WO2024051717A1 - Composé en tant qu'inhibiteur de plk1, son procédé de préparation et son utilisation - Google Patents

Composé en tant qu'inhibiteur de plk1, son procédé de préparation et son utilisation Download PDF

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WO2024051717A1
WO2024051717A1 PCT/CN2023/117138 CN2023117138W WO2024051717A1 WO 2024051717 A1 WO2024051717 A1 WO 2024051717A1 CN 2023117138 W CN2023117138 W CN 2023117138W WO 2024051717 A1 WO2024051717 A1 WO 2024051717A1
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alkyl
independently selected
alkoxy
alkynyl
alkenyl
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Chinese (zh)
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李冬冬
张晓敏
朱正诞
王冬冬
孙伟杰
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上海深势唯思科技有限责任公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • 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
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    • 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
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    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems
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    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
    • C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom

Definitions

  • the present invention provides a class of compounds as PLK1 inhibitors and their preparation methods and uses.
  • the compounds and compositions containing them can be used to prevent and/or treat tumor-related diseases.
  • PLK1 belongs to the Polo-like kinases (PLKs) family (including PLK1/2/3/4). It is a highly conserved Ser/Thr protein kinase that plays an important role in the normal operation of the cell cycle, centrosome maturation, and cytoplasmic separation. makes an important impact. PLK1 regulates the G2/M transition by phosphorylating downstream cell cycle proteins such as WEE1/CDK1; PLK1 inhibition causes cell mitosis to be arrested in the G2 phase and induces apoptosis (Sci Signal. 2018 Aug 14; 11(543):eaar4195). In addition, PLK1 also regulates cell functions other than mitosis. For example, PLK1 repairs damaged DNA and promotes tumor cell proliferation (Mol Cell.
  • PLK1 is overexpressed in most malignant tumors, including colorectal cancer, breast cancer, lung cancer, prostate cancer, leukemia and pancreatic cancer, mediating poor patient prognosis (Genes 2019,10,208; World J Gastroenterol 2005; 11(36) ):5644-5650).
  • PLK1 is highly related to multiple tumor-related targets and pathways. RAS mutations cause mitotic stress in cells, making tumor cells more dependent on PLK1 for mitosis. Interfering with the mitosis process can promote synthetic lethality in tumor cells.
  • PLK1 knockout or inhibition of PLK1 The kinase activity of RAS mutant cells arrests mitosis in the G2/M phase (Cell 137, 835–848, May 29, 2009); PLK1 can directly phosphorylate p53 protein to mediate p53 instability, or indirectly promote the phosphorylation of TOPORS and GTSE1, Degrade p53, causing it to lose its tumor suppressor effect; PLK1 directly stabilizes or promotes the expression of the oncogenic protein Myc, promoting the occurrence and development of tumors; PLK1 can also inhibit the phosphorylation of PTEN and activate the PI3K signaling pathway.
  • small molecules targeting the enzymatic activity of PLK1 have broad therapeutic effects on PLK1-related tumors.
  • the present invention provides a new PLK1 inhibitor that can be used to prevent and/or treat PLK1-related diseases, such as tumors.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt or deuterated product thereof:
  • E is independently selected from C, N, O;
  • T, M, Q are independently selected from N, CR3;
  • X, Y and Z are independently selected from N and CR5;
  • Ring A is selected from phenyl and contains 1-3 5-11-membered heteroaryl groups independently selected from N, O, and S;
  • Ring B is connected to the ring carbon atom or ring nitrogen atom of A ring;
  • R1 is independently C 1-4 alkyl
  • two R1 together with the C to which they are attached may form a 3-7 membered cycloalkyl group, which is optionally one or more independently selected from F , Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy group substitution
  • the alkyl, Alkenyl, alkynyl, and alkoxy groups are optionally selected from one or more groups independently selected from F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2 -4 alkynyl, C 1-4 alkoxy group substituted;
  • R2 is independently selected from H, F, Cl, Br, OH, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 Cycloalkyl, 3-7-membered heterocycloalkyl containing 1-3 independently selected from N, O, S, 5-11-membered heteroaryl containing 1-3 independently selected from N, O, S , -C(O)R8, -C(O)NR8R9, -S(O) 2 R8, -S(O) 2 NR8R9, -NR8R9, -P(O)R8R9, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl groups are optionally one or more independently selected from F , Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkyny
  • R3 is independently selected from H, F, Cl, Br, OH, CN, NO 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 cycloalkyl, 3-7-membered heterocycloalkyl containing 1-3 independently selected from N, O, S, 5-11-membered containing 1-3 independently selected from N, O, S Heteroaryl, -C(O)R8, -C(O)NR8R9, -S(O) 2 R8, -S(O) 2 NR8R9, -NR8R9, -NR8C(O)R9, -P(O)R8R9, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl groups are optionally replaced by one or Multiple independently selected from F, Cl, Br, OH, CN, -NH 2 , C 1-4
  • R4 is selected from H, F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3- 7 cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C 1 -4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy groups substituted;
  • R5 is independently selected from H, F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally one or more independently selected from F, Cl, Br, OH, CN, NH 2 , Substituted with C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy groups;
  • R6 is selected from NR8R9, NR8C(O)R9, C(O)NR8R9, C 1-4 alkyl, piperazinyl, bridged piperazinyl, spiropiperazinyl, the alkyl, piperazinyl, bridged piperazinyl Base, spiropiperazinyl is optionally substituted by one or more R7;
  • R6 together with its connected ring C atom, ring Y atom, and the bond between the ring C atom and ring Y atom, forms a 5-7 membered heterocycloalkane containing 1-3 independently selected from N, O, and S group, the ring may be optionally replaced by one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl , C 1-4 alkoxy group substituted, the alkyl, alkenyl, alkynyl, alkoxy group optionally by one or more independently selected from F, Cl, Br, OH, CN, NH 2. Substituted with C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy groups;
  • R8 and R9 are independently selected from H, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, the alkyl, alkenyl , Alkynyl and alkoxy groups are optionally substituted by one or more groups selected from F, Cl, Br, OH, CN, NH 2 ;
  • R8 and R9 When R8 and R9 are connected on the same atom, R8 and R9 together with the atoms to which they are connected can form a 3-7-membered heterocycloalkyl group containing 1-3 independently selected from N, O, and S.
  • the alkyl group is optionally one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1 -4 alkoxy groups substituted, the alkyl, alkenyl, alkynyl, alkoxy groups optionally by one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C Substituted with 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy groups;
  • n 0, 1, 2 or 3.
  • w 0, 1, 2.
  • the present invention provides a compound represented by the following formula (IA) or a pharmaceutically acceptable salt or deuterated product thereof:
  • T, M, Q are independently selected from N, CR3;
  • X, Y and Z are independently selected from N and CR5;
  • R1 is independently C 1-4 alkyl
  • the two R1 together with the C to which they are attached may form a 3-7 membered cycloalkyl group, which may optionally be one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy group substituted, the alkyl group , alkenyl, alkynyl, alkoxy is optionally one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C Substituted with 2-4 alkynyl and C 1-4 alkoxy groups;
  • R2 is independently selected from H, F, Cl, Br, OH, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 Cycloalkyl, 3-7-membered heterocycloalkyl containing 1-3 independently selected from N, O, S, 5-6-membered heteroaryl containing 1-3 independently selected from N, O, S , -C(O)R8, -C(O)NR8R9, -S(O) 2 R8, -S(O) 2 NR8R9, -NR8R9, -P(O)R8R9, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl groups are optionally one or more independently selected from F , Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkyny
  • R3 is independently selected from H, F, Cl, Br, OH, CN, NO 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 cycloalkyl, 3-7-membered heterocycloalkyl containing 1-3 independently selected from N, O, S, 5-6-membered containing 1-3 independently selected from N, O, S Heteroaryl, -C(O)R8, -C(O)NR8R9, -S(O) 2 R8, -S(O) 2 NR8R9, -NR8R9, -NR8C(O)R9, -P(O)R8R9, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl groups are optionally replaced by one or Multiple independently selected from F, Cl, Br, OH, CN, -NH 2 , C 1-4
  • R4 is selected from H, F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3- 7 cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C 1 -4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy groups substituted;
  • R5 is independently selected from H, F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally one or more independently selected from F, Cl, Br, OH, CN, NH 2 , Substituted with C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy groups;
  • R8 and R9 are independently selected from H, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, the alkyl, alkenyl , Alkynyl and alkoxy groups are optionally substituted by one or more groups selected from F, Cl, Br, OH, CN, NH 2 and C 1-4 alkyl;
  • R8 and R9 When R8 and R9 are connected on the same atom, R8 and R9 together with the atoms to which they are connected can form a 3-7-membered heterocycloalkyl group containing 1-3 independently selected from N, O, and S.
  • the alkyl group is optionally one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1 -4 alkoxy groups substituted, the alkyl, alkenyl, alkynyl, alkoxy groups optionally by one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C Substituted with 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy groups;
  • n 0, 1, 2 or 3;
  • n 0, 1, 2, 3, 4, 5, 6, 7 or 8.
  • T is N, M and Q are independently selected from CR3;
  • X, Y, Z are independently selected from CR5;
  • R1 is independently C 1-4 alkyl
  • the two R1 together with the C to which they are attached may form a 3-7 membered cycloalkyl group, which may optionally be one or more independently selected from Substituted with F, Cl, Br, OH, CN, NH 2 and C 1-4 alkyl groups;
  • R2 is independently selected from H, F, Cl, Br, OH, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 Cycloalkyl, -C(O)NR8R9, -S(O) 2 R8, -S(O) 2 NR8R9, -NR8R9, -P(O)R8R9, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl groups are optionally one or more independently selected from F, Cl, Br, OH, CN, Substituted with NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 cycloalkyl groups;
  • R3 is independently selected from H, F, Cl, Br, OH, CN, NO 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 cycloalkyl, 3-7-membered heterocycloalkyl containing 1-3 independently selected from N, O, S, 5-6-membered containing 1-3 independently selected from N, O, S Heteroaryl, -C(O)R8, -C(O)NR8R9, -S(O) 2 R8, -S(O) 2 NR8R9, -NR8R9, -NR8C(O)R9, -P(O)R8R9, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl groups are optionally replaced by one or Multiple independently selected from F, Cl, Br, OH, CN, NH 2 , C 1-4 al
  • R4 is selected from C 1-4 alkoxy, which is optionally substituted by one or more groups independently selected from F, Cl, Br;
  • R5 is independently selected from H, F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, and the alkyl group is optionally selected from one or more independently selected from F, Cl, Br, OH , CN, NH 2 groups substituted;
  • R8 and R9 are independently selected from H, OH, C 1-4 alkyl, C 1-4 alkoxy, and the alkyl and alkoxy groups are optionally one or more independently selected from F, Cl, Substituted by Br, OH, CN, NH 2 and C 1-4 alkyl groups;
  • n 0, 1, 2 or 3;
  • n 0, 1, 2, 3 or 4.
  • the present invention provides a compound represented by the following formula (IC) or a pharmaceutically acceptable salt or deuterated product thereof:
  • X and Y are independently selected from N and CR5;
  • R2 is independently selected from H, C 1-4 alkyl, -S(O) 2 R8, -P(O)R8R9, the alkyl group is optionally substituted by one or more groups independently selected from OH, C 1-4 alkoxy;
  • R3 is selected from H, F, Cl, Br, CN, C 1-4 alkyl
  • R4 is selected from C 1-4 alkyl, C 1-4 alkoxy, cyclopropyl, and the alkyl, alkoxy, cyclopropyl is optionally one or more independently selected from F, Cl, Substituted by Br, CN, OH groups;
  • R5 is independently selected from H, CN;
  • R7 is independently selected from H, C 1-4 alkyl, the alkyl is optionally substituted by one or more groups independently selected from F, Cl, Br, OH, CN;
  • R8 and R9 are independently selected from NH 2 and C 1-4 alkyl.
  • the present invention provides a compound represented by the following formula (ID) or a pharmaceutically acceptable salt or deuterated product thereof:
  • R3 is selected from H, F, Cl, Br, CN, methyl
  • R4 is selected from C 1-4 alkyl, C 1-4 alkoxy, cyclopropyl, and the alkyl, alkoxy, cyclopropyl is optionally one or more independently selected from F, Cl, Replaced by Br, CN, OH groups.
  • the present invention provides a compound represented by the following formula (IB) or a pharmaceutically acceptable salt or deuterated product thereof:
  • R1 is independently selected from H, methyl
  • R3 is selected from H, F, Cl, Br, methyl.
  • the present invention provides a compound represented by the following formula (IE) or a pharmaceutically acceptable salt or deuterated product thereof:
  • R1 is independently selected from H, methyl
  • R3 is selected from H, F, Cl, Br, methyl
  • R4 is selected from C 1-4 alkyl, C 1-4 alkoxy, which is optionally substituted by one or more groups independently selected from F, Cl, Br.
  • the present invention provides a compound represented by the following formula (IF) or a pharmaceutically acceptable salt or deuterated product thereof:
  • R3 is selected from H, F, Cl, Br, methyl
  • R4 is selected from C 1-4 alkyl, C 1-4 alkoxy, which is optionally substituted by one or more groups independently selected from F, Cl, Br; preferably Methoxy, trifluoromethoxy;
  • R6 is selected from
  • the compound of the present invention is selected from the following compounds or their pharmaceutically acceptable salts and deuterated products:
  • C 1-4 alkyl specifically refers to the independently disclosed methyl (i.e., C 1 alkyl), ethyl (i.e., C 2 alkyl), propyl (i.e., C 3 alkyl), butyl (i.e. C 4 alkyl).
  • examples of "containing 1-3 5-7-membered heterocycloalkyl groups independently selected from N, O, S” include but are not limited to tetrahydrofuran, thiolane, pyrrolidine, pyrrolidone, pyrrole pholine, dioxolane, oxazolidine, oxazolidinone, oxazoline, isoxazolidine, thiazolidine, isothiazolidine, thiazoline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, tetrazoline Hydropyran, dihydropyran, pyran, piperidine, piperidone, 1,4-dioxane, morpholine, morpholinone, piperazine, azepane, epoxide, sulfide Heterocycloheptane, 1,4-oxazalane, 1,4-thiazepane.
  • examples of "containing 1-3 3-7-membered heterocycloalkyl groups independently selected from N, O, and S” include, in addition to the above, but are not limited to ethylene oxide, ethylene sulfide Alkane, aziridine, oxetane, N-lactam ring, ⁇ -lactam ring, ⁇ -lactam ring, ⁇ -lactone.
  • examples of "containing 1-3 5-6-membered heteroaryl groups independently selected from N, O, S” include but are not limited to furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, Isothiazole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxadiazole, thiadiazole, pyridine, pyridone, pyrimidine, pyridazine, pyrazine, triazole Azine.
  • examples of "containing 1-3 5-11-membered heteroaryl groups independently selected from N, O, S” include but are not limited to the above.
  • benzazetidines benzo- ⁇ -lactam rings, benzo- ⁇ -lactones, benzoxdiones, benzofurans, benzothiophenes, benzopyrroles, benzopyrazoles, and benzimidazoles , benzothiazole, benzisothiazole, benzoxazole, benzisoxazole, benzotriazole, benzoxadiazole, benzothiadiazole, benzodioxane, benzomorpholine , benzopiperidine, benzopyran, benzopyridine, benzopyrimidine, benzotriazine, benzopiperidone, benzmorpholinone, benzazepine, benzazepine Ketone, pyridoazetidine, pyrido beta-lactam ring,
  • Compounds of the present invention may be asymmetric, eg, possess one or more stereocenters. All stereoisomers, such as enantiomers and diastereomers, are included within the scope of the invention unless otherwise specified.
  • compounds containing asymmetrically substituted carbon atoms can be isolated in either optically active or racemic form. Various methods for preparing optically active forms are known in the art, for example by resolution of racemic mixtures or by stereospecific synthesis.
  • the present invention also includes pharmaceutically acceptable salts of the compounds.
  • the compounds of the present invention can be prepared into pharmaceutically acceptable salts by reaction with non-toxic inorganic or organic acids.
  • Inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid, hydrogen sulfate, boric acid, hemi-sulfuric acid, etc.
  • organic acids such as formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, heptanoic acid, Undecanoic acid, palmitic acid, stearic acid, oleic acid, oxalic acid, malonic acid, adipic acid, lactic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, ascorbic acid, methanesulfonic acid, ethyl sulfonate Acid, benzenesulfonic acid,
  • the present invention also includes hydrates and solvates of the compounds.
  • the present invention also includes all forms of the compounds in which the atoms are in the various isotopes.
  • Isotopes include all atoms with the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium.
  • the present invention also includes prodrugs of said compounds.
  • Prodrug refers to a compound obtained by structural modification of the compound that is inactive or less active outside the patient's body, but undergoes enzymatic or non-enzymatic transformation in the patient's body to release the compound and exert medicinal effects.
  • the compounds of the present invention can be prepared by various methods disclosed in the literature.
  • the compounds of the present invention may be reacted in suitable solvents, and those skilled in the art of organic synthesis can readily select suitable solvents that do not substantially react with reactants, intermediates or products.
  • the reaction can be carried out in one solvent or in a mixture of more than one solvent.
  • the reaction may be carried out at a suitable temperature to prepare the compounds of the invention, for example between the solidification temperature of the solvent and the boiling point temperature of the solvent.
  • the method of preparing the compounds of the present invention involves the protection and deprotection of various chemical groups. Those skilled in the field of organic synthesis can easily determine whether protection and deprotection of chemical groups are needed and select appropriate protecting groups.
  • the reaction for preparing the compounds of the invention can be monitored using any method known in the art, such as nuclear magnetic resonance spectroscopy, infrared spectroscopy, mass spectrometry, chromatography, and the like.
  • the compounds of the present invention can be prepared, for example, by the following methods:
  • the synthesis reaction of Ib can be carried out in the presence of a base, a ligand and a catalyst in a solvent.
  • the solvent can be selected from tetrahydrofuran, 1,4-dioxane, tert-butanol, toluene, xylene, DME, dimethyl sulfoxide, N,N-dimethylformamide, etc.
  • the base is optional From lithium bistrimethylsilylamide, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, etc.;
  • ligands can be selected from Davephos, Xantphos, etc.;
  • catalysts can be selected from Pd 2 (dba) 3 , Pd(OAc) 2 , etc.
  • the synthesis reaction of I-c can be carried out in a solvent in the presence of a base.
  • the solvent can be selected from tetrahydrofuran, 1,4-dioxane, toluene, xylene, DME, dimethyl sulfoxide, N,N-dimethylformamide, etc. or any mixture thereof;
  • the base can be selected from bistrimethyl Lithium silylamide, lithium diisopropylamide, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, etc.
  • the synthesis reaction of I-d can be carried out in the presence of reaction reagents in a solvent.
  • the solvent can be selected from acetonitrile, tetrahydrofuran, toluene, methanol, 1,4-dioxane, etc. or any mixture thereof;
  • the reaction reagent can be selected from trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl chloride, etc.;
  • reaction reagents can be selected from phosphorus oxychloride, sulfoxide chloride, etc.; solvents can be selected from toluene, xylene, 1,4-dioxane, dichloromethane, etc. or any mixture thereof.
  • the synthesis reaction of compound (I) can be carried out in the presence of a base, a ligand and a catalyst in a solvent.
  • the solvent can be selected from 1,4-dioxane, tetrahydrofuran, water, methanol, toluene, xylene, dimethyl sulfoxide, N,N-dimethylformamide, etc.
  • the base can be selected from phosphoric acid Potassium, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, etc.
  • the ligand can be selected from triphenylphosphine, dppp, dppf, etc.
  • the catalyst can be selected from palladium acetate, tetrakis triphenylphosphine palladium, Pd 2 (dba) 3. Pd(dppf)Cl 2 , Pd(PPh 3 ) 2 Cl 2 , etc.
  • the synthesis reaction of II-b can be carried out in the presence of a base, a ligand and a catalyst in a solvent.
  • the solvent can be selected from 1,4-dioxane, tetrahydrofuran, water, methanol, toluene, xylene, dimethyl sulfoxide, N,N-dimethylformamide, etc.
  • the base can be selected from phosphoric acid Potassium, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, etc.
  • the ligand can be selected from triphenylphosphine, dppp, dppf, etc.
  • the catalyst can be selected from palladium acetate, tetrakis triphenylphosphine palladium, Pd 2 (dba) 3. Pd(dppf)Cl 2 , Pd(PPh 3 ) 2 Cl 2 , etc.
  • the synthesis reaction of compound I can be carried out in the presence of a base, a ligand and a catalyst in a solvent.
  • the solvent can be selected from tetrahydrofuran, 1,4-dioxane, tert-butanol, toluene, xylene, DME, dimethyl sulfoxide, N,N-dimethylformamide, etc.
  • the base is optional From potassium carbonate, sodium carbonate, cesium carbonate, lithium bistrimethylsilylamide, potassium tert-butoxide, sodium tert-butoxide, etc.
  • the ligand can be selected from BINAP, Davephos, Xantphos, etc.
  • the catalyst can be selected from Pd 2 ( dba) 3 , Pd(OAc) 2 , etc.
  • the synthesis reaction of III-c can be carried out in the presence of reaction reagents in a solvent.
  • the solvent can be selected from ethanol, methanol, water, etc. or any mixture thereof;
  • the reaction reagent can be a combination of cyanamide and hydrochloric acid, or a combination of S-methylisothiourea and potassium carbonate.
  • the synthesis reaction of III-f can be carried out in the presence of reaction reagents in a solvent.
  • the solvent can be selected from tetrahydrofuran, 1,4-dioxane, methanol, water, etc. or any mixture thereof; the reaction reagent can be selected from hydrochloric acid, sulfuric acid, etc.
  • the synthesis reaction of III-g can be carried out in the presence of reaction reagents in a solvent.
  • the solvent can be selected from N,N-dimethylformamide, toluene, xylene, etc. or any mixture thereof; the reaction reagent can be selected from N,N-dimethylformamide dimethyl acetal, etc.
  • the synthesis reaction of compound I can be carried out in the presence of a base in a solvent.
  • the solvent can be selected from isopropyl alcohol, methanol, ethanol, tert-butyl Alcohol, N,N-dimethylformamide, dimethyl sulfoxide, etc. or any mixture thereof;
  • the base can be selected from potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, potassium acetate, acetic acid Sodium etc.
  • the synthesis reaction of IV-b can be carried out in the presence of a base, a ligand and a catalyst in a solvent.
  • the solvent can be selected from 1,4-dioxane, tetrahydrofuran, water, methanol, toluene, xylene, dimethyl sulfoxide, N,N-dimethylformamide, etc.
  • the base can be selected from phosphoric acid Potassium, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, etc.
  • the ligand can be selected from triphenylphosphine, dppp, dppf, etc.
  • the catalyst can be selected from palladium acetate, tetrakis triphenylphosphine palladium, Pd 2 (dba) 3. Pd(dppf)Cl 2 , Pd(PPh 3 ) 2 Cl 2 , etc.
  • the synthesis reaction of IV-c can be carried out in the presence of reaction reagents in a solvent.
  • the solvent can be selected from dichloromethane, tetrahydrofuran, water, 1,4-dioxane, methanol, toluene, xylene, dimethyl sulfoxide, N,N-dimethylformamide, etc. or any mixture thereof;
  • reaction Reagents can be selected from Oxone, m-CPBA, etc.
  • the synthesis reaction of compound I can be carried out in the presence of a base in a solvent.
  • the solvent can be selected from N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, toluene, xylene, etc. or any mixture thereof;
  • the base can be selected from potassium tert-butoxide, tert. Sodium butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium acetate, sodium acetate, etc.
  • the synthesis reaction of Va can be carried out in the presence of a base, a ligand and a catalyst in a solvent.
  • the solvent can be selected from tetrahydrofuran, 1,4-dioxane, tert-butanol, toluene, xylene, DME, dimethyl sulfoxide, N,N-dimethylformamide, etc.
  • the base is optional From potassium carbonate, sodium carbonate, cesium carbonate, lithium bistrimethylsilylamide, potassium tert-butoxide, sodium tert-butoxide, etc.
  • the ligand can be selected from BINAP, Davephos, Xantphos, etc.
  • the catalyst can be selected from Pd 2 ( dba) 3 , Pd(OAc) 2 , etc.
  • the synthesis reaction of compound I can be carried out in the presence of a base, a ligand and a catalyst in a solvent.
  • the solvent can be selected from tetrahydrofuran, 1,4-dioxane, tert-butanol, toluene, xylene, DME, dimethyl sulfoxide, N,N-dimethylformamide, etc.
  • the base can be selected from bistrimethylsilane Lithium amide, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, etc.
  • ligands can be selected from Davephos, Xantphos, etc.
  • catalysts can be selected from Pd 2 (dba) 3 , Pd (OAc) 2 etc.
  • the compounds of the invention are able to inhibit PLK1. Therefore, according to another aspect of the invention, the invention provides a method of inhibiting PLK1 using a compound of the invention.
  • the present invention provides a method for preventing and/or treating PLK1-related diseases, wherein a therapeutically and/or preventive effective amount of a compound of the present invention or a pharmaceutical combination containing a compound of the present invention is administered to an individual in need thereof.
  • PLK1-related diseases include any disease directly and/or indirectly related to the expression and/or activity of PLK1, for example, diseases related to PLK1 overexpression; diseases that are prevented and/or treated by regulating, for example, inhibiting PLK1 activity, etc.
  • PLK1-related diseases include solid tumors, hematological tumors, etc.
  • solid tumors include, but are not limited to, colorectal cancer, lung cancer, breast cancer, prostate cancer, pancreatic cancer, gastric cancer, head and neck cancer, ovarian cancer, uterine cancer, glioma, liver cancer, esophageal cancer, bladder cancer, kidney cancer, lymphoma tumors, melanoma, osteosarcoma, etc.
  • examples of hematological tumors include but are not limited to leukemia, myelodysplastic syndrome, etc.
  • the invention provides the use of the compounds of the invention in the preparation of PLK1 inhibitors.
  • the present invention provides the use of the compounds of the present invention in the preparation of for the prevention and/or treatment of PLK1-related diseases.
  • the compounds of the present invention may be administered in the form of pharmaceutical compositions. Therefore, according to another aspect of the invention, the invention provides a pharmaceutical composition containing a compound of the invention and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention can be prepared by various methods disclosed in the literature.
  • the compounds or pharmaceutical compositions of the present invention can be administered by a variety of routes, depending on whether local or systemic treatment is desired and the area to be treated.
  • it can be administered orally, parenterally (e.g. intravenous, arterial, subcutaneous, intraperitoneal, intramuscular injection or infusion), intracranially e.g. intrathecally or intracerebroventricularly, transdermally, ocular, nasal, vaginal, rectal, pulmonary (e.g. Administer by inhalation or insufflation into powder or aerosol).
  • the pharmaceutical compositions of the present invention are generally provided in the form of tablets, capsules or solutions. Tablets may contain a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the carrier includes, but is not limited to, diluents, disintegrants, binders, lubricants, colorants or preservatives. Capsules include hard capsules and soft capsules.
  • the pharmaceutical composition of the present invention may be administered by intravenous injection, intramuscular injection, or subcutaneous injection. They are usually supplied as sterile aqueous solutions or suspensions or lyophilized powders, with appropriate pH and isotonicity adjusted.
  • the effective amount of a compound of the present invention will be determined by the specific use of the treatment, the mode of administration, and the condition of the individual in need thereof, e.g., the patient. Those skilled in the art will be able to determine effective amounts of compounds of the invention. Typical dosage ranges are, for example, 1 ⁇ g/kg/day to 1000 mg/kg/day.
  • the compounds of the invention can be used in combination with one or more other drugs.
  • Other drugs include immune checkpoint drugs, targeted drugs, chemotherapy drugs, etc.
  • Lithium solution in tetrahydrofuran (LiHMDS, 187 mL, 187.2 mmol) and N-methylpiperazine (12.5 g, 124.8 mmol) were heated to reflux overnight. Cool to room temperature, concentrate and dissolve the crude product in dichloromethane (200 mL). Wash the organic phase with water (50 mL ⁇ 2). Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the crude product. :water 10%-70%, +0.1% ammonia) was purified to obtain a light yellow solid product (13.0g).
  • compound 6-bromo-4-iodo-3-methyl-1-oxoisoindoline-2-carboxylic acid tert-butyl ester (1.3g, 2.88mmol) and dimethylphosphine oxide (292.0mg ,3.74mmol), tris(dibenzylideneacetone)dipalladium (265.0mg, 0.29mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (335.0mg, 0.58mmol) , triethylamine (874.3mg, 8.64mmol) was dissolved in 1,4-dioxane (10ml), and stirred at room temperature for 3 hours.
  • reaction solution is diluted with water (30 mL) and extracted with ethyl acetate (80 mL ⁇ 2). The combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product.
  • the crude product was purified by silica gel column chromatography (0-15% methanol/dichloromethane) to obtain a white solid (550.0 mg).
  • the system was evacuated and replaced with nitrogen three times, and heated to 100 °C for 5 hours. When the reaction is complete, cool the reaction to room temperature.
  • the reaction solution was diluted with water (10 mL), the aqueous phase was extracted with ethyl acetate (10 mL ⁇ 3), the organic phases were combined and washed with water (10 mL) and saturated aqueous sodium chloride solution (10 mL), and the organic phase was dried with anhydrous sodium sulfate. Filter and concentrate the filtrate to obtain crude product. After preparation and isolation, white solid PR-01-049 (39.7 mg) is obtained.
  • reaction system was replaced with nitrogen three times.
  • the reaction solution was stirred at 80°C for 5 hours.
  • LCMS detection showed that the reaction was complete.
  • the reaction solution was poured into water (5 mL), and extracted with ethyl acetate (10 mL ⁇ 3).
  • Dissolve thiophene-3-carboxylic acid (500.0 mg, 3.90 mmol) in tetrahydrofuran (20 mL), evacuate and replace with nitrogen three times, cool the system to -70°C, and slowly add n-butyllithium (6 mL, 1.6 M) dropwise to the system. Cyclohexane solution, 9.60mmol), while keeping the temperature below -55°C. After the dropwise addition is completed, continue to stir the reaction at -70°C for 1 hour, then slowly add acetone (0.38mL, 5.17mmol). After the dropwise addition is completed, The temperature of the system rose to 0°C, and the reaction was continued to stir at this temperature for 3 hours.
  • reaction solution was cooled, and ethyl acetate was added to the reaction solution. (10mL), washed with water and saturated brine, collected organic The phase was dried over anhydrous sodium sulfate, and the reaction solution was separated to obtain light yellow solid PR-01-070 (36.1 mg).
  • 6-(2-chloro-5-fluoropyrimidin-4-yl)-3,3-dimethylisoindol-1-one (100 mg, 0.34 mmol), 5-(4-methylpiperdine)
  • oxazin-1-yl)-2-(trifluoromethoxy)aniline 104 mg, 0.38 mmol
  • cesium carbonate 223 mg, 0.68 mmol
  • Naphthalene-2,2'-bisdiphenylphosphine BINAP, 43.6 mg, 0.07 mmol
  • palladium acetate 7.6 mg, 0.034 mmol
  • the reaction mixture was cooled to room temperature and concentrated in vacuo to remove most of the solvent. Pour into water (5 mL) and extract with ethyl acetate (30 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated. The solid was prepared alkaline to give a white solid (12.5 mg).
  • reaction solution was quenched by adding saturated ammonium chloride solution (20 mL), and extracted with ethyl acetate (20 mL ⁇ 3). Combine organic phases Wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain crude product.
  • Racemate PR-01-083 was separated and purified by SFC (chromatographic column: ChiralPak IB, 250 ⁇ 30mm ID, 5 ⁇ m; mobile phase: phase A: carbon dioxide, phase B: [MEOH+0.1% 7mol/L NH 3 ]; gradient :B%: 20%-20%, 10.8min; 120min), white solid PR-01-083A and PR-01-083B were obtained.
  • 6-(2-Chloro-5-fluoropyrimidin-4-yl)-3,3-dimethylisoindol-1-one (150.0 mg, 0.51 mmol), 5-(4-methylpiperazine- 1-yl)-2-(2,2,2-trifluoroethoxy)aniline (common int-6) (223.1mg, 0.77mmol), palladium acetate (15.7mg, 0.07mmol), 1,1'- Binaphthyl-2,2'-bisdiphenylphosphine (64.0mg, 0.10mmol) and cesium carbonate (502.6mg, 1.54mmol) were suspended in 1,4-dioxane (2mL), and heated to 100 under nitrogen protection.
  • 6-Bromo-4-iodoisoindol-1-one (4.2g, 12.43mmol), 4-dimethylaminopyridine (460.0mg, 3.77mmol) and triethylamine (5.0g, 49.41 mmol) was dissolved in dichloromethane (100 mL), di-tert-butyl dicarbonate (8.1 g, 37.11 mmol) was slowly added dropwise to the reaction system, and the reaction was carried out at room temperature for 18 hours. The reaction system was diluted with dichloromethane (50 mL), washed with water (100 mL), the organic phase was separated, dried, filtered, and spun to dryness.
  • 6-(2-Chloro-5-fluoropyrimidin-4-yl)-4-(2-hydroxyethyl)-3,3-dimethylisoindol-1-one (45.0 mg, 0.13 mmol), 5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)aniline (common int-1) (37.0mg, 0.13mmol), cesium carbonate (120.0mg, 0.37mmol), 1 , 1'-binaphthyl-2,2'-bisdiphenylphosphine (20.0mg, 0.03mmol) and palladium acetate (4.5mg, 0.02mmol) were dissolved in dioxane (2mL), under nitrogen protection, 100°C The reaction was carried out for 18 hours, the reaction system was spun to dryness, and the crude product was prepared by alkaline treatment to obtain a white solid (15.5 mg).
  • reaction solution was cooled and filtered, and the filtrate was diluted with water (30 mL), extracted with ethyl acetate (30 mL ⁇ 3), and concentrated to obtain an almost black oily substance, which was purified by preparative HPLC to obtain a white solid (60 mg).
  • reaction system was cooled, quenched with saturated aqueous ammonium chloride solution (1 mL), and extracted with ethyl acetate (2 mL).
  • the organic phase was dried, spun to dryness, and separated and purified through alkaline (H 2 O/MeCN (0.1% NH 3 ⁇ H 2 O)) preparation to obtain a white solid (14.1 mg).
  • reaction system was cooled, quenched with saturated aqueous ammonium chloride solution (1 mL), and extracted with ethyl acetate (2 mL). The organic phase was dried, spun to dryness, and white solid (13.5 mg) was obtained through preparation, separation and purification.
  • the reaction system was cooled, quenched with saturated aqueous ammonium chloride solution (1 mL), and extracted with ethyl acetate (2 mL). The organic phase was dried and spun to dryness, and the crude product was prepared by reverse-phase alkaline preparation to obtain a white solid (8.1 mg).
  • 1,2-dimethylpiperazine (22.8 mg, 0.20 mmol) and 1M lithium bistrimethylsilylamide (0.3 mL, 0.3 mmol) were added to the reaction solution.
  • the reaction solution was stirred at 70°C for 5 hours and the reaction was completed by LCMS.
  • the reaction solution was poured into water (5 mL), extracted with ethyl acetate (5 mL ⁇ 3), the organic phases were combined and concentrated to dryness. Alkaline preparative HPLC purified to obtain a light yellow solid (20.0 mg).
  • Racemate PR-01-123 was separated and purified by SFC (chromatographic column: ChiralPakC-IG, 250 ⁇ 21.2mm ID, 5 ⁇ m; mobile phase: A Phase: carbon dioxide, phase B: [MEOH+0.1% MEA]; gradient: B: 45%-45%, 8min; 120min) to obtain white solids PR-01-123A and PR-01-123B.
  • SFC chromatographic column: ChiralPakC-IG, 250 ⁇ 21.2mm ID, 5 ⁇ m; mobile phase: A Phase: carbon dioxide, phase B: [MEOH+0.1% MEA]; gradient: B: 45%-45%, 8min; 120min
  • the reaction solution was stirred at 100°C for 16 hours under nitrogen protection. LCMS showed that the reaction was complete.
  • reaction solution was diluted with water (30 mL), and extracted with ethyl acetate (30 mL ⁇ 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude black solid product. The crude product was purified by preparative HPLC to obtain a white solid (48.6 mg).
  • N-(5-bromo-2-(difluoromethoxy)pyridin-3-yl)-1,1-diphenylmethaneimine (2.3g, 5.70mmol)
  • N-methylpiperazine (685.2 mg, 6.84 mmol) of 1,4-dioxane suspension (25.0 mL)
  • tris(dibenzylideneacetone) dipalladium 522.0 mg, 0.57 mmol
  • 2-dicyclohexylphosphine-2′, 6'-dimethoxy-biphenyl 468.0 mg, 1.14 mmol
  • cesium carbonate 5.6 g, 17.19 mmol
  • the reaction system was stirred at 90°C for 2 hours under nitrogen protection. After the reaction is complete, add water (10.0 mL) to dilute the reaction solution, and extract with ethyl acetate (20 mL ⁇ 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product. The crude product was purified by preparative HPLC to obtain a yellow solid (17.0 mg).
  • N-(5-bromo-2-(2,2-difluorocyclopropyl)phenyl)-1,1-diphenylmethaneimine 350.0 mg, 0.85 mmol
  • N-methylpiperazine 102.1 mg, 1.02 mmol
  • sodium tert-butoxide 244.8 mg, 2.55 mmol
  • tris(dibenzylideneacetone) dipalladium 77.7 mg, 0.09 mmol
  • 1,1'-binaphthyl-2,2'- Bisdiphenylphosphine (105.7 mg, 0.17 mmol) was dissolved in toluene (8 mL) and reacted at 110°C for 3 hours.
  • the reaction solution was cooled and spun to dryness.
  • 1,4-dioxane to 1-(4-bromo-2-iodophenyl)cyclopropane-1-carbonitrile 500.0 mg, 1.44 mmol
  • diphenylmethane imine 312.5 mg, 1.72 mmol
  • 1,1'-binaphthyl-2,2'-bisdiphenylphosphine 178.9 mg, 0.29 mmol
  • tris(dibenzylideneacetone)dipalladium 263.2 mg, 0.29 mmol
  • cesium carbonate 1.g, 4.31mmol
  • the reaction solution was diluted with water (5 mL), and extracted with ethyl acetate (10 mL ⁇ 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product.
  • reaction solution was heated and refluxed under nitrogen protection for 6 hours until the raw materials were completely consumed. After the reaction solution was cooled, the solvent was removed in vacuo, diluted with water (5 mL), and extracted with ethyl acetate (15 mL ⁇ 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product. A white solid (20.7 mg) was obtained by basic preparation.
  • reaction solution was cooled and filtered, and the filtrate was diluted with water (30 mL), extracted with ethyl acetate (30 mL ⁇ 3), and concentrated to obtain an almost black oily substance, which was purified by preparative HPLC to obtain a white solid (55 mg).
  • reaction solution was cooled to room temperature, quenched with saturated aqueous ammonium chloride solution (1 mL), and extracted with ethyl acetate (10 mL ⁇ 3). The organic phases were combined, dried, filtered and spin-dried. The crude product was prepared by reverse phase formic acid to obtain a white solid (7.2 mg).
  • Racemate PR-01-113 was separated and purified by SFC (chromatographic column: ChiralPak AD, 250 ⁇ 30mm ID, 5 ⁇ m; mobile phase: Phase A: CO 2 ; Phase B: IPA (0.1% 7mol/L NH3in MeOH); gradient : B%: 30%; 7 min, 120 min), white solid PR-01-113A (13.0 mg) and white solid PR-01-113B (17.5 mg) were obtained.
  • SFC chromatographic column: ChiralPak AD, 250 ⁇ 30mm ID, 5 ⁇ m; mobile phase: Phase A: CO 2 ; Phase B: IPA (0.1% 7mol/L NH3in MeOH); gradient : B%: 30%; 7 min, 120 min), white solid PR-01-113A (13.0 mg) and white solid PR-01-113B (17.5 mg) were obtained.
  • Example 51 Synthesis of compounds DP-01-203, DP-01-203A, and DP-01-203B
  • the reaction system was cooled, quenched with saturated aqueous ammonium chloride solution (1 mL), and extracted with ethyl acetate (2 mL). The organic phase was dried and spin-dried.
  • a white solid (34.3 mg) was obtained by using reversed-phase formic acid.
  • Racemate DP-01-203 was separated and purified by SFC (chromatographic column: ChiralPak C-IG, 250 ⁇ 30mm ID, 5 ⁇ m; mobile phase: Phase A: CO 2 ; B: MeOH+0.1% NH 3 -H 2 O; Gradient: B%: 40%; 8.4min; 180min) to obtain white solid DP-01-203A (6.4mg) and white solid DP-01-203B (7.7mg).
  • Racemate DP-01-161 was separated and purified by SFC (chromatographic column: ChiralCel OX, 250 ⁇ 21.2mm ID, 5 ⁇ m; mobile phase: phase A: CO 2 ; phase B: IPA+0.1% NH 3 -H 2 O; Gradient: B%: 30%, 6.9min; 180min), white solid DP-01-161A (5.0mg) and white solid DP-01-161B (7.0mg) were obtained.
  • SFC chromatographic column: ChiralCel OX, 250 ⁇ 21.2mm ID, 5 ⁇ m; mobile phase: phase A: CO 2 ; phase B: IPA+0.1% NH 3 -H 2 O; Gradient: B%: 30%, 6.9min; 180min), white solid DP-01-161A (5.0mg) and white solid DP-01-161B (7.0mg) were obtained.
  • methylsulfonyl chloride (139.7mg, 1.22mmol) was added dropwise to triethylamine (164.5mg, 1.63mmol) and (4-(3-bromo-4-(trifluoromethoxy)phenyl) -1-methylpiperazin-2-yl)methanol (common int-14) (300.0 mg, 0.81 mmol) in anhydrous dichloromethane (5 mL) and stirred at room temperature for 1 hour.
  • dichloromethane 5 mL
  • Dioxane was added to 5'-pinacol borate ester spiro[cyclopropane-1,1'-isoindoline]-3'-one (common int-9) (300.0 mg, 1.05 mmol) at room temperature.
  • 5mL and water (1mL) were added with 2,4-dichloro-5-fluoro-6-methylpyrimidine (228.5mg, 1.26mmol), [1,1'-bis(diphenylphosphine)diocene Iron] palladium dichloride (79.8 mg, 0.11 mmol), potassium phosphate (669.9 mg, 3.16 mmol). Nitrogen was replaced three times, and the resulting mixture was stirred at 90°C for 4 hours.
  • Racemate DP-01-219 was separated and purified by SFC (chromatographic column: CHIRALPAK C-IG 5 ⁇ m 4.6*100mm ID, 5 ⁇ m; mobile phase: Phase A: CO 2 ; Phase B: EtOH (0.05% DEA v/v); Gradient: B%: 40.0%, 8 min) to obtain white solid DP-01-219A and white solid DP-01-219B.
  • SFC chromatographic column: CHIRALPAK C-IG 5 ⁇ m 4.6*100mm ID, 5 ⁇ m; mobile phase: Phase A: CO 2 ; Phase B: EtOH (0.05% DEA v/v); Gradient: B%: 40.0%, 8 min

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Abstract

L'invention concerne une classe de composés en tant qu'inhibiteurs de PLK1 tels que représentés par la formule (I). Le composé et la composition le contenant peuvent inhiber PLK1, et peuvent ainsi être utilisés pour prévenir et/ou traiter des maladies associées à PLK1, telles que des tumeurs.
PCT/CN2023/117138 2022-09-08 2023-09-06 Composé en tant qu'inhibiteur de plk1, son procédé de préparation et son utilisation WO2024051717A1 (fr)

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1860104A (zh) * 2003-07-30 2006-11-08 西克拉塞尔有限公司 作为激酶抑制剂的2－氨基苯基－4－苯基嘧啶
CN101044137A (zh) * 2004-08-20 2007-09-26 贝林格尔·英格海姆国际有限公司 作为plk抑制剂的2,4－二（氨基苯基）嘧啶
WO2009040399A1 (fr) * 2007-09-28 2009-04-02 Nerviano Medical Sciences S.R.L. Dérivés de pyrrolopyrimidine substitués, leur procédé de préparation et leur utilisation en tant qu'inhibiteurs de kinase
CN106810536A (zh) * 2015-11-30 2017-06-09 甘李药业股份有限公司 一种蛋白激酶抑制剂及其制备方法和医药用途
WO2022061273A1 (fr) * 2020-09-21 2022-03-24 Prelude Therapeutics, Incorporated Inhibiteurs de cdk et leur utilisation en tant que produits pharmaceutiques
WO2022133215A1 (fr) * 2020-12-18 2022-06-23 Prelude Therapeutics Incorporated Inhibiteurs de cdk et leur utilisation en tant que produits pharmaceutiques
CN115819418A (zh) * 2023-02-14 2023-03-21 山东绿叶制药有限公司 Plk1激酶抑制剂及其制备方法和应用
WO2023087027A1 (fr) * 2021-11-15 2023-05-19 Erasca, Inc. Inhibiteurs thiophènes de ulk1/2 et leur utilisation

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1860104A (zh) * 2003-07-30 2006-11-08 西克拉塞尔有限公司 作为激酶抑制剂的2－氨基苯基－4－苯基嘧啶
CN101044137A (zh) * 2004-08-20 2007-09-26 贝林格尔·英格海姆国际有限公司 作为plk抑制剂的2,4－二（氨基苯基）嘧啶
WO2009040399A1 (fr) * 2007-09-28 2009-04-02 Nerviano Medical Sciences S.R.L. Dérivés de pyrrolopyrimidine substitués, leur procédé de préparation et leur utilisation en tant qu'inhibiteurs de kinase
CN106810536A (zh) * 2015-11-30 2017-06-09 甘李药业股份有限公司 一种蛋白激酶抑制剂及其制备方法和医药用途
WO2022061273A1 (fr) * 2020-09-21 2022-03-24 Prelude Therapeutics, Incorporated Inhibiteurs de cdk et leur utilisation en tant que produits pharmaceutiques
WO2022133215A1 (fr) * 2020-12-18 2022-06-23 Prelude Therapeutics Incorporated Inhibiteurs de cdk et leur utilisation en tant que produits pharmaceutiques
WO2023087027A1 (fr) * 2021-11-15 2023-05-19 Erasca, Inc. Inhibiteurs thiophènes de ulk1/2 et leur utilisation
CN115819418A (zh) * 2023-02-14 2023-03-21 山东绿叶制药有限公司 Plk1激酶抑制剂及其制备方法和应用

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