WO2023280180A1 - 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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WO2023280180A1
WO2023280180A1 PCT/CN2022/104003 CN2022104003W WO2023280180A1 WO 2023280180 A1 WO2023280180 A1 WO 2023280180A1 CN 2022104003 W CN2022104003 W CN 2022104003W WO 2023280180 A1 WO2023280180 A1 WO 2023280180A1
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cycloalkyl
heterocycloalkyl
och
alkyl
haloalkyl
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PCT/CN2022/104003
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English (en)
French (fr)
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谢雨礼
吴应鸣
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 CN202280047404.9A priority Critical patent/CN117616029A/zh
Publication of WO2023280180A1 publication Critical patent/WO2023280180A1/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 specifically relates to a class of fused ring compounds with Wee1 kinase inhibitory effect, a preparation method thereof and the use of such compounds in the preparation of drugs for treating or preventing related diseases mediated by Wee1 Applications.
  • Wee-1 protein kinase is an important negative regulatory protein in cell cycle checkpoints.
  • Cell cycle checkpoints include the G1 phase checkpoint for the transition from G1 (cell resting phase) to the S phase (DNA synthesis phase), the G2 phase checkpoint for the transition from G2 (cell division preparation phase) to the M (cell division phase) phase, and the M The spindle checkpoint for the metaphase (middle phase of cell division) to anaphase (late phase of cell division) transition.
  • Wee-1 protein kinase plays an important role in the G2 phase checkpoint. The entry of cells into the M phase depends on the activity of CDK1 kinase.
  • Wee-1 inhibits the activity of CDK1 by phosphorylating Tyr 15 of the CDK1 protein, preventing cells from entering the M phase (cell division phase). Polo kinase kinase phosphorylates Wee-1, activates the degradation of Wee-1 protein, and promotes cells to enter the M phase. It can be seen that the activity of Wee-1 kinase determines the activity of G2 checkpoint, and then regulates the transition from G2 to M phase of cells [Cell Cycle, 2013.12(19): p.3159-64.].
  • Cell cycle checkpoints are mainly activated after DNA damage and play an important role in the repair of DNA in cells. Normal activation of cell cycle checkpoints arrests the cell cycle and promotes DNA repair. Inhibit the function of the checkpoint, the DNA damage cannot be repaired, and the cell undergoes apoptosis. Compared with normal cells, a variety of tumor cells mainly rely on the activation of G2 checkpoints to repair DNA damage and avoid apoptosis due to the impaired function of the important protein p53 in 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 the entry of unrepaired tumor cells into M2 after DNA damage. period, induce apoptosis [Curr Clin Pharmacol, 2010.5(3):p.186-91.].
  • 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 [J Cell Biol, 2011. 194(4): p.567-79.].
  • a large number of tumors including liver cancer, breast cancer, cervical cancer, melanoma and lung cancer [PLoS One, 2009.4(4): p.e5120.; Hepatology, 2003.37(3): p.534-43.; Mol Cancer, 2014.13 :p.72.]
  • the expression of Wee-1 was greatly increased.
  • Wee-1 kinase may be involved in the occurrence and development of tumor.
  • Studies on 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 [Cancer Biol Ther, 2010.9(7): p.514-22.; Mol Cancer Ther, 2009.8(11): p.2992-3000.].
  • the present invention provides a compound represented by general formula (1) or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • X is CH or N
  • Ring A is (C5-C11) partially unsaturated cycloalkyl or (5-11) partially unsaturated heterocycloalkyl;
  • Each R 1 is independently -H, -D, halogen, -OH, -(CH 2 ) n OR 8 , -(CH 2 ) n NR 8 R 9 , -OR 8 , -NR 8 R 9 , -CN , -C(O)NR 8 R 9 , -NR 9 C(O)R 8 , -NR 9 S(O) 2 R 8 , -S(O) p R 8 , -S(O) 2 NR 8 R 9 , (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl or (C3-C9) cycloalkyl, wherein said alkyl, haloalkyl, Alkenyl, alkynyl and cycloalkyl groups can each independently be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, halogen, R 8 , -
  • Y 1 is N or CR 4 ;
  • Y 2 is N or CR 5 ;
  • Y 3 is N or CR 6 ;
  • R 4 , R 5 and R 6 are each independently -H, -D, halogen, -OH, -(CH 2 ) n OR 8 , -(CH 2 ) n NR 8 R 9 , -OR 8 , -NR 8 R 9 , -CN, -C(O)NR 8 R 9 , -NR 9 C(O)R 8 , -NR 9 S(O) 2 R 8 , -S(O) p R 8 , -S(O ) 2 NR 8 R 9 , (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl or (C3-C9) cycloalkyl, wherein The alkyl, haloalkyl, alkenyl, alkynyl and cycloalkyl groups can each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen
  • Ring B is (C5-C11) partially unsaturated cycloalkyl or (5-11 membered) partially unsaturated heterocycloalkyl;
  • X 2 is a chemical bond
  • X 3 is CH, N or CR c ;
  • X4 is CH, N or CR d ;
  • X 5 is NR a or CH-R b ;
  • Each R 2 is independently -H, -D, halogen, R 8 , -OH, -(CH 2 ) n OR 8 , -(CH 2 ) n NR 8 R 9 , -OR 8 , -NR 8 R 9 , -CN, -C(O)NR 8 R 9 , -NR 9 C(O)R 8 , -NR 9 S(O) 2 R 8 , -S(O) p R 8 , -S(O) 2 NR 8 R 9 ⁇ (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C6-C14) aryl, ( 3-11 yuan) heterocycloalkyl or (5-11 yuan) heteroaryl, wherein the alkyl, haloalkyl, alkenyl, alkynyl,
  • R a is -H, -(CH 2 ) m OR 8 , -(CH 2 ) m NR 8 R 9 , (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C14) cycloalkyl Or (3-15 membered) heterocycloalkyl, wherein said alkyl, haloalkyl, cycloalkyl and heterocycloalkyl can be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, - D.
  • R 8 -OH, -(CH 2 ) n OR 8 , -(CH 2 ) n NR 8 R 9 , -OR 8 , -NR 8 R 9 , -CN, -C(O)NR 8 R 9 , -NR 9 C(O)R 8 , -NR 9 S(O) 2 R 8 , -S(O) p R 8 and -S(O) 2 NR 8 R 9 ;
  • R b is -H, -(CH 2 ) n OR 8 , -(CH 2 ) n NR 8 R 9 , (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C14) cycloalkyl or (3-15 membered) heterocycloalkyl, wherein said R 8 , R 9 , alkyl, haloalkyl, cycloalkyl and heterocycloalkyl can be optionally replaced by 1, 2, 3 or 4 of the following groups Substitution: -H, -D, halogen, R 8 , -OH, -(CH 2 ) n OR 8 , -(CH 2 ) n NR 8 R 9 , -OR 8 , -NR 8 R 9 , -CN, - C(O)NR 8 R 9 , -NR 9 C(O)R 8 , -NR 9 S(O) 2 R 8 , -S(O) p R 8
  • R c and R d are each independently -H, halogen, R 8 , -OH, -(CH 2 ) n OR 8 , -(CH 2 ) n NR 8 R 9 , -OR 8 , -NR 8 R 9 , -CN, -C(O)NR 8 R 9 , -NR 9 C(O)R 8 , -NR 9 S(O) 2 R 8 , -S(O) p R 8 , -S(O) 2 NR 8 R 9 , (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C6-C14) Aryl, (3-11 membered) heterocycloalkyl or (5-11 membered) heteroaryl, wherein the alkyl, haloalkyl, alkenyl, alkynyl, cyclo
  • R e is -H, -D, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy group, (C1-C6) haloalkoxy group, (C3-C9) cycloalkyl group, (C6-C14) aryl group, (3-11 member) heterocycloalkyl group or (5-11 member) heteroaryl group, wherein
  • the alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups can each independently be optionally replaced by 1, 2, 3 or 4
  • the following groups are substituted: -H, halogen, R 8 , -OH, -(CH 2 ) n OR 8 , -(CH 2 ) n NR
  • R f and R g are each independently -H, -D, -(CH 2 ) n OR 8 , -(CH 2 ) n NR 8 R 9 , -CN, (C1-C6)alkyl, (C1-C6 ) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C6-C14) aryl, (3-11) heterocycloalkyl or (5 -11-membered) heteroaryl, wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl can each independently be optionally replaced by 1, 2, 3 or Substituted by 4 of the following groups: -H, halogen, R 8 , -OH, -(CH 2 ) n OR 8 , -(CH 2 ) n NR 8
  • R 3 is (C1-C5) alkyl, (C1-C5) haloalkyl, (C2-C5) alkenyl, (C2-C5) alkynyl or (C3-C6) cycloalkyl, wherein said alkyl, Haloalkyl, alkenyl, alkynyl and cycloalkyl can each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -D, halogen, R 7 , R 8 , -OH, -( CH 2 ) n OR 8 , -(CH 2 ) n NR 8 R 9 , -OR 8 , -NR 8 R 9 , -CN, -C(O)NR 8 R 9 , -NR 9 C(O)R 8 , -NR 9 S(O) 2 R 8 , -S(O) p R 8 and -S(O) 2 NR 8 R 9 ;
  • R 7 is (C1-C5) haloalkyl, (C2-C5) alkenyl or (C2-C5) alkynyl;
  • R 8 and R 9 are each independently -H, (C1-C6) alkyl, (C1-C3) haloalkyl or (C3-C14) cycloalkyl, or R 8 and R 9 on the same nitrogen atom and The N atoms they are connected to can together form a (3-11 membered) heterocycloalkyl group, which can be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, R 10 and -OR 10 ;
  • R 10 is -H, (C1-C6) alkyl or (C3-C14) cycloalkyl
  • p is an integer of 0, 1 or 2
  • q is an integer of 1, 2, 3 or 4
  • s is an integer of 1, 2, 3 or 4
  • n is an integer of 0, 1, 2 or 3
  • m is 1, An integer of 2 or 3.
  • ring A is a (C5-C7) partially unsaturated cycloalkyl group or a (5-7 membered) partially unsaturated heterocycloalkyl group.
  • ring A is:
  • each R 1 is independently -H, -D, -F, -Cl, -Br, -I, -OH, -CH 2 OR 8 , -CH 2 NR 8 R 9 , -OR 8 , -NR 8 R 9 , -CN, -C(O)NR 8 R 9 , -NR 9 C(O)R 8 , -NR 9 S(O) 2 R 8 , -SR 8 , -S(O) 2 R 8 , -S(O) 2 NR 8 R 9 , (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl , (C2-C4) alkynyl or (C3-C6) cycloalkyl, wherein said alkyl, haloalkyl, alkenyl, alkynyl or (C3-C6) cycloalkyl, wherein said alkyl, haloalkyl, alkenyl
  • each R 1 is independently: -H, -D, -F, -Cl, -Br, -I, -OH, -CH 2 OCH 3. -CH 2 N(CH 3 ) 2 , -OCH 3 , -OCF 3 , -N(CH 3 ) 2 , -CN, -C(O)NH 2 , -C(O)NH(CH 3 ), -C(O)N(CH 3 ) 2 , -NHC(O)CH 3 , -N(CH 3 )-C(O)CH 3 , -NHS(O) 2 CH 3 , -N(CH 3 )- S(O) 2 CH 3 , -SCH 3 , -S(O) 2 CH 3 and -S(O) 2 NH 2 , -S(O) 2 NH(CH 3 ), -S(O) 2 N( CH 3 ) 2 , -CD 3 ,
  • R 4 , R 5 and R 6 are each independently -H, -D, -F, -Cl, -Br, -I, -OH, -CH 2 OR 8 , -CH 2 NR 8 R 9 , -OR 8 , -NR 8 R 9 , -CN, -C(O)NR 8 R 9 , -NR 9 C(O)R 8 , -NR 9 S(O) 2 R 8 , -SR 8 , -S(O) 2 R 8 , -S(O) 2 NR 8 R 9 , (C1-C3) alkyl, (C1-C3) haloalkyl, (C2 -C4) alkenyl, (C2-C4) alkynyl or (C3-C6) cycloalkyl, wherein said alkyl, haloalkyl, alkenyl, alkynyl or (C3-C6) cycloalkyl, wherein said alkyl, halo
  • R 4 , R 5 and R 6 are each independently: -H, -D, -F, -Cl, -Br, -I, -OH , -CH 2 OCH 3 , -CH 2 N(CH 3 ) 2 , -OCH 3 , -OCF 3 , -N(CH 3 ) 2 , -CN, -C(O)NH 2 , -C(O)NH (CH 3 ), -C(O)N(CH 3 ) 2 , -NHC(O)CH 3 , -N(CH 3 )-C(O)CH 3 , -NHS(O) 2 CH 3 , -N (CH 3 )-S(O) 2 CH 3 , -SCH 3 , -S(O) 2 CH 3 and -S(O) 2 NH 2 , -S(O) 2 NH(CH 3 ), -S( O) 2 N(CH 3 ), -CN, -C(O
  • ring B is a (C5-C8) partially unsaturated cycloalkyl group or a (5-8 membered) partially unsaturated heterocycloalkyl group; and R e is : -H, -D, -F, -CH 3 , -OCH 3 , or -CH2CH3 .
  • X 1 is:
  • X 2 is: a chemical bond
  • R b is -H, -(CH 2 ) 2 OR 8 , -NR 8 R 9 , - (CH 2 ) 2 NR 8 R 9 , (C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C6) cycloalkyl or (4-7 membered) heterocycloalkyl, wherein R 8 , R 9 , alkyl, haloalkyl, cycloalkyl and heterocycloalkyl can be independently and optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -D, -F, -OH, - CH 3 , -CH 2 OCH 3 , -(CH 2 ) 2 OCH 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCF 3 , -CH 2 N(
  • X 3 is: CH, N or CR c , wherein the R c is: -H, -F, -Cl, -Br, -I, -OH, -CH 3 , -CH 2 OCH 3 , -(CH 2 ) 2 OCH 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCF 3 , -CH 2 N(CH 3 ) 2 , -(CH 2 ) 2 N(CH 3 ) 2 , -N(CH 3 ) 2 , or -CN.
  • X 4 is: CH, N or CR d , wherein the R d is: -H, -F, -Cl, -Br, -I, -OH, -CH 3 , -CH 2 OCH 3 , -(CH 2 ) 2 OCH 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCF 3 , -CH 2 N(CH 3 ) 2 , -(CH 2 ) 2 N(CH 3 ) 2 , -N(CH 3 ) 2 , or -CN.
  • each R 2 is independently -H, -D, -F, -Cl, -Br, -I, -OH, -CH 2 OR 8 , -CH 2 NR 8 R 9 , -OR 8 , -NR 8 R 9 , -CN, -C(O)NR 8 R 9 , -NR 9 C(O)R 8 , -NR 9 S(O) 2 R 8 , -SR 8 , -S(O) 2 R 8 , -S(O) 2 NR 8 R 9 , (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl , (C2-C4) alkynyl, (C3-C6) cycloalkyl, phenyl, (4-8 member) heterocycloalkyl or (5-6 member) heteroaryl, wherein the alkyl, haloalkyl , alkenyl, alkynyl, (C3-C6)
  • each R 2 is independently: -H, -D, -F, -Cl, -Br, -I, -OH, -CH 2 OCH 3 , -CH 2 N(CH 3 ) 2 , -OCH 3 , -OCF 3 , -N(CH 3 ) 2 , -CN, -C(O)NH 2 , - C(O)NH(CH 3 ), -C(O)N(CH 3 ) 2 , -NHC(O)CH 3 , -N(CH 3 )-C(O)CH 3 , -NHS(O) 2 CH 3 , -N(CH 3 )-S(O) 2 CH 3 , -SCH 3 , -S(O) 2 CH 3 and -S(O) 2 NH 2 , -S(O) 2 NH(CH 3 ), -S(O) 2 N(CH 3 ) 2
  • R 3 is (C1-C4) alkyl, (C1-C4) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkyne or (C3-C5)cycloalkyl, wherein said alkyl, haloalkyl, alkenyl, alkynyl and cycloalkyl are each independently optionally substituted by 1, 2, 3 or 4 of the following groups: -H , -D, -F, -CN,
  • R 3 is:
  • 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 general formula (1) of the present invention, or its various isomers, Various crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used as active ingredients.
  • Another object of the present invention provides 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 composition Application for preparing medicines for treating, regulating or preventing diseases related to Wee-1 protein; the diseases are preferably cancers, and the cancers are blood cancers and solid tumors.
  • Another object of the present invention is also to provide a method for treating, regulating or preventing diseases related to Wee-1 protein, comprising administering to a subject a therapeutically effective amount of the compound represented by the general formula (1) of the present invention, or each of them Isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the above-mentioned pharmaceutical composition; the disease is preferably cancer, and the cancer is blood cancer and solid tumor.
  • the compounds of general formula (1) described above can be synthesized using standard synthetic techniques or known techniques combined with methods herein. In addition, 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 having 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), methods in Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3rd Ed., (Wiley 1999). The general methods of compound preparation can be varied by using appropriate reagents and conditions to introduce different groups into the formulas provided herein.
  • 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, etc., are not limited to those explained below.
  • the compound of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in the specification or known in the art. Such a combination can be easily performed 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 using the following general reaction scheme 1:
  • the embodiment of the compound of general formula (1) can be prepared according to general reaction scheme 1, wherein R 1 , R 2 , R 3 , R e , X 1 , X 2 , X 3 , X 4 , X 5 , X, Y 1 , Y 2 , Y 3 , s, q, ring A and ring B are as defined above, H represents hydrogen, N represents nitrogen, Z represents chlorine, bromine or iodine, S represents sulfur, O represents oxygen.
  • compounds 1-1 and 1-2 undergo a substitution reaction under basic conditions to generate compound 1-3, compound 1-3 generates compound 1-4 under acidic conditions, and compound 1-4 generates compound 1-4 under alkaline conditions.
  • Reaction under neutral conditions generates 1-5
  • compound 1-5 reacts with compound 1-6 to generate compound 1-7 under alkaline condition
  • compound 1-7 reacts with m-CPBA to generate compound 1-8
  • compound 1-8 and 1-9 undergoes a substitution reaction to generate the target compound 1-10.
  • “Pharmaceutically acceptable” here refers to a substance, such as a carrier or diluent, that does not abolish the biological activity or properties of the compound, and that is relatively nontoxic, e.g., does not cause unwanted biological effects or Interact in a harmful manner with any of its components.
  • the term "pharmaceutically acceptable salt” refers to a form of a compound which does not cause significant irritation to the organism to which it is administered and which does not abolish the biological activity and properties of the compound.
  • the pharmaceutically acceptable salt is obtained by reacting the compound of general formula (1) with an acid, such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid and other inorganic acids, formic acid, acetic acid , 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.
  • an acid such as hydrochloric acid, hydrobromic acid, hydro
  • references to pharmaceutically acceptable salts are understood to include solvent added forms or crystalline forms, especially solvates or polymorphs.
  • Solvates contain stoichiometric or non-stoichiometric solvents 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, and the organic solvent used includes but not limited to tetrahydrofuran, acetone, ethanol or methanol.
  • the compounds mentioned herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for purposes of the compounds and methods provided herein.
  • compounds of general formula (1) are prepared in different forms including, but not limited to, amorphous, pulverized and nano-particle sized forms.
  • the compound of the general formula (1) includes crystalline forms and may also be regarded as polymorphic forms.
  • 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, densities, hardness, crystal forms, 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 predominate.
  • the compounds of general formula (1) may have chiral centers and/or axial chirality and thus exist as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single non- Enantiomeric forms, and cis-trans isomeric forms occur.
  • Each chiral center or axial chirality will independently give rise to 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 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 compounds.
  • compounds can be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C).
  • radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C).
  • heavy hydrogen can be used to replace hydrogen atoms to form deuterated compounds.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Stability, enhanced curative effect, extended drug half-life in vivo and other advantages. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are encompassed within the scope of the invention.
  • ring B is named as an independent group (not combined with other rings).
  • ring B is fused with an adjacent group.
  • alkyl means a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 6 carbon atoms. Lower alkyl groups having 1 to 4 carbon atoms are preferred, 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 .
  • alkenyl refers to an unsaturated aliphatic hydrocarbon group containing carbon-carbon double bonds, including straight or branched chain groups of 1 to 14 carbon atoms. Lower alkenyl groups having 1 to 4 carbon atoms, such as vinyl, 1-propenyl, 1-butenyl or 2-methylpropenyl, are preferred.
  • 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.
  • cycloalkyl means a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), and if the carbocyclic ring contains at least one double bond, then a partially unsaturated cycloalkyl group may be referred to as "cycloalkyl". alkenyl", or if the carbocyclic ring contains at least one triple bond, a partially unsaturated cycloalkyl group may be referred to as a "cycloalkynyl”. Cycloalkyl groups can include monocyclic or polycyclic (eg, having 2, 3 or 4 fused rings) groups and spirocycles. In some embodiments, cycloalkyl groups are monocyclic.
  • cycloalkyls are monocyclic or bicyclic. Ring-forming carbon atoms of cycloalkyl groups can be optionally oxidized to form oxo or sulfide groups. Cycloalkyl also includes cycloalkylene. In some embodiments, cycloalkyl groups contain 0, 1, or 2 double bonds. In some embodiments, the cycloalkyl contains 1 or 2 double bonds (partially unsaturated cycloalkyl). In some embodiments, cycloalkyl groups can be fused with aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups.
  • cycloalkyl groups can be fused with aryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl and heterocycloalkyl groups. In some embodiments, a cycloalkyl group can be fused with an aryl group and a cycloalkyl group.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl , norpinenyl, norcarpanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexyl, etc.
  • alkoxy means 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-butoxyl.
  • alkoxy includes unsubstituted and substituted alkoxy, especially alkoxy substituted with one or more halogens.
  • Preferred alkoxy groups are selected from OCH 3 , OCF 3 , CHF 2 O, CF 3 CH 2 O, i- PrO, n- PrO, i- BuO, n- BuO or t- BuO.
  • aryl refers to a hydrocarbon aromatic group, aryl 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 phenanthrenyl.
  • aryloxy refers to an aryl group bonded to the rest of the molecule through an ether oxygen atom.
  • Examples of aryloxy include, but are not limited to, phenoxy and naphthyloxy.
  • arylene refers to a divalent aryl group as defined above.
  • arylene groups include, but are not limited to, phenylene, naphthylene, and phenanthrenylene.
  • heteroaryl refers to an aromatic group containing one or more heteroatoms (O, S or N), and the heteroaryl 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, isoquinolyl, furyl, thienyl, Isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, benzene Pyridyl, pyrrolopyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H- Pyrrolo[2,3-b]pyridyl,
  • heteroarylene refers to a divalent heteroaryl group as defined above.
  • heterocycloalkyl means a non-aromatic ring or ring system which may optionally contain as part of the ring structure one or more alkenylene groups having at least one group 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 a "heterocycloalkynyl".
  • Heterocycloalkyl groups can include monocyclic, bicyclic, spiro, or polycyclic (eg, having two fused or bridged rings) ring systems.
  • heterocycloalkyl 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 the heterocycloalkyl group can be optionally oxidized to form oxo or sulfide groups or other oxidized linkages (e.g., 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-forming carbon atom or a ring-forming heteroatom.
  • heterocycloalkyl groups contain 0 to 3 double bonds.
  • heterocycloalkyl groups contain 0 to 2 double bonds.
  • moieties having one or more aromatic rings fused to (i.e., sharing a bond with) the heterocycloalkyl ring such as piperidine, morpholine, azepine or Benzo derivatives such as thienyl.
  • a heterocycloalkyl group containing a fused aromatic ring may be attached via any ring-forming atom, including ring-forming atoms 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, quinyl, tetrahydrofuryl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolyl, tropane, 4,5,6,7-tetrahydrothiazolo[5,4 -c]pyridyl, 4,5
  • heterocycloalkylene refers to a divalent heterocycloalkyl group as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • halo or halogen substitution
  • appearing before the group name means that the group is partially or fully halogenated, that is, substituted by F, Cl, Br or I in any combination, preferably Substituted by F or Cl.
  • the 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 ring structure.
  • member is meant to indicate the number of skeletal 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. Chemical fragments are generally considered to be chemical entities contained in or attached to molecules.
  • keys with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter, with a straight solid-line bond and straight dashed keys Indicates the relative configuration of the stereocenter, with a wavy line Indicates wedge-shaped solid-line bond or dotted wedge key or with tilde Indicates a straight solid line key or straight dotted key
  • acceptable means that a formulation ingredient or active ingredient does not have an undue adverse effect on health for the general purpose of treatment.
  • treatment includes alleviating, suppressing or improving the symptoms or conditions of a disease; inhibiting the development of complications; improving or preventing the underlying metabolic syndrome; inhibiting the development of diseases or symptoms, Such as controlling the development of a disease or condition; alleviating a disease or a symptom; causing a disease or a symptom to regress; alleviating a complication caused by a disease or a symptom, or preventing or treating a symptom caused by a disease or a symptom.
  • a certain compound or pharmaceutical composition after administration, can improve a certain disease, symptom or situation, especially improve its severity, delay the onset, slow down the progression of the disease, or reduce the duration of the disease. Circumstances that may be attributable to or related to the administration, whether fixed or episodic, continuous or intermittent.
  • 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 thus exist as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single non- Enantiomers occur in the form of enantiomers.
  • the asymmetric centers that can exist depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently give rise to 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 invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • composition a compound or composition capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.
  • administered, administering, or administration means direct administration of the compound or composition, or administration of a prodrug, derivative, or analog of the active compound Wait.
  • the compound or pharmaceutical composition of the general formula (1) of the present invention can generally be used to inhibit Wee-1 kinase, and thus can be used to treat one or more diseases related to Wee-1 kinase activity. Therefore, in certain embodiments, the present invention provides a method for treating a Wee-1 kinase-mediated disorder, the method comprising administering a compound of general formula (1) of the present invention, or a pharmaceutical agent thereof, to a patient in need thereof. steps on an acceptable composition.
  • a method for treating cancer comprising administering an effective amount of any of the aforementioned pharmaceutical compositions comprising the compound of general structural formula (1) to an individual in need thereof.
  • said cancers include, but are not limited to, hematological malignancies (leukaemias, lymphomas, myelomas including multiple myeloma, myelodysplastic syndromes, and myeloproliferative syndromes) and solid tumors (cancers such as prostate, breast, lung, colon , pancreas, kidney, ovary and soft tissue cancer and osteosarcoma, and stromal tumors) etc.
  • the compounds of the present invention and their pharmaceutically acceptable salts can be made into various preparations, which contain the compounds of the present invention or their pharmaceutically acceptable salts and pharmaceutically acceptable excipients or carriers within the range of safe and effective amounts .
  • safe and effective amount means: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects.
  • the safe and effective dose of the compound is determined according to the specific conditions such as the age, condition, and course of treatment of the subject to be treated.
  • “Pharmaceutically acceptable excipient or carrier” means: one or more compatible solid or liquid filler or gel substances, which are suitable for human use and must be of sufficient purity and low enough toxicity .
  • “Compatibility” herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
  • Examples of pharmaceutically acceptable excipients or carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
  • cellulose and derivatives thereof such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as stearic acid, magnesium stearate
  • calcium sulfate such as soybean oil, sesame oil,
  • the compounds of the present invention When the compounds of the present invention are administered, they can 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 admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea, or
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, from such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • coatings and shell materials such as enteric coatings and others well known in the art. They may contain opacifying agents and, from such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • Examples of usable embedding components are polymeric substances and waxy substances.
  • the active compounds can also be in microencapsulated form, if desired, 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 used 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, etc.
  • inert diluents conventionally used 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
  • 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, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, 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 vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for topical administration of a compound 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 which 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 applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily
  • the dosage is usually 1-2000 mg, preferably 50-1000 mg.
  • factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
  • 1 H-NMR was recorded by a Varian Mercury 400 nuclear magnetic resonance apparatus, and the chemical shifts were expressed in ⁇ (ppm); the silica gel used for separation was 200-300 mesh, and the ratio of the eluent was volume ratio.
  • the present invention adopts the following abbreviations: Ac 2 O stands for acetic anhydride; (Boc) 2 O stands for di-tert-butyl dicarbonate; CDCl 3 stands for deuterated chloroform; EtOAc stands for ethyl acetate; Hexane stands for n-hexane; Liquid chromatography; MeCN stands for acetonitrile; DCM stands for dichloromethane; DIPEA stands for diisopropylethylamine; Dioxane stands for 1,4-dioxane; DMF stands for N,N-dimethylformamide; DMP stands for Dess -Martin oxidant; DMAP stands for 4-(dimethylamino)pyridine; DMSO stands for dimethyl sulfoxide; EtOH stands for ethanol; EtMgBr stands for ethyl magnesium bromide; hr stands for hour; IPA stands for isopropanol; min stands for minute ; K2 CO
  • Step 1 the synthesis of compound int_A-1-2:
  • Int_A-1-1 (50g, 284mmol), methylamine hydrochloride (57.5g, 851mmol) and TEA (144g, 1.42mol, 197mL) were dissolved in acetonitrile (600mL), and T 3 P (217g , 341mmol, 203mL, 50%purity), after addition, heated to 50°C for 16 hours.
  • the reaction solution was diluted with 1500 mL ethyl acetate, washed with NaHCO 3 aqueous solution (400 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain the crude product as a white solid (50 g, 264 mmol, yield: 93.1%). The crude product can be directly used in the next reaction.
  • Step 2 the synthesis of compound int_A-1-3:
  • Int_A-1-2 (50g, 264mmol) was dissolved in THF (500mL), and n-BuLi (2.5M, 275mL) was slowly added dropwise at -23°C under nitrogen protection. Then DMF (48.3 g, 660 mmol, 50.8 mL) was slowly added dropwise at -23 °C. Then HCl solution (6M, 300 mL) was slowly added dropwise at 20 °C. The reaction solution was diluted with 100 mL of water, extracted with ethyl acetate (500 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure to obtain a yellow solid (55 g, crude product). The crude product can be directly used in the next reaction.
  • int_A-1-6 (7 g, 32.4 mmol) was dissolved in anhydrous tetrahydrofuran (300 mL), and LiAlH 4 (6.14 g, 162 mmol) was added at 0°C. Under the protection of nitrogen, the mixture was heated to 25°C for 2 hours. Slowly add water to the reaction solution to quench the reaction while keeping the temperature of the reaction solution at 0-10°C. The reaction solution is diluted with 800 mL of ethyl acetate, washed with water (100 mL*3), and the organic phase is dried over anhydrous sodium sulfate.
  • Int_A-1 (1.5g, 7.41mmol) was subjected to chiral resolution by prep SFC (SFC chiral resolution conditions: instrument: Waters SFC350; 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: 200mL/min; The liquid was concentrated under reduced pressure and freeze-dried to obtain yellow oily int_A-2 (peak 1, configuration is speculated, 438 mg, yield: 29.20%) and yellow oily int_A-3 (peak 2, configuration is speculative, 450mg, yield: 30.00%).
  • SFC chiral resolution conditions instrument: Waters SFC350; 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: 200mL
  • Int_A-73-1 (100g, 504.6mmol) and methylamine (156.7g, 1.51mol, 30% purity) were dissolved in ethanol (1200mL), heated to 80°C for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure to obtain a crude product (213 g, yield: 99.9%), which can be directly used in the next reaction.
  • Step 2 the synthesis of compound int_A-73-3:
  • int_A-73-2 50g, 236.7mmol
  • palladium on carbon 25g, 10% purity
  • acetic acid 500mL
  • hydrogen pressure 50psi
  • Int_A-73-3 (33 g, 153.3 mmol) was dissolved in DMF (500 mL), and NaH (9.20 g, 230.0 mmol, 60% purity) was added to the solution at 0° C. under nitrogen protection. The reaction solution was reacted at 0°C for half an hour. MeI (32.64g, 223.0mmol, 14.32mL) was slowly added dropwise into the above reaction solution, and then heated to 25°C for 2 hours. LC-MS monitoring showed the reaction was complete. The reaction solution was poured into 1000 mL of ice water, and the aqueous phase was extracted with ethyl acetate (1000 mL*2).
  • int_A-73-4 (40g, 174.5mmol) was dissolved in H 2 SO 4 (400mL), and KNO 3 (19.40g, 191.9mmol) was slowly added at 0°C under nitrogen protection, and stirred at 0°C for half an hour after addition. TLC detection showed that the reaction was complete.
  • the reaction solution was poured into 1000 mL of ice water, and the aqueous phase was extracted with ethyl acetate (1000 mL*2). The organic phases were combined and washed with saturated brine (500mL*4), dried over magnesium sulfate, filtered and concentrated to obtain a crude product (95g, yield: 99.3%), which was directly used in the next reaction.
  • int_A-73-6 (12 g, 49.12 mmol) was dissolved in anhydrous tetrahydrofuran (500 mL), and LiAlH 4 (18.64 g, 491.2 mmol) was added at 0°C. Under nitrogen protection, the mixture was heated to 25°C for 16 hours.
  • Int_A-73 (10g, 46.30mmol) was subjected to chiral resolution by prep SFC (SFC chiral resolution conditions: instrument: Waters SFC350; column: DAICEL CHIRALPAK AD (250mm*50mm, 10um ); mobile phase: A: CO 2 , B: ethanol (0.1% NH 3 H 2 O); gradient: B%: 50%-50%; flow rate: 200mL/min; column temperature: 40°C), segment The solution was concentrated under reduced pressure and freeze-dried to obtain yellow oily substance A-74 (peak 1, configuration is speculated, 4.5 g, yield: 42.4%) and yellow oily substance A-75 (peak 2, configuration was speculated, 4.5 g, yield: 42.4%).
  • SFC chiral resolution conditions instrument: Waters SFC350; column: DAICEL CHIRALPAK AD (250mm*50mm, 10um ); mobile phase: A: CO 2 , B: ethanol (0.1% NH 3 H 2 O); gradient: B%: 50%-50%
  • the target intermediates A-4 to A-72 and A-76 to A-153 in Table 1 can be obtained.
  • Step 1 the synthesis of compound int_B-1-2:
  • Step 2 the synthesis of compound int_B-1-3:
  • reaction solution was cooled to room temperature, quenched by pouring into ice water, the aqueous phase was extracted with ethyl acetate (200mL*3), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was subjected to column chromatography ( Silica Flash Column, Eluent of 0-10% Ethyl acetate/Petroleum ether gradient) to obtain a yellow solid (14g, yield: 72.5%).
  • the mixture was poured into ice water, the aqueous phase was extracted with ethyl acetate (200 mL*3), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product (14.51 g).
  • the crude product can be directly used in the next reaction.
  • Int_B-1-8 (5.3 g, 24.76 mmol) was dissolved in dichloromethane (60 mL), and DMP (21.00 g, 49.52 mmol) was added. The mixture was reacted at room temperature for 5 hours. The reaction solution was filtered, and the filtrate was adjusted to pH 7-8 with saturated aqueous sodium bicarbonate solution, and the aqueous phase was extracted with dichloromethane (150 mL*3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography ( Silica Flash Column, Eluent of 0-50% Ethyl acetate/Petroleum ether gradient) to obtain a green oil (4g, yield: 76.2%).
  • the target intermediates B-5 to B-48 in Table 2 can be obtained.
  • Step 1 the synthesis of compound int_6-3:
  • Step 2 the synthesis of compound int_6-4:
  • Step 3 the synthesis of compound int_6-5:
  • Step 4 the synthesis of compound int_6-6:
  • Step 1 the synthesis of compound int_16-1:
  • Step 2 the synthesis of compound int_16-2:
  • Step 2 the synthesis of compound int_20-2:
  • Example 5 The compounds of the present invention inhibit recombinant protein Wee-1 enzyme activity test in vitro
  • the inhibitory effect of compounds on the enzyme activity of recombinant protein Wee-1 was determined by HTRF method. details as follows.
  • DMSO or serially diluted compound (up to 200nM, 1:5 serial dilution) and recombinant protein were incubated in kinase buffer at 37°C for 30 minutes, after adding Fluorescein-PolyGAT and ATP, the substrate was added to start the reaction. After reacting at room temperature for 90 minutes, add the antibody and detection solution, continue to incubate at room temperature for 60 minutes, and read the fluorescence value (excitation wavelength: 340nm, emission wavelength: 495nm and 520nm. Calculate the ratio of fluorescence intensity at 520nm/495nm, compare with the DMSO group, and then Compound inhibition percentages and IC50 were calculated. Results are shown in Table 4 below.
  • +++ means IC 50 less than or equal to 10nM
  • Embodiment 6 The compounds of the present invention have antiproliferative activity in vitro on MIA PaCa-2 cells
  • 3000/well MIA PaCa-2 cells were plated on a 384-well plate, and after overnight attachment, DMSO or a compound with a maximum concentration of 5 ⁇ M and a 1:5 gradient dilution was added. 72 hours after adding the drug, the cell survival was evaluated by measuring the ATP content in the cells. Comparing with the DMSO group, the percentage of inhibition of cell survival by the compound was calculated, and the IC 50 value was calculated. The results are shown in Table 5 below.
  • the compound of the present invention is to the antiproliferative activity of MIA PaCa-2 cell
  • Embodiment 7 Compounds of the present invention combined with gemcitabine (Gemcitabine) to MIA PaCa-2 cells in vitro anti-proliferation activity
  • 3000/well MIA PaCa-2 cells were plated in 384-well plates and 20nM Gemcitabine was added. After overnight attachment, DMSO or the compound with the highest concentration of 100nM was added in a 1:5 gradient dilution. 72 hours after adding the drug, the cell survival was evaluated by measuring the ATP content in the cells. Compared with the DMSO group, the percentage of inhibition of cell survival by the compound was calculated, and then the IC 50 value was calculated, and the results are shown in Table 6 below.

Abstract

一类作为Wee-1抑制剂的稠环化合物。具体的，涉及一种通式(I)所示的化合物及其制备方法，及通式(I)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抑制剂的应用。所述化合物及其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物可用于制备治疗或者预防和Wee-1蛋白激酶相关的疾病的药物。

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7月5日的中国专利申请2021107574524的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属涉及药物化学领域，更具体而言，涉及一类具有Wee1激酶抑制作用的稠环化合物，及其制备方法和该类化合物用于制备治疗或者预防由Wee1介导的相关疾病的药物中的应用。
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[Cell Cycle,2013.12(19):p.3159-64.]。
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[Curr Clin Pharmacol,2010.5(3):p.186-91.]。
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[J Cell Biol,2011. 194(4):p.567-79.]。在大量包括肝癌，乳腺癌，宫颈癌，黑色素瘤和肺癌等肿瘤中[PLoS One,2009.4(4):p.e5120.；Hepatology,2003.37(3):p.534-43.；Mol Cancer,2014.13:p.72.]，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[Cancer Biol Ther,2010.9(7):p.514-22.；Mol Cancer Ther,2009.8(11):p.2992-3000.]。
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。
发明内容
本发明提供了一种通式(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：
Figure PCTCN2022104003-appb-000001
通式(1)中：
X为CH或N；
环A为(C5-C11)部分不饱和环烷基或(5-11元)部分不饱和杂环烷基；
每个R 1独立地为-H、-D、卤素、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8、-S(O) 2NR 8R 9、
Figure PCTCN2022104003-appb-000002
(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基或(C3-C9)环烷基，其中所述烷基、卤代烷基、烯基、炔基和环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或2个相邻的R 1与他们所连接的原子能够共同组成(5-7元)杂环烷基或(C3-C9)环烷基，此杂环烷基和环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或A环上同一个碳原 子上的2个R 1与他们所连接的碳原子能够共同组成(4-7元)杂环烷基或(C3-C6)环烷基，此杂环烷基和环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
Y 1为N或C-R 4；
Y 2为N或C-R 5；
Y 3为N或C-R 6；
R 4、R 5和R 6各自独立地为-H、-D、卤素、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8、-S(O) 2NR 8R 9、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基或(C3-C9)环烷基，其中所述烷基、卤代烷基、烯基、炔基和环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或R 5和R 6与他们所连接的原子能够共同组成(5-9元)杂环烷基、(5-9元)杂芳基或(C5-C9)环烷基，此杂环烷基、杂芳基和环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
B环为(C5-C11)部分不饱和环烷基或(5-11元)部分不饱和杂环烷基；
X 1为
Figure PCTCN2022104003-appb-000003
X 2为化学键、
Figure PCTCN2022104003-appb-000004
X 3为CH、N或C-R c；
X 4为CH、N或C-R d；
X 5为N-R a或CH-R b；
每个R 2独立地为-H、-D、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8、-S(O) 2NR 8R 9、
Figure PCTCN2022104003-appb-000005
(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基，其中所述烷基、卤代烷基、烯基、炔基、环烷基、芳基、杂环烷基和杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或2个相邻的R 2与他们所连接的原子能够共同 组成(5-7元)杂环烷基或(C3-C9)环烷基，此杂环烷基和环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或B环上同一个碳原子上的2个R 2与他们所连接的碳原子能够共同组成(4-7元)杂环烷基或(C3-C6)环烷基，此杂环烷基和环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或R 2和一个相邻的R e与他们所连接的原子能够共同组成(5-7元)杂环烷基或(C3-C9)环烷基，此杂环烷基和环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
R a为-H、-(CH 2) mOR 8、-(CH 2) mNR 8R 9、(C1-C6)烷基、(C1-C6)卤代烷基、(C3-C14)环烷基或(3-15元)杂环烷基，其中所述烷基、卤代烷基、环烷基和杂环烷基可任选被1，2，3或4个下列基团取代：-H、-D、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
R b为-H、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、(C1-C6)烷基、(C1-C6)卤代烷基、(C3-C14)环烷基或(3-15元)杂环烷基，其中所述R 8、R 9、烷基、卤代烷基、环烷基和杂环烷基可任选被1，2，3或4个下列基团取代：-H、-D、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
R c和R d各自独立地为-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8、-S(O) 2NR 8R 9、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基，其中所述烷基、卤代烷基、烯基、炔基、环烷基、芳基、杂环烷基和杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
R e为-H、-D、卤素、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C1-C6)烷氧基、(C1-C6)卤代烷氧基、(C3-C9)环烷基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基，其中所述烷基、卤代烷基、烯基、炔基、烷氧基、卤代烷氧基、环烷基、芳基、杂环烷基和杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
R f和R g各自独立地为-H、-D、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-CN、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基，其中所述烷基、卤代烷基、烯基、炔基、环烷基、芳基、杂环烷基和杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或R f和R g与他们所连接的碳原子能够共同组成(4-7元)杂环烷基或(C3-C6)环烷基，此杂环烷基和环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或R f和一个相邻的R e与他们所连接的原子能够共同组成(C3-C9)环烷基或(3-11元)杂环烷基，其中所述环烷基和杂环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
R 3为(C1-C5)烷基、(C1-C5)卤代烷基、(C2-C5)烯基、(C2-C5)炔基或(C3-C6)环烷基，其中所述烷基、卤代烷基、烯基、炔基和环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-D、卤素、R 7、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
R 7为(C1-C5)卤代烷基、(C2-C5)烯基或(C2-C5)炔基；
R 8和R 9各自独立地为-H、(C1-C6)烷基、(C1-C3)卤代烷基或(C3-C14)环烷基，或同一个氮原子上的R 8和R 9与他们所连接的N原子能够共同组成(3-11元)杂环烷基，此杂环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 10和-OR 10；
R 10为-H、(C1-C6)烷基或(C3-C14)环烷基；和
p为0、1或2的整数，q为1、2、3或4的整数，s为1、2、3或4的整数，n为0、1、2或3的整数，m为1、2或3的整数。
在另一优选例中，其中所述通式(1)中，环A为(C5-C7)部分不饱和环烷基或(5-7元)部分不饱和杂环烷基。
在另一优选例中，其中所述通式(1)中，环A为：
Figure PCTCN2022104003-appb-000006
Figure PCTCN2022104003-appb-000007
在另一优选例中，其中所述通式(1)中，每个R 1独立地为-H、-D、-F、-Cl、-Br、-I、-OH、-CH 2OR 8、-CH 2NR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-SR 8、-S(O) 2R 8、-S(O) 2NR 8R 9、(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基、(C2-C4)炔基或(C3-C6)环烷基，其中所述烷基、卤代烷基、烯基、炔基和环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-OH、-OCH 3、-N(CH 3) 2和-CN；或2个相邻的R 1与他们所连接的原子能够共同组成(5-7元)杂环烷基或(C3-C6)环烷基，此杂环烷基和环烷基可任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN；或A环上同一个碳原子上的2个R 1与他们所连接的碳原子能够共同组成(4-7元)杂环烷基或(C3-C6)环烷基，此杂环烷基和环烷基可任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN。
在另一优选例中，其中所述通式(1)中，每个R 1独立地为：-H、-D、-F、-Cl、-Br、-I、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-OCF 3、-N(CH 3) 2、-CN、-C(O)NH 2、-C(O)NH(CH 3)、-C(O)N(CH 3) 2、-NHC(O)CH 3、-N(CH 3)-C(O)CH 3、-NHS(O) 2CH 3、-N(CH 3)-S(O) 2CH 3、-SCH 3、-S(O) 2CH 3和-S(O) 2NH 2、-S(O) 2NH(CH 3)、-S(O) 2N(CH 3) 2、-CD 3、-CD 2CD 3、
Figure PCTCN2022104003-appb-000008
Figure PCTCN2022104003-appb-000009
在另一优选例中，其中所述通式(1)中，R 4、R 5和R 6各自独立地为-H、-D、-F、-Cl、-Br、-I、-OH、-CH 2OR 8、-CH 2NR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-SR 8、-S(O) 2R 8、-S(O) 2NR 8R 9、(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基、(C2-C4)炔基或(C3-C6)环烷基，其中所述烷基、卤代烷基、烯基、炔基和环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-OH、-OCH 3、-N(CH 3) 2和-CN；或R 5和R 6与他们所连接的原子能够共同组成芳基、(5-6元)杂环烷基、(5-6元)杂芳基或(C5-C6)环烷基，此芳基、杂环烷基、杂芳基和环烷基可任选被1，2，3或4个 下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN；
在另一优选例中，其中所述通式(1)中，R 4、R 5和R 6各自独立地为：-H、-D、-F、-Cl、-Br、-I、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-OCF 3、-N(CH 3) 2、-CN、-C(O)NH 2、-C(O)NH(CH 3)、-C(O)N(CH 3) 2、-NHC(O)CH 3、-N(CH 3)-C(O)CH 3、-NHS(O) 2CH 3、-N(CH 3)-S(O) 2CH 3、-SCH 3、-S(O) 2CH 3和-S(O) 2NH 2、-S(O) 2NH(CH 3)、-S(O) 2N(CH 3) 2、
Figure PCTCN2022104003-appb-000010
Figure PCTCN2022104003-appb-000011
在另一优选例中，其中所述通式(1)中，结构单元
Figure PCTCN2022104003-appb-000012
为：
Figure PCTCN2022104003-appb-000013
Figure PCTCN2022104003-appb-000014
Figure PCTCN2022104003-appb-000015
在另一优选例中，其中所述通式(1)中，B环为(C5-C8)部分不饱和环烷基或(5-8元)部分不饱和杂环烷基；和R e为：-H、-D、-F、-CH 3、-OCH 3、
Figure PCTCN2022104003-appb-000016
或-CH 2CH 3。
在另一优选例中，其中所述通式(1)中，结构单元
Figure PCTCN2022104003-appb-000017
为：
Figure PCTCN2022104003-appb-000018
Figure PCTCN2022104003-appb-000019
Figure PCTCN2022104003-appb-000020
在另一优选例中，其中所述通式(1)中，X 1为：
Figure PCTCN2022104003-appb-000021
Figure PCTCN2022104003-appb-000022
在另一优选例中，其中所述通式(1)中，X 2为：化学键、
Figure PCTCN2022104003-appb-000023
Figure PCTCN2022104003-appb-000024
在另一优选例中，其中所述通式(1)中，当X 5为N-R a时，其中R a为-H、-(CH 2) 2OR 8、-(CH 2) 2NR 8R 9、(C1-C3)烷基、(C1-C3)卤代烷基、(C3-C6)环烷基或(4-7元)杂环烷基，其中所述烷基、卤代烷基、环烷基和杂环烷基可独立任选被1，2，3或4个下列基团取代：-H、-D、-F、-OH、-CH 3、-CH 2OCH 3、-(CH 2) 2OCH 3、-OCH 3、-OCH 2CH 3、-OCH(CH 3) 2、
Figure PCTCN2022104003-appb-000025
-OCF 3、-CH 2N(CH 3) 2、-(CH 2) 2N(CH 3) 2、-N(CH 3) 2和-CN。
在另一优选例中，其中所述通式(1)中，当X 5为N-R a时，其中R a为：-H、-(CH 2) 2OCH 3、-(CH 2) 2OH、-(CH 2) 2N(CH 3) 2、
Figure PCTCN2022104003-appb-000026
Figure PCTCN2022104003-appb-000027
在另一优选例中，其中所述通式(1)中，当X 5为CH-R b时，其中R b为-H、-(CH 2) 2OR 8、-NR 8R 9、-(CH 2) 2NR 8R 9、(C1-C3)烷基、(C1-C3)卤代烷基、(C3-C6)环烷基或(4-7元)杂环烷基，其中所述R 8、R 9、烷基、卤代烷基、环烷基和杂环烷基可独立任选被1，2，3或4个下列基团取代：-H、-D、-F、-OH、-CH 3、-CH 2OCH 3、-(CH 2) 2OCH 3、-OCH 3、-OCH 2CH 3、 -OCH(CH 3) 2、
Figure PCTCN2022104003-appb-000028
-OCF 3、-CH 2N(CH 3) 2、-(CH 2) 2N(CH 3) 2、-N(CH 3) 2和-CN。
在另一优选例中，其中所述通式(1)中，当X 5为CH-R b时，其中R b为：-H、-N(CH 3) 2、-N(CD 3) 2、-(CH 2) 2OCH 3、-(CH 2) 2OH、-(CH 2) 2N(CH 3) 2、
Figure PCTCN2022104003-appb-000029
Figure PCTCN2022104003-appb-000030
在另一优选例中，其中所述通式(1)中，X 3为：CH、N或C-R c，其中所述R c为：-H、-F、-Cl、-Br、-I、-OH、-CH 3、-CH 2OCH 3、-(CH 2) 2OCH 3、-OCH 3、-OCH 2CH 3、-OCH(CH 3) 2、-OCF 3、-CH 2N(CH 3) 2、-(CH 2) 2N(CH 3) 2、-N(CH 3) 2、
Figure PCTCN2022104003-appb-000031
或-CN。
在另一优选例中，其中所述通式(1)中，X 4为：CH、N或C-R d，其中所述R d为：-H、-F、-Cl、-Br、-I、-OH、-CH 3、-CH 2OCH 3、-(CH 2) 2OCH 3、-OCH 3、-OCH 2CH 3、-OCH(CH 3) 2、-OCF 3、-CH 2N(CH 3) 2、-(CH 2) 2N(CH 3) 2、-N(CH 3) 2、
Figure PCTCN2022104003-appb-000032
或-CN。
在另一优选例中，其中所述通式(1)中，每个R 2独立地为-H、-D、-F、-Cl、-Br、-I、-OH、-CH 2OR 8、-CH 2NR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-SR 8、-S(O) 2R 8、-S(O) 2NR 8R 9、(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基、(C2-C4)炔基、(C3-C6)环烷基、苯基、(4-8元)杂环烷基或(5-6元)杂芳基，其中所述烷基、卤代烷基、烯基、炔基、环烷基、苯基、杂环烷基和杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-OH、-CH 3、-OCH 3、-N(CH 3) 2和-CN；或2个相邻的R 2与他们所连接的原子能够共同组成(5-7元)杂环烷基或(C3-C6)环烷基，此杂环烷基和环烷基可任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN；或B环上同一个碳原子上的2个R 2 与他们所连接的碳原子能够共同组成(4-7元)杂环烷基或(C3-C6)环烷基，此杂环烷基和环烷基可任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN；或R 2和一个相邻的R e与他们所连接的原子能够共同组成(5-7元)杂环烷基或(C3-C6)环烷基，此杂环烷基和环烷基可任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN。
在另一优选例中，其中所述通式(1)中，其中所述通式(1)中，每个R 2独立地为：-H、-D、-F、-Cl、-Br、-I、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-OCF 3、-N(CH 3) 2、-CN、-C(O)NH 2、-C(O)NH(CH 3)、-C(O)N(CH 3) 2、-NHC(O)CH 3、-N(CH 3)-C(O)CH 3、-NHS(O) 2CH 3、-N(CH 3)-S(O) 2CH 3、-SCH 3、-S(O) 2CH 3和-S(O) 2NH 2、-S(O) 2NH(CH 3)、-S(O) 2N(CH 3) 2、
Figure PCTCN2022104003-appb-000033
Figure PCTCN2022104003-appb-000034
在另一优选例中，其中所述通式(1)中，结构单元
Figure PCTCN2022104003-appb-000035
为：
Figure PCTCN2022104003-appb-000036
Figure PCTCN2022104003-appb-000037
Figure PCTCN2022104003-appb-000038
Figure PCTCN2022104003-appb-000039
Figure PCTCN2022104003-appb-000040
Figure PCTCN2022104003-appb-000041
在另一优选例中，其中所述通式(1)中，R 3为(C1-C4)烷基、(C1-C4)卤代烷基、(C2-C4)烯基、(C2-C4)炔基或(C3-C5)环烷基，其中所述烷基、卤代烷基、烯基、炔基和环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-D、-F、-CN、
Figure PCTCN2022104003-appb-000042
Figure PCTCN2022104003-appb-000043
Figure PCTCN2022104003-appb-000044
在另一优选例中，其中所述通式(1)中，R 3为：
Figure PCTCN2022104003-appb-000045
Figure PCTCN2022104003-appb-000046
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：
Figure PCTCN2022104003-appb-000047
Figure PCTCN2022104003-appb-000048
Figure PCTCN2022104003-appb-000049
Figure PCTCN2022104003-appb-000050
Figure PCTCN2022104003-appb-000051
Figure PCTCN2022104003-appb-000052
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)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、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蛋白相关疾病的药物中的应用；所述疾病优选为癌症，所述癌症为血液癌和实体瘤。
本发明的再一个目的还提供治疗、调节或预防与Wee-1蛋白相关疾病的方法，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；所述疾病优选为癌症，所述癌症为血液癌和实体瘤。
通过合成和仔细研究了多类涉及具有Wee-1抑制作用的新化合物，发明人发现在通式(1)化合物中，化合物意外地具有很强的Wee-1抑制活性。
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)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。
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)化合物可采用下列一般反应流程1制备：
一般反应流程1
Figure PCTCN2022104003-appb-000053
通式(1)化合物的实施方式可根据一般反应流程1制备，其中R 1、R 2、R 3、R e、X 1、X 2、X 3、X 4、X 5、X、Y 1、Y 2、Y 3、s、q、A环和B环如上文中所定义，H表示氢，N表示氮，Z表示氯、溴或碘，S表示硫，O表示氧。如一般反应流程1所示,化合物1-1和1-2在碱性条件下发生取代反应生成化合物1-3，化合物1-3在酸性条件下生成化合物1-4，化合物1-4在碱性条件下反应生成1-5，化合物1-5与化合物1-6在碱性条件下反应生成化合物1-7，化合物1-7与m-CPBA反应生成化合物1-8，化合物1-8和1-9发生取代反应生成目标化合物1-10。
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、碳酸等无机酸，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，“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，“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。
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。
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 PCTCN2022104003-appb-000054
除非另有规定，“亚杂芳基”指二价的如上所定义的杂芳基。
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 PCTCN2022104003-appb-000055
Figure PCTCN2022104003-appb-000056
除非另有规定，“亚杂环烷基”指二价的如上所定义的杂环烷基。
除非另有规定，“氧代基”指＝O；例如，碳经一个氧代基取代形成的基团为“羰基
Figure PCTCN2022104003-appb-000057
硫经一个氧代基取代形成的基团为“亚硫酰基
Figure PCTCN2022104003-appb-000058
硫经二个氧代基 取代形成的基团为“磺酰基
Figure PCTCN2022104003-appb-000059
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 PCTCN2022104003-appb-000060
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 PCTCN2022104003-appb-000061
和楔形虚线键
Figure PCTCN2022104003-appb-000062
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022104003-appb-000063
和直形虚线键
Figure PCTCN2022104003-appb-000064
表示立体中心的相对构型，用波浪线
Figure PCTCN2022104003-appb-000065
表示楔形实线键
Figure PCTCN2022104003-appb-000066
或楔形虚线键
Figure PCTCN2022104003-appb-000067
或用波浪线
Figure PCTCN2022104003-appb-000068
表示直形实线键
Figure PCTCN2022104003-appb-000069
或直形虚线键
Figure PCTCN2022104003-appb-000070
除非另有说明，用
Figure PCTCN2022104003-appb-000071
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
本发明通式(1)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通式(1)化合物、或其药学上可接受的组合物的步骤。
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)化合物的药物组合物。其中所述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 PCTCN2022104003-appb-000072
)、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， 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：Ac 2O代表乙酸酐；(Boc) 2O代表二碳酸二叔丁酯；CDCl 3代表氘代氯仿；EtOAc代表乙酸乙酯；Hexane代表正己烷；HPLC代表高效液相色谱；MeCN代表乙腈；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；DMP代表Dess-Martin氧化剂；DMAP代表4-(二甲氨基)吡啶；DMSO代表二甲亚砜；EtOH代表乙醇；EtMgBr代表乙基溴化镁；hr代表小时；IPA代表异丙醇；min代表分钟；K 2CO 3代表碳酸钾；KOAc代表醋酸钾；KOH代表氢氧化钾；K 3PO 4代表磷酸钾；min代表分钟；MeOH代表甲醇；MeMgBr代表甲基溴化镁；MS代表质谱；MsOH代表甲磺酸；m-CPBA代表间氯过氧苯甲酸；n-BuLi代表正丁基锂；NMR代表核磁共振；Pd/C代表钯碳；Pd(PPh 3) 4代表四三苯基膦钯；Pd 2(dba) 3代表三(二亚苄基丙酮)二钯(0)；PE代表石油醚；POBr 3代表三溴氧磷；POCl 3代表三氯氧磷；TEA代表三乙胺；TFA代表三氟乙酸；T 3P代表1-丙基磷酸酐；XantPhos代表4,5-双二苯基膦-9,9-二甲基氧杂蒽；TLC代表薄层色谱；XPhos代表2-二环己基磷-2′,4′,6′-三异丙基联苯。
制备例1-3中间体A-1、A-2和A-3的合成
Figure PCTCN2022104003-appb-000073
步骤1：化合物int_A-1-2的合成:
Figure PCTCN2022104003-appb-000074
将Int_A-1-1(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,Chloroform-d)δ7.12-7.01(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[M+H] +.
步骤2：化合物int_A-1-3的合成:
Figure PCTCN2022104003-appb-000075
Int_A-1-2(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100mL水稀释，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,Chloroform-d)δ8.36-8.20(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[M+H] +.
步骤3：化合物int_A-1-4的合成:
Figure PCTCN2022104003-appb-000076
int_A-1-3(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)δ7.71-7.62(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[M+H] +.
步骤4：化合物int_A-1-5的合成:
Figure PCTCN2022104003-appb-000077
int_A-1-4(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[M+H] +.
步骤5：化合物int_A-1-6的合成:
Figure PCTCN2022104003-appb-000078
int_A-1-5(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/EtOAc＝1/0到1/2)得到黄色固体(1.44g,收率：33.5％)。
1H NMR:(400MHz,Chloroform-d)δ7.24(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[M+H] +.
步骤6：中间体A-1的合成:
Figure PCTCN2022104003-appb-000079
int_A-1-6(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)＝1/0到10/1)得到黄色油状物(6.25g,收率：95.5％)。
1H NMR:(400MHz,Chloroform-d)δ6.31(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[M+H] +.
步骤7：中间体A-2和A-3的合成:
Figure PCTCN2022104003-appb-000080
将int_A-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int_A-2(peak 1,构型为推测,438mg,收率：29.20％)和黄色油状物int_A-3(peak 2,构型为推测,450mg,收率：30.00％)。
A-2： 1H NMR:(400MHz,Chloroform-d)δ6.32(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[M+H] +.
A-3： 1H NMR:(400MHz,Chloroform-d)δ6.32(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[M+H] +.
制备例4-6中间体A-73、A-74和A-75的合成
Figure PCTCN2022104003-appb-000081
步骤1：化合物int_A-73-2的合成:
Figure PCTCN2022104003-appb-000082
将Int_A-73-1(100g,504.6mmol)和甲胺(156.7g,1.51mol,30％purity)溶于乙醇(1200mL)中，加热到80℃反应3小时。反应液冷却至室温，减压浓缩得到粗产品(213g,收率：99.9％％)，粗产物可直接用于下一步反应。
1H NMR:(400MHz,Chloroform-d).δ＝8.60(dd,J＝0.9,7.3Hz,1H),8.21(dd,J＝0.8,8.3Hz,1H),7.83-7.71(m,1H),3.57(s,2H)
步骤2：化合物int_A-73-3的合成:
Figure PCTCN2022104003-appb-000083
int_A-73-2(50g,236.7mmol)和钯碳(25g,10％purity)悬浮于乙酸(500mL)中，氢气加压(50psi)下在30℃搅拌40小时。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(90g,收率：29.4％)。
1H NMR:(400MHz,Chloroform-d).δ＝7.98-7.89(m,1H),7.33-7.21(m,2H),3.65(dd,J＝4.8,11.6Hz,1H),3.34-3.26(m,3H),2.92-2.73(m,2H),2.68-2.57(m,1H),2.06(qdd,J＝3.6,6.6,13.5Hz,1H),1.90-1.76(m,1H),1.70-1.54(m,1H)
步骤3：化合物int_A-73-4的合成:
Figure PCTCN2022104003-appb-000084
将int_A-73-3(33g,153.3mmol)溶于DMF(500mL)中，在氮气保护下于0℃向该溶液中加入NaH(9.20g,230.0mmol,60％purity)。反应液在0℃下反应半小时。将MeI(32.64g,223.0mmol,14.32mL)缓慢滴加入上述反应液中，随后升至25℃反应2小时。LC-MS监测显示反应结束。将反应液倒入1000mL冰水中，水相用乙酸乙酯萃取(1000mL*2)。有机相合并并用饱和食盐水洗(500mL*4)，硫酸镁干燥，有机相过滤，浓缩得到粗产物。柱层析(SiO 2,PE/EtOAc＝10/0到10/1)得到白色固体(80g,收率：75.9％)。
1H NMR:(400MHz,Chloroform-d).δ＝7.99-7.88(m,1H),7.30-7.14(m,2H),3.32-3.21(m,2H),2.99-2.85(m,2H),2.79-2.69(m,1H),2.27(td,J＝3.3,13.1Hz,1H),2.09-1.93(m,2H),1.90-1.80(m,1H)
步骤4：化合物int_A-73-5的合成:
Figure PCTCN2022104003-appb-000085
int_A-73-4(40g,174.5mmol)溶于H 2SO 4(400mL)中，氮气保护下在0℃，缓慢加入KNO 3(19.40g,191.9mmol)，加毕在0℃搅拌半小时。TLC检测显示反应完毕。将反应液倒入1000mL冰水中，水相用乙酸乙酯萃取(1000mL*2)。有机相合并并用饱和食盐水洗(500mL*4)，硫酸镁干燥，有机相过滤，浓缩得到粗产物(95g,收率：99.3％)，粗产物可直接用于下一步反应。
步骤5：化合物int_A-73-6的合成:
Figure PCTCN2022104003-appb-000086
int_A-73-5(30g,109.4mmol)和钯碳(15g,10％purity)悬浮于甲醇(500mL)中，氢气加压(25psi)下在25℃反应5小时。过滤除去钯碳，滤液减压浓缩，柱层析(SiO 2,PE/EtOAc＝10/0到10/7)得到黄色固体(13.20g,收率：16.5％)。
1H NMR(400MHz,Chloroform-d)δ＝7.31(d,J＝2.3Hz,1H),6.67(d,J＝2.3Hz,1H),3.90-3.50(m,2H),3.36-3.28(m,4H),2.91-2.81(m,1H),2.77-2.66(m,1H),2.34-2.25(m,1H),2.10-1.81(m,4H),1.45(s,3H)
步骤6：中间体A-73的合成:
Figure PCTCN2022104003-appb-000087
int_A-73-6(12g,49.12mmol)溶于无水四氢呋喃(500mL)，在0℃加入LiAlH 4(18.64g, 491.2mmol)。氮气保护下，混合物升温至25℃反应16小时。向反应液中缓慢加入Na 2SO 4.10H 2O(100g)淬灭反应，期间保持反应液温度在0～10℃，将反应液过滤并用二氯甲烷(500mL)洗涤滤饼，合并滤液后减压浓缩得到粗产物，粗产物柱层析(
Figure PCTCN2022104003-appb-000088
120g
Figure PCTCN2022104003-appb-000089
Silica Flash Column,Eluent of 0～10％MeOH/DCM)＝1/0到10/1)得到黄色油状物(9.4g,收率：88.5％％)。
1H NMR(400MHz,Chloroform-d)δ＝6.33(s,1H),6.22(dd,J＝0.7,1.5Hz,1H),3.96(d,J＝15.3Hz,1H),3.47(br s,2H),3.21(d,J＝15.3Hz,1H),2.94-2.81(m,1H),2.75-2.60(m,2H),2.43(s,3H),2.18-2.01(m,2H),1.88-1.76(m,1H),1.57(ddd,J＝3.2,5.4,12.6Hz,1H),1.51-1.37(m,1H),1.33(s,3H)
步骤6：中间体A-74和A-75的合成:
Figure PCTCN2022104003-appb-000090
将int_A-73(10g,46.30mmol)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:乙醇(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A-74(peak 1,构型为推测,4.5g,收率：42.4％)和黄色油状物A-75(peak 2,构型为推测,4.5g,收率：42.4％)。
A-74： 1H NMR:(400MHz,Chloroform-d).δ＝6.23(s,1H),6.13(s,1H),3.86(br d,J＝15.3Hz,1H),3.37(br s,2H),3.11(d,J＝15.3Hz,1H),2.86-2.71(m,1H),2.68-2.49(m,2H),2.33(s,3H),2.09-1.95(m,2H),1.79-1.68(m,1H),1.54-1.42(m,1H),1.34(td,J＝6.3,12.6Hz,1H),1.27-1.18(m,3H)
A-75： 1H NMR:(400MHz,Chloroform-d).δ＝6.23(s,1H),6.13(s,1H),3.86(br d,J＝15.3Hz,1H),3.37(br s,2H),3.12(d,J＝15.3Hz,1H),2.85-2.71(m,1H),2.68-2.50(m,2H),2.33(s,3H),2.10-1.95(m,2H),1.79-1.62(m,1H),1.53-1.41(m,1H),1.39-1.29(m,1H),1.25-1.13(m,3H)
使用上述合成方法，采用不同原料，可以得到表1中目标中间体A-4到A-72以及A-76到A-153。
表1
Figure PCTCN2022104003-appb-000091
Figure PCTCN2022104003-appb-000092
Figure PCTCN2022104003-appb-000093
Figure PCTCN2022104003-appb-000094
Figure PCTCN2022104003-appb-000095
Figure PCTCN2022104003-appb-000096
Figure PCTCN2022104003-appb-000097
Figure PCTCN2022104003-appb-000098
制备例7-9中间体B-1、B-2和B-3的合成
Figure PCTCN2022104003-appb-000099
步骤1：化合物int_B-1-2的合成:
Figure PCTCN2022104003-appb-000100
向int_B-1-1(90g,1.07mol,94.74mL)和丙烯腈(28.39g,534.97mmol,35.48mL)中加入四氢吡咯(1.92g,26.96mmol,2.25mL)和乙酸(236.44mg,3.94mmol,225.18uL)。混合物在氮气保护下升温至120℃反应16小时。反应液冷却至室温，减压浓缩除去乙酸得到粗产物(100g，收率：68.1％)，粗产物可直接用于下一步反应。
MS(ESI):138[M+H] +.
步骤2：化合物int_B-1-3的合成:
Figure PCTCN2022104003-appb-000101
向int_B-1-2(40g,291.59mmol)中加入硫酸(243.09g,2.48mol,132.11mL)。混合物在氮气保护下升温至40℃反应12小时。反应液冷却至室温，用氨水调pH值至7～8，过滤，减压干燥得到粗产物(20g，收率：25.4％)，粗产物可直接用于下一步反应。
MS(ESI):136[M+H] +.
步骤3：化合物int_B-1-4的合成:
Figure PCTCN2022104003-appb-000102
将int_B-1-3(17g,125.77mmol)溶于三氯氧磷(84.08g,548.38mmol,50.96mL)，缓慢加入N,N-二甲基苯胺(15.24g,125.77mmol,15.94mL)。混合物在氮气保护下升温至100℃反应8小时。反应液冷却至室温，倒入冰水中淬灭，水相用乙酸乙酯(200mL*3)萃取，有机相用无水硫酸钠干燥、减压浓缩得到粗产物，粗产物经柱层析(
Figure PCTCN2022104003-appb-000103
Silica Flash Column,Eluent of 0～10％Ethyl acetate/Petroleum ether gradient)得到黄色固体(14g,收率：72.5％)。
步骤4：化合物int_B-1-5的合成:
Figure PCTCN2022104003-appb-000104
将int_B-1-4(14g,91.14mmol)溶于甲苯(420mL)，缓慢加入三溴氧膦(57.48g,200.51mmol,20.38mL)。混合物在氮气保护下升温至130℃反应16小时。反应液冷却至室温，减压除去溶剂并用1M氢氧化钠水溶液调pH值至7～8。将混合物倒入冰水中，水相用乙酸乙酯(200mL*3)萃取，有机相用无水硫酸钠干燥、减压浓缩得到粗产物(14.51g)。粗产物可直接用于下一步反应。
MS(ESI):198[M+H] +.
步骤5：化合物int_B-1-6的合成:
Figure PCTCN2022104003-appb-000105
将int_B-1-5(15.50g,78.26mmol)溶于二氯甲烷(150mL)，缓慢加入m-CPBA(23.83g,117.39mmol,85％purity)。混合物在室温反应16小时。反应液用饱和碳酸氢钠水溶液调pH值至7～8。水相用乙酸乙酯(200mL*3)萃取，有机相用无水硫酸钠干燥、减压浓缩得到粗产物。粗产物经柱层析(
Figure PCTCN2022104003-appb-000106
Silica Flash Column,Eluent of 0～60％Ethyl acetate/Petroleum ether gradient)得到棕色固体(10g,收率：59.7％)。
步骤6：化合物int_B-1-7的合成:
Figure PCTCN2022104003-appb-000107
将int_B-1-6(7g,32.70mmol)溶于乙酸酐(104.32g,1.02mol,95.71mL)。混合物升温至120℃反应16小时。反应液冷却至室温，减压除去乙酸酐。残余物用饱和碳酸氢钠水溶液调pH值至7～8。水相用二氯甲烷(100mL*3)萃取，有机相用无水硫酸钠干燥、减压浓缩得到粗产物。粗产物经柱层析(
Figure PCTCN2022104003-appb-000108
Silica Flash Column,Eluent of 0～30％Ethyl acetate/Petroleum ether gradient)得到黄色油状物(7.1g,收率：84.8％)。
MS(ESI):256[M+H] +.
步骤7：化合物int_B-1-8的合成:
Figure PCTCN2022104003-appb-000109
将int_B-1-7(7.1g,27.72mmol)溶于乙醇(75mL)，加入KOH(1.63g,29.11mmol)。混合物在室温反应5小时。向反应液中加入30mL水，减压除去乙醇。水相用二氯甲烷(100mL*3)萃取，有机相用无水硫酸钠干燥、减压浓缩得到粗产物。粗产物经柱层析(
Figure PCTCN2022104003-appb-000110
Silica Flash Column,Eluent of 0～50％Ethyl acetate/Petroleum ether gradient)得到黄色油状物(5.3g,收率：89.3％)。
MS(ESI):214[M+H] +.
步骤8：化合物int_B-1-9的合成:
Figure PCTCN2022104003-appb-000111
将int_B-1-8(5.3g,24.76mmol)溶于二氯甲烷(60mL)，加入DMP(21.00g,49.52mmol)。混合物在室温反应5小时。反应液过滤，滤液用饱和碳酸氢钠水溶液调pH值至7～8，水相用二氯甲烷(150mL*3)萃取。有机相用无水硫酸钠干燥、减压浓缩得到粗产物。粗产物经柱层析(
Figure PCTCN2022104003-appb-000112
Silica Flash Column,Eluent of 0～50％Ethyl acetate/Petroleum ether gradient)得到绿色油状物(4g,收率：76.2％)。
MS(ESI):212[M+H] +.
步骤9：中间体B-1的合成:
Figure PCTCN2022104003-appb-000113
将int_B-1-9(3g,14.15mmol)溶于甲苯(10mL)，氮气保护下于0℃加入EtMgBr(3M,14.15mL)。混合物升至室温反应1小时。反应液用饱和氯化铵溶液淬灭，水相用乙酸乙酯(150mL*3)萃取。有机相用无水硫酸钠干燥、减压浓缩得到粗产物。粗产物经柱层析(
Figure PCTCN2022104003-appb-000114
Silica Flash Column,Eluent of 0～30％Ethyl acetate/Petroleum ether gradient)得到灰色固体(1.6g,收率：49.6％)。
MS(ESI):242[M+H] +.
步骤10：中间体B-2和B-3的合成:
Figure PCTCN2022104003-appb-000115
将B-1(1.6g,6.61mmol)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 2B:iso-propanol(0.05％DEA)；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B-3(peak 1,构型为推测,0.67g,收率：40.2％)和黄色油状物B-2(peak 2,构型为推测,0.69g,收率：41.4％)。
B-3： 1HNMR:(400MHz,DMSO-d 6)δ＝7.61(d,J＝7.8Hz,1H),7.43(d,J＝8.0Hz,1H),5.13(s,1H),2.91-2.82(m,1H),2.68(ddd,J＝5.5,8.5,16.6Hz,1H),2.15(ddd,J＝5.5,8.3,13.5Hz,1H),2.01-1.93(m,1H),1.89-1.78(m,1H),1.71-1.60(m,1H),0.84(t,J＝7.4Hz,3H).B-2： 1HNMR:(400MHz,DMSO-d 6)δ＝7.61(d,J＝8.0Hz,1H),7.43(d,J＝7.9Hz,1H),5.12(br s,1H),2.91-2.81(m,1H),2.73-2.63(m,1H),2.19-2.11(m,1H),1.96(ddd,J＝5.5,8.5,13.5Hz,1H),1.89-1.78(m,1H),1.70-1.59(m,1H),0.84(t,J＝7.4Hz,3H)
制备例10中间体B-4的合成
Figure PCTCN2022104003-appb-000116
步骤1：中间体B-4的合成:
将int_B-1-9(1g,4.72mmol)溶于四氢呋喃(10mL)，氮气保护下于0℃加入MeMgBr(3M,3.14mL)。混合物升至室温反应1小时。反应液用饱和氯化铵溶液淬灭，水相用乙酸乙酯(150mL*3)萃取。有机相用无水硫酸钠干燥、减压浓缩得到粗产物。粗产物经柱层析(
Figure PCTCN2022104003-appb-000117
Silica Flash Column,Eluent of 0～30％Ethyl acetate/Petroleum ether gradient)得到绿色油状物(0.44g,收率：38.9％)。
1HNMR:(400MHz,DMSO-d6)δ＝7.72-7.59(m,1H),7.43(d,J＝7.9Hz,1H),7.30(d,J＝7.9Hz,1H),5.25(s,1H),2.92-2.82(m,1H),2.75-2.66(m,1H),2.11-2.05(m,2H),1.41(s,3H)
MS(ESI):228[M+H] +.
使用上述合成方法，采用不同原料，可以得到表2中目标中间体B-5到B-48。
表2
Figure PCTCN2022104003-appb-000118
Figure PCTCN2022104003-appb-000119
Figure PCTCN2022104003-appb-000120
Figure PCTCN2022104003-appb-000121
实施例1化合物6的合成
Figure PCTCN2022104003-appb-000122
步骤1：化合物int_6-3的合成:
Figure PCTCN2022104003-appb-000123
将int_6-1(13.5g,58.06mmol)，int_6-2(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，残留物用乙酸乙酯(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(21g,收率98％)。
MS(ESI):369[M+H] +.
步骤2：化合物int_6-4的合成:
Figure PCTCN2022104003-appb-000124
将int_6-3(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1小时，LC-MS监测，反应完毕，反应液直接浓缩，残留物经柱层析(DCM/MeOH＝100/1到10/1)得到黄色固体(10g，收率79％)。
MS(ESI):223[M+H] +.
步骤3：化合物int_6-5的合成:
Figure PCTCN2022104003-appb-000125
将int_6-4(2.5g,10mmol)，B-4(2.28g,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到20/1)得到浅黄色固体(1.95g，收率50％)。
MS(ESI):370[M+H] +.
步骤4：化合物int_6-6的合成:
Figure PCTCN2022104003-appb-000126
将int_6-5(390mg,1.0mmol)溶于DCM(20mL)中，加入m-CPBA(305mg,1.5mmol,85％)，室温反应1小时。LC-MS监测，反应完毕，体系碳酸氢钠饱和溶液洗，有机相干燥，旋干得到粗产物(390mg，收率99％)，粗产物可直接用于下一步反应。
MS(ESI):386[M+H] +.
步骤5：化合物6的合成:
Figure PCTCN2022104003-appb-000127
将int_6-6(390mg,1.0mmol)溶于DMF(20mL)溶解，加入三氟乙酸(0.3ml，4.0mmol)，A-73(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，减压旋干，残留物经硅胶柱层析(DCM/MeOH＝100/1到10/1)，得到浅黄色固体化合物(72mg，收率13.2％)。
1H NMR(400MHz,cdcl3)δ8.79(d,J＝2.7Hz,1H),7.76–7.69(m,2H),7.49(s,1H),7.16(s,1H),7.12(s,1H),5.74–5.64(m,1H),5.02–4.99(m,1H),4.90(d,J＝17.1Hz,1H),4.81(d,J＝16.0Hz,1H),4.75–4.67(m,1H),4.15–4.01(m,1H),3.37–3.26(m,1H),3.04(s,0H),2.98–2.84(m,1H),2.75(dt,J＝16.8,8.2Hz,2H),2.49(d,J＝5.0Hz,3H),2.39–2.29(m,2H),2.25–2.12(m,1H),1.61(s,3H),1.49–1.41(m,1H),1.35(d,J＝1.7Hz,3H),1.25(d,J＝1.7Hz,2H).
MS(ESI):538[M+H] +.
实施例2化合物16的合成
Figure PCTCN2022104003-appb-000128
步骤1：化合物int_16-1的合成:
Figure PCTCN2022104003-appb-000129
将int_6-4(2.5g,10mmol)，B-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到20/1)得到浅黄色固体(1.56g，收率40.7％)。
MS(ESI):384[M+H] +.
步骤2：化合物int_16-2的合成:
Figure PCTCN2022104003-appb-000130
将int_16-1(780mg,2.0mmol)溶于DCM(20mL)中，加入m-CPBA(710mg,3mmol,85％)，室温反应1小时。LC-MS监测，反应完毕，体系碳酸氢钠饱和溶液洗，有机相干燥，旋干得到粗产物(780mg，收率99％)，粗产物可直接用于下一步反应。
MS(ESI):400[M+H] +.
步骤3：化合物16的合成:
Figure PCTCN2022104003-appb-000131
将int_16-2(780mg,1.95mmol)溶于DMF(20mL)溶解，加入三氟乙酸(0.3ml，4.0mmol)，A-73(506.2mg,2.3mmol)，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，减压旋干，残留物经硅胶柱层析(DCM/MeOH＝100/1到10/1)，得到浅黄色固体化合物(216mg，收率20％)。
MS(ESI):552[M+H] +.
实施例3化合物19的合成
Figure PCTCN2022104003-appb-000132
步骤1：化合物int_19-1的合成:
Figure PCTCN2022104003-appb-000133
将int_6-4(2.5g,10mmol)，B-2(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到20/1)得到浅黄色固体(1.6g，收率41％)。
MS(ESI):384[M+H] +.
步骤2：化合物int_19-2的合成:
Figure PCTCN2022104003-appb-000134
将int_19-1(780mg,2.0mmol)溶于DCM(20mL)中，加入m-CPBA(710mg,3mmol,85％)，室温反应1小时。LC-MS监测，反应完毕，体系碳酸氢钠饱和溶液洗，有机相干燥，旋干得到粗产物(775mg，收率97％)，粗产物可直接用于下一步反应。
MS(ESI):400[M+H] +.
步骤3：化合物19的合成:
Figure PCTCN2022104003-appb-000135
将int_19-2(780mg,1.95mmol)溶于DMF(20mL)溶解，加入三氟乙酸(0.3ml，4.0mmol)，A-75(506.2mg,2.3mmol)，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，减压旋干，残留物经硅胶柱层析(DCM/MeOH＝100/1到10/1)，得到浅黄色固体化合物(220mg，收率20％)。
1H NMR(400MHz,cdcl3)δ8.78(s,1H),7.71(d,J＝1.9Hz,2H),7.49(s,1H),7.13(s,1H),7.11(s,1H),5.73–5.61(m,1H),5.01(dt,J＝10.2,1.3Hz,1H),4.90(dt,J＝17.4,1.6Hz,1H),4.83(d,J＝5.8Hz,1H),4.69(dd,J＝15.7,6.7Hz,1H),4.00(d,J＝15.2Hz,1H),3.26(d,J＝15.2Hz,1H),3.08–3.00(m,1H),2.97–2.70(m,4H),2.66(d,J＝10.8Hz,1H),2.45(s,3H),2.37(td,J＝8.6,4.2Hz,1H),2.29–2.20(m,1H),2.14(dd,J＝16.8,9.4Hz,2H),2.01(dq,J＝14.8,7.4Hz,2H),1.81(t,J＝7.4Hz,1H),1.60(ddd,J＝12.8,5.5,3.3Hz,1H),1.44(td,J＝12.6,5.7Hz,1H),1.33(s,3H),0.98(t,J＝7.4Hz,3H).
MS(ESI):552[M+H] +.
实施例4化合物20的合成
Figure PCTCN2022104003-appb-000136
步骤1：化合物int_20-1的合成:
Figure PCTCN2022104003-appb-000137
将int_6-4(2.5g,10mmol)，B-3(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到20/1)得到浅黄色固体(1.65g，收率41％)。
MS(ESI):384[M+H] +.
步骤2：化合物int_20-2的合成:
Figure PCTCN2022104003-appb-000138
将int_20-1(780mg,2.0mmol)溶于DCM(20mL)中，加入m-CPBA(710mg,3mmol,85％)，室温反应1小时。LC-MS监测，反应完毕，体系碳酸氢钠饱和溶液洗，有机相干燥，旋干得到粗产物(778mg，收率97％)，粗产物可直接用于下一步反应。
MS(ESI):400[M+H] +.
步骤3：化合物20的合成:
Figure PCTCN2022104003-appb-000139
将int_20-2(780mg,1.95mmol)溶于DMF(20mL)溶解，加入三氟乙酸(0.3ml，4.0mmol)，A-75(506.2mg,2.3mmol)，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，减压旋干，残留物经硅胶柱层析(DCM/MeOH＝100/1到10/1)，得到浅黄色固体化合物(218mg，收率20％)。
1H NMR(400MHz,cdcl3)δ8.79(s,1H),7.72(d,J＝1.6Hz,2H),7.44(d,J＝22.9Hz,1H),7.11(s,2H),5.73–5.62(m,1H),5.01(dd,J＝10.2,1.3Hz,1H),4.93–4.80(m,2H),4.68(dd,J＝15.7,6.7Hz,1H),3.98(d,J＝15.3Hz,1H),3.24(d,J＝15.2Hz,1H),3.04(ddd,J＝16.4,9.0,4.5Hz,1H),2.97–2.70(m,4H),2.64(d,J＝10.8Hz,1H),2.44(s,3H),2.37(td,J＝8.7,4.3Hz,1H),2.28–2.20(m,1H),2.14(t,J＝9.4Hz,2H),2.01(dd,J＝14.0,7.3Hz,1H),1.85(t,J＝7.0Hz,2H),1.59(ddd,J＝8.7,5.5,2.7Hz,1H),1.45(dt,J＝12.6,6.3Hz,1H),1.33(s,3H),0.97(d,J＝7.4Hz,3H).
MS(ESI):552[M+H] +.
使用上述合成方法，采用不同原料(不同的中间体A、不同的中间体B以及其他不同的中间体)，可以得到表3中目标化合物1-5、7-15以及17、18、21-166。
表3
Figure PCTCN2022104003-appb-000140
Figure PCTCN2022104003-appb-000141
Figure PCTCN2022104003-appb-000142
Figure PCTCN2022104003-appb-000143
Figure PCTCN2022104003-appb-000144
Figure PCTCN2022104003-appb-000145
Figure PCTCN2022104003-appb-000146
Figure PCTCN2022104003-appb-000147
实施例5本发明化合物体外抑制重组蛋白Wee-1酶活试验
运用HTRF方法测定化合物对重组蛋白Wee-1酶活的抑制作用。具体如下。
DMSO或者梯度稀释的化合物(最高200nM,1:5梯度稀释)和重组蛋白在激酶缓冲液中37度孵育30分钟后，加入Fluorescein-PolyGAT和ATP后，加入底物启动反应。室温反应90分钟后，加入抗体和检测液，室温继续孵育60分钟后，读取荧光值(激发波长：340nm，发射波长495和520nm。计算520nm/495nm荧光强度比值，与DMSO组相比，进而计算化合物抑制百分比和IC 50。结果见下列表4。
表4本发明化合物对重组蛋白Wee-1的抑制活性(IC 50，nM)
化合物 IC 50 化合物 IC 50 化合物 IC 50 化合物 IC 50
1 +++ 2 +++ 3 +++ 4 +++
5 +++ 6 +++ 7 +++ 8 +++
9 +++ 10 +++ 11 +++ 12 +++
13 +++ 14 +++ 15 +++ 16 +++
17 +++ 18 +++ 19 +++ 20 +++
21 +++ 22 +++ 23 +++ 24 +++
25 +++ 26 +++ 27 +++ 28 +++
29 +++ 30 +++ 31 +++ 32 +++
33 +++ 34 +++ 35 +++ 36 +++
37 +++ 38 +++ 39 +++ 40 +++
41 +++ 42 +++ 43 +++ 44 +++
45 +++ 46 +++ 47 +++ 48 +++
49 +++ 50 +++ 51 +++ 52 +++
53 +++ 54 +++ 55 +++ 56 +++
57 +++ 58 +++ 59 +++ 60 +++
61 +++ 62 +++ 63 +++ 64 +++
65 +++ 66 +++ 67 +++ 68 +++
69 +++ 70 +++ 71 +++ 72 +++
73 +++ 74 +++ 75 +++ 76 +++
77 +++ 78 +++ 79 +++ 80 +++
81 +++ 82 ++ 83 ++ 84 ++
85 ++ 86 ++ 87 ++ 88 +++
89 +++ 90 +++ 91 +++ 92 +++
93 +++ 94 +++ 95 +++ 96 +++
97 +++ 98 +++ 99 +++ 100 +++
101 +++ 102 +++ 103 +++ 104 +++
105 +++ 106 +++ 107 +++ 108 +++
111 +++ 112 +++ 113 +++ 114 +++
115 +++ 116 +++ 117 +++ 118 +++
119 +++ 120 +++ 121 +++ 122 +++
123 +++ 124 +++ 125 +++ 126 +++
127 ++ 128 ++ 129 ++ 130 +++
131 +++ 132 +++ 133 +++ 134 +++
135 +++ 136 +++ 137 +++ 138 +++
139 +++ 140 +++ 141 +++ 142 +++
143 +++ 144 +++ 145 +++ 146 +++
147 +++ 148 +++ 149 +++ 150 +++
151 +++ 152 +++ 153 +++ 154 +++
155 +++ 156 +++ 157 +++ 158 +++
159 +++ 160 +++ 161 +++ 162 +++
163 +++ 164 +++ 165 +++ 166 +++
+++表示IC 50小于或等于10nM
++表示IC 50为10nM至50nM
+表示IC 50大于50nM。
从表4数据可知，本发明化合物对重组蛋白Wee-1的酶活性有较好的抑制活性。
实施例6本发明化合物对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。
表5本发明化合物对MIA PaCa-2细胞的抗增殖活性
Figure PCTCN2022104003-appb-000148
从表5数据可见本发明化合物对MIA PaCa-2细胞都具有较弱的抗增殖活性。
实施例7本发明化合物联合吉西他滨(Gemcitabine)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6。
表6本发明化合物联合吉西他滨(Gemcitabine)对MIA PaCa-2细胞的体外抗增殖活性
Figure PCTCN2022104003-appb-000149
从表6数据可见本发明化合物联合吉西他滨(Gemcitabine)对MIA PaCa-2细胞都具有较强的体外抗增殖活性。
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 (27)

  1. 一种如通式(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：
    Figure PCTCN2022104003-appb-100001
    通式(1)中：
    X为CH或N；
    环A为(C5-C11)部分不饱和环烷基或(5-11元)部分不饱和杂环烷基；
    每个R 1独立地为-H、-D、卤素、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8、-S(O) 2NR 8R 9、
    Figure PCTCN2022104003-appb-100002
    (C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基或(C3-C9)环烷基，其中所述烷基、卤代烷基、烯基、炔基和环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或2个相邻的R 1与他们所连接的原子能够共同组成(5-7元)杂环烷基或(C3-C9)环烷基，此杂环烷基和环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或A环上同一个碳原子上的2个R 1与他们所连接的碳原子能够共同组成(4-7元)杂环烷基或(C3-C6)环烷基，此杂环烷基和环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
    Y 1为N或C-R 4；
    Y 2为N或C-R 5；
    Y 3为N或C-R 6；
    R 4、R 5和R 6各自独立地为-H、-D、卤素、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、 -NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8、-S(O) 2NR 8R 9、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基或(C3-C9)环烷基，其中所述烷基、卤代烷基、烯基、炔基和环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或R 5和R 6与他们所连接的原子能够共同组成(5-9元)杂环烷基、(5-9元)杂芳基或(C5-C9)环烷基，此杂环烷基、杂芳基和环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
    B环为(C5-C11)部分不饱和环烷基或(5-11元)部分不饱和杂环烷基；
    X 1为
    Figure PCTCN2022104003-appb-100003
    X 2为化学键、
    Figure PCTCN2022104003-appb-100004
    X 3为CH、N或C-R c；
    X 4为CH、N或C-R d；
    X 5为N-R a或CH-R b；
    每个R 2独立地为-H、-D、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8、-S(O) 2NR 8R 9、
    Figure PCTCN2022104003-appb-100005
    (C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基，其中所述烷基、卤代烷基、烯基、炔基、环烷基、芳基、杂环烷基和杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或2个相邻的R 2与他们所连接的原子能够共同组成(5-7元)杂环烷基或(C3-C9)环烷基，此杂环烷基和环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或B环上同一个碳原子上的2个R 2与他们所连接的碳原子能够共同组成(4-7元)杂环烷基或(C3-C6)环烷基，此杂环烷基和环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或R 2和一个相邻的R e与他们所连接的原子能够共同组成(5-7元)杂环烷基或(C3-C9)环烷基，此杂环烷基和环烷基可任选被1，2，3或4个下列基团取 代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
    R a为-H、-(CH 2) mOR 8、-(CH 2) mNR 8R 9、(C1-C6)烷基、(C1-C6)卤代烷基、(C3-C14)环烷基或(3-15元)杂环烷基，其中所述烷基、卤代烷基、环烷基和杂环烷基可任选被1，2，3或4个下列基团取代：-H、-D、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
    R b为-H、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、(C1-C6)烷基、(C1-C6)卤代烷基、(C3-C14)环烷基或(3-15元)杂环烷基，其中所述R 8、R 9、烷基、卤代烷基、环烷基和杂环烷基可任选被1，2，3或4个下列基团取代：-H、-D、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
    R c和R d各自独立地为-H、卤素、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8、-S(O) 2NR 8R 9、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基，其中所述烷基、卤代烷基、烯基、炔基、环烷基、芳基、杂环烷基和杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
    R e为-H、-D、卤素、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C1-C6)烷氧基、(C1-C6)卤代烷氧基、(C3-C9)环烷基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基，其中所述烷基、卤代烷基、烯基、炔基、烷氧基、卤代烷氧基、环烷基、芳基、杂环烷基和杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
    R f和R g各自独立地为-H、-D、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-CN、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基，其中所述烷基、卤代烷基、烯基、炔基、环烷基、芳基、杂环烷基和杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或R f和R g与他们所连接的碳原子能够共同组成(4-7元)杂环烷基或(C3-C6)环烷基，此杂环烷基和环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、 -NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；或R f和一个相邻的R e与他们所连接的原子能够共同组成(C3-C9)环烷基或(3-11元)杂环烷基，其中所述环烷基和杂环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
    R 3为(C1-C5)烷基、(C1-C5)卤代烷基、(C2-C5)烯基、(C2-C5)炔基或(C3-C6)环烷基，其中所述烷基、卤代烷基、烯基、炔基和环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-D、卤素、R 7、R 8、-OH、-(CH 2) nOR 8、-(CH 2) nNR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-S(O) pR 8和-S(O) 2NR 8R 9；
    R 7为(C1-C5)卤代烷基、(C2-C5)烯基或(C2-C5)炔基；
    R 8和R 9各自独立地为-H、(C1-C6)烷基、(C1-C3)卤代烷基或(C3-C14)环烷基，或同一个氮原子上的R 8和R 9与他们所连接的N原子能够共同组成(3-11元)杂环烷基，此杂环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、R 10和-OR 10；
    R 10为-H、(C1-C6)烷基或(C3-C14)环烷基；和
    p为0、1或2的整数，q为1、2、3或4的整数，s为1、2、3或4的整数，n为0、1、2或3的整数，m为1、2或3的整数。
  2. 如权利要求1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，其中所述通式(1)中，环A为(C5-C7)部分不饱和环烷基或(5-7元)部分不饱和杂环烷基。
  3. 如权利要求2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，其中所述通式(1)中，环A为：
    Figure PCTCN2022104003-appb-100006
  4. 如权利要求1-3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，其中所述通式(1)中，每个R 1独立地为-H、-D、-F、-Cl、-Br、-I、-OH、-CH 2OR 8、-CH 2NR 8R 9、-OR 9、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、 -SR 8、-S(O) 2R 8、-S(O) 2NR 8R 9、(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基、(C2-C4)炔基或(C3-C6)环烷基，其中所述烷基、卤代烷基、烯基、炔基和环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-OH、-OCH 3、-N(CH 3) 2和-CN；或2个相邻的R 1与他们所连接的原子能够共同组成(5-7元)杂环烷基或(C3-C6)环烷基，此杂环烷基和环烷基可任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN；或A环上同一个碳原子上的2个R 1与他们所连接的碳原子能够共同组成(4-7元)杂环烷基或(C3-C6)环烷基，此杂环烷基和环烷基可任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN。
  5. 如权利要求4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，其中所述通式(1)中，每个R 1独立地为：-H、-D、-F、-Cl、-Br、-I、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-OCF 3、-N(CH 3) 2、-CN、-C(O)NH 2、-C(O)NH(CH 3)、-C(O)N(CH 3) 2、-NHC(O)CH 3、-N(CH 3)-C(O)CH 3、-NHS(O) 2CH 3、-N(CH 3)-S(O) 2CH 3、-SCH 3、-S(O) 2CH 3和-S(O) 2NH 2、-S(O) 2NH(CH 3)、-S(O) 2N(CH 3) 2、-CD 3、-CD 2CD 3、
    Figure PCTCN2022104003-appb-100007
    Figure PCTCN2022104003-appb-100008
  6. 如权利要求1-5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，其中所述通式(1)中，R 4、R 5和R 6各自独立地为-H、-D、-F、-Cl、-Br、-I、-OH、-CH 2OR 8、-CH 2NR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-SR 8、-S(O) 2R 8、-S(O) 2NR 8R 9、(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基、(C2-C4)炔基或(C3-C6)环烷基，其中所述烷基、卤代烷基、烯基、炔基和环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-OH、-OCH 3、-N(CH 3) 2和-CN；或R 5和R 6与他们所连接的原子能够共同组成芳基、(5-6元)杂环烷基、(5-6元)杂芳基或(C5-C6)环烷基，此芳基、杂环烷基、杂芳基和环烷基可任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN。
  7. 如权利要求6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，其中所述通式(1)中，R 4、R 5和R 6各自独立地为：-H、-D、-F、-Cl、-Br、-I、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-OCF 3、-N(CH 3) 2、-CN、-C(O)NH 2、-C(O)NH(CH 3)、-C(O)N(CH 3) 2、-NHC(O)CH 3、-N(CH 3)-C(O)CH 3、-NHS(O) 2CH 3、-N(CH 3)-S(O) 2CH 3、-SCH 3、-S(O) 2CH 3和-S(O) 2NH 2、-S(O) 2NH(CH 3)、-S(O) 2N(CH 3) 2、
    Figure PCTCN2022104003-appb-100009
    Figure PCTCN2022104003-appb-100010
  8. 如权利要求1-7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，其中所述通式(1)中，结构单元
    Figure PCTCN2022104003-appb-100011
    为：
    Figure PCTCN2022104003-appb-100012
    Figure PCTCN2022104003-appb-100013
    Figure PCTCN2022104003-appb-100014
  9. 如权利要求1-8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，其中所述通式(1)中，B环为(C5-C8)部分不饱和环烷基或(5-8元)部分不饱和杂环烷基；和R e为：-H、-D、-F、-CH 3、-OCH 3、
    Figure PCTCN2022104003-appb-100015
    或-CH 2CH 3。
  10. 如权利要求1-9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，其中所述通式(1)中，结构单元
    Figure PCTCN2022104003-appb-100016
    为：
    Figure PCTCN2022104003-appb-100017
    Figure PCTCN2022104003-appb-100018
    Figure PCTCN2022104003-appb-100019
  11. 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，其中所述通式(1)中，X 1为：
    Figure PCTCN2022104003-appb-100020
    Figure PCTCN2022104003-appb-100021
  12. 如权利要求1-11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，其中所述通式(1)中，X 2为：化学键、
    Figure PCTCN2022104003-appb-100022
    Figure PCTCN2022104003-appb-100023
  13. 如权利要求1-12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，其中所述通式(1)中，当X 5为N-R a时，其中R a为-H、-(CH 2) 2OR 8、-(CH 2) 2NR 8R 9、(C1-C3)烷基、(C1-C3)卤代烷基、(C3-C6)环烷基或(4-7元)杂环烷基，其中所述烷基、卤代烷基、环烷基和杂环烷基可独立任选被1，2，3或4个下列基团取代：-H、-D、-F、-OH、-CH 3、-CH 2OCH 3、-(CH 2) 2OCH 3、-OCH 3、-OCH 2CH 3、-OCH(CH 3) 2、
    Figure PCTCN2022104003-appb-100024
    -OCF 3、-CH 2N(CH 3) 2、-(CH 2) 2N(CH 3) 2、-N(CH 3) 2和-CN。
  14. 如权利要求13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，其中所述通式(1)中，当X 5为N-R a时，其中R a为：-H、-(CH 2) 2OCH 3、-(CH 2) 2OH、-(CH 2) 2N(CH 3) 2、
    Figure PCTCN2022104003-appb-100025
    Figure PCTCN2022104003-appb-100026
  15. 如权利要求1-12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，其中所述通式(1)中，当X 5为CH-R b时，其中R b为-H、-(CH 2) 2OR 8、-NR 8R 9、-(CH 2) 2NR 8R 9、(C1-C3)烷基、(C1-C3)卤代烷基、(C3-C6)环烷基或(4-7元)杂环烷基，其中所述R 8、R 9、烷基、卤代烷基、环烷基和杂环烷基可独立任选被1，2，3或4个下列基团取代：-H、-D、-F、-OH、-CH 3、-CH 2OCH 3、-(CH 2) 2OCH 3、-OCH 3、-OCH 2CH 3、-OCH(CH 3) 2、
    Figure PCTCN2022104003-appb-100027
    -OCF 3、-CH 2N(CH 3) 2、-(CH 2) 2N(CH 3) 2、-N(CH 3) 2和-CN。
  16. 如权利要求15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，其中所述通式(1)中，当X 5为CH-R b时，其中R b为：-H、-N(CH 3) 2、-N(CD 3) 2、-(CH 2) 2OCH 3、-(CH 2) 2OH、-(CH 2) 2N(CH 3) 2、
    Figure PCTCN2022104003-appb-100028
    Figure PCTCN2022104003-appb-100029
  17. 如权利要求1-16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，其中所述通式(1)中，X 3为：CH、N或C-R c，其中所述R c为：-H、-F、-Cl、-Br、-I、-OH、-CH 3、-CH 2OCH 3、
    Figure PCTCN2022104003-appb-100030
    -(CH 2) 2OCH 3、-OCH 3、-OCH 2CH 3、-OCH(CH 3) 2、-OCF 3、-CH 2N(CH 3) 2、-(CH 2) 2N(CH 3) 2、-N(CH 3) 2或-CN。
  18. 如权利要求1-16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，其中所述通式(1)中，X 4为：CH、N或C-R d，其中所述R d为：-H、-F、-Cl、-Br、-I、-OH、-CH 3、-CH 2OCH 3、
    Figure PCTCN2022104003-appb-100031
    -(CH 2) 2OCH 3、-OCH 3、-OCH 2CH 3、-OCH(CH 3) 2、-OCF 3、-CH 2N(CH 3) 2、-(CH 2) 2N(CH 3) 2、-N(CH 3) 2或-CN。
  19. 如权利要求1-18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，其中所述通式(1)中，每个R 2独立地为-H、-D、-F、-Cl、-Br、-I、-OH、-CH 2OR 8、-CH 2NR 8R 9、-OR 8、-NR 8R 9、-CN、-C(O)NR 8R 9、-NR 9C(O)R 8、-NR 9S(O) 2R 8、-SR 8、-S(O) 2R 8、-S(O) 2NR 8R 9、(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基、(C2-C4)炔基、(C3-C6)环烷基、苯基、(4-8元)杂环烷基或(5-6元)杂芳基，其中所述烷基、卤代烷基、烯基、炔基、环烷基、苯基、杂环烷基和杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-OCH 3、-N(CH 3) 2和-CN；或2个相邻的R 2与他们所连接的原子能够共同组成(5-7元)杂环烷基或(C3-C6)环烷基，此杂环烷基和 环烷基可任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN；或B环上同一个碳原子上的2个R 2与他们所连接的碳原子能够共同组成(4-7元)杂环烷基或(C3-C6)环烷基，此杂环烷基和环烷基可任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN；或R 2和一个相邻的R e与他们所连接的原子能够共同组成(5-7元)杂环烷基或(C3-C6)环烷基，此杂环烷基和环烷基可任选被1，2，3或4个下列基团取代：-H、-F、-Cl、-Br、-I、-CH 3、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-N(CH 3) 2和-CN。
  20. 如权利要求19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，其中所述通式(1)中，每个R 2独立地为：-H、-D、-F、-Cl、-Br、-I、-OH、-CH 2OCH 3、-CH 2N(CH 3) 2、-OCH 3、-OCF 3、-N(CH 3) 2、-CN、-C(O)NH 2、-C(O)NH(CH 3)、-C(O)N(CH 3) 2、-NHC(O)CH 3、-N(CH 3)-C(O)CH 3、-NHS(O) 2CH 3、-N(CH 3)-S(O) 2CH 3、-SCH 3、-S(O) 2CH 3和-S(O) 2NH 2、-S(O) 2NH(CH 3)、-S(O) 2N(CH 3) 2、
    Figure PCTCN2022104003-appb-100032
    Figure PCTCN2022104003-appb-100033
  21. 如权利要求1-20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，其中所述通式(1)中，结构单元
    Figure PCTCN2022104003-appb-100034
    为：
    Figure PCTCN2022104003-appb-100035
    Figure PCTCN2022104003-appb-100036
    Figure PCTCN2022104003-appb-100037
    Figure PCTCN2022104003-appb-100038
  22. 如权利要求1-21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，其中所述通式(1)中，R 3为(C1-C4)烷基、(C1-C4)卤代烷基、(C2-C4)烯基、(C2-C4)炔基或(C3-C5)环烷基，其中所述烷基、卤代烷基、烯基、炔基和环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-D、-F、-CN、
    Figure PCTCN2022104003-appb-100039
    Figure PCTCN2022104003-appb-100040
  23. 如权利要求22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，其中所述通式(1)中，R 3为：
    Figure PCTCN2022104003-appb-100041
    Figure PCTCN2022104003-appb-100042
  24. 如权利要求1-23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，其中所述化合物具有以下结构之一：
    Figure PCTCN2022104003-appb-100043
    Figure PCTCN2022104003-appb-100044
    Figure PCTCN2022104003-appb-100045
    Figure PCTCN2022104003-appb-100046
    Figure PCTCN2022104003-appb-100047
    Figure PCTCN2022104003-appb-100048
  25. 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1-24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、水合物或溶剂合物作为活性成分。
  26. 一种如权利要求1-24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25所述的药物组合物在制备治疗或预防由Wee-1介导的相关疾病的药物中的应用。
  27. 如权利要求26所述的应用，其中所述的疾病是癌症，所述癌症是血液癌和实体瘤。
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