CPBA (310 mg, 1.8 mmol) was added, and the reaction was carried out at room temperature for 1 h. LC-MS monitoring showed that the reaction was completed, the system was washed with a saturated solution of sodium bicarbonate, the organic phase was dried, spin-dried, and directly to the next step, ESI-MS m/z: 405.5 [M+H] + .
将上步所得中间体溶于DMF(10mL)中，加入B6-17(246mg,1.28mmol)，TFA(146mg,1.28mmol)，氩气保护，80℃反应10h。LC-MS监测，反应完毕。加入DCM(50mL)稀释，水(20mL*2)洗，有机相干燥，旋干，残留物经硅胶柱层析(DCM/MeOH＝100/1to10/1)，得到浅黄色固体化合物47(350mg,产率51％)。The intermediate obtained in the previous step was dissolved in DMF (10 mL), B6-17 (246 mg, 1.28 mmol), TFA (146 mg, 1.28 mmol) were added, and the reaction was carried out at 80° C. for 10 h under argon protection. LC-MS monitoring, the reaction was completed. DCM (50 mL) was added to dilute, washed with water (20 mL*2), the organic phase was dried, spin-dried, and the residue was subjected to silica gel column chromatography (DCM/MeOH=100/1 to 10/1) to obtain compound 47 as a pale yellow solid (350 mg, yield 51%).
1H NMR(400MHz,CDCl 3)δ8.81(s,1H),7.61(t,J＝7.9Hz,1H),7.43(s,1H),7.30(d,J＝7.8Hz,1H),6.95(s,1H),6.88(s,1H),6.66(d,J＝8.0Hz,1H),5.63(dd,J＝16.8,10.2Hz,1H),4.97(t,J＝13.2Hz,2H),4.86(d,J＝6.3Hz,2H),3.74(s,3H),3.50(s,2H),3.30(s,6H),2.72(d,J＝6.0Hz,2H),2.66(d,J＝5.8Hz,2H),2.44(s,3H),ESI-MS m/z:535.2[M+H] +。 1 H NMR (400 MHz, CDCl 3 ) δ 8.81 (s, 1H), 7.61 (t, J=7.9 Hz, 1H), 7.43 (s, 1H), 7.30 (d, J=7.8 Hz, 1H), 6.95 (s,1H),6.88(s,1H),6.66(d,J＝8.0Hz,1H),5.63(dd,J＝16.8,10.2Hz,1H),4.97(t,J＝13.2Hz,2H) ,4.86(d,J＝6.3Hz,2H),3.74(s,3H),3.50(s,2H),3.30(s,6H),2.72(d,J＝6.0Hz,2H),2.66(d, J=5.8 Hz, 2H), 2.44 (s, 3H), ESI-MS m/z: 535.2 [M+H] + .
实施例2-32、35-46以及48-116化合物2-32、35-46以及48-116的合成Examples 2-32, 35-46 and 48-116 Synthesis of compounds 2-32, 35-46 and 48-116
类似于化合物1、33、34以及47的合成，中间体A3-1至A3-23和B6-1至B6-79反应，可以得到表3中的目标化合物2-32、35-46以及48-116。Similar to the synthesis of compounds 1, 33, 34 and 47, intermediates A3-1 to A3-23 and B6-1 to B6-79 were reacted to obtain the target compounds 2-32, 35-46 and 48- 116.
表3化合物2-116结构Table 3 Structure of compound 2-116
Figure PCTCN2022075545-appb-000083
Figure PCTCN2022075545-appb-000083
Figure PCTCN2022075545-appb-000084
Figure PCTCN2022075545-appb-000084
Figure PCTCN2022075545-appb-000085
Figure PCTCN2022075545-appb-000085
Figure PCTCN2022075545-appb-000086
Figure PCTCN2022075545-appb-000086
Figure PCTCN2022075545-appb-000087
Figure PCTCN2022075545-appb-000087
Figure PCTCN2022075545-appb-000088
Figure PCTCN2022075545-appb-000088
Figure PCTCN2022075545-appb-000089
Figure PCTCN2022075545-appb-000089
Figure PCTCN2022075545-appb-000090
Figure PCTCN2022075545-appb-000090
Figure PCTCN2022075545-appb-000091
Figure PCTCN2022075545-appb-000091
Figure PCTCN2022075545-appb-000092
Figure PCTCN2022075545-appb-000092
实施例117化合物抑制Wee-1酶活性测定Example 117 Compound inhibition of Wee-1 enzyme activity assay
梯度稀释的化合物和酶混合后，室温(25℃)孵育15分钟后，1000rpm离心1分钟混和，加入5μL底物启动反应。室温反应60分钟后，加入5μL ADP-GLO试剂，1000rpm离心1分钟混和后，继续室温孵育60分钟，然后再加入10μL激酶检测试剂孵育60分钟，检测化学发光。与DMSO组对比，计算化合物抑制酶活百分比，进而计算IC 50。 The serially diluted compounds and enzymes were mixed, incubated at room temperature (25° C.) for 15 minutes, centrifuged at 1000 rpm for 1 minute to mix, and 5 μL of substrate was added to initiate the reaction. After 60 minutes of reaction at room temperature, 5 μL of ADP-GLO reagent was added, mixed by centrifugation at 1000 rpm for 1 minute, and incubated at room temperature for 60 minutes, and then 10 μL of kinase detection reagent was added to incubate for 60 minutes to detect chemiluminescence. Compared with the DMSO group, the percentage of compound inhibited enzyme activity was calculated, and then the IC 50 was calculated.
表4.本发明化合物抑制Wee-1激酶活性的IC 50(nM) Table 4. IC50 (nM) of the compounds of the invention for inhibition of Wee-1 kinase activity
Figure PCTCN2022075545-appb-000093
Figure PCTCN2022075545-appb-000093
从表4数据可以看出，本发明化合物对Wee-1激酶具有很强的抑制作用,式(1)和式(1A)中R 4为烷基，烷氧基或杂环烷基等，化合物均具有很强的抑制Wee-1激酶的活性，如化合物1和化合物32，活性比对照药物MK-1775提高了3倍左右。 It can be seen from the data in Table 4 that the compound of the present invention has a strong inhibitory effect on Wee-1 kinase. In formula (1) and formula (1A), R 4 is an alkyl group, an alkoxy group or a heterocycloalkyl group, etc., the compound All have strong inhibitory activity against Wee-1 kinase, such as compound 1 and compound 32, the activity is about 3 times higher than that of the control drug MK-1775.
实施例118:化合物对MIA PaCa-2细胞的体外抗增殖活性Example 118: In vitro antiproliferative activity of compounds on MIA PaCa-2 cells
3000/孔MIA PaCa-2细胞铺于384孔板，过夜贴壁后，加入DMSO或者最高浓度为5μM,1:5梯度稀释的化合物。加药后72小时，通过测定细胞内ATP含量，评价细胞存活。与DMSO组相比计算化合物抑制细胞存活的百分比，计算IC 50值，结果见下列表5。 3000/well MIA PaCa-2 cells were plated in a 384-well plate, and after overnight adherence, DMSO or compounds with a maximum concentration of 5 μM, 1:5 serial dilution were added. Cell survival was assessed by measuring intracellular ATP content 72 hours after dosing. The percent inhibition of cell survival by the compounds compared to the DMSO group was calculated and IC50 values were calculated and the results are shown in Table 5 below.
实施例119:化合物联合吉西他滨(Gemcitabine,GMC)对MIA PaCa-2细胞的体外抗增殖活性Example 119: In vitro antiproliferative activity of compound combined with gemcitabine (Gemcitabine, GMC) on MIA PaCa-2 cells
3000个/孔MIA PaCa-2细胞铺于384孔板并加入20nM Gemcitabine，过夜贴壁后，加入DMSO或者最高浓度为100nM，1:5梯度稀释的化合物。加药后72小时，通过测定细胞内ATP含量，评价细胞存活。与DMSO组相比，计算化合物抑制细胞存活的百分比，进而计算IC 50值，结果见下列表5。 3000 cells/well of MIA PaCa-2 cells were plated in 384-well plate and 20nM Gemcitabine was added. After overnight adherence, DMSO or compounds with a maximum concentration of 100nM, 1:5 serial dilution were added. Cell survival was assessed by measuring intracellular ATP content 72 hours after dosing. Compared with the DMSO group, the percentage of inhibition of cell survival by the compound was calculated, and then the IC50 value was calculated, and the results are shown in Table 5 below.
表5本发明化合物单药或联合GMC对MIA PaCa-2细胞的抗增殖活性Table 5 The anti-proliferative activity of the compound of the present invention alone or in combination with GMC on MIA PaCa-2 cells
Figure PCTCN2022075545-appb-000094
Figure PCTCN2022075545-appb-000094
Figure PCTCN2022075545-appb-000095
Figure PCTCN2022075545-appb-000095
从表5数据可见本发明化合物对MIA PaCa-2细胞都具有较强的抗增殖活性，如化合物32活性和对照药物MK-1775相比，提高了10倍以上。特别是本发明化合物具有更强的和GMC联用活性，如化合物11的IC 50小于1nM。本发明化合物具有很强的和GMC联用活性，预示其在临床上和化疗药物联用可能具有更好的效果。 From the data in Table 5, it can be seen that the compounds of the present invention have strong anti-proliferative activity on MIA PaCa-2 cells. For example, the activity of compound 32 is more than 10 times higher than that of the control drug MK-1775. In particular, the compounds of the present invention have stronger combined activity with GMC, for example, the IC 50 of compound 11 is less than 1 nM. The compound of the present invention has strong combined activity with GMC, which indicates that it may have better effect in clinical combination with chemotherapeutic drugs.
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。Although the specific embodiments of the present invention have been described above, those skilled in the art should understand that these are only examples, and various changes may be made to these embodiments without departing from the principle and essence of the present invention. Revise. Accordingly, the scope of protection of the present invention is defined by the appended claims.

Claims (10)

  1. 一种如通式(1)所示的化合物、其光学异构体或其药学上可接受的盐：A compound represented by the general formula (1), an optical isomer or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022075545-appb-100001
    Figure PCTCN2022075545-appb-100001
    通式(1)中：In general formula (1):
    m为0或1；m is 0 or 1;
    n为0或1；n is 0 or 1;
    v为1、2或3；v is 1, 2 or 3;
    X 1和X 2独立为CH、N、CF、CCl或CMe； X 1 and X 2 are independently CH, N, CF, CCl or CMe;
    W为N或CH；W is N or CH;
    R 1为C1-C6烷基、卤素取代C1-C3烷基、C3-C6环烷基、C3-C6环烷基取代C1-C6烷基、C3-C5烯基或C3-C5炔基； R 1 is C1-C6 alkyl, halogen substituted C1-C3 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted C1-C6 alkyl, C3-C5 alkenyl or C3-C5 alkynyl;
    R 2a和R 2b独立为H或C1-C3烷基，或R 2a和R 2b连同其所连接的C原子形成C3-C6环烷基； R 2a and R 2b are independently H or C1-C3 alkyl, or R 2a and R 2b together with the C atom to which they are attached form a C3-C6 cycloalkyl;
    R 3a和R 3b独立为H或C1-C3烷基，或R 3a和R 3b连同其所连接的C原子形成C3-C6环烷基； R 3a and R 3b are independently H or C1-C3 alkyl, or R 3a and R 3b together with the C atom to which they are attached form a C3-C6 cycloalkyl;
    R 4为卤素、CN、C1-C6烷基、C1-C6烷氧基、N(C1-C6烷基) 2、NH(C1-C6烷基)、C1-C6烷硫基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、芳基、杂芳基或(4-12元)杂环烷基，所述C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基、C3-C6环烷基、芳基、杂芳基和(4-12元)杂环烷基可任选被1-3个下列基团所取代：H、卤素、OH、CN、C1-C3烷基、C3-C6环烷基、C1-C3烷氧基、卤素取代C1-C3烷基、CN取代C1-C3烷基、C3-C6环烷基取代C1-C3烷基、C1-C3烷氧基取代C1-C3烷基、卤素取代C1-C3烷氧基或(4-7元)杂环烷基； R 4 is halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, N(C1-C6 alkyl) 2 , NH(C1-C6 alkyl), C1-C6 alkylthio, C2-C6 alkene base, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl, heteroaryl or (4-12 membered) heterocycloalkyl, the C1-C6 alkyl, C1-C6 alkoxy, C1- C6 alkylthio, C3-C6 cycloalkyl, aryl, heteroaryl and (4-12 membered) heterocycloalkyl can be optionally substituted with 1-3 of the following groups: H, halogen, OH, CN , C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen substituted C1-C3 alkyl, CN substituted C1-C3 alkyl, C3-C6 cycloalkyl substituted C1-C3 alkyl, C1-C3 alkoxy substituted C1-C3 alkyl, halogen substituted C1-C3 alkoxy or (4-7 membered) heterocycloalkyl;
    R 5和R 6独立为C1-C3烷基、氘代C1-C3烷基、C2-C6烯基、C2-C6炔基或C3-C6环烷基，或者R 5和R 6连同其所连接的原子形成(3-10元)杂环烷基； R 5 and R 6 are independently C1-C3 alkyl, deuterated C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl, or R 5 and R 6 together with which they are attached The atoms form (3-10 membered) heterocycloalkyl;
    每个R 7独立为H、卤素、CN、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、卤素取代C1-C6烷基或卤素取代C1-C6烷氧基； each R is independently H, halogen, CN, C1 - C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen-substituted C1-C6 alkyl, or halogen-substituted C1-C6 alkoxy;
    R 8为H、C1-C6烷基、C3-C6环烷基、氘代C1-C6烷基、卤素取代C1-C6烷基、CN取代C1-C6烷基、OH取代C1-C6烷基、C1-C3烷氧基取代C1-C6烷基、C3-C6环烷基取代C1-C6烷基或(4-7元)杂环烷基。 R 8 is H, C1-C6 alkyl, C3-C6 cycloalkyl, deuterated C1-C6 alkyl, halogen substituted C1-C6 alkyl, CN substituted C1-C6 alkyl, OH substituted C1-C6 alkyl, C1-C3 alkoxy substituted C1-C6 alkyl, C3-C6 cycloalkyl substituted C1-C6 alkyl or (4-7 membered) heterocycloalkyl.
  2. 如权利要求1所述的化合物、其光学异构体或其药学上可接受的盐，其中所述通式(1)中，
    Figure PCTCN2022075545-appb-100002
    为
    Figure PCTCN2022075545-appb-100003
    Figure PCTCN2022075545-appb-100004
    Figure PCTCN2022075545-appb-100005
    其中R 4为卤素、CN、C1-C6烷基、C1-C6烷氧基、N(C1-C6烷基) 2、NH(C1-C6烷基)、C1-C6烷硫基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、芳基、杂芳基或(4-12元)杂环烷基，所述C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基、C3-C6环烷基、芳基、杂芳基和(4-12元)杂环烷基可任选被1-3个下列基团所取代：H、卤素、OH、CN、C1-C3烷基、C3-C6环烷基、C1-C3烷氧基、卤素取代C1-C3烷基、CN取代C1-C3烷基、C3-C6环烷基取代C1-C3烷基、C1-C3烷氧基取代C1-C3烷基、卤素取代C1-C3烷氧基或(4-7元)杂环烷基；R 8为H、C1-C6烷基、C3-C6环烷基、氘代C1-C6烷基、卤素取代C1-C6烷基、CN取代C1-C6烷基、OH取代C1-C6烷基、C1-C3烷氧基取代C1-C6烷基、C3-C6环烷基取代C1-C6烷基或(4-7元)杂环烷基。     The compound of claim 1, an optical isomer or a pharmaceutically acceptable salt thereof, wherein in the general formula (1),
    Figure PCTCN2022075545-appb-100002
    for
    Figure PCTCN2022075545-appb-100003
    Figure PCTCN2022075545-appb-100004
    Figure PCTCN2022075545-appb-100005
    Wherein R 4 is halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, N(C1-C6 alkyl) 2 , NH(C1-C6 alkyl), C1-C6 alkylthio, C2-C6 Alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl, heteroaryl or (4-12 membered) heterocycloalkyl, the C1-C6 alkyl, C1-C6 alkoxy, C1 -C6 alkylthio, C3-C6 cycloalkyl, aryl, heteroaryl and (4-12 membered) heterocycloalkyl can be optionally substituted by 1-3 of the following groups: H, halogen, OH, CN, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen substituted C1-C3 alkyl, CN substituted C1-C3 alkyl, C3-C6 cycloalkyl substituted C1-C3 alkyl , C1-C3 alkoxy substituted C1-C3 alkyl, halogen substituted C1-C3 alkoxy or (4-7 member) heterocycloalkyl; R 8 is H, C1-C6 alkyl, C3-C6 cycloalkane base, deuterated C1-C6 alkyl, halogen substituted C1-C6 alkyl, CN substituted C1-C6 alkyl, OH substituted C1-C6 alkyl, C1-C3 alkoxy substituted C1-C6 alkyl, C3-C6 Cycloalkyl substituted C1-C6 alkyl or (4-7 membered) heterocycloalkyl.
  3. 如权利要求1所述的化合物、其光学异构体或其药学上可接受的盐，其中所述化合物具有通式(1A)所示的结构：The compound of claim 1, an optical isomer or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by the general formula (1A):
    Figure PCTCN2022075545-appb-100006
    Figure PCTCN2022075545-appb-100006
    通式(1A)中:In general formula (1A):
    v为1、2或3；v is 1, 2 or 3;
    W为N或CH；W is N or CH;
    R 1为C1-C6烷基、卤素取代C1-C3烷基、C3-C6环烷基、C3-C6环烷基取代C1-C6烷基、C3-C5烯基或C3-C5炔基； R 1 is C1-C6 alkyl, halogen substituted C1-C3 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted C1-C6 alkyl, C3-C5 alkenyl or C3-C5 alkynyl;
    R 2a和R 2b独立为H或C1-C3烷基，或R 2a和R 2b共所连的C原子形成C3-C6环烷基； R 2a and R 2b are independently H or C1-C3 alkyl, or the C atoms to which R 2a and R 2b are connected together form a C3-C6 cycloalkyl;
    R 4为卤素、CN、C1-C6烷基、C1-C6烷氧基、N(C1-C6烷基) 2、NH(C1-C6烷基)、C1-C6烷硫基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、芳基、杂芳基或(4-12元)杂环烷基，所述C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基、C3-C6环烷基、芳基、杂芳基和(4-12元)杂环烷基可任选被1-3个下列基团所取代：H、卤素、OH、CN、C1-C3烷基、C3-C6环烷基、C1-C3烷氧基、卤素取代C1-C3烷基、CN取代C1-C3烷基、C3-C6环烷基取代C1-C3烷基、C1-C3烷氧基取代C1-C3烷基、卤素取代C1-C3烷氧基或(4-7元)杂环烷基； R 4 is halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, N(C1-C6 alkyl) 2 , NH(C1-C6 alkyl), C1-C6 alkylthio, C2-C6 alkene base, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl, heteroaryl or (4-12 membered) heterocycloalkyl, the C1-C6 alkyl, C1-C6 alkoxy, C1- C6 alkylthio, C3-C6 cycloalkyl, aryl, heteroaryl and (4-12 membered) heterocycloalkyl can be optionally substituted with 1-3 of the following groups: H, halogen, OH, CN , C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen substituted C1-C3 alkyl, CN substituted C1-C3 alkyl, C3-C6 cycloalkyl substituted C1-C3 alkyl, C1-C3 alkoxy substituted C1-C3 alkyl, halogen substituted C1-C3 alkoxy or (4-7 membered) heterocycloalkyl;
    R 5和R 6独立为C1-C3烷基、氘代C1-C3烷基、C2-C6烯基、C2-C6炔基和C3-C6环烷基，或者R 5和R 6连同其所连接的原子形成(3-10元)杂环烷基； R 5 and R 6 are independently C1-C3 alkyl, deuterated C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C3-C6 cycloalkyl, or R 5 and R 6 together with the ones to which they are attached The atoms form (3-10 membered) heterocycloalkyl;
    R 7为H、卤素、CN、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、卤素取代C1-C6烷基或卤素取代C1-C6烷氧基； R 7 is H, halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen substituted C1-C6 alkyl or halogen substituted C1-C6 alkoxy;
    R 8为H、C1-C6烷基、C3-C6环烷基、氘代C1-C6烷基、卤素取代C1-C6烷基、CN取代C1-C6烷基、OH取代C1-C6烷基、C1-C3烷氧基取代C1-C6烷基、C3-C6环烷基取代C1-C6烷基或(4-7元)杂环烷基。 R 8 is H, C1-C6 alkyl, C3-C6 cycloalkyl, deuterated C1-C6 alkyl, halogen substituted C1-C6 alkyl, CN substituted C1-C6 alkyl, OH substituted C1-C6 alkyl, C1-C3 alkoxy substituted C1-C6 alkyl, C3-C6 cycloalkyl substituted C1-C6 alkyl or (4-7 membered) heterocycloalkyl.
  4. 如权利要求1-3中任一项所述的化合物、其光学异构体或其药学上可接受的盐，其中所述通式(1)或通式(1A)中，R 1为Me、Et、
    Figure PCTCN2022075545-appb-100007
    Figure PCTCN2022075545-appb-100008
    The compound according to any one of claims 1-3, its optical isomer or its pharmaceutically acceptable salt, wherein in said general formula (1) or general formula (1A), R 1 is Me, Et,
    Figure PCTCN2022075545-appb-100007
    Figure PCTCN2022075545-appb-100008
  5. 如权利要求1-4中任一项所述的化合物、其光学异构体或其药学上可接受的盐，其中所述通式(1)或通式(1A)中，
    Figure PCTCN2022075545-appb-100009
    为
    Figure PCTCN2022075545-appb-100010
    Figure PCTCN2022075545-appb-100011
    The compound of any one of claims 1-4, its optical isomer or a pharmaceutically acceptable salt thereof, wherein in said general formula (1) or general formula (1A),
    Figure PCTCN2022075545-appb-100009
    for
    Figure PCTCN2022075545-appb-100010
    Figure PCTCN2022075545-appb-100011
  6. 如权利要求1-5中任一项所述的化合物、其光学异构体或其药学上可接受的盐，其中所述通式(1)或通式(1A)中，R 4为Me、Et、CF 3、CHF 2、F、Cl、Br、I、CN、OMe、OEt、CN、SMe、SEt、OCF 3、NMe 2、NHMe、
    Figure PCTCN2022075545-appb-100012
    Figure PCTCN2022075545-appb-100013
    The compound according to any one of claims 1-5, its optical isomer or a pharmaceutically acceptable salt thereof, wherein in said general formula (1) or general formula (1A), R 4 is Me, Et, CF3 , CHF2 , F, Cl , Br, I, CN, OMe, OEt, CN, SMe, SEt, OCF3, NMe2 , NHMe,
    Figure PCTCN2022075545-appb-100012
    Figure PCTCN2022075545-appb-100013
    Figure PCTCN2022075545-appb-100014
    Figure PCTCN2022075545-appb-100014
  7. 如权利要求1-5中任一项所述的化合物、其光学异构体或其药学上可接受的盐，其中所述通式(1)或通式(1A)中，R 8为H、Me、Et、CD 3、
    Figure PCTCN2022075545-appb-100015
    Figure PCTCN2022075545-appb-100016
    The compound according to any one of claims 1-5, its optical isomer or a pharmaceutically acceptable salt thereof, wherein in said general formula (1) or general formula (1A), R 8 is H, Me, Et, CD 3 ,
    Figure PCTCN2022075545-appb-100015
    Figure PCTCN2022075545-appb-100016
  8. 如权利要求1-7中任一项所述的化合物、其光学异构体或其药学上可接受的盐，其中所述化合物具有以下结构之一：The compound of any one of claims 1-7, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound has one of the following structures:
    Figure PCTCN2022075545-appb-100017
    Figure PCTCN2022075545-appb-100017
    Figure PCTCN2022075545-appb-100018
    Figure PCTCN2022075545-appb-100018
    Figure PCTCN2022075545-appb-100019
    Figure PCTCN2022075545-appb-100019
    Figure PCTCN2022075545-appb-100020
    Figure PCTCN2022075545-appb-100020
    Figure PCTCN2022075545-appb-100021
    Figure PCTCN2022075545-appb-100021
    Figure PCTCN2022075545-appb-100022
    Figure PCTCN2022075545-appb-100022
  9. 一种药物组合物，其特征在于，其含有药学上可接受的赋形剂或载体，以及如权利要求1-8中任一项所述的化合物、其光学异构体或其药学上可接受的盐作为活性成分。A pharmaceutical composition, characterized in that it contains a pharmaceutically acceptable excipient or carrier, and the compound as claimed in any one of claims 1-8, its optical isomer or its pharmaceutically acceptable of salt as the active ingredient.
  10. 一种如权利要求1-8中任一项所述的化合物、其光学异构体或其药学上可接受的盐或如权利要求9所述的药物组合物在制备Wee-1抑制剂中的应用。A compound as claimed in any one of claims 1-8, its optical isomer or a pharmaceutically acceptable salt thereof or the pharmaceutical composition as claimed in claim 9 in the preparation of Wee-1 inhibitor application.
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