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WO2022171126A1 - 作为Wee-1抑制剂的稠环化合物 - Google Patents

作为Wee-1抑制剂的稠环化合物 Download PDF

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Publication number
WO2022171126A1
WO2022171126A1 PCT/CN2022/075655 CN2022075655W WO2022171126A1 WO 2022171126 A1 WO2022171126 A1 WO 2022171126A1 CN 2022075655 W CN2022075655 W CN 2022075655W WO 2022171126 A1 WO2022171126 A1 WO 2022171126A1
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Prior art keywords
alkyl
substituted
cycloalkyl
halogen
heterocycloalkyl
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PCT/CN2022/075655
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English (en)
French (fr)
Inventor
谢雨礼
樊后兴
钱立晖
Original Assignee
微境生物医药科技(上海)有限公司
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Priority to CN202280012622.9A priority Critical patent/CN116848117A/zh
Publication of WO2022171126A1 publication Critical patent/WO2022171126A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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 present invention relates to the field of medicinal chemistry, and more particularly, to a compound with Wee-1 kinase inhibitory effect, a preparation method thereof, and 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
  • X 1 and X 2 are independently CH or N;
  • R 1 is C1-C6 alkyl, halogen-substituted C1-C3 alkyl, C3-C6 cycloalkyl, -CH 2 (C3-C6) cycloalkyl, C3-C5 alkenyl or C3-C5 alkynyl;
  • R 2 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 members) heterocycloalkyl;
  • R 3 is H or C1-C3 alkyl
  • B is partially unsaturated C5-C7 cycloalkyl or partially unsaturated (5-7 membered) heterocycloalkyl.
  • the present invention provides a compound represented by the general formula (2), an optical isomer or a pharmaceutically acceptable salt thereof:
  • n 0 or 1
  • X 1 and X 2 are independently CH or N;
  • R 1 is C1-C6 alkyl, halogen-substituted C1-C3 alkyl, C3-C6 cycloalkyl, -CH 2 (C3-C6) cycloalkyl, C3-C5 alkenyl or C3-C5 alkynyl;
  • R 2 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 members) heterocycloalkyl;
  • R 3 is H or C1-C3 alkyl
  • A is aryl or heteroaryl, which may be optionally substituted by 1-3 R 6 , each R 6 is independently H, halogen, CN, C1-C6 alkyl, C1-C6 Alkoxy, C3-C6 cycloalkyl, (3-10 member) heterocycloalkyl, halogen substituted C1-C6 alkyl, halogen substituted C1-C6 alkoxy, OH substituted C1-C6 alkyl, cyano substituted C1-C6 alkyl, halogen substituted C3-C6 cycloalkyl, hydroxy substituted C3-C6 cycloalkyl, cyano substituted C3-C6 cycloalkyl, CF 3 substituted C3-C6 cycloalkyl, C1-C6 alkyl substituted C3-C6 cycloalkyl, C1-C6 alkyl-substituted (3-10-membered) heterocycloalkyl, halogen
  • the present invention provides a compound represented by general formula (1A), an optical isomer or a pharmaceutically acceptable salt thereof:
  • n 0 or 1
  • n 1, 2 or 3;
  • X is CH 2 , O or S
  • X 1 and X 2 are independently CH or N;
  • R 1 is C1-C6 alkyl, halogen-substituted C1-C3 alkyl, C3-C6 cycloalkyl, -CH 2 (C3-C6) cycloalkyl, C3-C5 alkenyl or C3-C5 alkynyl;
  • R 2 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 members) heterocycloalkyl;
  • R 1 is Me, Et, R 1 is preferably R 1 is more preferably
  • A is phenyl, pyridyl, pyrimidinyl or pyrazinyl, the benzene base, pyridyl, pyrimidinyl and pyrazinyl can be optionally substituted with 1-3 R 6 , each R 6 is independently H, halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C3- C6 cycloalkyl, halogen substituted C1-C6 alkyl, halogen substituted C1-C6 alkoxy, OH substituted C1-C6 alkyl, cyano substituted C1-C6 alkyl, halogen substituted C3-C6 cycloalkyl, hydroxy substituted C3-C6 cycloalkyl, cyano substituted C3-C6 cycloalkyl, CF 3 substituted
  • A is wherein v is 1, 2 or 3 and each R is independently H, halogen, Me, Et, OMe, R 6 is preferably H, F, Cl, Br, I, Me, Et, OMe, R 6 is more preferably H, F, Cl, R 6 is more preferably F,
  • A is preferably more preferably more preferably
  • the above-mentioned compounds, isomers or pharmaceutically acceptable salts are selected from:
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent and/or excipient, and the compound represented by the general formula (1) of the present invention, its optical isomer body or a pharmaceutically acceptable salt thereof as the active ingredient.
  • Another object of the present invention is to provide the compound represented by the general formula (1), its optical isomer or its pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition of the present invention for preparing treatment, regulation or prevention with Wee- 1. Application of medicines for related diseases.
  • 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, its An optical isomer or a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition.
  • the fused-ring compound represented by the general formula (1) has a strong Wee-1 inhibitory activity and a combined administration activity with the chemotherapeutic drug Gemcitabine (GMC).
  • GMC chemotherapeutic drug
  • the above results show that , the compound of the present invention may have better effect in clinical combination with chemotherapeutic drugs.
  • 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 of general formula (1) can be obtained synthetically or from commercial sources such as, but not limited to, Aldrich Chemical Co. (Milwaukee, Wis.) or Sigma Chemical Co. (St. Louis, Mo.
  • 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 of general formula (1), which is 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 B8 are further reacted to form target compound A5.
  • A, B, X 1 , X 2 , R 1 , R 2 , R 3 and m are as defined above, Y is Br, I or -B(OH) 2 , W is
  • “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.
  • ring B is named as an independent group (not merging with other rings).
  • the B ring is condensed with an adjacent group.
  • 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.
  • 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 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.
  • Cancers that can be treated with the compounds of the present invention include, but are not limited to, hematological malignancies (leukemias, lymphomas, myeloma including multiple myeloma, myelodysplastic syndromes and myelodysplastic syndromes) and solid tumors (cancers such as prostate, breast , lung, colon, pancreas, kidney, ovary and soft tissue cancer and osteosarcoma, and stromal tumor) and so on.
  • hematological malignancies leukemias, lymphomas, myeloma including multiple myeloma, myelodysplastic syndromes and myelodysplastic syndromes
  • solid tumors cancers such as prostate, breast , lung, colon, pancreas, kidney, ovary and soft tissue cancer and osteosarcoma, and stromal tumor
  • 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 dose 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
  • CuI represents cuprous iodide
  • DCM represents dichloromethane
  • DIPEA represents diisopropylethylamine
  • dioxane represents 1,4-dioxane
  • DMF stands for N,N-dimethylformamide
  • EA stands for ethyl acetate
  • EtOH stands for ethanol
  • h stands for hours
  • H 2 stands for hydrogen
  • H 2 SO 4 stands for sulfuric acid
  • K 2 CO 3 stands for potassium carbonate
  • KNO 3 stands for nitric acid Potassium
  • LC-MS for liquid phase-mass spectrometry
  • LiAlH 4 for lithium aluminum hydride
  • m-CPBA for m-chloroperoxybenzoic acid
  • mL for milliliters
  • MeOH for methanol
  • min min for minutes
  • NaBH(OAc) 3 n BuLi stands for n-
  • intermediates A3-2 to A3-47 can be obtained.
  • B5-1 (4.9, 19.9 mmol) and palladium on carbon (2 g, 19.9 mmol, 10% purity) were suspended in methanol (100 mL) and reacted at 25°C for 16 hours under hydrogen pressure (50 psi).
  • Step 7 Preparation of Compound B7-2 and Compound B7-3:
  • the B7-1 (1.5g, 7.41mmol) was chiral resolved by prep SFC (SFC chiral resolution conditions: instrument: Waters SFC350; chromatographic column: DAICEL CHIRALPAK AD (250mm*50mm, 10um); mobile phase: A: CO 2 , B: IPA (0.1% NH 3 H 2 O); gradient: B%: 50%-50%; flow rate: 200 ml/min; The segment liquid was concentrated under reduced pressure and lyophilized to obtain yellow oil B7-2 (peak 1,438 mg, yield: 29.20%) and yellow oil B7-3 (peak 2, 450 mg, yield: 30.00%).
  • intermediates B7-4 to B7-49 can be obtained.
  • A3-1 (390 mg, 1.0 mmol) was dissolved in DCM (20 mL), m-CPBA (259 mg, 1.5 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 (390 mg, 1.0 mmol) was dissolved in DCM (20 mL), m-CPBA (259 mg, 1.5 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 (390 mg, 1.0 mmol) was dissolved in DCM (20 mL), m-CPBA (259 mg, 1.5 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 saturated sodium bicarbonate solution, the organic phase was dried, spin-dried, and proceeded 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 IC 50 was calculated.
  • the compounds of the present invention have a strong inhibitory effect on Wee-1 kinase, such as compounds 1, 31, 87, 88, 89, 91 and other compounds.
  • the IC50 values of Wee-1 kinase are all less than 1.5nM, about 2 times higher than the control drug MK-1775.
  • 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 114 In vitro antiproliferative activity of compound combined with gemcitabine (Gemcitabine, GMC) on MIA PaCa-2 cells
  • the compound of the present invention has stronger anti-proliferative activity on MIA PaCa-2 cells, and the compound of the present invention has stronger combined activity with GMC, such as compound 34.
  • IC50 is less than 1 nM.
  • the compound of the present invention has stronger combined activity with GMC, which indicates that it may have better effect in clinical combination with chemotherapeutic drugs.

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Abstract

本发明公开了作为Wee-1抑制剂的稠环化合物。具体的，本发明涉及一种通式(1)所示的化合物及其制备方法，及通式(1)化合物及其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物作为Wee-1抑制剂在抗肿瘤药物制备中的用途。

Description

作为Wee-1抑制剂的稠环化合物
本申请要求申请日为2021年2月9日的中国申请CN202110179656.4和2021年7月5日的中国申请CN202110757479.3的优先权。本申请引用上述中国申请的全文。
技术领域
本发明涉及药物化学领域，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。
背景技术
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(细胞分裂准备期)到M(细胞分裂期)期转变的G2期检查点以及M期metaphase(细胞分裂期中期)到anaphase(细胞分裂期后期)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(细胞分裂期)。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。
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。
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，宫颈癌，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。
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。
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。
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。
发明内容
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：
Figure PCTCN2022075655-appb-000001
通式(1)中：
m为0或1；
X 1和X 2独立为CH或N；
R 1为C1-C6烷基、卤素取代C1-C3烷基、C3-C6环烷基、-CH 2(C3-C6)环烷基、C3-C5烯基或C3-C5炔基；
R 2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 3为H或C1-C3烷基；
A为芳基或杂芳基，所述芳基和杂芳基可任选被1-3个R 6取代，每个R 6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、卤素取代C1-C6烷氧基、OH取代C1-C6烷基、氰基取代C1-C6烷基、卤素取代C3-C6环烷基、羟基取代C3-C6环烷基、氰基取代C3-C6环烷基、CF 3取代C3-C6环烷基、-NR 7aR 7b、-N＝S(O)R 7aR 7b、-P(O)R 7aR 7b、-S(O) 2R 7a、-S(O) 2NR 7aR 7b、-NR 8P(O)R 7aR 7b、-NR 8S(O) 2R 7a、-NR 8C(O)R 7a、-N＝S(＝NR 8)R 7aR 7b或吡啶酮基，其中R 7a和R 7b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 7a和R 7b连同其所连接的原子形成(3-10元)杂环烷基，R 8为H或C1-C3烷基，或者R 8和R 7a连同其所连接的原子形成(3-10元)杂环烷基；
B为部分不饱和的C5-C7环烷基或部分不饱和的(5-7元)杂环烷基。
本发明提供了一种如通式(2)所示的化合物、其光学异构体或其药学上可接受的盐：
Figure PCTCN2022075655-appb-000002
通式(2)中：
m为0或1；
X 1和X 2独立为CH或N；
R 1为C1-C6烷基、卤素取代C1-C3烷基、C3-C6环烷基、-CH 2(C3-C6)环烷基、C3-C5烯基或C3-C5炔基；
R 2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 3为H或C1-C3烷基；
A为芳基或杂芳基，所述芳基和杂芳基可任选被1-3个R 6取代，每个R 6独立为H、卤素、CN、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、(3-10元)杂环烷基、卤素取代C1-C6烷基、卤素取代C1-C6烷氧基、OH取代C1-C6烷基、氰基取代C1-C6烷基、卤素取代C3-C6环烷基、羟基取代C3-C6环烷基、氰基取代C3-C6环烷基、CF 3取代C3-C6环烷基、C1-C6烷基取代C3-C6环烷基、C1-C6烷基取代(3-10元)杂环烷基、卤素取 代(3-10元)杂环烷基、羟基取代(3-10元)杂环烷基、-NR 7aR 7b、-N＝S(O)R 7aR 7b、-P(O)R 7aR 7b、-S(O) 2R 7a、-S(O) 2NR 7aR 7b、-NR 8P(O)R 7aR 7b、-NR 8S(O) 2R 7a、-NR 8C(O)R 7a、-N＝S(＝NR 8)R 7aR 7b或吡啶酮基，其中R 7a和R 7b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 7a和R 7b连同其所连接的原子形成(3-10元)杂环烷基，R 8为H或C1-C3烷基，或者R 8和R 7a连同其所连接的原子形成(3-10元)杂环烷基；B为部分不饱和的C5-C7环烷基、部分不饱和的(5-7元)杂环烷基或C1-C6烷基取代的部分不饱和的(5-7元)杂环烷基。
本发明提供了一种如通式(1A)所示的化合物、其光学异构体或其药学上可接受的盐：
Figure PCTCN2022075655-appb-000003
通式(1A)中:
m为0或1；
n为1、2或3；
X为CH 2、O或S；
X 1和X 2独立为CH或N；
R 1为C1-C6烷基、卤素取代C1-C3烷基、C3-C6环烷基、-CH 2(C3-C6)环烷基、C3-C5烯基或C3-C5炔基；
R 2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；
A为芳基或杂芳基，所述芳基和杂芳基可任选被1-3个R 6取代，每个R 6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、卤素取代C1-C6烷氧基、OH取代C1-C6烷基、氰基取代C1-C6烷基、卤素取代C3-C6环烷基、羟基取代C3-C6环烷基、氰基取代C3-C6环烷基、CF 3取代C3-C6环烷基、-NR 7aR 7b、-N＝S(O)R 7aR 7b、-P(O)R 7aR 7b、-S(O) 2R 7a、-S(O) 2NR 7aR 7b、-NR 8P(O)R 7aR 7b、-NR 8S(O) 2R 7a、-NR 8C(O)R 7a、-N＝S(＝NR 8)R 7aR 7b或吡啶酮基，其中R 7a和R 7b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 7a和R 7b连同其所连接的原子形成(3-10元)杂环烷基，R 8为H或C1-C3烷基，或者R 8和R 7a连 同其所连接的原子形成(3-10元)杂环烷基。
本发明的一些方案中，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，R 1为Me、Et、
Figure PCTCN2022075655-appb-000004
Figure PCTCN2022075655-appb-000005
R 1优选为
Figure PCTCN2022075655-appb-000006
R 1更优选为
Figure PCTCN2022075655-appb-000007
本发明的一些方案中，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为苯基、吡啶基、嘧啶基或吡嗪基，所述苯基、吡啶基、嘧啶基和吡嗪基可任选被1-3个R 6取代，每个R 6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、卤素取代C1-C6烷氧基、OH取代C1-C6烷基、氰基取代C1-C6烷基、卤素取代C3-C6环烷基、羟基取代C3-C6环烷基、氰基取代C3-C6环烷基、CF 3取代C3-C6环烷基、-NR 7aR 7b、-N＝S(O)R 7aR 7b、-P(O)R 7aR 7b、-S(O) 2R 7a、-S(O) 2NR 7aR 7b、-NR 8P(O)R 7aR 7b、-NR 8S(O) 2R 7a、-NR 8C(O)R 7a、-N＝S(＝NR 8)R 7aR 7b或吡啶酮基，其中R 7a和R 7b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 7a和R 7b连同其所连接的原子形成(3-10元)杂环烷基，R 8为H或C1-C3烷基，或者R 8和R 7a连同其所连接的原子形成(3-10元)杂环烷基。
本发明的一些方案中，其中所述通式(1)中，A为
Figure PCTCN2022075655-appb-000008
Figure PCTCN2022075655-appb-000009
其中v为1、2或3，每个R 6独立为H、卤素、Me、Et、OMe、
Figure PCTCN2022075655-appb-000010
Figure PCTCN2022075655-appb-000011
Figure PCTCN2022075655-appb-000012
Figure PCTCN2022075655-appb-000013
R 6优选为H、F、Cl、Br、I、Me、Et、OMe、
Figure PCTCN2022075655-appb-000014
Figure PCTCN2022075655-appb-000015
R 6更优选为H、F、Cl、
Figure PCTCN2022075655-appb-000016
Figure PCTCN2022075655-appb-000017
Figure PCTCN2022075655-appb-000018
R 6更优选为F、
Figure PCTCN2022075655-appb-000019
Figure PCTCN2022075655-appb-000020
本发明的一些方案中，其中所述通式(1)中，A为
Figure PCTCN2022075655-appb-000021
Figure PCTCN2022075655-appb-000022
Figure PCTCN2022075655-appb-000023
Figure PCTCN2022075655-appb-000024
优选为
Figure PCTCN2022075655-appb-000025
Figure PCTCN2022075655-appb-000026
Figure PCTCN2022075655-appb-000027
Figure PCTCN2022075655-appb-000028
更优选为
Figure PCTCN2022075655-appb-000029
Figure PCTCN2022075655-appb-000030
Figure PCTCN2022075655-appb-000031
更优选 为
Figure PCTCN2022075655-appb-000032
Figure PCTCN2022075655-appb-000033
本发明的一些方案中，其中所述通式(1)中，
Figure PCTCN2022075655-appb-000034
为
Figure PCTCN2022075655-appb-000035
Figure PCTCN2022075655-appb-000036
Figure PCTCN2022075655-appb-000037
Figure PCTCN2022075655-appb-000038
其中R 2为H、Me、Et、CD 3、
Figure PCTCN2022075655-appb-000039
Figure PCTCN2022075655-appb-000040
本发明的一些方案中，其中所述通式(1)中，
Figure PCTCN2022075655-appb-000041
为
Figure PCTCN2022075655-appb-000042
Figure PCTCN2022075655-appb-000043
Figure PCTCN2022075655-appb-000044
Figure PCTCN2022075655-appb-000045
优选为
Figure PCTCN2022075655-appb-000046
Figure PCTCN2022075655-appb-000047
Figure PCTCN2022075655-appb-000048
Figure PCTCN2022075655-appb-000049
更优选为
Figure PCTCN2022075655-appb-000050
Figure PCTCN2022075655-appb-000051
Figure PCTCN2022075655-appb-000052
更优选为
Figure PCTCN2022075655-appb-000053
本发明的一些方案中，上述化合物、异构体或药学上可接受的盐，其选自：
Figure PCTCN2022075655-appb-000054
Figure PCTCN2022075655-appb-000055
Figure PCTCN2022075655-appb-000056
Figure PCTCN2022075655-appb-000057
Figure PCTCN2022075655-appb-000058
Figure PCTCN2022075655-appb-000059
Figure PCTCN2022075655-appb-000060
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)所示的化合物、其光学异构体或其药学上可接受的盐作为活性成分。
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、其光学异构体或其药学上可接受的盐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。
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、其光学异构体或其药学上 可接受的盐或上述药物组合物。
本发明人通过充分的研究发现，结构如通式(1)所示稠环化合物具有很强的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。
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。
化合物的合成
下面具体地描述本发明通式(1)所示的化合物的制备方法，但这些具体方法不对本发明构成任何限制。
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。用于通式(1)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，如，但不限于Aldrich Chemical Co.(Milwaukee，Wis.)或Sigma Chemical Co.(St.Louis，Mo.)。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。
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)化合物的制备方法，其采用下列方法A制备：
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B8进一步反应生成目标化合物A5。
Figure PCTCN2022075655-appb-000061
上述反应方程式中，A、B、X 1、X 2、R 1、R 2、R 3和m的定义如前所述，Y为Br、I或-B(OH) 2，W为
Figure PCTCN2022075655-appb-000062
化合物的进一步形式
“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。
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。
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。
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。
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。
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。
术语
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”。
除非另有规定，为了化合物命名的方便起见，本申请中对B环的定义，是假设B环作为一个独立的基团(没有和其他环并环)来命名。在通式(1)中，B环是和相邻的基团稠合。
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。
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。
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。
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。
除非另有规定，“环烷基”是指非芳香族烃环系统(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。
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。
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。
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、三唑基、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 PCTCN2022075655-appb-000063
除非另有规定，“杂环烷基”指非芳香族环或环系统，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)环系统。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 PCTCN2022075655-appb-000064
Figure PCTCN2022075655-appb-000065
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。
“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。
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 PCTCN2022075655-appb-000066
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。
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。
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。
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。
除非另有说明，用楔形实线键
Figure PCTCN2022075655-appb-000067
和楔形虚线键
Figure PCTCN2022075655-appb-000068
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022075655-appb-000069
和直形虚线键
Figure PCTCN2022075655-appb-000070
表示立体中心的相对构型，用波浪线
Figure PCTCN2022075655-appb-000071
表示楔形实线键
Figure PCTCN2022075655-appb-000072
或楔形虚线键
Figure PCTCN2022075655-appb-000073
或用波浪线
Figure PCTCN2022075655-appb-000074
表示直形实线键
Figure PCTCN2022075655-appb-000075
或直形虚线键
Figure PCTCN2022075655-appb-000076
除非另有说明，用
Figure PCTCN2022075655-appb-000077
表示单键或双键。
特定药学及医学术语
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。
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。
“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。
“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。
“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。
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。
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。
治疗用途
本发明描述的化合物或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。
可用本发明化合物治疗的癌症包括但不限于，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(癌例如前列腺、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。
给药途径
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。
“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 PCTCN2022075655-appb-000078
)、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。
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。
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、蔗糖和阿拉伯胶；(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。
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。
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。
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。
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。
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。
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。
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。
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。
具体实施方式
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。
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。
本发明采用下述缩略词：CDCl 3代表氘代氯仿；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；DMF代表N,N-二甲基甲酰胺，EA代表乙酸乙酯；EtOH代表乙醇；h代表小时；H 2代表氢气；H 2SO 4代表硫酸；K 2CO 3代表碳酸钾；KNO 3代表硝酸钾；LC-MS代表液相-质谱；LiAlH 4代表氢化铝锂；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； nBuLi代表正丁基锂；NMR代表核磁共振；℃代表摄氏度；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，T 3P代表丙基磷酸酐。
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
Figure PCTCN2022075655-appb-000079
步骤1：化合物A0-1的合成
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] +。
步骤2：化合物A1-1的合成
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] +。
步骤3：化合物A3-1的合成
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] +。
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A3-47。
表1.中间体A3-2至A3-47的结构式
Figure PCTCN2022075655-appb-000080
Figure PCTCN2022075655-appb-000081
Figure PCTCN2022075655-appb-000082
Figure PCTCN2022075655-appb-000083
制备例2 2-甲基-2,3,7,8,9,9a-六氢-1H-苯丙[de]异喹啉-5-胺(中间体B7-1)的制备
Figure PCTCN2022075655-appb-000084
步骤1：化合物B2-1的合成:
将B1-1(50g,284mmol)，甲胺盐酸盐(57.5g,851mmol)和TEA(144g,1.42mol,197mL)溶于乙腈(600mL)中，室温下滴加T 3P(217g,341mmol,203mL,50％purity)，加毕，加热到50℃反应16小时。反应液用1500mL乙酸乙酯稀释，并用NaHCO 3水溶液(400mL*3)洗涤，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物为白色固体(50g,264mmol,收率:93.1％)。粗产物可直接用于下一步反应。
1H NMR:(400MHz,CDCl 3)δ:7.12-7.01(m,3H),6.10-5.71(m,1H),2.93(d,J＝4.9Hz,3H),2.83(br s,2H),2.79-2.71(m,2H),1.84-1.65(m,4H),MS(ESI):190.1[M+H] +.
步骤2：化合物B3-1的合成:
B2-1(50g,264mmol)溶于THF(500mL)中，氮气保护下，在-23℃缓慢滴加n-BuLi(2.5M,275mL)。随后在-23℃缓慢滴加DMF(48.3g,660mmol,50.8mL)。然后在20℃缓慢滴加HCl溶液(6M,300mL)。反应液用水(100mL)稀释，乙酸乙酯(500mL*3)萃取，有机相用无水硫酸钠干燥。有机相过滤、减压浓缩得到黄色固体(55g,粗产物)。粗产物可直接用于下一步反应。
1H NMR:(400MHz,CDCl 3)δ:8.36-8.20(m,1H),7.46-7.32(m,2H),6.84(s,1H),3.63-3.52(m,3H),2.99-2.92(m,3H),2.75-2.69(m,2H),2.01-1.90(m,2H),MS(ESI):200.1[M+H] +.步骤3：化合物B4-1的合成:
B3-1(55g,276mmol)和20g钯碳悬浮于甲醇(800mL)中，氢气加压(50psi)下在30℃搅拌过夜。过滤除去钯碳，滤液减压浓缩，柱层析(SiO 2,PE/EtOAc＝1/0到3/1)得到黄色固体(38.5g,收率:69.3％)。
1H NMR:(400MHz,DMSO-d 6)δ:7.71-7.62(m,1H),7.28-7.20(m,2H),3.42(dd,J＝5.6,11.9Hz,1H),3.25(t,J＝12.5Hz,1H),3.13-2.99(m,4H),2.87-2.69(m,2H),2.06-1.90(m,2H),1.75-1.61(m,1H),1.41-1.22(m,1H),MS(ESI):202.1[M+H] +.
步骤4：化合物B5-1的合成:
B4-1(3.1g,19.2mmol)溶于H 2SO 4(300mL)中，在0℃下，3小时内缓慢加入KNO 3(17.9g,177mmol)，加毕升至室温搅拌2小时。TLC检测显示反应完毕。反应液用500mL水稀释，大量固体析出，过滤得到沉淀物，干燥后得到黄色固体(79g,粗产物)。粗产物可直接用于下一步反应，MS(ESI):247.1[M+H] +.
步骤5：化合物B6-1的合成:
B5-1(4.9,19.9mmol)和钯碳(2g,19.9mmol,10％purity)悬浮于甲醇(100mL)中，氢气加压(50psi)下在25℃反应16小时。过滤除去钯碳，滤液减压浓缩，柱层析(SiO 2,PE/EA＝1/0到1/2)得到黄色固体B6-1(1.44g,收率：33.5％)。
1H NMR:(400MHz,CDCl 3))δ:7.24(d,J＝2.3Hz,1H),6.56(d,J＝2.0Hz,1H),3.67(br s,2H),3.32-3.25(m,2H),3.19-3.13(m,3H),3.09-2.97(m,1H),2.81-2.65(m,2H),2.07-1.90(m,2H),1.78-1.62(m,1H),1.37-1.23(m,1H),MS(ESI):217.2[M+H] +.
步骤6：化合物B7-1的合成:
B6-1(7g,32.4mmol)溶于无水四氢呋喃(300ml)，在0℃加入LiAlH 4(6.14g,162mmol)。氮气保护下，混合物升温至25℃反应2小时。向反应液中缓慢加入水淬灭反应，期间保持反应液温度在0～10℃，反应液用800mL乙酸乙酯稀释，并用水(100mL*3)洗 涤，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物，粗产物柱层析(SiO 2,DCM/(MeOH+1％NH 4OH)＝10/0到10/1)得到黄色油状物(6.25g,收率:95.5％)。
1H NMR:(400MHz,CDCl 3)δ:6.31(s,1H),6.21(s,1H),3.88(d,J＝15.1Hz,1H),3.62-3.34(br s,2H),3.26(d,J＝15.1Hz,1H),2.98-2.69(m,4H),2.42(s,3H),2.03(t,J＝10.7Hz,1H),1.92(tdd,J＝3.4,6.5,13.1Hz,1H),1.88-1.75(m,2H),1.34-1.17(m,1H),MS(ESI):203.2[M+H] +.
步骤7：化合物B7-2和化合物B7-3的制备:
Figure PCTCN2022075655-appb-000085
将B7-1(1.5g,7.41mmol)用制备超临界流体色谱(prep SFC)进行手性拆分(SFC手性拆分条件：仪器：Waters SFC350；色谱柱：DAICEL CHIRALPAK AD(250mm*50mm,10um)；流动相：A:CO 2，B:IPA(0.1％NH 3H 2O)；梯度：B％:50％-50％；流速：200ml/min；柱温：40℃)，将分段液进行减压浓缩、冻干，得到黄色油状物B7-2(peak 1,438mg,收率：29.20％)和黄色油状物B7-3(peak 2,450mg,收率：30.00％)。
B7-2： 1H NMR:(400MHz,CDCl 3)δ:6.32(s,1H),6.22(s,1H),3.88(d,J＝15.1Hz,1H),3.48(br s,2H),3.26(br d,J＝15.1Hz,1H),2.93(dd,J＝4.6,10.5Hz,1H),2.90-2.80(m,1H),2.79-2.64(m,2H),2.42(s,3H),2.02(t,J＝10.7Hz,1H),1.92(dtd,J＝3.6,6.5,9.8Hz,1H),1.87-1.79(m,2H),1.36-1.15(m,1H)
MS(ESI):203.2[M+H] +.
B7-3： 1H NMR:(400MHz,CDCl 3)δ:6.32(s,1H),6.22(s,1H),3.87(d,J＝15.3Hz,1H),3.47(br s,2H),3.26(d,J＝15.1Hz,1H),2.93(dd,J＝4.8,10.6Hz,1H),2.89-2.80(m,1H),2.80-2.65(m,2H),2.42(s,3H),2.02(t,J＝10.7Hz,1H),1.97-1.88(m,1H),1.87-1.75(m,2H),1.35-1.17(m,1H),MS(ESI):203.2[M+H] +.
采用不同的原料，类似中间体B7-1的合成，可以得到中间体B7-4至B7-49。
表2.中间体B7-4至B7-49的结构式
Figure PCTCN2022075655-appb-000086
Figure PCTCN2022075655-appb-000087
Figure PCTCN2022075655-appb-000088
Figure PCTCN2022075655-appb-000089
实施例1 2-烯丙基-1-(6-((二甲基(氧代)-λ 6-磺胺烯)氨基)吡啶-2-基)-6-((2-甲基-2,3，7,8,9,9a-六氢-1H-苯并[de]异喹啉-5-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
Figure PCTCN2022075655-appb-000090
将A3-1(390mg,1.0mmol)溶于DCM(20mL)中，加入m-CPBA(259mg,1.5mmol)，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] +。
将上步所得中间体溶于DMF(20mL)溶解，加入三氟乙酸(0.3ml，4.0mmol)，B7-1(242mg,1.2mmol)，80℃反应过夜，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(72mg，收率13.2％)
1H NMR(400MHz,CDCl 3)δ:8.79(s,1H),7.65(t,J＝7.9Hz,1H),7.51(d,J＝9.8Hz,1H),7.35(d,J＝7.8Hz,1H),7.17(d,J＝17.4Hz,2H),6.66(dd,J＝8.0,0.7Hz,1H),5.63(ddt,J＝16.6,10.3,6.3Hz,1H),5.04-4.97(m,1H),4.89(dt,J＝6.2,1.3Hz,2H),3.94(d,J＝15.2Hz,1H),3.31(s,6H),3.02-2.71(m,5H),2.45(s,3H),2.01-1.76(m,5H),LC-MS:545.3[M+H] +.
实施例86 (R)-2-烯丙基-1-(6-((二甲基(氧代)-λ 6-磺胺烯)氨基)吡啶-2-基)-6-((2-甲基-2,3，7,8,9,9a-六氢-1H-苯并[de]异喹啉-5-基)氨基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(化合物86)的合成
Figure PCTCN2022075655-appb-000091
将A3-1(390mg,1.0mmol)溶于DCM(20mL)中，加入m-CPBA(259mg,1.5mmol)，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] +。
将上步所得中间体溶于DMF(20mL)溶解，加入三氟乙酸(0.3ml，4.0mmol)，B7-3(242mg,1.2mmol)，80℃反应过夜，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86(85mg，收率15.6％)
1H NMR(400MHz,CDCl 3)δ:8.79(s,1H),7.65(t,J＝7.9Hz,1H),7.51(d,J＝9.8Hz,1H),7.35(d,J＝7.8Hz,1H),7.17(d,J＝17.4Hz,2H),6.66(dd,J＝8.0,0.7Hz,1H),5.63(ddt,J＝16.6,10.3,6.3Hz,1H),5.04-4.97(m,1H),4.89(dt,J＝6.2,1.3Hz,2H),3.94(d,J＝15.2Hz,1H),3.31(s,6H),3.02-2.71(m,5H),2.45(s,3H),2.01-1.76(m,5H),LC-MS:545.2[M+H] +.
实施例89 (S)-2-烯丙基-1-(6-((二甲基(氧代)-λ 6-磺胺烯)氨基)吡啶-2-基)-6-((2-甲基-2,3，7,8,9,9a-六氢-1H-苯并[de]异喹啉-5-基)氨基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(化合物89)的合成
Figure PCTCN2022075655-appb-000092
将A3-1(390mg,1.0mmol)溶于DCM(20mL)中，加入m-CPBA(259mg,1.5mmol)，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] +。
将上步所得中间体溶于DMF(20mL)溶解，加入三氟乙酸(0.3ml，4.0mmol)，B7-2(242mg,1.2mmol)，80℃反应过夜，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89(82mg，收率15.0％)
1H NMR(400MHz,CDCl 3)δ:8.79(s,1H),7.65(t,J＝7.9Hz,1H),7.51(d,J＝9.8Hz,1H),7.35(d,J＝7.8Hz,1H),7.17(d,J＝17.4Hz,2H),6.66(dd,J＝8.0,0.7Hz,1H),5.63(ddt,J＝16.6,10.3,6.3Hz,1H),5.04-4.97(m,1H),4.89(dt,J＝6.2,1.3Hz,2H),3.94(d,J＝15.2Hz,1H),3.31(s,6H),3.02-2.71(m,5H),2.45(s,3H),2.01-1.76(m,5H),LC-MS:545.2[M+H] +.
实施例2-85、87-88、以及90-93化合物2-85、87-88以及90-111的合成
类似于化合物1的合成，采用中间体A3-1至A3-47和B7-1至B7-49为反应原料，可以得到表3中的目标化合物2-85、87-88以及90-111。
表3 化合物2-85、87-88以及90-93结构
Figure PCTCN2022075655-appb-000093
Figure PCTCN2022075655-appb-000094
Figure PCTCN2022075655-appb-000095
Figure PCTCN2022075655-appb-000096
Figure PCTCN2022075655-appb-000097
Figure PCTCN2022075655-appb-000098
Figure PCTCN2022075655-appb-000099
Figure PCTCN2022075655-appb-000100
实施例112 化合物抑制Wee-1酶活性测定
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。
表4.本发明化合物抑制Wee-1激酶活性的IC 50(nM)
Figure PCTCN2022075655-appb-000101
Figure PCTCN2022075655-appb-000102
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,如化合物1、31、87、88、89、91等化合物的对Wee-1激酶的IC 50值均小于1.5nM，比对照药物MK-1775提高了2倍左右。
实施例113 化合物对MIA PaCa-2细胞的体外抗增殖活性
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。
实施例114 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
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。
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
Figure PCTCN2022075655-appb-000103
Figure PCTCN2022075655-appb-000104
从表5数据可知，和对照药物MK-1775相比，本发明化合物对MIA PaCa-2细胞具有较强的抗增殖活性，同时本发明化合物具有更强的和GMC联用活性，如化合物34的IC 50小于1nM。本发明化合物具有和GMC更强的联用活性，预示其在临床上和化疗药物联用可能具有更好的效果。
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。

Claims (12)

  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：
    Figure PCTCN2022075655-appb-100001
    通式(1)中：
    m为0或1；
    X 1和X 2独立为CH或N；
    R 1为C1-C6烷基、卤素取代C1-C3烷基、C3-C6环烷基、-CH 2(C3-C6)环烷基、C3-C5烯基或C3-C5炔基；
    R 2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 3为H或C1-C3烷基；
    A为芳基或杂芳基，所述芳基和杂芳基可任选被1-3个R 6取代，每个R 6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、卤素取代C1-C6烷氧基、OH取代C1-C6烷基、氰基取代C1-C6烷基、卤素取代C3-C6环烷基、羟基取代C3-C6环烷基、氰基取代C3-C6环烷基、CF 3取代C3-C6环烷基、-NR 7aR 7b、-N＝S(O)R 7aR 7b、-P(O)R 7aR 7b、-S(O) 2R 7a、-S(O) 2NR 7aR 7b、-NR 8P(O)R 7aR 7b、-NR 8S(O) 2R 7a、-NR 8C(O)R 7a、-N＝S(＝NR 8)R 7aR 7b或吡啶酮基，其中R 7a和R 7b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 7a和R 7b连同其所连接的原子形成(3-10元)杂环烷基，R 8为H或C1-C3烷基，或者R 8和R 7a连同其所连接的原子形成(3-10元)杂环烷基；
    B为部分不饱和的C5-C7环烷基或部分不饱和的(5-7元)杂环烷基。
  2. 一种如通式(2)所示的化合物、其光学异构体或其药学上可接受的盐：
    Figure PCTCN2022075655-appb-100002
    通式(2)中：
    m为0或1；
    X 1和X 2独立为CH或N；
    R 1为C1-C6烷基、卤素取代C1-C3烷基、C3-C6环烷基、-CH 2(C3-C6)环烷基、C3-C5烯基或C3-C5炔基；
    R 2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 3为H或C1-C3烷基；
    A为芳基或杂芳基，所述芳基和杂芳基可任选被1-3个R 6取代，每个R 6独立为H、卤素、CN、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、(3-10元)杂环烷基、卤素取代C1-C6烷基、卤素取代C1-C6烷氧基、OH取代C1-C6烷基、氰基取代C1-C6烷基、卤素取代C3-C6环烷基、羟基取代C3-C6环烷基、氰基取代C3-C6环烷基、CF 3取代C3-C6环烷基、C1-C6烷基取代C3-C6环烷基、C1-C6烷基取代(3-10元)杂环烷基、卤素取代(3-10元)杂环烷基、羟基取代(3-10元)杂环烷基、-NR 7aR 7b、-N＝S(O)R 7aR 7b、-P(O)R 7aR 7b、-S(O) 2R 7a、-S(O) 2NR 7aR 7b、-NR 8P(O)R 7aR 7b、-NR 8S(O) 2R 7a、-NR 8C(O)R 7a、-N＝S(＝NR 8)R 7aR 7b或吡啶酮基，其中R 7a和R 7b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 7a和R 7b连同其所连接的原子形成(3-10元)杂环烷基，R 8为H或C1-C3烷基，或者R 8和R 7a连同其所连接的原子形成(3-10元)杂环烷基；
    B为部分不饱和的C5-C7环烷基、部分不饱和的(5-7元)杂环烷基或C1-C6烷基取代的部分不饱和的(5-7元)杂环烷基。
  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，其中所述化合物中具有如通式(1A)所述的结构：
    Figure PCTCN2022075655-appb-100003
    通式(1A)中:
    m为0或1；
    n为1、2或3；
    X为CH 2、O或S；
    X 1和X 2独立为CH或N；
    R 1为C1-C6烷基、卤素取代C1-C3烷基、C3-C6环烷基、-CH 2(C3-C6)环烷基、C3-C5烯基或C3-C5炔基；
    R 2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；
    A为芳基或杂芳基，所述芳基和杂芳基可任选被1-3个R 6取代，每个R 6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、卤素取代C1-C6烷氧基、OH取代C1-C6烷基、氰基取代C1-C6烷基、卤素取代C3-C6环烷基、羟基取代C3-C6环烷基、氰基取代C3-C6环烷基、CF 3取代C3-C6环烷基、-NR 7aR 7b、-N＝S(O)R 7aR 7b、-P(O)R 7aR 7b、-S(O) 2R 7a、-S(O) 2NR 7aR 7b、-NR 8P(O)R 7aR 7b、-NR 8S(O) 2R 7a、-NR 8C(O)R 7a、-N＝S(＝NR 8)R 7aR 7b或吡啶酮基，其中R 7a和R 7b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 7a和R 7b连同其所连接的原子形成(3-10元)杂环烷基，R 8为H或C1-C3烷基，或者R 8和R 7a连同其所连接的原子形成(3-10元)杂环烷基。
  4. 如权利要求1或2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，R 1为Me、Et、
    Figure PCTCN2022075655-appb-100004
    Figure PCTCN2022075655-appb-100005
  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)中，A为苯基、吡啶基、嘧啶基或吡嗪基，所述苯基、吡啶基、嘧啶基和吡嗪基可任选被1-3个R 6取代，每个R 6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、卤素取代C1-C6烷氧基、羟基取代C1-C6烷基、氰基取代C1-C6烷基、卤素取代C3-C6环烷基、OH取代C3-C6环烷基、氰基取代C3-C6环烷基、CF 3取代C3-C6环烷基、-NR 7aR 7b、-N＝S(O)R 7aR 7b、-P(O)R 7aR 7b、-S(O) 2R 7a、-S(O) 2NR 7aR 7b、-NR 8P(O)R 7aR 7b、-NR 8S(O) 2R 7a、-NR 8C(O)R 7a、-N＝S(＝NR 8)R 7aR 7b或吡啶酮基，其中R 7a和R 7b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 7a和R 7b连同其所连接的原子形成(3-10元)杂环烷基，R 8为H或C1-C3烷基，或者R 8和R 7a连同其所连接的原子形成(3-10元)杂环烷基。
  6. 如权利要求5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，A为
    Figure PCTCN2022075655-appb-100006
    其中v为1、2或3，每个R 6独立为H、卤素、Me、Et、OMe、
    Figure PCTCN2022075655-appb-100007
    Figure PCTCN2022075655-appb-100008
    Figure PCTCN2022075655-appb-100009
  7. 如权利要求6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，A为
    Figure PCTCN2022075655-appb-100010
    Figure PCTCN2022075655-appb-100011
    Figure PCTCN2022075655-appb-100012
  8. 如权利要求1或2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 PCTCN2022075655-appb-100013
    为
    Figure PCTCN2022075655-appb-100014
    Figure PCTCN2022075655-appb-100015
    Figure PCTCN2022075655-appb-100016
    Figure PCTCN2022075655-appb-100017
    其中R 2为H、Me、Et、CD 3、
    Figure PCTCN2022075655-appb-100018
    Figure PCTCN2022075655-appb-100019
    Figure PCTCN2022075655-appb-100020
  9. 如权利要求8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 PCTCN2022075655-appb-100021
    为
    Figure PCTCN2022075655-appb-100022
    Figure PCTCN2022075655-appb-100023
    Figure PCTCN2022075655-appb-100024
  10. 如权利要求1-9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：
    Figure PCTCN2022075655-appb-100025
    Figure PCTCN2022075655-appb-100026
    Figure PCTCN2022075655-appb-100027
    Figure PCTCN2022075655-appb-100028
    Figure PCTCN2022075655-appb-100029
    Figure PCTCN2022075655-appb-100030
  11. 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1-10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。
  12. 一种如权利要求1-10中任一项所述的化合物、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如权利要求11所述的药物组合物在制备Wee-1抑制剂中的应用。
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